Abstract: Methods for preparing the Bruton's Tyrosine Kinase (“BTK”) inhibitor compound 2-{3?-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4?]bipyridinyl-2?-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided.

Abstract: Provided herein are methods of synthesizing quinazoline compounds comprising at least one atropisomeric center.

Abstract: Provided herein are methods to synthesize compounds useful in the treatment of cancer where such compounds comprise a quinazolinyl core moiety and at least one stereoisomeric or atropisomeric moiety.

Abstract: A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl) thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N?,N?-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

Abstract: A device for displaying a succession of periodic events, such as zodiac periods, which form an annual cycle, this display device including a periodic event indicator organ; a mechanism for managing a duration for displaying periodic events by the periodic event indicator organ, this management mechanism including a cam for managing a periodic event display duration arranged to control the change from the indication of a periodic event to the indication of a next periodic event by the periodic event indicator organ; a date indicator mechanism driven by a horological movement; a month finger controlled by the date indicator mechanism so as to advance the management cam by one pitch per month, and a periodic event finger disposed between the management cam and the periodic event indicator organ and arranged to drive the periodic event indicator organ during a change of periodic event.

Abstract: Provided herein are methods of synthesizing quinazoline compounds comprising at least one atropisomeric center.

Abstract: The invention provides crystalline forms of 2?-(7,7-dimethyl-1?H,7H-spiro[furo[3,4-b]pyridine-5,4?-piperidin]-1?-yl)-1,3-dihydro-4?H-spiro[indene-2,5?-[1,3]oxazol]-4?-one, and a process for converting Form A to Form B for use in medicaments for treatment of anxiety, depression, irritability, impaired social interactions and psychomotor coordination, and other indications. The invention further provides processes to manufacture 2?-(7,7-dimethyl-1?H,7H-spiro[furo[3,4-b]pyridine-5,4?-piperidin]-1?-yl)-1,3-dihydro-4?H-spiro[indene-2,5?-[1,3]oxazol]-4?-one. Also disclosed are compounds useful as intermediates in the methods of the invention.

Abstract: Methods for preparing the Bruton's Tyrosine Kinase (“BTK”) inhibitor compound 2-{3?-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4?]bipyridinyl-2?-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided.

Abstract: Provided herein are methods to synthesize compounds useful in the treatment of cancer where such compounds comprise a quinazolinyl core moiety and at least one stereoisomeric or atropisomeric moiety.

Abstract: A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective Pt/V/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N?,N?-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

Abstract: A mechanical horological movement (1) including at least one barrel system (2) for driving a set of wheels and power reserve detector. The detector (10) includes a control wheel (3) disposed opposite the cage of the barrel system (2) and is rotated by a complementary wheel (8) at the differential output to determine a power reserve level. An aperture (13) has a first end (21) to define a complete charge of the barrel system and a second end (22) to define a complete discharge. A lever (4) is rotatably mounted about a lever axis parallel to the axis of rotation of the control wheel. A contact element (5) disposed in the aperture contacts the second end during a zero power reserve indication. A portion of the lever contacts a component of the movement to stop its operation when power reserve indication is at zero.

Abstract: Methods for preparing the Bruton's Tyrosine Kinase (“BTK”) inhibitor compound 2-{3?-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4?]bipyridinyl-2?-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided.

Abstract: A device for displaying a succession of periodic events, such as zodiac periods, which form an annual cycle, this display device including a periodic event indicator organ; a mechanism for managing a duration for displaying periodic events by the periodic event indicator organ, this management mechanism including a cam for managing a periodic event display duration arranged to control the change from the indication of a periodic event to the indication of a next periodic event by the periodic event indicator organ; a date indicator mechanism driven by a horological movement; a month finger controlled by the date indicator mechanism so as to advance the management cam by one pitch per month, and a periodic event finger disposed between the management cam and the periodic event indicator organ and arranged to drive the periodic event indicator organ during a change of periodic event.

Abstract: A device for displaying a succession of periodic events, such as zodiac periors, which form an annual cycle, this display device including a periodic event indicator organ; a mechanism for managing a duration for displaying periodic events by the periodic event indicator organ, this management mechanism including a cam for managing a periodic event display duration arranged to control the change from the indication of a periodic event to the indication of a next periodic event by the periodic event indicator organ; a date indicator mechanism driven by a horological movement; a month finger controlled by the date indicator mechanism so as to advance the management cam by one pitch per month, and a periodic event finger disposed between the management cam and the periodic event indicator organ and arranged to drive the periodic event indicator organ during a change of periodic event.

Abstract: Provided herein are methods to synthesize compounds useful in the treatment of cancer where such compounds comprise a quinazolinyl core moiety and at least one stereoisomeric or atropisomeric moiety.

Abstract: Methods for preparing the Bruton's Tyrosine Kinase (“BTK”) inhibitor compound 2-{3?-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4?]bipyridinyl-2?-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided. Methods for preparing tricyclic lactam compounds are also provided.

Abstract: A device (1), and timepiece having the device, for displaying a succession of periodic events which form an annual cycle, including a periodic events indicator member (2) and a mechanism (4) for managing a duration during which the periodic events are displayed by the periodic events indicator member (2). The management mechanism includes a cam (8) for managing a duration during which the periodic events are displayed, which cam is arranged such that it controls the change from the indication of a periodic event to the indication of a subsequent periodic event by the periodic events indicator member, a periodic driver (10) for driving the management cam (8) and a member (6) disposed between the management cam and the periodic events indicator member and arranged such that it drives the periodic events indicator member (2) during a change in event. The device displays the periods of the zodiac.

Abstract: Methods for preparing the Bruton's Tyrosine Kinase (“BTK”) inhibitor compound 2-{3?-hydroxymethyl-1-methyl-5-[5-((S)-2-methyl-4-oxetan-3-yl-piperazin-1-yl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-[3,4?]bipyridinyl-2?-yl}-7,7-dimethyl-3,4,7,8-tetrahydro-2H,6H-cyclopenta[4,5]pyrrolo[1,2-a]pyrazin-1-one are provided. Methods for preparing tricyclic lactam compounds are also provided.

Abstract: A manufacturing process to a bis-mesylate salt 1b of the pan-RAF inhibitor 4-amino-n-(1-((3-chloro-2-fluorophenyl)amino)-6-methylisoquinolin-5-yl)thieno[3,2-d]pyrimidine-7-carboxamide. The process features a number of efficient key reactions, including a robust and scalable Pd-catalyzed carbonylation reaction to generate thienopyrimidine 2 and a highly chemoselective PtN/C-catalyzed nitro group reduction to access penultimate intermediate 7. The final amide coupling of 7 and 2 was accomplished by a mild and safe protocol employing N,N,N?,N?-tetramethylchloroformamidinium hexafluorophosphate (TCFH) as the coupling reagent, to produce a 1:1 adduct of the freebase and THF. The adduct afforded compound 1b with excellent yield, purity, and form stability on a multikilogram production scale after reaction with MsOH and recrystallization. The methods are able to produce a compound having upwards of 95% purity.

Abstract: A device (1), and timepiece having the device, for displaying a succession of periodic events which form an annual cycle, including a periodic events indicator member (2) and a mechanism (4) for managing a duration during which the periodic events are displayed by the periodic events indicator member (2). The management mechanism includes a cam (8) for managing a duration during which the periodic events are displayed, which cam is arranged such that it controls the change from the indication of a periodic event to the indication of a subsequent periodic event by the periodic events indicator member, a periodic driver (10) for driving the management cam (8) and a member (6) disposed between the management cam and the periodic events indicator member and arranged such that it drives the periodic events indicator member (2) during a change in event. The device displays the periods of the zodiac.