Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[CH:11][C:12]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:13](/[CH:15]=[CH:16]/[C:17]([O:19]CC)=O)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C[O-].[Na+]>C(Cl)Cl>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]2[C:12](=[CH:11][CH:10]=1)[N:22]([C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:24]=1[O:30][CH3:31])[C:17](=[O:19])[CH:16]=[CH:15]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1ccc(Br)cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1cc(Br)ccc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
A RBF was charged with (E)-ethyl 3-(5-(benzylthio)-2-((4-bromo-2-methoxyphenyl)amino)phenyl)acrylate (3.13 g, 6.28 mmol) and MeOH (31.4 ml) to give a yellow suspension. Sodium methoxide (25 wt % in MeOH) (0.271 ml, 1.256 mmol) was added. A reflux condenser was attached, and the flask was lowered into a 75° C. heating bath. The bath quickly spiked to ca. 80-85° C., but returned to 70-75° C. after 30 min. The reaction was stirred for 16 hrs, and the mixture was diluted with DCM and concentrated. The residue was purified by chromatography on silica gel (50-g SNAP Ultra column, 25-g silica gel loading column, 10-60% EtOAc/Heptane) to give 6-(benzylthio)-1-(4-bromo-2-methoxyphenyl)quinolin-2(1 H)-one (1.95 g, 4.31 mmol, 68.6% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) □=7.94 (d, J=9.5 Hz, 1 H), 7.78 (d, J=2.2 Hz, 1 H), 7.50 (d, J=2.1 Hz, 1 H), 7.43-7.16 (m, 8 H), 6.66 (d, J=9.6 Hz, 1 H), 6.47 (d, J=8.8 Hz, 1 H), 4.23 (s, 2 H), 3.69 (s, 3 H). m/z (ESI) 452.0 (M+H)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].O=[C:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.CCCCCC>[CH2:1]=[C:8]1[CH2:14][CH:13]2[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:10]([CH2:11][CH2:12]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Potassium tert-butoxide (0.62 g, 5.5 mmol) was added to a suspension of methyltriphenylphosphonium bromide (1.98 g, 5.5 mmol) in tetrahydrofuran (20 mL) and the resulting mixture was stirred at room temperature for one hour. A solution of tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (0.50 g, 2.2 mmol) in tetrahydrofuran (5 mL) was then added and the resulting mixture was stirred at 35° C. for two hours. The mixture was cooled, diluted with hexane (100 mL), filtered, and the filtrate was washed with water then brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20% ethyl acetate in hexanes) to give tert-butyl 3-methylene-8-azabicyclo[3.2.1]octane-8-carboxylate (0.45 g, 91% yield). GC-MS (EI) for C13H21NO2: 223 (M+).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([OH:27])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].N1C=CN=C1.[C:40]([Si:44]([CH3:47])([CH3:46])Cl)([CH3:43])([CH3:42])[CH3:41]>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@@H:10]([O:27][Si:44]([C:40]([CH3:43])([CH3:42])[CH3:41])([CH3:47])[CH3:46])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([CH3:25])[C:18]=1[CH3:26])[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(C[C@H](C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(C[C@H](C[C@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reaction time: 2.25 h

Procedure:
A solution of 1.153 g (2.445 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-phenyl-2(R)-[(2,3-dimethyl-4-methoxyphenyl)methyl]hexanoic acid, 1.372 g (20.05 mmol) of imidazole and 1.709 g (11.0 mmol) of tert-butyldimethylchlorosilane in 8.7 ml of abs. DMF is stirred at RT for 18 h under argon. After that, the reaction mixture is poured onto ice-water and the whole is extracted with ethyl acetate. The organic phase is washed with cold 10% citric acid solution and saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and evaporated on a RE at approximately 30° C. The resulting product is dissolved in 28.8 ml of methanol and 11.2 ml of THF, and this solution is treated, at RT, with 1.962 g of potassium carbonate in 11.2 ml of water. After having been stirred for 2.25 h, the reaction mixture is concentrated down to half its volume at approximately 30° C. and the residue is treated with ethyl acetate and (cold) 10% citric acid solution, and the phases are separated. The organic phase is washed a further two times with saline. The combined aqueous phases are reextracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated. The residue is purified by being chromatographed twice on silica gel (hexane:ethyl acetate, 1:1 and then 3:1), and the title compound is obtained. TLC Rf (hexane:ethyl acetate. 1:1)=0.42. FAB-MS (M+H)+ =586. IR (KBr) inter alia: 1711, 1485, 1260 and 1107 cm-1. 1H-NMR (CD3OD) inter alia: 7.30-7.06 (m, 5H); 6.91 and 6.65 (each d, each 1H); 6.00 and 5.41 (each d, in all 1H from NH); 3.75 (s, 3H); 2.21 and 2.12 (each s, each 3H); 1.31 and 1.21 (each s, in all 9H from Boc); 0.89 (s, 9H); 0.12 and 0.08 (each s, each 3H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([CH:9]=[C:10]([NH:14][C:15](=[O:17])[CH3:16])C(O)=O)=[CH:7][C:6]=1OC)(=[O:3])[CH3:2].[C:22](=O)=[O:23]>[Cu].N1C2C(=CC=CC=2)C=CC=1>[C:15]([NH:14][CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([O:4][C:1](=[O:3])[CH2:2][O:23][CH3:22])=[CH:19][CH:18]=1)(=[O:17])[CH3:16]
Reactant: O=C=O
Reactant: COc1cc(C=C(NC(C)=O)C(=O)O)ccc1OC(C)=O
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Product: COCC(=O)Oc1ccc(C=CNC(C)=O)cc1

Procedure:
18.0 g (0.06 mol) of 4-acetoxy-α-acetylamino-3-methoxy-cinnamic acid are heated with 30 ml of quinoline and 1.2 g of copper powder to 160°-170° C for 3 hours, in the course of which carbon dioxide is evolved. Thereafter, the quinoline is distilled off under reduced pressure and the residual mass is taken up in ethyl acetate. After filtering off the copper powder, the ethyl acetate solution is extracted with 25 ml of 1 N hydrochloric acid and is then washed with water and subsequently with sodium bicarbonate solution. The organic phase is dried over sodium sulphate and thereafter the solvent is removed by distillation under reduced pressure. The resulting oil yields 4-(2-acetylaminovinyl)-2-methoxy-acetoxy-benzene, of melting point 169°-170° C, from ethyl acetate.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:14]([C:16]([O:18]C)=[O:17])[N:15]=2)[C:8]([CH3:27])=[CH:7][N:6]=1)(=[O:3])[CH3:2].C1COCC1.[OH-].[Na+]>CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[O:12][C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[C:14]([C:16]([OH:18])=[O:17])[N:15]=2)[C:8]([CH3:27])=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(-c2cc(NC(C)=O)ncc2C)oc1-c1ccccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)Nc1cc(-c2nc(C(=O)O)c(-c3ccccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
To a round bottom flask was added methyl 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylate (2.30 g, 6.0 mmol), THF (20 mL), MeOH (30 mL), and 1M aqueous NaOH (25 mL). The reaction mixture was allowed to stir at rt overnight. The mixture was concentrated and 1M aqueous HCl was added until the solution became acidic. The mixture was filtered and the solid was dried to give 2-[2-(acetylamino)-5-methylpyridin-4-yl]-5-(2-chlorophenyl)-1,3-oxazole-4-carboxylic acid (Compound I-6) (1.4 g, 64%). LCMS (FA): m/z=372.2 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:32])[C@H:4]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:22][C:21]=2[CH:31]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[C:25]1([C:23]2[O:24][C:20]3[CH:19]=[CH:18][C:17]([CH2:16][O:15][C:13]([NH:12][C@H:4]([CH2:5][C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:3]([OH:32])=[O:2])=[O:14])=[CH:31][C:21]=3[N:22]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccc2oc(-c3ccccc3)nc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccc2oc(-c3ccccc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A solution (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenylpropionic acid methyl ester 59 (374 mg, 0.8 mmol) in dioxane (8 ml) was treated with a solution of lithium hydroxide hydrate (55 mg, 1.3 mmol) in water (4 mL) under an atmosphere of N2 and stirred for 3 hrs at room temperature. The mixture was acidified with 1N HCl, then extracted with ethyl acetate (25 ml). The ethyl acetate extract was washed, and dried. Evaporation of the solvent afforded the product which was recrystallized to yield 220 mg (60%) of (R)-2-(2-phenylbenzoxazol-5-ylmethoxycarbonylamino)-3-phenyl propionic acid 60, mp. 220.0-221.4° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=3)=[N:12][CH:13]=2)=[CH:4][CH:3]=1.[CH2:24]([C@@H:28]1[O:30][C@H:29]1[CH2:31]O)[CH2:25][CH2:26][CH3:27]>[C@H]1(C(O)=O)O[C@@H]1C(O)=O>[CH2:24]([C@@H:28]1[O:30][C@H:29]1[CH2:31][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH3:23])[CH:15]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[C@@H]1O[C@H]1CO
Reactant: CCCOc1cccc(-c2ncc(-c3ccc(O)cc3)cn2)c1
Agent: O=C(O)[C@H]1O[C@@H]1C(=O)O
Product: CCCC[C@@H]1O[C@H]1COc1ccc(-c2cnc(-c3cccc(OCCC)c3)nc2)cc1

Procedure:
5-(4-Hydroxyphenyl)-2-(3-propoxyphenyl)pyrimidine and (2S,3S)-3-butyloxiran-2-ylmethanol(preparation described in EP-0 046 033 and Journal of the American Chemical Society, Volume 109, 1987, page 5765) are reacted analogously to Example 1 to give 5-[4-((2S,3S)-3-butyloxiran-2-ylmethoxy)phenyl]-2-(3-propoxyphenyl)pyrimidine. ##STR43##
Reaction SMILES: [H-].[Na+].[NH:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1.CI.[C:13](OCC)(=O)C>CN(C)C=O>[CH3:13][N:3]1[C:10]2[N:6]([N:7]=[CH:8][CH:9]=2)[CH:5]=[CH:4]1
Reactant: CCOC(C)=O
Reactant: c1cc2[nH]ccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 62% sodium hydride (0.36 g) in N,N-dimethylformamide (6 ml) was added 1H-imidazo[1,2-b]-pyrazole (1 g) under ice-cooling Then, thereto was added dropwise methyl iodide (0.58 ml) at the same temperature After the mixture was stirred at room temperature for 4 hours, ethyl acetate was added thereto The precipitate was filtered off, and the organic solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel to give 1-methyl-1H-imidazo-[1,2-b]pyrazole (0.9 g).
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([CH2:11][CH2:12][C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:7][C:6]=2[CH:5]=[C:4]([F:21])[CH:3]=1.C([O-])(O)=O.[Na+].[C:27]1(B(O)O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(C)=O>O1CCOCC1.[Cl-].[Na+].O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:21][C:4]1[CH:3]=[C:2]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:10]2[O:9][C:8]([CH2:11][CH2:12][C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[N:7][C:6]=2[CH:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Fc1cc(Br)c2oc(CCC#Cc3ccccn3)nc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Fc1cc(-c2ccccc2)c2oc(CCC#Cc3ccccn3)nc2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 86.2 %

Procedure:
To a solution of 7-bromo-5-fluoro-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole (100 mg, 0.29 mmol, Example 82) in dioxane/aqueous saturated solution of NaHCO3 (1:1, 8 mL) were added Pd(PPh3)4 (33 mg, 29 μmol) and phenylboronic acid (53.0 mg, 0.43 mmol). The reaction mixture was stirred at 60° C. for 7 hours, then AcOEt and brine were added and the organic phase was discarded. The aqueous phase was extracted thrice with AcOEt. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by flash chromatography (DCM/MeOH 99:1) to yield 86 mg (0.25 mmol, 87%) of 5-fluoro-7-phenyl-2-(4-(pyridin-2-yl)but-3-ynyl)benzo[d]oxazole as an orange oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13]>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:12](=[O:13])[C:11]2[CH:15]=[CH:16][CH:17]=[C:18]([F:19])[C:10]=2[F:9])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1cccc(F)c1F
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1cccc(F)c1F
Yield: 92.3 %

Procedure:
3.31 g 3-amino-2-chloropyridine (25.8 mmol) and 20 mL pyridine were mixed in an ice bath. 5.0 g 2,3-difluoro-benzoyl chloride (28.4 mmol) was then added. After return to room temperature and reaction for 4 hr, the reaction was quenched by water. After extraction three times by ethyl acetate, an ethyl acetate layer was collected and washed by 1M HCl solution. After drying, filtration, concentration, and purification by silicon-gel column, 6.4 g solid was obtained, with a yield of 93%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:42][OH:43])[C:23]1[CH:24]=[CH:25][C:26]([F:41])=[C:27]([CH:40]=1)[CH2:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:43][N:42]=[C:22]([C:23]3[CH:24]=[CH:25][C:26]([F:41])=[C:27]([CH:40]=3)[CH2:28][N:29]([CH3:39])[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Reactant: CN(CCC(=O)OC(C)(C)C)Cc1cc(C(N)=NO)ccc1F
Product: CCc1ccccc1-c1ccc(-c2nc(-c3ccc(F)c(CN(C)CCC(=O)OC(C)(C)C)c3)no2)cc1COC

Procedure:
The title compound was prepared following procedure described for example 141, step 1, but starting from Intermediate 36 (162.20 mg; 0.60 mmol) and Intermediate 63 (185.47 mg; 0.57 mmol), the crude mixture was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1) to afford the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.42 (d, J=1.4 Hz, 1H), 8.23 (dd, J=7.1, 1.4 Hz, 1H), 8.17 (dd, J=7.9, 1.8 Hz, 1H), 8.12-8.08 (m, 1H), 7.41-7.10 (m, 6H), 4.27-4.17 (m, 2H), 3.66 (br s, 2H), 3.33 (s, 3H), 2.08 (t, J=7.0 Hz, 2H), 2.52-2.31 (m, 4H), 2.28 (s, 3H), 1.45 (s, 9H), 1.05 (t, J=7.5 Hz, 3H). LC/MS (Method B): 560.5 (M+H)+. HPLC (Method A) Rt 5.14 min (Purity: 94.0%).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:50])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=5[O:33][C@H:34]([CH2:36]C=C)[CH3:35])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:39])[C:12]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:46]([O:45][C@@H:40]([C:12]1[C:13]([CH3:39])=[CH:14][C:15]2=[N:19][C:18]3=[CH:17][N:16]2[C:11]=1[N:8]1[CH2:7][CH2:6][C:5]([CH3:50])([O:4][CH2:1][CH:2]=[CH:3][CH2:36][C@H:34]([CH3:35])[O:33][C:27]2[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:26]=2[C:22]2[CH:21]=[C:20]3[CH:25]=[CH:24][CH:23]=2)[CH2:10][CH2:9]1)[C:41]([O:43][CH3:44])=[O:42])([CH3:48])([CH3:47])[CH3:49]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Solvent: ClCCCl
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc3cn2c1N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)ccc1-c1cccc-3c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
A solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (0.21 g, 0.307 mmol, 1 equiv) and TsOH monohydrate (58 mg, 0.307 mmol, 1 equiv) in DCE (300 mL) was heated to 80° C. The Hoveyda Grubbs 2nd generation catalyst (19 mg, 0.031 mmol, 0.1 equiv) was added. The pale green brown solution was stirred for 2 h. Upon cooling to ambient temperature, the reaction was washed with saturated aqueous NaHCO3, dried (Na2SO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (0.20 g, 99%) as a yellow glass. LCMS (ESI, M+1): 656.25.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@H:11]([N:16]=[C:17]=[O:18])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:10])[C@H:11]([CH2:12][CH:13]([CH3:14])[CH3:15])[NH:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCCNCC1
Reactant: CC(C)C[C@H](N=C=O)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of (S)-α-benzyloxycarbonyl-γ-methylbutyl isocyanate (1.50 g) in ethyl acetate (60 ml) was added hexahydro-1H-azepine (722 mg) at room temperature. After being stirred for 30 minutes at the same temperature, the solution was washed with 5% HCl, 1M sodium bicarbonate solution and saturated sodium chloride solution successively, and dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo to give N-(hexahydro-1H-azepin-1-ylcarbonyl)-L-Leucine benzyl ester (2.06 g) as a crystal.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11](=[S:13])[NH2:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Br[CH:15]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[C:16]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:12]=[C:11]([CH:8]3[CH2:9][CH2:10][C:5]4([O:4][CH2:3][CH2:2][O:1]4)[CH2:6][CH2:7]3)[S:13][C:15]=2[C:26]2[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(C(=O)C(Br)c2ccc(C)cc2)cc1
Reactant: NC(=S)C1CCC2(CC1)OCCO2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(-c2nc(C3CCC4(CC3)OCCO4)sc2-c2ccc(C)cc2)cc1
Yield: 81 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decane-8-carbothioamide (Reference Example 94) (389 mg, 1.93 mmol) and 2-bromo-1-(4-methoxyphenyl)-2-(p-tolyl)ethanone (588 mg, 1.84 mmol) in acetonitrile (9.2 mL) was stirred at room temperature for 4 hours. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography (silica gel, n-hexane/ethyl acetate) to obtain the captioned compound (630 mg, 1.49 mmol, 81%) as a colorless amorphous product.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20][CH:21]([CH3:23])C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:28]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH:20]3[CH2:21][CH2:23][CH2:13][C@@H:12]([CH3:17])[CH2:4]3)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@@H]1CCCC(Nn2c(=O)c(C3=NS(=O)(=O)c4ccccc4N3)c(O)c3sccc32)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.06 g, 0.13 mmol) in tetrahydrofuran (6 mL) and methanol (0.011 mL, 0.26 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.1 mL, 0.2 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1M hydrochloric acid a pH of approximately 2-4, diluted with water (10 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 98:2 dichloromethane/methanol to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (m, 4 H) 1.08 (m, 1 H) 1.29 (m, 3 H) 1.60 (m, 3 H) 1.93 (m, 1 H) 3.04 (m, 1 H) 5.76 (d, J=3.31 Hz, 1 H) 7.14 (d, J=5.52 Hz, 1 H) 7.19 (d, J=8.46 Hz, 1 H) 7.26 (t, J=7.54 Hz, 1 H) 7.52 (dt, J=8.46, 1.47 Hz, 1 H) 7.65 ((d, J=8.09 Hz, 1 H) 7.73 (t, J=5.15 Hz, 1 H) 15.93 (s, 1 H). MS (ESI−) m/z 457 (M−H)−.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[CH:18]([CH2:21][CH2:22][F:23])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2.[CH:35]([C:37]([CH3:39])=[O:38])=[CH2:36]>C1COCC1>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][C:13]3[C:19](=[O:20])[C:18]([CH2:21][CH2:22][F:23])([CH2:36][CH2:35][C:37](=[O:38])[CH3:39])[CH2:17][C:14]=32)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(C)=O
Reactant: O=C1c2ccc3nn(Cc4ccccc4)cc3c2CC1CCF
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)CCC1(CCF)Cc2c(ccc3nn(Cc4ccccc4)cc23)C1=O
Temperature: 55 °C

Procedure:
To a solution of 2-benzyl-7-(2-fluoroethyl)-7,8-dihydrocyclopenta[e]indazol-6(2H)-one (11.8 g, 38.3 mmol) in dry THF (100 mL) were added 1,8-diazabicyclo[5.4.0]undec-7-ene (12 mL, 80 mmol) and methyl vinyl ketone (6.4 mL, 77 mmol) and the solution was heated to 55° C. After heating for 72 hours, analysis of an aliquot by 1H NMR showed the reaction to be complete. After cooling to room temperature, the solution was partitioned between 5% MeOH/CH2Cl2 and water and the organic phase was washed with 5% aqueous NaHCO3. The solvent was removed by evaporation under vacuum and the residue was purified by chromatography on silica gel (1:2 to 1:1 EtOAc/hexanes) to give 2-benzyl-7-(2-fluoroethyl)-7-(3-oxobutyl)-7,8-dihydrocyclopenta[e]indazol-6(2H)-one as an orange oil.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7](C#C)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:13]C1C=C(C=CC=1)C(O)=O.C[Al](C)C>CCCCCC>[C:1]([C:5]1[CH:6]=[C:7]([Br:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cccc(C(C)(C)C)c1
Reactant: O=C(O)c1cccc(Br)c1
Agent: C[Al](C)C
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(Br)c1

Procedure:
Reaction Scheme 4 discloses a specific synthetic route to 3-tert-butylphenylethyne (Compound 24) starting with meta bromobenzoic acid (Compound 25), which is treated with trimethylaluminum in hexane to yield 3-tert-butyl bromobenzene (Compound 26). 3-Tert-butyl bromobenzene 26 is thereafter converted into the ethyne derivative 24 through the trimethylsilyl ethyne intermediate 27 in steps similar to the steps described in connection with Reaction Scheme 3.