Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:21]=[CH:20][C:7]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:2].C[Si]([C:26]#[N:27])(C)C>>[CH2:1]([S:3][C:4]1[CH:21]=[CH:20][C:7]([NH:8][CH:9]([C:10]2[CH:15]=[CH:14][C:13]([S:16](=[O:19])(=[O:18])[NH2:17])=[CH:12][CH:11]=2)[C:26]#[N:27])=[CH:6][CH:5]=1)[CH3:2]
Reactant: C[Si](C)(C)C#N
Reactant: CCSc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1
Product: CCSc1ccc(NC(C#N)c2ccc(S(N)(=O)=O)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using 4-ethylthio-N-(4-sulfamoylbenzylidene)aniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a yellow powder (yield 100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:27][CH:28]=O)[C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:30][NH2:31]>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH2:27][CH2:28][NH:31][CH3:30])[C:16]([NH:18][C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)=[O:17])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(-c2ccc(C(CC=O)C(=O)Nc3cc(Cl)cc(Cl)c3)cc2)c1
Reactant: CN
Solvent: ClCCCl
Product: CNCCC(C(=O)Nc1cc(Cl)cc(Cl)c1)c1ccc(-c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
A mixture of 2-(3′-cyano-biphenyl-4-yl)-N-(3,5-dichloro-phenyl)-4oxo-butyramide (300 mg, 0.71 mmol) and MeNH2 (2M in THF, 1.77 mL, 3.54 mmol, 5 eq) in 1,2-dichloroethane (3.5 mL) was stirred at r.t. for 1 h and then Na(AcO)3BH (299 mg, 1.4 mmol, 2 eq) was added. The reaction mixture was stirred at r.t. for 16 h. The mixture was then partitioned between EtOAc (20 mL) and 10% NaHCO3 (10 mL) and the organic phase separated. The organic phase was washed with 10% NaHCO3 (10 mL×2), saturated brine (10 mL), dried (Na2SO4), and concentrated. Chromatography on silica gel (Et3N/MeOH/CH2Cl2 1:10:90) gave 56.5 mg (18%) of the title compound as a yellowish gum. 1H NMR (300 MHz, CDCl3): δ 7.89 (m, 2H), 7.72 (m, 1H), 7.61 (m, 7H), 7.14 (t, 1H), 4.04 (dd, 1H), 2.85 (t, 2H), 2.59 (s, 3H), 2.50 (m, 1H), 2.16 (m, 1H). MS(ESI): 438.0 (M+1), 440.0 (M+3).
Reaction SMILES: [Cl:1][C:2]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][C@@H:5]1[CH3:18])=[O:3].[CH3:19][C:20]1[CH:27]=[C:26]([CH3:28])[CH:25]=[CH:24][C:21]=1[CH2:22][OH:23]>>[ClH:1].[CH3:18][C@H:5]1[CH2:6][NH:7][CH2:8][C@@H:9]([CH3:10])[N:4]1[C:2]([O:23][CH2:22][C:21]1[CH:24]=[CH:25][C:26]([CH3:28])=[CH:27][C:20]=1[CH3:19])=[O:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: Cc1ccc(CO)c(C)c1
Product: Cc1ccc(COC(=O)N2[C@H](C)CNC[C@@H]2C)c(C)c1
Product: Cl

Procedure:
2,4-Dimethylbenzyl cis-2,6-dimethylpiperazine-1-carboxylate hydrochloride was prepared from cis 1-chlorocarbonyl-2,6-dimethyl-4-tert-butoxycarbonylpiperazine and 2,4-dimethylbenzyl alcohol according to the methods described for Examples 52 and 54 to give the product as a hygroscopic white solid (0.1384 g, 44% overall); (Found: C, 60.9; H, 8.1; N, 8.9%. C16H24N2O2.HCl.0.25H2O requires C, 60.6; H, 8.1; N, 8.8%); δH (400 MHz, DMSO-d6) 9.53 (2H, br), 7.19 (1H, d, J 7.6 Hz), 7.03 (1H, s), 6.99 (1H, d, J 7.6 Hz), 5.07 (2H, s), 4.29 (2H, m), 3.13 (2H, d, J 13.2 Hz), 3.04 (2H, dd, J 5.2 and 13.2 Hz), 2.27 (3H, s), 2.26 (3H, s) and 1.29 (6H, d, J 7.2 Hz).
Reaction SMILES: C(N(CC)CC)C.Cl.Cl.[NH2:10][C@H:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH3:19][CH2:20][CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1.[I-].ClC1C=CC=C[N+]=1C>O.C(#N)C>[CH2:22]([C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:10][C@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:30])=[N:27][CH:28]=1)[CH2:21][CH2:20][CH3:19]
Reactant: CCCCc1ccc(C(=O)O)nc1
Reactant: N[C@@H]1CN2CCC1CC2
Agent: C[n+]1ccccc1Cl
Agent: Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCCCc1ccc(C(=O)N[C@@H]2CN3CCC2CC3)nc1
Reaction time: 8 h
Yield: 95 %

Procedure:
1.5 ml of Acetonitrile and Triethylamine (700 uL, 5.0 mmol) was added to a flask charged with (S)-(−)-3-Aminoquinuclidine dihydrochloride (199 mg, 1.0 mmol) and Fusaric acid (197 mg, 1.1 mmol), followed by addition of 2-Chloro-1-methylpyridinium iodide (383 mg, 1.5 mmol) at room temperature. After stirring overnight, about 2 ml of water was added to reaction mixture to resolve a clear solution that was subsequently injected into a Preparative HPLC instrument for purification. Desired fractions were combined and concentrated under vacuum. (S)-5-butyl-N-(quinuclidin-3-yl)pyridine-2-carboxamide (273 mg, 95% yield) was isolated as clear brown colored oil. 1H NMR (400 MHz, Methanol-D4) δ (ppm): 8.52 (d, J=1.8 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.84 (dd, J=8.0 Hz, 1H), 4.50 (m, 1H), 3.82 (ddd, J=10.0, 3.0, 2.6 Hz, 1H), 3.49 (m, 1H), 3.37 (m, 3H), 2.76 (t, J=7.8 Hz, 2H), 2.38 (m, J=3.1 Hz, 1H), 2.26 (m, 1H), 2.12 (td, J=8.0, 3.1 Hz 2H), 1.96 (m, 1H), 1.68 (m, J=7.7 Hz, 2H), 1.40 (m, J=4.5 Hz, 2H), 0.97 (t, J=7.4 Hz, 3H). LCMS (ESI): m/z 288.1 (M+H [C17H25N3O]=288.20).
Reaction SMILES: Cl[C:2]1[C:12]2[CH2:11][CH2:10][N:9]([C:13]3[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=3)[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:3]=1.N1(C2N=C(O)C3CCN([C:45]4[C:50]([C:51]([F:54])([F:53])[F:52])=[CH:49][CH:48]=[CH:47][N:46]=4)CCC=3N=2)CCCCC1.O=P(Cl)(Cl)Cl.[CH3:62]C#N>CCOC(C)=O>[N:23]1([C:4]2[N:3]=[C:2]([NH:46][C:47]3[CH:48]=[CH:49][C:50]([C:51]([F:52])([F:53])[F:54])=[CH:45][CH:62]=3)[C:12]3[CH2:11][CH2:10][N:9]([C:13]4[C:18]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=4)[CH2:8][CH2:7][C:6]=3[N:5]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: CC#N
Reactant: FC(F)(F)c1cccnc1N1CCc2nc(N3CCCCC3)nc(Cl)c2CC1
Reactant: Oc1nc(N2CCCCC2)nc2c1CCN(c1ncccc1C(F)(F)F)CC2
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(Nc2nc(N3CCCCC3)nc3c2CCN(c2ncccc2C(F)(F)F)CC3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 35 %

Procedure:
4-Chloro-2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine. To a solution of 2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (435 mg, 1.11 mmol) in CH3CN (9 mL) was added POCl3 (0.41 mL, 4.43 mmol). After 1.5 h at 80° C., the mixture was cooled to rt, diluted with EtOAc, and quenched slowly with satd. aq. NaHCO3. The organic layers were combined, dried (Na2SO4), and concentrated. The crude residue was purified (FCC) to give the title compound (160 mg, 35%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:13](=O)[CH2:14]Br)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[S:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:13]1[N:44]=[C:42]([NH:41][C:31]2[CH:32]=[CH:33][C:34]([N:35]3[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]3)=[C:29]([O:28][CH3:27])[CH:30]=2)[S:43][CH:14]=1)[CH2:9][CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2nc([C@H](CC(C)C)NC(=O)OC(C)(C)C)cs2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 102 mg (0.33 mmol) (S)-[1-(2-bromo-acetyl)-3-methyl-butyl]-carbamic acid tert-butyl ester, 42 mg (0.33 mmol) N,N-diisopropyl ethyl amine and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea. The crude reaction was poured onto water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulphate, filtered and the solvent was evaporated under vacuo. The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 97 mg (69%) ((S)-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazol-4-yl}-3-methyl-butyl)-carbamic acid tert-butyl ester as a light yellow solid. MS ISP (m/e): 472.3 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.35 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.23 (d, 1H), 7.15 (d, 1H), 7.03 (s, 1H), 6.99 (d, 1H), 6.55 (s, 1H), 4.59 (m, 1H), 3.82 (s, 3H), 2.14 (s, 3H), 1.70-1.55 (m, 3H), 1.39 (s, 9H), 0.90 (s, 6H). α589=−43.2; T=20° C.; c=1 g/m100 ml, solvent=MeOH.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[CH:11]=[CH:10][C:9]([Cl:13])=[CH:8][C:7]=2[C:6]2[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:5]1=2)[CH:2]=[CH2:3].Br[C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[N:24][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:13][C:9]1[CH:10]=[CH:11][C:12]2[N:4]([CH2:1]/[CH:2]=[CH:3]/[C:20]3[CH:25]=[N:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[C:5]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C:6]=3[C:7]=2[CH:8]=1
Reactant: C=CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Reactant: Cc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(/C=C/Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)cn1
Temperature: 25 °C

Procedure:
5-Allyl-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.15 mmol, 1 equiv.) and 5-bromo-2-methylpyridine (198 mg, 1.15 mmol, 1 equiv.) were heated to 100° C. with palladium acetate (7.8 mg, 0.034 mmol), triphenyl phosphine (18 mg, 0.069 mmol) and triethyl amine (0.35 mL, 2 equiv.) in THF (6 mL) for 14 h. The reaction mixture was cooled to RT and diluted with THF (10 mL), filtered over a Celite bed and concentrated. The concentrate was dissolved in EtOAc (20 mL) and washed with water (5 mL) followed by brine. The organic layer was dried over anhydrous sodium sulfate, and evaporated under reduced pressure to obtain crude product that was purified by HPLC. 1H NMR (CD3OD) δ (ppm): 8.57 (s, 1H), 8.39-8.37 (d, 1H), 7.74-7.72 (d, 1H), 7.51 (s, 1H), 7.41 (d, 1H), 7.17 (d, 1H), 6.78-6.72 (m, 1H), 6.28-6.24 (d, 1H), 5.02(m, 2H), 4.7 (bs, 1H), 4.36 (bs, 1H), 3.87 (bs, 1H), 3.6 (bs, 1H), 3.29-3.24 (m, 2H), 3.12-3.10 (s, 3H), 2.7 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=2)=[CH:10][CH:9]=1)=[O:5]>C(O)C.CO.[Pd]>[CH3:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]2)=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1cccc(C)c1C(=O)NCc1ccc(-c2cc[nH]c(=O)c2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cc1cccc(C)c1C(=O)NCc1ccc(C2CCNC(=O)C2)cc1

Procedure:
To a solution of 2,6-dimethyl-N-(4-(2-oxo-1,2-dihydropyridin-4-yl)benzyl)benzamide (see compound 5 of example 3B) in ethanol/methanol (5:1), 10% Pd/C was added and the mixture was hydrogenated (1 atm) at 23° C. for 12 hours. The catalyst was filtered through celite pad and washed with methanol Filtrate and washings were combined and the solvent was then concentrated and chromatographed (SiO2, 3-15% EtOAc/MeOH) to provide the title compound. MS found for C21H24N2O2 as (M+H)+337.1 1H NMR (400 MHz, dmso-d6): δ: 8.76 (t, J=5.6 Hz, 1H); 7.52 (brs, 1H), 7.27-7.14 (m, 4H); 7.13-6.99 (m, 3H); 4.40 (d, J=6.4 Hz, 2H); 3.23-3.16 (m, 2H); 3003-2.98 (m, 1H); 2.35-2.21 (m 2H); 2.17 (s, 6H); 1.88-1.78 (m, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]([F:29])([F:28])[C:11]([NH:13][C@@H:14]([CH3:27])[C@H:15]([OH:26])[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([N+:23]([O-:25])=[O:24])[CH:17]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:15]([OH:26])[C@@H:14]([NH:13][C:11](=[O:12])[C:10]([F:29])([F:28])[F:9])[CH3:27])=[CH:17][C:18]=1[N+:23]([O-:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(O)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1

Procedure:
Benzyl bromide (22 mL) was added to a suspension of 2,2,2-trifluoro-N-[(1S,2R)-2-hydroxy-2-(4-hydroxy-3-nitrophenyl)-1-methylethyl]acetamide (55 g) and potassium carbonate (36.8 g) in N,N-dimethylformamide (529 mL) at room temperature with stirring, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated in vacuo, and ethyl acetate and water were added to the residue. The organic layer was separated, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to afford the title compound (73 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].Cl[C:16]1[C:17]([CH:22]2[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[C:17]([CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)=[N:18][CH:19]=[CH:20][N:21]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(c2nccnc2Cl)C1
Reactant: CNC(=O)c1ccc(B(O)O)cc1F
Product: CNC(=O)c1ccc(-c2nccnc2C2CN(C(=O)OC(C)(C)C)C2)cc1F

Procedure:
The compound was prepared analogously to Example 1 by using (3-fluoro-4-(methylcarbamoyl)phenyl)boronic acid (purchased from Combi Blocks) and tert-butyl 3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate. m/z=287 (M+1-100).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH:5]=O.[N+:11]([CH3:14])([O-:13])=[O:12].[OH-].[Na+]>C(O)C>[F:10][C:9]1[CH:8]=[CH:7][C:4](/[CH:5]=[CH:14]/[N+:11]([O-:13])=[O:12])=[CH:3][C:2]=1[F:1]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])/C=C/c1ccc(F)c(F)c1
Yield: 76.8 %

Procedure:
Using analogous reaction conditions and workup as described in example 1, 3,4-difluorobenzaldehyde (5 g, 35.1864 mmol) in ethanol (175 mL) was reacted math nitro methane (1.9 mL, 35.1864 mmol) and 10N NaOH (1.47 g, 36.9457 mmol) to afford 5 g of the product (76.80% yield). 1H NMR (CDCl3, 300 MHz): δ 7.92 (d, 1H), 7.58-7.0 (m, 4H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:14]=[C:13]([C:15]([C:25]2C=CC=C[CH:26]=2)([O:20][Si](C)(C)C)C(F)(F)F)[CH:12]=[C:11](F)[CH:10]=1.[F:32]C1C=C(C(C2SC=CN=2)=O)C=C(F)C=1.C1([Mg]Br)C=CC=CC=1.C([Mg]Br)=C>C1COCC1>[F:32][C:5]1[CH:4]=[C:3]([C:15]([OH:20])([C:13]2[CH:14]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:25][CH3:26])[CH:2]=[C:1]([SH:7])[CH:6]=1
Reactant: O=C(c1cc(F)cc(F)c1)c1nccs1
Reactant: C[Si](C)(C)OC(c1ccccc1)(c1cc(F)cc(F)c1)C(F)(F)F
Reactant: Sc1ccccc1
Agent: Br[Mg]c1ccccc1
Agent: C=C[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)(c1ccccc1)c1cc(F)cc(S)c1

Procedure:
Following the procedure described for Thiophenol 2, Step 3 and Thiophenol 1, Steps 2 and 3 but substituting 3,5-difluoropropiophenone (Lancaster) for (3,5-difluorophenyl)(thiazol-2-yl)methanone and phenylmagnesium bromide in THF (Aldrich) for vinylmagnesium bromide as starting material the title compound was obtained.
Reaction SMILES: [CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].[Cl-].O[NH3+:41].[C:42](=[O:45])([O-])[OH:43].[Na+]>CS(C)=O.C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:38][C:6]2[N:7]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[C:36]4[NH:41][C:42](=[O:45])[O:43][N:37]=4)=[CH:26][CH:25]=3)[C:8](=[O:22])[N:9]([CH2:12][C:13]([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)=[O:14])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc(F)cc3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
4′-{[6-Ethyl-3-[2-(4-fluorophenyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.70 g) was dissolved in dimethyl sulfoxide (5 mL), and the mixture was added to a mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.30 g) and dimethyl sulfoxide (10 mL), which had been stirred at 40° C. for 30 min in advance. The reaction mixture was stirred at 90° C. for 16 hr, diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography, dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.26 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (10 mL), HIO3 (0.44 g) was added and the mixture was stirred at room temperature overnight. Activated carbon was added to the reaction mixture and the mixture was heated to 45° C. and filtered. The filtrate was concentrated, and purified by preparative HPLC to give the title compound as colorless crystals (0.078 g, 16%).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.CN(C)CCC(N[C@]12CC[C@@H](C(C)=C)[C@@H]1[C@@H]1[C@@](C)(CC2)[C@@]2(C)[C@@H]([C@]3(C)[C@@H](CC2)C(C)(C)C(C2C=CC(C(O)=O)=CC=2)=CC3)CC1)=O.[N:87]1([CH2:96][C:97]([OH:99])=O)[C:95]2[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=2)[CH:89]=[CH:88]1>>[N:87]1([CH2:96][C:97]([NH:1][C@:2]23[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]2[C@@H:4]2[C@@:17]([CH3:20])([CH2:18][CH2:19]3)[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5]2)=[O:99])[C:95]2[C:90](=[CH:91][CH:92]=[CH:93][CH:94]=2)[CH:89]=[CH:88]1
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cn1ccc2ccccc21
Agent: C=C(C)[C@@H]1CC[C@]2(NC(=O)CCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cn3ccc4ccccc43)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 31 %

Procedure:
The title compound was prepared in 31% yield from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the same procedure as described for the preparation of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(3-(dimethylamino)propanamido)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid, except 2-(1H-indol-1-yl)acetic acid was used instead of 3-(dimethylamino)propionic acid hydrochloride in Step 1. LCMS: m/e 687.6 (M+H)+, 2.60 min (method 6). 1H NMR (400 MHz, 1:1 CDCl3:MeOD) δ=7.92 (d, J=8.5 Hz, 2H), 7.72 (d, J=7.8 Hz, 1H), 7.40-7.35 (m, 1H), 7.32-7.25 (m, 1H), 7.24-7.16 (m, 4H), 6.71 (dd, J=0.8, 3.3 Hz, 1H), 5.27 (dd, J=1.6, 6.1 Hz, 1H), 4.90 (s, 1H), 4.83 (s, 2H), 4.44 (s, 1H), 4.33 (d, J=1.8 Hz, 1H), 2.48 (d, J=12.5 Hz, 1H), 2.39-2.31 (m, 1H), 2.08 (dd, J=6.4, 17.2 Hz, 1H), 1.64 (d, J=16.6 Hz, 1H), 1.54 (d, J=8.0 Hz, 2H), 1.50 (s, 3H), 1.39 (br. s., 3H), 1.37-1.23 (m, 6H), 1.23-1.13 (m, 4H), 1.04 (br. s., 1H), 1.00 (s, 4H), 0.95 (s, 3H), 0.92 (s, 3H), 0.87 (s, 3H), 0.82 (s, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:31]=[CH:30][CH:29]=[CH:28]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=O.CO.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:28]=[CH:29][CH:30]=[CH:31]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:13]=[CH:14][CH:15]=2)[O:8][CH:9]=1
Reactant: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1CC(c2cccc(-c3nc(CO)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 40 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example 25) (88 mg, 0.2 mmol) in THF (1.5 mL) were added successively MeOH (0.012 mL) and lithium borohydride (6.5 mg, 0.3 mmol). The mixture was stirred at 40° C. for 1 h and then partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried and evaporated in vacuum. The residue was chromatographed on silica gel using EtOAc/hexane (1:2) as eluents to give the title compound (24 mg) as light-yellow solid.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:19]=[C:18]([C:20]4[NH:21][C:22]([C:25]5[O:26][C:27]([CH3:30])=[N:28][N:29]=5)=[CH:23][CH:24]=4)[CH:17]=[C:16]([O:31][C@@H:32]([CH3:36])[CH2:33][O:34]C)[CH:15]=3)=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.[Cl-].[NH4+]>ClCCl>[N:1]1([C:5]([C:7]2[CH:8]=[C:9]([Cl:37])[C:10]([O:13][C:14]3[CH:15]=[C:16]([CH:17]=[C:18]([C:20]4[NH:21][C:22]([C:25]5[O:26][C:27]([CH3:30])=[N:28][N:29]=5)=[CH:23][CH:24]=4)[CH:19]=3)[O:31][C@@H:32]([CH3:36])[CH2:33][OH:34])=[N:11][CH:12]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: COC[C@H](C)Oc1cc(Oc2ncc(C(=O)N3CCC3)cc2Cl)cc(-c2ccc(-c3nnc(C)o3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: Cc1nnc(-c2ccc(-c3cc(Oc4ncc(C(=O)N5CCC5)cc4Cl)cc(O[C@@H](C)CO)c3)[nH]2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.9 %

Procedure:
5-(Azetidin-1-ylcarbonyl)-3-chloro-2-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(5-methyl-1,3,4-oxadiazol-2-yl)-1H-pyrrol-2-yl]phenoxy}pyridine (370 mg, 0.706 mmol) synthesized in Example (71b) was dissolved in dichloromethane (10 mL), and boron tribromide (1.0 mol/L dichloromethane solution, 1.10 mL, 1.10 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1 hour under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with dichloromethane (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/dichloromethane=1%-3%) to afford the desired compound (205 mg, yield 57%) as a white solid.