Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[N:6]=[CH:5]2.[CH3:17][C@H:18]([NH2:27])[C@H:19]([OH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(#N)CCC.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu]I>[CH3:17][CH:18]([NH2:27])[CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[O:26][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[N:6]=[CH:5]2
Reactant: Ic1ccc2c(cnn2-c2ccccn2)c1
Reactant: C[C@H](N)[C@H](O)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: CC(N)C(Oc1ccc2c(cnn2-c2ccccn2)c1)c1ccccc1
Temperature: 125 °C
Reaction time: 2 h
Yield: 16.3 %

Procedure:
5-Iodo-1-pyridin-2-yl-1H-indazole (118b, 81 mg, 0.25 mmol), (1R,2S)-(−)-norephedrine (119 mg, 0.79 mmol) and butyronitrile (3 ml) were charged in a 7 ml vial. Copper(I) iodide (5.8 mg, 0.1 mol %) and cesium carbonate (261 mg, 0.8 mmol) were added, the vial was sealed and the solution was stirred (magnetic bar) at 125° C. for 2 h. Inorganic material was filtered off, and washed with ethyl acetate. The ethyl acetate phase was collected and concentrated and purified on silica with methanol:ethyl acetate 0:100 to 30:70 over 45 min. Pure fractions were pooled and concentrated to give 14 mg (16%) of 1-methyl-2-phenyl-2-(1-pyridin-2-yl-1H-indazol-5-yloxy)-ethylamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.[F:26][C:27]([F:37])([F:36])[CH2:28][N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1>>[CH3:24][C:21]1([CH3:25])[CH2:22][CH2:23][C:18]([C:4]2[CH:3]=[C:2]([C:32]3([OH:35])[CH2:33][CH2:34][N:29]([CH2:28][C:27]([F:26])([F:36])[F:37])[CH2:30][CH2:31]3)[CH:7]=[CH:6][C:5]=2[NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[CH:19][CH2:20]1
Reactant: O=C1CCN(CC(F)(F)F)CC1
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Product: CC1(C)CC=C(c2cc(C3(O)CCN(CC(F)(F)F)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1

Procedure:
The title compound was prepared as described in Example 1, step (h) using 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 1, step (g) and 1-(2,2,2-trifluoro-ethyl)-piperidin-4-one (WO 9621452). 1H-NMR (CD3OD; 400 MHz): δ 12.9 (br s, 1H), 9.62 (s, 1H), 8.21 (d, 1H, J=8.4 Hz), 7.63 (s, 1H), 7.38 (dd, 1H, J=8.4, 2.0 Hz), 7.24 (d, 1H, J=2.0 Hz), 5.73 (br s, 1H), 4.13 (m, 2H), 2.91-3.23 (m, 4H), 1.93-2.32 (m, 4H), 1.53 (m, 2H), 1.08 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C26H30F3N5O2, 502.5 (M+H). found 502.2.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18](C(F)(F)F)[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4].[Br:35]C1C2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=C(C=O)C=1>>[CH3:1][O:2][C:3]([CH:5]1[CH2:8][N:7]([CH2:9][C:10]2[CH:19]=[C:18]([Br:35])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:24][C@H:25]4[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[CH:16]=3)[N:11]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CN(Cc2cc(C(F)(F)F)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3nc(C=O)cc(Br)c3c2)CC1
Product: COC(=O)C1CN(Cc2cc(Br)c3cc(O[C@H]4CC[C@H](C(C)(C)C)CC4)ccc3n2)C1

Procedure:
Synthesized as per 1-[6-(trans-4-tert-Butyl-cyclohexyloxy)-4-trifluoromethyl-quinolin-2-ylmethyl]-azetidine-3-carboxylic acid methyl ester using 4-Bromo-6-(trans-4-tert-butyl-cyclohexyloxy)-quinoline-2-carbaldehyde as starting material. ESI-MS(M+H+): 489.20/491.20.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].[OH-].[Na+]>O1CCCC1.O>[CH2:25]([O:24][C:22]([NH:1][CH:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=1)[C:3]([O:5][CH3:6])=[O:4])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(N)c1cccc(OCc2ccccc2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OCc1ccccc1)c1cccc(OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a solution of methyl 2-amino-2-(3-(benzyloxy)phenyl)acetate (1.09 g, 4 mmol) in a mixture of tetrahydrofuran and water (1:1, 90 mL) at 0° C. was added benzyl chloroformate (0.57 mL, 4 mmol) and aqueous sodium hydroxide (4 N, 1 mL, 4 mmol) simultaneously. The mixture was stirred at 0° C. for one hour. The ice bath was removed and the reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and ethyl acetate (100 mL) and water (30 mL) were added. The layers were separated and the aqueous phase re-extracted with ethyl acetate (2×50 mL). The combined organic fractions were dried over magnesium sulfate, filtered and the solvent removed in vacuo. The residue was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in iso-hexane to afford the title compound (900 mg, 56%) as a brown oil.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:35][CH2:34]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH3:36][O:37][CH2:38][C:39](Cl)=[O:40]>>[CH3:36][O:37][CH2:38][C:39]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH:28]([F:30])[F:29])=[CH:22][C:21]=4[O:31][CH2:32][CH:33]4[CH2:34][CH2:35]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:40]
Reactant: COCC(=O)Cl
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3cc(F)c(OC(F)F)cc3OCC3CC3)ncnc12
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4cc(F)c(OC(F)F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-cyclopropylmethoxy-4-(1,1-difluoro-methoxy)-5-fluoro-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A189) and methoxy-acetyl chloride the title compound is obtained as colorless solid
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CN(C=O)C>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccnc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 50 °C

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride (20 mg, 0.093 mmol) was dissolved in a mixture of dichloromethane and aqueous saturated NaHCO3 and the organic layer was dried (MgSO4) and evaporated to give pyridine-3-sulfonyl chloride. tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added. The mixture was stirred for 10 minutes before pyridine-3-sulfonyl chloride (0.093 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes before TFA (2 mL) was added and the mixture was heated at 50° C. overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (2.6 mg) in the form of the trifluoroacetate salt. MS m/z 364 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([C:18](=[O:37])/[N:19]=[C:20]4/[S:21][C:22]5[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=5[N:24]/4[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[N:5][C:4]=1[C:38]([O:40][CH3:41])=[O:39])=[O:2].[BH4-].[Na+]>CO.C1COCC1>[OH:2][CH2:1][C:3]1[S:7][C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[C:11]([C:18](=[O:37])/[N:19]=[C:20]4/[S:21][C:22]5[CH:36]=[CH:35][CH:34]=[CH:33][C:23]=5[N:24]/4[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:12]=[CH:13][CH:14]=3)[CH2:9]2)=[N:5][C:4]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)/N=c4/sc5ccccc5n4COCC[Si](C)(C)C)c3C2)sc1CO
Temperature: 70 °C
Yield: 89 %

Procedure:
To compound 45C (2.08 g, 3.42 mmol) in MeOH (50 mL) and THF (20 mL) was added NaBH4 (0.259 g, 6.83 mmol). The reaction mixture was heated at 70° C. for 2 hours. The solvent was removed, and the residue was partitioned between EtOAc and water. The organic layer was isolated, and the aqueous layer was extracted with additional EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with 1:1/hexanes:EtOAc to provide 1.86 g of the desired product: 1H NMR (DMSO-d6): δ 8.24-8.26 (m, 1H), 7.94 (d, J=7.67 Hz, 1H), 7.70 (d, J=8.20 Hz, 1H), 7.52-7.56 (m, 1H), 7.34-7.42 (m, 3H), 6.00 (s, 2H), 5.77 (t, J=5.52 Hz, 1H), 5.13 (s, 2H), 4.83 (d, J=5.52 Hz, 2H), 3.67-3.75 (m, 7H), 3.03 (t, J=5.98 Hz, 2H), 0.87-0.91 (m, 2H), −0.18 (s, 9H). MS (ESI(+)): m/z 611 (M+H).
Reaction SMILES: [Cl:1]C1N(CC(OC(C)C)=O)C2C(C(CC)CC)=CC=C(Cl)C=2N=1.[Br:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[C:27](Cl)[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[Br:24][C:25]1([Cl:1])[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH2:26]1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Cl)n(CC(=O)OC(C)C)c12
Reactant: Nc1ccc(Br)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: NC1=CCC(Cl)(Br)C=C1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
A mixture of isopropyl [2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]acetate (Reference Example 10; 1.33 g, 3.72 mmol), 4-bromo-2-chloroaniline (1.92 g, 9.31 mmol), p-toluenesulfonic acid monohydrate (707.6 mg, 3.98 mmol) and xylene (10.0 mL) was stirred at 150° C. for 2 hr. After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate (×3). The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-15% ethyl acetate/n-hexane gradient mixture to give isopropyl {2-[(4-bromo-2-chlorophenyl)amino-4-chloro]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}acetate and 4-bromo-4-chloroaniline. The mixture was used for the next step without further purification.
Reaction SMILES: C(I)I.[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]([CH3:11])=[CH2:10])[CH3:5].[CH3:13]COC(C)=O>C(OCC)C>[CH2:4]([O:6][C:7](=[O:12])[CH2:8][C:9]1([CH3:13])[CH2:11][CH2:10]1)[CH3:5]
Reactant: CCOC(C)=O
Reactant: C=C(C)CC(=O)OCC
Solvent: ICI
Solvent: CCOCC
Product: CCOC(=O)CC1(C)CC1
Temperature: 60 °C

Procedure:
Zn—Cu couple (10.726 g) suspended in diethyl ether (20 ml) was treated at RT under an argon atmosphere with CH2I2 (14.86 g) and 3-methyl-but-3-enoic acid ethyl ester (3.9 g) and heated in a closed reaction vial at 60° C. for 20 h. The mixture was then cooled to RT, AcOEt (50 ml) were added and reaction mixture was filtered. The filter cake was washed with AcOEt, the combined filtrates washed with water (125 ml), dried over MgSO4 and then evaporated (applying a 40 mbar vacuum). This gave the desired (1-methyl-cyclopropyl)-acetic acid ethyl ester (4.4 g) as a brown liquid that was essentially pure (according to NMR) and used directly in the next reaction step.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: CCOC(=O)CNC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CCOC(=O)CNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (2.0 g) and ethyl N-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)glycinate (1.55 g) in 2-propanol (20 mL) was added piperidinium acetate (0.86 g). The reaction mixture was stirred at 70° C. for 2 hr and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (2.62 g).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:17]([OH:18])[C@@H:16]([OH:19])[C@@H:15]([CH3:20])[O:14][C@H:10]1[S:11][CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:28]([O:18][C@H:17]1[C@@H:16]([OH:19])[C@@H:15]([CH3:20])[O:14][C@@H:10]([S:11][CH2:12][CH3:13])[C@@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCS[C@@H]1O[C@H](C)[C@H](O)[C@H](O)[C@H]1OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS[C@@H]1O[C@H](C)[C@H](O)[C@H](OC(=O)c2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.7 %

Procedure:
To a solution of ethyl 2-O-benzyl-6-deoxy-1-thio-β-D-galactopyranoside (1.03 g, 3.45 mmol) and DMAP (126 mg, 1.0 mmol) in 10 mL of dry CH2Cl2 at −30° C. was added Et3N (1.92 mL, 13.8 mmol). Benzoyl chloride (0.4 mL, 3.45 mmol) was added to this mixture in a dropwise fashion, and the stirred at −30° C. for 3 hr. The reaction was then quenched by the addition of MeOH (2 mL) and the mixture was gradually warmed to room temperature after which the resulting mixture was diluted with EtOAc (250 mL). The solution was washed with saturated NaHCO3 solution (2×20 mL), water (30 mL), dried over Na2SO4, concentrated and purified by flash chromatography (3:1 to 1:1 hexane/EtOAc) to give 1.12 g (80%) of the title product. [α]D=96.9° (c=1, CHCl3); 1H NMR (CDCl3) 8.09-8.03 (m, 2H), 7.56 (t, 1H, J=7.4 Hz), 7.49 (m, 2H), 7.22 (m, 2H), 7.18 (m, 3H), 5.28 (dd, 1H, J=3.0, 9.6 Hz), 4.87 (d, 1H, J=10.6 Hz), 4.67 (d, 1H, J=10.6 Hz), 4.56 (d, 1H, J=9.7 Hz), 4.12 (m, 1H), 3.85 (t, 1H, J=9.8 Hz), 3.80 (m, 1H), 2.81 (m, 2H), 1.93 (d, 1H, J=6.7 Hz), 1.36 (m, 6H); 13C NMR (CDCl3) 166.2, 138.0, 133.7, 130.2, 130.1, 128.9, 128.7, 128.6, 128.2, 85.7, 78.1, 77.6, 76.5, 76.0, 74.7, 70.9, 25.6, 16.9, 15.4; MS: calcd for C22H26O5SNa 425.1. found m/z 425.2 (M+Na).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[C:12]1([CH2:18][CH2:19][N:20]2[C:24](Br)=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]([N:31]([CH2:69][CH2:70][CH3:71])[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[N:49]([C:50]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:48]=[N:47][N:46]=4)=[CH:35][CH:34]=3)=[N:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Cu]=O>[C:12]1([CH2:18][CH2:19][N:20]2[C:24]([NH:11][CH2:7][CH2:8][CH2:9][CH3:10])=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]([N:31]([CH2:69][CH2:70][CH3:71])[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[N:49]([C:50]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:48]=[N:47][N:46]=4)=[CH:35][CH:34]=3)=[N:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCN
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNc1c(C(=O)OCC)c(N(CCC)Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)nn1CCc1ccccc1

Procedure:
30 mg of reduced copper, 20 mg of copper(II) oxide, 83 mg of potassium carbonate and 5 ml of n-butylamine were added to 216 mg of N-[1-(2-phenylethyl)-5-bromo-4-ethoxycarbonylpyrazol-3-yl]-N-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-n-propylamine, and heated under reflux for 14 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane--ethyl acetate=7:1) to obtain 92 mg of the intended compound as a pale yellow, amorphous solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C@:17]3([C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[C@H:20]([C:30](O)=[O:31])[NH:19][C@H:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C#N)cc2)[C@H](c2cccc(Cl)c2F)[C@]12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 136 (0.3 g, 0.52 mmol), was reacted with diisopropylethylamine (0.34 g, 2.7 mmol), diphenylphosphinic chloride (0.35 g, 1.1 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (0.13 g, 1.1 mmol) to give chiral (2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 0.12 g, 41%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=O)[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(O)C.[Pt]=O>[CH3:15][CH:14]([NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCc1ccccc1
Reactant: CC(=O)CCCCOCCc1ccccc1
Agent: O=[Pt]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(CCCCOCCc1ccccc1)NCc1ccccc1
Yield: 97.4 %

Procedure:
The product of step (i) (4.16 g) and benzylamine (2.03 g) in toluene (50 ml) was refluxed using a Dean-Stark apparatus for 1 h. The toluene solution in ethanol (100 ml) was hydrogenated over pre-reduced 5% platinum oxide on charcoal (0.40 g). The reaction mixture was filtered (hyflo) and evaporated to give an oil (5.73 g) which was purified by FCC eluting with EA-CX (1:4)+1% TE to give the title compound as a yellow oil (4.51 g). T.l.c. (EA-CX 1:4+few drops TE) Rf 0.11.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[N:10][C:11]([CH:14]([F:16])[F:15])=[CH:12][CH:13]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:15][CH:14]([F:16])[C:11]1[N:10]=[CH:9][C:8]([NH2:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)F)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(C(F)F)nc1
Reaction time: 5 h
Yield: 82.6 %

Procedure:
To a solution of tert-butyl[6-(difluoromethyl)pyridin-3-yl]carbamate (1.11 g, 4.54 mmol) in dichloromethane (8 ml), trifluoroacetic acid (8 ml) was added at room temperature. The reaction mixture was stirred for 5 hours at the same temperature, and then was concentrated under reduced pressure. Dichloromethane and saturated aqueous sodium hydrogencarbonate were added to the resulting residue. The organic layer was taken, and the organic layer was dried over anhydrous sodium sulfate and filtered. Subsequently, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to flash silica gel chromatography, and the fraction obtained from an elution with hexane:ethyl acetate=2:1 was concentrated under reduced pressure to obtain the title compound (540 mg, 3.75 mmol, 82%) as a pale green oily substance.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[CH:6]=[CH:5][CH:4]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25](Cl)=[O:26].CN(C)C(=O)C>O>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:8]=1)[C:25]([C:21]1[S:20][CH:24]=[CH:23][CH:22]=1)=[O:26]
Reactant: O=C(Cl)c1cccs1
Reactant: CNc1cccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CN(C(=O)c1cccs1)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
A mixture of 2-(6-methylamino-2-pyridyl)-4H-1,3-benzothiazine-4-one (0.20 g, 0.74 mmol), 2-thiophenecarbonyl chloride (0.28 g, 1.9 mmol) and N,N-dimethylacetamide (10 ml) was stirred at 80° C. for 2 hrs. After cooling, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate solution and brine and dried. The solvent was evaporated. The residue was recrystallized from tetrahydrofuran-hexane to give the titled compound (0.23 g, 83%)
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[CH:7]=O)[CH3:2].[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([CH2:29][C:30]#[N:31])=[CH:28][C:23]=2[O:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27](/[C:29](=[CH:7]/[C:6]3[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=3)/[C:30]#[N:31])=[CH:28][C:23]=2[O:22][CH2:21]1
Reactant: N#CCc1ccc2c(c1)OCO2
Reactant: CCOc1cc(C=O)ccc1OCCCCCCO
Product: CCOc1cc(/C=C(\C#N)c2ccc3c(c2)OCO3)ccc1OCCCCCCO
Yield: 96 %

Procedure:
(2Z)-2-(1,3-benzodioxol-5-yl)-3-{3-ethoxy-4-[(6-hydroxyhexyl)oxy]phenyl}prop-2-enenitrile is prepared starting from 3-ethoxy-4-[(6-hydroxyhexyl)oxy]benzaldehyde and 1,3-benzodioxol-5-ylacetonitrile according the same procedure following for example 10 in 96% yield. This material proves chromatographically homogenous and displays spectral characteristics consistent with its assigned structure.