Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH:27]CC(OC(C)(C)C)=O)=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:36]([OH:42])([C:38](F)(F)F)=[O:37].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([CH2:14][C:15]([C:17]2[C:26]([CH2:38][C:36]([OH:42])=[O:37])=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]=2[NH2:27])=[O:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)CC(=O)c2ccc3ccccc3c2NCC(=O)OC(C)(C)C)CC1
Reactant: O=C(O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CC(=O)c2c(CC(=O)O)cc3ccccc3c2N)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][(1,1-dimethylethoxycarbonyl)methyl]aminonaphthalene (147 mg, 0.30 mmol) in CH2Cl2 (2.0 mL) was added TFA (3.0 mL). The resulting reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was evaporated in vacuo to afford an oil, which was diluted with water (15 mL), adjusted to pH 4.5 by saturated NaHCO3, then extracted by ethyl acetate (3×15 mL). The organic layer was evaporated in vacuo to afford 2-[((4-(ethoxycarbonyl)piperazin-1-yl)carbonylmethyl)carbonyl][carboxymethyl]-aminonaphthalene (90 mg) as a solid; NMR (CDCl3) 1.26 (t, 3), 3.24–3.30 (m, 2), 3.35–3.42 (m, 6), 3.57 (m, 2), 4.14 (q, 2), 4.52 (s, 2), 7.48 (d, 1), 7.58 (m, 2), 7.84–7.94 (m, 4) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH2:28])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)[N:3]=2)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COc1ccc(N)cc1OC
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: COc1ccc(Nc2nc(Nc3cc[nH]n3)cc3ccccc23)cc1OC

Procedure:
Similar procedure as described in example 273 was used, starting (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3,4-dimethoxy-phenylamine to give N1-(3,4-dimethoxy-phenyl)-N3-(1H-pyrazol-3-yl)-isoquinoline-1,3-diamine. LC-MS m/e 362(MH+).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH2:8][N:7]([C:9]2[C:18]([F:19])=[C:17]3[C:12]([C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15][N:16]3[CH2:20][CH3:21])=[CH:11][C:10]=2[F:26])[CH2:6][CH2:5][O:4]1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH2:20]([N:16]1[C:17]2[C:12](=[CH:11][C:10]([F:26])=[C:9]([N:7]3[CH2:6][CH2:5][O:4][CH:3]([CH2:2][N:27]4[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]4)[CH2:8]3)[C:18]=2[F:19])[C:13](=[O:25])[C:14]([C:22]([OH:24])=[O:23])=[CH:15]1)[CH3:21]
Reactant: C1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCl)C3)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN4CCCCC4)C3)c(F)c21

Procedure:
By the use of 7-(2-chloromethylmorpholino)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and piperidine, the reaction is similarly carried out as Example 34 to give 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-[2-(piperidinomethyl)morpholino]quinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)=[O:2].[NH2:12][CH:13]([CH2:19][OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:12][CH:13]([CH2:19][OH:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:9])=[CH:10][CH:11]=1)=[O:2]
Reactant: CCOC(=O)C(N)CO
Reactant: O=Cc1ccc(C(=O)O)cc1
Product: CCOC(=O)C(CO)NC(=O)c1ccc(C=O)cc1
Yield: 34 %

Procedure:
In an analogous manner to 39, 4-formyl benzoic acid (24) (1.0 g, 6.66 mmol) and ethyl 2-amino-3-hydroxypropanoate (975 mg, 7.33 mmol) were reacted to yield 600 mg (34%) of 41 as an off-white sticky solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16](I)=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[Cl:37]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:18][CH3:19])=[N:15][C:16]([Cl:37])=[C:10]2[CH:9]1[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1nc(I)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A cooled (−78° C.) solution of 3-ethyl-1-iodo-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (300 mg; 0.546 mmol) in anhydrous THF (4 ml) was treated dropwise with a solution of 1.6M n-BuLi in hexanes (0.34 ml; 0.546 mmol). The resulting solution was additionally stirred at −78° C. for 10 min., and was then treated dropwise with a solution of hexachloroethane (517 mg; 2.184 mmol; 4 eq.) in anhydrous THF (1 ml). The reaction mixture was further stirred at −78° C. for 1 h. The mixture was then quenched with water (0.2 ml), diluted with ether (30 ml), and was allowed to warm-up to rt. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. The crude was purified by FC (DCM/MeOH=100/3) to give the pure product 1-chloro-3-ethyl-8-[2-(4-trifluoromethyl-phenyl)-ethyl]-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (143 mg; 57%). LC-MS: tR=1.02 min.; [M+H]+=458.49 g/mol.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15](O)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[CH2:50]([C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1)[CH3:51]>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:58][C:56]3[CH:55]=[CH:54][CH:53]=[C:52]([CH2:50][CH3:51])[N:57]=3)=[O:16])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cccc(N)n1
Reactant: CC(C)(C)OC(=O)C[C@@H](CC1CCCC1)C(=O)N1N=CCC1C(=O)O
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCc1cccc(NC(=O)C2CC=NN2C(=O)[C@@H](CC(=O)OC(C)(C)C)CC2CCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79 %

Procedure:
To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours. After this time, 6-ethyl-2-pyridinamine (159 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the resulting residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The crude product residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to provide 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(6-ethyl-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (359 mg, 0.79 mmol, 79% yield) as a clear oil. MS: 457 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1.[NH2:20][C:21]1[C:22]([N:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([NH:36]C(=O)OC(C)(C)C)[CH2:31]2)=[C:23]2[CH2:29][CH2:28][O:27][C:24]2=[N:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[NH2:1][C:2]1[C:3]([C:17]([NH:20][C:21]2[C:22]([N:30]3[CH2:35][CH2:34][CH2:33][C@H:32]([NH2:36])[CH2:31]3)=[C:23]3[CH2:29][CH2:28][O:27][C:24]3=[N:25][CH:26]=2)=[O:19])=[N:4][C:5]([C:9]2[C:10]([F:16])=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])=[C:6]([F:8])[CH:7]=1
Reactant: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c(N)cnc3c2CCO3)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)Nc1cnc2c(c1N1CCC[C@H](N)C1)CCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.1 %

Procedure:
To a mixture of 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylic acid (15.9 mg, 0.0592 mmol), tert-butyl [(3S)-1-(5-amino-2,3-dihydrofuro[2,3-b]pyridin-4-yl)piperidin-3-yl]carbamate (19.8 mg, 0.0592 mmol) and HATU (72.9 mg, 0.192 mmol) DMF (1.50 mL) was added, followed by DIPEA (84.1 mg, 0.651 mmol). The reaction mixture was stirred at room temperature for 2 h, and then concentrated under reduced pressure. DCM (2.0 mL) was added to the residue, followed by TFA (2.0 mL). The mixture was stirred at room temperature for 30 min., and then concentrated under reduced pressure. The resulting residue was purified using RP-HPLC (XBridge™ C18 column, eluting with a gradient of MeCN/water containing 0.15% NH4OH, at flow rate of 30 mL/min.) to afford the title compound as a white solid (4.9 mg, 17%). LCMS calc. for C24H24F3N6O2 (M+H)+: m/z=485.2. found 485.2. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (br s, 1H), 8.86 (s, 1H), 7.60 (tt, J=8.3, 6.8 Hz, 1H), 7.40 (br s, 2H), 7.26 (t, J=8.2 Hz, 2H), 7.21 (d, J=11.5 Hz, 1H), 4.47 (t, J=9.0 Hz, 2H), 3.34 (t, J=8.5 Hz, 2H), 3.04-2.93 (m, 1H), 2.88-2.78 (m, 1H), 2.69-2.57 (m, 1H), 2.54-2.46 (m, 1H), 2.46-2.37 (m, 1H), 1.50-1.17 (m, 3H), 0.95-0.78 (m, 1H) ppm.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+]>C1COCC1.O.C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH:11](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[CH2:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: COC(=O)c1ccc(CC(/C=C/c2ccccc2OC)CCc2ccc(C#N)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COc1ccccc1/C=C/C(CCc1ccc(C#N)cc1)Cc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 744 mg (1.75 mmol) of methyl 4-[(3E)-2-[2-(4-cyanophenyl)ethyl]-4-(2-methoxyphenyl)but-3-en-1-yl]benzoate in 24 ml of THF and 24 ml of water is mixed with 84 mg (3.5 mmol) of lithium hydroxide and stirred at 50° C. for 12 h. After conversion is complete, the reaction solution is diluted with diethyl ether and water, and the phases are separated. The aqueous phase is acidified with 1 M hydrochloric acid and extracted with diethyl ether. The resulting organic phase is washed with sodium chloride solution, dried over sodium sulphate and evaporated. 606 mg (1.5 mmol, 97% of theory) of the title compound are obtained.
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.Br[C:12]1[C:17]([F:18])=[CH:16][C:15]([O:19][CH3:20])=[C:14]([F:21])[CH:13]=1.[NH:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1>>[F:18][C:17]1[CH:16]=[C:15]([O:19][CH3:20])[C:14]([F:21])=[CH:13][C:12]=1[N:22]1[CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24][CH2:23]1
Reactant: COc1cc(F)c(Br)cc1F
Reactant: CCOC(=O)C1CCNCC1
Agent: COc1ccc(Br)cc1C
Product: CCOC(=O)C1CCN(c2cc(F)c(OC)cc2F)CC1

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 4-bromo-2,5-difluoroanisole (4.460 g) and ethyl isonipecotate (3.70 mL), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, hexane: ethyl acetate=6:1) to provide ethyl 1-(2,5-difluoro-4-methoxyphenyl)piperidine-4-carboxylate (2.465 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([CH:12]=O)([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2].[F:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([CH2:12][NH:21][CH2:20][C:19]1[CH:22]=[CH:23][C:16]([F:15])=[CH:17][CH:18]=1)([CH3:11])[CH2:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:2]
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)C(C)(C=O)CCC(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(C)(CCC(C)C)CNCc1ccc(F)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 49.3 %

Procedure:
A solution of 2-formyl-2,5-dimethyl-hexanoic acid ethyl ester (126 mg, 0.629 mmol) in ethanol (3 mL) was treated with 4-fluorobenzylamine (87 mg, 0.692 mmol) and stirred at 60° C. for 18 h. The reaction mixture was allowed to cool to 25° C. and treated with glacial acetic acid (0.036 mL, 0.629 mmol) followed by sodium cyanoborohydride (48 mg, 1.26 mmol). The reaction was stirred for 1 h at 25° C., quenched with a 1.0 M aqueous sodium hydroxide solution (2 mL), extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by flash column chromatography (ISCO RediSep column, 0 to 40% ethyl acetate in hexanes) to give 2-[(4-fluoro-benzylamino)-methyl]-2,5-dimethyl-hexanoic acid ethyl ester (96 mg, 49%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.87 (d, 6H, J=6.0 Hz), 1.00-1.14 (m, 2H), 1.17 (s, 3H), 1.24 (t, 3H, J=7.0 Hz), 1.40-1.49 (m, 3H), 1.60 (sextet, 1H, J=6.1 Hz), 2.65 (dd, 2H, J1=108.4 Hz, J2=11.7, Hz), 3.74 (s, 2H), 4.12 (q, 2H, J=7.1 Hz), 6.98 (t, 2H, J=8.6 Hz), 7.26 (q, 2H, J=4.7 Hz). LC-MS (ESI) calculated for C18H28FNO2: 309.4, found 310.3 [M+H+].
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([CH3:27])([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1)=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14]([CH3:27])([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][CH:12]=1
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCN=[N+]=[N-])cc1)Oc1ccccc1
Agent: [Pd]
Product: CCOC(=O)C(C)(Cc1ccc(OCCN)cc1)Oc1ccccc1
Yield: 99.7 %

Procedure:
In a similar manner to that described in Reference example 1(d), a reaction was carried out using ethyl 3-[4-(2-azidoethoxy)phenyl]-2-methyl-2-phenoxypropionate (0.82 g), which is the product of Reference example 8(f), and palladium on carbon (5%, 123 mg) and the reaction mixture was treated to afford the title compound (0.76 g) as a syrup.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:26])([F:25])[C:8]([C:14]1[CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]([NH2:24])=[CH:16][CH:15]=1)([OH:13])[C:9]([F:12])([F:11])[F:10].O>N1C=CC=CC=1>[F:6][C:7]([F:25])([F:26])[C:8]([C:14]1[CH:15]=[CH:16][C:17]([NH:24][S:2]([CH3:1])(=[O:4])=[O:3])=[C:18]([C:19]([O:21][CH3:22])=[O:20])[CH:23]=1)([OH:13])[C:9]([F:10])([F:12])[F:11]
Reactant: COC(=O)c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1NS(C)(=O)=O
Reaction time: 8 h

Procedure:
Add 2.50 g (22 mmole) of methanesulfonyl chloride dropwise to 4.57 g (15 mmole) of methyl 5-(hexafluoro-2-hydroxy-2-propyl)anthranilate in 25 ml of pyridine and allow to stand overnight. Pour the reaction into H2O and extract with Et2O. Wash the Et2O with 1N HCl and extract with 1N NaOH. Acidify the NaOH and extract with Et2O. Dry, concentrate and recrystallize from Et2O-hexane to obtain 4'-(hexafluoro-2-hydroxy-2-propyl)-2'-(methoxycarbonyl)methanesulfonanilide; m.p. 147°-148° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][OH:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:28][S:29]([O:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][O:20][S:29]([CH3:28])(=[O:31])=[O:30])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:31])=[O:30]
Reactant: OCCCc1ccc(-c2ccc(CCCO)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1ccc(-c2ccc(CCCOS(C)(=O)=O)cc2)cc1
Reaction time: 8 h

Procedure:
3-[4′-(3-Hydroxy-propyl)-biphenyl-4-yl]-propan-1-ol (intermediate 14) (5.0 g,18.5 mmol) was dissolved in dichloromethane (100 mL) and triethylamine (6.0 g, 59 mmol) and subsequently methanesulfonyl chloride (4.6 g, 40 mmol) were added dropwise. The mixture was stirred overnight, washed with water (30 mL), evaporated in vacuo and the residue crystallized from benzene giving 4,4′-biphenyidipropanol bismethanesulfonate.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1.[N:21]1([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH2:33])=[CH:29][C:28]=2[C:34]([F:37])([F:36])[F:35])[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl.CO>[N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([NH:33][C:30]3[CH:31]=[CH:32][C:27]([CH2:26][N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[C:28]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:19])=[C:12]([CH3:20])[CH:11]=2)[CH:2]=1
Reactant: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)O
Reactant: Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(-n2cnc3cccnc32)ccc1CC(=O)Nc1ccc(CN2CCCC2)c(C(F)(F)F)c1

Procedure:
The title compound is prepared as described in Example 7 but using (4-imidazo[4,5-b]pyridin-3-yl-2-methyl-phenyl)-acetic acid (Step 60.1) and 4-pyrrolidin-1-ylmethyl-3-trifluoromethyl-phenylamine (disclosed in WO2005/051366). Title compound: ES-MS: 494.2 [M+H]+; tR=3.23 min (System 1); Rf=0.15 (CH2Cl2/MeOH, 95:5+0.1% NH3aq).
Reaction SMILES: Cl[C:2]1[CH:30]=[CH:29][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[CH:17]=[N:18][C:19]([N:22]4[CH2:26][CH2:25][CH2:24][S:23]4(=[O:28])=[O:27])=[CH:20][CH:21]=3)=[O:15])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:31]B(O)O>>[O:27]=[S:23]1(=[O:28])[CH2:24][CH2:25][CH2:26][N:22]1[C:19]1[N:18]=[CH:17][C:16]([C:14]([N:11]2[CH2:12][CH2:13][CH:8]([C:6](=[O:7])[C:5]3[CH:29]=[CH:30][C:2]([CH3:31])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[O:15])=[CH:21][CH:20]=1
Reactant: CB(O)O
Reactant: O=C(c1ccc(Cl)cc1)C1CCN(C(=O)c2ccc(N3CCCS3(=O)=O)nc2)CC1
Product: Cc1ccc(C(=O)C2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)nc3)CC2)cc1
Yield: 68.1 %

Procedure:
Using [4-(4-chlorobenzoyl)piperidin-1-yl][6-(1,1-dioxo-1λ6-isothiazolidin-2-yl)pyridin-3-yl]methanone (194 mg) described in Example 116 and methylboronic acid (110 mg) and by the reaction and treatment in the same manner as in Example 115, the title compound (126 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:32]C)=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[NH:24][C:25](=[O:31])[C:26]([O:28]CC)=[O:27])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[Cl-].[Li+].Cl>CN(C)C=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:32])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][C:16]=2[NH:24][C:25](=[O:31])[C:26]([OH:28])=[O:27])(=[O:10])=[O:11])[CH:8]=1)#[N:2]
Reactant: CCOC(=O)C(=O)Nc1cc(C(C)C)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1OC
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(NC(=O)C(=O)O)c1
Temperature: 140 °C
Reaction time: 4 h
Yield: 103.5 %

Procedure:
To a solution of 0.21 g of ethyl N-[2-[2-(5-cyano-2-methoxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]oxalamate in 3 mL of N,N-dimethylformamide was added 56 mg of lithium chloride, and the mixture was stirred at 140° C. for 4 hours. To the reaction mixture was added 1 mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure to give 0.198 g of N-[2-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-5-isopropylphenyl]oxalamic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36].[C:41]([O:45][C:46](=[O:49])[CH2:47]Br)([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])[O-].[Cs+].[Cs+].[NH4+].[Cl-]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:32])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:47][C:46]([O:45][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:49])[CH:11]3[C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=3[CH3:31])[C:5]2=[CH:4][CH:3]=1.[CH3:33][O:34][CH:35]([Si:37]([CH3:40])([CH3:39])[CH3:38])[CH3:36]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: COC(C)[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1ccc(F)cc1C1N(CC(=O)OC(C)(C)C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 48.5 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane (1.0 g, 1.67 mmol) prepared in example 55b in N,N-dimethyl-formamide (20 mL) at room temperature was added bromo-acetic acid tert-butyl ester (0.8 g, 4.1 mmol) and cesium carbonate (3.0 g, 9.20 mmol). The reaction mixture was stirred under nitrogen for 4 h, then poured into saturated aqueous NH4Cl solution. The mixture was extracted with ethyl acetate. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:Hexanes=1:4) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)-2,3-dihydro-1′-[(tert-butoxycarbonyl)methyl]-2,6′-dioxospiro[indole-3,3′-piperidine]-1-methoxyethyl trimethylsilane as a white foam (Yield 0.58 g, 48.7%).
Reaction SMILES: O=[C:2]1[C:10]2([CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][C:5]([C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20])=[CH:6][CH:7]=2.C[Si]([N:28]=[C:29]=[N:30][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:19]([C:18]1[CH:17]=[C:16]([C:5]2[CH:4]=[C:3]3[C:8](=[CH:7][CH:6]=2)[CH2:9][C:10]2([CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[C:2]3=[N:30][C:29]#[N:28])[CH:23]=[CH:22][CH:21]=1)#[N:20]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCOCC2)C3)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#CN=C1c2cc(-c3cccc(C#N)c3)ccc2CC12CCOCC2
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 3-(1-oxo-1,2′,3,3′,5′,6′-hexahydrospiro[indene-2,4′-pyran]-6-yl)benzonitrile (42 mg, 0.139 mmol) in anhydrous DCM (10 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 0.28 mL, 0.28 mmol) dropwise within 15 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (0.1 mL, 0.427 mmol) dropwise. The resulting mixture was stirred overnight. The reaction mixture was quenched with ice-water (20 g), and stirred for 20 min, then it was transferred to a separating funnel, the separated aqueous phase was extracted 2 times with DCM. The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give 44 mg of N-(5-(3-cyanophenyl)-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-3(1H)-ylidene)cyanamide as light brown solid which was used for next step without further purification. MS ESI+ve m/z 328 (M+H)30.