Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([OH:20])[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].Cl[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.CCCCCC>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=2)[C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][N:26]=3)[CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CC3)c2)cc1Oc1ccc([N+](=O)[O-])cn1
Temperature: 60 °C
Reaction time: 16 h
Yield: 98.9 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)-N-(3-hydroxy-4-methoxyphenyl)benzamide (3.11 g, 10.1 mmol) and 2-chloro-5-nitropyridine (1.60 g, 10.1 mmol) in N,N-dimethylformamide (150 mL) was added potassium carbonate (4.24 g, 30.7 mmol), and the mixture was stirred at 60° C. for 16 hr. The reaction solution was cooled to room temperature, and diluted with a mixed solvent (250 mL) of ethyl acetate and hexane (1:1). The solution was washed with water (200 mL×3), and the combined m aqueous layer was extracted with a mixed solvent (100 mL×3) of ethyl acetate and hexane (1:1). The combined organic layer was washed with saturated brine (100 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (4.3 g, 99%) as pale-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].[Cu](C#N)[C:20]#[N:21]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:20]#[N:21])=[CH:4][C:3]=1[C:9](=[O:10])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH3:18])=[CH:13][CH:12]=1
Reactant: N#C[Cu]C#N
Reactant: CCc1ccc(C(=O)c2cc(Br)ccc2N)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(C(=O)c2cc(C#N)ccc2N)cc1
Temperature: 180 °C
Yield: 87.4 %

Procedure:
A flask charged with (2-amino-5-bromo-phenyl)-(4-ethyl-phenyl)-methanone (0.10 g, 0.32 mmol), copper cyanide (0.0347 g, 0.41 mmol), and 1 mL of DMF was heated at 180° C. for 1 hour in a microwave reactor. The title compound was eluted from a 5 g SPE with 100% DCM to give 0.07 g (81%) of a white solid. 1H NMR (400 MHz, CDCl3) δ 7.84 (d, 1H), 7.58 (d, 2H), 7.50 (dd, 1H), 7.36 (d, 2H), 6.78 (d, 1H), 6.60 (br s, 2H), 2.78 (q, 2H), 1.30 (t, 3H). This was prepared according to example 41. 1H NMR (400 MHz, CD3OD) δ 8.60 (s, 1H), 7.90 (dd, 1H), 7.50 (m, 4H), 7.22 (d, 2H), 6.48 (s, 1H), 2.82 (q, 2H), 1.36 (t, 3H). Mass spectrum (ESI, m/z) calcd. for C21H16N4O 340.1, found 341.1 (M+H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:46])=[C:9]([CH2:11][O:12][C:13]2[CH:43]=[CH:42][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:27][CH:28]=[C:29]([C:31]([O:33]CC)=[O:32])[N:30]=4)=[CH:22][N:21]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[N:20]=3)=[CH:15][C:14]=2[O:44][CH3:45])[N:10]=1.O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:46])=[C:9]([CH2:11][O:12][C:13]2[CH:43]=[CH:42][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[S:27][CH:28]=[C:29]([C:31]([OH:33])=[O:32])[N:30]=4)=[CH:22][N:21]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[N:20]=3)=[CH:15][C:14]=2[O:44][CH3:45])[N:10]=1
Reactant: CCOC(=O)c1csc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/c2nc(C(=O)O)cs2)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 64.4 %

Procedure:
To a mixture of ethyl 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-1,3-thiazole-4-carboxylate (0.13 g), tetrahydrofuran (1 mL) and ethanol (1 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was heated under reflux for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the precipitated crystals were collected by filtration to give 2-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-1,3-thiazole-4-carboxylic acid as yellow crystals (0.08 g, yield 67%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 170-172° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](N(OC)C)=[O:19])[CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]([Mg]Br)=[CH2:26]>C1COCC1>[CH2:1]([O:8][C:9](=[O:24])[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C:18](=[O:19])[CH:25]=[CH2:26])[CH:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CON(C)C(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(=O)Cc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a solution of 15 g (45.7 mmol) of benzyl(3-{2-[methoxy(methyl)amino]-2-oxoethyl}phenyl)carbamate (from Step C) in 1000 mL anhydrous THF under nitrogen atmosphere cooled to 0° C. via ice/water bath was added dropwise via cannula a 1.0 M solution of vinyl magnesium bromide (100 mL in THF, 100 mmol) and the resulting solution stirred for 1 h at 0° C. The reaction was quenched by a slow addition of 500 mL 1 M HCl keeping the temperature below 5° C. and stirred for 30 min. The mixture was then extracted with ethyl acetate and the combined organics washed with water followed by brine. The organics were then dried over sodium sulfate, filtered, and concentrate under vacuum. The residue was purified by Biotage 75M flash eluting with 30% ethyl acetate in hexane to afford the title compound (11 g, 78%) as a light yellow solid. LC-MS: m/z (ES) 310 (MH)+, 332 (MNa)+. 1HNMR (500 MHz, CDCl3) δ: 7.44-7.36 (m, 7H), 7.18 (d, J=8.4 Hz, 2H), 6.70 (br s, 1H), 6.44 (dd, J=10.5, 17.6 Hz, 1H), 6.32 (dd, J=1.1, 17.6 Hz, 1H), 5.85 (dd, J=1.1, 10.5 Hz, 1H), 5.22 (s, 2H), 3.86 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([O:44]CC)=[O:43].[OH-:47].[Na+]>O1CCCC1.CO>[C:2]([C:10]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:4]([NH:3][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]/[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=2)[N:20]([CH2:28][CH2:29][CH2:30][O:31][C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)[C:19]=1[C:42]([OH:44])=[O:43])=[O:11])([OH:47])=[O:1]
Reactant: CCOC(=O)c1c(/C=C/CCCCN2C(=O)c3ccccc3C2=O)c2cc(F)ccc2n1CCCOc1cccc2ccccc12
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccccc1C(=O)NCCCC/C=C/c1c(C(=O)O)n(CCCOc2cccc3ccccc23)c2ccc(F)cc12
Temperature: 50 °C

Procedure:
A mixture of EXAMPLE 160A (531 mg) and potassium 1,3-dioxoisoindolin-2-ide (213 mg) in N,N-dimethylformamide (10 ml) was heated at 80° C. for 8 hours. The reaction was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate and was concentrated. The residue was purified by flash chromatography, eluting with 0-100% ethyl acetate in dichloromethane to give (E)-ethyl 3-(6-(1,3-dioxoisoindolin-2-yl)hex-1-enyl)-5-fluoro-1-(3-(naphthalen-1-yloxy)propyl)-1H-indole-2-carboxylate. This ester was dissolved in a mixture of tetrahydrofuran and methanol and 5 equivalents of aqueous NaOH (10%) was added. The mixture was heated at 50° C. for 5 hours. The reaction mixture was concentrated and the residue was dissolved in dimethyl sulfoxide and trifluoroacetic acid-methanol (3:1), and purified by RPHPLC to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) δ 13.06 (s, 2H), 8.25 (t, J=5.52 Hz, 1H), 8.19 (dd, J=7.83, 1.38 Hz, 1H), 7.86 (dd, J=7.21, 1.99 Hz, 1H), 7.74 (dd, J=7.52, 1.38 Hz, 1H), 7.60-7.69 (m, 2H), 7.43-7.58 (m, 5H), 7.34-7.41 (m, 2H), 6.99-7.16 (m, 2H), 6.85 (d, J=7.36 Hz, 1H), 6.15-6.32 (m, 1H), 4.65-4.96 (m, 2H), 4.13 (t, J=5.68 Hz, 2H), 3.20-3.29 (m, 2H), 2.20-2.36 (m, 4H), 1.49-1.67 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19](F)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([N:28]1[C:32]([C@H:33]2[CH2:38][CH2:37][CH2:36]C[C@@H:34]2[OH:39])=[CH:31][CH:30]=[N:29]1)[CH3:27].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:39][C@H:34]2[CH2:36][CH2:37][CH2:38][C@@H:33]2[C:32]2[N:28]([CH2:26][CH3:27])[N:29]=[CH:30][CH:31]=2)=[CH:18][C:17]=1[F:24])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(F)cc1F
Reactant: CCn1nccc1[C@H]1CCCC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1nccc1[C@H]1CCC[C@@H]1Oc1cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c2cscn2)cc1Cl
Yield: 42.5 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the tert-butyl[(5-chloro-2,4-difluorophenyl)sulfonyl](1,3-thiazol-4-yl)carbamic acid (WO 2010/079443; 222 mg, 0.540 mmol), (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclohexanol (100 mg, 0.515 mmol) prepared in Example 12a, sodium hydride (63%; 39.2 mg, 1.03 mmol) and DMF (5.0 mL), to yield the title compound (125 mg, 41%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([C:15]([Cl:18])=[CH:16][CH:17]=1)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[CH3:20][O:21][C:22]1[CH:35]=[CH:34][C:25]([O:26][CH2:27][CH2:28][CH2:29][S:30](Cl)(=[O:32])=[O:31])=[CH:24][CH:23]=1.C(N([CH:42]([CH3:44])[CH3:43])C(C)C)C>C(Cl)Cl>[Cl:18][C:15]1[C:4]([C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:6])=[C:3]([F:19])[C:2]([N:1]([S:30]([CH2:29][CH2:28][CH2:27][O:26][C:43]2[CH:42]=[CH:44][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)(=[O:32])=[O:31])[S:30]([CH2:29][CH2:28][CH2:27][O:26][C:25]2[CH:34]=[CH:35][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)(=[O:32])=[O:31])=[CH:17][CH:16]=1
Reactant: COc1ccc(OCCCS(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)c(C(=O)OCc2ccccc2)c1F
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(OCCCS(=O)(=O)N(c2ccc(Cl)c(C(=O)OCc3ccccc3)c2F)S(=O)(=O)CCCOc2ccc(OC)cc2)cc1
Temperature: -78 °C

Procedure:
A 100 mL, round-bottomed flask was charged with benzyl 3-amino-6-chloro-2-fluorobenzoate (1.0 g, 3.58 mmol), 3-(4-methoxyphenoxy)propane-1-sulfonyl chloride (2.84 g, 10.7 mmol), N-ethyl-N-isopropylpropan-2-amine (1.91 mL, 10.7 mmol) and DCM (15 mL). The reaction mixture was stirred at −78° C. until LC-MS showed that the starting material had been consumed (about 12 hours). Then the reaction mixture was cooled to room temperature and partitioned between EtOAc (500 mL) and water (200 mL). The phases were separated, and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield crude benzyl 6-chloro-2-fluoro-3-(3-(4-methoxyphenoxy)-N-(3-(4-methoxyphenoxy)propylsulfonyl)propylsulfonamido)benzoate. The crude product was used in the next step.
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:20])([CH3:19])[O:18][C:14]=3[CH:13]=[C:12]([C:21](O)=[O:22])[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4].[NH2:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=1>>[CH3:1][N:2]([CH3:27])[C:3]([C:5]1[CH:25]=[CH:24][C:8]([O:9][C:10]2[C:15]3[CH2:16][C:17]([CH3:19])([CH3:20])[O:18][C:14]=3[CH:13]=[C:12]([C:21]([NH:28][C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH2:35])=[O:34])=[CH:31][N:30]=3)=[O:22])[CH:11]=2)=[CH:7][C:6]=1[F:26])=[O:4]
Reactant: CN(C)C(=O)c1ccc(Oc2cc(C(=O)O)cc3c2CC(C)(C)O3)cc1F
Reactant: NC(=O)c1ccc(N)nc1
Product: CN(C)C(=O)c1ccc(Oc2cc(C(=O)Nc3ccc(C(N)=O)cn3)cc3c2CC(C)(C)O3)cc1F

Procedure:
The title compound was prepared in a similar manner as described for Example 144, from 4-(4-dimethylcarbamoyl-3-fluoro-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (143a) (80 mg, 0.21 mmol) and 6-aminonicotinamide (58.8 mg, 0.429 mmol) to give a brown solid (5 mg, 5% yield). 1H NMR (400 MHz, MeOD.) δ 8.82 (d, J=1.52 Hz, 1 H) 8.14-8.32 (m, 2 H) 7.31-7.44 (m, 1 H) 7.18 (dd, J=8.34, 1.26 Hz, 2 H) 6.80-6.97 (m, 2 H) 3.10 (s, 3 H) 2.98 (s, 3 H) 2.93 (s, 2 H) 1.47 (s, 6 H); LCMS for C26H25FN4O5 m/z 493.20 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C(O)C.C(OCC)(=O)C.[OH-].[Na+:35]>O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[N-:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].[Na+:35]
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2[n-]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Temperature: 25 °C

Procedure:
Esomeprazole obtained in example 14 (54.5 g; 157.78 mmol), was dissolved in a solution of aqueous NaOH (136.24 g; 4.88% w/w) and DM water (30 ml). The solution was washed with methylene chloride twice (200 ml×2). The aqueous layer was filtered and concentrated completely under reduced pressure to yield viscous mass. Ethanol was added to the viscous mass and concentrated under reduced pressure. Thereafter, ethyl acetate was added and concentrated to dryness under reduced pressure to yield solid mass. Further, ethyl acetate (400 ml) was added and stirred the mixture under reflux for 30 min. Cooled the reaction mass to 20-30° C. and stirred for 3 h. The separated solid was filtered, washed with ethyl acetate and dried under reduced pressure at 40° C. to yield esomeprazole sodium.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=2)[N:5]=[C:4]([NH2:16])[N:3]=1.C1C(=O)N([I:24])C(=O)C1>C(Cl)Cl.CO>[I:24][C:7]1[C:2]([CH3:1])=[N:3][C:4]([NH2:16])=[N:5][C:6]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]#[N:15])[CH:9]=1
Reactant: Cc1cc(-c2cccc(C#N)c2)nc(N)n1
Reactant: O=C1CCC(=O)N1I
Solvent: CO
Solvent: ClCCl
Product: Cc1nc(N)nc(-c2cccc(C#N)c2)c1I

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 3.2 g (12 mmol) 4-methyl-6-(3-cyano-phenyl)-pyrimidin-2-ylamine and 2.8 g (13 mmol) NIS. Yield after chromatography on silica gel with DCM/MeOH: 3.5 g (78%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.[CH2:11]([OH:14])[C:12]#[CH:13]>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.N1CCCC1>[OH:14][CH2:11][C:12]#[C:13][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: C#CCO
Reactant: OB(O)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNC1
Product: OCC#Cc1ccc(B(O)O)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
Pyrrolidine (100 mL) was added to a mixture of 4-iodophenylboronic acid (19.83 g, 80.01 mol) and Pd(Ph3P)4 (0.93 g, 0.80 mmol) and the mixture was stirred for 5 min to give a solution. The solution was cooled to 0° C. and propargyl alcohol (9.4 mL, 161.5 mol) was added. The resulting solution was stirred for 1 h at 0° C. and 18 h at room temperature and then concentrated in vacuo. The residue was diluted with 2 N NaOH (200 ml), washed with dichloromethane (2×100 mL), cooled to 0° C., and acidified with 10% HCl. The precipitated solids were isolated by filtration, washed with water and dried in vacuo to provided 12.76 g (91%) of the title compound as a tan solid. MS 175 (M−H)−.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:6]([C:20](=[O:29])[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:8]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:10]=1.II.FC(F)(F)C(O[I:37](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.O>[CH3:14][O:13][CH2:12][O:11][C:9]1[C:8]([I:37])=[C:7]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:6]([C:20](=[O:29])[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=2)=[C:5]([O:4][CH2:3][O:2][CH3:1])[CH:10]=1
Reactant: COCOc1cc(CC(=O)OC)c(C(=O)c2ccc(OC)cc2)c(OCOC)c1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COCOc1cc(OCOC)c(C(=O)c2ccc(OC)cc2)c(CC(=O)OC)c1I
Temperature: -30 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
Methyl 3,5-bis(methoxymethoxy)-2-(4-methoxybenzoyl)-phenylacetate (0.75 g, 1.9 mmol) obtained in Example 134, Step 2 was dissolved in dichloromethane (20 mL). The resulting solution was cooled to −30° C., and iodine (0.47 g, 1.9 mmol) and [bis(trifluoroacetoxy)iodo]benzene (0.8 g, 1.9 mmol) were successively added thereto in an atmosphere of argon, followed by stirring for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium thiosulfate, and the mixture was further stirred for one hour, while the temperature was raised to room temperature. To the reaction mixture was added water for liquid separation, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4-1/2) to obtain methyl 3,5-bis(methoxymethoxy)-2-iodo-6-(4-methoxybenzoyl)phenylacetate (0.95 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26]1[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=1[CH3:32].CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20]([NH:24][CH2:25][C:26]3[C:27](=[O:34])[NH:28][C:29]([CH3:33])=[CH:30][C:31]=3[CH3:32])=[O:21])[C:11]3[CH:16]=[N:15][N:14]([CH:17]([CH3:19])[CH3:18])[C:12]=3[N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)n1ncc2c(C(=O)O)cc(-c3ccc(Cl)cc3)nc21
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(Cl)cc3)nc3c2cnn3C(C)C)c(=O)[nH]1

Procedure:
The title compound was prepared in the same manner as described in example 109 using 6-(4-chlorophenyl)-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (70 mg, 0.222 mmol), DMSO (2 mL), 3-(aminomethyl)-4,6-dimethyl-2(1H)-pyridinone HCl salt (62.7 mg, 0.333 mmol), N-methylmorpholine (0.097 mL, 0.887 mmol), 1-hydroxy-7-azabenzotriazole (60.3 mg, 0.443 mmol) and EDC (85 mg, 0.443 mmol). The final product was collected as 77 mg (78%). LCMS E-S (M+H)=450.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (d, J=6.6 Hz, 6H), 2.13 (s, 3H), 2.22 (s, 3H), 4.41 (d, J=4.6 Hz, 2H), 5.34 (quin, J=6.7 Hz, 1H), 5.91 (s, 1H), 7.64 (d, J=8.6 Hz, 2H), 8.19 (s, 1H), 8.31 (d, J=8.6 Hz, 2H), 8.39 (s, 1H), 8.97 (t, J=4.7 Hz, 1H), 11.58 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([O:14]CC)=O)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.O.[NH2:18][NH2:19]>C(O)C.ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]([NH:18][NH2:19])=[O:14])[CH2:7]2)=[O:5])[CH2:3][CH2:2]1
Reactant: NN
Reactant: CCOC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Temperature: 80 °C
Yield: 100 %

Procedure:
In a round bottom flask equipped with reflux condenser, an orange solution of ethyl [(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetate (56.1 g, 249 mmol) in ethanol (356 mL) was treated with hydrazine monohydrate (242 mL, 4.98 mol). The resultant yellow solution was stirred at 80° C. (reflux) for 15 h. The reaction was cooled to room temperature and concentrated in vacuo. Ethanol (100 mL) was added and the reaction was concentrated (2×) to give a pale yellow clear oil. The oil was dissolved in dichloromethane (white solution observed), dried over MgSO4, concentrated in vacuo, and pumped under high vacuum overnight (16 h) to give the title compound as a clear pale yellow oil (249 mmol, quantitative). MS(ES)+ m/e 212.0 [M+H]+, 423.2 [2M+H]+.
Reaction SMILES: FC(F)(F)C1N=CC([OH:9])=CC=1.C(C1C=CC(CBr)=CC=1)#N.[OH:22][CH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#N)=[CH:26][CH:25]=1.F[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][N:34]=1>>[F:40][C:39]([F:42])([F:41])[C:36]1[CH:37]=[CH:38][C:33]([O:22][CH2:23][C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:9])=[CH:26][CH:25]=2)=[N:34][CH:35]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Oc1ccc(C(F)(F)F)nc1
Reactant: N#Cc1ccc(CO)cc1
Agent: N#Cc1ccc(CBr)cc1
Product: O=Cc1ccc(COc2ccc(C(F)(F)F)cn2)cc1

Procedure:
Instead of 6-(trifluoromethyl)pyridin-3-ol and 4-cyanobenzylbromide, 4-(hydroxymethyl)benzonitrile (1.87 g) and 2-fluoro-5-(trifluoromethyl)pyridine (1.55 g) were respectively used and treated by the same technique as in Reference Example 38-1 to give the titled compound as a pale yellow solid (1.49 g).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].[H-].[Na+].I[CH2:39][C:40]#[N:41]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH:10]2[CH:14]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)[CH2:13][N:12]([C:22]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:39][C:40]#[N:41])[CH2:28][CH2:29]3)=[O:23])[CH2:11]2)[CH3:9])=[O:7])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: N#CCI
Reactant: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCNCC2)CC1c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)c1ccc(Cl)c(C(F)(F)F)c1)C1CN(C(=O)C2CCN(CC#N)CC2)CC1c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 66.1 %

Procedure:
To a solution of 4-chloro-N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-N-methyl-3-trifluoromethyl-benzamide (216 mg, 0.382 mmol) in DMF (1 mL) was added sodium hydride (55% dispersion in mineral oil, 6 mg, 0.14 mmol). After stirring for 30 min at ambient temperature iodoacetonitrile (9 μl, 0.12 mmol) was added And the suspension was stirred for 18 h at this temperature. After the addition of further iodoacetonitrile (9 μl, 0.12 mmol) the resulting dark brown solution was stirred for further 5 h at ambient temperature. It was diluted with ethyl acetate (10 mL) and was washed with aqueous sodium carbonate (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic phases were dried over sodium sulfate. Purification by chromatography (SiO2, (ethyl acetate:triethylamine=95:5):methanol=100:0 to 70:30) afforded the title compound (45 mg, 88%) as a white foam. MS m/e: 567.1 [M]+.