Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)Cl.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:47](=[O:48])[N:16]2[C:17]([C:31]([O:33][CH:34]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[O:32])=[C:18]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[C@@H:19]([CH3:22])[S:20](=O)[C@H:15]12)=[O:12].CCOC(C)=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][C:11]([NH:13][CH:14]1[C:47](=[O:48])[N:16]2[C:17]([C:31]([O:33][CH:34]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[O:32])=[C:18]([CH2:23][S:24][C:25]3[N:29]([CH3:30])[N:28]=[N:27][N:26]=3)[C@@H:19]([CH3:22])[S:20][C@H:15]12)=[O:12]
Reactant: C[C@@H]1C(CSc2nnnn2C)=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2S1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Solvent: CN(C)C=O
Product: C[C@H]1S[C@@H]2C(NC(=O)Cc3cccs3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1CSc1nnnn1C
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A 0.38 ml portion of PCl3 was added to a solution of 326 mg of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate 1-oxide in 5 ml of DMF at -10° C., followed by stirring at the same temperature for 15 minutes. AcOEt and 5% aqueous NaHCO3 solution were added to the reaction solution to separate out the AcOEt layer. The AcOEt layer was washed with saturated aqueous NaCl solution and dried over Na2SO4, followed by distilling off the AcOEt under reduced pressure. The residue was added on a column of silica gel, and the fractions eluted with CH2Cl2.AcOEt (25:1) were collected, followed by distilling off the solvent under reduced pressure, thus yielding 225 mg (71%) of diphenylmethyl 7-(2-thienylacetamido)-2α-methyl-3-(1-methyl-1H-tetrazol-5-yl)thiomethylceph-3-em-4-carboxylate.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:13][C:14](=O)[C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:16]=2)=[CH:6][C:7]2[O:11][CH2:10][O:9][C:8]=2[CH:12]=1)(=[O:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:24]([O:23][C:17]1[CH:16]=[C:15]([C:14]2[CH2:2][C:1](=[O:3])[C:4]3[C:5](=[CH:6][C:7]4[O:11][CH2:10][O:9][C:8]=4[CH:12]=3)[N:13]=2)[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1cc(OCc2ccccc2)cc(C(=O)Nc2cc3c(cc2C(C)=O)OCO3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1cc(OCc2ccccc2)cc(C2=Nc3cc4c(cc3C(=O)C2)OCO4)c1
Reaction time: 12 h

Procedure:
Into a suspension of 164 (3.33 g, 0.0079 mmol) in 200 mL of 1,4-dioxane was added sodium hydroxide (2.50 g, 0.0635 mmol). The mixture was refluxed for 24 h. After the reaction mixture was evaporated, 100 mL of 10% ammonium chloride solution was added. The mixture was stirred for 12 h, and then the precipitate was collected and washed with water and acetone.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH3:9])[N:3]=1.[C:10]1(/[CH:16]=[CH:17]/B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:9][O:8][C:4]1[N:3]=[C:2](/[CH:17]=[CH:16]/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OB(O)/C=C/c1ccccc1
Reactant: COc1nccc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1nccc(/C=C/c2ccccc2)n1
Temperature: 95 °C
Yield: 96.1 %

Procedure:
A solution of 4-chloro-2-methoxypyrimidine (0.36 g, 2.5 mmol), trans-2-phenylvinylboronic acid (0.56 g, 3.8 mmol) and potassium carbonate (0.69 g, 5.0 mmol) in DMSO (8.0 mL) was purged with argon for 5 min. 1,1′-Bis(diphenylphosphino)ferrocenedichloropalladium(II) (0.18 g, 0.25 mmol) was added to the above solution. The reaction mixture was purged with argon for 5 min and then heated at 95° C. for 16 h. The reaction solution was cooled to room temperature, diluted with ethyl acetate, washed with water (2×) and brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography (silica gel hexanes/ethyl acetate 95:5 to 60:40) to afford the title compound (0.51 g, 96%) as a yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.47 (d, J=5.0 Hz, 1H), 7.92 (d, J=16.0 Hz, 1H), 7.61-7.58 (m, 2H), 7.42-7.35 (m, 3H), 7.01 (d, J=16.0 Hz, 1H), 6.94 (d, J=5.0 Hz, 1H), 4.07 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:29].[Mg+2].O>C(O)C>[CH3:1][C:2]1[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])=[CH:6][CH:5]=[N:4][C:3]=1[CH2:14][S+:15]([O-:29])[C:16]1[NH:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Agent: [Mg+2]
Solvent: O
Solvent: CCO
Product: Cc1c(OCC(F)(F)F)ccnc1C[S+]([O-])c1nc2ccccc2[nH]1
Reaction time: 4 h
Yield: 165.8 %

Procedure:
1.0 g (2.8 mmol) of 2-([3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl]-methyl)thio-1H-benzimidazole was dissolved in 20 Ml of 95% ethanol, and cooled to −20˜−10° C. 1.0 g (1.6 mmol) of 80% MMPP (magnesium monoperoxyphthalate) was added thereto, and the resulting mixture was stirred for 4 hours at the same temperature. Completion of the reaction was confirmed by TLC and HPLC, and 10 Ml of water was added to the reaction mixture, which was then stirred for 1 hour under ice-cooling. The reaction mixture was filtered to separate crystal, and thus separated crystal was washed with ice-cooled isopropanol-water mixture (1:1), and dried under reduced pressure, to give 0.98 g (Yield 95%) of Lansoprazole as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:25](OC)=[O:26])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=3[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21.[BH4-].[Li+]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=4[Cl:24])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH2:25][OH:26])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(OC)cc1Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCCCn3c2nc2c(Cl)ccc(CO)c23)c(Cl)c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 99.8 %

Procedure:
To a stirred solution of methyl 10-chloro-1-(2-chloro-4-methoxyphenyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole-7-carboxylate (336 mg, 0.800 mmol) in tetrahydrofuran (6 mL) was added lithium borohydride (69.7 mg, 3.20 mmol) at 0° C. After being stirred for 20 h at 60° C., the reaction mixture was diluted with ethyl acetate, quenched with aqueous ammonium chloride, washed with water and brine, dried over sodium sulfate, filtrated, and concentrated in vacuo to give the title compound as a colorless solid (318 mg, 0.798 mmol, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:36]1C=CC(OC)=C(S(Cl)(=O)=O)C=1>>[CH3:36][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=O)O)c(Cl)c3)cc21
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Cl
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CC3)cc1Cl

Procedure:
2-Chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 521.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 4 was performed using 5-chloro-2-methoxy-benzenesulfonyl chloride and yielded 2-chloro-4-{[1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid methyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][NH:37][C:38]2[S:39][CH2:40][C:41](=[O:43])[N:42]=2)[CH2:31][CH2:30]1>>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:40]3[S:39][C:38]([NH:37][CH2:36][CH2:35][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:42][C:41]3=[O:43])=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CN1CCN(CCNC2=NC(=O)CS2)CC1
Product: CN1CCN(CCNC2=NC(=O)C(=Cc3ccc4c(c3)c(I)nn4Cc3ccc(C(F)(F)F)cc3C(F)(F)F)S2)CC1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5-ylmethylene]-2-[2-(4-methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-[2-(4-Methyl-piperazin-1-yl)-ethylamino]-thiazol-4-one following General Procedure E.
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][NH2:15].[OH-].[K+].Cl>C(O)C>[C:2]1([C:1]2[CH2:9][CH:10]([C:11]([OH:13])=[O:12])[NH:15][N:14]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(O)C=CC(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1CC(c2ccccc2)=NN1

Procedure:
A mixture of 10.0 g of 3-benzoylacrylic acid, 1.8 g of hydrazine, and 3.7 g of potassium hydroxide in 30 ml. of aqueous ethanol (1:1) is stirred and heated at reflux for 2 hours. The cooled solution is treated with 5 ml of concentrated hydrochloric acid to pH 4.0 to precipitate 7.1 g of solid, melting point 180°-182° C. This material is dissolved in 40 ml of warm dimethylformamide and treated wit 140 ml of methanol to crystallize 3.9 g of the title compound, melting point 199°-201° C.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:12]>>[CH:1]1([C:7]([Cl:12])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)C1CCCCC1
Product: O=C(Cl)C1CCCCC1
Temperature: 30 °C
Reaction time: 4 h

Procedure:
The mixture of cyclohexylcarboxylic acid (40 g) and SOCl2 (60 mL) was heated at 30° C. for 30 min and then at 50° C. for 3-5 hrs. The volatile materials were removed in vacuum and the residue was used for the next reaction without further purification.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1.C(N(CC)CC)C.[C:47](Cl)(=[O:49])[CH3:48]>ClCCl>[C:47]([NH:1][C@H:2]1[C@@H:7]2[C@@H:5]([C@H:6]2[C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[C@:4]([NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[C@@H:3]1[CH2:30][S:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([CH3:39])[CH:33]=1)(=[O:49])[CH3:48]
Reactant: CC(=O)Cl
Reactant: Cc1cc(SC[C@@H]2[C@@H](N)[C@H]3[C@H](C(=O)OC(C)(C)C)[C@H]3[C@]2(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@](NC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)[C@@H]1CSc1ccc(F)c(C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.1 %

Procedure:
Di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-amino-2-(tert-butoxycarbonylamino)-3-[(4-fluoro-3-methyl-phenyl)sulfanylmethyl]bicyclo[3.1.0]hexane-2,6-dicarboxylate (0.15 g, 264.67 μmol) is dissolved in dichloromethane (10 mL). To this mixture is added triethylamine (55.34 μL, 397.01 μmol) and acetyl chloride (28.25 μL, 397.01 μmol). The mixture is stirred at ambient temperature for 10 minutes. The solvent is removed under reduced pressure to give a residue. The residue is purified by flash chromatography (10% to 100% ethyl acetate/hexanes) to give the title compound (100 mg, 164.27 μmol, 62.06% yield); 1H NMR (CD3Cl) δ 1.44 (t, 27H), 1.95 (s, 3H), 2.16 (m, 1H), 2.22 (s, 3H), 2.60 (dd, 1H), 2.78 (bs, 1H), 3.10 (dd, 1H), 4.59 (m, 1H), 5.50 (d, 1H), 6.92 (t, 1H), 7.06 (m, 1H), 7.11 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1>O1CCOCC1.C([O-])(O)=O.[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:15][O:16][C:17]1[N:22]=[CH:21][C:20]([C:2]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][NH:6]3)=[C:19]([CH3:26])[CH:18]=1
Reactant: FC(F)(F)c1cc(Br)c2cn[nH]c2c1
Reactant: COc1cc(C)c(B(O)O)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1cc(C)c(-c2cc(C(F)(F)F)cc3[nH]ncc23)cn1
Temperature: 140 °C
Yield: 45.6 %

Procedure:
A vial was charged with a mixture of 4-bromo-6-(trifluoromethyl)-1H-indazole (0.1 g, 0.377 mmol), (6-methoxy-4-methylpyridin-3-yl)boronic acid (0.082 g, 0.491 mmol) and PdCl2(dppf) (0.014 g, 0.019 mmol) in dioxane (8 mL) and aqueous saturated NaHCO3 (2 mL). The resulting light brown suspension was heated at 140° C. for 45 minutes in a microwave reactor. The reaction mixture was subsequently concentrated and the crude residue was purified by preparative HPLC, eluting with a gradient of 40-45% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 6.5 minutes. The product-containing fractions were combined and solvent was removed on a rotary evaporator. The crude product was extracted into DCM, was washed sequentially with aqueous saturated NaHCO3, water, and brine, and was dried over Na2SO4. The volatiles were removed in vacuo to give the title compound as a white solid (0.053 g, 0.172 mmol, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.14 (s, 3H), 3.91 (s, 3H), 6.88 (s, 1H), 7.29 (s, 1H), 7.97 (s, 2H), 8.12 (s, 1H), 13.71 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C15H12F3N3O, 308.1. found 308.15.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C:32]1([CH2:38][C:39]([N:41]=[C:42]=[O:43])=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCCC1.CCCCCC.C(OCC)(=O)C>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:42]([NH:41][C:39](=[O:40])[CH2:38][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:43])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]2[CH2:21][CH2:20][N:19]([CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH2:18][CH2:17]2)=[O:15])[CH:8]=1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4F)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4F)ccn3)CC2)CC1
Reaction time: 5 h
Yield: 61 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (811 mg) in tetrahydrofuran (50 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 17 ml) at room temperature, followed by stirring for 5 hours. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=97:3). Fractions containing the target compound were concentrated to give a residue, which was then suspended in ethyl acetate (8 ml) and hexane (16 ml). The crystals were filtered off and dried under aeration to provide the titled compound (629 mg, 61%) as white crystals.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:22][C:19]2[CH:18]=[CH:17][C:16]([S:13]([CH:8]3[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]3[CH3:12])(=[O:15])=[O:14])=[CH:21][CH:20]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CCN(C)C(S(=O)(=O)c2ccc(OCc3ccc(Cl)cc3)cc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CN1CCC(C(=O)O)CC1S(=O)(=O)c1ccc(OCc2ccc(Cl)cc2)cc1

Procedure:
[4-(4-Chloro-benzyloxy)-benzenesulfonyl-1-methylpiperidine-4-carboxylic acid was prepared starting from [4-(4-Chloro-benzyloxy)-benzenesulfonyl]-1-methylpiperidine-4-carboxylic acid ethyl ester (10.7 g, 24 mmol) dissolved in THF:Methanol (75:75 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 4.9 g (50%); off white solid; MS: 426.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22]Br)[CH:7]=1)[CH3:2].[CH3:25][CH:26]1[CH:30]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[O:29][C:28](=[O:37])[NH:27]1>>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[CH2:22][N:27]2[C@@H:26]([CH3:25])[C@@H:30]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:29][C:28]2=[O:37])[CH:7]=1)[CH3:2]
Reactant: CC1NC(=O)OC1c1ccccc1
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CBr)c1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(Cl)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [3-(2-bromomethyl-4-chloro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and (4S,5R)-(+4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+].CO>>[C:24]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:25]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccc(F)cc3)cccc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2cccc(Oc3ccc(F)cc3)c12
Temperature: 25 °C
Yield: 86.6 %

Procedure:
A mixture of 1-cyano-8-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (112 mg, 0.33 mmol), glycine (496 mg, 6.6 mmol), and a 0.5 M solution of sodium methoxide in methanol (12.5 mL, 6.25 mmol) was refluxed for 39 h before it was cooled to room temperature and concentrated in vacuo. Water (75 mL) was added and the pH of the yellow suspension was adjusted to pH=10 with 1 N HCl. The suspension was washed with methylene chloride (2×50 mL). The remaining aqueous layer was acidified to pH=3 with 1 N HCl. The resulting white precipitate was collected by filtration, washed with water, and dried in vacuo to give the title compound as a white solid (109 mg): 1H NMR (DMSO-d6, 200 MHz): δ=12.85 (bs, 1H), 9.57 (br s, 1H), 8.09 (d, 1H), 7.83 (t, 1H), 7.27 (m, 5H), 4.05 (d, J=5.8 Hz, 2H); MS: (+) m/z 382.00 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[CH3:17][C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:20][C:19]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9]([N:26]2[CH2:27][CH2:28][N:23]([C:21]3[S:22][C:18]([CH3:17])=[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)[CH2:24][CH2:25]2)=[O:16])[O:4][N:3]=1
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Reactant: Cc1sc(N2CCNCC2)nc1-c1ccccc1
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)c(C)s3)CC2)c1C
Temperature: 70 °C
Reaction time: 5 h
Yield: 60.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (244 mg, 0.848 mmol), 1-(5-methyl-4-phenyl-1,3-thiazol-2-yl)piperazine (200 mg, 0.771 mmol) and diisopropylethylamine (0.148 ml, 0.848 mmol) in dimethylsulfoxide (2.6 ml) was stirred at 70° C. for 5 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 186 mg (60.8%) of the desired product as a solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([C@@H:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([O:32]C)=[O:31])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[F:34].[OH-].[Na+]>CO.C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([C@@H:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30]([OH:32])=[O:31])=[O:24])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[F:34]
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccccc4[nH]3)c(F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccccc4[nH]3)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
Methyl (1R,2R)-2-{[4′-(1H-benzimidazol-2-ylamino)-3′-fluoro-1,1′-biphenyl-4-yl]-carbonyl}cyclopentanecarboxylate (100 mg, 0.22 mmol) was dissolved in methanol and treated with an excess of 1 N aqueous sodium hydroxide solution (2.19 mL, 2.19 mmol). The solution was stirred at rt for 1 h, and then was concentrated under reduced pressure. The residue was partitioned between water and ethyl acetate, and the aqueous layer was adjusted to pH 2 by the addition of 1 N aqueous HCl. The organic layer was separated, washed with brine, dried (MgSO4), and concentrated under reduced pressure to provide an orange oil. The oil was suspended in THF and stirred until a precipitate formed. The precipitate was collected by filtration and washed with additional THF to provide the title compound as a yellow solid (30 mg, 31%, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 13.12 (br s, 1H), 11.30 (br s, 1H), 8.12 (d, 2H), 7.96-7.76 (m, 5H), 7.46-7.42 (m, 2H), 7.30-7.26 (m, 2H), 4.15-4.07 (m, 1H), 3.27-3.19 (m, 1H), 2.21-2.12 (m, 1H), 2.05-1.96 (m, 1H), 1.86-1.55 (m, 4H); LC-MS m/z 444.4 (MH+), retention time 2.79 minutes.