Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[CH2:14][O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][O:17]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[O:15][CH2:14][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([CH2:3][OH:2])[CH:6]=2)[NH:10][N:9]=1
Reactant: COC(=O)c1ccc2[nH]nc(COC3CCCCO3)c2c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCc1ccc2[nH]nc(COC3CCCCO3)c2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
3-(Tetrahydro-pyran-2-yloxymethyl)-1H-indazole-5-carboxylic acid methyl ester (0.53 g crude, approximately 1.55 mmol) was taken in anhydrous THF (20 mL) and cooled to −10° C. A solution of lithium aluminium hydride (1.0 M solution in THF, 0.12 g, 3.10 mmol) was added drop-wise at −10° C. over a period of 15 minutes under nitrogen. Stirring continued at −10° C. for 1 hour and the reaction was then allowed to warm to room temperature and stirring continued at room temperature for 16 hours. The reaction mixture was carefully quenched with saturated aq. saturated ammonium chloride solution (100 mL). Then, reaction mixture was diluted with ethyl acetate (100 mL). The organic phase was separated, washed with brine (50 mL) and dried over anhydrous Na2SO4. Solvent was evaporated to give [3-(tetrahydro-pyran-2-yloxymethyl)-1H-indazol-5-yl]-methanol as a yellow gummy material. Yield: 0.40 g (crude). This product was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])[CH:7]=1.[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:20][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[S:8][CH2:9][C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ccccc1CSc1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1CSc1cc(Cl)ccc1N
Yield: 106.9 %

Procedure:
Following General Procedure L, the title compound (158 mg, crude) was prepared from methyl 2-(((5-chloro-2-nitrophenyl)thio)methyl)benzoate (163 mg, 0.48 mmol), Zn (780 mg, 12.0 mmol) and saturated aqueous NH4Cl (10 ml) in MeOH (5 ml) and THF (5 ml). The crude product was used in the next reaction without further purification.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2nccc3ccccc23)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c(C(=O)O)cn2-c1nccc2ccccc12
Reaction time: 24 h
Yield: 87.3 %

Procedure:
0.319 g (7.59 mmol) of lithium hydroxide monohydrate and 60 cm3 of water are added at 25° C. to 1.2 g (3.79 mmol) of 3-methoxycarbonyl-1-(isoquinol-1-yl)-5-methyl-1H-indole dissolved in 60 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 24 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 30 cm3 of water and then triturated with 11.4 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(isoquinol-1-yl)-5-methyl-1H-indole is obtained in the form of a white solid. Mass spectrum (EI): m/e 302 (M+·), m/e 257.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])C.[OH-].[K+]>C(O)C.C(OCC)(=O)C>[OH:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:26])=[O:3])=[C:8]([C:14](=[O:25])[NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=2[F:24])[CH:9]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C(=O)NCc1ccc(Br)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)COc1ccc(O)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C

Procedure:
A solution of [4-hydroxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester (0.773 g, 1.83 mmol)in ethanol (10 mL, 0.18 M) was cooled to 0° C. and treated with aq KOH (5 mL, 1.25 M) and warmed to room temperature. The solution was acidified to pH 1–2, diluted with ethyl acetate and washed with sat'd aq NaCL. The organic layer was dried over Na2SO4, filtered and concentrated to give [4-hydroxy-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid as a white crystaline solid: mp 244 dec.; 1H NMR (DMSO-d6, 300 MHz) δ 10.14 (br s, 1 H), 8.97 (t, J=5.4 Hz, 1 H), 7.75 (dd, J1=8.4 Hz, J2=0.3 Hz, 1 H), 7.48 (d, J=9.6 Hz, 1 H), 7.37–7.26 (m, 2 H), 6.46 (dd, J1=8.7 Hz, J2=2.1 Hz, 1 H), 6.40 (s, 1 H), 4.77 (s, 2 H), 4.47 (d, J=5.4 Hz, 2 Hz). Anal. calcd for C16H13BrFNO5: C, 48.26; H, 3.29; N, 3.52. Found C, 48.19; H, 3.52; N, 3.32.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]([C:21]([NH:23][CH:24]4[CH2:26][CH2:25]4)=[O:22])[CH:15]=3)=[CH:10][CH:9]=2)=[N:5][N:4]=1.[I-].[K+].CN(C=O)C.[NH:34]1[CH2:39][CH2:38][S:37][CH2:36][CH2:35]1>>[CH:24]1([NH:23][C:21]([C:16]2[CH:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([C:6]4[O:7][C:3]([CH2:2][N:34]5[CH2:39][CH2:38][S:37][CH2:36][CH2:35]5)=[N:4][N:5]=4)=[CH:9][CH:10]=3)[C:19]([CH3:20])=[CH:18][CH:17]=2)=[O:22])[CH2:26][CH2:25]1
Reactant: C1CSCCN1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CCl)o2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN3CCSCC3)o2)cc1

Procedure:
4′-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Intermediate 45) (37 mg) and potassium iodide (5 mg) were mixed in thiomorpholine (2 ml) and DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvents were evaporated under vacuum and the residue purified by bond-elut (silica), eluting with an ethyl acetate/cyclohexane gradient. After evaporation of the solvent this gave N-cyclopropyl-6-methyl-4′-[5-(thiomorpholin-4-ylmethyl)-1,3,4-oxadiazol-2-yl]-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1.[CH:35](=O)[CH3:36].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:35][CH3:36])[CH2:22][C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:33][CH3:34])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(F)cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc(F)cc1

Procedure:
4-Amino-5-chloro-N-((1-(5-(4-fluorobenzylamino)pentyl)piperidin-4-yl)methyl)-2-methoxybenzamide (1.8 g) as starting compound, acetaldehyde (0.25 ml) and sodium cyanoborohydride (0.28 g) were reacted and treated in the same manner as in Example 136 to give 1.0 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(4-fluorobenzyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:33]=[C:34]([C:36]1[CH:40]=[CH:39][S:38][CH:37]=1)[CH3:35]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:33]=[C:34](/[C:36]3[CH:40]=[CH:39][S:38][CH:37]=3)\[CH3:35])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: CC(=CBr)c1ccsc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccsc1
Temperature: 85 °C

Procedure:
2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (100 mg, 0.5 mmol) was dissolved in DMF (3 mL). potassium phosphate (212.4 mg, 1 mmol), Copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.51 mg, 0.1 mmol) were added. 3-(1-bromoprop-1-en-2-yl)thiophene (121.8 mg, 0.6 mmol) dissolved in DMF (2 mL) was added dropwise to the reaction mixture. Nitrogen was purged for 2 min and the reaction mixture heated at 85° C. overnight (prolonged heating required some cases). DMF was evaporated and water added to the reaction mixture. The precipitate obtained was filtered and purified through silica gel chromatography (100-200 mesh) using 0-3% MeOH: DCM as eluent. The compound was further purified through reverse phase purification. Yield: 80 mg. 1H NMR (CD3OD, oxalate salt) δ (ppm): 7.60 (s, 1H), 7.50 (m, 2H), 7.30 (s, 1H), 7.18 (s, 1H), 7.10 (m, 2H), 4.55 (m, 2H), 3.70 (m, 2H), 3.10 (m, 5H), 2.42 (s, 3H), 1.95 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH:7]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:29][CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:23]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:18]([O:17][C:15]([N:11]1[CH2:12][CH2:13][CH2:14][C@H:10]1[CH2:9][O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([N:35]2[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][O:29][CH2:28][C:24]3[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=3)[CH2:37][CH2:36]2)[CH:7]=1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: c1cncc(COCCC2CCNCC2)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cncc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(N2CCC(CCOCc3cccnc3)CC2)c1
Temperature: 25 °C
Yield: 89.4 %

Procedure:
To a solution of 3-bromo-5-[[1-(tert-butoxycarbonyl)-2(R)-pyrrolidinyl]methoxy]pyridine (147 mg, 0.41 mmol) and 4-[2-(3-pyridylmethoxy)ethyl]piperidine (99.8 mg, 0.45 mmol, 1.1 equiv.) in anhydrous toluene (2 mL) were added successively potassium tert-butoxide (75 mg, 0.61 mmol, 1.5 equiv.), tris(dibenzylideneacetone)dipalladium(0) (7.5 mg, 8.0 μmol, 0.02 equiv.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos; 14.3 mg, 24 μmol, 0.06 equiv.). The mixture was degassed and purged with Ar (3 cycles), then warmed by microwave irradiation under Ar. After reaction for 30-40 minutes at 130° C., the mixture was cooled to room temperature, diluted with EtOAc, and washed with brine. The solution was dried over Na2SO4 and evaporated, and the residue was purified by CC (SiO2, CH2Cl2/EtOAc 4:1 followed by CH2Cl2/MeOH 10:1). The product (182 mg, 89%) was obtained as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.56 (br, 2H), 7.80 (m, 3H), 7.46 (m, 1H), 6.94 (m, 1H), 4.51 (s, 2H), 4.12 (m, 2H), 3.83 (m, 1H), 3.66 (m, 2H), 3.54 (m, 2H), 3.39 (m, 2H), 2.76 (t, 2H, J=11.2 Hz), 2.01-1.80 (m, 5H), 1.63 (m, 4H), 1.46 (s, 9H), 1.33 (m, 2H).
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]1=[O:33])=[O:7])(C)(C)C.CCOCC.[ClH:39]>O1CCOCC1>[ClH:39].[C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[S:13][CH:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:10]1=[O:33])([OH:7])=[O:5]
Reactant: CCOC(=O)CNC1C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2SC1c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CCOC(=O)CNC1C(=O)N(CC(=O)O)c2ccccc2SC1c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of the compound obtained in Example 24 was dissolved in 10 ml of a 6N solution of hydrogen chloride in dioxane, and the resulting solution was stirred at room temperature for 2 hours. Then, ether was added thereto so as to cause crystallization. The precipitated crystals were separated by filtration and washed with ether to obtain 1.0 g of the desired compound.
Reaction SMILES: C([O:5][C:6](=[O:46])[C@H:7]([CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[NH:8][C:9](=[O:38])[CH2:10][N:11]([C:17](=[O:37])[C@H:18]([CH3:36])[NH:19][C@@H:20]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH3:35])=[O:30])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)(C)(C)C.CC(C)=O.CCOCC.[ClH:56]>C(OCC)(=O)C>[ClH:56].[CH2:32]([O:31][C:29]([C@H:20]([NH:19][C@H:18]([C:17]([N:11]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1)[CH2:10][C:9]([NH:8][C@H:7]([C:6]([OH:46])=[O:5])[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:38])=[O:37])[CH3:36])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:30])[CH2:33][CH2:34][CH3:35]
Reactant: CCCCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)C1CCCC1
Agent: Cl
Solvent: CCOCC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)[C@@H](CCc1ccccc1)N[C@@H](C)C(=O)N(CC(=O)N[C@@H](Cc1ccccc1)C(=O)O)C1CCCC1

Procedure:
N-[1(R)-Butoxycarbonyl-3-phenylpropyl]-L-alanyl-N-cyclopentylglycyl-L-phenylalanine tert-butyl ester (1 g) is dissolved in 14 ml of 3.4N hydrogen chloride in ethyl acetate, followed by addition of 2 ml of acetone. Then, 10 ml of ether is added and the solvent is decanted off. The residue is dried under reduced pressure to give 0.8 g of N-[1(R)-butoxycarbonyl-3-phenylpropyl]-L-alanyl-N-cyclopentylglycyl-L-phenylalanine hydrochloride as colorless powder.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1O)[CH3:17].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH3:33])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH3:17]
Reactant: CCOC(=O)/C(C)=C/c1ccc(O)c(OCC)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C(C)=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.9 %

Procedure:
0.8 mL (4.8 mmol) of triflic anhydride is added to a solution of 1.5 g (4 mmol) of ethyl (E)-3-(3-ethoxy-4-hydroxyphenyl)-2-methylacrylate and 1.6 mL (12 mmol) of triethylamine in 20 mL of dichloromethane at 0° C. The reaction mixture is stirred at room temperature for 1 hour. The medium is hydrolyzed in sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 1.65 g (100%) of ethyl (E)-3-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)-2-methylacrylate are obtained in the form of a brown oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:3]=1.[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[O:23][CH3:24]>>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)[N:3]=2)=[CH:18][C:17]=1[O:23][CH3:24]
Reactant: COc1cc(N)ccc1F
Reactant: Cc1cc(Cl)nc(-c2ccccn2)n1
Product: COc1cc(Nc2cc(C)nc(-c3ccccn3)n2)ccc1F

Procedure:
The title compound was prepared from 4-chloro-6-methyl-2-(2-pyridinyl)pyrimidine (82.3 mg, 0.4 mmol) and 4-fluoro-3-methoxyaniline (56.4 mg, 0.4 mmol) similar to Example 173 and was isolated as a white solid (96.7 mg, 78%). 1H NMR (CDCl3): 8.63 (d, J=4.2 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.65 (t, J=7.5 Hz, 1H), 7.42 (s, 1H), 7.20 (m, 1H), 7.0 (d, J=7.5 Hz, 1H), 6.90 (m, 1H), 6.69 (m, 1H), 3.71 (s, 3H), 2.30 (s, 3H),
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[S:9][C:10]([C:13]([O:15]CC)=[O:14])=[CH:11][N:12]=2)=[CH:4][CH:3]=1.CO.[OH-]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[S:9][C:10]([C:13]([OH:15])=[O:14])=[CH:11][N:12]=2)=[CH:18][CH:19]=1
Reactant: CCOC(=O)c1cnc(COc2ccc(Cl)cc2)s1
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cnc(COc2ccc(Cl)cc2)s1

Procedure:
A mixture of 10.9 of ethyl 2-(p-chlorophenoxymethyl)-thiazole-5-carboxylate, 165 ml of methanol, 10 ml of postassium hydroxide and 20 ml of water was refluxed for 30 minutes and was then cooled and extracted with ethyl acetate. The aqueous phase was acidified and 2-(p-chlorophenoxymethyl)-thiazole-5-carboxylic acid was extracted with ethyl acetate and then a mixture of chloroform-methanol. The combined extracts were dried and evaporated to dryness to obtain 7.9 g of a crystalline residue. The residue was crystallized from isopropanol to obtain 6.92 g of the desired acid and the latter in the form of its triethylamine salt was chromatographed over silica gel. Elution with first a 1-1 chloroform-ethyl acetate mixture and then a 90-10-1 methylene chloride-ethyl acetate-acetic acid mixture gave 6.7 g of raw product. The latter was purified by sublimation at 190° C under reduced pressure and was crystallized from isopropanol containing 10% water to obtain 5.23 g of 2-(p-chlorophenoxymethyl)-thiazole--carboxylic acid melting at 215° C.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:12])=[C:4]([C:10]#[N:11])[C:5](=[O:9])[NH:6][C:7]=1[CH3:8].CC([O-])=O.[Na+]>CC(O)=O.Cl.O=[Pt]=O.[Pd]>[NH2:11][CH2:10][C:4]1[C:5](=[O:9])[NH:6][C:7]([CH3:8])=[C:2]([F:1])[C:3]=1[CH3:12]
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1F
Agent: O=[Pt]=O
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1[nH]c(=O)c(CN)c(C)c1F
Reaction time: 6 h
Yield: 100.5 %

Procedure:
5-Fluoro-4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (1.0 g, 6.02 mmol) was suspended in 50 mL of HOAc at room temperature to give a dark brownish solution. NaOAc (1.0 g, 12.3 mmol, 2 equiv), PtO2 (20 mg) and 5% Pd/C (1.3 g) were charged into a 500 mL Parr bottle, followed by wetting with some acetic acid under nitrogen. The substrate solution was then added, and rinsed with another 50 mL of acetic acid. The mixture was hydrogenated under a pressure of 40 psi. There was initial drop of hydrogen pressure and the vessel was refilled. The mixture was hydroganted for 6 h. The mixture was filtered through Celite, and concentrated in vacuo to give a solid residue, which was suspended in 6 mL of conc. HCl to give a paste. The paste was filtered, and the cake was washed with 1 mL of conc HCl (in duplicate). The filtrate was concentrated in vacuo. The solid residue dissolved in 0.4 mL of conc. HCl and 6 mL of EtOH as a suspension, which was stored in the freezer for 2 h, followed by filtration. The cake was washed with 2 mL of cold EtOH (in duplicate). The solids were dried under vacuum at room temperature for 18 h to give the title compound as a cream-colored solid (1.03 g). LC-MS (ES) m/z=171 [M+H]+ and a dominant peak at 154. 1H NMR (400 MHz, DMSO-d6) δ ppm, 2.20 (d, J=3.0 Hz, 3 H), 2.22 (d, J=2.0 Hz, 3 H), 3.83 (q, J=5.2 Hz, 2 H), 7.99 (br. s., 3 H), 11.99 (br. s., 1 H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([OH:10])=[N:3][CH:2]=1.[CH2:11]([O:18][C:19](=[O:31])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH:28]=[O:29])[C:22]=1[F:30])C1C=CC=CC=1.[OH-].[K+].CO>Cl>[CH3:11][O:18][C:19](=[O:31])[NH:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[C:23]([CH:28]([OH:29])[C:9]2[C:5]3[C:4]([OH:10])=[N:3][CH:2]=[N:1][C:6]=3[NH:7][CH:8]=2)[C:22]=1[F:30]
Reactant: Oc1ncnc2[nH]ccc12
Reactant: O=Cc1c(F)ccc(NC(=O)OCc2ccccc2)c1F
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(O)c23)c1F
Temperature: 50 °C
Reaction time: 48 h
Yield: 92.5 %

Procedure:
In a reaction vessel, 7H-pyrrolo[2,3-d]pyrimidin-4-ol (37, 855 mg, 6.33 mmol) is combined with (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (33, 2.03 g, 6.96 mmol) and potassium hydroxide (1.06 g, 19.0 mmol) and 5 mL of methanol is added. The resulting solution is stirred at 50° C. for 2 days. The reaction is diluted with 1N hydrochloric acid and extracted with ethyl acetate, and the resulting solids collected by filtration and dried under vacuum. The organic layer is separated from the filtrate and the aqueous layer extracted twice more with ethyl acetate. The organic layers are combined and washed with water, brine, dried with magnesium sulfate and filtered. The filtrate is concentrated under vacuum and the resulting material is suspended in acetonitrile and sonicated for 1 hour. The solid is collected by filtration and dried under vacuum, then combined with the first solid collected to provide the desired compound (38, 2.05 g). MS (ESI) [M−H+]−=349.0.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([Cl:10])[CH:4]=1.Br[C:12]1[CH:17]=CC(O)=C(F)[CH:13]=1.IC(C)C.BrC(CC)C([O-])=O>>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH:12]([CH3:17])[CH3:13])=[C:5]([Cl:10])[CH:4]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: Oc1ccc(Br)cc1Cl
Agent: CCC(Br)C(=O)[O-]
Agent: [Br-]
Solvent: CC(C)I
Product: CC(C)Oc1ccc(Br)cc1Cl

Procedure:
The intermediate bromide, was prepared analogously to Step 1 in Example A(52), where 4-Bromo-2-chloro-phenol was substituted in place of 4-bromo-2-fluorophenol and 2-iodopropane instead of methyl □-bromobutyrate of that example.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:5]2.C1COCC1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:5]2
Reactant: CC(C)(C)[Si](OCCCCC1Cc2cc(Br)ccc2C1=O)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCCCCC1Cc2cc(Br)ccc2C1O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.6 %

Procedure:
The compound (2.03 g) obtained in Example 11-4 was dissolved in methanol (61 ml) and THF (31 ml) and added with sodium borohydride (0.442 g) under ice-cooling and the whole was stirred at room temperature for 2 hours. The reaction solution was added with a saturated aqueous ammonium chloride solution and then subjected to extraction with chloroform. The organic layer was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate), thereby obtaining the subject compound (1.54 g) as a yellow oily substance.