Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=NN(C)C)[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:21]>Cl>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[C:11](=[O:21])[CH:10]([CH3:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CC(C)C1=NN(C)C
Reactant: CO
Agent: Cl
Product: CC1CN(Cc2ccccc2)CC(C)C1=O

Procedure:
43 (1.7 g, 6.5 mmol) is dissolved in a 1.25M solution of HCl in methanol (20 ml, 25 mmol) and refluxed for 1.5 h The reaction mixture is evaporated under reduced pressure and dried at high vacuum. The residue (1.7 g of a colorless oil) is dissolved in ethyl acetate and treated with 5M NaOH. The organic layers are evaporated under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[C:3](C(O)=O)=[C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:5]([CH3:16])[C:6]=1[C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1
Reactant: CCOC(=O)Cc1c(C(=O)O)c(Br)c(C(=O)c2ccc(Cl)cc2)n1C
Solvent: CCOCC
Product: CCOC(=O)Cc1cc(Br)c(C(=O)c2ccc(Cl)cc2)n1C

Procedure:
A 7.2 g. sample of ethyl 4-bromo-3-carboxy-5-p- chlorobenzoyl-1-methylpyrrole-2-acetate is heated at 250° for 10 minutes under nitrogen. It is then cooled and dissolved in ether; the resulting ether solution is filtered, washed with sodium hydroxide solution, and then washed with water. After the ether is evaporated in vacuo, the residue is triturated with boiling hexane. Concentration of the hexane solution to a small volume in vacuo yields a crystalline precipitate, which is recrystallized from methanol to give ethyl 4-bromo-5-(p-chlorobenzoyl)-1-methylpyrrole-2-acetate as a white solid; m.p. 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH2:13][CH:14]([C:18]2([CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]2=[O:31])[C:15]([OH:17])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.CN1CCOCC1.Cl.[CH2:56]([O:63][NH2:64])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(Cl)Cl>[CH2:56]([O:63][NH:64][C:15](=[O:17])[CH:14]([CH2:13][NH:12][S:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)(=[O:11])=[O:10])[C:18]1([CH2:32][CH:33]([CH3:34])[CH3:35])[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]1=[O:31])[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)NCC(C(=O)O)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NCC(C(=O)NOCc2ccccc2)C2(CC(C)C)CCN(CCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 108.4 %

Procedure:
A solution of α-[[[(4-methoxyphenyl)sulfonyl]amino]methyl]-3-(2-methylpropyl)-2-oxo-1-(2-phenylethyl)-3-pyrrolidineacetic acid (290 mg, 0.577 mmol) in dry CH2Cl2 (5 mL) is treated with CDI (112 mg, 0.692 mmol). Afar 1 h, 4-methylmorpholine (0.095 mL, 0.866 mmol) and O-benzylhydroxyamine HCl (138 mg, 0.866 mmol) are added. The solution is stirred at room temperature under N2 for 65 h. The solvent had evaporated, and the residual gel is diluted with EtOAc (25 mL). The solution is washed with 1N HCl (10 mL), 1N NaOH (10 mL), and brine (10 mL). The organic layer is dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 380 mg of an oil. The oil is purified by silica gel chromatography (30 g SG; 50% EtOAc/hexane) to provide 249 mg (71%) of the title compound as an oil:
Reaction SMILES: C(N(CC)CC)C.[C:8]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[CH:23]1[C:35]2[CH:34]([CH2:36][O:37][C:38](Cl)=[O:39])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]=2[CH:26]=[CH:25][CH:24]=1>CC#N>[C:11]([O:10][C:8]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:38]([O:37][CH2:36][CH:34]2[C:33]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:27]3[C:35]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:39])=[CH:20][CH:21]=1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.6 %

Procedure:
Triethylamine (7.36 mL, 52.82 mmol, 1.1 eq) is added at 0° C. to a stirred solution of N—BOC-1,4-phenylene diamine (10.00 g, 48.02 mmol, 1.0 eq) in CH3CN (240 mL), followed by 9-fluorenylmethyloxycarbonyl chloride (14.90 g, 57.62 mmol, 1.2 eq). The resulting mixture is allowed to warm to room temperature. After 4 hours stirring at room temperature, the reaction mixture is filtered to afford 20.60 g of the crude product as a white powder which is used in the next step without any further purification.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)([CH3:26])[CH3:23]
Reactant: CC(C)=O
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Agent: Cl
Product: CC(C)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
2-Isopropyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline is prepared from 7-(3piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (520 mg, 1.5 mmol), MP-CNBH3 (3.2 g, 7.5 mmol), and acetone (1.1 mL, 15 mmol) via a procedure substantially analogous to Procedure C except that the SCX column is not used in purification. The product (210 mg, 44% yld) is isolated as a clear oil. MS(ES+)317.2(M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][O:5][C:4]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][CH2:25]4)=[CH:20][CH:19]=3)[C:11]([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)=[CH:12][C:3]1=2.CO>ClCCl>[NH2:28][C:24]1([C:21]2[CH:22]=[CH:23][C:18]([C:10]3[C:11]([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)=[CH:12][C:3]4[N:2]([CH3:1])[C:7](=[O:8])[CH2:6][O:5][C:4]=4[N:9]=3)=[CH:19][CH:20]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: CN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccsc3)cc21
Solvent: ClCCl
Solvent: CO
Product: CN1C(=O)COc2nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccsc3)cc21
Reaction time: 12 h
Yield: 29 %

Procedure:
Tert-butyl (1-(4-(1-methyl-2-oxo-7-(thiophen-3-yl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.051 mmol) was dissolved in dichloromethane (0.5 ml); this solution was added to a scx-2 catch and release cartridge (5 g), precalibrated using methanol (15 ml) and dichloromethane (15 ml). After allowing binding for 12 hours, the column was washed with methanol (6 ml), then the product eluted with 7M ammonia in methanol (4×2 ml). The combined product fractions were concentrated to dryness under reduced pressure to give the desired product as a white solid (5.8 mg, 30% yield). LCMS (Method D): RT=0.777 min, M+1=393. 1H-NMR (500 MHz, CD3OD) δ 7.35-7.29 (3H, m), 7.28-7.25 (1H, dd), 7.21-7.18 (1H, s), 7.17-7.14 (1H, dd), 7.07-7.03 (1H, dd), 6.71-6.67 (1H, dd), 4.80 (2H, s), 3.32 (3H, s), 2.51-2.37 (4H, m), 2.25-2.13 (1H, m).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH3:8].Cl[C:33]1[S:37][N:36]=[C:35]([CH3:38])[N:34]=1>O1CCCC1>[CH2:7]([O:9][C:10](=[O:31])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])([C:33]1[S:37][N:36]=[C:35]([CH3:38])[N:34]=1)[C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH3:8]
Reactant: Cc1nsc(Cl)n1
Reactant: CCOC(=O)CCCCCC(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCC(C(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)c1nc(C)ns1

Procedure:
Potassium tert-butoxide (12.2 g, 0.11 mol) followed by 2-tert-butoxycarbonyloctanedioic acid 1-tert-butyl ester 8-ethyl ester (2021037) (30.0 g, 83.8 mmol) was added portionwise to stirred tetrahydrofuran (170 mL) and then 5-chloro-3-methyl-1,2,4-thiadiazole (2009380) (11.3 g, 83.8 mmol) was added to the resultant slurry. The mixture was heated at reflux overnight before being quenched with water (150 mL) and extracted with dichloromethane (3×200 mL). The combined organic fractions were dried (MgSO4) and the solvent was removed under reduced pressure. The crude product was purified by flash chromatography (6:1 hexane/ethyl acetate) to afford 2-tert-butoxycarbonyl-2-(3-methyl[1,2,4]thiadiazol-5-yl)octanedioic aAcid 1-tert-butyl ester 8-ethyl ester (2021038) (10 g, 26%) as a yellow oil.
Reaction SMILES: C(OC(N1CCCCC1[C:14]1[N:22]2[C:17]([CH:18]=[N:19][C:20]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][CH:25]=3)=[N:21]2)=[CH:16][CH:15]=1)=O)(C)(C)C.F[C:37](F)(F)[C:38](O)=O>C(Cl)Cl>[N:30]1([C:27]2[CH:26]=[CH:25][C:24]([NH:23][C:20]3[N:19]=[CH:18][C:17]4=[CH:16][CH:15]=[C:14]([C:16]5[CH2:17][CH2:18][NH:19][CH2:37][CH:38]=5)[N:22]4[N:21]=3)=[CH:29][CH:28]=2)[CH2:31][CH2:32][O:33][CH2:34][CH2:35]1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Solvent: ClCCl
Product: C1=C(c2ccc3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)CCNC1
Temperature: 25 °C

Procedure:
Into a 8 dram vial, [2-(4-Morpholin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-piperidine-1-carboxylic acid tert-butyl ester (0.150 g, 0.315 mmol), Methylene chloride (5 mL) and Trifluoroacetic Acid (1 g, 9 mmol) were added and stirred at room temperature over night. The reaction was partitioned with Sat. NaHCO3 and DCM. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The desired product was purified via ISCO column chromatography with DCM and methanol as eluant (0 to 10% methanol). The collected fractions afforded (4-Morpholin-4-yl-phenyl)-[7-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.[C:20](#[N:22])C>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([C:17]=1[C:20]#[N:22])=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2
Reactant: CC#N
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Product: COc1ccncc1-c1[nH]c2ccc(C#N)cc2c1C#N

Procedure:
2-(4-Methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 128) is processed according to the method described in Example 140, using acetonitrile instead of dichloromethane, to give 2-(4-methoxy-pyridin-3-yl)-1H-indole-3,5-dicarbonitrile. MS (ESI) m/z 275.08 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH:33]=O)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]>>[CH2:18]([C:22]1[N:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:25]=[C:24]([CH2:33][NH:17][CH2:16][CH2:15][N:12]2[CH2:11][CH2:10][N:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)[CH2:14][CH2:13]2)[CH:23]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: COc1ccc(N2CCN(CCN)CC2)cc1
Reactant: CC(C)Cc1cc(C=O)nn1-c1ccccc1
Product: COc1ccc(N2CCN(CCNCc3cc(CC(C)C)n(-c4ccccc4)n3)CC2)cc1
Yield: 24.2 %

Procedure:
Compound 42 was prepared using the same method as that of Example 1 except that 4-(4-methoxyphenyl)piperazin-1-ylethylamine and 5-iso-butyl-1-phenylpyrazole-3-carbaldehyde were used.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:19]=1[Cl:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([O:28][C:29]([CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=[O:30])[CH3:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[N:10]=[C:9]1[C:18]1[CH:23]=[C:22]([N:34]2[CH2:35][CH2:36][CH:31]([C:29]([O:28][CH2:26][CH3:27])=[O:30])[CH2:32][CH2:33]2)[CH:21]=[CH:20][C:19]=1[Cl:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(Br)ccc2Cl)nc2cc(F)ccc21
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(Cl)c(-c3nc4cc(F)ccc4n3C(=O)OC(C)(C)C)c2)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 68 %

Procedure:
Method 3,4—Step d 2-(5-Bromo-2-chloro-phenyl)-5-fluoro-benzoimidazole-1-carboxylic acid tert-butyl ester (1.04 g, 2.46 mmol), piperidine-4-carboxylic acid ethyl ester (0.49 mL, 3.19 mmol) and cesium carbonate (3.99 g, 12.29 mmol) were placed into a dry Schlenk tube under nitrogen. At the same time palladium acetate (0.11 g, 0.49 mmol), and BINAP (0.46 g, 0.74 mmol) were placed into a dry 7 mL vial under nitrogen. Then dry toluene (4 mL) was added and the mixture was stirred 20 minutes under nitrogen before being added to the first flask. The reaction mixture was heated at 80° C. overnight, cooled to room temperature, salts were filtered off, the organic solution was concentrated under reduced pressure and crude was purified by flash chromatography (eluent: cyclohexane:AcOEt gradient from cyclohexane:AcOEt/5:1 to 1:2) to afford 0.84 g of the title compound (68%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[C:13]([F:28])=[CH:12][N:11]=1>>[F:28][C:13]1[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:25])[F:26])[CH:18]=2)=[N:15][C:10]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=2)=[N:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1cnc(Cl)nc1Nc1cccc(OC(F)(F)F)c1
Product: Oc1cccc(Nc2ncc(F)c(Nc3cccc(OC(F)(F)F)c3)n2)c1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 3-hydroxyaniline with 2-chloro-5-fluoro-N4-(3-trifluoromethoxyphenyl)-4-pyrimidineamine gave 5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-trifluoromethoxyphenyl)-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.61 (bs, 1H), 8.21 (d, 1H, J=4.2 Hz), 7.93 (bd, 1H, J=7.5 Hz), 7.78 (s, 1H), 7.43 (t, 1H, J=8.4 Hz), 7.03 (m, 4H), 6.43 (m, 1H); 19F NMR (DMSO-d6): −16097; LCMS: purity: 85%; MS (m/e): 381 (MH+).
Reaction SMILES: [OH:1][B:2]([OH:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.O[C:14]([C:17](O)([CH3:19])[CH3:18])([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[CH3:15][C:14]1([CH3:16])[C:17]([CH3:19])([CH3:18])[O:12][B:2]([C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)[O:1]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: CC(C)(O)C(C)(C)O
Solvent: Cc1ccccc1
Product: CC1(C)OB(c2ccc(C(=O)O)cc2)OC1(C)C

Procedure:
A solution of 4-(dihydroxyboryl)benzoic acid (1.66 g, 10 mmol) and pinacol (12 mmol) in toluene (70 mL) was refluxed in a Dean-Stark apparatus for 16 hours and concentrated. The concentrate was triturated with diethyl ether and filtered to provide the desired product of sufficient purity for subsequent use.
Reaction SMILES: [I-].[Li+].C[C:4]1(C)[S:9][CH2:8][CH2:7][N:6]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]#[C:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C@H:5]1[C:29]([O:31]C)=[O:30]>>[C:23]1([C:22]#[C:21][CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([S:10]([N:6]3[CH2:7][CH2:8][S:9][CH2:4][CH:5]3[C:29]([OH:31])=[O:30])(=[O:12])=[O:11])=[CH:14][CH:15]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H]1N(S(=O)(=O)c2ccc(OCC#Cc3ccccc3)cc2)CCSC1(C)C
Agent: [I-]
Agent: [Li+]
Product: O=C(O)C1CSCCN1S(=O)(=O)c1ccc(OCC#Cc2ccccc2)cc1

Procedure:
According to the procedure of Example 250, lithium iodide mediated ester cleavage of 0.282 g (0.61 mmol) of methyl (3S)-2,2-dimethyl-4-({4-[(3-phenyl-2-propynyl)oxy]phenyl)sulfonyl)3- thiomorpholinecarboxylate provided 0.215 g (79%) of (3S)-2,2-dimethyl4-({4-[(3-phenyl-2-propynyl)oxy]phenylsulfonyl)-3-thiomorpholine carboxylic acid as a white solid. Electrospray Mass Spec: 446.0 (M+H)+
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH2:12][OH:13])[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.C(N(CC)CC)C>CS(C)=O>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: OCc1csc(N2CCSCC2)n1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1csc(N2CCSCC2)n1

Procedure:
The reaction described in Preparation 44 was repeated, but using 1.2 g of 2-(thiomorpholin-4-yl)thiazol-4-ylmethanol, 2.65 g of sulfur trioxide pyridine complex, 1.68 g of triethylamine and 30 ml of dimethyl sulfoxide, giving the title compound as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]3[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]([CH3:20])=[C:12]3[C:21]#[N:22])[CH:9]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][S:38](Cl)(=[O:40])=[O:39])=[CH:33][CH:32]=1.C(N(CC)CC)C>ClCCl>[C:21]([C:12]1[CH:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[N:3]=[C:2]3[NH:1][S:38]([CH2:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)(=[O:39])=[O:40])[C:16]([C:17]#[N:18])=[C:15]([CH3:19])[NH:14][C:13]=1[CH3:20])#[N:22]
Reactant: O=S(=O)(Cl)Cc1ccc(F)cc1
Reactant: CC1=C(C#N)C(c2ccc3c(c2)c(N)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1=C(C#N)C(c2ccc3c(c2)c(NS(=O)(=O)Cc2ccc(F)cc2)nn3C(=O)OC(C)(C)C)C(C#N)=C(C)N1

Procedure:
To 100 mg (0.256 mmol) tert-butyl 3-amino-5-(3,5-dicyano-2,6-dimethyl-1,4-dihydropyridin-4-yl)-1H-indazole-1-carboxylate (Example 3A) in dichloromethane (4 ml) were added 160 mg (0.77 mmol) (4-fluorophenyl)methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine. The mixture was stirred at reflux for 12 h. Then, further batches of 160 mg (0.77 mmol) (4-fluorophenyl)-methanesulfonyl chloride and 0.11 ml (0.77 mmol) triethylamine were added, and the mixture was again stirred at reflux for 1 h. After concentration under reduced pressure, the residue was dissolved in ethyl acetate and washed with brine. The aqueous layer was re-extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by preparative RP-HPLC (acetonitrile/water gradient) to give 28 mg (19% of th.) of the title compound.
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH:14](CO)[CH2:13][CH2:12]1>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:14]1[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCNCC1
Reactant: COC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCC1CCNCC1)c1ccccc1
Yield: 88 %

Procedure:
In an argon atmosphere, a mixture of methyl benzoate (1.0 mmol), piperidin-4-ylmethanol (1.2 mmol), Zn4(OCOCF2)6O (1.25 mol % in terms of mole number) and toluene (1.7 ml) was heated to reflux for 18 hours, and as a result, piperidin-4-ylmethyl benzoate was obtained at a yield of 88%. The yield of N-benzoylpiperidin-4-ylmethyl benzoate was 12%.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:37]COC)=[C:15]([CH:36]=1)[CH2:16][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C.C1C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[F:10][C:11]1[CH:12]=[CH:13][C:14]([OH:37])=[C:15]([CH2:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:36]=1
Reactant: COCOc1ccc(F)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: Oc1ccc(F)cc1CCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
0.91 g of benzaldehyde, 4.00 g of 5-fluoro-2-methoxymethoxybenzyl-triphenylphosphonium chloride (prepared as described in Preparation 8) and 1.28 ml of DBU were allowed to react together in 40 ml of acetonitrile, subsequently treated, and purified by silica gel column chromatography, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent, in the same manner as described in Preparation 2, to give 2.04 g of an oily substance. 2.03 g of this oily substance were dissolved in 12 ml of a 1:2 by volume mixture of benzene and ethanol, and then 0.30 g of tris-(triphenylphosphine)rhodium(I) chloride were added to the resulting solution. The resulting mixture was stirred under a hydrogen atmosphere at atmospheric pressure and at 60° C. for 8 hours. At the end of this time, the reaction solution was filtered with a Celite (trade mark) filter aid. The filtrate was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 10:1 by volume mixture of hexane and ethyl acetate as the eluent. The purified substance was then dissolved in 10 ml of ethyl acetate, and then 10 ml of a 4N solution of hydrogen chloride in ethyl acetate were added to the resulting solution, with ice-cooling. The resulting mixture was allowed to stand at room temperature for 2 hours, after which it was concentrated by evaporation under reduced pressure, and purified by silica gel column chromatography, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.45 g (yield 79%) of the title compound as a solid substance.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]([C:25]([O:27]CC)=[O:26])([CH3:24])[CH3:23])=[CH:17][CH:16]=1)C.Cl>C(O)C.O>[C:25]([C:22]([CH3:24])([CH3:23])[CH2:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:30])=[O:5])=[CH:16][CH:17]=1)([OH:27])=[O:26]
Reactant: CCOC(=O)c1ccccc1COc1ccc(CC(C)(C)C(=O)OCC)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(Cc1ccc(OCc2ccccc2C(=O)O)cc1)C(=O)O
Yield: 91.7 %

Procedure:
A solution containing 30.2 g of potassium hydroxide in 150 ml 95% ethanol was added to 2-[4-(2-ethoxycarbonyl-2-methylpropyl)phenoxymethyl]benzoic acid ethyl ester (20.3 g) and warmed to reflux for 8 hours. The solution was cooled, diluted with water and adjusted to pH 5 with 6N HCl. Cooling overnight gave a precipitate which was collected and air dried to give 15.9 g of 2-[4-(2-carboxy-2-methylpropyl)phenoxymethyl]benzoic acid as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.[C:14](OCC)(=[O:19])[CH2:15][C:16]([CH3:18])=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:1][C:2]1[C:6]2[C:5](=[N:7][C:14]([OH:19])=[CH:15][C:16]=2[CH3:18])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1cc(O)nc2c1c(C)nn2-c1ccccn1
Temperature: 25 °C
Yield: 63.1 %

Procedure:
A solution of 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-amine (5.1 g, 29 mmol) and ethyl acetoacetate (3.8 g, 30 mmol) in acetic acid (14 mL) was stirred at 100° C. for 4 hours. The solution was cooled to room temperature and ethyl acetate was added thereto. The resulting crude crystals were collected by filtration, and recrystallized from ethanol to give the title compound (4.4 g, 62% yield).