Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][CH:6]=[CH:5][N:4]=1.O=[C:11]1[CH2:15][S:14][CH2:13][CH:12]1[C:16](OC)=[O:17]>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:11]2[CH2:15][S:14][CH2:13][C:12]=2[C:16](=[O:17])[NH:9][C:8]2[CH:7]=[CH:6][CH:5]=[N:4][C:3]1=2
Reactant: COC(=O)C1CSCC1=O
Reactant: CNc1ncccc1N
Solvent: Cc1ccccc1
Product: CN1C2=C(CSC2)C(=O)Nc2cccnc21

Procedure:
A solution of 3.4 g. of 2-methylamino-3-aminopyridine and 2.9 g. of methyl tetrahydro-4-oxo-3-thiophene carboxylate in 200 ml. of toluene is heated under reflux for 3 hours, during which 100 ml. of distillate is collected in a Dean-Stark trap. The solution is concentrated under reduced pressure and the solid residue is recrystallized from ethyl acetate to give pale yellow crystals, m.p. 240°-241°C.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@@:13]1([CH2:17][N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C@H:15]([CH3:16])[O:14]1>>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C@:13]([OH:14])([C@H:15]([N:1]1[CH:5]=[CH:4][N:3]=[N:2]1)[CH3:16])[CH2:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccccc1F
Reactant: c1c[nH]nn1
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccccc1F

Procedure:
Using 1H-1,2,3-triazole and (2R,3S)-2-(2-fluorophenyl)-3-methyl-2-[(1H-1,2, 4-triazol-1-yl)methyl]oxirane, Compound 44 and Compound 45 were obtained by the same way as in Example 30.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([N+:13]([O-:15])=[O:14])[C:7]=1[CH3:16])(=O)C.[OH-].[Na+].O>CO>[CH3:16][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[CH2:5][OH:4]
Reactant: CC(=O)OCc1c(C)ccc([N+](=O)[O-])c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO
Yield: 82.4 %

Procedure:
To a solution of 2,6-dimethyl-3-nitrobenzyl acetate (26.9 g) in methanol (266 ml) was added aqueous 1N sodium hydroxide solution (133 ml) at ambient temperature for 30 minutes. To the mixture was added water, and the precipitate was collected by filtration to give 2,6-dimethyl-3-nitrobenzyl alcohol (18.0 g) as pale yellow crystals.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=2)=[N:17][C:16]=1[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31]Br>O1CCCC1.CN(C)C=O>[CH3:14][C:15]1[O:19][C:18]([C:20]2[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[N:17][C:16]=1[CH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=1)[CH2:31][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc(-c2nc(Cc3cccc(CBr)c3)c(C)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc(Cc2nc(-c3ccc(C)cc3)oc2C)c1)C(=O)OCC
Yield: 82.2 %

Procedure:
To 15 ml of dry tetrahydrofuran and 7 ml of dry N,N-dimethylformamide, 0.88 g of 60% sodium hydride was added. To the mixture was added dropwise 4.40 g of diethyl malonate with stirring under ice-cooling. After 15-minute-stirring, a solution of 3.93 g of 3-{[5-methyl-2-(p-tolyl)oxazol-4-yl]methyl}benzyl bromide/5 ml of dry tetrahydrofuran was added and stirred for 1 hour under ice-cooling. The reaction solution was poured into ice-cold water, extracted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=5:1) to provide 3.95 g of the objective compound as colorless crystals.
Reaction SMILES: [O:1]=[C:2]([N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)[CH2:3][N:4]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[S:5]1.[CH2:20](Br)[CH:21]=[CH2:22].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:22]([N:17]1[CH2:18][CH2:19][N:14]([C:2](=[O:1])[CH2:3][N:4]2[C:8](=[O:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[S:5]2)[CH2:15][CH2:16]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: O=C(Cn1sc2ccccc2c1=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1CCN(C(=O)Cn2sc3ccccc3c2=O)CC1

Procedure:
Compound 10 (30 mg, 0.11 mmol) was treated with allyl bromide (16 mg, 0.13 mmol) and DIEA (40 mg, 0.31 mmol) in anhydrous CH2Cl2 (2 mL) at room temperature for 6 h. Allyl bromide then was removed by reduced pressure and the residue was washed by H2O to give the title compound after purification on a thin-layer silica-gel plate (20 cm×20 cm×2 mm) using CH2Cl2/MeOH (9:1) as the developing solution. C16H19N3O2S; white solid; mp 119-120° C.; IR vmax (neat) 3072, 2920, 2857, 2801, 1717, 1653, 1448, 1339, 1262, 1234, 1136, 1038, 1000, 924, 748 cm−1, 1H NMR (400 MHz, CDCl3) δ 8.02 (1H, d, J=8.0 Hz), 7.58 (1H, t, J=7.6 Hz), 7.53 (1H, d, J=8.0 Hz), 7.37 (1H, t, J=7.6 Hz), 5.80 (1H, m), 5.16 (2H, m), 4.69 (2H, s), 3.65 (2H, t, J=5.2 Hz), 3.57 (2H, t, J=5.2 Hz), 2.99 (2H, d, J=6.8 Hz), 2.45 (4H, m); 13C NMR (100 MHz, CDCl3) δ 165.5, 164.7, 134.1, 132.0, 126.7, 125.3, 120.2, 118.5, 61.5, 52.9, 52.5, 45.3, 44.8 (2×), 42.2, 29.8; ESI-HRMS calcd for C16H20N3O2S: 318.1274. found: m/z 318.1274 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5](=O)[CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[CH3:18]S(O)(=O)=O>ClCCl>[CH3:1][O:2][C:3](=[O:17])[CH2:4][C:5]1[C:13]2[CH:12]=[C:11]([CH3:18])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[S:7][CH:6]=1
Reactant: CS(=O)(=O)O
Reactant: COC(=O)CC(=O)CSc1cccc(OC)c1
Solvent: ClCCl
Product: COC(=O)Cc1csc2cc(OC)c(C)cc12

Procedure:
A solution of compound 78A from the preceding step (8.6 g, 32 mmol) in 30 mL of dichloromethane was added dropwise to 30 mL of methanesulfonic acid stirred under N2 at icebath temperature. The mixture was allowed to warn gradually to room temperature. After an hour 200 mL of icewater was cautiously added (vigorous reaction!), then the mixture was partitioned between a total of 300 mL of water and 350–400 mL of dichloro-methane. The organic layer was drawn off and washed with water, then 0.5M aq NaHCO3, and dried over MgSO4. The solvent was removed in vacuo, and the residue dissolved in a minimum of CHCl3/EtOAc (24:1) and passed slowly through a column of silica gel, eluting with several column volumes of the same solvent. The effluent was stripped of solvent in vacuo to leave the title compound as a clear amber syrup, contaminated with the other possible regio-isomer, but of sufficient purity for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[NH:5][CH3:6].[CH:10]([OH:12])=O>O>[Br:1][C:2]1[CH:3]=[C:4]([N:5]([CH3:6])[CH:10]=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CNc1cccc(Br)c1
Reactant: O=CO
Solvent: O
Product: CN(C=O)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
A solution of 3-bromo-N-methyl aniline (made as described by Lopez et al. in Tet. Lett., 1999, 40, 11, p2071-2074 incorporated herein by reference; 7.4 g, 39.5 mmol) in formic acid (20 mL) was refluxed for 3 h. The reaction mixture was then cooled to ambient temperature, diluted with water and extracted with diethyl ether. The organic phase was washed with saturated, aqueous sodium bicarbonate solution, water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to afford the title product as a dark brown oil.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:22])=O>CN(C=O)C>[Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([Cl:22])=[O:18])=[CH:11][CH:10]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(CC(=O)Cl)cc1

Procedure:
Under an argon atmosphere, to a mixture of 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetic acid (9) (1.80 g, 6.76 mmol) in CH2C2 (15 mL) was added DMF (4 drops) by a Pasteur pipette at room temperature. To this was added oxalyl dichloride (1.20 mL, 14.2 mmol) at 0° C. and the mixture was stirred for an hour while elevating to room temperature. The mixture was concentrated under reduced pressure to give crude 2-[4-(tert-butyldimethylsilyloxy)phenyl]acetyl chloride (10) as a colorless oil, which was used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1.[N:29]1([C@@H:34]2[CH2:39][CH2:38][CH2:37][CH2:36][C@H:35]2O)[CH2:33][CH2:32][CH2:31][CH2:30]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([O:18][CH:35]4[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]4[N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:16][CH:17]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[S:8][C:7]=2[CH:28]=1
Reactant: O[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(O)cc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OC3CCCCC3N3CCCC3)cc2)cc1
Yield: 34.9 %

Procedure:
6-Methoxy-2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)benzo[b]thiophene (1.27 g, 3.25 mmol), trans-2-pyrrolidinylcyclohexanol (1.10 g, 6.50 mmol), triphenylphosphine (1.70 g, 6.50 mmol), and DEAD (6.50 mmol) were converted to product by the procedure of Example 11 to give 615 mg of the title compound. Yield: 35%. MS(FD) 541(M+). IR (CHCl3) ν max 3009, 2940, 1645, 1597, 1476, 1254, 1166.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Li]CCCC.[C:17]([CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[OH:24][C:17]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1)[CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)(c2ccccc2)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 1-iodo-4-(trifluoromethyl)benzene (0.92 g, 3.4 mmol) in dry THF at −78° C. was added n-BuLi (3 mL, 1.6 M in hexane) dropwise and the mixture was stirred at the same temperature for 30 min. To this was added a solution of tert-butyl 4-benzoylpiperidine-1-carboxylate (1.0 g, 3.4 mmol) in minimum amount of dry THF dropwise and the resulting reaction mixture was allowed to warm up to rt over 2 h. The reaction was quenched with ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate and concentrated to afford tert-butyl 4-(hydroxy(phenyl)(4-(trifluoromethyl)phenyl)methyl)-piperidine-1-carboxylate (1.0 g, 66% yield) as a pale yellow solid which was used in the next step without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][CH2:6][CH:5]=[CH:4]1.[Cl:8][C:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12](Cl)=[CH:11][C:10]=1[Cl:19].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C>[Cl:8][C:9]1[C:10]([Cl:19])=[CH:11][C:12]([NH:2][CH:3]2[CH2:7][CH2:6][CH:5]=[CH:4]2)=[C:13]([N+:15]([O-:17])=[O:16])[CH:14]=1
Reactant: NC1C=CCC1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NC1C=CCC1

Procedure:
3-Aminocyclopentene hydrochloride (R. Vince and S. Daluge, J. Med. Chem. 1974, 17,578) (5.10 g, 42.8 mmol), 1,2,4-trichloro-5-nitrobenzene (Aldrich, 10.0 g, 42.8 mmol), and potassium carbonate (98%, Aldrich, 15.00 g, 107 mmol) were refluxed in t-butyl alcohol (100 mL) under nitrogen for 24 hours. Volatiles were evaporated in vacuo and the residue chromatographed on silica gel. Title compound was eluted with 20-30% chloroform-hexanes as an orange powder (5.14 g, 44%), m.p. 85°-86° C.; 1H-NMR(DMSO-d6) δ: 8.27 (s, 1, aromatic CH), 7.88 (d, J=7.3 Hz, 1, NH), 7.48 (s, 1, aromatic CH), 6.2-6.0 (m, 1, =CH), 6.0-5.8 (m, 1, =CH), 5.0- 4.7 (m, 1, NCH), 2.6-2.2 (m overlapping solvent, 3 CH), 1.8-1.5 (m, 1, 1/2CH2); mass spectrum(CI): 273 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:10])[CH:3]=1.[CH3:11][CH:12]1[CH2:17][C:16](=[O:18])[O:15][C:14](=[O:19])[CH2:13]1>C1COCC1>[Cl:10][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:18])[CH2:17][CH:12]([CH3:11])[CH2:13][C:14]([OH:19])=[O:15])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: N#Cc1ccc(N)cc1Cl
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)c(Cl)c1
Yield: 124.1 %

Procedure:
A solution of 4-amino-2-chlorobenzonitrile (500 mg, 3.28 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (420 mg, 3.28 mmol) in THF (15 mL) was stirred at 90° C. for 14 hr. The reaction solution was concentrated to give 5-(3-chloro-4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (1143 mg, 4.07 mmol, 124%) as a crude product.
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[N:14][N:15]=[C:11]3[N:10]3[N:16]=[CH:17][N:18]=[C:9]3[C:8]=2[CH2:19][CH2:20][OH:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:22]12([C:32](Cl)=[O:33])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2>N1C=CC=CC=1.C(Cl)Cl>[C:22]12([C:32]([O:21][CH2:20][CH2:19][C:8]3[C:9]4[N:10]([N:16]=[CH:17][N:18]=4)[C:11]4[N:12]([N:13]=[N:14][N:15]=4)[C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:33])[CH2:29][CH:28]3[CH2:27][CH:26]([CH2:25][CH:24]([CH2:30]3)[CH2:23]1)[CH2:31]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCc1c(-c2ccccc2)n2nnnc2n2ncnc12)C12CC3CC(CC(C3)C1)C2
Reaction time: 1 h

Procedure:
To a solution containing 1.4 g of 5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine-6-ethanol (0.005 mole) dissolved in 12 ml of pyridine is added 1.0 g of 1-adamantanecarbonyl chloride (0.005 mole). The reaction mixture is stirred for one hour and then allowed to stand overnight at room temperature. The reaction mixture is evaporated to dryness yielding a residue. The residue is taken up in methylene chloride, extracted with water, dried over sodium sulfate and evaporated to dryness yielding a crude product. The crude product is chromatographed on silica gel to yield 2-(5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidin-6-yl)ethyl tricyclo[3.3.1.13,7 ]decane-1-carboxylate having the structural formula ##STR25## and the azido tautomer thereof as a white solid having a melting point of 129°-130° C. and the following elemental analysis:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].Cl.[N+:19]([C:22]1[C:27]2[N:28]=[C:29]([N:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[S:30][C:26]=2[CH:25]=[CH:24][CH:23]=1)([O-:21])=[O:20]>O1CCCC1>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:34]1[CH2:35][CH2:36][N:31]([C:29]2[S:30][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[C:27]=3[N:28]=2)[CH2:32][CH2:33]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: O=[N+]([O-])c1cccc2sc(N3CCNCC3)nc12
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3c([N+](=O)[O-])cccc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 4-Nitro-2-piperazin-1-yl-benzothiazole hydrochloride in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C2C=CC(C([O:23][C@@H:24]3[CH2:32][C@@H:27]4[O:28][C:29](=[O:31])[CH2:30][C@@H:26]4[C@H:25]3[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]3[CH2:50][CH2:49][CH2:48][CH2:47][O:46]3)[CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=O)=CC=2)C=CC=CC=1.CO>C1(C)C=CC=CC=1>[OH:23][C@@H:24]1[CH2:32][C@H:27]([OH:28])[C@H:26]([CH2:30][CH2:29][OH:31])[C@H:25]1[CH2:33][CH2:34][C@@H:35]([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=C1C[C@@H]2[C@@H](CC[C@H](CCc3ccccc3)OC3CCCCO3)[C@H](OC(=O)c3ccc(-c4ccccc4)cc3)C[C@@H]2O1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CO
Product: OCC[C@@H]1[C@@H](CC[C@H](CCc2ccccc2)OC2CCCCO2)[C@H](O)C[C@@H]1O
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A 1.5 M solution of diisobutylaluminum hydride in toluene (12.6 mL, 18.9 mmol) was added dropwise to a stirred solution of a compound [9a] (2.0 g, 3.5 mmol) in toluene (60 mL) at room temperature. The mixture was stirred for 3 hour at the same temperature. Methanol (50 mL) was added dropwise to the stirred mixture at −5-+5° C. and the cooling bath was removed. The mixture was stirred for 1 hours at room temperature, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate 1:5 v/v) to obtain 1.0 g (73% yield) of the compound [12a]. 1H and 13C NMR are in agreement with the structure.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([Br:12])=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1B(O)O)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>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.C(COC)OC>[Br:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:13]=[O:14])=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)c2ccccc12
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1ccc(Br)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
A flask was charged with 230 g of 1,4-dibromonaphthalene, 121 g of 2-formylphenylboronic acid, and 18.5 g of tetrakis(triphenylphosphine)palladium(0) in an argon atmosphere. After the addition of 2.4 L of dimethoxyethane (DME) and 1.2 L of a 2 M sodium carbonate aqueous solution, the mixture was heat refluxed with stirring for 8 hours. The mixture was then cooled to room temperature. After removing the aqueous phase, the organic phase was washed with water and a saturated sodium chloride solution, and dried over magnesium sulfate. After removing magnesium sulfate by filtration, the organic phase was concentrated. The residue was purified by silica gel column chromatography to obtain 170 g of the target 1-bromo-4-(2-formylphenyl)naphthalene (yield: 67%).
Reaction SMILES: [N:1]1([S:10]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)(=[O:12])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH2:22][C:23]1[CH:24]=[C:25]([CH:29]([OH:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1>>[OH:31][CH:29]([C:25]1[CH:24]=[C:23]([NH:22][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([S:10]([N:1]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[CH2:3][CH2:2]3)(=[O:12])=[O:11])[CH:14]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:30]
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCc3ccccc32)c1
Reactant: CC(O)c1cccc(N)c1
Product: CC(O)c1cccc(NC(=O)c2cccc(S(=O)(=O)N3CCc4ccccc43)c2)c1

Procedure:
3-(indolin-1-ylsulfonyl)benzoic acid (3) (200 mg, 0.66 mmol) and 1-(3-aminophenyl)ethanol (75 mg, 0.55 mmol) using method C. The residue was purified using flash chromatography eluting with 0-50% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(3-(1-hydroxyethyl)phenyl)-3-(indolin-1-ylsulfonyl)benzamide as an off-white solid. Yield: 93 mg (40%). 1H-NMR: 10.46 (s, 1H), 8.37 (s, 1H), 8.25 (d, J=8.0 Hz, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.74-7.69 (m, 2H), 7.64 (d, J=8.5 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.29 (t, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 6.99 (dt, J=7.5, 7.5, 1.0 Hz, 1H), 5.19 (d, J=4.0 Hz, 1H), 4.75-4.68 (m, 1H), 3.98 (t, J=8.5 Hz, 2H), 2.93 (t, J=8.5 Hz, 2H), 1.32 (d, J=6.0 Hz, 3H).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[N:19]1([CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[NH2:34])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([NH:34][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH2:26][CH2:25][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[O:17])[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: Nc1ccccc1OCCN1CCCCC1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1ccccc1OCCN1CCCCC1
Yield: 60.3 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 303 mg of 2-(2-piperidin-1-ylethoxy)phenylamine and 300 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of dimethylformamide. 255 mg of 2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]-N-{2-[2-(piperidin-1-yl)ethoxy]phenyl}acetamide are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([OH:6])[CH:2]([OH:5])[CH2:3][CH3:4].CN(C)C=O.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].N1C=CN=C1>ClCCl>[Si:12]([O:6][CH2:1][CH:2]([OH:5])[CH2:3][CH3:4])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: CCC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(O)CO[Si](C)(C)C(C)(C)C
Reaction time: 10 h
Yield: 44.1 %

Procedure:
A 50 mL round bottom flask was charged with (±)-1,2-butanediol (1 g, 11.09 mmol) and to it was added dimethylformamide (8 mL) followed by tert-butyldimethylsilyl chloride (2.5 g, 16.64 mmol) and imidazole (1.88 g, 27.7 mmol). The reaction mixture was stirred for 10 hours after which it was diluted with dichloromethane and poured into a separatory finnel and washed with water (80 mL) and brine and dried over magnesium sulfate. After filtration and concentration the crude oil was purified by silica gel flash chromatography (hexanes:ethylacetate) to obtain 1 gm of pure desired product in 45% yield. 1H (CDCl3) δ (ppm): 3.6 (m, 1H), 3.5 (m, 1H), 3.4 (m, 1H), 2.4 (s, 1H), 1.44 (m, 2H), 0.99 (t, 3H), 0.9 (s, 9H), 0.06 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:37])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[C:19]([C:20](=[O:36])[C:21]4[C:26]([F:27])=[CH:25][CH:24]=[C:23]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[C:22]=4[F:35])=[CH:18][NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[F:35][C:22]1[C:23]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:24][CH:25]=[C:26]([F:27])[C:21]=1[C:20]([C:19]1[C:12]2[C:11]([NH:10][C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:37])=[O:2])=[CH:9][CH:8]=3)=[N:16][CH:15]=[N:14][C:13]=2[NH:17][CH:18]=1)=[O:36]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(Nc4ccc(C(=O)OC)cc4)c23)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(Nc4ccc(C(=O)O)cc4)c23)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
4-{5-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino}-benzoic acid methyl ester (P-1162, 26 mg, 0.05 mmol) is combined with 1 mL of methanol is added, 0.5 mL of tetrahydrofuran, and 0.5 mL of 2 M sodium hydroxide. The reaction is stirred at room temperature for 48 hours, then neutralized with 1 M hydrochloric acid and the volatile solvents are removed under vacuum. The remaining aqueous suspension is filtered to collect the solids, which are dried under vacuum to provide the desired compound (P-1163, 25 mg). MS (ESI) [M+H+]+=516.0.