Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(S(C)(=O)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 12.7 mmol) in DMF (35 mL) at 0° C. was added K2CO3 (5.3 g, 38.1 mmol). The reaction was stirred at 0° C. for 0.5 h and to this cold solution was slowly added CH3I (2.7 g, 19.1 mmol) drop wise. The reaction was stirred at r.t. overnight. After the reaction was completed, 80 mL of ice-water was added. The mixture was extracted with EA (60 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the obtained residue was purified on column chromatography (silica gel, ethyl acetate/petroleum ether=1:4) to give 2-bromo-1-methoxy-4-(methylsulfonyl)benzene (2.12 g, 63.0%) as yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][CH:35]1[CH2:37][CH2:36]1)(=[O:33])=[O:32]>>[CH:35]1([CH2:34][S:31]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=3)=[C:2]([F:1])[CH:7]=2)(=[O:32])=[O:33])[CH2:36][CH2:37]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(CC1CC1)c1ccccc1Br
Product: Nc1ncc(-c2ccc(-c3ccccc3S(=O)(=O)CC3CC3)cc2F)cn1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 1-bromo-2-((cyclopropylmethyl)sulfonyl)benzene. MS (ESI): mass calcd. for C20H18FN3O2S, 383.11; m/z found, 384.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=1.5, 2H), 8.11 (dd, J=7.9, 1.2, 1H), 7.80 (m, 1H), 7.72 (m, 1H), 7.62 (m, 1H), 7.46 (dd, J=7.6, 1.1, 1H), 7.37 (dd, J=11.8, 1.7, 1H), 7.28 (dd, J=7.9, 1.7, 1H), 6.93 (s, 2H), 2.91 (d, J=7.2, 2H), 0.78-0.69 (m, 1H), 0.45-0.37 (m, 2H), 0.13-0.05 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:28](I)[CH3:29]>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:19])[CH3:20])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: CCI
Reactant: CN(C)C=C1C(=O)N(c2cccc(O)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1

Procedure:
Title product of Example D1 (0.28 g, 1.0 mmole) in 2 ml of acetone was stirred under N2 with Na2CO3 (0.21 g, 2 mmoles) for 1 hour. Ethyl iodide (2.28 ml) and 0.5 g Na2CO3 were then added. The mixture was refluxed for 11 hours, cooled, salts removed by filtration and the filtrate stripped of solvent in vacuo. The residue was chromatographed on silica gel (15 cm×3.5 cm), eluting with 1:1 ethyl acetate:hexane. The resulting oil was crystallized from toluene/pentane to yield purified title product; 51.5 mg; 17%; m.p. 99°-102°.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([N:6]1[CH:15]([C:16]([OH:18])=O)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5].C(=O)=O.CC(C)=O.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:16]1(=[O:18])[CH:15]2[N:6]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[CH2:14]2)[C:4](=[O:5])[CH2:3][CH2:2][S:1]1
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: ClCCl
Solvent: CC(C)=O
Product: O=C1SCCC(=O)N2Cc3ccccc3CC12
Reaction time: 0.08 h

Procedure:
The compound produced in Example 2 is dissolved in about 500 milliliters methylene chloride and the solution is chilled under nitrogen to 15° C. in a dry ice-acetone mixture. 4-Dimethylaminopyridine is added and the mixture is stirred for five minutes. A slight excess of dicyclohexylcarbodiimide dissolved in methylene chloride is added with stirring. The chilling source is removed after 15 minutes and the solution is stirred overnight at room temperature. The volume of the reaction mixture is reduced on a rotary evaporator under reduced pressure to about 100 milliliters. A precipitate is removed by filtration and the filter residue is washed several times with methylene chloride. The filtrate and combined washings are washed successively with 1 N, HCl, saturated aqueous NaHCO3, water and saline and the solution is dried over MgSO4. Evaporation of the methylene chloride with a rotary evaporator under reduced pressure yields a white solid which is recrystallized from diethyl ether to yield the title compound.
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([C@@H:23]([OH:28])[CH2:24][N+:25]([O-])=O)[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H][H]>CO.[Pd]>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:23]([OH:28])[CH2:24][NH2:25])[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([C:19]([CH3:21])([CH3:20])[CH3:22])([CH3:18])[CH3:17])[Si:2]([C:5]([CH3:8])([CH3:6])[CH3:7])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)CN)cc1O[Si](C)(C)C(C)(C)C
Yield: 96 %

Procedure:
100 mg of optically active 1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol obtained in example 1 was dissolved in 10 ml of methanol, and 10 mg of 10% Pd/C was added to the solution, after which the mixture was reacted at 20° C. under the hydrogen pressure of 0.1 MPa for 20 hours, so as to obtain 89.3 mg of the intended compound (in a yield of 96%, with an optical purity of 94% e.e.).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=1.Cl[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1.O>CN(C=O)C>[Cl:3][C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1ccc(CNc2cc(Cl)nc(C)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc(Cl)nc(C)n2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 98.9 %

Procedure:
Sodium hydride (60 wt % in mineral oil) (0.340 g, 8.51 mmol) was added in one portion to a mixture of 6-chloro-N-(4-methoxybenzyl)-2-methylpyrimidin-4-amine (1.87 g, 7.09 mmol) and 1-(chloromethyl)-4-methoxybenzene (1.059 mL, 7.80 mmol) in DMF (50 mL) at 0° C. The resulting mixture was stirred at 0° C. for 5 min and then was warmed to 25° C. and stirred for 2 h. Water (200 mL) was then added, and the precipitated solid was collected by vacuum filtration, washed with water (150 mL), and dried in vacuo to furnish 6-chloro-N,N-bis(4-methoxybenzyl)-2-methylpyrimidin-4-amine (2.69 g, 7.01 mmol, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J=7.24 Hz, 4H); 6.86 (d, J=7.24 Hz, 4H); 6.26 (s, 1H); 4.65 (br. s., 4H); 3.80 (s, 6H); 2.53 (s, 3H). m/z (ESI, +ve ion) 384.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].S1C=CC=C1>C1COCC1.[Pd]>[NH2:26][C:23]1[CH:22]=[CH:21][C:20]([N:17]2[CH2:16][CH2:15][N:14]([S:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)(=[O:13])=[O:12])[CH2:19][CH2:18]2)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: C1CCOC1
Product: Nc1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)cc1
Yield: 86.7 %

Procedure:
A mixture of 1-(2-naphthalenylsulfonyl)-4-(4-nitrophenyl)-piperazine (7.5 mmol) in THF (150 ml) was hydrogenated at 50° C. with Pd/C 10% (1 g) as a catalyst in the presence of thiophene solution (0.5 ml). After uptake of H2 (3 equiv.), the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from 2-propanol. The formed precipitate was filtered off, washed with 2-propanol and dried (55° C., vacuum), yielding 2.39 g (87%) of 1-(4-aminophenyl)-4-(2-naphthalenylsulfonyl)-piperazine (interm. 7).
Reaction SMILES: Cl.[CH2:2]([N:4]([CH2:38][CH3:39])[CH2:5][CH2:6][O:7][CH:8]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[C:11](=[O:31])[C:10]=2[C:9]1([N+]([O-])=O)[N+:32]([O-])=O)[CH3:3].O.O.[Cl:42][Sn]Cl>>[ClH:42].[NH2:32][C:9]1[C:10]2[C:11](=[O:31])[C:12]3[C:17](=[C:16]([O:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:19]([O:21][CH3:22])=[CH:20][C:8]=1[O:7][CH2:6][CH2:5][N:4]([CH2:38][CH3:39])[CH2:2][CH3:3]
Reactant: Cl[Sn]Cl
Reactant: CCN(CC)CCOc1cccc2c1C1=C(C2=O)C([N+](=O)[O-])([N+](=O)[O-])C(OCCN(CC)CC)C=C1OC
Agent: Cl
Solvent: O
Product: CCN(CC)CCOc1cc(OC)c2c(c1N)C(=O)c1cccc(OCCN(CC)CC)c1-2

Procedure:
2,5-Bis-(2-diethylamino-ethoxy)-1-nitro-4-methoxy-1-nitro-fluoren-9-one hydrochloride (0.37 g, 0.70 mmol) and stannous chloride dihydrate (SnCl2.2H2O; 1.0 g, 0.7 mmol) are reacted as described in Example 9A to give the title compound which has the following structural formula: ##STR52##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:19]=1)[C:7]([C:9](=[CH:15][N:16]([CH3:18])C)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:8].N[C@H:22]1[CH2:27]C[CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1.C(=O)([O-])[O-].[K+].[K+].Cl>CN(C=O)C>[Br:1][C:2]1[CH:19]=[C:6]2[C:5](=[N:4][CH:3]=1)[N:16]([C@H:18]1[CH2:27][CH2:22][CH2:23][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:25]1)[CH:15]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]2=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn([C@H]2CCCN(C(=O)OC(C)(C)C)C2)c2ncc(Br)cc2c1=O
Temperature: 90 °C
Yield: 75.5 %

Procedure:
Ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate (Intermediate 3, 2.0 g, 5.79 mmol), (S)-tert-butyl 3-aminopiperidine-1-carboxylate (1.160 g, 5.79 mmol), and potassium carbonate (2.042 g, 7.38 mmol) were combined in DMF (10.0 mL). The reaction mixture was heated at 90° C. for 2 h. The reaction mixture was cooled to 0° C. and 1N HCl was slowly added until pH was 5. The resulting precipitate was collected by filtration, washed with water and dried overnight to yield a light yellow solid (2.10 g, 75%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:14][CH:15]([OH:30])[CH2:16][N:17]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18]1>C(O)C>[OH:30][CH:15]([CH2:14][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)[CH2:16][N:17]1[C:21](=[O:22])[C:20]([CH3:23])=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:18]1
Reactant: Cc1c(-c2ccccc2)on(CC(O)CCl)c1=O
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1c(-c2ccccc2)on(CC(O)CN2CCOCC2)c1=O
Yield: 88.7 %

Procedure:
1.55 g (17.9 mmoles) of morpholine and 2.46 g (17.9 mmoles) of anhydrous potassium carbonate powder were added to a solution of 4.00 g (14.9 mmoles) of 2-(3-chloro-2-hydroxypropyl)-4-methyl-5-phenyl-3-isoxazolone in 50 ml of ethanol, and the mixture was heated under reflux for 4 hours. At the end of this time, the reaction mixture was cooled by allowing it to stand, and then insoluble materials were removed by filtration. The filtrate was then concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel, using ethyl acetate containing 5% by volume methanol as the eluent, to give 4.21 g (yield 83.5%) of the title compound as a colorless syrupy substance.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:15]2[N:16]=[C:17]([C:19]3[C:20]([NH2:25])=[N:21][CH:22]=[CH:23][CH:24]=3)[O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1>O1CCCC1>[Br:1][C:23]1[CH:24]=[C:19]([C:17]2[O:18][C:14]3[CH:13]=[CH:12][CH:11]=[C:10]([F:9])[C:15]=3[N:16]=2)[C:20]([NH2:25])=[N:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Nc1ncccc1-c1nc2c(F)cccc2o1
Solvent: C1CCOC1
Product: Nc1ncc(Br)cc1-c1nc2c(F)cccc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
1-bromopyrrolidine-2,5-dione (427 mg) was added to a stirred solution of 3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (500 mg) dissolved in tetrahydrofuran (20 ml) over a period of 5 minutes. The resulting solution was stirred at 25° C. for 2 hours. The solvent was evaporated and the residue was washed with water and dried over P2O5 under reduced pressure to afford 5-bromo-3-(4-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (637 mg) as a solid. Mass spectrum: M+H+ 307-309, R.T. 3.95 min.
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][O:9][CH2:10][C:11]1[S:12][C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:23])[C:14]=2[N:24]=1)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[ClH:1].[ClH:1].[NH2:8][O:9][CH2:10][C:11]1[S:12][C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[C:15]([NH2:23])[C:14]=2[N:24]=1
Reactant: CC(C)(C)OC(=O)NOCc1nc2c(N)nc3ccccc3c2s1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NOCc1nc2c(N)nc3ccccc3c2s1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Hydrogen chloride (20 mL of a 4 M solution in 1,4-dioxane) was added to a stirred suspension of tert-butyl(4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxycarbamate (3.63 g, 10.5 mmol) in dichloromethane (80 mL). The reaction was stirred for 4.5 hours at room temperature and then concentrated under reduced pressure to provide 3.65 g of 2-(aminooxy)methyl[1,3]thiazolo[4,5-c]quinolin-4-amine trihydrochloride as a yellow solid.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[CH3:17][NH:18][CH3:19].C(O)C>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:18]([CH3:19])[CH3:17])=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Solvent: CCO
Product: CC(=O)N1CCc2c(sc(C)c2CCN(C)C)C1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 0.8 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 20 ml of 16.8% dimethylamine-ethanol solution in a pressure bottle was stirred at 80° C. for 5 hours and then the solvent was distilled away. To the residue was added water and extracted with ethyl acetate. The extract was washed with water, dried and concentrated in vacuo to give 0.4 g of 6-acetyl-3-(2-dimethylaminoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH:10]=[CH:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]>O1CCCC1.CO.[C].[Pd]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[S:16][C:15]([C:17]([OH:19])=[O:18])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C=Cc2ccc(C(=O)O)s2)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(C(=O)O)s2)cs1
Yield: 81.4 %

Procedure:
5-{2-[2-(Acetylamino)-1,3-thiazol-4-yl]vinyl}thiophene-2-carboxylic acid (900.0 mg, 3.058 mmol) was dissolved in a mixed solvent of tetrahydrofuran (250 ml) and methanol (100 ml). 20% Palladium carbon was added, and the mixture was hydrogenated at room temperature under 4 atm. After the completion of the reaction, the reaction mixture was filtered through celite, and the filtrate was concentrated under reduced pressure. Diethyl ether (100 ml) was added to the concentrated residue, and the precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give 5-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}thiophene-2-carboxylic acid (738.1 mg, 2.490 mmol, yield 81.4%) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[NH:12][C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16]I>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[N:12]([CH3:16])[C:11](=[O:13])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1CCC(c2ccc(Br)cc2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCC1c1ccc(Br)cc1
Reaction time: 0.33 h
Yield: 67 %

Procedure:
A solution of 5-(4-bromophenyl)-2-pyrrolidinone (preparation described in WO00/21958) (200 mg, 0.83 mmol) in dimethylformamide (5 ml) was treated with a solid suspension of sodium hydride (60% in mineral oil, 35 mg, 0.88 mmol). The reaction mix was allowed to stir for 20 minutes, then methyl iodide (124 mg, 0.88 mmol) was added and the whole mix stirred for a further 18 hours. The reaction mixture was quenched with a few drops of water then partitioned between dichloromethane (15 ml), and water (60 ml), the organic layer was removed and washed with water again (2×10 ml), then reduced to minimum volume under reduced pressure to give the title compound as a brown oil (141 mg, 67%).
Reaction SMILES: [OH2:1].C(OC(CC[N:9]1[CH2:14][CH2:13][N:12]([CH:15]=[O:16])[CH2:11][CH2:10]1)=O)C.OO>O.O.[O-][W]([O-])(=O)=O.[Na+].[Na+].C(OCC)(=O)C>[CH:15]([N:12]1[CH2:13][CH2:14][N:9]([OH:1])[CH2:10][CH2:11]1)=[O:16]
Reactant: O
Reactant: CCOC(=O)CCN1CCN(C=O)CC1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=CN1CCN(O)CC1
Reaction time: 1 h

Procedure:
Water (500 ml) was added to the above crude 4-ethoxycarbonylethyl-1-formylpiperazine (114 g) to dissolve and thereto sodium tungstate dihydrate (7.25 g) was added. Thereto 31% aqueous hydrogen peroxide solution (82 ml) was added dropwise at 30° to 35° C. and the mixture was stirred at the same temperature for 1 hour. After further stirring the mixture at room temperature for 3 hours and then with heating at 50° to 55° C. for 5 hours, ethyl acetate (300 ml) was added and the mixture was shaken. The aqueous layer was separated and water was distilled off under reduced pressure to give black-brown oil, which was then purified by silicagel column chromatography (silica gel 2 Kg, eluent: chloroform-methanol=10:1) and recrystallized from ethyl acetate to give 1-formyl-4-hydroxypiperazine (38.2 g), m.p. 118°-124° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([Br:10])[C:8]=1[OH:9].Cl.[CH3:16][O:17][NH2:18].C(O)C.C>N1C=CC=CC=1>[CH3:16][O:17][N:18]=[C:11]([C:5]1[CH:6]=[C:7]([Br:10])[C:8]([OH:9])=[C:3]([CH2:2][NH2:1])[CH:4]=1)[CH2:12][CH3:13]
Reactant: CON
Reactant: CCC(=O)c1cc(Br)c(O)c(CN)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCC(=NOC)c1cc(Br)c(O)c(CN)c1
Yield: 78.9 %

Procedure:
A solution of 9.0 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone and 9.0 g of O-methylhydroxylamine hydrochloride in 80 ml of pyridine and 40 m of ethanol is refluxed with heating for 25 minutes. Activated charcoal is added to the reaction mixture and then filtered off. The filtrate is concentrated under reduced pressure and to the residue are added 200 ml of ice-cold water and 6.0 g of sodium hydrogencarbonate and stirred. The insoluble substance is collected by filtration and washed with water and then dried to give 7.9 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone O-methyloxime as fine powdery solid, melting at 178°-178.5° C. with decomposition.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:17])[N:3]=1.[C:18](OC(=O)C)(=[O:20])C>O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:15][CH3:16])=[CH:12][CH:13]=2)[N:5]=[C:4]([NH:17][CH:18]=[O:20])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: CCOc1ccc(-c2cc(Cl)nc(N)n2)cc1
Solvent: O
Product: CCOc1ccc(-c2cc(Cl)nc(NC=O)n2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
A mixture of compound 4-chloro-6-(4-ethoxy-phenyl)-pyrimidin-2-ylamine (0.4 g, 1.6 mmol) and acetic anhydride (0.98 g, 9.61 mmol) was stirred at 80° C. for 12 hours. After completion the reaction mixture was poured into cold water (50 mL) and stirred for 10 to 15 minutes at temperature in the range of 20-40° C. The mixture was extracted with dichloromethane, washed with water, dried over anhydrous sodium sulphate, and concentrated. The residue thus obtained was purified by column chromatography using ethyl acetate-petroleum ether to afford the desired compound. Yield: 71%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].[H-].[Na+].[Na+].[I-].Br[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=1[C:32]([F:35])([F:34])[F:33]>CN(C=O)C.CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][C:23]=2[C:32]([F:34])([F:33])[F:35])[C:6]=1[CH3:14]
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Reactant: COC(=O)Cc1c(C)[nH]c2ccccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(C)n(Cc2ccc(S(C)(=O)=O)cc2C(F)(F)F)c2ccccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirring solution of (2-methyl-1H-indol-3-yl)-acetic acid methyl ester (2.0 g, 10.5 mmol) in dry DMF (25 ml) at 0° C., is added portionwise NaH (0.46 g, 11.5 mmol) as a 60% dispersion in mineral oil. The reaction mixture is stirred at 0° C. for 1.5 h then NaI (1.72 g, 11.5 mmol) and 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (3.65 g, 11.5 mmol) are added. The reaction mixture is stirred at room temperature for 16 h. The reaction mixture is poured into water (100 ml) and EtOAc (50 ml) is added. An emulsion is formed which is filtered. Brine (20 ml) is added to the filtrate and the organic phase is separated and dried (MgSO4). Evaporation in vacuo affords a brown oil. Purification by flash chromatography on silica gel using 5:1 iso-hexane:EtOAc, increasing polarity up to 3:1 iso-hexane:EtOAc, gives the desired product; [M+H]+ 440.
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]([C:21](OC)=[O:22])[C:17](OC)=[O:18])=[CH:12][CH:11]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4].C1COCC1>CO>[OH:18][CH2:17][CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:8]([O:7][C:3]([CH3:4])([CH3:6])[CH3:5])=[O:9])=[CH:11][CH:12]=1)[CH2:21][OH:22]
Reactant: COC(=O)C(C(=O)OC)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)c1ccc(C(CO)CO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of NaBH4 (1.23 g, 32.4 mmol) in MeOH (20 ml) was added a solution of dimethyl [4-(tert-butoxycarbonyl)phenyl]malonate (2.00 g, 6.49 mmol) in 3:2 MeOH:THF (18 mL). The reaction was stirred at room temperature for 2 h. It was then quenched with saturated NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated. Flash chromatography (0-10% MeOH/CH2Cl2) afforded tert-butyl 4-[2-hydroxy-1-(hydroxymethyl)ethyl]benzoate as a colorless solid. 1H NMR (CDCl3, 600 MHz) δ 7.93 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.2 Hz, 2H), 3.99 (ddd, J=10.8, 7.4, 5.1 Hz, 2H), 3.93 (dt, J=10.7, 5.2 Hz, 2H), 3.13 (tt, J=7.6, 5.5 Hz, 1H), 2.14 (t, J=5.3 Hz, 2H), 1.56 (s, 9H). MS: cal'd 275 (MH+), exp 275 (M)H+).