Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1.C([O-])(O)=O.[Na+].Cl[S:24]([C:27]1[CH:32]=[CH:31][C:30]([CH:33]=[CH:34][C:35]([OH:37])=[O:36])=[CH:29][CH:28]=1)(=[O:26])=[O:25].Cl>O1CCOCC1.O>[F:17][C:3]([F:2])([F:16])[C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][N:13]([S:24]([C:27]3[CH:28]=[CH:29][C:30](/[CH:33]=[CH:34]/[C:35]([OH:37])=[O:36])=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:12][CH2:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc(S(=O)(=O)N2CCN(c3cccc(C(F)(F)F)c3)CC2)cc1
Yield: 82.7 %

Procedure:
To a suspension of 1-(α,α,α-trifluoro-m-tolyl)piperazine hydrochloride (0.43 g, 1.62 mmol) in dioxane (5 mL) a solution of NaHCO3 (0.27 g, 3.24 mmol) in water (4 mL) and a solution of 3-(4-chlorosulfonyl-phenyl)-acrylic acid (8) (0.40 g, 1.62 mmol) were added and the resultant mixture was stirred at ambient temperature for 20 hours. The reaction mixture was poured into water (50 mL) and the pH of the medium was brought to ˜4 with 2 N HCl. The precipitated solid was filtered, washed with water, and dried in vacuum to give the title compound (0.59 g, 82%). 1H NMR (DMSO-d6, HMDSO), δ: 2.96-3.67 (8H, m, overlapped with a signal of water); 6.74 (1H, d, J=16.3 Hz); 7.01-7.57 (4H, m); 7.67 (1H, d, J=16.3 Hz); 7.82 (2H, d, J=8.4 Hz); 8.00 (2H, d, J=8.4 Hz); 12.71 (1H, br s).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].[N:26]([CH2:29][C:30](Cl)=[O:31])=[N+:27]=[N-:28]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:26]([CH2:29][C:30]([NH:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:8])=[O:31])=[N+:27]=[N-:28]
Reactant: [N-]=[N+]=NCC(=O)Cl
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N)C[C@H]12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(NC(=O)CN=[N+]=[N-])C[C@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (35 mg, 0.1 mmol) in anhydrous tetrahydrofuran (2 ml) is cooled to -25° C. and treated with 4-dimethylaminopyridine (15.9 mg, 0.13 mmol) and, dropwise over 5 minutes, with a solution of 2-azidoacetyl chloride (14.3 mg, 0.12 mmol) in tetrahydrofuran (0.5 ml). The resulting mixture is stirred under a nitrogen atmosphere at 0° C. for 4 hours. The mixture is diluted with ethyl acetate, washed with pH 3 phosphate buffer, water, 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on a silica gel thin layer preparative plate to afford the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][C:22]([CH3:30])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[NH2:23]>>[CH3:21][C:22]([NH:23][C:12]([C:10]1[CH:9]=[CH:8][C:7]([CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([C:24]1[N:28]=[C:27]([CH3:29])[O:26][N:25]=1)[CH3:30]
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Reactant: Cc1nc(C(C)(C)N)no1
Product: Cc1nc(C(C)(C)NC(=O)c2ccc(C3CCOCC3)c(OCC3CC3)n2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and α,α,5-trimethyl-1,2,4-oxadiazole-3-methanamine (CAN 1153831-97-0) as starting materials, MS (EI): m/e 401.1 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([NH:1][CH2:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: Cc1ccsc1CN
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)NCc1sccc1C

Procedure:
2-Aminomethyl-3-methylthiophene (H. D. Hartough, et al., J. Am. Chem. Soc., 70, 4018 [1948]) is dissolved in pyridine and treated with excess acetic anhydride overnight. The solvent is removed under reduced pressure, the residue dissolved in ethyl acetate and washed with dilute hydrochloric acid and sodium bicarbonate solution. The organic extract is dried over magnesium sulfate and evaporated to yield the desired compound.
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:16]1([C@@H:22]2[CH2:24][C@H:23]2[N:25]2[C:33](=[O:34])[CH:28]3[CH2:29][NH:30][CH2:31][CH2:32][N:27]3[C:26]2=[O:35])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([N:30]1[CH2:31][CH2:32][N:27]2[C:26](=[O:35])[N:25]([C@@H:23]3[CH2:24][C@H:22]3[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:33](=[O:34])[CH:28]2[CH2:29]1)=[O:9]
Reactant: O=C=Nc1ccccc1-c1ccccc1
Reactant: O=C1C2CNCCN2C(=O)N1[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccccc1-c1ccccc1)N1CCN2C(=O)N([C@@H]3C[C@H]3c3ccccc3)C(=O)C2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
[1,1′-Biphenyl]-2-yl-isocyanate (1.1 eq) was added to a stirred solution of A5 and DIPEA (3.0 eq) in DCM (0.09 M), and the mixture was stirred at RT for 1 h. The solvents were removed under reduced pressure and the residue was purified by column chromatography on silica gel, eluting with 10-80% EtOAc/petroleum ether to give the title compound in 76% yield. 1H NMR (400 MHz, DMSO-d6, 300K) δ 8.36 (1H, s), 7.43-7.38 (4H, m), 7.33-7.27 (7H, m), 7.20 (3H, m), 4.19 (1H, m), 3.93 (1H, m), 3.85-3.77 (2H, m), 2.86 (1H, m), 2.74 (2H, d, J=9.3 Hz), 2.67 (1H, m), 2.40-2.30 (1H, m), 1.58-1.48 (1H, m), 1.43-1.37 (1H, m). MS (ES+) C28H26N4O3 requires 466, found: 467 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]4[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]4)[O:23][C:22]3=[O:33])=[CH:16][C:15]=2[F:34])[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)=O)C>ClCCl>[F:34][C:15]1[CH:16]=[C:17]([N:21]2[CH2:25][C@H:24]([CH2:26][N:27]3[CH:31]=[C:30]([CH3:32])[N:29]=[N:28]3)[O:23][C:22]2=[O:33])[CH:18]=[C:19]([F:20])[C:14]=1[C:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=1
Reactant: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCN(Cc5ccccc5)CC4)c(F)c3)C(=O)O2)nn1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(C[C@H]2CN(c3cc(F)c(C4=CCNCC4)c(F)c3)C(=O)O2)nn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(5R)-3-[4-(1-Benzyl-1,2,3,6-tetrahydropyridin-4-yl)-3,5-difluorophenyl]-5-[(4-methyl-1,2,3-triazol-1-yl)methyl]oxazolidin-2-one (Example 39) (1.74 g, 3.74 mmol) was dissolved in dichloromethane (20 ml) and cooled to 0° C. Diisopropylethylamine (0.13 ml, 0.75 mmol) was added, followed by addition of 1-chloroethylchloroformate (0.48 ml, 4.48 mmol). It was stirred for 30 minutes, then allowed to warm to room temperature. After 16 hours, the reaction mixture was concentrated under vacuum. The intermediate chloroethylcarbamate was dissolved in methanol (20 ml) and heated to reflux. After 30 min, the reaction mixture was cooled to room temperature and concentrated under vacuum to give the title compound as the hydrochloride salt (1.5 g), which was used without further purification.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:21][O:22][C:23](=[O:36])[C@H:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH2:34])=[C:29]([F:35])[CH:28]=1)[CH3:25].COC(=O)COC1C=CC(CN)=C(F)C=1>>[CH3:21][O:22][C:23](=[O:36])[C@H:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:13]([C:12]2[C:11]([O:10][C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)=[N:19][CH:18]=[C:17]([F:20])[CH:16]=2)=[O:15])=[C:29]([F:35])[CH:28]=1)[CH3:25]
Reactant: O=C(O)c1cc(F)cnc1Oc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H](C)Oc1ccc(CN)c(F)c1
Agent: COC(=O)COc1ccc(CN)c(F)c1
Product: COC(=O)[C@@H](C)Oc1ccc(CNC(=O)c2cc(F)cnc2Oc2ccc3c(c2)OCO3)c(F)c1

Procedure:
The compound of Formula (5.0.32) was prepared in a manner analogous to that described in Preparation 20, substituting 2-(benzo[1,3]dioxol-5-yloxy)-5-fluoro-nicotinic acid and (R)-2-(4-aminomethyl-3-fluoro-phenoxy)-propionic acid methyl ester for the corresponding 2-(benzo-[[1,3]-dioxol-5-yloxy)-nicotinic acid and (4-aminomethyl-3-fluoro-phenoxy)-acetic acid methyl ester materials, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.CO.C[O-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([O:8][CH2:7][CH:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC1(C)OCC(CO)O1
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: CC1(C)OCC(COCc2ccccc2)O1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a 1000 ml round-bottom flask fitted with a thermometer, a nitrogen-introducing tube, and a stirrer were added 132.2 g (1.0 mol) of 2,2-dimethyl-1,3-dioxolane-4-methanol, 202.5 g (1.05 mol) of a 28% methanol solution of sodium methoxide, and 500 ml of toluene. With introduction of nitrogen thereinto, toluene was refluxed under reduced pressure for 1 hour to remove the methanol by evaporation. With maintaining the solution at 80° C., 126.6 g (1.0 mol) of benzyl chloride was added dropwise over a period of 2 hours using a dropping funnel, followed by another 2 hours of reaction. After completion of the reaction, the temperature was lowered to 60° C. and 10 g of KYOWAAD 600 was added, followed by 1 hour of stirring. After filtration of the reaction liquid, the solvent was removed and the residue was purified by distillation (b.p. 93-95° C./266 Pa) to obtain 4-(benzyloxymethyl)-2,2-dimethyl-1,3-dioxolane.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:18][CH:19]([F:21])[F:20])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:22]([Li])CCC.IC>C1COCC1>[C:1]1([C:7](=[N:14][C:15]([CH3:22])([CH2:18][CH:19]([F:20])[F:21])[C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CC(F)F)N=C(c1ccccc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)(CC(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
13.07 g (38.62 mmol) of rac-2-[(diphenylmethylene)amino]-4,4-difluorobutanonitrile from Example 67A were initially charged in 255 ml of abs. THF, and 15.6 ml (39.0 mmol) of n-butyllithium (2.5 N in hexane) were added at −78° C. under argon, and the mixture was stirred at −78° C. for a further 10 min. Subsequently, 22.6 g (154.46 mmol) of iodomethane were added to the reaction solution at −78° C. The reaction mixture was gradually brought to 0° C. over 3.5 h. After complete depletion of the starting material, the reaction solution was quenched with water at 0° C., ethyl acetate was added and the mixture was washed twice with saturated aqueous sodium chloride solution. The organic phase was dried over sodium sulphate, filtered and concentrated by rotary evaporation. The residue was purified by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate=15/1). 11.4 g of the target compound were obtained (91% of theory, 92% purity).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](B3OC(C)(C)C(C)(C)O3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2].Br[C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:34]3[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:36][CH:35]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:32])(=[O:3])[CH3:2]
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(CCC(=O)O)cc3)cc2[C@H](Nc2ccc(C#N)cn2)C[C@@H]1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 52 %

Procedure:
To a solution of 6-(((2S,4R)-1-acetyl-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)nicotinonitrile (for a preparation see Intermediate 5) (382 mg, 0.884 mmol) and 3-(4-bromophenyl)propanoic acid (243 mg, 1.060 mmol) in toluene (6 mL) and ethanol (6 mL) were successively added tetrakis(triphenylphosphine)palladium(0) (102 mg, 0.088 mmol) and potassium carbonate (366 mg, 2.65 mmol). The resulting mixture was stirred at 80° C. for 2 h, then partitioned between water and EtOAc. The layers were separated and the aqueous phase was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (25 g), eluting with EtOAc in cyclohexane (10-70%). The appropriate fractions were combined and concentrated under reduced pressure to give 3-(4-((2S,4R)-1-acetyl-4-((5-cyanopyridin-2-yl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)phenyl)propanoic acid (209 mg, 52%) as a white solid. LCMS (Formate, 2 min), Rt=0.91 min, MH+=455.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Br[CH2:27][CH:28]([O:31][CH3:32])[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>CC(=O)OCC>[CH3:30][O:29][CH:28]([O:31][CH3:32])[CH2:27][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[O:15][C:11]3[CH:10]=[C:9]([C:8]4[CH:3]([CH2:1][CH3:2])[CH2:4][C:5](=[O:25])[NH:6][N:7]=4)[CH:24]=[CH:23][C:12]=3[N:13]=2)=[CH:17][CH:18]=1
Reactant: COC(CBr)OC
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC(OC)OC)cc3)oc2c1

Procedure:
100 mg (298 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 38.5 μL (316 μmol) 2-bromo-1,1-dimethoxy-ethane, 125 mg (904 μmol) potassium carbonate and 3 ml DMF are stirred for 6 h at 150° C. and then at RT over the weekend. Then the mixture is diluted with EA, and extracted with 10% sodium carbonate solution and then with sat. saline solution. The solv. of the org. phase is eliminated i.V. The residue is purified on silica gel (eluant: DCM/methanol) the solv. of the corresponding fractions is eliminated i.V. and the residue is recrystallised with EA/cyclohexane.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([OH:9])[CH3:8])[S:5][CH:6]=1.C1C(=O)N([Br:17])C(=O)C1>CN(C=O)C.O>[Br:17][C:6]1[S:5][C:4]([CH:7]([OH:9])[CH3:8])=[N:3][C:2]=1[CH3:1]
Reactant: Cc1csc(C(C)O)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(C(C)O)sc1Br
Temperature: 50 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a solution of 1-(4-methylthiazol-2-yl)ethanol of preparation 95 (3.3 g, 22.9 mmol) in DMF (80 mL) was added NBS (4.47 g, 25.2 mmol), and the mixture was stirred at 50° C. for 2 hours. TLC (petroleum ether:EtOAc 3:1) indicated the reaction was completed. The mixture was diluted with H2O (100 mL) and extracted with EtOAc (80 mL×3). The combined organic extracts were washed with brine (80 mL×3), dried over sodium sulfate, and concentrated in vacuum to give the residue which was purified by a silica gel column eluting with petroleum ether:EtOAc=25:1-5:1 to give the title compound as a yellow solid (3.7 g, 74%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C=O)C>[CH2:21]([N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:9]1[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)c1cccc(NC(=O)OC(C)(C)C)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(N(Cc2ccccc2)C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-(tert-butoxycarbonylamino)benzoate (1.08 g) described in a document (Bioorg. Med. Chem. 2010, 18, 3175.) in DMF (40 mL) was added sodium hydride (258 mg). The reaction mixture was stirred at room temperature for 15 min, and benzyl bromide (613 μL) was added. The mixture was stirred for 1 hr and water was added. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[CH:3]1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(#N)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1ccnc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
To a solution of N-methylimidazole (10.0 g, 122 mmol) in acetonitrile (120 mL) was added benzoyl chloride (14.1 mL, 122 mmol) followed by triethylamine (17.0 mL, 122 mmol), while keeping the internal temperature at 5° C. The mixture was stirred 18 h at room temperature. After filtration, the filtrate was concentrated in vacuo, diluted with ethyl acetate (200 mL) and sequentially washed with sat. aq. sodium bicarbonate (150 mL), water (100 mL) and brine (100 mL). The organic layer was dried over MgSO4 and concentrated in vacuo.to afford (1-methyl-1H-imidazol-2-yl)(phenyl)methanone [21.0 g, yield 83%; HPLC/MS: m/z=187 (M+H); log P(HCOOH)=1.38].
Reaction SMILES: [CH2:1]=[C:2]1[CH2:6][CH2:5][CH2:4][O:3]1.[O:7]=[CH:8][C:9](=[CH2:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>>[CH3:10][C:9]1[CH2:11][CH2:1][C:2]2([O:3][CH2:4][CH2:5][CH2:6]2)[O:7][CH:8]=1
Reactant: C=C1CCCO1
Reactant: C=C(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1=COC2(CCCO2)CC1
Temperature: 75 °C

Procedure:
A stirred mixture of 20.0 g of 2-methylenetetrahydrofuran, 17.7 g of reagent grade methacrolein and 0.4 g of potassium carbonate was maintained at 75° C. under nigrogen atmosphere for 7 days. Distillation of the reaction mixture yielded 19.1 g of the desired product, b.p. 65°-66° C. (4 torr.).
Reaction SMILES: [O:1]=[C:2]1[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=[CH:4][NH:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Cl)=[CH:31][CH:30]=1>CN(C=O)C.O>[CH3:27][O:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([NH:8][CH:9]=[C:10]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:2]2=[O:1])=[CH:31][CH:30]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)C(=CNc1ccc[nH]c1=O)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(=CNc1cccn(Cc2ccc(OC)cc2)c1=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
Diethyl 2-((2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (7.50 g, 26.8 mmol) was dissolved in DMF (30 ml) and treated with potassium carbonate (7.40 g, 53.5 mmol) and 4-methoxybenzyl chloride (5.45 ml, 40.1 mmol). The mixture was stirred at ambient temperature overnight. The reaction was diluted with water (150 ml) and the solid that crashed out was collected by suction filtration. The solid was washed with water and dried to give diethyl 2-((1-(4-methoxybenzyl)-2-oxo-1,2-dihydropyridin-3-ylamino)methylene)malonate (9.00 g, 84.0% yield) as a light green solid. MS (M+H)+ 401.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][NH:15][CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=1.[C:31]([C:35]1[CH:36]=[C:37]([CH:40]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:42]=1)[CH2:38]Br)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]([CH2:16][CH:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:38][C:37]2[CH:36]=[C:35]([C:31]([CH3:33])([CH3:32])[CH3:34])[CH:42]=[C:41]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:40]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(OCCCNCC(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(C)c1cc(CBr)cc(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cccc(OCCCN(Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)CC(c2ccccc2)c2ccccc2)c1
Temperature: 45 °C
Reaction time: 18 h
Yield: 92.4 %

Procedure:
To a solution of {3-[3-(2,2-diphenyl-ethylamino)-propoxy]-phenyl}-acetic acid methyl ester (3) (0.40 g, 0.001 mol) in DMF (10 mL), was added 3,5-di-tert-butyl-benzyl bromide (0.30 g, 0.0011 mol) and powdered potassium carbonate (0.96 g, 0.007 mol), the reaction mixture was heated and stirred at 45° C. for 18 hours. After cooling, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, concentrated to an oil, which was purified by flash chromatography (9:1 Hexanes/EtOAc) to give the desired product as oil 0.56 g in 92% yield. 1H NMR (CDCl3) δ 7.19 (m, 10H), 7.12 (t, 2H), 7.01 (d, 2H), 6.82 (d, 1H), 6.63 (s, 1H), 6.59 (d, 1H), 4.17 (t, 1H), 3.67 (s, 3H), 3.62 (s, 2H), 3.57 (t, 2H), 3.55 (s, 2H), 3.10 (d, 2H), 2.58 (t, 2H), 1.77 (t, 2H), 1.26 (s, 18H). 13C NMR (CDCl3) δ 173.3, 160.6, 151.8, 145.1, 140.1, 136.5, 130.8, 129.8, 129.7, 129.6, 129.5, 127.6, 124.5, 122.6, 122.1, 117.0, 114.6, 67.3, 61.3, 53.4, 52.3, 51.2, 51.1, 42.7, 36.1, 32.9, 28.2.
Reaction SMILES: CC(C)=O.[Cl:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:16])[C:13](Cl)=[O:14])[CH:9]=[CH:10][CH:11]=1.[C:17]([C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[CH:25][C:26]=1[Cl:27])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:5][C:6]1[CH:7]=[C:8]([N:12]([CH3:16])[C:13](=[O:14])[O:28][C:23]2[CH:24]=[CH:25][C:26]([Cl:27])=[C:21]([C:17]([CH3:20])([CH3:18])[CH3:19])[CH:22]=2)[CH:9]=[CH:10][CH:11]=1
Reactant: CN(C(=O)Cl)c1cccc(Cl)c1
Reactant: CC(C)(C)c1cc(O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C(=O)Oc1ccc(Cl)c(C(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To 30 ml of acetone were added 2.04 g of N-(3-chlorophenyl)-N-methylcarbamoyl chloride, 1.84 g of 3-tert-butyl-4-chlorophenol and 1.6 g of anhydrous potassium carbonate, and the mixture was refluxed with heating for 48 hours. The reaction mixture was cooled down to room temperature and thereafter was poured into cold water. The product was extracted with benzene. The benzene solution was washed with water and a saturated aqueous solution of sodium chloride in this order, and was dried over anhydrous magnesium sulfate. Thereafter, benzene was distilled off. The residue was purified through a column chromatography (employing silica gel as carrier and benzen as developing solvent), and further recrystallized from hexane to give 3.2 g of 3-tert-butyl-4-chlorophenyl N-(3-chlorophenyl)-N-methylcarbamate, having melting point of 65°-67° C.