Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:24])[CH:3]=1.[CH2:25]1[O:27][C@@H:26]1[CH2:28][OH:29].C1COCC1.[ClH:35].O1CCOCC1>CCO>[ClH:1].[ClH:35].[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:18]3[CH2:19][CH2:20][N:21]([CH2:25][C@H:26]([OH:27])[CH2:28][OH:29])[CH2:22][CH2:23]3)[C:12]3[S:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[C:4]([F:24])[CH:3]=1
Reactant: Fc1cc(-c2nc(N3CCNCC3)c3sccc3n2)c(F)cc1Cl
Reactant: OC[C@@H]1CO1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: C1COCCO1
Product: OC[C@@H](O)CN1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3ccsc23)CC1
Reaction time: 21 h

Procedure:
A mixture of 870 mg of 2-(4-chloro-2,5-difluorophenyl)-4-piperazine-1-ylthieno[3,2-d]pyrimidine, 1.08 ml of (R)-glycidol and 15 ml of THF was stirred for 21 hours heated to reflux. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (chloroform-MeOH) to give a foam-like substance. After the obtained foam-like substance was dissolved in 10 ml of EtOH and was added to 2 ml of 4M HCl-dioxane solution, it was concentrated under reduced pressure to give a solid. This solid was recrystallized from ethanol to give 898 mg of (S)-3-{4-[2-(4-chloro-2,5-difluorophenyl)thieno[3,2-d]pyrimidine-4-yl]piperazine-1-yl}propane-1,2-diol dihydrochloride.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[CH3:23][CH:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[F:21][C:20]1[CH:19]=[CH:18][CH:17]=[C:16]([F:22])[C:15]=1[C:8]1[N:9]([CH3:14])[C:10](=[O:13])[C:11]([OH:12])=[C:6]([C:4]([NH:31][CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH3:23])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Reactant: CC(N)c1ccccc1
Product: CC(NC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O)c1ccccc1

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and α-methylbenzylamine (61 mg, 0.5 mmol). The title product was obtained as an off-white solid (24.6 mg, 64% yield). 1HNMR (500 MHz, CDCl3) δ: 12.39 (1H, s), 7.71 (1H, d, J=7.94 Hz), 7.54–7.48 (1H, m), 7.36–7.25 (5H, m), 7.06 (2H, dd, J=14.65, 8.54 Hz), 5.22 (1H, qt, J=7.02 Hz), 3.40 (3H, s), 1.58 (3H, d, J=7.02 Hz). HRMS (ESI) calcd for C20H16F2N3O3 (M−H): 384.1160; found: 384.1161.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([CH3:23])[CH:14]=3)[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[N:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[CH3:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:32]4[CH:31]=[N:30][C:29]([NH2:28])=[N:34][CH:33]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(-c4cnc(N)nc4)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-methyl-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example E.48) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.168 g, 72%). MS (ISP) 466.1 [(M+H)+]; mp 297° C.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][NH:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[C:32]([BH3-])#N.[Na+]>CO.ClC(Cl)C>[CH3:32][N:16]([CH2:15][CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)[CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)N1CCC(NCCc2ccc(Oc3ccccc3)cc2)CC1
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CN(CCc1ccc(Oc2ccccc2)cc1)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 17 h

Procedure:
A solution of 1,1-dimethylethyl 4-((2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate (about 9.4 mmol) in a mixture of methanol and dichloroethane (30 mL) was treated with a formaldehyde (37% solution in water). After the addition of sodium cyanoborohydride (710 mg, 11.26 mmol), the reaction was stirred for 17 hours. The reaction was concentrated. Purification on silica gel using a gradient of ethyl acetate in hexane gave 1,1-dimethylethyl 4-(methyl(2-(4-phenoxyphenyl)ethyl)amino)-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.Cl[Pd]Cl>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: [O-][n+]1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 80 °C
Yield: 34.5 %

Procedure:
4-Chloropyridine-N-oxide (3.0 g, 23 mmol), 4-trifluoromethylphenylboronic acid (6.57 g, 34.6 mmol), K2CO3 (4.8 g, 35 mmol) and PdCl2 (dppf) (470 mg, 0.57 mmol) were stirred in DMSO (40 mL) under vacuum for 30 min. The flask was flushed with nitrogen, and the mixture was heated to 80° C. for 10 min. Upon cooling, the mixture was diluted with methylene chloride and washed with 5% lithium chloride solution (5×), dried, concentrated, and the residue was purified by flash column chromatography (40 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 80% methylene chloride over 30 min at 40 mL/min) to provide the title compound (1.90 g, 34%) as a tan solid: ESI MS m/z 240 [M+H]+.
Reaction SMILES: [ClH:1].[C:2](=[NH:7])(OCC)[CH3:3].C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23]N>C(Cl)Cl.Cl.C(=N)(OCC)C>[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[NH:23][N:7]=[C:2]([Cl:1])[CH3:3]
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(C)=N
Reactant: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)=NNc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
A stirred solution of 13.6 grams (0.1100 mole) of ethyl acetimidate hydrochloride and 13.2 grams (0.1300 mole) of triethylamine in 100 grams of methylene chloride was cooled to about 0° C. for five minutes, and 17.7 grams (0.1000 mole) of 2,4-dichlorophenylhydrazine (1) was added. Upon completion of addition the reaction mixture stirred at 0° C. for about one hour, then it was allowed to warm to ambient temperature where it stirred for about two hours. GC analysis of the reaction mixture indicated the presence of a small amount of unreacted (1). An additional 0.6 gram of ethyl acetimidate hydrochloride was added (total 14.2 gram—0.1150 mole), and the reaction mixture was stirred for an additional one hour. After this time the reaction mixture was washed with about 20 mL of water and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a semi-solid residue. The residue was triturated with 20 mL of hexane, and the resultant solid was collected by filtration. The solid was washed with 50 mL of hexane and dried, yielding 20.4 grams (93.4% yield) of 2-(2,4-dichlorophenyl)hydrazidethaneimidic acid (A).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH2:10])(=[O:9])=[O:8])[CH:2]=1.[H-].[Na+].[C:13](=O)([O:39]C1C=CC=CC=1)[O:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27]3[CH:28]=[C:29]([Cl:36])[C:30]([C:32]([F:35])([F:34])[F:33])=[CH:31][C:26]=3[N:25]=[C:24]2[CH2:37][CH3:38])=[CH:19][CH:18]=1>CN(C=O)C.C(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([NH:10][C:13](=[O:39])[O:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C:27]4[CH:28]=[C:29]([Cl:36])[C:30]([C:32]([F:33])([F:35])[F:34])=[CH:31][C:26]=4[N:25]=[C:24]3[CH2:37][CH3:38])=[CH:21][CH:22]=2)(=[O:9])=[O:8])[CH:2]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCOC(=O)NS(=O)(=O)c2cccnc2)cc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 18.9 %

Procedure:
To a stirred solution of 3-pyridinesulfonamide (Rafik, Karaman; et al., J. Am. Chem. Soc., 1992, 114, 4889, 120 mg, 0.76 mmol) in DMF (3 mL) was added NaH (60% oil dispersion, 27 mg, 0.68 mmol) at room temperature. After 10 min., phenyl 2-[4-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl]ethylcarbamate (step 1, 313 mg, 0.64 mmol) was added, and the mixture was stirred for 9 h at 80° C. The mixture was diluted with ethyl acetate (50 mL), and washed with water and brine. The organic layer was dried (Na2SO4) and concentrated. Purification by TLC developing with dichloromethane/methanol (6:1) and TLC developing with dichloromethane/methanol (10:1) gave 67 mg (19%) of the title compound as colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:11]1[CH:16]2[CH2:17][CH2:18][CH:12]1[CH2:13][CH:14]([N:19]([C:23]1[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=1)[N:28](C1CCCCO1)[N:27]=[CH:26]3)[C:20](=[O:22])[CH3:21])[CH2:15]2)[CH2:9][CH3:10].C(=O)([O-])O.[Na+]>ClCCl>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([N:19]([CH:14]3[CH2:15][CH:16]4[N:11]([CH2:8][CH2:9][CH3:10])[CH:12]([CH2:18][CH2:17]4)[CH2:13]3)[C:20](=[O:22])[CH3:21])=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: CCCN1C2CCC1CC(N(C(C)=O)c1ccc3c(cnn3C3CCCCO3)c1)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1C2CCC1CC(N(C(C)=O)c1ccc3[nH]ncc3c1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 64643.6 %

Procedure:
Trifluoroacetic acid (0.2 ml) was added to a solution of N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)-N-(1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)-acetamide (35 mg, 0.0853 mmol) in dichloromethane (0.8 ml), and the resulting mixture was stirred at room temperature for 1.5 hours. The reaction solution was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract solution was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and then distilled under reduced pressure to remove the solvent, whereby N-(1H-indazol-5-yl)-N-(8-propyl-8-azabicyclo[3.2.1]oct-3-yl)acetamide (18 g, 64%) was obtained.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:4])=[O:3].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1ccccc1NS(C)(=O)=O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: COC(=O)Cc1ccccc1N(Cc1ccc(Cl)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(methylsulfonylamino)phenylacetate (2.00 kg) in dimethylformamide (10 l), under an atmosphere of nitrogen, is added 4-chlorobenzyl chloride (1.37 kg) all at once, followed by anhydrous potassium carbonate (1.18 kg). The mixture is heated at 75° and stirred for 4 hours, then cooled to room temperature overnight at which time it is poured into water (50 l). The resulting precipitate is dissolved in dichloromethane (4 l). The dichloromethane solution is washed with brine (500 ml), dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated in vacuo to give a solid which is air-dried overnight and vacuum-dried (0.3 mm Hg) at room temperature to yield methyl 2-[N-(4-chlorophenylmethyl)-methylsulfonylamino]phenylacetate mp 73°-75°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]([OH:10])[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH3:19]O>>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[CH:6]([OH:10])[C:7]([O:9][CH3:19])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)C(O)c1ccccc1[N+](=O)[O-]
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(O)c1ccccc1[N+](=O)[O-]

Procedure:
o-Nitromandelic acid (5 g.) and thionyl chloride (50 ml.) were mixed, heated under reflux on a steam bath for 1 hour and cooled, then the excess of thionyl chloride was removed on a rotary evaporator at room temperature. The crude o-nitromandeloyl chloride thus obtained was carefully mixed with methanol (70 ml.), and after the initial vigorous reaction had subsided, the mixture was heated under reflux on a steam bath for 1 hour, cooled, and the solvent evaporated under reduced pressure. The oil thus obtained was chromatographed on silica, and elution with diethyl ether/petroleum ether (b.p. 60°-80° C.), 6:4 by volume yielded methyl o-nitromandelate. The methyl o-nitromandelate thus obtained was reduced by the general process described under (a) above to give the required starting material;
Reaction SMILES: [C:1]1([C:7]2([OH:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:18][CH2:19][CH2:20][CH2:21][OH:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[OH:22][CH2:21][CH2:20][CH2:19][NH:18][C:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([OH:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Reactant: NCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Solvent: O
Product: OCCCNC1=Nc2ccccc2C1(O)c1ccccc1

Procedure:
3-Phenyl-3-hydroxy-3H-indol-2-one (4.5 g.) was heated under reflux with 3-aminopropanol (6.0 g.) in xylene (100 ml.) and toluene-p-sulphonic acid (150 mg) in an apparatus fitted with a water separator. After 24 hours the reaction mixture was cooled. The product crystallised and was filtered off and recrystallised from methanol to give the title compound, 3.81 g., m.p. 215°-217°C. (Found C, 72.4; H, 6.7; N. 9.9, C17H18N2O2 requires C, 72.3; H, 6.4; N, 9.9%).
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8](=[CH:10]N(C)C)[N:9]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:17].[OH-:20].[Na+]>O>[CH2:1]([C:5]1[NH:6][C:7]([Cl:17])=[C:8]([CH:10]=[O:20])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1=NC(=CN(C)C)C(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CCCCc1nc(C=O)c(Cl)[nH]1
Temperature: 100 °C
Yield: 93 %

Procedure:
A mixture of 1.00 g (5.12 mmol) of 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one and 3.20 g (20.48 mmol) of POCl3 was heated at 100° C. for 45 minutes. Then, 1.76 g of POCl3 was distilled off on the Rotavapor, and the residue was treated with 6 ml of ethyl acetate. The mixture thus obtained was added to 20 ml of water, and the water was stirred at room temperature for 5 minutes. Then, the pH was adjusted from 0.34 to 7, using 30 percent strength sodium hydroxide solution. The mixture was extracted twice, using 10 ml of ethyl acetate each time. The combined organic phases were dried (MgSO4), filtered and concentrated, and the residue was dried in a high vacuum. 0.89 g of 2-butyl-5-chloroimidazole-4-carbaldehyde was obtained; this product having a purity greater than 95 percent, according to H-NMR. This corresponds to a yield of 93 percent, based on the 2-butyl-4-dimethylaminomethylene-2-imidazolin-5-one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:22])[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([O:43]C(C)(C)C)=[O:42])[CH:36]=2)=[O:33])[N:9]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]([CH2:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:22])[C:11](=[O:30])[CH:10]([NH:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]([OH:43])=[O:42])[CH:36]=2)=[O:33])[N:9]=1
Reactant: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)OC(C)(C)C)c2)N=C(c2ccccc2F)c2cccc(C)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccccc1C(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)N=C(c2ccccc2F)c2cccc(C)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]- N′-(3-tert-butoxycarbonylphenyl)urea (170 mg) and trifluoroacetic acid (1.0 ml) in methylene chloride (2.0 ml) was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give a residue, which was washed with diisopropyl ether to afford N-[(3RS)-2,3-dihydro-5-(2-fluorophenyl)-9-methyl-1-(2-methylphenacyl)-2-oxo-1H-1,4-benzodiazepin-3-yl]-N′-(3-carboxyphenyl)urea (152.0 mg,98.0%) as a crystalline powder.
Reaction SMILES: [CH:1]([SiH:4]([CH:6]([CH3:8])[CH3:7])Cl)([CH3:3])[CH3:2].[Cl-].[NH4+].CC[CH2:13][CH2:14][CH3:15].[CH2:16]1COCC1>>[CH2:16]([SiH:4]([CH:6]([CH3:8])[CH3:7])[CH:1]([CH3:3])[CH3:2])[CH:14]([CH3:13])[CH3:15]
Reactant: CC(C)[SiH](Cl)C(C)C
Reactant: C1CCOC1
Reactant: CCCCC
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)C[SiH](C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
Diisopropylchlorosilane (16.4 mL, 96.1 mmol) was dissolved in THF (100 mL), and isobutylmagnesium bromide THF solution (1.0M, 100 mL) was added dropwise thereto under nitrogen for 30 minutes. Subsequently, cuprous bromide (286 mg, 2.00 mmol) was added to the resultant mixture, followed by stirring at 70° C. overnight. The reaction mixture was left to cool, and saturated aqueous ammonium chloride and n-pentane were added thereto. The formed organic layer was washed three times with water and once with saturated brine, followed by drying over sodium sulfate anhydrate. The solvent was removed, followed by purification through distillation under reduced pressure, whereby the Compound 40a was obtained as a colorless liquid (boiling point; 70 mmHg, 102 to 106° C. fraction, 8.26 g, 50%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=1>>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([Cl:9])=[CH:11][CH:12]=1
Reactant: BrCCCCCCBr
Reactant: OCCc1ccc(Cl)cc1
Product: Clc1ccc(CCOCCCCCCBr)cc1

Procedure:
(4.0 g), b.p. 169°/0.8 torr, from 1,6-dibromohexane (8.65 g) and 4-chlorobenzeneethanol (3.0 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[O:8])=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.ClCCl.CN(C)C=O>C(Cl)(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)(=[O:23])=[O:8])=[CH:5][N:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Nc1ncc(S(=O)c2cccnc2)s1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Nc1ncc(S(=O)(=O)c2cccnc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.5 %

Procedure:
A mixture of 2-amino-5-(3-pyridylsulfinyl)thiazole (1.6 g) and 3-chloroperbenzoic acid (1.8 g) in a mixture of chloroform (150 ml), dichloromethane (50 ml) and N,N-dimethylformamide (5 ml) was stirred at room temperature for 3 hours. The reaction mixture was extracted with diluted hydrochloric acid and washed with ethyl acetate. The aqueous layer was adjusted to pH 8.5 using sodium bicarbonate and the mixture was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1). The organic layer was washed with water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure and the residue was triturated with ethanol to give 2-amino-5-(3-pyridylsulfonyl)thiazole (0.30 g, yield: 17.5%).
Reaction SMILES: [C:1]1([C:7]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[Li+]>CN(C=O)C>[C:1]1([C:7]([C:8]2[NH:28][N:27]=[N:26][N:9]=2)([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:15][CH2:14][CH:13]2[CH2:19][CH2:18]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CC(CCN1CC2CCC1CC2)(c1ccccc1)c1cccnc1
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1ccc(C(CCN2CC3CCC2CC3)(c2cccnc2)c2nnn[nH]2)cc1

Procedure:
α-Phenyl-3-pyridylacetonitrile (U.S. Pat. No. 3,225,054) is reacted with 2-(2-chloroethyl)-2-azabicyclo[2.2.2]octane in toluene to provide 2-phenyl-2-(3-pyridyl)-4-(2-azabicyclo[2.2.2]oct-2-yl)butyronitrile. This nitrile is reacted with sodium azide in DMF containing lithium chloride to provide 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-1H-tetrazole. Reaction this tetrazole with acetic anhydride in pyridine provides 5-[1-phenyl-1-(3-pyridyl)-3-(2-azabicyclo[2.2.2]oct-2-yl)propyl]-2-methyl-1,3,4-oxadiazole, the oxalate salt melts at 171°-172° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[CH:3]1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>CN(C)P(=O)(N(C)C)N(C)C>[Si:19]([O:1][CH:2]1[CH2:6][C:5](=[O:7])[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:15]([O:17][CH3:18])=[O:16])[CH3:14])=[CH:3]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: COC(=O)C(C)CCCCSC1=CC(O)CC1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(C)CCCCSC1=CC(O[Si](C)(C)C(C)(C)C)CC1=O
Reaction time: 20 h
Yield: 57.8 %

Procedure:
726 mg of 4(RS)-hydroxy-2-(5-methoxycarbonyl-5-methylpentylthio)-2-cyclopentenone and 596 mg (3.96 mmoles) of t-butyldimethylsilyl chloride were dissolved in 10 ml of hexamethylphosphoric triamide, and the reaction was performed at 0° C. for 20 hours. After the reaction, the reaction mixture was extracted with ethyl acetate. The extract was dried and concentrated to give 2.09 g of a crude product. The crude product was chromatographed on a silica gel column using hexane/ethyl acetate (4/1) as an eluent to give 594 mg (1.54 mmoles; yield 58.3%) of 4(RS)-t-butyldimethylsilyloxy-2-(5-methoxycarbonyl-5-methyl-pentylthio)-2-cyclopentenone.
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=O.[C:13]([C:17]1[O:21][C:20]([C:22]([OH:24])=O)=[N:19][CH:18]=1)([CH3:16])([CH3:15])[CH3:14].[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@@H:30]([NH2:32])[CH3:31].C1CCN2C(=NCCC2)CC1>C1COCC1>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C@@H:30]([NH:32][C:22]([C:20]1[O:21][C:17]([C:13]([CH3:14])([CH3:15])[CH3:16])=[CH:18][N:19]=1)=[O:24])[CH3:31]
Reactant: C[C@H](N)c1cccs1
Reactant: CC(C)(C)c1cnc(C(=O)O)o1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: C[C@H](NC(=O)c1ncc(C(C)(C)C)o1)c1cccs1
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
A solution of carbonyl diimidazole (CDI) (2.42 g, 15 mmol) in THF (40 ml) is added to a stirred solution of 5-tert-butyl-oxazole-2-carboxylic acid (2.3 g, 13.6 mmol) in THF (40 ml). The mixture is stirred for 30 min, then (S)-(1-thiophen-2-yl-ethyl)-amine (2.59 g, 20.4 mmol) is added, followed 10 min later by a solution of DBU (2.24 ml, 15 mmol) in THF (20 ml). The mixture is refluxed for 16 h and the THF is then removed by distillation. The residue is dissolved in ethyl acetate and the organic solution is washed with 2N hydrochloric acid and then twice with water. The organic phase is dried over sodium sulfate and evaporated in vacuo. The residue is purified by flash column chromatography (silica gel, petroleum ether/ethyl acetate 7:3 v/v) to give (S)-5-tert-butyl-oxazole-2-carboxylic acid (1-thiophen-2-yl-ethyl)-amide (2.40 g, 63%) as an oil.