Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.O[C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][CH:6]([O:5][C:18]2[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=2)[CH2:7][CH2:8]1)=[O:13])[CH3:16]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Oc2ccc(C=O)cc2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 63.4 %

Procedure:
To a mixture of 1-(ethoxycarbonyl)piperidin-4-yl methanesulfonate (10 g) and 4-hydroxy benzaldehyde (5.8 g) in dry DMF (75 ml), K2CO3 (11 g) was added and the mixture was stirred at 80° C. for 12 h. At the end of this time, the reaction mixture was cooled, added water and extracted with EtOAc. The EtOAc extract was washed with 5% aqueous Na2CO3 solution followed by brine and dried over anhydrous sodium sulphate. The solvent was then removed by distillation under reduced pressure to give 7 g (63.6%) of the title compound as a semi solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9].Br[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[O:19]>CN(C=O)C>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18](=[O:19])[CH2:17][NH:9][NH:8][C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CNNC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (3 equivalents) was added to a solution of tert-butyl carbazate (500 mg, 3.8 mmol) in DMF at 0° C. After 10 minutes, 2-bromo-1-(4-methoxyphenyl)ethanone (1 equivalent) was added and the reaction stirred at 0° C. for 1 hour. After this time, the reaction was worked-up to give crude tert-butyl 2-[2-(4-methoxyphenyl)-2-oxoethyl]hydrazinecarboxylate. The material was carried through without purification. ESI-MI m/z [M+Na]+ 303.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](=[S:13])[NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].Br[CH2:15][C:16](=O)[CH3:17]>C(O)C>[CH3:17][C:16]1[N:12]=[C:11]([CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[S:13][CH:15]=1
Reactant: NC(=S)Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)CBr
Solvent: CCO
Product: Cc1csc(Cc2ccc([N+](=O)[O-])cc2)n1

Procedure:
A mixture of 2-(4-nitrophenyl)ethanethioamide (0.50 g), 1-bromo-2-propanone (0.43 g) and ethanol (20 mL) was heated under reflux for 1 hr. The reaction mixture was concentrated, and saturated aqueous sodium hydrogen carbonate was added to the residue. The mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography, and 4-methyl-2-(4-nitrobenzyl)-1,3-thiazole was obtained as pale-yellow crystals (0.37 g, yield 63%) from a fraction eluted with hexane-ethyl acetate (2:1-1:1, v/v). Recrystallization thereof from ethyl acetate-hexane gave colorless prism crystals. melting point: 81-82° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C([O-])(O)=O.[Na+].[C:19](OC(=O)C)(=[O:21])[CH3:20]>O>[C:19]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)(=[O:21])[CH3:20]
Reactant: Oc1cccc(Br)c1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Oc1cccc(Br)c1
Reaction time: 2 h
Yield: 99 %

Procedure:
To a stirred solution of 3-bromophenol (25 g, 145 mmol) in acetic anhydride (14 ml) was added a few drop of sulfuric acid, and the mixture was stirred for 2 hours. The mixture was poured into a solution of NaHCO3 (1.3 g, 15.5 mmol) in water (160 ml). The whole was extracted with diethylether. The organic layer was washed with saturated NaHCO3 aqueous solution, brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without purification. (31 g, 99% yield).
Reaction SMILES: Cl[CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][CH3:7].[CH3:8][C:9]([CH3:14])([CH3:13])[C:10](=[O:12])[CH3:11]>>[CH3:8][C:9]([CH3:14])([C:10](=[O:12])[CH2:11][CH2:2][CH:3]=[CH:4][CH:5]=[CH:6][CH3:7])[CH3:13]
Reactant: CC(=O)C(C)(C)C
Reactant: CC=CC=CCCl
Product: CC=CC=CCCC(=O)C(C)(C)C
Yield: 100 %

Procedure:
According to the procedure described in Example 2, from 19.4 g of 1-chloro-2,4-hexadiene and 17.4 g of 3,3-dimethyl-butan-2-one there are obtained 30 g of crude 2,2-dimethyl-6,8-decadien-3-one which are subjected to a fractional distillation.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(N(CC)CC)C.[N+:21]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([N+:33]([O-:35])=[O:34])[CH:32]=1)[C:27](Cl)=[O:28])([O-:23])=[O:22]>C1C=CC=CC=1>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH:6][C:27](=[O:28])[C:26]1[CH:25]=[C:24]([N+:21]([O-:23])=[O:22])[CH:32]=[C:31]([N+:33]([O-:35])=[O:34])[CH:30]=1)([O-:3])=[O:2]
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Yield: 8.1 %

Procedure:
2,4-dinitroaniline (18.05 g), triethylamine (12.97 g) and benzene (750 ml) were placed in a reaction vessel and stirred under the nitrogen atmosphere. To the reaction mixture, 3,5-dinitrobenzoyl chloride (25.00 g) was added and refluxed under heating for 6 hours. The reaction mixture was filtered in hot state and the filtrate was cooled to deposit crystals of 2',3,4',5-tetranitrobenzanilide which was collected by filtration. The product of 2',3,4',5-tetranitrobenzanilide (3.00 g) thus obtained, platinum/carbon (5%) (0.18 g) and dioxane (85 ml) were placed in a pressurized vessel and allowed to react under the hydrogen pressure of 1 to 3 kg/cm2 at 80° C. for 10 hours. After cooling, the catalyst was removed by filtration and dioxane was distilled off under the reduced pressure to obtain powder of 2',3,4',5-tetraaminobenzanilide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].C(O)(=O)C1C=CC=CC=1.[Cl:22][S:23](O)(=[O:25])=[O:24]>>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([Br:12])[C:9]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(Br)ccc1C(=O)O
Reactant: O=S(=O)(O)Cl
Agent: O=C(O)c1ccccc1
Product: COc1cc(Br)c(S(=O)(=O)Cl)cc1C(=O)O
Temperature: 80 °C

Procedure:
300 ml of chlorosulphonic acid of density 1.766 (4.55 mole) is placed in a 1 liter flask fitted with an agitator, a thermometer and a condenser, and 69.3 g of 2-methoxy-4-bromobenzoic acid (0.30 mole) is added in stages. The reaction is slightly exothermic and the temperature reaches 40° C. by the time all the benzoic acid has been added. The reaction medium is heated to 80° C. then returned to room temperature. The solution, which is brown, is poured slowly over 2 kg of crushed ice.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([C:10](=O)[CH:11]=O)[CH:7]=[CH:8][CH:9]=1.I.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]([NH:27][NH2:28])=[NH:26]>>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[C:25]1[N:27]=[N:28][CH:11]=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:15])([F:14])[F:1])[CH:5]=2)[N:26]=1
Reactant: O=CC(=O)c1cccc(OC(F)(F)F)c1
Reactant: N=C(NN)c1ccc(F)cc1F
Agent: I
Product: Fc1ccc(-c2nncc(-c3cccc(OC(F)(F)F)c3)n2)c(F)c1

Procedure:
(3-Trifluoromethoxyphenyl)oxoacetaldehyde was reacted with 2,4-difluorobenzenecarboximidic hydrazide hydriodide salt using the method described in Example 1 to give 3-(2,4-difluorophenyl)-5-(3-trifluoromethoxyphenyl)-[1,2,4]triazine as a yellow solid (655 mg): δH (400 MHz, CDCl3) 7.01-7.12 (2H, m), 7.47-7.51 (1H, m), 7.65 (1H, t, J 8.2 Hz), 8.15-8.18 (2H, m), 8.32-8.38 (1H, m), 9.64 (1H, s); m/z (ES+) 354.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][O:21][CH3:22].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]=O)[CH:24]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.CO>[CH3:22][O:21][CH2:20][C:7]1[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:29][C:25]2[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=2)[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=1
Reactant: COCc1nc2c(N)nc3ccccc3c2n1CCCCN
Reactant: O=Cc1cccnc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCc1nc2c(N)nc3ccccc3c2n1CCCCNCc1cccnc1
Reaction time: 0.08 h
Yield: 15.3 %

Procedure:
To a round-bottomed flask containing 1-(4-aminobutyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (10.0 g, 33.4 mmol) was added methanol (160 mL) followed by acetic acid (40 mL). The reaction was stirred for 5 minutes and pyridine 3-carboxaldehyde (5.4 g, 50.1 mmol) was added and the reaction was stirred overnight at ambient temperature. Sodium cyanoborohydride (1 M in THF, 33.4 mL, 33.4 mmol) was added to the resultant imine in portions over 10 minutes. After 45 minutes the solvent was evaporated to afford an oil. To the oil was added saturated aqueous sodium bicarbonate (200 mL) and the aqueous layer was washed with ethyl acetate (200 mL) and dichloromethane (200 mL). The product was extracted from the aqueous with 20% methanol (2×100 mL) in dichloromethane. The organic layers were combined and the solvent evaporated to afford crude 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (about 2 g). The aqueous layer was again extracted with 20% dimethylformamide (2×100 mL) in dichloromethane. The organic layers were combined and the solvent evaporated to afford crude 2-methoxymethyl-1-{4-[(pyridin-3-ylmethyl)amino]butyl}-1H-imidazo[4,5-c]quinolin-4-amine (about 2 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([O:11][CH3:12])=[CH:6][C:3]=1[CH:4]=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37]O)[CH3:33].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH2:32]([N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][CH2:37][O:10][C:8]1[C:7]([O:11][CH3:12])=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([F:1])[CH:9]=1)[CH3:33]
Reactant: COc1cc(C=O)c(F)cc1O
Reactant: CCN(CC)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)CCCOc1cc(F)c(C=O)cc1OC
Temperature: 0 °C

Procedure:
To 2-fluoro-4-hydroxy-5-methoxy-benzaldehyde (39, 1.20 g, 7.05 mmol, prepared as described in Scheme 12 of Example 15) in tetrahydrofuran (60.0 mL) were added triphenylphosphine (1.93 g, 7.35 mmol) and 3-(diethylamino)-propan-1-ol, (0.96 g, 7.30 mmol). The reaction was cooled to 0° C., followed by slow addition of diethyl azodicarboxylate (1.28 g, 7.35 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give a colorless oil (102, 0.90 g, 45.0%).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:14]#[N:15])[C:11]([NH2:13])=[NH:12].[F:16][C:17]([F:28])([F:27])[C:18](=O)[CH2:19][C:20](=O)[C:21]([CH3:24])([CH3:23])[CH3:22].[O-]CC.[Na+]>CS(C)=O.CC(=O)OCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[C:10]([C:11]1[N:13]=[C:20]([C:21]([CH3:22])([CH3:23])[CH3:24])[CH:19]=[C:18]([C:17]([F:16])([F:27])[F:28])[N:12]=1)[C:14]#[N:15]
Reactant: CC(C)(C)C(=O)CC(=O)C(F)(F)F
Reactant: N#CC(C(=N)N)=C1Nc2ccccc2S1
Agent: CC[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccccc3S2)n1
Temperature: 180 °C

Procedure:
2-[Benzothiazol-2(3H)-ylidene]-2-cyanoacetamidine (0.2 g, 0.92 mmol) was dissolved in dimethylsulfoxide (1 mL), and 1,1,1-trifluoro-5,5,-dimethyl-2,4-hexanedione (320 μL, 1.84 mmol) and sodium ethoxide (0.6 mL of 21 wt % solution in ethanol, 1.84 mmol) were added. The solution was heated to 180° C. under microwave irradiation for 20 min, dissolved in EA, and washed with 1N hydrochloric acid and then water. Removal of the solvent gave 2-[benzothiazol-2(3H)-ylidene]-2-[4-tert-butyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile as a beige solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.N1C=CC=CC=1.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N+:34]([O-:36])=[O:35])=[C:29]([CH:33]=1)[C:30](Cl)=[O:31]>ClCCl>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([N+:34]([O-:36])=[O:35])=[C:29]([CH:33]=1)[C:30]([NH:15][C:12]1[CH:11]=[N:10][C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:16])[F:17])[CH:4]=2)=[CH:14][N:13]=1)=[O:31]
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2cccc(C(F)(F)F)c2)cn1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 5-(3-(trifluoromethyl)phenyl)pyrazin-2-amine (1.3 g, 5.43 mmol, 1.00 equiv) in dichloromethane (15 mL), and pyridine (2 mL). This was followed by dropwise addition of a solution of 5-chloro-2-nitrobenzoyl chloride (1.2 g, 5.45 mmol, 1.00 equiv) in dichloromethane (5 mL) with stirring. The resulting solution was stirred for 2 h at 25° C. in an oil bath. The resulting solution was diluted with 100 mL of dichloromethane. The resulting mixture was washed with 2×50 mL of hydrogen chloride (aq), dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2 g (87%) of 5-chloro-2-nitro-N-(5-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)benzamide as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6])=[N+:31]=[N-:32]
Reactant: CN(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 2-(dimethylamino)ethyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (28a) (0.70 g, 1.5 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.22 g (3.0 mmol) of sodium azide (NaN3). After work-up, the crude material (28b) was used in the next step without further purification. MS (ESI) m/z 456.90 (M+H)+.
Reaction SMILES: CS([O:5][S:6]([CH3:9])(=[O:8])=[O:7])(=O)=O.[Si:10]([O:17][CH2:18][CH:19](O)[CH2:20][CH:21]([C:28]1[NH:29][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=2)=[C:31]2[C:36](=[O:37])[N:35]([CH3:38])[C:34](=[O:39])[N:33]([CH3:40])[C:32]=12)[C:22]1[S:23][CH:24]=[C:25]([Cl:27])[N:26]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH3:9][S:6]([O:5][CH:19]([CH2:20][CH:21]([C:22]1[S:23][CH:24]=[C:25]([Cl:27])[N:26]=1)[C:28]1[NH:29][C:30]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[CH:42]=2)=[C:31]2[C:36](=[O:37])[N:35]([CH3:38])[C:34](=[O:39])[N:33]([CH3:40])[C:32]=12)[CH2:18][O:17][Si:10]([C:13]([CH3:16])([CH3:14])[CH3:15])([CH3:11])[CH3:12])(=[O:7])=[O:8]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(O)CO[Si](C)(C)C(C)(C)C)c3nc(Cl)cs3)c2n(C)c1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3cccc(F)c3)[nH]c(C(CC(CO[Si](C)(C)C(C)(C)C)OS(C)(=O)=O)c3nc(Cl)cs3)c2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Methanesulfonic anhydride (347 mg, 1.989 mmol) was added to a solution of 7-(4-((tert-butyldimethylsilyl)oxy)-1-(4-chlorothiazol-2-yl)-3-hydroxybutyl)-5-(3-fluorophenyl)-1,3-dimethyl-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (590 mg, 0.995 mmol) and triethylamine (0.416 mL, 2.98 mmol) in DCM (30 mL). The mixture was stirred at room temperature 20 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound as a crude material which was used directly.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:5])[NH2:4].C(=O)([O-])[O-].[Na+].[Na+].[C:12](OCC)(=[O:17])[CH2:13][C:14]([CH3:16])=O.C(O)(=O)C>O>[OH:17][C:12]1[CH:13]=[C:14]([CH3:16])[N:4]=[C:3]([S:2][CH3:1])[N:5]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: CSC(=N)N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(C)cc(O)n1
Temperature: 25 °C
Reaction time: 60 h
Yield: 75.1 %

Procedure:
S-Methylisothiourea (22.26 g, 160 mmol) was added to a solution of sodium carbonate (16.9 g, 160 mmol) in water (50 mL) and stirred at room temperature until complete dissolution of the S-methylisothiourea. Ethyl acetoacetate (10.41 g, 80 mmol) was added to the mixture in one portion. After stirring for 60 hours at room temperature, the reaction was neutralized with acetic acid precipitating a white solid. The solid was collected, washed with water, and dried in vacuo to give 4-hydroxy-6-methyl-2-(methylthio)pyrimidine (9.38 g, 75%), m.p. 218°-221° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C(Cl)Cl.S(=O)(=O)(O)O.[C:25](O)([CH3:28])([CH3:27])[CH3:26]>[Cl-].[Na+].O>[C:25]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH:2]([CH3:1])[CH2:3][N:4]2[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)=[CH:12][CH:13]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(Cc1ccccc1)CN1CCCCC1
Reactant: CC(C)(C)O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(Cc1ccc(C(C)(C)C)cc1)CN1CCCCC1
Temperature: 20 °C

Procedure:
100 g of 1-(2-methyl-3-phenyl-propyl)-piperidine are added to 375 ml of methylene chloride. 255 g of 95-96% sulfuric acid are then added dropwise over a 1.5 hour period with rapid stirring while cooling with brine to an internal temperature of 10° C. The mixture is warmed to 20° C. and 42.5 g of tert.-butanol are added dropwise. The mixture is reacted at room temperature for 2 hours. The work-up is analogous to that described in Example 1. The crude product is purified by fractional distillation on a Goodloe silver column to yield pure 1-[3-(p-tert.butyl-phenyl)-2-methyl-propyl]-piperidine, b.p. 118° C./0.07 Torr.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O-:23])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[Na+].[CH2:27]([O:29][C:30]([O:32][CH2:33]I)=[O:31])[CH3:28]>>[OH:1][C@@H:2]([C@H:4]1[C:24](=[O:25])[N:6]2[C:7]([C:21]([O:23][CH2:33][O:32][C:30]([O:29][CH2:27][CH3:28])=[O:31])=[O:22])=[C:8]([S:11]/[CH:12]=[CH:13]\[C:14]3[S:18][CH:17]=[N:16][C:15]=3[CH2:19][OH:20])[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CCOC(=O)OCI
Agent: [Na+]
Product: CCOC(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Yield: 79.2 %

Procedure:
In the same manner as in Example 81, 203 mg of the title compound was prepared from 214 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethylthiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate and 146 mg of ethoxycarbonyloxymethyl iodide.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:7])=[O:6])[CH2:2]1.[C:27](O)(=O)[CH3:28].C(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CO>[CH2:27]([N:1]1[CH2:4][CH:3]([S:5]([C:8]2[CH:26]=[CH:25][C:11]3[N:12]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[C:13]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N:14][C:10]=3[CH:9]=2)(=[O:6])=[O:7])[CH2:2]1)[CH3:28]
Reactant: CC(=O)O
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(S(=O)(=O)C3CNC3)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCN1CC(S(=O)(=O)c2ccc3c(c2)nc(CC(C)(C)C)n3CCN(C)C)C1
Reaction time: 1 h

Procedure:
To a mixture of 2-(5-(azetidin-3-ylsulfonyl)-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (STEP A, 25 mg, 0.066 mmol), acetic acid (11 microL, 0.20 mmol) and acetaldehyde (75 microL, 1.3 mmol) in dichloromethane (1 mL) and methanol (0.5 mL) was added sodium triacetoxyborohydride (28 mg, 0.13 mmol) at room temperature. After 1 h, the mixture was concentrated. The residue was diluted with methanol (4 mL). The solution was filtered through SCX column and the column was washed with 1 mol/L ammonia in methanol solution (2 mL×2) to wash out the desired compound. The filtrate was concentrated in vacuo. The residue was purified by prep-LC-MS (“process A”).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH2:29]([O:31][C:32](=[O:37])[CH:33](Br)[CH2:34]Br)[CH3:30]>C1(C)C=CC=CC=1>[CH2:29]([O:31][C:32]([CH:33]1[CH2:34][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10][N:11]1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[CH3:19])=[O:37])[CH3:30]
Reactant: Cc1cc(F)ccc1NCCNCc1ccccc1
Reactant: CCOC(=O)C(Br)CBr
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CN(Cc2ccccc2)CCN1c1ccc(F)cc1C
Temperature: 135 °C

Procedure:
To N-benzyl-N′-(4-fluoro-2-methyl-phenyl)-ethane-1,2-diamine (15.1 g) in toluene (150 mL) was added N,N-diisopropylethylamine (33.8 mL) and 2,3-dibromopropionic acid ethyl ester (25.61 mL) in toluene (350 mL). The reaction mixture was heated to 135° C. for 18 h, cooled to room temperature, and the precipitated solid was removed by filtration. The solution was concentrated, and the crude material was redissolved in TBME and washed with an aqueous 2M solution of Na2CO3 and brine, dried (Na2SO4), filtered and evaporated. Chromatography (SiO2, n-heptane/ethyl acetate 97:3) gave 4-benzyl-1-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (5.5 g) as yellow oil, MS: 357.3 ([M+H]+) and 1-benzyl-4-(4-fluoro-2-methyl-phenyl)-piperazine-2-carboxylic acid ethyl ester (3.3 g) as yellow oil, MS: 357.1 ([M+H]+).
Reaction SMILES: CON(C)C(C1SC=NC=1)=O.[CH3:12][N:13]([CH3:26])[C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[CH:16][CH:15]=1.[CH3:27][N:28]1[C:32](C(C2SC=NC=2)=O)=[CH:31][N:30]=[CH:29]1>>[CH3:26][N:13]([CH3:12])[C:14]1[CH:15]=[CH:16][C:17]([C:18]([C:32]2[N:28]([CH3:27])[CH:29]=[N:30][CH:31]=2)=[O:19])=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1ccc(N(C)C)cc1
Reactant: Cn1cncc1C(=O)c1cncs1
Agent: CON(C)C(=O)c1cncs1
Product: CN(C)c1ccc(C(=O)c2cncn2C)cc1

Procedure:
The title compound was prepared by substituting N-methoxy-N-methylthiazole-5-carboxamide (Intermediate 11: step a) with 4-(dimethylamino)-N-methoxy-N-methylbenzamide then following the procedure described for the preparation of (1-methyl-1H-imidazol-5-yl)(thiazol-5-yl)methanone (Intermediate 13).