Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH2:9][CH3:10])=[N:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[CH2:23]([N:25](CC)CC)[CH3:24].C(Cl)(=O)C>C1C=CC=CC=1>[CH2:9]([N:8]1[C:7]2=[N:6][C:5]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=[C:2]2[N:25]=[C:23]1[CH3:24])[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCNc1nc(-c2ccccc2)c(-c2ccccc2)nc1Cl
Solvent: CC(=O)Cl
Solvent: c1ccccc1
Product: CCn1c(C)nc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 15 °C

Procedure:
2-Chloro-3-ethylamino-5,6-diphenylpyrazine, (3.10 g, 0.01 moles) is dissolved in benzene (50 ml) and then triethylamine (1.29 g, 0.013 moles) and acetyl chloride (1.00 g, 0.013 moles) are added. The solution is refluxed 41/2 hours, cooled to 15°C and filtered. The filtrate is diluted with ethanol (3ml), warmed briefly at 50°C and then all volatile materials evaporated. The resultant brown oil is treated with liquid ammonia (17 g) in ethanol (60 ml) in a bomb at 165°C for 12 hours. The solution is diluted with water (200 ml), cooled and the yellow precipitate filtered off. The solid is triturated with boiling 50% aqueous methanol, filtered, and the filtrate chilled. The product is collected by filtration. Yield 0.45 g (14%). It is recrystallized from benzene-heptane, m.p. 178.5°-180°C.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])=[O:5])[CH3:2].C(O)(=O)C.[ClH:21].OO>O>[Cl:21][C:13]1[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:8]([CH:12]=1)[C:9]([OH:11])=[O:10]
Reactant: Cl
Reactant: CCOC(=O)Nc1c(C)cccc1C(=O)O
Agent: OO
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)Nc1c(C)cc(Cl)cc1C(=O)O
Temperature: 37.5 °C
Reaction time: 1 h

Procedure:
A 2-L reactor equipped with overhead stirrer and thermocouple was charged with 150 g (0.672 mol) of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid (ca. 98% purity) and acetic acid (500 g). The resulting slurry was heated to 35-40° C. to give a solution, which was cooled to 30° C., and then hydrochloric acid (37%, 150 g, 1.5 mol, 2.2 eq) was added. The mixture was maintained at 30° C. while aqueous hydrogen peroxide (30%, 96 g, 0.85 mol, 1.25 eq) was added over about 1 h. The mixture was then warmed to 35° C. and held at that temperature for about 1 h. About 600 mL of water was metered in over about 30 minutes, while maintaining the temperature at 30-35° C. The mixture was cooled to 10° C., and the product was collected by filtration, and the wet cake was washed with water (3×100 mL); the third wash tested negative with KI-starch paper. The wet cake was dried to constant weight in a vacuum oven at 50° C. The crude yield was about 150 g (about 84% based on an estimated purity of 2-[(ethoxycarbonyl)amino]-3-methylbenzoic acid of 98% and estimated product purity of 95%). A portion of the crude product was first recrystallized from toluene and then recrystallized from aqueous methanol to give an analytical sample melting at 124-126° C.
Reaction SMILES: C([O:5][C:6]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:23])([F:22])[F:21])[O:11][N:10]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[OH:7][C:6]([CH2:8][C:9]1[N:13]=[C:12]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[C:20]([F:22])([F:23])[F:21])[O:11][N:10]=1)=[O:5]
Reactant: CC(C)(C)OC(=O)Cc1noc(-c2cnccc2C(F)(F)F)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)Cc1noc(-c2cnccc2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.7 %

Procedure:
12.4 g of 3-(tert-butoxycarbonylmethyl)-5-(4-trifluoromethyl-3-pyridyl)-1,2,4-oxadiazole are dissolved in 110 ml of dichloromethane and admixed with 57 ml of trifluoroacetic acid. The reaction mixture is stirred at room temperature for 1.5 hours and subsequently concentrated under reduced pressure. The residue is repeatedly taken up in dichloromethane and reconcentrated to remove any remaining trifluoroacetic acid. The mixture is finally triturated with diethyl ether, giving 8.1 g of the product as a white solid.
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[CH:4]/[CH2:5]Cl.[C:7]([NH2:18])(=[O:17])[C:8]1[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:10](N)=[O:11].[K].O>CN(C=O)C>[Cl:1][CH2:2][CH:3]=[CH:4][CH2:5][N:18]1[C:7](=[O:17])[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10]1=[O:11]
Reactant: ClC/C=C/CCl
Reactant: NC(=O)c1ccccc1C(N)=O
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC=CCCl
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
Trans-1,4-dichloro-2-butene (1.14 ml, 10.8 mmol) was dissolved in DMF (27 ml) and purged with argon. Potassium pthalamide (1.00 g, 5.40 mmol) was added to the solution and the reaction was allowed to stir at room temperature overnight. The reaction was then poured into water (75 ml), which precipitated a white solid. This solid was collected by filtration and purified using silica gel chromatography (3:1 Hex: EtOAc) to afford a 76% yield (961 mg) of a white solid.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16]O)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5].P(Cl)(Cl)Cl.[C-:24]#[N:25].[Na+].CS(C)=O>O>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][C:24]#[N:25])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [C-]#N
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(CO)cc2)CC1
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCCC[C@H]1CC[C@H](c2ccc(CC#N)cc2)CC1

Procedure:
27.9 g of 4-(trans-4-pentylcyclohexyl)benzyl chloride (obtained by chloromethylation of trans-4-pentyl-1-phenylcyclohexane or by esterification of 4-(trans-4-pentylcyclohexyl)benzoic acid, reduction of the methyl or ethyl ester obtained to give 4-(trans-4-pentylcyclohexyl)benzyl alcohol and reaction with PCl3) was added within 15 minutes at 60°, with stirring, to a mixture of 5.5 g of NaCN and 40 ml of dimethyl sulfoxide. The mixture was heated at 70° for 6 hours, cooled down, poured into water and 4-(trans-4-pentylcyclohexyl)phenylacetonitrile was obtained, m.p. 53°, c.p. -19°.
Reaction SMILES: [CH3:1][N:2]1[C:6]([OH:7])=[C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])[C:4]([CH3:17])=[N:3]1.[F:18][C:19]1[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=[C:23]([F:26])[C:24]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:18][C:19]1[CH:20]=[C:21]([N+:27]([O-:29])=[O:28])[CH:22]=[C:23]([F:26])[C:24]=1[O:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([CH3:17])[C:5]=1[C:8]1[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=1[F:16]
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Cc1nn(C)c(O)c1-c1c(F)cc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(C)c(Oc2c(F)cc([N+](=O)[O-])cc2F)c1-c1c(F)cc(F)cc1F
Temperature: 80 °C

Procedure:
1,3-Dimethyl-4-(2,4,6-trifluorophenyl)-1H-pyrazol-5-ol (i.e. the product of Step C) (0.310 g, 1.28 mmol), was combined with 3,4,5-trifluoronitrobenzene (157 μL, 1.35 mmol) and potassium carbonate powder (0.27 g, 2 mmol) in dry N,N-dimethylformamide (4 mL). This mixture was stirred and heated at 80° C. for 45 minutes and then allowed to cool. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (2×10 mL). The organic phase was washed with water and with brine, dried over MgSO4, and concentrated to leave a viscous residue. This residue was purified by column chromatography through silica gel eluted with a gradient of ethyl acetate (30% to 100%) in hexane to give the title product, a compound of the present invention, as an off-white solid (209 mg).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[Br:16][CH:17](O)[CH3:18].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br:16][CH2:17][CH2:18][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:4])=[O:5]
Reactant: CC(O)Br
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: O=S(=O)(OCCBr)C(F)(F)F
Temperature: -5 °C
Yield: 72 %

Procedure:
240 g of trifluoromethanesulfonic anhydride (0.85 mol) are added in 1.5 h, under inert atmosphere, to a solution of bromoethanol (57 mL; 0.80 mol) and 2,6-lutidine (104 mL; 0.89 mol) in CH2Cl2 cooled at −5° C. After 10 min the mixture is concentrated to one fourth the volume, then eluted through a small layer of silica gel (eluent n-hexane/EtOAc=9:1). By evaporation and drying, the desired product is obtained (147.2 g; 0.57 mol).
Reaction SMILES: [N+:1]([C:4]([N+:8]([O-:10])=[O:9])(O)[CH2:5]C)([O-:3])=[O:2].[C:11]([OH:18])(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl[CH:20](Cl)C>>[C:11]([O:18][CH2:20][C:4]([N+:8]([O-:10])=[O:9])([N+:1]([O-:3])=[O:2])[CH3:5])(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)O
Reactant: CC(Cl)Cl
Reactant: CCC(O)([N+](=O)[O-])[N+](=O)[O-]
Product: CCCCCC(=O)OCC(C)([N+](=O)[O-])[N+](=O)[O-]
Temperature: 70 °C
Yield: 93 %

Procedure:
Dinitropropanol (25.5 g, 0.17 mol), hexanoic acid (21.7 g, 0.19 mol), and 50 g of polyphosphoric acid were added to 50 mL of dichloroethane, and the resulting mixture was slowly stirred using a stirrer. The solution thus obtained was slowly heated to 70° C. and then reacted for 15 hr (overnight). After the reaction, the temperature of the reactor was lowered to room temperature, and the stirrer was powered off. When the temperature of the reactor was room temperature, the dichloroethane layer was decanted, followed by extraction with a 1 N sodium hydroxide aqueous solution and then distillation under reduced pressure, affording 2,2-dinitropropyl hexanoate (39.2 g, yield: 93%).
Reaction SMILES: [C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:23])/[CH2:8][CH2:9][C:10]1[C:15]([CH3:16])=[C:14]([O:17]C)[C:13]([CH3:19])=[C:12]([CH3:20])[C:11]=1[O:21]C)(=[O:3])[CH3:2]>C(#N)C.O.C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5]/[CH:6]=[C:7](\[CH3:23])/[CH2:8][CH2:9][C:10]1[C:11](=[O:21])[C:12]([CH3:20])=[C:13]([CH3:19])[C:14](=[O:17])[C:15]=1[CH3:16])(=[O:3])[CH3:2]
Reactant: COc1c(C)c(C)c(OC)c(CC/C(C)=C/COC(C)=O)c1C
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(=O)OC/C=C(\C)CCC1=C(C)C(=O)C(C)=C(C)C1=O
Reaction time: 0.33 h
Yield: 93.9 %

Procedure:
A solution of 3.83 g (12 mmol) of (E)-5-(2,5-dimethoxy-3,4,6-trimethylphenyl)-3-methyl-2-pentenyl acetate in acetonitrile (50 ml) was treated dropwise at 0° C. with a solution of ceric ammonium nitrate (16.4 g; 30 mmol) in water (50 ml). After completion of the addition the mixture was stirred for a further 20 minutes and diluted with water and chloroform. The organic phase was separated, washed with water, dried and concentrated to a yellow oil, yielding (E)-3-methyl-5-(2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-2-pentenyl acetate (3.27 g).
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:21])[NH:9][C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[N:36]1([CH2:42][C:43]2[CH:44]=[C:45]([CH:50]=[CH:51][CH:52]=2)[C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(N(C(C)C)C(C)C)C.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]1([NH:7][C:8](=[O:21])[NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([N:39]3[CH2:38][CH2:37][N:36]([CH2:42][C:43]4[CH:44]=[C:45]([CH:50]=[CH:51][CH:52]=4)[C:46]([O:48][CH3:49])=[O:47])[CH2:41][CH2:40]3)=[O:16])=[CH:19][CH:20]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1cccc(CN2CCNCC2)c1
Reactant: CCOC(=O)c1ccc(NC(=O)Nc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(CN2CCN(C(=O)c3ccc(NC(=O)Nc4ccccc4)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of ethyl 4-(3-phenylureido)benzoate (1.00 g, 3.90 mmol) in N,N-dimethylform-amide (20 mL) was added methyl 3-(piperazin-1-ylmethyl)benzoate bis(2,2,2-trifluoroacetate) (1.25 g, 2.70 mmol), N-ethyl-N-isopropylpropan-2-amine (0.94 mL, 5.40 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.40 g, 2.97 mmol, HOBT) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.57 g, 2,97 mmol, EDCl). The mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was taken up in ethyl acetate and washed with water (×2) and then saturated aqueous sodium chloride. The organic phase was dried on magnesium sulfate, filtered, concentrated under vacuum. Silica chromatography (10-40% ethyl acetate in n-hexanes) and recrystallisation from methanol gave the title compound (1.02 g).
Reaction SMILES: FC(F)(F)C(O)=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH2:20]CCNC)[C:13]=2[CH:25]=1.CC[N:28]([CH:32]([CH3:34])C)[CH:29]([CH3:31])C.C(OC(=O)C)(=O)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[C:14]([O:19][CH2:20][CH2:34][CH2:32][NH:28][C:29](=[O:4])[CH3:31])[C:13]=2[CH:25]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CCN(C(C)C)C(C)C
Reactant: CNCCCOc1cc(=O)oc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)NCCCOc1cc(=O)oc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.5 %

Procedure:
6-chloro-4-(3-methylamino-propoxy)-1-benzopyran-2-one trifluoroacetic acid salt (0.272 mmol, 100 mg) is suspended in 3 mL of DCM. DIEA (0.544 mmol, 95 μL) is added followed by acetic anhydride (0.816 mmol, 77.1 EL). After stirring for 1 hr at ambient temperature, the reaction mix is concentrated in vacuo and purified by reversed-phase HPLC to afford the title compound (39.0 mg, 49%). 1H NMR (DMSO-d6, 300 MHz) δ 7.95 (1H, br t), 7.79 (1H, d, J=2.5 Hz), 7.72 (1H, dd, J=2.5, 8.75 Hz), 7.46 (1H, d, J=8.75 Hz), 5.95 (1H, s), 4.23 (2H, t, J=6 Hz), 3.24 (2H, q, J=6 Hz), 1.95 (2H, m, J=6.25 Hz), 1.80 (3H, s); MS (ESI, Pos.) calcd for C14H14ClNO4 m/z [M+H]=296.1, found 296.2.
Reaction SMILES: C(OC(OCC)(O[CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])C)C.[C:15]1([OH:21])C=CC=C[CH:16]=1.[CH2:22]([OH:24])[CH3:23]>>[CH3:10][C:9]([CH3:11])([CH:8]=[CH2:7])[CH2:23][C:22]([O:21][CH2:15][CH3:16])=[O:24]
Reactant: CCOC(C)(OCC)OCC=C(C)C
Reactant: Oc1ccccc1
Reactant: CCO
Product: C=CC(C)(C)CC(=O)OCC
Yield: 72 %

Procedure:
A mixture of 2.02 g of 1,1-diethoxy-1-(3-methyl-2-buten-1-yloxy)ethane and 20 mg of phenol was heated for 12 hours at 150°-160°, during which time ethanol was evolved. Distillation of the residue gave 1.12 g (72% yield) of ethyl 3,3-dimethyl-4-pentenoate, b.p. 80°-83°/57 mm.
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].O.[CH2:7]1[CH:12]2[C:13]3[CH:25]=[CH:24][CH:23]=[CH:22][C:14]=3[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]2[CH2:10][CH2:9][NH:8]1>C(O)C>[OH:3][CH:2]([CH2:4][OH:5])[CH2:1][N:8]1[CH2:9][CH2:10][N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][C:14]3[CH:22]=[CH:23][CH:24]=[CH:25][C:13]=3[CH:12]2[CH2:7]1
Reactant: c1ccc2c(c1)Cc1ccccc1N1CCNCC21
Reactant: OCC1CO1
Solvent: CCO
Solvent: O
Product: OCC(O)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.6 %

Procedure:
A mixture of 0.41 g of glycidol and 0.9 ml of water was added, whilst ice-cooling, to a solution of 1 g of 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine dissolved in 2 ml of ethanol, and the mixture was stirred at room temperature for 5 hours; it was then concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and ethanol as the eluent, to afford 0.72 g (yield 56%) of the title compound as a colorless foam.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[C:14]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.[BH4-].[Na+]>CO.O>[C:14]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH:22][CH2:9][C:8]1[CH:11]=[CH:12][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)CCNCc1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.3 %

Procedure:
3.24 g (20 mmol) of 4-tert-butyl benzaldehyde, 3.63 g (20 mmol) of beta-alanine tert-butylester hydrochloride and 2.22 g (22 mmol) of triethyl amine were dissolved in 20 ml methanol and stirred at rt for 1 h. 1.11 g (30 mmol) of sodium borohydride were added in portions under nitrogen and the reaction mixture was stirred for 2 h at rt after complete addition. Water was added and the solvent was evaporated. The residue was extracted twice with diethyl ether. The combined organic layers were washed twice with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (silica gel, diethyl ether) to yield 4.62 g (79%) product as a colorless oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.34 (d, 2H), 7.25 (d, 2H), 3.76 (s, 2H), 2.86 (t, 2H), 2.45 (t, 2H), 1.44 (s, 9H), 1.31 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1.[NH2:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=2[N:19]=1.[C:28](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[N:10]([CH3:28])[C:11]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:12][C:6]=2[CH:5]=1)=[O:13]
Reactant: CS(=O)(=O)c1ccc2nc(N)sc2c1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1ccc(C(=O)OC)cc1N
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C
Yield: 78.9 %

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid methyl ester (1.64 g) was prepared by following General Procedure D starting from 3-amino-4-methylamino-benzoic acid methyl ester (0.9 g), 2-amino-6-methanesulfonyl-benzothiazole (1.14 g), 1,1′-thiocarbonyldiimidazole (1.07 g), and EDC (1.15 g). LC/MS: m/z 418.
Reaction SMILES: Cl[C:2]([O:4][CH2:5]Cl)=[O:3].[CH3:7][CH2:8][O:9][C:10]([C:12]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])[C:16]([C:25]([O:27][CH3:28])=[O:26])=[C:15]([CH3:29])[NH:14][C:13]=1[CH2:30][O:31][CH2:32][CH2:33][NH2:34])=[O:11].[Ca].[CH3:36][CH:37]([C:39]1[N:43]([CH2:44][CH2:45][C@@H:46]([OH:54])[CH2:47][C@@H:48]([OH:53])[CH2:49][C:50]([OH:52])=[O:51])[C:42]([C:55]2[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=2)=[C:41]([C:62]2[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=2)[C:40]=1[C:68]([NH:70][C:71]1[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=1)=[O:69])[CH3:38]>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:28][O:27][C:25]([C:16]1[CH:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:24])[C:12]([C:10]([O:9][CH2:8][CH3:7])=[O:11])=[C:13]([CH2:30][O:31][CH2:32][CH2:33][NH:34][C:2]([O:4][CH2:5][O:52][C:50](=[O:51])[CH2:49][CH:48]([OH:53])[CH2:47][CH:46]([OH:54])[CH2:45][CH2:44][N:43]2[C:39]([CH:37]([CH3:36])[CH3:38])=[C:40]([C:68](=[O:69])[NH:70][C:71]3[CH:72]=[CH:73][CH:74]=[CH:75][CH:76]=3)[C:41]([C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=3)=[C:42]2[C:55]2[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=2)=[O:3])[NH:14][C:15]=1[CH3:29])=[O:26]
Reactant: O=C(Cl)OCCl
Reactant: CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: [Ca]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1=C(COCCNC(=O)OCOC(=O)CC(O)CC(O)CCn2c(-c3ccc(F)cc3)c(-c3ccccc3)c(C(=O)Nc3ccccc3)c2C(C)C)NC(C)=C(C(=O)OC)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloromethyl chloroformate (2.85 g, 22 mmol) is added to amlodipine (10.5 g, 20 mmol) and pyridine (1.6 g) in 300 ml chloroform cooled in an ice bath. The reaction mixture is stirred at room temperature for 16 h, washed with water, dried (anhydrous sodium sulfate) and concentrated under reduced pressure. The residue is dissolved in dimethylformamide (50 ml) containing the calcium salt of atorvastatin (10.75 g, 0.018 mol) and the reaction mixture is heated at 80° C. for 20 h. The dimethylformamide is removed in vacuo and the residue is triturated with chloroform-hexane to yield the title compound the title compound of Example Two.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][C:3]=1[F:11].S(=O)(=O)(O)O.[OH2:17].[CH3:18][OH:19]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:19][CH3:18])=[O:17])=[CH:4][C:3]=1[F:11]
Reactant: O
Reactant: N#CCc1ccc(Br)c(F)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(Br)c(F)c1

Procedure:
(4-bromo-3-fluorophenyl)acetonitrile (40 g, 0.18 mol) was dissolved in 120 mL methanol, and 65 mL concentrated sulfuric acid were added. After heating at reflux overnight, the reaction mixture was cooled, and poured into 600 mL water, and the product was extracted with CH2Cl2. The combined extracts were washed with 10% sodium carbonate solution, dried, and concentrated to afford methyl (4-bromo-3-fluorophenyl)acetate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([OH:20])=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][C:18]([O:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:19][C:12]=3[O:11]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C=C2Oc3cc(O)ccc3C2=O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cccc(C=C2Oc3cc(OC(=O)c4ccccc4)ccc3C2=O)c1
Temperature: 25 °C

Procedure:
After 2-[(3-methoxyphenyl)methylene]-6-hydroxy-3(2H)-benzofuranone 0.5 g was dissolved in pyridine 5 ml, benzoyl chloride 0.282 ml was added, and the mixture was refluxed for 1.5 hours. The reaction mixture was cooled to room temperature, ethyl acetate 50 ml was added, and the mixture was washed with 2N-hydrochloric acid 50 ml once and with saturated sodium bicarbonate solution 50 ml. The ethyl acetate solution was dehydrated with anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting powder was dissolved in hexane 10 ml and ethyl acetate 5 ml, and the precipitated crystals were filtered and dried over phosphorous pentoxide at a temperature of 60° C. for four hours under reduced pressure to obtain the desired compound 221.5 mg.
Reaction SMILES: C([Li])CCC.CCCCCC.P(=O)(O)O.C([C:18]([CH2:23][CH3:24])([C:20]([OH:22])=[O:21])[F:19])C.[CH3:25][O:26][C:27]([CH2:29][CH2:30]CC=O)=[O:28]>C1COCC1>[F:19][C:18](=[CH:23][CH2:24][CH2:30][CH2:29][C:27]([O:26][CH3:25])=[O:28])[C:20]([OH:22])=[O:21]
Reactant: COC(=O)CCCC=O
Reactant: CCC(F)(CC)C(=O)O
Agent: O=[PH](O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC(=O)CCCC=C(F)C(=O)O
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
n-Butyl lithium (a hexane solution with f=1.69, 20.7 ml) was dissolved in THF (57 ml), and the solution was cooled to -78° C. To this solution, a solution of diethylcarboxyfluoromethane phosphonate (3.48 g, 16.3 mmol) in THF (25 ml) was dropwise added at -78° C. The mixture was stirred at the same temperature for 30 minutes. To this reaction solution, a solution of 4-methoxycarbonylbutanal (2.11 g, 16.3 mmol) in THF (16 ml) was dropwise added at -78° C., and the mixture was stirred at the same temperature. One hour later, the cooling bath was removed, and the mixture was stirred at room temperature for further one hour. Then, the reaction solution was cooled to 0° C., and water (40 ml) was added thereto. The mixture was vigorously stirred. The separated organic layer was extracted with a saturated sodium hydrogencarbonate aqueous solution (20 ml×2), and the extract solutions were combined with the previous aqueous layer, and the mixture was washed with ethyl ether (40 ml×2). The aqueous layer was adjusted to pH 4 by using hydrochloric acid under cooling with ice, and then sodium chloride was added to saturation. Then, the mixture was extracted with ethyl ether (40 ml×3), and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/acetone=4/1 (containing 0.1% of acetic acid)) to obtain 2-fluoro-6-methoxycarbonyl-2-hexenoic acid (2.34 g, a mixture of E- and Z-isomers, yield: 76%) as yellow oil.