Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[CH2:9][C:10]([OH:12])=[O:11].Cl>C1COCC1.O>[N:1]1([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)CBr
Reactant: c1c[nH]cn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cn1ccnc1
Reaction time: 8 h
Yield: 31.3 %

Procedure:
Imidazole (3.7 g, 54 mmol) was added to a suspension of sodium hydride (2.6 g of a 60% dispersion in oil, 60 mmol) in 50 ml dry THF. Bromoacetic acid (3.4 g, 24 mmol) was then added and the mixture stirred overnight. Water (1 ml) was then added and the solvent removed under reduced pressure. The residue was taken up in water (50 ml, pH>10), extracted with ether and the organic layer discarded. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted again with ether. The aqueous layer was evaporated to dryness. The oily residue was dissolved in absolute ethanol (EtOH) to precipitate NaCl, and recrystallized from acetone/methanol to give 1.22 g (7.5 mmol, 30%) pure product as the hydrochloride. 1H NMR: (DMSO-d6, 200 MHz) δ 9.20 (s, H2), 7.76 (d, J=1.5 Hz), 7.69 (d, J=1.5 Hz), 5.20 (s, CH2).
Reaction SMILES: [O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2.[CH3:25][O:26][CH2:27][C:28](O)=[O:29]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[O:1]1[C@@H:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][C@@H:12]2[O:20][C:28](=[O:29])[CH2:27][O:26][CH3:25])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][O:23][CH3:24])[CH:4]=[CH:5]2
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reactant: COCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](OC(=O)COC)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Reaction time: 2 h

Procedure:
4,5α-Epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (2.0 g, 6.1 mmol) and 4-dimethylaminopyridine (0.8 g, 6.5 mmol) were dissolved in absolute CH2Cl2 (20 ml) and methoxy acetic acid (6.1 mmol) was added dropwise whilst cooling with ice and the resulting mixture was stirred for 2 hours at this temperature. The reaction mixture was poured onto water (50 ml), the organic phase was washed twice more with 30 ml of water and dried over MgSO4. The solvent was evaporated off and the residue separated by flash chromatography (CH2Cl2 /MeOH 9/1).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[C:14]([C:18]([O:20][CH3:21])=[O:19])[NH:15]2)=[CH:11][C:10]=1[N+:22]([O-])=O)C1C=CC=CC=1>[Pd].O1CCCC1>[NH2:22][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[OH:8])[NH:15][C:14]([C:18]([O:20][CH3:21])=[O:19])=[CH:13]2
Reactant: COC(=O)c1cc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2[nH]1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1cc2cc(N)c(O)cc2[nH]1
Reaction time: 5 h

Procedure:
A mixture of 0.67 g (2.0 mmol) of methyl 6-benzyloxy-5-nitro-indole-2-carboxylate, 60 ml of tetrahydrofuran and 0.1 g of 10% Pd/C catalyst is hydrogenated for 5 h. The catalyst is filtered off and the filtrate containing the title compound is used immediately in the next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([O:9][CH2:10][CH3:11])[CH:3]=1.[Li]CCCC.[B:17](OC)([O:20]C)[O:18]C>C1COCC1>[CH2:10]([O:9][C:4]1[CH:3]=[C:2]([B:17]([OH:20])[OH:18])[CH:7]=[CH:6][C:5]=1[F:8])[CH3:11]
Reactant: COB(OC)OC
Reactant: CCOc1cc(Br)ccc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOc1cc(B(O)O)ccc1F
Reaction time: 4 h
Yield: 67.9 %

Procedure:
To a solution of 9A (3.86 g, 17.6 mmol) in THF (60 mL) at −78° C. was added n-BuLi (1.6 M in hexanes, 14.3 mL, 22.8 mmol). The mixture was stirred at −78° C. for 40 min before trimethyl borate (3.63 mL, 33 mmol) was added. The reaction was left stirring from −78° C. to rt over 4 h. It was quenched with 1.0 N HCl (40 mL), extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, the crude solid product was triturated with EtOAc/hexanes (1:4). After filtration, 9B (2.2 g, 69% yield) was collected as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.42 (t, J=7.03 Hz, 3H) 4.11 (q, J=7.03 Hz, 2H) 7.03 (dd, J=11.42, 8.35 Hz, 1H) 7.18-7.29 (m, 2H) 7.35 (d, J=7.91 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.[CH3:15][CH:16]([NH2:18])[CH3:17].CCN(C(C)C)C(C)C>C(O)C>[CH:16]([NH:18][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1)([CH3:17])[CH3:15]
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Reactant: CC(C)N
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1NC(C)C
Temperature: 60 °C
Yield: 91.9 %

Procedure:
A mixture of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate (10 g, 43.0 mmol), propan-2-amine (4.21 mL, 49.4 mmol) and DIEA (9.76 mL, 55.9 mmol) in ethanol (140 mL) was heated at 60° C. overnight. After cooling to room temperature, the solvent was concentrated under reduced pressure and water was added. The aqueous phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to give ethyl 4-(isopropylamino)-2-(methylthio)pyrimidine-5-carboxylate (10.10 g, 39.5 mmol, 92% yield) as a colorless oil. MS (ESI) m/z 256.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][CH2:8][S:9][CH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=[O:15])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>ClCCl.CN(C)C=O>[Cl:24][C:14]([C:13]1[CH:12]=[C:11]([CH:19]=[CH:18][CH:17]=1)[CH2:10][S:9][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:20])=[O:15]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Temperature: 0 °C

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (3.00 g, 10.14 mmol, 1.00 equiv) in dichloromethane (50 mL). This was followed by the addition of oxalyl dichloride (4.50 g, 35.43 mmol, 3.00 equiv) dropwise with stirring at 0° C. To this was added N,N-dimethylformamide (one drop). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 3.18 g (99%) of tert-butyl 3-(3-(chlorocarbonyl)benzylthio)propanoate as red oil.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[C:5]([O:9][C:10]([NH:12][C:13]1[CH:17]=[CH:16][S:15][C:14]=1[C:18]([NH:20][NH2:21])=[O:19])=[O:11])([CH3:8])([CH3:7])[CH3:6].O>C1COCC1>[O:2]=[C:1]1[O:19][C:18]([C:14]2[S:15][CH:16]=[CH:17][C:13]=2[NH:12][C:10](=[O:11])[O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[N:20][NH:21]1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1C(=O)NN
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccsc1-c1n[nH]c(=O)o1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 ml of a 20% toluenic phosgene solution are added dropwise to a solution of 240 mg of 3-(tert-butoxycarbonylamino)thiophene-2-carboxylic hydrazide in 5 ml of THF and the mixture is stirred at RT. After one hour, the mixture is admixed with 10 ml of water and, after brief digestion, extracted with ethyl acetate. After the ethyl acetate phase has been dried over sodium sulfate, the mixture is concentrated under reduced pressure and the remaining residue is used further without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[C:11](OC(=O)C)(=[O:13])[CH3:12].OP(O)(O)=O>>[CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1[S:6][C:7]([C:11](=[O:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1cccs1
Agent: O=P(O)(O)O
Product: COC(=O)Cc1ccc(C(C)=O)s1

Procedure:
A mixture of 2-thienylacetic acid methyl ester, 1.41 g. (0.01 mol) and acetic anhydride, 4.2 g. (0.04 mol) was heated at 70°-80° C. and 0.2 g. of 85% H3PO4 was added dropwise with mechanical stirring. The reaction was somewhat exothermic but cooling was not necessary. The mixture was maintained between 70°-80° C. for 3 hrs., and then, poured onto ice-water followed by extraction with ether. Organic layer was washed with water several times, dried over anhyd. MgSO4 and evaporated. The residue was distilled at 2 mmHg and a fraction between 160° C. and 172° C. was collected. This material was gradually crystallized and could be recrystallized from the mixture of light-petroleum and benzene. m.p. 43°-44° C. Yield; 1.39 g. (76.5%)
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[C:7]1([C:13]2[S:17][C:16](B(O)O)=[CH:15][CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.I[C:22]1[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:42])[CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:34][CH3:35])=[CH:27][C:23]=1[C:24]([NH2:26])=[O:25].C(OCC)(=O)C>O1CCOCC1.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:36]1([CH:33]([CH2:34][CH3:35])[C:32]([NH:31][C:28]2[CH:29]=[CH:30][C:22]([C:16]3[S:17][C:13]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[CH:14][CH:15]=3)=[C:23]([CH:27]=2)[C:24]([NH2:26])=[O:25])=[O:42])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCC(C(=O)Nc1ccc(I)c(C(N)=O)c1)c1ccccc1
Reactant: OB(O)c1ccc(-c2ccccc2)s1
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCC(C(=O)Nc1ccc(-c2ccc(-c3ccccc3)s2)c(C(N)=O)c1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
1.5 ml of saturated aqueous sodium carbonate solution, 37 mg (0.18 mmol) of 5-phenyl-2-thiopheneboronic acid and 14 mg (0.01 mmol) of tetrakis(triphenylphosphine)palladium are added to 50 mg (0.12 mmol) of the compound of Example 5A in 3 ml of dioxane. The mixture is stirred at 80° C. overnight and, after addition of 50 ml of ethyl acetate, extracted three times with 50 ml of water. The organic phase is dried over magnesium sulfate and freed of solvent under reduced pressure. The residue is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 10:90→95:5). 18 mg (30% of theory) of product are obtained.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[C:20](F)=[CH:21][C:22]([F:45])=[C:23]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:30][CH:31]=[N:32][N:33]=2)(=[O:27])=[O:26])[CH:24]=1>CS(C)=O>[Cl:18][C:19]1[C:20]([S:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)=[CH:21][C:22]([F:45])=[C:23]([S:25]([N:28]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[O:43][CH3:44])[C:29]2[S:30][CH:31]=[N:32][N:33]=2)(=[O:26])=[O:27])[CH:24]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: FC(F)(F)c1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Sc3cccc(C(F)(F)F)c3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To 3-(trifluoromethyl)thiophenol (0.116 g, 0.649 mmol) in dimethylsulfoxide (5 mL) was added potassium carbonate (0.254 g, 1.62 mmol) followed by 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 2, 0.250 g, 0.541 mmol). The reaction mixture was stirred at ambient temperature overnight. The mixture was partitioned between dichloromethane and water and the layers separated by phase separation cartridge. The organic layer was concentrated in vacuo and the resulting residue purified by silica gel flash column chromatography (10%-20% ethyl acetate in heptane gradient elution) to afford the title compound as a solid (0.215 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[C@@H:21]([C:23]([OH:25])=O)[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:35]>>[Cl:1][C:2]1[C:3]([F:33])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:31][CH3:32])=[C:16]([CH2:19][N:20]([C@@H:26]([CH3:30])[CH2:27][O:28][CH3:29])[C@@H:21]([C:23]([NH2:35])=[O:25])[CH3:22])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(=O)O
Reactant: [NH4+]
Agent: [Cl-]
Product: COC[C@H](C)N(Cc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC)[C@H](C)C(N)=O

Procedure:
N-({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)-N-[(1S)-2-methoxy-1-methylethyl]-D-alanine was coupled with ammonium chloride using a procedure analogous to the equivalent step in Example 16 to give the title product; 1H NMR Spectrum: (DMSO-d6) 1.07 (d, 3H); 1.24 (d, 3H); 2.99 (m, 1H); 3.18 (m, 4H); 3.47 (m, 2H); 3.83 (d, 1H); 3.89 (d, 1H); 3.97 (s, 3H); 6.98 (m, 1H); 7.21 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.60 (m, 2H); 8.37 (s, 1H); 8.44 (s, 1H); 9.64 (s, 1H); Mass Spectrum: (M+H)+ 476.
Reaction SMILES: [OH-:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4].[CH2:7]([CH:17]1[O:22][C:20](=[O:21])[CH2:19][CH2:18]1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[OH:22][CH:17]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][C:20]([O-:21])=[O:1].[CH3:2][N+:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCCCCCCCC1CCC(=O)O1
Reactant: [OH-]
Agent: C[N+](C)(C)C
Product: CCCCCCCCCCC(O)CCC(=O)[O-]

Procedure:
Using the procedure of Example 3, 13 g of a 25% aqueous solution of tetramethylammonium hydroxide is allowed to react with 6.79 grams of gamma-n-decyl-gamma-butyrolactone. After removal of water and extraction by n-hexane, a quantitative yield of purified tetramethylammonium gamma-hydroxytetradecanoate is obtained. This white solid product has good detergent properties even in hard water.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH:17]1([CH:20]([NH2:28])[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[CH2:19][CH2:18]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:28][CH:20]([CH:17]2[CH2:18][CH2:19]2)[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[N:3]=1
Reactant: NC(c1ccc(Cl)cc1)C1CC1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: Clc1ccc(C(Nc2nc(Cl)nc3c2ncn3C2CCCC2)C2CC2)cc1

Procedure:
2-Chloro-6-[(α-cyclopropyl-4-chlorobenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, α-cyclopropyl-4-chlorobenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][SH:9])[CH2:3][CH2:2]1.[Na].C1(C)C=CC=CC=1.Br[CH2:19][C:20](=[O:42])[C@@H:21]1[C@:38]2([CH3:39])[C@H:24]([C@H:25]3[C@H:35]([C:36](=[O:40])[CH2:37]2)[C@:33]2([CH3:34])[C@H:28]([CH2:29][C@H:30]([OH:41])[CH2:31][CH2:32]2)[CH2:27][CH2:26]3)[CH2:23][CH2:22]1>C(O)(C)C>[OH:41][C@@H:30]1[CH2:31][CH2:32][C@@:33]2([CH3:34])[C@@H:28]([CH2:27][CH2:26][C@@H:25]3[C@@H:35]2[C:36](=[O:40])[CH2:37][C@@:38]2([CH3:39])[C@H:24]3[CH2:23][CH2:22][C@@H:21]2[C:20](=[O:42])[CH2:19][S:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH2:29]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Reactant: SCCN1CCOCC1
Agent: [Na]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CSCCN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Reaction time: 0.08 h

Procedure:
2-Morpholinoethanethiol (1 ml.) was added to a warm solution of sodium (0.6 g.) in a mixture of dry toluene (30 ml.) and isopropyl alcohol (25 ml.). After 5 min., 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (2.0 g.) was added and the resulting mixture was stirred at 40° for 30 min. The mixture was then partitioned between water and ether and the organic layer was washed with water, dried (Na2SO4) and evaporated. The residue was subjected to preparative t.l.c. (EtOAc) to give title compound (150 mg.) as a white foam, [α]D + 73° (c 0.9); λmax. 243 nm. (ε 570).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[C:5]#[N:6].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[C:5]([C:4]1[CH:3]=[C:2]([N:1]([S:14]([CH3:13])(=[O:16])=[O:15])[S:14]([CH3:13])(=[O:16])=[O:15])[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=1)#[N:6]
Reactant: CS(=O)(=O)Cl
Reactant: N#Cc1cc(N)cc([N+](=O)[O-])c1
Solvent: ClCCl
Product: CS(=O)(=O)N(c1cc(C#N)cc([N+](=O)[O-])c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To a suspension of 3-amino-5-nitrobenzonitrile (161 mg, 0.987 mmol) in DCM (8 mL) was added TEA (0.55 mL, 3.95 mmol), followed by methanesulfonyl chloride (0.165 mL, 2.12 mmol). The reaction mixture was stirred at room temperature for 60 min., then diluted with DCM, washed with H2O, dried over Na2SO4, and concentrated. The crude solid was triturated with DCM and isolated by filtration to give Intermediate 76A (242 mg, 76%) as a white solid. HPLC: Rt=1.198 min. (CHROMOLITH® column 4.6×50 mm eluting with 10-90% aqueous methanol over 4 min. containing 0.1% TFA, 4 mL/min, monitoring at 220 nm). 1H NMR (500 MHz, CDCl3) δ ppm 8.65 (1H, s), 8.45 (1H, s), 7.98 (1H, s), 3.48 (6H, s).
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@@H:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8].[C:35](=O)(O)[O-].[Na+]>CO>[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@H:25]([C:26]([O:28][CH3:35])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8]
Reactant: O=C([O-])O
Reactant: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1C
Agent: [Na+]
Solvent: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)Nc1ccccc1[C@H]1[C@H](C(=O)OC)c2cc(OC)c(OC)cc2C(=O)N1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Thionyl chloride (10 mL) was added slowly to a suspension of cis 10 (0.75 g, 1.8 mmol) and trans 10 (1.35 g, 3.3 mmol) in methanol (100 mL) at 0° C. The resulting mixture was stirred for 6 h at 0° C. After completion of the reaction (TLC), the reaction mixture was poured slowly into a mixture of ice (200 g) and a saturated solution of sodium bicarbonate (100 mL). The resulting mixture was extracted with chloroform (3×150 mL), and the combined extracts were dried with sodium sulfate, filtered though a thin pad of silica gel, and evaporated to dryness to obtain 11 as amorphous glassy solid (2.1 g, 96%). IR (film) 1733, 1637 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1 H), 7.52 (d, J=7.7 Hz, 1 H), 7.25 (t, J=7.0 Hz, 1 H), 7.03 (t, J=7.5 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.73 (s, 1 H), 6.54 (s, 1 H), 5.45 (s, 1 H), 3.95 (s, 3 H), 3.89 (s, 1 H), 3.82 (s, 3 H), 3.72 (s, 3 H), 3.63 (s, 1 H), 3.03 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.06, 164.17, 155.49, 152.15, 149.18, 134.39, 132.53, 129.10, 126.67, 126.53, 125.93, 125.14, 121.60, 111.86, 110.17, 59.32, 56.29, 56.20, 53.27, 53.06, 48.66, 34.57; ESIMS m/z (rel intensity) 429 (MH+, 100), 451 (56); ESIHRMS m/z MH+ calcd. for C22H24N2O7, 429,1662; found, 429.1665.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[NH:11][C:10](=[O:12])[NH:9][CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[C:7]=1[C:20]([OH:22])=O.[C:23]1([CH2:29][CH2:30][CH2:31][NH2:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:23]1([CH2:29][CH2:30][CH2:31][NH:32][C:20]([C:7]2[CH:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[NH:9][C:10](=[O:12])[NH:11][C:6]=2[CH2:5][O:4][CH2:3][CH2:2][Cl:1])=[O:22])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCCc1ccccc1
Reactant: O=C1NC(COCCCl)=C(C(=O)O)C(c2cccc(Cl)c2)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C1NC(COCCCl)=C(C(=O)NCCCc2ccccc2)C(c2cccc(Cl)c2)N1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
205 mg (0.594 mmol) of 6-(2-chloroethoxymethyl)-4-(3-chlorophenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid and 96.4 mg (0.713 mmol) of 3-phenylpropylamine were dissolved in 10 ml of dichloromethane. 171 mg (0.891 mmol) of WSC hydrochloride was added to the obtained solution under cooling with ice, and they were stirred at room temperature overnight. After the concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate and then washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (dichloromethane/methanol=50/1 to 30/1) to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C@H:11]([C:15]([OH:17])=[O:16])[CH:12]([CH3:14])[CH3:13].[BH4-].[Na+]>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:10][C@@H:11]([CH:12]([CH3:14])[CH3:13])[C:15]([OH:17])=[O:16])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)[C@H](NCc1ccc(Br)cc1)C(=O)O

Procedure:
EP 1777224 describes the condensation of p-Bromobenzaldehyde with L-valine followed by reduction with sodium borohydride to give (S)-2-(4-bromobenzyl)amino-3-methylbutyric acid. (S)-2-(4-bromobenzyl)amino-3-methyl butyric acid is treated with valerylchloride to give (S)-2-(4-bromobenzyl)-pentanoyl-amino-3-methyl butyric acid. (S)-2-(4-bromobenzyl)-pentanoyl-amino-3-methyl butyric acid is treated with 2-(2H-tetrazol-5-yl)benzene-boronic acid in tetrahydrofuran, triphenylphosphine and palladiumacetate yield valsartan.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[N+:4]([O-:29])[CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: ClCCl
Product: COc1cc(-c2c(Cl)cc(C(F)(F)F)c[n+]2[O-])ccc1Cl
Reaction time: 16 h

Procedure:
A solution of 4.5 g (14 mmol) of 3-chloro-2-(4-chloro-3-methoxyphenyl)-5-trifluoromethylpyridine and 9.7 g (31 mmol) of 3-chloroperbenzoic acid in 80 ml of methylene chloride was stirred at 23° C. for 4 days and then at 40° C. for 16 h. The mixture was then extracted with 100 ml of 10% strength aqueous sodium bisulfate solution, with 100 ml of a 10% strength aqueous sodium bicarbonate solution and three times with 80 ml of water each time. The organic phase was concentrated, and the residue was chromatographed on silica gel with cyclohexane/ethyl acetate (5:1). Yield: 3.6 g (76%) of colorless crystals; melting point: 156°-157° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:16](OC1C=CC(CO)=CC=1)[CH2:17]CC>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][Cl:9])=[CH:6][CH:5]=1)[CH2:2][CH2:16][CH3:17]
Reactant: CCCCOc1ccc(CO)cc1
Reactant: CCOc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CCCCOc1ccc(CCl)cc1

Procedure:
Was synthesized following the same general procedure as that for the preparation of 4-ethoxybenzyl chloride; thionyl chloride (7.42 g, 69.2 mmol), 4-butoxybenzyl alcohol (9.45 g, 52.4 mmol), CH2Cl2 (145 mL).