Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2]C(CCl)=O.[CH2:7]([O:14][C:15]([NH:17][C@H:18]([C:26]([OH:28])=O)[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+].CCCCCC>CO.O1CCCC1>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C@H:26]([OH:28])[CH2:2][Cl:1])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(CCl)CCl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Solvent: C1CCOC1
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CCl)OCc1ccccc1
Temperature: 60 °C
Yield: 42.8 %

Procedure:
To a solution of 0.226 mol of N-benzyloxycarbonyl-L-phenylalanine chloromethyl ketone in a mixture of 807 mL of methanol and 807 mL of tetrahydrofuran at −2° C., is added 1.54 equiv. of solid sodium borohydride over one hundred minutes. The solvents are then removed under reduced pressure at 40° C. and the residue is dissolved in ethyl acetate (approx. 1 L). The solution is washed sequentially with 1M potassium hydrogen sulfate, saturated sodium bicarbonate and is then saturated sodium chloride solutions. After drying over anhydrous magnesium sulfate and filtering, the solution is removed under reduced pressure. To the. resulting oil is added hexane (approx. 1 L) and the mixture is warmed to 60° C. with swirling. After cooling to room temperature, the solids are collected and washed with 2 L of hexane. The resulting solid is recrystallized from hot ethyl acetate and hexane to afford 32.3 g (43% yield) of N-benzyloxycarbonyl-3(S)-amino-1-chloro-4-phenyl-2(S)-butanol, mp 150-151° C. and M+Li+=340.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH3:4].[OH:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+]>CC(O)C.C(OCC)(=O)C>[CH2:1]([O:6][C:7]1[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=1[CH2:9][OH:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCBr
Reactant: OCc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCCCOc1ccccc1CO

Procedure:
12.4 g (90.5 mmol) of butyl bromide, 11.2 g (90.5 mmol) of 2-hydroxybenzyl alcohol and 12.5 g (90.5 mmol) of potassium carbonate in 270 ml of 2-propanol are heated at reflux overnight. The suspension is cooled, taken up in ethyl acetate and washed with 1N aqueous sodium hydroxide solution and water, dried over magnesium sulfate and concentrated under reduced pressure.
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3]([O:5][CH3:6])=[O:4].[CH3:8][O:9][C:10](=[O:13])[CH:11]=[CH2:12].C[O-].[Na+]>>[Cl:1][C:2]([Cl:7])([CH2:12][CH2:11][C:10]([O:9][CH3:8])=[O:13])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)Cl
Reactant: C=CC(=O)OC
Agent: C[O-]
Agent: [Na+]
Product: COC(=O)CCC(Cl)(Cl)C(=O)OC

Procedure:
reacting methyl dichloroacetate and acrylic acid methyl ester with sodium methoxide to obtain dimethyl 2,2-dichloroglutarate;
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Si:10]([O:17][C:18]1[CH:23]=[C:22]([O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:21]=[CH:20][C:19]=1[CH:32]1[CH2:37][CH2:36][CH:35]([OH:38])[CH2:34][CH2:33]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>ClC(Cl)C>[CH:1]1([NH:7][C:8](=[O:9])[O:38][C@H:35]2[CH2:34][CH2:33][C@H:32]([C:19]3[CH:20]=[CH:21][C:22]([O:24][Si:25]([C:28]([CH3:29])([CH3:30])[CH3:31])([CH3:27])[CH3:26])=[CH:23][C:18]=3[O:17][Si:10]([C:13]([CH3:14])([CH3:15])[CH3:16])([CH3:12])[CH3:11])[CH2:37][CH2:36]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C=NC1CCCCC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C2CCC(O)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Solvent: CC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@H]2CC[C@H](OC(=O)NC3CCCCC3)CC2)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 40 °C

Procedure:
N,N-Diisopropylethylamine(199 μl) and cyclohexyl isocyanate (128 μl) were added to a stirred solution of 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50 mg) in dry dichloroethane (1 ml) at room temperature under argon. The reaction mixture was heated to 40° C. for 120 h, and was partitioned between water (50 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:2 v/v) to give the title compound as a pale yellow solid (30 mg, 47%); δH (CDCl3) 0.12 (6H, s), 0.18 (6H, s), 0.90 (9H, s), 0.95 (9H, s). 1.00-2.10 (18H, m), 2.70-2.80 (1H, m), 3.36-3.50 (1H, m), 4.40-4.48 (1H, m), 4.50-4.62 (1H, m), 6.20 (1H, d), 6.32 (1H, dd), 6.86 (1H, d).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH:21]C(=O)C)=[N:18][C:17]=3[CH3:25])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>Cl>[N:1]1([C:6]2[CH:7]=[C:8]([C:16]3[S:20][C:19]([NH2:21])=[N:18][C:17]=3[CH3:25])[CH:9]=[CH:10][C:11]=2[S:12]([CH3:15])(=[O:14])=[O:13])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(C)(=O)=O)c(-n3ccnc3)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Temperature: 100 °C

Procedure:
N-[5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-acetamide (AF2) (5.0 g, 13 mmol) is dissolved in 7M HCl (50 ml) and the solution is heated at 100° C. for 3 h. When cool the solution is brought to pH 8 by addition of aqueous NaOH whereupon the titled product precipitates. This is washed with ethanol followed by EtOAc, Et2O and dried.
Reaction SMILES: [Br-:1].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(#N)C.[O:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([CH2:34][CH2:35]O)=[CH:26]1>C1CCCCC1>[Br:1][CH2:35][CH2:34][C:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[O:25][CH:26]=1
Reactant: [Br-]
Reactant: OCCc1coc2ccccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: C1CCCCC1
Product: BrCCc1coc2ccccc12
Reaction time: 12 h
Yield: 83.8 %

Procedure:
Triphenylphosphane dibromide (5.52 g, 14.4 mmoles) was suspended in abs. acetonitrile (15 ml) under argon, the suspension was brought to 19° C. in a water-bath and 2-(benzofuran-3-yl)ethanol (2.11 g, 13.1 mmoles) in abs. acetonitrile (7 ml) was added in the course of 15 min. During the addition the temperature of the reaction mixture was kept between 19 and 21° C. The mixture was then left to stand for 12 hours without further cooling. The reaction mixture was filtered and the filtrate obtained was concentrated. The residue obtained was taken up in cyclohexane (20 ml), and the mixture was filtered over a silica gel layer (15 g) about 3 cm thick. The silica gel was washed with cyclohexane (5×20 ml) and the filtrate obtained was concentrated. 2.47 g 3-(2-bromoethyl)benzofuran were obtained as a yellowish oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[O-]CC.[Na+].Br[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22].O>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[CH:8]=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CC(C)CCBr
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c[nH]1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc([N+](=O)[O-])cn1CCC(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29 %

Procedure:
4-Nitro-1H-pyrrole-2-carboxylic acid ethyl ester (3.69 g, 20.04 mmol) was dissolved in 100 ml of hot anhydrous ethanol and the solution was cooled to room temperature. 30 ml of sodium ethoxide (about 1M) in ethanol was added. The reaction mixture was stirred at room temperature for 20 min and 1-bromo-3-methylbutane (8 ml) was added. The mixture was stirred at reflux for 6 h and cooled to room temperature and then poured into water. The pale yellow precipitates were collected by filtration, washed with water, and dried to give the product (1.48 g, 29%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][C:15]1=[O:23]>>[C:5]([C:19]1[CH:18]=[C:17]2[C:22](=[CH:21][CH:20]=1)[NH:14][C:15](=[O:23])[CH2:16]2)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1Cc2cc(C(=O)c3ccccc3)ccc2N1
Temperature: 185 °C
Reaction time: 0.08 h

Procedure:
A stirred slurry of 66 g. (0.5 mole) of aluminum chloride and 42.5 g. (0.3 mole) of benzoyl chloride was heated to 150° C. and then 133 g. (0.1 mole) of indolin-2-one was slowly added at a rate so that the temperature of the stirred reaction mixture was maintained at 180°-185° C. After addition the reaction mixture was stirred for five minutes at 185° C., cooled and poured into ice water. The 5-benzoylindolin-2-one which precipitated was collected and recrystallized from methanol; it melted at 204°-205° C. The yield was 17.5 g. (73%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.CO/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].O.P(Cl)(Cl)(Cl)=O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1
Reactant: CO/C=C/C(=O)OC
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 19 h
Yield: 64.4 %

Procedure:
2.53 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 2.32 g of methyl trans-3-methoxyacrylate, 0.3 g of water and 15 mL of acetonitrile were mixed, then, 2.51 g of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 19 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 2.17 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 65%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.CO/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25].O.P(Cl)(Cl)(Cl)=O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[C:9]=2/[CH:22]=[CH:23]/[C:24]([O:26][CH3:27])=[O:25])=[CH:4][CH:3]=1
Reactant: CO/C=C/C(=O)OC
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Reaction time: 21 h
Yield: 78.7 %

Procedure:
0.62 g of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 0.57 g of methyl trans-3-methoxyacrylate, 46 mg of water and 6.4 mL of glacial acetic acid were mixed, then, 66 mg of phosphorus oxychloride was added dropwise into the mixture at an inner temperature of 25° C., the added mixture was stirred for 21 hours at the same temperature to cause a reaction. After completion of the reaction, the same post treatment was conducted as in Example 1 to obtain 0.65 g of methyl trans-3-[3-(4-fluorophenyl)-1-isopropyl-1H-indol-2-yl]acrylate (yellow solid). Yield: 79%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[C:26]1([CH2:32][CH2:33][NH2:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:34][CH2:33][CH2:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CNCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (0.277 g, 0.79 mmol) and 2-phenylethylamine (0.15 mL, 1.18 mmol) in CH2Cl2 (4 mL) was added sodium triacetoxyborohydride (0.251 g, 1.18 mmol), and the reaction was stirred at room temperature for 2 hours. Analytical LCMS indicated that some starting material was still present, so additional 2-phenylethylamine (0.15 mL, 1.18 mmol) was added, along with acetic acid (1 drop), and the reaction was stirred overnight at room temperature. Analytical LCMS showed that starting material still remained, so additional sodium triacetoxyborohydride (0.260 g, 1.23 mmol) was added, and the reaction was stirred for 2.5 hours. Additional sodium triacetoxyborohydride (0.500 g, 2.36 mmol) was added, and the reaction was stirred for 1.5 hours, until no starting material was seen by analytical LCMS. The mixture was worked-up, and the residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][C:10](OC(C)(C)C)=[O:11].[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].Cl>C1(C)C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:9][CH:10]=[O:11]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC(C)(C)C)OC1CCCCO1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCC[C@H](CC=O)OC1CCCCO1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
I)a) 9.2 g of t-butyl (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanoate were dissolved in 115 ml of toluene while gassing with argon and with the exclusion of moisture and cooled to -75° C. 26.5 ml of a 1.2M solution of diisobutylaluminum hydride in toluene were then added dropwise in such a manner that the temperature did not exceed -70° C. After stirring at -75° C. for 1 hour there were added dropwise 7.4 ml of saturated aqueous ammonium chloride solution and subsequently 15.5 ml of 1N hydrochloric acid at -70° C. The mixture was then left to warm to room temperature. After stirring for 1 hour the organic phase was dried, filtered and evaporated. The material obtained was chromatographed on silica gel. There was obtained (R)-3-[(tetrahydro-2H-pyran-2-yl)oxy]tetradecanal as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([OH:26])[C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=1.[ClH:28].O1CCOCC1>CO>[ClH:28].[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:27])([OH:26])[C:22]([OH:24])=[O:23])=[CH:17][CH:16]=1
Reactant: COC(=O)C(C)(O)c1ccc(OCc2nc3ccc(OC)cc3n2C)cc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc2nc(COc3ccc(C(C)(O)C(=O)O)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (0.2 g), methanol (5 ml) and 4N hydrogen chloride/dioxane (10 ml) was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give crystals. The crystals were washed with a mixture of methanol and ether to afford the title compound (0.2 g, mp 193-195° C.).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[N+:21]([O-])=O>C(O)C.[Pd]>[NH2:21][C:3]1[CH:4]=[CH:5][C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH2:9]2)=[N:7][C:2]=1[NH2:1]
Reactant: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reaction time: 4 h

Procedure:
A solution of (R)-(1-(6-amino-5-nitropyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone (1.5 g, 4.7 mmol) in ethanol (20 mL) was added to a suspension of 10% palladium-on-carbon (800 mg) at room temperature. The mixture was hydrogenated for 4 h, filtered through Celite and washed with ethanol. The filtrate was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-].C(Cl)(Cl)Cl.Cl.[CH3:38][N:39]([CH3:43])[CH2:40][CH2:41]Cl>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:41][CH2:40][N:39]([CH3:43])[CH3:38])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.9 %

Procedure:
3 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepine-4(5H)-one and 6.4 g of barium hydroxide octahydrate were added with vigorous stirring to 60 ml of chloroform and 10 ml of water. A solution of 3.2 g of 2-(dimethylamino)-ethyl chloride-hydrochloride in 5 ml of water was added dropwise to the above mixture in the course of 5 minutes. Stirring was continued for 24 hours at room temperature and then for 8 hours at 40°. After cooling to room temperature the aqueous phase was separated and discarded and the chloroform was removed under vacuum. Petroleum-ether (40°-60°) was added to the viscous residue which induced crystallisation. The precipitated crystals were filtered off and dried under vacuum to yield 3.63 g of cis-(+)-2-(4'-methoxyphenyl)-3-hydroxy-5-(2'-dimethylaminoethyl)-2,3-dihydro-1,5-benzothiazepine-4(5H)-one; m.p. 88°; [α]D22 +169 (C=0.25 CH 3 OH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:10]([O:12][CH2:13][C:14](N)=[NH:15])[CH3:11]>>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:14]([CH2:13][O:12][CH2:10][CH3:11])[N:15]=1
Reactant: N#Cc1nccnc1N
Reactant: CCOCC(=N)N
Product: CCOCc1nc(N)c2nccnc2n1

Procedure:
A mixture of 36.0 g (0.30 mole) of 3-amino-2-pyrazinecarbonitrile [prepared according to A. Albert and K. Ohta, J. Chem. Soc. C, 1970, 1540] and 46.7 g of 2-ethoxyacetamidine in 700 ml of absolute control is refluxed for 2 hours 30 minutes under a nitrogen atmosphere. After cooling, the precipitate obtained is isolated by filtration. It is purified by recrystallization from ethanol. Yld: 52.0 g (84%), m.p. 152°-154° C.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][CH2:20]Cl.O>CN(C)C=O>[CH3:9][O:8][C:7]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH2:18][O:19][CH3:20]
Reactant: COCCl
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(C=O)ccc1OC
Temperature: 50 °C
Reaction time: 4 h
Yield: 89.9 %

Procedure:
To a solution of isovanillin (5.00 g, 32.9 mmol) in N,N-dimethylformamide (300 ml) were added potassium carbonate (5.00 g, 36.1 mmol) and chloromethyl methyl ether (2.91 g, 36.1 mmol), and the mixture was stirred for 4 hours at 50° C. The mixture was allowed to cool to room temperature, followed by addition of water. The mixture was extracted with ethyl acetate-toluene (3:1). The organic layer was washed with water and an aqueous saturated sodium chloride solution in the order, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified with silica gel chromatography (hexane:ethyl acetate=3:1) to give the subject compound (5.80 g, 89.9%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH2:14][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
To a solution of 4-cyanophenol (3.0 g, 25.2 mmol) and 3-fluorobenzyl bromide (3.1 mL, 25.2 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (8.71 g, 63.0 mmol), and the mixture was stirred for 1 hour at room temperature. Ethyl acetate and water were added to the reaction mixture, which was then partitioned, the organic layer was washed with water, then, dried over anhydrous magnesium sulfate, and the solvent was evaporated to obtain 4-(3-fluorobenzyloxy)-benzonitrile (5.31 g, 93%) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:10][N:9](CC2C=CC=CC=2)[CH2:8][CH2:7][N:6]1CC1C=CC=CC=1)[CH3:3]>C(O)C.C1CCCCC1.C(O)(=O)C.[Pd]>[CH3:1][N:2]([CH3:3])[CH2:4][CH:5]1[CH2:10][NH:9][CH2:8][CH2:7][NH:6]1
Reactant: CN(C)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCCCC1
Solvent: CCO
Product: CN(C)CC1CNCCN1

Procedure:
A 4.7 g portion of 2-dimethylaminomethyl-1,4-bis(phenylmethyl)piperazine was dissolved in a mixture of 50 ml of ethanol, 20 ml of cyclohexane and 10 ml of glacial acetic acid. A 2.0 g portion of 10% palladium on carbon was added, the mixture was refluxed overnight and then filtered. The filtrate was evaporated, 5 ml of saturated aqueous potassium bicarbonate was added to the residue and this was extracted several times with dichloromethane. The extracts were combined, dried, filtered and evaporated, giving a gum which solidified on standing, giving 1.02 g of N,N-dimethyl-2-piperazinemethanamine.
Reaction SMILES: CS(O)(=O)=O.N[C:7]1[N:12]=[C:11]([C:13]2[N:14]=[C:15]([C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])[NH:16][C:17]=2[C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])[CH:10]=[CH:9][C:8]=1[N+:33]([O-:35])=[O:34].S(=O)(=O)(O)[OH:37].N([O-])=O.[Na+].P([O-])(O)(O)=O.[Na+]>O.C1COCC1.CS(C)=O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[C:17]1[NH:16][C:15]([C:26]([CH3:31])([CH3:32])[C:27]([O:29][CH3:30])=[O:28])=[N:14][C:13]=1[C:11]1[CH:10]=[CH:9][C:8]([N+:33]([O-:35])=[O:34])=[C:7]([OH:37])[N:12]=1
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(N)n2)c(-c2ccc(F)cc2F)[nH]1
Reactant: O=S(=O)(O)O
Agent: CS(=O)(=O)O
Agent: O=N[O-]
Agent: O=P([O-])(O)O
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)(C)c1nc(-c2ccc([N+](=O)[O-])c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Temperature: 22.5 °C
Yield: 93 %

Procedure:
Under a nitrogen atmosphere methyl 2-[4-(6-amino-5-nitro-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate methanesulfonate (68.9 g, 134.2 mmol), dimethyl sulfoxide (275.5 mL), THF (116.2 mL), and water (303.2 mL) are added and the mixture is stirred at 20-25° C. Sulfuric acid 95-97% (93.6 mL) is added dropwise to the reaction mixture and the temperature is maintained below 30° C. The reaction mixture is cooled to 0-5° C., and a solution of sodium nitrite (18.6 g, 0.27 mmol) in water (82.7 mL) is added at 0-10° C. The reaction mixture is stirred for 1-2 h at this temperature. 10% Aqueous sodium dihydrogen phosphate (930.0 mL) is added dropwise to maintain the temperature below 25° C. The resulting mixture is stirred for 2-3 h at 15-25° C., and the solids are collected by filtration. The filtercake is washed with water (138 mL) and the solids are transferred into a reaction vessel. Methanol (566 mL) is added and the mixture is heated to 60-65° C. for 1-2 h. Water (87 mL) is added and the mixture is stirred at 60-65° C. for 1-2 h. The reaction mixture is cooled to 15-25° C. and the mixture is stirred at 15-25° C. for 2-4 h. The mixture is filtered, the cake is washed with methanol (87 mL), and is dried under a vacuum below 70° C. to provide the title compound as a yellow solid (53.28 g, 93%).