Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][C:10](=[O:11])[C@H:5]2[CH2:4][N:3]1[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[C:13]=1[CH3:21].[BH4-].[Na+]>CO.CC#N.CCOC(C)=O>[OH:11][C@H:10]1[CH2:9][CH2:8][CH2:7][N:6]2[C:2](=[O:1])[N:3]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([Cl:20])[C:13]=3[CH3:21])[CH2:4][C@H:5]12
Reactant: Cc1c(N2C[C@@H]3C(=O)CCCN3C2=O)ccc(C#N)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1c(N2C[C@@H]3[C@@H](O)CCCN3C2=O)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.8 %

Procedure:
A mixture of 78A (5 mg, 0.016 mmol) and sodium borohydride (5 mg) in MeOH:CH3CN (1:1, 1.0 mL) was stirred at rt for 2 h. The reaction was diluted with EtOAc, washed with water (2×2 mL), dried (MgSO4), filtered and concentrated to give the crude product. Purification by chiral preparative HPLC (Chiralpak AD, 25% IPA/heptane isocratic) provided 78B (4 mg): HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 2.40 min (100%); MS (ES) m/z 306 [M+1]+; Chiral analytical HPLC (ChiralPak AD OD 4.6×250 mm, 25% IPA/hexane isocratic) retention time 12.1 min (97.6% ee); MS (ES) nm/z 306.1 [M+1]+; HRMS calcd for C15H15ClN3O2 304.0853, Found 304.0846.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([Cl:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH:29]1([N:35]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH:36]2[CH3:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CC(C)=O.O>[CH:29]1([N:35]2[CH2:39][CH2:38][CH:37]([NH:40][C:5](=[O:7])[C:4]3[CH:8]=[C:9]([Cl:13])[C:10]([NH2:12])=[CH:11][C:3]=3[O:2][CH3:1])[CH:36]2[CH3:41])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CC1C(N)CCN1C1CCCCC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(C2CCCCC2)C1C
Reaction time: 0.75 h
Yield: 71.1 %

Procedure:
8 g of 2-methoxy-4-amino-5-chlorobenzoic acid (0.040 mole), 50 ml of acetone and 4 g of triethylamine (0.040 mole) are placed in a 250 ml flask fitted with an agitator, a thermometer and a dropping funnel. The suspension is cooled and 5.5 g of isobutyl chloroformate (0.040 mole) is added drop by drop between 0° and +5° C. The reaction medium is agitated for 45 minutes with the temperature kept between 0° and +5° C., then 8 g of 1-cyclohexyl-methyl-3-aminopyrrolidine (0.044 mole) is added drop by drop. The reaction is allowed to continue for 2 hours at room temperature, then 80 ml of water is added and the acetone is expelled. The product crystallises in the residual water. It is filtered and re-dissolved in 150 ml of water and 5 ml of concentrated hydrochloric acid. The solution is filtered with charcoal and the filtrate is made alkaline with 10 ml of ammonia (density 0.91). The viscous precipitate is decanted and dissolved in 80 ml of water and 5 ml of hydrochloric acid. The product is dissolved and the hydrochloride is precipitated very rapidly. It is drained, washed with water and dried at 50° C. 10.4 g of product is obtained and is dissolved hot in 100 ml of water. The solution is rendered alkaline with 10 ml of soda lye. The oily precipitate is crystallised by cooling. It is drained, washed with water and dried in an oven at 50° C.
Reaction SMILES: [CH:1]1([C:6]2[C:7]([OH:20])=[CH:8][C:9]([N+:17]([O-])=O)=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O>C(O)(=O)C.CO.[Zn]>[NH2:17][C:9]1[CH:8]=[C:7]([OH:20])[C:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:11][C:10]=1[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cc1cc(C2CCCC2)c(O)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)Cc1cc(C2CCCC2)c(O)cc1N
Reaction time: 2 h
Yield: 93.4 %

Procedure:
Methyl 2-(5-cyclopentyl-4-hydroxy-2-nitro-phenyl)acetate (30 mg, 0.11° mmol) was dissolved in acetic acid (1 mL) and water (0.5 mL) and treated with Zn dust (7 mg, 0.98 μL, 0.11 mmol) at room temperature. The mixture was stirred for 2 h then diluted with methanol (5 mL) and filtered. The filtrate was diluted with ethyl acetate, washed with 50% saturated NaHCO3 (2×20 mL), water, and brine. The solution was dried over Na2SO4, filtered, and dried down to provide methyl 2-(2-amino-5-cyclopentyl-4-hydroxyphenyl)acetate as an amber colored oil (25 mg, 93% yield). LC/MS m/z 249.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][CH:3]=1.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[N-:22]=[C:23]=[O:24].N[C:26]1[C:31]2[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=2[CH:29]=[CH:28][CH:27]=1>CCOC(C)=O.CN(C=O)C.CO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:23]([NH:22][C:26]2[C:31]3[O:32][CH2:33][C:34](=[O:36])[NH:35][C:30]=3[CH:29]=[CH:28][CH:27]=2)=[O:24])=[CH:4][CH:3]=1
Reactant: [N-]=C=O
Reactant: NCc1ccc(Cl)nc1
Reactant: Nc1cccc2c1OCC(=O)N2
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1COc2c(cccc2NC(=O)NCc2ccc(Cl)nc2)N1
Temperature: 80 °C
Yield: 12 %

Procedure:
Commercially available (6-chloropyridin-3-yl)methanamine (800 mg, 5.61 mmol) was dissolved in 40 ml of AcOEt and at 0° C. triphosgene (1.54 g, 5.6 mmol) was added to the solution. The mixture was warmed at 80° C. for 4 hours then evaporated and the residue was dissolved in 10 ml of DMF. The solution of the isocyanate was added dropwise to a solution in DMF (10 ml) of compound 1f (900 mg, 4.51 mmol) and the mixture was warmed at 80° C. for 8 hours. (TLC AcOEt 9.5/MeOH 0.5). The solvent was evaporated and the crude was dissolved in AcOEt (80 ml) and washed with water (1×40 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column gave 180 mg of a beige solid. Yield=12% 1HNMR (DMSO, 200 MHz) δ 4.31 (2H, d, J=5.6 Hz), 4.60 (2H, s), 6.47 (1H, dd), 6.81 (1H, t), 7.40 (1H, t), 7.50 (1H, d, J=8.2 Hz), 7.72 (2H, m), 8.13 (1H, bs), 8.34 (1H, bs), 10.66 (1H, bs); [M+1] 332.8 (C15H13ClN4O3 requires 332.74).
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1.C(N(CC)CC)C>C(OCC)C.C(OCC)(=O)C>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[O:21][CH2:2][C:3](=[O:10])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:14]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: COc1ccc(N=C=O)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1=C(Nc2ccc(OC)cc2)OCC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere, to a mixed solution of ethyl 4-chloroacetoacetate (0.82 mL, 6.0 mmol) and 4-methoxyphenyl isocyanate 1.1 g, 7.2 mmol) in diethyl ether/ethyl acetate (10 mL/1.0 mL) that cooled with ice bath, triethylamine (0.96 mL, 6.9 mmol) was added dropwise. The reaction mixture was stirred at ambient temperature for 1.5 h then the precipitate was collected by filtration, washed with diethyl ether, 1M hydrochloric acid solution, water and diethyl ether, and then dried to afford ethyl 2-[(4-methoxyphenyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate as solid (1.3 g, y. 78%).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([CH:6]1[CH2:13][C:9]2[S:10][CH:11]=[CH:12][C:8]=2[C:7]1=O)=O.O.[NH2:20][NH2:21].C(O)(=O)C>C(O)C>[Br:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]1[C:6]2[CH2:13][C:9]3[S:10][CH:11]=[CH:12][C:8]=3[C:7]=2[NH:21][N:20]=1
Reactant: O=C(c1ccccc1Br)C1Cc2sccc2C1=O
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccccc1-c1n[nH]c2c1Cc1sccc1-2
Temperature: 25 °C
Yield: 30.5 %

Procedure:
5-(2-Bromo-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (2.5 g, 8.2 mmol), hydrazine monohydrate (0.6 mL, 12 mmol), glacial acetic acid (1.5 mL) and ethanol (30 mL) was heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(2-Bromo-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.8 g, 2.5 mmol) as white solid in 30% yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[CH:2]1.[NH2:13][C:14]1[CH:26]=[CH:25][C:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:16][CH:15]=1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:21]([O:20][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])=[CH:26][CH:25]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)c1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 30.2 %

Procedure:
A solution of 1H-indole-6-carboxylic acid (1.00 g, 6.20 mmol), tert-butyl 4-aminobenzoate (1.20 g, 6.20 mmol), 4-methylmorpholine (3.14 g, 31.0 mmol), and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (3.53 g, 9.31 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 15 min, then 4-(dimethylamino)pyridine (758 mg, 6.20 mmol) was added, and the solution was stirred at 60° C. for 3 days. After cooling, the reaction mixture was partitioned between water, heptane, and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) followed by trituration in dichloromethane yielded 4-[(1H-indole-6-carbonyl)-amino]-benzoic acid tert-butyl ester (629 mg, 30%). White solid, MS (ISP): m/e 337.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.[Na].[CH:16](OCC)=O.[NH2:21][C:22]([NH2:24])=[S:23]>>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[C:10](=[O:12])[NH:21][C:22](=[S:23])[NH:24][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CCOC=O
Reactant: CCOC(=O)CCc1ccc(C)nc1
Reactant: NC(N)=S
Agent: [Na]
Product: Cc1ccc(Cc2c[nH]c(=S)[nH]c2=O)cn1

Procedure:
3-(6-Methyl-3-pyridyl)propenoic acid, m.p. 213.5°-215.5°, was prepared by reacting 6-methylpyridine-3-carboxaldehyde with malonic acid in pyridine with piperidine catalyst, and was converted into the corresponding ethyl ester m.p. 36°-37° which was reduced with hydrogen and palladium-on-charcoal catalyst to give ethyl 3-(6-methyl-3-pyridyl)-propionate (oil). This ester was reacted with sodium and ethyl formate and the product treated with thiourea to give 5-(6-methyl-3-pyridylmethyl)-2-thiouracil m.p. 240°-241° which was alkylated with methyl iodide in the pressure of sodium hydroxide at 70° to give 5-(6-methyl-3-pyridylmethyl)-2-methylthio-4-pyrimidone, m.p. 197°-198.5°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[N:24]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1.[C:32](Cl)(=[O:36])[O:33][CH2:34][CH3:35].CC1C(CSC2NC3C=CC=CC=3N=2)=NC=CC=1SCCN1CCOCC1>>[CH3:1][C:2]1[C:3]([CH2:21][S:22][C:23]2[N:24]([C:32]([O:33][CH2:34][CH3:35])=[O:36])[C:25]3[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=3[N:27]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1
Reactant: CCOC(=O)Cl
Reactant: Cc1c(SCCN2CCc3ccccc3C2)ccnc1CSc1nc2ccccc2[nH]1
Agent: Cc1c(SCCN2CCOCC2)ccnc1CSc1nc2ccccc2[nH]1
Product: CCOC(=O)n1c(SCc2nccc(SCCN3CCc4ccccc4C3)c2C)nc2ccccc21

Procedure:
The same reaction as in Example 17 was carried out except that 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)-ethylthio)-2-pyridyl)methylthio)-1H-benzimidazole was reacted with ethyl chlorocarbonate, in place of 2-((3-methyl-4-(2-morpholinoethylthio)-2-pyridyl)methylthio)-1H-benzimidazole, to give ethyl 2-((3-methyl-4-(2-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethylthio)-2-pyridyl)methylthio)-lH-benzimidazole-1-carboxylate 1/2. ethanol as crystals, melting point 134°-136° C. (dec.).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][C:18](OC)=[O:19])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1.O>O1CCCC1>[O:7]1[C:11]2([CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)[O:10][CH2:9][CH2:8]1
Reactant: COC(=O)CC1CCC2(CC1)OCCO2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
A suspension of 0.76 g of lithium aluminum hydride in 10 mL of tetrahydrofuran was cooled to 0° C. under a nitrogen atmosphere. To the suspension was added dropwise a solution of 2.18 g of methyl 1,4-dioxaspiro[4.5]decane-8-acetate in 10 mL of tetrahydrofuran, followed by stirring at room temperature for 3 hours. After the reaction mixture was cooled to 0° C., 1 mL of water was added thereto. The mixture was filtered through celite and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.73 g of 1,4-dioxaspiro[4.5]decane-8-ethanol represented by the following formula:
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([C:9]([OH:11])=O)=[CH:4][N:3]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[O:22]1[CH2:27][CH2:26][NH:25][C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2>CN(C)C(=O)C.O>[O:22]1[CH2:27][CH2:26][N:25]([C:9]([C:5]2[C:6]([OH:8])=[N:7][C:2]([OH:1])=[N:3][CH:4]=2)=[O:11])[C:24]2[CH:28]=[N:29][CH:30]=[CH:31][C:23]1=2
Reactant: O=C(O)c1cnc(O)nc1O
Reactant: c1cc2c(cn1)NCCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=C(c1cnc(O)nc1O)N1CCOc2ccncc21
Reaction time: 0.33 h
Yield: 21.4 %

Procedure:
2,4-dihydroxy-pyrimidin-5-carboxylic acid (125 mg, 0.80 mmol) was dissolved in N,N-dimethyl acetamide (3 ml) and then cooled to −150. Thionyl chloride (0.066 ml, 0.90 mmol) was added thereto at −15□ and the reaction mixture was stirred at −5□ for 20 minutes. The reaction mixture was cooled to −15□, and potassium carbonate (138 mg, 1.0 mmol) and 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (109 mg, 0.80 mmol) were added thereto dropwise. The reaction mixture was stirred at −5□ for 30 minutes, and then stirred at room temperature for 3 hours. After the completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=9:1. The fractions containing the product were collected and evaporated to obtain the target compound 59 as white solid (47 mg, 21%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-])=O.[BH4-].[Na+].[H][H]>CO.C(OCC)(=O)C.[Pd]>[OH:9][CH:8]([C:5]1[CH:4]=[C:3]([C:2]([CH3:1])=[CH:7][CH:6]=1)[NH2:11])[CH3:10]
Reactant: [H][H]
Reactant: CC(=O)c1ccc(C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(C(C)O)cc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice-cold solution of 4-methyl-3-nitroacetophenone (25 g, 139 mmol) in methanol (200 mL) is added sodium borohydride (6.2 g, 163 mmol) over 15 minutes. The mixture is stirred at room temperature for 1 hour, then is quenched with water. The mixture is rotary evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is dried (magnesium sulfate) and rotary evaporated to afford a light brown viscous oil. The oil is diluted with ethyl acetate (200 mL), 5% palladium-on-carbon (5 g) is added and the mixture is treated with hydrogen at 40 psi for 18 hours. The mixture is then filtered on Celite and the filtrate is rotary evaporated to afford 3-(1-hydroxyethyl)-6-methylaniline as a light yellow, pasty solid.
Reaction SMILES: C[C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]CC.O>C1C=CC=CC=1>[CH2:2]([O:3][CH2:4][C@H:5]([CH2:7][OH:8])[OH:6])[CH2:9][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13]
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Reactant: CC1(C)OC[C@@H](CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: c1ccccc1
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCOC[C@@H](O)CO
Temperature: 25 °C
Yield: 74.1 %

Procedure:
8.6 ml (76.08 mmol) of (R)-(−)-2,2-dimethyl-1,3-dioxolane-4-methanol, 15 grams of powdered potassium hydroxide and 27.5 grams (76.08 mmol) of 1-bromoeicosane were stirred in 150 ml benzene and refluxed for 6 hours, while removing the water formed by azeotropic distillation. The volume of the solvent was gradually reduced to about 70 ml. The reaction mixture was then cooled to room temperature and 150 ml of water was added. The reaction mixture was then extracted thrice with 150 ml diethyl ether, the combined organic phase was washed with 100 ml water, and the solvent was then removed under reduced pressure. The obtained residue was dissolved in 105 ml of a 90:10:5 (v/v) methanol:water:concentrated hydrochloric acid mixture, and the resulting solution was refluxed until the solution became clear. The solution was then cooled to room temperature and 100 ml water was added. The product was extracted with 150 ml chloroform, washed consecutively with 150 ml water, 150 ml saturated aqueous solution of sodium carbonate, and again with 150 ml water. The solvent was then removed under reduced pressure and the product was crystallized from 200 ml hexane, yielding 21.0 grams of pure 1-eicosanyl-sn-glycerol, which was dried in a desiccator under reduced pressure with phosphorus oxide. The yield was 81.5%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>C1COCC1.ClCCl>[Cl:28][CH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([NH:12][C:10]2[S:11][C:7]3[C:6]([CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:35])=[CH:32][CH:31]=1
Reactant: COc1ccc(C2CCOCC2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccc(CCl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccc(CCl)cc3)nc12
Reaction time: 60 h
Yield: 70.7 %

Procedure:
To a stirred solution of 250 mg (0.95 mmol) 4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-ylamine and 0.95 ml (5.53 mmol) N-ethyldiisopropylamine in 10 ml THF at room temperature was added dropwise a solution of 216 mg (1.14 mmol) 4-(chloromethyl)benzoyl chloride in 3 ml dichloromethane and stirring continued at room temperature for 60 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 280 mg (71%) 4-chloromethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-benzamide as a white crystalline solid. ES-MS m/e (%): 441 (M{37Cl}+Na+, 7), 439 (M{35Cl}+Na+, 21). 419 (M{37Cl}+H+, 41), 417 (M{35Cl}+H+, 100).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26](O)=[O:27])[CH:20]=4)[N:15]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:44][N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C1C=CN=CC=1)C.O.CN(C=O)C>[C:1]1([S:7]([CH2:10][C:11]2[S:12][CH:13]=[C:14]([C:16]3[C:17](=[O:29])[NH:18][C:19]4[C:24]([CH:25]=3)=[CH:23][CH:22]=[C:21]([C:26]([N:48]3[CH2:49][CH2:50][N:45]([CH3:44])[CH2:46][CH2:47]3)=[O:27])[CH:20]=4)[N:15]=2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc3cc(-c4csc(CS(=O)(=O)c5ccccc5)n4)c(=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(2-benzenesulfonylmethyl-thiazol-4-yl)-1H-quinolin-2-one-7-carboxylic acid (step (h), 0.1 g, 0.2 mmol), EDC (0.08 g, 0.4 mmol), HOBt (0.08 g, 0.6 mmol), DMAP (4 mg), and 4 mL of DMF were stirred for 15 min, and then 1-methyl piperazine (0.13 mL, 1.2 mmol) was added. The reaction was stirred at RT for 24 h. The reaction was diluted with 50 mL of H2O and extracted with EtOAc (4×). The combined EtOAc layers were washed with 0.5N HCl, saturated NaHCO3, and brine. The acidic aqueous layer was neutralized with 1N NaOH and extracted with EtOAc (3×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting solid was suspended in a minimum of EtOAc and filtered to give a solid. MS m/z: 509.4 (M+1). Anal. Calc'd for C25H24N4O4S2: C, 59.04; H, 4.76; N, 11.02. Found: C, 58.75; H, 4.87; N, 10.90.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH2:14])[N:6]=1.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=1[C:23]1[N:28]=[C:27](NCCNC2C=CC([N+]([O-])=O)=CN=2)[CH:26]=[CH:25][C:24]=1[C:42]1[NH:43][CH:44]=[CH:45][N:46]=1>>[NH2:14][C:7]1[N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:27]2[CH:26]=[CH:25][C:24]([C:42]3[NH:46][CH:45]=[CH:44][N:43]=3)=[C:23]([C:17]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=3[Cl:15])[N:28]=2)[CH:10]=[CH:9][C:8]=1[N+:11]([O-:13])=[O:12]
Reactant: NCCNc1ccc([N+](=O)[O-])c(N)n1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Product: Nc1nc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
{2-[(6-amino-5-nitro(2-pyridyl))amino]ethyl}[6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]amine was prepared from (2-aminoethyl)(6-amino-5-nitro(2-pyridyl))amine using the general method for [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH3:9].C([O-])([O-])=O.[Na+].[Na+].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.CO.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>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([CH3:9])=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([C:17]([F:28])([F:27])[F:16])=[CH:19][CH:20]=2)[CH:7]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(Cl)cc1Br
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: CO
Solvent: Cc1ccccc1
Product: Cc1ccc(Cl)cc1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 2-bromo-4-chloro-toluene (20.5 g) in toluene (100 mL) was added Pd(PPh3)4 (1 g) and the mixture was stirred at room temperature under N2 for 0.25 hours. A 2M solution of Na2CO3 (100 mL) was then added, followed by the dropwise addition of 4-trifluoromethylphenyl boronic acid (19 g) in MeOH (100 mL). The resulting mixture was heated under reflux for 48 hours. The mixture was then cooled to room temperature and the phases were separated. The organic layer was then dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with petroleum ether/AcOEt (90/10) to give the title compound (25.3 g) as a colorless liquid.