Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:12][CH:11]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(Cl)(Cl)(Cl)Br.C1CCN2C(=NCCC2)CC1>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[O:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[N:20]=2)=[CH:14][CH:15]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: COC(=O)C1COC(c2ccc(CNC(=O)OC(C)(C)C)cc2)=N1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Br
Product: COC(=O)c1coc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a solution of methyl 2-[4-(N-Boc-aminomethyl)-phenyl]4,5-dihydrooxazol-4-ylcarboxylate (25.5 g, 76.3 mmol) in dichloromethane (100 ml) was added CBrCl3 (8.23 ml, 83.9 mmol) and DBU (12.5 ml, 83.9 mmol). After stirring at room temperature overnight, the reaction was concentrated and the product isolated by flash chromatography over silica gel. Recrystallization from hot methanol provided methyl 2-[4-(N-Boc-aminomethyl)-phenyl]-oxazole-4-carboxylate (18.4 g, 55.4 mmol) as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C(C)=CC=CC=1.[OH-].[K+].Br[C:26]1[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([CH3:34])[CH:27]=1>Cl[Cu].O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:26]2[CH:32]=[C:31]([CH3:33])[C:29]([NH2:30])=[C:28]([CH3:34])[CH:27]=2)=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: Cc1cc(Br)cc(C)c1N
Agent: Cl[Cu]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1cc(Oc2ccc(Cc3ccccc3)cc2)cc(C)c1N
Reaction time: 12 h

Procedure:
A mixture of 64,4 g (0.35 mole) of p-benzylphenol, 500 ml of xylene and 28 g (0,45 mole) of pulverised potassium hydroxide is heated for 4 hours under reflux. The water formed is removed from the reaction mixture. Then 60 g (0,3 mole) of 4-bromo-2,6-dimethylaniline and 1 g of CuCl are added and the xylene is distilled off under nitrogen until the temperature in the reaction mixture is 160°-170°. The reaction mixture is stirred at this temperature for 12 hours, allowed to cool to 70°-80° C., and then taken up in 500 ml of toluene and filtered. The filtrate is diluted with diethyl ether, washed twice with 10% potassium hydroxide solution and three times with saturated sodium chloride solution, dried over sodium sulfate and concentrated. The residue is purified over a column of silica gel with a 1:3 mixture of ethyl acetate/hexane as eluant. The eluant is evaporated off to give 4-(p-benzylphenoxy)-2,6-dimethylaniline as a dark liquid which after a time forms crystals with a melting point of 61°-63° C.
Reaction SMILES: [I:1][CH3:2].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([C:14]([N:16]([CH2:18][C:19]2[N:26]3[C:22]([S:23][CH:24]=[CH:25]3)=[CH:21][N:20]=2)[CH3:17])=[O:15])[CH2:12][C@H:11]([S:27][C:28]2[C@H:29]([CH3:45])[C@@H:30]3[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:44])[N:31]3[C:32]=2[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]>>[I-:1].[CH2:3]([O:6][C:7]([N:9]1[C@H:13]([C:14]([N:16]([CH3:17])[CH2:18][C:19]2[N:20]([CH3:2])[CH:21]=[C:22]3[N+:26]=2[CH:25]=[CH:24][S:23]3)=[O:15])[CH2:12][C@H:11]([S:27][C:28]2[C@H:29]([CH3:45])[C@@H:30]3[C@@H:40]([C@H:41]([OH:43])[CH3:42])[C:39](=[O:44])[N:31]3[C:32]=2[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH2:10]1)=[O:8])[CH:4]=[CH2:5]
Reactant: CI
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)N(C)Cc3ncc4sccn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](C(=O)N(C)Cc3n(C)cc4scc[n+]34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.1 %

Procedure:
Iodomethane (0.84 g) is added to 37.0 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-(imidazo[5,1-b]thiazol-5-yl)methyl-N-methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, and the mixture is stirred in an argon atmosphere in a light-shielded state at room temperature for 18 hr. The excess reagent is removed by evaporation under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (chloroform:methanol=1:1) to give 36.3 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[N-methyl-N-(6-methylimidazo[5,1-b]thiazolium-5-yl)methylaminocarbonyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate iodide as a milky white amorphous material.
Reaction SMILES: [NH2:1][C:2]1[C:11]([S:12]CC2C=CC(OC)=CC=2)=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:3]=1[F:30].C(O)(C(F)(F)F)=O>C1(OC)C=CC=CC=1>[NH2:1][C:2]1[C:11]([SH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[F:29])[C:3]=1[F:30]
Reactant: COC(=O)c1cc(SCc2ccc(OC)cc2)c(N)c(F)c1Nc1ccccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 75 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-((4-methoxybenzyl)thio)benzoate (9.79 g, 22.7 mmol) in anisole (12 mL) was added CF3COOH (20 mL). After stirring at ambient temperature for 23 h, the solvent was removed in vacuo. To the residue was added water (30 mL). The mixture was neutralized with 25% aqueous ammonia and extracted with ethyl acetate (100 mL×3). The combined organic layer was washed with water (100 mL×3) and brine (100 mL) sequentially, dried over Na2SO4, filtered and concentrated to give the desired product (white solid, 5.28 g, 75% yield). The product was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1.[Br:28]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[C@H:4]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:5][C:6]1[CH:15]=[C:14]([Br:28])[C:9]2[NH:10][C:11](=[O:13])[O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1cc(Br)c2[nH]c(=O)oc2c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of (R)-2-benzyloxycarbonylamino-3-(2-oxo-2,3-dihydro-benzooxazol-6-yl)-propionic acid methyl ester (418 mg, 1.13 mmol), N-bromosuccinimide (221 mg, 1.24 mmol), silica gel (EM Scientific, 230–400 mesh, 2.51 g) and methylene chloride (70 mL) was stirred at room temperature for 16 h. Solvents were removed in vacuo and the residue was subjected to silica gel chromatography using ethyl acetate/hexanes (2:3) as eluent to afford the title compound. 1H-NMR (CD3COCD3, 500 MHz) δ 10.71 (s, 1H), 7.35–7.28 (m, 6H), 7.21 (s, 1H), 6.75 (d, J=7.5 Hz, 1H), 5.06 (d, 12.5 Hz, 1H), 5.02 (d, J=12.5 Hz, 1H), 4.56–4.51 (m, 1H), 3.73 (s, 3H), 3.26 (dd, J=14.0, 5.0 Hz, 1H), 3.03 (dd, J=14.0, 10.0 Hz, 1H); 13C-NMR (CD3COCD3, 125 MHz) δ 172.2, 156.4, 153.8, 144.4, 137.6, 133.7, 129.8, 128.7, 128.2, 128.0, 127.8, 110.1, 100.9, 66.3, 55.9, 52.0, 37.3; Mass spec. 448.03 (MH+).
Reaction SMILES: C(OC([NH:8][C@@:9]1([CH3:16])[C:13]2([CH2:15][CH2:14]2)[CH2:12][NH:11][CH2:10]1)=O)(C)(C)C.F[C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]2[C@@H:29]2[CH2:31][C@@H:30]2[F:32])=[CH:20][CH:19]=1.C(N(CC)CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl.CS(C)=O>[NH2:8][C@@:9]1([CH3:16])[C:13]2([CH2:14][CH2:15]2)[CH2:12][N:11]([C:18]2[C:27]([CH3:28])=[C:26]3[C:21]([C:22](=[O:36])[C:23]([C:33]([OH:35])=[O:34])=[CH:24][N:25]3[C@@H:29]3[CH2:31][C@@H:30]3[F:32])=[CH:20][CH:19]=2)[CH2:10]1
Reactant: Cc1c(F)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Reactant: CC(C)(C)OC(=O)N[C@]1(C)CNCC12CC2
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Cc1c(N2CC3(CC3)[C@](C)(N)C2)ccc2c(=O)c(C(=O)O)cn([C@@H]3C[C@@H]3F)c12
Temperature: 75 °C
Reaction time: 120 h

Procedure:
A mixture of (7S)-7-(tert-butoxycarbonylamino)-7-methyl-5-azaspiro[2.4]heptane (523 mg, 2.31 mmol), 7-fluoro-1-[(1R,2S)-2-fluorocyclopropyl]-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (538 mg, 1.927 mmol), triethylamine (0.537 mL, 3.85 mmol), and dimethyl sulfoxide (6 mL) was stirred in nitrogen atmosphere in an oil bath at 75° C. for 5 days, and in an oil bath at 85° C. for 2 days. To the reaction mixture was added 10% aqueous solution of citric acid (10 mL), and the mixture was extracted with ethyl acetate (50 mL). The organic layer was washed with water (10 mL×2) and saturated aqueous solution of sodium chloride (10 mL), and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel, 10 g; elusion by chloroform→chloroform:methanol, 98:2) to obtain a pale yellow foam solid. The purified pale yellow foam solid was dissolved in concentrated hydrochloric acid (8 mL) at room temperature, and after transferring the resulting acidic aqueous solution using 6N hydrochloric acid to a separatory funnel, solution was washed with chloroform (50 mL×8). To the aqueous layer was added 10 mol/l aqueous solution of sodium hydroxide to pH 12.0 in an ice bath, and hydrochloric acid was added to adjust the pH to 7.4. The solution was extracted with a mixed solvent of chloroform and methanol (chloroform:methanol, 9:1) (100 mL×3), and lower layer of a mixed solvent chloroform, methanol, and water (chloroform:methanol:water, 7:3:1) (100 mL). The organic layer was dried with anhydrous sodium sulfate, and after filtration, the filtrate was concentrated under reduced pressure. The concentrate was purified by recrystallization from ethanol-isopropanol system, and the crystals were dried under reduced pressure to obtain 332 mg (2 steps, 42%) of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][S:2]([CH3:5])(=[O:4])=[O:3].[H-].[Na+].CS(C)=O.C[O:13][C:14](=O)[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([NH:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=1>C(O)(=O)C.O>[CH3:26][O:25][C:17]1[CH:16]=[C:15]([C:14](=[O:13])[CH2:1][S:2]([CH3:5])(=[O:4])=[O:3])[CH:20]=[C:19]([O:21][CH3:22])[C:18]=1[NH:23][CH3:24]
Reactant: CS(C)(=O)=O
Reactant: CNc1c(OC)cc(C(=O)OC)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CNc1c(OC)cc(C(=O)CS(C)(=O)=O)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 44.2 g. of dimethylsulfone and 16 g. of sodium hydride (50% dispersion in oil) in 150 ml. of absolute dimethylsulfoxide was stirred at 50° C. for 4 hours under an atmosphere of nitrogen and the exclusion of moisture. 30.4 g. of 3,5-dimethoxy-4-(methylamino)-benzoic acid methyl ester were added and the mixture was stirred at 80° C. for 10 minutes and at 25° C. for 30 minutes. The mixture was then dissolved in 600 ml. of water and the solution was made neutral by the addition of glacial acetic acid. The precipitate was removed by filtration with suction, washed with water, dried and recrystallized from ethyl acetate, whereby there was obtained 3',5'-dimethoxy-4'-(methylamino)-2-(methylsulfonyl)-acetophenone having a melting point of 98°-99° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[NH2:20]C1C=CC2OC(=O)N(CC(N)=O)C=2C=1>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH2:20])[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: NC(=O)Cn1c(=O)oc2ccc(N)cc21
Product: Nc1ncc(F)c(Nc2ccc3c(c2)OCCO3)n1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 2-chloro-5-fluoro-N4-(3,4-ethylenedioxyphenyl)-4-pyrimidineamine with 2-[5-amino-2-oxo-1,3-benzoxazol-3(2H)-yl)acetamide gave N2-15-(N-aminocarbonylmethylene-2-oxo-1,3-oxazol-3(2H)-yl)phenyl]-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrmidinediamine. 1H NMR (CD3OD): δ 7.95 (d, 1H, J=8.4 Hz), 7.32 (dd, 1H, J=2.4 and 8.1 Hz), 7.24 (d, 1H, J=2.4 Hz), 7.19 (m, 2H), 6.95 (dd, 1H, J=2.7 and 9 Hz), 6.80 (d, 1H, J=9 Hz), 4.51 (s, 2H), 4.21 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([CH2:9][OH:10])[C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[CH2:13][OH:14].S(=O)(=O)(O)[OH:16].[OH2:20]>CC(C)=O.[O-2].[Cr+6].[O-2].[O-2]>[CH3:12][C:4]1[C:5]([CH3:11])=[C:6]([C:9]([OH:16])=[O:10])[C:7]([CH3:8])=[C:2]([CH3:1])[C:3]=1[C:13]([OH:14])=[O:20]
Reactant: O=S(=O)(O)O
Reactant: Cc1c(C)c(CO)c(C)c(C)c1CO
Reactant: O
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(C)=O
Product: Cc1c(C)c(C(=O)O)c(C)c(C)c1C(=O)O
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
2,3,5,6-Tetramethyl-p-xylene-α,α'-diol (5.0 g, 26 mmol) was suspended in 250 mL of distilled acetone, and cooled to 0° C. To a separate solution of chromium (VI) oxide (14.15 g, 0.14 ml) in 50 mL of water was dropwise added concentrated sulfuric acid (14.5 mL, 0.26 mol) at 0° C. during 45 minutes. This mixture was then added dropwise during 30 minutes to the acetone solution, with stirring at 0° C. The mixture was stirred vigorously at 0° C. for 1 hour, then at room temperature for 18 hours. The reaction mixture was concentrated by rotary evaporation, and 1 NHCl was added to attain pH 1. The product was precipitated by cooling, then was filtered, washed with water (3×) and diethyl ether (3×), and dried at high vacuum to afford 4.55 g (80%) of the product (HOOC--C6 (CH3)4 --COOH) as a white solid, m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:24]([F:27])([F:26])[F:25])=[C:11]([S:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.S([O-])(O[O-])(=O)=[O:29].[K+].[K+].[OH2:36]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:24]([F:26])([F:27])[F:25])=[C:11]([S:15]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)(=[O:29])=[O:36])[C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])O[O-]
Reactant: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Sc1ccc(Cl)c(Cl)c1
Reactant: O
Agent: [K+]
Solvent: CO
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 2-(p-chlorophenyl)-4-[(3,4-dichlorophenyl)thio]-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.0 g, 2.2 mmol) in methanol is treated with a solution of potassium peroxymonosulfate (2.95 g) in water (7.4 mL), stirred at 25° C. for 24 hours, diluted with additional methanol, treated with a solution of potassium peroxymonosulfate (2.7 g) in water (7.6 mL), stirred at 25° C. for 24 hours, and filtered to obtain a solid which is washed with water and dried to give the title product a white solid (mp >225° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH2:14][OH:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C>CS(C)=O.ClCCl>[C:1]([O:5][C:6]([N:8]1[C@@H:13]([CH:14]=[O:15])[CH2:12][O:11][C@@H:10]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](CO)CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C)CO[C@H]1CN(C(=O)OC(C)(C)C)[C@@H](C=O)CO1
Reaction time: 0.33 h

Procedure:
Add pyridine sulfur trioxide complex (4.82 g, 30.26 mmol) to (2R,5S)-2-(2,2-dimethylpropoxy)-5-hydroxymethylmorpholine-4-carboxylic acid tert-butyl ester (5.10 g, 16.81 mmol) and N,N-diisopropylethylamine (7.61 g, 58.83 mmol) in dimethylsulfoxide (42 mL) and dichloromethane (8 mL) at −4° C. Stir 20 minutes, pour into ice cold saturated aqueous sodium chloride. Extract with 10% ethyl acetate/hexanes. Wash with 0.1 N aqueous citric-acid and saturated aqueous sodium chloride. Dry (magnesium sulfate), filter and concentrate to give the desired compound of a colorless oil, which is used directly in the next step without further purification (5.02 g).
Reaction SMILES: C(O)(C)(C)C.[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9].[C:18]([O:29]C)(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CO>[C:18]([OH:29])(=[O:28])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].[O:6]=[CH:7][C@@H:8]([C@H:10]([C@@H:12]([C@@H:14]([CH2:16][OH:17])[OH:15])[OH:13])[OH:11])[OH:9]
Reactant: CCCCCCCCCC(=O)OC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CO
Solvent: CC(C)(C)O
Product: CCCCCCCCCC(=O)O

Procedure:
25 ml of tertiary butanol was added to a mixture of 5.00 g (27.64 mM) of glucose and 1.03 g (5.55 mM) of methyl caprinate, and 100 mg of thermostable lipase derived from Candida antarctica (sp-382, manufactured by NOVO Co.) immobilized into an acrylic resin was further added. Then, they were refluxed under heating while stirring for 24 hours with an addition of 10 g of molecular sieves 5A as a methanol remover, to obtain glucose monocaprinate (C10 glucose ester).
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:17](=[O:18])[C:16]2[C:15](=[O:19])[C:14]3[CH:13]=[CH:12][C:11]([Cl:20])=[CH:10][C:9]=3[NH:8][C:7]=2[C:6]([OH:21])=[N:5]1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.[K].Cl>CN(C=O)C>[Cl:20][C:11]1[CH:12]=[CH:13][C:14]2[C:15](=[O:19])[C:16]3[C:17](=[O:18])[N:4]([CH2:3][CH2:2][N:26]4[C:25](=[O:27])[C:24]5=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]5[C:22]4=[O:32])[N:5]=[C:6]([OH:21])[C:7]=3[NH:8][C:9]=2[CH:10]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Agent: Cl
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Yield: 78.9 %

Procedure:
2-(2-Bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione (5.00 g, 13.50 mM) and potassium phthalimide (10.50 g, 56.70 mM) were stirred and refluxed in DMF (100 mL) for 22 hours. The cooled yellow suspension was poured into dilute hydrochloric acid (1N, 1.0 L) with good stirring. A white precipitate formed and was collected. This solid was resuspended in aqueous methanol (50%, 1.0 L) and stirred/sonicated to give a fine white suspension. Filtration and resuspension in methanol (0.25 L) gave a free-flowing white suspension after sonication and brief warming. The solids were finally collected and washed with methanol to give the title compound (4.65 g, 79%) as a white powder, mp 349-352° C.; MS(CI): 437 (M+H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(#N)C.[N:9]1([CH2:14][CH:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH2:16]2)[CH2:13][CH2:12][CH2:11][CH2:10]1.C(N(CC)CC)C>O>[CH3:1][S:2]([N:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH:15]([CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:16]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: c1ccc2c(c1)CC(CN1CCCC1)CN2
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC(CN2CCCC2)Cc2ccccc21
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.65 ml) was added dropwise to an acetonitrile (20 ml) solution of 3-(pyrrolidin-1-yl)methyl-1, 2,3, 4-tetrahydroquinoline (Reference Example 47; 1.5 g) and triethylamine (2.9 ml) under ice-cooling. The reaction mixture was stirred at the same temperature for one hour, to which was added water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, then dried and concentrated. The residue was purified by alumina column chromatography (eluent: hexane to hexane/ethylacetate=7/1). The crystals were washed with IPE to obtain the entitled compound (1.20 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].[N:13]1([C:18]2[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=2)[CH:17]=[CH:16][CH:15]=[N:14]1>>[CH3:2][O:3][C:4](=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH2:22][C:21]1[CH:20]=[CH:19][C:18]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)=[CH:25][CH:24]=1
Reactant: O=Cc1ccc(-n2cccn2)cc1
Reactant: COC(=O)CCCCCCN
Agent: Cl
Product: COC(=O)CCCCCCNCc1ccc(-n2cccn2)cc1

Procedure:
The title compound of Step A was prepared from 7-amino-heptanoic acid methyl ester hydrochloride, of Preparation 1, and 4-pyrazol-1-yl-benzaldehyde, of Preparation 42, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 7.90 (m, 1H), 7.70 (d, 1H), 7.63 (d, 2H), 7.39 (d, 2H), 6.45 (m, 1H), 3.80 (s, 2H), 3.65 (s, 3H), 2.61 (t, 2H), 2.29 (t, 2H), 1.63-1.32 (m, 4H), 1.25 (m, 4H); MS 316 (M+1).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH:6][CH:7]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[N+:21]([C:24]1[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=1)([O-:23])=[O:22]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([CH:7]([NH:6][C:4]([CH2:3][NH:2][C:28](=[O:29])[C:27]2[CH:26]=[CH:25][C:24]([N+:21]([O-:23])=[O:22])=[CH:32][CH:31]=2)=[O:5])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: NCC(=O)NC(c1ccccc1)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CNC(=O)c1ccc([N+](=O)[O-])cc1)NC(c1ccccc1)c1ccc(Cl)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-[(4-chloro-phenyl)-phenyl-methyl]-acetamide hydrochloride (Example 3.1) and 4-nitrobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:12]=[N:13][N:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:15]=1)=[O:10].Br[CH2:23][C:24]([O:26]CC)=[O:25]>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:23][C:24]([OH:26])=[O:25])=[C:3]([C:9]([C:11]2[CH:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:15]=2)=[O:10])[CH:4]=1
Reactant: Cc1ccc(O)c(C(=O)c2cnn(-c3ccccc3)c2)c1
Reactant: CCOC(=O)CBr
Product: Cc1ccc(OCC(=O)O)c(C(=O)c2cnn(-c3ccccc3)c2)c1

Procedure:
Prepared from (2-hydroxy-5-methylphenyl)-(1-phenyl-1H-pyrazol-4-yl)-methanone and ethyl bromoacetate according to GP2 and GP3: LC/MS (an 10p8): Rt 3.08 min, m/z 356.6 [M+1]+; 1H NMR (CDCl3): δ2.37 (s, 3H), 4.78 (s, 2H), 6.97 (d, J=9.0 Hz, 1H), 7.33-7.51 (m, 5H), 7.73 (d, J=6 Hz, 2H), 8.16 (s, 1H), 8.51 (s, 1H), 11.21 (br s, 1H)
Reaction SMILES: C1C2NC3C(=CC=CC=3)C=2C=CC=1.[F:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([N+:30]([O-])=O)=[CH:28][C:27]([CH3:33])=[CH:26][N:25]=2)=[CH:20][CH:19]=1>>[F:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[C:24]3[N:25]=[CH:26][C:27]([CH3:33])=[CH:28][C:29]=3[NH:30][C:20]=2[CH:19]=1
Reactant: Cc1cnc(-c2ccc(CCCF)cc2)c([N+](=O)[O-])c1
Agent: c1ccc2c(c1)[nH]c1ccccc12
Product: Cc1cnc2c(c1)[nH]c1cc(CCCF)ccc12

Procedure:
General experimental procedure for carbazole formation was followed. Reaction was performed on a 8.9 mg scale of 2-(4-(3-fluoropropyl)phenyl)-5-methyl-3-nitropyridine. Isolated 3.6 mg (45%) of T793 as a white solid. 1H NMR (CD3OD): δ 8.48 (1H, d, J=1.6 Hz), 8.39 (1H, d, J=1.6 Hz), 8.21 (1H, d, J=8.4 Hz), 7.55 (1H, d, J=1.6 Hz), 7.34 (1H, d, J=8.4, 1.6 Hz), 4.52 (1H, t, J=6.0 Hz), 4.40 (1H, t, J=6.0 Hz), 2.97 (2H, t, J=7.6 Hz), 2.68 (3H, s), 2.03-2.15 (2H, m); MS: 243 (M+H+).