Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[N:27]1([C@@H:32]2[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30][CH2:29][CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:34]3[CH2:35][CH2:36][CH2:37][C@@H:32]([N:27]4[CH2:28][CH2:29][CH2:30][CH2:31]4)[CH2:33]3)=[O:20])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: C1CNC[C@H](N2CCCC2)C1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CCC[C@@H](N4CCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (R)-3-(pyrrolidin-1-yl)piperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.54 (d, J=9.09 Hz, 1H) 1.72-1.96 (m, 4H) 1.96-2.11 (m, 2H) 2.16 (br. s., 1H) 2.43 (s, 3H) 2.82-3.35 (m, 3H) 3.35-3.87 (m, 5H) 4.26 (br. s., 1H) 7.67 (d, J=8.08 Hz, 1H) 7.74 (s, 2H) 8.11 (d, J=8.08 Hz, 2H) 8.57 (d, J=2.02 Hz, 2H) 9.83 (br. s., 1H); ESI-MS m/z [M+H]+ 457.3.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH2:12][C:13](=O)[CH3:14].C([OH:23])C1C=CC=CC=1.O[Li].O.Cl>ClCCl>[F:1][C:2]1[C:7]([OH:23])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[C:13]([CH3:14])[NH:9]2
Reactant: OCc1ccccc1
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH.H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford 1.6 g of the desired compound which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 um 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH:water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [CH3:1][O:2]CCOC.[O:7]1[C:11]2[CH:12]=[C:13]([S:16]([CH:19]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=3[F:38])[C:20]3[C:21]([CH3:29])=[CH:22][C:23]([C:26]([NH2:28])=[O:27])=[N:24][CH:25]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8]1.C=O.[OH-].[Na+]>O>[O:7]1[C:11]2[CH:12]=[C:13]([S:16]([CH:19]([C:30]3[C:35]([F:36])=[CH:34][CH:33]=[C:32]([F:37])[C:31]=3[F:38])[C:20]3[C:21]([CH3:29])=[CH:22][C:23]([C:26]([NH:28][CH2:1][OH:2])=[O:27])=[N:24][CH:25]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:10]=2[CH:9]=[CH:8]1
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc2ccoc2c1
Reactant: COCCOC
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(C(=O)NCO)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc2ccoc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a 1,2-dimethoxyethane solution (5 ml) of 5-[(1-benzofuran-6-ylsulfonyl)(2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (210 mg, 0.457 mmol), an aqueous solution of formaldehyde (37%, 0.111 ml) and 1 N aqueous sodium hydroxide (0.023 ml) were added, and the mixture was stirred for 4 hours at room temperature. An aqueous solution of formaldehyde (37%, 0.111 ml) and 1 N aqueous sodium hydroxide (0.023 ml) were added to the reaction mixture, and the mixture was stirred for 5 hours at room temperature. An aqueous solution of formaldehyde (37%, 0.111 ml) was further added, and then the mixture was stirred for 18 hours at room temperature. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, and then was washed with water and saturated brine. The mixture was dried over magnesium sulfate and concentrated, and the resulting residue was subjected to flash silica gel column chromatography. The fraction obtained from an elution with hexane:ethyl acetate=2:3 was concentrated. The resulting solid was recrystallized from 2-propanol to obtain the title compound (138 mg, 0.273 mmol, 60%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[Na].S(=O)(=O)=O>CC(N(C)C)=O.O>[CH3:11][N:12]([CH3:21])[C:13]1[CH:20]=[CH:19][C:16]([C:17]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: NC(=O)c1ccccc1N
Reactant: CN(C)c1ccc(C=O)cc1
Agent: O=S(=O)=O
Agent: [Na]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CN(C)c1ccc(-c2nc(O)c3ccccc3n2)cc1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-aminobenzamide (1.36 g, 9.99 mmol, 1.00 equiv) in dimethylacetamide (25 mL), 4-(dimethylamino)benzaldehyde (1.49 g, 9.99 mmol, 1.00 equiv) and sulfonylideneoxidane sodium (1.6 g, 15.53 mmol, 1.50 equiv). The resulting solution was stirred overnight at 150° C. in an oil bath. The reaction mixture was cooled to 25° C. The resulting solution was diluted with 100 mL of water. The solids were collected by filtration. The solid was washed with 2×20 mL of water and 1×20 mL of petroleum ether. This resulted in 2.1 g (79%) of 2-[4-(dimethylamino)phenyl]quinazolin-4-ol as a gray solid. MS (ESI) m/z 266 ([M+H]+).
Reaction SMILES: [CH3:1][CH:2]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([O:36][C:37]([O:39][CH3:40])=[O:38])[CH2:22][C@@H:23]2[O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:18][CH:17]=3)[CH2:14][CH2:13]1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[OH:41]O>CO.O>[CH3:1][CH:2]([C@@H:12]1[C@:29]2([CH3:30])[C@H:15]([C:16]3[C@H:26]([CH2:27][CH2:28]2)[C@:24]2([CH3:25])[C:19]([CH2:20][C@@H:21]([O:36][C:37]([O:39][CH3:40])=[O:38])[CH2:22][C@@H:23]2[O:31][C:32]([O:34][CH3:35])=[O:33])=[CH:18][CH:17]=3)[CH2:14][CH2:13]1)[CH2:3][S:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:41])=[O:5]
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: OO
Solvent: CO
Solvent: O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CS(=O)(=O)c5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 29 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfinylpregna-5,7-diene in 1 ml of methanol was added 0.5 ml of a 30% aqueous solution of hydrogen peroxide and the mixture was stirred at ambient temperature for 6 hours. The reaction mixture was diluted with water and the methanol was distilled off under reduced pressure. The residue was extracted with methylene chloride, the extract was washed with an aqueous solution of sodium thiosulfate, water and an aqueous solution of sodium chloride, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 13 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylsulfonylpregna-5,7-diene, whose 1H NMR spectrum was identical with that obtained in Example 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[Br:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2cc(Br)c(OCc3ccccc3)cc2n1
Product: Cc1cc(N2CCCC2)c2cc(Br)c(OCc3ccccc3)cc2n1
Yield: 62.9 %

Procedure:
A mixture of 7-benzyloxy-6-bromo-4-chloro-2-methyl-quinoline (10.0 g, 27.6 mmol) and pyrrolidine (47 mL, 0.562 mol) was refluxed during 3 h. The mixture was cooled down and the pyrrolidine was evaporated under high vacuum. The residue was taken up in dichloromethane, washed with water and brine, dried over sodium sulfate, filtered and the solvents were evaporated under vacuum. 6.9 g of the title compound were obtained. Brown solid, ISP-MS: m/e=399.2 ([M+H]+).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[C:28]1([N:34]([C:41]2[CH:48]=[CH:47][C:44]([CH:45]=O)=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O1CCCC1>[C:28]1([N:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:48]=[CH:47][C:44]([CH:45]=[CH2:2])=[CH:43][CH:42]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a two necked flask, under argon atmosphere, 22.18 g (54.87 mmol) of methyl(triphenyl)phosphonium iodide are dissolved in 100 mL of freshly distilled tetrahydrofuran (THF). After the mixture is cooled to the temperature of 0° C., 1.5 eq. (6.16 g) of potassium tert-butoxide are incorporated. After 30 min of stirring at 0° C., a solution of 4-(N,N-diphenylamino)-benzaldehyde (10 g, 36.80 mmol) in 30 mL of THF is added to the mixture, drop by drop. The temperature of the medium is then left to return to ambient temperature and the stirring continued for 4 additional hours. The medium is then hydrolysed with a saturated sodium carbonate solution then extracted in dichloromethane. The organic phase is washed successively with water, a saturated NaCl solution then dried on Na2SO4. After filtration and evaporation, the crude product is purified on chromatography column on silica [eluent—hexane/ethyl ether: 80/20].
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:19](=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCc1ccccc1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -75 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (R)-(+)-4-benzyl-2-oxazolidinone (910 g, 5.14 mol) and 500 mg of 2,2'-dipyridyl as an indicator in tetrahydrofuran (9 L) at -78° C. was added over 30 minutes a 2.5M solution of BuLi in hexanes (2.03 L, 5.14 mol). The temperature of the reaction mixture was maintained at less than -55° C. during the addition. The reaction mixture was cooled to -75° C. and hydrocinnamoyl chloride (950 g, 5.63 mol) was added over 5 minutes. The reaction mixture was allowed to warm to 0° C., at which point the reaction mixture was judged to be complete by thin layer chromatography (hexanes/ethyl acetate, 2:1). The reaction was quenched by adding 10% aqueous sodium bicarbonate (3.6 L) and water (3.6 L). The aqueous phase was separated and extracted with ethyl acetate (3 L). The combined organic layers were washed with 5% aqueous sodium carbonate (3.6 L) and saturated aqueous sodium chloride (2 L), dried over magnesium sulfate, and concentrated in vacuo to approximately 2 L of a viscous yellow suspension. This slurry was dissolved in ethyl acetate (3 L), concentrated to a solid, and dissolved in ethyl acetate at 50° C. Hexanes (10.7 L) was added, and the mixture was slowly cooled to 10° C. resulting in the precipitation of solids which were stirred at 10° C. for 30 minutes. The solids were collected by filtration, washed with hexanes, and air-dried at ambient temperature yielding 1.4 kg (88%) of (R)-4-benzyl-3-(3-phenyl-propionyl)-oxazolidin-2-one as pale yellow needles: 1H NMR (300 MHz, CDCl3) δ 7.14-7.33 (m, 10H), 4.66 (m, 1H), 4.17 (t, J=3.4 Hz, 2H), 3.26 (m, 3H), 3.03 (t, J=7 Hz, 2H), 2.75 (dd, J=9.5, 13.4 Hz, 1H); IR 1787, 1761, 1699, 1390, 1375, 1308, 1208, 1203, 746, 699 cm-1 ; mp 102-104° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=O)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>ClCCl>[CH:25]1([O:31][CH2:32][CH2:33][CH:34]=[C:1]([Br:5])[Br:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: BrC(Br)(Br)Br
Reactant: O=CCCOC1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=CCCOC1CCCCC1
Reaction time: 0.08 h
Yield: 73.4 %

Procedure:
Subsequently, to a solution of carbon tetrabromide (36.5 g, 0.11 mol) in dichloromethane (120 ml) was added a solution of triphenylphosphine. (57.7 g, 0.22 mol) in dichloromethane (120 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred for 5 minutes. After stirring, to the reaction mixture was added a solution of the crude 3-cyclohexyloxypropionaldehyde (8.60 g) obtained above in dichloromethane (90 ml) with stirring while ice-cooling under a nitrogen atmosphere, and the resulting mixture was stirred at the same temperature for 25 minutes. After stirring, the reaction mixture was diluted with dichloromethane and washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (100:1–33:1) as the eluent to afford 4-cyclohexyloxy-1,1-dibromobut-1-ene (12.6 g, overall yield in two steps: 55%).
Reaction SMILES: ClCC=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CN
Reactant: ClCC=Cc1ccccc1
Product: CNCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The N-methylaminomethyl polystyrene resin is prepared as follows: To liquid methylamine, kept below −20° C., chloromethylstyrene copolymer (Merrifield resin) is added (˜1 g of resin per 10 ml of methylamine). The suspension is shaken in a pressure bottle at RT for 14 h. The resin is filtered off and washed with DMA (2×), H2O (2×), DMA (1×), CH3OH (2×), CH2Cl2 (3×), CH3OH (2×) and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N1C=CC=CC=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:24](Cl)=[O:25]>ClCCl>[N+:10]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:9]=[CH:8][C:6]=1[NH:7][C:24](=[O:25])[C:23]1[CH:22]=[C:21]([O:20][CH3:19])[C:29]([O:30][CH3:31])=[C:28]([O:32][CH3:33])[CH:27]=1)([O-:12])=[O:11]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cc(OC)c(OC)c(OC)c2)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 4-methoxy-2-nitroaniline (45 mmole, 6.8 g) in dichloromethane (120 ml) and pyridine (75 mmole, 6 ml) is added 3,4,5-trimethoxybenzoylchloride (50 mmole, 11.5 g) in dichloromethane (40 ml). The mixture is stirred at room temperature over night. The precipitate is filtered off and dried in vacuo to yield the title product as an orange solid (74%).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([C:12]3([CH2:15][OH:16])[CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[Si:24](OS(C(F)(F)F)(=O)=O)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Si:24]([O:16][CH2:15][C:12]1([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]3)[CH2:14][CH2:13]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: Cc1ccc2cccc(C3(CO)CC3)c2n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2cccc(C3(CO[Si](C)(C)C(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of (1-(2-methylquinolin-8-yl)cyclopropyl)methanol (0.050 g, 0.234 mmol) and triethylamine (0.065 mL, 0.47 mmol) in DCM (5 mL) was added TBSOTf (0.065 mL, 0.28 mmol) at ambient temperature and the reaction was stirred at ambient temperature for 1 hour. Saturated sodium bicarbonate (10 mL) and DCM (20 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (10:1 hexane/ethyl acetate) to give 8-(1-((tert-butyldimethylsilyloxy)methyl)cyclopropyl)-2-methylquinoline (0.071 g, 92.5%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][CH2:10][CH:11]1[CH2:16][C:15](=O)[O:14][C:12]1=[O:13].C(Cl)(=O)C>C1(C)C=CC=CC=1>[Cl:9][CH2:10][CH:11]1[CH2:16][C:15](=[O:14])[N:6]([C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]1=[O:13]
Reactant: O=C1CC(CCl)C(=O)O1
Reactant: Nc1ccc(F)cc1
Solvent: CC(=O)Cl
Solvent: Cc1ccccc1
Product: O=C1CC(CCl)C(=O)N1c1ccc(F)cc1
Temperature: 100 °C
Yield: 93 %

Procedure:
In a variant of (b), into a toluene solution of 33.3 g (0.3 moles) 4-fluoroaniline, a toluene solution of 44.6 g (0.3 moles) 2-chloromethylsuccinic acid anhydride were added dropwise at room temperature while stirring. The temperature of the mixture rose to 40° C. during the operation. To the suspension of the semi-anilide obtained, 0.35 moles of acetylchloride was added dropwise at 60° C. while stirring, the addition being carried out so slowly that the ensuing gas development could be easily controlled. After 3 hours the reaction mixture was heated to 100° C. and held at that temperature until the gas development was terminated. The semi-anilide thereby dissolved. When the reaction mixture was cooled down, the desired product crystallized. The actual yield was 93% of the theoretical yield.
Reaction SMILES: N1C=CN=C1.[C:6]1([P:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.II.CC[O:29]CC>C(Cl)Cl>[C:19]1([P:12](=[O:29])([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOCC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: II
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -2 °C
Reaction time: 0.25 h

Procedure:
A 12-L, three-neck, round-bottom flask equipped with a mechanical stirrer, thermocouple, nitrogen bubbler, and an additional funnel, was charged with imidazole (204 g, 2.99 mol, 6.0 equivalents), triphenylphosphine (300 g, 1.14 mol, 2.3 equivalents), and methylene chloride (2.5 L). The resulting solution was cooled to −2° C. and to this was added iodine (290 g, 1.14 mol, 2.3 equivalents). The resulting mixture was allowed to stir for 15 minutes, and then a solution of (12) (274 g, 0.50 mol) in methylene chloride (1.3 L) was added slowly, over 35 minutes. The resulting orange mixture was allowed to warm to room temperature where it was stirred for three hours. The reaction mixture was filtered, and the filtrate was washed successively with 2% aqueous sodium sulfite solution (1×2 L), 0.1 N aqueous hydrochloric acid solution (1×1.5 L), and saturated aqueous sodium chloride solution (1×1.5 L). The organics were then dried over anhydrous magnesium sulfate and filtered. The solvent was removed in vacuo to afford a yellow residue which was dissolved in ether (4 L) producing a white precipitate (triphenylphosphine oxide). The solution was filtered and the filtrate was evaporated in vacuo to afford 320 g of (13) as a yellow oil contaminated with triphenylphosphine oxide. This material was used in the next step without purification.
Reaction SMILES: N[C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.N[C@@H](C(O)=[O:29])CC1C2C(=CC=CC=2)NC=1.NC(C(O)=O)CC1C2C(=CC=CC=2)NC=1>>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C:2](=[O:29])[C:13]([OH:15])=[O:14])=[CH:5]1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: NC(Cc1c[nH]c2ccccc12)C(=O)O
Product: O=C(O)C(=O)Cc1c[nH]c2ccccc12

Procedure:
The “amino acid oxidase activity” for reaction 1 means an activity catalyzing the reaction shown in scheme (13). Generally, L-amino acid oxidase generates keto acid from the corresponding L-amino acid, while D-amino acid oxidase generates keto acid from the corresponding D-amino acid. Specifically, in accordance with the present invention, individually, a microorganism having L-amino acid oxidase activity may be used when L-tryptophan is used as the raw material, while a microorganism having D-amino acid oxidase activity may used when D-tryptophan is used as the raw material. Additionally, the preparation from DL-tryptophan is also applicable. When D- and L-amino acid oxidase is allowed to interact with DL-tryptophan, the intended indole-3-pyruvic acid may be quantitatively produced. When D- or L-amino acid oxidase interacts with DL-tryptophan, otherwise, the intended indole-3-pyruvic acid may be produced at a yield of 50%.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-])=O.[CH:10](O)=[O:11]>[Pt].[O-2].[V+5].[O-2].[O-2].[O-2].[O-2].[V+5]>[CH:10]([NH:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:11]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: O=CO
Agent: [Pt]
Agent: [V+5]
Agent: [O-2]
Product: O=CNc1ccccc1
Temperature: 92.5 °C
Yield: 79.9 %

Procedure:
Nitrobenzene (12.31 g, 100 mmol), formic acid (80%; 278 mL, 328.0 g), a sulfided platinum catalyst (5% Pt on charcoal, Engelhard No. 43045, lot No. 08554; dry weight 1.55 g) and vanadium(v) oxide (57 mg) were charged under argon in a double-walled 0.3 L stirring vessel with temperature control. The argon flow was stopped and the slurry was heated to 91-94° C. for 2 h. HPLC analysis of the reaction mixture indicated a 79.9% yield of formanilide, accompanied by 18.3% of aniline.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1.[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH3:18])[C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:22]([C:21]4[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=4[Cl:19])=[O:23])=[N:15][CH:16]=3)=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: O=C(Cl)c1ccccc1Cl
Reactant: Cc1cc2c(C)noc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2c(C)noc2cc1-c1ccc(NC(=O)c2ccccc2Cl)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of 5-(3,5-dimethylbenzo[d]isoxazol-6-yl)-2-pyridylamine (105) (14.5 mg, 0.06 mmol) in 1 ml DCM was added 2-chlorobenzoyl chloride (16 μl, 0.12 mmol) followed by addition of DIEA (63 μl). The resulting solution was stirred at r.t. for 2 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (120 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished N-[5-(3,5-dimethylbenzo[d]isoxazol-6-yl)(2-pyridyl)](2-chlorophenyl)carboxamide (106) (17.1 mg, yield: 75.4%, purity>95%) as off-white solid.