Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:27]=[C:26]([Cl:28])[N:25]=[C:24]([N:29]([CH2:34][CH2:35][CH3:36])[S:30]([CH3:33])(=[O:32])=[O:31])[CH:23]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C>ClCCl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[CH2:1]([C:8]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:11])[CH2:9][O:10][CH2:21][C:22]1[CH:23]=[C:24]([N:29]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:34][CH2:35][CH3:36])[N:25]=[C:26]([Cl:28])[CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CCCN(c1cc(CBr)cc(Cl)n1)S(C)(=O)=O
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: ClCCl
Product: CCCN(c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(Cl)n1)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl (1-benzyl-2-hydroxy-1-methylethyl)carbamate (250 mg, 0.94 mmol, intermediate IV) and N-[4-(bromomethyl)-6-chloropyridin-2-yl]-N-propylmethanesulfonamide (290 mg, 0.85 mmol) in dichloromethane (20 mL) was added silver triflate (290 mg, 1.13 mmol) and 2,6-ditertbutylpyridine polymer bound (1.84 g, 2.83 mmol, Aldrich 37, 782-1). The reaction mixture was stirred at 50° C. in an oil bath for 16 h and then irradiated under microwave (Smith Synthesizer) at 90° C. for 45, 60 and 90 min intervals (3 runs, with addition of additional silver triflate and 2,6-ditertbutylpyridine polymer bound before 2nd and 3rd run). The reaction mixture was filtered on celite, rinsed with dichloromethane, concentrated in vacuo and purified by flash chromatography (silica, 0-30% EtOAc/hexanes) to provide tert-butyl [1-benzyl-2-({2-chloro-6-[(methylsulfonyl)(propyl)amino]pyridin-4-yl}methoxy)-1-methylethyl]carbamate. 1H NMR (400 MHz, CDCl3) δ 7.34-7.16 (m, 7H), 4.56 (s, 2H), 4.50 (s, 1H), 3.83 (t, J=6.8 Hz, 2H), 3.66 (A of AB, d, J=9.2 Hz, 1H), 3.54 (B of AB, d, J=9.2 Hz, 1H), 3.15 (A of AB, d, J=13.2 Hz, 1H), 3.03 (s, 3H), 2.90 (B of AB, d, J=13.2 Hz, 1H), 1.64-1.50 (m, 2H), 1.47 (s, 9H), 1.26 (s, 3H), 0.92 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12](=O)[CH:13]=[CH2:14].[NH2:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]1[N:26]([C:23]2[CH:24]=[CH:25][C:20]([S:17]([NH2:16])(=[O:18])=[O:19])=[CH:21][CH:22]=2)[C:12]([CH3:11])=[CH:13][CH:14]=1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(C)=O
Reactant: O=Cc1ccc(Cl)cc1Cl
Product: Cc1ccc(-c2ccc(Cl)cc2Cl)n1-c1ccc(S(N)(=O)=O)cc1

Procedure:
2,4-Dichlorobenzaldehyde and but-3-en-2-one were treated according to the procedure outlined in General Procedure C followed by subjecting the resulting product to conditions outlined in General Procedure D along with p-aminosulfonyl phenylamine to obtain the titled compound. 1H NMR (CDCl3) δ ppm 2.20 (3H), 4.82 (2H), 6.12 (1H), 6.35 (1H), 7.15-7.90 (8H); MS (ESI) m/z 381/383.
Reaction SMILES: [Na].Br[C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[C-]#N.[Na+:10].[CH3:11][OH:12]>O>[CH3:11][O-:12].[Na+:10].[CH3:11][O:12][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccs1
Reactant: CO
Agent: [C-]#N
Agent: [Na+]
Agent: [Na]
Solvent: O
Product: COc1cccs1
Product: C[O-]
Yield: 76 %

Procedure:
2-Methoxythiophene was prepared by the procedures described in H. A. Keeystra et al., Tetrahedron, 1992, 48, 3633. Thus, a solution of sodium methoxide in methanol was prepared by adding sodium (2.12 g, 92.2 mmol) to methanol (14 ml). 2-Bromothiophene (10 g, 61.3 mmol) was added while maintaining reflux. Cuprous bromide (0.88 g, 6.1 mmol) was added and the mixture was maintained at reflux for 5.5 hours. A solution of sodium cyanide (3 g, 61.3 mmol) in water (30 ml) was added at 20-25° C. under vigorous stirring. The mixture was stirred until all solids dissolved, extracted with hexane, dried (Na2SO4), and concentrated to dryness. Distillation (90° C., 80 mmHg) gave 2-methoxythiophene (5.35 g, 76%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:13]=[C:12]([O:14][CH:15]([F:17])[F:16])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)Cl.F[B-](F)(F)F.[O:27]=[N+:28]=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[C:3]([C:9]2[C:13]([N+:28]([O-:29])=[O:27])=[C:12]([O:14][CH:15]([F:16])[F:17])[N:11]([CH3:18])[N:10]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cn1nc(-c2ncc(Cl)cc2F)cc1OC(F)F
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1nc(-c2ncc(Cl)cc2F)c([N+](=O)[O-])c1OC(F)F
Reaction time: 8 h
Yield: 93.6 %

Procedure:
4.0 g of 3-(3-fluoro-5chloro-2-pyridyl)-5-difluoromethoxy-1-methyl-[1H]-pyrazole (Example HIS) are initially introduced into 30 ml of methylene chloride. 3.83 g of nitronium tetrafluoroborate are added, while stirring and cooling in an ice-bath, and the mixture is subsequently stirred overnight at 22° C. The following day, it is poured onto water, and ethyl acetate is added. After extraction by shaking and separation of the phases, the organic phase is washed with dilute bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated in vacuo. 4.35 g of the desired title compound are obtained as a brown solid of melting point 108-109° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([NH2:13])[NH:10][N:9]=2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[CH:17][C:16]=1[O:29][CH3:30].CC1C=CC(S(O)(=O)=O)=CC=1>CCCCO>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:13][C:11]3[N:10]([N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:12]=3)[C:23](=[O:24])[CH:22]=2)=[CH:17][C:16]=1[O:29][CH3:30]
Reactant: CCOC(=O)CC(=O)c1ccc(Cl)c(OC)c1
Reactant: Nc1nc(-c2ccc(Cl)cc2)n[nH]1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCO
Product: COc1cc(-c2cc(=O)n3nc(-c4ccc(Cl)cc4)nc3[nH]2)ccc1Cl
Temperature: 130 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
To a solution of 3-(4-chlorophenyl)-1H-1,2,4-triazol-5-amine (100 mg, 0.51 mmol) in n-BuOH (1 ml) was added ethyl 3-(4-chloro-3-methoxyphenyl)-3-oxopropanoate (200 mg, 0.78 mmol) and TsOH (5 mg, 0.02 mmol), and the resulting mixture was stirred overnight at 130° C. The solids were collected by filtration and washed with methanol (2×5 ml) to afford 5-(4-chloro-3-methoxyphenyl)-2-(4-chlorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (56.6 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([OH:30])=O)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:56][O:57][C:58](=[O:68])[C:59]1[CH:64]=[C:63]([F:65])[C:62]([NH2:66])=[CH:61][C:60]=1[F:67].NC1C=CC=CC=1>C(Cl)Cl>[CH3:56][O:57][C:58](=[O:68])[C:59]1[CH:64]=[C:63]([F:65])[C:62]([NH:66][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:30])=[CH:61][C:60]=1[F:67]
Reactant: COC(=O)c1cc(F)c(N)cc1F
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(F)c(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Reaction time: 0.08 h

Procedure:
To a stirred solution of (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid (300 mg, 0.64 mmol) in methylene chloride (5 mL), DIPEA (Aldrich, 2.57 mmol, 0.45 ml) was added followed by diphenylphosphinic chloride (Aldrich, 1.93 mmol, 0.37 ml). The mixture was stirred for 5 min. and 4-amino-2,5-difluoro-benzoic acid methyl ester (Prepared by methylation of the corresponding acid. 201 mg, 0.76 mmol) was added and the mixture was stirred overnight. The reaction was quenched with 10% sodium carbonate (6 mL) and the mixture was stirred for 15 min. The organic layer was separated and the solvent was reduced to about 3 ml. The solution was loaded onto a 40 g silica gel column and eluted with 2% EtOAc/CH2Cl2 to give a mixture of the desired product and aniline. The crude was again chromatographed on a reverse phase column and eluted with 50-95% acetonitrile/water to give a white solid. 82 mg. (ES+) m/z Calcd: [(M+H)+]: 636. found: 636.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1B(O)O.C([O-])([O-])=O.[K+].[K+].O.Cl[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>COCCOC.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>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[C:25]1[C:30]([CH3:31])=[CH:29][C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1
Reactant: COc1cc(OC(F)(F)F)ccc1B(O)O
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
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: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(OC(F)(F)F)ccc1-c1ncc([N+](=O)[O-])cc1C
Temperature: 85 °C
Reaction time: 19 h

Procedure:
2-methoxy-4-trifluoromethoxybenzene boronic acid (72 g, 0.31 mol), K2CO3 (80.16 g, 0.58 mol) and water (100 ml) are added to a solution of 2-chloro-3-methyl -5-nitro-pyridine (50 g, 0.29 mol) in DME (500 ml) at room temperature. Pd(Ph3P)4 (3.35 g, 2.9 mmol) is added and the mixture is stirred at 85° C. for 19 hours. 500 ml of water is added and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. After removal of the solvent under reduced pressure, the residue is purified by flash column chromatography (hexane/EtOAc 9:1) to obtain 2-(2-methoxy-4-trifluoromethoxy-phenyl)-3-methyl-5-nitro-pyridine. Rf (hexane/EtOAc=9:1)=0.41.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([CH3:13])([CH3:12])[CH2:10][OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:14][CH2:15][CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Cl)=[CH:20][CH:19]=1.O>C(#N)C>[C:3]1([C:9]([CH3:13])([CH3:12])[CH2:10][O:11][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([O:17][CH2:16][CH2:15][F:14])=[CH:25][CH:24]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(CO)c1ccccc1
Reactant: FCCOc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(COCc1ccc(OCCF)cc1)c1ccccc1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
Sodium hydride (1.4 g; 60% in oil) was added to 20 ml of dry acetonitrile, and a solution of 4.4 g of 2-phenyl-2-methylpropyl alcohol in 10 ml of acetonitrile was added dropwise at 50° C. The mixture was heated under reflux for 30 minutes, and a solution of 5.4 g of 4-(2-fluoroethoxy)benzyl chloride in 10 ml of acetonitrile was added dropwise over 10 minutes. The mixture was further heated under reflux for 1 hour. The reaction mixture was cooled to room temperature, poured into water, and extracted with toluene. The toluene layer was washed with water and dried over anhydrous sodium sulfate. Toluene was evaporated under reduced pressure. The resulting crude ether was purified by silica gel (180 g) column chromatography (developing solvent: a 2:1 mixture of toluene and n-hexane) to give 6.5 g of 4-(2-fluoroethoxy)benzyl 2-phenyl-2-methylpropyl ether.
Reaction SMILES: [OH2:1].[O-:2][Mn]([O-])(=O)=O.[K+:7].[K+].[Mo:9]=[O:10].[OH-:11].[K+]>>[OH2:2].[OH2:1].[OH2:2].[OH2:2].[OH2:2].[O-:1][Mo:9]([O-:2])(=[O:11])=[O:10].[K+:7].[K+:7]
Reactant: O=[Mo]
Reactant: [OH-]
Reactant: O=[Mn](=O)([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[Mo](=O)([O-])[O-]

Procedure:
Solid Potassium Molybdate (K2MoO4) may be prepared by dissolving MoO3 in a basic aqueous solution of potassium hydroxide (KOH) and crystallizing the filtered product to yield potassium molybdate pentahydrate (K2MoO4.5H2O). The anhydrous salt may be prepared by heating to a sufficient temperature to liberate the water.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([I:8])[CH:3]=1.[C:9]([O:12]O)(=[O:11])[CH3:10]>>[C:9]([O-:12])(=[O:11])[CH3:10].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:1][C:2]1[CH:3]=[C:4]([I+2:8])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)OO
Reactant: Clc1cccc(I)c1
Product: CC(=O)[O-]
Product: Clc1cccc([I+2])c1
Reaction time: 12 h
Yield: 367.3 %

Procedure:
1-Chloro-3-iodobenzene (5.0 g, 21 mmol) was stirred at 30° C. Peracetic acid (40%, 8.35 mL, 50.3 mmol) was added drop wise to the solution and the reaction was allowed to stir for 12 h. The white solid that formed was filtered, washed 1 time with 10% acetic acid, and 3 times with hexanes and dried in vacuo to afford the title product (27.5 g, 92%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][CH:3]=1.[CH2:15]([Li])[CH2:16][CH2:17][CH3:18].[OH2:20]>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[C:6]([C:15]([C:16]2[C:5]([CH3:4])=[N:8][CH:9]=[CH:18][CH:17]=2)=[O:20])[CH:7]=1
Reactant: [Li]CCCC
Reactant: O
Reactant: CC(C)(C)C(=O)Nc1ccc(Cl)cc1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ncccc1C(=O)c1cc(Cl)ccc1NC(=O)C(C)(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a magnetically stirred solution of N-(4-chloro-phenyl)-2,2-dimethyl-propionamide (3.16 g, 14.9 mmol) in dry THF was added 2.5M n-butyllithium in hexane at −40° C. and the mixture was stirred at 0° C. for 2 h and a suspension of white solid resulted. A solution of the Weinreb amide (1.80 g, 10.0 mmol) in dry THF was added drop wise and the reaction was stirred at ambient temp overnight. The mixture was diluted with water and extracted with ethyl acetate and the organic layer was dried (MgSO4), filtered and concentrated. Chromatography on silica gel (20-30% EtOAc/Hexane) provided the desired N-[4-Chloro-2-(2-methyl-pyridine-3-carbonyl)-phenyl]-2,2-dimethyl-propionamide as a waxy bright yellow solid (2.28 g, 6.89 mmol): 1H NMR (CDCl3) δ 11.71 (s, 1H, NH), 8.82 (d, 1H, J=9.2 Hz), 8.67 (dd, 1H, J=4.8 Hz, J=1.8 Hz), 7.55 (m, 2H), 7.28 (d, 1H, J=2.5 Hz), 7.25 (m, 1H), 2.54 (s, 3H), 1.39 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:29][CH2:28][CH2:27][NH:26]3)=[N:9][C:10]=2[C:11]2[CH:24]=[CH:23][C:14]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:30][N:31]([CH3:38])[CH2:32]/[CH:33]=[CH:34]/[C:35](O)=[O:36]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:25]3[CH2:29][CH2:28][CH2:27][N:26]3[C:35](=[O:36])/[CH:34]=[CH:33]/[CH2:32][N:31]([CH3:38])[CH3:30])=[N:9][C:10]=2[C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[S:19][CH:20]=[CH:21][N:22]=3)=[O:16])=[CH:23][CH:24]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN(C)C/C=C/C(=O)O
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4nccs4)cc3)c12
Product: CN(C)C/C=C/C(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3nccs3)cc2)c2c(N)nccn12
Yield: 29.7 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(pyrrolidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(thiazol-2-yl)benzamide (intermediate 20) and (E)-4-(dimethylamino)but-2-enoic acid, to afford the title compound (18.9 mg, 29.7%). Data: UPLC (C) Rt: 1.38 min; m/z 517.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].CC(C)([O-])C.[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:18]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1ccc([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The starting 2-amino-5-nitrophenol (21.2 g, 0.14 mol) was dissolved in 350 mL THF. Solid potassium t-butoxide (15.85 g, 0.141 mol) was added slowly, with vigorous stirring. Then a solution of benzylbromide (in 150 mL THF) was added slowly and stirred at room temperature for 2 days. The solvent was removed and the crude oil poured into water (ca. 500 mL) and 3:1 ethyl acetate/methylene chloride (ca. 200 mL). The solid precipitate was filtered off and dried, then recrystallized in toluene to give 2-benzyloxy-4-nitro-phenylamine (9.1 g). The aqueous and organic layers were separated and the aqueous layer was extracted twice with 3:1 ethyl acetate/methylene chloride. The combined organic layers were washed with 5% sodium hydroxide (which formed three layers, and the middle layer contained the desired material by TLC), then the desired layer was washed twice with water, then brine, and dried over anhydrous magnesium sulfate, filtered and the solvent removed. The solid was recrystallized in toluene, filtered and dried to yield 12 g of 2-benzyloxy-4-nitro-phenylamine. (The total yield was 62%.). 1H NMR (CDCl3) 7.9-7.7 (m, 2H), 7.5-7.3 (m, 5H), 6.65 (d, 1H, J=8.68 Hz), 5.15 (s, 2H), 4.57 (br, 2H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:4][C@@H:3]1[C:17]([O:19]CC)=[O:18].O.[OH-].[Na+]>C(O)C>[CH2:10]([O:9][C:7]([N:5]1[CH2:6][C@H:2]([OH:1])[C@@H:3]([C:17]([OH:19])=[O:18])[CH2:4]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 0 °C
Yield: 226.9 %

Procedure:
639 g of 1-benzyl 3-ethyl (3S,4R)-4-hydroxypyrrolidine-1,3-dicarboxylate (equivalent to 1.03 mol) was dissolved in 3.02 L of ethanol and 3.02 L of water was added to the solution. While the mixture was stirred and cooled in an ice bath, a sodium hydroxide solution (formed by dissolving 124 g of sodium hydroxide (3.09 mol) in 3.02 L of water) was added dropwise at an internal temperature of 6.0 to 9.8° C. and the mixture was subsequently stirred at an internal temperature of 6 to 10° C. for 1 hour. This was followed by addition of 60.4 g of active carbon. The mixture was then taken out of the ice bath and stirred at room temperature for 30 minutes. The insoluble material was separated by filtration and washed with 1.21 L of water. The filtrate and the wash were combined and concentrated under reduced pressure. To the resulting residue, 3.02 L of diisopropyl ether was added and the mixture was stirred for 5 minutes. Subsequently, the mixture was allowed to standard the aqueous layer (bottom layer) was collected. To the aqueous layer, 3.02 L of diisopropyl ether was added and the mixture was stirred for 5 minutes. The mixture was allowed to stand again and the aqueous layer (bottom layer) was collected. While the aqueous layer was stirred, 0.54 L of 6 mol/L hydrochloric acid was added dropwise (pH changed from 12.8 to 1.5). To the resulting mixture, 4.83 L of ethyl acetate and 1.21 kg of sodium chloride were added and the mixture was stirred for 5 minutes. The mixture was then allowed to stand and the organic layer (top layer) was collected. To the organic layer, 3.02 L of 28% brine was added and the mixture was stirred for 5 minutes. The mixture was then allowed to stand again and the organic layer (top layer) was collected. To the organic layer, 302 g of anhydrous sodium sulfate was added and the mixture was stirred for 1 hour. The resulting solid was separated by filtration and washed with 0.90 L of ethyl acetate. The filtrate and the wash were combined and concentrated under reduced pressure to give 620 g of a crude product of the title compound as a pale brown solid. This product was used in the subsequent step without further purification.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[S:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][CH2:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([O:34][CH2:35]C2C=CC=CC=2)[CH:24]=1)=[O:22])=[O:18].[CH2:42]([N:44](CC)CC)[CH3:43].C(N=C=[O:53])C.Cl>CN(C=O)C.O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[S:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][CH2:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29]([OH:31])=[O:30])=[C:25]([O:34][C:35](=[O:53])[NH:44][CH2:42][CH3:43])[CH:24]=1)=[O:22])=[O:18]
Reactant: CCN=C=O
Reactant: O=C(O)COc1ccc(C(=O)CNC(=O)c2cc3c(s2)CCNC3)cc1OCc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)Oc1cc(C(=O)CNC(=O)c2cc3c(s2)CCNC3)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To the solution of the compound prepared in Example 50 (a) (280 mg, 0.512 mmole) in DMF were added triethylamine (0.1 ml) and ethyl isocyanate (50 μl), and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added water, and the mixture was acidified with 1N hydrochloric acid. The solution was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure. The oily product thus obtained was purified by column chromatography on silica gel with an eluent system of chloroform:methanol=100:1 to give 175 mg of the title compound as a pale yellow foam product (yield, 55%).
Reaction SMILES: [OH2:1].O.Cl([O-])(=O)(=O)=O.[Na+].Cl([O-])(=O)(=O)=O.[C:14]1([N:20]2[CH:24]=[C:23]([CH:25]=[N+](C)C)[C:22]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:14]1([N:20]2[CH:24]=[C:23]([CH:25]=[O:1])[C:22]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O
Reactant: C[N+](C)=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: O=Cc1cn(-c2ccccc2)nc1-c1ccc(Cl)cc1

Procedure:
The procedure described in the foregoing Example (54d) was modified, by omitting the direct hydrolysis with a mixture of ice and water. Instead, the reaction mixture was diluted by the addition of 500 milliliters methanol, and by the addition of a solution of 65 grams sodium perchlorate-monohydrate in methanol, [[1-phenyl-3-(p-chlorophenyl)-pyrazol-4-y]-methylene]-dimethylammonium perchlorate, having a melting point of 256°-258° C., was nearly quantitatively precipitated. This product was thereafter subjected to alkaline hydrolysis in a manner similar to that described in Example (54d) to produce the 1-phenyl-3-(p-chlorophenyl)-pyrazol-4-aldehyde.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH2:7].Cl[CH2:9][CH2:10][N:11]([CH2:34][CH2:35]Cl)[C:12]1[CH:32]=[C:31]([Cl:33])[C:15]2[O:16][C:17]3[C:26]([CH3:27])=[CH:25][C:24]([C:28]([OH:30])=[O:29])=[CH:23][C:18]=3[S:19](=[O:22])(=[O:21])[CH2:20][C:14]=2[CH:13]=1.[CH3:37]O>>[CH3:37][O:30][C:28]([C:24]1[CH:25]=[C:26]([CH3:27])[C:17]2[O:16][C:15]3[C:31]([Cl:33])=[CH:32][C:12]([N:11]4[CH2:10][CH2:9][N:7]([CH2:6][C:2]5[S:1][CH:5]=[CH:4][CH:3]=5)[CH2:35][CH2:34]4)=[CH:13][C:14]=3[CH2:20][S:19](=[O:22])(=[O:21])[C:18]=2[CH:23]=1)=[O:29]
Reactant: CO
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: NCc1cccs1
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4cccs4)CC3)cc(Cl)c1O2

Procedure:
Thiophenemethylamine (0.5 g 4.41 mmol) was added to a solution of Example 102j (0.6 g, 1.25 mmol) in methanol (10 mL), followed by the addition of n-tetrabutylammonium iodide (0.010 g, 0.027 mmol) in an atmosphere of nitrogen and sealed in a pressure reactor vessel at 110° C. for 6 h. It was processed as described in the synthesis of Example 129k to obtain the title compound as a white solid. Yield: 0.370 g, (55.38%); 1H NMR (DMSO-d6): δ 2.55-2.60 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.20-3.55 (m, 4H, 2CH2), 3.75 (s, 3H, CH3), 3.95 (s, 3H, OCH3), 4.65 (s, 2H, CH2), 6.75 (s, 1H, Ar), 6.90 (s, 1H, Ar), 6.95-7.05 (m, 2H, Ar), 7.30 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.40 (s, 1H, Ar); MS: m/e (CI+) 533 (M+1).