Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:4][PH:5](=[O:7])[O-:6])(=O)C.[Na+:8].[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][NH2:22])([O-:11])=[O:10].NN.[CH2:25](O)C>>[N+:9]([C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[NH:21][N:22]=[C:4]([P:5]([CH3:25])(=[O:7])[O-:6])[CH3:1])([O-:11])=[O:10].[Na+:8]
Reactant: CC(=O)C[PH](=O)[O-]
Reactant: CCO
Reactant: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: NN
Agent: [Na+]
Product: CC(=NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])P(C)(=O)[O-]

Procedure:
Sodium acetylmethylphosphinate (4.3 g) and 2,4-dinitrophenylhydrazine (5.9 g) were refluxed and stirred in ethanol (150 ml). After 1 hr the hydrazine had disappeared to be replaced by a yellow solid. The mixture was refluxed and stirred a further hour, cooled and the hydrazone filtered off, washed with a little cold ethanol and dried (8.0 g). The filtrate on evaporation gave residual material (1.4 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH:8]1([NH2:11])[CH2:10][CH2:9]1.[CH:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(OCC)(=O)C.CCCCCCC>[C:15]([O:14][C:12]([N:11]([CH:8]1[CH2:10][CH2:9]1)[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: NC1CC1
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)OC=O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCOC(=O)CCN(C(=O)OC(C)(C)C)C1CC1

Procedure:
The title compound was prepared from ethyl acrylate (1.09 ml, 10 mmol) and cyclopropylamine (0.69 ml, 10 mmol) according to Example 2a. Yield: 2.06 g (80%). ESI-MS: 258.2 (M+H)+, 202.2 (M+H—C4H8)+, 158.2 (M+H-Boc)+. Rf (silica gel; ethyl acetate/heptane, 1:4, v/v): 0.38.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]3[O:16][C:15](=[O:17])[N:14]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([N+:39]([O-:41])=[O:40])[CH:34]=4)[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1
Reactant: O=[N+]([O-])c1cccc(COCCOCCCCCCBr)c1
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc(C3CN(CCCCCCOCCOCc4cccc([N+](=O)[O-])c4)C(=O)O3)ccc2O1
Reaction time: 0.67 h
Yield: 101.8 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (4.40 g) in anhydrous DMF (75 ml) was treated under nitrogen at 0° with sodium hydride (60% dispersion in mineral oil, 1.04 g) and the mixture stirred for 40 min. A solution of 1-[(2-[(6-bromohexyl)oxy]ethoxy)methyl]-3-nitrobenzene (8.12 g) in DMF (10 ml) was added and the mixture stirred at 20° for 2 h. Phosphate buffer (pH 6.5, 100 ml) and water (100 ml) were added and the product extracted with EtOAc (4×100 ml). The combined organic layer was washed with water (3×100 ml) and dried (Na2SO4). The solvent was removed in vacuo to give a residue that was purified by Biotage. Elution with EtOAc-PE (1:1 then 3:2) followed by solvent evaporation in vacuo gave the title compound (9.50 g). LCMS RT=3.75 min, ES+ve 529 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](Cl)=[CH:4][C:3]=1[N+:10]([O-])=O.[H][H]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: O=[N+]([O-])c1cc(Cl)c(F)cc1F
Reactant: [H][H]
Product: Nc1ccc(F)cc1F

Procedure:
hydrogenating the 2,4-difluoro-5-chloronitrobenzene with hydrogen in the presence of a hydrogenation catalyst to form 2,4-difluoroaniline.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[N+]([C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O)([O-])=O.C(N(C(C)C)CC)(C)C.[BH4-].[Na+]>CO.C1(C)C=CC=CC=1>[CH2:17]([NH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)[C:16]1[CH:19]=[CH:20][CH:21]=[CH:14][CH:15]=1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: Nc1nc2ccccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CNc2nc3ccccc3[nH]2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 15.8 %

Procedure:
A 100 mL flask was charged with 1.0 g 2-aminobenzimidazole (7.51 mmol, 1.0 equiv), 1.13 g 3-nitrobenzaldehyde (7.51 mmol, 1.0 equiv), and 25 mL toluene. The flask was equipped with a Dean-Stark trap and reflux condenser and placed in a 110° C. bath. The solution was refluxed for 15.5 h, followed by the addition of 3 mL MeOH and 3 mL diisopropylethylamine. After refluxing an additional 29 h, the flask was removed, and the volatiles were removed under reduced pressure at 70° C. The remaining material was diluted with 50 mL MeOH, and cooled to 0° C. followed by the addition of 426 mg (11.27 mmol, 1.5 equiv) NaBH4. After stirring for 3 h, the solution was concentrated under reduced pressure, and the residue was applied directly to a SiO2 column (preflushed with 10% MeOH/CH2Cl2). The column was eluted with 10% MeOH/CH2Cl2 to give the product as an orange solid 320 mg (1.19 mmol). 1H NMR (DMSO-d6, 400 MHz) δ 11.0 (broad s, 1H), 8.25 (s, 1H), 8.11 (d, J=8.2 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.34 (m, 1H), 7.13 (t, J=3.7 Hz, 2 H), 6.86 (s, 2H), 4.64 (d, J=5.8 Hz, 2H); MS: ESI(+) m/z 269.2 (M+H+).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].C(O)(=O)C.[F:9][CH2:10][C:11]1[N:16]=[C:15]([OH:17])[CH:14]=[C:13]([OH:18])[N:12]=1>O>[F:9][CH2:10][C:11]1[N:16]=[C:15]([OH:17])[C:14]([N+:1]([O-:4])=[O:2])=[C:13]([OH:18])[N:12]=1
Reactant: Oc1cc(O)nc(CF)n1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1c(O)nc(CF)nc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of fluoroacetonitrile (11 g) in ethanol (10.9 mL)-diethyl ether (186 mL) was bubbled with hydrogen chloride under ice-cooling until the solution was saturated with hydrogen chloride with stirring, and the mixture was stirred at the same temperature for 4 hours. The precipitated crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give ethyl 2-fluoroacetimidate hydrochloride (24.9 g). This material was suspended in ethanol (50 mL). To the suspension was added ethanol (130 mL) containing ammonia (about 5 g), and the mixture was stirred at room temperature overnight. The crystals were collected by filtration. The collected crystals were washed with diethyl ether, and dried under reduced pressure to give 2-fluoroacetamidine hydrochloride (16.3 g). To a mixture of sodium methoxide (28% methanol solution, 83.6 mL) and methanol (145 mL) was added 2-fluoroacetamidine hydrochloride (16.3 g), followed by adding diethyl malonate (22.0 mL), and the mixture was heated at reflux for 11 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water (145 mL). The mixture was acidified by adding concentrated hydrochloric acid (18 mL), and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g). To a mixture of fuming nitric acid (36 mL) and acetic acid (18 mL) was added 2-fluoromethyl-4,6-dihydroxypyrimidine (20.1 g) slowly under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled in ice. To the mixture was added cold water, and the mixture was stirred at room temperature for 1 hour. The precipitated crystals were collected by filtration. The collected crystals were washed with water and diethyl ether, and dried under reduced pressure to give the title compound (16.8 g).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][NH:11][C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:39]([O:41][C:42](Cl)=[O:43])[CH3:40]>C1(C)C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:13][CH2:12][N:11]([C:42]([O:41][CH2:39][CH3:40])=[O:43])[C:10]([CH3:25])([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(CC2(C)CN(C(c3ccccc3)c3ccccc3)CCN2)cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C(c2ccccc2)c2ccccc2)CC1(C)Cc1ccc(OC)c(OC)c1
Yield: 93.4 %

Procedure:
21.6 g of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-piperazine (cf. Example 2) are dissolved with 5.2 g of triethylamine in 200 ml of dry toluene. Then a solution of 5.4 g of chloroformic acid ethyl ester in 50 ml of toluene is added dropwise with stirring. Thereafter, the mixture is stirred for a further 2 hours. After filtration, the filtrate is washed free of halide with water and evaporated to dryness. A yellowish oil, which is recrystallized from diisopropyl ether, is obtained as the residue. 22.7 g (94 percent of theory) of 1-diphenylmethyl-3-methyl-3-(3,4-dimethoxybenzyl)-4-carbethoxy-piperazine are obtained. m.p. = 113° C.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:8](O)=[O:9])[CH:2]=1.[NH2:21][C@@H:22]1[CH2:28][CH2:27][C@@H:26]([CH3:29])[N:25]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:24][C@H:23]1[OH:39].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[CH3:29][C@H:26]1[N:25]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)(=[O:32])=[O:31])[CH2:24][C@@H:23]([OH:39])[C@H:22]([NH:21][C:8](=[O:9])[CH:7]([C:3]2[CH:2]=[C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=2)[CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:28][CH2:27]1
Reactant: CC(C)CC(C(=O)O)c1cccc(-c2ccccc2)c1
Reactant: C[C@@H]1CC[C@@H](N)[C@H](O)CN1S(=O)(=O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(C(=O)N[C@@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)C[C@H]1O)c1cccc(-c2ccccc2)c1
Yield: 61.6 %

Procedure:
2-Biphenyl-3-yl-4-methyl-pentanoic acid (270 mg, 1.0 mmol, preparation described in J. Am. Chem. Soc. 1997, 120, 9114), and (3R,4R,7R)-4-Amino-7-methyl-1-(pyridine-2-sulfonyl)-azepan-3-ol (320 mg, 1.0 mmol, Example 1k), EDCI (190 mg, 1.0 mmol), HOBT (135 mg, 1.0 mmol) and diisopropylethylamine (1.7 g, 0.23 ml, 1.3 mmol) in DMF (5 ml) were stirred at RT for 4 h. The reaction mixture was diluted with EtOAc (20 ml), washed with H2O, brine, dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 40% EtOAc/hexanes) to yield the title compound (330 mg, 62%): 1H NMR (400 MHz, CDCl3): δ 8.55-8.60 (m, 1H), 8.00 (t, 1H), 7.80-7.90 (m, 1H), 7.65 (d, 2H), 7.25-7.55 (m, 8H), 5.50-5.60 (m, 1H), 4.00-4.10 (m, 1H), 3.70-3.85 (m, 1H), 3.50-3.70 (m, 2H), 2.90-3.05 (m, 1H), 2.00-2.10 (m, 2H), 1.30-1.85 (m, 5H), 0.90-0.95 (d, 9H); ESMS: 536.4 (M+H+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:15])(O)[CH:10]([CH3:13])[CH2:11][OH:12].C(N(CC)CC)C.ClCCl.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>O>[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)([O:12][CH2:11][CH:10]([CH3:13])[CH:9]([OH:15])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])(=[O:34])=[O:33]
Reactant: CC(CO)C(O)(O)Cc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC(C)C(O)Cc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.9 %

Procedure:
Under a nitrogen atmosphere, a mixture of 13.5 g (68.1 mmol) of 4-(2-fluorophenyl)-3-hydroxy-2-methylbutane-1,3-diol, 14.2 ml (21.3 mmol) of triethylamine, and 70 ml of dichloromethane was cooled with an ice bath and 13.0 g (68.1 mmol) of p-toluenesufonyl chloride was added to the mixture. After stirring overnight at room temperature, 100 ml of water was added thereto, followed by extraction 3 times each with 200 ml of dichloromethane, and the combined organic layer was dried with anhydrous sodium sulfate. After drying, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 21.1 g of the title compound as a colorless oil. (Yield: 88%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:9][CH:8]=1)[NH2:5].[NH:25]1[CH2:30][CH2:29][O:28][CH:27]([CH2:31][CH2:32][C:33]2([C:38](O)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH2:26]1>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[O:15])=[CH:11][CH:12]=1)[NH:5][C:38]([C:33]1([CH2:32][CH2:31][CH:27]2[O:28][CH2:29][CH2:30][NH:25][CH2:26]2)[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:39]
Reactant: O=C(O)C1(CCC2CNCCO2)CCCC1
Reactant: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)C1(CCC2CNCCO2)CCCC1
Yield: 62 %

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[[1-[(2-morpholinyl)ethyl]cyclopentyl]carbonyl]-L-phenylalanine methyl ester was prepared from 4-[[(2,6-Dichlorophenyl)carbonyl]amino]-L-phenylalanine methyl ester and 1-[(2-morpholinyl)ethyl]cyclopentane carboxylic acid using the general coupling procedure described in example 46 to provide a 62% yield. HRMS (C29H35Cl2B3O5): Obs. mass, 576.2531. Calcd. mass, 576.2582. (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][C:26]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:8]([F:17])([F:16])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])=[N:4][N:5]([CH2:25][C:26]([N:28]2[CH2:29][CH2:30][N:31]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH2:32][CH2:33]2)=[O:27])[C:6]=1[CH3:7]
Reactant: Cc1[nH]nc(C(F)(F)C(F)(F)C(F)(F)F)c1N
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1c(N)c(C(F)(F)C(F)(F)C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Amino-3-heptafluoropropyl-5-methyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=1/4) afforded the title compound as colorless oil. 1H NMR (400 MHz, CDCl3): 6.92–7.02 (m, 4H), 5.14 (s, 2H), 3.64–3.82 (m, 4H), 3.6 (s, 2H), 3.1–3.22 (m, 4H), 2.16 (s, 3H). 13C NMR (400 MHz, CD6CO): 160.4, 158, 146, 144.2, 119.8, 118.2, 52, 50.8, 50.6, 46, 42, 12.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([CH2:16][CH:17]=[CH2:18])(O)[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Br:8].C(N(SN(CC)CC)CC)C.[F-:34].[F-].[F-].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C:12]([F:34])([CH2:16][CH:17]=[CH2:18])[C:11]([C:19]([F:22])([F:21])[F:20])=[N:10]2)[CH:5]=[CH:6][C:7]=1[Br:8]
Reactant: [F-]
Reactant: C=CCC1(O)C(=O)N(c2ccc(Br)c(Cl)c2)N=C1C(F)(F)F
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCC1(F)C(=O)N(c2ccc(Br)c(Cl)c2)N=C1C(F)(F)F
Temperature: -3 °C
Reaction time: 1 h

Procedure:
4 g of 1-(3-chloro-4-bromophenyl)-3-trifluoromethyl-4-allyl-4-hydroxy-5-pyrazolone in 200 ml of methylene chloride were cooled to -10° C. and 2.7 ml of trifluoride diethylaminosulfide were added all at once. The mixture was stirred for one hour at -10° C./-3° C. 120 ml of a saturated solution of sodium bicarbonate were added and stirring was carried out for 10 minutes, followed by decanting, washing with water, drying and bringing to dryness. The residue was chromatographed on silica and eluted with a hexane-methylene chloride mixture (8-2) to obtain 1.1 g of 1-(3-chloro-4-bromophenyl)-3-trifluoromethyl-4-fluoro-4-allyl-5-pyrazolone.
Reaction SMILES: FC1[C:7](OC)=[CH:6][CH:5]=[CH:4][C:3]=1[S:10][CH2:11][CH2:12]C(O)=O.FC(F)(F)[C:18]([O:20][C:21](=O)[C:22]([F:25])(F)F)=O.C([O-])([O-])=[O:30].[Na+].[Na+]>FC(F)(F)C(O)=O>[F:25][C:22]1[C:21]([O:20][CH3:18])=[CH:7][CH:6]=[C:5]2[C:4]=1[CH2:3][S:10][CH2:11][C:12]2=[O:30]
Reactant: COc1cccc(SCCC(=O)O)c1F
Reactant: O=C([O-])[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1F)CSCC2=O
Temperature: 25 °C
Reaction time: 0.13 h
Yield: 77 %

Procedure:
The acid from Step 5 (7.63 g, 33 mmol) was dissolved in trifluoroacetic acid (12 mL), treated with trifluoroacetic anhydride (4 mL) and stirred at room temperature (8 minutes). The reaction was poured into 10% Na2CO3 (50 mL) and extracted with ethyl acetate, washed with brine, dried over MgSO4 and concentrated in vacuo to give 8-fluoro-7-methoxyisothiochroman-4-one (5.42 g, 77%) as a brown solid: mp 85°-92° C.; 1H NMR (CDCl3) 300 MHz 7.83 (d, J=8.9 Hz, 1H) 7.19 (t, J=8.5 Hz, 1H) 4.01 (s, 2H) 3.98 (s, 3H) 3.55 (s, 2H); 19F NMR (CDCl3) 300 MHz -141.24 (m).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([F:14])[CH:4]=1.[C:15]1([P:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl-:1].[F:14][C:5]1[CH:4]=[C:3]([CH2:2][P+:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=1
Reactant: CC1(C)Cc2cc(F)cc(CCl)c2O1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cc(F)cc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2O1
Product: [Cl-]

Procedure:
7-(chloromethyl)-5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran (647) (1 g, 4.66 mmol), triphenyl phosphine (1.22 g, 4.66 mmol) and toluene (46 mL) were heated at reflux for 48 hours. The reaction was filtered and the solid was washed with diethyl ether to provide ((5-fluoro-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methyl)triphenyl phosphonium chloride (648).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH:11]=[CH:10]1.C[CH:17]([S:20]([OH:23])(=[O:22])=[O:21])[CH2:18][CH3:19].[C:24]([NH2:28])(=[O:27])[CH:25]=[CH2:26].N(C(C)(C)C#N)=N[C:31](C)(C)C#N>CN(C)C=O>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1(=[O:13])[O:14][C:9](=[O:15])[CH:10]=[CH:11]1.[C:24]([NH:28][C:18]([CH3:19])([CH3:31])[CH2:17][S:20]([OH:23])(=[O:21])=[O:22])(=[O:27])[CH:25]=[CH2:26]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: C=CC(N)=O
Reactant: CCC(C)S(=O)(=O)O
Agent: O=C1C=CC(=O)O1
Solvent: CN(C)C=O
Solvent: C=Cc1ccccc1
Product: C=CC(=O)NC(C)(C)CS(=O)(=O)O

Procedure:
A reactor equipped with a stirrer, a thermometer and a reflux condenser was charged with 100 parts of dimethylformamide, 40 parts of styrene, 40 parts of maleic anhydride and 20 parts of acrylamide methylpropanesulfonic acid. After dissolution, 5 parts of azobisisobutyronitrile was added to carry out reaction at 80° C.-100° C. for 4 hours, giving a copolymer of styrene, maleic anhydride and 2-acrylamido-2-methylpropanesulfonic acid. The copolymer was isolated by reprecipitation with isopropyl alcohol and dried under reduced pressure.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[CH:12]1([C:15](=O)[CH2:16][C:17](OCC)=[O:18])[CH2:14][CH2:13]1>>[CH:12]1([C:15]2[CH:16]=[C:17]([OH:18])[N:1]([C:3]3[CH:8]=[C:7]([CH:6]=[CH:5][N:4]=3)[C:9]([OH:11])=[O:10])[N:2]=2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)CC(=O)C1CC1
Reactant: NNc1cc(C(=O)O)ccn1
Product: O=C(O)c1ccnc(-n2nc(C3CC3)cc2O)c1
Yield: 24 %

Procedure:
The title compound was prepared in 24% yield from 2-hydrazinylpyridine-4-carboxylic acid and ethyl 3-cyclopropyl-3-oxopropanoate according to the procedure for the preparation of Example 1. 1H NMR (400 MHz, CD3OD): δ 0.83-0.88 (2H, m), 1.05-1.09 (2H, m), 1.88-1.91 (1H, m), 4.86 (1H, s), 7.70 (1H, dd, J=5.2, 1.2 Hz), 8.54 (1H, d, J=5.2 Hz), 8.75 (1H, s). [M+H] Calc'd for C12H11N3O3, 246. Found, 246.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1.[B:16]1(B2OCC(C)(C)CO2)[O:21]CC(C)(C)C[O:17]1.C([O-])(=O)C.[K+]>CS(C)=O>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:4]([CH2:5][C:6]2[N:10]=[CH:9][NH:8][N:7]=2)=[CH:3][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: COc1ccc(Cc2nc[nH]n2)cc1I
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Cc2nc[nH]n2)cc1B(O)O
Temperature: 80 °C

Procedure:
A mixture of 3-(3-iodo-4-methoxybenzyl)-1H-1,2,4-triazole (Step B) (397 mg, 1.260 mmol), bis(neopentyl glycolato)diboron (342 mg, 1.512 mmol), potassium acetate (495 mg, 5.04 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (51.4 mg, 0.063 mmol) in DMSO (10 ml) was degassed flushing with nitrogen and heated at 80° C. overnight. The reaction was diluted with ethyl acetate and washed with water followed by brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the crude title product that was used without further purification. Mass spectrum (ESI) 234.3 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.Cl.[F:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(N(CC)CC)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[CH2:26][CH2:25][N:24]([CH2:8][C:7]3[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(CN2CCN(c3ccc(F)cc3)CC2)cc1

Procedure:
In the manner given in Example 1A, p-nitrobenzyl chloride is reacted with 1-(p-fluorophenyl)piperazine dihydrochloride in the presence of triethylamine to give 1-(p-fluorophenyl)-4-(p-nitrobenzyl)piperazine
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=[O:3].[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1.[CH2:18]([O:20]CC)[CH3:19]>>[CH3:7][O:8][C:9]1[CH:17]=[C:16]2[C:12]([C:13]([C:1](=[O:5])[C:2]([O:20][CH2:18][CH3:19])=[O:3])=[CH:14][NH:15]2)=[CH:11][CH:10]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc2cc[nH]c2c1
Reactant: CCOCC
Product: CCOC(=O)C(=O)c1c[nH]c2cc(OC)ccc12
Reaction time: 2 h

Procedure:
7.5 cm3 of oxalyl chloride are added dropwise, under argon and over a period of 30 minutes, to a solution of 8.3 g of 6-methoxyindole, prepared in accordance with the process described by P. L. Feldman and H. Rapoport, Synthesis, (1986), 736, in 100 cm3 of anhydrous diethyl ether. After stirring for two hours, the precipitate formed is separated by filtration and then suspended in 200 cm3 of ethanol.