Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[C@H:5]([OH:23])[CH2:6][NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[C:33](C1NC=CN=1)(=[O:35])[CH3:34].CO.[OH-].[Na+]>C(Cl)Cl>[ClH:1].[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[C:29]([F:31])[CH:28]=1)[CH2:24][C@H:4]([NH:3][C:33](=[O:35])[CH3:34])[C@H:5]([OH:23])[CH2:6][NH:7][C:8]1([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[CH:15]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)c1cccc(C2(NC[C@@H](O)[C@@H](N)Cc3cc(F)cc(F)c3)CCCCC2)c1
Reactant: CC(=O)c1ncc[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)CNC1(c2cccc(C(C)C)c2)CCCCC1
Reaction time: 0.25 h

Procedure:
The free base of compound 6 (1.6 g, 3.8 mmol) is dissolved in 20 mL of CH2Cl2 under nitrogen, and 0.87 g (7.9 mmol) of acetyl imidazole is added with stirring. After 15 min., 30 mL of methanol is added, followed by 15 mL of 1 N NaOH to saponify the ester that is formed along with the amide. The CH2Cl2 is removed in vacuo, and the mixture is neutralized with 1N KH2PO4. The product is extracted into ethyl acetate and the organic phase is washed with water, with 1 N NaHCO3, and with brine. The solution is dried over Na2SO4, filtered and concentrated to an oil, which is chromatographed over silica gel, eluting with 5%-7% methanol (containing 1% of NH4OH) in CH2Cl2. Product-containing fractions are pooled, concentrated, dissolved in a small volume of ethanol, and acidified with 0.6 N HCl in dry ether. Concentration from this solvent mixture affords a gel-like material. This can be dissolved in ethanol and ethyl acetate, and concentrated to 1.65 g (3.3 mmol, 87%) an off-white solid. This solid is triturated with ethyl acetate to remove a pale yellow mother liquor, leaving hydrochloride 7 as a white solid: 1H NMR (CDCl3+CD3OD drop) δ 7.44 (s, 1H), 7.37 (m, 2H), 7.29 (m, 1H), 6.70 (m, 2H), 6.62 (m, 1H), 3.94 (m, 1H), 3.87 (m, 1H), 3.0-2.94 (m, 2H), 2.64 (m, 4H), 2.36 (m, 1H), 2.09 (m, 2H), 1.84 (s, 3H), 1.79 (m, 2H), 1.59 (m, 1H), 1.5-1.3 (m, 3 H), 1.27 (d, J=7 Hz, 6H); IR (diffuse reflectance) 3343, 3254, 2958, 2937, 2866, 2497, 2442, 2377, 1660, 1628, 1598, 1553, 1460, 1116, cm −1. MS (EI) m/z (rel intensity) 458 (M+, 7), 415 (20), 230 (35), 202 (18), 201 (99), 200 (26), 159 (35), 157 (32), 133 (41), 129 (28), 117 (17). HRMS (ESI) calcd for C27H36N2O2F2+H1 459.2823, found 459.2837. Anal. Calcd for C27H36F2N2O2.HCl: C, 65.51; H, 7.53; N, 5.66; Cl, 7.16; F, 7.68. Found: C, 65.19; H, 7.70; N, 5.67. Found; Cl, 7.08.
Reaction SMILES: [C:1]([OH:9])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7].[Si](C=[N+:15]=[N-:16])(C)(C)C>C(Cl)Cl.CO>[C:1]([NH:15][NH2:16])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=[CH2:7]
Reactant: C=CCCCCC(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: C=CCCCCC(=O)NN
Reaction time: 0.5 h

Procedure:
To a solution of 6-heptenoic acid (1.24 g, 9.68 mmol) in methylene chloride (40 mL) and MeOH (10 mL) was added slowly TMSCHN2 (2M, 12.1 mL) at room temperature. The reaction mixture was stirred for additional 30 minutes. After the reaction was completed, the mixture was evaporated in vacuo. The residue was directly used for the next step without further purification. To the above residue in MeOH (20 mL) was added hydrazine monohydrate (5 mL) at room temperature. The reaction mixture was stirred at the same temperature overnight. The mixture was evaporated in vacuo. The residue was further dried by high vacuum overnight to provide the title compound. MH+143.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]1[C:15]([C:16]2(O)[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22]([C:25]#[N:26])[CH:23]=3)[NH:18][C:17]2=[O:28])=[CH:14][CH:13]=[CH:12][N:11]=1)[CH3:8].S(Cl)([Cl:32])=O>ClCCl>[Cl:32][C:16]1([C:15]2[C:10]([O:9][CH2:7][CH3:8])=[N:11][CH:12]=[CH:13][CH:14]=2)[C:24]2[C:19](=[CH:20][C:21]([F:27])=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][C:17]1=[O:28]
Reactant: CCOc1ncccc1C1(O)C(=O)Nc2cc(F)c(C#N)cc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOc1ncccc1C1(Cl)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
0.47 ml (5.81 mmol) of pyridine was added to 1.3 g (4.15 mmol) of 3-(2-ethoxypyridin-3-yl)-6-fluoro-3-hydroxy-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile in 30 ml of dichloromethane. After the reaction mixture had been cooled to 0° C., 0.42 ml (5.81 mmol) of thionyl chloride was added dropwise. The mixture was stirred at room temperature for one hour and then poured into ice-water. After stirring for 15 minutes, the organic phase was separated off. The aqueous phase was extracted several times with dichloromethane. The combined organic phase was dried over magnesium sulfate and filtered, and the solvent was removed in vacuo. 1.13 g of 3-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indole-5-carbonitrile were obtained as a solid which was employed without further purification in the next stage.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
7.00 g (30.6 mmol) of ethyl 4-bromobenzoate are dissolved in 60 ml of 1,2-dimethoxyethane and, under argon, 6.96 g (36.7 mmol) of 4-trifluoromethylphenylboronic acid, 271 mg of bis(triphenyl-phosphine)palladium(II) chloride and 40.7 ml of a 2 M aqueous sodium carbonate solution are added. The reaction mixture is then stirred under reflux for 12 hours. The mixture is subsequently cooled, filtered through 1 g of Extrelute, washed with dichloromethane and the solvent is removed in vacuo. The resulting crude product is purified by flash chromatography on silica gel 60 (mobile phase: cyclohexane/dichloromethane 2:1). 6.31 g (21.4 mmol, 70% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7](O)=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1.[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].C(OCC)(=O)C>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:17][CH:16]=[CH2:15])=[C:6]([I:9])[CH:5]=[C:4]([CH:10]([OH:12])[CH3:11])[N:3]=1
Reactant: C=CCBr
Reactant: CC(O)c1cc(I)c(O)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCc1c(I)cc(C(C)O)nc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
A solution of 2-chloro-3-hydroxy-4-iodo-6-(1-hydroxyethyl)-pyridine (3.6 g, 12 mmol) in 24 mL of N,N-dimethylformamide at 0° C. is treated with 480 mg (60% in oil, 12 mmol) of sodium hydride and stirred at room temperature for 1 h. The reaction is treated with 1.14 g (13.2 mmol) of allyl bromide and stirred for 2 h. The mixture is poured into 125 mL of ethyl acetate and washed with 4×50 mL of saturated sodium chloride, 2×25 mL of 50% saturated sodium carbonate and dried over potassium carbonate. The dried organics are concentrated in vacuo, diluted with 20 mL of hexanes, and chilled to -15° C. The solid is filtered to provide 3.61 g (89%) of 2-chloro-3-(1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine.
Reaction SMILES: [CH2:1]([C:3]1([C:12](Cl)=[O:13])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2].S(=O)(=O)(O)O.[CH3:20]COCC>>[CH2:1]([C:3]1([C:12](=[O:13])[CH3:20])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)[CH3:2]
Reactant: CCOCC
Reactant: CCC1(C(=O)Cl)Cc2ccccc2C1
Agent: O=S(=O)(O)O
Product: CCC1(C(C)=O)Cc2ccccc2C1

Procedure:
Second synthetic route disclosed in the same patent is following, as starting material was used 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester, which was prepared by methylation of 2,3-dihydro-1H-indene-2-carboxylic acid in the presence of sulphuric acid. The 2,3-dihydro-1H-indene-2-carboxylic acid methyl ester was reacted with N-isopropylcyclohexylamide and ethylbromide yielding 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid, then thionyl chloride was added and 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride was obtained. In the next step ethoxymagnesiummalonic acid ethyl ester in dry ether was added to 2,3-dihydro-2-ethyl-1H-indene-2-carboxylic acid chloride and reaction mixture was treated with sulphuric acid, and 1-(2,3-dihydro-2-ethyl-1H-inden-2-yl)ethanone was obtained, then the intermediate was stirred in methylene chloride and bromine was added by giving a new intermediate 2-bromo-1-(2,3-dihydro-2-methyl-1H-inden-2-yl)ethanone, to which was thereafter added formamide and hydrochloric acid yielding crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole. The last step involved hydrogenation of the crude product of 5-(2-ethyl-2,3-dihydro-1H-inden-2-yl)-1H-imidazole with 10% palladium on carbon.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]([CH2:17][N+:18]([O-])=O)[CH2:12][C:13](OC)=[O:14])=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1.[H][H]>CO.[Ni]>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]3[CH2:17][NH:18][C:13](=[O:14])[CH2:12]3)=[CH:8][CH:9]=2)[N:4]([CH2:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:3]=1
Reactant: [H][H]
Reactant: COC(=O)CC(C[N+](=O)[O-])c1ccc2c(C)cn(CCCc3ccccc3)c2c1
Agent: [Ni]
Solvent: CO
Product: Cc1cn(CCCc2ccccc2)c2cc(C3CNC(=O)C3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
A solution of methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-nitromethyl-propionate (0.296 g, Reference Example 38) in methanol (100 ml), under argon, was treated with excess Raney® nickel. The argon atmosphere was replaced by hydrogen at 1 atmosphere then the mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite. The filtrate was evaporated and the residual crude methyl 3-(3-methyl-1-{3-(phenyl)propyl}-1H-indol-6-yl)-3-aminomethyl-propionate was dissolved in sodium hydroxide solution (15 ml, 1N). After stirring at room temperature for 1 hour the reaction mixture was extracted three times with ethyl acetate (15 ml). The combined extracts were dried over sodium sulphate then evaporated. The residue was subjected to preparative layer chromatography on silica using a mixture of ethyl acetate and hexane (1:1, v/v) as eluent to yield the title compound (0.198 g) as an oil. NMR (CDCl3): δ 2.05-2.15(m); 2.30(s); 2.55-2.60(m); 2.65-2.70(m); 2.85-2.95(m); 3.30-3.40(m); 3.60-3.70(m); 3.90-4.00(m); 4.40-4.60(m); 6.80-7.40(m). M+332.1941.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:13](CC3C=CC(OC)=CC=3)[CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1.FC(F)(F)C(O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:23]([O:25][CH3:26])=[O:24])=[CH:7][C:6]=2[CH:27]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2N(Cc2ccc(OC)cc2)CCCC1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1=Cc2cc(Br)ccc2NCCCC1
Temperature: 80 °C
Reaction time: 7 h
Yield: 82.1 %

Procedure:
To a solution of methyl 9-bromo-1-(4-methoxybenzyl)-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (12.5 g) in toluene (62.5 ml) was added trifluoroacetic acid (62.5 ml) and the mixture was stirred under nitrogen atmosphere at 80° C. for 7 hours. After distilling off the solvent under reduced pressure, water was added at 0° C. and the mixture was neutralized with potassium carbonate, and extracted with ethyl acetate. After washing the organic layer with aqueous saturated sodium bicarbonate solution and saturated brine, the resultant was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate=9:1) and recrystallized from hexane:ethyl acetate to give methyl 9-bromo-2,3,4,5-tetrahydro-1H-1-benzoazonin-6-carboxylate (7.4 g) as yellow crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.CCN(C(C)C)C(C)C.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>O=S(Cl)Cl>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:15][CH:14]=2)=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: O=C(O)c1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: CC(C)(C)c1ccc(NC(=O)c2ccc(-c3ccccn3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from Example 1A (570 mg, 2.86 mmol) in SOCl2 (10 mL) was refluxed for 1 hour. The solution was allowed to cool to room temperature and SOCl2 was removed under reduced pressure. The residue was taken up in tetrahydrofuran (10 mL) and treated with DIEA (2.5 mL, 14.4 mmol, 5 eq) and 4-tert-butylaniline (0.41 mL, 2.57 mmol). After stirring overnight at room temperature, the tetrahydrofuran was removed under reduced pressure and replaced with ethyl acetate (20 mL). The ethyl acetate was washed with H2O and brine, dried (Na2SO4), filtered, and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel (eluant gradient from 7:3 hexanes:ethyl acetate to 1:1 hexanes:ethyl acetate) to provide the title compound as a solid. 1H NMR (300 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.71-8.74 (m, 1H), 8.23-8.26 (m, 2H), 8.07-8.10 (m, 3H), 7.94 (td, J=7.4 Hz, 2.1 Hz, 1H), 7.70-7.73 (m, 2H), 7.37-7.44 (m, 3H), 1.29 (s, 9H); MS (ESI+) m/z 331 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]([N:11]1[C:15](=[O:16])[C:14]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]2[C:12]1=[O:21])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=O.Cl.Cl.[NH2:24][CH:25]([C:29]1([SH:36])[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)[C:26]([OH:28])=[O:27].C([O-])(=O)C.[Na+]>C(O)C.O>[C:26]([CH:25]1[C:29]2([CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]2)[S:36][CH:1]([CH:3]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][CH:18]=[CH:19][CH:20]=[C:13]3[C:12]2=[O:21])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])[NH:24]1)([OH:28])=[O:27]
Reactant: CC(C)(C)OC(=O)C(C=O)N1C(=O)c2ccccc2C1=O
Reactant: CN1CCC(S)(C(N)C(=O)O)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CN1CCC2(CC1)SC(C(C(=O)OC(C)(C)C)N1C(=O)c3ccccc3C1=O)NC2C(=O)O
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 166.9 g (0.57 mole) of tert-butyl 2-formyl-2-phthalimido-acetate in 1150 ml of ethanol, preheated to 60° C., there is added a solution of 160 g (0.57 mole) of alpha-amino-4-mercapto-1-methyl-4-piperidineacetic acid dihydrochloride and 235.6 g (1.73 mole) of sodium acetate (crystallized with three molecules of water) dissolved in 1150 ml of water. The reaction mixture is stirred for about ten minutes and then left to stand for 24 hours. The precipitate is filtered off, washed with water and dried. 223 g of the gamma-isomer of tert-butyl 4-carboxy-8-methyl-alpha-phthalimido-1-thia-3,8-diazaspiro-[4.5]decane-2-acetate is obtained; Yield: 81%; M.P. 276°-278° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[C:9]([NH:19][CH2:20][CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[C:31]([NH:35][C:36](=[O:39])[CH2:37][CH3:38])[CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:11])=[CH:13][CH:14]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 57 was prepared from bis(4-chlorophenyl)acetic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 552.2 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[N+:18]([O-])([OH:20])=[O:19]>>[N+:18]([C:5]1[CH:6]=[C:1]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=1)([O-:20])=[O:19]
Reactant: c1ccc(-c2ccncn2)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cccc(-c2ccncn2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
A mixture of 4-phenylpyrimidine (10 g, 64 mmol) and conc. H2SO4 (33 ml) was added to a mixture of conc. H2SO4 (22 ml) and conc. HNO3 (16 ml) at 0° C. The resulting mixture was stirred at 0° C. for 2 hr, poured onto crushed ice, and extracted with CH2Cl2. The extract was washed with a 5% aqueous NaHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. The residue was triturated with isopropanol and the precipitate was filtered off and dried under reduced pressure to give (57) (6.4 g, 50%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([CH:19]=O)[C:3]=1[S:21][C:22]([F:25])([F:24])[F:23].Cl.[CH3:27][O:28][NH2:29]>N1C=CC=CC=1>[CH3:27][O:28][N:29]=[CH:19][C:4]1[C:3]([S:21][C:22]([F:25])([F:24])[F:23])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:17])[F:16])=[CH:9][C:8]=2[Cl:18])[N:5]=1
Reactant: CON
Reactant: Nc1c(SC(F)(F)F)c(C=O)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: CON=Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Temperature: 25 °C
Reaction time: 26 h
Yield: 42.5 %

Procedure:
A mixture of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylthio-1H-pyrazole-3-carboxaldehyde (0.66 g), methoxyamine hydrochloride (0.2 g) and pyridine was stirred at room temperature for 26 hours. Pyridine was evaporated and the residue dissolved in ethyl acetate/acetonitrile, washed with 1% aqueous HCl, dried (MgSO4) and evaporated. The residue was purified by silica gel column chromatography, eluting with hexane/ethyl acetate, to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylthio-1H-pyrazole-3-carboxaldehyde O-methyloxime (0.3 g) as a white solid m.p. 129-131.5° C. Compound 9.
Reaction SMILES: O=C1C(C2C=CC=CC=2)(C2C=CC=CC=2)CCCN1CC(O)=O.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]3[CH:47]=[CH:46][C:45](F)=[CH:44][CH:43]=3)[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][C:38](O)=[O:39])[C:32]2=[O:41])=[CH:27][CH:26]=1.[F:49][C:50]([F:62])([F:61])[C:51]1[CH:60]=[C:59]2[C:54]([CH2:55][CH2:56][NH:57][CH2:58]2)=[CH:53][CH:52]=1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[O:39]=[C:38]([N:57]1[CH2:56][CH2:55][C:54]2[C:59](=[CH:60][C:51]([C:50]([F:49])([F:62])[F:61])=[CH:52][CH:53]=2)[CH2:58]1)[CH2:37][N:33]1[CH2:34][CH2:35][CH2:36][C:31]([C:28]2[CH:27]=[CH:26][CH:25]=[CH:30][CH:29]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:32]1=[O:41]
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNCC2
Agent: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccc(C(F)(F)F)cc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid from Example 68E for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.43 (d, J=9.3, 2H), 7.36-7.15 (m, 11H), 4.74 (d, J=40.6, 2H), 4.31 (s, 2H), 3.88 (t, J=5.9, 1H), 3.70 (t, J=5.9, 1H), 3.54 (t, J=6.4, 2H), 2.93 (t, J=5.8, 2H), 2.72-2.56 (m, 2H), 1.93-1.81 (m, 2H); MS (DCI) m/z 493.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].O[CH:15]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)S([O-])(=O)=O.[Na+].C(O)C>O>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[N:1]=[C:15]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:3]=2[CH:4]=1
Reactant: O=S(=O)([O-])C(O)C1CCCCC1
Reactant: Nc1ccc(Cl)cc1NCCCO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCCCn1c(C2CCCCC2)nc2ccc(Cl)cc21
Yield: 58 %

Procedure:
A mixture of 40 parts of 3-[(2-amino-5-chlorophenyl)amino]-1-propanol, 87 parts of sodium α-hydroxycyclohexanemethanesulfonate and 200 parts of ethanol is stirred and refluxed for 10 minutes. The reaction mixture is diluted with water and the solvent is evaporated. The residue is extracted a few times with trichloromethane. The combined extracts are dried, filtered and evaporated. The oily residue is triturated in 2,2'-oxybispropane: a sticky tar precipitates. The 2,2'-oxybispropane is decanted and upon stirring at room temperature, the product is allowed to precipitate. It is filtered off and dried, yielding 34 parts (58%) of 6-chloro-2-cyclohexyl-1H-benzimidazole-1-propanol; mp. 120.1° C.
Reaction SMILES: N1CC[O:4]CC1.Cl[C:8]1(Cl)[CH2:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[N:10]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:9]1=[O:25].OS(O)(=O)=O>C(Cl)(Cl)Cl>[CH2:23]([O:22][C:20]([CH2:19][N:10]1[C:11]2[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH2:13][CH2:14][C:8](=[O:4])[C:9]1=[O:25])=[O:21])[CH3:24]
Reactant: C1COCCN1
Reactant: CCOC(=O)CN1C(=O)C(Cl)(Cl)CCc2ccccc21
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1C(=O)C(=O)CCc2ccccc21
Reaction time: 18 h

Procedure:
A mixture of morpholine (0.315 ml, 3.6 mmol) and 3,3-dichloro-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (0.5 g) was stirred under nitrogen at 110° for 18 hours. The solution was diluted to 10 ml with chloroform and cooled to 0°. 20% H2SO4 (1 ml) was added and the solution stirred for 2 hours at 0°. The solution was extracted with chloroform (2×20 ml) and the extracts washed with 2N HCl (2×10 ml) and saturated brine (5 ml). The solution was dried over magnesium sulfate and evaporated under reduced pressure to yield 1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2,3- dione. NMR (CDCl3): δ1.25 (t,3H); 2.6 (m,2H); 3.6 (m, 2H); 4.2 (q, 2H); 7.3 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[CH2:21]([O:10][C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:14])([F:15])[F:1])=[CH:13][CH:12]=1)[CH3:22]
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1ccc(C(F)(F)F)cc1

Procedure:
A suspension of 300 g of 4-trifluoromethylcinnamic acid (J. Org. Chem. 43:980 (1980) and 25 ml of concentrated sulfuric acid in 1.7 liters of ethanol is heated to reflux for 24 hours. The solution is concentrated, cooled, and filtered to give as a white solid, 4-trifluoromethylcinnamic acid ethyl ester, mp 40°-41° C.