Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:7]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:8](=[O:31])[CH2:9][C:10](=[O:30])[CH2:11][CH:12]([OH:29])[CH2:13][C:14]1([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[S:19][CH2:18][CH2:17][CH2:16][S:15]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[BH4-].[Na+]>C(Cl)Cl.CO>[CH2:32]([N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:8](=[O:31])[CH2:9][CH:10]([OH:30])[CH2:11][CH:12]([OH:29])[CH2:13][C:14]1([CH2:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)[S:15][CH2:16][CH2:17][CH2:18][S:19]1)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCN(CCCCCC)C(=O)CC(=O)CC(O)CC1(CCc2ccc(O)cc2)SCCCS1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CCCCCCN(CCCCCC)C(=O)CC(O)CC(O)CC1(CCc2ccc(O)cc2)SCCCS1
Reaction time: 3 h

Procedure:
A solution of the ketone 6e (242 mg, 0.44 mmol) in 6 mL of CH2Cl2 is added at 0° C. to a suspension of NaBH4 (50 mg, 1.32 mmol) in 9 mL of MeOH. After stiffing for 3 h at 0° C., the reaction medium is quenched by the addition of a saturated aqueous solution of NH4Cl. After dilution of the reaction medium in a CH2Cl2 and H2O mixture, it is extracted with CH2Cl2. The organic phases are then combined, dried over MgSO4, filtered and concentrated under vacuum. Purification is carried out on a silica column (cyclohexane/AcOEt 8:2) in order to produce the mixture of 4 non-separable diastereoisomers of the expected alcohol (173 mg, 0.03 mmol, 76%) in the form of a yellow oil.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)=[CH:8][C:7]=1[CH3:28].[K+].[Br-].C(O)(C(F)(F)F)=O>C(#N)C.O>[CH3:28][C:7]1[CH:8]=[C:9]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:29])=[O:2]
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccccn3)cc2)cc1C
Agent: [Br-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: O
Product: Cc1cc(SCc2ccc(OCc3ccccn3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 60A. mp 150° C.; IR (KBr) cm−1: 2917, 1723, 1605, 1511, 1490, 1217; 400 MHz 1HNMR (DMSO-d6): δ 12.95 (brs, 1H), 8.49-8.55 (s, 1H), 7.73-7.81 (m, 1H), 7.40-7.48 (m, 1H), 7.24-7.33 (m, 1H), 7.00-7.19 (m, 4H), 6.83-6.93 (m, 2H), 6.69 (d, 1H, J=8.5 Hz), 5.08 (s, 2H), 4.62 (s, 2H), 4.00 (s, 2H), 2.08 (s, 3H); HPLC: area %=96.24, r.t.=1.95 min., γ=214 nm, mobile phase=acetonitrile/water with 0.10% TFA; MS m/z 396 (M+1). Anal. Calc'd for C22H21NO4S: C, 66.82; H, 5.35; N, 3.54. found: C, 66.12; H, 5.09; N, 3.44.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5][NH2:6].[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[N:24]=[C:25]=[O:26])([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH:12]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([OH:1])[CH:3]=1)=[O:26])([CH3:13])[CH3:14]
Reactant: COc1ccc(CN)cc1O
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: Cc1ccccc1
Product: COc1ccc(CNC(=O)Nc2c(C(C)C)cccc2C(C)C)cc1O

Procedure:
Added to 40 ml of toluene were 600 mg (3.92 mmol) of 3-hydroxy-4-methoxybenzylamine and 810 mg (3.90 mmol) of 2,6-diisopropylphenyl isocyanate, and the mixture was stirred under reflux for 8 hours.
Reaction SMILES: [CH2:1]([CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1)[CH3:2].OS(O)(=O)=O.[N:18]1C2C(=CC=CC=2)C=CC=1.[N+]([O-])(O)=O.C([O-])(O)=O.[Na+].[OH-].[Na+]>O.[Pd].CCOC(C)=O.CCO>[NH2:18][C:9]1[CH:8]=[C:7]2[C:12]([CH:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6]2)=[CH:11][CH:10]=1
Reactant: c1ccc2ncccc2c1
Reactant: CCC1CCNc2ccccc21
Agent: [Pd]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CCC1CCNc2cc(N)ccc21
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 57 %

Procedure:
A 25-mL rb flask containing (R/S)-4-ethyl-1,2,3,4-tetrahydroquinoline (340 mg, 2.1 mmol) was cooled to -10° C., and conc. H2SO4 (5 mL) was added slowly. The resulting solution was warmed to rt to effect complete dissolution of the quinoline, then cooled again to -10° C. and stirred vigorously. Fuming HNO3 (85 μL) was added dropwise, slowly, and the reaction mixture turned dark red. After 10 min, the reaction mixture was poured onto cracked ice and diluted with water (5 mL). Sat'd NaHCO3 (80 mL) was added, and the pH was adjusted to pH 9 with 3.0M NaOH. This aqueous phase was extracted with EtOAc (3×75 mL), and the combined extracts were dried (Na2SO4),and concentrated under reduced pressure to yield a dark red oil. This crude material was placed into a 250-mL rb flask with 1:1 EtOAc/EtOH (40 mL) and 10% Pd on C (approx. 1 mol %). The vessel was evacuated and flushed with nitrogen three times, then stirred under an atmosphere of hydrogen for 16 h, filtered, and concentrated under reduced pressure to yield a yellow oil, which was purified by flash chromatography (silica gel, CH2 Cl2 /methanol, 9:1), affording 210 mg (57%) of the desired product as a dark yellow oil (Rf 0.50, CH2Cl2 /MeOH, 9:1). Data for (R/S)-7-amino-4-ethyl-1,2,3,4-tetrahydroquinoline: 1H NMR (400 MHz, CDCl3) 6.81 (d, 1H, J=8.1, 5-H), 6.02 (dd, 1H, J=8.0, 2.2, 6-H), 5.84 (d, 1H, J=2.3, 8-H), 3.48 (s, 2H, NH2), 3.27 (ddd, 1H, J=11.1, 11.1, 3.5, 2-H), 3.20 (ddd, 1H, J=9.8, 5.3, 4.5, 2-H), 2.55 (dddd, 1H, J=10.2, 5.2, 5.2, 5.2, 4H), 1.90 (dddd, 1H, J=9.6, 9.6, 9.6, 4.7, 3-H), 1.72 (m, 2H, 3-H, CH2CH3), 1.48 (m, 1H, CH2CH3), 0.96 (t, 3H, J=7.4, CH3).
Reaction SMILES: [N+:1]1([O-])[C:2]([CH3:8])=[CH:3][CH:4]=[CH:5][C:6]=1[CH3:7].S(OC)(OC)(=O)=O.COS([O-])(=O)=O.CO[N+:25]1C(C)=CC=C[C:26]=1C.[C-]#N.[K+]>O>[CH3:7][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:8])[N:1]=1)[C:26]#[N:25]
Reactant: CO[n+]1c(C)cccc1C
Reactant: Cc1cccc(C)[n+]1[O-]
Agent: COS(=O)(=O)[O-]
Agent: [C-]#N
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Product: Cc1cc(C#N)cc(C)n1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a stirred quantity of 2,6-lutidine-1-oxide (12.3 g, 100 mmol) was slowly added dimethyl sulphate (12.6 g, 100 mmol) at such a rate that the temperature of the reaction mixture was maintained at 80° C. throughout the addition. When the addition was complete (about one hour) the solution was stirred at that temperature for an additional 2 h. The salt crystallised upon cooling and was recrystallised from anhydrous acetone giving white prisms; m.p 96-97° C. Yield 18 g (73%). To a solution of this 1-methoxy-2,6-dimethylpyridinium methyl sulphate (11.65 g, 50 mmol) dissolved in water (50 ml), under nitrogen, was added a solution of potassium cyanide (10 g, 150 mmol) dissolved in 50 ml of water. The solution was allowed to stand at room temperature for 2 days at which time the nitrile, which had separated from the solution as long white needles, was removed by filtration, yielding 2.8 g of pure product (42%) δH (CDCl3, 500 MHz) 2.44 (6 H, s, 2×CH3), 4.2 (2 H, d, J 5, NHCH2), 6.78 (2 H, s, ArH); δC (CDCl3, 500 MHz) 157.83 (2×C), 122.71 (C), 118.2 (2×CH), 24.28 (2×CH3)
Reaction SMILES: [Na+:1].[Na+].[C:3]1([S:13]([O-:16])(=[O:15])=[O:14])[CH:8]=[CH:7][CH:6]=[C:5]([S:9]([O-:12])(=[O:11])=[O:10])[CH:4]=1.S(=O)(=O)(O)O.[N+:22]([O-])([OH:24])=[O:23].[OH-].[Ca+2].[OH-]>>[Na+:1].[Na+:1].[N+:22]([C:7]1[CH:8]=[C:3]([S:13]([O-:16])(=[O:15])=[O:14])[CH:4]=[C:5]([S:9]([O-:12])(=[O:11])=[O:10])[CH:6]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [Na+]
Product: O=[N+]([O-])c1cc(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])c1
Temperature: 0 °C

Procedure:
Additionally, the hexaphenyl ester intermediate compound of the invention is prepared by treating 1,3-benzenedisulfonic acid disodium salt with concentrated sulfuric acid at 80° C. then adding fuming nitric acid and heating at 85°-89° C. for four hours. The cooled mixture is added to ice-water, neutralized to pH 5-6 with calcium hydroxide and filtered. The aqueous mixture is adjusted to pH 10 with sodium carbonate and filtered. Evaporation of the filtrate produces a residue which is recrystallized from boiling water to give 5-nitrobenzene-1,3-disulfonic acid disodium salt. This material is refluxed 16 hours with thionyl chloride and dimethylformamide and filtered. The filtrate is concentrated to an oil which is crystallized from chloroform:carbon tetrachloride to give the disulfonyl chloride which is reacted with phenol in pyridine at elevated temperature for one hour. Addition of the cooled mixture to 10% aqueous sodium carbonate solution produces a product which is crystallized from ethanol to yield the nitro-diphenyl ester. Hydrogenation of the ester in ethyl acetate with 10% palladium on carbon catalyst for 6.5 hours yields an oil which is crystallized from benzene to give the amino-diphenyl ester. The amine in pyridine is heated with 1,3,6-naphthalenetrisulfony chloride. The mixture is poured into water and extracted with methylene chloride. The extract, after washing the dilute acid, is evaporated to a glass which is purified by column chromatography to yield the hexaphenyl ester intermediate compound of the invention. Treatment of the novel intermediate triphenyl and hexaphenyl esters with alkali metal ethoxide in dimethylsulfoxide at elevated temperature followed by acidification with acetic acid and precipitation with absolute ethanol provides the active complement inhibiting trialkali metal and hexaalkali metal salts of the invention.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C1(C)C=CC=CC=1.C(N(CC)CC)C.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClCCl>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O[C@H]1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)N1CC[C@H](O)C1
Temperature: 0 °C

Procedure:
A 0.5 g portion of (S)-3-hydroxypyrrolidine, as described in Example 42, was reconcentrated twice from toluene, dissolved in 80 ml of dichloromethane and cooled to 0° C. A 3.8 ml portion of triethylamine and 2.8 ml of benzylchloroformate were added with stirring. The reaction was stirred overnight, diluted with 300 ml of dichloromethane and extracted with 80 ml of 5% hydrochloric acid and 5% sodium bicarbonate solution. The aqueous phases were combined, saturated with sodium chloride and extracted with 3×150 ml of ethyl acetate. The organic phases were combined, dried, filtered and concentrated in vacuo. The residue was purified by chromatography (alumina) giving 940 g of (S)-3-hydroxy-1-pyrrolidinecarboxylic acid, phenylmethyl ester as a yellow oil [α]D26 =+21° (c, 1.054 methanol).
Reaction SMILES: C1([C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])C=CC=CC=1.[Cl:36][C:37]1[CH:42]=[C:41](I)[CH:40]=[C:39]([Cl:44])[CH:38]=1>>[Cl:36][C:37]1[CH:42]=[C:41]([C:7]#[C:8][C@@H:9]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)[CH:19]=2)(=[O:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])[CH:40]=[C:39]([Cl:44])[CH:38]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: O=C(O)C[C@@H](C#Cc1ccccc1)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1
Product: O=C(O)C[C@@H](C#Cc1cc(Cl)cc(Cl)c1)NS(=O)(=O)c1cccc(OCCCCNc2ccccn2)c1

Procedure:
The procedure for the preparation of the product of EXAMPLE 18 was repeated using 1,3-dichloro-5-iodobenzene (Aldrich) in the place of iodobenzene to provide the title product. 1H (CD3OD): δ 7.88 (1H, t); 7.82 (1H, d); 7.50 (1H, d); 7.45 (1H, t); 7.43 (1H, s); 7.36 (1H, s); 7.10 (1H, d); 7.03 (1H, d); 6.91 (2H, s); 6.88 (1H, t); 4.68 (1H, t); 4.04 (2H, t); 3.40 (2H, t); 2.78 (2H, d); 1.87 (4H, m).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[O:36][CH:37]=[CH:38][N:39]=1)CCC>O1CCCC1.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>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=2[CH3:23])[C:6]2[CH:5]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[C:2]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[C:10]=2[N:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(-c4ncco4)cc(N4CCOCC4)cc32)cccc1C(F)(F)F

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole (150 mg, 0.320 mmol), prepared as described in Example 63, 2-(tributylstannanyl)-1,3-oxazole (195 mg, 0.545 mmol) and Pd(Ph3P)2Cl2 (11.27 mg, 0.016 mmol) in Tetrahydrofuran (THF) (5 mL) was stirred at reflux temperature for 19 h. Conversion to the desired product is observed by LC/MS analysis, but the majority of the mixture is still SM. The reaction mixture was transferred in a microwavable vial and irradiated in a microwave reactor at 120° C. for 90 min. The reaction mixture was diluted with EtOAc and CHCl3, washed with aq sat sol NH4Cl, brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified on a silica gel column (ISCO, 0-70% EtOAc in Hexanes—no product peak observed—then 0-10% MeOH in CH2Cl2) to give desired product (94.8 mg, 0.204 mmol, 63.5% yield) as a yellow powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (s, 1H), 7.71 (d, J=2.27 Hz, 1H), 7.58 (d, J=7.83 Hz, 1H), 7.37 (s, 1H), 7.11 (t, J=7.83 Hz, 1H), 6.66 (d, J=2.27 Hz, 1H), 6.47 (d, J=7.83 Hz, 1H), 5.31 (s, 2H), 3.81-3.92 (m, 4H), 3.11-3.24 (m, 4H), 2.58 (s, 3H), 2.56 (s, 3H). MS (ES+) m/e 457.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:7](N)=[O:8].[CH2:10]([OH:12])[CH3:11]>CS(O)(=O)=O>[CH2:10]([O:12][C:7]([C:3]1[N:4]=[CH:5][NH:6][C:2]=1[NH2:1])=[O:8])[CH3:11]
Reactant: NC(=O)c1nc[nH]c1N
Reactant: CCO
Agent: CS(=O)(=O)O
Product: CCOC(=O)c1nc[nH]c1N
Yield: 45 %

Procedure:
A stirred solution of commercially available 5-amino-1H-imidazole-4-carboxamide (25 g, 198 mmol) in methanesulfonic acid (107 mL) and ethanol (400 mL) was stirred at reflux conditions for 12d, evaporated and water (300 mL) was added. While stirring and cooling (ice/water) sodium hydroxide solution (32%) was added until pH=6 was reached. The water layer was saturated with sodium chloride and extracted with ethyl acetate (3×200 mL). The combined organic layers were dried (MgSO4), evaporated and the crude product purified crystallization (ethyl acetate/ethanol) to yield 5-amino-1H-imidazole-4-carboxylic acid ethyl ester (13.7 g, 45%) as a light brown solid. MS (EI) 155.1 [(M)+]; mp 178° C.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH:17][C:18]2[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:10][CH2:9]1.[C:25](Cl)(=O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C(Cl)(Cl)Cl>[CH2:41]([C:42]1[N:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][O:8][CH2:13][CH2:12]2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=1)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH3:25]
Reactant: Nc1ccccc1NCCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCc1nc2ccccc2n1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.7 %

Procedure:
Triethylamine (0.42 ml) was added to a solution containing N-(3-morpholinopropyl)-1,2-benzenediamine (0.640 g) in chloroform (3.5 ml), and then a solution containing stearoyl chloride (0.825 g) in chloroform (3.5 ml) was added thereto while being cooled with ice. After being stirred for 3 hours at room temperature, the reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate aqueous solution and water successively, dried over sodium sulfate anhydride, and concentrated. Concentrated hydrochloric acid (2.25 ml) was added to a solution containing the residue (1.442 g) in ethanol (15 ml). After being stirred for 1.5 hours at 90° C., the reaction mixture was concentrated. The residue, with ethyl acetate added thereto, was washed with 1N sodium hydroxide aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated. The residue (1.296 g) was purified by silica gel column chromatography (silica gel 40 g, ethyl acetate), thereby yielding the entitled compound (1.088 g) as yellow solid.
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:21][CH:22]=2)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CC=C(c2ccc(Cl)cc2)CC1
Product: Clc1ccc(C2=CCN(CCCc3onc4c3CCCCC4)CC2)cc1

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)-n-butyrate, 3-(3-(4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.O.[Na].[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25]([N:28]1[CH2:30][CH2:29]1)(=[O:27])=[O:26])([O-:18])=[O:17].Cl>CC#N.O.CCCCCC.C(OCC)(=O)C>[CH:10]1[C:11]2[N:12]([CH2:30][CH2:29][NH:28][S:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])(=[O:26])=[O:27])[C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCn1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 0.29 h

Procedure:
Carbazole (1.10 g, 6.59 mmol) was dissolved in CH3CN (40 mL). Then sodium hydrate (0.33 g, 8.25 mmol) was added, and the mixture was stirred at room temperature for 15-20 min. Then, a solution of aziridine 56 (1.5 g, 7.89 mmol) in CH3CN (30 mL) was added in one portion. The resulting mixture was stirred for 1 h (TLC monitoring, eluent: hexane-ethyl acetate, 1:1), poured into water, acidified with HCl to pH 1, and stirred again at room temperature. Gradually, an orange product precipitated from the turbid solution. The precipitate was filtered, and washed with MeOH and ether. Yield of 51: 2.15 g (83%) as orange crystals.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([CH:11]2[CH2:13][CH2:12]2)=[CH:6][C:3]=1[C:4]#[N:5].C([O-])([O-])=[O:15].[K+].[K+].OO.O>CS(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([Cl:10])[C:7]([CH:11]2[CH2:12][CH2:13]2)=[CH:6][C:3]=1[C:4]([NH2:5])=[O:15]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1cc(C2CC2)c(Cl)nc1Cl
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(C2CC2)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 838.7 %

Procedure:
To a stirred mixture of compound 2,6-dichloro-5-cyclopropylnicotinonitrile (1.10 g, 5.16 mmol) and K2CO3 (351 mg, 2.58 mmol) in DMSO (10 mL) was added 30% H2O2 (1.90 mL, 15.5 mmol). The mixture was stirred for 2 hrs at rt. Then the mixture was poured into water and extracted with EtOAc. The separated organics was dried, concentrated and purified by column chromatography (Petroleum ether:EtOAc=10:1˜1:1) to give compound 2,6-dichloro-5-cyclopropylnicotinamide (5 g, 70%). 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.69 (s, 1H), 6.70 (s, 1H), 6.20 (s, 1H), 2.08 (m, 1H), 1.18 (m, 2H), 0.69 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[C:6]([CH3:14])=[C:5]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]=1[CH3:21].Br[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH3:30])=[CH:25][CH:24]=1>>[CH2:29]([C:26]1[CH:27]=[CH:28][C:23]([N:18]2[CH2:19][CH2:20][N:15]([C:5]3[C:4]([CH3:21])=[C:3]([O:2][CH3:1])[C:11]4[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=4[C:6]=3[CH3:14])[CH2:16][CH2:17]2)=[CH:24][CH:25]=1)[CH3:30]
Reactant: CCc1ccc(Br)cc1
Reactant: COc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: CCc1ccc(N2CCN(c3c(C)c4c(c(OC)c3C)OC(C)(C)C4)CC2)cc1
Yield: 24.4 %

Procedure:
By using 1-(7-methoxy-2,2,4,6-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (400 mg, 1.38 mmol) synthesized in Reference example 96 and 1-bromo-4-ethylbenzene (383 mg, 2.07 mmol), the reaction was carried out in the same manner as Reference example 59 to synthesize the title compound 133 mg (yield 25%). Melting point was 157 to 160° C. (hexane-ethyl acetate).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([OH:14])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO.CN(C=O)C.[Cl-].[Na+].O>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[C:12]([O:14][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13]
Reactant: O=C(O)c1c(O)ccc2ccccc12
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: O=C(OCc1ccccc1)c1c(O)ccc2ccccc12
Reaction time: 20 h
Yield: 57 %

Procedure:
A solution of 2-hydroxy-1-carboxynaphthalene (4.70 g, 25.0 mmol) and 20% cesium carbonate (20.3 mL, 12.5 mmol) in methanol (20 mL) was striped to dryness, dissolved in DMF (10 mL), treated with benzyl bromide (2.67 mL, 22.5 mmoL), stirred for 20 hours, diluted with brine, and extracted with ethyl acetate. The ethyl acetate was washed with water, 1 M NaOH, water and brine, dried (MgSO4), filtered, and concentrated to provide 3.98 g (57%) of the desired compound.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=1)[CH3:3].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][C:7]([CH3:15])([CH3:14])[C:6]=2[CH:5]=1)(=[O:1])[CH3:3]
Reactant: CC(O)c1ccc2c(c1)C(C)(C)CCC2
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)C(C)(C)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2.44 g (11.96 mmol) of 2-(1-hydroxyethyl)-8,8-dimethyl-5,6,7,8-tetrahydronaphthalene in 35 ml of methylene chloride was added 6.75 g (17.9 mmol) of pyridinium dichromate and 330 mg (1.68 mmol) of pyridinium trifluoroacetate. The mixture was stirred at room temperature for 24 h and then diluted with 35 ml of low-boiling petroleum ether. The mixture was filtered through a short column of anhydrous MgSO4 and silica and the filtrate then concentrated in-vacuo to give the title compound as a colorless oil. PMR (CDCl3): δ 1.30 (6H, s), 1.60-1.70 (2H, m), 1.72-1.84 (2H, m), 2.56 (3H, s), 2.78 (2H, t, J~6.1 Hz), 7.08 (1H, d, J~7.8 Hz), 7.61 (1H, dd, J~7.8 Hz, 1.9 Hz), 7.93 (1H, d, J~1.9 Hz).