Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10](=[O:15])[CH2:11][C:12]([CH3:14])=[O:13])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1(C)C=CC(S([N:25]=[N+:26]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1.[OH-].[K+]>C(OCC)C.ClCCl>[C:1]([O:6][CH2:7][C:8]([O:9][C:10](=[O:15])[CH2:11][C:12](=[O:13])[CH3:14])=[N+:25]=[N-:26])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: C=C(C)C(=O)OCC(=[N+]=[N-])OC(=O)CC(C)=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
2-Diazo-3-oxobutyroxyethyl methacrylate monomer was prepared as follows: a mixture of 2-acetoacetoxyethyl methacrylate (4.28 gm, 20 mmol, available from Eastman Chemical, Kingsport, Tenn.), dichloromethane (30 ml), and p-toluenesulfonyl azide (3.94 gm, 20 mmol) was cooled to 0° C. and then DBU (1,8-diazabicyclo[5.4.0]undec-7-ene, 4.48 ml, 30 mmol) was added dropwise. After the addition of DBU, the reaction mixture was stirred at room temperature for 15 minutes and then poured into a mixture of 10% KOH (100 ml) and diethyl ether (50 ml). The organic layer was separated and the aqueous layer was re-extracted with diethyl ether (50 ml). The organic extracts were combined and then washed sequentially with 3N HCl (50 ml), deionized water (2×50 ml) and saturated aqueous sodium chloride solution (50 ml). The organic layer was dried using anhydrous magnesium sulfate, filtered, and concentrated to give 4.39 gm of 2-diazo-3-oxobutyroxyethyl methacrylate as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 1.94 (s, 3H); 2.47 (s, 3H); 4.35-4.55 (m, 4H); 5.60 (s, 1H); 6.12 (s, 1H). IR: 2181 cm-1. Peak decomposition temperature: 156° C. (by DSC).
Reaction SMILES: C1N2CN3[CH2:10][N:4](C2)CN1C3.[F:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:19])CBr)=[CH:14][C:13]=1[C:22]([F:25])([F:24])[F:23].C(OCC)(=O)C.C(O)C.[ClH:35]>>[ClH:35].[NH2:4][CH2:10][C:16]([C:15]1[CH:20]=[CH:21][C:12]([F:11])=[C:13]([C:22]([F:25])([F:23])[F:24])[CH:14]=1)=[O:19]
Reactant: O=C(CBr)c1ccc(F)c(C(F)(F)F)c1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: NCC(=O)c1ccc(F)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
Add methenamine (1.10 equiv; 231.55 mmoles; 32.46 g) to a solution of 4-fluoro-3-(trifluoromethyl)phenacyl bromide (60.00 g 1.00 equiv; 210.50 mmoles) in ethyl acetate (450 mL; 4.60 moles). Stir the mixture at room temperature overnight. Remove the solvent in vacuo and triturate the solid in MTBE. Filter and dry under reduced pressure. Add ethanol (450 mL; 7.73 moles), followed by hydrogen chloride (150 mL; 8.30 equiv; 1.75 moles) and stir the mixture at room temperature overnight. Remove the solvent in vacuo and dry the solid in vacuo at 50° C. for a week to obtain 2-Amino-1-(4-fluoro-3-trifluoromethyl-phenyl)-ethanone hydrochloride (54.23 g; 100% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:31]=[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:42]#[N:43])[CH:33]=1)[C:10]([NH:12][C:13]1[N:18]=[CH:17][C:16]([N:19]([CH2:27][CH2:28][O:29][CH3:30])C(=O)OC(C)(C)C)=[CH:15][CH:14]=1)=[O:11])#[N:2].FC(F)(F)C(O)=O>ClCCl>[C:42]([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[CH2:35][O:34][C:32]1[CH:31]=[C:9]([CH:8]=[C:7]([O:6][CH2:5][C:4]2[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=2[C:1]#[N:2])[CH:33]=1)[C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19][CH2:27][CH2:28][O:29][CH3:30])=[CH:17][N:18]=1)=[O:11])#[N:43]
Reactant: COCCN(C(=O)OC(C)(C)C)c1ccc(NC(=O)c2cc(OCc3ccccc3C#N)cc(OCc3ccccc3C#N)c2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCNc1ccc(NC(=O)c2cc(OCc3ccccc3C#N)cc(OCc3ccccc3C#N)c2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.2 %

Procedure:
To a stirred solution of tert-butyl 6-({3,5-di(2-cyanobenzyloxy)benzoyl}amino)pyridin-3-yl(2-methoxyethyl)carbamate (237 mg) in dichloromethane (10 ml) was added trifluoroacetic acid (3 ml). The solution was stirred at ambient temperature for three hours. Volatile material was removed by evaporation. The residue was diluted in DCM (100 ml), washed with 2M sodium Hydroxide (50 ml), brine (50 ml), dried over MgSO4. Volatile material was removed by evaporation to give the title compound (190 mg) as a foam, 1H NMR δ (d6-DMSO): 3.22 (t, 2H), 3.28 (2, 3H), 3.50 (t, 2H), 5.31 (s, 4H), 6.92 (s, 1H), 7.12 (dd, 1H), 7.34 (s, 2H), 7.57 (m, 2H), 7.75 (m, 5H), 7.82 (d, 1H), 7.91 (d, 2H), 10.49 (br s, 1H). MS ES+ 534.41 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([CH3:11])=[CH:7][CH:8]=[CH:9][CH:10]=1)=O.[C:12]([C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=1)#[N:13].P(Cl)(Cl)(Cl)=O.[CH2:27]([N:29]1[CH2:34]CN[CH2:31][CH2:30]1)[CH3:28]>C(Cl)Cl.CO>[CH2:27]([N:29]1[CH2:30][CH2:31][N:2]([C:3]2[C:5]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH3:21])[CH:15]=3)[N:13]=2)[CH2:1][CH2:34]1)[CH3:28]
Reactant: COc1cc(C#N)ccn1
Reactant: CNC(=O)c1ccccc1C
Reactant: CCN1CCNCC1
Solvent: CO
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: CCN1CCN(c2nc(-c3ccnc(OC)c3)cc3ccccc23)CC1
Temperature: 100 °C
Yield: 9.2 %

Procedure:
To 3-(2-methoxypyridin-4-yl)isoquinolin-1-one (1.22 g) obtained by reacting N-methyl-o-toluamide (2.90 g) and 4-cyano-2-methoxypyridine (2.60 g) according to the method of Example 10-1 was added phosphorus oxychloride (25.7 g), and the resulting mixture was heated at 100° C. for 2 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water, an aqueous solution of saturated sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting 1-chloro-3-(2-methoxyphenyl)isoquinoline was reacted as it was with N-ethylpiperazine (20 ml) at 120° C. for 8 hr. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate and purified water. The ethyl acetate layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to the free compound of the title compound as a pale yellow oil (0.62 g, yield: 9.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([CH:19]=[O:20])=[CH:5][CH:4]=1.[Cl-].[Na+].S(=O)(=O)([OH:25])N>O1CCOCC1.O>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=3[C:7]=2[C:6]([C:19]([OH:25])=[O:20])=[CH:5][CH:4]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc(C=O)c2c1oc1ccc([N+](=O)[O-])cc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)c2c1oc1ccc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.2 %

Procedure:
4-Methoxy-8-nitro-dibenzofuran-1-carbaldehyde (1.03 g, 3.8 mmoles) is suspended in a mixture of dioxane (60 mL) and water (10 mL). Sodium chloride (0.445 g, 4.93 mmoles) and sulphamic acid (2.09 g, 21.6 mmoles) are added and the mixture is stirred at room temperature for 1 hour. The mixture is then diluted with water (100 mL) and extracted with AcOEt (200 mL). The organic layer is dried over Na2SO4 and the solvent is evaporated to yield 0.701 g of raw product which is employed in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:18](O)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[CH2:1]([O:8][C:9]([NH:11][C:12]1([CH2:18][OH:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1(C(=O)O)CCCCC1)OCc1ccccc1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(NC1(CO)CCCCC1)OCc1ccccc1
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 101.3 %

Procedure:
To a solution of 1-(benzyloxycarbonylamino)cyclohexane-1-carboxylic acid (4.16 g, 15.0 mmol) and N-methylmorpholine (1.81 mL, 16.5 mmol) in DME (15 mL) at 4° C. was slowly added isobutyl chloroformate (2.14 mL, 16.5 mmol) and the reaction mixture was stirred for 5 min, then filtered into a pre-cooled (4° C.) flask. Sodium borohydride (0.85 g, 22.5 mmol) in water (7 mL) wag added followed immediately by water (500 mL). The reaction was then warmed to 20° C. and stirred for 30 min. The reaction mixture was extracted with CH2Cl2 and concentrated under reduced pressure to yield 1-(benzyloxycarbonylamino)-1-(hydroxymethyl)cyclohexane (4.0 g, 100%): TLC (25% EtOAc/hex) Rf0.11.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[OH:5][C:6]1[CH:23]=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[OH:5][C:6]1[C:23]([N+:1]([O-:4])=[O:2])=[CH:22][C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:13][CH2:14][C:8]=2[CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2cc(O)c([N+](=O)[O-])cc2CC1
Reaction time: 1.5 h

Procedure:
Nitric acid (70%, 3.44 ml) was added dropwise over 40 min with vigorous stirring to 1,1-dimethylethyl 7-hydroxy-1,2,4,5-tetrahydro-benzo[d]azepine-3-carboxylate (14.2 g) in DCM with cooling in an ice bath. After additional 5 min silica gel (15 g) and sodium bicarbonate powder (5 g) were added and stirring was continued for 1.5 h. The mixture was filtered through a layer (1 cm) of silica gel and the solids washed with EtOAc. The resulting solution was concentrated and submitted to column chromatography to provide the title compound as a yellow solid (8.54 g).
Reaction SMILES: [Si]([O:8][CH:9]([CH:11]1[CH:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:13][C:12]1=[O:24])[CH3:10])(C(C)(C)C)(C)C>O1CCCC1.CO>[OH:8][CH:9]([CH:11]1[CH:14]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[NH:13][C:12]1=[O:24])[CH3:10]
Reactant: COc1ccc(SC2NC(=O)C2C(C)O[Si](C)(C)C(C)(C)C)cc1
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(SC2NC(=O)C2C(C)O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
600 mg (1.68 mmol) of rac -(αS*,3S*,4R*)-3-[1-(t-butyldimethylsilyloxy)ethyl]-4-[(p-methoxyphenyl)thio]-2-azetidinone are dissolved in 35 ml of tetrahydrofuran/methanol/12 percent hydrochloric acid (4:2:1), whereupon the solution is stirred at room temperature for 4 hours and worked-up as described in Example 2. There is obtained rac-(αS*,3S*,4R*) -3-(1-hydroxyethyl)-4-[(p-methoxyphenyl)thio]-2-azetidinone as a colourless oil; IR: 1765 cm-1.
Reaction SMILES: C([Si:4]1([C:11]2[CH:16]=[CH:15]C=CC=2)[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)CC.Br[C:18]1[CH:23]=[C:22](F)[C:21]([C:25]([Cl:28])=[CH:26][Cl:27])=[C:20](F)[CH:19]=1>>[CH2:11]([Si@H:4]1[CH2:5][CH2:6][C@H:7]([C:18]2[CH:23]=[CH:22][C:21]([C:18]3[CH:23]=[CH:22][C:21]([C:25]([Cl:28])=[CH:26][Cl:27])=[CH:20][CH:19]=3)=[CH:20][CH:19]=2)[CH2:8][CH2:9]1)[CH2:16][CH3:15]
Reactant: CCC[Si]1(c2ccccc2)CCC(=O)CC1
Reactant: Fc1cc(Br)cc(F)c1C(Cl)=CCl
Product: CCC[Si@H]1CC[C@H](c2ccc(-c3ccc(C(Cl)=CCl)cc3)cc2)CC1

Procedure:
The general procedure of Example 35 was repeated using 4-propyl-4-phenyl-4-silacyclohexanone instead of 4-pentyl-4-phenyl-4-silacyclohexanone, and 4-bromo-2,6-difluoro-1-(1,2-dichlorovinyl)benzene instead of 4-bromo-2,6-difluoro-1-(2,2-difluorovinyloxy)benzene, thereby obtaining the intended compound.
Reaction SMILES: [FH:1].[O:2]1[C:4]2([CH2:8][CH2:7][CH2:6][CH2:5]2)[CH:3]1[C:9]#[N:10].C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1.ClCCl>[F:1][C:4]1([CH:3]([OH:2])[C:9]#[N:10])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: N#CC1OC12CCCC2
Reactant: F
Agent: *CC*
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(O)C1(F)CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.1 %

Procedure:
Anhydrous dichloromethane (3 mL) and a 70% w/w solution of hydrogen fluoride (2.68 mL, 20.44 mmol) in pyridine are mixed in a polyethylene bottle at 0° C. under a nitrogen atmosphere. A solution of 1-oxa-spiro[2.4]heptane-2-carbonitrile (3.30 g, 26.76 mmol) in anhydrous dichloromethane (3.2 mL) is added slowly. The reaction is stirred at 0° C. for 1 h and at room temperature for 1 h. The mixture is cooled at 0° C. and a saturated solution of sodium carbonate is added carefully. The aqueous layer is extracted with diethyl ether. The organic layers are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered, and the solvent is removed. The residue is purified by chromatography in a 20 g silica gel cartridge eluting with hexane:diethyl ether (100:0 to 80:20) to obtain 1.7 g of desired compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 4.47 (d, 1H), 3.50 (bs, 1H), 2.12-1.67 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=S)[S:10][C:6]=2[C:5](=[O:12])[C:4](=[O:13])[O:3]1.C(Cl)Cl.C(Cl)Cl.CC(O)=[O:23]>C([O-])(=O)C.[Hg+]>[CH3:1][C:2]1([CH3:14])[C:7]2[S:8][C:9](=[O:23])[S:10][C:6]=2[C:5](=[O:12])[C:4](=[O:13])[O:3]1
Reactant: CC(=O)O
Reactant: CC1(C)OC(=O)C(=O)c2sc(=S)sc21
Agent: CC(=O)[O-]
Agent: [Hg+]
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=O)c2sc(=O)sc21

Procedure:
Mercury acetate (181 mg, 0.568 mmol) was added to a stirred solution of 4,4-dimethyl-2-thioxo-4H-[1,3]dithiolo[4,5-c]pyran-6,7-dione (4) (100 mg, 0.406 mmol) in CH2Cl2/AcOH (3:1). The reaction was followed by TLC (silica, CH2Cl2) and after ca. 30 min the mixture is filtered through a celite pad to remove the mercury salts. The resulting solution was washed first with water (3×15 mL) and then with sat. aqueous NaHCO3 (5×10 mL), and dried over MgSO4. Removal of the solvent under reduced pressure afforded pure 4,4-dimethyl-4H-[1,3]dithiolo[4,5-c]pyran-2,6,7-trione (5) a pale beige solid. Yield: 65 mg (70%). 1H-NMR spectrum in CDCl3 (ppm): 1.88 (s, 6H). 13C-NMR spectrum in CDCl3 (ppm): 184.5, 163.5, 160.4, 153.5, 128.3 84.2, 31.8. Selected IR (neat, cm−1): 1746, 1693, 1641, 1552, 1453. MS-ESI calculated for C7H8O4S2 [M+H]+230.98; found 230.78; calculated for C7H8O4S2Na [M+Na]+) 252.96; found 252.79.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].II.C[C:19]([CH3:22])([O-])[CH3:20].[K+].O.O1C[CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[C:13]([O:15][C:20]3[CH:19]=[CH:22][CH:28]=[CH:27][CH:26]=3)[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cc2ccc(O)cc2o1
Reactant: CC(C)(C)[O-]
Agent: II
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2ccc(Oc3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 69 %

Procedure:
To a mixed solution of 6-hydroxy-benzofuran-2-carboxylic acid ethyl ester (200 mg, 967 μmol) in tetrahydrofuran (4 mL) and N,N-dimethylformamide (4 mL) were added diphenylindonium iodine (395 mg, 967 μmol) and potassium t-butoxide (109 mg, 967 μmol) at 0° C., which was stirred at room temperature for 40 minutes under nitrogen atmosphere. After further stirring for 3 hours at 60° C., water was added to the reaction solution at room temperature followed by extraction with ethyl acetate, washing the organic layer with sat. NaCl, drying over anhydrous magnesium sulfate and filtering. The filtrate was concentrated under a reduced pressure and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to obtain the title compound (189 mg, 69%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([S:23](Cl)(=[O:25])=[O:24])[CH3:22].N1C=CC=CC=1>ClCCl>[NH3:1].[CH2:21]([S:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:20])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)(=[O:25])=[O:24])[CH3:22]
Reactant: CCCCCCN1CCC(C)(c2cccc(N)c2)CC1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CCC(C)(c2cccc(NS(=O)(=O)CC)c2)CC1
Product: N
Temperature: 25 °C
Reaction time: 20 h
Yield: 166.7 %

Procedure:
To 4-(3-aminophenyl)-N-hexyl-4-methylpiperidine (Preparation 56, 50.0 mg, 0.18 mmol) in dichloromethane (1 ml) was added ethanesulfonyl chloride (47 mg, 0.37 mmol) in dichloromethane (1 ml) and pyridine (30 mg, 0.37 mmol) in dichloromethane (1 ml) at room temperature. The solution was stirred at room temperature for 20 h, then it was concentrated in vacuo to give the crude product. This was purified by silica column chromatography eluting with ethyl acetate:hexane:0.880 ammonia (98:2:1) to give the title compound as a colourless oil (55 mg, 82%).
Reaction SMILES: NC1C([N+:8]([O-:10])=[O:9])=CC=CC=1C.[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1)[CH3:13].[N+]([O-])(O)=O>C(OC(=O)C)(=O)C>[CH2:12]([C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[C:16]([N+:8]([O-:10])=[O:9])[CH:15]=1)[CH3:13]
Reactant: CCc1ccc(N)cc1
Reactant: Cc1cccc([N+](=O)[O-])c1N
Solvent: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc(N)c([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 69.32 %

Procedure:
According to the method of synthesis for 2-amino-3-nitrotoluene (Organic Syntheses Collective Volume IV P.42-45) 6 g of 4- ethylaniline was added dropwise to 30 ml of acetic anhydride and then, the mixture was treated dropwise with 6.3 ml (100 m mol) of 70% nitric acid at 12°-13° C. After the mixture was stirred for some time at 10°-12° C., the reaction solution was poured into an ice water. Oily product was separated and heated with 15 ml of concentrated hydrochloric for one hour. The reaction solution was alkaline with dilute aqueous sodium hydroxide and then, partitioned with 100 ml of chloroform. The organic layer was washed with water and dried on anhydrous sodium sulfate. Removal of the solvent in vacuo gave 5.76 g (69.32%) of 4-ethyl-2-nitroaniline.
Reaction SMILES: C(O[C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[C:15]4[N+:21]([O-:23])=[O:22])C.O.[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH2:30])[CH3:26]>>[CH2:25]([N:27]([CH2:31][CH3:32])[CH2:28][CH2:29][NH:30][C:4]1[C:13]2[CH:12]=[CH:11][CH:10]=[C:9]3[N:14]4[C:18]([C:19](=[O:20])[C:7]([C:8]=23)=[CH:6][N:5]=1)=[CH:17][CH:16]=[C:15]4[N+:21]([O-:23])=[O:22])[CH3:26]
Reactant: CCOc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reactant: CCN(CC)CCN
Solvent: O
Product: CCN(CC)CCNc1ncc2c(=O)c3ccc([N+](=O)[O-])n3c3cccc1c23
Reaction time: 0.08 h

Procedure:
A solution of 4-ethoxy-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (4.45 g) in N,N-diethylethylenediamine (67 cc) is stirred at a temperature of about 20° C. After stirring for 5 minutes, crystals are formed. The mixture is stirred for a further 40 minutes and the dark red suspension thus obtained is then poured into iced water (335 cc). After filtering off the crystals, they are washed with water (3 × 10 cc) and then dried under reduced pressure (1 mm Hg) at 50° C. Crude 4-(2-diethylaminoethylamino)-10-nitro-7-oxo-7H-indolizino[7,6,5-de]isoquinoline (4.20 g) is thus obtained.
Reaction SMILES: Cl.[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]([C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:15]=[CH:14][N:13]=2)[NH2:11])=[CH:6][CH:5]=1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36]>CC#N.C([O-])(O)=O.[Na+]>[CH2:35]([O:34][C:33](=[O:37])[NH:11][C@@H:10]([C:7]1[CH:6]=[CH:5][C:4]([C:3]([F:22])([F:2])[F:23])=[CH:9][CH:8]=1)[C:12]1[C:17]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:15]=[CH:14][N:13]=1)[CH3:36]
Reactant: N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N[C@@H](c1ccc(C(F)(F)F)cc1)c1ncccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of (S)-(4-(trifluoromethyl)phenyl)(3-(trifluoromethyl)-pyridin-2-yl)methanamine (Intermediate 1) (0.0610 g, 0.190 mmol) and DIPEA (0.066 mL, 0.381 mmol) in MeCN (1 mL) was added ethyl carbonochloridate (0.027 mL, 0.286 mmol). The mixture was then stirred at rt overnight. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM. The organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting product was purified by silica gel chromatography: 5-50% EtOAc-hexanes to give the title compound as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 8.83 (d, J=4.30 Hz, 1H), 7.99 (d, J=7.24 Hz, 1H), 7.46-7.60 (m, 4H), 7.40 (dd, J=7.73, 4.79 Hz, 1H), 6.54 (d, J=7.43 Hz, 1H), 6.41 (d, J=8.22 Hz, 1H), 4.11 (q, J=7.17 Hz, 2H), 1.17-1.30 (m, 3H). MS (ESI pos. ion) m/z: 393.0 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])=[CH:4][CH:3]=1.Cl[C:29]1[N:30]=[N:31][CH:32]=[CH:33][CH:34]=1>>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C@:13]2([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:29]4[N:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:21][CH:22]=1
Reactant: Clc1cccnn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccnn2)cc1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 3-chloropyridazine in Step 4. LC-MS Method 2 tR=1.067, m/z=436.1; 1H NMR (CDCl3) 0.82 (m, 3H), 1.52 (d, 3H), 1.65 (m, 1H), 1.80-1.98 (m, 2H), 2.11-2.28 (m, 3H), 2.91 (m, 1H), 3.51 (t, 3H), 5.68 (m, 1H), 6.94-7.04 (m, 4H), 7.18 (m, 2H), 7.47 (m, 1H), 7.71 (d, 1H), 7.78 (d, 2H), 9.08 (d, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1O.[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)Cl
Reactant: Oc1ccc(F)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(F)cc1Cl
Yield: 125.6 %

Procedure:
2-Chloro-4-fluorophenol (83.4 g) was added to a solution of sodium hydroxide (27.7 g) in water (450 ml), and methyl chloroformate (69.2 g) was dropwise added thereto at a temperature below 10° C. Precipitated crystals were collected by filtration and washed with water to give methyl (2-chloro-4-fluorophenyl)formate (134.8 g). M.P., 69°-71° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][CH2:32][NH:33][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][N:11]=2)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(C(F)(F)F)cc1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-{[4-(trifluoromethyl)phenyl]amino}-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2% methanol in methylene chloride) to give a yellow solid (0.14 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.4 (m, 4 H) 3.4 (m, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.8 (m, 1 H) 6.9 (s, 1 H) 7.4 (d, J=8.3 Hz, 2 H) 7.7 (d, J=8.6 Hz, 2 H) 8.4 (s, 1 H) 8.9 (s, 1 H) 9.8 (s, 1 H).