Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(N(CC)CC)C.[N-:9]=[N+:10]=[N-:11].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18])#[N:14]>CN1CCCC1=O>[NH:9]1[C:13]([C:15]2[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=2[CH:17]=[O:18])=[N:14][N:11]=[N:10]1
Reactant: N#Cc1ccccc1C=O
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=Cc1ccccc1-c1nnn[nH]1
Temperature: 110 °C

Procedure:
20.3 g (147 mmol) of triethylamine hydrochloride and 21.0 g (322 mmol) of sodium azide are added to a solution of 14.0 g (107 mmol) of 2-cyano-benzaldehyde in 350 ml of 1-methyl-2-pyrrolidone and heated at 110° C. for 3 hours (argon atmosphere). The black reaction solution is poured into 0.6 liter of ice/37% HCl (20:1) and stirred thoroughly to complete the reaction. Extraction with 3 portions of ethyl acetate, washing the organic phases with 3× water and brine, drying (Na2SO4), concentration by evaporation and stirring in diethyl ether yield 2-(tetrazol-5-yl)-benzaldehyde; m.p. 130° C.; TLC: Rf=0.10 (CHCl3/methano/H2O/acetic acid=85:13:1.5:0.5).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19]>CN(C)P(N(C)C)(N(C)C)=O.O>[O:7]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:19])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: OCCCCCCCl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: OCCCCCCOc1ccccc1
Temperature: 110 °C

Procedure:
To a solution of 10.3 g of phenol in 25 ml of hexamethylphosphoramide is added 4.2 g of 57% sodium hydride in oil. After hydrogen evolution ceases, 13.6 g of 6-chlorohexan-1-ol in 25 ml of hexamethylphosphoramide is added and the mixture heated at 110° C. for 16 hours. The solution is cooled, diluted with water and extracted with ether. The ether extracts are washed with sodium hydroxide solution, dried (magnesium sulfate) and the solvent removed under vacuum to give white crystals, mp 69°-74° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH:13]1[CH:17]=[N:16][CH:15]=[N:14]1>CN(C)C=O>[N:13]1([C:2]2[C:11]3[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: c1nc[nH]n1
Solvent: CN(C)C=O
Product: Clc1ccc2c(-n3cncn3)ccnc2c1
Yield: 112.8 %

Procedure:
1.98 g of 4,7-dichloro-quinoline and 1.38 g of 1H-1,2,4-triazole are reacted in 10 ml of dimethyl formamide and worked up as described in Example 1. 2.6 g of 4-(1H-1,2,4-triazole-1-yl)-7-chloro-quinoline (Substance 2) are obtained.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][F:47])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)(=O)C>[CH2:13]([N:20]1[C:25](=[O:26])[C:24]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=3[C:40]3[NH:3][C:4](=[O:7])[O:5][N:41]=3)=[CH:30][CH:29]=2)=[C:23]([CH2:42][CH2:43][CH2:44][CH3:45])[N:22]=[C:21]1[CH2:46][F:47])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCCCc1nc(CF)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCc1nc(CF)n(Cc2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 43.1 %

Procedure:
A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogen carbonate (0.76 g) and dimethyl sulfoxide (3.5 mL) was stirred at 50° C. for 30 min, 4′-{[1-benzyl-4-butyl-2-(fluoromethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (0.35 g) was added, and the mixture was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (3.5 mL), N,N′-carbonyldiimidazole (0.18 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.17 g, 42%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7]C(=O)C)[CH:6]=1.[CH:11]([Mg]Br)=C.[CH2:15]1C[O:18][CH2:17][CH2:16]1>CCOC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:17]([CH3:11])([OH:18])[CH:16]=[CH2:15])[CH:6]=1
Reactant: C=C[Mg]Br
Reactant: CC(=O)Cn1cc(Br)cn1
Reactant: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CC(C)(O)Cn1cc(Br)cn1
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of 1-(4-bromo-1H-pyrazol-1-yl)propan-2-one (660 mg, 3.25 mmol) in THF (1 mL) was added vinyl magnesium bromide (1M in THF, 3.9 mL, 3.9 mmol) dropwise over 5 min. The resulting mixture was stirred for 1 h, diluted with 0.5 M HClaq and EtOAc and the layers separated. The organic phase was dried with MgSO4, filtered and concentrated in vacuo, then the crude residue was absorbed on silica gel and purified by column chromatography (0 to 100% EtOAc/Hex) to afford 1-(4-bromo-1H-pyrazol-1-yl)-2-methylbut-3-en-2-ol, MS ESI calcd. for C8H12BrN2O [M+H]+ 231. found 231.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH:14]2[CH2:16][CH2:15]2)(=O)=O)=CC=1.[C-:24]#[N:25].[Na+]>CS(C)=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@@H:13]([CH:14]2[CH2:15][CH2:16]2)[CH2:12][C:24]#[N:25])=[CH:22][CH:21]=1
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](c2ccc(Cl)cc2)C2CC2)cc1
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC[C@@H](c1ccc(Cl)cc1)C1CC1
Temperature: 90 °C
Yield: 87.3 %

Procedure:
A mixture of (2R)-2-(4-chlorophenyl)-2-cyclopropylethyl 4-methylbenzenesulfonate (11.00 g, 31.3 mmol) and NaCN (4.62 g, 94.3 mmol) in dimethyl sulfoxide (100 ml) is heated at to 90° C. for 3 hours. The dimethyl sulfoxide was removed in vacuo and the resulting mixture is partitioned between water (200 ml) and diethyl ether (200 ml). The organic layer is dried over anhydrous sodium sulfate and concentrated in vacuo. The residue chromatographed on silica gel eluting with ether:hexane (25:75) to afford the title compound as a colorless oil (5.62 g, 87%) which is characterized by 1HNMR, IR and mass spectral analyses.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=C/N(C)C.O.CC[O:18]C(C)=O>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]=[O:18]
Reactant: CCOC(C)=O
Reactant: CN(C)/C=C/c1nc2ccccc2o1
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1nc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To (E)-2-(benzo[d]oxazol-2-yl)-N,N-dimethylethenamine (1 g, 5.32 mmol) in THF (15 mL) at 0° C. was added water (15 mL) and NaIO4 (3.4 g, 16 mmol). The resulting mixture was stirred at 0° C. for 10 min, then at room temperature for 2 h. To the solution was added H2O and EtOAc and then the mixture was filtered. The clear solution was extracted with EtOAc and the organic phase was washed with aqueous NaHCO3 solution. The organic phase was concentrated and the residue was purified by column chromatography to give the title compound (120 mg). MS (ESI) m/z 148 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:18][C@H:17]([CH2:19][OH:20])[C@@H:15]([OH:16])[C@H:12]2[O:13][CH3:14])=[C:4](N)[N:3]=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1[OH:24]>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].CS(C)=O>[CH3:14][O:13][C@@H:12]1[C@H:15]([OH:16])[C@@H:17]([CH2:19][OH:20])[O:18][C@H:11]1[N:8]1[C:9]2[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:24])[C:5]=2[N:6]=[CH:7]1
Reactant: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(N)nc(N)nc21
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(N)nc21

Procedure:
2,6-Diamino-9-(2-O-methyl-β-D-ribofuranosyl)purine (9.5 g) in 0.1M sodium phosphate buffer (200 ml, pH 7.4) and DMSO (25 ml) was treated with adenosine deaminase (Type II Sigma) at RT for 4 days. The resulting suspension was cooled and filtered and the resulting filter cake washed with H2O and dried to a white solid (4.0 g). The solid was recrystallized from hot H2O to yield 2.9 g of product. m.p. 236°-238° C. 1H NMR (DMSO-d6 ) δ 3.3 (s, 3, OCH3), 3.53 and 3.6 (ABX, 2, H-5'), 3.87 (m, 1, H-4'), 4.15 (m, 1, H-2'), 4.25 (m, 1, H-3'), 5.13 (t, 1, 5'-OH), 5.23 (d, 1, 3'-OH), 5.8 (d, 1, H-1'), 6.48 (br s, 2, NH2), 7.96 (s, 1, H-8) and 10.68 (br s, 1, NH). Anal. Calcd. for C11H15N5O5.1/2H2O: C, 43.14; H, 5.26; N, 22.86. Found: C, 43.59; H, 5.34; N, 23.04.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([OH:43])(=[O:42])[CH3:41]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:40]([O-:43])(=[O:42])[CH3:41]
Reactant: CC(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Product: CC(=O)[O-]
Temperature: 40 °C
Reaction time: 5 h

Procedure:
Nilotinib base (3.00 g, 5.66 mmol) was suspended in glacial acetic acid (12 mL, 4V) and the resulting mixture was heated to 40° C. with stirring, leading to dissolution. Stirring was continued for another 5 h at the same temperature leading to gradual precipitation. The mixture was then cooled to −18° C. and maintained at this temperature over a period of 15 h, leading to the formation of a large solid block. The solid was allowed to warm to room temperature and then heated to 40° C. for 4 h leading to a viscous suspension. The suspension was filtered and the collected solid was dried in a vacuum oven (35 mmHg) at 40° C. for 24 h to give Nilotinib acetate form VI (1.57 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.ClC1C=C(Cl)C=CC=1C1[C:36]([C:37]2[NH:38][CH:39]=[CH:40][N:41]=2)=[CH:35][N:34]=[C:33]([NH:42][CH2:43][CH2:44][NH:45]C2C=CC([N+]([O-])=O)=CN=2)[N:32]=1>>[NH:38]1[CH:39]=[CH:40][N:41]=[C:37]1[C:36]1[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)=[N:32][C:33]([NH:42][CH2:43][CH2:44][NH:45][C:15]2[N:16]=[CH:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=2)=[N:34][CH:35]=1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(C(F)(F)F)cc3)n2)nc1

Procedure:
6-{[2-({5-imidazol-2-yl-4-[4-(trifluoromethyl)phenyl]pyrimidin-2-yl}amino)ethyl]-amino}pyridine-3-carbonitrile was prepared from 4-(trifluoromethyl)benzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:32][S:33]([N:36]([CH3:38])[CH3:37])(=[O:35])=[O:34])=[O:31])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21](O)=[O:22])[CH2:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C1(P([N:60]=[N+:61]=[N-:62])(C2C=CC=CC=2)=O)C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:32][S:33]([N:36]([CH3:37])[CH3:38])(=[O:34])=[O:35])=[O:31])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([C:21]([N:60]=[N+:61]=[N-:62])=[O:22])[CH2:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)CC(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CC(C(=O)N=[N+]=[N-])Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)N(C)C)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of the acid, 13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carboxylic acid, (427.2 mg, 0.79 mmol) in a mixture of PhMe/CH2Cl2 (6 ml/2 ml) at r.t. under N2 was added triethylamine (117 mg, 1.16 mmol), followed by diphenylphosphoryl azide (DPPA) (320 mg, 1.16 mmol). The mixture was stirred at r.t. for 4 hr. The volatiles were then evaporated. The residue was titurated with hydrochloric acid (3× 10 ml, 1N), dried and the crude azide, 13-cyclohexyl-10-((((dimethylamino)sulfonyl)amino)carbonyl)-3-(methyloxy)-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-6-carbonyl azide, was used without further purification Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=565.21, HPLC Rt=1.988 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:11][CH3:12])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:13].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[CH3:14][NH:1][C:2]1[CH:7]=[C:6]([C:8]([CH2:11][CH3:12])([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[OH:13]
Reactant: CCC(C)(C)c1ccc(O)c(N)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCC(C)(C)c1ccc(O)c(NC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Amino-4-tert-pentylphenol (5.00 g, 27.8 mmol) and potassium carbonate (3.88 g, 28.1 mmol) were mixed at RT for 2.5 hours in DMF (15 mL). Methyl iodide (1.20 mL, 19.3 mmol) was added and the mixture was stirred overnight at RT. Diluted the mixture with EtOAc and extracted with aqueous sodium bicarbonate and water. Dried the organic layers over sodium sulfate, filtered, concentrated and purified by silica gel chromatography (10-15% MTBE/hexanes). Concentrated the product fractions to yield the title compound.
Reaction SMILES: [Li+].CCC[CH2-].[F:6][C:7]1[CH:8]=[C:9]2[CH:15]=[CH:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C:10]2=[N:11][CH:12]=1.[I:26]I>CCCCCC.O1CCCC1.C(OCC)(=O)C>[F:6][C:7]1[CH:8]=[C:9]2[CH:15]=[C:14]([I:26])[N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=3)(=[O:17])=[O:18])[C:10]2=[N:11][CH:12]=1
Reactant: II
Reactant: Cc1ccc(S(=O)(=O)n2ccc3cc(F)cnc32)cc1
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3cc(F)cnc32)cc1
Temperature: -75 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
7.54 ml of a solution of N-butyllithium at 1.6 N in hexane is added, dropwise, maintaining the temperature of the medium in the region of −75° C., to a solution, cooled to approximately −78° C., of 3.5 g of 5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine in 100 ml of tetrahydrofuran. After agitation for approximately one hour at the same temperature, a solution of 6.12 g of bisublimated iodine in 50 ml of tetrahydrofuran is run in dropwise. After the temperature has returned to around 20° C., the reaction mixture is diluted with 600 ml of ethyl acetate, washed three times with 100 ml of a 5% aqueous sodium thiosulfate solution, dried over magnesium sulfate, treated with vegetable black, filtered, and concentrated to dryness under reduced pressure (13 kPa). The residue is taken up with 30 ml of diisopropyl ether, filter-dried, washed with three times 5 ml of diisopropyl ether, and dried under reduced pressure (13 kPa). 3.6 g of 5-fluoro-2-iodo-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine are obtained in the form of a solid, the characteristics of which are as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[C:6]([CH2:13][CH3:14])[C:5]=1O)([O-:3])=[O:2].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:5]1[C:6]([CH2:13][CH3:14])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1Cl

Procedure:
2,4-Dinitro-6-ethylphenol (10 g) was placed in a 250 ml round bottom flask, and phosphorous oxychloride (60 ml, Fisher) was added. N,N-diethylamiline (15 ml, Aldrich) was added portionwise, and the mixture became hot. The flask was placed under a condenser equiped with a drying tube heated on a steam bath for two hours and cooled. The mixture was then carefully poured onto ice, with stirring and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried over MgSO4 and evaporated to a dark oil which was columned on silica gel using 10% ethyl acetate petroleum ether. The evaporated filtrates gave a reddish oil, which solidified upon being pumped dry. The solid was recrystallized from ethyl acetate-petroleum ether to give pale yellow needles of 1-chloro-2,4-dinitro-6-ethylbenzene.
Reaction SMILES: N[C:2]1[C:7]([CH2:8][OH:9])=[N:6][C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([CH2:18][CH:19]([CH3:21])[CH3:20])[N+:3]=1[O-:22].C(#N)C.N(OCCC(C)C)=O.[ClH:34]>C(OCC)C>[CH2:11]([O:10][C:5]1[C:4]([CH2:18][CH:19]([CH3:21])[CH3:20])=[N+:3]([O-:22])[C:2]([Cl:34])=[C:7]([CH2:8][OH:9])[N:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl
Reactant: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(N)[n+]1[O-]
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)Cc1c(OCc2ccccc2)nc(CO)c(Cl)[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
There were mixed 2.17 g of 2-amino-5-benzyloxy-3-hydroxymethyl-6-isobutylpyrazine 1-oxide, 2.89 g of cuprous chloride, 1.42 g of cupric chloride and 22 ml of acetonitrile, and the mixture was stirred for 10 minutes at room temperature. Thereto was added 2.88 ml of isoamyl nitrite at room temperature. The mixture was stirred for 30 minutes, whereby an exothermic reaction of 40°-45° C. was taken place. (No cooling was made.) To the reaction mixture were added 60 ml of 2% hydrochloric acid and 50 ml of diethyl ether to cause phase separation. The aqueous layer was extracted with 50 ml of diethyl ether twice. The extract was combined with the above diethyl ether layer. The combined mixture was dried over magnesium sulfate. The solvent was removed by evaporation. The residue was purified by a silica gel column chromatography (eluting solvent: 50% by volume of ethyl acetate-n-hexane), followed by recrystallization by diethyl ether-n-hexane to obtain 1.73 g of 3-benzyloxy-6-chloro- 5-hydroxymethyl-2-isobutylpyrazine 1-oxide (Compound B-12) as pale yellow plate-like crystals having a melting point of 85.0°-88.0° C.
Reaction SMILES: C1(C)C=CC(S([N:10]2[C:27]3[C:13]4=[C:14]([CH:24]=[CH:25][CH:26]=3)[C@H:15]3[O:20][CH2:19][C:18](=O)[N:17]([CH3:22])[C@@H:16]3[CH2:23][C:12]4=[CH:11]2)(=O)=O)=CC=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH3:22][N:17]1[C@@H:16]2[CH2:23][C:12]3[C:13]4[C:27]([NH:10][CH:11]=3)=[CH:26][CH:25]=[CH:24][C:14]=4[C@H:15]2[O:20][CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(cccc42)[C@H]2OCC(=O)N(C)[C@@H]2C3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCO[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Yield: 24.3 %

Procedure:
A suspension of trans-4-(p-tolylsulphonyl)-4,6,6a,8,9,10a-hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1,4]-benzoxazin-8-one (3.0 gms; 0.008 m) and lithium aluminum hydride (3.0 gm; 0.08 m) in tetrahydrofuran (200 ml) is refluxed for 17 hours. The cooled solution is hydrolyzed with water (6 ml). The solid is filtered, and the organic solvent is dried over anhydrous sodium sulfate. After filtration, the solvent is removed under reduced pressure (20 mm). The gum is crystallized from methanol (2-5 ml) to yield 420 mg of trans-4,6,6a,8,9,10a-hexahydro-7-methyl-7H-indolo-[3,4 gh]-[1,4]-benzoxazine. This solid is purified by chromatography (silica, CHCl3 /NH4OH) to give 330 mg of trans-4,6,6a,8,9,10a-hexahydro-7-methyl-7-H-indolo-[3,4 gh]-[1,4]-benzoxazine; m.p. 175°-177° (softening at 100°).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH:15]=O)[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OP([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(OCC)=O)C.CN(C)C=O>O>[CH2:3]([N:10]1[CH:14]=[C:13](/[CH:15]=[CH:33]/[C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:12]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
Sodium hydride (60%, oily, 1.94 g) was added to a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), ethyl diethylphosphonoacetate (9.60 ml), and N,N-dimethylformamide (200 ml) at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid and then with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield ethyl(E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.50 g, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 88–89° C.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14]S(C)(=O)=O)[CH2:10]1)=[O:8])([CH3:3])[CH3:2].O[C:28]1[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:32][CH:33]=1>>[CH:1]([O:4][C:5]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][C:6]=1[C:7]([N:9]1[CH2:13][CH2:12][CH:11]([O:14][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[CH2:10]1)=[O:8])([CH3:3])[CH3:2]
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(OS(C)(=O)=O)C1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)C1
Yield: 45 %

Procedure:
Prepared in analogy to Example 3(c) from rac-methanesulfonic acid 1-(2-isopropoxy-5-methanesulfonyl-benzoyl)-pyrrolidin-3-yl ester (Example 14(a)) and 3-hydroxybenzotrifluoride. The crude material was purified by reversed phase HPLC (acetonitrile/water) to yield the title compound as an amorphous white solid (yield 45%). MS (m/e): 472.4 (M+H+, 100%).