Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([O:13][Si](C(C)(C)C)(C)C)[CH2:10][CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(O[Si](C)(C)C(C)(C)C)CC1CCNC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(O)CC1CCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
A solution containing 4 (5.9 g, 12.5 mmol) in anhydrous THF (100 mL) was cooled to 0° C. TBAF (1M/THF, 14 mL, 14.0 mmol) was added in one portion. After 5 h, the reaction mixture was diluted with EtOAc and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (1:1 to 1:3 hexanes/EtOAc) to afford 4.1 g (91%) of 5. 1H NMR (CDCl3, 300 MHz): δ7.31 (m, 5H), 5.93 (m, 1H), 5.07 (m, 2H), 4.37 (m, 1H), 4.03 (m, 1H) 3.51-3.06 (m, 4H), 2.05 (m, 1H), 1.77 (m, 1H), 1.44 (s, 9H) ppm. Mass spectrum, m/z [365.2] (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].CCOCC.Br.[CH3:23][CH:24]1[C:29](=[O:30])[CH2:28][CH2:27][NH:26][CH2:25]1>O>[CH2:1]([O:8][C:9]([N:26]1[CH2:27][CH2:28][C:29](=[O:30])[CH:24]([CH3:23])[CH2:25]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1CNCCC1=O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
To a mechanically stirred mixture of benzylchloroformate (33.1 mL, 232 mmol, 105 mol %), sodium bicarbonate (37.2 g, 442 mmol, 200 mol %), ether (250 mL), and water (250 mL) is added 3-methyl-4-piperidone hydrobromide salt (42.9 g, 221 mmol) in portions over 10 min. The resultant mixture is stirred for 2 h and the organic phase separated. The aqueous phase is extracted with ether (2×150 mL) and the combined organics dried (MgSO4), filtered, and concentrated to an oily residue. This residue crystallized on standing at 23° C. and was recrystallized from hexanes/ethyl acetate to give N-benzyloxycarbonyl-3-methyl-4-piperidone as a solid: 51.2 g; 93%; mp 33°-35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([C:14]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[C:23]5[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=5[N:25]=[CH:26][N:27]=4)[CH2:18][CH2:17]3)=[O:15])[CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:39].O1CCOCC1>C(Cl)Cl>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:10][NH:11][CH2:12][C@H:13]2[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8].[ClH:1].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:10][NH:11][CH2:12][C@@H:13]2[C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[C:23]4[C@H:30]([CH3:31])[CH2:29][CH2:28][C:24]=4[N:25]=[CH:26][N:27]=3)[CH2:18][CH2:17]2)=[O:15])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)C4CN(C(=O)OC(C)(C)C)CC4c4ccc(Cl)c(Cl)c4)CC3)c21
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@@H]4CNC[C@H]4c4ccc(Cl)c(Cl)c4)CC3)c21
Product: C[C@@H]1CCc2ncnc(N3CCN(C(=O)[C@H]4CNC[C@@H]4c4ccc(Cl)c(Cl)c4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the mixture of diastereomers of tert-butyl 3-(3,4-dichlorophenyl)-4-(1-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-4-carbonyl)pyrrolidine-1-carboxylate (34 mg, 0.061 mmol) in DCM (3.1 mL) was added to a 4.0M HCl solution in dioxane (1.1 mL, 4.25 mmol). The mixture was stirred at room temperature overnight. The solvents were removed in vacuo to give ((3S,4R)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone dihydrochloride and ((3R,4S)-4-(3,4-dichlorophenyl)pyrrolidin-3-yl)(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone dihydrochloride as a mixture of diastereomers (32 mg, 99%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([OH:11])=[CH:4][C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[Br:12]Br>C(O)(=O)C>[Br:12][C:4]1[C:5]2[S:9][CH:8]=[N:7][C:6]=2[CH:10]=[C:2]([CH3:1])[C:3]=1[OH:11]
Reactant: BrBr
Reactant: Cc1cc2ncsc2cc1O
Solvent: CC(=O)O
Product: Cc1cc2ncsc2c(Br)c1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-methylbenzo[d]thiazol-6-ol (5C) (140 mg, 0.84 mmol) in acetic acid (5 ml), was added bromine (40 μL) slowly. The reaction mixture was stirred at room temperature for 1 h. The precipitate was collected, washed with acetic acid, water and dried under high vacuum. LCMS-ESI+: calc'd for C8H6BrNOS: 244.0 (M+H+). Found: 244.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[N:4][CH:3]=1.[F:13][C:14]1[CH:20]=[C:19]([CH3:21])[C:18]([OH:22])=[CH:17][C:15]=1[NH2:16]>CC(O)CCC.Cl>[ClH:1].[Cl:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[N:4][CH:3]=[C:2]2[NH:16][C:15]1[CH:17]=[C:18]([OH:22])[C:19]([CH3:21])=[CH:20][C:14]=1[F:13]
Reactant: Cc1cc(F)c(N)cc1O
Reactant: Clc1ccc2nncc(Cl)c2c1
Agent: Cl
Solvent: CCCC(C)O
Product: Cc1cc(F)c(Nc2cnnc3ccc(Cl)cc23)cc1O
Yield: 95.8 %

Procedure:
A solution of 4,6-dichlorocinnoline (200 mg, 1 mmol) and 2-fluoro-5-hydroxy-4-methylaniline (169 mg, 1.2 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (4 ml) containing 7M isopropanolic hydrogen chloride (2 drops) was heated at reflux for 45 minutes. After cooling the solid was filtered off, washed with isopropanol followed by ether to give 6-chloro-4-(2-fluoro-5-hydroxy-4-methylanilino)cinnoline hydrochloride (326 mg, 95%).
Reaction SMILES: C1OCOC1CO.C(N(CC)CC)C.C12CC(C=C1)CC2C(Cl)=O.[CH:25]12[CH2:31][CH:28]([CH:29]=[CH:30]1)[CH2:27][CH:26]2[C:32]([O:34][CH2:35][CH:36]1[CH2:40][O:39][CH2:38][O:37]1)=[O:33]>O.C1(C)C=CC=CC=1>[CH:25]12[CH2:31][CH:28]([CH2:29][CH2:30]1)[CH:27]=[C:26]2[C:32]([O:34][CH:35]1[CH2:36][O:37][CH2:38][O:39][CH2:40]1)=[O:33]
Reactant: O=C(OCC1COCO1)C1CC2C=CC1C2
Agent: O=C(Cl)C1CC2C=CC1C2
Agent: OCC1COCO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(OC1COCOC1)C1=CC2CCC1C2
Reaction time: 5 h
Yield: 95 %

Procedure:
To a mixture of 104 g of glycerol formal, 111 g of triethylamine and 300 ml of toluene, 157 g of 5-norbornene-2-carbonyl chloride was added over one hour at 20° C. After 5 hours of stirring, 200 ml of water was added to stop the reaction and the mixture was allowed to separate. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 213 g of a mixture of (1,3-dioxolan-4-yl)methyl 5-norbornene-2-carboxylate and 1,3-dioxan-5-yl 5-norbornene-2-carboxylate (boiling point 111-115° C./530 Pa, yield 95%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[Cl:20][C:21]1[CH:38]=[CH:37][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH2:32][CH2:33][C:34]([OH:36])=O)=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]3[C:27]=2[CH2:32][CH2:33][C:34]3=[O:36])=[CH:37][CH:38]=1
Reactant: O=C(O)CCc1ccccc1Cc1ccc(Cl)cc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=C1CCc2c(Cc3ccc(Cl)cc3)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To stirred polyphosphoric acid, prepared from 100 g. of phosphorus pentoxide and 70 ml. of phosphoric acid, 5.0 g. of 3-[o-(p-chlorobenzyl)phenyl]propionic acid is added. The mixture is stirred at 110°-120° C for 2 hours. Upon addition of ice-water, yellow crystals separate out. These crystals are collected by filtration, washed with water and dried. The crystals are purified by column chromatography (silica gel; eluted with a 40 : 1 mixture of benzene and ethyl acetate. The described procedure gives 4-(p-chlorobenzyl)indan-1-one as crystals melting at 87°-88° C.
Reaction SMILES: Cl.[NH2:2][OH:3].CCN(CC)CC.[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:17][CH2:18][C:19]1[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=1>CCO>[OH:3][N:2]=[C:23]([C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][O:11]2)=[CH:26][CH:25]=1)[NH2:24]
Reactant: NO
Reactant: N#Cc1ccc(COC2CCCCO2)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NC(=NO)c1ccc(COC2CCCCO2)cc1
Reaction time: 0.67 h
Yield: 142.7 %

Procedure:
To a suspension of hydroxylamine hydrochloride (365 mg, 5.25 mmol) in EtOH (3 mL) was added Et3N (0.78 mL, 5.6 mmol) at room temperature under argon. A white precipitate formed. It was stirred at that temperature for 40 minutes. Then 4-[(tetrahydro-2H-pyran-2-yloxy)methyl]benzonitrile (Intermediate 26; 0.76 g, 3.5 mmol) in EtOH (2 mL) was added dropwise; the reaction mixture became clear. It was stirred at RT overnight. The crude obtained was purified by column chromatography with CH2Cl2 (A) and CH2Cl2/MeOH (95:5) (B) as eluents (0% to 80% B). The appropriate fractions were collected and the solvent removed to afford 1.25 g of sticky oil with some solids. It was dissolved in EtOAc/H2O (1:1, 150 mL). The organic layer was washed again with H2O (50 mL) and brine. It was dried over sodium sulphate, filtered and evaporated to afford the title compound (840 mg, 95%) as sticky oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([CH3:23])([C:18]3[N:19]=[N:20][NH:21][N:22]=3)[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[C:30](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:19]([CH3:30])[N:20]=[N:21][N:22]=3)([CH3:23])[CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:11])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: CC(CC1CC1)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)c1nn[nH]n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1C(C)(CC1CC1)NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.6 %

Procedure:
To a solution of 5-cyclopropyl-N-[2-cyclopropyl-1-methyl-1-(2H-tetrazol-5-yl)ethyl]-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxamide (example 150b, 100 mg, 0.244 mmol) in dry DMF (1.2 ml) was added potassium carbonate (43.8 mg, 0.317 mmol). The reaction mixture was stirred at room temperature for 10 minutes followed by addition of iodomethane (30.5 μl, 0.487 mmol). The reaction mixture was then stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate and extracted with water and brine. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by preparative HPLC to yield the title compound (11 mg, 11%) and also a second by-product as the regioisomer (40 mg, 39%). MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19]>C(Cl)Cl>[CH2:1]([S:8][CH2:17][C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)C1CC1
Reactant: SCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CSCc1ccccc1)C1CC1
Reaction time: 48 h

Procedure:
Benzyl mercaptan (15.6 ml, 0.133 mol) was stirred in DCM (100 ml), triethylamine (20.5 ml, 0.146 mol) added, the mixture cooled in an ice/acetone bath and 2-bromo-1-cyclopropyl-ethanone, prepared as in WO 03/074495, (21.77 g, 0.133 mol) dissolved in DCM (100 ml) was added dropwise. The mixture was stirred for 48 h, washed with water, then brine, dried over sodium sulphate and evaporated.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-:6])O.[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:52])[N:20]([C:39]2[CH:40]=[C:41]([C:48]([O:50][CH3:51])=[O:49])[C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]#[N:37])=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:52])[N:20]([C:39]2[CH:40]=[C:41]([C:48]([O:50][CH3:51])=[O:49])[C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:6][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1nc(C)n(-c2cc3c(c(C(=O)OC)c2)OCC3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(-c2cc3c(c(C(=O)OC)c2)OCC3)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 30.4 %

Procedure:
A mixture of hydroxylammonium chloride (0.31 g), sodium hydrogen carbonate (0.44 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, methyl 5-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]-2,3-dihydro-1-benzofuran-7-carboxylate (0.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (2.6 mL). N,N′-carbonyldiimidazole (0.055 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.051 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid 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 as a colorless solid (0.081 g, 31%).
Reaction SMILES: [Br-].[C:2]([CH2:4][CH2:5][CH2:6][CH2:7][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:3].[H-].[Na+].[S:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=2)[CH:37]=O)=[CH:30]1>CN(C)C=O.O.C(O)(=O)C>[S:29]1[CH:33]=[CH:32][C:31]([C:34]2[CH:35]=[C:36](/[CH:37]=[CH:7]/[CH2:6][CH2:5][CH2:4][C:2]#[N:3])[CH:39]=[CH:40][CH:41]=2)=[CH:30]1
Reactant: N#CCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc(-c2ccsc2)c1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: N#CCCC/C=C/c1cccc(-c2ccsc2)c1
Yield: 95.8 %

Procedure:
44.6 g of 4-cyanobutyltriphenylphosphonium bromide is dissolved in 250 ml of dimethylformamide, 4.2 g of 60% oily sodium hydride is added under ice cooling and stirring, then mixture is stirred at that temperature for 30 minutes, 18 g of 3-(3-thienyl)benzaldehyde is added, and the mixture is stirred at room temperature for further 20 hours. The reaction solution is diluted with water, acetic acid is added for neutralization, and then the solvent is distilled off under reduced pressure. The residue is led to two liquid phases using a system of water and ethyl ether, the organic layer is taken, washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue is purified by silica gel column chromatography [Wako gel C-100, 500 g; hexane/ethyl acetate=4/1] to obtain 23.2 g (E)-6-[3-(3-thienyl)phenyl]-5-hexenenitrile as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][C:11]=3[N:17]([CH3:26])[S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])=[N:5][CH:4]=1.C(N(CC)CC)C.Cl.[CH2:35]1[CH:40]2[CH2:41][NH:42][CH2:43][CH2:44][N:39]2[C:38](=[O:45])[CH2:37][O:36]1.CN(C)C=O>O>[CH3:26][N:17]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]([C:6]1[S:7][C:3]([CH2:2][N:42]3[CH2:43][CH2:44][N:39]4[CH:40]([CH2:35][O:36][CH2:37][C:38]4=[O:45])[CH2:41]3)=[CH:4][N:5]=1)=[CH:16]2)[S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19]
Reactant: O=C1COCC2CNCCN12
Reactant: CN(c1cccc2cc(-c3ncc(CCl)s3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(c1cccc2cc(-c3ncc(CN4CCN5C(=O)COCC5C4)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 44.2 %

Procedure:
A mixture of N-{2-[5-(chloromethyl)-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-methylthiophene-2-sulfonamide (150 mg), triethylamine (150 μL), hexahydropyrazino[2,1-c][1,4]oxazin-4(3H)-one hydrochloride (135 mg) and N,N-dimethylformamide (2 ml) was stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (85 mg, yield 45%) as a colorless amorphous form from a fraction eluted with ethyl acetate. MS 544 (M+1).
Reaction SMILES: [CH2:1]([N:3]([CH2:33]C)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])[CH3:2].CNCC[OH:39]>>[OH:39][CH2:2][CH2:1][N:3]([CH3:33])[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7]
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CNCCO
Product: CN(CCO)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 80.2 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (400 mg) obtained in Example 6 (4) and N-methylethanolamine (140 mg). This was purified by silica gel column chromatography to give the title compound (322 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10](Cl)=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH3:21][NH:22][CH3:23].O>C1COCC1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([N:22]([CH3:23])[CH3:21])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1
Reactant: CNC
Reactant: O=C(Cl)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reaction time: 16 h
Yield: 92.6 %

Procedure:
To the product from Example 168b (2.0 g, 6.4 mmol) in THF (25 mL) was added dimethylamine (0.6 g, 13.3 mmol) and the reaction stirred for 16 h. The reaction was poured into water and extracted with ethyl acetate. The organic layer washed with 5% HCL, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (1.9 g, 87%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][OH:15])[CH:8]=[CH:9][C:2]1=2.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.Cl.C(OCC)C>N1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][O:15][S:23]([C:20]3[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=3)(=[O:25])=[O:24])[CH:8]=[CH:9][C:2]1=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCC(O)c1ccc2sccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.9 %

Procedure:
In 54 ml of pyridine was dissolved 9.0 g of 1-(benzo[b]thiophen-5-yl)-2-(2-hydroxyethoxy)ethanol. To the solution was added, at -25° C., 7.2 g of p-toluenesulfonyl chloride. The mixture was allowed to stand at 0°-5° C. for 24 hours and further at room temperature for 4 hours. The reaction mixture was added to a mixture of 103 ml of 6N hydrochloric acid, 50 ml of ice water and 100 ml of diethyl ether. The resulting mixture was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 30 ml of diethyl ether. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography (eluant: toluene/ethyl acetate=10/1) to obtain 7.7 g of colorless oily 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[N:16]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])[CH:17]=[C:18]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])[N:19]=2)=[O:14])=[CH:8][CH:7]=1.[CH3:32][Mg]Br>O1CCCC1>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([C:15]2[N:16]([S:26]([N:29]([CH3:31])[CH3:30])(=[O:27])=[O:28])[CH:17]=[C:18]([CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH3:23])[N:19]=2)([OH:14])[CH3:32])=[CH:8][CH:7]=1
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(=O)Cc2ccc(Br)cc2)n1
Reactant: C[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(C)(O)Cc2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cerium Chloride (1.625 g, 6.59 mmol) was added to an ambient temperature solution of 2-[(4-bromophenyl)acetyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (Intermediate 8) (1 g, 2.2 mmol) in tetrahydrofuran (22 mL). After stirring at ambient temperature for 1 h, the reaction mixture was cooled to 0° C. and methylmagnesium bromide (3 M in diethyl ether) (2.2 mL, 6.59 mmol) was added. After stirring at 0° C. for a further 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% ethyl acetate/hexane afforded 2-[2-(4-bromophenyl)-1-hydroxy-1-methylethyl]-4-(2,2-dimethylbutyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[S:11](Cl)(Cl)=[O:12].[CH3:15][C:16]1([CH3:25])[CH2:21][O:20][P:19]([NH:23][CH3:24])(=[S:22])[O:18][CH2:17]1>N1C=CC=CC=1>[CH3:15][C:16]1([CH3:25])[CH2:17][O:18][P:19]([N:23]([CH3:24])[S:11]([CH2:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4])=[O:12])(=[S:22])[O:20][CH2:21]1
Reactant: CNC(=O)ON=C(C)SC
Reactant: O=S(Cl)Cl
Reactant: CNP1(=S)OCC(C)(C)CO1
Solvent: c1ccncc1
Product: CSC(C)=NOC(=O)NCS(=O)N(C)P1(=S)OCC(C)(C)CO1

Procedure:
Methyl N-[[[[[(5,5-dimethyl-2-thioxo-1,3,2-dioxaphosphorinan-2-yl)(methyl)amino]sulfinyl]methylamino]carbonyl]oxy]ethanimidothioate was prepared by the procedure employed in Example 9, by reacting methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate (2.43 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole), and 5,5-dimethyl-2-methylamino-2-thioxo-1,3,2-dioxaphosphorinan (2.93 g, 0.015 mole) in pyridine (10 ml). Recrystallization from chloroform-hexane afforded 3.0 g of needles of the formula below, mp 112~114°. ##STR33##