Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]#[C:7][CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl.O>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][C:7]#[C:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1cccs1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC#Cc1cccs1
Reaction time: 0.5 h

Procedure:
To a solution of 145 mg of 2a and 200 μl of triethyl amine in 2 ml of dichloromethane was added dropwise at 0° C. 80 μl of methanesulfonyl chloride in 1 ml of dichloromethane. The reaction mixture was stirred for ½ hr and then diluted with 10 ml of water and extracted with dichloromethane. The organic layer was washed with 1M K2CO3, dried and concentrated, to provide 210 mg of essentially pure 2b as an oil; Rf (heptane/ethyl acetate 1/1) 0.55. NMR (CDCl3): δ 2.03 (m, 2, CH2), 2.60 (t, 2, CH2), 4.40 (t, 2, CH2), 3.03 (s, 3, CH3SO2), 6.95, 7.13, 7.20 (3×m, 3, thiophene-H).
Reaction SMILES: [H-].[Na+].[CH:3]([C:5]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:6]=1[O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:4].C(O)(=O)C>CN(C=O)C>[CH3:20][O:19][C:15]1[C:6]2[O:7][C:8]([CH3:14])([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:3](=[O:4])[C:5]=2[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)Oc1c(C=O)cccc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)Oc2c(OC)cccc2C1=O
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
Sodium hydride (60% dispersion in oil, 6.61 g) was added to DMF (250 ml). To this solution, a solution of ethyl 2-(2-formyl-6-methoxyphenoxy)-propionate (34.56 g) in DMF (150 ml) was added dropwise at room temperature for 1 hour, and the resulting solution was stirred for another 30 minutes. Acetic acid (12 ml) was added to the reaction solution and the solution was concentrated. The solution was poured into water layer (300 ml) and the resultant was extracted twice with ethyl acetate (150 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing sodium sulfate by filtration, the solvent was removed under reduced pressure and the obtained residue was dissolved in dichloromethane (600 ml). To this solution, Celite (105 g) and pyridinium chlorochromate (44.52 g) were added and the solution was stirred at room temperature for 21 hours. Isopropyl alcohol (20 ml) was added to the reaction solution and the resulting solution was stirred for 15 minutes. One liter of hexane was added to the reaction solution and the resultant was filtered through Celite, followed by washing the precipitate with one liter of ether. The filtrate was washed with water (500 ml) and the aqueous layer was extracted with ether (200 ml). The organic layers were combined and washed with saturated brine, followed by drying over sodium sulfate. After removing the sodium sulfate by filtration, the solvent was removed under reduced pressure and the residue was purified by column chromatography (solvent: hexane/ethyl acetate=5/1-3/1) using silica gel to obtain the desired compound (20.39 g, yield: 60%).
Reaction SMILES: CP(C)C.[N:5]([C@H:8]1[C@@H:13]2[C@@H:11]([C@H:12]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C@@H:9]1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1)=[N+]=[N-].C(=O)(O)[O-].[Na+]>O1CCCC1.O>[NH2:5][C@H:8]1[C@@H:13]2[C@@H:11]([C@H:12]2[C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[C@:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:35])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[C@@H:9]1[O:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[C:40]([Cl:45])[CH:39]=1
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](N=[N+]=[N-])[C@H]1OCc1ccc(Cl)c(Cl)c1
Agent: CP(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@H](N)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 96.9 %

Procedure:
Add a 1M solution of trimethylphosphine in tetrahydrofuran (19.56 mL, 19.56 mmol) to di-tert-butyl (1S,2R,3R,4S,5R,6S)-4-azido-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]bicyclo[3.1.0]hexane-2,6-dicarboxylate (8.00 g, 13.04 mmol) in tetrahydrofuran (43.46 mL) and water (130.39 mL) at room temperature and stir overnight. Saturated aqueous sodium bicarbonate is added to the reaction then extracted with ethyl acetate (3×). The combined organics are washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure giving the title compound (7.42 g, 12.63 mmol, 97%). MS (m/z): 609/611 (M+Na).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](OC)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>O1CCCC1>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:19]=2[O:18][CH3:17])=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2ccccc12
Solvent: C1CCOC1
Product: COc1ccc(CNc2c([N+](=O)[O-])cc(Br)c3ccccc23)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 4-bromo-1-methoxy-2-nitronaphthalene (3,5 g, 12.5 mmol) in dry tetrahydrofuran (15 ml) was dropwise added 2,4-dimethoxybenzylamine (8,5 g, 41,6 mmol) in dry tetrahydrofuran (15 ml). The mixture was stirred at room temperature overnight and evaporated to dryness. The residue was submitted to flash chromatography (SiO2) eluting with toluene/ethyl acetate (1:1). The product was taken up in ethyl acetate and precipitated with light petroleum to give 4.1 g (78%) of the title compound. M.p. 104°-105° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=[O:10])[N:7]([CH3:12])[C:6]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2o1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
Commercially available 5-bromobenzo[d]oxazol-2(3H)-one (1.00 g, 4.67 mmol) was dissolved in DMF (23 mL), and the mixture was stirred at room temperature for 30 minutes after adding potassium carbonate (3.87 g, 28.0 mmol) and methyl iodide (0.87 mL, 14.0 mmol). Water was added to the mixture, and the mixture was stirred. The precipitated solid was filtered off and dried to give 5-bromo-3-methylbenzo[d]oxazol-2(3H)-one (839 mg, 79%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]([CH3:25])[C:20]([O:22]CC)=[O:21])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.CCCCCC>CO>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][O:18][CH:19]([CH3:25])[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)OCCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: CC(OCCc1ccc(-c2ccc(Cl)cc2)cc1)C(=O)O
Yield: 60.8 %

Procedure:
Potassium hydroxide (5.5 g.) was added to a solution of ethyl 2-{2-[4-(4-chlorophenyl)phenyl]-ethoxy}propionate (7.0 g.) in methanol (50 ml.), and the resultant solution was heated under reflux for 2 hours. The mixture was cooled and solvent removed by evaporation, the residue was mixed with water (50 ml.) and the solution obtained was extracted with ether (2×50 ml.) to remove non-acidic material. The aqueous phase was acidified with 4 N-hydrochloric acid to pH 2-3 and extracted with ethyl acetate (3×50 ml.). The extracts were washed with water, dried (MgSO4) and evaporated. The oil obtained, solidified on trituration with hexane to give 2-{2-[4-(4-chlorophenyl)phenyl]-ethoxy}propionic acid (3.9 g., 57%), m.p. 90°-92° C. (after recrystallisation from a mixture of hexane and toluene), molecular ion: M+ 304.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH2:12][CH3:13])[CH2:7][CH2:6]2)[O:4]CC1.Cl>CC#N>[O:4]=[C:5]1[CH2:10][CH2:9][CH:8]([CH:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])[CH2:12][CH3:13])[CH2:7][CH2:6]1
Reactant: CCC(NC(=O)OC)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: CC#N
Product: CCC(NC(=O)OC)C1CCC(=O)CC1

Procedure:
A solution of methyl N-(1-1,4-dioxaspiro[4.5]decan-8-ylpropyl)carbamate (as prepared in the previous step, 39 mg, 0.15 mmol, 1.00 equiv) in CH3CN (5 mL) and HCl (2M, 1 mL) was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The residue was diluted with 10 mL of aq. sodium bicarbonate (1M). The resulting solution was extracted with 2×20 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[CH3:5][S:6]([NH:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][C:11]=1[CH:12]=[O:13])(=[O:8])=[O:7].[OH-].[K+].Cl>C(O)C.O>[OH:13][CH:12]([C:11]1[CH:14]=[C:15]([CH:16]=[CH:17][C:10]=1[NH:9][S:6]([CH3:5])(=[O:8])=[O:7])[C:18]([O:20][CH3:21])=[O:19])[CH2:4][N+:1]([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(NS(C)(=O)=O)c(C=O)c1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(NS(C)(=O)=O)c(C(O)C[N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 25.1 %

Procedure:
Nitromethane (1.22 g, 0.02 mol) was added to an ice-cooled mixture of 2-(methanesulfonylamino)-5-(methoxycarbonyl)benzaldehyde (2.57 g, 0.01 mol) in ethanol and the mixture stirred for 10 min. To this mixture was added potassium hydroxide (1.23 g, 0.022 mol in 20 mL 90% ethanol) at 0° C. over a period of 20 min. The reaction mixture was further stirred at 0° C. for 0.5 h and then at room temperature for 4 h. The mixture was neutralized with 2N HCl and poured in water (100 mL). The mixture was extracted with chloroform, dried over sodium sulfate, filtered, and concentrated. The residue was passed through a column of silica gel eluting with chloroform:methanol (99:1 to 95:5). The desired pure fractions were combined, concentrated, recrystallized from ethyl acetate-hexane, and dried to give 0.8 g (25%) of methyl 3-[1-(R,S)-hydroxy-2-nitroethyl]-4-[(methylsulfonyl)amino]benzoate as off-white crystals, mp 148° C.
Reaction SMILES: C(O)(=O)C1C(=CC=CC=1)O.C1C=CC=CC=1.[C:17]([OH:28])(=[O:27])[C:18]1[C:19](=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:20]([OH:22])=O>NC1C=CC=CC=1.[Cu]>[C:20]1(=[O:22])[O:28][C:17](=[O:27])[C:18]2=[CH:26][CH:25]=[CH:24][CH:23]=[C:19]12
Reactant: O=C(O)c1ccccc1C(=O)O
Agent: [Cu]
Agent: O=C(O)c1ccccc1O
Solvent: c1ccccc1
Solvent: Nc1ccccc1
Product: O=C1OC(=O)c2ccccc21

Procedure:
Decarboxylation is not always a predictable reaction. For example, A. S. Sultanov, J. Gen. Chem. (USSR) 16 1835 (1946) as abstracted in CA 41:6223(e) discloses that salicylic acid may be decarboxylated by autoclaving the acid in the presence of copper bronze and benzene at 170° C. The acid alone decarboxylates at 205° C. while in the presence of aniline decarboxylation begins at 170° C. In the case of salicylic acid, aniline and copper bronze seem to be equal in catalytic ability. On the other hand, when phthalic acid is heated in aniline at 180° C., decarboxylation does not occur and instead phthalic anhydride is produced. Heating phthalic anhydride with copper bronze in chloroform at 180° C. gave a 22% yield of benzoic acid. Phthalic acid was found to decarboxylate to yield benzoic acid merely by heating in water at 235° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:18]=[CH:17][C:10]2[C:11](=O)[NH:12][S:13](=[O:15])(=[O:14])[C:9]=2[CH:8]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>COCCOCCOC>[Cl:20][C:11]1[C:10]2[CH:17]=[CH:18][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:8][C:9]=2[S:13](=[O:15])(=[O:14])[N:12]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C1NS(=O)(=O)c2cc(-c3ccccn3)ccc21
Solvent: COCCOCCOC
Product: O=S1(=O)N=C(Cl)c2ccc(-c3ccccn3)cc21
Temperature: 150 °C

Procedure:
A mixture of 6-(2-pyridinyl)-1,2-benzisothiazolin-3-one 1,1-dioxide (0.390 g, 1.57 mmol) and phosphorus pentachloride (0.397 g, 1.91 mmol) in diglyme (3.75 ml) was heated to 150° C. in an oil bath to give 3-chloro-6-(2-pyridinyl)-1,2-benzisothiazole-1,1-dioxide. After allowing the temperature to fall to 90° C., acetonitrile (15 ml) was added and then 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (0.503 g, 2.07 mmol) neat in one portion. Heating at 90°-95° C. was continued for three hours during which time a heavy precipitate formed. After coming to room temperature the mixture was filtered to give 0.530 g of a tan solid. Shaking with a mixture of methylene chloride and sat. aq. sodium bicarbonate, separation of the organic layer, extraction of the organic layer with methylene chloride, combination of the organic layers and extracts, drying over anhydrous magnesium sulfate, filtration and evaporation in vacuo gave the free base. Column chromatography on silica gel and recrystallization from methanol/methylene chloride/2-propanol gave 0.267 g of the title compound as a tan solid: m.p. 233°-234° C., IR(KBr) 3270, 1612, 1580, 1455, 1279, 1142, 1120 cm-1. 1H NMR (Me2SO d6) 9.45 (1H, m), 8.80 (1H, d), 8.72 (1H, s), 8.67 (1H, d), 8.50 (1H, d), 8.38 (1H, d), 8.35 (1H, d), 8.04 (1H, t), 7.88 (1H, s), 7.57 (1H, m), 3.57 (2H, t), 2.69 (2H, t), 2.31 (3H, s), 1.83 (4H, m).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][NH:9][C:10]1[CH:16]=[CH:15][C:14]([C:17]2[O:18][C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[N:21]=2)=[CH:13][C:11]=1[NH2:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:26](=O)[CH3:27].OOS([O-])=O.[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[O:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=[C:17]1[C:14]1[CH:15]=[CH:16][C:10]2[N:9]([CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:26]([CH3:27])=[N:12][C:11]=2[CH:13]=1
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)CNc1ccc(-c2nc3ccccc3o2)cc1N
Agent: O=C([O-])[O-]
Agent: O=S([O-])OO
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2cc(-c3nc4ccccc4o3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
To a solution of 2-(2-(tert-butoxycarbonylmethylamino)anilin-5-yl)benzoxazole (see Working Example 91-1) (120 mg, 0.353 mmol) in dimethylformamide (2 mL) was added an aqueous solution of acetaldehyde (approx. 90%, 66 μL, 1.06 mmol) and oxone (217 mg, 0.353 mmol), and this was stirred at room temperature for 2 hours. After the reaction was complete, aqueous potassium carbonate solution was added, this was filtered and washed with water. The crystals obtained were purified by silica gel column chromatography to yield the title compound (30.7 mg, 24% yield) as white crystals.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Reactant: C1CCNC1
Product: O=C(Nc1nc2cccc(N3CCCC3)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure and work up described for example 30, but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 50 mg; 0.16 mmol; 1.0 eq.) and pyrrolidine (1 mL) as a white solid (1 mg, 2%). HPLC, Rt: 1.81 min. (purity 97.3%). LC/MS, M+(ESI): 309.4, M−(ESI): 307.4.
Reaction SMILES: C([O:3][C:4](=[O:19])[CH:5]([O:16][CH2:17][CH3:18])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2)C.Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)[O:25][C:26]=1[CH3:27]>>[CH2:17]([O:16][CH:5]([CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:21][C:22]1[N:23]=[C:24]([C:28]3[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:33]=3)[O:25][C:26]=1[CH3:27])[CH:11]=[CH:10]2)[C:4]([OH:3])=[O:19])[CH3:18]
Reactant: CCOC(=O)C(Cc1ccc2[nH]ccc2c1)OCC
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Product: CCOC(Cc1ccc2c(ccn2Cc2nc(-c3ccc(C(F)(F)F)cc3)oc2C)c1)C(=O)O
Yield: 27 %

Procedure:
Starting from rac-2-ethoxy-3-(1H-indol-5-yl)-propionic acid ethyl ester and 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole, the title compound was obtained in 27% yield as a yellow solid. MS: (M+H)+ 473.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[O:13][C:12]2[CH:14]=[C:15]([F:21])[C:16]([S:18]([OH:20])=[O:19])=[CH:17][C:11]=2[O:10]1.[Cl:30]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])[O:13][C:12]2[CH:14]=[C:15]([F:21])[C:16]([S:18]([Cl:30])(=[O:20])=[O:19])=[CH:17][C:11]=2[O:10]1
Reactant: O=S(O)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1cc2c(cc1F)OC(c1ccc(F)cc1F)(c1ccc(F)cc1F)O2
Reaction time: 0.67 h

Procedure:
To a solution of 2,2-bis-(2,4-difluoro-phenyl)-6-fluoro-benzo[1,3]dioxole-5 sulfinic acid (3.2 g, 7 mmol) in chloroform (25 mL) was added N-chlorosuccinimide (1.0 g, 7 mmol, 1.0 eq.) at 20° C. After 40 min, the reaction mixture was filtered and the filtrate was evaporated. The residue was suspended in dichloromethane, dried over sodium sulfate and the solvent was removed in vacuo, affording the title product as a light yellow gum.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:16]1[CH2:20][CH2:19][CH2:18][O:17]1>O>[OH:17][CH2:16][CH2:20][CH2:19][CH:18]1[CH:19]2[CH2:20][CH2:16][O:17][CH:18]2[C:13]2[CH:14]=[C:8]([NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:9]=[CH:10][C:11]=2[NH:12]1
Reactant: OC1CCCO1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Solvent: O
Product: OCCCC1Nc2ccc(Nc3ccccc3)cc2C2OCCC12
Temperature: 25 °C
Yield: 86 %

Procedure:
The mixture of 4-(N-phenylamino)-aniline (2 mmol), 2-hydroxy-tetrahydrofuran (6 mmol) and InCl3 (0.2-0.4 mmol) in water (5 mL) was stirred at room temperature. The reaction was monitored by TLC. After 24 h stirring at room temperature, the reaction mixture was extracted with ethyl ether (3×20 mL). Removal of solvent and flash column chromatography gave 1,2,3,4-tetrahydroquinoline derivatives in 86% yield (cis:trans=46:54).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:27].[Na+]>CO>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH2:27])[CH2:16][CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCN(S(=O)(=O)c2cccc3cnccc23)CC1
Temperature: 20 °C
Reaction time: 24 h

Procedure:
To 50 ml of methanol were added 2.9 g of the thus obtained 1-(5-isoquinolinesulfonyl)-4-piperidone, 2.31 g of ammonium acetate and 0.63 g of sodium cyanoborohydride, followed by stirring at 20° C. for 24 hours. The methanol was removed under reduced pressure, and 100 ml of chloroform was added to the resultant product. Then, the mixture was washed twice with 50 ml each of water, washed once with 50 ml of a 50% aqueous sodium hydrogencarbonate solution, and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to obtain a residue. The residue thus obtained was subjected to purification by silica gel column chromatography (Wacogel C-200, 150 g; solvent: chloroform) to obtain 2.39 g of 1-(5-isoquinolinesulfonyl)-4-aminopiperidine [Compound (51)]. Compound (51) was analyzed to give the following data.
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:34]([O:36]CC=C)=[O:35])=[C:14]([CH2:17][N:18]3[C:31]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[S:19]3(=[O:33])=[O:32])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:71].C(OCC)(=O)C.C(C(CCCC)C(O)=O)C>ClCCl.C(OCC)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:33]=[S:19]1(=[O:32])[N:18]([CH2:17][C:14]2[C@H:15]([CH3:16])[C@@H:11]3[C@@H:10]([C@H:8]([OH:7])[CH3:9])[C:40](=[O:41])[N:12]3[C:13]=2[C:34]([O-:36])=[O:35])[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2.[Na+:71]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3c4ccccc4-c4ccccc4S3(=O)=O)[C@H](C)[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(CN3c4ccccc4-c4ccccc4S3(=O)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The product from step 1 (22 mg, 0.038 mmol) in dichloromethane (0.5 mL) was treated with triphenylphosphine (1.6 mg, 0.0061 mmol), 0.5M sodium 2-ethyl-hexanoate in ethyl acetate (0.021 mL, 0.011 mmol), 2-ethyl-hexanoic acid (0.007 mL, 0.044 mmol) and tetrakis(triphenylphosphine)palladium(0) (4.4 mg, 0.0038 mmol). The mixture was stirred at room temperature for 15 minutes, then diluted with ethyl ether (5 mL) and centrifuged. The solid pellet was washed with ether (1.5 mL), taken up in 20% acetonitrile in water (3 mL), and applied to a column of Bio-Rad Macro-Prep CM weak cation exchange resin (2 mL). The column was eluted with 20% acetonitrile in water. The product containing fractions were concentrated under vacuum and lyophilized to afford the title compound (13.4 mg) as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[NH:11][C:12](=S)[CH2:13][N:14]=1.[CH2:21]([O:23][CH:24]([O:27][CH2:28][CH3:29])[CH2:25][NH2:26])[CH3:22]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH3:20])[S:16][C:10]=2[N:11]=[C:12]([NH:26][CH2:25][CH:24]([O:27][CH2:28][CH3:29])[O:23][CH2:21][CH3:22])[CH2:13][N:14]=1
Reactant: CCc1cc2c(s1)NC(=S)CN=C2c1ccccc1Cl
Reactant: CCOC(CN)OCC
Solvent: CCO
Product: CCOC(CNC1=Nc2sc(CC)cc2C(c2ccccc2Cl)=NC1)OCC
Yield: 87.9 %

Procedure:
[b] A mixture of 20 g of 5-o-chlorophenyl-7-ethyl-1,2-dihydro-3H-thieno[2,3-e][1,4]diazepine-2-thione and 9.6 g of aminoacetaldehyde diethylacetal is added to 200 ml of ethanol, and the whole mixture is refluxed for 2.5 hours. While the reaction mixture is hot, an activated carbon is added to the reaction mixture. The whole mixture is filtered and the filtrate is cooled. The crystals formed are collected by suction filtration and washed with a small amount of ethanol to give 23 g of 5-o-chlorophenyl-2-(2,2-diethoxyethylamino)-7-ethyl-3H-thieno[ 2,3-e][1,4]diazepine melting at 143° - 146°C.