Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([F:27])=[C:8]([C@:10]23[O:18][CH2:17][CH2:16][C@H:15]2[CH2:14][S:13][C:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[N:11]3)[CH:9]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([F:27])=[C:8]([C@@:10]23[O:18][CH2:17][CH2:16][C@@H:15]2[CH2:14][S:13][C:12]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[N:11]3)[CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N=[N+]=[N-])ccc3F)OCC[C@H]2CS1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.5 %

Procedure:
A suspension of tert-butyl ((4aR,7aR)-7a-(5-azido-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (50 mg, 0.127 mmol), 10% Pd/C (135 mg, 0.127 mmol) in methanol (5525 μL) was stirred under hydrogen balloon at rt for 12 h. The reaction mixture was filtered and the filtrate was evaporated in vacuo to tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (44 mg, 0.120 mmol, 94% yield) as a yellowish oil. This material was used directly for the next reaction without purification. MS (M+H)+: 368.14.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11]P(=O)([O-])[O-])[CH:2]=1.[H-].[Na+].[CH:18]([C:20]1[CH:21]=[C:22]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[N:23]([CH3:25])[CH:24]=1)=O.O>C1COCC1>[CH3:25][N:23]1[CH:24]=[C:20](/[CH:18]=[CH:11]/[C:3]2[CH:2]=[N:1][C:10]3[C:5]([CH:4]=2)=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:21]=[C:22]1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=P([O-])([O-])Cc1cnc2ccccc2c1
Reactant: CCOC(=O)c1cc(C=O)cn1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(/C=C/c2cnc3ccccc3c2)cn1C
Reaction time: 0.17 h

Procedure:
3-Quinolinylmethylphosphonate (0.503 g, 1.93 mmol; see step (iii) above) was dissolved in anhydrous THF (2 mL) and NaH (0.273 g, 11.37 mmol) was then added in small portions to the solution and the resulting mixture was then aged for an additional 10 min. Ethyl 4-formyl-1-methyl-1H-pyrrole-2-carboxylate (0.313 g, 1.92 mmol; see Preparation 11 above) in anhydrous THF (3 mL) was added dropwise and the solution allowed to stir for 16 h. Water (5 mL) was added to the mixture (dropwise initially) during which time the sub-title compound precipitated as a yellow solid (0.201 g, 34%).
Reaction SMILES: C[O:2][C:3](=[O:23])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])=[CH:11][C:10]1=[O:22])[CH2:5][CH2:6][S:7][CH3:8].O1CCCC1.O.[OH-].[Li+]>O>[Cl:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH2:13][N:9]([C@@H:4]([CH2:5][CH2:6][S:7][CH3:8])[C:3]([OH:23])=[O:2])[C:10](=[O:22])[CH:11]=1
Reactant: COC(=O)[C@H](CCSC)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CSCC[C@@H](C(=O)O)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
A mixture of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid methyl ester (513 mg, 1.44 mmol) in a 1:1 solution of tetrahydrofuran:water (20 mL) was treated with lithium hydroxide monohydrate (120 mg, 2.88 mmol) and stirred for 1.5 h at 25° C. After such time, the mixture was concentrated in vacuo to remove the tetrahydrofuran and partioned between 1N aqueous hydrochloric acid (10 mL) and ethyl acetate (20 mL). The organic layer was separated, dried over sodium sulfate and concentrated in vacuo to afford (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methylsulfanyl-butyric acid (438 mg, 89%) as a light amber gum.
Reaction SMILES: [CH3:1][CH:2]([CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:21]=[C:20]([C:22](OC)=[O:23])[CH:19]=[CH:18][C:13]=2[C:14](OC)=[O:15])[CH:9]=[CH:10][CH:11]=1>C1COCC1>[OH:15][CH2:14][C:13]1[CH:18]=[CH:19][C:20]([CH2:22][OH:23])=[CH:21][C:12]=1[C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(-c2cccc(OCCC(C)CCCC(C)C)c2)c1
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCOc1cccc(-c2cc(CO)ccc2CO)c1
Reaction time: 4 h
Yield: 82.3 %

Procedure:
LiAH4 (9.4 g, 248 mmol) and 300 ml of THF were placed in a reaction vessel under N2. At RT, dimethyl 2-(3′-(3,7-dimethyl-octyloxy)phenyl)terephthalate (75.5 g, 177 mmol), dissolved in 120 ml of THF, was then slowly added dropwise. The mixture was subsequently stirred for 4 hours under reflux. After cooling, excess LiAlH4 was carefully destroyed by addition of H2O. Half-concentrated H2SO4 (about 50 ml) was then carefully added dropwise. The mixture became very viscous during this addition. After stirring further for 1 hour, a clear solution and, at the bottom of the flask, a slimy gray precipitate could be seen. The clear solution was decanted off and the solvent was taken off. The precipitate which remained was stirred with plenty of water and ethyl acetate, the organic phase was separated off after filtration, the solvent was taken off and combined with the first organic phase. The combined organic phases were taken up in ethyl acetate and extracted five times with water. After drying over MgSO4, the solvent was taken off. The resulting oil was stirred a number of times with hexane and dried in an oil pump vacuum. The product was obtained as a pure, light yellow, highly viscous oil (54 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]([I:11])=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[CH2:14]([N:10]1[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[C:7]=2[C:8]([I:11])=[N:9]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1nccc2[nH]nc(I)c12
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1nccc2c1c(I)nn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 60 %

Procedure:
To a mixture of 4-chloro-3-iodo-1H-pyrazolo[4,3-c]pyridine (6.3 g) and potassium hydroxide (2.5 g) in DMF (60 mL) was added benzyl bromide (4.6 g) at room temperature. The reaction mixture was stirred at room temperature for 4 hr. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (5.0 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:7][C:8]([C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)=[O:9])[CH:5]=[CH2:6].O>C1COCC1>[CH3:1][N:2]([CH3:3])[C:14]([C:13]1[CH:17]=[CH:18][C:10]([C:8]([O:7][CH2:4][CH:5]=[CH2:6])=[O:9])=[CH:11][CH:12]=1)=[O:15]
Reactant: CNC
Reactant: C=CCOC(=O)c1ccc(C(=O)Cl)cc1
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)c1ccc(C(=O)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 ml of dimethylamine (40% in water) were introduced into a round-bottomed flask and a solution of 2.5 g (11.6 mmol) of 4-(allyloxycarbonyl)benzoyl chloride in 50 ml of THF was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. 2.7 g (100%) of the expected amide were recovered in the form of a slightly yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[NH:1]1[C:9]2=[CH:8][N:7]=[CH:6][CH:5]=[C:4]2[C:3]([C:14](=[O:16])[CH3:15])=[CH:2]1
Reactant: c1cc2cc[nH]c2cn1
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1c[nH]c2cnccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
(Ref.: J. Org. Chem. 2002, 67, 6226-6227) 6-Azaindole (2.5 g, 21.25 mmol) is added to a stirred suspension of AlCl3 (11.3 g, 84.5 mmol) in CH2Cl2 (150 mL). After stirring at rt for 1 h, acetyl chloride (6.65 g, 84.5 mmol) is added drop wise and the resulting mixture is stirred for 18 h. The mixture is cooled to 0° C., quenched with MeOH (75 mL) and stirred for 1 h. Silica gel (40 mL), MeOH and DCM are added to the mixture, the solvents are removed under vacuum and the residue is purified by silica gel chromatography eluting with 10% MeOHl in DCM to afford 1-(1H-pyrrolo[2,3-c]pyridin-3-yl)-ethanone (1.52 g, 45%). MS: 161 (M+H); 1H NMR (300 MHz, CD3OD): δ 9.20 (s, 1H), 8.95 (s, H), 7.82(d, 1H), 8.72 (d, 1H), 8.43 (d, 1-H), 2.64(s, 3H).
Reaction SMILES: CN(C=O)C.I[C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3.C(N(CCCC)CCCC)CCC.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:38][O:37][C:33]([CH:34]=[CH:35][C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:36]
Reactant: Ic1ccc2[nH]c3ccccc3c2c1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCN(CCCC)CCCC
Product: COC(=O)C=Cc1ccc2[nH]c3ccccc3c2c1
Yield: 60.5 %

Procedure:
To a DMF solution (0.25 mL) of palladium acetate (38.0 mg, 0.17 μmol), compound (1) (0.50 g, 1.71 mmol) as well as tributylamine (0.41 μL, 1.71 mmol), methyl acrylate (0.38 L, 4.27 mmol) and H2O (1.0 mL) were added in this order. The reaction solution was allowed to react for 10 minutes at 160° C. using microwaves, and the reaction was traced by TLC to confirm the disappearance of compound (1). The palladium powder was removed by Kiriyama filtration, and then the residue was purified by column chromatography (HexH:AcOEt=3:1). Thus, compound (7) (0.26 g, 62%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24](=O)[C:23](=[C:35](SC)[S:36][CH3:37])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:42][NH2:43]>C(O)C>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:42][NH:43][C:35]([S:36][CH3:37])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: NN
Reactant: CSC(SC)=C1CCc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc2C1=O
Solvent: O
Solvent: CCO
Product: CSc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Temperature: 80 °C
Yield: 28.1 %

Procedure:
To a solution of tert-butyl(1-(4-(6-(bis(methylthio)methylene)-5-oxo-3-phenyl-5,6,7,8-tetrahydroquinolin-2-yl)phenyl)cyclobutyl)carbamate (200 mg, 0.35 mmol) in anhydrous ethanol (1.7 mL) was added hydrazine monohydrate (25 μL, 0.52 mmol). The reaction mixture was heated to 80° C. under a nitrogen atmosphere for 2 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure, purified by Biotage chromatography (silica, hexane:ethyl acetate, gradient elution from 90:10 to 80:20) to give the desired product as a yellow solid (53 mg, 28% yield). 1H-NMR (500 MHz, CDCl3) δ 7.94 (1H, s), 7.16-7.24 (4H, m), 7.11-7.16 (3H, m), 7.06-7.10 (2H, m), 3.16 (2H, t), 2.83 (2H, t), 2.35 (3H, s), 2.15-2.45 (4H, br m), 1.88-2.01 (1H, m), 1.64-1.77 (1H, m), 1.00-1.35 (9H, br m). LCMS (Method A) RT=6.94 min, M+H+=539.15.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[CH2:10][N+:11]([O-])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.[H][H]>CO.O=[Pt]=O>[NH2:11][CH2:10][C@@H:9]([NH:14][S@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])[C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: [H][H]
Reactant: CC(C)(C)[S@](=O)N[C@H](C[N+](=O)[O-])c1cc(F)cc(Br)c1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(C)(C)[S@](=O)N[C@H](CN)c1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)—N—((S)-1-(3-bromo-5-fluorophenyl)-2-nitroethyl)-2-methylpropane-2-sulfinamide (2.2 g, 5.99 mmol) was dissolved in MeOH (19.97 mL), flushed with N2 for 10 min, and then PtO2 (0.408 g, 1.797 mmol) was added. The reaction mixture was charged with hydrogen balloon and stirred at room temperature overnight. The reaction mixture was filtered through celite and washed by methanol and EtOAc. The filtrate was dried over Na2SO4, filtered and concentrated. The crude material was used in next step reaction without further purification. LCMS (m/z): 337.1/339.1 (MH+), 0.64 min.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:20])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:13][C:11]1[S:12][C:8]([NH2:7])=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[N:10]=1
Reactant: Cc1nc(-c2ccccc2C)c(NC(=O)OC(C)(C)C)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc(-c2ccccc2C)c(N)s1
Yield: 27.1 %

Procedure:
A solution of (2-methyl-4-o-tolyl-thiazol-5-yl)-carbamic acid tert-butyl ester (340 mg, 1.12 mmol, 1.0 equiv) in dichloromethane (10 mL) was treated with trifluoroacetic acid (0.7 mL, 9.00 mmol, 8.0 equiv) for 24 hours at ambient temperature. The mixture was concentrated under vacuum and the resultant residue dissolved in dichloromethane and washed sequentially with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride solution. The collected organic was dried over magnesium sulfate and filtered. The filtrate was passed through an Isolute® SCX-2 cartridge (eluting with dichloromethane, dichloromethane/methanol (1:1) and 2M ammonia in methanol) to afford 62.0 mg (27%) of 2-methyl-4-o-tolyl-thiazol-5-ylamine as a brown residue. LCMS (ESI) m+H=205.0; 1H NMR (400 MHz, CDCl3) δ: 7.33-7.18 (m, 4H), 3.54-3.45 (br, 2H), 2.58 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[N:14]=[C:13](Cl)[CH:12]=[CH:11][N:10]=1.Cl.Cl.[NH:18]1[CH2:21][CH:20]([C:22]2[NH:26][C:25]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:24]=3[N:23]=2)[CH2:19]1.C(OCC)(=O)C>O1CCOCC1.O>[Cl:31][C:29]1[CH:28]=[CH:27][C:25]2[NH:26][C:22]([CH:20]3[CH2:19][N:18]([C:13]4[CH:12]=[CH:11][N:10]=[C:9]([Cl:8])[N:14]=4)[CH2:21]3)=[N:23][C:24]=2[CH:30]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Clc1ccc2[nH]c(C3CN(c4ccnc(Cl)n4)C3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of triethylamine (0.17 mL, 1.25 mmol), 2,4-dichloropyrimidine (0.053 g, 0.36 mmol), and 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride, as prepared in preparation 5, (0.10 g, 0.36 mmol) in dioxane (1.25 mL) was stirred under argon atmosphere for 3 h at RT. Ethyl acetate and water were added, the resulting layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was purified by silica gel chromatography to give 5-chloro-2-(1-(2-chloropyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.069 g, 0.22 mmol, 61% yield).
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:20][O:21][CH3:22])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:27]=1[C:28](N(OC)C)=[O:29]>>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:28](=[O:29])[C:27]3[C:34]([CH3:38])=[CH:35][CH:36]=[CH:37][C:26]=3[O:25][CH3:24])=[N:3][CH:4]=[C:5]([Cl:23])[CH:6]=2)[CH2:20][O:21][CH3:22])(=[O:11])=[O:10])=[CH:13][C:14]=1[CH3:19]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C)c1
Reactant: COc1cccc(C)c1C(=O)N(C)OC
Product: COCN(c1cc(Cl)cnc1C(=O)c1c(C)cccc1OC)S(=O)(=O)c1ccc(Cl)c(C)c1

Procedure:
4-Chloro-N-[5-chloro-2-(2-methoxy-6-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-methyl-benzenesulfonamide was prepared from N-(2-Bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-methyl-benzenesulfonamide and 2,N-Dimethoxy-6,N-dimethyl-benzamide according to previously described procedure example 29. The product was purified by chromatography on silica gel using ethyl acetate-hexane. MS m/z: 509.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:15])[CH3:14])[C:6]([S:16][C:17]1[S:18][C:19]([CH3:22])=[N:20][N:21]=1)=[N:5]2.C1C=C(Cl)C=C(C(OO)=[O:31])C=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([CH:13]([CH3:14])[CH3:15])[C:6]([S:16]([C:17]1[S:18][C:19]([CH3:22])=[N:20][N:21]=1)=[O:31])=[N:5]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1nnc(Sc2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Solvent: ClCCl
Product: Cc1nnc(S(=O)c2nc3cc(Cl)c(Cl)cc3nc2C(C)C)s1
Reaction time: 8.5 h

Procedure:
A solution of 6,7-dichloro-2-isopropyl-3-(5-methyl-1,3,4-thiadiazol-2-ylsulfanyl)quinoxaline (168 mg, 0.45 mmol) prepared as described in example 1 in dichloromethane (6 ml) was stirred in a dry ice/acetone bath at −78° C. while mCPBA (142 mg, 0.45 mmol) was added. After 8.5 hours, the reaction was quenched by addition of a saturated solution of sodium bi-carbonate. The layers were separated and the aqueous layer was extracted twice with chloroform. Evaporation of the solvent yielded a pale yellow solid. The product was purified by flash column chromatography using ethyl acetate:hexanes 1:3 to afford the title compound.
Reaction SMILES: [Cl-:1].[Ca+2].[Cl-].[CH2:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:15][C:14]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:13]=3[CH2:12][CH:11](O)[C:10]=2[CH:22]=1)[CH3:5].Cl>C1C=CC=CC=1>[Cl:1][CH:11]1[C:10]2[CH:22]=[C:6]([CH2:4][CH3:5])[CH:7]=[CH:8][C:9]=2[S:15][C:14]2[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:13]=2[CH2:12]1
Reactant: CCc1ccc2c(c1)C(O)Cc1ccc(F)cc1S2
Reactant: [Cl-]
Agent: Cl
Agent: [Ca+2]
Solvent: c1ccccc1
Product: CCc1ccc2c(c1)C(Cl)Cc1ccc(F)cc1S2
Reaction time: 1 h

Procedure:
Powdered anhydrous calcium chloride (9 g) was added to a solution of 9.4 g of the foregoing alcohol in 120 ml of benzene and the suspension saturated over 2 hours under stirring with anhydrous hydrogen chloride. After 1 hour standing, the mixture was filtered, and the filtrate evaporated under reduced pressure. The required 10-chloro-8-ethyl-3-fluoro-10,11-dihydrodibenzo(b,f)thiepin was obtained in an almost theoretical yield (10.0 g); crystallization from petroleum ether yielded the pure substance melting at 68°-70° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][NH:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.CN(C1C=CC=CN=1)C>C(Cl)Cl.C(OC(=O)C)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:12])[C:5]2[C:10]([CH3:11])=[CH:9][N:8]([S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[C:6]=2[N:7]=1
Reactant: Cc1c[nH]c2nc(Cl)nc(Cl)c12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(C)c3c(Cl)nc(Cl)nc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.3 %

Procedure:
To a suspension of 2,4-dichloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (0.58 g, 2.86 mmol) in CH2Cl2 (6 mL) was added diisopropylethylamine (DIPEA) (0.56 mL, 3.14 mmol) and p-toluenesulfonyl chloride (TsCl) (0.57 g, 3.0 mmol), followed by dimethylaminopyridine (DMAP) (0.035 g, 0.286 mmol). After stirring at ambient temperature for 1 h, the solution was diluted with ethylacetate, and the organic layer was sequentially washed with 1N HCl, saturated NaHCO3, and brine. The organic extract was then dried over Na2SO4 and concentrated to give a crude residue, which was purified by flash column (hexanes/ethyl acetate, 5:1) to yield 2,4-dichloro-5-methyl-7-tosyl-pyrrolo[2,3-d]pyrimidine (0.38 g, 38%).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:33]([F:36])([F:35])[F:34])[S:7](=[O:26])(=[O:25])[C:8]2[CH:24]=[CH:23][CH:22]=[CH:21][C:9]=2[C:10]=1[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)=[O:4].O.[OH-].[Li+]>CO.O>[CH3:18][O:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[CH:21]=[CH:22][CH:23]=[CH:24][C:8]=3[S:7](=[O:26])(=[O:25])[N:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:36])([F:34])[F:35])[C:5]=2[C:3]([OH:4])=[O:2])[CH:12]=[C:13]([O:19][CH3:20])[CH:14]=1
Reactant: COC(=O)C1=C(c2cc(OC)cc(OC)c2)c2ccccc2S(=O)(=O)N1c1ccccc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1cc(OC)cc(C2=C(C(=O)O)N(c3ccccc3C(F)(F)F)S(=O)(=O)c3ccccc32)c1
Yield: 66 %

Procedure:
The solution of 4-(3,5-dimethoxy-phenyl)-2-(2-trifluoromethyl-phenyl)-1,1-dioxo-1,2-dihydro-1λ6-benzo[e][1,2]thiazine-3-carboxylic acid methyl ester (1.29 g, 2.5 mmol) and lithium hydroxide monohydrate (0.3 g 12.5 mmol) in 30 mL of MeOH and 15 mL water was refluxed for 2.5 hours and evaporated to an oil. The residue was dissolved in water, washed with ethyl ether, and the aqueous layer decanted. The aqueous layer was acidified to pH 1 with concentrated HCl and extracted into ethyl ether, washed with brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to a foam. The residue was chromatographed on 50 g silica gel eluted with chloroform, and the appropriate fractions were concentrated in vacuo and evaporated from ethyl ether giving a solid foam, 1.4 g, 66% yield. NMR spectra and elemental analysis were consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Cl)=[CH:19][CH:18]=1>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:21][C:20]1[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)[CH:6]=[CH:5]2
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccc(Cn2ccc3cc(Br)ccc3c2=O)cc1
Reaction time: 0.5 h

Procedure:
28.18 g (125.8 mmol) 6-Bromo-2H-isoquinolin-1-one (6) were dissolved in 200 ml Dimethylacetamide and 7.55 g (188.7 mmol) sodium hydride (60%) were added at room temperature. After stirring for 30 minutes, 29.94 g (188.7 mmol) 4-Methoxy-benzylchloride were added and stirring was continued at room temperature until complete conversion was detected. The solvent was removed under reduced pressure, the residue taken up in saturated sodium hydrogen carbonate-solution and extracted three times with dichloromethane. The organic layers were dried over magnesium sulfate and evaporated. Final purification was achieved by silicagel chromatography. Rt=1.93 min (Method B). Detected mass: 344.1 (M+H+).
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([Cl:26])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][C:14]([S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:27][CH2:28][C:29]([OH:31])=[O:30].C[O-].[Na+]>>[Cl:26][C:10]1[C:11]2[C:16](=[CH:15][C:14]([S:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)[C:17]([OH:18])=[C:8]([C:6]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:7])[N:9]=1
Reactant: CCCCOC(=O)c1nc(Cl)c2ccc(Sc3ccccc3)cc2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1nc(Cl)c2ccc(Sc3ccccc3)cc2c1O

Procedure:
194 mg of 1-chloro-4-hydroxy-6-phenylsulfanyl-isoquinoline-3-carboxylic acid butyl ester (0.5 mmol) were reacted with glycine and sodium methylate analogously to Example D-1 g). 155 mg of the title compound were obtained; 1H NMR (DMSO-d6): δ=9.19 (t, 1H), 8.18 (d, 1H), 7.52 to 7.79 (m, 7H), 4.00 (d, 2H).