Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:38]([N:40]([CH2:43][C@H:44]1[N:49]([CH2:50][CH2:51][C@@H:52]([NH:61][C:62]2[CH:67]=[CH:66][C:65]([S:68]([NH2:71])(=[O:70])=[O:69])=[CH:64][C:63]=2[S:72]([C:75]([F:78])([F:77])[F:76])(=[O:74])=[O:73])[CH2:53][S:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:48][CH2:47][O:46][CH2:45]1)[CH2:41][CH3:42])[CH3:39]>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:71][S:68]([C:65]3[CH:66]=[CH:67][C:62]([NH:61][C@H:52]([CH2:51][CH2:50][N:49]4[CH2:48][CH2:47][O:46][CH2:45][C@H:44]4[CH2:43][N:40]([CH2:41][CH3:42])[CH2:38][CH3:39])[CH2:53][S:54][C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)=[C:63]([S:72]([C:75]([F:76])([F:78])[F:77])(=[O:74])=[O:73])[CH:64]=3)(=[O:69])=[O:70])=[O:21])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CCN(CC)C[C@@H]1COCCN1CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](O[Si](C)(C)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Yield: 55 %

Procedure:
The title product (100 mg, yield: 55%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 89. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid, (INTERMEDIATE 13, 84 mg, 0.16 mmol) and 4-((R)-4-((R)-3-((diethylamino)methyl)morpholino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 92, 100 mg, 0.16 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, eluting with 0→20% MeOH/DCM for 19 minutes), providing the title product.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]#[C:13][Si](C)(C)C)[C:5]([NH:8]C(=O)C)=[N:6][CH:7]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[N:3]=[C:4]2[CH:12]=[CH:13][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ncc(Br)nc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Brc1cnc2[nH]ccc2n1
Yield: 43.2 %

Procedure:
To a solution of N-(5-Bromo-3-trimethylsilanylethynyl-pyrazin-2-yl)-acetamide (474 mg, 1.52 mmol) in THF (4 ml) was added dropwise a 1 M solution of tetra-n-butyl ammonium fluoride in THF (3.3 ml, 3.3 mmol). After stirring at reflux for 15 hours, the reaction mixture was concentrated in vacuum and water added. The aqueous layer was extracted three times with dichloromethane and the combined extracts were directly adsorbed on silica gel. Purification by silica gel chromatography with a gradient of ethyl acetate/hexanes afforded the title compound (130 mg, 43% yield) as a yellow solid. 1H-NMR (500 MHz, d6-DMSO) δ 12.38 (s br, 1H), 8.38 (s, 1H), 7.95 (d, 3.5 Hz, 1H), 6.61 (d, 3.5 Hz, 1H). MS: m/z 197.9/199.9 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(O)C.[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]([N:35]=[C:36]=[S:37])=[O:34])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:36]([NH:35][C:33](=[O:34])[C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)=[S:37])=[CH:18][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: Cc1ccc(C(=O)N=C=S)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. Commercially available 4-methyl-1-benzenecarbonyl isothiocyanate (50 μl) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (70 mg, yield 89%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([N:12]1[C:17]2[CH:18]=[C:19]([C:22]([NH:24][C:25]3[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=3)=[O:23])[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][CH2:13]1)(=[O:11])=[O:10].F[C:35]1C=CC(F)=C[C:36]=1S(Cl)(=O)=O>>[CH2:35]([O:30][C:29](=[O:31])[C:28]1[CH:32]=[CH:33][C:25]([NH:24][C:22]([C:19]2[CH:20]=[CH:21][C:16]3[O:15][CH2:14][CH2:13][N:12]([S:9]([C:3]4[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=4[F:1])(=[O:10])=[O:11])[C:17]=3[CH:18]=2)=[O:23])=[CH:26][CH:27]=1)[CH3:36]
Reactant: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2F)CCO3)cc1
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(F)ccc2F)CCO3)cc1

Procedure:
4-{[4-(2,5-Difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid, MS (ISP): m/e=472.9 (M−H), was prepared as described for example 14, steps 1 to 8. Step 7 was performed using 2,5-difluoro-benzenesulfonyl chloride and yielded 4-{[4-(2,5-difluoro-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 8.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[N:18]=[C:19]4[C:25]([C:26]([NH:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[CH:24][N:23]([CH2:32][O:33]CC[Si](C)(C)C)[C:20]4=[N:21][CH:22]=3)=[N:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][O:14][N:13]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]3[N:18]=[C:19]4[C:25]([C:26]([NH:28][CH:29]([CH3:30])[CH3:31])=[O:27])=[CH:24][N:23]([CH2:32][OH:33])[C:20]4=[N:21][CH:22]=3)=[N:7][N:8]2[CH2:11][C:12]2[CH:16]=[CH:15][O:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1cn(CO)c2ncc(-c3nn(Cc4ccon4)c4cc(Cl)ccc34)nc12
Reaction time: 120 h

Procedure:
2-(6-Chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide was dissolved in dichloromethane and to this was added trifluoroacetic acid (1.79 g, 1.21 mL, 15.7 mmol). The mixture was stirred for 120 h. A precipitate had formed which was filtered off. The filtrates were concentrated in vacuo and combined with the solid to give intermediate 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-5-(hydroxymethyl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (73 mg, 157 μmol). This was dissolved in 60:20:1 dichloromethane:methanol:ammonium hydroxide (10 mL), and the mixture was stirred for 2 h. The mixture was concentrated in vacuo, diluted with dichloromethane and reconcentrated to give 2-(6-chloro-1-(isoxazol-3-ylmethyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (67 mg, 154 μmol, 98.1%) as a white solid. MS (M+Na)+=458; 1H NMR (CDCl3) δ: 11.97 (br. s., 1H), 9.08 (s, 1H), 8.36 (d, J=8.3 Hz, 1H), 8.29 (d, J=1.5 Hz, 1H), 8.16 (d, J=3.0 Hz, 1H), 7.98-8.07 (m, 1H), 7.46 (s, 1H), 7.12 (dd, J=8.5, 1.3 Hz, 1H), 6.21 (d, J=1.5 Hz, 1H), 5.64 (s, 2H), 4.23-4.39 (m, 1H), 1.20-1.32 (m, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N+]([O-])=O)[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].O.Cl.C(OCC)(=[O:20])C>C1(C)C=CC=CC=1.[Fe]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([CH3:12])=[O:20])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1Br
Reactant: CCOC(C)=O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(CC(C)=O)cc1Br
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of 790 mg (2.90 mmol) of 1-(3-bromo-4-methoxyphenyl)-2-nitropropene (from Example 80, Step A) in 5.0 mL of toluene was combined with water (2.0 mL), iron powder (730 mg, 13.45 mmol), and ferric chloride (14.2 mg, 0.088 mmol) in a 25-mL three-neck round bottom flask fitted with a mechanical stirrer and reflux condenser. With vigorous agitation, the suspension was heated at 80° C., and 1.3 mL of conc. HCl was added over a period of 2 h via syringe. After the addition was completed, the heating and stirring were continued for an additional 30 min. After the reaction had cooled to RT, ethyl acetate (50 mL) was added to the solid was removed by filtration. The filtrate was washed with 20 mL of saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was filtered again and the filtrate was extracted with 2×40 mL of ethyl acetate. The combined ethyl acetate extracts were washed with 50 mL of brine. Drying over sodium sulfate and concentration afforded a red oil which was purified by flash column chromatography, eluting with 30% dichloromethane in hexane followed by dichloromethane, to give 411 mg of the title compound as a yellow syrup.
Reaction SMILES: [CH3:1][CH:2](O)[C:3]#[CH:4].[CH3:6][O:7][CH2:8][CH2:9][NH:10][CH3:11]>>[CH3:6][O:7][CH2:8][CH2:9][N:10]([CH3:11])[CH:2]([CH3:1])[C:3]#[CH:4]
Reactant: C#CC(C)O
Reactant: CNCCOC
Product: C#CC(C)N(C)CCOC

Procedure:
In analogy to example 37.5 and 37.6, 3-Butyn-2-ol and N-(Methoxyethyl)methylamine were converted to yield (2-Methoxy-ethyl)-methyl-(1-methyl-prop-2-ynyl)-amine as colorless oil, MS: 141 (M).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].O>CN(C)C=O>[N+:13]([C:8]1[C:7]([O:6][CH2:5][C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=2[CH2:2][N:24]2[C:23](=[O:25])[C:22]3=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]3[C:20]2=[O:30])=[CH:12][CH:11]=[CH:10][N:9]=1)([O-:15])=[O:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1ncccc1OCc1ccccc1CCl
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccccc1COc1cccnc1[N+](=O)[O-]
Yield: 47.3 %

Procedure:
A solution of 3-(2-chloromethylbenzyloxy)-2-nitropyridine (4.09 g) and potassium phthalimide (2.99 g) in N,N-dimethylformamide (41 ml) was stirred at 50° C. for 9.5 hours. The reaction mixture was poured into water (200 ml) and extracted twice with ethyl acetate (250 ml). The combined extract was washed with water and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resultant residue was recrystallized from ethyl acetate to give 2-nitro-3-(2-phthalimidomethylbenzyloxy)pyridine (2.7 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1.C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:13][N:14]1[CH2:19][CH2:18][CH:17]([N:10]2[C:11]3[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=3)[CH2:8][CH2:9]2)[CH2:16][CH2:15]1
Reactant: O=[N+]([O-])c1ccc2c(c1)NCC2
Reactant: CN1CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CN1CCC(N2CCc3ccc([N+](=O)[O-])cc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Nitroindoline (5 g) was dissolved in 200 mL of dichloroethane. N-Methyl-4-piperidone (5 g) was added to the mixture, followed by NaHB(OAc)3 (12 g) and 1 mL of glacial ACOH. The mixture was stirred at RT overnight. A saturated NaHCO3 (200 mL) solution was added to the reaction mixture and stirred for 1 h. The resulting mixture was separated by separation funnel. The organic layer was extracted once with saturated NaHCO3 solution and once with brine. The resulting organic layer was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography on silica gel with 2:1 EtOAc:MeOH to afford orange oil. MS: 262 (M+1). Calc'd. for C14H19N3O2−261.3.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[N:20]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:21].C(N(CC)CC)C.[F:29][C:30]([F:37])([F:36])[CH2:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[F:29][C:30]([F:37])([F:36])[CH2:31][S:32]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:18](=[O:19])[C:17]2[N:20]3[C:10](=[CH:11][N:12]=[C:13]3[CH:14]=[CH:15][CH:16]=2)[C:9]1=[O:21])(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: NCCCCn1c(=O)c2cccc3ncc(c1=O)n32
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1c2cccc3ncc(c(=O)n1CCCCNS(=O)(=O)CC(F)(F)F)n32
Yield: 38.7 %

Procedure:
To a suspension of 994 mg (3.0 mmol) of 4,5-dihydro-4-[4-(amino)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione.dihydrochloride in 50 ml of methylene chloride was added, while stirring under ice-cooling, 1.47 ml (10.5 mmol) of triethylamine. The mixture was stirred for 5 minutes, to which was added dropwise 0.66 g (3.6 mmol) of 2,2,2-trifluoroethanesulfonyl chloride. The reaction mixture was cooled with ice for one hour, which was stirred for 19 hours at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, which was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate), followed by washing with ether and dried to give 470 mg of the desired compound (38.7%, colorless solid), m.p.154.0-155.0° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]3)=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[Cl:2][C:3]1[CH:34]=[CH:33][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][N:20]3[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:42])=[O:18])[CH2:13][C@H:12]2[C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCCN2)C[C@H]1c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(C(=O)C2CCCCN2C(=O)c2ccccc2)C[C@H]1c1ccc(Cl)c(Cl)c1

Procedure:
Using the compound obtained in Example 545 and benzoyl chloride, and by the reaction and purification in the same manner as in Example 39, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:22])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[SH:7][C:4]1[S:3][C:2]([NH:1][C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[N:6][N:5]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1nnc(S)s1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nnc(S)s1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
61 g of 2-amino-5-mercapto-1,3,4-thiadiazole were dissolved in 230 ml of dimethylacetamide, and 40.8 ml of pyridine were added thereto. The resulting solution was cooled to a temperature not higher than 0° C., and 79 g of phenyl chlorocarbonate were added dropwise thereto. After completion of the dropwise addition, the solution was stirred for 1.5 hours at a temperature not higher than 0° C., and the reaction mixture was then poured into 1 liter of ice-water. Precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain the desired product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CCN(CC)CC.Cl[Si:17]([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([O:8][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH2:4][CH2:3]1
Reactant: C[Si](C)(C)Cl
Reactant: CN1CCC(=O)CC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CN1CC=C(O[Si](C)(C)C)CC1
Temperature: 110 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 1-methyl-piperidin-4-one (6.0 g, 53 mmol, 6.52 mL) and Et3N (14.16 g, 140 mmol, 19.5 mL) in 1,4-dioxane (20 mL) was added chlorotrimethylsilane (7.6 g, 70 mmol, 8.88 mL) drop wise during 30 min. The resultant reaction mixture was slowly heated to reflux at 110° C., stirred at the same temperature for 24 h, an additional amount of chlorotrimethylsilane (4.44 mL), heated for 24 h (take aliquot of it and run 1H NMR), cooled to room temp, filtered off the solid, solid was washed with n-pentane. The filtrate was concentrated on rotavaporator, and then diluted with n-pentane and filtered off the solid. The resultant solution was concentrated on rotavaporator followed by high vacuum furnished the 1-methyl-4-trimethylsilanyloxy-1,2,3,6-tetrahydro-pyridine (9.68 g, 1H NMR showed about 10:1 ratio of silylenolether and the starting material). The crude product was as such used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][O:47][CH3:48])[CH:43]=[N:42][CH:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][O:47][CH3:48])[CH:43]=[N:42][CH:41]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4cncn4CCOC)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4cncn4CCOC)cc2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-(2-methoxyethyl)imidazol-5-yl]methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.49 g) was dissolved in methylene chloride (14.7 ml), and a solution of metachloroperbenzoic acid (0.25 g) in methylene chloride (9.8 ml) was added dropwise to the solution at −78° C. The mixture was stirred for 15 minutes, and to the mixture was added an aqueous solution of saturated sodium thiosulfate, and the mixture was allowed to be warmed to room temperature. The mixture was extracted with ethyl acetate, washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[[1-(2-methoxyethyl)imidazol-5-yl]methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 308) (0.26 g).
Reaction SMILES: [C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([N:10](CC)CC)C.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:15][S:16]([NH2:10])(=[O:18])=[O:17].[CH3:15][S:16]([NH2:7])(=[O:18])=[O:17].[C:1]1([NH2:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: Nc1ccccc1
Product: CS(N)(=O)=O

Procedure:
A mixture of 4-(7-methyl-2,4-di-1-pyrrolidinyl-7H-pyrrolo- 2,3-d!pyrimidin-6-yl)phenylamine (EXAMPLE 188, 206 mg) in 40 ml of dichloromethane is cooled in an ice-water bath and treated with 0.15 ml of triethylamine followed by 0.05 ml of methanesulfonyl chloride. Three additional portions of methanesulfonyl chloride, 0.02 ml, 0.01 ml and 0.01 ml, are added in sequence over the next hour. The mixture is poured onto water, treated with aqueous saturated sodium bicarbonate and extracted with three portions of dichloromethane. The combined organic extracts are dried and concentrated to give a solid which is combined with previously isolated material (from a 50 mg run) and chromatographed over silica eluting with methanol/chloroform (3/97) to give the desired material which is recrystallized from hot acetonitrile to give the title compound, mp 245-248; NMR 7.49-7.47, 7.31-7.28, 6.42, 3.78-3.69, 3.64, 3.58-3.52, 3.36, 1.97-1.85δ.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][O:19][CH2:20][C:21](Cl)=[O:22]>>[CH3:18][O:19][CH2:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: COCC(=O)Cl
Product: COCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 84.1 %

Procedure:
Beginning with 13 mg (0.056 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 6.5 mg (0.059 mMol) methoxy-acetyl chloride, 14.2 mg (84%) of the title compound were recovered.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)#[N:8].Br[CH2:19][CH2:20][CH2:21][OH:22]>>[OH:22][CH2:21][CH2:20][CH2:19][N:15]1[C:16]2[C:12](=[CH:11][CH:10]=[C:9]([C:7]#[N:8])[CH:17]=2)[CH:13]=[CH:14]1
Reactant: OCCCBr
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: N#Cc1ccc2ccn(CCCO)c2c1
Reaction time: 0.25 h

Procedure:
0.776 mol (87 g) of potassium tert-butylate is added to a solution of 0.703 mol (100 g) of 6-cyanoindole in 2500 ml of tetrahydrofliran at 20° C. After 15 minutes' stirring, 1.41 mol (196 g) of 3-bromo-1-propanol are added and the reaction mixture is stirred for 24 hours at room temperature. After concentration, the residue is taken up in 1000 ml of dichioromethane, and the organic phase is washed with 500 ml of water an d then with 500 ml of a saturated sodium chloride solution. The organic phase is then dried and concentrated to yield the expected compound.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]([N:18]([C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)[CH3:19])(=[O:17])[CH3:16].C([O-])(=O)C.[Na+].O>C(O)C>[CH2:8]([N:5]1[CH2:6][CH2:7][CH:2]([NH:1][S:26]([C:23]2[CH:22]=[CH:21][C:20]([N:18]([C:15](=[O:17])[CH3:16])[CH3:19])=[CH:25][CH:24]=2)(=[O:28])=[O:27])[CH2:3][CH2:4]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: CC(=O)N(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(=O)N(C)c1ccc(S(=O)(=O)NC2CCN(Cc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-Amino-1-benzylpiperidine (3.63 ml, 17.8 mmol) was added to a suspension of the 4-(N-acetyl-N-methylamino)benzenesulfonyl chloride (4.00 g, 16.2 mmol) prepared in Preparative Example 12 and sodium acetate (2.65 g) in ethanol (40 ml). The obtained mixture was stirred at room temperature for 4 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give N-(1-benzyl-4-piperidyl)-4-(N-acetyl-N-methylamino)benzenesulfonamide as a colorless viscous oil. This oil was dissolved in 4N aqueous hydrochloric acid and the obtained solution was heated under reflux for 3 hours. The resulting mixture was concentrated to give a solid residue. This residue was recrystallized from ethyl acetate to give the title compound as a white crystal (highly hygroscopic one) (5.80 g, overall yield of two steps: 80%).