Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C[Al](C)C.[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([C@H:31]1[CH2:35][CH2:34][O:33][C:32]1=[O:36])[CH2:26][CH2:25][CH2:24]2>C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]([C@@H:31]([CH2:35][CH2:34][OH:33])[C:32]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12](=[O:15])[O:13][CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1)=[O:36])[CH2:26][CH2:25][CH2:24]2
Reactant: O=C1OCC[C@@H]1N1CCCc2cc(Cl)ccc21
Reactant: COC(=O)NS(=O)(=O)c1ccc(N)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Product: COC(=O)NS(=O)(=O)c1ccc(NC(=O)[C@H](CCO)N2CCCc3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring suspension of the methyl 4-aminophenylsulfonylcarbamate (111 mg, 0.48 mmol) and CH2Cl2 (1 mL) under N2, at 0° C., was added trimethylaluminum (0.24 mL, 0.48 mmol) dropwise over 20 minutes. The solution was stirred at ambient temperature for 30 minutes. The solution was cooled to 0° C. followed by the dropwise addition of (S)-3-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)dihydrofuran-2(3H)-one (100 mg, 0.40 mmol) in CH2Cl2 (1.0 mL) over 30 minutes. The solution was stirred at ambient temperature for 19 h. The solution was cooled to 0° C. and quenched by slow addition of aqueous 1.0 M HCl. The organic portion was washed with 1.0 N aqueous HCl (2×1.0 mL) and evaporated to dryness under reduced pressure. The crude product of (R)-methyl 4-(2-(6-chloro-3,4-dihydroquinolin-1(2H)-yl)-4-hydroxybutanamido)phenylsulfonylcarbamate was used without purification in the next step.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[O:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[C@H:12]1[CH2:13][OH:14].C(N(CC)CC)C>C(Cl)Cl>[O:11]1[C@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[C@H:12]1[CH:13]=[O:14]
Reactant: OC[C@H]1O[C@@H]1c1cccc(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C[C@H]1O[C@@H]1c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
A solution of 1.1 g of oxalyl chloride in 15 ml of methylene chloride is cooled to -65°-70° under argon and within a period of 2 minutes 1.5 g of dimethyl sulfoxide in 5 ml of methylene dichloride are added. After stirring for 10 minutes at -65°-70°, 1.7 g of (2R,3R)-2,3-epoxy-3-(3-trifluoromethylphenyl)-propanol in 15 ml of methylene chloride are added dropwise. After stirring for a further 30 minutes, 4 g of triethylamine are added dropwise, the temperature rising to -40°. The temperature is allowed to rise to 0° and the reaction mixture is poured onto phosphate buffer (pH 8). The organic phase is separated off and the aqueous phase is extracted with methylene chloride. The combined organic extracts are washed twice with brine, dried over sodium sulfate and concentrated by evaporation. Chromatography of the residue on silica gel with hexane/ethyl acetate (7:3) yields the title compound in the form of a colourless oil; IR (methylene chloride): 2820, 1730, 1330, 1165, 1125, 1070 cm-1. Rf =0.36 (hexane/ethyl acetate 3:2). [α]D20 (chloroform, 0.20%)=-17.5°±5°.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19]([C@H:21]([NH:26]C(=O)OC(C)(C)C)[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[CH3:1][C:2]1([CH3:34])[C:6]2[C:7]([O:11][C:12]3[N:17]=[CH:16][C:15]([NH:18][C:19](=[O:20])[C@@H:21]([C:22]([CH3:25])([CH3:24])[CH3:23])[NH2:26])=[CH:14][N:13]=3)=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)Nc1cnc(Oc2cccc3c2C(C)(C)CO3)nc1)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)COc2cccc(Oc3ncc(NC(=O)[C@H](N)C(C)(C)C)cn3)c21
Reaction time: 3 h
Yield: 106.5 %

Procedure:
To a solution of 1,1-dimethylethyl {(1R)-1-[({2-[(3,3-dimethyl-2,3-dihydro-1-benzofuran-4-yl)oxy]-5-pyrimidinyl}amino)carbonyl]-2,2-dimethylpropyl}carbamate (Intermediate 77, 13 mg) in dry dichloromethane (0.5 ml) cooled to 0° C., TFA (85 μl, 1.105 mmol) was added dropwise and the solution was stirred for 3 hours at that temperature. The volatiles were evaporated. The residue was dissolved with dichloromethane (2 ml) and an aqueous saturated solution of NaHCO3 was added (4 ml). The layers were separated and the aqueous layer was extracted twice with dichloromethane. The gathered organic layers were dried over sodium sulphate and evaporated to afford the title compound (10.9 mg).
Reaction SMILES: [CH:1]([N:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[C:6]1=[O:13])([CH2:3][CH3:4])[CH3:2].Cl.[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[NH:23][CH2:22][CH2:21]2>>[Br:15][C:16]1[CH:17]=[C:18]([O:25][CH3:26])[CH:19]=[C:20]2[C:24]=1[N:23]([C:7]1[C:6](=[O:13])[N:5]([CH:1]([CH3:2])[CH2:3][CH3:4])[CH:10]=[C:9]([Cl:11])[N:8]=1)[CH2:22][CH2:21]2
Reactant: CCC(C)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CCC(C)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 1-sec-butyl-3,5-dichloro-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 155–157° C.; 1H NMR (300 MHz, CDCl3): δ 6.90 (d, J=2.6 Hz, 1 H), 6.78 (s, 1 H), 6.76 (d, J=2.1 Hz, 1 H), 4.99–4.87 (m, 1 H), 4.34 (t, J=7.7 Hz, 2 H), 3.76 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.74–1.65 (m, 2 H), 1.34 (d, J=7.0 Hz, 3 H), 0.89 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C20H22N3O2BrCl (M+H)+: 412.0427; found m/z 412.0448.
Reaction SMILES: C[O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14][CH:15]=1
Reactant: CCOC(=O)COc1ccc(OC)cc1
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(O)cc1
Temperature: 0 °C
Reaction time: 0.62 h
Yield: 20 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged 20 mL of DCM to the stirred solvent was added ethyl (4-methoxyphenoxy)acetate (2 g, 9.5 mmol) and Borontribromide (1.85 g, 11.0 mmol) was added at 0° C. Then it was stirred at 0° C. for 30-45 min. After completion of the reaction (reaction monitored by TLC), reaction mass quenched with Sodium bicarbonate and concentrated the reaction mixture and extracted with ethyl acetate. The organic layer was washed with brine and dried by anhydrous Na2SO4 and evaporated to dryness, the resulting crude compound was purified by column chromatography on silica gel using petroleum ether and ethyl acetate as eluent to give the product (0.2 g Yield: 20%): 1H NMR (300 MHz, DMSO-d6): δ 8.97 (s, 1H), 6.72-6.75 (d, 2H), 6.64-6.67 (d, 2H), 4.62 (s, 2H) 4.11-4.18 (q, 2H), 1.18-1.22 (t, 3H).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28]>>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([NH:28][CH2:27][C:26]([F:30])([F:29])[F:25])=[O:24])=[CH:5][N:6]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccn3)noc2C)nc1
Product: Cc1onc(-c2ccccn2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 98 %

Procedure:
As described for example 272, 6-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (97.6 mg, 0.3 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (115 mg, 98%) which was obtained as a white solid. MS: m/e=393.4 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(N(CC)CC)C>O1CCCC1>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[CH:12][C:13]([S:15]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)(=[O:17])=[O:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc(S(=O)(=O)Cl)cc2CC1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2CC1
Temperature: 60 °C

Procedure:
A mixture of 3-acetyl-7-chlorosulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (4.0 g, 13.9 mmol), morpholine (1.8 ml, 20.8 mmol) and triethylamine (2.14 ml, 15.3 mmol) in tetrahydrofuran (120 ml) was heated at 60° C. for 3 h. The reaction mixture was then cooled, filtered and the filtrate evaporated in vacuo to give a yellow solid. Crystallisation from dichloromethane/n-hexane gave the title compound as an off-white solid (4.4 g, 94 Mass Spectrum AP+: Found 339 (MH+). C16H22N2SO4 requires 338.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[CH2:26][C:27](=[O:38])[C@@H:28]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH3:29].[I-].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[C:33]([O:32][C:31]([NH:30][C@@H:28]([CH3:29])[C:27](=[O:38])[CH2:26][NH:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:37])([CH3:36])([CH3:34])[CH3:35]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)CCl
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NCC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reaction time: 15 h
Yield: 73.4 %

Procedure:
To a stirred solution of L-phenylalanyl-L-leucine, t-butyl ester (6 mmol) in 10 ml of dimethylformamide (under argon) was added a solution of [(S)-3-chloro-1-methyl-2-oxopropyl]carbamic acid, 1,1-dimethylethyl ester (1.33 g, 6 mmol) in 20 ml of dimethylformamide, followed by sodium iodide (450 mg, 3 mmol) and sodium bicarbonate (504 mg, 6 mmol). The reaction mixture was allowed to stir for 15 hours, and the solvent was then evaporated (<25° C., vacuum pump). The yellow residue was taken up into ethyl acetate (250 ml) and washed with water (4×25 ml) and brine (25 ml), then dried (sodium sulfate) and evaporated to a yellow residue (3.44 g). This was applied to a column of silica gel (Merck, 230-400 mesh, 250 g) and eluted with hexane-ethyl acetate (1.25:1). Fractions 25-40 (~30 ml each, homogeneous on TLC) were pooled and concentrated yielding 2.29 g of a colorless oil. Rapid recrystallization from ethyl acetate-hexane afforded 1.61 g of the title compound as a powdery white solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][C:25](=O)[CH3:26])[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[O-].[Na+].Cl[C:33]1C=C[N:36]=[CH:35][N:34]=1>CO>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([O:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][NH:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][S:24][C:25]3[CH:26]=[CH:33][N:34]=[CH:35][N:36]=3)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccncn1
Reactant: CC(=O)SCCCC(=O)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(CCCSc1ccncn1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Reaction time: 0.33 h
Yield: 60.2 %

Procedure:
A solution of 1.00 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-4-(acetylthio)butyramide [prepared as described in step (a) above] in 10 ml of methanol was added to a mixture of 0.48 g of 28% w/v methanolic sodium methoxide and 5 ml of methanol, whilst ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. At the end of this time, 0.28 g of 4-chloropyrimidine was added to the mixture and the mixture was heated under reflux for 2 hours. The solvent was then removed by evaporation under reduced pressure, and water was added to the resulting residue, which was then extracted with ethyl acetate. The solvent was removed from the extract by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel, using a 1:9 by volume mixture of ethanol and chloroform as the eluent, to give 0.65 g (yield 60%) of the title compound as an oil.
Reaction SMILES: CO[C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:6]=1)=[O:4].[CH2:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH2:28])[CH:20]=[CH2:21].C([O-])(=O)C>O>[CH2:19]([N:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[CH2:27][NH:28][C:3]([C:5]1[C:14]2[O:13][CH2:12][CH2:11][O:10][C:9]=2[CH:8]=[C:7]([S:15](=[O:17])(=[O:18])[NH2:16])[CH:6]=1)=[O:4])[CH:20]=[CH2:21]
Reactant: COC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Reactant: C=CCN1CCCC1CN
Agent: CC(=O)[O-]
Solvent: O
Product: C=CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)cc2c1OCCO2
Yield: 64.7 %

Procedure:
145 g of methyl-7-sulfamoyl-1,4-benzodioxane-5-carboxylate, 48 g of water and 89 g of 1-allyl-2-aminomethylpyrrolidine were introduced into a balloon flask provided with a condenser. The mixture was heated on a water bath until a test sample was soluble in dilute acids and then 1 liter of water was added. The precipitated carboxamide was redissolved by acetate formation. The solution formed was filtered on carbon black and then the base was precipitated by the addition of 20% ammonia. The resulting crystals were dried off, washed with water, dried and purified by passing over hydrochloride (M.P.: 228°-230° C.) followed by transformation into a base by treatment with 20% ammonia. 131 g of N-(1-allyl-2-pyrrolidylmethyl)-7-sulfamoyl-1,4-benzodioxane-5-carboxamide was produced (M.P.: 143°-144° C.; yield: 64.8%). The structure was confirmed by nuclear magnetic resonance.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH2:4]P(=O)(OC)OC.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=[CH:4][C:3]2[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=2[Br:1])[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COP(=O)(Cc1ccccc1Br)OC
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=Cc2ccccc2Br)CC1
Reaction time: 1 h

Procedure:
A solution of dimethyl 2-bromobenzylphosphonate (45.66 g, 148.9 mmol) in THF was added slowly to a mixture of NaH (7.14 g of a 60% mineral oil dispersion, 178.5 mmol) in THF (200 ml) and the mixture was stirred for 1 hr. A solution of 1-(tert-butoxycarbonyl)-4-piperidinone (29.67 g, 148.9 mmol) in THF was added dropwise and the mixture was heated to reflux for 1.5 hr. The mixture was cooled and quenched with brine. The mixture was diluted with ethyl acetate, washed with water, and dried with brine. The organic layer was concentrated in vacuo to an oil. The oil was dissolved in acetonitrile and extracted with hexane. The acetonitrile layer was concentrated in vacuo to give 1-(tert-butoxycarbonyl)-4-[(2-bromophenyl)methylene]piperidine as an oil that solidified upon standing (48.3 g, 97%).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:34][CH2:35][CH:36]([O:39][CH3:40])[O:37][CH3:38]>C1COCC1>[CH2:4]([O:3][C:1](=[O:2])[NH:11][C@H:12]([CH:13]([CH3:14])[CH3:15])[C:16]([NH:34][CH2:35][CH:36]([O:39][CH3:40])[O:37][CH3:38])=[O:18])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(CN)OC
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
A solution of Cbz-D-Valine (500 g, 1.99 mol) and N-methylmorpholine (201.8 g, 1.99 mol) in anhydrous THF (8 L) was cooled to −15° C. and i-butyl chloroformate (299 g, 2.19 mol) was added dropwise under stirring. After 30 min, a solution of 1-amino-2,2-dimethyoxyethane (209.5 g, 1.99 mol) in THF (1 L) was added slowly and the temperature was maintained at −15° C. for 2 h. The reaction mixture was washed with brine (2 L) and the organic phase was concentrated to remove the THF. The residue was diluted with EtOAc (4 L), washed with 1N aq HCl (2×2 L), sat. aq. NaHCO3 (2 L) and sat. aq. Na2CO3 (2 L) and brine (1.5 L). After drying over Na2SO4, the organic solvent was removed under reduce pressure to afford (R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate as a white solid (670 g, yield 99.5%), which was used for next step without further purification. LC-MS m/z 360.9 [M+Na]+.
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C@H:25]3[N:29]([CH3:30])[CH2:28][C@@H:27]([N:31]([CH3:33])[CH3:32])[CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:16]2[CH:17]=[CH:18][C:19]3[N:20]([C:22]([C@H:25]4[N:29]([CH3:30])[CH2:28][C@@H:27]([N:31]([CH3:33])[CH3:32])[CH2:26]4)=[N:23][N:24]=3)[CH:21]=2)[CH2:6][CH2:5]1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CN(C)[C@H]1C[C@@H](c2nnc3ccc(F)cn23)N(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)[C@H]1C[C@@H](c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)N(C)C1
Reaction time: 0.33 h
Yield: 96.3 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 548 mg, 14.6 mmol) in dry DMF (10.0 mL) under nitrogen was treated with Intermediate 1 (800 mg, 4.9 mmol) and the mixture was stirred for 20 min. Intermediate 38c (1.28 g, 4.6 mmol) was added and the mixture was stirred at RT for 4 hours then quenched with MeOH. The mixture was further diluted with MeOH and applied to a pre-conditioned (MeOH) SCX-2 cartridge (25 g). The cartridge was eluted with MeOH then 2M NH3 in MeOH. The relevant product containing fractions were combined and concentrated in vacuo to give the title compound as a dark brown oil (1.8 g, 86%). LCMS (Method 3): Rt 0.6, m/z 407 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[N:12]=[CH:11][CH:10]=2)=[C:6]([CH:8]=1)[NH2:7].C1N=CN([C:24](N2C=NC=C2)=[O:25])C=1>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[N:13]([CH:14]4[CH2:18][CH2:17][CH2:16][CH2:15]4)[N:12]=[CH:11][C:10]=3[C:24](=[O:25])[NH:7][C:6]=2[CH:8]=1
Reactant: Nc1cc(Br)ccc1-c1ccnn1C1CCCC1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN1CCCC1=O
Product: O=c1[nH]c2cc(Br)ccc2c2c1cnn2C1CCCC1
Temperature: 150 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 100 mg of 5-bromo-2-(1-cyclopentyl-1H-pyrazol-5-yl)aniline in 2.5 mL of N-methylpyrrolidone was added 105 mg of CDI, followed by stirring at 150° C. for 2 hours using a microwave reactor, and cooling to room temperature. The precipitated solid was collected by filtration, washed with ethyl acetate, and then dried under reduced pressure to obtain 73 mg of 7-bromo-1-cyclopentyl-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][CH2:15]Cl)[CH3:13])(=[O:11])=[O:10].[F:17][C:18]1[CH:32]=[CH:31][C:21]2[NH:22][C:23]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:24][C:20]=2[CH:19]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][CH2:15][N:28]1[CH2:27][CH2:26][CH:25]([C:23]2[NH:22][C:21]3[CH:31]=[CH:32][C:18]([F:17])=[CH:19][C:20]=3[N:24]=2)[CH2:30][CH2:29]1)[CH3:13])(=[O:11])=[O:10]
Reactant: CN(CCCl)S(=O)(=O)c1cc(Br)ccc1Br
Reactant: Fc1ccc2[nH]c(C3CCNCC3)nc2c1
Product: CN(CCN1CCC(c2nc3cc(F)ccc3[nH]2)CC1)S(=O)(=O)c1cc(Br)ccc1Br

Procedure:
The title compound was prepared using the procedure described in Example 1 using 2,5-Dibromo-N-(2-chloroethyl)-N-methyl benzene sulfonamide (D10) and 4-(5-fluoro 1H benzimidazol-2-yl)piperidine (D17). MH+ 5731575/577.
Reaction SMILES: [C:1]([NH:9][CH:10]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[C:1]([NH:9][CH:10]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH:11]([OH:16])[C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)C(NC(=O)c1ccccc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C(O)C(NC(=O)c1ccccc1)n1ccnc1
Reaction time: 15 h
Yield: 78.6 %

Procedure:
Process variant (b) 28.5 g (0.1 mol) of 1-benzamido-3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one of melting point 140°-142° C. (prepared analogously to Example 8, in accordance with process (a)) were dissolved in 250 ml of methanol. 4 g (0.1 mol) of sodium borohydride were added in portions while stirring and cooling at 0° to 10° C. Stirring was continued for 15 hours at room temperature and 200 ml of water were added to the reaction mixture. The mixture was then extracted by shaking with 200 ml of methylene chloride and the organic phase as dried over sodium sulphate and concentrated by distilling off the solvent in vacuo. Boiling up with petroleum ether and a little ether caused the mixture to crystallize. 22.6 g (79% of theory) of 1-benzamido-3,3-dimethyl-1-imidazol-1-yl-butan-2-ol of melting point 143° C. were obtained.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:21][C@H:20]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]=[CH:11][C:10]=3[N:19]=[C:7]2[CH2:6]1)(=[O:4])=[O:3].C1C=C(Cl)C=C(C(OO)=[O:41])C=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:21][C@H:20]([CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[N:8]2[C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N+:12]([O-:41])=[CH:11][C:10]=3[N:19]=[C:7]2[CH2:6]1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3cnc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCC[C@H]1CN(S(C)(=O)=O)Cc2nc3c[n+]([O-])c4ccccc4c3n21
Reaction time: 1 h
Yield: 100 %

Procedure:
tert-Butyl 3-[(11S)-9-(methylsulfonyl)-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.16 g, 13.4 mmol) was dissolved in 110 mL of CH2Cl2 and treated with MCPBA (4.05 g, 57-86% pure material). After stirring for 1 hour, the reaction mixture was treated with 100 mL of 5% Na2CO3 solution and the layers were separated. The aqueous layer was then extracted with CH2Cl2 (2×50 mL). The combined organic layers were concentrated under reduced pressure to give tert-butyl 3-[(11S)-9-(methylsulfonyl)-5-oxido-8,9,10,11-tetrahydropyrazino[1′,2′:1,2]imidazo[4,5-c]quinolin-11-yl]propylcarbamate (6.37 g) as a golden foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:24]=2)=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:24]=2)=[O:42])=[C:6]([NH:8][S:9]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[CH:16]=2)(=[O:11])=[O:10])[CH:7]=1
Reactant: CS(=O)(=O)Nc1cccc(CSc2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(CS(=O)c2ccc(Cl)cc2NS(=O)(=O)c2cc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of N-[5-chloro-2-({3-[(methylsulfonyl)amino]benzyl}sulfanyl)phenyl]-1-benzofuran-2-sulfonamide (124 mg, 0.237 mmol) in CH2Cl2 (5 ml) was added mCPBA (57 mg, ˜0.237 mmol) and the reaction was stirred at room temperature for 1 hour. The reaction mixture was directly loaded onto Celite and purified by flash column chromatography on silica gel (50-100% EtOAc in hexane) to yield the title compound (78 mg, 61%).