Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21](OC)OC.[OH:26][CH:27]([CH:29]([OH:31])[CH3:30])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:16])([F:18])[F:17])[N:10]([CH3:19])[C:9]2=[O:20])=[CH:4][C:3]=1[CH:21]1[O:31][CH:29]([CH3:30])[CH:27]([CH3:28])[O:26]1
Reactant: CC(O)C(C)O
Reactant: COC(OC)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1OC(c2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)ccc2Cl)OC1C

Procedure:
30 g of 3-(4-chloro-3-dimethoxymethylphenyl)-2,4-dioxo-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine, 2.1 g of 2,3-dihydroxybutane and 0.3 g of p-toluenesulfonic acid were dissolved in 100 ml of anhydrous toluene, and the stirred solution was refluxed for 7 hours in the absence of water. For working up, the solution was washed in succession with water and 10% strength NaHCO3 solution, dried over Na2SO4 and evaporated down.
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([NH:15][OH:16])=[NH:14])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([Cl:24])=O>>[ClH:24].[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]2[N:14]=[C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[C:19]([C:18]([F:17])([F:28])[F:29])[CH:20]=3)[O:16][N:15]=2)[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCC(CC(=N)NO)CC1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: CCC(CC)N1CCC(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 12, starting from 2-((1-ethylpropyl)piperidin-4-yl)-N-hydroxyacetamidine and 3-trifluoromethylbenzoyl chloride.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([OH:18])=O)[CH:9]=[CH:10][C:11]=1[F:12]>C1(C)C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]([C@@H:13]2[CH2:15][C@H:14]2[C:16]([Cl:3])=[O:18])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)[C@@H]1C[C@H]1c1ccc(F)c(F)c1
Temperature: 35 °C
Reaction time: 6 h

Procedure:
Thionyl chloride (72.65 g, 1.21 molar equivalents) was added to the stirred toluene solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxylic acid (18 wt %, net 100.00 g, 504.62 mmol). The mixture was stirred at 35° C. for 6 hours, then concentrated under reduced pressure to give a solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarbonyl chloride. To a mixture of 28% ammonia aqueous solution (122.55 g, 4.00 molar equivalents), water (300.4 g) and ethyl acetate (700.2 g), the solution of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarbonyl chloride obtained above was gradually added with stirring below 10° C. The reaction mixture was allowed to stir below 10° C. for 1 hour. The mixture was neutralized with 35% hydrochloric acid, then the organic layer was separated and washed with water. The resultant solution was concentrated azeotropically under reduced pressure to give a slurry of (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxamide. The resultant slurry was heated to obtain a clear solution, and cooled for crystallization. Hexane was added to the slurry, then the precipitates were collected by filtration and dried to give (1R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxamide (net 91.12 g, Yield: 92%).
Reaction SMILES: CN1CCOCC1.[CH2:8]([O:15][C:16]([NH:18][C:19]([CH3:37])([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][N:31]=2)=[CH:26][CH:25]=1)[C:20]([OH:22])=O)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.C(OCC)(=O)C>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][C:19]([NH:18][C:16](=[O:17])[O:15][CH2:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([CH3:37])[C:20]([NH:38][CH2:39][CH:40]([OH:47])[CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][CH3:44])=[O:22])=[CH:29][CH:28]=2)=[N:31][CH:32]=1
Reactant: CCC(C)(C)CC(O)CN
Reactant: CC(Cc1ccc(-c2ccc(F)cn2)cc1)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C(C)(Cc1ccc(-c2ccc(F)cn2)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-methylmorpholine (186 mg, 1.84 mmol) was added to an ambient temperature solution of 2-{[(benzyloxy)carbonyl]amino}-3-[4-(5-fluoropyridin-2-yl)phenyl]-2-methylpropanoic acid (150 mg, 0.37 mmol), 1-amino-4,4-dimethylhexan-2-ol (214 mg, 1.48 mmol), 1-[3-(dimethylamino) propyl]-3-ethylcarbodiimide hydrochloride (84 mg, 0.44 mmol), and 1-hydroxybenzotriazole (67 mg, 0.44 mmol) in methylene chloride (5 mL). After stirring at ambient temperature overnight, the reaction mixture was poured into ethyl acetate and washed successively with saturated aqueous sodium bicarbonate and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 40-80% ethyl acetate/hexane afforded benzyl {1-[4-(5-fluoropyridin-2-yl)benzyl]-2-[(2-hydroxy-4,4-dimethylhexyl)amino]-1-methyl-2-oxoethyl}carbamate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N+:9]([O-])=O.[CH3:12][C:13]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:14]=1N>[Ni]>[CH3:12][C:6]1[CH:7]=[C:2]([CH3:1])[C:3]([NH2:9])=[C:4]([CH3:8])[CH:5]=1.[C:18]1([CH3:1])[CH:19]=[C:13]([CH3:12])[CH:14]=[C:16]([CH3:20])[CH:17]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1cccc(C)c1[N+](=O)[O-]
Agent: [Ni]
Product: Cc1cc(C)c(N)c(C)c1
Product: Cc1cc(C)cc(C)c1

Procedure:
The 2,6-dimethylnitrobenzene is reduced to the amine, i.e., 2,6-dimethylaniline in the presence of a Raney nickel catalyst at a temperature of 25° C. and a pressure of 70 atmospheres: ##STR5## Mesidine (2,4,6-trimethylaniline) can be obtained in a similar manner by nitration of mesitylene followed by reduction. The aromatic amine is then reduced to an aliphatic amine with hydrogen in the presence of a hydrogenation catalyst such as Rh/Al2O3 in the range of 150 atmospheres and a temperature range of 90°-100° C., thusly: ##STR6## The thus formed 2,6-dimethylcyclohexylamine is then phosgenated to 2,6-dimethylcyclohexylisocyanate in the presence of chlorobenzene or dichlorobenzene solvent using excess phosgene and a two-stage temperature reaction wherein the first stage is carried out at -20° to 20° C. and the second from 110° to 180° C. while maintaining the reaction at a pressure in the range of 1 to 15 atmospheres: ##STR7##
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:21]2[CH2:26][CH2:25][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)(=[O:29])=[O:28])[CH2:23][CH2:22]2)[CH:6]=[CH:7][CH:8]=1)=O.[NH:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.[BH4-].[Na+]>C(Cl)Cl.CO.CC(O)=O>[N:38]1([CH2:1][C:3]2[CH:4]=[C:5]([C:9]3[CH:10]=[C:11]4[C:15](=[C:16]([C:18]([NH2:20])=[O:19])[CH:17]=3)[NH:14][CH:13]=[C:12]4[CH:21]3[CH2:22][CH2:23][N:24]([S:27]([CH2:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:28])=[O:29])[CH2:25][CH2:26]3)[CH:6]=[CH:7][CH:8]=2)[CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: C1CCNC1
Reactant: NC(=O)c1cc(-c2cccc(C=O)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: NC(=O)c1cc(-c2cccc(CN3CCCC3)c2)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)c[nH]c12
Reaction time: 2 h
Yield: 8.1 %

Procedure:
To a solution of 5-(3-formylphenyl)-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indole-7-carboxamide (45.0 mg/0.086 mmol) in DCM/MeOH (1.0 ml/1.0 ml) was added pyrrolidine (0.043 mL, 0.517 mmol) and 1 drop of AcOH. The reaction mixture was stirred for 2 hr at r.t and then NaBH4 (17.0 mg, 0.086 mmol) was added. The reaction mixture was stirred for 30 min and concentrated and redissolved in 1.5 ml of DMSO. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (4 mg, 8%).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)=[N+:2]=[N-:3].C1C=CC2N(O)N=NC=2C=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:30][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:10])=[CH:11][CH:12]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1ccc(C(=O)O)cc1
Reactant: NCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Azidobenzoic acid (858 mg, 5.15 mmol), HOBt (704 mg, 5.15 mmol, 1.0 eq.) and benzylamine (0.745 ml, 6.70 mmol, 1.3 eq.) were dissolved in acetonitrile (6 ml) and DMF (6 ml), WSC (1.21 g, 6.19 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated, dissolved in ethyl acetate (50 ml), washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated at 30° C. or below to give the title compound as a pale-yellow solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[S:12][C:13]=1[CH2:14]O.C(N(S(F)(F)[F:32])CC)C.O>C1(C)C=CC=CC=1>[F:32][CH2:14][C:13]1[S:12][C:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[N:10][C:9]=1[CH2:8][O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1
Reactant: CCN(CC)S(F)(F)F
Reactant: OCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: FCc1sc(-c2cccc(C(F)(F)F)c2)nc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
Under a nitrogen atmosphere at 0° C., to a solution (7 mL) of the compound (500 mg, 1.3 mmol) obtained in Example 89c in toluene was added diethylaminosulfur trifluoride (DAST) (650 mg, 4.0 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (hexane-hexane/ethyl acetate=50/50) to give the title compound (350 mg, 70%) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[S:21]([C:25]1[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=1[NH2:27])(=[O:24])(=[O:23])[NH2:22]>C(O)(=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:27][C:26]3[CH:28]=[CH:29][CH:30]=[CH:31][C:25]=3[S:21](=[O:24])(=[O:23])[NH2:22])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccccc1NC(=O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 17.2 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (340 mg, 1 mmol) and o-sulfamoylaniline (180 mg, 1.05 mmol) to give 85 mg of the title compound (17%) after silica gel column chromatography of the crude product with 1% acetic acid/ethyl acetate as an eluent: mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.06 (bs, 1H), 9.36 (s, 1H), 8.01 (d, 1H, J=8.1 Hz), 7.85 (d, 2H, J=8.1 Hz), 7.60 (t, 1H, J=8.1 Hz), 7.58 (s, 2H), 7.32 (t, 1H, J=8.1 Hz), 7.23 (d, 1H, J=2 Hz), 7.16 (d, 1H, J=2 Hz), 5.17~5.27 (m, 1H), 3.07 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.82 (dm, 1H, J=17.1 Hz), 2.71~2.76 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.78~1.96 (m, 1H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[C:13]1([CH3:23])[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][NH2:22])=[O:20])[CH:14]=1>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=[N:22][NH:21][C:19](=[O:20])[C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH3:23])[CH:14]=1
Reactant: O=Cc1ccc2ccccc2n1
Reactant: Cc1cccc(C(=O)NN)c1
Solvent: CCO
Product: Cc1cccc(C(=O)NN=Cc2ccc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 36.2 %

Procedure:
A mixture of 3.3 gm (0.021 mole) of 2-quinolinecarboxaldehyde, 3.15 gm (0.021 mole) of m-toluic acid hydrazide and 150 ml of absolute ethanol is refluzed 10 hr. The hot solution is filtered then diluted with water until cloudy. The mixture is cooled to room temperature and then chilled. The solid is collected to give 2.2 gm (36%) of the title compound having a melting point of 187.5°-188° C. after recrystallizing from methylene chloride/diethyl ether.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12].C([NH2:22])C1C=CC=CC=1>>[NH2:22][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[S:11]([NH2:14])(=[O:13])=[O:12]
Reactant: NS(=O)(=O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: NCc1ccccc1
Product: Nc1ccc(N)c(S(N)(=O)=O)c1

Procedure:
The 2-chloro-5-nitro-benzenesulfonamide intermediate (prepared as described in schemes 11 and 12) can be treated with a benzylic amine, such as benzyl amine, to displace the chloro moiety. Hydrogenation under standard conditions can be used to remove the benzylic group and to reduce the nitro group at the same time to afford the desired 2,5-diamino-benzenesulfonamide intermediate.
Reaction SMILES: O[O:2][S:3]([O-:5])=O.[K+].[OH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1SC.[CH2:29]1COCC1.CO>O>[OH:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[C:17](=[O:28])/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[S:3]([CH3:29])(=[O:5])=[O:2]
Reactant: C1CCOC1
Reactant: O=S([O-])OO
Reactant: CSc1ccccc1/C=C/C(=O)c1cccc([N+](=O)[O-])c1O
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)(=O)c1ccccc1/C=C/C(=O)c1cccc([N+](=O)[O-])c1O
Reaction time: 12 h
Yield: 58 %

Procedure:
A solution of OXONE (3.7 g, 6 mmol) in H2O (15 ml) was added drop wise to a solution of (E)-1-(2-hydroxy-3-nitrophenyl)-3-(2-(methylthio)phenyl)prop-2-en-1-one 15 (315 mg, 1.0 mmol) in THF/MeOH (35 mL, 1:1) at room temperature. The reaction mixture was stirred for 12 h. The volatiles were removed under reduced pressure and the resulting precipitate was collected by filtration, rinsed with H2O and dried under vacuum. The crude residue was purified by flash chromatography eluting with CH2Cl2/MeOH (0-1%) to give 16 as a yellow solid (200 mg, yield 58%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16](=[O:24])[NH:17][CH2:18][CH:19]([CH2:22][OH:23])[CH2:20][CH3:21])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl>[CH:22]([CH:19]([CH2:20][CH3:21])[CH2:18][NH:17][C:16](=[O:24])[O:15][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:23]
Reactant: CCC(CO)CNC(=O)OC(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C=O)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 67.9 %

Procedure:
Oxalyl chloride (141 μL) was dissolved in methylene chloride (1 mL). To the solution, a solution of dimethyl sulfoxide (176 μL) in methylene chloride (1 mL) was added dropwise at −78° C., and the mixture was stirred for 15 minutes. A solution of the compound (168 mg) obtained in Step 5 in methylene chloride (2 mL) was added dropwise thereto at −78° C., and the mixture was stirred for 2 hours. Triethylamine (695 μL) was added thereto, and the mixture was heated to 0° C. and then stirred overnight. To the reaction solution, methylene chloride was added, and the organic layer was washed with water and saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=9/1-7/3) to obtain the title compound (113 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]([CH:12]1[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8].Br[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30]>CN(C=O)C.O>[CH2:7]([O:9][C:10]([C:12]1([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:18](=[O:19])[CH2:17][CH2:16][N:15]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:14][CH2:13]1)=[O:11])[CH3:8]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
6.7 g potassium carbonate was added to 7 g 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 50 mL DMF and stirred at RT. After 30 min 6.1 g ethyl bromoacetate was added and the reaction was stirred at RT over night. The reaction was diluted with water and extracted with ethyl acetate/hexane (1/1). The organic phase was washed with brine, dried and concentrated. The residue was purified by column chromatography on silica gel (15% ethyl acetate in hexane) to give 5.6 g of the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH3:13][S:14](Cl)(=[O:16])=[O:15]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:14]([CH3:13])(=[O:16])=[O:15])[CH:9]=[CH:10][C:3]=12
Reactant: Brc1ccnc2[nH]ccc12
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)n1ccc2c(Br)ccnc21
Reaction time: 0.25 h

Procedure:
4-Bromo-1H-pyrrolo[2,3-b]pyridine (250 mg, 1.27 mmol) was dissolved in 5 ml N—N, dimethylformamide. Sodium hydride was slowly added and the mixture was stirred for 15 minutes. Methanesulfonyl chloride (66 μl, 0.85 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction was extracted with ethyl acetate and washed with water. The organic phase was dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue (200 mg) was used in the next synthetic step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1.[CH3:23][N:24]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[CH2:25][CH2:26][NH:27][CH3:28].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:27]([CH3:28])[CH2:26][CH2:25][N:24]([CH3:23])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:22])[C:5]([C:19]([OH:21])=[O:20])=[CH:6][N:7]2[CH:16]1[CH2:18][CH2:17]1
Reactant: CNCCN(C)c1ccccn1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1c(N(C)CCN(C)c2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 100 °C
Reaction time: 3 h
Yield: 73.2 %

Procedure:
A mixture of 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (400 mg, 1.44 mmol), N,N′-dimethyl-N-(2-pyridyl)-1,2-ethanediamine (355 mg, 2.15 mmol) and triethylamine (0.300 mL, 2.15 mmol) in anhydrous DMSO (6 mL) was stirred at 100° C. for 3 h. Triethylamine (0.300 mL, 2.15 mmol) was added and the mixture was stirred at 100° C. for 3 h. After cooling, the reaction mixture was poured into ice-water (50 mL). The resulting precipitate was collected by filtration, washed with water and dried to give 5-Amino-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-7-[methyl[2-[methyl(2-pyridyl)amino]ethyl]amino]-4-oxoquinoline-3-carboxylic acid (480 mg, 73%) as a brown solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][C@H:5]1[C:17]2[C:16]3[C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:21][CH2:20]4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)#[N:2].[OH:33][Li].O.OO>CO>[C:1]([CH2:3][CH2:4][C@H:5]1[C:17]2[C:16]3[C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])[CH2:21][CH2:20]4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=[O:33])[NH2:2]
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC#N)CCC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCC(N)=O)CCC4)CC1
Temperature: 30 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-(2-cyanoethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (300 mg, 0.66 mmol, 1.00 equiv) in methanol (15 mL) was added LiOH.H2O (82 mg, 1.95 mmol, 3.00 equiv) and H2O2 (30%, 0.5 mL) at 0° C. and the resulting solution was stirred for 2 h at 30° C. The reaction was quenched with saturated aqueous sodium sulfite, extracted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1) to give 240 mg (77%) of tert-butyl N-(4-[[(13S)-13-(2-carbamoylethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>O1CCCC1.CO>[CH3:19][N:20]([CH3:22])[CH:21]=[N:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][C:10]3[N:12]=[CH:13][CH:14]=[N:15][C:9]=3[NH:8][C:7]=2[CH:16]=1
Reactant: NCc1ccc2c(c1)Nc1nccnc1S2
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C=NCc1ccc2c(c1)Nc1nccnc1S2
Temperature: 40 °C
Yield: 80.7 %

Procedure:
400 mg of 8-(aminomethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine was dissolved in tetrahydrofuran (5 ml)/methanol (5 ml). After adding 250 mg of N,N-dimethylformamide dimethyl acetal, the resulting mixture was heated to 40° C. for 1.5 hours. After distilling off the solvent under reduced pressure, the crystals thus precipitated were taken up by filtration and washed successively with diethyl ether and diisopropyl ether. Thus 400 mg of the title compound was obtained as yellow crystals.