Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[OH:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[CH2:16]1>C(Cl)Cl.O>[CH3:1][S:2]([O:13][CH2:14][CH:15]1[C:19]2([CH2:21][CH2:20]2)[NH:18][C:17](=[O:22])[CH2:16]1)(=[O:4])=[O:3]
Reactant: O=C1CC(CO)C2(CC2)N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCC1CC(=O)NC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methanesulfonyl chloride (0.40 g, 1.0 mmol) and triethylamine (0.22 mL, 1.6 mmol) were added to a solution of 7-(hydroxymethyl)-4-azaspiro[2.4]heptan-5-one (0.11 g, 0.78 mmol) in DCM (4 mL) at 0° C. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate (10 mL×3). The organic layers were combined and concentrated under reduced pressure to afford the crude product residue. The crude product residue was purified by silica gel chromatography (neat ethyl acetate, Rf=0.6) to afford (5-oxo-4-azaspiro[2.4]hept-7-yl)methyl methanesulfonate. 1H NMR (400 MHz, CDCl3) δ 5.87 (br s, 1H), 4.35-4.01 (m, 2H), 2.95 (s, 3H), 2.87-2.54 (m, 2H), 2.41-2.35 (m, 1H), 1.05-0.72 (m, 4H).
Reaction SMILES: C([NH:8][C:9]1[C:10]([CH3:29])=[C:11]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[C:12]2[O:16][CH2:15][CH2:14][C:13]=2[C:17]=1[CH3:18])C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:26]([C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:11]2[C:12]3[O:16][CH2:15][CH2:14][C:13]=3[C:17]([CH3:18])=[C:9]([NH2:8])[C:10]=2[CH3:29])=[CH:21][CH:22]=1)([CH3:28])[CH3:27]
Reactant: Cc1c2c(c(Cc3ccc(C(C)C)cc3)c(C)c1NCc1ccccc1)OCC2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(N)c(C)c(Cc2ccc(C(C)C)cc2)c2c1CCO2
Yield: 92 %

Procedure:
Using N-benzyl-7-(4-isopropylbenzyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 271, the title compound was synthesized in the same manner as in Reference Example 30. Yield 92%. Melting point: 114-115° C. (ethyl acetate-hexane).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[N:26]=1>O1CCCC1>[CH3:23][O:22][C:20]([C:15]1[C:14]([C:11]2[CH:12]=[CH:13][C:8]([CH2:7][NH:6][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([C:35]([F:37])([F:38])[F:36])[N:26]=3)=[CH:9][CH:10]=2)=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:21]
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNc2nc(C(F)(F)F)nc3ccccc23)cc1
Reaction time: 72 h
Yield: 110.8 %

Procedure:
Sodium acetate (2.34 g), 4'-aminomethyl(1,1'-biphenyl)-2-carboxylic acid, methyl ester (1.99 g) and 1.66 g of 4-chloro-2-trifluoromethylquinazoline were added to 50 mL of tetrahydrofuran. The resulting suspension was stirred at 40°-50° C. for 72 hours. All the THF was removed by evaporation and the residue was partitioned between ethyl acetate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified on silica gel chromatography to yield. 3.46 g (40%) of the desired product (M.P.=135°-142° C.): 1H NMR (DMSO-d6, 400 MHz) δ9.43 (t, J=6 Hz, 1H), 8.41 (d, 7.9 Hz, 1H), 7.88 (m, 2H), 7.70 (m, 2H), 7.58 (m, 1H), 7.43 (m, 4H), 7.25 (m, 2H), 4.85 (d, J=5.9 Hz, 2H), 3.56 (s, 3H); positive FAB MS m/e 438 (MH). Anal Calcd for C24H18F3N3O2.0.5H2O: C, 64.57; H, 4.29; N, 9.41. Found: C, 64.83; H, 4.02; N, 9.48.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:7])[S:5][CH:6]=1.C([Li])CCC.[CH2:13]([Sn:17](Cl)([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:15][CH3:16].O>C1COCC1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:13][CH2:14][CH2:15][CH3:16])[N:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Cc1nc(Br)cs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1csc(C)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 111.8 %

Procedure:
To a solution of 4-bromo-2-methylthiazole (950 mg, 5.3 mmol) in absolute THF (40 mL) at −78° C. was added dropwise n-butyllithium (2.7 mL, 1.6 M in hexane). The solution was stirred at −78° C. for 1 h, then tributyltinchloride (2.2 g, 6.8 mmol) was added, and the mixture was allowed to warm to room temperature. Water (90 mL) was poured into the reaction mixture and the phases were separated. The aqueous layer was extracted with diethyl ether (4×30 mL). The combined organic phases were dried over magnesium sulfate and the solvent was removed in vacuo. The resulting oil was purified by fractionated Kugelrohr distillation to give the title compound (2.3 g). The product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[O:12][CH2:13][C@H:14]1[O:16][CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:43])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([CH2:39][C@H:40]([NH2:42])[CH3:41])=[CH:35][CH:34]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:42][CH:40]([CH3:41])[CH2:39][C:36]1[CH:37]=[CH:38][C:33]([O:32][CH2:31][C:30]([O:29][CH3:28])=[O:43])=[CH:34][CH:35]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(C[C@@H](C)N)cc1
Reactant: c1ccc(COc2ccc(OC[C@@H]3CO3)cc2OCc2ccccc2)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(O)COc2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)cc1

Procedure:
The title compound was prepared from (S)-3-(3,4-dibenzyloxyphenoxy)-1,2-epoxypropane and (R)-4-(2-aminopropyl)phenoxyacetic acid methyl ester according to the method described in Procedure 13.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(Cl)(=O)C(Cl)=O.Cl.[CH3:39][NH:40][O:41][CH3:42]>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[C:3]([OH:31])=[C:4]([S:9]([N:12]([CH2:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:40]([O:41][CH3:42])[CH3:39])=[O:28])=[CH:24][CH:23]=2)[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)(=[O:10])=[O:11])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(CN(Cc2ccc(F)cc2)S(=O)(=O)c2cc(Cl)cc(Cl)c2O)cc1
Temperature: 25 °C
Yield: 65.2 %

Procedure:
To a suspension of 4-((3,5-dichloro-N-(4-fluorobenzyl)-2-hydroxyphenylsulfonamido)methyl)benzoic acid (0.726 g, 1.5 mmol) in DCM (20 mL) at rt was added oxalyl chloride (0.394 mL, 4.50 mmol) and a few drops of DMF. The mixture was stirred at rt to give a yellow solution. The reaction mixture was concentrated and the residue was dissolved in DCM. At 0° C., a mixture of N,O-dimethylhydroxylamine hydrochloride (0.439 g, 4.50 mmol) and TEA (1.045 mL, 7.50 mmol) were added. The resulting mixture was stirred at rt for 1 h. The mixture was diluted with DCM and washed with water and brine. The organic extract was dried, concentrated and purified by flash column chromatography (ISCO system, eluting with DCM/EtOAc) to give the desired product (0.516 g, 62%) as a light yellow solid. MS (ESI): 527.1 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[CH3:21][C:22]1([CH3:32])[N:26]2[CH2:27][CH2:28][NH:29][CH2:30][CH:25]2[C:24](=[O:31])[NH:23]1.C(N(CC)CC)C>CN(C)C=O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:5][CH2:4][CH2:3][CH2:2][N:29]2[CH2:28][CH2:27][N:26]3[C:22]([CH3:32])([CH3:21])[NH:23][C:24](=[O:31])[CH:25]3[CH2:30]2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(C(=CCCCBr)c2ccc(F)cc2)cc1
Reactant: CC1(C)NC(=O)C2CNCCN21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)NC(=O)C2CN(CCCC=C(c3ccc(F)cc3)c3ccc(F)cc3)CCN21
Temperature: 70 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
A mixture of 51 parts of 1,1'-(5-bromo-1-penten-1-ylidene)bis[4-fluorobenzene], 25.4 parts of hexahydro-3,3-dimethylimidazo-[1,5-a]pyrazin-1(5H)-one, 35.5 parts of N,N-diethylethanamine and 270 parts of N,N-dimethylformamide was stirred overnight at 70° C. After evaporation, the residue was taken up in trichloromethane. The organic layer was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 60 parts (94.0%) of 7-[5,5-bis(4-fluorophenyl)-4-pentenyl]hexahydro-3,3-dimethylimidazo[1,5-a]pyrazin-1(5H)-one as a residue (int. 24).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[C:11](Cl)(=[O:17])[CH2:12][CH2:13][C:14](Cl)=[O:15]>>[C@H:2]1([NH:1][C:11](=[O:17])[CH2:12][CH2:13][C:14]([NH:1][C@H:2]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3]2)=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: O=C(Cl)CCC(=O)Cl
Product: O=C(CCC(=O)N[C@@H]1CCc2ccccc21)N[C@@H]1CCc2ccccc21

Procedure:
This was prepared by the same procedure as in Example 73 starting from (R)-1-aminoindan (8.02 g, 60 mmole) and succinoyl chloride (2.32 g, 14 mmole), to give the white product, (1.30 g, 26.7%). Melting point: 266-9° C.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:17][CH3:18])=[C:6]([CH:12]2[CH2:15][C:14](=[O:16])[CH2:13]2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:10][C:8]1[C:7]([CH3:11])=[C:6]([CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15]2)[C:5]([O:17][CH3:18])=[C:4]([CH:1]([OH:3])[CH3:2])[CH:9]=1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C1CC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Product: COc1c(C(C)O)cc(Cl)c(C)c1C1CC(O)C1

Procedure:
This compound was prepared according to the procedure of Example 13 step 5, using of 3-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)cyclobutanone and sodium tetrahydroborate as the starting materials. LCMS calculated for C14H19ClO3Na (M+Na)+: m/z=293.1; Found: 293.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:13][C@@H:14]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:15]([O:17]C)=O)[C:5]([CH2:11]Cl)=[C:6]2[C:10]=1[NH:9][N:8]=[CH:7]2.[CH3:24][O:25][CH2:26][CH2:27][NH2:28].COC(=O)C[C@H]1C(=O)N(CC2CC2)CC2C3C=NNC=3C(Br)=CC=2C1>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:14]1[C:15](=[O:17])[N:28]([CH2:27][CH2:26][O:25][CH3:24])[CH2:11][C:5]2[C:6]3[CH:7]=[N:8][NH:9][C:10]=3[C:2]([Br:1])=[CH:3][C:4]=2[CH2:13]1
Reactant: COC(=O)C[C@H](Cc1cc(Br)c2[nH]ncc2c1CCl)C(=O)OC
Reactant: COCCN
Agent: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]ncc3c2CN(CC2CC2)C1=O
Product: COCCN1Cc2c(cc(Br)c3[nH]ncc23)C[C@@H](CC(=O)OC)C1=O
Yield: 66 %

Procedure:
(S)-dimethyl 2-((7-bromo-4-(chloromethyl)-1H-indazol-5-yl)methyl)succinate (400 mg, 0.99 mmol) and 2-methoxyethylamine were reacted in a manner analogous to the preparation of ((S)-4-Bromo-9-cyclopropylmethyl-8-oxo-3,6,7,8,9,10-hexahydro-2,3,9-triaza-cyclohept[e]inden-7-yl)-acetic acid methyl ester. Title compound was obtained as tan solid in 66% yield. MS m/e (M−H)−=408.1, 410.0.
Reaction SMILES: [NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1.[F:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:23]([Cl:24])=[CH:22][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:32][C:31]3[CH:34]=[CH:35][C:28]([F:27])=[CH:29][CH:30]=3)[CH2:14][CH2:15]2)=[O:7])=[C:4]([O:25][CH3:26])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCN)CC1
Reactant: O=Cc1ccc(F)cc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc(F)cc2)CC1
Yield: 89.7 %

Procedure:
4-Amino-N-(1-(5-aminopentyl)piperidin-4-ylmethyl)-5-chloro-2-methoxybenzamide (2 g) as starting compound and 4-fluorobenzaldehyde (0.71 g) were reacted and treated in the same manner as in Example 121 to give 2.3 g of 4-amino-5-chloro-N-((1-(5-(4-fluorobenzylamino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(Cl)(=O)C(Cl)=O.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(N(CC)CC)C>CN(C=O)C.ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:27]1[CH:28]=[CH:29][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=1)=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reaction time: 1 h

Procedure:
A 200-mL round bottom flask was fitted with thermometer, magnetic stirrer, and reflux condenser with nitrogen bypass. The flask was charged with 0.94 g (4 mmol) of 2-chloro-4-(methylsulfonyl)benzoic acid, 2 drops of DMF, and 20 mL of dichloromethane. Oxalyl chloride (0.56 g, 4.4 mmol) was added dropwise and the mixture was stirred for 1 hr. A solution consisting of 0.62 g (4 mmol) of 4-nitrophenol, 0.44 g (4.4 mmol) of triethylamine and 5 mL of dichloromethane was added slowly. The mixture was stirred for 1 hr, diluted with 100 mL of dichloromethane, washed twice with 100 mL portions of dilute aqueous sodium bicarbonate, once with water, dried over magnesium sulfate, filtered, and volatiles removed under reduced pressure to give the title product as 1.30 g of off-white solid, m.p. 123-125° C. 1H NMR (CDCl3): δ 3.14 (s, 3), 7.48 (m, 2), 8.00 (m, 1), 8.14 (m, 1), 8.21 (m, 1), 8.36 (m, 2).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[O:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 110.9 %

Procedure:
(RS) 2-Aminomethyl-piperidine-1-carboxylic acid tert butyl ester (0.21 g) and 2-chlorobenzoxazole (0.153 g) and triethylamine (0.1 g) were combined in tetrahydrofuran (10 ml) and stirred at room temperature for 4 hours. The mixture was partitioned between ethyl acetate and water, the organic phase dried and solvent removed at reduced pressure to give the title compound (0.36 g) as an oil that solidified on standing.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2].[CH2:27]([N:30]([CH2:32][CH2:33][CH3:34])O)[CH2:28][CH3:29].[H-].[Na+]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:30]([CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]=2[CH:26]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: CCCN(O)CCC
Agent: [H-]
Agent: [Na+]
Product: CCCN(CCC)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 15, 8-nitro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]-benzodiazepine is treated with a cold mixture of N,N-dipropylhydroxylamine and sodium hydride in dimethylformimide to give 8-nitro-1-[(dipropylamino)methyl]-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine, N1 -oxide.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][N:6]1[CH2:11][C:10]2[CH:12]=[C:13](/[CH:16]=[CH:17]/[C:18](=[O:32])[N:19]([CH3:31])[CH2:20][C:21]3[N:22]([CH3:30])[C:23]4[C:28]([CH:29]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:14]=[N:15][C:9]=2[NH:8][C:7]1=[O:33])C.[OH-].[Na+]>CO>[CH3:31][N:19]([CH2:20][C:21]1[N:22]([CH3:30])[C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:18](/[CH:17]=[CH:16]/[C:13]1[CH:14]=[N:15][C:9]2[NH:8][C:7](=[O:33])[N:6]([CH2:5][C:4]([OH:34])=[O:3])[CH2:11][C:10]=2[CH:12]=1)=[O:32]
Reactant: CCOC(=O)CN1Cc2cc(/C=C/C(=O)N(C)Cc3cc4ccccc4n3C)cnc2NC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1cnc2c(c1)CN(CC(=O)O)C(=O)N2
Yield: 47.7 %

Procedure:
A suspension of (E)-(6-{2-[methyl-(1-methyl-1H-indol-2-ylmethyl)carbamoyl]vinyl}-2-oxo-1,4-dihydro-2H-pyrido[2,3-d]pyrimidin-3-yl)acetic acid ethyl ester (0.40 g, 0.87 mmol) in methanol (30 mL) was treated with 1N NaOH (10 mL, 10 mmol). The mixture was heated at reflux for 2 h. After cooling, the methanol was evaporated. The residue was diluted with H2O (15 mL) and neutralized to pH 6 with 2N HCl. The solid was collected by filtration, and triturated subsequently with a mixture CH3CN/H2O (9:1, v/v), diethyl ether, and methanol to give the title compound (180 mg, 48%) as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H), 10.09-10.06 (m, 1H), 8.39-8.36 (m, 1H), 8.01-7.92 (m, 1H), 7.57-7.39 (m, 3H), 7.26-6.69 (m, 3H), 6.42-6.18 (m, 1H), 5.04-4.85 (m, 2H), 4.53-4.48 (m, 2H), 4.05-4.01 (m, 2H), 3.72-3.68 (m, 3H), 3.11-2.99 (m, 3H); MS (ESI) m/e 434 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](CC(N)=O)(=[O:10])=[O:9].Cl[CH2:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([CH2:16][C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])=[O:18])(=[O:10])=[O:9]
Reactant: NC(=O)CS(=O)(=O)c1ccccc1Br
Reactant: CCN(CC)C(=O)CCl
Product: CCN(CC)C(=O)CS(=O)(=O)c1ccccc1Br

Procedure:
The title compound was prepared in a manner similar to that described for 2-((2-bromophenyl)sulfonyl)acetamide using 2-chloro-N,N-diethylacetamide in Step A. 1H NMR (600 MHz, DMSO-d6) δ 8.01-7.97 (m, 1H), 7.91-7.87 (m, 1H), 7.66-7.60 (m, 2H), 4.75 (s, 2H), 3.47-3.39 (q, J=7.1, 2H), 3.25-3.14 (q, J=7.0, 2H), 1.18-1.09 (t, J=7.1, 3H), 0.99-0.87 (t, J=7.0, 3H).
Reaction SMILES: O1CCCCC1[O:7][CH:8]1[C:16]2[CH:15]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[OH:7][CH:8]1[C:16]2[CH:15]=[C:14]([S:17]([NH2:20])(=[O:19])=[O:18])[S:13][C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: NS(=O)(=O)c1cc2c(s1)CCCC2OC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(s1)CCCC2O
Temperature: 55 °C
Reaction time: 3 h
Yield: 0.3 %

Procedure:
To a solution of thoroughly dried product from Step C (5.9 g, 0.98 mol) in 140 ml absolute ethanol (warming necessary to promote solubility) was added 467 mg (0.0018 mol) pyridinium 4-toluenesulfonate (PPTS). After stirring under N2 at 55° C. for 3 hours, no reaction was detected by TLC. The solvent was removed under reduced pressure. Then, 125 ml absolute ethanol was added and PPTS was added until pH 3 was achieved. After 4 hours under N2 at 55° C. the solvent was removed under reduced pressure. The residue was chromatographed on silica gel first with 85:15 CHCl3 :CH3OH (v:v) and a second time with 90:10 CHCl3 :CH3OH (v:v) saturated with NH3. The product was recrystallized from H2O after decolorizing with charcoal, yielding 700 mg (17%) of product mp 102°-103° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH:9]=[C:10]([CH3:12])[NH2:11])=[CH:4][CH:3]=1.BrC1C=CC([C:21](=O)[CH2:22][C:23](=[O:25])C)=CC=1.[OH-].[NH4+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:9]2[CH:21]=[CH:22][C:23](=[O:25])[NH:11][C:10]=2[CH3:12])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(N)=CC(=O)c1ccc(Br)cc1
Reactant: CC(=O)CC(=O)c1ccc(Br)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(=O)ccc1C(=O)c1ccc(Br)cc1
Reaction time: 8 h

Procedure:
The intermediate 3-(4-bromophenyl)-1-methyl-3-oxo-1-propenamine, m.p. 126°-128° C., 56.8 g, was prepared following the procedure described in Example A-2 using 83 g of 1-(4-bromophenyl)-1,3-butanedione, 750 ml of methanol and 100 ml of concentrated aqueous ammonium hydroxide solution. The solid residue after stripping the reaction mixture to dryness on a rotary evaporator was treated with 500 ml of boiling n-hexane, the mixture allowed to stand at room temperature overnight, and, the product collected and dried at room temperature.
Reaction SMILES: CSC.B.O=[C:6]1[CH2:11][S:10](=[O:13])(=[O:12])[C:9]2[S:14][C:15]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:16][C:8]=2[NH:7]1>C1COCC1>[O:13]=[S:10]1(=[O:12])[CH2:11][CH2:6][NH:7][C:8]2[CH:16]=[C:15]([S:17](=[O:19])(=[O:20])[NH2:18])[S:14][C:9]1=2
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CC(=O)N2
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCN2
Temperature: 25 °C
Yield: 15.1 %

Procedure:
Borane dimethylsulfide in THF (4.4 ml, 10M, 44 mmol) was added slowly to a solution of 2,3-dihydro-2,4,4-trioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine (2.5 g, 8.9 mmol) in THF (10 ml) at 0° C. The reaction mixture was warmed to ambient temperature and stirred for an addidition hour. Excess borane was destroyed by the addition of 6N HCl and borane adducts were cleaved by heating at reflux for one hr. The solvent was removed and the residue was partitioned between water and ethyl acetate. The organic phase was washed with water and brine then dried over sodium sulfate. After filtration and evaporation of the solvent, the residue was chromatographed over silica gel with CHCl3 /MeOH/NH4OH (80:20:2). Fractions containing the desired product were combined, evaporated and the solid residue was triturated with ethyl acetate to yield 0.36 g 2,3-dihydro-4,4-dioxo-6-sulfamoyl-1H-thieno[2,3-b][1,4]thiazine, mp 250°-252° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[CH:6][CH:5]=[C:4]([CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20].Cl.[OH-].[Na+]>>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C:8]([C:7]1[C:2]([NH:21][CH2:19][CH3:20])=[N:3][C:4]([CH2:17][CH3:18])=[CH:5][CH:6]=1)=[O:16]
Reactant: CCN
Reactant: CCc1ccc(C(=O)c2cccc(Cl)c2)c(Cl)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(CC)ccc1C(=O)c1cccc(Cl)c1
Temperature: 100 °C
Reaction time: 4 h
Yield: 76 %

Procedure:
A mixture of 2-chloro-3-(3-chlorobenzoyl)-6-ethylpyridine (3.4 g, 12 mmol) and 70% ethylamine aqueous solution (15 ml) was sealed in a tube and stirred at 100° C. for 4 hours. The reaction solution was cooled to room temperature and then transferred into a separating funnel. This was acidified by adding 1 N hydrochloric acid, vigorously shaken and then alkalified by adding 1 N sodium hydroxide aqueous solution. This was extracted with chloroform, the resulting organic layer was dried over anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and then the filtrate was concentrated under a reduced pressure. Thereafter, the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give 3-(3-chlorobenzoyl)-6-ethyl-2-ethylaminopyridine (2.6 g, 76%) as a yellow oily material.