Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:10]1[NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[NH:14][C:15](=[O:16])[CH:9]1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Reactant: CCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 6 h

Procedure:
Add valeryl chloride (3.92 mL, 33.0 mmol) dropwise to a solution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (5.74 g, 30.0 mmol) and triethylamine (4.60 mL, 33.0 mmol) in anhydrous dimethylformamide (123 mL) and stir. After 6 hours, concentrate under reduced pressure to a residue and reconstitute the residue in a solution of isopropanol: chloroform (1:3, 500 mL). Stir overnight to give a solid and isolate the solid by suction filtration, washing the solid with dichloromethane. Vacuum dry the solid at ambient temperature 2 hours to afford the title compound. Wash the filtrate with a saturated aqueous solution of sodium bicarbonate (2×200 mL), and filter the extraction mixture to remove salt formed in the wash. Separate the organic phase and wash it with saturated aqueous sodium chloride (150 mL). Back extract the bicarbonate aqueous phase with dichloromethane. Combine all organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Triturate the residue in diethyl ether, filter the resulting solid, and wash it with diethyl ether; repeat 2×. Dry the solid at ambient temperature under vacuum to give the title compound: mass spectrum (APCI, m/e): 276 (M+1); NMR (1H, 300 MHz, DMSO-d): δ 10.68 (s, 2H), 8.23 (d, 1H, J=7.5 Hz), 7.20 (m, 4H), 4.71 (d, 1H, J=7.5 Hz), 2.25 (t, 2H, J=7.5 Hz), 1.43 (m, 2H), 1.25 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]1[C@@H:11]([NH:12]C([C@@H](O)CCN)=O)[C@H:10]([OH:20])[C@@H:9]([O:21][C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[C@H:23]2[OH:30])[C@H:8]([O:31][C@H:32]2[O:37][C@H:36]([CH2:38][NH2:39])[C@@H:35]([OH:40])[C@H:34]([OH:41])[C@H:33]2[NH2:42])[C@H:7]1[NH2:43]>[OH-].[Ba+2].[OH-]>[CH2:6]1[C@H:7]([NH2:43])[C@@H:8]([O:31][C@H:32]2[O:37][C@H:36]([CH2:38][NH2:39])[C@@H:35]([OH:40])[C@H:34]([OH:41])[C@H:33]2[NH2:42])[C@H:9]([O:21][C@@H:22]2[O:26][C@H:25]([CH2:27][OH:28])[C@H:24]([OH:29])[C@H:23]2[OH:30])[C@@H:10]([OH:20])[C@@H:11]1[NH2:12]
Reactant: NCC[C@H](O)C(=O)N[C@@H]1C[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@H](O)[C@H]2O)[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Ba+2]
Agent: [OH-]
Product: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O

Procedure:
In 250 parts by volume of an 0.5N aqueous solution of barium hydroxide is dissolved 5.0 parts of butirosin A. The solution is refluxed for 2 hours and then cooled. The solution is neutralized with 1 N sulfuric acid. The resulting precipitate of barium sulfate is removed off by centrifuge. The supernatant fluid is run onto a colume of 300 parts by volume of cation exchange resin (Amberlite CG-50(NH4 +-form) (Rohm and Haas Co.)). The colume is washed with water and eluted with 0.2 N aqueous ammonia. Fractions containing xylostasin which is detected by thin layer chromatography are pooled and concentrated under reduced pressure to dryness and lyophilized, whereby 3.8 parts of xylostasin as white powders are obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH3:10])=[C:8]([CH3:11])[S:7][C:6]1=[NH:12].CCN(CC)CC.[Br:20][C:21]1[CH:29]=[C:28]([C:30](Cl)=[O:31])[C:24]2[O:25][CH2:26][CH2:27][C:23]=2[CH:22]=1>C1COCC1>[Br:20][C:21]1[CH:29]=[C:28]([C:30](/[N:12]=[C:6]2\[S:7][C:8]([CH3:11])=[C:9]([CH3:10])[N:5]\2[CH2:4][CH2:3][O:2][CH3:1])=[O:31])[C:24]2[O:25][CH2:26][CH2:27][C:23]=2[CH:22]=1
Reactant: O=C(Cl)c1cc(Br)cc2c1OCC2
Reactant: COCCn1c(C)c(C)sc1=N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCn1c(C)c(C)s/c1=N\C(=O)c1cc(Br)cc2c1OCC2
Yield: 35.5 %

Procedure:
The product of Example 126A (0.20 g, 1.1 mmol), Et3N (0.45 mL, 3.2 mmol) and 5-bromo-2,3-dihydrobenzo[b]-furan-7-carbonyl chloride (Maybridge, 0.42 g, 1.6 mmol) in 35 mL THF were processed as in Example 126B. The resulting crude material was purified via flash column chromatography (SiO2, 7:3 hexanes:EtOAc) to afford the title compound (0.16 g, 0.39 mmol, 36% yield). 1H NMR (300 MHz, CDCl3) δ ppm 2.24 (s, 3H), 2.28 (s, 3H), 3.23 (t, J=8.5 Hz, 2H), 3.33 (s, 3H), 3.78-3.87 (m, 2H), 4.45-4.56 (m, 2H), 4.70-4.81 (m, 2H), 7.35-7.39 (m, 1H), 8.09 (d, J=20 Hz, 1H); MS (DCI/NH3) m/z 411, 413 (M+H)+; Anal. calculated for C17H19BrN2O3S.0.3H2O: C, 49.00; H, 4.74; N, 6.72. Found: C, 48.91; H, 4.36; N, 6.57.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH2:18]([C@H:20]1[N:29]([CH:30]([CH3:32])[CH3:31])[C:28]2[N:27]=[C:26]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([C:43](O)=[O:44])=[C:38]4[C:42]=3[O:41][CH2:40][CH2:39]4)[N:25]=[CH:24][C:23]=2[N:22]([CH3:46])[C:21]1=[O:47])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:43]([C:37]4[CH:36]=[CH:35][C:34]([NH:33][C:26]5[N:25]=[CH:24][C:23]6[N:22]([CH3:46])[C:21](=[O:47])[C@@H:20]([CH2:18][CH3:19])[N:29]([CH:30]([CH3:31])[CH3:32])[C:28]=6[N:27]=5)=[C:42]5[O:41][CH2:40][CH2:39][C:38]=45)=[O:44])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), 7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 22f (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 40 mL of dichloromethane. The reaction mixture was stirred for 2 hours. The resulting solution was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7R)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 44 (576 mg, yield: 38.0%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=S)[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4].IC.[N+:30]([CH3:33])([O-:32])=[O:31].[H-].[Na+]>O1CCCC1>[F:1][C:2]([F:27])([C:7]1[CH:8]=[CH:9][C:10]2[O:15][C:14]([CH2:18][F:19])([CH2:16][F:17])[CH:13]=[C:12]([N:20]3[CH2:24][CH2:23][CH2:22][C:21]3=[CH:33][N+:30]([O-:32])=[O:31])[C:11]=2[CH:26]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: FCC1(CF)C=C(N2CCCC2=S)c2cc(C(F)(F)C(F)(F)F)ccc2O1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: O=[N+]([O-])C=C1CCCN1C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)F)cc21
Temperature: 0 °C
Yield: 11.7 %

Procedure:
To a mixture of 0.16 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-thioxo-1-pyrrolidinyl)-2H-1-benzopyran, 0.78 g of iodomethane, 0.41 g of nitromethane and 6 ml of tetrahydrofuran was added 0.10 g of sodium hydride (60%) at room temperature with stirring. The mixture was refluxed with heating for 2 hours. After addition of ice water, the mixture was extracted with methylene chloride. The organic layer was washed with water and dried. The solvent was distilled off and the resultant residue was purified using silica gel column chromatography (developing solution, MeOH:CH2Cl2 =1:99) to obtain 0.02 g of 6-pentafluoroethyl-2,2-bisfluoromethyl-4-(2-nitromethylene-1-pyrrolidinyl)-2H-1-benzopyran represented by the following formula having a melting point of 195-197° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:8][CH:7]=1.[OH-].[Na+].CCOCC>O>[C:24]([O:23][C:21]([NH:20][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH3:19])=[CH:10][CH:11]=1)[C:3]([OH:28])=[O:2])=[O:22])([CH3:26])([CH3:27])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccccc1-c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
A solution of (S)-N-t-butoxycarbonylamino-3-(2'-methoxybiphenyl-4-yl)-propionic acid methyl ester (4.1 g in methanolic 1N sodium hydroxide (60 mL) is stirred at room temperature for 3 hours. Ether (30 mL) and water (30 mL) are added. The aqueous layer is separated and acidified with concentrated HCl, then extracted with ether (2×20 mL) and dried over anhydrous sodium sulfate. Evaporation of the solvent under reduced pressure gives (S)-N-t-butoxycarbonylamino-3-(2'-methoxybiphenyl-4-yl)-propionic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].O.[OH-].[Na+].[CH3:15][C:16]([CH3:18])=[O:17]>>[N+:1]([C:4]1[CH:5]=[C:6](/[CH:7]=[CH:15]/[C:16](=[O:17])[CH3:18])[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(C)=O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1cccc([N+](=O)[O-])c1
Yield: 78 %

Procedure:
The mixture of 3-nitrobenzaldehyde (15.1 g, 0.1 mol), acetone (20 mL) and water (40 mL) was slowly added 5% aqueous NaOH (8 mL) from a dropping funnel at 40° C. After the reactant disappeared in TLC monitoring, acetone was removed under reduced pressure. The residue was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated to give the (E)-4-(3-nitrophenyl)but-3-en-2-one (15 g, 78% yield) as a yellow oil. 1H NMR: (400 MHz, CDCl3) δ 8.31 (t, 1H), 8.15 (t, 1H), 7.83 (d, 1H), 7.52 (t, 1H), 7.44 (d, 1H), 6.70 (d, 1H), 2.33 (s, 3H).
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[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22][CH:23]2[CH:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][CH:25]([CH3:32])[CH2:24]2)=[O:21])=[CH:15][CH:14]=1.Br[CH:34]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CC(C)([O-])C.[K+].O>CN(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[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]([CH:34]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[C:20]([O:22][CH:23]2[CH:28]([CH:29]([CH3:31])[CH3:30])[CH2:27][CH2:26][CH:25]([CH3:32])[CH2:24]2)=[O:21])=[CH:15][CH:14]=1
Reactant: BrC1CCCCCC1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cc2ccc(OCc3ccc4ccccc4n3)cc2)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1CCC(C(C)C)C(OC(=O)[C@@H](c2ccc(OCc3ccc4ccccc4n3)cc2)C2CCCCCC2)C1
Reaction time: 4 h

Procedure:
1.3 kg of the compound from Example 6 are stirred with exclusion of moisture at -5° C. to +5° C. with 580 g of bromocycloheptane in 2.4 l of DMF. During the course of about 2 hours, a solution of 400 g of potassium tert-butoxide in 1.6 l of DMF is added. The mixture is stirred for a further 4 hours between -20° C. and -10° C. and 7.5 l of water are then added, during the course of which the title compound precipitates as a crude product. The crude product is centrifuged off, dried at 50° C. in vacuo and recrystallised twice using 6 l of ligroin; the solution is filtered hot in the first recrystallisation.
Reaction SMILES: [CH2:1]([C@H:4]1[C@:9]([C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=2[F:20])([CH3:10])[N:8]=[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:6]([CH3:37])([CH3:36])[S:5]1(=[O:39])=[O:38])[CH:2]=[CH2:3].[CH3:40][Si]([N-][Si](C)(C)C)(C)C.[K+].IC>C1COCC1>[CH2:1]([C:4]1([CH3:40])[S:5](=[O:38])(=[O:39])[C:6]([CH3:37])([CH3:36])[C:7]([N:21]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:8][C@@:9]1([C:11]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[CH:14]=[CH:13][C:12]=1[F:20])[CH3:10])[CH:2]=[CH2:3]
Reactant: C=CC[C@H]1[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: C=CCC1(C)[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S1(=O)=O
Reaction time: 0.25 h
Yield: 85 %

Procedure:
To a mixture of tert-butyl N-[(2S,3R)-2-allyl-3-(2-fluoro-5-nitro-phenyl)-3,6,6-trimethyl-1,1-dioxo-2H-1,4-thiazin-5-yl]-N-tert-butoxycarbonyl-carbamate (0.22 g, 0.38 mmol) in THF (2 mL) at −78° C. was added potassium bis(trimethylsilyl)amide, 1M in THF (1.13 ml, 1.13 mmol) and the solution was stirred for 15 minutes. Iodomethane (0.070 ml, 1.13 mmol) was added and the mixture was stirred at −78° C. for 0.5 h. The reaction was quenched by water, extracted with ethyl acetate. The combined extracts were washed with brine, dried and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a BioTage column (25 g), eluting with a gradient of 5% to 40% EtOAc in hexane, to provide tert-butyl N-[(5R)-6-allyl-5-(2-fluoro-5-nitro-phenyl)-2,2,5,6-tetramethyl-1,1-dioxo-1,4-thiazin-3-yl]-N-tert-butoxycarbonyl-carbamate (0.19 g, 85% yield) as a white solid. m/z (ESI) 606.1 (M+Na)+.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[O:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][O:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: c1cc(-c2c3c(nn2C2CCCC2)CCNCC3)co1
Yield: 83.6 %

Procedure:
The title compound (101 mg) was prepared according to Example 180 using 202 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 149 mg of 3-furanboronic acid. MS (ESI): exact mass calculated for C16H21N3O, 271.17. found, m/z 272.5 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.73-7.72 (m, 2H), 6.57-6.56 (m, 1H), 4.64 (m, 1H), 3.40-3.38 (m, 2H), 3.16-3.14 (m, 2H), 2.86-2.84 (m, 2H), 2.03-1.91 (m, 6H), 1.66-1.64 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])[CH2:11][CH2:10]1)=[O:5].[C:30](OC(=O)C)(=[O:32])[CH3:31].[OH-].[NH4+]>O>[C:30]([NH:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][CH:12]([N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[O:24])[CH2:13][CH2:14]1)=[O:5])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(F)ccc1C(=O)NCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Reaction time: 0.5 h

Procedure:
A mixture of 1 part of 2-amino-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluorobenzamide, 1 part of acetic acid anhydride and 15 parts of water is stirred for 30 minutes in a water-bath at 80°-90° C. The reaction mixture is cooled and alkalized with an ammonium hydroxide solution. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 0.5 parts of 2-(acetylamino)-N-{2-[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]ethyl}-4-fluorobenzamide; mp. 210° C.
Reaction SMILES: [CH2:1]([C:3]([CH2:9][CH3:10])=[C:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:2].[CH3:11][Li].O>CCOCC>[CH2:1]([C:3]([C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1)([CH3:11])[CH2:9][CH3:10])[CH3:2]
Reactant: [Li]C
Reactant: CCC(CC)=C1C=CC=C1
Solvent: O
Solvent: CCOCC
Product: CCC(C)(CC)C1=CC=CC1
Temperature: 25 °C
Yield: 61 %

Procedure:
To a solution of 8.00 g (59.6 mmol) of 6,6-diethylfulvene in 35 ml of ether, 60.0 ml (68.4 mmol) of an ether solution of methyllithium was dropwise added in a nitrogen atmosphere with ice cooling, followed by stirring at room temperature for one night. Then, 30 ml of water was added. The separated organic phase was washed with water and a saturated saline solution, then dried over magnesium sulfate and filtered. From the filtrate, the solvent was removed under reduced pressure to obtain a liquid. The liquid was subjected to vacuum distillation (92° C./40 mmHg) to obtain 5.50 g (36.6 mmol) of a light yellow liquid (yield: 61%). The analyzed values are given below.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1N.C(O[CH:15]=[C:16]([C:22]#[N:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>C1(C)C=CC=CC=1>[CH2:20]([O:19][C:17](=[O:18])[C:16]([C:22]#[N:23])=[CH:15][C:3]1[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:2]=1[CH3:1])[CH3:21]
Reactant: CCOC=C(C#N)C(=O)OCC
Reactant: Cc1cc([N+](=O)[O-])ccc1N
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)=Cc1ccc([N+](=O)[O-])cc1C

Procedure:
A mixture of 2-methyl-4-nitroaniline (38.0 g, 250 mmol), ethyl (ethoxymethylene)cyanoacetate (50.8 g, 300 mmol), and 200 ml of toluene was refluxed for 24 h, cooled, diluted with 1:1 ether-hexane, and filtered. The resulting white solid was washed with hexane-ether and dried to give 63.9 g, mp 180-210° C.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][NH:5][C:6]1[N:7]=[N+:8]([O-:21])[C:9]2[CH:15]=[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[CH:12][C:10]=2[N:11]=1.C[OH:24]>>[O-:21][N+:8]1[C:9]2[CH:15]=[C:14]3[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:13]3=[CH:12][C:10]=2[N+:11]([O-:24])=[C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:22])[CH3:1])[N:7]=1
Reactant: CO
Reactant: CN(C)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCCCC3
Product: CN(C)CCNc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CCCCC3

Procedure:
H2O2 (70%, 0.31 mL, ca. 6.2 mmol) was added dropwise to a stirred solution of TFAA (0.9 mL, 6.2 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 188 (186 mg, 0.6 mmol) and TFA (0.24 mL, 3.1 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 188 (43 mg, 23%) and (ii) 1,4-dioxide 189 (82 mg, 42%) as a red solid: mp (MeOH) 131-133° C.; 1H NMR δ 8.03 (s, 1H, H-11), 7.99 (s, 1H, H-5), 7.36 (br s, 1H, NH), 3.63 (br t, J=6.0 Hz, 2H, CH2N), 2.98-3.03 (m, 2H, CH2), 2.91-2.95 (m, 2H, CH2), 2.60 (br t, J=6.0 Hz, 2H, CH2N), 2.30 [s, 6H, N(CH3)2], 1.82-1.89 (m, 2H, H-8), 1.68-1.76 (m, 4H, H-7, H-9); 13C NMR δ 154.4, 149.7, 144.7, 137.1, 128.7, 119.8, 115.9, 57.5, 45.2 (2), 38.9, 37.0, 36.2, 31.8, 28.4, 28.2. Anal. calcd for C16H23N5O2.¼CH3OH: C, 60.0; H, 7.4; N, 21.5. Found: C, 59.9; H, 7.0; N, 21.5%.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1.Br>C(O)(=O)C>[OH:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:15])([CH3:14])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)N(C)C(=O)C2(C)C
Agent: Br
Solvent: CC(=O)O
Product: CN1C(=O)C(C)(C)c2ccc(O)cc21
Temperature: 110 °C
Reaction time: 2 h

Procedure:
To a solution of 6-methoxy-1,3,3-trimethyl-1,3-dihydro-indol-2-one (601 mg, 2.93 mmol, example 79) in acetic acid (880 μL) is added hydrobromic acid (48% in H2O) (8.8 mL). The resulting solution is heated to reflux (105°110° C.), stirred 2 hrs, then cooled to room temp and concentrated under reduced pressure. The residue is dissolved in EtOAc and the organic layer washed with water, brine, dried over MgSO4 and concentrated. The residue is purified by triturating with a small volume of ether to give the title compound as an off white solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([N:17]2[CH2:22][CH2:21][N:20]([C:2]3[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: c1ccc(N2CCNCC2)cc1
Product: Nc1ccc(N2CCN(c3ccccc3)CC2)nc1

Procedure:
Intermediate B-12 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 1-phenylpiperazine as starting materials. LCMS (ESI) calcd for [M+1]+ 255.2. found 255.1.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[F:19][C:20]1[CH:25]=[C:24]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:22][N:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:24]3[CH:23]=[CH:22][N:21]=[C:20]([F:19])[CH:25]=3)=[O:32])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: O=C(O)c1ncoc1-c1ccnc(F)c1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3ncoc3-c3ccnc(F)c3)cn2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 5-(2-fluoro-pyridin-4-yl)-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=0.90 min; [M+H]+=395.98.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24])=[CH:17][CH:16]=1>N1C=CC=CC=1>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][S:23]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[S:10]([NH2:13])(=[O:11])=[O:12])(=[O:25])=[O:24])=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)CCc1ccc(Cl)cc1
Reactant: COc1ccc(N)c(S(N)(=O)=O)c1
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)CCc2ccc(Cl)cc2)c(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a solution of 2-amino-5-methoxy-benzenesulfonamide (4.0 g, 19.80 mmol) in pyridine (60 mL), 2-(4-chloro-phenyl)-ethanesulfonyl chloride (4.73 g, 19.79 mmol) was added slowly at 0° C. The reaction mixture was stirred at RT for 16 h and then concentrated under reduced pressure at 35° C. The residue was then partitioned between ethyl acetate and 1N HCl. The organic layer was separated, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:1) to give the title compound (7.1 g, 88%).