Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(O)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
Methyl 2-({4-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.547 g, 1.45 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled to −20° C. Triethylamine (0.22 g, 2.17 mmol) was added dropwise followed by the dropwise addition of methylsulfonyl chloride (0.18 g, 1.59 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature. Excess of triethylamine was removed by addition of diethyl ether (5 ml) and filtering off the precipitate. The organic phase was washed with three portions of brine (10 ml) and dried (MgSO4). The solvent was removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.317 g of methyl 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (yield 48%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[C:4]([C@@H:6]([NH:15][C@@H:16]1[C:22](=[O:23])[N:21]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:20]2[CH:32]=[CH:33][CH:34]=[CH:35][C:19]=2[O:18][CH2:17]1)[CH2:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([OH:5])=[O:3]
Reactant: CCOC(=O)[C@H](CCC1CCCCC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCC2CCCCC2)C(=O)O)COc2ccccc21
Reaction time: 3 h
Yield: 84.9 %

Procedure:
In 10 ml of ethanol is dissolved 1.5 g of tert-butyl 3(S)-[1(S)-ethoxycarbonyl-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate obtained in Example 49, and 1N sodium hydroxide solution is added dropwise over a period of 15 minutes. After stirring for 3 hours, the solution is diluted with water (200 ml) and extracted with ethyl ether (100 ml). The aqueous layer is acidified slightly with 1N hydrochloric acid to deposit crystals. This product is collected by filtration and dried to give 1.2 g of tert-butyl 3(S)-[1(S)-carboxy-3-cyclohexylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as colorless needles, melting at 180°-183° C.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[CH2:10]1.[C:25](=O)([O:34]N1C(=O)CCC1=O)[O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:26][C:25]([NH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=2)[CH2:10]1)=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3N)C2)cc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Product: COC(=O)c1ccc(N2CCC[C@H](N[C@@H]3CCCC[C@H]3NC(=O)OCc3ccccc3)C2)cc1

Procedure:
Methyl 4-((S)-3-((1R,2R)-2-(benzyloxycarbonylamino)cyclohexylamino) piperidin-1-yl)benzoate was synthesized using methyl 4-((S)-3-((1R,2R)-2-aminocyclohexylamino)piperidin-1-yl)benzoate (98 mg, 0.296 mmol) and benzyl 2,5-dioxopyrrolidin-1-yl carbonate (73.7 mg, 0.296 mmol) according to General Procedure H to give 38 mg (20% yield) of yellow solid. Anal. Calcd. for C27H35N3O4 m/z 465.5, found: 466.1 (M+H)+; 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J=9.0 Hz, 2H), 7.30-7.18 (m, 3H), 7.16-7.09 (m, 2H), 7.05 (d, J=8.9 Hz, 2H), 4.93 (s, 2H), 3.84 (s, 3H), 3.72-3.47 (m, 3H), 3.47-3.11 (m, 4H), 2.29 (d, J=13.4 Hz, 1H), 2.12-1.99 (m, 2H), 1.96-1.77 (m, 5H), 1.61-1.29 (m, 4H).
Reaction SMILES: [ClH:1].Cl.Cl.[NH:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:26])=[NH:25])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.Cl.[C:31](=[NH:36])(OCC)[CH3:32].C(N(CC)CC)C.Cl>CO.O1CCOCC1>[ClH:1].[ClH:1].[ClH:1].[C:31]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][CH2:18]/[CH:19]=[CH:20]/[C:21]3[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:26])=[NH:25])=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=[NH:36])[CH3:32]
Reactant: N=C(N)c1cccc(/C=C/CNc2ccc(OC3CCNCC3)cc2)c1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: CO
Product: CC(=N)N1CCC(Oc2ccc(NC/C=C/c3cccc(C(=N)N)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 217.1 %

Procedure:
To a solution of 3-[3-[N-[4-(piperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzamidine trihydrochloride (345 mg) in methanol (20 ml) were added ethyl acetimidate hydrochloride (185 mg) and triethylamine (0.52 ml) at room temperature. The resulting mixture was stirred at room temperature for 12 hours. To the reaction mixture was added a 4M solution of hydrogen chloride in dioxane (1 ml) and the solution was concentrated in vacuo. The residue was purified by preparative HPLC (YMC-Pack ODS YMC) using 30% aqueous acetonitrile as an eluant to afford an amorphous solid. To a solution of the solid in methanol (10 ml) was added a 4M solution of hydrogen chloride in dioxane (0.5 ml) and the mixture was concentrated to dryness in vacuo. A solution of the residual solid in water (about 10 ml) was lyophilized to give the title compound (272 mg, yield 72%) as a yellow amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccc(F)cc43)c2cc1OC

Procedure:
To 6-fluoroindoline (274 mg, 2.0 mmol) in dry i-PrOH (10mL) was added 4-chloro-6,7-dimethoxy-quinazoline (225 mg, 1.0 mmol). The mixture was refluxed for 16 hours under an atmosphere of dry N2(g) and then the solvent was removed in vacuo. The residue was partitioned between CHCl3 and 1M NaOH, and the organic phase was washed with brine, dried over Na2SO4(g) and concentrated in vacuo. The residue (535 mg) was purified by flash chromatography on silica using 80%EtOAc/CH2 Cl2 to yield 4-(6-fluoro-2,3-dihydro-indol-1-yl)-6,7-dimethoxyquinazoline as its free base (293 mg) (GC/MS: 325 (M+); LC-MS: 326 (MH+); anal. RP18-HPLC RT: 4.37 min.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=2)[CH2:5][CH2:4]1.I[CH:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:24]([NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([NH:9][C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])[N:14]=2)[CH2:5][CH2:4]1)([CH3:26])[CH3:25]
Reactant: CC(C)I
Reactant: COc1ccccc1-c1csc(NC2CCC(CN)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1-c1csc(NC2CCC(CNC(C)C)CC2)n1
Temperature: 50 °C
Yield: 53 %

Procedure:
The reaction mixture of N-[4-(aminomethyl)cyclohexyl]-4-(2-methoxyphenyl)-1,3-thiazol-2-amine (1 equivalent), 2-iodopropane (1 equivalent), and potassium carbonate (2 equivalents) in DMF was heated at about 50° C. overnight. Water was then added to the reaction mixture and extracted with diethyl ether (3 times). Evaporation of the combined organic phase afforded a yellow oil which was purified by preparative TLC plates. The desired product was obtained as a yellow oil in 53% yield: ESIMS m/e=360 (MH+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([N:24]1[N:28]=[N:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36]O)=[CH:32][CH:31]=2)=[N:25]1)([CH3:23])[CH3:22].C(Br)(Br)(Br)[Br:39]>C(OCC)C>[Br:39][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:26]2[N:27]=[N:28][N:24]([C:21]([CH3:23])([CH3:22])[CH3:20])[N:25]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)n1nnc(Cc2ccc(CO)cc2)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)n1nnc(Cc2ccc(CBr)cc2)n1
Yield: 62.9 %

Procedure:
Triphenylphosphine (6.5 g, 25 mmol) was added to a solution of 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-methyl]benzenemethanol (3.0 g, 12.4 mmol) and carbon tetrabromide (8.3 g. 25 mmol) in diethyl ether (150 mL). After 3 hours the reaction mixture was concentrated and the residue purified by chromatography on silica gel eluting with a 9:1 mixture of hexane-ethyl acetate to give 5-[[4-(bromomethyl)phenyl]methyl]-2-(1,1-dimethylethyl)-2H-tetrazole (2.4 g. 7.8 mmol) in 63% yield, mp. 73°-74° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:4]2[N:5]([CH2:11][CH:12]([CH3:14])[N:13]=2)[C:6](=[O:10])[C:7]=1[N:8]=O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].N1C=CC=[CH:35][CH:34]=1.C(OC(=O)C)(=O)C>C(O)=O.C(#N)C>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][N:3]2[C:2]3[NH:1][C:34]([CH3:35])=[N:8][C:7]=3[C:6](=[O:10])[N:5]3[CH2:11][CH:12]([CH3:14])[N:13]=[C:4]23)=[CH:17][CH:18]=1
Reactant: c1ccncc1
Reactant: CC1CN2C(=O)C(N=O)=C(N)N(Cc3ccc(Cl)cc3)C2=N1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=CO
Solvent: CC(=O)OC(C)=O
Product: Cc1nc2c([nH]1)N(Cc1ccc(Cl)cc1)C1=NC(C)CN1C2=O
Temperature: 25 °C

Procedure:
The product of Procedure 99 was reduced with sodium dithionate in formic acid according to the method of Procedure 21. The resulting 7-amino-4-[(4-chlorophenyl)-methyl]-2,3-dihydro-6-formylamino-2-methylimidazo[1,2-a]pyrimidin-5-(8H)-one, 3.5 g. (0.0104 mole) in 7 ml. of pyridine and 7 ml. of acetic anhydride was refluxed for three 3 hrs. during which the mixture foamed and turned dark. The mixture was allowed to cool to room temperature and diluted with acetonitrile resulting in the formation of a white precipitate which was collected. Recrystallized from iPROH/MeOH, yield 800 mg., m.p. 290°-291° C.
Reaction SMILES: [CH2:1]([NH:3][CH:4](O)[CH3:5])[CH3:2].C(O[C:11]1([C:17]#[CH:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)(=O)C.C1C[O:22]CC1>Cl[Cu]>[CH2:1]([N:3]([C:11]1([C:17]#[CH:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH2:4][CH2:5][OH:22])[CH3:2]
Reactant: CCNC(C)O
Reactant: C#CC1(OC(C)=O)CCCCC1
Reactant: C1CCOC1
Agent: Cl[Cu]
Product: C#CC1(N(CC)CCO)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 1.17 ml (12 mmol) ethylaminoethanol in 8 ml THF were added 29.8 mg (0.3 mmol) CuCl, followed by 1 g (6.02 mmol) 1-ethynylcyclohexyl acetate. The solution was stirred at RT for 3 h, the solvent was removed and the residue dissolved in ether/2M HCl. The phases were separated, and after addition of NaOH (pH 11) to the aqueous phase, it was extracted with ether. The ether phase was dried over Na2SO4 and concentrated. Destillation by Kugelrohr yielded 2-[Ethyl-(1-ethynyl-cydohexyl)-amino]-ethanol as colorless oil, MS: 196 (MH+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:4]1.O[N:31]=[C:32]([NH2:37])[CH2:33][CH2:34][O:35][CH3:36]>>[CH3:36][O:35][CH2:34][CH2:33][C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:5]3[CH2:6][CH2:7][CH2:8][CH:3]([O:2][CH3:1])[CH2:4]3)=[O:10])[CH2:12]2)[O:29][N:31]=1
Reactant: COC1CCCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)C1
Reactant: COCCC(N)=NO
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCCC(OC)C3)C2)n1

Procedure:
250 mg (0.434 mmol, 72% pure) of 1-[(3-methoxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 207A) and 75.3 mg (0.478 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide were reacted according to the General Method 1. Yield: 105 mg (48% of theory).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[OH-].[Na+]>C1COCC1>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:19]=[CH:18][C:15]([CH2:16][N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:14][CH:13]=2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-isopropyl-piperazine-1-carbonyl)-benzaldehyde (4.0 g, 15.38 mmol) in THF (40 mL) was added morpholine (2.9 g, 33.83 mmol), and the resulting mixture was stirred at room temperature for 1 h before it was cooled to 0° C. with an ice bath. The reaction mixture was then treated with NaBH(OAc)3 (4.56 g, 21.53 mmol) in portions over 15 min. The resulting suspension was stirred at room temperature until it was deemed complete by HPLC. After completion, 10% NaOH (25 mL) was added and the reaction was vigorously agitated for 15 min. The phases were separated and the aqueous layer was extracted with THF (20 mL). The organic layers were combined, dried (MgSO4), filtered and concentrated to yield the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.Br[CH2:27][CH2:28][Cl:29]>>[CH3:1][C:2]1([CH3:25])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:27][CH2:28][Cl:29])[CH:4]=[N:3]1
Reactant: CC1(C)N=CC2=C3N=C(CCc4ccccc4)N=C3C(=O)CC2C1=O
Reactant: ClCCBr
Product: CC1(C)N=CC2=C3N=C(CCc4ccccc4)N=C3C(=O)C(CCCl)C2C1=O

Procedure:
Prepared analogous to Example 23 at room temperature from 4.3 gm of 7,7-dimethyl-2-phenethyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 2.2 gm of 2-bromo-1-chloro-ethane. The viscous oily crude product was directly further processed.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([S:20](=[O:29])(=[O:28])[NH:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:12][CH:11]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:30]([N:32]=[C:33]=[O:34])[CH3:31].Cl[C:36](OCC)=O>>[CH2:30]([NH:32][C:33]([N:25]1[CH2:24][CH2:23][CH:22]([NH:21][S:20]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:10]([C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:36])=[CH:11][CH:12]=2)(=[O:29])=[O:28])[CH2:27][CH2:26]1)=[O:34])[CH3:31]
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Reactant: CCN=C=O
Product: CCNC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)Nc3ccccc3C)c3ccccc23)CC1

Procedure:
The title compound was prepared according to the general procedure in Scheme 11, substituting 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid o-tolylamide for 4-(piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide, and ethyl isocyanate for ethyl chloroformate. Wt.: 26 mg (47%). 1H NMR (300 MHz, CDCl3) δ 8.65 (d, 1H), 8.46 (d, 1H), 8.32 (d, 1H), 8.03 (d, 1H), 7.77 (d, 1H), 7.70 (m, 2H), 7.64 (s, 1H), 7.30 (m, 2H), 7.20 (m, 2H), 4.81 (d, 1H), 4.28 (m, 1H), 3.66 (m, 2H), 3.27 (m, 1H), 3.17 (m, 2H), 2.71 (m, 2H), 2.32 (s, 3H), 1.65 (m, 1H), 1.25 (m, 2H), 1.07 (t, 3H); LC/MS m/z 493 (M−H)−.
Reaction SMILES: CC1(C)[O:6][CH:5](/[CH:7]=[CH:8]/[C:9]2[CH:10]=[C:11]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[C:14]2[C:15]4[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=4[O:17][C:13]=2[C:12]3([CH3:28])[CH3:27])[CH2:4][O:3]1>[Pd].CO>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[C:14]1[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[O:17][C:13]=1[C:12]2([CH3:28])[CH3:27]
Reactant: CC1(C)OCC(/C=C/c2ccc3c(c2)C(C)(C)c2oc4ccccc4c2C3=O)O1
Agent: [Pd]
Solvent: CO
Product: CC1(C)c2cc(CCC(O)CO)ccc2C(=O)c2c1oc1ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To the MeOH solution (5 ml) of 8-[(E)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-vinyl]-6,6-dimethyl-6H-benzo[b]naphtho[2,3-d]furan-11-one (125 mg), 10% Pd—C (25 mg) was added and the mixture was stirred overnight at room temperature under hydrogen atmosphere. The catalyst was removed by filtration. The residues obtained after concentration under reduced pressure were purified by HPLC to obtain the title compound (35 mg, 31%).
Reaction SMILES: CS(C)(=O)=O.Cl.[C:7](Cl)(=[NH:9])[NH2:8].C([O:13][C:14]([C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[Cl:25])[NH:18][C:17]=1[NH2:26])=O)C.O.N>C(Cl)(Cl)Cl.O>[NH2:8][C:7]1[NH:9][C:14](=[O:13])[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][C:23]=3[Cl:25])[NH:18][C:17]=2[N:26]=1
Reactant: N=C(N)Cl
Reactant: CCOC(=O)c1c(N)[nH]c2cccc(Cl)c12
Agent: CS(C)(=O)=O
Agent: Cl
Agent: N
Solvent: O
Solvent: ClC(Cl)Cl
Product: Nc1nc2[nH]c3cccc(Cl)c3c2c(=O)[nH]1
Temperature: 115 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1 g methyl sulfone was heated to melting. 7 (106.22 mg, 1.37 mmol) was added and the resulting mixture was stirred and heated at 110-120° C. to dissolve completely. 5 (200 mg, 0.837 mmol) was added in one part to the reaction mixture. Stirring was continued for 30 minutes. About 10 mL water was added to quench the reaction. Ammonia water was added to neutralize the reaction mixture. Solid precipitated out. This solid was filtered. Obtained solid was dissolved in chloroform and methanol, dried (using Na2SO4) and recrystallized. The overall yield was 78%. TLC Rf 0.33 (chloroform-methanol 1:1); mp>250° C.; 1H NMR (DMSO-d6) δ 6.57 (bs, 2H, 2-NH2, exch); 7.04-7.17 (m, 3H, phenyl); 10.41 (s, 1H, 9-NH, exch); 11.64 (s, 1H, 3-NH, exch). Anal. Calculated (C10H7ClN4O. 0.3CH3OH): C, 50.65; H, 3.38; N, 22.94; Cl, 14.52. Found: C, 50.91; H, 3.34; N, 22.60; Cl, 14.77.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Bromo-3-nitroquinolin-4-ol (42 g, 156 mmol) was suspended in POCl3 (130 mL) and brought to 102° C. under an atmosphere of N2. After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature. The resulting solids were collected by filtration, washed with H2O, and then partitioned with CH2Cl2 (3 L) and 2M Na2CO3 (500 mL). The organic layer was separated, washed with H2O (1×), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 33.7 g of 7-bromo-4-chloro-3-nitroquinoline as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[C:12]([NH2:16])([CH3:15])([CH3:14])[CH3:13]>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CC(C)(C)N
Product: Cc1cc(Br)ccc1C(=O)NC(C)(C)C

Procedure:
The sub-title compound was prepared by the method of example 18 step a) using 4-bromo-2-methylbenzoic acid and tertiary butylamine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][N:13]=[CH:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:34])[CH2:28][C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[O:35])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])=[O:11])=O)(C)(C)C>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:8][CH2:9][C:10]([NH:12][N:13]=[CH:14][C:15]1[CH2:16][S:17][C@@H:18]2[CH:25]([NH:26][C:27](=[O:34])[CH2:28][C:29]3[S:30][CH:31]=[CH:32][CH:33]=3)[C:24](=[O:35])[N:19]2[C:20]=1[C:21]([OH:23])=[O:22])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NCC(=O)NN=CC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Reaction time: 1 h
Yield: 61.8 %

Procedure:
A solution of 3-[2-(N-tertiary butoxycarbonylglycyl)hydrazono]methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (120 mg) in a mixture of anisole (0.6 ml) and trifluoroacetic acid (1.2 ml) is kept at 0° C for 1 hour. The reaction mixture is concentrated to remove trifluoroacetic acid, and the obtained residue is diluted with ether. The separated crystals are washed with ether and water and dried to give 3-(2-glycylhydrazono)methyl-7-(2-thienylacetamido)-3-cephem-4-carboxylic acid (60 mg). m.p. 204°-209° C (decomposition). Yield: 62%. IR: νmax Nujol 3260, 1767, 1660, 1600, 1585cm-1. UV: νmaxEtOH 235nm; 316nm (Saturated solution). NMR: δd 6-DMSO 3.58s2H, 3.9dd2H, 5.17d(4Hz)1H, 5.75dd(8;4Hz)1H, 6.80-7.47m3H, 8.20s1H, 9.13d(8Hz)1H.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1.Cl[C:19]([O:22]C(Cl)=O)(Cl)Cl>C1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:17]=[CH:16][C:14]([N:15]=[C:19]=[O:22])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCN(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: c1ccccc1
Product: CN1CCN(S(=O)(=O)c2ccc(N=C=O)cc2)CC1
Temperature: 25 °C

Procedure:
4-(4-Methylpiperazin-1-sulfonyl)aniline (0.5 g, 1.96 mmol) dissolved in anhydrous benzene was added dropwise to a solution of trichloromethylchloroformate (0.3 mL, 2.35 mmol) in anhydrous benzene at −10° C. The mixture was warmed to room temperature for 10 minutes, then heated to 90° C. for 2 h. The mixture was concentrated under reduced pressure to provide 4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl isocyanate as a solid, used as an intermediate in the production of Compound 105. IR: 1166, 1339, 2265 cm1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:13][C:14]([OH:16])=[O:15])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N+](=[CH2:19])=[N-]>>[CH3:19][O:15][C:14](=[O:16])[CH2:13][N:11]([S:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)(=[O:9])=[O:10])[CH3:12]
Reactant: CN(CC(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Reactant: C=[N+]=[N-]
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(Cl)cc1

Procedure:
2 Parts of N-p-chlorobezenesulfonyl-sarcosine is added to a diazomethane-ethereal solution. After the generation of nitrogen has ceased, the precipitated reaction product is collected by filtration to obtain 1.2 parts of N-p-chlorobenzenesulfonyl-sarcosine methyl ester, m.p. 80°-80.5° C.