Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-])=O)=[C:6]([NH2:8])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1.O.O.Cl[Sn]Cl>C1COCC1>[NH2:9][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[NH:8][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][C:14]([O:13][CH3:12])=[CH:15][CH:16]=1
Reactant: Nc1cc(Br)ccc1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cc(Br)ccc2N)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
In aflame dried, round bottom flask, 5-bromo-2-nitro-aniline (2) (10.66 g, 49.09 mmol), (scheme 1, Example 1), and 4-methoxybenzoyl chloride (8.37 g, 49.09 mmol) were added. The mixture was heated to 90° C. The melted solids were stirred overnight to give a yellow-brown solid. THF (250 mL) was then added and the solution was treated with SnCl2.2H2O (55.38 g, 245.45 mmol, 5.0 eq) and stirred at room temperature for 2 hrs. Approx. half of the THF was evaporated then 200 mL of EtOAc and 100 mL sat. NaHCO3 were added. The precipitated tin salt was taken out by filtration and a work-up was done on the filtrate with EtOAc. The combined organic layers were washed with water and brine and dried over MgSO4. Most of the EtOAc was evaporated then hexane was added and the precipitate was collected by filtration to give the title compound 114 as a beige powder (13.40 g, 85% yield). 1H NMR (DMSO-d6) δ(ppm): 9.52 (s, 1H), 7.93 (d, J=9.0 Hz, 2H), 7.34 (d, J=2.3 Hz, 1H), 7.08 (dd. J=8.6, 2.3 Hz, 1H), 7.02 (d, J=9.0 Hz, 2H), 6.71 (d, J=8.6 Hz, 1H) 5.10 (s, 2H), 3.82 (s, 3H).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11]C(=O)OCC3C=CC=CC=3)[C:9](=[O:22])[NH:8]2)[CH:5]=[N:4][CH:3]=[N:2]1>CCO.CO.[Pd]>[N:1]1([CH2:6][C@H:7]2[NH:8][C:9](=[O:22])[C@H:10]2[NH2:11])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: O=C(N[C@@H]1C(=O)N[C@@H]1Cn1cncn1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1

Procedure:
Prepared in an analogous manner to example 4, step 3 using benzyl ((2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (250 mg, 0.830 mmol) and Pd on C (10%, 125 mg) in EtOH:MeOH (4:1, 8.3 mL) for 3 h. The crude residue was used as such in following step. LCMS: Rt=0.13 min, m/z=168.1 (M+1) Method 2m_acidic.
Reaction SMILES: Br[C:2]1[C:3]([Cl:13])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6](=[O:12])[CH2:5]2.[N:14]1[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.COCCOC>ClCCl.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:13][C:3]1[C:2]([C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:12])[N:7]2[CH3:11]
Reactant: CN1C(=O)Cc2c1ccc(Br)c2Cl
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: COCCOC
Product: CN1C(=O)Cc2c1ccc(-c1cccnc1)c2Cl
Temperature: 100 °C

Procedure:
To 5-bromo-4-chloro-1-methyl-1,3-dihydro-indol-2-one (78 mg, 0.3 mmol) was added 3-pyridine boronic acid (CAS#1692-25-7, 50.2 mg, 0.41 mmol), 1,2-dimethoxyethane (2.5 mL) and 2 M aqueous sodium carbonate (0.410 mL, 0.82 mmol). The reaction mixture was degassed and placed under an argon atmosphere, at which time resin bound tetrakis(triphenylphosphine)palladium(0), specifically polystyrene triphenylphosphine palladium (0) [PS—PPh3-Pd(0) (Biotage), 0.09 mmol/g loading, (167 mg, 0.015 mmol)] was added. The reaction vessel was sealed and was heated by microwave irradiation at 100° C. for 75 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane and saturated aqueous sodium carbonate, and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 40 to 100%) to afford 4-chloro-1-methyl-5-pyridin-3-yl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 259.0636 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 3.27 (s, 3H), 3.62 (s, 2H), 6.85 (d, J=8.1 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.38-7.48 (m, 1H), 7.85 (d, J=7.8 Hz, 1H), 8.64 (dd, J=4.9, 1.6 Hz, 1H), 8.69 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.[CH:13]([CH:15]=O)=O.O>C(O)(C)C>[N:10]1[C:7]2[C:6](=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:9][CH:8]=2)[N:11]=[CH:15][CH:13]=1
Reactant: O=CC=O
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2nccnc2c1
Temperature: 80 °C
Yield: 93 %

Procedure:
To a stirred solution of 3,4-diamino-benzoic acid methyl ester (236, 2 g, 12.03 mmol) in isopropanol (50 mL) was added oxaldehyde as a 40% solution in water (13.23 mmol, 1.52 mL). The reaction mixture was heated at 80° C. for 2 hours, the solvent was removed under reduced pressure and the residue was dried under vacuum to yield 237a as a yellow solid (2.09 g, 93% yield). 1H NMR: (DMSO) δ 9.01 (s, 2H), 8.54 (d, J=1.6 Hz, 1H), 8.23 (dd, J=8.6, 2.0 Hz, 1H), 8.14 (dd, J=8.6, 0.6 Hz, 1H), 3.35 (s, 3H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Mg]Cl)(C)C.[Br:12][C:13]1[S:17][C:16]([C:18](=[O:24])[CH2:19][CH2:20]C(O)=O)=[CH:15][CH:14]=1.C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[Br:12][C:13]1[S:17][C:16]([C:18](=[O:24])[CH2:19][CH2:20][C:4](=[O:6])[CH2:3][C:1]#[N:2])=[CH:15][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(Br)s1
Reactant: N#CCC(=O)O
Agent: CC(C)[Mg]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: N#CCC(=O)CCC(=O)c1ccc(Br)s1
Yield: 69 %

Procedure:
To a solution of 2-cyanoacetic acid (13 g, 50 mmol) in THF (100 mL) was added dropwise i-PrMgCl (16 g, 250 mmol) at −78° C. for 1 h. A solution of 4-(5-bromothiophen-2-yl)-4-oxobutanoic acid (8A) and CDI (12 g, 74 mmol) in THF was added dropwise at −78° C. and the resultant mixture was stirred at −78° C. for 1 h and at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride (200 mL). The organic phase was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel column chromatography (PE:EA=5:1) to afford 8B as a black oil (9.7 g, 69%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[O:7][CH2:6][CH2:5]2.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25]>C1COCC1>[C:24]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:16])([C:12]([F:15])([F:13])[F:14])[O:7][CH2:6][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: CC1(C(F)(F)F)OCCc2cc(O)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a stirred solution of 6-hydroxy-1-methyl-1-trifluoromethylisochroman (79 g, 0.34 mol) and triethylamine (120 mL, 0.88 mol) in THF (680 mL) was added acetyl chloride (31 mL, 0.44 mol) at 0° C., and the mixture was stirred at room temperature for 1 hr. The reaction was quenched by adding aqueous 1 N-HCl (400 mL), and extracted with ethyl acetate (500 mL). The extracts were washed with aqueous saturated NaHCO3 (100 mL) and brine (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography (Silica-gel, 15×20 cm, 6% ethyl acetate/hexane) to afford 6-acetoxy-1-methyl-1-trifluoromethylisochroman (83 g, 89%) as a colorless oil. 1H-NMR(CDCl3): 7.36 (d, J=7.2 Hz, 1H), 6.98 (dd, J=7.2, 2.5 Hz, 1H), 6.91 (d, J=2.5 Hz, 1H), 4.18-4.08 (m, 1H), 3.92 (dt, J=11, 5.4 Hz, 1H), 2.86 (t, J=5.4 Hz, 2H), 2.30 (s, 1H), 1.66 (s, 3H).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.CCCCCC.[CH3:12][C:13]([CH3:32])([CH3:31])[C:14]#[C:15]/[CH:16]=[CH:17]\[CH2:18][N:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([CH3:30])=C)[CH:23]=1)[CH3:20]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC=CC=1>[C:13]([C:14]1[CH:15]=[CH:16][C:17]([CH2:18][N:19]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]=[CH2:30])[CH:23]=2)[CH3:20])=[CH:2][CH:1]=1)([CH3:12])([CH3:31])[CH3:32]
Reactant: C=C(C)c1cccc(CN(C)C/C=C\C#CC(C)(C)C)c1
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: c1ccccc1
Solvent: CCCCCC
Product: C=Cc1cccc(CN(C)Cc2ccc(C(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 49.4 %

Procedure:
Methyl triphenylphosphonium bromide (1.07 g; 3.00 mmol) was added to benzene (20 ml). While the mixture was stirred under nitrogen atmosphere at room temperature, n-butyl lithium in n-hexane (1.56 M: 1.9 ml; 3.00 mmol) was added dropwise. The mixture was stirred for 10 minutes, and Compound 5 (0.59 g; 2.00 mmol) in benzene (15 ml) was added dropwise thereto, followed by stirring for 3 hours at room temperature. Reaction was stopped by pouring the mixture into ice/water, followed by extraction with benzene (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=20:1), to thereby yield 0.29 g of the target compound as pale yellow oily matter (yield: 49.4%).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1.[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[CH:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:22][CH2:21][N:20]=[C:19]1[NH:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:6]=[C:5]([CH3:14])[CH:4]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)N1C=NCC1
Reactant: Cc1cc(N)n(-c2ccccc2)n1
Agent: Cl
Product: CC(=O)N1CCN=C1Nc1cc(C)nn1-c1ccccc1

Procedure:
5-Amino-3-methyl-1-phenyl pyrazole hydrochloride (37.8 g.) and -1-acetyl-2-imidazoline (27.4 g.) were reacted as described in Example I to give 35.4 g. product. mp 153°-162° (crystallized from CH3CN)
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[C:6]([CH3:9])=[CH:7][O:8][C:4]=2[CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.C(N(C(C)C)C(C)C)C>C(O)C>[CH3:9][C:6]1[C:5]2[CH:10]=[C:11]([CH3:12])[C:2]([N:1]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)=[CH:3][C:4]=2[O:8][CH:7]=1
Reactant: BrCCCCCBr
Reactant: Cc1cc2c(C)coc2cc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1cc2c(C)coc2cc1N1CCCCC1

Procedure:
A mixture of 8 g (49.6 mmole) of 6-amino-3,5-dimethylbenzofuran, 23 g (0.1 mole) of 1,5-dibromopentane, 12.9 g (0.1 mole) of N-ethyldiisopropylamine and 60 ml of ethanol is boiled under reflux for 18 hours. The residue obtained after concentration by evaporation in vacuo is taken up in methylene chloride and washed twice with dilute sodium bicarbonate solution. The organic phase is dried, concentrated by evaporation and the crude product is chromatographed with petroleum ether/methylene chloride over silica gel. Distillation of the pure fractions in a bulb tube (130°/10-1 torr) yields 3,5-dimethyl-6-piperidinobenzofuran having a melting point of 64°-66°.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](Br)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.S(Cl)([Cl:23])=O.[OH-].[Na+]>>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([Cl:23])[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(Br)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(F)c(Cl)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-cyclopropyl-6-fluoro-7-bromo-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.2 g) is added thionyl chloride (2 ml) and the mixture is refluxed for 1 hour. After cooling, the reaction mixture is poured into ice-water and made alkaline with 10% aqueous sodium hydroxide solution. After stirring for 30 minutes, the resultant is extracted with dichloromethane. The aqueous layer is made acidic with 10% hydrochloric acid and then extracted with dichloroethane. The solvent is concentrated and the residue is recrystallized from acetic acid to give 1-cyclopropyl-6-fluoro-7-chloro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (80 mg), as white crystals, m.p. 258°-260° C.
Reaction SMILES: [I-].[CH3:2]C(C)([O-])C.[K+].[CH3:8][C:9]([CH3:19])(/[CH:14]=[CH:15]/[C:16](=[O:18])[CH3:17])[C:10]([O:12][CH3:13])=[O:11]>CS(C)=O.O1CCCC1>[C:16]([CH:15]1[CH2:2][CH:14]1[C:9]([CH3:19])([CH3:8])[C:10]([O:12][CH3:13])=[O:11])(=[O:18])[CH3:17]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(C)(C)/C=C/C(C)=O
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COC(=O)C(C)(C)C1CC1C(C)=O
Reaction time: 14 h

Procedure:
A solution of trimethylsulfoxium iodide (506 mg, 2.297 mmol) and potassium tert-butoxide (258 mg, 2.297 mmol) in dimethylsulfoxide (6 mL) was stirred for 1.5 hours and then transferred via syringe to a solution of methyl (3E)-2,2-dimethyl-5-oxohex-3-enoate (340 mg, 1.998 mmol) in tetrahydrofuran (6 mL). The reaction mixture was stirred for 14 hours and then partitioned between diethyl ether (25 mL) and a 5:1 v:v mixture of water:saturated aqueous sodium bicarbonate solution (12 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (20 mL, 10 mL). The combined organics were washed with water (3×10 mL) and brine (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford methyl 2-(2-acetylcyclopropyl)-2-methylpropanoate which was carried on without further purification. MS ESI calc'd. for C10H17O3 [M+H]+ 185. found 185.
Reaction SMILES: [C:1]([O:17]C)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15])=[O:7].Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[C:10]1(=[O:15])[N:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:16])[C:13](=[O:14])[CH2:12][CH2:11]1
Reactant: COC(=O)CCCCC(=O)ON1C(=O)CCC1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)CCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of methyl succinimidyl adipate (4.5 g, 17.5 mmol), chlorotrimethylsilane (11.1 ml, 87.5 mmol) and sodium iodide (13.1 g, 87.5 mmol) in 10 ml of acetonitrile was heated at reflux for 12 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate. The reaction mixture was washed repeatedly with 5 percent aqueous sodium bisulfite until the organic solution was colorless. Then it was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to provide 3.2 g (71 percent yield by weight) of adipic acid monosuccinimidyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:22])[C:12]([S:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1.[OH:23]O.O.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[N:11]([CH3:22])[C:12]([S:15]([CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:23])=[N:13][CH:14]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: OO
Reactant: CN(C)CCCSc1ncc(C(=O)c2ccc(Cl)cc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN(C)CCCS(=O)c1ncc(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of (4-Chloro-phenyl)-[2-(3-dimethylamino-propylsulfanyl)-3-methyl-3H-imidazol-4-yl]-methanone (135 mg) in glacial acetic acid (4.00 mL) was added at rt H2O2 (82.0 μL; 30 wt. % in water). The reaction solution was stirred for 48 h at rt, and water (10.0 mL) was added. The solution was brought to pH=12 using NaOH (25% in water) and extracted with CH2Cl2 (250 mL, 2×50.0 mL). The combined organic layers were washed with water (3×20.0 mL) and were dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel (CHCl3/2 M NH3 in MeOH) to give the title compound (121 mg). M calc=353; M+H found=354; 1H NMR (400 MHz, CD3OD): δ 7.91-7.87 (m, 2H), 7.70 (s, 1H), 7.60-7.55 (m, 2H), 4.21 (s, 3H), 3.61-3.48 (m, 2H), 2.54-2.43 (m, 2H), 2.21 (s, 6H), 2.04-1.94 (m, 2H). The compound demonstrated useful biological activity when assessed with a [3H]-N-methylhistamine binding assay (see Table in Example XXV).
Reaction SMILES: [CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14]([OH:16])[CH2:13]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3].[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:4][C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:13][CH:14]([O:16][S:18]([CH3:17])(=[O:20])=[O:19])[CH2:15]2)[S:10][CH:11]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=CCOC(=O)c1csc(N2CC(O)C2)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCOC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.7 %

Procedure:
To a solution of 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-hydroxyazetidine (2.91 g, 11.1 mmol) (obtained as described in Reference Example 41(2)) in methylene chloride (146 ml) were added methanesulfonyl chloride (2.58 ml, 33.3 mmol) and triethylamine (4.67 ml, 33.3 mmol) in an ice bath. After stirring the mixture in the ice bath for 10 minutes, the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. To the residue were added ethyl acetate and diisopropyl ether, and then the mixture was filtered and the resulting residue was washed with diisopropyl ether to give 1-(4-allyloxycarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (2.71 g, yield 77%) as pale brown crystals.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:27])[CH2:11]1.[C:34](Cl)(=[O:38])[CH:35]([CH3:37])[CH3:36]>CN(C1C=CN=CC=1)C.ClCCl>[CH3:36][CH:35]([CH3:37])[C:34]([NH:9][CH:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:18][CH:17]=2)[CH2:13][N:12]([C:26]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)=[O:27])[CH2:11]1)=[O:38]
Reactant: CC(C)C(=O)Cl
Reactant: NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)NC1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
212 μl of triethylamine (1.52 mmol) and 18.6 mg of DMAP (0.152 mmol) were added to a solution of the compound from Example 57A (200 mg, 0.508 mmol) in dichloromethane (12 ml), and 80 μl of isobutyryl chloride (0.76 mmol) were then added at 0° C. The reaction mixture was warmed to RT and stirred overnight. The reaction solution was washed with aqueous 1 N hydrochloric acid and the organic phase was dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by preparative HPLC(RP18 column; acetonitrile/water gradient). Yield: 142 mg (65% of theory)
Reaction SMILES: [SH:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]1[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][S:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[CH:21]1([C:27]([S:1][CH2:2][C@@H:3]([CH3:14])[C:4]([N:6]2[C@H:10]([C:11]([OH:13])=[O:12])[CH2:9][S:8][CH2:7]2)=[O:5])=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: C[C@H](CS)C(=O)N1CSC[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C[C@H](CSC(=O)C1CCCCC1)C(=O)N1CSC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
2.4 g of (4R)-3-[(2S)-3-mercapto-2-methylpropanoyl]-4-thiazolidinecarboxylic acid and 2.8 g of potassium carbonate are dissolved in 50 ml of water. To this solution, 1.8 g of cyclohexanecarbonyl chloride is added dropwise with stirring under ice-cooling. After the addition, the mixture is stirred under ice-cooling for 1 hour and at room temperature for additional 1 hour. This reaction solution is washed with ethyl acetate, acidified with conc. hydrochloric acid, and extracted with ethyl acetate. The organic layer is washed with saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give oil, yield 3.5 g. The oil is purified by silica gel column chromatography to give the titled compound, yield 2.8 g (81%), mp. 79.5°-80° C. (benzene-n-hexane), [α]D23 -176.2° (c=1.0, methanol).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[C:29](C=P(CCCC)(CCCC)CCCC)#N.CO>C1(C)C=CC=CC=1>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]([C@H:12]2[CH2:17][CH2:16][C@H:15]([N:18]([CH3:29])[S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH3:28])(=[O:21])=[O:20])[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: Cc1ccccc1S(=O)(=O)N[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1
Reactant: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccccc1S(=O)(=O)N(C)[C@H]1CC[C@H](C(=O)N2CCN(C(C)C)CC2)CC1

Procedure:
A mixture of 41 mg (0.1 mmol) N-{trans-4-[(4-isopropylpiperazin-1-yl)carbonyl]cyclohexyl}-2-methylbenzenesulfonamide (example 4), 72 mg (0.3 mmol) cyanomethylene tri-n-butylphosphorane and 32 mg (1 mmol) methanol in 2 mL toluene was heated for 16 h to 110° C. After evaporation methanol and DMF were added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient of acetonitrile/water (0.1% NEt3). The combined product fractions were evaporated to dryness to yield 12.4 mg (29%) of the title compound. MS (m/e): 422.2 (MH+).
Reaction SMILES: C([Li])CCC.[CH2:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:14]1([NH:20][C:21]2[CH:30]=[C:29]3[C:24]([C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27][N:28]3[CH:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[C:23](F)[C:22]=2[F:41])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl>C1(C)C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:23]1[C:22]([F:41])=[C:21]([NH:20][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)[CH:30]=[C:29]2[C:24]=1[C:25](=[O:39])[C:26]([C:36]([OH:38])=[O:37])=[CH:27][N:28]2[CH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)c(F)c2c1=O
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(O)c1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)c(OCc3ccccc3)c2c1=O
Reaction time: 1 h

Procedure:
Under ice-cooling, 3.2 ml of n-butyl lithium (1.60 M hexane solution) was added to a 2.4 ml THF solution of 0.58 ml benzyl alcohol, followed by stirring for 1 hour. The solvent was evaporated under a reduced pressure, followed by the addition of 8.0 ml of toluene for suspension. The suspension prepared was added to a toluene suspension of 400 mg of 7-(cyclohexylamino)-1-cyclopentyl-5,6-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, which was prepared in a separate container, followed by stirring at room temperature for 6 hours. Then, 1 M hydrochloric acid was added to the reaction mixture, followed by extraction with chloroform and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent filtration, the solvent was evaporated under a reduced pressure. By recrystallizing the resulting residue using ethyl acetate, 400 mg of 5-(benzyloxy)-7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.