Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][CH:3]=[N:2]1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:15][CH2:16][C:17]([O-:19])=[O:18])C=CC=CC=1.[Li+]>>[S:1]1[C:5]([CH:6]=[CH:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:4][CH:3]=[N:2]1
Reactant: O=C([O-])CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccns1
Agent: [Li+]
Product: O=C(O)CC=Cc1ccns1

Procedure:
Reaction of isothiazole-5-carboxaldehyde with lithium 3-(triphenylphosphoranylidene)propanoate under standard Wittig conditions provides 4-(5-isothiazolyl)-3-butenoic acid which is reduced and cyclized with aluminum chloride to provide 4-oxo-4,5,6,7-tetrahydrobenzisothiazole. The 4-oxo compound is reacted with methylenetriphenyl phosphorane under standard Wittig conditions and a methylene is inserted into the resulting 4-methylene compound via a Simmons Smith reaction to provide 6,7-dihydrospiro[benzisothiazol-4(5H),1'-cyclopropane] which is oxidized with hydrogen peroxide in acetic acid to give 6,7-dihydrospiro[3-oxo-benzisothiazol-4(5H),1'-cyclopropane 1,1-dioxide (4-spirocyclopropyl tetrahydrosaccharin). This is chloromethylated according to the procedure of Preparation 1A to give 2-chloromethyl-4-spirocyclopropyl-4,5,6,7-tetrahydrosaccharin.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][OH:19])=[CH:16][C:3]1=2.C(Cl)Cl.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:30](=[O:31])([O:19][CH2:18][CH2:17][C:15]1[CH:14]=[CH:13][C:4]2[O:5][CH2:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:2](=[O:1])[C:3]=2[CH:16]=1)[NH:29][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1c2ccccc2COc2ccc(CCO)cc21
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A stirred solution of 2.54 g (0.01 mol) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol of Example 1, 20 ml of sieve dried CH2Cl2 and 1.55 g (0.013 mol) of phenylisocyanate was heated 20 hours under reflux with exclusion of moisture. The cooled solution was concentrated on a rotary evaporator to afford an oil which was dissolved in 10 ml of hot toluene. The solution was seeded with product (previously obtained by the method described herein), stirred until a thick suspension formed and allowed to stand overnight (about 16 hours) at ambient temperature. Filtration and drying in vacuo afforded 2.53 g (67.8%) of a colorless solid of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl carbanilate, m.p. 98°-99° C.
Reaction SMILES: [CH3:1]C1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.C([O:21][CH2:22][CH2:23][C:24]1([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:28][CH2:27][CH2:26][C:25]1=[O:29])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:29][C:25]12[CH2:26][CH2:27][CH2:28][C:24]1([C:30]([O:32][CH2:33][CH:34]=[CH2:35])=[O:31])[CH2:23][CH2:22][O:21]2
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C=CCOC(=O)C1(CCOC(C)=O)CCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1cc[nH+]cc1
Solvent: CO
Product: C=CCOC(=O)C12CCCC1(OC)OCC2
Temperature: 25 °C
Yield: 80 %

Procedure:
A reaction vessel was charged with 1,580 parts of methanol, 25 parts of PPTS, 254 parts of 2-(2-acetoxyethyl)-2-(2-propenyloxycarbonyl)cyclopentanone (14) obtained in Preparation Example 3 at room temperature. The mixture was refluxed for three hours with stirring. After cooling the reaction solution to room temperature, 30 parts of potassium carbonate was added and the mixture was stirred for one hour at room temperature. Insoluble matters were removed by filtration, the filtrate was washed with saturated brine, and the solvent was evaporated. The residue was distilled under reduced pressure to obtain 146 parts of the target compound (15) (yield: 80%).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH:21]1[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][N:21]3[CH2:27][CH2:26][CH2:25][N:24]([CH2:2][C:3]4[CH:8]=[C:7]([C:9]5[CH:10]=[C:11]([O:19][CH3:20])[C:12]([O:17][CH3:18])=[C:13]([O:15][CH3:16])[CH:14]=5)[CH:6]=[CH:5][N:4]=4)[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2ccnc(CCl)c2)cc(OC)c1OC
Product: COc1cc(-c2ccnc(CN3CCCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)ccn4)CC3)c2)cc(OC)c1OC

Procedure:
2-Chloromethyl-4-(3,4,5-trimethoxyphenyl)pyridine (195 mg) and homopiperazine (32 mg) were reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[N:14]([CH:17]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[N:25]([CH3:32])[N:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[CH2:19][CH:18]1O)=[N+:15]=[N-:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:14]([CH:17]1[CH2:23][CH2:22][O:21][CH:20]([C:24]2[N:25]([CH3:32])[N:26]=[CH:27][C:28]=2[N+:29]([O-:31])=[O:30])[CH2:19][CH:18]1[F:11])=[N+:15]=[N-:16]
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: Cn1ncc([N+](=O)[O-])c1C1CC(O)C(N=[N+]=[N-])CCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1CC(F)C(N=[N+]=[N-])CCO1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of deoxo-Fluor (50% in THF, 0.576 mL, 1.56 mmol) was added dropwise to an ice-cooled solution of 5-azido-2-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-ol (353 mg, 1.25 mmol, intermediate 27) in DCM (6 mL). The mixture was allowed to warm to room temperature whilst stirring for 16 hr before being cooled in an ice bath and saturated aqueous NaHCO3 (10 mL) slowly added. The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel chromatography (0-50% EtOAc/isohexane) gave 5-(5-azido-4-fluorooxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as a clear gum. To a solution of this gum (145 mg, 0.51 mmol) in THF (5 mL) and water (1 mL) was added triphenylphosphine (147 mg, 0.56 mmol) and the mixture heated at 60° C. for 2 hr. The mixture was diluted with EtOAc (10 mL) and washed with brine (2×5 mL). The organic layer was passed through a phase separation cartridge and concentrated under reduced pressure. The residue was dissolved in DCM (2 mL) and DIPEA (0.178 mL, 1.02 mmol) and di-tert-butyl dicarbonate (134 mg, 0.61 mmol) were added. The mixture was stirred at room temperature for 2 hr. Water (2 mL) was added and the mixture extracted with DCM (3×2 mL). The combined organic layers were passed though a phase separation cartridge, concentrated under reduced pressure and the residue purified via silica gel chromatography (0-50% EtOAc/isohexane) to give tert-butyl N-[5-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate as a clear gum (180 mg, 39% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 5.54 (dd, J=10.5, 4.2 Hz, 1H), 5.10-4.92 (m, 2H), 4.21-4.09 (m, 2H), 4.05 (s, 3H), 3.74-3.62 (m, 1H), 2.57-2.38 (m, 1H), 2.35-2.15 (m, 2H), 1.91-1.81 (m, 1H), 1.46 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:26][CH2:27][N:28]3[C@H:33]4[CH2:34][CH2:35][C@@H:29]3[CH2:30][CH:31]([N:36]3[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]=[C:37]3[CH3:45])[CH2:32]4)[CH2:13][CH2:12][N:11]([CH:14]([CH3:25])[C:15]([O:17]CC3C=CC=CC=3)=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:26][CH2:27][N:28]3[C@H:33]4[CH2:34][CH2:35][C@@H:29]3[CH2:30][CH:31]([N:36]3[C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=5[N:38]=[C:37]3[CH3:45])[CH2:32]4)[CH2:13][CH2:12][N:11]([CH:14]([CH3:25])[C:15]([OH:17])=[O:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C)C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C)C(=O)O)CC1
Yield: 77.8 %

Procedure:
A solution of benzyl 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoate (136 mg, 0.223 mmol) in 8 mL MeOH was stirred for 3 h under an atmospheric pressure of hydrogen and in the presence of catalytic 5% Pd/C. Filtration and evaporation afforded 2-(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)propanoic acid (90.0 mg, 78%) as a solid. 1H NMR (400 MHz, CDCl3), δ 7.69 (m, 1H), 7.40 (m, 1H), 7.26-7.12 (m, 4H), 7.09-6.95 (m, 2H), 5.37 (m, 1H), 3.85-3.55 (m, 5H), 2.81-1.77 (18H), 2.62 (s, 3H), 1.61-1.41 (3H); ESI-MS 517 (M−H).
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].[K].[CH3:6][S:7][C:8]1[C:13]([F:14])=[CH:12][NH:11][C:10](=[O:15])[N:9]=1>CN(C)C=O>[OH:3][CH2:2][CH2:1][N:11]1[CH:12]=[C:13]([F:14])[C:8]([S:7][CH3:6])=[N:9][C:10]1=[O:15]
Reactant: OCCBr
Reactant: CSc1nc(=O)[nH]cc1F
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nc(=O)n(CCO)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 77 %

Procedure:
Ethylene bromohydrin (0.023 mol) was added to a solution of the potassium salt of 4-methylthio-5-fluoropyrimid-2-one (0.015 mol) in dimethylformamide (65 ml) and the reaction mixture was stirred at room temperature for 24 h before evaporation at reduced pressure (1 mm Hg). The residue was extracted with chloroform, the solution was washed with aqueous 2 N NaOH, with water and was dried (MgSO4) before evaporation. The solid residue was recrystallized from acetone; yield 77%, m.p. 161°-162° C. (Found: C, 41.36; H, 4.62. Calc. for C7H9FN2O2S: C, 41.17; H, 4.44).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1.C(O)(=O)C>CO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([C:11]2[CH:20]=[CH:19][C:18]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1
Reactant: O=C(/C=C/c1cccnc1)c1ccc2c(c1)CCCC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(CCc1cccnc1)c1ccc2c(c1)CCCC2
Temperature: 25 °C
Reaction time: 6 h
Yield: 61.7 %

Procedure:
A mixture of [(E)-2-(3-pyridyl)ethenyl]-(5,6,7,8-tetrahydronaphthalen-2-yl)ketone (6.32 g), palladium black (150 mg) and acetic acid (3 ml) in MeOH (50 ml) was stirred under hydrogen atmosphere at room temperature for 6 hours. The catalyst was filtered off and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and brine, and dried. After removal of the solvent, the residue was recrystallized f rom hexane-ethyl acetate to give the titled compound (3.93 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15].C(N(CC)CC)C.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>ClCCl.CN(C)C1C=CN=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11]([CH2:13][O:14][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[O:10][N:9]=2)=[CH:4][C:3]=1[F:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCC1CC(c2ccc(Br)c(F)c2)=NO1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC1CC(c2ccc(Br)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
[3-(4-Bromo-3-fluorophenyl)-4,5-dihydroisoxazol-5-yl]methanol (7.518 g, 27.4 mmol) was dissolved in a mixture of triethylamine (4.59 ml, 33.0 mmol) and dichloromethane (100 ml). The resulting solution was cooled to 0° C., then a 1M solution of tert-butyldimethylsilylchloride (30.2 ml) in dichloromethane was added dropwise over 30 minutes. 4-Dimethylamino pyridine (0.67 g, 5.48 mmol) was added and the reaction mixture left to stir overnight at room temperature. The reaction mixture was washed with water (200 ml). The dichloromethane layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to yield 9.263 g (87%) of the desired compound as a colourless oil.
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18]CC2C=CC=CC=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]>C(O)C>[F:1][CH:2]([F:26])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([OH:18])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])[CH3:6]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@@H](C)COC(F)F)c1
Solvent: CCO
Product: COC(=O)c1cc(O)cc(O[C@@H](C)COC(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 345.6 %

Procedure:
Methyl 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-phenylmethoxy-benzoate (0.48 g, 1.1 mmol) was dissolved in ethanol (10 mL) and THF (10 mL) and the flask evacuated and purged with argon (3 times). 10% Palladium on carbon (140 mg) was added and the flask further evacuated and finally purged with hydrogen gas. The reaction mixture was stirred at RT for 20 hours until completion. The reaction mixture was evacuated and purged with argon (3 times) then the catalyst removed by filtration through Celite®. The filtrate was concentrated in vacuo to give the desired compound (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[N:19][OH:20])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(Cc2ccccc2)=NO)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution consisting of 1-(4-methoxy-phenyl)-2-phenyl-ethanone (commercially available, 1011 g, 4468 mmoles) in absolute ethanol (2 gallons) is added hydroxylamine hydrochloride (373 g, 5362 mmoles) and sodium acetate (440 g, 5362 mmoles.) The reaction mixture is stirred at room temperature for two days. The mixture is diluted with water (8 L) and the resultant mixture is stirred at room temperature for one hour. The mixture is subsequently filtered to give a solid, which is rinsed with water (3×4 L.) The product is dried to afford the synthetic intermediate 1-(4-methoxy-phenyl)-2-phenyl-ethanone oxime (948 g.)
Reaction SMILES: [O:1]1[C@:5]([CH3:22])([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:21])[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C@H:2]1[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[O:1]1[C@:5]([CH3:22])([CH2:6][CH2:7][CH2:8][C@H:9]([CH3:21])[CH2:10][CH2:11][CH2:12][C@H:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[C@@H:2]1[CH:3]=[O:4]
Reactant: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@]1(C)O[C@@H]1CO
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)CCC[C@@H](C)CCC[C@@]1(C)O[C@H]1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
1.70 g (5.45 mmol) of (2R,3R,7R,11R)-2,3-epoxy-3,7,11,15-tetramethylhexadecanol in 5 ml of methylene chloride was added dropwise while stirring at room temperature to a suspension of 1.6 g (5.45 mmol) of pyridinium chlorochromate in 50 ml of methylene chloride and the mixture was stirred at room temperature overnight. Celite was then added and the mixture was stirred with 100 ml of ether for 1 hour, subsequently filtered and rinsed with ether. The crude product was chromatographed on silica gel with toluene. There was obtained 1.46 g (87%) of (2R,3R,7R,11R)-2,3-epoxy-3,7,11,15-tetramethylhexadecanal, [α]D20 =-5.87° (c=1.5% in chloroform).
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(OC)n3)nc2CC(C)(C)C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(F)c(-c2ccc(COc3cc(CCC(=O)O)nc(OC)n3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methoxypyrimidin-4-yl)acrylic acid (530 mg) in THF (5.0 ml) and ethyl acetate (5.0 mL) was added 10% palladium-activated carbon (53 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (135 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[C:19](=O)OC(C)(C)C)=[CH:13][CH:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.O>C(O)=O.C=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:18]([CH2:26][CH2:27][O:28][CH3:29])[CH3:19])=[CH:15][N:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1
Reactant: COCCN(Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1)C(=O)OC(C)(C)C
Agent: C=O
Solvent: O=CO
Solvent: O
Product: COCCN(C)Cc1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Temperature: 70 °C
Yield: 67.3 %

Procedure:
tert-Butyl (6-(6-chloro-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (95 mg, 0.22 mmol) was dissolved in 0.75 ml of formic acid and 1.4 ml of formalin. The reaction was heated at 70° C. for 4 hours. The reaction was cooled to room temperature, water was added and the aqueous layer was extracted with DCM. The aqueous layer was carefully basified with solid potassium carbonate and extracted 3 times with DCM. The crude product was purified by chromatography using a gradient of 5% to 15% methanol in DCM to give 50 mg (66.0%) of a white powder.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([F:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:30]2[CH2:31][CH2:32][N:27]([CH:25]=[O:26])[CH2:28][CH2:29]2)[C:12]([F:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: O=CN1CCNCC1
Reactant: CC(=O)Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Product: CC(=O)Nc1c(F)c(N2CCN(C=O)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 1 (1), 5-acetylamino-1-cycloproply-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (m.p. 247°-248° C.) was allowed to react with 1-formylpiperazine to give 5-acetylamino-1-cyclopropyl-6,8-difluoro-7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:9][C:10]1[S:14][C:13]2=[N:15][C:16]([C:18](O)=[O:19])=[CH:17][N:12]2[CH:11]=1>>[Br:9][C:10]1[S:14][C:13]2=[N:15][C:16]([C:18]([NH:5][C:4]3[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=3)=[O:19])=[CH:17][N:12]2[CH:11]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: O=C(Nc1cccc(Cl)c1)c1cn2cc(Br)sc2n1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLVI, using 3-chloroaniline and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:19](=[N:27]O)(Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCO>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][O:11][C:9]=2[CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Cc1ccnc(Br)c1
Reactant: ON=C(Cl)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1-c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.4 %

Procedure:
To a stirred solution of Compound 16 (1.71 g, 8.0 mmol) and Et3N (2.23 mL, 16 mmol) in EtOH (16 mL) was added a solution of benzoylchloride oxime (1.62 g, 10.4 mmol) in EtOH (16 mL) over 90 min. The solution was stirred at 25° C. for 90 min. Then, the solution was heated to reflux for 24 h. The solution was cooled to 25° C. and concentrated. The crude material was taken up in CH2Cl2 (50 mL) and poured into saturated aqueous NaHCO3 (50 mL), extracted with CH2Cl2 (3×50 mL), dried (Na2SO4), and filtered. Flash chromatography (SiO2, 20% EtOAc-hexanes) provided the title compound (1.32 g, 4.19 mmol, 52%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[C:12]([C:43]([OH:45])=O)=[C:13]([N:28]([CH2:34][C:35]2[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=2[F:42])[C:29]([O:31]CC)=O)[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:46][C:47]1[CH:53]=[CH:52][C:50]([NH2:51])=[CH:49][CH:48]=1>>[CH2:1]([N:8]([CH2:10][C:11]1[C:12]2[C:43](=[O:45])[N:51]([C:50]3[CH:52]=[CH:53][C:47]([F:46])=[CH:48][CH:49]=3)[C:29](=[O:31])[N:28]([CH2:34][C:35]3[C:40]([F:41])=[CH:39][CH:38]=[CH:37][C:36]=3[F:42])[C:13]=2[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][O:26][CH3:27])=[O:24])=[CH:18][CH:17]=1)[CH3:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)N(Cc1c(F)cccc1F)c1sc(-c2ccc(NC(=O)NOC)cc2)c(CN(C)Cc2ccccc2)c1C(=O)O
Reactant: Nc1ccc(F)cc1
Product: CONC(=O)Nc1ccc(-c2sc3c(c2CN(C)Cc2ccccc2)c(=O)n(-c2ccc(F)cc2)c(=O)n3Cc2c(F)cccc2F)cc1
Yield: 88 %

Procedure:
The similar reaction as described in Example 5 by using 4-(N-benzyl-N-methylaminomethyl)-2-[N-(2,6-difluorobenzyl)-N-ethoxycarbonylamino]-5-[4-(3-methoxyureido)phenyl]thiophene-3-carboxylic acid (2.87 g, 4.49 mmol) and 4-fluoroaniline (0.64 ml, 6.735 mmol) gave the title compound (2.71 g, 88%) as pale yellow powders.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O>[Cl:14][C:15]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:16]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1Cl
Reactant: CCOC(=O)Cc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)Cc1cccc(-c2ccc(C(F)(F)F)cc2Cl)c1
Yield: 49.6 %

Procedure:
Ethyl 3-iodophenylacetate (2.90 g), 2-chloro-4-(trifluoromethyl)phenyl boronic acid (3.3 g), 2M aqueous sodium carbonate solution (5 mL), dioxane (10 mL) and dichloro-bis(triphenylphosphine)palladium(II) (350 mg) were heated at 80° C. for 30 min with stirring. The reaction mixture was then cooled, poured into water, extracted with ethyl acetate, and the organic layer was separated and concentrated under vacuum in the presence of Celite® to a solid residue. This solid residue was purified by medium pressure liquid chromatography on silica gel eluting with a gradient of ethyl acetate in hexanes to yield 1.7 g of the title compound. 1H NMR (CDCl3) δ 7.14 (s, 1H), 7.56 (d, 1H) 7.30-7.45 (m, 5H), 4.77 (q, 2H), 3.67 (s, 2H), 1.26 (t, 3H).