Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:39])[N:8]([C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[CH:29][CH:28]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[N:40]1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C(C)(C)C)(C)C)(=O)=O.[C:63]([O:66]CC)(=[O:65])C>ClCCl>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:39])[N:8]([C:27]2[CH:28]=[CH:29][C:30]([O:33][C:34]([CH3:38])([CH3:37])[CH2:35][OH:36])=[CH:31][CH:32]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:24]2[NH:40][C:63](=[O:65])[O:66][N:25]=2)=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cccc(C)n1
Reactant: CCCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc(C)n(-c2ccc(OC(C)(C)CO)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of 4′-({4-butyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (1.2 g) and 2,6-lutidine (0.34 mL) in dichloromethane (12 mL) was added tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.79 mL) at 0° C., and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. A mixture of the residue, hydroxylammonium chloride (1.5 g), sodium hydrogen carbonate (2.2 g) and dimethyl sulfoxide (10 mL) was stirred overnight at 90° C. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.54 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) were added, and the mixture was stirred at room temperature for 30 min. Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 4.4 mL) was added, and the mixture was stirred overnight at 50° C. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (0.67 g, 52%) as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:11]1(C)[C:12]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:14]=[CH:15][CH:16]=1.N1C=CC=C[CH:23]=1>>[CH3:23][C:15]1[CH:16]=[CH:11][C:12]([S:17]([O:10][CH2:9][C:3]2([O:2][CH3:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)(=[O:18])=[O:19])=[CH:13][CH:14]=1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: COC1(CO)CCOCC1
Reactant: c1ccncc1
Product: COC1(COS(=O)(=O)c2ccc(C)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-methoxytetrahydro-2H-pyran-4-yl)methanol (300 mg, 2.05 mmol) in pyridine (4 ml) at ambient temperature was added toluenesulfonic chloride (430 mg, 2.25 mmol) and the resulting mixture was stirred overnight at about 25° C. The stirred mixture was concentrated and the solid residue was dissolved in DCM and purified by silica gel chromatography using a 12 g column, eluting with 0-30% ethyl acetate in heptane to yield the desired compound “O” as a light yellow solid (360 mg). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.45-1.63 (m, 2H) 1.61-1.79 (m, 2H) 2.46 (s, 3H), 3.16 (s, 3H) 3.53-3.75 (m, 4H) 3.93 (s, 2H), 7.36 (d, J=8.20 Hz, 2H) 7.81 (d, J=8.20 Hz, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]2[C:21]([O:23]C)=[O:22])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].CO.O.[Li+].[OH-]>C1COCC1>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH:16]2[C:21]([OH:23])=[O:22])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)N2CCOCC2C(=O)O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
A solution of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid, methyl ester (0.1 g, 0.28 mmol) in 2.4 mL of THF:methanol:water [4:1:1] was cooled in an ice bath and 2N LiOH (0.3 mL, 0.59 mmol) was added. The reaction was stirred at 0° C. for 30 minutes and at room temperature for 2 hours. After evaporating the solvent, the residue was diluted with ether and filtered. The solid was dissolved in water, neutralized with 1N HCl to pH˜3 and extracted with dichloromethane. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to give 0.06 g of 4-([4-(2-butynyloxy)phenyl]sulfonyl}-morpholine-3-carboxylic acid. Yield˜69.8%. mp 40-42° C. Electrospray Mass Spec 338.1 (M—H)−.
Reaction SMILES: [CH3:1][CH:2]1[CH2:10][CH:9]([OH:11])[C:5](=[C:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[H][H]>CO>[CH3:1][C@H:2]1[CH2:10][CH:9]([OH:11])[C@@H:5]([CH:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1.[CH3:1][C@H:2]1[CH2:10][C@@H:9]([OH:11])[C@@H:5]([CH:6]([CH3:8])[CH3:7])[CH2:4][CH2:3]1
Reactant: [H][H]
Reactant: CC(C)=C1CCC(C)CC1O
Solvent: CO
Product: CC(C)[C@H]1CC[C@@H](C)CC1O
Product: CC(C)[C@H]1CC[C@@H](C)C[C@H]1O
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A 100 ml capacity autoclave was charged with 3.1 g (20 mmol) of pulegol, 6.2 mg (0.01 mmol) of Ru(OAc)2(dppe) and methanol (3 ml), and the mixture was stirred at 50° C. for 18 hours while forcing 3 Mpa of hydrogen. After completion of the reaction, the reaction solution was cooled to room temperature and concentrated. A 3.1 g portion of a mixture of menthol:neomenthol:neoisomenthol=96:1.7:2.3 was obtained. The yield was 95.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Br)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:37]1[CH:42]=[CH:41][CH:40]=[C:39](OB(O)O)[CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.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>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:39]3[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=3)[CH:17]=2)[N:12]=[C:11]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH:23]=2)[C:10]=1[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1cccnc1
Reactant: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(Br)cc2c1OCc1ccccc1
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: O
Solvent: C1COCCO1
Product: Cc1c(COc2cccc(OCC3CCOCC3)c2)nc2ccc(-c3cccnc3)cc2c1OCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of 4-(benzyloxy)-6-bromo-3-methyl-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (300 mg) in dioxane (10 mL) were added pyridin-3-yl boric acid (135 mg), tetrakis(triphenylphosphine)palladium(0) (65 mg), and a 1M aqueous sodium carbonate solution (1.60 mL), followed by stirring at 80° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, and water (20 mL) was added thereto, followed by extraction with chloroform (50 mL). The organic layer was washed sequentially with a saturated aqueous sodium hydrogen carbonate solution and saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=15/85) to obtain 4-(benzyloxy)-3-methyl-6-(pyridin-3-yl)-2-{[3-(tetrahydro-2H-pyran-4-ylmethoxy)phenoxy]methyl}quinoline (265 mg).
Reaction SMILES: [CH2:1]([N:6]=[C:7]=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:9][NH:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.O1CCCC1.C(N(CC)CC)C>O>[CH3:9][N:10]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27][CH3:28])=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:7]([NH:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:8]
Reactant: CNc1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Reactant: CCCCCN=C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
236 μL (1.84 mmol, 2 eq) of pentyl isocyanate are added to a solution of 250 mg (0.92 mmol, 1 eq) of methyl 3-(3′-methylaminobiphenyl-4-yl)propanoate (obtained as in 4c) in 5 mL of a 9/1 tetrahydrofuran/triethylamine mixture. The reaction mixture is stirred for 12 h at room temperature. The reaction is stopped by addition of 10 mL of water and then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (70/30 heptane/ethyl acetate). 245 mg of methyl 3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate are obtained. Yield=70%
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH:40]1([C:43](Cl)=[O:44])[CH2:42][CH2:41]1>>[F:39][C:2]([F:38])([F:1])[C:3]1[CH:33]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:31]=[CH:30][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:21]4[CH2:26][CH2:25][N:24]([C:43]([CH:40]5[CH2:42][CH2:41]5)=[O:44])[C@@H:23]([CH2:27][OH:28])[CH2:22]4)=[N:18][C:17]3=[O:29])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C1N=C(N2CCN[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: O=C1N=C(N2CCN(C(=O)C3CC3)[C@@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[4-(cyclopropylcarbonyl)-3-(R)-(hydroxymethyl)piperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(3-(R)-hydroxymethyl-piperazin-1-yl)-thiazol-4-one (example 139) and Cyclopropanecarbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1.[NH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(NC(C)C)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([NH:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])(=[O:19])=[O:18])=[CH:13][C:12]=2[CH3:21])=[O:9])[CH:3]=1
Reactant: CCOC(=O)CCCN
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1NC(=O)c1cc(Cl)ncn1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCNS(=O)(=O)c1ccc(NC(=O)c2cc(Cl)ncn2)c(C)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-(6-chloropyrimidine-4-carboxamido)-3-methylbenzene-1-sulfonyl chloride (Intermediate 30, 1.2 g; 3.47 mmol) in THF (100 ml) was treated with ethyl 4-aminobutanoate (720 mg; 4.34 mmol) and diisopropylamine (2 ml; 14.3 mmol). After stirring at RT for 18 hours the solvent was removed in vacuo and the residue redissolved in DCM and washed with water. The organic extracts were passed through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc. The title product was obtained as a white solid.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]2[CH:18]=[CH:19][C:20]3[C:25](=[O:26])[O:24][C:23]([CH3:28])([CH3:27])[O:22][C:21]=3[CH:29]=2)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[CH2:32]([C:35]1[CH:40]=[CH:39][C:38]([C:41]#[CH:42])=[CH:37][CH:36]=1)[CH2:33][CH3:34]>>[CH2:32]([C:35]1[CH:36]=[CH:37][C:38]([C:41]#[C:42][C:2]2[CH:31]=[CH:30][C:5]([CH2:6][N:7]([C:17]3[CH:18]=[CH:19][C:20]4[C:25](=[O:26])[O:24][C:23]([CH3:27])([CH3:28])[O:22][C:21]=4[CH:29]=3)[C:8](=[O:16])[CH2:9][CH2:10][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15]3)=[CH:4][CH:3]=2)=[CH:39][CH:40]=1)[CH2:33][CH3:34]
Reactant: C#Cc1ccc(CCC)cc1
Reactant: CC1(C)OC(=O)c2ccc(N(Cc3ccc(Br)cc3)C(=O)CCC3CCCC3)cc2O1
Product: CCCc1ccc(C#Cc2ccc(CN(C(=O)CCC3CCCC3)c3ccc4c(c3)OC(C)(C)OC4=O)cc2)cc1

Procedure:
The titled compound was prepared following the procedure N using N-(4-bromobenzyl)-3-cyclopentyl-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)propanamide and 4-propylphenylacetylene as a white powder (40%). M+ (ESI): 550.1. HPLC, Rt: 6.33 min (Purity: 100%).
Reaction SMILES: Br[C:2]1[C:3]([O:11][CH3:12])=[C:4]([C:7]([O:9][CH3:10])=[O:8])[S:5][CH:6]=1.CC1(C)COB([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)OC1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[CH3:12][O:11][C:3]1[C:2]([C:20]2[N:24]([CH3:25])[N:23]=[CH:22][CH:21]=2)=[CH:6][S:5][C:4]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1scc(Br)c1OC
Reactant: Cn1nccc1B1OCC(C)(C)CO1
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1scc(-c2ccnn2C)c1OC
Reaction time: 12 h
Yield: 852.2 %

Procedure:
Methyl 4-bromo-3-(methyloxy)-2-thiophenecarboxylate (250 mg, 0.10 mmol) [prepared according to Corral, C.; El-Ashmawy, M. B.; Lissavetzky, J.; Basilio, A.; Giraldez, A.; Eur. J. Med. Chem. Chim. Ther. 22; 1987; 251-254.], 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (250 mg, 1.20 mmol), Pd(PPh3)4 (58 mg, 49.8 μmol) and K2CO3 (550 mg, 3.98 mmol) in dioxane (5 mL) and H2O (1 mL) were combined in a sealed tube. After 12 h at 80° C., the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, 0.5% MeOH in DCM) affording the title compound (215 mg, 86%) as a brown residue: LCMS (ES) m/z=253 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=O)[CH:3]=1.Cl.[F:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][NH2:33])=[CH:28][CH:27]=1.CC([O-])=O.[Na+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])=[C:4]([C:16](=[N:33][O:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:3]=1
Reactant: O=C(c1cc(Cl)ccc1NS(=O)(=O)C(F)(F)F)C1CCCCC1
Reactant: NOc1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(Nc1ccc(Cl)cc1C(=NOc1ccc(F)cc1)C1CCCCC1)C(F)(F)F
Yield: 37.6 %

Procedure:
A solution of N-(4-chloro-2-cyclohexanecarbonylphenyl)trifluoromethanesulfonamide 29E (410 mg, 1.11 mmol), O-(4-fluorophenyl)hydroxylamine hydrochloride (200 mg, 1.22 mmol) and anhydrous NaOAc (100 mg, 1.22 mmol) in EtOH (20 mL) was stirred for 15 hours at RT. The reaction mixture was concentrated under vacuum and the residue purified by column chromatography (eluting with CH2Cl2/PE, 3:7 to CH2Cl2) to afford N-{4-chloro-2-[(4-flurophenoxyimino)cyclohexylmethyl]phenyl}trifluoromethanesulfonamide 169 (200 mg, 38%), as a white solid. 1H n.m.r. (200 MHz, CDCl3) δ 7.54, d, J=8.8 Hz, 1H; 7.43, dd, J=2.2 and 8.8 Hz, 1H; 7.24, d, J=2.2 Hz, 1H; 7.12-6.95, m, 5H; 2.56, m, 1H; 2.14, m, 1H; 1.93-1.65, m, 5H; 1.29, m, 4H.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH2:14].FC1C=CC(OC)=CC=1[C@@H:24]1[CH2:26][C@H:25]1[C:27]#N.C(Cl)(Cl)Cl.CC[OH:35]>O=[Pt]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:27](=[O:35])[CH:25]([CH3:24])[CH3:26]
Reactant: COc1ccc(F)c([C@@H]2C[C@H]2CN)c1
Reactant: CCO
Reactant: COc1ccc(F)c([C@@H]2C[C@H]2C#N)c1
Agent: O=[Pt]=O
Solvent: ClC(Cl)Cl
Product: COc1ccc(F)c([C@@H]2C[C@H]2CNC(=O)C(C)C)c1
Reaction time: 3 h

Procedure:
(trans)-2-(2-Fluoro-5-methoxyphenyl)cyclopropanemethanamine: A suspension of (trans)-2-(2-fluoro-5-methoxyphenyl)cyclopropane carbonitrile (5.0 g, 26 mmol), PtO2 (200 mg), and CHCl3 (10 mL) in EtOH (65 mL) was hydrogenated in a Parr apparatus at 55 psi for 3 h. The catalyst was filtered through a plug of celite and the solvents were removed. The resulting hydrochloride salt was then partitioned between CH2Cl2 and 10% K2CO3. The organic layer was separated, dried over K2CO3, and concentrated to afford the title compound as the free amine, 3.8 g (74%): 1H NMR (250 MHz, CDCl3) δ0.79-0.82 (m, 1H), 0.90-0.95 (m, 1H), 1.49 (br s, 2H), 1.70-1.76 (m, 1H), 1.82-1.86 (m, 1H), 2.60-2.74 (m, 2H), 3.75 (s, 3H), 6.35-6.42 (m, 1H), 6.50-6.62 (m, 1H), 6.85-6.90 (m, 1H).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:38]([O:40][CH3:41])=[O:39])=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C-:42]#[N:43].[Na+]>CN(C=O)C>[C:42]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:38]([O:40][CH3:41])=[O:39])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:21]2[C:20]2[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1)#[N:43]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(COS(=O)(=O)c1ccc(C)cc1)COc1ccccc1-3
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CC#N)COc1ccccc1-3
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
A solution of methyl 14-cyclohexyl-7(R,S)-({[(4-methylphenyl)sulfonyl]oxy}methyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.35 M) in DMF was treated with NaCN (1.2 eq.) and the resulting mixture was stirred overnight at RT. The reaction was quenched by addition of sat. aq. NaHCO3 and extracted into EtOAc. The combined organic layers were washed with brine, before being dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (PE/EtOAc 90:10) affording the product as a yellow foam (90%). (ES+) m/z 429 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2C(C#N)=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1.[OH-:21].[Na+].[CH2:23]([OH:25])[CH3:24]>>[CH:1]1([NH:4][C:5]2[C:24]([C:23]([OH:21])=[O:25])=[N:7][CH:8]=[C:9]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=2)[CH2:3][CH2:2]1
Reactant: [OH-]
Reactant: CCO
Reactant: N#Cc1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Agent: [Na+]
Product: O=C(O)c1ncc(Cc2ccc(F)cc2)cc1NC1CC1
Temperature: 100 °C
Yield: 99 %

Procedure:
A solution of 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarbonitrile (360 mg, 1.34 mmol) in ethanol (25 mL) was treated with sodium hydroxide (2 mL, 50% aqueous) and heated at 100° C. (bath temperature) for 14 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water and cooled in an ice bath. The solution was acidified by the slow addition of 6 NHCl (final pH˜3). The aqueous layer was extracted with ethyl acetate and the organics dried over sodium sulfate. Filtration and concentration gave 3-(cyclopropylamino)-5-[(4-fluorophenyl)methyl]-2-pyridinecarboxylic acid (385 mg, 99%) as a white powder. 1H NMR (400 MHz, CDCl3) δ 8.94 (br, 1 H), 7.93 (s, 1 H), 7.74 (s, 1 H), 7.30 (s, 1 H), 7.15 (dd, J=8.5, 5.5 Hz, 2 H), 7.00 (t, J=8.7 Hz, 2 H), 3.97 (s, 2 H), 2.40 (m, 1 H), 0.77 (m, 2 H), 0.54 (m, 2 H); MS m/z 287 M+1).
Reaction SMILES: [NH:1]([C:8]1[C:9](=[O:20])[C:10](=[N:13][C:14]2[CH:19]=CC=CC=2)[C:11]=1[OH:12])[C:2]1[CH:7]=CC=CC=1.[CH:21]([N:24]1[CH2:29][CH2:28]NCC1)([CH3:23])[CH3:22]>>[OH-:12].[OH:12][C:11]1[C:10](=[N+:13]2[CH2:14][CH2:19][N:24]([CH:21]([CH3:22])[CH3:23])[CH2:29][CH2:28]2)[C:9](=[O:20])[C:8]=1[N:1]1[CH2:2][CH2:7][N:1]([CH:8]([CH3:9])[CH3:11])[CH2:2][CH2:7]1
Reactant: CC(C)N1CCNCC1
Reactant: O=c1c(Nc2ccccc2)c(O)c1=Nc1ccccc1
Product: CC(C)N1CCN(c2c(O)c(=[N+]3CCN(C(C)C)CC3)c2=O)CC1
Product: [OH-]

Procedure:
A mixture of 4.0 grams of 2-anilino-3-hydroxy-4-(phenylimino)-2-cyclobuten-1-one and 3.9 grams of 1-isopropylpiperazine is heated at 200°-206° C. in an atmosphere of dry nitrogen for 30 minutes. The mixture is cooled and the resulting solid is comminuted, washed with anhydrous ethyl ether, dried and then recrystallized from water to give 1-[2-hydroxy-3-(4-isopropyl-1-piperazinyl)-4-oxo-2-cyclobuten-1-ylidene]-4-isopropyl-piperazinium hydroxide inner salt melting at about 194.5°-196.5° C.
Reaction SMILES: Cl.[N:2]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:24][C:25]1[C:34]([F:35])=[C:33](F)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1>C(#N)C>[NH2:24][C:25]1[C:34]([F:35])=[C:33]([N:9]2[CH2:10][CH2:11][CH2:12][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]2)[C:32]([F:37])=[C:31]2[C:26]=1[C:27](=[O:44])[C:28]([C:41]([OH:43])=[O:42])=[CH:29][N:30]2[CH:38]1[CH2:40][CH2:39]1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: c1cncc(-n2ccnn2)c1
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1c(F)c(N2CCCC(n3ccnn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 38.7 %

Procedure:
3-(1,2,3-triazol-1-yl)pyridine hydrochloride (63 mg, 0.33 mmol) and DBU (77 mg, 0.5 mmol) were added to a suspension of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acid (50 mg, 0.18 mmol) in acetonitrile (5 ml). The reaction mixture was refluxed for 48 hrs and then concentrated under vacuo. The residue was diluted with water and thus separated solid was filtered, washed with water, acetonitrile and dried to give 30 mg of desired product. m.p. 252-254° C.; 1H NMR (TFA) δ: 9.36 (s, 1H), 8.65 (s, 1H), 8.53 (s, 1H), 5.28 (m, 1H), 3.60-4.66 (m, 5H), 2.10-2.58 (m, 4H), 1.32-1.68 (m, 4H).
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:37])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:37][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1ccccc1-n1nc(C(C)(C)C)cc1N
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: COc1ccccc1-n1nc(C(C)(C)C)cc1NC(=O)Cc1ccc(-n2cnc3cccnc32)cc1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(2-methoxy-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 481.07 [M+H]+; tR=3.02 min (System 3).