Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21](=[O:24])[CH:22]=[CH2:23])=[CH:17][CH:18]=2)[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([CH3:25])[CH2:12][C:11]1([CH3:33])[CH3:32])(=[O:9])[CH3:8]>C1COCC1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]([CH2:22][CH2:23][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2])=[O:24])=[CH:17][CH:18]=2)[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([CH3:25])[CH2:12][C:11]1([CH3:33])[CH3:32])(=[O:9])[CH3:8]
Reactant: CCOCCO
Reactant: C=CC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O
Solvent: C1CCOC1
Product: CCOCCOCCC(=O)Nc1ccc2c(c1)C(C)(c1ccccc1)CC(C)(C)N2C(C)=O

Procedure:
Michael addition of 2-ethoxyethanol (19 mg) and 1-acetyl-6-acryloylamino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (8 mg) in THF (1 mL) was performed according to the method described in example 65.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:69][CH:66]1[CH2:67][CH2:68][N:64]([CH2:63][C:62]2[CH:70]=[CH:71][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:19]3[N:20]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:17][CH:18]=3)=[O:22])=[CH:60][CH:61]=2)[CH2:65]1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (35 mg, 0.10 mmol), EDCI (26 mg, 0.14 mmol), HOBt (19 mg, 0.15 mmol), DIPEA (0.03 mL, 0.19 mmol), 1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-ol hydrochloride (30 mg, 0.11 mmol) and DCM (10 mL).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[NH2:2].[CH:13]([O-])=[O:14].[Na+].C(OCC)=O.C(O)=O>C(O)C>[CH:13]([NH:2][NH:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)=[O:14]
Reactant: NNc1ccc(CC(=O)O)cc1
Reactant: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CCOC=O
Solvent: CCO
Product: O=CNNc1ccc(CC(=O)O)cc1
Yield: 56.7 %

Procedure:
p-Hydrazinophenylacetic acid (3.32 g, 0.02 M), sodium formate (2.72 g, 0.04 m), ethyl formate (49 g), formic acid (10 ml) was refluxed for one hour in ethanol (100 ml). The residue was removed by filtration and the filtrate on concentration afforded light-yellow crystals (2.2 g, 55 percent).
Reaction SMILES: [C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH:17]=[CH:18][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]4=[O:25])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(Cl)Cl.CCOC(C)=O>C(O)C.[Pd]>[C:1]12([CH2:11][C:12]([NH:14][C:15]3[CH:24]=[CH:23][CH:22]=[C:21]4[C:16]=3[CH2:17][CH2:18][N:19]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:20]4=[O:25])=[O:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c(=O)n(Cc3ccccc3)ccc12
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nc1cccc2c1CCN(Cc1ccccc1)C2=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 81.8 %

Procedure:
A 50 mL round-bottom flask was charged with a solution of 2-Adamantan-1-yl-N-(2-benzyl-1-oxo-1,2-dihydro-isoquinolin-5-yl)-acetamide (14 mg, 0.033 mmol) in absolute ethanol (6 mL) and 10% Pd/C (10 mg). The reaction vessel was evacuated and filled with hydrogen via balloon. The reaction suspension was stirred at room temperature under hydrogen (1 atm) for 17 h. The resulting mixture was filtered and the filtrate was concentrated on a rotary evaporator. The crude product was purified by prep. TLC using DCM/EtOAc (3:1) as the elutant affording the title compound (11.8 mg, 0.027 mmol, 84% yield) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[NH:20]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CN(C=O)C>[CH:8]1([CH2:11][CH2:12][O:13][C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]3[CH2:33][CH:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1
Reactant: BrCC1CCOCC1
Reactant: COc1nc2c(N)nc(OCCC3CC3)nc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1CC1CCOCC1
Temperature: 50 °C
Yield: 44.6 %

Procedure:
2-[(2-Cyclopropylethyl)oxy]-8-methoxy-9H-purin-6-amine trifluoroacetic acid salt (0.30 g) was heated with potassium carbonate (anhydrous, 0.46 g) in anhydrous DMF (5 mL) at 60° C. for 1 hour. The reaction was cooled to room temperature before 4-(bromomethyl) tetrahydro-2H-pyran (0.16 g) in anhydrous DMF (1 mL) was added. The reaction mixture was then heated to 50° C. overnight. The reaction was quenched into water (50 mL) and extracted with ethyl acetate (50 mL, 3 times). The organic layer was combined and washed with brine (50 mL). The organic layer was separated and dried by passing through a hydrophobic frit before being evaporated under reduced pressure to give oil). This material was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluent (20-60%). This material was purified by reverse phase chromatography (20-60% acetonitrile: water). This gave the title compound as a white solid (0.1279 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:22])=O>C(Cl)Cl>[CH3:1][CH:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([Cl:22])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)C(C(=O)O)c1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C(C(=O)Cl)c1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-methyl-2-phenylbutyric acid (891 mg; 5.0 mmol) and a catalytic amount of dry dimethylformamide (ca. 10 uL) in 10 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (0.65 mL; 7.5 mmol) dropwise. After 1 hour, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:5]1[CH:34]=[CH:33][C:8]2[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[O:25][C:24]4=[O:32])=[CH:18][CH:17]=3)[C:10](=[O:12])[S:11][C:7]=2[CH:6]=1.[CH3:41][OH:42]>S(=O)(=O)(O)O>[OH:42][C:41]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][N:9]2[C:8]3[CH:33]=[CH:34][C:5]([C:4](=[N:3][O:2][CH3:1])[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:6][C:7]=3[S:11][C:10]2=[O:12])=[CH:21][CH:20]=1)[C:24]([O:25][CH3:26])=[O:32]
Reactant: CO
Reactant: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC2C(=O)Oc3ccccc32)cc1
Agent: O=S(=O)(O)O
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(C(=O)OC)c2ccccc2O)cc1

Procedure:
1.5 g of the compound obtained in Step B, in 50 ml of methanol and 0.1 ml of concentrated sulphuric acid, are heated at reflux for 2 hours. The solvent is then evaporated off, the residue is hydrolysed and the precipitate obtained is chromatographed on silica gel (eluant: AcOEt/toluene 5/95).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:10])=[C:4]([OH:9])[C:5]([Cl:8])=[CH:6][CH:7]=1.CI.[C:13](=O)([O-])[O-].[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([O:9][CH3:13])[C:3]=1[F:10]
Reactant: O=C([O-])[O-]
Reactant: Oc1c(Cl)ccc(Br)c1F
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CI
Product: COc1c(Cl)ccc(Br)c1F
Yield: 96.9 %

Procedure:
A heterogeneous mixture of 3-bromo-6-chloro-2-fluorophenol (14.4 g, 0.064 mol), methyl iodide (13.5 g, 0.096 mol) and potassium carbonate (8.8 g, 0.064 mol) in acetonitrile (100 mL) was heated under reflux for 2 hours. The mixture was cooled, diluted with water (100 mL) and extracted with ethyl ether (2×150 mL). The combined extracts were dried and concentrated. The dark oil was purified by chromatography (5% ethyl acetate in hexanes) to give 1-bromo-4-chloro-2-fluoro-3-methoxybenzene (14.8 g, 0.062 mol): 1H NMR (CDCl3): δ 7.20 (m, 1H), 7.10 (dd, 1H), 4.0 (s, 3H).
Reaction SMILES: C(Cl)(=O)C1C=CC=CC=1.[S-:10][C:11]#[N:12].[NH4+].[C:14]1([NH:24][CH2:25][CH2:26][CH3:27])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1>CC(C)=O>[C:14]1([N:24]([CH2:25][CH2:26][CH3:27])[C:11]([NH2:12])=[S:10])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCCNc1cccc2ccccc12
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Solvent: O=C(Cl)c1ccccc1
Product: CCCN(C(N)=S)c1cccc2ccccc12
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
3.9 g of benzoyl chloride and 2.1 g of ammonium thiocyanate are introduced into anhydrous acetone in a three-necked flask under argon and maintained between 0° and 5° C., the reaction mixture is left stirring for 15 minutes and then 3.9 g of N-naphth-1-yl-N-propylamine, dissolved in acetone, are added dropwise. The reaction mixture is then heated at reflux for 1 hour and evaporated to dryness and the residue is taken up in concentrated hydrochloric acid, heated at reflux for 3 hours and allowed to return to room temperature. The organic products are extracted with diethyl ether and then successively basification is carried out with 33% sodium hydroxide, extraction is carried out with ethyl acetate, the organic phase is evaporated to dryness and the residue is purified on a column of silica gel eluted with a 75/25 (v/v) hexane/ethyl acetate mixture, to obtain 3.2 g of white crystals melting at 170°-171° C. 1H NMR (CDCl3): 0.86 (t, J=7.3, 3H, --CH2 --CH3), 1.68 (m, 2H, --CH2 --CH3), 3.72 (m, 2H, --CH2 --CH2 --CH3), 5.58 (m, 2H, --NH2), 7.37 (d, J=7.3, 1H, H2), 7.23 (m, 2H, H3 and H8), 7.75-7.80 (m, 2H, H6 and H7), 7.85-7.95 (m, 2H, H4 and H5).
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: O=c1cc(CO)occ1O
Reactant: COc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2coc(CO)cc2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.8 %

Procedure:
To a suspension of kojic acid (50 g: 0.32 Mol.) in dimethylformamide (300 ml) are added potassium carbonate (63 g: 1.42 Eq.) and p-methoxybenzyl bromide (92 g: 1.42 Eq.), and the mixture is stirred at room temperature for 2 hours. The reaction mixture is diluted with water (1liter) to give 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone (74.5 g). Yield: 81%. mp. 124°~130° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].[CH3:7][C:8]([C:11]1[CH:12]=[C:13]([S:21][C@@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2O)[CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:16]=1)([CH3:10])[CH3:9].FC(F)(F)C(O)=O.O>C(Cl)Cl>[CH3:10][C:8]([C:11]1[CH:12]=[C:13]([S:21][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@H:27]2[S:3][CH2:2][C:1]([O:5][CH3:6])=[O:4])[CH:14]=[C:15]([C:17]([CH3:18])([CH3:19])[CH3:20])[CH:16]=1)([CH3:7])[CH3:9]
Reactant: COC(=O)CS
Reactant: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2O)cc(C(C)(C)C)c1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Reaction time: 0.25 h

Procedure:
Methyl thioglycolate (2.65 g, 0.025 moles) was added by syringe to a solution of trans-2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexanol (5.0 g., 0,025 moles) in methylene chloride (10 ml). After stirring the reaction mixture for 15 minutes, trifluoroacetic acid (10 ml) was added by syringe, and the reaction mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into cold water (100 ml). After stirring for 30 minutes, the mixture was extracted with ethyl acetate. The aqueous layer was washed with ethyl acetate (50 ml). The combined ethyl acetate extracts were washed twice with 75 ml of water, dried over sodium sulfate, filtered and concentrated to give the crude product as an oil. The title compound was purified by silica gel chromatography and dried in a vacuum oven at 60° C. for 3 hours. The structure assignment was supported by NMR, infrared spectroscopy, and elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:36])[CH3:35])[CH:20]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl>[C:44]([NH:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([F:37])=[C:13]([NH:15][C:16]([NH:18][C:19]3[N:23]([C:24]4[CH:25]=[C:26]5[C:31](=[CH:32][CH:33]=4)[N:30]=[CH:29][CH:28]=[CH:27]5)[N:22]=[C:21]([CH:34]([CH3:35])[CH3:36])[CH:20]=3)=[O:17])[CH:14]=2)=[CH:4][CH:3]=1)(=[O:46])[CH3:45]
Reactant: CC(C)c1cc(NC(=O)Nc2cc(Oc3ccc(N)nc3)ccc2F)n(-c2ccc3ncccc3c2)n1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Oc2ccc(F)c(NC(=O)Nc3cc(C(C)C)nn3-c3ccc4ncccc4c3)c2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
1-(5-(6-aminopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0495 g, 0.099 mmol) was dissolved in DCM (1.0 mL), to which pyridine (0.49 mL, 6.0 mmol) and acetic anhydride (0.066 mL, 0.65 mmol) were added. The reaction mixture was stirred at RT for 12 h. The completed reaction was quenched with 2M NaHCO3 (12 mL) and extracted with EtOAc (25 mL). The organic layer was washed with H2O (15 mL) and brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 1-(5-(6-acetamidopyridin-3-yloxy)-2-fluorophenyl)-3-(3-isopropyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)urea (0.0234 g, 44% yield) as a yellow foam. It was converted to corresponding mesylate salt by reacting with MsOH (1.0 eq.). 1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 9.09 (s, 1H), 9.07-9.04 (m, 2H), 8.65 (d, J=8.0 Hz, 1H), 8.25 (d, J=2.0 Hz, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.11-8.07 (m, 2H), 8.02 (dd, J=8.8, 2.4 Hz, 1H), 7.85 (m, 1H), 7.75 (m, 1H), 4.48 (dd, J=8.8, 3.2 Hz, 1H), 7.24 (m, 1H), 6.67 (m, 1H), 6.40 (s, 1H), 2.92 (m, 1H), 2.31 (s, 3H), 2.08 (s, 3H), 1.24 (d, J=7.2 Hz, 6H); MS (ESI) m/z: 540.0 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([O:41][CH3:42])[C:38]=1[O:39][CH3:40])[C:33](Cl)=[O:34].O>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:33](=[O:34])[C:32]2[CH:31]=[C:30]([O:29][CH3:28])[C:38]([O:39][CH3:40])=[C:37]([O:41][CH3:42])[CH:36]=2)[CH:13]([C:17]([O:19][CH3:20])=[O:18])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of methyl 4-benzyloxycarbonylpiperazine-2-carboxylate (1.2 g) obtained in Reference Example 21, triethylamine (0.9 g) and dichloromethane (15 ml) is added dropwise, taking 5 minutes while stirring at 0° C., to a solution of 3,4,5-trimethoxybenzoyl chloride (1.08 g) in dichloromethane (10 ml). The reaction mixture is stirred at room temperature for 10 minutes, and then poured into water, followed by extraction with dichloromethane. The organic layer is washed with water and dried, then the solvent is distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane:ethyl acetate:acetone=2:2:1) to give methyl 4-benzyloxycarbonyl-1-(3,4,5-trimethoxybenzoyl)-piperazine-2-carboxylate as a colorless oily product (2.1 g).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[CH:9]=1)([CH3:4])[CH3:3].[Li]CCCC.Cl[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CCCCCC.O1CCCC1>[CH3:4][C:2]([Si:5]([CH3:18])([CH3:19])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][O:16][CH3:17])[C:9]=1[C:26](=[O:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH3:1])[CH3:3]
Reactant: CCOC(=O)C(=O)Cl
Reactant: COCOc1cccc(CO[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C(=O)c1c(CO[Si](C)(C)C(C)(C)C)cccc1OCOC
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a solution of (1,1-dimethylethyl)(dimethyl){[(3-{[(methyloxy)methyl]oxy}phenyl)methyl]oxy}silane (Intermediate 103, 3 g) in dry n-hexane (30 mL) a solution of BuLi in hexane (1.6M, 7.63 mL, 12.21 mmol) was added and the reaction mixture was stirred for 2 hours at room temperature The reaction mixture was cooled to −78° C. and it was added (via cannulation) to a solution of ethyl chloro(oxo)acetate (1.780 mL, 15.93 mmol) in dry tetrahydrofuran (20 mL) at −78° C. The reaction was quenched with water (20 ml) and extracted with ethyl acetate (2×30 ml). The organic layer was dried over sodium sulphate, filtered and evaporated and the residue was purified by flash chromatography (Biotage system) on silica gel using a 100 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 8:2 as eluents. This afforded the title compound as a yellow pale oil (2.67 g).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([N:7]=[C:8]=[O:9])([F:6])[F:5]>>[CH3:1][NH:2][C:8]([NH:7][C:4]([F:6])([F:5])[F:3])=[O:9]
Reactant: CN
Reactant: O=C=NC(F)(F)F
Product: CNC(=O)NC(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methylamine (3.1 grams; 0.1 mol) is placed into a glass ampule of 30 ml capacity and is cooled in an acetone-dry ice bath. Trifluoromethyl isocyanate (11.1 grams; 0.1 mol) is added to the ampule and the ampule is sealed. The reaction mixture is slowly warmed up to room temperature and is allowed to stand at this temperature for a period of about 1 hour. At the end of this time the ampule is opened and the contents removed and distilled under reduced pressure to yield N-methyl-N'-trifluoromethyl urea.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>>[C:24]1([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])=[O:2])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccccc4)noc3C(F)(F)F)c2)nc1
Yield: 57 %

Procedure:
As described for Example 18, 6-[4-(3-phenyl-5-trifluoromethyl-isoxazol-4-yl)-imidazol-1-yl]-nicotinic acid methyl ester (90 mg, 0.22 mmol), was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (60 mg, 57%) which was obtained as a white solid. MS: m/e=482.1 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[F:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([C@H:2]3[CH2:6][CH2:5][C@@H:4]([C:7]([O:9][CH2:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[O:8])[CH2:3]3)[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Fc1cccc(N2CCNCC2)c1
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)[C@@H]1CC[C@H](N2CCN(c3cccc(F)c3)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (R)-benzyl 3-oxocyclopentanecarboxylate (1.5 g, 6.87 mmol), 1-(3-fluorophenyl)piperazine (1.36 g, 7.56 mmol) in 1,2-dichloroethane (25 ml) were added 1-(3-fluorophenyl)piperazine (1.36 g, 7.56 mmol), glacial acetic acid (0.4 ml, 6.87 mmol) and Sodium triacetoxy borohydride (2.18 g, 10.31 mmol). The mixture was stirred at 25° C. for 24 h before removal of the solvent. The residue was treated with saturated sodium bicarbonate, extracted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography over silica gel using ethyl acetate in hexane as eluents to obtain the title compound as the major diastereomer (1.2 g, 45.7%).
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH:12]=[CH2:13])[S:3]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])=[O:4].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][O:9][C:7](=[O:8])[CH2:6][S:3]([N:2]([CH3:1])[CH2:11]/[CH:12]=[CH:13]/[C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)(=[O:4])=[O:5]
Reactant: C=CCN(C)S(=O)(=O)CC(=O)OC
Reactant: Brc1ccc(-c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)CS(=O)(=O)N(C)C/C=C/c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a solution of methyl 2-({methyl[allyl]amino}sulfonyl)acetate (300 mg, 1.4 mmol) and 4-bromobiphenyl (370 mg, 1.54 mmol) in acetonitrile (4 ml) was added triethylamine (0.3 ml, 2.1 mmol), palladium(II) acetate (17 mg, 0.07 mmol) and tri-ortho-tolyl phosphine (52 mg, 0.14 mmol) and the solution was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to ambient temperature, the solvent was evaporated and the residue was purified by flash chromatography on silica gel (dichloromethane as eluent) to give the title compound as a pale yellow solid (300 mg).
Reaction SMILES: C(O[C:4](=[O:15])[NH:5][S:6]([C:9]1[S:10][C:11]([Cl:14])=[CH:12][CH:13]=1)(=[O:8])=[O:7])C.[NH2:16][C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][C:22]([NH:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:23]([F:28])[CH:24]=2)[N:19]([CH:36]([CH3:38])[CH3:37])[CH:18]=1>C1(C)C=CC=CC=1>[Cl:14][C:11]1[S:10][C:9]([S:6]([NH:5][C:4]([NH:16][C:17]2[C:26](=[O:27])[C:25]3[C:20](=[CH:21][C:22]([NH:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:23]([F:28])[CH:24]=3)[N:19]([CH:36]([CH3:38])[CH3:37])[CH:18]=2)=[O:15])(=[O:7])=[O:8])=[CH:13][CH:12]=1
Reactant: CCOC(=O)NS(=O)(=O)c1ccc(Cl)s1
Reactant: CC(C)n1cc(N)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Solvent: Cc1ccccc1
Product: CC(C)n1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)c(=O)c2cc(F)c(NC3CCCCC3)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 65.7 %

Procedure:
287 mg of ethyl[(5-chloro-2-thienyl)sulfonyl]carbamate was dissolved in 5.0 ml of toluene, and 250 mg of 3-amino-7-(cyclohexylamino)-6-fluoro-1-isopropylquinolin-4(1H)-one was added, followed by overnight stirring at 110° C. The reaction mixture was cooled to room temperature and concentrated under a reduced pressure. Then, ethyl acetate was added and the insoluble materials were collected by filtration, thereby obtaining 280 mg of 5-chloro-N-({[7-(cyclohexylamino)-6-fluoro-1-isopropyl-4-oxo-1,4-dihydroquinolin-3-yl]amino}carbonyl)thiophene-2-sulfonamide.