Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[N+:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:7][NH:6][C:5]=1[O-:19])(=[O:3])[NH2:2].[C:20]([NH:23][C@@H:24]1[C@@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[O:26][C@@H:25]1Cl)(=[O:22])[CH3:21]>>[N+:16]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][N:8]2[C:4]([C:1]([NH2:2])=[O:3])=[C:5]([O:19][C@@H:25]3[O:26][C@H:27]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@H:24]3[NH:23][C:20](=[O:22])[CH3:21])[N:6]=[CH:7]2)=[CH:15][CH:14]=1)([O-:18])=[O:17]
Reactant: NC(=O)c1c([O-])[nH]c[n+]1Cc1ccc([N+](=O)[O-])cc1
Reactant: CC(=O)N[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](COC(C)=O)O[C@@H]1Cl
Product: CC(=O)N[C@H]1[C@H](Oc2ncn(Cc3ccc([N+](=O)[O-])cc3)c2C(N)=O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 33.8 %

Procedure:
Following a procedure similar to that of Example 1 but using 1.311 g of 5-carbamoyl-1-(4-nitrobenzyl)imidazolium-4-olate and 3.658 g of 2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-α-D-glucopyranosyl chloride there was obtained 1.0 g of 1-(4-nitrobenzyl)-4-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-glucopyranosyl)oxy-1H-imidazole-5-carboxamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CCOC(=O)c1oc2cccc(N)c2c1C
Product: CCOC(=O)c1oc2cccc(NS(=O)(=O)c3cccs3)c2c1C
Yield: 68 %

Procedure:
3-Methyl-4-(thiophene-2-sulfonylamino)-benzofuran-2-carboxylic acid ethyl ester was prepared from 4-amino-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 60, Step 1), and 2-thiophenesulfonyl chloride according to the procedure of Example 68, Step 1. Yield: 68%. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.3 (t, J=7.1 Hz, 3 H) 2.6 (s, 3 H) 4.4 (q, J=7.1 Hz, 2 H) 6.7 (dd, J=7.8, 0.8 Hz, 1 H) 7.2 (dd, J=4.9, 3.7 Hz, 1 H) 7.4 (m, 2 H) 7.6 (dd, J=8.3, 0.8 Hz, 1 H) 8.0 (dd, J=4.9, 1.4 Hz, 1 H) 10.2 (s, 1 H)
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9](/[CH:13]=[CH:14]/[CH3:15])=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17].[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[CH3:18][C:2]([CH3:1])([CH3:19])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([CH:13]3[CH:14]([CH3:15])[CH:22]3[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:10][CH:11]=2)[N:6]([CH3:16])[C:5]1=[O:17]
Reactant: C/C=C/c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(C)C1c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 100 °C

Procedure:
1-(2,2-Dimethylpropyl)-3-methyl-5-[(1E)-prop-1-en-1-yl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (33-1, 600 mg, 2.3 mmol, 1.0 equiv) was added to anhydrous toluene (4.8 mL). Ethyl diazoacetate (720 μL, 6.9 mmol, 3.0 equiv) was added and the resulting solution was heated to 100° C. for 18 h. Following this duration, LCMS showed complete consumption of 33-1. The reaction mixture was diluted with ethyl acetate (50 mL) and saturated NaHCO3 (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification by normal-phase HPLC (0-40% EtOAc:hexanes) provided 33-2 as a white solid. MS m/z (M+H): calculated=346.2127; observed=346.2134.
Reaction SMILES: C([O:8][CH2:9][CH:10]([O:20][CH2:21][N:22]1[CH:29]=[C:28]([I:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[CH2:11][O:12]CC1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO.[NH4+].[OH-]>C(Cl)Cl>[OH:12][CH2:11][CH:10]([O:20][CH2:21][N:22]1[CH:29]=[C:28]([I:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24])[CH2:9][OH:8]
Reactant: O=c1[nH]c(=O)n(COC(COCc2ccccc2)COCc2ccccc2)cc1I
Agent: ClB(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: O=c1[nH]c(=O)n(COC(CO)CO)cc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
To a solution of 45 (1.90 g, 3.64 mmol) in anhydrous CH2Cl2 (60 mL) at −78° C. was added BCl3 (1 M solution in CH2Cl2, 30 mL, 30 mmol) dropwise. The mixture was stirred at −78° C. under nitrogen for 2 h, then at −60° C. for another 4 h. MeOH (10 mL) was added to quench the reaction, followed by 14% NH4OH solution to adjust the mixture to pH 7. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with CH2Cl2/MeOH (9:1 to 4:1) to give the title compound 46 as a pale yellow solid (810 mg, 65%). 1NMR (DMSO-d6) δ 11.6 (s, 1H, NH), 8.19 (s, 1H, H-6), 7.20, 6.60 (2br, 2H, 2 OH), 5.15 (s, 2H, CH2N), 4.60 (m, 2H, CH2O), 3.53 (m, 1H, CHO), 3.41 (m, 2H, 2 CH2O).
Reaction SMILES: [C:1]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=[CH:5][C:4]([C:7]([N:9]2[CH2:13][C:12](=[N:14][O:15][CH3:16])[CH2:11][C@H:10]2[CH2:17][C:18](O)=[O:19])=[O:8])=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O[N:40]=[C:41]([NH2:45])[CH2:42][CH2:43][OH:44].N1C=CC=CC=1>O1CCCC1>[CH3:16][O:15][N:14]=[C:12]1[CH2:11][C@@H:10]([CH2:17][C:18]2[O:19][N:45]=[C:41]([CH2:42][CH2:43][OH:44])[N:40]=2)[N:9]([C:7]([C:4]2[CH:5]=[CH:6][C:1]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:2][CH:3]=2)=[O:8])[CH2:13]1
Reactant: CON=C1C[C@@H](CC(=O)O)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Reactant: NC(CCO)=NO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CON=C1C[C@@H](Cc2nc(CCO)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1
Yield: 32.3 %

Procedure:
To a solution of [(2S,4EZ)-1-(biphenyl-4-ylcarbonyl)-4-(methoxyimino)pyrrolidin-2-yl]acetic acid (Intermediate 7, 50 mg, 0.14 mmol) in tetrahydrofuran (2 ml) was added CDI (37 mg, 0.23 mmol). The reaction mixture was stirred 1 h30. A solution of N′,3-dihydroxypropanimidamide (16 mg, 0.16 mmol), pyridine (34 ml, 0.14 mmol) in tetrahydrofuran was then added and the reaction mixture was stirred at reflux overnight The solvent was removed and ethyl acetate was added. The organic phase was washed with citric acid 5%, NH4Cl, NaHCO3 then brine. The organic phase was dried (MgSO4), concentrated and purified on silica gel column chromatography (Ethyl acetate) to afford (3EZ,5S)-1-(biphenyl-4-ylcarbonyl)-5-{[3-(2-hydroxyethyl)-1,2,4-oxadiazol-5-yl]methyl}pyrrolidin-3-one O-methyloxime (19 mg). Yield: 27%. HPLC purity: 94%
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:22][NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:22][N:23]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2
Reactant: CNCCc1ccccc1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2nc(-c3ccccc3)c(N(C)CCc3ccccc3)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 8-mL sealed tube, was placed a solution of methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (150 mg, 0.44 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), N-methyl-2-phenylethanamine (177.6 mg, 1.32 mmol, 3.00 equiv), potassium carbonate (181.6 mg, 1.32 mmol, 3.00 equiv). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (100:1). This resulted in 153.3 mg (85%) of methyl 3-(methyl(phenethyl)amino)-2-phenylquinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]1(N)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.NC(N)=O>>[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: NC1CCCCC1
Reactant: NC(=O)NC1CCCCC1
Agent: NC(N)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
U.S. Pat. Nos. 2,253,528 and 2,257,717 disclose a preparation of monocyclohexylurea by reacting cyclohexylamine with an excess of urea and under an overpressure in an autoclave within a temperature range from 100° C. to the decomposition point of the monocyclohexylurea. During this reaction considerable proportions of dicyclohexylurea are produced which have to be separated off in an expensive manner.
Reaction SMILES: [CH2:1]([C:5]1[NH:10][C:9](=[O:11])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]=1[F:29].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:5]1[N:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][C:16]=2[F:29])[C:9](=[O:11])[CH:8]=[C:7]([CH3:12])[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCCc1nc(C)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 50 °C
Reaction time: 12 h
Yield: 29.3 %

Procedure:
To a solution of 2-butyl-6-methylpyrimidin-4(3H)-one (2.24 g) and 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (4.3 g) in acetonitrile (30 mL) was added potassium carbonate (3.72 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (1.48 g, 29%) as a colorless viscous substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11](Br)=[CH:10][CH:9]=2)=[O:4].[CH3:33]B(O)O.C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC=CC=1>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.O.C1COCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]3[O:31][CH2:30][CH2:29][C:28]=3[CH:32]=2)[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH3:33])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Reactant: CB(O)O
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: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(C)ccc2c(=O)n1Cc1ccc2c(c1)CCO2
Temperature: 100 °C
Reaction time: 12 h
Yield: 88.4 %

Procedure:
A mixture of 6-bromo-2-(2,3-dihydrobenzofuran-5-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (300 mg), methylboronic acid (180 mg), tetrakis(triphenylphosphine)palladium(0) (70 mg), potassium carbonate (250 mg), toluene (6 ml) and THF (3 ml) was stirred at 100° C. under a nitrogen atmosphere for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (230 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[C:33]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:38]=[CH:37][CH:36]=[C:35]([NH2:39])[CH:34]=1.C(N(CC)CC)C>ClCCl.CN(C=O)C>[C:33]1([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:38]=[CH:37][CH:36]=[C:35]([NH:39][C:18]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:22][CH:21]=2)=[O:19])[CH:34]=1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Reactant: Nc1cccc(-c2ccccc2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccccc5)c4)cc3)c(C#N)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a solution of 4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 2) (50 mg, 0.142 mmol) and a drop of DMF in dichloromethane (2 ml) was added oxalyl chloride (2M in dichloromethane) (84.91 μL, 0.170 mmol) at ambient temperature. Gas evolution was observed. The mixture was stirred for 1 hour at ambient temperature. Biphenyl-3-amine (28.74 mg, 0.170 mmol) in dichloromethane (1 ml) and triethylamine (59.172 μL, 0.424 mmol) were added to the activated acid. The mixture was stirred for 1 hour at ambient temperature. The crude mixture was purified on silica gel (EtOAc in hexanes gradient) to provide 55.6 mg of the title compound as a thin film (78%).
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[CH2:10][OH:11])=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24].O(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:22][S:23]([O:11][CH2:10][CH:9]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[CH2:8][CH2:7][O:6][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:21][CH:20]=1)(=[O:25])=[O:24]
Reactant: CS(=O)(=O)Cl
Reactant: OCC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Solvent: CC(C)OC(C)C
Solvent: c1ccncc1
Product: CS(=O)(=O)OCC(CCOc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 30.4 parts of β-[2-(4-bromophenoxy)ethyl]-2,4-dichlorobenzeneethanol, 11.5 parts of methanesulfonyl chloride, 100 parts of pyridine and 70 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed successively with a diluted hydrochloric acid solution and twice with water, dried, filtered and evaporated, yielding 34 parts of 4-(4-bromophenoxy)-2-(2,4-dichlorophenyl)butyl methanesulfonate as a residue.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([Cl:12])=[C:7]([OH:13])[CH:6]=[CH:5]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[Cl:12][C:8]1[C:9]2[C:4](=[CH:3][C:2]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[OH:13]
Reactant: Oc1ccc2cc(Br)ccc2c1Cl
Reactant: OB(O)c1ccccc1
Product: Oc1ccc2cc(-c3ccccc3)ccc2c1Cl

Procedure:
The title compound was prepared by reacting 6-bromo-1-chloro-naphthalen-2-ol (300 mg, 1.17 mmol) with phenylboronic acid (170.7 mg, 1.40 mmol) according to method A to yield 240 mg (81%) of white solid: mp 135-137° C.; 1H NMR (DMDO-d6): δ 7.33 (1H, d, J=8.85 Hz), 7.39 (1H, td, J=7.25 Hz, J=0.75 Hz), 7.51 (2H, t, J=7.59 Hz), 7.80 (2H, d, J=7.63 Hz), 7.88 (1H, d, J=8.96 Hz), 7.93 (1H, dd, J=8.85 Hz, J=1.19 Hz), 8.10(1H, d, J=8.84 Hz), 8.20 (1H, s), 10.53 (1H, s); MS (ESI) m/z253/255 (M−H)−.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C[O:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([CH2:22][CH2:23][NH2:24])=[CH:18][NH:19]2)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[NH2:24][CH2:23][CH2:22][C:17]1[C:16]2[C:20](=[CH:21][C:13]([OH:12])=[CH:14][CH:15]=2)[NH:19][CH:18]=1
Reactant: COc1ccc2c(CCN)c[nH]c2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: NCCc1c[nH]c2cc(O)ccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 68.2 %

Procedure:
Diisobutylaluminum hydride (1 M in toluene, 15 mL) was slowly added to a suspension of 2-(6-methoxy-1H-indol-3-yl)ethylamine (250 mg) in 20 mL of toluene. The resulting clear solution was refluxed for 10 h, then cooled to 0° C. and quenched by the careful addition of 20 mL of 1:1 methyl alcohol:water. The mixture was stirred for 15 min at rt and filtered to remove the precipitated aluminum salts. The solvent was evaporated to yield 158 mg of 3-(2-amino-ethyl)-1H-indol-6-ol.
Reaction SMILES: [Li+].[F:2][C:3]([F:23])([F:22])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH2:18][C:19]([O-:21])=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][C:53]=1[C:65]([F:68])([F:67])[F:66])([O-:51])=[O:50].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>O1CCCC1.CN(C)C=O>[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:60][CH2:61][N:62]([C:19](=[O:21])[CH2:18][CH2:17][CH2:16][CH:13]3[CH2:12][CH2:11][N:10]([C:7]4[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:22])[F:23])=[CH:9][CH:8]=4)[CH2:15][CH2:14]3)[CH2:63][CH2:64]2)=[CH:54][C:53]=1[C:65]([F:68])([F:66])[F:67])([O-:51])=[O:50]
Reactant: O=C([O-])CCCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(CCCC1CCN(c2ccc(C(F)(F)F)cc2)CC1)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of 4-[1-(4-trifluoromethyl-phenyl)-piperidin-4-yl]-butyric acid lithium salt (16 mg; 0.05 mmol, prepared in accordance with Example 133) in tetrahydrofuran (0.5 mL) is added a solution of tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) in dimethylformamide (0.25 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are then added and the reaction is stirred. After 3 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (16 mg; 0.028 mmol). The structure was confirmed using Protocol I-D. Calculated mass=587; observed mass=587; HPLC retention time=2.20 min.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20]Cl)=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1.[S:25]1[CH2:29][CH2:28][NH:27]C1.[H-].[Na+]>C1COCC1>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:24])[CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:27][CH2:28][CH2:29][SH:25])=[C:14]([O:22][CH3:23])[CH:13]=2)[CH2:4][CH2:3]1
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCCl
Reactant: C1CSCN1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCNCCS

Procedure:
Using 1.9 g of N-(trans-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (Example 138), 0.89 g of thiazolidine, 0.5 g of sodium hydride, and 30 ml THF, a reaction similar to that conducted in Example 180 was carried out. As a result, 0.45 g of N-(trans-4-methylcyclohexyl) -4-{2-[(2-mercaptoethyl)amino]ethoxy}-3-methoxycinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[C:16]3[C:11](=[C:12]([NH2:17])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:17][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:11]=2[N:10]=[CH:9][N:8]=[C:7]3[O:6][C:5]2[CH:18]=[CH:19][C:2]([F:1])=[C:3]([C:20]([F:23])([F:21])[F:22])[CH:4]=2)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: Nc1cccc2c(Oc3ccc(F)c(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Oc4ccc(F)c(C(F)(F)F)c4)ncnc23)c1F
Yield: 39.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using 4-(4-fluoro-3-(trifluoromethyl)phenoxy)quinazolin-8-amine (Intermediate-45, 60 mg, 0.18 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 80 mg, 0.27 mmol), oxalyl chloride (52 mg, 0.41 mmol), DMF (1 drop) and DIPEA (70 mg, 0.54 mmol) in CH2Cl2 (2 mL) to afford 42 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.93 (s, 1H), 8.91 (d, J=7.8 Hz, 1H), 8.80 (s, 1H), 8.17 (d, J=7.2 Hz, 2H), 7.96 (t, 1H), 7.85 (m, 2H), 7.69 (t, J=9.6 Hz, 1H), 7.37 (m, 2H), 4.31 (d, J=5.4 Hz, 2H), 1.14 (s, 9H); MS (m/z): 593.10 (M+H)+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][N:3]=[C:4]([C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH:5]([Br:19])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CON=C(CCC1CCCC1)c1ccc(Cl)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CON=C(c1ccc(Cl)cc1)C(Br)CC1CCCC1
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (1.120 g, 4.214 mmol) in carbon tetrachloride were added N-bromosuccinimide (812 mg, 4.425 mmol) and benzoyl peroxide (102 mg, 0.4 mmol). The resulting mixture was heated at reflux for 12 h. Upon cooling to room temperature, the solids were filtered and washed with diethyl ether. The filtrate was washed with aqueous solution of sodium bicarbonate, sodium thiosulfate and brine. It was then dried with anhydrous sodium sulfate and concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 1–2% ethyl acetate in hexanes yielded 2-bromo-1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (1.16 g, 80%) as yellow oil.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([Cl:35])=[CH:12][C:13]([CH3:34])=[C:14]([NH:16][C:17]([C:19]2[C@H:20]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])[CH:15]=1)(C)(C)C>C1COCC1.O.CC(O)=O>[Cl:35][C:11]1[C:10]([O:9][CH2:8][CH2:7][OH:6])=[CH:15][C:14]([NH:16][C:17]([C:19]2[C@H:20]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)[NH:21][C:22](=[O:26])[N:23]([CH3:25])[CH:24]=2)=[O:18])=[C:13]([CH3:34])[CH:12]=1
Reactant: Cc1cc(Cl)c(OCCO[Si](C)(C)C(C)(C)C)cc1NC(=O)C1=CN(C)C(=O)N[C@H]1c1ccc(F)cc1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Cl)c(OCCO)cc1NC(=O)C1=CN(C)C(=O)N[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The (S)-4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid{5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-4-chloro-2-methyl-phenyl}-amide from step 1 was dissolved in a mixture of 1 ml THF, 1 mL water, and 3 ml HOAc. This solution was stirred at room temperature for 18 hours, then diluted with water and extracted with ethyl acetate. The combined ethyl acetate layers were dried over Na2SO4, filtered and the solvent removed in vacuo. The residue was chromatographed in 3% MeOH/CH2Cl2 to give 50 mg of (S)-4-(4-Fluoro-phenyl)-1-methyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid[4-chloro-5-(2-hydroxy-ethoxy)-2-methyl-phenyl]-amide, MS (M+H)=434.