Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)N=1.ClC1N=C(C(F)(F)F)[CH:23]=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>C(#N)C.CN(C=O)C>[CH3:23][C:22]1[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)=[N:6][CH:7]=[CH:8][N:21]=1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: CN(C)C=O
Product: Cc1nccnc1N1C[C@@H]2CCNC[C@@H]21

Procedure:
The title compound was prepared in a manner analogous to Intermediate 27, substituting 2-chloro-3-methylpyrazine for 2-chloro-4-(trifluoromethyl)pyrimidine. In addition, DMF and K2CO3 at 95° C. was used in place of DIPEA and ACN.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:32][C:33]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]>>[Cl:32][C:33]1[CH:38]=[C:37]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:16])[CH:13]([CH3:15])[CH3:14])=[C:5]3[NH:17][C@H:18]2[CH2:19][CH2:20][C@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:22][CH2:23]2)[CH:36]=[C:35]([F:48])[C:34]=1[OH:49]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)C(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Product: CC(C)C(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1

Procedure:
Following general procedure D, tert-butyl trans-4-(6-bromo-3-isobutyrylquinolin-4-ylamino)cyclohexylcarbamate (49 mg, 0.100 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (102 mg, 0.375 mmol) to afford the crude product (56 mg) as an off-white solid: ESI MS m/z 556 [C30H35ClFN3O4+H]+.
Reaction SMILES: [F:1][CH:2]([F:33])[O:3][C:4]1[C:13]2[C:8](=[C:9]([F:20])[CH:10]=[CH:11][C:12]=2[O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[N:7]=[C:6]([CH2:21][CH3:22])[C:5]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.[CH:34]1([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)[CH2:36][CH2:35]1.N1C=CC=CC=1>O>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:14][C:12]1[CH:11]=[CH:10][C:9]([F:20])=[C:8]2[C:13]=1[C:4]([O:3][CH:2]([F:33])[F:1])=[C:5]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:39]3[CH:38]=[C:37]([CH:34]4[CH2:36][CH2:35]4)[CH:41]=[N:40]3)=[CH:26][CH:25]=1)[C:6]([CH2:21][CH3:22])=[N:7]2
Reactant: c1n[nH]cc1C1CC1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(B(O)O)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(-n2cc(C3CC3)cn2)cc1
Temperature: 40 °C
Yield: 79.3 %

Procedure:
A mixture of (4-{[4-difluoromethoxy-2-ethyl-8-fluoro-5-(2-methoxy-2-oxoethoxy) quinolin-3-yl]methyl}phenyl)boronic acid (0.1 g), 4-cyclopropyl-1H-pyrazole (0.047 g), cuprous acetate (0.078 g) and pyridine (3 mL) was heated at 40° C. for 24 hours. The mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulphate and then concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (1:0 to 7:3 by volume) gave title compound as pale green oil (0.09 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[CH:16]1([NH2:20])[CH2:19][CH2:18][CH2:17]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:20][CH:16]2[CH2:19][CH2:18][CH2:17]2)(=[O:10])=[O:9])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1C(F)(F)F
Reactant: NC1CCC1
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1C(F)(F)F
Yield: 96.1 %

Procedure:
According to general procedure C, 4-Bromo-2-trifluoromethyl-benzenesulfonyl chloride (0.50 g, 1.54 mmol) and cyclobutylamine (0.33 mL, 3.85 mmol) were stirred together in dry dichloromethane (2 mL) for 16 hours. 4-bromo-N-cyclobutyl-2-(trifluoromethyl)benzenesulfonamide (0.53 g, 96%) was provided after purification. MS (ESI) m/z 358. HPLC purity 100.0% at 210-370 nm, 9.9 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][N:7]=1.C(=O)(O)[O-].[Na+].Br[CH2:15][C:16](=O)[C:17]([O:19][CH3:20])=[O:18].O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[N:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC(=O)C(=O)CBr
Reactant: Nc1nccnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COC(=O)c1cn2ccnc(Cl)c2n1
Temperature: 80 °C
Yield: 70.7 %

Procedure:
To a solution of 3-chloropyrazin-2-amine (52 g, 401 mmol) in acetonitrile (750 mL) under N2 was added sodium bicarbonate (67.4 g, 803 mmol), and then methyl bromopyruvate (97 mL, 803 mmol). The mixture was then heated to 80° C. for 4 hours and then cooled to r.t. The reaction was then diluted water (2200 mL) and stirred for 30 minutes. The resulting solids were filtered, azeotroped with EtOAc (2 L), and dried overnight at 40° C. under vacuum and nitrogen sweep to give the title compound (60 g). LRMS (ESI) calc (M+H)+=212.0. found 212.0
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:9]1([C:7]2[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3](=[O:19])[CH:2]([NH:1][C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:27][CH:28]=3)[N:8]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1ccc(-c2ccccc2)cc1

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 4-phenylbenzoyl chloride (33.8 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 82° C.: (m.p. 274°-276° C.).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[C:27]([N:35]=[C:36]=[O:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.CC(=O)OCC.O>[C:27]([NH:35][C:36](=[O:37])[NH:1][C:2]1[O:3][C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)=[C:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1c(N)oc(-c2cccc(Cl)c2)c1Cc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(NC(=O)NC(=O)c2ccccc2)oc(-c2cccc(Cl)c2)c1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.3 %

Procedure:
To a solution of ethyl 2-amino-4-(4-chlorobenzyl)-5-(3-chlorophenyl)furan-3-carboxylate (38.9 mg, 0.1 mmol) in toluene (5 mL) was added benzoyl isocyanate (14.7 mg, 0.1 mmol). The reaction was stirred at RT for 2 h then diluted with EA (5 mL) and water (2 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep HPLC to give ethyl 2-(3-benzoylureido)-4-(4-chlorobenzyl)-5-(3-chlorophenyl)furan-3-carboxylate (12 mg, 22% yield) as a white solid. 1H NMR (DMSO-d6) δ: 12.41 (s, 1H), 11.51 (s, 1H), 8.10 (d, J=7.4 Hz, 2H), 7.75 (t, J=7.5 Hz, 1H), 7.63 (t, J=7.7 Hz, 2H), 7.60-7.51 (m, 3H), 7.48 (d, J=6.9 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.3 Hz, 2H), 4.34 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 1.23 (t, J=7.1 Hz, 3H). LCMS: MH+ 537 and TR=2.962 min.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:9]=2[CH:8]=1)(=O)=O.COC1C=CC2C=C([Sn](C)(C)C)CCCC=2C=1.[CH2:39]([O:46][C:47]1[CH:61]=[CH:60][C:50]([CH2:51][N:52]2[C:57](Br)=[CH:56][CH:55]=[CH:54][C:53]2=[O:59])=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]1[CH:61]=[CH:60][C:50]([CH2:51][N:52]2[C:57]([C:7]3[CH2:13][CH2:12][CH2:11][C:10]4[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:9]=4[CH:8]=3)=[CH:56][CH:55]=[CH:54][C:53]2=[O:59])=[CH:49][CH:48]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COc1ccc2c(c1)CCCC(OS(=O)(=O)C(F)(F)F)=C2
Reactant: O=c1cccc(Br)n1Cc1ccc(OCc2ccccc2)cc1
Agent: COc1ccc2c(c1)CCCC([Sn](C)(C)C)=C2
Product: COc1ccc2c(c1)CCCC(c1cccc(=O)n1Cc1ccc(OCc3ccccc3)cc1)=C2

Procedure:
Synthesized from 2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl trifluoromethanesulfonate according to an analogous synthetic method to Preparation Example 69, (2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)trimethyltin (3.25 g) and 1-(4-benzyloxybenzyl)-6-bromo-1H-pyridin-2-one (2.2 g) were used according to an analogous synthetic method to Example 1 to provide 1-(4-benzyloxybenzyl)-6-(2-methoxy-8,9-dihydro-7H-benzocyclohepten-6-yl)-1H-pyridin-2-one (646 mg). The total amount of this compound was used according to an analogous synthetic method to Example 22 described below to provide the title compound (404 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]([CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:8]([CH:10]([CH2:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])[CH2:11][CH2:12][C:13]([O:15]CC1C=CC=CC=1)=[O:14])=[O:9])=[O:5])[CH3:2]>C(O)C.[Pd]>[CH2:41]([O:40][C:38]([CH2:37][N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]([CH:10]([CH2:23][S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:39])[CH3:42]
Reactant: CCOC(=O)CN(CC(=O)OCC)C(=O)C(CCC(=O)OCc1ccccc1)CS(=O)(=O)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CN(CC(=O)OCC)C(=O)C(CCC(=O)O)CS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 96 h
Yield: 61.1 %

Procedure:
To a solution of benzyl 4-[N,N-bis(ethoxycarbonylmethyl)carbamoyl]-5-(2-naphthylsulfonyl)pentanoate (0.52 g) in ethanol (10 ml) was added 10% Pd-C (50 mg), and the mixture was hydrogenolyzed at atmospheric pressure and ambient temperature for 4 days. After the catalyst was filtered off, the filtrate was evaporated at reduced pressure. The residue was purified by flash column chromatography on silica eluting with chloroform/methanol (10:1), and recrystallized from isopropyl ether-hexane to give 0.27 g of 4-[N,N-bis(ethoxycarbonylmethyl)carbamoyl]-5-(2-naphthylsulfonyl)pentanoic acid.
Reaction SMILES: [F:1][C:2]1[CH:45]=[CH:44][C:5]([CH2:6][C@H:7]([NH:31][C:32]([C:34]2[NH:43][C:37]3=[CH:38][N:39]=[C:40]([Cl:42])[CH:41]=[C:36]3[CH:35]=2)=[O:33])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][N:17]([CH3:30])S(C3C=CC=CC=3[N+]([O-])=O)(=O)=O)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(OC(N1CCC(CN)CC1)=O)(C)(C)C.Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@H:7]([NH:31][C:32]([C:34]2[NH:43][C:37]3=[CH:38][N:39]=[C:40]([Cl:42])[CH:41]=[C:36]3[CH:35]=2)=[O:33])[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][CH3:30])[CH2:12][CH2:11]2)=[O:9])=[CH:44][CH:45]=1
Reactant: CN(CC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: Cl
Product: CNCC1CCN(C(=O)[C@H](Cc2ccc(F)cc2)NC(=O)c2cc3cc(Cl)ncc3[nH]2)CC1

Procedure:
Prepared according to EXAMPLE 191 from 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid [1-(S)-(4-fluorobenzyl)-2-(4-{[methyl-(2-nitrobenzenesulfonyl)amino]methyl}piperidin-1-yl)-2-oxoethyl]amide (synthesised according to Preparations 73-76 from the 4-aminomethylpiperidine-1-carboxylic acid tert-butyl ester starting material). m/z (ES+) free base=472.33 [M+H]+; RT=2.80 min. m/z (ES+) HCl salt=430.43 [M+H]+; RT=2.72 min.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:33][CH:34]([F:36])[F:35])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[OH-].[Li+]>O1CCCC1>[F:36][CH:34]([F:35])[O:33][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:37])=[O:2])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([N:28]2[CH2:29][CH2:30][CH2:31][CH2:32]2)=[O:27])=[CH:22][CH:21]=1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(C(=O)N2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of {4-difluoromethoxy-2-ethyl-8-fluoro-3-[4-(pyrrolidine-1-carbonyl)benzyl]quinolin-5-yloxy}acetic acid methyl ester (0.14 g), tetrahydrofuran (3.0 mL) and 1.0 M aqueous lithium hydroxide solution (0.55 mL) was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure and the residue was diluted with water. The pH of mixture was adjusted to 4 by the addition of sodium dihydrogenphosphate and the resulting precipitate was collected by filtration, washed with water and dried to afford title compound, 0.11 g.
Reaction SMILES: I[CH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)[C:10]2[C:5](=[CH:6][C:7]([O:30][CH3:31])=[C:8]([O:28][CH3:29])[CH:9]=2)[N:4]=1.[OH:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1>C(=O)([O-])[O-].[Ag+2].C1C=CC=CC=1>[CH3:29][O:28][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[O:30][CH3:31])[N:4]=[C:3]([CH2:2][O:32][C:33]1[N:34]([CH3:38])[CH:35]=[CH:36][N:37]=1)[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1
Reactant: CCOC(=O)c1c(CI)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: Cn1ccnc1O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(COc2nccn2C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 50 °C
Reaction time: 18 h
Yield: 9.4 %

Procedure:
A mixture of ethyl 2-iodomethyl-6,7-dimethoxy-4- (3,4-dimethoxyphenyl)quinoline-3-carboxylate (9.0 g), 2-hydroxy-1-methylimidazole (1.8 g), silver carbonate (I) (Ag2CO3) (5.1 g) and benzene (100 ml) was stirred at 50° C. for 18 hours. Then the insoluble materials were filtered off. The filtrate was washed with water, dried (MgSO4), and the solvent was distilled off. The residual oil was subjected to column chromatography on silica gel. From the fraction eluted with chloroform/ethyl acetate (5:1, v/v), ethyl 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-[(1-methyl-2-imidazolyl)oxymethyl]quinoline-3-carboxylate (0.8 g, 9%) was obtained and recrystallized from ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][NH:7][C:8](=[O:15])[NH:9][O:10][CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.[NH2:18][C@@H:19]([CH2:43][C:44]([NH:46][C:47]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45])[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:9][O:10][CH2:11][C:12]([NH:18][C@@H:19]([CH2:43][C:44](=[O:45])[NH:46][C:47]([C:60]2[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[C:20]([N:22]([C@@H:34]([CH3:42])[CH:35]([O:39][CH2:40][CH3:41])[O:36][CH2:37][CH3:38])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[C:28]3[C:33]=2[N:32]=[CH:31][CH:30]=[CH:29]3)=[O:21])=[O:14])=[O:15])=[CH:16][CH:17]=1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@@H](N)CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)CONC(=O)NCc1ccc(Cl)cc1
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2cccnc12)C(=O)[C@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)CONC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-(4-chlorobenzyl)ureidooxy)acetic acid (Compound VI-11) 60 mg (0.23 mmol) was coupled with (S)-2-amino-N1—((S)-1,1-diethoxypropan-2-yl)-N1-(quinolin-8-ylmethyl)-N4-tritylsuccinamide (Compound IV-20) 100 mg (0.16 mmol) to obtain the title compound.
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([N+]([O-])=O)=[C:11]([S:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[C:18]([Br:27])[CH:17]=2)(=[O:15])=[O:14])[CH:12]=1)=[O:7].C(O)(=O)C>C1COCC1.CCOC(C)=O>[CH3:4][O:5][C:6]([C:8]1[S:9][C:10]([S:2][CH3:1])=[C:11]([S:13]([C:16]2[CH:21]=[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=[C:18]([Br:27])[CH:17]=2)(=[O:15])=[O:14])[CH:12]=1)=[O:7]
Reactant: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c([N+](=O)[O-])s1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)c1cc(S(=O)(=O)c2cc(Br)cc(OC(C)(C)C)c2)c(SC)s1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
Sodium thiomethoxide (1M in EtOH, 4.4 mL, 4.4 mmol) was added dropwise to a −78° C. solution of 4-(3-bromo-5-tert-butoxy-benzenesulfonyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (1.91 g, 4.0 mmol) in THF (40 mL). The solution was stirred for 30 min at −78° C. and glacial acetic acid (1 mL) was added. The solution was diluted with EtOAc (60 mL), extracted with NaHCO3 (2×30 mL), water (2×20 mL), brine (30 mL), and was dried over sodium sulfate. Concentration of the solution in vacuo followed by SiO2 flash chromatography of the residue yielded the title compound (1.48 g, 76%). 1H-NMR (CDCl3): δ 8.01 (d, 1H, J=0.5 Hz), 7.74 (m, 1H), 7.66 (m, 1H), 7.37 (m, 1H), 3.99 (s, 3H), 2.48 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: C1O[CH:4]([C:5]2[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:6]=2[NH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:3]C1.Cl>CC(C)=O>[C:16]([NH:15][C:6]1[CH:7]=[CH:8][C:9]([O:13][CH3:14])=[C:10]([O:11][CH3:12])[C:5]=1[CH:4]=[O:3])([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)Nc1ccc(OC)c(OC)c1C1OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CCOC(=O)Nc1ccc(OC)c(OC)c1C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
2-(N-Carbethoxyamino)-5,6-dimethoxybenzaldehyde-ethyleneketal (5.0 g, 16.8 mM) is dissolved in acetone (36 ml) and aqueous HCl (3 ml of 1N solution). The mixture is stirred at room temperature for 4 hours. The solvent is removed in vacuo to give a yellow solid (3.9 g). Recrystallization from n-hexane gives the pure product as a yellow solid; yield 3.6 g (84.7%); m.p. 86°-88° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH2:5][OH:6].Br[CH:15]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([CH2:11][CH2:12][CH3:13])[C:9]=1[O:10][CH:15]([C:20]1[CH:25]=[CH:24][C:23]2[O:26][CH2:27][O:28][C:22]=2[CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCCc1cc(CO)cc(Cl)c1O
Reactant: COC(=O)C(Br)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1cc(CO)cc(Cl)c1OC(C(=O)OC)c1ccc2c(c1)OCO2
Temperature: 25 °C
Yield: 81 %

Procedure:
To a solution of 0.280 g (1.40 mmol) of the product of step C and 0.762 g () of methyl α-bromo-3,4-methylenedioxyphenylacetate in 3.0 mL of acetone was added 0.386 g (2.80 mmol) of finely powdered potassium carbonate and the mixture was stirred and heated at reflux for 2 hours. At this point, the reaction mixture was cooled to room temperature, filtered, and evaporated in vacuo. The residue was purified on a silica gel flash chromatography column eluted with 30% EtOAc-hexane. Evaporation of the purified fractions and solvent removal in vacuo afforded 0.445 g (81%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:20]([C:23]1[CH:28]=[C:27]([C:29](=[O:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[C:32]1[CH:37]=[CH:36][C:35]([C:38](=[O:40])[CH3:39])=[CH:34][CH:33]=1)([O-])=O.CCCCCC>ClC1C=CC=CC=1Cl>[CH:36]1[C:37]2[NH:20][C:23]3[C:24](=[CH:25][CH:26]=[C:27]([C:29](=[O:31])[CH3:30])[CH:28]=3)[C:32]=2[CH:33]=[CH:34][C:35]=1[C:38](=[O:40])[CH3:39]
Reactant: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Clc1ccccc1Cl
Solvent: CCCCCC
Product: CC(=O)c1ccc2c(c1)[nH]c1cc(C(C)=O)ccc12
Temperature: 180 °C

Procedure:
The mixture of triphenylphosphine (3.47 g, 13.24 mmol) and 1,1′-(2-nitro-[1,1′-biphenyl]-4,4′-diyl)diethanone (1.5 g, 5.30 mmol) in 1,2-dichlorobenzene (o-DCB) (15.90 mL) was heated at 180° C. under microwave irradiation for 1 h. The reaction mixture was cooled and poured in to the hexane (50 mL). Most of the impurities were removed by precipitation from hexane. The compound was further purified on silica gel ((0-100% EtOAc/Hexane). Fractions were concentrated to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([N:15]=[C:16]=[O:17])(=[O:14])=[O:13])([O:3][CH2:4][CH3:5])=[O:2].[NH2:18][C:19]1[N:24]=[C:23]([NH:25][CH3:26])[N:22]=[C:21]([O:27][C:28]([F:31])([F:30])[F:29])[N:20]=1>C(Cl)Cl>[CH3:26][NH:25][C:23]1[N:22]=[C:21]([O:27][C:28]([F:31])([F:29])[F:30])[N:20]=[C:19]([NH:18][C:16]([NH:15][S:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:13])=[O:14])=[O:17])[N:24]=1
Reactant: CCOC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CNc1nc(N)nc(OC(F)(F)F)n1
Solvent: ClCCl
Product: CCOC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(NC)nc(OC(F)(F)F)n1
Temperature: 22 °C
Reaction time: 30 h

Procedure:
3.1 g (0.012 mol) of 2-carboethoxybenzenesulfonyl isocyanate in 3 ml of methylene chloride were added over the course of 10 minutes to a stirred mixture of 2.5 g (0.012 mol) of 2-amino-4-methylamino-6-trifluoromethoxy-1,3,5-triazine and 150 ml of methylene chloride at 22° C., and the mixture was stirred at 22° C. for 30 hours. It was then concentrated under reduced pressure, stirred with methyl tert-butyl ether and filtered off with suction. Further washing with methanol and drying resulted in 3.8 g (67.4% of theory) of the title compound of melting point 182°-184° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]2[CH2:10][O:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:28]=[CH:27][C:18]([O:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[CH:17][CH:16]=1>CO>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH:8]([OH:9])[CH2:10][N:23]2[CH2:24][CH2:25][CH2:26][CH:21]([CH2:20][O:19][C:18]3[CH:27]=[CH:28][C:15]([C:14]([F:13])([F:29])[F:30])=[CH:16][CH:17]=3)[CH2:22]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(OCC2CCCNC2)cc1
Reactant: Clc1ccc(OCC2CO2)cc1
Solvent: CO
Product: OC(COc1ccc(Cl)cc1)CN1CCCC(COc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 79.3 %

Procedure:
2-(4-Chloro-phenoxymethyl)-oxirane (50 mg) and of 3-(4-Trifluoromethyl-phenoxymethyl)-piperidine (70 mg, 1.0 equivalent) in 4 mL of methanol were heated in a sealed tube at 100° C. for 16 hours, cooled to room temperature, transferred to a round-bottomed flask, and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel using as eluent a gradient of ethyl acetate in hexane containing 1% ammonium hydroxide. 95 mg of 1-(4-Chloro-phenoxy)-3-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-propan-2-ol was obtained (79%). Data for this mixture of amino alcohol diastereomers: MS 444 (M++1).