Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[F:28][C:29]([F:39])([F:38])[CH:30]([C:34]([F:37])([F:36])[F:35])[C:31](O)=[O:32]>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:23])([CH3:24])[C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:31](=[O:32])[CH:30]([C:29]([F:38])([F:28])[F:39])[C:34]([F:37])([F:36])[F:35])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: O=C(O)C(C(F)(F)F)C(F)(F)F
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC(=O)C(C(F)(F)F)C(F)(F)F)ccc2F)N=C1N

Procedure:
The coupling of [(S)-4-(5-amino-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate F2) and 3,3,3-trifluoro-2-trifluoromethyl-propionic acid followed by deprotection of the intermediate yielded the title compound as a white solid. MS (ESI): m/z=457.3 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]2[O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][NH:23][C:22](=[O:25])[NH:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18].Cl[CH2:27][C:28]1[CH:37]=[CH:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:29]=1>CN(C)C=O.O>[CH:3]12[CH2:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]2[O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][N:23]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[C:22](=[O:25])[N:21]([CH2:27][C:28]3[CH:37]=[CH:36][C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:29]=3)[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2CNC(=O)NC2)cc1OC1CC2CCC1C2
Reactant: ClCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C2CN(Cc3ccc4ccccc4n3)C(=O)N(Cc3ccc4ccccc4n3)C2)cc1OC1CC2CCC1C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.6 %

Procedure:
NaH (63 mg, 1.58 mmol, 1.0 eq, 60% oil dispersion) was added to a mixture of (0.500 g, 1.58 mmol, 1.0 eq) 5-[3-(bicyclo[2.2.1]hept-2-yloxy)4-methoxyphenyl]tetra-hydro-2(1H)-pyrimidinone and (0.279 g, 1.58 mmol, 1.0 eq) 2-chloromethylquinoline in 12 ml of anhydrous dimethylformamide. After stirring for 18 hours at room temperature, the reaction mixture was diluted with 250 ml of H2O and extracted with ethyl acetate. The ethyl acetate extract was washed once with H2O, once with brine, dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on a silica gel column, eluting with 21/2% CH3OH-CH2Cl2 to yield 50 mg of a solid, which was recrystallized from ethyl acetate-hexane to afford 45 mg, 5%, of a white crystalline solid. M.P.: 135°-136° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:17]([Cl:18])=[C:16]([Cl:19])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:22][CH3:23])[C:12]([O:20][CH3:21])=[N:13]2.N1C=CC=CC=1>ClCCl>[Cl:18][C:17]1[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:19])[N:13]=[C:12]([O:20][CH3:21])[C:11]([O:22][CH3:23])=[N:10]2
Reactant: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reaction time: 18 h
Yield: 88 %

Procedure:
Methoxyacetylchloride (27.3 ml, 32.4 g, 0.30 mol) was added to a stirred mixture of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 2) (73.8 g, 0.27 mol) and pyridine (26.4 ml, 25.89, 0.33 mol) in dichloromethane (1.2 liters) at room temperature under nitrogen. After 18 hours standing at room temperature, the mixture was washed with 2M aqueous hydrochloric acid solution followed by brine, then dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with methanol and filtered to give 6,7-dichloro-2,3-dimethoxy-5-methoxyacetamidoquinoxaline (82.09, 88%) as an off-white solid. mp 171-173° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:10][N:11]1C[CH2:15][CH2:14][CH2:13][CH:12]1CO>C(O)C>[CH3:1][N:2]([CH2:3][C:4]([O:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]1[CH3:10])=[O:5])[CH3:9]
Reactant: CN1CCCCC1CO
Reactant: CCOC(=O)CN(C)C
Solvent: CCO
Product: CN(C)CC(=O)OCC1CCCCN1C

Procedure:
A mixture of 75 g of ethyl N,N-dimethylglycinate, 75 g of 1-methyl-2-piperidylmethanol and 1 g of titanium tetra(n-butoxide) was heated at 45° C. until the amount of ethanol collected indicated the reaction was complete. After cooling a small amount of water was added, the mixture was filtered, and the filtrate was distilled under reduced pressure to provide N-methyl-2-piperidylmethyl N,N-dimethylaminoacetate.
Reaction SMILES: ClC(OCC(C)C)=O.[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:37])=[O:36])=[CH:31][CH:30]=1)=[O:26])(O)=[O:10].C([N:40](CC)CC)C.O.N>O1CCCC1.O>[C:9]([CH2:12][O:13][CH2:14][C@@H:15]1[CH2:19][C@@H:18]([O:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:17][N:16]1[C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][C:32]([N+:35]([O-:37])=[O:36])=[CH:33][CH:34]=1)=[O:26])(=[O:10])[NH2:40]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reaction time: 0.5 h

Procedure:
A solution of isobutyl chloroformate (0.60 g) in tetrahydrofuran (1 ml) was dropwise added to a solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.28 g) and triethylamine (0.82 ml) in tetrahydrofuran (13 ml) at -10°~-5° C., and the mixture was stirred at the same temperature for 30 minutes. The mixture was dropwise added to concentrated ammonia water (10 ml) at 0°-5° C. and the solution was stirred at the same temperature for 1 hour. The mixture was poured into water (50 ml) and extracted with chloroform (50 ml). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a syrup. The syrup was subjected to a column chromatography on silica gel (25 g) and eluted with a mixture of methanol and chloroform (2:98 V/V) to give (2S,4R)-2-(carbamoylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.00 g).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([C:7]1[CH:8]=[CH:9][C:10]([CH:13](O)[CH2:14][O:15][C:16]2[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=2)=[N:11][CH:12]=1)[CH3:6].O>C(Cl)(Cl)Cl>[Br:2][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([CH2:5][CH3:6])=[CH:12][N:11]=1)[CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1
Reactant: CCc1ccc(C(O)COc2ccc(C=O)cc2)nc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCc1ccc(C(Br)COc2ccc(C=O)cc2)nc1
Yield: 89.8 %

Procedure:
2.93 g (0.01 mol) PBr3 was added to a solution of 5 g (0.018 mol) 4-[2-(5-ethyl-pyridin-2-yl)-2-hydroxy-ethoxy]-benzaldehyde dissolved in 50 mL chloroform at 55-60° C. Reaction mixture was refluxed for 1 hr. Progress of the reaction was monitored by TLC and after completion of reaction, subsequent work-up in alkaline water furnished 3 g (50%) of desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[NH:14][CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[CH2:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH2:22][C:23]#[CH:24].Cl>CN(C=O)C>[CH2:21]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:14]1[CH2:13][C@@H:12]([C:10]2[CH:9]=[CH:8][C:6]3[O:7][C:2]([CH3:18])([CH3:1])[O:3][CH2:4][C:5]=3[CH:11]=2)[O:16][C:15]1=[O:17])[CH2:22][C:23]#[CH:24]
Reactant: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Reactant: C#CCCOCCCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCOCCCCCCN1C[C@@H](c2ccc3c(c2)COC(C)(C)O3)OC1=O
Reaction time: 1 h
Yield: 86.2 %

Procedure:
(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (10 g) in DMF (100 ml) was added dropwise to a stirred suspension of sodium hydride (60% oil dispersion, 2.33 g) in DMF (50 ml) with stirring under nitrogen and maintaining the internal temperature at 0°. Stirring was continued at 0-5° for 1 h. The mixture was recooled to 0° and a solution of 6-bromohexyl but-3-ynyl ether (14.7 g) in DMF (50 ml) was added over 1 min. The mixture was then stirred at 20-30° for 2 h. 2M HCl (9 ml) was added and the mixture was partitioned between water and diethyl ether. The aqueous layer was extracted with more diethyl ether and the combined organic layers were washed twice with brine. After drying (MgSO4) the solution was concentrated and loaded onto a column of silica gel (600 g) set up in diethyl ether:petroleum ether (bp 40-60°) (1:2). The column was eluted successively with this mixture, then (1:1) and then diethyl ether to give the title compound (13.88 g) LCMS RT=3.45 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]2[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]2=[O:22])[C:7]3=[O:23])=[O:40])=[CH:34][CH:33]=1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nc2ccc(CNC(=O)Nc3ccc(Cl)cc3)cc2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.47 g, 1.4 mmol) and triethylamine (0.27 mL, 2.0 mmol) in THF (8 mL) at 5-10° C., was added 4-chlorophenyl isocyanate (0.28 g, 1.8 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (˜1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-(4-chloro-phenyl)-3-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-urea as an off-white solid (400 mg, 63% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.18 min (98.9%); mp, 225-227° C.; 1HNMR (DMSO-d6) 2.15-2.20 (m, 1H, CHH), 2.56-2.91 (m, 6H, CHCH2, CH), 4.41 (d, J=5 Hz, 2H, CH2NH), 5.26 (dd, J=6, 11 Hz, 1H, CH), 6.81 (t, J=6 Hz, 1H, CH2NH), 7.23-7.95 (m, 7H, Ar), 8.80 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.93, 23.38, 30.61, 42.33, 56.54, 119.23, 120.01, 123.67, 124.57, 126.53, 128.42, 133.95, 139.05, 139.37, 145.74, 154.53, 155.09, 160.46, 169.47, 172.60. LCMS MH=454, 456; Anal Calcd For C22H20N5O4Cl+0.8H2O: C, 56.43; H, 4.65; N, 14.95; Cl, 7.57. Found: C, 56.45; H, 4.56; N, 14.87; Cl, 7.69.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[C:8]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:10][CH2:11][CH3:12])=[O:9]>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8](=[O:9])[CH:13]=[C:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[CH3:12]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CCOCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C1CCOCC1
Temperature: 50 °C
Reaction time: 16 h
Yield: 26 %

Procedure:
To a solution of tetrahydro-4H-pyran-4-one (5.0 g, 50 mmol) in 150 mL toluene at ambient temperature was added carbethoxymethylenetriphenyl phosphorane (17.4 g, 50 mmoL.). The mixture was warmed to 50° C. and allowed to stir for 16 h. The mixture was cooled to ambient temperature, concentrated under reduced pressure and purified by column chromatography (Si2O, 50% hexanes in EtOAc) to provide the title compound (2.2 g, 13 mmol, 26% yield). MS (DCI/NH3) m/z 171 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:19])=[CH:4][C:5]([N+:16]([O-])=O)=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=2)[CH:7]=1.O.O.[Sn](Cl)Cl>C(O)C>[NH2:16][C:5]1[CH:4]=[C:3]([F:19])[C:2]([Br:1])=[CH:7][C:6]=1[NH:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[N:10]=1
Reactant: Nc1nccc(Nc2cc(Br)c(F)cc2[N+](=O)[O-])n1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1nccc(Nc2cc(Br)c(F)cc2N)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of 4-N-(5-bromo-4-fluoro-2-nitrophenyl)pyrimidine-2,4-diamine (713 mg, 2.17 mmol) in ethanol (30 mL) was added tin(II) chloride dihydrate (1.72 g, 7.61 mmol) The reaction mixture was stirred at 60° C. for 1 hr. Upon completion, reaction mixture was evaporated to dryness and added to ice water (20 mL). The pH was adjusted to pH10 using sat Na2CO3 solution (30 mL) and EtOAc (30 mL) was added. Saturated Rochelle's salt (20 mL) was added and the mixture stirred until separate layers were observed. The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). Combined organics were washed with saturated Rochelles salt (15 mL) followed by brine solution (15 mL) and dried over Na2SO4, filtered and concentrated in vacuo to afford the title compound as a pale orange solid (500 mg, 68.7% yield); 1H NMR (250 MHz, DMSO) delta 8.11 (s, 1H), 7.75 (d, J=5.7 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 6.67 (d, J=11.1 Hz, 1H), 6.08 (s, 2H), 5.75 (d, J=5.7 Hz, 1H), 5.37 (s, 2H); LC-MS: m/z+299.75 (M+H)+.
Reaction SMILES: [OH-].[Na+].O.Cl.[C:5]([NH2:13])(=[NH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]([CH2:22][C:23](OCC)=[O:24])(=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)C>O>[C:6]1([C:5]2[N:13]=[C:23]([OH:24])[CH:22]=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:12]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2ccccc2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.4 %

Procedure:
To a ice cooled solution of sodium hydroxide (2.4 g, 60 mmol) in water (30 ml) was added benzamidine hydrochloride hydrate (9.4 g, 60 mmol) and ethyl benzoylacetate (12.1 g, 63 mmol). Ethanol (ca 30 ml) was added and the mixture was stirred at room temperature overnight. The solid was filtered off, washed with water and diethyl ether and dried which gave the title compound (9.0 g, 60%), (M+H)+1 249.
Reaction SMILES: Cl.[CH3:2][NH:3][CH2:4][CH:5]1[C:14]2[C:9](=[C:10]([O:15][CH3:16])[CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.O.OC1C2N=NNC=2C=CC=1.[S:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][C:34]([OH:36])=O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[CH2:8][CH2:7][CH2:6][CH:5]2[CH2:4][N:3]([CH3:2])[C:34](=[O:36])[CH2:33][C:29]1[S:28][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)Cc1cccs1
Reactant: CNCC1CCCc2c(OC)cccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc2c1CCCC2CN(C)C(=O)Cc1cccs1
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.5 %

Procedure:
The product from Example 17 (1.04 g), hydroxybenzotriazole hydrate (1.51 g) and thiopheneacetic acid (720mg) in dry THF (30 ml) at 0° C. was treated with dicyclohexylcarbodiimide (1.16 g). The reaction was warmed to room temperature and stirred for 18 hr. The mixture was filtered and concentrated. The residue was dissolved into EtOAc (60 ml) washed with 5% aq. HCl (15 ml), water (15 ml), 10% aq. KOH (15 ml), dried (MgSPO4) filtered and concentrated. Chromatography on SiO2 afforded 1.58 g of product as a viscous oil.
Reaction SMILES: [C:1]([C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)=[CH:12][C:11]=2/[CH:27]=[CH:28]\[C:29]([O:31]C)=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O1CCCC1>[C:1]([C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:24])([F:25])[F:26])=[CH:18][CH:17]=3)=[CH:12][C:11]=2/[CH:27]=[CH:28]\[C:29]([OH:31])=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)/C=C\c1cc(-c2ccc(OC(F)(F)F)cc2)ccc1Oc1ccc(C(C)(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(Oc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2/C=C\C(=O)O)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
A mixture of methyl (Z)-3-{4-[4-(tert-butyl)phenoxy]-4′-(trifluoromethoxy)biphenyl-3-yl}propenoate (590 mg, 1.293 mmol), methanol (1 ml), tetrahydrofuran (4 ml) and 2N aqueous sodium hydroxide (1.94 ml) was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, acidified by addition of 2N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (550 mg, 93.2%) as a pale yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[O:20])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.C(O)=O>O>[F:29][C:23]1[CH:24]=[C:25]([F:28])[CH:26]=[CH:27][C:22]=1[NH:21][C:19](=[O:20])[N:18]([CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:37])=[O:5])[S:12][CH:13]=1)[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)C(=O)Nc1ccc(F)cc1F
Solvent: O
Solvent: O=CO
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To 2-[(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (0.67 g) obtained in Example 319-1 was added formic acid (10 mL), and the mixture was stirred at room temperature overnight, stirred at 50° C. for 3 hr and further stirred at 70° C. for 4 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel chromatography (elution solvent hexane-ethyl acetate=1:1) to give the title compound (0.55 g) as a pale-brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH:13]=O)[CH2:9][CH2:8]1)=[O:5].[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:3]=1[C:4]([NH:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:27][C:26]2[CH:28]=[CH:29][CH:30]=[C:24]([F:23])[CH:25]=2)[CH2:9][CH2:8]1)=[O:5]
Reactant: Nc1cccc(F)c1
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CNc2cccc(F)c2)CC1)c1cc(C(F)(F)F)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 50 mL round-bottomed flask containing trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) (1.0 g, 3.0 mmol) and 3-fluoroaniline (0.29 mL, 3.0 mmol) in dry DCM (25 mL) is added sodium triacetoxyborohydride (953 mg, 4.49 mmol) in three portions over 1-2 minutes. The suspension is stirred at RT for 1 hour. 1N sodium hydroxide (25 mL) is added and the mixture is stirred at RT for 20 min. The mixture is then diluted with DCM (50 mL) and the DCM layer separated and washed with 1M HCl (25 mL) and brine (15 mL), dried (MgSO4), filtered and evaporated to give a colourless solid. The crude product is redissolved in DCM, absorbed directly onto silica gel and columned on silica gel using a 50 g pre-packed column and eluted with 30% EtOAc/isohexane. Product is isolated as a colourless oil which is triturated with diether ether-isohexane to afford the title compound as colourless crystals. [MH+ 429.24].
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1(S([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[CH:21]=3)[C:16]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[C:15]2[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([O:47]C)=[O:46])(=O)=O)C=CC=CC=1.[Na]>>[CH2:1]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:34]=[CH:33][C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:26]=3)[CH:21]=2)[C:16]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)=[C:15]1[CH2:43][C:44]([CH3:50])([CH3:49])[C:45]([OH:47])=[O:46])[CH:2]=[CH2:3]
Reactant: C=CCBr
Reactant: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Agent: [Na]
Product: C=CCn1c(CC(C)(C)C(=O)O)c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc21

Procedure:
The title compound was prepared under the conditions described in Step A and Step B of Example 38, but substituting allyl bromide for the benzenesulfonyl chloride from Example 38 (Step A). Anal. C, H, N for sodium salt·2 H2O Calc. C 66.38; H 5.74; N 4.69 Found C 66.57; H 5.75; N 4.73.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: O=C(Cl)C1CCCCC1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (550 mg, 90%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23])=O>C(C(C)=O)C>[CH2:10]([O:9][C:7]([C:5]1[N:6]2[CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])[N:1]=[C:2]2[S:3][CH:4]=1)=[O:8])[CH3:11]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: O=C(CBr)c1ccccc1[N+](=O)[O-]
Solvent: CCC(C)=O
Product: CCOC(=O)c1csc2nc(-c3ccccc3[N+](=O)[O-])cn12
Temperature: 25 °C
Yield: 79.4 %

Procedure:
In a typical run, 2.1 g of ethyl 2-aminothiazole-4-carboxylate (Combi-Blocks, 0.0123 mol) was mixed with 25 mL of methyl ethyl ketone along with 2-bromo-2′-nitroacetophenone (3.0 g, 0.0123 mol). The reaction mixture was stirred under reflux for 18 hours. It was then cooled to room temperature and filtered to remove some of the solids. The filtrate was concentrated to afford 3.10 g of 6-(2-nitro-phenyl)-imidazo[2,1-b]thiazole-3-carboxylic acid ethyl ester (MS, M++H=318).