Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21]S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[C:34]=1O>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][O:21][C:34]2[C:33]([F:32])=[CH:38][C:37]([F:39])=[CH:36][C:35]=2[F:40])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1c(F)cc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2COS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2ccccc2COc2c(F)cc(F)cc2F)CC1
Temperature: 50 °C
Reaction time: 6 h
Yield: 86.1 %

Procedure:
4-(2-Methanesulfonyloxymethylphenyl)piperidine-1-carboxylic acid t-butyl ester (27.0 g, 60.6 mmol, 1.0 eq.) was dissolved in MeCN (540 mL) and added to K2CO3 (25 g, 180 mmol, 3.0 eq.) and 2,4,6-trifluorophenol (13.5 g, 90.9 mmol, 1.5 eq.). The mixture was vigorously stirred at 50° C. for 6 hours, removed from the heat, and stirred overnight. The mixture was cooled at room temperature, and diluted with EtOAc (700 mL) and water (700 mL). The phases were separated, and the organic layer was washed twice with 1.0 M NaOH in water (2×400 mL) and saturated aqueous NaCl (1×400 mL), then dried over Na2SO4 and the solvent removed to yield crude 4-[2-(2,4,6-trifluorophenoxymethyl)-phenyl]piperidine-1-carboxylic acid t-butyl ester (25.0 g). The crude product was combined with smaller scale runs for a total of 30 g, and purified by chromatography (0-10% EtOAc in hexanes) to yield 4-[2-(2,4,6-trifluorophenoxymethyl)phenyl]piperidine-1-carboxylic acid t-butyl ester (22.0 g).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][OH:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1.O[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>ClCCl>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][O:15][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:25][CH:24]=3)=[CH:10][CH:9]=2)[N:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:3]=1
Reactant: Cc1cc(-c2ccccc2)nn1Cc1ccc(CO)cc1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OCc2ccc(Cn3nc(-c4ccccc4)cc3C)cc2)cc1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
To a mixture of {4-[(5-methyl-3-phenyl-1H-pyrazol-1-yl)methyl]phenyl}methanol (278 mg, 1.0 mmol), methyl 3-(4-hydroxyphenyl)propanoate (180 mg, 1.0 mmol), triphenylphosphine (393 mg, 1.5 mmol) and dichloromethane (5 mL) was added dropwise diethyl azodicarboxylate (40% toluene solution, 650 mg, 1.5 mmol) with stirring at room temperature, and the mixture was stirred at room temperature for 1 hr. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:2) to give the title compound (263 mg, yield 90%) as a yellow oil.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][Cl:26]>C(#N)C>[Cl:26][CH2:25][CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1CCN(CCCl)CC1
Reaction time: 96 h
Yield: 49.9 %

Procedure:
Benzyl piperazine-1-carboxylate (1.00 g, 4.54 mmol) and K2CO3 (1.255 g, 9.08 mmol) were dissolved in acetonitrile (12.87 ml) to form a suspension. 1-bromo-2-chloroethane (2.3 ml, 27.24 mmol) was added to the reaction mixture at r.t and the resulting mixture was stirred at this temperature for 96 hours. The reaction mixture was filtered, and the filtrate concentrated under reduced pressure. Purification by column chromatography (ISCO, silica gel column, eluting with 0→100% EtOAc in hexanes) gave the title compound (0.64 g, yield: 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]=1[N:13]=[C:14]=[O:15].C1(C)C=CC=CC=1.C[O:24][C:25]([NH:27][NH2:28])=O>C1C=CC=CC=1>[Cl:8][C:6]1[C:5]([O:9][CH2:10][CH2:11][CH3:12])=[CH:4][C:3]([N:13]2[C:25](=[O:24])[NH:27][NH:28][C:14]2=[O:15])=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)NN
Reactant: CCCOc1cc(N=C=O)c(F)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccccc1
Product: CCCOc1cc(-n2c(=O)[nH][nH]c2=O)c(F)cc1Cl
Reaction time: 8 h
Yield: 115.3 %

Procedure:
A solution of 2-fluoro-4-chloro-5-n-propoxyphenyl isocyanate (1.8 g) in benzene (10 ml) was added to a toluene solution containing methoxycarbonylhydrazine (0.71 g), and the resultant mixture was allowed to stand overnight. The precipitated crystals were collected by filtration and dissolved in a 4M aqueous sodium hydroxide solution (10 ml) under heating. To the resulting solution, conc. hydrochloric acid was added, and the precipitated crystals were collected by filtration to give 2.6 g of 4-(4-chloro-2-fluoro-5-n-propoxyphenyl)urazol. M.P., 181°-182° C. IR νmax (cm-1): 3150, 1710, 1680. NMR δ (ppm): 1.1 (3H, t), 4.0 (3H, q), 7.0 (1H, d), 7.3 (1H, d)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH2:22]>>[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:21]=1[NH:22][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1ccc(C)cc1N
Product: COc1ccc(C)cc1Nc1cc(C(F)(F)F)nc(-c2cccnc2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(3-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 2-methoxy-5-methylaniline (40 mg, 0.290 mmol) similar to Example 58 and isolated as a yellow solid (41 mg, 59%). 1H NMR (CDCl3): 9.66 (d, J=1.8 Hz, 1H), 8.74–8.70 (m, 2H), 7.98 (s, 1H), 7.55 (s, 1H), 7.44–7.40 (m, 1H), 6.99–6.95 (m, 1H), 6.88 (s, 1H), 6.85 (s, 1H), 3.89 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C>[CH:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][OH:12])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCCCc1ccccc1
Solvent: CC(=O)O
Product: OCCCCCC1CCCCC1
Reaction time: 22 h

Procedure:
To a portion of 100 mL glacial acetic acid, purged with argon, was added 5.62 g of PtO2 (Aldrich) followed by a solution of 25.00 g (152.2 mmol, Aldrich) of 5-phenyl-1-pentanol in 100 mL glacial acetic acid. The reaction vessel was evacuated and purged with H2 three times, the the reaction mixture was stirred under H2 (1 atm) of 22 hours. The reaction was not complete by thin layer chromatography. A second portion of 3.25 (Aldrich) of PtO2 was added and the reaction was stirred under H2 (1 atm) for an additional 32 hours. The mixture was filtered through a 0.4 μM polycarbonate filter, the filtrate was concentrated in vacuo and then azeotroped four times with toluene to give 28.08 g (164.9 mmol, 100%) of a cloudy liquid. 1H NMR indicated the crude material was about a 2:1 mixture of the alcohol title compound and the corresponding acetate.
Reaction SMILES: Cl.CO[C:4]1[CH:17]=[CH:16][C:7]([C:8](C2CCNCC2)=[O:9])=[CH:6][CH:5]=1.COC([C:22]1[CH:23]=[CH:24][C:25](C(O)=O)=[N:26][CH:27]=1)=O.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[C:8]([N:26]1[CH2:27][CH2:22][CH2:23][CH2:24][CH2:25]1)(=[O:9])[C:7]1[CH:6]=[CH:5][CH:4]=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 161.5 %

Procedure:
To a mixture of 4-(4-methoxybenzoyl)piperidine hydrochloride (2.00 g, 7.82 mmol, 1.0 eq) and 5-(methoxycarbonyl)pyridine-2-carboxylic acid (1.42 g, 7.82 mmol, 1.0 eq) in dimethylformamide (55 mL) was added triethylamine (2.72 mL, 19.55 mmol, 2.5 eq) followed by HATU (2.97 g, 7.82 mmol, 1.0 eq). The reaction was stirred at room temperature for 4 hours before partitioning between EtOAc (250 mL) and water-NaHCO3 (1:1, 200 mL). The organics were further washed with brine (150 mL), water (150 mL) and brine (150 mL), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography (silica, 4-5% MeOH—CH2Cl2) yielded the coupled product (2.39 g, 80%) as a white foam; 1H nmr (CDCl3) δ 9.08 (1H, m, pyH-6), 8.29 (1H, dd, J 8.5, 2.0 Hz, pyH-4), 7.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH), 7.60 (1H, d, J 8.0 Hz, pyH-3), 6.84 (2H, d, J 9.0 Hz, 2H of C6H4OCH3), 4.60 (1H, m, 1H of BzpipH-2, H-6), 3.87 (3H, s, 1×OCH3), 3.82 (1H, m, 1H of BzpipH-2, H-6), 3.77 (3H, s, 1×OCH3), 3.46 (1H, m, BzpipH-4), 3.19 (1H, ddd, J 14.0, 10.0, 4.0 Hz, 1H of BzpipH-2, H-6), 3.02 (1H, m, 1H of BzpipH-2, H-6), 1.95-1.90 (1H, m, 1H of BzpipH-3, H-5), 1.83-1.79 (3H, m, 3H of BzpipH-3, H-5); 13C nmr (CDCl3) δ 199.9, 166.6, 165.0, 163.5, 157.7, 149.6, 138.1, 130.5, 128.5, 126.3, 123.1, 113.9, 55.4, 52.5, 46.6, 42.6, 41.8, 28.8, 28.4; m/z: 383 [M+H]+ (found [M+H]+, 383.1515, C21H22N2O5 requires [M+H]+ 383.1602).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=3[F:19])[N:10]=[C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])[CH2:8]2)=[CH:4][CH:3]=1.[CH3:27][S:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>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.COCCOC>[F:19][C:13]1[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:12]=1[N:11]1[CH:7]([C:5]2[S:6][C:2]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([S:28][CH3:27])[CH:34]=3)=[CH:3][CH:4]=2)[CH2:8][C:9]([C:20]([F:26])([F:25])[C:21]([F:24])([F:23])[F:22])=[N:10]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(Br)s2)c(F)c1
Reactant: CSc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: CSc1cccc(-c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
5-(5-Bromo-thiophen-2-yl)-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (50.0 mg, 0.11 mmol) prepared in Step 8 of Preparation 13, 3-(methylthio)phenylboronic acid (28.0 mg, 0.17 mmol), Pd(PPh3)4 (12.5 mg, cat.) and a 2N sodium carbonate solution (500.0 uL) were added to a mixed solvent of ethanol (500.0 uL) and 1,2-dimethoxyethane (2.0 mL). The reaction mixture was stirred at 90° C. for 3 hours and then filtered through celite pad. A saturated solution of ammonium chloride was added to the filtrate, which was then extracted with ethyl acetate three times. The combined extract was washed with brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/6) to give 15.0 mg of the titled compound as a white liquid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2=[CH:8][N:9]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:6]2[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25]>O>[CH3:1][N:2]1[C:7]2=[C:8]3[N:9]([C:10]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[C:6]2[C:5](=[O:23])[N:4]([CH3:24])[C:3]1=[O:25])[CH2:17][CH2:18][CH2:19][C:20]3=[O:21]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCCC(=O)O)cc2n(C)c1=O
Solvent: O
Product: Cn1c(=O)c2c(-c3ccccc3)n3c(c2n(C)c1=O)C(=O)CCC3
Temperature: 80 °C

Procedure:
4-(1,3-Dimethyl-2,4-dioxo-5-phenyl-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl)-butyric acid (step 2)(1.3 g, 3.81 mmol) and polyphosphoric acid (10 g, 3.81 mmol) were combined and heated at 80° C. for 1 hour. The reaction mixture was cooled to RT, diluted with water and extracted with chloroform (4×). The combined organic extracts were passed through a hydrophobic frit and evaporated under reduced pressure. The title product was afforded as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[F:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=1>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:32]([F:31])=[CH:33][CH:34]=4)[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1ccc(F)cc1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 290 μl (2.5 mmol) of 4-fluorobenzoyl chloride, and after purification, 1 g (98%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-4-fluoro-N-methylbenzamide, with a melting point of 212° C., is obtained.
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH3:38])[CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH3:38])[CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1cc(C(N)CC(=O)O)ccc1OCc1ccccc1
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Product: COC(=O)CC(N)c1ccc(OCc2ccccc2)c(OC)c1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(3-methoxy-4-benzyloxy-phenyl)propionic acid. 1H NMR (CDCl3): δ 7.26-7.44 (m, 5H), 6.75-6.94 (m, 3H), 5.13 (s, 2H), 4.35 (t, 1H, J=5 Hz), 3.89 (s, 3H), 3.61 (s, 3H), 2.59 (d, 2H, J=5 Hz), 1.84 (d, 2H, J=5 Hz)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:16]OS(C)(=O)=O)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[NH:34]1[CH:38]=[CH:37][N:36]=[CH:35]1>>[CH2:1]([O:3][C:4]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14](=[O:33])[CH:15]([NH:22][S:23]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:16][N:34]2[CH:38]=[CH:37][N:36]=[CH:35]2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: c1c[nH]cn1
Reactant: CCOC(=O)Cc1ccc(NC(=O)C(COS(C)(=O)=O)NS(=O)(=O)c2ccc(F)cc2)cc1
Product: CCOC(=O)Cc1ccc(NC(=O)C(Cn2ccnc2)NS(=O)(=O)c2ccc(F)cc2)cc1

Procedure:
The procedure described in Example 79 was repeated, except that (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-methanesulfonyloxypropanamide (560 mg) was reacted with imidazole to obtain the desired (RS)-N-(4-(ethoxycarbonylmethyl)phenyl)-2-(4-fluorobenzenesulfonylamino)-3-(1H-imidazol-1-yl)propanamide (152.3 mg) together with a less polar by-product. The by-product was not investigated further.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11]C=[N:9][C:8]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:4][CH:3]=1.Cl.O1CCOCC1>CO>[ClH:1].[NH2:9][CH:8]([C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:11])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1ncoc1-c1ccc(Cl)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)C(N)C(=O)c1ccc(Cl)s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 199 %

Procedure:
To a solution of methyl 5-(5-chlorothiophen-2-yl)oxazol-4-carboxylate (12.6 g) in methanol (150 ml) was added 4N hydrogen chloride-dioxane solution (100 ml) under argon atmosphere, and the mixture was stirred at 70° C. for overnight. The reaction mixture was cooled and the solvent was removed under reduced pressure, and the resulting residue was triturated with acetone to obtain methyl 2-amino-3-(5-chlorothiophen-2-yl)-3-oxo-propionate hydrochloride (13.9 g) as colorless powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:16])[C:5]([Cl:17])=[CH:4][N:3]=1.[O:18]1[CH2:22][CH2:21][CH:20]([CH2:23]O)[CH2:19]1>>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([O:16][CH2:23][CH:20]3[CH2:21][CH2:22][O:18][CH2:19]3)=[CH:11][CH:12]=[CH:13][C:14]=2[F:15])[C:5]([Cl:17])=[CH:4][N:3]=1
Reactant: Oc1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: OCC1CCOC1
Product: Fc1cccc(OCC2CCOC2)c1Nc1nc(Cl)ncc1Cl

Procedure:
(2,5-Dichloro-pyrimidin-4-yl)-[2-fluoro-6-(tetrahydro-furan-3-ylmethoxy)-phenyl]-amine was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenol and (Tetrahydro-furan-3-yl)-methanol in an analogous manner to Example 1273c. Title compound isolated as a white solid (270 mg, 83%). MP=115-116, purity=96%, LCMS 358.48 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.20 (s, 1H), 7.25-7.22 (m, 1H), 6.86-6.82 (m, 2H), 6.76 (d, J=8.4 Hz, 1H), 4.00-3.97 (m, 2H), 3.83-3.76 (m, 3H), 3.63-3.58 (m, 1H), 2.67-2.63 (m, 1H), 2.07-2.01 (m, 1H), 1.68-1.64 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH:11]([NH:12]C=O)[C:5]=2[CH:4]=1)#[N:2].[ClH:15]>>[ClH:15].[C:1]([C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH:11]([NH2:12])[C:5]=2[CH:4]=1)#[N:2]
Reactant: N#Cc1cc2c(s1)CCCC2NC=O
Agent: Cl
Product: N#Cc1cc2c(s1)CCCC2N

Procedure:
A mixture of 4.8 grams of 2-cyano-N-formyl-4,5,6,7-tetrahydrobenzo[b]thien-4-amine in 70 ml. of 1N hydrochloric acid is refluxed for an hour and evaporated to dryness to afford 4.7 grams of 2-cyano-4,5,6,7-tetrahydrobenzo[b]thien-4-amine hydrochloride, melting point 241°C. to 246°C. (dec.).
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@@H:15]2[CH2:17][O:16]2)=[CH:11][CH:10]=1)([CH3:8])([CH3:7])[CH3:6]>CO>[C:5]([C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][C@H:15]2[O:16][C:2]([NH2:3])=[N:1][CH2:17]2)=[CH:11][CH:10]=1)([CH3:6])([CH3:7])[CH3:8]
Reactant: CC(C)(C)c1ccc(OC[C@@H]2CO2)cc1
Reactant: N#CN
Agent: [Na]
Solvent: CO
Product: CC(C)(C)c1ccc(OC[C@@H]2CN=C(N)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (2.92 g, 44.5 mmol) in methanol (40 mL) was added dropwise (S)-2-(4-tert-butylphenoxymethyl)-oxirane (9.18 g, 44.5 mmol). The reaction mixture was stirred at room temperature overnight after which the reaction mixture was concentrated to remove methanol. Anhydrous diethyl ether (150 mL) was added. The resulting white precipitate was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 4.53 g (41%) of (S)-5-(4-tert-butyl-phenoxymethyl)-(4,5-dihydro-oxazol-2-yl)amine.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].[NH2:25][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([NH:25][C:3]([C:5]2[NH:6][N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: COC(=O)c1cc(OCc2c(-c3ccc(F)cc3)noc2C)n[nH]1
Reactant: NN1CCCCC1
Product: Cc1onc(-c2ccc(F)cc2)c1COc1cc(C(=O)NN2CCCCC2)[nH]n1
Yield: 65 %

Procedure:
As described for example 8b, 5-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using 1-aminopiperidine instead of 4-aminomorpholine, to the title compound (78 mg, 65%), which was obtained as a white solid. MS: m/e=400.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([O:19]CC)=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:14])([F:16])[F:15])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Reaction time: 1 h
Yield: 97.9 %

Procedure:
To a solution of ethyl 4-fluoro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (147 mg, 0.48 mmol) in tetrahydrofuran (2.5 mL) was added a solution of lithium hydroxide (20 mg, 0.83 mmol) in water (2.5 mL). After stirring for one hour, the reaction mixture was acidified to pH=2 with 1M HCl, and extracted three times with dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate and rotoevaporated to obtain the title compound (130 mg, 0.47 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([O:19]CC)=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.C(O)C.[OH-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:24]=[C:23]([CH3:25])[C:22](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC(=O)COc1cc2c(=O)c(C)cn3c4ccc(Br)cc4c(c1)c23
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cn2c3ccc(Br)cc3c3cc(OCC(=O)O)cc(c1=O)c32
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.2 %

Procedure:
10-bromo-2-ethoxycarbonylmethyloxy-5-methyl-4H-pyrido [3,2,1-jk]carbazole-4-one (200 mg) obtained in Example 52 was suspended in a mixed solution of ethanol (10 ml) and methylene chloride (10 ml), and IN aqueous solution of sodium hydroxide (1 ml) was added to the suspension. The mixture was stirred at room temperature for 90 minutes, and the solvent was evaporated under reduced pressure. To the residue was added water and 1N hydrochloric acid to pH 1, and the crystals precipitated were recovered by filtration to obtain the title compound (170 mg, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][NH:10][C:9]2=[O:13])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)=[CH:19][CH:18]=1>CN(C)C=O>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][N:10]2[CH2:11][CH2:12][N:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=3)[C:9]2=[O:13])=[CH:19][CH:18]=1
Reactant: O=C1NCCN1c1ccnc(Cl)c1
Reactant: BrCCCCCCCOc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCCCCOc2ccc(Br)cc2)CCN1c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-chloro-4-pyridyl)-2-imidazolidinone (0.12 g, 0.63 mmol) dissolved in 10 mL dimethylformamide at 0° C. was added NaH (60% dispersion in mineral oil, 27.7 mg, 0.69 mmol). The mixture was stirred at room temperature for 30 minutes; then cooled in ice bath. 1-Bromo-4-[(7-bromoheptyl)oxy] benzene (0.22 g, 0.63 mmol) was added, and the mixture was stirred at room temperature for additional 4 hours. The reaction was quenched with MeOH, and the solvents were pumped off. A saturated aqueous NH4Cl solution (5 mL) and dichloromethane (10 mL) were added to the residue. The dichloromethane layer was dried over MgSO4, filtered, evaporated, and purified by column chromatography (ethyl acetate:MeOH=10:1) to give the product (i.e., Compound 8) as a white solid (0.19 g, 64%).