Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.[Cl-].[NH4+].CC([N:38](C)C)=O.CCN(C(C)C)C(C)C>C(OC(=O)C)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([NH2:38])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:21]=2[C:22]([F:23])([F:25])[F:24])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: CC(=O)N(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.7 %

Procedure:
Saponification of the ester of example 11 was achieved following the description for example 19, first step, to give 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid in 89% yield. To a solution of 6.0 g (12.34 mmol) 3-(2-chloro-6-fluorophenyl)-5-(1-(3-chlorophenyl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid and 1.98 g (37.021 mmol) ammoniumchlorid in 20 mL dry DMA 9.36 g (24.681 mmol) HBTU and 6.45 mL (37.021 mmol) DIPEA were added. The mixture was stirred 3 hours at r.t. Ethylacetate was added to the reaction mixture and it was washed twice with sodium hydrogen carbonate (5%, aq) and citric acid (5%, aq). The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed in the vacuum. The oily residue became solid by drying in the vacuum. The solid was washed with petroleum ether, filtrated and dried in the vacuum to yield 5.37 g (90%) of example 121. Result of LC/MS MH+: 484.83; 1H NMR (DMSO-d6; CCl4): 7.39-7.78 (7H, m, CH-arom./2H NH2), 8.43 (1H, s, CH-pyraz.)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:40])[CH3:39]>ClCCl>[C:38]([NH:1][CH2:2][CH2:3][NH:4][C:5]1[CH:25]=[C:24]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)[CH:23]=[CH:22][C:6]=1[CH2:7][NH:8][C:9](=[O:21])[C:10]1[CH:15]=[C:14]([O:16][CH3:17])[C:13]([CH3:18])=[C:12]([O:19][CH3:20])[CH:11]=1)(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCN)cc(OC)c1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc(C(=O)NCc2ccc(-c3noc(C)n3)cc2NCCNC(C)=O)cc(OC)c1C
Reaction time: 1.5 h
Yield: 34.2 %

Procedure:
To a solution of compound 44a (21 mg, 0.05 mmol) and pyridine (0.008 mL, 0.1 mmol) in dichloromethane (1 mL) was added acetyl chloride (0.004 mL, 0.055 mmol). The reaction mixture was stirred for 1.5 h, and additional acetyl chloride (0.004 mL) was added. After an additional 5 min, the reaction was quenched by addition of water and concentrated. The residue was purified by reverse phase HPLC (C18 column, water/acetonitrile gradient containing 0.1% TFA) to afford compound 45a (8 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH3:23][S:24][CH2:25][CH2:26][O:27][C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]([CH2:37][C:38](O)=[O:39])[C:33](=[O:41])[N:32]=1)=[O:29]>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:38](=[O:39])[CH2:37][N:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([O:27][CH2:26][CH2:25][S:24][CH3:23])=[O:29])=[N:32][C:33]1=[O:41])[CH3:2]
Reactant: CSCCOC(=O)Nc1ccn(CC(=O)O)c(=O)n1
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1ccc(NC(=O)OCCSC)nc1=O
Yield: 84.9 %

Procedure:
The title compound (2.60 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [4-N-(2-methylthioethoxycarbonyl)-cytosin-1-yl]-acetic acid (1.44 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 8.89 (t, 0.6H) 8.75 (t, 0.4H) 8.28 (dd, 1H) 8.19 (dd, 1H) 7.90 (d, 0.6H) 7.84 (d, 0.4H) 7.67 (m, 2H) 6.99 (m, 1H) 4.81 (s, 1.2H) 4.62 (s, 0.8H) 4.35 (s, 0.8H) 4.26 (t, 2H) 4.14 (q, 0.8H) 4.06 (s, 1.2H) 4.04 (q, 1.2H) 3.59 (t, 1.2H) 3.42 (m, 2.0H) 3.21 (q, 0.8H) 2.73 (t, 2H) 2.12 (s, 3H) 1.20 (t, 1.2H) 1.15 (t, 1.8H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:25]([F:28])([F:27])[F:26])=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[C:6](=O)[CH2:7][CH2:8][CH2:9][CH3:10].O.[NH2:31][NH2:32]>C(O)(=O)C>[CH2:7]([C:6]1[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3](=[O:2])[NH:31][N:32]=1)[CH2:8][CH2:9][CH3:10]
Reactant: NN
Reactant: CCCCC(=O)C(=C(C(=O)OC)C(F)(F)F)c1ccc(OC2CCCCC2)cc1
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1n[nH]c(=O)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Yield: 119.3 %

Procedure:
To a stirred solution of 3-(4-cyclohexyloxy-phenyl)-4-oxo-2-trifluoromethyl-oct-2-enoic acid methyl ester (3.40 mmol, 1.4 g) in glacial acetic acid (3 mL) was added hydrazine hydrate (61.7 mmol, 3 mL) and the reaction was heated at 100° C. for 12 h. After cooling, the volatiles were under reduced pressure to give 1.6 g of crude 6-butyl-5-(4-cyclohexyloxy-phenyl)-4-trifluoromethyl-2H-pyridazin-3-one. The ketone was treated with phosphorous oxychloride (21.8 mmol, 2.0 mL) and heated at 90° C. for 1 hour with stirring. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and shaken with water (30 mL). The layers were separated and the organic layer was washed with saturated NaHCO3 (2×30 mL), brine (30 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on a 40 g SiO2 cartridge eluting with ethyl acetate/hexanes gradient to afford 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-5-trifluoromethyl-pyridazine (0.65 g).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:20]([F:23])([F:22])[F:21])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>CS(Cl)(=O)=O.CCOC(C)=O>[CH3:41][S:42]([O:1][CH2:2][C@@H:3]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([OH:24])([C:16]([F:17])([F:18])[F:19])[C:20]([F:21])([F:22])[F:23])=[CH:11][CH:10]=2)[CH2:7][CH2:6][N:5]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:4]1)(=[O:44])=[O:43]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](CO)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)[C@@H](COS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A 150-mL round-bottomed flask was charged with tert-butyl (3R)-3-(hydroxymethyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.393 g, 0.857 mmol), DIPEA (0.450 mL, 2.58 mmol) and EtOAc (5 mL). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.095 mL, 1.2 mmol, Sigma-Aldrich, St. Louis, Mo.) was added dropwise. The mixture was stirred at 0° C. for 1 h. At that time, 4 drops of methanesulfonyl chloride was added and stirring at 0° C. resumed for 10 min. The material was directly purified by column chromatography (25 g of silica, 0 to 50% EtOAc in hexanes) to afford tert-butyl (3R)-3-(((methylsulfonyl)oxy)methyl)-4-(4-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)phenyl)-1-piperazinecarboxylate (0.311 g) as a white foam.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][CH3:21])=[CH:16][CH:15]=1>>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:21])[C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: Clc1ccnc2ccccc12
Reactant: CNc1ccc(OC)cc1
Product: COc1ccc(N(C)c2ccnc3ccccc23)cc1
Temperature: 140 °C
Yield: 74.2 %

Procedure:
A mixture of 4-chloroquinoline (50 mg, 0.31 mmol) and (4-methoxy-phenyl)-methyl amine (300 mg, 2.2 mmol) was heated in a sealed tube at 140° C. overnight. The crude product was purified by chromatography (20-40% ethyl acetate/hexanes) on silica gel to give the title compound (60 mg, 0.23 mmol, 74%). 1H NMR (CDCl3): 8.77 (d, 1H, J=5.1), 8.00-8.04 (m, 1H), 7.61-7.64 (m, 1H), 7.55 (ddd, 1H, J=1.5, 6.9, 8.4), 7.22 (ddd, 1H, J=1.5, 6.9, 8.1), 6.99 (d, 1H, J=4.8), 6.92 (m, 2H), 6.89 (m, 2H), 3.77 (s, 3H), 3.43 (s, 3H).
Reaction SMILES: [OH-].[Na+].C([S:6][C@H:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1)(=O)C.C(O)(=O)C>CO>[SH:6][C@H:7]1[CH:12]2[CH2:13][CH2:14][N:9]([CH2:10][CH2:11]2)[CH2:8]1
Reactant: CC(=O)S[C@@H]1CN2CCC1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: S[C@@H]1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.5 %

Procedure:
10N aqueous sodium hydroxide solution (30 cc) is added slowly to a solution of (3S)-3-(acetylthio)quinuclidine (29 g) in methanol (30 cc) maintained at approximately 25° C. The reaction mixture is stirred for 2 hours at a temperature in the region of 20° C. The pH of the reaction mixture is then brought to a value in the region of 9 by adding acetic acid (approximately 10 cc). The mixture obtained is extracted with methylene chloride (3×100 cc). The combined organic phases are dried over sodium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) and 30° C. The residue obtained is purified by distillation under reduced pressure (970 Pa). (3S)-3-Mercaptoquinuclidine (12 g) is thereby obtained in the form of white crystals which melt at 46° C. and distil at 95° C. under 970 Pa (αD20 =-118°, C=1.1, methanol).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[CH:17][C:18]2[S:22][C:21]([CH2:23]O)=[CH:20][C:19]=2[CH:25]=1>>[F:1][C:2]1[C:7]([O:8][CH2:23][C:21]2[S:22][C:18]3[CH:17]=[CH:16][C:15]([C:14]([F:26])([F:13])[F:27])=[CH:25][C:19]=3[CH:20]=2)=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([NH2:12])=[O:11]
Reactant: NC(=O)c1c(F)ccc(O)c1F
Reactant: OCc1cc2cc(C(F)(F)F)ccc2s1
Product: NC(=O)c1c(F)ccc(OCc2cc3cc(C(F)(F)F)ccc3s2)c1F
Yield: 3 %

Procedure:
Synthesised from 2,6-difluoro-3-hydroxybenzenecarboxamide and [5-(trifluoromethyl)-1-benzothiophen-2-yl]methanol according to Method C, scheme 3. Yield 3%, mp 150-152° C., HPLC-MS (method 1): m/z 386 [M−H]−, Rt=4.39 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:15](Cl)(Cl)=[S:16]>O1CCOCC1.O>[F:8][C:5]1[CH:4]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:2]([N:1]=[C:15]=[S:16])=[CH:7][CH:6]=1
Reactant: Nc1ccc(F)cc1-c1ccccc1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: Fc1ccc(N=C=S)c(-c2ccccc2)c1

Procedure:
Reaction of 2-amino-5-fluorobiphenyl (7.8 g) with thiophosgene (7.2 g) in a mixture of dioxan (15 ml) and water (60 ml) at ambient temperature for 2 hours yielded 5-fluoro-2-biphenylylisothiocyanate as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]3)=[O:16])[CH:10]=2)[C:5]([F:28])=[CH:4][N:3]=1.[OH:29][C:30]1[CH:31]=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>>[CH2:26]([O:25][C:23]([CH:20]1[CH2:21][CH2:22][N:17]([C:15]([C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([F:28])=[CH:4][N:3]=[C:2]([NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[C:30]([OH:29])[CH:31]=4)[N:7]=3)[CH:14]=[CH:13][CH:12]=2)=[O:16])[CH2:18][CH2:19]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Cl)ncc3F)c2)CC1
Reactant: Nc1cccc(O)c1
Product: CCOC(=O)C1CCN(C(=O)c2cccc(Nc3nc(Nc4cccc(O)c4)ncc3F)c2)CC1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-4-pyrimidineamine and 3-hydroxyaniline were reacted to provide N4-[3-[[4-(ethoxycarbonyl)piperidino]carbonyl]phenyl]-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine. 1H NMR (CD3OD): δ 7.93 (d, 1H, J=3.6 Hz), 7.89 (t, 1H, J=1.8 Hz), 7.83 (td, 1H, J=1.2 and 8.4 Hz), 7.41 (t, 1H, J=7.8 Hz), 7.11–6.95 (m, 4H), 6.41 (td, 1H, J=1.8 and 7.2 Hz), 4.44 (bd, 1H, J=12.9 Hz), 4.10 (q, 2H, J=7.2 Hz), 3.73 (bd, 1H, J=12.3 Hz), 3.18–2.98 (m, 2H), 2.67–2.55 (m, 1H), 2.05–1.53 (m, 4H), 1.23 (t, 3H, J=7.2 Hz); 19F NMR (282 MHz, CD3OD): −47483; LCMS: purity: 99%; MS (m/e): 480(MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:7](=[C:13]([C:16]4[O:20][N:19]=[C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[C:17]=4[C:27]([F:30])([F:29])[F:28])[O:14][N:15]=3)[CH2:8][N:9]([CH3:12])[C:10]=2[CH:11]=1.[CH2:31]([Sn](CCCC)(CCCC)C=C)[CH2:32]CC.[Cl-].[Li+]>O1CCOCC1.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>[CH3:12][N:9]1[C:10]2[CH:11]=[C:2]([CH:31]=[CH2:32])[CH:3]=[CH:4][C:5]=2[C:6]2=[N:15][O:14][C:13]([C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:17]=3[C:27]([F:29])([F:28])[F:30])=[C:7]2[CH2:8]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN1Cc2c(noc2-c2onc(-c3ccccc3)c2C(F)(F)F)-c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=Cc1ccc2c(c1)N(C)Cc1c-2noc1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 100 °C
Yield: 56 %

Procedure:
To a heterogeneous solution of 7-bromo-5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-4,5-dihydroisoxazolo[4,3-c]quinoline (Preparation 77E, 0.040 g, 0.084 mmol) in dioxane (5.0 mL) in a sealed tube was added sequentially tributyl(vinyl)stannane (0.027 mL, 0.092 mmol) and lithium chloride (10.7 mg, 0.252 mmol). The reaction mixture was degassed with nitrogen for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (9.71 mg, 8.40 μmol) was added, and the stirred reaction mixture was heated in an oil bath at 100° C. for 4 h overnight. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with dichloromethane (10 mL), filtered through a pad of Celite, and rinsed with dichloromethane (10 mL). The filtrate was concentrated, and the solid residue was purified by flash silica gel chromatography using a 5% mixture of ethyl acetate in hexane to give the crude product mixture. The crude mixture was chromatographed using reverse-phase preparative HPLC (Column: LUNA 5 u C18, 21×100 mm:Solvent MeOH(B)—H2O(A), 0.1% TFA: 0% B-100% B, Gradient Time 12 min, Stop Time 20 min, Flow Rate 20 ml/min, Wavelength 220 nM) to give 5-methyl-3-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-7-vinyl-4,5-dihydroisoxazolo[4,3-c]quinoline [0.020 g, 0.047 mmol, 56%] as a viscous, tan film. The product had an HPLC ret. time=3.85 min. (condition B); LC/MS M+1=424.1.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([NH2:14])=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.I[CH:16]([CH3:18])[CH3:17].C[O-].[Na+]>C1COCC1>[CH:16]([N:12]1[CH:13]=[C:9]([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=2)[C:10]([NH2:14])=[N:11]1)([CH3:18])[CH3:17]
Reactant: CC(C)I
Reactant: CSc1nccc(-c2c[nH]nc2N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1nccc(-c2cn(C(C)C)nc2N)n1
Temperature: 50 °C
Reaction time: 72 h

Procedure:
Intermediate 4-(2-(Methylthio)pyrimidin-4-yl)-1H-pyrazol-3-amine (10.0 g, 40 mmol) was dissolved in THF (200 mL), followed by addition of 2-iodopropane (6.3 mL, 63 mmol) and sodium methoxide (25% weight solution in methanol, 14.3 ml, 63 mmol). The mixture was heated at 50° C. with stirring under a nitrogen atmosphere for 3 d, then was concentrated under vacuum. The residue was taken up in ethyl acetate (200 mL) and washed with aqueous potassium carbonate solution and brine, then dried over sodium sulfate, filtered, and concentrated to provide a brown residue. The residue was chromatographed on silica gel (hexane/ethyl acetate eluant) to provide 1-isopropyl-4-(2-(methylthio)pyrimidin-4-yl)-1H-pyrazol-3-amine as a solid; 1H NMR 400 MHz (CDCl3) δ 8.23 (d, J=5.6 Hz, 1H), 7.60 (s, 1H), 6.83 (d, J=5.6 Hz, 1H), 5.23 (d, J=2.8 Hz, 2H), 4.21-4.25 (m, 1H), 2.50 (s, 3H), 1.37 (d, J=6.8 Hz, 6H); MS m/z: 250.1 (M+1).
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH2:47]([O:49][C:50](=[O:54])[CH2:51][CH2:52][NH2:53])[CH3:48]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21]([NH:53][CH2:52][CH2:51][C:50]([O:49][CH2:47][CH3:48])=[O:54])=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN
Reactant: CCC[C@H](c1ccc(C(=O)O)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(OC)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{(1S)-1-[(4-fluoro-1-naphthyl)(4-methoxyphenyl)methyl]butyl}benzoic acid in THF (5 mL) was added CDI (150 mg, 0.925 mmol) After stirring at room temperature for 30 minutes, β-alanine ethyl ester hydrochloride (150 mg, 0.977 mmol) was added, then the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc then washed with water, then brine. The organic layer was dried over MgSO4, filtered, then concentrated. The residue was purified by preparative reverse phase HPLC eluting with acetonitrile/water+0.1% TFA to afford the two diastereomers of the title compound.
Reaction SMILES: C1(C)C=CC(S([NH:10][C:11]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:12]=2/[CH:13]=[CH:14]/[C:15]([O:17][CH3:18])=[O:16])(=O)=O)=CC=1.Br[CH2:30][C:31]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[CH:35][N:34]=1)=[O:32]>>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:12]2[C:11](=[CH:22][CH:21]=[C:20]([O:23][C:24]([F:25])([F:26])[F:27])[CH:19]=2)[NH:10][C:30]=1[C:31]([C:33]1[CH:38]=[C:37]([CH2:39][CH3:40])[CH:36]=[CH:35][N:34]=1)=[O:32]
Reactant: COC(=O)/C=C/c1cc(OC(F)(F)F)ccc1NS(=O)(=O)c1ccc(C)cc1
Reactant: CCc1ccnc(C(=O)CBr)c1
Product: CCc1ccnc(C(=O)c2[nH]c3ccc(OC(F)(F)F)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-2-p-toluenesulfonylamino-5-(trifluoromethoxy)cinnamate (step 2 of Example 145) and 2-bromoacetyl-4-ethylpyridine (Preparation is described in Example 57).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][CH3:38])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][CH3:38])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid ethyl ester, (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid 1H NMR (400 MHz, CDCl3) δ8.06 (d, J=8.3 Hz, 2H), 7.67 (d, J=8.3 Hz, 2H), 7.63 (d, J=8.3 Hz, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.32 (t, J=7.3 Hz, 1H), 6.72 (s, 3H), 4.21 (t, J=6.4 Hz, 2H), 3.02 (t, J=6.1 Hz, 2H), 2.50 (t, J=7.6 Hz, 2H), 2.41 (s, 3H), 1.52 (s, 6H), 1.31-1.24 (m, 2H), 0.88 (t, J=7.3 Hz, 3H); MS (ES) m/e 500 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:18][N:17]=[C:16]1[CH2:24]O.CS(Cl)(=O)=O.[CH2:32]([NH2:35])[CH:33]=[CH2:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:19]([CH2:20][N:21]([CH3:23])[CH3:22])=[N:18][N:17]=[C:16]1[CH2:24][NH:35][CH2:32][CH:33]=[CH2:34]
Reactant: C=CCN
Reactant: CN(C)Cc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Agent: CS(=O)(=O)Cl
Product: C=CCNCc1nnc(CN(C)C)n1-c1ccccc1C(=O)c1ccccc1Cl

Procedure:
In the manner given in Example 47, 2'-chloro-2-[3-(hydroxymethyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone is treated first with methanesulfonyl chloride followed by allylamine to give 2'-chloro-2-[3-[(allylamino)methyl]-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.[F:12]/[CH:13]=[C:14](\[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)/[CH2:15]O.[Cl-].[Na+]>C1(C)C=CC=CC=1>[Cl:4][CH2:15]/[C:14](=[CH:13]/[F:12])/[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1
Reactant: OC/C(=C/F)CCc1ccc(F)cc1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: F/C=C(/CCl)CCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Combine oxalyl chloride (2.71 g, 21.4 mmol) and toluene (20 mL). Cool to 0° C. Add N,N-dimethylformamide (1.62 g, 22.2 mmol) as a solution in toluene (2 mL). Warm to ambient temperature. After 10 minutes, cool to 0° C. Add (E)-2-(fluoromethylene)-4-(p-fluorophenyl)butan-1-ol (4.0 g, 20.2 mmol). Warm to ambient temperature. After 18 hours, pour the reaction mixture into a saturated sodium chloride solution (100 mL). Extract the aqueous layer 3 times with toluene. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give the title compound. 1H NMR (CDCl3, 300 MHz) δ 2.52 (m, 2H), 2.75 (m, 2H), 3.91 (d, J=6 Hz, 2H), 6.65 (d, J=82.5 Hz, 1H), 6.95 (m, 2H), 7.15 (m, 2H).