Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[N:16]([C:28]4[CH:33]=[CH:32][C:31]([N:34]5[S:38](=[O:40])(=[O:39])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:36](=[O:49])[CH2:35]5)=[CH:30][CH:29]=4)[CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=4[Cl:27])[N:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[NH:50]1[CH2:55][CH2:54][NH:53][CH2:52][C:51]1=[O:56]>>[Cl:27][C:21]1[CH:22]=[C:23]([Cl:26])[CH:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:15]([CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:53]4[CH2:54][CH2:55][NH:50][C:51](=[O:56])[CH2:52]4)=[CH:3][CH:4]=3)=[CH:9][CH:10]=2)[N:16]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][C:36](=[O:49])[N:37]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[S:38]3(=[O:40])=[O:39])=[CH:30][CH:29]=2)[CH:17]=1
Reactant: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(Br)cc4)cc3)cc2)S1(=O)=O
Reactant: O=C1CNCCN1
Product: C[Si](C)(C)CCOCN1C(=O)CN(c2ccc(-n3cc(-c4ccc(Cl)cc4Cl)nc3Cc3ccc(-c4ccc(N5CCNC(=O)C5)cc4)cc3)cc2)S1(=O)=O

Procedure:
5-{4-[2-(4′-Bromo-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-2-(2-trimethylsilanyl-ethoxymethyl)-1,2,5-thiadiazolidine-3-one-1,1-dioxide (240 mg, 0.3 mmol) was treated as described in general procedure R using excess piperazin-2-one (301 mg, 3 mmol) to give 4-[4′-(4-(2,4-dichloro-phenyl)-1-{4-[1,1,4-trioxo-5-(2-trimethylsilanyl-ethoxymethyl)-[1,2,5]thiadiazolidin-2-yl]-phenyl}-1H-imidazol-2-ylmethyl)-biphenyl-4-yl]-piperazin-2-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[N+:24]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO.C(Cl)Cl.[Pt](=O)=O>[NH2:24][C:10]1[CH:11]=[C:12]([O:15][C:16](=[O:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)c1ccccc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(OC(=O)c2ccccc2)ccc1OCc1ccccc1
Yield: 79.3 %

Procedure:
A Parr hydrogenator was charged with platinum (IV) oxide (PtO2) (0.3 g) and a solution of benzoic acid 4-benzyloxy-3-nitro-phenyl ester(5.23 g, 15 mmol) (which was obtained in Example 15) in methanol (80 mL) and CH2Cl2 (40 mL). This mixture was then hydrogenated at 5 psi of hydrogen at 0˜10° C. for 2 hours. The reaction mixture was filtered through a short pad of celite and concentrated. Recrystallization from CH2Cl2/hexanes gave the title compound as a white solid (3.80 g, 79%); 1H NMR (300 MHz, CDCl3) δ 5.09(s, 2 H), 6.57(dd, J=10.1, 2.7 Hz, 1 H), 7.10(d, J=2.7 Hz, 1 H), 7.30–7.50(m, 8 H), 7.55–7.65(m, 1 H), 8.15–8.25(m, 2 H); MS (ES) m/z: 320.0 (MH+, 100%); HRMS Calcd. for C20H18NO3(MH+): 320.1281. Found: 320.1278.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([O:14]CC)=[O:13])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[C:20]([O:25][CH3:26])[CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+].Cl>CN1C(=O)CCC1.O>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:2]2[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)=[C:20]([O:25][CH3:26])[CH:19]=1
Reactant: CCOC(=O)c1nc2ccccc2nc1Cl
Reactant: COc1cc(F)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Temperature: 100 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
A mixture of ethyl 3-chloroquinoxaline-2-carboxylate (300 mg, 1.27 mmol), 4-fluoro-2-methoxy-phenol (289.0 μL, 2.54 mmol) and Cs2CO3 (826.3 mg, 2.54 mmol) in NMP (3.0 mL) was stirred at 100° C. for 3 hours. The reaction mixture was poured into water, the pH was adjusted to pH 6 with 1N HCl and the mixture was extracted with ethyl acetate (3×). The organics were combined, washed with brine, dried with Na2SO4, filtered and evaporated to dryness. Purification by column chromatography using a gradient of 0-10% MeOH in dichloromethane gave 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (360 mg, 90%) as a red oil. ESI-MS m/z calc. 314.07, found 315.1 (M+1)+; Retention time: 1.35 minutes (3 minutes run).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])[C:5]([OH:7])=O.O[NH:16][C:17](=[NH:36])[C:18]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:19]=1[CH:20]=[N:21][N:22]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30].C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:7][N:16]=[C:17]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH:20]=[N:21][N:22]4[CH2:27][C:28]([CH3:34])([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:36]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1Cl
Reactant: CCOC(=O)C(C)(C)Cn1ncc2c(C(=N)NO)cccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Cn1ncc2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
A mixture of 3-chloro-4-[(1-methylethyl)oxy]benzoic acid (D3) (245 mg, 1.143 mmol), ethyl 3-{4-[(hydroxyamino)(imino)methyl]-1H-indazol-1-yl}-2,2-dimethylpropanoate (D103) (348 mg, 1.143 mmol), in DMF (5 ml) at room temperature was treated with N-ethyl-N-(1-methylethyl)-2-propanamine (0.240 ml, 1.372 mmol) followed by HATU (522 mg, 1.372 mmol). The resulting mixture was stirred at room temperature for 1 hour and at 80° C. overnight and then for a further 4 hours, then cooled to room temperature and concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed twice with H2O then brine, dried and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel [gradient ethyl acetate/cyclohexane] gave the title compound (233 mg, 39%) as a cream solid. MS (ES) C25H27ClN4O4 requires 482, found 483 [M+H]+
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:22]([NH:24][CH2:25][CH:26]1[CH2:30][CH2:29][NH:28][CH2:27]1)[CH3:23].C(N(CC)CC)C>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:28]4[CH2:29][CH2:30][CH:26]([CH2:25][NH:24][CH2:22][CH3:23])[CH2:27]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCNCC1CCNC1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCNCC1CCN(c2c(F)c(C)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of 0.80 g (2.70 mmol) of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.41 g (3.20 mmol) of N-ethyl-3-pyrrolidinemethanamine, 0.82 g (8.10 mmol) of triethylamine, and 25 ml of acetonitrile was refluxed for four hours, then stirred at room temperature overnight. The precipitate was filtered, washed with acetonitrile and ether, and dried to give 0.90 g of the title compound, mp 198°-199° C.
Reaction SMILES: [CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-])=[CH:8][C:7]=2[N:6]=[CH:5]1)[CH3:2].ClC(Cl)(Cl)C([N:22]=C=O)=O.CO>ClCCl>[CH2:1]([O:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:22])[C:7]=2[N:6]=[CH:5]1)[CH3:2]
Reactant: CCOn1cnc2c[n+]([O-])c3ccccc3c21
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CCOn1cnc2c(N)nc3ccccc3c21
Temperature: 0 °C
Yield: 22.5 %

Procedure:
A solution of 1-ethoxy-5-oxido-1H-imidazo[4,5-c]quinoline (2.4 g, 10.5 mmol) in dichloromethane (75 mL) was cooled to 0° C., and trichloroacetyl isocyanate (1.9 mL, 16 mmol) was added. The reaction was stirred for ten minutes at 0° C. and then stirred overnight at room temperature. Methanol (15 mL) was added, and the mixture was stirred for 15 minutes and concentrated under reduced pressure. The residue was dissolved in methanol (15 mL), and sodium methoxide (0.5 mL of a 25% w/w solution in methanol) was added. The mixture was stirred at room temperature for three hours and concentrated under reduced pressure. The residue was stirred with methanol (15 mL) and water (15 mL), and a solid formed. The solid was collected by filtration, recrystallized from methanol/water, and purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 2 mL of aqueous ammonium hydroxide per liter of eluent). The resulting solid was recrystallized from methanol/water and dried overnight under vacuum to provide 0.54 g of 1-ethoxy-1H-imidazo[4,5-c]quinolin-4-amine as brown crystals, mp 179-181° C.
Reaction SMILES: Br[C:2]1[C:3]([Cl:19])=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC.O.[F-].[K+]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:19][C:3]1[C:2]([C:25](=[O:27])[CH3:26])=[CH:7][N:6]=[C:5]2[N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH:9]=[N:10][C:4]=12
Reactant: C[Si](C)(C)CCOCn1cnc2c(Cl)c(Br)cnc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)c1cnc2c(ncn2COCC[Si](C)(C)C)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.2 %

Procedure:
6-Bromo-7-chloro-3-{[2-(trimethylsilyl)ethoxy]methyl}-3H-imidazo[4,5-b]pyridine (379 mg, 1.05 mmol) in toluene (6 mL) was stirred with bis(triphenylphosphine)palladium(II) dichloride (106 mg, 0.151 mmol) and tributyl(1-ethoxyvinyl)tin (435 mg, 1.21 mmol) at 120° C. 4 hours. The reaction mixture was allowed to cool to room temperature and stirred with water (20 mL) and potassium fluoride (0.5 g) at room temperature for 1 hour. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was stirred with hydrogen chloride-methanol solution (10 wt %, 4 mL) at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1→3/1 (v/v)) to give the title compound as a yellow solid (89.6 mg, yield 26%).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[Si:14]([CH:2]([OH:1])[C@@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CC[C@H](CO)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g, 135 mmol) in anhydrous DMF (70 mL) was added tert-butyldiphenylsilyl chloride (18.14 g, 66 mmol, 17.2 mL), and the solution was stirred at room temperature under nitrogen atmosphere for 1 h. After removal of the solvent by evaporation, the residue was dissolved in CHCl3, washed with water and brine, dried (Na2SO4), filtered, and concentrated. After crystallization from hexane, the oily residue gave the title compound 4 as a white crystalline solid (20.8 g, 98%). M.P. 76° C.; 1H NMR (CDCl3) δ 7.68-7.65 (m, 4H, arom.), 7.47-7.39 (m, 6H, arom.), 4.63-4.61 (m, 1H, H-5), 3.90-3.87 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.70-3.67 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.69-2.65 (m, 1H, H-3), 2.56-2.52 (m, 1H, H-3), 2.32-2.23 (m, 2H, H-4), 1.06 (s, 9H, t-Bu).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:21]([O-:23])=[O:22])=[CH:4][C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[C:6]([OH:8])[CH:7]=1.[F:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:26][CH2:25][F:24])[C:5]([O:9][CH2:10][C:11]2[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]([F:19])[C:12]=2[F:20])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22]
Reactant: OCCF
Reactant: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1O
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(F)c(F)c1COc1cc([N+](=O)[O-])c(Cl)cc1OCCF
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrophenol (0.35 g), 2-fluoroethanol (71 mg) and triphenylphosphine (0.31 g) in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (40% toluene solution, 0.68 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=9/1−1/1) to give 2-chloro-4-(2-fluoroethoxy)-5-(2,3-difluoro-6-methoxybenzyloxy)-1-nitrobenzene (0.24 g). This material was dissolved in tetrahydrofuran (5 mL). To the solution were added methanol (3 mL) and nickel(II) bromide (7 mg). To the mixture was added sodium borohydride (70 mg) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1−1/1) to give the title compound (0.2 g).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C.O>[C:16]([O:15][C:13]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:10]([O:12][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:11])=[O:14])([CH3:19])([CH3:18])[CH3:17]
Reactant: ClCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 72 h
Yield: 95.8 %

Procedure:
To a stirred solution of Boc-Phe-OH (10 g, 37.7 mmoL) in DMF (50 mL) was added potassium carbonate (7.81 g, 56.5 mmol) followed by benzyl chloride (4.55 mL, 39.6 mmol) and the resulting suspension was stirred at 60° C. for 3 d. The mixture was diluted with water (400 mL) and extracted with ethyl acetate (75 mL, 2×25 mL). The combined organics were washed with brine (200 mL), water (3×100 mL) and brine (50 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated then chromatographed on silica gel eluting with 0%-20% ethyl acetate in hexanes. The product-containing fractions were concentrated in vacuo giving the title compound (12.84 g, 95%) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2C1CCCCO1.COC1C(O[C@@H]2CCC[C@H](NC(=O)CC)C2)=CC=C2C=1C=NN2.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][C:2]1[C:10]([O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][C@H:14]([N:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:13]2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2
Reactant: Cc1c(O[C@@H]2CCC[C@H](N(c3ccccc3)c3ccccc3)C2)ccc2c1cnn2C1CCCCO1
Agent: CCC(=O)N[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2OC)C1
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Product: Cc1c(O[C@@H]2CCC[C@H](N(c3ccccc3)c3ccccc3)C2)ccc2[nH]ncc12
Yield: 76.1 %

Procedure:
Under nitrogen, the N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine (82 mg, 0.172 mmol) obtained in Example 731, (a) was dissolved in isopropyl alcohol (4 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml), and the resulting mixture was stirred at room temperature for 20 hours. The solvent was distilled off under reduced pressure and a saturated aqueous sodium hydrogencarbonate solution was added to the residue, followed by extraction with ethyl acetate. The ethyl acetate layer was washed with water and then a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N,N-diphenylamine (52 mg, yield 76.8%) as a whitely yellow amorphous substance.
Reaction SMILES: FC1C=CC(C2N=C(C(=O)C)SN=2)=CC=1.[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH2:23])=[O:22])=[CH:19][CH:18]=1.Cl[C:27]([S:29]Cl)=[O:28]>>[F:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]2[O:22][C:27](=[O:28])[S:29][N:23]=2)=[CH:19][CH:18]=1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)c1ccc(F)cc1
Agent: CC(=O)c1nc(-c2ccc(F)cc2)ns1
Product: O=c1oc(-c2ccc(F)cc2)ns1

Procedure:
In still a further embodiment, 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be prepared according to the methodology and reagents of Scheme 16A. In this embodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated and subsequently converted to a 1,2,4-thiadiazole ring fragment during the preparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. Specifically, 4-fluorobenzamide is reacted with chlorocarbonylsulfenyl chloride to provide 5-(4-fluoro-phenyl)-1,3,4-oxathiazol-2-one. In one embodiment, the reaction is performed in toluene. In another embodiment, the reaction is performed at elevated temperatures of about 80° C. for about 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reacted with acetyl cyanide to provide 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)-ethanone. In one embodiment, this reaction is performed in 1,2-dichlorobenzene. In another embodiment, this reaction is performed at elevated temperatures of about 160° C. for about 20 hours. 1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:4][CH:3]=1.CN(C)[C:31](=[O:33])[CH3:32]>C(OCC)(=O)C.CCCCCC>[C:31]([C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:26])[CH2:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]2([CH3:28])[CH3:27])=[CH:6][CH:7]=1)(=[O:33])[CH3:32]
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2c1ccc(Br)cc1
Reactant: CC(=O)N(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(C2c3cc(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Yield: 20 %

Procedure:
Using N-(3-(4-bromophenyl)-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 284 and N,N-dimethylacetamide, the title compound was synthesized in the same manner as in Example 292. Yield: 20%. Melting point: 195-196° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]([C:3]1[CH2:4][C@H:5]2[C@@H:12]([CH:13]=1)[C:7]1(OCC[O:8]1)[CH2:6]2)=[CH2:2].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(#N)C.O>[CH:1]([C:3]1[CH2:4][C@H:5]2[C@@H:12]([CH:13]=1)[C:7](=[O:8])[CH2:6]2)=[CH2:2]
Reactant: C=CC1=C[C@@H]2[C@H](C1)CC21OCCO1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: C=CC1=C[C@H]2C(=O)C[C@H]2C1
Temperature: 25 °C

Procedure:
(±)-(1R,5S)-3-vinylspiro[bicyclo[3.2.0]hept-3-ene-6,2′-[1,3]dioxolane] (990 mg, 5.55 mmol) was dissolved in a mixed solvent of acetonitrile (16 mL) and water (7 mL). To the solution, 2 M sulfuric acid (2.60 mL) was added with stirring at room temperature. The mixture was stirred at room temperature for 7 hours, and the reaction solution was then neutralized by the addition of a saturated aqueous solution of sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The residue was filtered and concentrated under reduced pressure. Then, the compound of interest was obtained as an oil substance (710 mg, 55%, Major/Minor=2/1) in the same way as in Example (11-e) from the obtained (1R,5S)-3-vinylbicyclo[3.2.0]hept-3-en-6-one.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C(OC)=CC(CP(=O)(O)OCC)=C([Cl:97])C=3)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CC3(CO)COC3)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[C:25]([O:57][CH3:58])=[CH:26][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[C:55]([Cl:97])[CH:56]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Agent: CC1(C)OB(c2cnn(CC3(CO)COC3)c2)OC1(C)C
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-5-methoxybenzyl)phosphonate (Compound 56B, 200 mg, 0.306 mmol) and (3-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}oxetan-3-yl)methanol (Compound 44B, 94.5 mg, 0.321 mmol) to afford 175 mg of the title compound as a racemic mixture (61%). MS (ESI): m/z=931.68/933.72 [M+H]+. UPLC: tR=1.72 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]([OH:13])=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:14]([O:16][CH:17](OCC)OCC)[CH3:15].C(OC(=O)C)(=O)C>CN(C1C=CN=CC=1)C>[CH2:14]([O:16]/[CH:17]=[C:10]1\[N:9]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:13][C:11]\1=[O:12])[CH3:15]
Reactant: CCOC(OCC)OCC
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CCO/C=C1\N=C(c2ccccc2)OC1=O
Temperature: 140 °C
Yield: 46.7 %

Procedure:
To a mixture of 2-benzamidoacetic acid (2.5 g, 13.8 mmol), DMAP (0.017 g, 0.138 mmol) and triethoxymethane (2.3 ml, 13.8 mmol), was added acetic anhydride (2.6 ml, 27.6 mmol). The mixture was heated to 140° C. for 30 min. The solvent was removed in vacuo and purification by silica gel chromatography (0-30% ethyl acetate in hexanes) gave 1.4 g (47%) of (Z)-4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one as an orange solid. 1H NMR (400 MHz, CDCl3) 8.09-8.04 (m, 2H), 7.56-7.51 (m, 1H), 7.50-7.43 (m, 2H), 7.35 (s, 1H), 4.43 (q, 2H), 1.49 (t, 3H).