Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[CH2:17][OH:18])[CH2:5][CH2:4][CH2:3][CH2:2]1>ClCCl.[O-2].[O-2].[Mn+4]>[CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([S:15][CH3:16])[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[CH:17]=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2cc(CO)n(C3CCCC3)c2n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CSc1ncc2cc(C=O)n(C3CCCC3)c2n1
Reaction time: 16 h
Yield: 92.7 %

Procedure:
Manganese dioxide (5.56 g, 64.0 mmol) was added to a solution of compound 228 (3.37 g, 12.8 mmol) in dichloromethane (250 mL). After 16 h, the reaction contents were filtered through Celite and organics were removed in vacuo to provide compound 229 (3.10 g, 92.7% yield).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[O:13]=[S:14]1(=[O:31])[CH2:19][CH2:18][N:17]2[CH:20]=[CH:21][CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)[C:16]2=[N:15]1.[OH-].[Na+]>CS(C)=O>[CH:8]1([O:30][C:27]2[CH:26]=[CH:25][C:24]([C:23]3[C:16]4=[N:15][S:14](=[O:31])(=[O:13])[CH2:19][CH2:18][N:17]4[CH:20]=[CH:21][CH:22]=3)=[CH:29][CH:28]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=S1(=O)CCN2C=CC=C(c3ccc(O)cc3)C2=N1
Reactant: IC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(OC4CCCC4)cc3)C2=N1
Temperature: 130 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
A mixture of potassium carbonate (450 mg), iodocyclopentane (639 mg) and 4-(2,2-dioxido-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazin-9-yl)phenol (300 mg) in DMSO (3 mL) was stirred at 130° C. overnight. Then iodocyclopentane (639 mg) was added and the mixture was stirred at 150° C. for 5 hr. The mixture was poured into 1N NaOH aq. and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give crude product (81.1 mg). The crude product was purified by preparative HPLC (C18, eluted with H2O in acetonitrile containing 0.1% TFA). The desired fraction was neutralized with sat. NaHCO3 aq. and extracted with EtOAc. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (52.3 mg) as a white solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][N:55]([CH2:62][CH2:63]O)[C:56]([C:58]([CH3:61])([CH3:60])[CH3:59])=[O:57]>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:63][CH2:62][N:55]([CH3:54])[C:56]([C:58]([CH3:61])([CH3:60])[CH3:59])=[O:57])[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: CN(CCO)C(=O)C(C)(C)C
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN(C)C(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Diethyl azodicarboxylate (679 mg, 3.9 mmol) was added dropwise to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (918 mg, 3 mmol), triphenylphosphine (1 g, 3.9 mmol) and 2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (682 mg, 3.9 mmol), prepared as described below, in methylene chloride (20 ml) and the mixture stirred for 1 hour at ambient temperature. Further 2-(N-methyl-N-(t-butylcarbonyl)amino)ethanol (105 mg, 0.6 mmol), triphenylphosphine (786 mg, 3 mmol) and diethyl azodicarboxylate (522 mg, 3 mmol) were added and the mixture stirred for 30 minutes at ambient temperature. The mixture was concentrated to half volume by evaporation and purified by column chromatography eluting with methylene chloride/ether (7/3 increasing to 1/1) to give 6-methoxy-7-(2-(N-methyl-N-(t-butylcarbonyl)amino)ethoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (1.3 g, 98%).
Reaction SMILES: Br[CH:2]([CH2:18][CH2:19][CH3:20])[CH2:3][N:4]([N:13]1[CH:17]=[N:16][N:15]=[CH:14]1)[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[OH:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][CH2:20][CH2:19][CH2:18][CH2:2][CH2:3][N:4]([N:13]2[CH:17]=[N:16][N:15]=[CH:14]2)[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)=[CH:24][CH:23]=1
Reactant: CCCC(Br)CN(c1ccc(C#N)cc1)n1cnnc1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(N(CCCCCSc2ccc(O)cc2)n2cnnc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 4-[(2-Bromo-pentyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB03005, 500 mg, 1.5 mmol), 4-hydroxy-thiophenol (378 mg, 3.0 mmol) and potassium carbonate (414 mg, 3.0 mmol) in DMF (10 mL) was stirred for 12 hours at room temperature. The mixture was transferred into a separation funnel and ethyl acetate (50 mL) and water (50 mL) were added. The organic layer was separated, washed with brine (30 mL), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography (eluent: ethyl acetate, Rf: 0.43). The resulting yellow oil was dissolved in ethyl acetate and precipitated by addition of hexane to give an light yellow powder. Yield: 338 mg (59%). 1H-NMR (400 MHz, d6-DMSO) δ=1.40-1.54 (m, 6H), 2.77 (t, J=6.8 Hz, 2H), 3.79 (t, J=6.6 Hz, 2H), 6.61 (d, J=9.0 Hz, 2H), 6.72 (d, J=9.0 Hz, 2H), 7.20 (d, J=9.0 Hz, 2H), 7.72 (d, J=9.0 Hz, 2H), 8.96 (s, 2H), 9.55 (s, 1H. —OH). 13C-NMR (100 MHz, d6-DMSO) δ=25.66, 26.67, 29.35, 35.56, 53.86, 103.06, 113.89, 116.80, 119.84, 124.54, 133.39, 134.47, 144.09, 151.89, 157.26. LRMS (FAB+): 380.0 (100, [M+H]+). HRMS (FAB+) 380.15355 C20H22N5OS requires 380.154507.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:14])([F:13])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][OH:12])=[CH:7][CH:6]=1.Cl[C:16]1[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=1>C1COCC1>[F:3][C:4]([F:13])([F:14])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][O:12][C:16]2[CH:21]=[CH:20][N+:19]([O-:22])=[CH:18][CH:17]=2)=[CH:9][CH:10]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 28.9 %

Procedure:
To an ice-cold solution of NaH (40% oil dispersion, 231 mg) in THF (10 ml) was added (4-(trifluoromethyl)phenyl)methanol (815 mg) at 0° C. The reaction mixture was stirred at the same temperature for 10 min followed by the addition of 4-chloropyridine 1-oxide (500 mg) at 0° C. The resulting reaction mixture was stirred for 1 h at 0° C. and then warmed to room temperature. After 2 h, the reaction mixture was poured into ice-water and extracted with DCM twice. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (300 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1[C:12]([OH:14])=O)=[O:6])[CH:2]=[CH2:3].[CH:15]1(N=C=NC2CCCCC2)CCCCC1.CC1(C)OC(=O)CC(=O)O1.C(OCC)(=O)C>ClCCl.CN(C)C1C=CN=CC=1>[C:12]([C@@H:8]1[CH2:9][CH2:10][CH2:11][N:7]1[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])(=[O:14])[CH3:15]
Reactant: C=CCOC(=O)N1CCC[C@H]1C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1CCC[C@H]1C(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 43.8 %

Procedure:
To a solution of (2S)-1-allyloxycarbonyl-2-carboxypyrrolidine (10 g) in dichloromethane (100 ml) were added dicyclohexylcarbodiimide (9.8 g), Meldrum's acid (6.8 g) and 4-dimethylaminopyridine (5.8 g) at 0° C. After stirring for 24 hours at ambient temperature, the resulting precipitate was removed by filtration. The filtrate was washed with 1N hydrochloric acid solution, evaporated in vacuo. The residue was dissolved in a mixture of acetic acid (80 ml) and water (60 ml), and refluxed for 1 hour. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The solution was washed in turn with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (2:1, V/V) to give (2S)-2-acetyl-1-allyloxycarbonylpyrrolidine (4.1 g).
Reaction SMILES: OS(O)(=O)=O.O[CH2:7][CH:8]([NH:10][CH:11]([CH3:21])[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[OH:13])[CH3:9].[OH-].[Na+].[ClH:24]>ClCCl.C(OCC)C>[ClH:24].[F:20][C:16]1[CH:15]=[C:14]([CH:12]2[O:13][CH2:7][CH:8]([CH3:9])[NH:10][CH:11]2[CH3:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(CO)NC(C)C(O)c1cccc(F)c1
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC1COC(c2cccc(F)c2)C(C)N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To concentrated H2SO4 (75 ml) was added a solution of (1R*, 2S*)-2-[[(1RS)-2-hydroxy-1-methylethyl]amino]-1-(3-fluorophenyl)propanol (21.6 g, 0.095 mole) in dichloromethane (100 ml) at 0° C. The resulting mixture was stirred for 16 hours at room temperature and diluted with ice water. The aqueous phase was basified with 40% aqueous sodium hydroxide and extracted with diethyl ether. The diethyl ether layers were combined, washed with brine, dried (sodium sulfate), and concentrated under reduced pressure to yield the crude reaction product as the free base. The crude product was dissolved in diethyl ether and treated with ethereal hydrogen chloride. Recrystallization from ethanol-diethyl ether mixtures gave 17.7 g of (+-)-(2R*, 3R*, 5S*)-2-(3-fluorophenyl)-3,5-dimethylmorpholine hydrochloride as a white solid, m.p. 268°-269° C.
Reaction SMILES: [CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH2:17])[CH:9]=2)([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>ClCCl>[CH:1]([N:4]1[C:16]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH:17][C:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[CH:9]=2)([CH3:3])[CH3:2]
Reactant: CC(C)n1c2c(c3cc(N)ccc31)CCCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)n1c2c(c3cc(NC(=O)Oc4ccccc4)ccc31)CCCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.1 %

Procedure:
The N-isopropyl-6-amino-1,2,3,4-tetrahydrocarbazole (9.84 g) and 5.05 g of triethylamine were dissolved in 100 mL of dichloromethane, and added dropwise with 7.85 g of phenyl chloroformate. The reaction mixture was stirred at room temperature for 3 hours, then washed with 10% aqueous citric acid and then with saturated aqueous sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by silica gel chromatography (eluent: hexane/ethyl acetate=8/2) and recrystallized from a mixture of hexane and ethyl acetate, to obtain 2.27 g of N-isopropyl-6-phenoxycarbonylamino-1,2,3,4-tetrahydrocarbazole.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[C:4]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:3]1=2.[C:17](O)(=[O:19])[CH3:18].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:17]([O:1][CH:2]1[CH2:7][CH2:6][S:5](=[O:9])(=[O:8])[C:4]2[S:10][C:11]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:12][C:3]1=2)(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: NS(=O)(=O)c1cc2c(s1)S(=O)(=O)CCC2O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)OC1CCS(=O)(=O)c2sc(S(N)(=O)=O)cc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 111.9 %

Procedure:
5,6-Dihydro-4-hydroxy-4H-thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide (2.00 g, 0.0071 m), glacial acetic acid (0.92 g, 0.015 m) and 4-dimethylaminopyridine (0.085 g, 0.0007 m) were dissolved in dry tetrahydrofuran (30 ml) and the solution was cooled to 0° C. under nitrogen and stirred while a solution of dicyclohexylcarbodiimide (1.61 g, 0.0078 m) in dry tetrahydrofuran (10 ml) was added over 10 minutes. After stirring at 0° C. for 1 hour and at ambient temperature for 2 hours, an additional 0.46 g (0.0077 m) of glacial acetic acid was added and stirring was continued at ambient temperature for one hour more. The mixture was filtered and the solid was washed with tetrahydrofuran. The combined filtrate and washings were evaporated in vacuo to give a quantitative yield (2.31 g) of crude product. This material was combined with 1.14 g of identical product from a previous run and chromatographed on silica gel, eluting with 10% methanol-chloroform, to yield 2.57 g (75%) of product. Recrystallization from nitromethane afforded an analytical sample melting at 187.5°-188.5° C.
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][CH3:15])=[N:10][N:9]([C:16]3[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=3[Cl:25])[C:8]2=[O:26])=[C:4]([F:29])[CH:3]=1.[C:30]([NH:34][S:35]([C:38]1[CH:43]=[CH:42][C:41]([CH2:44][CH2:45][CH3:46])=[CH:40][C:39]=1B(O)O)(=[O:37])=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[CH2:12]([C:11]1[N:7]([CH2:6][C:5]2[CH:27]=[CH:28][C:2]([C:39]3[CH:40]=[C:41]([CH2:44][CH2:45][CH3:46])[CH:42]=[CH:43][C:38]=3[S:35](=[O:37])(=[O:36])[NH:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:3][C:4]=2[F:29])[C:8](=[O:26])[N:9]([C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=2[Cl:25])[N:10]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCc1ccc(S(=O)(=O)NC(C)(C)C)c(B(O)O)c1
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(Br)cc1F
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 43 %

Procedure:
Using the method of Example 28, Step F, 4-(4-bromo-2-fluorobenzyl)-5-n-butyl-2-(2-chloro-5-nitrophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 36, Step A) was coupled with 2-(N-t-butylsulfamoyl)-5-n-propylphenylboronic acid (from Example 20, Step B). Flash chromatography of the crude product on silica gel (gradient elution with 6:1 to 2:1 hexane-EtOAc) gave a 43% yield of the title compound as a cream-colored solid, mp 84°-86° C.; homogeneous by TLC (4:1 hexane-EtOAc).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][NH2:19])=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:6][CH:7]=1.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=O.Cl>CCOCC.CCO>[F:1][C:2]1[C:3]([NH:18]/[N:19]=[CH:25]/[C:21]2[S:20][CH:24]=[CH:23][CH:22]=2)=[N:4][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1cccc(COc2ncc(F)c(NN)n2)c1
Reactant: O=Cc1cccs1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1cccc(COc2ncc(F)c(N/N=C/c3cccs3)n2)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 76.7 %

Procedure:
A 20 mL vial was charged with 5-fluoro-4-hydrazinyl-2-(3-methoxybenzyloxy)-pyrimidine (74.7 mg, 0.283 mmol), EtOH (2 mL), thiophene-2-carbaldehyde (26 μL, 0.284 mmol) and 1 M HCl in Et2O (14 μL, 0.014 mmol) and heated at 50° C. on shaker. After 90 minutes, the reaction was cooled to room temperature concentrated on high vacuum to provide the title compound (77.8 mg, 77%) as a yellow solid: mp 136-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 11.46 (bs, 1H), 8.50 (bs, 1H), 8.16 (d, J=3.6 Hz, 1H), 7.64 (d, J=5.0 Hz, 1H), 7.41 (d, J=3.4 Hz, 1H), 7.28 (t, J=8.0 Hz, 1H), 7.12 (dd, J=3.8, 4.8 Hz, 1H), 7.04 (m, 2H), 6.88 (dd, J=2.4, 8.3 Hz, 1H), 5.27 (s, 2H), 3.73 (s, 3H); MS (ESI) m/z 359.2 (M+H)+, 357.2 (M−H)−.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:28]1([CH3:36])[CH:33]=[CH:32][C:31]([CH:34]=[O:35])=[CH:30][CH:29]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:34]([OH:35])[C:31]3[CH:32]=[CH:33][C:28]([CH3:36])=[CH:29][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccc(C)cc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 75 g. (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of p-tolualdehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete the mixture is stirred for 11/2 hrs. at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The solid residue is triturated with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(4-methyl-β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 148° to 150° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=2)[N:24]=[CH:23][CH:22]=1.Cl>CS(C)=O.O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][C:6]=2[CH:13]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(O)c1cc2cc(O)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4oc(C(=O)O)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-hydroxybenzofuran-2-carboxylic acid (Step a, 2.00 g, 11.23 mmol) in DMSO (23 mL) at RT was added cesium carbonate (11.0 g, 33.7 mmol). The reaction was stirred for 10 min followed by the addition of 4-chloro-6,7-dimethoxyquinoline (prepared by the method described in WO 03/33472) (1.75 g, 7.86 mmol). The reaction was stirred at 100° C. for 16 h. After cooling to RT, water was added. The aqueous layer was acidified with a 6M aqueous hydrochloric acid solution until pH=5, filtered and the solid was suspended in EtOAc. The organic phase was extracted with a 3M sodium hydroxide aqueous solution. After acidification of the aqueous layer, the title compound was isolated by filtration and dried under high vacuum.
Reaction SMILES: BrC1C=CC(OC2C=CC=CC=2)=C(C)C=1.[O:16]([C:23]1[CH:30]=[CH:29][C:28]([B:31]2[O:35][C:34]([CH3:37])([CH3:36])[C:33]([CH3:39])([CH3:38])[O:32]2)=[CH:27][C:24]=1[C:25]#N)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCCC.C(OCC)(=O)C>[C:17]1([O:16][C:23]2[CH:30]=[CH:29][C:28]([B:31]3[O:35][C:34]([CH3:36])([CH3:37])[C:33]([CH3:39])([CH3:38])[O:32]3)=[CH:27][C:24]=2[CH3:25])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(Oc3ccccc3)c(C#N)c2)OC1(C)C
Agent: Cc1cc(Br)ccc1Oc1ccccc1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(B2OC(C)(C)C(C)(C)O2)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in a 77% from 4-bromo-2-methyl-1-phenoxybenzene in a similar manner to that described for the preparation 2-phenoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)benzonitrile: 1H NMR (DMSO-d6, 400 MHz) δ 7.67(s, 1H), 7.50(d, 1H), 7.38(t, 2H), 7.14(t, 1H), 6.94(d, 2H), 6.80(d, 1H), 2.21(t, 3H); TLC (heptane/ethyl acetate 9:1) Rf0.6.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[C:16](=[O:19])[NH:17][N:18]=[C:10]3[C:9]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:36])[F:35])=[N:32][CH:33]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:15])[N:11]3[C:16](=[O:19])[N:17]([CH2:27][C:28]4[CH:33]=[N:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=4)[N:18]=[C:10]3[C:9]=2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(CCl)cn1
Reactant: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2n[nH]c(=O)n12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nc(-c2ccc(Cl)cc2)c(-c2ccccc2)c2nn(Cc3ccc(C(F)(F)F)nc3)c(=O)n12
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.4 %

Procedure:
To a stirred solution of 7-(4-chlorophenyl)-5-(methylthio)-8-phenyl-[1,2,4]triazolo[4,3-c]pyrimidin-3(2H)-one (100 mg, 0.27 mmol) in DMF (2 mL) at room temperature under argon was added 5-(chloromethyl)-2-(trifluoromethyl)pyridine (64.4 mg, 0.33 mmol), followed by K2CO3 (74.5 mg, 0.54 mmol). The resulting mixture was stirred at room temperature for 5 h. The crude product was purified by silica gel column chromatography eluted with ethyl acetate—hexanes, then lyophilized from 1,4-dioxane, to obtain the title compound (107.5 mg) as an off-white lyophilate. HPLC/MS: retention time=4.24 min, [M+H]30 =528.
Reaction SMILES: [Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[N:11]([O-])=O.[Na+].NC(N)=O>Cl.O>[Cl:1][C:2]1[C:8]([OH:9])=[CH:7][C:5]([NH:6][NH2:11])=[C:4]([F:10])[CH:3]=1
Reactant: O=N[O-]
Reactant: Nc1cc(O)c(Cl)cc1F
Agent: Cl
Agent: NC(N)=O
Agent: [Na+]
Solvent: O
Product: NNc1cc(O)c(Cl)cc1F
Reaction time: 1 h
Yield: 9.1 %

Procedure:
4-Chloro-2-fluoro-5-hydroxyaniline (10 g) was dissolved in conc. hydrochloric acid (130 ml) under heating, and the resultant mixture was cooled to 0° C. To the resulting mixture, there was dropwise added a solution of sodium nitrite (4.5 g) in water (20 ml). After completion of the addition, the mixture was further stirred at 5° to -5° C. for 1 hour, and urea was added thereto, whereby excessive sodium nitrite ion was decomposed. The resulting mixture was cooled to -30° to -25° C., and a solution of anhydrous stannous chloride (20.5 g) in conc. hydrochloric acid (40 ml) was added thereto, followed by stirring at -10° to 0° C. for 3 hours. The precipitated crystals were collected by filtration, washed with a small amount of water and dissolved in a 10% aqueous sodium hydroxide solution. The resultant solution was adjusted to pH 7 and extracted with ethyl acetate. The extract was dried and concentrated. The crystallized residue was washed with ether to obtain 1 g of 4-chloro-2-fluoro-5-hydroxyphenylhydrazine. m.p. 149°-150° C. (decomp.).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][O:6][C:5]2([CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)[O:4][CH2:3]1.[H-].[Na+].Cl[C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=1>CN(C=O)C>[CH3:1][C:2]1([CH3:14])[CH2:3][O:4][C:5]2([CH2:8][CH2:9][CH:10]([O:13][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][N:19]=3)[CH2:11][CH2:12]2)[O:6][CH2:7]1
Reactant: CC1(C)COC2(CCC(O)CC2)OC1
Reactant: N#Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)COC2(CCC(Oc3ccc(C#N)cn3)CC2)OC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Add dropwise a solution of 3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol, (1445 mg, 7.22 mmol) in DMF (2.1 mL) to a suspension of sodium hydride (433 mg, 10.82 mmol) in DMF (8.6 mL). Let the reaction mixture stir at room temperature for 1 h, then heat while stirring at 50° C. for 20 min. Add dropwise a solution of 6-chloro-nicotinonitrile (1200 mg, 8.66 mmol) in DMF (4.5 mL). Continue the heating at 60° C. and stirring overnight. Concentrate the reaction mixture to remove DMF. Wash the residue with water (15 mL) and extract with EtOAc/hexanes (20 mL). Dry the organic layer over sodium sulfate, filter and concentrate. Purify the residue by flash chromatography (eluent CH2Cl2/hexanes 2/1) to give 2000 mg (92% yield) of the title compound.