Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([O:34]C)([O:29][Si](C)(C)C)[C:25]([F:28])([F:27])[F:26])[N:9]=2)=[CH:4][CH:3]=1.[F-].[Cs+]>CO.CC(OC)(C)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[C:12]3[C:19]([CH3:22])=[N:20][O:21][C:11]=3[C@H:10]([CH2:23][C:24]([OH:29])([OH:34])[C:25]([F:28])([F:27])[F:26])[N:9]=2)=[CH:4][CH:3]=1
Reactant: COC(C[C@@H]1N=C(c2ccc(Cl)cc2)c2ccccc2-c2c(C)noc21)(O[Si](C)(C)C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: COC(C)(C)C
Solvent: CO
Product: Cc1noc2c1-c1ccccc1C(c1ccc(Cl)cc1)=N[C@H]2CC(O)(O)C(F)(F)F

Procedure:
To a cooled (0° C.) solution of crude (4S)-6-(4-chlorophenyl)-1-methyl-4-(3,3,3-trifluoro-2-methoxy-2-((trimethylsilyl)oxy)propyl)-4H-benzo[c]isoxazolo[4,5-e]azepine in MeOH (3 mL) was added CsF (0.048 g, 0.316 mmol). The reaction was maintained at 0° C. for 30-60 min or until complete conversion of starting material to the desired ketone/di-hydrate was observed. The reaction mixture was diluted with MTBE and aqueous 1 N HCl was added until a phase cut was observed. The aqueous phase was extracted with MTBE (3×), the combined organic phases were washed with water, dried over Na2SO4, and concentrated to give the desired product as an orange oil. The product 3-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-4-yl)-1,1,1-trifluoropropane-2,2-diol (0.121 g, 0.277 mmol, 96% yield) was used without further purification. LC/MS m/z 437 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11]C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][OH:25])[CH2:19]1.CC(C)([O-])C.[K+].C(O)(C)(C)C>C1(C)C=CC=CC=1>[NH:18]1[CH2:23][CH2:22][CH2:21][CH:20]([CH2:24][O:25][C:2]2[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:19]1
Reactant: Clc1ncccc1OCCOC1CCCCO1
Reactant: OCC1CCCNC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: OCCOc1cccnc1OCC1CCCNC1
Temperature: 50 °C
Reaction time: 48 h
Yield: 53.8 %

Procedure:
A solution of 2-chloro-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]pyridine (from Example 4; 100 mg, 0.39 mmol), 3-piperidinemethanol (65 μl, 0.58 mmol) and 1.0 M potassium tert-butoxide in tert-butanol (0.8 mL, 0.80 mmol) in 4 mL of toluene was heated at 100° C. for 1 day. The organic phase was washed with 3×2 mL of water and 2 mL of brine. The organic phase was shaken at 50° C. with 4 mL of 2.0 M acetic acid for 2 days. The aqueous phase was washed with 3×3 mL of ethyl acetate, made basic by addition of potassium hydroxide, saturated with sodium chloride and extracted with 3×2 mL of ethyl acetate. The organic phase was dried (MgSO4) and concentrated under reduced pressure to give 52 mg (0.21 mmol, 53%) of the title compound as a colorless oil. LC-UV purity 95%. MS m/z 253 (M+1)+, calc. 253 (M+1)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[C:21](OC(=O)C)(=[O:23])[CH3:22]>>[C:21]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH2:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: C=Cc1ccc(-c2ccc(O)cc2)cc1
Agent: O=S(=O)(O)O
Product: C=Cc1ccc(-c2ccc(OC(C)=O)cc2)cc1

Procedure:
10 g of 4-hydroxy-4'-vinylbiphenyl (5) obtained in Example 7 was heated to 100° C. together with a small amount of concentrated sulfuric acid in 20 ml of acetic anhydride to obtain 4-acetoxy-4'-vinylbiphenyl (3) nearly quantitatively. ##STR60##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[N:12][N:11]3[CH:23]=2)=[CH:4][CH:3]=1.[I:24]Cl.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([N:16]4[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]4)=[N:12][N:11]3[C:23]=2[I:24])=[CH:4][CH:3]=1
Reactant: ClI
Reactant: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)cn3n2)CC1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(I)n3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.8 %

Procedure:
To a solution, cooled to about 5° C., of 31.0 g (99.6 mmol) of 2-(4-fluorophenyl)-6-(4-methylpiperazin-1-yl)imidazo[1,2-b]pyridazine in chloroform is rapidly added dropwise a solution of 64.7 g (398 mmol) of iodine monochloride in 150 mL of methanol. Mild exothermicity and the formation of a precipitate during the addition are observed. After cooling to room temperature and stirring for 30 minutes, the mixture is poured into 2 L of aqueous 5% sodium thiosulfate solution saturated with sodium bicarbonate. After vigorous stirring until the mixture has decolorized, the product is extracted with chloroform. The organic phase is separated out, dried over sodium sulfate, filtered and concentrated under reduced pressure to give a brown solid. This solid is triturated in a mixture of 400 mL of diisopropyl ether and 50 mL of isopropanol at reflux. After cooling, 40 g of a beige-colored powder are isolated by filtration through a sinter funnel and drying under vacuum.
Reaction SMILES: [CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28]Cl)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1.[I-].[Na+].[Na].[NH:38]1[CH:42]=[N:41][CH:40]=[N:39]1>CC#N.CN(C=O)C>[CH:1]1([CH:4]([O:6][C:7](=[O:34])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]([CH:30]4[CH2:33][CH2:32][CH2:31]4)[C:17]4[C:22]([C:23]=3[C:24]#[N:25])=[CH:21][CH:20]=[C:19]([O:26][CH2:27][CH2:28][N:38]3[CH:42]=[N:41][CH:40]=[N:39]3)[CH:18]=4)=[CH:11][CH:10]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: c1nc[nH]n1
Reactant: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCCl)cc3n2C2CCC2)cc1)C1CC1
Agent: [I-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCCn4cncn4)cc3n2C2CCC2)cc1)C1CC1

Procedure:
To a solution of {4-[6-(2-chloroethoxy)-3-cyano-1-cyclobutyl-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester (1.46 g, 3.05 mmol) in CH3CN (10 mL) is added sodium iodide (1.84 g, 12.22 mmol). The resulting mixture is stirred at reflux temperature overnight. The solvent is evaporated and the residue is diluted with anhydrous DMF (20 mL) and then used without further purification. To 1 mL of the DMF solution containing the iodoethyl intermediate (0.153 mmol) is added the sodium salt of 1,2,4-triazole (0.31 mmol) and the reaction is stirred at room temperature overnight. The reaction mixture is diluted with 0.5 mL DMF and the desired product is purified by preparative LC to give {4-[3-cyano-1-cyclobutyl-6-(2-[1,2,4]triazol-1-yl-ethoxy)-1H-indol-2-yl]-phenyl}-carbamic acid 1-cyclopropyl-ethyl ester, compound 1329 (23 mg, 29%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH2:12]Br)[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH:6]([CH2:12][N:15]=[N+:16]=[N-:17])[CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CC(CBr)C1CCCC1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)CC(CN=[N+]=[N-])C1CCCC1
Temperature: 60 °C
Yield: 74.8 %

Procedure:
Preparation of 3-Azidomethyl-3-cyclopentyl-propionic acid ethyl ester—A solution of 3-bromomethyl-3-cyclopentyl-propionic acid ethyl ester (4.4 g, 28.5 mmol) and NaN3 (2.0 g, 31.4 mmol) in 25 mL of DMSO is warmed to 60° C. for 12 hours. The mixture is cooled to room temperature and diluted with 100 mL of H2O. Extraction with Et2O (3×50 mL) and drying over MgSO4 followed by evaporation of the Et2O gives 4.8 g (75% yield) of 3-azidomethyl-3-cyclopentyl-propionic acid ethyl ester as an oil. NMR (1H, 300 MHz, CDCl3) δ1.1 (2H, m); 1.2 (3H, t); 1.6 (4H, m); 1.8 (3H, m); 1.9 (1H, m); 2.4 (2H, dd); 3.4 (2H, dd); 4.1 (2H, q).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH2:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:15])[CH2:13][CH2:12][S:11][C:10]([NH:14][C:23](=[O:25])[CH3:24])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(Br)c2)CCSC(N)=N1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC1=NC(C)(c2cccc(Br)c2)CCS1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
To a 0° C. solution of 4-(3-bromo-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-ylamine (10 g, 35 mmoles, 1 equiv) and triethylamine (4.3 g, 42 mmoles, 1.2 equiv) in dichloromethane (70 mL) is added dropwise acetyl chloride (2.8 g, 35 mmoles, 1 equiv) over 5 minutes. The reaction is allowed to warm to ambient temperature. After 1 h, the reaction is diluted with dichloromethane and extracted with water. The organic layers are separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by silica gel chromatography eluting with hexane:ethyl acetate (1:1) to give the title compound (87% yield): MS (m/z): 327, 329 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:13])([F:12])[F:11].C(=O)([O-])[O-].[Cs+].[Cs+].[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:26][S:39]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)(=[O:41])=[O:40])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:25])[C:9]([OH:24])([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]([F:11])([F:13])[F:12]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC(c1ccc(OS(=O)(=O)c2ccccc2)cc1Cl)C(O)(c1cnc2ccccc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 39.3 %

Procedure:
To a suspension of 3-chloro-4-(3,3,3-trifluoro-2-hydroxy-1-methyl-2-quinolin-3-yl-propyl)-phenol (Example 179, 55 mg) and cesium carbonate (52 mg) in N,N-dimethylacetamide (1 ml) was added benzenesulfonyl chloride (25 mg). After being stirred at room temperature for 2 days, more benzenesulfonyl chloride (14 mg) was added and the mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine and with water and dried (MgSO4). The product was purified by chromatography (SiO2, cyclohexane=>cyclohexane/EtOAc 1:1) to give the title compound (29 mg) as an off-white solid. MS (m/e)=522.2 [M+H+].
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.[N+:12]([CH3:15])([O-:14])=[O:13].C([O-])(=O)C.[NH4+].O>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:15][N+:12]([O-:14])=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1F
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])cc1F

Procedure:
A solution of 3-fluoro-4-methoxybenzaldehyde [5.05 g, Intermediate (1)], nitromethane (5.3 mL) and ammonium acetate (6.3 g) in glacial acetic acid (60 mL) is heated at 110° C. for 16 hours, allowed to cool and poured into water (300 mL). The aqueous solution is extracted twice with EtOAc (200 mL). The combined extracts are washed with sodium bicarbonate solution (10%), with water, dried over sodium sulfate and evaporated affording 2-fluoro-1-methoxy-4-(2-nitro-vinyl)benzene [4.2 g, Intermediate (2)]. MS: 198 (M+H); 1H NMR (CDCl3): δ 7.9 (1H, d, J=10 Hz); 7.5 (1H, d, 10 Hz); 7.3 (2H, m); 6.95-7.15 (1H, m); 4 (3H, s).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH:29][S:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:23]1>COCCO.C(N(CC)CC)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH3:18])[C:13](=[O:19])[N:12]([CH3:20])[C:11]=2[N:10]=[C:9]1[N:22]1[CH2:28][CH2:27][CH2:26][CH2:25][CH:24]([NH:29][S:30]([C:33]2[CH:34]=[CH:35][C:36]([CH3:39])=[CH:37][CH:38]=2)(=[O:31])=[O:32])[CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NC2CCCCNC2)cc1
Reactant: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2)n(C)c1=O
Solvent: COCCO
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2CCCCN(c3nc4c(c(=O)n(C)c(=O)n4C)n3Cc3ccccc3)C2)cc1

Procedure:
7-Benzyl-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (2A) (1.03 g, 3.40 mmol) and N-(azepan-3-yl)-4-methylbenzenesulfonamide (6B) (1.00 g, 3.73 mmol) were dissolved in 2-methoxyethanol (30 ml) and triethylamine (2.4 ml), and the mixture was heated to 120° C. for 2 days. The solvents were evaporated and the crude product was dissolved in 100 ml of EtOAc and 100 ml of water. The aqueous phase was acidified with 1M potassium hydrogen sulphate until pH=2. The organic layer was separated and extracted with 50 ml of 1M aqueous potassium hydrogen sulphate, and 50 ml of brine, and dried over sodium sulphate. The solvent was evaporated and the crude product was purified by column chromatography on silica gel using EtOAc:heptane (1:1) as the eluent. Evaporation of the solvent gave compound (6C) as a white foam.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=1.[CH2:22]([CH:24]([NH2:27])[CH2:25][CH3:26])[CH3:23]>CN1CCCC1=O>[CH3:20][C:9]1[C:10]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[CH:3]=[C:2]([NH:27][CH:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[N:7]2[N:8]=1
Reactant: CCC(N)CC
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(C)c1
Solvent: CN1CCCC1=O
Product: CCC(CC)Nc1cc(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 125 °C

Procedure:
A mixture of 7-Chloro-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (60 mg, 0.2 mmol) and 1-ethylpropylamine (4 ml) in 1 ml of N-methylpyrro-lidinone was heated at 125° C. oil bath for 15 hrs. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated and purified through silica gel column chromatography using 20% ethyl acetate in hexane as eluent to give 35 mg of the title compound as a yellow solid. 1H NMR (CDCl3) ä 6.96(s, 2H), 6.00(d, 1H), 5.77(s, 1)H, 3.47 (m, 1H), 2.43(s, 3H), 2.32(s, 3H), 2.22(s, 3H), 2.05(s, 6H), 1.5-1.9(m, 4H), 1.04(t, 6H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[F:11].[Br:12]N1C(=O)CCC1=O.Cl(O)(=O)(=O)=O.CCCCCC>C(Cl)(Cl)(Cl)Cl>[CH3:10][O:9][C:5]1[CH:6]=[CH:7][C:8]([Br:12])=[C:3]([O:2][CH3:1])[C:4]=1[F:11]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc(OC)c1F
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Br)c(OC)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
2-fluoro resorcinol (prepared according to Patrick, T. B., et al., J. Org. Chem (1986), 51, 3242-4) (12.8 g, 100 mmol), potassium carbonate (42 g, 0.3 mol), and methyl iodide (25 mL, 0.4 mol) were mixed with acetone (300 mL) and refluxed for 6 hrs. The reaction was poured into ice-water (500 mL) and extracted in ethyl acetate (500 mL). The ethyl acetate was washed with water (200 mL×2), and brine (200 mL×1), dried over sodium sulfate, filtered, and solvent was removed to yield 14.2 grams (91%) of 1,3-dimethoxy 2-fluoro benzene. This fluoro-benzene intermediate (23.19 g, 148.5 mmoL), N-bromo succinimide (26.52 g, 149 mmol), and 300 uL of 70% aqueous perchloric acid (Aldrich Chemical, 3.4 mmoL) were mixed in carbon tetrachloride (100 mL) and stirred at room temperature for 1 hour. The mixture was filtered, and solvent was removed to obtain a yellow oil. The oil was subjected to silica-gel chromatography (silica gel, hexane mobile phase) to yield 33.28 grams (95%) of the 1,3-dimethoxy-4-bromo-2-fluorobenzene 12 compound as a yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:17]2[CH2:18][CH:14]([CH2:15][CH2:16]2)[C:13](=[O:19])[C:12]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=1)=[O:21].C(N(C(C)C)C(C)C)C>O1CCCC1>[C:1]([O:19][C:13]1[CH:14]2[CH2:18][CH:17]([C:11](=[O:10])[C:12]=1[C:20]([C:22]1[C:23]([CH3:32])=[N:24][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:26][CH:27]=1)=[O:21])[CH2:16][CH2:15]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(O)C2CCC(C2)C1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)ccc1C(=O)C1=C(OC(=O)c2ccccc2)C2CCC(C2)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., a solution of 0.562 g (0.0004 mol) of benzoyl chloride in 1 ml of tetrahydrofuran is added to a solution of 1.14 g (0.0035 mol) of 4-hydroxy-3-(2-methyl-6-trifluoromethylpyridine-3-carbonyl)bicyclo[3.2.1]oct-3-en-2-one and 0.517 g (0.004 mol) of ethyidiisopropylamine in 15 ml of tetrahydrofuran. The reaction mixture is stirred at 25° C. for 2 hours, evaporated and purified over silica gel (hexane/ethyl acetate 1:1). This gives 0.9 g (60%) of the title compound in the form of a yellowish resin. 1H NMR (CDCl3, ppm): 7.91-7.87, m, 3H; 7.64, t, J=7.5 Hz, 1 H; 7.5 0-7.40, m, 3H; 3.24, br t, J=4 Hz, 1 H; 3.14, br t, J=4 Hz, 1H; 2.70, s, 3H; 2.47, d, J=13.5 Hz, 1H; 2.40, 2.15, m, 3H; 1.95-1.8, m, 2H.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[NH2:10])=[N:6][CH:7]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:29][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36](N)=[C:35]([O:40][CH3:41])[CH:34]=1)[CH3:31]>>[CH3:31][N:30]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([NH:10][C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=2)=[O:11])=[C:35]([O:40][CH3:41])[CH:34]=1)[CH3:29]
Reactant: Cc1cnc(NC(N)=O)cn1
Reactant: COc1cc(CN(C)C)ccc1N
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Product: COc1cc(CN(C)C)ccc1NC(=O)Nc1cnc(C)cn1

Procedure:
144-Dimethylaminomethyl-2-methoxy-phenyl)-3-(5methyl-pyrazin-2-yl)urea. According to the diphenylphosphoryl azide method described above for compound 336, 4-dimethylaminomethyl-2-methoxy-phenylamine was converted to the (5-methyl-pyrazin-2-yl)-urea. The crude product was purified by preparative TLC, eluting with 5% MeOH in CH2Cl2. 1H NMR (400 MHz, d6-DMSO): δ 11.21 (s, 1H), 8.95 (s, 1H), 8.39 (s, 1H), 8.21 (d, J=7.83 Hz, 1H), 8.04 (s, 1H), 7.01 (s, 1H), 6.89 (d, J=7.83 Hz, 1H), 3.98 (s, 3H), 3.92 (s, 2H), 2.26 (s, 3H), 2.24 (s, 6H). MS APCI-Pos, M+1=316.0.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])=[N:11]1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[N:10]1[CH:14]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]3[CH2:22][CH2:23][N:24]([S:42]([CH3:41])(=[O:44])=[O:43])[CH2:25][CH:26]=3)[CH:16]=2)[CH2:13][C:12]([C:27]([F:32])([F:33])[C:28]([F:30])([F:31])[F:29])=[N:11]1
Reactant: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccnc(C3=CCNCC3)c2)c(F)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CC=C(c2cc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)ccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 15.5 %

Procedure:
1-(2,4-Difluoro-phenyl)-5-[2-(1,2,3,6-tetrahydropyridin-4-yl)-pyridin-4-yl]-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.06 mmol) prepared in Example 190, triethylamine (42.0 uL, 0.30 mmol) and methanesulfonyl chloride (7.0 uL, 0.09 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 18 hours, washed with distilled water, 1N hydrochloride, a saturated solution of sodium hydrogen carbonate, and 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=2/1) to give 5.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[O:6][CH:7]=1.[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][C:3]2[N:4]=[C:5](/[CH:8]=[CH:9]/[C:10]3[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=3)[O:6][CH:7]=2)=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(CCl)co2)cc1
Reactant: Oc1ccc(CCCCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCCl)cc3)co2)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
A suspension of 4-chloromethyl-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (13.4 g), 4-(4-chlorobutyl)phenol (8.63 g) and potassium carbonate (6.46 g) in DMF (200 ml) was stirred at 60° C. for 24 hr. The reaction mixture was combined with water to give crystals, which were collected by filtration and washed with methanol-water (2:1) to give crude 4-[[4-(4-chlorobutyl)phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (19.5 g) as colorless powders. A suspension of this product (18.5 g) and sodium iodide (31.8 g) in acetonitrile (240 ml) was refluxed for 22 hr. The reaction mixture was concentrated, diluted with ethyl acetate, successively washed with water, hypo-water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to give the titled compound (12.3 g) as colorless needle crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6](O)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]([F:20])([F:19])[C:11]1[CH:12]=[C:13]([NH:17]N)[CH:14]=[CH:15][CH:16]=1.C1(C)C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[F:9][C:10]([F:19])([F:20])[C:11]1[CH:16]=[CH:15][C:14]2[C:7]3[C:2]([OH:1])=[N:3][CH:4]=[CH:5][C:6]=3[NH:17][C:13]=2[CH:12]=1
Reactant: NNc1cccc(C(F)(F)F)c1
Reactant: Oc1ccnc(O)c1
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1nccc2[nH]c3cc(C(F)(F)F)ccc3c12
Temperature: 25 °C

Procedure:
A mixture 2,4-dihydroxypyridine and 3-trifluoromethylphenylhydrazine (2.6 equiv) in diphenyl ether was heated at reflux with a Dean Stark apparatus for 2 h as described by C. H. Nguyen in Tetrahedron 1987, 43, 527. The reaction was cooled to room temperature followed by the addition of toluene. The solid was collected and washed with toluene. The solid was then dissolved in EtOAc and purified by flash chromatography (EtOAc to 5% MeOH in EtOAc) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[C:12]([F:14])[C:11]([C:15]3(O)[CH2:20][CH2:19][S:18][CH2:17][CH2:16]3)=[C:10]([F:22])[CH:9]=2)[C:4]([CH3:7])=[CH:5][CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[S:18]1[CH2:17][CH:16]=[C:15]([C:11]2[C:12]([F:14])=[CH:13][C:8]([N:3]3[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]3[CH3:7])=[CH:9][C:10]=2[F:22])[CH2:20][CH2:19]1
Reactant: Cc1ccc(C)n1-c1cc(F)c(C2(O)CCSCC2)c(F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1cc(F)c(C2=CCSCC2)c(F)c1

Procedure:
A stirred solution of 4-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-2,6-difluorophenyl]tetrahydro-2H-thiopyran-4-ol (Step 2, 1.617 g, 5.00 mmol) and p-toluenesulfonic acid monohydrate (0.107 g) in benzene (20 mL) is heated at reflux using a Dean-Stark trap for 5 h, during which additional p-toluenesulfonic acid monohydrate (0.342 g) is added. Solvent is then removed under reduced pressure, and the residue is taken up in CH2Cl2 (60 mL), washed with saturated aqueous NaHCO3 (2×20 mL) and water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by chromatography on a Biotage Flash 40M 90 g silica gel cartridge, eluting with 2-5% EtOAc/Hexanes, affords the title compound, mp 118-119° C.; MS (ESI+) for C17H17F2NS m/z 306 (M+H)+.