Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH2:9])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:17](Cl)(=[O:19])[CH3:18]>C1COCC1.C(Cl)Cl>[C:1]([C:4]1[S:8][C:7]([NH:9][C:17](=[O:19])[CH3:18])=[N:6][C:5]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(=O)c1sc(N)nc1C
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1nc(C)c(C(C)=O)s1
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
5-Acetyl-2-amino-4-methylthiazole (P5) (12.35 g, 79 mmol) is suspended in THF/DCM 3:2 mixture (150 mL). The mixture was cooled down to 0° C. and pyridine (16 mL) is added, followed by the dropwise addition of acetyl chloride (8.43 mL, 119 mmol, 1.5 eq). The mixture was stirred 2 hours at 0° C. As the acetylation is complete, the reaction is quenched with addition of water (70 mL) and diluted with EtOAc (100 mL). The two phases are separated and the organic phase is washed with one portion of 10% citric acid solution. Organic layer is dried over MgSO4, filtrated and evaporated. The resulting crude mass is purified by crystallization in EtOAc/Cyclohexane mixture, to obtain N-(5-acetyl-4-methyl-1,3-thiazol-2-yl)acetamide (P6) as a colorless powder (13.13 g, 83.6% yield). 1H NMR (DMSO-d6) δ: 2.17 (s, 3H), 2.47 (s, 3H), 2.56 (s, 3H), 12.44 (br s, 1H). M− (ESI): 197.3; M+ (ESI): 199.3. HPLC, Rt: 1.7 min (purity: 99.7%).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:18]=[N:17][CH:16]=[CH:15][C:9]=3/[C:10](=[N:13]/[OH:14])/[C:11](=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+:23].[CH3:24][C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[N:28]=[C:27]([C:36]([F:39])([F:38])[F:37])[C:26]=1[CH:40]=O>C(O)(=O)C>[CH3:24][C:25]1[N:29]([CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)[N:28]=[C:27]([C:36]([F:39])([F:38])[F:37])[C:26]=1[C:40]1[N:13]([OH:14])[C:10]2[C:9]3[CH:15]=[CH:16][N:17]=[CH:18][C:8]=3[NH:7][C:6]3[N:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:11]=2[N:23]=1
Reactant: O=c1/c(=N\O)c2ccncc2[nH]c2ncccc12
Reactant: Cc1c(C=O)c(C(F)(F)F)nn1C1CCCCO1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1c(-c2nc3c(n2O)-c2ccncc2Nc2ncccc2-3)c(C(F)(F)F)nn1C1CCCCO1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of (6Z)-5H-dipyrido[2,3-b:4′,3′-f]azepine-5,6(11H)-dione 6-oxime (930 mg, 3.9 mmol), ammonium acetate (5.58 g, 72.4 mmol) and 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazole-4-carbaldehyde (2.03 g, 7.74 mmol) in acetic acid (5.6 mL) was stirred at 80° C. for 2 h. The reaction was cooled to ambient temperature and partitioned between water and 3:1 CHCl3:isopropanol. The phases were separated and the aqueous phase was washed with additional solvent. The combined organic phase was washed with water, sat'd NaHCO3, then sat'd NaCl, dried over MgSO4 and reduced to dryness in vacuo to leave 2-[5-methyl-1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-4-yl]imidazo[4,5-d]dipyrido[2,3-b:4′,3′-f]azepin-3(8H)-ol, which was used without further purification. MS (EI) m/z=484.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](SC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21].[CH:22]1C=C(Cl)C=C(C(OO)=O)C=1.[O-:33][S:34]([O-:37])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([S:34]([CH3:22])(=[O:37])=[O:33])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1[F:21]
Reactant: O=S([O-])([O-])=S
Reactant: COC(=O)c1ccc(F)c(-c2c(F)cc(SC)cc2F)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(S(C)(=O)=O)cc2F)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a solution of methyl 6-[2,6-difluoro-4-(methylthio)phenyl]-5-fluoropyridine-2-carboxylate (81.0 mg, 0.258 mmol) in DCM (1.2 mL) at 0° C. was added mCPBA (185 mg, 0.827 mmol). The reaction mixture was stirred at 0° C. for 2 h, followed by the addition of Na2S2O3 solution and then 1 M NaOH. The reaction mixture was stirred for 20 min. at room temperature, then extracted with DCM three times. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (78 mg, 87%). LCMS calc. for C14H11F3NO4S (M+H)+: m/z=346.0. Found: 346.2.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)C.[CH:8]([C:10]1[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:9]>C1COCC1.CS(C)=O>[CH3:19][O:18][C:12]1[CH:11]=[C:10]([CH:8]2[CH2:4][O:9]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: COc1cc(C=O)ccc1C#N
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(C2CO2)ccc1C#N
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cool solution of NaH (0.16 g, 3.9 mmol) in THF (40 mL) was added dropwise a solution of trimethylsulfonium iodide (0.91 g, 4.5 mmol) in DMSO (20 mL). The resulting mixture was stirred at 0° C. under N2 for 20 min. A solution of 4-formyl-2-methoxybenzonitrile (0.60 g, 3.72 mmol) in THF (20 mL) was added. The resulting reaction mixture was stirred at 0° C. under N2 for 1 hr, and then it was warmed gradually to room temperature and stirred at that temperature for 12 hr. The starting material was consumed as indicated by TLC (25% ethyl acetate/hexanes). The reaction mixture was cooled to 0° C. and quenched with dropwise addition of water. The mixture was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with water, brine, then dried (MgSO4) and filtered. The filtrate was concentrated in vacuo. The residue was purified via column chromatography (silica gel, 10-30% EtOAc-hexanes) to afford 2-methoxy-4-(oxiran-2-yl)benzonitrile: 1H NMR (CDCl3, 500 MHz) δ 7.57 (d, J=8 Hz, 1H), 6.99 (dd, J=1.1 Hz, J=1.2 Hz, 1H), 6.89 (s, 1H), 3.97 (s, 3H), 3.94-3.92 (m, 1H), 3.22 (dd, J=5.2, Hz, J=4.1 Hz, 1H), 2.77 (d, J=2.5 Hz, 1H); LC/MS: (IE, m/z) [M+1]+=176.33.
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[C-:2].[S:9]1[CH2:14][C:13](=O)[CH2:12][S:11][CH2:10]1.C(O)(=[O:18])C>O1CCCC1>[CH:2]([NH:1][C:3](=[C:13]1[CH2:12][S:11][CH2:10][S:9][CH2:14]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:18]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1CSCSC1
Reactant: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(NC=O)=C1CSCSC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of potassium tert.-butylate (27.2 g) in tetrahydrofurane (200 cc) is cooled to 0° C. A solution of ethyl isocyanoacetate (25 g) in tetrahydrofurane (150 cc) is added dropwise. The mixture is stirred for a further one hour at 0° C. and a solution of 1,3-dithiacyclohexan-5-one (29.6 g) in tetrahydrofurane (375 cc) is then added. The reaction mixture is stirred for a further 90 minutes at 0° C. Acetic acid (50 cc) is added and the precipitate is filtered off. The solvents are evaporated off under reduced pressure (20 mm Hg) at 30° C. The residue is taken up with methylene chloride (2,500 cc). Extraction is carried out with a mixture of water (500 cc) and a saturated aqueous solution of sodium bicarbonate (300 cc). The organic phase is again washed with water (500 cc) and dried over sodium sulphate. The solution is treated with decolorising charcoal, filtered and then concentrated to dryness under reduced pressure (20 mm Hg) at 30° C. The residue is vigorously stirred with ethyl ether (400 cc). The precipitate obtained is filtered off. Ethyl α-formylamino-(4,5-dihydro-1,3-dithiin-5-ylidene)-acetate (18.5 g) is thus obtained. The filtrate is concentrated to dryness under reduced pressure (20 mm Hg) at 20° C. The residue is purified by chromatography on a column (diameter 3.7 cm; height 47 cm) containing silica (250 g). Elution is carried out with a mixture (two liters) of methylene chloride and ethyl acetate (85/15 by volume). A mixture (4.4 g) of ethyl α-formylamino-(4,5-dihydro-1,3-dithiin-5-ylidene)-acetate and ethyl α-formylamino-(1,3-dithiin-5-yl)-acetate is thus obtained.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[CH3:28]N(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.ON1C2C=CC=CC=2N=N1.Cl.[OH:59][C@@H:60]([CH2:90]O)[CH2:61][N:62]1[CH:66]=[CH:65][C:64]([NH:67]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:63]1>ClCCl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])=[CH:14][C:13]2=[O:26])[C:9]([NH:67][C:64]2[CH:65]=[CH:66][N:62]([CH2:61][C:60]([OH:59])([CH3:90])[CH3:28])[N:63]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1CC(Oc2cc(Cl)ccc2Cl)=CC1=O
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCCC2)N2CC(Oc3cc(Cl)ccc3Cl)=CC2=O)n1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 30.3 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (160 mg, 0.4 mmol) in dichloromethane (5 mL) was gradually added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (82 mg, 0.4 mmol) and N,N-diisopropylethylamine (210 mg, 1.6 mmol) at room temperature, under nitrogen. After 15 min,, 1-hydroxybenzotriazole (61 mg, 0.4 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 160 mg, 0.4 mmol) were added to the reaction mixture. The reaction mixture was then stirred at 23° C. for 48 h. The reaction mixture was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium bicarbonate solution. The organic layer was then washed with a saturated aqueous sodium chloride solution, separated, dried over sodium sulfate and concentrated in vacuo to afford the crude product, which was purified by flash column chromatography (silica gel (100-200 mesh)) which afforded (S)-3-cyclohexyl-2-[4-(2,5-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (0.065 g, 30%) as a brown sticky liquid: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.80-1.01 (m, 2H), 1.05 (s, 3H), 1.06 (s, 3H), 1.07-1.20 (m, 3H), 1.50-1.84 (m, 8H), 3.89 (s, 2H), 4.19 (d, J=18.1 Hz, 1H), 4.60 (d, J=18.1 Hz, 1H), 4.66 (s, 1H), 4.92 (dd, J=10.5, 5.1 Hz, 1H), 4.95 (s, 1H), 6.44 (d, J=2.0 Hz, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 1H), 7.53 (d, J=2.0 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.75 (d, J=2.4 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].[CH3:12][NH:13][C:14](Cl)=[O:15]>C1(C(C)C)C=CC=CC=1>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:14](=[O:15])[NH:13][CH3:12]
Reactant: Oc1ccc2ccccc2c1
Reactant: CNC(=O)Cl
Solvent: CC(C)c1ccccc1
Product: CNC(=O)Oc1ccc2ccccc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 85 %

Procedure:
72 parts by weight of β-naphthol are dissolved in 250 parts by weight of cumene at 80° C. 46.7 parts by weight of methylcarbamyl chloride are stirred into this solution over a period of 10 minutes while nitrogen is simultaneously bubbled through the solution. The reaction is complete after 15 minutes. The hot reaction solution is cooled to 0° C and the precipitated β-naphthyl-N-methylcarbamate is isolated. The yield is 85% of theory.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH3:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([N:21]([CH3:31])[CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[CH:15]=[CH:14][C:13]=1[C:32]([F:35])([F:34])[F:33].[O-]CC.[K+].C(O)(=O)C>O1CCCC1.O>[CH3:31][N:21]([C:16]1[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([CH2:11][C:2](=[O:4])[C:1]([O:8][CH2:9][CH3:10])=[O:7])[C:13]([C:32]([F:34])([F:35])[F:33])=[CH:14][CH:15]=1)[CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1
Reactant: Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Reactant: CCOC(=O)C(=O)OCC
Agent: CC[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Cc1c(C(F)(F)F)ccc(N(C)CCOC2CCCCO2)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Diethyl oxalate (1.94 g, 13.2 mmol) and then a solution of 2-methyl-4-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-3-nitrobenzotrifluoride (2.40 g, 6.62 mmol) in tetrahydrofuran (40 ml) were added dropwise to a mixture of potassium ethoxide (1.11 g, 13.2 mmol) and tetrahydrofuran (60 ml) at room temperature. The reaction mixture was stirred at room temperature for 6 hours and then cooled to 3° C., and acetic acid (1.59 g, 26.5 mmol) was added dropwise. The reaction mixture thus obtained was poured into cold water and extracted twice with ethyl acetate. The extract solution was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain an oil of ethyl [3-[N-methyl-N-[2-(2-tetrahydro-2H-pyranyl)oxyethyl]amino]-2-nitro-6-trifluoromethylphenyl]pyruvate.
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+].O1CCCC1>CO.C(#N)C>[NH2:31][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:24])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CC[C@H](NS(C)(=O)=O)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1cc(Cl)c2cccnc2c1N1CC[C@H](NS(C)(=O)=O)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]methanesulfonamide (0.037 g, 0.10 mmol) and ammonium acetate (0.0775 g, 1.00 mmol) in methanol (0.3 mL) and acetonitrile (0.3 mL) was heated at 65° C. in a sealed tube for 1 hour. After cooling to room temperature, to the resulting mixture was added 1.0 M sodium cyanoborohydride in tetrahydrofuran (0.25 mL, 0.25 mmol). The reaction was heated at 65° C. overnight. The mixture was cooled to room temperature, quenched with sat. NaHCO3 solution, extracted with dichloromethane, dried over MgSO4, concentrated and purified on a preparative LCMS (pH 10) to give the desired product. LCMS calculated for C16H22ClN4O2S (M+H)+: m/z=369.1; Found: 369.1.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[C:10]1([CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=1)[OH:11].[OH-].[K+].Cl>O.CS(C)=O>[Cl:8][C:7]1[C:2]([O:11][C:10]2[CH:17]=[CH:16][C:14]([OH:15])=[CH:13][CH:12]=2)=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Oc1ccc(O)cc1
Reactant: Clc1cnc(Cl)c(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
A mixture of 2,3,5-trichloropyridine (2.5 g, 13.7 mm), hydroquinone (3.02 g, 27.4 mm), KOH (3.07 g, 54.8 mm) and DMSO (10 ml) is heated to 160° for 3 hours. The mixture is poured into water, acidified with dilute HCl and extracted with ether. The ethereal solution is washed, dried and evaporated to dryness. The crude product is chromatographed on silica gel to give crystalline 4-(3,5-dichloropyridyloxy)phenol.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1>>[Br-:13].[CH2:1]([N+:8]1[CH:12]=[CH:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: COc1ccc(CCCCBr)cc1
Reactant: CCCCCCCn1ccnc1
Product: CCCCCCC[n+]1ccn(CCCCc2ccc(OC)cc2)c1
Product: [Br-]
Temperature: 140 °C

Procedure:
A mixture of 2.5 g (0.015 mole) of 1-heptyl-1H-imidazole and 3.66 g (0.015 mole) of 1-(4-bromobutyl)-4-methoxybenzene is heated at 140° C. for about 2 hours. Follow the progress of the reaction by thin-layer chromatography on silica gel (methanol: 1M sodium chloride, 95:5). At the completion of the reaction, the cooled reaction product is triturated thoroughly with ether and on drying, provides the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][C:14]1[NH:18][N:17]=[C:16]([NH2:19])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:19][C:16]2[CH:15]=[C:14]([CH3:13])[NH:18][N:17]=2)[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2C(F)(F)F)n[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (1.06 g, 4.86 mmol), 5-methyl-1H-pyrazol-3-amine (472.2 mg, 4.86 mmol) and sodium carbonate (2.06 g, 19.4 mmol) in 100 mL of EtOH was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo. The crude solid was partitioned between EtOAc and water. The combined organic extracts were dried (Na2SO4), concentrated in vacuo, and purified by silica chromatography (EtOAc/hexanes: 1/1) to afford 2-chloro-N-(5-methyl-1H-pyrazol-3-yl)-5-(trifluoromethyl)pyrimidin-4-amine; ESMS m/z 278.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.O=[C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:34][CH:35]=2)[CH2:30][O:29]1.S(=O)(=O)(O)O>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:28]1[C:36]2[C:31](=[CH:32][C:33]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:34][CH:35]=2)[CH2:30][O:29]1
Reactant: O=C(O)CCc1ccc2c(c1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
To a stirred solution of 5-fluorooxindole (218 mg, 1.44 mmol) in anhydrous THF (10 ml) under nitrogen was added 1.0M LiHMDS/THF solution (2.9 ml, 2.9 mmol). After the mixture was stirred at room temperature for 10 minutes, 3-(1-Oxo-1,3-dihydro-isobenzofuran-5-yl)-propionic acid (100 mg, 0.48 mmol) was added. After the mixture was stirred at room temperature for 2 hours, 1 M sulfuric acid solution (10 ml) was added. The mixture was heated at 60° C. for 2 hours, and then poured into 150 ml of water. The resulting solid was filtered, rinsed with water, dried in vacuo to give the title compound as a yellow solid (96 mg, 59%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][CH2:16]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:34]=[CH:33][C:23]2[C:24]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:25][O:26][C:22]=2[CH:21]=1.C([O-])(=O)C([O-])=[O:37]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=[O:37])[CH2:15][CH2:16][N:30]3[CH2:29][CH2:28][CH:27]([C:24]4[C:23]5[CH:33]=[CH:34][C:20]([F:19])=[CH:21][C:22]=5[O:26][N:25]=4)[CH2:32][CH2:31]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCCl)C1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C([O-])C(=O)[O-]
Agent: Cl
Product: CC(=O)N1CCc2c(sc(C)c2C(=O)CCN2CCC(c3noc4cc(F)ccc34)CC2)C1

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 2.0 g of 6-acetyl-(3-chloropropyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 2.0 g of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine hydrochloride to give 0.5 g of 6-acetyl-3-(3-(4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl)propionyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 180°-182° C. as oxalate thereof.
Reaction SMILES: C([O:3][C:4](=[O:17])/[CH:5]=[CH:6]/[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[NH:9][CH:8]=1)C.[OH-].[Na+]>C1COCC1.CO.O>[CH3:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2/[CH:6]=[CH:5]/[C:4]([OH:17])=[O:3]
Reactant: CCOC(=O)/C=C/c1c[nH]c2ccc(C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2[nH]cc(/C=C/C(=O)O)c2c1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
(E)-ethyl-3-(5-methyl-1H-indol-3-yl)acrylate (1222.4 g, 5.33 mmol) prepared at Step 1 was dissolved in 32 ml of mixture solution (THF/methanol/H2O=2:1:1), after which NaOH acqueous solution (639.8 mg, 16.0 mmol) was added. After raising temperature to 50° C., stirring for 12 hr, neutralization with 10% hydrochoric acid to pH 4, and dilution with EtOAc, washing with water and brine, drying with anhydrous MgSO4, and concentration under reduced pressure followed. The concentrated residue was refined with silica gel chromatography (n-hexane:EtOAc=2:1) and dried to give target compound. (1070.5 mg, 99.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=2)[C:28]=1[CH2:39][CH:40]=[CH2:41])(=O)=O.O>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>[CH3:38][O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:39][CH:40]=[CH2:41])=[C:27]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:36]=[CH:35]2
Reactant: C=CCc1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OC)ccc12
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=CCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12
Yield: 74.7 %

Procedure:
4-Methoxyphenylboronic acid (10.15 g, 66.8 mmol), tripotassium phosphate hydrate (77.6 g, 278.3 mmol) and tetrakis(triphenylphosphine)palladium(0)(1.93 g, 1.67 mmol, 3 mol %) were added to a solution of 6-methoxy-1-(2-propenyl)-2-naphthyl trifluoromethanesulfonate (19.3 g, 55.66 mmol) in dioxane (300 ml), followed by heating under reflux for 8 hours under argon atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9), followed by recrystallization from hexane, to give 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (12.65 g, Yield 75%).