Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].Cl[C:12]([O:14][CH2:15][CH3:16])=O.C>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:15]([O:14][C:12]1[O:9][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[N:4]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOc1nc2ccccc2c(=O)o1
Reaction time: 2 h

Procedure:
To a solution of anthranilic acid (0.1 mol., 13.71 gm) in dry pyridine (100 ml) at room temperature under anhydrous conditions was added ethyl chloroformate (4 equiv., 38.25 ml) in a dropwise manner over 15 minutes. After stirring for 2 hours, excess pyridine was removed under reduced pressure at 40° C. (bath temperature) and the residue was stirred vigorously in ice cold water (250 ml) for 15 minutes. The pale yellow powder was collected by filtration, washed with water (100 ml), and air-dried to give 18.6 gm of crude product. The crude product was treated with active charcoal (2 gm) in ethyl acetate (150 ml) to afford a white solid after removal of solvent. Recrystallization from EtOAc-ether gave 17.02 (89%) of the title compound, 2-ethoxy-4H-3,1-benzoxazin-4-one, as colorless crystals; m.p. 88°-90.5° C.; IR (KBr): νmax 1760 cm-1 (C=O), 1630 cm-1 (C=N); H'NMR (CDCl3); δ1.46 ppm (t, J=7.1 Hz, 3H,)CH2CH3), 4.53 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 7.30-8.20 ppm (m, 4H, aromatic protons).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C)C=O>[CH2:12]([O:11][C:9]([CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:10])[CH:13]=[CH2:14]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: C=CCOC(=O)Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)Cc1cccc(OC(C)(C)C(=O)OCC)c1
Temperature: 80 °C
Reaction time: 60 h

Procedure:
Allyl 3-hydroxyphenylacetate (5.72 g, 32.9 mmol), potassium carbonate (6.82 g, 49.35 mmol), and ethyl 2-bromoisobutyrate (7.35 mL, 49.35 mmol) were dissolved in dimethylformamide (10 mL), and the mixture was stirred for 60 hours at 80° C. The reaction mixture was added to water, and the resultant mixture was extracted with diethyl ether, followed by washing sequentially with water and saturated brine, drying over magnesium sulfate, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=20/1), whereby the target compound was obtained (6.40 g, 20.90 mmol, 63.5%).
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH:2]=[O:3].[O:13]1[CH2:17][CH2:16][O:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C@H:24]1[C@@H:27]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26](=[O:39])[NH:25]1.C(N(CC)CC)C>O1CCCC1>[OH:3][CH:2]([N:25]1[C:26](=[O:39])[C@H:27]([NH:28][C:29](=[O:38])[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:24]1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH:14]1[O:13][CH2:17][CH2:16][O:15]1)[C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: O=CC(=O)OCc1ccccc1
Reactant: O=C(COc1ccccc1)N[C@H]1C(=O)N[C@H]1c1ccccc1C1OCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)N[C@H]1C(=O)N(C(O)C(=O)OCc2ccccc2)[C@H]1c1ccccc1C1OCCO1
Reaction time: 1.5 h

Procedure:
Freshly distilled benzyl glyoxylate (312 mg, 1.9 mmol) and freshly distilled tetrahydrofuran (15 ml) were stirred with 4A molecular sieves for one hour and then cooled in ice. To this solution was added the solid product from Example 5 (437 mg, 1.19 mmol) followed by the dropwise addition of triethylamine (240 mg, 2.37 mmol). The ice bath was removed and the reaction was stirred for 1.5 hours. The solution was filtered and the filtrate was evaporated to dryness. The residue was dissolved in chloroform and chromatographed on a silica gel column with a chloroform-ethyl acetate gradient as eluant to give the title product, 525 mg (83%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH:18]=[CH:19][CH3:20])[O:14][N:13]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.O>C(OCC)(=O)C>[C:6]1([C:12]2[CH:16]=[C:15]([C:17](=[O:21])[CH2:18][CH:19]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH3:20])[O:14][N:13]=2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: CC=CC(=O)c1cc(-c2ccccc2)no1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(CC(=O)c1cc(-c2ccccc2)no1)N1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyrrolidine (5 ml) was added to 1.1 g (5.2 mmol) of 3-phenyl-5-(2-butenoyl) isoxazole prepared above in the procedure (1). The resulting mixture was stirred at room temperature for 3 hours. Water and ethyl acetate were added to the reaction mixture, so that a product formed was extracted in an organic layer. The organic layer was collected, dried over anhydrous magnesium sulfate, and then concentrated, whereby 3-phenyl-5-{3-(1-pyrrolidinyl)butyryl}isoxazole was obtained as colorless oil.
Reaction SMILES: [C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=1)=[O:18])([OH:3])=[O:2].S(=O)(=O)(O)O.C(N(CC)CC)C.[CH2:42](O)[CH:43]=[CH2:44]>C(OCC)(=O)C>[CH2:44]([O:2][C:1]([CH2:4][O:5][CH2:6][C@@H:7]1[CH2:11][C@@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][N:8]1[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=1)=[O:18])=[O:3])[CH:43]=[CH2:42]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](COCC(=O)O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: C=CCO
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
A solution of (2S,4R)-2-(carboxymethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (5.20 g) in allyl alcohol (52 ml) was refluxed in the presence of sulfuric acid (0.5 ml) for 5 hours. After cooling, triethylamine (3.14 ml) was added to the mixture. The mixture was concentrated under reduced pressure to give a syrup. The syrup was dissolved in ethyl acetate (100 ml), washed in turn with water (100 ml) and brine (100 ml), dried over magnesium sulfate, and concentrated under reduced pressure to give (2S,4R)-2-(allyloxycarbonylmethyloxymethyl)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (6.05 g).
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6]OCC.[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([OH:21])([CH3:20])[CH3:19])[C:12]=1[NH2:13].C(=O)(O)[O-].[Na+]>C(O)C.C(Cl)Cl>[CH3:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:21][CH2:5][CH3:6])([CH3:19])[CH3:20])[C:12]=1[NH2:13]
Reactant: CCOCC
Reactant: Cc1cccc(C(C)(C)O)c1N
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(C)(C)c1cccc(C)c1N
Reaction time: 48 h
Yield: 93.1 %

Procedure:
In this example 0.03 moles of boron trifluoride ethyl etherate was added dropwise to a mixture containing 0.03 moles of 2-methyl-6-(1-hydroxy-1-methylethyl)-aniline in 50 ml of ethanol and 50 ml methylene chloride. The mixture was refluxed for two hours and then allowed to stand for two days. The mixture was then poured into about 700 ml of saturated aqueous sodium bicarbonate solution stirred and extracted with methylene chloride. The extract was filtered through diatomaceous earth, dried and evaporated affording 5.4 g of the title product as an oil.
Reaction SMILES: [Si:1]([O:18][C@@H:19]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:26][CH:25]=2)[C:20]1=[O:39])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:40](N(CC)C(C)C)([CH3:42])[CH3:41].C(Br)C=C>C(Cl)Cl>[CH2:42]([N:33]([C:34]1[S:35][CH:36]=[CH:37][N:38]=1)[S:30]([C:27]1[CH:28]=[CH:29][C:24]([N:21]2[CH2:22][CH2:23][C@@H:19]([O:18][Si:1]([C:14]([CH3:15])([CH3:17])[CH3:16])([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:20]2=[O:39])=[CH:25][CH:26]=1)(=[O:31])=[O:32])[CH:40]=[CH2:41]
Reactant: CC(C)(C)[Si](O[C@@H]1CCN(c2ccc(S(=O)(=O)Nc3nccs3)cc2)C1=O)(c1ccccc1)c1ccccc1
Reactant: CCN(C(C)C)C(C)C
Solvent: C=CCBr
Solvent: ClCCl
Product: C=CCN(c1nccs1)S(=O)(=O)c1ccc(N2CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2=O)cc1
Yield: 83.9 %

Procedure:
Synthesized according to General procedure 5. The reaction was set up with (R)-4-(3-(tert-butyldiphenylsilyloxy)-2-oxopyrrolidin-1-yl)-N-(thiazol-2 yl)benzene-sulfonamide (50.0 g, 86.6 mmol), CH2Cl2 (200 mL), N,N-diisopropylethylamine (30.2 mL, 173.2 mmol), and allylbromide (15.0 mL, 173.2 mmol). The residue was purified via silica gel using 50% EtOAc in hexanes to give the desired sulfonamide as a white solid (45.0 g, 72.7 mmol, 84% yield). 1H NMR (400 MHz, DMSO-d6) δ. 7.85-7.79 (m, 6H), 7.70 (dd, J=1.6, 7.7 Hz, 2H), 7.49-7.40 (m, 6H), 7.36 (d, J=4.7 Hz, 1H), 6.93 (d, J=4.7 Hz, 1H), 5.90-5.82 (m, 1H), 5.16 (dd, J=1.3, 10.3 Hz, 1H), 4.97 (d, J=1.3 Hz, 1H), 4.56-4.52 (m, 3H), 3.76-3.72 (m, 1H), 3.56-3.48 (m, 1H), 2.28-2.25 (m, 1H), 2.19-1.98 (m, 1H), 1.11 (s, 9H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[S:8])[NH2:7].Br[CH2:10][C:11](=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:8][CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:7]=1
Reactant: NC(=S)c1ccco1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: CCOC(=O)c1csc(-c2ccco2)n1

Procedure:
To a solution of 2-furan-thiocarboxamide (1.63 g) dissolved in dry ethanol (65 ml) with heating was added ethyl bromopyruvate (1.97 ml) and the mixture was refluxed for 30 minutes. Then the solvent was removed from the reaction mixture, and the residue was treated with water, neutralized with 4% aqueous sodium carbonate and extracted three times with ethyl acetate. The organic layer was washed with saturated aqueous NaCl, dried (anhydrous Na2SO4) and concentrated to give yellowish crystals of ethyl 2-(2-furyl)-4-thiazolecarboxylate (3.12 g).
Reaction SMILES: C(N[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)C=C.[OH:25][C@H:26]1[C@H:30]([OH:31])[CH2:29][NH:28][CH2:27]1>>[OH:25][C@H:26]1[C@H:30]([OH:31])[CH2:29][N:28]([C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:27]1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Product: COc1ccc2c(N3C[C@@H](O)[C@H](O)C3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3R,4R)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].I[CH3:13]>C1COCC1.C(OCC)C>[CH3:13][O:8][CH2:7][C@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1
Reactant: CC1(C)OC[C@H](CO)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC[C@H]1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol (9.8 g, 74.2 mmol) in anhydrous THF (150 mL) at 0° C. was added sodium hydride (60% in mineral oil) (3.26 g, 82 mmol) in 4 portions over 5 min (caution: gas evolution). The reaction was stirred for an additional 15 min at 0° C., then iodomethane (5.09 mL, 82 mmol) was added and the reaction was warmed to rt. After approximately 1 h at rt, the reaction was diluted with diethyl ether (100 mL), filtered and concentrated to 15-20 mL under vacuum. The yellow liquid was used in the next step without purification.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([NH2:15])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[BH3-][C:18]#N.[Na+].C=O>CO>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([NH:15][CH3:18])[C:6]=1[OH:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(N)c(O)c(C(C)(C)C)c1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CNc1cc(C(C)(C)C)cc(C(C)(C)C)c1O
Yield: 14.8 %

Procedure:
A mixture of 2,4-di-tert-butyl-6-amino-phenol (C-9) (5.08 g, 23 mmol), NaBH3CN (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) in methanol (50 mL) was stirred at reflux for 3 h. After removal of the solvent, the residue was purified by column chromatography (petroleum ether-EtOAc, 30:1) to give 2,4-di-tert-butyl-6-(N-methylamino)phenol (C-24) (800 mg, 15%). 1H NMR (DMSO-d6) δ 8.67 (s, 1H), 6.84 (s, 1H), 5.99 (s, 1H), 4.36 (q, J=4.8 Hz, 1H), 2.65 (d, J=4.8 Hz, 3H), 1.23 (s, 18H); ESI-MS 236.2 m/z (MH+).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:5]([CH3:23])=[C:6]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=2)[C:7]([O:13][CH3:14])=[C:8]([CH:10](Cl)[CH3:11])[CH:9]=1.[NH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]2[NH:31][N:32]=[CH:33][C:26]=12.O>CN(C)C=O>[NH2:24][C:25]1[N:30]=[CH:29][N:28]=[C:27]2[N:31]([CH:10]([C:8]3[C:7]([O:13][CH3:14])=[C:6]([C:15]4[CH:20]=[CH:19][N:18]=[C:17]([C:21]#[N:22])[CH:16]=4)[C:5]([CH3:23])=[C:4]([Cl:3])[CH:9]=3)[CH3:11])[N:32]=[CH:33][C:26]=12
Reactant: COc1c(C(C)Cl)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Reactant: Nc1ncnc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1c(C(C)n2ncc3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C#N)c1
Temperature: 30 °C
Reaction time: 8 h

Procedure:
Sodium hydride (20.0 mg, 0.50 mmol) was added to a mixture of 4-[3-chloro-5-(1-chloroethyl)-6-methoxy-2-methylphenyl]pyridine-2-carbonitrile (from Example 16, Step 3) (90 mg, 0.28 mmol), 4-aminopyrazolo[3,4-d]pyrimidine (from Acros Organics) (57 mg, 0.42 mmol) in N,N-dimethylformamide (4 mL) and the reaction was stirred at 30° C. overnight. The mixture was treated with water and then filtered to provide the desired product. LCMS calculated for C21H19ClN7O (M+H)+: m/z=420.1; Found: 420.1
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([CH2:12][C:13]([CH3:15])=O)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C>[CH3:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([N:27]3[CH2:28][CH2:29][N:30]([CH:13]([CH3:15])[CH2:12][C:8]4[C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=5[O:10][CH:9]=4)[CH2:31][CH2:32]3)[CH:26]=1)[N:23]=[CH:22][CH:21]=[CH:20]2
Reactant: COc1cccc2c(CC(C)=O)coc12
Reactant: Cc1cc(N2CCNCC2)c2ncccc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cccc2c(CC(C)N3CCN(c4cc(C)cc5cccnc45)CC3)coc12

Procedure:
6-methyl-8-{4-[2-(7-methoxy-1-benzofuran-3-yl)-1-methylethyl)piperazin-1-yl]quinoline was prepared by generally following the procedure outlined in example 35, step 2, starting from the 1-(7-methoxy-1-benzofuran-3-yl)acetone (204 mg, 1 mmol) and 6-methyl-8-piperazino quinoline (227.0 mg, 1 mmol) in 1,2-dichloroethane (100 ml) and acetic acid (1 ml), sodium triacetoxyborohydride (422 mg, 2 mmol). The product was purified by silica-gel column chromatography by eluting it initially with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a yellow oil. Yield: 40 mg (9%); (M+H): 416; 1HNMR (400 MHz, CDCl3): δ 8.86˜8.79 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 8.02˜7.56 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H), 7.56˜6.80 (m, 7 H), 3.89 (s, 3H), 3.50˜2.60 (m, 11H); 2.50 (s, 3H) 1.12˜114 (d, J=7.0 Hz, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17]([C:19]1([CH2:23][OH:24])[CH2:22][O:21][CH2:20]1)[CH3:18].O>CS(C)=O>[CH2:17]([C:19]1([CH2:23][O:24][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:22][O:21][CH2:20]1)[CH3:18]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCC1(CO)COC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: CCC1(COc2ccc([N+](=O)[O-])cc2)COC1
Temperature: 70 °C
Yield: 98.6 %

Procedure:
To a solution of 4-fluoronitrobenzene (3.76 mL, 35.4 mmol) in DMSO (35 mL) at room temperature was added cesium carbonate (7.09 mL, 89.0 mmol) followed by 3-ethyl-3-oxetanemethanol (4.48 mL, 42.5 mmol). The mixture was heated to 70° C. for 2 hours. After cooling water was added and the resulting precipitate was filtered, washed with water, and dried in a vacuum oven to provide the title compound (8.28 g, 98% yield).
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]([NH:30][C:31](=O)[C:32]([F:35])([F:34])[F:33])=[C:8]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)#[N:3]>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[C:31]1[NH:30][C:7]2[C:8]([CH:10]=1)=[CH:9][C:4]([C:2]#[N:3])=[CH:5][CH:6]=2
Reactant: N#Cc1ccc(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(C(F)(F)F)cc2c1
Temperature: 25 °C
Yield: 108.7 %

Procedure:
({5-Cyano-2-[(trifluoroacetyl)amino]phenyl}methyl)(triphenyl)phosphonium chloride (Intermediate 2, 50.41 g, 95 mmol) was heated in DMF (180 ml) at 140° C. for 7 h. The mixture was cooled to room temperature and the solvents were evaporated. This residue was combined with the corresponding residue from another experiment (wherein Intermediate 2, 7.9 g, 15.05 mmol was heated in DMF (50 ml) at 155° C. for 2 h). The combined residues were azeotroped with toluene (100 ml×2). The resulting residue was treated with diethyl ether (500 ml) and the precipitate filtered and washed with diethyl ether (100 ml). The filtrate was evaporated and the resulting orange oil (˜60 g) was dissolved in DCM (200 ml) and stirred at room temperature. Iso-hexane was added until the cloudyness remained (˜400 ml) and the mixtured stirred for 3 days. No precipitate was observed so the mixture was evaporated and chromatographed (Biotage 75L, eluting with dichloromethane) to give the title compound as a colourless solid (21.7 g);
Reaction SMILES: [CH3:1][C:2]([OH:26])([CH3:25])[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][CH:6]=1.C(O[K])=O>O.C1COCC1.[Pd]>[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][C:2]([CH3:25])([OH:26])[CH3:1])=[CH:6][CH:7]=3)[N:12]=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 45 °C
Reaction time: 21 h
Yield: 97.6 %

Procedure:
To a solution of 2-methyl-1-((4-(4-nitrophenoxy)quinolin-7-yl)oxy)propan-2-ol (2.8 g, 7.9 mmol) and HCOOK (4.6 g, 55.3 mmol) in water (4 mL) and THF (12 mL) was added 10% Pd/C (0.24 g). The reaction mixture was stirred at 45° C. for 21 hours and then cooled to room temperature. The mixture was filtered through a Celite pad. The organic phase was separated and washed with brine (20 mL). The aqueous phase was extracted with EtOAc (15 mL). The combined organic phases were concentrated in vacuo and the residue was dried in vacuo at 50° C. overnight to give the title compound as a yellow solid (2.5 g, 97.7%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:40][CH3:41])=[C:8]([NH:31][C:32]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[C:9](/[CH:12]=[CH:13]/[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16](C(C3SC=CC=3C)=O)[N:15]=2)=[CH:10][CH:11]=1.[CH2:42]([NH:44][CH2:45][CH2:46][OH:47])[CH3:43].[I-].[Na+].[OH-].[Na+]>CN(C)C(=O)C.O>[CH2:42]([N:44]([CH2:45][CH2:46][OH:47])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:40][CH3:41])=[C:8]([NH:31][C:32]([C:34]2[S:35][CH:36]=[CH:37][C:38]=2[CH3:39])=[O:33])[C:9](/[CH:12]=[CH:13]/[C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][N:15]=2)=[CH:10][CH:11]=1)[CH3:43]
Reactant: COc1c(OCCCCl)ccc(/C=C/c2nn(C(=O)c3sccc3C)c3ccccc23)c1NC(=O)c1sccc1C
Reactant: CCNCCO
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(CCO)CCCOc1ccc(/C=C/c2n[nH]c3ccccc23)c(NC(=O)c2sccc2C)c1OC
Temperature: 90 °C
Reaction time: 3 h
Yield: 34.7 %

Procedure:
A solution of (E)-N-(3-(3-chloropropoxy)-2-methoxy-6-{2-[1-(3-methylthiophene-2-carbonyl)-1H-indazol-3-yl]vinyl}phenyl)-3-methylthiophene-2-carboxamide (0.30 g, 0.49 mmol) obtained in Step 4 in N,N-dimethylacetamide (6.0 mL) was added with 2-(ethylamino)ethanol (0.97 mL, 9.9 mmol) and sodium iodide (0.11 g, 0.74 mmol), followed by stirring at 90° C. for 3.0 hours. After cooling the reaction mixture to room temperature, aqueous sodium hydroxide solution (2.0 mol/L, 3.0 mL) was added and the mixture was stirred for 1.0 hour. The mixture was added with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [amino-silica gel chromatorex (trade mark) NH, manufactured by Fuji Silysia; hexane/ethyl acetate=60/40 to ethyl acetate] and crystallized from hexane/ethyl acetate (1/1) to obtain Compound 339 (91 mg, 34%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][C:13]=1[CH3:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][N:23]1[C:32]2[NH:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=3[NH:28][CH2:27][C:26]=2[CH:25]=[N:24]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[C:1]([O:5][C:6](=[O:7])[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([N:28]2[CH2:27][C:26]3[CH:25]=[N:24][N:23]([CH3:22])[C:32]=3[NH:31][C:30]3[CH:33]=[CH:34][CH:35]=[CH:36][C:29]2=3)=[O:18])=[CH:14][C:13]=1[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C(=O)O)ccc1OCCCC(=O)OC(C)(C)C
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3ccccc32)ccc1OCCCC(=O)OC(C)(C)C
Yield: 18 %

Procedure:
WSCD (391 mg, 2.06 mmol) and DMAP (133 mg, 1.09 mmol) were added to a solution of 4-(3-tert-butoxycarbonyl-propoxy)-3-methyl-benzoic acid from Example E42 (275 mg, 0.94 mmol) and 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (191 mg, 0.95 mmol) in dichloromethane (30 ml) and triethylamine (0.28 ml, 2.01 mmol). The mixture was heated at reflux for 72 h, washed with 0.3M KHSO4, saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (80 mg, 18%).
Reaction SMILES: [CH3:1][C:2]1[CH:17]=[CH:16][C:5]([CH:6]([N:13]=[C:14]=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[NH3:18]>CCOCC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([NH:13][C:14]([NH2:18])=[S:15])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(C(N=C=S)c2ccccc2)cc1
Reactant: N
Solvent: CCOCC
Product: Cc1ccc(C(NC(N)=S)c2ccccc2)cc1

Procedure:
A solution of 22 g (0.092 mole) of 4-methylbenzhydrylisothiocyanate in 250 ml of dry ether at 0° is treated with anhydrous NH3 for 3 hours while stirring. The mixture is stirred an additional 1.5 hours at 0° to 10° C during which time the crude product precipitates as a white solid. Filtration and washing with Et2O affords the product; mp 167°-8° C.