Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[OH-].[K+].S(O[CH:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:21])(C1C=CC(C)=CC=1)(=O)=O.O>O1CCOCC1>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][CH:20]([CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OC(C)COCc2ccccc2)cc1
Reactant: OCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(COCc1ccccc1)OCCCCO
Temperature: 102 °C
Reaction time: 4 h
Yield: 58.3 %

Procedure:
HO(CH2)4OH (37 g), potassium hydroxide (23 g) and dioxane (200 ml) were charged into a four necked flask and heated to an internal temperature of 102° C. to dissolve potassium hydroxide. A solution of TsOCH(CH3)CH2OCH2Ph (63.7 g) obtained in Example 2-1 in dioxane (65 ml), was dropwise added over a period of 1 hour and stirred for 4 hours. The mixture was left to cool, then added to water (350 ml) and extracted three times with dichloromethane (100 ml). The organic layer was washed with water (20 ml). It was dried over magnesium sulfate, filtered and then concentrated by an evaporator to obtain a crude product (52 g). It was purified by silica gel column chromatography to obtain the above-identified compound (27.6 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:18][C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[O:20])[S:9][C:10]=1[C:11]([C:13]1[CH:17]=[CH:16][NH:15][CH:14]=1)=[O:12].[H-].[Na+].[CH3:29]I.O>CN(C=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH:18][C:19]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)=[O:20])[S:9][C:10]=1[C:11]([C:13]1[CH:17]=[CH:16][N:15]([CH3:29])[CH:14]=1)=[O:12]
Reactant: CI
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)c2cc[nH]c2)s1)c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1ccc(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Compound 353 (105 mg, 0.288 mmol) was dissolved in DMF (1.4 mL), and 55% sodium hydride (25.3 mg, 0.576 mmol) and methyl iodide (0.0179 mL, 0.288 mmol) were added thereto, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:1) to afford the entitled Compound 354 (97.0 mg, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=O)=[CH:5][CH:4]=1.CC1C=CC(N=[CH:21][C:22]2[C:23]([NH2:31])=[CH:24][C:25]3[O:29][CH2:28][O:27][C:26]=3[CH:30]=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C:8]3[C:9]([C:10]=2[CH:11]=1)=[N:31][C:23]1[CH:24]=[C:25]2[O:29][CH2:28][O:27][C:26]2=[CH:30][C:22]=1[CH:21]=3
Reactant: Cc1ccc(N=Cc2cc3c(cc2N)OCO3)cc1
Reactant: COc1ccc2c(c1)C(=O)CC2
Product: COc1ccc2c(c1)-c1nc3cc4c(cc3cc1C2)OCO4
Yield: 44.6 %

Procedure:
Using the procedure of Example 1, 6-methoxyindan-1-one (162 mg, 1 mmol) is reacted with 6[[(4-methylphenyl)imino]methyl]-1,3-benzodioxol-5-amine (255 mg, 1 mmol) to yields 7-methoxy-10H-1,3-dioxolo[4,5-g]indeno[1,2-b]quinoline (130 mg, 44.6% of theory).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([C:22](=O)[CH2:23][CH2:24][CH3:25])[C:17](OCC)=[O:18])=[CH:11][CH:10]=1)#[N:2].[CH2:27]([O:30][CH:31]1[CH2:36][CH2:35][CH:34]([NH:37][C:38]2[NH:42][CH:41]=[N:40][N:39]=2)[CH2:33][CH2:32]1)[CH:28]=[CH2:29]>>[O:18]=[C:17]1[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:10][CH:11]=2)=[C:22]([CH2:23][CH2:24][CH3:25])[N:39]2[N:40]=[CH:41][N:42]=[C:38]2[N:37]1[CH:34]1[CH2:33][CH2:32][CH:31]([O:30][CH2:27][CH:28]=[CH2:29])[CH2:36][CH2:35]1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OCC
Reactant: C=CCOC1CCC(Nc2nnc[nH]2)CC1
Product: C=CCOC1CCC(n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc23)CC1
Temperature: 250 °C
Reaction time: 0.33 h
Yield: 23.6 %

Procedure:
A mixture of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (4 g) and N-[4-(prop-2-en-1-yloxy)cyclohexyl]-4H-1,2,4-triazol-3-amine (1.3 g) was stirred at 250° C. for 20 min under microwave irradiation. The obtained reaction mixture was purified by silica gel column chromatography to give the title compound as a colorless solid (0.7 g, 24%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.C1C(=O)N([Br:16])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:8][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(Cl)nn1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ccc(CBr)nn1
Temperature: 25 °C
Yield: 26.5 %

Procedure:
A solution of 3-Chloro-6-methyl-pyridazine 10A (5.12 g, 40 mmol) and NBS (8.90 g, 50 mmol) in CCl4 (300 mL) was refluxed under light (200 w) for 4 hours. The reaction mixture was cooled to room temperature and filtered. The solid residue was washed thoroughly with Cl4C and filtered. The filtrates was combined, concentrated to small volume and loaded on to a silica gel column. The column was eluted with 50% hexane/ethyl acetate to give 2.2 g of desired product (10B) which was dried in vacuum and used immediately in next step. ESI-MS:m/z 206.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:12][Mg]Cl.O1CCCC1.C(O)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9]([CH3:10])=[CH2:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(F)c(Br)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)c1ccc(F)c(Br)c1
Yield: 41.6 %

Procedure:
1-(3-Bromo-4-fluorophenyl)ethanone (5.0 g, 23.0 mmol) was dissolved in toluene (100 mL), a 3.0 M methylmagnesium chloride-tetrahydrofuran solution (11.5 mL, 34.6 mmol) was added dropwise with stirring under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. Subsequently, acetic acid (1 mL) was added with stirring under ice cooling, and the mixture was stirred with heating to reflux for 4 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added with stirring under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1, v/v) to give the title compound (2.06 g; yield, 42%) as a colorless oily substance.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([O:17][CH3:18])[CH:8]=[C:9]([CH:12]3OCC[O:13]3)[CH:10]=2)[O:5][C:4]([CH3:20])([CH3:19])[CH:3]=1.C(=O)=O.C([Li])CCC.S([Cl:33])(C)(=O)=O>C1COCC1>[Cl:33][C:2]1[C:11]2[C:6](=[C:7]([O:17][CH3:18])[CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[O:5][C:4]([CH3:20])([CH3:19])[CH:3]=1
Reactant: COc1cc(C2OCCO2)cc2c1OC(C)(C)C=C2Br
Reactant: CS(=O)(=O)Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(C=O)cc2c1OC(C)(C)C=C2Cl
Temperature: 0 °C

Procedure:
366 mg of 4-bromo-6-[1,3]dioxolan-2-yl-8-methoxy-2,2-dimethyl-2H-chromene (1.07 mmol) was dissolved in 4 ml of abs. THF and treated at −78° (dry-ice bath) with 0.735 ml n-butyl lithium (1.6M, n-hexane, 1.1 eq.). 15 min. later, 0.114 ml of mesyl chloride (1.1 eq.) was added and the dry-ice bath replaced by an ice-bth. After 30 min. the reaction mixture was poured onto crushed ice/concentrated HCl and vigorously stirred to cleave the acetal. Twofold extraction with ether, washing with NaCl, drying over magnesium sulfate, and evaporation of the solvents left a crude product which was purified by flash chromatography (SiO2 with n-hexane/AcOEt=87/13) to yield 77 mg of the title compound as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[C:7]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1Br
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ncccc1OCC1CC1
Temperature: 80 °C

Procedure:
2-bromo-pyridin-3-ol Compound 1a (6.4 g, 36.8 mmol) was dissolved into DMF (100 mL), then bromomethyl-cyclopropane Compound 1b (5.0 g, 37 mmol) and K2CO3 (7.5 g, 54.3 mmol) were added. The mixture was stirred and heated at 80° C. for 2 hrs. Excess DMF was removed on a rotary evaporator. The brown residue was mixed with Et2O (150 mL), then washed with H2O and dried over Na2SO4. The solvent was evaporated from the dry solution to provide 2-bromo-3-cyclopropylmethoxy-pyridine Compound 1c (7.04 g, yield 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12].CCCCCC>C(OCC)(=O)C>[C:2]1([NH:8][C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([NH2:13])=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1
Reactant: NC(=O)c1ccccc1N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NC(=O)c1ccccc1Nc1ccccc1
Yield: 69.7 %

Procedure:
Following the general procedure, bromobenzene (55 μL, 0.5 mmol) was coupled with 2-aminobenzamide (102 mg, 0.75 mmol) with the reaction time of 15 h. Chromatography on silica gel column with 1:1 hexane:ethyl acetate gave 74 mg (70%) of the title compound as a white solid.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:17][C:18]([C:20]1[S:21][C:22]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C(=O)[O-])(C)C.Cl.O1CCOCC1>CO>[NH2:5][CH2:9][CH:10]([NH:17][C:18]([C:20]1[S:21][C:22]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:23][CH:24]=1)=[O:19])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cn1nccc1-c1ccc(C(=O)NC(CN(C(=O)[O-])C(C)(C)C)c2ccccc2)s1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cn1nccc1-c1ccc(C(=O)NC(CN)c2ccccc2)s1
Reaction time: 4 h
Yield: 107.6 %

Procedure:
1,1-dimethylethyl[2-({[5-(1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-2-phenylethyl]carbamate (56 mg, 0.131 mmol) was dissolved in MeOH (2 mL) and treated with excess 4M HCl in dioxane (656 μL, 2.62 mmol). After 4 h, the solution was concentrated affording the title compound (46 mg, quant.) as a yellow solid: LC-MS (ES) m/z 327 (M+H)+, 1H NMR (d6-DMSO, 400 MHz) δ 9.46 (d, J=8.2 Hz, 1H), 8.27 (bs, 1H), 8.20 (d, J=4.0 Hz, 1H), 7.48-7.75 (m, 3H), 7.37-7.40 (m, 2H), 7.31-7.33 (m, 1H), 6.58 (d, J=1.9 Hz, 1H), 5.21-5.30 (m, 1H), 3.97 (s, 3H), 3.36-3.41 (m, 1H), 3.19-3.25 (m, 1H).
Reaction SMILES: [CH2:1]([C:8]1[C:9](=[O:16])[NH:10][NH:11][C:12]=1[CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>O1CCCC1.C(O)(=O)C>[C:17]([N:11]1[C:12]([CH:13]([CH3:14])[CH3:15])=[C:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:16])[NH:10]1)(=[O:19])[CH3:18]
Reactant: CC(C)c1[nH][nH]c(=O)c1Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)n1[nH]c(=O)c(Cc2ccccc2)c1C(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 77 %

Procedure:
4-Benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.50 g) was dissolved in tetrahydrofuran (6.0 g) at room temperature. Acetic anhydride (0.708 g) and acetic acid (0.0208 g) was added to the solution successively. After the reaction mixture was stirred at room temperature for 15 hours, the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (The product was eluted with dichloromethane at first, and then n-hexane/ethyl acetate=4/1) to give 1-acetyl-4-benzyl-1,2-dihydro-5-isopropyl-3H-pyrazol-3-one (1.38 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.O[Li].O.Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 120 h
Yield: 91.1 %

Procedure:
A mixture of methyl 1-(4-fluorophenyl)-indole-5-carboxylate 1m (0.58 g, 2.15 mmol) and LiOH.H2O (0.36 g, 8.6 mmol) in THF (15 mL) and H2O (10 mL) was stirred at room temperature for 5 days. Aqueous 10% HCl solution was added to the reaction mixture to adjust pH=3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 1n (0.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:32][O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:30]=O)=[O:27])([CH3:24])([CH3:23])[CH3:22].C([BH3-])#N.[Na+].C(O)(=O)C>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:12][O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:10][NH:11][CH2:30][CH:29]([NH:28][C:26]([O:25][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:27])[CH2:32][O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)COCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CN)COCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CNC[C@@H](COCc1ccccc1)NC(=O)OC(C)(C)C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.1 %

Procedure:
The product from Example 17B (0.35 g, 1.25 mmol) and the product from Example 17A (0.36 g, 1.29 mmol) in absolute ethanol (12 mL) were treated with sodium cyanoborohydride (94 mg, 1.50 mmol) and a catalytic amount of acetic acid. The resulting mixture was stirred at ambient temperature overnight. The mixture was partitioned between water (40 mL) and ethyl acetate (3×40 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel (hexanes:ethyl acetate, 1:1) to provide the title compound (0.15 g, 22%).
Reaction SMILES: ClC1C=CC2C3C(=CN=CC=3)C(C=C)OC=2C=1.OC[C@@H]([N:25]1[C:33](=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]1=[O:35])CC(C)C.C(P(C(C)(C)C)C1(C(C)C)CC(C(C)C)=CC(C(C)C)=C1C1C=CC=CC=1)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:26]1(=[O:35])[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:33](=[O:34])[NH:25]1
Reactant: CC(C)C[C@@H](CO)N1C(=O)c2ccccc2C1=O
Agent: [Pd+2]
Agent: C=CC1Oc2cc(Cl)ccc2-c2ccncc21
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21
Temperature: 80 °C
Yield: 26.8 %

Procedure:
To a stirred suspension of 8-chloro-5-vinyl-5H-chromeno[3,4-c]pyridine (0.2 g, 0.821 mmol), (5)-2-(1-hydroxy-4-methylpentan-2-yl)isoindoline-1,3-dione (0.609 g, 2.462 mmol), 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (0.209 g, 0.492 mmol), and cesium carbonate (0.401 g, 1.231 mmol) in toluene (25 mL) was added palladium (II) acetate (0.055 g, 0.246 mmol). Nitrogen gas was bubbled through the mixture for 5 min, and then the reaction mixture was heated to 80° C. for 14 h. The reaction was diluted with ethyl acetate (25 mL) and filtered through celite. The filtrate was washed with water (1×20 mL) and brine (1×20 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (60% ethyl acetate in hexanes) to afford 24(2S)-4-methyl-1-(5-vinyl-5H-chromeno[3,4-c]pyridin-8-yloxy)pentan-2-yl)isoindoline-1,3-dione (0.3 g, 0.660 mmol, 40% yield for three steps). LCMS (ESI) m/e 455.2 [(M+H)+, calcd for C28H27N2O4 455.2]; LC/MS retention time (Method C): tR=2.16 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][C:15]([OH:17])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]>O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10])[C:15](=[O:17])[CH2:14][CH2:13]2
Reactant: COc1cc(CCC(=O)O)cc(OC)c1OC
Solvent: O
Product: COc1cc2c(c(OC)c1OC)C(=O)CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
A mixture of 3-(3,4,5-trimethoxyphenyl)propionic acid (9.40 g, 39.1 mmol) and polyphosphoric acid (50 g) was stirred for 2 hours at 80° C. To the reaction mixture was added water, which was subjected to extraction with ethyl acetate. The extract solution was washed with brine, which was dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was recrystallized from ethyl acetate/isopropyl ether to give 7.71 g (yield 89%) of the above-titled compound, m.p. 114-115° C.
Reaction SMILES: [CH3:1][Mg]I.[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12])(=[O:7])=[O:6]>C1COCC1>[CH3:4][S:5]([C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH3:1])[CH:13]=[CH:14][CH:15]=1)(=[O:6])=[O:7]
Reactant: CS(=O)(=O)c1cccc(C=O)c1
Reactant: C[Mg]I
Solvent: C1CCOC1
Product: CC(O)c1cccc(S(C)(=O)=O)c1
Temperature: 0 °C
Yield: 32.5 %

Procedure:
Methylmagnesium iodide (3M in THF, 13.2 mL, 4.4 mmol) was added dropwise via syringe at 0° C. to 3-(methylsulfonyl)benzaldehyde (0.74 g, 4.0 mmol) in THF (15 mL). The resulting reaction mixture was stirred at 0° C. until no more conversion to product occurred (monitored by GC-MS). The reaction was quenched with saturated ammonium chloride, the aqueous phase was extracted with EtOAc and the organic phase was washed with saturated sodium bicarbonate, brine, dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash column chromatography on silica (EtOAc:hexane 1:4) to give the title compound (260 mg) that was used in the next step without any further purification (approximate purity 50%).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:5]=2[CH:6]=1.[N:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1.CCOC(C)=O.CCOCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[N:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:3][C:4]3[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[C:5]=3[CH:6]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccncc1
Reactant: O=C1CCCc2sc(Br)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1CCCc2sc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.9 %

Procedure:
In a 250 mL round bottomed flask were placed 2-bromo-6,7-dihydro-1-benzothiophen-4(5H)-one (3.69 g, 16.0 mmol), pyridine-4-boronic acid (3.0 g, 24.5 mmol), and then suspended in 1,4-dioxane (50 mL). To the mixture were added cesium carbonate (18.7 g, 57.3 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (910 mg, 1.1 mmol) and water (50 mL). The mixture was refluxed for 16 h with vigorous stirring. The mixture was allowed to cool to rt and was then diluted with EtOAc (100 mL), which was washed with water (50 mL) and brine (50 mL). Insoluble materials were removed by filtration through Celite pad. The combined aqueous phase was extracted with EtOAc (50 mL). The combined organic phase was dried over anhydrous MgSO4 and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by prepacked silica gel (120 g) column chromatography eluted with a 50% to 100% EtOAc/hexane. Concentration of appropriate fractions afforded colorless crystalline solid which was suspended in ether (50 mL) and then stirred for 15 min and then ultra-sonicated. The remaining crystalline materials were collected by filtration to obtain the title compound (2.6 g; 71%). From mother liquid, 2nd crop of the title compound (760 mg; 21%) has been obtained. LCMS: (FA) ES+ 230. 1H NMR (300 MHz, d6-DMSO) δ: 8.57 (dd, 2H), 7.95 (s, 1H), 7.67 (dd, 2H), 3.08 (2H, t), 2.50-2.54 (m, 2H), 2.10-2.19 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1(C)C=CC=CC=1.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.CCOC(C)=O>[C:10]1([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=2)[CH:7]=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cncc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
A mixture of commercially available 5-bromonicotinaldehyde (5.070 g; 26.43 mmol), phenylboronic acid (4.934 g; 39.65 mmol), and Pd(PPh3)4 (1.527 g; 1.32 mmol) in toluene (65 ml) and aq. 2 M Na2CO3 (59 ml) was heated to reflux, under nitrogen, for 2.5 h. After cooling to rt, water and AcOEt were added. The separated aq. layer was further extracted with AcOEt. The mixed organic layers were washed with brine, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (heptane/AcOEt=1/1) afforded 5-phenylnicotinaldehyde as a yellow oil. LC-MS (conditions A): tR=0.61 min.; [M+H]+: 184.48 g/mol.
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:30][CH3:31])=[C:24]([C:27](=[O:29])[NH2:28])[CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[CH:12][C:11]=2[C:32]([F:35])([F:34])[F:33])C=CC=CC=1.[CH3:37][NH2:38]>>[C:27]([C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][C:23]=1[O:30][CH3:31])[N:20]=[CH:19][CH:18]=[C:17]2[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([NH:38][CH3:37])=[O:7])=[C:11]([C:32]([F:34])([F:33])[F:35])[CH:12]=1)(=[O:29])[NH2:28]
Reactant: CN
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(C(F)(F)F)c3)c2cc1C(N)=O
Product: CNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(C(N)=O)cc23)cc1C(F)(F)F
Reaction time: 0.17 h

Procedure:
After adding [4-(6-carbamoyl-7-methoxy-4-quinolyl)oxy-2-trifluoromethylphenyl]carbamic acid phenyl ester (25 mg) to methylamine 2N tetrahydrofuran solution (1.00 ml), the mixture was stirred for 10 minutes. The precipitated crystals were filtered out and washed with tetrahydrofuran to obtain the title compound (10 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[CH:22]=[N:23]O)=[C:9]1[CH3:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OC(=O)C)(=O)C.CCOC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=2)[C:10]([S:18][C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=2)[C:22]#[N:23])=[C:9]1[CH3:28])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Sc2cccc(C=NO)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Product: Cc1c(Sc2cccc(C#N)c2)c2ccc(Cl)cc2n1Cc1ccccc1
Temperature: 135 °C

Procedure:
3-(1-Benzyl-6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzaldehyde oxime from the previous step was dissolved in acetic anhydride (0.500 mL) and the reaction was heated to 135° C. overnight. The reaction mixture was diluted with EtOAc then concentrated and purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.