Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]([CH:12]2[C:16](=O)[CH2:15][N:14]([CH3:18])[C:13]2=[O:19])[CH:11]=1.O.Cl>ClC1C=CC=CC=1Cl.CCCCCC>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:16]3[CH2:15][N:14]([CH3:18])[C:13](=[O:19])[C:12]=3[C:10]=2[CH:11]=1
Reactant: CN1CC(=O)C(c2cc(Cl)ccc2Oc2ccccc2)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CN1CC2=C(C1=O)c1cc(Cl)ccc1Oc1ccccc12
Temperature: 85 °C
Reaction time: 0.5 h

Procedure:
Anhydrous aluminium chloride (5 g) was added to a reaction mixture containing 3-(5-chloro-2-phenoxyphenyl)-1-methylpyrrolidine-2,4-dione (1 g) in 1,2-dichlorobenzene (5 mL) at ambient temperature. The reaction mixture was stirred at about 85° C. for about 2 hours and 30 minutes, then cooled to ambient temperature. A mixture of water and concentrated hydrochloric acid (50 mL:5 mL) was added dropwise. The contents were stirred for about 30 minutes. Hexane (10 mL) was added. The contents were stirred for about 15 minutes, filtered, washed with hexane (10 mL) and dried in air at about 30° C. for about 15 hours followed by further drying at about 50° C. under reduced pressure to obtain 11-chloro-2-methyl-2,3-dihydro-1H-dibenzo [2,3:6,7]oxepino[4,5-c]pyrrol-1-one.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22]CN1C(OCC1C=CC=CC=1)=O.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCCCC1CC[N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1>>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:35][CH3:36])[N:6]2[CH2:16][CH2:17][CH2:18][CH2:19][CH:24]1[CH2:23][CH2:22][N:69]([C:72]([O:74][CH2:75][C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)=[O:73])[CH2:68][CH2:67]1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCBr)CC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3C(=O)OCc3ccccc3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 31 from 2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine trifluoroacetate and phenylmethyl 4-(4-bromobutyl)-1-piperidinecarboxylate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[N:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH2:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[N:4][N:3]=2)=[CH:21][CH:22]=1
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: Cc1ccc(N)cc1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.384 g (1.5 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine and 0.482 g (4.5 mmol) p-toluidine is stirred for 1.5 h at 90° C. under a nitrogen atmosphere. The reaction mixture is then distributed between 30 ml acetate and 20% aqueous potassium carbonate solution. The organic phase washed with water and dried over anhydrous sodium sulfate is evaporated and the residue purified on silica gel by flash chromatography using acetate/methanol mixtures (50:1 to 9:1). Title compound is obtained after crystallization of the product-containing fractions from acetonitrile and drying under HV; m.p. 152-153° C.; ESI-MS: (M+H)+=327.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([I:11])=[CH:9][N:8]([CH2:12][C:13]3[N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:16]4[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=4[N:14]=3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH4+:28].[OH-]>CO>[I:11][C:10]1[C:3]2[C:2]([NH2:28])=[N:7][CH:6]=[N:5][C:4]=2[N:8]([CH2:12][C:13]2[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:16]3[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=3[N:14]=2)[CH:9]=1
Reactant: Clc1ncnc2c1c(I)cn2Cc1nc2ccccc2n1-c1ccccc1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncnc2c1c(I)cn2Cc1nc2ccccc2n1-c1ccccc1
Yield: 42 %

Procedure:
A solution of 4-chloro-5-iodo-7-(1-phenyl-1H-benzoimidazol-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (1.0 g, 2 mmol) in NH4OH (5 mL) and MeOH (10 mL) was stirred at 90° C. in a sealed tube overnight. Then the mixture was filtered. The precipitate was purified by P-TLC to give 140 (0.4 g, yield 42%) as a white solid. LCMS (ESI), M+H+=465.04 1HNMR (400 MHz, DMSO) δ 5.518 (s, 2H), 6.574 (s, 2H), 7.128 (s, 2H), 7.210-7.232 (m, 2H), 7.343 (s, 1H), 7.521-7.622 (m, 6H), 7.968 (s, 1H)
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][Mg]Br>C1COCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]([OH:12])([CH3:13])[CH3:11]
Reactant: CC(=O)c1c(F)ccc(F)c1F
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(C)(O)c1c(F)ccc(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(2,3,6-trifluorophenyl)ethanone (1.74 g, 10 mmol) in THF (10 mL) was added methyl magnesium bromide (7 mL, 21 mmol) at 0° C. The mixture was stirred at 0° C. for 1 hour. The reaction was quenched by addition of saturated aqueous ammonium chloride and was then extracted with EtOAc. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to afford 2-(2,3,6-trifluorophenyl)propan-2-ol. (74).
Reaction SMILES: [Br: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=[O:12].[CH3:13][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Br: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([OH:12])[CH3:13]
Reactant: C[Mg]Br
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)C(=O)Nc2ccc(Br)cc21
Temperature: 25 °C
Yield: 28.7 %

Procedure:
A solution of 5-bromoisatin (5.0 g, 22 mmol) in dry THF (50 cm3) under N2 was cooled to 0° C. and treated drop-wise with methyl magnesium bromide (3M in diethylether, 14.7 cm3, 44 mmol) and the mixture was allowed to warm up-to room temperature. The reaction was poured into sat. ammoniurn chloride solution, then extracted into EtOAc (×3). The combined organic layers were then washed with water, brine, dried (MgSO4) and evaporated. The residue was then purified by column chromatography (SiO2, EtOAc: hexane, gradient elution) to afford 5-bromo-3-hydroxy-3-methyl-1,3-dihydro-indol-2-one (1.53 g, 6.32 mmol, 29%): 1H NMR (DMSO-d6) δ 1.38 (s, 3H), 5.99 (s, 1H), 6.77 (d, 1H, J=1.7 Hz), 7.38 (s, 1H, br); MS ((−) ESI) m/z 240/242 (M)−.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1.[CH:26]([S:28]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:30])=[O:29])=[CH2:27].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>[C:31]1([S:28]([CH:26]=[CH:27][C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[N:14]([CH2:15][CH2:16][CH2:17][O:18][CH:19]([CH3:21])[CH3:20])[C:13]([CH2:22][O:23][CH2:24][CH3:25])=[N:12][C:7]=4[CH:8]=[N:9][C:10]=3[CH:11]=2)(=[O:30])=[O:29])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(C=CS(=O)(=O)c4ccccc4)ccc3c2n1CCCOC(C)C
Temperature: 100 °C
Yield: 49.4 %

Procedure:
7-Bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline (1.00 g, 2.46 mmol), phenyl vinyl sulfone (0.852 g, 5.06 mmol), palladium(II) acetate (12 mg, 0.05 mmol), and tris(2-tolyl)phosphine (32 mg, 0.10 mmol) were added to a pressure tube. Triethylamine (1.37 mL, 9.84 mmol) and acetonitrile (5 mL) were added. The tube was flushed with nitrogen, sealed with a TEFLON plug and heated at 100° C. for 96 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was initially purified by flash column chromatography (silica gel, eluting with a gradient of 50%-100% ethyl acetate in hexanes, followed by a gradient of 2%-6% methanol in ethyl acetate). Recrystallization of the resulting solid from acetonitrile provided 0.600 g 7-(2-benzenesulfonylvinyl)-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline as a yellow crystalline solid.
Reaction SMILES: [CH2:1]([CH:4]1[C:17]2[C:12](=[C:13]([Cl:18])[CH:14]=[CH:15][CH:16]=2)[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[O:5]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH:28]12[CH2:37][CH:32]3[CH2:33][CH:34]([CH2:36][CH:30]([CH2:31]3)[CH:29]1[N:38]=[C:39]=[O:40])[CH2:35]2>C(Cl)Cl>[CH:30]12[CH2:36][CH:34]3[CH2:33][CH:32]([CH2:37][CH:28]([CH2:35]3)[CH:29]1[NH:38][C:39]([N:9]1[CH2:10][CH2:11][C:6]3([C:12]4[C:17](=[CH:16][CH:15]=[CH:14][C:13]=4[Cl:18])[CH:4]([CH2:1][CH:2]=[CH2:3])[O:5]3)[CH2:7][CH2:8]1)=[O:40])[CH2:31]2
Reactant: C=CCC1OC2(CCNCC2)c2c(Cl)cccc21
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1OC2(CCN(C(=O)NC3C4CC5CC(C4)CC3C5)CC2)c2c(Cl)cccc21
Reaction time: 19 h
Yield: 69.3 %

Procedure:
To a stirred solution of 3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine] (0.0190 g), and DIEA (0.5 mL) in CH2Cl2 (2 mL) was added 2-adamantyl isocyanate (0.0138 g, 0.0778 mmol) at rt. After 19 h, the solvents were removed in vacuo and the residue was purified by reversed-phase HPLC (Phenomenex® Luna 5μ C18(2) 100A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 4 min, flow rate 25 mL/min) to afford N-(2-adamantyl)-3-allyl-7-chloro-3H-spiro[isobenzofuran-1,4′-piperidine]-1′-carboxamide (0.0220 g, 97%). LC-MS Method 1 tR=2.33 min, m/z 443, 441 (MH+); 1H NMR (400 MHz, CDCl3) δ=7.24-7.20 (m, 2H), 7.09-7.05 (m, 1H), 5.87-5.77 (m, 1H), 5.25 (t, J=5.7 Hz, 1H), 5.15-5.08 (m, 2H), 3.98 (br s, 1H), 3.94-3.88 (m, 2H), 136-3.28 (m, 2H), 2.66-2.38 (m, 4H), 1.95-1.25 (m, 16H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Br[C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:25])[CH3:24])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 42.5 °C

Procedure:
Ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (32.25 g) of Formula (I) is dissolved in N,N-dimethylformamide (258 ml) at room temperature. Tert.-butyl 2-bromoisobutyrate (38.47 g) and anhydrous potassium carbonate (47.61 g) are added and the resulting suspension is heated to 40-45° C. for 20-25 hrs. The reaction mass is cooled to 30-32° C. and it is added slowly to water. The resulting slurry is stirred at 25-30° C. for about one and a half hours. The product is filtered, washed with water and dried under reduced pressure. Yield: 50 g (93.37%), water content <1.0% w/w; Chromatographic purity (HPLC) >98%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[N:10]([C:22]([CH:25]=O)=[CH:23][CH:24]=3)[N:11]=[C:12]([CH:19]([CH3:21])[CH3:20])[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.Cl.[NH2:28]O.C([O-])=O.[Na+]>C(O)=O>[C:25]([C:22]1[N:10]2[N:11]=[C:12]([CH:19]([CH3:20])[CH3:21])[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9]2=[CH:24][CH:23]=1)#[N:28]
Reactant: CCOC(=O)c1c(C(C)C)nn2c(C=O)ccc2c1-c1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: CCOC(=O)c1c(C(C)C)nn2c(C#N)ccc2c1-c1ccc(F)cc1
Yield: 72.7 %

Procedure:
A solution of ethyl 4-(4-fluorophenyl)-7-formyl-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate (200 mg, 0.564 mmol), hydroxylamine hydrochloride (51.0 mg, 0.734 mmol), and sodium formate (69.1 mg, 1.02 mmol) in formic acid (2 mL) were refluxed for 2 h. The mixture was evaporated to give a green gum. The gum was partitioned between ethyl acetate (10 mL) and saturated sodium bicarbonate (5 mL). The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and evaporated to give a green gum. Flash silica gel column chromatography eluting with ethyl acetate-hexane=1-10 to 1-8 gave ethyl 7-cyano-4-(4-fluorophenyl)-2-isopropylpyrrolo[1,2-b]pyridazine-3-carboxylate as an yellow crystal (144 mg, 72.6%).
Reaction SMILES: [C:1]([C:4]1[N:9]=[C:8]([C:10]2[CH2:15][CH2:14]C(C)(C)[CH2:12][CH:11]=2)[C:7]([NH:18][C:19]([C:21]2[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=2)=[O:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:28][Mg+].[Br-].[CH2:31]1[CH2:35]OC[CH2:32]1>>[CH3:32][CH:31]1[CH2:35][CH2:14][CH2:15][C:10]([C:8]2[C:7]([NH:18][C:19]([C:21]3[NH:22][C:23]([C:26]#[N:27])=[CH:24][N:25]=3)=[O:20])=[CH:6][CH:5]=[C:4]([C:1]([OH:3])([CH3:28])[CH3:2])[N:9]=2)=[C:11]1[CH3:12]
Reactant: CC(=O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1
Reactant: C1CCOC1
Reactant: C[Mg+]
Agent: [Br-]
Product: CC1=C(c2nc(C(C)(C)O)ccc2NC(=O)c2ncc(C#N)[nH]2)CCCC1C
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of 5-cyano-1H-imidazole-2-carboxylic acid [6-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-pyridin-3-yl]-amide (as prepared in the previous step, 6 mg, 0.016 mmol) in THF (1 mL) was added MeMgBr (3 M in THF, 41 μL, 0.072 mmol). After 20 min another 2.5 equivalents of MeMgBr was added and the reaction was allowed to warm to room temperature and quenched with saturated aqueous NaHCO3 (2 mL). The slurry was filtered through a 5-g Sep-Pak SPE column and concentrated in vacuo. The crude product was purified by silica gel chromatography (250-mg, 3-mL Supelco Si tube, gradient CHCl3-2% CHCl3-MeOH) to afford 2.6 mg (43%) of the title compound as a white solid. 1H-NMR (CD3OD; 400 MHz): δ 8.44 (d, 1H, J=8.5 Hz), 7.90 (s, 1H), 7.42 (d, 1H, J=8.5 Hz), 5.86 (s, 1H), 2.39-2.37 (m, 2H), 1.99-1.94 (m, 2H), 1.51 (t, 1H, J=6.3 Hz), 1.43 (s, 6H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C21H25N5O2, 380.2 (M+H), found 380.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:4][C:3]=1C1(C=CC=CC1)CO.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl>>[Cl:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[NH:1][C:27](=[O:33])[O:26][CH:24]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:3]=3[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccc(-c2cccc(Cl)c2)cc1C1(CO)C=CC=CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(-c3cccc(Cl)c3)cc2C(c2ccccc2)O1

Procedure:
Prepared from 1-(4-amino-3′-chloro-biphenyl-3-yl)-benzyl alcohol and triphosgene according to the procedure of Example 9. Off-white solid: mp 177-178° C.; 1H-NMR (DMSO-d6) δ10.5 (s, 1H), 7.68 (dd, 1H, J=8.7, 1.7 Hz), 7.62 (t, 1H, J=1.74 Hz), 7.54-7.5 (m, 1H), 7.48-7.34 (m, 8H), 7.04 (d, 1H, J=8.7 Hz), 6.6 (s, 1H); MS (ESI) m/z 336 ([M+H]+, 30%)
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1Br)[CH3:7].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.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>[CH2:6]([O:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[C:11]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:7]
Reactant: CCOC(=O)c1cccc(OC)c1Br
Reactant: OB(O)c1ccccc1
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(OC)c1-c1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
2M Aqueous sodium bicarbonate (10 mL) was added to a suspension of 2-bromo-3-methoxybenzoic acid ethyl ester (2.06 g, 7.7 mmol), benzeneboronic acid (1.11 g), and tetrakis(triphenylphosphine)palladium(0) (0.30 g) in toluene (35 mL) under a nitrogen atmosphere. The mixture was stirred at 80° C. for 2 hours, poured into water, and extracted with diethyl ether. The organic layer was evaporated, and the residue was chromatographed, eluting with hexane/acetone (3:1) to give a semisolid oil. Recrystallization from diethyl ether/hexane gave 3-methoxy-2-phenylbenzoic acid ethyl ester as colorless crystals (0.69 g, 34%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[C:14]([NH2:18])([CH3:17])([CH3:16])[CH3:15]>C(Cl)Cl>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Br)s1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Br)s1
Yield: 83.4 %

Procedure:
A mixture of 5-bromothiophene-2-carboxylic acid (10.0 g, 48 mmol) and thionyl chloride (3.5 ml, 48 mmol) was boiled under reflux for 3 hrs. Excess of thionyl chloride was removed by distillation under reduced pressure. The residue was taken up in DCM (30 ml) and a solution of tert-butylamine (7.0 g, 96 mmol) in DCM (30 ml) was added with stirring, the temperature of the mixture being kept below 10° C. The resulting solution was stirred at 25° C. for 12 hrs, washed with water (3×20 ml) and dried over MgSO4. The combined washings were basified to pH11 with 5M KOH(aq) and extracted with DCM (3×100 ml) and dried over MgSO4. The combined organic solutions were evaporated under reduced pressure to give the crude product (12.5 g). Recrystallization from (C6H12/CHCl3) gave the pure amide (10.5 g) as a white solid. MS (ES+): 263 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24]CN.C([O-])([O-])=O.[K+].[K+].C[N:36](C=O)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:36][CH2:24][C:23]([CH3:27])([CH3:22])[CH3:28])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CN(C)C=O
Reactant: CC(C)(C)CCN
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C1=Cc2cc(Cl)c(NCC(C)(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Example 7a, Step 2) (0.5 g, 1.54 mmole) and 3,3-dimethylbutylamine (0.13 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil (0.6g, 98%). No further purification was performed: GCMS m/z 391.00 (M+).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]=O)=[C:6]([OH:10])[CH:5]=[CH:4][CH:3]=1.Cl[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[C:7]2[CH:8]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCl
Reactant: O=Cc1c(O)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2c(Br)cccc2o1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 6-bromo-2-hydroxybenzaldehyde (4.48 g), ethyl chloroacetate (3.55 g) and powdered potassium carbonate (6.16 g) in N,N-dimethylformamide (56 ml) was stirred at 120° C. for one hour. Insoluble materials were filtered off and the solvent was removed under reduced pressure. Ethyl acetate and water were added to the residue, and the mixture was acidified by hydrochloric acid solution. The layers were separated and the organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of hexane and toluene (1:1) to afford 4-bromo-2-ethoxycarbonylbenzofuran (4.20 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.[F:48][C:49]([F:60])([F:59])[C:50]1[CH:51]=[C:52](B(O)O)[CH:53]=[CH:54][CH:55]=1.[O:61]1[CH2:66][CH2:65][CH:64]=[CH:63][C:62]1=[O:67]>O1CCOCC1>[F:48][C:49]([F:60])([F:59])[C:50]1[CH:51]=[C:52]([CH:64]2[CH2:65][CH2:66][O:61][C:62](=[O:67])[CH2:63]2)[CH:53]=[CH:54][CH:55]=1
Reactant: O=C1C=CCCO1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC(c2cccc(C(F)(F)F)c2)CCO1
Reaction time: 0.5 h

Procedure:
(Acetylacetonato)bis(ethylene)rhodium (I) (180 mg) was dissolved in 1,4-dioxane (144 mL). Racemic BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene) (867 mg) was added at room temperature, followed by stirring for 30 minutes. Subsequently, water (14.4 mL) and 3-(trifluoromethyl)phenylboronic acid (5.29 g) were added, followed by stirring for 10 minutes. Then, 5,6-dihydro-2H-pyran-2-one (2 mL) was added and the mixture was reacted at 100° C. for 12 hours. The reaction solution was partitioned with ethyl acetate and water. Then, the organic layer was washed with a saturated sodium bicarbonate solution and dried over magnesium sulfate. Concentration under reduced pressure gave an oil. The oil was purified by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 60%) to obtain the title compound (2.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)O)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:20]=2)[N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(O)c2ccc(OC)c(OCc3ccccc3)c2)cc1OCc1ccccc1
Reactant: c1nc[nH]n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(c2ccc(OC)c(OCc3ccccc3)c2)n2cncn2)cc1OCc1ccccc1
Yield: 85 %

Procedure:
Bis-(3-benzyloxy-4-methoxyphenyl)methanol (1.60 g, 3.50 mmol), 1,2,4-triazole (0.48 g, 6.95 mmol) and p-TSA (160 mg) dissolved/suspended in toluene (230 mL) were heated at reflux with a Dean-Stark separator for 24 h. The reaction mixture was allowed to cool, and the solvent was removed in vacuo. The resulting residue was dissolved in EtOAc (100 mL) and the organic layer was washed with H2O (3×100 mL), dried (MgSO4) and the solvent was removed in vacuo. The crude product was purified using Flashmaster II (EtOAc/Hexane) to give the title compound (1.51 g, 84%, mp 96-99° C.) as a yellow oil which solidified after standing for a prolonged period; δH (400 MHz, CDCl3) 7.95 (1H, s, NCHN), 7.67 (1H, s, NCHN), 7.34-7.24 (10H, m, ArH), 6.81 (2H, d, J=8.4, ArH), 6.58-6.48 (5H, m, ArH), 5.00 (4H, s, 2×CH2), 3.84 (6H, s, 2×CH3); δC (100 MHz, CDCl3) 152.3 (CH), 149.9 (2×C), 148.2 (2×C), 143.4 (CH), 136.7 (2×C), 130.5 (2×C), 128.7 (4×CH), 128.1 (2×CH), 127.5 (4×CH), 121.1 (2×CH), 114.1 (2×CH), 118.8 (2×CH), 71.2 (2×CH2), 67.4 (CH), 56.4 (2×CH3); LRMS (FAB+) 507.2 (M+, 20%), 439.2 (100), 349.2 (15), 257.2 (15), 91.1 (35); HRMS (FAB+) Found 507.2159, C31H29N3O4 requires 507.2158; Found: C, 73.00%; H, 5.73%; N, 8.31%, C31H29N3O4 requires: C, 73.35%; H, 5.76%; N, 8.28%.