Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])=O.Cl.[NH2:16]O.O.C(=O)([O-])O.[Na+]>C(O)=O>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:16]
Reactant: COC(=O)c1ccc(C=O)c(OC)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: COC(=O)c1ccc(C#N)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
To a solution (20 ml) of methyl 4-formyl-3-methoxybenzoate (870 mg, 4.48 mmol) in formic acid was added hydroxylamine hydrochloride (405 mg, 5.82 mmol), and the mixture was stirred at room temperature for 1 hr. The temperature was raised to 50° C., and the mixture was further stirred for 24 hrs. Water was added to the reaction mixture, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was dried over anhydrous MgSO4, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1:0-7:3, v/v) to give the title compound (780 mg, 91%) as a colorless oil.
Reaction SMILES: ClC1C=CC=CC=1.Cl.[F:9][C:10]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:11]=1[NH2:12].[C:18]12([NH:28][C:29]#[N:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2>Cl.CO>[C:18]12([NH:28][C:29]([NH:12][C:11]3[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:10]=3[F:9])=[NH:30])[CH2:27][CH:22]3[CH2:23][CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2
Reactant: N#CNC12CC3CC(CC(C3)C1)C2
Reactant: Nc1ccc(F)cc1F
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CO
Product: N=C(Nc1ccc(F)cc1F)NC12CC3CC(CC(C3)C1)C2

Procedure:
A single neck glass 100 ml round bottom flask was charged with chlorobenzene (20 ml), 2,4-difluoroaniline hydrochloride (prepared from the free base, Aldrich, by dissolving in 5% HCl in MeOH and concentrating, 2.0 g, 12 mmol) and 1-adamantylcyanamide (2.13 g, 12 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10](Cl)=[O:11])[CH2:7]1.C(=O)([O-])[O-].[K+].[K+].[CH2:22]([NH2:25])[C:23]#[CH:24]>O1CCCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]([NH:25][CH2:22][C:23]#[CH:24])=[O:11])[CH2:7]1
Reactant: C#CCN
Reactant: Cc1cccc(OC2CN(C(=O)Cl)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCNC(=O)N1CC(Oc2cccc(C)c2)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 72.9 %

Procedure:
A stirred mixture of 3.92 g (0.01 mole) of crude (57.59%) 3-(3-methylphenoxy)-1-azetidinecarbonyl chloride and 1.4 g (0.01 mole) of potassium carbonate in 15 ml of tetrahydrofuran was treated with 0.55 g (0.01 mole) of 2-propynylamine added dropwise from a needle and syringe. After 10 min, approximately 1 g of ice was added and stirring continued for 18 hr. The reaction mixture was diluted with 200 ml of water and the oil which separated slowly solidified. The precipitated solid was collected by filtration to yield 4.7 g of crude wet product. After air drying, the solid was recrystallized from benzene-ligroin to yield 1.78 g (72.9%) of fine white crystals, m.p. 140°-142° C.
Reaction SMILES: [C:1](=[O:4])([O-])[O-:2].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([C:19](=C)[C:20](O)=O)[CH:12]=[C:13]([O:17][CH3:18])[C:14]=1[O:15][CH3:16].C.[H][H]>[Pd].O>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([CH2:19][CH2:20][C:1]([OH:2])=[O:4])[CH:10]=[C:9]([O:8][CH3:7])[C:14]=1[O:15][CH3:16]
Reactant: [H][H]
Reactant: C=C(C(=O)O)c1cc(OC)c(OC)c(OC)c1
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: [K+]
Solvent: O
Product: COc1cc(CCC(=O)O)cc(OC)c1OC
Yield: 167.5 %

Procedure:
6.8 g of potassium carbonate were added to a solution of 21.44 g of 3,4,5-trimethoxyphenylpropenoic acid and 45 ml of water and the mixture was hydrogenated for one hour under a pressure of 1200-1300 mbar in the presence of 1.8 g of activated charcoal with 10% of palladium during which 2.1 liters of hydrogen were absorbed. Filtration was carried out, followed by washing with water and acidifying with 50 ml of hydrochloric acid (2N). The product was separated off, washed with water and dried under reduced pressure at ambient temperature to obtain 19.8 g of the expected product melting at 102-103° C.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:8]2[C:9](=[O:16])[O:10][C:11]([O:13][CH2:14][CH3:15])=[N:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[C:17]1([P:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[Br-:1].[CH2:14]([O:13][C:11]1[O:10][C:9](=[O:16])[C:8]2[C:3]([CH2:2][P+:23]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:4][CH:5]=[CH:6][C:7]=2[N:12]=1)[CH3:15]
Reactant: CCOc1nc2cccc(CBr)c2c(=O)o1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c(=O)o1
Product: [Br-]
Temperature: 60 °C
Yield: 148.6 %

Procedure:
A solution of 5-bromomethyl-2-ethoxy-4H-3,1-benzoxazin-4-one (3.15 gm), prepared as described in Example VI above, and triphenylphosphine (5.44 gm) in toluene was heated at 60° C. for 6 hours. The insoluble precipitate was filtered, and the mother liquor was reduced to half of its original volume and refiltered, yielding 9 gm of 1-(2-ethoxy-4H-3,1-benzoxazin-4-on-5-yl)-methyl-triphenylphosphonium bromide, m.p. (turns yellow at) 125° C. IR: 1740, 1640 cm-1 ;, decom. 135°-140° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[S:9][C:10]=1[NH2:11])=O)C.[CH:16]([NH2:18])=O>>[N:11]1[C:10]2[S:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6]=2[C:4]([OH:3])=[N:18][CH:16]=1
Reactant: NC=O
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Product: Oc1ncnc2sc3ccccc3c12
Temperature: 25 °C

Procedure:
The solution of 10 millimol IX in 15 milliliter milliliter formamide was stirred at 100° C. for 3 hours then cooled down to room temperature. The reaction mixture was poured onto crushed ice with continuous stirring then collected by filtration. The product was washed with water and n-hexane, then dried.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]([O:36]CC)=[CH2:35])CCC.Cl>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:5]4=[N:6][CH:7]=[C:2]([C:34](=[O:36])[CH3:35])[CH:3]=[C:4]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2s1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)c1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 17.4 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.109 mmol) from Example 29, tributyl(1-ethoxyvinyl)tin (79 mg, 0.218 mmol) and TEA (22 mg, 0.218 mmol) in anhydrous DMF (1 mL) at rt was flushed with a stream of argon for 15 min. To the resulting mixture was added tetrakis(triphenylphosphine)palladium (0) (19 mg, 0.0165 mmol). The reaction vessel was sealed and the mixture was heated with stirring at 110° C. for 1.5 h. After cooling to rt, aq 2 M HCl (500 μL) was added and the mixture was stirred for 1 h. The reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford 1-(3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)ethanone (8 mg, 17%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.00 (d, J=1.5 Hz, 1H), 8.76 (s, 1H), 8.64 (s, 1H), 7.99 (d, J=7.5 Hz, 1H), 7.68 (s, 1H), 7.20-7.32 (m, 2H), 5.53 (s, 2H), 4.76 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.68 (s, 3H), 2.04 (m, 1H), 1.87 (m, 1H), 1.55-1.65 (m, 2H), 1.10-1.30 (m, 4H). LCMS (ESI) m/z 422 (M+H)+.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11](I)[CH:12]=1)[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)[CH2:7]2.COC(=O)[C:30](Cl)([F:32])[F:31]>CN(C=O)C.[Cu]I>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[C:11]([C:30]([F:32])([F:1])[F:31])[CH:12]=1)[C:9](=[O:14])[N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)[CH2:7]2
Reactant: COC(=O)C(F)(F)Cl
Reactant: [F-]
Reactant: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Agent: [Cu]I
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2c(cc(F)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 181.6 %

Procedure:
CuI (0.129 g, 0.68 mmol) and potassium fluoride (0.039 g, 0.68 mmol) were added under an N2 atmosphere to a solution 5-fluoro-7-iodo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.260 g, 0.58 mmol) and chloro-difluoro-acetic acid methyl ester (0.072 mL, 0.098 mmol) in DMF (4 mL). The mixture was stirred at 140° C. for 18 h. The reaction was cooled and the solvent evaporated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-trifluoromethyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.070 g, 31%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.41 (s, 2H), 4.85 (s, 2H) 7.23-7.58 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Br)[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:18][O:19][C:20](=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][NH:15][CH:12]2[CH2:11][CH2:10][N:9]([C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:17]=[CH:16][C:5]=4[N:6]=3)[CH2:14][CH2:13]2)[CH:23]=1
Reactant: NC1CCN(c2nc3ccc(Cl)cc3s2)CC1
Reactant: COC(=O)Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cccc(CNC2CCN(c3nc4ccc(Cl)cc4s3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A mixture of 1-(6-chlorobenzothiazole-2-yl)piperidine-4-ylamine (500 mg), (3-bromomethylphenyl)acetic acid methyl ester (454 mg), potassium carbonate (284 mg) and dimethylformamide (6 mL) was stirred at room temperature for 1 hour. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over sodium sulphate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatograph on silica gel to give the title compound (434 mg). Yield: 55%.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)[C:6]=2[CH:23]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31]>>[CH2:9]1[O:8][C:7]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)([C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[C:6]2[CH:23]=[C:2]([C:27]3[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=3)[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1COC(c2cccs2)(c2cccs2)c2cc(Br)ccc2N1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C1COC(c2cccs2)(c2cccs2)c2cc(-c3ccc(F)c(Cl)c3)ccc2N1

Procedure:
Prepared from 7-bromo-5,5-dithien-2-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.27 (s, 1H), 7.68 (m, 4H), 7.48 (t, J=8.8 Hz, 1H), 7.38 (m, 1H), 7.27 (d, J=8.5 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 7.04 (dd, J=5.0, 3.6 Hz, 2H), 6.93 (dd, J=3.6, 1.2 Hz, 2H), 4.22 (s, 2H); MS (ES) m/z 456 (M+H)+; Anal. Calc. For C23H15ClFNO2S2: C, 60.59; H, 3.32; N, 3.07. Found: C, 60.35; H, 3.28; N, 2.91.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([F:15])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[O:16]COC)=[O:4].O.[O-2].[O-2].[O-2].O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.[Al+3].[Al+3]>ClCCl>[F:15][C:13]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([OH:16])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:14]=1
Reactant: COCOc1c(C(=O)OC)cc(F)c2ccccc12
Agent: O=[Si]=O
Agent: [Al+3]
Agent: [O-2]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(F)c2ccccc2c1O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 61.1 %

Procedure:
To a mixture of 0.375 g of 4-fluoro-1-methoxymethoxynaphthalene-2-carboxylic acid methyl ester and 375 mg of montmorillonite K-10 clay was added 10 ml of dry dichloromethane. The mixture was stirred at room temperature for 35 minutes. The suspension was diluted with dry dichloromethane and filtered. The residue was washed with ethyl acetate and the combined filtrate concentrated to a white solid. The material was purified by flash chromatography on silica gel, eluting with ethyl acetate/heptanes to provide 0.191 g of 4-fluoro-1-hydroxynaphthalene-2-carboxylic acid, methyl ester.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.C(N(CC)CC)C.[CH3:32][N:33]1[C:37]([CH3:38])=[CH:36][C:35]([CH2:39][N:40]2[C:48]3[CH:47]=[CH:46][CH:45]=[C:44]([NH2:49])[C:43]=3[C:42]([CH2:50][CH3:51])=[N:41]2)=[N:34]1>CN1C(=O)CCC1.[OH-].[Na+].CCOC(C)=O>[CH3:32][N:33]1[C:37]([CH3:38])=[CH:36][C:35]([CH2:39][N:40]2[C:48]3[C:43](=[C:44]([NH:49][C:10]([C:3]4[N:4]5[CH:9]=[CH:8][CH:7]=[CH:6][C:5]5=[N:1][CH:2]=4)=[O:12])[CH:45]=[CH:46][CH:47]=3)[C:42]([CH2:50][CH3:51])=[N:41]2)=[N:34]1
Reactant: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(N)c12
Reactant: O=C(O)c1cnc2ccccn12
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1nn(Cc2cc(C)n(C)n2)c2cccc(NC(=O)c3cnc4ccccn34)c12
Temperature: 87 °C
Reaction time: 0.5 h
Yield: 45.5 %

Procedure:
To a suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (45.1 mg, 0.278 mmol) in NMP (5 mL) was added 2,4,6-trichlorobenzoyl chloride (43.5 μL, 0.278 mmol) and triethylamine (38.8 μL, 0.278 mmol). The reaction mixture was stirred for 30 minutes. 1-((1,5-Dimethyl-1H-pyrazol-3-yl)methyl)-3-ethyl-1H-indazol-4-amine (50 mg, 0.186 mmol) was added to the reaction mixture, which was heated to 87° C. for 3 hours. The mixture was cooled to ambient temperature, and diluted with 10% NaOH aqueous solution (5 mL) and EtOAc (20 mL). The organic phase was washed with water and brine, then concentrated under reduced pressure. The residue was triturated with Et2O to give final product (35 mg). MS (ES+APCI) m/z=414 (M+H).
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=1.[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]=[CH:29][N:30](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1.CCN(C(C)C)C(C)C.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[CH:16][C:17](=[O:51])[N:18]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]3[N:28]([CH2:2][C:3]4[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[C:5]([O:11][CH3:12])[CH:4]=4)[CH:29]=[N:30][CH:31]=3)=[CH:22][N:21]=2)[CH:19]=1
Reactant: COc1cc(CO)ccc1C#N
Reactant: O=c1ccc(Cl)cn1-c1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cn1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(Cn2cncc2Cc2ccc(-n3cc(Cl)ccc3=O)nc2)ccc1C#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution (-78° C.) of 4-hydroxymethyl-2-methoxy-benzonitrile from step 2 (100 mg, 0.61 mmol) and 5-chloro-5'-(1-trityl-1H-imidazol-4-ylmethyl)-[1,2']bipyridinyl-2-one from Example 23, Step 5 (325 mg, 0.613 mmol) in CH2Cl2 (3 ml) was added DIEA (235 μl, 1.35 mmol) followed immediately by the addition of Tf2O (103 μl, 0.92 mmol). The reaction mixture was stirred at -78° C. for 1 hour and was then transferred to an ice bath and stirred at 0° C. for another hour. The solvent was removed in vacuo. The residue was then dissolved in MeOH (3 ml) and heated to 60° C. for 8 hours. The MeOH was then removed in vacuo and the residue treated with saturated NaHCO3 (5 mL) and extracted with CH2Cl2 (2×10 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography [4% MeOH(5% NH4OH)/CH2Cl2) to yield the final product.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][NH:11]3)=[CH:4][C:3]=2[O:2]1.C(C/[C:28](=[CH:32]\[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)/[C:29]([OH:31])=O)(O)=O.C(N(CC)CC)C.ClCCl>C1COCC1>[CH3:3][O:2][C:1](=[O:9])[C:36]1[CH:35]=[CH:34][C:33](/[CH:32]=[CH:28]/[C:29](=[O:31])[N:11]2[CH2:12][C:13]3[C:22](=[O:23])[C:21]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[NH:15][C:14]=3[CH:10]2[C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)=[CH:38][CH:37]=1
Reactant: O=C(O)C/C(=C\c1ccccc1)C(=O)O
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)NC2
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(/C=C/C(=O)N2Cc3c([nH]c4ccccc4c3=O)C2c2ccc3c(c2)OCO3)cc1

Procedure:
Following the procedure outlined in Example 20, 1,2,3,4-tetrahydro-3-(3,4-methylenedioxyphenyl)-9H-pyrrolo-[3,4-b]quinolin-9-one (398 mg, 1.30 mmol) (prepared as in Example 5) was reacted with the acid chloride of (E)-carboxymethyl cinnamic acid (301 mg, 1.34 mmol), in the presence of triethylamine (0.54 mL, 3.87 mmol) in a 1:1 mixture of dichloromethane:THF (40 mL) to yield the product as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH2:12])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]([NH:17][C:18]1([C:21](O)=[O:22])[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]([NH:12][C:21]([C:18]3([NH:17][C:15](=[O:16])[C:14]([F:13])([F:24])[F:25])[CH2:19][CH2:20]3)=[O:22])[CH2:7][CH2:8][O:9]2)=[CH:4][CH:3]=1
Reactant: NC1CCOc2cc(Br)ccc21
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Product: O=C(NC1(C(=O)NC2CCOc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-7-bromo-chroman-4-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido) cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-7-bromo-chroman-4-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light yellow solid. MS: 453.2 (M−H−).
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[N+](C1C=CC=CC=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25].Cl>O>[OH:2][C:1]1[CH:3]=[C:4]([OH:5])[CH:6]=[CH:7][C:8]=1[C:22]([CH2:23][CH:24]([CH3:26])[CH3:25])=[O:27]
Reactant: CC(C)CC(=O)Cl
Reactant: Oc1cccc(O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=[N+]([O-])c1ccccc1
Product: CC(C)CC(=O)c1ccc(O)cc1O

Procedure:
Resorcinol, 5.506 g (50.00 mmol), was added to 45 ml of nitrobenzene and stirred cooling with cold water and 13.3 g (100 mmol, 2.00 equivalents) of aluminum chloride was added piecemeal and they were stirred, with a calcium chloride tube attached. Then, 6.03 g (50.0 mmol, 1.00 equivalent) of isovaleryl chloride was slowly added dropwise, stirred at room temperature for one hour, and further heated stirring at 90° C. for six hours. When the evolution of an acidic gas ceased, the resultant mixture was poured into dilute hydrochloric acid (prepared from 40 ml of concentrated hydrochloric acid and 160 ml of cold water) with stirring, and then extracted by ether. The ether layer was washed with saturated brine and removed by distillation under a reduced pressure. The residue, with water added piecemeal, was distilled under a reduced pressure and distilled off nitrobenzene by steam distillation method. The residue was extracted again by ether, washed with saturated brine, dried over sodium sulfate, and distilled to remove the solvent and obtain 8.952 g of a red viscous oily substance. This oily substance was purified by silica gel column chromatography (20 g of Wako Gel C-200, eluted with hexane:ether at varying ratios=8:2-7:3) to obtain 4.37 g of (2,4-dihydroxyphenyl) (2-methylpropyl) ketone (52) in the form of light yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=[C:10]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([CH2:28][CH2:29][C:30]([NH:21][S:18]([C:10]2[CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=3)[C:13]([O:14][CH3:15])=[C:12]([CH:16]=[O:17])[CH:11]=2)(=[O:19])=[O:20])=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COc1c(C=O)cc(S(N)(=O)=O)cc1-c1cccc(N)c1
Reactant: O=C(Cl)CCc1ccccc1
Product: COc1c(C=O)cc(S(=O)(=O)NC(=O)CCc2ccccc2)cc1-c1cccc(N)c1

Procedure:
Proceeding as in Reference 21, but substituting 3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide and 3-phenylpropionyl chloride, gave N-(3-phenylpropionyl)-3′-amino-5-formyl-6-methoxy-biphenyl-3-sulfonamide.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([N+:22]([O-])=O)[N:4]=1)[CH3:2].[NH4+].[Cl-]>CO.C1COCC1.CCOC(C)=O.[Zn]>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:22])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[CH3:2]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1nc(N)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of crude 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.280 g, 3.93 mmol) in MeOH (15 mL) and THF (15 mL) was treated with NH4Cl (8.42 g, 157 mmol), cooled to 0° C., treated portion-wise with zinc dust (2.57 g, 39.3 mmol), warmed to RT as the cooling bath expired and stirred overnight. The mixture was diluted with EtOAc, the solids removed via filtration through diatomaceous earth, washed with warm 2:1 EtOAc/MeOH and the filtrate concentrated to dryness. The residue was treated with EtOAc, heated to reflux, cooled to RT and the solids removed via filtration. The filtrate was again treated with EtOAc, heated to reflux and the solid collected via hot filtration. The filtrate was concentrated to dryness, purified via silica gel chromatography (MeOH/EtOAc) and combined with the above-isolated solid to afford 6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (929 mg, 80%). 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J=5.8 Hz, 1 H), 8.22 (s, 1 H), 7.93 (s, 1 H), 7.18 (d, J=8.7 Hz, 1 H), 7.12 (d, J=2.4 Hz, 1 H), 6.51 (dd, J=5.7, 2.4 Hz, 1 H), 6.36 (d, J=8.7 Hz, 1 H), 5.97 (s, 2 H), 3.84-3.83 (m, 3 H), 2.39 (q, J=7.6 Hz, 2 H), 1.04 (t, J=7.5 Hz, 3 H); MS (ESI) m/z: 296.1 (M+H+).