Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C@H:5]([CH3:28])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH3:21])[CH:16]=[N:15][C:14]=2[N:13]([CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:11]1=[O:12])(=O)C.Cl.O1CCOCC1>CO>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[CH2:22][N:13]1[C:14]2[N:15]=[CH:16][N:17]([CH3:21])[C:18]=2[C:19](=[O:20])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C@H:5]([OH:4])[CH3:28])[C:11]1=[O:12]
Reactant: CC(=O)O[C@H](C)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2c(ncn2C)n(Cc2ccco2)c1=O
Temperature: 25 °C
Yield: 80.9 %

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-3-(2-furylmethyl)-7-methylxanthine (0.42 g, 1.07 mmol) in methanol (20 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4 M, 0.80 ml, 3.21 mmol) and the mixture was refluxed for 5 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure. The residue was treated with saturated aqueous sodium bicarbonate solution (25 ml) and the mixture was extracted with dichloromethane (3×25 ml). The combined extracts were washed with saturated aqueous sodium chloride solution (2×25 ml), dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to provide (R)-3-(2-furylmethyl)-1-(5-hydroxyhexyl)-7-methylxanthine (0.30 g, 80% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[Li]CCCC.C[O:18][B:19](OC)[O:20]C.O>C(OCC)C>[N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:2]([B:19]([OH:20])[OH:18])[CH:3]=1
Reactant: Brc1cnc2ccccc2c1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: OB(O)c1cnc2ccccc2c1
Reaction time: 0.25 h
Yield: 92 %

Procedure:
A solution of 3-bromoquinoline (14.6 g (0.07 mole)) in 50 ml of diethylether was added at -40° under argon to a solution of 2 M n-BuLi (37.5 ml (0.075 mole) (in cyclohexane)) in 50 ml Et2O. The reaction mixture was stirred 15 minutes and 0.075 mole (7.8 g, 8.5 ml) trimethylborate was added rapidly over 2 minutes. The mixture was stirred 15 minutes at 0° C. and 4 ml of H2O was added and stirring continued for 30 minutes. The volatiles were evaporated in vacuo to a yellow tar resi-due. The residue was dissolved in 150 ml ethyl alcohol to which was added 4 ml of acetic acid and reflux-ed for 45 minutes. The volatiles were evaporated in vacuo to a yellow oily residue. The residue was stirred with 40 ml of ether to give a yellow solid which was filtered, washed with ether and dried to give 11.14 g of a solid. The solid was stirred in 100 ml of water and filtered to give 3.26 g of a solid after air drying. The crude product was used directly in the next step.
Reaction SMILES: [N:1]1([C:6]2[CH:26]=[CH:25][C:9]([CH2:10][C:11]3[C:12]([CH3:24])=[C:13]([F:23])[C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:27][C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[F:23][C:13]1[C:12]([CH3:24])=[C:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH:5]=[CH:4][CH:3]=[N:2]3)=[CH:26][CH:25]=2)[CH:20]=[C:15]2[C:14]=1[CH2:21][N:27]([C@@H:28]1[C@@H:33]([OH:34])[CH2:32][CH2:31][O:30][CH2:29]1)[C:16]2=[O:17]
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)c(F)c1C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(-n3cccn3)cc2)cc2c(c1F)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 43.8 %

Procedure:
A mixture of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-3-fluoro-2-formyl-4-methylbenzoate (0.21 g), (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (0.07 g), anhydrous magnesium sulfate (0.14 g) and THF (4.00 mL) was stirred at room temperature for 6 hr under nitrogen atmosphere. The insoluble substance was removed by filtration, and the filtrate was concentrated. The residue was dissolved in a mixed solvent of methanol (4.00 mL)-THF (4.00 mL), sodium triacetoxyborohydride (0.25 g) was added thereto, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.11 g).
Reaction SMILES: [C:1]([CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([N+:14]([O-:16])=[O:15])=[CH:10][CH:11]=2)[NH:6]1)([CH3:4])([CH3:3])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[C:1]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C1Cc2ccc([N+](=O)[O-])cc2N1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(C)(C)c1cc2ccc([N+](=O)[O-])cc2[nH]1
Yield: 80.6 %

Procedure:
To a solution of 2-tert-butyl-6-nitroindoline (2.0 g, 9.1 mmol) in 1,4-dioxane (20 mL) was added DDQ (6.9 g, 30 mmol) at room temperature. The mixture was heated at reflux for 2.5 h before being filtered and concentrated under vacuum. The residue was purified by column chromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80%). 1H NMR (300 MHz, CDCl3) δ 8.30 (br. s, 1H), 8.29 (s, 1H), 8.00 (dd, J=2.1, 8.7 Hz, 1H), 7.53 (d, J=9.3 Hz, 1H), 6.38 (s, 1H), 1.43 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][NH2:22])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24].O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[C:15]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:21][NH:22][C:23]2=[O:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2CN)CC1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(N2C(=O)NCc3ccccc32)CC1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
The obtained 1-(tert-butoxycarbonyl)-4-[(2-aminomethylphenyl)amino]-piperidine (219 mg) was dissolved in toluene (5 ml), added with 1,1′-carbonyldiimidazole (128 mg) and stirred at 100° C. for 1.5 hours. The reaction mixture was added with water (10 ml) and extracted twice with ethyl acetate (10 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: hexane:ethyl acetate=1:2→1:3) to obtain 130 mg of the title compound. Yield: 17% (for the three steps).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:14]([O:18][C:19](=[O:29])[NH:20][C:21]1[CH:26]=[C:25]([CH2:27]Br)[CH:24]=[CH:23][N:22]=1)([CH3:17])([CH3:16])[CH3:15]>C1COCC1>[CH2:12]([O:11][C:3](=[O:10])[CH:4]([CH2:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([NH:20][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:29])[CH:26]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cc(CBr)ccn1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccnc(NC(=O)OC(C)(C)C)c1)C(=O)OCC
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
To a solution of NaH (80%, 0.17 g, 4.00 mmol) in THF (5 mL) at 0° C. under argon was added diethyl malonate (0.64 g, 4.00 mmol). After the mixture was stirred for 15 min the mixture was added to a refluxed mixture of (4-bromomethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (1.00 g, 3.48 mmol) in THF (10 mL), and the mixture was refluxed for 2 h. The mixture was concentrated under reduced pressure and the residue was partitioned between water and chloroform. The organic layer was washed with water and brine and dried. After filtration and evaporation of the solvent, the crude product was purified by flash chromatography (MeOH/CH2Cl2, 1:100) to give 2-(2-tert-butoxycarbonylamino-pyridin4-ylmethyl)-malonic acid diethyl ester (0.80 g, 55%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[N+:11]([O-:13])=[O:12].O[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1)[CH:6]=[C:5]2[N+:11]([O-:13])=[O:12]
Reactant: OC1CCOC1
Reactant: O=[N+]([O-])c1c[nH]c2ccc(F)cc12
Product: O=[N+]([O-])c1cn(C2CCOC2)c2ccc(F)cc12
Yield: 18 %

Procedure:
The title compound was prepared from 5-fluoro-3-nitro-indole and 3-hydroxytetrahydrofuran in 18% yield according to the general procedure for Preparation 31A. The minor isomer was not isolated or characterized. 1H NMR (400 MHz, CDCl3): δ 2.21-2.27 (1H, m), 2.60-2.69 (1H, m), 3.95-4.01 (1H, m), 4.05-4.09 (1H, m), 4.20-4.25(2H, m), 5.07-5.10 (1H, m), 7.13 (1H, td, J=2.4, 8.8 Hz), 7.44 (1H, dd, J=4.0, 8.8 Hz), 7.98 (1H, dd, J=2.4, 9.2 Hz), 8.28 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[NH:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: O=Cc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Brc1ccc2nc(-c3ccccc3)[nH]c2c1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
4-Bromobenzene-1,2-diamine (0.5 g, 2.67 mmol), benzaldehyde (0.284 g, 2.67 mmol), and 4-methylbenzenesulfonic acid (0.046 g, 0.267 mmol) in DMF (8 mL) were combined and heated at 100° C. for 1 hour in a microwave reactor. The reaction mixture was subsequently diluted with EtOAc, washed with brine (4×100 mL), concentrated, and purified by CombiFlash® chromatography, eluting with a gradient of MeOH (0-30%) in DCM over 120 minutes. The product-containing fractions were combined and concentrated to give the title compound as light yellow liquid (0.48 g, 66%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][CH:9]1[C:8](=[O:12])[NH:7][C:6]2[CH:13]=[C:2]([CH:16]=[CH:15][C:14]([NH2:18])=[O:17])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: C=CC(N)=O
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CO
Solvent: CCN(CC)CC
Product: CC1Oc2ccc(C=CC(N)=O)cc2NC1=O
Yield: 36 %

Procedure:
726 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is stirred in 1.5 ml of triethylamine with 0.267 g of acrylamide as well as 8 mg of palladium(II) acetate and 46 mg of tri-ortho-toluyl-phosphine for several hours at 100° C. The product is taken up in methanol and purified by column chromatography with an ethanol/ethyl acetate mixture. Yield 36%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].O[CH:28]1[CH2:32][CH2:31][O:30][CH2:29]1>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9](=[O:10])[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH:28]2[CH2:32][CH2:31][O:30][CH2:29]2)=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: OC1CCOC1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(O)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(OC2CCOC2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-hydroxy-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and rac-3-hydroxy-tetrahydrofuran in analogy to Example 9c): MS (ISP): 466.1 and 468.3 (M+H)+, 366.0 and 368.0 ((M-Boc)+H)+ (100%).
Reaction SMILES: [NH2:1][C:2]1[CH:42]=[CH:41][C:40]([F:43])=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.[CH3:44][O:45][CH2:46][CH2:47][CH2:48][C:49](Cl)=[O:50]>>[F:43][C:40]1[CH:41]=[CH:42][C:2]([NH:1][C:49](=[O:50])[CH2:48][CH2:47][CH2:46][O:45][CH3:44])=[C:3]([CH:39]=1)[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:37])([CH3:38])[CH3:36])=[O:33])[CH2:7]1
Reactant: COCCCC(=O)Cl
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cc(F)ccc2N)cc1
Product: COCCCC(=O)Nc1ccc(F)cc1COC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOCc2ccccc2OC)cc1

Procedure:
Analogously to Example 116b, 0.487 g of tert-butyl 3-(2-amino-5-fluorobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.322 g of 4-methoxybutyryl chloride are reacted. The title compound is obtained as a beige oil. Rf=0.22 (1:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:7][C:8]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](Cl)=[O:11]>>[OH:7][C:8]1[C:16]([CH2:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:11]
Reactant: c1ccccc1
Reactant: CCc1cccc(C(=O)Cl)c1O
Product: CCc1cccc(C(=O)c2ccccc2)c1O
Yield: 58.1 %

Procedure:
This compound (44.67g) was prepared from benzene (172g.,2.2 mole) and 2-hydroxy-3-ethyl benzoic acid chloride (63.15g,0.34 mole), using the same conditions as in Example 30. The b.p. of the compound was 123°-126°C./0.14mm, ηD22 1.6081,νmax.(film) 1630cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([OH:12])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20].S(=O)(=O)(O)O>C(#N)C>[C:1]([C:5]1[CH:11]=[C:10]([O:12][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][C:6]=1[OH:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(O)c(C(C)(C)C)cc1O
Reactant: CC(C)(C)C(=O)O
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)C(=O)Oc1cc(C(C)(C)C)c(O)cc1C(C)(C)C
Yield: 78 %

Procedure:
Under argon atmosphere, a solution of 11.12 g of 2,5-di-t-butylhydroquinone and 10.1 ml of anhydrous trimethylacetic acid in 200 ml of acetonitrile was stirred with a catalytic amount of sulfuric acid at room temperature for a whole day and night. After the reaction mixture was evaporated under reduced pressure, the concentrate was dissolved in diisopropyl ether. This solution was washed with a saturated aqueous sodium bicarbonate solution, then saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 5% ethyl acetate) to give 11.9 g of 2,5-di-t-butyl-4-trimethylacetoxyphenol as a white solid (yield 78%).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].[N+:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-])=[O:10].C1N2CCN(CC2)C1>C(O)C>[CH:3]1([C:1]2[O:10][N:9]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:2]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CCOC(=O)C[N+](=O)[O-]
Reactant: C#CC1CCCCC1
Agent: C1CN2CCN1CC2
Solvent: CCO
Product: CCOC(=O)c1cc(C2CCCCC2)on1
Temperature: 80 °C
Yield: 97.2 %

Procedure:
To a mixture of ethynylcyclohexane (0.600 g; 5.44 mmol) and ethyl 2-nitroacetate (1.23 mL; 10.87 mmol) in ethanol (9 mL) in an Ace pressure tube was added 1,4-diazobicyclo[2.2.2]octane (DABCO, 0.070 g; 0.60 mmol). The tube was heated at 80° C. for 96 h. The mixture was evaporated. The flash chromatography on silica gel (eluent: 20 to 80% dichloromethane in heptane) of the residue provided 1.18 g (97%) of ethyl 5-cyclohexylisoxazole-3-carboxylate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH:12]([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17])=[CH2:13]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH:12]=[CH2:13])[CH:15]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: C=Cc1cccc(N)c1
Product: C=Cc1cccc(NC(=O)c2cc(Cl)ccc2O)c1

Procedure:
This material was prepared according to the method of Example 1 using 5-chlorosalicylic acid and 3-vinylaniline, with reagents and solvents employed in similar molar ratios. 1HNMR (500 MHz, DMSO-d6): δ 5.32 (m, 1H, C═CH2 cis), 5.83 (m, 1H, C═CH2 trans), 6.75 (m, 1H, ArCH═CH2), 7.02 (m, 1H, H3), 7.28 (m, 1H, H6′), 7.37 (m, 1H, H5′), 7.49 (m, 1H, H4), 7.62 (m, 1H, H4′), 7.80 (m, 1H, H2′), 7.90 (m, 1H, H6).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:38])=[C:5]([C:29]([O:36]C)=[C:30]([O:34][CH3:35])[C:31]=1[O:32][CH3:33])[CH2:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:9]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:33][O:32][C:31]1[C:3](=[O:2])[C:4]([CH3:38])=[C:5]([CH2:6][C:7]2[CH:20]=[CH:19][C:10]([C:11]([N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)=[O:12])=[C:9]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:8]=2)[C:29](=[O:36])[C:30]=1[O:34][CH3:35]
Reactant: COc1c(C)c(Cc2ccc(C(=O)N3CCCCC3)c(OCc3ccccc3)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)N3CCCCC3)c(OCc3ccccc3)c2)=C(C)C1=O
Yield: 69.9 %

Procedure:
N-[4-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-benzyloxybenzoyl]piperidine (129 mg, 0.2485 mmol) was dissolved in a mixed solution of acetonitrile (15 ml) and water (5 ml) and after adding thereto CAN (341 mg, 0.6222 mmol) at room temperature, the solution was stirred at room temperature for 1 hour. The reaction solution was diluted with water and then extracted with ether. The extract was washed with water and then dried, and the solvent was removed by distillation. The residue was purified by flash column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (85 mg, 0.1738 mmol, 70%).
Reaction SMILES: CC(C)(OC([N:7](C(OC(C)(C)C)=O)[C:8]1[C:13]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[C:12]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([NH:28][C:29]([C:31]3[C:36](=[O:37])[C:35]([C:38]4[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=4)=[CH:34][N:33]([CH3:45])[CH:32]=3)=[O:30])=[C:23]([F:46])[CH:22]=2)[CH:11]=[CH:10][N:9]=1)=O)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[C:13]([C:14]2[CH:15]=[N:16][N:17]([CH3:19])[CH:18]=2)=[C:12]([O:20][C:21]2[C:26]([F:27])=[CH:25][C:24]([NH:28][C:29]([C:31]3[C:36](=[O:37])[C:35]([C:38]4[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=4)=[CH:34][N:33]([CH3:45])[CH:32]=3)=[O:30])=[C:23]([F:46])[CH:22]=2)[CH:11]=[CH:10][N:9]=1
Reactant: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c3-c3cnn(C)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3-c3cnn(C)c3)cc2F)c(=O)c(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
A solution of N-(4-(2-[bis[(1,1-dimethylethoxy)carbonyl]amino]-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide (0.115 g, 0.15 mmol) in CH2Cl2 (5 mL) was treated with TFA (0.35 mL, 4.62 mmol) and the solution was stirred at RT for 3 h. The solvent was removed in vacuo and the residue was partitioned between satd NaHCO3 solution (30 mL) and EtOAc (30 mLl). The aqueous layer was extracted with EtOAc (25 mL) and the combined organics were washed with brine, dried (Na2SO4) and concentrated in vacuo to afford N-(4-(2-amino-3-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)-2,5-difluorophenyl)-5-(4-fluorophenyl)-1-methyl-4-oxo-1,4-dihydropyridine-3-carboxamide as off-white solid (82 mg, 97% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.43 (s, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.49 (dd, J=12.6 Hz, 7.3 Hz, 1H), 8.15 (d, J=2.3 Hz, 1H), 7.88 (s, 1H), 7.75 (d, J=5.8 Hz, 1H), 7.69 (m, 2H), 7.59 (d, J=0.8 Hz, 1H), 7.41 (dd, J=11.2 Hz, 7.4 Hz, 1H), 7.27 (t, J=8.9 Hz, 2H), 6.00 (d, J=5.8 Hz, 1H), 5.69 (s, 2H), 3.91 (s, 3H), 3.85 (s, 3H); MS (ESI) m/z: 547.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([F:11])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[CH3:12][N:13](C=O)C>[C-]#N.[C-]#N.[Zn+2]>[F:11][C:3]1[C:2]([C:12]#[N:13])=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: Fc1ccc2cc[nH]c2c1Br
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1c(F)ccc2cc[nH]c12

Procedure:
To a solution of 7-bromo-6-fluoro-1H-indole (D140) (1.0 g) in DMF (15 ml) were added Zn(CN)2 (2.2 g) and then Pd(PPh3)4 (1.1 g) in a microwave tube, then N2 atmosphere was bubbled in. The sealed vial was irradiated in the microwave at 150° C. for 2 hours. After cooling, DCM (80 mL) was added to the resulting mixture which was filtered and the filtrate was concentrated. The crude product was purified by column chromatography to afford 6-fluoro-1H-indole-7-carbonitrile (D141) (0.5 g) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([OH:18])=O)=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[C:25]1[CH:26]=[CH:27][C:28]([NH2:31])=[N:29][CH:30]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([CH2:15][C:16]([NH:31][C:28]3[CH:27]=[CH:26][C:25]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][N:19]=4)=[CH:30][N:29]=3)=[O:18])=[CH:10][N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)Cc1cnc(-c2ccnc(F)c2)c(F)c1
Reactant: Nc1ccc(-c2cnccn2)cn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Cc1cnc(-c2ccnc(F)c2)c(F)c1)Nc1ccc(-c2cnccn2)cn1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)acetic acid 205-6 (50 mg, 0.2 mmol), 5-(pyrazin-2-yl)pyridin-2-amine 86-3 (34 mg, 0.2 mmol), 1,3-dicyclohexylcarbodiimide (50 mg, 0.24 mmol) and 4-(dimethylamino)pyridine (4 mg, 0.04 mmol) in DMF (0.9 mL) was stirred at room temperature for 10 hours. The crude product was filtered and the filtrate was subjected directly for reverse phase HPLC to give 2-(2′,3-difluoro-2,4′-bipyridin-5-yl)-N-(5-(pyrazin-2-yl)pyridin-2-yl)acetamide 205 as white solid. MS m/z 405.2 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 11.16 (s, 1H), 9.31 (d, 1H), 9.12 (d, 1H), 8.72 (dd, 1H), 8.63 (d, 1H), 8.61-8.60 (m, 1H), 8.52 (dd, 1H), 8.41 (d, 1H), 8.21 (d, 1H), 7.94 (dd, 1H), 7.88 (dd, 1H), 7.64 (s, 1H), 4.01 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:29](=[O:30])[C:28]5[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cccc(C(F)(F)F)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3-trifluoromethyl-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3-(trifluoromethyl)benzoyl chloride (131 μl, 0.89 mmol). The title compound was obtained as light brown powder (195 mg, 50%).