Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:26][CH2:25][C:19]3([CH2:24][CH2:23][N:22]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CCNCC4)CC3)n2)cn1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(Nc2ncc(Cl)c(NC3CCC4(CC3)CCN(S(C)(=O)=O)CC4)n2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a suspension of 5-chloro-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(3-azaspiro[5.5]undecan-9-yl)pyrimidine-2,4-diamine (0.16 g, 0.43 mmol) in anhydrous DCM (10.0 mL) were added DMAP (0.011 g, 0.092 mmol) and Et3N (0.15 mL, 1.10 mmol), followed by methanesulfonyl chloride (0.076 g, 0.66 mmol) at 0° C. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=10/1) to give the product as a light yellow solid (0.14 g, 72%).
Reaction SMILES: [CH3:1][N:2]1[N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[CH:4]=[CH:3]1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:1][N:2]1[CH:3]=[C:4]2[C:5]([N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[C:7]2[OH:17])=[N:6]1
Reactant: Cn1ccc2nc(-c3ccccc3)cc(=O)n21
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cn1cc2c(O)cc(-c3ccccc3)nc2n1
Reaction time: 1.5 h

Procedure:
152 g. of 1-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7(1H)-one (0.67 mol.) in 500 ml. of diphenyl ether are heated at 250°, while stirring, for 90 minutes. After standing overnight, the crystallized 2-methyl-6-phenyl-2H-pyrazolo[3,4-b]pyridin-4-ol is filtered off, washed with ether and dried at 70°, yield; 146.6 g. (96%); m.p.241°-243°. A sample recrystallized from acetonitrile melts at 242°-244°.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH3:11].C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)C>[C:20]1([NH:19][C:3](=[O:5])[CH:2]2[O:1][CH:6]2[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC[K]
Reactant: O=C(O)C1OC1C(=O)O
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CCOC(=O)C1OC1C(=O)Nc1ccccc1
Yield: 50.1 %

Procedure:
To a suspension of monoethyl potassium epoxysuccinate (1.7 g) in ethyl ether (30 ml), oxalyl chloride (1.2 g) in ethyl ether was added dropwise with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. To the reaction mixture, aniline (1.6 g) in ethyl ether was added dropwise with stirring under ice-cooling, and the mixture was stirred at room temperature for an hour. The precipitate produced was filtered off and the filtrate was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The crude product was purified by chromatography using silica gel as an absorbent and benzene as an eluent, and then recrystallized from n-hexane-acetone to give 1.0 g of ethyl N-phenyl-2,3-epoxysuccinamate (Compound No. 1). m.p. 83°-84° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[NH2:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[F:17][C:18]1[CH:41]=[CH:40][C:21]([CH2:22][N:23]([CH3:39])[C:24]2[N:29]=[C:28]([C:30]3[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=3)[CH:27]=[N:26][CH:25]=2)=[CH:20][CH:19]=1>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][NH:9][C:36]([C:32]2[S:31][C:30]([C:28]3[CH:27]=[N:26][CH:25]=[C:24]([N:23]([CH2:22][C:21]4[CH:40]=[CH:41][C:18]([F:17])=[CH:19][CH:20]=4)[CH3:39])[N:29]=3)=[N:34][C:33]=2[CH3:35])=[O:37])[CH:12]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)O
Solvent: NCc1ccccc1
Product: Cc1nc(-c2cncc(N(C)Cc3ccc(F)cc3)n2)sc1C(=O)NCc1cccnc1
Yield: 82 %

Procedure:
Part C. Following the procedure described in Example 1 (Part A), making variations as required to replace benzylamine with 3-(aminomethyl)-pyridine to react with 2-{6-[(4-fluoro-benzyl)-methyl-amino]-pyrazin-2-yl}-4-methyl-thiazole-5-carboxylic acid, the title compound was obtained in 82% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.55-8.60 (m, 2H), 8.48 (d, J=4.0 Hz, 1H), 8.06 (s, 1H), 7.65-7.70 (m, 1H), 7.21-7.28 (m, 3H), 6.95-7.02 (m, 2H), 6.25 (bs, 1H), 4.78 (s, 2H), 4.56 (d, J=4.0 Hz, 2H), 3.11 (s, 3H), 2.69 (s, 3H); MS (ES+) m/z 449.2 (M-1-1), Rt=1.33 min.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:14][CH:15]=2)[C:10]([C:25]2[N:26](C(OC(C)(C)C)=O)[C:27]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:29][CH:28]=3)=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[CH2:18]([O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][N:9]=[C:10]2[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][C:30]([O:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)=[CH:29][CH:28]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(OCCN4CCOCC4)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(COc2ccc3[nH]nc(-c4cc5cc(OCCN6CCOCC6)ccc5[nH]4)c3c2)cc1
Yield: 98.8 %

Procedure:
1.0 g of 5-benzyloxy-3-[1-tert-butoxycarbonyl-5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]indazole-1-carboxylic acid tert-butyl ester are stirred at ambient temperature for 18 hours in 6 ml of a 4M hydrochloric acid solution in dioxane. The product is filtered through sintered glass, and rinsed with dioxane to obtain 692.4 mg of 5-benzyloxy-3-[5-(2-morpholin-4-ylethoxy)-1H-indol-2-yl]-1H-indazole.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:20][C@H:21]2[C@@H:25]3[O:26]C(C)(C)[O:28][C@@H:24]3[C@@H:23]([CH2:31][OH:32])[CH2:22]2)=[N:12][C:13]([CH2:18][CH3:19])=[N:14][C:15]=1[O:16]C.Cl>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([CH2:18][CH3:19])=[N:12][C:11]=1[NH:20][C@@H:21]1[CH2:22][C@H:23]([CH2:31][OH:32])[C@@H:24]([OH:28])[C@H:25]1[OH:26]
Reactant: CCc1nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c(-c2nc3ccccc3s2)c(OC)n1
Agent: Cl
Solvent: CO
Product: CCc1nc(N[C@@H]2C[C@H](CO)[C@@H](O)[C@H]2O)c(-c2nc3ccccc3s2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 14 (48 mg, 0.108 mmol) was suspended in MeOH (3 ml) and 3 M HCl (3) was added. The mixture was stirred at room temperature for 18 h. The mixture was evaporated to dryness to give the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:20][CH2:19]1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[OH:36]>>[Cl:29][C:30]1[CH:31]=[C:32]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12]([CH:14]2[CH2:16][CH2:15]2)=[O:13])=[C:5]3[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)[CH2:20][CH2:19]2)[CH:33]=[CH:34][C:35]=1[OH:36]
Reactant: O=C(c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1
Reactant: OB(O)c1ccc(O)c(Cl)c1
Product: O=C(c1cnc2ccc(-c3ccc(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N2CCCC2)CC1)C1CC1

Procedure:
Following general procedure D, {6-bromo-4-[trans-4-(pyrrolidin-1-yl)cyclohexylamino]quinolin-3-yl}(cyclopropyl)methanone (24 mg, 0.054 mmol) was reacted with 3-chloro-4-hydroxyphenylboronic acid (26 mg, 0.150 mmol) to afford the desired product (22 mg, 83%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 9.14 (s, 1H), 8.34 (s, 1H), 8.01 (dd, J=8.8, 1.8 Hz, 1H), 7.92 (d, J=8.7 Hz, 1H), 7.70 (d, J=2.2 Hz, 1H), 7.52 (dd, J=8.5, 2.3 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.18 (s, 1H), 3.24 (s, 4H), 3.07 (s, 1H), 2.90-2.78 (m, 1H), 2.34 (d, J=14.5 Hz, 4H), 2.02 (s, 4H), 1.73-1.51 (m, 4H), 1.26-1.15 (m, 2H), 1.15-1.02 (m, 21-1); ESI MS m/z 490 [C29H32ClN3O2+H]+; HPLC 98.9% (AUC), tR=10.90 min.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>C1COCC1.O>[N:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=[O:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(C(=O)CN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.7 %

Procedure:
A mixture of 2-bromo-1-[4-(methyloxy)phenyl]ethanone (3.5 g, 15.28 mmol) and sodium azide (1.490 g, 22.92 mmol) in THF (40 mL) and water (13.33 mL) was stirred at 25° C. for 2 hours. The mixture was diluted with water (150 mL), and extracted with Et2O (3×100 mL), dried (Na2SO4), filtered, concentrated to afford the title compound (3.0 g) as a pink solid. 1H NMR (400 MHz, DMSO-d6): δ 3.87 (s, 3H), 4.83 (s, 2H), 7.07 (d, 2H), 7.93 (d, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[CH:4][C:5]([CH3:22])=[C:6]([C:8]2[C:9](=[O:21])[N:10]([CH2:19][CH3:20])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([Cl:18])[CH:12]=3)[CH:7]=1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[Cl:18][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[C:8]([C:6]3[C:5]([CH3:22])=[CH:4][C:3]([F:23])=[C:2]([NH:1][C:31]([NH:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[O:32])[CH:7]=3)[C:9](=[O:21])[N:10]2[CH2:19][CH3:20])=[CH:15][N:14]=1
Reactant: O=C=Nc1ccccc1
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2C)cc2cnc(Cl)cc21
Solvent: C1CCOC1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2C)cc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
A solution of Example A6 (0.200 g, 0.603 mmol) and TEA (0.126 mL, 0.904 mmol) in THF (6 mL) was treated with phenyl isocyanate (0.066 mL, 0.603 mmol and stirred at RT overnight. The resulting solid was collected via filtration and dried to afford 1-(5-(7-chloro-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-methylphenyl)-3-phenylurea (211 mg, 78% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.01 (s, 1H), 8.77 (s, 1H), 8.51 (d, J=2.3 Hz, 1H), 8.01-7.98 (m, 2H), 7.73 (s, 1H), 7.41 (dd, J=8.3, 1.2 Hz, 2H), 7.25 (dd, J=8.5, 7.3 Hz, 2H), 7.17 (d, J=12.2 Hz, 1H), 6.97-6.90 (m, 1H), 4.27 (q, J=7.1 Hz, 2H), 2.07 (s, 3H), 1.21 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 451.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:14]O)[C:9]([O:11][CH2:12][CH3:13])=[O:10].[NH2:16][C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1>CO>[C:18]1([CH3:23])[C:17]([NH:16][CH:14]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Br:1])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)C(=CO)c1ccccc1Br
Reactant: Cc1ccccc1N
Solvent: CO
Product: CCOC(=O)C(=CNc1ccccc1C)c1ccccc1Br
Reaction time: 18 h
Yield: 94.9 %

Procedure:
To a solution of ethyl 2-(2-bromophenyl)-3-hydroxyacrylate (1 g, 3.88 mmol) in methanol (10 mL) was added o-toluidine (0.416 g, 3.88 mmol) via syringe at room temperature. After being stirred for 18 hours at the same temperature, solvent was removed under reduced pressure to give the crude product of ethyl 3-(o-toluidino)-2-(2-bromophenyl)acrylate (1.326 g, 95%), which was used in the next step without further purification. LRMS (M+H+) m/z: calcd 359.05. found 359.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([C:23](=O)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH2:11][C:12]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=3)=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C([O-])(=O)C.[NH4+:35]>CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([C:14]4[CH:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[CH:21][CH:22]=4)[NH:35][C:23]=3[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC(=O)c1ccc(C(=O)CC(C(=O)c2ccccn2)c2ccc3c(c2)OCO3)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CO
Product: NC(=O)c1ccc(-c2cc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)cc1

Procedure:
4-(3-Benzo[1,3]dioxol-5-yl-4-oxo4-pyridin-2-ylbutanoyl)benzamide (1.69 g; 4.2 mmol) and ammonium acetate (2.1 g; 27.3 mmol) were reacted together according to the method described in Bioorg. Med. Chem. Letters, 1998, 8, 2689-2694. The title compound was isolated as a brown powder from methanol (126 mg; 8%). 1H NMR (DMSO) δ: 6.04 (2H, s), 6.82-6.93 (4H, m), 7.18-7.32 (3H, m), 7.63-7.74 (1H, m), 7.86-7.96 (5H, m), 8.61 (1H, d, J=4 Hz), 11.63 (1H, brs); m/z (LCMS): 383.9 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH:24]=[CH2:25])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])[CH3:2].[CH3:27][O:28][CH2:29][CH2:30][NH2:31].C([O-])([O-])=O.[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH:24]=[CH2:25])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1[NH:31][CH2:30][CH2:29][O:28][CH3:27])=[O:5])[CH3:2]
Reactant: C=CCn1c(=O)c(C(=O)OCC)c(Cl)c2cnc(-c3ccccc3)nc21
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=CCn1c(=O)c(C(=O)OCC)c(NCCOC)c2cnc(-c3ccccc3)nc21

Procedure:
To 0.9 g. (0.0024 mole) of 8-allyl-5-chloro-7,8-dihydro-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester in 30 ml. of ethanol was added 0.17 g. (0.0024 mole) of 2-methoxyethylamine and 0.25 g. (0.0024 mole) of Na2CO3. This mixture was heated at reflux for 4 hours, then filtered and the filtrate chilled. Yellow crystals formed and were collected on a filter. Recrystallization from ethanol gave 0.5 g. of product--m.p. 155°-158° C.
Reaction SMILES: S(O)(O)(=O)=O.N[C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1.[BrH:18].N([O-])=O.[Na+]>C(Cl)Cl.O>[Br:18][C:7]1[S:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][N:11]=1
Reactant: Nc1nnc(-c2ccccc2)s1
Reactant: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Brc1nnc(-c2ccccc2)s1
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 74 %

Procedure:
A mixture of 2-amino-5-phenyl-1,3,4-thiadiazole sulfate (Aldrich, 2.5 g, 9.08 mmol) and 48% aqueous HBr (10 mL) was cooled to 5° C. and a solution of NaNO2 (0.69 g, 9.99 mmol) H2O (10 mL) was added dropwise at a rate so the internal temperature is maintained at approximately 5° C. The mixture was stirred for 15 min after the addition, then CuBr (0.69 g, 4.8 mmol) was added portion-wise so as to maintain the temperature at approximately 5° C. After the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was diluted with 20 mL CH2Cl2 and 10 mL H2O. The organic layer was separated and concentrated under reduced pressure to provide the title compound (1.63 g, 6.76 mmol, 74% yield). MS (DCl/NH3) m/z 241, 243 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([O:8][CH:9]2[CH2:12][CH:11]([NH:13][S:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=2)O1>O1CCOCC1.O.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]>[CH3:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][CH:11]2[CH2:12][CH:9]([O:8][C:3]3[C:2]([C:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH:33]=4)=[CH:7][CH:6]=[CH:5][N:4]=3)[CH2:10]2)(=[O:16])=[O:15])=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3Br)C2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3C3=CCN(C(=O)OC(C)(C)C)CC3)C2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide (397 mg, 1 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (335 mg, 1.1 mmol) and NaCO3 (212 mg, 2 mmol) in 1,4-dioxane (60 mL) and H2O (6 mL) was added Pd(dppf)Cl2 (36.6 mg, 0.05 mmol). The reaction mixture was stirred at 110° C. under N2 overnight. The reaction mixture was filtered through CELITE® and washed with CH2Cl2. The organic layer was concentrated and the crude product was purified by silica gel column to give tert-butyl 2-(3-(4-methylphenylsulfonamido)cyclobutoxy)-5′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate (351 mg, 0.7 mmol, yield 70%). ESI-MS (M+1): 500 calc. for C26H33N3O5S 499.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].O>S(=O)(=O)(O)O>[N+:1]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: O=C1Cc2ccccc2N1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
Fuming nitric acid (1.58 ml, 39.4 mmol) was added dropwise to a solution of oxindole (5 g, 37.5 mmol) in concentrated sulphuric acid (25 ml) cooled by an ice bath and maintained below 5° C. The mixture was stirred for 30 minutes at 0° C. and then poured into water. The precipitate was collected by filtration and thoroughly washed with water. The solid was suspended in 50% acetic acid (100 ml) and heated at 90° C. for 1 hour. The mixture was allowed to cool, the solid product was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide at 40° C. to give 5-nitrooxindole (3.2 g, 48%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]2[N:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[O:30][N:29]=2)[CH:27]=1)[C:22](O)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]2[N:32]=[C:31]([C:33]([F:35])([F:34])[F:36])[O:30][N:29]=2)[CH:27]=1)[C:22]([NH:15][CH2:14][C:13]([C:10]1[S:11][CH:12]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[N:9]=1)([CH3:17])[CH3:16])=[O:23]
Reactant: O=C(O)c1cc(F)cc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(F)cc2)cs1
Product: CC(C)(CNC(=O)c1cc(F)cc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(F)cc2)cs1
Yield: 32 %

Procedure:
This compound was synthesized from 2-(4-(4-fluorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 3-fluoro-5-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (23 mg, yield 32%): 1H NMR (400 MHz, CDCl3) δ 8.32 (br s, 1H), 8.23 (br t, J=5 Hz, 1H), 7.94 (br d, J=8 Hz, 1H), 7.86-7.75 (m, 3H), 7.06-7.00 (m, 2H), 3.78 (d, J=4 Hz, 2H), 1.55, (s, 6H). MS (ESI) m/z: Calculated for C23H17F6N4O2S: 508.10. found: 509.1 (M+H)+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[Li]CCCC.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=[O:19].[Li]>C1COCC1>[OH:19][CH:18]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1)[C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1cc(Br)c2ccccc2n1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(O)c2cc(C)nc3ccccc23)cc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
4-Bromo-2-methylquinoline from (4a) (1.0 g, 4.5 mmol) was dissolved in 10 mL of anhydrous THF and the resulting solution was cooled to -78° C. A solution of n-BuLi (3.0 mL, 1.6 M, 4.8 mmol) was added slowly and the resulting solution was maintained at −78° C. for 5 min. Meanwhile, in another flask methyl 4-formylbenzoate (0.9 g, 5.4 mmol) was dissolved in 20 mL of anhydrous THF and the resulting solution was cooled to −78° C. before the lithium reagent made above was cannulated. The whole mixture was stirred for 30 min and quenched with MeOH. The solution was diluted with ethyl acetate and washed with H2O and brine. After dried over MgSO4, the organic solution was filtered and concentrated. The residue was purified on silica gel to provide methyl 4-[hydroxy(2-methyl-4-quinolinyl)methyl]benzoate (0.9 g, 65%). MS (AP+): 308 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[Li]CCCC.B(OC)(OC)OC.[Br:22]Br>C1COCC1>[Br:22][C:7]1[C:6]([CH3:8])=[CH:5][C:4]([NH2:9])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C)cc(N)c1
Reactant: BrBr
Agent: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(N)cc(C)c1Br
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3,5-dimethyl-phenylamine (400 mg) in THF (35 mL) was added n-BuLi (1.45 mL, 2.5 M solution in hexane) at −78° C. The mixture was stirred at −78° C. for 20 min, allowed to warm up to −40° C. for 5 min, and then was cooled down to −78° C. again. After 10 min, B(OMe)3 (0.4 mL) was added dropwise. The mixture was stirred at −78° C. for 2.5 h, warmed up to 10° C. slowly, and then was cooled down to −78° C. again. Bromine (0.185 mL) was added dropwise to the mixture. The mixture was stirred at −78° C. for 1.5 h, and allowed to warm up to 0° C. for 1 h. The reaction was quenched with saturated NaHCO3 aqueous solution and 20% Na2S2O3 aqueous solution. The aqueous layer was extracted with EtOAc, and the organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, EtOAc:Hexane=5:95 to 40:60) to give 4-bromo-3,5-dimethyl-phenylamine as a white solid: MS (m/z) 200 (M+1); 1H NMR (CDCl3, 400 MHz) δ 6.43 (s, 2H), 3.52 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: C[O-].[Na+].[C:4]([C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])(=[O:6])[CH3:5].[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16]>CO>[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:5][C:4]([C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[C:10]#[N:11])=[O:6])=[CH:19][CH:18]=1)#[N:16]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: CC(=O)c1cccc(C#N)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(C=CC(=O)c2cccc(C#N)c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.8 %

Procedure:
Part A. Sodium methoxide (25% in MeOH, 1.5 mL, 6.8 mmol) was added dropwise to a solution of 3-acetylbenzonitrile (0.987 gm, 6.8 mmol) and 4-cyanobenzaldehyde (0.891 gm, 6.8 mmol) in dry methanol. Within 5 minutes, a precipitate began to form. The mixture was stirred at room temperature for 4 hrs and diluted with methanol. The solids were filtered off, washed with cold methanol and dried to give 3-[3-(4-cyanophenyl)-1-oxo-2-propenyl]benzonitrile as a white solid 1.7 gm (97%). MS: (M+H)+ 259; 1H NMR (CDCl3): 7.55 (d, 1H), 7.65 (t, 1H), 7.75 (s, 4H), 7.85 (m, 2H), 8.25 (d, 1H), 8.30 (s, 1H).