Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([C:11]#[N:12])[C:5]=2[CH:4]=[CH:3][CH:2]=1>N.[Ni].CCO>[NH2:12][CH2:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[CH:3][CH:2]=[N:1]2
Reactant: N#Cc1cccc2ncccc12
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1cccc2ncccc12
Reaction time: 19 h

Procedure:
To a solution of 0.1173 g (0.76 mmol) 11 in 10 mL NH3 saturated EtOH was added a 1 mL slurry of Raney nickel (50wt. % in EtOH). After 19 h under H2 at atmospheric pressure, the reaction mixture was diluted with 20 mL EtOH and filtered over celite. The celite was washed with 200 mL EtOH, and the filtrate was concentrated in vacuo. Purification by flash chromatography (20×120 mm silica gel, linear gradient 5-7% (10% NH4OH:MeOH):CH2C2) provided 12. 1H NMR (CDCl3, 400 MHz) δ 8.937 (dd, 1H, J=1.56, 4.12 Hz, ArH); 8.475 (d, 1H, J=8.14 Hz, ArH); 8.033 (d, 1H, J=8.50 Hz, ArH); 7.681 (t, 1H, J=7.78 Hz, ArH); 7.546 (d, 1H, J=7.04 Hz, ArH); 7.450 (dd, 1H, J=4.16, 8.55 Hz, ArH); 4.347 (s, 2H, ArCH2); MS (Electrospray): m/z 159.0 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[N:14][C:15]3[N:16]([C:22](=[O:24])[NH2:23])[CH2:17][CH2:18][CH2:19][C:20]=3[CH:21]=2)[CH:11]=1)C.[OH-].[Li+]>CCO.O>[C:22]([N:16]1[C:15]2[N:14]=[CH:13][C:12]([C:10]3[CH:11]=[C:6]([CH2:5][C:4]([OH:25])=[O:3])[CH:7]=[N:8][CH:9]=3)=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)(=[O:24])[NH2:23]
Reactant: CCOC(=O)Cc1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NC(=O)N1CCCc2cc(-c3cncc(CC(=O)O)c3)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.2 %

Procedure:
A mixture of [5-(8-carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-3-yl]-acetic acid ethyl ester (1.0 g, 2.9 mmol) and lithium hydroxide (123 mg, 5.1 mmol) in EtOH (10 mL) and H2O (10 mL) are stirred at room temperature for 16 h. The reaction is concentrated to remove the EtOH and the remaining aqueous mixture is treated with 1N HCl and diluted with EtOAc. The solid formed is filtered, rinsed and dried to give 500 mg of the titled product.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[N:10]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)=[O:15])[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-])=O>CO>[NH2:1][C:4]1[C:9]2[N:10]([CH2:13][C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:26])[F:24])[CH:18]=3)=[O:15])[CH:11]=[N:12][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cn1cnc2cccc([N+](=O)[O-])c21)Nc1cccc(C(F)(F)F)c1
Solvent: CO
Product: Nc1cccc2ncn(CC(=O)Nc3cccc(C(F)(F)F)c3)c12

Procedure:
To a solution of 2-(7-nitro-1H-benzoimidazol-1-yl)-N-[3-(trifluoromethyl)phenyl]acetamide, described above, (0.4 g, 1.1 mmol) in methanol (15 mL) 10% Pd/C (60 mg) was added. The mixture was hydrogenated at atmospheric pressure until the consumption of hydrogen ceased (1 h). The catalyst was removed by filtration through Celite, and the resulting clear solution was concentrated to dryness to yield the title compound, 0.36 g (99%). MS (ESI) m/z: 335.07 [M+H]. 1H NMR (400 MHz, DMSO-D6) δ ppm 4.91 (s, 2H) 5.33 (s, 2H) 6.50 (m, 1H) 6.89 (t, J=7.6 Hz, 1H) 6.97 (m, 1H) 7.41 (d, J=7.6 Hz, 1H) 7.56 (t, J=7.8 Hz, 1H) 7.77 (m, 1H) 7.99 (s, 1H) 8.07 (s, 1H) 10.84 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:20])[CH3:19])=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[Na+].[CH:24]1([C:30]([Cl:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl>CC(C)=O>[ClH:32].[CH:24]1([C:30]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:13][CH2:14][CH:15]([OH:21])[CH2:16][NH:17][CH:18]([CH3:19])[CH3:20])=[C:6]3[C:11]=2[NH:10][C:9](=[O:12])[CH2:8][CH2:7]3)=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CC(C)NCC(O)COc1ccc(O)c2c1CCC(=O)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CC(C)NCC(O)COc1ccc(OC(=O)C2CCCCC2)c2c1CCC(=O)N2
Yield: 45.5 %

Procedure:
0.66 g of 8-hydroxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril was suspended in 10 ml of acetone, and 3.0 ml of 1 N sodium hydroxide was added thereto to form a homogeneous solution. To the resulting solution was added dropwise 0.35 g of cyclohexylcarbonyl chloride dissolved in a small amount of acetone under ice-cooling and stirring. After the reaction mixture was allowed to stand under ice-cooling for 30 minutes, the mixture was adjusted to a pH of 3 with 1 N hydrochloric acid. The solvent was evaporated, and the residue was dissolved in water and then extracted with chloroform. The aqueous layer was concentrated to dryness under reduced pressure, and the residue was subjected to silica gel chromatography using chloroform-methanol (8:1 by volume) as an eluent. The solvent was evaporated, and the residue was recrystallized from methanol-diethyl ether to obtain 0.45 g of 8-cyclohexylcarbonyloxy-5-(2-hydroxy-3-isopropylaminopropoxy)-3,4-dihydrocarbostyril hydrochloride as colorless flake-like crystals having a melting point of 227°-228° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([N+:17]([O-])=O)[CH:5]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:6]([NH2:17])[CH:5]=1
Reactant: COC(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(NC2CCCCC2)c(N)c1
Yield: 0.1 %

Procedure:
Compound 50 (10.57 g, 37.9 mol) was hydrogenated in MeOH (130 mL) over 5% Pd/C (150 mg) under H2 for 30 minutes. The reaction was filtered through Celite and the solution was evaporated to give a brown solid (9.4 g, 99%). MS (ESI) 249.17 (M+H+).
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[NH2:4].[CH3:15][N:16]1[C:20]([C:21](O)=O)=[CH:19][CH:18]=[N:17]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CC(C)([O-])C.[K+]>O.O1CCCC1>[CH3:15][N:16]1[C:20]([C:21]2[O:1][N:2]=[C:3]([C:5]3[CH:6]=[CH:7][C:8]([C:11]([F:13])([F:12])[F:14])=[CH:9][CH:10]=3)[N:4]=2)=[CH:19][CH:18]=[N:17]1
Reactant: Cn1nccc1C(=O)O
Reactant: NC(=NO)c1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cn1nccc1-c1nc(-c2ccc(C(F)(F)F)cc2)no1
Reaction time: 16 h
Yield: 29.8 %

Procedure:
N′-hydroxy-4-(trifluoromethyl)benzene carboximidamide (450 mg) was added to a tetrahydrofuran (8.8 mL) suspension that contained 1-methyl-1H-pyrazol-5-carboxylic acid (450 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (465 mg) and 1-hydroxybenzotriazole monohydrate (328 mg) at a room temperature, and the obtained solution was then stirred for 16 hours. Thereafter, potassium tert-butoxide (1.11 g) and tetrahydrofuran (4.4 mL) were added to the reaction solution, and the obtained mixture was then stirred at a room temperature for 3 hours. Thereafter, water was added to the reaction solution, and the obtained mixture was then extracted with ethyl acetate. The organic layer was washed with a saturated saline, and was then dried over anhydrous magnesium sulfate, followed by vacuum concentration. The residue was purified by column chromatography (silica gel cartridge, hexane:ethyl acetate=75:25 to 50:50), so as to obtain the title compound (193 mg) in the form of a colorless solid.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][O:6][C@@H:5]([CH3:8])[O:4][C@H:3]1[CH2:9][OH:10].[C:11]([Si:15]([CH3:18])([CH3:17])Cl)([CH3:14])([CH3:13])[CH3:12].N1C=CN=C1>CN(C)C=O.C(OCC)(=O)C>[O:10]([CH2:9][C@H:3]1[C@H:2]([OH:1])[CH2:7][O:6][C@@H:5]([CH3:8])[O:4]1)[Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:18])[CH3:17]
Reactant: C[C@@H]1OC[C@@H](O)[C@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H]1OC[C@@H](O)[C@H](CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 105.1 %

Procedure:
A mixture of (2R,4S,5R)-5-hydroxy-4-hydroxymethyl-2-methyl-1,3-dioxane (13.0 g), t-butyldimethylchlorosilane (14.5 g) and imidazol (13.1 g) in N,N-dimethylformamide (130 ml) was stirred at room temperature for 2 hours and the mixture was diluted with ethyl acetate (500 ml). The solution was washed successively with water, diluted hydrochloric acid, saturated aqueous sodium hydrogen carbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2R,4S,5R)-4-t-butyldimethylsiloxymethyl-5-hydroxy-2-methyl-1,3-dioxane (24.2 g) as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3](=[O:25])[C@@H:4]1[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C:19](=[O:23])[CH2:20]2)[C@:16]2([CH3:17])[C@H:11]([CH2:12][C@H:13]([OH:24])[CH2:14][CH2:15]2)[CH2:10][CH2:9]3)[CH2:6][CH2:5]1.O1CCCC1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>CCOCC>[OH:24][C@@H:13]1[CH2:14][CH2:15][C@@:16]2([CH3:17])[C@@H:11]([CH2:10][CH2:9][C@@H:8]3[C@@H:18]2[C:19](=[O:23])[CH2:20][C@@:21]2([CH3:22])[C@H:7]3[CH2:6][CH2:5][C@@H:4]2[C:3](=[O:25])[CH2:2][N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[CH2:12]1
Reactant: C1COCCN1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CBr)[C@@]3(C)CC(=O)[C@@H]12
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 21-bromo-3α-hydroxy-5α-pregnane-11,20-dione (1.6 g) in refluxing tetrahydrofuran (40 ml) was treated with morpholine (0.7 ml) under nitrogen for 3 hr and then poured into ether. The ethereal solution was washed successively with 5% aqueous sodium bicarbonate and water, dried (Na2SO4) and evaporated. The residue was partitioned between a mixture of 2N-hydrochloric acid (6 ml), water (200 ml), acetone (20 ml) and methylene chloride (120 ml). The aqueous phase was treated with 2N-sodium hydroxide (6 ml) and sodium chloride (20 g) and the resulting mixture was extracted with methylene chloride. The extracts were washed with water, dried (Na2SO4) and evaporated to give title compound (1.5 g) as a white foam, [α]D + 81° (c 1.1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]2[N:17]=[CH:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.C([Li])CCC.CCCCCC.CON(C)[C:38](=[O:40])[CH3:39]>C1COCC1.CC(O)=O>[C:7]1([C:5]2[N:6]=[C:2]([CH2:1][C:38]([CH3:39])=[O:40])[S:3][C:4]=2[C:13]2[N:17]=[CH:16][N:15]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[N:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Cc1nc(-c2ccccc2)c(-c2ncn(C3CCCCO3)n2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a solution of 3-(2-methyl-4-phenyl-1,3-thiazol-5-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazole (32.6 g, 100 mmol) in THF (1.8 L), was dropwise added 1.6M solution of n-butyllithium in hexane (150 mL, 240 mmol) at −78° C. over 1 h, and the mixture was stirred for 1 h at the same temperature. To the reaction mixture was dropwise added a solution of N-methoxy-N-methylacetamide (10.3 g, 100 mmol) in THF (600 mL) at −78° C. over 3 h. After addition, the mixture was stirred for 30 min at the same temperature. The reaction mixture was neutralized by the addition of AcOH (13.8 mL), and the mixture was allowed to warm to rt. The solvent was evaporated under reduced pressure and then, to the residue, were added EtOAc (400 mL) and saturated aqueous ammonium chloride (300 mL). The aqueous layer was extracted with EtOAc, the combined organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate, and then insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc/hexane=5/95→80/20) to give the title compound (28.4 g, 74%) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[I-].C[N+]1C=CN([C:19](=[O:28])[N:20]([CH3:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)C=1.C(N(CC)CC)C>C(#N)C>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[O:1][C:19](=[O:28])[N:20]([CH3:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccccc1
Reactant: Oc1ccc2ccccc2n1
Agent: [I-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc2ccccc2n1)c1ccccc1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
A solution of 2-hydroxyquinoline (0.44 g, 3.00 mmol), 1-methyl-3-(methyl-phenyl-carbamoyl)-3H-imidazol-1-ium iodide (1.03 g, 3.00 mmol) and triethylamine (0.42 ml, 3.00 mmol) in acetonitrile (15 ml) was stirred at room temperature for 18 hours. More acetonitrile (60 ml) was added and the solution was heated at 50° C. for 3 days. The solvent was evaporated in vacuo and the residue was purified by flash column chromatography (SiO2, ethyl acetate:heptane (40:60)) yielding the title compound (0.33 g, 40% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=O)[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12](=[S:31])[C:11]3([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC1(CC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Solvent: Cc1ccccc1
Product: CCC1(CC)C(=S)Nc2ccc(-c3cccc(Cl)c3)cc21

Procedure:
The title compound was prepared from 5-(3-chloro-phenyl)-3,3-diethyl-1,3-dihydro-indol-2-one compound (100 mg) and Lawesson's reagent (100 mg) in toluene (10 ml) at reflux, according to General Procedure A, to afford the product (0.023 g) as a yellow solid: 1H NMR (DMSO-d6) δ 12.73 (br s, 1H), 7.77 (t, 1H, J=1.8 Hz), 7.75 (d, 1H, J=1.6 Hz), 7.68–7.62 (m, 2H), 7.48 (t, 1H, J=7.9 Hz), 7.40 (d, 1H, J=8.3 Hz), 7.09 (d, 1H, J=8.1 Hz), 2.07–2.00 (m, 2H), 1.86–1.79 (m, 2H) and 0.37 (t, 6H, J=7.3 Hz): MS ((−)-APCI) m/z 314/316 [M−H]−.
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:7]=1N.OS(O)(=O)=O.[I:22]I.[O-]S([O-])=O.[Na+].[Na+]>O>[Br:5][C:6]1[C:12]([C:13]([F:16])([F:15])[F:14])=[CH:11][CH:10]=[CH:9][C:7]=1[I:22]
Reactant: II
Reactant: Nc1cccc(C(F)(F)F)c1Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: O=S([O-])[O-]
Solvent: O
Product: FC(F)(F)c1cccc(I)c1Br
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
An ice-cold solution of NaNO2 (0.15 g) in water (0.5 mL) is added to a mixture of 2-bromo-3-trifluoromethyl-aniline (0.48 g), concentrated H2SO4 (2 mL), and water (1.8 mL) at ca. 5° C. The mixture is stirred in the cooling bath for 20 min and then poured into a solution of KI (0.56 g) and I2 (0.56 g) in water (0.5 mL). After gas evolution ceases, the mixture is heated to 40° C. and stirred at this temperature for 1 h. The mixture is cooled to room temperature and aqueous Na2SO3 solution is added. The resulting mixture is extracted with ethyl acetate, and the combined extracts are dried (Na2SO4) and concentrated. The solvent is evaporated and the residue is chromatographed (cyclohexane/ethyl acetate 95:5→90:10) to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[C:11]([CH3:18])[CH:10]=2)=[O:8])=[CH:5][N:4]=[CH:3]1.[NH4+].[Cl-]>CC(C)=O.O.[Zn]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]([C:6]2[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)=[O:8])=[CH:10][C:11]=1[CH3:18]
Reactant: Cc1cc(C(=O)c2cncn2C)ccc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(=O)c2cncn2C)ccc1N
Reaction time: 1 h

Procedure:
Zn (2.66 g, 40.7 mmol) was added in 2 portions over a period of 2 minutes to a mixture of (1-methyl-1H-imidazol-5-yl)(3-methyl-4-nitrophenyl)methanone (2.0 g, 8.1 mmol, Intermediate 14: step b) and NH4Cl (2.18 g, 40.7 mmol) in acetone (18.5 mL) and water (8.2 mL) at 0° C. After stirring for 1 hour, the reaction mixture was filtered through Celite®, rinsing with EtOAc. Acetone and EtOAc were removed on a rotary evaporator and the aqueous layer was filtered and the solids dried under vacuum to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13]CC)=O)=[CH:5]2.[H-].[Na+].[C:18](OCCCC)(=O)[CH:19]=C.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]3[CH2:18][CH2:19][C:11](=[O:13])[C:6]3=[CH:5][C:4]=2[CH:3]=1
Reactant: C=CC(=O)OCCCC
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C1CCn2c1cc1cc(Br)ccc12
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of ethyl 5-bromo-1H-indole-2-carboxylate (30 g, 112 mmol) in toluene (500 mL) was added portionwise sodium hydride (60% dispersion in mineral oil, 9.40 g, 235 mmol). Vigorous gas evolution was observed. The resulting white suspension was heated to 110° C. Butyl acrylate (35.1 mL, 246 mmol) was added dropwise (using a syring pump) over 24 h while stirring vigorously at an internal temperature of 110° C. Additional butyl acrylate (10 mL) was added in one portion and stirring was continued at 110° C. for 4 h followed by additional sodium hydride (60% dispersion in mineral oil, 5 g) and butyl acrylate (10 mL). 4 h later, butyl acrylate (6 mL) was added. Stirring was continued at 110° C. for a total of 48 h. The reaction was cooled in an ice-bath and 2 M HCl (400 mL) was added carefully. The layers were separated and the aqueous layer was extracted with dichloromethane (2×200 mL). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. The resulting orange residue was dissolved in acetic acid (900 mL) and water (100 mL). The orange solution was refluxed 16 h before the solvents were removed under vacuum. To the residue was added dichloromethane (300 mL). The resulting precipitate was collected by filtration and rinsed twice with dichloromethane to provide the title compound. LCMS m/z=250.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 3.20 (t, J=6.1 Hz, 2H), 4.46 (t, J=6.1 Hz, 2H), 6.92 (s, 1H), 7.46 (dd, J=8.8, 1.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.98 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH2:1]=[C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)[CH3:3].N1C2C(=CC=CC=2)C=N1>CO.[Pd]>[CH:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([CH3:3])[CH3:1]
Reactant: C=C(C)c1ccc2[nH]ncc2c1
Agent: [Pd]
Agent: c1ccc2[nH]ncc2c1
Solvent: CO
Product: CC(C)c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A 2:3 mixture of 5-(prop-1-en-2-yl)-1H-indazole and 1H-indazole (0.9 g), 10% Pd/C (0.2 g) in 150 mL of methanol was stirred at room temperature under H2 balloon for 3 hours. Pd/C was filtered off and the filtrate was concentrated under reduced pressure to give crude 5-isopropyl-1H-indazole (0.85 g) as an oil. LCMS: (M+H)+=161.
Reaction SMILES: N[CH2:2][C:3]1([OH:13])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.N([O-])=O.[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH:8]1[C:7]2[CH2:6][CH2:5][CH2:4][C:3](=[O:13])[CH2:2][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: NCC1(O)CCCc2ccccc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CCCc2ccccc2C1
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 1-aminomethyl-1-hydroxy-1,2,3,4-tetrahydronaphthalene (19 g) in 10% acetic acid in water (380 ml) was dropwise added sodium nitrite (11 g) in water (56 ml) at 5° C., and the mixture was stirred at the same temperature for 2 hours. The resulting mixture was diluted with ethyl acetate and separated. The organic layer was successively washed with water, saturated aqueous sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (hexane-ethyl acetate) to give 5,7,8,9-tetrahydrobenzocyclohepten-6-one (9.3 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:17]([C:19]1[N:23]([CH3:24])[C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)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]>[CH3:24][N:23]1[C:22]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=[C:19]1[C:17]#[N:18]
Reactant: O=S(=O)(c1ccc(Br)cc1)N1CCOCC1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cn1c(C#N)ccc1-c1ccc(S(=O)(=O)N2CCOCC2)cc1
Reaction time: 16 h
Yield: 8.3 %

Procedure:
According to general procedure B, 4-[(4-bromophenyl)sulfonyl]morpholine (122 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 1-methyl-5-[4-(morpholin-4-ylsulfonyl)phenyl]-1H-pyrrole-2-carbonitrile (11 mg, 8%) was provided after purification. MS (ESI) m/z 331. HPLC purity 100.0% at 210-370 nm, 9.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [C@H:1]12[CH2:7][C@H:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]([C@@H:10]([NH:15][C:16]([C:18]1[NH:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[C:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[N:51][C:52]([C:55](O)=[O:56])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)#[N:42].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>[C:41]([C:43]1[CH:44]=[CH:45][C:46]([C:49]2[CH:50]=[N:51][C:52]([C:55]([N:5]3[CH2:6][C@@H:1]4[CH2:7][C@H:4]3[CH2:3][N:2]4[C:8]([C@@H:10]([NH:15][C:16]([C:18]3[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:17])[C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:56])=[CH:53][CH:54]=2)=[N:47][CH:48]=1)#[N:42]
Reactant: N#Cc1ccc(-c2ccc(C(=O)O)nc2)nc1
Reactant: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[C@H](NC(=O)c1cc2ccccc2[nH]1)C(=O)N1C[C@@H]2C[C@H]1CN2C(=O)c1ccc(-c2ccc(C#N)cn2)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 10 ml vial was added N-{(1S)-1-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylcarbonyl]-2,2-dimethylpropyl}-1H-indole-2-carboxamide (100 mg, 0.268 mmol), EDC (128 mg, 0.670 mmol), HOBt (41.0 mg, 0.268 mmol), 5-cyano-2,3′-bipyridine-6′-carboxylic acid (74.7 mg, 0.322 mmol) mmol), CH2Cl2 (2.8 ml), DMF (5.0 ml) and DIEA (0.187 ml, 1.072 mmol). The mixture was stirred at room temperature for 1 h, then at 60° C. for 3 h. After cooling to room temperature, the mixture was diluted with CH2Cl2 and sat. Na2CO3. The organic layer was passed over a phase separator, concentrated and purified by reverse phase HPLC: 30×75 mm sunfire column 50 ml/min, 0.1% TFA, 20-60% ACN/Water over 14 min. The fractions containing the product were combined and diluted with CH2Cl2 and sat. NaHCO3. The organic layer was separated, passed over a phase separator and concentrated to afford the desired product as an off white solid (75 mg, 0.132 mmol) as an off white solid. LCMS (m/z): 562.3 (M+H). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.99 (s, 1H), 1.02-1.07 (m, 4H), 1.10 (s, 4H), 1.74-2.12 (m, 2H), 3.37-4.10 (m, 4H), 4.25-5.26 (m, 3H), 6.82-7.68 (m, 5H), 7.87-7.79 (m, 5H), 8.85-9.52 (m, 2H), 11.44-11.92 (m, 1H).