Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:17]Br>C(O)(=O)C>[NH2:1][C:2]1[C:11]([Br:17])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1ccc2cccnc2c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 401 mg of 7-aminoquinoline in 15 mL of glacial acetic acid are added 913 mg of sodium acetate followed by a solution of 0.14 mL of bromine in 15 mL of glacial acetic acid. The resulting yellow slurry is stirred at room temperature for 2 hours. The brown mixture is rotary evaporated and the residue is diluted with water and ethyl acetate. The mixture is basified using 1 N sodium hydroxide and decanted. The organic layer is washed with water followed by brine. The combined aqueous layers are extracted with ethyl acetate; the combined organic layers are dried over magnesium sulfate and rotary evaporated. The residue is purified by flash column chromatography on silica gel, eluting with 20% to 50% ethyl acetate/hexanes followed by recrystallization from hexanes/methylene chloride to provide 521 mg of 7-amino-8-bromoquinoline as a pale brown solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][CH:23]([N:26]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:22]2)[CH3:10])[C:5]([C:37]#[N:38])=[C:4]([CH3:39])[N:3]=1.O.NN>C(O)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22]2)[CH3:10])[C:5]([C:37]#[N:38])=[C:4]([CH3:39])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC(N3C(=O)c4ccccc4C3=O)C2)c1C#N
Agent: NN
Solvent: CC#N
Solvent: CCO
Solvent: O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CC[C@H](N)C2)c1C#N
Temperature: 75 °C
Yield: 92.8 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-(((S)-1-(6-(3-(1,3-dioxoisoindolin-2-yl)pyrrolidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile (peak 2 of PREPARATION 13, 10 mg, 0.019 mmol) and hydrazine monohydrate (0.019 mL, 0.38 mmol) in ethanol (2 mL). The mixture was heated to 75° C. for 3 hours, then diluted with acetonitrile, and directly purified by preparative HPLC (basic mode, 20-45% ACN/water gradient). The product-containing fractions were combined, concentrated, and lyophilized to give the title compound as a white solid (6.9 mg, 92%). The absolute configuration of the stereocenter on the pyrrolidine ring was not determined, but was assigned the opposite configuration of EXAMPLE 7. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.41 (d, J=6.32 Hz, 3H), 1.63-1.74 (m, 1H), 2.16 (dd, J=12.25, 7.20 Hz, 1H), 2.25 (s, 3H), 2.71 (dd, J=9.09, 4.80 Hz, 1H), 3.04 (td, J=8.27, 5.18 Hz, 1H), 3.60 (t, J=6.32 Hz, 1H), 3.71-3.85 (m, 3H), 5.75 (d, J=6.82 Hz, 1H), 6.42-6.51 (m, 1H), 7.07 (br s, 2H), 7.18 (d, J=7.58 Hz, 1H), 7.51 (d, J=3.28 Hz, 1H), 7.68-7.78 (m, 1H); ESI-MS m/z [M+H]+ calc'd for C20H25N9, 392. found 392.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:12])[C:10]=1[CH3:11])[N:7]([CH:13]=[O:14])[CH:6]([CH3:15])[CH2:5]2.Cl[CH2:17][C:18]([CH3:20])=[CH2:19].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:15][CH:6]1[CH2:5][C:4]2[C:8](=[C:9]([CH3:12])[C:10]([CH3:11])=[C:2]([O:1][CH2:19][C:18]([CH3:20])=[CH2:17])[CH:3]=2)[N:7]1[CH:13]=[O:14]
Reactant: Cc1c(O)cc2c(c1C)N(C=O)C(C)C2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)COc1cc2c(c(C)c1C)N(C=O)C(C)C2
Temperature: 60 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
A suspension of 2,3-dihydro-5-hydroxy-2,6,7-trimethyl-1H-indole-1-carbaldehyde (0.5 g, 2.4 mmol), 3-chloro-2-methyl-1-propene (0.29 mL, 2.9 mmol) and potassium carbonate (0.50 g, 3.6 mmol) in DMF (6 mL) was stirred at 60° C. for 14 hours under the nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate two times. The combined organic layers were washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel columns chromatography (hexane-ethyl acetate 3:1) to obtain 0.60 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH:9]=[CH2:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:13]([O:12][C:8](=[O:11])[CH:9]=[CH:10][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C=Cc1cncnc1
Temperature: 80 °C
Yield: 36.3 %

Procedure:
4.25 g 5-bromopyrimidine, 8.83 g tert.-butyl acrylate, 900 mg palladium (II) acetate, 1.79 g triphenylphosphane and 351 mg triethylamine were charged to a closed glass vial and heated with stirring to 80° C. over night. The mixture was evaporated under vacuum, the residue dissolved in ethyl acetate and filtered over a pad of silica. The filtrate was evaporated to yield 2.0 g of crude 3-pyrimidin-5-yl-acrylic acid tert.-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([OH:20])=[N:8][C:6]=2[N:7]=1.[H-].[Na+].[CH3:23]I>CN(C)C=O>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9](=[O:20])[N:8]([CH3:23])[C:6]=2[N:7]=1
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(O)nc2n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(-c2c(Cl)cccc2Cl)cc2cnc(N)nc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 49.1 %

Procedure:
To a mixture of 2-amino-6-(2,6-dichlorophenyl)pyrido[2,3-d]pyrimidin-7-ol (3.7 g) from Example 11 in dimethylformamide was added NaH (50% suspension in mineral oil, 0.64 g). The resulting slurry was heated at 65° C. for 0.5 hour until a solution formed. It was then cooled to 50° C. and a solution of methyl iodide (2.0 g) in dimethylformamide (10 mL) was added dropwise to the reaction. The reaction mixture was warmed and kept between 60° C.-80° C. for 3 hours. Upon cooling to room temperature, the reaction mixture was poured into ice water. The insoluble white product was filtered, washed with water, and recrystallized from ethanol using charcoal to give 1.9 g of 2-amino-6-(2,6-dichlorophenyl)-8-methyl-pyrido[2,3 -d]pyrimidin-7(8H)-one, mp 235°-237° C.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:29][CH:30]([OH:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]([CH2:29][C:30](=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCCCCCCCC(O)Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCCCC(=O)Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reaction time: 0.17 h
Yield: 89.3 %

Procedure:
To a mixture of 15 ml of methylene chloride and 1.2 ml of pyridine was gradually added 2 g of chromic anhydride under cooling to 0° C. to -5° C. and after stirring the mixture for 10 minutes at 0° to -3° C., a solution of 0.9 g of 3,4-dibenzyloxyphenyl-2-undecanol in 3 ml of methylene chloride was added to the mixture. After further stirring the mixture for 20 minutes at 0° to 10° C., the supernatent methylene chloride solution was concentrated under reduced pressure. The residue was applied to silica gel column chromatography and eluted with toluene to provide 0.8 g of 1-(3,4-dibenzyloxyphenyl)-2-undecanone.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][C:28]([CH:31]=[CH2:32])=[CH:27][CH:26]=4)=[N:21]3)[N:15]2[CH2:18][CH3:19])=[C:11]([NH2:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([N:20]3[CH:24]=[CH:23][C:22]([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=4)=[N:21]3)[N:15]2[CH2:18][CH3:19])=[C:11]([NH2:33])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc(-c2ccn(-c3nc4c(N)nc(NCc5ccccc5)nc4n3CC)n2)cc1
Agent: [Pd]
Solvent: CO
Product: CCc1ccc(-c2ccn(-c3nc4c(N)nc(NCc5ccccc5)nc4n3CC)n2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N2 benzyl-8-[3-(4-vinylphenyl)pyrazol-1-yl]-9-ethyl-9H-purine-2,6-diamine, a compound of Formula I (25 mg, 0.05 mmoles), was dissolved in methanol (2 mL), and to this solution was added 20% w/w Pd/C. The reaction mixture was stirred at room temperature under hydrogen at 1 atmosphere. After 2 hours, the reaction mixture was filtered over celite, solvent evaporated under reduced pressure, and the residue obtained was purified by preparative TLC (eluting with 1:1 EtOAc:Hexanes) to give N2 benzyl-8-[3-(4-ethylphenyl)pyrazol-1-yl]-9-ethyl-9H-purine-2,6-diamine as a yellow solid. Similarly, reduction of N2 benzyl-8-[4-allylpyrazol-1-yl]-9-ethyl-9H-purine-2,6-diamine affords N2 benzyl-8-[4-propylpyrazol-1-yl]-9-ethyl-9H-purine-2,6-diamine.
Reaction SMILES: C([O:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:21]([NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:10]1)C1C=CC=CC=1.CCN(C(C)C)C(C)C.C(N)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl.CCOC(C)=O>[C:24]([NH:23][C:21]([C@@H:11]1[CH2:10][C@@H:9]([OH:8])[CH2:13][N:12]1[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 7 h
Yield: 72 %

Procedure:
The N-protected acid (17.5 g, 75.6 mmol, described in section (a) of example 1) was dissolved in CH2Cl2 (300 mL) and DIEA (13 mL, 76.6 mmol). tert-Butylamine (8.73 mL, 83.1 mmol ) was added to the solution, followed by the addition of BOP (40 g, 90.7 mmol) and DIEA (13 mL, 151 mmol). The mixture was stirred at room temperature for 7 h and then diluted with EtOAc. The organic phase was separated, washed with a saturated aqueous solution of NaHCO3 (2×), H2O (2×) and brine (2×), dried (MgSO4) and evaporated to dryness. The solid residue was triturated with Et2O/EtOAc (9:1), collected on a filter, washed with Et2O and dried to provide N-tert-butyl-1-(tert-butyloxycarbonyl)-4(R)-hydroxypyrrolidine-2(S)-carboxamide (15.6 g, 72%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-:11])=[O:10].[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([OH:32])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1>>[Cl:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([Cl:34])[C:18]=1[NH:19][C:20]1[C:29]2[C:24](=[C:25]([O:32][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N+:9]([O-:11])=[O:10])[C:26]([O:30][CH3:31])=[CH:27][CH:28]=2)[O:23][C:22](=[O:33])[CH:21]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O
Reactant: O=[N+]([O-])c1ccccc1CBr
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCc1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from 1-(bromomethyl)-2-nitrobenzene and 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxy-2H-chromen-2-one (Example 29) following the procedure outlined in Example 25. 1H NMR (400 MHz, DMSO-d6): δ 9.55 (s, 1H), 8.81 (s, 2H), 8.12 (dd, 1H), 8.05 (d, 1H), 7.99 (d, 1H), 7.82 (td, 1H), 7.62 (td, 1H), 7.22 (d, 1H), 5.43 (s, 2H), 4.65 (s, 1H), (s, 3H); MS (ESI): 487.8.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](Cl)=[O:7].[CH3:9][N:10]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[C:13]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[C:12]([C:27]#[N:28])[C:11]1=[O:29]>N1C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([N:24]1[CH2:25][CH2:26][N:21]([C:13]2[C:14]3[C:19](=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=3)[N:10]([CH3:9])[C:11](=[O:29])[C:12]=2[C:27]#[N:28])[CH2:22][CH2:23]1)=[O:7]
Reactant: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Reactant: O=C(Cl)c1ccco1
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)c(N1CCN(C(=O)c3ccco3)CC1)c(C#N)c(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 58.7 %

Procedure:
2-Furoyl chloride (148 μL, 1.5 mmol) was added to a stirred solution of Compound 28 (282 mg, 1.0 mmol) in pyridine (5 mL) under argon at 0° C. The solution was allowed to come to room temperature and further stirred overnight. The solution was poured into ice water and the solids formed were filtered. The solids were washed by excess water, dried, and recrystallized by ethyl acetate to yield 221 mg (59%) of white solids. M.P. 231° C. 1H NMR (DMSO-d6): δ 2.41 (s, 3H), 3.56 (s, 3H), 3.63 (m, 4H), 3.95 (m, 4H), 6.66 (dd, J=1.5, 3.6 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 7.48 (d, J=8.7 Hz, 1H), 7.59 (dd, J=1.2, 8.8 Hz, 1H), 7.69 (s, 1H), 7.88 (s, 1H). EIMS m/z 399 (M+23). Anal. (C21H20N4O3) C, H, N.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][S:11][C:12]1[N:17]2[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1)=O)(C)(C)C.[ClH:24]>CO>[ClH:24].[ClH:24].[NH2:8][CH2:9][CH2:10][S:11][C:12]1[N:17]2[C:18]([N+:21]([O-:23])=[O:22])=[CH:19][N:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCSc1cccc2ncc([N+](=O)[O-])n12
Agent: Cl
Solvent: CO
Product: NCCSc1cccc2ncc([N+](=O)[O-])n12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 5-[2-(tert-butoxycarbonylamino)ethylthio]-3-nitroimidazo[1,2-a]pyridine (364 mg, 1.08 mmoles) in methanol (3 ml) was added conc. hydrochloric acid (2 ml) and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off to obtain 340 mg of the desired product (quantitative, brown solid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[N:5]([CH3:11])[N:4]=1.O1CCCC1.S(Cl)(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([N:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[CH:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:8]([C:6]5[N:5]([CH3:11])[N:4]=[C:3]([O:2][CH3:1])[CH:7]=5)=[O:10])[CH:23]=4)=[CH:31][N:30]3[N:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: COc1cc(C(=O)O)n(C)n1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)cc1N
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)ccc2C)n(C)n1
Yield: 82 %

Procedure:
In the same manner as in Example 55 and using 3-methoxy-1-methyl-1H-pyrazole-5-carboxylic acid (62.5 mg, 0.400 mmol), tetrahydrofuran (5 mL), thionyl chloride (69.1 μL, 0.796 mmol), N,N-dimethylformamide (2 drops), N-[6-(3-amino-4-methylphenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (117 mg, 0.362 mmol) and N,N-dimethylacetamide (6 mL) as starting materials, the title compound (137 mg, 82%) was obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[NH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:33]([N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([CH2:16][CH2:15][CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:18]1)(=[O:35])[CH3:34]
Reactant: Clc1ccc(N2CCN(CCCc3c[nH]c4c3CCCC4)CC2)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)n1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)c2c1CCCC2

Procedure:
3-(3-(4-(4-Chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole (0.5 g) obtained in Example 161 and triethylamine (0.6 ml) were dissolved in dichloromethane (10 ml) and acetyl chloride (0.3 g) was added under ice-cooling with stirring. The reaction mixture was stirred for 2 hours at room temperature and an aqueous potassium carbonate solution is added, and the chloroform layer was separated. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography to give 1-acetyl-3-(3-(4-(4chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16](=[O:24])[NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11](B(O)O)[CH:12]=2)[N:7]=1.Br[C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[CH:32]2>CN(C=O)C.C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:15]=[C:14]([C:16]([NH:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)=[O:24])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][CH:33]=[CH:32]4)[CH:12]=2)[N:7]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(B(O)O)cc12
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(-c2ccco2)nc2ccc(-c3ccc4[nH]ccc4c3)cc12
Temperature: 90 °C
Reaction time: 0.08 h
Yield: 6.4 %

Procedure:
To a sealed tube under argon atmosphere was added (2-(furan-2-yl)-4-(pyridin-3-ylcarbamoyl)quinolin-6-yl)boronic acid (0.120 g) in DMF (4 ml) and the vessel was purged with argon under stirring for 5 minutes. After 5 minutes, a 2N aqueous solution of potassium carbonate was added (1.8 ml, 11 eq) and the tube was purged with argon under stirring for 5 minutes. 5-bromoindole (0.057 g, 0.9 eq) was then added and the vessel was purged with argon under stirring for 15 minutes. Finally tetrakistriphenylphosphine palladium(0) (0.011 g, 0.03 eq.) was added under argon and the tube was sealed. The reaction mixture was heated to 90° C. for 5 hours. The completion of the reaction was monitored by TLC using ethyl acetate:hexanes (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted with ethyl acetate (10 ml) and then washed with water (5*10 ml). The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation and the crude product was subjected to purification by high performance liquid chromatography to provide 2-(furan-2-yl)-6-(1H-indol-5-yl)-N-(pyridin-3-yl)quinoline-4-carboxamide (0.008 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.34 (s, 1H), 11.19 (s, 1H), 9.00 (m, 1H), 8.41 (m, 1H), 8.35 (m, 1H), 8.30 (m, 1H), 8.20 (m, 1H), 8.12 (m, 2H), 7.85 (m, 1H), 7.70 (m, 1H), 7.4 (m, 1H), 7.58 (m, 1H), 7.50 (m, 2H), 7.43 (m, 1H), 7.12 (m, 1H), 6.54 (m, 1H); m/z 431.2 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3([CH:29]=[CH:28][C:27](=[O:30])[CH:26]=[CH:25]3)[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]3[CH:29]=[CH:28][C:27](=[O:30])[CH:26]=[CH:25][C:16]3=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CC2(C=C1)N=C(N1CCN(Cc3ccccc3)CC1)C=C2c1ccccc1
Solvent: ClCCl
Product: O=c1ccc2c(-c3ccccc3)cc(N3CCN(Cc4ccccc4)CC3)n2cc1
Temperature: 20 °C
Yield: 71.9 %

Procedure:
2-(4-Benzyl-1-piperazinyl)-4-phenyl-1-azaspiro[4.5]deca-1,3,6,9-tetraen-8-one (14.6 g) is heated for 10 minutes to a temperature of about 200° C. After being cooled to a temperature of about 20° C., the residue obtained is dissolved in methylene chloride (500 cc) and the solution is poured into silica (300 g) contained in a column 4.2 cm in diameter. Elution is performed first with pure methylene chloride (4 liters); the corresponding eluate is rejected. Elution is then performed with a mixture of methylene chloride and methanol (90:10 by volume) (3 liters) and the eluate is evaporated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. After recrystallization of the residue in acetonitrile (200 cc), 3-(4-benzyl-1-piperazinyl)-1-phenyl-7H-pyrrolo[1,2-a]azepin-7-one (10.5 g), m.p. 157° C., is obtained.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@H:5]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C:6]([OH:8])=[O:7].O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C([BH3-])#N.[Na+]>C1COCC1.O>[CH2:13]([O:12][C:10]([NH:9][C@@H:5]([CH2:4][CH2:3][CH2:2][NH:1][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)[C:6]([OH:8])=[O:7])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(NCCC[C@H](NC(=O)OCc2ccccc2)C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(S)-5-amino-2-(benzyloxycarbonylamino)pentanoic acid (50 g, 188 mmol) was dissolved in THF (800 mL) and water (100 mL). Tert-butyl 4-oxopiperidine-1-carboxylate (37 g, 188 mmol) was added and the reaction was stirred for 1 hour. The reaction was cooled to 0° C. and sodium cyanoborohydride (12 g, 188 mmol) was added and the reaction stirred at ambient temperature overnight. The reaction was concentrated to provide (S)-2-(benzyloxycarbonylamino)-5-(1-(tert-butoxycarbonyl)piperidin-4-ylamino)pentanoic acid, which was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:3]1[CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[O:6][C:2]=1[CH3:1]
Reactant: COC(=O)c1ccc(C)o1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(Br)c(C)o1
Temperature: 0 °C
Yield: 89.6 %

Procedure:
To a solution of methyl 5-methyl-2-furancarboxylate (1.5 g, 10.70 mmol) and aluminum trichloride (2.14 g, 16.06 mmol) in chloroform (21 ml) at 0° C. was added bromine (0.77 ml, 14.99 mmol). The resulting solution stirred at 0° C. and warmed to RT over 12 h. This reaction was run in batches (1.5 g and 1 g) and the batches were combined, added to ice and partitioned between H2O-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified by column chromatography (0.5-10% EtOAc in hexanes) affording the title compound (2.1 g, 54%) as a white solid; LCMS (ES) m/z=219, 221 (M, M+2)+.
Reaction SMILES: [Li+].[B-](CC)(CC)CC.[CH3:9][C:10]([Si:13]([CH3:34])([CH3:33])[O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]1[CH2:27]OS(C)(=O)=O)([CH3:12])[CH3:11]>C1COCC1>[CH3:11][C:10]([Si:13]([CH3:34])([CH3:33])[O:14][C@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:16]1[CH3:27])([CH3:9])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1COS(C)(=O)=O
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.1 %

Procedure:
Superhydride (45.8 mL, 1M, 45.8 mmol) was added dropwise to an ice cold solution of 1,1-dimethylethyl(2R,3S)-3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}-1-pyrrolidinecarboxylate (4.69 g, 11.47 mmol) in THF. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was quenched with i-propanol until gas evolution ceased. The reaction was diluted with saturated NaHCO3 then extracted with ethyl acetate, dried over MgSO4 and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography to yield the title compound (2.69 g, 8.5 mmol). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.0 (s, 6 H) 0.8 (s, 9 H) 1.0 (m, 3 H) 1.4 (s, 9 H) 1.6 (m, 1 H) 2.0 (m, 1 H) 3.3 (m, 2 H) 3.5 (m, 1 H) 4.0 (m, 1 H). ES+=316.22.