Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5]CC)=[O:4].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[I-].[Na+]>C(#N)C>[Br:1][CH2:2][C:3]([O-:5])=[O:4].[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: CCOC(=O)CBr
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: O=C([O-])CBr

Procedure:
The bis(methylhydrazine)terpyridine of Part A (3.50 g, 82 mmol), ethyl bromoacetate (13.2 mL, 820 mmol), 2,6-lutidine (9.6 mL, 820 mmol), and sodium iodide (0.35 g, 2 mmol) were added to 350 mL of acetonitrile, and the solution was refluxed under N2 for 48 hours, when an additional 4.1 mL (370 mmol) of ethyl bromoacetate and 4.8 mL (410 mmol) of 2,6-lutidine were added. The reaction solution was refluxed for an additional 48 hours, and cooled. A copious amount of white salt resulting from excess bromoacetate and lutidine was filtered and discarded. The filtrate was concentrated, and the concentrated material was dissolved in dichloromethane, and extracted two times with dilute aqueous sodium chloride. The organic phase was concentrated under high vacuum until free of odors of bromoacetate and lutidine. The crude oil was purified on a Woelm silica gel column (36×2 in.). The column was eluted initially with 100% dichloromethane followed by 50/1 dichloromethane/acetone, with gradual increase of the concentration of acetone to 25/1 dichloromethane/acetone. Concentration of purified fractions gave 2.91 g (46%) of light straw-colored oil. A fraction of the purified oil, upon standing at room temperature, crystallized, and after trituration with methanol gave a white solid, mp 100°-103° C. Anal. calcd for C40H49N 7 O9 : C, 62.24; H, 6.40; N, 12.70. Found: C, 62.31; H, 6.32; N, 12.69. The NMR and IR spectra were consistent with the assigned structure, and the product was homogeneous by TLC.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[O:21][CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17]2)=[CH:12][CH:11]=1.[ClH:29]>O1CCOCC1>[ClH:29].[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[O:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(-c3nc4ccccc4[nH]3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc2[nH]c(-c3ccc(C4CNCCO4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
tert-Butyl 2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)morpholine-4-carboxylate (330 mg, 0.87 mmol) was dissolved in dioxane (12 ml) and a solution of HCl in dioxane (4M, 3.25 ml, 13 mmol) was added. The reaction mixture was stirred overnight at room temperature. The solid was filtered off, washed with ether and dried in vacuo at 60° C. to afford 2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)morpholine hydrochloride (232 mg, 85%) as an off-white solid. MS (ISP): 280.1 ([M+H]+).
Reaction SMILES: [Na+].Br[C:3]1[CH:4]=[C:5]([S:13]([O-:16])(=[O:15])=[O:14])[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[ClH:62]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[ClH:62].[C:17]1([C:3]2[CH:4]=[C:5]([S:13]([OH:16])(=[O:15])=[O:14])[C:6]3[CH:7]=[CH:8][N:9]=[CH:10][C:11]=3[CH:12]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1ccccc1
Reactant: O=S(=O)([O-])c1cc(Br)cc2cnccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Product: O=S(=O)(O)c1cc(-c2ccccc2)cc2cnccc12
Temperature: 70 °C

Procedure:
Add 7-Bromo-isoquinoline-5-sulfonic acid sodium salt (17.8 g, 55.7 mmol), phenylboronic acid (10.2 g, 83.5 mmol), N)N-dimethylformamide (178 mL), 1M sodium carbonate (111 mL, 111 mmol), palladium acetate (0.125 g, 0.56 mmol) and 1,4-bis(diphenylphosphino)butane (0.285 g, 0.67 mmol) to a flask. Heat the slurry to 70° C. for 40 minutes. Cool and filter the solids from the reaction. Add 5N hydrochloric acid to the filtrate until a thick precipitate forms. Filter the precipitate and wash the filter cake with water and then with acetone. Dry the solid in a vacuum oven at 40° C. to provide the title compound as a yellow solid. 1H NMR (DMSO, 500.0 MHz): δ 9.87 (s, 1H), 9.15 (d, 1H, J=6.5 Hz), 8.79 (s, 1H), 8.70-8.75 (m, 2H), 7.87 (d, 2H, J=8.5 Hz), 7.63 (t, 2H, J=7.5 Hz), 7.54 (t, 1H, J=7.5 Hz).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:26][OH:27]>N1C=CC=CC=1>[I:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:19]([CH3:20])=[CH:18][C:17]3[C:16]([CH3:22])([CH3:21])[CH2:15][CH2:14][C:13]([CH3:24])([CH3:23])[C:12]=3[CH:11]=2)=[N:26][OH:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc2c(cc1C(=O)c1cccc(I)c1)C(C)(C)CCC2(C)C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc2c(cc1C(=NO)c1cccc(I)c1)C(C)(C)CCC2(C)C

Procedure:
A mixture of 3-iodophenyl-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)methanone (6 g, 13.9 mmol), hydroxylamine hydrochloride (4.8 g, 69.5 mmol) and 4 A molecular sieves in pyridine (17 ml) is refluxed for 8 h. The reaction medium is extracted with ethyl acetate and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. The two isomers (cis and trans) are separated by flash chromatography on a column of silica.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[CH:19]1([NH2:28])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1>>[CH:19]1([NH:28][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][N:17]=[CH:18][C:10]=2[NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH2:20]1
Reactant: NC1CCc2ccccc21
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Product: O=C(NC1CCc2ccccc21)c1ccncc1Nc1ccc(I)cc1F

Procedure:
N-(2,3-dihydro-1H-inden-1-yl)-3-[(2-fluoro-4-iodophenyl)amino]isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.43 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.57 mmol of indanylamine. LC/MS [10.69 min; 474 (M+1)]
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[NH:5][C:6]1[C:11]([CH2:12][NH2:13])=[CH:10][CH:9]=[CH:8][N:7]=1.[O:17]1CCC[CH2:18]1>CC(C)=O>[I:1][C:2]1[CH:3]=[C:4]([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[CH2:12][NH:13][C:18]2=[O:17])[CH:14]=[CH:15][CH:16]=1
Reactant: NCc1cccnc1Nc1cccc(I)c1
Reactant: C1CCOC1
Solvent: CC(C)=O
Product: O=C1NCc2cccnc2N1c1cccc(I)c1

Procedure:
To a solution of 3.3 g of 2-(m-iodoanilino)-3-aminomethylpyridine and 30 ml of dry tetrahydrofuran was added 3.2 g of N,N'-carbonyldiimidazole and the mixture was heated under reflux for 12 hours. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was dissolved in acetone. The acetone solution was placed on a column of alumina and eluted with acetone. The eluate was concentrated and left to yield 2.5 g of 1-(m-iodophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless needles, melting at 175° - 177° C.
Reaction SMILES: O[CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][N:5](C)[C:6](=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39]N1C(=O)CCC1=O>C(Cl)Cl>[Br:39][CH:2]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:3][CH2:4][NH:5][CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(CCC(O)c1ccccc1)C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CNCCC(Br)c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 22.4 %

Procedure:
tert-Butyl [3-hydroxy-3-phenylpropyl]methylcarbamate (0.52 g, 1.96 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Triphenylphosphine (1.02 g, 3.9 mmol) was added followed by N-bromosuccinimide (0.59 g, 3.3 mmol) and the mixture was stirred for 45 minutes. The reaction mixture was loaded directly onto silica gel and immediately purified via Isco chromatography (Redisep, silica, gradient 0-30% ethyl acetate in hexane) to afford 100 mg of (3-bromo-3-phenyl-propyl)-methyl-amine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[O:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)[C:5]([O:8][CH3:9])=[CH:6][CH:7]=1.[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:5]1[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[O:20][C:21]5[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=5[CH:23]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]([N:1]2[C:37](=[O:38])[C:31]3[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=3)[C:40]2=[O:39])=[CH:7][CH:6]=1
Reactant: COc1ccc(N)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Product: COc1ccc(N2C(=O)c3ccc(C(=O)O)cc3C2=O)cc1-c1nc2cc(-c3cc4ccccc4o3)ccc2o1

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-6-methoxyphenyl)-5-(2-benzofuranyl)benzoxazole (105 mg, 0.29 mmol) and 1,2,4-benzenetricarboxylic anhydride (57 mg, 0.29 mmol) the title compound was obtained (98 mg, 63%). 1H NMR (DMSO) δ 13.74(s, 1H), 8.43(dd, 1H), 8.32(d, 2H), 8.21(d, 1H), 8.10(d, 1H), 8.02(dd, 1H), 7.92(d, 1H), 7.72(dd, 1H), 7.67(t, 2H), 7.54(s, 1H), 7.47(d, 1H), 7.31(m, 2H), 4.03(s, 3H). MS 531.2 m/z (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+:20]=[N-:21])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([O-:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:25]>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+:20]=[N-:21])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:25])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(=O)[O-])C1
Reactant: N
Solvent: CO
Product: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)C1

Procedure:
In a still different procedure (Reaction Scheme E below), in which the order of steps is somewhat changed, the methyl dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthoate (XXV) can be treated with ammonia in methanol under pressure to yield the corresponding dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydronaphthalene-1-carboxamide (XXXIX). Conversion of the azide group to an amino group with hydrazine and Raney nickel yields a dl-2-benzyloxy-6-amino-5,6,7,8-tetrahydronaphthalene-1-carboxamide (XXXXI). This compound can be treated directly with hydrogen in the presence of a palladium catalyst to remove the benzyl group and yield a compound according to formula Ib above wherein R2 and R3 are both hydrogen. Alternatively, the benzyloxy derivative can be alkylated with a lower aldehyde and sodium cyanoborohydride to yield a dl-2-benzyloxy-6-dialkylamino-5,6,7,8-tetrahydronaphthalene-1-carboxamide (XXXXI) which compound, upon treatment with hydrogen in the presence of a palladium catalyst, yields a compound of this invention (Ib) where R2 and R3 are individually Me, Et or n-Pr.
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[C:7]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[C:6](OS(C(F)(F)F)(=O)=O)[CH2:5][CH2:4][CH2:3]1.[CH2:28]([SnH3])[CH:29]=[CH2:30].[Cl-].[Li+]>O1CCOCC1>[CH2:30]([C:6]1[CH2:5][CH2:4][CH2:3][C:2]([CH3:27])([CH3:1])[C:7]=1[CH2:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH:29]=[CH2:28]
Reactant: CC1(C)CCCC(OS(=O)(=O)C(F)(F)F)=C1CC(=O)OCc1ccccc1
Reactant: C=CC[SnH3]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: C=CCC1=C(CC(=O)OCc2ccccc2)C(C)(C)CCC1
Yield: 91.8 %

Procedure:
A solution of benzyl 2-[6,6-dimethyl-2-(trifluoromethylsulfonyloxy)cyclohexen-1-yl]acetate (2.30 g, 5.66 mmol) in dioxane (10 mL) was purged with argon. Then, allyl stannane (2.10 mL, 6.79 mmol), palladium triphenylphosphine tetrakis (327 mg, 0.28 mmol) and lithium chloride (360 mg, 8.49 mmol) were added. The solution was heated to reflux for 7 h and was then concentrated to give a crude yellow oil, which was purified by flash chromatography eluting with cyclohexane and ethyl acetate (25/1) to give the title compound as a colourless oil (1.55 g, 92%). 1H NMR (400 MHz, CDCl3) δ 7.33-7.40 (5H, m), 5.72 (1H, ddt, J=16.8, 10.5, 6.2 Hz), 5.11 (2H, s), 4.97 (1H, dt, J=16.8, 1.5 Hz), 4.96 (1H, dt, J=10.5, 1.5 Hz), 3.11 (2H, s), 2.71 (2H, d, J=6.2 Hz), 2.00 (2H, t, J=6.2 Hz), 1.58-1.65 (2H, m), 1.46-1.50 (2H, m), 0.97 (6H, s) ppm.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:16]([CH3:17])[C:15](=[O:18])[C:14]2[NH:19][CH:20]=[CH:21][C:13]=2[C:12]=1[C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:30][C:31]1[CH:39]=[CH:38][C:34]2=[N:35][O:36][N:37]=[C:33]2[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[N:35]1[O:36][N:37]=[C:33]2[CH:32]=[C:31]([CH2:30][N:19]3[C:14]4[C:15](=[O:18])[N:16]([CH3:17])[C:11]([CH:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:7]([O:9][CH3:10])=[O:8])=[C:12]([C:22]5[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=5)[C:13]=4[CH:21]=[CH:20]3)[CH:39]=[CH:38][C:34]=12
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2cc[nH]c2c(=O)n1C
Reactant: BrCc1ccc2nonc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)cc2)c2ccn(Cc3ccc4nonc4c3)c2c(=O)n1C
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A solution of methyl 2-(tert-butoxy)-2-(6-methyl-7-oxo-4-(p-tolyl)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (10 mg, 0.026 mmol) and 5-(bromomethyl)benzo[c][1,2,5]oxadiazole (22.28 mg, 0.105 mmol) in Acetonitrile (1 mL) was treated with cesium carbonate (34.1 mg, 0.105 mmol) and the resultant was stirred at 70° C. for 2 hours. The mixture was cooled to ambient temperature, water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was used crude in the next step without further purification. LC/MS (m/z) ES+=515 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=[CH:4][C:3]1=2.O[C:22]1[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH2:30][Si](C)(C)C)=[O:27])=[CH:24][CH:23]=1.Cl.CN(C)CCCN=C=NCC.CCOCC>CN(C=O)C>[CH3:1][C:2]1([CH3:20])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[C:8]2[CH:7]=[C:6]([C:17]([O:19][C:22]3[CH:36]=[CH:35][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=3)=[O:18])[CH:5]=[CH:4][C:3]1=2
Reactant: C[Si](C)(C)CCOC(=O)c1ccc(O)cc1
Reactant: CC1(C)CC=C(c2cccs2)c2cc(C(=O)O)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OC(=O)c2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1

Procedure:
A solution of 5,5-dimethyl-5,6-dihydro-8-(2-thienyl)-naphthalene-2-carboxylic acid (Compound E6, 79.0 mg, 0.280 mmol), 2-trimethylsilylethyl 4-hydroxybenzoate (73.3 mg, 0.308 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (70.0 mg, 0.364 mmol), and 4-N,N-dimethylaminopyridine (44.5 mg, 0.364 mmol) in 2.0 mL DMF was stirred overnight at room temperature. Et2O (100 mL) was added and the solution washed with H2O, 5% HCl, saturated aqueous NaCO3, and saturated aqueous NaCl before being dried over MgSO4. Removal of the sovents under reduced pressure and column chromatography (10% EtOAc-hexanes) of the residual off afforded the title compound as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:4][C:3]1=O.P(Cl)(Cl)([Cl:16])=O>C(#N)C>[Cl:16][C:3]1[CH:2]([CH3:1])[CH2:6][N:5]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:4]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CN(c2cccnc2)NC1=O
Solvent: CC#N
Product: CC1CN(c2cccnc2)N=C1Cl
Temperature: 75 °C

Procedure:
In another embodiment, 4-methyl-1-(pyridin-3-yl)pyrazolidin-3-one (1) in acetonitrile is chlorinated with phosphoryl chloride and the mixture is heated to about 75° C. The 3-(3-chloro-4-methyl-4,5-dihydro-1H-pyrazol-1-yl)pyridine (2) can be isolated and purified by standard techniques.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([C:13](O)=[O:14])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3].C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9][CH2:8]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
To a solution of 1-allyloxycarbonyl-4-carboxypiperidine (37 g) in tetrahydrofuran (400 ml) were added triethylamine (31 ml) and isobutyl chloroformate (27 ml) at -30° C. After stirring for 30 minutes at 0° C., the precipitate was filtered off. The obtained solution was added dropwise to the solution of sodium borohydride (13 g) in water (100 ml) at 0° C. After stirring for 1 hour at 0° C., sodium chloride was added to saturate the aqueous layer, and the organic layer was separated. The dried organic layer was evaporated and then the residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (1:1-1:2, V/V) to give 1-allyloxycarbonyl-4-hydroxymethylpiperidine (24 g).
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][CH2:12][C@@H:13]([NH:20][C:21]1[C:30]2[C:25](=[C:26]([C:31](=[O:33])[NH2:32])[CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)C1C=CC=CC=1>CCO.[Pd]>[NH2:10][CH2:11][CH2:12][CH:13]([NH:20][C:21]1[C:30]2[C:25](=[C:26]([C:31]([NH2:32])=[O:33])[CH:27]=[CH:28][CH:29]=2)[N:24]=[CH:23][N:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NC(=O)c1cccc2c(N[C@H](CCNC(=O)OCc3ccccc3)c3ccccc3)ncnc12
Agent: [Pd]
Solvent: CCO
Product: NCCC(Nc1ncnc2c(C(N)=O)cccc12)c1ccccc1
Yield: 54.5 %

Procedure:
[(R)-3-(8-Carbamoyl-quinazolin-4-ylamino)-3-phenyl-propyl]-carbamic acid benzyl ester (20 mg, 0.04 mmol) was dissolved in EtOH (5 mL) and treated with 5% Pd/C under 1 atm of H2. Upon completion the reaction was filtered through a pad of celite, and the pad was washed with EtOH. The crude material was purified by silica gel (10% MeOH/CH2Cl2) to afford the desired compound (7 mg, 50%). LCMS (ESI) 322 (M+H)
Reaction SMILES: F[C:2]1[N:7]=[C:6]([N:8]2[C:16]3[CH:15]=[C:14]([C:17]4[CH:22]=[N:21][CH:20]=[C:19]([CH3:23])[N:18]=4)[N:13]=[CH:12][C:11]=3[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].Br.Br.[NH:30]1[CH2:36][CH:35]([OH:37])[CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.CC(O)C>[CH3:23][C:19]1[N:18]=[C:17]([C:14]2[N:13]=[CH:12][C:11]3[CH:10]=[N:9][N:8]([C:6]4[N:7]=[C:2]([N:30]5[CH2:36][CH:35]([OH:37])[CH2:34][NH:33][CH2:32][CH2:31]5)[C:3]([C:24]([F:27])([F:25])[F:26])=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH:22]=[N:21][CH:20]=1
Reactant: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(F)n2)n1
Reactant: OC1CNCCNC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)O
Solvent: CS(C)=O
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2ccc(C(F)(F)F)c(N3CCNCC(O)C3)n2)n1
Temperature: 120 °C
Yield: 10.8 %

Procedure:
A mixture of 1-[6-fluoro-5-(trifluoromethyl)-2-pyridyl]-6-(6-methylpyrazin-2-yl)pyrazolo[4,3-c]pyridine (0.213 mmol; 79.9 mg), 1,4-diazepan-6-ol dihydrobromide (1.07 mmol; 297 mg), and cesium carbonate (2.13 mmol; 696 mg) in DMSO (2 mL) and IPA (4 mL) in a sealed pressure vial was heated at 120° C. overnight. The mixture was cooled to room temperature, and then filtered through Celite®. The filtrate was concentrated and the residue was purified by reverse phase HPLC to afford 219 as an off-white solid (10.8 mg, 11%). 1H NMR (400 MHz, DMSO) δ 9.59-9.53 (s, 1H), 9.48-9.43 (s, 1H), 9.38-9.33 (s, 1H), 8.79-8.75 (s, 1H), 8.66-8.62 (s, 1H), 8.22-8.17 (d, J=8.5 Hz, 1H), 7.57-7.52 (d, J=8.5 Hz, 1H), 4.76-4.67 (s, 1H), 3.98-3.88 (d, J=10.4 Hz, 3H), 3.75-3.66 (d, J=14.1 Hz, 1H), 3.65-3.55 (dd, J=15.3, 8.4 Hz, 1H), 3.15-3.07 (m, 1H), 3.06-2.99 (m, 1H), 2.87-2.79 (dd, J=13.7, 3.4 Hz, 1H), 2.76-2.68 (dd, J=13.6, 5.8 Hz, 1H), 2.69-2.62 (s, 3H); MS (ESI) m/z: 471.1 [M+H]+
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:16]=[C:17]1[CH2:22][C:21](=O)[CH2:20][CH2:19][NH:18]1>C1C=CC=CC=1.C(#N)C.CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][C:13]=2[O:14][CH3:15])[NH:10][C:21]2[CH2:20][CH2:19][NH:18][C:17](=[O:16])[CH:22]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(N)cc1OC1CCCC1
Reactant: O=C1CCNC(=O)C1
Solvent: c1ccccc1
Solvent: CC#N
Solvent: CO
Product: COc1ccc(NC2=CC(=O)NCC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.7 %

Procedure:
0.60 g (2.89 mmole) of the 3-cyclopentyloxy-4-methoxyaniline produced in Example 1(2) and 0.33 g (2.89 mmole) of 2, 4-dioxopiperidine were dissolved in solution of 15 ml of benzene, 4 ml of acetonitrile, and 1 ml of methanol and the mixture was stirred at room temperature for 24 hours. After the reaction, the solvent was removed in vacuo and the residue was triturated with ether. The precipitated brown crystal was collected by filtration, then dried in vacuo to obtain the title compound 0.88 g (yield 100%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[NH:8][C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=3)[CH:2]=1.[H-].[Na+].[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:24](Cl)=[O:25]>C1COCC1>[CH3:20][C:21]1[CH:22]=[C:23]([CH:27]=[C:28]([CH3:30])[CH:29]=1)[C:24]([N:8]1[C:9]2[C:14](=[CH:13][C:12]([C:16]#[N:17])=[CH:11][CH:10]=2)[CH:15]=[C:7]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:25]
Reactant: N#Cc1ccc2[nH]c(-c3cccnc3)cc2c1
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)n2c(-c3cccnc3)cc3cc(C#N)ccc32)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-pyridin-3-yl-1H-indole-5-carbonitrile (Example 8, 200 mg, 0.913 mmol) at 0° C. in THF (6 mL) is added 60% sodium hydride (72 mg, 1.826 mmol) and the mixture is stirred for 10 min at 0° C. The reaction mixture is then warmed to room temperature and stirred for 30 min. 3,5-Dimethyl-benzoyl chloride (460 mg, 2.740 mmol) in THF (2 mL) is added dropwise at 0° C. and the reaction is stirred at room temperature for 1 h. The reaction is quenched by adding saturated sodium bicarbonate. The THF is removed under vacuum, and the resulting residue is purified by silica gel flash chromatography (ethyl acetate-heptane, 0:1 to 1:1). The resulting product is further purified by HPLC using an X-bridge RP18 and an acetonitrile-0.1% ammonia hydroxide gradient to yield 1-(3,5-dimethyl-benzoyl)-2-pyridine-3-yl-1H-indole-5-carbonitrile. 1H NMR (400 MHz, CDCl3) δ ppm 2.25 (s, 6H), 6.88 (s, 1H), 7.10 (s, 1H), 7.14 (dd, J=7.6, 5.3 Hz, 1H), 7.22 (s, 2H), 7.50-7.56 (m, 2H), 7.70 (d, J=8.8 Hz, 1H), 8.01 (s, 1H), 8.43 (dd, J=4.8, 1.5 Hz, 1H), 8.62 (s, 1H). HRMS (ESI) m/z 352.1452 [(M+H)+: Calcd for C23H18N3O: 352.1450].
Reaction SMILES: [I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:18]([CH3:20])[CH3:19].[Cl-].[NH4+]>CN(C=O)C>[I:1][C:2]1[C:10]2[CH:9]=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)I
Reactant: Ic1c[nH]c2ncncc12
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)n1cc(I)c2cncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a mixture of 5-iodo-7H-pyrrolo[2,3-d]pyrimidine (Preparation 201, 2.90 g, 12.0 mmol) and cesium carbonate (5.78 g, 17.8 mmol) in DMF (45 mL) was added 2-iodopropane (1.78 mL, 17.8 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was then poured onto saturated aqueous ammonium chloride (500 mL) and a solid precipitated. The solid was collected by filtration, rinsed with water (200 mL) and dried under reduced pressure for 17 hours to afford the title compound as a brown solid in 77% yield, 2.61 g.