Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7](=[O:31])[CH:8]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:13][CH2:12]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[CH:1]1([CH:7]([OH:31])[CH:8]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][CH3:24])[CH2:15][CH2:16]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccccc1N1CCN(CCC(C(=O)C2CCCCC2)c2ccccc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccccc1N1CCN(CCC(c2ccccc2)C(O)C2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.2 %

Procedure:
Into a solution of 1.21 g of Compound 5d in 60 ml of dichloromethane at −78° C., was dropped 11.5 ml of 1 M solution of diisobutylaluminum hydride (DIBAL-H) in toluene. The mixture was stirred at −78° C. for 1 h, quenched at 40° C. with a saturated aqueous solution of NH4Cl and extracted with chloroform. The collected organic layers were washed with water, dried (Na2SO4) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography eluting with petroleum ether-EtOAc-2 N ammonia in methanol 30:70:2 to give 1.06 g (80%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])(=[O:38])[CH:35]([CH3:37])O>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=2)[O:31][CH:35]([CH3:37])[C:34]([O:39][CH2:40][CH2:41][CH2:42][CH3:43])=[O:38])=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)C(C)O
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3cccc(O)c3)cc2)cccc1[N+](=O)[O-]
Product: CCCCOC(=O)C(C)Oc1cccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 61F and butyl lactate was processed as described in Example 62A to provide the title compound.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[Cl:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[C:11]([N+:16]([O-:18])=[O:17])[CH:10]=1>S(=O)(=O)(O)O.O>[C:5]([NH:13][C:12]1[CH:14]=[CH:15][C:9]([Cl:8])=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17])(=[O:7])[CH3:6]
Reactant: Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 50 °C

Procedure:
To a mixture of 50 ml of acetic anhydride and two drops of sulfuric acid was added 34.5 grams of 4-chloro-2-nitroaniline in several portions. At the end of addition, the solution was heated at 50° C. for one hour and then allowed to cool. 300 ml of cold water was added to the solution to induce precipitation of crystals, which were removed by filtration and washed with water. There were obtained the crystals of 2-acetylamino-5-chloronitrobenzene in a yield of 41.8 grams.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].N1C=CC=CC=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>ClCCl>[C:31]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][CH:13]=[C:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=CNc1ncnc2ccc(N)cc12)C(=O)OCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(=CNc1ncnc2ccc(NC(C)=O)cc12)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A mixture of diethyl [(6-amino-4-quinazolinylamino)methylene]propanedioate (3.03 g), pyridine (3.63 g) and dichloromethane (93 ml) was ice-cooled. To the mixture was added acetic anhydride (1.88 g). The reaction mixture was stirred for 30 minutes under ice-cooling and then for 2 hours and 15 minutes at ambient temperature. Ice water was added to the mixture. The resultant mixture was extracted with chloroform. The organic layer was washed three times with water and with aqueous solution saturated with sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a residue, which was purified by a column chromatography on silica gel (developing solvent: chloroform) and recrystallized from chloroform, ethyl acetate and hexane to give crystalline diethyl [(6-acetamido-4-quinazolinylamino)methylene]-propanedioate (2.2 g).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N+:19]([O-:21])=[O:20])=[C:6]3[C:11](=[CH:12][CH:13]=2)[C:10](=[O:14])[N:9]([C@H:15]([CH3:18])[CH2:16][OH:17])[CH:8]=[CH:7]3)[CH2:3][CH2:2]1.[C:22](OC(=O)C)(=[O:24])[CH3:23].N1C=CC=CC=1.C(Cl)Cl>>[C:22]([O:17][CH2:16][C@H:15]([N:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[C:5]=2[N+:19]([O-:21])=[O:20])[C:10]1=[O:14])[CH3:18])(=[O:24])[CH3:23]
Reactant: C[C@H](CO)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC[C@@H](C)n1ccc2c([N+](=O)[O-])c(C3CC3)ccc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottom flask was charged with (R)-6-cyclopropyl-2-(1-hydroxypropan-2-yl)-5-nitroisoquinolin-1(2H)-one (30 mg, 0.0001 mol), acetic anhydride (0.015 mL, 0.00016 mol), pyridine (0.015 mL, 0.00019 mol) and methylene chloride (4 mL, 0.06 mol), and was stirred at room temperature overnight. The solvent was removed under reduced pressure and the product was taken onto the next step without purification.
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[CH2:12][C:13](=O)[CH3:14].C([OH:23])C1C=CC=CC=1.O[Li].O.Cl>ClCCl>[F:1][C:2]1[C:7]([OH:23])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:12]=[C:13]([CH3:14])[NH:9]2
Reactant: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: OCc1ccccc1
Agent: Cl
Agent: [Li]O
Solvent: ClCCl
Solvent: O
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
To a solution of 1-(2,3-difluoro-6-nitrophenyl)-propan-2-one (2.5 g, 82% purity by HPLC analysis, 9.54 mmol) were added benzyl alcohol (2.5 mL) and LiOH.H2O (1.07 g, 25.58 mmol). The reaction mixture was then heated to 100-110° C. and stirred for 4 hours until HPLC analysis indicated complete reaction. After cooling to RT, the reaction mixture was diluted with dichloromethane (18 mL) and neutralized to pH 6-7 with 1 N HCl. The layers were separated and the organic phase was washed with brine and collected. With stirring, heptane (30-25 mL) was added to the organic solution whereupon crystallization was initiated. The resulting slurry was cooled to 0-5° C. and stirred for an additional 1 h. The slurry was then filtered and the filter cake was washed with heptane. The yellow-brown solids were then dried in vacuo at 50° C. for 12-15 h to afford 1.6 g of the desired compound which was 95% pure by HPLC analysis. HPLC method: Column: YMC Pack Cyano 3 um 4.6×50 mm Solvent A: 0.05% TFA in MeOH:Water (20:80), Solvent B: 0.05% TFA in MeOH:water (20:80), Wavelength: 254 nm Flow Rate: 3 mL/min. Gradient Time: 3 min. Final % B: 100 Initial Hold: 0.5 min. Start % B: 0. Typical Retention Times: SM, 1.2 min; Product 2.2-2.3 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24](=[O:27])[CH:25]=[O:26])[CH3:22]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:21]([O:23][C:24](=[O:27])[CH:25]([OH:26])[CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH3:22]
Reactant: CCOC(=O)C=O
Reactant: CCCC(=O)Cc1ccc(OCc2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCC(=O)C(c1ccc(OCc2ccccc2)cc1)C(O)C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(4-benzyloxy-phenyl)-pentan-2-one (2.98 mmol, 11.4 g), oxo-acetic acid ethyl ester solution in toluene (8 mL, 50% solution in toluene) and triethylamine (2 mL) was stirred at ambient temperature for 24 h. The volatiles were removed under reduced pressure, and the resultant residue was purified by flash silica gel chromatography using by eluting with 30% ethyl acetate in hexanes to provide 3-(4-benzyloxy-phenyl)-2-hydroxy-4-oxo-heptanoic acid ethyl ester.
Reaction SMILES: [CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:4]2[CH:13]=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:14])[CH:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc(C2CC2)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C2CC2)ccc1C(=O)O
Temperature: 25 °C
Yield: 100 %

Procedure:
Methyl 4-cyclopropyl-2-methylbenzoate (32.00 g, 168 mmol), 250 mL of 5 M aqueous sodium hydroxide, and 150 mL of methanol were stirred at 85° for 18 hr. Cooled the reaction mixture to room temperature and concentrated in vacuo. Dissolved the white residue in 500 mL of water, cooled the solution in an ice bath, and added 120 mL of concentrated hydrochloric acid. A white precipitate formed. Extracted the aqueous mixture with 2×250 mL EtOAc. Combined the organic extracts and washed with 250 mL brine. Dried the solution over MgSO4 and concentrated in vacuo to obtain 4-cyclopropyl-2-methylbenzoic acid as an off-white solid (29.52 g, 168 mmol). MS (ESI) MS (ESI) 175.0 (M-H)−.
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])([CH3:4])([CH3:3])[CH3:2].Br[CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[C:1]([O:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH:8][CH2:12][CH:13]([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(CBr)OCC
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Product: CCOC(CN[C@@H](C)C(=O)OC(C)(C)C)OCC

Procedure:
L-Alanine-t-butyl ester was allowed to react with 2-bromo-1,1-diethoxyethane in substantially the same manner as in Working Example 52 to afford the title compound as a yellowish brown oily product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([CH:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[CH3:26])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].C(N(CC)CC)C.[CH3:40][N:41]([CH3:45])[C:42](Cl)=[O:43]>ClCCl>[NH2:24][C:19]1[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:16]2[CH:15]=[C:14]([CH:25]([N:27]3[CH2:28][CH2:29][N:30]([C:42]([N:41]([CH3:45])[CH3:40])=[O:43])[CH2:31][CH2:32]3)[CH3:26])[CH:13]=[N:12][C:11]=2[NH:10][C:4]2[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[N:18]=1
Reactant: CN(C)C(=O)Cl
Reactant: COc1ncc(Nc2ncc(C(C)N3CCNCC3)cc2-c2nc(C)nc(N)n2)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ncc(Nc2ncc(C(C)N3CCN(C(=O)N(C)C)CC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 42.7 %

Procedure:
A mixture of 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(1-(piperazin-1-yl)ethyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.141 g, 0.321 mmol) in dichloromethane (5 mL) was chilled to 0° C. in an ice bath, then triethylamine (0.224 mL, 1.604 mmol) was added to the mixture while stirring. After 10 min, dimethylcarbamic chloride (Aldrich; 0.104 g, 0.962 mmol) was added into the mixture slowly via syringe. After the addition, the ice bath was removed and the mixture was allowed to stir under inert atmosphere overnight. The mixture was diluted with chloroform (20 mL) and water (10 mL). The organic layer was extracted with chloroform (3×10 mL). The combined organic extracts were dried (magnesium sulfate), filtered and concentrated in vacuo. The crude material was adsorbed onto silica gel and purified by chromatography through a silica-gel column (25 g) eluting with a 20% mixture of 10:1 methanol/ammonium hydroxide in dichloromethane to give 4-(1-(5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)ethyl)-N,N-dimethylpiperazine-1-carboxamide (0.070 g, 0.137 mmol, 42.7% yield) as a tan solid. 1H NMR (400 MHz, CDCl3) δ 12.34 (s, 1H) 9.40 (d, J=2.15 Hz, 1H) 8.17-8.23 (dd, 1H) 8.12 (d, J=2.54 Hz, 1H) 8.09 (d, J=2.15 Hz, 1H) 4.04 (s, 3H) 3.10-3.98 (m, 9H) 2.85 (s, 6H) 2.56 (s, 3H) 1.88 (d, J=6.85 Hz, 3H). m/z (ESI, +ve ion) 533 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:7][C:6](=[O:8])[NH:5][C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]1=2.[CH2:23]([O:25][CH:26](OCC)[O:27][CH2:28][CH3:29])[CH3:24]>>[CH2:23]([O:25][CH:26]([O:27][CH2:28][CH3:29])[N:5]1[C:4]2[CH:9]=[CH:10][C:11]([C:13]3[CH:14]=[C:15]([CH:18]=[C:19]([F:21])[CH:20]=3)[C:16]#[N:17])=[CH:12][C:3]=2[C:2]([CH3:22])([CH3:1])[O:7][C:6]1=[O:8])[CH3:24]
Reactant: CCOC(OCC)OCC
Reactant: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21
Product: CCOC(OCC)N1C(=O)OC(C)(C)c2cc(-c3cc(F)cc(C#N)c3)ccc21
Temperature: 160 °C
Yield: 33 %

Procedure:
A mixture of 3-(4,4-Dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6yl)-5-fluoro-benzonitrile (0.25 g, 0.84 mmol) and triethylorthoformate (50 mL) was heated at 160° C. for 12 hours. The excess triethylorthoformate was removed in vacuo and purification via chromatography (silica gel, 20% ethyl acetate/hexane) gave 3-(1-diethoxymethyl-4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzo[d][1,3]oxazin-6-yl)-5-fluoro-benzonitrile (0.116 g, 33%) as a white solid: mp 123-124° C.; 1H-NMR (DMSO-d6) δ 7.97 (d, 1H, J=8.68 Hz), 7.66 (bs, 1H), 7.53-7.44 (m, 2H), 7.35-7.32 (m, 2H), 6.65 (s, 1H), 3.88-3.78 (m, 2H), 3.73-3.61 (m, 2H), 1.77 (s, 6H), 1.27 (t, 6H), J=7.05 Hz); MS (ESI) m/z 295 ([M−H]−, 100%, lower MW ion consistent with loss of diethyl acetal); Anal. Calc. For C21H23FN2O4: C, 66.32; H, 5.82; N, 7.03. Found: C, 65.89; H, 5.92; N, 6.66.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][CH:5]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH2:7][CH2:8]I.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>O1CCCC1>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:3]=1[O:4][CH:5]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH2:7][CH2:8][N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1
Reactant: Clc1ccc(Cl)c(OC(CCCI)c2cccs2)c1
Reactant: CN1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: C1CCOC1
Product: CN1CCN(CCCC(Oc2cc(Cl)ccc2Cl)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30 %

Procedure:
The product from Example 19 step (c) (0.35 g, 0.83 mmol) was dissolved in anhydrous tetrahydrofuran (10 ml) and N-methylpiperazine (0.25 g, 2.49 mmol) added and stirred at room temperature for, 18 h. The precipitated white solid was filtered off and discarded. The filtrate was evaporated and the residue dissolved in methanol and placed on a CC SCX resin. After washing with methanol (150 ml), the product was liberated with 7N ammonia in methanol (100 ml). The solvents were evaporated and the residue dissolved in methanol, treated with one equivalent of fumaric acid, and stirred for ten minutes. The solvent was removed in vacuo and the solid residue recrystallised from hot isopropanol to afford the title compound (0.13 g, 30%).
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][N:38](COCC[Si](C)(C)C)[C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[C:23]([F:26])([F:25])[F:24])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([CH2:3][C:4]1([N:27]2[CH:31]=[C:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH:29]=[N:28]2)[CH2:7][N:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]=3[C:23]([F:25])([F:26])[F:24])=[O:15])[CH2:10][CH2:9]2)[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCN(C(=O)Nc6ccncc6C(F)(F)F)CC5)C4)c3)ncnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCC1(n2cc(-c3ncnc4[nH]ccc34)cn2)CN(C2CCN(C(=O)Nc3ccncc3C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 20 mL vial was charged with 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide (56 mg, 0.1 mmol), trifluoroacetic acid (1.5 mL, 19 mmol) and methylene chloride (1.5 mL). The mixture was stirred at room temperature for 1 hour and concentrated in vacuum. The residue was dissolved in 3 mL of a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, HPLC purification (method B) gave the title compound 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[3-(trifluoromethyl)pyridin-4-yl]piperidine-1-carboxamide. LC-MS: 551.2 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2]>[Pd].C1(C)C(C)=CC=CC=1>[C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH:18]=[CH:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2]
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Agent: [Pd]
Solvent: Cc1ccccc1C
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c4ccccc4ccc32)ccc1O
Reaction time: 24 h

Procedure:
A mixture of 7.6 g. (0.02 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole, 9.1 g. of 10% palladium on carbon, and 350 ml. of xylene was heated under reflux with stirring under nitrogen for 24 hours and then filtered. The filtrate was concentrated to 135 ml. and cooled. The solid which separated was collected and recrystallized from xylene to provide 3.6 g. (48%) of yellow crystals, m.p. 241.5°-242.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:19][C@H:20]([C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)[CH3:21])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1COC1CCCC1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COC2CCCC2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(cyclopentyloxy)methyl]benzoic acid (step 1) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]([C:9]2[S:13][C:12]([NH2:14])=[N:11][C:10]=2[C:15]2[CH:19]=[CH:18][O:17][CH:16]=2)=[O:8])[CH2:3][CH2:2]1.[Cl:20][C:21]1[N:22]=[CH:23][CH:24]=[C:25]([CH:29]=1)[C:26](Cl)=[O:27]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Cl:20][C:21]1[CH:29]=[C:25]([C:26]([NH:14][C:12]2[S:13][C:9]([C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)=[O:8])=[C:10]([C:15]3[CH:19]=[CH:18][O:17][CH:16]=3)[N:11]=2)=[O:27])[CH:24]=[CH:23][N:22]=1
Reactant: O=C(Cl)c1ccnc(Cl)c1
Reactant: Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: O=C(Nc1nc(-c2ccoc2)c(C(=O)C2CCOCC2)s1)c1ccnc(Cl)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 36.3 %

Procedure:
Compound 610 (100 mg, 0.359 mmol) was dissolved in pyridine (3 mL), and 6-chloroisonicotinoyl chloride (560 mg, 3.18 mmol) and DMAP (4.40 mg, 0.0360 mmol) were added thereto, followed by stirring at 80° C. for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was poured into a saturated aqueous solution of sodium hydrogencarbonate, and the precipitated solid was collected by filtration. The resulting solid was purified through silica gel column chromatography (hexane:ethyl acetate=3:1), followed by recrystallizing from a mixed solvent of ethanol and water to afford the entitled Compound 616 (54.5 mg, 36%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH2:7][CH2:6]2.[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15]>C(O)C.C(O)(=O)C>[C:18]([O:17][C:13]([NH:14][N:15]=[C:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)NN
Reactant: COc1ccc2c(c1)CCC2=O
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC2=NNC(=O)OC(C)(C)C

Procedure:
A solution of 5-methoxyindan-1-one (5.46 g) and tert-butyl carbazate (4.45 g) in ethanol (100 ml) and glacial acetic acid (1 drop) was stirred and boiled under reflux for 2 hours. The volume was reduced by half under reduced pressure and the solid which crystallized was collected by filtration to give 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:15][C:10]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)([CH3:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(C)(C)Br
Reactant: Cc1cccc(O)c1
Product: COC(=O)C(C)(C)Oc1cccc(C)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 36, using the m-cresol instead of the p-cresol and the methyl α-bromoisobutyrate instead of the methyl bromoacetate.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][OH:24])=[CH:21][CH:20]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:10][C:8]1[CH:9]=[C:4]([O:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[N:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: COc1ccc(CO)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)nc(-c3ccccc3)n2)cc1
Reaction time: 1.5 h
Yield: 99.8 %

Procedure:
NaH (60%) (469 mg, 11.73 mmol) was added in portions to a stirred solution of 4,6-dichloro-2-phenyl-pyrimidine (2.2 g, 9.78 mmol) and 4-methoxy benzyl alcohol (1.62 mg, 11.73 mmol) in dry THF (55 ml) at 0° C. After 1.5 h, NaHCO3 (aq) was added. Some solvent was evaporated and the residue was extracted with DCM, dried (MgSO4), filtered and evaporated to give the title compound, (3.19 g, 100%), MS (M+H)+327.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2)=[O:2].C1COCC1.[C:24]1([Mg]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl-].[NH4+]>C(Cl)Cl>[OH:2][CH:1]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:3]1[CH:4]=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:13])[N:7]2[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]2
Reactant: Br[Mg]c1ccccc1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C(O)c2ccccc2)c2ccccn2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (0.400 mg, 1.63 mmol) in 30 mL 1:1 THF:CH2Cl2 at −20° C. was added phenylmagnesium bromide (0.979 mL, 1.96 mmol, 2.0 M in THF) dropwise. The reaction was allowed to warm to rt. After 30 minutes, saturated aqueous ammonium chloride was added, and the mixture was filtered and concentrated to provide crude ethyl 1-[hydroxy(phenyl)methyl]-4-oxo-4H-quinolizine-3-carboxylate as a yellow solid. To a solution of the resultant residue (115 mg, 0.356 mmol) in 4 mL 1:2:1 DMSO:MeOH:H2O was added sodium hydroxide (0.100 g, 2.50 mmoL). The reaction was heated to 60° C. for 1 h, cooled to rt, and subjected to purification via reverse phase HPLC to yield the title compound that gave a mass ion (ES+) of 296.2 for M+H+.