Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[N:5]1[CH:15]1[CH2:20][CH2:19][N:18](CC2C=CC=CC=2)[CH2:17][CH2:16]1)([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[C].[Pd]>[CH:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6](=[O:14])[N:5]1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1c2ccccc2NC(=O)N1C1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)C1c2ccccc2NC(=O)N1C1CCNCC1
Temperature: 25 °C
Yield: 100 %

Procedure:
Into a solution of 2.30 g (6.33 mmol) of 4-isopropyl-3-(1-benzylpiperidin-4-yl)-3,4-dihydro-2(1H)-quinazolinone in 127 ml of methanol, 0.23 g (0.11 mmol) of 10% palladium carbon (50% wet) and 1.60 g (25.3 mmol) of ammonium formate were added and refluxed under stirring and heating for 4 hours. After cooling to room temperature, the reaction mixture was filtered. To the filtrate, 0.5% aqueous sodium hydroxide solution and chloroform were added and stirred. The separated oil layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (chloroform/methanol/triethylamine 90/10/5) to give 1.73 g (6.33 mmol) of the above-titled compound.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[NH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH2:20])=[O:19])=[C:12]2[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].C(OC(=O)C)(=O)C.C(N(CC)CC)C>ClCCl>[C:3]([NH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH2:20])=[O:19])=[C:12]2[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])(=[O:4])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: NC(=O)c1[nH]c2ccc(N)cc2c1S(=O)(=O)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 48 h

Procedure:
5-Amino-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide trifluoroacetate salt (22 mg, 0.050 mmol, 1.0 equiv) was suspended in 3 mL of dichloromethane. Acetic anhydride (10 μL, 0.006 mmol, 1.2 equiv) and triethylamine (0.020 μL, 0.13 mmol, 2.5 equiv) were added and the reaction was stirred for 48 hours. The solvent was removed in vacuo and the title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 367.3 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21](Cl)=[O:22])[CH:8]=2)[CH:3]=1.[CH2:24]([NH2:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].O>O1CCCC1>[OH:1][C:2]1[C:11]([C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:21]([NH:40][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[O:22])[CH:8]=2)[CH:3]=1
Reactant: O=C(Cl)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Reactant: CCCCCCCCCCCCCCCCN
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCNC(=O)c1ccc2cc(O)c(C(=O)Nc3ccccc3)cc2c1
Temperature: 30 °C
Yield: 35.9 %

Procedure:
A dispersion of 6.5 g of 2-hydroxy-3-phenylaminocarbonyl-6-chlorocarbonylnaphthalene in 20.0 g of dry tetrahydrofuran was added with 9.2 g of n-hexadecylamine solution in 30 g of dry tetrahydrofuran and reacted under reflux for 12 hours. To the reaction mixture, 30 g of water was added and the precipitates were collected by filtration, washed with water and thus obtained crystal was washed with 30 g of methanol under reflux. The obtained mixture was cooled to 30° C. and filtrated, washed with methanol and dried to provide 3.8 g of 2-hydroxy-3-phenylaminocarbonyl-6-n-hexadecylaminocarbonyl naphthalene (decomposition point: 257.2° C.).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[NH:18]([CH2:22][CH2:23][OH:24])[CH2:19][CH2:20][OH:21]>O1CCOCC1>[OH:21][CH2:20][CH2:19][N:18]([C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16])[CH2:22][CH2:23][OH:24]
Reactant: OCCNCCO
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: C1COCCO1
Product: COC(=O)c1cc([N+](=O)[O-])c(N(CCO)CCO)c([N+](=O)[O-])c1
Yield: 81.1 %

Procedure:
A solution of methyl 4-chloro-3,5-dinitrobenzoate (XIV) (10.0 g, 0.036 mol) and diethanolamine (7.66 g, 0.073 mol) in p-dioxane (60 mL) was stirred at 50° C. for 5 h. Volatiles were removed under reduced pressure, and the residue was adsorbed directly onto silica gel and chromatographed. Elution with EtOAc/petroleum ether (1:10) gave foreruns, and subsequent elution with EtOAc/petroleum ether (3:2) gave methyl 4-[N,N-bis(2-hydroxyethyl)amino]-3,5-dinitrobenzoate (XV: X=OH, Z=OMe) (9.61 g, 80%), mp (CHCl3 /petroleum ether) 101°-103° C. 1H NMR (CDCl3) δ 8.52 (s, 2 H, ArH-2,6), 3.97 (s, 3 H, COOCH3), 3.76 (dxt, J=6.5, 4.7 Hz, 4 H, CH2OH), 3.26 (t, J=4.7 Hz, 4 H, NCH2), 2.76 (t, J=6.5 Hz, 2 H, OH). 13C NMR δ 163.14 (COOCH3), 145.50 (C-4), 142.54 (C-3,5), 131.19 (C-2,6), 123.59 (C-1), 59.16 (CH2OH)1, 54.58 (CH2N), 53.14 (OCH3). Anal. (C12H15N3O8) C,H,N.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:19]([NH:21][C@H:22]([C:31]([NH:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[Pd]>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:19]([NH:21][C@H:22]([C:31]([NH:33][C@H:34]([C:42]([O:44][CH3:45])=[O:43])[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:32])[CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:7])([CH3:6])[CH3:8]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)OCc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)[C@@H](C)OC(C)(C)C

Procedure:
4.3 g of Z-Thr(tBu)-Gln-Asp(OtBu)-Phe-OCH3 in 300 ml of methanol are hydrogenated with 1 g of 10% strength palladium on charcoal catalyst in the usual manner and after completion of the hydrogen uptake the mixture is filtered and the filtrate evaporated. The evaporation residue, a solid colourless foam, is employed for the next stage without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](S(C)(=O)=O)[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2].N1CC[O:29]CC1>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[O:29])[N:9]([CH3:21])[C:10](=[O:20])[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(S(C)(=O)=O)n(C)c(=O)c1OCc1ccccc1
Reactant: C1COCCN1
Product: CCOC(=O)c1[nH]c(=O)n(C)c(=O)c1OCc1ccccc1
Yield: 30 %

Procedure:
5-Benzyloxy-2-methanesulfonyl-1-methyl-6-oxo-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (0.215 g, 0.58 mmol) was reacted with morpholine as described in the preparation of compound 1J. Chromatography on silica gel (elution toluene-ethyl acetate 8:2 to 6:4) gave first 0.050 g (30% yield) of 5-benzyloxy-1-methyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidine-4-carboxylic acid ethyl ester as white crystals; mp 184–187° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.34 (3H, t, J=7.1 Hz, CH3), 3.40 (3H, s, NCH3), 4.39 (2H, q, J=7.1 Hz, OCH2), 5.16 (3H, s, OCH2), 7.35–7.5 (5H, m, aromatics), 8.12 (1H, broad s, NH). Anal. Calcd for C15H16N2O5: C, 59.20; H, 5.30; N, 9.20. Found: C, 59.20; H, 5.08, N 9.19 . The end fractions then gave 0.102 g (47% yield) of the title ester as a white syrup. 1HNMR 400 MHz (CDCl3) δ (ppm): 1.29 (3H, t, J=7.1 Hz, CH3), 3.20 (4H, m, NCH2), 3.53 (3H, s, NCH3), 3.82 (4H, m, OCH2), 4.32 (2H, q, J=7.1 Hz, OCH2), 5.17 (2H, s, OCH2), 7.29–7.49 (5H, m, aromatics). HRMS (FAB POS) calculated for C19H24N3O5 [M+H+]: 374.171596. found: 374.1709485
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](Br)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([C:28]2[CH:29]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:31]=[C:26]([F:25])[CH:27]=2)=[C:6]([CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Reactant: Cc1c(Br)ccc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1c(-c2cc(F)cc(C(F)(F)F)c2)ccc(N)c1C#N
Temperature: 80 °C
Reaction time: 7 h
Yield: 103 %

Procedure:
Under a dry nitrogen atmosphere, 0.5 gram (0.0004 mole) of tetrakis(triphenylphosphine)palladium(0) was added to a stirred mixture of 2.8 grams (0.0132 mole) of 2-amino-5-bromo-6-methylbenzonitrile (prepared as in Step C of Example 1), 35 mL of aqueous 2M sodium carbonate and 50 mL of toluene. To this was then added dropwise a solution of 3.3 grams (0.0159 mole) of 3-fluoro-5-trifluoromethylphenylboronic acid in 10 mL of ethanol. Upon completion of addition, the reaction mixture was warmed to about 80° C., where it was stirred for seven hours. After this time the reaction mixture was poured into 200 mL of water. The mixture was then extracted with four 100 mL portions of ethyl acetate. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was subjected to column chromatography on silica gel. Elution was accomplished with methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 4.0 grams of 2-amino-6-methyl-5-(3-fluoro-5-trifluoromethylphenyl)benzonitrile, mp 96°-97° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Br-].[CH3:2][C:3]1[CH2:8][CH2:7][CH2:6][C:5]([CH3:10])([CH3:9])[C:4]=1[CH:11]=[CH:12][CH:13]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14].[H-].[Na+].[CH3:36][C:37]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[CH:42]=[C:41]([CH3:48])[C:38]=1[CH:39]=O.O>CN(C)C=O>[CH3:47][O:46][C:43]1[CH:42]=[C:41]([CH3:48])[C:38]([CH:39]=[C:13]([CH3:14])[CH:12]=[CH:11][C:4]2[C:5]([CH3:9])([CH3:10])[CH2:6][CH2:7][CH2:8][C:3]=2[CH3:2])=[C:37]([CH3:36])[C:44]=1[CH3:45]
Reactant: CC1=C(C=CC(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Reactant: COc1cc(C)c(C=O)c(C)c1C
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(C=C(C)C=CC2=C(C)CCCC2(C)C)c(C)c1C

Procedure:
A solution of [4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-yl]triphenylphosphonium bromide (prepared from 17.2 g of 4-(2,6,6-trimethyl-1-cyclohexen-1-yl)-3-buten-2-ol and 30.4 g of triphenylphosphonium hydrogen bromide in 150 mL of N,N-dimethylformamide (DMF)) was stirred under nitrogen in an ice bath and NaH (4.25 g, 50% oil dispersion) was added in portions. The mixture was stirred in the cooling bath for an additional hour and a solution of 2,3,6-trimethyl-p-anisaldehyde (15.8 g, 0.089 mol) in 50 mL of DMF was added dropwise within 15 min. The resulting mixture was stirred at room temperature for 18 hrs and heated to 50°-60° C. for 11/2 hrs. After cooling, the mixture was poored into 3 liters of water and extracted with hexane. The hexane extract was washed with 400 mL of a MeOH:H2O mixture (6:4, v/v) and water (400 mL). After drying over Na2SO4, the solvent was evaporated in vacuo to give 24.1 g of crude product as a brown oil. The pure product was obtained as a pale yellow oil from vacuum distillation of the crude product, bp. 152°-153° C. (0.075 mm of Hg); MS (CI): 339 (m+ +1).
Reaction SMILES: C([O:4][C:5]([CH3:27])([C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=2)=[N:10][N:11]=1)[CH3:6])(=O)C.[OH-].[Na+].O1CCCC1.CO>C(OCC)(=O)C>[CH3:26][S:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]2[CH:13]=[C:12]([C:9]3[O:8][C:7]([C:5]([OH:4])([CH3:6])[CH3:27])=[N:11][N:10]=3)[CH:17]=[CH:16][N:15]=2)=[CH:20][CH:21]=1
Reactant: CSc1ccc(Nc2cc(-c3nnc(C(C)(C)OC(C)=O)o3)ccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CSc1ccc(Nc2cc(-c3nnc(C(C)(C)O)o3)ccn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.6 %

Procedure:
A mixture of 1-methyl-1-[5-[2-[[4-(methylthio)phenyl]amino]-4-pyridyl]-1,3,4-oxadiazol-2-yl]ethyl acetate (192 mg, 4.99 mmol), 1 M aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (61.2 mg, yield 36%) as yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH2:14])=[CH:12][CH:13]=1)=[O:8])[CH3:2].[CH3:23]CN(C(C)C)C(C)C.COS(OC)(=O)=O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[C@H:5]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[NH:6][C:7]([C:9]1[S:10][C:11]([NH:14][CH3:23])=[CH:12][CH:13]=1)=[O:8])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N)s1)C(=O)OCC
Solvent: COS(=O)(=O)OC
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(NC)s1)C(=O)OCC
Temperature: 60 °C
Reaction time: 42 h
Yield: 15.5 %

Procedure:
A solution containing N-(5-aminothiophene-2-carbonyl)-L-glutamic acid diethyl ester (III-3 where R2 is H) (1.78 g, 5.42 mmol), (i-Pr)2NEt (1.0 mL, 0.74 g, 5.7 mmol), and Me2SO4 (0.59 mL, 0.79 g, 6.2 mmol) in 20 mL N,N-dimethylformamide (DMF) was warmed at 60° C. for 2 hours, then left at 20°-25° C. for 42 hours. The solution was evaporated in vacuo (1 mm, bath 25°-30° C.), and the residue was dissolved in EtOAc-cyclohexane (1:1 by volume) for application to a silica gel column. Elution by the same solvent system afforded fractions homogeneous by TLC of the product. Fractions were combined and evaporated to afford 16% yield (287 mg) of N-[5-(methylamino)thiophene-2-carbonyl]-L-glutamic acid diethyl ester (III-3) R2 =CH3 as an amber oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][NH:30][CH:31]3[CH3:34])=[CH:26][CH:25]=2)=[CH:18][N:17]=1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:30]3[CH2:29][CH2:28][C:27]4[C:32](=[CH:33][C:24]([C:19]5[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=5)=[CH:25][CH:26]=4)[CH:31]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: COc1ncc(-c2ccc3c(c2)C(C)NCC3)c(OC)n1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: COc1ncc(-c2ccc3c(c2)C(C)N(C(=O)c2cc4ncc(Br)cn4n2)CC3)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 7-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([F:21])([F:20])[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[N:8]=[C:7]2[S:22][CH3:23].[CH3:24][N:25](C=O)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].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N>[F:20][C:12]([F:21])([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][N:14]=1)[C:9]1[N:8]=[C:7]([S:22][CH3:23])[C:6]2[C:11](=[C:2]([C:24]#[N:25])[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(Br)cccc12
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CSc1nc(C(F)(F)c2ccc(F)cn2)nc2c(C#N)cccc12
Temperature: 90 °C
Yield: 64 %

Procedure:
To a mixture of 8-bromo-2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline (300 mg, 0.75 mmol), tris(dibenzylideneacetone)dipalladium (69 mg, 0.075 mmol), 1,1′-bis(diphenylphosphino)ferrocene (49 mg, 0.088 mmol), and zinc cyanide (110 mg, 0.93 mmol) was added DMF (6 mL). The reaction flask was evacuated and flushed with argon (3×) and then the mixture was heated at 90° C. overnight. The resulting mixture was partitioned between EtOAc and water and the organic layer was washed with 2N NH4OH (3×) and brine (1×), dried over sodium sulfate, and concentrated under reduced pressure onto Celite. The mixture was purified by silica gel flash chromatography eluting with 0-50% EtOAc/hexanes to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-(methylthio)quinazoline-8-carbonitrile (168 mg, 64%). LC-MS (ESI) m/z 347 (M+H)+.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.[Br:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([C:12]2([C:9]3[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][CH:8]=3)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Brc1ccccc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 51.5 %

Procedure:
Solid aluminum trichloride (0.68 mL, 5.1 mmol) was added to a solution of tert-butyl 4-(4-chlorophenyl)-4-hydroxypiperidine-1-carboxylate (0.40 g, 1.3 mmol) in bromobenzene (5.4 mL, 51.3 mmol) at 0° C. under nitrogen. After being stirred at 0° C. for 4 hours, the mixture was quenched with ice and concentrated under reduced pressure. The mixture was dissolved in 1N LiOH (30 mL) and extracted with EtOAc (2×30 mL). The combined organics were dried with Na2SO4, filtered and concentrated. The crude product was directly taken up in EtOAc (4 mL) and aqueous Na2CO3 solution (2M, 4 mL). Di-tert-butyldicarbonate (0.851 g, 3.9 mmol) was added in one portion. The mixture was stirred at 23° C. overnight. The next day, two layers were separated, and the aqueous layer was further extracted with EtOAc (2×10 mL). The combined organics were dried over Na2SO4, concentrated, and purified by column chromatography (0-40% EtOAc/hexanes) to give tert-butyl 4-(4-bromophenyl)-4-(4-chlorophenyl)piperidine-1-carboxylate (0.302 g, 51% yield). 1H NMR (CDCl3, 400 MHz) δ 7.46 (d, J=7.2 Hz, 2 H), 7.32 (d, J=6.9 Hz, 2 H), 7.19 (d, J=7.0 Hz, 2 H), 7.12 (d, J=7.3 Hz, 2 H), 3.54 (br s, 2H), 2.35 (br s, 2 H), 1.54 (br s, 2H), 1.43 (s, 11H). LCMS: M+1 452.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:11]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O[C:32]1(O[Si](C)(C)C)[CH2:34][CH2:33]1)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][N:10]=[C:11]([N:19]3[CH2:20][CH2:21][N:22]([CH:32]4[CH2:34][CH2:33]4)[CH2:23][CH2:24]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2n[nH]c(N3CCNCC3)c2-c2ccncc2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Clc1ccc(-c2[nH]nc(N3CCN(C4CC4)CC3)c2-c2ccncc2)cc1
Reaction time: 0.08 h
Yield: 63 %

Procedure:
To a solution of 3-(4-chlorophenyl)-4-(4-pyridyl)-5-(4-piperazinyl)pyrazole (1.95 g; 5.8 mmoles; prepared as set forth in Example A-169) and acetic acid (3.6 g, 60 mmol) containing 5A molecular sieves (6 g) was added [(1-ethoxycyclopropyl)oxy]trimethylsilane (6 g, 35 mmol). After stirring for 5 minutes, sodium cyanoborohydride (1.7 g, 26 mmol) was added and the mixture was refluxed under a nitrogen atmosphere for 6 hours. The reaction mixture was filtered hot and the filtrate concentrated in vacuo. Water (50 mL) was added and the solution made basic with 2N sodium hydroxide. The resultant gel was extracted with dichloroethane and the combined organic extracts dried (MgSO4). Evaporation again yielded a gel which was treated with hot methanol. Upon cooling, the product crystallized to give 1.4 g (63%) of 1-[5-(4-chlorophenyl)-4-(4-pyridinyl)-1H-pyrazol-3-yl)-4-cyclopropylpiperazine, m.p. 264-265° C. Anal. Calc'd. for C21H22ClN5.1.5H2O: C, 61.99; H, 6.19; N, 17.21. Found: C, 62.05; H, 5.81; N, 16.81.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[N-:11]=[N+:12]=[N-:13].[Na+].CCOC(C)=O.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[N:11]([CH2:2][CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1)=[N+:12]=[N-:13]
Reactant: BrCCOC1CCCCO1
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(2-bromo-ethoxy)-tetrahydro-pyran (1.00 mL, 6.62 mmol), NaN3 (4.34 g, 66 mmol) and tetrabutylammonium iodide (245 mg, 0.66 mmol) in DMF (7.0 mL) was stirred at RT for 18 h. The reaction mixture was poured into a mixture of EtOAc/water. The organic phase was washed with water, brine and then dried (MgSO4), filtered and concentrated in vacuo to give the crude product. The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 0:100 to 20:80 as the eluent to afford the title compound as colourless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=1)=[O:7].[CH2:28]([C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=1)[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:28]([C:32]1[CH:33]=[CH:34][C:35]([NH:36][CH2:2][C:3]2[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=2)[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:9]=2)=[O:7])=[CH:37][CH:38]=1)[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)Cc1ccc(N)cc1
Reactant: CCOC(=O)CCCn1cc(C(=O)c2cccc(CCl)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)c2cccc(CNc3ccc(CC(C)C)cc3)c2)c2ccccc21
Temperature: 100 °C
Yield: 42.2 %

Procedure:
A mixture of ethyl 4-[3-[3-(chloromethyl)benzoyl]-indol-1-yl]butyrate (42.1 mg), 4-isobutylaniline (18.0 mg) and potassium carbonate (30.3 mg) in N,N-dimethylformamide (5 ml) was heated at 50° C. for 20 hours and at 100° C. for 2.5 hours. The mixture was worked up in an usual manner and purified by this layer silica gel chromatography eluting with a mixture of chloroform, hexane and ethyl acetate (6:2:1) to give ethyl 4-[3-[3-[(4-isobutylphenyl)aminomethyl]benzoyl]indol-1-yl]butyrate (23 mg) as an oil.