Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11](=O)[CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.C(O)C.C(O[CH:20](OCC)[CH2:21][NH:22][NH2:23])C.Cl>O1CCOCC1.C(OCC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:11]([CH3:12])=[N:23][N:22]3[CH:21]=[CH:20][NH:10][C:9]=23)=[CH:4][CH:3]=1
Reactant: CCOC(CNN)OCC
Reactant: CC(=O)C(C#N)c1ccc(C)cc1
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(C)nn3cc[nH]c23)cc1
Yield: 72.3 %

Procedure:
A mixture of 1.7 g of 2-(4-methylphenyl)-3-oxo-butyronitrile, 20 ml of ethanol and 1.5 g of 2,2-diethoxyethylhydrazine was heated under reflux for 7 hours. At the end of this time, 30 ml of 4N hydrogen chloride in dioxane were added, and then the whole mixture was heated under reflux for a further 30 minutes. After the mixture had been cooled, diethyl ether was added to precipitate crystals. These were collected by filtration and partitioned between ethyl acetate and dilute aqueous ammonia. The organic phase was separated, washed with water and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, to leave a residue, which was recrystallized from a mixture of ethyl acetate and hexane, to give 1.5 g of the title compound. The physical and chemical properties of this compound were the same as those of the compound prepared as described in Example 36.
Reaction SMILES: [C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]CCCCCCC.CC=CCCCCC>>[C:1]([O:20][CH3:21])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH3:11]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OC
Agent: CC=CCCCCC
Product: CC=CCCCCCCCC(=O)OC
Reaction time: 17 h
Yield: 5 %

Procedure:
Reaction was carried out in the same manner as in Example 1, except that a mixture of 1 ml of methyl oleate and 1 ml of 2-octene was used in place of 1 ml of the methyl oleate, the reaction temperature was 70° C., and the reaction time was 17 hours. There were obtained methyl 9-undecenoate in a yield of about 5% and methyl 9-pentadecanoate in a yield of about 7% (estimated from the chromatogram). Besides, metathesis products were obtained independently from methyl oleate and 2-octene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:21][CH2:20][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[C:18]([F:19])=[C:10]3[C:9]2=[O:22])[C:3]=1[CH2:23][OH:24].ClCCl.[C:28](Cl)(=[O:30])[CH3:29]>C(N(CC)CC)C>[C:28]([O:24][CH2:23][C:3]1[C:4]([N:8]2[CH2:21][CH2:20][N:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[C:18]([F:19])=[C:10]3[C:9]2=[O:22])=[N:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:30])[CH3:29]
Reactant: O=C1c2c(F)c3c(n2CCN1c1nccc(Cl)c1CO)CCCC3
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCc1c(Cl)ccnc1N1CCn2c3c(c(F)c2C1=O)CCCC3
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A round-bottomed flask was charged with 231a (600 mg, 1.72 mmol), dichloromethane (50 mL), and triethylamine (5 mL). The solution was stirred at 0° C. for 0.5 h and acetyl chloride (135 mg, 1.72 mmol) was added slowly. The mixture was stirred at 0° C. for another 2.5 h. It was then evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 9:1 petroleum ether/ethyl acetate to afford 231b (605 mg, 90%) as a yellow solid. MS-ESI: [M+H]+ 392.1
Reaction SMILES: Cl.[CH3:2][C:3]12[C:24](=[O:25])[CH2:23][CH2:22][CH:4]1[CH:5]1[C:10]([CH2:11][CH2:12]2)=[C:9]([CH2:13][CH2:14][C:15]2([CH3:20])OCC[O:16]2)[C:8](=[O:21])[CH2:7][O:6]1>CC(C)=O>[CH3:2][C:3]12[C:24](=[O:25])[CH2:23][CH2:22][CH:4]1[CH:5]1[C:10]([CH2:11][CH2:12]2)=[C:9]([CH2:13][CH2:14][C:15](=[O:16])[CH3:20])[C:8](=[O:21])[CH2:7][O:6]1
Reactant: CC1(CCC2=C3CCC4(C)C(=O)CCC4C3OCC2=O)OCCO1
Agent: Cl
Solvent: CC(C)=O
Product: CC(=O)CCC1=C2CCC3(C)C(=O)CCC3C2OCC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3 N Hydrochloric acid (0.85 mL) was added to a stirred solution of the crude 3a-Methyl-6-[2-(2-methyl-[1,3]dioxolan-2-yl)-ethyl]-1,2,4,5,9a,9b-hexahydro-3aH-9-oxa-cyclopenta[a]naphthalene-3,7-dione in acetone (50 mL) at room temperature. The reaction mixture was stirred at room temperature for 0.5 h. The reaction was quenched with saturated sodium bicarbonate aqueous solution (50 mL), and then the acetone was removed under reduced pressure. The residue was diluted with brine (50 mL), extracted with ethyl acetate (2×100 mL), and the combined organic layer was dried with magnesium sulfate. The resulting solution was filtered and the solvent evaporated to yield an oil, which was used in subsequent steps without further purification.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[C:6]([NH:8][CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:11])=[O:7].[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH:29]=O.[BH3-]C#N.[Na+]>CC(O)=O.CO>[OH:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:29][N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][NH:12][C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:20]=[CH:21][CH:22]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:4]=2)[CH2:15][CH2:16]1
Reactant: COc1ccc(C=O)cc1O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2CCC(CNC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)CC2)cc1O
Temperature: 60 °C
Reaction time: 15 h

Procedure:
To a solution of 4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (20.0 mg, 0.058 mmol) and 3-hydroxy-4-methoxybenzaldehyde (33 mg)in 5% CH3COOH/CH3OH (1.0 mL) was added NaBH3CN (16.5 mg) in 5% CH3COOH/CH3OH (1.0 mL). The reaction mixture was stirred at 60° C. for 15 h. The reaction mixture was loaded onto Varian™ SCX column and washed with CH3OH (15 mL). Product was eluted using 2 N NH3—CH3OH (5 mL) and the eluant was concentrated to afford 1-(3-hydroxy-4-methoxybenzyl)-4-[{N-(3-(trifluoromethyl)benzoyl)glycyl}aminomethyl]piperidine (Compound No. 1452) (25.8 mg, 92%): The purity was determined by RPLC/MS (91%); ESI/MS m/e 480 (M++H, C24H28F3N3O4).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])=[CH:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[C:10]2=[N:11][CH:12]=1.[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45])[CH:39]=[O:40]>C1COCC1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[C:9]2[C:10](=[N:11][CH:12]=[C:7]([CH:39]([C:38]3[CH:41]=[C:42]([O:46][CH3:47])[C:43]([O:44][CH3:45])=[C:36]([O:35][CH3:34])[CH:37]=3)[OH:40])[CH:8]=2)[NH:13][CH:14]=1
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(Br)cc12
Reactant: COc1cc(C=O)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccccc1-c1c[nH]c2ncc(C(O)c3cc(OC)c(OC)c(OC)c3)cc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 38.1 %

Procedure:
A solution 1.5M n-BuLi in hexanes (160 μL, 0.24 mmol) was added to a solution of the 5-bromo-3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (91.5 mg, 0.20 mmol) in 2 ml THF at −78° C. The mixture was stirred at −78° C. for 30 minutes before 3,4,5-trimethoxy-benzaldehyde (94.2 mg, 0.48 mmol) in 3 mL of THF was added. The mixture was stirred at −78° C. for 1 hour and then at 0° C. for 30 minutes, quenched with MeOH, and then concentrated. The crude residue was purified by silica gel chromatography using a gradient of ethyl acetate in hexanes to give [3-(2-Methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-(3,4,5-trimethoxy-phenyl)-methanol (32 mg, 38% yield) as a white solid. MS: m/z 420.1 [MH+].
Reaction SMILES: C(OC([N:8]([CH2:16][CH:17]=[CH2:18])/[N:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([NH:8]/[N:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:17]=[CH2:18]
Reactant: C=CCN(/N=C/C(=O)OCC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN/N=C/C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
To a solution of E-ethyl 2-(2-t-butoxycarbonyl-2-allylhydrazono)acetate (8.65 g, 33.7 mmol) in dichloromethane (60 ml) was added trifluoroacetic acid (15 ml) at 3° C. After being stirred at room temperature for 1 hour, concentrated in vacuo. The residue was added to a saturated aqueous sodium hydrogen carbonate solution (300 ml), and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give 1.87 g of E-ethyl 2-(2-allylhydrazono)acetate (yield 35%) as oil.
Reaction SMILES: C([N:8]1[CH:12]2[CH:13]3[N:17]([CH:18]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[C:19]4[CH:31]=[CH:30][C:22]([C:23]([N:25]([CH2:28][CH3:29])[CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=4)[CH:16]([CH:9]1[CH2:10][CH2:11]2)[CH2:15][CH2:14]3)C1C=CC=CC=1.C(N1C2C3N(C(C4C=CC=C(OC)C=4)C4C=CC(C(N5CCCC5)=O)=CC=4)C(CC2)C1CC3)C1C=CC=CC=1>>[CH:13]12[CH2:11][CH2:10][CH:9]3[CH:16]([CH2:15][CH2:14][CH:12]1[NH:8]3)[N:17]2[CH:18]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)[C:19]1[CH:20]=[CH:21][C:22]([C:23]([N:25]2[CH2:26][CH2:27][CH2:29][CH2:28]2)=[O:24])=[CH:30][CH:31]=1
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(OC)c2)N2C3CCC2C2CCC3N2Cc2ccccc2)cc1
Agent: COc1cccc(C(c2ccc(C(=O)N3CCCC3)cc2)N2C3CCC4C2CCC3N4Cc2ccccc2)c1
Product: COc1cccc(C(c2ccc(C(=O)N3CCCC3)cc2)N2C3CCC4NC3CCC42)c1
Yield: 90 %

Procedure:
The procedure of Example 5.1 was repeated, but using in place of the compound prepared in Example 4.1 the compound {4-[(7-benzyl-2,7-diazatricyclo[4.4.0.03,8]dec-2-yl)-(3-methoxyphenyl)methyl]phenyl}-pyrrolidin-1-yl-methanone of Example 4.8. The compound {4-[(2,7-diazatricyclo[4.4.0.03,8]dec-2-yl)-(3-methoxyphenyl)methyl]phenyl}-pyrrolidin-1-yl-methanone was obtained. Yield: 90%; IR (nujol) (λ=cm−1) 1680 (C═O), 3100 (NH); 1H-NMR (CDCl3) δ 1.10-2.20 (m, 11H); 2.25-2.35 (m, 2H); 2.95-3.05 (m, 2H); 3.30-3.40 (m, 3H); 3.55-3.75 (m, 3H); 3.78 (s, 3H); 4.96 (s, 1H); 7.00-7.09 (m, 2H); 7.15-7.30 (m, 2H); 7.40-7.55 (m, 4H). Anal. calc. for C27H33N3O2: C, 75.14; H, 7.71; N, 9.74. Found: C, 74.98; H, 7.69; N, 93.73.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[C:11](#[N:13])[CH3:12].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@H:29]([N:40]([CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:30](OCC2C=CC=CC=2)=[O:31])=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[NH4+].[Cl-]>C1COCC1.O>[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C@H:29]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:30](=[O:31])[CH2:12][C:11]#[N:13])=[CH:24][CH:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: -45 °C
Reaction time: 0.25 h
Yield: 36.4 %

Procedure:
A solution of sodium bis(trimethylsilyl) amide (1 M in THF, 330 mL) at −45° C., was treated dropwise with acetonitrile (18.8 mL, 360 mmol) and the mixture was stirred for 15 minutes at −45° C. and then cooled to −78 ° C., treated dropwise with a solution of the product from Example 23A (53.5 g, 110 mmol) in THF (150 mL), warmed to −45° C., stirred for 1 hour, treated with solid NH4Cl (40 g), warmed to 5° C., treated with water, warmed to 25° C. and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. Precipitation from ethanol gave the product (19.0 g, 36% yield).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]=[CH:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:18][O:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:48])[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][C:38]=1[F:47].O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:16][CH:15]([OH:17])[CH:14]=[CH:13]3)[N:9]=[C:10]([C:24]3[CH:23]=[CH:22][C:21]([NH:35][C:36](=[O:48])[C:37]4[CH:42]=[CH:41][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:39][C:38]=4[F:47])=[C:20]([O:19][CH3:18])[CH:25]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2C1C=CC(O)C1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(C3C=CC(O)C3)c3ncnc(N)c23)ccc1NC(=O)c1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Yield: 97.1 %

Procedure:
A mixture of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-2-cyclopenten-1-ol (0.12 g, 0.35 mmol), N1-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2-fluoro-4-trifluoromethylbenzamide (0.23 g, 0.53 mmol), tetrakis(triphenyl-phosphine)palladium(0) (0.02 g, 0.02 mmol) and sodium carbonate monohydrate (0.11 g, 0.88 mmol) was heated in a mixture of ethylene glycol dimethyl ether (6 mL) and water (3 mL) at 85° C. for 6 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC to yield N1-{4-[4-amino-1-(4-hydroxy-2-cyclopentenyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-2-fluoro-4-trifluoromethylbenzamide (0.18 g, 0.34 mmol) as a white solid: 1H NMR (DMSO-d6, 400 MHz) δ 9.89 (dd, 1H), 8.31(d, 1H), 8.26 (s, 1H), 8.00 (t, 1H), 7.88 (d, 1H), 7.75 (d, 1H), 7.32 (s, 1H), 7.29 (d, 1H), 6.90 (br, 2H), 6.09 (d, 1H), 5.93 (d, 1H), 5.76 (m, 1H), 5.31 (m, 1H), 4.74 (m, 1H), 3.94 (s, 3H), 2.84 (m, 1H), 2.02 (m, 1H); RP-HPLC (Hitachi HPLC, Hypersil C18, 5 μm, 100 A, 250×4.6 mm; 25%-100% acetonitrile-0.05M ammonium acetate over 10 min, 1 mL/min) Rt 8.50 min. MS: MH+ 529.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:19][C:20]2[C:21]3[N:28]([CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH:27]=[CH:26][C:22]=3[N:23]=[CH:24][N:25]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[ClH:39]>O1CCCC1>[ClH:1].[ClH:39].[NH2:31][CH2:30][CH2:29][N:28]1[C:21]2[C:20]([NH:19][C:4]3[CH:5]=[CH:6][C:7]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=4)=[C:2]([Cl:1])[CH:3]=3)=[N:25][CH:24]=[N:23][C:22]=2[CH:26]=[CH:27]1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Agent: Cl
Solvent: C1CCOC1
Product: NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 60 °C
Reaction time: 20 h

Procedure:
A mixture of tert-butyl {2-[4-({3-chloro-4-[3-(trifluoromethyl)phenoxy]phenyl}amino)-5H-pyrrolo[3,2-d]pyrimidin-5-yl]ethyl}carbamate (1.12 g), 2N hydrochloric acid (15 mL) and tetrahydrofuran (30 mL) was stirred at 60° C. for 20 hrs. The solvent was evaporated under reduced pressure, ethanol was added, and the mixture was further concentrated. The precipitated crystals were collected by filtration and the crystals were washed with ethyl acetate to give the title compound (1.07 g) as pale-yellow crystals.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].O1CC[CH2:18][CH2:17]1>CS(C)=O>[Si:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:17]#[CH:18])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCCBr
Reactant: C1CCOC1
Solvent: CS(C)=O
Product: C#CCCCCCCO[Si](C)(C)C(C)(C)C
Temperature: 4 °C
Reaction time: 24 h
Yield: 73.8 %

Procedure:
6-Bromo-1-(t-butyldimethylsilyloxy)hexane (20 g, 110.42 mmol) was dissolved in dry dimethyl sulfoxide (500 ml) and tetrahydrofuran (50 ml) and cooled to 0° C. under argon atmosphere, to which was added lithium acetylide ethylene diamine complex (28.0 g, 304.74 mmol) and the resulting solution was stirred for 1 day at 4° C. After the reaction was completed, the mixture was poured in ice-water and extracted with ethyl ether. The organic solvent was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. This crude product was purified by column chromatography on silica gel, eluting with ethyl acetate:n-hexane=1:40. After removal of the solvent, 18 g of the title compound was obtained as colorless oil. (yield: 73.8%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[NH:22][C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[O:16])[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([NH:14][C:15]([C:17]2[S:18][CH:19]=[CH:20][C:21]=2[NH:22][C:23]2[C:24]3[CH:31]=[CH:30][NH:29][C:25]=3[N:26]=[CH:27][N:28]=2)=[O:16])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2sccc2Nc2ncnc3[nH]ccc23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCNC1)c1sccc1Nc1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
To a 20 mL flask with magnetic stir bar was added 3-{[3-(7H-Pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (100 mg, 0.23 mmol) in dichloromethane (2 mL). To the stirred solution was added trifluoroacetic acid (2.0 mL, 26.0 mmol) and the solution was stirred at 25° C. for 1 h. The solution was concentrated on a rotary evaporator and purified by preparative HPLC to afford 3-(7H-Pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid piperidin-3-ylamide as a yellow solid (14 mg, 13%) (HPLC: 99%, RT: 2.81 min). 1H NMR (DMSO-d6) 12.02 (br s, 1H), 11.30 (s, 1H), 8.68-8.52 (m, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.40 (s, 1H), 8.23 (d, J=7.7 Hz, 1H), 7.82 (d, J=5.5 Hz, 1H), 7.38 (dd, J=3.3, 2.2 Hz, 1H), 6.43 (dd, J=3.6, 1.8 Hz, 1H), 4.31-4.18 (m, 1H), 3.40-3.17 (m, 2H), 2.89-2.77 (m, 2H), 1.96-1.85 (m, 2H), 1.74-1.60 (m, 2H); MS (m/z) 343 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:31][CH2:30][C@@H:29]([N:32]4[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]4)[CH2:28][CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]5[CH2:25][CH2:24][CH2:23][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12.[C:39]1(=O)CCCCC1>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@H:26]3[CH2:27][CH2:28][C@@H:29]([N:32]4[CH2:33][CH2:34][N:35]([CH3:38])[CH2:36][CH2:37]4)[CH2:30][CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[S:19][C:20]5[CH2:25][CH2:24][CH2:23][CH2:39][C:21]=5[N:22]=4)=[CH:13][CH:12]=3)[C:3]=12
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCC6)cc4)c4c(N)ncnc43)CC2)CC1
Reactant: O=C1CCCCC1
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Nc5nc6c(s5)CCCC6)cc4)c4c(N)ncnc43)CC2)CC1

Procedure:
The procedure described for cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-amine was used to convert cyclohexanone (310 μL, 3.00 mmol) to the title compound. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.8-8.6 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4,5,6,7-tetrahydro-1,3-benzothiazol-2-amine as an orange powder (0.022 g, 0.040 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 7.62 min; MS (MH)+ 544.
Reaction SMILES: ClC1C=CC(C2N(C3C=CC(OC)=CC=3)N=C(CCCO)C=2)=CC=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:36]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=3)[N:35]=[C:34]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH:33]=2)=[CH:28][CH:27]=1.[Br:50]C1C(CCCO)=NN(C2C=CC(OC)=CC=2)C=1C1C=CC(Cl)=CC=1>>[Br:50][C:33]1[C:34]([CH2:45][CH2:46][C:47]([OH:49])=[O:48])=[N:35][N:36]([C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:32]=1[C:29]1[CH:28]=[CH:27][C:26]([Cl:25])=[CH:31][CH:30]=1
Reactant: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(-n2nc(CCCO)c(Br)c2-c2ccc(Cl)cc2)cc1
Agent: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Product: COc1ccc(-n2nc(CCC(=O)O)c(Br)c2-c2ccc(Cl)cc2)cc1

Procedure:
Substituting Compound 2 for the acid 12 in Example 37 afforded 4-bromo-5-(4-chlorophenyl)-3-(3-hydroxypropyl)-1-(4-methoxyphenyl)pyrazole, as an off-white solid, 87%, mp=118.5°-120°. (compound No. 183) MS, m/e 420 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH3:22][O:23][CH2:24][CH2:25]Br>CC(CC)=O.O>[CH2:1]([C:3]1[N:4]([CH2:25][CH2:24][O:23][CH3:22])[N:5]=[C:6]([C:11]([NH2:13])=[O:12])[C:7]=1[N+:8]([O-:10])=[O:9])[CH3:2]
Reactant: COCCBr
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CCc1c([N+](=O)[O-])c(C(N)=O)nn1CCOC
Temperature: 25 °C
Reaction time: 70 h
Yield: 73.8 %

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (25 g, 0.136 Mol), sodium carbonate (18 g, 0.17 Mol) and sodium iodide (20.4 g, 0.136 Mol) were suspended in ethyl methyl ketone (125 mL) at room temperature. 2-bromoethyl methyl ether (12.8 mL, 0.142 Mol) was added and the mixture was heated to reflux and stirred for 70 hours. The mixture was cooled to ambient temperature and water (250 mL) was added. The resultant slurry was warmed to reflux and held at that temperature for 30 min before cooling to room temperature. The resultant precipitate was granulated at room temperature for 3 h, filtered and vacuum dried to afford 5-ethyl-1-(2-methoxyethyl)-4-nitro-1H-pyrazole-3-carboxamide as a yellow crystalline solid 24.3 g, 74%. Data as reported for Example (g)(i).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]([O:40][C:41]([N:43]1[CH2:48][CH2:47][CH:46]([CH2:49]O)[CH2:45][CH2:44]1)=[O:42])([CH3:39])([CH3:38])[CH3:37].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:49][CH:46]2[CH2:47][CH2:48][N:43]([C:41]([O:40][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:42])[CH2:44][CH2:45]2)[CH:7]=1
Reactant: Oc1cccc(COc2ccccc2Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(COc2cccc(COc3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
To a solution of 272 mg (0.809 nunol) of 3-[(2-chlorophenoxy)methyl]phenol, as prepared in the preceding step, in methylene chloride (5 mL) containing 275 mg (1.05 mmol) of triphenylphosphine and 208 mg (0.97 mmol) of N-(tert-butoxycarbonyl)-4-piperidinemethanol, as prepared in step (b) of Example 1, was added slowly 165 μL (1.04 mmol) of diethyl azodicarboxylate. The reaction mixture was stirred at ambient temperature for 1 h. The reaction mixture was quenched with water, extracted into diethyl ether, dried (MgSO4), and flash chromatographed (hexane/ethyl acetate (1:4 to 1:2)) to give 221 mg (58% yield) of the title compound as a colorless oil. 1H-NMR (300 MHz, CDCl3) δ 7.38 (dd, 1 H, J=1.5, 7.8 Hz), 7.28 (t, 1 H, J=8.1 Hz), 7.15-7.21 (m, 1 H), 8.82-7.03 (m, 5 H), 5.13 (s, 2 H), 3.82 (d, 2 H, J=6.4 Hz), 2.74 (t, 2 H), 1.91-2.00 (m, 1 H), 1.84 (d, 2 H), and 1.47 (s, 9 H). Mass spectrum (MALDI-TOF; α-cyano-4-hydroxycinnamic acid matrix) calcd. for C24H30ClNO4S: 454.2 (M+Na). Found: 454.4.