Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[CH2:27]1[CH2:31]O[CH2:29][CH2:28]1.BrCC1CC1>CN(C=O)C.C(OCC)(=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:29][CH:28]3[CH2:31][CH2:27]3)[C:4]=2[CH:3]=1
Reactant: C1CCOC1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Agent: BrCC1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2CC2CC2)cn1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
6-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 100 mg, 0.36 mmole) was azeotroped with toluene (3 mL) and dissolved in DMF (1 mL). To the solution was added sodium hexamethyldisilazide, 1M in THF (0.4 mL, 0.4 mmole) and the reaction was stirred at room temperature for 20 minutes. Bromomethylcyclopropane (78 uL, 108 mg, 0.8 mmole) was added and the reaction was stirred at room temperature for 6 hours. Ethyl acetate (25 mL) was added and the solution was washed with water (3×10 mL) and with brine (5 mL), dried and evaporated in vacuo. The crude product was purified using preparative TLC eluting with ethyl acetate to afford the title compound (98 mg, 82%). 1H-NMR (CDCl3, 500 MHz): δ 0.23 (m, 2H), 0.55 (m, 2H), 1.12 (m, 1H), 4.03 (s, 3H), 4.07 (d, J=6.31 Hz, 2H), 6.54 (d, J=0.95 Hz, 1H), 7.45 (t, J=0.95 Hz, 1H), 7.61 (s, 1H), 7.71 (d, J=0.95 Hz, 1H), 8.61 (d, J=0.95 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:17]([O:21][C:22]([N:24]([CH2:26][CH2:27][C:28](O)=[O:29])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18].Cl.N1C=CC=C(CC(O)=O)C=1>>[C:17]([O:21][C:22]([N:24]([CH2:26][CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:25])=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(CCC(=O)Nc1ncn(Cc2ccccc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 17, using 1.92 g (8.96 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide which was prepared in the same manner as in Reference Example 2 and 3-(N-t-butyloxycarbonyl-N-methylamino)propionic acid, instead of 3-pyridylacetic acid hydrochloride, to obtain 2.56 g of 4-(3-(N-t-butyloxycarbonyl-N-methylamino)propanoylamino)-1-benzyl-5-imidazole carboxamide (yield 72%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[NH:8][CH:7]=1.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26].N1C=CN=C1.CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[CH:13]=2)[NH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccc(O)cc12)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccc(O[Si](C)(C)C(C)(C)C)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.3 %

Procedure:
To a solution of Example 400A (1.20 g, 3.59 mmol) in DMF (20 mL) was added t-butyldimethylsilyl chloride (649 mg, 4.3 mmol), imidazole (293 mg, 4.3 mmol) and DMAP (50 mg) at rt. The reaction mixture was stirred at rt for 16 hours. EtOAc (100 mL) was added and the mixture was washed with brine (100 mL) and water (100 mL). The organic phase was concentrated and the residual oil was purified by flash chromatography (10-40% EtOAc in hexane) to give the desire product (1.6 g, 100%). MS (DCI) m/z 466 (M+18)+.
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22](Cl)=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[O:29][CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.O>CN1CCCC1=O>[CH2:10]([O:17][C:18]1[CH:27]=[C:26]2[C:21]([C:22]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[N:23][CH:24]=[N:25]2)=[CH:20][C:19]=1[O:29][CH3:30])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Sodium hydride (400 mg of an 80% suspension in paraffin oil, 13.3 mmol) was added to a solution of phenol (1.26 g, 13.3 mmol) in dry 1-methyl-2-pyrrolidinone (20 ml) and the mixture stirred for 10 minutes. 7-Benzyloxy-4-chloro-6-methoxyquinazoline (1.6 g, 5.3 mmol), (prepared as described for the starting material in Example 4 but with an aqueous work up), was then added and the reaction mixture heated at 110° C. for 2 hours. The mixture was allowed to cool, water was added and the mixture extracted with ethyl acetate (3×100 ml). The combined extracts were then washed with 2M sodium hydroxide solution, water and brine. Removal of the solvent under reduced pressure gave 7-benzyloxy-6-methoxy-4-phenoxyquinazoline (1.6 g, 84%) as a yellowish solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH2:18][CH:19]([CH3:21])[CH3:20])/[C:13]([NH:28][C:25]2[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)CO/N=C(/C(=O)O)c1ccc(S(C)(=O)=O)c(Cl)c1
Reactant: Cn1ccc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)CO/N=C(/C(=O)Nc1ccn(C)n1)c1ccc(S(C)(=O)=O)c(Cl)c1
Reaction time: 2 h
Yield: 95.3 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-isobutoxyimino-acetic acid (104 mg, 0.31 mmol), 1-methyl-1H-pyrazol-3-ylamine (30 mg, 0.31 mmol) and N,N-diisopropylethylamine (163 μL, 0.94 mmol) were combined in methylene chloride (1.5 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (119 mg, 0.31 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-isobutoxyimino-N-(1-methyl-1H-pyrazol-3-yl)-acetamide (122 mg, 95%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H21ClN4O4S [M+] 412.10, found 413 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 0.94 (d, J=6.7 Hz, 6 H, 2×CH3), 2.05 (m, 1 H, CH), 3.29 (s, 3 H, SO2CH3), 3.84 (s, 3 H, NCH3), 4.06 (d, J=6.8 Hz, 2 H, OCH2), 6.68 (d, J=2.3 Hz, 1 H, Ar), 7.28 (d, J=2.3 Hz, 1 H, Ar), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.69 (d, Jm=1.5 Hz, 1 H, Ar), 8.19 (d, Jo=8.2 Hz, 1 H, Ar), 9.13 (brs, 1 H, NH).
Reaction SMILES: [C:1]([C:4]1[C:9]2[S:10][CH:11]=[C:12]([CH2:13][CH3:14])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([OH:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[CH2:13]([C:12]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH3:20])=[O:2])[C:9]=2[S:10][CH:11]=1)[CH3:14]
Reactant: CO
Reactant: CCc1csc2c(C(=O)O)cccc12
Agent: O=S(=O)(O)O
Product: CCc1csc2c(C(=O)OC)cccc12

Procedure:
7-Carboxy-3-ethylbenzo[b]thiophene (3.20 g) and concentrated sulfuric acid were stirred in methanol (100 ml) at 60° C. for 16 hr. The reaction mixture was concentrated and chloroform mixture was added thereto. The mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. The chloroform was separated, and the residue was dried over magnesium sulfate, and concentrated to give the objective compound (3.04 g).
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:10]=[C:11]([CH:15]2[C:28]3[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]=3[NH:22][C:21]3[CH2:20][CH2:19][CH2:18][C:17](=[O:30])[C:16]2=3)[CH:12]=[CH:13][CH:14]=1)([O-:8])=[O:7].[H-].[Na+].Cl[CH2:34][O:35][CH2:36][CH3:37]>C(O)(=O)C>[CH2:36]([O:35][CH2:34][N:22]1[C:21]2[CH2:20][CH2:19][CH2:18][C:17](=[O:30])[C:16]=2[CH:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=2)[C:28]2[C:27](=[O:29])[CH2:26][CH2:25][CH2:24][C:23]1=2)[CH3:37]
Reactant: O=C1CCCC2=C1C(c1cccc([N+](=O)[O-])c1)C1=C(CCCC1=O)N2
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCOCN1C2=C(C(=O)CCC2)C(c2cccc([N+](=O)[O-])c2)C2=C1CCCC2=O
Temperature: -10 °C
Reaction time: 0.33 h

Procedure:
In 10 ml. of dimethylformamide was suspended 0.5 g. of 9-(3-nitrophenyl)-1,8-dioxo-1,2,3,4,5,6,7,8,9,10-decahydroacridine and after adding to the suspension 0.2 g. of a 50% oil dispersion of sodium hydride, the mixture was stirred for 1.5 hours at room temperature. After cooling the mixture to -10° C., 0.5 ml. of chloromethoxyethane was added thereto, the temperature of the mixture was elevated to room temperature over a period of about 20 minutes, stirred for 2 hours and the mixture was cooled again to -10° C. Then, after adding to the reaction product 0.5 ml. of glacial acetic acid and 20 ml. of water, the product was extracted three times each time with 5 ml. of ether. The extracts were combined, washed with 5 ml. of saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and then ether was distilled away. The residue became crystallized by the addition of 5 ml. of ethanol. The crystals were filtered, dissolved in 2 ml. of chloroform and recrystallized by the addition of ethanol and 0.4 g. of pale brown prismatic crystals of 10-ethoxymethyl-9-(3-nitrophenyl)-1,8-dioxo- 1,2,3,4,5,6,7,8,9,10-decahydroacridine melting at 222° C. were obtained.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1)=O)(C)(C)C>CO.Cl.O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[O:22])[N:18]([CH3:20])[CH:19]=2)=[CH:11][CH:10]=1
Reactant: COC(=O)c1cc(-c2ccc(NC(=O)OC(C)(C)C)cc2)cn1C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccc(N)cc2)cn1C
Reaction time: 6 h

Procedure:
5 (1 g, 3.027 mmol) was dissolved in a small volume of MeOH and 4M HCl in dioxane (15 mL) was added slowly to the stirring solution. The reaction mixture was stirred for 6 hours at which point TLC showed completion of reaction. Excess solvent was evaporated under vacuum to obtain a brown coloured solid 7. The solid product was subjected to flash chromatography (n-hexane/EtOAc 9:1) to give pure 7 (065 g, 94.2%). IR (FTIR, vmax/cm−1): 3366, 2987, 1688, 1629, 1566, 1422, 1372, 1262, 1181, 1103, 1067, 951, 821, 784, 756; 1H-NMR (400 MHz, CDCl3): δ 7.28 (2H, d, J=8.4 Hz), 7.11 (1H, d, J=2.0 Hz), 6.96 (1H, d, J=2.0 Hz), 6.68 (d, 2H, J=8.0 Hz), 3.94 (s, 3H), 3.83 (s, 3H); 13C-NMR (100 MHz, CDCl3): δ 161.7, 144.7, 126.2, 125.4, 125.2, 115.5, 114.4, 51.0, 36.8; EIMS m/z (+EI) calc. for C13H14N2O2 (M)+ 230.26. found 231.1 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(NC(C)C)(C)C.[Li].C1C=CC(N[S:30]([C:33]([F:36])([F:35])[F:34])(=[O:32])=[O:31])=CC=1.[O:37]1CCCC1>>[F:34][C:33]([F:36])([F:35])[S:30]([O:37][C:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH:12]=1)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Reactant: O=S(=O)(Nc1ccccc1)C(F)(F)F
Reactant: C1CCOC1
Agent: [Li]
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a −70° C. stirred solution of N-Boc-piperidone (500 mg, 2.5 mmol) in tetrahydrofuran (11 mL) was added lithium diisopropylamine (1.37 mL of a 2 M solution in tetrahydrofuran, 2.75 mmol). The reaction mixture was stirred for 2 h, warmed to 0° C., and N-phenyltriflamide (955 mg, 2.67 mmol) was added. The solution was allowed to warm to room temperature and was stirred for 12 h. The reaction mixture was concentrated under reduced pressure. Purification by flash column chromatography (3:1 hexanes/ethyl acetate) afforded tert-butyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (240 mg): 1H NMR (300 MHz, CDCl3) δ 5.77 (s, 1H), 4.05 (m, 2H), 3.63 (m, 2H), 2.45 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[CH:10]3[CH2:19][S:20][CH2:21][CH:9]23)=[CH:4][CH:3]=1.[OH:22]OS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+]>CO.O.CCOC(C)=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[O:17][C:16]3[C:11](=[CH:12][C:13]([OH:18])=[CH:14][CH:15]=3)[C@@H:10]3[CH2:19][S@@:20](=[O:22])[CH2:21][C@H:9]23)=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: Oc1ccc(C2Oc3ccc(O)cc3C3CSCC32)cc1
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=[S@]1C[C@H]2[C@@H](C1)c1cc(O)ccc1O[C@H]2c1ccc(O)cc1
Yield: 81.8 %

Procedure:
To a solution of enantiomer A of 4-(4-hydroxy-phenyl)-1,3a,4,9b-tetrahydro-3H-5-oxa-2-thia-cyclopenta[a]naphthalen-8-ol 11d (20 mg, 0.066 mmol) in MeOH/H2O (1:1, 3 mL) add oxone (40 mg, 0.066 mmol). Stir the reaction at room temperature for 30 minutes. Add 1.0 M Na2SO3 and stir the reaction for 5 minutes. Dilute with EtOAc and wash with saturated sodium bicarbonate. Extract aqueous layer with EtOAc (2×). Combine organic extracts, dry (Na2SO4), filter and concentrate to afford 4-(4-hydroxy-phenyl)-2-oxo-1,2,3,3a,4,9b-hexahydro-5-oxa-2λ4-thia-cyclopenta[a]naphthalen-8-ol 13 (17 mg, 0.054 mmol, 85%). 1H NMR (δ, 400 MHz, MeOD) 7.44 (d, 2H, J=8.8 Hz), 6.85 (d, 2H, J=8.8 Hz), 6.75 (d, 1H, J=8.8 Hz), 6.70 (d, 1H, J=2.8 Hz), 6.61 (dd, 1H, J=8.8, 2.8 Hz), 5.19 (s, 1H), 4.19 (dd, 1H, J=6.2, 6.2 Hz), 3.76 (d, 1H, J=7.9 Hz), 3.06-2.94 (m, 1H), 2.84 (dd, 1H, J=14.1, 5.3 Hz), 2.62 (dd, 1H, J=13.0, 5.5 Hz), 2.29 (dt, 1H, J=5.2, 14.0 Hz). HPLC (Zorbax C18 column; 10 to 100% CH3CN/H2O for 10 min then 100% CH3CN for 5 min; 1 mL/min; tr 7.17 min). LRMS calcd for C17H15O4S: 315.1; found (ES−, M−H): 315.2.
Reaction SMILES: [Na].O=[C:3]1[CH2:8][C:7]([CH3:10])([CH3:9])[CH:6]([CH2:11][CH2:12]O)[C:5]([CH3:14])=[CH:4]1.CC12[O:24][CH2:23][CH2:22]C1C(C)(C)CC=C2.CC12OCCC1C(C)(C)CC(=O)C2>>[CH3:14][C:5]1[CH:6](/[CH:11]=[CH:12]/[C:23]([CH3:22])=[O:24])[C:7]([CH3:10])([CH3:9])[CH2:8][CH2:3][CH:4]=1
Reactant: CC1(C)CC=CC2(C)OCCC12
Reactant: CC1=CC(=O)CC(C)(C)C1CCO
Agent: CC1(C)CC(=O)CC2(C)OCCC12
Agent: [Na]
Product: CC(=O)/C=C/C1C(C)=CCCC1(C)C

Procedure:
Identification has been carried out by mass spectrum as stated above. The composition can be characterized by the presence of compounds 1 [2-(4-hydroxy-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and 2 [2-(4-keto-2,6,6-trimethylcyclohex-2-en-1-yl)ethanol] and especially 3 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]non-2-ene] and 4 [1,5,5-trimethyl-9-oxa-bicyclo[4.3.0]nonan-3-one]. (See Table A).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([NH:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)=[C:16]([O:29][CH3:30])[CH:15]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:32][NH:33][CH3:34].C[Al](C)C>O1CCCC1.CCCCCCC>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][NH:11][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]([N:33]([CH3:34])[CH3:32])=[O:2])=[CH:15][C:16]=1[O:29][CH3:30]
Reactant: COC(=O)C(NCCc1ccc(OCc2cccc(F)c2)c(OC)c1)c1ccccc1
Reactant: CNC
Agent: C[Al](C)C
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: COc1cc(CCNC(C(=O)N(C)C)c2ccccc2)ccc1OCc1cccc(F)c1
Yield: 52 %

Procedure:
This compound was synthesized according to the procedure described in Scheme 6, step B, using 115 mg of 2-[2-[4-(3-fluoro-benzyloxy)-3-methoxy-phenyl]-ethylamino]-2-phenyl-acetic acid methyl ester (0.27 mmol), 1.06 ml (2.1 mmol) of a 2 M solution of dimethylamine in tetrahydrofuran and 0.53 ml (1.06 mmol) of a 2 M solution of trimethyl aluminium in heptane. 66 mg (52% yield) of the title compound were isolated as a white solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[CH:3][C:2]1=[O:7].[CH2:8]([N:15]([CH2:21]OC)[CH2:16][Si](C)(C)C)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:8]([N:15]1[CH2:21][C@H:4]2[CH2:5][CH2:6][O:1][C:2](=[O:7])[C@H:3]2[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1C=CCCO1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1OCC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Reaction time: 2 h

Procedure:
To a stirred solution of 5,6-dihydro-2H-pyran-2-one* (136 g, 1.39 mole) in dichloromethane (2 L) at -20° C. was added N-benzyl-N-(methoxymethyl)-N-trimethylsilylmethyl amine (80% pure) (D12, 450 g, 1.5 mole). To this solution was added trifluoroacetic acid in dichloromethane (140 ml, 1 molar solution) at -20° C. The reaction was then transferred at -20° C. under a small positive pressure of nitrogen via a double ended needle to a second flask on a water bath at 30° C. As the cold mixture warmed up an exothermic reaction occurred and the rate of addition was controlled to maintain gentle reflux. When addition was complete and the reaction had subsided the solution was allowed to stand at room temperature for 2 h. The reaction was then washed with saturated aqueous potassium carbonate solution, dried (Na2SO4) and concentrated in vacuo to a gum. Vacuum distillation afforded the title compound as a single main fraction b.p. 180°-190° C. 0.5mmHg (D20, 180.9 g, 0.73 mole, 56%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14].N#N.O>C(OCC)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(F)cc1
Reactant: NCCCO
Agent: N#N
Solvent: CCOCC
Solvent: O
Product: N#Cc1ccc(NCCCO)cc1
Yield: 84 %

Procedure:
A mixture of 4-fluorobenzonitrile (1.0 g, 8.26 mmol) and 3-aminopropanol (4.54 g, 58.7 mmol) was refluxed under an inert atmosphere (N2) for 15 h. Water (500 mL) and diethyl ether (500 mL) were then added, and the resulting organic layer separated, dried (Na2SO4) and concentrated. The residue was purified by column chromatography (heptane:EtOAc; 1:3) to give the sub-title compound in 84% yield.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.Br[CH2:22][C:23]1[C:24]([CH3:35])=[N:25][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:27][CH:28]=1>C(COC)OC>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([CH2:22][C:23]3[C:24]([CH3:35])=[N:25][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[N:27][CH:28]=3)[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: Cc1nc(-c2ccccc2)ncc1CBr
Reactant: Oc1ccc(N2CCNCC2)cc1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccccc2)ncc1CN1CCN(c2ccc(O)cc2)CC1
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.2 %

Procedure:
A solution of 1.05 g of triethylamine in 20 ml of absolute dimethoxyethane was added dropwise over 30 minutes with stirring to a mixture of 1.78 g (10 mmol) of 1-(4-hydroxyphenyl)piperazine, 3.05 g of 95% strength 5-bromomethyl-4-methyl-2-phenylpyrimidine (=11 mmol) and 80 ml of absolute 1,2-dimethoxyethane at 45° C. The mixture was stirred for a further 1 hour at 45° C. and 3 hours at 80° C., the solvent was evaporated in vacuo, the residue was taken up in CH2Cl2 water and neutralized to pH 6-7, the phases were separated, and the aqueous phase was extracted three times with CH2Cl2. The combined CH2Cl2 extracts were dried, filtered and evaporated in vacuo. The crystalline residue (3.7 g) was recrystallized from methanol. 2.35 g (65% of theory) of pure 4-(4-hydroxyphenyl)-1-(4 -methyl-2-phenylpyrimidin-5-ylmethyl)piperazine, melting point 201°-202° C., were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[N:11]([C:17]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:12]=[CH:13][C:14]=3[C:15]#[N:16])=[CH:4][CH:3]=1.[OH2:24]>CS(C)=O.ClCCl>[NH2:9][C:10]1[N:11](/[C:17](=[N:18]/[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)/[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:24])[N:12]=[CH:13][C:14]=1[C:15]#[N:16]
Reactant: O
Reactant: N#Cc1cnn2c(NC3CCCC3)c(-c3ccc(Br)cc3)[nH]c12
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#Cc1cnn(/C(=N/C2CCCC2)C(=O)c2ccc(Br)cc2)c1N
Temperature: 25 °C
Yield: 21.7 %

Procedure:
A dilute solution of 2-(4-bromophenyl)-3-(cyclopentylamino)-1H-imidazo[1,2-b]pyrazole-7-carbonitrile (500 mg, 1.35 mmol) in DMSO (100 mL) was stored at RT for more than 60 days. The yellow DMSO solution was poured into water (1 L) and the organic compound was extracted into ethyl acetate (2×75 mL). The combined extracts were washed with water and brine solution. The organic layer was dried over anhydrous MgSO4, filtered and concentrated to give the crude yellow solid which was not soluble in dichloromethane even at hot condition. Then, after cooling to RT, the solids were collected by filtration and washed with dichloromethane and the 1H NMR of this solid indicated that it is mostly starting material. Whereas, the mother liquor was removed under vacuum and the crude residue was purified using an ISCO (80 g) column eluting with 0-35% ethyl acetate in hexanes. The pure fractions were combined and the solvent was removed under vacuum to obtain 113 mg (21.7% yield) of (E)-5-amino-1-(1-(cyclopentylimino)-2-(4-bromophenyl)-2-oxoethyl)-1H-pyrazole-4-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ: 1.40-1.80 (br m, 8H), 3.63 (p, 1H), 7.72 (s, 1H), 7.78 (d, J=6.1 Hz, 2H), 7.83 (d, J=6.2 Hz, 2H), 8.14 (br s, 2H). LC/MS calcd. for C17H16BrN5O (m/e) 386.25, obsd. 387.2 (M+H, ES+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:10])[CH:7](N)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([N:13](CC)CC)C.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]>ClCCl>[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:13][CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:10])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:19]#[C:20][CH3:21]
Reactant: CCN(CC)CC
Reactant: CC(N)C(=O)OC(C)(C)C
Reactant: CC#CCOc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc1
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To tert-butyl-2-aminopropanoate (2.0 g, 11.0 mmol) in 20 mL of dichloromethane at 0° C. was added triethylamine (6.75 mL, 48.4 mmol) followed by 4-(2-butynyloxy)phenylsulfonyl chloride (2.94 g, 12.1 mmol). An additional 10 mL of dichloromethane was added to the thick slurry. The mixture was stirred overnight then diluted with dichloromethane and washed sequentially with water, 2N aqueous citric acid and brine, then dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave a solid that was triturated with hexanelethyl acetate to give tert-butyl 3-({[4-(2-butynyloxy)phenyl]sulfonyl}amino)propanoate (3.88 g) as an off-white solid, mp 63-65° C. Analysis for C17H23NO5S: Calc'd: C, 57.77; H, 6.56; N, 3.96. Found: C, 57.68; H, 6.42; N, 3.90. Electrospray Mass Spec 354.2 (M+H)+.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[CH:6][CH:5]=1.Cl.[Cl:12][C:13]1[CH:14]=[C:15]([NH:19]N)[CH:16]=[CH:17][CH:18]=1.[CH3:21][N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][N:19]2[C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([Cl:12])[C:14]=3[C:24]3[CH2:23][N:22]([CH3:21])[CH2:27][CH2:26][C:25]2=3)=[CH:5][CH:6]=1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1cccc(Cl)c1
Reactant: Clc1ccc(CCBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCc2c(c3c(Cl)cccc3n2CCc2ccc(Cl)cc2)C1

Procedure:
The title compound is prepared by following Method 8 by using 1-(2-bromoethyl)-4-chlorobenzene, 3-chlorophenylhydrazine hydrochloride, triethylamine and N-methyl-4-piperidone