Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:37][C:38]([NH2:40])=[S:39].C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C>[NH2:40][C:38]1[S:39][CH:2]=[C:3]([CH2:4][C:5]([NH:7][CH:8]2[C:34](=[O:35])[N:10]3[C:11]([C:18]([O:20][CH:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]23)=[O:6])[N:37]=1
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reactant: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(/C=C/Cl)CS[C@H]23)cs1
Temperature: 30 °C
Yield: 71.9 %

Procedure:
To a solution of benzhydryl 7-(4-bromo-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.2 g) in a mixture of tetrahydrofuran (15 ml) and ethyl alcohol (15 ml) was added thiourea (0.46 g). The mixture was stirred for an hour at 30° C., poured into an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with 10% aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (0.83 g).
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([O:23][C:24]([F:27])([F:26])[F:25])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[F:27][C:24]([F:25])([F:26])[O:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: NNc1nc2ccc(OC(F)(F)F)cc2s1
Product: O=C(NNc1nc2ccc(OC(F)(F)F)cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4e was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1 mmol) and 2-hydrazino-6-trifluoromethoxybenzothiazole (319 mg, 1.5 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 287 mg, 87%).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:12]#[N:13])=[N:8][C:9]=2[CH2:10]O)[CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[Br:15][CH2:10][C:9]1[N:8]=[C:7]([C:12]#[N:13])[CH:6]=[CH:5][C:4]=1[CH:1]1[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C2CC2)c(CO)n1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CC2)c(CBr)n1
Yield: 70.3 %

Procedure:
A solution of 5-cyclopropyl-6-hydroxymethyl-pyridine-2-carbonitrile (0.1 g, 0.6 mmol), CBr4 (0.8 g, 1.2 mmol), PPh3 (0.3 g, 1.2 mmol) in THF (10 mL) was stirred for 12 h at 40° C. The solvent was removed under reduced pressure and the crude product purified by flash column chromatography (silica gel, 3 g, eluting with 25% ethyl acetate in petroleum ether) to give the title compound (0.1 g, 74%) as yellow solid; MS (EI): m/e=236.9 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]2[O:24][CH2:23]2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]([OH:24])[CH2:23][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:18][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Brc1ccc(CCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a sample of pure sodium hydride (1.60 g, 66.58 mmol, 1.4 equiv) under a N2 atmosphere was added DMF (40 mL). The mixture was cooled to 0° C. and imidazole (4.86 g, 71.34 mmol, 1.5 equiv) was added in many small portions over 1 h. Stirring was continued for an additional 0.5 h at 0° C. To the mixture was added dropwise the neat epoxide 12a (10.80 g, 47.56 mmol, 1 equiv); the epoxide container was rinsed with DMF (10 mL) and the rinse solution was added to the reaction mixture. The mixture was stirred at 0° C. for 0.5 h and then at rt for 24 h. Monitoring by TLC (silica gel, EtOAc) confirmed the completion of the reaction. Water (20 mL) was added, the mixture cooled to 0° C., and more water (200 mL) was added without stirring. After 1 h at 0° C. an additional 100 mL of water were added. The white solid was removed by filtration and washed with water (3×250 mL), and then with hexanes (200 mL). High-vacuum drying gave the imidazole-alcohol 13a (11.80 g, 39.98 mmol, 84%) as a white solid: mp 121-122° C., Rf=0.08 (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 1.68-1.82 (m, 2H), 2.68-2.76 (m, 1H), 2.82-2.89 (m, 1H), 3.75-3.94 (m, 3H), 6.80 (s, 1H), 6.84 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 Adz, CDCl3): δ 31.3, 36.0, 54.1, 69.5, 119.9, 128.5, 130.4, 131.6, 140.6; HAS (EI) Calcd. for C13H15BrN2O: 294.0368 (M+). Found: 294.0375.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[NH:9]1.I[CH:23]([CH3:25])[CH3:24]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C@@H:14]3[C:18]([CH3:20])([CH3:19])[C@@:11]([CH3:21])([CH2:12][CH2:13]3)[C:10]=2[N:9]1[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)I
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3ccccc3F)c(=O)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c2c(c(=O)n1-c1ccccc1F)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Reaction time: 18 h
Yield: 4.1 %

Procedure:
A mixture of a (4S,7R)-2-(2-fluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 12; 150 mg, 0.52 mmol) and 2-iodopropane (105 μL, 1.05 mmol) in N,N-dimethylformamide (2 mL) in a microwave reaction tube was heated to 100° C. and stirred for 18 h. The reaction mixture was allowed to cool, diluted with saturated sodium bicarbonate, and extracted twice with ethyl acetate. The organic extracts were combined, washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO CombiFlash® Sg100c chromatography system with an Isco 12 g column, eluting with 25-100% ethyl acetate/hexanes followed by crystallization from dichloromethane to give (4S,7R)-2-(2-fluoro-phenyl)-1-isopropyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (7 mg, 4%) as an yellow solid. ES(+)-MS (M+H) 329.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH:7]([C:18]2[C:26]3[C:21](=[C:22]([CH2:27][S:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH:8]2C(=O)O[C:11](C)([CH3:15])[O:10][C:9]2=[O:17])=[CH:5][N:6]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Br:1][C:2]1[S:3][C:4]([CH:7]([C:18]2[C:26]3[C:21](=[C:22]([CH2:27][S:28][CH3:29])[CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)[CH2:8][C:9]([O:10][CH2:11][CH3:15])=[O:17])=[CH:5][N:6]=1
Reactant: CSCc1cccc2c(C(c3cnc(Br)s3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1cnc(Br)s1)c1c[nH]c2c(CSC)cccc12

Procedure:
19 mg (0.29 mmol) of copper powder were added to 3.57 g (81% purity, 5.87 mmol) of the compound from Example 24A in 15 ml of pyridine and 8 ml of ethanol. The reaction mixture was heated under reflux for 5 h and then the copper was filtered off through kieselguhr. The filtrate was concentrated, the residue was stirred with diethyl ether/dichloromethane, and the precipitated solid was filtered off. The filtrate was concentrated and purified by preparative HPLC (acetonitrile/water gradient). 1.24 g (46% of theory) of the title compound were obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1.[C:25](#[N:27])[CH3:26].[H-].[Na+]>CN(C)C=O.O1CCCC1>[O:2]=[C:3]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)=[CH:6][CH:5]=1)[CH2:26][C:25]#[N:27]
Reactant: CC#N
Reactant: COC(=O)c1ccc(CCc2cc(OC)c(OC)c(OC)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(CCc2ccc(C(=O)CC#N)cc2)cc(OC)c1OC
Temperature: 65 °C

Procedure:
To a solution of 10 g (30 mmol) of methyl-4-[2-(3,4,5-trimethoxyphenyl)ethyl]benzoate and 1.74 ml (33 mmol) of acetonitrile in a mixture of 30 ml of dry N,N-dimethylformamide and 20 ml of dry tetrahydrofuran was added, portionwise under a nitrogen atmosphere at 0° C., 3 g (76 mmol) of a 60% suspension of sodium hydride in mineral oil. The resulting suspension was heated under a flow of nitrogen to 65° C. and maintained at this temperature for 2 hours. After cooling to 25° C., the resultant mixture was quenched with 3 ml of methanol and the solvent was removed in vacuo. The resultant residue was dissolved in 60 ml of water, acidified with 2N hydrochloric acid to a pH between 4 and 5 and then extracted with ethyl acetate. The combined organic phase was then washed successively with water and saturated sodium chloride solution and dried over magnesium sulfate, after which time the solvent was removed under reduced pressure. The crude product was then purified on silica gel employing a mixture of ethyl acetate and hexane in a 1:1 ratio as the eluent to yield a white crystalline solid.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[C:7]1(/[C:13](/[CH2:42][CH3:43])=[C:14](\[C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[CH:36]=[C:35]([CH:40]=[O:41])[CH:34]=[CH:33]3)/[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:19]=[CH:18]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(C)=O.O>[C:7]1(/[C:13](/[CH2:42][CH3:43])=[C:14](\[C:30]2[CH:31]=[C:32]3[C:37](=[CH:38][CH:39]=2)[CH:36]=[C:35]([C:40]([OH:2])=[O:41])[CH:34]=[CH:33]3)/[C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[N:19]=[CH:18]3)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC/C(=C(/c1ccc2cc(C=O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC/C(=C(/c1ccc2cc(C(=O)O)ccc2c1)c1ccc2c(cnn2C2CCCCO2)c1)c1ccccc1
Reaction time: 3 h

Procedure:
Potassium permanganate (5 mL of 1.0 M aqueous solution) was added to a solution of (E)-6-(2-phenyl-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)-2-naphthaldehyde (240 mg, 0.49 mmol) and acetone:H2O (2:1, 15 mL) at room temperature. The reaction was stirred for 3 h, quenched with sat. Na2SO3, acidified to pH 5 with 1.0 M aqueous HCl soln, and then extracted with 2× EtOAc. The organic layers were combined, washed with water then brine, dried over Na2SO4, and concentrated. The crude material was used without further purification. LCMS: 419 [(M-THP+H)+H]+.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[Br:13][CH2:14][CH2:15][CH2:16]Br.C(N(CC)CC)C>>[Br:13][CH2:14][CH2:15][CH2:16][O:1][N:2]1[C:3](=[O:12])[C:4]2[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]1=[O:7]
Reactant: BrCCCBr
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCCCBr
Yield: 53.4 %

Procedure:
This compound was produced by modifications of the methods used J. Med. Chem., 1991, 34, 1071 starting with N-hydroxyphthalimide (10.0 g, 61.3 mmol), 1,3-dibromo-propane (24.8 g, 123 mmol) and triethylamine (12.4 g, 123 mmol). The crude material was purified by flash chromatography through silica gel using chloroform to give 2-(3-bromo-propoxy)-isoindole-1,3-dione (9.30 g, 53%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 7.81 (m, 2H), 7.73 (m, 2H), 4.34 (t, 2H), 3.68 (t, 2H), 2.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:22])/[CH:10]=[C:11]1\[S:12][C:13]([CH3:21])=[C:14]([CH3:20])[N:15]\1[CH2:16][CH2:17][CH2:18][CH3:19].C([O-])(O)=O.[Na+].Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCOC(C)=O.O>[CH2:16]([N:15]1[C:14]([CH3:20])=[C:13]([CH3:21])[S:12]/[C:11]/1=[CH:10]\[C:9]([C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[NH:1][C:29](=[O:30])[O:31][CH2:32][CH3:33])=[O:22])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1N
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1cc(Cl)ccc1NC(=O)OCC
Yield: 97.8 %

Procedure:
To a solution of Example 139 (17 mg, 0.05 mmol) and NaHCO3 (42 mg, 0.5 mmol) in EtOAc (5 mL) and H2O (5 mL) was added dropwise at room temperature a solution of ethyl chloroformate (0.06 mL, 0.06 mmol) in EtOAc (3 mL) and the reaction was continued for the next 4 h. The ethyl acetate layer was separated, washed with brine, dried with anhydrous MgSO4 and concentrated under reduced pressure. The residue was chromatographed (EtOAc as eluent) to afford 20 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 0.94 (t, J=7 Hz, 3H), 1.24 (t, J=7 Hz, 3H), 1.37 (sextet, J=7 Hz, 2H), 1.62 (quintet, J=7 Hz, 2H), 2.10 (s, 3H), 2.14 (s, 3H), 4.13 (m, 4H), 6.56 (s, 1H), 7.42 (dd, J=9 Hz, 3 Hz, 1H), 7.96 (d, J=3 Hz, 1H 8.23 (d, J=9 Hz, 1H), 11.98 (s, 1H); MS (DCI/NH3) m/z 409 (M+H)+. Anal calcd for C20H25ClN2O3S: C, 58.74; H, 6.16; N, 6.85. Found: C, 59.02; H, 5.98; N, 6.31.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C:12]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C:12]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([O:16][CH3:17])=[O:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(C)(C)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Solvent: CCO
Product: COC(=O)C1(C(C)(C)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Reaction time: 8 h
Yield: 74.8 %

Procedure:
Methyl (4S)-4-[(tert-butoxycarbonyl)amino]-1-(1-hydroxy-1-methylethyl)cyclopent-2-ene-1-carboxylate (1.4 g, 4.7 mmol) was dissolved in ethanol (30 mL) in a Parr flask and purged with N2. 10% Palladium on carbon (0.14 g; was added and the mixture was shaken overnight under nitrogen at 50 psi. The mixture was filtered through celite, washed with methylene chloride and concentrated to give the desired product (1.06 g, 86%).
Reaction SMILES: C([NH:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1)=O.[ClH:17]>CO>[ClH:17].[NH2:3][C:4]1[N:9]=[C:8]([C:10](=[N:14][O:15][CH3:16])[C:11]([OH:13])=[O:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CON=C(C(=O)O)c1cccc(NC=O)n1
Agent: Cl
Solvent: CO
Product: CON=C(C(=O)O)c1cccc(N)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 100.2 %

Procedure:
A mixture of 2-(6-formamidopyridin-2-yl)-2-methoxyiminoacetic acid (syn isomer) (5.0 g.) and concentrated hydrochloric acid (2.34 g.) in methanol (50 ml.) was stirred for 40 minutes at ambient temperature. After the removal of methanol from the reaction mixture under reduced pressure, the residue was pulverized in diethyl ether, collected by filtration and then dried to give a pale brown powder of 2-(6-aminopyridin-2-yl)-2-methoxyiminoacetic acid hydrochloride (syn isomer) (5.2 g.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)[CH:3]=1.N.[H][H]>CO.[OH-].[Pd+2].[OH-].[C]>[N:7]1[CH:2]=[CH:3][C:4]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:15])[CH2:12][CH2:13]2)=[N:5][CH:6]=1
Reactant: [H][H]
Reactant: CC(C)(C)COC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Agent: [Pd+2]
Agent: N
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)COC(=O)N1CCN(c2ccncn2)CC1
Yield: 33.1 %

Procedure:
2,2-Dimethylpropyl 4-(6-chloropyrimidin-4-yl)-1-piperazinecarboxylate (68 mg) obtained in Example 4 was dissolved in methanol (3 mL), and 0.5 ml of aqueous ammonia and a catalytic amount of palladium hydroxide-carbon were added thereto, and stirred in a hydrogen atmosphere at room temperature for 2 hours, and the reaction liquid was filtered. The filtrate was evaporated, and the resulting residue was diluted with ethyl acetate, washed with water and saturated saline water, and dried with anhydrous sodium sulfate. The solvent was evaporated away and the resulting residue was isolated and purified through thin-layer silica gel chromatography (hexane/ethyl acetate=1/1) to obtain 20 mg of the entitled compound as an oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1>>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Reactant: COc1cccc(O)c1
Product: COc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-methoxy-phenol to give [1-(3-methoxy-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 333(MH+).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:50]([CH3:52])[CH3:51])[CH:47]([CH3:49])[CH3:48])[CH:41]=1)[C:36]([OH:38])=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[CH3:57][N:58]1[CH:62]=[CH:61][C:60]([NH2:63])=[N:59]1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][C@@H:43]([CH3:56])[CH2:44][O:45][Si:46]([CH:53]([CH3:55])[CH3:54])([CH:47]([CH3:49])[CH3:48])[CH:50]([CH3:52])[CH3:51])[CH:41]=1)[C:36]([NH:63][C:60]1[CH:61]=[CH:62][N:58]([CH3:57])[N:59]=1)=[O:38])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1ccc(N)n1
Reactant: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[Si](OC[C@H](C)Oc1cc(OCc2ccccc2)cc(C(=O)Nc2ccn(C)n2)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 78.4 %

Procedure:
HATU (23.5 g, 61.8 mmol) was added to 3-(benzyloxy)-5-{(1S)-1-methyl-2-[(triisopropylsilyl)oxy]ethoxy}benzoic acid (23.6 g, 51.5 mmol), followed by addition of DMF (140 mL), and cooled to 0° C. 1-Methyl-1H-pyrazole-3-amine (6.00 g. 61.8 mmol) was added followed by DIPEA (21.3 mL) and the reaction was stirred under argon at 0° C. for 3 hours. The solvent was evaporated and the residue was dissolved in ethyl acetate (500 mL) and washed with citric acid solution (200 mL), sodium hydrogen carbonate solution (150 mL), and saturated brine solution (2×150 mL). The organic layer was separated and dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:4 to 1:1 ethyl acetate:hexanes, afforded the title compound as a colourless oil (21.7 g). 1H NMR δ (CDCl3): 1.05 (s, 18H), 1.05-1.1 (m, 3H), 1.3 (d, 3H), 3.7 (m, 1H), 3.8 (s, 3H), 3.9 (m, 1H), 4.5 (m, 1H), 5.1 (s, 2H), 6.7 (s, 1H), 6.8 (s, 1H), 7.0 (m, 2H), 7.1 (s, 1H), 7.3 (s, 1H), 7.35-7.5 (m, 5H), 8.5 (s, 1H). m/z 538 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[CH2:31][NH2:32]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:32][CH2:31][CH:26]4[CH2:27][CH2:28][CH2:29][CH2:30][O:25]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NCC1CCCCO1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCC3CCCCO3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (tetrahydro-2H-pyran-2-yl)methanamine. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.31 (m, 2H) 1.32-1.45 (m, 2H) 1.77-1.91 (m, 4H) 2.40-2.46 (m, 3H) 3.37-3.49 (m, 1H) 3.65-3.82 (m, 1H) 4.58 (br. s., 1H) 7.65 (dd, J=7.83, 1.52 Hz, 1H) 7.73 (s, 1H) 7.77 (d, J=7.83 Hz, 1H) 8.16 (br. s., 1H) 8.25-8.65 (m, 3H) 8.80-9.01 (m, 1H) 12.36-13.83 (m, 1H). MS m/z [M+H]+418.2.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.C[N:18](C=O)C>C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:18])=[O:6]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: NC(=O)c1cccc(I)c1
Yield: 90 %

Procedure:
3-Iodo-benzamide was prepared using a modification of the procedure by Remsen. (Remsen; Reid Am. Chem. J. 1899, 21, 289.) 3-Iodo-benzoic acid (28.68 g, 116 mmol) was stirred in CH2Cl2 (200 mL) at 23° C. under argon. Oxalyl chloride (30.2 mL, 349 mmol) was added slowly, and slow gas evolution was observed. DMF (0.1 mL) was then added, accelerated gas evolution considerably, and the reaction was stirred for. 2 h. Solvent was removed, and the brown oily residue was dissolved in THF (50 mL) and added to a solution of 18% aqueous NH4OH (260 mL) at 0° C. After stirring the mixture for 15 min, the liquid was decanted off, and the remaining sludge was acidified with 1 N HCl. The white solid was collected by filtration, washed with water, and dried under vacuum to give 25.68 g (90%) of 3-iodo-benzamide compound 32. 1H NMR (DMSO-d6) δ 8.21 (1 H, t, J=1.5 Hz), 8.05 (1 H, s), 7.87 (2 H, dd, J=8.1, 1.5 Hz), 7.47 (1 H, s), 7.25 (1 H, t, J=7.8 Hz); IR (KBr) 3343, 3164, 1661, 1628, 1561, 1424, 1389, 1125. Anal. (C7H6INO) C, H, N.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15](=[O:18])[CH:16]=[CH2:17])=[CH:10][CH:9]=1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([Si:23]([O:18][C:15](=[CH:14][C:11]1[CH:10]=[CH:9][C:8]([F:7])=[CH:13][CH:12]=1)[CH:16]=[CH2:17])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C=CC(=O)Cc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC(=Cc1ccc(F)cc1)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
To a solution of 104 mL (104.0 mmol, 1.2 equiv.) of a 1.0M solution of potassium tert-butoxide in THF and 100 mL dry THF under nitrogen atmosphere at −78° C. was added a solution of 14.2 g (86.6 mmol, 1 equiv.) of 1-(4-fluorophenyl)but-3-en-2-one (step B) and 13.0 g (86.6 mmol)tert-butylchlorodimethylsilane in 100 mL dry THF. The reaction mixture was stirred at −78° C. for 6 hr and at RT for 6 hr then quenched by the addition of 50 mL water. The resulting mixture was warmed to RT, diluted with 150 mL hexanes, transferred to a separatory funnel and the organic layer separated. The organic layer was washed with 50 mL brine, dried over anhydrous magnesium sulfate, filtered and the solvent evaporated under vacuum to give 20.5 g of the crude title compounds which were used without further purification. 1H-NMR (CDCl3): δ: 7.52 (2H, m), 6.98 (2H, m), 6.33 (1H, dd, J1=13.2 Hz, J2=8.5 Hz), 5.97 (1H, s), 5.52 (1H, d, J=13.2 Hz), 5.17 (1H, d, J=8.5 Hz).