Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Si](C)(C)[CH3:3].[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([OH:13])=[O:12]>CO>[NH:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]([O:13][CH3:3])=[O:12]
Reactant: O=C(O)c1ccc[nH]1
Reactant: C[Si](C)(C)Cl
Solvent: CO
Product: COC(=O)c1ccc[nH]1
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Chlorotrimethylsilane (17.9 mL, 141 mmol, 2.5 equiv) is added in one portion to a solution of pyrrole-2-carboxylic acid (6.28 g, 56.5 mmol) in dry methanol (100 mL) under N2 at rt. After stirring overnight, the reaction mixture is concentrated in vacuo, redissolved in dichloromethane, washed with water, dried (Na2SO4) and concentrated to give 4.62 g of methyl pyrrole-2-carboxylate as a tannish semi-crystalline solid (65%), which was used without further purification. 1H NMR (CDCl3) d 9.3 (br s, 1H), 6.96 (br m, 1H), 6.92 (br m, 1H), 6.29 (br q, 1H), 3.86 (s, 3H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)[CH2:7][C@@H:6]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:25]([C@H:6]1[CH2:7][N:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)[CH:12]=2)[CH2:9][CH2:10][N:5]1[CH2:4][CH2:3][OH:2])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC(=O)CN1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(CCO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 12 h
Yield: 73.1 %

Procedure:
A solution of [(S)-2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-acetic acid methyl ester (110 mg, 0.25 mmol) in THF (2 mL) at room temperature was treated with a 1 N THF solution of lithium aluminum hydride (750 μL, 0.75 mmol) and allowed to stir for 12 h. The reaction mixture was quenched with an aqueous 15% NaOH solution (250 μL) followed by water (250 μL) and THF (2 mL). The reaction mixture was then treated with MgSO4, filtered, and evaporated. The residue was then dissolved in EtOAc (3 mL), retreated with MgSO4, filtered, and evaporated to afford the title compound as an oil (75 mg, 73%). 1H NMR (CDCl3) 7.33-7.20 (m, 5H), 6.75 (d, J=8.6, 1H), 6.40 (d, J=2.6, 1 H), 6.34 (dd, J=8.6, 2.9, 1H), 4.67-4.64 (m, 1H), 3.78 (s, 3H), 3.76-3.65 (m, 2H), 3.22-2.74 (m, 12H), 1.88-1.67 (m, 6H), 1.62-1.58 (m, 2H). 13C NMR 148.5, 146.5, 144.7, 139.6, 129.5 (CH), 128.8 (CH), 126.5 (CH) 113.4 (CH), 108.1 (CH), 106.5 (CH), 80.5 (CH), 61.6 (CH), 58.1 (CH2), 56.9 (CH3), 55.5 (CH2), 53.9 (CH2), 49.7 (CH2), 48.4 (CH2), 33.0 (CH2), 33.0 (CH2), 24.2 (CH2). LC/MS (Method A) 4.81 min, [M+1]+ 411.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20](O)=[O:21])[CH2:16][CH2:15]1)=[O:13]>>[CH3:10][O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([NH:9][CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:21])[CH2:16][CH2:15]1)=[O:13]
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: NCCc1ccccc1
Product: COC(=O)[C@H]1CC[C@H](C(=O)NCCc2ccccc2)CC1

Procedure:
The product was prepared from benzeneethanamine and 1,4-trans cyclohexanedicarboxylic acid monomethyl ester by the method described in Example 6 (a) mp 120°-124°.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:30])[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.[H-].[Na+].[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([CH:40]=[O:41])[C:35]=1[NH:42][C:43](=[O:48])[C:44]([CH3:47])([CH3:46])[CH3:45]>O1CCCC1>[F:33][C:34]1[C:35]([NH:42][C:43](=[O:48])[C:44]([CH3:46])([CH3:45])[CH3:47])=[C:36]([CH:40]([OH:41])[CH:16]([CH:17]2[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:21][CH2:22]2)[C:15]([O:14][CH3:13])=[O:30])[CH:37]=[CH:38][CH:39]=1
Reactant: CC(C)(C)C(=O)Nc1c(F)cccc1C=O
Reactant: COC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C1CCN(C(=O)OC(C)(C)C)CC1)C(O)c1cccc(F)c1NC(=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Diisopropylamine (3.40 mL, 24.2 mmol) was dissolved in tetrahydrofuran (70 mL). The mixture was cooled to −78° C. Butyllithium (2 M in cyclohexane, 12.2 μL, 24.4 mmol) was added dropwise to the reaction. The mixture was held at −78° C. with stirring and held for 20 minutes. A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate (5.20 g, 20.2 mmol) in tetrahydrofuran (15 mL) was added to the mixture dropwise. The mixture was held at −78° C. with stirring and held for 45 min. In a separate flask, sodium hydride (60% in mineral oil, 970 mg, 24.3 mmol) was washed with hexanes then suspended in tetrahydrofuran (50 mL). The mixture was cooled to 0° C. A solution of N-(2-Fluoro-6-formylphenyl)pivalamide (4.50 g, 20.2 mmol) in tetrahydrofuran (20 mL) was added to the mixture dropwise. The mixture was held at 0° C. with stirring and held for 1 h. The above prepared aldehyde mixture was added to the ester mixture dropwise over 1.25 h. The mixture was held at −78° C. with stirring and held for 1 h. The reaction was quenched with aqueous ammonium chloride, warmed to room temperature, and diluted with water. The mixture was extracted ethyl acetate (2×) and the aqueous phase was discarded. The material was dried (magnesium sulfate), filtered, and concentrated to dryness. Silica gel chromatography gave the title compound as white foam in 81% yield. Mass spec.: 381.2 (M-C4H8O2+H)+.
Reaction SMILES: [CH2:1]([C:3]([CH2:16]C)([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11](Br)=[CH:10][C:8]=2[N:9]=1)C.[C:18]([O:22][CH2:23][CH3:24])(=[O:21])[CH:19]=[CH2:20].C(N(CC)C(C)C)(C)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:16][C:3]([CH3:1])([CH3:15])[CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([CH:20]=[CH:19][C:18]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][C:8]=2[N:9]=1
Reactant: C=CC(=O)OCC
Reactant: CCC(C)(CC)Cc1nc2cc(Br)ccc2o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)C=Cc1ccc2oc(CC(C)(C)C)nc2c1
Temperature: 100 °C
Yield: 98.1 %

Procedure:
A mixture of 2-(2,2-diethylpropyl)-5-bromobenzoxazole (0.60 g, 0.00225 mol), ethyl acrylate (1.08 g, 0.0108 mol), palladium acetate (0.051 g, 0.00023 mol), trintolylphosphine (0.135 g,0.0045 mol) and N,N-diisopropylethylamine (0.585 g, 0.0045 mol) was heated at 100° C. for 6 hours. The mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate:dichloromethane 3:97, to give ethyl 3-[2-(2,2-dimethylpropyl)benzoxazol-5-yl]propenoate (0.634 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([S:21]C#N)=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].SC[C@H]([C@@H](CS)O)O.P([O-])([O-])([O-])=O>CCO>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([SH:21])=[C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(SC#N)c(C(C)(C)C)cc21
Agent: O=P([O-])([O-])[O-]
Agent: O[C@H](CS)[C@H](O)CS
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2cc(S)c(C(C)(C)C)cc21

Procedure:
The title compound was prepared according to General Method 14 using 6-tert-butyl-5-thiocyanato-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (prepared in Example KK; 2.0 g, 6.6 mmol), dithiothreitol (1.21 g, 7.9 mmol), EtOH (100 mL), and phosphate buffer (pH: 7.5. 10 mL). The crude product was used without any purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>>[CH:13]1([N:19]2[CH2:24][CH2:23][N:22]([C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:11])[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: C1CCC(N2CCNCC2)CC1
Product: O=C([C@@H]1C[C@H]1c1ccccc1)N1CCN(C2CCCCC2)CC1

Procedure:
This example was prepared according to Example 1 by employing trans-2-phenyl-1-cyclopropanecarbonyl chloride and 1-cyclohexylpiperazine, which is commercially available from, for example, Sigma-Aldrich Corporation, to afford title compound as a white solid. m/z (ES+) M+1=313.2; HPLC tR=1.76 min. 1H NMR (500 MHz, CDCl3) δ 7.28-7.24 (m, 2H), 7.19-7.15 (m, 1H), 7.10 (d, J=7.9 Hz, 2H), 3.67-3.53 (m, 4H), 2.58-2.49 (m, 4H), 2.47 (dt, J=8.9, 1.3 Hz, 1H), 2.29-2.22 (m, 1H), 2.00-1.92 (m, 1H), 1.79 (dd, J=17.7, 3.4 Hz, 4H) 1.66-1.58 (m, 2H) 1.26-1.16 (m, 5H) 1.15-1.0 (m, 1H).
Reaction SMILES: COC[O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35]([NH:38][CH2:39][CH2:40][CH2:41][C:42]([F:48])([F:47])[C:43]([F:46])([F:45])[F:44])(=[O:37])=[O:36])[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22]COC)=[CH:18][CH:17]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1.C([O-])(O)=O.[Na+].CCCCCC.C(OCC)(=O)C>C1COCC1.C(O)(C)C.Cl>[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][S:35]([NH:38][CH2:39][CH2:40][CH2:41][C:42]([F:47])([F:48])[C:43]([F:44])([F:45])[F:46])(=[O:36])=[O:37])[C:10]([C:16]3[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=3)([CH3:15])[CH2:11][O:12]2)=[CH:7][CH:6]=1
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCCCCCCCS(=O)(=O)NCCCC(F)(F)C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCCS(=O)(=O)NCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.1 %

Procedure:
7-Methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylaminosulfonyl)nonyl]chroman (8.0 mg, 0.0113 mmol) was dissolved in a solvent mixture of THF (0.2 ml) and isopropanol (0.2 ml), 5N-HCl aqueous solution (0.6 ml) was added dropwise thereto, and the mixture was stirred at room temperature for 3 days. After the reaction was completed, the mixture was cooled, and then saturated aqueous NaHCO3 solution was added thereto. The resulting mixture was extracted with chloroform and washed with saturated saline solution. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue thus obtained was subjected to silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give (3RS,4RS)-7-hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[9-(4,4,5,5,5-pentafluoropentylaminosulfonyl)nonyl]chroman (0.78 mg, yield 11%).
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[C@H:3]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=O.[NH2:16][C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>CO>[CH3:15][CH:2]([CH3:1])[C@H:3]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][NH:16][C@H:17]([C:19]([O:21][CH3:22])=[O:20])[CH3:18]
Reactant: COC(=O)[C@H](C)N
Reactant: CC(C)[C@@H](C=O)OCOCC[Si](C)(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@H](C)NC[C@@H](OCOCC[Si](C)(C)C)C(C)C
Reaction time: 17 h

Procedure:
3-methyl-2-(S)-(2-trimethylsilylethyloxy)methyloxybutanal (1.0 eq) was stirred in methanol at room temperature with L-Alanine, methyl ester (0.8 eq; Bachem). Sodium cyanoborohydride (0.5 eq) was added to the solution, and the reaction was stirred for 17 hours. The reaction was made alkaline by addition of aqueous saturated NaHCO3 solution. The mixture was extracted with dichloromethane, dried over sodium sulfate, and concentrated in vacuo. The residue was purified via radial chromatography using 20% ethyl acetate in hexanes to afford the title intermediate as a colorless oil.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1)=[N+:2]=[N-:3].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=[CH:15][CH:14]=1)#[CH:12]>C(N(CC)C(C)C)(C)C.[Cu]I>[F:10][C:7]1[CH:8]=[CH:9][C:4]([N:1]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]4)=[CH:17][CH:18]=3)[N:3]=[N:2]2)=[CH:5][CH:6]=1
Reactant: C#Cc1ccc([C@H]2CN(C(=O)OC(C)(C)C)CCO2)cc1
Reactant: [N-]=[N+]=Nc1ccc(F)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3cn(-c4ccc(F)cc4)nn3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.4 %

Procedure:
1-Azido-4-fluorobenzene (24 mg, 0.174 mmol) was dissolved in N,N-diisopropylethylamine (0.75 ml), then (S)-tert-butyl 2-(4-ethynylphenyl)morpholine-4-carboxylate (50 mg, 0.175 mmol) was added followed by copper(I) iodide (33 mg, 0.174 mmol). The mixture was stirred at room temperature for 3 h. The green mixture was concentrated on the rotavap, silica gel (0.5 g) was added and after short grinding the mixture was put on a silica gel column for purification. Flash chromatography (5 g silica gel, 30% ethyl acetate in heptane) yielded a white solid (21 mg, 28%). MS (ISP): 369.1 ([M-tBu+H]+), 425.2 ([M+H]+).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O.[NH2:34][NH2:35].O>CN(C=O)C>[CH2:25]([C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:35][N:34]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NN
Reactant: O=C(Cc1ccccc1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Solvent: CN(C)C=O
Solvent: O
Product: O=c1c2c(Cc3ccccc3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 3 h

Procedure:
To a suspension of 4-hydroxy-3-phenylacetyl-1-(3-trifluoromethoxyphenyl)-1,8-naphthyridin-2(1H)-one (220 mg, 0.50 mmol) produced in Synthesis Example 1 in DMF (4 mL) was added hydrazine monohydrate (purity of 80%, 80 μL), and the mixture was stirred at 100 to 110° C. for 3 hours. To the reaction solution was added water. The resulting precipitate was separated by filtration, washed with water, and dried to give 3-benzyl-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4(5H)-one as a form of crystal (204 mg, yield 94%).
Reaction SMILES: Cl[C:2]1[C:3]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:4][C:5]2[N:6]([C:8](=[O:22])[N:9]([CH2:11][C:12]3[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=2)[N:7]=1.[F:30][C:31]1[C:36](B(O)O)=[CH:35][CH:34]=[CH:33][N:32]=1.ClC1C=CC(C2C(C3C=CC=CC=3)=NN3C(=O)N(CC4C=NC(C(F)(F)F)=CC=4)N=C3C=2)=CC=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:3]2[C:2]([C:36]3[C:31]([F:30])=[N:32][CH:33]=[CH:34][CH:35]=3)=[N:7][N:6]3[C:8](=[O:22])[N:9]([CH2:11][C:12]4[CH:13]=[N:14][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:16][CH:17]=4)[N:10]=[C:5]3[CH:4]=2)=[CH:28][CH:27]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(Cl)nn12
Agent: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3ccccc3)nn12
Product: O=c1n(Cc2ccc(C(F)(F)F)nc2)nc2cc(-c3ccc(Cl)cc3)c(-c3cccnc3F)nn12
Yield: 40.9 %

Procedure:
The title compound (41 mg, 42%) as a yellow solid was prepared from 6-chloro-7-(4-chlorophenyl)-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (88 mg, 0.2 mmol) and 2-fluoropyridin-3-ylboronic acid (56 mg, 0.4 mmol) according to the procedures described for 7-(4-chlorophenyl)-6-phenyl-2-((6-(trifluoromethyl)pyridin-3-yl)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (Example 9). LC/MS (method A): retention time=3.38 min, (M+H)+=501. 1H NMR (CDCl3, 400 MHz): δ 8.84 (s, 1H), 8.14 (d, J=1.96 Hz, 1H), 7.97-8.01 (m, 1H), 7.68-7.76 (m, 2H), 7.46 (s, 1H), 7.34 (d,J=8.56 Hz, 2H), 7.04 (d,J=8.56 Hz, 2H), 6.89 (dd,J=8.56, 2.93 Hz, 1H), 5.34 (s, 2H).
Reaction SMILES: [C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH:26]=[CH2:27])([F:25])[F:24])([F:22])[F:21])([F:19])[F:18])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2].[IH:28]>>[C:1]([C:5]([C:8]([C:11]([C:14]([C:17]([C:20]([C:23]([CH2:26][CH2:27][I:28])([F:24])[F:25])([F:21])[F:22])([F:18])[F:19])([F:16])[F:15])([F:13])[F:12])([F:10])[F:9])([F:7])[F:6])([F:4])([F:3])[F:2]
Reactant: I
Reactant: C=CC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)CCI

Procedure:
The same process as in Example 1 was conducted except that 41 g of CF3(CF2)7CH═CH2, 12 g of activated carbon instead of AlI3, and 12 g of hydrogen iodide gas were used. CF3(CF2)7CH2CH2I was produced at a conversion rate of 20% and at a selectivity of 100%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[C:6]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=3)[CH:7]=[CH:8][N:9]=2)[N:4]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2[CH:7]=[CH:8][N:9]=[C:10]3[C:5]=2[N:4]=[C:3]([O:2][CH3:1])[CH:12]=[CH:11]3)=[N:14][CH:15]=1
Reactant: COc1ccc2nccc(-c3ccc(C)cn3)c2n1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc2nccc(-c3ccc(CBr)cn3)c2n1
Temperature: 25 °C
Yield: 71 %

Procedure:
To a stirred solution of 2-methoxy-8-(5-methylpyridin-2-yl)[1,5]naphthyridine (1.2 g, 4.78 mmole), in dry CCl4 (150 mL) at RT was added NBS (1.02 g, 5.73 mmole) and benzoylperoxide (0.12 g, 0.48 mmole). After 18 h at reflux, the reaction contents were cooled to RT and filtered through a scintered-glass funnel washing with CHCl3. Concentration under vacuum and purification on silica (EtOAc) afforded the title compound (1.12 g, 71%) as light yellow solid: (EtOAc): LC-MS (ES) m/e 330 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)[O:21][CH:22]=1>>[CH:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:31][CH2:32][C:23]=1[C:20]1[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]3[CH:15]=[CH:14][N:13]=[CH:12]3)=[CH:4][CH:3]=2)[N:19]=1
Reactant: ClCc1coc(C2=Cc3ccccc3CC2)n1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Product: C1=C(c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)CCc2ccccc21
Yield: 42 %

Procedure:
In substantially the same manner as in Working Example 37, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(3,4-dihydro-2-naphthyl)oxazole to give 2-(3,4-dihydro-2-naphthyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 42%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 99-100° C.
Reaction SMILES: [CH2:1]([C:3]1[C:9]([CH2:10][CH3:11])=[CH:8][C:6]([NH2:7])=[C:5]([N+:12]([O-])=O)[CH:4]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:10]([C:9]1[C:3]([CH2:1][CH3:2])=[CH:4][C:5]([NH2:12])=[C:6]([NH2:7])[CH:8]=1)[CH3:11]
Reactant: CCc1cc(N)c([N+](=O)[O-])cc1CC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1cc(N)c(N)cc1CC
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.7 %

Procedure:
4,5-Diethyl-2-nitroaniline (23) (567 mg, 2.92 mmol) was dissolved in ethyl acetate (20 mL). To this solution was added 10% Pd-C (142 mg, 20%; Aldrich). The mixture was agitated at room temperature under a pressure of 35 psi (H2) for 5 h. The catalyst was removed through a column of Celite (5 g) and washed with ethyl acetate (3×20 mL). The filtrates were combined and evaporated in vacuo to give 4,5-diethyl-1,2-diaminobenzene 24 (459 mg, 96%) as a colorless solid; mp 114-116° C. (lit. mp 114-115° C.; Lambooy, J. P., J. Am. Chem. Soc. 71:3756 (1949)); 1H NMR (CDCl3, 300 MHz) δ 1.158 (t, 6H, J=7.5 Hz), 2.498 (q, 4H, J=7.5 Hz), 2.908 (br, s, 4H), 6.555 (s, 2H).
Reaction SMILES: [CH:1]1([N:6]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][CH:3]=[CH:2]1.C([O-])(O)=[O:27].[Na+].ClC1C=C(C=CC=1)C(OO)=O>C(Cl)Cl>[C@H:2]12[O:27][C@H:3]1[CH2:4][CH2:5][C@@H:1]2[N:6]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N+:23]([O-:25])=[O:24])(=[O:16])=[O:15])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N(C1C=CCC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N([C@H]1CC[C@@H]2O[C@@H]21)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of tert-butyl cyclopent-2-en-1-yl((2-nitrophenyl)sulfonyl)carbamate (2.75 g, 7.46 mmol) and NaHCO3 (1.254 g, 14.93 mmol) in CH2Cl2 (60 mL) was added in one portion meta-chloroperoxybenzoic acid (2.58 g, 14.93 mmol). The resulting reaction mixture was stirred overnight at RT. The reaction mixture was diluted with CH2Cl2 and washed with 20% aqueous Na2SO3 solution, saturated NaHCO3 solution and water. The organic phase was dried over MgSO4 and concenrated. The title compound was obtained after crystallization from EtOAc as white crystals (2.01 g, 68%): TLC (heptane-EtOAc 1:1) Rf=0.48; tR=1.20 min (UPLC 1), tR=1.12 min (LC-MS 3); ESI-MS: 329 [M-isobutylene]+ (LC-MS 3).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:15])([CH3:14])[C:11]([NH2:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1([C:19]2[N:23](C)[C:22]([CH:25]=[O:26])=[CH:21]N=2)CC1>>[CH2:1]([O:8][CH2:9][C:10]([C:11]1[N:23]([CH3:19])[C:22]([CH:25]=[O:26])=[CH:21][N:13]=1)([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(COCc1ccccc1)C(N)=O
Reactant: Cn1c(C=O)cnc1C1CC1
Product: Cn1c(C=O)cnc1C(C)(C)COCc1ccccc1

Procedure:
2-(2-Benzyloxy-1,1-dimethyl-ethyl)-3-methyl-3H-imidazole-4-carbaldehyde was prepared from 3-benzyloxy-2,2-dimethyl-propionamide in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C(O)C.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:37][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:3]=1)=[O:15]
Reactant: NCc1ccccc1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(C)c(CNC(=O)c2cc(NCc3ccccc3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
To a 10 mL microwave vial were sequentially added 6-chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.100 g, 0.267 mmol), ethanol (2.0 mL) and then benzylamine (0.350 mL, 3.21 mmol) via syringe at once. The sealed contents were irradiated at 140° C. for 3 hr. The contents were transferred to a heat block and heated at 135° C. for 16 hr., and then at 145° C. for an additional 12 h. After cooling to room temperature, the contents were diluted with CH2Cl2 and pre-absorbed onto silica gel. The crude product was purified by silica gel chromatography (dry loaded, eluent; gradient of 5-80% DCM and chloroform containing 10% 2M Ammonia (in methanol)). The isolated solid was triturated with MTBE, filtered, and washed with additional MTBE. The collected solid was dried in vacuum oven at 45° C. overnight to afford the final product as 0.067 g (55%). LCMS E-S (M+H)=445.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.38 (d, J=6.57 Hz, 6H), 2.12 (s, 3H), 2.20 (s, 3H), 4.31 (d, J=5.05 Hz, 2H), 4.56 (d, J=6.06 Hz, 2H), 4.92 (quin, J=6.69 Hz, 1H), 5.88 (s, 1H), 6.69 (s, 1H), 7.18-7.25 (m, 1H), 7.26-7.35 (m, 2H), 7.35-7.43 (m, 2H), 7.77 (t, J=5.94 Hz, 1H), 7.83 (s, 1H), 8.47 (t, J=5.05 Hz, 1H), 11.55 (br. s., 1H).