Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([C:36]([F:39])([F:38])[F:37])=[N:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=1)=O)C>O1CCCC1>[F:39][C:36]([F:37])([F:38])[C:13]1[C:12]([CH2:10][OH:9])=[CH:16][N:15]([C:17]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:14]=1
Reactant: CCOC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Temperature: -12.5 °C
Reaction time: 0.75 h
Yield: 108.4 %

Procedure:
A solution of lithium aluminum hydride in THF (1.0 M; 1.6 mL, 1.6 mmol) was added to a cooled (˜−15° C.) solution of 3-trifluoromethyl-1-trityl-1H-pyrazole-4-carboxylic acid ethyl ester (0.64 g, 1.4 mmol) in anhydrous tetrahydrofuran (15 mL). The solution was stirred at −10 to −15° C. for 45 min and then quenched at −10° C. with a solution of Rochelle's salt (2 mL). The mixture was stirred for 10 min and then the cooling bath was removed. Ethyl acetate (25 mL) was added and the mixture was stirred for 30 min, then it was filtered and the filter cake was washed with ethyl acetate. The filtrate was dried (magnesium sulfate), filtered, evaporated, and held under high vacuum over the weekend to give (3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)-methanol (0.62 g, quantitative) as a tacky white oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:38]([C:41]1[CH:42]=[C:43]([N:47]=[C:48]=[O:49])[CH:44]=[CH:45][CH:46]=1)(=[O:40])[CH3:39]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:48]([NH:47][C:43]2[CH:44]=[CH:45][CH:46]=[C:41]([C:38](=[O:40])[CH3:39])[CH:42]=2)=[O:49])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 17 h
Yield: 31.1 %

Procedure:
In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (56 mg, 0.133 mmol) was dissolved in tetrahydrofuran (2 mL) and triethylamine (24 μL, 0.172 mmol) and 3-acetylphenylisocyanate (22 μL, 0.160 mmol) were added. The reaction mixture was stirred for 17 hours. One-half of the original reaction mixture (1 mL) was concentrated in vacuo then purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (24 mg, 62%). 1H NMR (400 MHz, DMSO, 120° C.), δ: 8.32 (s, 1H), 7.91 (t, 1H, J=2), 7.58 (m, 1H), 7.48 (m, 1H), 7.33 (t, 1H, J=8), 7.15 (m, 2H), 6.99 (m, 2H), 5.98 (d, 1H, J=10), 4.04 (bd, 1H, J=13), 3.89 (bm, 4H), 3.20 (bs, 2H), 2.96 (m, 2H), 2.86 (m, 2H), 2.50 (s, 3H), 2.46 (m, 2H), 1.90 (m, 1H), 1.62 (bm, 4H), 1.43 (2s, 9H), 1.20 (m, 1H). HRMS (ESI), C32H42FN4O5 m+/z: calc.=581.3139, found=581.3141.
Reaction SMILES: [OH-:1].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[O:7]>C(O)(=O)C>[OH:3][C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]([OH:7])[CH:6]([C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[OH:3])[OH:1]
Reactant: [OH-]
Reactant: O=Cc1ccccc1O
Agent: [Na+]
Solvent: CC(=O)O
Product: Oc1ccccc1C(O)C(O)c1ccccc1O
Yield: 46 %

Procedure:
The electrolytic cell was charged with 100 milliliters of 1.5 molar aqueous sodium hydroxide and 10.0 grams (0.082 mole) of 2-hydroxybenzaldehyde (salicylaldehyde). The electrolysis was conducted at a constant current of 3.0 amperes and a temperature of 28° C to 32° C over a 1-hour period. The cathode potential was -1.67 volts versus the saturated calomel electrode. Upon completion of the electrolysis, the solution was acidified to about 6.3 by the addition of glacial acetic acid and extracted with three 100-milliliter portions of ethyl acetate. The ethyl acetate extracts were combined, washed with three 100-milliliter portions of water, and dried over anhydrous magnesium sulfate. Evaporation of the solvent in vacuo and drying of the resulting oil material in a vacuum dessicator yielded 9.3 grams (46.0 percent) of 1,2-bis(2-hydroxyphenyl)-ethane-1,2-diol (2,2'-dihydroxyhydrobenzoin) as a mixture of oil and crystals. The identity of the material was confirmed by nuclear magnetic resonance spectroscopy in pyridine-d5.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:19]C1C=CC=CC=1N.N1C=CC=CC=1C=O>>[Cl:19][C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[N:8]1[N:12]=[N:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:9]1
Reactant: Nc1ccccc1Cl
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Agent: O=Cc1ccccn1
Product: Clc1ccccc1-n1nnc(-c2ccccn2)n1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 2-chloroaniline (38.27 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(2-chlorophenyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [N:1]1([CH:6]2[C:14]3[N:13]=[CH:12][CH:11]=[CH:10][C:9]=3[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.Cl.[Pt]=O>[N:1]1([CH:6]2[CH:14]3[CH:9]([CH2:10][CH2:11][CH2:12][NH:13]3)[CH2:8][CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1cnc2c(c1)CCC2N1CCCC1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: C1CNC2C(C1)CCC2N1CCCC1

Procedure:
6.4 g of the product of Step B in 64 ml of methanol and 6.4 ml of concentrated hydrochloric acid were hydrogenated in the presence of platinum oxide for 5 hours under 1700 mbars and then filtered. The solvent was evaporated to dryness at 40° C. maximum under reduced pressure. The residue was taken up in 20 ml of water, alkalized with about 10 ml of a 32% solution of sodium hydroxide, extracted with methylene chloride, washed with water, dried, and taken to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of ethyl acetate, methanol and triethylamine (80-15-5) to obtain:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24]>CO.O>[O:25]=[C:23]([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5](=[O:14])[C:6]2[N:7]([CH2:11][CH2:12][CH3:13])[CH:8]=[N:9][C:10]=2[N:2]([CH3:1])[C:3]1=[O:15].[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15]
Reactant: CC(=O)CCCCBr
Agent: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCn1cnc2c1c(=O)n(CCCCC(C)=O)c(=O)n2C

Procedure:
437.2 g of 3-methyl-7-propylxanthine are suspended in a mixture of 240 g of methanol and 321 g of water and induced to dissolve at elevated temperature with 160 g of 50% strength sodium hydroxide solution, and subsequently at the boiling point 358 g of 1-bromo-5-hexanone are added and the mixture is heated to reflux for 41/2 hours. After cooling, unreacted 3-methyl-7-propylxanthine is separated off and the alcohol is removed by distillation. The aqueous solution is adjusted to pH 11 with sodium hydroxide solution and extracted with methylene chloride. 1-(5-Oxohexyl)-3-methyl-7-propylxanthine is obtained with melting point 69°-70° C. in approximately 90% yield (based on reacted 3-methyl-7-propylxanthine) from the residue of the methylene chloride solution after recrystallization from 5.2 of diisopropyl ether.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1.[O-:23][S:24]([O-:26])=[O:25].[Na+:27].[Na+].O>CCO>[Na+:27].[CH2:16]([O:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][S:24]([O-:26])(=[O:25])=[O:23])=[CH:10][CH:11]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S([O-])[O-]
Reactant: BrCCCCCCCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
A stirred mixture of 10.1 (0.9 g, 2.50 mmol) and anhydrous Na2SO3 (0.423 g, 3.36 mmol) in EtOH (20 mL)/H2O (10 ml) was heated under reflux (6 h) or microwaved using a CEM-discover system (ram time: 2 min, hold time: 5 min, temperature: 150° C., pressure: 250 psi, power: 250 W). The reaction mixture was cooled to room temperature and the solvent evaporated under reduced pressure. The residue obtained was scrupulously dried under high vacuum and the crude product (10.1, pale yellow solid) was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].C[CH2:42][O:43][C:44]([CH3:46])=O>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:9]2[CH:10]=[CH:11][C:46]([CH2:44][O:43][CH3:42])=[CH:13][CH:8]=2)=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reactant: CCOC(C)=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(-c2ccc(COC)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 140 °C

Procedure:
A mixture of [(1S,2S)-1-({(4-bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (78 mg, 0.146 mmol), arylboronic acid (0.18 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and K2CO3 (38 mg, 0.27 mmol) in CH3CN/H2O (3.5/0.5 mL) was heated in a microwave at 140° C. for 20 min. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to ISCO (12 g column, 0-50% EtOAc in hexane over 25 min) to give the desired products. MS (MH+ 576).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=O)(=[O:3])[CH3:2].Cl.C[NH:24][OH:25].[C:26]([O-])(=O)C.[Na+]>CO.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([CH3:21])=[C:7]2[C:15](=[C:16]([CH3:19])[C:17]=1[CH3:18])[O:14][C:10]1([CH2:11][CH2:12][CH2:13]1)[CH2:9][C:8]2=[N:24][O:25][CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC1(CCC1)O2
Reactant: CNO
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CON=C1CC2(CCC2)Oc2c(C)c(C)c(OC(C)=O)c(C)c21
Yield: 82.6 %

Procedure:
A mixture of 5,7,8-trimethyl-4-oxo-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate (110 mg), N-methylhydroxylamine hydrochloride (64 mg), and sodium acetate (63 mg) in methanol (5 mL) was refluxed for 5 h. The mixture was diluted with ethyl acetate, washed with water and brine, dried and evaporated to give 100 mg of 4-(methoxyimino)-5,7,8-trimethyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-yl acetate, which was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[N:12](CCOC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1.Cl>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:33][CH3:34])=[C:6]([C:8]2[NH:12][N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH:7]=1
Reactant: COc1ccc(F)cc1-c1c(NC(=O)c2cnn3cccnc23)cnn1CCOC[Si](C)(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1ccc(F)cc1-c1[nH]ncc1NC(=O)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 6 h
Yield: 91.8 %

Procedure:
To a solution of N-(5-(5-fluoro-2-methoxyphenyl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (330 mg, 0.68 mmol) in 14 mL ethanol was added HCl (1.0 mL of a 6 M solution in water, 6.0 mmol). The reaction mixture was then stirred at 70° C. for 6 hours. After cooling to room temperature, a light yellow precipitate formed, which was filtered off and rinsed with methanol and diethyl ether. The filtrate was reduced in volume to precipitate more product, which was filtered off. The combined collected solids were dried under vacuum to yield 220 mg (92%) of N-(5-(5-fluoro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=353.1; 1H NMR (400 MHz, DMSO-d6) δ: 9.68 (s, 1H), 9.32 (dd, 1H), 8.77 (dd, 1H), 8.63 (s, 1H), 8.19 (s, 1H), 7.30 (m, 4H), 3.82 (d, 3H).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH3:20])[N:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:21])[C:18]2[C:13](=[N:14][C:15]([CH2:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cccc(CC)n1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2nc(CC)ccc2c1=O
Yield: 80 %

Procedure:
The product of Example 3c (7.16 g, 0.024 mol) was heated in diphenyl ether following the procedure in Example 1b giving the title compound (4.73 g, 79%) as a tan solid.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:12]2[N:13]([C:17]([C:22]([O:24]C)=[O:23])=[C:18]([CH2:20][CH3:21])[N:19]=2)[N:14]=[CH:15][CH:16]=1.Cl>C(O)C>[CH3:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:12]2[N:13]([C:17]([C:22]([OH:24])=[O:23])=[C:18]([CH2:20][CH3:21])[N:19]=2)[N:14]=[CH:15][CH:16]=1
Reactant: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1nc2c(-c3ccc(C)cc3C)ccnn2c1C(=O)O

Procedure:
A 5N aqueous sodium hydroxide solution (0.603 mL, 3.0 mmol) was added to a solution of methyl 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazine-3-carboxylate (373 mg, 1.20 mmol) in ethanol (15 mL), and the mixture was heated under reflux for 1 hour. 5N hydrochloric acid (0.603 mL) was added thereto under ice-cooling and the solvent was evaporated, to give 8-(2,4-dimethylphenyl)-2-ethylimidazo[1,2-b]pyridazine-3-carboxylic acid as a crude compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([NH2:14])[CH2:12][NH2:13].[BH4-].[Na+].Cl>CO>[NH2:13][CH2:12][CH2:11][NH:14][CH:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: CC(=O)c1cccc(O)c1
Reactant: NCCN
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(NCCN)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3′-Hydroxyacetophenone (1.0 g) and ethylenediamine (1.47 ml) were dissolved in methanol (10 ml), and the solution was stirred at room temperature for 16 hours. The mixture was added with sodium borohydride (277.9 mg), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was added with 1 N hydrochloric acid, and then the solvent was evaporated. The residue was added with potassium carbonate and distilled water, thereby made alkaline, and then extracted with a mixed solvent of chloroform-ethanol (10:1), and the organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform:methanol:28% aqueous ammonia=10:1:0.1 to 5:1:0.1) to obtain the title compound (59.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[Mg].CON(C)[C:15](=[O:23])[C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[N:18][CH:17]=1>C(OCC)C.C1COCC1>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:15](=[O:23])[CH2:4][C:3]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=2[F:1])=[CH:17][N:18]=1
Reactant: Fc1ccc(CBr)c(F)c1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Cc1ccc(F)cc1F)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
2,4-Difluorobenzyl bromide (9.0 ml, 70 mmol) was added dropwise to a suspension of magnesium (1.8 g, 75 mmol) in diethyl ether (50 ml) under an atmosphere of dry nitrogen at a sufficient rate to maintain a gentle reflux. The resulting solution was stirred for 15 minutes at room temperature and was then added dropwise to a solution of the product of part (i) (10.0 g, 50 mmol) in THF (70 ml) at -70° C. under an atmosphere of nitrogen. The mixture was warmed to room temperature, stirred for 2 hours then quenched with dilute hydrochloric acid (2M, 50 ml). The layers were separated and the aqueous phase was extracted with diethyl ether (2×50 ml). The combined extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica by elution with ether/hexane (1:1). The appropriate fractions were combined, evaporated under reduced pressure and the crude product was triturated with diethyl ether to give the title compound as a yellow solid, (10.7 g), m.p. 93°-95° C. Found: C,58.01; H,2.99; N,5.17; C13H8ClF2NO requires: C,58.33; H,3.01; N,5.23%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(OP(Cl)(OCC)=O)C.[CH3:37][C:38]([CH3:50])([CH2:41][C:42]#[C:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[CH:39]=O.[NH2:51][OH:52]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:39]([NH:51][OH:52])[C:38]([CH3:37])([CH3:50])[CH2:41][C:42]#[C:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C=O)CC#Cc1ccccc1
Reactant: NO
Reactant: CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(CC#Cc1ccccc1)C(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)NO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
To a solution of 1-(4-fluorophenyl)-4-(methylsulfonyl)piperazine (Intermediate B1; 600 mg; 2.32 mmol) in THF (10 mL) was added Lithiumbis(trimethylsilyl)amide (4.65 mL of a 1.00 M solution in THF; 4.65 mmol) at −78° C. under N2. After 30 min, diethylchlorophosphate (0.38 mL; 2.56 mmol) was added and the mixture was stirred at −78° C. for one hour. A solution of 2,2-dimethyl-5-phenylpent-4-ynal (prepared as described by Cossy et al., 1997, Journal of Organic Chemistry, 62(23), 7900-7901, 432 mg; 2.32 mmol) in THF (5 mL) was cannulated and the reaction mixture was allowed to warm to rt and stirred for 12 h. Hydroxylamine (4.1 mL; 70 mmol was then added and the mixture was heated at 60° C. for 3 h. It was finally concentrated under reduced pressure, redissolved in is EtOAc, washed with a saturated solution of NH4Cl and with brine, dry over magnesium sulfate, filtrated and concentrated. Purification of the crude by flash chromatography on silica (EtOAc:c-Hex; gradient from 20:80 to 50:50) gave the title compounds as a yellow oil (710 mg, 66% yield). HPLC, Rt: 4.15 min (purity: 95.9%). LC/MS, M+(ESI): 460.2. 1H NMR (DMSO-d6) δ: 7.37 (m, 2H), 7.23 (m, 3H), 6.96 (m, 2H), 6.86 (m, 2H), 3.60 (dd, J=14.2, 10.1 Hz, 1H), 3.61 (m, 4H), 3.34 (dd, J=10.1, 1.8 Hz, 1H), 3.12 (m, 5H), 2.37 (AB, J=15.9, Δ=49.3 Hz, 2H), 1.12 (s, 3H), 1.14 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])C=C.C[O-].[Na+].CC(O)(CCC=C(C)CCCC(C)C)C#C>>[CH3:15][C:8]([CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:7][CH2:6][CH2:5][C:2](=[O:16])[CH3:1]
Reactant: C=CC(C)(O)CCC=C(C)CCCC(C)C
Agent: C#CC(C)(O)CCC=C(C)CCCC(C)C
Agent: C[O-]
Agent: [Na+]
Product: CC(=O)CCC=C(C)CCCC(C)C
Temperature: 150 °C

Procedure:
To 630 g of the crude 3,7,11-trimethyl-1,6-dodecadien-3-ol thus obtained, 0.16 g of a methanolic sodium methoxide (concentration: 28%) was added, then the resulting mixture was heated at 150° C. for 1 hour to decompose unreacted 3,7,11-trimethyl-6-dodecen-1-yn-3-ol. Thereafter, the resultant solution was simple distilled under a pressure of 7 to 12 mmHg to collect 520 g of a fraction having a boiling point of 120 to 135° C. Analysis by gas chromatography (column: DC-550, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 160° C.) revealed that this fraction contained 93.7% of 3,7,11-trimethyl-1,6-dodecadien-3-ol (yield on the basis of 6,10-dimethyl-5-undecen-2-one: 78.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16](OC3C=CC(N)=CC=3)[N:15]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1>CCOC(C)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([NH:13][C:14]2[CH:19]=[N:18][CH:17]=[C:16]([C:4]3[CH:3]=[CH:8][C:7]([C:36]([C:33]4[CH:34]=[CH:35][C:30]([C:29]([F:40])([F:39])[F:28])=[CH:31][CH:32]=4)=[O:37])=[CH:6][C:5]=3[NH2:13])[N:15]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(Nc2cncc(Oc3ccc(N)cc3)n2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(-c3ccc(C(=O)c4ccc(C(F)(F)F)cc4)cc3N)n2)cc(OC)c1OC
Yield: 46 %

Procedure:
Using Method LL with 2-(3,4,5-trimethoxyphenylamino)-6-(4-aminophenyloxy)-pyrazine (50 mg, 0.14 mmol) and 4-trifluoromethyl-phenylcarbonyl chloride (35 mg, 0.17 mmol), and purification by column chromatography (AcOEt), the title compound was obtained (34 mg). Yield: 46%. 1H NMR (250 MHz, DMSO-d6) δ 3.65 (s, 3H, [CH3O]4), 3.85 (s, 6H, [CH3O]3+5), 7.28 (s, 2H, Harom2′+6′), 7.95 (d, 4H, Harom 3+5 and Harom 2″+6″ J=8.5 Hz), 8.15-8.21 (m, 4H, and Harom 2+6, Harom 3″+5″ and HPz 5), 8.53 (s, 1H, HPz 3), 9.57 (s, 1H, NH), 10.66 (s, 1H, NHamide). m/z 525.2 [(M+H)+ calcd for C27H23F3N4O4 524.2].
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[N:11]=[C:10]([C:12]([O:14]C)=O)[CH:9]=[CH:8][CH:7]=1)[CH3:2].[CH3:18][C:19]#[N:20]>>[CH2:16]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[N:11]=[C:10]([C:12](=[O:14])[CH2:18][C:19]#[N:20])[CH:9]=[CH:8][CH:7]=1)[CH3:17]
Reactant: CCC(CC)COc1cccc(C(=O)OC)n1
Reactant: CC#N
Product: CCC(CC)COc1cccc(C(=O)CC#N)n1

Procedure:
CH3CN addition to methyl 6-(2-ethylbutoxy)picolinate following the method described in Example 6 gave 3-(6-(2-ethylbutoxy)pyridin-2-yl)-3-oxopropanenitrile as a yellow oil which was used in the next step without further purification. Yield (1.2 g, quant.).
Reaction SMILES: [C:1]1([CH:7]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CC#N.C(OCC)(=O)C>[C:25]([N:15]1[CH2:16][CH2:17][CH:12]([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH3:11])=[O:9])[CH2:13][CH2:14]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C(c1ccccc1)C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)C(c1ccccc1)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a stirring solution of compound 92 (0.159 g, 0.682 mmol) and triethylamine (0.2 mL, 1.435 mmol) in MeCN (10 mL) was added benzoyl chloride (0.10 mL, 0.862 mmol) and the reaction mixture was stirred for 2 h at room temperature. The reaction was diluted with ethyl acetate, washed with sat. aq. Na2CO3, water, brine, dried over Na2SO4, filtered and concentrated to afford the desired compound (0.196 g, 85%) as a colorless oil. LRMS (ESI): (calc) 337.41 (found) 338.35 (MH)+