Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([F:19])[CH:18]=1)[C:15](=O)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:30])=O>>[Cl:30][C:15]1[C:16]2[C:11](=[CH:10][C:9]([N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][C:17]=2[F:19])[CH:12]=[CH:13][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]ccc2cc(N(Cc3ccccc3)Cc3ccccc3)cc(F)c12
Product: Fc1cc(N(Cc2ccccc2)Cc2ccccc2)cc2ccnc(Cl)c12
Temperature: 100 °C
Yield: 89 %

Procedure:
A mixture of 19D (0.622 g, 1.74 mmol) and phosphorous oxychloride (6 mL) was heated at 100° C. for 1.5 h. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with toluene. Ice was added to the residue, followed by sodium hydroxide (1N solution) until the pH was basic. The mixture was extracted with methylene chloride (3×), and the combined organic layers were washed with saturated sodium bicarbonate solution and brine, dried (MgSO4), and dried in vacuo to give 19E (0.583 g, 89%) as a yellow solid.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(O)=O.S(=O)(=O)(O)O.[CH2:17]=[CH:18][CH2:19][CH3:20].C=C(C)C>CCCCCCC>[C:1]([O:8][CH2:17][CH2:18][CH2:19][CH3:20])(=[O:7])[CH2:2][CH2:3][C:4]([CH3:6])=[O:5]
Reactant: C=CCC
Reactant: CC(=O)CCC(=O)O
Agent: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: CCCCCCC
Solvent: O=CO
Product: CCCCOC(=O)CCC(C)=O
Temperature: 150 °C

Procedure:
A 5 cc autoclave is charged with 1 cc of heptane and 1 cc of an aqueous solution containing 2 mmoles of levulinic acid and 2 mmoles of formic acid. 5 wt. % sulfuric acid is added as a catalyst. The reactor is pressurized to 0.69 MPa with 1-butene and heated to 150° C. for 0.5 hours while maintaining a constant pressure of isobutene. After cooling, the organic phase is separated. A mixture of butyl formate and butyl levulinate is formed as product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N:16]3[C:20](=[O:21])[NH:19][C:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:17]3)=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][C:14]1[N:13]=[C:12]([N:16]2[C:20](=[O:21])[NH:19][C:18]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:17]2)[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:31]2[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=2)[CH:7]=1
Reactant: Cc1nc(-n2nc(CC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-n2nc(CC(C)(C)C)[nH]c2=O)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 85 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
1-(5-((2-Chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-neopentyl-1H-1,2,4-triazol-5(4H)-one (0.15 g, 0.40 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.11 g, 0.52 mmol), and K2CO3 (0.14 g, 1.04 mmol) were suspended in a solution of dioxane (2.0 mL) and water (0.40 mL). The suspension was sonicated and sparged with Ar for 10 min. Pd(PPh3)4 (0.05 g, 0.04 mmol) was added and the reaction mixture was stirred at 85° C. for 12 h, allowed to cool to RT, diluted with water (5 mL), and extracted with EtOAc (5×10 mL). The combined organics were dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (MeOH/DCM) to afford 1-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-neopentyl-1H-1,2,4-triazol-5(4H)-one (0.124 g, 69%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.83 (s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.38 (s, 2H), 2.33 (s, 3H), 0.98 (s, 9H); MS (ESI) m/z: 420.2 (M+H+).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH:13]=[CH:14][CH2:15][NH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[C:28]1[S:32][C:31]([NH2:33])=[N:30][N:29]=1>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:17]=[CH:18][CH:19]=2)[O:11][CH2:12][CH:13]=[CH:14][CH2:15][NH:16][C:28]2[S:32][C:31]([NH2:33])=[N:30][N:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC=CCOc1cccc(CN2CCCCC2)c1
Reactant: Nc1nnc(Br)s1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1nnc(NCC=CCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
0.6 g (2.3 mmol) of 4-[3-(1-piperidinylmethyl)phenoxy]2-butene-1-amine, 0.35 ml of triethylamine and 0.42 g (2.3 mmol) of 5-bromo-1,3,4-thiadiazole-2-amin are heated under reflux in 20 ml of THF for 3 hours. Solid triethylammonium bromide is filtered off, the filtrate is concentrated by evaporation and the oily residue is purified by preparative layer chromatography.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:27][S:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[CH:35]2>ClCCl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([C:35]3[C:34]4[C:38](=[C:30]([CH2:29][S:28][CH3:27])[CH:31]=[CH:32][CH:33]=4)[NH:37][CH:36]=3)([CH3:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CCOC(=O)CC(C)(O)c1ccc2c(c1)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)CC(C)(c1ccc2c(c1)OCCO2)c1c[nH]c2c(CSC)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
600 mg (2.25 mmol) of the compound from Example 91A and 0.21 ml (2.70 mmol) of trifluoroacetic acid were added to 399 mg (2.25 mmol) of the compound from Example 8A in 4 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 576 mg (60% of theory) of the title compound.
Reaction SMILES: Br[CH:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([N:13]([CH3:28])[C:14](=[O:27])[C:15]3[CH:20]=[CH:19][C:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:3]1=[O:29].[NH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>>[CH:21]1([C:18]2[CH:19]=[CH:20][C:15]([C:14]([N:13]([CH3:28])[C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][CH:2]([N:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[C:3]4=[O:29])=[CH:8][CH:9]=3)=[O:27])=[CH:16][CH:17]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNCC1
Reactant: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(Br)C2=O)cc1
Product: CN(C(=O)c1ccc(C2CCCCC2)cc1)c1ccc(N2CCC(N3CCCCC3)C2=O)cc1

Procedure:
N-[4-(3-Bromo-2-oxopyrrolidin-1-yl)phenyl]-4-cyclohexyl-N-methylbenzamide was reacted with piperidine by method L. This resulted in the product with the molecular weight of 459.64 (C29H37N3O2); MS (ESI): 460 (M+H+).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24](=[O:27])[CH2:25][CH3:26]>>[CH2:23]([N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])[C:24](=[O:27])[CH2:25][CH3:26]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCC(=O)CBr
Product: CCC(=O)Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 55 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 1-bromo-2-butanone were reacted by the same way with the example 1 to obtain the titled compound (196 mg, yield: 55%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[CH:10]#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>C(N(CC)CC)C.C(OCC)(=O)C.[Cu]I>[C:10]([C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])#[C:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1cccc(Br)c1
Reactant: C#CCCCCCCCCCC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
To a solution of 3-bromobenzaldehyde (26.5 g) and (25.0 g) 1-dodecyne in triethylamine (105 ml) was added bis(triphenylphosphine)palladium(I)chloride (1.73 g) followed by copper(I) iodide (0.24 g). The resultant mixture was stirred in the dark at 55° C. for 7 hrs, under nitrogen. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and filtered. The filtrate was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to yield 37.7 g 3-(1-dodecynyl)benzaldehyde. The filtrate was an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Cl[C:11]1[N:16]=[C:15]([Cl:17])[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]=12>>[Cl:17][C:15]1[N:14]=[C:13]2[N:18]([CH3:21])[N:19]=[CH:20][C:12]2=[C:11]([NH:1][CH2:2][CH2:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:16]=1
Reactant: NCCc1cccnc1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Product: Cn1ncc2c(NCCc3cccnc3)nc(Cl)nc21

Procedure:
Reaction of 3-(2-aminoethyl)pyridine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave (6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-(2-pyridin-3-yl-ethyl)-amine.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].C1COCC1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>[OH-].[Na+].O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][CH:2]([CH2:6][CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3]([OH:5])=[O:4])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: NC(CC1CCCCC1)C(=O)O
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCCC1)NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(RS)-phenylalanine (500.2 mg) was dissolved in H2O (50 ml) and 2N NaOH (1.5 ml). Rh/Al2O3 catalyst (500.5 mg) was added, and the whole was stirred overnight under a hydrogen atmosphere at atmospheric pressure. After the reaction was completed, Rh/Al2O3 was separated by filtration. The filtrate was concentrated to give crude (RS)-2-amino-3-cyclohexylpropanoic acid. Then, the crude (RS)-2-amino-3-cyclohexylpropanoic acid was dissolved in 2N NaOH (15.08 ml). THF (15 ml) and then 4-chlorobenzenesulfonyl chloride (3.196 g) were added, and the whole was stirred at room temperature overnight under argon. The reaction mixture was diluted with water, washed with ethyl acetate, acidified with 2N HCl and extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with a saturated saline solution, and dried over Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 80 g, ethyl acetate) and then by preparative TLC to obtain (RS)-2-(4-chlorobenzenesulfonylamino)-3-cyclohexylpropanoic acid (200.9 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: O=[N+]([O-])c1ccc(-n2cccn2)c(F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(-n2cccn2)c(F)c1
Yield: 100.6 %

Procedure:
A suspension of 1-(2-fluoro-4-nitrophenyl)-1H-pyrazole (1.80 g, 8.70 mmol) and Pd—C (10%, 0.200 g) in MeOH (20 mL) (containing 10 drops of 6N HCl) was hydrogenated under balloon H2 overnight. The mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was dried on vacuum to give 3-fluoro-4-(1H-pyrazol-1-yl)benzenamine as a solid (1.55 g). MS 178.3 (M+H)
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[N:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>N1C=CC=CC=1>[Cl:23][C:20]1[CH:21]=[N:22][C:12]([NH:11][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:13]([CH:19]=1)[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CCOC(=O)c1cc(Cl)cnc1N
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(Cl)cnc1NC(=O)Cc1ccccc1
Temperature: 130 °C

Procedure:
Phenylacetyl chloride (0.21 mL, d=1.169, 1.6 mmol) was added to ethyl 2-amino-5-chloronicotinate (143) (159.6 mg, 0.7956 mmol) in a 10 mL round-bottom flask. A stir bar and pyridine (1.0 mL, distilled) were added. The mixture was heated to reflux (130° C., oil bath) with stirring under nitrogen. The resulting solution was refluxed for 1 h, then cooled to room temperature. The reaction mixture was quenched with water (5 mL) and extracted with chloroform (3×10 mL). The combined organic extracts were washed with sat. NaHCO3 (3×10 mL) and water (3×10 mL), dried (MgSO4), and rota-evaporated to dryness, leaving an orange liquid. This liquid was chromatographed on silica gel (30 g, Mallinckrodt, grade 62, mesh 60-200) and eluded with hexanes-EtOAc (1:4, 250 mL). The desired fractions were collected (Rf =0.79) and rota-evaporated to dryness, leaving an orange solid. Crystallization from ethanol afforded the title compound as yellow needles, 110 mg (43.6%), mp 113.5°-114° C.; 1H NMR (CDCl3): δ1.38 (t, J=7.2, 3, CH3CH2), 3.90 (s, 2, benzylic), 4.34 (q, J=7.2, 2, CH3CH2O), 7.38 (m, 5, phenyl), 8.22 (d, J=2.4, 1, py), 8.54 (d, J=2.4, 1, py), 10.64 (s, 1, NH); IR (KBr): 3427, 3196, 1743, 1640, 1600, 1409, 1272, 1218, 1136, 1096, 796; HPLC: 100%; LRMS: 318 (M+, 25), 202 (20), 201 (10), 200 (60), 183 (15), 181 (40), 154 (10), 128 (10), 118 (100 ), 91 (80), 65 (25), 39 (10); HRMS Calcd: 318.0771. Found: 318.0772.
Reaction SMILES: [CH3:1][OH:2].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4]1>>[CH3:1][O:2][CH2:4][CH:5]([OH:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCC1CO1
Reactant: CO
Product: CCCCCCCCC(O)COC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The same reactor that was used in Production Example 5 was charged with 64 g (2 mol) of methanol and 2 g of boron trifluoride diethyl ether complex and then the mixture was raised to 60° C. Then, 156.2 g (1 mol) of 1,2-epoxydecane was added dropwise to the mixture over one hour and the resulting mixture was kept as it was for 3 hours. The reaction was terminated just after confirming that 1,2-epoxydecane left unreacted was less than 1% by gas chromatography and then the reaction mixture was cooled. Thereafter, methanol was removed in the same manner as in Production Example 5 to obtain 2-hydroxydecyl methyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: OB(O)c1ccncc1
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2ccncc2)cc1
Temperature: 80 °C
Yield: 35.2 %

Procedure:
The 4-bromo-benzoic acid ethyl ester (1.00 g, 4.37 mmol), pyridine-4-boronic acid (537 mg, 4.37 mmol), and tetrakis(triphenylphosphine)palladium(0) (757 mg, 0.655 mmol) were degassed under nitrogen. The solids were dissolved in 15 mL of 1,4-dioxane and 2.6 mL of 2M sodium carbonate solution. The mixture was heated to 80° C. overnight completion and allowed to cool to room temperature. The contents were partitioned between ethyl acetate and water, and the aqueous was extracted with ethyl acetate. The combined organic was washed with water, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography (silica gel eluted with 1:1 hexanes:EtOAc, Rf=0.2) to afford the pure 4-pyridin-4-yl-benzoic acid ethyl ester as a pale yellow solid (350 mg, 35%). 1H NMR (CDCl3, 400 MHz) δ 8.71 (d, J=4.4 Hz, 2H), 8.16 (d, J=8.0 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.53 (d, J=4.4 Hz, 2H), 4.42 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H). LCMS (APCI+) m/z 228 [M+H]+; Rt=2.81 min.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[CH2:30]([NH:33][CH3:34])[CH:31]=[CH2:32]>CN(C)C(=O)C>[CH2:30]([N:33]([CH3:34])[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1)[CH:31]=[CH2:32]
Reactant: C=CCNC
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: C=CCN(C)C/C=C/COC[C@H]1CC[C@H](CN(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with N-allyl-methyl-amine in N,N-dimethylacetamide at room temperature to yield trans-N-{4-[4-(allyl-methyl-amino)-(E)-but-2-enyloxymethyl]-cyclohexylmethyl}-N-methyl-4-trifluoromethyl-benzenesulfonamide as light yellow viscous oil, MS: 489 (MH+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]>CC(C)=O>[CH3:1][S:2][C:5]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:6]=1[C:7]#[N:8]
Reactant: N#Cc1ccc(C(F)(F)F)cc1Cl
Reactant: C[S-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CSc1cc(C(F)(F)F)ccc1C#N
Temperature: 32.5 °C
Reaction time: 2.5 h

Procedure:
Sodium thiomethoxide (37 g of a 21% aqueous solution, 0.11M) was added during 2 hours to a solution of 2-chloro-4-trifluoromethylbenzonitrile (20.56 g, 0.099M) in acetone (34 g) with stirring at 30-35° C. After a further 2.5 hours at 30-35° C. and 3 hours at 60° C., a further addition of sodium thiomethoxide (3.4 g of a 21% aqueous solution, 0.01M) was made. The mixture was maintained at 60° C. for 2 hours, cooled and the organic phase evaporated to give 2-methylthio-4-trifluoromethylbenzonitrile (20.3 g), m.p.80° C. The yield of product was 91%, with a purity of 97%.
Reaction SMILES: C([O:8][C:9]1[N:10]=[N:11][C:12]([C:23]#[C:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:13][C:14]=1[O:15]CC1C=CC=CC=1)C1C=CC=CC=1>CO.O1CCCC1>[OH:15][C:14]1[C:9](=[O:8])[NH:10][N:11]=[C:12]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=2)[CH:13]=1
Reactant: FC(F)(F)c1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Solvent: C1CCOC1
Solvent: CO
Product: O=c1[nH]nc(CCc2cccc(C(F)(F)F)c2)cc1O
Yield: 27 %

Procedure:
Prepared as described for 4-hydroxy-6-(2-phenethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-{2-[3-(trifluoromethyl)phenyl]ethynyl}pyridazine (Intermediate 15) except that the reaction was carried out in a mixture of methanol and tetrahydrofuran (2:1). The crude material was purified by reverse phase chromatography, eluting with 5-80% acetonitrile/water with a 0.05% formic acid modifier in the water. The crude product was recrystallised from ethanol/heptane to give a white solid (yield=27%).
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.Cl.[CH3:13][C:14]1([CH3:39])[C:23]2[C:18](=[CH:19][C:20]([N+:35]([O-])=O)=[C:21]([NH:24][C:25](=O)[C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)[CH:22]=2)[NH:17][C:16](=[O:38])[CH2:15]1.N1C2C(=CC=CC=2)CCC1=O>N1C=CC=CC=1>[CH3:13][C:14]1([CH3:39])[C:23]2[CH:22]=[C:21]3[NH:24][C:25]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[N:35][C:20]3=[CH:19][C:18]=2[NH:17][C:16](=[O:38])[CH2:15]1
Reactant: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])NC(=O)CC3(C)C)cc1
Agent: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C1CCc2ccccc2N1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc3cc4c(cc3[nH]2)C(C)(C)CC(=O)N4)cc1
Reaction time: 2 h

Procedure:
4.7 g. (20 mmole) of the above compound were mixed in 50 ml. pyridine, while cooling with ice, with 3.7 g. (22 mmole) 4-methoxybenzoyl chloride. After 2 hours at 25° C., the reaction mixture was poured on to ice, acidified with 2N hydrochloric acid, extracted with methylene chloride, dried and evaporated to give 6.9 g. (93% of theory) 4,4-dimethyl-6-(4-methoxybenzoylamino)-7-nitro-1,2,3,4-tetrahydroquinolin-2one; 1,2,3,4-tetrahydroquinolin-2-one; m.p. 288-290° C.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([F:49])([C:45]([F:48])([F:47])[F:46])[C:41]([F:44])([F:43])[F:42])=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]([F:49])([C:41]([F:42])([F:43])[F:44])[C:45]([F:47])([F:48])[F:46])=[CH:38][CH:39]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)#[N:2]
Reactant: FC(F)(F)C(F)(c1ccc(CCl)cc1)C(F)(F)F
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2)Cc2ccc(C#N)cc2)cc1

Procedure:
A solution of 150 mg (0.365 mmol) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate (enantiomer 1, Example 51A) in 3 ml of dry acetonitrile is mixed with 139 mg (0.47 mmol) of 1-(chloromethyl)-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]benzene [prepared as described in EP 0 009 787-A2] and 100 mg (0.73 mmol) of anhydrous potassium carbonate and then heated under reflux for 12 h. The mixture is then filtered and the filtrate is evaporated to dryness. The residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 4:1). 210 mg (0.31 mmol, 86% of theory) of an oil are isolated.