Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:38])=[C:11]([C@@H:15]2[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35](O)=[O:36])[CH:12]=[CH:13][CH:14]=1.CCN(C(C)C)C(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:76]=[CH:75][C:67]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])=[C:66]([F:77])[CH:65]=1>C(Cl)Cl>[C:71]([O:70][C:68](=[O:69])[C:67]1[CH:75]=[CH:76][C:64]([NH:63][C:35]([C@H:16]2[C@H:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([Cl:8])[C:10]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:32])[CH3:34])[NH:17]2)=[O:36])=[CH:65][C:66]=1[F:77])([CH3:74])([CH3:72])[CH3:73]
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)OC(C)(C)C)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In a 25 mL round-bottomed flask, (2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxylic acid compound with 2,2,2-trifluoroacetic acid (1:1) (200 mg, 344 μmol, Eq: 1.00), was combined with CH2Cl2 (4.5 ml) to give a yellow solution. DIPEA (178 mg, 1.38 mmol, Eq: 4) and diphenylphosphinic chloride (244 mg, 1.03 mmol, Eq: 3) were added and the reaction was stirred at RT for 20 minutes. Tert-butyl 4-amino-2-fluorobenzoate (72.7 mg, 344 μmol, Eq: 1.00) was added and the reaction mixture was stirred at RT overnight. The crude reaction mixture was concentrated under vacuum. The crude material was purified by flash chromatography (silica gel, 40 g, 10% to 20% EtOAc in hexanes) to give a white solid as the product. 215 mg. MS (ES+) m/z Calcd: [(M+H)+]: 660, fund: 660.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([OH:12])=O)[C:7]([O:13][CH3:14])=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[C:15]1([C:21]2[N:30]=[C:24]3[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][N:23]3[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>C(#N)C.O.C1COCC1>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:29][C:27]3[CH:26]=[CH:25][C:24]4[N:23]([N:22]=[C:21]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:30]=4)[CH:28]=3)=[O:12])[C:7]([O:13][CH3:14])=[N:6][CH:5]=2)[CH2:2][CH2:3]1
Reactant: COc1ncc(C2CC2)nc1C(=O)O
Reactant: Nc1ccc2nc(-c3ccccc3)nn2c1
Agent: CCCP(=O)=O
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ncc(C2CC2)nc1C(=O)Nc1ccc2nc(-c3ccccc3)nn2c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 57.2 %

Procedure:
In a 5 ml round bottomed flask 6-cyclopropyl-3-methoxypyrazine-2-carboxylic acid (40 mg, 206 μmol), 2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-amine (47.6 mg, 227 μmol) and THF (1 ml) were mixed to form a solution. Then propylphosphonic anhydride in ethyl acetate 50% (328 mg, 301 μl, 515 μmol) and N,N-diisopropylethylamine (106 mg, 144 μl, 824 μmol) were added and the mixture heated to 70° C. for 2 hours. The reaction mixture was allowed to cool to room temperature, then 1.5 ml of acetonitrile:water (1:1) was added and the mixture stirred for 10 minutes. The precipitate formed was then filtered off, washed with 1 ml of acetonitrile:water (1:1) and 1 ml acetonitrile, then dried in vacuo to give 6-cyclopropyl-3-methoxy-N-(2-phenyl-[1,2,4]triazolo[1,5-a]pyridin-6-yl)pyrazine-2-carboxamide (45.5 mg, 57.2%) as a yellow solid. MS: m/z=387.2 (M+H+).
Reaction SMILES: [F:1][CH2:2][CH:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])CC=C.[Mn]([O-])(=O)(=O)=O.[K+].[C:21]([OH:24])(=[O:23])[CH3:22]>O>[F:1][CH2:2][CH:3]([NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:22][C:21]([OH:24])=[O:23]
Reactant: C=CCC(CF)NC(=O)OC(C)(C)C
Reactant: CC(=O)O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)NC(CF)CC(=O)O
Reaction time: 8 h

Procedure:
1-Fluoro-2-tert-butoxycarbonylamino-4-pentene (1.02 g, 5 mmoles), dissolved in glacial acetic acid (15 ml), is added to potassium permanganate (2.37 g, 15 mmoles) in water (75 ml), and kept overnight at room temperature. After destroying the excess of permanganate with 10% sodium bisulfite solution and saturating with sodium chloride, the mixture is extracted twice with ether. Evaporation gives 4-fluoro-3-tert-butoxycarbonylamino-1-butanoic acid (776 mg) as a white solid which on recrystallization from ether/petroleum ether affords 676 mg (61%) of pure material, m.p. 112°-112.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15]Cl)[CH:7]=[C:6]2[CH:17]=[O:18].[I-:19].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][I:19])[CH:7]=[C:6]2[CH:17]=[O:18]
Reactant: COc1ccc2c(c1)c(C=O)cn2CCCCCl
Reactant: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc2c(c1)c(C=O)cn2CCCCI
Temperature: 25 °C

Procedure:
A stirred solution of 5-methoxy-1-(4-chlorobutyl)indole-3-carboxaldehyde and sodium iodide in acetonitrile under argon is heated under reflux for 18 h, cooled to room temperature and partitioned between ether and water. The combined organic extracts are washed (aqueous sodium metabisulfite solution, water, brine), dried (sodium sulfate) and concentrated in vacuo to give the product.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=O.Cl.Cl[CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C=O)C>[CH3:11][O:10][C:7]1[CH:8]=[CH:9][C:2]2[O:1][C:14]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[CH:4][C:3]=2[CH:6]=1
Reactant: COc1ccc(O)c(C=O)c1
Reactant: ClCc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2oc(-c3ccncc3)cc2c1
Temperature: 150 °C
Reaction time: 6 h
Yield: 63.3 %

Procedure:
A mixture of 0.64 g of 2-hydroxy-5-methoxybenzaldehyde, 0.72 g of 4-(chloromethyl)pyridine hydrochloride, 1.74 g of potassium carbonate, 0.70 g of potassium iodide and 15 ml of DMF was stirred at 80° C. for 3 hours and subsequently at 150° C. for 6 hours. The reaction mixture was cooled to room temperature. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layers were combined and washed with water and saturated brine and dried over sodium sulfate, then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.60 g of 4-(5-methoxybenzofuran-2-yl)pyridine (hereinafter, referred to as “Present Active Compound 2”).
Reaction SMILES: C([O:4][C:5]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][C:6]=1[C:7]([NH:9][C:10]1[S:11][C:12]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[N:14]=1)=[O:8])(=O)C.[OH-].[Na+].Cl>C(O)C>[Br:29][C:26]1[CH:27]=[CH:28][C:5]([OH:4])=[C:6]([CH:25]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([N:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)=[C:13]([C:15]([CH3:17])([CH3:18])[CH3:16])[N:14]=1)=[O:8]
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)c(N2CCCCC2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1nc(NC(=O)c2cc(Br)ccc2O)sc1N1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.3 %

Procedure:
2-Acetoxy-5-bromo-N-{4-[(1,1-dimethyl)ethyl]-5-piperidinothiazol-2-yl}-benzamide (crude product, 84.3 mg) was dissolved in ethanol (3 mL). 2N Aqueous sodium hydroxide (0.1 mL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (54.1 mg, 36.3%; 2 steps) as a white powder.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:24]=[CH:23][C:7]([CH2:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([CH2:15][C@H:16]3[C@H:21]([NH2:22])[CH2:20][CH2:19][CH2:18][O:17]3)[CH2:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[C:32]([C:35]1[CH:36]=[C:37]([N:41]=[C:42]=[O:43])[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([C:35]1[CH:36]=[C:37]([NH:41][C:42]([NH:22][C@@H:21]2[CH2:20][CH2:19][CH2:18][O:17][C@H:16]2[CH2:15][N:11]2[CH2:12][CH2:13][CH2:14][C@@H:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:24][CH:23]=3)[CH2:10]2)=[O:43])[CH:38]=[CH:39][CH:40]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)c1cccc(N=C=O)c1
Reactant: N[C@@H]1CCCO[C@H]1CN1CCC[C@@H](Cc2ccc(F)cc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1cccc(NC(=O)N[C@@H]2CCCO[C@H]2CN2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 0.01 h
Yield: 64.9 %

Procedure:
To a solution of (2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-ylamine dihydrochloride (16 mg, 0.043 mmol—prepared according to Part I) and excess triethylamine (100 μL, 0.719 mmol) in methylene chloride (1 mL) was added 3-acetylphenyl isocyanate (6.9 mg, 0.043) dissolved in methylene chloride (1 mL). The resulting yellow solution was shaken vigorously for 20 sec, and allowed to stand at 23° C. for 10 min. The solution was then concentrated in vacuo, and the resulting residue was purified by flash chromatography (5% methanol in methylene chloride) to yield the desired urea (13 mg, 65%) as a pale yellow oil. MS (ESI), m+/z: (M+H)+=468.3.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[C:10]=1[CH:17]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:8][C:9]1[C:10]([CH2:17][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc(C(O)c2c(OC)cccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: COc1ccc(Cc2c(O)cccc2OC)cc1
Reaction time: 24 h
Yield: 88.2 %

Procedure:
To a solution of (2-benzyloxy-6-methoxyphenyl)-(4-methoxyphenyl)-methanol (2.13 g, 6.08 mmol) in methanol (50 mL), a 20% palladium hydroxide catalyst (0.32 g) was added and furthermore 2N—HCl (1.8 mL) was added thereto. The reaction mixture was stirred under a hydrogen atmosphere for 24 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.31 g, 89%).
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:14]=[C:13]([O:15][CH2:16][CH:17]=[CH2:18])[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=1.[OH-].[K+]>C1COCC1.CO>[CH2:16]([O:15][C:13]1[CH:12]=[C:6]([C:7]([N:9]([CH3:11])[CH3:10])=[O:8])[CH:5]=[C:4]([CH:14]=1)[C:3]([OH:19])=[O:2])[CH:17]=[CH2:18]
Reactant: C=CCOc1cc(C(=O)OC)cc(C(=O)N(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCOc1cc(C(=O)O)cc(C(=O)N(C)C)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2 g (7.6 mmol) of 5-allyloxy-N,N-dimethyl-isophthalamic acid methyl ester in 16.8 ml of THF/MeOH (1:1) 8.4 ml of 1 M KOH (1.1 eq.) are added at 0° C. The mixture is stirred at rt for 3 h. The organic solvents are removed under reduced pressure, and the aqueous phase is acidified with HCl to pH 2 and extracted with DCM/EtOH (80:20) (2×38 ml). The combined organic layers are washed with 8 ml of water, dried over sodium sulfate and evaporated to give the product in the form of a colorless solid (m.p.: 93-95° C.).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-])=O)[CH:5]=[C:6]([CH3:9])[C:7]=1[Cl:8]>C(O)C.[Pd]>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:5]=[C:6]([CH3:9])[C:7]=1[Cl:8])[NH2:10]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)c(C)c(Cl)c1Cl
Yield: 20 %

Procedure:
A solution of 5.0 grams (0.03 mole) of 3,4-dichloro-2,5-dimethyl-1-nitrobenzene in 70 milliliters of ethanol was hydrogenated at room temperature at 50 psi in the presence of 0.25 gram of 10% palladium on activated carbon as a catalyst. Working up the reaction mixture gave 1.21 grams (0.006 mole) of 3,4-dichloro-2,5-dimethylaniline as a yellow solid having a melting point of 72° C.-76° C. NMR analysis of the product indicated the following:
Reaction SMILES: [CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16](I)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:29][OH:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1.[C:41]1([N:47]2[CH:51]=[C:50](B3OC(C)(C)C(C)(C)O3)[CH:49]=[N:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[CH3:1][Si:2]([CH3:40])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([C:50]3[CH:49]=[N:48][N:47]([C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:51]=3)=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23][CH2:22][C:21]([CH2:29][OH:30])([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:19]2)[CH:9]=1
Reactant: CC1(C)OB(c2cnn(-c3ccccc3)c2)OC1(C)C
Reactant: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1(CO)CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4cnn(-c5ccccc5)c4)c3n2)CC1
Temperature: 90 °C
Yield: 72.4 %

Procedure:
A mixture of ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate (270 mg, 0.383 mmol), 1-phenyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (135 mg, 0.498 mmol), PdCl2(dppf)CH2Cl2 (31.3 mg, 0.038 mmol), and K3PO4 (244 mg, 1.15 mmol) in dioxane/H2O (3/0.3 mL) was degassed and then heated at 90° C. for 16 h. After cooling, the reaction mixture was diluted with EtOAc and washed with H2O and brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-40% EtOAc/Hexanes, Rf=0.55 in 50% EtOAc) to afford ethyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-(1-phenyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-1-(hydroxymethyl)cyclohexanecarboxylate as a pale yellow solid (200 mg). HPLC-MS TR=3.06 min (UV 254 nm, 5 min method); mass calculated for formula C37H56N6O5Si2 720.4, observed LCMS m/z 721.3 (M+H).
Reaction SMILES: [CH:1]1([NH:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[O:21])=[CH:15][CH:14]=1>O1CCCC1>[CH:1]1([N:9]([OH:10])[C:20]([NH:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:21])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(N=C=O)cc1
Reactant: ONC1CCCCCCC1
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)N(O)C2CCCCCCC2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.2 %

Procedure:
A solution containing cyclooctyl hydroxylamine (Compound 36 Part B, 2.0 g, 14 mmol) in tetrahydrofuran (50 mL) was slowly charged with 4-methoxyphenyl isocyanate (2.0 mL, 15 mmol). The reaction mixture was allowed to stir at ambient temperature for 20 hours. A white precipitate was isolated by filtration then washed with cold hexane. A second crop was isolated from the filtrate. The solids were combined and dried to provide 3.2 g of the desired product as a white solid, m.p. 166°-167° C. Analysis: Calculated for C16H24N2O3 : %C, 65.73; %H, 8.27; %N, 9.58; Found: %C, 65.31; %H, 7.98; %N, 9.47.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([CH:29]=O)=[CH:21]1>>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:21]1
Reactant: O=Cc1csc2ccccc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4csc5ccccc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1-benzothiophene-3-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1-benzothiophen-3-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:11][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Br)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.6 %

Procedure:
To a stirred solution of 2-(4-bromo phenyl) acetonitrile (20 g, 102.04 mmol) in dry tetrahydrofuran (200 mL) was added sodium bis(trimethylsilyl)amide (18.71 g, 102.04 mmol) at 0° C. under a nitrogen atmosphere. After stirring for 20 minutes at room temperature, methyl iodide (14.48 g, 102 mmol) was added and then stirred for 1 h at room temperature. The reaction mixture was quenched with an aqueous ammonium chloride solution and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water (2×100 mL), a saturated aqueous sodium chloride solution (2×25 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (3-4% ethyl acetate/hexanes) afforded 2-(4-bromo-phenyl)-propionitrile as a light yellow liquid (11.5 g, 53.6%).
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:22](Br)[C:23]#[CH:24]>>[CH2:24]([O:11][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:15][CH2:16][C:17]([CH3:21])=[C:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:23]#[CH:22]
Reactant: C#CCBr
Reactant: CC(=CCOc1ccc(C(=O)O)cc1)CCC(C)=C(C)C
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC(C)=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(3,6,7-trimethylocta-2,6-dienyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(3,6,7-trimethylocta-2,6-dienyl)oxy]benzoic acid propargyl ester; nD24 = 1.5349.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH2:29])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>O1CCCC1.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([NH:29][S:38]([CH3:37])(=[O:40])=[O:39])[C:25]([F:26])([F:27])[F:28])=[CH:4][CH:3]=1
Reactant: NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)NC(c1ccc(Cl)c2nc3n(c12)CCCN3c1c(Cl)cc(Cl)cc1Cl)C(F)(F)F
Yield: 90.3 %

Procedure:
To a mixture of 1-[9-chloro-1-(2,4,6-trichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]-2,2,2-trifluoroethanamine (80.0 mg, 0.165 mmol) and triethylamine (0.0460 mL, 0.330 mmol) in tetrahydrofuran (2 mL) was added methanesulfonyl chloride (0.0153 mL, 0.198 mmol) at 0° C. The resultant mixture was stirred at room temperature for 30 min and diluted with aqueous sodium bicarbonate. The resultant mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (83.7 mg, 0.149 mmol, 90%).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([S:8][C:9]2[CH:17]=[C:16]3[C:12]([CH2:13][O:14][C:15]3=[O:18])=[CH:11][C:10]=2[N+:19]([O-])=O)[S:6][CH:7]=1)[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:19][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][C:9]=1[S:8][C:5]1[S:6][CH:7]=[C:3]([CH2:1][CH3:2])[N:4]=1)[C:15](=[O:18])[O:14][CH2:13]2
Reactant: CCc1csc(Sc2cc3c(cc2[N+](=O)[O-])COC3=O)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CCc1csc(Sc2cc3c(cc2N)COC3=O)n1

Procedure:
A mixture of 6-(4-ethyl-2-thiazolylthio)-5-nitro-3H-isobenzofuran-1-one (750 mg, 2.33 mmol), Fe powder (600 mg, 10.7 mmol) and NH4Cl (150 mg, 2.8 mmol) in 45 mL of EtOH:H2O (2:1) was refluxed for 1.5 h. The hot mixture was filtered through celite and the celite was washed several times with hot EtOH:THF (4:1). Solvent was evaporated in vacuo and the residue was partitioned between H2O and EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated. The solid title compound so obtained was used without purification in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1
Reactant: COc1cccc(O)c1C
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc([N+](=O)[O-])cn2)c1C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
To a solution of 2-methyl-3-(methyloxy)phenol (Intermediate 59, 1.3 g) in DMF (50 mL) was added sodium hydride (60% in mineral oil, 480 mg, 0.012 molat 0° C. and the mixture was stirred for 30 minutes. 2-Chloro-5-nitropyridine (1.9 g, 0.012 mol, Aldrich) was added and the mixture was heated at 60° C. for 3 hours. The mixture was poured into H2O (100 mL) and extracted with ethyl acetate (4 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue which was purified by column chromatography on silica gel (PE:EtOAc=10:1) to afford the title compound (2.3 g) as a liquid.