Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[C-:24]#[N:25].[K+].C(OCC)(=O)C>CS(C)=O.O>[C:24]([CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)#[N:25]
Reactant: COc1ccc(-c2noc(CCl)c2-c2ccc(OC)cc2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2noc(CC#N)c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
A 500 mg of 5-chloromethyl-3,4-bis(4-methoxyphenyl)isoxazole was dissolved in a mixed solvent of dimethylsulfoxide (3 ml) and water (1 ml). To the solution, 122 mg of potassium cyanide was added, and the mixture was stirred at room temperature for 18 hours. A 80 ml of ethyl acetate was added to the mixture. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 210 mg (yield 43.1%) of a desired 5-cyanomethyl-3,4-bis(4-methoxyphenyl)isoxazole.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20](SC)=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.O[O:26][S:27]([O-:29])=O.[K+].[CH3:31]O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([S:27]([CH3:31])(=[O:29])=[O:26])=[CH:21][CH:22]=3)=[N:10][NH:11][C:12]=2[C:13]([F:14])([F:16])[F:15])=[CH:6][CH:7]=1
Reactant: O=S([O-])OO
Reactant: CSc1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Yield: 91 %

Procedure:
To a solution of the pyrazole from Step 2 (4.0 g, 11.4 mmol) in 150 mL methanol was added a solution of Oxone® (14.0 g, 22.7 mmol) in 50 mL water. After 1 hour the solids were filtered off, washed with ethyl acetate and the filtrate concentrated in vacuo. This mixture was partitioned between ethyl acetate and water, and the organic layer washed with brine, dried over MgSO4 and reconcentrated in vacuo. Recrystallization from chloroform gave 4-(4-fluorophenyl)-3-[4(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (3.98 g, 91%) as a pale yellow solid: mp 219°-220° C. Elemental analysis for C17H12N2F4SO2Calc'd.: C, 53.12, H, 3.15, N, 7.29, S, 8.34. Found: C, 52.85, H, 3.12, N, 7.21, S, 8.61
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]([OH:12])=[CH:10][C:9]([C:13]([F:16])([F:15])[F:14])=[N:8]1.Cl[C:18]1[N:19]=[N:20][CH:21]=[C:22]([O:24][CH3:25])[CH:23]=1.C1(C)C=CC=CC=1.N1C(C)=CC=CC=1C>ClCCl>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([O:12][C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=2)[N:19]=[N:20][CH:21]=1
Reactant: Oc1cc(C(F)(F)F)nn1C1CCCCO1
Reactant: COc1cnnc(Cl)c1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1cnnc(Oc2cc(C(F)(F)F)nn2C2CCCCO2)c1
Yield: 59.3 %

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-ol (2.37 g, 0.010 mole), 3-chloro-5-methoxypyridazine (1.39 g, 0.0096 mole), toluene (60 mL), and 2,6 lutidine (1.5 g, 0.014 mole) were heated and held at reflux for 3 hours. The mixture was cooled, diluted with 100 mL of dichloromethane, and washed with 1% hydrochloric acid followed by 1% sodium hydroxide solution. The washed solution was dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel using ethyl acetate/cyclohexane to give 5-methoxy-3-[[1-(tetrahydro-2H-pyran-2-yl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]oxy]pyridazine (1.96 g, 59% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[O:9][CH:8]([CH2:10][NH2:11])[CH2:7][C:6]=2[CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29](=[O:30])[NH:11][CH2:10][CH:8]1[CH2:7][C:6]2[CH:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:5]=2[O:9]1
Reactant: NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)NCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Yield: 97.6 %

Procedure:
Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine (2.20 g, 7.28 mmol) with diisopropylethylamine (2.94 g, 22.7 mmol) and methyl chloroformate (1.08 g, 11.4 mmol) generally according to the procedure described for Intermediate 12 provided 2.30 g (93%) of (±)-methyl(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylcarbamate as a white solid. mp 100-103° C.; Anal. calcd. for C17H22ClNO3: C, 63.06; H, 6.85; N, 4.33. Found: C, 63.16; H, 6.3; N, 4.25.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH2:29]>C(#N)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28][NH:29][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[C:15]3[S:16][CH:17]=[CH:18][C:14]=3[O:13][N:12]=2)[CH:6]=1
Reactant: BrCCOc1cccc(-c2noc3ccsc23)c1
Reactant: NCc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Clc1ccccc1CNCCOc1cccc(-c2noc3ccsc23)c1

Procedure:
The title compound is prepared from 3-[3-(2-bromo-ethoxy)-phenyl]-thieno[2,3-d]isoxazole, potassium carbonate, 2-chlorobenzylamine and acetonitrile essentially as described above in example 35. Purity by LC/MS (APCI)=99%, [M+H]+=385.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[C:11]([O:18][CH3:19])[CH:10]=1)=[O:8])C.O.Cl>O1CCOCC1>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[C:11]([O:18][CH3:19])[CH:10]=1)([OH:8])=[O:6]
Reactant: CCOC(=O)c1ccc(B(O)O)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(C(=O)O)ccc1B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
Lithium hydroxide monohydrate (0.092 g) was added to a mixture of 4-ethoxycarbonyl-2-methoxyphenylboronic acid (0.049 g), water (1 mL) and 1,4-dioxane (1 mL), and the mixture was stirred at room temperature overnight. 2 mol/L hydrochloric acid (1.09 mL) was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The residue was washed with water to afford the title compound (0.035 g).
Reaction SMILES: [C:1]([CH2:3][C:4](OCC)=[O:5])#[N:2].[NH2:9][C:10]([NH2:12])=[S:11].[Na].OC1C=CC=CN=1>C(O)(=O)C.O.CO>[NH2:2][C:1]1[CH:3]=[C:4]([OH:5])[N:12]=[C:10]([SH:11])[N:9]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC#N
Agent: Oc1ccccn1
Agent: [Na]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Nc1cc(O)nc(S)n1
Yield: 82 %

Procedure:
0.57 g. of ethyl cyanoacetate and 0.38 g. of thiourea are heated under reflux in 3 ml. of methanol in the presence of 1.17 g. of the sodium salt of 2-hydroxypyridine. After completion of reaction, 4 ml. of water is added, and the solution is neutralized with 0.58 ml. of acetic acid, to deposit the desired monohydrate crystals. Yield: 82%. The ultraviolet absorption spectrum agrees closely with the literature values.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:18][C:19]([OH:21])=O.[C:24]([CH:27]1[CH2:32][N:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[CH3:39])[CH2:30][CH2:29][NH:28]1)(=[O:26])[NH2:25].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:9]1[CH:8]=[CH:7][C:6]([CH2:18][C:19]([N:28]2[CH2:29][CH2:30][N:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])[CH2:32][CH:27]2[C:24](=[O:26])[NH2:25])=[O:21])=[C:5]([O:4][CH2:3][C:2]([F:1])([F:23])[F:22])[CH:10]=1
Reactant: Cc1ccccc1N1CCNC(C(N)=O)C1
Reactant: O=C(O)Cc1ccc(Oc2ccccn2)cc1OCC(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1N1CCN(C(=O)Cc2ccc(Oc3ccccn3)cc2OCC(F)(F)F)C(C(N)=O)C1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-(2-pyridyloxy)phenylacetic acid (0.10 g, 0.31 mmol) from Step 4 above and 2-carbamoyl-4-(2-methylphenyl)piperazine (0.08 g, 0.35 mmol) from Step 4 of Example 1 in DMF (2 mL) was added HOBT (0.06 g, 0.35 mmol), EDC (0.10 g, 0.5 mmol), and DIEA (0.09 mL, 0.5 mmol). The solution was stirred at ambient temperature for 14 h and the solvent was removed under reduced pressure. The residue was partitioned between EtOAc (50 mL) and saturated aqueous NaHCO3 (2×25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 95:5 CH2Cl2 :MeOH as eluant. The product-containing fractions were evaporated under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[NH2:16][C:17]1[C:18](Cl)=[N:19][CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[NH2:16][C:17]1[C:18]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:5])=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccnc1Cl
Reactant: Nc1ccccc1C(=O)c1ccccc1
Solvent: ClCCl
Product: Nc1cccnc1Nc1ccccc1C(=O)c1ccccc1
Temperature: 180 °C
Reaction time: 3 h
Yield: 3.6 %

Procedure:
A stirred mixture of 39.4 g (0.20 mole) of 2-aminobenzophenone and 28.3 g (0.22 mole) of 3-amino-2-chloropyridine was heated at 180° C. under nitrogen atmosphere for 1.5 hr. The mixture was allowed to cool somewhat and 200 ml of methylene chloride was added slowly. After stirring for 3 hr and standing overnight at room temperature, 40.1 g of solid was filtered off and recrystallized twice from methanolisopropyl ether giving 4.3 g, presumably the hydrochloride salt; m.p. 187°-90° C. This solid was dissolved in a mixture of water-methanol, basified with 3 N sodium hydroxide and extracted with methylene chloride. The combined methylene chloride extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from isopropyl ether (charcoal) to give 2.1 g of product; m.p. 91°-3° C. Drying prior to analysis was overnight at room temperature/0.02 mm Hg.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([OH:11])[C:4]=2[O:3]1.[CH2:13]([N:15]([CH2:18]C)CC)C.CC(C)=[O:22]>O>[CH3:13][NH:15][C:18](=[O:22])[O:11][C:10]1[C:4]2[O:3][C:2]([CH3:12])([CH3:1])[CH2:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CCN(CC)CC
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: CC(C)=O
Solvent: O
Product: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Temperature: 25 °C

Procedure:
3.35 g (0.025 moles) of 2,3-dihydro-2,2-dimethyl-benzofuran-7-ol are reacted with 6 g (0.025 moles) of N-methylcarbamoyl-benzoic acid sulfimide in 15 ml of acetone, in the presence of 2.56 g (0.025 moles) of triethyl amine, at 50° C. for 15 minutes. The reaction mixture is then cooled to room temperature, diluted with 100 ml of water; the precipitate is filtered off, washed with water and dried. 3.1 g of 2,3-dihydro-2,2-dimethyl-benzofurane-7-yl methyl-carbamate are obtained, melting at 150° to 152° C. Benzoic acid sulfimide can be recovered by precipitation from the mother liquor with an acid.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)#[N:2].N(C1C2CCCCC=2C(C#N)=CC=1)=C=O.[OH:33][C@H:34]1[C@@H:41]2[N:37]([C:38](=[O:55])N(C3C4CCCCC=4C(C#N)=CC=3)[C:40]2=[O:42])[CH2:36][CH2:35]1>>[OH:33][C@H:34]1[C@@H:41]2[N:37]([C:38](=[O:55])[N:7]([C:6]3[CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=4)[C:3]([C:1]#[N:2])=[CH:9][CH:8]=3)[C:40]2=[O:42])[CH2:36][CH2:35]1
Reactant: N#Cc1ccc(N2C(=O)[C@@H]3[C@H](O)CCN3C2=O)c2c1CCCC2
Reactant: COc1ccc(-c2cc(N)ccc2C#N)cc1
Agent: N#Cc1ccc(N=C=O)c2c1CCCC2
Product: COc1ccc(-c2cc(N3C(=O)[C@@H]4[C@H](O)CCN4C3=O)ccc2C#N)cc1

Procedure:
The title compound was prepared from compound 49A by procedures analogous to those described in Experiment 2E and 2F. HPLC: 96% at 3.24 min (retention time) (Conditions: YMC S5 C18 (4.6×50 mm); Eluted with 0% to 100% B, 8 min gradient, 3 min hold. (A=90% H2O—10% MeOH—0.1% H3PO4 and B=10% H2O—90% MeOH—0.1% H3PO4); Flow rate at 2.5 mL/min UV detection at 220 nm). LC/MS m/z 364 [M+H]+.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH:30]=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[C:1]([C:2]1[CH2:30][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:12]2=[C:11]([CH:5]3[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[C:19]3[CH:18]=[CH:17][C:16]([C:20]([O:22][CH3:23])=[O:21])=[CH:15][C:14]=3[N:13]2[CH:3]=1)#[N:4]
Reactant: C=CC#N
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3C=O)[nH]c2c1
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C=C(C#N)Cc1ccccc1-3
Temperature: 100 °C

Procedure:
Acrylonitrile (2 mL of 1.52 M in 1,4-dioxane, 3.04 mmol) was added to methyl 3-cyclohexyl-2-(2-formylphenyl)-1H-indole-6-carboxylate (200 mg, 0.55 mmol) in a microwave vial. The vial was sealed and Triton® B (50 μL, 0.11 μmol) was added via syringe. The vial was heated in a microwave apparatus for 1 hr at 100° C. The solution was concentrated and the residue dissolved in methylene chloride. The solution was applied to a silica gel thick layer plate. The plated was eluted with hexanes-ethyl acetate (8:2). The product containing band was extracted with methylene chloride-methanol (3×). The combined extracts were concentrated and the residue recrystallized from methanol to afford the titled compound as a tan solid. MS m/z 397 (MH); 1H NMR (300 MHz, CHLOROFORM-D) δ ppm 1.16-2.25 (m, 10 H) 2.90-3.10 (m, 1 H) 3.20-3.34 (m, 1 H) 3.60-3.75 (m, 1H) 3.95 (s, 3 H) 7.28-7.49 (m, 4 H) 7.76 (s, 1 H) 7.86-7.97 (m, 2 H) 8.13 (s, 1 H).
Reaction SMILES: [Br-:1].[CH2:2]([N+:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.N1CCCCC1.CCOCC>CO>[Br-:1].[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N+:8]=2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:19][CH:18]=1
Reactant: CCCCCC[n+]1ccccc1C
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCNCC1
Solvent: CCOCC
Solvent: CO
Product: CCCCCC[n+]1ccccc1C=Cc1ccc(N(C)C)cc1
Yield: 53.9 %

Procedure:
1-Hexyl-2-methylpyridinium bromide (7.8 g, 0.03 mole) and 4-dimethylaminobenzaldehyde (6.0 g, 0.04 mole) were refluxed in methanol (50 ml) in the presence of piperidine (1.0 ml) under nitrogen for four hours. On cooling and the addition of about 100 ml of ether a solid crystallised which was collected and washed with a little isopropanol to give 2-[4-(dimethylamino)styryl]-1-hexylpyridinium bromide (6.3 g), melting point 217°-218° (decomposition).
Reaction SMILES: C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][OH:33])[CH2:26]1.[Cl:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2([C:45](O)=[O:46])[CH2:44][CH2:43][CH2:42]2)=[CH:37][CH:36]=1>C(Cl)Cl>[Cl:34][C:35]1[CH:36]=[CH:37][C:38]([C:41]2([C:45]([N:25]3[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]([CH2:32][OH:33])[CH2:26]3)=[O:46])[CH2:44][CH2:43][CH2:42]2)=[CH:39][CH:40]=1
Reactant: OCC1CCCCNC1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(N1CCCCC(CO)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 95 %

Procedure:
tPrEtN (1.78 mL, 10.2 mmol) and pyBrOP (2.39 g, 5.12 mmol) were added at room temperature to a stirring solution of azepan-3-yl-methanol (0.4392 g, 3.41 mmol) and 1-(4-Chlorophenyl)-cyclobutanecarboxylic acid (1.0778 g, 5.12 mmol) in CH2Cl2 under N2. When the reaction was complete, the reaction was subjected to aqueous work-up. Silica gel purification (4:1 to 2:3 Hexanes: Ethyl acetate) provided the desired product in 95% yield (1.0395 g). LRMS: 321.91.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20]([CH2:23][NH2:24])[CH2:19][CH2:18]1>CCO>[F:16][C:17]1([F:25])[CH2:22][CH2:21][CH:20]([CH2:23][NH:24][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])[CH2:19][CH2:18]1
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCC(F)(F)CC1
Agent: Cl
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCC(F)(F)CC2)c([N+](=O)[O-])c1

Procedure:
N-(4-Fluoro-3-nitrophenyl)acetamide (1.15 g, 5.84 mmol) and [(4,4-difluorocyclohexyl)methyl]amine hydrochloride (1.30 g, 7.59 mmol) were stirred in 30 mL of EtOH containing TEA (2.40 mL, 17.5 mmol) at 80° C. for 48 h. The solvent was evaporated. The residue was dissolved in EtOAc and washed with aqueous 5% KHSO4 solution, saturated aqueous NaHCO3 solution, saturated aqueous NaCl solution and dried over anhydrous Na2SO4. The product was crystallized from EtOAc. The left over mother liquor was purified by flash chromatography on silica gel using hexane/acetone (2:1) as eluent. Yield: 1.50 g (78%); 1H NMR (400 MHz, CDCl3) δ 1.33-1.47 (m, 2 H), 1.66-1.77 (m, 2 H), 1.77-1.86 (m, 1 H), 1.89-1.93 (m, 1 H), 1.93-1.97 (m, 1 H), 2.10-2.17 (m, 2 H), 2.18 (s, 3 H), 3.23 (dd, J=6.74, 5.76 Hz, 2 H), 6.83 (d, J=9.37 Hz, 1 H), 7.15 (s, 1 H), 7.80 (dd, J=9.18, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 2 H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][N:10]3[C:15]=2[C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:13][C:12]([C:24]2([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)=[N:11]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][C:24]1([C:12]2[N:13]=[C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[C:15]3=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:8]=[CH:9][N:10]3[N:11]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2nc(NCc3ccccn3)c3c(-c4ccccc4)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.9 %

Procedure:
To a stirred solution of tert-butyl (1-(5-phenyl-4-((pyridin-2-ylmethyl)amino) pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (200 mg, 0.438 mmol) in DCM (15 mL) was added TFA (0.169 mL, 2.19 mmol) and the reaction mixture was stirred at RT for 5 h then concentrated under reduced pressure. The residue was dissolved in (100 mL) and washed with 10% NaHCO3 solution (2×30 mL). The combined organic portion was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified using CombiFlash ISCO (REDISEP®, SiO2, 12 g, 50% EtOAc/petroleum ether) to give 2-(1-aminocyclopropyl)-5-phenyl-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (120 mg, 77.0%) as brown solid. LCMS Condition B-41: retention time 0.62 min, [M+1]=357.1. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.80-0.87 (m, 2H), 1.13-1.18 (m, 2H), 4.68 (d, J=4.8 Hz, 2H), 6.68 (d, J=2.7 Hz, 1H), 7.02 (s, 1H), 7.22-7.30 (m, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.41-7.58 (m, 5H), 7.68-7.80 (m, 2H), 8.34-8.40 (m, 1H).
Reaction SMILES: C(O[CH2:5][C:6](=O)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=O)C.[NH2:14]/[C:15](/[CH3:22])=[CH:16]\[C:17]([O:19][CH2:20][CH3:21])=[O:18].[F:23][C:24]([F:34])([F:33])[C:25]1C=[CH:31][CH:30]=[CH:29][C:26]=1C=O.[OH-].[K+]>C(O)C>[CH3:22][C:15]1[NH:14][C:12]2[CH2:11][O:10][C:8](=[O:9])[C:7]=2[CH:6]([C:5]2[CH:31]=[CH:30][CH:29]=[CH:26][C:25]=2[C:24]([F:34])([F:33])[F:23])[C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: CCOC(=O)/C=C(/C)N
Reactant: CCOC(=O)CC(=O)COC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1=C(C)NC2=C(C(=O)OC2)C1c1ccccc1C(F)(F)F

Procedure:
50 millimols each of ethyl 4-acetoxy-3-oxo-butyrate, ethyl 3-aminocrotonate and 2-trifluoromethylbenzaldehyde in 100 ml of ethanol were boiled under reflux for 24 hours, 2 g of potassium hydroxide were then added, and the mixture was boiled for a further hour. After the mixture had cooled, the product was precipitated with a water/sodium chloride mixture and was recrystallized from methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][NH:15][C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@H:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[CH3:14][N:15]([C@@H:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][C@H:17]1[N:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:11](=[O:13])[CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Reactant: CN[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Product: CN(C(=O)Cc1ccc([N+](=O)[O-])cc1)[C@@H]1c2ccccc2CC[C@H]1N1CCCC1
Yield: 92 %

Procedure:
Using the procedure of Step C of Example 1, 770 mg of (p-nitrophenyl) acetic acid and 700 mg of the product of Step B of Example 1 were reacted to obtain 1.4 g of crude product which was purified by chromatography on silica (eluant: methylene chloride 90, methanol 10) to obtain 1.1 g of product which was crystallized from ethyl ether to obtain 480 mg of product. Two crystallizations from isopropanol were effected to obtain 300 mg of the expected product melting at 135° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([CH2:11][CH2:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31].O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:21])[C:5]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][Cl:31])([CH2:11][CH2:12][CH2:13][C:14]([F:19])([F:20])[C:15]([F:17])([F:18])[F:16])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: ClCCCCCCBr
Reactant: CCOC(=O)C(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(CCCCCCCl)(CCCC(F)(F)C(F)(F)F)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
To a solution of (4,4,5,5,5-pentafluoropentyl)malonic acid diethyl ester (1 g, 3.12 mmol) in tetrahydrofuran (15 ml) was added sodium hydride (175 mg, 4.37 mmol), which was then stirred for 30 min at rt. 1-Bromo-6-chlorohexane (0.7 ml, 4.68 mmol) was added to this reaction mixture and the reaction mixture was refluxed overnight. When the reaction was completed, water was added to the reaction mixture and extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:ethyl acetate=30:1) to give the title compound (760 mg, yield: 56%) as a colorless liquid.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](O)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:21])=O>>[CH2:1]([O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([Cl:21])=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCCCOc1ccc(C(=O)Cl)cc1

Procedure:
40 ml of thionyl chloride was added to 2.0 g of p-octyloxybenzoic acid, andthe mixture was refluxed under heat for 2 hours. Then, excess of thionyl chloride was distilled off to obtain p-octyloxybenzoic acid chloride. 20 ml of dry pyridine was added thereto, and the 4-hydroxy-4'-α-dodecyloxypropanoyloxybiphenyl dissolved in 40 ml of dry benzene was further added. The mixture was then refluxed for 5 hours, charged into ice water, and extracted with ether. The extract was purifiedwith a silica gel column chromatography to obtain 4'-α-dodecyloxypropanoyloxybiphenyl ester of 4-octyloxybenzoic acid.