Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9](=[O:44])[CH:10]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:11][C:12]1[N:13]=[CH: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)C1C=CC=CC=1.[OH-].[K+].C1COCC1>CO.O>[C:40]([O:39][C:37]([NH:36][CH:10]([CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:17]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:16]=1)[C:9]([OH:44])=[O:8])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)O
Yield: 94.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1-trityl-1H-imidazol-4-yl)-propionic acid benzyl ester (6 g, 10.22 mmol) in MeOH (20 mL) was added potassium hydroxide (1.14 g, 20.44 mmol) in water (10 mL). THF (25 mL) was added to homogenise the solution. The solution was stirred for 1 hour and the solvents removed. Water was added and extracted with Et2O. The aqueous layer was acidified with dilute aqueous HCl and extracted with Et2O. The Et2O was washed with water, brine, dried over MgSO4 and filtered. The solvent was removed to give the title compound (4.792 g, 94%). ESMS 498 (M+H+) Mpt 101.5-103.6° C. 1H NMR (CDCl3) δ 1.35 (9H, s), 3.25 (1H, dd, J=5.37, 14.9), 3.39 (1H, dd, J=4.83, 14.9), 4.46-4.52 (1H, m), 5.66, (1H, d, J=5.91), 6.83 (1H, s), 7.07-7.10 (3H, m), 7.26-7.30 (8H, m), 7.42-7.45 (4H, m), 8.13 (1H, s). 13C NMR (CDCl3) δ 28.26, 29.00, 53.07, 76.14, 78.98, 120.88, 128.21, 128.32, 129.63, 133.68, 137.22, 141.52, 154.90, 173.60.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:38][CH2:39][F:40].O>CS(C)=O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([NH:13][CH:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[CH2:15][O:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([CH2:38][CH2:39][F:40])[CH2:20][CH2:19]3)=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1
Reactant: FCCBr
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(NC(COCC1CCN(CCF)CC1)c1ccccc1Cl)c1ccc2c(Cl)c[nH]c2c1
Yield: 32.9 %

Procedure:
To a solution of 3-chloro-N-[1-(2-chlorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (600 mg, 1.3 mmol) in 6 mL of DMSO was added potassium carbonate (716 mg, 5.2 mmol) and 2-bromo-1-fluoroethane (0.10 mL, 1.1 mmol). The reaction was allowed to stir at room temperature overnight after which time water was added and the resulting precipitate was isolated by filtration. Purification of the filtrate (SiO2: EtOAc) provided 178 mg (28%) of the title compound.
Reaction SMILES: [C:1]([C:3]([C@@H:16]1[CH2:20][CH2:19][N:18](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].Br.C1(O)C=CC=CC=1>ClCCl>[C:1]([C:3]([C@@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: Cc1ccc(S(=O)(=O)N2CC[C@@H](C(C#N)(c3ccccc3)c3ccccc3)C2)cc1
Agent: Br
Solvent: ClCCl
Solvent: Oc1ccccc1
Product: N#CC(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
A mixture containing 3-(S)-(+)-(1-cyano-1,1-diphenylmethyl)-1-tosylpyrrolidine (49 g--see Preparation 6(B)), 48% aqueous hydrobromic acid (500 ml) and phenol (50 g) was heated under reflux for 1.25 hours then allowed to cool to room temperature. The mixture was extracted with ether (50 ml) to remove an upper layer of purple oil, then with 2:1 ether/hexane (150 ml). The aqueous layer was extracted with dichloromethane (4×100 ml), the dichloromethane extracts were combined, washed with 10% aqueous sodium hydroxide (3×50 ml), then dried (MgSO4) and concentrated in vacuo to give an oil. The original ether extract was concentrated in vacuo to give an oil which was dissolved in dichloromethane (100 ml) and washed with 10% aqueous sodium hydroxide (3×50 ml). The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give an oil which was combined with that obtained from the initial dichloromethane extraction. The combined oils were then dissolved in dichloromethane (200 ml) and washed with 10% aqueous sodium hydroxide solution (2×50 ml). The dichloromethane solution was dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 24.3 g, [α]25D +6.0° (c 1.0, CH2Cl2).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([F:21])([F:20])[F:9])=[CH:3][CH:4]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: c1ccccc1
Product: Nc1ccc(-c2ccccc2C(F)(F)F)cc1
Yield: 44.1 %

Procedure:
A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 3.80 g (20 mmol) of 2-(trifluoromethyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 14 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 10% EtOAc/hexane to afford 2.09 g (44%) of the aniline. 1H NMR (CDCl3) δ: 7.72 (d, 1H); 7.53 (t, 1H); 7.41 (t, 1H); 7.32 (d, 1H); 7.13 (d, 2H); 6.73 (d, 2H); 3.74 (br s, 2H).
Reaction SMILES: [N:1]1[N:2]=[N:3][N:4]2[CH:9]=[C:8]([C@@H:10]3[CH2:12][O:11]3)[CH:7]=[CH:6][C:5]=12.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>C(O)C>[CH:13]1([NH:17][CH2:12][C@@H:10]([C:8]2[CH:7]=[CH:6][C:5]3[N:4]([N:3]=[N:2][N:1]=3)[CH:9]=2)[OH:11])[CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCC1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CCO
Product: O[C@@H](CNC1CCC1)c1ccc2nnnn2c1

Procedure:
A solution of 0.75 g (4.62 mmol) of (R)-2-(tetrazolo [1,5-a]pyrid 6-yl)oxirane and 1.838 ml (22.8 mmol) of cyclobutyl amine in 1.8 ml of absolute ethanol was heated at 100° C. in a sealed reaction tube for 2 hours. The reaction mixture was concentrated to dryness under reduced pressure, wt. 0.997 g. Tlc, mass spectrum and 1H NMR spectra are consistent with good purity and chemical structure.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH:7]([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:8][OH:9].[C:14]([OH:25])(=O)[CH2:15][CH2:16][S:17][S:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22]>C(C(C)=O)C(C)C>[C:21]([O:23][CH2:8][CH:7]([NH2:6])[CH2:10][CH2:11][CH2:12][CH3:13])(=[O:22])[CH2:20][CH2:19][S:18][S:17][CH2:16][CH2:15][C:14]([O:9][CH2:8][CH:7]([NH2:6])[CH2:10][CH2:11][CH2:12][CH3:13])=[O:25]
Reactant: CCCCC(N)CO
Reactant: O=C(O)CCSSCCC(=O)O
Agent: CS(=O)(=O)O
Solvent: CC(=O)CC(C)C
Product: CCCCC(N)COC(=O)CCSSCCC(=O)OCC(N)CCCC
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
6.1 g of methanesulfonic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise, under an atmosphere of nitrogen and at 70° C., to 7.0 g of 2-amino-1-hexanol (manufactured by Aldrich Co., Ltd.). After stifling for 10 minutes, 6.3 g of 3,3′-dithiodipropionic acid (manufactured by Wako Pure Chemical Industries, Ltd.) was added, and the resulting mixture was heated to 120° C. The mixture was then stirred at 120 to 129° C. for a further 3 hours. Following completion of the reaction, the reaction mixture was cooled to room temperature and then added gradually to 100 mL of methyl isobutyl ketone (manufactured by Wako Pure Chemical Industries, Ltd.). After stifling for 1 hour, the precipitated crystals were collected by filtration and dried at 50° C., yielding the methanesulfonate salt of di(2-aminohexyl) 3,3′-dithiodipropionate.
Reaction SMILES: [C:1](=[S:12])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)SC.[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH3:16].[NH2-].[Na+].Cl>C1(C)C=CC=CC=1.O>[CH3:13][CH:14]([CH3:18])[C:15](=[O:17])[CH2:16][C:1]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[S:12]
Reactant: CC(=O)C(C)C
Reactant: CSC(=S)OCc1ccccc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)C(=O)CC(=S)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.7 %

Procedure:
A solution of S-methyl O-benzyl dithiocarbonate (6.90 g) and 3-methylbutan-2-one (3.00 g) in toluene (20 mL) was added dropwise to a suspension of sodium amide (2.71 g) in toluene (60 mL) at 0° C. over a 5-minute period. The mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water, and the mixture was acidified by addition of 1 mol/L hydrochloric acid. The resulting mixture was extracted with diethyl ether, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=10/1) to give the title compound (5.90 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:34]([O-])=O)=[C:13]([NH:15][C:16]3[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]([F:30])([F:29])[F:28])[N:20]=3)[CH:14]=2)[CH2:4][CH2:3]1.[CH:37](O)=O>[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]3[N:34]=[CH:37][N:15]([C:16]4[S:17][C:18]([C:31]([NH2:33])=[O:32])=[C:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=5[C:27]([F:30])([F:29])[F:28])[N:20]=4)[C:13]=3[CH:14]=2)[CH2:4][CH2:3]1
Reactant: O=CO
Reactant: CN1CCN(Cc2ccc([N+](=O)[O-])c(Nc3nc(-c4ccccc4C(F)(F)F)c(C(N)=O)s3)c2)CC1
Agent: [Pd]
Product: CN1CCN(Cc2ccc3ncn(-c4nc(-c5ccccc5C(F)(F)F)c(C(N)=O)s4)c3c2)CC1
Reaction time: 18 h

Procedure:
A mixture of 0.060 g (0.12 mmole) of 2-[5-(4-methyl-piperazin-1-ylmethyl)-2-nitro-phenylamino]-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (VI.17c) in 7 mL of formic acid and 0.007 g of 10% palladium on carbon catalyst was stirred under an atmosphere of hydrogen for 18 hours. The mixture was filtered through a pad of Diatomaceous earth, washing the filter pad with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-75:25) gave 0.034 g of 2-[6-(4-methyl-piperazin-1-ylmethyl)-benzoimidazol-1-yl]-4-(2-trifluoromethyl-phenyl)-thiazole-5-carboxylic acid amide (I.17) as a white solid. MH+/Z=501
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.[C:15]([CH:17]=[C:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)#[N:16].N12CCCN=C1CCCCC2>C(#N)C>[C:15]([CH2:17][C:18]1([N:12]2[CH:13]=[C:9]([B:4]3[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]3)[CH:10]=[N:11]2)[CH2:19][CH2:20][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:22][CH2:23]1)#[N:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(=CC#N)CC1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CCC(CC#N)(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.3 g, 0.022 mol) in acetonitrile (50 mL) was added tert-butyl 4-(cyanomethylene)piperidine-1-carboxylate (4.9 g, 0.022 mol), followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (3.3 mL, 0.022 mol). The resulting mixture was stirred at room temperature overnight. After being evaporated to dryness, the residue was purified on silica gel, eluting with 0-100% EtOAc in hexanes, to give the desired product (5.62 g, 61%). LCMS (M+H) 417.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:18]=[C:17]2[C:12]([C:13]([N:22](C(=O)CC)[C:23](=[O:26])[CH2:24][CH3:25])=[C:14]([CH3:21])[C:15](=[O:20])[N:16]2[CH3:19])=[CH:11][C:10]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1.CO.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.CCOC(C)=O>[Cl:37][C:34]1[CH:35]=[CH:36][C:31]([C:10]2[CH:11]=[C:12]3[C:17](=[N:18][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[N:16]([CH3:19])[C:15](=[O:20])[C:14]([CH3:21])=[C:13]3[NH:22][C:23](=[O:26])[CH2:24][CH3:25])=[CH:32][CH:33]=1
Reactant: CCC(=O)N(C(=O)CC)c1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(=O)Nc1c(C)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the product of step A (1.56 g) in THF (12 mL) was added methanol (3 mL) and Cs2CO3. The reaction stirred overnight at room temperature before it was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution. The concentrated residue was purified by flash chromatography on silica gel with an EtOAc/hexane gradient elution affording the title compound. HPLC/MS: 499.8 (M+1), 501.8 (M+3); Rt=3.95 min.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[I:11]([O-])(=O)=O.[K+].[I-].[K+]>O.OS(O)(=O)=O>[OH:1][C:2]1[C:10]([I:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(O)nc1
Reactant: [O-][I+2]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [I-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1cnc(O)c(I)c1
Temperature: 60 °C

Procedure:
6-Hydroxynicotinic acid (20 g) in water (200 ml) and H2SO4 (80 ml) was heated to 90° C. for 1 hour. Potassium iodate (0.42 equivalent) and potassium iodide (0.96 equivalent) were both added portionwise over 2 hours. After a further hour at 90° C. the mixture was cooled to 60° C. and added to 1 kg of ice. The brown solid was filtered off, dried and taken up in DMF (30 ml)/EtOH(1 litre). Sodium metabisulfite was added until the brown colour disappeared and the mixture was poured onto ice (2 kg), a further 1.5 litre water added and the white solid filtered to give title compound (16.5 g). NMR δ(DMSO) 12.95 (1H, broad), 12.35 (1H, broad), 8.36 (1H, d), 8.03 (1H, d)
Reaction SMILES: [C:1]12([CH2:11][NH2:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:13][C:14]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16](O)=[O:17]>>[Br:13][C:14]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:15]=1[C:16]([NH:12][CH2:11][C:1]12[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2)=[O:17]
Reactant: NCC12CC3CC(CC(C3)C1)C2
Reactant: O=C(O)c1cc(F)ccc1Br
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(F)ccc1Br

Procedure:
Prepared according to the method of Example 41 from 1-adamantanemethylamine (0.1 ml) and 2-bromo-5-fluorobenzoic acid (0.123 g) to give the title compound as a white solid (0.140 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22](O)=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:34][C:35]([F:42])([C:38]([F:41])([F:40])[F:39])[CH2:36][NH2:37]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:17](=[O:18])[C@@H:16]([NH:19][C:20](=[O:25])[CH2:21][C:22]([NH:37][CH2:36][C:35]([F:42])([F:34])[C:38]([F:41])([F:40])[F:39])=[O:23])[C:15]2[CH:26]=[CH:27][CH:28]=[CH:29][C:14]=2[C:13]2[CH:30]=[CH:31][CH:32]=[CH:33][C:12]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(F)(F)C(F)(F)F
Reactant: O=C(O)CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21
Product: O=C(CC(=O)N[C@@H]1C(=O)N(CCOCc2ccccc2)c2ccccc2-c2ccccc21)NCC(F)(F)C(F)(F)F

Procedure:
Using N—[(S)-5-(2-benzyloxy-ethyl)-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-malonamic acid and N-(2,2,3,3,3-pentafluoro-propyl amine, the title compound was prepared in the same manner as example 1c (73%). White solid. MS: m/e=576(M+H+).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([CH2:16][NH2:17])[CH2:10][CH2:9][N:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30](Cl)=[O:31]>C(Cl)Cl>[Cl:27][C:28]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:29]=1[C:30]([NH:17][CH2:16][C:5]1([CH2:4][CH:1]2[CH2:2][CH2:3]2)[CH2:6][CH2:7][N:8]([S:11]([CH2:14][CH3:15])(=[O:13])=[O:12])[CH2:9][CH2:10]1)=[O:31]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: CCS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(CNC(=O)c2ccc(Cl)cc2Cl)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1-[4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidin-4-yl]methanamine (I-5, 250 mg, 1.0 mmol) in CH2Cl2 (10 mL) at 0° C. was treated with i-Pr2NEt (1 mL, 5.7 mmol), 2,4-dichlorobenzoyl chloride (200 μL, 1.43 mmol), and stirred for 15 min before being warmed to room temperature. After 1 h, the reaction was quenched with the addition of 1 M aqueous NaOH (10 mL) and stirred 1 h before being extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried (Na2SO4), concentrated under reduced pressure, and purified by reverse phase HPLC to afford 2,4-dichloro-N-{[4-(cyclopropylmethyl)-1-(ethylsulfonyl)piperidin-4-yl]methyl}benzamide (I-6) as an off-white amorphous solid. Analytical LCMS: single peak (214 nm), 3.328 min. 1H NMR (CDCl3, 300 MHz) δ 7.64 (d, J=8.4 Hz, 1 H), 7.46 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 6.39 (t, J=8 Hz, 1H), 3.63 (d, J=6.3 Hz, 2H), 3.41 (m, 2H), 3.35 (m, 2H), 2.98 (q, J=7.2 Hz, 1H), 1.68 (m, 5H), 1.39 (m, 5H), 0.68 (m, 1H), 0.56 (d, J=8 Hz, 1H). HRMS m/z 433.1091 (C19H26Cl2N2O3S+H+ requires 433.1091).
Reaction SMILES: [O:1]1[C@H:7]([CH2:8][CH2:9]CCCCCCCCCCCCC)[C@H:2]1[C:3]([O:5][CH3:6])=[O:4]>CO>[O:1]1[C@H:7]([CH2:8][CH3:9])[C@H:2]1[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCCCCCCCCCCCCCC[C@H]1O[C@@H]1C(=O)OC
Solvent: CO
Product: CC[C@H]1O[C@@H]1C(=O)OC

Procedure:
In 500 ml of methanol were dissolved 62.4 g (0.2 mol) of the methyl (2S,3R)-2,3-epoxyoctadecanoate (V-1) obtained in (3) above and 7.4 g (0.2 mol) of sodium hydroxide, and the solution was stirred for 3 hours. After confirming disappearance of the compound (V-1) by TLC, methanol was evaporated. The resulting concentrate was adjusted to pH 5 to 6 with 500 ml of diluted hydrochloric acid and extracted with 500 ml of ethyl acetate. After drying, ethyl acetate was evaporated, and the resulting crude crystals were recrystallized from a 5-fold volume of heptane to afford 42.6 g (0.15 mol; yield: 75%) of the title compound (V-2) (melting point: 186° C.).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]#[N:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([CH:13]([C:14]#[N:15])[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CCOC(=O)CBr
Reactant: N#CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 67.4 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)phenylacetonitrile (8.30 g) in tetrahydrofuran (80 ml) was cooled to −78° C. under an argon gas atmosphere, and a solution (1.9 M, 17.3 ml) of sodium hexamethyldisilazane in tetrahydrofuran was added dropwise. After the completion of the dropwise addition, the solution was stirred at 10° C. for 15 min, and cooled to −78° C. again. To the solution was added ethyl bromoacetate (5.48 g), and the mixture was stirred at room temperature for 16 hr. The reaction solution was partitioned between ethyl acetate and water, and the ethyl acetate layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate 100:0-70:30) to give the title compound (7.50 g, yield 67%) as a brown oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>O.CC([O-])=O.CC([O-])=O.[Pd+2].[Cu]I.CN(C=O)C>[CH3:20][Si:19]([C:17]#[C:18][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:16])[N:7]3[CH2:15][CH2:14][NH:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1)([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: O=c1c2ccc(Br)cc2nc2n1CCNC2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(=O)n3c(nc2c1)CNCC3
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 56.8 %

Procedure:
A flask was charged with 9-bromo-3,4-dihydro-1H-pyrazino[2,1-b]quinazolin-6(2H)-one (200 mg, 0.71 mmol, 1 equiv), ethynyltrimethylsilane (206 mg, 2.1 mmol, 3 equiv), Pd(OAc)2 (31.5 mg, 0.14 mmol, 0.2 equiv), PPh3 (165 mg, 0.63 mmol, 0.9 equiv), CuI (13 mg, 0.07 mmol, 0.1 equiv), Et3N (353 mg, 3.5 mmol, 5 equiv) and DMF (20 mL). A vacuum was applied and the reaction mixture was back filled with nitrogen three times. The mixture was stirred at 70° C. for 3.5 hours. After it was cooled to room temperature, the reaction mixture was diluted with H2O and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, then concentrated under reduced pressure. 120 mg of desired product was obtained MS (ESI): 298 (MH+).
Reaction SMILES: [Br:1]Br.[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[C:8]1[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=1[C:13]#[N:14].C([O-])(=O)C.[Na+].S(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:1][C:7]1[O:3][C:4]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:5][CH:6]=1
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccco1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Br)o1
Reaction time: 0.25 h

Procedure:
Bromine (0.71 g, 4.42 mmol) is added to a solution of 2-(2-furyl)-5-(trifluoromethyl)pyrrole-3-carbonitrile (1.00 g, 4.42 mmol) and sodium acetate (0.36 g, 4.42 mmol) in acetic acid. The reation mixture is stirred for 15 minutes and poured into a 1% sodium bisulfite solution. The solids are filtered from the aqueous mixture, dried overnight under high vacuum and recrystallized from ethyl acetate and hexane to obtain the title product as red crystals (1.21 g, 90%, mp 224°-226° C.