Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([CH:15]([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([CH3:4])([CH3:3])[CH3:2].[S:27](Br)([C:30]1[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=1)(=[O:29])=[O:28].N1C=CC=CC=1>CCOC(C)=O>[C:22]([O:21][C:19]([NH:18][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:26])=[CH:13][C:12]([S:14][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=[C:11]([CH:15]([CH3:16])[CH3:17])[CH:10]=1)=[O:20])([CH3:24])([CH3:23])[CH3:25]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: CC(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc1S
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using (2-tert-butyoxycarbonylamino-4-isopropyl-5-mercapto-phenyl)-carbamic acid tert-butyl ester (prepared in Example TT-1; 22.1 mmol), tosyl bromide (5.2 g, 22 mmol), pyridine (5 mL), and EtOAc (50 mL). The crude product was purified by flash chromatography (5%-60% EtOAc in hexanes as eluents). 1H-NMR (CDCl3): δ0.97 (s, 6 H), 1.53 (s, 18 H), 2.4 (s, 3 H), 3.2 (m, 1 H), 7.11 (br s, 1 H), 7.22 (d, 2 H), 7.28 (s, 1 H), 7.36 (s, 1 H), 7.5 (d, 2 H), 7.75 (br s, 1 H).
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]([NH2:16])=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][N:11]([CH3:15])[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CN1CCCN(c2cc(N)c([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: CN1CCCN(c2cc(N)c(N)cc2F)CC1
Yield: 102.9 %

Procedure:
20.9 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)-2-nitrophenylamine in solution in 750 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 2 g of palladium-on-charcoal at 25° C. for 16 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. 19.1 g of 4-fluoro-5-(4-methylperhydro-1,4-diazepin-1-yl)benzene-1,2-diamine in the form of a black oil are isolated. 1H NMR (300 MHz, DMSO-d6, δ in ppm): 1.82 (m, 2H); 2.26 (s, 3H); 2.56 (m, 4H); 3.11 (m, 4H); 4.19 (broad m, 4H); from 6.22 to 6.31 (m, 2H). EI m/z=238: M+. (base peak)—m/z=223: (M-CH3)+—m/z=168: (M−C4H8N)+—m/z=70: C4H8N+—m/z=57: C3H7N+.
Reaction SMILES: [OH-].[Na+].CO.[CH2:5]([N:9]([C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH:6]([CH3:8])[CH3:7].Cl>O>[CH2:5]([N:9]([C:21](=[O:29])[CH2:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)[CH:6]([CH3:7])[CH3:8]
Reactant: COC(=O)CCCC(=O)N(CCc1c[nH]c2ccccc12)CC(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)CN(CCc1c[nH]c2ccccc12)C(=O)CCCC(=O)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
1.5 ml of an aqueous 10% sodium hydroxide solution and 10 ml of a mixture of methanol and water (1:1) were added to 0.63 g of N-isobutyl-N-(4-methoxycarbonylbutyryl)-tryptamine (i.e., 3-[2-(N-isobutyl-4-methoxycarbonylbutanamido)ethyl]-indole). The mixture was stirred at 60° C. for 30 minutes. After the reaction was completed, the mixture was evaporated to remove solvent. The residue thus obtained was adjusted to a pH of 2.0 with 10% hydrochloric acid, and then extracted with chloroform. The extract was washed with water and concentrated. 0.6 g of N-isobutyl-N-(4-carboxybutyryl)-tryptamine (i.e., 3-[2-(N-isobutyl-4-carboxybutanamido)ethyl]-indole) were thereby obtained. Yield: 99.3%
Reaction SMILES: [C:1]([O:20][CH2:21][C@H:22]1[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24][C@@H:23]1[OH:36])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[OH-].[K+].[I-].[Na+]>O1CCOCC1.O.C(O)(=O)C>[CH2:37]([O:36][C@@H:23]1[C@@H:22]([CH2:21][O:20][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:26][C@@H:25]([N:27]2[CH:34]=[C:33]([F:35])[C:31](=[O:32])[NH:30][C:28]2=[O:29])[CH2:24]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ClCc1ccccc1
Reactant: O=c1[nH]c(=O)n([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)n([C@H]2C[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)cc1F
Temperature: 40 °C
Reaction time: 4 h
Yield: 70.6 %

Procedure:
A 10 g quantity of 2'-deoxy-5'-O-trityl-5-fluorouridine was dissolved in 100 ml of dioxane. To the solution were added 2.9 ml of benzyl chloride, 6.9 g of particles of potassium hydroxide and 3.56 g of sodium iodide. The mixture was stirred at 40° C. for 4 hours, and 2.9 ml of benzyl chloride and 1.15 g of potassium hydroxide were added and stirred for 1 hour. Thereto was added water to dissolve the potassium hydroxide in water. The solution was adjusted to a pH of about 3 with acetic acid and extracted with ethylene dichloride. The extract was washed with water and the ethylene dichloride layer was dried over anhydrous sodium sulfate. The sodium sulfate was separated by filtration and the solvent was distilled off, giving 8 g of 2'-deoxy-3'-O-benzyl-5'-O-trityl-5-fluorouridine as an oil.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([O:28]C)=[O:27])[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3].[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1>[CH2:1]([NH:4][C:5]1[N:6]([C:23]2[CH:24]=[C:25]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:26]([OH:28])=[O:27])[C:7](=[O:22])[C:8]([Cl:21])=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[N:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)OC)ccc1C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCNc1nc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a suspension of methyl 3-[2-(allylamino)-5-chloro-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 2) (1.59 g, 3.34 mmol) in dioxane (7 mL) was added 2N NaOH (2.51 mL, 5.01 mmol). Stirred at ambient temperature for 1 h, cooled (0° C.), added 5% citric acid to precipitate the product, filtered precipitate, and dried in vacuo to give the desired compound as a white solid (1.30 g, 84%). 1H NMR (CD3OD/400 MHz) δ8.08 (m, 1H), 7.81 (s, 1H), 7.56 (m, 2H), 7.00 (t, 2H, J=8.4 Hz), 5.80 (m, 1H), 5.51 (s, 2H), 5.07 (m, 2H), 3.93 (m, 2H), 2.14 (s, 3H). ESHRMS m/z 462.1006 (M+H calculated for C22H19ClF2N3O4 requires 462.1027).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=3[O:24][CH3:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:28]1[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=1>>[F:23][C:19]1[C:18]([O:24][CH3:25])=[C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:28]4[C:33]([CH3:34])=[CH:32][CH:31]=[CH:30][N:29]=4)=[O:5])[N:7]=[CH:8]3)[CH:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)N(C)OC)c2)c1
Reactant: Cc1cccnc1Br
Product: COc1c(F)cccc1-c1cccc(-n2cnc(C(=O)c3ncccc3C)c2)c1

Procedure:
This compound is prepared by method C using compound 12h and 2-bromo-3-methylpyridine
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]1([N:17]2[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:36]=[CH:35][C:34]([CH2:37][OH:38])=[CH:33][CH:32]=4)[N:27]=3)[CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>>[C:11]1([N:17]2[C:21]([C:22]([F:23])([F:24])[F:25])=[C:20]([C:26]3[O:30][N:29]=[C:28]([C:31]4[CH:32]=[CH:33][C:34]([CH:37]=[O:38])=[CH:35][CH:36]=4)[N:27]=3)[CH:19]=[N:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A 50 mL round bottom flask was flame dried and cooled under a stream of dry nitrogen. DCM (25 mL) followed by oxalyl chloride (6.79 mL, 13.59 mmol) (2M in DCM) were added to the flask and it was cooled in an acetone/dry ice bath. Dimethyl sulfoxide (1.47 mL, 20.71 mmol) was added dropwise. After 10 minutes, (4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)methanol (2.5 g, 6.47 mmol) was added in small portions over 5-10 minutes providing a pale yellow slurry. After stirring for 5 minutes, DIPEA (9.27 mL, 53.1 mmol) was added dropwise. The cloudy mixture began to clear up, then became cloudy again with the color fading from pale yellow to off-white during the course of the addition. After 5 minutes, the cooling bath was removed and the reaction was allowed to slowly warm to room temperature. After stirring at room temperature for 3 hours the solvents were evaporated and the residue was partitioned between EtOAc (100 mL) and 0.5 N KHSO4 (70 mL). The EtOAc phase was washed with 50 mL each 1N HCl, water, sat. aq. NaHCO3, water and brine, then dried over MgSO4, filtered and evaporated. The solid was slurried in hexanes (with ˜5% EtOAc) with sonication and heating, then cooled to room temperature and filtered. The solids were washed with hexanes, air dried and placed under vacuum to afford 4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (1.55 g). The compound had an HPLC retention time=2.04 min.−Column: PHENOMENEX® Luna 5u C18 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=385.17.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:23]([OH:26])[C:24]#[CH:25])[CH:16]=[C:17]([O:21][CH3:22])[C:18]=1[O:19][CH3:20]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:25]#[C:24][CH:23]([C:15]2[CH:16]=[C:17]([O:21][CH3:22])[C:18]([O:19][CH3:20])=[C:13]([O:12][CH3:11])[CH:14]=2)[OH:26])=[C:4]([CH3:10])[N:3]=1
Reactant: C#CC(O)c1cc(OC)c(OC)c(OC)c1
Reactant: Cc1nc(N)nc(N)c1I
Product: COc1cc(C(O)C#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 79.9 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1-(3,4,5-Trimethoxyphenyl)prop-2-yn-1-ol (444 mg) as per the general procedure to afford 3-(2,4-Diamino-6-methylpyrimidin-5-yl)-1-(3,4,5-trimethoxyphenyl) prop-2-yn-1-ol as a yellow powder (275 mg, 80%): Rf=0.12 (9:1, CHCl3:MeOH); mp=174-176° C.; 1H NMR (DMSO-d6) δ 6.85 (s, 2H), 6.27 (s, 2H), 5.98 (d, J) 5.6 Hz, 1H), 5.53 (d, J) 5.4 Hz, 1H), 3.78 (s, 6H), 3.65 (s, 3H), 2.19 (s, 3H), 1.51 (d, J) 7.1 Hz, 3H); 13C NMR (DMSO-d6) δ 167.1, 164.3, 161.2, 152.7, 138.3, 136.7, 103.7, 99.1, 87.9, 79.5, 63.6, 60.0, 55.8, 22.5; HRFAB [M+Li] 351.1638 (calculated C17H20N4O4Li: 351.1645).
Reaction SMILES: [BrH:1].C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH3:14])=[CH:6][CH:5]=1>>[BrH:1].[CH3:14][CH:11]1[C:12]2[C:7](=[CH:6][CH:5]=[C:4]([OH:3])[CH:13]=2)[CH2:8][CH2:9][NH:10]1
Reactant: COc1ccc2c(c1)C(C)NCC2
Agent: Br
Product: CC1NCCc2ccc(O)cc21

Procedure:
Hydrobromic acid (48%, 46 mL) was added to the 7-methoxy-1-methyl-1,2,3,4-tetrahydro-isoquinoline (2.55 g) and the resulting mixture was heated at reflux for 16 h. Evaporation of the hydrobromic acid, followed by trituation with ethyl acetate (3×) afforded 1-methyl-1,2,3,4-tetrahydro-isoquinolin-7-ol hydrogen bromide (3.04 g).
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].COC(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)S([C:41]1C=CC(F)=C[C:42]=1/C=C\CO)(=O)=O)=O.N1CCCC1>>[N:3]1([CH2:4]/[CH:5]=[CH:6]\[C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[S:14]([NH:17][C:18]2[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]3[C:21]([CH:22]4[CH2:32][CH:23]4[CH2:24][O:25]3)=[CH:20][CH:19]=2)(=[O:16])=[O:15])[CH2:42][CH2:41][CH2:2][CH2:1]1
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Solvent: C1CCNC1
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CN2CCCC2)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzenesulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and pyrrolidine as a brown oil.
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:15]=[O:16]>C1(C)C(C)=CC=CC=1>[CH3:1][NH:2][C:3]([N:5]([CH3:6])[C:15]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[F:7])=[O:16])=[O:4]
Reactant: CNC(=O)NC
Reactant: O=C=Nc1ccccc1F
Solvent: Cc1ccccc1C
Product: CNC(=O)N(C)C(=O)Nc1ccccc1F
Reaction time: 16 h

Procedure:
To a solution of 8.8 g (0.1 mol) of 1,3-dimethyl urea dissolved in 30 ml of xylene there was added a solution of 13.7 g (0.1 mol) of 2-fluorophenylisocyanate dissolved in 30 ml of xylene. The resulting mixture was refluxed for 4 hours and then allowed to stand at ambient temperature for 16 hours. During this time the product crystallized and was removed by filtration. The product weighed 15.8 g. The NMR spectrum had a doublet at 2.86 ppm, a singlet at 3.25 ppm, and a multiplet structure at 7.2 ppm, characteristic of a biuret structure.
Reaction SMILES: C(OC(=O)[NH:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]1
Reactant: CC(C)N1CCC(NC(=O)OCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)N1CCC(N)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude product (6.32 g) containing benzyl(1-isopropylpiperidin-4-yl)carbamate obtained in Example 382-(1) is dissolved in ethanol (100 ml), and thereto is added 10% palladium on carbon (600 mg), and the mixture is stirred at ambient temperature under hydrogen atmosphere overnight. The insoluble materials are removed by filtration, and the filtrate is concentrated under reduced pressure, and subjected to azeotropic distillation with toluene. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/1, then chloroform/methanol=20/1, and further 10/1) to give 4-amino-1-isopropylpiperidine (1.90 g). The resulting 4-amino-1-isopropylpiperidine is treated with 4N hydrogen chloride in dioxane to give 4-amino-1-isopropylpiperidine dihydrochloride.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([F:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[C:13]=1[F:20].[CH2:21]([C@H:25]1[CH2:30][CH2:29][C@H:28]([C@H:31]2[CH2:36][CH2:35][C@H:34]([CH2:37]I)[CH2:33][CH2:32]2)[CH2:27][CH2:26]1)[CH2:22][CH2:23][CH3:24].Cl>CN(C=O)C>[Cl:3][C:4]1[C:9]([F:10])=[C:8]([CH3:11])[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:37][C@H:34]2[CH2:35][CH2:36][C@H:31]([C@H:28]3[CH2:29][CH2:30][C@H:25]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:26][CH2:27]3)[CH2:32][CH2:33]2)=[C:14]([F:19])[C:13]=1[F:20]
Reactant: Cc1ccc(-c2ccc(O)c(F)c2F)c(Cl)c1F
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CI)CC2)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](COc3ccc(-c4ccc(C)c(F)c4Cl)c(F)c3F)CC2)CC1
Reaction time: 1 h

Procedure:
In a mixture of 0.7 g (60% oiliness, corresponding to 17.6 mmol) of sodium hydride and 5 ml of DMF was added by drops a solution of 4.0 g (14.7 mmol) of the 2′-chloro-2,3,3′-trifluoro-4-hydroxy-4′-methylbiphenyl in 20 ml of DMF at room temperature and stirred at the same temperature for 1 hour. Subsequently, a solution of 8.0 g (22.0 mmol) of trans-4-(trans-4-butylcyclohexyl)-1-iodomethylcyclohexane in 20 ml of DMF was added by drops to the reaction solution at room temperature, stirred at the same temperature for 1 hour, and then refluxed for 3 hours. After termination of the reaction, the reaction solution was poured into 50 ml of a diluted hydrochloric acid and extracted with 150 ml of toluene. The organic layer thus obtained was washed with a diluted aqueous sodium hydroxide solution thrice and water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure and the residue was subjected to silica gel column chromatography (eluent: heptane/toluene=7/3) to obtain 4.6 g of a crude 2′-chloro-2,3,3′-trifluoro-4′-methyl-4-((trans-4-(trans-4-butylcyclohexyl)cyclohexyl)methoxy)biphenyl. This product was recrystallized from a mixed solvent of ethanol/ethyl acetate to obtain 3.3 g of the subject compound. (Yield: 44.6%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[CH:20]1(Br)[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.O>[CH:20]1([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: BrC1CCCC1
Reactant: COc1ccc(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C=O)cc1OC1CCCC1
Temperature: 70 °C

Procedure:
To a solution of 3-hydroxy-4-methoxy-benzaldehyde (commercially available) (1 eq) was taken in dimethylformamide (10 mL), was added potassium iodide (0.1 eq) and potassium carbonate (2 eq). The reaction mixture was stirred at 70° C. and cyclopentyl bromide (2 eq) was added dropwise. The resulting reaction mixture was stirred at 70-80° C. for 16 hours. The reaction mixture was cooled and diluted with water, extracted with ethyl acetate and washed with saturated solution of sodium chloride. The organic solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography to furnish the title compound.
Reaction SMILES: C1(CN2CCN(C3[CH:16]=[CH:15][C:14]([NH:17][C:18]4[C:19]5[N:20]([N:29]=[CH:30][N:31]=5)[C:21]([C:24]5[CH:25]=[N:26][NH:27][CH:28]=5)=[CH:22][N:23]=4)=CC=3)CC2)CC1.BrC1N2N=CN=C2C(NC2C=C[C:46]([N:49]3[CH2:54][CH2:53][N:52]([CH:55]([CH3:57])[CH3:56])[CH2:51][CH2:50]3)=[C:45]([C:58]([F:61])([F:60])[F:59])[CH:44]=2)=NC=1>>[CH:55]([N:52]1[CH2:53][CH2:54][N:49]([C:46]2[CH:16]=[CH:15][C:14]([NH:17][C:18]3[C:19]4[N:20]([N:29]=[CH:30][N:31]=4)[C:21]([C:24]4[CH:25]=[N:26][NH:27][CH:28]=4)=[CH:22][N:23]=3)=[CH:44][C:45]=2[C:58]([F:61])([F:60])[F:59])[CH2:50][CH2:51]1)([CH3:57])[CH3:56]
Reactant: CC(C)N1CCN(c2ccc(Nc3ncc(Br)n4ncnc34)cc2C(F)(F)F)CC1
Reactant: c1nc2c(Nc3ccc(N4CCN(CC5CC5)CC4)cc3)ncc(-c3cn[nH]c3)n2n1
Product: CC(C)N1CCN(c2ccc(Nc3ncc(-c4cn[nH]c4)n4ncnc34)cc2C(F)(F)F)CC1

Procedure:
This compound may be prepared using methods as described for Compound 46, using (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-(4-isopropylpiperazin-1-yl)-3-trifluoromethylphenyl]amine. LCMS: Rt=0.99 (95%), m/z (ESI) 472 (M+H)+.
Reaction SMILES: [C:1]([NH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][OH:21])=[O:19])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(NC(=O)CCCCC(O)=[O:39])CCCCCCCCC.OO>CS(O)(=O)=O>[CH2:1]([NH:12][C:13](=[O:39])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][OH:21])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCNC(=O)CCCCC(=O)O
Reactant: CCCCCCCCCC(=O)NCCCCCC(=O)OO
Agent: CS(=O)(=O)O
Agent: OO
Product: CCCCCCCCCCNC(=O)CCCCC(=O)OO
Temperature: -15 °C

Procedure:
6-Decylamino-6-oxoperoxycaproic acid was prepared according to the procedure described in Example I for N-decanoyl-6-aminoperoxycaproic acid. Thus, the methyl ester of 6-decylamino-6-oxocaproic acid (29.9 g, 0.10 mol), hydrogen peroxide (17.0 g, 0.50 mol), and 98% methanesulfonic acid (60 mL) were reacted at room temperature for 2 hrs., the reaction mixture poured over ice, and the peroxyacid extracted into 125 mL of 60° C. ethyl acetate. The aqueous layer was discarded and the warm ethyl acetate solution was washed with two 100 mL portions of water. The ethyl acetate solution was transferred to a 250 mL Erlenmeyer flask (rinsed with 25 mL ethyl acetate), reheated to 60° C., and then cooled to -15° C. The crystals of N-decylamino-6-oxoperoxycaproic acid were collected by filtration, washed twice with 50 mL of ice-cold ethyl acetate and air dried. Yield was 21.6 g having peroxyacid AvO of 4.49% (theoretical Yield=30.1 g of 5.32% AvO), and mp 77°-85° C.
Reaction SMILES: C(O)(=O)C.[Si]([O:12][C@H:13]1[CH2:17][N:16]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:15](=[O:24])[CH2:14]1)(C(C)(C)C)(C)C.Br[CH2:26][CH2:27][O:28][C:29]1[CH:44]=[CH:43][C:32]([O:33][C:34]2[S:35][C:36]3[C:37]([N:42]=2)=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:31][CH:30]=1.C(N(CC)C(C)C)(C)C.Cl>CO.CC#N.C(Cl)Cl>[OH:12][C@H:13]1[CH2:17][N:16]([CH:18]2[CH2:19][CH2:20][N:21]([CH2:26][CH2:27][O:28][C:29]3[CH:30]=[CH:31][C:32]([O:33][C:34]4[S:35][C:36]5[C:37]([N:42]=4)=[N:38][CH:39]=[CH:40][CH:41]=5)=[CH:43][CH:44]=3)[CH2:22][CH2:23]2)[C:15](=[O:24])[CH2:14]1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=O)N(C2CCNCC2)C1
Reactant: BrCCOc1ccc(Oc2nc3ncccc3s2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CO
Product: O=C1C[C@@H](O)CN1C1CCN(CCOc2ccc(Oc3nc4ncccc4s3)cc2)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 23.2 %

Procedure:
To a solution of (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-1-(piperidin-4-yl)pyrrolidin-2-one acetate (159 mg, 0.44 mmol, 1.2 equiv.) in MeOH was added Dowex resin (550A ion exchange) to free-base the amine. The resin was filtered and the filtrate was concentrated to an oil. To a solution of this oil in CH3CN (1.9 mL) was added 2-[4-(2-bromoethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine (130 mg, 0.37 mmol) and N,N-diisopropylethylamine (97 μL, 0.56 mmol, 1.5 equiv.). The resulting solution was stirred at 70° C. for 20 h. The solution was then cooled to rt and partitioned between satd. aq. NaHCO3 (20 mL) and CH2Cl2 (20 mL). The organic layer was washed with brine (20 mL), dried, filtered, and concentrated to give the crude product as a dark orange solid. To a solution of this oil (185 mg, 0.325 mmol) in CH2Cl2 (3.3 mL) was added HCl (4 M in dioxane, 1.79 mL, 22.0 equiv.). The reaction was stirred at rt for 2.5 h and then concentrated. The residue was dissolved in water (20 mL), and the pH adjusted to ˜pH 7 with 1 M aq. NaOH. The mixture was then extracted with CH2Cl2 (2×15 mL) followed by EtOAc (2×15 mL) and the organic layers (CH2Cl2 and EtOAc) were individually washed with water (30 mL each). The combined organic layers were dried, filtered and concentrated to give the crude product as a white solid. The crude product was purified using preparative reversed phase HPLC to afford the desired product as a white solid (39 mg, 26%). 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.00 (dd, J=7.9, 1.6, 1H), 7.35-7.30 (m, 2H), 7.19 (dd, J=7.9, 4.9, 1H), 6.97-6.93 (m, 2H), 4.36-4.27 (m, 1H), 4.16-4.07 (m, 2H), 4.05-3.92 (m, 1H), 3.44-3.35 (m, 1H), 3.28-3.19 (m, 1H), 3.13-3.03 (m, 2H), 2.87-2.79 (m, 1H), 2.70-2.64 (m, 1H), 2.51-2.40 (m, 1H), 2.32-2.20 (m, 2H), 1.97-1.75 (m, 3H), 1.74-1.69 (m, 2H). MS (ESI): mass calcd. for C23H26N4O4S, 454.2; m/z found, 455.1 [M+H]+.