Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][OH:7].C(N(CC)C(C)C)(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[F:1][C:2]([F:9])([F:8])[CH2:3][O:4][CH2:5][CH2:6][O:7][S:20]([CH3:19])(=[O:22])=[O:21]
Reactant: OCCOCC(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCOCC(F)(F)F
Reaction time: 2 h

Procedure:
Combine 2-hydroxyethyl 2,2,2-trifluoroethyl ether (0.5 mmol) and N,N-diisopropylethylamine (1 mmol) in dichloromethane (20 mL). Cool in a ice-bath. Add dropwise, methanesulfonyl chloride (0.6 mmol). After 2 hours, extract with 1M hydrochloric acid solution and 5% sodium bicarbonate solution. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to give the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](O)=[O:7])#[N:2].C(Cl)(=O)C([Cl:18])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:18])=[O:7])#[N:2]
Reactant: N#Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
111 g of 3-cyano-2,4,5-trifluoro-benzoic acid, 84 g of oxalyl chloride and a few drops of dimethylformamide in 930 ml of dry methylene chloride are stirred at room temperature for 5 hours. The reaction mixture is concentrated by evaporation and the residue is distilled in vacuo.
Reaction SMILES: [CH3:1][Li].[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=O)=[N:5]1>C1COCC1>[CH3:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:15])[CH3:1])=[N:5]1
Reactant: [Li]C
Reactant: Cn1nc(C(=O)O)c2ccccc21
Solvent: C1CCOC1
Product: CC(=O)c1nn(C)c2ccccc12

Procedure:
Methyl lithium (1.58M solution in ether; 13.8 ml) was added dripwise to a stirred, cold (-60°) solution of 1-methyl-1H-indazole-3-carboxylic acid (1.77 g) in dry THF (60 ml) under nitrogen and stirring was continued while warming to 0° over 2 h. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml), and the layers were separated. The aqueous layer was further extracted with dichloromethane (2×50 ml ) and the combined organic layers were washed with brine (2×50 ml ), dried and evaporated in vacuo. The residual solid (1.8 g) was purified by FCC eluting with System B (1:4) to give the title compound (1.3 g, m.p. 86°-88°.
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.C(OC(=O)C)=O.[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][CH2:17]1.[OH-].[Na+]>C(O)=O>[C@H:16]1([N:15]([CH3:14])[CH:5]=[O:7])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)OC(C)=O
Reactant: CN[C@@H]1CCCc2ccccc21
Agent: CC(=O)OC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN(C=O)[C@@H]1CCCc2ccccc21
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
Acetic anhydride (54.1 g) was chilled to 0° C. and stirred as 98% formic acid (33.1 g) was added over 30 minutes, keeping the temperature below 5° C. The solution was warmed to 50° C., held at this temperature for 15 minutes, and chilled to 5° C. The resulting solution of acetic-formic anhydride was added over 5 minutes to a stirred, chilled solution of (R)(-)-N-methyl-1,2,3,4-tetrahydro-1-naphthylamine (19.08 g) in 98% formic acid (19.08 ml), keeping the temperature below 10° C. The reaction solution was warmed to room temperature, stirred for 1 hour, poured into an ice-water mixture (200 g) and stirred for 30 minutes. The mixture was basified to pH 9 with 10N aqueous sodium hydroxide solution (about 230 ml) and extracted with dichloromethane (3×200 ml). The combined extracts were back-washed with 1N aqueous hydrochloric acid (100 ml), then water (100 ml), and evaporated under vacuum to give the title compound (21.63 g, 96.6%) as a solid, m.p. 53°-55° C.; Rf 0.80 (silica; chloroform, methanol; 95:5).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[I:11][C:12]1[CH:13]=[N:14][NH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].C>N1C=CC=CC=1.ClCCl.[Cu]=O>[I:11][C:12]1[CH:13]=[N:14][N:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH:16]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Ic1cn[nH]c1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1-n1cc(I)cn1
Yield: 76.2 %

Procedure:
A mixture of 1-fluoro-2-nitrobenzene (14.5 g, 0.1 mol), 4-iodopyrazole (20 g, 0.1 mol), potassium carbonate anhydrous (14 g, 0.1 mol) and catalytical amounts of copper(II) oxide in pyridine (35 ml) was heated to reflux for 16 hours. After cooling, the mixture was diluted with dichloromethane (1 litre). Activated charcoal (12 g) was then added and the mixture was heated to reflux for 1 hour. After cooling, it was filtered through celite. The filtrate was evaporated and the remaining oil was purified by silica gel chromatography using ethyl acetate and hexane as eluents, giving 4-iodo-1-(2-nitro-phenyl)-1H-pyrazole (24 g).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1.CCOCC>[CH3:10][N:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[N:7][CH:6]=1)[CH3:11]
Reactant: CN(C)Cc1ccc(Br)nc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)Cc1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
1-(6-Bromopyridin-3-yl)-N,N-dimethylmethanamine (1.15 g, 5.4 mmol) was dissolved in 30 mL of THF and 80 mL of anhydrous ether. After the solution was cooled to −78° C., 2.60 mL of n-butyllithium (2.5 M, 6.40 mmol) was slowly dropped through a syringe in 10 min. After being stirred at −78° C. for 30 minutes, 1,4-cyclohexanedione mono-ethylene ketal (1.01 g, 6.4 mmol) was added. The reaction mixture was allowed to warm up to room temperature during two hours and then quenched by addition of 10 mL of water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 20-40% methanol in EtOAc and 0.5% NH4OH, 0.85 g oil was obtained (54% yield), MS: (M+H)+ 293.2.0.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[C:5]([CH:10]=[O:11])=[CH:4][CH2:3]1.[CH2:12]([OH:16])[CH:13](O)[CH3:14].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][CH:13]1[CH2:12][O:16][CH:10]([C:5]2[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([CH3:1])[CH2:3][CH:4]=2)[O:11]1
Reactant: CC1CC=C(C=O)C(C)(C)C1
Reactant: CC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CC=C(C2OCC(C)O2)C(C)(C)C1
Yield: 65.1 %

Procedure:
4,6,6-Trimethyl-1-cyclohexen-1-carbaldehyde (2 g, 13 mmole), 1,2-propanediol (4 g, 53 mmole) and p-toluenesulfonic acid (50 mg) were refluxed in 20 ml of toluene, with water separation in a Dean-Stark apparatus, during 6 h. The resulting solution was washed with a NaHCO3 solution and the crude product distilled at a bath temperature of 80°/0.5 hPa, to obtain 1.78 g of the desired product in the form of a mixture of isomers.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:21])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>CC(C)=O>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:21][CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[C:11]([CH:20]=1)[C:12]([N:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1c(C)c(Cc2ccc(OCC(=O)OC(C)(C)C)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Yield: 78.1 %

Procedure:
N-[5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoyl]morpholine (0.200 g, 0.465 mmol) was dissolved in acetone (30 ml) and after adding thereto anhydrous sodium carbonate (0.077 g, 0.558 mmol) and tert-butyl bromoacetate (0.109 g, 0.558 mol), the solution was refluxed under heating for 3 hours. The reaction solution was filtered, the filtrate was concentrated and the obtained residue was purified by silica gel column chromatography (hexand:ethyl acetate=2:1) to obtain the titled compound (0.198 g, 0.363 mmol, 78%).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3](=[O:28])[NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)=[CH:9][CH:8]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:26])[CH3:27]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: NCCN1CCCCC1
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCN3CCCCC3)cc2)CC1
Yield: 70 %

Procedure:
By the same procedure as described in the example 56, synthesis was carried out starting with 4-[1-[3-(isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester and using 1-(2-aminoethyl)piperidine. Then, the product was recrystallized using acetonitrile and hexane to give the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8](=[NH:20])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[N:3]=1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=[O:33])[C:29]([F:32])([F:31])[F:30]>C(O)(C)C>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[N:9]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)[CH2:27][C:28]([OH:33])([C:29]([F:32])([F:31])[F:30])[N:20]=2)[N:3]=1
Reactant: O=C(CBr)C(F)(F)F
Reactant: Cc1cccc(C(=N)Nc2ccc(S(C)(=O)=O)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1cccc(C2=NC(O)(C(F)(F)F)CN2c2ccc(S(C)(=O)=O)cc2)n1
Yield: 20.7 %

Procedure:
To a mixture of the amidine of Step 1 (4.9 g, 16.95 mmol) and sodium bicarbonate (2.85 g, 33.9 mmol) in isopropanol (300 ml), 3-bromo-1,1,1-trifluoroacetone (2.65 ml, 25.4 mmol) was added. After heating at 80°-85° C. for 24 hours, the reaction mixture was cooled and filtered. The residue was washed with methylene chloride and the combined organic fractions were dried over sodium sulfate, filtered and concentrated. The crude mixture (9 g) was chromatographed (silica gel, ethyl acetate/isopropanol/ammonium hydroxide 95/5/0.5) to give 2-methyl-6-[4-hydroxy-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-4,5-dihydro-1H-imidazol-2-yl]pyridine (1.4 g, 21%) as a white solid: Anal. Calc'd. for C17H16N3SO3F3 : C, 51.12, H, 4.02, N, 10.52. Found: C, 51.43, H, 3.96, N, 10.06.
Reaction SMILES: I[CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1.[N-:23]=[N+:24]=[N-:25].[Na+].O>CN(C=O)C>[N:23]([CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([F:15])[C:12]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([F:22])[CH:10]=2)[CH2:4]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1OC(CI)CN1c1cc(F)c(-c2cccnc2)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1CN(c2cc(F)c(-c3cccnc3)c(F)c2)C(=O)O1
Reaction time: 2 h

Procedure:
(±)-5-(Iodomethyl)-3-[4-(3-pyridyl)-3,5-difluorophenyl]-2-oxazolidinone (PREPARATION 5, 577 mg, 1.31 mmol) in DMF (dried over 4A sieves, 15 ml) is combined with sodium azide (681 mg, 10.5 mmol, 8 eq). The reaction is placed under an atmosphere of nitrogen and heated to 55°. After 2 hr, the reaction is added to water (100 ml) and then extracted with ethyl acetate (4×25 ml). The combined organic extracts are combined and are washed with water then brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The crude azide is suitable for reduction without further purification. An analytical sample is prepared by prepatative TLC (silica gel) eluting with acetonitrile/chloroform (10/90). The appropriate fractions are pooled and concentrated to give the title compound, mp 97-98° ; FTIR (mull) cm-1 3483, 2110, 1746, 1640, 1417, 1237, 1064 and 716; MS (EI, m/z) 331, 274, 258, 232, 217, 190 and 43; NMR (CDCl3) 8.72, 8.63, 7.79, 7.42-7.38, 7.34, 4.90-4.82, 4.11, 3.88, 3.77 and 3.63 δ.
Reaction SMILES: [CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[OH:16])[CH3:2].Br[CH2:23][C:24]#[C:25][Si](C)(C)C.[OH-].[Na+]>CS(C)=O.O>[CH2:1]([C:3]1([CH2:17][C:18]([O:20][CH3:21])=[O:19])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[O:16][CH2:25][C:24]#[CH:23])[CH3:2]
Reactant: C[Si](C)(C)C#CCBr
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(O)cccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: C#CCOc1cccc2c3c([nH]c12)C(CC)(CC(=O)OC)OCC3
Yield: 82.2 %

Procedure:
A mixture of methyl 1-ethyl-1,3,4,9-tetrahydro-8-hydroxy-pyrano[3,4-b]indole-1-acetate (6 g, 20.8 mmol), 3-bromo-1-trimethylsilyl-1-propyne [4.8 g, 25 mmol, prepared according to R. B. Miller, Synth. Comm., 2, 267 (1972)] and 2.5N--NaOH (10 mL, 25 mmol) in DMSO (60 mL) was heated under nitrogen for 30 minutes at 120° C. Upon cooling, the micture was diluted with 2 volumes of water, acidified with 2N--KHSO4 solution and extracted with ether. The extracts were dried (Na2SO4) and concentrated in vacuo. The residual oil (7 g) was flash-chromatographed (silica Merck-60, chloroform) to provide methyl 1-ethyl-1,3,4,9-tetrahydro-8-[(2-propynyl)oxy]-pyrano[3,4-b]indole-1-acetate (5.6 g, 83%) as an oil.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:7][C@H:6]([N:8]=[N+:9]=[N-:10])[CH2:5]1)(O)=[O:2].C(Cl)(=O)C([Cl:14])=O>ClCCl.CN(C)C=O>[N:8]([C@@H:6]1[CH2:7][C@H:4]([C:1]([Cl:14])=[O:2])[CH2:5]1)=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)O)C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)Cl)C1
Temperature: 23 °C

Procedure:
A solution of cis-3-carboxycyclobutyl azide (1.86 g, 13.2 mmol) in dichloromethane (30 ml) was treated with oxalyl chloride (1.5 ml, 17.2 mmol) followed by one drop of N,N-dimethylformamide. The reaction mixture was stirred at 23° C. until the evolution of gas ceased (0.5-1 h) and the solvent was evaporated in vacuo leaving a yellow oil; 2.0 g, 95% ir (neat) νmax : 2100 (N3) and 1785 cm-1 (C=O of acylchloride).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1.[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:2]1[N:3]=[C:4]([CH2:7][OH:8])[S:5][CH:6]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OCc1nc(Br)cs1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Product: OCc1nc(-c2ccccc2OCc2ccccc2)cs1
Temperature: 90 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
To a mixed solution of the compound (900 mg, 4.6 mmol) obtained in Example 30a, 2-benzyloxyphenylboronic acid (1.3 g, 5.6 mmol) and 2M aqueous sodium carbonate solution (2.8 mL, 5.6 mmol) in 1,2-dimethoxyethane-ethanol (v/v=3/1, 12 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (380 mg, 0.46 mmol), and the mixture was stirred at 90° C. overnight. The resulting salt was filtered and removed, and the solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=60/40) to give the title compound (1.2 g, 88%) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[O:26]([C:33]1[CH:43]=[CH:42][C:36]([CH:37]=[CH:38][C:39](O)=[O:40])=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH:8][C:39](=[O:40])[CH:38]=[CH:37][C:36]2[CH:42]=[CH:43][C:33]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:34][CH:35]=2)=[CH:4]1
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Reactant: O=C(O)C=Cc1ccc(Oc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Yield: 55 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (1.0 g), triethylamine (0.54 mL), 4-phenoxycinnamic acid (0.94 g), WSC.HCl (0.75 g), and methylene chloride (40 mL), to give the captioned compound (0.93 g, 55%) as an oily product.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]2)[C:7]2[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:6]=2[N:5]=1)[CH3:3].Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:6]2[N:5]=[C:4]([C@@H:2]([NH:1][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:3])[N:8]([CH:9]3[CH2:12][CH:11]([C:13]#[N:14])[CH2:10]3)[C:7]=2[CH:15]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CC(C#N)C1
Yield: 32.1 %

Procedure:
3-[2-((S)-1-Aminoethyl)-6-fluorobenzoimidazol-1-yl]cyclobutanecarbonitrile (0.075 g, 0.29 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.070 g, 0.29 mmol) and DIPEA (0.26 mL, 1.45 mmol) in 2-propanol (5 mL) was stirred at 90° C. in a sealed microwave tube for 16 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue loaded onto an Isolute® SCX-2 cartridge which was washed with DCM and MeOH, then the product eluted with 2M NH3/MeOH then concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 100% DCM—10% methanol in DCM to give 399 as a solid (0.035 g, 32%). LCMS (Method K): RT 2.76 min [M+H]+ 376.0. 1H NMR (MeOD-d4) δ: 8.33 (1H, br s), 8.05 (1H, br s), 7.53-7.61 (2H, m), 6.97-7.04 (1H, m), 6.02 (1H, br s), 5.76-5.87 (1H, m), 3.38-3.49 (2H, m), 3.21-3.30 (2H, m), 2.76-2.88 (1H, m), 2.37-2.47 (1H, m), 1.76 (3H, d, J=6.1 Hz)
Reaction SMILES: [CH3:1][C:2]([CH3:9])=[CH:3][CH2:4][CH2:5][C@@H:6]([OH:8])[CH3:7].CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>C(Cl)Cl>[CH3:7][C@H:6]([O:8][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][CH2:4][CH:3]=[C:2]([CH3:9])[CH3:1]
Reactant: CC(C)=CCC[C@H](C)O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)=CCC[C@H](C)OS(C)(=O)=O
Temperature: 5 °C
Yield: 75.7 %

Procedure:
(S)-6-Methyl-hept-5-en-2-ol (2.64 g, 20.58 mmol) and DIEA (6.45 mL, 37.0 mmol) were dissolved in anhydrous DCM (28 mL), the reaction mixture was cooled to 5° C., mesyl chloride (1.91 mL, 24.7 mmol) was added dropwise, and the reaction mixture was allowed to slowly warm to RT. After 18 h at RT the reaction mixture was diluted with DCM (100 mL), washed with water (3×35 mL), brine (35 mL), dried with MgSO4, solvent was concentrated to give a dark oil which was purified by SiO2 flash chromatography using Hexane-EtOAc to give the title compound as an oil (3.213 g, 76%). TLC, Hexane-DCM-EtOAc, 40:40:20, 2 Rf 0.70 (developed with KMnO4 stain). H1 NMR (CDCl3): • 5.08 (m, 1H), 4.80 (m, 1H), 2.99 (s, 3H), 2.10 (m, 2H), 1.75 (m, 1H), 1.69 (s, 3H), 1.62 (m, 1H), 1.61 (s, 3H), 1.43 (d, 3H, J=6.5 Hz).
Reaction SMILES: [NH2:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>C(Cl)Cl.C(OCC)(=O)C>[CH2:32]([NH:34][C:35](=[O:36])[NH:1][C:2]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16](=[O:31])[C:17]3[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([C:27]([F:28])([F:29])[F:30])[CH:18]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3]1)[CH3:33]
Reactant: CCN=C=O
Reactant: NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCNC(=O)NC1(CN2CCC(CNC(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)CCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of N-((1-((1-aminocyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (100 mg, 0.28 mmol) in CH2Cl2 (5 mL) was added ethyl isocyanate (0.05 mL, 0.63 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours and then diluted with ethyl acetate. The organic fraction was washed with sat. NaHCO3, and then brine and dried over Na2SO4. The solvent was removed and the crude was purified by HiTOPs to provide N-((1-((1-(3-ethylureido)cyclopentyl)methyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[C:26]([CH2:33]Br)=[N:27][C:28]([Cl:32])=[CH:29][C:30]=1[CH3:31]>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:33][C:26]3[C:25]([Br:24])=[C:30]([CH3:31])[CH:29]=[C:28]([Cl:32])[N:27]=3)[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1cc(Cl)nc(CBr)c1Br
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Cl)nc(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1Br

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (30.6 g, 98 mmol) in THF (800 mL) was added NaH (60% dispersion in mineral oil) (3.35 g, 84 mmol). After stirring the reaction at room temperature for 10 minutes, 3-bromo-2-(bromomethyl)-6-chloro-4-methylpyridine (16.7 g, 55.8 mmol) was added as a solution in THF (300 mL). The reaction was stirred at room temperature for 16 hours and then quenched with saturated NH4Cl (200 mL). The mixture was diluted with EtOAc (1 L). The organic layer was separated, washed with water (500 mL) and brine (500 mL), dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 50% EtOAc/heptanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloro-4-methylpyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one. LCMS=530.8, 532.8 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.81 (s, 2H), 7.18 (s, 1H), 5.87 (d, J=8.3 Hz, 1H), 5.04 (d, J=17.2 Hz, 1H), 4.42 (m, 1H), 4.32 (d, J=17.3 Hz, 1H), 2.43 (s, 3H), 0.80 (d, J=6.6 Hz, 3H).