Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.CCN(CC)CC.[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](Cl)=[O:37]>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:36](=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32][Br:31])=[CH:7][CH:6]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=O)Nc2ccc(N)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NC(=O)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
The deprotected amine (368 mg, 0.70 mmol) was stirred in dry CH2Cl2 (10 mL) under N2 atmosphere and NEt3 (98 μL, 0.70 mmol) was added to give a clear brown solution. 5-Bromovaleryl chloride (140 μL, 1.05 mmol, 1.5. equiv.) was added followed by triethylamine (98 μL, 0.70 mmol). The reaction mixture was stirred at rt for 16 h then diluted with CH2Cl2 (1×20 mL) and washed with 1 M aqueous hydrochloric acid (1×20 mL), 1 M aqueous sodium hydroxide (1×20 mL) and saturated brine (1×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo to give a crude yellow chalky solid which was purified by column chromatography on silica (50% ethyl acetate/petroleum ether) to give 29 (153 mg, 48%) as a yellow solid.
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[NH:13]2)C1C=CC=CC=1>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:20]([O:22][CH3:23])=[O:21])[NH:13]2
Reactant: COC(=O)c1cc2c(OCc3ccccc3)c(OC)ccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2c(O)c(OC)ccc2[nH]1
Yield: 90.8 %

Procedure:
5% Palladium on carbon (0.3 g) and methyl 4-benzyloxy-5-methoxyindole-2-carboxylate (2.0 g) in ethyl acetate (30 ml) were vigorously stirred under an atmosphere of hydrogen for 16 hours. The reaction was filtered through celite and the concentrated in vacuo to give the product as a cream solid (1.29 g, 91%); NMR d (CD3SOCD3) 3.74 (s, 3H), 3.82 (s, 3H), 6.80 (d, 1H), 7.00 (d, 1H), 7.16 (s, 1H), 9.10 (s, 1H), 11.58 (brs, 1H); M/z (+) 222 (MH+).
Reaction SMILES: [CH2:1]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25]C)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([C:8]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1C1(Cc2ccccc2)C(=O)N(C)c2ccccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN1C(=O)C(Cc2ccccc2)(c2ccccc2O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
25 g (0.073 mol) of 3-benzyl-1-methyl-3-(2-methoxyphenyl)- indolin-2-one are dissolved in 250 ml of methylene chloride. The solution is cooled to 0°-5° and a solution of 7 ml (0.074 mol) of boron tribromide in 50 ml of methylene chloride is added dropwise over the course of 30 minutes, and the mixture is then stirred at room temperature for 1 hour and poured onto ice-water. The organic phase is separated off, washed twice with water, dried over magnesium sulfate and concentrated. 17.8 g of crystalline product of melting point 188°-190° C. are obtained.
Reaction SMILES: [NH2:1][CH:2]([CH3:7])[CH:3]([OH:6])[CH2:4][OH:5].N[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>ClCCl.[Cl-].[Na+].O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:9]([NH:1][C@H:2]([CH3:7])[C@@H:3]([OH:6])[CH2:4][OH:5])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(N)C(O)CO
Reactant: NC(c1ccccc1)c1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](NC(c1ccccc1)c1ccccc1)[C@@H](O)CO
Temperature: 25 °C

Procedure:
3-Aminobutane-1,2-diol was similarly prepared as described in Tetrahedron: Asymmetry, 1995, 6(9), 2329-2342. Briefly, to a solution of (2S,3S)-trans-3-methyloxirane-2-methyl-4-nitrobenzoate (10.0 g, 42.2 mmol) (Fluka) in dichloromethane (150 mL) under argon, was combined with titanium isopropoxide (25 mL, 84.3 mmol), and stirred for minutes at room temperature. Aminodiphenyl-methane (14.5 mL, 84.4 mmol) was added, and the reaction was stirred at room temperature overnight. A solution of 10% sodium hydroxide in saturated brine was added and the suspension was stirred for 2 hours. The mixture was filtered and extracted with 0.2M hydrochloric acid. The acidic layers were extracted with dichloromethane and discarded. The acidic layer was basified with sodium hydroxide pellets until pH 9, and then extracted into dichloromethane. The layers were separated, and the organic layer was dried over magnesium sulfate, and concentrated in vacuo to give an oil that was purified by flash column chromatography using 2:1 to 1:1 hexanes:ethyl acetate and 2:1 ethyl acetate:hexane as eluants to give 2.6 g of (R,R)-3-(benzhydrylamino)butane-1,2-diol.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[OH:13][C:14]1[C:15]([CH3:24])=[C:16]([CH:21]=[CH:22][CH:23]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:24][C:15]1[C:14]([O:13][CH2:2][C:3]2[CH:12]=[CH:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=2)=[CH:23][CH:22]=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COC(=O)c1cccc(O)c1C
Product: COC(=O)c1cccc(OCc2ccc3ccccc3c2)c1C
Yield: 92 %

Procedure:
2-Bromomethylnaphthalene was reacted with methyl 3-hydroxy-2-methylbenzoate (Tetrahedron, 1969, 25, 4249) using the conditions described in Example 1 to give methyl 2-methyl-3-(naphth-2-ylmethoxy)benzoate in 92% yield, m.p. 47°-48° C. (recrystallised from a mixture of diethyl ether and pentane). The product so obtained was reacted with thiazol-2-yl-lithium using the procedure described in the 3rd paragraph of the portion of Example 3 which is concerned with the preparation of starting materials to give, after purification of the product by column chromatography using a 49:1 v/v mixture of toluene and ethyl acetate as eluent, 3-(naphth-2-ylmethoxy)-2-methylphenyl 2-thiazolyl ketone as an oil in 72% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:17]#[N:18])=[CH:7][CH:8]=2)[N:3]=1.[OH:19]O.[OH-].[Na+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:17]([NH2:18])=[O:19])=[CH:7][CH:8]=2)[N:3]=1
Reactant: OO
Reactant: Cc1cc(N2CCCC2)c2ccc(C#N)cc2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(N2CCCC2)c2ccc(C(N)=O)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A solution of 2-methyl-4-pyrrolidin-1-yl-quinoline-7-carbonitrile (100 mg, 0.42 mol) in dichloromethane (1 mL) was treated at 0° C. with 30% aq. hydrogen peroxide solution (0.5 mL), tetrabutylammonium hydrogen sulfate (29 mg, 84 mmol), and 20% aq. sodium hydroxide solution (0.5 mL). After removal of the ice bath, the two-phase mixture was stirred at r.t. for 2 h, then the organic layer was separated, washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, dichloromethane/methanol 9:1) afforded the title compound (65 mg, 60%). Light brown solid, ISP-MS m/e=256.1 ([M+H]+).
Reaction SMILES: [CH2:1]([S:7][C:8]1[S:18][C:11]2=[N:12][C:13](I)=[CH:14][C:15](=[O:16])[N:10]2[N:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cu](C#N)[C:20]#[N:21].[C-]#N.[Na+].C(Cl)(Cl)Cl>CN(C)C=O.O>[C:20]([C:13]1[N:12]=[C:11]2[S:18][C:8]([S:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[N:9][N:10]2[C:15](=[O:16])[CH:14]=1)#[N:21]
Reactant: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Reactant: N#C[Cu]C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCCCSc1nn2c(=O)cc(C#N)nc2s1
Temperature: 100 °C
Reaction time: 1 h
Yield: 51.5 %

Procedure:
In 100 ml of dimethylformamide, 6 g of 2-hexylthio-7-iodo-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was dissolved. To this solution, 1.77 g of copper cyanide and 0.97 g of sodium cyanide were added and the solution was stirred at 100° C. for 1 hour. After the reaction mixture was cooled to room temperature, it was wxtracted with chloroform and water. The organic layer was washed with water and dried over anhydrous sodium sulfate. Florisil® was added to the organic layer and it was shaken. The solvent was distilled off, and 2.3 g of 7-cyano-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[C:9](Cl)(=[O:13])[CH:10]([CH3:12])[CH3:11]>O>[C:9]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:13])[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)OOC(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type D with two reactors of type B connected downstream in series. 1.22 kg/l·h of a 26% by weight solution of tert-butyl hydroperoxide and 17% by weight of potassium hydroxide in water and 0.32 kg/l·h of isobutyroyl chloride are fed to the first reactor. The metering rates are based on the total volume of the reactor arrangement in litres. Cooling with cooling water keeps the internal temperature in the first reactor at 26° C. and in the two downstream reactors at 20° C. The reaction mixture withdrawn from the third reactor is mixed with 0.79 kg/l·h of demineralized water and 0.14 kg/l·h of isododecane, and the organic phase is removed. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with demineralized water, and then dried with calcium chloride. 0.54 kg/l·h of a 75% by weight solution of tert-butyl peroxyisobutyrate in isododecane is obtained (86.0% based on isobutyroyl chloride).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH2:24]([N:26]1[C:30]([C:31](O)=[O:32])=[CH:29][C:28]([CH3:34])=[N:27]1)[CH3:25]>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:31]([C:30]2[N:26]([CH2:24][CH3:25])[N:27]=[C:28]([CH3:34])[CH:29]=2)=[O:32])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: CCn1nc(C)cc1C(=O)O
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Product: CCn1nc(C)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.89 min; [M+H]+=484.3.
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[C:4]([CH2:17][CH3:18])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.N[C:21]1[C:25]([C:26]#[N:27])=C[NH:23][N:22]=1>C(O)(=O)C>[CH2:17]([C:4]1[CH:3]=[N:2][C:19]2[N:23]([N:22]=[CH:21][C:25]=2[C:26]#[N:27])[C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)[CH3:18]
Reactant: CCC(=CN(C)C)C(=O)c1cccc(C(F)(F)F)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: CCc1cnc2c(C#N)cnn2c1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 4.0 g of 3-dimethylamino-2-ethyl-3'-trifluoromethylacrylophenone and 1.5 g of 3-amino-4-cyanopyrazole in 75 ml of glacial acetic acid was refluxed for two hours to give 6-ethyl-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, m.p. 135°-137° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH:23]=CC)[CH:14]=C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:14]=[CH:23][C:18]3[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=3)[O:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=C[C@H](COS(=O)(=O)c1ccc(C)cc1)Oc1ccccc1C=CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
To a solution of (2R)-2-{2-[1-propenyl]phenoxy}-3-butenyl 4-methyl-benzenesulfonate (3.61 g, 10.1 mmol) in dichloromethane (100 mL) is added bis(tricyclopentylphosphine)benzylidene ruthenium (IV) dichloride (1.49 g, 2.01 mmol) and the reaction mixture is stirred at room temperature for 16 hours. The solvent is removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, ethyl acetate:hexanes 3:7) provides 2.48 g (78% y, >97% ee) of (2R)-2H-chromen-2-ylmethyl 4-methylbenzenesulfonate as a pale green crystalline solid. [α]D25=+175.12 (c 9.99 in methanol, >97% ee); Rf=0.40 (silica, ethyl acetate:hexanes 3:7); Anal. Calcd. for C11H16O4S: C, 64.54; H, 5.10. Found: C, 64.85; H, 5.05.
Reaction SMILES: [OH:1][C:2]([CH3:17])([CH3:16])[C@@H:3]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[NH:4][C:5]1[CH2:9][S:8][C:7](=[O:10])[N:6]=1.[F:18][C:19]([F:40])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([CH:29]=O)[CH2:25][CH2:24]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:40][C:19]([F:18])([F:39])[C:20]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:21]=1[CH2:22][N:23]1[CH2:28][CH2:27][CH:26](/[CH:29]=[C:9]2/[C:5]([NH:4][C@H:3]([C:11]([N:13]([CH3:15])[CH3:14])=[O:12])[C:2]([OH:1])([CH3:17])[CH3:16])=[N:6][C:7](=[O:10])[S:8]/2)[CH2:25][CH2:24]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CN(C)C(=O)[C@@H](NC1=NC(=O)SC1)C(C)(C)O
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CN(C)C(=O)[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(C)(C)O
Temperature: 60 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 3-hydroxy-N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-L-valinamide (300 mg) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (392 mg) in 2-propanol (5 mL) was added piperidinium acetate (168 mg) at room temperature. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (170 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N:12]=[CH:13][N:14](C)C.Cl.[CH3:18][O:19]N>C(O)C>[CH3:18][O:19][N:14]1[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=[CH:13]1
Reactant: CON
Reactant: CN(C)C=Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CCO
Product: COn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Yield: 39.9 %

Procedure:
A solution of N′-(4-chloroquinolin-3-yl)-N,N-dimethylimidoformamide (10.9 g, 46.6 mmol) and O-methylhydroxylamine hydrochloride (3.9 g, 47 mmol) in ethanol (100 mL) was heated at reflux for 4.5 hours. An analysis by LC/MS indicated the reaction was incomplete, and additional O-methylhydroxylamine hydrochloride (2.0 g, 24 mmol) was added. The reaction was heated at reflux overnight, allowed to cool to room temperature, and concentrated under reduced pressure. The work-up and purification procedures described in Part C of Example 19 were followed with the modification that chromatographic purification was carried out eluting with 5% methanol in dichloromethane containing 3 mL of aqueous ammonium hydroxide per liter of eluent. 1-Methoxy-1H-imidazo[4,5-c]quinoline (approximately 3.7 g) was obtained as a red solid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([OH:32])=O)[S:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[CH2:45][CH2:44][C:43]3[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=3[NH:41][C:40]2=[O:50])[CH2:35][CH2:34]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.CCOC(C)=O>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([N:33]3[CH2:34][CH2:35][CH:36]([N:39]4[CH2:45][CH2:44][C:43]5[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=5[NH:41][C:40]4=[O:50])[CH2:37][CH2:38]3)=[O:32])[S:18]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cccc(F)c1NCCN1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)SC1c1cccc(F)c1NCCN1CCCCC1

Procedure:
2-((5S)-2-(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (319.0 mg, 0.685 mmol), 4,5-dihydro-3-(piperidin-4-yl)-1H-benzo[d][1,3]diazepin-2(3H)-one (336.1 mg, 1.370 mmol), EDC (262.6 mg, 1.370 mmol) and HOBT (209.8 mg, 1.370 mmol) were stirred at RT in DMF (4 mL) overnight. Transferred mixture to a separatory funnel with EtOAc and water. The aqueous layer was extracted with EtOAc (3×), the organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude was dissolved in DMSO and purified by reverse phase semi-prep chromatography (CH3CN/water mobile phase) to give 3-(1-(2-((5S)-2-(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-4,5-dihydro-1H-benzo[d][1,3]diazepin-2(3H)-one. LC/MS: 692.34 (M+1) Rt=2.24 min (10-90% 3/5 min (gradient/run) w/formic acid).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.[CH2:25](Br)[CH3:26].C(N(CC)CC)C.O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)=[C:11]([CH2:13][C:14]([O:16][CH2:25][CH3:26])=[O:15])[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1ccc(Cl)cc1
Reactant: CCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 33.3 g of 2-p-chlorophenyl-5-p-chlorophenoxy-4-oxazoleacetic acid in 100 ml of dimethylformamide were added 40 ml of ethyl bromide and 40 ml of triethylamine. The mixture was stirred at room temperature for 40 minutes and then allowed to stand overnight. To the resulting mixture were added water and ethyl acetate and then the mixture was shaken. The organic layer was washed successively with water, diluted hydrochloric acid and water, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was recrystallized from a mixture of n-hexane and ethyl acetate to give 34.3 g of the title compound as white crystals, melting at 70°-72° C.
Reaction SMILES: [H-].[Na+].C(O)(C)(C)C.[CH3:8][C:9]1[N:19]=[CH:18][CH:17]=[CH:16][C:10]=1[C:11]([O:13]CC)=[O:12].[CH:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>CN(C=O)C.O.C(O)(=O)C>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH:20]=[CH:8][C:9]2[N:19]=[CH:18][CH:17]=[CH:16][C:10]=2[C:11]([OH:13])=[O:12])=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1cccnc1C
Reactant: COc1ccc(C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: CC(=O)O
Product: COc1ccc(C=Cc2ncccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of NaH (60% dispersion in mineral oil, 7.4 g, 0.185 mole), tert-butanol (11.12 g, 0.15 mole), and anhydrous DMF (100 mL) was carefully warmed at 80° C. until gas evolution ceased, then was cooled to 0° C. under argon. A solution of ethyl 2-methylnicotinate (7.7 mL, 0.050 mole) in anhydrous DMF (17 mL) was added dropwise over 3 min, and the reddish-orange mixture was stirred at 0° C. for 1 hr. A solution of para-anisaldehyde (7.3 mL, 0.060 mL) in anhydrous DMF (17 mL) was added dropwise over 3 min, and the reaction was allowed to warm to RT. The mixture was stirred overnight, then was poured into ice water (200 mL), and the solution was acidified to pH 6 with glacial acetic acid. The volume was adjusted to 1 L with H2O, the flask was scratched with a glass rod, and the mixture was allowed to stand at RT for several hr, then in the refrigerator overnight. The solid was collected by suction filtration and washed with H2O. Recrystallization from boiling absolute EtOH gave the title compound (5.31 g, 42%, two crops) as yellow needles: 1H NMR (250 MHz, DMSO-d6) δ 8.70 (dd, J=4.6, 1.7 Hz, 1H), 8.18 (dd, J=7.9, 1.7 Hz, 1H), 7.95 (d, J=15.8 Hz, 1H), 7.83 (d, J=15.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 2H), 7.34 (dd, J=7.9, 4.6 Hz, 1H), 6.99 (d, J=8.7 Hz, 2H), 3.79 (s, 3H); MS (ES) m/e 256 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C@H:10]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:9]23)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=O>>[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][C@H:10]3[CH2:13][NH:14][CH2:15][C@@H:9]23)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCN(c3cncc(O)c3)[C@@H]2C1
Solvent: O=C(O)C(F)(F)F
Product: Oc1cncc(N2CC[C@H]3CNC[C@H]32)c1
Yield: 38 %

Procedure:
The product of Example 82B (3.21 mmol) and trifluoroacetic acid was processed according to the procedure described in Example 64C to provide the title compound (0.250 g, 1.22 mmol, 38% yield over two steps). MS (DCI/NH3) m/z 206 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:35])[C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)c1ccccc1

Procedure:
The title compound, white solid (17 mg, 72%), MS (ISP) m/z=436.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (20 mg, 0.0543 mmol) and benzoic acid.