Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:41]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:39]=[C:38]([C:46]([F:49])([F:48])[F:47])[CH:37]=2)[CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[O:23])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.[Li+].[OH-].C(O)(C(F)(F)F)=O>O.CC#N>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][N:9]=[CH:10][NH:11][C:12]1[CH:13]=[C:14]([C:22]([NH:24][CH2:25][C:26]([NH:28][CH:29]([C:36]2[CH:37]=[C:38]([C:46]([F:47])([F:48])[F:49])[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=2)[CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[O:23])[CH:15]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:17]=1
Reactant: CCOC(=O)CC(NC(=O)CNC(=O)c1cc(NC=NN)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NN=CNc1cc(C(=O)NCC(=O)NC(CC(=O)O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.4 %

Procedure:
To 600 mg (0.00082 mole) of the product of Example 38 in 12 ml of H2O and 12 ml of CH3CN was added 140 mg (0.0033 mole) of LiOH. The reaction was stirred at room temperature for 1.5 hours. The pH was lowered to 2.5 with TFA and the product isolated by reverse phase prep HPLC to yield (after lyophilization) 520 mg of (±) β-[[2-[[[3-[(aminoiminomethyl)amino]-5-(trifluoromethyl)phenyl]carbonyl]amino]acetyl]amino]-3,5-bis(trifluoromethyl)benzenepropanoic acid, trifluoroacetate salt as a white solid.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:14](=[O:15])[C:13]2[C:12]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[N:11][C:10]([NH:24][C@@H:25]3[CH2:30][CH2:29][CH2:28][CH2:27][C@@H:26]3[NH:31]C(=O)OC(C)(C)C)=[N:9][C:8]=2[CH2:7]1>C(O)(C(F)(F)F)=O>[NH2:31][C@H:26]1[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]1[NH:24][C:10]1[N:11]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)[C:13]2[C:14](=[O:15])[NH:6][CH2:7][C:8]=2[N:9]=1
Reactant: COc1ccc(CN2Cc3nc(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(Nc4cccc(C)c4)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Nc2nc(N[C@@H]3CCCC[C@@H]3N)nc3c2C(=O)NC3)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
A mixture of crude tert-butyl (1S,2R)-2-(6-(2,4-dimethoxybenzyl)-5-oxo-4-(m-tolylamino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-ylamino)cyclohexylcarbamate (235 mg, 0.390 mmol) in TFA (5 mL) was stirred at 60° C. for 2 h and was then purified by reverse phase preparative HPLC. The fractions were collected, concentrated under reduced pressure, diluted in EtOAc, and basified with an aqueous saturated solution of NaHCO3. The organic extract was dried and concentrated under reduced pressure to give the title compound as a white solid (60 mg, 44%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.33-1.60 (m, 10 H), 2.32 (s, 3 H), 3.16 (m, 2 H), 3.92 (br s, 1 H), 4.14 (s, 2 H), 6.88 (d, J=7.07 Hz, 1 H), 7.13 (br s, 1 H), 7.22 (t, J=7.45 Hz, 1 H), 7.34-7.55 (m, 1 H), 7.70 (br s, 1 H), 8.01 (br s, 1 H), 8.58 (br s, 1 H). [M+H] calc'd for C19H24N6O, 353; found, 353.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][C:11]([O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[Al](Br)(Br)Br.[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]#[N:27].[ClH:30]>>[Cl:24][C:25]([Cl:29])([Cl:28])[C:26]1[N:27]=[C:26]([C:25]([Cl:28])([Cl:24])[Cl:30])[N:27]=[C:1]([C:3]2[CH:4]=[CH:5][C:6]([S:9][CH2:10][C:11]([O:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[CH:7][CH:8]=2)[N:2]=1
Reactant: N#Cc1ccc(SCC(=O)OC2CCCCC2)cc1
Reactant: N#CC(Cl)(Cl)Cl
Reactant: Cl
Agent: Br[Al](Br)Br
Product: O=C(CSc1ccc(-c2nc(C(Cl)(Cl)Cl)nc(C(Cl)(Cl)Cl)n2)cc1)OC1CCCCC1

Procedure:
The mixed solution of 10 g of cyclohexyl 2-(4-cyanophenylthio)acetate (36.3 mmol), 0.8 g of AlBr3, and 50 g of trichloroacetonitrile was bubbled with dry HCl at room temperature.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([OH:23])[CH2:11][O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:24][C:25]([F:41])([F:40])[O:26][C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:1]([O:8][CH2:9][C@H:10]([O:23][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[CH:31]=[CH:32][C:27]([O:26][C:25]([F:24])([F:40])[F:41])=[CH:28][CH:29]=2)=[CH:38][CH:37]=1)[CH2:11][O:12][Si:13]([CH:14]([CH3:16])[CH3:15])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[Si](OC[C@H](O)COCc1ccccc1)(C(C)C)C(C)C
Reactant: Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)[Si](OC[C@H](COCc1ccccc1)Oc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)(C(C)C)C(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
1,1′-Diisopropyl azodicarboxylate (7.70 mL, 0.039 mol) was added dropwise at 5° C. to a solution of the alcohol 79 (12.40 g, 0.037 mol), 4′-(trifluoromethoxy)[1,1′-biphenyl]-4-ol (reported by Edsall et al., 2003, via Suzuki coupling of 4-bromophenol and boronic acid 44) (8.29 g, 0.033 mol) and triphenylphosphine (10.26 g, 0.039 mol) in anhydrous benzene (25 mL) and the solution was stirred at 20° C. for 18 h. The product was adsorbed directly onto silica by concentration under reduced pressure, and chromatography on silica gel, eluting with EtOAc/petroleum ether (1:19), gave 4-[((1S)-2-(benzyloxy)-1-{[(triisopropylsilyl)oxy]methyl}ethyl)oxy]-4′-(trifluoromethoxy)-1,1′-biphenyl (80) (14.30 g, 69%) as a colourless oil: [α]19 +5.9° (c, 6.95, CHCl3); 1H NMR (CDCl3) δ 7.72 (d, J=8.8 Hz, 2H), 7.58 (d, J=8.8 Hz, 2H), 7.40 (d, J=8.8 Hz, 2H), 7.35-7.24 (m, 5H), 7.06 (d, J=8.8 Hz, 2H), 4.64-4.57 (m, 1H), 4.52 (s, 2H), 3.98-3.87 (m, 2H), 3.76-3.65 (m, 2H), 1.08-0.98 (m, 21H). APCI MS m/z 576 [M+H]+.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:17]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@H:11]1[N:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:37])[CH2:23][NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:35])[F:33])[CH:27]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N[C@H]1CCCC[C@H]1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN([C@@H]2CCCC[C@@H]2NCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To a mixture of benzaldehyde (0.061 mL, 0.6 mmol) and N-(2-{[(3R)-1-(cis-2-aminocyclohexyl)pyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (0.278 g, 0.60 mmol) in CH2Cl2 (10 mL) was added NaB(OAc)3H (0.128 g, 0.60 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed (EtOAc to EtOAc:MeOH:Et3N=9:1:0.5) to give 0.21 g of the title compound. MS (EI) calcd: (M+H)+=503.3; found: 503.4.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])[C:9]=1CN)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[O:26]>O1CCCC1>[N:27]1([C:25]([OH:26])=[O:1])[CH:31]=[CH:30][N:29]=[CH:28]1.[F:24][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([F:23])[C:17]=1[NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9]=1[NH-:27]
Reactant: NCc1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(O)n1ccnc1
Product: [NH-]c1c(Nc2c(F)cccc2F)cccc1Oc1ccccc1
Temperature: 25 °C

Procedure:
The product of example 1c above, 2-phenoxy-6-(2,6-difluorophenylamino)benzylamine, (0.159 g 0.49 mmol) was dissolved in dry tetrahydrofuran (6 mL) and stirred under argon at room temperature. 1,1′-Carbonyldiimidazole (0.102 g, 0.63 mmol) dissolved in dry tetrahydrofuran (4 mL) was added and the mixture stirred at room temperature, and then heated to reflux The solvent was evaporated in vacuo, to give a crude product which was flash chromatographed on silica gel eluted with 0–3% methanol in methylene chloride to give an intermediate imidazole-1-carboxylic acid[2-(2,6-difluorophenylamino)-6-phenoxyphenylamide. The imidazole-1-carboxylic acid[2-(2,6-difluorophenylamino)-6-phenoxyphenylamide was dissolved in tetrahydrofuran (5 mL) and sodium hydride hydride, dry, 95% (0.025 g, 1 mmol) was added. The resulting mixture was stirred for four hours under argon. The solvent was evaporated and the residue was partioned between ethyl acetate and water. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated to give the crude product which was then chromatographed on silica gel eluted with 0–20% ethyl acetate in CH2Cl2 to give the title compound as a white amorphous solid. mp 199–201° C.
Reaction SMILES: C(O[C:6](=O)[N:7](C)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:6][NH:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:26])[F:25])[CH:18]=2)=[CH:14][CH:15]=1
Reactant: CN(CCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]-ethyl}-carbamic acid tert-butyl ester (300 mg, 0.759 mmol, 1 eq) was dissolved in dry DCM (3 ml) under argon atmosphere and TFA (290.6 μl, 5 eq) was added. Reaction mixture was stirred for overnight. In the reaction mixture was added more DCM (15 ml) and was extracted with saturated NaHCO3 (3×15 ml) and brine. Organic layer was dried over anhydrous Na2SO4, filtered and evaporated to give a product methyl-{2-[4-(3-trifluoromethyl-phenoxy)-phenyl]ethyl}-amine (211.5 mg, yield=82.1%, purity=87%). [M+H]+=296.31 1H NMR (300 MHz; CDCl3) δ/ppm 2.44 (s, 3H), 2.74-2.89 (m, 4H), 6.90-6.98 (m, 2H), 7.09-7.22 (m, 4H), 7.27-7.33 (m, 1H), 7.35-7.45 (m, 1H)
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1.[Cl-].[Mg+2].[Cl-].C(N(CC)CC)C.[CH2:23]=[O:24]>C(#N)C.O>[Cl:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[C:6]([C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1)[CH:23]=[O:24]
Reactant: C=O
Reactant: Cc1cc(Cl)c(C(C)C)cc1O
Agent: [Cl-]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(Cl)c(C(C)C)c(C=O)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 31.8 %

Procedure:
The 4-chloro-5-isopropyl-2-methylphenol (5.0 g, 27.08 mmole) and magnesium chloride (3.87 g, 40.61 mmole) were mixed in acetonitrile (150 mL) and the mixture was cooled to 0° C. (ice bath). Triethylamine (10.28 g, 101.55 mmole) followed by para-formaldehyde (5.48 g, 182.79 mmole) were added to above mixture, which was stirred at 0° C. for 1 hour. The mixture was warmed to room temperature and then heated to 90° C. for 1 week. The contents were poured into water (100 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo to give an off-white solid which was subject to flash chromatography (silica gel) and eluted with 100% CH2Cl2 to give an off-white solid (1.83 g, 32%): GCMS m/z 212.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(C(C)C)C(C)C.[NH:24](C(OC(C)(C)C)=O)[NH2:25].Cl>ClCCl.O1CCOCC1>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:24][NH2:25])=[O:5]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: ClCCl
Product: NNC(=O)c1cccc(C(F)(F)F)c1Cl
Reaction time: 8 h

Procedure:
To a solution of 2-chloro-3-(trifluoromethyl)benzoyl chloride (15 g, 61.7 mmol, commercially available from e.g. Apollo) and DIPEA (12.94 ml, 74.1 mmol) in anhydrous dichloromethane (DCM) (200 ml) cooled to 0° C. in an ice bath was slowly added 1,1-dimethylethyl hydrazinecarboxylate (8.97 g, 67.9 mmol) under an atmosphere of argon and the mixture was allowed to reach steadily room temperature overnight. It was quenched with water (100 mL), the phases were separated and the aqueous extracted with DCM (2×50 mL). The combined organics were washed with brine (50 mL) and dried over MgSO4. The orange oil isolated (circa 25 g) was the impure BOC-protected hydrazide. It was then dissolved in 1,4-Dioxane (100 ml) and treated with HCl (4M in dioxane) (154 ml, 617 mmol) overnight at room temperature. The slurry was concentrated at the buchi to obtain a yellow solid which was triturated with Et2O to afford a white coloured solid, then applied to 4×10 g SCX cartridges, washed with MeOH and finally eluted with NH3 (2M in MeOH). The basic fractions were concentrated to afford the desired product in 3.5 g as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH2:15]=O.[CH3:17][CH:18]1[C:22](=[O:23])[NH:21][C:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:19]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:17][C:18]2([CH3:15])[C:22](=[O:23])[NH:21][C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[N:19]2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CC1N=C(c2ccccc2)NC1=O
Reactant: C=O
Product: COc1ccccc1N1CCN(CC2(C)N=C(c3ccccc3)NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 1-(2-methoxyphenyl)piperazine (2.4 g) and 37-40% aqueous formaldehyde solution was stirred at ambient temperature under nitrogen for 10 minutes, then a suspension of 4-methyl-2-phenyl-2-imidazolin-5-one (2.58 g) in industrial methylated spirit (100 ml) was added in one portion. The stirred mixture was heated under reflux for 48 hours, then the solvent was removed in vacuo. The residue was triturated with a 2:1 mixture of cyclohexane and ether, undissolved solid was removed by filtration, then the filtrate was allowed to concentrate at ambient temperature. The resulting solid was collected by filtration. Further concentration of the filtrate yielded a second crop of solid. The two crops of solid were combined and dried in vacuo at ambient temperature to give 4-[4-(2-methoxyphenyl)piperazin-1-ylmethyl]-4-methyl-2-phenyl-2-imidazolin-5-one 1.1 hydrate as a colourless solid (0.2 g), m.p. 86-89° C.
Reaction SMILES: ClC(Cl)(Cl)C[O:4][C:5](=O)[NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25].[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35]>CCCCCC.C(OCC)(=O)C>[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH:35][C:5]([NH:6][C:7]1[C:8]([CH3:27])=[C:9]([CH3:26])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([CH3:22])[CH3:23])=[CH:19][CH:20]=3)[C:11]=2[C:24]=1[CH3:25])=[O:4]
Reactant: CN(C)CCN
Reactant: Cc1c(C)c2c(c(C)c1NC(=O)OCC(Cl)(Cl)Cl)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1c(C)c2c(c(C)c1NC(=O)NCCN(C)C)C(c1ccc(C(C)C)cc1)CO2
Yield: 54 %

Procedure:
Using 2,2,2-trichloroethyl(3-(4-isopropylphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 138 and 2-(dimethylamino)ethylamine, the title compound was synthesized in the same manner as in Example 143. Yield: 54%. Melting point: 133-134° C. (hexane-ethyl acetate).
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1C1C=CC(=O)NC=1.[CH3:16][C:17]1C=CC(S(C)(=O)=O)=C[CH:22]=1.[CH3:27][N:28]([CH:30]=[O:31])[CH3:29]>>[CH3:27][N:28]1[CH:29]=[C:22]([N:3]2[CH:4]=[CH:5][N:6]=[CH:7][CH2:8]2)[CH:17]=[CH:16][C:30]1=[O:31]
Reactant: O=c1ccc(-c2cnccn2)c[nH]1
Reactant: Cc1ccc(S(C)(=O)=O)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cn1cc(N2C=CN=CC2)ccc1=O

Procedure:
Sodium hydride (0.75 g) is added to a stirred solution of 5-(2-pyrazinyl)-2(1H) pyridone (2.2 g) in DMF (150 ml). Methyl p-toluene sulfonate (4.0 g) is added to the stirred reaction mixture after 5 minutes of stirring. After 35 minutes reaction time at RT, the reaction mixture is filtered and the filtrate evaporated in vacuum. The oily solid residue is washed with ether, filtered and the dry solid treated with hot acetone. The acetone is filtered and the filtrate evaporated, yielding a solid. The ether filtrate from above is evaporated, yielding a solid which after washing with decane is combined with the acetone filtrate solid. The combined solids are recrystallized from toluene and decane (treated with charcoal and filtered while hot) resulting in the desired 1-methyl pyridone compound, M.P. 165.5°-166.5° C.
Reaction SMILES: [Br:1][C:2]1([CH:16]=[CH:15]N=[C:13]([CH:17]([OH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:12]1)C(NC1C=CC=CC=1)=O.[CH3:25][CH2:26][N:27](C1C=CC=CC=1)[CH2:28]C.C([N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])C>>[Br:1][C:2]1[CH:16]=[CH:15][C:28]2[N:27]=[C:26]([C:25]3[CH:40]=[CH:39][N:38]=[CH:41][CH:42]=3)[O:24][CH:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:13]=2[CH:12]=1
Reactant: O=C(Nc1ccccc1)C1(Br)C=CN=C(C(O)c2ccccc2)C1
Reactant: CCN(CC)CC
Reactant: CCN(CC)c1ccccc1
Product: Brc1ccc2c(c1)C(c1ccccc1)OC(c1ccncc1)=N2
Yield: 85 %

Procedure:
4-Bromo-2-(α-hydroxybenzyl)-isonicotinanilide (12.8 g) was treated as in Synthesis 6 except that triethylamine was replaced by diethylaniline (6.0 ml). The titled compound was obtained in an amount of 10.3 g (yield: 85%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:42])[CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][NH:18][C:19](=[O:42])[CH2:20][CH2:21][S:22][C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCOCCOCCOCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCOCCOCCOCCNC(=O)CCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 121.3 %

Procedure:
Methanesulfonyl chloride (0.55 mL, 7.1 mmol) was added to a 0° C. solution of N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide (3.38 g, 6.45 mmol) and triethylamine (1.08 mL, 7.74 mmol) in dichloromethane (33 mL). The solution was allowed to warm to room temperature. After 4 hours, the solution was diluted with dichloromethane and washed with water (2×) and brine. The organic phase was dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 4.71 g of 13-oxo-17,17,17-triphenyl-3,6,9-trioxa-16-thia-12-azaheptadec-1-yl methanesulfonate, which was concentrated from toluene and used in Part C.
Reaction SMILES: C([O:3][C:4](=O)[C:5](=[CH:12][C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[CH:15][C:14]=1[N+:20]([O-])=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])C.CCOC(C)=O.CCCCCC>C(O)C.[Pd]>[CH2:10]([O:9][C:7](=[O:8])[CH2:6][CH:5]1[CH2:12][C:13]2[C:14](=[CH:15][CH:16]=[C:17]([OH:19])[CH:18]=2)[NH:20][C:4]1=[O:3])[CH3:11]
Reactant: CCOC(=O)CC(=Cc1cc(O)ccc1[N+](=O)[O-])C(=O)OCC
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)CC1Cc2cc(O)ccc2NC1=O
Reaction time: 20 h
Yield: 43.5 %

Procedure:
A solution of 2-(5-hydroxy-2-nitro-benzylidene)-succinic acid diethyl ester (3.8 g, 12 mmol) in ethanol (35 mL) was hydrogenated over 10% Pd—C (0.8 g) at 25° C. and 1 atm. After 20 h, the catalyst was filtered through diatomaceous earth and washed with ethanol (3×35 mL). The filtrate was concentrated giving a mixture of solid and foam (2.8 g). Flash chromatography (190 g silica; 20%, then 40% EtOAc-hexane) gives the title compound (1.3 g, 45% yield) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][C@H:8]3[C@H:9](O)[N:10](C(OCC(Cl)(Cl)Cl)=O)[C:4]=2[C:3]=1[O:28][CH3:29]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[CH:9]=[N:10][C:4]=2[C:3]=1[O:28][CH3:29]
Reactant: COc1cc2c(c(OC)c1C)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc2c(c(OC)c1C)N=CC1CCCN1C2=O
Yield: 94.4 %

Procedure:
10% Cd/Pb couple (1.34 g; 10.7 mmol Cd) was added to a rapidly stirring solution of 193 (1 g; 2.14 mmol) in a mixture of THF (15 ML) and 1 N NH4OAc (15 mL). After 3.5 hours the reaction was diluted with EtOAc (150 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent yielded the product (194) as a white glass (554 mg, 2.021 mmol, 94%). 1H NMR (270 MHz, CDCl3) (mixture of imine and methyl ether forms) δ 7.72 (imine, d, J=4.39, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 3.88-3.51 (m, 3H+2H+1H), 2.37-2.04 (m, 4H), 2.22 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ 164.65, 161.41, 156.79, 153.47, 133.87, 126.29, 124.27, 105.71, 60.98, 55.80, 55.70, 53.71, 46.70, 29.52, 29.34, 24.13, 9.33.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]23[CH:17]=[CH:18][CH:19]=[CH:20][C:14]2=[CH:13][C:12]([CH2:21][N:22]2[CH2:27][CH2:26][C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)([C:28]#[N:29])[CH2:24][CH2:23]2)=[CH:11][CH:10]3[C:9]1=[O:36].N1([C:43]([O-])=[O:44])CCCCC1.C(C1(C2C=CC=CN=2)CCN(C(OC(C)(C)C)=O)CC1)#N>>[OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[N:8]1[CH2:16][C:15]2[C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:12]([CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:44][CH3:43])[N:31]=4)([C:28]#[N:29])[CH2:24][CH2:23]3)=[CH:11][C:10]=2[C:9]1=[O:36]
Reactant: N#CC1(c2ccccn2)CCN(CC2=CC3C(=O)N([C@H]4CCCC[C@@H]4O)CC34C=CC=CC4=C2)CC1
Reactant: O=C([O-])N1CCCCC1
Agent: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Product: COc1cccc(C2(C#N)CCN(Cc3cc4c(c5ccccc35)CN([C@H]3CCCC[C@@H]3O)C4=O)CC2)n1

Procedure:
The titled compound was prepared employing the procedures described for the construction of 1-({2-[(1S,2S)-2-hydroxycyclohexyl]-3-oxo-2,3-dihydro-1H-benzo[d]isoindol-5-yl}methyl)-4-(pyridine-2-yl)piperidine-4-carbonitrile in Example 1, substituting tert-butyl 4-cyano-4-methoxypyridin-2-yl)piperidine-1-carboxylate for tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate. The resultant white solid gave proton NMR spectra consistent with theory and a mass ion (ES+) of 511.2715 for [M+H]+[calc'd for C31H35N4O3, [M+H]+=511.2704]: 1H NMR (400 MHz, CDCl3) δ 8.19-8.11 (m, 2H), 7.90-7.83 (m, 2H), 7.68 (s, 1H), 7.67-7.52 (m, 3H), 5.04-4.92 (m, 2H), 4.59-4.54 (m, 2H), 4.17-4.11 (m, 2H), 3.78-3.71 (m, 2H), 2.23-2.19 (m, 2H), 1.96-1.81 (m, 4H), 1.64-1.20 (m, 1H) ppm.