Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9](O)[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5].C(Cl)[Cl:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCCCCCC.C(Cl)(Cl)(Cl)Cl>[CH3:2][O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([Cl:20])[CH2:8][N:7]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:5]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: ClCCl
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCCC
Product: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Temperature: 4 °C
Reaction time: 0.75 h
Yield: 89 %

Procedure:
Via chloride: A solution of 374 g (1.48 mol) (2S,4R)-4-hydroxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 1.61 CH2Cl2 was treated with 680 g (2.6 mol) triphenylphosphine, cooled to 3-5° C. and treated in 10 min with 1.241 (12.8 mol) CCl4, after 2 h at this temperature cooling was stopped, the reaction temperature was raised during 2 h to 35° C. It was cooled down to 20° C. and stirred for further 45 min. After addition of 4 l of n-heptane, the reaction was evaporated to 2.9 l, cooled to 0° C., filtered, the residue was treated twice the same way, the third time by dissolving the residue again in 2 l of CH2Cl2. The solvents were evaporated and filtered through silica gel with hexane/tert.-butyl-methylether 9:1 as eluent. Evaporation of the solvents gave 347 g (89%) of (2S,4S)-4-chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 246 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]1[O:31][CH2:30]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CO>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@H:25]1[CH:29]([OH:31])[CH2:30][S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18]
Reactant: COc1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1CO1
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(SCC(O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 1.5 h

Procedure:
4-Methoxythiophenol (1.0 ml) and triethylamine (1.0 ml) were added to (2S)-1-(t-butoxycarbonyl)-2-(1,2-epoxyethyl)-pyrrolidine (1.57 g) as obtained in Example 1-A) in methanol (50 ml), and the mixture was stirred for 1.5 hours under reflux. The reaction mixture was concentrated and the residue was poured into ice-water, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate and concentrated. The residue was recrystallized from a mixted solution of hexane-ethyl acetate to give 2.16 g of the title compound as colorless needles.
Reaction SMILES: Br[C:2]1[C:3](Cl)=NC(Cl)=N[CH:7]=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C@@H:19]([C:29]2[CH:31]=[CH:3][CH:2]=[CH:7][CH:30]=2)[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Product: CC(C)(C)OC(=O)NC[C@@H](Nc1nc(Cl)ncc1Br)c1ccccc1

Procedure:
Intermediate J was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-2-phenyl-ethyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-2-phenyl-ethyl]carbamate. 1H NMR (600 MHz, DMSO-d6) δ ppm 1.32 (s, 9H) 3.29-3.50 (m, 2H) 5.12-5.24 (m, 1H) 7.10 (t, J=5.27 Hz, 1H) 7.21 (t, J=6.88 Hz, 1H) 7.26-7.34 (m, 4H) 7.89 (d, J=7.32 Hz, 1H) 8.24 (s, 1H). LCMS (ESI) 427 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH2:18][O:19][C:20](/[N:22]=[N:23]/[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:21]>O1CCOCC1>[C:1]([C:5]1[CH:6]=[C:7]([SH:16])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[N:22]([C:20]([O:19][CH2:18][CH3:17])=[O:21])=[N:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: C1COCCO1
Product: CCOC(=O)N=NC(=O)OCC
Reaction time: 2 h

Procedure:
Combine 3,5-di-t-butyl-4-hydroxythiophenol (751 mg), diethylazodicarboxylate (496μL, 3.15 mmol) and p-dioxane (5 mL). Place under an argon atmosphere and stir for 2 hours to give a complex of 3,5-di-t-butyl-4-hydroxythiophenol and diethyl azodicarboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:8]([C:11]([CH:16](C)C)(NCC)[CH3:12])(C)[CH3:9].CC(C)C#C>CN(C)C=O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][CH:11]([CH3:16])[C:8]#[C:9][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CCNC(C)(C(C)C)C(C)C
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CC(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C#Cc1ccccn1
Temperature: 85 °C
Yield: 73.5 %

Procedure:
To a degassed solution of 2-bromopyridine (0.604 mL, 6.33 mmol), bis(triphenylphosphine)palladium(II) chloride (0.267 g, 0.380 mmol), copper (I) iodide (0.060 g, 0.316 mmol), and diisopropyldiethylamine (3.61 mL, 25.3 mmol) in N,N-dimethylformamide (20 mL) was added 3-methylbut-1-yne (0.647 g, 9.49 mmol). The reaction mixture was heated to 85° C. for 16 h, cooled to room temperature, and diluted with ethyl acetate (150 mL). The mixture was washed with a 10% aqueous solution of lithium chloride (2×100 mL), washed with a 2M aqueous solution of ammonium hydroxide (100 mL), washed with brine, and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes/ethyl acetate (3/2) afforded (3-methylbut-1-ynyl)pyridine (696 mg, 4.65 mmol, 73% yield). The compound had an HPLC retention time=1.02 min.—Column: YMC COMBISCREEN® ODS-A 4.6×50 mm S-5; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH—90% Water—0.1% TFA; Solvent B=90% MeOH—10% water—0.1% TFA. LC-MS: M+1=146.32. 1H NMR (400 MHz, CDCl3) δ ppm 1.29 (s, 3H), 1.30 (s, 3H), 2.82 (dt, J=13.80, 6.90 Hz, 1H), 7.18 (dd, J=7.65, 4.89 Hz, 1H), 7.37 (d, J=7.78 Hz, 1H), 7.61 (td, J=7.72, 1.13 Hz, 1H), and 8.55 (d, J=4.77 Hz, 1H).
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[CH3:7][NH:8][CH2:9][CH2:10][NH2:11]>C(O)(C)C.[Cu].[Cu]Cl>[CH3:7][N:8]([C:2]1[S:6][CH:5]=[N:4][CH:3]=1)[CH2:9][CH2:10][NH2:11]
Reactant: Brc1cncs1
Reactant: CNCCN
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CC(C)O
Product: CN(CCN)c1cncs1
Yield: 6.7 %

Procedure:
37 mg (0.6 mmol) copper and 172 mg (1.7 mmol) copper(I) chloride were added to a solution of 1.15 ml (10.5 mmol) 5-bromothiazol and 5.6 ml (63.0 mmol) N-methyl-ethylene-diamine in isopropanol (6 ml). Heating was subsequently performed for 1 h to 70° C. Concentration was subsequently performed in a vacuum. The residue was received with brine (40 ml) and DCM (20 ml) and the phases were separated. The organic phase was dried over MgSO4, filtered and concentrated in a vacuum. CC (DCE/EtOH/conc. NH4OH 5:1:0.06) was performed with the residue, whereby 104 mg (0.7 mmol, 6%) N1-methyl-N1-(thiazol-5-yl)ethane-1,2-diamine was obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=S)[N:6]([CH2:13][CH2:14][CH3:15])[C:5]2=[O:16].C(Cl)([Cl:19])=O>C1(C)C(C)=CC=CC=1>[Cl:19][C:7]1[N:6]([CH2:13][CH2:14][CH3:15])[C:5](=[O:16])[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([I:1])[CH:3]=2)[N:8]=1
Reactant: O=C(Cl)Cl
Reactant: CCCn1c(=S)[nH]c2ccc(I)cc2c1=O
Solvent: Cc1ccccc1C
Product: CCCn1c(Cl)nc2ccc(I)cc2c1=O
Temperature: 87.5 °C

Procedure:
2,3-Dihydro-6-iodo-3-propyl-2-thioxo4(1H)-quinazolinone (50 g, 0.144 mol) was slurried in xylene (283 g) and heated to 85-90° C. Phosgene (12.0 mL, 0.159 mol) was added. Heating was continued until the thioquinazolinedione was consumed by thin layer chromatography analysis (340 minutes). The excess phosgene was removed by codistillation with xylene at atmospheric pressure. The distillation was ceased when the distillate weight reached 37.9 g. The solution was cooled to room temperature and used directly in Step 3.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>CS(C)=O>[CH2:5]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N+:18]([O-:20])=[O:19])=[CH:12][CH:11]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCCCOc1ccc(CC[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.2 %

Procedure:
To an acetic acid (4.4 mL) and dimethyl sulfoxide (75 mL) solution of 1-butoxy-4-((E)-2-nitro-vinyl)-benzene (4.44 g, 20.1 mmol) described in Manufacturing Example 67-1-2 was added sodium borohydride (1.22 g, 32.2 mmol) at room temperature while cooling appropriately. This mixture was stirred for 4 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (3.42 g, 76%).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1>CC#N>[Br:8][C:6]1[N:7]=[C:2]([NH:17][CH2:16][CH:13]2[CH2:14][CH2:15][O:10][CH2:11][CH2:12]2)[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: Nc1ncc(Br)nc1Br
Solvent: CC#N
Product: Nc1ncc(Br)nc1NCC1CCOCC1
Temperature: 80 °C
Yield: 61.8 %

Procedure:
To a scintillation vial containing 3,5-dibromopyrazin-2-amine (500 mg, 1.977 mmol) and TEA (0.551 ml, 3.95 mmol) was added MeCN (6 ml) and (tetrahydro-2H-pyran-4-yl)methanamine (300 mg, 1.977 mmol). The homogenous reaction mixture was capped and heated to 80° C. in a oil bath for 36 hr. The reaction mixture was concentrated to dryness, diluted with EtOAc and washed with sat NaHCO3, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (30% EtOAc/Hexane) to yield 6-bromo-N2-((tetrahydro-2H-pyran-4-yl)methyl)pyrazine-2,3-diamine (351 mg, 1.222 mmol, 61.8% yield).
Reaction SMILES: C([N:8]1[CH2:17][C:16]2[NH:15][C:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]=3[CH:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[C:24]([Br:29])[CH:23]=3)[C:11]=2[C:10](=[O:30])[CH2:9]1)C1C=CC=CC=1.Cl[C:32]([O:34][CH:35]1[CH:40]([C:41]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)([CH3:43])[CH3:42])[CH2:39][CH2:38][CH:37]([CH3:50])[CH2:36]1)=[O:33].C1(C(C)(C)C2CCC(C)CC2O)C=CC=CC=1>C1COCC1>[Br:29][C:24]1[CH:23]=[C:22]([CH:12]2[C:11]3[C:10](=[O:30])[CH2:9][N:8]([C:32]([O:34][C@@H:35]4[CH2:36][C@H:37]([CH3:50])[CH2:38][CH2:39][C@H:40]4[C:41]([CH3:42])([C:44]4[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=4)[CH3:43])=[O:33])[CH2:17][C:16]=3[NH:15][C:14]3[CH2:18][CH2:19][C:20](=[O:21])[C:13]2=3)[CH:27]=[CH:26][C:25]=1[F:28]
Reactant: O=C1CCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CN(Cc3ccccc3)CC1=O)N2
Reactant: CC1CCC(C(C)(C)c2ccccc2)C(OC(=O)Cl)C1
Agent: CC1CCC(C(C)(C)c2ccccc2)C(O)C1
Solvent: C1CCOC1
Product: C[C@@H]1CC[C@@H](C(C)(C)c2ccccc2)[C@H](OC(=O)N2CC(=O)C3=C(C2)NC2=C(C(=O)CC2)C3c2ccc(F)c(Br)c2)C1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of the product from Example 5A (1.9 g, 4.0 mmol) in THF (30 mL) was treated with 8-phenylmenthol chloroformate prepared from (−)-8-phenylmenthol as described in (Yamamoto, Y., J. Amer. Chem. Soc. (1992), 114, 121-125) (1.45 g, 4.92 mmol) in THF (10 mL), stirred for 3 days at ambient temperature and partitioned between aqueous sodium bicarbonate and methylene chloride. The organic layer as separated, dried with sodium sulfate, filtered and concentrated to provide a mixture of diasteromeric carbamates. The diastereomeric mixture was subjected to column chromatography over silica gel (20% hexanes/ethyl acetate) to provide the title compound (0.32 g) as the less polar diastereomer and mixed fractions containing both diastereomers (0.9 g).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:38](=[O:39])[C:37]3[CH:36]=[CH:35][C:34]([N:31]4[CH2:30][CH2:29][N:28]([CH3:27])[CH2:33][CH2:32]4)=[CH:42][CH:41]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: CN1CCN(c2ccc(C(=O)O)cc2)CC1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: CN1CCN(c2ccc(C(=O)N[C@H]3CC[C@H](CCN4CCCCC4c4coc5cccc-5c4)CC3)cc2)CC1

Procedure:
The title compound, off-white solid (56 mg, 42%), MS (ISP) m/z=529.4 [(M+H)+], mp 242° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-(4-methyl-piperazin-1-yl)-benzoic acid.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=O)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]#[N:22])=[CH:16][CH:15]=1.[O-]CC.[ClH:26]>O.C(O)C>[ClH:26].[C:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][CH:16]=1)=[C:2]([C:3]1[CH:4]=[CH:5][N:6]=[CH:7][CH:8]=1)[OH:10])#[N:22]
Reactant: N#CCc1ccc(F)cc1
Reactant: CCOC(=O)c1ccncc1
Agent: CC[O-]
Agent: Cl
Agent: [Na]
Solvent: CCO
Solvent: O
Product: N#CC(=C(O)c1ccncc1)c1ccc(F)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
17.3 g (0.75 mol) of metallic sodium were treated dropwise with 250 ml of absolute ethanol. 75.8 g (0.5 mol) of ethyl isonicotinate and 67.6 g (0.5 mol) of 4-fluorophenylacetonitrile were added to the ethoxide. The reaction mixture was stirred at 100° C. for 15 min. The mixture was then cooled in an ice bath and treated with 600 ml of dist. water. On acidifying to pH 1 using 90 ml of conc. HCl, the title compound deposited as a yellow precipitate. The precipitate was filtered off, washed with dist. water and dried over P2O5 in vacuo. Yield: 85.0 g (62%).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)([CH2:9][CH2:10][C:11]([OH:13])=[O:12])[CH2:4][CH2:5][C:6]([OH:8])=O)#[N:2].Cl[C:25]1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:11]([CH:10]1[CH2:9][C:3]([C:1]#[N:2])([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH2:4][CH2:5][C:6]1=[O:8])([O:13][CH3:25])=[O:12]
Reactant: COc1ccc(C(C#N)(CCC(=O)O)CCC(=O)O)cc1OC
Reactant: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccc(OC)c(OC)c2)CCC1=O
Yield: 94 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 34.25 gm. (0.098 mole) of the dimethyl ester of 4-cyano-4-(3.4-dimethoxyphenyl)pimelic acid (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid and using 640 ml. of the tetrahydrofuran, 22.0 gm. (0.196 mole) of the potassium tert-butoxide and 155 ml. of the 2.5 N of the aqueous acetic acid instead of the 700 ml. the 24.4 gm. (0.218 mole), and the 175 ml. respectively, there is prepared 29.2 gm. (94% yield) of 2-carbomethoxy-4-cyano-4-(3,4-dimethoxyphenyl)cyclohexanone as crystals having a melting range of 110° to 113° C. An analytical sample recrystallized from a mixture of ethyl acetate and cyclohexane melts in the range of 112.5° to 114.5° C.
Reaction SMILES: FC(F)(F)C([O-])=O.C([NH:10][C@@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:29]([OH:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:24]([C:26](=[O:28])[NH2:27])[CH3:25])([CH3:23])[CH3:22])[CH2:16][S:17][C@H:12]12)=O.C(#N)C.[ClH:37].CO>>[ClH:37].[NH2:10][C@@H:11]1[C:32](=[O:33])[N:13]2[C:14]([C:29]([O-:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([C@@H:24]([C:26](=[O:28])[NH2:27])[CH3:25])([CH3:23])[CH3:22])[CH2:16][S:17][C@H:12]12
Reactant: C[C@H](C(N)=O)[N+](C)(C)C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: CO
Solvent: CC#N
Product: C[C@H](C(N)=O)[N+](C)(C)C/C=C/C1=C(C(=O)[O-])N2C(=O)[C@@H](N)[C@H]2SC1
Reaction time: 1 h

Procedure:
The compound (0.5 g) of Example 23 was dissolved at room temperature in a 4% (w/v) hydrochloric acid-methanol solution (5 ml), followed by stirring for 1 hour. Acetonitrile (50 ml) was added, and a precipitate thus formed was collected by filtration. The precipitate was washed with acetonitrile and acetone to obtain the target product (0.31 g). Infrared spectrum (cm-1, Nujol): 1780, 1690.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([C:15]([NH2:17])=[O:16])[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[H][H].[C:22]([OH:25])(=[O:24])[CH3:23]>[Pd]>[C:22]([OH:25])(=[O:24])[CH3:23].[F:18][C:2]([F:1])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([NH2:17])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: NC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
Palladium on activated carbon (moistened with about 50% water, 0.3 g/mmol) was added to a solution of 500 mg (1.88 mmol) of 5-[4-(trifluoromethyl)phenyl]pyridine-3-carboxamide (Example 50A) in 60 ml of acetic acid, and the mixture was hydrogenated in a 60 bar hydrogen atmosphere at 85° C. overnight. The catalyst was then filtered off through a filter layer and washed repeatedly with ethanol. The combined filtrates were concentrated under reduced pressure. This gave 0.61 g (98% of theory) of the target compound, which was reacted without any further purification steps.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([N:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH:18][CH2:17][CH:16]([N:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[N:21][CH2:20]1)[CH2:15][CH:12]1[CH2:14][CH2:13]1)=[O:6]
Reactant: NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1
Reactant: O=C(O)c1c(F)cccc1Cl
Product: O=C(NCC(CC1CC1)N1C=CC(C(F)(F)F)=NC1)c1c(F)cccc1Cl

Procedure:
From 2-chloro-6-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyrimidin-3-yl)propan-1-amine. LCMS (MH+): m/z=402.1, tR (minutes, Method D)=0.77
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH:24]1[C:28]([C:29]([OH:31])=[O:30])=[CH:27][C:26]([C:32](O)=[O:33])=[N:25]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[Cl:23][C:19]1[CH:18]=[C:17]([C:14]2[CH:15]=[CH:16][C:11]([CH2:10][C@@H:3]([NH:2][C:32]([C:26]3[NH:25][N:24]=[C:28]([C:29]([OH:31])=[O:30])[CH:27]=3)=[O:33])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Reactant: O=C(O)c1cc(C(=O)O)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1cc(C(=O)O)n[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of Intermediate 8-1 (130 mg, 0.367 mmol), 1H-pyrazole-3,5-dicarboxylic acid (74.5 mg, 0.477 mmol), EDCl (91 mg, 0.477 mmol) and HOBt (64.5 mg, 0.477 mmol) in DMF (3 mL) is added triethylamine (149 mg, 0.203 mmol) and the mixture is stirred at room temperature for 18 hours. Any insoluble material is removed by filtration and the filtrate is chromatographed by HPLC using a gradient of 10% MeCN/water to 100% MeCN (+0.1% TFA). Lyophilization of the proper fractions gives the title compound; HPLC Retention time 1.31 minutes (condition C); MS 456.2 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.07 Hz, 3H), 2.54-2.67 (m, 2H), 2.84-2.97 (m, 2H), 4.02 (q, J=7.07 Hz, 2H), 4.54 (m, 1H), 7.11 (s, broad, 1H), 7.32 (d, J=8.08 Hz, 2H), 7.39 (m, 1H), 7.46 (t, 1H), 7.62 (d, J=8.08 Hz, 3H), 7.69 (s, 1H), 8.41 (s, broad, 1H).
Reaction SMILES: [Cl:1][C:2]1[NH:10][CH:9]=[N:8][C:7]2[C:3]=1[N:4]=[CH:5][N:6]=2.O[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21].C(N(CC)C(Cl)=O)C>CC#N>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:12][N:13]1[CH2:17][CH:16]([CH2:18][CH2:19][CH3:20])[CH2:15][C:14]1=[O:21]
Reactant: CCCC1CC(=O)N(CO)C1
Reactant: Clc1[nH]cnc2ncnc1-2
Agent: CCN(CC)C(=O)Cl
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2cnc3c(Cl)ncnc32)C1
Temperature: 100 °C
Yield: 99 %

Procedure:
A mixture of 6-chloro-1H-purine x165 (2 g, 12.93 mmol, 1 eq), 1-(hydroxymethyl)-4-propylpyrrolidin-2-one x2 (2.44 g, 15.53 mmol, 1.2 eq) and N,N-diethylcarbamoylchloride (332 mg, 1.293 mmol, 0.1 eq) in MeCN (30 ml) is heated at 100° C. in microwave apparatus during 5 hours. After cooling, the solvent is evaporated and the crude is purified on silicagel (CH2Cl2/MeOH (+NH4OH 10%) 95/5) to yield 3.8 g of 1-[(6-chloro-9H-purin-9-yl)methyl]-4-propylpyrrolidin-2-one x166 as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20]Br>C(C(C)=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:20][CH2:19][Br:18])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: BrCCBr
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCCBr
Temperature: 80 °C
Yield: 53.9 %

Procedure:
To a stirred solution of 5′-bromo-2′-hydroxyacetophenone (10 g, 46.5 mmol) in methyl ethyl ketone (100 mL) was added K2CO3 (13.5 g, 97.7 mmol) followed by 1,2-dibromoethane (20 mL, 232.5 mmol). The reaction mixture was heated at a mild reflux temperature (ca. 80° C.) for 16 h at which point the reaction flask was cooled to room temperature. The resultant solids were filtered off and the solvent removed by rotary evaporation under reduced pressure. The residue was dissolved in Et2O/EtOAc (4:1, 500 mL) and the precipitated solid (the alkylation dimer) was removed by filtration. The filtrate was washed with 2 N NaOH (100 mL) and the organic portion was dried over Na2SO4 and concentrated in vacuo to give crude 1-(5-bromo-2-(2-bromoethoxy)phenyl)ethanone (8.07 g, 55%)