Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20]C)=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.Br>C(O)(=O)C>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Agent: Br
Solvent: CC(=O)O
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Temperature: 10 °C
Reaction time: 0.15 h

Procedure:
Thebaine (2.0 g) was dissolved in warm glacial acetic acid (10 ml) then chilled in an ice/water bath. A 45% w/v solution of anhydrous hydrogen bromide in glacial acetic acid (6 ml, 2.7 g HBr) was added dropwise with stirring over 9 minutes. Stirring was continued for 20 minutes during which time a fine precipitate separated. Methanol (75 ml) was added to a solution of sodium hydroxide (12.72 g) in water (75 ml). This solution was chilled (10° C.) and sodium borohydride (247 mg) added. The above slurry of 8-bromodihydrocodeinone hydrobromide in acetic acid was added portionwise to the sodium hydroxide-sodium borohydride mixture with vigorous stirring over 34 minutes keeping the temperature below 10° C. by means of an ice bath. After the addition, the mixture was allowed to stir for 30 minutes. Chloroform (50 ml) was added, the mixture stirred vigorously, allowed to settle and the layers separated. The aqueous phase was extracted with fresh chloroform (2 × 20 ml). The combined chloroform extracts were washed with brine (3 × 50 ml), dried (Na2SO4) and evaporated under reduced pressure. Final traces of solvent were removed under high vacuum. The fluffy off-white solid (1.85 g) displayed one major spot on TLC and one major peak on GLC, both of which corresponded to codeine. Codeinone was absent, and only minor amounts of other alkaloidal substances were present.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.O>CN(C)C=O.C(O)(=O)C>[C:20]1([S:26]([NH:2][CH:3]2[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=3)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NC1c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2c(n3ccnc13)C(NS(=O)(=O)c1ccccc1)c1ccccc1-2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 30.6 %

Procedure:
To a suspension of 0.6 g of 10-amino-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 30 ml of anhydrous dimethylformamide, maintained under a nitrogen atmosphere at a temperature in the region of -10° C., are successively added 0.29 g of benzenesulphonyl chloride and a solution of 0.4 g of triethylamine in 2 ml of anhydrous dimethylformamide and the mixture is stirred for 1 hour 30 minutes at the same temperature. 0.29 g of benzenesulphonyl chloride is added and the mixture is stirred for 2 hours 30 minutes, while allowing the temperature to rise gradually to 10° C. The insoluble material formed is removed by filtration and the filtrate is concentrated to dryness under reduced pressure (10 mmHg; 1.3 kPa) at 100° C. The product obtained (1.72 g) is dissolved in 6 ml of acetic acid at 40° C. and, after addition of 40 ml of distilled water, the solution is stirred for 1 hour. The insoluble material formed is separated out by filtration, washed twice with 4 ml in total of distilled water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.19 g of 10-benzenesulphonamido-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one is thus obtained, melting at 216° C. [N.M.R. spectrum: [300 MHz; (CD3)2SO d6 ; δ in ppm]: 5.71 (d, J=8.5 Hz, 1H: --CH-- 10); 6.34 and 7.77 (2d broad, J=8 Hz, 1H each: --H6 and --H9); 7.08 and 7.36 (2t broad, J=8 Hz, 1H each: --H7 and --H8); 7.56 and 7.74 (2s, 1H each: --H of the imidazole); 7.68 (t, J=7.5 Hz, 2H: --H at 3 and --H at 5 of the phenylsulphonyl); 7.78 (t, J=7.5 Hz, 1H: --H at 4 of the phenylsulphonyl); 7.95 (d, J=7.5 Hz, 2H: --H at 2 and --H at 6 of the phenylsulphonyl); 8.62 (d, J=8.5 Hz, 1H: --NHCO-- at 10); 12.46 (broad s, 1H: --CONH-- of the ring)].
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:22]2[CH2:31][CH2:30][C:25]3([O:29][CH2:28][CH2:27][O:26]3)[CH2:24][CH2:23]2)(=O)=O)=CC=1>CN(C=O)C>[O:26]1[C:25]2([CH2:30][CH2:31][CH:22]([N:3]3[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]3)[CH2:23][CH2:24]2)[O:29][CH2:28][CH2:27]1
Reactant: Cc1n[nH]c(C)c1I
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C2CCC3(CC2)OCCO3)c(C)c1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,5-dimethyl-4-iodopyrazole (400.0 mg, 1.802 mmol) in DMF (7 mL, 100 mmol) was added sodium hydride (56.20 mg, 2.342 mmol), and the mixture was stirred at rt for 10 min. A solution of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (619.1 mg, 1.982 mmol), prepared according to U.S. Pat. No. 4,360,531 example 1.B, in DMF was added, and the mixture was heated to 50° C. overnight. The material was extracted with EtOAc, and washed with water (3×). The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 20-30% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ=1.61-1.80 (m, 6H), 1.94-2.06 (m, 2H), 2.08 (s, 3H), 2.25 (s, 3H), 3.82-3.93 (m, 4H), 4.23 (tt, J=11.5, 3.7 Hz, 1H). MS (ES+): m/z=364.07 (100) [MH+]. HPLC: tR=1.51 min (polar—3 min, UPLC-ACQUITY).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>CC(O)=O.CCO.[Fe]>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][C:10]=1[NH2:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1OCc1ccccc1
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 2-benzyloxy-1-nitro-4-trifluoromethylbenzene (1.0 g. 3.4 mmol) in 16 mL HOAc/EtOH (1:3) is added iron powder and the mixture is refluxed for 2 h. The mixture is cooled to RT and water is added and it is extracted with EtOAc. The organic phase is dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound as a reddish oil.
Reaction SMILES: [C:1]12([CH2:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Cl.C(Cl)[Cl:20]>CO.O=[Pt]=O>[ClH:20].[C:1]12([CH2:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: c1cc(CC23CC4CC(CC(C4)C2)C3)ccn1
Reactant: ClCCl
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: C1CC(CC23CC4CC(CC(C4)C2)C3)CCN1
Reaction time: 24 h
Yield: 62 %

Procedure:
A mixture of 4-(1-adamantylmethyl)pyridine (500 mg, 2.20 mmol) and PtO2 (15 mg) in MeOH (20 mL) containing concd HCl (1 mL) was allowed to shake under H2 (25-30 psi) for 24 h. NMR analysis showed only about 45% reaction. An additional portion of catalyst was added and the reaction was allowed to proceed as above for an additional 24 h. The analysis now showed about 70% reaction. The reaction was allowed to proceed at 50 psi for a final 24 h (72 h total). A crystalline solid was observed in the reaction mixture. The addition of CH2Cl2 and warming dissolved this material. The analysis now showed ˜95% reaction. The catalyst was removed by filtration (Celite) and the solvent was removed to give a yellow solid. The solid was dissolved in boiling MeOH (12 mL) and the solution was hot filtered. The filtrate was concd to 8 mL and was cooled in an ice bath to give a suspension. The solid was collected, was washed with ice cold MeOH (3×1 mL) and was dried in vacuo (100° C., 0.005 Torr) to give the title compound as a pale yellow crystalline solid (365 mg, 62%): mp >300° C.; 1H NMR (DMSO-d6) 0.95 (d, J =4.5, 2H), 1.22-1.78 (m, 17H), 1.90 (s, 3H), 2.81 (dd, J=22 and 11, 2H), 3.13 (d, J=12, 2H), 8.68 (bs, 1H), 8.89 (bs, 1H).
Reaction SMILES: OC(C[PH:11]([CH2:13][S:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1)=[O:12])(CC(C)C)C(O)=O.C(N1C=CN=C1)(N1C=CN=C1)=[O:26].O=C1CCC2=CN(C3C=CC=CC=32)CCCCCCN1>C1COCC1>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[S:14][CH2:13][PH:11](=[O:12])[OH:26]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)CC(O)(C[PH](=O)CSc1ccc2ccccc2n1)C(=O)O
Agent: O=C1CCc2cn(c3ccccc23)CCCCCCN1
Solvent: C1CCOC1
Product: O=[PH](O)CSc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A single stereoisomer of 2-(hydroxy) (quinolin-2-ylthiomethyl)phosphinoylmethyl-4-methylpentanoic acid (300 mg, 0.81 mmol) and 1,1'-carbonyldiimidazole (174 mg, 1.0 mmol) were stirred at 0° C. in 6 mL THF for 11/2 hours. (10S)-10-Amino-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19),13(18),14,16-tetraene (270 mg, 0.95 mmol) was added to the solution and the resulting mixture was allowed to warm to room temperature and then stirred for 18 hours. The THF was removed by evaporation and the residue dissolved in 60 mL ethyl acetate. The ethyl acetate was washed with 10 mL H2O, 10 mL brine, dried with MgSO4 and evaporated to yield (10S)-[4-methyl-2-(9-oxo-1,8-diazatricyclo[10.6.1.013,18 ]nonadeca-12(19) 13(18)14,16-tetraen-10-ylcarbamoyl)pentyl](quinolin-2-ylthiomethyl)phosphinic acid as a yellow oil. Purification was carried out by reverse phase HPLC using a gradient of acetonitrile and 50 mm NH4OAc buffer as the eluents. The more polar stereoisomer was isolated (30 mg) at 41% acetonitrile, and the less polar stereoisomer (10 mg) at 43% acetonitrile. The fractions were lyophilized to off-white powders, MS: 635 (MH+).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:19]=[CH:18][C:9]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[O:20]1[CH:22]([CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:21]1.[OH:31][P:32]([OH:35])([OH:34])=[O:33]>CO.C(O)C>[P:32](=[O:31])([OH:35])([OH:34])[OH:33].[OH:20][CH:22]([CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:21][N:15]1[CH2:16][CH2:17][N:12]([C:10](=[O:11])[C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:19][CH:18]=2)[CH2:13][CH2:14]1
Reactant: CS(=O)(=O)Nc1ccc(C(=O)N2CCNCC2)cc1
Reactant: c1ccc(OCC2CO2)cc1
Agent: O=P(O)(O)O
Solvent: CCO
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)N2CCN(CC(O)COc3ccccc3)CC2)cc1

Procedure:
To a solution of 13.31 g (47 mmol) 1-[4-[(methylsulfonyl)amino]benzoyl]piperazine in 50 mL methanol add 6.4 mL (47 mmol) 1,2-epoxy-3-phenoxypropane. Stir the reaction mixture at roomtemperature under a nitrogen atmosphere. Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride: MeOH, 9:1). When the reaction is complete, remove the solvents in vacuo toobtain an oil. Dissolve the oil in ethanol with one equivalent of H3PO4 and remove the solvents to obtain the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:13][C@H:14]([C:16]([OH:18])=O)[CH3:15])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH2:25])[CH3:21]>C(Cl)(Cl)Cl.CO>[CH2:20]([O:22][C:23](=[O:29])[C@H:24]([CH:26]([CH3:28])[CH3:27])[NH:25][C:16](=[O:18])[C@H:14]([CH3:15])[NH:13][C:11](=[O:12])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH3:21]
Reactant: CCOC(=O)[C@@H](N)C(C)C
Reactant: C[C@H](NC(=O)Cc1cccc([N+](=O)[O-])c1)C(=O)O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1)C(C)C

Procedure:
Following General Procedure C and using N-(3-nitrophenylacetyl)-L-alanine (from Example Dli above) and L-valine ethyl ester hydrochloride (Aldrich), the title compound was prepared as a solid. The reaction was monitored by tlc (Rf=0.2 in 97:3 CHCl3/MeOH) and the product was purified by silica gel chromatography using 97:3 CHCl3/MeOH as the eluent.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[CH2:10]([O:12][C:13](=[O:17])[C:14]#[C:15][CH3:16])[CH3:11].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[C:15](/[O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[F:9])\[CH3:16])[CH3:11]
Reactant: Oc1cccc(Br)c1F
Reactant: CC#CC(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1cccc(Br)c1F
Yield: 69.5 %

Procedure:
To a stirred mixture of 3-bromo-2-fluoro-phenol (19.5 g, 0.102 mol) and ethyl-2-butynoate (22.0 g, 0.196 mol) in tetrahydrofuran (100 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (15.6 g, 0.102 mol) slowly. After addition was complete the mixture was stirred at reflux for overnight. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The mixture was filtered and evaporated, and the residue dried under high vacuum which afforded (E)-3-(3-bromo-2-fluoro-phenoxy)-but-2-enoic acid ethyl ester as a brown oil (21.5 g, 69%) and used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:18]([O:26][C:27](ON1C(=O)CCC1=O)=[O:28])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C.C(=O)([O-])[O-].[K+].[K+]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:15]([OH:17])=[O:16])[NH:14][C:27]([O:26][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)O
Reactant: O=C(OCCc1ccccc1)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 111.1 %

Procedure:
N,N'-disuccininyl carbonate (5.12 g), 2.44 g of phenethyl alcohol and 0.49 g of 4-dimethylaminopyridine were stirred in methylene choride for 3 days. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The residue was crystallized from ether. The crystals were collected by filtration to give 3.5 g of N-(phenethyloxycarbonyloxy)succinimide (mp. 69°-72° C.). N6 -t-butoxycarbonyl-L-lysine (2.53 g) was dissolved in a mixture of 30 ml of acetonitrile and 50 ml of 5% potassium carbonate, and 2.9 g of N-(phenethyloxycarbonyloxy)succinimide was added. The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed with chloroform. The aqueous layer was acidified with 10% citric acid, and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure to give 4.5 g of N6 -t-butoxycarbonyl-N2 -phenethyloxycarbonyl-L-lysine as an oily substance. An aliquot (1.26 g) of the oily substance and N,N'-disuccinimidyl carbonate were stirred in ethyl acetate for 3 hours, and then an ethyl acetate solution containing 1.0 g of (2S,3aS,7aS)-1-(gamma-D-glutamyl)octahydro-1H-indole-2-carboxylic acid and 0.256 g of pyridine was added, and the mixture was further stirred for 5 hours. The reaction mixture was extracted with 5% sodium bicarbonate solution. The extract was acidified with 10% citric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was dissolved in 20 ml of trifluoroacetic acid, left to stand at room temperature for 20 minutes, and thereafter concentrated to dryness under reduced pressure. The residue was subjected to CHP20P column chromatography (0%→60% acetonitrile/water gradient). Fractions containing the desired product were concentrated to dryness under reduced pressure. The residue dissolved in dioxane/water, and lyophilized to give 0.3 g of the captioned compound.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:21])[CH3:20])#[CH:11]>>[C:19]([N:18]1[C:13]2[C:12](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=[C:11]1[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)(=[O:21])[CH3:20]
Reactant: C#Cc1ccccc1NC(C)=O
Reactant: N#Cc1ccc(I)cc1
Product: CC(=O)n1c(-c2ccc(C#N)cc2)cc2ccccc21
Yield: 36 %

Procedure:
The general procedure was used to convert 4-iodobenzonitrile and N-(2-ethynylphenyl)acetamide to the title product. Purification by flash chromatography gave the analytically pure product as a white solid, 36% yield. 1H NMR (300 MHz, DMSO) δ 8.16-8.13 (d, J=8.4, 1H), 7.95-7.92 (d, J=8.6, 2H), 7.76-7.73 (d, J=8.4, 2H), 7.67-7.65 (d, J=7.7, 1H), 7.42-7.36 (dt, J=7.3, 1.5, 1H), 7.33-7.28 (dt, J=7.7, 1.1, 1H) 6.94 (s, 1H), 2.28 (s, 3H). 13C NMR (75 MHz, DMSO) δ 171.42, 139.15, 139.09, 137.98, 133.23, 130.31, 129.57, 126.25, 124.40, 121.99, 119.54, 116.08, 113.63, 111.49, 28.56. Anal. Calcd. for C17H12N2O: C, 78.44; H, 4.65; N, 10.76. Found C, 78.19; H, 4.63; N, 10.68. m.p.: 158-160° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1.[CH2:22]([NH2:25])[CH2:23][CH3:24]>CCO>[CH2:22]([NH:25][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:11][C:12]1[CH:21]=[CH:20][C:17]([O:18][CH3:19])=[C:14]([O:15][CH3:16])[CH:13]=1)[CH2:23][CH3:24]
Reactant: CCCN
Reactant: COc1ccc(Cn2cnc3c(Cl)ncnc32)cc1OC
Solvent: CCO
Product: CCCNc1ncnc2c1ncn2Cc1ccc(OC)c(OC)c1

Procedure:
A reaction mixture containing 5.14 g (16.8 mmol) of 6-chloro-9-veratrylpurine, 7.0 ml (84.9 mmol) of propylamine and 60 ml of EtOH was refluxed for 2.5 hrs. Evaporation of the reaction mixture gave a residual solid which was recrystallized from acetone to give the crude product; yield 4.78 g (87.0%) mp 117°-120°. Further recrystallizations of the crude white material from acetone gave the analytical material; mp 122°-125°.
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:15][C:16]([C@@H:18]1[CH2:22][C@H:21]([SH:23])[CH2:20][N:19]1[S:24]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=1)(=[O:26])=[O:25])=[O:17])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1.[Li+].[OH-].C(S)[C@@H](O)[C@H](O)CS>C1COCC1>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][C@H:4]([NH:15][C:16]([C@@H:18]2[CH2:22][C@H:21]([SH:23])[CH2:20][N:19]2[S:24]([C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)(=[O:26])=[O:25])=[O:17])[C:3]([OH:37])=[O:2])=[CH:7]1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1C[C@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Agent: O[C@H](CS)[C@H](O)CS
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1C[C@H](S)CN1S(=O)(=O)c1ccc2ccccc2c1
Yield: 8.7 %

Procedure:
243 mg (4.5 mmol) (S)-3-(1H-Indol-3-yl)-2-[[(2S,4S)-4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-amino]-propionic acid methyl ester in 13.5 ml THF were treated 22.5 ml 0.1M LiOH in the presence of 209 mg (13.5 mmol) DTT at RT for 72h. The solution was acidified with 1MKHSO4KHS04 and the inorganic phase was extracted with EtOAc. The combined organic phases were washed with brine and were dried with Na2SO4. Column chromatography with CH2Cl2:MeOH 9:1, followed by trituration with hexane yielded 204 mg (86%) (S)-3-(1H-Indol-3-yl)-2-[[(2S,4S)-4-mercapto-1-(naphthalene-2-sulfonyl)-pyrrolidine-2-carbonyl]-amino]-propionic acid as white solid, mp 130° C., MS: 522 (M-H)−.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7](O)([CH3:9])[CH3:8])=[CH:5][CH:4]=1.[ClH:15]>[Cl-].[Zn+2].[Cl-]>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:12]=[CH:11][C:6]([C:7]([Cl:15])([CH3:9])[CH3:8])=[CH:5][CH:4]=1
Reactant: CC(C)(O)c1ccc(C(F)(F)F)cc1
Reactant: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)(Cl)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
The alcohol from step A above (54 g, 0.27 mol) is treated with ethereal HCl (1.3 L, 1M) followed by anhydrous zinc chloride (53 mL, 1M in ether) and the reaction allowed to stir for 22 h at room temperature. The reaction is then washed with water, aqueous 2 N NaOH, dried over MgSO4, concentrated and purified by silica gel chromatography (8:1 hexane to ethyl acetate) to give 4-trifluoromethyl-α,α-dimethylbenzyl chloride of sufficient purity to carry to the next step; yield: 50.5 g (85%).
Reaction SMILES: Cl.[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:41][C:42](O)=[O:43])[CH2:37][CH2:36]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].[NH2:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51]>>[C:2]([C:6]1[N:11]=[CH:10][C:9]([C:12]2[N:13]([C:33]([N:35]3[CH2:36][CH2:37][N:38]([CH2:41][C:42]([NH:48][C:49]([CH3:53])([CH3:52])[CH2:50][OH:51])=[O:43])[CH2:39][CH2:40]3)=[O:34])[C@@:14]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)([CH3:25])[C@@:15]([C:18]3[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=3)([CH3:17])[N:16]=2)=[C:8]([O:45][CH2:46][CH3:47])[CH:7]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(N)CO
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)O)CC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)NC(C)(C)CO)CC1

Procedure:
In a manner analogous to the method described in examples 99, {4-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-acetic acid hydrochloride (example 94) was coupled with 2-amino-2-methyl-propan-1-ol (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C39H51Cl2N6O4 [(M+H)+] 737.3344, observed 737.3342.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C:8]2[N:13]=[C:12](I)[C:11]3[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:10]=3[N:9]=2)[CH:7]=1.[CH3:21][O:22][C:23](=[O:31])[C:24]1[C:29]([NH2:30])=[CH:28][CH:27]=[N:26][CH:25]=1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:21][O:22][C:23](=[O:31])[C:24]1[C:29]([NH:30][C:12]2[C:11]3[CH2:15][C:16]([CH3:19])([CH3:18])[CH2:17][C:10]=3[N:9]=[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[F:20])[N:13]=2)=[CH:28][CH:27]=[N:26][CH:25]=1
Reactant: COC(=O)c1cnccc1N
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(I)c2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1CC(C)(C)C2
Temperature: 85 °C
Yield: 33.6 %

Procedure:
To a solution of 2-(5-Chloro-2-fluoro-phenyl)-4-iodo-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidine (500 mg, 1.24 mmol), 4-Amino-nicotinic acid methyl ester (208 mg, 1.37 mmol), Pd(OAc)2 (14 mg, 62.09 μmol) and Rac-BINAP (60 mg, 93.14 μmol) in dry dioxane (10 mL) was added Cs2CO3 (607 mg, 1.86 mmol). The mixture was heated for 12 h at 85° C., cooled and evaporated. The residue was purified by chromatography (CH2Cl2, 0-10% MeOH) to give the desired product (178 mg, 34% yield).