Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:5]=[C:4]([Cl:14])[N:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[C:37]([O:41][C:42](=[O:48])[NH:43][CH2:44][CH2:45][CH2:46][NH2:47])([CH3:40])([CH3:39])[CH3:38].C(N(C(C)C)CC)(C)C.Cl>CN(C)C=O>[C:37]([O:41][C:42](=[O:48])[NH:43][CH2:44][CH2:45][CH2:46][NH:47][C:11](=[O:13])[CH2:10][CH2:9][S:8][C:6]1[CH:5]=[C:4]([Cl:14])[N:3]=[C:2]([NH2:1])[N:7]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: Nc1nc(Cl)cc(SCCC(=O)O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCNC(=O)CCSc1cc(Cl)nc(N)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.4 %

Procedure:
3-(2-Amino-6-chloropyrimidin-4-ylsulfanyl)propionic acid (240 mg) obtained in Step 1 above and N-hydroxybenzotriazole (180 mg, 1.33 mmol) were placed in a reaction vessel, and then N,N-dimethylformamide (4.0 ml) was added thereto. 1-Ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (255 mg, 1.33 mmol), 3-aminopropylcarbamic acid tert-butyl ester (155 mg, 0.89 mmol), and diisopropylethylamine (0.79 ml, 4.52 mmol) were added to the solution. The resulting mixture was stirred at room temperature for 4 hours. The reaction was stopped with 1N hydrochloric acid, and the solution was extracted with ethyl acetate. The ethyl acetate solution was sequentially washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and a saturated aqueous sodium chloride solution. The washed ethyl acetate solution was dried over anhydrous sodium sulfate (10 g). After filtration, the filtrate was concentrated under reduced pressure to yield {3-[3-(2-amino-6-chloropyrimidin-4-ylsulfanyl)propionylamino]propyl}carbamic acid tert-butyl ester (175 mg).
Reaction SMILES: [Na].Br[CH:3]([CH2:13][C:14]([Cl:17])([Cl:16])[Cl:15])[C:4]([CH3:12])([CH3:11])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]>C(O)(C)(C)C.C1C=CC=CC=1>[Cl:15][C:14]([Cl:17])([Cl:16])[CH2:13][CH:3]1[C:4]([CH3:12])([CH3:11])[CH:5]1[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)CC(C)(C)C(Br)CC(Cl)(Cl)Cl
Agent: [Na]
Solvent: c1ccccc1
Solvent: CC(C)(C)O
Product: CCOC(=O)C1C(CC(Cl)(Cl)Cl)C1(C)C
Yield: 85.9 %

Procedure:
To a solution of 46 mg of sodium in a mixture of 12 ml of t-butanol and 6 ml of benzene was added, at room temperature, 709 mg of ethyl 4-bromo-6,6,6-trichloro-3,3-dimethylhexanoate. The mixture was treated as described in Example XII A to produce 470 mg (86% yield) of ethyl 2-(β,β,β-trichloroethyl)-3,3-dimethylcyclopropanecarboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].[OH-].[K+:33].C(OCC)(=O)C.Cl>O>[OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][N:26]=3)(=[O:23])=[O:22])=[CH:19][CH:20]=2)=[CH:9][C:3]=1[C:4]([O-:6])=[O:5].[K+:33]
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cccnc1NS(=O)(=O)c1ccc(C#Cc2ccc(O)c(C(=O)[O-])c2)cc1
Yield: 54.4 %

Procedure:
Ethyl 2-hydroxy-5-[[4-[(3-methyl-2-pyridinylamino)sulfonyl]phenyl]ethynyl]benzoate (15.5g, 35 mmol) was refluxed in potassium hydroxide (10 g, 0.15 mol) in water (100 ml) for I h. After cooling to ca 70° C., ethyl acetate (50 ml) was added and hydrochloric acid was added to reach pH 7-8. Cooling with sniffing and then filtration gave directly 8.5 g of the product (51%).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])[CH3:2].[CH:10]([C:12]([CH3:14])=O)=[CH2:11]>C(O)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:4]=1[N:5]=[CH:11][CH:10]=[C:12]2[CH3:14])[CH3:2]
Reactant: CCc1ccccc1N
Reactant: C=CC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)O
Product: CCc1cccc2c(C)ccnc12
Temperature: 70 °C
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirred solution of 2-ethylaniline (1 g. 8.2 mmol.) in acetic acid (10 ml), activated silferc (1.32 g. ferric chloride 8.2 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred for 5 minutes and methyl vinyl ketone (MVK) (0.63 g, 9 mmol) was added slowly over a period of 15 minutes. The reaction mixture was heated to 70° C. and maintained between 70-75° C. for one hour. Anhydrous zinc chloride (1.12 g. 8.2 mmol) was added and the reaction was further refluxed for two hours. The reaction mixture was cooled, filtered, basified with 10% NaOH solution, extracted with ethyl acetate (3×20 ml), dried over Na2SO4 and evaporated to give the product; Yield 60%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]2[CH2:23][C@@H:22]([C:24]3[CH:35]=[CH:34][C:27]4[O:28][C:29]([CH3:33])([CH3:32])[O:30][CH2:31][C:26]=4[CH:25]=3)[O:21][C:20]2=[O:36])[CH:5]=[CH:6][CH:7]=1.[N+:37]([C:40]1[CH:41]=[C:42]([CH:46]=[CH:47][CH:48]=1)[C:43](Cl)=[O:44])([O-:39])=[O:38].C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[CH3:33][C:29]1([CH3:32])[O:28][C:27]2[CH:34]=[CH:35][C:24]([C@H:22]3[O:21][C:20](=[O:36])[N:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][C:4]4[CH:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]5[CH:46]=[CH:47][CH:48]=[C:40]([N+:37]([O-:39])=[O:38])[CH:41]=5)[CH:7]=[CH:6][CH:5]=4)[CH2:23]3)=[CH:25][C:26]=2[CH2:31][O:30]1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)c5cccc([N+](=O)[O-])c5)c4)C(=O)O3)ccc2O1
Reaction time: 2.5 h
Yield: 73.8 %

Procedure:
A solution of (5R)-3-{6-[2-{[(3-aminophenyl)methyl]oxy}ethoxy]hexyl}-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (2.20 g) in pyridine (20 ml) under nitrogen was treated with 3-nitrobenzoyl chloride (819 mg) and the mixture was stirred at 20° for 2.5 h. Sat. sodium bicarbonate solution (100 ml) was added and the mixture was extracted with dichloromethane (2×50 ml). The combined extracts were dried (Na2SO4) and the solvent evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Elution with EtOAc-PE (2:1) gave the title compound (2.11 g). LCMS RT=3.71 min, ES+ve 648 (MH)+.
Reaction SMILES: [O:1]=[C:2]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=2)[CH:27]=1)[C@@H:3]([N:11]([CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H-].[Na+].[CH3:40]I.Cl>CN(C=O)C>[CH3:40][N:25]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=2)[CH:27]=1)[C:2](=[O:1])[C@@H:3]([NH:11][CH2:19][C:20]1[N:21]=[CH:22][S:23][CH:24]=1)[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C)OC(=O)N(Cc1cscn1)[C@@H](Cc1ccccc1)C(=O)Nc1cccc(-c2ccncc2)c1
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)[C@H](Cc1ccccc1)NCc1cscn1)c1cccc(-c2ccncc2)c1
Yield: 43.8 %

Procedure:
Amide 34.8.F (40 mg, 0.08 mmol) was dissolved in DMF, treated with NaH (3 mg, 0.08 mmol) and then MeI (5 μl, 0.08 mmol). The reaction mixture was partitioned with H2O/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated. The residue was purified on a prepHPLC (C18, ACN:H2O:0.1% TFA, gradient). The desired fractions were combined and partitioned with NaHCO3 (sat)/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 22 mg. The residue was treated with HCl (4.0 M, dioxane) and concentrated to dryness. The solid was partitioned with NaHCO3 (sat)/EtOAc. The organic layer was dried with sodium sulfate, filtered, and concentrated to yield 34.8 (15 mg). LC-MS (+esi, M+H+=429.1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([SH:8])[CH:3]=1.Cl[CH2:10][CH2:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:14].C(N(CC)CC)C>O1CCCC1>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13](=[O:14])[CH2:12][CH2:11][CH2:10][S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:20][CH:19]=1
Reactant: Cc1cccc(S)c1
Reactant: O=C(CCCCl)c1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cccc(SCCCC(=O)c2ccc(F)cc2)c1
Yield: 98.8 %

Procedure:
A solution of 3-thiocresol (25.0 g, 0.2 mole) and 4-chloro-4'-fluorobutyrophenone (40.1 g, 0.2 mole) in tetrahydrofuran (200 ml) was treated with triethylamine (22.3 g, 0.22 mole) and refluxed for six hours under nitrogen. The mixture was concentrated in vacuo, and the residue was partitioned between diethyl ether (200 ml) and water (200 ml). The organic layer was washed three times with sodium hydroxide (1N), water, and brine; dried over anhydrous magnesium sulfate, filtered, and concentrated to a pure oil by tlc (n-butyl chloride) to yield the title compound (57.0 g, 99%); IR(nujol): C=O @ 1686 cm-1 ; NMR(CDCl3, TMS): δ2.08(m,2H,CH2), 2.30(s,3H,ArCH3), 3.00(t,2H,CH2 --CO), 3.10(t,2H,S--CH2), 6.9-7.17(m,4H, 1,3-substituted phenyl), [7.10(d of d, 2H) and 7.97(m,2H) p-F-phenyl]; Anal. Calcd. for C17H17FNOS, MW 288.38: C,70.80; H,7.97; S,11.12. Found: C,70.79; H,6.01; S,11.18. Mass spectrum m/e 288,150.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][OH:15])[N:13]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23](OC)=[O:24])=[CH:19][CH:18]=1.O>CN(C)C=O>[C:3]1([C:9]2[S:10][CH:11]=[C:12]([CH2:14][O:15][C:17]3[N:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[N:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: OCc1csc(-c2ccccc2)n1
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2csc(-c3ccccc3)n2)nc1
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
Sodium hydride (60%, oily, 1.40 g) was added to a solution of 2-phenyl-4-thiazolylmethanol (6.69 g) and methyl 6-chloro-3-pyridinecarboxylate (6.01 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.33 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (11.3 g) was added to the reaction mixture, which was stirred for 30 minutes at room temperature. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 6-(2-phenyl-4-thiazolylmethoxy)-3-pyridylmethanol (5.81 g, yield 56%) as colorless crystals from the fraction eluted with tetrahydrofuran. This was recrystallized from tetrahydrofuran-hexane. Melting point: 134–135° C.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([Cl:8])[S:4][C:3]=1[C:9]([OH:11])=O.S(Cl)([Cl:14])=O.CN(C=O)C>ClCCCl>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([Cl:8])[S:4][C:3]=1[C:9]([Cl:14])=[O:11]
Reactant: O=C(O)c1sc(Cl)c(Cl)c1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1sc(Cl)c(Cl)c1Cl
Temperature: 25 °C

Procedure:
A mixture of 20.4 g (0.088 mole) of 3,4,5-trichloro-2-thiophenecarboxylic acid, 7.3 mL (0.1 mole) of thionyl chloride, 0.2 mL of DMF and 80 mL of 1,2-dichloroethane was heated at reflux temperature for 3 h. The reaction mixture became a clear solution after 1 h of heating. The mixture was allowed to cool to RT, concentrated in vacuo and exposed to high vacuum to give 22.0 g (>98% wt) an oil which solidified upon standing to an off-white powder, mp 37°-41° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)COc1ccc(I)cc1

Procedure:
The subject compound was prepared starting from 4-iodophenol and t-butyl bromoacetate in the same manner as Reference example 6-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:39][CH:36]2[CH2:38][CH2:37]2)[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: BrCC1CC1
Product: COc1ccc(CC2c3c(OCC4CC4)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with cyclopropyl-methyl bromide
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)CCC(C)C)ccc1OCc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CC(C)O
Product: COc1cc(C(=O)CCC(C)C)ccc1OCc1ccccc1
Yield: 82.4 %

Procedure:
The previously obtained 63.0 g of 1-(4'benzyloxy-3'-methoxyphenyl)-4-methylpentanol was dissolved in 310 ml of acetone. To this mixture, Jones reagent was added dropwise at 0° to 10° C. while cooling in an ice bath. After the completion of dropping, 50 ml of isopropyl alcohol was added to the solution and the resultant mixture was stirred at room temperature until the solution turned to green. Subsequently, the reaction solution was extracted with 400 ml of dichloromethane three times. The extraction solution obtained was washed with 300 ml of water, 300 ml of saturated aqueous sodium hydrogen carbonate solution, and 300 ml of brine, in this order. After dried over anhydrous magnesium sulfate, the solution was concentrated under reduced pressure, affording a brown crystal. The crystal were recrystallized from ether-hexane, affording 51.6 g of 4'-benzyloxy-3'-methoxy-4-methylvalerophenone (82.6% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:6]=[CH:7][CH:8]=O.[C:16]([CH2:18][C:19]([OH:21])=[O:20])#[N:17]>>[C:19](/[C:18](=[CH:8]/[CH:7]=[CH:6]/[C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]([OH:13])=[C:11]([O:14][CH3:15])[CH:10]=1)/[C:16]#[N:17])([OH:21])=[O:20]
Reactant: N#CCC(=O)O
Reactant: COc1cc(C=CC=O)cc(OC)c1O
Product: COc1cc(/C=C/C=C(\C#N)C(=O)O)cc(OC)c1O

Procedure:
The compound was prepared as described in Example 3 by adding 3,5-dimethoxy-4-hydroxycinnamaldehyde (0.15 g, 0.72 mmol) to cyanoacetic acid (0.061 g, 0.72 mmol). After refluxing for 1 h and recrystallization from ethanol a yellow solid was obtained (0.15 g, 75%). The product gave the following analytical data:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:13]=[C:12]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[CH:15]2)[N:11]=[C:10]2[C:6]=1[NH:7][C:8](=[O:31])[N:9]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])=O.[NH2:32]C1C(C(OC)=O)=NC(N2C3C=CC=CC=3N=C2)=NC=1NC1C=CC=CC=1OC.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[N:14]1([C:12]2[N:11]=[C:10]3[C:6]([NH:7][C:8](=[O:31])[N:9]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH3:30])=[C:5]([C:3]([NH2:32])=[O:2])[N:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1
Reactant: COC(=O)c1nc(-n2cnc3ccccc32)nc2c1[nH]c(=O)n2-c1ccccc1OC
Reactant: COC(=O)c1nc(-n2cnc3ccccc32)nc(Nc2ccccc2OC)c1N
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: COc1ccccc1-n1c(=O)[nH]c2c(C(N)=O)nc(-n3cnc4ccccc43)nc21
Yield: 62 %

Procedure:
Methyl-2-(1H-benzo[d]imidazol-1-yl)-9-(2-methoxyphenyl)-8-oxo-8,9-dihydro-7H-purine-6-carboxylate. A solution of methyl 5-amino-2-(1H-benzo[d]imidazol-1-yl)-6-(2-methoxyphenylamino)pyrimidine-4-carboxylate (0.300 g, 0.769 mmol), 1,1′-carbonyldiimidazole (0.311 g, 1.922 mmol), and dichloromethane (10 mL) was reacted as described in General Procedure F. The reaction mixture was filtered to give the titled compound as white solid (0.200 g, 62%). 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.44-8.41 (m, 1H), 7.76-7.73 (m, 1H), 7.64-7.55 (m, 2H), 7.38-7.29 (m, 3H), 6.22-7.16 (m, 1H), 4.02 (s, 3H), 3.79 (s, 3H); MS (ESI) m/z 417.5 [M+1]+.
Reaction SMILES: B(Br)(Br)Br.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1>ClCCl.C([O-])(O)=O.[Na+]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)[CH2:13][NH:14][CH3:15])=[CH:8][CH:7]=1
Reactant: CNCC(c1ccc(Br)cc1)c1ccc(OC)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNCC(c1ccc(O)cc1)c1ccc(Br)cc1
Temperature: 25 °C

Procedure:
Boron tribromide (7.8 ml, 1.0M in dichloromethane) was added slowly to a solution of [2-(4-Bromo-phenyl)-2-(4-methoxy-phenyl)-ethyl]-methyl-amine (500 mg, 1.56 mmol) in dichloromethane (8 ml) at 0° C., under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature and then stirred for a further hour. The mixture was poured on to ice and then diluted with dichloromethane and saturated NaHCO3 solution. The organic layer was dried (MgSO4), filtered and concentrated to afford the desired product. LC/MS: (PS-B3) Rt 2.76 [M+H]+306.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:14])([CH3:13])[CH2:11][NH2:12].C([O-])([O-])=O.[K+].[K+].O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:12][CH2:11][C:10]([CH3:14])([CH3:13])[CH3:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)CN
Reactant: Clc1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CNc1ccnc(Cl)n1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
2,4-Dichloropyrimidine (25 g, 0.16 moles) and 2,2-dimethyl-propylamine (25 ml, 0.21 moles) are dissolved in 250 ml of THF and K2CO3 (33.1 g, 0.24 mmoles) is added at rt. The mixture is refluxed at rt for 8 h. Water is added and the organic layer is extracted with AcOEt, washed with brine, dried over magnesum sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 22 g of desired (2-chloro-pyrimidin-4-yl)-(2,2-dimethyl-propyl)-amine in 67% yield.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([OH:35])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:4])([CH3:3])[CH3:2].CN(C1C=CC=CN=1)C.[C:46](Cl)(=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61]>ClCCl>[C:1]([O:5][C:6](=[O:36])[CH2:7][CH2:8][S:9][CH2:10][CH:11]([O:35][C:46](=[O:62])[CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH3:61])[CH2:12][O:13][C:14](=[O:34])[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(O)CSCCC(=O)OC(C)(C)C
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CSCCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
A solution of 6-hydroxy-7-octadecylcarbamoyloxy-4-thiaheptanoic acid t-butyl ester as obtained in Reference Example 7 (2.98 g), dimethylaminopyridine (820 mg) and palmitoyl chloride (1.54 g) in dichloromethane (10 ml) was stirred at room temperature for 30 minutes, followed by solvent concentration under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1) to yield the title compound (3.425 g, yield 79%) as a colorless wax-like substance.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][C@@H:3]([C:7]([NH2:9])=[O:8])[NH:2]2.[CH2:10]([O:17][C:18]([NH:20][C@@H:21]([C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][C:27]([OH:35])([CH2:28]3)[CH2:26]1)[CH2:32]2)[C:22](O)=[O:23])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:7]([C@@H:3]1[CH2:4][C@H:5]2[C@H:1]([CH2:6]2)[N:2]1[C:22](=[O:23])[C@@H:21]([NH:20][C:18](=[O:19])[O:17][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:25]12[CH2:34][CH:29]3[CH2:30][CH:31]([CH2:33][C:27]([OH:35])([CH2:28]3)[CH2:26]1)[CH2:32]2)(=[O:8])[NH2:9]
Reactant: O=C(N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2)OCc1ccccc1
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Product: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
Path B: Coupling reaction of (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide or its salts of Formula-III with (2S)-2-{[(benzyloxy)carbonyl]amino}-2-(3-hydroxyadamantan-1-yl)acetic acid of formula-XIV to give benzyl N-[(1S)-2-[(1S,3S,5S)-3-carbamoyl-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate of formula-XV, can be carried out in a suitable solvent, for example, tetrahydrofuran, N,N-dimethyl formamide, 1,4-dioxane or ethyl acetate using a coupling agent for example, 1,3-dicyclohexyl carbodiimide (DCC), 1-ethyl-3-(3′-dimethylaminoporpyl)carbodiimide (EDAC), 1-propane phosphonic acid cyclic anhydride or N-[(dimethyl amino)-1H-1,2,3-triazolo[4,5-b]pyridylmethylene]-N-methyl methanaminium hexafluoro phosphate N-oxide (HATU) and optionally a catalyst, for example, 1-hydroxybenzotriazole (HOBT) or 7-aza-1-hydroxy benzotriazole (HOAt) and optionally, with a base, for example, N,N-dimethylamino pyridine (DMAP), triethylamine, N,N-diisopropyl ethyl amine, or N-methyl morpholine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7]2.[OH-].[K+]>>[Br:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7]2
Reactant: COC(=O)c1cc2ccc(OC)c(Br)c2[nH]1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2cc(C(=O)O)[nH]c2c1Br

Procedure:
Following the general procedure of PREPARATION 63 and making non-critical variations but starting with methyl 7-bromo-6-methoxyindole carboxylate (PREPARATION 81, 0.36 g) and potassium hydroxide (0.11 g), the title compound is obtained, NMR (300 MHz, CD3OD) 7.58, 7.20, 6.96 and 3.93 δ.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[C:4]([F:21])[CH:3]=1.C1C(=O)N([Br:29])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][Br:29])=[CH:6][C:5]([C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=2)=[C:4]([F:21])[CH:3]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1c(C(F)(F)F)ccc(-c2cc(CBr)c(Cl)cc2F)c1=O
Yield: 81.4 %

Procedure:
2.63 g (8.23 mmol) of 3-(4-chloro-2-fluoro-5-methylphenyl)-1-methyl-6-trifluoromethyl-2(1H)-pyridone and 1.46 g (8.23 mmol) of NBS were dissolved in 100 ml of carbon tetrachloride. Then, 0.27 g (1.67 mmol) of 2,2′-azobisisobutyronitrile was slowly added thereto with stirring under heating and refluxing. Then, the mixture was further reacted for 5 hours. After cooling, the insoluble substances were filtered off, and the organic layer was washed with water and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 2.67 g (yield: 81%) of the desired product. Melting point: 117-118° C.