Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]([O-:4])=O.[Na+].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[CH2:15][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CCO>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[C:14](=[O:23])[C:15](=[N:2][OH:4])[C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)C(=O)CC(=O)c1c(Cl)cccc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(=NO)C(=O)c1c(Cl)cccc1Cl

Procedure:
Slowly bubble N2O3 gas (generated by the dropwise addition of concentrated HCl into an aqueous solution of sodium nitrite) into a stirred solution of ethyl 4-(2,6-dichlorophenyl)-2,4-dioxobutanoate (14.4 g, 50 mmol) in EtOH (300 mL) until the reaction is complete (as determined by TLC). Remove the EtOH by evaporation under reduced pressure and partition the residue between EtOAc and water. Dry the organic extract over MgSO4 and evaporate in vacuo to obtain the title compound which is used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:12])[C:8]([CH3:11])([CH3:10])[O:9][C:4]=2[CH:3]=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH3:10][C:8]1([CH3:11])[C:7](=[O:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]2[CH:19]=[CH:20][C:2]([NH:1][S:22]([CH3:21])(=[O:24])=[O:23])=[CH:3][C:4]=2[O:9]1
Reactant: CC1(C)Oc2cc(N)ccc2N(c2ccccc2)C1=O
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc(NS(C)(=O)=O)ccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-amino-2,2-dimethyl-4-phenyl-2H-1,4-benzoxazin-3(4H)-one (compound obtained in Reference Example 1(3), 50 mg) in chloroform (2 mL) were added dropwise successively methanesulfonyl chloride (22 μL) and pyridine (30 μL) under ice-cooling and the mixture was stirred at room temperature for 18 hours. To the reaction mixture was added a saturated sodium hydrogencarbonate solution, and the mixture was extracted with chloroform. The organic layer was washed successively with water, 10% HCl solution and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on NH-silica gel (solvent; n-hexane/ethyl acetate=1/1→ethyl acetate) to give N-(2,2-dimethyl-3-oxo-4-phenyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)methanesulfonamide (55 mg) as a colorless powder. MS (APCI) m/z: 347 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH3:29])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[CH:14][CH:13]=1)=[O:11].O[C:31]1C=CC(C(=O)CCC)=CC=1>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH:9]([CH2:29][CH3:31])[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][Si:19]([CH:23]([CH3:25])[CH3:24])([CH:26]([CH3:28])[CH3:27])[CH:20]([CH3:21])[CH3:22])=[CH:14][CH:13]=1)=[O:11]
Reactant: CC(Sc1ccccc1O)C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1
Reactant: CCCC(=O)c1ccc(O)cc1
Product: CCC(Sc1ccccc1O)C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1

Procedure:
The intended compound was obtained according to the method of Reference Example 1-1-(1), (2), (3), according to a method similar to it, and according to a combination of the method with an ordinary method, but using 4′-hydroxybutyrophenone as the starting material. 1HNMR (400 MHz, CDCl3, ppm): 1.02-1.19 (18H, m), 1.21-1.32 (3H, m), 1.80-2.05 (211, m), 4.36 (1H, t, J=6.9 Hz), 6.77-7.02 (4H, m), 7.22-7.37 (2H, m), 7.77-7.79 (2H, m)
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[CH2:6][S:7][CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)CSCc1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCO
Product: COC(=O)CSCc1ccccc1N

Procedure:
Methyl (o-nitrobenzylthio)-acetate (24.4 g) was dissolved in ethanol (500 ml). Raney nickel was added and the mixture was hydrogenated at room temperature and 1 atm. of hydrogen pressure. The title compound was obtained as an oil after filtration and evaporation of the reaction mixture.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([O:24]C)=[O:23])=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:4]>O.CO>[C:3]([C:6]1[CH:7]=[C:8]([C:12]2[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:14][C:15]3[C:20]([N:21]=2)=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][CH:16]=3)[CH:9]=[CH:10][CH:11]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(-c3cccc(C(=O)O)c3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
A solution of NaOH (68.7 mg, 1.72 mmol, 5.00 equiv) in water (3 mL) was added dropwise with stirring to a solution of methyl 3-(3-carboxyphenyl)-2-phenylquinoxaline-6-carboxylate (131.9 mg, 0.33 mmol, 1.00 equiv. in methanol (10 mL). The resulting solution was stirred overnight at 50° C. in an oil bath. The mixture was concentrated by vacuum; the pH was adjusted to 3-4 with 1N hydrochloric acid, the solid precipitate was filtered and washed with ether, affording 60 mg (49%) of 3-(3-carboxyphenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N:12]4[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]4=[O:19])=[CH:8][N:7]3[C:20]=2[CH3:21])[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][O:18][C:15]2[CH:16]=[CH:17][N:12]([C:9]3[CH:10]=[CH:11][C:6]4[N:7]([C:20]([CH3:21])=[C:4]([CH:1]5[CH2:3][CH2:2]5)[N:5]=4)[CH:8]=3)[C:13](=[O:19])[CH:14]=2)=[CH:29][CH:28]=1)([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: Cc1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc(C(C)(C)C)cc4)cc3=O)cn12
Reaction time: 17 h
Yield: 47 %

Procedure:
To a solution of 1-(2-cyclopropyl-3-methylimidazo[1,2-a]pyridin-6-yl)-4-hydroxypyridin-2(1H)-one (200 mg) in DMF (3 ml) were added 1-(bromomethyl)-4-(tert-butyl)benzene (178 mg) and potassium carbonate (197 mg) at room temperature, and the mixture was stirred for 17 h. The mixture was poured into water, and the resultant solid was collected by filtration. The solid was recrystallized from acetone to give the title compound (143 mg) as white crystals.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:3]1.Br[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[Cl:12][C:11]1[C:6]([CH:4]2[CH2:5][N:2]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[CH2:3]2)=[N:7][CH:8]=[CH:9][N:10]=1
Reactant: Clc1nccnc1C1CNC1
Reactant: Brc1ccc2ccccc2n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1nccnc1C1CN(c2ccc3ccccc3n2)C1
Temperature: 110 °C
Reaction time: 19 h
Yield: 42.7 %

Procedure:
A mixture of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (163 g, 0.79 mol), 2-bromoquinoline (164 g, 0.79 mol, 1 eq., Combi-Blocks) and cesium carbonate (772 g, 2.37 mol, 3 eq., Aldrich) in anhydrous DMF (6.5 L) was heated to 110° C. and stirred for 19 h. After cooling to RT, the mixture was transferred to 50 L separatory funnel and diluted with water (13 L). Then it was extracted with ethyl acetate (20 L×2) and the organic extracts were combined, washed with water (8 L), brine (8 L), dried and concentrated. The resulting residue was purified by column chromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1). All fractions containing desired compound were combined and concentrated. The obtained solid was triturated with MTBE (250 mL), washed with MTBE (100 mL×2) and dried to obtain 100 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. The mother liquor was concentrated and purified by column chromatography and trituration with MTBE again to give 4.5 g of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity. Yield: 45% for two steps.
Reaction SMILES: I[N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:11]([Si:13]([CH2:18][CH3:19])([CH2:16][CH3:17])[C:14]#[CH:15])[CH3:12].C(N(CC)CC)C>[Cu]I.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.CN(C=O)C>[CH2:14]([Si:13]([C:11]#[C:12][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[NH:2][CH:3]=[CH:4]2)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:15]
Reactant: C#C[Si](CC)(CC)CC
Reactant: In1ccc2ccccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC[Si](C#Cc1ccc2[nH]ccc2c1)(CC)CC
Temperature: 60 °C

Procedure:
To a scintillation vial was added -iodo-1H-indole (1.1 eq.), triethyl(ethynyl)silane (1 eq.), triethylamine (5 eq.), and anhydrous DMF (0.2 M). Vacuumed and nitrogen flushed for three times. CuI (0.1 eq.) and bis(triphenylphosphine)dichloro-palladium(II) (0.1 eq) were added. The vial was sealed and heated at 60° C. overnight. Upon completion of the reaction as monitored by TLC, the content of the vial was loaded onto a silica gel column pretreated with hexanes. Column was washed with hexanes and diethylether until all eluents containing product were collected. Carefully distill off hexanes and ether using rotary evaporator with minim heating afforded product 5-((triethylsilyl)ethynyl)-1H-indole as colorless oil, which was carried directly on to the next step.
Reaction SMILES: [IH:1].Cl[C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][N:4]=1.[OH-].[Na+]>>[I:1][C:3]1[CH:8]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[N:6]=[CH:5][N:4]=1
Reactant: Clc1cc(-c2cccs2)ncn1
Reactant: I
Agent: [Na+]
Agent: [OH-]
Product: Ic1cc(-c2cccs2)ncn1
Reaction time: 20 h
Yield: 93.6 %

Procedure:
Aqueous solution of HI (63.5 g, 496.5 mol, 13.9 equiv) was charged to 4-chloro-6-thiophen-2-yl-pyrimidine (3, 7.0 g, 35.6 mmol) and stirring was continued for 20 h. Reaction mixture was then made slightly alkaline (pH˜10) by using 5% NaOH solution. Subject compound was precipitated out, filtered, washed well with distilled water and dried under vacuum to yield 9.6 g of 4 (Yield=94.1%).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12]([CH3:14])([CH3:13])[C:11]2[C:6](=[CH:7][C:8]([CH2:15][CH3:16])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:19][CH2:20][C@H:21]([OH:23])[CH3:22]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:15]([C:8]1[CH:7]=[C:6]2[C:11]([C:12]([CH3:13])([CH3:14])[C:4]3[CH:3]=[CH:2][N:19]([CH2:20][C@H:21]([OH:23])[CH3:22])[C:5]=32)=[CH:10][CH:9]=1)[CH3:16]
Reactant: C[C@@H](O)CN
Reactant: CCc1ccc2c(c1)C(=O)C(CC=O)C2(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2(C)C
Reaction time: 0.75 h
Yield: 91.1 %

Procedure:
A solution of 2.3 g of (RS)-2-(2-oxoethyl)-6-ethyl-3,3-dimethyl-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 40 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 3:2). 2.45 g (91%) of (R)-1-(7-ethyl-4,4-dimethyl-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a red oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH3:22].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH3:22])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNC(=O)c1ccccc1

Procedure:
Using the general method of Example 1, 1-(4-aminobutyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (0.55 g, 1.8 mmol) was reacted with benzoyl chloride (0.26 g, 1.8 mmol) to provide N1-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]benzamide as a solid, m.p. 173-174° C. 1H NMR (500 MHz, DMSO-d6) δ 8.80 (broad s, 2H), 8.46 (t, J=6.0 Hz, 1H), 8.20 (d, J=8.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.4 Hz, 2H), 7.67 (t, J=7.4 Hz, 1H), 7.49 (m, 2H), 7.43 (t, J=7.5 Hz, 2H), 4.63 (t, J=7.0 Hz, 2H), 3.34 (m, 2H), 2.97 (t, J=7.0 Hz, 2H), 1.85 (m, 4H), 1.72 (quintet, J=7.0 Hz, 2H), 1.01 (t, J=7.0 Hz, 3H); MS (EI) m/e 401.2210 (401.2216 calcd for C24H27N5O).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.F[C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:11][C:10]1[C:2]([Cl:1])=[CH:3][C:4]2[N:8]([C:13]3[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=3)[CH:7]=[N:6][C:5]=2[CH:9]=1
Reactant: Clc1cc2nc[nH]c2cc1Cl
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(-n2cnc3cc(Cl)c(Cl)cc32)cc1
Temperature: 100 °C
Yield: 61.8 %

Procedure:
A mixture of 5,6-dichlorobenzimidazole (94 mg, 0.50 mmol), 4-fluorobenzaldehyde (0.064 mL, 0.60 mmol), and potassium carbonate (83 mg, 0.60 mmol) in dimethylsulfoxide (3 mL) was heated at 100° C. for 3 h. The mixture was cooled to room temperature, and water was added. The precipitated product was collected by filtration and washed with water and ethanol to afford 5,6-dicloro-1-(4-formylphenyl)benzimidazole (90 mg, 62%).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].O1CCCC1.[CH3:18][C:19]([CH3:29])([CH2:27][CH3:28])[CH:20]([CH2:23][C:24](=O)[CH3:25])[CH:21]=O>Cl.C(OCC)(=O)C>[CH3:18][C:19]([C:20]1[CH:23]=[C:24]([CH3:25])[N:1]([N:2]2[C:3](=[O:12])[C:4]3[C:5](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]2=[O:7])[CH:21]=1)([CH3:29])[CH2:27][CH3:28]
Reactant: CCC(C)(C)C(C=O)CC(C)=O
Reactant: NN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(C)(C)c1cc(C)n(N2C(=O)c3ccccc3C2=O)c1
Reaction time: 0.33 h
Yield: 77.6 %

Procedure:
N-aminophthalimide (476 mg) and 5N hydrochloric acid (5 drops) were added to the tetrahydrofuran solution (20 mL) of the compound prepared in Example 54 (1 g). The reaction mixture was stirred for 20 minutes under argon gas atmosphere. Ethyl acetate (100 mL) was added to the reaction mixture. The reaction mixture was washed by a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride. The organic layer was dried with anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (Yamazen corporation, high flash 2 L, n-hexane→ethyl acetate/n-hexane=1/4) to obtain the title compound (675 mg) having the following physical data.
Reaction SMILES: Cl[CH:2]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C>[NH2:15][C:13]1[S:14][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([CH:9]([CH3:11])[CH3:10])[N:12]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)C(Cl)CC(C)C
Solvent: CCO
Product: CCOC(=O)c1sc(N)nc1C(C)C
Yield: 39.7 %

Procedure:
Utilizing the procedure of Example 1, a mixture of 1.97 g (0.01 mol) of ethyl 2-chloro-4-methyl-pentanoate, 0.76 g (0.01 mol) of thiourea and 30 ml of ethanol was held at reflux for 18 hours. Ethanol was removed under reduced pressure. The residue was crystallized from hexane. The solid precipitates were dissolved in ether. The ether solution was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from benzene-ether to give 0.85 g (39.6%) of ethyl 2-amino-4-isopropyl-5-thiazolecarboxylate, m.p. 173°-176° C.
Reaction SMILES: [CH:1]([OH:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.[N+:10]([C:13]1[CH:34]=[CH:33][C:16]([CH2:17][C@@H:18]([C:30](O)=[O:31])[NH:19][C:20](=[O:29])[C:21]2[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:14]=1)([O-:12])=[O:11]>O1CCCC1>[CH:1]([O:4][C:30](=[O:31])[C@H:18]([CH2:17][C:16]1[CH:15]=[CH:14][C:13]([N+:10]([O-:12])=[O:11])=[CH:34][CH:33]=1)[NH:19][C:20](=[O:29])[C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:28])([CH3:3])[CH3:2]
Reactant: CC(C)O
Reactant: O=C(N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: CC(C)OC(=O)[C@H](Cc1ccc([N+](=O)[O-])cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 50 °C
Reaction time: 120 h

Procedure:
Isopropanol (130 mL), tetrahydrofuran (50 mL) and sulfuric acid (0.44 mL) were added to 4-nitro-N-(2,6-dichlorobenzoyl)-L-phenylalanine (2.95 g, 7.70 mmol) and stirred at 50° C. for 5 days. After removing the solvent under reduced pressure, the obtained solid material was washed with water and dried to obtain 3.28 g of a white solid material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][OH:28])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1.[C:34](O)(=[O:37])[CH2:35][CH3:36]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][C@@H:23]([CH2:27][O:28][C:34](=[O:37])[CH2:35][CH3:36])[CH2:22]2)[NH:12][C:11]([C:29]2[N:33]=[CH:32][NH:31][N:30]=2)=[N:10]1
Reactant: CCC(=O)O
Reactant: CCOC(=O)C1=C(CN2CCO[C@@H](CO)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Product: CCOC(=O)C1=C(CN2CCO[C@@H](COC(=O)CC)C2)NC(c2nc[nH]n2)=NC1c1ccc(F)cc1Br
Yield: 38.2 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(((R)-2-(hydroxymethyl)morpholino)methyl)-2-(1H-1,2,4-triazol-3-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 3.8 mmol) was reacted with propionic acid (0.37 g, 5 mmol) according to the procedure as described in Example 49 to give the title compound as yellow oil (0.84 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C@@H:1]1([N:8]2[CH:15]=[CH:14][C:12]([NH2:13])=[N:11][C:9]2=[O:10])[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1.[I:16]I>CO.ClCCl>[I:16][C:14]1[C:12]([NH2:13])=[N:11][C:9](=[O:10])[N:8]([CH:15]=1)[C@@H:1]1[O:7][C@H:4]([CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: II
Reactant: Nc1ccn([C@H]2CC[C@@H](CO)O2)c(=O)n1
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(=O)n([C@H]2CC[C@@H](CO)O2)cc1I
Reaction time: 4 h
Yield: 82.8 %

Procedure:
A solution of 2',3'-dideoxycytidine (2.11 g, 10 mmol, Raylo) and mercuric acetate (3.35 g, 10.5 mmol, Fisher) in 50 mL of methanol was refluxed for 19 hours. The resulting white suspension was diluted with methanol (50 mL) and dichloromethane (100 mL). Iodine (3.05 g, 12 mmol) was added and the suspension was stirred at 25°. After 4 hours, the free base form of AG3X4A resin (20 mL, 38 meq, Bio-Rad) was added and hydrogen sulfide was bubbled into the reaction for 15 minutes. Complete precipitation of mercury(II) was verified by TLC. The reaction was filtered through filter aid and the filter aid was washed with 1:1 methanol-dichloromethane. The filtrate was evaporated onto silica gel (10 g) and the loaded silica gel was placed on top of a 150 g silica gel column. Elution with 5%, 10% and 20% methanol in dichloromethane afforded 2.79 g (83%) of iodide 19 as a colorless crystalline solid. Two recrystallizations from boiling water afforded, after vacuum-drying at 50°, large, analytically-pure prisms (mp: d 178°).
Reaction SMILES: Br[CH:2]([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>C1(C)C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH3:8])[CH3:7]
Reactant: C1COCCN1
Reactant: CCOC(=O)C(C)Br
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1CCOCC1
Temperature: 25 °C
Reaction time: 10 h
Yield: 84 %

Procedure:
Ethyl 2-bromopropionate (0.125 moles) was diluted with 75 ml of toluene, and morpholine (0.3 moles) was added thereto, followed by stirring for 10 hours at room temperature. White solid was removed by filtration, and then the filtrate was distilled to obtain 2-morpholinopropionic acid ethyl ester (0.105 moles).
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[CH:5]([CH:10]([OH:12])[CH3:11])[CH2:4][CH:3]=1.[CH:13](O)=[O:14]>O>[CH3:1][C:2]1[CH2:7][C:6]([CH3:8])([CH3:9])[CH:5]([CH:10]([O:12][CH:13]=[O:14])[CH3:11])[CH2:4][CH:3]=1
Reactant: CC1=CCC(C(C)O)C(C)(C)C1
Reactant: O=CO
Solvent: O
Product: CC1=CCC(C(C)OC=O)C(C)(C)C1
Yield: 47.2 %

Procedure:
20.0 g of 1,5,5-trimethyl-4-(1-hydroxyethyl)-cyclohex-1-ene are introduced into a 1 liter three-necked flask provided with a mechanical stirrer, a heater, a dropping funnel and a reflux condenser fitted with a calcium chloride drying tube. 273 g of formic acid are then added in the course of 1/2 hour, whilst maintaining the temperature of the reaction mixture between 0° and 5°. After the end of the addition, the temperature of the composition is maintained at 5°. The composition is then slowly heated over 2 hours to 20°-25°. The mixture is then poured into 200 ml of water and extracted with benzene. The combined benzene extracts are washed successively with water, a solution of sodium bicarbonate and, finally, with water again. After distillation of the solvent over a water bath, the crude ester is distilled under a pressure of 0.05 mm of mercury. 11.0 g of 1,5,5-trimethyl-4-(1-formyloxyethyl)-cyclohex-1-ene are obtained, having the following physical constants:
Reaction SMILES: C(N(CC)CC)C.[NH:8]=[C:9](OC)[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH:20]([NH:22][NH2:23])=O>CO>[N:22]1[N:23]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[NH:8][CH:20]=1
Reactant: COC(=N)CCCCC(=O)OC
Reactant: NNC=O
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CCCCc1nnc[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.4 %

Procedure:
Add methanol (1 mL) and triethylamine (0.36 mL; 1.0 equiv; 2.58 mmoles) to a vial containing methyl 6-imino-6-methoxy-hexanoate (0.542 g; 1.00 equiv; 2.58 mmoles), followed by a solution of formylhydrazine (0.155 g 1.0 equiv; 2.58 mmoles) in methanol (3 mL). Stir at room temperature for 18 hours, then heat to 70° C. for 3 hours. Concentrate the mixture, then dilute with ethyl acetate (30 mL) and filter. Concentrate the filtrate to afford methyl 5-(4H-1,2,4-triazol-3-yl)pentanoate (0.498 g; 105%) as a colorless oil: MS (m/z): 184 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:36]2[CH2:35][CH2:34][N:33]([C:27]3[CH:26]=[C:25]([O:24][CH3:23])[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=3)[CH2:38][CH2:37]2)=[O:18])=[CH:7][C:6]([CH3:19])=[C:5]([CH2:20][CH2:21][CH3:22])[N:4]=1
Reactant: COc1cc(OC)cc(N2CCNCC2)c1
Reactant: CCCc1nc(OC)c(NC(=O)Oc2ccccc2)cc1C
Product: CCCc1nc(OC)c(NC(=O)N2CCN(c3cc(OC)cc(OC)c3)CC2)cc1C
Yield: 57 %

Procedure:
Phenyl N-(2-methoxy-5-methyl-6-propylpyridin-3-yl)carbamate and 1-(3,5-dimethoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.