Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6](=[O:21])[CH2:7][C:8]([NH:10][C:11]1[C:12]([C:17]([O:19]C)=O)=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:9].O>C1COCC1>[OH:19][C:17]1[C:12]2[C:11](=[CH:16][CH:15]=[CH:14][N:13]=2)[NH:10][C:8](=[O:9])[C:7]=1[C:6]([O:5][CH3:4])=[O:21]
Reactant: COC(=O)CC(=O)Nc1cccnc1C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1c(O)c2ncccc2[nH]c1=O
Reaction time: 8 h

Procedure:
Sodium methoxide (0.73 g, 13.5 mmol) was added to 2 methyl 3-[(3-methoxy-3-oxopropanoyl)amino]pyridine-2-carboxylate (0.9 g, 3.4 mmol) dissolved in THF (20 mL). The reaction was stirred overnight. Water was added and the solvents removed. The residue was dissolved in water and purified by reverse phase HPLC eluting with a gradient of 5-40% acetonitrile/water (0.1% TFA) to give the product as a yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29][CH3:30])=[O:28])=[N:11][N:12]([CH:18]([C:25]#[N:26])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:14]([O:16]C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N>CO.[Rh]>[CH2:1]([O:8][C:9]1[C:10]([C:27]([O:29][CH3:30])=[O:28])=[N:11][N:12]2[CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:25][NH:26][C:14](=[O:16])[C:13]=12)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nn(C(C#N)c2ccccc2)c(C(=O)OC)c1OCc1ccccc1
Agent: [Rh]
Agent: N
Solvent: CO
Product: COC(=O)c1nn2c(c1OCc1ccccc1)C(=O)NCC2c1ccccc1
Reaction time: 8 h

Procedure:
To a solution of dimethyl 4-benzyloxy-1-[cyano(phenyl)methyl]-1H-pyrazole-3,5-dicarboxylate (1.0 g, 2.47 mmol) in anhydrous MeOH (100 mL) through which nitrogen had been bubbled was added rhodium on alumina (50 mg). The mixture was then treated with ammonia gas for 5 minutes and stirred under an atmosphere of hydrogen gas overnight. The mixture was filtered through celite and the filter cake was washed with MeOH. The filtrate was concentrated and purified by reverse phase chromatography on a C-18 column using a gradient elution of 95-5% H2O (0.1% TFA)/CH3CN (0.1% TFA). Collection and concentration of the appropriate fractions afforded the title product as an off-white solid. 1H NMR (400 MHz, d6-DMSO) δ 8.28 (s, 1H), 7.49-7.47 (m, 2H), 7.40-7.32 (m, 6H), 6.96-6.93 (m, 2H), 5.77 (s, 1H), 5.40-5.27 (m, 2H), 4.04-3.99 (m, 1H), 3.78 (s, 3H), 3.76-3.59 (m, 1H); ES MS (M+1)=378.
Reaction SMILES: [CH:1]1([NH:4][S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH:1]1([N:4]([CH3:17])[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN(C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
To a mixture of N-cyclopropyl-2-nitrobenzenesulfonamide (5.63 g), potassium carbonate (4.82 g) and N,N-dimethylformamide (60 mL), methyl iodide (2.17 mL) was added and stirred at room temperature for 6 hours. The reaction mixture was evaporated under reduced pressure, and the residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; n-hexane:diethyl ether=1:0-1:1) to give N-cyclopropyl-N-methyl-2-nitrobenzenesulfonamide (5.35 g) as a brown solid.
Reaction SMILES: [ClH:1].O1CCOC[CH2:3]1.C(OC([NH:15][C@H:16]1[CH2:24][O:23][C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][CH2:17]1)=O)(C)(C)C>CO>[ClH:1].[NH2:15][C@H:16]1[CH2:24][O:23][C@H:19]([C:20]([O:22][CH3:3])=[O:21])[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](C(=O)O)OC1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H]1CC[C@@H](N)CO1
Reaction time: 20 h
Yield: 100 %

Procedure:
4N hydrochloric acid/1,4-dioxane solution (20 ml) was added to a methanol (5 ml) solution of 2,6-anhydro-5-[(tert-butoxycarbonyl)amino]-3,4,5-trideoxy-L-erythro-hexonic acid (Eur. J. Org. Chem., 2003, 2418-2427) (1.00 g, 4.08 mmol) at room temperature and the resulting mixture was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure to give 0.80 g (100%) of the title compound.
Reaction SMILES: [C:1]([CH:6]1[C:11](=[O:12])[CH2:10][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)[CH2:8][C:7]1=[O:22])(=O)[CH2:2][CH2:3][CH3:4].[Cl-].[CH2:24]([O:26][NH3+:27])[CH3:25].C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:26][NH:27][CH2:4][CH2:3][CH2:2][CH:1]=[C:6]1[C:7](=[O:22])[CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)[CH2:10][C:11]1=[O:12])[CH3:25]
Reactant: CCCC(=O)C1C(=O)CC(c2ccc(CCC)cc2)CC1=O
Reactant: CCO[NH3+]
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1ccc(C2CC(=O)C(=CCCCNOCC)C(=O)C2)cc1

Procedure:
15.0 parts by weight of 2-butyryl-5-(4-n-propylphenyl)-cyclohexane-1,3-dione is reacted with 5.1 parts by weight of ethoxyammonium chloride and 4.5 parts by weight of anhydroud sodium acetate in 120 parts by volume of ethanol, and worked up as in Example 1. There is obtained 2-(ethoxyaminobutylidene)-5-(4-n-propylphenyl)-cyclohexane-1,3-dione (active ingredient No. 4).
Reaction SMILES: [C:1]12([C:11]3O[C:13]([CH2:16][CH2:17][CH3:18])=[N:14][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C([O-])=O.[CH3:26][NH3+:27]>>[C:1]12([C:11]3[N:27]([CH3:26])[C:13]([CH2:16][CH2:17][CH3:18])=[N:14][N:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C[NH3+]
Reactant: CCCc1nnc(C23CC4CC(CC(C4)C2)C3)o1
Agent: O=C([O-])C(F)(F)F
Product: CCCc1nnc(C23CC4CC(CC(C4)C2)C3)n1C

Procedure:
2-(1-Adamantyl)-5-propyl-1,3,4-oxadiazole (I) (49 mg, 0.2 mmol) and methylammonium trifluoroacetate (290 mg, 2 mmol, prepared by combining equimolar amounts of methylamine and trifluoroacetic acid in ether followed by concentration in vacuo) were stirred together in a sealed vial at 150° for 18 h. The residue was partitioned with methylene chloride and water, the organic layer washed with 10% K2CO3 and brine. The aqueous phase was extracted with methylene chloride (6×), the combined extracts dried (MgSO4) and concentrated in vacuo. The residue was purified by reverse phase HPLC on a C-18 silica gel column using an acetonitrile-0.1% trifluoroacetic acid gradient to afford 3-(1-adamantyl)-4-methyl-5-propyl-4H-1,2,4-triazole (4-3). MS: 260 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][CH2:28][OH:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12]([NH:26][CH2:27][CH2:28][OH:29])[N:13]=1
Reactant: NCCO
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCO)nc21

Procedure:
The product of Example 44, and 2-aminoethanol were reacted by the procedure of Example 60 to afford the title compound 4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-2-(2-hydroxy-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=387 (MH+). Rt=1.94 min
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([OH:15])=[C:7]([CH2:16][C:17]([CH3:19])=[CH2:18])[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:32])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:12])([CH3:13])[CH3:14])=[CH:9][C:8]2[O:15][C:17]([CH2:19][OH:32])([CH3:18])[CH2:16][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(C)Cc1c(O)cc(C(C)(C)C)c(OC(C)=O)c1C(C)(C)C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CO)O2
Yield: 69.5 %

Procedure:
In 200 ml of chloroform was dissolved 10.0 g of 4-acetoxy-3,5-di-t-butyl-2-(2-methyl-2-propenyl)phenol synthesized in accordance with JP 6-206842 A/94, and 11.0 g of m-chloroperbenzoic acid was added thereto, followed by heating under reflux for one day. After cooling, a saturated aqueous solution of sodium thiosulfate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (25% ethyl acetate in n-hexane) to give 7.3 g (yield: 70%) of 5-acetoxy-4,6-di-t-butyl-2-hydroxymethyl-2-methyl-2,3-dihydrobenzofuran (rotational isomer mixture) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.[CH2:10]([NH2:14])[CH:11]([CH3:13])[CH3:12].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].O1CCCC1>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([NH:14][CH2:10][CH:11]([CH3:13])[CH3:12])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)CN
Reactant: COc1cccc(Cl)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cccc(NCC(C)C)n1
Temperature: 70 °C
Reaction time: 8 h
Yield: 7 %

Procedure:
To a mixture of 2-chloro-6-methoxypyridine (357 μL, 3 mmol), isobutylamine (596 μL, 6.00 mmol) and Caddick's Catalyst (prepared according to the literature reference Org. Biomol. Chem. 2008, 6, 2820) (35.3 mg, 0.060 mmol) under nitrogen, was added lithium hexamethyldisilazide in tetrahydrofuran (THF) (1 M, 3.750 mL, 3.75 mmol). This was warmed to 70° C. and stirred overnight, then cooled for analysis. The reaction was then further heated by microwaves to 150° C. for 30 minutes. After cooling, purification was attempted by flash silica (Si) chromatography (0-50% dichloromethane-cyclohexane gradient), but this failed to provide adequate separation. Purification was then repeated by flash silica (Si) chromatography (0-65% dichloromethane-cyclohexane gradient) to isolate the title compound (37.8 mg). LCMS (2 min, formic) Rt 0.75 min, m/z (ES+) 181 (M+H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20](Cl)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1.[OH:34][CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:15]=[C:16]([S:20]([N:38]4[CH2:39][CH2:40][CH:35]([OH:34])[CH2:36][CH2:37]4)(=[O:22])=[O:21])[CH:17]=[CH:18][CH:19]=3)[N:9]=2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:3]=1
Reactant: OC1CCNCC1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)Cl)c3)n2)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)N4CCC(O)CC4)c3)n2)n1
Yield: 57.4 %

Procedure:
The title compound was prepared from 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonyl chloride (example I.2) (0.200 g, 0.409 mmol) by treatment with commercially available 4-hydroxypiperidine [CAS-no. 5382-16-1] (0.207 g, 2.05 mmol) in THF (5 mL) at 23° C. for 16 h. Diluted with EtOAc, washed with 5% citric acid, sat. NaHCO3-sol. and brine, dried organic layer over Na2SO4. Removal of the solvent in vacuum left a crude product, which was purified by silica gel column chromatography with EtOAc followed by trituration with diethyl ether/heptane to give the title compound (0.130 g, 57%) as a white solid. MS (ISP) 554.3 [(M+H)+]; mp 195° C.
Reaction SMILES: BrC1C=C(N2C3=NC=CC(C4[O:20]C=CC=4)=C3C(C(C)C)=N2)C=CC=1C#N.[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35]2[CH:42]=[C:41]([N:43]3[C:47]4=[N:48][CH:49]=[CH:50][C:51]([C:52]5[O:53][CH:54]=[CH:55][CH:56]=5)=[C:46]4[C:45]([CH:57]([CH3:59])[CH3:58])=[N:44]3)[CH:40]=[CH:39][C:36]=2[C:37]#[N:38])[CH2:30][CH2:29]1>>[OH:27][C@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35]2[CH:42]=[C:41]([N:43]3[C:47]4=[N:48][CH:49]=[CH:50][C:51]([C:52]5[O:53][CH:54]=[CH:55][CH:56]=5)=[C:46]4[C:45]([CH:57]([CH3:59])[CH3:58])=[N:44]3)[CH:40]=[CH:39][C:36]=2[C:37]([NH2:38])=[O:20])[CH2:30][CH2:29]1
Reactant: CC(C)c1nn(-c2ccc(C#N)c(N[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3ccco3)c12
Reactant: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-c3ccco3)c12
Product: CC(C)c1nn(-c2ccc(C(N)=O)c(N[C@H]3CC[C@H](O)CC3)c2)c2nccc(-c3ccco3)c12

Procedure:
According to Example 1(6), a crude product of 2-(trans-4-hydroxycyclohexylamino)-4-{(3-isopropyl-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile was prepared using compound (10a) instead of compound (1e) and was used in the subsequent reaction without being purified. According to Example 1(7), compound (10) (the second stage yield: 59%) was prepared as a white solid using 2-(trans-4-hydroxycyclohexylamino)-4-{3-isopropyl-4-(furan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl}benzonitrile instead of compound (1f).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([CH3:12])[CH:3]=1.[H-].[Na+].Cl[C:16]([F:23])([F:22])C(OCC)=O>CN(C)C=O>[F:22][CH:16]([F:23])[O:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH3:11])[N:5]=[C:4]([CH3:12])[CH:3]=1
Reactant: CCOC(=O)C(F)(F)Cl
Reactant: COc1nc(C)cc(O)c1C#N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(C)cc(OC(F)F)c1C#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 21 %

Procedure:
To a solution of 4-hydroxy-2-methoxy-6-methylnicotinonitrile (2.0 g, 12.2 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (880 mg, 36.6 mmol) at 0° C. and the mixture was stirred for 0.5 hour, Ethyl 2-chloro-2,2-difluoroacetate (5.4 g, 39.0 mmol) was added with vigorous stirring, over the course of 20 min. The suspension was warmed to 80° C. overnight under N2. The mixture was quenched into Na2CO3 (200 mL). It was partitioned between water (500 mL) and ethyl acetate (500 mL), the organic layer was dried and concentrated to afford the crude, which was purified by flash column (PE:EA=20:1) to afford 4-(difluoromethoxy)-2-methoxy-6-methylnicotinonitrile (550 mg yellow solid, 22.0% yield).
Reaction SMILES: [Cl:1][CH:2]([CH2:10][CH2:11][Cl:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[CH3:13]O>Cl>[Cl:1][CH:2]([CH2:10][CH2:11][Cl:12])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:13])=[O:8]
Reactant: O=C(O)CCCCC(Cl)CCCl
Reactant: CO
Agent: Cl
Product: COC(=O)CCCCC(Cl)CCCl
Yield: 98.6 %

Procedure:
9 g (0.042 moles) of (+)-6,8-dichlorooctanoic acid are dissolved in 120 ml of methanol containing 0.45 ml of aqueous hydrochloric acid at 37% by weight. The solution is refluxed for two hours, the solvent is evaporated at reduced pressure, 17 ml of toluene are added and the obtained solution is washed twice with 10 ml of water. The toluene phase is concentrated under vacuum, thus obtaining 9.4 g of methyl (+)-6,8-dichlorooctanoate (yield=98.6%).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=O)=[C:6]([NH:11][C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[N:5]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:3]=1.Cl.C(O)(C)C.C(OCC)(OCC)OCC.C([O-])(O)=O.[Na+].[CH:45]1([NH2:48])[CH2:47][CH2:46]1>>[CH:45]1([NH:48][C:2]2[N:3]=[C:4]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[N:5]=[C:6]3[C:7]=2[N:8]=[CH:9][N:11]3[C@@H:12]2[CH2:16][C@H:15]([CH2:17][OH:18])[CH:14]=[CH:13]2)[CH2:47][CH2:46]1
Reactant: CC(C)C(=O)Nc1nc(Cl)c(NC=O)c(N[C@H]2C=C[C@@H](CO)C2)n1
Reactant: NC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(OCC)OCC
Product: CC(C)C(=O)Nc1nc(NC2CC2)c2ncn([C@H]3C=C[C@@H](CO)C3)c2n1
Temperature: 41 °C
Reaction time: 2 h
Yield: 71.6 %

Procedure:
Under nitrogen atmosphere, N-{4-chloro-5-formamido-6-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enylamino]pyrimidin-2-yl}isobutyramide (20.0 g, 56.53 mmol) was dissolved in an anhydrous solution of HCl/isopropanol 2M (170 ml, 339.17 mmol). The mixture was heated at 40-42° C. for 2 h. The resulting solution was cooled to 8-10° C., then triethyl orthoformate (28.2 ml, 169.59 mmol) was added and the reaction mixture was stirred at the same temperature for 2 h. NaHCO3 (28.50 g, 339.17 mmol) was added slowly, stirred 30 min and the salts were filtered off. To the resulting clear solution, NaHCO3 (4.75 g, 56.53 mmol) and cyclopropylamine (19.6 ml, 282.65 mmol) were added, the mixture was refluxed for 1 h and the salts were filtered off. The solution was evaporated and the syrup was dissolved in hot isopropanol (200 ml). This mixture was cooled to 0-2° C. and the resulting slurry filtered off. The solid was dried under vacuum at 30° C. There was obtained 14.42 g (72%) of (−)-N-{6-(cyclopropylamino)-9-[(1R,4S)-4-(hydroxymethyl)cyclopent-2-enyl]-9H-purin-2-yl}isobutyramide as a white powder. HPLC analysis: 94.4%+4.0% Abacavir.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)C.Cl.[OH:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[OH:28])[CH2:22][CH2:23][NH2:24].C(O)CCC>O>[ClH:13].[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([NH:6][CH2:5][CH:4]2[C:25]3[C:21](=[CH:20][C:19]([OH:18])=[C:27]([OH:28])[CH:26]=3)[CH2:22][CH2:23][NH:24]2)=[CH:12][CH:11]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CNc1ccc(Cl)cc1)OCC
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1ccc(Cl)cc1)NCC2

Procedure:
p-Chloroanilinoacetaldehyde diethyl acetal (486 mg) and 3,4-dihydroxyphenethylamine hydrochloride (378 mg) were added to a mixture of n-butyl alcohol (4 ml) and water (0.4 ml) and then the mixture was refluxed for 3.5 hours. The above-mentioned acetal (0.24 g) was further added thereto and the resultant mixture was refluxed for 3 hours. The reaction mixture was treated in a conventional manner to give 1-(p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. This product was identified by thin-layer chromatography on silica gel [Developing solvent: (n-butyl alcohol:acetic acid:water=8:1:1)] with an authentic sample, mp 91° to 93° C., which was obtained by reacting 1-(N-benzyloxycarbonyl-p-chloroanilinomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride obtained in Example 1(D) with conc. hydrochloric acid and acetic acid.
Reaction SMILES: Br[C:2]1[C:3]([F:28])=[C:4]([C:24]([F:27])=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8].C([Li])CCC.C(O)(=[O:36])C.OO>O1CCCC1>[F:28][C:3]1[C:2]([OH:36])=[CH:26][CH:25]=[C:24]([F:27])[C:4]=1[CH2:5][O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]1[CH2:22][CH3:23])=[O:8]
Reactant: CC(=O)O
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(Br)c1F
Agent: OO
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OCc1c(F)ccc(O)c1F
Temperature: -78 °C
Yield: 28 %

Procedure:
(R)-2-Ethyl-piperazine-1,4-dicarboxylic acid 4-tert-butyl ester 1-(3-bromo-2,6-difluoro-benzyl) ester (3.9 g, 8 mM) was dissolved in tetrahydrofuran (120 mL), trisopropylborate (3.1 g, 17 mM) was added and the mixture was cooled to −78° C. At this low temperature n-butyllithium (7.8 mL, 1.6N) was added drop by drop with stirring. The mixture was stirred for 45 min at −78° C., for another 45 min at −50° C. and for 15 min at 0° C. Acetic acid (4.4 mL, 50%) was added slowly with stirring (0–5° C.), followed by hydrogen peroxide (1.3 mL, 35%). Stirring continued with cooling for another 45 min and for 1 h at room temperature. The mixture was partitioned between water and diethylether, organic phases were pooled, washed with water, sodium thiosulfate solution (5%), brine and dried with Na2SO4 to yield after evaporation a light yellow oil (4.1 g). This residue was purified by column chromatography (silica gel; n-hexane/ethylacetate 1:1) to yield 0.93 g (28%) of the product as a colorless oil. MS (ISP): 418.2 (M+NH4)+.
Reaction SMILES: [N+:1]([C:4]1[NH:8][CH:7]=[N:6][CH:5]=1)([O-:3])=[O:2].[CH:9](O)=O>S(OC)(OC)(=O)=O>[CH3:9][N:8]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=[CH:7]1
Reactant: O=CO
Reactant: O=[N+]([O-])c1cnc[nH]1
Solvent: COS(=O)(=O)OC
Product: Cn1cncc1[N+](=O)[O-]
Yield: 82 %

Procedure:
202 parts of 5-nitroimidazole is dissolved in 600 parts of formic acid (90% by weight), 250 parts of dimethyl sulfate is added and the whole is heated for 6 hours. The formic acid is distilled off in vacuo. 420 parts of water is added to the residue, the whole cooled to from 0° to 5° C. and the unreacted 5-nitroimidazole (60 parts) is centrifuged off. The mixture is adjusted to pH 10 with aqueous ammonia solution (25% by weight) and the precipitate is separated at 0° to 5° C. 130 parts of 1-methyl-5-nitroimidazole having a melting point of 58° to 60° C. is obtained; this is equivalent to a yield of 82% of theory based on reacted 4(5)-nitroimidazole.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([OH:10])=O)[CH2:3][CH2:2]1.S(Cl)([Cl:13])=O>>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([Cl:13])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(O)CC1CCOCC1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CC1CCOCC1
Temperature: 25 °C

Procedure:
A solution of tetrahydropyran-4-yl acetic acid (Combi-Blocks, Inc., 0.18 g, 1.2 mmol) in thionyl chloride (7 mL, 96 mmol, excess) was refluxed for 1 h then was cooled to ambient temperature and concentrated under reduced pressure. The residue was azeotroped twice with 10 mL of benzene to remove any remaining thionyl chloride. The resulting acid chloride was used without further purification.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][C:36]([CH2:39][NH2:40])=[CH:35][CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:14]=[CH:15][C:16]([C:17]([NH:40][CH2:39][C:36]3[CH:37]=[CH:38][N:33]=[CH:34][CH:35]=3)=[O:18])=[CH:20][CH:21]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Reactant: NCc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCc4ccncc4)cc3)oc2C)cc1
Yield: 72.8 %

Procedure:
Method E. Reaction of oxalyl chloride (178 λL, 2.0 mmol) and benzoic acid 4 (379 mg, 1.0 mmol) with subsequent coupling to 4-pyridinylmethylamine (114 λL, 1.1 mmol) gave benzamide 10 (336 mg, 71%) as a white powder: mp (EtOAc) 169-172° C.; 1H NMR δ 9.24 (t, J=5.9Hz, 1 H, CONH), 8.50 (dd, J=4.4, 1.6Hz, 2 H, H-2′, H-6′), 8.03 (dd, J=8.6, 1.8Hz, 2 H, H-2, H-6), 7.92 (dd, J=8.6, 1.8Hz, 2 H, H-3, H-5), 7.67 (d, J=8.3Hz, 2 H, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 7.32 (dd, J=4.4, 1.6Hz, 2 H, H-3′, H-5′), 4.63 (s, 2 H, CH2SO2), 4.51 (d, J=5.9Hz, 2 H, CH2N), 2.41 (s, 3 H, CH3), 2.14 (s, 3 H, CH3); 13C NMR δ 165.7, 158.0, 150.0, 148.9 (2), 148.4, 144.5, 135.6, 135.3, 129.7 (2), 128.9, 128.3 (2), 128.1 (2), 126.0, 125.5 (2), 122.2 (2), 53.0, 41.8, 21.1, 9.7; MS m/z 462.8 (MH+, 100%). Anal. calcd for C25H23N3O4S: C, 65.06; H, 5.02; N, 9.10. Found: C, 65.10; H, 4.96; N, 9.10%.
Reaction SMILES: [CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][NH:6][C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[CH:19]=[CH:18][S:17]3)=[O:13])[CH2:3]1.[CH3:22][C:23]1[S:24][C:25]([C:31]2[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[CH3:1][CH:2]1[CH2:9][C@H:8]2[C@H:4]([CH2:5][N:6]([C:28]([C:26]3[N:27]=[C:23]([CH3:22])[S:24][C:25]=3[C:31]3[CH:32]=[C:33]([CH3:37])[CH:34]=[CH:35][CH:36]=3)=[O:29])[C@@H:7]2[CH2:10][NH:11][C:12]([C:14]2[N:15]=[C:16]3[N:20]([CH:21]=2)[CH:19]=[CH:18][S:17]3)=[O:13])[CH2:3]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: CC1C[C@H]2CN[C@H](CNC(=O)c3cn4ccsc4n3)[C@H]2C1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(C)C[C@@H]3[C@H]2CNC(=O)c2cn3ccsc3n2)c1

Procedure:
prepared by reaction of imidazo[2,1-b]thiazole-6-carboxylic acid-[(1S,2S,5R)-7-methyl-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-methyl-5-m-tolyl-thiazole-4-carboxylic acid.