Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C@@H:3]([NH2:8])[CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=[S:21]>>[CH3:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]1[NH:8][C@H:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[CH2:2][S:21]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CC(C)C[C@H](N)CO
Product: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was converted to (1R)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1R)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4R)-2-(2-methyl -4-nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to afford (4R)-2-(2-methyl-4-nitrophenylimino)-3,4-diisobutyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[CH:6]2.[OH-].[K+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:23][CH:22]=1>C1(C)C=CC=CC=1.O.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH3:15])=[N:8][C:7]([OH:16])=[C:6]2[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][CH:22]=1
Reactant: COc1cc2cc(O)nc(C)c2cc1OC
Reactant: BrCc1ccc(Oc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2c(C)nc(O)c(Cc3ccc(Oc4ccccc4)cc3)c2cc1OC
Temperature: 140 °C
Reaction time: 0.83 h

Procedure:
To a solution of 6,7-dimethoxy-1-methylisoquinolin-3-ol CCH 18060 (152 mg, 693 μmol) in toluene (15 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. KOH solution (0.38 mL, 0.76 mmol) at RT followed by 1-(bromomethyl)-4-phenoxybenzene (191 mg, 726 μmol) and the mixture was stirred at 140° C. for 50 min under microwave irradiation then at 160° C. for 50 min under microwave irradiation. After cooling to RT, the mixture was diluted with H2O (10 mL) before extraction with EtOAc (50 mL). The organic phase was isolated and the aqueous phase was further extracted with CH2Cl2 (50 mL). Both organic phases were washed with brine (10 mL), combined, dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:3) gave 43 mg of 6,7-dimethoxy-1-methyl-4-(4-phenoxybenzyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.09 M HCl solution in MeOH (3 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-1-methyl-4-(4-phenoxybenzyl)isoquinolin-3-ol hydrochloride 5 as a brown solid (47 mg, 15% yield).
Reaction SMILES: N1C=CC=CC=1.Cl[C:8]([O:10][CH3:11])=[O:9].[CH:12]([NH:15][S:16]([Cl:19])(=[O:18])=[O:17])([CH3:14])[CH3:13].C(Cl)Cl>O>[CH3:11][O:10][C:8]([N:15]([CH:12]([CH3:14])[CH3:13])[S:16]([Cl:19])(=[O:18])=[O:17])=[O:9]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: COC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)N(C(C)C)S(=O)(=O)Cl
Temperature: 22 °C
Reaction time: 0.17 h
Yield: 67 %

Procedure:
39.6 parts of pyridine are added in the course of 15 minutes at 10° C., whilst stirring, to a mixture of 47.2 parts of methyl chloroformate and 78.8 parts of isopropylsulfamic acid chloride in 330 parts of methylene chloride. The reaction mixture is then stirred for 10 minutes at 22° C. Thereafter, the mixture is stirred for 8 minutes with 350 parts of water at 6° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 72.1 parts (67% of theory) of N-methoxycarbonyl-N-isopropylsulfamic acid chloride, of boiling point 60°-64° C./0.13 mbar and nD25 =1.4540, are obtained.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:11][C:12]1[C:17]([C:18]#[N:19])=[CH:16][C:15]([Br:20])=[CH:14][N:13]=1.Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[Br:20][C:15]1[CH:16]=[C:17]([C:18]#[N:19])[C:12]([NH:11][C:22](=[O:23])[O:24][CH3:25])=[N:13][CH:14]=1
Reactant: COC(=O)Cl
Reactant: N#Cc1cc(Br)cnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)Nc1ncc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Lithium bis(trimethylsilyl)amide in THF (1.0 N, 22 mL, 22 mmol) was added to a stirred solution of 2-amino-5-bromopyridine-3-carbonitrile (2.0 g, 10 mmol) in THF (30 mL) at −78° C. and the mixture was stirred at this temperature for 30 minutes. Methyl chloroformate (1.06 g, 11.1 mmol) was added and the mixture was warmed to room temperature and stirred for 2 hours. It was cooled in ice bath and quenched with saturated aqueous ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL) and the combined organic fractions were washed with brine (2×50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by LC (elution with 10% ethyl acetate in petroleum ether) to afford the carbamate (1.43 g, 63%). 1H NMR (400 MHz, CDCl3) δ 3.85 (s, 3H), 7.45 (br s, 1H), 8.05 (s, 1H), 8.65 (s, 1H). LCMS (M−1, 254.0).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[NH:10][CH2:9]2)=[N:6][CH:7]=1.[H-].[Na+].I[CH3:17]>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[O:12][C:11](=[O:13])[N:10]([CH3:17])[CH2:9]2)=[N:6][CH:7]=1
Reactant: O=C1NCC(c2ccc(Br)cn2)O1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CC(c2ccc(Br)cn2)OC1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.1 %

Procedure:
Compound 14b (350 mg, 1.44 mmol) was dissolved in dried tetrahydrofuran, cooled to 0° C. NaH (86.4 mg, 2.16 mmol) was added, and iodomethane (0.18 mL, 2.88 mmol) was added dropwise. After the addition was completed, the reaction mixture was raised to room temperature for reacting overnight. The reaction was monitored by TLC (petroleum ether/ethyl acetate=5/1). After the reaction completed, the mixture was diluted with water, and extracted with ethyl acetate. The organic phase was combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. Column chromatography (petroleum ether/ethyl acetate=8/1) afforded 315 mg of white solid (compound 14c), yield 85%.
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:8]3[C:31]([C:32]4[CH:41]=[CH:40][C:35]5[N:36]=[C:37]([CH3:39])[O:38][C:34]=5[CH:33]=4)=[CH:30][N:29](COCC[Si](C)(C)C)[C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH:21]4[CH2:24][O:23][CH2:22]4)=[O:19])=[CH:16][C:15]=3[O:27][CH3:28])[N:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(OC2CCCC2)C2C(C3C=CC4N=C(C)OC=4C=3)=CN(COCC[Si](C)(C)C)C=2N=1.NC1C=CC(C(NC2COC2)=O)=CC=1OC.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([O:6][C:7]2[C:8]3[C:31]([C:32]4[CH:41]=[CH:40][C:35]5[N:36]=[C:37]([CH3:39])[O:38][C:34]=5[CH:33]=4)=[CH:30][NH:29][C:9]=3[N:10]=[C:11]([NH:13][C:14]3[CH:26]=[CH:25][C:17]([C:18]([NH:20][CH:21]4[CH2:22][O:23][CH2:24]4)=[O:19])=[CH:16][C:15]=3[O:27][CH3:28])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)NC2COC2)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cc(C(=O)NC2COC2)ccc1N
Solvent: C1COCCO1
Product: COc1cc(C(=O)NC2COC2)ccc1Nc1nc(OC2CCCC2)c2c(-c3ccc4nc(C)oc4c3)c[nH]c2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
4-((4-(Cyclopentyloxy)-5-(2-methylbenzo[d]oxazol-6-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxy-N-(oxetan-3-yl)benzamide. To a degassed mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-methoxy-N-(oxetan-3-yl)benzamide (1.2 equiv) and cesium carbonate (3 equiv) in 1,4-dioxane (0.1 M) was added palladium acetate (0.2 equiv) and 2,2′-bis-diphenylphosphanyl-[1,1′]binaphthalenyl (0.2 equiv). The reaction was stirred at 100° C. for 2 h. The reaction mixture was cooled to room temperature, and concentrated. The residue was purified by silica gel chromatography (0-5% DCM in methanol) to afford the title compound (crude) as a yellow solid which was used in the next step without further purification. MS (ESI) m/z 686.1 [M+1]+.
Reaction SMILES: [CH:1]1[C:6]([C:7]2[C:16](=[O:17])[C:15]3[CH:14]=[CH:13][C:12](O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=[CH:11][C:10]=3[O:9][CH:8]=2)=[CH:5][CH:4]=[C:3](O)[CH:2]=1.C1C(C2C(=O)C3C(O)=CC(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)=CC=3OC=2)=CC=C(O)C=1.COC1C=C2C(C(C3C=CC(O)=CC=3)=COC2=CC=1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)=O.C1C(C2C(=O)C3C=CC(O)=CC=3OC=2)=CC=C(O)C=1.C1C(C2C(=O)C3C(O)=CC(O)=CC=3OC=2)=CC=C(O)C=1.COC1C=C2C(=O)C(C3C=CC(O)=CC=3)=COC2=CC=1O.C1C(C2C(=O)C3C=CC(O[C@@H]4O[C@H](COC(CC(O)=O)=O)[C@@H](O)[C@H](O)[C@H]4O)=CC=3OC=2)=CC=C(O)C=1.C1C(C2C(=O)C3C(=CC(O[C@@H]4O[C@H](COC(CC(O)=O)=O)[C@@H](O)[C@H](O)[C@H]4O)=CC=3O)OC=2)=CC=C(O)C=1.COC1C=C2C(C(C3C=CC(O)=CC=3)=COC2=CC=1O[C@@H]1O[C@H](COC(CC(O)=O)=O)[C@@H](O)[C@H](O)[C@H]1O)=O.COC[C@H]1O[C@@H](OC2C=CC3C(C(C4C=CC(O)=CC=4)=COC=3C=2)=O)[C@H](O)[C@@H](O)[C@@H]1O.CC(OC[C@H]1O[C@@H](OC2C=C3OC=C(C4C=CC(O)=CC=4)C(=O)C3=CC=2OC)[C@H](O)[C@@H](O)[C@@H]1O)=O>C(O)C>[O:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16](=[O:17])[C:7]([C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][CH:5]=2)=[CH:8]1
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc12
Agent: COC[C@H]1O[C@@H](Oc2ccc3c(=O)c(-c4ccc(O)cc4)coc3c2)[C@H](O)[C@@H](O)[C@@H]1O
Agent: COc1cc2c(=O)c(-c3ccc(O)cc3)coc2cc1O
Agent: COc1cc2c(=O)c(-c3ccc(O)cc3)coc2cc1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: CCO
Product: O=c1c(-c2ccccc2)coc2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A sample corresponding to 1 to 10 mg of isoflavones was precisely weighed, and 25 mL of 70% (v/v) ethanol was added to the sample. After extraction with stirring for 30 minutes at room temperature, the extract was centrifuged. The residue was further extracted twice in the same way as in the above. Extract solutions from three extractions in total were combined, adjusted to a volume of 100 mL with 70% (v/v) ethanol, and then filtered with a 0.45 μm PVDF filter to obtain a test solution. In a confirmatory test of isoflavones, the peaks of the test solution were confirmed at about the same retention times as compared with 12 kinds of standard samples, namely, daidzin, genistin, glycitin, daidzein, genistein, glycitein, malonyl daidzin, malonyl genistin, malonyl glycitin, acetyl daidzin, acetyl genistin and acetyl glycitin (all manufactured by Waco Pure Chemical Industries, Inc.). In a quantitative test, the concentrations of 12 isoflavones in the test solution were quantified (as equivalent converted into daidzin) using daidzin standard samples as standard. The true isoflavone concentrations were calculated by multiplying the obtained values by the following quantification constants: daidzin (1.000), genistin (0.814), glycitin (1.090), malonyl daidzin (1.444), malonyl genistin (1.095), malonyl glycitin (1.351), acetyl daidzin (1.094), acetyl genistin (1.064), acetyl glycitin (1.197), daidzein (0.583), genistein (0.528), and glycitein (0.740). The total amount of isoflavones was determined from the sum of the concentrations of all isoflavones. HPLC conditions of the test solutions and the standard solutions are shown in Table 1.
Reaction SMILES: [CH3:1][C@H]1OC(=O)C2C(O)=CC(O)=C(Cl)C=2CC(=O)C=CC=C[C@H]2O[C@H]2C1.C(O)(=O)CCCCCCCCCCCCCC.[CH:43]1([N:49]=[C:50]=[N:51][CH:52]2[CH2:57][CH2:56][CH2:55]CC2)CCCCC1>O1CCCC1>[CH3:1][N:49]([C:50]1[CH:55]=[CH:56][CH:57]=[CH:52][N:51]=1)[CH3:43]
Reactant: C[C@@H]1C[C@@H]2O[C@@H]2C=CC=CC(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCCCCCCCCCCCCC(=O)O
Agent: C[C@@H]1C[C@@H]2O[C@@H]2/C=C\C=C\C(=O)Cc2c(Cl)c(O)cc(O)c2C(=O)O1
Solvent: C1CCOC1
Product: CN(C)c1ccccn1

Procedure:
Following a procedure similar to that described in Example 12, but using 500 mg of radicicol, 830 mg of pentadecanoic acid, 15 ml of dry tetrahydrofuran, 707 mg of dicyclohexylcarbodiimide and a catalytic amount of dimethylaminopyridine, 782 mg of the title compound were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:16]Cl.[BH4-].[Na+]>CO>[CH3:11][O:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:16][N:7]1[CH2:8][CH2:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1
Reactant: COc1ccc(CCl)cc1OC
Reactant: c1cnc2ccncc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN2CCc3ncccc3C2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1,6-naphthyridine (5.2 g, 0.04 mol) and 3,4-dimethoxybenzyl chloride (8.95 g, 0.048 mol) was refluxed for 3 hours. The precipitated quatenary salt was separated by filtration, dissolved in technical grade methanol (400 ml) and sodium borohydride (15.1 g, 0.4 mol) was added portionwise under ice cooling. After stirring overnight at room temperature, the reaction mixture was evaporated in vacuo, water added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The residue was purified by alumina column chromatography (eluted successively with n-hexane, benzene and chloroform). The resulting residue was recrystallized from ether-n-hexane to afford the Compound No. 46 (6.5 g, 57.2%) as colorless prisms, mp. 76°-77° C.
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[F:22][C:23]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:27][C:24]=1[C:25]#[N:26].[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH:29]=[CH:30][C:23]=2[F:22])[N:2]([CH3:1])[N:3]=1
Reactant: CCCCCCc1ccc(F)c(C#N)c1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: CCCCCCc1ccc(F)c(-c2nc(-c3ccccc3Cl)nn2C)c1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 71.8 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (2.06 g), 2-fluoro-5-hexylbenzonitrile (1.23 g), anhydrous aluminum chloride (0.88 g) and o-dichlorobenzene (5 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, the reaction mixture is dissolved in chloroform (200 ml), washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline in this order, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.60 g of desired compound (refractive index: 1.5779).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:18][C@H:17]2[C@@H:8]([C@@H:9]3[C@@H:14]([CH2:15][CH2:16]2)[CH2:13][C@@:12]2([CH3:24])[C:19]([C:22]#[N:23])=[CH:20][CH2:21][C@@H:11]2[CH2:10]3)[CH2:7][CH2:6]1.COCO[C@H]1C[C@H]2[C@@H]([C@@H]3[C@@H](CC2)C[C@@]2(C)C(OS(C(F)(F)F)(=O)=O)=CC[C@@H]2C3)CC1>CCOC(C)=O.[Pd]>[CH3:1][O:2][CH2:3][O:4][C@H:5]1[CH2:18][C@H:17]2[C@@H:8]([C@@H:9]3[C@@H:14]([CH2:15][CH2:16]2)[CH2:13][C@@:12]2([CH3:24])[C@H:19]([C:22]#[N:23])[CH2:20][CH2:21][C@H:11]2[CH2:10]3)[CH2:7][CH2:6]1
Reactant: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@@]4(C)C(C#N)=CC[C@@H]4C[C@@H]32)C1
Agent: [Pd]
Agent: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@@]4(C)C(OS(=O)(=O)C(F)(F)F)=CC[C@@H]4C[C@@H]32)C1
Solvent: CCOC(C)=O
Product: COCO[C@@H]1CC[C@H]2[C@@H](CC[C@H]3C[C@]4(C)[C@@H](CC[C@H]4C#N)C[C@@H]32)C1
Reaction time: 3 h

Procedure:
To a solution of compound 49 (250 mg containing the aromatic impurity carried over from compound 48) in EtOAc (40 mL) was added Pd/C (100 mg) at room temperature. Hydrogenation was carried out under 60 psi H2. After 3 h, the pressure was released and the mixture was filtered through Celite which was washed with EtOAc (100 mL). Solvent was removed and the residue was purified by flash column chromatography (silica gel eluted with 10% EtOAc in hexanes) to give compound 50 (250 mg containing the aromatic impurity carried over from compound 48): 1H NMR (CDCl3) δ 4.64 (s, 2H), 3.85-3.80 (m, 1H), 3.34 (s, 3H), 0.83 (s, 3H); 13C NMR (CDCl3) δ 121.2, 94.3, 71.8, 54.9, 48.3, 47.9, 46.7, 44.9, 44.4, 39.7, 38.1, 37.9, 36.6, 33.8, 33.7, 30.0, 28.3, 26.3, 26.2, 23.7, 14.2.
Reaction SMILES: [CH3:1][C:2](=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]C.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[C:20]=1[N:29]=[C:30]=[O:31].C([N-]C(C)C)(C)C.[Li+]>>[O:16]=[C:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:1][C:30]([NH:29][C:20]1[C:19]([O:18][CH3:17])=[CH:24][C:23]([O:25][CH3:26])=[CH:22][C:21]=1[O:27][CH3:28])=[O:31]
Reactant: COc1cc(OC)c(N=C=O)c(OC)c1
Reactant: CCCCCCCCCCCCCC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CCCCCCCCCCCCC(=O)CC(=O)Nc1c(OC)cc(OC)cc1OC

Procedure:
The title compound was prepared from 2-pentadecanone (0.54 g, 0.0023 mol), 2,4,6-trimethoxyphenyl isocyanate (prepared from 2,4,6-trimethoxyaniline hydrochloride and phosgene (2.5 eq)) and lithium diisopropylamide (0.0023 mol) using the procedure described in Example 1.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][O:11]C(=O)C)[N:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CO>O>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][OH:11])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(COC(C)=O)cs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(=O)Nc1nc(CO)cs1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
Mass (m/e): 214 (M30) . (2) A mixture of 2-acetylamino-4-acetoxymethylthiazole (72 g), potassium carbonate (23.2 g), methanol (1.1 l) and water (0.1 l) was stirred for 3 hours and 20 minutes at ambient temperature. An insoluble material was filtered off and the filtrate was neutralized with 2N hydrochloric acid and evaporated. To the residue was added a mixture of chloroform and methanol (100 ml, 1:1 V/V) and the mixture was heated. An insoluble material was filtered off and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (10:1 V/V) to give 2-acetylamino-4-hydroxymethylthiazole (41.11 g).
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9](Cl)[N:8]=1>O>[NH2:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][CH:10]=[C:9]([O:2][CH3:1])[N:8]=1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(N)n1
Temperature: 15 °C
Yield: 86.5 %

Procedure:
Sodium methoxide, 7.78 gm (0.144 mole) and methanol 50.0 ml were mixed and cooled to 15° C. To this solution, 25.0 gm of 2-amino-6-chloro-3-nitropyridine (0.144 mole) was added while maintaining the temperature at 15° C. by external cooling. The resulting mixture was heated to 25°–30° C. and maintained at this temperature for 4–5 hrs with constant stirring. The completion of reaction was monitored by TLC. After the completion of reaction, the reaction mixture was poured in water. The precipitate thus obtained was filtered and washed with water. On drying 21.0 gm of 2-amino-3-nitro-6-methoxypyridine (86.5% yield) was obtained, with the HPLC purity of 99.0%. Melting point 167°–169° C.; 1HNMR (CDCl3) δ3.89 ppm (s, -3H, OCH3), 66.14–6.16 ppm (d, 1H), 68.24–8.27 ppm (d, 1H), 68.16 ppm (s, -2H, —NH2)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[CH:12]2)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18](=[O:20])[CH3:19])[N:13]=[CH:12]2
Reactant: CC(=O)n1ncc2cc(OCc3ccccc3)ccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)n1ncc2cc(O)ccc21
Yield: 60.5 %

Procedure:
A suspension of 1 g of 1-(5-benzyloxyindazol-1-yl)ethanone, 1.42 g of ammonium formate and 0.59 g of palladium-on-charcoal at 10% in ethanol is refluxed for 16 hours. After returning to 20° C., the reaction mixture is filtered through a bed of celite and the filtrate is evaporated under reduced pressure. The crude compound thus obtained is triturated in 10 ml of diisopropyl ether and then filtered and dried under reduced pressure to obtain 400 mg of 1-(5-hydroxy-indazol-1-yl)-ethanone, which is characterized.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8].[CH3:10][CH:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:10][C:11]1([CH2:1][CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8])[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17]
Reactant: CC1C(=O)CCC1=O
Reactant: C=CCCCC(=O)C=C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCCCC(=O)CCC1(C)C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 30 h

Procedure:
1,7-Octadien-3-one(1.782 g), 2-methyl-1,3-cyclopentanedione (2 g) and triethylamine (4 ml) are added to ethyl acetate (40 ml) and the mixture is stirred at room temperature for 30 hours. The triethylamine and ethyl acetate are evaporated off and the residue is purified by silica gel column chromatography (methylene chloride) to recover 2.744 g of the above-indicated compound. [IR 1723 cm-1, 1641 cm-1, 918 cm-1 ; NMR 1.02 ppm (3H, singlet, --CH3), 4.7-6.2 (3H, multiplet, vinyl)].
Reaction SMILES: [CH:1]1([C:6]2([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]3)[CH2:11][C:10]([OH:12])=[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)[C:8](=[O:25])[O:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl>O1CCOCC1>[CH:1]1([C:6]2([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:31][CH2:32][NH:33][CH2:34][CH2:35]3)[O:7][C:8](=[O:25])[C:9]([CH2:13][C:14]3[N:24]=[C:17]4[N:18]=[C:19]([CH3:23])[CH:20]=[C:21]([CH3:22])[N:16]4[N:15]=3)=[C:10]([OH:12])[CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(CC3=C(O)CC(CCCCC4CCN(C(=O)OC(C)(C)C)CC4)(C4CCCC4)OC3=O)nc2n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCCCC4CCNCC4)(C4CCCC4)OC3=O)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(4-{2-cyclopentyl-5-[(5,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-6-oxo-3,6-dihydro-2H-pyran-2-yl}butyl)piperidine-1-carboxylate (example B(41)) (0.47 g, 0.8 mmol) was dissolved in dioxane (1 mL) and 4N HCl in dioxane (1 mL). The reaction was stirred overnight at room temperature. Solvents were removed and the residue was purified using a Dionex system (30-70% CH3CN/H2O (0.1% AcOH). H NMR (400 MHz, DMSO-d6): δ 1.37-1.70 (m, 20 H), 2.63-2.85 (m, 12 H), 3.69-3.95 (m, 4H), 7.98 (s, 1H), 11.12 (s, 1H). Anal. Calcd. For C27H39N5O3.1.0HCl. 1.5 H2O: C, 59.49; H, 7.95; N, 12.85, Found: C, 59.60; H, 8.04; N, 12.95. ESIMS (MH+): 482.