Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH2:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:25]([C:34](OC)=[O:35])=[CH:24]2)=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.O>O1CCCC1>[CH3:7][N:8]([CH2:15][CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[CH:27]=[C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:25]([CH2:34][OH:35])=[CH:24]2)=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: COC(=O)c1cn(Cc2ccc(OCCN(C)c3ccccn3)cc2)cc1-c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(CCOc1ccc(Cn2cc(CO)c(-c3ccccc3)c2)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
Lithium aluminium hydride (305 mg) was added to a solution of methyl 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolecarboxylate (1.78 g) in tetrahydrofuran (40 ml) at 0° C., and the mixture was stirred at room temperature for 6 hours. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and [1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]methanol (1.45 g, yield: 87%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][C:2]1([CH:18]=[O:19])[CH2:17][CH2:16][CH2:15][C:4]2([O:8][C:7](=[O:9])[N:6]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5]2)[CH2:3]1.CO.[BH4-].[Na+]>C1COCC1>[OH:19][CH2:18][C:2]1([CH3:1])[CH2:17][CH2:16][CH2:15][C:4]2([O:8][C:7](=[O:9])[N:6]([CH2:10][C:11]([CH3:13])([CH3:14])[CH3:12])[CH2:5]2)[CH2:3]1
Reactant: CC(C)(C)CN1CC2(CCCC(C)(C=O)C2)OC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)CN1CC2(CCCC(C)(CO)C2)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
The 7-methyl-3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decane-7-carbaldehyde intermediate product from step 1 (7.19 g, 26.9 mmol) was dissolved in THF (108 mL) and MeOH (27 mL) and treated with sodium borohydride (1.22 g, 32.3 mmol). The reaction was stirred at rt for 2 h and quenched with water (1 mL) and 1 N HCl (75 mL). The product was extracted into EtOAc (2×100 mL). The combined organics were dried over Na2SO4, filtered, and concentrated onto florisil for purification on a 120 g silica gel column (10-50% EtOAc/hexanes, 30 min gradient; 50% EtOAc/hexanes, 10 min; 50-75% EtOAc/hexanes, 10 min gradient; 85 mL/min elution; 254 nm detection) to afford the title compound (6.23 g, 75% combined yield with step 1). 1H NMR (400 MHz, CDCl3) δ 3.30-3.38 (m, 2H), 3.29 (s, 2H), 3.06 (d, J=14.05 Hz, 1H), 2.94 (d, J=14.05 Hz, 1H), 1.95-2.03 (m, 1H), 1.64-1.72 (m, 1H), 1.53-1.64 (m, 3H), 1.29-1.43 (m, 3H), 1.09 (s, 3H), 0.96 (s, 9H). MS (m/z) 270.2 (M+H+).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:25]=[CH:24][C:7]2[N:8]([CH3:23])[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH2:11][C:12](=[CH:13][C:14]([O:16]CC)=[O:15])[C:6]=2[CH:5]=1)[CH3:2].[OH-].[K+].Cl>C(O)C>[CH2:1]([S:3][C:4]1[CH:25]=[CH:24][C:7]2[N:8]([CH3:23])[C:9]3[CH:22]=[CH:21][CH:20]=[CH:19][C:10]=3[CH:11]=[C:12]([CH2:13][C:14]([OH:16])=[O:15])[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)C=C1Cc2ccccc2N(C)c2ccc(SCC)cc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCSc1ccc2c(c1)C(CC(=O)O)=Cc1ccccc1N2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.1 %

Procedure:
A mixture of 27.3 g of 2-ethylthio-5-methyl-11-ethoxycarbonylmethylene-10,11-dihydro [5H] dibenzo (b,f) azepine in 750 ml of ethanol was stirred until complete dissolution occured and then 120 g of potassium hydroxide were added. The mixture was held at room temperature for 30 minutes and then was poured into a mixture of 2 kg of ice and 270 ml of hydrochloric acid. The mixture was stirred for 30 minutes and was extracted with methylene chloride. The organic phase was washed with water, dried over magnesium sulfate and distilled to dryness under reduced pressure. The 23 g of product were dissolved in 200 ml of refluxing ethyl acetate and the solution was filtered and was slightly concentrated. Crystallization was induced and the mixture was iced for 30 minutes and then vacuum filtered. The recovered precipitate was washed with ethyl acetate and dried under reduced pressure to obtain 19.64 g of 2-ethylthio-5-methyl-11 -carboxymethyl [5H] dibenzo (b,f) azepine which was used as is for the next step. For analysis, the product was crystallized from ethyl acetate and was a yellow crystalline solid melting at 164°C.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]1([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][CH:7]=1>>[Cl:4][C:8]1[CH:7]=[C:6]([CH3:13])[C:11]([OH:12])=[CH:10][CH:9]=1
Reactant: Cc1ccccc1O
Reactant: O=S(=O)(Cl)Cl
Product: Cc1cc(Cl)ccc1O
Yield: 84 %

Procedure:
The chlorination of aromatic compounds with sulfuryl chloride is generally known. For example, DuBois in Z. F. Chem. 705 (1866) reported that treatment of molten phenol with an equal molar amount of sulfuryl chloride yields only p-chlorophenol. Sulfuryl chloride was first reported as a chlorinating agent for o-cresol by Sah and Anderson in J. Am. Chem. Soc. 63, 3164 (1941). Their data showed that o-cresol reacted with sulfuryl chloride to yield 84% of the 4-chloro-o-cresol.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][NH2:12]>C(O)C>[NH:11]([C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: NN
Solvent: CCO
Product: NNc1ncccc1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
To a suspension of 14.3 g of 2-chloro-3-nitropyridine in 90 mL of anhydrous ethanol was slowly added over 2-3 min with swirling 18 mL of 95% hydrazine. A new solid took the place of the chloro compound as spontaneous warming occurs. After 20 min at room temperature, filtration and washing with ethanol gave 15 g of 2-hydrazino-3-nitropyridine as a straw-yellow solid. To 4 g of the crude hydrazine suspended in 24 mL of anhydrous ethanol was added 16 mL of 95% hydrazine, and the mixture was warmed on a hot plate until the solid dissolved to give a deep red-colored solution and a spontaneous reaction set in with bubbling. The mixture was removed from the source of heat and the reaction allowed to proceed. After 5 min, the mixture was again heated to the boiling point and removed from the hot plate for 5 min. The mixture was treated twice more in this manner after which the deeply-colored solution had become lighter in color (reddish yellow). The solution was evaporated in a warm bath with a water aspirator to a brown oily material which was dissolved in 12 mL of water and acidified (Congo Red) with conc. HCl. Recrystallization from water (Norite) gave 1.10 (31%) of the hydroxytriazole as yellow-colored crystals, mp 203°-211° dec.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.Cl.[NH2:29][OH:30].C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[CH:20]=[C:19]([O:21][CH2:22][CH:23]=[C:24]([Cl:26])[Cl:25])[CH:18]=[C:17]([Cl:27])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:29][OH:30])=[NH:14])=[CH:15][CH:16]=1
Reactant: N#Cc1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1

Procedure:
1.1 g of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-benzonitrile, 247 mg of hydroxylamine hydrochloride and 430 mg of triethylamine are stirred for 48 hours at 80° C. in 25 ml of ethanol. The reaction mixture is poured onto water and extracted with ethyl acetate. Concentration of the organic phase and crystallisation from diethyl ether yield 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine having a melting point of 144-146° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:27])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH:24]=[CH:25][CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([CH:24]=[CH:25][CH3:26])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:27]
Reactant: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC=Cc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
The mixture 2-[3-methyl-2-(1-propenyl)-benzoylamino]-indan-2-carboxylic acid ethyl ester (142) (340 mg, 0.94 mmol) and KOH (700 mg, 12.5 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (30 mL) and acidified with conc. HCl until no more precipitate came out of the water. The precipitate is filtered to give a pure product (143) as white solid (315 mg, 100%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[OH:14].[OH-].[Na+]>O>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[O:14][C:2]([O:4][CH3:5])=[O:3]
Reactant: Oc1ccc(F)cc1F
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
Methyl chloroformate (16.35 ml, 0.173 mol) was added to a solution of 2,4difluorophenol (25 g, 0.192 mol) and sodium hydroxide (8.1 g, 0.203 mol) in water (140 ml). The mixture was stirred at ambient temperature for 2 hours and then extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and the volatiles removed by evaporation to give 2,4-difluoro-1-methoxycarbonyloxybenzene (32 g, 89%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][C:29]([CH3:34])([C:31](O)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.N1C=CC=CC=1>[C:18]([NH:28][C:29]([CH3:34])([C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.00 g, 13.0 mmol) was dissolved in a solvent mixture of dimethylformamide (200 ml) and pyridine (100 ml). To this solution, N-carbobenzyloxy-α-methylalanine (4.64 g, 19.5 mmol) and WSC-HCl (3.48 g, 19.5 mmol) were added and the mixture was stirred at 50° C. for 48 hours. The reaction mixture was condensed under reduced pressure, and the residue was subjected to extraction using a solvent mixture (chloroform--methanol =4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol=25:1). The crude crystals were subjected to a recrystallizing procedure from chloroform--methanol. As a result, 2.55 g of the title compound was obtained as colorless powdery crystals (43.7%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].[NH:23]1[CH:27]=[CH:26][CH:25]=[N:24]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([N:23]2[CH:27]=[CH:26][CH:25]=[N:24]2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Reactant: c1cn[nH]c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-n2cccn2)c1

Procedure:
To a stirred solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (0.15 g, 0.367 mmol) in 1 ml DMF was added pyrazole (0.062 g, 0.917 mmol), CuI (0.03667 mmol), 1,10-phenanthroline (0.0734 mmol) and Cs2CO3 (0.734 mmol). The mixture was subjected to microwave irridation at 150° C. for 45 minutes. The reaction mixture was diluted with ethyl acetate, washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4′-Methyl-5-pyrazol-1-yl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide, MS (M+H)=350.
Reaction SMILES: F[C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.NC1C=CC=[C:17]([O:21]C)C=1O>>[CH3:17][O:21][C:2]1[C:11]2[O:10][CH:9]([CH2:12][NH2:13])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: NCC1CNc2cccc(F)c2O1
Reactant: COc1cccc(N)c1O
Product: COc1cccc2c1OC(CN)CN2

Procedure:
This compound is obtained using the same reaction sequence and the same experimental conditions as those used for the synthesis of intermediate 2b but replacing 2-amino-6-fluorophenol with 2-amino-6-methoxyphenol. This gives the title compound of formula (2e).
Reaction SMILES: [CH:1]1([OH:5])[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[C:8]([C:12]1[N:13]=[C:14](Cl)[C:15]2[N:20]=[N:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:16]=2[N:17]=1)([CH3:11])([CH3:10])[CH3:9].C(O)=O>CN(C=O)C>[C:8]([C:12]1[N:13]=[C:14]([O:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)[C:15]2[N:20]=[N:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:16]=2[N:17]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: OC1CCC1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(OC2CCC2)c2nnn(Cc3ccccc3Cl)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.4 %

Procedure:
A mixture of cyclobutanol (173 mg, 2.4 mmol) and NaH (4.8 mg, 0.12 mmol) in DMF (1 mL) was stirred for 30 min at room temperature. 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine (26.9 mg, 0.08 mmol) was added and the mixture was stirred at room temperature overnight. Formic acid added and the mixture was subjected to preparative HPLC purification on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid. The product containing fractions were evaporated to yield 4 mg (13%) of the title compound. MS (m/e): 372.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:10]=[C:11]1[O:15][C:13](=[O:14])[CH2:12]1>C(O)C>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH:5][C:13](=[O:14])[CH2:12][C:11]([CH3:10])=[O:15]
Reactant: C=C1CC(=O)O1
Reactant: COc1ccccc1N
Solvent: CCO
Product: COc1ccccc1NC(=O)CC(C)=O
Temperature: 85 °C

Procedure:
2.4 kg/h (19.5 mol/h) of 2-methoxyaniline, 1.98 kg/h (23.1 mol/h) of diketene (purity 98%) and 6.9 kg/h of aqueous 30% strength ethanol are reacted separately but simultaneously as described in Example 1. The product stream of about 0.3 l, produced under reflux at about 85° C. and kept to a constant volume by pumping out, is cooled down to about 15° C., and the reaction product is crystallized out and separated from the 5.8 kg/h of mother liquor by filtration. The light-colored solids are washed with 5.8 kg/h of aqueous 30% strength ethanol and dried, leaving 3.8 kg/h (18.3 mol/h) of 2'-methoxyacetoacetanilide, corresponding to 94% of yield based on amine. The purity of the product is better than 99.5%.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:10][CH:9]2[NH:11][CH:6]([CH2:7][CH2:8]2)[CH2:5]1.[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13].C(N1C2CCC1CN(C)C2)(OCC)=O>>[CH2:12]([NH:14][C:15]([N:11]1[CH:9]2[CH2:8][CH2:7][CH:6]1[CH2:5][N:4]([CH3:3])[CH2:10]2)=[O:16])[CH3:13]
Reactant: CN1CC2CCC(C1)N2
Reactant: CCN=C=O
Agent: CCOC(=O)N1C2CCC1CN(C)C2
Agent: Cl
Product: CCNC(=O)N1C2CCC1CN(C)C2
Yield: 33.6 %

Procedure:
3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (3.0 g, 0.0151 mole), prepared as described in Example 5, was reacted with 1.21 ml (0.0151 mole) ethyl isocyanate in a procedure as described for 8-carbethoxy-3-methyl-3,8-diazabicyclo[3.2.1]octane in Example 6. The crude desired product, as the free base, was purified by chromatography on alumina with chloroform elution. An hydrochloride salt was made by treatment of a solution of the free base in diethyl ether with ethanolic hydrogen chloride and filtering to collect 1.0 g (28% yield) white solid exhibiting a dual melting point of 100°-140° C and 191°-202° C until dried 2 hours at 126° C in vacuo after which the desired product hydrochloride salt melted at 205°-215° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([SH:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][C:13]([CH3:15])=O.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:13]([CH3:15])([CH3:12])[O:8][C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: CC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC1(C)OC(=O)c2cc(Cl)ccc2S1
Yield: 25.4 %

Procedure:
A mixture of 5-chloro-2-mercapto-benzoic acid (2.5 g, 13.25 mmol) (commercial available from Biogene Organics), acetone (7.9 g, 136 mmol), (+/−) camphor sulfonic acid (1.54 g, 6.63 mmol) and 4A moleculare sieves (1.5 g) in CHCl3 was heated to reflux for 3 days. Reaction mixture was diluted with CH2Cl2 (100 mL) and then washed with saturated NaHCO3 aqueous solution (2×50 mL). Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude residue was passed through a pad of silica gel and eluted with CH2Cl2. Filtrate was concentrated to provide the title compound (769 mg). 1H NMR (200 MHz, CDCl3): δ (ppm)=8.15 (d, J=2.4 Hz, 1H), 7.44 (dd, J=8.3, 2.0 Hz, 1H), 7.21 (d, J=8.3 Hz, 1H), 1.83 (s, 6H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28](O)=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH2:35]([O:37][C:38](=[O:48])[C@H:39]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH2:40])[CH3:36].C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.CCOC(C)=O>[C:1]1([C:7]2[N:8]=[C:9]([C:18]3[CH:19]([CH2:24][C:25]4[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=4)[C:28]([NH:40][C@@H:39]([CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:38]([O:37][CH2:35][CH3:36])=[O:48])=[O:29])[CH2:20][CH2:21][CH2:22][CH:23]=3)[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1cccc(CC2CCCC=C2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.5 %

Procedure:
To a mixture of 3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl]methyl}benzoic acid (150 mg, 0.345 mmol), L-phenylalanine ethyl ester hydrochloride (103 mg, 0.448 mmol) and diisopropylethylamine (0.078 ml , 0.448 mmol) in DMF (5 ml) was added 1-hydroxybenzotrioxazole (70 mg, 0.518 mmol) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (132 mg, 0.690 mmol). After stirring the mixture at room temperature for 4 hours, the reaction mixture was diluted with EtOAc (30 ml), washed with 1N hydrochloric acid, water, saturated sodium hydrogencarbonate solution, water, and brine. The resultant mixture was dried over magnesium sulfate, and evaporated in vacuo. The resultant residue was purified by silica gel column chromatography (hexane:EtOAc, 3:1 elution) to give ethyl (2S)-2-{3-{[2-(4,5-diphenyloxazol-2-yl)-2-cyclohexen-1-yl)methyl}benzoylamino}-3-phenylpropionate (197.1 mg, 94%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[N:3]=[CH:2]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:20][C:21]1[CH:22]=[C:23]([CH:40]=[CH:41][CH:42]=1)[O:24][C:25]1[CH:26]=[CH:27][C:28]2[N:29]([N:31]=[C:32]([NH:34][C:35]([CH:37]3[CH2:39][CH2:38]3)=[O:36])[N:33]=2)[CH:30]=1>CN(C)C=O.CN(C)C(=O)C>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([O:24][C:23]4[CH:22]=[C:21]([NH:20][C:6]([C:4]5[N:3]=[CH:2][O:1][CH:5]=5)=[O:8])[CH:42]=[CH:41][CH:40]=4)=[CH:30][N:29]3[N:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Reactant: O=C(O)c1cocn1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1)c1cocn1
Yield: 45.9 %

Procedure:
In the same manner as in Example 18-4 and using 1,3-oxazole-4-carboxylic acid (146 mg, 1.29 mmol), tetrahydrofuran (10 mL), oxalyl chloride (168 μL, 1.93 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (200 mg, 0.647 mmol), N,N-dimethylformamide (2 drops) and N,N-dimethylacetamide (10 mL) as starting materials, the title compound (120 mg, 46%) was obtained as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[NH:14][C:13]3[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[N:9]([CH3:18])[C:8]=3[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28]Br>CN(C=O)C>[Cl:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([F:34])[C:27]=1[CH2:28][N:14]1[C:13]2[C:12](=[O:15])[N:11]([CH3:16])[C:10](=[O:17])[N:9]([CH3:18])[C:8]=2[N:7]=[C:6]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Fc1cccc(Cl)c1CBr
Reactant: Cn1c(=O)c2[nH]c(C3CCCC3)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(nc(C3CCCC3)n2Cc2c(F)cccc2Cl)n(C)c1=O
Temperature: 60 °C
Yield: 14.7 %

Procedure:
A solution of 8-cyclopentyl-1,3-dimethylxanthine (100 mg, 0.40 mmol) and K2CO3 (80 mg, 0.58 mmol) was treated with 2-chloro-6-fluorobenzyl bromide (142 mg, 0.64 mmol) dissolved in 400 μL DMF. The reaction mixture was sealed and heated to 60° C. for 24 hrs. The reaction mixture was cooled and purified by preparative thin layer chromatography (silica gel, 1 mm plate, EM Science 20×20 cm silica gel 60 F264) eluting with EtOAc:hexane (1:1) to give 23 mg (14% yield) of the title compound as a white solid: 1H NMR (CDCl3, 400 MHz) 7.29-7.11 (m, 2H), 7.01-6.85 (m, 1H), 5.86 (s, 2H), 3.54 (s, 3H), 3.38 (s, 3H); 3.02-2.81 (m, 1H), 1.83-1.43 (m, 8H); MS (ESP+) m/e 391 (MH+); TLC(EtOAc:hexanes/1:1) Rf=0.58.