Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:30])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:29]=[CH:28][C:12]2[CH:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[C:14]3[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=3[CH2:16][CH2:17][C:11]=2[CH:10]=1)C.C1COCC1.[OH-].[Li+]>O.CO>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][CH2:22][CH:13]1[C:12]2[CH:28]=[CH:29][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])=[CH:10][C:11]=2[CH2:17][CH2:16][C:15]2[CH:18]=[CH:19][CH:20]=[CH:21][C:14]1=2
Reactant: CCOC(=O)CCCOc1ccc2c(c1)CCc1ccccc1C2CCCN(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a solution of 875 mg of 7 (2.1 mmol) in 10 ml of freshly distilled THF was added a solution of 875 mg of lithium hydroxide in 10 ml of water and 5 ml of methanol. The reaction was allowed to stir at room temperature 18 hours and concentrated to remove THF and methanol. The aqueous residue was adjusted to pH 6 with 6N HCl. This was extracted with 3×100 ml of dichloromethane. The pH of the aqueous part was readjusted to 6 again after first extraction. The combined organic part was dried (Na2SO4) and concentrated to give 790 mg (2.0 mmol, 97%) of 8 as white amorphous solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CCOCC.C([O:14][C:15](=O)[C:16]([CH3:21])([CH3:20])[CH:17]([CH3:19])[CH3:18])C>C(C1C=CC=CC=1)C>[CH3:20][C:16]([CH3:21])([CH:17]([CH3:19])[CH3:18])[CH2:15][OH:14].[CH3:20][C:16]([CH3:21])([CH:17]([CH3:19])[CH3:18])[CH2:15][OH:14]
Reactant: CCOC(=O)C(C)(C)C(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CCc1ccccc1
Product: CC(C)C(C)(C)CO
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A 500 mL round-bottom-flask equipped with a stir bar was flushed with Ar and charged with 50 mL dry THF and a 1 M solution of LAH in Et2O (87.5 mL, 87.5 mmol, 0.625 equiv). The solution was cooled to 0° C. with an ice bath and the above ethyl ester (22.1 g, 140 mmol, 1.0 equiv) (approximately a 50% solution in ethylbenzene) was added dropwise at such a rate that the solution did not reflux (required 50 min). After addition of the ester, the reaction was stirred at 0° C. for 2 h and then at ambient temperature for 14 h. The reaction solution was re-cooled to 0° C. and carefully quenched by addition of EtOAc. 1 N NaOH was added until a granular precipitate formed (7.5 mL). The mixture was filtered on a pad of diatomaceous earth which was then washed 3×100 mL Et2O. The organics were combined and dried over Na2SO4. The solution was decanted and concentrated in vacuo to yield 2,2,3-trimethyl-butanol 2,2,3-trimethyl-butanol as a nearly colorless oil (11.7 g of alcohol in 15.4 g of a mix with ethylbenzene). The crude product was used without further purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:17][C:18]1[CH:26]=[CH:25][C:21]([CH:22]2[O:24][CH2:23]2)=[CH:20][CH:19]=1.[H-].[Na+].C(O)(C(F)(F)F)=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:16][CH2:15][C:6]2[N:7]([CH2:23][CH:22]([C:21]3[CH:25]=[CH:26][C:18]([CH3:17])=[CH:19][CH:20]=3)[OH:24])[C:8]3[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: Cc1ccc(C2CO2)cc1
Reactant: CCN1CCc2[nH]c3ccc(C)cc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2c(c3cc(C)ccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 14.3 %

Procedure:
2-Ethyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole (214 mg, 1 mmol), 4-methylstyrene oxide (1 mL, 7.5 mmol) and NaH (120 mg, 3 mmol) were heated in DMF (4 mL) at 120° C. for 16 h (overnight) to obtain 50 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min., injection vol. 5 mL). 1H NMR (CDCl3, TFA salt) δ (ppm): 13.20 (bs, 1H), 7.4-7.0 (m, 7H), 5.05-4.97 (m, 1H), 4.70 (t, 1H), 4.25-4.10 (m, 3H), 3.70-3.60 (m, 1H), 3.40-3.10 (m, 5H), 2.5 (s, 3H), 2.38 (s, 3H), 1.41 (t, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[Br-:7].[CH2:19]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH3:8]
Reactant: CCCCCCCCCCCCBr
Reactant: c1ccncc1
Product: CCCCCCCCCCCC[n+]1ccccc1
Product: [Br-]

Procedure:
Dodecyl pyridinium bromide (DDPB) was prepared in a stirred three neck flask (250 ml) fitted with a reflux condenser and a type j thermocouple probe. Heat was supplied by a Glascol mantel controlled with an IR2 digital temperature controller. In each test, 64.2 grams of alcohol, glycol or glycol ether, 20.7 grams of pyridine (0.26 mole) and 65.1 grams (0.26 mole) of 1-bromo dodecane were placed in the flask. The flask was heated with stirring to 85° C. An exotherm was encountered which caused the temperature to rise to about 100° C. The temperature controller was adjusted to 95° C. and this temperature was maintained throughout the preparation. At set times, samples were drawn and the bromide concentration was determined on a Mettler Model 25 autotitrator using the chloride specific ion silver nitrate method. The reaction was terminated when the bromide concentration reached 96% of the theoretical value.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.N([F:44])(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O>C1COCC1>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([F:44])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Solvent: C1CCOC1
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(F)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butylitium at −78° C. After stirring at −78° C. for 10 min, (PhSO2)2NF was added and the resulting mixture was stirred at −78° C. for 30 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with brine and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the title compound. 1H NMR(CDCl3) d 6.77(s, 1H), 6.73(s, 1H), 6.08(s, 1H), 3.3(m, 1H), 2.12(s, 3H), 2.09(s, 6H), 2.08(s, 3H), 1.4-1.8(m, 4H), 0.97(t, 6H), ppm.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:28]=[C:29]([OH:36])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34].O>CN(C)C=O>[CH3:26][C:27]1[CH:28]=[C:29]([O:36][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:30]=[CH:31][C:32]=1[N+:33]([O-:35])=[O:34]
Reactant: Cc1cc(O)ccc1[N+](=O)[O-]
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCCCOc1ccc([N+](=O)[O-])c(C)c1
Temperature: 110 °C
Reaction time: 60 h
Yield: 112.9 %

Procedure:
1-Bromooctadecane (43.54 g, 0.131 mol) and potassium carbonate (54.15 g, 0.392 mol) were added to a solution of 3-methyl-4-nitrophenol (20 g, 0.131 mol) in dimethylformamide (120 mL) The reaction mixture was heated to 110° C. and stirred at this temperature for 60 hours. The reaction mixture was cooled and poured into water (2 L), stirred for 0.5 hour and extracted with methylene chloride (1 L). The organic extract was washed with 5% aqueous solution sodium bicarbonate (0.5 L), water (2×0.6 L), dried over sodium sulfate and concentrated to give (60 g) of crude product. This product was used in the next step without purification.
Reaction SMILES: [C:1]([O-:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[C:13]([O-:24])(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([O-:19])=[O:18])[CH:15]=1.OCC(C)(CO)C.[C:32]([OH:43])(=[O:42])[C:33]1[CH:41]=[CH:40][C:36]([C:37]([OH:39])=[O:38])=[CH:35][CH:34]=1.CO.CO.C1CCCCC1>>[CH:14]1([C:9]2[C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=[C:2]([C:1]([O-:12])=[O:11])[CH:10]=2)[CH2:22][CH2:21][CH2:20][CH2:16][CH2:15]1.[C:13]([O-:24])(=[O:23])[C:14]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([O-:19])=[O:18])[CH:15]=1.[C:32]([O-:43])(=[O:42])[C:33]1[C:34](=[CH:35][C:36](=[CH:40][CH:41]=1)[C:37]([O-:39])=[O:38])[C:6]([O-:8])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: O=C([O-])c1ccc(C(=O)[O-])cc1
Agent: CC(C)(CO)CO
Agent: O=C([O-])c1cccc(C(=O)[O-])c1
Solvent: CO
Solvent: C1CCCCC1
Product: O=C([O-])c1ccc(C(=O)[O-])c(C(=O)[O-])c1
Product: O=C([O-])c1ccc(C(=O)[O-])c(C2CCCCC2)c1

Procedure:
The terephthalate or isophthalate from Stage I is in the form of a neopentyl glycol or cyclohexane dimethanol terephthalic acid oligomer which is then reacted in in Stage II with trimellitic anhydride or acid to provide a neopentyl or cyclohexane-terephthalate or isophthalate-trimellitate. The mole ratio of the neopentyl or cyclohexane terephthalate or isophthlate to the trimellitic anhydride or acid is in the range of between about 2.5 and about 5.5.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([CH3:11])=[CH:6]C=1C#N.[OH-:12].[Na+].[CH3:14][CH2:15][OH:16]>>[NH2:1][C:2]1[CH:9]=[C:8]([Br:10])[C:7]([CH3:11])=[CH:6][C:14]=1[C:15]([OH:12])=[O:16]
Reactant: [OH-]
Reactant: Cc1cc(C#N)c(N)cc1Br
Reactant: CCO
Agent: [Na+]
Product: Cc1cc(C(=O)O)c(N)cc1Br
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 2-amino-4-bromo-5-methylbenzonitrile (2.95 g, 14.0 mmol) in a mixture of EtOH (21 mL) and 2 M aqueous NaOH (34.9 mL, 69.9 mmol) was heated at reflux overnight. After cooling to room temperature, the ethanol was removed under reduced pressure, and the aqueous residue was diluted with water. After adjustment of the pH to about 5 with concentrated aqueous HCl, the mixture was stirred for 30 min and the precipitate was collected by filtration and washed with water. The resulting wet solid was dissolved in EtOAc, washed with brine, dried and concentrated to provide 2-amino-4-bromo-5-methylbenzoic acid as a pale yellow solid (2.92 g, 91% yield). Mass spectrum m/z 212, 214 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([C:8]([O:10]C)=[O:9])=[CH:5][C:4]=1[C:12]1[N:16]([CH3:17])[N:15]=[CH:14][CH:13]=1)[CH3:2].[Br:18]N1C(=O)CCC1=O.[OH-].[Na+]>O1CCCC1>[Br:18][C:13]1[CH:14]=[N:15][N:16]([CH3:17])[C:12]=1[C:4]1[CH:5]=[C:6]([C:8]([OH:10])=[O:9])[S:7][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1sc(C(=O)OC)cc1-c1ccnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of methyl 5-ethyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (300 mg, 1.2 mmol) [Prepared in Example 98] and N-bromosuccinimide (213 mg, 1.2 mmol) in Tetrahydrofuran (5.99 ml) was stirred in a sealed tube for 1 h at 70° C. Aqueous sodium hydroxide (4.0 ml, 23.97 mmol) was added in one portion and the solution stirred an additional 1 h. The reaction mixture was then partitioned between H2O-DCM and the pH of the aqueous phase was adjusted to ˜4 and washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated then purified via column chromatography (silica, 20% EtOAC in hexanes) yielding 4-(4-bromo-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylic acid (378 mg, 1.2 mmol, 100% yield) as a yellow oil: LCMS (ES) m/e 314, 316 (M, M+2)+.
Reaction SMILES: [CH3:1][N:2]([CH3:31])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[CH2:16][N:17]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]([NH:26][OH:27])=[NH:25])=[N:18]2)=[N:11][CH:12]=1.N1C=CC=CC=1.Cl[C:39](OCC)=[O:40]>CN(C=O)C>[CH3:31][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:14]=[C:15]([CH:28]=[CH:29][CH:30]=2)[CH2:16][N:17]2[C:22](=[O:23])[CH:21]=[CH:20][C:19]([C:24]3[NH:25][C:39](=[O:40])[O:27][N:26]=3)=[N:18]2)=[N:11][CH:12]=1
Reactant: CCOC(=O)Cl
Reactant: CN(C)CCCOc1cnc(-c2cccc(Cn3nc(C(=N)NO)ccc3=O)c2)nc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CN(C)CCCOc1cnc(-c2cccc(Cn3nc(-c4noc(=O)[nH]4)ccc3=O)c2)nc1

Procedure:
500 mg (1.18 mmol) of 1-{3-[5-(3-dimethylaminopropoxy)pyrimidin-2-yl]-benzyl}-N-hydroxy-6-oxo-1,6-dihydropyridazine-3-carboxamidine are dissolved in 15 ml of DMF, and 286 μl (3.54 mmol) of pyridine are added. 124 μl (1.30 mmol) of ethyl chloroformate are subsequently added with stirring, and the solution is stirred at 80° C. for 15 and subsequently at 100° C. for 72 h. The reaction mixture is evaporated, and the residue is purified by means of preparative HPLC; yield: 21.2 mg of “A227” trifluoroacetate; HPLC: Rt=2.07 min; LC-MS: 450 (M+H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[N:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([F:18])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH:19]([CH3:21])[CH3:20])[N:3]=1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N)n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cc(-c2ccc(F)c3ccccc23)nc(N(S(C)(=O)=O)S(C)(=O)=O)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2-Amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine (0.374 g) was dissolved in dichloromethane (25 mL) and cooled to 0° C. Triethyl amine (0.5 mL) was added to the solution and methanesulfonyl chloride (0.12 mL) in dichloromethane (5 mL) was added dropwise. After stirring the mixture for 15 miutes, another portion of triethyl amine (0.25 mL) and methanesulfonyl chloride (0.12 mL) were added sequentially. After 15 minutes, the process was repeated and tlc examination showed a single new product. The reaction mixture was evaporated to dryness and purified by silica gel chromatography, eluting with ethyl acetate/hexane mixture. The colorless crystalline material was recrystallized from hexane-ether to afford 2-(bis-methanesulfonyl)amino-4-(4-fluoronaphth-1-yl)-6-isopropylpyrimidine, (354 mg), m.p. 143.8-144.2° C.
Reaction SMILES: C1(C2(C3C=CC=CC=3)OB(C)N3CCC[C@H]23)C=CC=CC=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:25][CH:24]=1.CO>O1CCCC1>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C@@H:29]([OH:39])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:28]=1
Reactant: COC(=O)CCCCCC(=O)c1ccc(F)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCCC[C@H](O)c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 98.4 %

Procedure:
To a solution of (R)-3,3-diphenyl-1-methyltetrahydro-1H,3H-pyrrolo[1,2-c] [1,3,2]oxazaborole (1.1 g) in tetrahydrofuran (20 ml) was added at 0° C. 1M tetrahydrofuran solution of boranetetrahydrofuran complex (4 ml). To this solution were added dropwise a solution of methyl 7-(4-fluorophenyl)-7-oxoheptanoate (10.0 g, 39.6 mmol) in tetrahydrofuran (20 ml) and 1M tetrahydrofuran solution of boranetetrahydrofuran complex (20 ml), simultaneously, taking 25 minutes. The mixture was stirred for 30 minutes at the same temperature range, to which was added methanol (20 ml), followed by stirring for 30 minutes at room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to a silica gel column chromatography to give methyl (S)-7-(4-fluorophenyl)-7-hydroxyheptanoate (9.91 g). Physico-chemical properties and spectral data of this product are shown in [Table 7]. Likewise, Compound 1-2 was prepared.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[CH:33]=1)=[O:9]
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Reactant: Cc1cccc(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)c2cc(Br)ccc2OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Solid 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method B; 200 mg, 0.651 mmol) was added to a stirred suspension of CDI (106 mg, 0.651 mmol) in THF (6 ml) under nitrogen at 20° C. The reaction mixture was stirred at room temperature for 10 min and m-toluidine (69.8 mg, 0.65 mmol) was added dropwise. After refluxing for 14 h, the reaction mixture was concentrated to obtain crude product. The crude product was dissolved in 20 ml of CH2Cl2 and the organic phase was washed with 2M hydrochloric acid (5 ml), water (5×2 ml), dried over sodium sulphate and evaporated in vacuo to give yellow solid. The crude product was further purified by silica gel chromatography eluting with hexane:ethyl acetate (10:1) to yield the title compound. 120 mg.
Reaction SMILES: [H][H].[CH:3]([CH:5]1[CH2:10][CH:9]2[CH2:11][CH:7]([C:8]2([CH3:13])[CH3:12])[CH:6]1[CH3:14])=O.[NH3:15]>C(O)C.[Co]>[NH2:15][CH2:3][CH:5]1[CH2:10][CH:9]2[CH2:11][CH:7]([C:8]2([CH3:13])[CH3:12])[CH:6]1[CH3:14]
Reactant: CC1C(C=O)CC2CC1C2(C)C
Reactant: [H][H]
Reactant: N
Agent: [Co]
Solvent: CCO
Product: CC1C(CN)CC2CC1C2(C)C

Procedure:
150 g of Raney cobalt, suspended in 1,000 ml of ethanol and 3.5 kg of ammonia, are heated to 80° C in a stirred autoclave, and hydrogen is then introduced until the total pressure is 150 bars. 2,020 g of (-)-3-formylpinane are pumped in over 6 hours. The pressure is kept constant by replenishing with hydrogen. After completion of the reaction, the autoclave is allowed to cool and the pressure is then released. The reaction product, weighing 3,450 g, is worked up by fractional distillation, giving 1,450 g of structurally pure (-)-3-aminomethylpinane, which boils at 100° C at 11 mm Hg and has an optical rotation of [α]D23 = -32.6° (pure).
Reaction SMILES: [C:1]([C:4]1[CH2:5][CH:6]([C:14]([O:16][CH3:17])=[O:15])[CH:7]([CH2:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])(=O)[CH3:2].S(NN)(C1C=CC(C)=CC=1)(=O)=O>C(O)C>[CH3:11][O:10][C:8]([CH:7]1[CH2:12][CH2:13][C:4](=[CH:1][CH3:2])[CH2:5][CH:6]1[C:14]([O:16][CH3:17])=[O:15])=[O:9]
Reactant: COC(=O)C1CC=C(C(C)=O)CC1C(=O)OC
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Solvent: CCO
Product: CC=C1CCC(C(=O)OC)C(C(=O)OC)C1
Yield: 80 %

Procedure:
17 g of dimethyl 1,2,3,6-tetrahydro-4-acetyl-phthalate, prepared as described in Example 1, was refluxed in anhydrous ethanol with 14.6 g of tosylhydrazine. After removal of the solvent, 24 g of dimethyl 1,2,3,6-tetrahydro-4-(1-tosylhydrazono-ethyl)-phthalate (IV) crystallized from water: m.p. 162°-163° C m/z 408 (M+.). This compound was dissolved in chloroform, and treated at 0° C with 14 ml of catechol borane Sodium acetate was added to the reaction mixture, which was then refluxed. After washing with water, the solvent was evaporated off and the residue was purified by chromatography on a column of silica gel giving 10 g of the title compound (yield 80%): m/z 226 (M+.);
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]3[N:37]=[CH:38][N:39]=[C:9]23)[CH2:4][CH2:3]1.C(O[CH:44]([OH:47])[CH2:45]O)(=O)C.CC1C=CC(S(O)(=O)=O)=CC=1.[C:59](=O)([O-])[OH:60].[Na+]>C1(C)C=CC=CC=1>[OH:60][CH2:59][CH:45]1[CH2:44][O:47][C:2]2([CH2:7][CH2:6][CH:5]([N:8]3[C:13](=[O:14])[C:12]([CH2:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[C:28]5[NH:32][C:31](=[O:33])[O:30][N:29]=5)=[CH:20][CH:21]=4)=[C:11]([CH2:34][CH2:35][CH3:36])[N:10]4[N:37]=[CH:38][N:39]=[C:9]34)[CH2:4][CH2:3]2)[O:1]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: CC(=O)OC(O)CO
Reactant: O=C([O-])O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC3(CC2)OCC(CO)O3)c2ncnn12
Temperature: 50 °C
Reaction time: 15 h
Yield: 23 %

Procedure:
A mixture of 4-(4-oxocyclohexyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.30 g), 1,2-dihydroxyethyl acetate (0.15 g), 4-methylbenzenesulfonic acid (0.011 g) and toluene (20 mL) was heated under reflux for 24 hr using a Dean-Stark trap. The reaction mixture was added to saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in 1 M aqueous sodium hydroxide solution (3 mL), tetrahydrofuran (3 mL) and methanol (3 mL), and the mixture was stirred at 50° C. for 15 hr. The solvent was evaporated under reduced pressure, the residue was adjusted to pH 7 with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography and HPLC to give the title compound as a colorless solid (0.081 g, 23%).
Reaction SMILES: [SH:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.[Na].[CH2:8](Br)[CH2:9][CH3:10]>C(O)C>[CH2:8]([S:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1)[CH2:9][CH3:10]
Reactant: CCCBr
Reactant: Sc1nc[nH]n1
Agent: [Na]
Solvent: CCO
Product: CCCSc1nc[nH]n1
Temperature: 25 °C

Procedure:
3-Mercapto-1,2,4-triazole (20.2 g.) was added to a solution of 4.8 g. sodium in 150 ml. absolute ethanol. When dissolution was complete 24.6 g. propyl bromide was added. The stirred mixture was gradually heated to boiling under reflux, refluxed for 1 hour, cooled to room temperature and filtered. The filtrate was distilled to dryness under reduced pressure and the residue was dissolved in ether. The resulting solution was filtered, dried over anhydrous sodium sulphate and distilled under reduced pressure to give 3-propylthio-1,2,4 triazole, b.p. 143°-144° C./1 mm. This product solidified, m.p. 53°-56° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][S:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C>[N:21]1[CH:22]=[CH:23][CH:24]=[N:25][C:20]=1[N:4]1[CH2:3][CH2:2][N:1]([CH2:7][CH2:8][S:9][C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]3=[N:12][N:11]=2)[CH2:6][CH2:5]1
Reactant: c1ccn2c(SCCN3CCNCC3)nnc2c1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: c1cnc(N2CCN(CCSc3nnc4ccccn34)CC2)nc1
Yield: 45 %

Procedure:
4.8 g of 3-[2-(piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine, prepared in Example 79, and 2.1 g of 2-chloropyrimidine are heated under reflux in 140 ml of isopropanol in the presence of 2.5 g of potassium carbonate. After heating for 2 hours, the medium is cooled, the mineral substances are filtered off and the filtrate is concentrated. The oily residue is filtered on silica gel (eluent: chloroform/methanol 90/10). The resulting residue crystallizes from an ethyl ether/isopropyl ether mixture to give 2.8 g of 3-[2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethylmercapto]1,2,4-triazolo(4,3-a)pyridine in the form of crystals melting at 126°-7° C.