Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[N:10](S(C3C=CC(C)=CC=3)(=O)=O)[C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)=O)C.[C:40]1([Li])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCOCC>O1CCCC1>[C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])[CH:14]=[CH:13][CH:12]=3)(=[O:3])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: CCOC(=O)c1ncc2c(c1COC)c1c(Cc3ccccc3Cl)cccc1n2S(=O)(=O)c1ccc(C)cc1
Reactant: [Li]c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COCc1c(C(=O)c2ccccc2)ncc2[nH]c3cccc(Cc4ccccc4Cl)c3c12
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 16 %

Procedure:
To a solution of 1.2 g (0.0021 mol) of 5-(2-chlorobenzyl)-4-methoxymethyl-9-tosyl-β-carboline-3-carboxylic acid ethyl ester in 60 ml of absolute tetrahydrofuran is slowly added 2.4 ml of a 2-molar solution of phenyllithium in bezene/ether at -70° C. under argon protection. The reaction mixture is stirred for another 15 minutes at -70° C. then for 3 hours at room temperature and finally for one hour at 35° C. The it is concentrated by evaporation. The residue is taken up in 150 ml of ethyl acetate. The solution in succession is washed with citric acid solution, water, sodium bicarbonate solution, water, saturated common salt solution and once more with water, dried and concentrated by evaporation. After chromatography on silica gel with equal parts of toluene and ethyl acetate and recrystallization from ethanol, 0.15 g (16% of theory) of 3-benzoyl-5-(2-chlorobenzyl)-4-methoxymethyl-β-carboline is obtained, melting point 147°-148° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[N:10].[CH2:12]([O:14]CC)C>CO>[NH:10]=[C:9]([O:14][CH3:12])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH3:2])=[O:11]
Reactant: COC(=O)CCCCC#N
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: COC(=N)CCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
Bubble hydrogen chloride (g) through a 0° C. solution of 5-cyano-pentanoic acid methyl ester (3.0 mL; 1.00 equiv; 22.02 mmoles) in methanol (5 mL), and ethyl ether (10 mL) for 1 hour. Allow the solution to warm to room temperature then add 50 mL ethyl ether, stir vigorously for 15 minutes, then filter and collect the resulting precipitate. Wash the solid with ethyl ether to afford methyl 6-imino-6-methoxy-hexanoate (3.82 g; 83%): 1H NMR (DMSO) δ 1.47-1.62 (m, 4H), 2.31 (t, 2H), 2.59 (t, 2H), 3.56 (s, 3H), 4.03 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][CH2:18][OH:19])[N:16]=2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>CO.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([C:12]2[NH:13][CH:14]=[C:15]([CH2:17][CH2:18][OH:19])[N:16]=2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(-c2nc(CCO)c[nH]2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COc1cc(-c2nc(CCO)c[nH]2)ccc1N
Reaction time: 16 h

Procedure:
0.144 g (0.547 mmol) 2-[2-(3-methoxy-4-nitro-phenyl)-1H-imidazol-4-yl]-ethanol are dissolved in 100 ml of methanol and combined with 0.08 g (5%) palladium on charcoal. The reaction mixture is hydrogenated for 16 h at 20° C. and 4 bar H2 pressure. The palladium on charcoal is suction filtered and the methanol is eliminated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:10])[CH:6]=[C:7]([CH:9]=1)[OH:8].[CH2:11](I)[CH:12]=[CH2:13]>>[CH2:11]([O:10][C:5]1[CH:6]=[C:7]([OH:8])[CH:9]=[C:3]([O:2][CH3:1])[CH:4]=1)[CH:12]=[CH2:13]
Reactant: COc1cc(O)cc(O)c1
Reactant: C=CCI
Product: C=CCOc1cc(O)cc(OC)c1

Procedure:
5-Methoxyresorcinol and allyl iodide were processed as described in Example 88C to provide the title compound. MS (DCI) m/z 181 (M+H)+.
Reaction SMILES: [C:1]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[CH:16]=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([CH:23]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:20][CH2:21][CH3:22])=[O:19]>O1CCCC1>[CH2:4]([O:3][C:1]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:23][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:2])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=CC1CCCN1C(=O)OCc1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-carbobenzyloxypyrrolidine-2-carboxaldehyde (1.17 g, 5.00 mmol) in anhydrous tetrahydrofuran at -78° C. was added (carboethoxymethylene)-triphenylphosphorane (2.09 g, 6.00 mmol. 1.2 eq) as a solid portionwise. The resulting reaction mixture was stirred at room temperature under nitrogen for 2 hours, and then heated at reflux under nitrogen for 1 hour. The reaction mixture was evaporated under reduced pressure and the residue was column chromatographed using silica gel (approximately 100 g) and elution with 20% diethyl ether in hexanes to afford the title compound as a clear, colorless oil (1.11 g, 3.65 mmol, 73%): 1H NMR (CDCl3) δ 7.34-7.25 (m, 5H), 6.89-6.76 (m, 1H), 5.88-5.74 (m, 1H), 5.18-5.05 (m, 2H), 4.60-4.43 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.55-3.40 (m, 2H), 2.11-2.00 (m, 1H), 1.90-1.75 (m, 3H), 1.28 (t, J=7.1 Hz, 3H); 13C NMR (CDCl3) [Note: due to slow nitrogen inversion two conformers of the products are seen by NMR spectroscopy] δ 166.3, 154.7, 147.9, 147.4, 136.6, 128.4, 127.9, 120.9, 66.9, 65.8, 60.4, 58.1, 57.7, 46.8, 46.4, 31,6, 30.8, 23.5, 22.8, 22.6, 15.3, 14.2.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([Cl:12])[CH2:4][C:5](Cl)([Cl:10])[C:6]([F:9])([F:8])[F:7].C(CN)O>CN(C)C=O>[Cl:10][C:5](=[CH:4][CH:3]([Cl:12])[CH:2]([CH3:1])[CH3:13])[C:6]([F:7])([F:8])[F:9]
Reactant: CC(C)C(Cl)CC(Cl)(Cl)C(F)(F)F
Solvent: CN(C)C=O
Solvent: NCCO
Product: CC(C)C(Cl)C=C(Cl)C(F)(F)F
Temperature: 96 °C
Reaction time: 5 h
Yield: 71 %

Procedure:
A mixture comprising 5-methyl-2,2,4-trichoro-1,1,1-trifluorohexane (51.5 g), monoethanolamine (6.1 g), cuprous chloride (0.1 g) and dimethylformamide (100 ml) is stirred and heated at 96° C. (internal temperature) under a nitrogen atmosphere. When the initial green colour of the mixture is discharged further aliquots of monoethanolamine are added until a geen colour persists and GLC analysis shows that the starting material has been consumed. The reaction is complete after 5 hours. The crude product is isolated by precipitation with water, extraction with dichloromethane and removal of the solvent under reduced pressure. Distillation affords 2,4-dichloro-5-methyl-1,1,1,trifluorohex-2-ene (71%), b.p. 79°-82° C./100 mm Hg; 'Hnmr (CDCl3)τ9.2-8.8 (q, 6H); 8.2-7.8 (m, H); 5.6-5.3 (m, H); 3.9-3.4 (pair of doublets, H).
Reaction SMILES: [CH2:1]([C:4]1[C:9]([C:10](OCC)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[OH:11][CH2:10][C:9]1[C:4]([CH2:1][CH2:2][CH3:3])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCc1ncccc1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCc1ncccc1CO
Yield: 90 %

Procedure:
Ethyl 2-n-propylpyridine-3-carboxylate was reduced with lithium aluminum hydride by the general synthetic principle outlined in example 1, step 4, to afford 3 hydroxymethyl-2-n-propylpyridin as a yellow oil in 90% yield. 1H--NMR (CDCl3, 200 MHz) δ: 0.98 (t, 3 H); 1.72 (sextet, 2 H); 2.75 (t, 2 H); 3.35 (br s, 1 H); 4.74 (s, 2 H); 7.12 (dd, 1 H); 7.74 (dd, 1 H); 8.39 (dd, 1 H).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16](Cl)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=1)[NH2:23].C(=O)([O-])O.[Na+]>C(O)(C)C>[C:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:16]([NH:23][C:22]3[CH:24]=[CH:25][C:26]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:35])([F:36])[F:37])[CH:29]=4)=[C:20]([Cl:19])[CH:21]=3)=[N:15][CH:14]=[N:13][C:12]=2[CH:11]=[CH:10]1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(Oc2cccc(C(F)(F)F)c2)c(Cl)c1
Reactant: CC(=O)OCCCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(=O)OCCCCn1ccc2ncnc(Nc3ccc(Oc4cccc(C(F)(F)F)c4)c(Cl)c3)c21
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 50.1 %

Procedure:
To a solution of 4-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)butyl acetate (302 mg) in isopropyl alcohol (2.24 mL) was added 3-chloro-4-[3-(trifluoromethyl)phenoxy]aniline (421 mg), and the mixture was stirred in an oil bath at a temperature of 100° C. for 3.5 hrs. The reaction mixture was allowed to cool to room temperature, 5% aqueous sodium hydrogen carbonate solution (35 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×3). The organic layer washed successively with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel chromatography (eluent:hexane/ethyl acetate=95/5→20/80). The object fraction was concentrated under reduced pressure and dried to give the title compound (293 mg) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[CH:5]=1)[CH3:2].[Br:11]N1C(=O)CCC1=O>C(Cl)Cl>[Br:11][C:5]1[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: CCOC1=CC(=O)CCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CCOC1=C(Br)C(=O)CCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of 3-ethoxy-2-cyclohexenone (70 g, 499 mmol) in CH2Cl2 (300 mL) as a solvent at 0° C. under argon atmosphere was added in portions N-bromosuccinimide (91 g, 511 mmol) over a period of 1 hour. The suspension was stirred at 0° C. for 1 hour and then at room temperature for 2 hours. The solvent was removed in vacuo and CH2Cl2 added. The solution was washed twice with a cold saturated NaHCO3 solution and with cold H2O, then dried over anhydrous MgSO4, the solvent removed in vacuo and the resulting solid residue was triturated several times with Et2O, the resulting solid dried in vacuo to afford 101 g (92% yield) of the desired product as white crystals which were characterized as follows:
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9]>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9]
Reactant: COC1CCCCC1=O
Agent: [Pd]
Product: COc1ccccc1O

Procedure:
A suspension of 800 mg. of 5% palladium on charcoal (half of which has been used for a previous dehydrogenation) in 100 gm. of distilled 2-methoxycyclohexanone was stirred and refluxed under a pressure of 9 p.s.i. After 5 hours approximately 75% of the ketone was converted. The reaction was stopped and the crude product separated by filtration. Distillation afforded a high yield of o-methoxyphenol with virtually no residue in the still pot. The catalyst can be reused with no additional fresh catalyst added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Cl[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[S:11][C:12]1[N:13]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2
Reactant: ClCCc1ccncc1
Reactant: COc1ccc(OC)c(Sc2nc3c(N)ncnc3[nH]2)c1
Product: COc1ccc(OC)c(Sc2nc3c(N)ncnc3n2CCc2ccncc2)c1

Procedure:
The title compound was prepared from 8-(2,5-dimethoxy-phenylsulfanyl)-9H-purin-6-ylamine and 4-(2-chloro-ethyl)-pyridine by a procedure similar to examples 1 and 2. The compound was purified by preparative HPLC. 1H NMR (CD3OD) δ 8.68 (d, J=6.4 Hz, 2H), 8.27 (s, 1H), 7.84 (d, J=6.4 Hz, 2H), 7.06-6.98 (m, 3H), 4.75 (t, J=6.8 Hz, 2H), 3.75 (s, 3H), 3.74 (s, 3H), 3.53 (t, J=6.8 Hz, 2H); LC-MS [M+H]+ 409.1
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(ccn2-c2cccc(C#N)c2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
A solution of 4.0 g (16.1 mmole) of 3-(5-methoxy-1-indolyl)benzonitrile of Example 9a in 160 ml glacial acetic acid under nitrogen at 15°-20° C. was treated with 3.14 g (49.9 mmole, 3.1 equivalents) sodium cyanoborohydride. The reaction mixture was permitted to warm to room temperature and stir overnight (about 16 hours). The resulting solution was poured over ice (200 ml), made basic using 50% NaOH (165 ml) and extracted with chloroform (350 ml total). The combined organic extracts were washed with water (400 ml), brine (400 ml), dried over Na2SO4, and concentrated to give 3.90 g (96.8%) of the crude indoline as an oil. Crystallization from hot ethyl acetate-hexane afforded 1.87 g (46.4% overall) of 3-(5-methoxy-1-indolinyl)benzonitrile, m.p. 92.5°-93.5° C.
Reaction SMILES: [S:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[N:17]=[CH:9][C:8]1[CH:11]=[CH:12][C:5]([S:1](=[O:4])(=[O:3])[NH2:2])=[CH:6][CH:7]=1
Reactant: NS(=O)(=O)c1ccc(C=O)cc1
Reactant: Cc1ccc(N)cc1C
Product: Cc1ccc(N=Cc2ccc(S(N)(=O)=O)cc2)cc1C

Procedure:
Following a procedure similar to that described in Example 1(i), but using 4-sulfamoylbenzaldehyde and 3,4-dimethylaniline as starting materials, the title compound was obtained as a yellow powder (yield 60%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[C@@H:4]([NH:26][C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])[CH2:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][C@@H:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:16][CH:15]=3)[CH2:12][O:13][C:8]=2[CH:7]=1.C=O.F[C:40](F)(F)C(O)=O.C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]([C@@H:4]1[CH2:5][C:6]2[CH:7]=[C:8]3[O:13][CH2:12][C@H:11]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21](=[O:23])[CH3:22])=[CH:18][CH:19]=4)[O:10][C:9]3=[CH:24][C:25]=2[CH2:40][N:26]1[C@H:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:28][CH3:29])=[O:36]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](N[C@@H](Cc1ccc2c(c1)OC[C@H](c1ccc(OC(C)=O)cc1)O2)C(=O)OC)c1ccccc1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OC(C)=O)cc1)O3
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(S)-3-[(S)-2-(4-Acetoxy-phenyl)-2,3-dihydro-benzo[1,4]dioxin-6-yl]-2-((S)-1-phenyl-propylamino)-propionic acid methyl ester (110 mg) was dissolved in 32 mL dry dioxane and 20 mg paraformaldehyde and 8 mL trifluoroacetic acid were added. The reaction stirred 48 h at rt. NaHCO3 was added until a pH of 7 was achieved, then the mixture was extracted with EtOAc. The organic extract was washed with brine and dried over Na2SO4 and evaporated. The residue was purified by silica gel flash chromatography (9:1 to 8:2 hexanes/EtOAc) to give 120 mg desired product. LCMS (m/z): 503.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[CH:5][C:4]([C:7]2(O)[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)=[CH:3][CH:2]=1.Cl>C1COCC1.O>[C:1]1([CH3:17])[CH:2]=[CH:3][C:4]([C:7]2[CH2:15][C:14]3[C:9]([CH:8]=2)=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:5][CH:6]=1
Reactant: Cc1ccc(C2(O)Cc3ccccc3C2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C2=Cc3ccccc3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 93 %

Procedure:
To a solution of 2-(p-tolyl)-2-indanol (17.27 g, 77.01 mmol) in THF (200 mL) was added a solution of concentrated hydrochloric acid (40 mL) in water (60 mL). The solution was stirred at room temperature overnight (12 h). The solid was collected and washed with pentane (50 mL) and then tetrahydrofuran (50 mL) to give 14.77 g of 2-(p-tolyl)-1H-indene. 1 H-N.M.R. (CDCl3) d 2.43(s, 3H), d 3.83 (br s, 2H), d 7.20-7.35(m, 5H), d 7.45(br d, J=7.1 Hz, 2H), d 7.55(br d, J=7.1 Hz, 2H), d 7.60 (br d, J=7.1 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[C:5]#[N:6].Cl[CH2:13][CH2:14][CH2:15][C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH2:17][CH2:16][CH2:15][C:14]#[CH:13])[C:5]#[N:6]
Reactant: C#CCCCCl
Reactant: Cc1cc(C#N)cc(C)c1O
Agent: CN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C#CCCCOc1c(C)cc(C#N)cc1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
A mixture of 40 g 3,5-dimethyl-4-hydroxybenzonitrile, 32 ml 5-chloro-1-pentyne (d=0.968) and 74.63 g milled potassium carbonate in 25 ml N-methylpyrrolidine was heated under nitrogen at 100° C. with stirring for four hours. The mixture, after cooling to room temperature and addition of 300 ml water, was extracted with ethyl acetate. The ethyl acetate extracts were washed with aqueous 2N sodium hydroxide solution and saturated sodium chloride solution, dried (MgSO4) and then concentrated in vacuo. The residue was subjected to flash filtration (activated magnesium silicate; ether/hexane) and the filtrate was concentrated in vacuo to give, after recrystallization (methyl alcohol/0° C.) 34.64 g of the title compound.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]3C(=O)C4=CC=CC=C4C3=O)=[C:18]([C:31](=[O:34])[CH2:32][Cl:33])[N:17]=[CH:16]2)[C@@H:6]1[Cl:35])(=[O:3])[CH3:2].O.NN>ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([NH2:20])=[C:18]([C:31](=[O:34])[CH2:32][Cl:33])[N:17]=[CH:16]2)[C@@H:6]1[Cl:35])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N2C(=O)c3ccccc3C2=O)[C@H](Cl)[C@@H]1OC(C)=O
Agent: NN
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)CCl)c2N)[C@H](Cl)[C@@H]1OC(C)=O

Procedure:
Compound (38) obtained in step (4) above (310 mg) was dissolved in dichloromethane (12 ml), to which was then added hydrazine monohydrate (0.032 ml) under cooling at 0° C. The resultant mixture was stirred at that temperature for 1 hour to conduct the reaction intended and thereby afford the titled compound (39). The resulting reaction solution containing compound (39) was filtered and the filtrate was concentrated to leave a solid, which was purified by silica gel column chromatography (developer solvent: toluene-ethyl acetate, 1:2), to yield the titled compound (39) as a colorless solid (221 mg). Yield: 95%.
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[OH-].[Na+].Cl[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]>O>[C:11]([NH:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4])([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: N[C@@H](CO)C(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
L-Serine (20.00 g, 190.3 mmol) was dissolved in water, and aqueous sodium hydroxide was added to adjust the pH of the solution to about 8.5 while maintaining the temperature at about 25° C. Benzyl chloroformate (36.0 g, 211.0 mmol) was added while the pH was maintained between 8.3 and 8.5 by the addition of aqueous sodium hydroxide and the temperature was maintained at about 30° C. The mixture was stirred for about 2 hours. The reaction mixture was extracted with methylene chloride. The phases were separated, and the pH of the aqueous phase was adjusted to about 7 with concentrated hydrochloric acid. The aqueous phase was heated to about 40° C. under low vacuum to remove any residual methylene chloride. Water was added and the aqueous solution was heated to about 60° C. The pH was adjusted to about 2 with concentrated hydrochloric acid while maintaining the temperature at about 60° C. The solution was cooled to about 50° C. while stirring and seed crystals were added. With stirring, cooling was continued to about 0° C. to complete the crystallization. The product was collected and the cake was washed with cold (about 5° C.) water. The product was dried under vacuum at about 40° C. to afford carbobenzyloxy-L-serine.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:57][CH2:58][CH3:59])[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:8]=1[C:9]([O:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[O:10])[CH3:3]>C(O)(=O)C>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:57][CH2:58][CH3:59])[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[C:8]=1[C:9]([O:11][CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCCc1nc(C(C)O)c(C(=O)OCOC(=O)C(C)(C)C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 60.8 %

Procedure:
Following a procedure similar to that described in Example 35(c), but using 2.87 g of pivaloyloxymethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] and 75% v/v aqueous acetic acid. 1.21 g of the title compound was obtained as a powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][CH3:20])=[C:6]([C:8]([CH3:18])([CH3:17])[CH2:9][C:10]2([C:13]([F:16])([F:15])[F:14])[CH2:12][O:11]2)[CH:7]=1.[N:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([NH2:36])[C:30]=3[CH:29]=[N:28]2)=[CH:23][CH:22]=1>>[F:14][C:13]([F:16])([F:15])[C:10]([CH2:12][NH:36][C:31]1[CH:32]=[CH:33][CH:34]=[C:35]2[C:30]=1[CH:29]=[N:28][N:27]2[C:24]1[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=1)([OH:11])[CH2:9][C:8]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[O:19][CH3:20])([CH3:18])[CH3:17]
Reactant: COc1ccc(F)cc1C(C)(C)CC1(C(F)(F)F)CO1
Reactant: Nc1cccc2c1cnn2-c1ccncc1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(CNc1cccc2c1cnn2-c1ccncc1)C(F)(F)F

Procedure:
Prepared similarly to Example 1 from racemic 2-{2-[5-fluoro-2-(methyloxy)phenyl]-2-methylpropyl}-2-(trifluoromethyl)oxirane and 1-(4-pyridinyl)-1H-indazol-4-amine (Intermediate 5).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].O>O1CCCC1>[CH3:3][C:4]([CH2:23][C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:26][CH:25]=1)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CC(=O)Nc1ccc(CCl)cc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(Cc1ccc(NC(C)=O)cc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Suspend sodium hydride (10.1 g, 0.21 mol) in tetrahydrofuran (300 mL), place under a nitrogen atmosphere and cool to 0° C. Add, by dropwise addition, diethyl methylmalonate (34.8 g, 0.2 mol). Stir for 30 minutes at 0° C. and add 4-acetamidobenzyl chloride (38.6 g, 0.21 mol). Heat at reflux for 5 hours, cool and pour into water (400 mL). Extract with ethyl acetate (3×600 mL), dry (MgSO4) and evaporate the solvent in vacuo to give diethyl methyl-(4-acetamido)benzylmalonate.