Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])O[C:4](=[O:9])[CH:3]=1.[NH2:10][CH2:11][C:12]1[N:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1>O>[OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:10]([CH2:11][C:12]2[CH:17]=[N:16][C:15]([CH3:18])=[CH:14][N:13]=2)[C:4](=[O:9])[CH:3]=1
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1cc(O)cc(=O)o1
Solvent: O
Product: Cc1cnc(Cn2c(C)cc(O)cc2=O)cn1
Temperature: 100 °C
Yield: 62.7 %

Procedure:
A mixture of 4-hydroxy-6-methyl-2-pyrone (5.0 g, 0.04 mol) and 5-aminomethyl-2-methylpyrazine (5.0 g, 0.041 mol) in water (25.0 ml) was heated at 100° C. for 1 h under argon atmosphere. The reaction mixture was cooled, and filtered the yellow precipitate. It was washed with ethanol, and dried in vacuo to afford the title compound (5.8 g, 63%) as a pale yellow powder: 1H NMR (DMSO-d6/400 MHz) δ10.43 (br, 1H), 8.38 (d, 2H, J=5.2 Hz), 5.77 (d, 1H, J=2.0 Hz), 5.58 (d, 1H, J=2.0 Hz), 4.92 (s, 2H), 2.24 (s, 3H), and 2.22 (s, 3H); ESMS m/z 232 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[N:4]([C:8]([CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[Br:17]N1C(=O)CCC1=O.O>ClCCl>[Br:17][C:10]1[N:9]=[C:8]([CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([CH3:1])[C:3]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nccn2c(C3CCOCC3)ncc12
Solvent: O
Solvent: ClCCl
Product: Cc1nccn2c(C3CCOCC3)nc(Br)c12
Temperature: 50 °C
Yield: 93.5 %

Procedure:
To a solution of 8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine (0.888 mmol, 193 mg) in dichloromethane (10 mL) was added N-bromosuccinimide (0.888 mmol, 158 mg) and the reaction mixture was heated at 50° C. (bath temperature) for 15 min. Dichloromethane and water were added, the organic layer separated, washed with an aqueous sodium hydrogencarbonate solution, dried (sodium sulfate) and concentrated in vacuo to afford 246 mg of 1-bromo-8-methyl-3-(tetrahydro-2H-pyran-4-yl)imidazo[1,5-a]pyrazine.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35](OCC)=[O:36])=[N:29][C:28]=3[S:27][CH:26]=2)=[CH:21][CH:20]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:83]2[CH:87]=[N:86][C:85]([O:88][CH2:89][CH2:90][O:91][C:92]3[CH:93]=[C:94]([CH2:98][NH2:99])[CH:95]=[CH:96][CH:97]=3)=[N:84]2)C=CC=CC=1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:33]3[C:32](=[O:34])[NH:31][C:30]([C:35]([NH:99][CH2:98][C:94]4[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH2:90][CH2:89][O:88][C:85]5[N:86]=[CH:87][NH:83][N:84]=5)[CH:93]=4)=[O:36])=[N:29][C:28]=3[S:27][CH:26]=2)=[CH:21][CH:20]=1
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccc(OC)cc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: COc1ccc(-c2csc3nc(C(=O)NCc4cccc(OCCOc5nc[nH]n5)c4)[nH]c(=O)c23)cc1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 5-(4-methoxyphenyl)-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 80 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (123.6 mg, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:20][C:21](O)=[O:22])[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.[CH2:24]([NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:21](=[O:22])[CH2:20][N:9]([C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[S:10]([C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: CCNCc1ccccn1
Reactant: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(OC)nc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(6-methoxy-pyridin-3-yl)-(3-methyl-pyridine-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:15])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH:10]([OH:14])[CH2:11][CH:12]=[CH2:13].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[CH2:16]([O:14][CH:10]([CH2:11][CH:12]=[CH2:13])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:15])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: C=CCC(O)Cc1ccccc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccccc1C)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (4.9 g, 127.8 mmol) in THF (150 ml) was added 1-o-tolylpent-4-en-2-ol (15 g in THF, 85.22 mmol) at 0° C. stirred for 30 min. Then added benzylbromide (17.85 g, 102.2 mmol) at 0° C. then reaction mixture was stirred for room temperature for 16 h. Then quenched with ice cold H2O and concentrated under reduced pressure to afford crude compound. The title compound was separated by separation method-A and E. (Yield 13.0 g).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[CH:6][C:7]=1[CH3:8].C1C(=O)N([Cl:18])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][CH:5]=[C:6]([Cl:18])[C:7]=1[CH3:8]
Reactant: COc1nccc(C)c1Br
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1ncc(Cl)c(C)c1Br
Temperature: 80 °C
Reaction time: 3 h
Yield: 85.4 %

Procedure:
3-bromo-2-methoxy-4-methylpyridine (100 mg) was added to DMF (575 μL). NCS (72.5 mg) was added to the solution, and the mixture was stirred at 80° C. for three hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 5% to 30%) to give the title compound (100 mg).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][C:7]([SH:12])=[N:6][C:5]=2[NH:4][CH:3]=1.[OH-].[Na+].[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1)=[O:19]>CO.COCCOC>[Cl:15][C:16]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:17]=1[C:18]([C:20]1[CH:21]=[CH:22][C:23]([CH2:24][S:12][C:7]2[NH:8][C:9](=[O:11])[C:10]3[C:2]([CH3:1])=[CH:3][NH:4][C:5]=3[N:6]=2)=[CH:26][CH:27]=1)=[O:19]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cc1c[nH]c2nc(S)[nH]c(=O)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1c[nH]c2nc(SCc3ccc(C(=O)c4ccc(Cl)cc4Cl)cc3)[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 60.9 %

Procedure:
In methanol (18.7 ml) was suspended 5-methyl-2-mercapto-7H-pyrrolo[2,3-d]pyrimidin-4(3H)-one (1.36 g) followed by addition of 1N-sodium hydroxide (7.88 ml) for dissolution. Then, under ice-cooling, a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (3.09 g) in DME (8 ml) was added dropwise. The mixture was stirred at room temperature for 4 hours and the resulting crystalline precipitate was collected by filtration and rinsed with water. The crystals were further rinsed with 50% ethanol/water, methanol and ether, dried, and recrystallized from DME (1,2-dimethoxyethane) to provide the title compound (2.03 g). 1H-NMR (DMSO-d6) δ: 2.23(3H,s), 4.48(2H,s), 6.65(1H,s), 7.53(1H,d,J=8.2Hz), 7.59(1H,dd,J=1.6,8.8Hz), 7.64(2H,d,J=8.4Hz), 7.69(2H,d,J=8.4Hz), 7.80(1H,d,J=1.6Hz), 11.40(1H,s), 11.96(1H,s).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:2].[CH2:24](O)[CH2:25][OH:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[O:2]1[CH2:24][CH2:25][O:26][CH:1]1[C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[C:11](=[O:20])[C:12]2=[CH:19][CH:18]=[CH:17][CH:16]=[C:13]2[C:14]1=[O:15]
Reactant: OCCO
Reactant: O=Cc1cccc(OCCCN2C(=O)c3ccccc3C2=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: O=C1c2ccccc2C(=O)N1CCCOc1cccc(C2OCCO2)c1
Yield: 92.5 %

Procedure:
N-[3-(3-formylphenoxy)propyl]phthalimide (29 g) was dissolved in 400 ml of benzene, and 11.67 g of ethylene glycol and 1.8 g of p-toluenesulfonic acid were added, and the mixture was heated under reflux for 7 hours while water was removed by using a Dean-Stark trap. After the reaction, the reaction mixture was cooled and the benzene layer was washed successively with a 1N aqueous NaOH solution, water, and a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 30.63 g (yield 92%) of N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}phthalimide.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17])=O)C1C=CC=CC=1>CO.[C].[Pd]>[C:19]1([NH:18][C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccccc1)[C@@H]1CCCN1
Yield: 97.7 %

Procedure:
In 150 ml of methanol was dissolved 4.87 g of compound (93) and the compound was hydrogenated using 487 mg of 10% palladium-carbon as a catalyst. The catalyst was filtered off and the filtrate was concentrated to provide 2.79 g of (S)-N-phenyl-2-pyrrolidinecarboxamide (94).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C([Mg]Br)C.[CH2:16]=[O:17].C(N(CC)CC)C>C1(C)C=CC=CC=1.CCOCC.C1COCC1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:16]=[O:17])[C:6]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1O
Reactant: C=O
Agent: CC[Mg]Br
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(C=O)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
Into a 500 ml reactor thoroughly dried and purged with argon, 7.51 g (50 mmol) of 2-tert-butylphenol and 54 ml of THF were introduced. To the reactor, 18.53 ml of an ether solution containing 55.6 mmol of ethylmagnesium bromide was dropwise added at 0° C., then the temperature of the system was slowly raised to room temperature, and the reaction solution was stirred at room temperature for 1 hour. Then, 180 ml of toluene was added, and the system was heated to 100° C. to distill off about 40 ml of a mixed solution of ether and THF, whereby an opaque white slurry was obtained. After the slurry was cooled to room temperature, 3.75 g (125 mmol) of paraformaldehyde and 10.45 ml (75 mmol) of triethylamine were added, followed by stirring at 88° C. for 1 hour. The reaction solution was allowed to cool to room temperature and then quenched with 10% hydrochloric acid. The organic layer was concentrated and purified by a silica gel column to obtain 6.22 g (yield: 70%) of 3-t-butylsalicylaldehyde.
Reaction SMILES: [CH2:1]([O:4][C:5]([C@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]([N:19]1[CH2:23][CH2:22][CH2:21][C@@H:20]1[C:24]([O:26][CH2:27][CH:28]=C)=[O:25])=[O:18])=[O:6])[CH:2]=C>ClCCl.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[N:8]12[CH2:9][CH2:10][CH2:11][C@@H:7]1[C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH:28][CH2:27][O:26][C:24](=[O:25])[C@@H:20]1[N:19]([CH2:23][CH2:22][CH2:21]1)[C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:30]
Reactant: C=CCOC(=O)[C@H]1CCCN1C(=O)CCCCC(=O)N1CCC[C@@H]1C(=O)OCC=C
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: O=C1OCC=CCOC(=O)[C@H]2CCCN2C(=O)CCCCC(=O)N2CCC[C@H]12
Temperature: 50 °C
Reaction time: 8 h
Yield: 28 %

Procedure:
A mixture of 420 mg (1 mmol) (R)-1-{6[-(R)-2-alloxycarbonyl-pyrrolidin-1-yl]-6-oxo-hexanoyl}-pyrrolidine-2-carboxylic acid allyl ester and 40 mg benzylidene-bis(tricyclohexylphosphine)dichlororuthenium in 30 ml dry dichloromethane was stirred at 50° C. overnight. Removal of the solvent and chromatography on silicagel with ethylacetate/acetone with a ratio of 8/2 gave 110 mg (28%) (12R,21R)-14,19-dioxa-1,8-diaza-tricyclo[19.3.0.0 8,12]tetracos-16-ene-2,7,13,20-tetraone as light yellow oil, MS m/e (%): 393 (M+H+, 100).
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].C(N(CC)CC)C.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C1(C)C=CC=CC=1>[S:14]([O:5][CH2:4][C@H:2]1[O:3][CH2:1]1)([CH3:13])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CO1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OC[C@@H]1CO1
Temperature: 0 °C
Yield: 80 %

Procedure:
To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine (8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 m) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy-1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92°-95° C./0.1 mm; [α]D22 =23.7° (c=5.16, CH3OH); 1H NMR (CDCl3) 4.5 (1H, d of d, J=12, J=3), 4.1 (1H, d of d, J=12, J=6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H, m).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][C:6](=[O:15])[CH2:7][C@@H:8]([CH3:14])[CH2:9][C:10]([O:12]C)=[O:11].O.[OH-].[Li+].[Cl-].[NH4+].C(OCC)(=O)C>C(O)(C)C.O>[CH3:17][Si:2]([CH3:1])([CH3:16])[CH2:3][CH2:4][O:5][C:6](=[O:15])[CH2:7][C@@H:8]([CH3:14])[CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)C[C@H](C)CC(=O)OCC[Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: C[C@@H](CC(=O)O)CC(=O)OCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the solution of 3-(S)-Methyl-pentanedioic acid methyl ester 2-trimethylsilanyl-ethyl ester in iso-propanol and water was added lithium hydroxide monohydrate and stirred for two hours at RT. The reaction mixture was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](OCC)=[O:12])[N:8]([CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=2)=O)[N:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[NH4+:33].O>C(O)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]2[C:11](=[O:12])[NH:33][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:21][CH:20]=3)=[CH:16][N:8]2[N:7]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)c1cc(C(=O)OCC)n(CC(=O)c2ccc(C(C)(C)C)cc2)n1
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(=O)[nH]c(-c3ccc(C(C)(C)C)cc3)cn2n1
Temperature: 25 °C

Procedure:
A solution of 1.04 g (2.71 mmol) 1-[2-(4-tert-butyl-phenyl)-2-oxo-ethyl]-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 2.08 g (27.1 mmol) ammonium acetate in 20 ml acetic acid is stirred for 44 hours at 110° C. The reaction mixture is cooled to room temperature and excess water is added. The resulting precipitate is filtered off, and washed with water. The residue is chromatographed on a silica gel column with dichloromethane/methanol as eluent to give 6-(4-tert-butyl-phenyl)-4-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester as colourless crystals; HPLC/MS 2.41 (A), [M+H] 340.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[N+:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)([O-:26])=[O:25].C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31](=[O:32])[C:30]3[CH:29]=[CH:28][C:27]([N+:24]([O-:26])=[O:25])=[CH:35][CH:34]=3)=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N1c2ccc(NC(=O)c3ccc([N+](=O)[O-])cc3)cc2C(C)(c2ccccc2)CC1(C)C

Procedure:
Acylation of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg) with 4-nitrobenzoyl chloride (12 mg) and N,N-diisopropylethylamine (22 μl) in tetrahydrofuran (1 ml) was performed according to the method described in example 6.
Reaction SMILES: [CH3:1][C:2]12[O:9][CH:8]1[CH2:7][C:6]1([CH3:11])[CH2:10][CH:3]2[CH2:4][CH2:5]1.B(F)(F)F.O(CC)CC>C1(C)C=CC=CC=1>[CH3:11][C:6]12[CH2:10][CH:3]([CH2:4][CH2:5]1)[CH:2]([CH3:1])[C:8](=[O:9])[CH2:7]2
Reactant: CC12CCC(C1)C1(C)OC1C2
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC1C(=O)CC2(C)CCC1C2
Temperature: 30 °C
Reaction time: 6 h
Yield: 88.2 %

Procedure:
2,6-Dimethyl-3-oxa-tricyclo[4.2.1.0*2,4*]nonane (381 g, 2.51 mol, obtained as above in EXAMPLE II) was fed into a solution of boron trifluoride diethyletherate (BF3.O(C2H5)2, BF3, 35 g, 0.251 mol) in toluene (500 mL) while the pot temperature was maintained at about 30° C. and the aging process continued for 6 hours. The reaction mixture was subsequently quenched with water and washed with a Na2CO3 solution. Fractional distillation of the organic layer provided 1,4-dimethyl-bicyclo[3.2.1]octan-3-one (337 g) having a boiling point of 43° C. at a pressure of 1 mmHg
Reaction SMILES: [CH3:1][C@@H:2]([NH2:15])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1.[N:16]1[N:17]=[N:18][N:19]2[CH:24]=[C:23]([C@@H:25]3[CH2:27][O:26]3)[CH:22]=[CH:21][C:20]=12>CO>[CH3:1][C@@H:2]([NH:15][CH2:27][C@@H:25]([C:23]1[CH:22]=[CH:21][C:20]2[N:19]([N:18]=[N:17][N:16]=2)[CH:24]=1)[OH:26])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[NH:6][CH:5]=1
Reactant: COc1ccc2[nH]cc(C[C@@H](C)N)c2c1
Reactant: c1cc2nnnn2cc1[C@@H]1CO1
Solvent: CO
Product: COc1ccc2[nH]cc(C[C@@H](C)NC[C@H](O)c3ccc4nnnn4c3)c2c1

Procedure:
A solution of 553 mg of partially resolved (R)-1-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl amine (R. A. Glennor et al, Biol Psychiatry, 18,493 (1983) and 452 mg of (R)-2-(tetrazolo[1,5-a]pyrid-6-yl)oxirane in 10 ml of methanol under nitrogen was heated at reflux for 24 hours. The reaction mixture was concentrated under reduced pressure and the residue (1.0 g) purified by careful preparative TLC on silica gel (95:5:0.5 CH2Cl2 :MeOH:NH4OH) to give 515 mg of (R)-α-[[(1(R)-methyl-2-(5-methoxy-1H-indol-3-yl)ethyl)amino]methyl]tetrazolo[1,5-a]pyridine-6-methanol plus 11.6 mg of the adduct resulting from the small amount of (S)-amine present in the starting material.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CN(C)[C:9]([C@H:11]1[CH2:16][C@@H:15]2[CH2:17][CH2:18][N:12]1[C@@H:13]([CH:31]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:14]2[NH:19][CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])=[O:10].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:30][O:29][C:22]1[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=1[CH2:20][NH:19][C@@H:14]1[C@@H:15]2[CH2:17][CH2:18][N:12]([C@H:11]([CH2:9][OH:10])[CH2:16]2)[C@@H:13]1[CH:31]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(OC)c(CN[C@H]2[C@H]3CCN([C@@H](C(=O)N(C)C)C3)[C@H]2C(c2ccccc2)c2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(OC)c(CN[C@@H]2[C@@H]3CCN([C@H](CO)C3)[C@@H]2C(c2ccccc2)c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
Into a suspension of lithium aluminum hydride (LiAlH4) (92 mg, 2.4 mmole) in dry THF (10 ml) at 0° C. was added a solution of compound 35 (417 mg, 0.8 mmole) in dry THF (10 ml) and heated at reflux for 1 hour. Na2SO4 /10H2O was added to the reaction mixture and stirred for 30 minutes. After cooling, the solids were removed by filtration and washed with THF. The filtrate was evaporated, added excess 10% HCl/MeOH and concentrated down. The resulting oil was purified by recrystallization from MeOH-Ether. The white crystal was collected by filtration and dried in vacuo to give compound 41 2HCl salt (240 mg, 0.44 mmole, 55%).
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[Cl:10].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Cl)[CH3:13]>>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][O:11][C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=1)[CH3:13]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCOC(CCl)OCC
Agent: [K+]
Agent: [OH-]
Product: CCOC(COc1ccc(Cl)c(Cl)c1)OCC
Temperature: 90 °C

Procedure:
Potassium hydroxide (66 g) and 3,4-dichlorophenol (163 g) were placed in a reaction flask equipped with a distillation head, dropping funnel, thermometer and mechanical stirrer. This mixture was gradually heated to achieve solution and then 250 g of chloroacetaldehyde diethyl acetal was added while the temperature was maintained at 90° C. After the addition was complete, the temperature was allowed to increase in order to distill off water and unreacted chloroacetaldehyde diethyl acetal. The distillate separated into layers which were recovered by conventional techniques. The lower layer was dried and subsequently returned to the reaction flask where it was heated (without distillation) at 190° C. for 2 hours. The contents of the reaction flask were cooled to room temperature and poured into an ice-water mixture and extracted with methylene chloride. The methylene chloride solution was washed with 300 ml of 2N NaOH, dried, and distilled. After removal of the starting material, 276.3 g of the desired, 3,4-dichlorophenoxyacetaldehyde diethyl acetal was obtained, b.p. 125° C. (0.04 mm Hg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=O)[CH2:15]Br)=[CH:4][CH:3]=1.C(O)(=O)C.[CH:22]([NH2:24])=[NH:23].O>C(N)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[N:23]=[CH:22][NH:24][CH:15]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)CBr)cc1
Reactant: N=CN
Solvent: NC=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2ccccc2-c2c[nH]cn2)cc1
Yield: 24.6 %

Procedure:
A vigorously stirred solution of 1.0 g (3.5 mmol) of 4-methyl-2'-bromoacetyl-1,1'-biphenyl and 1.86 g of formamidine acetate in 10 mL of formamide was heated at 150° C. for 6 hours. The reaction mixture was cooled, poured into 100 mL of water and the resultant mixture extracted several times with ether. The combined extracts were washed with water (3×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography over silica gel, eluting with hexane/ethyl acetate (1:1) to yield 200 mg (0.86 mmol, 24%) of the product. FAB-MS (Li spike): calculated for C16H14N2 234; found 241 (M+Li). 1H NMR (200 MHz, CDCl3); 2.34 (s, 3H), 6.61 (s, 1H), 7.10 (m, 4H), 7.30 (m, 3H), 7.48 (s, 1H), 7.68 (dd, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:29])[CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[ClH:30]>C(OCC)(=O)C>[ClH:30].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:29])[CH2:20][NH2:21])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(NC(=O)CNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc(CCc2ccc(NC(=O)CN)cc2)cs1
Temperature: 25 °C
Reaction time: 103 h

Procedure:
To a solution of tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)amino]-2-oxoethylcarbamate (100 mg) in ethyl acetate (1 ml) was added 4N hydrogen chloride in ethyl acetate (1 ml), and the mixture was stirred at ambient temperature for 103 hours. The precipitated solid was filtered and washed with ethyl acetate to give N-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)-2-aminoacetamide hydrochloride (80 mg).