Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7](Cl)=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].C(N(CC)CC)C.[CH2:30]([NH2:33])[CH2:31][CH3:32]>CN(C=O)C.C(OCC)(=O)C>[OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([NH:33][CH2:30][CH2:31][CH3:32])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3]
Reactant: CCCN
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCNC1=C(C(=O)OCc2ccccc2)N2C(=O)C(C(C)O)C2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of benzyl 6-(1-hydroxyethyl)-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (48 mg) in anhydrous DMF (1 ml) is cooled in an ice bath and stirred while triethylamine (28 μl) and propylamine (12.4 μl) are added. The resulting solution is allowed to warm to room temperature (25° C.) and kept there for 1 hour. The solution is diluted with ethyl acetate (10 ml), washed with water (5×2 ml), pH 3 phosphate buffer (2 ml), 5% NaHCO3 (2 ml), and brine, dried with MgSO4, filtered, and evaporated in vacuo to provide benzyl 6-(1-hydroxyethyl)-3-propylamino-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[CH:16]=N[CH:14]=[CH:13][N:12]=1.[C:17](=O)([O-])[O-].[K+].[K+]>C(O)C>[N:10]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:2][N:12]2[CH:13]=[CH:14][CH:17]=[CH:16][C:11]=12
Reactant: Nc1cnccn1
Reactant: CCOC(=O)C(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)c1cn2ccccc2n1
Temperature: 25 °C
Yield: 61.3 %

Procedure:
A solution of 7.8 g (40 mmol) of ethyl bromopyruvate and in 40 mL of ethanol is treated with 3.76 g (30.0 mmol) of 2-aminopyrazine and heated to reflux temperature for 16 hr. The reaction mixture is cooled to room temperature and treated with 10 g of potassium carbonate. The mixture is filtered through Celite and the solvent removed in vacuo to yield the crude material. The resulting residue is flash chromatographed with initially 1% methanol in dichloromethane to afford 3.5 g (46%) ethyl imidazolo[1,2-a]pyridine-2-carboxylate.
Reaction SMILES: CCCCCC.C([Li])CCC.[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[CH3:27][S:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=[O:34])=[CH:31][CH:30]=1.O>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH:33]([C:32]1[CH:35]=[CH:36][C:29]([S:28][CH3:27])=[CH:30][CH:31]=1)[OH:34])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CSc1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
In a nitrogen stream, an n-butyllithium hexane solution (1.59 M, 6.92 mL) was added dropwise to a solution of 1-benzyloxy-2-bromobenzene (2.89 g, 11.0 mmol) in THF (38 mL) at −78° C. and the mixture solution was stirred at the same temperature for 30 minutes. To this solution, a solution of 4-methylsulfanylbenzaldehyde (1.67 g, 11.0 mmol) in THF (12 mL) was added dropwise at −78° C. The reaction mixture was stirred at the same temperature for one hour, and then water was added thereto and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:5)] to obtain the title compound (2.14 g, 58%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C([N-]C(C)C)(C)C.[Li+].CN([CH:20]=[O:21])C>C1COCC1>[Br:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Brc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1cnccc1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
A suspension of 4-bromopyridine hydrochloride (5.0 g, 25.7 mmol) in THF (100 mL) was purged with N2 and cooled to −78° C. A solution of lithium diisopropylamide (2.0 M solution in heptane/THF/ethylbenzene, 27.0 mL, 54.0 mmol) was added over 3 minutes. After 30 minutes, DMF (8.56 mL, 110.6 mmol) was added. The reaction mixture was stirred at −78° C. for 15 minutes before rapidly warming to room temperature in a water bath. The reaction was allowed to stir at ambient temperature for 18 hours. The reaction was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, evaporated, and chromatographed (Analogix 150 g silica gel column eluting with a gradient of 100% heptane 50% EtOAc/heptane over 1 hour) to give 1.50 g (31%) of the title compound as a light yellow solid. MS m/z 186 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24]>C(Cl)Cl>[CH2:26]([O:25][C:23](=[O:24])[NH:1][CH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CN)C1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.8 %

Procedure:
To a stirring solution of (S)-tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate (1.5 g, 7.5 mmol) in 25 mL CH2Cl2 was added triethylamine (2.1 mL, 15 mmol) at 0° C., followed by the dropwise addition of benzyl chloroformate (1.58 mL, 11.2 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The mixture was quenched with water, and the aqueous layer was extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 3% MeOH in CH2Cl2 gave benzyl((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (1.5 g, 60%). LC/MS: m/z: 335.5 (M+H)+ at 3.01 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][C:7](=[O:9])[NH:6][N:5]=[C:4]1[C:10]1[CH:28]=[CH:27][C:13]2[N:14]=[C:15]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][CH:23]=O)=[CH:19][CH:18]=3)[O:16][C:12]=2[CH:11]=1)[CH3:2].C(O)(=O)C.[CH3:33][CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN(C=O)C>[CH2:1]([CH:3]1[C:4]([C:10]2[CH:28]=[CH:27][C:13]3[N:14]=[C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:21][CH2:22][CH2:23][N:37]5[CH2:38][CH2:39][CH:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:25][CH:26]=4)[O:16][C:12]=3[CH:11]=2)=[N:5][NH:6][C:7](=[O:9])[CH2:8]1)[CH3:2]
Reactant: CC1CCNCC1
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCC=O)cc3)oc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCCN4CCC(C)CC4)cc3)oc2c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
11 mg (29 μmol) {4-[6-(4-ethyl-6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-benzoxazol-2-yl]-phenoxy}-acetaldehyde are placed in 2 mL DCM and 250 μL DMF. 1.70 μL (29 mmol) acetic acid and 3 μL (42 μmol) 4-methylpiperidine are added and the mixture is stirred for 20 min at RT. Then 9 mg (42 μmol) sodium triacetoxyborohydride are added and the mixture is stirred overnight at RT. The reaction mixture is diluted with DCM and extracted successively with 10% sodium carbonate solution and sat. saline solution. The solv. of the organic phase is eliminated i.V. and the residue is purified through KG. (DCM/MeOH+ammonia) the solv. of the corresponding fractions is eliminated i.V. and the residue is crystallised from EN petroleum ether.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.N1C=CC=CC=1.[O:17](S(C(F)(F)F)(=O)=O)[S:18]([C:21]([F:24])([F:23])[F:22])(=O)=[O:19]>ClCCl.O>[F:22][C:21]([F:24])([F:23])[S:18]([O:10][C:7]1[CH:8]=[CH:9][C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=1)(=[O:19])=[O:17]
Reactant: Oc1ccc2ccoc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Oc1ccc2ccoc2c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.7 %

Procedure:
To a stirred solution of benzofuran-6-ol (17.0 g, 127 mmol) in pyridine (20 g, 254 mmol) and dichloromethane (200 mL) was added Tf2O (53.7 g, 190 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford a crude product that was purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford benzofuran-6-yl trifluoromethanesulfonate (30.0 g, 88.0% yield). 1H NMR (300 MHz, CDCl3) δ: 7.72 (d, J=2.1, 1H), 7.67 (d, J=8.7, 1H), 7.48 (d, J=1.5, 1H), 7.19 (dd, J=8.7, 2.1, 1H), 6.82-6.91 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([N:29]1[CH2:34][CH2:33][CH:32](C(O)=O)[CH2:31][CH2:30]1)[CH:26]([CH3:28])[CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[C:62](=[O:65])([O-])[O-].[NH4+:66].[NH4+].C(=O)(O)[O-].[Na+]>C1COCC1.N1C=CC=CC=1>[F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C@H:25]([N:29]1[CH2:34][CH2:33][CH:32]([C:62]([NH2:66])=[O:65])[CH2:31][CH2:30]1)[CH:26]([CH3:28])[CH3:27])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: O=C([O-])[O-]
Reactant: [NH4+]
Reactant: CC(C)[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCC(C(=O)O)CC1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(C)[C@H](c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1)N1CCC(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (R)-1-{-1-[2-({[3,5-bis(trifluoromethyl)benzyl](2-methyl-2H-tetrazol-5-yl)amino}methyl)-4-(trifluoromethyl)phenyl]-2-methylpropyl}piperidine-4-carboxylic acid (0.510 g, 0.76 mMol) in THF (5 mL) was added ditert-butyl dicarbonate (0.21 g, 0.99 mMol) and ammonium carbonate (0.078 g, 0.99 mMol) at 0° C. To this solution was added pyridine (0.037 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The extracts were washed with saturated solution of sodium hydrogen sulfate and brine. The organic extract was dried and purified by flash chromatography to afford the product (0.314 g., 65%) 1HNMR (400 MHz. CDCl3) δ 7.80 (s, 1H), 7.60 (d, 2H), 7.50 (m, 1H), (7.20, m, 1H), 7.25 (d, 1H), 5.20 (m, 2H), 4.90 (d, 1H), 4.70 (dd, 2H), 4.50 (dd, 1H, 4.20 (s, 3H), 3.60 (d, 1H), 3.0 (m, 1H), 2.80 (m, 1H), 2.20 (m, 1H), 1.80 (m, 2H), 1.70 (m, 4H), 0.8 (d, 3H), 0.6 (d, 3H). MS (ES+) Calc 665.60, Found 666.7 (M+1)
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[CH:8][CH:9]=1.Cl.[N:12]([O-])=O.[Na+].[CH2:16]([C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)[CH3:17]>O.[OH-].[Na+]>[CH2:2]([O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]=[N:12][C:23]2[CH:22]=[CH:21][C:20]([OH:24])=[CH:19][C:18]=2[CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:1]
Reactant: CCOc1ccc(N)cc1
Reactant: O=N[O-]
Reactant: CCc1cccc(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOc1ccc(N=Nc2ccc(O)cc2CC)cc1
Temperature: 3 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
0.8 mol (109.8 g) of p-phenetidine and 2.1 mol (450 ml) of 16% hydrochloric acid were charged to a round bottomed flask. With cooling of the suspension to about 3° C., 59.2 g (0.8 mol) of NaNO2 dissolved in 320 ml of water was added dropwise over 2.5 hr. During this process the temperature was maintained between 1° and 4° C. After completion of the addition, the mixture was stirred for another 3 hr at 0°-3° C., and was allowed to stand overnight in a refrigerator. A solution of 0.8 mol (97.7 g) of 3-ethylphenol in 800 ml of 2N sodium hydroxide cooled to 5° C. was added dropwise to this suspension at 2° C., over a period of 2 hr, under stirring. An orange-yellow suspension resulted. The reaction mixture was allowed to warm up to room temperature, and was stirred an additional 1 hr. The raw product was then separated by suction filtration and was washed with cold, distilled water. The filter cake was boiled with 2 L of 50:50 ethanol/water mixture, followed by filtration. The resulting 2-phase mixture was allowed to cool under stirring. A brown-red solid precipitated, which was separated by suction filtration, followed by neutral washing. After drying, the product was obtained in a yield of 61% of theoretical.
Reaction SMILES: [CH2:1]1[CH2:11][CH2:10][N:9]2C(=NCCC2)[CH2:3][CH2:2]1.[C:12]([O:16][C:17](=[O:21])[CH2:18][C:19]#[N:20])([CH3:15])([CH3:14])[CH3:13].I[CH2:23][CH2:24][CH3:25]>CN(C=O)C.CCOC(C)=O>[C:12]([O:16][C:17](=[O:21])[C:11]([C:10]#[N:9])([CH2:1][CH2:2][CH3:3])[CH2:23][CH2:24][CH3:25])([CH3:13])([CH3:14])[CH3:15].[C:12]([O:16][C:17](=[O:21])[CH:18]([C:19]#[N:20])[CH2:2][CH2:1][CH3:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)CC#N
Reactant: CCCI
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(C#N)(CCC)C(=O)OC(C)(C)C
Product: CCCC(C#N)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
DBU was added slowly to a solution of cyano-acetic acid tert-butyl ester (6.03 g) in DMF (100 mL) at rt, followed by addition of 1-iodopropane (9.58 mL); the reaction mixture was stirred in an oil bath (bath temperature=80° C.) overnight subsequently. The reaction was cooled, diluted with EtOAc, then washed with cold water, dil. NaCl solution; EtOAc phase was dried over anhydrous sodium sulfate, filtered, concentrated, the residue was column purified to give 2-cyano-2-propyl-pentanoic acid tert-butyl ester (6.87 g) and 2-cyano-pentanoic acid tert-butyl ester (420 mg). 2-Cyano-2-propyl-pentanoic acid tert-butyl ester (1H NMR in CDCl3, δ in ppm) 1.502 (s, 9H), 1.9-1.2 (m, 8H), 0.96 (t, 6H, J=7.0 Hz). 2-Cyano-pentanoic acid tert-butyl ester (1H NMR in CDCl3, δ in ppm) 3.39 (t, 1H, J=7.0 Hz), 1.95-1.83 (m, 2H), 1.6-1.55 (m, 2H), 1.51 (s, 9H), 0.98 (t, 3H, J=7.2 Hz).
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[CH:28]=[C:29]([NH:33][C:34](=[O:39])[CH2:35][CH:36]([CH3:38])[CH3:37])[CH:30]=[CH:31][CH:32]=2)[CH2:23][CH2:22]1>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([C:27]3[CH:28]=[C:29]([NH:33][C:34](=[O:39])[CH2:35][CH:36]([CH3:37])[CH3:38])[CH:30]=[CH:31][CH:32]=3)[CH2:23][CH2:22]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CC(C)CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccccc3)c3ccccc3)CC2)c1

Procedure:
Example 13 was prepared from diphenylacetyl chloride and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-3-methylbutanamide according to the procedures described in Scheme 8: 1H NMR (400 MHz, CDCl3) δ 10.79–10.51 (br, 1H), 8.85–8.67 (m, 1H), 8.01–7.81 (br, 1H), 7.70 (d, 1H, J=7.2 Hz), 7.47–7.14 (m, 11H), 6.89 (d, 1H, J=7.2 Hz), 5.03 (s, 1H), 3.53–3.26 (m, 4H), 2.96–2.80 (m, 2H), 2.78–2.52 (m, 3H), 2.44–2.14 (m, 2H), 2.26 (d, 2H, J=6.0 Hz), 2.14–1.94 (m, 3H), 1.94–1.76 (m, 2H), 1.10 (d, 6H, J=6.4 Hz); ESMS m/e: 512.3 (M+H)+; Anal. Calc. (HCl salt) C33H42ClN3O2.0.60CH2Cl2: C, 67.36; H, 7.27; N, 7.01. Found: C, 67.08; H, 7.57; N, 7.36.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[CH2:10]([CH2:14][C:15](=O)[CH3:16])[C:11]([CH3:13])=O.C(O)(=O)C>C1(C)C=CC=CC=1.O.O.O.C([O-])(=O)C.[Na+]>[CH3:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([N:1]2[C:15]([CH3:16])=[CH:14][CH:10]=[C:11]2[CH3:13])[CH:7]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Cc1cc(C)nc(N)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(C)nc(-n2c(C)ccc2C)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
A mixture of 2-amino-4,6-dimethylpyridine (20.0 g, 164 mmol), acetonylacetone (30 mL, 170 mmol), acetic acid (2.0 mL, 35 mmol), and sodium acetate trihydrate (200 mg, 1.5 mmol) in 140 mL of toluene was heated to reflux for 48 h in a flask connected to a Dean-Stark trap. After cooling to room temperature, the reaction mixture was washed with 50 mL each of 2.5 N aqueous sodium hydroxide, water, and saturated aqueous sodium chloride. The organic layer was dried (sodium sulfate), decanted, and evaporated. The residue was distilled through a 1×10 cm Vigreaux column to give 29.09 g (89% yield) of 4,6-dimethyl-2-(2,5-dimethylpyrrol-1-yl)pyridine as an almost colorless liquid boiling at 93-97° C. (0.05 mm).
Reaction SMILES: [C:1](=[S:3])=S.[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[CH2:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[CH:7][CH:6]=1.[C:35]1([CH2:41][N:42]2[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=[C:43]2[CH2:51][CH:52]2[CH2:57][CH2:56][N:55]([CH2:58][CH2:59][NH2:60])[CH2:54][CH2:53]2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCCC1>[CH3:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[N:14]=[C:13]2[CH2:21][CH:22]2[CH2:23][CH2:24][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:26][CH2:27]2)=[CH:7][CH:6]=1.[N:60]([CH2:59][CH2:58][N:55]1[CH2:56][CH2:57][CH:52]([CH2:51][C:43]2[N:42]([CH2:41][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=2)[CH2:53][CH2:54]1)=[C:1]=[S:3]
Reactant: S=C=S
Reactant: NCCN1CCC(Cc2nc3ccccc3n2Cc2ccccc2)CC1
Agent: Cc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3cccnc32)cc1
Solvent: C1CCOC1
Product: S=C=NCCN1CCC(Cc2nc3ccccc3n2Cc2ccccc2)CC1
Yield: 89 %

Procedure:
To a stirred and cooled (-10° C.) mixture of 20.8 parts of carbon disulfide, 9 parts of N,N-methanetetraylbis[cyclohexanamine] and 135 parts of tetrahydrofuran was added dropwise a solution of 15 parts of 4-[[1-(phenylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidineethanamine in tetrahyrofuran at a temperature below -10° C. The reaction mixture was allowed to reach room temperature and the solvent was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and the filtrate was evaporated, yielding 15 parts (89%) of 2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1-(phenylmethyl)-1H-benzimidazole (385).
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].[CH3:5][CH:6]([OH:9])[C:7]#[CH:8].CCN(CC)CC.[O-]Cl.[Na+]>C(Cl)Cl>[CH3:2][C:1]1[CH:8]=[C:7]([CH:6]([OH:9])[CH3:5])[O:4][N:3]=1
Reactant: C#CC(C)O
Reactant: CC=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(C)O)on1
Reaction time: 18 h
Yield: 20.4 %

Procedure:
To a stirring solution of 5.2 mL (84.9 mmol) of acetaldehyde oxime, 6.7 mL (85.5 mmol) of 3-butyn-2-ol, and 1.2 mL (8.6 mmol) of Et3N in 20 mL of CH2Cl2 at 0° C. was added 275 mL of NaOCl over a period of 2 h 45 min. The ice bath was removed and stirring was continued at r.t. for 18 h. Chloroform was added, and the layers were separated. The organic layer was extracted with CHCl3 (2×) and with the extract of a mixture of (80 mL CHCl3: 10 mL H2O: 10 mL MeOH) (2×). The combined extracts were dried over Na2SO4, filtered and concentrated. Purification by flash silica gel chromatography (2% MeOH/CHCl3) provided 2.2 g of 1-(3-methylisoxazol-5-yl)ethanol as an orange-yellow oil in 20% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23]#[N:24])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3.ClC1C(OCC#[N:47])=CC2CCC3(CCC)C(C=2C=1Cl)=CCCC3>>[ClH:1].[Cl:1][C:2]1[C:3]([O:21][CH2:22][C:23](=[NH:47])[NH2:24])=[CH:4][C:5]2[CH2:6][CH2:7][C:8]3([CH2:18][CH2:19][CH3:20])[C:13]([C:14]=2[C:15]=1[Cl:16])=[CH:12][C:11](=[O:17])[CH2:10][CH2:9]3
Reactant: CCCC12CCCC=C1c1c(cc(OCC#N)c(Cl)c1Cl)CC2
Reactant: CCCC12CCC(=O)C=C1c1c(cc(OCC#N)c(Cl)c1Cl)CC2
Product: CCCC12CCC(=O)C=C1c1c(cc(OCC(=N)N)c(Cl)c1Cl)CC2
Product: Cl

Procedure:
By carrying out the reaction as described in Example 4, Step B, except that the racemic 2-[(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]acetonitrile is replaced by an equal amount of (+)2-[(3,4-dichloro-6,7,8,8a,9,10-hexahydro-8a-propyl-2-phenanthrenyl)oxy]acetonitrile, there is obtained (+)2-[(3,4-dichloro-6,7,8,8a,9,10-hexahydro-6-oxo-8a-propyl-2-phenanthrenyl)oxy]ethanimidamide hydrochloride.
Reaction SMILES: [C:1]([C:4]1[C:8](=[O:9])[NH:7][C:6]2=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14][C:5]=12)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O.O>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][N:7]1[C:8](=[O:9])[C:4]([C:1](=[O:3])[CH3:2])=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=[C:6]12)[CH3:27]
Reactant: CC(=O)c1c2cccccc-2[nH]c1=O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c2cccccc-2c(C(C)=O)c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a warm suspension of 3-acetyl-1,2-dihydrocyclohepta[b]pyrrole-2-one [1.87 g, described by T. Nozoe et al., Bull. Chem. Soc. Japan, 38, 306 (1965)] in dimethyl formamide (DMF, 25 ml), potassium carbonate (1.66 g) and ethyl bromoacetate (2.84) were added successively. The mixture was stirred at 25° C. for 18 hr and then diluted with water. The precipitate was collected and dried to give 3-acetyl-1,2-dihydro-2-oxocyclohepta[b]pyrrole-1-acetic acid ethyl ester, mp 162°-165° C.; nmr (CDCl3) δ1.33 (t, J=7 Hz, 3H), 2.75 (s, 3H), 4.25 (q, J=7 Hz, 2H), 4.9 (s, 2H), 7.4 (m, 4H), 9.4 (d, J=10 Hz, 1H).
Reaction SMILES: Br.Br[CH:3]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=1)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)=O.C1([CH2:33][CH2:34][C:35]([NH2:37])=[S:36])C=CC=CC=1.C(=O)([O-])O.[Na+]>CN(C=O)C>[Br:12][C:8]1[CH:7]=[C:6]([C:4]2[N:37]=[C:35]([CH2:34][CH3:33])[S:36][C:3]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:14]=2)[CH:11]=[CH:10][CH:9]=1.[NH2:19][C:15]1[CH:14]=[C:13]([C:3]2[S:36][C:35]([CH2:34][CH3:33])=[N:37][C:4]=2[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=2)[CH:18]=[CH:17][N:16]=1
Reactant: NC(=S)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(Br)C(=O)c2cccc(Br)c2)ccn1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(-c2cccc(Br)c2)c(-c2ccnc(N)c2)s1
Product: CCc1nc(-c2cccc(Br)c2)c(-c2ccnc(NC(=O)OC(C)(C)C)c2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %
Yield: 27 %

Procedure:
To a solution of 2-bromo-1-(3-bromophenyl)-2-[2-(tert-butoxycarbonylamino)-4-pyridyl]ethanone hydrobromide (22 g, 51 mmol) in N,N,-dimethylformamide (100 mL) was added thiopropionamide (4.3 g, 49 mmol), and the mixture was stirred for 2 hours at room temperature. Into the reaction mixture was poured an aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extracts were washed with water, then, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=4:1), then, recrystallized from hexane-ethyl acetate to obtain 4-(3-bromophenyl)-5-[2-(tert-butoxycarbonylamino)-4-pyridyl]-2-ethyl-1,3-thiazole (6.0 g, yield 27%) and 5-(2-amino-4-pyridyl)-4-(3-bromophenyl)-2-ethyl-1,3-thiazole (1.4 g, yield 8%).