Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]1[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1)#[N:13]>C1COCC1>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:3][CH2:4][C:5]2[C:6](=[O:11])[NH:7][CH:8]=[CH:9][CH:10]=2)=[O:19])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: O=c1[nH]cccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C(=O)OCc2ccc[nH]c2=O)cc1
Reaction time: 0.5 h
Yield: 28.54 %

Procedure:
In Example 3, 0.0723 g of 60% NaH was dispersed in mineral oil (0.64 mmol) and was suspended in 50 mL of THF in a 100 mL RBF under the presence of argon gas. Then, 0.2026 g (1.62 mmol) of 3-(hydroxymethyl)pyridine-2(1H)-one was slowly added into the solution. This solution was stirred for 30 min with gentle heating before 0.2661 g (1.61 mmol) of 4-cyanobenzoyl chloride was added. The reaction was stirred with gentle heating for 48 hours. The reaction was quenched with 20 mL of and was washed with ethyl acetate (4×20 mL) and the organic layers combined. The organic layer was washed with brine (3×20 mL) before being dried of MgSO4. The solvent was evaporated in vacuo to produce a white solid. The product was purified with silica gel column chromatography using 10% methanol in dichloromethane as eluent. The yield of the reaction was 0.1175 g (28.54% yield). MP: 200-203° C. IR (cm−1): 3406.04 (m, broad), υ (O—H), 3113.07 (m, broad), υ (N—H), 1728.71 (m), υ (C═O), 1617.96 (s), υ (C═C aromatic). 1H NMR (DMSO-d6, 500 MHz) δ: 5.17 (s, 2H), 6.23 (t, J=6.6 Hz, 1H), 7.42 (dd, J=4.5, 2.0 Hz, 1H), 7.63 (dd, J=4.7, 1.1 Hz, 1H), 8.02 (d, J=4.8, 2H), 8.10 (d, J=4.7, 2H), 11.80 (s, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[CH3:6][N:7]([CH3:10])[C:8]#[N:9].[ClH:11]>O1CCOCC1.CCOCC>[ClH:11].[CH3:6][N:7]([CH3:10])[C:8]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[NH:9]
Reactant: c1cn[nH]c1
Reactant: CN(C)C#N
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN(C)C(=N)n1cccn1
Temperature: 25 °C
Yield: 77.8 %

Procedure:
To a solution of pyrazole (1.01 g, 14.8 mmol) and dimethylcyanamide (1.20 mL, 14.8 mmol) in 1,4-dioxane (15 mL) was added HCl (4.0 N in 1,4-dioxane, 3.8 mL, 15.2 mmol) and the resultant mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and diluted with dry ether (15 mL) to precipitate a yellow solid. The resultant precipitate was allowed to settle to the bottom of the flask (overnight) and the supernatant solution was decanted. The solid was dried under vacuum and provided the title compound (2.01 g, 78%). ES-MS m/z 139 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([CH3:15])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([Si](C)(C)C)([F:19])([F:18])[F:17].Cl>O1CCCC1.O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:14])[C:16]([F:19])([F:18])[F:17])[C:10]([CH3:15])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nn(Cc2ccccc2)cc1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nn(Cc2ccccc2)cc1C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71 %

Procedure:
To a solution of 1-benzyl-3-methyl-1H-pyrazole-4-carbaldehyde (compound 314.2, 1.20 g, 5.99 mmol) in tetrahydrofuran (15 mL) was added CF3SiMe3 (1.33 mL, 9.01 mmol) and TBAF (0.11 mL, 0.11 mmol, 1M solution in THF). The mixture was stirred for 10 min at room temperature under nitrogen. This was followed by the addition of aqueous HCl (6 M) (1 mL). The reaction mixture was stirred for another 10 min at room temperature, then diluted with 50 mL of H2O. The aqueous phase was extracted with 3×20 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate/petroleum ether (1/5-1/2) as the eluent to furnish 1.15 g (71%) of the title compound as a light yellow solid.
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[C@@H:32]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][CH:20]=[C:19]2[C:24]2[CH:25]=[CH:26][C:27]([O:30][C@H:32]([CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][CH:29]=2)[CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)[C@@H](O)Cc1ccccc1
Reactant: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O)cc2)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCCCOc1cccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 49.8 %

Procedure:
To a solution of 4-[l-(3-decyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenol (1.40 g, 3.45 mmol), ethyl (S)-2-hydroxy-3-phenylpropanoate (1.00 g, 5.18 mmol) and triphenylphosphine (1.36 g, 5.18 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.31 g, 5.18 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.00 g (yield: 49.8%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:14][C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[C:3]1=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7]3.[Al+3].[Cl-].[Cl-].[Cl-].[Br:20]Br.O>C(Cl)Cl>[Br:20][C:12]1[CH:13]=[C:4]2[C:3](=[O:15])[CH:2]([CH3:1])[CH2:14][C:5]2=[C:6]2[C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7]2
Reactant: BrBr
Reactant: CC1Cc2c(ccc3c2CCCC3)C1=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC1Cc2c(cc(Br)c3c2CCCC3)C1=O
Reaction time: 1 h

Procedure:
In a three-necked round-bottom 500 ml flask equipped with a reflux condenser, dropping funnel with pressure-equalizing, and mechanical stirrer a solution of 55.0 g (0.275 mol) of 2-methyl-1,2,6,7,8,9-hexahydro-3H-cyclopenta[a]naphthalen-3-one in 50 ml of CH2Cl2 was added dropwise with vigorous stirring for 1 h at −10° C. to a suspension of 92 g (0.69 mol) of AlCl3 in 100 ml of CH2Cl2. This mixture was stirred additionally for 1 h at this temperature; then 14.2 ml (44.0 g, 0.275 mol) of bromine was added dropwise with vigorous stirring for 1 h. The resulting mixture was stirred for 2 h at −10° C. and then overnight at ambient temperature, and, then, it was poured on 1000 cm3 of cold water. The organic layer was separated, the aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined extract was washed with saturated aqueous Na2SO3 to eliminate bromine and with aqueous Na2CO3. It was then dried over K2CO3, and evaporated to dryness. Fractional distillation gave a yellowish liquid, b.p. 195-198° C./4 mm Hg. Yield 58.3 g (76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O.CN(C)C=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1
Reaction time: 0.25 h

Procedure:
A slurry of 22.5 g. (0.15 mole of 4-methoxybenzoic acid in benzene at reflux is treated with 12.5 ml. (0.15 mole) of thionyl chloride and 1 ml. of N,N-dimehtyl formamide. After stirring for 15 minutes the solution is evaporated and cooled to provide 4methoxybenzoyl chloride as a yellow solid. The solid is dissolved in carbon disulfide and added to 20 g. (0.15 mole) of aluminum chloride slurried in 200 ml. of carbon sulfide. To this mixture is added 30 g. (0.15 mole) of 2,6-di(t-butyl)phenol. After stirring for two hours at room termperature, the resulting mixture is poured into a dilute hydrochloric acid-ice mixture, then extracted with three portions of dichloromethane. The organic layer is dried, then evaporated to provide a residue which is recrystallized twice from a benzene-hexane mixture to provide 4-(4-methoxybenzoyl)-2,6-di(t-butyl)phenol, m.p. 141°-142.5° C.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[CH:12]1([C:18]([NH:20][NH2:21])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:18]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:19])/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(=O)C1CCCCC1
Product: CCCCCCN1C(=O)/C(=N\NC(=O)C2CCCCC2)c2ccccc21
Yield: 45 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 3 and cyclohexanecarbohydrazide according to the synthetic method E. The resulting solid was washed with ethanol. Yield: 45%. 1H NMR (DMSO-d6): δ δ 0.85 (t, J=6.8 Hz, 3H), 1.24-1.83 (m, 19H), 3.74 (t, J=6.9 Hz, 2H), 7.15 (t, J=7.5 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.45 (t, J=7.8 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.59 (d, 3H), 12.34 (br s, isomer 1: 50%, 0.5; H), 13.00 (br s, isomer 2: 50%, 0.5; H), both isomer are in the same proportion. 13C NMR (DMSO-d6): δ 14.33(CH3), 22.42 (CH2), 25.48 (CH2), 26.34 (CH2), 25.83 (CH2), 27.37 (CH2), 31.29 (CH2), 39.64 (CH2), 110.52 (CH), 119.78 (C), 123.48 (CH), 131.79 (CH), 143.27 (C═N), (C═O). HRMS (ES+) calcd for C21H30N3O2 (M+H+), m/e, 356.2328. found, 356.2333.
Reaction SMILES: Br[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[CH:7][CH:6]=2.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)[CH3:23]>>[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=3)=[CH:26][CH:25]=1)[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(Br)nc2c1
Reactant: CCc1ccc(B(O)O)cc1
Product: CCc1ccc(-c2nc3cc(C(=O)O)ccc3nc2-c2ccccc2)cc1
Yield: 50.6 %

Procedure:
The product was obtained via a Suzuki coupling reaction using the method previously shown in Example 20, Step 3, using methyl 3-bromo-2-phenylquinoxaline-6-carboxylate (100 mg, 0.29 mmol, 1.00 equiv) and 4-ethylphenylboronic acid (62.3 mg, 0.42 mmol, 1.50 equiv) as reactants. Purification via silica gel column (dichloromethane/methanol (5:1)) yielded 52 mg (49%) of 3-(4-ethylphenyl)-2-phenylquinoxaline-6-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=C(C)C)[CH:7]2[CH2:6][CH2:5]1.[O:16]=[O+][O-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[C:12](=[O:16])[CH:7]2[CH2:6][CH2:5]1
Reactant: O=[O+][O-]
Reactant: CC(C)=C1C2CCC1c1c(Cl)cccc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C1C2CCC1c1c(Cl)cccc12
Temperature: -40 °C

Procedure:
In a 20 liter reactor, 600 g of 5-chloro-9-isopropylidene-1,2,3,4-tetrahydro-1,4-methano-naphthalene (27.43 mol) were charged in a mixture of 13 l CH2Cl2 and 0.5 l of MeOH. The reaction mixture was cooled down at −40° C. and an ozone stream (55 kg/h) was feed until change of color. After elimination of the ozone residue, PPh3 (23.83 mol) was added and reaction mixture was heated to ambient temperature. The purification was done via chromatography. 421 g white solid product was isolated with a purity >98%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]=[CH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1.C(Cl)Cl>[Pd].CCO>[CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]([O:12][CH3:13])=[CH:10][CH:11]=1
Reactant: COC(=O)C=Cc1ccc(OC)nc1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)CCc1ccc(OC)nc1
Yield: 97.3 %

Procedure:
A suspension of 3-(6-methoxy-pyridin-3-yl)-acrylic acid methyl ester (1.2 g, 6.21 mmol, 1 eq) and Pd/C, 10% (330 mg, 0.05 eq, 10%) was stirred in a DCM (15 ml)/absolute EtOH (15 ml) solvent mixture under hydrogen atmosphere for 1 hour at room temperature. Palladium was filtered off over a celite pad, the solvent was evaporated and obtained was 3-(6-methoxy-pyridin-3-yl)-propionic acid methyl ester (1.18 g, yield=93%, purity=95%) in form of yellowish oil. MS: [M+H]+=196.15 1H NMR (300 MHz; CDCl3) δ/ppm 2.59 (t, J=7.75 Hz, 2H), 2.88 (t, J=7.75 Hz, 2H), 3.67 (s, 3H), 3.91 (s, 3H), 6.68 (d, J=8.46 Hz, 1H), 7.42 (dd, J=7.42 Hz, J=2.40 Hz, 1H), 8.00 (d, J=2.40 Hz, 1H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][OH:22])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]#[C:18][CH2:19][CH2:20][CH2:21][O:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC#Cc1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
440 mg (1.5 mmol) 5-[1-(4-Fluoro-phenyl)-1H-indol-5-yl]-pent-4-yn-1-ol in 15 ml CH2Cl2 were treated with 0.15 ml (1.8 mmol) methane sulfonyl chloride and 0.63 ml (4.5 mmol) triethyl amine at 0° C. for 10 min. The solution was stirred at RT for 2 h and was diluted with CH2Cl2. The organic phase was extracted with 1M HCl and water, and dried over Na2SO4. Evaporation yielded 400 mg (71%) Methanesulfonic acid 5-[1-(4-fluoro-phenyl)-1H-indol-5-yl]-pent-4-ynyl ester as light yellow viscous oil, MS: 372 (MH+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:10])[F:11])=[CH:4][CH:5]=2)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)Nc2ccc(C(F)(F)F)nc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-trifluoromethylpyridin-3-ylamine (1.0 g, 6.17 mmol) and 4-amino-3-nitrobenzoic acid (1.12 g, 6.17 mmol) in DMF (25 mL) was added HATU (3.5 g, 9.23 mmol) followed by NEt3 (1.77 ml, 9.23 mmol). The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, and filtered. The solvent was removed under reduced pressure and the residue was purified by flash chromatography using a heptane/EtOAc (1:1 then followed by 100% EtOAc) to give 4-amino-3-nitro-N-(6-trifluoromethylpyridin-3-yl)-benzamide as a red solid.
Reaction SMILES: COC1C=CC(C([O:22][CH2:23][C@H:24]2[O:28][C@@H:27]([N:29]3[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]3=[O:31])[CH2:26][C@@H:25]2[OH:38])(C2C=CC=CC=2)C2C=CC(OC)=CC=2)=CC=1.[Cl-].[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH:51]([CH3:62])[CH2:52][O:53][C:54](N1C=C[N+](C)=C1)=[O:55])([O-:44])=[O:43]>ClCCl>[N+:42]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH:51]([CH3:62])[CH2:52][O:53][C:54]([O:38][C@@H:25]1[C@@H:24]([CH2:23][OH:22])[O:28][C@@H:27]([N:29]2[CH:37]=[C:35]([CH3:36])[C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:26]1)=[O:55])([O-:44])=[O:43]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: CC(COC(=O)n1cc[n+](C)c1)c1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](OC(=O)OCC(C)c3ccccc3[N+](=O)[O-])[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 92.8 %

Procedure:
A solution of 2 g 5′-O-(4,4′-dimethoxytrityl)thymidine (3) (3.67 mmol) in 20 ml dichloromethane is added dropwise at 0° C. to 1.2 equiv N3-[2-(2-nitrophenyl)propoxycarbonyl]-N-methylimidazolium chloride (2) (4.4 mmol) in 30 ml dichloromethane through a molecular sieve 4 Å within 10 minutes. The reaction mixture was stirred at 0° C. overnight, then extracted using 0.5% HCl (100 ml), dried via Na2SO4 and evaporated. 10% trichloroacetic acid (70 ml) in dichloromethane is added to the organic phase and stirred for 2 minutes. Thereafter, the deep-red solution is extracted twice using saturated NaHCO3 (100 ml), dried via Na2SO4 and evaporated. Purification via flash chromatography (0-10% methanol in toluene/ethyl acetate (5:4)) yielded 1.53 g (93%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].B(F)(F)F.CCOCC.[CH2:28]=[C:29]([CH3:31])[CH3:30]>C(#N)C>[CH3:28][C:29]1([CH3:31])[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([CH3:18])[CH:16]=2)[NH:11][CH:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:30]1
Reactant: Cc1ccc(/N=C/c2cccc([N+](=O)[O-])c2)cc1
Reactant: C=C(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc([N+](=O)[O-])c1)N2

Procedure:
A 2000 mL of autoclave was charged with [1-(3-nitro-phenyl)-meth-(E)-ylidene]-p-tolyl-amine (44.5 g, 0.185 mmol), acetonitrile (500 mL), boron trifluoride etherate (30 mL). The mixture was cooled with liquid nitrogen, and then isobutene was added quickly. The resultant mixture was stirred at room temperature for 60 h. The reaction mixture was washed with brine, water, dried over magnesium sulfate, concentrated. The residue was washed with ethyl acetate and the desired 4,4,6-trimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline was obtained by filtration (53 g).
Reaction SMILES: Br.C(OC([N:12]1[CH2:17][CH2:16][C:15]2[N:18]=[C:19]([NH:21][C:22]([NH:24][CH2:25][C:26]3[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=3[O:34][CH3:35])=[NH:23])[S:20][C:14]=2[CH2:13]1)=O)C1C=CC=CC=1.C(=O)([O-])[O-]>C(O)(=O)C.CO>[CH3:35][O:34][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]([O:32][CH3:33])[C:26]=1[CH2:25][NH:24][C:22]([NH:21][C:19]1[S:20][C:14]2[CH2:13][NH:12][CH2:17][CH2:16][C:15]=2[N:18]=1)=[NH:23]
Reactant: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CN(C(=O)OCc1ccccc1)CC2
Agent: Br
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cccc(OC)c1CNC(=N)Nc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.2 ml HBr (33% in glacial acetic acid) were added to 150 mg benzyl-2-{[[(2,6-dimethoxybenzyl)amino](imino)methyl]amino}-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylat (0.28 mmol) in 2 ml glacial acetic acid, and the mixture was stirred for 2 hours at room temperature. After reaction completion, the mixture was evaporation-concentrated, was filtered over C18 Chromabond (water/CH3CN+0.1% glacial acetic acid; 0-30%), and the free base was obtained by stirring with polymer-bound carbonate in methanol. 60 mg; ESI-MS [M+H+]=348.15.
Reaction SMILES: [NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:10]=1.S(=O)(=O)(O)[OH:25].[OH-].[Na+]>CO>[NH2:1][CH:2]([OH:23])[C@H:3]([CH3:22])[CH2:4][CH2:5][C:6]1[S:7][C:8]([C:11](=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: C[C@H](CCc1ccc(C#CCCCC2CCCCC2)s1)C(N)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](CCc1ccc(C(=O)CCCCC2CCCCC2)s1)C(N)O
Yield: 91 %

Procedure:
(2R)-Amino-2-methyl-4-[5-(5-cyclohexylpent-1-ynyl)thiophen-2-yl]butan-1-ol (126 mg, 0.41 mmol) obtained in Example 1 was dissolved in methanol (2 ml), and 6N sulfuric acid (2 ml) was added thereto followed by heating under reflux for 4 hours. After the reaction solution was made alkaline with a 1N aqueous sodium hydroxide solution, the resulting solution was extracted with dichloromethane. The dichloromethane layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (130 mg, 91% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[N+:14]([CH:17]=[C:18](SC)SC)([O-:16])=[O:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH2:9][CH2:10][NH:11][C:18]2=[CH:17][N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1
Reactant: NCCCNCc1ccc(Cl)cc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1NCCCN1Cc1ccc(Cl)cc1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
N-(4-chlorobenzyl)trimethylenediamine (8.45 g) and 1-nitro-2,2-bis(methylthio)ethylene (6.60 g) were heated under reflux in 100 ml of ethanol for 16 hours. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration and washed with a small amount of ethanol to give 1-(4-chlorobenzyl)-2-(nitromethylene)tetrahydropyrimidine (9.8 g) represented by the following formula. Melting point: 172°-174° C. ##STR10##
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:20][C:21](O)=[O:22])([C:17](O)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][NH3+:26].[Cl-].C(N(CC)CC)C>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2([C:17](=[O:18])[N:26]([O:25][CH3:24])[C:21](=[O:22])[CH2:20]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[NH3+]
Reactant: O=C(O)CC1(C(=O)O)CCN(C(=O)OCc2ccccc2)CC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON1C(=O)CC2(CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To a solution of (1-benzyloxycarbonyl-4-carboxypiperidin-4-yl)acetic acid (3.64 g) in dimethylformamide (30 ml) dicyclohexylcarbodiimide (2.57 g) was added, and this was followed by stirring at room temperature for 30 minutes. o-Methylhydroxylamine hydrochloride (0.95 g) and triethylamine (1.56 ml) were then added, and this was followed by stirring at room temperature for 30 minutes. The resulting precipitates were removed, and the solvent was evaporated under reduced pressure. To the resulting residual oily compound acetic anhydride (20 ml) and anhydrous sodium acetate (0.39 g) were added, and this was followed by stirring at 100° C. for 30 minutes. After the completion of the reaction, the solvent was removed, and the residual oil was dissolved in 50 ml ethyl acetate. The resulting solution was sequentially washed with a saturated aqueous solution of sodium hydrogencarbonate, 1N hydrochloric acid and water, and dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure; the resulting residual solid was recrystallized from ethyl ether-petroleum ether to obtain 2.1 g of a colorless crystal having a melting point of 98° C.