Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.[C:12]([NH2:18])(=[O:17])[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[C:12]([C:13](=[CH:7][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[N:3][N:2]([CH3:1])[CH:6]=1)[C:14]([OH:16])=[O:15])(=[O:17])[NH2:18]
Reactant: Cn1cc(C=O)c([N+](=O)[O-])n1
Reactant: NC(=O)CC(=O)O
Solvent: c1ccncc1
Product: Cn1cc(C=C(C(N)=O)C(=O)O)c([N+](=O)[O-])n1

Procedure:
When the reaction of 1-methyl-3-nitropyrazole-4-aldehyde and malonic acid monoamide in pyridine is carried out at 70° C., then, as intermediate product, there can be isolated 2-carbamoyl-3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid. For decarboxylation, 0.1 g. of this product is stirred in 1 ml. pyridine for 1.5 hours at a bath temperature of 120° C. The reaction mixture is then cooled, ice-cold semi-concentrated hydrochloric acid is added thereto and the precipitated crystals are filtered off with suction, washed with water and dried. There is obtained 0.02 g. 3-(1-methyl-3-nitropyrazolyl)-acrylamide.
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>FC(F)(F)C(O)=O>[O:8]=[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][NH:10]1
Reactant: COC(=O)c1ccc(OCc2ccc(OC)cc2)nc1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(=O)[nH]c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
Methyl 6-(4-methoxybenzyloxy)nicotinate (2.66 g, 9.73 mmol) obtained in Step 2 and anisole (10.6 mL) were dissolved in trifluoroacetic acid (15 mL), followed by stirring at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure, and saturated sodium hydrogencarbonate was added to the resulting residue, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The precipitated solid was collected by filtration to afford methyl 2-oxo-1,2-dihydropyridine-5-carboxylate (1.33 g, 89%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/OC)([CH3:4])([CH3:3])[CH3:2].[NH2:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([O:29][CH2:30][CH2:31][CH3:32])=[CH:24][N:23]=1>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[C:8]2=[CH:17][NH:20][CH2:21][C:22]1[CH:27]=[C:26]([OH:28])[C:25]([O:29][CH2:30][CH2:31][CH3:32])=[CH:24][N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Reactant: CCCOc1cnc(CN)cc1O
Solvent: CN(C)C=O
Product: CCCOc1cnc(CNC=C2C(=O)NC(=O)c3ccc(C(C)(C)C)cc32)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
An amount of 50.0 mg (0.193 mmol) of (4E)-6-tert-butyl-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione, is dissolved in N,N-dimethylformamide (3 mL), followed by the addition of 35 mg (0.193 mmol) of 2-aminomethyl-5-propoxy-pyridin-4-ol. All solids dissolved and after the mixture is stirred at room temperature for 2 hours, the solution is evaporated to dryness in vacuo, treated with acetonitrile, filtered and washed several times with fresh acetonitrile and dried to give 52 mg of the title compound as a light pink solid (66% yield); mp 162-178° C. dec, MS data ES(+) 410.4 m/e.
Reaction SMILES: [CH3:1][C@:2]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[C:14]=3[CH:15]=2)[CH2:6][CH2:5][CH2:4][NH:3]1.[CH3:20][O:21][C:22](=[O:25])[CH2:23]Br.CCN(C(C)C)C(C)C>CC#N.C(Cl)Cl>[CH3:20][O:21][C:22](=[O:25])[CH2:23][N:3]1[CH2:4][CH2:5][CH2:6][C@@:2]1([C:7]1[NH:8][C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[C:14]=2[CH:15]=1)[CH3:1]
Reactant: COC(=O)c1cccc2[nH]c([C@@]3(C)CCCN3)cc12
Reactant: COC(=O)CBr
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN1CCC[C@]1(C)c1cc2c(C(=O)OC)cccc2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 59.7 %

Procedure:
(R)-Methyl 2-(2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate (190 mg, 0.74 mmol) was dissolved in CH3CN (25 ml) and methylbromoacetate (250 mg, 1.6 mmol). DIPEA (350 mg, 2.7 mmol) was then added. The reaction mixture was stirred at room temperature for about 20 hours. The reaction mixture was then diluted with CH2Cl2 (15 ml) and washed with water three times. The organic layer was dried with MgSO4 and concentrated to give 146 mg of (R)-methyl 2-(1-(2-methoxy-2-oxoethyl)-2-methylpyrrolidin-2-yl)-1H-indole-4-carboxylate. 1H NMR (CDCl3-d) δ 7.85 (d, 1H, J=7.8 Hz), 7.13-7.29 (m, 3H), 4.92 (s, 2H), 3.95 (s, 3H), 3.70 (s, 3H), 3.56-3.62 (m, 2H), 1.95-2.06 (m, 4H), and 1.94 (s, 3H). MS (ESI) m/e [M+1]+ 331.0.
Reaction SMILES: Cl.Cl.Cl.[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1.[C:29]1([CH2:35][C:36](Cl)=[O:37])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CO>ClCCl>[NH:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:36](=[O:37])[CH2:35][C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: C1=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CCNC1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccccc1)N1CC=C(c2cc3c(Nc4ccc5[nH]ncc5c4)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1H-indazol-5-yl)-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine tri-hydrochloride (73.6 mg, 0.2 mmol) and phenylacetyl chloride (31 mg, 0.2 mmol) in dichloromethane (1.5 mL) was added i-Pr2NEt (0.1 mL). The resulting mixture was stirred at rt for 3 h. MeOH (0.3 mL) was added to quench the reaction. Solvents were removed and the residue was dissolved in DMF (≈2 mL), which was purified by mass-directed HPLC to obtain the title compound. 1H-NMR (DMSO-d6, 400 MHz): δ=2.34 (m, 2H), 3.72 (t, J=5.6 Hz, 2H), 3.80 (d, J=17.6 Hz, 2H), 4.21 (d, J=35.6 Hz, 2H), 6.40 (s, 1H), 6.73 (d, J=38.4 Hz, 1H), 7.22-7.34 (m, 4H), 7.51 (d, J=8.8 Hz, 1H), 7.63 (m, 1H), 8.04 (s, 1H), 8.25 (d, J=4.4 Hz, 1H), 8.37 (t, J=7.2 Hz, 1H), 9.33 (d, J=13.6 Hz, 1H), 11.92 (d, J=14.8 Hz, 1H), 12.97 (s, 1H). MS (ES+): m/z 450.07 [MH+]. HPLC: tR=2.17 min (ZQ2000, polar—5 min).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH2:13][CH3:14])[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)[CH3:2].FC(F)(F)C(O)=O.[N+:24]([O-])([O-:26])=[O:25].[K+]>O>[N+:24]([C:11]1[C:12]([CH2:13][CH3:14])=[C:3]([CH2:1][CH3:2])[CH:4]=[C:5]2[C:10]=1[NH:9][C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:26])=[O:25]
Reactant: O=[N+]([O-])[O-]
Reactant: CCc1cc2[nH]c(=O)c(=O)[nH]c2cc1CC
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2[nH]c(=O)c(=O)[nH]c2c([N+](=O)[O-])c1CC
Yield: 69.1 %

Procedure:
6,7-Diethyl-2,3-quinoxalinedione 25 (218 mg, 1.0 mmol) was added to trifluoroacetic acid (8 mL; Sigma). To this suspension was added potassium nitrate (121.2 mg, 1.2 mmol; Baker) in one portion with stirring under N2. The reaction was stirred at room temperature for 48 h. Trifluoroacetic acid was evaporated in vacuo to give a residue. Water (10 mL) was added to this residue with vigorous stirring. A yellow solid precipitated, which was collected by suction filtration and dried in vacuo to give 182 mg (69%) of the title compound 26 as a yellow solid; mp 270-272° C. (dec.); 1H NMR (DMSO-d6, 300 MHz) δ 1.137 (m, 6H), 2.622 (m, 4H), 7.088 (s, 1H), 11.762 (s, 1H), 12.028 (s, 11H). EIMS m/e 263 (100, M+). (HPLC purity 100%).
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]([CH3:26])[C:9]1[C:14]2[N:15]=[C:16]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Reactant: C1CNCCN1
Product: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCNCC3)nc12

Procedure:
This compound was prepared analogous to Example 118 from 8-(N-benzyl-methylamino)-2-chloro-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 121°-123° C.) and piperazine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([OH:7])[CH3:6].C(Cl)(=O)C.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20]>C(Cl)(Cl)Cl.O>[CH3:6][C:5]([C:17]1[CH:16]=[CH:15][C:14]([O:19][CH3:20])=[C:13]([Cl:12])[CH:18]=1)=[O:7]
Reactant: COc1ccccc1Cl
Reactant: CCO
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)=O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 76 %

Procedure:
A 5 L round bottomed flask equipped with mechanical stirrer, reflux condenser, constant pressure addition funnel and nitrogen inlet was charged with anhydrous aluminum chloride (281 g, 2.104 mol) and 1 L of ethanol-free chloroform. The solution was maintained at 0° C. with an ice bath while a solution of acetyl chloride (162 g, 2.28 mol) in 300 mL of chloroform was added from the addition funnel over 25 minutes. To this solution was added 2-chloroanisole (250 g, 1.75 mol) in 250 mL of chloroform over 1 hour. The solution was stirred at room temperature for 16 hours and the contents of the flask were poured into a mixture of ice and water. The phases were separated and the aqueous phase extracted with dichloromethane and combined with the original organic phase, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a solid that was crystallized from dichloromethane/hexane to give 3-chloro-4-methoxyacetophenone (246 g, 76%) that was used directly in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[CH3:16][C:17]1[CH:22]=[C:21](B(O)O)[CH:20]=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([C:21]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:16])[CH:22]=2)[C:11]=1[CH3:12]
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Reactant: Cc1cc(B(O)O)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)ccn1

Procedure:
The Suzuki coupled product was prepared according to Procedure F using 2,4-dichloro-5,7-difluoro-3-methylquinoline (0.50 g, 2.02 mmol), 2-methylpyridin-4-ylboronic acid (0.28 g, 2.02 mmol), palladium tetrakistriphenylphosphine (0.23 g, 0.20 mmol), potassium carbonate (0.56 g, 4.03 mmol) in toluene (4 mL) at 100° C. for 44 h to give 4-chloro-5,7-difluoro-3-methyl-2-(2-methylpyridin-4-yl)quinoline as a white solid. Mass Spectrum (ESI) m/e=305.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][CH:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH2:14][CH2:15][C:16](=[O:26])[N:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])[OH:7])[CH3:2].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.C(O)(C)C.O>CC(C)=O>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][C:6]([C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:27])[CH2:14][CH2:15][C:16](=[O:26])[N:17]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:18])=[O:7])[CH3:2]
Reactant: CCOC(=O)CC(O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOC(=O)CC(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of (3RS)-3-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl) propionyl]pyrrolidin-2-yl]-3-hydroxypropionic acid ethyl ester (230 mg) in acetone (1 ml) was cooled to -30° C. Excess Jones' reagent was added dropwise to the solution. The mixture was stirred for 1 hr at the same temperature, and for 1 hr at -20° C., and for 1 hr at -10° C. Isopropyl alcohol was added to the reaction solution. Water was added to the mixture. The mixture was extracted with EtOAc. The extract was washed, dried, and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (98 mg) having the following physical data:
Reaction SMILES: [CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH:4]=[CH2:5].[CH2:18](O)CCCC=C>>[CH2:1]([O:6][C:7]([NH:9][C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:8])[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:18]
Reactant: C=CCCCOC(=O)N[C@@H](CCCC)C(=O)O
Reactant: C=CCCCCO
Product: C=CCCCCOC(=O)N[C@@H](CCCC)C(=O)O

Procedure:
N-[(Hex-5-en-1-yloxy)carbonyl]-L-norleucine was prepared according to the procedure for N-[(pent-4-en-1-yloxy)carbonyl]-L-norleucine by using 5-hexenol instead of 4-pentenol. LRMS (ESI) m/z 258 [(M+H)+; calcd for C13H24NO4: 258].
Reaction SMILES: [O:1]=[C:2]([CH3:10])[CH2:3]P(=O)(OC)OC.[Li+].[Cl-].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH:23]=O)[CH:14]=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[C:15]([CH:23]=[CH:3][C:2](=[O:1])[CH3:10])[CH:14]=1
Reactant: O=Cc1cnc2ccccc2c1
Reactant: COP(=O)(CC(C)=O)OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C=Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethyl (2-oxopropyl)phosphonate (3.1 g,19.1 mmol), anhydrous LiCl (972 mg, 23 mmol), and 3-quinoline carboxaldehyde 6-1 (3.0 g,19.1 mmol) in anhydrous acetonitrile (70 mL), was treated with DBU (2.9 mL, 19.1 mmol) and the resulting suspension stirred at room temperature for 1 h. The solvent was removed at reduced pressure and the resulting residue partitioned between brine and methylene chloride. The organic layer was removed, dried, and concentrated to afford a yellow solid which was recrystallized from ethyl acetate/hexanes to afford 22-1 as an off-white solid.
Reaction SMILES: [CH3:1][C:2](O)([CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].OP(O)(O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[Na]>[CH3:1][C:2]1([CH3:3])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[S:6][CH2:5][CH2:4]1
Reactant: CC(C)(O)CCSc1ccccc1
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na]
Product: CC1(C)CCSc2ccccc21
Reaction time: 24 h
Yield: 86.2 %

Procedure:
A mixture of 15.00 grams (0.076 mol) of 2-methyl-4-(phenylthio)-2-butanol, 12.75 grams of H3PO4, 27.0 grams (0.190 mol) of P2O5 [this is added in three equal portions every 8 h]and 60 mL of sodium-dried benzene was boiled under N2 for 24 hours in a 250-mL, round-bottom flask equipped with a condenser and nitrogen inlet. The resulting, cooled heterogeneous mixture was separated and the P2O5 layer was extracted with ether. The combined organic layers were washed with H2O, brine, dried with Na2SO4 (4 h). Evaporation and vacuum distillation gave 11.68 grams (86.0%) of 4,4-dimethylthiochroman as a clear colorless liquid: bp 75°-82° C./0.1 mm; 1H NMR (DCCl3) δ1.29 [s, 6 H, (CH3)2C]1.92 [m, 2 H, ArSCH2CH2 ]3.00 [m, 2 H, ArSCH2CH2 ]6.90-7.32 [m, 4 H, Ar-H]; 13C NMR (DCCl3) ppm 22.8 [ArSCH2CH2 ], 29.9 [(CH3)2C]32.6 [(CH3)C], 37.4 [ArSCH2CH2 ], 123.7, 125.7, 126.1, 126.2, 131.5, 141.5. ##STR13##
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@@H:9]([C:15]([OH:17])=[O:16])[CH2:10][CH2:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:4])[CH3:3].[CH3:18][C:19]([O:22][C:23]([NH:25]/[C:26](/N1N=CC=C1)=[N:27]/[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[O:24])([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)Cl>[C:31]([O:30][C:28]([N:27]=[C:26]([NH:25][C:23]([O:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:24])[NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]([NH:8][C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[C:15]([OH:17])=[O:16])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N[C@H](CCCCN)C(=O)O
Reactant: CC(C)(C)OC(=O)/N=C(/NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N=C(NCCCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.5 %

Procedure:
A solution of N-α-Boc-D-lysine 12 (10.0 g, 40.6 mmol) in CH2Cl2 (200 mL) was charged with N,N′-bis-Boc-1-guanylpyrazole (11.3 g, 36.6 mmol) and triethylamine (11.0 mL, 81.3 mmol). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was washed with 10% aqueous citric acid (2×100 mL) and the solvent was removed under reduced pressure. The residue was dissolved in 1 N NaOH (300 mL), 1 N HCl was added to adjust the pH to 5-6, and the mixture was extracted with CH2Cl2 (500 ml). The CH2Cl2 layer was separated and the aqueous layer was extracted with CH2Cl2 (2×250 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford compound 8 (18.5 g, 94%) as a white solid: 1H NMR (400 MHz, CD3OD) δ 4.13-4.03 (m, 1H), 3.36 (t, J=6.8 Hz, 2H), 1.91-1.77 (m, 1H), 1.74-1.55 (m, 3H), 1.52 (s, 9H), 1.51-1.38 (m, 2H), 1.47 (s, 9H), 1.43 (s, 9H).
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3].[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH2:34])[CH2:23][CH3:24])[CH3:21].Cl>C(#N)C>[CH2:20]([N:22]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[CH2:32][CH2:33][NH:34][C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2=[CH:16][S:17][C:18]([CH3:19])=[C:5]12)=[O:3])[CH2:23][CH3:24])[CH3:21]
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: Cc1scc2c1N(C(=O)Cl)c1ccccc1NC2=O
Agent: Cl
Solvent: CC#N
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccccc2NC(=O)c2csc(C)c21
Yield: 53 %

Procedure:
Prepared analogously to Example 1 from 4-(chlorocarbonyl)-4,9-dihydro-3-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and (-)-2-[2-[(diethylamino)methyl]-piperidin-l-yl]ethanamine in a yield of 53% of theory. Colourless crystals, m.p. 132°-133° C. (acetonitrile); [α]D20 =-14.00° (dilute aqueous hydrochloric acid).
Reaction SMILES: [C:1]12([C:11](Cl)=[O:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Br:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C(N(CC)CC)C>O1CCCC1>[C:1]12([C:11]([O:17][CH2:16][C:15]([Br:14])([F:19])[F:18])=[O:12])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC(F)(F)Br
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OCC(F)(F)Br)C12CC3CC(CC(C3)C1)C2

Procedure:
In tetrahydrofuran, 1-adamantanecarbonyl chloride and 2-bromo-2,2-difluoroethanol were mixed and ice cooled. Triethylamine was added to the mixture. By standard separation operation and solvent distillation, 2-bromo-2,2-difluoroethyl 1-adamantanecarboxylate was obtained. This compound was converted into a sodium sulfinate with sodium dithionite and then oxidized with hydrogen peroxide, yielding the target compound, sodium 2-(1-adamantanecarbonyloxy)-1,1-difluoroethane-sulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14](C#N)=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:24](=[O:27])([O-])[OH:25].[Na+]>O.C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]3=[N:13][C:14]([C:24]([OH:25])=[O:27])=[CH:15][CH:16]=[C:11]3[NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc2[nH]nc(-c3cccc(F)c3)c2n1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]nc(-c3cccc(F)c3)c2n1
Temperature: 100 °C

Procedure:
140 mg of 3-(3-fluorophenyl)-1H-pyrazolo[4,3-b]-pyridine-5-carbonitrile was added to a mixed solution of 1 mL water, 1 mL concentrated sulfuric acid and 1 mL glacial acetic acid, and heated under 100° C. for 3 hours. The reaction solution was added with 25 mL of ice-cooled water, neutralized with sodium hydrogen carbonate, and the precipitated crystals were collected by filtration. The crystals collected by filtration were washed with cold water, and dried under reduced pressure, to give 150 mg of a crude product of the title compound as a colorless powder.
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH:16]=[C:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(O)C.C(CN)O>O>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([O:20][CH3:21])=[CH:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1
Reactant: COC1=CC=C2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Solvent: CCO
Solvent: O
Solvent: NCCO
Product: COC1=CC[C@H]2[C@H]3Cc4ccc(OC)c5c4[C@@]2(CCN3C)[C@H]1O5
Temperature: 70 °C
Yield: 91.3 %

Procedure:
Thebaine (142.86 g of 70 wt % material containing 30 wt % water, 100.00 g, 0.321 mol), p-toluene sulfonyl hydrazide (131.58 g, 0.706 mop and ethanol (400 ml) were stirred and heated to 70° C. Ethanol amine (43.16 g, 0.706 mol) was added to this solution over a 1 h period. The reaction was heated for a further 10 h at this temperature and then allowed to cool to room temperature. The reaction was diluted with water (400 ml) and the pH adjusted to >9.30 with concentrated (28.0-30.0%) ammonium hydroxide (30 ml) and cooled to <5° C. The product was isolated by filtration and washed with 1% v/v ammonium hydroxide in water (400 ml) to give 8,14-dihydro-thebaine as a white amorphous solid (91.94 g, 91.3% yield, 99.29 wt % by assay, with 0.16 wt % of the 6-β-parzone methyl ether impurity).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[C:13]2[CH2:14][CH:15](Cl)[C:16]3[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:17]=3[S:18][C:12]=2[CH:11]=[CH:10][CH:9]=1.C(O)C.O>O1CCCC1>[F:23][C:21]1[CH:20]=[CH:19][C:17]2[S:18][C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([Cl:7])[C:13]=3[CH2:14][CH2:15][C:16]=2[CH:22]=1
Reactant: Fc1ccc2c(c1)C(Cl)Cc1c(Cl)cccc1S2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc2c(c1)CCc1c(Cl)cccc1S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.6 %

Procedure:
0.7g of lithium aluminum hydride was suspended in 20ml of tetrahydrofuran, to the resulting suspension was added dropwise with stirring 2.1g of 9-chloro-11-chloro-2-fluoro-10,11-dihydrodibenzo[b,f]thiepin dissolved in 10ml of anhydrous tetrahydrofuran and the mixture was stirred at room temperature for 0.5hr., further under reflux condition for 3.5 hrs., while preventing the moisture. After completion of the reaction, an excess of lithium aluminum hydride was decomposed by adding ethanol and water, and filtered off using celite. The filtrate was evaporated to obtain the residue, which was chromatographed on silica gel, eluted with chloroform, and there was obtained 1.2g(67.0% of yield) of 2-fluoro-9-chloro-10,11-dihydrodibenzo[b,f]thiepin as pale green viscous oily substance.