Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.O.[Sn](Cl)Cl.[CH3:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:8]=1[S:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[N+:23]([O-])=O.CCOC(C)=O.O>CCO.Cl>[NH2:23][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:15]=1[S:14][C:8]1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:7]=1[CH3:6])[C:19]#[N:20]
Reactant: Cc1ccc(C)c(Sc2ccc(C#N)cc2[N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C)c(Sc2ccc(C#N)cc2N)c1
Temperature: 70 °C
Yield: 74 %

Procedure:
A mixture of Tin (II) chloride dihydrate (25.218 g, 112.0 mmol) in EtOH (85.0 mL) and conc. HCl (12 M, 15.0 mL) was stirred at 70° C. until a clear solution was formed. Compound 24 (8.0 g, 28.14 mmol) was then added over 10 min. The solution was kept slightly refluxing during addition. The reaction was monitored with TLC (25% EtOAc in hexanes, Rf=0.65). The reaction was complete after refluxing for 1.5 hrs as indicated by the absence of the starting material (TLC). Water (35 mL) was added and the resulting solution was allowed to cool to room temperature. Precipitation occurred during cooling. The mixture was further cooled and stirred for 30 min at 15° C. The precipitate was filtered, washed with water, and dried under vacuum to yield compound 25 as a white solid (5.30 g, 95% HPLC purity, 65% yield). 1H NMR (500 MHz, DMSO-d6): δ 7.20 (d, J=8 Hz, 1H), 7.07 (d, J=2 Hz, 1H), 7.04 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 6.90 (dd, J1=2 Hz, J2=8 Hz, 1H), 6.85 (s, 1H), 5.72 (s, 2H), 2.26 (s, 3H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.N1[CH2:28][CH2:27][NH:26][CH2:25]C1>C1COCC1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:6][N:7]1[C:8]([C:9]2[S:17][C:12]3[N:13]=[CH:14][N:15]=[CH:16][C:11]=3[CH:10]=2)=[C:27]([C:28]2[CH:5]=[CH:4][CH:3]=[CH:20][CH:19]=2)[N:26]=[CH:25]1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Reactant: C1CNCCN1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(Cn2cnc(-c3ccccc3)c2-c2cc3cncnc3s2)cc1OC
Yield: 96.2 %

Procedure:
N-(3,4Dimethoxybenzyl)-N-[thieno[2,3-d]pyrimidin-6-ylmethylidene]amine (intermediate 14) (76 mg), PhTosMIC (99 mg) and piperazine (31 mg) in THF (5 mL) were stirred under an inert atmosphere for 6 days. The reaction mixture was diluted with EtOAc and water. The organic layer was separated and the aqueous layer extracted with EtOAc (2×15 mL). The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with hexane:EtOAc (1:4) afforded the title compound as a pale yellow solid (50 mg, 48%);
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])#[CH:14].[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][N+:30]([O-])=[O:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[O:31][N:30]=1
Reactant: C#Cc1ccccc1OC
Reactant: COC(=O)CCCC[N+](=O)[O-]
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCc1cc(-c2ccccc2OC)on1
Yield: 112.6 %

Procedure:
Add 1,4-phenylenediisocyanate (19.22 g, 120.0 mmol) to a stirred solution of 1-ethynyl-2-methoxy-benzene (2204901, 5.29 g, 40.0 mmol) and 5-nitro-pentanoic acid methyl ester (7.91 g, 49.1 mmol) in toluene (300 mL, anhydrous) and stir under N2. Add triethylamine (16.7 mL, 120.0 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 12.4 g yellow oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (14.0 g, 74%). MS (IS) 276 (M+1)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([C:10](=[O:24])[C:11]([CH3:23])([CH3:22])[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][NH:17][C@@H:16]([CH3:20])[C:15]2=[O:21])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[Cl:25][C:26]1[CH:31]=[C:30]([N:32]=[C:33]=[O:34])[CH:29]=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]>>[Cl:25][C:26]1[CH:31]=[C:30]([NH:32][C:33]([N:17]2[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][C:11]([CH3:23])([CH3:22])[C:10]([N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)=[O:24])[C:15](=[O:21])[C@@H:16]2[CH3:20])=[O:34])[CH:29]=[CH:28][C:27]=1[C:35]([F:38])([F:37])[F:36]
Reactant: O=C=Nc1ccc(C(F)(F)F)c(Cl)c1
Reactant: C[C@@H]1NCCN(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)C1=O
Product: C[C@H]1C(=O)N(CCC(C)(C)C(=O)N2CCC3(CC3)[C@H](O)C2)CCN1C(=O)Nc1ccc(C(F)(F)F)c(Cl)c1
Yield: 53 %

Procedure:
In analogy to the procedure described in Example 30, (S)-1-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-3,3-dimethyl-4-oxo-butyl]-3-methyl-piperazin-2-one (intermediate 28) and 1.2 eq. of 2-chloro-4-isocyanato-1-trifluoromethyl-benzene (intermediate 16) gave the titled compound in 53% yield as off-white foam. MS: 559.23 (MH+, Cl).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13]Cl)[C:6]=2[CH:15]=1.[F:16][C:17]([F:31])([F:30])[C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[N:8][N:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:27]3[CH2:26][CH2:25][N:24]([C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:30])([F:31])[F:16])[CH:19]=4)[CH2:29][CH2:28]3)[C:6]=2[CH:15]=1
Reactant: ClCCCCn1nnc2ccc(Cl)cc21
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)c1cccc(N2CCN(CCCCn3nnc4ccc(Cl)cc43)CC2)c1
Temperature: 25 °C
Yield: 64.7 %

Procedure:
6-chloro-1-(4-chlorobutyl)-1H-benzotriazole (8.75 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 3-trifluoro methylphenylpiperazine (6.9 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 8.5 g compound (I-54) with a yield of 64.7%. ESI-MS [M+H]+: m/z 437.2.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.C([Mg]Cl)(C)C.[SiH4].[CH:12]([Si:15]([CH:19]([CH3:21])[CH3:20])([O:17][CH3:18])Cl)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH:12]([Si:15]([CH:1]([CH3:2])[CH3:5])([CH:19]([CH3:21])[CH3:20])[O:17][CH3:18])([CH3:14])[CH3:13]
Reactant: CO[Si](Cl)(C(C)C)C(C)C
Reactant: C1CCOC1
Agent: CC(C)[Mg]Cl
Agent: [SiH4]
Solvent: Cc1ccccc1
Product: CO[Si](C(C)C)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To the mixture of the silanes containing diisopropylmethoxychlorosilane as obtained from the disproportionation reaction in (b) above, was added 150 ml of toluene to dissolve the mixture, thereby to obtain a toluene solution of the said silane mixture. The THF solution of isopropyl magnesium chloride (Grignard reagent) as prepared in (a) above was added dropwise through a dropping funnel to the toluene solution of said silane mixture at 40° C.-50° C. over 1 hour. Then the resulting mixture was stirred at 70° C. for 4 hours. Thus, the Grignard reagent was reacted with the diisopropylmethoxychlorosilane contained in the said toluene solution, to produce triisopropylmethoxysilane. To the resulting reaction solution was added dropwise 40 ml of a saturated aqueous ammonium chloride solution to dissolve the magnesium salt in the latter. The organic layer was separated from the aqueous layer and the organic layer, was distilled to afford 28 g of triisopropylmethoxysilane as a fraction boiling at 85° C.-86° C./20 mm Hg. The yield was 73%.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]1([S:18]([NH:21][C:22](=[NH:25])SC)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(#N)C>[C:12]1([S:18]([NH:21][C:22]([NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]2[NH:5][CH:4]=[N:3][C:2]=2[CH3:1])=[NH:25])(=[O:19])=[O:20])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)NS(=O)(=O)c1ccccc1
Solvent: CC#N
Product: Cc1nc[nH]c1CSCCNC(=N)NS(=O)(=O)c1ccccc1
Yield: 20.4 %

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (5.93g.) and N-benzenesulphonyl-S-methylisothiourea (8.0g.) in acetonitrile (100 ml.) was heated under reflux for 24 hours. Concentration, followed by chromatographic purification on a column of silica gel with benzene - methanol (10:1) and recrystallisation from aqueous ethanol and then acetonitrile afforded N-benzenesulphonyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethyl]guanidine (2.5 g.) m.p. 149°-150°.
Reaction SMILES: [CH:1]12[CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]1[CH:2]2[N:3]1[C:9]1[C:16]([F:17])=[C:15]([F:18])[C:12]([CH:13]=O)=[C:11]([F:19])[C:10]=1[F:20].[C:21]([C:23]1[C:24](=[C:31]([C:34]#[N:35])[C:32]#[N:33])[O:25][C:26]([CH3:30])([CH3:29])[C:27]=1[CH3:28])#[N:22]>C(O)(=O)C.N1C=CC=CC=1>[CH:5]12[CH2:8][CH:1]([CH2:7][CH2:6]1)[CH:2]1[CH:4]2[N:3]1[C:9]1[C:16]([F:17])=[C:15]([F:18])[C:12]([CH:13]=[CH:28][C:27]2[C:26]([CH3:29])([CH3:30])[O:25][C:24](=[C:31]([C:32]#[N:33])[C:34]#[N:35])[C:23]=2[C:21]#[N:22])=[C:11]([F:19])[C:10]=1[F:20]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(C)C
Reactant: O=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC1(C)OC(=C(C#N)C#N)C(C#N)=C1C=Cc1c(F)c(F)c(N2C3C4CCC(C4)C32)c(F)c1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In a 100-mL round bottom flask with stirbar was added 4-(3-aza-tricyclo[3.2.1.02,4]oct-3-yl)-2,3,5,6-tetrafluoro-benzaldehyde (0.35 g, 1.23 mmol), 2-(3-cyano-4,5,5-trimethyl-5H-furan-2-ylidene)-malononitrile (0.39 g, 2 mmol), pyridine (5 mL) and acetic acid (several drops). The mixture was stirred under nitrogen at room temperature for 3 days. TLC showed that one red fluorescent product had formed as the main product. The reaction was stopped. The product mixture was poured into ice-water (500 mL) and vigorously stirred for 4 h. The crude products were extracted with CH2Cl2 (100 mL×5). The combined organic layer was dried over anhydrous MgSO4. After removing solvent, the crude organic product was adsorbed on silica gel, placed at the top of a silica column and eluted (hexane/EtOAc=2/1). Fraction containing only the first red fluorescent product were combined and concentrated to give a red solid, which was recrystallized from 1-propanol to give the final product as red needles. Mp 233° C. IR (neat): 2951, 2228, 1573, 1481, 1390, 1366, 1163, 1107, 983, 962 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.64 (d, J=16.8 Hz, 1H), 7.23 (d, J=16.8 Hz, 1H), 2.70 (br s, 4H), 1.80 (s, 6H), 1.63-1.51 (m, 3H), 1.34-1.27 (m, 2H), 0.98-0.92 (m, 1H); 13C NMR (100 MHz, CDCl3): 176.4, 173.4, 148-139 (m), 132.5, 118.8 (t), 111.4, 110.6, 109.9, 97.6, 95.3 (m).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:15])([CH3:14])OCC>O1CCCC1>[Br:5][CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:15])([CH3:14])[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: CCO[Si](C)(C)CCCCBr
Solvent: C1CCOC1
Product: C=C[Si](C)(C)CCCCBr
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 79.8 %

Procedure:
A 3 l reactor was charged under nitrogen with 11 of vinyl magnesium bromide in THF (tetrahydrofuran) and 184 g of 4-bromobutyl-dimethyl-ethoxysilane were added slowly at room temperature. The mixture was then refluxed at 70° C. for 16 h. After cooling on ice, the mixture was quenched with 407 g of a 20% HBr (w/w) solution, after which it was stirred for another 1.5 h. The THF layers were separated from the aqueous layers and neutralized with aq. sodium hydrogen carbonate solution. The THF was evaporated and the residue was distilled in the presence of 1 g Pt/C to obtain 135.8 g (79.8%) of pure 4-bromobutyl-dimethyl-vinylsilane
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[CH:10]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2.[OH-].[Na+].C(=O)=O.CC(C)=O>O.CC(C)=O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([N:12]2[CH2:13][CH:14]3[CH2:17][CH2:18][CH:10]([CH2:16][CH2:15]3)[CH2:11]2)[N:7]=1
Reactant: C1CC2CCC1CNC2
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: Clc1nc(Cl)nc(N2CC3CCC(CC3)C2)n1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
Two hundred and eighty grams (1.5 mole) of cyanuric chloride is dissolved in 1.4 l. of acetone, then 1.8 l. of water is added and the mixture cooled to -10° C. using a dry-ice/acetone bath. 130 g. (1.0 mole) of 3-azabicyclo[3.2.2]nonane slurried in 200 ml. of acetone is then added all at once and the reaction is allowed to stir at -10° C. for 15 minutes. 100 ml. of 10 N NaOH is then added all at once giving rise to a small exotherm. After cooling to -10° C. using the dry-ice/acetone bath, the reaction mixture is stirred without further cooling for 3.8 hours allowing the temperature to rise to about 20° C. Two liters of water is then added, the precipitate filtered off and then washed with water. The precipitate is then dissolved in chloroform, excess water separated, the chloroform solution dried over magnesium sulfate and filtered through Magnesol®. The Magnesol® is then washed with chloroform, solvent removed in vacuo and recrystallized from dichloromethane-hexanes giving 170 g. of needles, m.p. 153°-154° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[C:3]=1[SH:10].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl.Cl>N1C=CC=CC=1>[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][S:10][C:3]1[C:4](=[O:9])[O:5][C:6]([CH3:8])=[CH:7][C:2]=1[OH:1]
Reactant: Fc1cccc(CCl)c1
Reactant: Cc1cc(O)c(S)c(=O)o1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)c(SCc2cccc(F)c2)c(=O)o1
Temperature: 90 °C
Yield: 53 %

Procedure:
4-Hydroxy-3-mercapto-6-methyl-2-pyrone (50 g., 0.317 mole) and m-fluorobenzylchloride (45.8 g., 0.317 mole) were dissolved in pyridine (250 ml.). The temperature rose from 20° to 36°C. The resulting solution was heated at 90°C. for two hours and poured over ice and 500 ml. of concd. hydrochloric acid. This mixture was extracted with methylene chloride. The extract was dried (MgSO4) and the solvent removed by evaporation. The residue was mixed with hexane, filtered and dried, yielding 44.6 g. (53 percent) of the desired product. Recrystallization from benzene gave the pure product as a white solid, m.p. 123.5°-124°C.
Reaction SMILES: C[O:2][C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O.C(O)C>[Pd].O1CCCC1>[O:2]=[C:3]1[CH2:4][CH2:5][C:6]2[C:7](=[CH:8][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:15][CH:16]=2)[NH:17]1
Reactant: CCOC(=O)c1ccc(/C=C/C(=O)OC)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a mixture of 1.8 g of ethyl 4-[(1E)-3-methoxy-3-oxoprop-1-en-1-yl]-3-nitrobenzoate, 32 ml of ethanol and 32 ml of tetrahydrofuran was added 640 mg of 10% palladium/carbon under an argon atmosphere, followed by 2 hours of stirring at room temperature under a hydrogen atmosphere. The reaction solution was filtrated through celite and the organic solvent in the filtrate was removed under reduced pressure. To the residue were added 50 ml of methanol and 2 drops of concentrated hydrochloric acid, followed by 30 minutes of stirring at 60° C. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and water and chloroform were added to the residue, followed by an operation for separation. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain 1.16 g of ethyl 2-oxo-1,2,3,4-tetrahydroquinoline-7-carboxylate as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:18][C:17]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH3:19])[NH:10][C:9]=2[CH2:8][NH:7]1)=[O:5])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[C:15]([CH3:19])[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1Cc2c([nH]c3cccc(C)c23)CN1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(cn1)[nH]c1cccc(C)c12
Temperature: 15 °C
Reaction time: 1 h
Yield: 61.4 %

Procedure:
2.58 g of 5-methyl-1,2,3,4-tetrahydro-β-carbolin-3-carboxylic acid ethyl ester is dissolved in 40 ml of absolute toluene, cooled to 15° C., 2.72 g of dichlorodicyanobenzoquinone is added thereto and the whole is stirred for 1 hour at this temperature. The mixture is then diluted with ethyl acetate, extracted several times by shaking with dilute ammonia and then with saturated common salt solution, dried over calcium sulphate and concentrated in vacuo. Chromatography on silica gel with a chloroform-ethanol gradient yields 1.56 g of 5-methyl-β-carbolin-3-carboxylic acid ethyl ester of melting point 221°-223° C. (decomposition).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23]CC1C=CC=CC=1)=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[CH:1]([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([OH:23])=[CH:14][CH:13]=3)=[O:6])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Agent: [Pd]
Solvent: CCO
Product: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(O)cc3c12
Yield: 84.8 %

Procedure:
At room temperature and under normal pressure, 7 g (18 mmol) of 6-benzyloxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is hydrogenated in 600 ml of ethanol with 7 g of palladium/carbon (10%) as well as hydrogen for 8.5 hours. After the mixture has been removed from the catalyst by filtration, it is concentrated, thus obtaining 4.8 g (90% yield) of 6-hydroxy-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester which is further reacted without any additional purification.
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[C:42]([F:43])=[CH:41][N:40]([CH3:44])[C:39](=[O:45])[CH:38]=1>>[F:43][C:42]1[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:34])[CH3:35])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)=[CH:38][C:39](=[O:45])[N:40]([CH3:44])[CH:41]=1
Reactant: Cn1cc(F)c(Br)cc1=O
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cc(=O)n(C)cc2F)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 4-bromo-5-fluoro-1-methyl-1H-pyridin-2-one following a procedure analogous to that described in Example 76. Mass spectrum (ESI+): m/z=479 [M+H]+. The compound that had been obtained as an oil crystallized on standing. The solid was dried at 80° C. under vacuum. Melting points: 120-125° C. with evolution of gas followed by recrystallization and melting at 183-184° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH2:11][C@@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:11][C@@H:12]([C:23]([OH:25])=[O:24])[CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:15]=1)=[O:5]
Reactant: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)c1ccccc1Cl
Product: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)c1ccccc1Cl
Yield: 83 %

Procedure:
The same procedure is used as in Example 1, o-chlorobenzoyl chloride and D-tryptophane being used. Yield 83%. Melting point 74° to 83° C.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH3:18])[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11])=O)(C)(C)C.[CH3:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:28])=[O:27])=[CH:24][CH:25]=1.O>C(OCC)(=O)C>[C:20]1([CH3:19])[CH:21]=[CH:22][C:23]([S:26]([OH:29])(=[O:27])=[O:28])=[CH:24][CH:25]=1.[NH2:8][C@@H:9]([CH3:18])[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)OCC(C)(C)C
Temperature: 65 °C
Yield: 79 %

Procedure:
The conversion was carried out using a 22 L 3-neck open head flask equipped with a mechanical stirrer and an internal thermocouple. To a stirred solution of (S)-neopentyl 2-(tert-butoxycarbonylamino)propanoate (900 g, 3.47 mol) in 14 L of ethyl acetate was added PTSA.H2O (660 g, 3.47 mol, 98% reagent grade, Product No 161993, Aldrich) and heated at 65° C. for 10 h. The mixture was cooled to give white solid at room temperature and cooled at ice bath for 30 min prior to filtration. The mixture solution was filtered and dried in a vacuum oven (40° C., Welch Model 2034, ca. 10 mmHg) for 15 hr to yield 907 g (2.74 mol, 79%) of desired product.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17].S(Cl)([Cl:20])=O.N1C=CC=CC=1>O1CCCC1>[Cl:20][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][C:7]1=[O:17]
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(=O)n(CCCCO)c2ccccc12
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1[nH]c(=O)n(CCCCCl)c2ccccc12

Procedure:
A mixture of 1-(4-hydroxybutyl)-2,4(1H,3H)-quinazolinedione 290 mg), thionyl chloride (0.54 ml), and pyridine (98 mg) in tetrahydrofuran (10 ml) was refluxed for 2 hours. After evaporation of the solvents, the residue was dissolved in chloroform, washed in turn with water, saturated sodium bicarbonate and brine, dried over magnesium sulfate, and evaporated. Crude material was crystallized from ethyl ether-isopropyl ether to give 1-(4-chlorobutyl)-2,4(1H,3H)-quinazolinedione (226 mg) as a powder.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]1[C:11]1[CH:16]=[C:15]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([CH2:31][O:32]C(=O)C)[C:18]=2[CH2:36][O:37]C(=O)C)[CH:14]=[CH:13][N:12]=1.C[O-].[Na+].C(O)(=O)C>CO>[O:1]=[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]1[C:11]1[CH:16]=[C:15]([C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH3:30])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:20]=[C:19]([CH2:31][OH:32])[C:18]=2[CH2:36][OH:37])[CH:14]=[CH:13][N:12]=1
Reactant: COc1cc2cc(COC(C)=O)c(COC(C)=O)c(-c3ccnc(-n4cc([N+](=O)[O-])ccc4=O)c3)c2cc1OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4cc([N+](=O)[O-])ccc4=O)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of 1-{2-[2-oxo-1,2-dihydro-5-nitropyridin-1-yl]-4-pyridyl}-2,3-bis(acetoxymethyl)-6,7-dimethoxynaphthalene (1.83 g) in methanol (50 ml) is added sodium methoxide (0.72 g) under ice-cooling. The mixture is stirred at room temperature for one hour. To the mixture is added acetic acid (0.8 ml) under ice-cooling, and the mixture is concentrated under reduced pressure to remove the solvent. To the residue are added chloroform and an aqueous sodium hydrogen carbonate solution, and the chloroform layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:acetone=3:1), and crystallized from ethyl acetate to give 1-{2-[2-oxo-1,2-dihydro-5-nitropyridin-1-yl]-4-pyridyl}-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (0.81 g,) which is listed in Table 1.