Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1.[CH3:18][Mg+].[Br-]>C1COCC1>[CH3:17][O:16][CH:3]([O:2][CH3:1])[C:4]1[C:13]([CH:14]([OH:15])[CH3:18])=[CH:12][C:11]2[CH2:10][CH2:9][CH2:8][NH:7][C:6]=2[N:5]=1
Reactant: COC(OC)c1nc2c(cc1C=O)CCCN2
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COC(OC)c1nc2c(cc1C(C)O)CCCN2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridine-3-carbaldehyde (intermediate 41, 13.5 g, 49.7 mmol) in THF (250 ml) at 0° C. was slowly added a solution of MeMgBr (3M in diethylether, 66.3 ml, 199 mmol) in THF (250 ml). The reaction mixture was allowed to warm to room temperature and stirred 3 h. Additional MeMgBr (16.6 ml, 49.7 mmol) was added at room temperature and the reaction mixture was stirred for approximately 30 minutes. The reaction mixture was quenched with saturated aqueous NH4Cl solution (150 ml) and water (100 ml) and extracted with EtOAc (2×). The combined organic phases were dried using Na2SO4, filtered and concentrated to yield the title compound as a yellow solid. (UPLC-MS 3) tR 0.44 min, ESI-MS 253.1 [M+H]+. 1H NMR (600 MHz, DMSO-d6) δ 7.33 (s, 1H), 6.36 (s, 1H), 5.18-5.10 (m, 1H), 5.03 (s, 1H), 4.65 (d, 1H), 3.31-3.26 (m, 6H), 3.26-3.21 (m, 2H), 2.69-2.62 (m, 2H), 1.82-1.71 (m, 2H), 1.20 (d, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[NH:40]N>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:40][C:35]3[C:36]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:37][CH:38]=[CH:39][C:34]=3[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3cccc(F)c3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3cccc(F)c3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(3-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 512.2 (M+H)+.
Reaction SMILES: [CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=O)[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1.[CH2:29]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](CC(=C)C5[C@]4(C)CCCC5)[C@@H]2C3)C)O1>>[CH2:1]1[CH2:14][O:13][C:8]23[O:9][CH2:10][CH2:11][O:12][C:3]2([C@:4]2([CH2:27][CH2:26][C@H:25]4[C@@H:15]([C:16](=[CH2:29])[CH2:17][CH:18]5[C@:23]4([CH3:24])[CH2:22][CH2:21][CH2:20][CH2:19]5)[C@@H:6]2[CH2:7]3)[CH3:5])[O:2]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCCCC1CC(=O)[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C=C1CC2CCCC[C@]2(C)[C@H]2CC[C@@]3(C)[C@@H](CC45OCCOC43OCCO5)[C@H]12
Yield: 85 %

Procedure:
The 3,3:17,17-Bis(ethylendioxy)-7-methyleneandrostane was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)androstane-7-one by the procedure described above for the preparation of 3,3:17,17-bis(ethylendioxy)-6-methyleneandrostane (Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 4.67 (1H, m), 4.60 (1H, m), 3.86 (8H, m), 2.20-1.10 (20H, m), 0.97 (3H, s), 0.86 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:7]([OH:9])=O)=[CH:5][N:6]=1.C(Cl)([Cl:12])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:7]([Cl:12])=[O:9])=[CH:5][N:6]=1
Reactant: O=C(Cl)Cl
Reactant: Cc1ncc(C(=O)O)s1
Solvent: Cc1ccccc1
Product: Cc1ncc(C(=O)Cl)s1
Reaction time: 2 h

Procedure:
In a similar apparatus to Example 1,5.7 g (0.04 mole) of 2-methylthiazole-5-carboxylic acid were suspended in 100 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 390 ml/hr for 10 hours (0.17 mole). After completion of the blowing, stirring was continued for additional 2 hours. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 5.7 g of 2-methylthiazole-5-carboxylic acid chloride. Its purity and yield were 95.0% and 95.0%, respectively. NMR (δCDCl 3/TMS, ppm): 2.79(3H,s).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C:2]([CH3:4])=[CH2:3].[F:8][C:9]([F:13])=[C:10]([F:12])[Cl:11]>C1(C=CC(O)=CC=1)O>[CH3:3][C:2]1([C:1]([O:6][CH3:7])=[O:5])[CH2:4][C:9]([F:13])([F:8])[C:10]1([Cl:11])[F:12]
Reactant: C=C(C)C(=O)OC
Reactant: FC(F)=C(F)Cl
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1(C)CC(F)(F)C1(F)Cl
Temperature: 140 °C
Yield: 53.9 %

Procedure:
174 g (1.74 mol) of methyl methacrylate and 1.5 g of hydroquinone are initially introduced into an autoclave, and 200 g (1.74 mol) of trifluorochloroethylene are added at -70° C. 7 bar of nitrogen are injected, and the mixture is then heated to 140° C. The pressure which is established at this temperature is increased to 28 bar by injecting more nitrogen. The mixture is maintained at 140° C. for 17 hours and then allowed to cool, the pressure is released, and the mixture is distilled. In this process, 203 g (54% of theory) of methyl 1-methyl-2-chloro-2,3,3-trifluoro-cyclobutane-1-carboxylate are obtained in form of a liquid of boiling point 57° C. at 17 mbar.
Reaction SMILES: [C:1]([C:3]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1)#[CH:2].C([Mg]Br)C.[CH2:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[CH:4]=[C:3]([C:1]#[C:2][CH2:23][OH:24])[C:9]=2[CH:10]=1
Reactant: C#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: C=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
A solution of 13.5 g of 10-ethynyl-8-chloro-dibenzo[ b,f] thiepin in 150 ml. of absolute tetrahydrofuran is treated dropwise at room temperature with 52 ml. of a 1-M solution of ethylmagnesium bromide solution in tetrahydrofuran. After stirring the mixture for an additional hour, 1.85 g of paraformaldehyde are pyrrolyzed and led through the mixture in gaseous form. The solution, having now warmed to about 50° C., is stirred for an additional 30 minutes and then poured onto a saturated, aqueous ammonium chloride solution. By extraction with benzene and subsequent chromatography on silica gel using benzene/methanol (20:1) as the eluant, there is obtained 3-(8-chloro-dibenzo[ b,f] thiepin-10-yl)-2-propyn-1-ol which melts at 111°-113° C. after recrystallization from ethyl acetate/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1.[CH2:24]([N:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](=[O:36])[C:28]1=[O:37])[C:25]#[CH:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:26]#[C:25][CH2:24][N:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:29](=[O:36])[C:28]3=[O:37])[CH:17]=[CH:18][C:13]=2[N:12]2[C:20]([CH3:23])=[N:21][N:22]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1ccc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCN1C(=O)C(=O)c2ccccc21
Product: Cc1nnc2n1-c1ccc(C#CCN3C(=O)C(=O)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was prepared by reacting 6-(2-chlorophenyl)-8-iodo-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine with 1-(2-propynyl)-1H-indole-2,3-dione [ref. A. Lindquist, p. Lagerstrom and R. Dahlbom, Acta Pharm. Suecica 9, 99 (1972)] as described in Example 9. The crude product was purified by chromatography over 40 fold amount of silica gel using 5% (V/V) of ethanol in methylene chloride. Crystallization from ethyl acetate qave yellow crystals of 1-[3-[6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-8-yl]-2-propynyl]-1H-indole 2,3-dione with m.p. 210°-212° C. These crystals contained according to microanalysis and pmr-spectrum 0.25 molar amounts of ethyl acetate.
Reaction SMILES: C(OC([N:8]=[C:9]([NH:40]C(OC(C)(C)C)=O)[NH:10][C:11]1[CH:12]=[C:13]([CH:17]([O:21][P:22]([C@@H:25]([NH:29][S:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:32])=[O:31])[CH:26]([CH3:28])[CH3:27])([OH:24])=[O:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:10]([C:11]1[CH:12]=[C:13]([CH:17]([O:21][P:22]([CH:25]([NH:29][S:30]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:31])=[O:32])[CH:26]([CH3:28])[CH3:27])([OH:24])=[O:23])[C:18]([OH:20])=[O:19])[CH:14]=[CH:15][CH:16]=1)[C:9]([NH2:40])=[NH:8]
Reactant: CC(C)[C@H](NS(=O)(=O)Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)Cc1ccccc1)P(=O)(O)OC(C(=O)O)c1cccc(NC(=N)N)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 12.5 %

Procedure:
To a solution of 2-(3-(N′,N″-di(t-butoxycarbonyl)guanidino)phenyl)-2-((1R)-(1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid (0.53 mmol) in 3 mL of methylene chloride was added TFA (3 mL, 39 mmol). After stirring for 1.5 hours at ambient temperature, the solution was concentrated. Purification by HPLC provided 33.0 mg (12%, 4 steps) of 2-(3-guanidinophenyl)-2-((1-(benzylsulfonyl)amino-2-methylpropyl)(hydroxy)phosphinoyloxy)ethanoic acid as white fluffy solid; NMR (DMSO-d6) 0.92 (m, 6), 2.01 (m, 1), 3.5 (m, 2), 4.54-4.26 (overlapping AB q, 2), 5.74 (overlapping doublets, 1), 7.22 (m, 1), 7.29-7.46 (m, 14), 9.78 (m, 1).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C(=O)O)c(C)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(C(=O)Cl)c(C)c1
Reaction time: 3 h

Procedure:
2,4-Dimethylbenzoic acid (1.502 g, 10 mmol, commercially available from e.g. Sigma-Aldrich, Fluka or Alfa Aesar) in dichloromethane (DCM) (40 mL) was cooled to 0° C., before oxalyl chloride (0.963 mL, 11.00 mmol) and a few drops of DMF (cat.) were added. The solution was then stirred under argon for 3 hours. The solvent was then evaporated in vacuo and the remaining residue was azeotroped with toluene (2×20 mL) to yield the product in 1.639 g.
Reaction SMILES: [CH2:1]([O:3][P:4]([N:9]=[C:10]=[O:11])([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:12][CH2:13][CH2:14][N:15]1[C:23]2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=[C:19]([NH2:26])[C:18]=2[N:17]=[C:16]1[CH3:27]>>[NH2:26][C:19]1[C:18]2[N:17]=[C:16]([CH3:27])[N:15]([CH2:14][CH2:13][NH:12][C:10]([NH:9][P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])=[O:11])[C:23]=2[C:22]([CH3:24])=[C:21]([CH3:25])[N:20]=1
Reactant: CCOP(=O)(N=C=O)OCC
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Product: CCOP(=O)(NC(=O)NCCn1c(C)nc2c(N)nc(C)c(C)c21)OCC

Procedure:
Using the method of Examples 118-133, diethoxyphosphinyl isocyanate was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 399.1926.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[CH2:13][N:12](C(OCC2C=CC=CC=2)=O)[C@H:11]([C:24]([CH3:26])=[CH2:25])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C.[Pd]>[CH2:1]([O:8][C@H:9]1[CH2:13][NH:12][C@H:11]([CH:24]([CH3:26])[CH3:25])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@@H]1C[C@@H](OCc2ccccc2)CN1
Reaction time: 17 h

Procedure:
Benzyl (2S,4R)-4-(benzyloxy)-2-isopropenylpyrrolidine-1-carboxylate (1.00 g, 2.84 mmol) was dissolved in ethanol (40 mL) and then 5% Pd—C (100 mg) was added to the solution. The flask was purged with hydrogen and then shaken on a Parr under 53 psi atmosphere of hydrogen for 17 hours. The reaction was then flushed with nitrogen and filtered through Celite on a glass frit and washed with methanol. The filtrate was concentrated and chromatographed on silica gel (1% triethylamine/10% methanol/89% ethyl acetate) to furnish the amine as a pale yellow oil, 0.53 g (85%). LC/MS (M+H)+ m/z=220.2; 1H NMR (CDCl3) 7.33 (m, 5H), 4.49 (m, 2H), 4.12 (m, 1H), 3.19 (dd, 1H), 3.00 (m, 2H), 2.05 (m, 1H), 1.96 (bs, 1H), 1.49 (m, 2H), 1.00 (d, 3H), 0.91 (d, 3H).
Reaction SMILES: CC[C@@H]1[C@@H]2[N:9]3[CH2:11][CH2:12][C:13]4[C:17]5[CH:18]=[C:19](OC)[CH:20]=[CH:21][C:16]=5N[C:14]=4[C@@H]2C[C@@H](C3)C1.[S:24]1C=CC2C=CC=CC1=2.[C-]#N>>[C:11]([CH2:12][C:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[S:24][CH:14]=1)#[N:9]
Reactant: CC[C@H]1C[C@H]2C[C@H]3c4[nH]c5ccc(OC)cc5c4CCN(C2)[C@@H]13
Reactant: c1ccc2sccc2c1
Agent: [C-]#N
Product: N#CCc1csc2ccccc12

Procedure:
The synthesis of ibogaine analogs 7a-c is outlined in FIG. 2, wherein the benzo[b]thiophene is chloromethylated to yield 1, then reacted with cyanide ion to yield 3-cyanomethylbenzothiophene (2), which is reduced with LiAlH4 /AlCl3 to yield the corresponding primary amine 3. The latter was acetylated with acetic anhydride and the resulting amide was reduced with borane-tetrahydrofuran to yield 5. Refluxing of the 5 with a preselected styrene oxide in EtOH and subsequent cyclization of the corresponding secondary alcohol provided the compounds 7a, (R=H) 7b (R=NO2) and 7c (R=Br). The compounds were characterized by 1H NMR and purity was determined by combustion analysis. Cyclization was associated with a 0.1δ upfield shift in the methine proton signal. The hydrochlorides were prepared by passing HCl gas through a solution of the corresponding free bases in EtOH.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.[CH3:14][CH:15]1[NH:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[N+:11]([C:4]1[CH:3]=[C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16][CH:15]2[CH3:14])[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9])([O-:13])=[O:12]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=[N+]([O-])c1ccc(F)cc1[N+](=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC1CN(C(=O)OC(C)(C)C)CCN1c1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
4-Fluoro-1,2-dinitrobenzene (0.93 g, 5.0 mmol, commercially available from Oakwood Products) and tert-butyl 3-methylpiperazine-1-carboxylate (1.0 g, 5.0 mmol) were dissolved in 3 mL of DMA, and 3 mL of diisopropylethylamine was added. The mixture was stirred at 50° C. overnight, and then cooled to room temperature, separated between ethyl acetate and water. The combined organic were washed with water, brine, dried with anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column (20% to 40% ethyl acetate in hexanes) to give 1.0 g of tert-butyl 4-(3,4-dinitrophenyl)-3-methylpiperazine-1-carboxylate. 1H-NMR (400 MHz, CDCl3): δ 8.05 (d, 2H), 6.84 (m, 2H), 3.90-4.10 (m, 3H), 3.05-3.60 (m, 4H), 1.50 (s, 9H), 1.10 (s, 3H). MS (EI): 367 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH:17]=[CH:18]4)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:6])[CH2:2][CH3:3].[H][H]>C(O)C.[Pd]>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10]([CH:15]3[CH2:20][CH:19]4[CH2:21][CH:16]3[CH2:17][CH2:18]4)=[N:9][C:8]=2[N:7]([CH2:22][CH2:23][CH3:24])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(C3CC4C=CC3C4)nc2n(CCC)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC3C4)nc2n(CCC)c1=O
Yield: 39.1 %

Procedure:
1.0 g (3.1 mmol) of 1,3-dipropyl-8-(5-norbornen-2-yl)xanthine are hydrogenated under pressure in 30 ml of ethanol, with the addition of palladium/charcoal, until no further uptake of hydrogen can be detected. The catalyst is filtered off, the filtrate is concentrated by evaporation and the residue is chromatographed on silica gel (Ch2Cl2 /CH3OH 99:1). 0.4 g of the title compound are obtained in the form of white crystals (39% of theory), m.p. 136°-138° C.
Reaction SMILES: [ClH:1].N[N:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[CH2:7][O:6][CH2:5][CH2:4]1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[ClH:1].[CH3:14][N:15]1[CH2:20][CH2:19][C:18]2[N:3]3[C:9]4[C:10](=[CH:11][CH:12]=[CH:13][C:8]=4[CH2:7][O:6][CH2:5][CH2:4]3)[C:17]=2[CH2:16]1
Reactant: CN1CCC(=O)CC1
Reactant: NN1CCOCc2ccccc21
Agent: Cl
Product: CN1CCc2c(c3cccc4c3n2CCOC4)C1

Procedure:
By a procedure similar to that described in Example 110, 1-amino-1,2,3,5-tetrahydro-4,1-benzoxazepine hydrochloride is reacted with 1-methyl-4-piperidone to yield the title compound, m.p. 286°-288° .
Reaction SMILES: [C:1]([O:6][CH:7]([O:10][C:11](=[O:27])[CH2:12][CH:13]([CH2:18][NH:19]C(OC(C)(C)C)=O)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29]>C(Cl)Cl>[OH:34][C:28]([C:30]([F:33])([F:32])[F:31])=[O:29].[C:1]([O:6][CH:7]([O:10][C:11](=[O:27])[CH2:12][CH:13]([CH2:18][NH2:19])[CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:8][CH3:9])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CCC(OC(=O)CC(CNC(=O)OC(C)(C)C)CC(C)C)OC(=O)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(OC(=O)CC(CN)CC(C)C)OC(=O)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 80 %

Procedure:
Compound 24 (0.3 g, 0.77 mmol) was dissolved in CH2Cl2 (5 mL) and TFA (4.5 mL) was added and maintained in an ice water bath for 30 minutes. The solution was then warmed to room temperature and stirred for 5 hours. After concentrating and drying, 0.25 g of 3-aminomethyl-5-methyl-hexanoic acid 1-isobutyryloxy-propyl ester TFA salt 25 was obtained (Yield: 80%). 1HNMR (CDCl3, 500 MHz) δ0.87-0.95 (m, 6H), 1.15-1.65 (m, 4H), 1.18-1.28 (m, 2H), 1.52-1.67 (m, 1H), 1.71-1.82 (m, 2H), 2.18-2.31 (m, 1H), 2.39-2.46 (m, 1H), 2.51-2.62 (m, 2H), 3.02 (br s, 1H), 3.19 (br s, 1H), 6.89 (t, J=5.5 Hz, 1H), 7.48 (br s, 2H); 13CNMR (CDCl3, 125 MHz) δ 7.29, 7.35, 14.69, 18.39, 18.42, 18.48, 18.52, 21.70, 21.73, 22.43, 24.90, 26.18, 31.05, 31.13, 33.93, 36.92, 37.08, 41.26, 41.47, 44.73, 44.79, 66.05, 91.73, 91.83, 172.58, 172.69, 176.43.
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2]1.[Si:9](OC1CCC(N2CC(B3OC(C)(C)C(C)(C)O3)=CN2)C1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>>[C:12]([Si:9]([CH3:11])([CH3:10])[O:7][CH:3]1[CH2:4][CH2:5][CH2:6][CH:1]([OH:8])[CH2:2]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: OC1CCCC(O)C1
Reactant: CC1(C)OB(C2=CNN(C3CCC(O[Si](C)(C)C(C)(C)C)C3)C2)OC1(C)C
Product: CC(C)(C)[Si](C)(C)OC1CCCC(O)C1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 1,3-cyclohexanediol by a procedure analogous to Intermediate 28, Step A. 1H NMR (300 MHz, CDCl3): δ 4.0-4.2 (m, 1H), 3.8-3.95 (m, 1H), 1.3-2.4 (m, 9H), 0.86 (s, 9H), 0.05 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](Br)=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:63]([NH:66][C:67]([NH:69][C:70]([CH3:74])([CH3:73])[CH2:71][OH:72])=[O:68])[CH:64]=[CH2:65].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@H:10]1[C:40]1[CH:45]=[C:44]([CH2:46][C:47]2[CH:52]=[CH:51][C:50](/[CH:65]=[CH:64]/[CH2:63][NH:66][C:67]([NH:69][C:70]([CH3:74])([CH3:73])[CH2:71][OH:72])=[O:68])=[CH:49][CH:48]=2)[C:43]([CH3:54])=[CH:42][C:41]=1[O:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(Br)cc1
Reactant: C=CCNC(=O)NC(C)(C)CO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1cc(OCc2ccccc2)c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc(/C=C/CNC(=O)NC(C)(C)CO)cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 39.7 %

Procedure:
To an acetonitrile solution (5.4 mL) of (1S)-1,5-anhydro-2,3,4,6-tetra-O-benzyl-1-[2-(benzyloxy)-5-(4-bromobenzyl)-4-methylphenyl]-D-glucitol (0.48 g, 0.539 mmol) were added N-allyl-N′-(2-hydroxy-1,1-dimethylethyl)urea (223 mg, 1.29 mmol), palladium(II) acetate (24 mg, 0.108 mmol), tri-O-tolylphosphine (66 mg, 0.216 mmol) and triethylamine (273 mg, 2.69 mmol), and the mixture was stirred at 120° C. for 20 minutes with microwave manufactured by Biotage. The reaction solvent was evaporated under reduced pressure. Thus obtained residue was purified with silica gel column chromatography (chloroform and then chloroform:methanol=50:1) to obtain the title compound (210 mg, 40%) as a pale yellow amorphous compound.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH:6]=1.[N+:10]([CH3:13])([O-:12])=[O:11]>>[CH3:1][CH:2]1[CH:6]([CH2:13][N+:10]([O-:12])=[O:11])[C:5]([CH3:8])([CH3:7])[CH2:4][C:3]1=[O:9]
Reactant: C[N+](=O)[O-]
Reactant: CC1=CC(C)(C)CC1=O
Product: CC1C(=O)CC(C)(C)C1C[N+](=O)[O-]

Procedure:
2,4,4-trimethyl-cyclopent-2-en-1-one is reacted with nitromethane to give 2,4,4-trimethyl-3-nitromethyl-cyclopentanone which, after treatment with a base, is converted into 1-formyl-3-oxo-2,5,5-trimethyl-cyclopentane either with the aid of an oxidizing agent, such as potassium permanganate, ozone, or with a hydrohalic acid, a mineral acid or titanium trichloride.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17](O)=[O:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Cl-].N>CO>[C:1]([O:5][C:6](=[O:20])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][OH:18])[N:15]=1)([CH3:9])[CH3:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CC(=O)O)cs1
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCO)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}acetic acid (127 g) synthesized in Example 3 was added to 1M-borane/tetrahydrofuran complex (800 mL) under ice-cooling, and the mixture was stirred at room temperature for 8 hr. The reaction mixture was ice-cooled, methanol (400 mL) was added dropwise. After warming to room temperature, the mixture was stirred for 1 hr. Then, saturated aqueous ammonia chloride (300 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (110 g) as a slightly yellow oil.
Reaction SMILES: [N+:1]([CH:3]([CH3:11])[C:4]([O:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:5])#[C-:2].C(N(CCCC)CCCC)CCC>ClC1C=CC=CC=1>[CH3:11][C:3]1[N:1]=[CH:2][O:5][C:4]=1[O:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [C-]#[N+]C(C)C(=O)OCCCC
Solvent: CCCCN(CCCC)CCCC
Solvent: Clc1ccccc1
Product: CCCCOc1ocnc1C

Procedure:
A continuously operated dividing wall column (4.8 m×64 mm) packed with 3×3 mm V2A Raschig rings and a dividing wall of height 2.4 m having 60 theoretical plates was charged with a mixture of 13.1% by weight of n-butyl α-isocyanopropionate (R1=n-butyl, R2=methyl), 32.2% by weight of monochlorobenzene and 50.1% by weight of tri-n-butylamine.