Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15]O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][N:40]2[C:39](=[O:41])[C:38]3=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]3[C:36]2=[O:46])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCCC(CO)C1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCCC(CN2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
1-(tert-Butoxycarbonyl)perhydroazepin-3-yl methanol (1.13 g, 4.93 mmol) was dissolved in tetrahydrofuran (10 mL). To this solution, triphenylphosphine (1.60 g, 5.92 mmol) and phthalimide (871 mg, 5.92 mmol) were added and the mixture was stirred at room temperature for 5 min. A 40% toluene solution of diethyl azodicarboxylate (3.23 mL, 7.40 mmol) was then added and the mixture was stirred at room temperature for 4 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine and was dried over magnesium sulfate, followed by evaporation of the solvent. Purification of the residue by silica gel column chromatography (hexane:ethyl acetate=10:1->2:1) gave 1.27 g (72%) of the desired compound as a colorless powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH2:2]1.C(N(CC)CC)C.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.CCOC(C)=O>[C:32]1([CH2:38][C:39]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]([NH:9][C:10]3[N:15]=[C:14]([N:16]4[C:20]5[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=5[N:18]=[CH:17]4)[CH:13]=[CH:12][N:11]=3)[CH3:8])[CH2:2]2)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 51.7 %

Procedure:
To a solution of 2-[1-(piperidin-3-yl)-ethylamino]-4-[benzimidazol-1-yl]pyrimidine (EXAMPLE 18) (28.2 mg, 0.087 mmol) in CH2Cl2 (1.0 mL) was added triethylamine (18 μL, 0.131 mmol) followed by phenylacetyl chloride (17 μL, 0.131 mmol) at 0° C. The reaction mixture was gradually warmed to room temperature and stirred for 5 h. The reaction mixture was diluted with EtOAc (10 mL), washed with saturated aqueous NaHCO3 followed by brine, and dried over Na2SO4. The crude product was purified by preparative thin layer chromatography (1:1 acetone:hexane) to yield 19.8 mg of the title compound. Presence of rotamers in Partial 1H NMR (500 MHz, CDCl3): δ 8.6 (s, 1H); 8.36 (d, J=5.3 Hz, 1H); 8.14 (m, 1H); 7.86 (m, 1H); 7.4-7.22 (aromatic H's, 7H); 6.78 (m, 1H); 4.67 (m, 1H); 3.73 (s, 2H); 1.31 (d, J=6.8 Hz, 1.5H); 1.11 (d, J=6.8 Hz, 1.5H). Mass spectrum 441.4 (ESI, M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[O:11][C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]2[O:12][CH:3]12.[C:14]1([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:1][C:2]1([CH3:13])[O:11][C:10]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[CH:4]([N:21]2[CH:22]=[CH:23][N:24]=[C:20]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:3]1[OH:12]
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC1(C)Oc2ccncc2C2OC21
Product: CC1(C)Oc2ccncc2C(n2ccnc2-c2ccccc2)C1O

Procedure:
Following the procedure in Example 1, using (±)-2,2-dimethyl-1a,7b-dihydro-2H-1,3-dioxa-6-aza-cyclopropa[a]naphthalene and 2-phenyl-1H-imidazole as starting materials, the title compound was prepared as a pale yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.[CH3:17][C:18]([CH3:20])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]2[O:1][C:18]([CH3:20])([CH3:17])[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[C:3]=2[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2c(c1)-n1cccc1C(C)(C)O2

Procedure:
The mixture of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (4.0 g), acetone (40 ml) and p-toluenesulfonic acid (0.8 g) in toluene (80 ml) was heated under reflux for 15 hours under stirring. The solvent was removed by evaporation and to the residue was added a mixture of ethyl acetate and water. The mixture was adjusted to pH 8 with potassium carbonate and the separated organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of toluene and n-hexane (1:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo. The residue was triturated with a mixture of diisopropyl ether and n-hexane to give 8-methoxycarbonyl-4,4-dimethyl-4H-pyrrolo[2,1-c][1,4]-benzoxazine.
Reaction SMILES: BrC1C=CC(Br)=CC=1.[C:9]1(C=CC(O)=C[CH:11]=1)[OH:10].[F:17][C:18]([F:34])([F:33])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][CH:22]=1>>[CH3:11][C:9]([C:23]1[CH:22]=[C:21]([O:20][CH2:19][C:18]([F:33])([F:34])[F:17])[CH:26]=[CH:25][C:24]=1[O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[O:10]
Reactant: FC(F)(F)COc1ccc(OCC(F)(F)F)cc1
Reactant: Oc1ccc(O)cc1
Solvent: Brc1ccc(Br)cc1
Product: CC(=O)c1cc(OCC(F)(F)F)ccc1OCC(F)(F)F

Procedure:
Compound [III] is prepared by a multi-stage process, comprising the conversion of 1,4dibromobenzene or hydroquinone to 1,4-bis(2,2,2-trifluoroethoxy)benzene, which is acetylated to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The acetophenone is then oxidized to form the corresponding benzoic acid derivative, which is then converted to its acid chloride and reacted either with 2-(aminomethyl)piperidine to form the Flecainide product in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide in two steps.
Reaction SMILES: [Br:1][C:2]1[C:6]2[S:7][C:8](C(O)=O)=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[S:4][CH:3]=1>N1C2C(=CC=CC=2)C=CC=1>[Br:1][C:2]1[C:6]2[S:7][CH:8]=[C:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:5]=2[S:4][CH:3]=1
Reactant: CCCCCCCCCCCCc1c(C(=O)O)sc2c(Br)csc12
Solvent: c1ccc2ncccc2c1
Product: CCCCCCCCCCCCc1csc2c(Br)csc12
Temperature: 200 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
In a 1 L three-neck round-bottom flask, the compound E (about 43.5 g, about 101 mmol) was placed, and dissolved in quinoline (about 250 ml), after which the solution was heated to about 200° C. and stirred for about 30 minutes. The stirred solution was cooled, and was then extracted with ethyl acetate (about 2 L), after which the extracted organic layer was washed two times with about 5 N hydrochloric acid solution (about 500 ml), washed with about 2N hydrochloric acid (about 500 ml), and washed with brine (about 500 ml). The organic layer was dried over magnesium sulfate, filtered, concentrated under reduced pressure, and then subjected to column chromatography using hexane, thus obtaining about 31.6 g (y=about 80%) of 6-bromo-3-dodecyl-thieno[3,2-b]thiophene F. 1H NMR of the obtained compound F was as follows.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[Mg].C[O:14]C[NH-].[C:17](O)(=O)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24]>C(OCC)C>[CH2:11]=[CH:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4](=[O:14])[CH2:3][CH2:2][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=[CH2:17]
Reactant: C=CCCCCCC(=O)O
Reactant: COC[NH-]
Reactant: C=CCCCCCCCCBr
Agent: [Mg]
Solvent: CCOCC
Product: C=CCCCCCCCCC(=O)CCCCCC=C
Reaction time: 1 h

Procedure:
A Grignard solution was prepared under nitrogen from 2.15 g (8.53 mmol) of 10-bromodec-1-ene and 249 mg (10.22 mmol) of magnesium powder in 20 mL of diethyl ether. The fresh Grignard solution was slowly added dropwise under a N2 atmosphere at 0° C. to a solution of 790 mg (4.26 mmol) of the methoxymethyl amide of oct-7-enoic acid and 10 mL of diethyl ether. Stirring was then continued at 20° C. for one hour. The charge was carefully quenched with Na4Cl solution and then extracted twice with diethyl ether. The organic phase was again washed with water, dried and concentrated. Column chromatographic fractionation furnished 820 mg (3.11 mmol) of octadeca-1,17-dien-8-one.
Reaction SMILES: C([N:3]([CH2:6][CH3:7])[CH2:4]C)C.CN.C(Cl)C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO>[CH2:6]([NH:3][CH3:4])[CH:7]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCC=Cc1ccccc1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Product: CNCC=Cc1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
Triethylamine (0.66 g; 6.55 mmol) was added to 40% solution of methylamine in methanol (20 ml). While the mixture was stirred at room temperature, cinnamyl chloride (1.00 g; 6.55 mmol) was added dropwise. After completion of the addition, the mixture was stirred for 20 hours at room temperature, and excess methylamine and methanol were removed under reduced pressure. The residue was taken up in a mixture of diethyl ether and 2N hydrochloric acid (100 ml-100 ml), and the aqueous layer was neutralized with aqueous sodium hydroxide solution, followed by extraction with chloroform (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, to thereby yield 0.80 g of the target compound as yellow oily matter (yield: 83.0%).
Reaction SMILES: [CH2:1]([N:8]([CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])O)[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[CH2:1]([N:8]([CH2:13][CH:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Br:22])[Cl:25])[CH2:9][CH2:10][C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCN(Cc1ccccc1)CC(O)c1ccccc1Br
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: N#CCCN(Cc1ccccc1)CC(Cl)c1ccccc1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 94 g of product obtained in Step 2 are dissolved in 400 ml of methylene chloride. At ambient temperature, within a period of 1 hour, 90.5 ml of thionyl chloride are poured in dropwise. After stirring for 12 hours at ambient temperature, the reaction mixture is evaporated to dryness and then taken up in ether and filtered. The solid is taken up in 500 ml of 10% aqueous sodium carbonate solution and 1 litre of methylene chloride. After separating off, drying and evaporating under reduced pressure, 90.2 g of expected product are obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH3:44])=[CH:38][CH:37]=1)[C:9]1[N:10]2[C:14]([N:15]=[C:16]3[N:22]([C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)[CH2:21][CH:20]=[CH:19][CH2:18][C:17]=13)=[CH:13][CH:12]=[N:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([N:8]([C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH3:44])=[CH:40][CH:41]=1)[C:9]1[N:10]2[C:14]([N:15]=[C:16]3[N:22]([C@H:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=13)=[CH:13][CH:12]=[N:11]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CC=CC3)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c3c(nc4ccnn24)N([C@H]2CCCN(C(=O)OC(C)(C)C)C2)CCCC3)cc1

Procedure:
tert-Butyl(S)-3-{10-[tert-butoxycarbonyl-(4-ethoxyphenyl)amino]-6,9-dihydro-1,4,5,10a-tetraazacyclohepta[f]inden-5-yl}piperidine-1-carboxylate (12.5 mg) was hydrogenated in the presence of palladium-carbon (15 mg) in ethanol (1.2 mL) under a hydrogen atmosphere. After the reaction, the palladium-carbon was filtered off, and the filtrate was concentrated. The residue was used for the subsequent reaction without purification.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][C:4](=[O:8])[CH2:5][CH2:6][CH3:7].[CH2:9]([Mg]Br)[CH:10]=[CH2:11].C(Br)C=C.[NH4+].[Cl-].Cl>C(OCC)C>[OH:8][C:4]([CH2:9][CH2:10][CH3:11])([CH2:5][CH2:6][CH3:7])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CC[Mg]Br
Reactant: CCCC(=O)CCC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC(O)(CCC)CCC
Temperature: 0 °C

Procedure:
113 g of 4-heptanone in 1000 ml of dry diethyl ether was slowly added to a solution of allylmagnesium bromide, prepared from 36.5 g of Mg and 178 g of allyl bromide in 500 ml dry diethyl ether. After the addition the mixture was refluxed for 10 hrs. The reaction mixture was poured on a mixture of 150 g ice, 450 ml of 20% NH4Cl and 350 ml of 5M HCl. The ether phase was separated and the water phase extracted with diethyl ether (3×100 ml). The combined organic phases were then washed with a Na2CO3 -solution and water, dried with Na2SO4 and evaporated. The residue was distilled. Yield: 142 g (b.p. 38°-40° C./0.1 torr)
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:8]\[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:30])/[C:5]([OH:7])=[O:6])[CH3:2]>CO.[Pd]>[CH2:1]([O:3][CH:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:30])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCO/C(=C\c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O
Agent: [Pd]
Solvent: CO
Product: CCOC(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1C)C(=O)O
Yield: 88.6 %

Procedure:
A suspension of 100 mg of 2Z-ethoxy-3-{2-methyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-acrylic acid and 26 mg of Pd/C (10%) in 2 ml of MeOH was hydrogenated at 22° C./1 bar for 2 d. The suspension was filtered, the filtrate evaporated and dried to give 89 mg (89%) of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][C:13](=C)[CH2:14]O.S(=O)(=O)(O)O.[Cl:22][CH2:23]Cl>>[ClH:22].[NH2:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:23])[C:5]2[O:9][C:13]([CH3:14])([CH3:12])[CH2:10][C:4]=2[C:3]=1[CH3:11]
Reactant: C=C(C)CO
Reactant: Cc1cc(O)c(C)c(C)c1N
Reactant: ClCCl
Agent: O=S(=O)(O)O
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Product: Cl
Yield: 14.4 %

Procedure:
4-Amino-2,3,5-trimethylphenol (2.0 g, 13.2 mmol) and 2-methyl-2-propenol (1.15 g, 15.8 g) were heated under reflux in dichloromethane (20 ml) together with sulfuric acid (2 ml) for 18 hours. The reaction mixture was washed with aqueous saturated sodium bicarbonate solution, dried and then concentrated. The residue was purified by silica gel column chromatography (isopropyl ether). The purified product was converted into its hydrochloride and it was crystallized from ethanol-isopropyl ether to obtain the desired compound (460 mg, yield: 14.4%), m.p. 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[N:6][CH:7]=1.[CH3:21][C:22](=O)[CH2:23][C:24](=O)[CH3:25]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:21])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[N:6][CH:7]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(Cl)cn3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cn3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from (5-chloro-pyridin-2-yl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 2,4-pentanedione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[O:11]=[C:10]1[NH:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[NH:14][CH2:13][CH:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
2-tert-Butoxycarbonylamino-3-(2-nitrophenyl)aminopropionic acid (325 mg) was dissolved in methanol (50 ml). 10% Palladium carbon (50 mg) was added thereto, and the mixture was stirred at room temperature for one hour under hydrogen atmosphere. The resultant mixture was filtrated, and the filtrate was concentrated under reduced pressure to thereby obtain 2-tert-butoxycarbonylamino-3-(2-aminophenyl)aminopropionic acid, which was suspended in toluene (30 ml), and the mixture was refluxed with heat by use of a Dean-Stark so as to remove water for 3 hours. The resultant mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=20:1). Diisopropyl ether was added thereto for crystallization, and the mixture was filtrated to thereby obtain 210 mg of the title compound (yield: 76%).
Reaction SMILES: [CH2:1]([S:17][CH2:18][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:20][NH2:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:28][CH2:29][CH2:30][CH2:31][S:32](NCC(OC)CSCCCCCCCCCCCCCCCC)(=[O:34])=[O:33]>>[Cl:28][CH2:29][CH2:30][CH2:31][S:32]([NH:21][CH2:20][CH:19]([N:22]1[N:26]=[N:25][C:24]([CH3:27])=[N:23]1)[CH2:18][S:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:34])=[O:33]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)OC
Reactant: CCCCCCCCCCCCCCCCSCC(CN)n1nnc(C)n1
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)n1nnc(C)n1

Procedure:
3-Hexadecylthio-2-(5-methyl-2H-tetrazol-2-yl)propylamine IVh1 is allowed to react and worked up by the same procedure as described in (4). The summary of the experimental condition and the physical data of the product are listed in Table 7.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:4]([OH:6])=[O:5].S(Cl)([Cl:23])=[O:22].[CH2:25](O)[CH3:26]>>[ClH:23].[NH2:2][C@H:3]([CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:4]([O:6][CH2:25][CH3:26])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: CCO
Reactant: N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CCOC(=O)[C@H](N)CCCNC(=O)OC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 18 h

Procedure:
A solution of 12.5 g of (2R)-2-amino-5-[(benzyloxy)carbonyl]aminopentanoic acid hydrochloride in 200 cm3 of ethanol is cooled to a temperature in the region of −20° C. 6.5 cm3 of thionyl chloride are added dropwise and the mixture is then stirred at a temperature in the region of 20° C. for 18 hours. The reaction medium is concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. to give 13 g of ethyl (2R)-2-amino-5-[(benzoyloxy)carbonyl]aminopentanoate hydrochloride [mass spectrum: DCI m/z=295 MH+].
Reaction SMILES: Br[C:2]1[C:3]([C:10]#[N:11])=[CH:4][S:5][C:6]=1[N+:7]([O-:9])=[O:8].C([Sn](CCCC)(CCCC)[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)CCC>>[N+:7]([C:6]1[S:5][CH:4]=[C:3]([C:10]#[N:11])[C:2]=1[C:17]1[S:18][C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[N:21]=1)([O-:9])=[O:8]
Reactant: N#Cc1csc([N+](=O)[O-])c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2s1
Product: N#Cc1csc([N+](=O)[O-])c1-c1nc2ccccc2s1

Procedure:
5-nitro-4-(benzo[d]thiazol-2-yl)thiophene-3-carbonitrile was prepared from 4-bromo-5-nitrothiophene-3-carbonitrile (0.16 g, 0.67 mmol) and 2-(tributylstannyl)benzo[d]thiazole (0.45 g, 1.07 mmol) according to protocol R. Retention time (min)=0.381, method [4], MS(ESI) 288.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1COCC1.CCOCC>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:15]([OH:16])([CH3:17])[CH3:14])=[CH:6][CH:7]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(I)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(O)c1ccc(Br)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 63.5 %

Procedure:
To 2-bromo-5-iodo-pyridine (2.974 g, 10.2 mmol) in a mixture of THF (15 mL) and ether (20 mL) at −78° C. is added dropwise n-butyl lithium (2.5 M in hexane, 4 L, 10.2 mmol). The mixture is stirred at −78° C. for 30 min, then acetone (anhydrous, 0.749 uL, 10.2 mmol) is added drop wise. The mixture is slowly warmed up to −50° C. over 1.5 h and is quenched with saturated ammonium chloride, extracted with ethyl acetate. The organic phase is separated, dried and rotavaped. The residue is purified by silica gel chromatography (10-20% ethyl acetate in heptane) to give the title compound as white solid (1.40 g, 64%).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:37][C:38]1[NH:39][C:40](=[O:43])[NH:41][N:42]=1>CN(C=O)C.O>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([CH2:37][C:38]2[NH:39][C:40](=[O:43])[NH:41][N:42]=2)[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: O=c1[nH]nc(CCl)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]nc(CN2CC[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](c3ccccc3)C2)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 29.3 %

Procedure:
To a mixed solution of the compound (0.15 g) obtained in Example 1 and potassium carbonate (0.047 g) in DMF (2 ml) and water (0.02 ml), 5-(chloromethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (0.046 g) synthesized by the method described in the document (e.g., Tetrahedron Letters, Vol. 41, pages 8661-8664) was added at 0° C., and the reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the title compound as colorless crystals (0.050 g, 29%).
Reaction SMILES: O.[ClH:2].Cl.[NH2:4][CH2:5][C:6]([CH2:8][NH2:9])=O.[CH3:10][O:11][NH3+:12].[Cl-].[CH3:14]O>>[ClH:2].[CH3:10][O:11][N:12]=[C:6]1[CH2:8][NH:9][CH:14]=[N:4][CH2:5]1
Reactant: NCC(=O)CN
Reactant: CO
Reactant: CO[NH3+]
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: CON=C1CN=CNC1
Reaction time: 48 h
Yield: 36 %

Procedure:
1,3-Diaminoacetone dihydrochloride monohydrate (2.61 g, 14.6 mmol) was dissolved in refluxing methanol. To this solution o-methylhydroxylamine hydrochloride (2.43 g, 29.2 mmol) was added. After reflexing for 48 hours the solvents were evaporated. The crude product was dissolved in methanol and an excess of trimethylorthoformate was added to the reaction mixture which was heated to reflux. After 24 hours the solvent was removed in vacuo. crystallization from methanol/ethyl acetate afforded 850 mg (36%) of a light-brown crystalline material. Mp. 170.7° C.