Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-])=O)=[C:6]([NH:8][C@H:9]([CH2:13][CH3:14])[C:10](O)=[O:11])[CH:7]=1.C([C@H]1NC2C(=CC(F)=CC=2)NC1=O)C>>[CH2:13]([C@H:9]1[NH:8][C:6]2[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:7]=2)[NH:15][C:10]1=[O:11])[CH3:14]
Reactant: CC[C@@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O
Agent: CC[C@H]1Nc2ccc(F)cc2NC1=O
Product: CC[C@H]1Nc2cc(F)ccc2NC1=O
Yield: 54 %

Procedure:
(2R)-2-(5-Fluoro-2-nitrophenylamino)-butyric acid was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-3,4-dihydroquinoxalin-2(1H)-one (54%). MS (ESI) m/z 195 ([M+H]+); HRMS: calcd for C10H11FN2O, 194.08558; found (ESI_FT), 195.08807; Anal. Calcd for C10H11FN2O: C, 61.85; H, 5.71; N, 14.42. Found: C, 61.77; H, 5.76; N, 14.33.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C=C(CC(N[C@@H](C2C=CC=CC=2)C(N[C@H]2[C@@H](C3C=CC=CC=3)SCCNC2=O)=O)=O)C=C(F)C=1.[Br:59]C1C=C(C=O)SC=1>>[CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[S:19][CH:20]=[C:21]([Br:59])[CH:22]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)/C(=C/c1cccs1)NC(=O)OCc1ccccc1
Reactant: O=Cc1cc(Br)cs1
Agent: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)N[C@@H]1C(=O)NCCS[C@@H]1c1ccccc1)c1ccccc1
Product: COC(=O)/C(=C/c1cc(Br)cs1)NC(=O)OCc1ccccc1

Procedure:
A method similar to that used for the preparation of (99a) was used except that the reaction product was passed through a Dowex ion exchange resin 50×2-200 and 4-bromo-2-thiphenecarboxaldehyde (955 mg) was used as the aldehyde component to afford the desired product (1.52 g ). 1H NMR (300 MHz, CDCl3) δ 3.79 (s, 3H), 5.24 (s, 2H), 5.99 (br., 1H), 7.20-7.37 (m, 7H), 7.67 (s, 1H). LC/MS: 2.37 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:24]2[CH2:29][CH2:28][CH2:27][CH2:26][C@@H:25]2[OH:30])[C:12]3=[O:31])=[CH:4][CH:3]=1.[CH3:32][S-:33].[Na+]>CS(C)=O.C(OCC)(=O)C>[OH:30][C@H:25]1[CH2:26][CH2:27][CH2:28][CH2:29][C@@H:24]1[N:13]1[C:12](=[O:31])[C:11]2[C:16](=[C:17]3[N:22]([CH3:23])[CH2:21][CH:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[C:6]([S:33][CH3:32])=[N:7][CH:2]=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: C[S-]
Reactant: CN1CC=Cc2c(Cc3ccc(Cl)nc3)cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c21
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CSc1ncccc1Cc1cc2c(=O)n([C@H]3CCCC[C@@H]3O)cnc2c2c1C=CCN2C
Temperature: 100 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]-10-methyl-9,10-dihydropyrido[3,2-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.11 mmol) in 2 mL of DMSO was added sodium thiomethoxide (0.024 g, 0.34 mol). The mixture was heated in a sealed tube at 100° C. for 15 h, cooled to room temperature, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, and again via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 448.9 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 9.05 (br s, 1H), 8.86 (br s, 1H), 8.41 (br s, 1H), 8.02 (s, 1H), 7.86 (br s, 1H), 7.76 (d, J=8.2 Hz, 1H), 7.43 (d, J=8.5 Hz, 1H), 4.80 (s, 2H), 4.56 (s, 2H), 4.22 (br s, 1H), 3.13 (s, 3H), 2.61 (s, 3H), 2.11 (br s, 1H), 1.87-1.72 (m, 5H), 1.48-1.39 (m, 3H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13]1([CH:23]2[CH2:25][O:24]2)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[ClH:26]>CC(C)=O.C(OCC)(=O)C>[ClH:26].[CH3:7][N:8]([CH2:10][CH2:11][O:12][CH2:25][CH:23]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1)[OH:24])[CH3:9]
Reactant: CN(C)CCO
Reactant: c1ccc2c(C3CO3)cccc2c1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CN(C)CCOCC(O)c1cccc2ccccc12
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 13.2 g of potassium tert-butoxide and 47.2 ml of 2-(N,N-dimethylamino)ethanol was heated to 80° C. Thereto was dropwise added 40.0 g of 2-(1-naphthyl)oxirane in 3.5 hours. The resulting mixture was stirred for 1.5 hours at 80°-85° C. The reaction mixture was cooled and added to a mixture of 100 ml of ethyl acetate and 100 ml of ice water. The resulting mixture was adjusted to pH 11.5 with 6N hydrochloric acid. The organic layer was separated. The aqueous layer was extracted with 50 ml of ethyl acetate. The extract was combined with the previously separated organic layer. The combined organic layer was washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was subjected to distillation to obtain a fraction having a boiling point of 152°-163° C./0.6-0.8 mm Hg. The oily product obtained was dissolved in 200 ml of acetone. Into the solution was blown hydrogen chloride gas with ice cooling. The resulting crystals were collected by filtraiton, washed with acetone, and dried to obtain 22.7 g of 2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride (compound No. 228).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:12]=[C:13]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([NH:17][C:32](=[O:33])[CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[N:15][CH:16]=2)=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(-c2cnc(NC(=O)Cc3ccccc3)c(Cc3ccccc3)n2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 20.3 %

Procedure:
Under an argon atmosphere, 5-(4-acetoxyphenyl)-2-amino-3-benzylpyrazine (c-19) (194 mg, 607 μmol) was dissolved in pyridine (2 mL) and to this was added 4-(dimethylamino)pyridine (7.8 mg, 64 μmol) and cooled to 0° C. To this was added phenylacetyl chloride (160 μL, 1.21 mmol) and stirred for 2 h after warming to room temperature. To this was added saturated aqueous solution of sodium bicarbonate to stop the reaction and after collecting the precipitate by filtration using a Kiriyama funnel, the residue was dried in vacuo to give 5-(4-acetoxyphenyl)-3-benzyl-2-(phenylacetylamino)pyrazine (c-30) as a colorless solid (53.9 mg, 20.3%). Rf=0.24 (n-hexane/ethyl acetate=3/2). Mp. 228-231° C. UV (MeOH, 0.3% DMSO) λmax (log ε) 318 (4.19), 290 (4.17), 259 (4.24). 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.68 (s, 2H), 4.07 (s, 2H), 7.01-7.08 (AA′BB′, 2H), 7.11-7.22 (m, 3H), 7.23-7.29 (m, 3H), 7.31-7.38 (m, 4H), 8.07-8.14 (AA′BB′, 2H), 8.93 (s, 1H), 10.57 (s, 1H). IR (KBr, cm−1) 706, 851, 918, 1157, 1206, 1223, 1346, 1366, 1410, 1449, 1495, 1543, 1576, 1670, 1755, 3248. HRMS (FAB+) m/z 438.1806 (M+H, C27H24N3O3 requires 438.1818).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11].[N+:18]([CH:21]([N+:23]([O-:25])=[O:24])[CH3:22])([O-:20])=[O:19]>CCOCC>[N+:18]([C:21]([N+:23]([O-:25])=[O:24])([CH3:22])[CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])([O-:20])=[O:19]
Reactant: CC([N+](=O)[O-])[N+](=O)[O-]
Reactant: C=C(C(=O)OC)C(=O)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COC(=O)C(CC(C)([N+](=O)[O-])[N+](=O)[O-])C(=O)OC
Reaction time: 1 h
Yield: 71.9 %

Procedure:
Triethylamine was added dropwise to a solution of 1.4 g (0.010 mol) of dimethyl methylenemalonate and 1.6 g (0.0133 mol) of 1,1-dinitroethane in 15 ml of ether at 0°, until yellow coloration persisted in the solution. The solution was allowed to stand 1 hr at ambient temperature and was then washed with 10% sodium bicarbonate, 1 N hydrochloric acid and water. The solution was dried over sodium sulfate, and the solvent was removed under vacuum. Column chromatography on a 100 g column of silica gel (CCl4 --CH2Cl2) and recrystallization of the product (methylene chloride-hexane, -78°) gave 1.9 g (72%) of dimethyl 2,2-dinitropropylmalonate, a white crystalline solid, mp 44°: NMR (CDCl3) 3.75 (s, 6 H, CH3), 3.1-3.5 (m, 3 H, CHCH2) and 2.13 (s, 3 H, C--CH3); IR (neat) 1730 (C=O) and 1570 cm-1 (NO2).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:11])[CH2:9][CH3:10].[C:12](OCC)(=O)[C:13]([O:15]CC)=[O:14].[O-]CC.[Na+].Cl>C(O)C.C(O)(=O)C.O>[CH3:10][C:9]1[C:8](=[O:11])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[O:1][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCC(=O)c1ccccc1O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C(=O)O)oc2ccccc2c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 12.8 %

Procedure:
2'-Hydroxypropiophenone (15.02 g) and diethyl oxalate (17.54 g) were added to a solution of sodium ethoxide in ethanol (prepared from 6.90 g of sodium and 200 ml of ethanol), and the mixture was heated for 2.5 hours while refluxing. The mixture was cooled, poured over 2N HCl (320 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:3, v/v) to yield an oily substance (4.26 g). This oily substance was dissolved in acetic acid-concentrated hydrochloric acid (1:1, 30 ml) and heated for 1 hour while refluxing. After cooling, the reaction mixture was poured over water (150 ml) and stirred at room temperature for 10 minutes. The separated crystals were collected by filtration to yield 3-methyl-4-oxo-4H-1-benzopyran-2-carboxylic acid (2.62 g, 13%), which was then recrystallized from ethanol to yield colorless prisms having a melting point of 192° to 193° C.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][N:6]1[C:18]2[CH2:17][CH2:16][C@@H:15]([NH2:19])[CH2:14][C:13]=2[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:11]=2.[OH-].[Na+]>CO.C(O)(C(F)(F)F)=O.O>[CH3:5][N:6]1[CH:18]2[CH:13]([CH2:14][C@H:15]([NH2:19])[CH2:16][CH2:17]2)[C:12]2[C:7]1=[CH:8][CH:9]=[C:10]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH:11]=2
Reactant: Cn1c2c(c3cc(S(=O)(=O)c4ccccc4)ccc31)C[C@H](N)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CN1c2ccc(S(=O)(=O)c3ccccc3)cc2C2C[C@H](N)CCC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 18.6 %

Procedure:
A freshly prepared solution of sodium cyanoborohydride (0.91 g, 14.48 mmol) in CH3OH (3.0 mL) was added dropwise to a 0° C. solution of (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,9-tetrahydro-1H-carbazol-3-amine (1.02 g, 2.99 mmol) in TFA (7.5 mL), then stirred at room temperature for 3 hours. The reaction was diluted with H2O (40 mL) cooled to 0° C. and made basic by the addition of 50% NaOH. The reaction mixture was extracted with EtOAc, washed with brine, dried over MgSO4 and concentrated in vacuo to give a colorless foam which was recrystallized from CH3OH/EtOAc to give 0.19 g (19%) of (3R)-9-methyl-6-(phenylsulfonyl)-2,3,4,4a,9,9a-hexahydro-1H-carbazol-3-amine as a colorless as a mixture of cis and trans isomers: mp 217.0-219.3° C.; MS m/z 343.2 (M++H).
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18](=[O:23])[C:19](Cl)=[N:20]O)[CH3:16].Cl>CCO>[C:1]([C:9]1[C:19]([C:18]([O:17][CH2:15][CH3:16])=[O:23])=[N:20][O:11][C:10]=1[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cl)=NO
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1noc(O)c1C(=O)c1ccccc1

Procedure:
To a cooled and stirred solution of sodium ethoxide, obtained from sodium (2.3 g, 0.1 mol) and anhydrous EtOH (60 ml), a solution of ethyl benzoylacetate (9.6 g, 0.05 mol) in the same solvent (5 ml) was slowly added. A solution of ethylcloro(hydroximino)acetate (7.55 g, 0.05 mol) in anhydrous EtOH (10 ml) was added in a dropwise manner (over 1 h period). The mixture was neutralized with 6N HCl and the alcoholic layer was evaporated. After dilution with cold water (150-200 mL), the suspension was extracted with ethyl ether and the aqueous layer was acidified with 6N HCl to afford the product which was recovered by filtration (45% yield).
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5](=[O:16])[C:6]([CH3:15])([CH3:14])[C:7]([O:9]C(C)(C)C)=[O:8].C(OCC)(=O)C.O>ClCCl.C(O)(C(F)(F)F)=O>[CH3:1][C:2]([CH3:18])([CH3:17])[CH2:3][O:4][C:5](=[O:16])[C:6]([CH3:15])([CH3:14])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)COC(=O)C(C)(C)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)COC(=O)C(C)(C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a solution of the obtained 2,2-dimethylmalonic acid t-butyl ester (2,2-dimethylpropyl)ester (12 g) in dichloromethane (100 mL), TFA (20 mL) was added, and the resulting mixture was stirred at room temperature for 3 hours. Ethyl acetate and water were added to the mixture. After shaking the resulting mixture, the organic layer was collected, sequentially washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The desiccant was filtered off, and toluene was added to the filtrate obtained, after which the resulting mixture was concentrated under reduced pressure to obtain the captioned compound (8.7 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](Cl)=[O:7])#[N:2].[CH3:15][N:16]([CH3:24])[CH:17]=[CH:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([C:18](=[CH:17][N:16]([CH3:24])[CH3:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])#[N:2]
Reactant: CCOC(=O)C=CN(C)C
Reactant: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(F)c(F)c(C#N)c1F
Reaction time: 2 h

Procedure:
A solution of 55 g of 3-cyano-2,4,5-trifluoro-benzoylchloride in 50 ml of toluene is added dropwise to a solution of 36.5 g of ethyl 3-dimethylamino-acrylate and 26.5 g of triethylamine in 140 ml of toluene such that the temperature remains between 50 and 55° C. Stirring is then carried out at 50° C. for a further 2 hours. The reaction mixture is concentrated in vacuo and employed in the next stage without further working up.
Reaction SMILES: C[N:2](C)/[CH:3]=[N:4]\[C:5]([C:7]1[S:8][C:9]2[CH2:10][CH2:11][O:12][C:13]3[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:14]=3[C:15]=2[N:16]=1)=O.C(OC([N:33]1[CH2:38][CH2:37][CH:36]([NH:39]N)[CH2:35][CH2:34]1)=O)C1C=CC=CC=1>>[Br:21][C:19]1[CH:18]=[CH:17][C:14]2[C:15]3[N:16]=[C:7]([C:5]4[N:39]([CH:36]5[CH2:37][CH2:38][NH:33][CH2:34][CH2:35]5)[N:2]=[CH:3][N:4]=4)[S:8][C:9]=3[CH2:10][CH2:11][O:12][C:13]=2[CH:20]=1
Reactant: CN(C)/C=N\C(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3C3CCNCC3)nc1-2

Procedure:
8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid 1-dimethylamino-meth-(Z)-ylideneamide was reacted with 4-Hydrazino-piperidine-1-carboxylic acid benzyl ester to give 8-bromo-2-(2-piperidin-4-yl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene. MS(ESI+) 432.0/434.0.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:6]([NH:8][CH2:9][C:10]([NH:12][C@H:13]([C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([NH2:21])=[O:20])=[O:16])[CH3:14])=[O:11])=[O:7])[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(N)=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](N)C(=O)NCC(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(N)=O

Procedure:
1.1 g of Z-Val-Gly-Ala-Pro-NH2 are dissolved in 50 ml of 80 % strength methanol and the solution is hydrogenated in the presence of 0.3 g of palladium on charcoal (10 % Pd). When the hydrogen uptake has ended the catalyst is filtered off, the solution evaporated and the residue dried in a high vacuum at 35° C. bath temperature. Hereupon the tetrapeptide H-Val-Gly-Ala-Pro-NH 2 is obtained as a colourless substance, Rf-Value = 0.20 (silica gel plates, system chloroform-methanol = 1:1).
Reaction SMILES: C1OC2C(=CSC=2)[O:3]C1CO.[CH:12]1([N:18]=[C:19]=[N:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(C1C=CC(C2C=CC(OC(CCC)C(O)=O)=CC=2)=CC=1)#N>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:21]1([NH:20][C:19]([NH:18][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[O:3])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: OCC1COc2cscc2O1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCCC(Oc1ccc(-c2ccc(C#N)cc2)cc1)C(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 1 h

Procedure:
2.20 g of a mixture of 80% of EDT-methanol and 20% of hydroxy-PDT (corresponding to 12.9 mmol; 10.3 mmol based on the main component EDT-methanol), 2.10 g (10.2 mmol) of N,N′-dicyclohexylcarbodiimide and 1 spatula tip of 4-(dimethylamino)pyridine are dissolved in 80 ml of CH2Cl2 and cooled in an ice bath. 3.00 g (10.2 mmol) of [(4′-cyano-1,1′-biphenyl-4-yl)oxy]valeric acid (see formula) are added a spatula at a time to the cold (0° C.) solution while stirring. Remaining [(4′-cyano-1,1′-biphenyl-4-yl)oxy]valeric acid is dissolved in 20 ml of CH2Cl2 and added to the reaction. After 1 hour, the reaction is continued at room temperature. After a further 48 hours, the colourless precipitate formed (N,N′-dicyclohexylurea) is filtered off. The clear, colourless solution is washed in succession with 3×75 ml of 1 N HCl, 3×75 ml of saturated NaHCO3 solution and 3×75 ml of saturated NaCl solution. The organic phase is dried over MgSO4, the desiccant is filtered off and the solvent is removed on a rotary evaporator. This gives 4.70 g of crude product.
Reaction SMILES: CN(C=O)C.[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:28].C(=O)([O-])[O-].[K+].[K+].[C:35]1([C:41](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O>[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19]2[C:14](=[C:15]([CH2:20][CH:21]3[S:25][C:24](=[O:26])[N:23]([C:41]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)[C:22]3=[O:27])[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][C:11]1=[O:28]
Reactant: O=C1NC(=O)C(Cc2cccc3c2CCC(=O)N3CCCO)S1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1CCc2c(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cccc2N1CCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
A DMF solution (10 ml) of 1.0 g (2.99 mmol) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]thiazolidine-2,4-dione and 0.455 g (3.29 mmol) of potassium carbonate was cooled with ice, and 0.876 g (3.04 mmol) of triphenylmethylchloride was added thereto, followed by stirring at room temperature overnight. Water was added to the reaction liquid and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and once with saturated sodium chloride solution, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1→ethyl acetate). The purified product was concentrated under reduced pressure and evaporated to dryness, giving 700 mg (40.6% yield) of 5-[1-(3-hydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-5-ylmethyl]-3-tritylthiazolidine-2,4-dione as a colorless amorphous solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[O:24]1[CH2:29][CH2:28][O:27][C:26]2=[C:30]([C:33](O)=[O:34])[S:31][CH:32]=[C:25]12>>[Cl:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:33]([C:30]2[S:31][CH:32]=[C:25]3[C:26]=2[O:27][CH2:28][CH2:29][O:24]3)=[O:34])=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c(-c2cccc(Cl)c2)s1
Reactant: O=C(O)c1scc2c1OCCO2
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2scc3c2OCCO3)c(-c2cccc(Cl)c2)s1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-[5-(3-chloro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 2,3-Dihydro-thieno[3,4-b][1,4]dioxine-5-carboxylic acid. LC-MS (basic): tR=0.86 min; [M+H]+=516.3.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:6](=[O:7])[NH:5][C:3]1=[O:4].[Br:9]Br>O1CCOCC1>[Br:9][CH:8]1[N:2]([CH3:1])[C:3](=[O:4])[NH:5][C:6]1=[O:7]
Reactant: CN1CC(=O)NC1=O
Reactant: BrBr
Solvent: C1COCCO1
Product: CN1C(=O)NC(=O)C1Br
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1-Methylhydantoin (114 g (1 mol); manufactured by Junsei Chemical Corporation) was dissolved in 1000 mL of dioxane (manufactured by Junsei Chemical Corporation). Trifluoroboron ether complex (0.1 g; manufactured by Tokyo Chemical Industry Co., Ltd.) was added to the solution, and the temperature was raised to 70° C. with stirring. Bromine (160 g (1 mol); manufactured by Junsei Chemical Corporation) was added dropwise thereto at 70° C. over a period of about 60 min. After the completion of dropwise addition, the solvent was removed by distillation under reduced pressure to give a crude crystal of 5-bromo-1-methylhydantoin.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:19]([O-])=O)[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>N1C=CC=CC=1.O>[NH2:19][C:11]1[CH:10]=[C:6]([CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc([N+](=O)[O-])c(-c2ccccc2)c([N+](=O)[O-])c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Product: Nc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred solution of 3,5-dinitro-4-phenylbenzoic acid (135 g) in a mixture of pyridine (625 ml) and water (625 ml), sodium dithionite (235 g) is added in portions during about 30 minutes, keeping the temperature at 12°-15° C by external cooling. After additional stirring at this temperature for about 15 minutes, the resulting solution is acidified by the addition of conc. hydrochloric acid (750 ml), keeping the temperature below 25° C by the addition of ice to the reaction mixture. The mixture is left for about 20 hours, and the resulting precipitate is then collected by filtration, washed with water and dried. After recrystallization from aqueous ethanol, 3-amino-5-nitro-4-phenylbenzoic acid is obtained with a melting point of 247°-249° C (dec.).