Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].Cl[C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[O:8][C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: Oc1c(Cl)cncc1Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from 3,5-dichloropyridin-4-ol (370 mg, 2.26 mmol) and methyl 5-chloro-4-nitro-thiophene-2-carboxylate (500 mg, 2.26 mmol). The title compound was obtained as a solid (510 mg, 65% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.65 (2H, s), 8.26 (1H, s), 3.93 (3H, s). MS m/z: 348.00, 350.99 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([CH:15]=[O:16])=[C:13]([CH2:17][CH3:18])[CH:12]=[C:11]([CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:14]([CH2:15][OH:16])=[C:13]([CH2:17][CH3:18])[CH:12]=[C:11]([CH3:19])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(C)nc(OCc2ccccc2)c1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCc1cc(C)nc(OCc2ccccc2)c1CO
Reaction time: 1 h
Yield: 85 %

Procedure:
To a 0° C. solution of 2-(benzyloxy)-4-ethyl-6-methylpyridine-3-carbaldehyde (Cpd CC, 323 mg, 1.28 mmol) in methanol (4.27 mL) was added sodium borohydride (54 mg, 1.41 mmol). After 1 hour, the reaction mixture was concentrated under vacuum then diluted with ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (5 mL), then dried over sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by column chromatography (heptane/EtOAc) to give [2-(benzyloxy)-4-ethyl-6-methylpyridin-3-yl]methanol (Cpd DD, 280 mg, 85% yield) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19]O)[CH:6]=1.P(Br)(Br)[Br:23].C([O-])(O)=O.[Na+]>COCCOC>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][Br:23])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CO)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CBr)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.2 %

Procedure:
To [3-(4-bromo-2-hydroxymethyl-phenoxy)-phenyl]-acetic acid methyl ester (3 g, 8.5 mmol) in DME (30 mL) under N2 was added phosphorus tribromide (1.2 mL, 12.8 mmol), and the reaction was stirred at room temperature for 6 hours. The solution was cooled to 0° C. and adjusted to pH 6 with saturated aqueous NaHCO3, and the mixture was extracted with EtOAc. The crude material was purified by silica gel chromatography to give the desired product as a colorless oil (3 g).
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([CH2:18][CH3:19])[C:15]([NH2:17])=[S:16])[CH:8]=2)[N:3]=1.[CH:20]([CH:22](Cl)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=O>CN(C)C=O>[CH3:1][C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:15]3[S:16][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:20][N:17]=3)[CH2:18][CH3:19])[CH:8]=2)[N:3]=1
Reactant: CCN(Cc1ccc2nc(C)[nH]c(=O)c2c1)C(N)=S
Reactant: CCOC(=O)C(Cl)C=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc(N(CC)Cc2ccc3nc(C)[nH]c(=O)c3c2)s1
Temperature: 100 °C
Yield: 21.8 %

Procedure:
A mixture of the thiourea (4.67 g), ethyl formylchloroacetate (Archiv der Pharmazie, 1953, 286, 494: 2.55 g) and dimethylformamide (25 ml) was stirred and heated to 100° C. for 1 hour. The mixture was cooled, filtered and the filtrate was evaporated. The residue was partitioned between methylene chloride and a saturated aqueous sodium bicarbonate solution. The organic solution was dried over sodium sulphate, filtered and evaporated. The residue was purified by trituration in ethyl acetate to give ethyl 2-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl) N-ethylamino]thiazole-5-carboxylate (1.37 g), m.p. 188°-192° C.
Reaction SMILES: [SH:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Br[CH2:20][C:21]1[S:22][CH:23]=[CH:24][CH:25]=1>>[C:12]1([N:11]2[C:10](=[O:18])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]2[S:1][CH2:20][C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: BrCc1cccs1
Reactant: O=c1c2ccccc2nc(S)n1-c1ccccc1
Product: O=c1c2ccccc2nc(SCc2cccs2)n1-c1ccccc1
Yield: 37.4 %

Procedure:
The title compound was prepared in a yield of 37.4%, using 2-mercapto-3-phenyl-4(3H)-quinazolinone in place of 3- isobutyl-2-mercapto-4(3H)-quinazolinone and 2-bromomethylthiophene in place of 2-chloromethylpyridine hydrochloride.
Reaction SMILES: [BH4-].[Li+].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([NH:15][CH:16]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]2[CH2:33][C@H:34]([C:36](OC)=[O:37])[N:35]=[C:17]12)=[O:14].CO.O>C1COCC1>[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[CH2:11][CH2:12][C:13]([NH:15][CH:16]1[N:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]2[CH:29]=[CH:30][CH:31]=[CH:32][C:19]=2[N:18]2[CH2:33][C@H:34]([CH2:36][OH:37])[N:35]=[C:17]12)=[O:14]
Reactant: COC(=O)[C@H]1CN2C(=N1)C(NC(=O)CCc1ccc(Cl)cc1Cl)N=C(c1ccccc1)c1ccccc12
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(CCc1ccc(Cl)cc1Cl)NC1N=C(c2ccccc2)c2ccccc2N2C[C@H](CO)N=C12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Lithium borohydride (6.5 mg, 0.3 mmol) was added to a solution of (2R)-3-(2,4-dichlorophenyl)-N-{1,2-dihydro-2-methoxycarbonyl-6-phenyl-4H-imidazo [1,2-a][1,4]benzodiazepin-4-yl}propanamide (160 mg, 0.3 mmol) in THF (20 mL) and the mixture was stirred at room temperature for 18 h. The mixture was cooled to 0° C. and methanol then water were added. The solvent was evaporated under reduced pressure, ethyl acetate was added and the mixture was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (97.5:2.5) to give (2R)-3-(2,4-dichlorophenyl)-N-{1,2-dihydro-2-hydroxymethyl-6-phenyl-4H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanamide as a foam.
Reaction SMILES: CC(C)([O-])C.[K+].C1(C)C(S([CH2:16][N+:17]#[C-])(=O)=O)=CC=CC=1.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[N:40]=[C:41]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:42][C:43]=3[CH3:44])=[CH:33][CH:32]=2)[N:22]=1.CO>C(COC)OC.O>[CH3:20][C:21]1[N:22]=[C:23]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][C:39]3[N:40]=[C:41]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=4)[O:42][C:43]=3[CH3:44])=[CH:33][CH:32]=2)[C:24]([CH2:25][C:16]#[N:17])=[CH:27][CH:28]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: Cc1ccc(C=O)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: Cc1ccc(CC#N)c(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)n1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77.7 %

Procedure:
To a mixture of potassium t-butoxide (0.47 g) and dimethoxyethane (8 mL) was added a solution (8 mL) of toluenesulfonylmethylisocyanide (0.43 g) in dimethoxyethane at −78° C. Furthermore, a solution (8 mL) of 6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]nicotinaldehyde (0.84 g) in dimethoxyethane was added to the reaction mixture. The reaction mixture was stirred at −78° C. for 1 hr. Methanol (10 mL) was added to the reaction mixture at room temperature and the mixture was heated under reflux for 30 min. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel, column chromatography to give crystals (0.67 g, 79%) of 2-[6-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]acetonitrile from a fraction eluted with ethyl acetate-hexane (1:6, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 122-123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1Cl)([O-:3])=[O:2].Cl.[O:15]([NH2:17])[CH3:16].C(N(CC)CC)C>C(#N)C>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:17][O:15][CH3:16])([O-:3])=[O:2]
Reactant: CON
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CONc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Yield: 53 %

Procedure:
2,4-Dinitrochlorobenzene (4.05 g (20.0 mmol)) and methoxylamine hydrochloride (2.00 g (23.9 mmol)) were dissolved in 15 ml of acetonitrile. To this mixture, under ice cooling and with stirring, triethylamine (7.00 ml (50.2 mmol)) was added. After being stirred for 24 hours at room temperature, the resulting black solution was concentrated under reduced pressure.Water and dilute hydrochloric acid were added to the residue and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was then subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent, to give 2.26 g (53%) of N-(2,4-dinitrophenyl)-O-methylhydroxylamine as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.Cl.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=1.NC1C=CC(C(F)(F)F)=CC=1>CO.C(Cl)(Cl)Cl>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CSc1ncnc2cc(N)ncc12
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Nc1cc2ncnc(Nc3ccc(C(F)(F)F)cc3)c2cn1
Temperature: 180 °C
Reaction time: 0.03 h
Yield: 63.2 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (390 mg, 2.03 mmol), 4-aminobenzotrifluoride hydrochloride (0.40 g, 2.02 mmol) and 4-aminobenzotrifluoride (1.61 g, 10.0 mmol) is stirred at 180° C. for 2 min. The resulting product is neutralized with excess NaHCO2, dissolved in MeOH/CHCl3, dried onto alumina and chromatographed over alumina (4-7% MeOH/CH2Cl2) to give 7-amino-4-(4-trifluoromethylanilino)pyrido[4,3-d]pyrimidine (390 mg, 63%) as a cream solid. Analytically pure material was obtained by further chromatography over silica gel (5% MeOH/CH2Cl2) to give pale yellow needles. 1H NMR (DMSO) δ 10.09 (1H, brs), 9.40 (1H, s), 8.48 (1H, s), 8.13 (2H, d, J=8.2 Hz), 7.74 (2H, d, J=8.7 Hz), 6.72 (2H, brs), 6.40 (1H, s).
Reaction SMILES: O[CH:2]([CH3:14])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5]>CC#N.Cl[Cu]>[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:5])/[CH:3]=[CH:2]/[CH3:14]
Reactant: CC(O)CC(=O)OCc1ccccc1
Agent: Cl[Cu]
Solvent: CC#N
Product: C/C=C/C(=O)OCc1ccccc1
Temperature: 60 °C
Yield: 81.8 %

Procedure:
Benzyl 3-hydroxyl-butanoate (Sakaki et al., Chem. Pharm. Bull., 37, p. 2952 (1989)) (0.46 g, 2.4 mmol), CuCl (11 mg, 5 mol %), and 1 (0.7 g, 110 mol %) were combined in 20 mL of dry CH3CN and heated to 60° C. for 16 h. The reaction mixture was cooled and evaporated, followed by isolation according to the general procedure to give benzyl crotonate (0.346 g, 83%) as a mobile oil: IR 3060, 3030, 1720; 1H NMR δ 7.40-7.20 (m, 5H), 7.00 (dq, 1H, J=15.5, 6.9), 5.86 (dq, 1H, J=16.0, 1.6), 5.18 (s, 2H), 1.83 (dd, 3H, J=1.7, 6.9).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11]OS(C1C=CC(C)=CC=1)(=O)=O.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH:32]1[CH2:36][CH2:35][NH:34][CH2:33]1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:34]1[CH2:35][CH2:36][CH:32]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])[CH2:33]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccccc3O2)cc1
Reactant: COc1ccccc1C1CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1C1CCN(C[C@H]2COc3ccccc3O2)C1
Temperature: 120 °C

Procedure:
Toluene-4-sulfonic acid (R)-1-(2,3-dihydro-benzo[1,4]dioxin-2-yl)methyl ester (0.156 mmol), 3-(2-methoxyphenyl)pyrrolidine HCl (1.55 mmol, 32 mg), K2CO3 (0.342 mmol, 47 mg) and acetonitrile (1 ml) were mixed and heated in a microwave reactor at 120 ° C. for 2.5 h. The reaction mixture was filtrated and the solution was absorbed on silica. Flash chromatography, using a gradient of heptane/EtOAc as eluent, gave 20 mg g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:14][O:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH:22]=O)[CH2:17]1.[NH2:24][C@H:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:26]([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[NH4+].[Cl-]>ClCCl.O.CC(O)=O>[CH3:27][CH:26]([CH3:28])[C@H:25]([NH:24][CH2:22][C@H:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([O:15][CH2:14][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])[CH2:17]1)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](C=O)C3)c(C)o2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2nc(CO[C@@H]3CCC[C@H](CN[C@H](C(=O)OC(C)(C)C)C(C)C)C3)c(C)o2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
511 mg of cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexanecarbaldehyde, 0.9 ml of HOAc and 310 mg of tert-butyl (S)-valinate are dissolved in 5 ml of abs. dichloromethane. 500 mg of molecular sieve 4 Å are then added, and the suspension is cooled to 0° C. 414 mg of sodium triacetoxyborohydride are added a little at a time. This suspension is stirred at 0° C. for 2 h, 3 ml of saturated NH4Cl solution are then added and the suspension is stirred for a further 10 min. In each case 10 ml of water and dichloromethane are added, the phases are separated, the aqueous phase is extracted with dichloromethane and the combined organic phases are dried over MgSO4 and concentrated, which gives 760 mg of tert-butyl (S)-3-methyl-2-{[cis-3-(5-methyl-2-p-tolyloxazol-4-ylmethoxy)cyclohexylmethyl]-amino}butyrate. C28H42N2O4 (470.66); MS (ESI): 471.50 (MH+).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH:7]=[C:8]2[N:12]([CH3:13])[C:11](=[O:14])[N:10]([N:15]([C:31](=[O:33])[CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:17][C:18](=[O:20])[OH:19])[C:9]2=[O:34])=[CH:5][CH:4]=1)#[N:2]>CO>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[N:12]([CH3:13])[C:11](=[O:14])[N:10]([N:15]([C:31](=[O:33])[CH3:32])[C@H:16]([C:21]([NH:23][C@H:24]([C:28]([OH:30])=[O:29])[CH:25]([CH3:27])[CH3:26])=[O:22])[CH2:17][C:18](=[O:19])[OH:20])[C:9]2=[O:34])=[CH:35][CH:36]=1
Reactant: CC(=O)N([C@@H](CC(=O)O)C(=O)N[C@H](C(=O)O)C(C)C)N1C(=O)C(=Cc2ccc(C#N)cc2)N(C)C1=O
Solvent: CO
Product: CC(=O)N([C@@H](CC(=O)O)C(=O)N[C@H](C(=O)O)C(C)C)N1C(=O)C(Cc2ccc(CN)cc2)N(C)C1=O
Reaction time: 12 h

Procedure:
150 mg of (5-(4-cyanobenzylidene)-1-methyl-2,4-dioxoimidazolidin-3-yl)-acetyl-L-aspartyl-L-valine are dissolved in 40 ml of methanol. After addition of 50 mg of 10% strength Pd-on-charcoal, hydrogenation is carried out at room temperature for 12 hours, the catalyst is filtered off, the filtrate is concentrated and the product is freeze-dried.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([OH:16])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:34]=[CH:35][CH:36]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[CH:8]=2)[C:3]=1[C:14]([N:40]1[CH2:39][CH2:38][N:37]([C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=2)[CH2:42][CH2:41]1)=[O:16]
Reactant: Nc1onc(-c2cccc(F)c2)c1C(=O)O
Reactant: COc1cccc(N2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4cccc(F)c4)noc3N)CC2)c1
Yield: 82.6 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(3-fluorophenyl)isoxazol-4-carboxylic acid (409 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (601 mg, 1.52 mmol, 82%) was obtained.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[CH3:9]>CC#N>[CH3:11][N:10]([CH2:8][C:9]#[C:9][CH2:8][N:10]1[CH2:13][CH2:14][CH2:12][CH2:11]1)[C:1](=[O:7])[CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCN(CC)CC
Reactant: O=C1CCC(=O)O1
Solvent: CC#N
Product: CN(CC#CCN1CCCC1)C(=O)CCC(=O)O

Procedure:
Intermediate compount 004 (557 mg, 3.66 mmol) was added to a solution of succinic anhydride (330 mg, 3.30 mmol) and triethylamine (20.51 mL, 3.66 mmol) in MeCN was removed under a stream of N2, and the crude product was chromatographed on a silica gel column (CHCl3 /MeOH/AcOH, 10/10/1) to give N-Methyl-N-[4-(1-pyrrolidinyl)-2-butynyl]-3-carboxypropanamide as a light brown solid. MS (CI-NH3), m/e 253 (MH+); TLC (CHCl3 /MeOH/AcOH: 10/10/1), Rf 0.34; 1H NMR (CDCl3) δ1.82 (br s, 4 H), 2.48 (t, J=5.8 Hz, 2 H), (t, J=5.8 Hz, 2 H), 2.68 (br s, 4 H), 2.93 & 3.06* (s, 3 H), 3.44 (s, 2 H), 4.11 & 4.21* (s, 2 H).
Reaction SMILES: CC1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9](CCOC3C=CC=CC=3)C2=O)[S:4][C:3]=1C(O)=O.[F:25][C:26]1[CH:47]=[CH:46][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41](O)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:28][CH:27]=1.Cl.Cl.CC1SC=C(CN)N=1>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([CH2:30][N:31]2[CH2:35][CH2:34][N:33]([C:36]3[S:40][C:39]([C:41]([NH:9][CH2:10][C:11]4[N:7]=[C:5]([CH3:6])[S:4][CH:3]=4)=[O:42])=[C:38]([CH3:44])[CH:37]=3)[C:32]2=[O:45])=[CH:46][CH:47]=1
Reactant: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Reactant: Cc1cc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(CN)cs1
Agent: Cl
Product: Cc1nc(CNC(=O)c2sc(N3CCN(Cc4ccc(F)cc4)C3=O)cc2C)cs1
Yield: 71 %

Procedure:
Following the procedures as described in Example 55, making variations as required to replace 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylic acid with 5-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylic acid to react with (2-methylthiazol-4-yl)methanamine dihydrochloride, the title compound was obtained as a colorless solid in 71% yield: 1H NMR (300 MHz, CDCl3) δ 7.30-7.23 (m, 2H), 7.07-6.99 (m, 3H), 6.28 (t, J=5.2 Hz, 1H), 6.10 (s, 1H), 4.63 (d, J=5.2 Hz, 2H), 4.43 (s, 2H), 3.83-3.75 (m, 2H), 3.47-3.39 (m, 2H), 2.71 (s, 3H), 2.49 (s, 3H); MS (ES+) m/z 445.2 (M+1).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21].Br[CH2:23][CH2:24][CH2:25][Cl:26].C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[Cl:26][CH2:25][CH2:24][CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]1[CH:16]=[CH:15][C:14]2[O:17][C:18]([CH3:20])=[CH:19][C:13]=2[C:12]1=[O:21]
Reactant: Cc1cc2c(=O)n(Cc3nc4ccccc4[nH]3)ccc2o1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc2c(=O)n(Cc3nc4ccccc4n3CCCCl)ccc2o1
Temperature: 25 °C

Procedure:
5-(1H-Benzimidazol-2-ylmethyl)-2-methyl-5H-furo[3,2-c]pyridine-4-one (0.75 g), 1-bromo-3-chloropropane (1.3 ml), and potassium carbonate (0.95 g) were added to 50% hydrous acetonitrile (16 ml). The mixture was heated overnight under reflux. The reaction mixture was cooled to room temperature. Water was added thereto, followed by extraction by ethyl acetate. The organic layer was dried over sodium sulfate, and condensed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1). The purified product was condensed to dryness under reduced pressure to give the title compound (0.18 g) as a colorless oily matter.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:28])([CH3:27])[C:21]=3[CH:29]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH:31]O>>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH3:30])[C:20]3[NH:25][C:24](=[O:26])[O:23][C:22]([CH3:27])([CH3:28])[C:21]=3[CH:29]=2)=[O:31])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(SCCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1
Reactant: OO
Product: CC(=O)Nc1ccc(S(=O)CCCCOc2cc(C)c3c(c2)C(C)(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 2 from 6-[4-(4-acetamido-phenylmercapto)-butoxy]-4,4,8-trimethyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl.N1C=CC=C[CH:3]=1.[C:8]([O:12][C:13](=[O:39])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:28]=2)[N:23]=[CH:22][C:21]=1[NH2:38])([CH3:11])([CH3:10])[CH3:9]>C1(C)C=CC=CC=1>[C:8]([O:12][C:13](=[O:39])[NH:14][CH2:15][CH2:16][CH2:17][CH2:18][N:19]1[C:20]2[C:29]3[CH:28]=[C:27]([O:30][CH2:31][C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:26]=[CH:25][C:24]=3[N:23]=[CH:22][C:21]=2[N:38]=[CH:3]1)([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCCCn1cnc2cnc3ccc(OCc4ccccc4)cc3c21

Procedure:
For Examples 70-72, the following procedure was used. Under a nitrogen atmosphere, the reagent from the table below (1.5 equivalents) and pyridine hydrochloride (0.01-0.02 equivalents) were added to a solution of tert-butyl{4-[3-amino-6-(benzyloxy)quinolin-4-ylamino]butyl}carbamate (29-36 mmol, 1 equivalent) in toluene (200 mL), and the reaction was heated at reflux for three to five hours. The toluene was removed under reduced pressure. The residue was dissolved in a small amount of toluene, which was removed under reduced pressure. This was repeated three times. The resulting solid was dried under high vacuum at 100° C. to provide the tert-butyl{4-(8-benzyloxy-1H-imidazo[4,5-c]quinolin-1-yl]butyl}carbamate with the substituent indicated in the table below.