Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([CH2:25][CH:26]=[CH2:27])[C:22]([OH:24])=[O:23]>C(OCC)(=O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](=[O:19])[N:11]([CH3:20])[C:10]=1[CH:21]([CH2:25][CH2:26][CH3:27])[C:22]([OH:24])=[O:23]
Reactant: C=CCC(C(=O)O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Product: CCCC(C(=O)O)c1c(-c2ccc(C)cc2C)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.7 %

Procedure:
A solution of 2-(4-(2,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)pent-4-enoic acid (69 mg, 0.162 mmol,) in ethyl acetate (2 mL) was treated with platinum(IV) oxide (8.12 mg, 0.036 mmol) and the mixture was stirred at room temperature under an atmosphere of H2 for 1 hour. The mixture was filtered and the filtrate was purified by reverse phase hplc afford the title compound (31 mg, 52%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.45-8.52 (m, 1 H) 7.43-7.54 (m, 2 H) 7.07-7.23 (m, 2 H) 6.97-7.03 (m, 1 H) 6.81-6.92 (m, 1 H) 3.79-3.97 (m, 1 H) 3.59 (s, 3 H) 2.42 (s, 3 H) 1.94-2.10 (m, 3 H) 1.54-1.74 (m, 2 H) 1.19-1.30 (m, 2 H) 0.72-0.88 (m, 3 H). LC/MS (m/z) ES+=364 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]#[N:18])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-:8].Br.CC(O)=[O:22].[OH-].[Na+]>O>[NH2:1][C:2]1[C:3]([C:17]([NH2:18])=[O:22])=[N:4][C:5]([C:9]2[CH:14]=[CH:13][C:12](=[O:15])[N:11]([CH3:16])[CH:10]=2)=[CH:6][N+:7]=1[O-:8]
Reactant: CC(=O)O
Reactant: Cn1cc(-c2c[n+]([O-])c(N)c(C#N)n2)ccc1=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(-c2c[n+]([O-])c(N)c(C(N)=O)n2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarbonitrile 4-oxide (97 g) was added to 25% hydrogen bromide solution of AcOH (700 ml) at 25-30° C. The mixture was stirred for 2 hours at ambient temperature. To the mixture was added 12% aq. NaOH (2100 ml) and water (1000 ml). The mixture was stirred overnight at the refrigerator. The resultant precipitated crystals were collected by filtration, and washed with water, and dried in vacuo, to give 3-amino-6-(1-methyl-6-oxo-1,6-dihydro-3-pyridyl)-2-pyrazinecarboxamide 4-oxide as powder (52 g).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:10]=[C:11]([C:21](=[O:23])[CH3:22])[CH:12]=[C:13]([S:15]([F:20])([F:19])([F:18])([F:17])[F:16])[CH:14]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C(=O)([O-])O.[Na+]>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:31][S:32]([N:8]([S:32]([CH3:31])(=[O:34])=[O:33])[C:9]1[CH:10]=[C:11]([C:21](=[O:23])[CH3:22])[CH:12]=[C:13]([S:15]([F:20])([F:16])([F:17])([F:18])[F:19])[CH:14]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CC(=O)c1cc(N(S(C)(=O)=O)S(C)(=O)=O)cc(S(F)(F)(F)(F)F)c1
Reaction time: 2 h

Procedure:
1-[3-Amino-5-(pentafluorosulfanyl)phenyl]ethanone trifluoroacetic acid salt (100 mg, example 4d) was dissolved in methylene chloride (10 ml), triethylamine (120 μl) was added, and methanesulfonyl chloride (21 μl) was added while stirring. After 2 h, the mixture was left to stand overnight and then further methanesulfonyl chloride (20 μl) was added. After a further 2 h, the solvent was drawn off and the residue was taken up with ethyl acetate and water, and adjusted to pH 9 with saturated sodium hydrogencarbonate solution, and the aqueous phase was extracted twice more with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile and freeze-dried. 36 mg of the title compound were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[CH:10]=[CH:9][C:8]=1[CH3:22])[CH3:2].Cl.O1CCOCC1>ClCCl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][N:6]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:7]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH:10]=[CH:9][C:8]=1[CH3:22])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)OC(C)(C)C)ccc1C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(CCC(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To dichloromethane (8.8 ml) were added the compound (1.79 g, 4.40 mmol) obtained in step B and 4N hydrochloric acid-dioxane solution (8.8 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with dichloromethane, washed with water, and dried over sodium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.21 g, yield 79%) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.[CH3:35][S:36]([NH:39][C:40](=O)[O:41]CC)(=[O:38])=[O:37].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[C:8]3[N:9]([C:13]([C:28]4[CH:29]=[CH:30][C:31]([NH:32][C:40]([NH:39][S:36]([CH3:35])(=[O:38])=[O:37])=[O:41])=[CH:33][CH:34]=4)=[C:14](/[CH:16]=[CH:17]/[C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[N:15]=3)[N:10]=[CH:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)NS(C)(=O)=O
Reactant: Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)NC(=O)Nc1ccc(-c2c(/C=C/c3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)cc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a mixture of compound 10b (82 mg, 0.18 mmol) and compound 12a (0.14 g, 0.86 mmol) in DMF (2 mL) was added DIEA (0.16 mL, 0.91 mmol). The mixture was stirred at 100° C. for 2 h. The solution was cooled down, and diluted with DCM (10 mL). The organic layer was washed with 1 N HCl solution (10 mL) and brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (0-10% CH3OH/DCM) to give the title compound 50 as a red solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.96 (s, 1H), 8.31 (d, J=8.6 Hz, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.94 (dd, J=13.6, 8.2 Hz, 2H), 7.83 (d, J=8.6 Hz, 1H), 7.66-7.77 (m, 5H), 7.57-7.63 (m, 2H), 7.51-7.57 (m, 1H), 6.40 (d, J=5.9 Hz, 1H), 4.03-4.14 (m, 4H), 3.83-3.92 (m, 4H), 3.17 (s, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H27N7O4S: 570.2 (M+H). Found 570.4.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].[Li+].[OH-].C(Cl)(=O)C(Cl)=O.[CH:20]1([NH2:23])[CH2:22][CH2:21]1>C1COCC1.CO.C([O-])(O)=O.[Na+]>[CH:20]1([NH:23][C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=2)=[O:4])[CH2:22][CH2:21]1
Reactant: COC(=O)c1ccc(Br)cn1
Reactant: NC1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1CC1)c1ccc(Br)cn1
Reaction time: 12 h

Procedure:
To a solution of 5-bromo-pyridine-2-carboxylic acid methyl ester (1.0 eq.) (see Synth. Commun., 1997, 27, 515) in THF:MeOH (2:1; 0.2M) was added aqueous LiOH (1M; 3.0 eq.). The mixture was stirred for 12 h, concentrated and dried under vacuum. The residue was diluted in CH2Cl2 (0.2M), oxalyl chloride (8.0 eq.) was added and the mixture was stirred for 3h, concentrated, dried under vacuum and diluted in CH2Cl2 (0.2M). Cyclopropylamine (10 eq.) was added and the mixture was stirred for 2 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 9:1) afforded the title compound as a yellow solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[CH:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH:49][CH3:50])=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[CH3:33][O:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][CH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]2[O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][CH2:48][NH:49][CH3:50])=[CH:38][CH:37]=2)=[CH:19][CH:18]=1
Reactant: CNCCCN1CCCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Agent: Cl
Solvent: CO
Product: CNCCCN1CCCc2ccc(COC3CNCCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21

Procedure:
In analogy to the procedure described in example 4(b), the (3RS,4RS)-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-3-[1-(3-methylamino-propyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3RS,4RS)-[3-[7-[4-[4-[3-(2-methoxy-benzyloxy)-propoxyl]-phenyl]-piperidin-3-yloxymethyl]-3,4-dihydro-2H-quinolin-1-yl]-propyl]-methyl-amine as a light yellow oil; MS: 588 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[CH:15][CH:14]=2)[C:4]([CH3:28])=[N:3]1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=2)[CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)[C:4]([CH3:28])=[N:3]1
Reactant: COC(=O)CCc1ccc(OCc2cccc(-c3c(C)nn(C)c3C)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nn(C)c(C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100.3 %

Procedure:
To a mixed solution of methyl 3-(4-{[3-(1,3,5-trimethyl-1H-pyrazol-4-yl)benzyl]oxy}phenyl)propanoate (0.406 g, 1.07 mmol) in methanol (5 mL) and tetrahydrofuran (5 mL) was added 2 M aqueous sodium hydroxide solution (1.5 mL), and the mixture was stirred at room temperature for 20 hr. Water was added to the reaction mixture, and the mixture was neutralized with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (0.391 g, quantitative) as colorless needle crystals. MS: m/z 365 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[N:15][C:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:11]3[C:10]([I:25])=[N:9]2)=[CH:4][CH:3]=1.C=O.[BH3-][C:29]#N.[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1>[I:25][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][CH3:29])=[CH:3][CH:4]=2)[N:9]=1
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)Nc1ncnc2c1c(I)nn2-c1ccc(N)cc1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(-n2nc(I)c3c(NC(=O)OC(C)(C)C)ncnc32)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 32.8 %

Procedure:
To a solution of tert-butyl 1-(4-aminophenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (29) (500 mg, 1.11 mmol) in THF (15 mL) was added HCHO solution (135 mg, 1.66 mmol, 37% solution in water) under N2. The reaction was warmed to 30° C. for 4 h and then NaBH3CN (70 mg, 1.11 mmol) was added. The reaction mixture was stirred for 1 h at 30° C. followed by the addition of NaBH(OAc)3 (235 mg, 1.11 mmol). The reaction mixture was stirred overnight at 30° C. The reaction mixture was quenched with sat. aqueous NaHCO3 and extracted with 85% DCM/IPA (15 mL×3). The organic solution was dried and concentrated. The residue was purified by flash chromatography to provide tert-butyl 3-iodo-1-(4-(methylamino)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylcarbamate (30) (170 mg, 33%) as a yellow solid. LC-MS (ESI): m/z (M+1) 467.0.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:11](=[CH:17]/OCC)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:21][C@@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:11](=[CH:17]/[NH:21][C@@H:22]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][OH:24])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: CCO/C=C(\C(=O)OCC)C(=O)c1cc(Br)cnc1Cl
Reactant: CC(C)C[C@H](N)CO
Solvent: ClCCl
Product: CCOC(=O)/C(=C\N[C@H](CO)CC(C)C)C(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.3 %

Procedure:
The crude ethyl (2Z)-2-[5-bromo-2-chloropyridin-3-yl)carbonyl]-3-ethoxyprop-2-enoate (Intermediate 13, 3.2 g) was dissolved in dichloromethane (30 mL) and (2S)-2-amino-4-methylpentan-1-ol (2.17 g, 14.7 mmol) was added. The mixture was stirred for 30 min at room temperature. Dichloromethane (70 mL) was added to the reaction mixture and the mixture was washed with water (2×100 mL). The organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to give a thick mass which was purified by flash column chromatography. The product was eluted with the gradient of 20% ethyl acetate/petroleum ether to afford colorless thick mass 2.5 g (80%) of ethyl (2Z)-2-[(5-bromo-2-chloropyridin-3-yl)carbonyl]-3-{[(2S)-1-hydroxy-4-methylpentan-2-yl]amino}prop-2-enoate.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)C(C)(C)C)nn1
Yield: 87 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (280 mg, 1 mmol) was converted, using pivaloyl chloride instead of methoxyacetyl chloride, to the title compound (320 mg, 87%) which was obtained as a white solid. MS: m/e=367.1 [M+H].
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:11])[NH:5][O:6][CH2:7][C:8]([OH:10])=O)[CH3:2].[NH2:12][C@@H:13]([CH2:37][C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:40][CH:39]=1)[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:15]>>[C:45]([O:44][C:41]1[CH:40]=[CH:39][C:38]([CH2:37][C@H:13]([NH:12][C:8](=[O:10])[CH2:7][O:6][NH:5][C:4]([NH:3][CH2:1][CH3:2])=[O:11])[C:14]([N:16]([C@@H:28]([CH3:36])[CH:29]([O:33][CH2:34][CH3:35])[O:30][CH2:31][CH3:32])[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)=[O:15])=[CH:43][CH:42]=1)([CH3:48])([CH3:46])[CH3:47]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CCNC(=O)NOCC(=O)O
Product: CCNC(=O)NOCC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(3-ethylureidooxy)acetic acid (Compound VI-13) 48 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:8]=1[CH:9]=O)C.[BH4-].[Na+].P(Br)(Br)[Br:23]>C(O)(=O)C>[Br:23][CH2:4][C:5]1[O:6][C:7]2[C:14]([F:15])=[CH:13][C:12]([F:16])=[CH:11][C:8]=2[CH:9]=1
Reactant: CCOC(COc1c(F)cc(F)cc1C=O)OCC
Reactant: BrP(Br)Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Fc1cc(F)c2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 61.2 %

Procedure:
A stirred solution of 17 (380 mg, 1.39 mmol) in acetic acid (10 mL) was refluxed for 24 h. After cooling, the solution was evaporated to dryness. The crude product (300 mg) was dissolved in EtOH (5 mL). NaBH4 (73 mg, 1.98 mmol) was added portionwise at 0° C., with vigorous stirring. The suspension was stirred at 0° C. for 15 min and then at room temperature for 1.5 h. Solvents were evaporated off in-vacuo. The crude residue (280 mg) was dissolved in toluene (20 mL) and the solution was cooled to 0° C. PBr3 (142 μL, 1.52 mmol) was added dropwise over 15 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 18 (210 mg, 61%). 1H NMR (500 MHz, CDCl3): δ: 7.03 (1H, d, J=7.50 Hz, H-4), 6.87 (1H, t, J=9.80, H-5), 6.79 (1H, s, H-3), 4.59 (2H, s, 2-CH2).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3[CH:10]=[CH:9][CH:8]([CH:4]2C=C1)C3.C(C(Cl)C1C=CC=CC=1)=C.[N+]([C:24]1C=C([N+]([O-])=O)C=C[C:25]=1[OH:33])([O-])=O.[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(C(C)=O)C>[CH:25]([O:33][CH2:1][C:5]1[CH:4]=[CH:8][CH:9]=[CH:10][CH:6]=1)=[CH2:24]
Reactant: O=[N+]([O-])c1ccc(O)c([N+](=O)[O-])c1
Reactant: C1=CC2C3C=CC(C3)C2C1
Agent: C=CC(Cl)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCC(C)=O
Product: C=COCc1ccccc1
Temperature: 25 °C
Yield: 95 %

Procedure:
45 g (0.25 equivalent) of a dicyclopentadiene skeleton phenolic resin (DPP-3H, special phenolic resin, available from Nippon Petrochemical Co., Ltd.), 38.1 g of vinylbenzyl chloride (CMS-AM; purity of 91%; 0.25 mol; m-/p-isomers: 50/50 wt % mixture; available from Seimi Chemical Co., Ltd.), 2.4 g of tetra-n-butylammonium bromide, 0.038 g of 2,4-dinitrophenol, and 200 g of methyl ethyl ketone were charged into a 1-liter four-necked flask equipped with a thermoregulator, a stirrer, a cooling condenser, and a dropping funnel and dissolved under stirring. 40 g of a 50 wt % aqueous solution of NaOH (NaOH purity of 95%, 0.475 mol) was added dropwise at 75° C. to the obtained solution over 20 minutes, and the whole was stirred at 75° C. for additional 4 hours. After the obtained reaction mixture was cooled to room temperature, the mixture was neutralized with 2N hydrochloric acid, and 100 g of toluene was added. An organic layer was then washed with 300 g of distilled water three times. After methyl ethyl ketone was removed under reduced pressure, a reaction product was precipitated in 300 ml of methanol to collect a solid matter through filtration, which was then dried at 50° C. in a vacuum oven to obtain a vinylbenzyl ether compound at an yield of 95%. The obtained compound is designated as Compound 19.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][OH:19])[CH:12]=1)[C:5]([O:7]CC)=[O:6])[CH3:2].[F:20][C:21]([F:32])([F:31])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]=[C:29]=[O:30])[CH:23]=1>>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH2:18][O:19][C:29]([NH:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:20])([F:31])[F:32])[CH:23]=2)=[O:30])[CH:12]=1)[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1cccc(CCO)c1)OCC
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CCOC(Cc1cccc(CCOC(=O)Nc2cccc(C(F)(F)F)c2)c1)C(=O)O

Procedure:
Using ethyl 2-ethoxy-3-[3-(2-hydroxyethyl)phenyl]propanoate and α,α,α-trifluoro-m-tolylisocyanate, the title compound was obtained in the same manner as described in Example 160b).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=O)[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:10](=[S:39])[N:11]([CH3:28])[CH:12]=[N:13][C:14]=1[C:15]1[O:16][C:17]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[N:18][N:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=O
Solvent: Cc1ccccc1
Product: Cn1cnc(-c2nnc(Cc3ccc(F)cc3)o2)c(OCc2ccccc2)c1=S
Yield: 50 %

Procedure:
5-Benzyloxy-6-[5-(4-fluoro-benzyl)-[1,3,4]oxadiazol-2-yl]-3-methyl-3H-pyrimidin-4-one was treated with 0.62 equiv of Lawesson's reagent at 80-85° C. in toluene for 5-7 h. TLC showed one major product formation with some substrate still present. Chromatography (eluted with 70%-90% EtOAc/hexane) gave ˜50% yield of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([Cl:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([Cl:26])[CH:18]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2ccc([N+](=O)[O-])c(Cl)c2)c2cc(Cl)ccc2CC1C
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N1N=C(c2ccc(N)c(Cl)c2)c2cc(Cl)ccc2CC1C
Reaction time: 0.75 h
Yield: 28.4 %

Procedure:
3.93 g (10 mmoles) of (±)-3-acetyl-4,5-dihydro-8-chloro-1-(3-chloro-4-nitrophenyl)-4-methyl-3H-2,3-benzodiazepine are dissolved in a mixture of 30 cm3 of methanol and 30 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by chromatography over a column containing silica gel and using a mixture of ethyl acetate and hexane, then the product is recrystallized from a mixture of ethyl acetate and hexane. Thus, 1.03 g (30%) of the title compound are obtained in the form of yellow solids melting at 143–144° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[CH3:32][Si:33]([CH3:40])([CH3:39])[CH2:34][CH2:35][O:36][CH2:37]Cl>C1COCC1.CCOC(C)=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:37][O:36][CH2:35][CH2:34][Si:33]([CH3:40])([CH3:39])[CH3:32])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1csc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)n1
Reactant: C[Si](C)(C)CCOCCl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of methyl 2-(8-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)thiazole-4-carboxylate (14 g, 31.1 mmol) in THF (150 mL) was added TEA (6.3 g, 62.1 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.77 g, 46.6 mmol). The mixture was stirred at r.t. for 4 h. The mixture was diluted with EtOAc (400 mL) and washed with 3% HCl, water and brine. Evaporation of solvent gave 18.2 g of product. LC/MS (APCI): m/z 580.9 (M+H).