Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[NH:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1.CN(C)[CH:29]=[CH:30][C:31](=O)[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[N:26]=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:30]=[CH:29][N:25]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C(=O)C=CN(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 170 °C
Yield: 34 %

Procedure:
A mixture of N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]guanidine dinitrate (298 mg, 0.80 mmol), ethyl 4-dimethylamino-2-oxo-but-3-enoate (171 mg, 1.0 mmol) and potassium carbonate (69 mg, 0.5 mmol) in ethanol (2 mL) was heated in a sealed tube in a microwave oven to 170° C. for 0.5 h. The mixture was cooled, diluted with ethyl acetate (30 mL), and then washed with saturated sodium carbonate solution (10 mL) and with brine (10 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-20% methanol as eluent to give the title compound (96 mg, 34%) as a pale-yellow solid. MS ISP (m/e): 354.2 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=8.67 (d, 1H), 7.91 (d, 1H), 7.64 (s, 1H), 7.45 (s, 1H), 7.44 (d, 1H), 7.19 (d, 1H), 7.02 (dd, 1H), 6.88 (s, 1H), 4.47 (q, 2H), 3.91 (s, 3H), 2.30 (s, 3H), 1.44 (t, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][S:8][C:9]2[NH:13][N:12]=[N:11][N:10]=2)=[CH:5][CH:4]=1.[N+](=[CH2:18])=[N-]>CO.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:10]=[N:11][N:12]([CH3:18])[N:13]=2)=[CH:14][CH:15]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[N:13]([CH3:18])[N:12]=[N:11][N:10]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(CSc2nnn[nH]2)cc1
Reactant: C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(CSc2nnn(C)n2)cc1
Product: COc1ccc(CSc2nnnn2C)cc1
Reaction time: 1 h
Yield: 36 %
Yield: 65 %

Procedure:
To a solution of 5-p-methoxybenzylthiotetrazole (7.00 g: 31.5 mMol.) in methanol (150 ml) is added under ice cooling a solution of diazomethane in ether (produced from 14 g of N-nitrosomethylurea), and the mixture is stirred for 1 hour and then concentrated. The residue is purified by Lobar column chromatography (toluene: ethyl acetate=5:1) to give 5-p-methoxybenzylthio-2-methyltetrazole [4.86 g: NMR δ(CDCl3) ppm: 3.78(s, 3H), 4.29(s, 3H), 4.38(s; 2H), 6.81-6.85, 7.30-7.34 (A2B2, 4H). IR ν(CHCl3) cm-1 : 1611, 1512, 1390, 1324, 1303. colorless oil. Yield: 65%] and 5-p-methoxybenzylthio-1-methyltetrazole [2.71 g: NMR δ(CDCl3) ppm: 3.79(s, 3H), 3.80(s, 3H), 4.49(s, 2H), 6.82-6.86, 7.27-7.31(A2B2, 4H). IR ν(CHCl3) cm-1 : 1613, 1513, 1465, 1305. colorless crystals. Yield: 36%].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.O=S(Cl)[Cl:22]>C(Cl)Cl>[Cl:22][CH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:5][CH:6]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl

Procedure:
0.875 g (3.27 mmol) of the above prepared [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol was dissolved in 16 ml of CH2Cl2 and treated dropwise at 0° C. with 0.48 ml (2 eq.) of SOCl2. The reaction mixture was kept at 0° C. for 5 Min. and at RT for 30 Min. Pouring onto crashed ice/NaHCO3, twofold extraction with AcOEt, washing with water, drying over sodium sulfate and evaporation of the solvents afforded 0.875 g of pure title compound as light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C>CCOCC>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH3:21])[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
8 g (0.024 Mol) of trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine are reacted in 300 ml of ether with 4.6 g (0.026 Mol) of 4-chlorobenzoylchloride in the presence of 2.7 g (0.026 Mol) of triethylamine. 10.3 g of the title compound are obtained, melting point 152°-154° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=O)(C)(C)C.Cl.ClC1[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=[C:29]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[OH:44])[N:28]=1.C(N(CC)CC)C>O1CCOCC1.C(Cl)Cl>[OH:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=1[C:29]1[N:28]=[C:6]([N:8]2[CH2:12][CH2:11][C@@H:10]([CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:9]2)[C:36]2[C:31](=[CH:32][C:33]([CH3:37])=[CH:34][CH:35]=2)[N:30]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc2c(N3CC[C@@H](CNC(=O)OCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
A solution of benzyl ((S)-1-(tert-butoxycarbonyl)pyrrolidin-3-yl)methylcarbamate (0.20 g, 0.60 mmol) and 4 M HCl in dioxane (10 mL) was stirred for 3 h at room temperature. After evaporating the solvent under reduced pressure, the solid was triturated with Et2O and dried under vacuum, then taken up in CH2Cl2 (10 mL). To this solution was added 2-(4-chloro-7-methylquinazolin-2-yl)phenol (0.16 g, 0.60 mmol) and triethylamine (0.25 mL, 1.8 mmol). The reaction mixture was stirred at room temperature overnight, then diluted with CH2Cl2 and washed with water. The organic extracts were dried over Na2SO4, filtered, and concentrated. Purification via silica gel chromatography using 0-40% EtOAc in hexanes gave benzyl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)pyrrolidin-3-yl)methylcarbamate as a colorless oil (0.19 g, 68%). LC/MS: m/z 469.1 (M+H)+ at 2.58 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[NH2:39][C@@H:40]([CH3:43])[CH2:41][OH:42].C(=O)([O-])[O-].[K+].[K+].O>C1COCC1>[C:20]([N:19]1[C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([CH2:2][NH:39][C@@H:40]([CH3:43])[CH2:41][OH:42])=[CH:8][CH:7]=2)=[N:16][N:17]=[N:18]1)([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C[C@H](N)CO
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](CO)NCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole made as described in Preparation 1 (9.7 g, 17.4 mmol), (2S)-2-aminopropan-1-ol (3.9 g, 52.3 mmol), and potassium carbonate (2.4 g, 17.4 mmol), in THF (170 mL) was stirred at room temperature overnight. Water (100 mL) was added, and the aqueous phase was extracted with EtOAc (3×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Silica gel chromatography gave intermediate (5a).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:29])[C:9]2[CH:28]=[CH:27][C:12]3[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]4[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:30][S:31]([CH:34]([C:36]1[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=1)[CH3:35])(=[O:33])=[O:32]>>[ClH:1].[CH3:30][S:31]([CH:34]([C:36]1[CH:37]=[CH:38][C:39]([NH:42][C:2]2[N:7]=[C:6]([N:8]([CH3:29])[C:9]3[CH:28]=[CH:27][C:12]4[N:13]([CH3:26])[C:14]([NH:16][CH2:17][C:18]5[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:40][CH:41]=1)[CH3:35])(=[O:32])=[O:33]
Reactant: CC(c1ccc(N)cc1)S(C)(=O)=O
Reactant: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Product: COc1ccc(CNc2nc3cc(N(C)c4ccnc(Nc5ccc(C(C)S(C)(=O)=O)cc5)n4)ccc3n2C)cc1
Product: Cl

Procedure:
The title compound was prepared following the procedure of example two with N5-(2-chloro-pyrimidin-4-yl)-N2-(4-methoxy-benzyl)-1,N5-dimethyl-1H-benzoimidazole-2,5-diamine (82 mg, 0.20 mmol) and 4-(1-Methanesulfonyl-ethyl)-phenylamine (47 mg, 0.20 mmol) as a white solid (49 mg, 40%). 1H NMR (300 MHz, d6-DMSO+NaHCO3) δ 9.24 (s, 1H), 7.75-7.80 (M, 3H), 7.60 (br s, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.26 (d, J=7.8 Hz, 3H), 7.12 (s, 1H), 6.89 (d, J=8.4 Hz, 3H), 5.66 (d, J=6.0 Hz, 1H), 4.53 (d, J=5.7 Hz, 2H), 4.40 (m, 1H), 3.72 (s, 3H), 3.58 (s, 3H), 3.43 (s, 3H), 2.76 (s, 3H), 1.59 (d, J=7.2 Hz, 3H). MS (ESI) m/z=572 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.[C:25](OCC(Cl)=O)(=[O:27])[CH3:26].[OH-].[Na+].Cl>COCCOC.CO>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:26]2[CH2:25][OH:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: Cc1c(Cl)cccc1Cn1c(CO)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (1 g, 2.73 mmol) in 1,2-Dimethoxyethane (DME) (20 ml) at 0° C. was added acetoxyacetyl chloride (0.586 ml, 5.45 mmol). The mixture was stirred at room temperature for 2 h, then stirred at 50° C. overnight. The mixture was quenched with methanol and concentrated. To the resulting residue in Methanol (12 ml) was added 6N NaOH (0.9 mL, 5.45 mmol). The mixture was stirred at room temperature for 60 min, then acidified (˜pH 5) with 1N HCl. The solvent was removed and the residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. Reversed-phase HPLC purification provided 4-[(3-chloro-2-methylphenyl)methyl]-5-(hydroxymethyl)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (250 mg, 22%); LC/MS: MS (ES+) m/e 407 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.43 (s, 3H), 3.51 (m, 4H), 3.67 (m, 4H), 4.32 (d, J=5.6 Hz, 2H), 5.57 (s, 2H), 5.64 (t, J=5.6 Hz, 1H, OH), 6.51 (d, J=7.6 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[CH:11][C:10]=2[C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH2:21][CH2:22][C:23]3=[O:28])[CH2:6][O:5][CH2:4]1.C(N(CC)CC)C.[C:36](Cl)(=[O:41])[O:37][CH:38]([CH3:40])[CH3:39].COC1C(OC)=CC=C(C2C=CC=C3C=2CCC3=O)C=1OCC1(CNC(=O)C)COC1>ClCCl>[CH:38]([O:37][C:36](=[O:41])[NH:1][CH2:2][C:3]1([CH2:7][O:8][C:9]2[C:10]([C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH2:21][CH2:22][C:23]4=[O:28])=[CH:11][CH:12]=[C:13]([O:17][CH3:18])[C:14]=2[O:15][CH3:16])[CH2:4][O:5][CH2:6]1)([CH3:40])[CH3:39]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CN)COC2)c1OC
Agent: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(C)=O)COC2)c1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CNC(=O)OC(C)C)COC2)c1OC

Procedure:
To a stirring solution of 4-[2-(3-Aminomethyl-oxetan-3-ylmethoxy)-3,4-dimethoxy-phenyl]-indan-1-one (Compound 191) (150 mg, 0.3916 mmol) in dichloromethane (15 mL), were added triethylamine (118 mg, 1.174 mmol) and isopropyl carbonochloridate (95 mg, 0.783 mmol) and the resultant reaction mixture was subjected to the conditions used in the preparation of Compound 192 to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)=[CH:12][N:11]=[N:10][C:9]=2[NH:21][NH2:22])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=O)[C:31](O)=[O:32])=[CH:26][CH:25]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]2[CH:12]=[N:11][N:10]3[C:31](=[O:32])[C:30]([C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[N:22][N:21]=[C:9]3[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:15][CH:16]=1
Reactant: O=C(O)C(=O)c1ccc(F)cc1
Reactant: NNc1nncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Product: O=c1c(-c2ccc(F)cc2)nnc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12

Procedure:
The title compound was prepared using the method described in Example 1E, reacting 1-(4,5-bis(4-chlorophenyl)pyridazin-3-yl)hydrazine with 2-(4-fluorophenyl)-2-oxoacetic acid to give 8,9-bis(4-chlorophenyl)-3-(4-fluorophenyl)-4H -pyridazino[6,1-c][1,2,4]triazin-4-one. HPLC retention time=3.84 min; MS observed=463 (M+H); 1H NMR (CDCl3, 500 MHz) δ 8.76 (s, 1H), 8.58–8.53 (m, 2H), 7.39–7.34 (m, 4H), 7.31–7.25 (m, 2H), 7.22–7.13 (m, 4H).
Reaction SMILES: C1(CC(Cl)=O)C=CC=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([CH3:33])[C:27]=1[CH3:34].[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1(C)C=CC=CC=1.C(O)C>[C:35]1([CH2:41][C:42]([N:44]=[C:45]=[S:46])=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:45]([NH:44][C:42](=[O:43])[CH2:41][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[S:46])=[C:28]([CH3:33])[C:27]=1[CH3:34]
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C(Cc1ccccc1)N=C=S
Agent: O=C(Cl)Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)Cc4ccccc4)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
2-Phenylethanoyl isothiocyanate was prepared using commercially available 2-phenylethanoyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 2-phenylethanoyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 58%).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[C:26]([O:35][CH3:36])=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:19]3)[CH2:14][C:15](O)=[O:16])[N:12]=2)[CH2:4][CH2:3]1.[CH3:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]2[S:9][CH:10]=[C:11]([CH:13]([N:18]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]4[C:26]([O:35][CH3:36])=[CH:27][CH:28]=[C:29]5[C:34]=4[N:33]=[CH:32][CH:31]=[CH:30]5)[CH2:20][CH2:19]3)[CH2:14][C:15]([N:41]3[CH2:42][CH2:43][N:38]([CH3:37])[CH2:39][CH2:40]3)=[O:16])[N:12]=2)[CH2:6][CH2:7]1
Reactant: CN1CCNCC1
Reactant: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)O)c2csc(N3CCC(O)CC3)n2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2cccnc2c1N1CCCN(C(CC(=O)N2CCN(C)CC2)c2csc(N3CCC(O)CC3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.2 %

Procedure:
DMF (3.0 mL) was added to the product from step 2 (309 mg, 0.60 mmol), followed by N-methylpiperazine (0.08 mL, 0.72 mmol), and Et3N (0.17 mL, 1.20 mmol). HATU (274 mg, 0.72 mmol) was then added to the mixture, and the reaction was stirred for 2 h at room temperature. The solution was then diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was dried over MgSO4, filtered, and concentrated to give the crude. This was purified by silica gel chromatography (99:1 to 90:10 CH2Cl2:(9:1 MeOH:NH4OH)) and lyophilized from MeCN/H2O to give the product (122 mg, 34% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.84 (dd, 1H, J=1.4, 4.2 Hz), 8.02 (dd, 1H, J=2.0, 8.0 Hz), 7.51 (d, 1H, J=8.8 Hz), 7.29 (d, 1H, J=8.8 Hz), 7.21 (dd, 1H, J=4.2, 8.2 Hz), 6.44 (s, 1H), 4.35 (bs, 1H), 3.95 (s, 3H), 3.95-3.76 (m, 2H), 3.67-3.45 (m, 7H), 3.24-2.78 (m, 8H), 2.42-2.33 (m, 2H), 2.28 (s, 3H), 2.32-2.10 (m, 5H), 2.02-1.92 (m, 4H), 1.68-1.58 (m, 2H). MS (ES) m/z 594.5 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([NH:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:11][C@@H:10]([C:28](=[O:48])[N:29]([CH:45]2[CH2:47][CH2:46]2)[CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CCO>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@H:10]([C:28](=[O:48])[N:29]([CH:45]2[CH2:47][CH2:46]2)[CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[CH:32]=2)[CH2:11][C@H:12]([NH:14][CH2:15][CH2:16][NH2:17])[CH2:13]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCCN3C(=O)c4ccccc4C3=O)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Agent: NN
Solvent: O
Solvent: CCO
Product: COCCCn1cc(CN(C(=O)[C@@H]2C[C@H](NCCN)CN(C(=O)OC(C)(C)C)C2)C2CC2)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of (3R*,5S*)-3-{Cyclopropyl-[1-(3-methoxy-propyl)-1H-indol-3-ylmethyl]-carbamoyl}-5-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethylamino]-piperidine-1-carboxylic acid tert-butyl ester (160 mg, 0.24 mmol) and hydrazine monohydrate (18 uL, 0.37 mmol) in EtOH is stirred at 60° C. After 6 h, the reaction mixture is cooled down to room temperature. The solution is filtered through celite pad and the solvent is evaporated in vacuo to afford the title compound as yellow material. MS: 528 [M+H]+; tR (HPLC, ACQUITY UPLC™ BEH C18 1.7 μm, 50×2.1 mm; 5% CH3CN+0.1% TFA/H2O+0.1% TFA for 0.5 min then 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 1.5 min, flow 0.5 ml/min): 2.93 min.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[C:3]=1[CH:10]([OH:14])/[CH:11]=[CH:12]\[CH3:13].CC1C(C(O)/C=C\C)C(C)(C)CCC=1>>[CH3:1][C:2]1[CH:3]([C:10](=[O:14])/[CH:11]=[CH:12]/[CH3:13])[C:4]([CH3:8])([CH3:9])[CH2:5][CH2:6][CH:7]=1
Reactant: C/C=C\C(O)C1=C(C)CCCC1(C)C
Agent: C/C=C\C(O)C1C(C)=CCCC1(C)C
Product: C/C=C/C(=O)C1C(C)=CCCC1(C)C

Procedure:
By replacing in the above procedure cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-1-cyclohexene by cis-2,6,6-trimethyl-1-[1-hydroxy-2-butenyl]-2-cyclohexene, trans-2,6,6-trimethyl-1-crotonoyl-2-cyclohexene was obtained which had the following characteristics:
Reaction SMILES: [CH:1]([N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10])=[CH:2][CH2:3][CH3:4].[C:11](OC)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=1>CN(C)C=O>[CH:1]([N:5]1[CH2:9][CH2:8][CH:7]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[N:14][CH:13]=2)[C:6]1=[O:10])=[CH:2][CH2:3][CH3:4]
Reactant: CCC=CN1CCCC1=O
Reactant: COC(=O)c1cccnc1
Solvent: CN(C)C=O
Product: CCC=CN1CCC(C(=O)c2cccnc2)C1=O
Temperature: 90 °C
Yield: 94.5 %

Procedure:
Sodium hydride (8.63 g, 0.36 mol of 60% dispersion in a mineral oil) was washed with toluene to remove mineral oil. To this 20 ml of dimethylformamide (DMF), 1-(but-1-enyl)pyrrolidin-2-one (25 g, 0.1798 mol) and a solution of methyl nicotinate (20.94 g, 0.152 mol) in 15 ml of DMF were added. The reaction mixture was heated at 90° C. for 2 hrs. DMF was partially removed under reduced pressure, 50 ml water added, further cooled to 0-10° C. and pH adjusted to 7 using HCl. The reaction mixture was extracted with ethyl acetate and dried over Na2SO4. After removing the solvent under reduced pressure a yellow solid was obtained, which on recrystallisation with diisopropyl ether gave 1-(but-1-enyl)-3-nicotinoyl-pyrrolidin-2-one (II, 35.1 g, 94% yield), 95% HPLC, M.R: 65-66° C. 1H NMR (CDCl3): δ 9.3 (1H, d), 8.8 (1H, d), 8.41 (1H, dt), 7.4 (1H, m), 6.76 (1H, d), 5.0 (1H, m), 4.5 (1H, m), 3.57-3.67 (2H, m), 2.7 (1H, m), 2.3 (1H, m), 2.0 (2H, m), and 1.0 (3H, t). 13C-NMR (CDCl3): δ 194.4, 167.1, 153.7, 150.4, 137.0, 134.4, 131.2, 123.3, 114.9, 51.7, 44.2, 23.2, 22.3, and 14.26. IR: 2966, 2937, 2855, 2847, 1631, 1613, 1489 Cm−1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[CH:19][CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[C:11]2[C:15](=[O:16])[C:14]3[CH:17]=[CH:18][CH:19]=[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)[C:13]=3[O:12]2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1C(=Cc2c[nH]c3ccccc23)Oc2c(CN3CCNCC3)cccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0305 g, 0.0664 mmol) in methylene chloride (2 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, the resulting residue was added with saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated to obtain (Z)-2-[(1H-indol-3-yl)methylene-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.0220 g, 95%).