Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[NH2:64][CH2:65][CH:66]1[CH2:68][CH2:67]1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:66]1([CH2:65][NH:64][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[N:7][C:8]([CH3:12])=[N:9]3)=[CH:4][CH:3]=2)[CH2:68][CH2:67]1
Reactant: NCC1CC1
Reactant: Cc1nc(N2CCCC2)c2ccc(Br)cc2n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: Cc1nc(N2CCCC2)c2ccc(NCC3CC3)cc2n1
Yield: 46.9 %

Procedure:
A suspension of 0.15 g (0.513 mmol) of 7-bromo-2-methyl-4-pyrrolidin-1-yl-quinazoline, 21.3 mg (0.034 mmol) racemic BINAP, 3.8 mg (0.017 mmol) of palladium(II)acetate and 65.8 mg (0.685 mmol) of sodium tert-butylate in toluene (8 ml) was treated at RT with 0.365 g (5.13 mmol) of aminomethyl cyclopropane and then heated to reflux under an argon atmosphere for 20 h. The reaction mixture was then filtered by suction over fiberglass filter paper and the filtrate was partitioned between EtOAc and water. The layers were separated, the organic layer dried over sodium sulphate and concentrated in vacuo. The residue was applied to silica gel column with CH2Cl2/MeOH/NH4OH (10:1:0.2) as eluent. Combination of the purified fractions and concentration in vacuo gave 68 mg (46.9%) of the desired cyclopropylmethyl-(2-methyl-4-pyrrolidin-1-yl-quinazolin-7-yl)-amine as brown viscous oil. ISP mass spectrum, m/e: 283.2 (M+1 calculated for C17H22N4: 283).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH2:16])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:25]([NH:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[O:26])[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1c(Br)cnn1C
Yield: 84.8 %

Procedure:
3-(4-Bromo-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.260 g, 0.92 mmol) was treated with 4-chlorophenyl isocyanate (0.144 g, 0.92 mmol, 1.0 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 1 (0.340 g, 0.78 mmol, 84%) as a white solid. LCMS m/z (%)=435 (M+H79Br35Cl, 27), 437 (M+H81Br35Cl, 100), 439 (M+H81Br37Cl, 25). 1H NMR (400 MHz, CDCl3) δ: 7.56 (s, 1H), 7.44 (dd, J=2.7, 8.9 Hz, 1H), 7.34 (d, J=9.0 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.19 (d, J=2.7 Hz, 1H), 6.59 (s, 1H), 6.47 (s, 1H), 3.84 (s, 3H), 3.74 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)#[CH:2].[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]\I)[CH3:12]>>[CH2:11]([O:13][C:14](=[O:18])[CH:15]=[CH:16][C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH2:10])=[CH:5][CH:4]=1)[CH3:12]
Reactant: C#Cc1ccc(C=C)cc1
Reactant: CCOC(=O)/C=C\I
Product: C=Cc1ccc(C#CC=CC(=O)OCC)cc1

Procedure:
The general procedure was used to convert 1-Ethynyl-4-vinyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (10% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (420 mg, 95% yield). 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (d, J=8.3, 2H), 7.39-7.37 (d, J=8.3, 2H), 6.73-6.66 (dd, J=17.5, 10.8, 1H), 6.38-6.35 (d, J=11.4, 1H), 6.14-6.12 (d, J=11.4, 1H), 5.81-5.77 (d, J=17.6, 1H), 5.33-5.30 (d, J=10.9, 1H), 4.29-4.24 (q, J=7.1, 2H), 1.35-1.32 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.92, 139.62, 132.12, 129.28, 127.83, 123.14, 119.76, 101.77, 86.19, 60.44, 21.66, 14.42. Anal. Calcd. for C14H14O2: C, 79.62; H, 6.24; Found C, 79.37; H, 6.48.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:8][C:9](O)([CH2:12][CH3:13])[CH2:10][CH3:11].P(=O)(O)(O)O>C1C=CC=CC=1>[CH3:8][C:9]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: CCC(C)(O)CC
Reactant: Oc1ccccc1
Agent: O=P(O)(O)O
Solvent: c1ccccc1
Product: CCC(C)(CC)c1ccc(O)cc1
Yield: 91 %

Procedure:
A mixture of phenol (396 g, 4.2 mol), 3-methyl-3-pentanol (230 g. 2.25 mol), 85% phosphoric acid (50 g, 0.43 mol) and benzene (1.5 liters) was refluxed and the azeotroped water was collected in a Dean Stark trap (53 ml). The reaction mixture was cooled and transferred to a separatory funnel. A small bottom layer was separated and the top (organic) layer was washed with 500 ml portions of water until the pH of the washes was 7 (neutral). The solvent was removed on a rotary evaporator. Distillation of the residual oil under vacuum gave the desired 4-(3-methylpent-3-yl)phenol: 365 g, 91% yield; bp 112° C. (1.0 mm); mol wt. 178 (ms); nmr, 0.68 (6H, t, J=8 2-methyls), 1.26 (3H, s, methyl), 1.4-2.0 (4H, m, --CH2 --), 6.28 (1H, s, hydroxyl), 6.8-7.3 (4H, m, aromatics); ir, 3260, 2980, 2940, 2890, 1615, 1600, 1515, 1466, 1380, 1250, 1190, 1120, 830 cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].[Cl:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C3CCCCO3)=[CH:22][CH:21]=2)=O)=[CH:14][CH:13]=1>C1COCC1.[Zn].Cl[Ti](Cl)(Cl)Cl>[Cl:11][C:12]1[N:17]=[CH:16][C:15](/[C:18](/[C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)=[C:1](\[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)/[CH2:2][CH3:3])=[CH:14][CH:13]=1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Reactant: CCC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Temperature: 80 °C
Yield: 41 %

Procedure:
To a stirred mixture of Zn powder (8.06 g, 6 eq) in dry THF at rt under N2 was slowly added TiCl4 (6.8 mL, 3 eq). The resulting mixture was heated to 80° C. and refluxed for 1 h. After cooling to rt, a mixture of propiophenone (8.2 g, 3.0 eq) and (6-chloropyridin-3-yl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (6.5 g, 1.0 eq) in dry THF was added. The resulting mixture was refluxed for additional 2 h, then quenched with saturated aq. Na2CO3 solution, extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give a Z/E mixture of the product (6.3 g, 92%, Z/E=1/1). The Z/E mixture was recrystallized in petroleum ether/CH2Cl2 to give the pure Z-isomer (2.8 g, 41% yield). 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.06-7.25 (m, 8H), 6.97 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.0 Hz, 2H), 2.51 (q, J=7.6 Hz, 2H), 0.94 (t, J=7.6 Hz, 3H); m/z=336 [M+1]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]([NH2:18])=[S:17])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][C:21](=O)[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25].C(N(CC)CC)C>CO>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:20]=[C:21]([CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[N:18]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=S)Nc1ncccc1OCc1ccccc1
Reactant: COC(=O)CCC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Yield: 81.4 %

Procedure:
1-(3-(Benzyloxy)pyridin-2-yl)thiourea (3.30 g, 12.7 mmol), methyl 5-bromo-4-oxopentanoate (3.19 g, 15.3 mmol) (prepared according to Synthetic Communications (1994) 2557-2562), and triethylamine (3.10 mL, 22.3 mmol) were heated in methanol (100 mL) at reflux for 3 hours according to the method of Example 2, Step C, to provide methyl 3-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (3.82 g, 81.3% yield) as a light yellow powder: 1H NMR (DMSO-d6) δ 9.93 (bs, 1H), 7.86 (d, 1H), 7.57 (d, 2H), 7.34-7.42 (m, 4H), 6.89 (m, 1H), 6.63 (s, 1H), 5.26 (s, 2H), 3.60 (s, 3H), 2.85 (t, 2H), 2.69 (t, 2H). Mass spectrum (esi) m/z=370 (100).
Reaction SMILES: [NH2:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:11])=[CH:3]1.[C:12]1(=[O:22])[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>C(Cl)(Cl)Cl>[CH3:11][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([NH:1][C:12]([C:13]2[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])=[O:22])[CH:3]=1
Reactant: Cc1cn(N)c2ccccc12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cc1cn(NC(=O)c2ccccc2C(=O)O)c2ccccc12
Temperature: 25 °C
Yield: 105.6 %

Procedure:
A suspension of 2.0 g of N-amino-3-methylindole, 140 ml of dry chloroform and 2.74 g of phthalic anhydride was stirred at reflux for 4 hours. The suspension was allowed to cool to room temperature, concentrated to approximately 50 ml, filtered and the residue washed with chloroform to provide 4.25 g of a white solid. Recrystallization from ethyl acetate provided 3.18 g (79.0%) of 2-[[(3-methyl(indol-1-yl)amino]carbonyl]benzoic acid, m.p. 191°-193° C.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[NH2:13][C:14]1[CH:22]=[C:21]2[C:17]([CH:18]=[CH:19][NH:20]2)=[CH:16][CH:15]=1.C1(C)C=CC=CC=1>CN(C=O)C>[NH:20]1[C:21]2[C:17](=[CH:16][CH:15]=[C:14]([NH:13][C:2](=[O:4])[C:1]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[NH2:6])[CH:22]=2)[CH:18]=[CH:19]1
Reactant: Nc1ccc2cc[nH]c2c1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Nc1ccccc1C(=O)Nc1ccc2cc[nH]c2c1
Yield: 52.7 %

Procedure:
A mixture of isatoic anhydride (5.06 g, 31 mmol), 6-aminoindole (4.103 g, 31 mmol), toluene (300 mL) and DMF (30 mL) was heated to reflux for 18 hours. The reaction was cooled, filtered, and chromatographed to yield 4.103 g (53%) of the title compound as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:9](=O)[CH2:8][S:7][CH2:6]1)=[O:4].[NH2:11]O.N>>[NH2:11][C:9]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][S:7][CH:8]=1
Reactant: COC(=O)C1CSCC1=O
Reactant: NO
Agent: N
Product: COC(=O)c1cscc1N

Procedure:
Diazotization of methyl 4-aminothiophene-3-carboxylate with sodium nitrite followed by treatment with dimethylamine provides methyl 4-[(dimethylamino)diazenyl]thiophene-3-carboxylate. Treatment of the ester with ammonia gave the required 4-[dimethylamino)diazenyl]thiophene-3-carboxamide (compd. No. 13). The methyl 4-aminothiophene-3-carboxylate is produced using known procedures in the prior art (33, 34, 35). Thus addition of methyl acrylate to methyl thioglycolate provided methyl 3-[(methoxycarbonyl)methylthio]propanoate in quantitative yield, which on cyclization in presence of sodium methoxide gave methyl 4-oxo-2,3,5-trihydrothiophene-3-carboxylate. Treatment of methyl 4-oxo-2,3,5-trihydrothiophene-3-carboxylate with hydroxylamine followed by basification with ammonia gave methyl 4-aminothiophene-3-carboxylate.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=O)[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[CH3:1][N:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[S:22])[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:3]1
Reactant: Cn1cc(-c2ccccc2)c(=O)c(-c2ccccc2)n1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cn1cc(-c2ccccc2)c(=S)c(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 1 g. portion of the product of Example 4 was dissolved in 10 ml. of pyridine and heated under reflux for 4 hours with 1 g. of P2S5. The solution was then poured into ice water and stirred for 30 minutes. The precipitate was recovered by filtration and crystallized from hexane-isopropyl alcohol. The yield was 1 g. of 1-methyl-3,5-diphenyl-4(1H)-pyridazinethione, m.p. 122°-23°C., which was identified by infrared, nuclear magnetic resonance and ultraviolet analyses, and by mass spectrometry.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[SH2:17]>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]=[CH:6][C:7]=1[C:8](=[S:17])[NH2:9]
Reactant: S
Reactant: Cc1ccncc1C#N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccncc1C(N)=S
Temperature: 25 °C
Reaction time: 16 h
Yield: 86 %

Procedure:
To a solution of compound (14)(9.2 g, 77.9 mmol) in dimethylformamide (500 ml) was added triethylamine (800 mg, 7.79 mmol; 10 mol %), and the mixture was stirred at room temperature for 16 hrs. while introducing hydrogen sulfide gas. The solvent was concentrated and the obtained residue was partitioned between dichloromethane and brine. The aqueous layer was extracted with dichloromethane. The extracts were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was recrystallized from a small amount of ethyl acetate to give the title compound (10.2 g, 86%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[C:11]1[CH:22]=[CH:21][C:14]([C:15]([O:17][CH2:18][CH:19]=[CH2:20])=[O:16])=[CH:13][CH:12]=1>>[CH2:18]([O:17][C:15]([C:14]1[CH:21]=[CH:22][C:11]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:12][CH:13]=1)=[O:16])[CH:19]=[CH2:20]
Reactant: C=CCOC(=O)c1ccc(I)cc1
Reactant: NC(=O)c1ccccc1
Product: C=CCOC(=O)c1ccc(NC(=O)c2ccccc2)cc1
Yield: 90.9 %

Procedure:
Using general procedure A, benzamide (150 mg, 1.24 mmol) was coupled with allyl 4-iodobenzoate (300 mg, 1.04 mmol). The crude product was purified by flash chromatography on silica gel (2×15 cm; hexane-ethyl acetate 3:1; 10 mL fractions). Fractions 8-15 provided 266 mg (91% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 8.14-8.09 (m, 2H), 8.00 (br s, 1H), 7.93-7.88 (m, 2H), 7.80-7.75 (m, 2H), 7.63-7.58 (m, 1H), 7.56-7.51 (m, 2H), 6.07 (ddt, J=17.2, 11.7, 5.6 Hz, 1H), 5.45 (dq, J=17.2, 1.4 Hz, 1H), 5.32 (dq, J=11.7, 1.4 Hz, 1H), 4.85 (dt, J=5.6, 1.4 Hz, 2H).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[N:15][CH:16]=2)[CH2:8][CH2:7][NH:6]1)([O-:3])=[O:2].C[O:19][C:20](=O)[C:21]#[CH:22]>CO>[Cl:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][N:9]2[C:5]3=[C:4]([N+:1]([O-:3])=[O:2])[CH:22]=[CH:21][C:20](=[O:19])[N:6]3[CH2:7][CH2:8]2)=[CH:16][N:15]=1
Reactant: C#CC(=O)OC
Reactant: O=[N+]([O-])C=C1NCCN1Cc1ccc(Cl)nc1
Solvent: CO
Product: O=c1ccc([N+](=O)[O-])c2n1CCN2Cc1ccc(Cl)nc1
Yield: 52.3 %

Procedure:
A mixed solution of 2-nitromethylene-3-(2-chloro-5-pyridylmethyl) imidazolidine (12.7 g), propiolic acid methylester (4.2 g) and methanol (100 ml) was refluxed under heating for about 20 hours. Subsequently methanol was distilled off under reduced pressure, and the residue was refined by a silica-gel column chromatography to give the desired 1,2,3,5-tetrahydro-1-(2-chloro-5-pyridylmethyl)-8-nitroimidazo[1,2-a] pyridin-5-one (8 g).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[C:12]([O:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:35](=[O:36])[CH2:34][NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])[CH2:4][CH2:5]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)CNC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 38 %

Procedure:
A solution of 4-(aminomethyl)-1-(tert-butoxycarbonyl)piperidine (5.72 g) in CH2Cl2 (150 mL) was treated with Et3N (3.51 g), N-(9-fluorenylmethyloxycarbonyl)glycine (7.93 g, 26.7 mmol), EDCI (3.80 g) and HOBt (4.33 g). After the reaction mixture was stirred at room temperature for 5 h, the mixture was washed with water (100 mL×3) and brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated. Recrystallization from CH3CN/CH3OH (150 mL/1 mL) at 0° C. afforded 1-(tert-Butoxycarbonyl)-4-[{N-(9-fluorenylmethyloxycarbonyl)glycyl}aminomethyl]piperidine (5.7 5 g, 44%) as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH:21]([CH:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[CH2:27][CH2:26][NH:25]1)([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:8][NH:9][C:10](=[O:19])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:25]1[CH2:26][CH2:27][C:28]2[C:33](=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:24]1[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CCCCCCCBr)NOCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(C(C)C)NCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)C(C(C)C)N(CCCCCCCC(=O)NOCc1ccccc1)CC2

Procedure:
In a manner analogous to that of example 1(b), 8-bromo-octanoic acid benzyloxy-amide (example 1(a); 0.3 g, 1.1 mmol) was reacted with 1-isopropyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.1 mmol) in the presence of potassium carbonate (0.15 g, 1.1 mmol) and DMF as solvent to give 8-(1-isopropyl-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-octanoic acid benzyloxyamide as an almost colorless wax (yield 0.1 g, 20%; purified by column chromatography using silica gel and ethyl acetate as eluent). MS (M+H+)=483.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2O[C:16]([CH3:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>[Cl-].[Mg+2].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:27]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]([CH3:19])=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)o1
Agent: [Cl-]
Agent: [Mg+2]
Product: Cc1nnc(C2CCN(C(=O)OC(C)(C)C)CC2)n1Cc1ccccc1
Temperature: 150 °C
Yield: 70.4 %

Procedure:
4-(5-Methyl-[1,3,4]oxadiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (5 g, 18.7 mmol) (see reference WO 0039125), benzylamine (2.5 ml, 22 mmol) and magnesium chloride (100 mg) were heated at 150° C. for 1 hour, a further quantity of benzylamine (2.5 ml, 22 mmol) was added and the mixture was heated at 150° C. for 4 hours. The reaction mixture was cooled to room temperature and the reaction mixture was purified by chromatography on silica gel using methanol in dichloromethane as eluant (3:97). The material isolated was triturated with diethyl ether to give the title compound as a white solid (4.69 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)=[O:5])[CH3:2].[NH2:22][C@@H:23]([CH3:40])[CH2:24][N:25]1[CH:29]=[CH:28][C:27]([C:30]2[CH:37]=[C:36]([F:38])[C:33]([C:34]#[N:35])=[C:32]([Cl:39])[CH:31]=2)=[N:26]1>>[Cl:39][C:32]1[CH:31]=[C:30]([C:27]2[CH:28]=[CH:29][N:25]([CH2:24][C@@H:23]([NH:22][C:11]([C:9]3[N:10]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[CH:8]=3)=[O:13])[CH3:40])[N:26]=2)[CH:37]=[C:36]([F:38])[C:33]=1[C:34]#[N:35]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: CCOC(=O)c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Product: CCOC(=O)c1nc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(F)c(C#N)c(Cl)c3)n2)cn1COCC[Si](C)(C)C

Procedure:
The title compound was prepared using the procedure described in Example 32(e) starting from 2-(ethoxycarbonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxylic acid (3.18 mmol, 1 g) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (3.18 mmol, 890 mg). The product was purified by flash-chromatography. Yield 1.6 g. 1H-NMR (400 MHz; DMSO-d6): δ −0.01 (s, 9H), 0.80 (t, 2H), 1.15 (d, 3H), 1.30 (t, 3H), 3.48 (t, 2H), 4.34-4.49 (m, 5H), 5.69 (s, 2H), 6.98 (d, 1H), 7.78-7.82 (m, 2H), 7.87 (s, 1H), 8.03 (s, 1H), 8.21 (d, 1H). LC-MS: [M+1]=575.11.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([CH3:34])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([CH:48]=[CH:49][CH:50]=1)[CH2:46][NH2:47]>C(#N)C>[CH3:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:47][CH2:46][C:45]4[CH:48]=[CH:49][CH:50]=[C:43]([O:42][CH3:41])[CH:44]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1C
Reactant: COc1cccc(CN)c1
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1cccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C)c(C)c2)C3)c1
Yield: 59.4 %

Procedure:
To a suspension of 2,2,2-trichloro-1-{10-[(2,2′-dimethyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 6 (0.538 g, 1.0 mmol) and dimethyl sulfoxide (0.35 mL, 4.9 mmol, 5 eq.) in acetonitrile (6 mL) was added 3-methoxybenzylamine (0.26 mL, 2.0 mmol, 2 eq.) and the reaction mixture was heated to reflux for 45 hours. The cooled reaction mixture was then concentrated in vacuo to remove acetonitrile. The oily residue was dissolved in ethyl acetate (25 mL), washed with 1N sodium hydroxide (25 mL), water (25 mL) and brine (25 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the crude product (0.59 g) as a brown foam. Purification by flash chromatography using a solvent gradient of 20 to 40% ethyl acetate in hexane gave the title compound (330 mg, 59%) as a pale yellow solid. MS [(+)ESI, m/z]: 556 (M+H]+.HRMS [(+)ESI, m/z]: 556.25884 [M+H]+. Calcd for C36H34N3O3: 556.26002. Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N 7.56. Found: C, 77.50; H, 6.10; N 7.43.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]([C:12]1[CH:13]=[C:14]([CH2:31][NH:32][CH3:33])[CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH2:21][CH3:22])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[C:36]1(=[O:42])[O:41][C:39](=[O:40])[CH2:38][CH2:37]1>C1COCC1>[F:35][C:2]([F:1])([F:34])[C:3]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[Sn:18]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][CH3:22])[CH2:31][N:32]([CH3:33])[C:39](=[O:40])[CH2:38][CH2:37][C:36]([OH:41])=[O:42])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: O=C1CCC(=O)O1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(CNC)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc(CN(C)C(=O)CCC(=O)O)cc1C(OCOC)(C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 89.7 %

Procedure:
Compound 14 (114 mg, 184 μmol) was dissolved in freshly distilled THF (3 mL) under nitrogen atmosphere and succinic anhydride (37 mg, 368 μmol) was added. After overnight at 20° C., the solvent was removed under reduced pressure and dissolved in n-hexane. The white precipitate was removed by filtration and the filtrate evaporated to dryness. The residue was purified over silica gel by dichloromethane/methanol (95/5) to give 119 mg (165 μmol, 90% yield) of a colorless oil.