Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]3)=[O:11])[CH:8]=[CH:9][C:2]=12.[H-].[Na+].[CH3:21]I>CN(C)C=O.O>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]([N:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:21])[CH2:14][CH2:13]3)=[O:11])[CH:8]=[CH:9][C:2]=12
Reactant: CI
Reactant: O=C(c1ccc2nonc2c1)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC1CCN(C(=O)c2ccc3nonc3c2)CC1
Reaction time: 3 h
Yield: 30.3 %

Procedure:
1-(Benzofurazan-5-ylcarbonyl)-4-hydroxypiperidine (840 mg, 3.40 mmol) was dissolved in dimethylformamide (12 mL) and treated with 60% sodium hydride (150 mg, 3.75 mmol) for 30 minutes. Methyl iodide (650 mg, 4.54 mmol) was added, and, after 3 hours at room temperature, the reaction mixture was further treated with the same quantities of sodium hydride and methyl iodide as above and allowed to stand for 16 hr. The reaction solution was diluted with water and product was extracted into ethyl acetate. The organic solution was washed with water and saturated sodium chloride and dried over MgSO4. The crude product was purified by decolorization with charcoal in ethanol, twice chromatographed on silica gel by elution with hexane/ethyl acetate (2:1), and finally by kugelrohr distillation at 125-140° C. to yield 1-(benzofurazan-5-ylcarbonyl)-4-methoxypiperidine (269 mg, 30%) as a pale yellow oil. IR: 1639, 1440, 1274, 1101, and 1089 cm−1. 1H NMR (500 MHz): δ 7.91 (1H, dm, J=9.2 Hz), 7.85 (1H, t, J=1.1 Hz), 7.43 (1H, dd, J=9.2 and 1.2 Hz), 3.90-4.05 (1H, m), 3.55-3.72 (2H, m), 3.53 (1H, sept, J=3.5 Hz), 3.38 (3H, s), 3.20-3.35 (1H, m), 1.90-2.02 (1H, m), 1.65-1.85 (2H, m), and −1.65 ppm (1H, m).
Reaction SMILES: [OH:1][C@H:2]([C@@H:14]([NH:19][C:20](=[O:43])[O:21][C@H:22]([CH2:27][N:28]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[N:29]1)[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:7])=[O:6].O[C@@H]([C@@H](NC(=O)O[C@H](CN1C=CC(C2C=CC(C(F)(F)F)=CC=2)=N1)C(C)(C)C)CCCC)CNS(C1C=CC=CN=1)(=O)=O>>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:5]([NH:4][CH2:3][C:2]([C@@H:14]([NH:19][C:20](=[O:43])[O:21][C@H:22]([CH2:27][N:28]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=2)=[N:29]1)[C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:15][CH2:16][CH2:17][CH3:18])=[O:1])(=[O:6])=[O:7]
Reactant: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Product: CCCC[C@H](NC(=O)O[C@H](Cn1ccc(-c2ccc(C(F)(F)F)cc2)n1)C(C)(C)C)C(=O)CNS(=O)(=O)c1ccccn1

Procedure:
(1S)-2,2-Dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{[(2-pyridinylsulfonyl)amino]acetyl}pentylcarbamate was prepared as in example 3g (27% yield) except that (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (3S)-1-(1,3-benzothiazol-2-yl)-4,4-dimethylpyrrolidinyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate were substituted for (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-2,2-dimethyl-1-({3-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. 1H-NMR (300 MHz, DMSO-d6): δ 8.67 (d, J=6 Hz, 1H), 8.13–8.03 (m, 2H), 7.88 (d, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 2H), 7.65 (dd, J=7 Hz, J=5 Hz, 1H), 7.45 (d, J=8 Hz, 1H), 7.27 (t, J=8 Hz, 1H), 7.04 (t, J=8 Hz, 1H), 4.89 (d, J=4 Hz, 1H), 4.15-3.95 (m, 5H), 3.53–3.40 under DMSO peak (m, 2H), 1.60 (m, 1H), 1.42 (m, 1H), 1.23 (m, 4H), 1.09 (s, 3H), 1.06 (s, 3H), 0.82 (m, 3H); ES-LCMS m/z 560 (M+H); HRMS C26H33N5O5S2 m/z 560.2001 (M+Na)+Cal; 560.2010 (M+Na)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:27][C:28]1([CH3:35])[O:32][CH:31]([CH2:33]O)[CH2:30][O:29]1>ClCCl.O>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([O:9][CH2:33][CH:31]1[CH2:30][O:29][C:28]([CH3:35])([CH3:27])[O:32]1)=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: CC1(C)OCC(CO)O1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccccc1C(=O)OCC1COC(C)(C)O1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The solution from 2-acetoxybenzoic acid (10.0 g, 55.5 mmol) in dichloromethane (200 ml) is treated with triethylamine (7.7 ml, 55.5 mmol), cooled to 0° C., treated dropwise with ethyl chloroformate (5.3 ml, 55.5 mmol), stirred at 0° C. for 1 h and filtered. The filtrate is added at room temperature to a solution of (±)-2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane (7.33 g, 55.5 mmol) and triethylamine (50 ml) in dichloromethane (100 ml). After 4 h, water (50 ml) is added and the mixture is stirred. The organic phase is washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and water, dried over magnesium sulphate and concentrated. The residue is purified by column chromatography on silica gel 60 (hexane/ethyl acetate =15/1). Yield: 8.4 g.
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][C:5](=[O:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O.[Na].[OH-].[K+]>>[CH3:1][CH:2]([CH3:14])[CH2:3][CH2:4][C:5](=[O:13])[C:6]([OH:8])=[O:7]
Reactant: CC(C)CCC(=O)C(=O)OC(C)(C)C
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CCC(=O)C(=O)O

Procedure:
t-Butyl 5-methyl-2-oxohexanoate is readily hydrolyzed under suitably mild conditions at room temperature (i.e., 25°-30° C.). Suitable reactions include hydrolysis directly to the acid form using trifluoracetic acid [reaction (3)] or hydrolysis with dilute bases such as sodium or potassium hydroxide followed by acidification with dilute mineral acids such as hydrochloric, sulfuric, or nitric acids. ##EQU5## Trifluoroacetic acid can be used as a solvent for the reaction shown (3). When trifluoroacetic acid is the hydrolyzing reagent, this step can be accomplished before the hydrogenation step. The acid is recovered by volatization of the trifluoroacetic acid. If hydrolysis is done with dilute base, followed by acidification with mineral acid, the acid is then extracted in the same manner as described for the extraction of the ester in step (a).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12]C)[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH2:15]2)[CH:3]=1.B(Br)(Br)Br>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([N:14]2[CH2:20][CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[CH2:15]2)[CH:3]=1
Reactant: COc1ccc2nc(N3CCCc4ccccc4C3)cc(Cl)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc2nc(N3CCCc4ccccc4C3)cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a solution of 2-(4-chloro-6-methoxy-quinolin-2-yl)-2,3,4,5-tetrahydro-1H-2-benzazepine (800 mg, 2.37 mmol) in 15 mL of dichloromethane was added slowly a solution of boron tribromide (0.558 mL, 5.9 mmol). The resulting mixture was stirred at room temperature for 30 minutes, followed by stirring at 40° C. for 2 hours. After cooled to room temperature, the reaction mixture was carefully quenched with sodium bicarbonate (20 mL), and then extracted with dichloromethane (10 mL×3). The organic layers were combined and washed with brine (20 ml), then dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica gel (ethyl acetate/hexane, 1:5) to give 500 mg of product (yield was 65%).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([N:7]=[C:8](NC#N)[NH:9][C@@H:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])=[CH:3][CH:2]=1.Cl.[O:39]1CCOCC1.N(C1C=CC(C2C=CC=CC=2)=CC=1)=C=O>C(Cl)Cl.CCOC(C)=O>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:39])[NH:9][C@@H:10]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:11]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:12])=[CH:3][CH:2]=1
Reactant: C1COCCO1
Reactant: N#CNC(=Nc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCCN1CCCC1
Agent: Cl
Agent: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2ccccc2)cc1)N[C@@H](Cc1ccccc1)C(=O)NCCCN1CCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a solution of [(S)-2-phenyl-1-(3-pyrrolidin-1-yl-propylcarbamoyl)-ethyl]-carbamic acid tert-butyl ester (Example 1, step A) (0.083 g, 0.22 mmol) in CH2Cl2 (3 mL), a 4 M solution of HCl in dioxane (0.55 mL, 2.2 mmol) was added, and the mixture was stirred for 3 h at rt. The solvents were removed. The residue was treated with CH2Cl2, and the solvent was removed again under reduced pressure. The residue was dissolved in CH2Cl2 (3 mL), and at 0° C., TEA (0.56 g, 0.55 mmol) was added followed by 4-isocyanato-biphenyl (0.052 g, 0.264 mmol). The mixture was warmed to rt over a period of 2 h and was then diluted with EtOAc (100 mL). The organic layer was washed with saturated NaHCO3 (25 mL) and brine (25 mL), and was dried (Na2SO4). The solvent was removed, and the residue was purified by flash column chromatography using 0–20% MeOH (1% NH4OH)/CH2Cl2 to afford 0.08 g (77%) of the desired product. MS (electrospray): mass calculated for C29H34N4O2, 470.27; m/z found, 471.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.56–7.48 (m, 4H), 7.42–7.36 (m, 4H), 7.33–7.22 (m, 6H), 4.47 (t, J=7.1 Hz, 1H), 3.20–3.16 (m, 2H), 3.07 (dd, J=13.6, 7.1 Hz, 1H), 2.99 (dd, J=13.6, 7.1 Hz 1H), 2.51 (br m, 4H), 2.42 (m, 2H), 1.77 (br m, 4H), 1.65 (m, 2H).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:5][CH2:4]C[CH2:2]1.[O:23]=[S:24]1(=[O:30])CCC(N)C1>>[O:23]=[S:24]1(=[O:30])[CH2:4][CH2:5][CH:1]([NH:6][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH2:2]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(NC2CCS(=O)(=O)C2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (1,1-dioxidotetrahydro-3-thienyl)amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.91 (s, 3H), 2.22 (m, 1H), 2.29 (s, 3H), 2.20-2.26 (m, 1H), 2.80-2.91 (m, 1H), 2.95 (bs, 1H), 3.05-3.15 (m, 1H), 3.18-3.24 (m, 1H), 4.69 (bs, 2H), 4.80-4.89 (m, 2H), 5.92 (bs, 1H), 7.17 (t, J=3.9 Hz, 1H), 7.34 (d, J=5.8 Hz, 1H), 7.64 (t, J=6.4 Hz, 1H), 8.57 (d, J=2.8 Hz, 1H); MS (ESI) m/z 348.8 (M+1)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11](O)=O)=[CH:6][CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[C:50]([CH:58]=[CH:59][C:60]=1[NH:61][CH2:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])=[O:52]>>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[N:61]([CH2:62][CH2:63][CH:64]([CH3:66])[CH3:65])[C:60]3[CH:59]=[CH:58][C:50]([C:51]([N:53]([CH2:56][CH3:57])[CH2:54][CH3:55])=[O:52])=[CH:49][C:48]=3[N:47]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(CC(=O)O)cc1
Reactant: CCN(CC)C(=O)c1ccc(NCCC(C)C)c(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2CCC(C)C)cc1
Yield: 90 %

Procedure:
Following general procedure 13B, (4-ethoxyphenyl)acetic acid (0.110 g, 0.612 mmol), HATU (0.233 g, 0.611 mmol), DIPEA (0.15 m, 0.86 mmol), and 3-amino-N,N-diethyl-4-(isopentylamino)benzamide (0.154 g, 0.556 mmol) were combined. The crude product was purified by column chromatography (19:1 CH2Cl2:MeOH) to provide the title compound (0.211 g, 90%). 1H-NMR (CD3OD): δ 7.67 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.30 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 7.16 (d, J=9.2 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.28 (s, 2H), 4.12 (m, 2H), 3.98 (q, J=7.6 Hz, 2H), 3.57 (br s, 2H), 3.34 (br s, 2H), 1.62–1.48 (m, 1H), 1.34 (t, J=7.6 Hz, 3H), 1.36–1.07 (overlapping 2×br s and m, 8H), 0.88 (d, J=6.8 Hz, 6H). MS (ES) (M+H)+=422. Anal. Calcd for C26H35N3O2.1.7 TFA.0.2H2O: C, 57.05; H, 6.04; N, 6.79. Found: C, 57.11; H, 6.09; N, 6.69.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:2].[C:10]([CH:18]([C:24](=O)[CH3:25])[CH2:19][C:20]([O:22][CH3:23])=[O:21])(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C>[CH3:25][C:24]1[C:18]([CH2:19][C:20]([O:22][CH3:23])=[O:21])=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:1]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:8]=2[CH3:9])[N:2]=1
Reactant: Cc1ccncc1NN
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccccc1
Solvent: CCO
Product: COC(=O)Cc1c(C)nn(-c2cnccc2C)c1-c1ccccc1

Procedure:
0.315 g (2.049 mmol) of 3-hydrazino-4-methylpyridine in 5.00 ml of ethanol was added to 0.400 g (1.708 mmol) of methyl 3-benzoyl-4-oxopentanoate, and the mixture was stirred under reflux for 8 h. The solvent was removed under reduced pressure giving, after chromatography of the residue, 0.305 g (47% of theory) of a reddish wax-like solid. 1H-NMR (CDCl3): see Table 2.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:12][C:13]([C:15]1([CH2:35][O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:19][N:18]=[C:17]([C@@H:20]([NH:24][C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH:21]([CH3:23])[CH3:22])[CH2:16]1)=[O:14])[C:9](=[O:11])[CH3:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:28]([O:27][C:25]([NH:24][C@H:20]([C:17]1[CH2:16][C:15]([CH2:35][O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:13]([NH:12][C@H:8]([C:9](=[O:11])[CH3:10])[CH2:7][C:6]([OH:43])=[O:5])=[O:14])[O:19][N:18]=1)[CH:21]([CH3:22])[CH3:23])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)C1(COc2ccccc2)CC([C@@H](NC(=O)OCc2ccccc2)C(C)C)=NO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)[C@H](CC(=O)O)NC(=O)C1(COc2ccccc2)CC([C@@H](NC(=O)OCc2ccccc2)C(C)C)=NO1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (3S)-3-{3-[(1S)-1-phenylmethyloxycarbonylamino-2-methyl-propyl]-5-phenoxymethyl-4,5-dihydro-isoxazole-5-carbonyl-amino}-4-keto-pentanoic acid t-butyl ester (less polar diastereomer) (44 mg) in CH2Cl2 (2 mL) at 0° C. was treated with TFA (1 mL). The reaction mixture was stirred for 2 h while slowly warming to room temperature. Concentration gave the title compound (compound 10, quantitative).
Reaction SMILES: C1(S(O)=O)C=CC=CC=1.[Na].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C([NH:29][C:30]1[C:31]2[CH:61]=[CH:60][CH:59]=[CH:58][C:32]=2[C:33]2[CH:34]([CH2:56][Cl:57])[CH2:35][N:36]([C:39]([C:41]3[NH:42][C:43]4[C:48]([CH:49]=3)=[CH:47][C:46]([O:50][CH3:51])=[C:45]([O:52][CH3:53])[C:44]=4[O:54][CH3:55])=[O:40])[C:37]=2[CH:38]=1)C=C>ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:57][CH2:56][CH:34]1[C:33]2[C:32]3[CH:58]=[CH:59][CH:60]=[CH:61][C:31]=3[C:30]([NH2:29])=[CH:38][C:37]=2[N:36]([C:39]([C:41]2[NH:42][C:43]3[C:48]([CH:49]=2)=[CH:47][C:46]([O:50][CH3:51])=[C:45]([O:52][CH3:53])[C:44]=3[O:54][CH3:55])=[O:40])[CH2:35]1
Reactant: C=CCNc1cc2c(c3ccccc13)C(CCl)CN2C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=S(O)c1ccccc1
Solvent: ClCCl
Product: COc1cc2cc(C(=O)N3CC(CCl)c4c3cc(N)c3ccccc43)[nH]c2c(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
Benzenesulfinic acid, sodium salt (25 mg, 0.15 mmol) and camphorsulfonic acid (40 mg, 0.17 mmol) were added to a solution of 10a (30 mg, 0.059 mmol) in dichloromethane (5 mL). Pd(Ph3P)4 (5 mg, 0.004 mmol) was added and the reaction mixture was stirred at an ambient temperature for 30 min. The mixture was purified directly via a silica gel column. Elution with EtOAc/petroleum ether (1:1) gave 1-(chloromethyl)-3-[(5,6,7-trimethoxy-1H-indol-2-yl)carbonyl]-1,2-dihydro-3H-benzo[e]indol-5-amine (11a) (22 mg, 80%), spectroscopically identical to an authentic sample (Atwell et al., J. Org Chem., 1998, 63, 9414).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:32])[NH:6][C:7]([C:15]1[N:20]=[C:19]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:28]([O:30]C)=[O:29])[CH2:23][CH2:22]3)[CH:18]=[CH:17][CH:16]=1)=[N:8]2.[OH-].[Li+]>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:32])[NH:6][C:7]([C:15]1[N:20]=[C:19]([N:21]3[CH2:22][CH2:23][N:24]([CH2:27][C:28]([OH:30])=[O:29])[CH2:25][CH2:26]3)[CH:18]=[CH:17][CH:16]=1)=[N:8]2
Reactant: COC(=O)CN1CCN(c2cccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(CC(=O)O)CC4)n3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of methyl 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetate (0.156 g, 0.35 mmol) in THF (10 mL), water (5 mL) and methanol (3 mL) was added lithium hydroxide (0.043 g, 1.77 mmol). The reaction was stirred for 2 h at rt. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (5 mL) and acidified with 1N HCl to pH 4.5-5.0. The precipitated solids were collected by filtration, washed with water and dried under high vacuum to give 2-(4-(6-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)pyridin-2-yl)piperazin-1-yl)acetic acid (0.135 g, 91%) as a yellow solid: mp 225° C. dec.; 1H NMR (400 MHz, DMSO-d6) δ 11.08 (s, 1H), 7.72-7.79 (m, 1H), 7.67-7.72 (m, 1H), 7.07 (d, J=8.59 Hz, 1H), 6.78 (d, J=1.56 Hz 1H), 6.58 (d, J=1.56 Hz, 1H) 3.91 (s, 3H), 3.86 (s, 3H), 3.63-3.74 (m, 4H), 3.23 (s, 2H), 2.65-2.74 (m, 4H); ESI MS m/z 426 [M+H]+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([CH2:8][NH:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:12][CH3:13])[CH2:6][CH3:7].[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([N:9]([CH2:8][CH:5]([CH2:6][CH3:7])[CH2:4][CH2:3][CH2:2][CH3:1])[CH2:10][CH:11]([CH2:12][CH3:13])[CH2:14][CH2:15][CH2:16][CH3:17])=[O:23]
Reactant: O=C(Cl)CCCCl
Reactant: CCCCC(CC)CNCC(CC)CCCC
Product: CCCCC(CC)CN(CC(CC)CCCC)C(=O)CCCCl

Procedure:
Step A is conducted starting from 2,2′-diethylhexylamine and 4-chlorobutanoyl chloride and leads to 4-chloro-N,N-bis(2-ethylhexyl)butanamide (Yield: quantitative) for which the 1H and 13C NMR characterisations give:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH:7]([NH2:13])[C:8]2([CH3:12])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:16][C:17]1[C:20](=[O:21])[C:19](=O)[C:18]=1[NH:23][C:24]1[C:25]([OH:35])=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([N:29]([CH3:31])[CH3:30])=[O:28])C>CO>[OH:35][C:25]1[C:24]([NH:23][C:18]2[C:17](=[O:16])[C:20](=[O:21])[C:19]=2[NH:13][CH:7]([C:5]2[O:6][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:8]2([CH3:12])[CH2:9][O:10][CH2:11]2)=[CH:34][CH:33]=[C:32]2[C:26]=1[C:27](=[O:28])[N:29]([CH3:31])[CH2:30]2
Reactant: Cc1ccc(C(N)C2(C)COC2)o1
Reactant: CCOc1c(Nc2cccc(C(=O)N(C)C)c2O)c(=O)c1=O
Solvent: CO
Product: Cc1ccc(C(Nc2c(Nc3ccc4c(c3O)C(=O)N(C)C4)c(=O)c2=O)C2(C)COC2)o1
Temperature: 55 °C
Yield: 4 %

Procedure:
287 mg (1.58 mmol) of C-(5-methylfuran-2-yl)-C-(3-methyloxetan-3-yl)methylamine in 3 ml of methanol were added to a suspension of 235 mg (0.78 mmol) of 3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)-2-hydroxy-N,N-dimethylbenzamide in 20 ml of methanol at 55° C. The reaction medium was heated at 55° C. for 24 hours and then concentrated to dryness. The residue was chromatographed on silica gel (40 g prepacked column, 30 ml/min, 100% dichloromethane then 4% of methanol). A residue of 130 mg was obtained and was purified by preparative TLC (eluent: 50/50/1 ethyl acetate/acetone/water). 52 mg were obtained and then precipitated from dimethyl sulfoxide and filtered off 15 mg of product were obtained in the form of a white solid. Yield=4%, HPLC=98.56%
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]1[C:21]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([O:46][CH2:47][CH3:48])=[C:28]([C:30]2[NH:35][C:34](=[O:36])[C:33]3=[C:37]([CH3:45])[N:38]=[C:39]([CH:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)[N:32]3[N:31]=2)[CH:29]=1)=[O:22])=O)(C)(C)C.FC(F)(F)C(O)=O>>[CH2:47]([O:46][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([CH:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)=[O:22])=[CH:29][C:28]=1[C:30]1[NH:35][C:34](=[O:36])[C:33]2=[C:37]([CH3:45])[N:38]=[C:39]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[N:32]2[N:31]=1)[CH3:48]
Reactant: CCOc1ccc(NC(=O)C2CN(C(=O)OC(C)(C)C)CCN2C(=O)OC(C)(C)C)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(NC(=O)C2CNCCN2)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
132 mg (0.198 mmol) of the compound from example 48 are treated with 5 ml of trifluoroacetic acid for 90 minutes; the solution is then concentrated, dichloromethane and 10% strength NaHCO3 solution are added to the residue and the organic phase is dried and concentrated under reduced pressure.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH:21]C(=O)OC(C)(C)C)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].[ClH:29]>O1CCOCC1>[ClH:29].[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][CH2:20][NH2:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2cnc3ccccc3c2n1CCCN
Temperature: 25 °C

Procedure:
tert-butyl 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylcarbamate (˜-80 g) was dissolved in 1,4-dioxane (400 mL) with gentle heating. Hydrochloric acid (55 mL of 4.0 M in 1,4-dioxane) was added in a single portion and the reaction was heated to reflux. The reaction was monitored by HPLC. Additional acid (150-200 mL) was added and the reaction mixture was refluxed until the reaction was complete. The reaction mixture was cooled to ambient temperature. A solid was isolated by filtration to give ˜72 g of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine hydrochloride. This material was combined with that from a previous experiment and then dissolved in water (400 mL). The solution was neutralized with solid potassium carbonate. At pH 7 a solid precipitated. The solid was isolated by filtration and then dissolved in water (1500 mL). The pH was adjusted to pH 10 with solid potassium carbonate. The solution was extracted with chloroform until HPLC analysis showed that no amine remained in the aqueous layer. The organic layers were combined and then concentrated under reduced pressure to provide 45 g of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6](N)[CH:5]=1.C(I)[I:20].[N+]([O-])([O-])=O>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:20])[CH:5]=1
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cn2)c1
Reactant: ICI
Agent: O=[N+]([O-])[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
3-Amino-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamy nitrate using the procedure of step 5 of preparation 5, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.