Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6].[C:15]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])([CH3:17])[CH3:16].N1C=CN=C1>CN(C=O)C>[Si:19]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](/[CH:10]=[CH:11]/[CH2:12][O:13][CH3:14])[CH:9]=1)[CH:5]=[O:6])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:21])[CH3:20]
Reactant: COC/C=C/c1cc(O)cc(C=O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COC/C=C/c1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1

Procedure:
3-Hydroxy-5-[(1E)-3-methoxyprop-1-en-1-yl]benzaldehyde (1 eq.) from the previous step and tert-butylchlorodimethylsilane (1 eq.) were combined in DMF (0.5 M). To this solution was then added imidazole (1.5 eq.), and the reaction mixture was stirred at rt for 16 h. The resulting solution was quenched with water and extracted with ether/hexanes (1:1 v/v). The combined organic extracts were washed with brine, dried over MgSO4, and filtered through a plug of SiO2. Concentration of the filtrate in vacuo afforded the title compound as a pale yellow oil.
Reaction SMILES: [O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:8][C:9]([CH3:13])([CH3:12])[CH:10]=O.[NH2:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:8][C:9]([CH3:13])([CH3:12])[CH:10]=[N:14][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)C=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)C=NC(c1ccccc1)c1ccccc1

Procedure:
A 100-mL round-bottomed flask containing a stir bar was charged with Na2SO4 (8.0 g) and CH2Cl2 (40 mL). Trimethylacetaldehyde (8) (7.65 mL, 52 mmol, 1.3 equiv) and aminodiphenylmethane (9) (6.89 mL, 40 mmol, 1.0 equiv) were added sequentially via syringe while stirring. The flask was capped with a plastic stopper, and the mixture was stirred at room temperature. The mixture became cloudy after 5 min. After stirring for 1 h, the solution was decanted into a 200-mL round-bottomed flask, rinsing with CH2Cl2 (4×5 mL) and concentrated to 8-10 mL using a rotary evaporator. The flask was then maintained at 1 torr for 10 min. A 5-cm diameter fritted disk funnel was filled with a 2-cm high layer of silica gel. The funnel was rinsed with a solution of 20:1:0.5 hexanes/Et2O/triethylamine (50 mL) under reduced pressure, followed by a solution of 20:1 hexanes/Et2O (50 mL). The oil prepared above was dissolved in 20:1 hexanes/Et2O (25 mL) and rinsed through the frit into a tared 250-mL round-bottomed flask under reduced pressure, rinsing with 20:1 hexanes/Et2O (4×25 mL). The mixture was concentrated (30 torr→1 torr) to provide a clear, pale yellow oil that solidified into a white solid. The solid was broken up into approximately 1-cm diameter pieces using a spatula, and was maintained at 1 torr for another 15 min to provide N-(2,2-dimethyl propylidene)diphenylmethanamine (2a) as a white solid in approximately 98% 1H-NMR purity. The product was used in the next step without further purification. Yield: 9.93 g (39.6 mmol, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])[CH:7]=[CH:8][CH:9]=1)([O-])=O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:5]=[C:6]([P:10](=[O:17])([O:11][CH2:12][CH3:13])[O:14][CH2:15][CH3:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOP(=O)(OCC)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CCOP(=O)(OCC)c1cccc(N)c1
Yield: 69.8 %

Procedure:
A solution of diethyl (3-nitrophenyl)phosphonate (520 mg, 2.0 mmol) and SnCl2 (1.8 g, 8 mmol) in EtOH (50 mL) was heated at reflux for 12 h. The mixture was then filtered and the filtrate concentrated in vacuo to yield a crude product, which was purified by preparative HPLC to afford 320 mg of desired diethyl (3-aminophenyl)phosphonate (yield: 69%).
Reaction SMILES: Cl.[CH2:2]([C:4]1[CH:5]=[C:6]([NH:16][C:17]([NH:19][CH2:20][C@H:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)=[O:18])[CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[CH3:3].Cl[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)=[O:30]>C(N(CC)CC)C>[CH2:2]([C:4]1[CH:5]=[C:6]([NH:16][C:17]([NH:19][CH2:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][N:23]([CH2:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[O:30])[CH2:22]2)=[O:18])[CH:7]=[C:8]([C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:9]=1)[CH3:3]
Reactant: CCc1cc(NC(=O)NC[C@H]2CCCNC2)cc(-c2nnnn2C)c1
Reactant: O=C(CCl)c1ccc(F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCc1cc(NC(=O)NC[C@@H]2CCCN(CC(=O)c3ccc(F)cc3)C2)cc(-c2nnnn2C)c1
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of (S)-1-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-piperidin-3-ylmethyl-ureahydrochloride (50 with 2-chloro-4′-fluoroacetophenone (27 mg, 158 μmol) and minutes. Additional triethylamine (73 μL, 526 μμmol) and 2-chloro-4′-fluoroacetophenone (ca. 5 mg) were added and stirring was continued for 60 minutes more. The mixture was concentrated under vacuum, and the residue was purified by flash chromatography, eluting with 3% methanol in dichloromethane, containing 0.3% aqueous ammonia, to provide a tan glassy solid (51 mg, 81%). 1H NMR (300 MHz, CDCl3) δ8.02 (m, 3H), 7.70 (s, 1H), 7.59 (s, 1H), 7.13 (m, 3H), 6.64 (bs, 1H), 4.20 (s, 3H), 3.85 (ab, J=18 Hz, 2H), 3.30 (m, 2H), 2.9-2.6 (m, 4H), 2.37 (m, 2H), 2.0-1.6 (m, 5H), 1.25 (t, J=8 Hz, 3H). Mass spec (ES+) m/z 480.4 (M+H+).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:37]=[CH:36][C:23]([CH2:24][N:25]5[CH2:28][CH:27]([C:29]([O:31]C(C)(C)C)=[O:30])[CH2:26]5)=[CH:22][CH:21]=4)[N:16]=3)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO>Cl.O1CCOCC1>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]3[O:19][N:18]=[C:17]([C:20]4[CH:21]=[CH:22][C:23]([CH2:24][N:25]5[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]5)=[CH:36][CH:37]=4)[N:16]=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)C1CN(Cc2ccc(-c3noc(CCC4(c5ccccc5)CCCCC4)n3)cc2)C1
Reaction time: 5 h
Yield: 21 %

Procedure:
The glassy solid tert-butyl 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate was dissolved in 3 mL of 4N HCl in dioxane, and the mixture was stirred for 5 h. The reaction was followed by LC/MS and was evaporated and dried in vacuo. The residue was purified by prep. HPLC (Phenomenex S10 30×100 mm, 40 min gradient time, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.1% TFA; Final solvent: 90% aq. MeOH—0.1% TFA) to give the 1-(4-(5-(2-(1-phenylcyclohexyl)ethyl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylic acid (47.5 mg, yield=21%) as a white solid. LC/MS: m/e 446.17 (M+H)+. 1H NMR (400 MHz, CD3OD): δ ppm 8.1 (d, J=8.28 Hz, 2H), 7.61 (d, J=8.28 Hz, 2H), 7.40-7.46 (m, 2H), 7.32-7.39 (m, 2H), 7.14-7.21 (m, 1H), 4.49 (s, 2H), 4.36 (d, J=7.28 Hz, 4H), 3.66-3.77 (m, 1H), 2.55-2.69 (m, 2H), 2.2-2.33 (m, 2H), 2.04-2.19 (m, 2H), 1.33-1.79 (m, 8H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: ClCCN1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCN2CCCCC2)cc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.5 %

Procedure:
To a solution of 4-hydroxybenzoic acid ethyl ester (5.0 g) in N,N-dimethylformamide (50 ml) were sequentially added potassium carbonate (6.2 g) and 1-(2-chloroethyl)piperidine (8.3 g), and the solution was stirred for 1.5 hours at 60° C. The solution was filtered through celite pad, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to obtain 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (8.3 g). To a solution of 4-(2-piperidin-1-ylethoxy)benzoic acid ethyl ester (34g) dissolved in ethanol (200 ml) was added an aqueous solution of 2N sodium hydroxide (100 ml), and the solution was refluxed for 1 hour. Ethanol was evaporated in vacuo, water was added and stirred, the solid that was precipitated by adding 2N hydrochloric acid (180 ml) was filtered to provide the title compound (28.2 g).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[O:7]2)[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](Cl)=[O:30])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([N:1]2[CH2:6][CH2:5][C:4]3([CH2:10][C:9]4[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=4[O:7]3)[CH2:3][CH2:2]2)=[O:30])=[CH:24][CH:23]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: c1ccc2c(c1)CC1(CCNCC1)O2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(CC(=O)N2CCC3(CC2)Cc2ccccc2O3)cc1

Procedure:
A stirred suspension of 3.5 g of 2,3-dihydrospiro[benzofuran-2,4'-piperidine], Example 7 and 7.5 g of sodium bicarbonate in 40 ml of chloroform are reacted with a solution of 4.4 g of 4-methoxyphenylacetyl chloride in 10 ml of chloroform and thereafter treated according to the procedure of Example 13 to provide a yellow oil. The oil is chromatographed on a silica column with a 3% methyl alcohol in chloroform eluant to provide a white solid which is recrystallized thrice from hexane to provide the product, 2,3-dihydro-1'-[(4-methoxyphenyl)acetyl]spiro[benzofuran-2,4'-piperidine], mp 87°-88° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1.S(O)(O)(=O)=O.CS[C:19](=[NH:21])[NH2:20]>[OH-].[Na+]>[C:19]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])[CH2:3][CH2:2]1)(=[NH:20])[NH2:21]
Reactant: O=C(O)CCC1CCNCC1
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: N=C(N)N1CCC(CCC(=O)O)CC1
Reaction time: 8 h
Yield: 102.5 %

Procedure:
500 mg of 4-piperidinepropionic acid are added at 2° C. to a solution of 553 mg of S-methyl-isothiourea sulphate in 3.2 ml of 2N sodium hydroxide solution. After leaving to stand at room temperature overnight the separated crystals are filtered off, washed with water, acetone and ether and dried. There are obtained 600 mg of 1-amidino-4-piperidinepropionic acid, m.p. above 275° C.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:11][CH:10]=2)[C:5]([C:28]2[CH:47]=[CH:46][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]([O:36]CC)=[O:35])=[CH:30][CH:29]=2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>C1COCC1.CO>[CH3:1][C:2]1[N:6]([CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:13][CH:14]=2)[C:5]([C:28]2[CH:29]=[CH:30][C:31]([O:32][C@H:33]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]([OH:36])=[O:35])=[CH:46][CH:47]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H](Cc1ccccc1)Oc1ccc(-c2ccc(C)n2CCc2ccc(OCCCCCCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)n1CCc1ccc(OCCCCCCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[5-methyl-1-{2-[4-(6-phenylhexyloxy)phenyl]ethyl}-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (760 mg, 1.21 mmol) in THF (30 ml) and methanol (15 ml) was added 1N aqueous potassium hydroxide solution (7 ml, 7 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate anhydride, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 561 mg (yield: 77.1%)
Reaction SMILES: [OH:1][C:2]([C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[O:12][C:13]1[C:18]([NH:19][C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH2:6][CH:7]=[CH2:8])[CH2:3][CH:4]=[CH2:5].S(=O)(=O)(O)O.[C:42](=O)(O)[O-].[Na+]>CO>[CH3:42][O:1][C:2]([C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][CH:36]=1)[O:12][C:13]1[C:18]([NH:19][C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=2)=[O:21])=[CH:17][CH:16]=[CH:15][N:14]=1)([CH2:6][CH:7]=[CH2:8])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCC(O)(CC=C)c1cccc(Oc2ncccc2NC(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: C=CCC(CC=C)(OC)c1cccc(Oc2ncccc2NC(=O)Nc2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C

Procedure:
To a solution of Example 640 (120 mg, 0.24 mmol) in dry methanol (15 mL) was added concentrated sulfuric acid (2 mL) at rt. The mixture was heated to 100° C. for 72 h and cooled down to rt. A saturated solution of sodium bicarbonate was slowly added and the mixture was extracted with dichloromethane. Evaporation afforded a residue which was purified by reverse phase preparative HPLC. (M+H)+=514. 1H NMR (400 MHz, DMSO-d6) δppm 2.62 (m, 4 H), 3.08 (s, 3H), 5.03 (m, 4H), 5.55 (m, 2H), 7.31 (m, 7H), 7.57 (d, 2H, J=9.1 Hz), 7.70 (dd, J=5.0, 1.7 Hz, 1H), 8.55 (dd, J=7.8, 1.5 Hz, 1H), 8.72 (s, 1H), 9.56 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH:19]([CH3:23])[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][N:16]=[CH:15]1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:13][C:6]=1[C:7]([NH:22][CH2:21][CH2:20][CH:19]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH3:23])=[O:9]
Reactant: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CC(CCN)n1ccnc1
Product: Cc1ccc(N)c(C(=O)NCCC(C)n2ccnc2)c1

Procedure:
When 5-methylisatoic anhydride was reacted with 3-(1H-imidazol-1-yl)butanamine by the procedure of Example 11, the above compound, mp 128°-130° C., was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[NH2:16])[CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[I:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[CH3:27])[C:21](O)=O.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CC(O)=O>[I:17][C:18]1[CH:19]=[C:20]([C:21]2[NH:1][C:2]3[CH:3]=[C:4]([CH2:5][N:6]4[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]4)[CH:13]=[CH:14][C:15]=3[N:16]=2)[CH:24]=[CH:25][C:26]=1[CH3:27]
Reactant: CN1CCN(Cc2ccc(N)c(N)c2)CC1
Reactant: Cc1ccc(C(=O)O)cc1I
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 30.2 %

Procedure:
A mixture of 1-(3,4-diaminobenzyl)-4-methylpiperazine (10 mmol), 3-iodo-4-methylbenzoic acid (2.6 g, 10 mmol), EDCI (11 mmol), and HOBt (11 mmol) in dry DMF (25 mL) was stirred at ambient temperature for 24 hrs. The mixture was then evaporated in vacuo and the crude residue was dissolved in CH2Cl2 (100 mL) was washed with water (100 mL), brine (100 mL) and then dried by Na2SO4, filtered and concentrated. The residue obtained was dissolved in AcOH (30 mL) and heated at reflux for 3 hrs. The reaction mixture was evaporated in vacuo and the residue was purified by silica gel chromatography (eluent: 10% MeOH in CH2Cl2, MeOH was added 0.5% Et3N) to give a yellow solid (1.35 g, 30.3%). 1H NMR (300 MHz, CDCl3) δ: 8.50 (1H, s), 7.94-7.97 (1H, d, J=9.0 Hz), 7.53-7.56 (1H, d, J=9.0 Hz), 7.52-7.55 (1H, d, J=9.0 Hz), 7.30 (1H, s), 7.20-7.23 (1H, d, J=9.0 Hz), 3.60 (2H, s), 2.54 (8H, brs), 2.45 (3H, s), 2.32 (3H, s).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>C(Cl)Cl.O1CCOCC1>[ClH:36].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([NH:23][C:24]2[S:25][CH:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=2)=[CH:11][N:10]=1
Reactant: COc1cc2c(Nc3nc(-c4ccccc4)cs3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc2c(Nc3nc(-c4ccccc4)cs3)cnc(CN)c2cc1OC
Temperature: 25 °C
Reaction time: 21 h
Yield: 71 %

Procedure:
[6,7-Dimethoxy-4-(4-phenyl-thiazol-2-ylamino)isoquinolin-1-ylmethyl]carbamic acid tert-butyl ester (44 mg, 0.0853 mmol) in CH2Cl2 (1 mL) was added a 4.0 M HCl solution in dioxane (0.21 mL) at room temp. After the reaction mixture was stirred at room temperature for 21 h, the suspension was filtered. The yellow solid was further dried in vacuo to give (1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-(4-phenyl-thiazol-2-yl)amine hydrochloride salt (26.1 mg; 71%). 1H-NMR (D2O): δ, 8.82 (s, 1H), 7.09-7.00 (m, 6H), 6.69 (s, 1H), 6.51 (s, 1H), 4.43 (s, 2H), 3.70 (s, 3H), 3.59 (s, 3H); MS: calculated for C21H21N4O2S (M−Cl) 393.0; found: 393.0.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=1)[C:11]([NH:13][C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)=[O:12].Cl[C:29]1[C:34]([Cl:35])=[CH:33][C:32]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:31][N:30]=1>C(#N)C>[Cl:35][C:34]1[C:29]([O:7][C:8]2[CH:9]=[C:10]([CH:21]=[C:22]([O:24][CH:25]([CH3:27])[CH3:26])[CH:23]=2)[C:11]([NH:13][C:14]2[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=2)=[O:12])=[N:30][CH:31]=[C:32]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])[CH:33]=1
Reactant: Cc1cnc(NC(=O)c2cc(O)cc(OC(C)C)c2)cn1
Reactant: O=C(c1cnc(Cl)c(Cl)c1)N1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1cnc(NC(=O)c2cc(Oc3ncc(C(=O)N4CCCC4)cc3Cl)cc(OC(C)C)c2)cn1
Temperature: 120 °C
Yield: 73.1 %

Procedure:
Cesium carbonate (782 mg, 2.4 mmol) was added to a solution of 3-hydroxy-5-[(1-methylethyl)oxy]-N-(5-methylpyrazin-2-yl)benzamide (230 mg, 0.8 mmol) and 2,3-dichloro-5-(pyrrolidin-1-ylcarbonyl)pyridine (234 mg, 0.96 mmol) in acetonitrile (5 mL) and the stirred mixture heated in a microwave reactor at 120° C. for 2 hours. The mixture was cooled to RT and the acetonitrile evaporated in vacuo. The residue was partitioned between water (25 mL) and ethyl acetate (50 mL), the organic layer washed with brine, dried (MgSO4) and evaporated to a residue which was chromatographed on silica, eluting with 75% ethyl acetate in isohexane, to give the desired compound (290 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.[O:15]1[CH2:19][C:18](=[O:20])[NH:17][C:16]1=[O:21].CN(C)C(N(C)C)=N>O1CCCC1>[N:6]1([CH2:5][CH2:4][CH2:3][CH2:2][N:17]2[C:18](=[O:20])[CH2:19][O:15][C:16]2=[O:21])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: BrCCCCn1ccc2ccccc21
Reactant: O=C1COC(=O)N1
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: O=C1COC(=O)N1CCCCn1ccc2ccccc21

Procedure:
A solution of 3 g (11.90 mmol) of 1-(4-bromobutyl)-1H-indole, prepared in stage 2.1., of 2.41 g (23.80 mmol) of 1,3-oxazolidin-2,4-dione (J. Med. Chem., 1991, 34, 1538-1544) and of 2.74 g (23.80 mmol) of 1,1,3,3-tetramethylguanidine in 30 ml of tetrahydrofuran is brought to reflux for 14 hours under an inert atmosphere.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].CI.[C:15](OCC)(=O)C>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[CH3:15]
Reactant: Brc1cccc2[nH]ccc12
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Br)cccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 4-bromoindole (5 g, TCI) in DMF (30 ml) was added with 60% sodium hydride (1.14 g) under ice cooling and stirred for 10 minutes. The mixture was added dropwise with methyl iodide (3.18 ml, TCI), stirred for 10 minutes, then warmed to room temperature and further stirred for 30 minutes. The reaction mixture was poured into ice water and added with ethyl acetate (300 ml) for extraction. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, saturated aqueous ammonium chloride and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=10:1) to obtain the title compound (Intermediate 51, 4.95 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1.[N+:19]([O-])([OH:21])=[O:20].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][CH:2]([CH3:18])[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[C:13]([N+:19]([O-:21])=[O:20])[CH:12]=[CH:11][C:10]=3[N:9]=[C:8]([NH2:17])[C:7]=2[N:6]=[CH:5]1
Reactant: CC(C)Cn1cnc2c(N)nc3ccccc3c21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CC(C)Cn1cnc2c(N)nc3ccc([N+](=O)[O-])cc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (28.3 g, 0.118 mol) in concentrated sulfuric acid (150 mL) was cooled to 5° C. A solution of 70% nitric acid (8.4 mL, 0.130 mol) in sulfuric acid (30 mL) was added in portions over a period of one hour. The reaction temperature was maintained below 10° C. The solution was allowed to warm to ambient temperature, stirred for two hours, and then poured into 500 g of ice. The resulting solution was made basic with the addition of ammonium hydroxide while keeping the solution cold. A precipitate formed, was isolated by filtration, washed with water, and dried to provide 1-(2-methylpropyl)-8-nitro-1H-imidazo[4,5-c]quinolin-4-amine as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:10]([NH:12][C@H:13]([C:14](=[O:15])[NH:41][CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Reactant: NCCc1ccccn1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCCc1ccccn1

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid and 2-(2-aminoethyl)pyridine (35 mg) according to Method B to give the title compound (56 mg). 1H-NMR (400 MHz, CD3OD) d 8.52 (d, J=4.6 Hz, 1H), 7.97 (m, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.46-7.17 (m, 8H), 7.03 (d, J=8.6 Hz, 1H), 4.78 (s, 2H), 4.46 (m, 1H), 4.23 (dd, J=5.2 Hz, J=9.4 Hz, 1H), 3.41 (m, 1H), 2.74 (dd, J=8.9 Hz, J=13.6 Hz, 1H), 1.35 (s, 9H); HRMS m/z 634.2651 (calc. of monoisotopic mass for C33H38N4O9 gives 634.2639).