Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14](O)=[O:15].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1cccnc1)c1cc(Br)ccc1OCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat pyridin-3-amine (79 mg, 0.84 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 87; 200 mg, 0.56 mmol), EDC (213 mg, 1.11 mmol) and HOBT (170 mg, 1.11 mmol) in DMF (3 ml) at room temperature. The reaction mixture was stirred at 25° C. overnight. Water (25 ml) was added and the solid was filtered, washed with water (15 ml), and dried in vacuo. The residue was further purified with Prep-TLC (eluate: dichloromethane:methanol=25:1) to yield the title compound as a white solid. 76 mg.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9](=[O:43])[CH2:10][C:11]1[CH:42]=[CH:41][CH:40]=[CH:39][C:12]=1[CH2:13][CH2:14][C:15]1[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH:31]C(=O)OC(C)(C)C)[CH3:30])=[CH:25][CH:24]=2)[N:16]=1>C(Cl)Cl>[NH2:31][CH:29]([C:26]1[CH:27]=[CH:28][C:23]([NH:22][C:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[CH:39]=[CH:40][CH:41]=[CH:42][C:11]=3[CH2:10][C:9]([NH2:8])=[O:43])[C:20]([CH3:21])=[CH:19][N:18]=2)=[CH:24][CH:25]=1)[CH3:30]
Reactant: Cc1cnc(Nc2ccc(C(C)NC(=O)OC(C)(C)C)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2ccc(C(C)N)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.8 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl (1-(4-((4-(2-(2-amino-2-oxoethyl)phenethyl)-5-methylpyrimidin-2-yl)amino)phenyl)ethyl)carbamate (A132) (0.099 g, 0.20 mmol) in DCM (5 mL) and the resulting mixture stirred at room temperature for 3 hours. The volatiles were evaporated under reduced pressure then 2 M aqueous K2CO3 solution (10 mL) and water (15 mL) were added to the residue. The resulting suspension was sonicated for 1 minute, filtered and the filter cake dried to give the title compound 34 as a light tan solid (77 mg, 97%); 1H NMR (300 MHz, d6-DMSO) δ 9.26 (s, 1H), 8.15 (s, 1H), 7.67 (d, J=8.6 Hz, 2H), 7.42 (s, 1H), 7.23 (d, J=8.6 Hz, 2H), 7.14-7.23 (m, 4H), 6.92 (s, 1H), 3.92 (d, J=6.4 Hz, 1H), 3.50 (s, 2H), 3.32 (brs, 2H), 3.02-3.07 (m, 2H), 2.88-2.90 (m, 2H), 2.06 (s, 3H), 1.23 (d, J=6.5 Hz, 3H). LCMS-B: rt 4.691 min; m/z 390 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[C:8]([CH2:15][C:16]([OH:18])=O)([CH3:14])[CH2:7][CH2:6]2)#[N:2].O.[NH2:20][NH2:21].C(O)(=O)C>O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[C:8]([CH3:14])([CH2:15][C:16](=[O:18])[NH:20][N:21]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:2]
Reactant: CC1(CC(=O)O)CCc2cc(C#N)ccc2C1=O
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CC12CCc3cc(C#N)ccc3C1=NNC(=O)C2

Procedure:
A mixture of 6-cyano-2-methyl-1-oxo-1,2,3,4-tetrahydro-2-naphthyl acetic acid (3.5 g), hydrazine hydrate (20 ml), acetic acid (20 ml) and water (40 ml) was stirred under reflux for 4 hours. The reaction mixture was cooled and the precipitated solid filtered off. Recrystallisation from DMF/ethanol gave 8-cyano-4a-methyl-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (2.5 g; m.p.>300°); ν(Nujol mull) 3315, 3210, 2214, 1675, 1635, 1615, 1590 and 844 cm-1 ; δ(DMSO-d6) 1.06, (3H,s,CH3), 1.80 (2H,m,5-H) 2.40 (2H,m,4-H), 2.92 (2H,m,6-H), 7.61 (1H,m,9-H), 7.70 (1H, s, 7-H), 8.13 (1H,d,10-H), 11.05 (1H,s,NH).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[C:13]([O-])(O)=O.[Na+].IC>CN(C=O)C>[CH3:13][O:11][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=1
Reactant: O=C([O-])O
Reactant: CSc1ccc(CC(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc(SC)cc1
Yield: 97 %

Procedure:
1.82 g (10 mmol) of the 4-methylthiophenylacetic acid were dissolved in 30 mL of DMF and 1.34 g (16 mmol) of NaHCO3 are then added; the agitation mixture is stirred for 15 min approx. Next, 1.9 mL of ICH3 are added while keeping agitation at room temperature for 24 h. Once this time elapsed the mixture is poured on water/ice. As no precipitation occurs ether is added and extracted. The organic phase is washed with water and after drying on sodium sulfate anhydride, the organic phase is concentrated in a rotary evaporator getting 1.92 g (9.7 mmol, 97% yield) of colorless oil which spectroscopic data confirm the expected structure. This product will be used in the next step of the synthesis process without purification as it provides a single stain in TLC (eluting dichloromethane/methanol 9/1).
Reaction SMILES: [CH:1]([NH2:3])=[O:2].[H-].[Na+].C(OC([C:11]1[N:15]2[CH:16]=[C:17]([C:20]3[C:24]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=4)=[N:23][N:22]4[CH2:32][CH2:33][CH2:34][C:21]=34)[CH:18]=[CH:19][C:14]2=[N:13][CH:12]=1)=O)C>CN(C=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:31][C:27]1[N:26]=[C:25]([C:24]2[C:20]([C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([C:1]([NH2:3])=[O:2])=[CH:12][N:13]=4)[CH:16]=3)=[C:21]3[CH2:34][CH2:33][CH2:32][N:22]3[N:23]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cnc2ccc(-c3c(-c4cccc(C)n4)nn4c3CCC4)cn12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2nn3c(c2-c2ccc4ncc(C(N)=O)n4c2)CCC3)n1
Temperature: 155 °C
Yield: 99 %

Procedure:
Add formamide (36 mL) to a suspension of sodium hydride (2.04 g, 60% dispersion in mineral oil, 51.1 mmol) and 6-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-imidazo[1,2-a]pyridine-3-carboxylic acid ethyl ester (3.6 g, 9.29 mmol) in DMF (15 mL) over 10 min. Heat at 155° C. for 40 min, cool, dilute with ethyl acetate, and carefully dilute with saturated aqueous sodium bicarbonate. Filter any un-dissolved solid and wash with ethyl acetate. Concentrate the remaining organic layer and adsorb onto a 1:1 mixture of SiO2 and Celite®. Flash chromatography using ethyl acetate methanol mixtures followed by trituration of the combined lots in diethyl ether gives the titled compound (3.32 g, 99%) as a white solid. TOF MS ES+ exact mass calculated for C10H9IN2O2 (p+1): m/z=359.1620 Found: 359.1617.
Reaction SMILES: [CH:1]1([CH2:10][C:11]([N:13]2[CH2:20][CH2:19][CH2:18][C@H:14]2[C:15]([OH:17])=O)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:21][O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1.C1(CC(C2SCN[C@@H]2C(O)=O)=O)C2C(=CC=CC=2)CC1.S1CCNC1>>[CH3:21][O:22][C:23](=[O:29])[C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:15](=[O:17])[C@@H:14]1[CH2:18][CH2:19][CH2:20][N:13]1[C:11](=[O:12])[CH2:10][CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Agent: C1CSCN1
Agent: O=C(CC1CCc2ccccc21)C1SCN[C@@H]1C(=O)O
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)CC1C=Cc2ccccc21
Yield: 75 %

Procedure:
A colorless oil of 1-[1-(2-indenylacetyl)-L-prolyl]-L-proline methyl ester was prepared in the same manner as in Example 1, except that 1-(2-indenylacetyl)-L-proline and L-proline methyl ester were used instead of 3-(2-indanylacetyl)-L-thioproline and thiazolidine, respectively (yield: 75%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C.C(Cl)Cl>O1CCCC1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:24])[O:14][C@@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[CH:18][CH:17]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](O)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](OC(=O)Nc2ccc(Cl)cc2)C1

Procedure:
Into a solution of (R)-(-)-N-tert-butoxycarbonyl-3-piperidinol (Reference Example 2) (23 g) in dry tetrahydrofuran (20 ml) were added 4-chlorophenyl isocyanate (1.43 ml) and triethylamine (1.87 mi) successively at room temperature with stirring, and then the mixture was stirred at room temperature for 10 hours. The reaction mixture was distilled under reduced pressure to give residues which was adsorbed on ca. 20 g of silica gel with employment of 50 ml of methylene chloride and purified through column chromatography (alumina, n-hexane:ethyl acetate =5:1) to give (R)-(+)-N-tert-butoxycarbonyl-3-piperidyl 4-chlorophenylcarbamate (3.07 g) of colorless prism crystal.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([NH2:15])=[S:14])=[O:10])=[CH:3][CH:2]=1.C(=O)([O-])O.[K+].C([CH:23](Br)[C:24](=O)[C:25]([O-:27])=[O:26])C.F[C:31](F)(F)[C:32](OC(=O)C(F)(F)F)=O.N1C(C)=CC=CC=1C>COCCOC>[CH2:7]([O:8][C:9]([NH:11][CH2:12][C:13]1[S:14][CH:23]=[C:24]([C:25]([O:27][CH2:31][CH3:32])=[O:26])[N:15]=1)=[O:10])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CCC(Br)C(=O)C(=O)[O-]
Reactant: NC(=S)CNC(=O)OCc1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [K+]
Solvent: COCCOC
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)c1csc(CNC(=O)OCc2ccccc2)n1
Temperature: -20 °C
Reaction time: 8 h
Yield: 84.6 %

Procedure:
To a solution of N-benzyloxycarbonylglycine thioamide (1.49 g, 6.64 mmol) in 1,2-dimethoxyethane (25 mL) was added potassium hydrogen carbonate (2.66 g, 26.56 mmol) and ethylbromopyruvate (3.47 mL, 27.54 mmol) at −20° C. and the mixture stirred at −20° C. overnight. The mixture was filtered through a pad of celite and the filtrate was concentrated and the residue was dissolved in 1,2-dimethoxyethane. After cooling to −20° C., a solution of trifluoroacetic anhydride (2.85 mL, 20.52 mmol) and 2,6-lutidine (5.14 mL, 44.29 mmol) in 1,2-dimethoxyethane (10 mL) was added dropwise over 10 minutes. After stirring for 45 minutes, the solution was concentrated and partitioned between chloroform and water. The organic layer was concentrated and the residue was purified by flash chromatography on silica gel eluting with 60% ethyl acetate in hexanes to provide the title product (1.8 g, 85%): MS (DCI/NH3) m/z 321 (M+H)+.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.[CH3:9][C:10]1[O:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][C:11]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1>[Cl:8][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[C:11]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[O:14][C:10]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)o1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 100.5 %

Procedure:
NCS (709 mg, 5.31 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-furancarboxylate (967 mg, 4.39 mmol) in Tetrahydrofuran (THF) (20 mL) at room temperature. The mixture was heated to 70° C. for 1 hour. 6N NaOH (20 mL, 120 mmol) was then added and the mixture stirred at 70° C. for an additional 2 h. The mixture was partitioned between CHCl3 and H2O and the pH of the aqueous phase was adjusted to ˜3 with 6N HCl. The organic layer was separated, dried with Na2SO4 and concentrated affording the title compound (1.13 g, 4.41 mmol, quant.) which was used without further purification: LC-MS (ES) m/z=241 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:34])[C@H:23]([CH2:25][CH2:26][C:27](=[O:33])[O:28]C(C)(C)C)[NH2:24])[CH:16]=1)=[CH:8][CH:7]=2)(=[O:3])[NH2:2].Cl>C(Cl)Cl.O1CCOCC1>[C:1]([C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][C:22](=[O:34])[C@H:23]([CH2:25][CH2:26][C:27](=[O:28])[OH:33])[NH2:24])[CH:16]=1)=[CH:8][CH:7]=2)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)Nc1cccc(COc2ccc3[nH]c(C(N)=O)cc3c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1cc2cc(OCc3cccc(NC(=O)[C@@H](N)CCC(=O)O)c3)ccc2[nH]1
Reaction time: 1 h
Yield: 51 %

Procedure:
2-Carbamoyl-5-[3-(O-tert-butyl-α-glutamylamino)benzyloxy]-1H-indole (0.29 g; 0.62 mmol) in solution in CH2Cl2 (2 ml) was treated under argon with HCl (2N) in dioxan (4 ml). The mixture was stirred for one hour, evaporated and the residue was purified on OASIS resin, eluting with H2O/CH3CN 80/20 to give 2-carbamoyl-5-[3-(α-glutamylamino)benzyloxy]-1H-indole.
Reaction SMILES: C([O-])([O-])=[O:2].[K+].[K+].[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:17][C:18]#[N:19])=[CH:13][NH:14]2)=[CH:10][CH:9]=1.O.OO>CS(C)=O>[Br:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12]([CH2:17][C:18]([NH2:19])=[O:2])=[CH:13][NH:14]2)=[CH:10][CH:9]=1
Reactant: N#CCc1c[nH]c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)Cc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Powdered K2CO3 (408 mg, 2.95 mmol, 1.60 eq.) was heated to 50° C. in DMSO (3 mL) for 20 min, then cooled to rt. 6-Bromo-1H-indole-3-acetonitrile (434 mg, 1.85 mmol) was dissolved in DMSO (3 mL) and added to the reaction slurry. Water (0.2 mL) and aqueous 30% H2O2 (0.46 mL, 4.0 mmol, 2.2 eq.) were added, and the reaction mixture was stirred for 2–3 hours at rt. The reaction was quenched with 1N HCl and extracted with EtOAc. The organic layer was washed with 1.5 N sodium thiosulfate and dried (MgSO4). The solvent was removed in vacuo, and the residue crystallized from CH2Cl2 to give 273 mg (55%) of the title compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:34]1[CH:39]=[CH:38][C:37]([C:40]2[C:44]3[C:45](=[O:49])[NH:46][CH:47]=[CH:48][C:43]=3[O:42][CH:41]=2)=[CH:36][CH:35]=1.[N:50]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH:53]=[CH:52][C:51]=1[CH2:60][CH2:61]O.Cl>C1COCC1.CC(=O)OCC>[N:34]1[CH:35]=[CH:36][C:37]([C:40]2[C:44]3[C:45](=[O:49])[N:46]([CH2:61][CH2:60][C:51]4[CH:52]=[CH:53][C:54]5[C:59](=[CH:58][CH:57]=[CH:56][CH:55]=5)[N:50]=4)[CH:47]=[CH:48][C:43]=3[O:42][CH:41]=2)=[CH:38][CH:39]=1
Reactant: OCCc1ccc2ccccc2n1
Reactant: O=c1[nH]ccc2occ(-c3ccncc3)c12
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1c2c(-c3ccncc3)coc2ccn1CCc1ccc2ccccc2n1
Temperature: 15 °C
Reaction time: 8 h
Yield: 36.3 %

Procedure:
To a solution of triphenylphosphine (247 mg, 0.942 mmol) in THF (10 mL), DIAD (0.321 mL, 1.65 mmol) was added. The mixture was cooled to 15° C. 3-(Pyridin-4-yl)furo[3,2-c]pyridin-4(5H)-one (100 mg, 0.471 mmol) and 2-(quinolin-2-yl)ethanol from example from example a1 were added. After stirring overnight at room temperature, EA and 2M HCl were added. The phases were separated and extracted with EA. The organic phase was washed with water. The acidic aqueous phase was basified with 2M NaOH and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give 69 mg of the title compound (36.3%) as hydrochloride salt as dark yellow solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:7](Cl)(=[O:9])=[O:8])[S:5][CH:6]=1.[OH:11][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.C(N(CC)CC)C.C(OCC)(=O)C>C(OC)(C)(C)C>[CH3:1][C:2]1[N:3]=[C:4]([S:7]([O:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[N:13]2)(=[O:9])=[O:8])[S:5][CH:6]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1csc(S(=O)(=O)Cl)n1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1csc(S(=O)(=O)On2nnc3ccccc32)n1

Procedure:
Under atmosphere of argon, to a solution of 4-methylthiazol-2-sulfonyl chloride in methyl t-butyl ether (0.20 M, 20 ml), 1-hydroxybenzotriazole (549 mg) and triethylamine (0.57 ml) were added under stirring with cooled on ice bath, and the mixture was stirred for 1 hour at room temperature. To the reaction mixture, ethyl acetate was added. The organic layer was washed with water three times, with a saturated aqueous solution of sodium chloride once successively, dried over an anhydrous magnesium sulfate and concentrated to give the compound of the present invention (1.1 g) having the following physical data.
Reaction SMILES: [CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2]1.[I:10]Cl.O>CC(O)=O>[CH2:1]1[O:9][C:4]2[CH:5]=[CH:6][C:7]([I:10])=[CH:8][C:3]=2[O:2]1
Reactant: c1ccc2c(c1)OCO2
Reactant: ClI
Solvent: CC(=O)O
Solvent: O
Product: Ic1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 56.7 %

Procedure:
To a solution of 1,2-methylenedioxybenzene (24.4 g, 0.20M) in AcOH (30 ml) was added ICl (40 g, 0.250M) in AcOH (50 ml) at room temperature over 0.5 hour. The reaction mixture was stirred for an additional three hours, then poured into H2O and extracted twice with ether. The organic extracts were washed with NaHSO3, saturated NaHCO3, H2O, dried (MgSO4), and evaporated in vacuo. The product was distilled under vacuum at 70° C. to give 3,4-methylenedioxyiodobenzene as a pale orange liquid (28.1 g, 57% yield). NMR (CDCl3) δ 5.85 (s, 2H, O--CH2 --O), 6.50 (d, 1H, J=8 Hz, H6), 7.10 (m, 2H, J=8 Hz, J=2 Hz, H2 and H5); MS: 248 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[C:11]1[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][C:12]1=[O:21])[O:6][CH2:5]2.[C:22](Cl)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:21])[C:11]2=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:10][CH:9]=2)[CH2:5][O:6]1
Reactant: Nc1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Nc2ccc(Cl)cc2C1=C1OCc2cc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)ccc21
Yield: 44.9 %

Procedure:
A solution of 3-(5-Amino-3H-isobenzofuran-1-ylidene)-5-chloro-1,3-dihydro-indol-2-one (75 mg, 0.251 mmol), trityl chloride (84 mg, 0.301 mmol) and triethylamine (53 μμl, 0.377 mmol) in DMF (2.0 ml) was stirred at room temperature for 1.25 hours. The mixture was partitioned between EtOAc and water. The EtOAc layer was washed with brine, dried with Na2SO4 and rotary evaporated. The yellow solid was precipitated from CHCl3 to give 5-chloro-3-[5-(trityl-amino)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a bright yellow solid (61 mg, 45%).
Reaction SMILES: [OH:1][C@@H:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][C:12]([CH:15]=O)=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17].[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1[CH2:28][C:29](=[O:35])[NH:30]2.N1CCCCC1>C(O)C>[Br:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:31]2[C:27]=1/[C:28](=[CH:15]/[C:12]1[NH:11][C:7]3[CH2:8][CH2:9][CH2:10][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)[C:5](=[O:17])[C:6]=3[C:13]=1[CH3:14])/[C:29](=[O:35])[NH:30]2.[OH:1][CH:2]([CH2:18][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[CH2:3][N:4]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:11][CH:12]=[C:13]([CH3:14])[C:6]=2[C:5]1=[O:17]
Reactant: O=C1Cc2c(Br)cccc2N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3cccc(Br)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CCC2
Product: Cc1c[nH]c2c1C(=O)N(CC(O)CN1CCOCC1)CCC2
Temperature: 45 °C
Reaction time: 16 h
Yield: 184.3 %

Procedure:
(S)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-1,4,5,6,7,8-hexa hydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 78f (40 mg, 0.12 mmol) and 4-bromo-1,3-dihydro-indol-2-one (25 mg, 0.12 mmol) were dissolved in 1.5 ml of ethanol, and added with 6 μl of piperidine to the solution at room temperature. Upon completion of the addition, the reaction mixture was stirred at 45° C. for 16 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was naturally cooled to room temperature, and filtered. The filter cake was washed with anhydrous ethanol (1 ml×2) and dried to obtain the title compound (S,Z)-2-(4-bromo-2-oxoindolin-3-ylidene)methyl)-5-(2-hydroxy-3-morpholinoprop yl)-3-methyl-5,6,7,8-tetrahydropyrrolo[3,2-c]azepin-4(1H)-one 81 (34 mg, yield 54%) as a yellow solid.
Reaction SMILES: Br.CN(C)[CH:4]=[CH:5][C:6]1[C:11]([C:12]#[N:13])=[CH:10][CH:9]=[CH:8][N:7]=1.CC(O)=[O:17]>>[OH:17][C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[N:13][CH:12]=2)[N:7]=1
Reactant: CC(=O)O
Reactant: CN(C)C=Cc1ncccc1C#N
Agent: Br
Product: Oc1ccc2cnccc2n1
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of 30% HBr in AcOH (200 mL) was added dropwise with mechanical stirring at 40° to a solution of N,N-dimethyl-2-(3-cyano-2-pyridyl)ethenamine (10.8 g, 0.062 m) in AcOH (100 mL). After the addition, the slurry was stirred at 55° for 2 hours. The mixture was then evaporated to dryness and the residue treated with ice and saturated aqueous Na2CO3. The aqueous layer was filtered and the filtrate extracted with Et2O. The aqueous layer was placed in a continuous extractor with CHCl3 to yield 7.0 g of a crude product. Sublimation of this product at 160°-180° (0.1 mm) yielded 5.1 g (56%) of hydroxy-1,6-naphthyridine. An analytical sample was prepared by crystallization from CH3OH: m.p. 243-244.5.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.[NH2:30][C:31]1[C:40]2[N:41]=[C:42]([CH2:49][O:50][CH2:51][CH3:52])[N:43]([CH2:44][C:45]([CH3:48])([OH:47])[CH3:46])[C:39]=2[C:38]2[CH:37]=[CH:36][C:35](Br)=[CH:34][C:33]=2[N:32]=1.[C:54]([O:58][CH3:59])(=[O:57])[CH:55]=[CH2:56]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:30][C:31]1[C:40]2[N:41]=[C:42]([CH2:49][O:50][CH2:51][CH3:52])[N:43]([CH2:44][C:45]([OH:47])([CH3:48])[CH3:46])[C:39]=2[C:38]2[CH:37]=[CH:36][C:35](/[CH:56]=[CH:55]/[C:54]([O:58][CH3:59])=[O:57])=[CH:34][C:33]=2[N:32]=1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)(C)O
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(N)nc3cc(/C=C/C(=O)OC)ccc3c2n1CC(C)(C)O
Temperature: 120 °C

Procedure:
A thick walled glass reaction vessel was charged with anhydrous DMF (2 mL), palladium (II) Acetate (0.01 equivalents (eq)), tri-o-tolylphosphine (0.02 eq) and triethylamine (3 eq). To this orange solution was added a solution of 1-[4-amino-7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol in 50 mL anhydrous DMF followed by the addition of methyl acrylate (1.0 eq). The reaction mixture was purged with nitrogen, sealed and heated at 120° C. overnight, and slowly cooled to room temperature. The reaction mixture was concentrated to dryness and then slurried in water (50 mL). Saturated potassium carbonate solution (25 mL) was added. The mixture was extracted with dichloromethane (4×50 mL). The combined extracts were concentrated under reduced pressure and purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with 0-25% CMA in chloroform) to provide Methyl(2E)-3-[4-amino-2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]prop-2-enoate as a white solid.