Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([O:11][CH3:12])=[CH:4][C:3]=1[N:13]1[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:15][CH2:14]1>CCOC(C)=O.CO>[CH3:1][C:2]1[C:3]([N:13]2[CH2:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][S:22]([CH3:25])(=[O:23])=[O:24])[CH2:15][CH2:14]2)=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:7]=1)[NH2:8]
Reactant: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(N2CCCN(CCS(C)(=O)=O)CC2)c(C)cc1N
Reaction time: 2 h
Yield: 90 %

Procedure:
1-[2-Methyl-5-(methyloxy)-4-nitrophenyl]-4-[2-(methylsulfonyl)ethyl]hexahydro-1H-1,4-diazepine (0.70 g, 1.9 mmol) was placed in a 200 mL high pressure vessel and dissolved in 40 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/C (0.51 g, 0.132 mmol) was added followed quickly by a rubber septum. The vial was evacuated and filled with N2 six times to remove any oxygen. The vial was then pressurized with H2 (60 psi). The solution stirred for 2 h. The vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to afford the title compound of step C (0.585 g, 1.71 mmol, 91%). 1H NMR (400 MHz, DMSO-d6) δ 6.54 (s, 1H), 6.38 (s, 1H), 4.27 (br. s., 2H), 3.67 (s, 3H), 3.24 (t, J=6.59 Hz, 2H), 3.02 (s, 3H), 2.86-2.97 (m, 6H), 2.75 (t, J=5.49 Hz, 2H), 2.68-2.73 (m, 2H), 2.05 (s, 3H), 1.74-1.81 (m, 2H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.ClCCCl.[Cl-].[Al+3].[Cl-].[Cl-].[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:22]=1[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33]>ClC(Cl)C.ClCCl>[OH:27][C:25]1[CH:26]=[C:21]([OH:20])[C:22]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:23][C:24]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5]
Reactant: COC(=O)CCCCc1ccc(O)cc1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)CCCCc1cc(C(=O)c2ccccc2C(=O)O)c(O)cc1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 2-liter round-bottomed flask was charged with 12.83 g (86.6 mmoles) of phthalic anhydride and a stir bar. Anhydrous 1,2-dichloroethane (190 ml) was added. The flask was flushed with argon, and a reflux condenser was added to the flask. A drying tube was added to the top of the condenser. The mixture was stirred for 30 minutes. (The solid did not dissolve completely.) Then 28.6 g (214.5 mmoles) of aluminum chloride was added (by momentarily removing the condenser). Most solids were dissolved; a greenish-yellow solution results. Stirring was continued for another 30 minutes while a solution of 18.5 g (82.5 mmoles) of methyl-5-(2,4-dihydroxyphenyl)-pentanoate (5a) in 130 ml of dichloroethane was made. This solution was poured into the flask, the headspace was flushed with argon, and the condenser was replaced. With good stirring, the solution in the flask was heated to a light reflux for 30 to 60 minutes. The solution in the flask became slightly warm and turned dark. HCl gas was evolved for about 10-20 minutes. Then the solution was cooled to room temperature. A tarry precipitate formed. The reaction was concentrated to a gum. To this material a mixture of ice (400 g) and concentrated HCl (200 ml) was added followed by 500 ml of ethyl acetate. The flask was capped with a septum and placed on an orbital shaker until all solid dissolved. The mixture was transferred to a 2-liter separatory funnel. The organic layer was separated, washed with 400 ml of 1 N HCl, 2×200 ml of saturated NaCl and dried over sodium sulfate. Concentration afforded an oil. To this material, 200 ml of dichloromethane was added. The resulting solution was sonicated for 30 minutes, and then cooled to −20° C. for 2 hours. The crystalline precipitate was filtered off, washed with 2:1 hexanes/dichloromethane, followed by 4:1 hexanes/dichloromethane and dried. Yield was 20.0 g (65%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])#[CH:2].C(N(CC)CC)C.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][N:26]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH2:41]3)=[CH:36][CH:35]=2)[N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:12][C:10](=[O:11])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:27]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:23][N:24]=[C:25]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([CH:40]3[CH2:41][CH2:42][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:44][CH2:45]3)=[CH:36][CH:35]=2)[N:26]=1)[CH3:14]
Reactant: C#Cc1ccccc1C(C)C(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)c1ccccc1C#Cc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 120 °C
Yield: 54.1 %

Procedure:
A solution of methyl 2-(2-ethynylphenyl)propanoate (I51) (0.074 g, 0.39 mmol) in dimethylformamide (2 mL) and triethylamine (0.183 mL, 1.31 mmol) was added to a mixture of tert-butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I45) (0.150 g, 0.328 mmol), Pd(PPh3)2Cl2 (0.023 g, 0.033 mmol), CuI (0.0090 g, 0.049 mmol) and triphenylphosphine (0.013 g, 0.049 mmol) in dimethylformamide (2 mL). The reaction mixture was heated under microwave irradiation at 120° C. for 15 minutes. The reaction was cooled and the mixture diluted with EtOAc and passed through a plug of Celite washing with ethyl acetate (50 mL). Water (50 mL) was added and the layers separated. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL) and dried over Na2SO4. After filtration the solvent was removed under reduced pressure to give a dark brown residue. The residue was purified by column chromatography on silica gel (0-20% EtOAc in cyclohexane) to yield the title compound (I52) (0.108 g, 54%) as a brown viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH:18]2[CH2:20][CH2:19]2)[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[C:5]2=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]2[N:3]=1.[NH2:26][C:27]1[C:28]([Cl:49])=[C:29]([N:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][C:36]2=[O:48])[CH:30]=[C:31]([C:33]#[N:34])[CH:32]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[Cl:49][C:28]1[C:27]([NH:26][C:2]2[N:7]=[C:6]([N:8]([CH:18]3[CH2:19][CH2:20]3)[CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=3)[C:5]3=[N:21][CH:22]=[C:23]([C:24]#[N:25])[N:4]3[N:3]=2)=[CH:32][C:31]([C:33]#[N:34])=[CH:30][C:29]=1[N:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37][C:36]1=[O:48]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C#N)cc(N)c2Cl)C(=O)C1
Reactant: COc1ccc(CN(c2nc(Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(C(=O)OC(C)(C)C)CC4=O)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Temperature: 80 °C
Yield: 74.3 %

Procedure:
A mixture of 2-chloro-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (72.8 mg, 0.205 mmol), tert-butyl 4-(3-amino-2-chloro-5-cyanophenyl)-3-oxopiperazine-1-carboxylate (60 mg, 0.171 mmol), palladium(II) acetate (12 mg, 0.053 mmol), XANTPHOS (12 mg, 0.021 mmol), DPPF (12 mg, 0.022 mmol) and cesium carbonate (145 mg, 0.445 mmol) in Dioxane (2 mL) was evacuated and back filled with nitrogen three time and was heated at 80° C. for 3 h. LC-MS showed reaction was complete. The reaction mixture was filtered through a pad of Celite, rinsed with EtOAc, DCM and the filtrate was concentrated and purification via flash chromatography (0-10% MeOH in DCM, 12 g) gave tert-butyl 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-oxopiperazine-1-carboxylate (85 mg) as a yellow oil.
Reaction SMILES: Br[C:2]1[C:3]([C:16]([CH3:19])([CH3:18])[CH3:17])=[N:4][N:5]([CH3:15])[C:6]=1[NH:7]C(=O)OC(C)(C)C.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)C.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>[C:16]([C:3]1[C:2]([C:22]2[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=2)=[C:6]([NH2:7])[N:5]([CH3:15])[N:4]=1)([CH3:17])([CH3:18])[CH3:19]
Reactant: OB(O)c1cccnc1
Reactant: Cn1nc(C(C)(C)C)c(Br)c1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cn1nc(C(C)(C)C)c(-c2cccnc2)c1N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 25.4 %

Procedure:
tert-Butyl (4-bromo-3-tert-butyl-1-methyl-1H-pyrazol-5-yl)carbamate (Intermediate I, 1.7 g, 5.12 mmol), pyridine-3-boronic acid (1.26 g, 10.23 mmol), and Pd(PPh3)4 (295 mg, 0.26 mmol) were dissolved in ethanol (25 mL), and Na2CO3 (2 M aqueous solution, 25 mL) was added. The mixture was degassed for 10 min. The reaction mixture was then heated to 80° C. for 16 h. The mixture was diluted with ethyl acetate, the solid was filtered off, and the filtrate was treated with TFA (5 mL). The mixture was stirred for 30 min before being concentrated under reduced pressure. The crude was dissolved in methanol and filtered though a C8-silica plug. HPLC purification with gradient elution from 5 to 60% acetonitrile in water afforded 300 mg (25%) of the title compound. 1H NMR (300 MHz, CD3OD) δ 8.73 (d, 1H), 8.64 (s, 1H), 8.14 (d, 1H), 7.81 (dd, 1H), 3.73 (s, 3H), 1.20 (s, 9H). ES-MS m/z 231.2 (MH+); HPLC RT (min) 0.23.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH2:24][OH:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([CH:24]=[O:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reaction time: 0.33 h
Yield: 85.4 %

Procedure:
A mixture of 17.62 g (135.6 mmole) oxalyl chloride and 250 mL DCM in a dry ice acetone bath was treated with a solution of 21.19 g (271.2 mmole) DMSO in 150 mL DCM over 20 minutes. After stirring for 20 minutes, a solution of 24.327 g 1-(t-butoxycarbonyl)-4-hydroxymethyl-piperidine (from Step 1 above) in 150 mL DCM was added over one hour. After an additional 15 minutes, 57.17 (565 mmole) triethylamine in 150 mL DCM was added over half an hour. The reaction mixture was allowed to warm up over night in the cooling bath. The reaction mixture was concentraed under vacuum to remove about 400 mL DCM, and the residue was partitioned between 1 L ether and 300 mL water. To this was added 200 mL 1 N NaOH, the layers were separated, and the organic layer was washed with 150 mL 1 N NaOH (2×), water (3×), and saturated brine, dried over sodium sulfate, and concentrated to give 22.562 g crude product. FC (10-60% ethyl acetate in hexanes) gave 20.58 g title compound as slightly yellowish oil. RF: 0.29 (3:1 v/v hexanes/EtOAc); 1H NMR (500 MHz) δ 9.68 (d, J=0.7 Hz, 1H), 3.96-4.02 (m, 2H), 2.92-2.97 (m, 2H), 2.40-2.45 (m, 1H), 1.88-1.94 (m, 2H), 1.53-1.64 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>O>[C:9]12([NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[NH:7]1)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2
Reactant: O=C1CCCCC1
Reactant: Nc1ccccc1N
Solvent: O
Product: c1ccc2c(c1)NC1(CCCCC1)N2
Yield: 59.5 %

Procedure:
In a procedure similar to that described by H. Suschitszky in Croatica Chemica Acta, 59, 57-77 (1986), o-phenylenediamine (108 g, 1.0 mol) was dissolved in 1 liter hot water on a steam bath. With vigorous stirring and heating, cyclohexanone (98 g, 1.0 mol) was added in a rapid stream. After 5 minutes a brown gum formed; after 15 minutes a solid resulted. Stirring was continued for a total of 35 minutes. The slurry was cooled in an ice bath and then filtered to yield 112 g (59.5%) 1,3-dihydrobenzimidazole-2-spirocyclohexane. To a stirred solution of this compound (50 g, 0.266 mol) in 1 liter dichloromethane chloride was added, in several portions, 100 g MnO2. The resulting slurry was stirred vigorously for 30 minutes and filtered. The solids were washed with dichloromethane and the filtrate evaporated to obtain an oil. The oil was dissolved in 200 ml, ligroin, and the solution cooled to -10° C. The resulting solid was filtered to yield 46 g (93%) 2H-benzimidazole-2-spirocyclohexane. A solution of 2-chloroethyl methyl sulfide (19.8 g, 0.20 mol) and thiourea (15.2 g, 0.20 mol) in 50 ml absolute alcohol was refluxed for 6 hours. To this was added a solution of KOH (22.4 g, 0.40 mol) in 100 ml methanol, and the resulting slurry refluxed for 45 minutes. After cooling to 30°, 37.2 g (0.20 mol) of freshly prepared 2H-benzimidazole-2-spirocyclohexane was added in portions. The mixture was stirred at room temperature for 10 minutes and then at reflux for 2 minutes. After cooling, the mixture was evaporated to a thick slurry; 100 ml dichloromethane was added and the mixture evaporated. This was repeated and the residue treated with 100 ml water and 200 ml dichloromethane. The organic layer was separated, washed with water, dried over MgSO4, filtered and evaporated. The residue was chromatographed through silica gel using an increasingly polar mixture of dichloromethane and acetonitrile. Product fractions were combined and evaporated to give 7.0 g 5'-(2-methylthioethylthio)-1',2'-phenylenediamine. A stirred solution of the phenylenediamine (5.0 g, 0.027 mol) in 50 ml acetic acid was treated with sodium nitrite (2.6 g, 0.037 mol), in 5 ml water, over 30 seconds at room temperature. The mixture was stirred for 15 minutes and then evaporated. The residue was treated with 50 ml water and 50 ml dichloromethane. The organic layer was dried over MgSO4, filtered, and evaporated. Solid was chromatographed through silica gel using an increasingly polar mixture of dichloromethane chloride and acetone. The isolated product was recrystallized from ethyl acetate to yield 3.2 g (62%) 6'-(2-methyl-thioethylthio)benzotriazole, I-139.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:10]=[CH:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[N:7]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>CN(C)C=O>[Cl:18][C:13]1[CH:12]=[C:11]([N:8]2[CH:9]=[CH:10][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:7]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: O=C(CCl)Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCOCC1)Nc1ccn(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 100 °C
Yield: 87.5 %

Procedure:
A mixture of 2-chloro-N-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)acetamide (0.22 g, 0.74 mmol), morpholine (71 mg, 0.81 mmol), potassium carbonate (0.22 g, 1.62 mmol) and sodium iodide (0.11 g, 0.74 mmol) in dry dimethylformamide (5 ml) was stirred and warmed at 100° C., overnight, in a dry nitrogen atmosphere. The solvent was evaporated in vacuo and water was added to the crude residue. The dark solid precipitated was filtered and dried yielding a crude product purified by crystallization in ethyl acetate, and 0.23 g of N-(1-(3,4-dichlorophenyl)-1H-pyrazol-3-yl)-2-morpholinoacetamide was obtained as a beige colour solid with m.p.=125-127° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH2:24]([O:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][N:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][CH2:32][CH2:33][O:34][C:35]1[N:36]=[CH:37][C:38]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]5[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=5)[C:5]=4[C:4]=3[CH:3]=2)=[CH:39][CH:40]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2ccc(OCCOCc3ccccc3)nc2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(OCCOCc5ccccc5)nc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 50 mg, 0.132 mmol) and 2-(2-benzyloxy-ethoxy)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 19.1.1, 65 mg, 0.184 mmol) to give the title compound as a white solid. (HPLC: tR 3.12 min (Method A); M+H=521 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.95 (s, 1H), 8.33-8.24 (m, 1H), 8.16-8.05 (m, 2H), 7.93-7.86 (m, 1H), 7.81-7.75 (m, 1H), 7.51-7.45 (m, 1H), 7.40-7.22 (m, 5H), 7.01-6.93 (m, 1H), 4.55 (s, 2H), 4.47 (t, 2H), 3.92 (s, 3H), 3.78 (t, 2H), 3.57 (s, 3H), 1.97 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[C:5]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:4]=2[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:27]1([C:30]([NH:1][C:2]2[N:6]([CH3:7])[C:5]3[CH:8]=[C:9]([O:12][C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:16]=[CH:17][CH:18]=4)[CH:10]=[CH:11][C:4]=3[N:3]=2)=[O:31])[CH2:29][CH2:28]1
Reactant: Cn1c(N)nc2ccc(Oc3cccc(NC(=O)OC(C)(C)C)c3)cc21
Reactant: O=C(Cl)C1CC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cn1c(NC(=O)C2CC2)nc2ccc(Oc3cccc(NC(=O)OC(C)(C)C)c3)cc21
Yield: 64.7 %

Procedure:
Using tert-butyl {3-[(2-amino-1-methyl-1H-benzimidazol-6-yl)oxy]phenyl}carbamate (2.45 g, 6.91 mmol), pyridine (100 mL), cyclopropanecarbonyl chloride (3.0 mL, 33.1 mmol) and N,N-dimethylpyridine-4-amine (258 mg, 2.11 mmol) as starting materials, and in the same manner as in Example C1(v), the title compound (1.89 g, 65%) was obtained as a pale-brown amorphous substance.
Reaction SMILES: [CH:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.C1(C[NH:48][C:49]2[CH:50]=[C:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:64])([CH3:63])[CH3:62])[CH:52]=[CH:53][CH:54]=2)CCCCC1>CN(C=O)C.O>[CH:1]1([C:7]([NH:48][C:49]2[CH:50]=[C:51]([CH2:55][CH2:56][CH2:57][NH:58][C:59](=[O:65])[O:60][C:61]([CH3:63])([CH3:62])[CH3:64])[CH:52]=[CH:53][CH:54]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Reactant: O=C(O)C1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCCc1cccc(NC(=O)C2CCCCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of cyclohexanecarboxylic acid (21) (0.23 ml, 1.79 mmol), TBTU (0.56 g, 1.74 mmol) and iPr2EtN (0.33 ml, 1.89 mmol) in DMF (20 ml) was added tert-butyl 3-(3-(cyclohexylmethylamino)phenyl)propylcarbamate (17) (0.40 g, 1.59 mmol) in DMF (5 ml). The mixture was stirred at room temperature for 18 h and then diluted with water. The solution was extracted with ethyl acetate and the combined extracts were washed with water, aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by flash chromatography (5 to 50% EtOAc-hexanes gradient) gave tert-butyl 3-(3-(cyclohexanecarboxamido)phenyl)propylcarbamate (22) as a colorless oil. Yield (0.455 g, 78%); Yield (0.2 g, 32%); 1H NMR (400 MHz, CDCl3) δ 7.43 (br s, 1H), 7.26-7.28 (m, 2H), 7.20 (t, J=7.6 Hz, 1H), 7.08 (br s, 1H), 6.89-6.91 (m, 1H), 3.12 (t, J=6.0 Hz, 2H), 2.61 (t, J=8.4 Hz, 2H), 2.17-2.23 (m, 1H), 1.93-1.96 (m, 2H), 1.74-1.86 (m, 3H), 1.65-1.72 (m, 2H), 1.48-1.59 (m, 1H), 1.31-1.42 (m, 2H), 1.43 (s, 9H), 1.22-1.38 (m, 4H).
Reaction SMILES: C(N(CC)CC)C.[OH:8][N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19].Cl.Cl[CH2:22][C:23]1[S:24][C:25]2[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N:28]=[C:27]([NH2:35])[C:26]=2[N:36]=1>CN(C)C=O>[NH2:35][C:27]1[C:26]2[N:36]=[C:23]([CH2:22][O:8][N:9]3[C:10](=[O:19])[C:11]4[C:12](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:14])[S:24][C:25]=2[C:34]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:28]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Nc1nc2ccccc2c2sc(CCl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Nc1nc2ccccc2c2sc(CON3C(=O)c4ccccc4C3=O)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.3 %

Procedure:
Triethylamine (7.3 mL, 52 mmol) was added to a solution of N-hydroxyphthalimide (3.42 g, 21.0 mmol) in N,N-dimethylformamide (DMF) (50 mL). 2-(Chloromethyl)[1,3]thiazolo[4,5-c]quinolin-4-amine hydrochloride (5.0 g, 18 mmol) was added to the resulting deep red solution, and the reaction was stirred overnight at ambient temperature. A precipitate formed and was isolated by filtration, washed with dichloromethane, and dried in a vacuum oven to provide 3.34 g of 2-[(4-amino[1,3]thiazolo[4,5-c]quinolin-2-yl)methoxy]-1H-isoindole-1,3(2H)-dione as a tan solid. The filtrate was concentrated under reduced pressure, and the residue was mixed with dichloromethane, filtered, washed with dichloromethane, and dried in a vacuum oven overnight to provide an additional 2.06 g of product.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])[CH2:10][C:11](=[O:13])[CH3:12])[CH2:2][CH2:3][CH3:4].[CH:18]([O-])([O-])OC.CO.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][CH:17]=1)[NH:8][C:9](=[O:14])/[CH:10]=[C:11](\[O:13][CH3:18])/[CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cccc(NC(=O)CC(C)=O)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CCCCc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
A mixture of 8.5 g of m-(n-butyl)-acetylacetanilide, 5.7 g of methyl orthoformate, 80 ml of methanol and 0.3 g of p-toluene sulfonic acid was stirred at 20° C for 16 hours and after the addition of 100 ml of toluene and 0.6 ml of quinoline, the mixture was heated at 140° C for one hour while distilling the toluene-methanol azeotrope. After refluxing for 30 minutes, another 100 ml of toluene were added thereto and the reaction was completed when the solvent was evaporated. The residue was chromatographed over silica gel and elution with an 8-2 mixture of methylene chloride and ethyl acetate yielded 6.3 g of m-(n-butyl)-3-methoxy-crotonanilide melting at 36° C.