Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:5]=1[OH:11].[H-].[Na+].[C:15]([O:19][C:20]([NH:22][CH2:23][CH2:24][CH2:25]Br)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:25][CH2:24][CH2:23][NH:22][C:20]([O:19][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:21])=[CH:6][C:5]=1[OH:11]
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCCCNC(=O)OC(C)(C)C)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a 0° C. stirred solution of 2,4-dihydroxybenzoic acid methyl ester (5 g, 30 mmol) in dry DMF (100 mL) was added sodium hydride (1.2 g of a 60% suspension in mineral oil, 30 mmol). After 1 h, the solution was warmed to ambient temperature and stirred for 1 h. To the solution was added N-t-butyloxycarbonyl-3-bromopropylamine (10.6 g, 45 mmol). The reaction was stirred at ambient temperature for 24 and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (250 mL) and washed with water (2×200 mL) and brine (100 mL). The EtOAc layer was dried (MgSO4), filtered, and the solvent was removed under reduced pressure. The residue was purified by pressurized silica gel column chromatography using 1:4 EtOAc:hexanes as eluant. The product-containing fractions were pooled and the solvent was removed under reduced pressure. The resulting oil crystallized from ether to give 4-(3-(t-butyloxycarbonylamino)propyloxy)-2-hydroxybenzoic acid methyl ester (51% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]1([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH:23]3[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O=S(Cl)Cl>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:26]2[CH2:27][CH2:28][CH:23]([N:20]3[CH2:21][CH2:22][CH:17]([CH2:16][C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH2:18][CH2:19]3)[CH2:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: O=C1CCC(N2CCC(Cc3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Fc1ccc(C2=CCC(N3CCC(Cc4ccccc4)CC3)CC2)cc1

Procedure:
4-Fluorophenyl magnesium bromide (10 mmole) and 4-[4-(phenylmethyl)-1-piperidinyl]cyclohexanone (7.38 mmole) were reacted by the method described in Example 13 to give the intermediate mixture of cis and trans alcohols. This crude mixture was then dehydrated using SOCl2 in CH2Cl2 by the method described in Example 35 to give the crude product which was purified by chromatography on silica gel using ethyl acetate as the eluent. The pure product was converted the HCl salt in acetone using 12N HCl (23.3% overall, mp: 214-217° C.). Calc'd for C24H28NF.HCl.0.25H2O: C, 73.83%; H, 7.62%; N, 3.59%. Found: C, 73.85%; H, 7.61%; N, 3.56%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([N+:11]([O-])=O)=[C:8]([CH3:10])[CH:9]=1)[CH3:2].[OH2:14].NN>CCO.[Pd]>[NH2:11][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][C:8]=1[CH2:10][OH:14]
Reactant: CCOc1ccc([N+](=O)[O-])c(C)c1
Reactant: O
Agent: [Pd]
Agent: NN
Solvent: CCO
Product: CCOc1ccc(N)c(CO)c1
Temperature: 90 °C

Procedure:
To a solution of (5-ethoxy-2-nitro-phenyl)-methane (592 mg, 3.0 mmol) in absolute EtOH (20 mL) at rt was added 150 mg of Pd/C (Aldrich, 10 wt. % on activated carbon), followed by slow addition of hydrazine hydrate (1.5 mL). The resulting reaction mixture was refluxed at 90° C. for 1h. It then cooled to rt, filtered through Celite, and then concentrated in vacuo to afford crude (2-amino-5-ethoxy-phenyl)-methanol as a pale yellow oil: MS (ESI) 168 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:10][CH2:9]2)[C:5]([NH2:25])=[C:4]([NH2:26])[N:3]=1.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:32]=O>>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:25]=[C:32]([C:31]3[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH3:27])[CH:30]=3)[NH:26]2)=[C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14](=[O:24])[CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[CH2:12][CH2:13]2)[N:7]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: Nc1nc(N)c(N)c(N2CCN(C(=O)COc3ccc(Cl)cc3)CC2)n1
Product: COc1ccc(-c2nc3c(N4CCN(C(=O)COc5ccc(Cl)cc5)CC4)nc(N)nc3[nH]2)cc1OC
Yield: 57 %

Procedure:
This compound was synthesized from 2,5,6-triamino-4-[4-(4-chlorophenoxyacetyl)piperazin-1-yl]pyrimidine and 3,4-dimethoxybenzaldehyde yielding the pure title compound in 57% yield.
Reaction SMILES: [F:1][C:2]([P:8](C(F)(F)C(F)(F)F)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])([F:7])[C:3]([F:6])([F:5])[F:4].[OH-].[K+].P(Cl)(Cl)(Cl)(Cl)[Cl:26]>COCCOC.O>[P:8]([Cl:26])([C:9]([C:10]([F:13])([F:12])[F:11])([F:15])[F:14])[C:2]([C:3]([F:6])([F:5])[F:4])([F:7])[F:1]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)C(F)(F)P(Cl)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.16 g (3.0 mmol) of tris(pentafluoroethyl)phosphine, (C2F5)3P, in 1,2-dimethoxyethane is treated with an excess (6 mmol) of a 1.5 M solution of KOH in water. The mixture is stirred at room temperature for 30 min, and the solvent is removed in vacuo. The residue is taken up in 1,2-dimethoxyethane, and an excess of PCl5 (6 mmol) is added, giving bis(pentafluoroethyl)phosphinous acid chloride, (C2F5)2PCl, identified as described above.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:9]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>CCOCC.C1COCC1>[CH2:9]([N:16]1[CH:17]2[CH2:23][CH2:22][CH:21]1[CH2:20][C:19]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:24])[CH2:18]2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC1(c2ccccc2)CC2CCC(C1)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of phenylmagnesium bromide in ether (3 M, 2.3 mL) was added dropwise to a solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (1.0 g, 4.6 mmol) in THF (20 mL) that had been cooled to 0° C. The mixture was stirred for 3 hours and a solution of saturated aqueous ammonium chloride was added and the products extracted into diethyl ether, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 10-30% ethyl acetate/hexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.5 g) as an oil. LCMS m/z 294.4 [M+H]+. R.T.=2.59 min (Analytical Method 4).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[S:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[C:9](OS(C(F)(F)F)(=O)=O)[C:7]=2[N:8]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.CC(N=P(N1CCCC1)(N1CCCC1)N1CCCC1)(C)C.ClCCl>O1CCOCC1.Cl[Pd]Cl>[F:24][C:25]1[CH:30]=[CH:29][C:28]([C:9]2[C:7]3[N:8]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=3[S:11][C:10]=2[C:12]([O:14][CH3:15])=[O:13])=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1sc2cnc(SC)nc2c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: CC(C)(C)N=P(N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1sc2cnc(SC)nc2c1-c1ccc(F)cc1
Temperature: 120 °C
Yield: 78.4 %

Procedure:
A mixture of 200 mg of methyl 2-(methylsulfanyl)-7-{[(trifluoromethyl)sulfonyl]oxy}thieno[3,2-d]pyrimidine-6-carboxylate 4 (example 1), 216 mg of 4-fluorophenylboronic acid, 19 mg of dichloropalladium (dppf) and 322 mg of BTPP in 2.5 ml of dioxane under argon is microwave-heated at 120° C. in a sealed tube for 1 h. The medium is taken up with dichloromethane and filtered. The organic phase is washed three times with water, then dried over magnesium sulfate, filtered, and then concentrated under vacuum so as to give a yellow solid. The crude is purified on 80 g of silica, elution being carried out with 0-20% of methanol in dichloromethane, so as to obtain 135 mg of methyl 7-(4-fluorophenyl)-2-(methylsulfanyl)thieno[3,2-d]pyrimidine-6-carboxylate in the form of a yellow solid.
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=[C:5]([C:14]2[CH:19]=[CH:18][C:17](C)=[CH:16][CH:15]=2)[O:6][C:7]=1[C:8]1[CH:13]=CC=CC=1.CC(=NO)C(=O)CC.[F:29][C:30]([F:40])([F:39])C1C=C(C=CC=1)C=O>>[CH2:8]([C:7]1[O:6][C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([C:30]([F:40])([F:39])[F:29])[CH:19]=2)=[N:4][C:3]=1[CH2:2][I:1])[CH3:13]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Agent: CCC(=O)C(C)=NO
Product: CCc1oc(-c2cccc(C(F)(F)F)c2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, pentane-2,3-dione-2-oxime and 3-trifluoromethyl-benzaldehyde gave 5-ethyl-4-iodomethyl-2-(3-trifluoromethylphenyl)-oxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:10]=[N:11][C:12]([NH:15][NH2:16])=[CH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[C:17](OCC)(=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[N:11]([C:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:16][N:15]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: NNc1ccc(Nc2cccc(Cl)c2)nn1
Solvent: CCO
Product: CCOC(=O)Cc1nnc2ccc(Nc3cccc(Cl)c3)nn12
Reaction time: 0.5 h

Procedure:
(Step 5-i) N-(3-chlorophenyl)-6-hydrazinylpyridazin-3-amine (1 g, 4.25 mmol)) was taken up in ethanol (10 mL) and diethyl malonate (2 g, 12.76 mmol) was added. After microirradiation at 150° C. for 30 min, the reaction mixture was concentrated to dryness, taken up in ethyl acetate, and filtered to give the product, ethyl 2-(6-(3-chlorophenylamino)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)acetate, as a solid (1.1 g, 3.3 mmol, 78% yield).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:12]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=2.[OH-].[Na+]>CO.O>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:12]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][C:17]([C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCc4ccccc4C3)nc2c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of methyl 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylate (110 mg, 0.26 mmol, 1.00 equiv, 95%) in methanol (15 mL). This was followed by the addition of a solution of sodium hydroxide (55.7 mg, 1.39 mmol, 5.00 equiv) in water (1.5 mL) dropwise with stiffing. The resulting solution was stirred for overnight at 50° C. in an oil bath. The resulting solution was concentrated under vacuum. The residue was diluted with water. The pH value of the aqueous solution was adjusted to 3-4 with 1N hydrogen chloride. The resulting solids were collected by filtration and washed with methanol. This resulted in 68.1 mg (66%) of 3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-phenylquinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[F:23].[CH2:24]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[C:25]#[CH:26]>C(N(CC)CC)C>[F:23][C:3]1[CH:4]=[C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:7][C:2]=1[C:26]#[C:25][CH2:24][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Br)c(F)c1
Reactant: C#CCN1CCCC1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(C#CCN2CCCC2)c(F)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
A 100 mL Schlenk flask was charged with (4-bromo-3-fluorophenyl)(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)methanone (1.10 g, 2.90 mmol), tetrakis(tri-phenylphosphine)Palladium(0) (0.34 g, 0.29 mmol, 10 mol %), cuprous iodide (0.11 g, 0.58 mmol, 20 mol %), triethylamine (20 mL), and 1-(prop-2-ynyl)pyrrolidine (0.63 g, 5.80 mmol), and the flask was flushed with nitrogen three times. The mixture was stirred at 80° C. for 2 h. The solvent was evaporated under vacuum and the residue was purified by column chromatography to afford the desired product as a yellow solid (0.43 g, 36.4% yield).
Reaction SMILES: Br[CH:2]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][C@@H:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])[CH3:3].[CH3:17][C:18]1[NH:19][C:20]2[C:25]([C:26]=1[CH3:27])=[CH:24][C:23]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:22][CH:21]=2>>[CH3:12][O:11][C:9](=[O:10])[C@@H:8]([O:7][C:6]1[CH:5]=[C:4]([CH:2]([N:19]2[C:20]3[C:25](=[CH:24][C:23]([C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])=[CH:22][CH:21]=3)[C:26]([CH3:27])=[C:18]2[CH3:17])[CH3:3])[CH:16]=[CH:15][CH:14]=1)[CH3:13]
Reactant: COC(=O)[C@H](C)Oc1cccc(C(C)Br)c1
Reactant: C=CCOC(=O)c1ccc2[nH]c(C)c(C)c2c1
Product: C=CCOC(=O)c1ccc2c(c1)c(C)c(C)n2C(C)c1cccc(O[C@@H](C)C(=O)OC)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 2, Example 1, using (2S)-methyl 2-(3-(1-bromoethyl)phenoxy)propanoate and allyl 2,3-dimethyl-1H-indole-5-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[CH2:1]([O:3][C:4]1[C:5]([O:14][CH3:15])=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=1)[CH3:2]
Reactant: CCOc1ccc(C(=O)OC)cc1OC
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOc1cc([N+](=O)[O-])c(C(=O)OC)cc1OC
Temperature: 50 °C

Procedure:
Dissolved 5.00 g (23.7 mmol) methyl 4-ethoxy-3-methoxybenzoate in 25 ml acetic acid under N2 and added 6.1 ml (95.1 mmol) 69% nitric acid dropwise over 30 minutes. Heated to 50° C. for 1.5 hours and poured onto ice bath. Extracted with chloroform, washed with dilute sodium hydroxide solution and filtered through magnesium sulfate. Stripped solvent and dried in vacuo, giving 5.268 of off-white solid: mass spectrum (electrospray m/e): M+H=255.8.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])/[CH:27]=[CH:28]/[C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.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>[NH2:25][C:4]1[C:3]([C:30]#[C:29]/[CH:28]=[CH:27]/[CH2:26][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#C/C=C/CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#C/C=C/CNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 45.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl (2E)-2-penten-4-yn-1-ylcarbamate (194 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (199 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3]1=[O:20].[C:21]1([N:27]=[C:28]=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[O:9]=[C:8]1[N:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[NH:4][C:3](=[O:20])[CH:2]1[NH:1][C:28]([NH:27][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:29]
Reactant: O=C=Nc1ccccc1
Reactant: NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Solvent: ClCCl
Product: O=C(Nc1ccccc1)NC1C(=O)Nc2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a slurry of 3-amino-1-phenyl-1,5-dihydro-benzo [b] [1,4]-diazepine-2,4-dione (0.398 g) in dichloromethane (5 ml) was added phenyl isocyanate (0.177 g) gradually with stirring at ambient temperature. The reaction mixture was stirred two hours at ambient temperature after which time a cream precipitate was separated by filtration to provide the title compound (0.413 g). 1H NMR (300 MHz, DMSO-d6): d 4.97 (d, J=7.5 Hz, 1H), 6.88-6.97 (m, 3H), 7.13-7.47 (m, 12H), 9.16 (s, 1H), 10.78 (br s, 1H); TLC (CH2Cl2 /CH3OH,19:1): Rf =0.21
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:16][O:17][C:18]([CH:20]1[CH2:24][C:23](=[O:25])[N:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19]>CN(C1C=CN=CC=1)C.C1(C)C=CC=CC=1.CCOC(C)=O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:32][C:29]1[CH:28]=[CH:27][C:26]([N:22]2[C:23](=[O:25])[CH2:24][CH:20]([C:18]([O:17][CH3:16])=[O:19])[CH2:21]2)=[CH:31][CH:30]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C1CC(=O)N(c2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)C1
Temperature: 180 °C

Procedure:
A mixture of 4-chloro-6,7-dimethoxy-quinoline (1.0 g, 4.45 mmol), 1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (1.6 g, 6.7 mmol) and DMAP (0.55 g, 4.45 mmol) in 30 mL of toluene (in 5 microwave tubes) was heated in a microwave (Personal Chemistry, Emrys Optimizer) at 180° C. for 1 h. The reaction mixture was cooled to RT and diluted with 60 mL of EtOAc. The solution was washed with 20 mL of satd. NaHCO3 followed by 20 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was further purified with silica gel column chromatography (100% EtOAc to 15% MeOH in EtOAc) to provide colorless glass. MS (ESI pos. ion) m/z: 423.2 (M+H). Calc'd Exact Mass for C23H22N2O6: 422.43.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13]C)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:27])C>>[CH:1]1([N:7]2[C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10](=[O:11])[O:12][C:13]2=[O:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NC1CCCCC1
Product: O=c1oc(=O)n(C2CCCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 81A for the product of Example 3A (0.171 g, 35%). 1H NMR (300 MHz, CDCl3) δ 1.37 (m, 4H), 1.73 (m, 2H), 1.91 (m, 2H), 2.47 (ddd, J=24.82, 12.32, 3.31 Hz, 2H), 5.28 (tt, J=12.27, 3.72 Hz, 1H), 7.24 (dd, J=6.99, 4.04 Hz, 1H), 8.41 (dd, J=7.72, 2.21 Hz, 1H), 8.70 (dd, J=4.78, 2.21 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:30])[CH3:29])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([N:17]4[CH2:21][CH2:20][CH2:19][C:18]4=[O:22])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:23]=1)[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[NH4+:43].C1(S(Cl)(=O)=O)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:43][C:9]1[C:8]2[N:23]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:24][CH2:25][CH2:26][O:27][CH:28]([CH3:29])[CH3:30])[C:7]=2[C:16]2[CH:15]=[CH:14][C:13]([N:17]3[CH2:21][CH2:20][CH2:19][C:18]3=[O:22])=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2cnc3cc(N4CCCC4=O)ccc3c2n1CCCOC(C)C
Reactant: [NH4+]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(N4CCCC4=O)ccc3c2n1CCCOC(C)C
Temperature: 2 °C
Reaction time: 16 h

Procedure:
1-[2-Ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one (0.38 g) was dissolved in chloroform (10 mL). 3-Chloroperoxybenzoic acid (60% pure, 0.37 g) was added in one portion and the mixture was allowed to stir for 16 hours. Ammonium hydroxide (10 mL) was added and the biphasic mixture was cooled to 2° C. with an ice/water bath. Benzenesulfonyl chloride (0.22 mL) was added and the reaction was stirred for 3 hours. The layers were separated and the aqueous fraction was extracted with chloroform. The combined organic fractions were sequentially washed with water and saturated aqueous sodium chloride; dried over anhydrous sodium sulfate; filtered and concentrated under reduced pressure. The residue was purified by column chromatography on a Biotage Horizon™ High-Performance Flash Chromatography instrument using a silica gel cartridge. The polar component of the eluent was chloroform:methanol:ammonium hydroxide 80:18:2 (CMA). The purification was carried out eluting with chloroform:CMA in a gradient from 99:1 to 73:27. Fractions containing product were combined and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to afford 0.14 g of 1-[4-amino-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinolin-7-yl]pyrrolidin-2-one as a white solid, mp 165-167° C.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].C(N(CC)CC)C.[C:21]1([C:27](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>ClCCl>[C:21]1([C:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: OCCOCCOCCOCCO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: OCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 96.7 %

Procedure:
To tetraethylene glycol (213.65 g, 1.1 mol) and triethylamine (20.24 g, 27.8 ml, 200 mmol) in dry dichloromethane (1500 ml) was added dropwise triphenylmethyl chloride (27.88 g, 100 mmol) in dry dichloromethane (500 ml). This solution was left to stir under argon at room temperature for 24 hours. After 24 hours, the reaction was concentrated in vacuo to give a mixture of product and starting material as a yellow oil. This oil was then re-dissolved in dichloromethane (1000 ml), partitioned with sat. aq. NaHCO3 (500 ml), water (3×400 ml) and finally sat. aq. NaCl (500 ml). The organic layer was separated, dried over anhydrous sodium sulphate and concentrated in vacuo to give the title compound as a yellow oil (42.2 g, 95%) which was used without further purification.
Reaction SMILES: NC(N)=S.ClCC([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[CH:10]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=O>C(O)C>[CH3:20][O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[O:21][CH3:22])[CH:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:9][CH2:18][CH2:17]2
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)N(C(=O)CCl)CC2
Agent: NC(N)=S
Solvent: CCO
Product: COc1cc2c(cc1OC)C(c1ccccc1)NCC2

Procedure:
Heat a mixture of thiourea (45 mg), the product of step B and ethanol (8 mL) at reflux for 3 h. Remove the solvent in vacuo, dissolve the residue in chloroform and filter. Concentrate the filtrate to give 153 mg of the title compound. 1H NMR (CDCl3): δ7.4-7.18 (5H, m); 6.63 (1H, s); 6.24 (1H, s); 5.03 (1H, s); 3.85 (3H, s); 3.61 (3H, s); 3.28-2.65 (4H, m); 2.3 (1H, br. s).