Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12].[F:30][C:31]1[CH:36]=CC(F)=[CH:33][C:32]=1[N+]([O-])=O.C([N:43]([CH2:46][CH3:47])CC)C>C(O)C>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[C:11]([NH:13][C:14]1([C:20]([NH:22][CH:23]2[CH2:28][CH2:27][N:26]([C:33]3[CH:32]=[C:31]([F:30])[CH:36]=[CH:47][C:46]=3[NH2:43])[CH2:25][CH:24]2[OH:29])=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:12]
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Reactant: CCN(CC)CC
Reactant: O=C(NC1(C(=O)NC2CCNCC2O)CCCCC1)c1cc2ccccc2o1
Agent: Cl
Solvent: CCO
Product: Nc1ccc(F)cc1N1CCC(NC(=O)C2(NC(=O)c3cc4ccccc4o3)CCCCC2)C(O)C1

Procedure:
To the solution of 4-[N-[1-[N-(benzofuran-2-ylcarbonyl)amino]cyclohexanecarbonyl]amino]-3-piperidinol hydrochloride (6.0 g) obtained in Step 2 of Example 1 in 50 ml of ethanol, were added 3.7 ml 2,5-difluoronitrobenzene and 4.8 ml triethylamine. The reaction mixture was refluxed overnight and concentrated. The resulting residue was filtered and dried to give 7.2 g of the titled compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11](SC)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1.ClC1C=C(C=CC=1)C(OO)=O.CCN(C(C)C)C(C)C.[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([C:43]2[CH:49]=[CH:48][C:46]([NH2:47])=[CH:45][CH:44]=2)[CH2:39][CH2:38]1>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]2[CH:9]=[N:10][C:11]([NH:47][C:46]3[CH:45]=[CH:44][C:43]([N:40]4[CH2:39][CH2:38][N:37]([CH3:36])[CH2:42][CH2:41]4)=[CH:49][CH:48]=3)=[N:12][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: CSc1ncc2c(=O)n(C)nc(C)c2n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(C)c(=O)c2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of Example 1C (100 mg, 0.450 mmol) in dichloromethane (1.5 mL) was added meta-chloroperoxybenzoic acid (122 mg, 0.495 mmol) in a single portion. After 1 hour, the reaction mixture was partitioned between 10% sodium thiosulfate solution and ethyl acetate. The layers were separated, and the organic layer was washed with saturated sodium bicarbonate solution, dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (3 mL). Hunig's base (157 μl, 0.900 mmol) and 4-(4-methylpiperazin-1-yl)aniline (86 mg, 0.450 mmol) were added to the solution, and the reaction mixture was heated at 100° C. overnight. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure. The crude residue was purified by RP-MPLC (125 g C-18 silica gel), eluting with a gradient of 5 to 50% acetonitrile in water each containing 0.1% TFA, to provide the title compound. MS ESI(+) m/z 366.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6): δ ppm 10.33 (s, 1H), 9.22 (s, 1H), 7.77-7.62 (m, 2H), 6.99-6.91 (m, 2H), 3.63 (s, 3H), 3.20-3.02 (m, 4H), 2.46-2.43 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30]OS(C)(=O)=O.[NH:37]1[CH:41]=[CH:40][N:39]=[CH:38]1.[H-].[Na+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([F:36])[C:5]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:20])[CH3:21])=[C:13]([F:24])[CH:12]=3)=[CH:8][C:7](=[O:25])[C:6]=2[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][N:37]1[CH:41]=[CH:40][N:39]=[CH:38]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCOS(C)(=O)=O)c(F)cc(F)c3o2)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCn4ccnc4)c(F)cc(F)c3o2)cc1F
Reaction time: 4.5 h
Yield: 87.9 %

Procedure:
719 mg (1.37 mmol) of the above 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-(3-methanesulfonyloxypropylamino)-4H-1-benzopyran-4-one was dissolved in 30 mL of dimethylformamide under argon atmosphere, 932 mg (13.7 mmol) of imidazole and 657 mg (16.4 mmol) of sodium hydride (60% oil dispersion) were added and the mixture was stirred for 4.5 hours. Water was added to the reaction solution and the mixture was extracted once with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:l) to give 600 mg of 6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-5-[3-(imidazol-1-yl)propylamino]-4H-1-benzopyran-4-one (yield: 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2.[N+:12]([O-:15])(O)=[O:13].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:16]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:15])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)(=[O:18])[CH3:17]
Reactant: O=[N+]([O-])O
Reactant: COc1ccc2c(c1)CCN2
Reactant: CC(=O)OC(C)=O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(C)=O)CC2
Reaction time: 1 h
Yield: 62 %

Procedure:
To a solution of 5-(methyloxy)-2,3-dihydro-1H-indole (10.4 g, 54.4 mmol, 1.0 eq) in acetic anhydride (150 mL) was added dropwise fuming nitric acid (3.43 g, 54.4 mmol, 1.0 eq) at 0° C., then the mixture was stirred for 1 hour at r. t. After stirring for 1 hour the yellow precipitate which formed was filtered via Buchner funnel and washed with water and dried in vacuo to give 1-acetyl-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole as a yellow solid (8.0 g, 62% yield). 1H-NMR (CDCl3, 300 MHz) δ 8.43 (s, 1H), 7.31 (s, 1H), 4.13 (t, 2H), 3.87 (s, 3H), 3.22 (t, 2H), 2.14 (s, 3H).
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[Si:9]([O:26][CH:27]1[CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]1)([C:22]([CH3:25])([CH3:24])[CH3:23])([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O.O>[C:22]([Si:9]([O:26][CH:27]1[CH2:32][CH2:31][C:30]2([O:33][CH2:4]2)[CH2:29][CH2:28]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH3:25])([CH3:23])[CH3:24]
Reactant: C[S+](C)(C)=O
Reactant: CC(C)(C)[Si](OC1CCC(=O)CC1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)[Si](OC1CCC2(CC1)CO2)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of sodium hydride (60% in mineral oil, 441 mg, 11.0 mmol) in dimethylsulfoxide (7 mL) was added trimethylsulfoxonium iodide (2.53 g, 11.5 mmol) at room temperature, and the mixture was stirred at room temperature for 30 min. To this mixture was added a solution of 4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexanone (3.53 g, 10.0 mmol, Okamura, William H. et al., J. Org. Chem., 1993, 58, 600) in dimethylsulfoxide (35 mL) dropwise at room temperature, and the mixture was stirred at room temperature for 2 h. Then the mixture was diluted with water (600 mL), and extracted with diethyl ether (200 mL×4). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel eluting with ethyl acetate/n-hexane (1:10), and then purified with plate TLC eluting with ethyl acetate/n-hexane (1:15) to give 459 mg (13%, trans) and 390 mg (11%, cis) of the title compound as a colorless oil respectively.
Reaction SMILES: O1CCCC1.[CH2:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](Cl)=[N:18][OH:19])=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9].[C:21]([C:23]1[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=1)#[CH:22].C(N(CC)CC)C>O>[CH2:6]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]3[C:24]([NH2:29])=[N:25][CH:26]=[CH:27][CH:28]=3)[O:19][N:18]=2)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9]
Reactant: C#Cc1cccnc1N
Reactant: CCCCc1ccc(CC(Cl)=NO)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCc1ccc(Cc2cc(-c3cccnc3N)on2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-butyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.665 mmol) described in Manufacturing Example 70-1-3 and 3-ethynyl-pyridin-2-ylamine (50 mg, 0.424 mmol) described in Manufacturing Example 1-2-3 was added triethylamine (232 μL, 1.66 mmol) at room temperature, which was stirred for 8 hours at 50° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (55 mg, 18%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]\[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8].FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]\[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(/C=C(/C(=O)OC(C)(C)C)c2ccco2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(/C=C(/C(=O)O)c2ccco2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Combine (E)-2-(fur-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester (112 mg, 0.19 mmol) and trifluoroacetic acid (2 mL) in dichloromethane (5 mL). After 2 hours, evaporate in vacuo, add dichloromethane and evaporate in vacuo to give the title compound.
Reaction SMILES: [Li]CCCC.[CH3:6][C:7]#[N:8].CO[C:11](=[O:25])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[N:20]=[CH:21]N(C)C>C1COCC1>[CH3:19][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[NH:20][CH:21]=[C:6]([C:7]#[N:8])[C:11]2=[O:25]
Reactant: CC#N
Reactant: COC(=O)c1cccc(OC)c1N=CN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc2c(=O)c(C#N)c[nH]c12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 77.5 %

Procedure:
To 35.0 mL of THF was added 26.6 mL (66.4 mmol) of n-BuLi solution during 5 min at −78° C. To the stirred solution was added a solution of 3.55 mL (67.9 mmol) of CH3CN in 65 mL of THF during 10 min which time the solution became white suspension, and then continued to stir for 15 min at −78° C. To the suspension was added a solution of 5.8 g (24.5 mmol) of 2-(Dimethylamino-methyleneamino)-3-methoxy-benzoic acid methyl ester in 45 mL of THF during 30 min, and then continued to stir 30 min at −78° C. during which time the mixture gradually became clear. The solution was quenched with 8.5 mL of HOAc. The resulting thick slurry was stirred and warmed to room temperature. After most of the solvent was evaporated, the residue was diluted with cold water. The separate solid was collected by filtration and washed with water. After drying in vacuo, this afforded 3.8 g of the product as an off white solid in 77.6% of yield, m.p. 270° C. (dec.), mass spectrum (electrospray, m/e): M+H 201.1
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:25])([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)[C:14]([F:17])([F:16])[F:15]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:22][C:21]1[CH:20]=[CH:19][C:18]([C:13]([F:12])([F:25])[C:14]([F:15])([F:16])[F:17])=[CH:24][CH:23]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: Nc1ccc(C(F)(F)C(F)(F)F)cc1
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cnc(Cl)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 11.2 using 5-bromo-6-chloro-nicotinic acid and 4-pentafluoroethyl-aniline to afford a white crystalline solid. HPLC (Condition 4) tR=6.61 min, UPLC-MS (Condition 3) tR=1.32 min, m/z=429 [M−H]−.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[F:13].[CH3:14][Si:15]([CH3:18])([CH3:17])Cl.C1COCC1>CCCCCC.O>[F:6][C:7]1[C:8]([F:13])=[CH:9][CH:10]=[CH:11][C:12]=1[Si:15]([CH3:18])([CH3:17])[CH3:14]
Reactant: Fc1ccccc1F
Reactant: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: C[Si](C)(C)c1cccc(F)c1F
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
12.5 ml of a 1.6-molar solution of n-butyllithium in hexane is added dropwise at 0° C. to a mixture of 0.02 mol of 1,2-difluorobenzene, 0.02 mol of trimethylchlorosilane and 25 ml of THF. After stirring at room temperature for 1.5 hours, the reaction mixture is poured into water, the phases are separated, and the aqueous phase is extracted with 2×50 ml of methylene chloride. Drying over magnesium sulfate, evaporation of the solvent and chromatography give the pure product.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[N:19](C(C)=C)[C:18]3=[O:30])[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl.C(O)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:17]3[C:21]4[CH:22]=[C:23]([CH3:26])[CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:30])[CH2:10][CH2:9]2)=[O:7])=[CH:31][CH:32]=1
Reactant: C=C(C)n1c(=O)n(CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)c2cc(C)ccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc2[nH]c(=O)n(CCCN3CCC(C(=O)c4ccc(F)cc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
A mixture of 4.5 parts of 3-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-5-methyl-1-(1-methylethenyl)-2H-benzimidazol-2one, 24 parts of a concentrated hydrochloric acid solution, 80 parts of ethanol and 50 parts of water is stirred for 2 hours at room temperature. The reaction mixture is evaporated and the residue is stirred in water. The whole is alkalized with ammonium hydroxide. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 4-methyl-2-pentanone, yielding 1 part (25%) of 1-{3-[4-(4-fluorobenzoyl)-1-piperidinyl]propyl}-1,3-dihydro-6-methyl-2H-benzimidazol-2-one; mp. 149.7° C
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH2:19][O:18][CH2:17]1.O.C(#N)C>ClCCl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:20](=[O:21])[CH2:19][O:18][CH2:17][C:16]([OH:23])=[O:22])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: O=C1COCC(=O)O1
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: [N-]=[N+]=NCCOCCOCCOCCNC(=O)COCC(=O)O
Reaction time: 8 h

Procedure:
To a solution of 11-azido-3,6,9-trioxaundecanamine (10.9 g, 50.0 mmol) in dichloromethane (100 ml) was added diglycolic anhydride (6.38 g, 55.0 mmol). The reaction mixture was stirred overnight. HPLC analysis (column Vydac 218TP54; solvents: A=water/0.1% TFA and B=acetonitrile/0.1% TFA; gradient 4-16% B over 20 min; flow 1.0 ml/min; UV detection at 214 and 284 nm), showed complete conversion of starting material to a product with retention time 18.3 min. The solution was concentrated to give quantitative yield of a yellow syrup. The product was analysed by LC-MS (ES ionisation) giving [MH]+ at 335 as expected. 1H (500 MHz) and 13C (125 MHz) NMR spectroscopy was in agreement with structure The product was used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=2[F:20])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN1CCOCC1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[C:43]([O:47][C:48](=[O:55])[N:49]([CH2:51][CH2:52][O:53][NH2:54])[CH3:50])([CH3:46])([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[C:43]([O:47][C:48](=[O:55])[N:49]([CH2:51][CH2:52][O:53][NH:54][C:5]([C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([F:1])[C:3]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[F:20])=[O:7])[CH3:50])([CH3:46])([CH3:44])[CH3:45]
Reactant: CN(CCON)C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CN(CCONC(=O)c1ccc(F)c(F)c1Nc1ccc(I)cc1F)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 73.3 %

Procedure:
A solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid (3.11 g, 7.91 mmol) in tetrahydrofuran (20 mL) was cooled with a −40° C. bath and treated with N-methylmorpholine (0.87 mL, 7.9 mmol). Diphenylphosphinic chloride (2.00 mL, 10.5 mmol) was added dropwise over 5 min and the reaction mixture was stirred for 90 min, during which time the temperature of the cooling bath slowly warmed to 0° C. The reaction mixture was again cooled to −40° C. and (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (2.00 g, 10.5 mmol) was added as a solution in tetrahydrofuran (6 mL). After an additional 10 min, N-methylmorpholine (1.33 mL, 12.1 mmol) was added. The temperature of the cooling bath was allowed to warm to ambient temperature over 4 h and the reaction mixture was further stirred overnight. The reaction was diluted with ethyl acetate (40 mL) and washed with saturated aqueous ammonium chloride (2×10 mL). The organics were dried over magnesium sulfate, concentrated and purified by silica gel chromatography. Elution with 35% ethyl acetate-hexanes afforded [2-({1-[3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (3.28 g, 73% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ 11.84 and 11.75 (br s, 1H total), 8.66 (br s, 1H), 7.54 (dd, J=10.9, 1.6 Hz, 1H), 7.36 (br t, J=8.8 Hz, 1H), 7.33 (br d, J=8.8 Hz), 7.20 (m, 1H), 6.64 (m, 1H), 3.85 (t, J=5.2 Hz, 2H), 3.34 (br s, 2H), 2.81 and 2.79 (br s, 3H total), 1.34 and 1.32 (s, 9H total); 19F NMR (376 MHz, DMSO-d6) δ −128.0 (d, J=32.9 Hz), −133.0, −144.2 (d, J=17.7 Hz); MS (APCI−)=564.1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[CH3:28][C:29]1([CH3:36])[O:33][CH:32]([CH2:34]O)[CH2:31][O:30]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:14]4[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:24])[C:6]([C:25]([O:27][CH2:34][CH:32]3[CH2:31][O:30][C:29]([CH3:36])([CH3:28])[O:33]3)=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)CC1
Reactant: CC1(C)OCC(CO)O1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)OCC2COC(C)(C)O2)cn3C2CC2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
1-cyclopropyl-6-fluoro-4-oxo-7-(4-propylpiperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid (8.86 g, 23.70 mmol) was dissolved in anhydrous dichloromethane (370 ml) under argon. 2,2-dimethyl-1,3-dioxolane-4-methanol (4.71 g, 35.60 mmol), triethylamine (9.59 g, 94.80 mmol) and HBTU (9.90 g, 26.10 mmol) were added and the reaction mixture was stirred at room temperature for three days (exclusion of light). The reaction mixture was washed with saturated NaHCO3 solution (500 ml), aqueous (pH 5) hydrochloric acid (500 ml) and water (500 ml) successively. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure, yielding 10.28 g (89%) of a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[C:19]([CH3:31])[CH:18]=1)=[N:9][CH:10]=[N:11]2.[C:32]([OH:36])(=O)[CH2:33][OH:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O>[OH:34][CH2:33][C:32]([N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=3)=[C:19]([CH3:31])[CH:18]=1)=[N:9][CH:10]=[N:11]2)=[O:36]
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c12
Reactant: O=C(O)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2ccc(Nc3ncnc4cccc(OCCN(C)C(=O)CO)c34)cc2C)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
5-[2-(Methylamino)ethoxy]-N-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}quinazolin-4-amine (32 mg, 0.077 mmol) and glycolic acid (6 mg, 0.085 mmol) were dissolved in DMA (10 ml). HATU (32 mg, 0.085 mmol) was added, and the mixture was stirred at ambient temperature for 16 hours. The mixture was concentrated in vacuo, and the residue purified by reverse-phase HPLC, eluting with 5 to 50% acetonitrile in H2O containing 0.2% TFA. The appropriate fraction was evaporated, and the residue dissolved in methanol/DCM (1:1, 25 ml). The mixture was neutralised by stirring overnight with tetraalkylammonium carbonate, polymer bound. The mixture was filtered, and the filtrate was evaporated. Crystallisation from ethyl acetate/iso-hexane gave 2-hydroxy-N-methyl-N-(2-{[4-({3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)quinazolin-5-yl]oxy}ethyl)acetamide as a white crystalline solid (22 mg, 60%); NMR Spectrum (DMSO-d6, 400 MHz, 373K) 2.26 (s, 3H), 2.48 (s, 3H), 3.02 (s, 3H), 3.95 (t, 2H), 4.02-4.11 (m-3H), 4.55 (t, 2H), 6.96 (d, 1H), 7.20 (d, 1H), 7.23 (m, 2H), 7.38 (d, 1H), 7.65 (dd, 1H), 7.70 (d, 1H), 7.73 (dd, 1H), 8.20 (m, 1H), 8.49 (s, 1H), 9.77 (s, 1H); Mass spectrum MH+ 473.9
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([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:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[NH:28]1[C:32]2[CH2:33][CH2:34][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:36][C:31]=2[N:30]=[CH:29]1.ClCCl>O>[C:9]([N:28]1[C:32]2[CH2:33][CH2:34][CH:35]([C:37]([O:39][CH3:40])=[O:38])[CH2:36][C:31]=2[N:30]=[CH:29]1)([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:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)C1CCc2[nH]cnc2C1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C1CCc2c(ncn2C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
Triethylamine (4.7 ml) and chlorotriphenylmethane (9.37 g) were added to a mixture of methyl 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylate (6.73 g) and dichloromethane (70 ml), followed by stirring at room temperature overnight. Water was added to the reaction solution, followed by extraction with dichloromethane, the organic layer was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform) to obtain a mixture (10.13 g) of methyl 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylate and methyl 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-6-carboxylate. Methanol (50 ml), water (20 ml) and sodium hydroxide (4.78 g) were added to the obtained mixture, followed by heating to reflux overnight. The reaction solution was concentrated, water and concentrated hydrochloric acid (8 ml) were added to the residue, and the precipitated solid was collected by filtration, washed with water and acetone and dried under reduced pressure to obtain a mixture (7.07 g) of 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid and 1-trityl-4,5,6,7-tetrahydro-1H-benzimidazole-6-carboxylic acid, as a colorless solid.