Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH:14][C:15](=O)[C:16]([F:25])([F:24])[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)(=[O:3])[NH2:2].C(N(CC)CC)C.C[Si](Cl)(C)C>ClCCCl>[F:24][C:16]([F:25])([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[C:15]1[N:2]=[C:1]([OH:3])[C:4]2[C:5](=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=2)[N:14]=1
Reactant: COC(=O)c1ccc(C(N)=O)c(NC(=O)C(F)(F)c2ccc(F)cc2)c1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COC(=O)c1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Temperature: 85 °C
Yield: 90.2 %

Procedure:
To a solution of methyl 4-carbamoyl-3-(2,2-difluoro-2-(4-fluorophenyl)acetamido)benzoate (1.3 g, 3.5 mmol) in DCE (20 mL) were added triethylamine (20 mL, 142 mmol) and trimethylsilyl chloride (6.7 mL, 53.2 mmol and the mixture was heated 85° C. overnight. The mixture was allowed to cool to rt, and then was concentrated under reduced pressure. The residue was partitioned between EtOAc (150 mL) and H2O (100 mL), and the separated aqueous phase was extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with MeOH with sonication, and the solid was collected by filtration to afford methyl 2-(difluoro(4-fluorophenyl)methyl)-4-hydroxyquinazoline-7-carboxylate (1.1 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 3.91 (s, 3H), 7.39 (t, 2H), 7.78 (t, 2H), 8.06 (d, 1H), 8.16 (s, 1H), 8.27 (d, 1H), 13.34 (s, 1H); LC-MS (ESI) m/z 349 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O.O1CCOCC1>[ClH:19].[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Oc1ccc(Cl)cc1OC1CNC1
Reaction time: 18 h

Procedure:
To 3-(5-Chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.80 g, 2.7 mmol) in EtOAc (2 mL) was added 4M HCl in dioxane (5 mL). After 18 h, EtOAc was added and the resulting white solid filtered to give 2-(azetidin-3-yloxy)-4-chloro-phenol hydrochloride as a white solid. To a CH2Cl2 (25 mL) solution of this compound was added Et3N (0.30 g, 0.42 mL, 3.0 mmol) and TFAA (0.58 g, 0.38 mL, 2.8 mmol). After 18 h, H2O was added and the reaction extracted with CH2Cl2 (2×). The combined organics were dried and concentrated to give 0.54 g (74% yield 2 steps) of the title compound as a brown oil that was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH:37]=[CH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:38][CH:37]=[CH2:36])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: C=CCBr
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: C=CCOc1ccc(OC)c2c1C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with allyl bromide
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=1)([CH3:14])[CH3:13])[CH2:2]2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10](=[O:23])[NH:11][C:12]([C:15]1[CH:16]=[C:17]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:18]([F:21])=[CH:19][CH:20]=1)([CH3:14])[CH3:13])[CH2:2]2
Reactant: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CC(C)(NC(=O)OC1CN2CCC1CC2)c1ccc(F)c(-c2ccc(F)cc2)c1
Yield: 117.1 %

Procedure:
Using general procedure E, 1-azabicyclo[2.2.2]oct-3-yl[2-(3-bromo-4-fluorophenyl)propan-2-yl]carbamate (125 mg, 0.324 mmol), 4-fluoroboronic acid (64 mg, 0.46 mmol) and palladium (II) acetate gave the title compound as a white solid (76 mg, 56%). 1H NMR (400 MHz, CDCl3) δ 7.48 (t, 2H), 7.44-7.29 (m, 2H), 7.21-7.00 (m, 3H), 5.27 (s, 1H), 4.68-4.55 (m, 1H), 3.29-2.10 (m, 6H), 1.67 (d, J=9.4 Hz, 6H), 2.01-0.69 (m, 5H) ppm. 13C NMR (100 MHz, CDCl3) δ 163.9, 161.4, 159.8, 157.3, 154.8, 143.5, 132.2, 130.9, 127.9, 127.8, 127.4, 125.9, 125.8, 116.2, 116.0, 115.7, 115.5, 71.4, 66.1, 55.9, 47.6, 46.7, 30.0, 39.7, 25.6, 24.8, 19.8 ppm. Purity: 98% UPLCMS (210 nm): retention time 0.96 min; (M+1) 400.9.
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[C@H:3]([NH2:10])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][O:21][CH3:22]>CC#N>[CH3:22][O:21][CH2:20][CH2:19][NH:10][C@@H:3]([CH:2]([CH3:11])[CH3:1])[CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: CC(C)[C@H](N)CN1CCCC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN[C@H](CN1CCCC1)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(S)-3-Methyl-1-(pyrrolidin-1-yl)butan-2-amine (0.24 g, 1.54 mmol), which is commercially available, and potassium carbonate (0.139 mL, 2.30 mmol) was slurried in MeCN. 1-Bromo-2-methoxyethane (0.147 mL, 1.54 mmol) was added and the reaction was stirred at rt for 2 h. LMCS showed only traces of the desired product. DIPEA (0.535 mL, 3.07 mmol) was added and the resultant mixture was stirred at rt over night and heated at 60° C. for 4 h. The mixture was cooled to rt and diluted with water (50 mL) and DCM (50 mL). The two layers were separated and the water layer was extracted with DCM (3×100 mL). The organic layers were combined and washed with brine (100 mL), passed through phase separator and concentrated under reduced pressure to give the title compound (0.31 g, 97%). The obtained crude product was used without further purification. LCMS (M+H)+: 215.
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:47])[NH:21][CH2:22][C:23]([N:25]2[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@@H:28]([C:36]([O:38]C)=[O:37])[S:27][C@H:26]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:24])[CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]([C@H:11]([C:13]1[CH:14]=[C:15]([NH:19][C:20](=[O:47])[NH:21][CH2:22][C:23]([N:25]2[C@@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C@H:28]([C:36]([OH:38])=[O:37])[S:27][C@H:26]2[C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[O:24])[CH:16]=[CH:17][CH:18]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc([C@H](C)C(=O)OCc3ccccc3)c2)[C@H]1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](C(=O)OCc1ccccc1)c1cccc(NC(=O)NCC(=O)N2[C@H](C(=O)OC(C)(C)C)S[C@@H](C(=O)O)[C@@H]2c2ccccc2)c1
Yield: 51.1 %

Procedure:
The process is performed as in Example 3, but starting with 0.3 g of methyl (2S,4S,5S)-3-{2-{3-[(S)-3-(1-benzyloxycarbonylethyl)phenyl]ureido}acetyl}-2-tert-butoxycarbonyl-4-phenyl-5-thiazolidinecarboxylate and 4.5 ml of aqueous 0.1N sodium hydroxide solution. 0.15 g of (2S,4S,5R)-3-{2-{3-[(S)-3-(1-benzyloxycarbonylethyl)phenyl]ureido}acetyl}-2-tert-butoxycarbonyl-4-phenyl-5-thiazolidinecarboxylic acid is thus obtained in the form of a white solid melting at 96° C., [α]D25 =+6°±1° (c=0.46; MeOH); 1H NMR (250 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.45 (d, J=7.5 Hz, 3H: CH3); 1.51 (s, 9H: CH3 of the tert-butyl); 3.66 and 4.05 (broad d and d respectively, J=17.5 Hz, 1H each: COCH2N); 3.77 (q, J=7.5 Hz, 1H: CHCOO); 4.19 (d, J=4 Hz, 1H: H at C5 of the ring); 5.12 (s, 2H: OCH2); 5.71 (s, 1H: H at C2 of the ring); 5.77 (d, J=4 Hz, 1H: H at C4 of the ring); 6.85 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH)); 7.15 (t, J=7.5 Hz, 1H: aromatic H (meta to the CH); from 7.20 to 7.50 (mt, 10H: aromatic H); 7.72 (broad d, J=7.5 Hz, 2H: H ortho to the phenyl at position 4).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])=[CH:16][C:15]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[CH:14][CH:13]=2.C(N(CC)CC)C>ClCCl>[CH2:33]([O:32][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[CH:10][C:9]3[N:8]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:19]([CH2:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH3:22])[C:18]=3[C:17]=2[CH:16]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)(CNc1c(N)cnc2ccc(OCc3ccccc3)cc12)NC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.2 %

Procedure:
Ethoxyacetyl chloride (3.5 mL, 32.0 mmol) was added to a solution of tert-butyl [2-(3-amino-6-benzyloxyquinolin-4-ylamino)-1,1-dimethylethyl]carbamate (12.71 g, 29.1 mmol) and triethylamine (8.1 mL, 58.2 mmol) in approximately 250 mL of anhydrous dichloromethane. After stirring for 2 hours, the volatiles were removed under reduced pressure and the resulting brown residue was dissolved in ethanol, followed by the addition of 8.1 mL of triethylamine. The reaction was heated at reflux for 2.5 days and then cooled to ambient temperature. The solvent was removed under reduced pressure and dichloromethane was added. The solution was sequentially washed with aqueous sodium bicarbonate (2×) followed by brine; dried over sodium sulfate; filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on a HORIZON HPFC system. A silica gel cartridge was used eluting with a gradient of 0-15% CMA in chloroform to provide 8.4 g of tert-butyl [2-(8-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethylethyl]carbamate as an orange foam.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17])(=O)C.[OH-].[Na+]>C(O)C>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:7][C:6]=1[N+:16]([O-:18])=[O:17]
Reactant: CCCCSc1ccc(NC(C)=O)c([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCSc1ccc(N)c([N+](=O)[O-])c1

Procedure:
3 G. of 1-acetamido-4-n-butylthio-2-nitrobenzene (prepared according to Example I) is hydrolyzed by treatment with 6 ml. 5N NaOH and 6 ml. ethanol on the steam bath for one hour. The mixture is concentrated and extracted with chloroform. Removal of the solvent leaves 1-amino-4-n-butylthio-2-nitrobenzene as a red oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C:9](=[N:20]O)[CH2:8][CH:7]1[CH3:22])=[O:5])[CH3:2].[OH-].[K+]>C(O)C.[Al].[Ni]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2C(=NO)CC1C
Agent: [Ni]
Agent: [Al]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N)C[C@@H]1C
Reaction time: 0.58 h
Yield: 64.9 %

Procedure:
To a stirred solution of 4-hydroxyimino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (11.0 g, 34.1 mmol) in ethanol (100 mL) and aqueous 2N KOH (102 mL, 205 mmol) was added aluminum-nickel alloy (11.7 g, 136 mmol) in portions over 15 min. The reaction was stirred for 35 min, then filtered through a pad of Celite®, rinsing with ethanol. The volatiles were removed in vacuo, and the resulting aqueous phase was extracted with ethyl acetate (3×150 mL). The combined organic phases were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to give 16.32 g of crude product. Purification by silica gel chromatography using 0-4% methanol in dichloromethane as eluent afforded the title compound (6.51 g, 65%): 1H NMR (CDCl3) δ1.19 (d, 3H, J=6 Hz), 1.25 (m, 1H), 1.28 (t, 3H, J=7 Hz), 2.4 (m, 1H), 3.76 (m, 1H), 3.86 (s, 3H), 3.90 (s, 3H), 4.10-4.35 (m, 2H), 4.5 (m, 1H), 6.96 (s, 1H), 7.0 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=1[C:10]([O:12]C)=[O:11].FC(F)(F)S(O[CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])(=O)=O>CC(=O)CC>[F:7][C:8]1[CH:17]=[C:16]([O:18][CH2:25][CH2:26][C:27]([F:30])([F:29])[F:28])[CH:15]=[CH:14][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: O=S(=O)(OCCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)c1ccc(OCCC(F)(F)F)cc1F
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 40 %

Procedure:
Potassium carbonate (663 mg) was added to a 2-butanone (6 mL) solution of methyl 2-fluoro-4-hydroxybenzoate (compound described in U.S. Pat. No. 5,990,142 A1, 340 mg) and 3,3,3-trifluoropropyl trifluoromethanesulfonate (compound described in Tetrahedron, (1988), 44, 5375-5388, 590 mg). The mixture was stirred at 75° C. for 1.5 hours, and then the solvent was evaporated. To the obtained residue were added methanol (8 mL) and a 2 M sodium hydroxide aqueous solution (2 mL). The mixture was stirred at 60° C. for 1.5 hours, and the solvents (mainly methanol) were evaporated. To the residue was added water (15 mL), and the mixture was changed to acidic by adding 1 M hydrochloric acid thereto while stirring. The precipitated crystalline solid was collected by filtration, washed with water, and dried under reduced pressure to give 203 mg of the title compound (white crystal, yield: 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([NH2:6])=[O:5].C(N(CC)CC)C.Cl[C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>C1COCC1>[NH2:6][C:4]([C:3]1[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=1[NH:1][C:20](=[O:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:5]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NC(=O)c1c(N)cccc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(=O)Nc1cccc(F)c1C(N)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
To a solution of 2-amino-6-fluorobenzamide (3.80 g, 24.7 mmol) and triethylamine (2.99 g, 29.6 mmol) in THF (50 mL) was added dropwise ethyl chloroglyoxylate (3.70 g, 27.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 3 hr. The mixture was partitioned between ethyl acetate and water, and the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was suspended in ethanol, and the insoluble material was collected by filtration to give ethyl ((2-(aminocarbonyl)-3-fluorophenyl)amino)(oxo)acetate as a white powder (4.95 g, 79%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[CH:6][CH:5]=1.C(I)[I:19].[N+]([O-])(OCCC(C)C)=O>>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=2)[CH:7]=[C:6]([I:19])[CH:5]=1
Reactant: ICI
Reactant: COC(=O)c1cccc(-c2ccc(C)cn2)c1
Agent: CC(C)CCO[N+](=O)[O-]
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cn2)c1

Procedure:
5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester was treated with methylene iodide and isoamyl nitrate using the procedure of step 5 of preparation 6, to afford 3-iodo-5-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester, MS (M+H)=353.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([F:27])[C:24]([O:28][CH3:29])=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.C([O:39][C@@H:40]([CH3:44])[C:41](Cl)=[O:42])(=O)C>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[C:24]([O:28][CH3:29])[C:25]([F:27])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:41](=[O:42])[C@@H:40]([OH:39])[CH3:44])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)cc1F
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f45) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(I)c(F)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 3-fluoro-4-iodobenzoic acid (1.3 g, 4.9 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. was added oxalyl chloride (1.2 mL, 15.0 mmol) followed by catalytic DMF (7 drops). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, and then concentrated in vacuo to provide 1.2 g of 3-fluoro-4-iodobenzoyl chloride as a yellow solid. The acid chloride (600 mg, 2.1 mmol) was dissolved in anhydrous CH2Cl2, and dimethylamine (2.1 mL, 4.2 mmol, 2M in THF) was added followed by triethylamine (0.6 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with CH2Cl2. The organic layer was washed with water, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting solid was stirred with diethyl ether and filtered to afford 353 mg of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (dd, 1H), 7.32 (dd, 1H), 7.04 (dd, 1H), 2.97 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[NH:5][C:4]=2[N:3]=1.C([O-])([O-])=O.[Na+].[Na+].Br[CH2:24][CH2:25][CH2:26][C:27]#[N:28].N1CCOCC1.Cl>CN(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.O.C(OCC)(=O)C>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:24][CH2:25][CH2:26][C:27]#[N:28])[C:4]=2[N:3]=1
Reactant: N#CCCCBr
Reactant: C=CCn1c(Cl)nc2[nH]c(=O)n(C)c(=O)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2[nH]c(Cl)nc2n(CCCC#N)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To a mixture of 8-chloro-1-methyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (70 mg, 0.292 mmol) and Na2CO3 (37 mg, 0.35 mmol) in DMF (3 ml) was added 4-bromobutyronitrile (0.035 ml, 0.35 mmol). The mixture was stirred at room temperature overnight, before degassing under a gentle vacuum and introducing nitrogen. Pd(PPh3)4 (50 mg, 0.044 mmol) and morpholine (0.254 ml, 2.92 mmol) was then added sequentially. After two hours stirring at room temperature further fresh Pd(PPh3)4 (50 mg, 0.044 mmol) was added and stirring continued overnight. The reaction mixture was partioned between ethyl acetate (20 ml) and water (20 ml) adding a small amount of 2M HCl to aid separation. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed down an amino-propyl SPE (5 g), eluting with MeOH followed by 3-5% AcOH/MeOH. The product fraction was concentrated to afford the title compound 39.7 mg (51%); NMR; δH (400 MHz, d6-DMSO) 1.91-2.00 (m, 2H), 2.55 (t, 2H, J=7 Hz), 3.22 (s, 3H), 4.03 (t, 2H, J=7 Hz), 14.49 (br.s, 1H); m/z 268.1 [MH+].
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:31][C:32](=[O:43])[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Br)=[CH:37][CH:36]=1)[CH3:34])C>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=1)[O:24][CH2:41][C:38]1[CH:37]=[CH:36][C:35]([CH:33]([CH3:34])[C:32]([OH:43])=[O:31])=[CH:40][CH:39]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: CCOC(=O)C(C)c1ccc(CBr)cc1
Product: CC(C(=O)O)c1ccc(COc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)cc1

Procedure:
Prepared using the procedure in Example 56 except using 3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenol and 2-(4-Bromomethyl-phenyl)-propionic acid ethyl ester as the halide. MS (ESI) m/z 542.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1.Br>O>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]([OH:16])=[O:15])[C:9]([CH3:13])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(C(=O)O)c(C)nc2c1
Agent: Br
Solvent: O
Product: Cc1nc2cc(O)ccc2cc1C(=O)O

Procedure:
Ethyl 7-hydroxy-2-methylquinoline-3-carboxylate (V), where R3 is —CH3, is obtained in two steps from commercially available or synthetically accessible 7-methoxy-2-methylquinoline-3-carboxylic acid. Demethylation of 7-methoxy-2-methylquinoline-3-carboxylic acid, employing methods previously described, for example, HBr in H2O, at temperatures ranging from 80° C. to about 100° C., preferably ° C. for a period of 0.5 h to 24 h, preferably about 2 h provides 7-hydroxy-2-methylquinoline-3-carboxylic acid. Subsequent esterification of 7-hydroxy-2-methylquinoline-3-carboxylic acid employing methods previously described, provides ethyl 7-hydroxy-2-methylquinoline-3-carboxylate (V), where R3 is —CH3.
Reaction SMILES: [C:1]([N:4]([CH2:13][C:14]([OH:16])=O)[C:5]1[CH:12]=[CH:11][C:8]([O:9][CH3:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:21][CH:20]=1>>[C:1]([N:4]([CH2:13][C:14]([N:25]([CH2:26][CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)=[O:16])[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[CH:11][CH:12]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(N(CC(=O)O)C(C)=O)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)CN(C(C)=O)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(acetyl)-2-(p-anisidino)acetic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(acetyl)-2-(p-anisidino)acetyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-acetyl-2-(p-anisidino)acetyl]-4-(p-anisidino)butyric acid (M.P. 97° to 100°).