Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]([NH:15]C(=O)OC(C)(C)C)[CH:12]=[CH:13][CH:14]=2)[CH:3]=1.[O:23]([C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>C(O)CCC>[NH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:34][C:33]3[CH:32]=[CH:31][C:30]([O:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:36][CH:35]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: Nc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: CCCCO
Product: Nc1cccc(Nc2cc(Nc3ccc(Oc4ccccc4)cc3)ncn2)c1
Yield: 39.3 %

Procedure:
A solution of tert-butyl 3-(6-chloropyrimidin-4-ylamino)phenylcarbamate (200 mg, 0.6 mmol), 4-phenoxyaniline (346 mg, 1.8 mmol) and concentrated HCl (45 mg, 1.2 mmol) in n-butanol (8 mL) was subjected to microwave irradiation (160° C., 20 min). The reaction mixture was quenched with NaHCO3 solution (2 mL) and extracted with EtOAc (2×10 mL). The combined EtOAc extract was washed with water (5 mL), brine (5 mL), was dried over Na2SO4 and was concentrated under reduced pressure. The residue was further purified by column chromatography (SiO2, 60-120, Chloroform/methanol, 9/1) to give N4-(3-aminophenyl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (87 mg, 37.8%) as a brown solid.
Reaction SMILES: [C:1]([O:5][P:6]([O-:13])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+](C)(C)C.[Cl:19][CH2:20]I>C(COC)OC>[P:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])([O:13][CH2:20][Cl:19])=[O:7]
Reactant: CC(C)(C)OP(=O)([O-])OC(C)(C)C
Reactant: ClCI
Agent: C[N+](C)(C)C
Solvent: COCCOC
Product: CC(C)(C)OP(=O)(OCCl)OC(C)(C)C

Procedure:
The conversion of di-tert-butyl phosphite into the corresponding phosphate is performed by a slight modification of the method published by Zwierzak and Kluba (Zwierzak, A and Kluba, M., 1971). Di-tert-butyl phospohite (40.36 mmole) is combined with potassium bicarbonate (24.22 mmole) in 35 ml of water. The solution is stirred in an ice bath and potassium permanganate (28.25 mmole) is added in three equal portions over one hour's time. The reaction as then allowed to continue at room temperature for an additional half hour. Decolorizing carbon (600 mg) is then incorporated as the reaction is heated to 60° C. for 15 minutes. The reaction is then vacuum filtered to remove solid magnesium dioxide. The solid is washed several times with water. The filtrate is then combined with one gram of decolorizing carbon and heated at 60° C. for an additional twenty minutes. The solution is again filtered to yield a colorless solution, to which a slight excess of concentrated HCl is slowly added with efficient stirring in an ice bath. The addition of acid causes the precipitation of the di-tert-butyl phosphate free acid. The free acid is then filtered and washed with ice cold water. The compound is then converted to the salt form by dissolving the free acid in acetone and adding an equal molar amount of tetramethylammonium hydroxide while keeping the reaction cooled by a salt/ice bath with efficient stirring. The resulting clear solution is placed under reduced pressure to give 7.16 grams of crude product. This product is then recrystallized by refluxing in dimethoxyethane and slow cooling at room temperature to give 6.52 g of pure product (57% yield). 12.75 mmole of the tetramethylammonium di-tert-butyl-phosphate is then mixed with 70 ml of dimethoxyethane and brought to reflux. Twenty-five grams of chloroiodomethane is then added and stirred for one and a half hours. The reaction is then filtered and the filtrate is placed under reduced pressure to remove excess chloroiodomethane and solvent. The two products are then separated via flash column chromatography. The stationary phase is normal phase silica (30 g). The mobile phase consists of ethyl acetate and hexane in a 3 to 7 (v/v) ratio respectively. The chloromethyl di-tert-butyl phosphate is isolated as a pale gold oil (63% yield): 1H NMR (CDCl3, 300 MHz) δ 1.51 (s, 12H), 5.63 (d, 2H, J=14.8). Mass spectrum (FAB+, GLY) 259 (M+1).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[C:21]([Cl:23])[C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][C:18]=3[O:33][CH3:34])=[O:16])[CH2:6][C:5]=12.FC(F)(F)S(O[C:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CN(C)C=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[Cl:23][C:21]1[C:20]([C:41]2[CH2:46][CH2:45][CH2:44][CH2:43][CH:42]=2)=[CH:19][C:18]([O:33][CH3:34])=[C:17]([CH:22]=1)[C:15]([N:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[CH2:10][N:4]2[CH:3]=[CH:2][CH:1]=[C:5]2[CH2:6]1)=[O:16]
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Reactant: O=S(=O)(OC1=CCCCC1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(C2=CCCCC2)c(Cl)cc1C(=O)N1Cc2cccn2Cc2ccccc21
Temperature: 60 °C
Yield: 70.5 %

Procedure:
(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-[5-chloro-2-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone of Step E (0.220 g, 0.459 mmol), cyclohex-1-en-1-yl trifluoromethanesulfonate (0.116 g, 0.505 mmol) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.011 g, 0.014 mmol) were combined in N,N-dimethylformamide (2.3 mL). 2 M aqueous sodium carbonate (1.15 mL, 2.30 mmol) was added and the reaction heated to 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was diluted ethyl acetate and washed with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. Flash column chromatography on silica gel eluting with a solvent gradient from 30 to 40% ethyl acetate in hexane afforded the title compound (0.140 g) as an oil. The oil was dissolved in diethyl ether/petroleum ether and concentrated to afford an amorphous white solid.
Reaction SMILES: S(=O)(=O)(O)O.O.[OH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1.Cl>CO.C(O)(C)C>[OH:7][C:8]1[C:16]([CH:8]([CH3:16])[CH3:9])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[CH:11]([CH3:12])[CH3:10]
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: CC(C)c1cc(C(=O)O)cc(C(C)C)c1O
Temperature: 62.5 °C

Procedure:
360 ml sulphuric acid was added slowly to 25 ml chilled water at 10-15° C. to a round bottom flask supplied with a mechanical stirrer. To this stirred mass was charged p-hydroxy benzoic acid 100 g (0.72M) lot wise followed by Isopropyl alcohol 130 g (2.16M) at a temperature below 15° C. The reaction mass was finally heated to 60-65° C. for 4 hrs. After reaction completion the reaction mass was quenched in caustic solution and washed two times with toluene (400 ml). The aqueous layer obtained was acidified using aq. HCl solution. Precipitated solid was washed twice, each time with 250 ml of hot water and dried to obtain crude product. Crude solid was dissolved in 350 ml of methanol and treated with activated carbon, filtered and added into 1000 ml chilled water at about 10-15° C. The precipitate was filtered off and washed twice with 200 ml of water each time. After drying under vacuum at 70-75° C. up to a constant weight, 4-hydroxy-3,5-diisopropyl benzoic acid was obtained.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]([C:50]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=[CH:52][CH:51]=2)[C:13]2[CH:25]=[CH:24][C:23]3[C:22]4[C:17](=[CH:18][C:19]([N:26]([C:37]5[CH:42]=[CH:41][C:40]([CH:43]6OCC[O:44]6)=[CH:39][CH:38]=5)[C:27]5[C:36]6[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=6)[CH:30]=[CH:29][CH:28]=5)=[CH:20][CH:21]=4)[C:16]([CH3:49])([CH3:48])[C:15]=3[CH:14]=2)=[CH:8][CH:7]=1.Cl>CC(C)=O>[CH3:48][C:16]1([CH3:49])[C:17]2[CH:18]=[C:19]([N:26]([C:37]3[CH:38]=[CH:39][C:40]([CH:43]=[O:44])=[CH:41][CH:42]=3)[C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH:30]=[CH:29][CH:28]=3)[CH:20]=[CH:21][C:22]=2[C:23]2[C:15]1=[CH:14][C:13]([N:12]([C:9]1[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=1)[C:50]1[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[CH:53]=[CH:52][CH:51]=1)=[CH:25][CH:24]=2
Reactant: CC1(C)c2cc(N(c3ccc(C4OCCO4)cc3)c3cccc4ccccc34)ccc2-c2ccc(N(c3ccc(C4OCCO4)cc3)c3cccc4ccccc34)cc21
Agent: Cl
Solvent: CC(C)=O
Product: CC1(C)c2cc(N(c3ccc(C=O)cc3)c3cccc4ccccc34)ccc2-c2ccc(N(c3ccc(C=O)cc3)c3cccc4ccccc34)cc21

Procedure:
To a three-neck round-bottom flask, were added 2.42 g N2,N7-bis(4-(1,3-dioxolan-2-yl)phenyl)-9,9-dimethyl-N2,N7-di(naphthalen-1-yl)-9H-fluorene-2,7-diamine and in 250 mL acetone. 20 mL 2 M hydrochloric acid solution was added slowly to the reaction mixture through an addition funnel. After TLC showed the reaction was done, the solvent was removed by evaporation. 400 mL Ethyl acetate was added, and the reaction mixture was extracted using DI water (4×200 mL). The organic layer was dried over sodium sulfate. After filtration, the solvent was removed by evaporation. The product (1.7 g) was purified by flash chromatography using hexane, and 5% and up to 15% ethyl acetate in hexane. The structure was confirmed by NMR.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[C:9]2[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][CH:18]=1)[O:14][C:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([NH2:1])[C:5]=2[CH:6]=[CH:7][N:8]=1
Reactant: O=[N+]([O-])c1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Oc3cccc(C(F)(F)F)c3)nccc12
Yield: 94.7 %

Procedure:
The title compound was prepared following the procedure described in Step 3 of Intermediate-1 using 5-nitro-1-(3-(trifluoromethyl)phenoxy)isoquinoline (200 mg, 0.59 mmol), iron powder (267 mg, 4.7 mmol), and NH4Cl (312 mg, 5.9 mmol) in EtOH (4 mL) and water (1 mL) to afford 170 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 7.79 (d, J=5.7 Hz, 1H), 7.70-7.50 (m, 6H), 7.40 (t, J=7.8 Hz, 1H), 6.93 (d, J=7.2 Hz, 1H), 6.02 (br s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22]C(C)C)=[C:18]([O:26]C(C)C)[CH:17]=1)=[CH:13][C:12]([O:30][CH3:31])=[C:11]([O:32][CH3:33])[CH:10]=2)=[O:5])[CH3:2].O>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:34][N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([OH:26])[CH:17]=1)=[CH:13][C:12]([O:30][CH3:31])=[C:11]([O:32][CH3:33])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(OC(C)C)c(OC(C)C)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1c(Cn2cncn2)nc2cc(OC)c(OC)cc2c1-c1ccc(O)c(O)c1
Reaction time: 6 h
Yield: 20.5 %

Procedure:
To a solution of 4-(3,4-diisopropoxyphenyl)-6,7-dimethoxy-2-(1,2,4 -triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (116.0 mg) in dichloromethane (2.5 ml), titanium tetrachloride (TiCl4) (288 mg) was added at 0° C., followed by stirring at the same temperature for 6 hours. The reaction mixture was poured over water and extracted with chloroform. The chloroform layer was washed by sequential additions of a saturated aqueous sodium hydrogen carbonate solution and water and then dried (MgSO4), after which the solvent was distilled off. The residual oily substance was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (7:3, v/v) to yield 4-(3,4-dihydroxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl)quinoline-3-carboxylic acid ethyl ester (20.0 mg, 21%) having a melting point of 122 to 124° C.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][C:8]2[O:12][C:11]([CH2:14][CH2:15][CH:16]3OCC[O:17]3)([CH3:13])[CH2:10][C:9]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2]>C(O)(=O)C>[C:1]([O:4][C:5]1[C:6]([C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:7][C:8]2[O:12][C:11]([CH2:14][CH2:15][CH:16]=[O:17])([CH3:13])[CH2:10][C:9]=2[C:21]=1[C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CCC1OCCO1)O2
Solvent: CC(=O)O
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CCC=O)O2

Procedure:
5-Acetoxy-2-[2-(1,3-dioxa-2-cyclopentyl)ethyl]-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran (17.3 g) was dissolved in 80% acetic acid (150 ml) and the solution was heated under reflux for 1 h. After cooling the solution, the acetic acid was distilled off under vacuum and, after addition of water, the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (25% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2-(2-formylethyl)-2-methyl-2,3-dihydrobenzofuran quantitatively (15.53 g) as a colorless oil.
Reaction SMILES: ClC1C=C([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[O:10])C=CC=1.[CH3:28][NH2:29]>C(O)C>[Cl:27][C:23]1[CH:22]=[C:21]([S:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][C:9](=[O:10])[CH2:8][NH:29][CH3:28])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cc1cccc(Cl)c1)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1
Reactant: CN
Solvent: CCO
Product: CNCC(=O)Nc1ccc(S(=O)(=O)c2cccc(Cl)c2)cc1

Procedure:
A mixture of 6.0 g of 3-chlorophenyl-4'-(m-chlorophenylsulfonyl)acetanilide, 1100 ml of methylamine and 20 ml of ethanol was refluxed for 3.5 hours. The solvent was evaporated and the residue partitioned between dichloromethane and water. The dichloromethane portion was evaporated and the residue crystallized from ethanol giving 2.48 g of the desired product, mp 110°-112° C.
Reaction SMILES: [Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([CH:16]([C:18]2[C:19]([Cl:25])=[N:20][CH:21]=[N:22][C:23]=2[Cl:24])[OH:17])[C:9]=1[F:26])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[Si:1]([C:8]1[C:13]([F:14])=[C:12]([F:15])[N:11]=[C:10]([C:16]([C:18]2[C:19]([Cl:25])=[N:20][CH:21]=[N:22][C:23]=2[Cl:24])=[O:17])[C:9]=1[F:26])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(O)c2c(Cl)ncnc2Cl)c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)c1c(F)c(F)nc(C(=O)c2c(Cl)ncnc2Cl)c1F
Temperature: 25 °C
Reaction time: 120 h
Yield: 75.4 %

Procedure:
A mixture of [4-[tert-butyl(dimethyl)silyl]-3,5,6-trifluoro-2-pyridyl]-(4,6-dichloropyrimidin-5-yl)methanol (1.21 g, 2.85 mmol) and Manganese (IV) oxide (3.72 g, 42.78 mmol) in DCM (53 mL) was stirred at ambient temperature for 5 days. After this time, further Manganese (IV) oxide (992 mg, 11.4 mmol) was added and stirred at ambient for 2 hours. The reaction mixture was filtered through a celite cartridge, washing through with DCM, and the filtrate concentrated in vacuo to leave the sub title product as a white solid (908 mg, 74.8% Yield). H1 NMR (400 MHz, DMSO) δ 9.15 (1H, s), 0.94 (9H, s) and 0.45 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1.[N-:20]=[N+:21]=[N-:22].[Na+].O1CCOCC1.[Si](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[NH:22][N:21]=[N:20][N:8]=2)=[CH:4][C:3]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cc1ccc(C(N)=O)cc1B1OC(C)(C)C(C)(C)O1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-c2nnn[nH]2)cc1B1OC(C)(C)C(C)(C)O1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
4-Methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.27 g, 1.0 mmol) and sodium azide (0.20 g, 3.1 mmol) were added to dioxane (5.2 mL, 1.0 mmol) before silicon tetrachloride (0.12 mL, 1.0 mmol) was added. The reaction mixture was heated to 85° C. for 7 h when two spots were observed by tlc. The reaction mixture was stirred at 60° C. overnight. The reaction mixture was diluted with 50 mL chloroform, partitioned with brine (saturated, aqueous), washed 2 times with 50 mL of chloroform, separated, dried over sodium sulfate, and concentrated in vacuo to give the title compound. MS (ES+): 287 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:25]=[C:26]1[NH:30][C@H:29]([CH2:31][O:32][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:28][O:27]1>>[C:33]([O:32][CH2:31][C@@H:29]1[CH2:28][O:27][C:26](=[O:25])[N:30]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[C:18]([CH3:24])[N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4COC(=O)c4ccccc4)cc3)CC2)nc1C
Yield: 96.7 %

Procedure:
By reaction and treatment in the same manner as in Preparation Example 91 and using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (2.18 g) described in Preparation Example 176 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.11 g), the title compound (2.56 g) was obtained.
Reaction SMILES: O.O.[F-].[K+].[Cl:5][C:6]1[CH:11]=[CH:10][C:9](B2OCCCO2)=[C:8]([F:18])[C:7]=1[O:19][CH3:20].[NH2:21][C:22]1[C:27]([F:28])=[C:26](Br)[N:25]=[C:24]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH:23]=1.CC#N>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.O>[NH2:21][C:22]1[C:27]([F:28])=[C:26]([C:9]2[CH:10]=[CH:11][C:6]([Cl:5])=[C:7]([O:19][CH3:20])[C:8]=2[F:18])[N:25]=[C:24]([C:30]([O:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH:23]=1
Reactant: COc1c(Cl)ccc(B2OCCCO2)c1F
Reactant: CC(C)OC(=O)c1cc(N)c(F)c(Br)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1c(Cl)ccc(-c2nc(C(=O)OC(C)C)cc(N)c2F)c1F
Temperature: 69 °C
Reaction time: 1 h

Procedure:
In a 50 mL three-neck round bottom flask was charged potassium fluoride dihydrate (12.0 mmol), 2-(4-chloro-2-fluoro-3-methoxyphenyl)-1,3,2-dioxaborinane (5.40 mmol), isopropyl 4-amino-6-bromo-5-fluoropicolinate (4.0 mmol), MeCN (15 mL), and H2O (5 mL). The resulting mixture was sparged with N2 for 15 min then Pd(PPh3)2Cl2 (0.006-0.08 mmol) was added. The resulting suspension was sparged for 20 min then heated to 68-70° C. After 1 h of stirring, an aliquot (1-2 μL) was taken and diluted with MeCN (2 mL). The aliquot was analyzed by HPLC by monitoring the consumption of starting material 4-(acetylamido)-5-fluoropicolinate ester. After the reaction was deemed complete the heating mantle was removed and the mixture was cooled to ambient temperature and was diluted with MeCN/toluene/H2O (75 mL, 3/1/1); if needed, extra volume of the solvent mixture was added to dissolve the solids. The layers were then separated using a reparatory funnel. The product assay was then determined using an internal standard (hexanophenone): mp=177-179° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.52 (d, JF-H=6.8 Hz, 1H), 7.47 (dd, J=8.4, 1.6 Hz, 1H), 7.29 (dd, J=8.4, 7.2 Hz, 1H), 6.70 (s, 2H), 5.12 (p, J=6.4 Hz, 1H), 3.93 (s, 3H), 1.30 (d, J=6.4 Hz, 6H); 13C NMR (100.6 MHz, DMSO-d6) δ 163.6, 154.4, 151.2, 148.0, 145.5, 144.0 (dd, JF-C=38.3, 4.2 Hz), 143.7 (d, JF-C=2.9 Hz), 139.0 (d, JF-C=13.6 Hz), 128.2 (d, JF-C=3.1 Hz), 126.0 (d, JF-C=3.4 Hz), 125.4 (d, JF-C=3.5 Hz), 123.9 (dd, JF-C=14.2, 3.5 Hz), 112.5 (d, JF-C=5.1 Hz), 68.5, 61.5 (d, JF-C=4.0 Hz), 21.6; 19F {1H} NMR (376.5 MHz, DMSO-d6) δ −129.4 (d, JF-F=25.6 Hz), −142.8 (d, JF-F=25.6 Hz); MS Calcd. for C16H15ClF2N2O3: 356.1. Found: 356 (M+), 270.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:18]([OH:20])=[O:19])[C:8]2=[O:25].Cl.[O:27]1[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.C(N(CC)C(C)C)(C)C.[N-]=C=O>CC(N(C)C)=O.C(Cl)Cl>[CH3:24][C:23]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[N:9]1[C:8](=[O:25])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([O:4][CH2:3][CH2:2][N:30]3[CH2:31][CH2:32][CH2:33][O:27][CH2:28][CH2:29]3)[CH:6]=2)[N:11]=[CH:10]1
Reactant: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCCl)cc2c1=O
Reactant: C1CNCCOC1
Agent: Cl
Agent: [N-]=C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1ccc(C(=O)O)cc1-n1cnc2ccc(OCCN3CCCOCC3)cc2c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.5 %

Procedure:
To a stirred solution of 3-[6-(2-chloroethoxy)-4-oxoquinazolin-3(4H)-yl]-4-methylbenzoic acid (0.50 g), 1,4-oxazepane hydrochloride (0.77 g), N,N-diisopropylethylamine (0.98 ml) and KI (0.47 g) in DMA (2 ml) was heated to 120° C. for 30 minutes in a microwave (Personal Chemistry Emrys Optimizer with 300 W magnetron). The reaction mixture was diluted with methylene chloride (20 ml), CombiZorb isocyanate resin (loading 1.03 mmol/g from Agilent) (6 g) added and stirred at room temperature for 16 hours. The resin was removed by filtration and the filtrate washed with water (50 ml). The aqueous phase was purified by column chromatography on an ion exchange column (isolute SCX column from International Sorbent Technology Limited, Henoed, Mid-Glamorgan, UK) using initially methanol and then a 99:1 mixture of methanol and aqueous ammonia solution to give 4-methyl-3-[6-[2-(1,4-oxazepan-4-yl)ethoxy]-4-oxoquinazolin-3(4H)-yl]benzoic acid (0.31 g); NMR Spectrum: (DMSOd6) 1.87 (m, 2H), 2.10 (s, 3H), 2.91 (m, 2H), 3.02 (m, 4H), 3.66 (m, 4H), 4.20 (m, 2H), 7.46 (m, 2H), 7.58 (s, 1H), 7.69 (d, 1H), 7.81 (s, 1H), 7.93 (d, 1H), 8.16 (s, 1H); Mass Spectrum: M+H+ 424.
Reaction SMILES: [Na].[CH2:2]([CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:3]=[CH2:4].[CH3:16][O:17][CH2:18][CH2:19]Br>C(O)C.O>[CH3:16][O:17][CH2:18][CH2:19][C:5]([CH2:2][CH:3]=[CH2:4])([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: COCCBr
Reactant: C=CCC(C(=O)OCC)C(=O)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C=CCC(CCOC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
Metallic sodium (15 g, 230 mmol) was dissolved in dry ethanol (250 mL) with cooling in an ice bath, under nitrogen, and diethyl allylmalonate (Lancaster Synthesis, Windham, Mass.) (105 g, 525 mmol) in absolute ethanol (50 mL) was added dropwise under nitrogen. The mixture was stirred at room temperature for 1 h. and 2-bromoethyl methyl ether (87.57 g, 630 mmol) in absolute ethanol (50 mL) was then added dropwise. The mixture was heated at reflux for 3 h and then cooled to room temperature. The precipitate solid was filtered and washed with ethanol (2×100 mL). The residue obtained upon concentration of the filtrate was diluted with water (1 L). The mixture was extracted with ether (2×150 mL), dried over MgSO4 and concentrated to give the diester ether 2 (118 g, 87%) as a viscous liquid. IR (KBr) υmax 3069, 2971, 2927, 1734, 1640, 1459, 1443, 1382, 1361, 1284, 1223, 1196, 1119, 1077, 1031, 922, 856 cm−1: 1HNMR (CDCl3) δ1.24 t, J=7.0 Hz, 6 H), 2.17 (t, J=6.4 Hz, 2 H), 2.68 (d, J=7.1 Hz, 2 H), 3.2 (s, 3 H), 3.41 (t, J=6.5 Hz, 2 H), 4.17 (dis q, 4 H), 5.04-5.12 (m, 2 H), 5.63-5.79 (m, 1 H); 13CNMR (CDCl3) δ13.98, 32.05, 37.31, 55.08, 58.52, 61.13, 68.34, 118.93, 132.49, 170.17; mass spectrum (EI), m/z (rel itensity) 259 (M++1.16), 227 (20), 213 (19), 200 (37), 185 (13), 167 (17), 154 (25), 153 (65), 139 (38), 125 (25), 108 (100), 81 (30), 79 (31), 67 (23), 59 (23), 53 (23).