Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O/[N:6]=[C:7]1\[CH2:8][CH2:9][C:10]2[C:15]\1=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)(=O)=O.B(F)(F)F.CS(Cl)(=O)=[O:24].C(Cl)Cl>ClCCCl.Cl[Ti](Cl)(Cl)Cl>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:6][C:7]2=[O:24])=[CH:11][CH:12]=1
Reactant: COc1ccc2c(c1)/C(=N/OS(C)(=O)=O)CC2
Reactant: CS(=O)(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1ccc2c(c1)C(=O)NCC2
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.7 %

Procedure:
To the solution of intermediate 17 (7.76 g, 30.4 mmol) in 1,2-dichloroethane (150 mL) was added BF3 (5.52 mL, 48.7 mmol, in MeOH), MsCl (3.8 mL, 48.7 mmol) and TiCl4 (5.35 mL, 48.7 mmol). The mixture was stirred at rt for 5 h. CH2Cl2 (150 mL) was then added to the reaction mixture. The solution was washed with water and brine. The water layer was neutralized by aqueous Na2CO3 to pH=7 and was extracted with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The crude product was purified by flash chromatography on silica gel column (elution with PE/EtOAc=4:1) to give 7-methoxy-3,4-dihydroisoquinolin-1(2H)-one (intermediate 18) (5.1 g, 95%) as a white solid.
Reaction SMILES: [N+](C1C=CC(COC(=O)/[C:11](/[N:22]2[CH:25]([S:26]S(C3C=CC(C)=CC=3)(=O)=O)[CH:24](NC(=O)COC3C=CC=CC=3)[C:23]2=[O:48])=[C:12](\OCC2C=CC=CC=2)/[CH3:13])=CC=1)([O-])=O.[N+](C1C=CC(COC(=O)/C=C\C)=CC=1)([O-])=O.N12CCCCC1C=NCCC2.C(Cl)Cl>O1CCCC1>[S:26]1[C@@H:25]2[CH2:24][C:23](=[O:48])[N:22]2[CH:11]=[CH:12][CH2:13]1
Reactant: C/C(OCc1ccccc1)=C(/C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C(NC(=O)COc2ccccc2)C1SS(=O)(=O)c1ccc(C)cc1
Agent: C/C=C\C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C1=NCCCN2CCCCC12
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1C[C@H]2SCC=CN12
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A solution of 731 mg (1 mmol) of a 1:1 mixture consisting of 2-[4-(p-toluenesulphonylthio)-3-phenoxyacetamido-2-oxoazetidin-1-yl]-3-benzoxy-crotonic acid p-nitrobenzyl ester and the corresponding isocrotonic acid p-nitrobenzyl ester in a mixture of 0.185 ml (1.2 mmols) of 1,5-diazabicyclo[5.4.0]undec-5-ene in 20 ml of dry tetrahydrofurane is stirred for precisely 35 minutes at room temperature. 50 ml of methylene chloride are added to the mixture and the whole is washed successively with dilute hydrochloric acid, water and dilute aqueous sodium bicarbonate solution. The organic phase is dried over sodium sulphate and concentrated by evaporation in vacuo. The residue is chromatographed on 25 mg of acid-washed silica gel, using toluene/ethyl acetate (3:1). A mixture consisting of the ceph-2-em compound and the ceph-3-em compound in the ratio of about 3:1 is obtained; this mixture can be separated by repeated chromatography into the pure isomers, giving 7β-phenoxyacetamido-3-benzoxy-ceph-2-em-4α-carboxylic acid p-nitrobenzyl ester of melting point 160° C.-162° C. (diethyl ether/pentane); IR spectrum (methylene chloride), characteristic bands at 5.6, 5.7, 5.9 and 7.4μ, and 7β-phenoxyacetamido-3-benzoxy-ceph-3-em-4-carboxylic acid p-nitrobenzyl ester in the form of a colourless foam, IR spectrum (methylene chloride): characteristic bands at 5.6, 5.8 sh, 5.9, 7.9 and 8.4μ.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].C([O-])([O-])=O.[K+].[K+].[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O.O1CCOCC1>[CH2:21]([O:28][C:29]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCCCCCCCCCCC(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCCCCCCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35 %

Procedure:
To a suspension of 11-aminoundecanoic acid (17) in 1:1 water/dioxane (160 mL total) was added K2CO3 (10.28 g, 74.51 mmol) followed by the slow addition over 30 min of benzylchloroformate (CbzCl, 4.55 mL, 32.29 mmol), and the mixture was stirred at room temperature for 2 h. The solid was then removed by filtration, washed with water (3×30 mL) and dried in a vacuum oven at 40° C. for 72 h to afford a white solid 18 (2.91 g, 35% yield): 1H NMR (500 MHz, CD3OD) δ 1.36 (m, 12H), 1.50 (m, 2H), 1.62 (m, 2H), 2.18 (m, 2H), 3.08 (m, 2H), 5.14 (s, 2H), 7.38 (m, 5H); m/z (ESI) 336 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1.[CH3:13][O-:14].[Na+].CO>C(OCC)(=O)C>[CH3:13][O:14][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[N:3]=1
Reactant: Oc1ccc2ccc(Cl)nc2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1ccc2ccc(O)cc2n1
Yield: 79 %

Procedure:
2-Chloro-quinolin-7-ol (4.2 g, 23.4 mmol, 1.0 eq) is added at room temperature to a stirred solution of sodium methoxide in methanol (15% weight, 200 mL, 561.6 mmol, 24.0 eq) and the resulting mixture is heated under reflux for 20 hours. Solvent is removed, the residue is dissolved in water (50 mL) and neutralized with acetic acid, followed by extraction with ethyl acetate (3×50 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 6:1, v/v) to afford 2-methoxy-quinolin-7-ol as a yellow solid (3.3 g, 79% yield).
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][C:3]=1[C:16]#[N:17].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+]>O.N1C=CC=CC=1>[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][C:3]([C:16]#[N:17])=[C:2]2[NH:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1
Reactant: Cc1nc2cc(N)ccc2s1
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Agent: CCOC(C)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1cc2ncc(C#N)c(Nc3ccc4sc(C)nc4c3)c2cc1OC
Yield: 94.4 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-quinolin-3-carbonitrile, 0.237 g of 5-amino-2-methylbenzothiazole dihydrocholride, 0.158 g of pyridine, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 20 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate to pH 9. The product was collected, washed with water, and dried to give 0.356 g of 6,7-dimethoxy-4-(2-methyl-benzothiazol-5-ylamino)-quinoline-3-carbonitrile as a solid, mp 118-120° C.; mass spectrum (EI, m/e): M 376.0973.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11]([O:17][C:18]3[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=3[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:12][CH:13]=[N:14]2)=[CH:9][C:8]=1[O:33][CH3:34].[N:35]1([CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][C:21]1[CH:22]=[CH:23][C:18]([O:17][C:11]2[C:10]3[C:15](=[CH:16][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:43]4[CH2:44][CH2:45][CH:40]([N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[CH2:41][CH2:42]4)=[C:8]([O:33][CH3:34])[CH:9]=3)[N:14]=[CH:13][CH:12]=2)=[C:19]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])[CH:20]=1
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCCl
Reactant: C1CCN(C2CCNCC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCN1CCC(N2CCCC2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 92.2 %

Procedure:
(2-{[7-(4-Chlorobutoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (60 mg), 4-(1-pyrrolidinyl)piperidine (60 mg), and potassium carbonate (90 mg) was suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (69 mg, yield 90%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)=[O:20])=[CH:15][CH:14]=1.[CH3:39][Mg]Br>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)=[CH:23][CH:22]=2)([OH:20])[CH3:39])=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.7 %

Procedure:
To a -78° C. solution in THF (20 mL) of bis(4-(2-quinolylmethoxy)phenyl) ketone (992 mg, 2 mmol), prepared as in step 1, was added methylmagnesium bromide (3M solution in ethyl ether, 0.8 mL, 2.4 mmol) and the resulting mixture was stirred at room temperature for 12 hours. The mixture was then quenched with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by chromatography on silica gel (methylene chloride-ethyl acetate 4:1) to afford 920 mg (90%) of 1,1-bis(4-(2-quinolylmethoxy)phenyl)ethanol: mp 129°-131° C.; 1H NMR (300 MHz, DMSO-d6) d 1.74 (s, 3H), 5.32 (s, 4H), 5.48 (s, 1H), 6.95 (d, 4H, J=9 Hz), 7.30 (d, 4H, J=9 Hz), 7.63 (m, 4H), 7.78 (m, 2H), 8.01 (m, 4H), 8.39 (d, 2H, J=8 Hz); MS (DCl--NH3) m/e 513 (M+H)+. Anal. Calc'd. for C34H28N2O3 : C, 79.67; H, 5.51; N, 5.46. Found: C, 79.48; H, 5.62; N, 5.25.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([OH:9])=[O:8].[CH3:10][Si](C=[N+]=[N-])(C)C>CO.O1CCOCC1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cn1cccc1C(=O)O
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)c1cccn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 1-methyl-2-pyrrolecarboxylic acid (1.03 g, 8.22 mmol) in MeOH (5 mL) and dioxane (5 mL) at room temperature, trimethylsilyldiazomethane (2M in ether, 5.0 mL, 10.0 mmol) was added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo to give methyl 1-methyl-2-pyrrolecarboxylate as a volatile oil (1.14 g).
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]([CH3:18])([CH2:16][CH3:17])[CH2:10][C:11]1[N:12]=[CH:13][NH:14][CH:15]=1.[CH3:19][N:20]([CH3:25])[S:21](Cl)(=[O:23])=[O:22]>C(COC)OC>[CH3:8][C:9]([CH3:18])([CH2:16][CH3:17])[CH2:10][C:11]1[N:12]=[CH:13][N:14]([S:21]([N:20]([CH3:25])[CH3:19])(=[O:23])=[O:22])[CH:15]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: CCC(C)(C)Cc1c[nH]cn1
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)cn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
N-Methylmorpholine (54 mL, 0.48 mol) was added to a solution of 4-(2,2-dimethylbutyl)-1H-imidazole (36 g, 0.24 mol) in dimethoxyethane (360 mL). After warming to 40° C., N,N-dimethylsulfamoyl chloride (38 mL, 0.36 mol) was added over 15 min. After stirring at 40° C. for 2 h, N-methylmorpholine (11 mL) and N,N-dimethylsulfamoyl chloride (8 mL) were added. After stirring for additional 2 h, the reaction mixture was cooled and filtered rinsing with ether. The filtrate was extracted with ether and the combined extracts were washed with brine, dried (magnesium sulfate), filtered, concentrated in vacuo. Chromatography over silica gel afforded the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]>C1COCC1.C(OCC)(=O)C.[Pd]>[CH3:1][C:2]([CH3:35])([CH3:34])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10][O:11][C:12]2[N:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:25]1[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=1[F:33]
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(C=CC(=O)O)nc(OC)n3)nc2CC(C)(C)C)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(F)c(-c2ccc(COc3cc(CCC(=O)O)nc(OC)n3)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.4 %

Procedure:
To a solution of 3-(6-((6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methoxy)-2-methoxypyrimidin-4-yl)acrylic acid (530 mg) in THF (5.0 ml) and ethyl acetate (5.0 mL) was added 10% palladium-activated carbon (53 mg) and, under a hydrogen atmosphere, the mixture was stirred at room temperature for 2 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (135 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9](=[O:11])[CH3:10])[C:3]=1[NH2:4].N1C=CC=CC=1.[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(Cl)Cl>[Cl:18][CH2:19][C:20]([NH:4][C:3]1[C:5]([C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=[CH:8][C:2]=1[CH3:1])=[O:21]
Reactant: O=C(Cl)CCl
Reactant: CC(=O)c1cccc(C)c1N
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)c1cccc(C)c1NC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Methyl-6-acetylaniline (25 g) and pyridine (26.5 g) in 1 liter methylene chloride were cooled in an ice-acetone bath. A solution of chloroacetyl chloride (37.9 g) in 100 ml methylene chloride was dripped in slowly. The solution was stirred at room temperature for 2 hours, washed with 10% HCl, 10% NaOH, dried (MgSO4) and stripped. Yield: the title product as a white solid, MP 88°-89° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[N:8]12[CH2:15][CH2:14][CH:11]([CH2:12][CH2:13]1)[C@@H:10]([C:16]([Cl:18])=[O:17])[CH2:9]2.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.O1CCOCC1>CN(C=O)C>[ClH:18].[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([NH:19][C:16]([C@@H:10]3[CH:11]4[CH2:14][CH2:15][N:8]([CH2:13][CH2:12]4)[CH2:9]3)=[O:17])=[CH:21][CH:22]=2)=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: O=C(Cl)[C@H]1CN2CCC1CC2
Reactant: Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1)[C@H]1CN2CCC1CC2
Temperature: 100 °C
Reaction time: 18 h

Procedure:
480 mg (3.50 mmol) of potassium carbonate are added to a mixture, prepared under argon, of 490 mg (2.33 mmol) of (3R)-quinuclidine-3-carbonyl chloride hydrochloride (Example 5A) and 250 mg (1.17 mmol) of 4-amino-4′-nitrobiphenyl in 11 ml of a 10:1 mixture of dioxane and DMF. The reaction mixture is stirred at 100° C. for 18 h and then concentrated. The residue is suspended in methanol and filtered. The filtration residue is washed with water, mixed with 20 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. The above filtrate is purified by preparative HPLC. The product fractions are concentrated, taken up in 5 ml of a 3:1 mixture of acetonitrile and 1 N hydrochloric acid, again concentrated and dried under high vacuum. 291 mg (61.7% of theory) of the title compound are obtained from the filtration residue, and a further 65 mg (12.4% of theory) are obtained from the filtrate, in this way.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](Br)[CH:8]=2)[N:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20].FC1C=CC(C2C=C3C(=CC=2)N=CN=C3O)=CC=1>>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:24][CH:25]=3)[CH:8]=2)[N:3]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Nc1nc(OCC(F)(F)F)c2cc(Br)ccc2n1
Agent: Oc1ncnc2ccc(-c3ccc(F)cc3)cc12
Product: CC(=O)Nc1ccc(-c2ccc3nc(N)nc(OCC(F)(F)F)c3c2)cc1
Yield: 82 %

Procedure:
This compound, synthesized from 2-amino-6-bromo-4-(2,2,2-trifluoro-ethoxy)-quinazoline and 4-acetamido-phenylboronic acid in 82% yield using the procedure described for the synthesis of 6-(4-fluorophenyl)-4-hydroxy-quinazoline, was characterized by its mass spectrum as follows: MS (m/z): 377 ([M+H]+, 100)
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4].[CH3:18][Si](C)(C)N[Si](C)(C)C.[Na].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([CH3:18])[CH2:10][CH2:9][CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6]1)=[O:4]
Reactant: COC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
To a −78 ° C. stirred solution of Intermediate 53 (2.22 g, 9.13 mmol) in dry THF (30 ml) was added NaHMDS (sodium hexamethyldisilazane) (1.0 M in THF, 10.03 mmol) dropwise. The reaction was stirred at this temperature for 30 minutes and then iodomethane (0.682 ml, 10.95 mmol) was added dropwise. The reaction was allowed to warm to room temperature overnight with good stirring. The reaction was cooled and then quenched with saturated NH4Cl. The layers were separated and the aqueous layer was extracted three times with 20 ml of EtOAc and the organic extracts were combined. The organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The oil was purified by silica chromatography using hexanes/EtOAc (0→15%) to yield 2.25 g (95.8%) of 3-methyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (Intermediate 54). 1H NMR (400 MHz, CDCl3) δ ppm 1.0 (s, 3H), 1.3 (s, 9H), 1.4 (m, 2H), 1.9 (m, 2H), 3.0 (d, J=13.2 Hz, 1H), 3.1 (m, 1H), 3.3 (m, 1H), 3.5 (s, 3H), 3.7 (d, J=13.4 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[CH:9]1[O:31][CH:12]2[CH2:13][O:14][Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)[O:18][CH:11]2[CH:10]1[O:32][C:33](=[O:35])[CH3:34].C(N(CC)CC)C.F.F.F.C(N(CC)CC)C>ClCCl>[O:1]=[C:2]1[NH:7][C:6](=[O:8])[CH:5]=[CH:4][N:3]1[CH:9]1[CH:10]([O:32][C:33](=[O:35])[CH3:34])[CH:11]([OH:18])[CH:12]([CH2:13][OH:14])[O:31]1
Reactant: CC(=O)OC1C2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OCC2OC1n1ccc(=O)[nH]c1=O
Agent: F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1C(O)C(CO)OC1n1ccc(=O)[nH]c1=O

Procedure:
The Tips protecting group is removed from Compound 5 as illustrated in the literature (Protective Groups in Organic Synthesis, 3rd edition, 1999, pp. 239 and references therein, Greene, T. W. and Wuts, P. G. M., eds, Wiley-Interscience, New York). To a solution of 5 (1 eq.) in anhydrous dichloromethane is added triethylamine (2 eq.) and triethylamine trihydrofluoride (2 eq.). The reaction mixture is monitored by thin layer chromatography until complete at which point the reaction mixture is diluted with additional dichloromethane, washed with aqueous NaHCO3, dried over anhydrous Na2SO4, and evaporated. The resulting Compound 6 is optionally purified by silica gel chromatography.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23](O)=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH2:30]([NH2:32])[CH3:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[C:18]([C:23]([NH:32][CH2:30][CH3:31])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: CCN
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1ncccc1[C@H]1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
A solution of 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (30.0 mg, 0.0764 mmol) (from step 2) in N,N-dimethylformamide (1.0 mL) was treated with ethylamine (10.8 μL, 0.191 mmol) followed by N,N-diisopropylethylamine (66.6 μL, 0.382 mmol) and stirred at room temperature for 5 min. The reaction mixture was subsequently treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate [Aldrich #: 226084](50.7 mg, 0.115 mmol) and stirred at room temperature for 1 h. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (23 mg, 71%) as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (t, J=5.9 Hz, 1H), 8.58 (dd, J=4.6, 1.4 Hz, 1H), 7.49 (dd, J=8.0, 4.6 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.54-6.41 (m, 1H), 4.64-4.45 (m, 2H), 3.43-3.24 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.15 (t, J=7.2 Hz, 3H); LCMS calculated for C22H22N5O4 (M+H)+: m/z=420.2. found: 420.2.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1.[CH2:29]([O:31][CH:32]([O:43][CH2:44][CH3:45])[N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][C:34]1=[O:42])[CH3:30]>C1(C)C=CC=CC=1.C1COCC1>[CH2:44]([O:43][CH:32]([O:31][CH2:29][CH3:30])[N:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]([C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][O:27][CH3:28])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:34]1=[O:42])[CH3:45]
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Reactant: CCOC(OCC)N1C(=O)Cc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(OCC)N1C(=O)C(c2ncnc3cc(OCCOC)c(OC)cc23)c2ccccc21
Reaction time: 2 h
Yield: 72.4 %

Procedure:
Potassium bis(trimethylsilyl)amide (48 ml of a 0.5M solution in toluene, 24 mmol) was rapidly added to a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (3.2 g, 11.9 mmol) and 1-diethoxymethyloxindole (4.0 g, 14.9 mmol), (prepared according to Synthesis 1975, 168), in THF (240 ml) at ambient temperature. After 2 hours, the precipitate was filtered off and washed with ether. The filtrate was evaporated. The residue was mixed with the precipitate and partitioned between methylene chloride and water and the organic phase washed with saturated aqueous sodium chloride solution. The organic layer was driied (MgSO4) and the solvent removed by evaporation. The residue was purified by column flash chromatography using methylene chloride/methanol (95/5) as eluent. The purified product was triturated with a mixture of ether and petroleum ether to give 4-(1-diethoxymethyloxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline (4.03 g, 74%) as a red orange solid.