Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([OH:5])[CH3:4].[CH:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:14][C:15]([CH3:17])=O>>[CH:6](=[CH:4][C:3]([CH:14]=[CH:15][C:17]1[CH:11]=[CH:12][CH:7]=[CH:8][CH:9]=1)=[O:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCO
Reactant: O=Cc1ccccc1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Reaction time: 0.25 h

Procedure:
To an aqueous solution of sodium hydroxide (200 grams (g) in one liter of water) was added ethanol (1.6 liters; purity greater than 95%) and the resultant mixture was stirred well. Another mixture having acetone (29 g) and benzaldehyde (106 g) was added to this solution under stirring. A yellow colored precipitate was observed. The stirring was continued for about 15 minutes (min). Subsequently additional acetone (29 g) and benzaldehyde (106 g) were added and the mixture was stirred for another 45 min. The yellow colored precipitate was separated by filtration, washed with water (2 liters), and dried at room temperature to get 223 g of crude dibenzalacetone. Melting point of the compound was obtained as 104-106° C. This product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].[H-].[Na+].Br[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[CH2:28]([O:27][C:25](=[O:26])[CH2:24][O:20][C:4]1[CH:5]=[C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)[CH:18]=[CH:19][C:3]=1[C:1]#[N:2])[CH3:29]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 80.9 %

Procedure:
To a solution of 2-hydroxy-4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzonitrile (D10) (300 mg, 1.12 mmol) in THF (50 mL) was added NaH (95 mg, 60%, 2.36 mmol) portion- wise. The mixture was stirred at room temperature for 5 minutes, followed by the slow addition of ethyl bromoacetate (0.262 mL, 2.36 mmol). The reaction was heated at 70° C. overnight. After the cooling of the reaction solution to room temperature, the mixture was filtered. The filtrate was evaporated under vacuum. The residue was purified using reverse phase chromatography, eluting from 5% MeOH/H2O to 90% MeOH/H2O, afforded 320 mg of the title compound in 81% yield. 1H NMR 400 MHz (DMSO-d6) δ: 9.25 (s 1H), 7.78 (d, J=8.0 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 7.14 (d, J=1.6 Hz, 1H), 7.08 (dd, J=1.6, 7.6 Hz, 1H), 6.86 (d, J=2.0 Hz, 1H), 6.64 (dd, J=2.4, 8.8 Hz, 1H), 5.00 (s, 2H), 4.97 (s, 2H), 4.13 (q, J=6.8 Hz, 2H), 1.16 (t, 6.8 Hz, 3H); MS (ES) m/z: 354 (M+H)+; HPLC purity: 99.11% (220 nm), 99.14% (254 nm).
Reaction SMILES: Cl.Cl.[N+:3]([C:6]1[C:7]([NH2:23])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]3[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]=3[CH:22]=2)[CH:11]=1)([O-:5])=[O:4].Cl[C:25]1[C:34]2[CH2:33][C:32]([CH3:36])([CH3:35])[CH2:31][CH2:30][C:29]=2[N:28]=[CH:27][N:26]=1.C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN1CCCC1=O>[CH3:35][C:32]1([CH3:36])[CH2:31][CH2:30][C:29]2[N:28]=[CH:27][N:26]=[C:25]([N:18]3[CH2:17][C:16]4[CH:22]=[C:12]([C:10]5[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[C:7]([NH2:23])=[N:8][CH:9]=5)[CH:13]=[CH:14][C:15]=4[O:21][CH2:20][CH2:19]3)[C:34]=2[CH2:33]1
Reactant: Nc1ncc(-c2ccc3c(c2)CNCCO3)cc1[N+](=O)[O-]
Reactant: CC1(C)CCc2ncnc(Cl)c2C1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c([N+](=O)[O-])c5)cc4C3)c2C1
Yield: 81.7 %

Procedure:
A solution of 3-nitro-5-(2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)pyridin-2-amine dihydrochloride (540 mg, 1.50 mmol), 4-chloro-6,6-dimethyl-5,6,7,8-tetrahydroquinazoline (270 mg, 1.37 mmol, reagent preparation 3), and diisopropylethylamine (970 mg, 7.49 mmol) in N-methylpyrrolidinone (3 mL) was stirred at 120° C. for 18 h. After cooling to room temperature ethyl acetate (100 mL) was added, the formed precipitate was filtered off, the organic filtrate was washed with saturated sodium bicarbonate (50 mL), water (2×50 mL), and brine (50 mL), dried over sodium sulfate, filtered and concentrated to afford crude 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]-3-nitropyridine-2-amine (0.5 g) as a brown solid which was used in the next step without further purification. MS (EI) for C24H26N6O3: 447 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]2[C:9](=[O:15])[NH:10][C:11](=[S:14])[NH:12][CH:13]=2)[CH:4]=[N:3]1.I[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([C:33]([F:36])([F:35])[F:34])[CH:27]=2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][S:14][C:11]3[NH:12][CH:13]=[C:8]([CH2:7][C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[C:9](=[O:15])[N:10]=3)=[CH:20][CH:21]=2)=[CH:27][C:28]=1[C:33]([F:34])([F:35])[F:36]
Reactant: FC(F)(F)c1cc(Oc2ccc(CCI)cc2)ccc1Cl
Reactant: Cn1cc(Cc2c[nH]c(=S)[nH]c2=O)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(Cc2c[nH]c(SCCc3ccc(Oc4ccc(Cl)c(C(F)(F)F)c4)cc3)nc2=O)cn1
Temperature: 120 °C
Yield: 21.9 %

Procedure:
A mixture of 5-[(1-methyl-1H-pyrazol-4-yl)methyl]-2-thioxo-2,3-dihydro-4(1H)-pyrimidinone (98 mg, 0.442 mmol), 4-chloro-3-(trifluoromethyl)phenyl 4-(2-iodoethyl) phenyl ether (157 mg, 0.368 mmol) and DIPEA (0.193 mL, 1.104 mmol) in chloroform (2 mL) was heated with a microwave reactor at 120° C. for 0.5 h. Purification via reverse phase flash chromatography then afforded the title compound (42 mg, 21.91% yield). LCMS: rt=3.63 min, [M+H+]=521
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.C(N([CH2:23][CH3:24])CC)C.[C:25](Cl)(=[O:35])[C:26]1[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:28](Cl)=[O:29]>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:16]=[CH:17][C:2]([O:1][C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:24]3[CH:23]=[CH:15][CH:10]=[CH:11][CH:12]=3)=[O:7])=[CH:16][CH:17]=2)=[O:29])=[CH:3][CH:4]=1)=[O:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(OCc1ccccc1)c1ccc(O)cc1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(OCc1ccccc1)c1ccc(OC(=O)c2ccccc2C(=O)Oc2ccc(C(=O)OCc3ccccc3)cc2)cc1

Procedure:
Into a 500 ml four-neck flask equipped with a condenser tube and a thermometer are charged 56 g of benzyl p-hydroxybenzoate, 25 g of triethylamine and 160 ml of toluene. A solution of 25 g of phthalic dichloride in 100 ml of toluene is added dropwise with stirring while maintaining the mixture at 0°-3° C. over 3 hours. After addition, the mixture is further allowed to react at 0°-3° C. for 1 hour. Then the reaction product is filtered, the filtrate solution is washed with 500 ml of water twice and concentrated under diminished pressure to distill the toluene off, and thereafter, 100 ml of hexane is added to the solution with stirring to give white crystals. The product is recrystallized from a mixture solvent of hexane-ethyl acetate (1:1) to yield di(p-benzyloxycarbonylphenyl)phthalate melting at 100°-103° C. as white crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH:11]([OH:31])[CH2:12][CH2:13][S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:19]=2)(=[O:16])=[O:15])[CH2:3][CH2:2]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>C(Cl)Cl>[CH3:33][S:34]([O:31][CH:11]([C:10]([NH:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)=[O:32])[CH2:12][CH2:13][S:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:19]=1)(=[O:16])=[O:15])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(NCCN1CCOCC1)C(O)CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC(CCS(=O)(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)NCCN1CCOCC1
Reaction time: 1 h
Yield: 92.5 %

Procedure:
Part H: A cooled solution of 2.1 g (5 mmol) of N1-(2-morpholinoethyl)-2--hydroxy-4-[(3-phenoxybenzyl)sulfonyl]butanamide from Part G in 55 mL of anhydrous CH2Cl2 was treated with 0.5 mL (0.8 g, 7 mM) of methanesulfonyl chloride, followed by 1.0 mL (0.7 g, 7 mM) of triethylamine. After 1 hour, the reaction was concentrated in vacuo, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted with ethyl acetate (1×). The organic layers were combined and washed with brine, dried (MgSO4) and concentrated to yield 2.5 g of 1-[(2-morpholinoethyl)amino]carbonyl-3-[(3-phenoxybenzyl)sulfonyl]propyl methanesulfonate suitable for the next reaction.
Reaction SMILES: [C:1]([O:5][CH2:6][C@@H:7]([OH:16])[CH2:8][C:9](=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(OC)(=O)C.CCN(CC)CC>CO>[C:1]([O:5][CH2:6][C@@H:7]([OH:16])[CH2:8][C@@H:9]([OH:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)CC(=O)C[C@H](O)COC(C)(C)C
Solvent: COC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C[C@H](O)C[C@H](O)COC(C)(C)C
Temperature: 30 °C
Reaction time: 21 h
Yield: 65 %

Procedure:
Methyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate synthesized in the same manner as in Example 5, except for replacing t-butyl acetate with methyl acetate was used. That is, 16.9 mg (0.01 mmole) of Ru2Cl4 ((R)-BINAP)2 (NEt3) was weighed, and 500 mg (2.15 mmole) of methyl (5S)-6-t-butoxy-5-hydroxy-3-oxohexanoate and 50 ml of methanol were added thereto to form a solution. The solution was transferred to a 100 ml-volume autoclave whose atmosphere had been displaced with nitrogen, and the solution was stirred at 30° C. for 21 hours under a hydrogen pressure of 50 kg/cm2 to conduct hydrogenation. The solvent was removed by distillation, and the residue was purified by silica gel column chromatography (diethyl ether/hexane: 5/1 by volume) to obtain 323 mg (yield: 65%) of methyl (3R,5S)-6-t-butoxy-3,5-dihydroxyhexanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([SH:23])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.C(N(CC)CC)C.O>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([S:23][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2[nH]c(S)nc2-c2ccc(F)cc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2[nH]c(SCc3ccc4ccccc4n3)nc2-c2ccc(F)cc2)cc1
Yield: 95.8 %

Procedure:
A solution of 4-(4-fluorophenyl)-5-(4-(methylsulfonyl)phenyl]-1H-imidazole-2-thiol (Example 49) (100 mg, 0.29 mmol), 2-chloromethylquinoline hydrochloride (62 mg, 0.29 mmol) and triethylamine (60 mg, 0.58 mmol) in 2-propanol (5 ml) was heated at reflux under an argon atmosphere for 4 hours. The reaction was cooled, poured into water (25 ml) and extracted with ethyl acetate. After drying over sodium sulfate, the solvent was removed and the residue was purified by chromatography on silica gel using 50% ethyl acetate in toluene as the eluent to give 136 mg (85%) of the desired product. Although initially an oil, this material crystallized on standing: mp 179-182° C. Anal. Calc'd. for C26H20N3O2FS2.5H2O (MW 498.60): C, 62.63; H, 4.25; N, 8.43; S, 12.86. Found: C, 62.98; H, 4.43; N, 8.03; S, 12.60.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([O:12]CC)=[O:11])[C:5]=2[N:6]=1.[OH-].[Na+].O>CO>[Br:1][C:2]1[S:3][C:4]2[CH2:9][CH2:8][CH:7]([C:10]([OH:12])=[O:11])[C:5]=2[N:6]=1
Reactant: CCOC(=O)C1CCc2sc(Br)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C1CCc2sc(Br)nc21
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of the product from step A (4.92 g, 17.82 mmol) was dissolved in methanol (20 mL) and added dropwise to a mixture of of 5 N NaOH (4.25 mL, 21.25 mmol), water (16 mL) and methanol (30 mL). After addition was complete the mixture was stirred for 2 h. The methanol was removed by evaporation and the pH of the remaining aqueous was adjusted to ˜2.5 with conc. HCl. The mixture was saturated with solid NaCl and extracted with EtOAc (×3); combined EtOAc layers washed with sat. NaCl, dried over Na2SO4 and treated with activated charcoal overnight. The filtered mixture was evaporated. The residue was triturated with EtOAc, and the solid filtered to give 1.94 g of the desired product. The mother liquors were evaporated and purified by MPLC using a gradient rising from 100% Hexanes to 100% EtOAc in Hexanes to give a further 0.82 g of the title product (2.76 g in total, 62%) as an off white solid. 1H NMR (500 MHz CDCl3) δ: 4.04 (m, 1H), 3.02-3.08 (m, 1H), 2.88-2.94 (m, 1H), 2.78-2.83 (m, 2H).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[O:19])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:20]Br.O>C(O)(=O)C.C(OCC)(=O)C>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10](=[O:19])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=2[F:18])([Br:20])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)c2cc(F)ccc2F)CC1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(Br)(C(=O)c2cc(F)ccc2F)CC1
Reaction time: 0.21 h

Procedure:
To a stirred solution of 11.2 g of 1-acetyl-4-(2,5-difluorobenzoyl)piperidine in 225 ml of glacial acetic acid was added dropwise over 0.5 hr a solution of 13.5 ml (42.1 g) of bromine in 115 ml of glacial acetic acid at a rate such that the temperature remained between 10°-12° C. The mixture was stirred for an additional 10-15 mins, poured into water, extracted twice with ethyl acetate, and the solvent evaporated to provide an oil. The oil was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated to provide product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4]Br.[CH3:13][C:14]1([CH3:20])[CH2:18][O:17][NH:16][C:15]1=[O:19].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C.O1CCOCCOCCOCCOCCOCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH2:4][N:16]1[C:15](=[O:19])[C:14]([CH3:20])([CH3:13])[CH2:18][O:17]1
Reactant: O=[N+]([O-])c1cccc(Cl)c1CBr
Reactant: CC1(C)CONC1=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC1(C)CON(Cc2c(Cl)cccc2[N+](=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.7 %

Procedure:
A mixture of 2-chloro-6-nitrobenzyl bromide (17.5 g, 0.07 mole), 4,4-dimethyl-3-isoxazolidinone (11.5 g, 0.1 mole), potassium carbonate (13.8 g, 0.1 mole), and 1,4,7,10,13,16-hexaoxacyclooctadecane (0.5 g, 0.002 mole) in acetonitrile (500 ml) was stirred at ambient temperature overnight. The reaction mixture was poured into ethyl acetate (500 ml) and the mixture washed with water (3×200 ml). The dried (magnesium sulfate) ethyl acetate layer was concentrated under reduced pressure to yield a liquid. The liquid product was subjected to chromatography on silica gel, eluting with 1:9 ethyl acetate:heptane. The appropriate fractions were combined and concentrated under reduced pressure to yield a white solid. The solid was recrystallized from ethyl acetate to yield 10.5 g of 2-[(2-chloro-6-nitrophenyl)methyl]-4,4-dimethyl-3-isoxazolidinone, m.p. 86°-88° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]=[C:11]1[C:20]2[C:15](=[C:16]([C:21](Cl)=[O:22])[CH:17]=[CH:18][CH:19]=2)[O:14][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:12]1.Cl.[N:35]1([CH2:40][C:41]2[N:46]=[C:45]([NH2:47])[CH:44]=[CH:43][CH:42]=2)[CH2:39][CH2:38][CH2:37][CH2:36]1.O>CC#N>[O:10]=[C:11]1[C:20]2[C:15](=[C:16]([C:21]([NH:47][C:45]3[CH:44]=[CH:43][CH:42]=[C:41]([CH2:40][N:35]4[CH2:39][CH2:38][CH2:37][CH2:36]4)[N:46]=3)=[O:22])[CH:17]=[CH:18][CH:19]=2)[O:14][C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:12]1
Reactant: O=C(Cl)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Reactant: Nc1cccc(CN2CCCC2)n1
Agent: Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(CN2CCCC2)n1)c1cccc2c(=O)cc(-c3cccc(C(F)(F)F)c3)oc12
Temperature: 60 °C
Yield: 39.7 %

Procedure:
DIPEA (125 mL, 0.705 mmol) was added to a solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-chromene-8-carbonyl chloride 37 (83 mg, 0.235 mmol) and 6-(pyrrolidin-1-ylmethyl)pyridin-2-amine hydrochloride 49 (75 mg, 0.353 mmol) in CH3CN (15 mL). The reaction mixture was heated at 60° C. for 12 h, cooled to room temperature and poured into H2O. The mixture was extracted with CH2Cl2. The combined organics were dried (MgSO4) and concentrated. The crude residue was purified by MPLC eluting with CH2Cl2/MeOH (0-10%) to give Compound 243 (46 mg, 40% yield). MS (ESI) calcd for C27H22F3N3O3: 493.16. found: 494 [M+H].
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.Br[C:60]1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=CC=3OC)N=2)=CC=1.CC1C(B2OC(C)(C)C(C)(C)O2)=CN(CC2(CO)COC2)N=1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]6)[C:42]([CH3:60])=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Agent: Cc1nn(CC2(CO)COC2)cc1B1OC(C)(C)C(C)(C)O1
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)c(C)n2)COC1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (Compound 38C, 124 mg, 0.200 mmol) and (3-{[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}oxetan-3-yl)methanol (Compound 60B, 75 mg, 0.24 mmol) to give the desired product. MS (ESI): m/z 909.76/911.76 [M+H]+. UPLC: tR=1.63 min (analytical 2 min).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[C:10]=1[C:20](=[O:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(O)(C)C.CO>O>[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH3:19])[C:10]=1[CH:20]([CH3:21])[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(C)nc2ccccc2c1NCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Solvent: CO
Product: Cc1nc2ccccc2c(NCc2ccccc2)c1C(C)O
Reaction time: 1 h
Yield: 89.4 %

Procedure:
A solution prepared from 1-(4-benzylamino-2-methyl-3-quinolinyl)-ethanone (4 g), sodium borohydride (1 g), 75 ml of isopropanol and 25 ml of methanol was stirred one hour at 45°, cooled, stirred with 500 ml of water and extracted with dichloromethane. The organic extract was washed with water and saturated sodium chloride and dried over anhydrous sodium sulfate, filtered and evaporated to 4 g of solid. This material was purified by flash chromatography (silica, 10% methanol in dichloromethane) to give 3.6 g of solid, mp 176°-177°.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11]Cl)[CH:9]=[CH:10][C:4]=2[O:3]1.[OH:13][C:14]1[CH:15]=[C:16]([NH:20][C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][CH:2]1[CH2:6][C:5]2[CH:7]=[C:8]([CH2:11][O:13][C:14]3[CH:15]=[C:16]([NH:20][C:21]([N:23]([O:25][CH3:26])[CH3:24])=[O:22])[CH:17]=[CH:18][CH:19]=3)[CH:9]=[CH:10][C:4]=2[O:3]1
Reactant: CC1Cc2cc(CCl)ccc2O1
Reactant: CON(C)C(=O)Nc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)Nc1cccc(OCc2ccc3c(c2)CC(C)O3)c1
Temperature: 80 °C
Reaction time: 4 h
Yield: 70.7 %

Procedure:
2.8 g of 2,3-dihydro-2-methyl-5-benzofuranylmethyl chloride and 3.0 g of 1-(3-hydroxyphenyl)-3-methoxy-3-methylurea were dissolved into 20 ml of dried N,N-dimethylformamide, and 2.5 g of anhydrous potassium carbonate was added thereto. After the mixture was stirred at 80° C. for 4 hours, the reaction mixture was poured into water and extracted with ethyl acetate. After the organic layer was washed with water, it was dried over anhydrous magnesium sulfate and ethyl acetate was dried off. The residue was subjected to silica gel column chromatography using ethyl acetate/n-hexane (1/2) as a developer to obtain 3.7 g of Compound No. 46 shown in Table 2.
Reaction SMILES: [CH2:1]([OH:12])[C@H:2]([OH:11])[C@H:3]1[O:8][C:6](=[O:7])[C@@H:5]([OH:9])[C@H:4]1[OH:10].CO[C:15](OC)([CH3:17])[CH3:16].[C:20]1(C)[CH:25]=CC(S(O)(=O)=O)=C[CH:21]=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.CC(C)=O.C(OCC)(=O)C>[CH3:16][C:15]1([CH3:17])[O:11][CH:2]([CH:3]2[O:8][C:6](=[O:7])[CH:5]3[O:9][C:20]([CH3:25])([CH3:21])[O:10][CH:4]23)[CH2:1][O:12]1
Reactant: COC(C)(C)OC
Reactant: O=C1O[C@H]([C@@H](O)CO)[C@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OCC(C2OC(=O)C3OC(C)(C)OC32)O1
Yield: 85 %

Procedure:
m.p. 155° C. (from ethyl acetate) [α]D20 -76.6° (c, 1.99 in CHCl3), was prepared from L-gulonolactone in 85% yield as previously described by Fleet in copending application Ser. No. 249,153, filed Sept. 26, 1988. According to this method, the title compound is synthesized by treatment of L-gulonolactone with acetone and 2,2-dimethoxypropane and a catalytic amount of p-toluenesulfonic acid under dry nitrogen for 36 hours (h) followed by stirring with an excess of sodium bicarbonate, removing the solvent under reduced pressure, dissolving the residue in dichloromethane, washing with water, drying the organic extracts (MgSO4), removing the solvent under reduced pressure and recrystallizing from ethyl acetate to give a white crystalline solid.