Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:18])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[F:17])=[CH:4][N:3]=1.[CH3:19][S-:20].[Na+].C(OCC)C>CN(C)C=O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[CH2:9][C:8]([C:5]1[CH:6]=[CH:7][C:2]([S:20][CH3:19])=[N:3][CH:4]=1)=[O:18]
Reactant: C[S-]
Reactant: O=C(Cc1ccc(F)cc1F)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.3 %

Procedure:
A solution of the product of part (ii) (23.9 g, 89 mmol) in N,N-dimethylformamide (DMF) (105 ml) was treated with sodium methanethiolate (6.6 g, 94 mmol) and the resulting suspension was stirred for 2 hours at room temperature. The mixture was poured into diethyl ether (1000 ml) and the suspension was washed with water (2×500 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was triturated with diethyl ether to afford the title compound as a yellow solid, (3.3 g).
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[CH:4]=[CH:5][C:6]([F:24])=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=2[C:17]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH:18]=2)[CH:8]=1.S(Cl)([Cl:28])=O>C(Cl)Cl.CN(C=O)C>[Cl:28][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([C:7]2[CH:8]=[C:3]([CH:2]([F:25])[F:1])[CH:4]=[CH:5][C:6]=2[F:24])=[C:10]([C:17]2[C:21]([CH3:23])([CH3:22])[CH2:20][CH2:19][CH:18]=2)[CH:11]=1
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)F)ccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(C(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98 %

Procedure:
To a solution of T26.3 (0.1666 g, 0.481 mmol) in dry DCM (3 mL) and dry DMF (0.06 mL) was added thionyl chloride (0.07 mL, 0.96 mmol) at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford T26 (172.1 mg, 98% yield). 1H NMR (500 MHz, CDCl3) δ ppm 7.46 (2H, m), 7.39 (1H, m), 7.33 (1H, m), 7.28 (1H, d, J=1.7 Hz), 7.17 (1H, m), 6.62 (1H, t), 5.51 (1H, td, J=2.3, 1.0 Hz), 4.64 (2H, s), 2.24 (2H, td, J=7.1, 2.4 Hz), 1.68 (2H, m), 0.85 (6H, s).
Reaction SMILES: [C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2].Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[O:20][CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[O:4][C:5]2[CH:13]=[C:12]([O:14][CH2:16][C:17]3[CH:34]=[CH:33][CH:32]=[C:19]([O:20][CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=4)[CH:18]=3)[CH:11]=[CH:10][C:6]=2[C:7](=[O:9])[CH:8]=1)#[N:2]
Reactant: N#Cc1cc(=O)c2ccc(O)cc2o1
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: N#Cc1cc(=O)c2ccc(OCc3cccc(OCc4ccc5ccccc5n4)c3)cc2o1
Temperature: 0 °C

Procedure:
To 2-cyano-7-hydroxy-4-oxo-4H-1-benzopyran (11.87 mmoles) and 2-((3-chloromethylphenoxy)methyl)quinoline (11.87 mmoles) in dimethylsulfoxide (20 ml) is added powdered sodium hydroxide (0.475g). After one week the reaction mixture is poured into ice water and the resulting precipitate collected and purified by HPLC to give 2-cyano-7-(3-(quinolin-2-ylmethoxy)benzyloxy)-4-oxo-4H-1-benzopyran which is used directly in the next step.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:16])[C:10]=1[CH3:17])([CH3:7])[CH3:6])[CH3:2].[F:19][C:20]([F:39])([F:38])[O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[CH:24][CH:23]=1>>[CH2:1]([O:3][C:4](=[O:18])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:32][CH2:31][CH2:30][C:29]#[C:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][C:20]([F:19])([F:38])[F:39])=[CH:23][CH:24]=2)=[C:11]([F:16])[C:10]=1[CH3:17])([CH3:6])[CH3:7])[CH3:2]
Reactant: CS(=O)(=O)OCCCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)c(F)c1C
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCCC#Cc2ccc(OC(F)(F)F)cc2)c(F)c1C

Procedure:
In analogy to the procedure described in example 20A], 2-(3-fluoro-4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 33H]) and methanesulfonic acid 5-(4-trifluoromethoxy-phenyl)-pent-4-ynyl ester (example 1G]) yielded the title compound as light yellow viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH2:12][CH2:11][CH2:10][C:9](=[N:13]O)[CH:8]=2)[CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16].Cl>C(O)(=O)C>[C:15]([NH:13][C:9]1[CH:8]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: ON=C1C=C(c2cccnc2)CCC1
Agent: Cl
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(-c2cccnc2)c1
Reaction time: 3 h

Procedure:
To a mixture containing 28.9 g. of 3-(3-pyridinyl)-2-cyclohexen-1-one oxime, 42 ml. of acetic acid and 42 ml. of acetic anhydride was passed gaseous hydrogen chloride whereupon the temperature rose to about 120° C. The hydrogen chloride was passed continuously into the reaction mixture until the temperature fell to about 50° C. The reaction mixture was allowed to stand for three hours and then concentrated in vacuo to yield, as a glassy material, 3-(3-acetamidophenyl)pyridine. To this material was added 100 ml. of water and 25 ml. of concentrated hydrochloric acid and the resulting mixture was refluxed for sixteen hours and concentrated in vacuo to yield a yellow solid. The solid was taken up in water and the solution was made alkaline with 35% aqueous sodium hydroxide solution. The alkaline solution was extracted three times with ethylene dichloride. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield an oil. The oil was distilled under reduced pressure, collecting the fraction boiling at 141°-145° C. at 0.15 mm. to yield, first as a yellow oil which crystallized on cooling, 17.7 g. of 3-(3-aminophenyl)pyridine, m.p. 72°- 74° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8](Cl)Cl)=[N:4][N:5]([CH3:7])[CH:6]=1.[FH:11].[FH:12].F.C(N(CC)CC)C.[OH-].[Na+]>>[Br:1][C:2]1[C:3]([CH:8]([F:12])[F:11])=[N:4][N:5]([CH3:7])[CH:6]=1
Reactant: F
Reactant: Cn1cc(Br)c(C(Cl)Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: Cn1cc(Br)c(C(F)F)n1
Temperature: 0 °C

Procedure:
At 160° C., 4-bromo-3-dichloromethyl-1-methylpyrazole (3.0 g; 0.01 mol; 90% pure according to GC analysis) was stirred with triethylamine trishydrofluoride (25 g, 0.16 mol) under autogenous pressure (<1 bar) for 1 h. After venting, the reaction mixture is added to ice (200 g), made alkaline with aqueous sodium hydroxide solution and extracted three times with methyl tert-butyl ether (100 ml). The combined organic phases were washed successively with dilute hydrochloric acid (100 ml) and a saturated aqueous NaCl solution (100 ml) and dried over magnesium sulfate, and the solvent was removed under reduced pressure. 4-Bromo-3-difluoromethyl-1-methylpyrazole was isolated in a purity of 81.3% (GC analysis) with a yield of 2.0 g (70%).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B(O)O)[C:8]=2[CH3:13])[N:3]=1.Br[C:18]1[C:23]2[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[O:26][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.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>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:18]3[C:23]4[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[O:26][C:22]=4[CH:21]=[CH:20][CH:19]=3)[C:8]=2[CH3:13])[N:3]=1
Reactant: CC1(C)Oc2cccc(Br)c2C1=O
Reactant: Cc1c(B(O)O)ccc2nc(N)nc(N)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)ccc2nc(N)nc(N)c12
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A solution of 2.1 grams (0.010 mole) of (2,4-diamino-5-methylquinazolin-6-yl)boronic acid in 25 mL of N,N-dimethylformamide is stirred, and 2.1 grams (0.009 mole) of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone (prepared in Step C of this Example), 2.8 grams (0.020 mole) of potassium carbonate, and 0.31 gram (catalyst-3 mole %) of tetrakis(triphenylphosphine)palladium(0) are added. The reaction mixture is then warmed to 90° C., where it is stirred for about 16 hours. After this time the reaction mixture is poured into water. The resultant precipitate is collected by filtration and dried, yielding 2,4-diamino-5-methyl-6-(2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)quinazoline.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([C:11]2[CH:12]=[C:13]([CH2:21]O)[C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:21][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:11]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2ccccc2)cc2ccccc12
Solvent: ClC(Cl)Cl
Product: ClCc1cc(-c2ccccc2)cc2ccccc12
Reaction time: 15 h

Procedure:
Thionyl chloride (0.78 cc) is added in the course of 10 minutes to a stirred solution, cooled beforehand to 0° C., of 3-phenyl-1-naphthalenemethanol (1 g) in chloroform (20 cc), and the temperature is then allowed to rise to room temperature (approximately 20° C.) The mixture is stirred for 15 hours at this temperature and the solvent evaporated under reduced pressure. 1-Cloromethyl-3-phenylnaphthalene (1.1 g) is obtained, the proton NMR spectrum of which, in deuterated chloroform, shows the following characteristics:
Reaction SMILES: [OH:1]/[N:2]=[C:3](\[C:10]1[N:14]([CH3:15])[N:13]=[CH:12][N:11]=1)/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]1[N:29]=[C:28]([N:30]2[C:38](=[O:39])[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]2=[O:40])[CH:27]=[CH:26][CH:25]=1>CC#N>[CH3:15][N:14]1[C:10]([C:3](=[N:2][O:1][CH2:23][C:24]2[N:29]=[C:28]([N:30]3[C:31](=[O:40])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:38]3=[O:39])[CH:27]=[CH:26][CH:25]=2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][CH:12]=[N:13]1
Reactant: Cn1ncnc1/C(=N\O)c1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1c1cccc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cn1ncnc1C(=NOCc1cccc(N2C(=O)c3ccccc3C2=O)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.3 %

Procedure:
To a stirred solution of ((Z)-N-hydroxy-1-(1-methyl-1H-1,2,4-triazol-5-yl)-1-phenylmethanimine (7 g, 34.61 mmol, 1.0 eq.) in 500 ml of MeCN was added Cs2CO3 (12.40 g, 38.07 mmol, 1.1 eq.) followed by Kl (0.575 g, 3.46 mmol, 0.1 eq.) in one portion. The resulting suspension was stirred for 5 mins before addition of 2-[6-(bromomethyl)pyridin-2-yl]-1H-isoindole-1,3(2H)-dione (10.97 g, 34.61 mmol, 1.0 eq.) in one portion. The reaction was stirred for 4 h at room temperature. The solid was removed by filtration and washed with 250 ml of fresh MeCN. The filtrate was evaporated, and 500 ml of EtOAc were added. The organic layer was washed with H2O and dried over MgSO4 then concentrated. Chromatography of the crude on silica gel gave 2-{6-[({[(1-methyl-1H-1,2,4-triazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}-1H-isoindole-1,3(2H)-dione (11.27 g, 74% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([CH:19]([OH:26])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:27]([F:30])([F:29])[F:28].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=3)=[O:26])=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:27]([F:30])([F:28])[F:29]
Reactant: O=S(=O)(Nc1cc(Cl)cnc1C(O)c1ccncc1)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: O=C(c1ccncc1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(hydroxy-pyridin-4-yl-methyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (15 mg, 0.03 mmol) and PCC (15 mg) was stirred at room temperature for 2 h. It was then treated with small amount of silica gel and filtered. The filtrate was concentrated under reduced pressure to provide the crude ketone. 1H NMR (400 MHz, CDCl3) δ 10.90 (br s, 1H), 8.78 (dd, J=4.4, 1.6 Hz, 2 H), 8.35 (d, J=2.0 Hz, 1 H), 8.19-8.17 (m, 2 H), 7.98 (dd, J=8.4, 2.0 Hz, 1 H), 7.65-7.61 (m, 3 H). MS m/z: 476.0 (M+H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([SH:10])=[CH:4][C:3]=2[O:2]1.[C:11]([O:15][C:16]([NH:18][C@H:19]([C:32]([O:34][CH3:35])=[O:33])[CH2:20]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:11]([O:15][C:16]([NH:18][C@H:19]([C:32]([O:34][CH3:35])=[O:33])[CH2:20][S:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: COC(=O)[C@H](COS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Reactant: Sc1ccc2c(c1)OCO2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CSc1ccc2c(c1)OCO2)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
After 27.7 g of (3,4-methylenedioxy)thiophenol and 74 g of methyl N-(t-butoxycarbonyl)-O-tosyl-L-serinate were dissolved in 200 ml of chloroform, 20 g of triethylamine were added at room temperature, followed by stirring overnight. The reaction mixture was washed with water and then extracted with ethyl acetate. The extract so obtained was dried over anhydrous magnesium sulfate. After the solvent was distilled off, 49 g of crude oil were obtained. The crude oil was recrystallized from an ethyl acetatehexane system, whereby 42 g of methyl N-t-butoxycarbonyl-S-[(3,4-methylenedioxy)phenyl]cysteinate were obtained (yield: 66%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[N:17]=[C:16]([NH2:25])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(O)=O.CO>[N:11]1([C:14]2[CH:19]=[C:18]([CH:20]3[CH2:24][CH2:23][O:22][CH2:21]3)[N:17]=[C:16]([NH2:25])[N:15]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(C3CCOC3)nc(N)n2)CC1
Agent: Cl
Solvent: O=CO
Solvent: CO
Product: Nc1nc(C2CCOC2)cc(N2CCNCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
A solution of 4-[2-amino-6-(tetrahydro-furan-3-yl)-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (600 mg, 1.72 mmol) in formic acid (10 mL) was treated with 6.0 N HCl (2 mL) and stirred for 2 h at rt. The mixture was diluted with MeOH (10 mL) and concentrated. This process was repeated twice, yielding 295 mg of a white solid as the hydrochloride salt. The crude material was chromatographed (2 M NH3 in MeOH/CH2Cl2) to afford 133 mg (50%) of the free base as an off-white solid. MS (ESI): mass calcd. for C12H19N5O, 249.1; m/z found, 250.2 [M+H]+. 1H NMR (CDCl3): 6.86 (s, 1H), 4.78 (br s, 2H), 3.98-4.07 (m, 2H), 3.83-3.90 (m, 2H), 3.54-3.58 (m, 4H), 3.22 (p, J=15.0, 7.3, 1H), 2.89-2.93 (m, 4H), 2.10-2.30 (m, 4H).
Reaction SMILES: O[C:2]1[C:3](=[O:17])[O:4][CH:5]([CH2:13][CH2:14][CH2:15][OH:16])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:29])[O:26][CH2:27][CH3:28].Cl>O1CCCC1>[OH:16][CH2:15][CH2:14][CH2:13][CH:5]1[O:4][C:3](=[O:17])[C:2]([C:25]([O:26][CH2:27][CH3:28])=[O:29])=[C:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: O=C1OC(CCCO)C(c2ccccc2)=C1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(c2ccccc2)C(CCCO)OC1=O

Procedure:
3-Hydroxy-5-(3-hydroxypropyl)-4-phenyl-2(5H)-furanone (25 mg) was dissolved in tetrahydrofuran (6 ml), and triethylamine (0.018 ml) was added with ice-cooling and stirring, followed by dropwise addition of ethyl chlorocarbonate (0.012 ml). The mixture was stirred at the same temperature for 5 minutes, and the reaction mixture was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The solvent was then distilled off. The remaining oil was purified by preparative thin layer chromatography (silica gel; developer: 4% methanol-chloroform) to give ethyl 5-(3-hydroxypropyl)-2-oxo-4-phenyl-2,5-dihydro-3-furancarboxylate (30 mg) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:14][C:15]([N:17]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[CH:21]=2)[CH3:18])=[O:16])[CH2:10][C:11](O)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CCOC(C)=O.O>[F:33][C:30]([F:31])([F:32])[C:22]1[CH:21]=[C:20]([CH2:19][N:17]([CH3:18])[C:15](=[O:16])[CH2:14][CH:9]([CH2:10][CH2:11][OH:12])[C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=1
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)CC(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
3,4-Dichloro-β[2-[[3,5-bis-(trifluoromethyl)phenylmethyl]methylamino]-2-oxoethyl]-benzenepropanoic acid (6.1 g) in EtOAc (75 mL) was treated with carbonyldiimidazole (2.43 g) and N,N-dimethylaminopyridine (150 mg). The resulting solution was stirred at room temperature for 15 minutes and then heated at 50° C. for two hours. The reaction mixture was cooled to 0° C. and treated with a solution of NaBH4 (1.8 g) in H2O (30 mL), warmed slowly to room temperature and stirred for 12 hours. The reaction mixture was diluted with EtOAc (150 mL) and washed with 1N HCl (1×100 mL), sat. NaHCO3 (1×100 mL) and water (1×100 mL). The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to yield the crude compound as a oil. Silica gel chromatography eluting with 0-10% MeOH/CH2Cl2 gave the title compound (5.7 g). Mass spectrum (FAB): 502.0791.
Reaction SMILES: C([NH:11][CH2:12][C:13](=[O:34])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC1C=CC=CC=1)=[O:25])=[O:17])(OCC1C=CC=CC=1)=O.[ClH:35].[H][H]>[Pd].CC(O)C>[ClH:35].[NH2:11][CH2:12][C:13](=[O:34])[CH2:14][CH2:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:17]
Reactant: O=C(CCC(=O)OCCCCCC(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Product: NCC(=O)CCC(=O)OCCCCCC(=O)O
Yield: 73.9 %

Procedure:
This compound was prepared from the product of 9b (0.45 g; 0.96 mmol), 12 M HCl (0.08 mL; 0.96 mmol), 10% Pd/C (100 mg), hydrogen gas, and 2-propanol (25 mL) using the procedure in Example 8d. 0.20 g (77%) product was obtained (white solid).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3]1.Br[CH2:18][CH2:19][O:20][CH3:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:21][O:20][CH:19]([N:6]1[C:5]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:4]=2[O:3][C:2]([CH3:16])([CH3:1])[C:7]1=[O:8])[CH3:18]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2NC1=O
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(C)N1C(=O)C(C)(C)Oc2ccc([N+](=O)[O-])cc21
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (300 mg, 1.35 mmol, 1 equiv), 1-bromo-2-methoxyethane (0.32 mL, 3.38 mmol, 2.5 equiv.) and Cs2CO3 (880 mg, 2.70 mmol, 2.0 equiv.) in 6 mL of DMF was heated to 60° C. and stirred at this temperature overnight. The reaction mixture was then partitioned between EtOAc and water. The organic layer was separated and concentrated. The residue was purified by column chromatography using a mixture of EtOAC/hexane (1:4) as eluent to give the product as a clear oil (quantitative yield).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]1([C:37]([OH:41])([C:39]#[CH:40])[CH3:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:40]#[C:39][C:37]([OH:41])([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH3:38])=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[C:20]([OH:22])=[O:21])([CH3:29])([CH3:27])[CH3:28]
Reactant: C#CC(C)(O)c1ccccc1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#CC(C)(O)c3ccccc3)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-7-(3-hydroxy-3-phenylbut-1-ynyl)-3-methylnaphthalen-2-yl)acetic acid (88) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 2-phenylbut-3-yn-2-ol. 1H-NMR: 400 MHz, (CD3OD) δ: 7.76 (d, J=8 Hz, 1H), 7.69 (s, 1H), 7.64 (d, J=8 Hz, 2H), 7.57 (m, 3H), 7.46 (d, J=8 Hz, 1H), 7.33 (m, 5H), 5.18 (s, 1H), 2.61 (s, 3H), 1.75 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M—OH]+ calcd for C33H30ClO3: 509.1; found: 508.8.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][N:3]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[OH-].[K+]>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][N:6]2[CH2:5][CH2:4][N:3]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([CH3:1])[CH2:7]2)=[CH:10][CH:11]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.67 h
Yield: 98.4 %

Procedure:
To a solution of D1 (4.62 g, 13.78 mmol) and KOH (7.79 g, 138.8 mmol) in MeOH (100 mL) was added wet (50% w/w water) 10% Pd/C (4 g) catalyst and the mixture was hydrogenated at room temperature and atmospheric pressure for 40 minutes. The catalyst was removed by filtration and the filtrate concentrated in vacuo. The residue was partitioned between DCM and water and aqueous layer further extracted with DCM (×2). The combined organics were washed with brine, dried and concentrated to give the title compound as a colourless gum (4.14 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 7.10 (2H, d), 6.64 (2H, d), 4.16 (1H, br.s), 3.78 (1H, m), 3.62 (2H, s), 3.42 (1H, d), 3.28 (1H, d), 3.08 (1H, td), 2.74 (1H, m), 2.58 (1H, m), 2.06 (1H, dd), 1.95 (1H, m), 1.46 (9H, s), 1.21 (3H, d).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=3[O:21][CH2:22][CH3:23])[O:10][C:9](=O)[C:8]=2[CH:25]=1)([OH:3])=[O:2].[OH-].[NH4+:27]>[OH-].[Na+]>[C:1]([C:4]1[CH:25]=[C:8]2[C:7](=[CH:6][CH:5]=1)[N:12]=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[C:14]=1[O:21][CH2:22][CH3:23])[NH:27][C:9]2=[O:10])([OH:3])=[O:2]
Reactant: [NH4+]
Reactant: CCOc1c(OC)cccc1-c1nc2ccc(C(=O)O)cc2c(=O)o1
Agent: [Na+]
Agent: [OH-]
Product: CCOc1c(OC)cccc1-c1nc2ccc(C(=O)O)cc2c(=O)[nH]1

Procedure:
The yield is 5 g of 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-4H-3,1-benzoxazin-4-one (m.p.=175°-177° C.), which are reacted at room temperature first with 70 ml of 32% ammonium hydroxide for 4 hours and then with 20 ml of 2N NaOH overnight. After acidification with 4N HCl, the precipitate is filtered off and crystallized from ethanol to give 6-carboxy-2-(2'-ethoxy-3'-methoxy-phenyl)-3,4-dihydro-4-oxo-quinazoline (3 g; m.p. 228°-229° C.).