Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.C(O)(=O)C>[C].[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCC(=O)O)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc(CCCC(=O)O)cc1
Reaction time: 9 h

Procedure:
After 4-(4-methoxyphenyl)-4-oxobutanoic acid (40 g) was added to (not completely dissolved in) a mixed solvent of acetic acid (100 ml) and THF (100 ml), 10% palladium-carbon (50%-wet) (4 g) was added thereto and the resulting mixture was stirred for 9 hours under a hydrogen atmosphere (0.4 MPa). The catalyst was removed by filtration through Celite and toluene was added to the residue. The solvent was distilled off under reduced pressure to obtain 4-(4-methoxyphenyl)butanoic acid quantitatively.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C(O)=O)(F)(F)F>C(Cl)Cl>[NH:12]1[CH2:13][CH2:14][C@H:10]([O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](OC(=O)c2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O[C@H]1CCNC1)c1ccccc1
Yield: 191.9 %

Procedure:
tert-Butyl(3S)-3-(benzoyloxy)pyrrolidine-1-carboxylate (635 mg, 2.18 mmol) was treated with 20% CF3CO2H in CH2Cl2 (20 mL) overnight at room temperature. The volatiles were removed in vacuo to give the subtitled compound (800 mg).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5](=O)[NH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:16]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([Cl:16])=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cccc2c(=O)[nH]cc(Br)c12
Product: Cc1cccc2c(Cl)ncc(Br)c12
Temperature: 0 °C
Yield: 92 %

Procedure:
A stirred solution of 4-bromo-5-methylisoquinolin-1(2H)-one (Intermediate-4) (10 g, 42 mmol) in POCl3 (50 mL) was heated to 100° C. for 30 min. The reaction mixture was then poured into ice-water, extracted with CH2Cl2 (3×200 mL), washed with water (2×200 mL), dried over Na2SO4, filtered and concentrated to obtain desired compound (10 g, 92%).
Reaction SMILES: [OH-:1].[Na+].C[O:4][C:5](=[O:36])/[C:6](/[NH:15][C:16](=[O:35])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23]/[CH:24]=[C:25](/O)\[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[CH:19][C:18]=1[Cl:34])=[CH:7]/[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14].Cl>O>[Cl:34][C:18]1[CH:19]=[C:20]([CH:23]([OH:1])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)[CH:21]=[CH:22][C:17]=1[C:16]([NH:15]/[C:6](=[CH:7]\[C:8]1[S:12][C:11]([CH3:13])=[N:10][C:9]=1[CH3:14])/[C:5]([OH:4])=[O:36])=[O:35]
Reactant: COC(=O)/C(=C/c1sc(C)nc1C)NC(=O)c1ccc(C/C=C(/O)c2cccc(O)c2)cc1Cl
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1nc(C)c(/C=C(\NC(=O)c2ccc(C(O)/C=C/c3cccc(O)c3)cc2Cl)C(=O)O)s1
Temperature: 25 °C
Reaction time: 5 h
Yield: 50.7 %

Procedure:
An aqueous 1N solution of sodium hydroxide (0.55 mL, 0.55 mmol) was added to a suspension of rac.-(Z)-2-[[2-chloro-4-[(E)-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid methyl ester (Example 231; 90 mg, 0.175 mmol) in water (3 mL). The reaction mixture was stirred at room temperature for 5 h and then acidified with 1N hydrochloric acid solution (0.55 mL). The mixture was stirred for 30 min, then the solid was filtered off, washed with water, dried and evaporated. The crude acid was purified by reverse phase HPLC and lyophilized to give rac.-(Z)-2-[[2-chloro-4-[(E)-1-hydroxy-3-(3-hydroxyphenyl)prop-2-en-1-yl]benzoyl]amino]-3-(2,4-dimethylthiazol-5-yl)propenoic acid (43 mg, 51% yield) as a colorless solid.
Reaction SMILES: C(O[CH:4]=[C:5]([C:9](=O)[CH3:10])[C:6](=[O:8])[CH3:7])C.[F:12][C:13]([F:18])([F:17])[CH2:14][NH:15][NH2:16].Cl>CO>[CH3:10][C:9]1[N:15]([CH2:14][C:13]([F:18])([F:17])[F:12])[N:16]=[CH:4][C:5]=1[C:6](=[O:8])[CH3:7]
Reactant: CCOC=C(C(C)=O)C(C)=O
Reactant: NNCC(F)(F)F
Agent: Cl
Solvent: CO
Product: CC(=O)c1cnn(CC(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 51 %

Procedure:
To a solution of 3-(ethoxymethylene)pentane-2,4-dione (Perkin 1. 2000, 1455-1460, 1.95 g, 12.5 mmol) in MeOH (33 ml) was added a solution of 2,2,2-trifluoroethylhydrazine (1.54 g, 13.5 mmol) and conc.HCl (2.6 ml) in MeOH (10 ml) (pre-cooled at 0° C.) dropwise at −15° C. The resulting mixture was then stirred for 24 h at rt. After removal of the solvent at rt, the residue was basified with 2N NaOH aq, and the aqueous layer was extracted several times with EtOAc. The combined organic extracts were dried over Na2SO4, and concentrated in vacuo to give the crude product as a single regioisomer (1.41 g, 51% yield). 1H NMR (300 MHz, CDCl3) δ 2.46 (3H, s), 2.62 (3H, s), 4.66 (1H, d, J=6.0 Hz), 4.72 (1H, d, J=9.0 Hz), 7.92 (1H, s). MS (ESI) m/z 207 (M+H)+
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[N:17]=[CH:16][CH:15]=[CH:14][C:8]=1[C:9]([O:11][CH2:12]C)=[O:10])[CH2:4][CH3:5])[CH3:2].C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:26])C>>[CH2:1]([CH:3]([N:6]1[C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9](=[O:10])[O:11][C:12]1=[O:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NC(CC)CC
Product: CCC(CC)n1c(=O)oc(=O)c2cccnc21

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 64A for the product of Example 3A (0.120 g, 57%). MS (ESI+) m/z 223.1 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 0.87 (t, J=7.54 Hz, 6H), 1.88 (m, 2H), 2.21 (s, 2H), 5.43 (s, 1H), 7.24 (dd, J=6.99, 4.04 Hz, 1H), 8.42 (dd, J=7.72, 1.84 Hz, 1H), 8.68 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25].O>CN(C)C=O>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([N:17]([CH2:25][CH:24]=[CH2:23])[C:18](=[O:20])[CH3:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: C=CCBr
Reactant: CC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCN(C(C)=O)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 1 h

Procedure:
To 3.0 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide in 250 ml of dimethylformamide under argon, was added 0.6 g of sodium hydride (50% in oil). This mixture was stirred for 1 hour, then 1.07 ml of allyl bromide was added. The mixture was stirred overnight, then poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined, dried and evaporated in vacuo. The residue was chromatographed as described in Example 1. The active fractions were combined, evaporated and the solid recrystallized from ethyl acetate-hexane, giving 1.46 g of the desired product as tan crystals, mp 114°-115° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][C:23]([C:28](=[O:30])[NH2:29])=[CH:24][CH:25]=4)[NH:20][C:19]=3[N:18]=[CH:17][N:16]=2)[CH2:10]1)(C)(C)C.CC1C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:7][CH2:8][CH:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[C:27]3[C:26]4[C:21](=[CH:22][C:23]([C:28]([NH2:29])=[O:30])=[CH:24][CH:25]=4)[NH:20][C:19]=3[N:18]=[CH:17][N:16]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4cc(C(N)=O)ccc4c23)CCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: NCC1CN(c2ncnc3[nH]c4cc(C(N)=O)ccc4c23)CCO1
Yield: 92.3 %

Procedure:
[4-(7-Carbamoyl-9H-pyrimido[4,5-b]indol-4-yl)-morpholin-2-ylmethyl]-carbamic acid tert-butyl ester (5.5 mg, 0.013 mmol) was suspended in methanol and loaded onto a MP-TsOH SPE cartridge which had been pre-conditioned with methanol. The deprotected product was then eluted off using 2 N ammonia in methanol and concentrated in vacuo to give the title compound as an off-white solid (4 mg, 0.012 mmol). LC-MS (2) Rt 1.08 min; m/z 327 (ES+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.ClCCl.O.C(#N)C>[CH3:8][C:6]1[CH:7]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=[CH:4][N:5]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Cl)ncn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1cc(-c2ccccc2)ncn1
Yield: 46 %

Procedure:
First, into a recovery flask equipped with a reflux pipe, 4.90 g of 4-chloro-6-methylpyrimidine, 4.80 g of phenylboronic acid, 4.03 g of sodium carbonate, 0.16 g of bis(triphenylphosphine)palladium(II)dichloride (abbreviation: Pd(PPh3)2Cl2), mL of water, and 10 mL of acetonitrile were put, and the air in the flask was replaced with argon. This reaction container was subjected to irradiation with microwaves (2.45 GHz, 100 W) for one hour to be heated. Here, into the flask, 2.28 g of phenylboronic acid, 2.02 g of sodium carbonate, 0.082 g of Pd(PPh3)2Cl2, 5 mL of water, and 10 mL of acetonitrile were further put, and the reaction container was heated again by irradiation with microwaves (2.45 GHz, 100 W) for one hour. After that, water was added to this solution and extraction with dichloromethane was carried out. The obtained solution of the extract was washed with a saturated aqueous solution of sodium carbonate, water, and then with saturated saline, and dried with magnesium sulfate. The solution which had been dried was filtered. The solvent of this solution was distilled off, and then the obtained residue was purified by silica gel column chromatography using dichloromethane and ethyl acetate as a developing solvent in a volume ratio of 9:1, so that a pyrimidine derivative Hmppm, which was the objective substance, was obtained (orange oily substance, yield of 46%). Note that the irradiation with microwaves was performed using a microwave synthesis system (Discover, produced by CEM Corporation). A synthesis scheme (b-1) of Step 1 is illustrated below.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[OH:12].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=S)=[CH:16][CH:15]=1>C(O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[O:12][C:3]3[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=3[N:1]=2)=[CH:16][CH:15]=1
Reactant: S=C=Nc1ccc(Br)cc1
Reactant: Nc1cc(C(F)(F)F)ccc1O
Solvent: CCO
Product: FC(F)(F)c1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.6 %

Procedure:
2-Amino-4-(trifluoromethyl)phenol (250 mg, 1.41 mmol) and 1-bromo-4-isothio-cyanatobenzene (302 mg, 1.41 mmol) were stirred in ethyl alcohol at ambient temperature for 18 h. The flask was charged with 1-[3-(dimethylamino)propyl]-3-ethylcarhodiimide hydrochloride (EDCI) (405 mg, 2.12 mmol), and the mixture was stirred for 2 h before being heated at reflux overnight. The reaction was allowed to cool to rt and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with 2 N aqueous hydrochloric acid solution and water, dried (Na2SO4), and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 85:15 hexanes/ethyl acetate to provide the title compound (315 mg, 62%). LC-MS m/z 357.1 (MH+), retention time 4.20 minutes.
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:30])=[CH:9][C:10]([O:28][CH3:29])=[CH:11][C:12]=3[C:13]32[CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>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.CN(C=O)C>[F:30][C:8]1[C:7]2[O:6][C:5]3[C:14](=[CH:15][C:2]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)=[CH:3][CH:4]=3)[C:13]3([CH2:19][S:18][C:17]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[N:16]3)[C:12]=2[CH:11]=[C:10]([O:28][CH3:29])[CH:9]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Reactant: COc1cc(F)c2c(c1)C1(CSC(NC(=O)OC(C)(C)C)=N1)c1cc(Br)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(F)c2c(c1)C1(CSC(NC(=O)OC(C)(C)C)=N1)c1cc(-c3cnccn3)ccc1O2
Temperature: 110 °C
Reaction time: 3 h

Procedure:
A 10 ml resealable tube was charged with tert-butyl 7′-bromo-4′-fluoro-2′-methoxy-5H-spiro[thiazole-4,9′-xanthene]-2-ylcarbamate (300 mg, 0.606 mmol), tetrakis(triphenylphosphine)palladium (70.0 mg, 0.061 mmol) and DMF (3.03 ml) and 2-(tributylstannyl)pyrazine (402 mg, 1.090 mmol). The mixture was stirred for 3 hr at 110° C. The mixture was partitioned between EtOAc and water. The organic layer was washed twice with water, filtered through celite and concentrated under reduced pressure. The solids were triturated with hexane to remove excess tin residue before being filtered. Purification by silica gel chromatography (10-80% CH2Cl2/MeOH/NH4OH in CH2Cl2) to provide tert-butyl 4′-fluoro-2′-methoxy-7′-(pyrazin-2-yl)-5H-spiro[thiazole-4,9′-xanthene]-2-ylcarbamate.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[Cl:15])=[C:6]([Cl:16])[N:5]=[C:4]([S:17][CH3:18])[N:3]=1.[CH:19]([NH2:22])([CH3:21])[CH3:20]>ClCCl>[Cl:16][C:6]1[N:5]=[C:4]([S:17][CH3:18])[N:3]=[C:2]([NH:22][CH:19]([CH3:21])[CH3:20])[C:7]=1[C:8]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15]
Reactant: CSc1nc(Cl)c(-c2c(F)cccc2Cl)c(Cl)n1
Reactant: CC(C)N
Solvent: ClCCl
Product: CSc1nc(Cl)c(-c2c(F)cccc2Cl)c(NC(C)C)n1
Temperature: 22.5 °C
Reaction time: 5 h
Yield: 11.9 %

Procedure:
A solution of 37.5 g (324 mmol) of the product of step b in 150 ml of anhydrous dichloromethane was treated with 24 g (406 mol) of isopropylamine and stirred for five hours at approximately 20 to 25° C. Then, the solvent was distilled off, the residue was taken up in ethyl acetate and washed with dilute HCl, water and dilute NaHCO3 solution, dried and freed from solvent. Following chromatography on silica gel (cyclohexane/methyl tert-butyl ether 100:1 to 19:1), 13.4 g of the title compound were obtained from the residue in the form of colorless crystals of m.p. 94-98° C., which were employed in the next step without further purification.
Reaction SMILES: CC1C=CC(S(OCC2CC3C=CC=C(CC4C=CC=CC=4)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[CH2:33]([C:40]1[C:48]2[O:47][CH:46]([CH2:49][N:50]=[N+]=[N-])[CH2:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[N-]=[N+]=[N-]>[Pd]>[CH2:33]([C:40]1[C:48]2[O:47][CH:46]([CH2:49][NH2:50])[CH2:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: [N-]=[N+]=NCC1Cc2cccc(Cc3ccccc3)c2O1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Cc4ccccc4)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Product: NCC1Cc2cccc(Cc3ccccc3)c2O1
Yield: 79 %

Procedure:
Treatment of (±)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (6.53 g, 16.6 mmol) with sodium azide (4.30 g, 66.2 mmol) generally according to the procedure described for Intermediate 98 afforded (±)-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methyl azide. Treatment of the azide with palladium on carbon (0.40 g, 10 wt. %) generally according to the procedure described for Example 1 gave 3.62 g (79%) of (±)-1-(7-benzyl-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 107-111° C. (dec); Anal. calcd. for C16H17NOHCl: C, 69.69; H, 6.58; N, 5.08. Found: C, 68.56; H, 6.66; N, 4.92.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:12]2[CH2:13][CH2:14][CH2:15][C@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[O:16])(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: Cl
Product: O=C(OCc1ccccc1)[C@@H]1CCCN1S(=O)(=O)c1ccc(F)cc1

Procedure:
The title compound was prepared by a similar method to Example 1 from L-proline benzyl ester hydrochloride and 4-fluorobenzenesulphonyl chloride. The crude product was purified by column chromatography on silica gel eluting with dichloromethane to afford benzyl (2S)-1-[(4-fluorophenyl)sulfonyl]-2-pyrrolidinecarboxylate as a clear oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][N:6]=1)([CH3:3])[CH3:2].[OH:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](=[O:31])[CH3:30])=[CH:23][CH:22]=1>>[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([O:20][C:21]2[CH:22]=[CH:23][C:24](/[CH:27]=[CH:28]/[C:29](=[O:31])[CH3:30])=[CH:25][CH:26]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(=O)/C=C/c1ccc(O)cc1
Reactant: CC(C)Oc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(=O)/C=C/c1ccc(Oc2ccc(OC(C)C)nc2)cc1

Procedure:
2-Isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (3.24 g, 12.33 mmol) and (E)-4-(4-hydroxyphenyl)but-3-en-2-one (2.0 g, 12.33 mmol) were reacted in analogy to example 50a. Yield: 304 mg (8%), M+H+: 298.2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([OH:15])=O)[CH:8]=1.[NH2:22][C:23]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>C(OCC)(=O)C.C(N(CC)CC)C.C(Cl)Cl>[C:7]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([NH:22][C:23]2[CH:35]=[C:34]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[CH:33]=[CH:32][C:24]=2[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])=[O:15])[CH:8]=1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1NC(=O)c1cccc(-c2ccccc2)c1
Reaction time: 0.33 h
Yield: 6.6 %

Procedure:
4.0 mL of methylene chloride, 0.015 mL of N-dimethylformamide and 0.050 mL of oxalyl chloride were added to 99 mg of 3-biphenylcarboxylic acid at room temperature sequentially and stirred at the same temperature for 20 minutes. 0.16 mL of triethylamine and 0.13 g of tert-butyl 2-amino-4-phenoxybenzoate were added to the reaction mixture at room temperature sequentially and stirred at the same temperature for 10 minutes. Ethyl acetate and 1.0 mol/L hydrochloric acid were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium chloride aqueous solution, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; chloroform] to obtain 14 mg of tert-butyl 2-(biphenyl-3-carboxamido)-4-phenoxybenzoate as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.C[Si]([C:15]([F:18])([F:17])[F:16])(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[C:15]([F:18])([F:17])[F:16])=[C:4]([F:10])[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Br)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
To a 0° C. solution of 4-bromo-2-fluorobenzaldehyde (1.00 g, 4.93 mmol) in tetrahydrofuran (50 mL) was added trimethylsilyl trifluoromethane (0.77 mL, 4.9 mmol) dropwise over 5 minutes. The reaction was stirred at 0° C. for 10 minutes. Then tetrabutylammonium fluoride (0.49 mL, 0.49 mmol, 1 M in tetrahydrofuran) was slowly added and the reaction was allowed to gradually warm to room temperature and stir for 3 days. The reaction was concentrated and the residue was taken up in dichloromethane. The solution was washed once with 1 N aqueous hydrochloric acid and once with brine. The organics were dried over magnesium sulfate, filtered, and concentrated. Purification by column chromatography (0-50% ethyl acetate/heptanes) gave the title compound (1.0 g, 75%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.48 (d, J=7.61 Hz, 1H), 7.39 (d, J=1.76 Hz, 1H), 7.29 (dd, J=9.56, 1.95 Hz, 1H), 5.33-5.40 (m, 1H), 2.70 (d, J=5.46 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:8][C:7]2=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1>C1(C)C=CC=CC=1>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:6]([C:7](=[S:30])[CH:8]=2)=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:13][CH:14]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(-c2cc(=O)c3cccc(C)c3o2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc(=S)c3cccc(C)c3o2)cc1
Yield: 125.9 %

Procedure:
Compound I-23 was prepared according to the general method described above in Scheme 1. A stirred mixture of 8-methyl-4′-methoxyflavone (200.0 mg, 0.75 mmol), Lawesson's reagent (182.3 mg, 0.45 mmol) and anhydrous toluene (4.0 mL) was refluxed under N2 for 1.5 hr. The solvent was removed under vacuum and the residue was purified by silica gel chromatography (20% ethyl acetate/hexane) to give 2-(4-Methoxy-phenyl)-8-methyl-chromene-4-thione (160.0 mg, 75.5% yield) as a red solid. Thione was used in next step without further purification. LC/MS: (M+H) 283.1. LC/Method A/8.967 min, 90.0% purity by area %.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:19].C(N(CC)CC)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([O:1][CH:2]1[CH2:7][O:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[N:4][N:3]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:23][CH:22]=1)=[O:19])(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)N1N=C(c2cccc(C(F)(F)F)c2)OCC1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC1COC(c2cccc(C(F)(F)F)c2)=NN1C(=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 21.0 g 5,6-dihydro-5-hydroxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide (prepared in C above), 13.0 ml triethylamine, and 6.5 ml acetic anhydride was stirred at room temperature for 3 h. The mixture was then concentrated under vacuum to produce a solid residue. The solid residue was taken up in 400 ml dichloromethane and washed twice with 100 ml saturated sodium bicarbonate. The organic phase was then dried over sodium sulfate and concentrated under vacuum to produce 5,6-dihydro-5-acetyloxy-2-[3-(trifluoromethyl)phenyl]-N-[4-(trifluoromethyl)phenyl]-4H-1,3,4-oxadiazine-4-carboxamide. The structure was confirmed by 1H NMR.