Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])[CH:7]=1.N[C:32]1C=C2C(=[CH:39][CH:40]=1)NN=C2C1C=CC=CC=1.FC1C=CC(S(C)(=O)=O)=C(S(Cl)(=O)=[O:55])C=1>N1C=CC=CC=1>[CH:40]([O:55][CH:26]([CH3:25])[CH3:21])([CH3:39])[CH3:32].[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:27]([CH3:30])(=[O:29])=[O:28])=[C:6]([S:8]([NH:11][C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][N:16]=[C:15]3[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Reactant: CS(=O)(=O)c1ccc(F)cc1S(=O)(=O)Cl
Agent: CS(=O)(=O)c1ccc(F)cc1S(=O)(=O)Nc1ccc2[nH]nc(-c3ccccc3)c2c1
Solvent: c1ccncc1
Product: CC(C)OC(C)C

Procedure:
5-Fluoro-2-methylsulfonyl-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide can be prepared as described in Example 2 from 0.52 g of 5-amino-3-phenyl-1H-indazole, 5 ml of pyridine and 0.68 g of 5-fluoro-2-methylsulfonylbenzenesulfonyl chloride. The residue obtained is purified by chromatography on a column of 50 g of silice (particle size 40-63 μm), eluting with pure dichloromethane. After recrystallization from 5 ml of acetonitrile and washing with acetonitrile and then with diisopropyl ether, 0.07 g of 5-fluoro-2-methylsulfonyl-N-(3-phenyl-1H-indazol-5-yl)benzenesulfonamide is obtained in the form of a white solid melting at 224° C. (analysis: C20H16FN3O4S2, % calculated C, 53.92; H, 3.62; F, 4.26; N, 9.43; O, 14.37; S, 14.40. % found C, 53.74; H, 3.31; N, 9.35; S, 14.10).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:19])[NH:6][C:7]1[N:8]([CH2:16][CH2:17][OH:18])[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:22][C@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]1[N:33]2[CH:34]=[C:35]([O:38][C@H:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[C@@H:42]([NH2:49])[CH2:41][CH2:40]3)[CH:36]=[CH:37][C:32]2=[N:31][N:30]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:49][C@@H:42]2[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:39]([O:38][C:35]3[CH:36]=[CH:37][C:32]4[N:33]([C:29]([N:24]5[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]5[CH3:22])=[N:30][N:31]=4)[CH:34]=3)[CH2:40][CH2:41]2)=[O:19])[N:8]([CH2:16][CH2:17][OH:18])[N:9]=1)([CH3:13])([CH3:14])[CH3:15]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(CCO)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4CCO)c4ccccc43)cn12
Temperature: 100 °C
Reaction time: 4 h
Yield: 15.3 %

Procedure:
A mixture of Intermediate 110b (143 mg, 0.40 mmol), Intermediate 81d (1151 mg, 0.40 mmol) and DIPEA (82 μL, 0.50 mmol) in dioxane (5 mL) was stirred at 100° C. for 4 h. After cooling, the reaction mixture was concentrated in vacuo and then partitioned between water and DCM. The aqueous phase was extracted with DCM (×3) and the combined organic layers were washed with brine, dried through a phase separator and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 3-15% MeOH in DCM followed by MDAP (Method 7) purification, to afford the title compound (36 mg, 15%) as a glassy white solid. LCMS (Method 5): Rt 4.02 min, m/z 587 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.92 (3H, d, J=6.3 Hz), 1.21 (9H, s), 1.44-1.57 (2H, m), 1.60-1.74 (2H, m), 1.74-1.87 (2H, m), 1.88-2.22 (4H, m), 2.86-2.96 (1H, m), 3.12-3.20 (2H, m), 3.63-3.71 (2H, m), 3.95 (2H, t, J=6.0 Hz), 4.82-4.91 (1H, m), 5.00 (1H, br s), 5.54 (1H, t, J=4.3 Hz), 6.07 (1H, s), 7.10 (1H, d, J=8.6 Hz), 7.22 (1H, dd, J=9.8, 2.2 Hz), 7.26-7.32 (1H, m), 7.35-7.42 (3H, m), 7.65 (1H, d, J=10.8 Hz), 7.71 (1H, d, J=2.1 Hz), 8.19-8.23 (1H, m).
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][C:4]([NH:7][CH:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3([CH2:22][CH2:23][OH:24])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:10][CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1[C:38](Cl)=[O:39].[OH-].[K+]>O1CCCC1.O.CO>[OH:24][CH2:23][CH2:22][C:16]1([CH2:15][CH2:14][N:11]2[CH2:10][CH2:9][CH:8]([N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:25])=[CH:6][CH:5]=3)[C:38]([C:34]3[O:33][CH:37]=[CH:36][CH:35]=3)=[O:39])[CH2:13][CH2:12]2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc(NC2CCN(CCC3(CCO)CCOCC3)CC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCO)CCOCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-[4-[2-[4-(p-toluidino)piperidin-1-yl]ethyl]tetrahydropy-ran-4-yl]ethanol (synthesized in Example 80) (239 mg) in tetrahydrofuran (3 mL) was added triethylamine (0.29 mL) and 2-furoyl chloride (0.17 mL) sucessively. The reaction solution was stirred at room temperature for 30 minutes. To the reaction solution were added methanol (4 mL) and a 3N aqueous potassium hydroxide solution (2 mL). The reaction solution was stirred at room temperature for additional 15 minutes. Water was added to the reaction solution and it was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by chromatography [silica gel, chloroform-methanol (30:1)] to give the title compound (210 mg).
Reaction SMILES: [F:1][C:2]([F:21])([C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH2:3][CH2:4][S:5]([CH2:8][C:9]#[N:10])(=[O:7])=[O:6].N1CCCC1C(O)=O.C1O[C:33]2([CH2:38][CH2:37][C:36](=O)[CH2:35][CH2:34]2)[O:32]C1>C1(C)C=CC=CC=1>[O:32]=[C:33]1[CH2:38][CH2:37][CH:36]([CH:8]([S:5]([CH2:4][CH2:3][C:2]([F:1])([F:21])[C:11]([F:19])([F:20])[C:12]([F:17])([F:18])[C:13]([F:14])([F:15])[F:16])(=[O:7])=[O:6])[C:9]#[N:10])[CH2:35][CH2:34]1
Reactant: N#CCS(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: O=C(O)C1CCCN1
Solvent: Cc1ccccc1
Product: N#CC(C1CCC(=O)CC1)S(=O)(=O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.7 %

Procedure:
A mixture of 5.40 g of (3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile, 60 ml of toluene, 0.18 g of DL-proline and 2.77 g of 1,4-cyclohexanedione monoethylene ketal was heated and stirred for 3 hours under the reflux condition. After 40 ml of toluene was distilled off, the reaction mixture was cooled to room temperature. The mixture was cooled to 0° C. and then 0.61 g of sodium borohydride was added thereto. To the reaction mixture was added 3 ml of N,N-dimethylformamide. The mixture was stirred at room temperature for 6 hours and then cooled to 0° C. Thereto 50 ml of water and 50 ml of ethyl acetate were added. While the reaction mixture was stirred, 20 ml of an aqueous 1N hydrochloric acid solution was added dropwise, followed by extraction with 100 ml of ethyl acetate twice. An organic layer was washed with 100 ml of an aqueous saturated sodium hydrogen carbonate solution, 100 ml of an aqueous saturated sodium chloride solution and 100 ml of water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolve to 14 ml of acetic acid and 6 ml of water. The mixture was heated to 100° C. and stirred for 8 hours. After the reaction mixture was cooled to room temperature, 100 ml of ethyl acetate was added thereto. The mixture was added slowly into 100 ml of an aqueous saturated sodium hydrogen carbonate solution. The solution was stirred for 1 hour, followed by extraction with 100 ml of ethyl acetate twice. Organic layers were combined, washed with 100 ml of an aqueous saturated sodium hydrogen carbonate solution and 100 ml of an aqueous saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.94 g of 2-(4-oxocyclohexyl)-2-(3,3,4,4,5,5,6,6,6-nonafluorohexylsulfonyl)acetonitrile (hereinafter, referred to as the present compound (62)) represented by the formula:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([F:19])[CH:13]=2)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:28][OH:29].C([O-])(O)=O.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:9]/[C:10](/[C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([F:19])[CH:13]=2)=[N:28]\[OH:29])[CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: Cc1cc(C(=O)CC(c2cccc(Br)c2)c2ccccc2C)cc(F)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(CC(c2cccc(Br)c2)c2ccccc2C)=N/O)cc(F)n1

Procedure:
In analogy to example 74, step 7, from 3-(3-bromo-phenyl)-1-(2-fluoro-6-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of NaHCO3 was prepared the title compound as a white foam, MS (ESI+): m/z=427.0801 ([M+H]+, 1Br).
Reaction SMILES: [CH:1]([C:4]1([CH3:21])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=2[C:12]([O:14][CH3:15])=[O:13])=[N:5]1)([CH3:3])[CH3:2].[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([N:7]1[C:8](=[O:9])[C:4]([CH:1]([CH3:3])[CH3:2])([CH3:21])[N:5]=[C:6]1[C:10]1[N:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:24])[CH3:23]
Reactant: COC(=O)c1ccc(C)nc1C1=NC(C)(C(C)C)C(=O)N1
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(C)nc1C1=NC(C)(C(C)C)C(=O)N1C(C)=O

Procedure:
A solution of 33.2 g of methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-6-methylnicotinate in 350 mL of acetic anhydride is stirred and heated at reflux for 4 hours. The solution is concentrated in vacuo, and the residue is triturated with 2:1 hexane-ether to give the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[CH2:11][CH2:10][CH2:9][CH:8]3[CH2:13][CH2:14][O:15][C:6]([C:7]=23)=[CH:5][N:4]1[O:16][CH3:17].[C:18](OC(=O)C)(=[O:20])[CH3:19].N1C=CC=CC=1>O>[C:18]([CH:10]1[CH2:11][C:12]2[CH:3]([O:2][CH3:1])[N:4]([O:16][CH3:17])[CH:5]=[C:6]3[O:15][CH2:14][CH2:13][CH:8]([C:7]=23)[CH2:9]1)(=[O:20])[CH3:19]
Reactant: CC(=O)OC(C)=O
Reactant: COC1C2=C3C(=CN1OC)OCCC3CCC2
Solvent: c1ccncc1
Solvent: O
Product: COC1C2=C3C(=CN1OC)OCCC3CC(C(C)=O)C2
Reaction time: 2 h

Procedure:
A mixture of 1,2,3a, 4,5,6-hexahydro-7,8-dimethoxypyrano[2,3,4-de]isoquinoline (10.0 g), described in Example 56, acetic anhydride (60.0 ml) and pyridine (0.5 ml) is heated on the steam bath for 4 hr. The mixture is poured into water and stirred for 2 hr. The mixture is extracted with chloroform and the extracts are washed with sodium bicarbonate solution and then with brine. The organic solution is dried and evaporated to leave the title compound. A sample, crystallized from isopropanol, had m.p. 100°- 102° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>CN(C)C=O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:1][CH:16]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ncnc2cc(Cl)ccc12
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(=CNc1ncnc2cc(Cl)ccc12)C(=O)OCC
Temperature: 150 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
A mixture of 4-amino-7-chloroquinazoline (1.3 g) and diethyl ethoxymethylenepropanedioate (1.72 g) in N,N-dimethylformamide (6 ml) was stirred for 2 hours at 150° C. The resultant mixture was cooled to ambient temperature and poured into ice-water to give crystals, which were separated by filtration, washed with water and recrystallized from ethanol to give a mixture (1.65 g) of diethyl [(7-chloro-4-quinazolinylamino)methylene]propanedioate and ethyl 9-chloro-4-oxo-4H-pyrimido[1,2-c]quinazoline-3-carboxylate. The mixture was subjected to a column chromatography using silica gel (developing solvent: a mixture of benzene and ethyl acetate (10:1)) to give purified crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7]O)[CH:6]=1.S(Cl)([Cl:18])=O>ClCCl>[Br:1][C:2]1[C:3]([C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])=[N:4][N:5]([CH2:7][Cl:18])[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCn1cc(Br)c(C(F)(F)C(F)(F)F)n1
Solvent: ClCCl
Product: FC(F)(F)C(F)(F)c1nn(CCl)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6.49 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole-1-ylmethanol was dissolved to 60 ml of dichloromethane. 3.2 ml of thionyl chloride was added to the solution, followed by stirring at room temperature for overnight. The reaction mixture was concentrated under reduced pressure to obtain 6.84 g of 4-bromo-1-(chloromethyl)-3-(pentafluoroethyl)-1H-pyrazole.
Reaction SMILES: C([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:29]=[C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][CH:32]=4)[C:27]4[C:22](=[CH:23][C:24]([O:40][CH3:41])=[C:25]([O:38][CH3:39])[CH:26]=4)[N:21]=3)[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)(C)(C)C>FC(F)(F)C(O)=O>[CH3:39][O:38][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:40][CH3:41])[N:21]=[C:20]([N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:42])=[O:5])=[CH:8][CH:9]=3)[CH2:15][CH2:16]1)[N:29]=[C:28]2[NH:30][C:31]1[CH:32]=[CH:33][C:34]([CH3:37])=[CH:35][CH:36]=1
Reactant: COc1cc2nc(N3CCC(Nc4ccc(C(=O)OC(C)(C)C)cc4)CC3)nc(Nc3ccc(C)cc3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2nc(N3CCC(Nc4ccc(C(=O)O)cc4)CC3)nc(Nc3ccc(C)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 12 h
Yield: 139.1 %

Procedure:
A solution of (16) (0.040 g, 0.07 mmol) in trifluoroacetic acid (5 mL) was capped with a drying tube and stirred at 25° C. for 12 h. The reaction mixture was evaporated to a light brown solid residue (0.05 g, quantitative yield); 1H NMR (DMSO) δ 12.10 (br s, 1H), 10.56 (br s, 1H), 7.92 (s, 1H) 7.67 (d, 2H, J=8.5), 7.51 (d, 2H, J=8.3), 7.27 (s, 1H), 7.26 (d, 2H, J=7.9), 6.64 (d, 2H, J=8.4), 4.32 (d, 2H, J=12.6), 3.91 (s, 3H), 3.89 (s, 3H), 3.68 (m, 1H), 3.36 (t, 2H, J=10.7), 2.32 (s, 3H), 2.05 (d, 2H, J=8.0), 1.47 (m, 2H); 13C NMR (DMSO) δ 167.4, 157.2, 155.4, 151.4, 150.7, 147.0, 136.4, 135.0, 134.6, 131.2, 129.1, 124.0, 117.0, 111.2, 104.3, 102.2, 99.1, 56.3, 56.1, 47.9, 43.5, 30.8, 20.6; HRMS (FAB) m/z 514.2459 M+H)+ (C29H31N5O4 requires 514.2454); Anal. (C29H31N5O4 ·1CF3COOH·11/4H2O) C, H, N.
Reaction SMILES: [NH:1]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][C:4](=O)[OH:5].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>COCCOC.O>[C:17]([O:16][C:14]([NH:1][C@H:2]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3][CH2:4][OH:5])=[O:15])([CH3:19])([CH3:20])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCOCC1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
To a solution of Boc-L-Asp-OtBu (3.00 g, 10.4 mmol) in 1,2-dimethoxyethane (10 mL) was added at −15° C. 4-methylmorpholine (1.14 mL, 10.4 mmol) and isobutyl chloroformate (1.35 mL, 10.4 mmol). After stirring for 10 min at −15° C. the precipitate was filtered off and washed with cold 1,2-dimethoxyethane (20 mL). To the filtrate was added at −15° C. a solution of sodium borohydride (0.59 g, 15.6 mmol) in water (5 mL). After 5 min water (250 mL) was added. The reaction mixture was extracted with ethyl acetate (3×100 mL), the combined organic layers dried over sodium sulphate, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>C(#N)C.C(OCC)(=O)C>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:21]
Reactant: O=C(Cc1ccccc1O)OCc1ccccc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(Cc1ccccc1OCCCBr)OCc1ccccc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5.2 g of potassium carbonate and 40 cm3 of 1,3-dibromopropane are added to a solution of 4.84 g of benzyl [(2-hydroxy)phenyl]acetate in 100 cm3 of acetonitrile. The mixture is stirred at the reflux temperature for 20 hours and then cooled to room temperature before being filtered. The filtrate is concentrated to dryness under reduced pressure and the residue obtained is taken up in 200 cm3 of ethyl acetate. The solution is washed with twice 100 cm3 of water then with 150 cm3 of brine, and is dried over magnesium sulphate and concentrated under reduced pressure (2.7 kPa). The oil obtained is chromatographed on a silica gel column (particle size 0.06-0.200 height 30 cm, diameter 5 cm), eluting with a mixture of cyclohexane and ethyl acetate (95:5 by volume) and collecting fractions of 100 cm3. Fractions 18 to 28 are concentrated to dryness under reduced pressure (2.7 kPa). 2.0 g of benzyl [2-(3-bromopropoxy)phenyl]acetate are obtained in the form of an oil.
Reaction SMILES: C(C[C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]=[CH:9][C:10]([OH:12])=[O:11])(O)=O.C[N:17](C)[CH:18]=[O:19]>N>[NH2:17][C:18]([C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:19]
Reactant: O=C(O)C=Cc1cccc(CC(=O)O)c1
Reactant: CN(C)C=O
Agent: N
Product: NC(=O)c1cccc(C=CC(=O)O)c1

Procedure:
A solution of 3-carboxymethylcinnamic acid (427 g) (Example 2(a)) in dimethyl formamide (4.25 1) and aqueous ammonia (specific gravity 0.88, 8.5 1) was stored at room temperature for 4 days, concentrated to ca 11 1, and then treated with ice (8 kg) and concentrated hydrochloric acid (1 1). The precipitated title product was washed with water and dried, m.p. >260° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:20][OH:21])=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:35]([F:37])[F:36].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][C:18](=[O:29])[C:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:20][O:21][CH:35]([F:37])[F:36])=[CH:11][C:10]=1[O:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)ccc1OCc1ccccc1
Reactant: FC(F)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: COCCOC
Product: COc1cc(CCNC(=O)C(=COC(F)F)c2ccc(Cl)cc2)ccc1OCc1ccccc1

Procedure:
1.48 g (3.38 mmol) of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl)acrylamide, 4.3 g (8.46 mmol) of 10% aqueous potassium hydroxide solution, 220 mg (0.677 mmol) of tetrabutylammonium bromide and 15 ml of ethylene glycol dimethyl ether were mixed and chlorodifluoromethane gas was blown thereto at room temperature. After a sample was taken out from the reaction mixture and the disappearance of the starting material was confirmed by thin layer chromatography, 5% hydrochloric acid was added to the reaction mixture, which was followed by extracted with ethyl acetate, washed with 5% hydrochrolic acid, saturated aqueous sodium bicarbonate solution and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was washed with hexane to give 1.45 g of N-[2-(4-benzyloxy-3-methoxyphenyl)ethyl]-2-(4-chlorophenyl)-3-difluoromethoxyacrylamide (the present compound 1453).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:19])[NH:12][CH2:13][CH:14](OC)OC)=[CH:7][CH:6]=1)(=O)C.[CH3:20][S:21](O)(=[O:23])=[O:22].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>CCOC(C)=O>[CH3:20][S:21]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:19][CH:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)O
Reactant: COC(CNC(=O)c1ccc(OC(C)=O)cc1)OC
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1ccc(-c2ncco2)cc1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
In a similar manner as described in Pandit, C. R. et al., “Preparation of 2-Substituted Oxazoles”, Synth. Commun. 32, 2427-2432 (2002), 4-(2,2-dimethoxyethylcarbamoyl)phenyl acetate (43 g, 160.88 mmol) was stirred and treated with Eaton's reagent (380 ml; 7.7 wt. % phosphorus pentoxide in methanesulfonic acid, Aldrich #38,081-4). After 15 minutes, the internal temperature of the reaction was raised to about 130° C. and held for about 3 hours. The reaction was followed by TLC analysis (2:1 EtOAc:Hex) with only a single new UV active spot observed. The reaction mixture was allowed to cool to about 40° C. and was then cooled in an ice bath to about 3° C. The reaction was poured into 2 L of ice water and extracted with ethyl acetate (1.4 L). The organic layer was washed with water (1 L). The combined aqueous layers were extracted with ethyl acetate (2×1 L). The combined organic layers were washed with water (2×) and brine, dried, treated with silica gel and charcoal, and concentrated. The residue was dissolved in methylene chloride and treated with hexane until a precipitate was seen. The mixture was treated with charcoal, filtered, and concentrated to give 53.3 g of 4-(oxazol-2-yl)phenyl methanesulfonate (>100% th.; 90% pract.) which contained 1.2 equivalents of methyl methanesulfonic acid; 1H NMR (CDCl3) δ 8.07 (d, 2H), 7.71 (d, 1H), 7.36 (d, 2H), 7.22 (d, 1H), 3.16 (s, 3H) ppm.
Reaction SMILES: O.[NH2:2][C:3]1[CH:8]=[C:7]([OH:9])[N:6]=[C:5]([SH:10])[N:4]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH2:15]Br>>[NH2:2][C:3]1[N:4]=[C:5]([S:10][CH2:15][C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[N:6]=[C:7]([OH:9])[CH:8]=1
Reactant: Nc1cc(O)nc(S)n1
Reactant: Fc1ccc(CBr)cc1F
Solvent: O
Product: Nc1cc(O)nc(SCc2ccc(F)c(F)c2)n1

Procedure:
The subtitle compound was prepared according to the procedure of Example 1 step 1) treating 4-amino-6-hydroxy-2-mercaptopyrimidine monohydrate (2.0 g) with 3,4-difluorobenzyl bromide (2.66 g) to afford the subtitle compound as a white solid. Yield: 3.35 g. 1H NMR. δ(DMSO) 7.54 (1H, m), 7.32 (2H, m), 6.58 (2H, bs), 4.96 (1H, bs), 4.29 (2H, s).
Reaction SMILES: [CH3:1][C:2]1([CH3:6])[CH2:5][NH:4][CH2:3]1.Cl[CH2:8][CH:9]([N:11]1[CH:15]([CH3:16])[CH2:14][N:13]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:12]1=[O:24])[CH3:10].Cl>>[Cl:23][C:19]1[CH:18]=[C:17]([N:13]2[CH2:14][CH:15]([CH3:16])[N:11]([CH:9]([CH3:10])[CH2:8][N:4]3[CH2:5][C:2]([CH3:6])([CH3:1])[CH2:3]3)[C:12]2=[O:24])[CH:22]=[CH:21][CH:20]=1
Reactant: CC(CCl)N1C(=O)N(c2cccc(Cl)c2)CC1C
Reactant: CC1(C)CNC1
Agent: Cl
Product: CC(CN1CC(C)(C)C1)N1C(=O)N(c2cccc(Cl)c2)CC1C

Procedure:
The title compound is prepared pursuant to the procedure of Example 4 from 3,3-dimethylazetidine and 3-(2-chloro-1-methylethyl)-1-(m-chlorophenyl)-4-methyl-2-imidazolidinone. B.p. 200° C./0.6 mm Hg. The corresponding hydrochloride melts at 162°-164° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:2]1=2.[Br:13]Br.O>C(O)(=O)C.[Fe]>[Br:13][C:7]1[CH:8]=[C:9]([C:10]([OH:12])=[O:11])[C:2]2[O:1][CH2:5][CH2:4][C:3]=2[CH:6]=1
Reactant: BrBr
Reactant: O=C(O)c1cccc2c1OCC2
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)cc2c1OCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.4 %

Procedure:
To an ice-cooled acetic acid solution (5 ml) of 2,3-dihydrobenzo[b]furan-7-carboxylic acid (15a) (0.33 g, 2.0 mmol) there was added iron (8 mg, 0.14 mmol) and bromine (0.32 g, 2.0 mmol) in 1 ml of acetic acid. The mixture was stirred at room temperature for 18 hours and then poured into water (20 ml). After cooling in the freezer for 11/2 hours the product was collected on a filter, and recrystallized from ethyl acetate to give 0.24 g (50.3%) of 15b as a white crystalline solid, mp 228°-229° C.