Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.Cl.Cl.[CH3:41][N:42]([CH3:47])[CH:43]1[CH2:46][NH:45][CH2:44]1.CN(C)C1CNC1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:45]3[CH2:46][CH:43]([N:42]([CH3:47])[CH3:41])[CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CN(C)C1CNC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 102.7 %

Procedure:
DIPEA (0.341 mL, 1.96 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(pyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 20, 254 mg, 0.61 mmol) and N,N-dimethylazetidin-3-amine dihydrochloride (Intermediate 26, 106 mg, 0.61 mmol) in DMA (4 mL) and the mixture was heated to 100° C. for 0.5 h. Further N,N-dimethylazetidin-3-amine (35 mg, 0.19 mmol) was then added and the mixture was heated at 100° C. for a further 2 h and was then left at r.t. overnight. The mixture was purified directly by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M methanolic ammonia and was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (310 mg, 102%) as an orange solid, which was used without further purification; 1H NMR: 2.14 (6H, s), 3.08-3.18 (1H, m), 3.76 (2H, dd), 3.89 (3H, s), 4.02-4.11 (2H, m), 6.28 (1H, s), 7.12 (1H, td), 7.30-7.39 (1H, m), 8.12 (1H, s), 8.37 (1H, br s), 8.42 (1H, s), 8.68 (1H, s), 8.83 (1H, d), 8.94 (1H, d); m/z: ES+ MH+ 495.56.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][OH:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:8]1([C:6]2([C:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:18][CH2:17][CH2:16][O:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OCCO
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a round-bottom flask were added 4-methylbenzophenone (11, 5.0 g, 25.5 mmol, 1.0 equiv.), ethylene glycol (57 mL, 1020 mmol, 40.0 equiv.), para-toluenesulfonic acid monohydrate (147 mg, 0.77 mmol, 0.03 equiv.), and toluene (65 mL, 0.4 M). The biphasic reaction mixture was stirred vigorously at reflux with a Dean-Stark trap for 4 days. The reaction mixture was cooled to room temperature. The reaction mixture was washed with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Mg504, filtered, and concentrated. Recrystallization from hexanes yielded 12 (4.58 g, 75%) as a white solid. 1H-NMR (500 MHz, CDCl3) δ 7.58-7.55 (m, 2H), 7.45-7.40 (d, 2H, J=8.0 Hz), 7.38-7.35 (m, 2H), 7.33-7.30 (m, 1H), 7.18 (d, 2H, J=8.0 Hz), 4.09 (s, 4H), 2.37 (s, 3H). 13C-NMR (125 MHz, CDCl3): δ 142.2, 139.1, 137.7, 128.7, 128.0, 127.9, 126.1, 126.0, 109.4, 64.8, 21.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]1([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:16](=[O:17])[O:15][C:9]3([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Br)cc1C1(O)CCCCC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Product: O=C1Nc2ccc(Br)cc2C2(CCCCC2)O1

Procedure:
Prepared from 1-(2-amino-5-bromo-phenyl) cyclohexanol and carbonyl diimidazole according to the procedure of Example 2. Off-white solid: mp 208-210° C. 1H-NMR (DMSO-d6) δ 10.26 (s, 1H), 7.45 (d, 1H, J=2.2 Hz), 7.39 (dd, 1H, J=8.2, 2.2 Hz), 6.81 (d, 1H, J=8.3 Hz), 1.90-1.97 (m, 2H), 1.80-1.85 (m, 5H), 1.25-1.35 (m, 1H); MS (APC1) m/z 296 ([M+H]+, 68%)
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=O.[N:9]1(N)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.B(F)(F)F.CCOCC.C(OCC)(=O)C>C(O)C>[CH2:7]([O:6][C:1]([C:2]1[N:9]2[CH2:10][CH2:11][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([CH:4]=1)[C:17]2=3)=[O:5])[CH3:8]
Reactant: NN1CCc2ccccc21
Reactant: CCOC(=O)C(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1cc2cccc3c2n1CC3
Yield: 16.5 %

Procedure:
Ethyl pyruvate (3.7 ml, 33.3 mmol) was added to a solution of 2,3-dihydro-indol-1-ylamine (4.216 g, 31.4 mmol) in absolute ethanol (40 ml). The mixture was heated to reflux for 1 hour before being evaporated to dryness. The residue was dissolved in acetic acid (40 ml) and boron trifluoride etherate (4.0 ml 31.4 mmol) added. The mixture was heated to reflux for 1 hour then poured into ethyl acetate (200 ml). The ethyl acetate was washed with water (1 L), saturated sodium hydrogen carbonate (2×300 ml) and brine (100 ml). After drying over anhydrous magnesium sulfate the mixture was evaporated to dryness and the residue purified by flash column chromatography (SiO2, 7% to 10% EtOAc in hexanes) to afford 4,5-dihydro-pyrrolo[3,2,1-hi]indole-2-carboxylic acid ethyl ester as a yellow solid (1.117 g). 400 MHz 1H NMR (DMSO-d6) δ: 7.35 (d, J=6.8 Hz, 1H), 7.12 (s, 1H), 7.04-6.99 (m, 2H), 4.73 (t, J=6.8 Hz, 2H), 4.37 (q, J=7.2 Hz, 2H), 3.77 (t, J=6.8 Hz, 2H), 1.41 (t, 6.8 Hz, 3H); LCMS: 216 [M+H].
Reaction SMILES: [Br:1][CH:2]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH3:3].[CH3:13][Si](C=[N+]=[N-])(C)C>C(OCC)C.CO>[CH3:13][O:9][C:8](=[O:10])[C:7]1[CH:11]=[CH:12][C:4]([CH:2]([Br:1])[CH3:3])=[CH:5][CH:6]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(Br)c1ccc(C(=O)O)cc1
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1ccc(C(C)Br)cc1

Procedure:
A solution of 4-(1-bromo-ethyl)-benzoic acid (2.70 g, 11.8 mmol) in diethyl ether (20 mL) and methanol (5 mL) was cooled to 0° C. and treated with trimethylsilyldiazomethane (2 M in diethylether, 11.8 mL). After 1 h at 0° C. the solvents were removed under reduced pressure, the residue was re-dissolved in ethyl acetate (20 mL) and washed with aqueous NaHCO3 solution. The organic layer was collected, dried over MgSO4 and evaporated under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCO.CN(C)C=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[C:47]([O:50]CC)(=[O:49])[CH3:48]>>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:48][C:47]([OH:50])=[O:49]
Reactant: CCOC(C)=O
Reactant: OCCCCCCCCCCC(O)c1ccccc1O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: O=C(O)CCCCCCCCC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A 100 mL flask was charged with 1-(2-Hydroxy-phenyl)-undecane-1,11-diol (5.0 g, 18.9 mmol) and 50 mL of dimethyl formamide. To this was added pyridinium dichromate (32.9 g, 87.5 mmol). (The addition was mildly exothermic.) The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 mL of ethyl acetate and washed with 200 mL of water, 30 mL of 4% aqueous hydrochloric acid, 30 mL water, and finally with 30 mL of brine. The organic layer was then stirred with 10 g of silica gel for 15 minutes, dried with sodium sulfate, filtered, and solvent removed under reduced pressure. The off-white crude product was recrystallized from ethanol/water. The product (0.5 g, 10%) was isolated as an off-white solid, mp 85-87° C. Combustion analysis: Found: C, 69.01, H, 8.36%; C16H22O4 requires C, 69.54; H, 8.02%; 1H NMR (d6-DMSO): δ 12.0, s, 1H (COOH); δ 7.9 dd, 1H (aryl H); δ 7.5, dt, 1H, (aryl H); δ 6.9, complex multiplet, 2H (aryl H's), 3.1, t, 2H (CH2 α to carbonyl); δ 2.2, t, 2H(CH2 α to COOH); δ 1.6, multiplet, 2H (CH2 β to carbonyl), δ 1.5, multiplet, 2H (CH2 β to COOH), δ 1.3, multiplet, 8H (rest of CH2's).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:2]1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH:25]=O>>[Cl:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH:3]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:13])=[O:14])[CH2:2]1
Reactant: O=S(=O)(NC1CNc2ccccc2C1)c1ccccc1
Reactant: O=Cc1cccc(Cl)c1
Product: O=S(=O)(NC1Cc2ccccc2N(Cc2cccc(Cl)c2)C1)c1ccccc1

Procedure:
The title compound was prepared from 162B and 3-chlorobenzaldehyde by procedures analogous to those described in Example 22A. HPLC: 99% at 3.94 min (retention time) (Conditions. Phenom Prime S5, C18 (4.6×50 mm); Eluted with 0% to 100% B, 4 min gradient (A 90% H2O−10% MeOH−0.1% TFA and B=10% H2O−90% MeOH−0.11% TFA); Flow rate at 4.0 mL/min, UV detection at 220 nm). MS (ES): m/z 413 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][C:26]=4[O:28][C@@H:29]([CH3:34])[C:30](OC)=[O:31])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1.[CH3:35][NH2:36]>>[CH3:35][NH:36][C:30](=[O:31])[C@@H:29]([O:28][C:26]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:27]=1[C:18]([NH:17][C:13]1[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[N:9]=[CH:10]3)=[N:19][CH:20]=[N:21]2)[CH3:34]
Reactant: CN
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4ccccn4)c3)c12
Yield: 46 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(pyridin-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (250 mg, 0.55 mmol) was reacted with methylamine to give the title compound as a beige solid (110 mg, 46%); NMR Spectrum 1.65 (d, 3H), 2.67 (d, 3H), 5.16 (q, 1H), 5.77 (s, 2H), 6.96 (d, 1H), 7.00 (d, 1H), 7.29 (m, 1H), 7.36 (d, 1H), 7.72 (m, 4H), 8.17 (s, 1H), 8.38 (m, 1H), 8.53 (m, 3H), 10.68 (br s, 1H); Mass spectrum MH+ 454.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[C:8](C)=[CH:9][NH:10][C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14].Br[CH2:16][C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[C:27]([F:35])[CH:26]=2)[N:24]=1)=[O:18].[H-].[Na+]>CN(C=O)C>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][N:10]([CH2:16][C:17]([NH:19][C:20]3[S:21][CH:22]=[C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[C:27]([F:35])[CH:26]=4)[N:24]=3)=[O:18])[C:6]=2[C:5](=[O:12])[N:4]([CH3:13])[C:3]1=[O:14]
Reactant: Cc1c[nH]c2c(=O)n(C)c(=O)n(C)c12
Reactant: O=C(CBr)Nc1nc(-c2ccc(C(F)(F)F)c(F)c2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(ccn2CC(=O)Nc2nc(-c3ccc(C(F)(F)F)c(F)c3)cs2)n(C)c1=O

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (50 mg, 0.279 mmol) with 2-bromo-N-[4-(3-fluoro-4-trifluoromethylphenyl)-1,3-thiazol-2-yl]acetamide (128 mg, 0.334 mmol) in the presence of NaH (10 mg, 0.418 mmol) in dry DMF (5.0 mL) to give 75 mg of the product as a white solid; 1H NMR (δ ppm, DMSO-d6, 300 MHz) 3.17 (s, 3H), 3.40 (s, 3H), 5.33 (s, 2H), 6.24 (s, 1H), 7.36 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.90-8.01 (m, 3H), 12.77 (br s, 1H); APCI-MS (m/z) 482.07 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:17][C:18]([CH3:20])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1CCCCC1>[CH2:23]([O:22][C:16](=[O:21])[CH:17]=[C:18]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:20])[CH3:24]
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Solvent: O
Product: CCOC(=O)C=C(C)Nc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 9987.2 %

Procedure:
20 g (98.4 mmol)of 3-benyloxyaniline, 12.6 ml (0.984 mmol) of ethyl acetoacetate and 0.189 g (1 mmol) of p-toluenesulfonic acid monohydrate in 32 ml of cyclohexane were heated at reflux for 5.5 h in the presence of a water separator funnel. The reaction mixture was cooled to RT, some solid material was filtered off by suction and the filtrate was concentrated in vacuo to give 30.6 g (99%) of the desired 3-(3-benzyloxy-phenylamino)-but-2-enoic acid ethyl ester as a yellow oil. This was used without further purification in the next reaction step.
Reaction SMILES: [O:1]=[C:2]1[CH:8]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=1.N1C=CC=CC=1NCCCOC1C=CC2CC(CC(OCC)=O)C(=O)NCC=2C=1>>[O:1]=[C:2]1[CH:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6]2[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH2:20][CH2:21][N:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:17][C:5]=2[CH2:4][N:3]1[CH2:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:40][CH:39]=1
Reactant: COC(=O)CC1Cc2ccc(OCCCN(C(=O)c3ccccc3)c3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Agent: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2CNC1=O
Product: O=C(O)CC1Cc2ccc(OCCCN(C(=O)c3ccccc3)c3ccccn3)cc2CN(Cc2ccc(C(F)(F)F)cc2)C1=O
Yield: 10 %

Procedure:
According to the procedure of Example 1(c) except substituting methyl(±)-3-oxo-8-[3-[N-(pyridin-2-yl)-N-(benzoyl)amino]-1-propyloxy]-2-(4-trifluoromethylbenzyl)-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, for the ethyl (±)-8-[3-(2-pyridylamino)-1-propyloxy]-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate, the crude title compound was prepared. Purification by ODS chromatography (10-80% CH3CN/H2O containing 0.1% TFA over 1 h), concentration and lyophilization gave the title compound (0.025 g, 10%): MS (ES) m/e 632.4 (M+H)+. Anal. Calcd for C35H32 F3N3O5.0.85 CF3CO2H: C, 60.50; H, 4.54; N, 5.74. Found: C, 60.22; H, 4.35; N, 5.77.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].S(Cl)(Cl)=O.CC1C=CC(CC)=CN=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: CCc1ccc(C)nc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 70 °C
Reaction time: 1.17 h

Procedure:
6.84 g of 1-(4-bromo-3-methylphenyl-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 13.7 g of toluene and 4.46 g of thionyl chloride were fed, and the mixture was heated to 70° C. 3.64 g of 2-methyl-5-ethylpyridine was slowly added in dropwise, and the mixture was stirred for 70 minutes at 70° C. The mixture was cooled to room temperature, and separated by adding 6.84 g of water. The organic phase was washed with a diluted aqueous solution of sodium hydroxide, and the solvent was distilled off under reduced pressure. 6.60 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-buten-1-one was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(O)CC.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]([C:20]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([O:11][CH3:10])[CH:21]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1Cl
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCO
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2nc(Cl)ncc2C)cc1OC
Temperature: 110 °C
Yield: 56.4 %

Procedure:
To a solution of 2,4-dichloro-5-methylpyrimidine (244 mg, 1.5 mmol) and methyl 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (210 mg, 1.0 mmol) in toluene (3 mL) were added n-propanol (1 mL), aqueous sodium bicarbonate (2 M, 1.5 μL) and tetrakis(triphenylphosphine)palladium[0](116 mg, 0.1 mmol). The reaction was heated at 110° C. for 40 h, then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous layer was extracted twice further with ethyl acetate and the combined organic fractions were washed with water, brine then dried (sodium sulfate), filtered and concentrated. Silica gel chromatography using 30-60% ethyl acetate/petroleum spirit as eluent provided methyl 4-(2-chloro-5-methylpyrimidin-4-yl)-2-methoxybenzoate as a cream solid (165 mg, 56%); LC-ESI-MS (method B): rt 6.2 min.; m/z 293.3/295.3 [M+H]+.
Reaction SMILES: [C:1](O)(=[O:4])[CH2:2][CH3:3].C1C=NC2N(O)N=NC=2C=1.[CH3:16][O:17][C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH:28]=[C:27]([Br:29])[C:26]([CH3:30])=[C:25]([NH2:31])[C:24]2=[O:32])=[CH:20][CH:19]=1.C(Cl)CCl>C(Cl)Cl.CN(C=O)C>[C:1]([NH:31][C:25]1[C:24](=[O:32])[N:23]([CH2:22][C:21]2[CH:33]=[CH:34][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH:28]=[C:27]([Br:29])[C:26]=1[CH3:30])(=[O:4])[CH2:2][CH3:3]
Reactant: COc1ccc(Cn2cc(Br)c(C)c(N)c2=O)cc1
Reactant: CCC(=O)O
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(=O)Nc1c(C)c(Br)cn(Cc2ccc(OC)cc2)c1=O
Reaction time: 8 h
Yield: 44.3 %

Procedure:
To a solution of 2-(S)-tbutoxycarbonylamino-3-[4′-(1″-tbutoxycarbonyl-1″-methyl)ethyl]benzene]propanoic acid (3.20 g, 7.88 mmol) in methylene chloride (20 ml,) and DMF (5 mL) at 0° C. were added HOAT (1.07 g) and 1-(4-methoxybenzyl)-5-bromo-4-methyl-3-amino-2-pyridone (2.80 g, 8.67 mmol). EDC (1.66 g) and TMP (1.04 mL) were added, and the mixture was stirred coming to rt overnight. The methylene chloride was evaporated and DMF (25 mL) was added. Additional EDC (0.80 ;), HOAT (0.50 g) and TMP (0.5 mL) were added. After 3 hours the mixture was diluted with ethyl acetate, and washed with 1N HCl, aqueous sodium bicarbonate and brine. The organic phase was dried (MgSO4), filtered and evaporated. Chromatography of the residue over silica gel (ethyl acetate/hexane 1/3) gave 1-[2′-(S)-tbutoxycarbonylamino-)′-[4″-(1′″-tbutoxycarbonyl-1′″-methyl)ethyl]benzene]propanoylamino-5-bromo-1-(4-methoxybenzyl)-4-methyl-2-pyridone (2.48 g, 3.49 mmol, 44%).
Reaction SMILES: [CH3:1][CH:2]=[CH:3][C:4]([C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[CH:11]2)=[O:5].[NH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([CH2:9][CH2:8][C:7]2[C:12]3[C:13](=[C:9]([CH3:10])[CH:8]=[CH:10][CH:11]=3)[CH:14]=[CH:15][C:6]=2[C:4]([C:3]2[CH:2]=[CH:1][C:7]3[C:6](=[CH:15][CH:14]=[CH:13][C:12]=3[CH3:11])[C:4]=2[CH2:3][CH2:2][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:5])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC=CC(=O)c1cccc2ccccc12
Reactant: C1CCNCC1
Product: Cc1cccc2c(CCN3CCCCC3)c(C(=O)c3ccc4c(C)cccc4c3CCN3CCCCC3)ccc12

Procedure:
5-methylacryloylnaphthalene (21.8 mg) and piperidine (9.1 mg) were reacted at 50° C. for 5 hours.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:17].[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:17]=[C:5]1[C:4]2[C:14](=[CH:15][CH:16]=[C:2]([C:24]3[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:18]#[N:19])[CH:3]=2)[O:13][C:7]2([CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH2:6]1
Reactant: O=C1CC2(CCOCC2)Oc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCOCC2)O3)c1
Temperature: 120 °C
Reaction time: 0.58 h
Yield: 43.8 %

Procedure:
A mixture of 6-bromo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-4-one (300 mg, 1 mmol), 3-cyanophenylboronic acid (298 mg, 2 mmol), Cs2CO3 (2 M, 4 mL) and Pd(PPh3)2Cl2 (80 mg) in 1,4-dioxane (10 mL) under Ar was stirred under microwave at 120° C. for 35 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified bypreparative TLC to give 3-(4-oxo-2′,3′,5′,6′-tetrahydrospiro[chroman-2,4′-pyran]-6-yl)benzonitrile (140 mg, 43%). 1H-NMR (CDCl3): 1.81-1.85 (m, 2H), 2.00-2.04 (d, 2H), 2.80 (s, 2H), 3.78-3.87 (m, 4H), 7.14 (d, 1H), 7.52-7.56 (t, 1H), 7.61-7.64 (d, 1H), 7.71-7.74 (d, 1H), 7.78 (d, 1H), 7.80 (s, 1H), 8.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[C:11]2[C:5]([C:6]([Cl:16])=[C:7]([O:13][CH2:14][CH3:15])[O:8][C:9]2=[O:10])=[CH:4][CH:3]=1.[C:17]1([N:23]=[C:24]=[S:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CCl.CO>C1COCC1>[Cl:16][C:6]1[C:5]2[C:11](=[CH:12][C:2]([NH:1][C:24](=[S:25])[NH:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[C:9](=[O:10])[O:8][C:7]=1[O:13][CH2:14][CH3:15]
Reactant: CCOc1oc(=O)c2cc(N)ccc2c1Cl
Reactant: S=C=Nc1ccccc1
Agent: CCl
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1oc(=O)c2cc(NC(=S)Nc3ccccc3)ccc2c1Cl
Yield: 55 %

Procedure:
This compound was preparation by reaction of 7-amino-4-chloro-3-ethoxyisocoumarin with phenyl isothiocyanate at r.t. in THF for 24 hrs. The product was obtained as yellow solid: yield 55%, m.p. 176°-177° C. (dec.); TLC, Rf =0.76 (CH3Cl:MeOH=9:1), MS m/e=374 (M+). Anal. Calcd. for C18H15N2O3ClS: C, 57.62; H, 4.00. Found: C, 57.77; H, 4.04.
Reaction SMILES: [Cl:1][C@@H:2]([CH3:22])[CH2:3][C@H:4]([CH3:21])[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[CH2:23]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)[CH2:24][CH3:25].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(Cl)Cl>[CH2:23]([C:26]1[CH:31]=[CH:30][C:29]([O:17][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][C:12]([C:9]3[CH:8]=[CH:7][C:6]([O:5][C@@H:4]([CH3:21])[CH2:3][C@@H:2]([Cl:1])[CH3:22])=[CH:11][CH:10]=3)=[CH:13][CH:14]=2)=[CH:28][CH:27]=1)[CH2:24][CH3:25]
Reactant: CCCc1ccc(O)cc1
Reactant: C[C@H](Cl)C[C@H](C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Product: CCCc1ccc(OC(=O)c2ccc(-c3ccc(O[C@@H](C)C[C@H](C)Cl)cc3)cc2)cc1
Yield: 62.3 %

Procedure:
0.47 g of (S,S)-4-[4'-(3"-chloro-1"-methylbutoxy)phenyl]benzoic acid, 0.20 g of 4-n-propylphenol, 0.32 g of dicyclohexylcarbodiimide, 0.04 g of 4-pyrrolidinopyridine and 6 ml of methylene chloride were stirred together at room temperature for five hours. The dicyclohexyl urea thus precipitated was filtered and the filtrate was desolvated. The crude product thus obtained was purified by silica gel column chromatography with the use of a mixture of n-hexane and ethyl acetate (17:3) as a developing solvent. Thus 0.4 g of the title compound was obtained.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[CH2:10]([K])[CH2:11][CH2:12][CH3:13].C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:21][C:3](=[O:5])[CH:2]2[O:1][CH:6]2[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:8])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1OC1C(=O)O
Reactant: CCCC[K]
Reactant: Nc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Product: CCCCOC(=O)C1OC1C(=O)Nc1ccccc1
Yield: 49.9 %

Procedure:
Following the procedure of Example 34, mono-n-butyl potassium epoxysuccinate (1.06 g) was successively treated with oxalyl chloride (0.63 g) and aniline (1.03 g) to give 0.61 g of butyl N-phenyl-2,3-epoxysuccinamate (Compound No. 52) as colorless oil.