Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.[NH2:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]2>CC#N.C(O)CCC>[F:9][C:5]1[C:6]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[N:7][C:2]([NH:27][C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33](=[O:38])[CH2:32][CH2:31]3)=[N:3][CH:4]=1
Reactant: OCC1CCNCC1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CC#N
Product: O=C1CCc2cc(Nc3ncc(F)c(N4CCC(CO)CC4)n3)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
A mixture of 2,4-dichloro-5-fluoropyrimidine (167 mg, 1.00 mmol), 4-piperidinemethanol (115 mg, 1.00 mmol) and DIEA (0.400 mL, 2.30 mmol) in CH3CN (4 mL) was stirred at room temperature for 2 h. It was concentrated in vacuo. The residue was dissolved in nBuOH (6 mL). 3 mL of the nBuOH solution was taken, to which 6-amino-3,4-dihydroquinolin-2(1H)-one (88 mg, 0.54 mmol) was added. The solution was stirred at 116° C. for 20 h. nBuOH was removed in vacuo. The residue was purified by HPLC to give the titled compound (52 mg). MS 372.3 (M+H); UV 208.8, 275.8 nm.
Reaction SMILES: [F:1][C:2]([F:27])([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])/[CH:3]=[CH:4]/[CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2>C(OCC)(=O)C.[Pd]>[F:27][C:2]([F:1])([C:22](=[O:26])[CH2:23][CH2:24][CH3:25])[CH2:3][CH2:4][CH2:5][C@H:6]1[C@H:13]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[CH2:12][C@H:11]2[C@@H:7]1[CH2:8][C:9](=[O:21])[O:10]2
Reactant: CCCC(=O)C(F)(F)/C=C/C[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(=O)C(F)(F)CCC[C@@H]1[C@H]2CC(=O)O[C@H]2C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
To a solution of (1S,5R,6R,7R)-6-{(E)-4,4-difluoro-5-oxo-2-octenyl}-7-tetrahydropyranyloxy-2-oxabicyclo[3.3.0]octan-3-one (31) (5.57 g) in ethyl acetate was added 5% Pd/C (catalytic amount) and the resulting mixture was shaken under a hydrogen atmosphere at room temperature for 7 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the tile compound (32) as a crude product. Yield: 5.48 g (97.8%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])[C:16]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH:39]([F:41])[F:40])=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl.CO>[ClH:37].[Cl:37][C:35]1[CH:34]=[CH:33][C:32]([O:38][CH:39]([F:40])[F:41])=[C:31]([C:16]2[C:17]([NH:19][C:20]([C:22]3[CH:23]=[N:24][N:25]4[CH:30]=[CH:29][CH:28]=[N:27][C:26]=34)=[O:21])=[CH:18][N:14]([CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:15]=2)[CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(NC(=O)c3cnn4cccnc34)c(-c3cc(Cl)ccc3OC(F)F)n2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: O=C(Nc1cn(C2CCNCC2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.6 %

Procedure:
4-{3-(5-Chloro-2-difluoromethoxyphenyl)-4-[(pyrazolo[1,5-a]pyrimidine-3-carbonyl)amino]pyrazol-1-yl}piperidine-1-carboxylic acid tert-butyl ester (600 mg, 0.97 mmol) was dissolved in DCM (3 mL) and TFA (3 mL) was added. The mixture was allowed to stir at room temperature for 30 minutes. The solvent was evaporated and the residue was dissolved in MeOH and loaded onto an SCX-2 cartridge which had been conditioned with MeOH. After flushing with MeOH, the product was eluted with 2M ammonia in MeOH. Evaporation gave a glass which was purified by HPLC (Method 3). Appropriate fractions were combined and evaporated to afford an off-white solid. The solid was dissolved in MeOH and 1.25M methanolic HCl (1 mL) was added. The solvent was evaporated, azeotroped three times with methanol and triturated with ethyl acetate to afford the title compound as an off-white solid (144 mg, 28%). LCMS (Method 5) [M+H]+=488.0, RT=2.93 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.76 (s, 1H), 9.35 (dd, 1H, J=1.6, 7.0 Hz), 8.98 (d, 1H, J=9.9 Hz), 8.69 (dd, 1H, J=1.7, 4.3 Hz), 8.67 (s, 1H), 8.38 (s, 1H), 7.65-7.62 (m, 2H), 7.30 (dd, 1H, J=4.2, 7.2 Hz), 7.26 (t, 1H, J=73.6 Hz), 4.66-4.57 (m, 1H), 3.47-3.42 (m, 2H), 3.17-3.03 (m, 2H), 2.32-2.18 (m, 4H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:12].CS(C)=O>CCOCC>[CH2:11]([O:13][C:14](=[O:22])[CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: CCOC(=O)CC1CCNCC1
Reactant: CC(=O)c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: CCOCC
Product: CCOC(=O)CC1CCN(c2ccc(C(C)=O)cc2)CC1
Temperature: 150 °C

Procedure:
A microwave vial was charged with 4′-fluoroacetophenone (1.2 Ml, 10.4 mmol, 1.0 equiv) and 2-(piperidin-4-yl)-acetic acid ethyl ester (3.5 g, 20.7 mmol, 2.0 equiv) in 20 Ml DMSO. The homogeneous reaction was heated to 150° C. for 20 min. The cooled reaction was then diluted with ether and washed sequentially with saturated ammonium chloride, water, and brine. The organic extracts were then dried over sodium sulphate, filtered, and concentrated in vacuo. Purification by flash chromatography (10-40% EtOAc in hexanes) afforded the title compound: 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.32 (t, J=7.07 Hz, 3 H) 1.47 (d, J=12.13 Hz, 2 H) 1.62 (br.s., 1 H) 1.90 (d, J=12.63 Hz, 2 H) 2.04-2.15 (m, J=11.18, 11.18, 7.45, 7.45, 3.79, 3.66 Hz, 1 H) 2.33 (d,J=7.07 Hz, 2 H) 2.57 (s, 3 H) 2.97 (td, J=12.57, 2.15 Hz, 2 H) 3.93 (d, J=12.88 Hz, 2 H) 4.20 (q, J=7.07 Hz, 2H) 6.96 (d, J=6.82 Hz, 2 H) 7.92 (d, J=9.09 Hz, 2 H); (M+H)+ 290.1.
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:7][CH:6]=1.C(=O)(O)[O-].[Na+].[H][H]>C(O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C=CCCCCn2ccnc2)cc1
Reactant: [H][H]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CCCCCCn2ccnc2)cc1

Procedure:
Add 1 ml water to 400 mg of the compound prepared in Example 72, then add 100 mg sodium bicarbonate followed by 25 ml ethanol. Add 100 mg PtO and add hydrogen under 30 psi for 20 hr. Partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride then 5% methanol/methylene chloride to yield the title compound.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=[C:12]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=3)[C:11]=2[CH:34]=1)(=O)=O.[CH:37]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)=[O:38].C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([C:12]2[C:11]3[CH:34]=[C:7]([C:42]4[CH:43]=[CH:44][C:39]([CH:37]=[O:38])=[CH:40][CH:41]=4)[CH:8]=[CH:9][C:10]=3[N:16]3[C:17]([CH3:20])=[N:18][N:19]=[C:15]3[C@H:14]([CH2:21][C:22]([NH:24][CH2:25][CH3:26])=[O:23])[N:13]=2)=[CH:32][CH:31]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(OS(=O)(=O)C(F)(F)F)ccc2-n2c(C)nnc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCNC(=O)C[C@@H]1N=C(c2ccc(Cl)cc2)c2cc(-c3ccc(C=O)cc3)ccc2-n2c(C)nnc21
Temperature: 120 °C

Procedure:
(S)-6-(4-Chlorophenyl)-4-(2-(ethylamino)-2-oxoethyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-8-yl trifluoromethanesulfonate (for a preparation see intermediate 3) (500 mg), 4-formylphenylboronic acid (166 mg), potassium carbonate (638 mg) and bis(triphenylphosphine)palladium(II) chloride (64.8 mg) were added to a 20 ml microwave vial. Ethanol (9 ml) and toluene (9 ml) were added to the vial. The reaction mixture was heated in a microwave at 120° C. for 20 min. The reaction mixture was filtered through Celite™ and the filter bed was washed with ethanol. The solvent was evaporated, and the residue was chromatographed (0-5% methanol:DCM) to give (S)-2-(6-(4-chlorophenyl)-8-(4-formylphenyl)-1-methyl-4H-benzo[f][1,2,4]triazolo[4,3-a][1,4]diazepin-4-yl)-N-ethylacetamide (327 mg) as a brown solid. LCMS (formate): MH+ 498/500, RT 0.98 min
Reaction SMILES: [NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]2[C:33]1=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([OH:27])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5].CN(C=O)C.[CH2:50](Br)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[NH:1]([C:28]([O:30][CH2:31][CH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[C:44]1=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:29])[CH2:2][CH2:3][C:4]([NH:6][C@H:7]([C:12]([NH:14][C@H:15]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:26])[CH2:21][CH:22]([CH3:23])[CH3:24])=[O:18])[CH3:16])=[O:13])[C@H:8]([CH2:10][CH3:11])[CH3:9])=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@H](C)[C@H](NC(=O)CCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1

Procedure:
The Fmoc-β-Ala-Ile-Ala-Leu (SEQ ID NO:37), (24.34 g, 0.04 mol) is added into a round bottom flask with DMF (350 mL) and a magnetic stirrer. After the tetrapeptide is dissolved, benzyl bromide (4.76 mL, 0.04 mol), followed by cesium carbonate (13.04 g, 0.04 mol), is added to the solution with stirring. The reaction mixture is stirred at room temperature for 1.5 hrs. Then, the reaction mixture is slowly poured into a flask with 450 mL of iced water. A large amount of white solid precipitates out which is collected by suction filtration. The product is washed with water (2×200 mL) and placed in a vacuum desiccator.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O.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>[C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH:12]=[C:11]([C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:14])[N:10]=[CH:9]2)[CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cn(-c2cccc(Br)c2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(c1ccccc1)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Temperature: 70 °C

Procedure:
A solution of 7 (250 mg, 0.76 mmol), phenylboronic acid (102 mg, 0.84 mmol) and Na2CO3 (244 mg, 2.3 mmol) in DME/H2O 4:1 (10 mL) was thoroughly purged with argon, after which Pd(PPh3)2Cl2 (36 mg; 0.05 mmol) was added and the mixture was heated to 70° C. for 21 h. The solvents were removed in vacuo and the residue was purified by column chromatography (1 to 5% methanol in CH2Cl2 to give 100 mg (41%) pure 8. HRMS (ESI+): m/z=324.3814 [M+H]
Reaction SMILES: [N:1]([Sn](CCCC)(CCCC)CCCC)=[N+:2]=[N-:3].[F:17][C:18]([F:52])([F:51])[C:19]1[CH:20]=[C:21]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:22][N:23]([C:42]#[N:43])[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:26]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:25]1=2.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[F:50][C:47]([F:48])([F:49])[C:45]1[CH:44]=[C:21]([CH:20]=[C:19]([C:18]([F:17])([F:51])[F:52])[CH:46]=1)[CH2:22][N:23]([C:42]1[NH:3][N:2]=[N:1][N:43]=1)[CH:24]1[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][CH:34]([CH3:36])[CH3:35])=[O:32])[C:26]2[CH:37]=[C:38]([Cl:41])[CH:39]=[CH:40][C:25]1=2
Reactant: CC(C)OC(=O)N1CCCC(N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ccc(Cl)cc21
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2ccc(Cl)cc21
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Add azidotributyltin (0.19 mL, 0.68 mmol) to a solution of (+/−)-isopropyl 5-[(3,5-bistrifluoromethyl-benzyl)-cyano-amino]-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate (180 mg, 0.34 mmol) in toluene (3.6 mL). Stir the mixture at 80° C. overnight. Cool down the mixture to room temperature; add ethyl acetate and 1N HCl (8.2 mL) and stir at room temperature for 1 h. Separate the layers, wash the organic phase with saturated KF, then with brine, dry over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with dichloromethane/methanol, and then by reverse phase purification to provide 198 mg (quantitative) of the title compound. MS (ES−): 575 (M−H).
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC(OP(OC2C=CC=CC=2)([N:19]=[N+:20]=[N-:21])=O)=CC=1.[C:29]([O:33][C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][N:49]2[C:53]3[CH:54]=[C:55]([C:59](O)=[O:60])[CH:56]=[C:57]([CH3:58])[C:52]=3[N:51]=[C:50]2[CH2:62][CH2:63][CH3:64])=[CH:44][CH:43]=1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.[Na+].[Cl-]>[C:29]([O:33][C:34]([C:36]1[C:37]([C:42]2[CH:43]=[CH:44][C:45]([CH2:48][N:49]3[C:53]4[CH:54]=[C:55]([C:59]([N:19]=[N+:20]=[N-:21])=[O:60])[CH:56]=[C:57]([CH3:58])[C:52]=4[N:51]=[C:50]3[CH2:62][CH2:63][CH3:64])=[CH:46][CH:47]=2)=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:35])([CH3:30])([CH3:32])[CH3:31]
Reactant: CCCc1nc2c(C)cc(C(=O)O)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1nc2c(C)cc(C(=O)N=[N+]=[N-])cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
DIPEA (0.43 mL, 25 mmol) and diphenylphosphonic azide (489 μL, 2.3 mmol) were added to a solution of 3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (1.0 g, 2.1 mmol; prepared as described in Preparation 3) in DMF (15 mL). The mixture was stirred at room temperature for 16 hours, diluted with saturated aqueous NaCl (100 mL), then extracted with EtOAc (200 mL). The organic layer was evaporated to dryness to yield crude Intermediate (10a). MS m/z: [M+H+] calcd for C30H31N5O3, 510.2. found 510.6.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=[CH:15][C:14]([C:17](O)=[O:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[C:11]1(/[CH:20]=[CH:21]\[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:12]=[CH:13][C:14]([C:17]([N:8]2[CH2:9][CH2:10][C:5]3[CH:4]=[CH:3][O:2][C:6]=3[CH2:7]2)=[O:18])=[CH:15][CH:16]=1
Reactant: c1cc2c(o1)CNCC2
Reactant: O=C(O)c1ccc(/C=C\c2ccccc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(/C=C\c2ccccc2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 0.269 g (1.2 mmol) of (Z)-4-stilbenecarboxylic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1) to yield the desired product.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=1[Cl:24]>C1(C)C(C)=CC=CC=1.C(Cl)(Cl)Cl>[O:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:14][C:13]=1[Cl:24]
Reactant: Clc1nc2ccccc2o1
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)Cc1ccc(Nc2nc3ccccc3o2)c(Cl)c1
Temperature: 25 °C
Yield: 78.9 %

Procedure:
In xylene (10 ml), 2-chlorobenzoxazole (743 μl, 6.51 mmol) and ethyl 4-amino-3-chlorophenylacetate (1.30 g, 6.51 mmol) were heated under reflux for 2 hours. After cooling to room temperature, the reaction mixture was diluted with chloroform (50 ml). The mixture was washed with water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane/ethyl acetate (9:1, v/v) eluate fractions, ethyl (4-(2-benzoxazolyl)amino-3-chlorophenyl)acetate (1.70 g, 79%) was obtained as a pale yellow solid.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.[C:17]1([CH3:27])[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[C:18]=1[Mg]Br.[I:28]I>ClCCl>[I:28][C:7]1[C:6]([O:8][CH3:9])=[CH:5][CH:4]=[C:3]([O:10][CH3:11])[C:2]=1[C:18]1[C:19]([CH3:24])=[CH:20][C:21]([CH3:23])=[CH:22][C:17]=1[CH3:27]
Reactant: COc1ccc(OC)c(F)c1
Reactant: II
Reactant: Cc1cc(C)c([Mg]Br)c(C)c1
Agent: [Li]CCCC
Solvent: ClCCl
Product: COc1ccc(OC)c(-c2c(C)cc(C)cc2C)c1I
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
To an oven-dried 500-mL round bottom flask equipped with a magnetic stir bar was added 2-fluoro-1,4-dimethoxybenzene (6 g, 38.4 mmol, 1 equiv). The flask was purged with N2, and anhydrous degassed tetrahydrofuran (250 mL) was added. The solution was cooled to −78° C., and n-butyllithium (15.4 mL, 38.4 mmol, 1 equiv, 2.5 M in hexanes) was added dropwise over 12 minutes The mixture was stirred for another 30 minutes, and mesitylmagnesium bromide (38.4 mL, 38.4 mmol, 1 equiv, 1 M in tetrahydrofuran) was slowly added over 16 minutes. The reaction mixture was stirred at −78° C. for an additional hour, then removed from the cold bath to warm to room temperature. After 2 hours at room temperature, the reaction mixture was cooled in an ice bath to 0° C. and added a fresh solution of iodine (46.1 mL, 46.1 mmol, 1.2 equiv, 1 M in tetrahydrofuran) was added dropwise over 10 minutes. The flask was removed from the ice bath and stirred for an additional hour. Then the reaction mixture was concentrated to afford a red oil. The oil was dissolved in dichloromethane (100 mL), washed with aqueous saturated sodium thiosulfate (2×50 mL) and brine (50 mL), dried over sodium sulfate, filtered, and concentrated to furnish a brown-yellowish oil. Purification of the crude product by column chromatography (330-g column; gradient: 1.5 column volumes heptane, ramp up to 89:11 heptane:ethyl acetate over 8 column volumes, hold at 89:11 for 2 column volumes) followed by crystallization in heptane (20 mL) and a minimal amount of methyl tert-butyl ether, filtration, washing with cold heptane, and drying under vacuum afforded the title compound (6.64 g, >99 area % by HPLC, 45% yield). 1H NMR (400 MHz, CDCl3) δ ppm 6.99-6.96 (m, 2H), 6.94 (d, J=8.9 Hz, 1H), 6.82 (d, J=8.9 Hz, 1H), 3.90 (s, 3H), 3.69 (s, 3H), 2.37 (s, 3H), 1.93 (s, 6H). 13C NMR (100 MHz, CDCl3) δ ppm 152.4, 150.9, 137.6, 136.7, 135.8, 135.3, 127.7, 110.9, 109.3, 94.5, 56.9, 56.4, 21.6, 20.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[CH2:10]([S:12]([NH2:15])(=[O:14])=[O:13])[CH3:11].[CH:16]1([Mg]Br)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Br:1][C:2]1[CH:9]=[C:6]([CH:7]([CH:16]2[CH2:18][CH2:17]2)[NH:15][S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cncc(Br)c1
Reactant: CCS(N)(=O)=O
Reactant: Br[Mg]C1CC1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)NC(c1cncc(Br)c1)C1CC1
Temperature: -40 °C
Reaction time: 4 h
Yield: 67.4 %

Procedure:
A mixture of 5-bromonicotinaldehyde (372 mg, 2 mmol), ethanesulfonamide (273 mg, 2.500 mmol) and titanium(IV) isopropoxide (1172 μl, 4.00 mmol) in toluene (20 mL) was heated to reflux for 2 h. After concentration, the residue was dissolved in THF (25 mL) and cooled to −40° C. A solution of cyclopropylmagnesium bromide (10 mL, 5.00 mmol) was added dropwise and the resulting mixture was slowly warmed up to −20° C. and stirred at this temperature for 4 h. After quenching by saturated NH4Cl solution, filtration, extraction with CH2Cl2, the solution was dried over Na2SO4, and concentrated. The residue was purified by flash column (ethyl acetate/heptane, v/v, 10%-35%) and yielded the title product as oil (430 mg). 1H NMR (400 MHz, CDCl3): δ 0.2-0.3 (m, 1H), 0.4-0.5 (m, 1H), 0.5-0.6 (m, 1H), 0.6-0.7 (m, 1H), 1.0-1.1 (m, 1H), 1.1-1.2 (m, 3H), 2.55-2.75 (m, 2H), 3.6-3.7 (m, 1H), 4.51 (brd, J=4.8 Hz, 1H), 7.73 (s, 1H), 8.42 (s, 1H), 8.51 (s, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].C(N(CC)CC)C.[CH3:15][C:16]([Si:19](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:19]([O:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])([C:16]([CH3:18])([CH3:17])[CH3:15])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)CO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 500ml round-bottom flask equipped with a magnetic stir-bar, N2inlet was added ethyl glycolate (10g, 96.0mmoles, 1eq) and dry CH2Cl2(200ml, 0.5M). This was followed by the addition of triethylamine (40ml, 0.288moles, 3eq) and DMAP (1.17g, 9.6mmoles, 10mol %) followed by the dropwise addition of TBDPSCl (27.5ml, 0.106moles, 1.1eq) in dry CH2Cl2(20ml). The reaction mixture was allowed to stir at room temperature overnight at which time the reaction mixture was diluted with CH2Cl2and washed with 1N HCl, saturated sodium bicarbonate, H2O and dried over Na2SO4. After filtration the volatiles were removed in vacuo to yield 30g (91%) of titled compound.
Reaction SMILES: [H-].[Na+].Cl.[CH2:4]([O:8][NH2:9])[CH:5]=[CH:6][CH3:7].[C:10]([CH:13]1[C:18](=[O:19])[CH2:17][CH:16]([CH2:20][CH2:21][S:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH2:15][C:14]1=[O:33])(=O)[CH3:11].Cl>CN(C)C=O.O>[CH2:4]([O:8][NH:9][C:10](=[C:13]1[C:18](=[O:19])[CH2:17][CH:16]([CH2:20][CH2:21][S:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:30])([F:32])[F:31])=[CH:27][CH:28]=2)[CH2:15][C:14]1=[O:33])[CH3:11])[CH:5]=[CH:6][CH3:7]
Reactant: CC=CCON
Reactant: CC(=O)C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCONC(C)=C1C(=O)CC(CCSc2ccc(C(F)(F)F)cc2)CC1=O
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To the suspension of 0.3 g of sodium hydride (60% oil dispersion) in 10 ml of dimethylformamide, 0.09 g of 2-butenyloxyamine hydrochloride was added under cooling with ice-water bath and then stirred. After 30 minutes, 0.21 g of 2-acetyl-5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione was added to the resulting solution which was then stirred for 7 hours under cooling with ice-water bath. The reaction solution was poured into water, acidified with dilute hydrochloric acid and extracted with ether. After removing ether, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.22 g of 2-[1-(2-butenyloxyamino)ethylidene]5-[2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.