Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:34]1>>[CH:27]1([CH2:26][N:10]2[C:9]3[N:8]=[C:7]([CH2:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:36]5[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=5)(=[O:40])=[O:39])=[CH:31][CH:30]=4)[NH:15][C:14]=3[C:13](=[O:16])[N:12]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:11]2=[O:25])[CH2:28][CH2:29]1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: Nc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Product: Cn1cc(S(=O)(=O)Nc2ccc(Cc3nc4c([nH]3)c(=O)n(Cc3ccccc3F)c(=O)n4CC3CC3)cc2)cn1

Procedure:
Prepared from 8-(4-amino-benzyl)-3-cyclopropylmethyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 1-methyl-1H-pyrazole-4-sulfonyl chloride. Off-white solid; EI-HRMS m/e calculated for C27H26FN7O4S (M+) 563.1751, found 563.1752.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.Cl[C:45]([O:47][CH3:48])=[O:46]>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:45](=[O:46])[O:47][CH3:48])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with methyl chloroformate (0.0087 mL, 0.11 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.23 (s, 1 H), 3.06-3.20 (m, 2 H), 3.25-3.32 (m, 2 H), 3.36-3.43 (m, 2 H), 3.45 (s, 3 H), 3.55 (d, J=10.95 Hz, 2 H), 3.69 (t, J=12.2 Hz, 2 H), 3.78 (d, J=6.74 Hz, 2 H), 4.00 (d, J=12.35 Hz, 2 H), 4.15 (s, 2 H), 4.31 (t, J=5.76 Hz, 2 H), 7.12-7.19 (m, 2 H), 7.38-7.45 (m, 2 H), 8.16 (s, 1 H), 8.55 (s, 1 H), 9.91 (br. s., 1 H), 10.39 (t, J=6.60 Hz, 1 H); ES+ MS: 528 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Br:12])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[N:17][N:16]=[C:15]1[SH:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][CH:3]=[C:2]2[S:19][C:15]1[N:14]([CH3:13])[CH:18]=[N:17][N:16]=1
Reactant: Cn1cnnc1S
Reactant: Clc1ccnc2ccc(Br)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1cnnc1Sc1ccnc2ccc(Br)cc12
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.7 %

Procedure:
A capped vial was charged with 4-chloro-6-bromoquinoline (500 mg, 2.06 mmol), 4-methyl-4H-[1,2,4]triazole-3-thiol (238 mg, 2.06 mmol), potassium carbonate (427 mg, 3.09 mmol), and DMF (5 mL). The reaction mixture was stirred at 60° C. for 18 h then at 90° C. for another 24 h, and cooled to room temperature. The reaction mixture was poured onto water (50 mL), and the resulting precipitate was filtered, washed with water and dried in a vacuum oven at 70° C. overnight to provide 600 mg of 6-bromo-4-(4-methyl-4H-[1,2,4]triazol-3-ylsulfanyl)-quinoline as a white solid (91% yield): 1H NMR (DMSO-d6) δ 3.63 (s, 3H), 6.90 (d, 1H), 8.02 (m, 2H), 8.40 (d, 1H), 8.74 (d, 1H), 8.92 (s, 1H); MS (m/z) 321, 323 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]2[CH:9]=[C:10]([CH:27]=[CH:28][C:29]=2F)[C:11]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=3)[CH2:15][CH2:14]2)=[O:12])=[C:5]([CH3:7])[N:6]=1.Cl.[NH:32]1[CH2:35][CH2:34][CH2:33]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.CC#N>[N:32]1([C:29]2[CH:28]=[CH:27][C:10]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:9][C:8]=2[C:4]2[NH:3][C:2]([CH3:1])=[N:6][C:5]=2[CH3:7])[CH2:35][CH2:34][CH2:33]1
Reactant: C1CNC1
Reactant: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2F)[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1nc(C)c(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)ccc2N2CCC2)[nH]1
Temperature: 120 °C
Reaction time: 48 h
Yield: 27.1 %

Procedure:
Into a 10-mL sealed tube, was placed a solution of 4-(1-(3-(2,4-dimethyl-1H-imidazol-5-yl)-4-fluorobenzoyl)piperidin-4-yl)benzonitrile (compound 25.1, 200 mg, 0.50 mmol) in 1,4-dioxane (4 mL). Azetidine hydrochloride (50 mg, 0.53 mmol) and cesium carbonate (500 mg, 1.53 mmol) were added and the mixture was stirred for 48 h at 120° C. behind a blast shield. The mixture was cooled and the solids were removed by filtration. The filtrate was concentrated under reduced pressure and the crude product was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-001(SHIMADZU)): Column, SunFire Prep C18 OBD Column, 5 um, 19*150 mm; mobile phase, Water with 50 mmol NH4HCO3 and CH3CN (33.0% CH3CN up to 46.0% in 10 min, up to 100.0% in 3 min, down to 33.0% in 1 min); Detector, Waters 2489, 254 & 220 nm. The fractions containing pure compound were combined and lyophilized to yield 59.6 mg (27%) of the title compound as a white solid m/z (ES+) 440 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1.C(N(CC)CC)C>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:21][CH2:22][CH2:23][OH:24])[O:13][C:12](=[O:14])[N:11]([C@H:15]3[CH2:20][CH2:19][CH2:18][N:17]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=4)[CH2:16]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCNC1
Reactant: FC(F)(F)c1ccc(Br)nc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1O[C@@](CCCO)(c2ccc(F)cc2)CCN1[C@H]1CCCN(c2ccc(C(F)(F)F)cn2)C1
Yield: 7 %

Procedure:
A mixture of (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one (100 mg, 0.30 mmol), 2-bromo-5-(trifluoromethyl)pyridine (67 mg, 0.36 mmol), and triethylamine (91 mg, 0.90 mmol) in acetonitrile was heated to reflux for 3 h. The reaction mixture was concentrated. The residue was purified by preparative TLC and preparative HPLC to afford (R)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-3-((S)-1-(5-(trifluoromethyl)pyridin-2-yl) piperidin-3-yl)-1,3-oxazinan-2-one (10.09 mg, 7%). LC-MS Method 2 tR=1.34 min, m/z=482. 1H NMR (400MHz, CDCl3): 1.28 (m, 1H), 1.64 (m, 2H), 1.76 (m, 3H), 1.92 (m, 2H), 2.18 (m, 1H), 2.27 (m, 1H), 2.77 (m, 3H), 3.21 (m, 1H), 3.52 (t, 2H), 3.83 (broad, 1H), 4.11 (d, 1H), 4.25 (d, 1H), 6.57 (d, 1H), 7.03 (t, 2H), 7.23 (m, 2H), 7.54 (d, 1H), 8.29 (s, 1H).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH:7](=O)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Cl>[OH-].[K+]>[C:1]([C:3](=[CH:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([OH:6])=[O:5])#[N:2]
Reactant: N#CCC(=O)O
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: N#CC(=CC=Cc1ccccc1)C(=O)O
Temperature: 35 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
To a solution of cyano acetic acid in 200 ml of 10% aqueous potassium hydroxide was added trans-cinnamaldehyde (26 g). The mixture was stirred at 35° C. for 2 hrs. and acidified with 100 ml of conc. hydrochloric acid. The solid was collected and washed to yield 2-cyano-5-phenyl-2,4-pentadienoic acid (36 g, 90% yield), m.p. 196° C. Recrystallized from ethanol yielded pure product, m.p. 211° C.
Reaction SMILES: O.[C:2]([NH:9][C@@H:10]([C:15]([OH:17])=O)[CH2:11][CH:12]([CH3:14])[CH3:13])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:29]([O:36][C:37](=[O:43])[C@H:38]([CH:40]([CH3:42])[CH3:41])[NH2:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl(O)(=O)(=O)=O.C(N=C=NCCCN(C)C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O>[CH2:29]([O:36][C:37](=[O:43])[C@H:38]([CH:40]([CH3:41])[CH3:42])[NH:39][C:15](=[O:17])[C@@H:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[NH:9][C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)[C@H](N)C(=O)OCc1ccccc1
Reactant: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)C
Reaction time: 2 h
Yield: 110.2 %

Procedure:
0.749 g (3.00 mmol) of Boc-D-leucine monohydrate, 1.252 g (3.30 mmol) of L-valine benzyl ester p-toluenesulfonate and 0.811 g (6.00 mmol) of N-hydroxybenzotriazole were dissolved in 15 ml of dichloromethane. The resulting mixture was cooled with ice, and admixed with 0.504 ml (3.60 mmol) of triethylamine and 1.108 g (4.20 mmol) of 97% 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide perchlorate. The reaction mixture was stirred for 2 hours, and then further stirred at room temperature for 4 hours. After the completion of the reaction, 30 ml of water and 5 ml of a 1% aqueous citric acid solution were added to the reaction mixture. The crystals thus deposited were filtered off. The organic layer successively was washed with 20 ml of water, 20 ml of a saturated aqueous sodium hydrogen carbonate solution and 10 ml of water, dried over anhydrous sodium sulfate, and distilled to remove the solvent therefrom, whereby 1.390 g of crude Boc-D-leucyl-L-valine benzyl ester product were obtained as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]2[OH:14])=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=[O:14])=[CH:6][CH:7]=1
Reactant: OC1CCCCC1c1ccc(F)cc1
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=C1CCCCC1c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.7 %

Procedure:
bii) Alternatively, to a solution of rac-2-(4-fluoro-phenyl)-cyclohexanol (7.5 g, 39 mmol) in dry DMSO (67 mL) was added triethylamine (27 mL, 190 mmol) under argon and the resulting mixture cooled to 0° C. and then a solution of sulfur trioxide pyridine complex (18.4 g, 116 mmol) in dry DMSO (98 mL) was added dropwise over 15 min. After 1 h, the mixture was diluted with water (200 mL) and the product extracted with DCM (2×100 mL). The combined organic extracts were then dried over sodium sulfate, followed by filtration and evaporation. Purification by filtration through silica gel, eluting with ethyl acetate:hexane (1:4) afforded the title compound (7.1 g, 95%) as white crystals. MS: m/e=192.1 (M).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[I:12]I>S([O-])([O-])(=O)=O.[Ag+2]>[I:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]([CH3:1])=[CH:3][C:4]=1[NH2:5]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Product: Cc1cc(N)c(I)cc1[N+](=O)[O-]

Procedure:
3-Methyl-4-nitroaniline was treated with iodine and silver sulfate to give 2-iodo-5-methyl-4-nitroaniline. Treatment of the nitroaniline with 2-(trimethylsilyl)acetylene under the typical Sonogashira conditions gave 5-methyl-4-nitro-2-[(trimethylsilyl)ethynyl]aniline, which was treated with a base in an aqueous methanolic solution to give 2-ethynyl-5-methyl-4-nitroaniline. A subsequent base-induced cyclization at an elevated temperature gave 5-nitro-6-methylindole, which was treated under a high pressure hydrogenation condition to provide 5-amino-6-methylindole.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:31][CH2:32][Cl:33])(C1C=CC(C)=CC=1)(=O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][N:9]2[CH2:31][CH2:32][Cl:33])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c[nH]c2cc(Cl)ccc2c1=O
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1cn(CCCl)c2cc(Cl)ccc2c1=O
Temperature: 100 °C

Procedure:
To a mixture containing 23.4 g of ethyl 7-chloro-1,4-dihydro-4-oxoquinoline-3-carboxylate and 6.9 g of 65% sodium hydride was added 90g of 2-tosyloxyethyl chloride. The resulting mixture was heated at 100° C for 4 hours. After concentration to dryness, the residue was extracted with chloroform. The extract was washed with water, and dried over anhydrous sodium sulfate. The solvent was removed by the distillation to leave a solid which was recrystallized from ethanol to give ethyl 7-chloro-1-(2-chloroethyl)-1,4-dihydro-4-oxo-quinoline3-carboxylate, m.p. 207.5°-209.5° C.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[NH:19]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)C(C)=O.Cl.C>C(O)C.[OH-].[Na+].N1C=CC=CC=1>[NH2:19][C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:18][C:15]2[S:16][CH:17]=[C:13]([C:4]3[CH:5]=[C:6]([C:9]([F:10])([F:12])[F:11])[CH:7]=[CH:8][C:3]=3[F:2])[N:14]=2)(=[O:31])=[O:30])=[CH:25][CH:24]=1
Reactant: Nc1nc(-c2cc(C(F)(F)F)ccc2F)cs1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: Nc1ccc(S(=O)(=O)Nc2nc(-c3cc(C(F)(F)F)ccc3F)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.5 %

Procedure:
A mixture of 0.5 g of 4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.38 g of 4-acetaminobenzenesulfonyl chloride was stirred for 2 hours with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and stirred at room temperature for 30 minutes. The separated solid was dissolved in a mixture of 20 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The 4-acetamino-N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-benzenesulfonamide, which separated upon neutralization with concentrated hydrochloric acid, was suspended in 9 ml of 6N hydrochloric acid and boiled for 36 hours. The mixture was cooled, treated with 30 ml of ethanol and neutralized with 2N sodium hydroxide solution. Recrystallization of the product, which thereby separated, from 20 ml of 50% ethanol yielded 0.21 g of 4-amino-N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]benzenesulfonamide as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-])=O.[Cl-].[NH4+]>CC(C)=O.O.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1/C=C/c1ccc(O)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(C)=O
Solvent: O
Product: Nc1cc(O)ccc1/C=C/c1ccc(O)cc1
Yield: 81.2 %

Procedure:
To a solution of the product of 3-nitro-4-[(E)-2-(4-hydroxyphenyl)-vinyl]phenol (216 mg, 0.84 mmol) in acetone (6 mL) was added a solution of ammonium chloride (89.9 mg, 1.68 mmol) in 2 mL of water. The mixture was heated to reflux, and the oil bath was removed. Zinc dust (164.8 mg, 2.5 mmol) was added in small portions to the reaction mixture to maintain a moderate reaction. After the reaction subsided an additional portion of zinc (82.4 mg, 1.25 mmol) was added. The reaction mixture was then heated to reflux for an additional 2 h. The precipitate was removed by filtration, washed with acetone (2×20 mL) and with ethyl acetate (2×30 mL). The combined washings were concentrated in vacuo and the crude product was purified by column chromatography using 5% methanol in dichloromethane to afford 3-Amino-4-[(E)-2-(4-hydroxy-phenyl)vinyl]phenol (155 mg, 72%). MS (ES) m/z: 228.11 (M+1), 134.06; 13C-NMR (DMSO-d6): δ 158.3, 156.9, 147.9, 130.4, 130.2, 127.9, 126.9, 124.5, 122.0, 115.9, 115.5, 114.2, 105.4, 102.2. Mp. 229-232° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH2:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=1[OH:38])[CH2:26][CH3:27]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:38][C:29]3[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:28]=3[CH2:25][CH2:26][CH3:27])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CCCc1ccc(C(F)(F)F)cc1O
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CCCc1ccc(C(F)(F)F)cc1Oc1nc(C(=O)NC(C)c2cc(F)c(NS(C)(=O)=O)c(F)c2)co1
Yield: 53.4 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with give 2-propyl-5-trifluoromethyl-phenol (54 mg, 0.26 mmol) to give the title compound (38 mg, 54%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20]O>CC(O)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH2:20][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][C:4]=1[C:9](=[O:14])[C:10]([F:12])([F:13])[F:11]
Reactant: COc1ccc(CO)cc1OC
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Solvent: CC(C)O
Product: COc1ccc(CNc2ccc(Cl)cc2C(=O)C(F)(F)F)cc1OC
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 68 %

Procedure:
4-Chloro-2-trifluoroacetylaniline (4.96 g, 40 mmol) and 3,4-dimethoxybenzyl alcohol (7.39 g, 44 mmol) were added to 2-propanol (40 mL). TSOH (76 mg, 0.4 mmol) was added and the mixture heated to 60° C. and held 3.5 hours. The solution was concentrated in vacuo to 1/2 the original volume, diluted with water (10 mL) and stirred at room temperature. The resulting slurry was filtered and the product dried in vacuo at 30° C. to give 10.16 g (68%) of the title compound as a yellow powder. An analytical sample was obtained by recrystallization from acetonitrile: mp 82-84° C.; 1H NMR (CDCl3) δ 9.05 (brs, 1H), 7.75 (brt, J=2 Hz, 1H), 7.35 (dd, J=2, 8 Hz, 1H), 6.8 (d, J=8 Hz, 3H), 6.75 (d, J=8 Hz, 1H), 4.43 (d, J5 Hz, 2H), 3.88 (s, 3H), 3.87 (s, 3H); 13C NMR (CDCl3) δ 179.9, 151.9, 149.4, 148.7, 137.4, 130.8, 130.8, 130.7, 129.4, 119.4, 114.5, 111.5, 111.4, 110.3, 56.1, 56.0, 47.0; 19F NMR (CDCl3) δ -69.61.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:7][CH:6]=1)[CH3:4].C[O-].[Na+].[CH2:23](Br)[CH:24]=[CH2:25]>O>[CH2:25]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])=[O:13])=[CH:9][CH:10]=1)[CH3:4])[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: COC(=O)CNC(=O)Nc1ccc(C(C)=NO)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: C=CCON=C(C)c1ccc(NC(=O)NCC(=O)OC)cc1

Procedure:
A solution of N-[4-(1-hydroxyiminoethyl)phenyl]-N'-methoxycarbonylmethylurea in 25% methanolic sodium methoxide (1.0 equivalent) is treated at room temperature with 1.1 equivalent of allyl bromide. The reaction mixture is stirred until the temperature falls to about 20° C. The reaction mixture is then poured into cold water and extracted with diethyl ether. The ether solution is dried over MgSO4 and filtered, and the solvent is removed by rotary evaporator to yield N-[4-(1-allyloxyiminoethyl)phenyl-N'-methoxycarbonylmethylurea.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[C:19]2[O:18][C:17]([C:20]3([CH3:25])[O:24][CH2:23][CH2:22][O:21]3)=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)[CH3:10]>C(Cl)(Cl)(Cl)Cl>[Br:1][CH:9]([C:11]1[C:19]2[O:18][C:17]([C:20]3([CH3:25])[O:24][CH2:23][CH2:22][O:21]3)=[CH:16][C:15]=2[CH:14]=[CH:13][CH:12]=1)[CH3:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc2cc(C3(C)OCCO3)oc12
Solvent: ClC(Cl)(Cl)Cl
Product: CC(Br)c1cccc2cc(C3(C)OCCO3)oc12
Temperature: 0 °C

Procedure:
28.0 g of recrystallized N-bromosuccinimide were added to a solution of 32.5 g of 7-ethyl-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran in 480 ml of carbon tetrachloride. The resulting suspension was stirred and heated under reflux for 12 hours. The mixture was cooled overnight at 0°C, precipitated succinimide was filtered off and the filtrate was evaporated at 30°C under reduced pressure. There was thus obtained crude 7-(1'-bromoethyl)-2-(2-methyl-1,3-dioxolan-2-yl) benzofuran which was used immediately in the next stage. The structure of this compound was confirmed by spectral data.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([Mg]Br)=[CH:17][CH:16]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:18]2[CH:19]=[CH:20][C:15]([Cl:14])=[CH:16][CH:17]=2)([OH:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Cl)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 1-t-butoxycarbonyl-3-pyrrolidinone (0.57 g, 3.23 mmol) in THF (10 mL) was added 4-chlorophenyl magnesium bromide (1.0 M, 5.2 mL) under the protection of argon at 0° C. The reaction was stirred at room temperature for 1 hour then quenched by the addition of saturated aqueous NH4OH (8 mL). The aqueous layer was extracted with EtOAc (50 mL×2), dried over MgSO4 and concentrated in vacuo. Chromatographic purification on silica gel (Hexane/EtOAc=3/1) provided 0.57 g 1-t-butoxycarbonyl -3-(4-chlorophenyl)-3-hydroxypyrrolidine (60%). m/z 298 (m+1)