Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[CH2:22]([C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[CH3:23].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:22][CH3:23])=[CH:25][CH:26]=1)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Reactant: CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(CC)cc3)cc2OC1C(F)(F)F
Temperature: 100 °C

Procedure:
To 4.05 g (12.5 mmole) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 30 mL of DMF was added 1.86 g (15.2 mmole) of 4-ethylphenol and 2.42 g (17.5 mmole) of potassium carbonate. The stirred mixture was heated to 100° C. for 8 h, allowed to cool and treated with 100 mL of water. The mixture was extracted three times with diethyl ether, the combined filtrates filtered through 30 g of silica and the filtrates concd in vacuo to afford a crude product. Recrystallization from methanol-water afforded 4.43 g (83%) of a yellow, crystalline solid: mp 109-110° C.; 1H NMR (d6-acetone/400 MHz) 1.22 (t, 3H, J=7.5 Hz), 1.30 (t, 3H, J=7.1 Hz), 2.66 (q, 2H, J=7.6 Hz), 4.28 (m, 2H), 5.81 (q, 1H, J=7.0 Hz), 6.44 (s, 1H), 7.04 (d, 2H, J=8.8 Hz), 7.31 (d, 2H, J=8.6 Hz), 7.67 (s, 1H), 7.86 (s, 1H); 19F NMR (d6-acetone/400 MHz) −79.5 (d, 3F, J=6.8 Hz); 13C NMR (d6-acetone/100 MHz) 13.8, 15.4, 61.3, 70.8 (q, J=32.8 Hz), 105.5, 115.2, 115.9, 117.5, 119.9, 123.8 (q, J=287.1 Hz), 129.8, 131.2, 135.5, 141.5, 153.1, 153.2, 157.4, 163.4; MS (ES+) 427 (M+1, 100); HRMS (ES+) m/z calcd for (C21H18O4ClF3) 427.0918, found 427.0921.
Reaction SMILES: [CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][N:9]3[C:10]=2[C:2]=1[C:3]1[C:4](=O)[CH2:5][CH2:6][CH2:7][C:8]=13.Cl.[NH2:18][OH:19].Cl>N1C=CC=CC=1>[CH:1]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][N:9]3[C:10]=2[C:2]=1[C:3]1[C:4](=[N:18][OH:19])[CH2:5][CH2:6][CH2:7][C:8]=13
Reactant: NO
Reactant: O=C1CCCc2c1c1cccc3c1n2CC3
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1CCCc2c1c1cccc3c1n2CC3
Yield: 35.9 %

Procedure:
A mixture of 4,5,8,9-tetrahydropyrrolo[3,2,1-jk]carbazol-10(7H)-one (364 mg) and hydroxylamine hydrochloride (479 mg) in pyridine (50 ml) was heated to 50° for 60 h, and was then poured into 2N hydrochloric acid (100 ml). The resultant precipitate was filtered off, washed with water (50 ml), and dried in vacuo at 50° for 6 h to give the title compound (140 mg). Filtration of the precipitate that formed subsequently in the filtrate gave a further crop of the title compound (104 mg), m.p. 271°-272°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([N:15]=[C:16]=[O:17])[CH2:13][CH3:14].C(N(CC)CC)C.C(O)C>C(#N)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[NH:1][C:16](=[O:17])[N:15]([CH2:12][CH2:13][CH3:14])[C:4]2=[O:6]
Reactant: CCCN=C=O
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCn1c(=O)[nH]c2ccc(I)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5.0 g (0.019 mol) 2-amino-5-iodobenzoic acid, 1.9 g (0.012 mol) n-propyl isocyanate, and 1.9 g (0.019 mol) triethylamine in 190 mL of acetonitrile was stirred at ambient temperature overnight. An additional 1.9 g (0.012 mol) of n-propyl isocyanate was added and stirring continued at ambient temperature for an additional 72 h. The reaction was then concentrated by atmospheric pressure distillation to deliver 7.8 g of an oil which solidified upon standing under reduced pressure. A 3.6 g portion of this crude material was subjected to heating neat at 190° C. for 0.75 h. The resulting reaction mass was cooled, treated with approximately 20 mL ethanol, agitated, and filtered. The filter cake was subsequently washed with ether and dried to deliver 1.8 g of the title compound, 1H NMR (300 MHz, Me2SO--d6): δ0.87 (s,3H); 1.50-1.69 (m,2H); 3.83 (t,2H); 6.99 (d,1H); 7.94 (dd,1H); 8.16 (d,1H); 11.50 (bs,1H).
Reaction SMILES: C(O)C[CH2:3][CH2:4][OH:5].C(C(CO)(CO)CC)O.C(C(CO)(C)C(O)=O)O.CC1(C)CC(C[N:34]=[C:35]=[O:36])(C)CC(N=C=O)C1>CC(C)=O>[N-:34]=[C:35]=[O:36].[NH2:34][C:35]([O:5][CH2:4][CH3:3])=[O:36]
Reactant: OCCCCO
Reactant: CC1(C)CC(N=C=O)CC(C)(CN=C=O)C1
Agent: CC(CO)(CO)C(=O)O
Agent: CCC(CO)(CO)CO
Solvent: CC(C)=O
Product: CCOC(N)=O
Product: [N-]=C=O
Reaction time: 7 h

Procedure:
An autoclave was charged with a mixture of 246.7 parts of polycaprolactonediol (number average molecular weight 2000), 7.4 parts of 1,4-butanediol, 5.1 parts of trimethylolpropane, 17.9 parts of dimethylolpropionic acid, 123.0 parts of IPDI and 400 parts of acetone, followed by introducing nitrogen gas so as to be replaced, reacting at 80° C. for 7 hours to obtain an acetone solution of an isocyanate (NCO)-terminating urethane prepolymer having a NCO content of 1.67%, cooling the acetone solution at 30° C., adding 13.5 parts of triethylamine, adding 600 parts of water, distilling off the acetone at 50 to 60° C. under vacuum to obtain a 40.0% solid content water based urethane resin emulsion C-2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[N:7]3[CH2:14][CH:13]([CH3:15])[CH2:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:17]=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CCN(CC)CC>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:15][CH:13]1[CH2:14][N:7]2[C:8](=[N:9][C:10]3[CH:11]=[C:2](/[CH:17]=[CH:18]/[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH:3]=[CH:4][C:5]=3[C:6]2=[O:16])[CH2:12]1
Reactant: CC1Cc2nc3cc(Br)ccc3c(=O)n2C1
Reactant: C=Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1Cc2nc3cc(/C=C/c4ccccc4)ccc3c(=O)n2C1
Temperature: 25 °C
Yield: 61.6 %

Procedure:
A solution of 6-bromo-2-methyl-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (100 mg, 0.36 mmol), styrene (75 mg, 0.72 mmol), Pd (PPh3)4 (45 mg, 0.036 mmol), PPh3 (1 mg, 0.0036 mmol) and Et3N (182 mg, 1.8 mmol) in DMF (10 mL) was stirred at 140° C. under N2 for 8 hours. After cooled to room temperature, the mixture was diluted with H2O and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na2SO4. Then the filtrate was concentrated and purified by column chromatography to give the desired product (67 mg). MS (ESI): 303 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 8.13-8.10 (d, J=8.3 Hz, 1H), 7.87-7.84 (d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.70-7.68 (d, J=7.5 Hz, 2H), 7.56-7.47 (m, 2H), 7.44-7.40 (m, 2H), 7.35-7.30 (m, 1H), 4.29-4.22 (dd, J=11.7, 7.8 Hz, 1H), 3.68-3.62 (dd, J=11.7, 6.8 Hz, 1H), 3.38-3.29 (dd, J=17.2, 8.1 Hz, 1H), 2.91-2.83 (dd, J=17.2, 7.5 Hz, 1H), 2.75-2.67 (m, 1H), 1.18-1.16 (d, J=6.7 Hz, 3H). mGluR5 PAM EC50: +++.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([Br:38])[CH:36]=5)[N:31]=[CH:30][C:29]4=[O:39])[CH2:22][CH2:21]3)C(=O)OC(C)(C)C)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][NH:12][CH:20]3[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][N:28]4[C:37]5[C:32](=[CH:33][CH:34]=[C:35]([Br:38])[CH:36]=5)[N:31]=[CH:30][C:29]4=[O:39])[CH2:24][CH2:25]3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(Br)cc32)CC1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=c1cnc2ccc(Br)cc2n1CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.5 %

Procedure:
To 20 mL of a chloroform solution containing 0.47 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-bromo-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 20 mL of trifluoroacetic acid was added and stirred at room temperature for 12 hours. After solvents of the reaction mixture were removed under reduced pressure and the residue was alkalized by aqueous saturated sodium hydrogen carbonate solution, it was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; chloroform: methanol=10:1], to give 280 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-bromoquinoxalin-2(1H)-one as a pale brown foam.
Reaction SMILES: Cl.[N:2]1([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:25])([F:24])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>C(Cl)Cl>[C:39]([N:5]1[CH2:6][CH2:7][N:2]([C:8]2[N:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18]=[C:19]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:20][C:21]=3[C:22]([F:24])([F:25])[F:23])=[O:16])=[CH:10][CH:9]=2)[CH2:3][CH2:4]1)(=[O:41])[CH3:40]
Reactant: O=C(Nc1ccc(N2CCNCC2)nc1)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (6-piperazin-1-yl-pyridin-3-yl)-amide hydrochloride salt (65 mg, 0.13 mmol) in methylene chloride (5 mL) was added triethylamine (0.15 mL). The mixture was cooled in an ice bath and acetyl chloride (12 □L) was added. The mixture was stirred at room temperature for 30 minutes and partitioned between methylene chloride and brine. The organic layer was dried over sodium sulfate and the solvents were evaporated. The residue was first dried in vacuum and then triturated with methanol (3 mL) to give 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid [6-(4-acetyl-piperazin-1-yl)-pyridin-3-yl]-amide (21 mg) as a solid. LC-MS calcd for C22H20F3N5O3 (m/e) 459.2, obsd 460.0 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [C:1](O)(=O)[CH2:2][CH2:3][CH3:4].[OH:7][C:8](CBr)=[C:9]([N:13]1[C:16](=[O:17])[CH:15]([NH:18][C:19](=[O:27])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:14]1[S:28][CH:29]=O)[C:10]([O-:12])=[O:11].[CH2:33](S)[CH3:34]>C(Cl)(Cl)Cl>[C:21]1([CH2:20][C:19]([NH:18][CH:15]2[C:16](=[O:17])[N:13]3[C:9]([C:10]([O:12][CH:1]([C:34]4[CH:33]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:2]4[CH:10]=[CH:9][CH:8]=[CH:4][CH:3]=4)=[O:11])=[C:8]([OH:7])[CH2:29][S:28][C@H:14]23)=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=CSC1C(NC(=O)Cc2ccccc2)C(=O)N1C(C(=O)[O-])=C(O)CBr
Reactant: CCCC(=O)O
Reactant: CCS
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
To 0.410 g. (1.05 mmol.) of mercuric acetate in a mixture of 10 ml. of chloroform and 10 ml. of butyric acid are added 0.529 g. (1 mmol.) of 3-hydroxy-4-bromo-2-(2-formylthio-4-oxo-3-phenylacetamido-1-azetidinyl)-2-butenoate, benzhydryl ester, in 10 ml. of chloroform. The mixture is stirred for 15 minutes at 10° C., after which time the solution becomes cloudy. Ethyl mercaptan is added to the mixture, and the mixture then is filtered through activated charcoal and a filter aide. The resulting filtrate is evaporated, and a residue comprising benzhydryl 7-phenylacetamido-3-hydroxy-3-cephem-4-carboxylate is obtained.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2C(O)=O.C(=O)(O)[O-].[Na+].[I-:23].[Na+].II>ClC(Cl)C.O.ClCCl>[I:23][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:17])([F:16])[F:1])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C(O)c1n[nH]c2ccc(OC(F)(F)F)cc12
Reactant: [I-]
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: FC(F)(F)Oc1ccc2[nH]nc(I)c2c1
Temperature: 100 °C
Reaction time: 0.75 h
Yield: 66.8 %

Procedure:
To a mixture of 5-(trifluoromethoxy)-1H-indazole-3-carboxylic acid (0.2 g, 813 μmol), and sodium bicarbonate (225 mg, 104 μL, 2.68 mmol) in dichloroethane (2 mL) and water (2.00 mL) were added in one portion sodium iodide (317 mg, 2.11 mmol) and iodine (268 mg, 1.06 mmol) and the mixture heated at 100° C. (oil bath temperature) with vigorous stirring for 45 minutes. After cooling to 25° C. the mixture was diluted with dichloromethane, then washed with 10% Na2S2O3 and saturated NaHCO3. The organics were dried (MgSO4) and concentrated to an off-white solid which was dissolved in dichloromethane, cyclohexane added to promote solid formation, and allowed to stand. The solid was separated by filtration and dried to give 3-iodo-5-(trifluoromethoxy)-1H-indazole (178 mg, 543 μmol, 67%) as white needles. MS (M−H)−=326.8; 1H NMR (CDCl3) δ: 7.51 (d, J=9.1 Hz, 1H), 7.40 (s, 1H), 7.32-7.38 (m, 1H).
Reaction SMILES: [CH2:1](N(CC)CC)C.[O:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20]3[N:21]=[C:22]([N:30]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:31][CH2:32][OH:33])[C:23]4[CH2:29][NH:28][CH2:27][CH2:26][C:24]=4[N:25]=3)=[CH:15][CH:14]=2)=[CH:11][N:10]=[CH:9]1.CI>CN(C=O)C>[CH3:1][N:28]1[CH2:27][CH2:26][C:24]2[N:25]=[C:20]([NH:19][C:16]3[CH:17]=[CH:18][C:13]([C:12]4[O:8][CH:9]=[N:10][CH:11]=4)=[CH:14][CH:15]=3)[N:21]=[C:22]([N:30]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH2:31][CH2:32][OH:33])[C:23]=2[CH2:29]1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: CCN(CC)CC
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
Triethylamine (0.038 ml, 0.27 mmol) was added to 2-((2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.058 g, 0.14 mmol, Example 1) in DMF (2 mL). Methyl iodide (9.28 μl, 0.15 mmol) was added and the reaction mixture was stirred for 1 h at 25° C. The solution was concentrated under reduced pressure and the product purified by preparative HPLC to give 2-((6-methyl-2-(4-(oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (0.022 g, 36.7%). MS (ESI+)/(ESI−) m/z 443/441
Reaction SMILES: Br[C:2]1[C:3]([CH3:14])=[CH:4][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[N:6][CH:7]=1.B([C:18]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:19]=1[O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])(O)O>>[Cl:30][C:28]1[CH:27]=[CH:26][C:19]([O:20][C@@H:21]([CH3:25])[C:22]([OH:24])=[O:23])=[C:18]([C:2]2[CH:7]=[N:6][C:5]([N:8]([CH3:13])[S:9]([CH3:12])(=[O:11])=[O:10])=[CH:4][C:3]=2[CH3:14])[CH:29]=1
Reactant: Cc1cc(N(C)S(C)(=O)=O)ncc1Br
Reactant: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O
Product: Cc1cc(N(C)S(C)(=O)=O)ncc1-c1cc(Cl)ccc1O[C@@H](C)C(=O)O

Procedure:
The title compound was prepared by the method of example 155 using the product from step (ii) and the product from example 151 step (iv). Yield 0.125 g.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([OH:21])[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.Br[C:23]1[CH:28]=[CH:27][C:26]([CH:29]([F:31])[F:30])=[CH:25][CH:24]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:23]3[CH:28]=[CH:27][C:26]([CH:29]([F:31])[F:30])=[CH:25][CH:24]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1
Reactant: FC(F)c1ccc(Br)cc1
Reactant: Cn1ccc(NC(=O)c2cc(O)c3c(c2)OC(C)(C)C3)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(F)F)cc3)c3c(c2)OC(C)(C)C3)n1
Temperature: 160 °C
Yield: 12.1 %

Procedure:
A mixture of 4-hydroxy-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide (31a) (102 mg, 0.36 mmol), 1-bromo-4-difluoromethyl benzene (110 mg, 0.53 mmol), Cs2CO3 (174 mg, 0.53 mmol) and CuI (1 mg) in DMF (5 mL) was heated for 2 hr at 160° C. in the microwave. The mixture was filtered and the filtrate was purified by reverse phase chromatograph to give a white solid (18 mg, 12% yield). 1H NMR (400 MHz, CDCl3) δ 9.92 (d, J=2.02 Hz, 1 H) 8.52 (s, 1 H) 7.72 (dd, J=10.36, 1.77 Hz, 1 H) 7.64 (d, J=8.34 Hz, 1 H) 7.28 (s, 1 H) 7.09 (t, J=7.96 Hz, 1 H) 7.05 (s, 1 H) 6.97 (s, 1 H) 6.77 (d, J=2.02 Hz, 1 H) 3.78 (s, 3 H) 2.98 (s, 2 H) 1.51 (s, 6 H); LCMS for C22H21F2N3O3 m/z 414.00 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:11])=O.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.O>C1(C)C(C)=CC=CC=1>[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:18]2[CH:2]3[C:3]([CH2:4][CH2:5][CH2:6][CH2:7]3)=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:9]2=[O:11])=[CH:20][CH:21]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C1CCCCC1C(C(=O)O)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1C(c2ccccc2)=C2CCCCC2N1c1ccc(O)cc1
Yield: 82 %

Procedure:
92.8 g of 2-(2-oxo-cyclohexyl)-2-phenyl acetic acid and 44 g of 4-aminophenol in 800 cm3 of xylene were stirred and heated under reflux, as indicated in Example 1a), until the water formed in the reaction has been totally eliminated. This took 2 hours (volume collected: 14.2 cm3 ; theoretical: 14.4 cm3). After the distillation of 400 cm3 of solvent, the residue was cooled. The precipitate produced was collected and recrystallized from methylcellosolve to give 100 g (82%) of 1-(4-hydroxyphenyl)-2-oxo-3-phenyl-2,4,5,6,7,7a-hexahydro-indole (m.p. 241° C).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][C:25]#[N:26])[CH:10]=[C:11]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[C:12]=1[Cl:13].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>CCOCC>[Cl:6][C:7]1[CH:8]=[C:9]([CH2:23][CH2:24][C:25]#[N:26])[CH:10]=[C:11]([CH2:14][OH:15])[C:12]=1[Cl:13]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CCC#N)cc(Cl)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CCCc1cc(Cl)c(Cl)c(CO)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a THF (0.1 M) solution of 3-[3,4-dichloro-5-({[(1,1-dimethylethyl)(dimethyl)silyl]oxy}methyl)phenyl]propanenitrile (1 eq.) from the previous step was added TBAF (1.0 M THF solution, 1.2 eq.). The resulting solution was stirred at RT for 3 h. The reaction was then diluted with ether and quenched with water. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→3:7 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: C(SCS(C(C)C)=O)(C)C.[O:11]1CCC[CH2:12]1.[H-].[Na+].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:23]Br>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH2:23][CH:12]=[O:11])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: C1CCOC1
Reactant: COc1ccc(CBr)cc1OC
Agent: CC(C)SCS(=O)C(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CC=O)cc1OC
Reaction time: 1 h
Yield: 35 %

Procedure:
1.80 g of isopropyl isopropylthiomethyl sulfoxide was dissolved in 15 ml. of tetrahydrofuran, and under cooling with ice, 240 mg of sodium hydride was added, and the solution was stirred for one hour. 2.31 g of 3,4-dimethoxybenzyl bromide was added, and the mixture was stirred for 20 hours at room temperature, and for 3 hours at 35°C. 100 ml. of methylene chloride was added. After separating the insoluble water by filtration, the filtrate was concentrated at reduced pressure. The residue was dissolved in 20 ml. of tetrahydrofuran, and with the addition of 10 drops of concentrated sulfuric acid, the solution was stirred for 10 hours at 50°C. 500 mg of sodium bicarbonate was added, and the mixture was stirred for 30 minutes at room temperature. Then, the insoluble matter was separated by filtration. The filtrate was concentrated at reduced pressure, and the residue was subjected to column chromatography to give 631 mg of (3,4-dimethoxyphenyl)acetaldehyde in a yield of 35%.
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[CH2:22]([C:24]1[O:25][C:26]2[C:27](=[C:29](N)[CH:30]=[CH:31][CH:32]=2)[N:28]=1)[CH3:23].[OH2:34]>C(#N)C.C(#N)C.O.C(OC(C)C)(C)C>[CH2:22]([C:24]1[O:34][C:29]2[C:30](=[O:4])[CH:31]=[CH:32][C:26](=[O:25])[C:27]=2[N:28]=1)[CH3:23]
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCc1nc2c(N)cccc2o1
Reactant: O
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CCc1nc2c(o1)C(=O)C=CC2=O
Temperature: -5 °C

Procedure:
A solution of [bis(trifluoroacetoxy)iodo]benzene (2.2 eq.) in a mixture of acetonitrile and water (80/20) is added dropwise to a solution of 2-ethyl-1,3-benzoxazol-4-amine (1 eq.) in the same acetonitrile/water mixture maintained at −5° C. The reaction medium is then diluted with water followed by extracting with dichloromethane. The resulting organic phase is washed with water, followed by drying over sodium sulphate and concentrating in order to produce a brown paste. Purification by medium pressure chromatography on silica gel produces, after taking up in diisopropyl ether, a yellow crystalline solid. Melting point: 99° C.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:27])[C@H:15]([CH2:19][CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:16][CH:17]=C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:28]=[O+][O-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]([CH2:19][CH2:20][C:21]1([CH3:26])[O:25][CH2:24][CH2:23][O:22]1)[CH2:16][CH:17]=[O:28])=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[O+][O-]
Reactant: C=CC[C@@H](CCC1(C)OCCO1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC1(CC[C@H](CC=O)C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)OCCO1
Temperature: 25 °C

Procedure:
To a stirred solution of 1-10 (16.0 g, 42.8 mmol) and Sudan III dye (10 mg) in dichloromethane (500 mL) at −78° C. was bubble ozone until the color of the dye was discharged (45 min.), after which time the solution was purged with argon for 0.5 h. Triphenylphosphine (16.9 g, 64.3 mmol) was added and the solution was allowed to warm to ambient temperature for 3 h. The reaction mixture was concentrated at reduced pressure and the resulting oil was purified by flash column chromatography (silica gel, 10 to 20% ethyl acetate/dichloromethane) to give 1-11 as an oil which crystallized on standing.