Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17]([C:19]3[N:20]=[C:21]([CH3:31])[S:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:18])=[CH:7][C:6]=2[CH:32]=1.CC1C(S([O-])(=O)=O)=CC(OC)=[C:36]([N:46]=NC2C(O)=CC=C3C=2C=CC(S([O-])(=O)=O)=C3)C=1.[Na+].[Na+].[Cu]C#N>>[C:36]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][N:12]3[C:17]([C:19]3[N:20]=[C:21]([CH3:31])[S:22][C:23]=3[C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)=[O:18])=[CH:7][C:6]=2[CH:32]=1)#[N:46]
Reactant: COc1cc(S(=O)(=O)[O-])c(C)cc1N=Nc1c(O)ccc2cc(S(=O)(=O)[O-])ccc12
Reactant: Cc1nc(C(=O)N2CCCCC2Cc2cc3cc(Br)ccc3o2)c(-c2ccc(F)cc2)s1
Agent: N#C[Cu]
Agent: [Na+]
Product: Cc1nc(C(=O)N2CCCCC2Cc2cc3cc(C#N)ccc3o2)c(-c2ccc(F)cc2)s1

Procedure:
The title compound (19 mg) was prepared from (RS)-1-[2-(5-bromo-benzofuran-2-ylmethyl)-piperidin-1-yl]-1-[5-(4-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone, E129 (420 mg) and copper(I)cyanide according to a procedure similar to that described for Example 67.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[CH:14]=[N:15][OH:16])[N:4]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27]Br>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[Cl:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[CH:25]=[CH:26][CH2:27][O:16][N:15]=[CH:14][C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:11][C:5]1[N:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=1
Reactant: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Reactant: Clc1cccc(C=CCBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(OC)nc(Oc2ccccc2C=NOCC=Cc2cccc(Cl)c2)n1
Yield: 61.5 %

Procedure:
5.5 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime and 4.6 g of 3-chlorocinnamyl bromide were dissolved in 30 ml of dry acetone containing 2.7 g of anhydrous potassium carbonate. The solution was heated for 5 hours under stirring and reflux. After the reaction mixture was allowed to cool down, the acetone was distilled out under reduced pressure and the resulting residue was dissolved in 200 ml of ethyl acetate. The ethyl acetate solution was washed with water and the organic layer was dried over anhydrous sodium sulfate. The solution was then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate: 4:1) to obtain 5.2 g of O-(3-chlorocinnamyl)-2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime as a semi-solid substance.
Reaction SMILES: [CH3:1][C:2]([N:4]([CH3:6])C)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][C:18]2[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[O:15])=[CH:10][CH:9]=1.C[CH2:28][O:29]C(C)=O>C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][C:18]2[S:22][C:21]([S:23]([N:4]3[CH2:2][CH2:1][C@@H:28]([OH:29])[CH2:6]3)(=[O:25])=[O:24])=[CH:20][CH:19]=2)=[O:15])=[CH:10][CH:9]=1
Reactant: O=C(NCc1ccc(S(=O)(=O)Cl)s1)c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Reactant: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCc1ccc(S(=O)(=O)N2CC[C@@H](O)C2)s1)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a suspension of R-3-pyrrolidinol hydrochloride (530 mg, 429 mmol) and DMA (0.75 ml, 14.3 mmol) in CH2Cl2/DMF 1:1 was added a solution of 5-({[1-(4-Chlorophenyl)-methanoyl]-amino}-methyl)-thiophene-2-sulfonyl chloride 1b (1.0 g, 2.86 mmol). At the end of addition the suspension disappeared. The reaction mixture was stirred overnight. 100 ml EtOAc were added and the excess of amine was extracted with HCl (1N), followed by washings with brine. The organic layers were dried over MgSO4 and evaporated to dryness to provide 351a (1.14 g, 99.9%) as a colourless foam: H1 NMR (DMSO d6) δ 9.34 (t, J=5.8 Hz, 1H), 7.89 (d, J=8.7 Hz, 2H), 7.49 (d, J=3.8 Hz, 1H), 7.55 (d, J=8.7 Hz, 2H), 7.13 (d, J=3.8 Hz, 1H), 4.95 (d, J=3.4 Hz, 1H), 4.65 (d, J=5.6 Hz, 2H), 4.16 (m, 1H), 3.40-3.20 (m, 5H), 3.00 (m, 1H), 3.35-3.23 (m, 3H), 1.80-1.60 (m, 2H), M/Z APCI: 401.2 (M+1), 398.9 (M−1).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: Fc1cccc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Product: O=C(c1cccc(F)c1)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1

Procedure:
This compound is prepared by method C using compound 12e and 1-bromo-3-fluorobenzene
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[C:6]([C:12]([O:14][CH3:15])=[O:13])#[C:7][C:8](OC)=[O:9].[SH-:16].[Na+]>>[C:3]([C:2]1[S:16][C:6]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:8]=1[OH:9])(=[O:5])[CH3:4]
Reactant: COC(=O)C#CC(=O)OC
Reactant: CC(=O)CCl
Reactant: [SH-]
Agent: [Na+]
Product: COC(=O)c1cc(O)c(C(C)=O)s1

Procedure:
According to the description in Synth. Commun., 1996, 26, 1083, methyl 2-acetyl-3-hydroxythiophene-5-carboxylate was synthesized with chloroacetone, dimethyl acetylene dicarboxylate and sodium hydrosulfide as starting materials (yield: 60%).
Reaction SMILES: CN(O)[C:3]([CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[N:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:11]=1)=[O:4].ClC1C=CC(C2N(C3C=CC([O:46]C)=CC=3)N=C(CCCO)C=2)=CC=1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[N:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[N:11]=[C:7]([CH2:6][CH2:5][C:3]([OH:46])=[O:4])[CH:8]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(-n2nc(CCC(=O)N(C)O)cc2-c2ccc(Cl)cc2)cc1
Reactant: COc1ccc(-n2nc(CCCO)cc2-c2ccc(Cl)cc2)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Product: COc1ccc(-n2nc(CCC(=O)O)cc2-c2ccc(Cl)cc2)cc1

Procedure:
Known methods of synthesizing tepoxalin include the following. U.S. Pat. No. 4,826,868 describes reacting the alcohol, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanol with Jones reagent to form the acid, 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-1H-pyrazole-3-propanoic acid, which is reacted with dimethylformamide and oxalyl chloride in tetrahydrofuran (“THF”) which is then reacted with methylhydroxylamine hydrochloride and triethylamine in THF.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][C@H:12]1[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:33])[C@H:13]1[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O.[C:46]1(C)[CH:51]=[CH:50][C:49]([S:52]([O-:54])=[O:53])=[CH:48][CH:47]=1.[Na+].[CH3:57]C(C)=O>O.[N+]([O-])([O-])=O.[Ag+]>[C:48]1([CH3:57])[C:49]([S:52]([S:11][C@H:12]2[N:15]([CH:16]([C:30]([CH3:32])=[CH2:31])[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)=[O:18])[C:14](=[O:33])[C@H:13]2[NH:34][C:35](=[O:44])[CH2:36][O:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)(=[O:53])=[O:54])=[CH:50][CH:51]=[CH:46][CH:47]=1
Reactant: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: CC(C)=O
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: C=C(C)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-nitrobenzyl 2-[(3R,4R)-4-[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XVIIIc, 3.25 g, 0.005 mole) in acetone (90 mL) and water (10 mL) was treated at room temperature with silver nitrate (1.06 g, 0.00625 mole), followed by treatment with a solution of sodium p-toluenesulfinate hydrate (0.90 g, 0.050 mole) in acetone (70 mL)--water (10 mL). The slurry was stirred for 1 h at room temperature under darkness. It was then filtered through Celite, which was washed with acetone. The volume of the filterate was reduced in vacuo, and the product was extracted into ether (3×250 mL). The ether phase was dried over magnesium sulfate and concentrated. Flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the pure title product, XVIIId, as a solid (2.053 g, 62%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]O)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C[CH2:52][N:53](C(C)C)[CH:54](C)C.CS(Cl)(=O)=O>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:20][C:21]([NH:23][C@@H:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C@@H:27]([O:34][C:35]3[CH:36]=[CH:37][C:38]4[N:39]([C:41]([N:44]5[CH2:49][CH2:48][CH2:47][CH2:46][C@@H:45]5[CH3:50])=[N:42][N:43]=4)[CH:40]=3)[CH2:26][CH2:25]2)=[O:22])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][N:53]([CH3:54])[CH3:52])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCN(C)C)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
To a solution of Intermediate 186c (293 mg, 0.44 mmol) and DIPEA (304 μL, 1.76 mmol) in DCM (10 mL) was added methanesulfonyl chloride (103 μL, 1.33 mmol). The reaction mixture was stirred at RT for 1 hour. The mixture was concentrated in vacuo. The residue was taken up in THF (2 mL) and dimethylamine solution in THF (2M, 3.3 mL) was added. The reaction mixture was heated at 60° C. in a sealed tube for 72 h. The reaction mixture was cooled to RT and concentrated in vacuo. The product was purified by HPLC using a gemini C18 column and using a gradient of 20-35%+0.1% Formic acid over 10 minutes. The combined fractions were evaporated under reduced pressure and crystallised by MeCN/Et2O to afford the title compound as a white solid (90 mg, 30%). LCMS (Method 3): Rt 3.01 min, m/z 706 [MH+]. NMR (300 MHz, d6-DMSO): 0.91 (3H, d, J=6.7 Hz), 1.23 (9H, s), 1.46-1.54 (2H, m), 1.63-1.72 (2H, m), 1.75-1.76 (2H, m), 2.00-2.18 (2H, m), 2.43 (6H, s), 2.66 (2H, t, J 5.8 Hz), 2.85-2.95 (2H, m), 3.12-3.20 (4H, m), 4.10 (2H, t, J=5.4 Hz), 4.78-4.86 (1H, m), 5.52 (1H, t, J=4.0 Hz), 6.33 (1H, s), 6.95-6.99 (2H, m), 7.06-7.14 (2H, m), 7.19 (1H, dd, J=10.0 Hz), 7.25-7.32 (3H, m), 7.33-7.42 (2H, m), 7.58 (1H, d, J=10.6 Hz), 7.63 (1H, d, J—1.8 Hz), 8.17 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[N:14]=[C:13]1[N:8]([CH2:9][CH2:10][CH2:11][O:12]1)[C:7]2=[O:16].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:30][CH:29]3[NH:31][CH:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:20][CH:19]=1.C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:15]=1[NH:14][C:13](=[O:12])[N:8]([CH2:9][CH2:10][CH2:11][N:31]1[CH:29]3[CH2:28][CH2:27][CH:26]1[CH2:25][N:24]([C:21]1[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=1)[CH2:30]3)[C:7]2=[O:16]
Reactant: Clc1ccc(N2CC3CCC(C2)N3)cc1
Reactant: O=c1c2cccc(Cl)c2nc2n1CCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: O=c1[nH]c2c(Cl)cccc2c(=O)n1CCCN1C2CCC1CN(c1ccc(Cl)cc1)C2
Temperature: 120 °C
Yield: 83.3 %

Procedure:
8-Chloro-3,4-dihydro-2H-1-oxa-4a,9-diaza-anthracen-10-one (6.18g, 26.02 mmol), 3-(4-Chloro-phenyl)-3,8-diaza-bicyclo[3.2.1] octane (HCl salt) (5.62 g, 21.68 mmol), triethylamine (3.6 ml, 26.02 mmol), p-toluene sulfonic acid (0.74 g, 3.90 mmol) were combined in dimethyl acetamide (38 ml) and heated at 120° C. for 15 hours. The reaction was cooled to room temperature, diluted with H2O and filtered the tan precipitate. Dissolved the tan solid in chloroform (400 ml), dried over magnesium sulfate, and concentrated to an off-white solid. Silica gel flash chromatography using 5% methanol/chloroform as the eluent yielded 8-Chloro-3-{3-[3-(4-chloro-phenyl)-3,8-diaza-bicyclo[3.2.1]oct-8-yl]-propyl}-1H-quinazoline-2,4-dione (8.3 g, 83.3%) as an off-white solid; Mp. 194-196° C. Maleate salt was formed by dissolving the solid in chloroform (100 ml) and maleic acid (2.52 g, 1.2 eq) in ethyl acetate (20 ml) was added. The mix was concentrated and the off-white solid was washed with ethyl acetate to yield maleate salt (8.95 g). A portion was recrystallized from acetonitrile yielding off-white crystalline solid which had the following properties: Mp. 186-188° C.; 1H NMR DMSO-d6 δ: 11.07 (brd s, 1H), 9.50 (brd s, 1H), 7.92 (dd, J=1.2, 6.6 Hz, 1H, 7.79 (dd, J=1.2, 6.6 Hz, 1H), 7.26-7.17 (m, 3H), 6.89 (d, J=9.1 Hz, 2H), 6.00 (s, 2H), 4.09 ( brd s, 2H), 3.99 (t, J=6.6 Hz, 2H), 3.70-3.65 (m, 2H), 3.17-2.98 (m, 4H), 2.20-2.00 (m, 4H), 1.95-1.86 (m, 2H). 13C NMR DMSO-d6 δ: 167.87, 162.14, 150.76, 149.18, 137.06, 136.53, 129.338, 127.26, 123.85, 119.35, 116.84, 116.63, 61.11, 52.08, 49.48, 38.43, 24.28, 23.88. IR (KBr): 3399, 3367, 32223, 3161, 3074, 2967, 2839, 2410, 1904, 1722, 1656, 1615, 1598, 1499, 1458, 1407, 1351, 1314, 1242, 1234, 1169, 1109, 1098, 1086,1059, 1032, 1003, 982, 945, 922, 863, 829, 814, 774, 756, 731, 691, 663, 580, 532, 513, 495, 480, 468, 445, 426, 407, (cm−1). Analysis calculated for C23H24Cl2N4O2.C4H4O4: C, 56.36; H, 4.90; N, 9.74; Found: C, 56.10; H, 5.06; N, 9.83
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][OH:8])[CH:4]=[N:3][CH:2]=1.[CH3:9][S:10](Cl)(=[O:12])=[O:11]>CN(C1C=CN=CC=1)C.CCN(CC)CC>[N:1]1[CH:6]=[C:5]([CH2:7][O:8][S:10]([CH3:9])(=[O:12])=[O:11])[CH:4]=[N:3][CH:2]=1
Reactant: OCc1cncnc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cncnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a mixture of pyrimidin-5-yl-methanol, DMAP and NEt3 was slowly added MsCl at 0° C. and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was extracted with water and dichloromethane. The organic phase was dried on Na2SO4, filtered and the solvent was evaporated. Silica gel column chromatography (Ethyl acetate/hexane 1:1) gave the title compound in 40% yield.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[O:35][C:36]([C:39]3[CH:44]=[CH:43][C:42]([CH2:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=3)=[N:37][N:38]=2)=[CH:30][CH:29]=1)(C(C)(C)C)(C)C.C1COCC1>C(OCC)(=O)C>[CH2:45]([C:42]1[CH:41]=[CH:40][C:39]([C:36]2[O:35][C:34]([C:31]3[CH:30]=[CH:29][C:28]([CH2:27][OH:26])=[CH:33][CH:32]=3)=[N:38][N:37]=2)=[CH:44][CH:43]=1)[CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)Cc1ccc(-c2nnc(-c3ccc(CO[Si](C)(C)C(C)(C)C)cc3)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(-c2nnc(-c3ccc(CO)cc3)o2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.5 %

Procedure:
Tetrabutylammonium fluoride (1.0 M in THF, 2.0 mL) was added to a solution of 2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)phenyl]-5-(4-isobutylphenyl)-1,3,4-oxadiazole (0.50 g, 1.18 mmol) and THF (10 mL) and stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate (100 mL), washed with water and brine, dried (Na2SO4,), filtered and concentrated in vacuo to give the title compound (0.322 g, 88% yield) as a white solid.
Reaction SMILES: Cl/[CH:2]=[CH:3]\[C:4]#[C:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N)CCC.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>[Cu]I.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.C1COCC1>[O:7]([CH2:6][C:5]#[C:4]/[CH:3]=[CH:2]\[C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cl/C=C\C#CCOc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Solvent: C1CCOC1
Product: C[Si](C)(C)C#C/C=C\C#CCOc1ccccc1
Reaction time: 7 h
Yield: 62.7 %

Procedure:
To a 1 L flask under Argon was added CuI (5.24 g, 27 mmol) and Pd(PPh3)4 (4.9 g, 4 mmol) and the catalyst covered with 500 mL of degassed THF. To this solution was added the product of step (a) (42.7 g, 220 mmol) and degassed butylamine (44 mL, 440 mmol). To this solution was added trimethylsilyl acetylene (29 g, 290 mmol) and the reaction mixture was stirred for 7 h. Air was bubbled through the solution for 15 min and the reaction mixture filtered through celite and washed with pentane. The filtrate was washed several times with water and the aqueous fractions extracted with ether. The organic fractions were combined, dried (MgSO4) and concentrated. The residue was chromatographed over silica gel (hexane) to give 35.1 g of a tan oil (62%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:6][CH:5]=1)([O-])=O.[Sn](Cl)Cl.O>C(OCC)(=O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]([NH2:15])=[N:12][O:13][N:14]=2)=[CH:8][CH:9]=1
Reactant: Nc1nonc1-c1ccc([N+](=O)[O-])cc1
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccc(-c2nonc2N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.8 %

Procedure:
4-(4-Nitrophenyl)-1,2,5-oxadiazol-3-amine (0.500 g, 2.42 mmol), tin dichloride (1.61 g, 8.49 mmol), and water (0.306 mL, 17.0 mmol) were combined in ethyl acetate (20 mL) in a round bottom flask, and the mixture was stirred at room temperature overnight. The solvent was removed and methylene chloride was added, and the mixture was washed three times with aqueous NaOH. The organic phase was dried over MgSO4, filtered, and concentrated to afford the title compound as a yellow solid (400 mg, 94%).
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5]Br.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][CH2:2][C:3]([CH2:9][F:10])([CH3:8])[C:4](=[O:7])[CH2:5][O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: CC(CF)(CF)C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(CF)(CF)C(=O)COc1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 70.9 %

Procedure:
215 g (1 mole) of 3,3-bisfluoromethyl-1-bromobutan-2-one were added dropwise to a stirred mixture of 162 g (1 mole) of 3-trifluoromethylphenol and 180 g (1.3 moles) of powdered potassium carbonate in 1,200 ml of acetone at 20° to 30° C. The mixture was stirred at 50° C. for 6 hours the inorganic salt was filtered off and the filtrate was concentrated. The residue was distilled under a high vacuum. 210 g of 3,3-bisfluoromethyl-1-(3-trifluoromethylphenoxy)-butan-2-one of boiling point 114°-18° C./0.6 mm Hg were obtained. ##STR10##
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[CH:11][CH:10]=1.C(O)(=O)C.I>O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1
Reactant: COc1ccc(-c2ccc(F)cc2C)cc1
Agent: I
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(F)ccc1-c1ccc(O)cc1

Procedure:
To a solution of 2.1 grams of 4-(2'-methyl-4'-fluorophenyl)-anisole in 50 ml. of boiling acetic acid is added 5 ml. of hydriodic acid and the boiling continued for 3 hours. Water is added and the reaction mixture cooled and the 4-(2'-methyl-4'-fluorophenyl)-phenol crystallizes. Further purification is then achieved by recrystallization of the solid from aqueous ethanol to yield 4-(2'-methyl-4'-fluorophenyl)-phenol.
Reaction SMILES: C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:21][O:22][C:23]1[N:28]2[N:29]=[C:30]([CH:32]=[N:33]O)[CH:31]=[C:27]2[C:26]([C:35]2[CH:36]([CH3:42])[CH2:37][C:38](=[O:41])[NH:39][N:40]=2)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:21][O:22][C:23]1[N:28]2[N:29]=[C:30]([C:32]#[N:33])[CH:31]=[C:27]2[C:26]([C:35]2[CH:36]([CH3:42])[CH2:37][C:38](=[O:41])[NH:39][N:40]=2)=[CH:25][CH:24]=1
Reactant: COc1ccc(C2=NNC(=O)CC2C)c2cc(C=NO)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C2=NNC(=O)CC2C)c2cc(C#N)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.8 %

Procedure:
Triethylamine (0.291 mL) and trifluoroaceticanhydride (0.116 mL) were added to a suspension of the compound of Example 344 (63.0 mg) in methylene chloride (6 mL). The mixture was stirred at room temperature for 1 hour. Subsequently, a saturated aqueous sodium bicarbonate solution was added and the mixture was stirred for 30 min. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was dried over anhydrous magnesium sulfate. Evaporation of the solvent and subsequent purification of the residue by silica gel column chromatography (NH type, methylene chloride:methanol=9:1) afforded the title compound as a pale yellow powder (31.3 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][Br:11].B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:12]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][Br:11]
Reactant: COc1ccc(C(=O)c2ccc(OCCBr)c(Br)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a stirred solution of (3-bromo-4-(2-bromoethoxy)phenyl)(4-methoxyphenyl)methanone (0.6 g, 1.0 e q) in 50 mL CH2Cl2 was added BBr3 (3.0 eq, 0.4 mL) dropwise. After addition, the mixture was stirred at rt overnight, concentrated, and purified by column chromatography with petroleum ether:EtOAc=2:1 to give the desired product (0.36 g, 62% yield). 1H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.70-7.79 (m, 3H), 6.90-7.00 (m, 3H), 4.43 (t, J=6.4 Hz, 2H), 3.72 (t, J=6.0 Hz, 2H).