Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([CH3:11])[N:7]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[CH3:23])[C:6]=2[CH:5]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:3]=1.C([Sn](CCCC)(CCCC)[C:35]1[O:36][CH:37]=[CH:38][N:39]=1)CCC>O1CCCC1.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>[CH3:11][C:8]1[N:7]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[C:14]=2[CH3:23])[C:6]2[CH:5]=[C:4]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:3]=[C:2]([C:35]3[O:36][CH:37]=[CH:38][N:39]=3)[C:10]=2[N:9]=1
Reactant: Cc1c(Cn2c(C)nc3c(Br)cc(N4CCOCC4)cc32)cccc1C(F)(F)F
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1c(Cn2c(C)nc3c(-c4ncco4)cc(N4CCOCC4)cc32)cccc1C(F)(F)F

Procedure:
A mixture of 4-bromo-2-methyl-1-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-6-(4-morpholinyl)-1H-benzimidazole (150 mg, 0.320 mmol), prepared as described in Example 63, 2-(tributylstannanyl)-1,3-oxazole (195 mg, 0.545 mmol) and Pd(Ph3P)2Cl2 (11.27 mg, 0.016 mmol) in Tetrahydrofuran (THF) (5 mL) was stirred at reflux temperature for 19 h. Conversion to the desired product is observed by LC/MS analysis, but the majority of the mixture is still SM. The reaction mixture was transferred in a microwavable vial and irradiated in a microwave reactor at 120° C. for 90 min. The reaction mixture was diluted with EtOAc and CHCl3, washed with aq sat sol NH4Cl, brine, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The residue was purified on a silica gel column (ISCO, 0-70% EtOAc in Hexanes—no product peak observed—then 0-10% MeOH in CH2Cl2) to give desired product (94.8 mg, 0.204 mmol, 63.5% yield) as a yellow powder. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.87 (s, 1H), 7.71 (d, J=2.27 Hz, 1H), 7.58 (d, J=7.83 Hz, 1H), 7.37 (s, 1H), 7.11 (t, J=7.83 Hz, 1H), 6.66 (d, J=2.27 Hz, 1H), 6.47 (d, J=7.83 Hz, 1H), 5.31 (s, 2H), 3.81-3.92 (m, 4H), 3.11-3.24 (m, 4H), 2.58 (s, 3H), 2.56 (s, 3H). MS(ES+) m/e 457.1 [M+H]+
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19].CC[O:23]CC>>[ClH:13].[C:1]([N:7]1[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12]1)(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCC(=O)CCCl
Reactant: CCCCCCN1CCNCC1
Product: CCCCCC(=O)N1CCN(CCC(=O)CCC)CC1
Product: Cl
Temperature: 120 °C

Procedure:
A mixture of 1.8 g (0.01 mole) of n-hexyl piperazine and 1.9 g (0.014 mole) of 1-chloro-3-hexanone was heated to 120° C. for 5 minutes. The reaction product was slurried with ether, filtered and crystallized from acetonitrile to yield 4.2 g of product having a melting point of 162°-164° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.[NH2:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CS(C)=O>[CH:18]([OH:22])=[O:46].[C:34]1([CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][NH:25][C:4]2[N:3]=[C:2]([NH:40][CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][O:46][CH2:45][CH2:44]3)[N:10]=[C:9]3[C:5]=2[N:6]=[CH:7][N:8]3[C@H:11]2[C@H:15]([OH:16])[C@H:14]([OH:17])[C@@H:13]([C:18]3[O:22][N:21]=[C:20]([CH2:23][CH3:24])[N:19]=3)[O:12]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCCN1CCOCC1
Reactant: CCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)n1
Solvent: CS(C)=O
Product: CCc1noc([C@H]2O[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCOCC5)nc43)[C@H](O)[C@@H]2O)n1
Product: O=CO
Temperature: 80 °C

Procedure:
A mixture of Intermediate 4 (0.034 g, 0.062 mmol), 4-(2-aminoethyl)morpholine (0.041 ml, 0.31 mmol) and DMSO (0.03 ml); in a sealed vial (e.g. Reacti-vial™) was heated at 80° C. for 28 h. Purification by Autoprep. HPLC afforded the title compound after freeze drying as a white solid (0.015 g). LC/MS system A Rt=3.67 mins, m/z=642MH+
Reaction SMILES: ClC(Cl)(Cl)C(Cl)(Cl)Cl.[F:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][NH:17][C:18]([N:20]2[CH:25]3[CH2:26][CH2:27][CH:21]2[CH2:22][CH2:23][CH2:24]3)=O)=[N:14][CH:15]=1.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:25]12[N:20]([C:18]3[N:14]4[CH:15]=[C:10]([F:9])[CH:11]=[CH:12][C:13]4=[N:16][N:17]=3)[CH:21]([CH2:27][CH2:26]1)[CH2:22][CH2:23][CH2:24]2
Reactant: O=C(NNc1ccc(F)cn1)N1C2CCCC1CC2
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Fc1ccc2nnc(N3C4CCCC3CC4)n2c1
Temperature: 60 °C
Reaction time: 3.5 h
Yield: 76.6 %

Procedure:
Hexachloroethane (296 mg, 1.25 mmol) was added portionwise over 5 min at RT to a stirred mixture of Intermediate 122b (165 mg, 0.62 mmol), triethylamine (350 μL, 2.50 mmol) and triphenylphosphine (327 mg, 1.25 mmol) in THF (10 mL). The reaction mixture was stirred for 3.5 h and then heated to 60° C. overnight. The temperature was increased to 70° C. for 5 days, then cooled and concentrated in vacuo. The residue was taken up in dioxane, and re-treated with hexachloroethane (150 mg, 0.63 mmol) and triethylamine (200 μL, 1.43 mmol) at 115° C. overnight. The mixture was cooled and concentrated in vacuo. The residue was taken up in methanol and loaded onto an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH and concentrated in vacuo to give the title compound (117 mg, 76%). LCMS (Method 3): Rt 2.88 min, m/z 247 [MH+].
Reaction SMILES: [CH2:1]([O:3][CH:4]1[O:8][C:7](=[O:9])[CH:6]=[CH:5]1)[CH3:2].[Br:10]Br>C(Cl)(Cl)(Cl)Cl>[Br:10][C:5]1[CH:4]([O:3][CH2:1][CH3:2])[O:8][C:7](=[O:9])[CH:6]=1
Reactant: CCOC1C=CC(=O)O1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC1OC(=O)C=C1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.7 %

Procedure:
This procedure may be carried out in a manner similar to that described by C. Escobar, et al., Ann. Quim. (1971), 67, 43-57.). To a solution of 5-ethoxy-5H-furan-2-one (II, R1=Et) (10.0 g, 78.0 mmol) in carbon tetrachloride (50 mL) at 0° C. is added over 0.5 h a solution of bromine (4.05 mL, 78.2 mmol) in carbon tetrachloride (25 mL). The reaction is stirred 1 h at 0° C., then 2 h at room temperature. The solvents are removed under reduced pressure and the residue was short-path distilled at pump vacuum (about 0.5 mm). The fraction collected at 100° C.-120° C. provided 4-bromo-5-ethoxy-5H-furan-2-one (13.2 g, 82% yield) as a yellow oil. 1H-NMR (500 MHz, CDCl3) δ 6.24 (s, 1H), 5.63 (s, 1H), 3.71 (m, 1H), 3.63 (m, 1H), 1.14 (t, J=7.1 Hz, 3H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:45])[C:20]4[C:21]([O:37][C:38]=3[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[N:25](COCC[Si](C)(C)C)[N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[NH2:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19](=[O:45])[C:20]4[C:21]([O:37][C:38]=3[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[C:22]3[C:26](=[CH:27][CH:28]=4)[NH:25][N:24]=[CH:23]3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5c4cnn5COCC[Si](C)(C)C)c3=O)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5[nH]ncc54)c3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.2 %

Procedure:
To a solution of (1-{-4-[4-oxo-2-phenyl-7-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-pyrano[2,3-e]indazol-3-yl]-phenyl}-cyclobutyl)-carbamic acid tert-butyl ester (67 mg, 0.13 mmol) in DCM (2.0 mL), was added TFA (500 μL, 6.7 mmol). The reaction mixture was stirred at RT for 1 hour. The solution was diluted with methanol (10 mL) and loaded onto an SCX-2 cartridge. The cartridge was washed repeatedly with methanol before elution with 2 M ammonia in methanol. The eluent was collected and concentrated in vacuo. The resulting residue was subjected to flash chromatography (SiO2, gradient 7-10% methanol in DCM) to give the title compound as a light pink solid (25 mg, 47%). 1H NMR (400 MHz, DMSO-d6): δ 8.54 (d, J=1 Hz, 1H), 8.00 (d, J=9 Hz, 1H), 7.63 (dd, J=1 and 9 Hz, 1H), 7.52-7.49 (m, 2H), 7.44-7.34 (m, 5H), 7.17-7.14 (m, 2H), 2.41-2.33 (m, 2H), 2.11-2.03 (m, 2H), 2.03-1.92 (m, 1H), 1.70-1.60 (m, 1H). LCMS (Method E): RT=3.09 min, [M+H]+=407.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[O:10])=[CH:4][CH:3]=1.Br[CH2:20][C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH2:12][CH:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:20][C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[CH2:14]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(NCC1CNCCO1)Nc1ccc(Cl)cc1
Reactant: BrCc1ccc2ccccc2c1
Product: O=C(NCC1CN(Cc2ccc3ccccc3c2)CCO1)Nc1ccc(Cl)cc1
Yield: 34.2 %

Procedure:
Example 23 was prepared in an analogous manner to Example 19 using a mixture of Intermediate 9 (0.01 g) and 2-(bromomethyl)naphthalene (0.009 g) to give the title compound (0.0052 g). LC-MS (System A): Rt 2.81 mins, Mass Spectrum m/z 410 [MH+].
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([CH3:30])[C:8]([CH:19]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]([O:22]CC)=[O:21])=[C:9]2[C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[C:31]([C:33]1[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=1)#[CH:32]>>[C:26]([O:25][CH:19]([C:8]1[C:7]([CH3:30])=[CH:6][C:5]2[C:10](=[CH:11][C:2]([C:32]#[C:31][C:33]3[N:37]([CH3:38])[CH:36]=[N:35][CH:34]=3)=[CH:3][CH:4]=2)[C:9]=1[C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[C:20]([OH:22])=[O:21])([CH3:28])([CH3:29])[CH3:27]
Reactant: C#Cc1cncn1C
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)cc2ccc(Br)cc2c1-c1ccc(Cl)cc1
Product: Cc1cc2ccc(C#Cc3cncn3C)cc2c(-c2ccc(Cl)cc2)c1C(OC(C)(C)C)C(=O)O

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-3-methyl-7-((1-methyl-1H-imidazol-5-yl)ethynyl)naphthalen-2-yl)acetic acid (81) was prepared by the method of Example 67 from ethyl 2-(7-bromo-1-(4-chlorophenyl)-3-methylnaphthalen-2-yl)-2-tert-butoxyacetate using 5-ethynyl-1-methyl-1H-imidazole. 1H-NMR: 400 MHz, (CD3OD) δ: 8.80 (br s, 1H), 7.87 (d, J=8 Hz, 1H), 7.76 (s, 1H), 7.58 (m, 5H), 7.48 (s, 1H), 7.33 (d, J=8 Hz, 1H), 5.18 (s, 1H), 3.92 (s, 3H), 2.63 (s, 3H), 0.98 (s, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C29H28ClN2O3: 487.2; found: 487.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].[CH:43]1([N:49]([CH:60]([CH3:62])[CH3:61])[CH2:50][CH2:51][NH:52][C:53](N2C=CN=C2)=[O:54])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:43]1([N:49]([CH:60]([CH3:62])[CH3:61])[CH2:50][CH2:51][NH:52][C:53]([NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@H:16]3[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]3)=[C:9]([NH:28][CH2:29][CH:30]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:8]=2)=[O:6])=[O:54])[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Reactant: CC(C)N(CCNC(=O)n1ccnc1)C1CCCCC1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCCN(C(C)C)C4CCCCC4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purine-2-carboxamide (Preparation 10) and N-{2-[cyclohexyl(isopropyl)amino]ethyl}1H-imidazole-1-carboxamide (Preparation 29) by a similar method to Example 1.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Mg:12].[CH3:13][N:14]([CH3:29])[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24](=O)[CH2:23][CH2:22][CH2:21]2.[Cl-].[NH4+]>O1CCCC1>[C:19]1([Mg:12][Br:1])[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[CH:27][CH:18]=1.[C:2]1([C:24]2[C:25]3[C:20](=[CH:19][C:18]([O:17][CH2:16][CH2:15][N:14]([CH3:29])[CH3:13])=[CH:27][CH:26]=3)[CH2:21][CH2:22][CH:23]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: [Mg]
Reactant: CN(C)CCOc1ccc2c(c1)CCCC2=O
Reactant: Brc1cccc2ccccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Br[Mg]c1cccc2ccccc12
Product: CN(C)CCOc1ccc2c(c1)CCC=C2c1cccc2ccccc12
Yield: 25.3 %

Procedure:
1-Naphthylmagnesium bromide was prepared by the addition of 1-bromonaphthalene (9.6 g, 0.046 mole) to magnesium (1 g) in tetrahydrofuran (25 ml). 6-(2-dimethylaminoethoxy)-1-tetralone (9.8 g, 0.046 mole) in tetrahydrofuran 75 ml) was added over 1/2 hour and the reaction mixture refluxed for 2 hours. After cooling, saturated ammonium chloride solution was added and the organic layer separated. Removal of the solvent gave an oil which after chromatography on alumina, eluting with ether - light petroleum (b.p. 60°-80°) gave 1-(1-naphthyl-3,4-dihydro-6(2-dimethylaminoethoxy)naphthalene (2.0 g, 15%) as a colourless oil which was converted to the hydrochloride salt m.p. 168°-170° C.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([NH:13]S(C)(=O)=O)=[C:5](I)[CH:4]=1)#[N:2].[C:19]([Si:23]([O:26][C:27]([CH3:31])([CH3:30])[C:28]#[CH:29])([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].CCN(CC)CC.O>CN(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.[Cu]I>[C:19]([Si:23]([CH3:25])([CH3:24])[O:26][C:27]([C:28]1[NH:13][C:6]2[C:5]([CH:29]=1)=[CH:4][C:3]([C:1]#[N:2])=[C:8]([C:9]([F:12])([F:11])[F:10])[CH:7]=2)([CH3:30])[CH3:31])([CH3:22])([CH3:21])[CH3:20]
Reactant: C#CC(C)(C)O[Si](C)(C)C(C)(C)C
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c(C#N)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O[Si](C)(C)C(C)(C)C)c1cc2cc(C#N)c(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
N-(4-Cyano-2-iodo-5-trifluoromethyl-phenyl)-methanesulfonamide (1.95 g, 5.0 mmol), tert-Butyl-(1,1-dimethyl-prop-2-ynyloxy)-dimethyl-silane (992 mg, 5.0 mmol), PdCl2(PPh3)2, (175 mg, 0.25 mmol), CuI (95 mg, 0.5 mmol), NEt3 (1.4 mL, 10.0 mmol), was mixed in DMF (15 mL) and stirred at room temperature for 16 hours. Water was added and the mixture was extracted twice with ethyl acetate. The organic layers were washed with 10% LiCl solution, dried over magnesium sulfate, filtered, evaporated to a brown oil. The brown oil was purified by column chromatography eluting with 1, 3, and 10% ethyl acetate/hexanes. The product was obtained as a white solid (306 mg, 16%). 1H NMR (CDCl3) δ 8.75 (s, 1H), 7.92 S, 1H), 7.67 (s, 1H), 6.27 (d, J=1.2 Hz, 1H), 1.58 (s, 6H), 0.85 (s, 9H), 0.3 (s, 6H). MS (m/z): 405 (MNa+), 381 (MH−).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9]C)[CH:4]=1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C.C1(C)C=CC=CC=1>[OH:9][C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][C:6]=1[C:14]([C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[F:11])=[O:15]
Reactant: COc1cccc(OC)c1
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(O)cc1O)c1ccccc1F
Temperature: 60 °C

Procedure:
m-dimethoxybenzene (27.6 g) and o-fluorobenzoyl chloride (31.7 g) are dissolved in 200 ml of dichloroethane and AlCl3 (28.0 g) is added portionwise. After two hours an additional 56 g of AlCl3 is added and the reaction mixture warmed at 60° C. for 1.5 hours. It is then poured into H2O and extracted with ethylacetate. Drying and evaporation gives a crystalline compound. Trituration with toluene gives 2,4-dihydroxy-2'-fluorobenzophenone, mp 109°-111° C.
Reaction SMILES: C(C1C=CC(CN([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)C)=CC=1)(C)(C)C.O(C1C=C(C)C=CC=1)C1C=CC=CC=1.[Br:42]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[O:19]([C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[CH2:12][Br:42])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(Cc1ccc(C(C)(C)C)cc1)Cc1cccc(Oc2ccccc2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: Cc1cccc(Oc2ccccc2)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc(Oc2ccccc2)c1

Procedure:
Following the process to be described below, Compound 1 was prepared. Namely, 10.16 g of m-phenoxytoluene, 9.82 g of N-bromosuccinimide and 0.15 g of benzoyl peroxide were weighed and added to 90 ml of carbon tetrachloride as a solvent. The resulting mixture was heated under reflux for 3 hours to conduct a reaction. The reaction mixture was allowed to cool down, the insoluble matter was filtered off, and the filtrate was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent: chloroform), whereby 10.9 g of 3-phenoxybenzyl bromide were obtained. In 20 ml of N,N-dimethylformamide, 2.79 g of N-(4-tert-butylbenzyl)methylamine and 1.67 g of sodium carbonate were mixed, to which a solution of 3.77 g of 3-phenoxybenzyl bromide in 25 ml of N,N-dimethylformamide was added dropwise under ice cooling. The temperature of the reaction mixture was allowed to rise to room temperature, at which a reaction was allowed to proceed for 12 hours. Chloroform and water were added to the reaction mixture to conduct liquid-liquid extraction. An organic layer was collected and then washed with water and a saturated aqueous solution of sodium chloride. The resulting solution was dried over anhydrous sodium sulfate and was then concentrated. The concentrate was purified by chromatography on a silica gel column (eluent:hexane:chloroform:ethyl acetate=9:1:0→0:10:0→0:0:100). Relevant fractions were concentrated, whereby 4.49 g of N-(4-tertiary-butylbenzyl)-N-methyl-3-phenoxybenzylamine (Compound 1) were obtained (yield: 87.8%). The following is its NMR data (CDCl3 δ ppm): 1.28(9H,s), 2.18(3H,s), 3.476(2H,s), 3.483(2H,s), 6.86-7.35(13H,m).
Reaction SMILES: [NH2:1][OH:2].CO.[C:5]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1)#[N:6]>O1CCCC1>[NH2:6][C:5](=[N:1][OH:2])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:15][CH:14]=2)=[N:11][CH:12]=1
Reactant: NO
Reactant: COC(=O)C(C)(C)COc1ccc(-c2ccc(C#N)cn2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)COc1ccc(-c2ccc(C(N)=NO)cn2)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
50% Aqueous hydroxylamine solution (40 g) was added to a methanol (100 mL) and tetrahydrofuran (100 mL) solution containing methyl 3-[4-(5-cyanopyridin-2-yl)-phenoxy]-2,2-dimethylpropanoate (6.0 g), and the mixture was stirred at 80° C. for 4 hours. After cooling the reaction mixture to room temperature, the mixture was concentrated under reduced pressure. To the obtained residue were added ethyl acetate and water, and the liquids were separated. The organic layer was separated, washed with water, and dried over anhydrous sodium sulfate. Ether was added to the solid residue obtained by concentrating the mixture under reduced pressure to pulverize the same, and the solid was collected by filtration and dried to obtain methyl 3-(4-{5-[amino(hydroxyimino)methyl]pyridin-2-yl}phenoxy)-2,2-dimethylpropanoate (5.8 g).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(N(CC)CC)C>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:29]3[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccc(C)cc2)=NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Triethylamine (3.75 g, 37.1 mmol) was added dropwise to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 12, Step A) (10.0 g, 37.1 mmol) and p-toluenesulfonyl chloride (7.07 g, 37.1 mmol) in dichloromethane (100 mL) at 0° C. Further portions of p-toluenesulfonyl chloride (0.35 g, 1.83 mmol) and triethylamine (0.19 g, 1.88 mmol) were added. The reaction mixture was then allowed to warm to room temperature and was stirred overnight. The mixture was then diluted with dichloromethane (200 mL) and washed with water (3×70 mL). The organic phase was dried and evaporated to leave the title product as an oil (13.7 g, 87% yield), which slowly formed crystals. Product recrystallized from ethyl acetate/hexanes melted at 99.5-100° C.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH3:7])(=[O:4])=[O:3].C1COCC1.C([Li])CCC.[P:18](Cl)(=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>CCCCCC>[CH2:6]([O:5][S:2]([CH2:1][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])(=[O:4])=[O:3])[CH3:7]
Reactant: CCOP(=O)(Cl)OCC
Reactant: CCOS(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOP(=O)(CS(=O)(=O)OCC)OCC
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of methanesulfonic acid, ethyl ester (11.00 mL, 0.1068 mol) in THF (200.0 mL, 2.466 mol) at −78° C. was added 2.500 M of n-butyllithium in hexane (50.00 mL) over 15 minutes and the mixture was stirred for 20 minutes. Phosphorochloridic acid, diethyl ester (10.0 mL, 0.0694 mol) was added to the mixture at −78° C. The mixture was stirred for 3.5 hours, allowing to warm to 0° C. The reaction was quenched with 5M ammonium chloride in water (100 mL) and the mixture was concentrated in vacuo to remove THF. The aqueous was extracted with EtOAc (2×150 mL) and the organics were combined and concentrated in vacuo. The product was purified by flash chromatography (0 to 100% EtOAc/Hexanes) to yield the product as an oil (9.07 g, 50%+10.4 g of a mixed fraction).