Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.N1C=CC=CC=1.O>O1CCOCC1.C([O-])(=O)C.[Cu+]>[F:11][C:12]1[CH:17]=[CH:16][C:15]([N:3]2[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]2=[O:1])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccnc1O
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: O=c1c([N+](=O)[O-])cccn1-c1ccc(F)cc1
Temperature: 80 °C
Yield: 86.8 %

Procedure:
To a solution of 2-hydroxy-3-nitropyridine (Aldrich, 3.0 mmol, 420 mg) in 1,4-dioxane (20 mL), were added 4-fluorophenyl boronic acid (Combi-block, 6.0 mmol, 840 mg), copper(I) acetate (Aldrich, 4.5 mmol, 815 mg) and pyridine (2 mL). The reaction was heated at 80° C. for 20 h. After cooling to room temperature, 30 mL of cold water was added. The solid formed was collected by filtration, washed with ammonium hydroxide and water, and dried under vacuum to give the desired product (610 mg, 87% yield) as a solid. MS(ESI+) m/z 235.30 (M+H)+.
Reaction SMILES: [C:1]12([C:7]3=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=[C:6]3[O:5][CH2:4]1)[CH2:3][CH2:2]2.CN(C)C=O.Cl[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][N:20]=1>>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([O:12][C:8]2[C:7]3[C:1]4([CH2:4][O:5][C:6]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]4)=[N:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Oc1cccc2c1C1(CC1)CO2
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a solution of spiro[1-benzofuran-3,1′-cyclopropan]-4-ol (Reference Intermediate 214, 70 mg) in dry N,N-dimethylformamide (2 ml) potassium carbonate (89 mg, 0.647 mmol) and then 2-chloro-5-nitropyridine (75 mg, 0.475 mmol) were added and the reaction mixture was stirred for 3 hours at 100° C. The reaction was quenched with brine (1 ml), diluted with water (2 ml) and extracted with ethyl acetate (3×10 ml). The organic layer was dried over sodium sulphate, filtered and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 9:1 as eluents affording the title compound as a white solid (100 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:10]O.[OH-].[K+].CI>O>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: Cc1ccc(O)cc1C
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Product: COc1ccc(C)c(C)c1
Yield: 81 %

Procedure:
To 3,4-dimethylphenol(19.3 g, 0.16 mol), methanol(150 ml) and KOH(9.65 g, 0.25 mol) were added and then refluxed for 2 hrs. Methyl iodide(36.5 g, 0.25 mol) was added thereto, refluxed for 3 hours and then followed by addition of water(150 ml). The resulting mixture was extracted with ethylacetate and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[C:18]([C:25]([F:28])([F:27])[F:26])[CH:17]=3)=[O:15])[CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:3]=1.CN(C(O[N:39]1N=NC2C=[CH:43][CH:44]=[CH:45][C:40]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.N1CC=CC1.ClCl>O1CCCC1>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C@@H:9]([NH:13][C:14](=[O:15])[C:16]3[CH:24]=[CH:23][C:19]([C:20]([N:39]4[CH2:40][CH:45]=[CH:44][CH2:43]4)=[O:22])=[C:18]([C:25]([F:26])([F:28])[F:27])[CH:17]=3)[CH2:10][O:11][CH3:12])=[N:8][C:4]=2[CH:3]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COC[C@H](NC(=O)c1ccc(C(=O)O)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: C1=CCNC1
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](NC(=O)c1ccc(C(=O)N2CC=CC2)c(C(F)(F)F)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 23 %

Procedure:
Prepared analogously to Example 1g from 4-{N-[(1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-methoxyethyl]aminocarbonyl}-2-trifluoromethylbenzoic acid, TBTU, diisopropylethylamine, and 3-pyrroline in tetrahydrofuran. Yield: 23%; C23H20ClF3N4O3 (492.88); mass spectrum: (M+H)+=493/495 (chlorine isotope) and (M−H)−=491/493 (chlorine isotope).
Reaction SMILES: O.O.O.O.O.[O-:6][Si:7]([O-:9])=[O:8].[Na+:10].[Na+].[S:12](=[O:16])(=[O:15])([OH:14])[OH:13].O=O>>[Si:7]([OH:13])([OH:9])([OH:6])[OH:8].[S:12]([O-:16])([O-:15])(=[O:14])=[O:13].[Na+:10].[Na+:10]
Reactant: O=S(=O)(O)O
Reactant: O=[Si]([O-])[O-]
Agent: O=O
Agent: [Na+]
Solvent: O
Product: O=S(=O)([O-])[O-]
Product: O[Si](O)(O)O
Reaction time: 1.5 h

Procedure:
About 15 parts by weight of granular sodium metasilicate pentahydrate are slowly added to about 8 parts by weight of concentrated sulfuric acid while agitating and keeping the temperature below 100° C. The reaction takes place under ambient pressure; oxygen is evolved and the reaction is complete in 1 to 2 hours, thereby producing a white granular silicic acid compound and sodium sulfate. The mixture is washed with water, filtered to remove the salt and water, thereby recovering the silicic acid compound. The silicic acid compound is air dried at 25° to 75° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:11]([C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][NH2:21])=[C:16]([CH3:24])[CH:15]=1)[CH:12]=[CH2:13].C(N(CC)CC)C.O>C1C=CC=CC=1>[CH2:11]([C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][NH:21][C:2]2[C:3]3[CH:10]=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[C:16]([CH3:24])[CH:15]=1)[CH:12]=[CH2:13]
Reactant: Clc1ncnc2sccc12
Reactant: C=CCc1ccc(OCCN)c(C)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: c1ccccc1
Product: C=CCc1ccc(OCCNc2ncnc3sccc23)c(C)c1
Yield: 83 %

Procedure:
3.4 g (0.02 mole) of 4-chlorothieno[2,3-d]pyrimidine, 3.8 g (0.02 mole) of 2-(4-allyl-2-methylphenoxy)ethylamine and 2 g (0.02 mole) of triethylamine were dissolved in 50 ml of benzene, and the solution was heated under reflux for 6 hours. At the end of this time, water was added to the reaction mixture, after which it was extracted with benzene. The extract was dried over anhydrous sodium sulphate and the solvent was distilled off, after which the residue was subjected to column chromatography through silica gel, eluted with a 9:1 by volume mixture of benzene and ethyl acetate, to give 5.4 g (yield 83%) of the desired Compound No. 8, in the form of pale yellow crystals melting at 97°-99° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:7]=[CH:6][NH:5][C:4]=1[C:8]([O:10][CH3:11])=[O:9].[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.N1C=CC=CC=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([N:5]2[CH:6]=[CH:7][C:3]([C:2]([F:1])([F:12])[F:13])=[C:4]2[C:8]([O:10][CH3:11])=[O:9])=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1[nH]ccc1C(F)(F)F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1c(C(F)(F)F)ccn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of the product prepared in Step B (1160 mg, 6.0 mmol, 1 eq), 4-chlorophenylboronic acid (2.9 g, 18.0 mmol, 1 eq), Cu(OAc)2 (2.18 g, 12.0 mmol, 2 eq), 4A molecular sieves (3 g), pyridine (1.94 mL, 4.0 mmol, 4 eq) in DCM (40 mL) was stirred at room temperature for 2 days. The resulting suspension was filtered through CELITE, washed with DCM, and concentrated. The resulting residue was dry packed and purified by flash chromatography (120 g column) eluting with 4 to 8% EtOAc/heptane to yield methyl 1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrole-2-carboxylate.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.S[C:7]1[S:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=2[N:11]=1>>[Cl:4][C:7]1[S:8][C:9]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:10]=2[N:11]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Product: FC(F)(F)c1ccc2sc(Cl)nc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Sulfuryl chloride (9.09 g, 67.33 mmol) was added with stirring to 2-mercapto-5-(trifluoromethyl)benzothiazole (2.64 g, 11.22 mmol) over a period of 5 minutes. The reaction mixture was then allowed to stand for approximately 1 h. Ice water was added to the reaction mixture with stirring to decompose the excess of sulfuryl chloride, and the product was then extracted with ethyl acetate. The organic layer was washed with water (3×) and brine, dried over anhydrous Na2SO4 and concentrated. The resulting solid was dissolved in EtOAc and filtered though a short silica-gel column, eluting with EtOAc, to give 2-chloro-5-(trifluoromethyl)benzothiazole (2.50 g, 94%). LC-MS m/z 238.0 (MH+), ret. time 2.55 min; 1H NMR (400 MHz, DMSO-d6) δ 7.81 (d, 1H), 8.38 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl[C:31]1[S:32][C:33]2[CH:39]=[C:38]([Cl:40])[CH:37]=[CH:36][C:34]=2[N:35]=1.S1C2C=CC=CC=2N=C1NC1C=CC(C2C=CC(C(=O)CC(C)(C)C(O)=O)=CC=2)=CC=1>>[Cl:40][C:38]1[CH:37]=[CH:36][C:34]2[N:35]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14](=[O:29])[CH2:15][CH:16]([CH2:21][CH2:22][C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=5)[C:17]([OH:19])=[O:18])=[CH:10][CH:9]=4)=[CH:6][CH:7]=3)[S:32][C:33]=2[CH:39]=1
Reactant: Clc1ccc2nc(Cl)sc2c1
Reactant: COC(=O)C(CCc1ccccc1)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: CC(C)(CC(=O)c1ccc(-c2ccc(Nc3nc4ccccc4s3)cc2)cc1)C(=O)O
Product: O=C(CC(CCc1ccccc1)C(=O)O)c1ccc(-c2ccc(Nc3nc4ccc(Cl)cc4s3)cc2)cc1
Yield: 24.7 %

Procedure:
This compound was prepared from methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-4-oxo-2-(2-phenylethyl)butanoate (78 mg, 0.20 mmol), 2,6-dichloro-1,3-benzothiazole (61.6 mg, 0.30 mmol) in a similar manner to the method described for 4-[4′-(1,3-benzothiazol-2-ylamino)-1,1′-biphenyl-4-yl]-2,2-dimethyl-4-oxobutanoic acid, providing 26.7 mg (25%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (br s, 1H), 7.75-8.05 (m, 9H), 7.60 (d, 1H), 7.10-7.40 (m, 6H), 3.50 (q, 1H), 3.10 (m, 1H), 2.85 (m, 1H), 2.65 (m, 2H), 1.80 (m, 2H). LC-MS m/z 541.3 (MH+), ret. time 4.07 min.
Reaction SMILES: C[Si]([C:5]#[CH:6])(C)C.C(N(CC)CC)C.I[C:15]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[CH:22]=2)[N:17]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:16]=1.[CH2:37]([N:44]=[N+:45]=[N-:46])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C1COCC1.CO.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>[CH2:37]([N:44]1[CH:6]=[C:5]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=4)[CH:22]=3)[N:17]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:16]=2)[N:46]=[N:45]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cn1cc(-c2cnc3c(c2)c(I)cn3C(=O)OC(C)(C)C)cn1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3c(c2)c(-c2cn(Cc4ccccc4)nn2)cn3C(=O)OC(C)(C)C)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3.4 0.09 ml (0.63 mmol) of trimethylsilylacetylene and 0.12 ml (0.84 mmol) of triethylamine are added successively to a suspension, kept under argon, of 6 mg (0.009 mmol) of bis(triphenylphosphine)palladium dichloride, 3 mg (0.016 mmol) of copper(I) iodide and 178 mg (0.42 mmol) of tert-butyl 3-iodo-5-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylate in 2 ml of THF, and the mixture is stirred at room temperature for one hour under argon. Then, for the removal of excess trimethylsilylacetylene, argon is passed through the reaction mixture for 5 minutes. 0.45 ml (0.45 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF are subsequently added, and the reaction mixture is stirred at room temperature for 30 minutes. A solution of 58 mg (0.42 mmol) of benzyl azide in 2 ml of methanol is then added, and the reaction mixture is stirred at room temperature for 48 hours. The reaction mixture is adsorbed onto kieselguhr and chromatographed on a silica-gel column with petroleum ether/ethyl acetate as eluent, giving tert-butyl 3-(1-benzyl-1H-1,2,3-triazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2,3-b]pyridine-1-carboxylate as colourless crystals; ESI 456.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([NH:36][NH2:37])=[CH:28][CH:27]=1>>[Cl:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([N:36]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:37]2)=[CH:28][CH:27]=1
Reactant: NNc1ccc(Cl)c2ccccc12
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(C(F)(F)F)cc2)ccc1=O
Product: O=c1ccn(-c2ccc(C(F)(F)F)cc2)nc1-c1ccnn1-c1ccc(Cl)c2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethyl-phenyl)-1H-pyridazin-4-one (A-22) and (4-chloro-naphthalen-1-yl)-hydrazine according to the method described for example 1. MS: M=467.2 (M+H)+
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[C:9]([O:22][CH3:23])=[CH:10][C:11]2[O:16][C:15](=[O:17])[C:14]3[CH2:18][CH2:19][CH2:20][C:13]=3[C:12]=2[CH:21]=1.[C:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(=O)/C=C/C([O-])=O>CC(OC)(C)C.C(O)(C)C>[CH3:23][O:22][C:9]1[C:8]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:33]2[CH2:34][CH2:35][CH:30]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:31][CH2:32]2)=[CH:21][C:12]2[C:13]3[CH2:20][CH2:19][CH2:18][C:14]=3[C:15](=[O:17])[O:16][C:11]=2[CH:10]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCCBr)CCC3
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: COc1cc2oc(=O)c3c(c2cc1OCCCCCN1CCC(c2ccccc2)CC1)CCC3
Yield: 37 %

Procedure:
Method B (20 h at 80° C.); starting materials: 8-(5-bromopentyloxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 85) and 4-phenylpiperidine; yield 37%; fusion point 103°-105° C. (from isopropanol and TBME). Fumarate: method E; yield 94%; fusion point 176°-178° C. (from isopropanol and TBME).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].Cl.[NH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:22]([F:25])([F:24])[F:23])=[O:19])=[CH:12][C:11]=1[C:36]([F:39])([F:38])[F:37].CCN(C(C)C)C(C)C>ClCCl>[C:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][CH:21]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[C:22]([F:23])([F:24])[F:25])=[O:19])=[CH:12][C:11]=1[C:36]([F:37])([F:38])[F:39])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: CC(C)C(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)C(=O)NCc1ccc(/C=C/C(=O)NC(c2cccc(C(F)(F)F)c2)C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
30 mg (1.2 eq, 0.28 mmol) of isobutyryl chloride were dissolved in 1 ml of dichloromethane. To this were added 113 mg (1.0 eq, 0.24 mmol) of the hydrochloride of (2E)-3-[4-(aminomethyl)-3-(trifluoromethyl)phenyl]-N-{2,2,2-trifluoro-1-[3-(trifluoromethyl)phenyl]ethyl}acrylamide from Stage 5 and 93 mg (3 eq) of Hünig's base. The mixture was stirred at room temperature for 16 h and then concentrated. The crude product was purified by means of preparative HPLC (Phenomenex Gemini C18 5 μm; 125A; Aqua 50×21.2 mm; gradient: 0-1.5 min 78% water, 20% acetonitrile, 1.5-10.0 min linear gradient to 18% water, 80% acetonitrile, 10.0-14.00 min 18% water, 20% acetonitrile; modifier: 10% NH4HCO3 added at 2 ml/min). This gives 57 mg (44%) of (2E)-3-{4-[(isobutyrylamino)methyl]-3-(trifluoromethyl)phenyl}-N-{2,2,2-trifluoro-1-[3-(trifluoro-methyl)phenyl]ethyl}acrylamide.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C([O-])([O-])=O.[Na+].[Na+].[O:16](S(C(F)(F)F)(=O)=O)[S:17]([C:20]([F:23])([F:22])[F:21])(=O)=[O:18]>C(Cl)Cl>[F:21][C:20]([F:23])([F:22])[S:17]([O:8][C:6]1[CH2:7][CH:2]([CH3:1])[CH2:3][C:4](=[O:9])[CH:5]=1)(=[O:18])=[O:16]
Reactant: CC1CC(=O)CC(=O)C1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(=O)C=C(OS(=O)(=O)C(F)(F)F)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 5-methylcyclohexane-1,3-dione (1 equiv) in DCM (0.4M) was added Na2CO3 (1.0 equiv.) and cooled to 0° C. Added Tf2O (1.0 equiv.) in DCM (5M) dropwise over 1 hr at 0° C. under a nitrogen atmosphere. Upon addition, the reaction was stirred for 2 hr at room temperature (dark red solution). The solution was filtered and to the filtrate was added saturated NaHCO3 (carefully), then extracted the organics, dried with brine, then Na2SO4, and concentrated. The crude was purified via SiO2 column chromatography eluting with DCM and hexanes (1:1) or alternatively via a neutral alumina plug eluting with DCM to afford 5-methyl-3-oxocyclohex-1-enyl trifluoromethanesulfonate in 30% or 67% yield respectively. The triflate decomposes upon storage and should be used immediately for the next reaction. LC/MS=259.1/300.1 (M+H and M+CH3CN); Rt=0.94 min, LC=3.84 min.
Reaction SMILES: [H-].[Na+].O[CH2:4][CH:5]([CH2:37][OH:38])[CH2:6][CH2:7][C:8]1([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[C:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)=[O:24])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:39]I.[C:41](=[O:44])([O-])O.[Na+]>CN(C)C=O>[CH3:39][O:38][CH2:37][CH:5]([CH2:4][O:44][CH3:41])[CH2:6][CH2:7][C:8]1([CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([N:22]([C:30]3[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][N:31]=3)[C:23]([C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)=[O:24])[CH2:18][CH2:17]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: Cc1ccc(N(C(=O)c2ccco2)C2CCN(CCC3(CCC(CO)CO)CCCCC3)CC2)nc1
Reactant: O=C([O-])O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC(CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1)COC
Reaction time: 0.67 h

Procedure:
After adding sodium hydride (60% dispersion in mineral oil) (179 mg, 4.47 mmol) to a solution of N-[1-[2-[1-(4-hydroxy-3-hydroxymethylbutyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (1.00 g, 2.01 mmol) in N,N-dimethylformamide (3 mL) while cooling on ice, the mixture was stirred for 40 minutes. Next, methyl iodide (0.15 mL, 2.41 mmol) was added, stirring was continued for 1 hour, and saturated aqueous sodium hydrogencarbonate (10 mL) was added. Extraction was performed with ethyl acetate, and the extract was washed with saturated aqueous sodium chloride (10 mL) and then dried over anhydrous magnesium sulfate. The residue obtained after filtering and concentration under reduced pressure was purified by silica gel column chromatography (150 g NH silica Chromatorex DM2035, hexane:ethyl acetate=1:1-chloroform:methanol=8:2) to obtain the title compound (100 mg) and a furancarboxylic acid ester of N-[1-[2-[1-(4-methoxy-3-hydroxymethylbutyl)cyclohexyl]ethyl]piperidin-4-yl]-N-(5-methylpyridin-2-yl)-2-furancarboxamide (91 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:5]([O:28][CH3:29])[C:4]=1B(O)O.[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53](Br)=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:47])[CH3:34].C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH2:33]([O:35][C:36](=[O:57])[C@H:37]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:4]2[C:3]([O:2][CH3:1])=[CH:8][C:7]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:25])[CH3:26])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:6][C:5]=2[O:28][CH3:29])=[CH:52][CH:51]=1)[NH:38][C:39](=[O:48])[C:40]1[C:41]([Cl:47])=[CH:42][CH:43]=[CH:44][C:45]=1[Cl:46])[CH3:34]
Reactant: CCOC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: COc1cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccc(-c2c(OC)cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Yield: 97.9 %

Procedure:
A mixture of 2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]benzeneboronic acid (5.2 g), N-(2,6-dichlorobenzoyl)-4-bromo-L-phenylalanine ethyl ester (1.71 g), Pd(PPh3)4 (0.44 g) and K2CO3 (1.59 g) in DME/H2O (20 mL/0.5 mL) was heated at 80° C. for 24 h under N2. The mixture was worked up and purified in a similar procedure as described in Example 8-3) to yield 2.9 g of N-(2,6-dichlorobenzoyl)-4-[2,6-dimethoxy-4-[(t-butyldiphenylsilyloxy)methyl]phenyl]-L-phenylalanine ethyl ester. ESMS: m/z 770 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][CH3:13])[N:9]=[C:8]([C:14]([NH2:16])=O)[CH:7]=1.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][CH2:12][CH3:13])[N:9]=[C:8]([C:14]#[N:16])[CH:7]=1
Reactant: CCCn1nc(C(N)=O)cc1CCCCCl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1nc(C#N)cc1CCCCCl
Yield: 18139.9 %

Procedure:
5-(4-Chlorobutyl)-1-propyl-1H-pyrazole-3-carboxamide (30.95 g, 0.127 mmol) in toluene (250 mL) was treated with phosphorous oxychloride (24.86 mL, 0.267 mol). The solution was heated at reflux for 40 minutes. The reaction was worked-up as described in Part D of Examples 37-39, with the exception that chloroform was used in place of methyl tert-butyl ether, to yield 5.20 g of 5-(4-chlorobutyl)-1-propyl-1H-pyrazole-3-carbonitrile as an oil. 1H-NMR (300 MHz, CDCl3) δ 6.43 (s, 1H), 4.04 (t, J=7.3 Hz, 2H), 3.62-3.53 (m, 2H), 2.70-2.58 (m, 2H), 1.94-1.76 (m, 6H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][CH3:9].[Mg].II.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH:25]=[O:26]>O1CCCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH3:9])=[C:2]([CH:25]([C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[OH:26])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1Br
Reactant: O=Cc1ccco1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C(O)c1ccco1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Approximately 10 ml of a solution of 3-bromo-4′-chloro-4-ethylbiphenyl (40.0 g, 135.3 mmol) in tetrahydrofuran (200 ml) is added to magnesium turnings in a dry flask, followed by a crystal of iodine. The mixture is allowed to stand without stirring for 30 minutes, then stirred once and warmed until the orange coloured mixture becomes colourless. The remainder of the 3-bromo-4′-chloro-4-ethylbiphenyl solution is added dropwise over 30 minutes with external heating applied as necessary to maintain a gentle reflux. Once the addition is complete, the mixture is heated to reflux for 2-3 hours, until only trace residues of magnesium remain. The mixture is cooled to room temperature, and then cooled further in an ice-bath. A solution of 2-furaldehyde (13.05 g, 135.8 mmol) in tetrahydrofuran (80 ml) is added dropwise over 35 minutes, and the mixture is stirred at room temperature overnight.