Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][N:33]3COCC[Si](C)(C)C)=[CH:29][CH:28]=2)[CH:23]=[C:24]([F:26])[CH:25]=1.C(OCC)(=O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C:27]2[CH:35]=[C:34]3[C:30]([C:31]([NH:44][C:45](=[O:49])[CH2:46][CH2:47][CH3:48])=[N:32][NH:33]3)=[CH:29][CH:28]=2)[CH:23]=[C:24]([F:26])[CH:25]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3cc(F)cc(F)c3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3cc(F)cc(F)c3)ccc12
Temperature: 66 °C
Yield: 43.7 %

Procedure:
14 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 1.1 g of N-[6-(3,5-difluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran. The reaction medium is heated at about 66° C. for 18 hours. The heating is then stopped and 100 cm3 of ethyl acetate are added. This mixture is washed with 2×50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered through a sinter funnel and evaporated under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with cyclohexane/ethyl acetate (60/40 by volume) and collecting 35 cm3 fractions. The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 2×5 cm3 of diisopropyl ether. This mixture is filtered through a sinter funnel and dried under reduced pressure (90 Pa; 50° C.) to give 340 mg of N-[6-(3,5-difluorophenyl)-1H-indazol-3-yl]butanamide in the form of a white solid melting at 260° C.
Reaction SMILES: [Cl:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:3]=1[C:4](=[O:5])[CH3:15]
Reactant: CON(C)C(=O)c1cccc(F)c1Cl
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)c1cccc(F)c1Cl
Temperature: 0 °C
Yield: 95 %

Procedure:
To a 2L flask was added 2-chloro-3-fluoro-N-methoxy-N-methylbenzamide (41.49 g, 191 mmol) and tetrahydrofuran (800 mL). The solution was cooled to 0° C., then methylmagnesium chloride, 3.0M solution in THF (254 mL, 763 mmol) was added dropwise through addition funnel. The mixture was gradually warmed to 5° C. The reaction was quenched with 5N HCl (190 mL) until it is acidic and extracted with EtOAc twice. The organic solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude was purified by flash chromatography on silica gel (330 g, 0-50% EtOAc/hexane in 20 min) to give 1-(2-chloro-3-fluorophenyl)ethanone as a colorless oil (31.3 g, 95% yield). MS m/z=173 [M+H]+. Calculated for C8H6ClFO: 172.6.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[C@@H:20]2[O:25][C:24](=[O:26])[CH2:23][C@@H:22]([OH:27])[CH2:21]2)=[CH:4][CH:3]=1.[OH-:28].[Na+:29]>C(O)C>[Na+:29].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]([CH3:17])([CH3:16])[C:9]=2/[CH:18]=[CH:19]/[CH:20]([OH:28])[CH2:21][CH:22]([OH:27])[CH2:23][C:24]([O-:25])=[O:26])=[CH:6][CH:7]=1
Reactant: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/[C@H]2C[C@H](O)CC(=O)O2)C(C)(C)C1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)CC(c2ccc(F)cc2)=C(/C=C/C(O)CC(O)CC(=O)[O-])C(C)(C)C1
Reaction time: 0.5 h

Procedure:
To a solution of 1.17 g (3.14 mmoles) of the lactone prepared in Step 11, and 21 ml of ethanol was added 3.14 ml of 1N NaOH (3.14 mmoles). After stirring for 30 minutes, the ethanol was removed in vacuo. The residue was redissolved in 50 ml of HPLC grade H2O and extracted twice with hexane. The water layer was freeze-dried to yield a white powder. M.P. 160°-190° C. (dec).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1.[C:25](O)(=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[NH:5][C:6](=[O:18])[CH:7]([CH3:17])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1
Reactant: CCCCCC(=O)O
Reactant: COC(=O)[C@H](CCCCN)NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1
Product: CCCCCC(=O)NCCCC[C@H](NC(=O)C(C)Nc1ccc(Cl)c(Cl)c1)C(=O)OC

Procedure:
Following General Procedure D and using N-[N-(3,4-dichlorophenyl)-D,L-alanyl]-L-lysine methyl ester (from Example 21 above) and hexanoic acid (Aldrich), the title compound was prepared. The reaction was monitored by tlc (Rf=0.38 in 60% CH2CH2/10% hexanes/27% EtOAc/3% MeOH) and purification was by flash chromatography using 60% CH2CH2/10% hexanes/ 27% EtOAc/3% MeOH as the eluent.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[Mg].[CH3:10][S:11][C:12]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=3)[C:15](=[O:27])[C:14]=2[CH:13]=1>O1CCCC1>[CH3:10][S:11][C:12]1[CH:25]=[CH:24][C:23]2[S:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:26])[CH:20]=3)[C:15]([CH:2]3[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]3)([OH:27])[C:14]=2[CH:13]=1
Reactant: CSc1ccc2sc3cc(F)ccc3c(=O)c2c1
Reactant: CN1CCC(Cl)CC1
Agent: [Mg]
Solvent: C1CCOC1
Product: CSc1ccc2c(c1)C(O)(C1CCN(C)CC1)c1ccc(F)cc1S2
Yield: 60.1 %

Procedure:
To a Grignard-solution prepared from 130 grams of 4-chloro-1-methylpiperidine and 24 grams of magnesium turnings in 500 milliliters of dry tetrahydrofuran was added 174 grams of 2-methylthio-6-fluoro-thioxanthene-9-one in portions while stirring and cooling in an ice-salt mixture. The reaction temperature was kept below 10 degrees Centigrade. The cooling bath was then removed and the reaction mixture was stirred at 35-40 degrees Centigrade for 1.5 hours. The reaction mixture was then poured into a mixture of ice, water and ammonium chloride. The crystalline precipitate which was obtained upon cooling was sucked off, washed with water and dissolved in 10% aqueous acetic acid. The solution was treated with charcoal, extracted three times with 100 milliliters of ether and then made alkaline with 10 N sodium hydroxide solution. After cooling the precipitated base was sucked off, washed with water, suspended in 100 milliliters of acetone, filtered, again suspended in 100 milliliters of acetone, and then filtered and dried to yield 142 grams of 2-methylthio-6-fluoro-9-(1-methyl-4-piperidyl)-thioxanthen-9-ol which melted at 180-189 degrees Centigrade. The analytically pure compound melts at 192-195 degrees Centigrade after recrystallization from diethylether.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O:24]=[C:25]1[NH:29][C@H:28]([CH2:30][O:31]C(=O)C2C=CC=CC=2)[CH2:27][O:26]1>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:29]4[C@H:28]([CH2:30][OH:31])[CH2:27][O:26][C:25]4=[O:24])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1N[C@H](COC(=O)c2ccccc2)CO1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Yield: 48.9 %

Procedure:
By reaction and treatment in the same manner as in Example 19 and using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (2.1 g) described in Preparation Example 77 and benzoic acid (R)-2-oxooxazolidin-4-ylmethyl ester (1.3 g), the title compound (1 g) was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[Cl:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]=3[C:13](=[O:33])[C:12]=2[C:11](F)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:7][C:8]1[C:21]2[C:20](=[O:22])[C:19]3[CH:18]=[N:17][CH:16]=[C:15]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[C:14]=3[C:13](=[O:33])[C:12]=2[C:11]([NH:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])=[CH:10][CH:9]=1
Reactant: CN(C)CCN
Reactant: COc1ccc(COc2cncc3c2C(=O)c2c(F)ccc(Cl)c2C3=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2cncc3c2C(=O)c2c(NCCN(C)C)ccc(Cl)c2C3=O)cc1
Reaction time: 3 h

Procedure:
A pyridine solution (0.4 mL) of N, N-dimethylethylenediamine (0.049 g) is added to 9-chloro-6-fluoro-4-(p-methoxybenzyloxy)benzo[g ]isoquinoline-5,10-dione of Preparative Example 29 (0.011 g) and the resultant solution is stirred under a nitrogen atmosphere for 1.75 h at room temperature. The excess amine and pyridine are removed under a slow stream of nitrogen. The residue is placed under vacuun for 3 h and purified by silica gel column chromathography commencing with 1% to 2% methanol in dichloromethane. The removal of the eluents yields 9-chloro-6-[(2-dimethylaminoethyl)amino]-4-(p-methoxybenzyloxy)benzo[g]isoquinoline-5,10-dione as a purple solid (10 mg).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[F:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]([C:17]3[N:18]=[CH:19][N:20]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[CH:21]=3)=[C:15]([CH3:31])[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1>>[CH:1]1([NH:4][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][CH:30]=[C:22]([N:20]3[CH:21]=[C:17]([C:16]4[C:12]([C:8]5[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[CH:7]=5)=[N:13][O:14][C:15]=4[CH3:31])[N:18]=[CH:19]3)[CH:23]=2)[CH2:3][CH2:2]1
Reactant: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)O)c2)cn1
Reactant: NC1CC1
Product: Cc1onc(-c2cccc(F)c2)c1-c1cn(-c2cccc(C(=O)NC3CC3)c2)cn1
Yield: 38 %

Procedure:
As described for Example 71c, cyclopropylamine was converted, using 3-{4-[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid (100 mg, 0.28 mmol) instead of 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid, to the title compound (42 mg, 38%) which was obtained as an off-white solid. MS: m/e=403.0 [M+H]+.
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[N:22]1([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: ClCCCN1CCCCC1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCN3CCCCC3)cc2c1
Yield: 29.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 1-(3-chloropropyl)piperidine (121 mg, 0.75 mmol) were converted to the title compound (78 mg, 30%). MS(ESI+) m/z 336.1 (M+H)+.
Reaction SMILES: C1O[CH:4]([C:5]2[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=2[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:3]C1.Cl>C1COCC1.CO>[CH2:16]([O:15][C:6]1[CH:7]=[CH:8][C:9]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:10][C:5]=1[CH:4]=[O:3])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C2OCCO2)c1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C=O)c1
Reaction time: 4 h
Yield: 96.6 %

Procedure:
A solution of 2-benzyloxy-5-methylsulphonylbenzaldehyde ethylene acetal (28.6 g) in THF (100 ml) and MeOH (100 ml) containing 2N HCl (50 ml) was stirred for 4 hours. The reaction mixture was concentrated to half its volume and water (100 ml) was added. The solid product was filtered and dried to give 2-benzyloxy-5-methylsulphonylbenzaldehyde yield 24 g m.p. 129° C.
Reaction SMILES: [C:1]1([CH2:7][C@H:8]([OH:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.Cl>N1C=CC=CC=1>[C:1]1([CH2:7][C@H:8]([O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@@H](O)Cc1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H](C)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
(2R)-1-Phenyl-2-propanol (0.5 ml, 3.65 mmol) was added dropwise to a solution of p-toluenesulfonyl chloride (0.73 g, 3.83 mmol) in pyridine) (3 ml) at 0° C. The mixture was stirred at 0° C. under nitrogen for 30 minutes then at room temperature overnight. The reaction mixture was poured into 2M hydrochloric acid (75 ml) and extracted with diethyl ether (2×50 ml). The extracts were washed with 2M hydrochloric acid (50 ml), saturated sodium hydrogen carbonate (50 ml) and brine (50 ml), combined, dried (MgSO4) and concentrated in vacuo to give the title compound as a white solid (0.95 g, 90%); δH (250MHz, CDCl3) 1.30 (3H, d, J 6.2Hz, CHCH3), 2.42 (3H, s, ArCH3), 2.77 (1H, dd, J 13.8, 6.6Hz, CH(OTs)CHAHBPh), 2.92 (1H, dd, J 13.8, 6.6Hz, CH(OTs)CHAHBPh), 4.74 (1H, m, CHOTs), 7.03 (2H, m, ArH), 7.20 (5H, m, ArH), 7.62 (1H, m. ArH).
Reaction SMILES: [OH:1][C:2]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][C:5]([CH:6]=[N:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].[H][H]>CO.Cl.[Pd]>[OH:1][C:2]1[C:14]([C:15]([CH3:17])([CH3:16])[CH3:18])=[CH:13][C:5]([CH2:6][NH:7][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(C=Nn2ccnc2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(CNn2ccnc2)cc(C(C)(C)C)c1O

Procedure:
28.7 g of 1-(4-hydroxy-3,5-di-tert.-butylbenzylideneamino)imidazole are dissolved in 500 ml of methanol, whereupon 96 ml of 1N hydrochloric acid and 3 g of palladium/carbon are added and the mixture is hydrogenated at normal pressure and room temperature. After 2.2 l of hydrogen have been taken up, the catalyst is removed by filtration and the filtrate is evaporated. Eight hundred (800) ml of methylene chloride and 300 ml of water are added to the residue. The mixture is neutralized (pH=7) with saturated sodium bicarbonate solution while agitating. Then, the methylene chloride phase is separated and the aqueous phase is extracted twice with 100 ml of methylene chloride each time. The methylene chloride phases are combined, dried and evaporated. The residue is recrystallized from ethanol/water (3:1), and there is obtained 1-(4-hydroxy-3,5di-tert.-butylbenzylamino)imidazole of m.p. 178°-180°.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:11]([C:21](O)=[O:22])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][C:26](=[O:38])[C:27]1[CH:36]=[C:35]([NH2:37])[CH:34]=[C:29]([C:30]([O:32][CH3:33])=[O:31])[CH:28]=1>>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[C:35]([NH:37][C:21]([C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]=2[CH2:13][CH:14]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:22])[CH:36]=[C:27]([C:26]([O:25][CH3:24])=[O:38])[CH:28]=1
Reactant: O=C(O)c1ncn(Cc2ccccc2)c1CC1CCCCCC1
Reactant: COC(=O)c1cc(N)cc(C(=O)OC)c1
Product: COC(=O)c1cc(NC(=O)c2ncn(Cc3ccccc3)c2CC2CCCCCC2)cc(C(=O)OC)c1
Yield: 20 %

Procedure:
The product of step b above (310 mg, 1.00 mmol) was reacted with 5-amino-isophthalic acid dimethyl ester (210 mg, 1.00 mmol) using essentially the same procedure as in Example 20, step d. The crude product was purified by flash column chromatography (silica, DCM/ethyl acetate 92:8) to afford colourless foam (110 mg, 20%). 1H NMR (300 MHz,CDCl3) 9.36 (1H, s), 8.53 (2H, s), 8.40 (1H, s), 7.35 (4H, m), 7.08 (2H, m), 5.12 (2H, s), 3.94 (6H, s), 1.90-1.22 (13H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][N:12]=1.C([O-])(=O)C.[K+]>CCO.O>[F:10][C:11]1[C:16]([C:2]2[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH2:9])[N:3]=2)=[CH:15][C:14]([O:20][CH3:21])=[CH:13][N:12]=1
Reactant: COc1cnc(F)c(B(O)O)c1
Reactant: Cc1nc(N)nc(Cl)n1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1cnc(F)c(-c2nc(C)nc(N)n2)c1
Temperature: 100 °C

Procedure:
To a 20 mL microwave reaction tube was added 4-chloro-6-methyl-1,3,5-triazin-2-amine (Example 9, 1.02 g, 7.05 mmol), 2-fluoro-5-methoxypyridin-3-ylboronic acid (1.67 g, 9.77 mmol), Am-Phos (Aldrich, 0.255 g, 0.360 mmol) and potassium acetate (Aldrich, 2.11 g, 21.5 mmol) in EtOH (10 mL) and water (1 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 20 min. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 mL). Layers were separated and insoluble material was collected (precipitate 1). The aqueous phase was further extracted with 10% isopropanol in chloroform (3×100 mL). Each organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. Upon addition of DCM to the crude product, precipitate came out and the solid was collected via filtration. The first precipitate (precipitate 1) and the solid from extraction were all desired product (1.17 g, 70.3%). 1H NMR (400 MHz,CDCl3) δ ppm 8.08 (dd, J=7.53, 3.23 Hz, 1H) 7.97 (dd, J=3.03, 1.86 Hz, 1H) 5.47 (br. s., 2H) 3.92 (s, 3H) 2.54 (s, 3H). m/z (ESI, positive ion): 236.0 (M+H)+.
Reaction SMILES: [C:1]([CH:3]1[CH2:12][CH2:11][C:6]2([O:10]CCO2)[CH2:5][CH2:4]1)#[CH:2].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17](I)[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.C(N(CC)CC)C>C(#N)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>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([C:2]#[C:1][CH:3]2[CH2:4][CH2:5][C:6](=[O:10])[CH2:11][CH2:12]2)[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: C#CC1CCC2(CC1)OCCO2
Reactant: FC(F)(F)c1cc(I)cc(C(F)(F)F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CCC(C#Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3.9 grams (0.022 mole) of 8-ethynyl-1,4-dioxaspiro[4.5]decane, 10.5 grams (0.031 mole) of 3,5-di(trifluoromethyl)phenyl iodide (prepared in Step A of this Example), 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper(I) iodide in 100 mL of acetonitrile is stirred at ambient temperature for about 18 hours. After this time the reaction mixture is concentrated under reduced pressure to a residue. The residue is then stirred for about 2 hours with 150 mL of aqueous 1N hydrochloric acid. After this time the mixture is extracted with three 100 mL portions of ethyl acetate. The combined extracts are washed with an aqueous solution of 10% lithium chloride. The organic layer is dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure, yielding 4-[3,5-di(trifluoromethyl)phenylethynyl]cyclohexanone.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:21]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]([CH2:5][C:6]2[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=2)[CH:1]2[CH2:2][CH2:3]2)=[CH:31][CH:32]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(=O)c1cccc(CNC2CC2)c1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CN(Cc2ccc(C(C)(C)C)cc2)C2CC2)c1
Temperature: 25 °C
Yield: 39.5 %

Procedure:
3′-(N-cyclopropylaminomethyl)acetophenone (0.30 g; 1.59 mmol) and potassium carbonate (0.31 g; 2.27 mmol) were added to N,N-dimethylformamide (15 ml). While the mixture was stirred at room temperature, 4-tert-butylbenzyl bromide (0.29 g; 1.51 mmol) in N,N-dimethylformamide (5 ml) was added dropwise. The mixture was stirred for 1 hour at room temperature, and the reaction was stopped by pouring the mixture into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=15:1), to thereby yield 0.20 g of the target compound as colorless transparent oily matter (yield: 39.5%).
Reaction SMILES: [ClH:1].[OH:2][C@H:3]([CH3:22])[C@H:4]([NH:14]C(=O)OC(C)(C)C)[C:5]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[C:7]([F:13])[CH:6]=1.CCCCCC>O1CCOCC1>[ClH:1].[NH2:14][C@H:4]([C:5]1[CH:6]=[C:7]([F:13])[C:8]([F:12])=[C:9]([F:11])[CH:10]=1)[C@H:3]([OH:2])[CH3:22]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCCC
Product: C[C@@H](O)[C@H](N)c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 4 N hydrogen chloride in dioxane (10 mL) was added to a solution of tert-butyl [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]carbamate (2.85 g) in dioxane (10 mL) at room temperature, and the reaction solution was stirred at room temperature for five hours. Hexane (80 mL) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for 20 minutes. The resulting solid was separated by filtration to obtain (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propane-2-ol hydrochloride (2.16 g). DIEA (1.59 mL), WSC (880 mg), and HOBT (620 mg) were added to a solution of (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid trifluoroacetate (1.00 g) and (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propan-2-ol hydrochloride (664 mg) in DMF (25 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The resulting solid was washed with heptane to obtain (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]amide (1.10 g). (E)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}valeric acid [(1R,2R)-2-hydroxy-1-(3,4,5-trifluorophenyl)propyl]amide (1.10 g) was dissolved in DMF (25 mL). 60% sodium hydride (104 mg) was added to the reaction solution at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system), solidified with ethyl acetate and heptane, and separated by filtration to obtain 780 mg of the title compound. The property values of the compound are as follows.