Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([C:10]2[CH:11]=[C:12]([C:22](O)=[O:23])[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[N:14][CH:15]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:30][NH2:31].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C)C=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:30][NH:31][C:22]([C:12]1[C:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[N:14][CH:15]=[C:10]([C:5]2[CH:4]=[C:3]([CH3:2])[CH:8]=[C:7]([CH3:9])[CH:6]=2)[CH:11]=1)=[O:23]
Reactant: COc1ccc(CN)cc1OC
Reactant: Cc1cc(C)cc(-c2cnc(-c3cccnc3)c(C(=O)O)c2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CNC(=O)c2cc(-c3cc(C)cc(C)c3)cnc2-c2cccnc2)cc1OC
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.3 g, 1.20 mmol) in dioxane (6 mL) was added 3,5-dimethylphenyl boronic acid (0.452 g, 3.01 mmol), cesium carbonate (1.17 g, 3.61 mmol), tricyclohexylphosphine (0.101 g, 0.362 mmol), and tris(dibenzylideneacetone)-dipalladium (0.166 g, 0.181 mmol), and stirred at 95° C. overnight. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and filtered, concentrated and purified via normal phase chromatography (0->5% MeOH in DCM) afforded methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate as a yellow foam. ESI+ MS [MH]+ C20H18N2O2=319.25. To a solution of methyl 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylate (0.385 g, 1.20 mmol) in tetrahydrofuran (3 mL) and methanol (3 mL) was added potassium hydroxide (0.122 g, 2.17 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+ C19H16N2O2=305.0. To a solution of the bis HCl salt form of 5-(3,5-dimethylphenyl)-2,3′-bipyridine-3-carboxylic acid (0.390 g, 1.03 mmol) and 3,4-dimethoxybenzylamine (0.173 g, 1.03 mmol) in dimethylformamide (5 mL) was added EDC (0.029 g, 0.191 mmol), HOBt (0.317 g, 2.06 mmol) and triethylamine (0.720 mL, 5.16 mmol) and the system was stirred in the microwave at 100° C. for 15 minutes. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was purified using normal phase chromatography (0->10% MeOH in DCM) to afford the title compound (1-3) as a white powder. 1H NMR (500 MHz, CDCl3) δ 8.98-9.00 (m, 2H), 8.65-8.66 (m, 1H), 8.17 (d, J=2 Hz, 1H), 7.98-8.00 (m, 1H), 7.28-7.30 (m, 3H), 7.11 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.41-6.67 (m, 2H), 5.72 (br s, 1H), 4.42 (d, J=6 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 2.43 (s, 6H). HRMS [M+H] C28H27N3O3 calc'd 454.2125, found 454.2107.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]#[C:15][C:16]2[N:20]3[N:21]=[CH:22][CH:23]=[CH:24][C:19]3=[N:18][CH:17]=2)[CH2:9]1)(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:18]1[CH:17]=[C:16]([C:15]#[C:14][CH:10]2[CH2:11][CH2:12][CH2:13][NH:8][CH2:9]2)[N:20]2[C:19]=1[CH:24]=[CH:23][CH:22]=[N:21]2
Reactant: CC(C)(C)OC(=O)N1CCCC(C#Cc2cnc3cccnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C(#CC1CCCNC1)c1cnc2cccnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 121.5 %

Procedure:
To a solution of 1-BOC-3-(2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl)piperidine (0.39 g, 1.2 mmol) in CH2Cl2 (10 mL) was added TFA (1.23 g, 10.8 mmol), the mixture was stirred at rt overnight and evaporated in vacuo. To the residue was added 10 mL 10% K2CO3 solution, extracted with EtOAc (20 mL×3), dried with Na2SO4, after filtration, and the filtrate was evaporated under reduced pressure to give 0.33 g product as yellow oil (107.0%). 1H NMR (300 MHz, CDCl3) δ: 8.43 (1 H, d, J=4.5 Hz), 7.93-7.97 (1 H, dd, J=1.8 and 9.0 Hz), 7.91 (1 H, s), 7.05-7.09 (1 H, dd, J=4.5 and 9.0 Hz), 2.82-2.98 (4 H, m), 2.08-2.11 (1 H, m), 1.75-1.84 (2 H, m), 1.53-1.58 (2 H, m).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9](=[C:14]2[CH2:17][N:16](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:15]2)[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.C1(CC2C=CC=CC=2)C=CC=CC=1>CO.Cl.CCOCC.[Pd]>[NH:16]1[CH2:17][CH:14]([CH:9]([C:4]2[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:15]1
Reactant: COC(=O)C(=C1CN(C(c2ccccc2)c2ccccc2)C1)c1cc(F)cc(F)c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: c1ccc(Cc2ccccc2)cc1
Solvent: CCOCC
Product: COC(=O)C(c1cc(F)cc(F)c1)C1CNC1
Reaction time: 18 h

Procedure:
A mixture of 0.406 g (1 mmol) of methyl (3,5-difluorophenyl)[1-(diphenylmethyl)azetidin-3-ylidene]acetate and 25 mg of 10% Pd/C in 10 mL of methanol and 1 mL of 1M HCl in ether was shaken under 40 psi H2 for 18 h. The mixture was filtered through CELITE and the solid residue was washed with 30 mL of methanol. The filtrate was concentrated to afford a mixture of the title compound and diphenylmethane, which was not separated but was used directly in the next step; Mass Spectrum: m/e=242 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12].[CH2:13](O)[CH3:14]>>[CH:13]([C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[O:7][CH2:8][C:4]=2[C:3]=1[CH3:12])=[CH2:14]
Reactant: Cc1c(Br)ccc2c1COC2=O
Reactant: CCO
Product: C=Cc1ccc2c(c1C)COC2=O
Temperature: 140 °C

Procedure:
5-Bromo-4-methyl-2-benzofuran-1(3H)-one (598 mg, 4.47 mmol), potassium vinyl trifluoroborate (507 mg, 2.23 mmol), PdCl2(dppf)-CH2Cl2Adduct (182 mg, 0.223 mmol), and TEA (0.622 mL, 4.47 mmol) were added to 10 mL ethanol in a 20 mL microwave tube. The tube was sealed and degassed, then heated to 140° C. for 20 min. Analysis by LC-MS showed product peak. The reaction mixture was diluted with ethyl acetate, washed with brine twice, dried and evaporated to dryness. The crude product was purified by MPLC chromatography using a 120 g Redi-sep column and 0-80% EtOAc/Hexane solvent system to yield 5-ethenyl-4-methyl-2-benzofuran-1(3H)-one. 1H-NMR (500 MHz, CDCl3): δ ppm 7.76 (d, J=8 Hz, 1H), 7.03(dd, J=11, 17 Hz, 1H), 5.84 (d, J=17 Hz, 1H), 5.55 (d, J=11 Hz, 1H), 5.29 (s, 2H), 2.34 (s, 3H); LC-MS: M+1=175;
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:22]Br>C(Cl)(Cl)Cl>[Br:22][CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Temperature: 5 °C
Reaction time: 18 h
Yield: 42.1 %

Procedure:
A solution of 32.5 g (163 mmol) of tert-butyl 4-oxo-piperidine-1-carboxylate in 200 ml of chloroform was treated with 24.0 g (168 mmol) of disodium hydrogen phosphate and cooled to 5° C. A solution of 27.9 g (175 mmol) of bromine in 75 ml of chloroform was added dropwise during 1 hour, thereafter the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was worked-up by extraction with ice-water and methylene chloride, the organic phase was dried over magnesium sulphate, filtered and the solvent was distilled off in a water-jet vacuum. The crude product (38 g) was chromatographed on silica gel with methylene chloride and ethyl acetate as the eluent. The thus-obtained product was recrystallized from ethyl acetate and n-hexane. There were obtained 19.1 g (42% of theory) of tert-butyl 3-bromo-4-oxo-piperidine-1-carboxylate as a pale yellow solid; MS: 277, 279 (M)+.
Reaction SMILES: [OH:1][CH2:2][C:3]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5].[CH3:18][S:19](Cl)(=[O:21])=[O:20].C(N(CC)CC)C>C(Cl)Cl>[CH3:18][S:19]([O:1][CH2:2][C:3]([O:14][CH2:15][CH2:16][CH3:17])([CH3:13])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)=[O:5])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CCCOC(C)(CO)C(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCOC(C)(COS(C)(=O)=O)C(=O)c1ccc(Cl)cc1
Temperature: -40 °C
Yield: 42.1 %

Procedure:
To 11 g (44 mmole) of crude 2-hydroxymethyl-2-propoxy-4'-chloropropiophenone (Example 96d) in 50 ml of methylene chloride was added 4.5 g (39 mmole) of methanesulfonyl chloride. The mixture was cooled to -40° C. and then 6.0 g (60 mmole) of triethylamine was slowly added. The mixture was allowed to warm to room temperature over 1 hour and was then washed with water, dilute aqueous hydrochloric acid, and brine. It was then dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using diethyl ether and hexanes to yield 5.5 g of the title compound, an oil.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([NH2:14])[N:9]=1.Cl[C:16]1[C:17]2[CH2:27][CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[C:18]=2[N:19]=[C:20]([NH2:22])[N:21]=1>>[NH2:14][C:10]1[N:9]=[C:8]([NH:7][CH2:6][CH2:5][N:4]([CH3:3])[C:16]2[C:17]3[CH2:27][CH2:26][CH2:25][C:24]4[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=4[C:18]=3[N:19]=[C:20]([NH2:22])[N:21]=2)[CH:13]=[CH:12][N:11]=1
Reactant: Nc1nc(Cl)c2c(n1)-c1ccccc1CCC2
Reactant: CNCCNc1ccnc(N)n1
Agent: Cl
Product: CN(CCNc1ccnc(N)n1)c1nc(N)nc2c1CCCc1ccccc1-2

Procedure:
The product from Example 2A (95 mg, 0.237 mmol) and the product from Example 1C (50 mg, 0.203 mmol) were combined under the conditions described in Example 1F to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.62-7.67 (m, 1H) 7.58 (d, J=5.43 Hz, 1H) 7.28-7.37 (m, 2H) 7.23-7.28 (m, 1H) 6.89 (s, 1H) 5.94 (s, 2H) 5.82 (s, 2H) 5.70 (d, J=5.76 Hz, 1H) 3.43-3.55 (m, 4H) 2.99-3.04 (m, 3H) 2.50-2.58 (m, 2H) 2.15 (dd, J=16.11, 5.93 Hz, 4H); MS (ESI+) m/z 377.0 (M+H)+.
Reaction SMILES: [OH-:1].[Na+].[F:3][C:4]([F:17])([F:16])[C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:13]=1[NH:12][C:11](=[O:14])[C:10]2=O.[F:18][C:19]([F:24])([F:23])[C:20]([CH3:22])=O.Cl>O>[F:18][C:19]([F:24])([F:23])[C:20]1[CH:22]=[C:10]([C:11]([OH:1])=[O:14])[C:9]2[C:13](=[C:5]([C:4]([F:17])([F:16])[F:3])[CH:6]=[CH:7][CH:8]=2)[N:12]=1
Reactant: [OH-]
Reactant: O=C1Nc2c(cccc2C(F)(F)F)C1=O
Reactant: CC(=O)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Temperature: 110 °C

Procedure:
A mixture of 100 parts by volume of water, 8.8 parts of sodium hydroxide, 43.2 parts of 7-trifluoromethyl-isatin and 27.4 parts of 1,1,1-trifluoroacetone is heated for 8 hours at 110° C. in an autoclave. When the mixture has cooled, 2 N hydrochloric acid is added, whilst stirring, until the pH has reached 2.7 and the precipitate formed is filtered off and dried at 70° C. and about 20 mbar. 60 parts of 2,8-bis-(trifluoromethyl)-quinoline-4-carboxylic acid, ie. 97.1% of theory, are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.O.ClCCl.[CH2:16]([NH2:20])[CH:17]([CH3:19])[CH3:18]>>[CH3:18][CH:17]([CH3:19])[CH2:16][NH:20][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)CN
Reactant: FC(F)(F)c1ccnc(Cl)n1
Solvent: ClCCl
Solvent: O
Product: CC(C)CNc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyrimidine (548 mg, 3 mmol) in isobutylamine (1.5 mL) was stirred at room temperature for 17 hours. To the mixture was added water (5 mL) and dichloromethane (5 mL). The organic layer was separated and purified by flash silica (Si) chromatography (0-100% dichloromethane-cyclohexane gradient) to give the title compound (455 mg) as a colourless oil. LCMS (2 min, formic) Rt 1.20 min, m/z (ES+) 220 (M+H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1.[N:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([CH3:41])[CH:35]=1>C(#N)C>[Br-:1].[CH3:41][C:36]1[CH:35]=[N+:34]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10](=[O:33])[CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:14][CH:13]=3)[CH:4]=2)[CH:39]=[CH:38][C:37]=1[CH3:40]
Reactant: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(CBr)c2)cc1
Reactant: Cc1ccncc1C
Solvent: CC#N
Product: CCCCCCCCCCCCCCOc1ccc(CC(=O)Nc2cccc(C[n+]3ccc(C)c(C)c3)c2)cc1
Product: [Br-]
Yield: 82.8 %

Procedure:
A mixture of 1.5 g of N-[3-(bromomethyl)phenyl]-4-(tetradecyloxy)benzeneacetamide and 933.5 mg of 3,4-lutidine in 25 ml of acetonitrile is refluxed under argon for 4 hours. The solvent is evaporated and the residue mixed with ether. The solid is collected via centrifugation, washed with ether several times and vacuum dried to give 1.5 g of the desired product as a gray-white powder, m.p. 125°-128° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[CH:6][C:7]=1[F:8].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25](O)=O)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(OCC)(=O)C>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][C:25]1[NH:9][C:5]2[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=2[N:10]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: Nc1cc(F)c(F)cc1N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCCC1Cc1nc2cc(F)c(F)cc2[nH]1
Reaction time: 4 h
Yield: 15.7 %

Procedure:
4,5-Difluoro-benzene-1,2-diamine (1.00 g, 6.9 mmol) and 2 carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (Beckett et al, J. Med. Chem., 563,1969) (1.69 g, 6.9 mmol) were heated at 120° C. with stirring, under argon for 4 h. A further portion of 2-carboxymethyl-piperidine-1-carboxylic acid tert-butyl ester (0.85 g) was added and heating was continued for a further 2 h. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate (2×) and brine, dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0-30% ethyl acetate-pentane) to give a yellow solid which was triturated with diethyl ether to afford the title compound as a pale brown solid (0.38 g, 15%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: COCCN
Reactant: N#Cc1cccc(CBr)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
To a stirred solution of 2-methoxyethylamine (5.73 mL, 0.0612 mol) and triethylamine (4.05 mL, 0.0306 mol) in dry DCM (100 mL), was added 3-(bromomethyl)benzonitrile (6 g, 0.0306 mol) in portions over a period of 10 min at 0° C. After being stirred at RT for 5 h, the reaction mixture washed with water (2×100 mL), dried using sodium sulphate and concentrated under reduced pressure. The obtained crude was purified using column chromatography on silica gel (chloroform/methanol) to afford the title compound as a pale yellow liquid (5 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.64-7.68 (m, 2H), 7.48-7.52 (m, 1H), 3.73 (s, 2H), 3.35-3.38 (m, 2H), 3.21 (s, 3H), 2.59-2.61 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([S:11][C:12]3[CH:13]=[C:14]([CH:16]=[CH:17][CH:18]=3)[NH2:15])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[CH3:28][C:29]1[CH:30]=[CH:31][N:32]2[C:37]=1[C:36](=[O:38])[N:35]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:34]([C@@H:45]([NH3+:47])[CH3:46])=[N:33]2.[F-].[Cs+].C(N(CC)C(C)C)(C)C>C(O)(C)(C)C>[NH2:15][C:14]1[CH:13]=[C:12]([S:11][C:10]2[C:3]3[C:2]([NH:47][C@H:45]([C:34]4[N:35]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[C:36](=[O:38])[C:37]5=[C:29]([CH3:28])[CH:30]=[CH:31][N:32]5[N:33]=4)[CH3:46])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:9]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)CCOCn1cc(Sc2cccc(N)c2)c2c(Cl)ncnc21
Reactant: Cc1ccn2nc([C@H](C)[NH3+])n(-c3ccccc3)c(=O)c12
Agent: [Cl-]
Agent: [Cs+]
Agent: [F-]
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12

Procedure:
3-((4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)thio)aniline (100 mg, 0.25 mmol) was treated with (S)-1-(5-methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethanaminium chloride (67 mg, 0.25 mmol), cesium fluoride (15 mg, 0.10 mmol), N,N-diisopropylethylamine (400 μl, 2.3 mmol) and tert-butanol (0.78 ml) according to Preparation 163. The residue (100 mg, 80% purity) was used in the next synthetic step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18](Br)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:8][C:7]=1[CH3:22].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C1(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)C=CC=CC=1.C(O)C>[CH3:1][O:2][C:3](=[O:23])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[C:18]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)[CH:17]=[C:16]([C:29]3[CH:30]=[CH:31][C:26]([C:25]([F:36])([F:35])[F:24])=[CH:27][CH:28]=3)[CH:15]=2)=[CH:8][C:7]=1[CH3:22]
Reactant: COC(=O)COc1ccc(OCc2cc(Br)cc(Br)c2)cc1C
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: COC(=O)COc1ccc(OCc2cc(-c3ccc(C(F)(F)F)cc3)cc(-c3ccc(C(F)(F)F)cc3)c2)cc1C

Procedure:
[4-(3,5-Dibromo-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester 13 (0.0375 g, 0.088 mmol) is dissolved in dioxane (1 mL). 4-Trifluoromethyl-phenylboronic acid (0.0514 g, 0.27 mmol) is added, followed by water (0.01 mL), ethanol (0.01 mL), potassium carbonate (0.0557 g, 0.4 mmol), and tetrakis-(triphenylphosphino)palladium (0.117 g, 0.01 mmol). The mixture is stirred under nitrogen and subjected to microwave (170° C. for 10 min). The resulting orange suspension is filtered, the solids are washed with more dioxane, and the resulting solution is concentrated and purified by silica gel chromatography (10% to 25% ethyl acetate in hexanes) to yield [4-(3,5-bis(4-trifluoromethylphenyl)-benzyloxy)-2-methyl-phenoxy]-acetic acid methyl ester as an oil. 1H-NMR (400 MHz, CDCl3) δ=7.77-7.64 (m, 8H), 7.52 (s, 2H), 7.34 (s, 1H), 6.88 (d, J=2.8 Hz, 1H), 6.76 (dd, J=9.0, 2.8 Hz, 1H), 6.68 (d, J=9.2 Hz, 1H), 5.14 (s, 2H), 4.61 (s, 2H), 3.80 (s, 3H), 2.95 (s, 3H). 19F-NMR (376 MHz, CDCl3) δ=−62.4.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=1>C(OCC)C>[Cl:4][C:12]1[CH:11]=[C:10]([CH2:13][CH:14]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:9]=[CH:8][C:7]=1[OH:6]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CCOCC
Product: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)Oc1ccccc1
Reaction time: 8 h

Procedure:
A solution of sulfuryl chloride (0.71 ml) in diethyl ether (5 ml) was added dropwise to a solution of ethyl 3-(4-hydroxyphenyl)-2-phenoxypropionate (1.43 g) in diethyl ether (20 ml) at ambient temperature. The mixture was stirred for 8 hour and allowed to stand overnight. The reaction mixture was partitioned between ethyl acetate and water. The ethyl acetate layer was separated and washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified via chromatography on a silica gel column using hexane/ethyl acetate=10/3 as the eluant to afford the desired compound (1.09 g) as a colorless oil.
Reaction SMILES: C1CCCCCCC1.[CH2:9]1[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1>>[CH:17]1[C:18]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: C1CCC2CCCCC2C1
Solvent: C1CCCCCCC1
Product: c1ccc2ccccc2c1

Procedure:
Similarly, when Example 1(a) is repeated except that cyclooctane is replaced by a stoichiometrically equivalent amount of decalin, a corresponding yield of naphthalene is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[C:14]1(=[O:20])[O:19][C:17](=[O:18])[CH2:16][CH2:15]1.CC(=O)OCC.CO>CCOCC>[O:20]=[C:14]([NH:11][CH:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=1)[CH3:10])[CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C1CCC(=O)O1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Solvent: CO
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(NC(=O)CCC(=O)O)c1cccc(C(F)(F)F)c1
Reaction time: 72 h
Yield: 54.5 %

Procedure:
A solution of 5.0 g (26.5 mmol) of 1-(3-(trifluoromethyl)phenyl)ethylamine in ether (6 ml) was added dropwise in the course of 30 min to a suspension of 2.33 g (23.3 mmol) of succinic anhydride in ether (28 ml). Stirring was then carried out for 72 h at RT. The resulting precipitate was filtered off with suction and dried for 1 h in vacuo at 40° C. CC (EA/MeOH 1:4) of the residue yielded 3.68 g (12.7 mmol, 55%) of 4-oxo-4-(1-(3-(trifluoromethyl)phenyl)ethylamino)-butanoic acid (S2).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]2[N:20]=[C:19]([N:21]([CH3:23])[CH3:22])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)[CH2:5][CH2:4]1.C(N(C(C)C)CC)(C)C.[CH3:33][CH:34]([S:36](Cl)(=[O:38])=[O:37])[CH3:35]>C(Cl)Cl>[CH3:22][N:21]([CH3:23])[C:19]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([NH:10][CH2:9][C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][S:36]([CH:34]([CH3:35])[CH3:33])(=[O:38])=[O:37])[CH2:4][CH2:5]2)[N:20]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CN(C)c1nc(NC[C@H]2CC[C@H](CN)CC2)nc2ccccc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)NC[C@H]1CC[C@H](CNc2nc(N(C)C)c3ccccc3n2)CC1
Temperature: 4 °C
Reaction time: 12 h

Procedure:
To a suspension of trans-N2-(4-aminomethyl-cyclohexylmethyl)-N4,N4-dimethyl-quinazoline-2,4-diamine obtained in step A of example 15 (227 mg, 0.72 mmol) in CH2Cl2 (4 mL) was added diisopropylethylamine (263 μL, 1.51 mmol). The mixture was cooled at 4° C. and a solution of 2-propanesulfonyl chloride (108 mg, 0.76 mmol) in CH2Cl2 (1 mL) was added below 5° C. The reaction mixture was stirred at ambient temperature for 12 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 66% EtOAc in hexane) to give trans-propane-2-sulfonic acid {4-[(4-dimethylamino-quinazolin-2-ylamino)-methyl]-cyclohexylmethyl}-amide (135 mg, 45%) as a pale yellow solid.