Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li][CH2:2]CCC.CCN(C(C)C)C(C)C.[C:15]1(=[O:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CI>C1COCC1>[CH3:2][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:15]1=[O:22]
Reactant: O=C1CCCCCC1
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
n-BuLi (2M solution) (35.86 mmol, 17.93 mL) was slowly added at 0° C. to a solution of DIPEA (5 mL, 35.86 mmol) in THF (45 mL). After stirred for 30 min at 0° C. the solution was cooled to −78° C. Cycloheptanone (4.0 gms, 4.2 mL, 35.66 mmol, 1.0 eqv) was added drop wise and the resulting mixture was stirred for 30 min at −78° C. before adding methyl iodide (2.96 mL, 47.4 mmol, 1.33 eq). The cooling bath was removed and the solution was allowed to reach ambient temperature and stirred at RT for 15 hours before being quenched with aqueous saturated NH4Cl. The mixture was extracted with DCM. The organic layer was washed with 0.1 M aqueous HCl and aqueous saturated NaHCO3, dried over Na2SO4, filtered, and evaporated. The residue was purified by short path distillation to give 2.8 g of 2-methyl-cycloheptanone (62% yield).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)(=[O:4])[CH2:2][CH3:3]>C(O)(C)C.[Ru]>[OH:4][CH:1]([C:5]1[CH:13]=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)[CH2:2][CH3:3]
Reactant: CCC(=O)c1ccc2c(c1)OCO2
Agent: [Ru]
Solvent: CC(C)O
Product: CCC(O)c1ccc2c(c1)OCO2

Procedure:
Into a 250-ml multiple-necked flask were introduced, under nitrogen flow, 30 g of 5-propanoylbenzo[1,3]dioxol (0.268 mol) dissolved in 100 ml of methanol. At 25° C., 7 g of NaBH4 (0.185 mol) dissolved in 50 ml of methanol were dripped in 20 minutes; then the reaction mixture was brought to reflux. After 2 hours the mixture was cooled, the methanol was removed at reduced pressure, and the mixture was diluted with 100 ml of HCl 2M and extracted twice with CH2Cl2. The reunited organic phases were washed with 100 ml of H2O and concentrated at reduced pressure to obtain 30.07 g of dense, clear oil, the analysis of which—GC, MS, NMR (1H, 13C, DEPT)—was in conformity with the desired product. Alternatively, 5-(α-hydroxypropyl)benzo[1,3]dioxol was prepared as follows: Into a 1-litre autoclave, 30 g of 5-propanoylbenzo[1,3]dioxol (0.168 mol) dissolved in 150 ml of isopropanol and 1 g of Ru/C 5% were poured. The autoclave was closed, rendered inert with nitrogen, and brought to the pressure of 1 bar with H2 under stirring. The mixture was left under stirring with H2 pressure constant at 1 bar for 1 hour; then it was washed with N2 and filtered. By evaporation of the solvent at reduced pressure, 30 g of a dense oil were obtained, the analysis of which—GC, MS, NMR (1H,13C, DEPT)—was in conformity with the desired product.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH:24]([CH3:26])[CH3:25])=[N:8][C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])=[CH:13][CH:12]=[C:11]([Cl:23])[CH:10]=2)=[O:5])C.[OH-].[Na+]>C(O)C>[Cl:23][C:11]1[CH:10]=[C:9]2[C:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])=[C:6]([C:4]([OH:5])=[O:3])[C:7]([CH:24]([CH3:25])[CH3:26])=[N:8]2)=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1c(C(C)C)nc2cc(Cl)ccc2c1-c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1nc2cc(Cl)ccc2c(-c2ccccc2F)c1C(=O)O

Procedure:
The title compound was prepared in analogy to example 6 step B from a mixture of 7-chloro-4-(2-fluoro-phenyl)-2-isopropyl-quinoline-3-carboxylic acid ethyl ester and 1N NaOH in ethanol. White solid. MS (ESI): 344.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH2:13]([NH2:16])[CH:14]=[CH2:15].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(OCC)C.C(O)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][C:10]([CH3:12])=[N:11][C:2]=1[NH:16][CH2:13][CH:14]=[CH2:15]
Reactant: C=CCN
Reactant: COC(=O)c1ccc(C)nc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: C=CCNc1nc(C)ccc1C(=O)OC

Procedure:
A stirred mixture of 9.25 g. (0.05 mole) of methyl 2-chloro-6-methylnicotinate, 2,85 g. (0.05 mole) of allylamine and 5.3 g. (0.05 mole) of sodium carbonate in 50 ml. of ethanol was heated under reflux for 5 hours. The mixture was filtered and the filtrate was evaporated in a rotary evaporator. The residue was diluted with 50 ml. of water and was extracted with 50 ml. of diethyl ether. The ether layer was dried over magnesium sulfate, filtered and was evaporated. The residue was passed through a neutral aluminum oxide column using ethyl acetate as the eluent. Evaporation of the ethyl acetate gave 3.1 g. of product. A small amount of this oil was dissolved in diethyl ether containing a few drops of ethanol and this solution was acidified with an ethereal hydrochloric acid solution. The precipitate which formed was collected and was recrystallized from ethyl acetate to give 2-allylamino-6-methylnicotinic acid methyl ester, m.p. 140°-2° C.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][CH:4]=1.[F-].[K+].F[C:15]1[CH:16]=[C:17]2[C:22](=[O:23])[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1.S1(CCCC1)(=O)=O>>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=1[O:9][C:15]1[CH:16]=[C:17]2[C:22](=[O:23])[O:21][C:19](=[O:20])[C:18]2=[CH:24][CH:25]=1
Reactant: Oc1ccccc1C(F)(F)F
Reactant: O=C1OC(=O)c2cc(F)ccc21
Agent: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: O=C1OC(=O)c2cc(Oc3ccccc3C(F)(F)F)ccc21
Temperature: 190 °C

Procedure:
Following the general procedure of Example 12, 0.47 parts of α,α,α-trifluoro-o-cresol, 0.23 parts of KF and 0.44 parts of 4-fluorophthalic anhydride in 1.56 parts of sulfolane were heated for 4 hours at 190° C., with stirring. The mixture contained 67 percent (by area) of the above product as identified by GC/MS.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.FC1C(C(F)(F)F)=CC=CC=1C(O)=O.[CH3:27][CH:28]1[C:33]2[N:34]=[CH:35][N:36]=[C:37]([C:38]3[N:42](C4CCCCO4)[N:41]=[CH:40][CH:39]=3)[C:32]=2[CH2:31][CH2:30][NH:29]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([N:29]1[CH2:30][CH2:31][C:32]2[C:37]([C:38]3[NH:42][N:41]=[CH:40][CH:39]=3)=[N:36][CH:35]=[N:34][C:33]=2[CH:28]1[CH3:27])=[O:6]
Reactant: O=C(O)c1ccc(F)c(Cl)c1Cl
Reactant: CC1NCCc2c(-c3ccnn3C3CCCCO3)ncnc21
Agent: O=C(O)c1cccc(C(F)(F)F)c1F
Product: CC1c2ncnc(-c3ccn[nH]3)c2CCN1C(=O)c1ccc(F)c(Cl)c1Cl

Procedure:
The title compound was prepared in a manner analogous to Example 74 substituting 2,3-dichloro-4-fluorobenzoic acid for 2-fluoro-3-(trifluoromethyl)benzoic acid in the synthesis of Intermediate 44 and the product of Example 112, step g for Intermediate 43. MS (ESI) mass calcd. C18H14Cl2FN5O, 405.1. m/z found 406.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 9.04-8.89 (m, 1H), 7.79-7.70 (m, 1H), 7.56-7.28 (m, 2H), 7.07-6.96 (m, 1H), 5.71-5.62 (m, 1H), 3.73-3.32 (m, 3H), 3.29-3.07 (m, 1H), 1.78-1.54 (m, 3H).
Reaction SMILES: [F:1][C:2]1([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[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.[C:27]1(=[O:37])[NH:31][C:30](=[O:32])[C:29]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:28]12.[K].O>CN(C=O)C>[O:32]=[C:30]1[C:29]2[C:28](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:27](=[O:37])[N:31]1[CH2:15][C:2]1([F:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: Cc1ccc(S(=O)(=O)OCC2(F)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(F)(CN2C(=O)c3ccccc3C2=O)CC1
Temperature: 150 °C

Procedure:
To a solution of 3-2 (6.78 g, 17.5 mmol) in 70 mL DMF was added potassium phthalimide (4.21 g, 22.7 mmol) and the mixture was heated at 150° C. for 2.5 h. The mixture was allowed to cool to ambient temperature, poured into H2O (150 mL), and extracted with EtOAc (3×150 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo, giving 11.0 g of crude 3-3 as a tan solid. 1H NMR (CDCl3, 300 MHz): 7.85 (dd, J=5.4, 3.0 Hz, 2H), 7.76 (dd, J=5.4, 3.0 Hz, 2H), 3.96 (br, 2H), 3.04 (m, 2H), 1.70 (m, 6H), 1.43 (s, 9H); MS (Electrospray): m/z 385.2 (M+Na), 347.3 (M−Me+H).
Reaction SMILES: [CH3:1][C:2]1[C:3](/[C:16](/[Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([O:25]CC)=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.CC1C(/C(/[Si](C)(C)C)=C/S2C=CC=C2C(OCC)=O)=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][C:2]1[C:3](/[C:16](/[Si:28]([CH3:29])([CH3:31])[CH3:30])=[CH:17]/[C:18]2[S:22][C:21]([C:23]([OH:25])=[O:24])=[CH:20][CH:19]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:12])([CH3:13])[C:10]=2[CH:11]=1
Reactant: CCOC(=O)c1ccc(/C=C(/c2cc3c(cc2C)C(C)(C)CCC3(C)C)[Si](C)(C)C)s1
Agent: CCOC(=O)C1=CC=C[SH]1/C=C(/c1cc2c(cc1C)C(C)(C)CCC2(C)C)[Si](C)(C)C
Product: Cc1cc2c(cc1/C(=C/c1ccc(C(=O)O)s1)[Si](C)(C)C)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure C, ethyl(Z)-5-[2-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trimethylsilyl)vinyl]thiophene-2-carboxylate (Compound 15, 0.050 g, 0.11 mmol) was hydrolyzed to give the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([Cl:13])(=[O:12])=[O:11])=[CH:9][C:4]=2[CH2:3][CH2:2]1.Cl.Cl.[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH2:31])[CH:18]3[CH2:17]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:13].[CH2:16]1[C:26]2=[C:27]3[C:22](=[CH:23][CH:24]=[CH:25]2)[CH2:21][CH2:20][N:19]([CH2:28][CH2:29][CH2:30][NH:31][S:10]([C:8]2[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=2)(=[O:12])=[O:11])[CH:18]3[CH2:17]1
Reactant: NCCCN1CCc2cccc3c2C1CC3
Reactant: O=S(=O)(Cl)c1ccc2c(c1)CCO2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(NCCCN1CCc2cccc3c2C1CC3)c1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
2,3-Dihydro-benzofuran-5-sulfonyl chloride (24.05 mg, 0.11 mmol) was added to a solution of 3-(2,2a,4,5-Tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propylamine dihydro-chloride (28.92 mg, 0.1 mmol) and N,N′-diisopropylethylamine (51.7 mg, 0.4 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (33 mg, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]=1[OH:12].CO.C[O-].[Na+].[CH2:18]([OH:21])[CH:19]=[CH2:20].C1(C)C=CC=CC=1>>[C:8]([C:4]1[CH:5]=[C:6]([CH2:20][CH2:19][CH2:18][OH:21])[CH:7]=[C:2]([CH3:1])[C:3]=1[OH:12])([CH3:9])([CH3:11])[CH3:10]
Reactant: C=CCO
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(CCCO)cc(C(C)(C)C)c1O
Temperature: 210 °C
Reaction time: 7 h
Yield: 52 %

Procedure:
A pressure container was charged with 62.7 g (0.38 mol) of 2-methyl-6-t-butylphenol and 7.3 g (0.038 mol) of a methanol solution containing 28% of sodium methoxide. Then the mixture was heated under reduced pressure to distill 6.5 g (0.2 mol) of methanol. Thereafter, 22.2 g (0.92 mol) of allyl alcohol and 18.7 g (0.19 mol) of toluene were added to the reaction system, the atmosphere in the reaction system was replaced by nitrogen and then, the reaction system was tightly closed. Then, the reaction system was raised up to 210° C. and kept at that temperature for 7 hours. Then, the reaction mixture was cooled to room temperature. A sample of the reaction solution was analyzed by gas-chromatography. The desired product, 3-(3-t-butyl-4-hydroxy-5-methylphenyl)propanol was obtained in a yield of 52%.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]([O:17][CH2:18][CH3:19])=[CH2:16])CCC>[Cu]I.CN(C=O)C>[CH2:18]([O:17][C:15]([C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1)=[CH2:16])[CH3:19]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: COc1cccnc1Br
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C=C(OCC)c1ncccc1OC
Temperature: 80 °C
Yield: 84.3 %

Procedure:
Add copper (I) iodide (38 mg, 0.2 mmol) to a mixture of 2-bromo-3-methoxy-pyridine (188 mg, 1.0 mmol), tributyl(1-ethoxyvinyl)tin (0.68 mL, 2.0 mmol), and DMF (anhydrous, 4 mL) in a sealed tube. Flush with N2, seal, heat at 80° C. for 3 h. Purify the mixture by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford 2-(1-ethoxy-vinyl)-3-methoxy-pyridine (151 mg, 84%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]2([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N+:21]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.O1CCOCC1.C1(C)C=CC=CC=1>[N+:21]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8](=[O:20])[CH2:9][C:10]3([C:16]([O:18][CH3:19])=[O:17])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:4][CH:3]=2)=[CH:26][CH:25]=1)([O-:23])=[O:22]
Reactant: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCOCC1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1(CC(=O)c2ccc(-c3ccc([N+](=O)[O-])cc3)cc2)CCOCC1
Temperature: 85 °C
Yield: 79.3 %

Procedure:
Methyl 4-[2-(4-bromophenyl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (820 mg, 2.40 mmol) and 4-nitrophenyl boronic acid (481 mg, 2.88 mmol) were combined in a dry flask under argon. Toluene (20 mL) and dioxane (5 mL) were added, and the resulting solution was degassed for 30 minutes by a flow of argon. The degassing was continued during the addition of saturated aqueous sodium carbonate (6 mL) and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), 1:1 complex with dichloromethane (98 mg, 0.12 mmol). The resulting mixture was then heated at 85° C. for 16 h before it was cooled to rt. Water was added, and the aqueous layer was extracted twice with ethyl acetate. The combined organic phases were then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (Biotage Flash 40) using 1:1 ethyl acetate/hexane to afford methyl 4-[2-(4′-nitro-1,1′-biphenyl-4-yl)-2-oxoethyl]tetrahydro-2H-pyran-4-carboxylate (730 mg, 79%). LC-MS ret. time 3.03; m/z 383.9 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.65–1.73 (m, 2H), 2.17–2.21 (m, 2H), 3.37 (s, 2H), 3.68 (s, 3H), 3.71–3.78 (m, 4H), 7.70 (d, 2H), 7.77 (d, 2H), 8.02 (d, 2H), 8.31 (d, 2H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([C:9]1[N:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:10]=1[C:11](OC)=[O:12])[CH3:8].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:7]([C:9]1[C:10]([CH2:11][OH:12])=[CH:15][CH:16]=[C:17]([CH3:19])[N:18]=1)[CH3:8]
Reactant: CCc1nc(C)ccc1C(=O)OC
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(C)ccc1CO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 83.4 %

Procedure:
To a mixture of lithium aluminum hydride (220 mg) and THF (dry) (15 mL) was added a solution of methyl 2-ethyl-6-methylnicotinate (519 mg) in THF (dry) (5 mL) at 0° C. The mixture was stirred at 0° C. under nitrogen atmosphere for 20 min. To the mixture was added sodium sulfate decahydrate (1.8 g) and the mixture was stirred overnight. After filtrating, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (365 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[N:8]1([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cccc(N2CCCC2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(N4CCCC4)n3)cnc2n1
Yield: 26.8 %

Procedure:
2-Bromo-6-(pyrrolidin-1-yl)pyridine (481 mg, 2.1 mmol) (prepared by the method of T. Sammakia et al., J. Org. Chem., 1999, 64(13), 4652-4664) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (1.4 mmol) by the method of Example 1 to give 3-[6-(pyrrolidin-1-yl)pyridin-2-yl]-7-trifluoromethylimidazo[1,2-α]pyrimidine (125 mg) as a white solid: δH (360 MHz, DMSO) 2.02 (4H, t, J 6.5), 3.51 (4H, bs), 6.43 (1H, d, J 8.4), 7.27 (1H, d, J 7.7), 7.63 (1H, t, J 7.9), 7.71 (1H, d, J 7.4), 8.72 (1H, s), 10.51 (1H, d, J 7.4); m/z (ES+) 334 (M++H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([O:32]C)=[O:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1)=[O:11])[CH3:2].[OH-].[Na+]>CO>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[C:14]([CH:18]2[C:27]([CH3:29])([CH3:28])[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:30]([OH:32])=[O:31])[CH:24]=3)[NH:19]2)[CH:15]=[CH:16][CH:17]=1)=[O:11])[CH3:2]
Reactant: CCN1CCCC1CNC(=O)c1cccc(C2Nc3ccc(C(=O)OC)cc3CC2(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN1CCCC1CNC(=O)c1cccc(C2Nc3ccc(C(=O)O)cc3CC2(C)C)c1

Procedure:
A mixture of methyl 2-(3-((1-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (44 mg, 0.1 mmol) in methanol (1.6 mL) and 1 M sodium hydroxide aqueous solution (1.27 mL, 1.27 mmol) was heated to reflux for 30 min, LC-MS showed the reaction was complete and only the desired product formed. The solvent was concentrate in vacuo and the residue was dissolved in water and acidified with 1 M hydrochloric acid solution. The off-white precipitated solid was collected by filtration to afford mg of 2-(3-((1-ethylpyrrolidin-2-yl)methylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid was a white solid. Yield: 58.7%. MS (ESI+APCI) M+1=436.3.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:21]CC3C=CC=CC=3)[C:9]=2[O:13]CC2C=CC=CC=2)[C:4]1=[O:29].C(O[C:38]1[C:47](OCC2C=CC=CC=2)=[CH:46][CH:45]=[C:44]2[C:39]=1[CH2:40][CH2:41][CH:42](NC(=O)C(F)(F)F)C2=O)C1C=CC=CC=1.[BrH:64]>>[BrH:64].[OH:13][C:9]1[C:8]([OH:21])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH2:11][CH2:12][CH:3]([NH:2][CH2:42][CH2:41][CH2:40][C:39]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:38]=1)[C:4]2=[O:29]
Reactant: NC1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1=O
Reactant: O=C1c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2CCC1NC(=O)C(F)(F)F
Agent: Br
Agent: Cl
Product: O=C1c2ccc(O)c(O)c2CCC1NCCCc1ccccc1

Procedure:
20 Parts of 2-amino-5,6-dibenzyloxy-3,4-dihydro-1(2H)-naphthalenone hydrochloride is subjected to a procedure similar to that described in Reference Example 11 and the resultant 5,6-dibenzyloxy-2-trifluoroacetamido-3,4-dihydro-1(2H)-naphthalenone is reacted with 60 parts of 3-phenylpropanol p-toluenesulfonic acid ester under the same conditions as set forth in Reference Example 11. The reaction product is then hydrolyzed in a 47 % aqueous solution of hydrogen bromide to obtain 3 parts of 5,6-dihydroxy-2-(3-phenylpropylamino)-3,4-dihydro-1(2H)-naphthalenone hydrobromide melting at 215°-217° C (decomposition).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH3:8][O:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[NH2:17])=[O:11]>C(O)=O>[CH3:8][O:9][C:10]([C:12]1[S:13][CH:14]=[CH:15][C:16]=1[NH:17][CH:1]=[O:3])=[O:11]
Reactant: COC(=O)c1sccc1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: COC(=O)c1sccc1NC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
Formic acid (40 mL) was added to acetic anhydride (60 mL) while cooling in an ice bath. Solid 3-amino-2-thiophenecarboxylic acid methyl ester (77, 10.3 g, 66 mmol) was added to the cold solution in small portions. The cooling bath was removed and the resulting suspension was stirred at room temperature for 4 hours. The reaction mixture was diluted with water (100 mL) and the solid product collected by vacuum filtration to yield 3-(formylamino)-2-thiophenecarboxylic acid methyl ester (10.3 g, 85% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:3]=1[O:4][C:5]1[CH:41]=[CH:40][CH:39]=[CH:38][C:6]=1[CH2:7][O:8][CH2:9][CH:10]1[CH2:37][CH2:36][C:13]2[N:14](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:15]=[N:16][C:12]=2[CH2:11]1.ClC1C=C(Cl)C=CC=1OC1C=CC=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1.C(O)(=O)C>O>[Cl:1][C:2]1[CH:45]=[C:44]([Cl:46])[CH:43]=[CH:42][C:3]=1[O:4][C:5]1[CH:41]=[CH:40][CH:39]=[CH:38][C:6]=1[CH2:7][O:8][CH2:9][CH:10]1[CH2:37][CH2:36][C:13]2[NH:14][CH:15]=[N:16][C:12]=2[CH2:11]1
Reactant: Clc1ccc(Oc2ccccc2COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c(Cl)c1
Agent: Clc1ccc(Oc2ccccc2COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c(Cl)c1
Solvent: CC(=O)O
Solvent: O
Product: Clc1ccc(Oc2ccccc2COCC2CCc3[nH]cnc3C2)c(Cl)c1
Temperature: 70 °C

Procedure:
A soution of a mixture of 5-[2-(2,4-dichlorophenoxy)benzyloxymethyl]-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-[2-(2,4-dichlorophenoxy)benzyloxymethyl]-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole (356 mg, 0.55 mmol) in a mixture of glacial acetic acid (9 ml) and water (1 ml) was heated to 70° C. for 2 hours. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using DCM/methanol/−25% aqueous ammonia as eluent, to give 175 mg of the title compound. HPLC method C: elution at 11.42 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[N:24]1([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([C:37]3[CH:42]=[CH:41][C:40](B4OC(C)(C)C(C)(C)O4)=[CH:39][CH:38]=3)=[O:36])[CH2:31][CH2:30]2)[CH2:28][CH2:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:40]3[CH:41]=[CH:42][C:37]([C:35]([N:32]4[CH2:31][CH2:30][CH:29]([N:24]5[CH2:25][CH2:26][CH2:27][CH2:28]5)[CH2:34][CH2:33]4)=[O:36])=[CH:38][CH:39]=3)=[CH:17][C:9]1=2
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Reactant: CC1(C)OB(c2ccc(C(=O)N3CCC(N4CCCC4)CC3)cc2)OC1(C)C
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 19 %

Procedure:
1-(5-Chloro-2-trifluoromethylbenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (40 mg) was reacted with (4-(pyrrolidin-1-yl)piperidin-1-yl)-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]methanone as in General Procedure 4A to give the title compound as an orange foam (19% yield). M.p. (foam), LCMS: m/z=487.19, 1H-NMR (CDCl3, 400 MHz) δ 1.43-1.62 (m, 3H), 1.65-1.99 (m, 3H), 2.21-2.30 (m, 2H), 2.52-2.61 (m, 6H), 2.87-3.08 (m, 3H), 3.47-3.51 (m, 2H), 3.65-3.71 (m, 2H), 4.62 (s, 2H), 5.02 (s, 1H), 6.59 (d, J=1.5 Hz, 1H), 7.31-7.39 (m, 5H), 7.50 (s, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.74 (s, 1H).