Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=1.[CH3:12][CH2:13][O:14][C:15](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[CH2:13]([O:14][C:15](=[O:16])/[CH:17]=[CH:18]/[C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:2][C:3]2[C:8]([CH3:9])=[N:7][C:6]([CH3:10])=[C:5]([CH3:11])[N:4]=2)=[CH:23][CH:24]=1)[CH3:12]
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1
Reactant: Cc1nc(C)c(CBr)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OCc2nc(C)c(C)nc2C)cc1
Temperature: 90 °C
Yield: 76.7 %

Procedure:
Adding 2-bromomethyl-3,5,6-trimethylpyrazine (2.15 g, 0.01 mol), p-hydroxyl ethyl cinnamate (2.30 g, 0.012 mol), anhydrous potassium carbonate (2.76 g, 0.02 mol), and DMF (50 mL) into a 100 mL three-necked bottle in turn, heating to 90° C., stifling to react for 10 hours, TLC [V(petroleum ether):V(ethyl acetate)=3:1 as developing agent] detecting shows that reaction is complete, (Rf of raw material=0.6, Rf of product=0.5), filtering to obtain filtrate, adding 40 mL water, extracting with chloroform (3×40 mL), incorporating the chloroform layer and wishing with water (2×30 mL), drying with anhydrous sodium sulfate, recycling chloroform under reduced pressure to obtain a light yellow oily matter, separating with a silica column, wherein eluant is V(petroleum ether):V(ethyl acetate)=3:1, collecting product, recycling the solution under reduced pressure to obtain 2.5 g white crystalloid of (E)-3-(4-((3,5,6-Trimethylpyrazin-2-yl)methoxy)-phenyl)acrylic acid ethyl ester, a yield is 76.7%, m.p. 90-92° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]2[CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=1.C(N(CC)C(C)C)(C)C>CC#N>[CH:1]1([CH2:4][CH2:5][N:6]([CH2:24][C:25]2[CH:37]=[CH:36][C:28]([O:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:27]([CH3:38])[CH:26]=2)[C:7]2[CH:8]=[C:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(-c2cccc(NCCC3CC3)c2)cc1
Reactant: CCOC(=O)COc1ccc(CBr)cc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)COc1ccc(CN(CCC2CC2)c2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 83.5 %

Procedure:
To a solution of N-(2-cyclopropylethyl)-N-[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]amine (100 mg, 0.33 mmol) in anhydrous MeCN (7 mL) under nitrogen at room temperature was added ethyl [4-(bromomethyl)-2-methylphenoxy]acetate (94 mg, 0.33 mmol) and N,N-diisopropyethylamine (57.5 μl, 0.33 mmol). The resultant solution was heated to reflux and stirred for 2.5 h. The reaction mixture was allowed to cool to room temperature and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (2×10 mL) and water (10 mL). The organic solution was passed through a hydrophobic frit and the solvent was removed in vacuo. Purification by SPE (5 g Silica cartridge) eluted with 1:200–1:100 EtOAc:cyclohexane afforded the title compound as a colourless oil (141 mg).
Reaction SMILES: Br[CH2:2][C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6]1=[O:16])=[O:4].[P:17]([O:22]C)([O:20][CH3:21])[O:18][CH3:19]>C1(C)C=CC=CC=1>[O:4]=[C:3]([N:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][O:7][C:6]1=[O:16])[CH2:2][P:17](=[O:22])([O:20][CH3:21])[O:18][CH3:19]
Reactant: O=C(CBr)N1C(=O)OC[C@H]1c1ccccc1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(CC(=O)N1C(=O)OC[C@H]1c1ccccc1)OC
Temperature: 25 °C
Yield: 51.2 %

Procedure:
A solution of (R)-3-(2-bromoacetyl)-4-phenyloxazolidin-2-one (175 g, 616 mmol) and trimethyl phosphite (83.3 g, 671 mmol) in toluene (870 mL) was heated to reflux for 16 h. The reaction mixture was cooled to ambient temperature and the solvent was concentrated under reduced pressure to give a brown colored gum, which was triturated with 1:1 CH2Cl2 and hexanes (250 mL) to provide a brown solid. The solid was collected by filtration under reduced pressure and washed with CH2Cl2 (50 mL) to provide the product (98.8 g) as light brown solid.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:25]3[C:21](=[CH:22][CH:23]=[N:24]3)[N:20]=[C:19]3[C:15]=2COC3)=[CH:10][CH:9]=1.[C:26]1(C)[CH:31]=CC(S(O)(=O)=O)=[CH:28][CH:27]=1>CO>[N:24]1[N:25]2[C:21]([N:20]=[C:19]3[C:15](=[C:14]2[C:11]2[CH:10]=[CH:9][C:8]([OH:7])=[CH:13][CH:12]=2)[CH2:28][CH2:27][CH2:26][CH2:31]3)=[CH:22][CH:23]=1
Reactant: c1cc2nc3c(c(-c4ccc(OC5CCCCO5)cc4)n2n1)COC3
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
8-[4-(Tetrahydro-pyran-2-yloxy)-phenyl]-5H,7H-6-oxa-1,4,8a-triaza-s-indacene (500 mg, 2.5 mmol) was suspended in methanol and added with p-toluenesulfonic acid (50 mg) was catalyst. The mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The residue was carried on to the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.ClCCl.C(=O)([O-])[O-].[K+].[K+].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][N:10]([CH2:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[S:28]([CH3:27])(=[O:30])=[O:29])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ccc(CCNCc2ccncc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)N(CCc1ccc(Cl)cc1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 7.4 g. portion of 4-[2-(4-chlorophenyl)ethylaminomethyl]pyridine was dissolved in 50 ml. of dichloromethane, and to it were added 4 g. of potassium carbonate and 4 g. of methanesulfonyl chloride. The mixture was stirred at ambient temperature overnight, and then 100 ml. of additional dichloromethane was added, followed by 200 ml. of water. The organic phase was separated, washed with water, dried and concentrated under vacuum. The residue was chromatographed on silica gel, using acetone as the eluant. The product-containing fractions were combined and evaporated, and the residue crystallized upon standing. The solids were triturated with petroleum ether and filtered and dried to obtain 4.0 g. of the desired product, m.p. 96°-99°.
Reaction SMILES: [CH:1]1([C:4](=[O:29])[C:5](=[CH:25]OCC)[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1.Cl.[NH2:31]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH:1]1([C:4]2[O:29][N:31]=[CH:25][C:5]=2[C:6](=[O:7])[C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:3][CH2:2]1
Reactant: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(c1ccc(C(F)(F)F)cc1Sc1ccccc1)c1cnoc1C1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
A mixture of 3-cyclopropyl-2-ethoxymethylene-1-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (7 g), hydroxylamine hydrochloride (1.24 g) and sodium acetate (1.5 g) in ethanol was stirred at 25° C. for 2 hours. The mixture was then poured into water and extracted with ethyl acetate. The solution was dried over anhydrous sodium sulphate and filtered. The filtrate was evaporated and the residue purified by column chromatography on silica, using a mixture of ethyl acetate and hexane as eluent. The resulting solution was evaporated and the residue crystallized from cyclohexane to give 3.06 g of 5-cyclopropyl-4-(2-phenylsulphenyl-4-trifluoromethylbenzoyl)isoxazole (compound 1), m.p. 115° C.
Reaction SMILES: [CH3:1][CH:2]([CH:5]([CH3:11])[CH2:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:3]=[O:4].[CH3:12][C:13](C)([O-])[CH3:14].[K+].C(Cl)C=C>CN(C=O)C>[CH3:1][C:2]([CH:5]([CH2:6][C:7]([CH3:9])([CH3:8])[CH3:10])[CH3:11])([CH2:14][CH:13]=[CH2:12])[CH:3]=[O:4]
Reactant: CC(C)(C)[O-]
Reactant: CC(C=O)C(C)CC(C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C=CCCl
Product: C=CCC(C)(C=O)C(C)CC(C)(C)C
Yield: 12.2 %

Procedure:
In a similar manner to Example 6, 100 g of the aldehyde from Example 72 at a purity of 96% (0.61 mole) in 50 ml of DMF, 80 g of potassium t-butoxide (0.68 mole) in 500 ml of DMF, and 53 g of allyl chloride (0.69 mole) in 50 ml of DMF were reacted in the usual manner. In this way 90.5 g of crude O- and C-alkylates (65.7:9.6) and 12.2% of starting material were produced. The crude product was heated at 155°-170° C. for 3 hours to afford 87 g of crude aldehyde. This material was distilled to afford 51 g of purified product (43% yield). BP 45° C./0.15 mmHg; 1H-NMR (300 MHz), δ0.89 (9H, s), 0.93 (3H, s), 0.94 (1H, m), 0.98 (3H, d, J=6.84 Hz), 1.2 (1H, m), 1.84 (1H, m), 2.18 (1H, m), 2.35 (1H, m), 5.06 (2H, m), 5.67 (1H, m), 9.45 (1H, s); 13C-NMR (75 MHz), δ13.99, 16.69, 18.15, 30.03, 32.54, 38.98, 46.38, 53.29, 118.23, 133.47, 207.26; IR (Neat), 2960, 2700, 1730, 1640, 1480, 1370, 920 cm-1 ; MS (m/e), 181 (M+ -15), 98, 83, 69, 57 (Base);
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:16][CH:15]=2)=[N:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(-c2ccc(O)cc2)nc1
Reactant: BrCCCCCCCCC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCc1ccc(-c2ccc(OCCCCCCCCC3CCCC3)cc2)nc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A mixture of 0.157 g of 4-(5-heptyl-2-pyridyl)-phenol, 0.153 g of (8-bromooctyl)-cyclopentane, 6 ml of dimethylformamide and 0.24 g of finely powdered potassium carbonate was stirred at 55° C. for 3 hours. The reaction mixture was partitioned between water and diethyl ether. The organic phase was washed with water and with saturated sodium chloride solution, dried over magnesium sulphate, filtered and the filtrate was concentrated. Chromatography of the crude product (0.28 g) on 10 g of silica gel with hexane/ethyl acetate 37:3 (v/v) and two-fold recrystallization of the product-containing fractions from 3 ml of hexane each time gave 0.16 g of pure 5-heptyl-2-[4-(8-cyclopentyl-octyloxy)-phenyl]-pyridine; m.p. (C-SI) 38.3° C., SI -SC 56.9° C., cl.p. (SC -I) 72.6° C.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7](=[O:13])[NH:8][C:9](=[O:12])[NH:10][CH:11]=1.Br[CH2:15][CH2:16][CH2:17][Cl:18].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:18][CH2:17][CH2:16][CH2:15][N:10]1[CH:11]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:7](=[O:13])[NH:8][C:9]1=[O:12]
Reactant: O=c1[nH]cc(-c2cccs2)c(=O)[nH]1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c(=O)n(CCCCl)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 7 h
Yield: 21.5 %

Procedure:
A mixture of 5-(thiophen-2-yl)pyrimidine-2,4(1H,3H)-dione (Prep22, 1 g, 5.15 mmol), 1-bromo-3-chloropropane (0.81 g, 5.15 mmol) and potassium carbonate (0.71 g, 5.15 mmol) in DMF (10 ml) was stirred at room temperature for 7 hours, then the mixture was diluted with water and extracted with ethyl acetate. Organic phase was evaporated and the crude was purified by a FC (eluent P:E=3:1, 1:1) to afford the title compound (300 mg, y=21%)
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(OC)(OC)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:28](OCC)[CH3:29]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]=[CH:9][C:10]([O:12][CH2:28][CH3:29])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: CCOCC
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Product: CCOC(=O)C=CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4.22 g of 3-(4-chlorobenzoyl)-acrylic acid in 40 ml of dimethylformamide were added 3.68 g of dimethyl sulfate and 1.36 g of potassium carbonate, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added diethyl ether. The mixture was washed, in turn, with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over magnesium sulfate. The diethyl ether was removed from the mixture by evaporation, and the residue was recrystallized from hexane to give 2.68 g of ethyl 3-(4-chlorobenzoyl)acrylate.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][OH:12])[CH2:3]1.[CH:14](O)=[O:15]>>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH2:11][O:12][CH:14]=[O:15])[CH2:3]1
Reactant: CC1(C)CC(CO)c2ccccc21
Reactant: O=CO
Product: CC1(C)CC(COC=O)c2ccccc21
Yield: 82 %

Procedure:
17.6 g (0.1 mol) of 1,1-dimethyl-3-hydroxymethylindane (IX) and 46.0 g (1.0 mol) of formic acid were reacted at room temperature for 16 hours while stirring. After the reaction, surplus formic acid was removed under reduced pressure. The residue was extracted with ether, washed with aqueous sodium bicarbonate, and dried over anhydrous magnesium sulfate. The solvent was removed from the organic layer and the residue was distilled under reduced pressure to produce 16.8 g (0.82 mol) of (1,1-dimethylindane-3-yl)methylformate at a yield of 82%. The product was a colorless, transparent liquid having a woody, green odor similar to green tea with a scent of rush.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22](O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.O>[Br:16][C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:25]=1)[C:22]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)=[O:23]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cncc(Br)c1
Yield: 34 %

Procedure:
A solution of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (326 mg, 1.58 mmol), 5-bromonicotinic acid (300 mg, 1.5 mmol), HATU (627 mg, 1.65 mmol) and TEA (181.8 mg, 1.8 mmol) in DCM (15 mL) was stirred at 22° C. for 2 h, at which time the reaction mixture was diluted with water and extracted with DCM. The combined organic layers were dried and concentrated and the residue was purified by column chromatography to give title compound that was used in the next step without further purification (200 mg, Yield 34%). LCMS (m/z): 390/392 (M+1/M+2).
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].[ClH:18].[Cl:19][CH2:20][C:21]1[C:22]([NH:33][CH2:34][C:35]([F:38])([F:37])[F:36])=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1.C(Cl)Cl>[ClH:19].[ClH:18].[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[C:22]([NH:33][CH2:34][C:35]([F:38])([F:36])[F:37])=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2nc(NCC(F)(F)F)c(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCC(F)(F)F)c2cc(OC)c(OC)cc12
Temperature: 160 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
To a stirred solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (342 mg, 1.47 mmol) in THF (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxy-N-(2,2,2-trifluoroethyl)quinolin-2-amine hydrochloride SLA 41070 (500 mg, 1.47 mmol) at RT followed by a 2 N aq. LiOH solution (1.47 mL, 2.94 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (150 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent EtOAc:MeOH=100:0 to 97:3) followed by a second purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 95:5) provided, after evaporation and drying, 233 mg of 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol as a brown solid. This free base was dissolved in CH2Cl2 (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.49 M HCl solution in MeOH (3.05 mL). The reaction mixture was stirred for 5 min at RT then concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxy-2-(2,2,2-trifluoroethylamino)quinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 45 as a yellow solid (200 mg, 24% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[O:18][CH2:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][CH3:28])[CH:22]=1)[CH2:2][CH2:3][CH3:4].[CH2:29]([N:37]=[C:38]=[O:39])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:1]([O:5][C:6]1[CH:11]=[C:10](/[CH:12]=[C:13](\[O:18][CH2:19][CH3:20])/[C:14]([O:16][CH3:17])=[O:15])[CH:9]=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([N:27]([CH3:28])[C:38]([NH:37][CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:39])[CH:22]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C=NCCc1ccccc1
Reactant: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1-c1cccc(NC)c1
Product: CCCCOc1cc(/C=C(\OCC)C(=O)OC)ccc1-c1cccc(N(C)C(=O)NCCc2ccccc2)c1
Yield: 75.4 %

Procedure:
40 mg (0.1 mmol) of methyl (Z)-3-(2-butoxy-3′-methylaminobiphenyl-4-yl)-2-ethoxyacrylate and 16 mg (0.11 mmol) phenethyl isocyanate are heated at 85° C. by microwave in an Emrys Optimizer machine for 20 minutes. The residue obtained is purified by chromatography on a column of silica eluted with a 95/5 and then 90/10 heptane/ethyl acetate mixture. 40 mg (72%) of methyl (Z)-3-[2-butoxy-3′-(1-methyl-3-phenethylureido)biphenyl-4-yl]-2-ethoxyacrylate are obtained.
Reaction SMILES: C(OC1C=CN(C2C=CC(OCCN3CCCCC3)=CC=2)C(=O)C=1)C1C=CC=CC=1.[F:31]C1C=CC(COS(C)(=O)=O)=CN=1.[CH2:44]([O:51][C:52]1[CH:57]=[CH:56][N:55]([C:58]2[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH2:66][N:67]3[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]3)=[CH:60][N:59]=2)[C:54](=[O:73])[CH:53]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.FC1C=CC(CBr)=CC=1>>[F:31][C:48]1[CH:49]=[CH:50][C:45]([CH2:44][O:51][C:52]2[CH:57]=[CH:56][N:55]([C:58]3[CH:63]=[CH:62][C:61]([O:64][CH2:65][CH2:66][N:67]4[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]4)=[CH:60][N:59]=3)[C:54](=[O:73])[CH:53]=2)=[CH:46][CH:47]=1
Reactant: CS(=O)(=O)OCc1ccc(F)nc1
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cn1
Agent: Fc1ccc(CBr)cc1
Agent: O=c1cc(OCc2ccccc2)ccn1-c1ccc(OCCN2CCCCC2)cc1
Product: O=c1cc(OCc2ccc(F)cc2)ccn1-c1ccc(OCCN2CCCCC2)cn1

Procedure:
Example 25 was repeated except that 4-benzyloxy-1-{4-[2-(1-piperidinyl)ethoxy]phenyl}-1H-pyridin-2-one and 2-fluoro-5-methanesulfonyloxymethylpyridine were replaced with 4-benzyloxy-1-[5-(2-piperidin-1-ylethoxy)pyridin-2-yl]-1H-piridin-2-one (Example 20) and 4-fluorobenzyl bromide, to provide the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21]C(=O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3](=[O:25])[CH2:4][CH2:5][C:6]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCOC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)CCc1cc(C(C)=O)ccc1OCCCCCO
Temperature: 25 °C
Reaction time: 21 h
Yield: 96.8 %

Procedure:
A solution of 4.22 g (12.06 mmol) of 2-[[5-(acetyloxy)pentyl]oxy]-5-acetylbenzenepropanoic acid methyl ester and 0.1 g of p-toluenesulfonic acid monohydrate in 50 mL of methanol was stirred and refluxed for 3.5 hr and stirred at room temperature for 21 hr. Most of the methanol was removed in vacuo and the residue was diluted with water and worked-up with ether in the usual manner (the combined ether extracts were additionally washed with saturated aqueous sodium bicarbonate). The product was purified by flash chromatography on silica gel, eluting with 1:2 hexane-ethyl acetate. There was obtained 3.6 g (97%) of 2-[(5-hydroxypentyl)oxy]-5-acetylbenzenepropanoic acid methyl ester as a viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4]P(OCC)(OCC)=O.CC(C)([O-])C.[K+].[C:20]1([S:26]([N:29]2[C:37]3[C:32](=[C:33]([Br:38])[CH:34]=[CH:35][CH:36]=3)[CH:31]=[C:30]2[C:39](=O)[CH3:40])(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]=[C:39]([C:30]1[N:29]([S:26]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:27])=[O:28])[C:37]2[C:32]([CH:31]=1)=[C:33]([Br:38])[CH:34]=[CH:35][CH:36]=2)[CH3:40]
Reactant: CC(=O)c1cc2c(Br)cccc2n1S(=O)(=O)c1ccccc1
Reactant: CCOP(=O)(CC(=O)OC)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C=C(C)c1cc2c(Br)cccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Yield: 769.1 %

Procedure:
Methyldiethylphosphonoacetate (366 mg, 0.97 mmol) was dissolved in DMF (8 mL) under nitrogen, cooled in an ice bath, and treated with potassium t-butoxide (434 mg, 3.87 mmol). The ice bath was removed and allowed to warm to room temperature over 30 min. 1-(1-Benzenesulfonyl-4-bromo-1H-indol-2-yl)ethanone (366 mg, 0.97 mmol) dissolved in DMF (4 mL) was added and the reaction heated at 50° C. for 1.5 h. The reaction was allowed to cool and poured into ethyl acetate/saturated ammonium chloride solution. The aqueous was washed with more ethyl acetate. Then the pH was lowered and the aqueous washed a third time with ethyl acetate. The organic portions were washed with brine, dried (MgSO4), filtered and evaporated to give 3.24 g brown oil. The material was purified by column chromatography using (5:1) hexane:ethyl acetate to give 207 mg (28%) of a crude foam. The material was used without further purification. MS [EI+] 434, 436 (M+H)+.