Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[OH-].[Na+].[CH2:4]([O:10][C:11](Cl)=[O:12])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].ClC([O-])=O.C(=O)([O-])[O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22](CCCCCC)[C:21]=1[S:32]([OH:35])(=[O:34])=[O:33]>CC(CC)=O.O>[C:11](=[O:12])([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:32]([OH:35])(=[O:33])=[O:34])[O:10][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCc1cccc(OC(=O)[O-])c1S(=O)(=O)O
Reactant: CCCCCCOC(=O)Cl
Agent: O=C([O-])Cl
Agent: [Na+]
Agent: [Na]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCCCOC(=O)Oc1ccccc1S(=O)(=O)O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Into a reactor as described in Example 1 and with similar procedure there were charged 40.9 kg of water and, with agitation, 24.5 kg of sodium 4-phenolsulfonate. After an additional 10 minutes of agitation, there was added 9.7 kg of 50%, by weight, sodium hydroxide over a period of 15 minutes. There were then added 9.72 g of product and 68.1 kg of methylethyl ketone. After heating the mixture to 50° C. there was added 19.5 kg of n-hexylchloroformate over a period of 15 minutes. During addition of the chloroformate the batch temperature increased to about 65° C. and the reaction allowed to proceed with agitation for a period of 30 minutes at a temperature in the range of 65° C.-70° C. After completion of the reaction the mixture was cooled to below 50° C. and allowed to settle into two phases. The top organic layer containing n-hexylsulfophenyl carbonate was separated from the bottom saturated layer, and was washed with 22.72 kg of a 33 percent aqueous solution of sodium sulfate. After thorough mixing the mixture was allowed to settle. The top organic layer was separated from the bottom salt layer and the procedure with sodium sulfate repeated two more times. The organic layer was pan dried with vacuum. About 45.4 kg of n-hexyl sulfophenyl carbonate was obtained which contained 0.92 percent di-n-hexyl carbonate as indicated by analysis (gc) of a cyclohexane extract.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][CH2:4][NH:3]1.Br.Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][C@@H:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:4][CH2:5][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:7]1
Reactant: BrCc1ccccn1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1Cc1ccccn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of (S)-2-methyl-4-N—BOC-piperazine (400 mg, 1.997 mmol) and 2-(bromomethyl)pyridine hydrobromide (505 mg, 1.997 mmol) in anhydrous THF (5 ml) was added triethylamine (0.7 ml, 4.99 mmol) and the resulting mixture stirred at RT for 3 days. The mixture partitioned between water and EtOAc; organic layer washed with sat. NaCl, dried over MgSO4, filtered and evaporated. The residue purified by column chromatography (eluent: 5% MeOH in DCM) to give 320 mg (55%) to afford the title compound as a yellow oil. 1H NMR (CDCl3): 1.14 (d, J 6.2 Hz, 3H), 1.47 (s, 9H), 2.25 (t, J 9.5 Hz, 1H), 2.51 (m, 1H), 2.70 (d, J 11.6 Hz, 1H), 2.84 (brs, 1H), 3.15 (t, J 10.1, 1H), 3.47 (d, J 14.2 Hz, 1H), 3.69 (d, J 13.0 Hz, 1H), 3.75 (brs, 1H), 4.08 (d, J 14.0, 1H), 7.17 (dd, J 7.1 and 5.3, 1H), 7.45 (d, J 7.8, 1H), 7.66 (m, 1H), 8.56 (d, J=4.7 Hz, 1H).
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C(N(CC)C(C)C)(C)C.[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[N:41]=[C:42]=[O:43].Cl>C1(C)C=CC=CC=1>[F:33][C:34]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:35]=1[NH:41][C:42](=[O:43])[N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]([CH3:22])([CH3:23])[C:19]([OH:21])=[O:20])=[CH:15][CH:16]=1)[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNCCc1ccc(CC(C)(C)C(=O)O)cc1
Reactant: O=C=Nc1ccc(F)cc1F
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCN(CCc1ccc(CC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid (23 mg, 0.072 mmol), and N,N-diisopropylethylamine (0.152 mmol, 0.0264 mL) dissolved in toluene (2 mL) was added 2,4-difluorophenylisocyanate (0.0796 mmol, 0.0094 mL). The mixture was allowed to stir at room temperature for 72 hours, then was poured over 1 M HCl (5 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2 M HCl (2×), brine (2×), dried over anhydrous sodium sulfate, and concentrated to give a clear film. The crude product was chromatographed on silica gel (Merck silica gel 60, art#9385-3) eluting with 5% methanol/methylene chloride to give 3-(4-{2-[3-(2,4-difluoro-phenyl)-1-heptyl-ureido]-ethyl}-phenyl)-2,2-dimethyl-propionic acid as a clear film (18.5 mg, 54%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]1[O:9][CH2:8]1>C(O)C>[OH:5][CH2:4][CH2:3][CH2:2][NH:1][CH2:8][CH:7]([OH:9])[CH2:6][O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCCCCOCC1CO1
Reactant: NCCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCOCC(O)CNCCCO
Temperature: 80 °C
Yield: 135 %

Procedure:
A 300-ml two-necked flask equipped with a stirrer and a dropping funnel was charged with 25.1 g (0.33 mol) of 3-amino-1-propanol and 6.00 g of ethanol, and the contents were heated and stirred at 80° C. in a nitrogen atmosphere. After 9.00 g (33 mmol) of tetradecyl glycidyl ether were added dropwise over 2 hours, the resultant mixture was stirred further for 1 hour. The reaction mixture was poured into 400 ml of ice water and stirred for 1 hour. Crystals formed were then collected by filtration and recrystallized from methanol, thereby obtaining 15.4 g (yield: 92%) of the title compound (IIa-5).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1O.CS(Cl)(=O)=O.[NH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C>[CH3:1][C:2]1([CH3:14])[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:11][CH3:12])[CH:3]1[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1cccc2c1CC(C)(C)C2O
Reactant: C1CCNCC1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc2c1CC(C)(C)C2N1CCCCC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Triethylamine (10 ml) is added to a stirred solution of the 1-hydroxy indane of Step 2. above (8.4 g) in methylene chloride (190 ml) at RT under nitrogen; the mixture is cooled to 0° C. and methanesulfonyl chloride (4 ml) is added. The mixture is stirred for three hours at RT, cooled to 0° C., piperidine (128 ml) added and stirred at RT overnight. Sat'd aq. sodium bicarbonate is added to the mixture and the organic phase separated, washed with aq. sodium bicarbonate, sat'd NaCl, dried, filtered and the filtrate evaporated in vacuo affording the desired product as an oil.
Reaction SMILES: [Na].[C:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[N:12])=[N:9][CH:10]=1)([OH:4])=[O:3].N[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[SH:20]>C(O)C>[S:20]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:12]=[C:11]1[C:8]1[CH:7]=[CH:6][C:5]([C:2]([OH:4])=[O:3])=[CH:10][N:9]=1
Reactant: N#Cc1ccc(C(=O)O)cn1
Reactant: Nc1ccccc1S
Agent: [Na]
Solvent: CCO
Product: O=C(O)c1ccc(-c2nc3ccccc3s2)nc1

Procedure:
Sodium (7.7 mmol) is added to a flask containing 70 ml of ethanol. As soon as the sodium has dissolved, 7 mmol of 5-carboxy-2-cyanopyridine and 8.4 mmol of 2-amino-thiophenol are added and the solution is refluxed for 24 h. The solid formed is filtered off, redissolved in ethanol and water, the solution is made acidic (pH=3) with 2N HCl and evaporated. The residue is dissolved in 100 ml of hot ethyl acetate, the salts are filtered off and the filtrate on cooling gives crystals of the title compound, m.p. >300°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH3:16])=[O:5])[CH3:2].[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([CH3:29])OS1(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:27]([CH3:29])[CH2:28][NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([Cl:15])[C:9]=2[CH3:16])=[O:5])[CH3:2]
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1cc2ccc(Cl)c(C)c2[nH]1
Product: CCOC(=O)c1cc2ccc(Cl)c(C)c2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 6-chloro-7-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[C:28]([O:30][CH3:31])[CH:27]=[CH:26][C:4]=1[CH2:5][N:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2Br)[C@H:8]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[OH:25])[CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)CC(O)=O.C1(C)C=CC=CC=1>O1CCOCC1.[Cu]I>[Cl:24][C:22]1[CH:21]=[CH:20][C:19]2[O:25][C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C@H:9]3[CH2:10][N:6]([CH2:5][C:4]4[CH:26]=[CH:27][C:28]([O:30][CH3:31])=[CH:29][C:3]=4[O:2][CH3:1])[CH2:7][C@@H:8]3[C:18]=2[CH:23]=1
Reactant: COc1ccc(CN2C[C@@H](c3cc(Cl)ccc3O)[C@H](c3ccccc3Br)C2)c(OC)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc(CN2C[C@@H]3c4ccccc4Oc4ccc(Cl)cc4[C@H]3C2)c(OC)c1
Temperature: 25 °C
Yield: 108.5 %

Procedure:
A mixture of racemic trans-2-(1-(2,4-dimethoxybenzyl)-4-(2-bromophenyl)pyrrolidin-3-yl)-4-chlorophenol (6.8 g, 13.54 mmol), cesium carbonate (8.83 g, 27.1 mmol, 2.0 eq.), N,N-dimethylglycine (558 mg, 5.42 mmol; 0.4 eq.) and CuI (1.03 g, 5.42 mmol; 0.4 eq.) in dioxane (75 ml) was heated to reflux temperature overnight while stirring under inert nitrogen atmosphere to give 90% conversion according to LC-MS (M+1=422, 424 found). The reaction mixture was cooled to room temperature and was then filtered over a glass filter. The residual salts were washed with dioxane (25 ml). The combined filtrates were concentrated under vacuum to give the crude product as a brown oil. Toluene (150 ml) was added and the resulting solution was washed with concentrated aqueous ammonia (25 ml; 25%). The toluene layer was separated and dried with Na2SO4. Concentration under vacuum gave crude trans-5-chloro-2,3,3a,12b-tetrahydro-2-(2,4-dimethoxybenzyl)-1H-dibenz[2,3:6,7]-oxepino[4,5-c]pyrrole (6.2 g) in quantitative yield as a brown oil, with ca. 70% purity according to LC-MS analysis. The product was used without further purification.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]([O:26]C)=[O:25])[CH2:18]2)=[N:11][C:12]=1[S:13][CH2:14][CH2:15][CH3:16])=[O:6].Cl>O.CO.CCOC(C)=O.C(Cl)Cl>[CH3:3][N:4]([CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[C:5]([C:7]1[CH:8]=[CH:9][C:10]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]([OH:26])=[O:25])[CH2:18]2)=[N:11][C:12]=1[S:13][CH2:14][CH2:15][CH3:16])=[O:6]
Reactant: CCCSc1nc(N2CCC[C@@H](CC(=O)OC)C2)ccc1C(=O)N(C)C1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: CCCSc1nc(N2CCC[C@@H](CC(=O)O)C2)ccc1C(=O)N(C)C1CCOCC1
Temperature: 18 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A solution of sodium hydroxide (0.130 g, 3.25 mmol) in water (1.63 mL) was added dropwise to a stirred solution of methyl [(3S)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-yl}piperidin-3-yl]acetate (293 mg, 0.65 mmol) in MeOH (5 mL) at 18° C., over a period of 1 minute. The resulting solution was stirred at 18° C. for 20 hours. The reaction mixture was adjusted to pH 4.5 with 2M HCl and the reaction mixture was diluted with EtOAc (50 mL), and washed sequentially with water (20 mL) and saturated brine (20 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The residue was dissolved in DCM (10 ml) and the slight suspension filtered through a nylon millipore filter to remove the solid. Evaporation gave the product, [(3S)-1-{5-[methyl(tetrahydro-2H-pyran-4-yl)carbamoyl]-6-(propylthio)pyridin-2-yl}piperidin-3-yl]acetic acid (281 mg, 100%), as a white solid
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH2:15]([NH:17][C:18]([NH:20][C:21]1[N:39]=[C:24]2[CH:25]=[C:26]([C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:27]=[C:28]([C:29]([NH:31][NH2:32])=[O:30])[N:23]2[N:22]=1)=[O:19])[CH3:16]>O1CCOCC1>[C:1]([NH:32][NH:31][C:29]([C:28]1[N:23]2[N:22]=[C:21]([NH:20][C:18]([NH:17][CH2:15][CH3:16])=[O:19])[N:39]=[C:24]2[CH:25]=[C:26]([C:33]2[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:27]=1)=[O:30])(=[O:3])[CH3:2]
Reactant: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NN)n2n1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(C(=O)NNC(C)=O)n2n1

Procedure:
Acetic anhydride (0.95 mL, 10 mmol), triethylamine (1.2 mL, 8.6 mmol) and the product of Step 1 (0.996 g, 2.93 mmol) in dioxane (100 mL) was refluxed for 6 h. The solution was cooled and the product was filtered, washed with water and then dried to give 1-[5-(N′-acetyl-hydrazinocarbonyl)-7-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-3-ethyl-urea as a solid ACPI-MS Found: [M+H]+=383.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[H-].[Na+].[C:19](Cl)(=[O:21])[CH3:20]>C1C=CC=CC=1>[C:19]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:21])[CH3:20]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
A solution of 61.3 g (280 mmol) of benzyl (L)-pyroglutamate in 400 ml of benzene is added over 2 hours to a suspension of 13.4 g of NaH (280 mmol) in 50 ml of dry benzene. After stirring for one hour at ordinary temperature, a solution of 22.7 g (290 mmol) of acetyl chloride in 150 ml of benzene is run in and the mixture is heated at 55° for 5 hours and then stirred for 24 hours at ordinary temperature, washed with 2×150 ml of water, dried and evaporated. The product is distilled under reduced pressure; boiling point=150°-60° C. (0.25 mm Hg). This gives 60% of a pure product of Rf=0.63 (A).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24]C4CCCCO4)=[CH:20][CH:19]=3)[C:16]([C:32]([F:35])([F:34])[F:33])(O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:36]C4CCCCO4)[CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:24][C:21]1[CH:20]=[CH:19][C:18]([C:17]2[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([I:1])=[CH:7][CH:6]=3)[O:9][C:10]3[C:15]([C:16]=2[C:32]([F:35])([F:33])[F:34])=[CH:14][C:13]([OH:36])=[CH:12][CH:11]=3)=[CH:23][CH:22]=1
Reactant: OC1(C(F)(F)F)c2cc(OC3CCCCO3)ccc2OC(c2ccc(I)cc2)C1c1ccc(OC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Oc1ccc(C2=C(C(F)(F)F)c3cc(O)ccc3OC2c2ccc(I)cc2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
A mixture of 2-(4-iodo-phenyl)-6-(tetrahydro-pyran-2-yloxy)-3-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-4-trifluoromethyl-chroman-4-ol (3.0 g, 5.7 mmol) and TsOH (0.6 g, 3.18 mmol) in toluene (60 mL) was refluxed for 18 h, removing water with a Dean Stark trap. The mixture was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (PE/EA=10/1-4/1) to afford a white solid (1.5 g). 1H NMR (DMSO-d6): δ 9.17 (s, 1H), 9.07 (s, 1H), 7.56-7.54 (m, 2H), 7.35-6.95 (m, 5H), 6.67-6.50 (m, 4H), 5.73 (s, 1H). LCMS: 509 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.Cl.NC1C=CC(C=CC(O)=O)=CC=1>>[ClH:1].[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:5]=[CH:4][N:3]=[CH:2]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCC(F)(F)F
Agent: Cl
Agent: Nc1ccc(C=CC(=O)O)cc1
Product: COc1cc2cncnc2cc1OCC(F)(F)F
Yield: 113.9 %

Procedure:
An analogous reaction to that described in example 3c, but starting with 4-chloro-6-methoxy-7-(2,2,2-trifluoroethoxy)quinazoline (4.50 g, 15.4 mmol) and 4-aminocinnamic acid hydrochloride (3.07 g, 15.4 mmol) yielded 4-(4-(2-carboxy)ethenyl)anilino)-6-methoxy-7-(2,2,2-trifluoroethoxy)quinazoline hydrochloride (5.17 g, 74% yield) as a white solid:
Reaction SMILES: [OH-].[Li+].[CH2:3]([NH:7][C:8](=[O:33])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:30][CH2:31][CH3:32])/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6].C(O)(=O)C>O1CCCC1>[CH2:3]([NH:7][C:8](=[O:33])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](/[CH:23]=[C:24](\[O:30][CH2:31][CH3:32])/[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2)c1
Yield: 100.9 %

Procedure:
2.9 mL (2.9 mmol) of aqueous 1 M lithium hydroxide solution are added to a solution of 0.8 g (1.9 mmol) of ethyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylate in 10 mL of tetrahydrofuran. The reaction medium is heated at reflux for 20 hours. After cooling, 3 mL (2.9 mmol) of 1 N acetic acid are added and the reaction medium is extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, filtered and evaporated. 760 mg (100%) of (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-ethoxyacrylic acid are obtained in the form of a white solid with a melting point of 126° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]1=O)[CH3:2].[ClH:13]>P(Cl)(Cl)(Cl)=O>[Cl:13][C:4]1[N:3]([CH2:1][CH3:2])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=1
Reactant: CCn1c(=O)[nH]c2ccccc21
Reactant: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1c(Cl)nc2ccccc21
Yield: 77 %

Procedure:
1-Ethyl-2-benzimidazolinone (100 g, 0.62 mol) was dissolved in phosphorus oxychloride (475 mL) with stirring and heated to reflux temperature. Hydrogen chloride gas was passed into the refluxing solution for 4 h. Excess phosphorous oxychloride was removed on a rotary evaporator at 70° C. The residue was poured into a stirred mixture of aqueous potassium carbonate solution and methylene chloride. The mixture was basified with 50% sodium hydroxide solution and the methylene chloride layer was separated, dried (Na2SO4), concentrated, and distilled to obtain 86 g (77%) of oil, bp 110°-115° C./2-0.3 mmHg, which crystallized on standing; mp 50°-52° C.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[C:3](=O)[CH2:4][C:5]#[N:6].Cl.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[F:1][C:2]([F:12])([C:3]1[CH:4]=[C:5]([NH2:6])[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=1)[C:8]([F:9])([F:11])[F:10]
Reactant: N#CCC(=O)C(F)(F)C(F)(F)F
Reactant: NNc1ccccc1
Agent: Cl
Solvent: CCO
Product: Nc1cc(C(F)(F)C(F)(F)F)nn1-c1ccccc1
Temperature: 90 °C
Yield: 43.4 %

Procedure:
A stirred mixture of 4,4,5,5,5-pentafluoro-3-oxopentanenitrile (500 mg, 2.66 mmol) and phenylhydrazine hydrochloride (386 mg, 2.66 mmol) in ethanol (5 mL) was heated at 90° C. for 4 h. The reaction mixture was concentrated under reduced pressure, and the obtained oil purified by silica gel flash column chromatography (eluting with a gradient of 100% petroleum ether to 10% ethyl acetate in petroleum ether) to afford 3-(perfluoroethyl)-1-phenyl-1H-pyrazol-5-amine (320 mg, 43%) as a solid. 1H NMR (400 MHz, CDCl3) 87.51-7.60 (m, 4H), 7.45 (m, 1H), 5.91 (s, 1H), 3.96 (brs, 2H); LC-MS (ESI) m/z 278 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][N:22]=4)=[O:20])[CH2:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[CH:5][CH:4]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][OH:41].O>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:18][N:17]([C:19]([C:21]4[CH:26]=[C:25]([O:27][CH2:39][CH2:40][OH:41])[CH:24]=[CH:23][N:22]=4)=[O:20])[CH2:16]3)=[CH:11][C:10]=2[O:28][CH3:29])=[CH:30][CH:31]=1)[CH3:2]
Reactant: OCCBr
Reactant: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(O)ccn4)C3)cc2OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(COc2ccc(C3CN(C(=O)c4cc(OCCO)ccn4)C3)cc2OC)cc1
Temperature: 80 °C
Reaction time: 11 h
Yield: 80 %

Procedure:
To a suspension of {3-[4-(4-ethylbenzyloxy)-3-methoxyphenyl]azetidin-1-yl}-(4-hydroxypyridin-2-yl)-methanone (9.6 g) prepared in Example 4 (4) and K2CO3 (40 g) in DMF (90 mL) was added 2-bromoethanol (9.6 mL). The reaction mixture was stirred at 80° C. for 11 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over Na2SO4. The solvent was removed under reduced pressure. Diisopropyl ether was added to the residue. The precipitated solid was collected on a filter and dried to give the title compound (8.4 g, 80%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH3:18])[CH2:10][CH:11]=[CH2:12])=[CH:5][C:4]=1[F:19])#[N:2].C12BC(CCC1)CCC2.C([O-])(O)=[O:30].[Na+].OO>C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:13]2[CH:17]=[CH:16][N:15]=[C:14]2[CH3:18])[CH2:10][CH2:11][CH2:12][OH:30])=[CH:5][C:4]=1[F:19])#[N:2]
Reactant: C=CCC(c1ccc(C#N)c(F)c1)n1ccnc1C
Reactant: O=C([O-])O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nccn1C(CCCO)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the olefin from Step J (1.303 g, 5.11 mmol) in 10 mL of THF at 0° C. was added a solution of 9-borabicyclo[3.3.1]nonane in THF (50 mL, 25.5 mmol, 0.5 M). After one hour, the reaction was warmed to room temperature for 3 hours, then recooled to 0° C. A solution (20 mL) of sat. aq. NaHCO3 and 30% aq. H2O2 (2:1) was added, and the reaction was warmed to room temperature. After 30 minutes, the mixture was partitioned between CHCl3 and aq. NaHCO3 solution, and the aqueous phase was extracted with CHCl3. The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (5-8% MeOH/CH2Cl2, then rechromatographed using 50-100% acetone/CH2Cl2) provided the titled compound as a pale yellow oil.