Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:9]1[N:14]=[C:13]([CH:15]=[O:16])[CH:12]=[CH:11][CH:10]=1.[C:17]1([N:23]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B2OC(C)(C)C(C)(C)O2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1.O.CO.CO>[CH:15]([C:13]1[N:14]=[C:9]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH2:31][N:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:10]=[CH:11][CH:12]=1)=[O:16]
Reactant: O=Cc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1B1OC(C)(C)C(C)(C)O1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1-c1cccc(C=O)n1)c1ccccc1
Temperature: 80 °C
Yield: 84 %

Procedure:
A mixture of water (160 mL) and methanol (40 mL) was combined with sodium carbonate (3.80 g, 35.9 mmol), and the mixture was sparged with nitrogen for 30 min. In a separate flask were combined, under nitrogen, 6-bromo-2-pyridinecarboxaldehyde (2.67 g, 14.4 mmol), tert-butyl phenyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate (5.87 g, 14.4 mmol), tetrakis(triphenylphosphinio)palladium (0.829 g, 0.718 mmol), and toluene (150 mL). The water-methanol solution was added via cannula to the toluene solution, and the biphasic mixture was heated to 80° C. overnight. At this time 1H NMR spectroscopic analysis of an aliquot indicated that the reaction was complete. The clear yellow organic layer was separated, dried with brine, then over magnesium sulfate. The crude product was purified by chromatography on silica using 1:1 hexanes:dichloromethane elutant and increasing the strength by addition of up to 10% EtOAc. The product was isolated as a sticky oil (4.7 g, 840%). 1H NMR (CD2Cl2, 500 MHz): 10.0 (s, 1H), 7.83-7.92 (m, 2H), 7.56 (d, 1H), 7.50 (d, 1H), 7.44 (m, 1H), 7.36 (m, 2H), 7.17 (t, 2H), 7.01 (t, 1H), 7.0 (br d, 2H), 5.11 (s, 2H), 1.34 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[F:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: Nc1ccccc1F
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Product: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluoroaniline to give the title compound 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.53 (s, 3H), 7.15 (m, 3H), 8.25 (m, 1H), 7.44 (m, 1H), 10.31 (s, 1H), 11.35 (br s, 1H). LC MS (m/e)=298 (MH+).
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:27])[C:11]2[O:17][C:16]3[C:18]([Cl:23])=[CH:19][C:20]([NH2:22])=[CH:21][C:15]=3[CH2:14][S:13](=[O:25])(=[O:24])[C:12]=2[CH:26]=1)=[O:7].C(=O)(O)[O-].[Na+].[C:33](O)(=[O:35])[CH3:34]>O.C1COCC1>[CH3:4][O:5][C:6]([C:8]1[CH:9]=[C:10]([CH3:27])[C:11]2[O:17][C:16]3[C:18]([Cl:23])=[CH:19][C:20]([N:22]([CH2:2][CH2:1][OH:3])[CH2:34][CH2:33][OH:35])=[CH:21][C:15]=3[CH2:14][S:13](=[O:25])(=[O:24])[C:12]=2[CH:26]=1)=[O:7]
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N)cc(Cl)c1O2
Reactant: CC(=O)O
Reactant: C1CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N(CCO)CCO)cc(Cl)c1O2
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethylene oxide (120 mL) was added to a stirred solution of compound of Example 1 (4.5 g, 12.26 mmol) in acetic acid (50 mL), water (50 mL) and THF (20 mL) mixture at −70° C., over a period of 1 h and then stirred at 25° C. for 14 h. The reaction mixture was cooled; pH was adjusted to 7 using 10% aqueous solution of sodium bicarbonate. The reaction mixture was extracted with ethyl acetate (3×250 mL). Combined organic layer was washed with brine (2×100 mL) and dried over sodium sulphate. Solvent was removed and the resulting crude product was purified by column chromatography (silica gel, ethyl acetate/pet ether) to obtain the title compound. Yield: 4 g (72%); mp 199-201° C.; 1H NMR (DMSO-d6, 300 MHz): δ 2.62 (s, 3H, CH3), 3.40 (t, 4H, 2CH2), 3.51 (t, 4H, 2CH2), 3.85 (s, 3H, OCH3), 4.80 (t, 2H, 20H), 5.11 (s, 2H, CH2), 6.76 (s, 1H, Ar), 6.83 (s, 1H, Ar), 8.06 (s, 1H, Ar), 8.13 (s, 1H, Ar); MS: m/e (ES+) 456 (M+1).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[C:30](OC)=[O:31]>CCCCCC.C1COCC1>[N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][O:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[CH2:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][CH:36]=1)[CH:30]=[O:31]
Reactant: COC(=O)c1cccc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1cccc(Cc2cccc(OCc3ccc4ccccc4n3)c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diisobutyl aluminum hydride (0.01 mol) in hexane is added dropwise to a solution of methyl 3-(3-(2-quinolinylmethyloxy)benzyl)benzoate (0.01 mol) in 100 ml of THF at 0° C. The reaction mixture is stirred at 0° C. for 30 minutes and then quenched with methanol and Rochelle salt. Extraction with ethyl acetate and purified by column chromatography gives 3-(3-(2-quinolinylmethyloxy)benzyl)benzaldehyde.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:58][N:59]1[CH2:64][CH2:63][CH2:62][C@H:61]([NH2:65])[CH2:60]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:65][C@H:61]5[CH2:62][CH2:63][CH2:64][N:59]([CH3:58])[CH2:60]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN1CCC[C@H](N)C1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)N[C@H]2CCCN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and (S)-1-methylpiperidin-3-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17-1.26 (m, 2H) 1.29-1.46 (m, 3H) 1.55-1.73 (m, 5H) 1.75-1.90 (m, 6H) 2.23 (br s, 3H) 2.64-2.78 (m, 1H) 2.79-2.95 (m, 1H) 3.31 (s, 3H) 3.90-4.01 (m, 1H) 3.94 (s, 3H) 4.07 (t, J=12.63 Hz, 2H) 4.37-4.53 (m, 1H) 7.47 (dd, J=8.46, 1.64 Hz, 1H) 7.51 (d, J=1.77 Hz, 1H) 7.91 (s, 1H) 8.10 (d, J=7.33 Hz, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H). [M+H] calc'd for C28H37F2N7O3 558. found 558.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:7]([NH2:9])=[O:8])[CH3:2].[Cl:15][CH2:16][C:17](=O)[CH2:18]Cl>>[Cl:15][CH2:16][C:17]1[N:9]=[C:7]([C:6]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[O:8][CH:18]=1
Reactant: CCOc1cc(C(N)=O)ccc1OC
Reactant: O=C(CCl)CCl
Product: CCOc1cc(-c2nc(CCl)co2)ccc1OC
Yield: 49.4 %

Procedure:
Using 29.4 g of 3-ethoxy-4-methoxybenzamide and 57 g of 1,3-dichloro-2-propanone and following the procedure of Reference Example 55, 19.9 g of white powdery 4-chloromethyl-2-(3-ethoxy-4-methoxyphenyl)oxazole was obtained.
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.[CH3:26][C:27](O)(C#C)C.[OH-].[K+]>C1COCC1.C(N(CC)CC)C.C(O)(C)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:26]([C:2]1[N:3]=[CH:4][N:5]([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)#[CH:27]
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C#Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.4 %

Procedure:
To a stirred solution of 4-iodo-1-trityl-1H-imidazole (830 mg, 1.96 mmol) and Pd(Ph3P)2Cl2 (40 mg, 3 mol %) in THF (8 mL) and triethylamine (2 mL) was added 2-methyl-but-3-yn-2-ol (0.30 mL, 3.10 mmol) and the reaction vessel was evacuated and backfilled with nitrogen three times to remove atmospheric oxygen. Copper (I) iodide (40 mg, 10 mol %) was added and the reaction was stirred at room temperature for 5 h. After this time the solvent was removed under vacuum and the residue was filtered through a plug of silica gel (eluent=2:1 hexane:ethyl acetate) to give the crude alkynol product. This material was dissolved in isopropanol (10 mL) and treated with potassium hydroxide (150 mg, 2.67 mmol). The reaction mixture was heated to 70° C. for 4 h and then concentrated under vacuum and purified by silica-gel chromatography (eluent=4:1 hexane:ethyl acetate) to afford the product as a white solid (258 mg, 41% yield over two steps). 1H-NMR (CDCl3) δ 7.41 (s, 1H), 7.38-7.31 (m, 9H), 7.13-7.07 (m, 6H), 7.05 (d, J=1 Hz), 3.05 (s, 1H).
Reaction SMILES: CC[O:3][C:4]([CH:6]1[C:8]([CH3:10])([CH3:9])[CH:7]1[CH:11]=C(C)C)=[O:5].[Mn]([O-])(=O)(=O)=[O:16].[K+].[OH2:21].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O>[CH3:9][C:8]1([CH3:10])[CH:7]([C:11]([OH:16])=[O:21])[CH:6]1[C:4]([OH:3])=[O:5]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)C1C(C=C(C)C)C1(C)C
Reactant: O
Agent: O=S([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C)C(C(=O)O)C1C(=O)O
Temperature: 10 °C
Reaction time: 4 h

Procedure:
To solution of ethyl chrysanthemumate (200 g) in acetone (1200 mL) at 40-45° C. was added potassium permanganate (KMnO4) (580 g) as a solid in 10 equal portions. After each addition of KMnO4, the exotherm that ensued was allowed to subside before the addition of the next portion of KMnO4. Upon completion of KMnO4 addition, the reaction mixture was stirred for another 4 h. After cooling the reaction mixture to about 10° C. water (1200 mL) was added. The resulting slurry was transferred to a mixture of sodium sulfite (600 g) and water (600 mL) with a 400 mL water rinse. The reaction mixture was cooled to 10° C., and 98% sulfuric acid (400 mL) while maintaining the temperature below 30° C. The layers were separated and the aqueous layer was extracted with methyl tert-butyl ether (MTBE) (800 mL). The organic solutions were combined and any water that settled was removed. The organic solution was concentrated under atmospheric pressure and about 700 mL. MTBE (800 mL) was added and the mixture was concentrated again to about 700 mL. The hot solution was cooled to about 50° C. and MTBE (800 mL) was added. The MTBE solution was cooled further to 10° C. and 25% NaOH solution (456 mL) was added while maintaining the temperature below 25° C. The aqueous layer was separated and then heated at 50° C. After 2 h, the mixture was cooled to 5° C. and acidified to pH 2-3 with 35% HCl solution (about 340 mL). The aqueous mixture was extracted twice with EtOAc (1000 mL+500 mL). The EtOAc layer was concentrated under atmospheric pressure to about 600 mL whereupon toluene (1000 mL) was added. Further concentration of this solution under reduced pressure to about 600 mL led to the precipitation of the product. The suspension was cooled to 5° C. filtered, and the filter cake washed with 100 mL of toluene. The wet product was dried under reduced pressure to give 100 g of caronic acid as a mixture of the cis- and trans-isomers.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[CH:18]([N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([CH3:20])[CH3:19]>>[ClH:1].[CH:18]([N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)=[CH:4][N:3]=2)[CH2:23][CH2:22]1)([CH3:20])[CH3:19]
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)nc2)cc1
Reactant: CC(C)N1CCNCC1
Product: CC(C)N1CCN(c2ncc(-c3ccc(C(F)(F)F)cc3)cn2)CC1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyrimidine and 1-isopropylpiperazine.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5].IC.[C:36](=O)([O-])[O-].[K+].[K+].CS(C)=O>C(OCC)C>[CH3:36][O:1]/[N:2]=[C:3](/[C:9]1[N:10]=[C:11]([NH:14][C:15]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:12][CH:13]=1)\[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOCC
Solvent: CI
Product: CCOC(=O)/C(=N\OC)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 74.2 %

Procedure:
To ethyl (Z)-2-(hydroxyimino)-2-[2-(triphenylmethyl)aminothiazol-4-yl]acetate(46 g) were added iodo methane(28.4 g), potassium carbonate (27.6 g) and dimethylsulfoxide(500 ml), and the mixture was stirred for 5 hours at room temperature. After ethyl ether(2 l) was added to the reaction mixture, the mixture was washed 5 times with distilled water(500 ml). The separated organic layer was dehydrated with anhydrous magnesium sulfate, filtered, and then concentrated. The residue was chromatographed over silica gel to give the above-indicated compound (35.2 g) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:30][S:31](O)(=[O:33])=[O:32].P(Cl)(Cl)(Cl)(Cl)Cl>ClCCl.C1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C@@H:11]([N:13]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([S:31]([Cl:30])(=[O:33])=[O:32])[CH2:19][CH2:18]3)[CH2:14][CH3:15])[CH3:12])=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: CCN(CC1CCNCC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCN(CC1CCN(S(=O)(=O)Cl)CC1)[C@@H](C)Cc1ccc2c(c1)CCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine (0.2 grams, 0.66 mmole) and triethylamine (0.15 grams, 1.48 mmole) in dichloromethane (4 ml) at 0° C. was added dropwise a solution of chlorosulfonic acid (0.08 grams, 0.66 mmol) in dichloromethane (0.5 ml). The mixture was stirred at room temperature for 16 hours, and the solvent was removed under reduced pressure. To the residue was added benzene (4 ml) and phosphorous pentachloride (0.14 grams, 0.67 mmole). The mixture was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and 1N sodium hydroxide. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give (S)-N-[2-(2,3-dihydrobenzofuran-5-yl)-1-methylethyl]-N-ethyl-(1-chlorosulfonylpiperidin-4-ylmethyl)amine as a viscous oil (0.18 grams, 70%), M+H 401.
Reaction SMILES: [NH2:1][CH:2]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:16]1([CH2:22][C:23](Cl)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCOCC1>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([CH:2]([NH:1][C:23](=[O:24])[CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][C:4]([OH:6])=[O:5])=[CH:12][CH:11]=1
Reactant: NC(CC(=O)O)c1ccc(Cl)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1ccc(Cl)cc1

Procedure:
9.6 g of 3-amino-3-(4-chlorophenyl)propionic acid are dissolved in 200 ml of dioxane and about 50 ml of 1N NaOH in order to reach pH=10.5-11.5. The medium is cooled to +5° C. and 6.34 ml of phenylacetyl chloride are then gradually added, while maintaining the mixture at pH=10.5-11.5 and at a temperature of between +5° C. and +10° C.. Stirring is continued for 1 and a half hours and the medium is then concentrated to one-half before diluting with 500 ml of water. The resulting mixture is washed twice with EtOAc and then acidified to pH=1-2 by addition of 6N HCl The solid is drained, washed with water and dried to give 14 g of the expected compound.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[CH3:8][N:9]([CH3:18])[C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].CCN(C(C)C)C(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([NH:36][C:37]2[C:38]3[C:45]4[CH2:46][CH2:47][NH:48][CH2:49][C:44]=4[S:43][C:39]=3[N:40]=[CH:41][N:42]=2)[CH:32]=[CH:33][C:34]=1[Cl:35].CCN=C=NCCCN(C)C>C(Cl)Cl.O>[Cl:28][C:29]1[CH:30]=[C:31]([NH:36][C:37]2[C:38]3[C:45]4[CH2:46][CH2:47][N:48]([C:5](=[O:7])/[CH:4]=[CH:3]/[CH2:2][N:15]5[CH2:14][CH2:13][N:12]([C:10]([N:9]([CH3:18])[CH3:8])=[O:11])[CH2:17][CH2:16]5)[CH2:49][C:44]=4[S:43][C:39]=3[N:40]=[CH:41][N:42]=2)[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: Clc1ccc(Nc2ncnc3sc4c(c23)CCNC4)cc1Cl
Reactant: O=C(O)/C=C/CBr
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N1CCN(C/C=C/C(=O)N2CCc3c(sc4ncnc(Nc5ccc(Cl)c(Cl)c5)c34)C2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.9 %

Procedure:
(2E)-4-Bromobut-2-enoic acid (106 mg, 0.64 mmol) and piperazine-1-carboxylic acid dimethylamide (107 mg, 0.68 mmol) were dissolved in DCM (5.0 mL), and DIPEA (111 mg, 0.85 mmol) was added. The mixture was stirred at rt for 2 h. Subsequently, the compound from Example 15A (150 mg, 0.43 mmol), DIPEA (55 mg, 0.43 mmol) and EDCI (82 mg, 0.43 mmol) were added. The reaction mixture was stirred at rt overnight. Then, water was added, and the mixture was extracted three times with DCM. The combined organic layers were dried over sodium sulfate. The solvent was removed in vacuo, and the residue was purified by preparative HPLC to yield 59 mg (24%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:21][NH2:22].O>CN(C)C=O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][C:10](=[O:20])[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[N:22]2[CH3:21])=[CH:18][CH:17]=1
Reactant: CN
Reactant: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C2CC(=O)CC(c3ccc(C)cc3)N2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
1,5-Bis(4-methylphenyl)-1,4-pentadien-3-one (20aa, 0.32 g, 1.2 mmol) was dissolved in dimethyl formamide (9 ml). Methylamine (51, 0.5 ml, 5.8 mmol, 40% in water) was added and the mixture stirred for 72 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.26 g (75%) of a white solid: mp 120-121° C. [expected mp 105-107° C.]; 1H NMR δ 1.79 (s, 3H), 2.36 (s, 6H), 3.10 (d, 2H, J=14.9 Hz), 2.79 (t, 2H, J=13.1 Hz), 3.35 (dd, 2H, J=11.9, 2.4 Hz), 7.15 (d, 4H, J=8.0 Hz), 7.21 (d, 4H, J=7.9 Hz); 13C NMR: δ 21.2, 40.7, 50.9, 70.0, 126.9, 129.4 137.2, 140.2, 207.1.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[CH:4][CH:3]=1.[N+:10]([CH:13]([CH3:15])[CH3:14])([O-:12])=[O:11]>COCCOCCOC>[CH3:14][C:13]([N+:10]([O-:12])=[O:11])([CH3:15])[CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)[N+](=O)[O-]
Solvent: COCCOCCOC
Product: CC(C)(Cc1ccc(O)cc1)[N+](=O)[O-]
Temperature: 38 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
A mixture of 4-hydroxybenzyl alcohol (100.08 g, 806 mmol), 2-nitropropane (400 mL, 4.45 mol) and diglyme (800 mL) was heated to 38° C. Potassium L-butoxide (45.29 g, 403.6 mmol) was added, and the mixture was heated to reflux at 132° C. with a Dean-Stark trap. Water began collecting in the trap, and continued at a high rate for approximately 1.5 h. When water collection slowed (around 2.5 h) then portions of solvent (30-40 mL each) were removed every thirty minutes. During the water collection and solvent removal the temperature rose from 132° C. to 149° C. After 4 h less than 1% of the 4-hydroxybenzyl alcohol remained by HPLC analysis. The heating mantle was removed, and the reaction mixture was allowed to cool. When the temperature was 100° C. water (200 mL) was added, and the solution was allowed to cool to room temperature. Solvent was removed on a rotary evaporator under vacuum until 593 g of solution remained. Water (500 mL) and EtOAc (500 mL) were added and the layers were separated (layer separation was poor, but addition of 20% aqueous NaCl was ineffectual). The aqueous layer was extracted with EtOAc (200 mL), and the combined organic layers were extracted with 1N HCl (500 mL) and water (300 mL). The organic layer was distilled in vacuo to 261 g of oil to which EtOAc was added (160 mL). Heptane (3.4 L) was added rapidly with vigorous stirring for 30 min, and the product crystallized to yield a beige solid (112.36 g, 71% yield, >98% purity by HPLC analysis). Another crop of crystals may be obtained from the filtrate by concentrating and filtering the solids, or by concentrating more fully to a solution and adding heptane to crystallize. NMR. E.A.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].Cl[CH:36]1[CH2:40][O:39][C:38](=[O:41])[O:37]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([O:34][CH:36]3[CH2:40][O:39][C:38](=[O:41])[O:37]3)=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: O=C1OCC(Cl)O1
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1nc2cccc(C(=O)OC3COC(=O)O3)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Yield: 16.8 %

Procedure:
A solution of 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (1.0 g), 4-chloro-1,3-dioxolan-2-one (0.41 g) and triethylamine in DMF was stirred at 90° C. for 12 hrs. The reaction mixture was concentrated, and the residue was dissolved in chloroform and 1N hydrochloric acid. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.20 g, 22%) as a colorless solid.