Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([Br:8])=[C:6](Br)[CH:5]=[C:4]([Br:10])[CH:3]=1.[CH:11](=[O:13])[CH3:12]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([Br:10])[CH:5]=[C:6]([CH:11]([OH:13])[CH3:12])[C:7]=1[Br:8]
Reactant: CC=O
Reactant: Fc1cc(Br)cc(Br)c1Br
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)cc(F)c1Br
Temperature: -70 °C
Reaction time: 2 h

Procedure:
120 g (0.36 mol) of 6-fluoro-1,2,4-tribromobenzene in 120 ml of tetrahydrofuran are added dropwise to 290 ml (0.38 mol, 1.3 M solution in tetrahydrofuran) of isopropylmagnesium chloride/lithium chloride complex cooled to −70° C., and the mixture is stirred at −50° C. for 2 h. The mixture is subsequently cooled to −70° C., before 17.6 g (0.4 mol) of acetaldehyde in 40 ml of tetrahydrofuran are added dropwise. The batch is slowly warmed to −20° C. and then quenched by the addition of saturated ammonium chloride solution.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8](SC)=[C:9](O)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31].C[S:37]([CH3:39])=O>O>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:7])=[C:39]([CH:6]=1)[S:37][CH:29]([CH3:35])[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CS(C)=O
Reactant: CCOC(=O)C(C)Br
Reactant: CSc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)C(C)Sc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1C
Temperature: 25 °C
Reaction time: 7 h

Procedure:
5-(2-Chloro-4-trifluoromethylphenoxy)-2-(methylthio)phenol (9.5 grams; 0.0296 mole), potassium carbonate (16.56 grams; 0.12 mole) ethyl 2-bromopropionate (7.79 ml; 0.06 mole) and dimethylsulfoxide (150 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture was stirred at room temperature for a period of about 7 hours. After this time the reaction mixture poured into 600 ml of water. The resulting mixture was then extracted three times with 100 ml portions of methylene chloride. The extracts were combined and washed with water. The washed extract was then dried using a phase separator. The dried solution was stripped of solvent under aspirator pressure leaving a clear oil as the residue. The residue was chromatographed through a clay column using hexane and ethyl acetate as the eluant. Fourteen fractions were collected and fraction 12 was stripped of solvents to yield the desired product ethyl 2-[5-(2-chloro-4-trifluoromethylphenoxy)-2-methylthiophenoxy]propionate as a white crystalline solid melting at 70° to 71° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[CH:10][C:9]([CH:22]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:8][C:7]=2I)[CH2:3][CH2:2]1.[C:33]([Cu])#[N:34]>CN1C(=O)CCC1>[C:33]([C:7]1[CH:8]=[C:9]([CH:22]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:10]=[C:11]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][CH:17]=2)[C:6]=1[O:5][CH2:4][CH:1]1[CH2:3][CH2:2]1)#[N:34]
Reactant: N#C[Cu]
Reactant: CCOC(=O)C(CC(C)C)c1cc(I)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(CC(C)C)c1cc(C#N)c(OCC2CC2)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 200 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
To a stirred solution of ethyl 2-(6-(cyclopropylmethoxy)-5-iodo-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.25 g, 0.447 mmol) in NMP (10 mL) was added CuCN (50 mg, 0.536 mmol) at RT under inert atmosphere. The reaction mixture was stirred at 200° C. temperature over a period of 2 h. After completion of starting material (by TLC), the reaction mixture was cooled to RT and extracted with EtOAc (3×20 mL). Combined organic layers were washed with water (3×15 mL), brine and dried over Na2SO4. After filtration and evaporation, the crude material was purified by column chromatography to afford ethyl 2-(5-cyano-6-(cyclopropylmethoxy)-4′-(trifluoromethyl) biphenyl-3-yl)-4-methylpentanoate (0.125 g) a solid.
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH3:17])[N:11]=1.[CH3:18][C:19]([CH3:23])=[CH:20][CH2:21]Br.O>C1COCC1.C(OCC)(=O)C>[Cl:9][C:10]1[N:15]=[C:14]([Cl:16])[CH:13]=[C:12]([CH2:17][CH2:21][CH:20]=[C:19]([CH3:23])[CH3:18])[N:11]=1
Reactant: CC(C)=CCBr
Reactant: Cc1cc(Cl)nc(Cl)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)=CCCc1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
The above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at −78° C. was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added. The organic layer was separated, the solvent was removed in vacuo, and the residue was chromatographed (ethyl acetate/hexane, 1/1 9) to give 2.06 g (74%) of 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (1H NMR (CDCl3) δ 7.15 (s, 1), 5.10 (t, 1), 2.80 (t, 2), 2.45 (m, 2), 1.70 (s, 3), 1.55 (s, 3). To a solution of NaIO4 (17 g, 81 mmol) and KMnO4 (251 mg, 1.59 mmol) in water was added K2CO3 (1.29 g, 9.38 mmol) and 2,4-dichloro-6-(4-methyl-3-pentenyl)pyrimidine (2.06 g, 8.9 mmol) in t-butanol. After stirring for 16 hours, the reaction was acidified to pH 3 and extracted with ethyl acetate. The organic layer was extracted with aqueous NaHCO3. The aqueous layer was acidified to pH 3 and extracted with ethyl acetate. The organic layer was dried and the solvent removed in vacuo to give 980 mg of 3-(2,4-dichloropyrimidin-6-yl)propionic acid (the compound of formula (XIX)), 1H NMR (CDCl3) δ 7.30 (s, 1), 3.05 (t, 2), 2.90 (t, 2). The acid was coupled to piperonylamine under standard conditions with isobutyl chloroformate and N-methylmorpholine to give the compound of formula (XX). Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60° C.) to give N-[(1,3-benzodioxol-5-yl)ethyl]-6-chloro-2-(1H-imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=2[N:8]=[C:7]1[C:17]1[C:18]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2Cl)=[N:19][CH:20]=[CH:21][CH:22]=1.[CH3:35][O:36][C:37](=[O:46])C1C=CC(CO)=CC=1>>[CH3:35][O:36][C:37](=[O:46])[C:28]1[CH:27]=[CH:26][C:25]([CH2:24][O:23][C:18]2[C:17]([C:7]3[N:6]([CH2:5][C:4]4[CH:32]=[CH:33][CH:34]=[C:2]([Cl:1])[CH:3]=4)[C:10]4[CH:11]=[C:12]([F:16])[C:13]([F:15])=[CH:14][C:9]=4[N:8]=3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:30][CH:29]=1
Reactant: Fc1cc2nc(-c3cccnc3OCc3ccccc3Cl)n(Cc3cccc(Cl)c3)c2cc1F
Reactant: COC(=O)c1ccc(CO)cc1
Product: COC(=O)c1ccc(COc2ncccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 1-(3-chloro-benzyl)-2-(2-chloro-pyridin-3-yl)-5,6-difluoro-1H-benzoimidazole (Example 11, intermediate) and 4-hydroxymethyl-benzoic acid methyl ester (CAS Reg. No. 6908-41-4). Colorless sticky solid (34%). MS (Turbo Spray): m/z=519.9 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[N:5]=[CH:4][N:3]=1.N(C(C)(C)C#N)=N[C:15](C)(C)[C:16]#N.[Br:25][N:26]1[C:30](=O)[CH2:29][CH2:28][C:27]1=O>C(Cl)(Cl)(Cl)Cl>[Br-:25].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:12][N+:26]([CH2:15][CH3:16])([CH2:30][CH3:29])[CH2:27][CH3:28])[N:5]=[CH:4][N:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc2ncnc(Cl)c12
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CC[N+](CC)(CC)Cc1cccc2ncnc(Cl)c12
Product: [Br-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 430.8 %

Procedure:
To a mixture of 1B (373 mg, 2.09 mmol), 2,2′-azobisisobutyronitrile (37.2 mg, 0.209 mmol) and N-bromosuccinimide (395 mg, 2.40 mmol) under N2 was added CCl4 (10 ml). The mixture was degassed under vacuum, purged twice with N2, and heated to 80° C. for 1 h. The mixture was allowed to cool to room temperature and the solid was removed by filtration. The filtrate was washed with cold, dilute sodium bicarbonate solution and cold brine, dried over sodium sulfate and concentrated under vacuum. The resulting solid was dissolved in THF (3 ml) and triethylamine (0.7 ml) was added. The mixture was allowed to stir at room temeperature overnight. The newly formed solid was collected by filtration, washed with THF and diethyl ether, dried under a flow of nitrogen, then under high vaccum to give 14A (323 mg, 43%) as a solid. 1H-NMR (400 MHz, DMSO-d6): 8.47 (s, 1H), 7.94 (m, 2H), 7.64 (dd, J1=6.8 Hz, J2=0.8 Hz, 1H), 5.38 (s, 2H), 3.07 (q, J=7.2 Hz, 6H), 1.27 (t, J=7.2 Hz, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=O)[N:3]=[CH:2]1.[CH2:8]([NH:15][CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[NH3:1].[CH2:8]([N:15]([CH2:6][C:4]1[N:3]=[CH:2][NH:1][CH:5]=1)[CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCCNCc1ccccc1
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: N
Product: OCCN(Cc1ccccc1)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 4-imidazolecarboxaldehyde (14 g, 145.7 mmol) and N-benzylethanolamine (26.4 g, 174.8 mmol) in tetrahydrofuran (200 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (37.06 g, 174.8 mmol) was added portionwise over 40 minutes, and the reaction stirred at room temperature for 18 hours. The reaction was quenched by the addition of water (150 mL), the mixture neutralised using saturated sodium bicarbonate solution, and then extracted with dichloromethane (3×300 mL). The combined organic extracts were dried (MgSO4) and evaporated under reduced pressure to give a yellow oil. This was purified by column chromatography on silica gel using an elution gradient of dichloromethane:methanol:0.88 ammonia (95:5:0 to 90:10:1) to afford the title compound, 18.1 g.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:9][C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2].Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([O:3][C:4]1[N:9]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:8](=[O:10])[CH:7]=[C:6]([CH3:11])[N:5]=1)[CH3:2]
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCOc1nc(C)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
To a solution of 2-ethoxy-6-methylpyrimidin-4(3H)-one (4.9 g) and 4′-(bromomethyl)biphenyl-2-carbonitrile (10.3 g) in acetonitrile (120 mL) was added potassium carbonate (5.24 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound (6.15 g, 56%) as a colorless solid.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25](O)[CH2:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1.O>C1(C)C=CC=CC=1>[F:13][C:14]1[C:19]([F:20])=[C:18]([O:21][CH2:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH:25]=[CH:26][CH:27]1[CH2:32][CH2:31][CH:30]([CH:33]2[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:35][CH2:34]2)[CH2:29][CH2:28]1
Reactant: CCCCCC1CCC(C2CCC(CC(O)c3c(C)cc(OCC)c(F)c3F)CC2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC1CCC(C2CCC(C=Cc3c(C)cc(OCC)c(F)c3F)CC2)CC1

Procedure:
0.16 g of p-toluenesulfonic acid monohydrate was added to the compound (9) having been dissolved in 60 mL of toluene, and the mixture was heated under stirring by using a Dean-Stork trap until completion of azeotrope of water. After terminating the reaction by adding water, the aqueous layer was extracted with toluene, washed with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography and then subjected to recrystallization to obtain 11.2 g of 1-(2,3-difluoro-4-ethoxy-6-methylphenyl)-2-(4-(4-pentylcyclohexyl)cyclohexyl)ethene (Compound 1-3-3-10) as colorless crystals.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]12([NH:21][C:22](=[O:40])[C:23]([CH2:38][OH:39])([CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][CH:13]([CH2:14]3)[CH2:12]1)[CH2:18]2.C(N(CC)CC)C>C(Cl)Cl>[C:11]12([NH:21][C:22](=[O:40])[C:23]([CH:38]=[O:39])([CH2:24][C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[CH2:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:12][CH:13]3[CH2:14][CH:15]([CH2:16][CH:17]([CH2:19]3)[CH2:18]1)[CH2:20]2
Reactant: O=C(NC12CC3CC(CC(C3)C1)C2)C(CO)(Cc1ccncc1)Cc1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=CC(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Yield: 163.3 %

Procedure:
To a well-stirred dry ice/acetone bath chilled solution of oxalyl chloride (163,μl, 1.91 mmol) in methylene chloride (4.5 ml), a solution of dimethyl sulfoxide (259 μl, 3.6 mmol) in methylene chloride (2.25 ml) was added dropwise while maintaining the temperature below -55° C. After stirring the reaction at that temperature for 5 minutes, N-adamantan-1-yl-2-hydroxymethyl-3-pyridin-4-yl-2-pyridin-4-ylmethyl-propion-amide (700 mg, 1.73 mmol) in methylene chloride (2.25 ml) was added, and the reaction was stirred for 30 minutes. Triethylamine (1.20 ml, 8.65 mmol) was added, and the reaction was stirred for 5 minutes before removing the cooling bath. After stirring for 20 minutes at ambient temperature, the reaction was quenched by addition to water/methylene chloride (40 ml of each). The mixture was then extracted three times with 40 ml portions of methylene chloride. The combined extracts were dried (anhydrous sodium sulfate) and concentrated in vacuo to afford a yellow oil (1.14 g). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution initially with methanol/methylene chloride=3:97 in volume, and increasing the methanol concentration during elution finally to methanol/methylene chloride=1:9 in volume) afforded the title compound (475 mg) as an oil.
Reaction SMILES: C(N([CH2:6][CH3:7])CC)C.[O:8]=[CH:9][C@H:10]([C@@H:12]([C@@H:14]([C@H:16]([CH3:18])[OH:17])[OH:15])[OH:13])[OH:11].[CH2:19](N)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C[N:31](C)[CH:32]=[O:33]>>[O:8]=[CH:9][C@H:10]([C@@H:12]([C@@H:14]([C@H:16]([CH3:18])[OH:17])[OH:15])[OH:13])[OH:11].[CH2:19]([C:6](=[CH2:7])[C:32]([NH2:31])=[O:33])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CN(C)C=O
Reactant: CCN(CC)CC
Reactant: CCCCCCCCCCN
Agent: C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)C=O
Product: C=C(CCCCCCCCCC)C(N)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of pNAS (1.0 g, 5.91 mmol) in dimethylformamide (DMF, 50 mL) was added triethylamine (1.0 mL), followed by the dropwise addition of the L-fucose derivative 22 (356 mg, 1.18 mmol, 20 mol % with respect to pNAS). The solution was stirred at room temperature for 16 h, and subsequently heated to 40° C. for 18 h. The solution was cooled and n-decylamine (233 mg, 25 mol % with respect to pNAS) was added as a solution in DMF (1 mL). The clear solution was stirred at room temperature for 12 h, followed by dialysis against water using dialysis tubing with a cut-off of 12,000-14,000 kD. The product was recovered by lyophilization. Yield 74%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CC(C)=O>[CH2:29]([O:22][C:18]1[CH:17]=[C:16]([CH2:15][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:21]=[CH:20][CH:19]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCOC(=O)C(Cc1cccc(O)c1)NC(=O)OC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(Cc1cccc(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 88 %

Procedure:
158 (760 mg, 1 equivalent) was dissolved in 15 ml of acetone, then potassium carbonate (373 mg, 1.1 equivalent) and benzylbromide (1.1 équivalent, 323 μl) were added successively. The reaction mixture was let overnight at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with 10% citric acid, saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 159 as white solid (860 mg, 88%). 1H NMR (CDCl3): δ 1.38 (t, 3H, J=7.4 Hz), 1.69 (s, 9H), 3.22 (m, 2H), 4.31 (q, 2H, J=7.4 Hz), 4.71 (s, 2H), 5.13 (m, 1H), 5.20 (s, 2H), 6.90 (d, 1H, J=7.1 Hz), 6.94 (s, 1H), 7.01 (d, 1H, J=8.2 Hz), 7.36 (t, 1H, J=7.7 Hz), 7.49 (m, 1H), 7.56 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][C:14]([CH3:34])([CH3:33])[CH2:15][C:16]([N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:21][CH:20]([NH:28][C:29]([O:31][CH3:32])=[O:30])[CH2:19]2)=[O:17])[CH2:11][O:10]C1(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])[NH:28][CH:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:18]([C:16](=[O:17])[CH2:15][C:14]([CH3:34])([CH3:33])[CH2:13][C@H:12]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:11][OH:10])[CH2:19]1
Reactant: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)NC1Cc2ccccc2N(C(=O)CC(C)(C)C[C@@H](CO)NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3.1 g of 4(S)-[4-(3(R,S)-methoxycarbonylamino-3,4-dihydro-2H-quinolin-1-yl)-2,2-dimethyl-4-oxo-butyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester and 104 mg of p-toluenesulfonic acid monohydrate in 49 ml of methylene chloride under argon is stirred at room temperature for 3.5 hours. More p-toluenesulfonic acid monohydrate (200 mg) is added and the mixture is stirred at room temperature for 1.5 hours The solution is concentrated. The title compound is obtained as a white solid from the residue by means of flash chromatography (SiO2 60 F). Rf=0.14 (3:1 EtOAc-heptane); Rt=3.91 (gradient I).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]([C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH2:21])=[C:11]([C:15]([O:17]CC)=O)[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:26])[CH3:2].[NH3:27]>C1(C)C=CC=CC=1.CO.C(Cl)(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:21][NH:27][C:15](=[O:17])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:26])[CH3:2]
Reactant: C=C(C(=O)OC)c1c(C(=O)OCC)c(OC)c2n1[C@@H](C)CN(CC)C2=O
Reactant: N
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: Cc1ccccc1
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]cc(C(=O)OC)c32)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of ethyl (4S)-2-ethyl-8-(methoxy)-6-[1-(methoxycarbonyl)vinyl]-4-methyl-1-oxo-1,2,3,4-tetrahydro-pyrrolo[1,2-a]-pyrazine-7-carboxylate (0.19 g, 0.54 mmol) in a mixture of toluene (10 mL) and methanol (4 mL) was treated with a saturated solution of ammonia in methanol (10 mL). The mixture was stirred at rt overnight. The product mixture concentrated under vacuum to provide the corresponding cyclization product. Treatment of the above intermediate (0.34 g, 1.01 mmol) and manganese(IV) oxide (0.26 g, 3.04 mmol) in toluene (10 mL) was heated in a sealed tube in an oil bath 80° C. overnight. The reaction mixture was cooled to rt, diluted with chloroform (100 mL) and filtered through a pad of Celite. The filtrate was concentrated under vacuum. The filtrate was subjected to column chromatography on silica gel eluting with ethyl acetate. Collection and concentration of appropriate fractions provided the titled compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[C:6]([O:8]CC)=[O:7].O.O1CCOCC1>C(N(CC)CC)C>[OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)NCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(O)C(=O)NCCO

Procedure:
To 730.7 g (5 moles) of diethyl oxalate was added dropwise at room temperature a solution of 61.1 g (1 mole) of ethanolamine in 500 ml of acetone and, after the addition finished, treatment of the mixture by distillation under reduced pressure to remove the formed ethanol and the acetone and an excess amount of diethyl oxalate yielded ethyl 2-hydroxyethyloxamate. A mixture of 80.5 g (0.5 moles) of this ethyl 2-hydroxyethyloxamate, 50.6 g (0.5 moles) of triethylamine (hereinafter, referred to as TEA), 20.0 g of water, and 1000 ml of dioxane was warmed under reflux for 8 hours and treated with solvent removal followed by dehydration yielded a triethylamine salt of 2-hydroxyethyloxamic acid. A mixture of 11.7 g (0.05 moles) of this triethylamine salt of 2-hydroxyethyloxamic acid and 5.1 g (0.05 moles) of TEA was treated with dehydration by molecular sieve and then, dissolved with warming into 300 ml of THF. To this THF solution was added dropwise under a refluxing condition during 0.5 hours a solution of 5.2 g (0.05 moles) of methacrylic acid chloride in 30 ml of THF and, after the addition finished, the mixture was further stirred under the condition for 6 hours and treated with fractional extraction to get methacryloyloxyet hyloxamic acid of the following structure: ##STR17## Besides, identification of the methacrylolyloxyethyloxamic acid 1 was carried out with 13C-NMR spectra analysis (ppm, in CDCL3) and the results were 17.93 for (2), 38.86 for (6); 62.35 for (5), 120.59 for (1), 138.86 for (3), 158.01 for (7), 160.56 for (8), and 167.06 for (4).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:42])=[C:11]([CH:39]=[CH:40][CH:41]=1)[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH:26]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>C(Cl)Cl.C([SiH](CC)CC)C>[ClH:8].[ClH:8].[Cl:8][C:9]1[C:10]([F:42])=[C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(Nc3cccc(Cl)c3F)ncnc2cc1OC1CCNCC1
Product: Cl
Reaction time: 1 h
Yield: 317.4 %

Procedure:
Trifluoroacetic acid (50 ml) was added to a solution of tert-butyl 4-({4-[3-chloro-2-fluoroanilino]-6-methoxyquinazolin-7-yl}oxy)piperidine-1-carboxylate (750 mg, 1.49 mmol) in methylene chloride (1 ml) and triethylsilane (1 ml) and the solution stirred for 1 hour. The reaction mixture was then evaporated under reduced pressure and the residues re-dissolved in EtOAc (5 ml). This solution was then treated with 1M HCl/diethylether (1 ml) followed by more diethylether (50 ml) to give a white precipitate. The resulting solids were collected following centrifugation and dried under vacuum to give N-(3-chloro-2-fluorophenyl)-6-methoxy-7-(piperidin-4-yloxy)quinazolin-4-amine dihydrochloride as a white solid (750 mg); 1H NMR Spectrum: (DMSO-d6): 2.00-2.20 (m, 2H), 2.25-2.45 (m, 2H), 3.15-3.50 (m, 4H), 4.15 (s, 3H), 5.02 (m, 1H), 7.48 (m, 1H), 7.60-7.85 m, 3H), 8.35 (s, 1H), 8.85 (s, 1H), 9.56 (bs, 2H); Mass Spectrum: (M+H)+ 403.