Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH2:6][N:7]([CH3:9])[CH3:8])=[CH2:5].CO[CH2:13][N:14]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:15][Si](C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[CH3:1][O:2][C:3]([C:4]1([CH2:6][N:7]([CH3:9])[CH3:8])[CH2:5][CH2:13][N:14]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:15]1)=[O:10]
Reactant: C=C(CN(C)C)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CN(C)C)CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.8 %

Procedure:
To a cold solution of 2-dimethylaminomethyl-acrylic acid methyl ester (0.266 g, 1.86 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzyl-amine (1.43 ml, 5.59 mmol) in dichloromethane (25 ml) was added at 0° C. trifluoroacetic acid (83 μl, 1.12 mmol). The resulting solution was warmed to room temperature and stirred for 72 hours. Saturated aq. NaHCO3 (60 ml) was added to the reaction mixture and stirred for 10 minutes. Diluted with dichloromethane (50 ml) and the organic layer was separated. The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica get eluting with a solution of ethyl acetate in hexanes (1:2) followed by CH2Cl2/MeOH/NH4OH (9/1/0.01) to give the title compound (400 mg, 78%).
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH2:12]([NH:15][CH2:16][CH2:17][CH:18]=[O:19])[C:13]#[CH:14]>C1C=CC=CC=1>[CH2:12]([N:15]([CH2:16][CH2:17][CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11])[C:13]#[CH:14]
Reactant: C#CCNCCC=O
Reactant: CS(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: C#CCN(CCC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5 -methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 3-propargylaminopropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass rection vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 3-[1-propargyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl) ureido]propionaldehyde.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=O)=O.O>CC(C)=O.[Cl-].[Na+].O>[I:1][CH2:8][CH2:9][CH2:10][C@H:11]([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: [I-]
Reactant: C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](CCCI)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Anhydrous sodium iodide (600 mg, 4.0 mmol, 2 equiv) is added to a solution of (S)-1-methanesulfonyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 7 (622 mg, 2.0 mmol) in 3.0 ml of absolute acetone. The mixture is stirred for 2 h at 50° C. 10 ml of a mixture of brine and water (1:1) are added, and the mixture is extracted with diethyl ether (3×20 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 20:1) affords (S)-1-iodo-5-(tert-butyidimethylsilyloxy)-4-methyl-pentane 8 (647 mg, 94%) as a colourless oil. FG 342.34; 13C-NMR (100 MHz, CDCl3): δ=68.1, 35.1, 34.3, 31.3, 26.0, 16.7, 7.4, −5.3
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:34][CH2:33][C@H:32]([O:35][CH2:36][C:37](=[O:39])[CH3:38])[CH2:31][CH2:30]1.C[Si](C)(C)[C:42]([F:45])([F:44])[F:43].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[C@H:29]1[CH2:30][CH2:31][C@H:32]([O:35][CH2:36][C:37]([OH:39])([CH3:38])[C:42]([F:45])([F:44])[F:43])[CH2:33][CH2:34]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(O)C(F)(F)F)CC2)c2ncnn12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4′-({5-Oxo-4-[trans-4-(2-oxopropoxy)cyclohexyl]-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (0.30 g) and trimethyl(trifluoromethyl)silane (0.20 g) were dissolved in tetrahydrofuran (3 mL), tetrabutylammonium fluoride (0.22 mL, 1.0 M tetrahydrofuran solution) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 hr. Trimethyl(trifluoromethyl)silane (0.20 g) and tetrabutylammonium fluoride (0.22 mL, 1.0 M tetrahydrofuran solution) were added, and the mixture was stirred at 0° C. for 1 hr and then at room temperature for 16 hr. The reaction mixture was added to 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.092 g, 27%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].[CH:20](O)=O>>[CH3:10][O:9][C:6]1[C:7]2[N:8]=[CH:20][NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:5]=1
Reactant: O=CO
Reactant: CCCN(CCC)CCc1ccc(OC)c(N)c1N
Product: CCCN(CCC)CCc1ccc(OC)c2nc[nH]c12

Procedure:
1.2 g of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dipropylamine is heated under reflux with 20 ml of formic acid for 3 hours. The solution is concentrated. The residue is taken up in water, made alkaline with potassium carbonate, and extracted with ethyl acetate. The organic phase is dried over sodium sulfate and concentrated after the drying agent has been removed by filtration. The residue is chromatographed on silica gel with a mixture of dichloromethane/methanol, thus obtaining 0.42 g of 7-methoxy-4-[2-(N,N-dipropylamino)ethyl]benzimidazole as an oil.
Reaction SMILES: [F-].[K+].O[C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH:7]=[O:8].FC1C=CC=CC=1[N+]([O-])=O.O>CS(C)=O>[F:14][CH:13]([F:15])[O:12][C:11]1[CH:4]=[CH:5][C:6]([CH:7]=[O:8])=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(OC(F)F)c(O)c1
Agent: O=[N+]([O-])c1ccccc1F
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=Cc1ccc(OC(F)F)cc1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 153.5 %

Procedure:
To a stirred suspension of potassium fluoride (372 mg, 6.4 mmol) in dry DMSO (10 ml) was added a solution of 3-hydroxy-4-difluoromethoxy benzaldehyde (1.0 gm, 5.3 mmol) in DMSO (10 ml). The reaction contents were heated at 140° C. for 10 min. A solution of 2-fluoronitrobenzene (747 mg, 5.3 mmol) in DMSO (5 ml) was added to the above suspension and the reaction mixture was stirred at 140° C. for 3.5 h. The reaction mixture was cooled to room temperature and the contents were poured into water (200 ml) and extracted with ethyl acetate (100 ml×3). The organic extracts were combined and washed with 1N sodium hydroxide (50 ml×2), water and brine and dried over anhydrous sodium sulfite. The dried organic layer was concentrated in vaccuo to obtain 3-2-nitrophenoxy)-4-difluoromethoxy benzaldehyde as a pale yellow solid (1.4 gm).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=O)[CH3:3].B.C1COCC1.C1COCC1>CO>[CH3:3][CH:2]([NH:4][CH2:5][C@H:7]1[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10][CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH3:1]
Reactant: CC(C)NC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)NC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 50 °C
Yield: 40.5 %

Procedure:
A 500-mL round-bottomed flask was charged with di-tert-butyl (2R)-2-((1-methylethyl)carbamoyl)-1,4-piperazinedicarboxylate (1.77 g, 4.76 mmol, step 1), BH3.THF (1.0 M in THF, 15.0 mL, 15.0 mmol) and THF (60 mL). The mixture was heated at 50° C. for 12 h. After allowing the reaction to cool to room temperature, additional BH3.THF (1.0 M in THF, 5.0 mL, 5.0 mmol) was added. The mixture was then heated at 50° C. for 1.5 h. The reaction mixture was allowed to cool to room temperature and MeOH (20 mL) was slowly added. The solvent was removed in vacuo and the crude product was purified by column chromatography (100 g of silica gel, 0 to 10% iPrOH (with 10% NH4OH) in CHCl3) to afford di-tert-butyl (2S)-2-(((1-methylethyl)amino)methyl)-1,4-piperazinedicarboxylate (0.69 g) as a clear oil.
Reaction SMILES: CC([N:5]([C@@H:9]([C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([O:30][CH3:31])[CH:24]=2)=[CH:18][CH:17]=1)=[O:14])[CH:10]([CH3:12])[CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:19]2[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:5])=[CH:17][CH:18]=2)=[CH:24][C:25]=1[O:30][CH3:31]
Reactant: COc1cc(Oc2ccc(NC(=O)[C@@H](C(C)C)N(C(=O)[O-])C(C)(C)C)cc2)ccc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Oc2ccc(NC(=O)[C@H](N)C(C)C)cc2)ccc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 1,1-dimethylethyl((1R)-2-methyl-1-{[(4-{[4-methyl-3-(methyloxy)phenyl]oxy}phenyl)amino]carbonyl}propyl)carbamate (Intermediate 82, 110 mg) in dry dichloromethane (3 mL), TFA (1 mL, 12.98 mmol) was added and the reaction mixture was stirred for 1 hour at room temperature. The solvent and the excess of TFA were evaporated and the residue was purified by SCX cartridge (5 g) to afford the title compound as a yellow pale solid (68 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([F:13])([F:12])[F:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[H-].[Na+]>CN(C=O)C>[CH2:14]([N:1]([CH2:10][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[C:10]([F:11])([F:12])[F:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(N)c(C(F)(F)F)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-5-cyanobenzotrifluoride (1.0 g, 5.37 mmol, 1 eq) and benzyl bromide (2.55 mL, 21.5 mmol, 4.0 eq) in dry DMF (10 mL) was added at rt NaH (970 mg, 21.5 mmol, 4 eq) portion-wise under Ar(g). The reaction mixture was stirred at rt overnight, and was then partitioned with H2O (30 mL) and extracted with EtOAc (5×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (1:0-9:1) to yield the product, 2, as a pale yellow solid (1.66 g, 85%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6].[CH3:15]CN(CC)CC.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.O>ClCCl>[CH3:15][CH2:1][CH2:2][CH2:3][NH:4][C:5]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([CH3:7])[CH3:6]
Reactant: CCCNC(C)(C)CC1CCCCC1
Reactant: CCN(CC)CC
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CCCCNC(C)(C)Cc1ccccc1
Temperature: 25 °C
Yield: 134.6 %

Procedure:
To a solution of compound D-3-7 (100 g, 380 mmol) and Et3N (76.8 g, 760 mmol) in dichloromethane (1.5 L), cooled to 0° C., is added triflic anhydride (Tf2O) (107.0 g, 380 mmol) via an addition funnel. Upon complete addition of Tf2O the solution is then warmed to room temperature for 5 h. The reaction mixture is then treated with H2O and dichloromethane and the organic phase is separated. The organic phase is washed with brine and dried over anhydrous Na2SO4. The mixture is then filtered and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound D-3-8 (105 g, 70% yield).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=[C:8]([O:19][CH3:20])[N:7]=[C:6]([C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:5]=1.[C:27]([C:31]1[S:35][C:34]([S:36](Cl)(=[O:38])=[O:37])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([C:31]1[S:35][C:34]([S:36]([NH:3][C:4]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[C:8]([O:19][CH3:20])[N:7]=[C:6]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[N:5]=2)(=[O:38])=[O:37])=[CH:33][CH:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)s1
Reactant: COc1ccccc1Oc1c(N)nc(-c2ncccn2)nc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)s2)nc(-c2ncccn2)nc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
92 mg of NaH (65%) were added at room temperature to a solution of 162.5 mg of 4-amino-6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine in 10 ml of tetrahydrofuran, the solution was stirred at room temperature for 11/2 hours and subsequently 162.5 mg of 5-tert-butyl-thiophene-2-sulphonyl chloride were added at the same temperature. The mixture was stirred at room temperature for a further 2 hours, poured on to ice/water, extracted with ethyl acetate, the aqueous phase was acidified and extracted with methylene chloride. The combined, organic phases were dried over magnesium sulphate and concentrated on a rotary evaporator. The residue was chromatographed over silica gel with methylene chloride/methanol (20/1) as the eluent. 5-tert-Butyl-N-[6-methoxy-5-(2-methoxy-phenoxy)-2,2'-bipyrimidin-4-yl]-thiophene-2-sulphonamide was obtained as a yellow powder. MS: 463 (M-SO2).
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:16])[CH2:7]P(OCC)(OCC)=O)C.[O:17]=[C:18]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32]([CH:36]=O)[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1.O>O1CCCC1>[O:17]=[C:18]1[N:29]([C@H:30]2[CH2:35][CH2:34][CH2:33][C@H:32](/[CH:36]=[CH:7]/[C:6]([OH:5])=[O:16])[CH2:31]2)[C:21]2=[C:22]3[CH:28]=[CH:27][NH:26][C:23]3=[N:24][CH:25]=[C:20]2[NH:19]1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/[C@H]1CCC[C@H](n2c(=O)[nH]c3cnc4[nH]ccc4c32)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% in oil) (7 mg) in tetrahydrofuran (1 ml) was added dropwise ethyl(diethoxyphosphoryl)acetate (53 μl). After stirring at ambient temperature for 5 minutes, trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexanecarbaldehyde (50 mg) was added and stirred at ambient temperature for overnight. The reaction mixture was poured into water, and extracted with EtOAc and tetrahydrofuran. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. The residue was purified by preparative thin layer chromatography eluting with dichloromethane:methanol=10:1. The fractions containing desired compound were combined and evaporated. The residue was dissolved in dioxane (250 μl), and 1M NaOH solution (176 μl) was added, then stirred at 110° C. for 2 hours. After cooling to the ambient temperature, 1M HCl (176 μl) and pH 4 buffer (5 ml) was added to the reaction mixture. Resulting precipitates were collected by filtration and washed with water to give (2E)-3-[trans-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)cyclohexyl]acrylic acid (11.0 mg) as a brown powder.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([OH:9])=[O:8])=[O:4].O[N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20].C(N=C=NC(C)C)(C)C>C(OCC)(=O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:10]([CH3:12])[CH3:11])[C:7]([O:9][N:14]1[C:18](=[O:19])[CH2:17][CH2:16][C:15]1=[O:20])=[O:8])=[O:4]
Reactant: O=C1CCC(=O)N1O
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)ON1C(=O)CCC1=O)C(C)C
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
Compound I can be prepared according to the procedures described in U.S. Provisional Patent Application No. 61/243,596, filed Sep. 18, 2009. To a mixture of (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (19.66 g, 112 mmol) and N-hydroxysuccinimide (13.29 g, 116 mmol) was added ethyl acetate (250 ml), and the mixture was cooled to 0-5° C. Diisopropylcarbodiimide (13.88 g, 110 mmol) was added and the reaction mixture was stirred at 0-5° C. for about 1 hour. The reaction mixture was warmed to room temperature. The solids (diisopropylurea by-product) were filtered and rinsed with ethyl acetate. The filtrate was concentrated in vacuo to an oil. Isopropyl alcohol (200 ml) was added to the oil and the mixture was heated to about 50° C. to obtain a homogeneous solution. Upon cooling, crystalline solids formed. The solids were filtered and washed with isopropyl alcohol (3×20 ml) and dried to give (S)-2,5-dioxopyrrolidin-1-yl 2-(methoxycarbonylamino)-3-methylbutanoate as a white solid (23.2 g, 77% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](Cl)=[O:17])=[CH:10][CH:9]=1>>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:17])=[CH:10][CH:9]=1
Reactant: COc1ccc(CCC(=O)Cl)cc1
Reactant: NCC(=O)O
Product: COc1ccc(CCC(=O)NCC(=O)O)cc1

Procedure:
Prepared in analogy to example 2.1 from glycine and 3-(4-methoxy-phenyl)-propionyl chloride (CA [15893-42-2]). MS (m/e): 236.1 (MH−, 100%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:45])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([O:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][C:32]=2[O:43][CH3:44])=[O:29])[CH:5]=[CH:6][CH:7]=1.[C:46]([O:50][C:51]([NH:53][CH2:54][C:55](O)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]>>[C:46]([O:50][C:51]([NH:53][CH2:54][C:55]([O:40][CH2:39][CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:41]=[CH:42][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:45])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:26])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:43][CH3:44])[CH:33]=1)=[O:56])=[O:52])([CH3:49])([CH3:48])[CH3:47]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1cc(C(=O)OCCO)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Product: COc1cc(C(=O)OCCOC(=O)CNC(=O)OC(C)(C)C)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F

Procedure:
In a manner similar to the method described in Example 3, 2-hydroxyethyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate was reacted with 2-(tert-butoxycarbonylamino)acetic acid to give 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-(2-tert-butoxycarbonylamino-acetoxy)-ethyl ester. MS (ES+) m/z calcd. for C40H45Cl2F2N4O8: [(M+H)+]: 817. found: 817.
Reaction SMILES: Cl.Cl.NC1C=C(C2C(C3C=CC(O)=C(N)C=3)=NC3C(=CC=C(C(O)=O)C=3)N=2)C=CC=1O.[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[NH2:42])[C:36]([OH:38])=[O:37].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([C:51]([C:53]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)=O)=O)=[CH:47][CH:46]=1>>[CH3:62][O:61][C:58]1[CH:57]=[CH:56][C:55]([C:53]2[C:51]([C:48]3[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:50][CH:49]=3)=[N:32][C:33]3[C:41](=[CH:40][CH:39]=[C:35]([C:36]([OH:38])=[O:37])[CH:34]=3)[N:42]=2)=[CH:60][CH:59]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: Nc1ccc(C(=O)O)cc1N
Agent: Cl
Agent: Nc1cc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(O)c(N)c2)ccc1O
Product: COc1ccc(-c2nc3ccc(C(=O)O)cc3nc2-c2ccc(OC)cc2)cc1

Procedure:
Briefly, the AB2 monomer, 2,3-bis(3-amino-4-hydroxyphenyl)quinoxaline-6-carboxylic acid dihydrochloride, is synthesized by condensing 3,4-diaminobenzoic acid and 4,4′-dimethoxybenzil to afford 2,3-bis(4-methoxyphenyl) quinoxaline-6-carboxylic acid, followed by demethylation in hydrobromic acid in acetic acid to form 2,3-bis(4-hydroxyphenyl) quinoxaline-6-carboxylic acid. The latter is then nitrated using nitric acid (70% conc.) in acetic acid at room temperature, yielding 2,3-bis(3-nitro-4-hydroxyphenyl) quinoxaline-6-carboxylic acid. The desired monomer is prepared by catalytic reduction in the presence of palladium catalyst in 10% hydrochloric acid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20]Br.O>C(O)C>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:16][CH2:17][C:18]#[C:19][CH2:20][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: BrCC#CCOC1CCCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C(#CCOC1CCCCO1)COc1ccccc1

Procedure:
To a solution of 2.35 g (0.025 mol) of phenol in 20 ml of absolute ethanol, there was added 1.10 g (0.0275 mol) of sodium hydroxide. The mixture was refluxed until complete disolution and 2.92 g (0.0125 mol) of 1-bromobut-2-yn-4-ol tetrahydropyranyl ether were added, and the reflux resumed for 2 additional hours. It was then cooled, poured into water and extracted with ether. The organic extracts were washed with 20% aqueous sodium hydroxide solution and water, dried and evaporated in vacuo. The residue was purified by column chromatography on 50 g of silica gel, using hexane-ethyl acetate (98:2) as eluant, to yield 4-phenoxybut-2-yn-1-ol tetrahydropyranyl ether, as an oil.
Reaction SMILES: C[N+]1([O-])CC[O:5]CC1.[F:9][C:10]([F:40])([F:39])[C:11]1[CH:12]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=C)[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[F:18][C:17]([F:20])([F:19])[C:15]1[CH:14]=[C:13]([C@H:21]([O:23][C@@H:24]2[C@@H:29]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[C@H:28]([CH:37]=[O:5])[CH2:27][CH2:26][O:25]2)[CH3:22])[CH:12]=[C:11]([C:10]([F:39])([F:40])[F:9])[CH:16]=1
Reactant: C=C[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)cc1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O[C@H]1OCC[C@@H](C=O)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
N-Methylmorpholine N-oxide (1 g, 8.6 mmol) and osmium tetroxide (2 ml, 2.5% solution in tert-butanol) were added to a solution of (2R,3R,4S)-2-[(1R)-1-(3,5-bis(trifluoromethyl)phenyl)ethoxy]-3-(4-fluorophenyl)-4-vinyl-tetrahydropyran (see Example 147 in WO 00/56727; 2 g, 4.3 mmol) in tetrahydrofuran (25 ml) and water (10 ml). The mixture was stirred at room temperature for one hour before sodium periodate (9 g, 43 mmol) was added. This mixture was stirred for 45 minutes and then filtered through Celite™. The filtrate was diluted with ethyl acetate (50 ml) and washed with brine. The organic extracts were dried and concentrated. The residue was chromatographed on silica gel eluting with ethyl acetate/iso-hexanes to give the title compound (1.6 g, 80%).