Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: IC.[CH3:3][C:4]1[N:5]=[C:6]([NH:9][C:10]2[N:15]=[CH:14][C:13]([OH:16])=[CH:12][C:11]=2[O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:7][CH:8]=1.[C:24](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][O:16][C:13]1[CH:12]=[C:11]([O:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]([NH:9][C:6]2[S:7][CH:8]=[C:4]([CH3:3])[N:5]=2)=[N:15][CH:14]=1
Reactant: Cc1csc(Nc2ncc(O)cc2Oc2ccccc2)n1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cnc(Nc2nc(C)cs2)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (0.0362 g, 0.255 mmol) is added to a mixture of 6-(4-methylthiazol-2-ylamino)-5-phenoxypyridin-3-ol (0.255 mmol) and potassium carbonate (0.0794 g, 0.574 mmol) in DMF (3 mL) and stirred overnight at room temperature. The reaction mixture is partitioned between water and ether. The organic layer is washed with water, dried, and concentrated. The residue is purified by silica gel chromatography, eluting with 15-20% EtOAc in hexanes, to afford the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([OH:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[CH3:21][N:2]([CH3:1])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([O:14][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: CCOC(=O)C(C(=O)N(C)C)=C(O)c1ccc(Cl)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C(=O)N(C)C)=C(OC(=O)c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a well stirred mixture of 12.4 g of N,N-dimethylalphaethoxycarbonyl-beta-hydroxy-2,4-dichlorocinnamamide, 4.0 g of triethylamine and 150 ml of dry ether at 4° C. was added dropwise benzoyl chloride at such a rate that the temperature did not exceed 5° C. The reaction was allowed to warm up to room temperature, stirred at this temperature for 2 hours, the cooled again to 4° C. The solids were filtered off and the filtrate concentrated under reduced pressure to yield 12.0 g of a white solid. The solid was crystallized from ether/hexane to yield 8.0 g of the desired product, m.p. 106° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([CH3:23])[CH3:22])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30].C(OCC)(=O)C.CCCCCC>C(O)(=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH:21]([CH3:23])[CH3:22])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CC(=O)O
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OC(C)C)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 6-hydroxy-7-methoxy-1-(3-ethoxy-benzyl)-isoquinoline-4-carbaldehyde (60 mg, 0.17 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (235 mg, 1.70 mmol) and 2-iodopropane (0.085 mL, 0.85 mmol) at room temperature. The reaction mixture was heated 85° C. for 2 hrs. The solvent was evaporated and the residue was purified on a flash chromatography (Merck Silica gel 60, 70–230 mesh, 50% ethyl acetate/hexane) to afford product 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a colorless oil. The crude product was used without further purification. To a stirred solution of 1-(3-ethoxy-benzyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde in acetic acid (2 mL) was added selenium dioxide (189 mg, 1.70 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-isopropoxy-7-methoxy-isoquinoline-4-carbaldehyde as a major product (31 mg, 46% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([N:7]=[CH:8][C:9](=[O:26])[N:10]2[CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][C:18](=O)[CH2:17][CH:16]2[C:22]([O:24][CH3:25])=[O:23])=[CH:5][CH:4]=1.[O:27]1[C:36]2[CH:35]=[C:34]([CH2:37][NH2:38])[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C.ClCCl>[O:27]1[C:36]2[CH:35]=[C:34]([CH2:37][NH:38][CH:18]3[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][N:10]4[C:11]5[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=5)[N:7]=[CH:8][C:9]4=[O:26])[CH:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17]3)[N:33]=[CH:32][C:31]=2[O:30][CH2:29][CH2:28]1
Reactant: NCc1cc2c(cn1)OCCO2
Reactant: COC(=O)C1CC(=O)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)C1CC(NCc2cc3c(cn2)OCCO3)CCN1CCn1c(=O)cnc2ccc(OC)cc21
Reaction time: 1 h
Yield: 45.1 %

Procedure:
To 10 mL of a dichloromethane solution containing 0.10 g of methyl 1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)-4-oxopiperidine-2-carboxylate, 2 mL of a dichloromethane solution containing 55 mg of 1-(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-yl)methaneamine and 32 μL of acetic acid were added at room temperature, and stirred at the same temperature for 1 hour, thereafter, 8 μL of acetic acid was further added, and stirred for 2.5 hours. To the reaction mixture, 59 mg of sodium triacetoxyborohydride was added, and stirred for 1 hour. To the reaction mixture, aqueous saturated sodium hydrogen carbonate solution and chloroform were added. The organic layer was separated, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography [eluent; chloroform:methanol=50:1], to give 64 mg of methyl 4-((2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)amino)-1-(2-(7-methoxy-2-oxoquinoxalin-1(2H)-yl)ethyl)piperidine-2-carboxylate as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[F:9].[H-].[Na+].IC.Cl[CH2:15]Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:15])=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(S)ccc1Br
Reactant: ClCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1ccc(Br)c(F)c1
Reaction time: 0.08 h
Yield: 86 %

Procedure:
A solution of 4-bromo-3-fluoro-benzenethiol (225 mg, 1.09 mmol) in tetrahydrofuran (3 ml) was cooled to 0° C. Sodium hydride (60% dispersion in mineral oil, 52 mg, 1.31 mmol) was added and the mixture was stirred for 5 minutes. Iodomethane (78 μl, 1.25 mmol) was then added and the mixture was allowed to return to room temperature with stirring over 20 minutes. Dichloromethane (10 ml) was added and the reaction was quenched with 1 M aqueous hydrochloric acid. The layers were separated and the organic layer was washed with water, dried (MgSO4), then concentrated in vacuo. The residue was purified by flash chromatography (Si-PPC, pentane:diethyl ether, gradient 100:0 to 90:10) to afford the title compound as a bright yellow oil (208 mg, 86%). 1H NMR (CDCl3, 400 MHz) 7.43 (1H, dd, J=8.4, 7.2), 7.00 (1H, dd, J=9.4, 2.3), 6.91 (1H, ddd, J=8.4, 2.1, 0.7), 2.48 (3H, s).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH3:6])=[O:4].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.COC1C=CC=CC=1OC>>[CH3:6][O:5][C:3]([CH2:2][O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4]
Reactant: Oc1ccccc1
Reactant: COC(=O)CCl
Solvent: COc1ccccc1OC
Product: COC(=O)COc1ccccc1

Procedure:
Illustrative Embodiment 1 is repeated with a feed mixture of 94 g of methyl chloroacetate, 68 g of phenol and 5 g of dimethoxybenzene (as a gas chromatograph standard). A catalyst of 22 percent Y2O3 on α-Al2O3 produces methyl phenoxy acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@H:18]3[C@H:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=4[F:31])[CH2:21][N:20]([C:32]4[N:33]=[N:34][C:35](Cl)=[CH:36][CH:37]=4)[CH2:19]3)=[O:17])[CH2:11][CH2:10][N:9]2[S:39]([CH3:42])(=[O:41])=[O:40])=[CH:4][CH:3]=1.C(O)(=[O:45])C>>[NH3:9].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([C@H:18]3[C@H:22]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=4[F:31])[CH2:21][N:20]([C:32]4[CH:37]=[CH:36][C:35](=[O:45])[NH:34][N:33]=4)[CH2:19]3)=[O:17])[CH2:11][CH2:10][N:9]2[S:39]([CH3:42])(=[O:40])=[O:41])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: COc1ccc([C@@H]2CN(c3ccc(Cl)nn3)C[C@H]2C(=O)N2CCCC(c3ccc(Cl)cc3)N(S(C)(=O)=O)CC2)c(F)c1
Product: COc1ccc([C@@H]2CN(c3ccc(=O)[nH]n3)C[C@H]2C(=O)N2CCCC(c3ccc(Cl)cc3)N(S(C)(=O)=O)CC2)c(F)c1
Product: N
Yield: 93 %

Procedure:
The compound of example 108 (100 mg, 0.157 mmol) was dissolved in acetic acid (5 mL). The resulting solution was thoroughly degassed and stirred at reflux under nitrogen overnight. The reaction was concentrated in vacuo and residue diluted by adding sodium hydrogen carbonate solution (25 mL) and extracted with EtOAc (3×25 mL). The combined organic extracts were washed with sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried with sodium sulphate, filtered and concentrated in vacuo to give the crude residue. Purification by column chromatography on silica gel using dichloromethane:methanol:0.88 ammonia (92.5:7.5:0.75) gave 90 mg (93%) of the title compound as a mixture of epimers as an off white foam.
Reaction SMILES: [Li]CCCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[N:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].Br[CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1.Cl>C1COCC1.O>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][CH2:25][CH2:24][CH2:13][C:14]2[N:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[CH:28][CH:29]=1
Reactant: Cc1ncccc1C(=O)O
Reactant: Fc1ccc(CCCBr)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccnc1CCCCc1ccc(F)cc1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
4.4 ml (11.0 mmol, 2.5M in hexane) of BuLi solution were added dropwise at −10° C. to a solution of 1.54 ml (11.0 mmol) of diisopropylamine in THF (10 ml). Stirring was then carried out for a further 30 min at −10° C. This solution was added dropwise at −75° C. to a solution of 685 mg (5.0 mmol) of 2-methyl-nicotinic acid in THF (2 ml). Stirring was then carried out for 30 min at −75° C. and for 60 min at 0° C., followed by cooling to −55° C. At that temperature, 1.62 g (7.5 mmol) of 1-(3-bromopropyl)-4-fluorobenzene were added and the reaction solution was stirred for 1 h at −55° C. After warming to RT and stirring for a further 16 h at RT, water (30 ml) and conc. hydrochloric acid (3 ml) were added. Extraction with EA (2×30 ml) was then carried out. The combined organic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA), yielding 1.28 g (4.7 mmol, 93%) of 2-(4-(4-fluorophenyl)butyl)-nicotinic acid.
Reaction SMILES: C([Al]CC(C)C)C(C)C.C1COCC1.C([O:17][C:18]([C:20]1[S:24][C:23]2=[CH:25][N:26]=[CH:27][N:22]2[C:21]=1[C:28](OCC)=[O:29])=O)C>C(OCC)C.O>[OH:17][CH2:18][C:20]1[S:24][C:23]2=[CH:25][N:26]=[CH:27][N:22]2[C:21]=1[CH2:28][OH:29]
Reactant: CCOC(=O)c1sc2cncn2c1C(=O)OCC
Agent: CC(C)C[Al]CC(C)C
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCc1sc2cncn2c1CO
Reaction time: 1 h
Yield: 80.4 %

Procedure:
A 1.33 ml potion of a 1.5M diisobutylaluminum hydridetoluene solution was added dropwise to 5 ml of an anhydrous THF solution containing 268 mg of 2,3-bis(ethoxycarbonyl)imidazo[5,1-b]thiazole in an argon atmosphere at -78° C., and the mixture was then stirred at the same temperature for 1 hour. Then, the reaction solution was diluted with 5 ml of diethyl ether, and 1.5 ml of water was then added thereto. After stirred at room temperature for 2 hours, the solution was filtered through Celite. The filtrate was dried over anhydrous magnesium sulfate and then filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by a silica gel column chromatograph to obtain 148 mg of the title compound as a colorless crystal.
Reaction SMILES: [C:1](N)(=O)C.COC(OC)[N:8]([CH3:10])[CH3:9].[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:22])[C:19]=1[NH:20][NH2:21].O1CCOCC1CC(O)=O>O1CCOCC1>[Br:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:22])[C:19]=1[N:20]1[C:10]([CH3:1])=[N:8][CH:9]=[N:21]1
Reactant: NNc1c(F)cncc1Br
Reactant: CC(N)=O
Reactant: COC(OC)N(C)C
Agent: O=C(O)CC1COCCO1
Solvent: C1COCCO1
Product: Cc1ncnn1-c1c(F)cncc1Br
Temperature: 130 °C
Reaction time: 2 h

Procedure:
Acetamide (136.7 mg, 2.315 mmol), 1,1-dimethoxy-N,N-dimethyl-methanamine (382.0 mg, 425.9 μL, 3.206 mmol), in dioxane was heated at 45-50° C. under 150 mm Hg vacuum for 2 h. The reaction mixture was concentrated in vacuo. To the residue, (3-bromo-5-fluoro-4-pyridyl)hydrazine (367 mg, 1.781 mmol) and dioxane-acetic acid (1/1) was added and the mixture was heated at 130° C. for 1 h then at 160° C. for 2 h. At RT, the residue was loaded on a SCX column, washed with MeOH/DCM mixture. The filtrate is concentrated in vacuo yielding pure 3-bromo-5-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)pyridine as a dark oil. MS (ES+) 257.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[OH:9].O[CH:11]([CH2:23][CH3:24])[CH2:12][CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.O>[CH3:20][C:17]([O:16][C:15](=[O:21])[N:14]([CH2:13][CH2:12][CH:11]([O:9][C:3]1[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=1[Cl:1])[CH2:23][CH3:24])[CH3:22])([CH3:18])[CH3:19]
Reactant: CCC(O)CCN(C)C(=O)OC(C)(C)C
Reactant: Oc1cc(Cl)ccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCC(CCN(C)C(=O)OC(C)(C)C)Oc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.7 %

Procedure:
2,5-Dichlorophenol (325 mg, 2.00 mmol) and (3-hydroxypentyl)methylcarbamic acid, 1,1-dimethylethyl ester (217 mg, 1.00 mmol) were dissolved in tetrahydrofuran (10 ml). To the resulting solution was added triphenylphosphine (393 mg, 1.50 mmol) and then diethyl azodicarboxylate (0.240 ml, 1.52 mmol). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted three times with diethyl ether. The combined organic fractions were washed with 1N sodium hydroxide solution twice and then brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 180 mg (50%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(N(CC)CC)C.Cl[Si](C)(C)C.[CH2:38]=[O:39].FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClCCl>[OH:1][C:2]1[C:3]([C:11]2([CH2:38][OH:39])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C:12]2=[O:25])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: C=O
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2cccnc21
Agent: C[Si](C)(C)Cl
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2cccnc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a solution of 3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (2.75 g, 8.08 mmol) in anhydrous dichloromethane (40.0 mL) were added triethylamine (4.91 g, 48.5 mmol) and chlorotrimethylsilane (3.51 g, 32.3 mmol) under nitrogen at 0° C. The reaction mixture was stirred at 0° C. for 2 h and diluted with anhydrous dichloromethane (50.0 mL). The organic layer was washed with water (2×25.0 mL), dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The gummy brown residue was dissolved in THF (40.0 mL) followed by the addition of formaldehyde solution (2.20 mL, 80.8 mmol, 37 wt % in water) and ytterbium (III) trifluoromethanesulfonate (1.25 g, 2.02 mmol). The reaction mixture was stirred at ambient temperature for 36 h and diluted with dichloromethane (100 mL). The organic layer was washed with saturated NaHCO3 (50.0 mL), saturated ammonium chloride (50.0 mL) and water (50.0 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness to afford the title compound (2.85 g, 98%): 1H NMR (300 MHz, CDCl3) δ 10.02 (s, 1H), 8.29 (dd, 1H), 7.72 (dd, 1H), 7.13 (dd, 1H), 6.55 (s, 1H), 6.46 (s, 1H), 5.86 (dd, 2H), 4.37 (dd, 2H), 3.77-3.84 (m, 2H), 3.25 (br, 1H), 1.63-1.77 (m, 2H), 1.36-1.22 (m, 4H), 0.85 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 179.9, 156.6, 152.3, 148.4, 147.5, 141.5, 133.8, 124.3, 118.7, 111.3, 107.9, 101.9, 101.4, 64.3, 59.1, 39.9, 31.6, 27.2, 22.3, 13.9; MS (ES+) m/z 371.1 (M+1).
Reaction SMILES: O[C:2]1[N:7]=[C:6](O)[CH:5]=[C:4]([CH3:9])[N:3]=1.P(Cl)(Cl)([Cl:12])=O.CCN(C1C=CC=CC=1)CC.[OH-].[Na+].[Na+].[Cl-:29]>>[Cl:29][C:2]1[N:7]=[C:6]([Cl:12])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: [Cl-]
Reactant: Cc1cc(O)nc(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)c1ccccc1
Product: Cc1cc(Cl)nc(Cl)n1

Procedure:
45 g (0.36 M) of 2,4-dihydroxy-6-methyl-pyrimidine have been treated with phosphorous oxychloride in the presence of diethylaniline. After having been refluxed during 3 hours the reaction mixture was cooled and the excess of phosphorous oxychloride was decomposed over ice, then the mixture was neutralized with NaOH, saturated with a NaCl solution and extracted with ether. By separation and evaporation of the ethereal extracts there was obtained a residue which was distilled to yield 57 g of the title compound at B.p. 99°/11 Torr.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([OH:23])(=O)[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.[NH2:25][CH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33]C)=[O:32])=[CH:29][CH:28]=1.C(N(CC)CC)C>O1CCCC1>[C:31]([C:30]1[CH:35]=[CH:36][C:27]([CH2:26][NH:25][C:13](=[O:23])[CH:14]=[CH:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:28][CH:29]=1)([OH:33])=[O:32]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: COC(=O)c1ccc(CN)cc1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (3.71 g) is added to an ice-cold stirred solution of cinnamic acid (3.13 g) in 30 mL tetrahydrofuran. After stirring for an additional 1 hr, methyl 4-(aminomethyl)benzoate hydrochloride (4.7 g) and triethylamine (3.23 mL) are added and the final mixture stirred while immersed in an ice water bath for an additional 30 min, followed by stirring overnight at room temperature. After removal of the solvent by rotary evaporation, the residue is taken up in chloroform (250 mL) and extracted with water (200 mL), 1N HCl (3×50 mL), water 100 mL), saturated sodium bicarbonate (100 mL), brine (100 mL) and the final chloroform layer dried over anhydrous magnesium sulfate. After evaporation of the solvent in vacuo, the crude product (2.74 g) is suspended in 100 mL tetrahydrofuran and 20 mL 2N NaOH and the mixture stirred at room temperature overnight. The mixture is then made acidic by addition of excess 1N HCl, and the precipitate recovered by filtration. After washing the filter cake with water and pressing to remove as much water as possible, the white solid is crystallized from methanol/2N HCl as N-(4-carboxybenzyl)cinnamamide, m.p. 238°-239° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@:9]1([CH3:17])[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C@@H:53]([C@@H:71]1[CH2:75][CH2:74][CH2:73][N:72]1[C:76](=[O:95])[CH2:77][C@@H:78]([O:93][CH3:94])[C@@H:79]([N:84]([CH3:92])[C:85](=[O:91])[C@H:86]([CH:88]([CH3:90])[CH3:89])[NH2:87])[C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:56]>ClCCl.CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@:9]1([C:14]([NH:87][C@H:86]([C:85]([N:84]([CH3:92])[C@@H:79]([C@@H:80]([CH3:83])[CH2:81][CH3:82])[C@H:78]([O:93][CH3:94])[CH2:77][C:76]([N:72]1[CH2:73][CH2:74][CH2:75][C@H:71]1[C@H:53]([O:52][CH3:51])[C@@H:54]([CH3:70])[C:55]([NH:57][C@H:58]([C:66]([O:68][CH3:69])=[O:67])[CH2:59][C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)=[O:56])=[O:95])=[O:91])[CH:88]([CH3:89])[CH3:90])=[O:16])[CH3:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@]1(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@]1(C)CCCCN1C(=O)OC(C)(C)C)C(C)C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
To a solution of #156 (106 mg, 0.436 mmol, 1 eq.) in dichloromethane (3 mL) and N,N-dimethylformamide (0.5 mL) was added diisopropylethylamine (0.228 mL, 1.31 mmol, 3 eq.) followed by HATU (205 mg, 0.523 mmol, 1.2 eq.). The reaction was stirred for 15 minutes and #114 (276 mg, 0.436 mmol, 1 eq.) was added and stirred at room temperature for 2 hours. The reaction was diluted with dichloromethane (10 mL) and washed with 10% citric acid (3×5 mL). The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated in vacuo. Purification of the residue by silica gel chromatography (Gradient: 0 to 80% acetone in heptane) afforded #160 (145 mg, 39%). LC-MS (protocol Q1): m/z 858.8 [M+H+], retention time=1.12 minutes.
Reaction SMILES: [C:1]([Li])([CH3:4])(C)[CH3:2].[CH3:6][C:7]([CH3:21])([CH3:20])[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1)=[O:9].CN(C)CCN(C)C.C1C[O:33]CC1>CCCCC.C(O)(=O)C.CC(C)=O>[CH3:6][C:7]([CH3:21])([CH3:20])[C:8]([N:10]1[CH2:19][CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]1[C:1]([OH:33])([CH3:4])[CH3:2])=[O:9]
Reactant: [Li]C(C)(C)C
Reactant: C1CCOC1
Reactant: CC(C)(C)C(=O)N1CCc2ccccc2C1
Agent: CN(C)CCN(C)C
Solvent: CCCCC
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)N1CCc2ccccc2C1C(C)(C)O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 1.64 M tert-butyllithium in n-pentane (12 mL) was added to a mixture of 2-(2,2-dimethylpropanoyl)-1,2,3,4-tetrahydroisoquinoline (3.0 g), tetramethylethylenediamine (2.2 ml), and THF (40 mL) at −78° C. The reaction liquid was stirred at −78° C. for 10 minutes. Then, acetone (1.8 mL) was further added to the liquid at −78° C., followed by stirring at −78° C. for 1 hour. Acetic acid (2 mL) was added to the reaction liquid, and the temperature was raised to room temperature. The reaction liquid was evaporated under reduced pressure. EtOAc and water were added thereto, followed by liquid separation. The organic layer was washed sequentially with an aqueous 5% citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-EtOAc) to obtain 2-[2-(2,2-dimethylpropanoyl)-1,2,3,4-tetrahydroisoquinolin-1-yl]propan-2-ol (2.62 g).