Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH3:9].[C:10]1([CH3:22])[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH2:20][CH2:19][NH:18][C:17]2=[O:21])[CH:11]=1.N[C@@H]1CCCC[C@H]1N>O1CCOCC1.[Cu]I>[Br:8][C:4]1[C:3]([CH3:9])=[C:2]([N:18]2[CH2:19][CH2:20][N:16]([C:12]3[CH:11]=[C:10]([CH3:22])[CH:15]=[CH:14][CH:13]=3)[C:17]2=[O:21])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1c(Br)cccc1Br
Reactant: Cc1cccc(N2CCNC2=O)c1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Solvent: C1COCCO1
Product: Cc1cccc(N2CCN(c3cccc(Br)c3C)C2=O)c1
Temperature: 120 °C
Reaction time: 21.5 h
Yield: 71.4 %

Procedure:
A suspension of 1,3-dibromo-2-methylbenzene (185 mg, 0.740 mmol), 1-m-tolylimidazolidin-2-one (50 mg, 0.284 mmol), copper (I) iodide (5.40 mg, 0.028 mmol), tripotassium phophosphate (120 mg, 0.567 mmol) and (+/−)-trans-1,2-diaminocyclohexane (3.4 μL, 0.028 mmol) in 1,4-dioxane (1 mL) was purged with nitrogen and heated at 120° C. in a sealed tube. After 21.5 h, the mixture was concentrated and the residue was purified by column chromatography (eluting with a gradient from hexane to 50:50 hexane-EtOAc) to provide 1-(3-bromo-2-methylphenyl)-3-m-tolylimidazolidin-2-one as a white solid (70 mg, 70%). 1H NMR (400 MHz, chloroform-d) δ 7.51-7.54 (1 H, m), 7.49 (1 H, s), 7.34 (1 H, dd, J=8.05, 1.94 Hz), 7.24 (2 H, d, J=8.05 Hz), 7.11 (1 H, t, J=7.91 Hz), 6.90 (1 H, d, J=7.49 Hz), 3.98-4.04 (2 H, m), 3.81-3.87 (2 H, m), 2.38 (3 H, s), 2.36 (3 H, s). Mass spectrum m/z 345, 347 (M+H)+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][OH:5].[N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1>C(O)C>[Br-:1].[OH:5][CH2:4][CH2:3][CH2:2][N+:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1
Reactant: Cc1ccncc1
Reactant: OCCCBr
Solvent: CCO
Product: Cc1cc[n+](CCCO)cc1
Product: [Br-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 96 %

Procedure:
Anhydrous ethanol (250 mL) was added to a two-neck, 1 L round-bottomed flask, flushed with nitrogen, followed by addition of 3-bromo-1-propanol (60.0 g, 0.4317 mol) and 4-picoline (43.8 g, 0.4701 mol). The mixture was heated with stirring at 60° C. for 24 hours under nitrogen. The reaction was stopped and the contents in flask were transferred to a one-neck round-bottomed flask. The solvent was removed under vacuum leaving the product as a viscous, dark yellow-orange liquid. The product was washed within the same flask with diethyl ether (4×100 mL) and any remaining solvent was removed under vacuum. The yield of N-(3-hydroxypropyl)-4-picolinium bromide was 96.6 g (96% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.98 (2H, d, J=6.8 Hz), 8.00 (2H, d, J=6.8 Hz), 4.64 (2H, t, J=7.0 Hz, 7.0 Hz), 3.44 (2H, t, J=6.0 Hz, 6.0 Hz), 2.62 (3H, s), 2.06 (2H, p, J=6.8 Hz, 6.0 Hz, 6.0 Hz, 6.8 Hz). IR (neat): 3332 cm−1 (O—H), 1642 cm−1 (>C═N—C), 1518 cm−1 (C—C aromatic).
Reaction SMILES: FC(F)(F)C(O)=O.O.[C:9]([C:13]1[CH:64]=[CH:63][C:16]2[NH:17][C:18]([CH2:20][CH2:21][CH:22]3[CH2:25][CH:24]([N:26]([CH2:31][C@@H:32]4[C@H:36]5[O:37]C(C)(C)[O:39][C@H:35]5[C@H:34]([N:42]5[C:46]6[N:47]=[CH:48][N:49]=[C:50]([NH:51]CC7C=CC(OC)=CC=7OC)[C:45]=6[CH:44]=[CH:43]5)[CH2:33]4)[CH:27]4[CH2:30][CH2:29][CH2:28]4)[CH2:23]3)=[N:19][C:15]=2[CH:14]=1)([CH3:12])([CH3:11])[CH3:10].C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[NH2:51][C:50]1[C:45]2[CH:44]=[CH:43][N:42]([C@@H:34]3[CH2:33][C@H:32]([CH2:31][N:26]([CH:24]4[CH2:23][CH:22]([CH2:21][CH2:20][C:18]5[NH:17][C:16]6[CH:63]=[CH:64][C:13]([C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][C:15]=6[N:19]=5)[CH2:25]4)[CH:27]4[CH2:28][CH2:29][CH2:30]4)[C@@H:36]([OH:37])[C@H:35]3[OH:39])[C:46]=2[N:47]=[CH:48][N:49]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C3CCC3)C3CC(CCc4nc5cc(C(C)(C)C)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)c1ccc2[nH]c(CCC3CC(N(C[C@H]4C[C@@H](n5ccc6c(N)ncnc65)[C@H](O)[C@@H]4O)C4CCC4)C3)nc2c1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
Trifluoroacetic Acid (10 ml, 200 mmol) added to a mixture of Water (1 ml, 80 mmol) and 7-((3aS,4R,6R,6aR)-6-(((3-(2-(5-(tert-butyl)-1H-benzo[d]imidazol-2-yl)ethyl)cyclobutyl)(cyclobutyl)amino)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)-N-(2,4-dimethoxybenzyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.61 g, 0.80 mmol) at RT. The reaction was stirred o/n at RT and was quenched by the addition of Triethylsilane (0.26 ml, 1.6 mmol). The volatiles were removed in vacuo and resulting and the residue was taken up in MeOH (15 mls),500 mg K2CO3 and 8 drops of water were added and the reaction was stirred at RT for 1 hour. The mixture was filtered and the filter cake was washed with MeOH (10 ml). The filtrate was concentrated and the resulting residue purified by flash chromatogrpahy (DCM/7N NH3 in MeOH 90:10) to give the desired product (0.13 g) as a colorless foam. MS (ESI+) for C33H45N7O2 m/z 572.2 [M+H]+; MS (ESI−) for C33H45N7O2 m/z 570.2 [M−H]−; HPLC purity >90% (ret. time, 2.850 min.) 1H NMR (400 MHz, d4-MeOH) δH 8.083 (s, 1H), 7.492 (s, 1H), 7.412-7.392 (m, 1H), 7.309-7.286 (m, 1H), 7.220-7.205 (m, 1H), 6.620-6.610 (d, J=4.0 Hz, 1H), 4.321-4.283 (m, 1H), 3.888-3.848 (m, 1H), 3.505-3.417 (m, 0.5H (methine of trans isomer)), 3.231-3.147 (m, 0.5H) (methine of cis isomer)), 3.051-2.953 (m, 1H), 2.871-2.732 (m, 3H), 2.583-2.501 (m, 1H), 2.441-2.368 (m, 1H), 2.244-2.205 (m, 3H), 2.170-1.833 (m, 9H), 1.695-1.560 (m, 4H), 1.384 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][C:12]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH:13]=1.C(N(CC)CC)C>ClCCl>[O:11]=[C:12]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]=2[CH2:13]1
Reactant: OC1=Cc2ccccc2C=Cc2ccccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1Cc2ccccc2C=Cc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (5 ml) in dry dichloromethane (75 ml) at -78° C. under nitrogen was added, dropwise. dimethyl sulphoxide (8.75 ml), and the solution stirred at -78° C. for 15 minutes. A solution of 5-hydroxy-dibenzo[a,e]cyclooctene (11.1 g) in dichloromethane (75 ml) was added over 5 minutes at -78° C. and the solution stirred for 15 minutes, then triethylamine (30 ml) was added and the mixture allowed to warm to room temperature. The mixture was washed with water (100 ml), 1N hydrochloric acid (50 ml) water (100 ml), brine (50 ml) then dried and evaporated to give the crude ketone which was recrystallised from ethyl alcohol/hexane (10.0 g), mp 112°-6 ° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][OH:10].N1C=CC=CC=1.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>O1CCCC1.CN(C)C1C=CN=CC=1>[C:17]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[NH:2][CH3:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: CNc1ccccc1CO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: O
Solvent: C1CCOC1
Product: CNc1ccccc1COC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution (50 mL) of [2-(methylamino)phenyl]methanol (1.37 g: synthesized according to the method described in WO 01/32652) in tetrahydrofuran were added pyridine (1.05 mL), acetic anhydride (1.23 mL) and 4-dimethylaminopyridine (0.18 g), and the mixture was stirred at room temperature for 8 hrs. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed successively with a 5% aqueous copper (II) sulfate solution (50 mL), a saturated aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by flash silica gel column chromatography (eluted with ethyl acetate:hexane=1:5, then 1:3) to give the title compound (0.38 g) as a white solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 57 %

Procedure:
3.48 g (10 mmol) of Compound 27 obtained in Example 27 was dissolved in 100 ml of dimethylformamide under argon atmosphere, 1.32 ml of ethyl bromoacetate and 1.23 g of potassium tert-butoxide were added under ice-cooling and the mixture was stirred at room temperature for 25 minutes. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate to give 3.20 g (57%) of 2-[4-(N-acetyl-N-ethoxycarbonylmethylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [N:1]([C@@H:4]1[C@@H:8]([CH2:9][OH:10])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3].[C:19](Cl)(=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>N1C=CC=CC=1>[N:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][C:19](=[O:35])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[O:7][C@@H:6]([N:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[N:13][C:12]2=[O:18])[CH2:5]1)=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1cnc(=O)n([C@H]2C[C@H](N=[N+]=[N-])[C@@H](CO)O2)c1
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCC(=O)OC[C@H]1O[C@@H](n2cc(C)cnc2=O)C[C@@H]1N=[N+]=[N-]
Reaction time: 2 h
Yield: 29 %

Procedure:
1-(3-Azido-2,3-dideoxy-β-D-erythro-pentofuranosyl)-5-methyl-2(1H)-pyrimidinone (0.25 g, 1 mMol) was dissolved in 11 mL anhydrous pyridine at 0° C. under a nitrogen atmosphere. Freshly distilled palmitoyl chloride (2.5 mL) was added all at once and the reaction stirred for 2 hrs. The solvents were evaporated away and the residue applied to a silica gel column eluted with 1:6 EtOAc/hexane (v/v). Appropriate fractions were combined and evaporated to give the title compound 0.14 g (0.29 mMol; 29%); mp =65°-67° C.; UV (nm) EtOH: λmax =228 (ε=13400), λmin =212 (ε=10300); 1H NMR (DMSO-d6) δ7.03(d, J=1.37 Hz, 1H, H6), 5.90(dd, J=1.76 Hz, 6.45 Hz, 1H, H1 '), 5.34(s, 1H, H4), 4.50(s, 1H, H3 '), 4.30-4.24(m, 1H, H4 '), 3.93-3.70(m, 2H, H5 '), 2.91(t, J=12.7 Hz, 2H, --C(O)CH2 -- ), 2.57-2.26(m, 2H, H2 '), 1.73(s, 3H, 5-CH3), 1.54-0.80(m, 29 H, palmitoyl).
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C1CO[C:13]2([C:19]3[CH:20]=[CH:21][C:22]([CH2:24][C:25](N)=[O:26])=[CH:23][C:18]=3[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]2=3)[O:12]1.CC(C)=[O:36].CCCCCC>>[CH:21]1[C:20]2[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=3[C:13](=[O:12])[C:19]=2[CH:18]=[CH:23][C:22]=1[CH2:24][C:25]([OH:36])=[O:26]
Reactant: NC(=O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Reactant: CC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
11.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is refluxed for 2 hours in 70 ml. of acetic acid and 105 ml. of concentrated hydrochloric acid. The mixture is cooled and diluted, then extracted with ether. The ethereal solution is extracted with aqueous sodium carbonate and the extract acidified and extracted with ethyl acetate to afford a 70% yield of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [C:1](=[O:4])([O-])[NH2:2].N[C@H:6]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:7][N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:16]=2[F:23])=[C:11]([CH3:24])[N:10](CC2C(C(F)(F)F)=CC=CC=2F)[C:9]1=[O:37].C([O-])([O-])=O.[K+].[K+].C(=O)=O>O.CN(C=O)C>[F:23][C:16]1[C:17]([O:21][CH3:22])=[CH:18][CH:19]=[CH:20][C:15]=1[C:12]1[C:13](=[O:14])[N:8]([CH2:7][C@H:6]([NH:2][C:1](=[O:4])[C:12]([CH3:15])([CH3:13])[CH3:11])[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:9](=[O:37])[NH:10][C:11]=1[CH3:24]
Reactant: COc1cccc(-c2c(C)n(Cc3c(F)cccc3C(F)(F)F)c(=O)n(C[C@H](N)c3ccccc3)c2=O)c1F
Reactant: NC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2c(C)[nH]c(=O)n(C[C@H](NC(=O)C(C)(C)C)c3ccccc3)c2=O)c1F
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 70 %

Procedure:
DMF (anhydrous, 70 mL) was added to carbamate residue 3a (7.5 g, 19.7 mmol) and the mixture was cooled to 0° C. t-BOC-(1R)-amino-2-amino-1-phenylethane acetate salt (6.41 g, 21.6 mmol) was added followed by K2CO3 (4.08 g, 29.6 mmol). The mixture was stirred for ˜3 hours (all carbamate 3a (tR=11.5 minute in HPLC method 1) was converted to urea intermediate (tR=10.5 minute in HPLC method 1)). The temperature was raised to 60° C. to control the CO2 release. The mixture was heated for 2-3 hours then 210 mL of water was slowly added over 30-60 minutes maintaining the temperature at 60° C. The slurry was stirred for 30-60 minutes at 50-60° C. and was cooled down to 25° C. over 30-60 minutes. The slurry was filtered and the cake was washed with 210 mL water to remove the residual base. The cake was dried at 10 mm/50° C. to give 6.5 g (70% yield) of off-white fine needle crystal 3b. Alternately, the cake may be washed with acetonitrile/water 2:1 before drying.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][C:11]([C:25]2[O:26][C:27]([CH2:30][CH3:31])=[N:28][N:29]=2)([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].CO>C(OCC)(=O)C>[C:32]([O-:37])(=[O:36])[C:33]([O-:35])=[O:34].[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH+:8]1[CH2:13][CH2:12][C:11]([C:25]2[O:26][C:27]([CH2:30][CH3:31])=[N:28][N:29]=2)([N:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15](=[O:18])[CH2:16][CH3:17])[CH2:10][CH2:9]1.[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH+:8]1[CH2:9][CH2:10][C:11]([N:14]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:15](=[O:18])[CH2:16][CH3:17])([C:25]2[O:26][C:27]([CH2:30][CH3:31])=[N:28][N:29]=2)[CH2:12][CH2:13]1
Reactant: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CCN(CCc2cccs2)CC1
Reactant: O=C(O)C(=O)O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(=O)N(c1ccccc1)C1(c2nnc(CC)o2)CC[NH+](CCc2cccs2)CC1
Product: O=C([O-])C(=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 158.7 %

Procedure:
To a solution of 1-[2-(2-thienyl)ethyl]-4-(ethyl-1,3,4-oxadiazolyl)-4-(N-phenylpropionamido)piperidine (660 mg, 1.50 mmol) in ethyl acetate (20 ml), oxalic acid (136 mg, 1.51 mmol, in 3 ml EtoAc) was added dropwise. The resulting mixture was heated to 70° C. and methanol added dropwise until it became a clear solution. The solution was cooled to room temperature on standing for 2 hours. The precipitate was filtered to afford the product (630 mg, 1.19 mmol) as a white crystalline compound, mp 160°-162° C. Anal. Calcd. for C24H30N4O2S.C2H2O4 : C,59.07; H,6.10; H,10.60 Found: C,59.08; H,6.26; N,10.45. ##STR34##
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([OH:15])[CH:14]=3)[C:6]=2[N:5]([CH2:16][CH2:17][CH3:18])[CH2:4][C:3]=1[CH3:19].[OH-].[Na+].Cl[C:23]([F:28])([F:27])C(O)=O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[N:8]=[CH:9][C:10]3[N:11]([CH2:12][N:13]([O:15][CH:23]([F:28])[F:27])[CH:14]=3)[C:6]=2[N:5]([CH2:16][CH2:17][CH3:18])[CH2:4][C:3]=1[CH3:19]
Reactant: CCCN1CC(C)=C(Cl)C2=C1N1CN(O)C=C1C=N2
Reactant: O=C(O)C(F)(F)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN1CC(C)=C(Cl)C2=C1N1CN(OC(F)F)C=C1C=N2
Temperature: 150 °C

Procedure:
5.51 g (0.02 mol) 4-chloro-3-methyl-1-propyl-9H-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol (Intermediate A25) and 2 g (0.05 mol) sodium hydroxide were dissolved in 20 ml dimethylformamide. After 10 min stirring 2.53 ml (0.03 mol) chlorodifluoroacetic acid was added dropwise. The mixture was heated 5 h at 150° C. bath temperature with stirring. After cooling the product was extracted with ethyl acetate (200 ml, 300 ml), the combined organic phases were washed with water (2×100 ml), the organic phase was dried over sodium sulfate, filtered off, and evaporated to dryness.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:22])[NH:9][CH:10]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:11][C:12]([OH:14])=O)=[CH:3][CH:2]=1.[NH2:29][CH:30]([C:35]1[CH:40]=[CH:39]C(C)=CC=1)CC(O)=O.[N:42]([C:45]1C=CC(C2C=CC=CC=2)=C[CH:46]=1)=C=O>C(Cl)Cl>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([NH:7][C:8](=[O:22])[NH:9][C@@H:10]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:11][C:12]([NH:42][CH2:45][CH2:46][N:29]2[CH2:30][CH2:35][CH2:40][CH2:39]2)=[O:14])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(N)CC(=O)O)cc1
Reactant: Cc1ccc(C(CC(=O)O)NC(=O)Nc2ccc(-c3ccccc3)cc2)cc1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc([C@@H](CC(=O)NCCN2CCCC2)NC(=O)Nc2ccc(-c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
3-(3-Biphenyl-4-yl-ureido)-3-p-tolyl-propionic acid. To a solution of 3-amino-3-(p-tolyl)propionic acid (0.50 g, 2.79 mmol) and TEA (0.26 g, 2.56 mmol) in CH2Cl2 (28 mL) cooled to 0° C., was added 4-isocyanato-biphenyl (0.55 g, 2.79 mmol). The mixture was stirred at 0° C. for 30 min and was then brought to rt and stirred for an additional 3 h. The solvent was removed, water (20 mL) was added to the clear residue, and the mixture was then chilled to 0° C. and acidified using 1 N HCl. The resulting precipitate was collected by filtration, washed with copious amounts of H2O, and dried under vacuum to afford 0.87 g (83%) of the desired product as a white solid. MS (electrospray): mass calculated for C23H22N2O3, 374.16; m/z found, 413.0 [M+Na]+. 1H NMR (400 MHz, DMSO-d6): 8.74 (s, 1H), 7.65–7.29 (m, 9H), 7.25 (d, J=8.1 Hz, 2H), 7.14 (d, J=7.9 Hz, 2H), 6.64 (d, J=8.5 Hz, 1H), 5.11–5.06 (m, 1H), 2.74–2.67 (m, 2H), 2.27 (s, 3H).
Reaction SMILES: BrC[CH2:3][CH2:4][CH2:5][CH2:6][O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[CH3:15][Mg+:16].[Br-:17]>O(CC)CC>[CH3:13][C:11]([Si:8]([CH3:9])([CH3:10])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:15][Mg:16][Br:17])([CH3:12])[CH3:14]
Reactant: C[Mg+]
Reactant: [Br-]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCBr
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCC[Mg]Br

Procedure:
A mixture of Mg turnings (0.6 g, 24 mmole), [(5-bromo-1-pentyl)oxy]-(1,1-dimethylethyl)dimethylsilane (0.5 mL), and MeMgBr (0.2 mL, 3 M) in dry OEt2 (5 mL) was stirred and heated to reflux for 5 minutes under an inert atmosphere. A solution of [(5-bromo-10-pentyl)oxy](1,1-dimethyl-ethyl)dimethylsilane (5.62 g, 20 mmole) and MeMgBr (0.2 mL, 3 M) in dry OEt2 (20 mL) was added dropwise at a rate to maintain a gentle, unassisted reflux. After addition was complete, the reaction was heated at reflux for 45 minutes. The solution of Grignard reagent was then cooled and used immediately in the next reaction.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].C(N)CN.C(O)(=[O:13])CC.[C:15]([O-:19])(=[O:18])[CH2:16][OH:17].O=O>>[C:1]([OH:5])(=[O:4])[CH:2]=[O:3].[C:16]([OH:13])(=[O:17])[C:15]([OH:19])=[O:18]
Reactant: CCC(=O)O
Reactant: O=C([O-])CO
Reactant: O=C(O)CO
Agent: *CC*
Agent: O=O
Solvent: NCCN
Product: O=C(O)C(=O)O
Product: O=CC(=O)O
Temperature: 15 °C
Reaction time: 5.5 h

Procedure:
Into a 2.5-cm ID×20 cm glass column equipped with a 20-μm polyethylene bed support was placed 10 mL of a solution containing glycolic acid (0.25M), ethylenediamine (0.33M), propionic acid (0.075M, HPLC internal standard), and flavin mononucleotide (0.2 mM). The column and its contents were cooled to 15° C., then 2.5 IU of spinach glycolate oxidase and 27,000 IU of Aspergillus niger catalase (co-immobilized on Eupergit C) were added to the solution. Oxygen was then passed through the porous bed support and bubbled through the reaction mixture at a rate of 10 mL/min. The reaction was monitored by taking a 100 μL aliquot of the reaction mixture at regular intervals, mixing the aliquot with 300 μL of 0.1N sulfuric acid to quench the reaction, filtering the aliquot and analyzing by HPLC. After 5.5 hours, the yields of glyoxylic acid, oxalic acid, and formic acid were 98%, 2%, and 0%, respectively, with complete conversion of glycolic acid. The final activities of glycolate oxidase and catalase were 95% and 65% of their initial values.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:12]([NH:11][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)=[O:20])[CH:43]=[CH:44][CH:45]=1
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(C)n4)c3)c2cc1OC
Yield: 13 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 165A (0.114 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.028 g, 13%). 1H NMR (300 MHz, CDCl3) δ 9.53 (br, 1H), 8.63 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.41 (t, 1H), 7.32 (m, 2H), 7.12 (s, 1H), 7.01 (d, 1H), 6.28 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.92 (s and t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][CH2:15][CH:16]([OH:27])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>C(O)CCC>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH2:17][CH:16]([OH:27])[CH2:15][CH2:14][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccccc1OCC(O)CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCO
Product: COc1ccccc1OCC(O)CCN1CCN(c2ccccc2)CC1
Yield: 63.1 %

Procedure:
This compound was prepared according to the procedure of Example 78. A mixture of 3.2 g (0.02 mole) of 1-phenylpiperazine, 4.8 g (0.02 mole) of 4-chloro-1-(2-methoxyphenoxy)-2-butanol and 8.0 g (0.075 mole) of anhydrous sodium carbonate in 100 ml of 1-butanol gave 4.5 g (64%) of white powder, m.p. 101°-102° C. Recrystallizing solvent used was iropropyl alcohol.