Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:11][NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=1)=[O:14])[C:6]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)([OH:23])[CH2:5]2.C=O.O.[C:34]1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]1=[N:11][N:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)=[O:14])[CH2:34][O:23][C:6]1([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(NN=C1c2ccc(F)cc2CC1(O)c1ccc(F)cc1)Nc1ccc(Br)cc1
Agent: C=O
Solvent: O
Solvent: CC#N
Product: O=C(Nc1ccc(Br)cc1)N1COC2(c3ccc(F)cc3)Cc3cc(F)ccc3C2=N1
Yield: 447.8 %

Procedure:
A mixture of 0.80 g (0.0017 moles) of the product obtained in Step C, 0.25 g (0.0027 moles) of paraformaldehyde, 50 mg of p-toluene sulfonic acid monohydrate and 45 mL of acetonitrile was refluxed for 30 minutes. The resulting mixture was partitioned between chloroform and saturated aqueous sodium bicarbonate and the aqueous layer was extracted three times with chloroform. The combined organic layers were dried over magnesium sulfate and concentrated to give a yellow solid. The solid was triturated with methanol/water, and dried under vacuum to afford 0.57 g of a yellow solid, m.p. 208°-209° C.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:16]([O-:19])(O)=[O:17].[Na+]>N1C=CC=CC=1.CCCCCC>[C:4]([Si:1]([CH3:3])([CH3:2])[O:19][C:16]([O:8][Si:1]([CH3:3])([CH3:2])[C:4]([CH3:7])([CH3:6])[CH3:5])=[O:17])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC(=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a stirred solution of triethylsilyloxy keto diol 6 (883 mg, 2.31 mmol) in 35 mL of pyridine under nitrogen at 0° C. was added dropwise 0.485 mL(2.771 mmol) of TBSOTf. The solution was then warmed to room temperature. After 2 h at room temperature, the solution was diluted with 100 mL of hexane and poured into 150 mL of a saturated aqueous NaHCO3 solution. The organic layer was separated, and the aqueous layer was extracted with two 100 mL portions of hexane. The organic layers were combined, and washed with 50 mL of a 10% aqueous CuSO4 solution followed by 20 mL of H2O, and dried over anhydrous Na2SO4. Removal of the solvent followed by flash chromatography purification (2.5% EtOAc/hexane) to give 1.122 g of t-butyldimethylsilyloxy ketone 7 (98% yield) as a white solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[C:18]([N:25]1[CH2:32][CH2:31][CH2:30][C@H:26]1[C:27](O)=[O:28])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH2:11]([O:10][C:8]([C@H:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][C:27]([CH:26]2[CH2:30][CH2:31][CH2:32][N:25]2[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:28])[CH2:3][CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NC1CCC(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
To a stirred solution of benzyl 4-aminocyclohexanecarboxylate (900 mg, 3.9 mmol), boc-proline (830 mg, 3.9 mmol), HOBt (521 mg, 3.9 mmol), and triethylamine (1.6 ml, 11.6 mmol) in CH2Cl2 (30.0 ml) was added EDC.HCl (1.1 g, 5.8 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hr, and concentrated in vacuo. Water was added to the residue, and extracted with EtOAc. The extract was washed with sat. NaHCO3, 2-M citric acid, and sat. NaHCO3, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with n-hexane-EtOAc (6:1, v/v) as eluent to give benzylcis-4-[(1-tert-butoxycarbonyl-2-pyrrolidinyl)carbonylamino]cyclohexanecarboxylate (600 mg, 36%) as an amorphous solid. 1H-NMR (CDCl3) δ1.44 (s, 9H), 1.50-1.90 (m, 12H), 2.20-2.26 (m, 1H), 3.25-3.50 (m, 2H), 3.80-3.90 (m, 1H), 4.10-4.25 (m, 1H), 5.12 (s, 2H), 7.35-7.36 (m, 5H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8](=[O:19])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:27](Cl)(=[O:31])[C:28]([CH3:30])=[CH2:29]>C(Cl)Cl>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11](/[CH:10]=[CH:9]/[C:8]([N:5]2[CH2:6][CH2:7][CH:2]([O:1][C:27](=[O:31])[C:28]([CH3:30])=[CH2:29])[CH2:3][CH2:4]2)=[O:19])=[CH:16][CH:15]=1
Reactant: C=C(C)C(=O)Cl
Reactant: COc1ccc(/C=C/C(=O)N2CCC(O)CC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CCN(C(=O)/C=C/c2ccc(OC)cc2)CC1

Procedure:
A solution of 6.65 g of 4-hydroxy-(E)-1-[3-(4-methoxy-phenyl)acryloyl]-piperidine in 50 ml of methylene chloride was treated with 4 ml of triethylamine at 0° C. while gassing with argon. 2.7 ml of methacryloyl chloride were added dropwise within 15 minutes. Subsequently, the reaction mixture was concentrated to dryness in a vacuum. Chromatographic purification of the residue on silica gel with ether/hexane (vol. 4:1) gave 4.21 g of 2-methyl-acrylic acid (E)-I-[3-(4-methoxy-phenyl)-acryloyl]-piperidin-4-yl ester as a colourless oil. λmax (methylene chloride)=292.5 nm (ε=22775 l mol-1 cm-1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[N:7]=[C:6]([N:16]2[CH2:21][CH2:20][S:19](=[O:22])[CH2:18][CH2:17]2)[C:5]=1[N+:23]([O-:25])=[O:24])[CH3:2].[C:26]1(=[O:32])[O:31][C:29](=[O:30])[CH2:28][CH2:27]1>O1CCOCC1>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][N:13]([C:26](=[O:32])[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:14][CH2:15]2)[N:7]=[C:6]([N:16]2[CH2:17][CH2:18][S:19](=[O:22])[CH2:20][CH2:21]2)[C:5]=1[N+:23]([O-:25])=[O:24])[CH3:2]
Reactant: O=C1CCC(=O)O1
Reactant: CCOc1nc(N2CCNCC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]
Solvent: C1COCCO1
Product: CCOc1nc(N2CCN(C(=O)CCC(=O)O)CC2)nc(N2CCS(=O)CC2)c1[N+](=O)[O-]

Procedure:
3.75 gm (0.01 mol) of 6-ethoxy-5-nitro-4-(1-oxido-thiomorpholino)-2-piperazino-pyrimidine (m.p. 223°-224°C) were refluxed together with 2.0 gm (0.02 mol) of freshly distilled succinic acid anhydride in 50 ml of dioxane for 1 hour. The reaction solution was then evaporated to dryness, and the solid residue was recrystallized from ethyl acetate/isopropanol. Yield: 2.0 gm (42.5% of theory); m.p. 198°-200°C.
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:16]=[CH:15][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Br[CH2:18][CH2:19][CH2:20][Cl:21].C(N(CC)CC)C>O1CCCC1>[Cl:21][CH2:20][CH2:19][CH2:18][N:12]1[CH2:11][CH2:10][C:9]2[CH:15]=[CH:16][C:6]([O:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[CH2:14][CH2:13]1
Reactant: CS(=O)(=O)Oc1ccc2c(c1)CCNCC2
Reactant: ClCCCBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)Oc1ccc2c(c1)CCN(CCCCl)CC2
Yield: 52.6 %

Procedure:
A mixture of 7-methanesulfonyloxy-2,3,4,5-tetrahydro-1H-3-benzazepine (1.75 g, 7.3 mmol), 1-bromo-3-chloropropane (0.80 ml, 8.1 mmol) and triethylamine (3 ml, 21.5 mmol) in anhydrous tetrahydrofuran (25 ml) was heated at reflux for 5 h. The mixture was cooled, evaporated in vacuo and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The aqueous layer was extracted with ethyl acetate (100 ml) and the combined organics washed with brine (150 ml), dried (Na2SO4) and evaporated in vacuo. Purification by chromatography on silica gel using 10-70% ethyl acetate in hexane gradient elution gave the title compound as a pale orange oil (1.22 g, 53%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].S(Cl)([Cl:17])=O>>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C@H:6]([C:10]([Cl:17])=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: O=S(Cl)Cl
Reactant: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)O
Product: CC(C)[C@H](NC(=O)C(F)(F)F)C(=O)Cl
Reaction time: 0.25 h

Procedure:
A solution of 1 g. of N-trifluoroacetyl-L-valine in 5 ml. of thionyl chloride was cooled to 5° C. and stirred for 15 minutes. The excess thionyl chloride was removed under reduced pressure under a stream of dry nitrogen gas, affording N-trifluoroacetyl-L-valyl chloride as an oil.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-]#N.[K+]>>[C:5]1([C:6](=[O:7])[C:6]([C:5]2[CH:8]=[CH:9][C:2]([C:1](=[O:10])[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:18])=[CH:3][CH:4]=2)=[O:7])[CH:8]=[CH:9][CH:2]=[CH:3][CH:4]=1
Reactant: O=Cc1ccccc1
Reactant: O=Cc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [K+]
Product: O=C(C(=O)c1ccc(C(=O)C(=O)c2ccccc2)cc1)c1ccccc1

Procedure:
The benzoinic condensation of terephthalaldehyde (625 g) with benzaldehyde (2000 g) is effected in conditions strictly identical to those of example 1, while using 300 g of potassium cyanide, which represents 50% of the stoichiometrical proportion. The yield of pure bis-benzoin is 1516 g (94%). This product, when oxidized, yields 90% of very pure 1,4-bis (phenylglyoxyloyl) benzene. The tetraketone yield thus averages 85% with respect to the reacted terephthalic aldehyde.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH:26]C(OCC1C=CC=CC=1)=O)[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:3])[CH3:2]>CCOC(C)=O.CO.[Pd]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C@H:12]([NH2:26])[C:13](=[O:25])[NH:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)Nc1ccc2ncccc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCCCC[C@H](N)C(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirring solution of (7S)-7-benzyloxycarbonylamino-7-(quinolin-6-ylcarbamoyl)-heptanoic acid tert-butyl ester (11.0 g, 21.8 mmol) in EtOAc and MeOH was added 10% Pd/C. The reaction was charged with H2, degassed and refilled with hydrogen three times. The slurry was stirred at RT for 2 h at balloon pressure, then filtered through a plug of Celite, and solvent was removed under reduced pressure. The hydrogenolysis of the ester yielded 8.0 g (99%) of a thick oil solid after 19 h. 1H NMR (CDCl3) δ 8.9-7.3 (7H, m), 3.96 (1H, m), 2.31 (2H, t), 2.0-1.2 (17H, m). MS (ESI): (MH+) 372.2.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([N:6]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C@@H:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)[CH2:9][C@@:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])([CH3:26])[C:7]1=[O:32])[CH2:4][CH3:5].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([S:39](Cl)(=[O:41])=[O:40])[CH:34]=1>N1C=CC=CC=1>[Cl:25][C:21]1[CH:20]=[C:19]([C@@H:10]2[C@@H:11]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[N:6]([C@@H:3]([CH2:4][CH3:5])[CH2:2][NH:1][S:39]([C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)(=[O:41])=[O:40])[C:7](=[O:32])[C@:8]([CH2:27][C:28]([O:30][CH3:31])=[O:29])([CH3:26])[CH2:9]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC[C@@H](CN)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)c1cccnc1
Solvent: c1ccncc1
Product: CC[C@@H](CNS(=O)(=O)c1cccnc1)N1C(=O)[C@@](C)(CC(=O)OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1

Procedure:
A solution of methyl 2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate (13 mg, 0.027 mmol; Example 196, Step A) and pyridine-3-sulfonyl chloride (4.84 mg, 0.027 mmol) in pyridine (0.3 mL) was stirred at 110° C. for 4 h. Chromatography on silica gel (0 to 60% EtOAc in hexanes) gave methyl 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetate. This was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to 95% CH3CN in water, with 0.1% TFA) gave the title compound as a 1:1 complex with 2,2,2-trifluoroacetic acid.
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][S:9][CH2:8][CH2:7]2)[NH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[OH:26].Cl>C(Cl)(Cl)Cl>[O:12]=[C:4]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:2](=[O:26])[C:6]2([CH2:11][CH2:10][S:9][CH2:8][CH2:7]2)[NH:5]1
Reactant: CO
Reactant: N#Cc1ccc(N2C(=N)C3(CCSCC3)NC2=O)cc1C(F)(F)F
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(N2C(=O)NC3(CCSCC3)C2=O)cc1C(F)(F)F

Procedure:
Using the procedure of Example 2, 2.34 g of the product of Example 12, 25 ml of methanol and 5 ml of chloroform were reacted and 4.5 ml of 2N hydrochloric acid were added. The reaction medium was refluxed for one hour and after purification on silica with methylene chloride-acetone: 95-5 as eluant, crystallization from isopropanol was carried out to obtain 368 mg of the expected product (white crystals) melting at 209-210° C.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CN=C1.[Si:12](Cl)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].O>CN(C=O)C>[O:6]([CH2:5][CH2:4][CH2:3][C:2]#[CH:1])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: C#CCCCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.1 %

Procedure:
5.00 g (59.4 mmol) of pent-1-yn-5-ol were dissolved in 50 ml of dry DMF, and 10.10 g (149 mmol, 2.5 eq.) of imidazole and 9.40 g (62.4 mmol, 1.1 eq.) of TBS-Cl were added. After 12 hours of stirring at RT, 250 ml of water were added and the mixture was extracted with 3×150 ml of MTBE. The organic phase was washed 3× with in each case 100 ml of water and then dried over MgSO4. Purification by column chromatography gave 11.10 g (53.5 mmol, 90%) of 5-(tert-butyldimethylsiloxy)pent-1-yne as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH:3]([C:5]1[S:6][C:7]([Br:10])=[CH:8][CH:9]=1)[OH:4].[Na].O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[Br:10][C:7]1[S:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:11])[F:12])=[CH:9][CH:8]=1
Reactant: OC(c1ccc(Br)s1)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na]
Solvent: O
Solvent: ClCCl
Product: O=C(c1ccc(Br)s1)C(F)(F)F

Procedure:
2.93 g (0.011 mol) of 2,2,2-trifluoro-1-(5-bromo-2-thienyl)ethanol and 0.19 g (0.0006 mol) of tetrabutylammonium hydrogen sulfate are dissolved in 100 ml of methylene chloride at room temperature. 6.9 ml (0.014 mol) of an approximately 12% strength sodium hyochlorite solution are metered in within 5 minutes with vigorous stirring and the mixture is stirred for a further 4 hours at room temperature. The reaction mixture is added to 100 ml of water, the phases are separated, the aqueous phase is extracted several times with methylene chloride and the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying the organic phase with sodium sulfate, the volatiles are distilled off. Following distillation of the crude product in a kugelrohr (0.3 mbar, 40°-60° C. bath temperature), 0.48 g (39% of theory) of 5-bromo-2-trifluoroacetylthiophene. nD20 : 1.5309.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].O.[CH2:28](O)[CH2:29][OH:30]>S(=O)(=O)(O)O>[OH:30][CH2:29][CH2:28][O:19][C:18](=[O:20])[C@H:17]([CH3:21])[N:16]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: OCCO
Reactant: CC(C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: C[C@@H](C(=O)OCCO)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Yield: 56 %

Procedure:
A solution of (S)-2-(4-chlorophenyl-α-methyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole) and concentrated sulfuric acid (4 drops) in ethylene glycol (50 ml) was refluxed under nitrogen for three hours, and then poured into a saturated sodium bicarbonate solution (200 ml). Water (50 ml) was added and the product was extracted into two portions of ethyl acetate. The combined organic layers were washed twice with water and once with a saturated sodium chloride solution, dried over magnesium sulfate, treated with charcoal and filtered. Evaporation of the solvents under reduced pressure gave 1.9 g (56% yield) of solid which was dissolved in hot isopropyl ether (with a little isopropyl alcohol added). The solution was stirred and cooled to room temperature to precipitate a solid. The mixture was cooled in the freezer, the solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at room temperature overnight to give 1.44 g of title compound, mp 112°-113.5° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4]Cl.[I-].[Na+].[C:19]1([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[OH:1][CH:2]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH2:10][CH2:9]2)[CH2:3][CH2:4][N:28]1[CH2:29][CH2:30][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:26][CH2:27]1
Reactant: O=C1CCc2cc(C(O)CCCl)ccc2N1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCc2cc(C(O)CCN3CCC(c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2.6 Grams of 6-(1-hydroxy-3-chloropropyl)-3,4-dihydrocarbostyril and 1.8 g of sodium iodide were mixed in 60 ml of dimethylformamide and the mixture was stirred at a room temperature for 7 hours. Then 2.0 g of triethylamine and 2.5 g of 4-phenyl-piperidine were added to the mixture and stirred at a room temperature for 24 hours. The reaction mixture was poured into 200 ml of 1%-sodium hydrogen-carbonate aqueous solution and was extracted with chloroform. The chloroform layer was washed with water and dried, chloroform was removed by distillation. The residue thus obtained was recrystallized from ethanol to obtain 2.5 g of 6-[1-hydroxy-3-(4-phenyl-1-piperidyl)propyl]-3,4-dihydro-carbostyril in colorless plate-like crystals.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:45]=[CH:44][C:27]([C:28]([NH:30][C@H:31]([C:39]([O:41]CC)=[O:40])[CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[O:29])=[CH:26][CH:25]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1.[OH-].[Na+]>O.C(O)C>[NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:13][N:14]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([NH:30][C@H:31]([C:39]([OH:41])=[O:40])[CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[O:29])=[CH:44][CH:45]=3)[CH2:15][C:16]3[C:17](=[O:23])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(Cc2ccc3nc(N)nc(O)c3c2)Cc2c[nH]c(=O)[nH]c2=O)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1nc(O)c2cc(CN(Cc3c[nH]c(=O)[nH]c3=O)c3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)ccc2n1
Reaction time: 1.5 h

Procedure:
Diethyl N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamate (0.327 g) was suspended in a mixture of water (7 ml) and ethanol (2 ml) and treated with 1 N NaOH aq. (6 mol. eq.) Vigorous shaking gave a solution within 30 min. After a further 1.5 hr. the solution was clarified by filtration and the pH brought to 4.0 using 1 N HCl aq. A particulate precipitate of the product resulted. It was freed from inorganic ions by three cycles of suspension-centrifugation-decantation. The amorphous white solid was dried at 40° C. in vacuo, to yield the pure diacid, N-(4-(N-(2-amino-4-hydroxy-6-quinazolinyl)methyl-N-(5-uracilyl)methyl-amino)benzoyl)-L-glutamic acid (CB 3743), as its dihydrate (68%), m.p. 250°-255° C. The structure was confirmed by elemental analysis (C,H,N) and by uv spectroscopy (spectrum determined in 0.1 N NaOH eq.). λ(nm) (ε) maxima: 310 (29,200), 276.5 (22,000), 230 (50,700); minima: 282.5 (21,500), 251.5 (11,600).
Reaction SMILES: Br[C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1.[F:16][C:17]([F:26])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:18][NH2:19].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:16][C:17]([F:26])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:18][NH:19][C:2]1[C:3](=[O:15])[N:4]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: NCC(F)(F)c1ccccc1
Reactant: CCOC(=O)Cn1c(C)cnc(Br)c1=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1c(C)cnc(NCC(F)(F)c2ccccc2)c1=O
Temperature: 25 °C
Yield: 75.6 %

Procedure:
To a stirred suspension of 3-bromo-1-(ethoxycarbonylmethyl)-6-methylpyrazinone (750 mg, 2.75 mmol), as prepared in step 5 of Example 2, in toluene (30 mL) was added 2,2-difluoro-2-phenylethylamine (900 mg, 5.75 mmol), as prepared in the preceding step. The mixture was refluxed for two days under nitrogen. The solution was allowed to cool to room temperature, and ethyl acetate (50 mL) was added. The diluted reaction mixture was washed with 10% HCl (2×20 mL) and the aqueous layer was extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (50 mL), brine, and dried over Na2SO4. After evaporating the solvent, the solid was collected and washed with 15% ethyl acetate in hexane to give the title compound as an off-white solid (730 mg, 76%). 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.43 (m, 3H), 6.67 (s, 1H ), 6.14 (s(br), 1H), 4.70 (s, 2H), 4.24 (q, 2H, J=7.1 Hz), 4.09 (td, 2 H, J=14.3, 6.5 Hz), 2.11 (s, 3H), 1.29 (t, 3H, J=7.1 Hz).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][C:13]([CH3:21])([CH:16]([OH:20])[CH:17]([CH3:19])[CH3:18])[CH2:14]O>C1(C)C(C)=CC=CC=1>[CH:17]([CH:16]1[C:13]([CH3:21])([CH3:14])[CH2:12][O:6][C:1](=[O:11])[C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:5])[O:20]1)([CH3:19])[CH3:18]
Reactant: CC(C)C(O)C(C)(C)CO
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1C
Product: CC(C)C1OC(=O)c2ccccc2C(=O)OCC1(C)C
Temperature: 1 °C
Yield: 57.5 %

Procedure:
A solution of 114.82 g (0.10 mole) of phthalic anhydride and 16.31 g (0.11 mole) of 2,2,4-trimethyl-1,3-pentanediol (TMPD) in 250 mL of xylene was heated for 96 hr as described in Examples 1-3. Xylene was removed on a rotary evaporator at 20 torr, at a base temperature of 68° C. The residue (30.0 g) was diluted with 30 mL of methanol and the resulting slurry cooled to 1° C., filtered, and washed with methanol which had been chilled to -20° C. to give 15.9 g (58% yield) of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione, which was 99.9% pure by vapor phase chromatography (vpc). The methanol washing from recovery of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione contained, on a methanol-free basis, 16.4% of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione, while the residue from stripping xylene from the original reaction mixture contained 41.2% of 7-Isopropyl-8,8-dimethyl-8,9-dihydro-7H-6,10-dioxabenzocyclononene-5,11-dione.