Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.CC[O:6][C:7]([C@@H:9]([NH:18][C@H:19]([C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22])[CH3:20])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8].Cl>C(O)C>[CH3:20][C@H:19]([NH:18][C@H:9]([C:7]([OH:8])=[O:6])[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:21]([N:23]1[C@H:31]([C:32]([OH:34])=[O:33])[CH2:30][C@@H:29]2[C@@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28]2)=[O:22]
Reactant: CCOC(=O)[C@H](CCc1ccccc1)N[C@@H](C)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[C@H](N[C@@H](CCc1ccccc1)C(=O)O)C(=O)N1[C@H](C(=O)O)C[C@H]2CCCC[C@@H]21
Reaction time: 19 h

Procedure:
A solution of NaOH (0.96 g, 22.68 mmol; assay=94.52%), water (22 ml), ethanol (22 ml, technical grade, contains ˜5% 2-propanol) and Trandolapril (4.5 g, 10.42 mmol; assay=99.7%) was stirred at an internal temperature ranging from about 20° C. to about 25° C. for 19 hours. After an in process control showed an almost complete saponification (by HPLC), the clear solution was acidified at a temperature ranging from about 20° C. to about 25° C. with 2N aqueous hydrochloric acid to a pH of 3.8 (22.8 mmol; the solution was seeded during acidification and the crystallization started at pH=4.6). The suspension was stirred at a temperature ranging from about 20° C. to about 25° C. (the stirring time in this case after pH adjustment was 47 hours and the pH was adjusted from 3.71 to 3.82 by an addition of 1 drop of 2N aqueous NaOH solution; generally a maximum stirring time of 5 to 6 hours at this pH is sufficient) and then filtered off. The wet product was washed with water (30 ml) and dried in vacuo (1-5 mbar) for 15 hours at 40° C. to give Trandolaprilat (yield: 4.0 g, 9.06 mmol, 86.9%; assay=91.15%; water content: 1.02-1.12%, ethanol content: 7.52-8.44%, 2-propanol content: 0.26-0.29, chloride content=not detected).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[OH:53])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:71])([CH3:70])[CH3:69])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2].[CH3:73]I>C(OCC)(=O)C.[Ag]=O>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[O:53][CH3:73])[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH:6]([O:64][Si:65]([C:68]([CH3:69])([CH3:70])[CH3:71])([CH3:67])[CH3:66])[CH2:5][C:4]1=[O:72])[CH3:2]
Reactant: CI
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(O)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Agent: O=[Ag]
Solvent: CCOC(C)=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC(OC)c4ccccc4)C(OC)C3)C(C)C(O[Si](C)(C)C(C)(C)C)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 17-ethyl-1-hydroxy-14-(tert-butyldimethylsiloxy)-12-[2'-(4"-(2"'-phenyl-2"'-hydroxyethyloxy)-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (27 mg) in methyl iodide (0.5 ml) under nitrogen atmosphere was added silver oxide and the reaction was stirred at room temperature for 48 hours. The reaction was then diluted with ethyl acetate and filtered through a silica gel pad. The filtrate was concentrated and purified by column chromatography on silica gel eluting with 60% hexane:40% ethyl acetate to give the desired compound (12.6 mg).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25]([OH:27])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([C:35](=[N:37]O)[NH2:36])[CH:32]=[CH:33][CH:34]=1>>[F:28][C:29]1[CH:30]=[C:31]([C:35]2[N:37]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:27][N:36]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: NC(=NO)c1cccc(F)c1
Product: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(F)c3)no2)C1

Procedure:
250 mg (about 0.52 mmol) of the compound from Example 49A and 89 mg (0.58 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 26 mg (10% of theory).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].[NH2-:11].[Na+]>>[NH2:11][C:4]1[C:3]([CH2:1][CH3:2])=[C:8]([CH2:9][CH3:10])[CH:7]=[CH:6][N:5]=1
Reactant: [NH2-]
Reactant: CCc1ccncc1CC
Agent: [Na+]
Product: CCc1ccnc(N)c1CC

Procedure:
2-Amino-3,4-diethylpyridine is prepared by reacting 40.5 g. 3,4-diethylpyridine with 11.7 g sodium amide at a temperature of 250° in the presence of paraffin oil. The so-formed 2-amino-3,4-diethylpyridine is purified by distillation and is substituted for the 2-amino-3,4-dimethylpyridine in Example 7 to obtain the named compound.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9](Br)(=[O:11])[CH3:10]>O>[C:9]([N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([OH:8])[C:2]1=[O:1])(=[O:11])[CH3:10]
Reactant: CC(=O)Br
Reactant: Oc1cccnc1O
Solvent: O
Product: CC(=O)n1cccc(O)c1=O

Procedure:
2,3-Dihydroxypyridine (5.55 g) is refluxed with acetylbromide (10 ml) overnight. The reaction mixture is allowed to cool and water (10 ml) is added. The resulting suspension is extracted with methylene chloride and the methylene chloride solution is dried over Na2SO4 and evaporated. The resultant residue is recrystallised from petroleum ether (80°-100° C.) to give 1-acetyl-3-hydroxypyrid-2-one as white crystals (2.8 g), m.p. 140°-141° C.; νmax (nujol) 1680, 3120 cm-1 ; δ(d6DMSO), 2.2 (s, 3H), 6.1 (t, 1H), 6.65 (m, 1H), 7.2 (d, 1H).
Reaction SMILES: [O:1]1[CH2:5]CCC1.C(OC[CH2:11][O:12][C:13]1[CH:14]=[N:15][C:16]([N:19]2[C:24](=[O:25])[C:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]4[NH:43][N:42]=[N:41][N:40]=4)=[CH:29][CH:28]=3)=[C:22]([CH2:44][CH2:45][CH2:46][CH3:47])[N:21]=[C:20]2[CH3:48])=[N:17][CH:18]=1)(=O)C.[OH-:49].[Li+]>O>[NH:40]1[C:39]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[C:30]2[CH:31]=[CH:32][C:27]([CH2:26][C:23]3[C:24](=[O:25])[N:19]([C:16]4[N:17]=[CH:18][C:13]([O:12][CH2:11][C:5]([OH:1])=[O:49])=[CH:14][N:15]=4)[C:20]([CH3:48])=[N:21][C:22]=3[CH2:44][CH2:45][CH2:46][CH3:47])=[CH:28][CH:29]=2)=[N:43][N:42]=[N:41]1
Reactant: CCCCc1nc(C)n(-c2ncc(OCCOC(C)=O)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: C1CCOC1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Product: CCCCc1nc(C)n(-c2ncc(OCC(=O)O)cn2)c(=O)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
To the mixture solution of tetrahydrofuran (2 mL) and water (2 mL) containing 2-{2-(5-{[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-4-butyl-2-methyl-6-oxopyrimidin-1 (6H)-yl)pyrimidin-5-yl oxy}ethyl acetate (22 mg, 0.038 mmol), lithium hydroxide (8 mg, 0.29 mmol) was added and stirred at 50° C. for 1 hr. The reaction mixture was added water and extracted with chloroform. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resulting residues were subjected to silica gel column chromatography (chloroform/methanol) to obtain the target compound (15 mg, 72%) as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[CH:10]=[N:11][OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[OH:12][N:11]=[C:10]([Cl:13])[C@@H:8]1[CH2:9][C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: ON=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of the crude trans-2-phenylcyclopropanecarbaldehyde oxime rac-I-6C (04 g, 2.51 mmol) in DMF (5 mL) and cooled at 0°C. N-chlorosuccinimide (0.37 g, 2.7 mmol) was added portionwise. The reaction mixture was slowly warmed to rt and stirred fo(14 h. The reaction was quenched with saturated NaCl (aq.) and extracted with Et2O. The organics were collected, washed with water, brine, dried over Na2SO4, filtered, and concentrated under vacuum. The crude was purified by column chromatography on silica gel with hexane-EtOAc (5 to 20% gradient as eluant) to yield trans-N-hydroxy-2-phenylcyclopropanecarbimidoyl chloride.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=[O:11])=[CH:5][CH:4]=1.C[Si]([CH:19]=[N+:20]=[N-:21])(C)C.C(OCC)C>C1COCC1.C(#N)C>[N+:20](=[CH:19][C:10](=[O:11])[CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1)=[N-:21]
Reactant: O=C(Cl)Cc1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CC#N
Product: [N-]=[N+]=CC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Under an argon atmosphere, p-trifluoromethylphenylacetyl chloride (52) prepared above was dissolved in THF (2 mL) and acetonitrile (2 mL), and cooled to 0° C. To this was slowly added a solution of trimethylsilyldiazomethane in diethyl ether (2.0 M, 4.00 mL, 8.00 mmol), which was stirred overnight (20 hours) after warming up to room temperature. After being concentrated under reduced pressure, the residue was purified by silica gel flash column chromatography (n-hexane/diethyl ether=1/1) to give 1-diazo-3-[4-(trifluoromethyl)phenyl]propan-2-one (53) as a pale yellow oily substance (666 mg, 2.92 mmol, 72.9%, 2 steps).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:31]([O:38][CH2:39][CH2:40][NH:41][CH:42]1[CH2:44][CH2:43]1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O.O>[Si:31]([O:38][CH2:39][CH2:40][N:41]([CH:42]1[CH2:43][CH2:44]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:19][CH2:20][CH2:21]2)[N:11]=1)=[O:29])([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CC1
Reactant: O=C(O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To a stirred solution mixture of 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (283) (300 mg, 0.74 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (8d) (329 mg, 1.48 mmol) in dimethylformamide (5 mL) were added N,N-diisopropylethylamine (0.4 mL, 2.22 mmol) and HATU (423 mg, 1.11 mmol). After stirring at room temperature for 1 h, water (50 mL) was added and the mixture was extracted with ethyl acetate (3×20 mL). The combined organic part was washed with water (3×50 mL) and brine (2×30 mL) and dried and concentrated. The crude product was purified by Combi-Flash column (eluted at 20-30% ethyl acetate in hexane) to get 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (284) (430 mg, 96.32%) as a yellow solid.
Reaction SMILES: N1([C:6](N2C=CN=C2)=[O:7])C=CN=C1.N1C=CN=C1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]2[C:25]([NH2:47])=[N:26][N:27]([C:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:20]=1.Cl.[F:49][C:50]1([F:54])[CH2:53][NH:52][CH2:51]1>C(Cl)Cl>[Cl:18][C:19]1[N:24]=[CH:23][C:22]2[C:25]([NH:47][C:6]([N:52]3[CH2:53][C:50]([F:54])([F:49])[CH2:51]3)=[O:7])=[N:26][N:27]([C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:21]=2[CH:20]=1
Reactant: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: FC1(F)CNC1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: O=C(Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
Di(1H-imidazol-1-yl)methanone (197 mg, 1.217 mmol) was added to a stirred mixture of 1H-imidazole (166 mg, 2.434 mmol) and 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine (250 mg, 0.608 mmol) in CH2Cl2 (4 ml) and the mixture was stirred at room temperature for overnight. The second day, 3,3-difluoroazetidine hydrochloride (190 mg) was added and the mixture was heated at 50° C. for 3 hours, LCMS and TLC showed clean reaction. The mixture was directly loaded to a silica gel column eluting with EtOAc/Hexane=0% to 100% gradient to give N-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)-3,3-difluoroazetidine-1-carboxamide (320 mg, 0.604 mmol, 99% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(N(CC)CC)C.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:29]([NH:42][C:41]2[CH:43]=[CH:44][C:38]([F:37])=[CH:39][C:40]=2[CH3:45])=[O:35])=[C:18]([CH3:24])[CH:17]=1
Reactant: Cc1cc(F)ccc1N
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)Nc4ccc(F)cc4C)cc3C)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethyl-aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml), and a solution of triphosgene (92 mg) in dichloromethane was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, 4-fluoro-2-methylaniline (42 μl) was added to the reaction solution, and the mixture was stirred at room temperature overnight. A saturated aqueous sodium hydrogencarbonate solution was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was dried over sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in a minor amount of to chloroform, and a large amount of ether was added to the solution to precipitate a crystal which was then collected by filtration to give 108 mg (yield 74%) of the title compound.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.C([O-])([O-])=[O:11].[K+].[K+].[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)([O-:18])=[O:17]>CC(C)=O>[N+:16]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([OH:11])[OH:7])=[CH:4][CH:3]=1)([O-:18])=[O:17]
Reactant: OCc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1Cc1ccc(C(O)O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.6 %

Procedure:
Step 1) To a solution of para-hydroxybenzyl alcohol (2.0 g, 16.1 mol; Aldrich) dissolved in dry acetone (15 mL) was added K2CO3 (4.45 g, 32.2 mmol, 2.0 eq.) and ortho-nitrobenzylbromide (3.83 g, 17.7 mmol, 1.1 eq). The mixture was stirred at ambient temperature for 16 hr and then the solution was concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and then the organic layer was washed with H2O (2×30 mL), brine (30 mL) and dried over MgSO4. The product was recrystallized from Et2O/hexanes to give yellow needles (2.0 g, 60%) of para-(ortho-nitrobenzyl)-hydroxybenzyl alcohol. 1H NMR (CDCl3, 400 MHz) d=8.16 (1H, dd, J=8.2, 1.3 Hz), 7.88 (1H, dd, 7.9, 1.0 Hz), 7.68 (1H, dt, J=7.5, 1.2 Hz), 7.51-7.46 (1H, m), 7.32-7.26 (2H, m), 6.98-6.95 (2H, m), 5.48 (2H, s), 4.61 (2H, s); 13C NMR (CDCl3, 100 MHz) d=157.6, 133.9, 128.7, 128.5, 128.2, 124.9, 114.8, 66.8, 64.9;
Reaction SMILES: N1CCCCC1.[CH3:7][O:8][C:9]1[CH:16]=[CH:15][C:12](C=O)=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[CH:20].[C:21]([CH2:24][C:25]([NH:27][C:28]1[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=1[C:30]([OH:32])=[O:31])=[O:26])(O)=O.CC(O)=O>C1(C)C=CC=CC=1>[CH3:7][O:8][C:9]1[CH:16]=[C:15](/[CH:21]=[CH:24]/[C:25]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[O:26])[CH:12]=[CH:11][C:10]=1[O:17][CH2:18][C:19]#[CH:20]
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Reactant: C#CCOc1cc(C=O)ccc1OC
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: C#CCOc1ccc(/C=C/C(=O)Nc2ccccc2C(=O)O)cc1OC
Yield: 63.5 %

Procedure:
Piperidine (0.70 mL, 7.1 mmol) was added to a suspension of 4-methoxy-3-propargyloxybenzaldehyde (1.34 g, 7.06 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (1.50 g, 6.72 mmol) in toluene (5.0 mL) and treated according to Procedure 2, acidifying with 20% AcOH. The crude product was recrystallised from EtOH, filtered and washed with cooled EtOH to afford (E)-2-[[3-(3-methoxy-4-(prop-2-ynyloxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (1.50 g, 64%) as a yellow crystalline solid; mp 183-185° C.; δH (400 MHz, DMSO-d6) 3.58 (t, J=2.0 Hz, 1H, HC≡C), 3.81 (s, 3H, OCH3), 4.87 (d, J=2.0 Hz, 2H, OCH2), 6.75 (d, J=15.6 Hz, 1H, CH═CHCO), 7.03 (d, J5′,6′=8.4 Hz, 1H, H5′), 7.16 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.29 (d, J5′,6′=8.4 Hz, 1H, H6′), 7.44 (s, 1H, H2′), 7.54 (d, J=15.6 Hz, 1H, CH═CHCO), 7.60 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.61 (d, J5,6=8.0 Hz, 1H, H6), 11.34 (s, 1H, NH), 13.60 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 55.6, 56.1, 78.4, 79.2, 112.0, 112.6, 116.6, 120.0, 120.3, 122.7, 123.5, 127.0, 131.1, 134.0, 141.1, 141.5, 146.6, 151.0, 164.1, 169.5; HRMS (ESI) calculated for C20H17NO6 [M+Na]+ 374.0999. found 374.1002; vmax 750, 1029, 1135, 1217, 1506, 1582, 1667, 3270, 3520 cm−1.
Reaction SMILES: Cl[CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:17]1([N:23]2[C:26]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:25][C:24]2=[O:32])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>CC(=O)CC>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH:2]([N:29]1[CH2:28][CH2:27][C:26]2([N:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:24](=[O:32])[CH2:25]2)[CH2:31][CH2:30]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C1CC2(CCNCC2)N1c1ccccc1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCC(C)=O
Product: O=C(c1ccccc1)C(c1ccccc1)N1CCC2(CC1)CC(=O)N2c1ccccc1
Reaction time: 4 h
Yield: 89.3 %

Procedure:
A suspension of 2-chloro-1,2-diphenyl-ethanone (0.23 g, 1 mmol), 1-phenyl-1,7-diazaspiro[3.5]nonan-2-one (0.2 g, 0.9 mmol) and sodium bicarbonate (0.23 g) in 2-butanone was boiled for 4 h with stirring. The mixture was cooled, the solvent was removed in vacuo and the residue was purified by chromatography on silica gel with ethylacetate/hexane (1:2) to yield 0.33 g (87%) of the title compound. MS: m/e=411.3 (M+H+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])[C@@H:9]([NH2:14])[CH2:10][CH:11]([CH3:13])[CH3:12].CN1C=CC(NC(=O)[C@@H](N2[CH2:33][C:32]([O:34][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42]([OH:45])([CH3:44])[CH3:43])[CH:36]=3)=[CH:31][C:30]2=[O:46])CC(C)C)=N1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:15])[C@@H:9]([N:14]1[CH2:33][C:32]([O:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([CH2:41][C:42]([OH:45])([CH3:43])[CH3:44])[CH:36]=2)=[CH:31][C:30]1=[O:46])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[C@H](N)C(=O)Nc1cnccn1
Reactant: CC(C)C[C@@H](C(=O)Nc1ccn(C)n1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)C[C@@H](C(=O)Nc1cnccn1)N1CC(Oc2cccc(CC(C)(C)O)c2)=CC1=O
Temperature: 100 °C
Yield: 22.5 %

Procedure:
A mixture of (S)-2-amino-4-methyl-pentanoic acid pyrazin-2-ylamide (prepared as in Example 245, 0.400 g, 1.92 mmol), (E)-4-bromo-3-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (prepared as in Example 235, 0.462 g, 1.29 mmol) and N,N-diisopropylethylamine (0.734 g, 5.69 mmol) in acetonitrile (16.6 mL) were sealed in a tube and heated at 100° C. for 12 h. The mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate (20 mL) and water (20 mL) and the phases separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in tetrahydrofuran (5 mL), sealed in an Emry Optimizer microwave tube and microwaved at 160° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 5% to 35% ethyl acetate/hexanes) to afford (S)-2-{4-[3-(2-hydroxy-2-methyl-propyl)-phenoxy]-2-oxo-2,5-dihydro-pyrrol-1-yl}-4-methyl-pentanoic acid pyrazin-2-ylamide (127 mg, 22%) as a tan solid: HR-ES-MS m/z calculated for C24H30N4O4 [M+H]+ 439.234, observed 439.2341; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91 (d, J=6.9 Hz, 3H), 0.93 (d, J=6.9 Hz, 3H), 1.04 (s, 6H), 1.39-1.70 (m, 2H), 1.72-1.87 (m, 1H), 2.66 (s, 2H), 4.21 (d, J=18.4 Hz, 1H), 4.36 (s, 1H), 4.55 (d, J=18.4 Hz, 1H), 4.83 (s, 1H), 5.02 (dd, J=10.9, 4.5 Hz, 1H), 6.94-7.19 (m, 3H), 7.34 (t, J=7.5 Hz, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.41 (d, J=1.5 Hz, 1H), 9.26 (s, 1H), 11.16 (s, 1H).
Reaction SMILES: C(OC([N:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:15][OH:16])[CH2:7]1)=O)C.[OH-].[K+]>C(O)(C)C.O>[OH:16][CH2:15][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:13]=1[CH2:14][NH:6][CH2:7]2
Reactant: CCOC(=O)N1Cc2cccc(CO)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: OCc1cccc2c1CNC2
Yield: 72.4 %

Procedure:
3.03 g of 2-ethoxycarbonyl-4-hydroxymethylisoindoline and 2.91 g of potassium hydroxide were dissolved in a mixture of 25 ml isopropyl alcohol and 2.5 ml of water. The mixture was heated under refluxing for 3 days. After the addition of water, the resulting reaction mixture was extracted with chloroform. The extract was washed with brine, concentrated, and recrystallized from carbontetrachloride to give 1.48 g of 4-hydroxymethylisoindoline.