Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([F:15])=[CH:12][CH:13]=2)[C:8]([CH2:16][C:17]2[C:18]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:7]1[CH3:32])C.[OH-].[K+]>C1COCC1.O>[C:26]1([S:23]([C:18]2[C:17]([CH2:16][C:8]3[C:9]4[C:14](=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=4)[N:6]([CH2:5][C:4]([OH:33])=[O:3])[C:7]=3[CH3:32])=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:25])=[O:24])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(Cc2cccnc2S(=O)(=O)c2ccccc2)c2cc(F)ccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of [3-(2-benzenesulfonyl-pyridin-3-ylmethyl)-5-fluoro-2-methyl-indol-1-yl]-acetic acid ethyl ester (1.20 g, 2.56 mmol) in THF (26 ml) was added a solution of potassium hydroxide (0.43 g, 7.68 mmol) in water (9 ml). The resulting solution was stirred at room temperature for 3.5 h. THF was removed in vacuo and the remaining aqueous layer was acidified with aqueous HCl (0.1 M, 25 ml). The product was collected by filtration, washed with water and dried in vacuo to afford 1.12 g (100%) of the title compound (LCMS RT=4.58 min, M+-H 437.2).
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]1[C:18]2[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[NH:12][CH:11]=1.[F:20][C:21]1[CH:22]=[N:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26](Cl)=[O:27].N1C=CC=CC=1.Cl>O1CCCC1>[F:20][C:21]1[CH:22]=[N:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=1)[C:26]([NH:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([CH3:19])[CH:17]=3)[NH:12][CH:11]=2)=[C:2]([F:1])[N:7]=1)=[O:27]
Reactant: Cc1cnc2[nH]cc(Cc3ccc(N)nc3F)c2c1
Reactant: COc1ncc(F)cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ncc(F)cc1C(=O)Nc1ccc(Cc2c[nH]c3ncc(C)cc23)c(F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
In a reaction flask, 6-fluoro-5-(5-methyl-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (137, 100 mg, 0.3902 mmol) was combined with 5-fluoro-2-methoxy-nicotinoyl chloride (151, 81.37 mg, 0.4292 mmol), 3.00 mL of tetrahydrofuran, and pyridine (0.06312 mL, 0.7804 mmol). The reaction was stirred at room temperature overnight, then poured into aqueous 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was purified by silica gel column chromatography, eluting with 1-5% methanol in dichloromethane. Appropriate fractions were combined and concentrated under vacuum to provide the desired compound (P-2168, 100 mg). MS (ESI) [M+H+]+=409.9.
Reaction SMILES: COC(=O)C[C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH2:31]([O:33][C:34](=[O:42])C1C=CC(I)=CC=1)[CH3:32].[CH2:43](N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:23]([O:22][C:19]1([C:16]2[CH:15]=[CH:14][C:13]([C:12]#[C:11][C:8]3[CH:7]=[CH:6][C:5]([C:34]([O:33][CH2:31][CH3:32])=[O:42])=[CH:10][CH:9]=3)=[CH:18][C:17]=2[CH3:43])[CH2:21][CH2:20]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCN(CC)CC
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)cc2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCc4ccccc4)CC3)c(C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-methyl-benzene (Intermediate 76, 90.0 mg, 0.34 mmol) and ethyl-4-iodo benzoate (Reagent A, 95.0 mg, 0.34 mmol) in triethylamine (6 mL) was treated with copper(I)iodide (23.0 mg, 0.12 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (80 mg, 0.11 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 68.0 mg (54%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:14]([O-])([O-:16])=[O:15].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]=1[OH:13])([O-:16])=[O:15]
Reactant: Oc1ccccc1-c1ccccc1
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(-c2ccccc2)c1O
Reaction time: 24 h
Yield: 23.8 %

Procedure:
2-phenylphenol (3.00 g, 17.6 mmol) was dissolved in methylene chloride(40 ml) followed by the addition of sodium nitrate (1.65 g, 19.4 mmol). The addition of sulfuric acid (25 ml/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(900 mg, 24%). 1H NMR (CD3COCD3): δ 8.19 (d,1H), 7.79 (d,1H), 7.64 (d, 2H), 7.50 (t, 2H), 7.45 (t, 1H), 7.22 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11](Cl)=[O:12])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14]([SH:16])[CH3:15].C(N(CC)CC)C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11](=[O:12])[S:16][CH2:14][CH3:15])=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1cc2cccc(Cl)c2s1
Reactant: CCS
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CCSC(=O)c1cc2cccc(Cl)c2s1
Reaction time: 8 h

Procedure:
17.8 g of the 7-chloro-2-benzo[b]thiophenecarboxylic acid chloride prepared in B above, was dissolved in toluene (100 ml), treated with ethanethiol (6.2 ml) followed by dropwise addition of a solution of triethylamine (11.2 ml) in toluene (6 ml) at 15° C., with vigorous stirring, to produce a reaction mixture. The reaction mixture was allowed to come to ambient temperature and then stirred overnight. Water (60 ml) was then added to the reaction mixture and the resultant organic layer was separated. The organic layer was washed with water (50 ml), then with hydrochloric acid (50 ml, 1N), dried (MgSO4), filtered and evaporated, to produce 18,8 g of S-ethyl 7-chloro-2-benzo[b]thiophenecarbothioate.
Reaction SMILES: O1CCCCC1[O:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH2:12].Cl.[O-:19][C:20]#[N:21].[K+]>O>[OH:7][CH:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH2:11][NH:12][C:20]([NH2:21])=[O:19]
Reactant: CCCCCC(CCCN)OC1CCCCO1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCCCC(O)CCCNC(N)=O

Procedure:
To a stirred suspension of 4-(2-tetrahydropyranyloxy)-nonylamine (4.8 g., 0.02 mole) in water (75 ml.) is added just enough 10% hydrochloric acid to effect solution. Then potassium cyanate (1.62 g., 0.02 mole) is added and the reaction is heated gently on the steam bath for one hour, during which time an oil separates. The reaction mixture is cooled and extracted with ether (2 × 75 ml.). The ether is dried over sodium sulfate then concentrated in vacuo to give 4-hydroxynonylurea as a residual oil. The 4-hydroxynonylurea is taken up in pyridine (20 ml.) and acetic anhydride (2.0 g., 0.02 mole) is added. The reaction is stirred eight hours at room temperature then poured into water (100 ml.), and extracted with ether (2 × 100 ml.). The ether is washed with 5% hydrochloric acid, brine, and dried over sodium sulfate. Removal of the solvent in vacuo affords the subject compound as a residual oil.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:7][CH:6]=1.CN1CCOCC1.ClC(OCC(C)C)=O.Cl.C([O:42][C:43](=[O:51])[CH2:44][C@H:45]([NH2:50])[CH2:46][N:47]=[N+:48]=[N-:49])C1C=CC=CC=1.CN(C1C=CC=CN=1)C>CN(C=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12](=[O:18])[CH2:13][CH2:14][C:15]([NH:50][C@@H:45]([CH2:46][N:47]=[N+:48]=[N-:49])[CH2:44][C:43]([OH:51])=[O:42])=[O:17])=[CH:9][CH:10]=1
Reactant: [N-]=[N+]=NC[C@@H](N)CC(=O)OCc1ccccc1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)O)cc1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: [N-]=[N+]=NC[C@@H](CC(=O)O)NC(=O)CCC(=O)Nc1ccc(C=NN)cc1
Reaction time: 0.08 h

Procedure:
4-[[4-(aminoiminomethyl)phenyl]amino]-4-oxobutanoic acid hydrochloride prepared in Example 1, Step 1 (4.6 g, 18.5 mmol) was added to dry DMF (250 ml) followed by N-methylmorpholine (1.8 g, 18.5 mmol) and isobutyl chloroformate (2.8 g, 17 mmol) at 25° C. The mixture was stirred for 5 min. Benzyl-3-amino-4-azido-(3S)-butyrate hydrochloride (1 eq; from Step 1, Example 22) was added followed by dimethylaminopyridine. After 1 h the solvent was removed under reduced pressure and the product purified by reverse phase chromatography (water/acetonitrile) to result in 3.0 g of a white solid. A portion (750 mg) of the benzyl ester was subjected to the saponification conditions as previously described and purified by reverse phase chromatography (water/acetonitrile) to result in 340 mg of a white solid: 1H NMR (d6 -DMSO) δ2.44 (m, 4H), 2.6 (m, 2H), 3.35 (bs, 2H), 4.18 (m, 1H), 7.78 (s, 4H), 8.1 (d, 1H,J=8 Hz), 8.27 (bs, 2H), 9.15 (bs, 2H), 10.40 (s, 1H); MS (FAB) m/z 362.1 (MH+).
Reaction SMILES: [C:1]1([OH:8])[CH:6]=[CH:5][CH:4]=[C:3]([OH:7])[CH:2]=1.Cl[Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(N(CC)CC)C>ClCCl>[C:13]([Si:10]([CH3:12])([CH3:11])[O:7][C:3]1[CH:2]=[C:1]([OH:8])[CH:6]=[CH:5][CH:4]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
1,3-Benzenediol (5 g, 45 mmol) in dichloromethane (150 mL) was treated with chloro(t-butyl)dimethylsilane (7.5 g, 50 mmol) and triethylamine (5 g, 50 mmol). The resulting mixture was stirred at rt for 16 h then concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with 6N NaOH, then concentrated in vacuo. The residue was purified by column chromatography eluting with 20% ethyl acetate in hexane to afford the title compound (4.3 g, 42%). MS (ES+) m/e 225 [M+H]+.
Reaction SMILES: Br[C:2]([CH3:9])(C)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:10][C:11]1[C:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:13][NH:14][CH:15]=1.[C:22]1(C2C=CNN=2)C=CC=CC=1>>[CH2:9]([CH:2]([N:14]1[CH:15]=[C:11]([CH3:10])[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13]1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4])[CH3:22].[CH3:6][N:5]([CH3:7])[C:3](=[O:4])[CH2:2][CH:9]([CH3:22])[N:14]1[CH:15]=[C:11]([CH3:10])[C:12]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:13]1
Reactant: Cc1c[nH]nc1-c1ccccc1
Reactant: c1ccc(-c2cc[nH]n2)cc1
Reactant: CN(C)C(=O)C(C)(C)Br
Product: CCC(C(=O)N(C)C)n1cc(C)c(-c2ccccc2)n1
Product: Cc1cn(C(C)CC(=O)N(C)C)nc1-c1ccccc1

Procedure:
Following the procedure of Example 121, but substituting 2-bromo-N,N-dimethylbutyramide for 2-bromo-N,N,2-trimethylpropionamide, and 4-methyl-3-phenylpyrazole for 3-phenylpyrazole, there were obtained the already described α-ethyl-N,N,4-trimethyl-3-phenylpyrazole-1-acetamide and N,N,β,4-tetramethyl-3-phenylpyrazole-1-propionamide having a boiling point of 170°/0.2 mm.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:57]([O:59][CH:60]1[CH2:64][CH2:63][CH2:62][CH2:61]1)=[O:58]>ClCCl>[Si:1]([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@@H:16]([O:17][C:18]3[N:40]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:21]4=[N:22][C:23]([C:27]5[CH:32]=[CH:31][C:30]([C@@H:33]6[CH2:38][CH2:37][C@H:36]([NH:39][C:57](=[O:58])[O:59][CH:60]7[CH2:64][CH2:63][CH2:62][CH2:61]7)[CH2:35][CH2:34]6)=[CH:29][CH:28]=5)=[C:24]([Cl:26])[CH:25]=[C:20]4[N:19]=3)[C@H:12]2[O:11][CH2:10]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](N)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reactant: O=C(Cl)OC1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2Oc1nc2cc(Cl)c(-c3ccc([C@H]4CC[C@@H](NC(=O)OC5CCCC5)CC4)cc3)nc2n1COCC[Si](C)(C)C
Reaction time: 2 h

Procedure:
(cis)-4-(4-(2-((3R,3aR,6R,6aS)-6-(tert-Butyldimethylsilyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)-6-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)phenyl)cyclohexanamine (30 mg) and triethylamine (12 μL) are dissolved in dichloromethane (2 mL), treated with cyclopentyl chloroformate (6.5 μL) and stirred for 2 hours. Triethylamine (12 μL) and cyclopentyl chloroformate (6.5 μL) are added and the mixture is stirred for 12 hours. Then triethylamine (24 μL) and cyclopentyl chloroformate (13 μL) are added and the mixture is stirred for 2 hours. The mixture is partitioned between dichloromethane and saturated aqueous NH4Cl solution. The organic phase is dried (MgSO4) and concentrated. The crude product is used directly in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]C1CCCCO1)[C:7]([O:9][CH3:10])=[O:8].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:14][C:13]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH:3]=[C:2]([CH3:21])[CH3:1]
Reactant: COC(=O)c1ccc(OC2CCCCO2)c(C=C(C)C)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: COC(=O)c1ccc(O)c(C=C(C)C)c1
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a stirred mixture of T13.1 (0.460 g, 2 mmol) in MeOH (8 mL) was added PPTS (0.04 g, 0.2 mmol). The reaction mixture was then stirred for 24 hours and then concentrated in vacuo. The residue was purified on silica gel (0-20% EtOAc in hexanes) to yield T13.2 as a colorless oil (0.320 g, 98% yield).
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH2:26]([O:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1)[CH3:27].Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:33](=[O:34])[C:32]4[CH:31]=[CH:30][C:29]([O:28][CH2:26][CH3:27])=[CH:37][CH:36]=4)[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)Cl)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.50 g, 1.4 mmol) and 4-ethoxybenzoyl chloride (0.26 g, 1.4 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.28 g, 2.8 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 2 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered and purified by column chromatography (C18 reverse phase column). The product fractions were combined, concentrated and dried in vacuo providing N-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-4-ethoxy-benzamide as a white solid (0.26 g, 46% yield); mp 269-271° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 5.75 (96.56%); 1H NMR (DMSO-d6) δ 1.34 (t, 3H, CH3), 1.90-2.08 (m, 1H, CHH), 2.27-2.45 (m, 1H, CHH), 2.55-2.68 (m, 1H, CHH), 2.80-3.03 (m, 1H, CHH), 4.09 (q, 2H, CH2), 4.30 (d, 1H, CHH), 4.41 (d, 1H, CHH), 4.58 (d, 2H, CH2 and CHH), 5.10 (dd, J=4.5, 13.0 Hz, 1H, CH), 6.99 (d, J=8.3 Hz, 2H, Ar), 7.44 (d, 1H, Ar), 7.54 (s, 1H, Ar), 7.69 (d, 1H, Ar), 7.87 (d, J=8.5 Hz, 2H, Ar), 8.99 (t, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.53, 22.49, 31.18, 42.64, 47.12, 51.56, 63.28, 113.92, 122.01, 122.90, 126.19, 127.02, 129.09, 130.30, 142.35, 144.20, 160.92, 165.75, 167.93, 170.98, 172.85; LCMS: MH=422; Anal. Calcd for C23H23N3O5+0.5H2O: C, 64.18; H, 5.62; N, 9.76. Found: C, 64.03; H, 5.45; N, 9.63.
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([CH2:11][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5]1)([CH3:3])[CH3:2].[H-].[Na+].[N:22](OCCC(C)C)=[O:23]>C1COCC1.CCOC(C)=O>[CH:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][C:6]([C:11](=[N:22][OH:23])[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:19])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1nc(CC(=O)c2ccccc2)ccc1=O
Reactant: CC(C)CCON=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)n1nc(C(=NO)C(=O)c2ccccc2)ccc1=O
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen atmosphere, 2-isopropyl-6-(2-oxo-2-phenylethyl)-3(2H)-pyridazinone (513 mg) was added to a suspension of NaH (60% dispersion in mineral oil) (84 mg) in THF (5 ml) and the mixture was stirred at 45-50° C. for 30 minutes. After addition of isoamyl nitrite (0.27 ml), the mixture was stirred at the same temperature for 8 hours. The mixture was dissolved in EtOAc, washed with 1N HCl and brine and dried over MgSO4. The mixture was concentrated under reduced pressure and subjected to column chromatography on silica gel eluting with a mixture of n-hexane and EtOAc (50:50 v/v) to give 1-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-2-phenyl-1,2-ethanedione 1-oxime as a solid (185 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[F:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([C:8](=[O:9])[C:7]3[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[CH2:23][CH2:22]2)=[O:20])=[CH:27][CH:28]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc(F)cc1)C1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
4-Nitrobenzoyl chloride (3.08 g) was added slowly to a stirred mixture of 4-(4-fluorobenzoyl)piperidine hydrochloride (4.0 g) and triethylamine (4.98 g) in methylene chloride (110 ml) at room temperature. The resulting mixture was stirred at this temperature for 1 hour, washed with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine, dried over magnesiun sulfate and concentrated in vacuo. The residue was recrystallized from a mixture of acetone and methanol to give 4-(4-fluorobenzoyl)-1-(4-nitrobenzoyl)piperidine (5.0 g) as colourless crystals.
Reaction SMILES: [CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][NH:7][CH2:6][CH2:5]2)[O:3][CH2:2]1.C(N(CC)CC)C.[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([O-:20])=[O:19]>C(OCC)(=O)C>[CH2:1]1[O:10][C:4]2([CH2:9][CH2:8][N:7]([S:27]([C:24]3[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:26][CH:25]=3)(=[O:28])=[O:29])[CH2:6][CH2:5]2)[O:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.3 %

Procedure:
A solution of 4-piperidone ethylene ketal (1.28 ml, 10 mmol) and triethylamine (1.4 ml, 10 mmol) in ethyl acetate (20 ml) was treated with a dropwise addition of 4-nitro-phenylsulphonyl chloride (1.4 ml, 10 mmol) in ethyl acetate (20 ml) and stirred at room temperature for 2 h. The mixture was washed with water, dilute HCl, saturated sodium bicarbonate solution and brine, dried over sodium sulphate and evaporated to leave the title compound as a solid (2.8 g), MS (+EI) 328 (M+), 1H NMR (CDCl3) 8.38 (2H, d, J 8.8 Hz), 7.96 (2H, d, J 8.8 Hz), 3.90 (4H, s), 3.22 (4H, t, J 5.7 Hz), 1.80 (4H, t, J 5.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[C:5]([CH:7](OC)[O:8]C)[N:6]=1.C(O)(=O)C(O)=O.O.Cl>C1COCC1>[Cl:1][C:2]1[O:3][C:4]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)=[C:5]([CH:7]=[O:8])[N:6]=1
Reactant: COC(OC)c1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1nc(Cl)oc1-c1ccc(C(F)(F)F)cc1
Yield: 83 %

Procedure:
A mixture of Example 52D (1.59 g, 4.94 mmol) and oxalic acid (0.71 g, 7.9 mmol) in THF (16 mL)/water (8 mL) was stirred at ambient temperature for 2 hr. Additional oxalic acid (0.71 g, 7.9 mmol) and THF (16 mL) were added and the reaction mixture was stirred for 2 additional hr. HCl (4 N in dioxane, 5 mL) was then added and the reaction mixture was stirred 16 hr at ambient temperature, and then quenched by addition of saturated aq Na2CO3 solution (10 mL). The mixture was partitioned between Et2O and H2O, and the separated aqueous phase was extracted with Et2O. The combined organic extract was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified on silica gel (Analogix® Intelliflash 280™; SF25-120 g column; 100% hexane 7 min, then 0% to 20% EtOAc/hexanes eluant, 23 min) which yielded 1.13 g (83%) of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.98 (s, 1H), 8.27-8.21 (m, 2H), 7.97 (dd, J=9.0, 0.6, 2H). MS (DCI+) m/z 293 (M+NH4).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[NH2:16])=[O:14])[CH3:2].[CH3:19][S:20]([CH2:23][C:24](=O)[CH3:25])(=[O:22])=[O:21]>O1CCCC1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:18])[C:13]([N:15]([CH3:17])[N:16]=[C:24]([CH3:25])[CH2:23][S:20]([CH3:19])(=[O:22])=[O:21])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N
Reactant: CC(=O)CS(C)(=O)=O
Solvent: C1CCOC1
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)N(C)N=C(C)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 22 h
Yield: 33.9 %

Procedure:
To a 20 ml volume two-necked flask, 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-39) (0.50 g), tetrahydrofuran (anhydrous) (9 ml), and 1-methylsulfonyl-2-propanone (7-2-1) (0.30 g) were added under a nitrogen atmosphere and stirred at room temperature for 22 hours. The reaction mixture was concentrated under reduced pressure. The residue was subjected to column chromatography (hexane:acetone=3:1) to give 0.25 g of 1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]-1-methyl-2-(1-methylsulfonyl-2-propylidene)hydrazine ((4-34-(1)-39).