Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])[CH2:8][CH2:7][CH2:6]1)=[O:4].[F-].[K+].[F:19][C:20]([F:36])([F:35])[C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][CH:27]2[CH2:32][CH2:31][CH2:30][NH:29][CH2:28]2)=[CH:23][CH:22]=1>C(#N)C.C1COCC1>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1([C:3](=[O:4])[CH2:2][N:29]2[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:25][C:24]3[CH:33]=[CH:34][C:21]([C:20]([F:19])([F:35])[F:36])=[CH:22][CH:23]=3)[CH2:28]2)[CH2:8][CH2:7][CH2:6]1
Reactant: FC(F)(F)c1ccc(OCC2CCCNC2)cc1
Reactant: COc1ccccc1C1(C(=O)CCl)CCC1
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccccc1C1(C(=O)CN2CCCC(COc3ccc(C(F)(F)F)cc3)C2)CCC1
Reaction time: 8 h
Yield: 30.1 %

Procedure:
2-Chloro-1-[1-(2-methoxy-phenyl)-cyclobutyl]-ethanone (55 mg) in 2 mL acetonitrile was treated with freshly flamed-dried KF on Celite (200 mg) and 3-(4-trifluoromethyl-phenoxymethyl)-piperidine (66 mg, 1.1 equiv). The mixture was stirred overnight, diluted with THF (5 mL), filtered, concentrated in vacuo and purified on silica gel to give the desired 1-[1-(2-methoxy-phenyl)-cyclobutyl]-2-[3-(4-trifluoromethyl-phenoxymethyl)-piperidin-1-yl]-ethanone (32 mg, 30%). Data for this amino ketone: MS 462 (M+l); 1H NMR (300 MHz, CDCl3) partial: δ 6.8-7.6 (m, 8H), 3.85-3.95 (m, 2H, methylene adjacent to aryl ether), 3.09 (s, 2H, methylene adjacent to keto and amine moieties).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][CH3:12])=[N:7][C:6]=2[C:5]([N+:13]([O-])=O)=[C:4]([F:16])[CH:3]=1>[Pd].C(OCC)(=O)C.[H][H]>[NH2:13][C:5]1[C:6]2[N:7]=[C:8]([CH2:11][CH3:12])[O:9][C:10]=2[C:2]([Cl:1])=[CH:3][C:4]=1[F:16]
Reactant: CCc1nc2c([N+](=O)[O-])c(F)cc(Cl)c2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCc1nc2c(N)c(F)cc(Cl)c2o1
Yield: 96.7 %

Procedure:
Step 5 Palladium on activated carbon (10%, 0.1 g) was added to a solution of 7-chloro-2-ethyl-5-fluoro-4-nitrobenzoxazole (0.86 g) in ethyl acetate (80 ml) and hydrogen was bubbled through the suspension for 5 hours. After filtration and evaporation, 4-amino-7-chloro-2-ethyl-5-fluorobenzoxazole(0.73 g) was obtained as the single product.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.F[C:21]1[C:26]([C:27]2[N:35]=[C:34]([CH3:36])[N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][O:38]2)=[CH:25][C:24]([CH2:43][C:44]2[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:52])=[O:51])=[CH:46][CH:45]=2)=[CH:23][N:22]=1>C1COCC1>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:21]2[C:26]([C:27]3[N:35]=[C:34]([CH3:36])[N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4[CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][O:38]3)=[CH:25][C:24]([CH2:43][C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH3:53])(=[O:51])=[O:52])=[CH:46][CH:45]=3)=[CH:23][N:22]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2F)c2ncn(C3CCCCO3)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reaction time: 0.5 h

Procedure:
6-methoxy-3-aminopyridine (Aldrich) (214 μL, 2.00 mmol) was dissolved in THF (1.80 mL) and cooled in an ice bath. LiHMDS (2.00 mL, 1.0 M in THF, 2.0 mmol) was added dropwise over 5 min. The resulting dark brown solution was stirred for 30 min prior to use. A solution of 6-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (92.6 mg, 0.192 mmol) in THF (1.0 mL) was cooled in an ice bath and treated dropwise with 0.85 mL of the above anilide solution (0.425 mmol) over 15 min, resulting in a deep red solution. 85% Conversion to desired product was observed by LCMS (215 nm) 5 min after completion of addition in a clean reaction. The reaction was checked after another 30 min and appeared to have stalled, so an additional 0.20 mL of the anilide solution was added dropwise. The mixture was stirred for 10 min, and then quenched by the addition of water (0.2 mL). The product was extracted into EtOAc from saturated aqueous NaHCO3, dried (MgSO4), concentrated and purified by flash chromatography (50% to 60% to 70% EtOAc/hexane) to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine (94.5 mg, 0.161 mmol, 84% yield) as a dark yellow foam. 1H NMR (400 MHz, CDCl3) δ 12.44 (s, 1H); 9.61 (d, J=2.15 Hz, 1H); 8.41 (d, J=2.74 Hz, 1H); 8.25 (s, 1H); 8.19 (dd, J=8.80, 2.74 Hz, 1H); 8.14 (d, J=2.15 Hz, 1H); 7.86 (d, J=8.22 Hz, 2H); 7.47 (d, J=8.02 Hz, 2H); 6.77 (d, J=8.80 Hz, 1H); 5.86 (d, J=10.37 Hz, 1H); 4.20 (d, J=11.35 Hz, 1H); 4.10 (s, 2H); 3.95 (s, 3H); 3.77-3.85 (m, 1H); 3.01 (s, 3H); 2.89 (s, 3H); 1.97-2.23 (m, 3H); 1.62-1.91 (m, 3H). m/z (ESI, +ve ion) 586.1 (M+H)+.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1(I)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: IC1CCCCCCC1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Product: CCOC(=O)/C(=N\OC1CCCCCCC1)C(C)=O
Yield: 69 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (2.Og) was treated with cyclooctyl iodide as described in Example 4a, Method 1, to give the title compound as a colourless liquid (2.35 g, 69%). νmax (film) 2930, 1740, 1695 cm-1, δH (CDCl3) 1.31 (3H, t), 1.4-2.0 (14H, m), 2.38 (3H, s), 4.33 (2H, q), 4.4 (1H, m). [Mass spectrum, +ve ion, MH+ (270)].
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26]>>[CH2:2]([O:9][C:10]1[CH:11]=[C:12]([C:16]2([F:23])[CH2:21][CH2:20][N:19]([CH2:26][CH2:25][C:24]([O:28][CH3:29])=[O:27])[CH2:18][CH:17]2[CH3:22])[CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C=CC(=O)OC
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Agent: Cl
Product: COC(=O)CCN1CCC(F)(c2cccc(OCc3ccccc3)c2)C(C)C1
Yield: 81 %

Procedure:
This compound was prepared from 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride and methyl acrylate as described in Step 1 of Example 4 in 81% yield.
Reaction SMILES: [C:1]([C:9]1[CH:28]=[CH:27][C:12]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:11][C:10]=1[OH:29])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:31][C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:20][C:19]1[O:18][C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:16][C:15]=1[CH2:14][O:13][C:12]1[CH:27]=[CH:28][C:9]2[C:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[C:31]([C:32]([O:34][CH3:35])=[O:33])[O:29][C:10]=2[CH:11]=1
Reactant: COC(=O)CBr
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(C(=O)c2ccccc2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1oc2cc(OCc3nc(-c4ccccc4)oc3C)ccc2c1-c1ccccc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 54.9 %

Procedure:
A mixture of 4-(4-benzoyl-3-hydroxyphenoxymethyl)-5-methyl-2-phenyl-1,3-oxazole (54.93 g), methyl bromoacetate (32.88 g), potassium carbonate (19.76 g) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. A mixture of the obtained residue, 1,8-diazabicyclo[5.4.0]-7-undecene (21.77 g), and toluene (750 mL) was heated under reflux for 20 hrs with azeotropic removal of water. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:8, v/v) to give methyl 6-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]-3-phenyl-1-benzofuran-2-carboxylate as colorless crystals (34.36 g, yield 55%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 139-140° C.
Reaction SMILES: [C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[NH:18][CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[N+:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1)([O-:34])=[O:33]>CC#N.O>[C:1]([O:5][CH:6]([C:10]1[N:15]([CH3:16])[C:14](=[O:17])[C:13]2[N:18]([CH2:39][C:38]3[CH:41]=[CH:42][C:35]([N+:32]([O-:34])=[O:33])=[CH:36][CH:37]=3)[CH:19]=[CH:20][C:12]=2[C:11]=1[C:21]1[C:22]([CH3:31])=[C:23]2[C:28](=[CH:29][CH:30]=1)[O:27][CH2:26][CH2:25][CH2:24]2)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3[nH]ccc23)ccc2c1CCCO2
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CC#N
Solvent: O
Product: Cc1c(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3c2ccn3Cc2ccc([N+](=O)[O-])cc2)ccc2c1CCCO2

Procedure:
The title compound was prepared in a manner similar to that described in Example 41 from 2-(tert-butoxy)-2-(6-methyl-4-(5-methylchroman-6-yl)-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetic acid and 4-nitrobenzyl bromide and was isolated by reverse phase chromatography (10-90% MeCN/H2O-0.1% TFA, 12 min) on an achiral column. 1H NMR (400 MHz, CHLOROFORM-d) ppm 8.15-8.23 (m, 2H) 7.31-7.42 (m, 3H) 6.97-7.05 (m, 1H) 6.71-6.80 (m, 1H) 5.80-6.03 (m, 3H) 5.15-5.44 (m, 1H) 4.16-4.26 (m, 2H) 3.61-3.71 (m, 3H) 2.64-2.76 (m, 2H) 2.07-2.16 (m, 2H) 1.93-2.06 (m, 3H) 0.98-1.19 (m, 9H); LCMS (m/z) ES+=560 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9](Br)=[CH:10][CH:11]=2)[CH:6]=1)=[O:4].[CH3:18][O:19][C:20]1[CH:21]=[C:22](OB(O)O)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]([C:5]1[C:14]([O:15][CH3:16])=[CH:13][C:12]2[C:7](=[CH:8][C:9]([C:24]3[CH:23]=[CH:22][CH:21]=[C:20]([O:19][CH3:18])[CH:25]=3)=[CH:10][CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COc1cccc(OB(O)O)c1
Reactant: COC(=O)c1cc2cc(Br)ccc2cc1OC
Product: COC(=O)c1cc2cc(-c3cccc(OC)c3)ccc2cc1OC
Yield: 66 %

Procedure:
The compound is prepared by the reaction of 7-bromo-3-methoxy-2-naphthoic acid methyl ester (2.2 g, 7.45 mmol, 1 eq) with 3-methoxyphenylboric acid (1.37 g, 8.95 mmol, 1.5 eq) according to method A. Purification by column chromatography with a gradient of hexane/dichloromethane 1/1 to 3/7 and dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 66%, 1.58 g.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].C(OC([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)=O)(C)(C)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55]>>[F:38][C:2]([F:39])([F:1])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:50]3[CH2:51][CH2:52][N:47]([S:54]([CH3:53])(=[O:56])=[O:55])[CH2:48][CH2:49]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Reactant: CS(=O)(=O)Cl
Product: Cc1ccccc1-c1nc(N2CCN(S(C)(=O)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 75 %

Procedure:
In a similar manner to Example 24, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg), 1-(t-butoxycarbonyl)piperazine (33.5 mg) and methylsulfonylchloride (0.04 mL) were reacted to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(methylsulfonyl)piperazine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine (74.1 mg, 75%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[N:22]=[CH:23][N:24]=[C:4]2[CH:3]=1.[N:25]1([C:30]2[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1>>[N+:19]([C:15]1[C:16]([NH2:18])=[N:17][C:12]([NH:11][CH2:10][CH2:9][NH:8][C:6]2[N:5]3[N:22]=[CH:23][N:24]=[C:4]3[CH:3]=[C:2]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)[CH:31]=3)[N:7]=2)=[CH:13][CH:14]=1)([O-:21])=[O:20]
Reactant: Nc1nc(NCCNc2nc(Cl)cc3ncnn23)ccc1[N+](=O)[O-]
Reactant: OB(O)c1cccc(N2CCCC2)c1
Product: Nc1nc(NCCNc2nc(-c3cccc(N4CCCC4)c3)cc3ncnn23)ccc1[N+](=O)[O-]

Procedure:
In analogy to the procedure described for Example 94, 17.5 mg (28% of theory) of the product are obtained as a solid starting from 50 mg (0.133 mmol) of N6-{2-[(7-chloro[1,2,4]triazolo-[1,5-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 55A) by coupling with 25.3 mg (0.13 mmol) of (3-pyrrolidin-1-ylphenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(=O)c1ccccc1O
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Cl)cc3)CC2)c1
Product: CC(=O)c1ccccc1OC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Cl)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-chlorophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-acetylphenol: ESMS m/e: 533.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][CH2:12][CH2:13][C:14]([OH:16])=O.[CH3:17][C:18]1([CH3:26])[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[O:19]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:17][C:18]1([CH3:26])[O:23][C:22](=[O:24])[CH:21]([C:14](=[O:16])[CH2:13][CH2:12][NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[C:20](=[O:25])[O:19]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Cc1ccc([N+](=O)[O-])cc1NCCC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc([N+](=O)[O-])cc1NCCC(=O)C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Methyl-5-nitro-phenylamino)-propionic acid [2.95 gm, 13.2 mmol], 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum's acid (2.08 gm, 14.5 mmol), and 4-dimethylaminopyridine (DMAP) [2.42 gm, 198 mmol) in anhy. dichloromethane (70 ml) at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (EDC.HCl) [3.04 gm, 158 mmol), and the resulting solution was stirred overnight at room temperature. The reaction mixture was washed (50 ml×4) with 5% potassium bisulfate (aq). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum, thereby affording crude 2,2-Dimethyl-5-[3-(2-methyl-5-nitro-phenylamino)propionyl]-[1,3]dioxane-4,6-dione (7), that was dissolved in 60 ml of ethyl acetate and refluxed for 4 hrs, The reaction mixture was cooled to room temperature and concentrated under vacuum. The crude product obtained was further purified by silica gel chromatography (eluent: 2% methanol in chloroform) to give desired produced i.e., 1-(2-Methyl-5-nitro-phenyl)-piperidine-2,4-dione [8] as yellow solid [Yield: 1.91 gm, 58.6%]
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([OH:11])([CH3:10])[CH3:9].C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>O1CCCC1>[OH:11][C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:21]1([OH:24])[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1)([CH3:10])[CH3:9]
Reactant: CN1CCC(=O)CC1
Reactant: CC(C)(O)c1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN1CCC(O)(c2ccccc2C(C)(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.7 %

Procedure:
To a stirred solution of 2-(2-bromophenyl)propan-2-ol (step 1, 6.91 g, 32.1 mmol) in tetrahydrofuran (32 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (46.5 mL, 73.9 mmol) at −78° C. for 20 min and the mixture was stirred for 1 h at the same temperature. To the mixture was added dropwise a solution of 1-methylpiperidin-4-one (5.09 g, 45.0 mmol) in tetrahydrofuran (18 mL) at −78° C. for 10 min. This resulting mixture was slowly warmed up to room temperature and stirred for 18 h at the same temperature. The reaction mixture was quenched by the addition of water, and concentrated to give an orange residue. The crude material was partitioned between diethyl ether and water, and then the organic layer washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (5/1), dichloromethane/methanol (10/1), then dichloromethane/methanol/triethylamine (10/1/1) to afford 4.62 g (58%) of the title compound as a slight yellow syrup:
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:12]([C:13]#[N:14])=[CH:11][N:10](COCC[Si](C)(C)C)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(NC2N(C[O:36]CC[Si](C)(C)C)N=CC=2C#N)C=CC=CC=1.Cl.C([O-])([O-])=O.[Na+].[Na+]>CCO.O>[C:1]1([NH:7][C:8]2[C:12]([C:13]([NH2:14])=[O:36])=[CH:11][NH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1ncc(C#N)c1Nc1ccccc1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)c(Nc2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: NC(=O)c1c[nH]nc1Nc1ccccc1
Temperature: 0 °C

Procedure:
To a solution containing a mixture of 3-(phenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile and 5-(phenylamino)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrazole-4-carbonitrile (2.6 g, 7.8 mmol) in EtOH (40.3 mL) was added 2N aqueous HCl (40.3 mL). The resulting mixture was heated at 0° C. for 1 hour. The mixture was cooled to ambient temperature and carefully neutralized with 3N aqueous Na2CO3 until pH ˜9. The solution was further diluted with H2O (400 mL), the layers were partitioned and the aqueous mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude residue was adsorbed on silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 0-100% EtOAc/DCM) to afford the title compound, which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:41]=[CH:40][CH:39]=[CH:38][C:30]=4[C:31]([O:33]C(C)(C)C)=[O:32])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45].Cl>O1CCOCC1.C([SiH](CC)CC)C>[CH3:1][C:2]1([CH3:46])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[CH2:44][CH2:43][C:17]3([N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:20][N:19]([CH2:28][C:29]4[CH:41]=[CH:40][CH:39]=[CH:38][C:30]=4[C:31]([OH:33])=[O:32])[C:18]3=[O:42])[CH2:16][CH2:15]2)[C:3]1=[O:45]
Reactant: CC(C)(C)OC(=O)c1ccccc1CN1CN(c2ccccc2)C2(CCN(CCCN3C(=O)C(C)(C)c4ccccc43)CC2)C1=O
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C(=O)N(CCCN2CCC3(CC2)C(=O)N(Cc2ccccc2C(=O)O)CN3c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-((8-(3-(3,3-dimethyl-2-oxoindolin-1-yl)propyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (0.17 g, 0.27 mmol) was added 4M solution of HCl in dioxane (3 mL) and triethylsilane (0.1 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo, washed with acetonitrile and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.8 g); 1H NMR (DMSO-d6): δ 1.28 (s, 6H), 1.98 (d, 2H, J=10.4 Hz), 2.07 (t, 2H, J=6.4 Hz), 2.90-2.96 (m, 2H), 3.27 (br, 2H), 3.54-3.61 (m, 4H), 3.77 (t, 2H, J=6.8 Hz), 4.66 (s, 2H), 4.92 (s, 2H), 6.80 (t, 1H, J=7.2 Hz), 6.98 (d, 2H, J=8 Hz), 7.06 (t, 1H, J=7.6 Hz), 7.16 (d, 1H, J=7.6 Hz), 7.20-7.32 (m, 4H), 7.37 (d, 1H, J=7.2 Hz), 7.42 (t, 1H, J=8 Hz), 7.57 (t, 1H, J=7.6 Hz), 7.92 (d, 1H, J=8 Hz), 10.21 (br, 1H), 13.19 (br, 1H); MS for C34H38N4O4 m/z 567.22 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([NH:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[CH:27][CH:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([N:31]([CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:28]2[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=2)=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: COC(=O)CCCNc1ccc(OC)cc1
Product: COC(=O)CCCN(C(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)acetic acid and methyl 4-(p-anisidino)butyrate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-4-(p-anisidino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]-4-(p-anisidino)butyric acid (M.P. 105° to 108°).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:29]=[CH:28][C:15]([C:16]([O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(Cl)(=O)C(Cl)=O.[C:36]1([CH:43]=[CH:42][CH:41]=[C:39](O)[CH:38]=1)[OH:37].C(N(CC)CC)C>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([O:11][C:12]1[CH:29]=[CH:28][C:15]([C:16]([O:18][C:19]2[CH:27]=[CH:26][C:22]([C:23]([O:25][C:39]3[CH:41]=[CH:42][CH:43]=[C:36]([OH:37])[CH:38]=3)=[O:24])=[CH:21][CH:20]=2)=[O:17])=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Reactant: Oc1cccc(O)c1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(O)c3)cc2)cc1

Procedure:
Compound 16 (2.05 g, 5.2 mmol) was suspended in toluene (100 mL), and refluxed with oxalyl chloride (2.0 mL, 23.2 mmol) for five hours. Volatile components were removed, and the white solid was taken in CH2Cl2 (50 mL) and added dropwise while stirring to a solution containing resorcinol (1.23 g, 11.2 mmol), triethylamine (5.4 mL, 39 mmol), and DMAP (0.06 g, 0.52 mmol). Following stirring at room temperature for 12 hours, the mixture was then refluxed for twenty four hours. The solvent was removed under reduced pressure, and the residue purified by column chromatography (CH2Cl2:EtOH, 10:0.03, and then CH2Cl2:EtOH, 10:0.3). The product was then recrystallized from ethanol. Yield (1.6 g, 64%). 1H NMR: δH (CDCl3; 300 MHz): 0.92 (3 H, t, 3J=6.9 Hz, CH3), 1.23-1.60 (14 H, m, CH2), 1.86 (2 H, m, O—CH2—CH2), 4.07 (2 H, t, 3J=6.5 Hz, O—CH2), 6.15 (1 H, bs, OH), 6.69 (2 H, m, Ar—H), 6.78 (1 H, d, 3J=8.3 Hz, Ar—H), 7.01 (2 H, d, 3J=8.9 Hz, Ar—H), 7.25 (1 H, t, 3J=8.5 Hz, Ar—H), 7.38 (2 H, d, 3J=8.8 Hz, Ar—H), 8.18 (2 H, d,3J=8.9 Hz, Ar—H), 8.27 (2 H, d, 3J=8.8 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 29.5, 29.7, 29.8, 30.0, 32.3, 68.8, 109.8, 113.8, 113.9, 114.9, 121.2, 122.6, 127.2, 130.5, 132.3, 132.9, 152.0, 155.8, 157.4, 164.3, 165.0, 165.3.