Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.CN(C)C=O.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.Cl.[C:24]1([NH2:31])[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1>O>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:30][C:27]2[CH:28]=[CH:29][C:24]([NH2:31])=[CH:25][CH:26]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Nc1ccc(N)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Nc2ccc([N+](=O)[O-])cn2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Triethylamine (35 ml) was added into dimethylformamide (50 ml) including 2-chloro-5-nitropyridine (1) (9.5 g, 60 mmol) and para-phenylenediamine hydrochloride (10.9 g, 60 mmol), and stirred at the room temperature for 14 hours. After the reaction having been completed, the solution was poured into water, and the resultant solid was filtered and then N-(5-nitropyridin-2-yl) para-phenylenediamine was obtained as a brown solid. This solid was dissolved in ethanol (800 ml) and added with 5%-palladium carbon (2 g) so as to cause a hydrogen substitution, and then reduced at 70° C. under the normal pressure for 6 hours. After the reaction having been completed, the celite filtering was applied to remove the palladium carbon, and then it was washed by using a mixed solvent of ethyl acetate and hexane, thus obtained N-(5-amino-pyridin-2-yl) para-phenylenediamine (8.8 g, 75%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.N1C=CC=CC=1>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]#[N:16])[CH:10]=2)=[CH:17][CH:18]=1
Reactant: N#Cc1cc(Cc2ccc([N+](=O)[O-])cc2)ccn1
Agent: [Pd]
Solvent: c1ccncc1
Solvent: CCO
Product: N#Cc1cc(Cc2ccc(N)cc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
10% Degussa Pd on carbon (40 mg, 0.38 mmol) was flushed with nitrogen then diluted in ethanol (5 mL). 4-(4-Nitro-benzyl)-pyridine-2-carbonitrile (250 mg, 1.05 mmol) in ethanol (5 mL) and pyridine (42 mg, 0.52 mmol) was subsequently added, and the mixture was flushed again with nitrogen prior to placing a hydrogen balloon on the flask. The mixture was stirred at rt overnight then filtered through Celite® and concentrated. The residue was dissolved in ethyl acetate and filtered through a silica gel plug, eluting with 50-100% ethyl acetate in hexanes, to give 4-(4-amino-benzyl)-pyridine-2-carbonitrile (134 mg, 61%). 1H NMR (CHCl3-d) δ 8.55 (d, J=5.2 Hz, 1H), 7.46 (s, 1H), 7.30 (d, J=4.8 Hz, 1H), 6.93 (d, J=8.3 Hz, 2H), 6.66 (d, J=8.2 Hz, 2H), 3.91 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([CH3:22])[CH3:21])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23](N=C(N(C)C)N(C)C)([CH3:26])([CH3:25])[CH3:24].BrCC(C)C>C(#N)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:24][CH:23]([CH3:26])[CH3:25])[C:12]2[C:17]([O:18][CH3:19])=[CH:16][C:15]([CH:20]([CH3:22])[CH3:21])=[CH:14][N:13]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: COc1cc(C(C)C)cnc1NS(=O)(=O)c1ccc(F)cc1
Solvent: CC(C)CBr
Solvent: CC#N
Product: COc1cc(C(C)C)cnc1N(CC(C)C)S(=O)(=O)c1ccc(F)cc1
Yield: 72.4 %

Procedure:
The title compound (46.8 mg) was prepared from 4-fluoro-N-(5-isopropyl-3-methoxypyridin-2-yl)benzenesulfonamide (55 mg, 0.170 mmol), 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.068 mL, 0.339 mmol) in acetonitrile (4 mL) and 1-bromo-2-methylpropane (0.037 mL, 0.339 mmol) following the procedure described for Example 40. LCMS (2 min, formic) Rt 1.34 min, m/z (ES+) 381 (M+H).
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH:26]1[C:34]2[C:29](=[CH:30][C:31]([Br:35])=[CH:32][CH:33]=2)[CH2:28][CH2:27]1)[C:7]([NH:9][CH:10]([CH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1)[C:11]([O:13]C)=[O:12])=[O:8])(=O)C.[OH-].[Na+].Cl>CO>[Br:35][C:31]1[CH:30]=[C:29]2[C:34](=[CH:33][CH:32]=1)[CH:26]([CH:6]([CH2:5][SH:4])[C:7]([NH:9][C@H:10]([C:11]([OH:13])=[O:12])[CH2:15][C:16]1[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=1)=[O:8])[CH2:27][CH2:28]2
Reactant: COC(=O)C(Cc1ccc2ccccc2n1)NC(=O)C(CSC(C)=O)C1CCc2cc(Br)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(N[C@@H](Cc1ccc2ccccc2n1)C(=O)O)C(CS)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The compound obtained in Example 25 is dissolved in 2 ml of degassed methanol. After 10 minutes' stirring at room temperature, 6 eq. of a degassed 1M sodium hydroxide solution are added to the solution. The resulting solution is stirred at room temperature under argon. The progress of the reaction is monitored by HPLC. When the reaction is complete; the solution is rendered acidic to pHr. 1 with 1N hydrochloric acid. The methanol is removed in vacuo, 10 ml of water are added to the residue and extraction is carried out with 10 ml of chloroform. The organic phase is separated off, dried over Na2SO4, concentrated in vacuo, and purified by HPLC chromatography.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[NH:7][C:8](=[O:13])[CH:9]=[C:10](Cl)[N:11]=1)[CH3:2].Cl.[NH:16]1[CH2:21][CH2:20][O:19][CH:18]([CH2:22][OH:23])[CH2:17]1.[Na+].[Cl-].C(Cl)Cl>CS(C)=O.C(N(CC)CC)C.C(OC(C)C)(C)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][C:6]1[NH:7][C:8](=[O:13])[CH:9]=[C:10]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([CH2:22][OH:23])[CH2:17]2)[N:11]=1)[CH3:2]
Reactant: OCC1CNCCO1
Reactant: CCOC(=O)Cc1nc(Cl)cc(=O)[nH]1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)OC(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(N2CCOC(CO)C2)cc(=O)[nH]1
Temperature: 85 °C
Yield: 14 %

Procedure:
Under argon, in a 500 ml round-bottomed flask equipped with a thermometer and a condenser, 10 g of (4-chloro-6-oxo-1,6-dihydropyrimidin-2-yl)acetic acid ethyl ester (example 25b, step 5b) and 9.6 g of morpholin-2-yl-methanol hydrochloride obtained previously are successively placed in 200 ml of DMSO and 16.1 ml of triethylamine. The reaction medium is heated for 22 h at 85° C. After returning to ambient temperature (20° C.), the reaction medium is poured into a saturated NaCl solution, and the mixture is extracted with 8×250 ml of ethyl acetate. The organic extracts are combined, dried over magnesium sulfate, filtered, and evaporated under reduced pressure. A solid is obtained which is slurried in diisopropyl ether containing 10% of methylene chloride. The solid is filtered off, and rinsed twice and then once with pentane. [4-(2-Hydroxymethylmorpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetic acid ethyl ester is isolated (1.9 g; yield=14%) in the form of a beige solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6]CC)=O)#[N:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:19](=[O:23])/[CH:20]=[CH:21]/[CH3:22])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].O1CCCC1>C(O)(C)(C)C.Cl>[F:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][N:18]2[C:19](=[O:23])[CH2:20][C@@H:21]([CH3:22])[C@H:3]([C:1]#[N:2])[C:4]2=[O:6])=[CH:14][CH:15]=1
Reactant: CCOC(=O)CC#N
Reactant: C/C=C/C(=O)NCCc1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: C[C@@H]1CC(=O)N(CCc2ccc(F)cc2)C(=O)[C@H]1C#N
Temperature: 80 °C
Yield: 93.5 %

Procedure:
A solution of ethyl cyanoacetate (4.26 mL, 40 mmol) and trans-2-butenoic acid [2-(4-fluoro-phenyl)ethyl]amide (4.15 g, 20 mmol) in tert-butanol (60 mL) was treated with a solution of potassium tert-butoxide in tetrahydrofuran (1.0 M, 40 mL, 40 mmol) and the mixture was heated at 80° C. The mixture was cooled to room temperature after 16.5 hours and diluted with 1.0 N aqueous hydrochloric acid. The mixture was concentrated under vacuum to remove the organic solvents, providing a suspension of solid in the aqueous residue. This was collected by filtration, dried, and purified by recrystallization from 95% ethanol to provide a white solid (5.13 g, 93%). 1H NMR (300 MHz, CDCl3) δ7.19 (m, 2H), 7.00 (t, J=9 Hz, 2H), 4.02 (m, 2H), 3.41 (d, J=11 Hz, 1H), 2.91 (m, 1H), 2.83 (t, J=8 Hz, 2H), 2.5-2.3 (m, 2H), 1.31 (d, J=6 Hz, 3H). Mass spec (CI) m/z 275.0 (M+H+, 100%).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=O)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]>CCO>[Si:14]([O:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[N:30]=[C:29]([CH:32]=[N:2][NH:1][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][O:12][CH3:13])[CH:6]=[CH:5][N:4]=1)[CH:28]=[CH:27]2)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16]
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc2ccc(C=O)nc12
Reactant: COCCOc1ccnc(NN)c1
Solvent: CCO
Product: COCCOc1ccnc(NN=Cc2ccc3cccc(O[Si](C)(C)C(C)(C)C)c3n2)c1
Temperature: 25 °C
Yield: 55.9 %

Procedure:
2-Hydrazinyl-4-(2-methoxyethoxy) pyridine (0.076 g, 0.415 mmol) and 8-(tert-butyldimethylsilyloxy) quinoline-2-carbaldehyde (0.119 g, 0.415 mmol) were heated to reflux in EtOH (2 mL) for 16 hours. After cooling to ambient temperature the reaction mixture was filtered and washed with EtOH to provide 105 mg (56%) of desired product as an orange solid.
Reaction SMILES: [BH4-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>C(O)C.O>[OH:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=Cc1cccc(O)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Oc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium borohydride (1.52 g) was added to a stirred solution of 3-hydroxybenzaldehyde (4.9 g) and piperidine (6.8 g) in ethanol (25 ml) cooled in an ice-water bath. The mixture was stirred at ambient temperature for 16 hours and then poured into water (250 ml) and the resulting mixture acidified with 2N hydrochloric acid. The acidified mixture was extracted with ethyl acetate and the aqueous phase was made alkaline by the addition of aqueous ammonia solution (S.G. 0.880) to yield N-3-hydroxybenzylpiperidine (m.p. 135°-139° C.) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:11]([N:13]1[CH2:17][C@@H:16]([CH3:18])[CH2:15][C@H:14]1[C:19]1[NH:20][C:21]([C:24]2[CH:29]=[C:28]3[CH2:30][O:31][C:32]4[CH:59]=[C:58]5[C:35]([CH:36]=[CH:37][C:38]6[N:42]=[C:41]([C@@H:43]7[CH2:47][C@H:46]([CH2:48][O:49][CH3:50])[CH2:45][N:44]7[C:51](OC(C)(C)C)=[O:52])[NH:40][C:39]=65)=[CH:34][C:33]=4[C:27]3=[CH:26][CH:25]=2)=[CH:22][N:23]=1)=[O:12])[C@@H:7]([CH2:9][CH3:10])[CH3:8])=[O:4].[CH3:60][O:61][C:62]([NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])C(O)=O)=[O:63].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:60][O:61][C:62](=[O:63])[NH:64][C@@H:65]([CH:69]([CH3:71])[CH3:70])[C:51]([N:44]1[CH2:45][C@@H:46]([CH2:48][O:49][CH3:50])[CH2:47][C@H:43]1[C:41]1[NH:40][C:39]2[C:58]3[C:35]([CH:36]=[CH:37][C:38]=2[N:42]=1)=[CH:34][C:33]1[C:27]2[C:28]([CH2:30][O:31][C:32]=1[CH:59]=3)=[CH:29][C:24]([C:21]1[NH:20][C:19]([C@@H:14]3[CH2:15][C@H:16]([CH3:18])[CH2:17][N:13]3[C:11](=[O:12])[C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[C@H:7]([CH3:8])[CH2:9][CH3:10])=[N:23][CH:22]=1)=[CH:25][CH:26]=2)=[O:52]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)OC(C)(C)C)[nH]c54)cc2-3)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: CC[C@@H](C)[C@H](NC(=O)OC)C(=O)N1C[C@@H](C)C[C@H]1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@H](COC)CN6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1
Reaction time: 3 h
Yield: 71.3 %

Procedure:
tert-butyl(2S,4S)-2-[9-(2-{(2S,4S)-1-[N-(methoxycarbonyl)-L-alloisoleucyl]-4-methylpyrrolidin-2-yl}-1H-imidazol-5-yl)-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (105 mg, 0.13 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3 h and then concentrated under reduced pressure. The crude residue was treated with (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (32 mg, 0.18 mmol), HATU (59 mg, 0.16 mmol) and DMF (1.3 mL), then N-methylmorpholine (0.043 mL, 0.39 mmol) was added dropwise. After 3 h, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl{(2S)-1-[(2S,4S)-2-(9-{2-[(2S,4S)-1-{(2S,3R)-2-[(methoxycarbonyl)amino]-3-methylpentanoyl}-4-methylpyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-4-(methoxymethyl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (80 mg, 71%).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1.[CH3:7][C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([CH3:18])[C:9]=1[NH2:10]>>[CH3:7][C:8]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[C:11]([CH3:18])[C:9]=1[NH:10][C:2]1[CH2:6][CH2:5][CH2:4][N:3]=1
Reactant: ClC1=NCCC1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1N
Product: Cc1cc([N+](=O)[O-])cc(C)c1NC1=NCCC1

Procedure:
A mixture of 2-chloro-1-pyrroline, prepared as in Example 1, and 19.9 g (0.12 mole) of the aniline product of Example 6 were heated at reflux overnight, according to the general method of Example 8. The title compound was isolated and used for subsequent reactions without further purification. Structure assignment was supported by nmr and infrared spectra.
Reaction SMILES: Br[C:2]1[S:15][C:5]2[C:6]3[CH:14]=[N:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][N:18]=1>>[S:15]1[C:5]2[C:6]3[CH:14]=[N:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[CH:3]=[C:2]1[C:20]1[CH:21]=[CH:22][C:17]([NH2:16])=[N:18][CH:19]=1
Reactant: Nc1ccc(B(O)O)cn1
Reactant: Brc1cc2c(s1)-c1cnccc1OCC2
Product: Nc1ccc(-c2cc3c(s2)-c2cnccc2OCC3)cn1

Procedure:
Following Example 52, 2-bromo-4,5-dihydropyrido[4,3-b]thieno[2,3-d]oxepine and 2-aminopyridine-5-boronic acid, pinacol ester were reacted to give 105. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.27 (d, J=2.2, 1H), 8.22 (d, J=5.5, 1H), 7.67 (dd, J=2.6, 8.6, 1H), 7.22 (s, 1H), 6.99 (d, J=5.4, 1H), 6.51 (d, J=8.6, 1H), 6.25 (s, 2H), 4.37 (t, J=4.8, 2H), 3.20 (t, J=4.8, 2H). MS: (ESI+) 296.1
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:22][C:23]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:36]1([C:34]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[C:23]([NH:22][C:19]([C:16]3[CH:17]=[N:18][C:13]([N:7]4[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]4)=[CH:14][CH:15]=3)=[O:21])[CH:35]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)c1ccc(N2CCCCC2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 3.031 mL of oxalyl chloride were sequentially added to 69 mg of 6-(piperidin-1-yl)pyridine-3-carboxylic acid at room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 54 mg of tert-butyl 2-amino-4-phenylbenzoate, 3.7 mL of methylene chloride and 6.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenyl-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:7][CH:6]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:29][N+:30]([CH3:32])=[CH2:31].[I-]>C1COCC1.O>[CH3:29][N:30]([CH2:32][CH:4]([C:5]1[CH:17]=[CH:16][C:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])=[CH:7][CH:6]=1)[C:3]([O:2][CH3:1])=[O:18])[CH3:31]
Reactant: COC(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: C=[N+](C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CN(C)C)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of tert-butyl 4-(2-methoxy-2-oxoethyl)benzoate (800 mg, 3.20 mmol) in THF (15 mL) was cooled to −78° C. before adding lithium hexamethyldisilazide (1M in THF, 4.16 mL, 4.16 mmol) dropwise. After 15 minutes, Eschenmoser's salt (1.18 g, 6.40 mmol) was added in one portion. The reaction was stirred at −78° C. for 5 minutes, warmed to room temperature, and stirred an additional 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was then extracted with 1N HCl. The acidic aqueous layer was neutralized with sat. NaHCO3 and extracted with EtOAc. The new organic extracts were dried over MgSO4 and evaporated to yield tert-butyl 4-{1-[(dimethylamino)methyl]-2-methoxy-2-oxoethyl}benzoate as a white solid. 1H NMR (CDCl3) δ 7.91 (d, J=8.5 Hz, 2H), 7.35 (d, J=8.2 Hz, 2H), 3.84 (dd, J=9.7, 5.6 Hz, 1H), 3.65 (s, 3H), 3.10 (dd, J=12.3, 9.7 Hz, 1H), 2.47 (dd, J=12.3, 5.6 Hz, 1H), 2.24 (s, 6H), 1.55 (s, 9H). MS (ESI) calcd [M+H]+ 308.1, found 308.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[C:6]([CH3:24])=[C:5]2[CH2:25][C:26](NCC(O)=O)=[O:27].C([O:40]C(=O)CNC(=O)CC1C2C(=CC=C(F)C=2)C(=CC2C=C(OC)C(OC)=C(OC)C=2)C=1C)C1C=CC=CC=1>C(O)C.[OH-].[Na+].O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[CH:11][C:12]1[CH:13]=[C:14]([O:22][CH3:23])[C:15]([O:20][CH3:21])=[C:16]([O:18][CH3:19])[CH:17]=1)[C:6]([CH3:24])=[C:5]2[CH2:25][C:26]([OH:40])=[O:27]
Reactant: COc1cc(C=C2C(C)=C(CC(=O)NCC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Reactant: COc1cc(C=C2C(C)=C(CC(=O)NCC(=O)OCc3ccccc3)c3cc(F)ccc32)cc(OC)c1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(C=C2C(C)=C(CC(=O)O)c3cc(F)ccc32)cc(OC)c1OC
Reaction time: 18 h

Procedure:
N-[5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetyl]-glycine. Benzyl-N-[5-fluoro-2-methyl-1-(3,4,5-trimethoxy-benzylidene)-3-indenylacetyl]-glycinate (0.03 mol) in a mixture of 25 ml of anhydrous ethanol and 2.5 ml of 1 N sodium hydroxide is allowed to stand at room temperature for 18 h. The solution is diluted with water and extracted with ether. The aqueous layer is acidified with dilute hydrochloric acid and the organic product is extracted with ethyl acetate, washed with water and dried over sodium sulfate. Evaporation of the solution gives N-[5-fluoro-2-methyl-1-(3,4,5-trimethoxybenzylidene)-3-indenylacetic acid, the corresponding indenyl acyl glycine is obtained.
Reaction SMILES: O[CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C(N(S(F)(F)[F:35])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:35][CH2:2][C:3]1[NH:4][C:5]([CH3:28])=[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=C(C)NC(CF)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2.5 h
Yield: 15.3 %

Procedure:
Diethyl 1,4-dihydro-2-(hydroxymethyl)-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylate (0.1 g, 0.25 mmoles) in dry methylene chloride (5 ml) was added to a stirred solution at -60° of diethylaminosulphur trifluoride (0.068 ml, 0.55 mmoles) in dry methylene chloride (10 ml) over 10 minutes. The reaction mixture was allowed to reach room temperature over 2.5 hours, poured into aqeuous sodium bicarbonate (15 ml) and the aqueous layer extracted with methylene chloride (2×). The organic extracts were washed with water, dried (MgSO4) and the solvent was evaporated. The residue was chromatographed on silica eluting with ethyl acetate/methylene chloride mixtures to give the title compound (0.015 g); identical with that prepared in Example 94.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][CH2:15][OH:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[C:1]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[CH2:14][CH:15]=[O:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)C(CCO)CC2
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc2c(c1)C(CC=O)CC2
Yield: 98 %

Procedure:
Prepared in an analogous manner to that described in Example 4, by oxidizing 2-(6-tert-butyl-1-indanyl)-1-ethanol (8.53 g, 32.1 mmole, 82.3% pure) in dichloromethane (50 ml), by means of PCC (Fluka, 15.0 g, 68 mmole) in dichloromethane (100 ml). After the treatment described and bulb-to-bulb distillation (120°/15Pa), there was obtained the above-mentioned compound with a purity of 84% (6.01 g, yield 72.7%). Further purification by chromatography provided the desired compound 98% pure, presenting the following analytical characters:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[C:31]([S:34][CH2:35][CH:36]([CH3:40])[C:37](Cl)=[O:38])(=[O:33])[CH3:32]>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:37](=[O:38])[CH:36]([CH3:40])[CH2:35][S:34][C:31](=[O:33])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Reactant: CC(=O)SCC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of L-prolyl-L-phenylalanine tert-butyl ester (1.0 g) [prepared by the method described in Ann. Chem. 680, 132-141 (1964)] in dichloromethane at about -30° C. were added N-methylmorpholine (0.32 g) and then dropwise 3-acetylthio-2-methylpropanoyl chloride (0.57 g). The mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour. The reaction mixture was washed successively with 4% sodium bicarbonate, water, 10% citric acid, and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel with chloroform to give 1-(3-acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([O:17]CC)=O)=[C:5]2[OH:20].[C:21]([NH:34][NH2:35])(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:35][NH:34][C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:17])=[C:5]2[OH:20]
Reactant: CCCCCCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(CC)c1=O
Product: CCCCCCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(CC)c1=O

Procedure:
Reagents: Comp 36 (0.36 mmols, 0.12 g); dodecanoyl hydrazine (0.4 mmols, 0.08 g). Yield: 0.15 g (80%), white solid, m.p.=146° C.-147° C.