Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[NH:15][C:14](=O)[CH2:13][NH:12][C:11]2=O)[CH:6]=[CH:5][N:4]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][CH:10]2[CH2:11][NH:12][CH2:13][CH2:14][NH:15]2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(CC2NC(=O)CNC2=O)ccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(CC2CNCCN2)ccn1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a 100-mL round-bottomed flask was added 3-((2-methoxy-4-pyridinyl)methyl)-2,5-piperazinedione (398 mg, 1.69 mmol) and borane methyl sulfide complex (0.64 mL, 6.77 mmol, Aldrich, St. Louis, Mo.) in THF (10 mL). The reaction mixture was stirred at 70° C. for 2 h and allowed to cool to room temperature. The reaction mixture was diluted with MeOH (1 mL), followed by 1N NaOH (12 mL), and extracted with DCM (2×50 mL). The organic extract was washed with saturated NaCl (10 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the 2-((2-methoxy-4-pyridinyl)methyl)piperazine as a colorless viscous oil, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([CH:12]([OH:16])[CH2:13][CH2:14][CH3:15])[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[C:1]1([C:7]2[CH:11]=[C:10]([C:12](=[O:16])[CH2:13][CH2:14][CH3:15])[S:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCC(O)c1cc(-c2ccccc2)ns1
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCC(=O)c1cc(-c2ccccc2)ns1
Reaction time: 2 h

Procedure:
To 35 ml of dichloromethane, were added 1.73 g (7.42 mmol) of 3-phenyl-5-(1-hydroxybutyl)isothiazole, 1.1 g (13.4 mmol) of sodium acetate and 2.88 g of "Frolisil" (trade mark). While the resultant mixture was vigorously stirred at room temperature, 2.88 g (13.4 mmol) of pyridinium chlorochromate were added at once. After the reaction mixture was stirred for 2 hours, an insoluble material was filtered off and the solvent was then distilled off. The residue was purified by silica gel chromatography (eluent: 20:1 n-hexane/ethyl acetate), whereby 3-phenyl-5-butyrylisothiazole was obtained as colorless crystals.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:26]#[N:27])([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)[CH2:7][CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)C>[Ni]>[CH:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:24]=[CH:25][C:16]=1[C:6]1([CH2:7][CH2:8][O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:26][NH:27][C:4](=[O:3])[CH2:5]1
Reactant: CCOC(=O)CC(C#N)(CCOC1CCCCO1)c1ccc2ccccc2c1
Agent: [Ni]
Product: O=C1CC(CCOC2CCCCO2)(c2ccc3ccccc3c2)CN1
Yield: 57.8 %

Procedure:
3-Cyano-3-naphthalen-2-yl-5-(tetrahydro-pyran-2-yloxy)-pentanoic acid ethyl ester (003F143) (1.6154 g, 4.23 mmol) was hydrogenated at 40 psi over Raney nickel (10g) for 16 hours. The slurry was filtered and the filtrate was concentrated in vacuo. The residue was chromatographed on silica gel with a gradient from 50% ethyl acetate in hexane to 5% methanol in dichloromethane to give 0.8305 g (83%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]2[C:9]([C:10](Cl)=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C([O-])(=O)C.[Na+]>C(OCC)(=O)C.C(O)(C)C.[OH-].[OH-].[Pd+2]>[CH2:1]([O:3][C:4]([C:6]1[N:14]2[C:9]([CH:10]=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ccc2c(Cl)ncnn12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc2cncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.3 %

Procedure:
A mixture of 4-chloro-pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester (120 mg), palladium hydroxide on carbon (20%, 40 mg) and sodium acetate (600 mg) in a mixture of ethyl acetate and isopropanol (5/1, 12 mL) was stirred at room temperature under hydrogen atmosphere (balloon pressure) overnight. The resulting mixture was filtered and a CELITE™ pad, the filtrate was evaporated under reduced pressure. The crude residue was purified by flash chromatography to give 45 mg of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:21]1[CH2:30][CH2:31][OH:32])=[O:19])([CH3:16])([CH3:15])[CH3:14].[C:33]1(O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH3:29])=[O:27])[CH2:22][CH:21]1[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCO)C1
Reactant: Oc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)N1CCN(C(=O)OC(C)(C)C)C(CCOc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.7 %

Procedure:
A solution of diethyl azodicarboxylate (0.74 ml, 4.7 mmol) in anhydrous dichloromethane (3 ml) was added to a stirred, ice-methanol cooled solution of (RS)-1-(tert-butoxycarbonyl)-2-(2-hydroxyethyl) -4-methoxycarbonylpiperazine (D7) (1.35 g, 4.69 mmol), phenol (0.441 g, 4.69 mmol) and triphenylphosphine (1.23 g, 4.69 mmol) in anhydrous dichloromethane (40 ml). The mixture was stirred at room temperature for 18 h then evaporated in vacuo. The residue was chromatographed on silica gel eluting with 10-20% ethyl acetate in hexane to give the title compound (1.43 g, 84%). 1H NMR (CDC13) δ: 1.38 (9H, m), 1.85-2.20 (2H, m), 2.75-3.20 (3H, m), 3.72 (3H, s), 3.80-4.20 (5H, m), 4.39 (1H, broad m), 6.75-7.00 (3H, m), 7.15-7.35 (2H, m).
Reaction SMILES: ClC(OCC)=O.[I:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11](O)=[O:12].C(N(CC)CC)C.[BH4-].[Na+].C(=O)=O.Cl>O1CCCC1.O>[I:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][OH:12]
Reactant: O=C(O)c1cccc(I)c1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: O=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc(I)c1
Reaction time: 0.5 h

Procedure:
Ethyl chloroformate (1.02 g, 11.1 mmol) in dry tetrahydrofuran (5 ml) was added slowly over 10 min to a stirred solution of 3-iodobenzoic acid (1.98 g, 7.98 mmol) and triethylamine (0.500 g, 11.6 mmol) in dry tetrahydrofuran at −8° (ice/salt/water bath). The yellow mixture soon became cloudy. It was shielded from light and stirred at −8° for 0.5 h, after which it was filtered to remove the triethylammonium chloride precipitate. The filtrate was added slowly to a suspension of sodium borohydride (0.795 g, 21.1 mmol) in water (30 ml) in a three necked flask, equipped with a thermometer, and connected to nitrogen, making sure that the temperature of the mixture is kept below 10° during the addition. Gas evolution (carbon dioxide) was observed. After the addition was completed, the mixture was stirred, shielded from light, at room temperature for 22 h under nitrogen. The resultant cloudy mixture was acidified with aqueous hydrochloric acid (10%) to pH˜1. The layers were separated, and the aqueous layer was extracted with ether (×3). The combined ether extract and tetrahydrofuran layer was washed with aqueous sodium hydroxide (×1, 10%) and then with water (×1). Drying with magnesium sulphate, and concentration gave 3-iodobenzyl alcohol (11) a pale yellow oil (1.02 g, 54%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.[Br:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21](Br)[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.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>[Br:16][C:17]1[CH:18]=[C:19]([OH:24])[CH:20]=[C:21]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=2)[CH:22]=1
Reactant: Oc1cc(Br)cc(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1cc(-c2cc(O)cc(Br)c2)cn1
Temperature: 800 °C
Yield: 37 %

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (750 mg; 3.6 mmol; 1.0 eq.), 3,5-Dibromo-phenol (4.54 g; 18.0 mmol; 5.0 eq.), bis(triphenylphosphine)palladium(II) chloride (253 mg; 0.36 mmol; 0.1 eq.) and potassium carbonate (2.49 g; 18.02 mmol; 5 eq.) were suspended in DMF (80 mL) and water (1 mL). The reaction mixture was then heated at 800° C. for 16 h in a sealed tube. It was filtered through Celite and the filtrate was concentrated under reduced pressure. Purification by flash chromatography on silica (n-heptane:EtOAc, gradient from 95:5 to 10:90) afforded the title compound as a clear oil (337 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ 10.01 (brs, 1H), 8.14 (s, 1H), 7.83 (d, J=0.7 Hz, 1H), 6.96 (d, J=1.7 Hz, 1H), 6.92 (dd, J=2.1, 1.5 Hz, 1H), 6.76 (t, J=2.0 Hz, 1H), 3.84 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BrH:11].[Br:12]CC(C1C=C(C)C=CN=1)=O>>[BrH:12].[Br:11][CH2:2][C:1]([C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][N:5]=1)=[O:3]
Reactant: CC(=O)c1ncccc1C
Reactant: Cc1ccnc(C(=O)CBr)c1
Agent: Br
Product: Cc1cccnc1C(=O)CBr

Procedure:
* 2-Bromoacetyl-3-methylpyridine hydrobromide was prepared from 2-acetyl-3-methylpyridine (T. A. Crabb et al., Org. Magn. Reson., 1982, 20, 242) according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:46]=[CH:47][CH:48]=1)[C:8]([NH:10][C:11]1[C:12]([CH3:45])=[C:13]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([NH:38][C:39](=[O:44])[C:40]([F:43])([F:42])[F:41])=[C:26]([CH:37]=2)[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:9].C(OC([NH:56][CH2:57][C:58](O)=[O:59])=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:56][CH2:57][C:58]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:46]=[CH:47][CH:48]=1)[C:8]([NH:10][C:11]1[C:12]([CH3:45])=[C:13]([C:20]([C:22]2[CH:23]=[CH:24][C:25]([NH:38][C:39](=[O:44])[C:40]([F:41])([F:42])[F:43])=[C:26]([CH:37]=2)[C:27]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[O:28])=[O:21])[N:14]2[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]2)=[O:9])=[O:59]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Cc1c(NC(=O)c2cccc(OCCN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(NC(=O)c2cccc(OCCNC(=O)CN)c2)c2ccccn2c1C(=O)c1ccc(NC(=O)C(F)(F)F)c(C(=O)OCc2ccccc2)c1

Procedure:
By following the process described in stage G of Example 42, the coupling of benzyl 5-[(1-{[3-(2-aminoethoxy)benzoyl]amino}-2-methylindolizin-3-yl)carbonyl]-2-[(trifluoroacetyl)amino]benzoate (described in stage F, Example 42) with N-tert-butoxycarbonylglycine is carried out. The compound obtained is then deprotected with trifluoroacetic acid to give the amine according to the process described in stage F of Example 42.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH2:13][OH:14])[CH:9]=[CH:10][C:11]=1[I:12])[CH2:2][CH2:3][CH3:4]>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][C:11]=1[I:12])[CH:13]=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(CO)ccc1I
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCCCOc1cc(C=O)ccc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
89.5 g (0.875 mol, 7 eq) of manganese dioxide are added to a solution of 38.30 g (0.125 mol, 1 eq) of (3-butoxy-4-iodophenyl)methanol in 250 mL of dichloromethane. The reaction medium is stirred at room temperature for 18 hours and then filtered through silica gel. The solvent is evaporated off to give 29.61 g of 3-butoxy-4-iodobenzaldehyde in the form of an orange-colored oil. Yield=78%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[F:17][CH:18]([F:35])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:28]=[N:29][C:30]([CH:33]=[CH2:34])=[CH:31][CH:32]=2)=[CH:22][CH:21]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd]>[F:35][CH:18]([F:17])[O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:28]=[N:29][C:30](/[CH:33]=[CH:34]/[C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][O:12]3)[N:6]=[CH:5]4)=[CH:31][CH:32]=2)=[CH:22][CH:21]=1
Reactant: C=Cc1ccc(Nc2ccc(OC(F)F)cc2)nn1
Reactant: Ic1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: FC(F)Oc1ccc(Nc2ccc(/C=C/c3ccc4c(cnn4C4CCCCO4)c3)nn2)cc1
Temperature: 90 °C

Procedure:
To a solution of 5-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (0.1 g, 0.305 mmol) in ACN (5 mL) were added N-(4-(difluoromethoxy)phenyl)-6-vinylpyridazin-3-amine (0.080 g, 0.305 mmol), tri-o-tolylphosphine (0.037 g, 0.122 mmol), and triethylamine (0.127 mL, 0.914 mmol). The reaction mixture was purged with nitrogen for 5 min. Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (0.032 g, 0.030 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. The reaction mixture was filtered through a pad of celite and rinsed with ethyl acetate. The organic layer was concentrated and purified by flash chromatography on silica gel using ethyl acetate/hexane to give (E)-N-(4-(difluoromethoxy)phenyl)-6-(2-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)vinyl)pyridazin-3-amine as apale yellow solid (0.13 g, 87%). LCMS (ES-API), m/z 464.6 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([OH:16])=O)[CH:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]([NH2:31])[CH3:30])[CH:26]=[CH:27][CH:28]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([CH:18]3[CH2:20][CH2:19]3)[C:10](=[O:17])[N:11]([CH2:13][C:14]([NH:31][CH:29]([C:25]3[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[CH3:30])=[O:16])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CC(N)c1cccc(C(F)(F)F)c1
Reactant: O=C(O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(NC(=O)Cn1cc(-c2ccc(Br)cc2)n(C2CC2)c1=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.119 mmol) of 4-(4-bromophenyl)-3-cyclopropyl-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 129A, 24.7 mg (0.130 mmol) of 1-[3-(trifluoromethyl)phenyl]ethylamine and 19.2 mg (0.142 mmol) of HOBt are placed in 1.5 ml of dimethylformamide and treated with 29.6 mg (0.154 mmol) of EDC hydrochloride. This is stirred overnight at room temperature, then stirred with 15 ml of water, and the resulting precipitate is isolated and this crude product purified by preparative HPLC [Method 13]. 23 mg (38% of theory) of the target compound are thus obtained.
Reaction SMILES: C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N.C(SC)(=S)O[CH:28]([C:30]1[C:31]([O:65][CH3:66])=[N:32][C:33](/[C:36](/[C:55]2[CH:60]=[CH:59][C:58]([C:61]([CH3:64])([CH3:63])[CH3:62])=[CH:57][CH:56]=2)=[CH:37]/[C@H:38]2[CH2:42][CH2:41][C:40](=[O:43])[N:39]2[CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=2[O:53][CH3:54])=[CH:34][CH:35]=1)[CH3:29].O>C1(C)C=CC=CC=1>[C:61]([C:58]1[CH:59]=[CH:60][C:55](/[C:36](/[C:33]2[CH:34]=[CH:35][C:30]([CH2:28][CH3:29])=[C:31]([O:65][CH3:66])[N:32]=2)=[CH:37]\[C@@H:38]2[N:39]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=3[O:53][CH3:54])[C:40](=[O:43])[CH2:41][CH2:42]2)=[CH:56][CH:57]=1)([CH3:63])([CH3:62])[CH3:64]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C(C)OC(=S)SC)c(OC)n2)c(OC)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1ccc(/C(=C/[C@H]2CCC(=O)N2Cc2ccc(OC)cc2OC)c2ccc(C(C)(C)C)cc2)nc1OC
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 71.6 %

Procedure:
Tributyltin hydride (91 μL) and azobisisobutyronitrile (8.5 mg) were added to a solution of O-[1-(6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridin-3-yl)ethyl] S-methyl carbonodithioate (109 mg) in toluene (2 mL), and the mixture was stirred at 120° C. for 30 minutes. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give (5R)-5-[(E)-2-(4-tert-butylphenyl)-2-(5-ethyl-6-methoxypyridin-2-yl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one as a colorless oil (65 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][CH:25]=1)[O:18][CH2:19][C:20](O)=[O:21])=[O:14])[CH3:11]>ClCCCl>[Cl:3][C:20](=[O:21])[CH2:19][O:18][C:17]1[CH:16]=[C:15]([CH:25]=[CH:24][CH:23]=1)[C:13]([O:12][CH2:10][CH3:11])=[O:14]
Reactant: CCOC(=O)c1cccc(OCC(=O)O)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(OCC(=O)Cl)c1

Procedure:
32.5 ml (0.45 mol) of thionyl chloride and 10 μl of N,N-dimethylformamide are added to a solution of 20.0 g (89.2 mmol) of [3-(ethoxycarbonyl)phenoxy]acetic acid (A. Banerjee, M. M. Adak, S. Das, S. Banerjee, S. Sengupta, Indian Chem. Soc., 1987, 64, 1, 34-37) in 200 ml of 1,2-dichloroethane. The mixture is refluxed for 1 hour and is then concentrated to dryness and dried under vacuum at 50° C. overnight and used as it is in the subsequent stage.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[CH3:22][CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][CH3:28].C([BH3-])#N.[Na+]>ClCCl.C(O)(=O)C>[CH3:22][CH2:23][CH2:24][CH:25]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:17][OH:18])([CH2:19][OH:20])[CH2:15][CH2:14][C:13]1=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)CCC
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCC(CCC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-(hydroxymethyl)pyrrolidin-2-one (0.15 g, 0.51 mmol) from Example 6 in 1 mL of dichloromethane and 0.3 mL of acetic acid was treated with 4-heptanone (0.175 g, 1.53 mmol) and sodium cyanoborohydride (0.05 g, 0.8 mmol). The resulting mixture was stirred at ambient temperature for 12 h after which time addition 4-heptanone (0.175 g, 1.53 mmol), sodium cyanoborohydride (0.05 g, 0.8 mmol) and acetic acid (0.3 mL) were added. Stirring was continued for 12 h. The reaction mixture was quenched with 10 mL of a saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetic (3×50 mL). The combined extracts were dried and concentrated. The residue was purified by chromatography (silica gel; 5% ethanol in ether) to give 0.15 g (75%) of 1-[2-(4-heptylamino)-4-methoxycarbonylphenyl]-5,5-bis-(hydroxymethyl)pyrrolidin-2-one as a white solid, mp 139-140° C.
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.N1C=CC=CC=1C=O.[CH2:35]([O:42][C:43](=[O:52])[C:44]1[CH:49]=[C:48]([NH2:50])[CH:47]=[CH:46][C:45]=1[CH3:51])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([O:42][C:43](=[O:52])[C:44]1[CH:49]=[C:48]([NH:50][C:24]([C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:25])[CH:47]=[CH:46][C:45]=1[CH3:51])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(O)c1nc(-c2ccccn2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(N)cc1C(=O)OCc1ccccc1
Agent: O=Cc1ccccn1
Product: Cc1ccc(NC(=O)c2nc(-c3ccccn3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)cc1C(=O)OCc1ccccc1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carboxylic acid (prepared according to the procedure of Example 70, steps a and b, with the modification that pyridine-2-carboxaldehyde was used instead of 2-dimethylamino-benzaldehyde in step a) was reacted with 5-amino-2-methyl-benzoic acid benzyl ester according to the procedure of Example 177, step a to afford 5-{[5-(2-adamantan-1-yl-ethyl)-2-pyridine-2-yl-1H-imidazole-4-carbonyl]-amino}-2-methyl-benzoic acid benzyl ester. The benzyl group was removed following the procedure of Example 1, step e, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 13.18 (1H, br s), 9.71 (1H, br s), 8.66 (1H, d), 8.32 (1H, s), 8.25 (1H, d), 7.96 (1H, td), 7.86 (1H, dd), 7.44 (1H, m), 7.24 (1H, d), 2.98 (2H, m), 2.48 (3H, s),1.94 (3H, br s), 1.63 (6H, m), 1.53 (6H, m), 1.42 (2H, m). The product was converted to the L-tartaric acid salt and lyophilised from water/dioxan. Found: C, 59.07; H, 6.40; N, 8.28%. C33H38N4O8.2.0 mols H2O requires: C, 59.10; H, 6.31; N, 8.35%.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:9](C(OCC)=O)[C:10]([O:12]CC)=O)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.NC1C(Cl)=NC(C(C(OCC)=O)C(OCC)=O)=CC=1.C(OCC)(=O)CC(OCC)=O>Cl>[Cl:8][C:5]1[N:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:10](=[O:12])[CH2:9]2
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(Cl)ccc1N
Agent: CCOC(=O)C(C(=O)OCC)c1ccc(N)c(Cl)n1
Agent: Cl
Solvent: CCOC(=O)CC(=O)OCC
Product: O=C1Cc2nc(Cl)ccc2N1

Procedure:
The mixture containing 3-amino-2-bis(ethoxycarbonyl)methyl-6-chloropyridine, 3-amino-6-bis(ethoxycarbonyl)methyl-2-chloropyridine and diethyl malonate was taken up in 6N HCl solution (700 mL) and heated at reflux for 5 hours. After removing the aqueous acid in vacuo, the residue was taken up in water and again concentrated to yield 5-chloro-4-azaoxindole as a brown solid which was dried in the air. The yield was 7.04 g. (32% overall from 2,6-dichloro-3-nitropyridine). An analytical sample was prepared by recrystallization from isopropanol; m.p. 250°-254° C. (dec.).
Reaction SMILES: [C:1]([NH:9][N:10]=[C:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](OC)=[O:13])(=O)[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.O.[NH2:23][NH2:24]>N1C=CC=CC=1>[CH:2]1([C:1]2[N:23]([NH2:24])[C:12](=[O:13])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:10][N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: NN
Reactant: COC(=O)C(=NNC(=O)C1CCCCC1)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Nn1c(C2CCCCC2)nnc(-c2ccccc2)c1=O
Yield: 19.6 %

Procedure:
28.8 g (0.1 mol) of phenylglyoxylic acid methyl ester-2-hexahydrobenzoylhydrazone and 10 g of hydrazine hydrate (0.2 mol) were stirred in 100 ml of pyridine, which had been dried over potassium hydroxide, for 45 minutes at 100°C and the mixture was subsequently cooled. Thereupon, the mixture solidifed to a paste. 100 ml of water were added and the whole was stirred for some hours and the product filtered off. After washing with water and drying, 5.3 g (19.7% of theory) of 3-cyclohexyl-4-amino-6-phenyl-5-H-1,2,4-triazin-5-one were obtained in colorless flakes of melting point 178°-180°C.