Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([Sn](C)(C)C)=[N:17][N:18]2[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)=[CH:14][CH:13]=1)[CH3:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45](I)=[N:46][C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1(C)C=CC=CC=1.[Cu]I.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:31]([O:35][C:36]([N:38]1[CH2:43][CH2:42][C:41]2[N:44]([CH2:48][O:49][CH2:50][CH2:51][Si:52]([CH3:55])([CH3:54])[CH3:53])[C:45]([C:16]3[C:15]4[C:19](=[CH:20][C:12]([C:4]5[CH:5]=[C:6]([F:11])[C:7]([O:9][CH3:10])=[CH:8][C:3]=5[CH2:1][CH3:2])=[CH:13][CH:14]=4)[N:18]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:17]=3)=[N:46][C:40]=2[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c([Sn](C)(C)C)nn(C3CCCCO3)c2c1
Reactant: CC(C)(C)OC(=O)N1CCc2c(nc(I)n2COCC[Si](C)(C)C)C1
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(-c3nc4c(n3COCC[Si](C)(C)C)CCN(C(=O)OC(C)(C)C)C4)nn(C3CCCCO3)c2c1
Temperature: 100 °C
Yield: 74.2 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-1-(tetrahydro-pyran-2-yl)-3-trimethylstannanyl-1H-indazole (Preparation 18, 735 mg, 1.53 mmol) in toluene (6 mL) was added 2-iodo-1-(2-trimethylsilanyl-ethoxymethyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (Preparation 22, 805 mg, 1.68 mmol), copper (1) iodide (60 mg, 310 μmol) and tetrakis(triphenylphosphine) palladium(0) (173 mg, 150 μmol). The reaction mixture was degassed with nitrogen, heated at 100° C. for 18 hours, cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 20% EtOAc in toluene to give the title compound as a foam (801 mg) in a 74% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O1CCCC1.C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)([C:14]([OH:16])=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(CC2(C(=O)OCc3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1ccc(CC2(C(=O)O)CCN(C(=O)OC(C)(C)C)CC2)cc1

Procedure:
To a solution of 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid 4-benzyl ester 1-tert-butyl ester (10.65 mmol; 4.98 g) in tetrahydrofuran (20 mL) and ethanol (40 mL) was added 10% palladium on carbon (3 g), and the resulting mixture was hydrogenated under 50 psi of hydrogen pressure for 5 hours at room temperature. The catalyst was removed via filtration, and the filtrate was evaporated to yield 4-(4-methoxycarbonyl-benzyl)-piperidine-1,4-dicarboxylic acid mono-tert-butyl ester. 1H-NMR (CDCl3): 7.95 (2H, d), 7.19 (2H, d), 3.90 (3H, s), 2.92 (4H, m), 2.05 (2H, s), 1.40-1.70 (4H, m), 1.45 (9H, s).
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN(C)C=O>[CH2:24]([N:26]([CH2:2][C:3]1[O:7][C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)=[N:5][N:4]=1)[CH2:27][CH3:28])[CH3:25]
Reactant: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccccc2C1=O
Reactant: CCNCC
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nnc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)o1
Yield: 84.6 %

Procedure:
0.33 g (1 mmol) of 3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one was stirred at room temperature overnight with 2 ml (2 mmol) of diethylamine and 5 ml of N,N-dimethylformamide. After evaporation of the reaction mixture and chromatography of the residue on silica gel while eluting with ethyl acetate/ethanol 9/1 there was obtained 0.31 g (84%) of 3-(5-diethylaminomethyl-1,3,4-oxadiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 235°-238°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH2:12])=[CH:7][CH:6]=[CH:5]2.[CH2:13]([N:20]([CH2:24][CH2:25]Cl)[CH2:21][CH2:22]Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(C(C)C)CC)(C)C.C(O)(C)C>C(OCC)(=O)C>[CH2:13]([N:20]1[CH2:24][CH2:25][N:12]([C:8]2[C:9]3[C:4](=[CH:3][C:2]([F:1])=[CH:11][CH:10]=3)[CH:5]=[CH:6][CH:7]=2)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: Nc1cccc2cc(F)ccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Fc1ccc2c(N3CCN(Cc4ccccc4)CC3)cccc2c1
Yield: 75.4 %

Procedure:
To a 125 ml round-bottomed flask equipped with condenser and N2 inlet were added 1.0 g (6.21 mmol) of 6-fluoro-1-amino naphthalene, 1.8 g (7.76 mmol) of N-benzyl bis(2-chloroethyl)amine, 3.3 ml (19.2 mmol) of diisopropylethylamine, and 50 ml isopropanol. The reaction was refluxed 24 hours, cooled, and evaporaated to an oil. The oil was taken up in ethyl acetate, washed with waterand brine, dried over sodium sulfate, and evaporated to an oil. The oil was chromatographed on silica gel using methylene chloride as eluent to afford 1.5 g (75.5%) of an oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH:34]3[CH2:36][CH2:35]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:37]([S:39](Cl)(=[O:41])=[O:40])[CH3:38]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])[N:18]=[C:17]([CH:34]3[CH2:36][CH2:35]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCN
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)NCCOc1nc(C2CC2)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
According to Example 40) 256 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide was reacted with ethanesulfonylchloride to give 120 mg 4-tert.-butyl-N-[6-(2-ethanesulfonylamino-ethoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-pyrimidin-4-yl]-benzene-sulfonamide. LC-MS: tR=5.79 min. [M−1]−=603.90.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]C.C1(C#C)C=CC=CC=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[C:22]#N>C(#N)C1C=CC=CC=1>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:21]([C:22]#[C:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH:20]=1
Reactant: COc1cccc(C#N)c1
Reactant: C#CCCCCCC
Solvent: C#Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: CCCCCCC#Cc1cccc(OC)c1
Reaction time: 23 h
Yield: 80 %

Procedure:
The procedure was identical to Example 1, with the exception that 1-octyne (0.590 ml; 0.441 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 3-methoxybenzonitrile (0.245 ml; 0.266 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 23 h at 65° C. showed the presence of 1.60 mmol (80% yield) of 1-methoxy-3-(1-octynyl)benzene and no remaining 3-methoxybenzonitrile in the reaction mixture.
Reaction SMILES: I[C:2]1([CH2:17][C:18]([OH:20])=[O:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1.C1CCCCC=1.[N+:27]([O-:32])([N+]([O-])=O)=[O:28]>C(Cl)(Cl)Cl>[N+:27]([C:2]1([CH2:17][C:18]([OH:20])=[O:19])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:9]=[C:5]2[CH:6]=[CH:7][CH:8]=[C:4]2[O:3]1)([O-:32])=[O:28]
Reactant: O=C(O)CC1(I)OC2=CC=CC2=CC1c1ccccc1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: C1=CCCCC1
Product: O=C(O)CC1([N+](=O)[O-])OC2=CC=CC2=CC1c1ccccc1
Reaction time: 20 h

Procedure:
To a solution of 2.2 g. (5.8 mmoles) of 2-iodo-3-phenyl-7-benzofuranacetic acid, 1 g. (5.8 mmoles) of cyclohexene and 175 ml. of chloroform is added 0.9 g. (10 mmoles) of dinitrogen tetroxide in 15 ml. of chloroform. The mixture is stirred for 20 hours, washed with water and made basic with sodium hydroxide. The chloroform layer is acidified with hydrochloric acid, washed with water twice and dried, then evaporated to provide 2-nitro-3-phenyl-7-benzofuranacetic acid, identical to the sample prepared in Example 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22](O)=[O:23]>>[CH3:18][C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([CH3:28])[CH:27]=1)[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:23]
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: Cc1cc(C)cc(C(=O)O)c1
Product: Cc1cc(C)cc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)c1
Yield: 94.3 %

Procedure:
Beginning with 10.0 mg (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 19.6 mg (0.131 mMol) 3,5-dimethylbenzoic acid, 15.0 mg (95%) of the title compound were recovered.
Reaction SMILES: Br[CH2:2][C:3]([O:5]CC)=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:34][CH:35]=[N:36][C:37]#[N:38])[C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:26])[C:21](=[O:27])[CH:20]=[C:19]3[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[CH:11][CH:10]=1.[K].[CH3:40][C:41](O)(C)C.O>CS(C)=O.C(OCC)(=O)C>[CH2:40]([CH:2]([C:3]([OH:5])=[O:4])[N:34]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=1)[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]([CH3:26])[C:21](=[O:27])[CH2:20][CH:19]2[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:35]=[N:36][C:37]#[N:38])[CH3:41]
Reactant: Cn1c(=O)cc(-c2ccccc2)c2cc(C(NC=NC#N)c3ccc(Cl)cc3)ccc21
Reactant: CC(C)(C)O
Reactant: CCOC(=O)CBr
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C(=O)O)N(C=NC#N)C(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1ccccc1)CC(=O)N2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-bromoacetate (2.45 ml) was added dropwise at 5° C. to a solution of intermediate (5-c) (9 g) and 2-methyl-2-propanol potassium salt (2.37 g) in dimethyl sulfoxide (100 ml) and the mixture was stirred at room temperature overnight. Water and ethyl acetate were added, the organic layer was decanted, dried (MgSO4), filtered off and evaporated till dryness. The product was used without further purification, yielding (±)-ethyl N-[(4-chlorophenyl)(2,3-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)-methyl]-N-[(cyanoimino)methyl]glycine (interm. 5-d).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C:31]([C:34](=[O:39])[NH:35][CH2:36][CH2:37][OH:38])([CH3:33])[CH3:32])=[CH:19][CH:18]=1)#[N:2].CCN(C(C)C)C(C)C.[CH3:49][C:50]([Si:53](Cl)([CH3:55])[CH3:54])([CH3:52])[CH3:51].[OH-].[Na+]>CN(C1C=CN=CC=1)C.C1COCC1>[C:50]([Si:53]([CH3:55])([CH3:54])[O:38][CH2:37][CH2:36][NH:35][C:34]([C:31]([CH3:33])([O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[O:23][C:20]1[CH:19]=[CH:18][C:17]([NH:16][C:4]2[C:5]3[N:6]([CH:9]=[C:10]([C:13]([OH:15])=[O:14])[C:11]=3[CH3:12])[N:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:22][CH:21]=1)[CH3:32])=[O:39])([CH3:52])([CH3:51])[CH3:49]
Reactant: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO)cc3)c12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C(=O)O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4OC(C)(C)C(=O)NCCO[Si](C)(C)C(C)(C)C)cc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of 433F (164 mg, 0.31 mmol), DIEA (0.27 ml, 1.55 mmol), DMAP (7.6 mg, 0.062 mmol) and TBSCl (140 mg, 0.93 mmol) in THF (4 ml) was stirred under argon at rt for 2 h. 1N NaOH (0.70 ml, 0.70 mmol) was added. The resulting mixture was stirred at rt for 1 h. Removal of the solvent followed by flash chromatography of the residue of silica gel (2%-5% MeOH—CH2Cl2) gave 433G (75 mg, 38%) as a yellow oil. It has a retention time of 7.43 min (standard LC1 method, 8 min run). MS Found: (M+H)+=644.0
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1B(O)O.[OH:12]O>O1CCCC1.[OH-].[Na+]>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:12]
Reactant: OO
Reactant: OB(O)c1cccc(F)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1cccc(F)c1Cl
Reaction time: 2 h

Procedure:
To a solution of 2-chloro-3-fluorophenylboronic acid (5.0 g) in tetrahydrofuran (50 mL) and 1M aqueous NaOH (30 mL) at 0° C. was added 30% hydrogen peroxide solution (4 mL), and the reaction was stirred for 2 hours. The reaction was quenched with saturated aqueous Na2S2O3 solution, acidified with concentrated aqueous HCl, and extracted twice with ethyl acetate. The combined extracts were washed with brine, concentrated, and chromatographed on silica gel using 10% ethyl acetate/hexanes as eluent to give the product.
Reaction SMILES: C(OC([NH:8][C:9]([CH3:48])([CH3:47])[CH2:10][O:11][C:12]1[CH:46]=[CH:45][C:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[C:33]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH:32]=[CH:31][C:30]=3[CH2:29]2)=[CH:14][CH:13]=1)=O)(C)(C)C.FC(F)(F)C(O)=O.O1CCCC1.N>ClCCl>[NH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:16][CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[C:33]([O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])[CH:32]=[CH:31][C:30]=3[CH2:29]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)NC(=O)OC(C)(C)C)cc2)c1
Agent: N
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(OCC(C)(C)N)cc2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.3 %

Procedure:
To a solution of pivalic acid 6-{2-{[4-(2-tert-butoxycarbonylamino-2-methylpropoxy)benzyl]ethylamino}-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (90 mg) in dichloromethane (1.5 ml) was added trifluoroacetic acid (0.2 ml), and the solution was stirred for 1.5 hours at room temperature. The solution was neutralized by sequentially adding tetrahydrofuran and aqueous ammonia, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (72 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][OH:9])=[CH:4][CH:3]=1.[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C(C2C=CC=CC=2)=[N+](Cl)[O-])C=CC=CC=1>C(O)C>[C:11]1([CH:10]=[N+:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[O-:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: ONc1ccc(Cl)cc1
Agent: [O-][N+](Cl)=C(c1ccccc1)c1ccccc1
Solvent: CCO
Product: [O-][N+](=Cc1ccccc1)c1ccc(Cl)cc1

Procedure:
p-Chlorophenylhydroxylamine (0.05 moles) was dissolved in warm 95% ethanol (20 cc) and was treated with benzaldehyde (0.05 moles) with vigorous stirring. The solid which formed was collected, washed with 95% ethanol, and recrystallized from ethanol to give 512 g. of α-phenyl-N-chlorophenylnitrone (m.p. 179°-82°).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1.O>CS(C)=O.C(OCC)(=O)C>[N+:8]([C:4]1[CH:3]=[C:2]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH2:19][CH2:18]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: C1CC(N2CCOCC2)CCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cccc(N2CCC(N3CCOCC3)CC2)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
1-Fluoro-3-nitro-benzene (1.00 g, 0.00709 mol) and Potassium carbonate (1.47 g, 0.0106 mol) were dissolved in Dimethyl sulfoxide (7.50 mL) and 4-Piperidin-4-yl-morpholine (2.41 g, 0.0142 mol) was added. The reaction was allowed to stir overnight at 90° C. Upon completion of the reaction, the mixture was diluted with ethyl acetate and was poured over water. Combined extracts were then washed with brine and the organics were dried over magnesium sulfate, filtered and reduced. The crude mixture was purified by Isco flash column chromatography (Hexane/Ethyl Acetate). Combined fractions were reduced en vacuo to afford 1.60 g of 4-[1-(3-Nitro-phenyl)-piperidin-4-yl]-morpholine.
Reaction SMILES: [K].[CH2:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[N:12][NH:13][C:7]=2[N:6]=[C:5]1[SH:14])[CH3:3].[CH3:15]I>CN(C=O)C>[CH2:2]([N:4]1[C:9](=[O:10])[C:8]2[CH:11]=[N:12][NH:13][C:7]=2[N:6]=[C:5]1[S:14][CH3:15])[CH3:3]
Reactant: CCn1c(S)nc2[nH]ncc2c1=O
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CCn1c(SC)nc2[nH]ncc2c1=O
Reaction time: 1 h
Yield: 65.1 %

Procedure:
To a solution of 5-ethyl-6-mercapto-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one potassium (5.0 g) in DMF (40 ml) was added methyl iodide (3.65 g) and the mixture was stirred for 1 hour. This reaction mixture was concentrated and the residue was diluted with water. The resulting crystals were collected by filtration and rinsed with water to provide 5-ethyl-6-methylthio-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one as colorless solid (2.908 g).
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10]([O:21][CH3:22])([O:19][CH3:20])[C:11](=[O:18])[CH2:12][CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C)P(N(C)C)(N(C)C)=O>O1CCCC1.[Cl-].[NH4+]>[CH3:22][O:21][C:10]([O:19][CH3:20])([O:9][CH3:8])[C:11](=[O:18])[CH2:12][CH:13]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CCC(=O)C(OC)(OC)OC
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C(CC(=O)C(OC)(OC)OC)Cc1ccccc1
Temperature: -78 °C

Procedure:
To a solution of 0.98 ml diisopropylamine in 13 ml anhydrous tetrahydrofuran 4.29 ml 1.5M n-butyllithium (in hexane solution) was added under nitrogen gas atmosphere, while stirring the solution at -78° C. After the mixture was stirred for 15 minutes, a solution of 1.18 g dimethyl 2-oxoglutarate dimethyl ketal in 7 ml anhydrous tetrahydrofuran was added over a period of 15 minutes, then the resulting mixture was stirred for 15 minutes. A solution of 0.76 ml benzyl bromide and 0.28 ml hexamethylphosphoramide in 7 ml anhydrous tetrahydrofuran was added over a period of 5 minutes, and the resulting mixture was stirred at -78° C. for 30 minutes. The reaction mixture, after raising temperature to -20° C. over a period of 2 hours with stirring, was diluted with a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The resulting extract was washed with water and dried (MgSO4), then the solvent was evaporated. The resulting residue was eluted with hexane-ethyl acetate (5:1→2:1) via column chromatography using silica gel to yield 1.64 g dimethyl 4-benzyl-2-oxoglutarate dimethyl ketal in the form of a light yellow oily substance.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[CH:23][N:22]=[C:21]([NH:31][CH2:32][CH2:33][NH:34]C2N=CC(C#N)=CC=2)[N:20]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[C:19]1[C:24]([C:25]2[NH:26][CH:27]=[C:28]([CH3:30])[N:29]=2)=[CH:23][N:22]=[C:21]([NH:31][CH2:32][CH2:33][NH:34][C:2]2[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][N:7]=2)[N:20]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1c[nH]c(-c2cnc(NCCNc3ccc(C#N)cn3)nc2-c2ccc(Cl)cc2Cl)n1
Product: Cc1c[nH]c(-c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)n1

Procedure:
[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine was prepared from 6-chloro-3-nitropyridine using the general method for 6-[(2-{[4-(2,4-dichlorophenyl)-5-(4-methylimidazol-2-yl)pyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9]Cl)=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[NH2:25][CH2:26][C:27]1[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]([C:6]2[C:7]3[CH2:8][CH2:9][N:25]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)[C:2]=3[N:3]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:5]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: NCc1cccnc1
Reactant: COc1cccc(-c2nc(N3CCOCC3)nc(Cl)c2CCCl)c1
Product: COc1cccc(-c2nc(N3CCOCC3)nc3c2CCN3Cc2cccnc2)c1

Procedure:
In the same manner as Example 1-A-01, from 4-[4-chloro-5-(2-chloroethyl)-6-(3-methoxyphenyl)-pyrimidin-2-yl]-morpholine and 3-aminomethylpyridine, the desired compound was obtained.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.[CH:18]1[CH:19]=CC2N(O)N=[N:24][C:22]=2[CH:23]=1.CCN(C(C)C)C(C)C.N1CCCC1.CCN=C=NCCCN(C)C>CN(C=O)C>[O:17]=[C:15]([N:24]1[CH2:19][CH2:18][CH2:23][CH2:22]1)/[CH:14]=[CH:13]/[C:8]1[CH:7]=[C:6]2[C:11](=[N:10][CH:9]=1)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]2
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CCCC3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (50 mg, 0.20 mmol), DMF (4.8 mL), HOBt (32 mg, 0.23 mmol), DIPEA (78 μL, 0.47 mmol), pyrrolidine (20 μL, 0.23 mmol) and EDAC (45 mg, 0.23 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was diluted in dichloromethane and washed with water. The organic layer was concentrated to dryness and the residue was purified on preparative TLC (eluent: dichloromethane/MeOH, 95/5) to give the title compound (33 mg, 62%) as a white solid.
Reaction SMILES: Cl.O.[C:3]([O:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[CH:11]=[CH:10][C:9]=1[Cl:17])(=[O:5])[CH3:4]>C(O)C.[Fe]>[C:3]([O:6][C:7](=[O:18])[C:8]1[CH:13]=[C:12]([NH2:14])[CH:11]=[CH:10][C:9]=1[Cl:17])(=[O:5])[CH3:4]
Reactant: CC(=O)OC(=O)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(=O)OC(=O)c1cc(N)ccc1Cl
Yield: 88.2 %

Procedure:
24 g of iron powder was added to a solution of 1.6 ml of concentrated HCl, 16.8 ml of water, and 70 ml of ethanol. 29.6 g of the 2-chloro-5-nitrobenzoyl acetate prepared above in Step 2 dissolved in 45 ml of ethanol, was then added to the mixture in three equal portions. The resultant reaction mixture was refluxed for 5 hours. An additional 2.4 g of iron and 0.1 ml of concentrated HCl was then added to the reaction mixture. The reaction mixture was then refluxed for an additional one hour, filtered through Celite and evaporated. 100 ml of water was then added to the evaporated material and the resultant mixture was extracted with 100 ml of ether. The ether solution was washed with water, dried over magnesium sulfate, and evaporated, to produce 22.9 g of 5-amino-2-chlorobenzoyl acetate as an oil.