Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:24](=[O:26])[NH:23][CH:22]=[N:21][C:20]=3[O:19][CH:18]=2)=[CH:13][CH:12]=1)[CH3:10]>C(#N)C.ClC(Cl)(Cl)Cl>[CH2:9]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:24](=[O:26])[NH:23][CH:22]=[N:21][C:20]=3[O:19][C:18]=2[I:1])=[CH:15][CH:16]=1)[CH3:10]
Reactant: CCc1ccc(-c2coc3nc[nH]c(=O)c23)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCc1ccc(-c2c(I)oc3nc[nH]c(=O)c23)cc1
Temperature: 25 °C

Procedure:
Add 7.0 g (31.3 mmol) of N-iodosuccinimide to a solution of 5.0 g (20.9 mmol) of 5-(4-ethylphenyl)furo[2,3-d]pyrimidin-4(3H)-one in 250 ml of acetonitrile/tetrachloromethane (1:1). Stir the resulting suspension under reflux for two hours. After cooling to room temperature, concentrate the reaction mixture under reduced pressure. Stir the residue in ethyl acetate and filter. Add water to the filtrate. After removal of the organic phase, extract the aqueous phase repeatedly with ethyl acetate. Concentrate the combined organic phases under reduced pressure. Take up the residue in ethyl acetate and chromatograph it on silica gel (eluent: cyclohexane/ethyl acetate 1:1→1:2). Stir the resulting solid in diethyl ether/n-pentane and filter. 1.4 g (85% purity, 16% of theory) of the target compound are obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.CS(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[O:27][CH:28]=2)=[CH:18][CH:17]=1)(=O)=O>>[CH3:1][C:2]1[N:3]([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[O:27][CH:28]=3)=[CH:20][CH:21]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: CS(=O)(=O)OCCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: Cc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Yield: 42 %

Procedure:
In substantially the same manner as in Working Example 8, 2-methylimidazole was allowed to react with 4-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]butyl methanesulfonate to give 4-[4-[4-(2-methyl-1-imidazolyl)butyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 42%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 122-123° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[C:22]([Cl:27])[CH:21]=3)[CH2:9][C:8]([CH2:29][CH3:30])([CH3:28])[C:7]=2[N:6]=1)=[O:4].[OH-].[Na+]>O1CCCC1.CO.O>[Cl:27][C:22]1[CH:21]=[C:20]([CH:10]2[CH2:9][C:8]([CH2:29][CH3:30])([CH3:28])[C:7]3[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13][C:12]=3[N:11]2[CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:25]=[CH:24][C:23]=1[F:26]
Reactant: CCC1(C)CC(c2ccc(F)c(Cl)c2)N(CCC(C)C)c2ccc(C(=O)OC)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCC1(C)CC(c2ccc(F)c(Cl)c2)N(CCC(C)C)c2ccc(C(=O)O)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.8 %

Procedure:
To a solution of 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid methyl ester (100 mg, 0.2 mmol) in tetrahydrofuran (2 mL) and methanol (2 mL) was added 3 N sodium hydroxide (1 mL). The reaction mixture was stirred at room temperature for 16 hours, and then diluted with water (10 mL), extracted with diethyl ether (20 mL). The organic layer was discarded. The aqueous layer was acidified with concentrated hydrochloric acid to pH 4 and extracted with ethyl acetate (40 mL×3), and the combined organics were dried over anhydrous Na2SO4. The solvent was removed in vacuo and purified by preparative HPLC to afford 6-(3-chloro-4-fluoro-phenyl)-8-ethyl-8-methyl-5-(3-methyl-butyl)-5,6,7,8-tetrahydro-[1,5]naphthyridine-2-carboxylic acid (30 mg, 31.3%) as a yellow oil. MS (ESI+) [(M+H)+] 419.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:11]2[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[CH:25][CH:24]=1.Cl.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([CH2:27][OH:28])=[CH:25][CH:24]=2)[C:11]2[S:12][CH:13]=[C:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: CC(C)c1csc(NCCc2ccc(F)cc2)n1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)c1csc(N(CCc2ccc(F)cc2)Cc2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of N-[2-(4-fluorophenyl)ethyl]-4-isopropyl-1,3-thiazole-2-amine (550 mg), sodium hydride (80 mg) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 1 hr. Methyl 4-(bromomethyl)benzoate (500 mg) was added to the reaction mixture under ice-cooling, and the mixture was allowed to warm to room temperature and further stirred for 1 hr. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9-1:1 in volume ratio) to give a yellow oil. The yellow oil was dissolved in tetrahydrofuran (30 mL) and lithium aluminum hydride (80 mg) was added by small portions under ice-cooling. The reaction mixture was stirred under ice-cooling for 30 min and sodium sulfate 10 hydrate (1.0 g) was added. The mixture was allowed to warm to room temperature and stirred for 30 min. The resulting precipitate was filtered off and the filtrate was concentrated to give the title compound (720 mg, yield 90%) as a yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:27][CH2:28][CH3:29])[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[CH:9]=[O:10])[CH3:2].P([O-])(O)(O)=[O:31].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>C(O)(C)(C)C.C(OCC)(=O)C.O>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:6]2[C:7](=[O:11])[C:8]([C:9]([OH:31])=[O:10])=[C:3]([CH2:1][CH3:2])[N:4]=[C:5]2[CH2:27][CH2:28][CH3:29])=[CH:14][CH:15]=1)#[N:26]
Reactant: O=P([O-])(O)O
Reactant: CCCc1nc(CC)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(CC)c(C(=O)O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a solution of 4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), sodium dihydrogen phosphate (0.93 g) and 2-methyl-2-butene (4 mL) in tert-butyl alcohol (10 mL)—water (8 mL) was added sodium chlorite (0.7 g), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a colorless solid (0.53 g, 100%).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:21]COC)=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:18])\[C:15]([OH:17])=[O:16])[CH3:2]>CC(C)=O>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([OH:21])=[C:6]([O:19][CH3:20])[CH:7]=[C:8]2/[CH:13]=[C:14](/[CH3:18])\[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OCOC)c12
Solvent: CC(C)=O
Product: CCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Yield: 87.4 %

Procedure:
66 g of (Z)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-methylpropenoic acid was dissolved in 700 ml of acetone in which nitrogen has been preliminarily bubbled, and 43 ml of concentrated hydrochloric acid was gradually added while stirring at room temperature in a stream of nitrogen under light-shielded conditions. After stirring at room temperature for 1.5 hours, the reaction mixture was gradually poured into water to crystalize. The crystals were filtered, washed with water and dried to obtain 50.0 g of the titled compound as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH2:18][C:19]([O:21]C)=[O:20])[CH2:13][C:14]([O:16]C)=[O:15])[C:6]2=[O:11].O1CCCC1>C(=O)([O-])[O-].[K+].[K+]>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]([CH2:13][C:14]([OH:16])=[O:15])[CH2:18][C:19]([OH:21])=[O:20])[C:6]2=[O:11]
Reactant: COC(=O)CC(CC(=O)OC)N1Cc2c(N)cccc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Nc1cccc2c1CN(C(CC(=O)O)CC(=O)O)C2=O
Temperature: 50 °C
Reaction time: 5 h
Yield: 81 %

Procedure:
A mixture of dimethyl 3-(4-amino-1,3-dihydro-1-oxo-2H-isoindol-2-yl)-glutarate (5 g) and tetrahydrofuran (14 ml) in 20% potassium carbonate solution (45 ml) was stirred for 5 hours by heating up to 50° C. The aqueous phase was separated and concentrated to dryness under reduced pressure. The concentrate was stirred with methanol (50 ml) for 30 min. After filter, the filtrate concentrated to dryness and was mixed with isopropanol (50 ml) for crystal growing for 2 hours at room temperature. The resulting mixture was filtered and dried under reduced pressure to give 3.7 g of target yield as a white solid. yield: 81%. Melting point test showed that the product began to melt at 90° C. and the final melting point was not apparently observed.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1)[CH3:10]>>[CH2:9]([O:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:10]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1
Product: CCOc1cccc(-c2ccc(N)cc2)c1
Yield: 53.9 %

Procedure:
The title compound (200 mg) was prepared from 4-bromoaniline (300 mg, 1.74 mmol) and 3-ethoxyphenylboronic acid (380 mg, 2.29 mmol) as a colourless liquid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.33 (d, J 8.5, 2H), 7.26-7.22 (m, 1H), 7.06 (d, J 7.9, 1H), 7.01 (s, 1H), 6.75 (dd, J 5.8, 8.1, 1H), 6.60 (d, J 8.5, 2H), 5.20 (s, 2H), 4.04 (q, J 7, 2H), 1.16 (t, J 7, 3H).
Reaction SMILES: O/[CH:2]=[C:3]1\[C:4](=[O:13])[NH:5][C:6]2[C:11]\1=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=2.O/C=C1\C(=O)NC2C\1=CC=CC=2.NC1C=CNN=1.[NH2:32][C:33]1[CH:37]=[C:36]([C:38]2[O:39][CH:40]=[CH:41][CH:42]=2)[NH:35][N:34]=1>O1CCCC1>[O:39]1[CH:40]=[CH:41][CH:42]=[C:38]1[C:36]1[NH:35][N:34]=[C:33]([NH:32][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[CH3:12])[NH:5][C:4]2=[O:13])[CH:37]=1
Reactant: Nc1cc(-c2ccco2)[nH]n1
Reactant: Cc1cccc2c1/C(=C/O)C(=O)N2
Agent: Nc1cc[nH]n1
Agent: O=C1Nc2ccccc2/C1=C/O
Solvent: C1CCOC1
Product: Cc1cccc2c1C(=CNc1cc(-c3ccco3)[nH]n1)C(=O)N2

Procedure:
The named compound is prepared by substituting E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one for E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one and substituting 3-amino-5-(2-furyl)-pyrazole for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-4-methyl-1,3-dihydro-indol-2-one (0.110 gms.) is reacted with 0.2065 gms. of 3-amino-5-(2-furyl)-pyrazole by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: [CH:1]1[C:14]2=[C:15]3[C:16]4[C:11]([CH:12]=[CH:13]2)=[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.C([O:23][C:24](=[O:29])[CH2:25][CH2:26][CH:27]=[O:28])C>O1CCOCC1.Cl>[CH:1]1[C:14]2=[C:15]3[C:16]4[C:11]([CH:12]=[CH:13]2)=[C:10]2[CH:17]=[CH:18][CH:19]=[CH:20][C:9]2=[CH:8][C:7]=4[CH:6]=[CH:5][C:4]3=[CH:3][CH:2]=1.[O:28]=[CH:27][CH2:26][CH2:25][C:24]([OH:29])=[O:23]
Reactant: CCOC(=O)CCC=O
Agent: Cl
Agent: c1ccc2c(c1)cc1ccc3cccc4ccc2c1c34
Solvent: C1COCCO1
Product: O=CCCC(=O)O
Reaction time: 6 h

Procedure:
Next, benzo[a]pyrene-4-oxobutyric acid (compound 2b) was synthesized from compound 1b. Compound 1b (890 mg; 2.3 mmol) was dissolved in a mixture of dioxane (5 ml) and 2.4 N aqueous hydrochloric acid (5 ml), and the mixture was stirred for 6 hours under reflux with heating. The reaction mixture was extracted with dichloromethane, the organic layer was washed with water, and the solvent was then removed under a reduced pressure. The residue was washed with dichloromethane to obtain 555 mg (67% yield) of compound 2b as a position-isomer mixture.
Reaction SMILES: N[C@H](C(O)=O)C(C)C.[OH-].[Na+].[CH3:11][S:12]([O-:14])=[O:13].[Na+].Br[C:17]1[CH:18]=[C:19]([C:29]([NH:31][CH2:32][C:33]2[C:34](=[O:41])[NH:35][C:36]([CH3:40])=[CH:37][C:38]=2[CH3:39])=[O:30])[C:20]2[CH:21]=[N:22][N:23]([CH:26]([CH3:28])[CH3:27])[C:24]=2[CH:25]=1>[Cu]I.O.CS(C)=O>[CH3:39][C:38]1[CH:37]=[C:36]([CH3:40])[NH:35][C:34](=[O:41])[C:33]=1[CH2:32][NH:31][C:29]([C:19]1[C:20]2[CH:21]=[N:22][N:23]([CH:26]([CH3:28])[CH3:27])[C:24]=2[CH:25]=[C:17]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:18]=1)=[O:30]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: [Cu]I
Agent: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2cc(S(C)(=O)=O)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 10 mL microwave vial containing a stirring mixture of L-valine (8.42 mg, 0.072 mmol), NaOH (0.024 mL, 0.072 mmol), and DMSO (1.6 mL) were added sodium methanesulfinate (0.065 g, 0.539 mmol), copper(I) iodide (6.85 mg, 0.036 mmol) and 1-Ethyl-3-methylimidazoliym bromide (0.014 g, 0.072 mmol). After stirring for 15 min, 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (0.15 g, 0.359 mmol) was added. The reaction vial was sealed and the mixture was stirred with heating at 90° C. (heat block) for 18 h. The contents were then irradiated (microwave) at 130° C. for 2 hr. After cooling to RT, the reaction mixture was poured onto 50 mL of water and stirred. The contents were extracted with hot 30% THF/EtOAc (2×) (need to heat to break up emulsion). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 5-75% chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The isolated product was concentrated from DCM and MTBE, and dried under hi vacuum. The title compound was collected as 75 mg (49%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6H) 2.13 (s, 3H) 2.22 (s, 3H) 3.30 (s, 3H) 4.38 (d, J=4.80 Hz, 2H) 5.23 (quin, J=6.57 Hz, 1H) 5.90 (s, 1H) 8.02 (d, J=1.01 Hz, 1H) 8.45 (s, 1H) 8.52 (s, 1H) 8.77 (t, J=4.80 Hz, 1H) 11.56 (s, 1H); LCMS: (M+H)+=417.1.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:19])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[C:10]=2[F:18])=[N:5]1.[NH:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[C:28]([C:30](O)=[O:31])[N:29]=2)[N:22]=[CH:21]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:17][C:11]1[C:10]([F:18])=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:28]3[N:29]=[C:25]([C:23]4[N:22]=[CH:21][NH:20][CH:24]=4)[S:26][CH:27]=3)=[O:31])[CH3:19])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1
Reactant: O=C(O)c1csc(-c2c[nH]cn2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2F)n1)NC(=O)c1csc(-c2c[nH]cn2)n1

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-3-fluorobenzonitrile (0.3 g, 1.07 mmol), 2-(1H-imidazol-4-yl)thiazole-4-carboxylic acid (0.25 g, 1.29 mmol), HOBt (0.22 g, 1.61 mmol), DIPEA (0.56 mL, 3.23 mmol) and EDCI (0.31 g, 1.61 mmol) in 10 mL DMF as solvent using the method described in Example 34(d). Yield 65 mg. 1H NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 4.40 (m, 2H), 4.60 (m, 1H), 6.80 (dd, 1H), 7.24 (d, 1H), 7.30 (m, 1H), 7.56 (m, 2H), 7.70 (d, 1H), 8.02 (s, 1H), 8.08 (m, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][OH:16])[CH3:11])=[CH:6][CH:5]=1)[CH3:2].O[C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]2=[O:48])=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[N:12][O:13][CH2:14][CH2:15][O:16][C:18]2[CH:50]=[CH:49][C:21]([CH2:22][CH:23]3[S:27][C:26](=[O:28])[N:25]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:24]3=[O:48])=[CH:20][CH:19]=2)[CH3:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOc1ccc(C(C)=NOCCO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOc1ccc(C(C)=NOCCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)cc1
Yield: 99.9 %

Procedure:
Following a procedure similar to that described in Example 1(a), but using 447 mg of 2-[1-(4-ethoxyphenyl)ethylideneaminooxy]ethanol (prepared as described in Preparation 29), 931 mg of 5-(4-hydroxybenzyl)-3-tritylthiazolidine-2,4-dione, 577 mg of triphenylphosphine and 366 mg of diethyl azodicarboxylate, 1.34 g of the title compound were obtained as a foam-like solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[N:42](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:7]([C:14]([O:16][CH2:17][C:18]2[O:19][C:20](=[O:24])[O:21][C:22]=2[CH3:23])=[O:15])=[C:8]([C:10]([OH:13])([CH3:12])[CH3:11])[N:9]=1)[CH3:2]>C(O)(=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[C:38]3[NH:42][N:41]=[N:40][N:39]=3)=[CH:28][CH:27]=2)[C:7]([C:14]([O:16][CH2:17][C:18]2[O:19][C:20](=[O:24])[O:21][C:22]=2[CH3:23])=[O:15])=[C:8]([C:10]([OH:13])([CH3:11])[CH3:12])[N:9]=1)[CH3:2]
Reactant: CCOCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CCOCc1nc(C(C)(C)O)c(C(=O)OCc2oc(=O)oc2C)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 89.2 %

Procedure:
Following a procedure similar to that described in Example 82 (b), but detritylating 456 mg of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl 2-ethoxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] with a 25% v/v aqueous solution of acetic acid, 286 mg of the title compound were obtained as crystals, melting at 166°-167.5° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:28]=3[CH:29]=[CH:30][CH:31]=[N:32]4)[N:17]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[NH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][NH:15][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][N:19]=[C:18]([NH:25][CH2:26][C:27]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:28]=3[CH:29]=[CH:30][CH:31]=[N:32]4)[N:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCC(CNc2nc(NCc3cccc4ncccc34)ncc2[N+](=O)[O-])CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2nc(NCc3cccc4ncccc34)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
[4-({5-Nitro-2-[(quinolin-5-ylmethyl)-amino]-pyrimidin-4-ylamino}-methyl)-cyclohexyl]-carbamic acid tert-butyl ester (197 mg, 0.39 mmol) was dissolved in CH2Cl2 (10 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was treated with 3M Na2CO3 and the organic phase was separated. The organic phase was dried over Na2SO4 and concentrated. Silica gel purification using a mixture of 10:1:0.3 CH2Cl2:MeOH:Et3N yielded 120 mg of the title compound as a light yellow solid (79%), m/z 406.4 [M−1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:12]=[CH:11]2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Temperature: 25 °C
Yield: 85 %

Procedure:
Palladium(0) (10% w/w on carbon, 50% wet, 1.25 g, 47.8 mmol) was added to a solution of ethyl 1-(4-nitrophenyl)-1H-imidazole-4-carboxylate (for a preparation see Intermediate 86) (12.5 g, 47.8 mmol) and ammonium formate (7.54 g, 120 mmol) in ethanol (250 mL). The reaction mixture was refluxed for 4 h then cooled to room temperature and filtered through celite. The solvent was removed in vacuo to give ethyl 1-(4-aminophenyl)-1H-imidazole-4-carboxylate (9.41 g, 40.7 mmol, 85%) as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=O)[N:10]=2)[CH:7]=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)[N:10]=2)[CH:7]=1
Reactant: COc1ccc(N2CCN(C(=O)c3cn4cc(Cl)ccc4n3)CC2)cc1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Reaction time: 8 h
Yield: 15.4 %

Procedure:
To 1-[(6-chloroimidazo[1,2-a]pyridin-2-yl)carbonyl]-4-(4-methoxy-phenyl)piperazine (0.182 g) in THF (6 mL) is added borane-methyl sulfide complex (Aldrich; 0.14 mL). Additional THF (4 mL) is added and the mixture is stirred overnight, after which it is quenched with the dropwise addition of methanol. The mixture is concentrated under reduced pressure and then acetone/6N HCl (10/1) is added. The resulting mixture is stirred for 40 min and then concentrated under reduced pressure. The residue is partitioned between dichloromethane and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate, concentrated, and the residue chromatographed on silica gel using methanol/dichloromethane (2/98 to 4/96) to give 0.027 g of the title compound; mp 111-112° C.; IR (mineral oil) 1512, 1254, 1498, 1035, 830 cm-1. 1H NMR (CDCl3) δ2.74, 3.13, 3.76, 3.77, 6.82, 6.90, 7.12, 7.52, 7.54, 8.13.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47](O)=[O:48]>CN(C)C=O>[Br:41][C:42]1[C:43]([CH3:59])=[CH:44][C:45]([O:51][CH2:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)=[C:46]([CH:50]=1)[C:47]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:48]
Reactant: Nc1ccnnc1
Reactant: Cc1cc(OCc2ccccc2)c(C(=O)O)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)c(C(=O)Nc2ccnnc2)cc1Br
Reaction time: 0.17 h

Procedure:
4-Pyridazinamine (207 mg, 2.18 mmol), diisopropylethylamine (0.52 ml, 2.97 mmol) and HATU (904 mg, 2.38 mmol) were added to a solution of 5-bromo-4-methyl-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 9; 636 mg, 1.98 mmol) in N,N-dimethylformamide (10 ml). The mixture was stirred for 2 hours, after 10 minutes a solid had crashed out of solution. The solid was filtered and washed with ethyl acetate (10 ml) to yield the title compound. 475 mg.