Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:28][C:29]1[C:44]([F:45])=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:46])[CH:30]=1>O1CCCC1>[NH2:42][C:40]([C:36]1[CH:35]=[C:34]([O:33][C:32]2[C:31]([F:46])=[CH:30][C:29]([NH:28][C:14]([C:11]3([C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:44]([F:45])[CH:43]=2)[CH:39]=[CH:38][N:37]=1)=[O:41]
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 0.25 h
Yield: 21 %

Procedure:
1-(4-Fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.35 g) was dissolved in tetrahydrofuran (25.0 ml) under a nitrogen atmosphere, and triethylamine (1.06 ml) was added dropwise while cooling in an ice water bath, followed by stirring for 15 min. Then thionyl chloride (0.439 ml) was added at the same temperature, followed by stirring for 1.5 hr. To the reaction mixture was added dropwise at the same temperature a mixture of 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (1.0 g), tetrahydrofuran (12 ml) and triethylamine (1.06 ml), followed by stirring at 0° C. for 24 hr and 45 min. The reaction mixture was partitioned between ethyl acetate (70 ml) and a 2N aqueous solution of sodium hydroxide (15 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (15 ml) twice, 1N hydrochloric acid (15 ml) three times and a saturated aqueous solution of sodium hydrogencarbonate (10 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, 1:2, then ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a white solid (372.8 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][C:29]([F:36])([F:35])[C:30]([O:32]CC)=[O:31])=[CH:24][CH:23]=3)[CH:15]=2)=[C:9]([CH3:37])[CH:8]=1)[CH3:2].O1CCCC1.O.[OH-].[Li+].Cl>O.C(O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH3:37])[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH:21][C:22]3[CH:23]=[CH:24][C:25]([CH2:28][C:29]([F:35])([F:36])[C:30]([OH:32])=[O:31])=[CH:26][CH:27]=3)[CH:15]=2)=[C:11]([CH3:13])[CH:12]=1)[CH3:2]
Reactant: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CC(F)(F)C(=O)OCC)cc3)c2)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOCCOc1cc(C)c(-c2cccc(CNc3ccc(CC(F)(F)C(=O)O)cc3)c2)c(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 66 %

Procedure:
A mixture of ethyl 3-[4-({[4′-(2-ethoxyethoxy)-2′,6′-dimethylbiphenyl-3-yl]methyl}amino)phenyl]-2,2-difluoropropanoate (665 mg, 1.30 mmol), tetrahydrofuran (15 mL), ethanol (10 mL), water (10 mL) and lithium hydroxide monohydrate (162 mg, 3.89 mmol) was stirred at room temperature for 3 hr. The reaction mixture was neutralized with 1 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (20%-100% ethyl acetate/hexane), and the residue was recrystallized from ethyl acetate-hexane to give the title compound (415 mg, yield 66%) as colorless crystals.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[C:19](=[CH2:20])[S:18][CH:17]([C:21]([O:23][CH3:24])=[S:22])[CH:16]=2)[N:14]=1.[Br:25]CC(C1C=C(C(OC)=S)SC=1C)=O.FC1C=CC=CC=1NC(N)=S>>[BrH:25].[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2[CH:16]=[C:17]([C:21]([O:23][CH3:24])=[S:22])[S:18][C:19]=2[CH3:20])[N:14]=1
Reactant: C=C1SC(C(=S)OC)C=C1c1csc(Nc2ccccc2F)n1
Reactant: COC(=S)c1cc(C(=O)CBr)c(C)s1
Agent: Br
Agent: NC(=S)Nc1ccccc1F
Product: COC(=S)c1cc(-c2csc(Nc3ccccc3F)n2)c(C)s1
Yield: 70 %

Procedure:
Methyl 4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methlylthiothiophene-2-carboxylate hydrobromide: Methyl 4-(2-bromoacetyl)-5-methylthiothiophene-2-carboxylate (60 mg, 0.19 mmol) was allowed to react with 2-fluorophenyl thiourea as described in Example 154, step (a) to give 55.6 mg (70% yield) of methyl 4-{2-[(2-fluorophenyl)amino](1,3-thiazol-4-yl)}-5-methylthiothiophene-2-carboxylate hydrobromide. 1H NMR (DMSO-d6, 300 MHz) δ 2.68 (s, 3H), 3.83 (s, 3H), 6.96-7.04 (m, 1H), 7.14-7.29 (m, 3H), 7.35 (s, 1H), 8.06, 8.14 (s, 1H rotomer), 8.61 (td, 1H rotomer, J=1.5, 8.5 Hz), 10.14, 10.30 (s, 1H rotomer); Mass Spectrum (ESI) m/z calcd. for C16H13FN2O2S3, 380.48 (M+H), found 381.1.
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5].[C:8]([O:11][CH2:12][CH:13]([NH:19][C:20]([C:22]1[C:27]([I:28])=[C:26]([NH2:29])[C:25]([I:30])=[C:24]([C:31]([NH:33][CH:34]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[CH2:35][O:36][C:37](=[O:39])[CH3:38])=[O:32])[C:23]=1[I:45])=[O:21])[CH2:14][O:15][C:16](=[O:18])[CH3:17])(=[O:10])[CH3:9]>CC(N(C)C)=O>[C:37]([O:36][CH2:35][CH:34]([NH:33][C:31]([C:24]1[C:25]([I:30])=[C:26]([NH:29][C:1](=[O:6])[CH2:2][CH2:3][CH:4]=[CH2:5])[C:27]([I:28])=[C:22]([C:20]([NH:19][CH:13]([CH2:12][O:11][C:8](=[O:10])[CH3:9])[CH2:14][O:15][C:16](=[O:18])[CH3:17])=[O:21])[C:23]=1[I:45])=[O:32])[CH2:40][O:41][C:42](=[O:44])[CH3:43])(=[O:39])[CH3:38]
Reactant: CC(=O)OCC(COC(C)=O)NC(=O)c1c(I)c(N)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reactant: C=CCCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: C=CCCC(=O)Nc1c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c(I)c(C(=O)NC(COC(C)=O)COC(C)=O)c1I
Reaction time: 16 h
Yield: 89 %

Procedure:
4-Pentenoyl chloride (11.9 g, 100 mmol) was added to a stirred solution of N,N'-bis-[2-(acetyloxy) -1-[(acetyloxy)-methyl]ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (47.75 g, 50 mmol) in dimethylacetamide (400 mL) at room temperature and the mixture was stirred for 16 hours. Dimethylacetamide was removed in vacuo and the residue dissolved in ethyl acetate (600 ml). The solution was washed with aqueous sodium bicarbonate (10%, 2×150 mL) and with water (2×100 mL) and brine (150 mL). The organic layer was dried and the solvent removed to obtain the crude product as an off-white solid. Further purification by crystallization from a mixture of acetone (250 mL) and hexane (75 mL) afforded the title A compound (42.5 g), m.p. 162°-64°. TLC: Rf 0.55 in ethyl acetate. Mass Spectrum: m/z 956 (M+H)+, 830, 653.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2[O:15][CH3:16].C(N(CC)CC)C.C([SiH](CCCCCC)CCCCCC)CCCCC.CN(C)[CH:45]=[O:46]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C(C2C=CC=CC=2)CCP)C=CC=CC=1>[CH:45]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[C:5]2[O:15][CH3:16])=[O:46]
Reactant: COc1c(C(N)=O)cnc2ccc(I)cc12
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Solvent: CCN(CC)CC
Product: COc1c(C(N)=O)cnc2ccc(C=O)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
A mixture of 6-iodo-4-methoxy-quinoline-3-carboxylic acid amide (example 1d) (1.3 g, 4 mmol), triethylamine (1.4 mL, 3.5 mmol), diphenylpropylphosphine (dpp, 45 uL, 0.2 mmol) and palladium(II) acetate (45 mg, 0.2 mmol) in dry N,N-dimethylformamide (30 mL) in pressure tube was stirred under carbon monoxide at 75 psi at room temperature for 10 min. After addition of trihexylsilane (0.2.9 mL, 8 mmol), the mixture was then stirred under carbon monoxide at 75 psi at 80° C. for 4 h. The reaction was allowed to cool to 25° C. and then extracted with methylene chloride (2×150 mL). The combined organic layers were successively washed with water (3×50 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 20%-100% ethyl acetate in hexanes in 30 min) afforded 6-formyl-4-methoxy-quinoline-3-carboxylic acid amide (0.58 g, 64%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[C:6]2[C:7]([NH:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1)=O>CC(O)=O.[Zn]>[OH:1][C:2]1[CH:12]=[C:6]2[C:5](=[CH:4][CH:3]=1)[C:10](=[O:11])[NH:9][CH2:7]2
Reactant: O=C1NC(=O)c2cc(O)ccc21
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1NCc2cc(O)ccc21
Reaction time: 0.67 h
Yield: 20.9 %

Procedure:
To a solution of 5-hydroxyphthalimide (19.8 g, 121 mmol) in AcOH (500 mL) was slowly added zinc dust (47.6 g, 729 mmol) in portions, then the mixture was heated at the reflux temp. for 40 min., filtered hot, and concentrated under reduced pressure. The reaction was repeated on the same scale and the combined oily residue was purified by column chromatography (1.1 Kg SiO2; gradient from 60% EtOAc/40% hexane to 25% MeOH/75% EtOAc) to give 5-hydroxyisoindolin-1-one (3.77 g): TLC (100% EtOAc) Rf 0.17; HPLC ES-MS m/z 150 ((M+H)+).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH:11]([S:13]([F:16])(=[O:15])=[O:14])=[CH2:12].O>C(O)(C)C>[F:16][S:13]([CH2:11][CH2:12][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)(=[O:15])=[O:14]
Reactant: C=CS(=O)(=O)F
Reactant: CCNc1cccc(C)c1
Solvent: CC(C)O
Solvent: O
Product: CCN(CCS(=O)(=O)F)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Ethyl-m-toluidine (66.5 g) (0.05 m) is dissolved in isopropyl alcohol (75 ml) and vinylsulfonyl fluoride (55 g 0.5) is added dropwise over 1.25 hr. The reaction exotherms to 38° C. and the reaction mixture is stirred for 1 hr. at ambient temperature and drowned into 500 ml of ice and water. The product is collected by filtration, washed with water, and dried in air. The product melts at 32°-34° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=[N:11]OC)[C:7]([O:9][CH3:10])=[O:8].C(O)=O>CO.O.[Zn]>[NH2:11][CH:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: CON=C(C(=O)OC)c1ccco1
Agent: [Zn]
Solvent: O=CO
Solvent: O
Solvent: CO
Product: COC(=O)C(N)c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.5 %

Procedure:
To a magnetically stirred solution of methyl 2-(furan-2-yl)-2-(methoxyimino)acetate (17.50 g, 96 mmol) in 300 mL of MeOH was added 200 mL of a solution of 50% formic acid in water. The reaction mixture was cooled to 0° C. (ice bath) and zinc dust (18.74 g, 287 mmol) was added. After stirring at room temperature for 18 hr, the reaction mixture was filtered through a plug of Celite and the plug was washed with MeOH. Solvent was removed on the rotary evaporator and the yellow residue was dissolved in 50 mL of water, basified to pH 10 with a saturated solution of Na2CO3 and extracted with 3×100 mL of EtOAc. After drying (MgSO4) the organic extracts, solvent removal gave 10.2 g of methyl 2-amino-2-(furan-2-yl)acetate as an orange liquid.
Reaction SMILES: [CH:1]1(/[CH:5]=[CH:6]\[CH2:7][C@@H:8]([C:17]2[O:18][CH:19]=[C:20]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:21]=2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+]>C(O)C.[OH-].[Pd+2].[OH-]>[CH:1]1([CH2:5][CH2:6][CH2:7][C@@H:8]([C:17]2[O:18][CH:19]=[C:20]([C:22]([N:24]([CH3:26])[CH3:25])=[O:23])[N:21]=2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C(=O)c1coc([C@H](C/C=C\C2CCC2)CC(=O)OC(C)(C)C)n1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)C(=O)c1coc([C@H](CCCC2CCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Yield: 93.7 %

Procedure:
A solution of tert-butyl (3R,5Z)-6-cyclobutyl-3-{4-[(dimethylamino)carbonyl]-1,3-oxazol-2-yl}-5-hexenoate (Preparation 119) (260 mg, 0.72 mmol) in ethanol (15 ml) was treated with palladium hydroxide (250 mg) followed by ammonium formate (500 mg) and the mixture was stirred at reflux for 3 hours. The reaction mixture was allowed to cool to room temperature and was filtered through arbacel. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate and filtered. The solvent was removed under reduced pressure to afford the title compound as a colourless oil (246 mg).
Reaction SMILES: S([O:6][CH3:7])(OC)(=O)=O.[CH2:8]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:28][CH3:29])[C:22]=2[O:26][CH3:27])[NH:17][C:16]1=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[K+]>>[CH2:8]([N:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:28][CH3:29])[C:22]=2[O:26][CH3:27])[N:17]([CH3:16])[C:7]1=[O:6])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc2[nH]c(=O)n(Cc3ccccc3)c(=O)c2c1OC
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Product: COc1ccc2c(c1OC)c(=O)n(Cc1ccccc1)c(=O)n2C
Temperature: 80 °C

Procedure:
Dimethyl sulfate (1.442 g, 1.08 ml, 11.43 mM) was added to 3-benzyl-5,6-dimethoxyquinazolin-2,4(1H, 3H)-dione (1.20 g, 3.7 mM). The mixture was heated to 80° C. (oil bath temperature) and then heated at 80°-84° C. for five minutes with vigorous stirring. A white solid was present at all times. Aqueous KOH (~15 ml of a 5N aqueous solution) was added dropwise at 80°-90° C. until the pH of the reaction mixture became basic and stayed basic. Addition of the aqueous KOH took ~20 minutes. A white solid was present during the addition. The mixture was cooled in an ice-H2O bath and the white solid filtered, washed well with H2O (20 ml) and dried to give 1.00 g crude product. mp 149°-152° C. Recrystallization from isopropanol (50 ml) afforded the title compound as a white solid; 0.80 g (66.1%); mp 153°-155° C. CDCl3 (TMS) 7.10-7.80 (m, 6H, 7-H, 10-H, 11-H, 12-H, 13-H, 14-H), 6.82 (d, 1H, J8,7 =10 Hz, 8-H), 5.25 (s, 2H, 9-H), 3.95 (s, 3H, 5 or 6-OCH3), 3.88 (s, 3H, 5 or 6-OCH3), 3.53 (s, 3H, 1-CH3), M+ 326.
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][C:4]([CH3:7])=[C:3]1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:9].[C:17]([O:21][C:22]([NH:24][C@@H:25]([CH3:29])[C:26](O)=[O:27])=[O:23])([CH3:20])([CH3:19])[CH3:18].C(N(CC)C(C)C)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C(OCC)(=O)C.O>[CH3:7][C:4]1[CH:5]=[CH:6][N:2]([NH:1][C:26](=[O:27])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][C:17]([CH3:19])([CH3:18])[CH3:20])[CH3:29])[C:3]=1[C:8](=[O:9])[NH:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccn(N)c1C(=O)Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn(NC(=O)[C@H](C)NC(=O)OC(C)(C)C)c1C(=O)Nc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
1-Amino-3-methyl-N-phenyl-1H-pyrrole-2-carboxamide (5.30 g, 24.62 mmol) was dissolved in 35 mL ethyl acetate and (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (6.50 g, 34.35 mmol) was added. The mixture was cooled in an ice bath and N,N-diisopropylethylamine (19.8 mL, 113.68 mmol) was added dropwise. After 15 min stirring, maintaining the reaction temperature at 0° C., T3P® (50% in ethyl acetate, 14.3 mL, 48.04 mmol) was added dropwise and the reaction was stirred at room temperature for 3 h. Further (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (3.25 g, 17.17 mmol) was added and the mixture was stirred at room temperature overnight. Further N,N-diisopropylethylamine (20 mL, 114 mmol) and T3P® (50% in ethyl acetate, 14.3 mL, 48.04 mmol) were added dropwise at 0° C. and the reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic phase was dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was purified using Isolera® Purification System (0% to 60% hexane-ethyl acetate) to obtain 7.15 g (75% yield) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]=[CH:7][C:8]3[CH:9]=[CH:10][C:11]([CH3:16])=[N:12][C:13]=3[C:14]=2[N:15]=1.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Co+2:27].[N+]([O-])([O-])=O.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[Na+]>O.CO>[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[Co+3:27].[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[CH:9]=[CH:10][C:11]([CH3:16])=[N:12]3)[N:15]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[CH:9]=[CH:10][C:11]([CH3:16])=[N:12]3)[N:15]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14](=[C:13]3[C:8](=[CH:7][CH:6]=2)[CH:9]=[CH:10][C:11]([CH3:16])=[N:12]3)[N:15]=1.[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33].[Cl:32]([O-:36])(=[O:35])(=[O:34])=[O:33]
Reactant: [Co+2]
Agent: Cc1ccc2ccc3ccc(C)nc3c2n1
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [Co+3]
Temperature: 4 °C

Procedure:
Neocuproine (1.00 g, 0.00480 mole) and cobalt (II) nitrate hexahydrate (0.466 g, 0.00160 mole) were dissolved in 30 ml 2:1 water-methanol with stirring in a 60° water bath. Sodium perchlorate solution (3.5 ml 1.5M) was added rapidly with stirring. A flaky pink precipitate was formed immediately. After cooling at 4° C., the product was collected by vacuum filtration and dried in vacuum. Yield=86%. IR: 2800-3700, 1630, 1600, 1570, 1500, 1425, 1390, 1360, 1300, 1030-1150, 860, 730, 625 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:14][C:13]3[C:12](=[O:15])[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][NH:9][C:8]=3[C:7](=[O:21])[C:6]=2[CH:22]=1.CI.[C:25](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:25][N:9]1[CH:10]=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12](=[O:15])[C:13]2[O:14][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:22][C:6]=3[C:7](=[O:21])[C:8]1=2
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1c[nH]c2c(=O)c3cc(Cl)ccc3oc2c1=O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C)c2c(=O)c3cc(Cl)ccc3oc2c1=O
Reaction time: 3 h
Yield: 88 %

Procedure:
A mixture of ethyl 8-chloro-4,10-dihydro-4,10-dioxo-1H-1-benzopyrano[3,2-b]pyridine-3-carboxylate (0.5 g, 0.0016 mole), methyl iodide (0.5 g, 0.0035 mole) and potassium carbonate (0.23 g, 0.0017 mole) in dimethyl formamide (25 ml) was stirred at 100° for 3 hrs. under nitrogen. The reaction mixture was cooled. The product, which precipitated, was filtered, washed with water and dried. Recrystallization from DMF gave white crystals (0.47 g, 90%), m.p. 295°-297°.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([O:10]CC)=[O:9])[CH:4]=1.[OH-].[Na+].Cl>[Cl-].[Na+].O>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=1
Reactant: CCOC(=O)c1cc(CO)on1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(CO)on1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 95.7 %

Procedure:
The mixture of Ethyl 5-(hydroxymethyl)isoxazole-3-carboxylate (1.5 g; 8.76 mmol) and 1M sodium hydroxide (18 mL; 18 mmol) was stirred at room temperature for 3.5 h. Brine (40 mL) was added and the pH of the solution was adjusted to 2 by addition of 6N hydrochloric acid. The acidic solution was extracted with 8×60 mL of ethyl acetate. Organic extracts were dried over magnesium sulfate. Evaporation of the solvent produced 1.20 g (95%) of 5-(hydroxymethyl)isoxazole-3-carboxylic acid as a white solid which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Li]C(C)(C)C.[CH3:11][C:12]1([CH3:43])[CH2:21][CH:20]=[C:19](OS(C(F)(F)F)(=O)=O)[C:18]2[CH:17]=[C:16]([N:30]=[N:31][C:32]3[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]1=2>C1COCC1.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:43][C:12]1([CH3:11])[CH2:21][CH:20]=[C:19]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[C:18]2[CH:17]=[C:16]([N:30]=[N:31][C:32]3[CH:33]=[CH:34][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:41][CH:42]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: c1ccsc1
Reactant: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N=Nc2ccc3c(c2)C(c2cccs2)=CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a cold solution (−78° C.) of thiophene (0.07 ml, 0.75 mmol) in 1.5 ml of THF was added t-BuLi (0.457 ml, 0.75 mmol, 1.7 M in pentane) and stirred for 2 h. To this solution, ZnCl2 (168 mg, 1.2 mmol) in 1.5 ml of THF was added. The resulting solution was warmed to room temperature, stirred for 1 h and was added (via cannula) to a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-trifluoromethylsulfonyloxy-naphthalen-2-yl)azo]benzoate (Compound D11, 150 mg, 0.30 mmol) and tetrakis(triphenylphosphine)palladium(0) (10.6 mg) in 2.5 ml of THF. The resulting mixture was heated at 50° C. for 2.5 h. The reaction was diluted with sat, aqueous NH4Cl and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated to an oil. The crude product was purified by flash chromatography (silica, ethyl acetate:hexane 5:95) to afford the title compound as a red foam.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[C:19]2[C:20]([O:24][CH3:25])=[N:21][CH:22]=[CH:23][C:18]=2[S:17][CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:25][O:24][C:20]1[C:19]2[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:16][S:17][C:18]=2[CH:23]=[CH:22][N:21]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: COc1nccc2scc(Br)c12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1nccc2scc(N3CCN(c4cnccc4C)C3=O)c12
Yield: 40 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 65 mg, 0.3668 mmol) was reacted with 3-bromo-4-methoxy-thieno[3,2-c]pyridine (98.4 mg, 0.4034 mmol), 1,4-dioxane (20 mL), copper iodide (6.9 mg, 0.03668 mmol), trans-1,2-diamino cyclohexane (12.6 mg, 0.1100 mmol) and potassium phosphate (194.6 mg, 0.91704 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 50 mg of the product (40.3% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10](=[O:16])[CH2:9]2)=[CH:4][C:3]=1[C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:48]([C:50]1[N:51]=[C:52]([C:63]([O-])=[O:64])[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=1)#[N:49].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:17]1([C:3]2[CH:4]=[C:5]([CH:8]3[CH2:9][C:10](=[O:16])[N:11]([CH3:15])[C:12](=[O:14])[CH2:13]3)[CH:6]=[CH:7][C:2]=2[NH:1][C:63]([C:52]2[N:53]([CH2:55][O:56][CH2:57][CH2:58][Si:59]([CH3:62])([CH3:61])[CH3:60])[CH:54]=[C:50]([C:48]#[N:49])[N:51]=2)=[O:64])[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: CN1C(=O)CC(c2ccc(N)c(C3=CCCCC3)c2)CC1=O
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1C(=O)CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCCCC3)c2)CC1=O
Yield: 26.6 %

Procedure:
A solution of 266 mg (0.891 mmol) of 4-(4-amino-3-cyclohex-1-enyl-phenyl)-1-methyl-piperidine-2,6-dione (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 623 mg (1.34 mmol) of PyBroP, 300 mg (0.981 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)), and 466 μL (2.67 mmol) of DIEA at RT for 16 h. The mixture was diluted with CH2Cl2 (30 mL) and washed with saturated aqueous NaHCO3 (1×30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromagography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 130 mg (27%) of the title compound as an off-white solid: Mass spectrum (ESI, m/z): Calcd. for C29H37N5O4Si, 548.3 (M+H). found 547.9.