Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[NH:6][NH:7][N:8]([CH:22]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[C:9]=1[CH2:10][O:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:4].C[O:30][C:31](=[O:62])[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH:38]C(C2C(COC3C=CC=CC=3)=NN(C3C(Cl)=CC=CC=3Cl)N=2)=O)[CH:33]=1>>[C:12]12([O:11][CH2:10][C:9]3[N:8]([CH:22]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[NH:7][NH:6][C:5]=3[C:3]([NH:38][C:34]3[CH:33]=[C:32]([CH:37]=[CH:36][CH:35]=3)[C:31]([OH:62])=[O:30])=[O:4])[CH2:13][CH:14]3[CH2:15][CH:16]([CH2:17][CH:18]([CH2:20]3)[CH2:19]1)[CH2:21]2
Reactant: COC(=O)C1=C(COC23CC4CC(CC(C4)C2)C3)N(C2CCCCCC2)NN1
Reactant: COC(=O)c1cccc(NC(=O)c2nn(-c3c(Cl)cccc3Cl)nc2COc2ccccc2)c1
Product: O=C(Nc1cccc(C(=O)O)c1)C1=C(COC23CC4CC(CC(C4)C2)C3)N(C2CCCCCC2)NN1

Procedure:
5-(Adamantan-1-yloxymethyl)-1-cycloheptyl-3H-[1,2,3]triazole-4-carboxylic acid methyl ester was converted to the corresponding acid (as in Example 28, step c) which was then coupled to methyl 3-aminobenzoate (as in Example 28, step d). Hydrolysis of the methyl ester (as in Example 28, step e) resulted in the preparation of 3-{[5-(adamantan-1-yloxymethyl)-1-cycloheptyl-3H-[1,2,3]triazole-4-carbonyl]-amino}-benzoic acid. 1H NMR (d6-DMSO) 12.91 (1H, s), 10.62 (1H, s), 8.51 (1H, m), 7.98-7.95 (1H, m), 7.68 (1H, d, J=9 Hz), 7.47-7.42 (1H, m), 4.98 (2H, s), 4.71-4.66 (1H, m), 2.48-2.07 (7H, m), 1.80-1.54 (20H, m). The material was further analysed as its N-methyl D-glucamine salt.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:9]=[C:10]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([CH2:31][CH2:32][OH:33])(=[O:30])=[O:29])[CH:11]=[CH:12][C:13]=1[NH:14]C(OC(C)(C)C)=O)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[CH:9]=[C:10]([C:22]2[C:23]([S:28]([CH2:31][CH2:32][OH:33])(=[O:30])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:11]=[CH:12][C:13]=1[NH2:14]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2S(=O)(=O)CCO)cc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccc(-c2ccccc2S(=O)(=O)CCO)cc1N
Yield: 97.7 %

Procedure:
[4-tert-butoxycarbonylamino-2′-(2-hydroxy-ethanesulfonyl)-biphenyl-3-yl]-carbamic acid tert-butyl ester (0.233 g, 0.476 mmol) in a solution of 4M HCl in dioxane (6 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc, and the solution was washed with saturated sodium bicarbonate and water (pH=7). The organic layer was dried over Na2SO4, filtered, and the filtrate was concentrated in vacuo to provide the title compound as a yellow oil (0.136 g, 98%).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C>O1CCCC1>[S:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[C:2]1[B:15]([OH:20])[OH:16]
Reactant: c1cc2sccc2cn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc2cnccc2s1
Reaction time: 0.08 h

Procedure:
To a stirring mixture consisting of thieno[3,2-c]pyridine (2.0 g) in anhydrous tetrahydrofuran (25 mL) at −40° C. was added a solution consisting of 1.6 M n-butyllithium in hexanes (10 mL) over several minutes (dropwise at first followed by a slow, steady stream). The reaction mixture was stirred for five minutes and triisopropyl borate (4.2 mL) was subsequently added. The cold bath was removed and the mixture was allowed to stir for one hour. Water (2 mL) was added to the stirring mixture, which caused a pale yellow solid to precipitate instantly. The precipitate was collected by vacuum filtration and the solids were rinsed lightly with water (giving a cloudy yellow filtrate) and subsequently with diethyl ether (giving a dark orange filtrate). The aqueous portion of the filtrate was separated from the organic solvent, and then diluted with 1,4-dioxane (100 mL) and the solution was concentrated under reduced pressure. Addition of 1,4-dioxane (100 mL) to the concentrate and subsequent concentration under reduced pressure was repeated twice to afford a yellow powder (0.8 g) upon final evaporation.
Reaction SMILES: [Na].[CH2:2]([C:9]1[N:13]([CH3:14])[N:12]=[N:11][N:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O:20][N:21]=O)CC(C)C.CCOCC>C(O)C.O>[OH:20][N:21]=[C:2]([C:9]1[N:13]([CH3:14])[N:12]=[N:11][N:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)CCON=O
Reactant: Cn1nnnc1Cc1ccccc1
Agent: [Na]
Solvent: CCOCC
Solvent: O
Solvent: CCO
Product: Cn1nnnc1C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46.2 %

Procedure:
To a suspension of sodium hydroxyde (115 mg, 2.9 mmol) in 1.5 mL ethanol was added 500 mg of 5-benzyl-1-methyl-1H-tetrazole (2.9 mmol). The mixture was stirred 15 min at room temperature. A solution of isoamylnitrite (353 mg, 3 mmol) in 1 mL ethanol was then added dropwise and the mixture was stirred at room temperature for 16 h. Ether and water were then added and the layers were separated. The aqueous phase was washed with ether and then acidified with HCl 0.1M. The resulting neutral solution was extracted 3 times with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated to afford 272 mg of the title compound (Z:E mixture) as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:12]=[C:11]([CH:13]([O:15][CH2:16][C:17]3([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[CH3:14])[C:10]3[C:6](=[CH:7][N:8](COCC[Si](C)(C)C)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[CH:1]1([C:4]2[CH:12]=[C:11]([CH:13]([O:15][CH2:16][C:17]3([C:30]4[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=4)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[CH3:14])[C:10]3[C:6](=[CH:7][NH:8][N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C2CC2)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: O=C(O)C(F)(F)F
Product: CC(OCC1(c2ccc(F)cc2)CCNCC1)c1cc(C2CC2)cc2c[nH]nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
(±)-tert-Butyl 4-((1-(5-cyclopropyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate(70.5 mg, 0. 113 mmol) was dissolved in trifluoroacetic acid (50% in dichloromethane, 1 mL) and stirred at room temperature overnight. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 40.5 mg of (±)-5-cyclopropyl-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-2H-indazole (91%). The crude amine (40.5 mg, 0. 103 mmol) in dichloromethane (2 mL) was cooled to 0° C. and treated with di-tert-butyl dicarbonate (44.9 mg, 0.206 mmol). The reaction was stirred at 0° C. for 1 h and was quenched by addition of 2 M ammonia in methanol and concentrated. The residue was purified by column chromatography (1%→30% EtOAc/Hex) to give 30 mg (59%) as oil. LC/MS (HPLC method 3): tR=3.15 min, 494.12(MH)+.
Reaction SMILES: C([N:8]([CH2:24][CH2:25][C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([NH:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH:33]=2)[NH:28][C:27]=1[C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:15][CH:14]=1)C1C=CC=CC=1.C(O)(=O)C.[H][H]>O1CCCC1.CO.[OH-].[OH-].[Pd+2].O>[CH3:48][C:43]1[CH:42]=[C:41]([C:27]2[NH:28][C:29]3[C:34]([C:26]=2[CH2:25][CH2:24][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[CH:17][CH:18]=2)=[CH:33][C:32]([NH:35][C:36]([N:38]([CH3:39])[CH3:40])=[O:37])=[CH:31][CH:30]=3)[CH:46]=[C:45]([CH3:47])[CH:44]=1
Reactant: [H][H]
Reactant: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCN(CCCCc2ccc(NS(C)(=O)=O)cc2)Cc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(C)cc(-c2[nH]c3ccc(NC(=O)N(C)C)cc3c2CCNCCCCc2ccc(NS(C)(=O)=O)cc2)c1
Temperature: 25 °C

Procedure:
To a stirred solution of N-{4-[4-(benzyl-{2-[2-(3,5-dimethylphenyl)-5-(3,3-dimethylureido)-1H-indol-3-yl]ethyl}amino)butyl]phenyl}methanesulfonamide (17 mg in a mixture of 4 mL tetrahydrofuran and 1.5 mL methanol) was added 7 mg of 10% palladium hydroxide on carbon catalyst followed by acetic acid (0.020 mL of a 30% solution in water). The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 45 minutes the reaction was flushed with nitrogen, filtered over diatomaceous earth and concentrated in vacuo. Purification by flash chromatography (methylene chloride:methanol:ammonium hydroxide, 91:9:1) gave the title compound (14.5 mg). m/e=576 (M+H)
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4](NCCO)[N:3]=1.F[C@@H]1[C@@H](CO)[O:19][C@@H:18](N2C=CC(=O)NC2=O)[CH2:17]1.[N-]=[N+]=[N-].[K+].[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H](O)C1>P([O-])([O-])([O-])=O.[K+].[K+].[K+].CO>[OH:19][CH2:18][CH2:17][NH:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[CH:4][N:3]=1
Reactant: Nc1nc(NCCO)c2nc[nH]c2n1
Reactant: O=c1ccn([C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Agent: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OCCNc1ncc2nc[nH]c2n1
Temperature: 45 °C
Reaction time: 432 h
Yield: 19 %

Procedure:
2-Amino-6-((2-hydroxyethyl)amino)-9H-purine (0.55 g, 2.6 mmoles) and 2',3'-dideoxy-3'-fluorouridine (0.50 g, 2.2 mmoles) were suspended in 50 ml 10 mM potassium phosphate buffer, pH 7.0, containing 0.04% potassium azide. Purine nucleoside phosphorylase (1120 I.U.) and thymidine phosphorylase (10,000 I.U.) (Krenitsky, et al., Biochemistry, 20, 3615, 1981 and U.S. Pat. No. 4,381,344) immobilized on DEAE cellulose was added and the suspension was stirred at 45° C. After 18 days, 150 ml MeOH was added to the reaction mixture. The resulting mixture was applied to a column containing AG1-X2 (OH-- form, 2.5×10 cm) and eluted with MeOH. Fractions containing product were pooled, concentrated, and flash chromatographed on silica gel 2.5×20 cm) with dichloromethane:methanol:acetone (96:2:2). Solvent was removed and lyophilization yielded 0.14 g of 2-amino-9-(2,3-dideoxy-3-fluoro-β-D-erythro-pentofuranosyl)-6-((2-hydroxyethyl)amino-9H-purine (19%): mp 144° C.; [α]D20 -29.4° C. (c=0.5, DMF); UV λmax (ε×10-3) at pH 7, 282 (12.0); at pH 13, 281 (13.213.9); 1H NMR (300 MHz, DMSO-d6) δ7.93 (s, 1H, H8), 7.14 (b, 1H, NH), 6.21 (dd, 1H, H1', J=9.4 Hz, J=5.6 Hz), 5.85 (bs, 2H, NH2), 5.30-5.35 (m, 2H, OH5' and H3'), 4.74 (b, 1H, OH), 4.18 (dt, 1H, H4', J=27.1 Hz, J=4.4 Hz), 3.42-3.62 (b, 6H, H, H5',H5", NCH2CH2O), 2.76-3.01 and 2.49-2.63 (m, 2H, H2' and H2"); MS (ci) 313 (M+1), 293 (M-F), 195 (MH2 --C5H8FO2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH2:13][CH:12]([C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[Cl-].[Al+3].[Cl-].[Cl-].[C:29](Cl)(=[O:31])[CH3:30].Cl>O.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:16]([C:29](=[O:31])[CH3:30])=[CH:15][C:14]2[CH2:13][CH:12]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:11]3[CH:6]([C:5]=2[CH:4]=1)[CH2:7][CH2:8][CH2:9][CH2:10]3
Reactant: COc1ccc(C2Cc3ccc(OC)cc3C3CCCCC23)cc1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(C2Cc3cc(C(C)=O)c(OC)cc3C3CCCCC23)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 55.6 %

Procedure:
Combine 6-Methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthrene (0.13 g, 0.4 mmol) and methylene chloride (6 ml). Cool to −5° C. and add aluminum chloride (0.11, 0.81 mmol) followed by acetyl chloride (0.032 g, 0.4 mmol). After 2 hours, add ice, water and 1N HCl. Filter precipitate and rinse filtrate with sodium bicarbonate solution solution followed by brine. Remove solvent in vacuo, and chromatograph on silica gel with 17% ethyl acetate/hexanes to yield the titled compound (0.081 g, 55%). 1H NMR (CDCl3). MS m/z 365, (M+1).
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[C:17](=[CH:18][CH:19]=1)[O:16][C:10]1([CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[CH2:9][C:8]2=[O:20])([OH:4])=[O:3].[C:21]([O-:24])(O)=[O:22].[Na+]>O1CCOCC1.O.CCOCC.[OH-].[Na+]>[C:2]([C:5]1[CH:6]=[C:7]2[C:17](=[CH:18][CH:19]=1)[O:16][C:10]1([CH2:11][CH2:12][N:13]([C:21]([O:24][C:5]([CH3:6])([CH3:19])[CH3:2])=[O:22])[CH2:14][CH2:15]1)[CH2:9][C:8]2=[O:20])([OH:4])=[O:3]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc2c(c1)C(=O)CC1(CCNCC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)c1cc(C(=O)O)ccc1O2
Temperature: 25 °C
Reaction time: 13 h

Procedure:
6-Carboxy-4-oxospiro(chroman-2,4′-piperidine) hydrochloride (15.0 g, 50.3 mmol) was dissolved in 1,4-dioxane (150 ml) and H2O (150 ml), NaHCO3 (10.6 g, 126 mmol) and DIBOC (13.2 g, 60.4 mmol) were added thereto in this order. After stirred at room temperature for 13 h, the reaction mixture was diluted with Et2O and 5N NaOH aq. (12.1 ml). The aqueous layer was washed with Et2O and acidified with 6N HCl aq. (PH=ca. 3), then extracted with CHCl3. The organic layer was washed with brine and dried over MgSO4. The desiccant was removed through filtration and the filtrate was concentrated under reduced pressure. The residue was triturated with MeOH—H2O and the insoluble solid was collected through filtration to obtain the intended compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH3:13])=[C:4]([CH2:8][OH:9])[CH:5]=[CH:6][CH:7]=1>C1C=CC=CC=1.O=[Mn]=O>[Cl:1][C:2]1[C:3]([O:10][CH2:11][CH2:12][CH3:13])=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH:8]=[O:9]
Reactant: CCCOc1c(Cl)cccc1CO
Agent: O=[Mn]=O
Solvent: c1ccccc1
Product: CCCOc1c(Cl)cccc1C=O
Reaction time: 48 h
Yield: 37.8 %

Procedure:
MnO2 (3.40 g, 39.2 mmol) was added to a stirring solution of (3-chloro-2-propoxyphenyl)methanol (1.12 g, 5.60 mmol) in benzene (54 mL) under N2. After stirring for 48 h, the solution was filtered over diatomaceous earth, the pad rinsed with CH2Cl2 (100 mL), and the solution concentrated to a clear oil. Purification by column chromatography (silica gel, hexanes/EtOAc, 98:2) gave the title compound (0.42 g, 38%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.85 (d, J=1.6 Hz, 1H), 7.73 (d, J=1.6 Hz, 1H), 7.32 (t, J=7.8 Hz, 1H), 4.04 (t, J=6.4 Hz, 2H), 1.85-1.78 (m, 2H), 1.03 (t, J=7.3
Reaction SMILES: P([O-])([O-])(O)=O.[Na+].[Na+].CO.[CH2:10]1[O:37][C:13]2([CH2:19][CH2:18][CH:17]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:14]2[CH2:15][CH:16]3S(C2C=CC=CC=2)(=O)=O)[O:12][CH2:11]1>O1CCCC1.[Na].[Hg]>[CH2:11]1[O:12][C:13]2([CH2:19][CH2:18][CH:17]3[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:14]2[CH2:15][CH2:16]3)[O:37][CH2:10]1
Reactant: O=S(=O)(c1ccccc1)C1CC2N(Cc3ccccc3)C1CCC21OCCO1
Agent: O=P([O-])([O-])O
Agent: [Hg]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(CN2C3CCC2C2(CC3)OCCO2)cc1
Yield: 89 %

Procedure:
The procedure described in Synth. Commun., 25:3681-3690 (1995) to prepare the analogous 8-methyl compounds was used. In a three-neck flask equipped with a thermometer, an argon inlet, and a powder funnel were placed sodium hydrogenphosphate (dibasic) (7.10g, 50.0 mmol), and dry methanol (8 mL). A solution of (±)-6-benzenesulfonyl-8-benzyl-8-aza-bicyclo[3.2.1]octan-2-one ethylene acetal (J. Heterocyclic Chem., 34:1139-1146(1997) (2.00 g, 5.0 mmol) in tetrahydrofuran (16 mL) was added. Sodium mercury amalgam (20% sodium) (5 g) was added portionwise with stirring at such a rate as to keep the temperature below 50° C. The mixture was stirred an additional 1.5 h at ambient temperature. The organic solution was decanted away from the inorganic residue. The inorganic residue was washed with tetrahydrofuran (3×8 mL). The combined organic portion was concentrated under reduced pressure. The residue was dissolved in water (32 mL) and extracted with dichloromethane (4×16 mL). The combined extract was washed with brine (20 mL), dried (sodium sulfate), filtered, and the solvent was evaporated under reduced pressure to give crude product (1.21 g, 89%) as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[N:6][C:7]=1Cl.[O:10]1CC[CH2:12][CH2:11]1.[OH-].[Na+]>[C].[Pd].C(O)C>[CH2:11]([O:10][C:3]1[C:2]([NH2:1])=[CH:7][N:6]=[CH:5][N:4]=1)[CH3:12]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: C1CCOC1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1ncncc1N
Temperature: 25 °C
Reaction time: 24 h
Yield: 94.3 %

Procedure:
A mixture of 5-amino-4,6-dichloropyrimidine (5.00 g, 30.5 mmol), tetrahydrofuran (100 ml), sodium hydroxide (2.44 g, 61.0 mmol), ethanol (100 ml) and 10% palladium-carbon (500 mg) was stirred under a hydrogen atmosphere at room temperature for 1 day, insolubles were filtered off and an organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to obtain the desired product (4.00 g, 94.3%) as an oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH:13]1([CH2:19][CH:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)O)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.B(F)(F)F.CCOCC>O1CCOCC1>[CH:22]1([CH2:20][CH:19]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: OC(CC1CCCCC1)c1ccccc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: O=c1oc2ccccc2c(O)c1C(CC1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.9 %

Procedure:
To a time-dried flask containing a mixture of 650 mg of 4-hydroxycoumarin and 1.01 g of 2-cyclohexyl-1-phenylethanol of Preparation 19 in 20 mL of dioxane under an argon atmosphere is added 2.5 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=l with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is adsorbed onto silica and flash column chromatographed with 30% to 60% ethyl acetate in hexanes to yield 110 mg of the title product as a tan solid.
Reaction SMILES: C[O:2][C:3]([NH:5][N:6]=[C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([F:28])([F:27])[F:26])[CH:18]=2)=[CH:14][CH:15]=1)[CH3:8])=O.C(=O)([O-])[O-].[K+].[K+].CCCCCCC>C(#N)C.O.C(OCC)(=O)C.CC(OC)(C)C>[CH3:8][C:7]1[N:9]([C:10]2[CH:11]=[N:12][C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([F:27])([F:28])[F:26])[CH:18]=3)=[CH:14][CH:15]=2)[C:3](=[O:2])[NH:5][N:6]=1
Reactant: COC(=O)NN=C(C)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(-n3c(C)n[nH]c3=O)cn2)cc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 71 %

Procedure:
To a solution of methyl-2-[1-({6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}amino)ethylidene]hydrazinecarboxylate (Intermediate 33, 360 mg, 0.90 mmol) in 3 mL of acetonitrile and some drops of water, potassium carbonate (187 mg) was added. The resulting solution was stirred at room temperature for 24 hrs until complete conversion. The mixture was diluted with water (5 mL) and ethyl acetate (5 mL) and phases were separated. The aqueous phase was back-extracted with ethyl acetate (2×20 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give 280 mg as pale orange foam. This material was dissolved in MTBE (1 mL) and n-heptane was added until a solid precipitated. This was collected by filtration to give 234 mg of the title compound as white solid.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[NH2:6][C:7]1[C:8]([C:13]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])=[O:14])=[N:9][O:10][C:11]=1[CH3:12].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>ClCCl>[F:22][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:15]=1[C:13]([C:8]1[C:7]([NH:6][C:3](=[O:4])[CH2:2][Br:1])=[C:11]([CH3:12])[O:10][N:9]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: Cc1onc(C(=O)c2c(F)cccc2F)c1N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1onc(C(=O)c2c(F)cccc2F)c1NC(=O)CBr
Yield: 77 %

Procedure:
Bromoacetyl bromide (44 g, 222 mmoles) was added slowly to a mixture of (4-amino-5-methylisoxazol-3-yl)-2,6-difluorophenylmethanone of Example XIIIc (48 g, 202 mmoles) in dichloromethane (400 ml) with 2N sodium carbonate (125 ml) and saturated sodium chloride, dried (sodium sulfate) and evaporated to glve 72 g of an oil. The residue (3.0 g) was flash chromatographed (25% ethyl acetate:hexane) to yield 2.3 g (77%) of a solid, melting point 76°-80° C.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:23][O:24][C:25](=[O:41])[CH:26]([NH:30][C:31](=[O:40])[C:32]1[C:37]([Cl:38])=[CH:36][CH:35]=[CH:34][C:33]=1[Cl:39])[CH2:27][CH:28]=[CH2:29].I[C:43]1[CH:48]=[CH:47][C:46]([N:49]([CH:56]([CH3:58])[CH3:57])[C:50]2[N:55]=[CH:54][CH:53]=[CH:52][N:51]=2)=[CH:45][CH:44]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C>[CH3:23][O:24][C:25](=[O:41])[CH:26]([NH:30][C:31](=[O:40])[C:32]1[C:33]([Cl:39])=[CH:34][CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:27]/[CH:28]=[CH:29]/[C:43]1[CH:48]=[CH:47][C:46]([N:49]([CH:56]([CH3:58])[CH3:57])[C:50]2[N:51]=[CH:52][CH:53]=[CH:54][N:55]=2)=[CH:45][CH:44]=1
Reactant: CC(C)N(c1ccc(I)cc1)c1ncccn1
Reactant: C=CCC(NC(=O)c1c(Cl)cccc1Cl)C(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C/C=C/c1ccc(N(c2ncccn2)C(C)C)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 80 °C
Reaction time: 6 h
Yield: 66.9 %

Procedure:
Under an argon atmosphere, palladium acetate (316.7 mg) and tris(2-methylphenyl)phosphine (411.8 mg) were added to a suspension of 2-(2,6-dichlorobenzamido)pent-4-enoic acid methyl ester (4.09 g), N-(4-iodophenyl)-N-isopropylpyrimidin-2-amine (4.59 g) and potassium carbonate (2.80 g) in DMF (50 ml), and the resulting mixture was stirred at 80° C. for 6 hours. After cooling the reaction solution to room temperature, ethyl acetate was added thereto and the resulting mixture was washed twice with water and once with saturated brine, followed by drying the organic layer over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/chloroform=2/1→1/2). The obtained crude product was purified again by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=10/1→4/1) to obtain (E)-2-(2,6-dichlorobenzamido)-5-[4-(isopropyl-pyrimidin-2-ylamino)phenyl]pent-4-enoic acid methyl ester (4.65 g).