Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[C:3]1([CH:11]=[C:9]([OH:10])[CH:8]=[C:6]([OH:7])[CH:5]=1)O.[C:12]([C:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=1)(=[O:14])[CH3:13].C(O)(=O)C>COCCO.C(OCC)(=O)C.O>[OH:7][C:6]1[CH:8]=[C:9]([OH:10])[C:11]2[CH:20]3[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19]3)[C:12](=[O:14])[CH2:13][C:3]=2[CH:5]=1
Reactant: CC(=O)C1=CCCCC1
Reactant: Oc1cc(O)cc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C1Cc2cc(O)cc(O)c2C2CCCCC12
Temperature: 50 °C

Procedure:
To a flask equipped with a stirrer, dropping funnel, condenser and gas inlet tube maintained under a nitrogen atmosphere, there is added 50 g (0.89) moles of potassium hydroxide in one liter of 2-methoxyethanol. Stirring is initiated and 100 g(0.79mole) of anhydrous phloroglucinol is added in three portions, followed by the addition of 100 g (0.80 mole) of 1-acetyl-cyclohexene while maintaining the temperature at 50°C. The resulting solution is refluxed at 140°C for 4 hours. After cooling there is then added gradually 53.6 g. of acetic acid while obtaining a pH of approximately 7. The solvent is then removed in vacuo, and the residue is further heated in vacuo in a bath at 70°C, to obtain a viscous residue. The resulting residue is dissolved in ethyl acetate and water; washed twice with water, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to obtain a brown solid. The resulting solid is recrystallized from ethyl acetate/cyclohexane to give 2,4-dihydroxy-4b,5,6,7,8,8a,9,10-octahydro-9 -oxo-phenanthrene. m.p. 220°-223°C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][C:11](=[O:14])[CH2:10]2)=[C:4]([F:15])[CH:3]=1.[BH4-].[Na+].[OH-].[Na+].C(OCC)(=O)C>C(O)C.C1COCC1>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10]2)=[C:4]([F:15])[CH:3]=1
Reactant: O=C1CCC(c2cc(F)c(Br)cc2F)C1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: OC1CCC(c2cc(F)c(Br)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To 15.0 g (54.5 mmol) of 3-(4-bromo-2,5-difluorophenyl) cyclopentanone in 150 ml of absolute ethanol and 10 ml of THF was added 2.5 g (65.4 mmol) of sodium borohydride portionwise. The reaction mixture was stirred for 21/2 hours at room temperature, then poured into a mixture of 250 ml of 1.0 N NaOH and 250 ml of ethyl acetate. The organic phase was washed with water, dried (MgSO4), and concentrated. The crude product was chromatographed over silica gel, eluting with 80:20 CHCl3 :EtOAc, to give 10.8 g (72%) of the desired product as a yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[C:23]([N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2].O>[N:27]1([C:23](=[O:26])[CH:24]=[CH:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][O:18]4)=[CH:12][CH:11]=3)=[CH:4][CH:3]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: Ic1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1
Reactant: C=CC(=O)N1CCOCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C=Cc1ccc(NCc2ccc(OC3CCCCO3)cc2)cc1)N1CCOCC1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a solution of (4-iodo-phenyl)-[4-(tetrahydro-pyran-2-yloxy)-benzyl]-amine (0.265 g, 0.65 mmol) in 2 mL dimethylformamide was added 4-acryloylmorpholine (0.110 g, 0.78 mmol), Pd(OAc)2 (0.029 g, 0.13 mmol), and triethylamine (0.20 mL, 1.43 mmol). The reaction was stirred at 90° C. for 2 hr. Triphenylphosphine (0.101 g, 0.38 mmol) and additional Pd(OAc)2 (0.032 g, 0.14 mmol) were added and the reaction mixture was stirred at 90–100° C. for 18 hr. The reaction mixture was cooled, water was added, and the aqueous solution was washed ethyl acetate (3×). The combined organic layers were dried (magnesium sulfate) and concentrated. Medium pressure silica gel chromatography (33% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded the title compound of Step A. MS 423.0 (M+1)+
Reaction SMILES: C1C=CC(CNS(C2C=CC3N=NN(O)C=3C=2)(=O)=O)=CC=1.Cl.N1C=CC=CC=1.[O:29]1[C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=[N:30]1.[N:37]1([C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[NH2:45])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1.ClCCl>[N:37]1([C:43]2[CH:49]=[CH:48][CH:47]=[CH:46][C:44]=2[NH:45][C:34]([C:33]2[O:29][N:30]=[CH:31][CH:32]=2)=[O:35])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1
Reactant: Nc1ccccc1N1CCCCC1
Reactant: O=C(Cl)c1ccno1
Agent: Cl
Agent: O=S(=O)(NCc1ccccc1)c1ccc2nnn(O)c2c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccno1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To PS-HOBt resin (0.1 mmol) was added anhydrous dichloromethane (“DCM”) (1 mL) followed by pyridine (0.5 mmol) and isoxazole-5-carbonyl chloride (Lancaster) (0.3 mmol). The mixture was shaken at room temperature for 3 h and was then filtered. The resin was washed successively with tetrahydrofuran (“THF”) (3×) and DCM (3×) and dried in vacuo. To this acylated resin was added a solution of 2-piperidinoaniline (Lancaster) (0.05 mmol, 0.5 eq) in anhydrous THF (1 mL) and the mixture was shaken at room temperature for 16 h. The mixtue was then filtered and the resin washed with THF and DCM as described above. The combined filtrate and washings were concentrated under reduced pressure to yield the product. Yield: 100%. MS: 272 (M+1). LC/MS purity: 100%. 1HNMR (CDCl3, 300 MHz): δ 8.2 (d, 1H), 7.85 (t, 2H), 7.55 (m, 1H), 7.4 (m, 2H), 3.8-3.2 (bm, 4H), 2.7-1.9 (bm, 4H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)[C:5]([N:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[N:6][CH:7]=1.N1C=CC=[CH:36][CH:35]=1.C(B1OB(C=C)OB(C=C)O1)=C.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[C:11]([O:10][C:9]([N:8]([C:5]1[C:4]([C:23]2[O:24][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:27]=2)=[N:3][C:2]([CH:35]=[CH2:36])=[CH:7][N:6]=1)[C:16](=[O:17])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: c1ccncc1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CB1OB(C=C)OB(C=C)O1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: C=Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c2nnc(-c3ccccc3)o2)n1
Temperature: 60 °C
Yield: 100 %

Procedure:
To a solution of tert-butyl N-[5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl]-N-tert-butoxycarbonyl-carbamate (500 mg, 0.96 mmol) in toluene (2 mL) and ethanol (2 mL) was added pyridine; 2,4,6-trivinyl-1,3,5,2,4,6-trioxatriborinane (290 mg, 1.2 mmol), K2CO3 (533 mg, 4 mmol) and Pd(PPh3)4 (112 mg, 0.1 mmol). The reaction mixture was heated at 60° C. under an atmosphere of nitrogen for 1 h. The reaction mixture was filtered, concentrated and the crude material obtained was purified via silica gel column chromatography using EtOAc/hex gradient to obtain tert-butyl N-tert-butoxycarbonyl-N-[3-(5-phenyl-1,3,4-oxadiazol-2-yl)-5-vinyl-pyrazin-2-yl]carbamate (449 mg, 100%).
Reaction SMILES: [C:1]([CH2:6][S:7][C:8]1[S:9][CH:10]=[CH:11][C:12]=1[CH:13]=O)([O:3][CH2:4][CH3:5])=[O:2].C1CCN2C(=NCCC2)CC1>CO>[S:7]1[C:8]2[S:9][CH:10]=[CH:11][C:12]=2[CH:13]=[C:6]1[C:1]([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CSc1sccc1C=O
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cc2ccsc2s1
Temperature: 25 °C
Yield: 45 %

Procedure:
To a solution of 2-(carboethoxymethylthio)-3-formylthiophene (from step c) in MeOH (200 mL) was added DBU (0.6 mL, 4.0 mmole) at 0° C. After 1 hr the mixture was warmed to RT and concentrated. The residue was taken up in EtOAc, washed with 10% HCl, H2O (3×), dried (MgSO4, and concentrated. Flash chromatography on silica gel (50% toluene/hexanes) gave the title compound (3.84 g, 45% over 4 steps) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.40 (d, J=5.2 Hz, 1H), 7.26 (d, J=5.2 Hz, 1H), methyl ester 3.92 (s, 3H), ethyl ester 4.38 (q, J=7.1 Hz, 2H)) and 1.41 (t, J=2.4 Hz, 3H).
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Br:17])C(=O)C1>C(#N)C>[Br:17][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C1NCc2ccsc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: O=C1NCc2cc(Br)sc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,5-Dihydro-thieno[2,3-c]pyrrol-6-one (0.365 g, 2.63 mmol) is dissolved in acetonitrile (10 mL), and NBS (0.47 g, 2.63 mmol) is slowly added at −10° C. The reaction mixture is stirred at room temperature overnight. The solvent is removed in vacuo and the residue taken-up in EtOAc and washed with 1M NaOH. The organic phase is dried over MgSO4, filtered and concentrated in vacuo. The crude is purified by silica gel column chromatography eluting with a 50:50 mixture and then 50:70 petroleum ether-EtOAc. The title compound is isolated (91.1 mg, 16%). HPLC (254 nm): Rt 2.55 min (70.3%), m/z 218/220 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([CH2:9][C:10]([O-:12])=O)=[N:4][C:3]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[Na+].[CH3:20][CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:31])[C:27]=2[F:30])[NH:22]1>>[F:30][C:27]1[C:26]([F:31])=[CH:25][CH:24]=[C:23]2[C:28]=1[CH2:29][CH:21]([CH3:20])[N:22]2[C:10](=[O:12])[CH2:9][C:5]1[NH:6][C:7](=[O:8])[C:2]([F:1])=[C:3]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[N:4]=1
Reactant: CC1Cc2c(ccc(F)c2F)N1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Agent: [Na+]
Product: CC1Cc2c(ccc(F)c2F)N1C(=O)Cc1nc(N2CCOCC2)c(F)c(=O)[nH]1
Yield: 57.1 %

Procedure:
The product is prepared by following the procedure described in example 1a (step 5a) using 140 mg of sodium (5-fluoro-4-morpholin-4-yl-6-oxo-1,6-dihydropyrimidin-2-yl)acetate obtained in step 2a of example 6a and 93 mg of (−)-2-methyl-4,5-difluoro-2,3-dihydro-1H-indole (reference example 2a). After silica column purification: eluent 98/02 dichloromethane/methanol, 117 mg of 2-[2-((+)-4,5-difluoro-2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl]-5-fluoro-6-morpholin-4-yl-3H-pyrimidin-4-one are obtained in the form of a solid, the characteristics of which are the following:
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7].C(O)C.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:19][O:18][C:14]([CH2:15][S:16][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:7])=[O:17]
Reactant: O=Cc1cccc(CBr)c1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CCO
Product: COC(=O)CSCc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 1.00 g of 3-(bromomethyl)benzaldehyde and 20 ml of ethanol were added 0.65 ml of methyl thioglycolate and 0.47 g of potassium carbonate, and the mixture was stirred at room temperature for 2.5 hours. To the reaction mixture was added diethyl ether, this was washed with an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.36 g of oily 3-[(methoxycarbonylmethylthio)methyl]benzaldehyde [Compound No. (u)].
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[NH:17][CH3:18])=[O:5].C(O[C:28](=[O:30])[CH3:29])(=O)C>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[C:12]2[N:17]([CH3:18])[C:28](=[O:30])[CH3:29])=[O:5]
Reactant: CNc1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C)c1ccnc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A suspension of 8-(2,6-dichlorobenzoylamino)-4-methylaminoquinoline (130 mg) in acetic anhydride (2 ml) was heated at 120° C. for 3 hours. The solvent was removed in vacuo and the residue was dissolved in methanol (3 ml). To a solution was added 1N sodium hydroxide solution (0.5 ml) and the mixture was stirred for 30 minutes. The solvent was removed in vacuo and the residue was washed with hot 50% ethanol (2 ml) and filtered. The residue was washed with hot 95% ethanol (1 ml) and the filtrate was allowed to stand to ambient temperature. The resulting precipitates were collected by filtration and dried to give 8-(2,6-dichlorobenzoylamino)-4-(N-methylacetamido)quinoline (90 mg).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21].[H-].[Na+].COCCOCCN(CCOCCOC)CCOCCOC>CN(C=O)C.O.Cl[Cu]>[F:21][C:20]([F:23])([F:22])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2
Reactant: O=C1CCCc2cc(O)ccc21
Reactant: FC(F)(F)c1ccccc1I
Agent: Cl[Cu]
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCCc2cc(Oc3ccccc3C(F)(F)F)ccc21
Temperature: 50 °C
Yield: 18 %

Procedure:
To a solution of 6-hydroxy-1-tetralone (2.5 g, 15.4 mmol) and 2-iodobenzotrifluoride (25 g, 92 mmol) in DMF (50 mL) was added NaH (0.74 g, 60%, 18.5 mmol) at rt. The mixture was heated to 50° C. until the solid was dissolved and then cooled. To the mixture was added CuCl (1.53 g, 15.4 mmol), followed by tris(dioxa 3,6-heptyl)amine (1.65 mL, 5.15 mmol). The mixture was heated at 145° C. overnight. The reaction was diluted with water, extracted with EtOAc, washed with brine, dried (Na2SO4), and concentrated. Purification by silica gel chromatography (0-20% EtOAc/hexanes) gave 850 mg (18%) of the title compound as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.09-2.16 (2H, m), 2.63 (2H, t, J=6.2 Hz), 2.91 (2H, t, J=6.1 Hz), 6.82 (1H, d, J=2.4 Hz), 6.86 (dd, 1H, J=8.6, 2.4 Hz), 7.05 (1H, d, J=8.2 Hz), 7.27 (1H, td, J=8.2, 0.6 Hz), 7.51-7.56 (1H, m), 7.71 (1H, dd, J=7.8, 1.2 Hz), 8.07 (1H, d, J=8.2 Hz). [M+H] calc'd for C17H13F3O2, 307. found 307.
Reaction SMILES: [OH-].[Na+].C([O:6][CH:7]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])(=O)C.S(=O)(=O)(O)O>CO>[OH:6][CH:7]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23]
Reactant: CCCCCCCCC(/C=C/C=C/c1ccccc1CCCCCO)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCC(O)/C=C/C=C/c1ccccc1CCCCCO
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
6.7 ml of a 0.5 normal sodium hydroxide solution is added to a solution of 270 mg of 5-[2-[(1E,3E)-(5RS)-5-acetoxy-1,3-tridecadienyl]-phenyl]-pentan-1-ol (produced in example 1) in 11.7 ml of methanol and the reaction mixture is stirred for 16 hours at 25° C. Then, it is cooled to 0° C. and acidified with a 0.5 normal sulfuric acid to pH=6. It is extracted three times with methylene chloride and the organic phase is dried on sodium sulfate. It is concentrated by evaporation in a vacuum, and the residue is chromatographed on silica gel. With hexane/50-80% of ethyl acetate as a mobile solvent, 184 mg of the title compound is obtained as a colorless oil.
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)CCC.C1(C)C=CC=CC=1>C(OCC)(=O)C.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>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:2]1[N:6]2[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc2ncc(I)n2c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2ncc(-c3ccccn3)n2c1
Yield: 75.4 %

Procedure:
A mixture of methyl 3-iodoimidazo[1,2-a]pyridine-6-carboxylate (1.00 g, 3.30 mmol), 2-(tri-n-butylstannyl)pyridine (2.44 mg, 6.62 mmol), tetrakis(triphenylphosphine)palladium(0) (381 mg, 0.33 mmol) and toluene (50 mL) was heated under reflux overnight. After cooling, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=4/1-1/1) to give the title compound (630 mg, yield 75%) as colorless crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][CH2:29][CH:30]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][N:28]([C:41]([CH:38]4[CH2:40][CH2:39]4)=[O:42])[CH2:29][CH:30]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH3:31])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNCC(C)c4ccccc4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN(CC(C)c4ccccc4)C(=O)C4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-(4′-{3-Methyl-4-[(2-phenyl-propylamino)-methyl]-isoxazol-5-yl}-biphenyl-4-yl)-cyclopropanecarboxylic acid ethyl ester and cyclopropanecarbonyl chloride.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH2:18][NH:17][C:16](=[O:20])[CH2:15]1)(=[O:13])=[O:12].Br[C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>O.CCOC(C)=O.[Cu]I>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:22]2[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=2)[C:16](=[O:20])[CH2:15]1)(=[O:13])=[O:12]
Reactant: FC(F)(F)c1cccnc1Br
Reactant: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1c1ncccc1C(F)(F)F
Temperature: 110 °C
Yield: 3.2 %

Procedure:
An oven-dried microwave vial was charged with of 4-(naphthalene-2-sulfonyl)-piperazin-2-one (100 mg, 0.34 mmol), 2-bromo-3-trifluoromethyl pyridine (115.3 mg, 0.51 mmol), powdered anhydrous potassium carbonate (94 mg, 0.68 mmol), and CuI (6.5 mg, 0.034 mmol). The vial was purged and back-filled with N2. Anhydrous 1,4-dioxane (1.2 mL) was added, followed by 3.7 μL (0.034 mmol) of N,N′-dimethyl-1,2-ethylenediamine. The blue suspension was heated in a 110° C. oil bath for 48 hr. After cooling to room temperature, the brown suspension was diluted with H2O and EtOAc. The layers were separated, and the aqueous layer washed with EtOAc (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by prep HPLC to provide 4.8 mg (3.2%) of 4-(Naphthalene-2-sulfonyl)-1-(3-trifluoromethyl-pyridin-2-yl)-piperazin-2-one as a light yellow solid.
Reaction SMILES: Br[CH2:2][C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[O:18][CH2:2][C:3](=[O:9])[CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)CC(=O)CBr
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cccc(OCC(=O)CC(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
A stirred solution of the product from Step B (1.626 grams) in dry DMF (18 mL) was combined with 3-methoxyphenol (1.256 grams) and cesium carbonate (3.292 grams). The mixture was stirred for 2.5 hours. The reaction was partitioned between isopropyl acetate and pH4 pthalate buffer. The organic was washed twice with water, dried over magnesium sulfate and filtered. Concentration furnished an oil from which the title compound was isolated by chromatography over silica gel (4:1 hex/ethyl acetate).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[S:17])[N:6]([CH:16]=1)[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:19]([Sn](=O)CCCC)CCC.CI>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH3:19][O:9][C@@H:8]1[C@H:10]([OH:11])[C@@H:12]([CH2:13][OH:14])[O:15][C@H:7]1[N:6]1[CH:16]=[C:2]([CH3:1])[C:3](=[O:18])[NH:4][C:5]1=[S:17]
Reactant: CCCC[Sn](=O)CCCC
Reactant: Cc1cn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=S)[nH]c1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cc(C)c(=O)[nH]c1=S
Temperature: 50 °C

Procedure:
To a stirred solution of 5-methyl-2-thiouridine (0.500 g, 1.8 mmol) in DMF (10 ml) is added dibutyltin oxide (0.500 g, 2.0 mmol), tetrabutyl ammonium iodide (0.738 g, 2 mmol), and methyl iodide (1.022 g, 7.2 mmol). The reaction flask is sealed and heated at 50° C. for 16 hours. The mixture is cooled and another portion of methyl iodide is added (1.022 g, 7.2 mmol) and the reaction heated for an. additional 16 hours. At the end of this time, the reaction mixture is cooled to room temperature and diluted with methylene chloride and chromatographed using a methylene chloride/methanol gradient. The appropriate fractions are collected and concentrated to give 2′-O-methyl-5-methyl-2-thiouridine.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[N:16]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])[CH3:17].Cl>C(O)C>[CH3:22][O:21][CH2:20][CH2:19][CH2:18][N:16]([CH3:17])[C:10]1[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:2]=[O:1])[CH:8]=2)[NH:12][N:11]=1
Reactant: COCCCN(C)c1n[nH]c2ccc(C3OCCCO3)cc12
Agent: Cl
Solvent: CCO
Product: COCCCN(C)c1n[nH]c2ccc(C=O)cc12
Temperature: 90 °C

Procedure:
To a solution of 131 mg (0.429 mmol) 5-(1,3-dioxan-2-yl)-N-(3-methoxypropyl)-N-methyl-1H-indazol-3-amine (Example 50A) in ethanol (7.0 ml) were added 1.43 ml (4.29 mmol) 3 M hydrochloric acid, and the solution was heated to 90° C. for 30 min. After cooling, the mixture was concentrated under reduced pressure. The remaining material (107 mg, 99% of th.) was used in the next step without further purification.