Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][N:29]([C:32](Cl)=[O:33])[C:28]1=[O:35]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH:16][C:32]([N:29]3[CH2:30][CH2:31][N:27]([CH2:26][CH2:25][O:24][CH3:23])[C:28]3=[O:35])=[O:33])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1
Reactant: COCCN1CCN(C(=O)Cl)C1=O
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCCN1CCN(C(=O)Nc2ccc(Oc3ccnc(Cl)c3)c(C)n2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.8 %

Procedure:
A 0° C. mixture of Example A7 (0.350 g, 1.485 mmol) and pyridine (0.251 mL, 3.12 mmol) in DCM (10 mL) was treated with a solution of Example B4 (0.368 g, 1.782 mmol) in DCM (5 mL) and stirred at RT overnight. The mixture was treated with satd. NaHCO3, extracted with DCM (2×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified twice via silica gel chromatography (MeOH/DCM) to afford N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide (487 mg, 81%) as a yellow oil. MS (ESI) m/z: 406.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=2)[CH:17]=1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1>>[CH:27]1([NH:31][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([N:16]3[CH:17]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[CH:15]3)=[CH:19][CH:20]=2)[CH2:30][CH2:29][CH2:28]1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)O)cc2)cn1
Reactant: NC1CCC1
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc(C(=O)NC3CCC3)cc2)cn1
Yield: 11 %

Procedure:
As described for Example 71c, 4-[4-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazol-1-yl]-benzoic acid (100 mg, 0.29 mmol) was converted, using cyclobutylamine instead of cyclopropylmethylamine, to the title compound (13 mg, 11%) which was obtained as an off-white solid. MS: m/e=398.9 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:14](SC)=[N:15][CH2:16][Si](C)(C)C)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][CH:11]=[N:10]1)#[N:2].[Cl:23][C:24]1[CH:29]=[C:28]([C:30]([C:32]([F:35])([F:34])[F:33])=[CH2:31])[CH:27]=[C:26]([Cl:36])[N:25]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:23][C:24]1[CH:29]=[C:28]([C:30]2([C:32]([F:33])([F:34])[F:35])[CH2:31][C:14]([C:5]3[CH:6]=[CH:7][C:8]([N:9]4[CH:13]=[N:12][CH:11]=[N:10]4)=[C:3]([CH:4]=3)[C:1]#[N:2])=[N:15][CH2:16]2)[CH:27]=[C:26]([Cl:36])[N:25]=1
Reactant: C=C(c1cc(Cl)nc(Cl)c1)C(F)(F)F
Reactant: CSC(=NC[Si](C)(C)C)c1ccc(-n2cncn2)c(C#N)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C2=NCC(c3cc(Cl)nc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Reaction time: 0.5 h
Yield: 46 %

Procedure:
To the crude solution of methyl 3-cyano-4-(1H-1,2,4-triazol-1-yl)-N-[(trimethylsilyl)methyl]benzenecarbimidothioate (Japanese patent application JP2008-143120) was added 2,6-dichloro-4-(3,3,3-trifluoroprop-1-en-2-yl)pyridine (0.15 g) and the resultant mixture was cooled to −10° C. Additionally, a solution of tetrabutylammonium fluoride (0.70 mL of 1.0 M in THF) in THF was added over 10 minutes under argon atmosphere. The reaction mixture was stirred for 30 minutes at the same temperature and returned to room temperature gradually, and then stirred 3 hours. Water was added to the reaction liquor, and aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a saturated aqueous brine, and subsequently dried over magnesium sulfate. After filtering the reaction mixture, the solvent was distilled off under reduced pressure, and the resulting mixture was purified by silica gel chromatography, to obtain 5-[3-(2,6-dichloropyridin-4-yl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.14 g) at a yield of 46%.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH2:12][CH2:13][N:14]=[C:7]1[CH:6]=[CH:5]2.[SH:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.CCN(C(C)C)C(C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:12]1[N:8]2[C:9]3[C:4]([CH:5]=[CH:6][C:7]2=[N:14][CH2:13]1)=[CH:3][C:2]([S:15][C:16]1[CH:17]=[C:18]([C:22]2([OH:28])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1)=[CH:11][CH:10]=3
Reactant: Ic1ccc2c(c1)C=CC1=NCCN12
Reactant: OC1(c2cccc(S)c2)CCOCC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: OC1(c2cccc(Sc3ccc4c(c3)C=CC3=NCCN34)c2)CCOCC1
Temperature: 80 °C

Procedure:
2a (175 mg, 0.59 mmol) and 4-(3-mercapto-phenyl)-tetrahydro-pyran-4-ol (2b, 150 mg, 0.71 mmol) were combined in 1,4-dioxane (6 mL) and degassed with N2 for 10 minutes. iPr2NEt (0.33 mL, 1.8 mmol) was added, followed by Pd2dba3 (14 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16 mg, 0.03 mmol). The mixture was degassed with N2 for an additional 10 minutes, and then heated to 80° C. for 24 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (0-20% MeOH in EtOAc) to give the desired product, 2c.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27](O)=[O:28])[N:11]=1.CCN(CC)CC.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[CH3:52][N:53]1[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]1>C(Cl)Cl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:17]=2)[N:12]([CH2:26][C:27]([N:56]2[CH2:57][CH2:58][N:53]([CH3:52])[CH2:54][CH2:55]2)=[O:28])[N:11]=1
Reactant: Cc1cccc(C)c1Nc1nn(CC(=O)O)c2cc(Nc3ccccc3)ccc12
Reactant: CN1CCNCC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Nc1nn(CC(=O)N2CCN(C)CC2)c2cc(Nc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 100 mg (0.26 mmol) of 2-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-indazol-1-yl)acetic acid 69 (Example 34) in DCM (10 mL) at room temperature was treated with Et3N (43 μL, 1.2 eq) followed with Bop-Cl (73 mg, 1.1 eq) and 1-methylpiperazine (35 μL, 1.2 eq). The mixture was stirred at room temperature for 3 hours before it was quenched with water (5 mL). The organic layer was separated and washed with water, brine, dried over sodium sulfate and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (eluens: DCM:MeOH:NH4OH, 20:1:0.2) to give the title compound 70. 1H-NMR (CDCl3) δ 2.28 (s, 6H), 2.32 (s, 3H), 2.35-2.45 (m, 4H), 3.59-3.69 (m, 4H), 4.98 (s, 2H), 5.91 (s, 1H), 7.04 (t, J=7.3 Hz, 1H), 7.08-7.16 (m, 3H), 7.19 (s, 1H), 7.32 (t, J=8.4 Hz, 2H), 7.47 (s, 1H), 7.58 (d, J=7.7 Hz, 2H). Mass Spectrum (ESI) m/e=471 (M+1).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>O.C(O)(=O)C>[F:5][C:6]([F:15])([F:16])[C:7](=[O:14])[C:8](=[N:1][OH:3])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)C(F)(F)F
Temperature: 15 °C
Reaction time: 2 h

Procedure:
A solution of sodium nitrite (0.29 mmol) in 35 mL of water was added dropwise over 50 minutes to a stirred, ice-cooled solution of 22.8 g of ethyl 4,4,4-trifluoroacetoacetate (0.12 mmol) in 30 mL of acetic acid. The reaction was continued for 2 hours, with gradual warming to 15° C. Water and acetic acid were removed under reduced pressure (azeotroped with toluene). The crude product was partitioned between ethyl acetate and saturated aqueous potassium hydrogen carbonate solution. The layers were separated. The ethyl acetate layer was washed with saturated aqueous potassium hydrogen carbonate solution and brine, dried over sodium sulfate and concentrated to yield 21.4 g of the title A compound as a light yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH2:14][C:15](Cl)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[C:19]1([C:25]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:33]3[CH:29]([CH2:30][NH:31][CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[C:43]1([C:25]2([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:33]3[CH:29]([CH2:30][N:31]([C:15](=[O:16])[CH2:14][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:32]3)[C:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])([OH:34])[CH2:27][CH2:26]2)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Reactant: O=C(Cl)Cc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccccc1C1(O)CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3)CC21
Reaction time: 24 h

Procedure:
0.35 cm3 of triethylamine and then 0.33 cm2 of phenylacetyl chloride are added to a suspension of 1.1 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindol-4-ol hydrochloride in 25 cm3 of dry dichloromethane at room temperature. The reaction mixture is stirred at this temperature for 24 hours, diluted with 200 cm3 of dichloromethane, washed with 100 cm3 of a saturated solution of sodium bicarbonate, with 100 cm3 of water (twice) and then with an aqueous saturated solution of sodium chloride, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a Merck silica gel column (particle size 0.04-0.06 mm, diameter 2 cm, height 22 cm) by eluting under a nitrogen pressure of 50 kPa with a mixture of cyclohexane and ethyl acetate (55/45 by volume) and collecting fractions of 20 cm3. Fractions 11 to 18 are combined and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is crystallized from 70 cm3 of acetonitrile and the crystals are filtered off and dried. 0.5 g of (3aRS,4RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-2-(phenylacetyl)perhydroisoindol-4-ol is obtained in the form of a white solid.
Reaction SMILES: [CH:1](=[C:8]1[CH2:17][CH2:16][C:11]2(OCC[O:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(C)=O.Cl.O>[CH:1](=[C:8]1[CH2:17][CH2:16][C:11](=[O:12])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C(=C1CCC2(CC1)OCCO2)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(=Cc2ccccc2)CC1
Reaction time: 4 h
Yield: 96.2 %

Procedure:
Under vigorous stirring, at rt, 8-benzylidene-1,4-dioxaspiro-[4.5]-decane (1.8 g, 7.81 mmol) was dissolved in a acetone/HCl (10% v/v) mixture (70 mL:35 mL) and left to stir 4 h. The crude mixture was diluted in water and extracted with AcOEt (3×40 mL). The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated to dryness to afford pure title compound (1.4 g, 96%) as colorless oil. 1H NMR (CDCl3): δ 2.44 (t, J=7.0 Hz, 2H), 2.53 (t, J=6.8 Hz, 2H), 2.65-2.72 (m, 2H), 2.74-2.80 (m, 2H), 6.49 (s, 1H), 7.21-7.27 (m, 3H), 7.32-7.39 (m, 2H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20](Cl)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4].[O:29]1[CH:33]=[CH:32][CH:31]=[C:30]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([NH:5][C:6]1[N:11]=[C:10]([C:12]2[C:13]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:14][N:15]3[C:20]([C:30]4[O:29][CH:33]=[CH:32][CH:31]=4)=[CH:19][CH:18]=[CH:17][C:16]=23)[CH:9]=[CH:8][N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(Cl)cccc23)n1
Reactant: OB(O)c1ccco1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCNc1nccc(-c2c(-c3ccc(F)cc3)nn3c(-c4ccco4)cccc23)n1
Temperature: 25 °C
Yield: 39.4 %

Procedure:
A solution of N-butyl-4-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]pyrimidin-2-amine (35 mg, 0.089 mmol), 2-furylboronic acid (30 mg, 0.27 mmol), sodium carbonate (155 μL, 2.0 M aqueous, 0.31 mmol), and dichlorobis(triphenylphosphine)palladium(II) (3 mg, 0.004 mmol) was heated at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. Filtration and concentration, followed by flash chromatography (4:1 hexanes:ethyl acetate) provided N-butyl-4-[2-(4-fluorophenyl)-7-(2-furyl)pyrazolo[1,5-α]pyridin-3-yl]pyrimidin-2-amine (15 mg, 39%) as a yellow solid. Rf 0.19 (4:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 8.35 (d, 1H), 8.11–8.07 (m, 2H), 7.73 (m, 2H), 7.63 (s, 1H), 7.57 (d, 1H), 7.43 (t, 1H), 7.16 (t, 2H), 6.66 (m, 1H), 6.41 (d, 1H), 5.17 (m, 1H), 3.50 (q, 2H), 1.67 (m, 2H), 1.49 (m, 2H), 0.99 (t, 3H); MS m/z 428 (M+1).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C:17]([CH2:21][NH2:22])([CH3:20])[CH2:16]1)=[N:10][C:9]([O:23][CH3:24])=[CH:8][CH:7]=2.[O:25]=[C:26]1[CH2:31][S:30][C:29]2[CH:32]=[CH:33][C:34]([CH:36]=O)=[N:35][C:28]=2[NH:27]1>CO>[F:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][C:17]([CH2:21][NH:22][CH2:36][C:34]3[CH:33]=[CH:32][C:29]4[S:30][CH2:31][C:26](=[O:25])[NH:27][C:28]=4[N:35]=3)([CH3:20])[CH2:16]1)=[N:10][C:9]([O:23][CH3:24])=[CH:8][CH:7]=2
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2ncc(F)c(CCN3CCC(C)(CN)C3)c2n1
Agent: Cl
Solvent: CO
Product: COc1ccc2ncc(F)c(CCN3CCC(C)(CNCc4ccc5c(n4)NC(=O)CS5)C3)c2n1
Reaction time: 24 h
Yield: 23.5 %

Procedure:
To a solution of the HCl salt of (±)-[(1-{2-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]ethyl}-3-methyl-3-pyrrolidinyl)methyl]amine (100 mg, 0.257 mmol) in MeOH (3 mL) were added NaHCO (215 mg, 2.57 mmol) followed by 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (51 mg, 0.317 mmol). After 24 h at 25° C., NaBH (15 mg, 0.398 mmol) was added. After 1 h, the reaction was concentrated and the residue was partitioned between DCM-H O. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over MgSO, concentrated and purified via column chromatography (silica, 4% MeOH in DCM (1% NH OH)) yielding the title compound (30 mg, 24%) as a brown oil: LC/MS (ES) m/e 497 (M+H)+; 1H NMR (CDCl3, 400 MHz) δ 8.8 (bs, 1H), 8.65 (s, 1H), 8.22 (d, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.19 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12 (s, 3H), 3.83 (s, 2H), 3.51 (s, 2H), 3.46-3.50 (m, 2H), 2.9 (m, 4H), 2.5 (m, 3H), 2.3 (m, 1H), 1.85 (m, 1H), 1.55 (m, 1H), 1.1 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18](Cl)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([O:29][C:30]([NH:32][CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(CC)CC)C>ClCCl>[CH2:1]([O:8][N:9]1[C:14](=[O:15])[C:13]2[CH:16]=[C:17]([F:21])[C:18]([N:35]3[CH2:36][CH2:37][CH:33]([NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])[CH2:34]3)=[N:19][C:12]=2[N:11]([CH2:22][CH3:23])[C:10]1=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(Cl)nc21
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)nc21
Yield: 85.7 %

Procedure:
Following the procedure of Example X-2, the reaction of 3-benzyloxy-7-chloro-1-ethyl-6-fluoro-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example N-2, 200 mg, 0.572 mmol) with 3-(N-tert-butoxycarbonylamino)pyrrolidine (117 mg, 0.629 mmol) in dichloromethane (5 mL) in the presence of triethylamine (0.087 mL) afforded 245 mg of the title compound as a solid, mp 157-159° C.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@:9]([OH:59])([C@@H:17]([C:38](=[O:58])[NH:39][C@H:40]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:49][C:50]#[C:51][CH3:52])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])OCC[O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[Cl-].[Na+].O>C(#N)C>[CH2:49]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:40]([NH:39][C:38]([C@@H:17](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@:9]([OH:59])([CH2:8][CH2:7][OH:6])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])=[O:58])[C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:47][CH:46]=1)[C:50]#[C:51][CH3:52]
Reactant: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC2(CCCCCCC)OCCO2)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-2-(4-but-2-ynyloxy-phenyl)-1-ethoxycarbonyl-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (3.92 g, 4.49 mmol) was dissolved in acetonitrile (43 mL), and an aqueous solution of 0.5 M citric acid (19 mL, 9.50 mmol) was then added. The mixture was then stirred at 60° C. for 2.5 hours. The reaction solution was cooled to room temperature, and a mixture of a saturated aqueous solution (3.0 mL) of sodium chloride and water (60 mL) was then added. The solution was extracted three times with 20% ethyl acetate/n-hexane (32 mL). The organic layers were combined, then washed twice with a saturated aqueous solution (32 mL) of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was then distilled off under reduced pressure to obtain 3.24 g (4.54 mmol, quant) of No. 5328627.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:29]I>ClCCl.C([O-])(=O)C.[Ag+]>[CH2:1]([O:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:22]([CH3:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[C:19]3[C:15]=2[CH2:16][CH2:17][CH2:18]3)=[CH:11][C:10]=1[I:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)cc1)CCC2
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(I)c1)CCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.5 %

Procedure:
To a solution of 4-(4-benzyloxyphenoxy)-5-methyl-7-nitroindane (3.21 g) in dichloromethane (15 mL) was added silver acetate (1.86 g). After adding iodine (2.60 g), the mixture was stirred under an argon atmosphere in the dark at room temperature for 2 days. The insoluble material was removed by filtration. The filtrate was washed with an aqueous solution of sodium sulfite (1.7 g/40 mL), a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.18 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[OH:28])[CH:21]=[CH:20][N:19]=1>>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[CH:18]=[N:19][CH:20]=[CH:21]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: Oc1cccc2ccncc12
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Product: FC(F)(F)c1ccc(-c2cc(Oc3cccc4ccncc34)ncn2)cc1

Procedure:
The title compound was prepared from 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example 2(a), Method A) and isoquinolin-8-ol (MonomerChem) under the conditions of Example 6. Mp: 194–195° C. MS (ESI, pos. ion m/z: 3682. (M+1).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH3:13][CH:14]([CH3:19])[C:15]([O:17][CH3:18])=[O:16].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26]>C1COCC1>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([C:25](=[O:26])[C:14]([CH3:19])([CH3:13])[C:15]([O:17][CH3:18])=[O:16])[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]
Reactant: COC(=O)C(C)C
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(C)(C)C(=O)c1ccc(OC)c(OC)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
124 ml of diisopropylamine is dissolved in 500 ml of THF under a blanket of dry nitrogen and cooled to 0° C. and 550 ml n-BuLi (1.6M in hexane) is added dropwise. Next, the mixture is cooled to minus 40° C., using an acetone/N2 bath, and 100 ml methyl 2-methylproponate is added. The resulting mixture is stirred for an additional 15 min at minus 40° C., after which 160.5 g of 3,4-dimethoxybenzoyl chloride dissolved in 750 ml of THF is added dropwise in 60 min during which the temperature is kept below −40° C. The cooling bath is removed and stirring is continued for 60 min at RT. 150 ml of 4M hydrochloric acid is added and the THF layer is separated and washed with 100 ml of water, 200 ml 1M of sodium carbonate and 100 ml of brine, dried over MgSO4 and concentrated in vacuo.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[S:23][C:22]([CH:24]4OCCC[O:25]4)=[N:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].Cl.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[S:23][C:22]([CH:24]=[O:25])=[N:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(c2nc(-c3cnc(C4OCCCO4)s3)cc3ccccc23)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN1CCN(c2nc(-c3cnc(C=O)s3)cc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
1-(1-Ethylpiperazin-4-yl)-3-[2-(1,3-dioxan-2-yl)thiazol-5-yl]isoquinoline (205 mg) was dissolved in tetrahydrofuran (4 ml), followed by the addition of 1N hydrochloric acid (3 ml), and the resulting mixture was stirred at room temperature for 8 hr. The reaction solution was basified by adding 8N sodium hydroxide thereto, and then extracted with in ethyl acetate. The resulting organic layer was washed with water, dried (over MgSO4) and evaporated, to give the title compound as a colorless oil (155 mg, yield; 80%).