Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:21])[F:22])=[CH:14][CH:13]=3)[CH2:16][CH2:17]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 0.25 h

Procedure:
A 100-mL round-bottomed was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (0.54 g, 1.65 mmol, published PCT patent application no. WO 2006/094842), 10 mL of CH2Cl2, and 5-bromo-2-thiophenesulfonyl chloride (0.43 g, 1.65 mmol, Sigma-Aldrich, St. Louis, Mo.). To this was added triethylamine (0.28 mL, 2.06 mmol). After 15 min at room temperature, the mixture was diluted with 10 mL of CH2Cl2 and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0-50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.83 g) as a white solid.
Reaction SMILES: Cl[CH:2]([C:7]([CH3:9])=O)[C:3]([O:5][CH3:6])=[O:4].[C:10]([NH2:18])(=[S:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCO>[CH3:9][C:7]1[N:18]=[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[S:17][C:2]=1[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(Cl)C(C)=O
Reactant: NC(=S)c1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccccc2)nc1C
Yield: 41.8 %

Procedure:
A solution of methyl 2-chloroacetoacetate (1.86 g, 12.4 mmol) and thiobenzamide (1.7 g, 12.4 mmol) in EtOH (50 mL) was refluxed for 18 h. The mixture was evaporated to dryness and the resulting oil was purified by flash chromatography to give methyl 4-methyl-2-phenylthiazole-5-carboxylate (1.21 g, 42%) as a colourless oil: 1H NMR (300 MHz, CDCl3) δ (TMS) 8.0-7.9 (m, 2H, arom), 7.5-7.4 (m, 3H, arom), 3.87 (s, 3H, OMe), 2.76 (s, 3H, Me-thiazole). Analysis calculated for C12H11NO2S: C 61.78; H 4.75; N 6.00; S 13.74. Found: C 61.56; H 4.71; N 5.82; S 14.61.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:20][C:19](=[O:21])[O:18][CH2:17][C:16]=2[CH:22]=1)(=O)C.C(O)(=O)C>O.CO>[OH:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:20][C:19](=[O:21])[O:18][CH2:17][C:16]=2[CH:22]=1
Reactant: CC(=O)OCCCCOc1ccc2c(c1)COC(=O)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: O=C1Nc2ccc(OCCCCO)cc2CO1
Temperature: 0 °C

Procedure:
A solution of 24 gm (0.6 mol) of sodium hydroxide in 100 ml of water is added dropwise to a solution of 150 gm (0.537 mol) of 6-(4-acetoxy-butoxy)-4H-3,1-benzoxazin-2-one in 500 ml of methanol, under stirring, at 10° to 15° C. After the mixture has been stirred for one hour at ambient temperature, first ice water and then 60 ml of glacial acetic acid are added. The product precipitated is subjected to suction filtration and recrystallized from water.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]2[C:9]3[N:10]([N:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=3)[C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(O)(=[O:24])C>>[CH3:15][O:14][C:11]1[N:10]2[N:16]=[C:17]([CH:19]([CH3:21])[CH3:20])[CH:18]=[C:9]2[C:8]([C:5]2[CH:4]=[CH:3][C:2](=[O:24])[NH:7][N:6]=2)=[CH:13][CH:12]=1
Reactant: CC(=O)O
Reactant: COc1ccc(-c2ccc(Cl)nn2)c2cc(C(C)C)nn12
Product: COc1ccc(-c2ccc(=O)[nH]n2)c2cc(C(C)C)nn12
Temperature: 90 °C
Reaction time: 3 h

Procedure:
The compound of Example 268 (50 mg) was dissolved in acetic acid (2 mL) and the solution was stirred at 90° C. for 3 hours. Subsequently, the solvent was concentrated and the residue was purified by silica gel column chromatography (methanol:ethyl acetate 1:9) to afford the title compound as a pale yellow powder (26 mg).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[CH2:15][OH:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:26])[CH3:25].Cl>C(Cl)Cl.O1CCOCC1>[C:24]([O:16][CH2:15][C:13]1[C:12]2[C:7]([CH:6]=[C:5]3[C:14]=1[CH:1]=[CH:2][CH:3]=[CH:4]3)=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: OCc1c2ccccc2cc2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)OCc1c2ccccc2cc2ccccc12
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 61 %

Procedure:
A solution of 9-anthracenemethanol (15.0 g, 72 mmole) and triethylamine (7.3 g, 72 mmole) in methylene chloride (100 ml) and 1,4-dioxane (120 ml) was cooled. Acetyl chloride (6.8 g, 86.4 mmole) was added dropwise to the solution at 5°-10° C. and reacted with stirring for 2.5 hours at same temperature. After reaction, the reaction mixture was poured into ice-cold H2O (350 ml), acidified with 10% aqueous HCl, extracted with methylene chloride (100 ml). The resulting organic layer was washed with H2O (100 ml×1), saturated aqueous sodium bicarbonate (100 ml×1) and H2O (100 ml×1), dried over anhydrous MgSO4 and evaporated. The residual crude solid (17.7 g) was recrystallized from n-hexane to give 11.0 g of 9-anthrylmethyl acetate as yellow needles having a melting point of 110.0°-111.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[CH2:23][C:24]1[O:25][CH:26]=[CH:27][CH:28]=1>C(OCC)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccco1
Reactant: CCOC(=O)N1CCC(c2c[nH]c3cc(F)ccc23)CC1
Solvent: CCOCC
Product: CCOC(=O)N1CCC(c2cn(Cc3ccco3)c3cc(F)ccc23)CC1
Reaction time: 15 h
Yield: 100 %

Procedure:
This compound was prepared following the procedure described in example 13 (part B) at room temperature for 15 hours, starting with 0.3 g (1.0 mmol) of 4-(6-fluoro-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester and 2.7 mL (1.6 mmol) of a freshly prepared 0.61 M solution of 2-bromomethylfuran in ethyl ether. After standard work-up, 0.38 g (100% of yield) of 4-(6-fluoro-1-furan-2-ylmethyl-1H-indol-3-yl)-piperidine-1-carboxylic acid ethyl ester were obtained.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].O.O.[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34]>C1C=CC=CC=1>[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[C:32]([OH:37])(=[O:36])[C:33]([OH:35])=[O:34].[N:18]1([CH2:17][CH2:16][N:12]2[CH2:13][CH2:14][CH:10]([O:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: ClCCN1CCCCC1
Reactant: C1CCN(CCOC2CCNC2)CC1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C1CCN(CCOC2CCN(CCN3CCCCC3)C2)CC1
Yield: 32 %

Procedure:
A solution of 10.0 g. (0.051 mole) of 3-(2-piperidinoethoxy)pyrrolidine and 10.4 g. (0.07 mole) of 1-(2-chloroethyl)piperidine in 200 ml. dry benzene was stirred with 28 g. (0.2 mole) of potassium carbonate at reflux for 15 hr. After cooling, the reaction mixture was filtered and concentrated. The residual oil was molecularly distilled to give a slightly impure product which when treated with three equivalents of oxalic acid dihydrate gave 9.3 g. of the trioxalate salt, m.p. 155°-162° C. (32% yield). The salt was recrystallized from methanol to give 5.8 g. of white crystalline salt, m.p. 177°-179° C.
Reaction SMILES: [CH:1]1([C:5]([OH:7])=[O:6])[CH2:4][CH2:3][CH2:2]1.OS(O)(=O)=O.O.[CH3:14][CH2:15]O>>[CH:1]1([C:5]([O:7][CH2:14][CH3:15])=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C1CCC1
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOC(=O)C1CCC1
Yield: 69 %

Procedure:
To a solution of cyclobutanecarboxylic acid (50 g, 500 mmol) in EtOH (1.2 L) was slowly added H2SO4 (20 mL) at room temperature. The solution was stirred at reflux overnight, and then cooled and poured into H2O. The aqueous layer was extracted with ether. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give ethyl cyclobutanecarboxylate as a colorless oil (44 g, 69%). 1H NMR (400 MHz, CDCl3-d3) δ 4.04 (q, 2H), 3.04 (m, 1H), 2.12 (m, 4H), 1.88 (m, 2H), 1.18 (t, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.C(S[C:18](=[O:39])[CH2:19][C@H:20]([NH:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])C1C=CC=CC=1.Cl.[NH2:41][C@@H:42]([CH2:48][SH:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44]>CN(C=O)C.O>[C:35]([O:34][C:32]([NH:31][C@@H:20]([CH2:19][C:18]([NH:41][C@@H:42]([CH2:48][SH:49])[C:43]([O:45][CH2:46][CH3:47])=[O:44])=[O:39])[C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)SCc1ccccc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)[C@@H](N)CS
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](CS)NC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
DIPEA (0.098 ml, 0.563 mmol) was added to a solution of (S)-benzyl 4-(benzylthio)-2-((tert-butoxycarbonyl)amino)-4-oxobutanoate (Compound 5b-1) (201.5 mg, 0.469 mmol) and (R)-ethyl 2-amino-3-mercaptopropanoate hydrochloride (104.5 mg, 0.563 mmol) in DMF (1.2 ml) and water (0.3 ml), and the mixture was stirred at 50° C. for three hours. Water was then added to the reaction solution, and the mixture was purified by reverse phase silica gel column chromatography (10 mM aqueous ammonium acetate solution/methanol=80/20→0/100) to afford (S)-benzyl 2-((tert-butoxycarbonyl)amino)-4-(((R)-1-ethoxy-3-mercapto-1-oxopropan-2-yl)amino)-4-oxobutanoate (Compound 5c-1) (133 mg, 67%).
Reaction SMILES: Br.[CH2:2]([O:4][C:5]([C:7]1[C:8]([CH2:22][CH2:23][CH3:24])=[N:9][S:10][C:11]=1[NH:12][C:13]([O:15]C1C=CC=CC=1)=O)=[O:6])[CH3:3].[CH3:25][NH2:26]>>[CH2:2]([O:4][C:5]([C:7]1[C:8]([CH2:22][CH2:23][CH3:24])=[N:9][S:10][C:11]=1[NH:12][C:13]([NH:26][CH3:25])=[O:15])=[O:6])[CH3:3]
Reactant: CN
Reactant: CCCc1nsc(NC(=O)Oc2ccccc2)c1C(=O)OCC
Agent: Br
Product: CCCc1nsc(NC(=O)NC)c1C(=O)OCC

Procedure:
4-Ethoxycarbonyl-5-phenoxycarbonylamino-3-n-propylisothiazol hydrobromide (41.5 g.) was heated at reflux in ethanolic methylamine (33% w/v; 100 ml.) for 15 minutes. The solution was filtered and on cooling deposited white crystals, which were filtered off and washed with water to give 1-(4-ethoxycarbonyl-3-n-propylisothiazol-5-yl)-3-methylurea (18.5 g.), m.p. 173°-174° C.
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([N:13]1[CH2:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@@:15]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[F:32])([C:23]#[N:24])[C@H:14]1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:39])[C:34]=1[F:40])=[O:12].[Li+].[OH-]>C1COCC1.O>[Cl:39][C:35]1[C:34]([F:40])=[C:33]([C@@H:14]2[C@:15]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=3[F:32])([C:23]#[N:24])[C@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:17][N:13]2[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:41])=[O:2])=[O:12])[CH:38]=[CH:37][CH:36]=1
Reactant: COC(=O)c1ccccc1NC(=O)N1C[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)C[C@@H]1CN(C(=O)Nc2ccccc2C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 23 h
Yield: 94.8 %

Procedure:
To a mixture of rac-2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]amino}-benzoic acid methyl ester (53.0 mg, 0.0883 mmol, Example C3) in THF (3 mL) was added a solution of LiOH (Aldrich, 21.8 mg, 0.52 mmol) in water (2 mL) and the reaction mixture was stirred at rt for 23 hrs. The reaction mixture was partly concentrated and quenched with 1 N HCl (pH 4-5), extracted with EtOAc, and washed with water, saturated NaCl. The organic phase was separated, and dried over Na2SO4. The mixture was then concentrated to give 2-{[(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carbonyl]-amino}-benzoic acid (49.1 mg, 95%). HRMS (ES+) m/z Calcd for C30H27Cl2F2N3O3+H [(M+H)+]: 586.1471; Found: 586.1474.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:8][C:7]1[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[CH:3][C:4]([O:28][CH3:29])=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccnc2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 60.6 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 74.29 mg, 0.165 mmol) pyridin-3-ylboronic acid (24.30 mg, 0.198 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.691 mg, 4.12 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (6.24 mg, 8.24 μmol) and potassium phosphate (105 mg, 0.494 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (749 μl) and water (74.9 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (4×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM) to give 1-(5-fluoro-2-methoxy-4-(pyridin-3-yl)phenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (49.13 mg, 0.100 mmol, 60.4% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.53 (br. s., 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.67 (dd, J=1.3, 4.7 Hz, 1H), 8.57 (d, J=1.7 Hz, 1H), 8.14 (d, J=5.8 Hz, 2H), 7.96-7.87 (m, 1H), 7.86-7.78 (m, 1H), 7.63-7.54 (m, 1H), 7.45-7.36 (m, 2H), 3.73 (s, 3H). m/z (ESI) 494.1 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:5][CH:4]=1)=[CH2:2].N1C=CC=CC=1C1C=CC=CN=1.Br[CH:34]([C:39]1[CH:40]=[C:41]([Cl:47])[C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=1)[C:35]([F:38])([F:37])[F:36]>ClC1C=CC=CC=1Cl.Cl[Cu]>[F:38][C:35]([F:36])([F:37])[CH:34]([C:39]1[CH:40]=[C:41]([Cl:47])[C:42]([Cl:46])=[C:43]([Cl:45])[CH:44]=1)/[CH:2]=[CH:1]/[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]2=[O:20])=[CH:7][CH:8]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=Cc1ccc(NN2C(=O)c3ccccc3C2=O)cc1
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Nc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1
Temperature: 180 °C
Yield: 77.8 %

Procedure:
To a stirred solution of 2-(4-vinylphenylamino)isoindoline-1,3-dione (0.3 g, 1.1 mmol) in 1,2-dichlorobenzene (5 mL) were added CuCl (0.022 g, 0.273 mmol), 2,2-bipyridyl (0.07 g, 0.46 mmol) and 5-(1-bromo-2,2,2-trifluoroethyl)-1,2,3-trichlorobenzene (0.77 g, 2.27 mmol). The reaction mixture was degassed with argon for 30 min and was heated at 180° C. for 2 h. The reaction mixture was then concentrated under reduced pressure, and the residue was purified by column chromatography (SiO2, O-30% EtOAc in petroleum ether) to afford the title compound as a solid (450 mg, 75%): mp 187-189° C.; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 7.96 (m, 4H), 7.82 (s, 2H), 7.37 (d, J=8.8 Hz, 1H), 6.73 (d, J=8.4 Hz, 2H), 6.61 (m, 2H), 6.58 (m, 1H), 4.59 (m, 1H); ESIMS m/z 523.05 ([M−H]−).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]3)[N:15]3[N:32]=[CH:33][CH:34]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[N:15]3[N:32]=[CH:33][CH:34]=[C:14]3[N:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:35]=[CH:36][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[CH:17]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](N)C3)n3nccc3n2)cc1
Reaction time: 6 h

Procedure:
(R)-tert-butyl 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-3-ylcarbamate was dissolved in CH2Cl2. Trifluoroacetic acid was added and the mixture was let stirred for 6 hours. The reaction mixture was concentrated to dryness in vacuo, and part of the residue was purified by preparatory HPLC (20-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.97 (s, 1H), 8.13 (d, J=2.3 Hz, 1H), 8.11-8.03 (m, 2H), 8.03-7.97 (m, 2H), 7.64-7.57 (m, 2H), 7.48 (s, 1H), 6.40 (d, J=2.3 Hz, 1H), 4.23 (br. s., 1H), 3.97 (br. s., 2H), 3.47 (d, J=7.1 Hz, 2H), 3.28 (br. s., 1H), 2.08 (br. s., 1H), 1.96 (br. s., 1H), 1.85-1.64 (m, 2H), 1.46 (s, 6H); ESI-MS: m/z 377.4 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6].[H-].[Na+].[CH3:37]I>C1COCC1>[CH3:37][O:1][CH:2]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:3][NH:4][C:5]([C:7]1[N:8]=[N:9][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:30])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]([F:28])([F:29])[F:27])[CH2:15][CH2:14]2)=[CH:11][CH:12]=1)=[O:6]
Reactant: CC(C)(C)C(O)CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(CNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.2 %

Procedure:
To a solution of 6-[4-(2-trifluoromethylbenzoyl)piperazin-1-yl]pyridazine-3-carboxylic acid (2-hydroxy-3,3-dimethylbutyl)amide (81.6 mg, 0.17 mmol) in THF (1.0 mL) was added sodium hydride (5.0 mg, 0.19 mmol), followed by methyl iodide (15 mL, 0.26 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then the solvent was removed. The gummy material was diluted with dichloromethane (5 mL), washed with water (2×2 mL), dried over MgSO4 and filtered off the solid. After the solvent was concentrated into dryness, the crude material was subjected to column chromatography eluted sequentially with ethyl acetate:hexane (1:1) and ethyl acetate to obtain 25.3 mg (30%) of the product as solid. m.p. 65-68° C. 1H NMR (300 MHz, CDCl3) δ 7.73-7.69, 7.62, 7.53, 7.33, 6.98-6.93, 4.18-3.59, 3.48, 3.41, 3.37-3.26, 3.18, 3.03-2.98, 1.76, 0.98, 0.75. 13C NMR (75 MHz, CDCl3) δ 167.6, 166.4, 158.9, 149.8, 149.3, 134.3, 132.4, 129.5, 129.4, 129.3, 129.1, 127.2, 126.9-126.7, 112.7, 88.1, 61.7, 61.4, 52.7, 52.0, 46.4, 44.7, 44.6, 44.5, 44.4, 41.3, 41.2, 40.5, 35.8, 35.3, 35.0, 26.0, 25.9, 25.7. MS (ES+) m/z 508 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1([C:28]#[C:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(#N)C.N12CCCN=C1CCCCC2.Cl>>[CH:23]1(/[C:28](/[N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)=[CH:29]\[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: COC(=O)C#CC1CCCC1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)/C=C(\C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 38.2 %

Procedure:
To a stirred suspension of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (17, 12.08 g, 38.31 mmol) and methyl 3-cyclopentylprop-2-ynoate (18, 8.970 g, 45.97 mmol, 1.2 equiv) in acetonitrile (76 mL, 1400 mmol) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 2.92 mL, 19.2 mmol, 0.5 equiv). The resulting reaction mixture was stirred at room temperature for 2 h. When LCMS showed the reaction was deemed complete, the reaction mixture was quenched with water (50 mL) and 1 N aqueous HCl solution (20 mL). The quenched reaction mixture was adjusted to pH 4 after treatment with 1 N aqueous HCl solution. The mixture was then extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, dried over magnesium sulfate (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by Combiflash (SiO2, 0-50% EtOAc/hexane gradient elution) to afford (E)-methyl 3-cyclopentyl-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)acrylate (21, 6.838 g, 17.92 g theoretical, 38% in yield) as a colorless, very viscous oil. For 19: 1H NMR (CDCl3, 400 MHz) δ ppm 8.93 (s, 1H), 8.55 (bs, 1H), 8.44 (s, 1H), 7.49 (d, 1H, J=3.5 Hz), 6.86 (d, 1H, J=3.5 Hz), 6.34 (s, 1H), 5.74 (s, 2H), 4.56 (m, 1H), 3.84 (s, 3H), 3.60 (t, 2H, J=8.2 Hz), 2.01 (m, 2H), 1.96 (m, 4H), 1.77 (m, 2H), 0.98 (t, 2H, J=8.2 Hz), 0.00 (s, 9H); C24H33N5O3Si (MW, 467.64), LCMS (EI) m/e 468.2 (M++H).
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24]>C(O)CC(C)C>[ClH:1].[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([N:25]1[CH2:26][CH2:27][N:28]([C:2]2[N:11]=[C:10]([NH2:12])[C:9]3[C:4](=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[C:7]([Cl:13])[CH:8]=3)[N:3]=2)[CH2:29][CH2:30]1)=[O:24]
Reactant: COc1c(Cl)cc2c(N)nc(Cl)nc2c1OC
Reactant: O=C(c1ccco1)N1CCNCC1
Solvent: CC(C)CCO
Product: COc1c(Cl)cc2c(N)nc(N3CCN(C(=O)c4ccco4)CC3)nc2c1OC
Product: Cl
Yield: 74 %

Procedure:
A mixture of 2,6-dichloro-4-amino-7,8-dimethoxyquinazoline (1.50 g., 5.47 mmole) and 1-(2-furoyl)piperazine (1.08 g., 5.99 mmole) was refluxed in 40 ml. isoamyl alcohol for 2 hours and then cooled overnight. The resulting solid was filtered and recrystallized from methanol/ether to yield 1.83 g. (74%) of pure final product, M.P., 208°-9° C.