Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5].[Br-].[C:30]([Zn+])([CH3:33])([CH3:32])[CH3:31]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:31][CH:30]([CH3:33])[CH3:32])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])[N:8]=1)=[O:5]
Reactant: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1c(F)cccc1F
Reactant: CC(C)(C)[Zn+]
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of 2,6-difluoro-N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)benzamide (for a preparation see Example 73)(75 mg, 0.148 mmol) in THF (1 ml) was added tetrakis(triphenyl-phosphine)palladium (0) (17.1 mg, 0.015 mmol, Aldrich). To the solution was added 0.5 M t-butylzinc bromide in THF (0.6 ml, 0.30 mmol, Aldrich) and the mixture stirred at 80° C. under nitrogen for 3 h. A further amount of tetrakis (triphenylphosphine) palladium (0) (30 mg) and then 0.5 M t-butylzinc bromide in THF (1 ml, 0.5 mmol) was added to the mixture at ambient temperature. The mixture was heated to 80° C. for a further 3 h. The solvent was removed in vacuo and the residue dissolved in 1:1 MeOH:DMSO ml×2 and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a brown gum (12 mg); LCMS: (System 4) MH+=438, tRET=3.47 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:23]=[C:22]([CH2:24][CH3:25])[CH:21]=[CH:20][C:10]=1[O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][C:13]=1[F:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C.[CH2:32]([O:39][C:40](Cl)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40](=[O:41])[NH:16][C:15]1[CH:17]=[CH:18][C:12]([O:11][C:10]2[CH:20]=[CH:21][C:22]([CH2:24][CH3:25])=[CH:23][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:13]([F:19])[CH:14]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCc1ccc(Oc2ccc(N)cc2F)c(OCc2ccccc2)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: CCOC(=O)Cl
Product: CCc1ccc(Oc2ccc(NC(=O)OCc3ccccc3)cc2F)c(OCc2ccccc2)c1
Yield: 107.8 %

Procedure:
According to the procedure of example 44(a) except substituting 4-(4-ethyl-2-methoxyphenoxy)-3-fluoroaniline for 4-[2-(benzyloxy)-4-ethylphenoxy]-3-fluoroaniline (200 mg; 0.59 mmol) and ethylchloroformate by benzylchloroformate (150 μL; 0.73 mmol), the title compound (300 mg; quantitative) was prepared as a brown solid and used without further purification.
Reaction SMILES: [CH3:1][C:2]([NH:25]C(=O)OC(C)(C)C)([CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]([CH3:23])[CH2:16][CH2:17][O:18]3)=[CH:10][CH:11]=1)=[O:4].C(O)(C(F)(F)F)=O>ClCCl>[NH2:25][C:2]([CH3:1])([CH3:24])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[CH:15]([CH3:23])[CH2:16][CH2:17][O:18]3)=[CH:10][CH:11]=1)=[O:4]
Reactant: CC1CCOc2cccc(Oc3ccc(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)cn3)c21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1CCOc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c21
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
In a 50 mL round-bottomed flask tert-butyl N-[1,1-dimethyl-2-[[6-(4-methylchroman-5-yl)oxy-3-pyridyl]amino]-2-oxo-ethyl]carbamate (Intermediate 214, 63.3 mg, 0.093 mmol), was dissolved in Dichloromethane (DCM) (3 mL) to give a pale yellow solution. The reaction mixture was cooled at 0° C. and TFA (3 mL, 38.9 mmol) was added. The reaction mixture was stirred at 0° C. for 2 hours. The reaction mixture was evaporated in vacuo to give the crude product as a pale yellow oil. The residue was charged on a 2 g SCX cartridge. It was then flushed with 40 mL of MeOH followed by 40 mL of 2M solution of ammonia in MeOH. The Ammonia eluate was evaporated in vacuo to give the title compound (22.9 mg) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([C:13]2[CH:21]=[CH:20][C:19]3[N:18]([CH3:22])[C:17]4[CH2:23][CH:24]5[NH:28][CH:27]([C:16]=4[C:15]=3[C:14]=2[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25]5)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc([N+](=O)[O-])c4)ccc31)C1CCC(C2)N1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Cn1c2c(c3c(C(=O)OC(C)(C)C)c(S(=O)(=O)c4cccc(N)c4)ccc31)C1CCC(C2)N1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
To a solution of the product of step A (48 mg, 0.09 mmol) in EtOH (2 mL) and water (1 mL) was added iron powder (27 mg, 0.48 mmol) and ammonium chloride (5.7 mg, 0.10 mmol). The mixture was heated at reflux for 3 h, cooled to ambient temperature and filtered through a celite bed. The filtrate was extracted with chloroform and the organic layer dried over sodium sulfate then concentrated in vacuo. The residue was purified by flash column chromatography (SiO2, 7:3 hexane/ethyl acetate) to give tert-butyl 2-(3-aminophenyl)sulfonyl-5-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (28 mg, 62%) as a pale yellow solid: 1H NMR (CDCl3, 300 MHz) δ 8.18 (s, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.29 (d, J=8.7 Hz, 2H), 7.17-7.23 (m, 2H), 6.74 (dd, J=7.3, 1.2 Hz, 1H), 5.17-5.36 (m, 1H), 4.57-4.88 (m, 1H), 3.85 (s, 2H), 3.60 (s, 3H), 3.28-3.40 (m, 1H), 2.48 (d, J=16.5 Hz, 1H), 2.17-2.33 (m, 2H), 1.91-1.97 (m, 1H), 1.54-1.65 (m, 1H), 1.37 (br s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]3[O:29][CH2:30][O:31][C:25]=3[CH:24]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]4[O:29][CH2:30][O:31][C:25]=4[CH:24]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(Cl)nc2s1
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCO4)nc(-n3ccnc3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of imidazole with 2-chloro-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine gives 2-(imidazol-1-yl)-6-trifluoromethyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:27][CH2:26][CH:25]([C:28](O)=[O:29])[C:24]1=[O:31])[CH3:16].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:28]([CH:25]1[CH2:26][CH2:27][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:15][CH3:16])[C:24]1=[O:31])=[O:29]
Reactant: CCc1ccccc1N1CCC(C(=O)O)C1=O
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccccc1N1CCC(C(=O)NCCc2c[nH]c3ccc(Cl)cc23)C1=O
Yield: 53 %

Procedure:
This compound was prepared according to method E with 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.433 mmol), 1-(2-ethylphenyl)-2-oxopyrrolidine-3-carboxylic acid (0.101 g; 0.433 mmol), PyBOP (0.225 g; 0.433 mmol), N,N diisopropylethylamine (0.186 mL; 1.08 mmol) in DMF (3 mL). The crude mixture was purified flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.094 g (53%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-1-(2-ethylphenyl)-2-oxopyrrolidine-3-carboxamide as a white solid.
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].Cl[C:10]1[N:15]=[C:14]([NH:16][C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([F:29])=[CH:12][N:11]=1.[F:30][C:31]1[CH:32]=[C:33]2[C:39](B3OC(C)(C)C(C)(C)O3)=[CH:38][N:37]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:51])=[O:50])[C:34]2=[N:35][CH:36]=1>O.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[F:29][C:13]1[C:14]([NH:16][C@@H:17]([C:25]([CH3:28])([CH3:27])[CH3:26])/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:15][C:10]([C:39]2[C:33]3[C:34](=[N:35][CH:36]=[C:31]([F:30])[CH:32]=3)[N:37]([S:49]([C:52]3[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=3)(=[O:50])=[O:51])[CH:38]=2)=[N:11][CH:12]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(F)cnc32)cc1
Reactant: CCOC(=O)/C=C/[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Product: CCOC(=O)/C=C/[C@@H](Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)ncc1F)C(C)(C)C
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
K3PO4 (1.078 g, 5.079 mmol) was dissolved in water (3.2 mL) and added to a solution of (R,E)-ethyl 4-((2-chloro-5-fluoropyrimidin-4-yl)amino)-5,5-dimethylhex-2-enoate, 37a, (0.534 g, 1.693 mmol) in 2-methyl-THF (10.7 mL) and the mixture was purged with nitrogen for 30 minutes. 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 7a, (0.775 g, 1.862 mmol) was added and the nitrogen purging was continued for an additional 15 min. X-Phos (0.048 g, 0.102 mmol) and Pd2(dba)3 (0.031 g, 0.034 mmol) were added and the mixture was heated at 80° C. overnight. After cooling to room temperature, the reaction mixture was diluted with water and extracted with EtOAc. The layers were separated and the organic phase was washed with brine, dried over MgSO4, filtered and evaporated to dryness. The crude residue was dissolved in a minimum volume of dichloromethane and purified by silica gel chromatography (0-100% EtOAc/hexanes gradient) to afford 650 mg of desired product: 1H NMR (400 MHz, CDCl3) δ 8.57-8.38 (m, 2H), 8.30 (s, 1H), 8.11 (dd, J=10.5, 5.5 Hz, 3H), 7.08 (dt, J=36.7, 18.3 Hz, 1H), 6.01 (d, J=15.7 Hz, 1H), 5.11 (d, J=8.7 Hz, 1H), 4.97-4.77 (m, 1H), 4.19 (q, J=7.1 Hz, 2H), 2.39 (d, J=10.7 Hz, 3H), 1.27 (q, J=7.4 Hz, 4H), 1.10 (s, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, RT=3.99 minutes (M+H) 570.01.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[O:23]1[C:28]2[CH:29]=[CH:30][C:31]([NH:33][C:34]([NH2:36])=[NH:35])=[CH:32][C:27]=2[O:26][CH2:25][CH2:24]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:35]=[C:34]([NH:33][C:31]4[CH:30]=[CH:29][C:28]5[O:23][CH2:24][CH2:25][O:26][C:27]=5[CH:32]=4)[N:36]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: N=C(N)Nc1ccc2c(c1)OCCO2
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Solvent: O=[N+]([O-])O
Product: O=C1Cc2cnc(Nc3ccc4c(c3)OCCO4)nc2-c2ccc(Cl)cc2N1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-guanidine nitrate were converted to I-28 (71%): HRMS Calcd. for C20H15ClN4O3: 395.091, Found 395.0912.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[S:21][C:20]3[C:15](=[N:16][CH:17]=[CH:18][C:19]=3[O:22][C:23]3[CH:28]=[CH:27][C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)=[S:31])=[CH:25][C:24]=3[F:43])[CH:14]=2)=[N:11][CH:12]=1>CC(O)=O>[F:43][C:24]1[CH:25]=[C:26]([NH:29][C:30]([NH:32][C:33](=[O:42])[CH2:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[S:31])[CH:27]=[CH:28][C:23]=1[O:22][C:19]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:14]=[C:13]([C:10]3[CH:9]=[CH:8][C:7]([CH:2]=[O:1])=[CH:12][N:11]=3)[S:21][C:20]=12
Reactant: O=C(Cc1ccc(F)cc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(C5OCCCO5)cn4)sc23)c(F)c1
Solvent: CC(=O)O
Product: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccc(F)cc5)cc4F)c3s2)nc1
Temperature: 90 °C
Yield: 57.8 %

Procedure:
A suspension of crude 32 (35.10 g) in AcOH 80% (576 mL) in a 1 L round-bottom flask was heated at 90° C. for 18 h, cooled to r.t. to form a precipitate which was collected by filtration to give 33 (18.41 g, 32.8 mmol, 58% yield over two steps) as a beige solid. MS (m/z): 561.1 (M+1)
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[C:13]([O:32][CH3:33])=[N:14][NH:15][C:16]=3[N:17]([CH2:29][O:30][CH3:31])[S:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:20])=[O:19])=[CH:11][C:6]=2[O:5][CH2:4]1.[C:34]([O:37][CH2:38][CH2:39]Br)(=[O:36])[CH3:35]>O1CCCC1>[C:34]([O:37][CH2:38][CH2:39][N:14]1[C:13]([O:32][CH3:33])=[C:12]([C:10]2[CH:9]=[CH:8][C:7]3[O:3][CH2:4][O:5][C:6]=3[CH:11]=2)[C:16]([N:17]([CH2:29][O:30][CH3:31])[S:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)(=[O:20])=[O:19])=[N:15]1)(=[O:36])[CH3:35]
Reactant: CC(=O)OCCBr
Reactant: COCN(c1[nH]nc(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCN(c1nn(CCOC(C)=O)c(OC)c1-c1ccc2c(c1)OCO2)S(=O)(=O)CCc1ccccc1
Reaction time: 0.17 h

Procedure:
Sodium hydride (60% dispersion in oil, 162 mg) was added at room temperature under an atmosphere of nitrogen to a solution of N-[4-(1,3-benzodioxol-5-yl)-3-methoxy-1H-pyrazol-5-yl]-N-(methoxymethyl)-2-phenyl-1-ethanesulfonamide (Preparation 55) in anhydrous tetrahydrofurane. After 10 minutes, 2-bromoethyl acetate (446 μl) was added and the reaction mixture was refluxed overnight. At room temperature, some more 2-bromoethylacetate (446 μl) was added and the reaction was refluxed for 24 h. Then at room temperature, some more sodium hydride (50 mg) was added and the reaction was refluxed for 24 h. At room temperature, the reaction was quenched by the addition of an aqueous saturated solution of ammonium chloride (5 ml), water (10 ml) and the mixture was extracted with ethyl acetate (3×10 ml). The combined organic fractions were washed with brine (20 ml), dried on sodium sulfate and concentrated under reduced pressure to yield a dark oil which was purified by column chromatography (silica, 10 g), eluted with hexane:ethyl acetate (4:1) then (2:1) yielding the title compound as a colourless oil (92 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([CH:41]=[CH:42][CH:43]=4)[C:35](N(OC)C)=[O:36])[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:44][Mg]Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@@H:13]([NH:17][C:18]3[N:23]=[C:22]([C:24]4[N:31]5[C:27]([S:28][CH:29]=[CH:30]5)=[N:26][C:25]=4[C:32]4[CH:33]=[C:34]([C:35](=[O:36])[CH3:44])[CH:41]=[CH:42][CH:43]=4)[CH:21]=[CH:20][N:19]=3)[CH2:12]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Mg]Cl
Reactant: CON(C)C(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(-c2nc3sccn3c2-c2ccnc(N[C@@H]3CCCN(S(=O)(=O)c4ccc(Cl)cc4)C3)n2)c1
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 3-(5-{2-[(R)-1-(4-chloro-benzenesulfonyl)-piperidin-3-ylamino]-pyrimidin-4-yl}-imidazo[2,1-b]thiazol-6-yl)-N-methoxy-N-methyl-benzamide (0.10 g, 0.157 mmol) in anhydrous tetrahydrofuran (THF) (3.0 mL) at 0° C. was added a solution of methyl magnesium chloride (3.0 M in THF) (0.523 mL, 1.57 mmoL). The mixture was stirred for 3 hours, then quenched with saturated aqueous ammonium chloride solution (1 mL). Product was extracted with 10 mL of dichloromethane, washed with water (5 mL×2), dried over sodium sulfate and concentrated. Product was purified by flash chromatography on silica gel (40% dichloromethane in ethyl acetate) to afford 0.085 g (91%) of the title compound as a pale yellow solid. M.p.=124-127° C. 400 MHz 1H NMR (DMSO-d6 at 60° C.) δ: 8.70 (br. s, 1H), 8.17 (m, 1H), 8.12 (d, J=5.6 Hz, 1H), 7.9 (d, J=7.6 Hz, 1H), 7.86-7.84 (m, 1H), 7.77-7.74 (m, 2H), 7.67-7.65 (m, 2H), 7.62 (t, J=8.0 Hz, 1H), 7.42 (d, J=4.8 Hz, 1H), 7.15 (d, J=7.6 Hz, 1H), 6.38 (d, J=5.2 Hz, 1H), 3.93 (bs, 1H), 3.74-3.72 (m, 1H), 3.48-3.45 (m, 1H), 2.57 (s, 3H), 2.49-2.45 (m, 1H), 2.32 (t, J=10.4 Hz, 1H), 1.90-1.82 (m, 2H), 1.59-1.56 (m, 1H), 1.39-1.32 (m, 1H); LCMS: 594 [M+H].
Reaction SMILES: C(OC([N:8]1[C:12]2C=CC=N[C:11]=2[C:10]([C:17]#[C:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([O:26][C:27]3[CH:32]=[C:31]([C:33]#[N:34])[CH:30]=[C:29]([Cl:35])[CH:28]=3)[CH:20]=2)=[N:9]1)=O)(C)(C)C>CCO.[Pd]>[Cl:35][C:29]1[CH:30]=[C:31]([CH:32]=[C:27]([O:26][C:21]2[CH:20]=[C:19]([CH2:18][CH2:17][C:10]3[C:11]4[C:12](=[N:8][CH:12]=[CH:11][CH:10]=4)[NH:8][N:9]=3)[CH:24]=[CH:23][C:22]=2[Cl:25])[CH:28]=1)[C:33]#[N:34]
Reactant: CC(C)(C)OC(=O)n1nc(C#Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2)c2ncccc21
Agent: [Pd]
Solvent: CCO
Product: N#Cc1cc(Cl)cc(Oc2cc(CCc3n[nH]c4ncccc34)ccc2Cl)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 250 mg (0.50 mmol) of tert-butyl-3-{[4-chloro-3-(3-chloro-5-cyanophenoxy)phenyl]ethynyl}-1H-pyrazolo[3,4-]pyridine-1-carboxylate in 10 mL of absolute EtOH was hydrogenated at 1 atm pressure (balloon) over 250 mg of 10% Pd on carbon catalyst. After approximately 24 hours, the reaction mixture was filtered through a pad of Celite, and the filtrate concentrated in vacuo to a yellow oil. The crude intermediate oil was dissolved in 1 mL TFA, and the solution stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to provide the crude product as a dark oil. The dark oil was purified by reversed phase preparative LC on a Gilson apparatus to give the desired product as a fluffy off-white solid. MS M+=409. 1H NMR (CDCl3): 3.17 (t, 2H), 3.31 (t, 2H), 6.94 (m, 2H), 7.09 (m, 2H), 7.15 (q, 1H), 7.32 (t, 1H), 7.39 (d, 1H), 7.80 (dd, 1H), 8.54 (dd, 1H), 10.5-11.5 (very br, 1H).
Reaction SMILES: [CH2:1]([S:7][C:8]1[N:12]=[CH:11][N:10](COCC[Si](C)(C)C)[C:9]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([S:7][C:8]1[N:12]=[CH:11][NH:10][C:9]=1[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCSc1ncn(COCC[Si](C)(C)C)c1-c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCCCCSc1nc[nH]c1-c1cccnc1

Procedure:
To a solution of anhydrous THF (30 ml) containing 74B (0.29 g, 0.74 mmol) were added 2.2 ml (3 eq) of TBAF (1.0 M in THF) under N2. After the addition, the resulting solution was refluxed for 18 hours and subsequently concentrated in vacuo. Ethyl acetate was added and the organic layer was washed with a concentrated NaHCO3 solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was purified by flash chromatography (ethyl acetate) to afford 3-(5-hexylsulfanyl-3H-imidazol-4-yl)-pyridine. (77) as an oil (0.14 g, 71%). 1H-NMR (400 MHz, CDCl3): δ 9.25 (bs, 1H), 8.53 (dd, J=5 Hz, 2 Hz, 1H), 8.42-8.35 (m, 1H), 7.78 (s, 1H), 7.38-7.34 (m, 1H), 2.79-2.69 (m, 2H), 1.53-1.44 (m, 2H), 1.33-1.09 (m, 6H), 0.80 (t, J=7 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:24]1[CH:33]=[CH:32][C:31]2[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=2[CH:25]=1.[OH-].[Na+]>>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=2)=[CH:9][C:8]=1[C:24]1[CH:33]=[CH:32][C:31]2[C:30]([CH3:35])([CH3:34])[CH2:29][CH2:28][C:27]([CH3:37])([CH3:36])[C:26]=2[CH:25]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCN)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCCCN)ccc21
Yield: 86.6 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 300 mg (0.6 mmol) of ethyl 4′-(4-aminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate with 240 mg (6 mmol) of sodium hydroxide. 245 mg of 4′-(4-aminobutoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=250° C., yield=86%).
Reaction SMILES: [Se](=O)=O.[OH2:4].[C:5]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)(=[O:7])[CH3:6]>O1CCOCC1>[O:7]=[C:5]([C:8]1[O:9][CH:10]=[CH:11][CH:12]=1)[CH:6]=[O:4]
Reactant: O
Reactant: CC(=O)c1ccco1
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: O=CC(=O)c1ccco1
Temperature: 55 °C

Procedure:
A mixture of 55 g of selenium dioxide, 11 ml of water and 150 ml of dioxane was heated at 55° C. until solution was complete. A 55 g portion of 2-acetylfuran was added, the mixture was refluxed for 4 hours, then filtered and evaporated. The residue was dissolved in dichloromethane, treated with activated charcoal, filtered and evaporated. The residue was distilled, giving 28 g of α-oxo-2-furanacetaldehyde.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[O:13])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[NH:18][CH:17]=1.[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C)C=O.O>[O:13]=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:3])[N:5]1[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]#[N:26])[CH:23]=2)[N:18]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:17]=1
Reactant: N#Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc2c(c1)c(CCN1C(=O)c3ccccc3C1=O)cn2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.16 g) was added to a solution of 3-[2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl]-1H-indole-5-carbonitrile (2.0 g) in dry dimethylformamide (40 ml) under nitrogen. After 0.5 hour. benzyl chloride was added and after a further 2 hours the mixture was diluted with water (150 ml) and extracted with ethyl acetate (3×40 ml). Evaporation of the washed (H2O) and dried (MgSO4) extract gave a red oil which was triturated with ether and then crystallised from ethanol to give the title compound as yellow microcrystals (1.2 g) m.p. 182°-4° C. T.L.C. Silica, ether Rf 0.45.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:27]=1[C:28]([O:30]C)=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC#N.[OH-].[Na+]>CO>[CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([NH:24][CH2:25][C:26]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:27]=1[C:28]([OH:30])=[O:29])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CO
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)O)c(OCc1ccccc1)c2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a suspension of intermediate 154, methyl 2-((3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamido)methyl)-5-fluorobenzoate. (500 mg, 1.01 mmol) in MeOH (10 mL) and CH3CN (5 mL) was added 1N NaOH (2 mL) and the mixture stirred at room temperature for 2 hrs. The mixture was concentrated in vacuo and the residue purified by reverse phase column chromatography (YMC, C-18 ODS, 10–25% CH3CN/H2O) to provide 90 mg (Yield 19%) of the title compound as an off-white powder: LC/MS m/z 482 (M+H).