Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:38][CH3:39]>C(#N)C>[CH2:38]([N:5]1[C:6]2[C:11](=[CH:10][C:9]([F:23])=[CH:8][CH:7]=2)[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C@H:3]([CH2:1][CH3:2])[C:4]1=[O:24])[CH3:39]
Reactant: CC[C@@H]1C(=O)Nc2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: CC[C@@H]1C(=O)N(CC)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 96.6 %

Procedure:
To a stirred solution of (3R)-3-ethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one (0.20 g, 0.61 mmol) in acetonitrile (5 mL) under nitrogen was added potassium carbonate (0.050 g, 0.36 mmol), cesium carbonate (0.11 g, 0.33 mmol) and iodoethane (0.15 mL, 0.29 g, 1.9 mmol). The reaction was stirred for 10 h at 50° C. and then 5 h at 63° C. The solvent was evaporated, and the residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water. The organic layer was concentrated in vacuo and purified via Biotage Horizon® (SiO2, gradient from 5% EtOAc/hexane to 33% EtOAc/hexane) to yield 0.21 g (96%) of (3R)-1,3-diethyl-6-fluoro-4-(4-methoxybenzoyl)-3,4-dihydroquinoxalin-2(1H)-one. MS (ESI) m/z 357 ([M+H]+); HRMS: calcd for C20H21FN2O3, 356.16090; found (ESI+), 357.16057.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:27])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=2[CH:26]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:28][O:29][C:30]([C:32]1[C:33]([Cl:39])=[N:34][C:35](Cl)=[CH:36][CH:37]=1)=[O:31].C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C=O)C.O>[CH3:28][O:29][C:30](=[O:31])[C:32]1[CH:37]=[CH:36][C:35]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:27])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:23][C:22](=[O:24])[N:21]([CH3:25])[C:20]=4[CH:26]=3)[C:11]([F:12])([F:13])[F:14])=[C:2]([Cl:1])[CH:7]=2)=[N:34][C:33]=1[Cl:39]
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Reactant: COC(=O)c1ccc(Cl)nc1Cl
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(C(C)C(O)(c3ccc4oc(=O)n(C)c4c3)C(F)(F)F)c(Cl)c2)nc1Cl
Reaction time: 0.17 h
Yield: 87 %

Procedure:
5-[2-(2-Chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-3-methyl-3H-benzooxazol-2-one (157 mg, obtained in Example 172) was added to a solution of methyl-2,6-dichloropyridine-3-carboxylate (81 mg, [CAS Reg. No. 65515-28-8]) in DMF (3 mL) followed by the addition of triethylamine (0.071 mL). Stirring was continued for 10 minutes at r.t. Then 1,4-diazabicyclo[2.2.2]octane (7 mg) was added. The mixture was stirred over night at r.t. The reaction mixture was poured into water, extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, gradient of heptane in ethyl acetate) to give the desired compound as a colorless foam (195 mg, 87%). MS (neg. ion, m/e)=569.2 [(M−H)−].
Reaction SMILES: [C:1]1([CH2:7][O:8][N:9]2[C:15](=[O:16])[N:14]3[CH2:17][C@H:10]2[CH2:11][CH2:12][C@H:13]3[C:18]([OH:20])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl>[CH2:7]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][C@@H:22]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]1)=[O:20])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of (2S,5R)-6-(phenylmethoxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (53 mg, 0.192 mmol) in dry dichloromethane (2 mL) was added a solution of tert-butyl (3R)-3-aminopyrrolidine-1-carboxylate (55 mg, 0.288 mmol), triethylamine (0.061 mL, 0.441 mmol), HOBT (44.1 mg, 0.288 mmol), and EDC (55.2 mg, 0.288 mmol) sequentially at room temperature under nitrogen. The reaction was stirred at room temperature for six hours. The reaction mixture was concentrated under vacuum and the residue was purified by HPLC on a 30×100 mm Waters Sunfire column eluted with 15% to 100% CH3CN+0.05% TFA/water+0.05% TFA over 15 minutes to afford the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([OH:13])=O)=[CH:5][CH:4]=1)[CH3:2].O>CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6]([CH2:9][CH2:10][C:11]2=[O:13])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCC(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: CCc1ccc2c(c1)C(=O)CC2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A 13.0 g sample of 3-(4-ethylphenyl)propanoic acid was dissolved in 125 g of Eaton's reagent and the mixture was heated at 50° C. with stirring for 3 hours. The resulting mixture was cooled and poured into water. The mixture obtained was extracted with ethyl acetate and the organic extract was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The residue was distilled and the 7.8 g colorless liquid fraction boiling at 95°-100° C. under 0.5 mm Hg (66 Pascals) pressure was collected to obtain 6-ethyl-1-indanone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[CH2:15]([Mg]Br)[CH2:16][CH3:17]>>[CH3:14][O:13][C:9]1[CH:8]=[C:5]([C:6](=[O:7])[CH2:15][CH2:16][CH3:17])[CH:4]=[C:3]([O:2][CH3:1])[C:10]=1[O:11][CH3:12]
Reactant: CCC[Mg]Br
Reactant: COc1cc(C=O)cc(OC)c1OC
Product: CCCC(=O)c1cc(OC)c(OC)c(OC)c1

Procedure:
Substantially the same procedure as in Process 1 of Example 48 was repeated using 3,4,5-trimethoxybenzaldehyde (43.12 g) and propylmagnesium bromide (1.0 M tetrahydrofuran solution, 330 ml) to give 1-(3,4,5-trimethoxyphenyl)-1-butanone (17.43 g).
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](Cl)=[O:38])([O-:33])=[O:32]>ClCCl.CN(C1C=CN=CC=1)C>[N+:31]([C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH:9]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[N:8][C:4]=2[CH:3]=1)=[O:38])([O-:33])=[O:32]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(N)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3cccc([N+](=O)[O-])c3)ccc21
Temperature: 25 °C
Reaction time: 144 h

Procedure:
To a solution of ethyl 3-(5-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate (250 mg, 809 μmol) in dichloromethane (15 mL) was added triethylamine (280 μL, 2.03 mmol), 3-nitrobenzoyl chloride (375 mg, 2.03 mmol) and DMAP (10 mg, 81 μmol). The solution was stirred at room temperature for 144 hours, and was then evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of dichloromethane and methanol (97:3) to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=5.53 min, MH+ 459].
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].II.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[Br:14][C:8]1[CH:9]=[C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])[NH:6][CH:7]=1
Reactant: BrBr
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: II
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1cc(Br)c[nH]1)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To a 100 mL 3-neck round bottom equipped with a dropping funnel was added trichloroacetyl pyrrole (50 g, 236.4 mmol) and CCl4 (1.0 L). After trichloroacetyl pyrrole was dissolved, the reaction was cooled to 0° C. and iodine (0.176 g) was added to the reaction. At this time, a solution of bromine (12 mL) in CCl4 (100 mL) was added dropwise very slowly to the reaction through a dropping funnel over 20 minutes and the resulting mixture was stirred at 0° C. for additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 10% Na2S2O3 solution, saturated NaHCO3 solution and brine (2×). The organic layer was dried and concentrated to give 50 g (60%) of the title compound as a white solid. LCMS (condition A): m/z=287.8, 289.8, 290.8−ve. 1H NMR (400 MHz, CDCl3) δ ppm: 12.8 (1H, br.s), 7.56 (1H, m), 7.33 (1H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14]([N:16]3[CH2:19][CH:18]([O:20][Si](C(C)(C)C)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:17]3)=[O:15])=[N:10][C:9]=2[CH3:38])=[CH:4][C:3]=1[S:39]([CH3:42])(=[O:41])=[O:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([NH:13][C:14]([N:16]3[CH2:17][CH:18]([OH:20])[CH2:19]3)=[O:15])=[N:10][C:9]=2[CH3:38])=[CH:4][C:3]=1[S:39]([CH3:42])(=[O:41])=[O:40]
Reactant: Cc1nc(NC(=O)N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1nc(NC(=O)N2CC(O)C2)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Reaction time: 0.5 h

Procedure:
A stirred solution of 3-(tert-butyl-diphenyl-silanyloxy)-azetidine-1-carboxylic acid [5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazole-2-yl]amide (162c) (0.15 g, 0.23 mmol) in THF (2 ml) at room temperature is treated with tetrabutylammonium fluoride (1.0 M in THF, 0.23 ml, 0.23 mmol). After 30 minutes, the reaction was complete. Purification by preparative LC-MS affords the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH:22]=[CH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1>[Pd].C(OCC)(=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([S:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:13]=[C:12]([CH3:21])[C:11]=2[CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1C=Cc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccc2)c(Sc2cc(Cl)cc(Cl)c2)c1CCc1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 93.3 %

Procedure:
A suspension containing 95 mg of 5-(3,5-dichlorophenylthio)-3-methyl-1-phenyl-4-styryl-1H-pyrazole and 75 mg of 10% palladium on activated carbon in 10 ml of ethyl acetate was stirred under hydrogen (1 atm) at rt for 40 h. The suspension was filtered on Celite® and the filtrate was evaporated to leave 89 mg of 5-(3,5-dichlorophenylthio)-3-methyl-4-(2-phenylethyl)-1-phenyl-1H-pyrazole as a colourless gum. Mass spectrum (EI) m/z 438[M]+. 1H NMR (DMSO-d6) 2.14 (s, 3H), 2.68 (t, 2H), 2.77 (t, 2H), 6.85 (d, 2H), 7.09 (d, 2H), 7.16 (t, 1H), 7.24 (t, 2H), 7.33-7.48 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH3:11].S([CH2:23][N+:24]#[C-])(C1C=CC(C)=CC=1)(=O)=O.CC([O-])(C)C.[K+]>COCCOC.CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:11])[C:23]#[N:24]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C(C)=O)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)(C)O
Product: COc1ccc(C(C)C#N)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2′-chloro-4′-methoxyacetophenone (18.5 g, 0.10 mol) and tosylmethylisocyanide (TOSMIC, 21.5 g, 0.11 mol) in dry 1,2-dimethoxyethane (100 mL) was cooled to −10° C. A solution of t-BuOK (22.4 g, 0.20 mol) in dry t-BuOH (250 mL) was added slowly keeping the temperature below 5° C. The homogeneous orange solution was stirred for 2 h/0° C. and 1 h/25° C. The resulting suspension was evaporated to a slurry. Water (200 mL) was added and extracted with Et2O (3×150 mL). The organic phase was dried (Na2SO4) and the solvent was removed under reduced pressure leaving an orange oil. Yield: 19 g (97%). GCMS: >98%
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][C:5]([C:11]#[N:12])=[C:6]([OH:10])[C:7]=1[C:8]#[N:9].CI.[C:15](=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>C(#N)C>[CH3:1][S:2][C:3]1[S:4][C:5]([C:11]#[N:12])=[C:6]([O:10][CH3:15])[C:7]=1[C:8]#[N:9]
Reactant: CSc1sc(C#N)c(O)c1C#N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1c(C#N)sc(SC)c1C#N

Procedure:
6 g of 2-methylthio-3,5-dicyano-4-hydroxythiophene 10 ml of methyl iodide, 10 g of potassium carbonate, and 3 ml of triethylamine are refluxed in 300 ml of acetonitrile while stirring. After 2 hours the reaction mixture is filtered warm and evaporated to dryness. The residue is taken up in 200 ml of methylene chloride and washed successively with a solution of potassium carbonate in water and with water. The methylene chloride solution is then dried and evaporated to dryness. After recrystallisation of the residue from isopropanol, the desired product is obtained in a yield of 4.0 g; melting-point 132° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: NCc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCc3ccccc3)nc(Cl)nc21

Procedure:
2-Chloro-6-(benzylamino)-9-(2-propyl)purine is prepared from 2,6-dichloro-9-(2-propyl)purine (see Example 15 for preparation), benzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].I[CH2:19][CH3:20].C(N(CC)C(C)C)(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:19][CH3:20])[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Reactant: CCI
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68 %

Procedure:
To a stirred solution of methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate, from preparation 19 (10.5 g, 43 mmol) in tetrahydrofuran (215 mL) at room temperature under dry nitrogen was added iodoethane (3.8 mL, 48 mmol) and N,N-diisopropylethylamine (8.3 mL, 48 mmol) in single portions. The resulting mixture was stirred at room temperature under dry nitrogen for 72 hours, then quenched by the addition of water (200 mL) and extracted with ethyl acetate (2×250 mL). The combined organic layers were dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with a 2:1 pentane:ethyl acetate mixture increasing polarity to 1:1. This afforded the title compound as a clear oil (7.9 g, 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(Cl)Cl.[CH3:28][O:29][C:30]([CH:32]1[CH2:37][CH2:36][CH:35]([C:38]2[CH:43]=[C:42]([N:44]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[CH2:45][O:46][CH2:47][CH2:48][Si:49]([CH3:52])([CH3:51])[CH3:50])[N:41]3[N:61]=[CH:62][C:63](I)=[C:40]3[N:39]=2)[CH2:34][CH2:33]1)=[O:31]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:51][Si:49]([CH3:50])([CH3:52])[CH2:48][CH2:47][O:46][CH2:45][N:44]([CH2:53][O:54][CH2:55][CH2:56][Si:57]([CH3:60])([CH3:59])[CH3:58])[C:42]1[N:41]2[N:61]=[CH:62][C:63]([C:5]3[CH:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[C:40]2[N:39]=[C:38]([CH:35]2[CH2:36][CH2:37][CH:32]([C:30]([O:29][CH3:28])=[O:31])[CH2:33][CH2:34]2)[CH:43]=1
Reactant: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Reactant: CC1(C)OB(c2ccc(Cl)nc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(-c4ccc(Cl)nc4)c3n2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 75.6 %

Procedure:
2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.55 mmol, 131 mg), K3PO4 (1.36 mmol, 290 mg), and PdCl2(dppf).CH2Cl2 (0.045 mmol, 37 mg) is added to a solution of 4-{7-[Bis-(2-trimethylsilanyl-ethoxymethyl)-amino]-3-iodo-pyrazolo[1,5-a]pyrimidin-5-yl}-cyclohexanecarboxylic acid methyl ester (0.45 mmol, 300 mg) in dioxane (3.8 mL). To this suspension is added distilled H2O (0.38 mL). The resulting solution is stirred at 90° C. under argon for 18 hours. The reaction mixture is concentrated in vacuo and then purified via silica gel chromatography (0% to 60% ethyl acetate in hexanes gradient) to yield the title compound (220 mg, 75% yield) as yellow oil. LC-MS: 646 [M+H].
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(O[K])(C)(C)C>C1(C)C=CC=CC=1.C(Cl)Cl.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]>[N:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[NH:12][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Brc1ccc2ccccc2n1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC(C)(C)O[K]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: c1ccc(Nc2ccc3ccccc3n2)nc1
Yield: 45 %

Procedure:
2-Bromoquinoline, I (500 mg, 2.40 mmol), 2-aminopyridine (249 mg, 2.64 mmol), tBuOK (404 mg, 3.60 mmol), (±)-BINAP (6 mg, 0.01 mmol) and Pd2(dba)3 (5.5 mg, 0.006 mmol) were stirred in toluene (10 mL) at 90° C. under Ar(g) for 21 h. The reaction mixture was then diluted with CH2Cl2 (10 mL) and silica was added, followed by the removal of the solvent under reduced pressure. The resulting dry load material was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:1 then 100:2) to furnish II as a colourless oil (344 mg, 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1B(O)O)(=[O:19])[CH3:18].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:17]([O:20][CH2:21][C:22]1[C:23]([N:31]2[CH2:42][CH2:41][N:40]3[C:33](=[CH:34][C:35]4[CH2:36][C:37]([CH3:44])([CH3:43])[CH2:38][C:39]=43)[C:32]2=[O:45])=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[O:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:19])[CH3:18]
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)no1
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)on3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C
Yield: 33.9 %

Procedure:
A 50-mL round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 283a (150 mg, 0.53 mmol), {3-[(acetyloxy)methyl]-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-4-yl}boronic acid 199e (834 mg, 2.1 mmol), Pd(dppf)Cl2 (21 mg, 0.026 mmol), K3PO4 (224 mg, 0.053 mmol), sodium acetate (87 mg, 1.1 mmol), acetonitrile (10 mL), and water (5 drops). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h. Then it was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the residue was washed with acetonitrile to afford the 283b (100 mg, 34%) as white solid. MS-ESI: [M+H]+ 557.3
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16](C)[CH2:15]2)=[CH:11][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:36]([O:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:37]>ClCCl>[O:38]([C:36]([N:16]1[CH2:15][CH:14]([O:13][C:12]2[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:28])[F:27])=[CH:10][CH:11]=2)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17]1)=[O:37])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN1Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Oc1ccccc1)N1Cc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C

Procedure:
To a cold solution of 2-methyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline of Example 4 (23 g, 0.075 mole) in 150 ml dichloromethane, is added 25 g K2CO3, followed by a solution of phenyl chloroformate (15.6 g, 0.1 mole) in 100 ml dichloromethane. After stirring at ambient temperature for twenty hours, the mixture is filtered, and the solvent evaporated to an oil, which solidifies to a solid upon trituration with hexanes, 24 g (80%), m.p. 72° C. A sample of this material is recrystallized twice from hexanes, to yield 2-phenoxycarbonyl-1,2,3,4-tetrahydro-4-(p-trifluoromethylphenoxy)isoquinoline, m.p. 101°-3° C.
Reaction SMILES: C(O)C.[NH3:4].[Cl:5][C:6]1[C:11]([C:12](OC)=[O:13])=[C:10]([S:16](Cl)(=[O:18])=[O:17])[CH:9]=[CH:8][CH:7]=1>O1CCOCC1>[Cl:5][C:6]1[C:11]2[C:12](=[O:13])[NH:4][S:16](=[O:18])(=[O:17])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)c1c(Cl)cccc1S(=O)(=O)Cl
Reactant: N
Solvent: C1COCCO1
Solvent: CCO
Product: O=C1NS(=O)(=O)c2cccc(Cl)c21
Temperature: 60 °C

Procedure:
150 ml of ethanol saturated with ammonia were added dropwise over a period of 30 minutes to a solution of 38.2 gm (0.141 mol) of methyl 6-chloro-2-chlorosulfonyl-benzoate in 150 ml of dioxane at 30°-50° C. Subsequently, the reaction mixture was heated for 2 hours at 40° C. and for 2 hours more at 60° C. After cooling, the reaction mixture was evaporated, treated with ether and filtered. The filter cake was boiled with water, filtered while hot, and the filtrate was acidified with hydrochloric acid. Yield: 19.8 gm (64.5% of theory) of 4-chloro-1,2-benzoisothiazol-3(2H)-one-1,1-dioxide.