Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([NH2:16])[CH2:10][N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22]([C:28]3[N:29]=[C:30]4[C:36]([C:37](O)=[O:38])=[CH:35][N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[C:31]4=[N:32][CH:33]=3)=[N:23][N:24]2[CH3:27])=[CH:20][CH:19]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>C(#N)C.C(OCC)(=O)C.O>[CH3:8][C@@H:9]([NH:16][C:37]([C:36]1[C:30]2[C:31](=[N:32][CH:33]=[C:28]([C:22]3[C:21]4[C:25](=[CH:26][C:18]([F:17])=[CH:19][CH:20]=4)[N:24]([CH3:27])[N:23]=3)[N:29]=2)[N:34]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[CH:35]=1)=[O:38])[CH2:10][N:11]1[CH:15]=[CH:14][CH:13]=[N:12]1
Reactant: C[C@@H](N)Cn1cccn1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Cn1cccn1)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 81 %

Procedure:
(R)-1-Methyl-2-pyrazol-1-yl-ethylamine trifluoroacetate (crude from Step 4) was dissolved in acetonitrile (1.8 ml) to which was then added 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.18 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (87 mg, 0.27 mmol) and N,N-diisopropylethylamine (0.16 ml, 0.91 mmol). The reaction was stirred at room temperature for 18 h and then water and ethyl acetate were added. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sodium chloride solution and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to afford 89 mg (81%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-methyl-2-pyrazol-1-yl-ethyl)-amide.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:21][N:22]([CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)C(=O)OC(C)(C)C.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>CCCCO.C(Cl)Cl>[Br:1][C:2]1[C:3]([N:32]2[CH2:33][CH2:34][CH:30]([NH:22][CH3:21])[CH2:31]2)=[C:4]2[C:10]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccnc1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: CNC1CCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (100 mg, 0.30 mmol), tert-butyl methyl(pyrrolidin-3-yl)carbamate (240 mg, 1.19 mmol) and DIEA (0.0520 mL, 0.30 mmol) in n-BuOH (3 mL) were stirred at 143° C. (bath) for 24 hours. The solvent was removed. The residue was dissolved in ethyl acetate (20 mL), washed with water (10 mL), brine (10 mL), and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (ethyl acetate:MeOH, 10:1) to give a solid. This solid was dissolved in DCM (3 mL), and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (1 mL) and 2N HCl in ether (3 mL) was added. The solid formed was collected by filtration to give N-(5-Bromo-4-(3-(methylamino)pyrrolidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (93 mg, 59% yield) as a solid. 1H NMR (400 MHz, D2O) δ 9.14 (d, 1H), 8.83 (dd, 1H), 8.71 (dt, 1H), 8.23 (s, 1H), 7.98 (dd, 1H), 7.44 (s, 1H), 4.02-3.96 (m, 1H), 3.76-3.68 (m, 3H), 3.65-3.59 (m, 1H), 2.22-2.13 (m, 1H), 1.93-1.84 (m, 1H); LCMS (APCI+) m/z 415, 417 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][N:3]=1.C[CH2:12][N:13](C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CN.C1COCC1>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:13][CH3:12])=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(O)c1ccnc(Cl)n1
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNC(=O)c1ccnc(Cl)n1
Temperature: 25 °C

Procedure:
2-Chloropyrimidine-4-carboxylic acid (Maybridge Chemicals, Maybridge, UK, 0.523 g, 3.30 mmol), DIPEA (0.48 mL, 2.75 mmol) and PyBop (1.717 g, 3.30 mmol) were weighed into a 150 mL round bottomed flask and dissolved in dioxane (15 mL). The solution was stirred at RT, then cooled to 0° C., and stirred for 5 min. Methylamine, 2.0 M in THF (2.75 mL, 5.50 mmol) was added, and the solution became a thick suspension. The suspension was stirred at 0° C. for 2.5 h. No further progression was seen, so an additional equivalent of MeNH2 was added, and the mixture was stirred for another 4 h. EtOAc was added and the mixture was washed with water (50 mL), 1 N NaOH (2×50 mL) and brine (50 mL). The material was dried over MgSO4, filtered and concentrated and used without purification. MS (ESI, pos. ion) m/z: 171.9 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)C.C1(C)C=CC=CC=1>[C:11]1([C:2]2[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CCc1ncccc1Br
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CCc1ncccc1-c1ccccc1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
To a stirred solution of (3-bromo-pyridin-2-yl)-acetonitrile (158) (1 g, 5.07 mmol) and phenyl boronic acid (928 mg g, 7.16 mmol) in a solvent mixture of toluene (25 mL) and ethanol (25 mL) was added K2CO3 (2.1 g, 15.23 mmol). The mixture was degassed by argon, X-Phos (484 mg, 1.01 mmol) and Pd(triphenyl phosphine)4 (586 mg g, 0.51 mmol) were added and the mixture was again degassed. The reaction mixture was refluxed (110° C.) for 4 h. Silica thin layer chromatography was performed (30% ethyl acetate in hexane, Rf=0.45). The catalyst was filtered off through a celite bed, washing with ethyl acetate (3×50 mL) was conducted, the mixture was concentrated, the crude product was purified by a CombiFlash column (eluted at 15% ethyl acetate in hexane) to get (3-phenyl-pyridin-2-yl)-acetonitrile (159) (930 mg, 94.34%) as a light yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH2:14][CH:15]3[CH2:17][CH2:16]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:18][N:19](C=O)C>CCOC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[C-]#N.[Zn+2].[C-]#N.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]>[CH:15]1([CH2:14][NH:13][C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([C:18]#[N:19])=[N:7][CH:6]=3)[N:9]=2)[CH2:17][CH2:16]1
Reactant: Brc1ccc(-c2csc(NCC3CC3)n2)cn1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: N#Cc1ccc(-c2csc(NCC3CC3)n2)cn1
Temperature: 115 °C
Reaction time: 6 h
Yield: 38 %

Procedure:
Slurry 6-bromo-3-(2-cyclopropylmethylamino-thiazol-4-yl)-pyridine (1.1 g, 3.6 mmol), 1,1′-bis-(diphenylphosphino)ferrocene (320 mg, 0.6 mmol), zinc cyanide (337 mg, 2.9 mmol) and tris(dibenzylideneacetone)dipalladium(0) (231 mg, 0.25 mmol) in wet DMF (6 mL). Stir the mixture in a sealed tube at 115° C. for 6 h. Cool the mixture to room temperature, dilute with EtOAc (50 mL) and wash with 5% aqueous sodium chloride (3×30 mL). Collect the organic layer and concentrate in vacuo. Purify the residue by chromatography on silica gel (40 g) eluting with hexane/(THF with 1% methanol) (4:1) to obtain the desired intermediate (350 mg, 38%). MS (ES+) m/z: 257.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:21]=[C:20]([CH2:22]O)[CH:19]=[CH:18][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH3:2].C(Br)(Br)(Br)[Br:25].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:25][CH2:22][C:20]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH2:13][C:14]([O:16][CH3:17])=[O:15])=[C:4]([O:3][CH2:1][CH3:2])[CH:21]=1
Reactant: BrC(Br)(Br)Br
Reactant: CCOc1cc(CO)ccc1Oc1ccccc1CC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOc1cc(CBr)ccc1Oc1ccccc1CC(=O)OC
Temperature: 25 °C
Yield: 87.7 %

Procedure:
To a stirred and cooled (0° C.) solution of 1.15 g (3.64 mmol) of the product of Step B dissolved in 18 mL of CH2Cl2 was added 1.51 g (4.55 mmol) of carbon tetrabromide and 1.19 g (4.55 mmol) of triphenylphosphine. After the addition the reaction mixture was stirred 30 minutes and allowed to warm to room temperature. The mixture was then evaporated in vacuo and purified on a silica gel flash chromatography column eluted with 15% ethyl acetate/hexane to afford 1.21 g (88%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[C:7]([C:17]([O:19]C)=[O:18])=[CH:8][C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:10][C:4]=2[N:3]=1.[CH3:21][C:22]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br.C(=O)([O-])[O-].[K+].[K+].[OH-].[Li+]>CN(C)C=O.O1CCCC1.O>[CH3:21][C:22]1[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:3]1[C:4]2[CH:10]=[C:9]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[C:7]([C:17]([OH:19])=[O:18])[C:5]=2[N:6]=[C:2]1[CH3:1]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C)[nH]c12
Reactant: Cc1cccc(CBr)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cccc(Cn2c(C)nc3c(C(=O)O)cc(N4CCOCC4)cc32)c1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 20.02 %

Procedure:
To a solution of methyl 2-methyl-5-(4-morpholinyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 26, step d (0.2 g, 0.726 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was added 2,3-dimethylbenzyl bromide (0.289 g, 1.453 mmol) and potassium carbonate (0.301 g, 2.179 mmol). The resulting reaction mixture was stirred for 3 h at 80° C. The solution was cooled to room temperature and poured into water and was extracted with EtOAc. The combined organic phase was washed with Brine and concentrated. The residue was purified on Biotage Isolera purification system using a Biotage 10 g SNAP silica gel cartridge and eluted with a gradient of DCM to 5% MeOH/DCM over 10 column volumes. The expected compound was collected and evaporated to yield a tan solid. The tan solid was dissolved in tetrahydrofuran (THF) (10.00 mL) followed by the addition of 1M lithium hydroxide solution (10 mL, 10 mmol). The reaction was stirred at 50° C. for 2 h. The reaction was cooled to room temperature and the organic solvent was removed in vacuo. The solution was diluted with water (20 mL) and acidified with 1 N HCl. The mixture was then filtered and the grey solid was purified by reversed phase HPLC with a gradient of acetonitrile (0.1% TFA) and water (0.1% TFA v/v) (20-50%) over 10 minutes. The appropriate fractions were collected and evaporated to yield the desired product (55.2 mg, 0.145 mmol, 20.02% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.31 (s, 3H) 2.36 (s, 3H) 2.85 (s, 3H) 3.13-3.24 (m, 4H) 3.80-3.96 (m, 4H) 5.49-5.61 (m, 2H) 6.29-6.38 (m, 1H) 6.94-6.99 (m, 1H) 7.00-7.07 (m, 1H) 7.14-7.23 (m, 1H) 7.72 (m, 1H). MS(ES+) m/e 379.8 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](=O)([O-])[O-].[K+].[K+].CI.C(OCC)(=O)C>CN(C)C=O>[CH3:20][O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NC(CC1CCCCC1)C(=O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-cyclohexyl-propionic acid (3.0 g, 11.1 mmol) and potassium carbonate (1.5 g, 11.1 mmol) in N,N-dimethylformamide (20 mL) was added methyl iodide (0.795 μL; 12.1 mmol). The reaction mixture was stirred at room temperature overnight. To the reaction mixture was added ethyl acetate (100 mL) and the solution was washed with water (3×100 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to give the title intermediate as an oil (3.1 g) which was used directly in the next step.
Reaction SMILES: Br[C:2]1[C:3](=[O:20])[O:4][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[SH:30])([CH3:23])[CH3:22].N1CCCCC1>ClCCl>[OH:8][C:7]1[CH2:6][C:5]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][C:3](=[O:20])[C:2]=1[S:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH:21]([CH3:23])[CH3:22]
Reactant: CC(C)c1ccccc1S
Reactant: CC(C)CCC1(c2ccccc2)CC(O)=C(Br)C(=O)O1
Solvent: ClCCl
Solvent: C1CCNCC1
Product: CC(C)CCC1(c2ccccc2)CC(O)=C(Sc2ccccc2C(C)C)C(=O)O1

Procedure:
The title compound was prepared as described in General Method 6 from 2.0 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6-(3-methylbutyl)-6-phenyl-2H-pyran-2-one (prepared in example CCC), 2.2 mmol of 2-isopropylbenzenethiol, and 2.2 mmol of piperidine in 30 mL of dichloromethane. The crude product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 64°-66° C.). 1H NMR (DMSO-d6) δ0.80 (m, 6H), 0.95 (m, 1H), 1.17 (t, 7H), 1.42 (m, 1H), 1.93 (m, 2H), 3.20 (m, 1H), 3.45 (2H+H2O), 5.84 (d, 1H), 6.55 (t, 1H), 6.93 (t, 1H), 7.12 (d, 1H), 7.40 (m, 5H).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][N:12]2[C:16]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:15][N:14]=[CH:13]2)[NH:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([N:2]1[C@H:3]([CH2:11][N:12]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)=[CH:15][N:14]=[CH:13]2)[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:32]
Reactant: N#Cc1ccc(Cc2cncn2C[C@@H]2Cc3ccccc3CN2)cc1
Reactant: COc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)N2Cc3ccccc3C[C@H]2Cn2cncc2Cc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-{3-[(S)-1,2,3,4-tetrahydro-isoquinolin-3-yl-methyl]-3H-imidazol-4-yl-methyl}-benzonitrile (0.16 g, 0.487 mmol), 3-methoxybenzoic acid (0.074 g, 0.487 mmol), 1-hydroxybenzotriazole (0.075 g, 0.487 mmol), EDC (0.093 g, 0.487 mmol) and N-methylmorpholine (0.2 ml, 1.95 mmol) in 5 ml DMF was stirred for 18 hr at 25° C. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The ethyl acetate layer was dried with saturated sodium chloride and magnesium sulfate. Evaporation in vacuo of the ethyl acetate layer yielded the crude product. Purification was done on silica gel using methylene chloride:methanol:amonia hydroxide 98:2:0.2 and yielded the title compound.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[C:6]([O:10][C:11]([O:13][NH:14]C(=O)OC(C)(C)C)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)C(C)C)(C)C.O>ClCCl>[C:6]([O:10][C:11]([O:13][NH:14][C:1](=[O:4])[CH:2]=[CH2:3])=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)NOC(=O)OC(C)(C)C
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)NOC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of acryloyl chloride dissolved in dry dichloromethane was cooled at 0° C. with an ice bath. A mixture of tert-butyl N-(tert-butoxycarbonyloxy)carbamate (31) and N,N-diisopropylethylamine in dry dichloromethane was added. Water was added after 16 hours of reaction and the layers were separated. The organic solution was washed with diluted hydrochloric acid, a saturated sodium bicarbonate solution, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by flash chromatography using a mixture of hexane and ethyl acetate (90:10). The purification gave N-(tert-butoxycarbonyl), N-(tert-butoxycarbonyloxy)acrylamide (32).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:8][CH2:7]1.[O-:22][C:23]#[N:24].[Na+].[OH-].[Na+]>C(O)(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH:12]2[CH2:13][CH2:14][N:15]([C:23]([NH2:24])=[O:22])[CH2:16][CH2:17]2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
4-(3,4-Dichlorophenoxy)-1,4′-bipiperidine (2.0 g) was dissolved in glacial acetic acid (0.608 ml), the solution was diluted with water (6 ml) and added with stirring to a solution of sodium cyanate (0.395 g) in warm water (3 ml). The reaction was allowed to stand for 30 mins. 2M Sodium hydroxide solution was added until the solution was alkaline. The resulting precipitate was collected and washed with water followed by dichloromethane and then dried to leave the sub-title compound (1.3 g; ES+ 372/374).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[C:7](=[O:12])[N:6]([CH2:13][CH:14]1[CH2:16][CH2:15]1)[CH2:5]2.CN[C@@H]1CCCC[C@H]1NC.[I-:27].[Na+]>C(O)CCC.C(OCC)(=O)C.[Cu]I>[CH:14]1([CH2:13][N:6]2[CH2:5][C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([I:27])[CH:3]=3)[C:7]2=[O:12])[CH2:16][CH2:15]1
Reactant: [I-]
Reactant: Cc1cc(Br)cc2c1C(=O)N(CC1CC1)C2
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1cc(I)cc2c1C(=O)N(CC1CC1)C2
Temperature: 120 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
To a solution of 5-Bromo-7-methyl-2-cyclopropylmethyl-2,3-dihydro-isoindol-1-one (1.0 g, 3.56 mmol) in butanol (10 ml), (1R,2R)-N,N′-dimethylcyclohexane-1,2-diamine (204 mg, 1.42 mmol), copper(I) iodide (140 mg, 0.714 mmol) and sodium iodide (1.08 g, 14.3 mmol) were added. The resulting mixture was stirred at 120° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, brine, dried over anhydrous sodium sulphate, filtered, concentrated. Column chromatography (30% EtOAc/Hexanes) provided the title compound (1.07 g, 92%) as a colourless solid. 1H NMR (300 MHz, CDCl3): δ 7.65 (s, 1H), 7.59 (s, 1H), 4.42 (s, 2H), 3.46-3.44 (d, 2H), 2.70 (s, 3H), 1.04-1.02 (m, 1H), 0.61-0.57 (m, 2H), 0.34-0.31 (m, 2H)
Reaction SMILES: CC(=NO)C(C)=NO.[BH4-].[Na+].[Cl:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH:15]=[C:16]1[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22].C(O)(=O)C>O.[OH-].[Na+].C1COCC1.CN(C=O)C>[Cl:11][C:12]1[CH:13]=[C:14]([CH:23]=[CH:24][C:25]=1[O:26][CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:15][CH:16]1[S:20][C:19](=[O:21])[NH:18][C:17]1=[O:22]
Reactant: O=C1NC(=O)C(=Cc2ccc(OCC3CCCCC3)c(Cl)c2)S1
Agent: CC(=NO)C(C)=NO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCC3CCCCC3)c(Cl)c2)S1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To the suspension containing CoCl2.6H2O (3.98 mg, 0.014 mmol) and dimethylglyoxime (66.13 mg, 0.57 mmol) in 10 ml of water, 4 drops of 1.0N NaOH and NaBH4 (370.06 mg, 9.62 mmol) were subsequently added. The mixture was cooled to 0° C., and 5-(3-chloro-4-(cyclohexylmethoxy)benzylidene)thiazolidine-2,4-dione (1 g, 2.83 mmol) in 15 ml of THF-DMF (2:1) was added thereto over 20 minutes. The mixture was stirred at room temperature for 18 hours, to which acetic acid was then added until the pH thereof reached about 6. The mixture was diluted with water and extracted with ethyl acetate and water. The organic layer was washed with water several times, dried with anhydrous magnesium sulfate, filtered and solvent-evaporated. The residual oil was chromatographed on silica gel to afford 5-(3-chloro-4-(cyclohexylmethoxy)benzyl)thiazolidine-2,4-dione (Derivative 117 of the above formula) as white solid (0.8 g, yield: 79%).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[C:26]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:27]=[C:28]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:23]2=[N:22][C:21]=1[CH3:43])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.O.C(OCC)(=O)C>C1COCC1>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][O:29][C:28]1[C:23]2[N:24]([C:20]([C:18](=[O:19])[NH:17][C@H:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:9][OH:8])=[C:21]([CH3:43])[N:22]=2)[CH:25]=[C:26]([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:27]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2F)c2nc(C)c(C(=O)N[C@@H](CO[Si](C)(C)C(C)(C)C)c3ccccc3)n2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2F)c2nc(C)c(C(=O)N[C@@H](CO)c3ccccc3)n2c1
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
To a solution of 370 mg of ethyl 3-{[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-phenylethyl]carbamoyl}-8-[(2-fluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-6-carboxylate in 12 ml of THF was added 1.22 ml of a 1 M tetrabutylammonium fluoride/THF solution, followed by stirring for 30 minutes. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 220 mg of ethyl 8-[(2-fluorobenzyl)oxy]-3-{[(1R)-2-hydroxy-1-phenylethyl]carbamoyl}-2-methylimidazo[1,2-a]pyridine-6-carboxylate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[CH2:27][CH3:28])=[CH:4][C:3]=1[F:29].C([Sn](CCCC)(CCCC)[C:35]1[S:39][CH:38]=[N:37][CH:36]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:35]2[S:39][CH:38]=[N:37][CH:36]=2)=[C:3]([F:29])[CH:4]=1)[CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncs1
Reactant: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(Br)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)nc2)c1-c1ccc(-c2cncs2)c(F)c1
Yield: 48.5 %

Procedure:
A mixture of 5-(5-(4-bromo-3-fluorophenyl)-4-ethyl-3-trifluoromethyl-1H-pyrazol-1-yl)-2-pyridinesulfonamide from step 4 of Example 19 (450 mg, 0.912 mmol), 5-tributylstannyl-1,3-thiazol (410 mg, 1.095 mmol), tetrakis(triphenylphosphine)palladium (105 mg, 0.091 mmol), lithium chloride (97 mg, 2.281 mmol) in 1,4-dioxane (11 ml) was stirred at reflux for 5 h. After cooling, the mixture was diluted with ethyl acetate, washed with water. The organic layer was dried (MgSO4) and concentrated. This was purified on silica gel eluting with ethyl acetate/hexane (1:3/1:2) to afford 220 mg (48.5%) of the titled compound as a slight yellow solid.