Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.[Cl:13][C:14]1[N:15]=[C:16](Cl)[C:17]2[C:22]([CH3:23])=[CH:21][S:20][C:18]=2[N:19]=1>>[Cl:13][C:14]1[N:15]=[C:16]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:17]2[C:22]([CH3:23])=[CH:21][S:20][C:18]=2[N:19]=1
Reactant: Cc1csc2nc(Cl)nc(Cl)c12
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1csc2nc(Cl)nc(NCCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 2,4-dichloro-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-chloro-5-methyl-4-(3,4-methylenedioxyphenethylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][O:17]2)[C:12](O)=[O:13])[C:8](=[O:21])[CH:7]=1.[NH2:26][C:27]1[CH:31]=[CH:30][N:29]([CH2:32][C:33]([CH3:36])([OH:35])[CH3:34])[N:28]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>ClCCl>[OH:35][C:33]([CH3:36])([CH3:34])[CH2:32][N:29]1[CH:30]=[CH:31][C:27]([NH:26][C:12](=[O:13])[C@@H:11]([N:9]2[CH2:10][C:6]([O:5][C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[O:2][CH3:1])=[CH:7][C:8]2=[O:21])[CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][O:17]2)=[N:28]1
Reactant: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCO2)C(=O)O)C1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1OC1=CC(=O)N([C@@H](CC2CCCO2)C(=O)Nc2ccn(CC(C)(C)O)n2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.7 %

Procedure:
A solution of (S)-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-furan-2-yl)-propionic acid (90 mg, 0.26 mmol) in dichloromethane (10 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 45 mg, 0.29 mmol), Benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (140 mg, 0.31 mmol) and N,N-diisopropylethylamine (100 mg, 0.78 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford (S)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(tetrahydro-furan-2-yl)-propionamide (45 mg, 36%) as a yellow solid: LR-ES-MS m/z calculated for C25H32N4O6 [M]+ 484, observed [M+H]+ 485; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H) 1.06 (br. s., 3H) 1.35-2.11 (m, 6H) 3.54-3.79 (m, 3H) 3.81 (s, 3H) 3.89 (s, 2H) 4.18, 4.22 (2×d, J=18.0, 1H) 4.45 (d, J=18.0 Hz, 1H) 4.68 (s, 1H) 4.70 (s, 1H) 4.77-4.91 (m, 1H) 6.40-6.48 (m, 1H) 6.95-7.06 (m, 1H) 7.18-7.25 (m, 1H) 7.25-7.36 (m, 2H) 7.51-7.56 (m, 1H) 10.70, 10.73 (2×s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]1=[O:17].[H-].[Na+].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].Cl>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH2:5][N:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:7]1=[O:17]
Reactant: CCOC(=O)CBr
Reactant: O=c1[nH]c2ccccc2c(=O)n1Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(=O)n(Cc2ccc(Cl)c(Cl)c2)c(=O)c2ccccc21
Temperature: 0 °C

Procedure:
To a suspension of 3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazoline (1 g) in N,N-dimethylformamide (15 ml) was added sodium hydride (60% in mineral oil, 0.17 g) with stirring at 0° C. and the mixture was stirred for 15 minutes at the same temperature. To this mixture was added ethyl bromoacetate (0.45 ml) and the mixture was stirred for 1 hour at room temperature. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried and evaporated to give a residue. Thus obtained product was purified by recrystallization from isopropyl ether to give ethyl 2-[3-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (1.21 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][CH:10]=2)[O:3]1.[C:21](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.ClCCl>[CH3:21][N:15]([C:12]1[CH:11]=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:14][CH:13]=1)[S:16]([CH3:19])(=[O:18])=[O:17]
Reactant: O=C([O-])[O-]
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Agent: [K+]
Solvent: CI
Solvent: ClCCl
Solvent: CC(C)=O
Product: CN(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of N-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide (0.50 g, 1.7 mmol) and potassium carbonate (0.28 g, 2.0 mmol) in acetone (10 mL) was added methyl iodide (0.12 mL, 2.0 mmol). The mixture was stirred at room temperature for 18 hours under an atmosphere of nitrogen then diluted with dichloromethane (20 mL), filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was subjected to high vacuum for 18 hours. N-Methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-methanesulfonamide was isolated as a yellow solid (0.50 g, 95%) and was used without further purification. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.83 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.8 Hz, 2H), 3.34 (s, 3H), 2.82 (s, 3H), 1.34 (s, 12H). MS=312 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[CH:5]=[CH:6][C:7]=1[I:8].[O:10](C(OC(C)(C)C)=O)[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=O.O.CCOC(C)=O>O1CCOCC1.CN(C1C=CN=CC=1)C>[C:14]([O:13][C:11](=[O:10])[NH:9][C:4]1[CH:5]=[CH:6][C:7]([I:8])=[C:2]([F:1])[CH:3]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Nc1ccc(I)c(F)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc(I)c(F)c1
Yield: 96 %

Procedure:
A solution of compound 143 (13.67 g, 57.7 mmol) in 1,4-dioxane (100 mL) was treated with BOC2O (13.83 g, 63.4 mmol, 1.1 equiv) and DMAP (700.0 mg, 5.8 mmol, 0.1 equiv) at room temperature. The resulting reaction mixture was then warmed up to refluxing for 4 h. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was treated with H2O (100 mL) and EtOAc (100 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (2×100 mL) and saturated NaCl aqueous solution (100 mL), dried over MgSO4, and concentrated in vacuo. The residue was further dried in vacuo to afford the crude, desired (3-fluoro-4-iodo-phenyl)-carbamic acid tert-butyl ester (compound 144, 18.67 g, 19.44 g theoretical, 96%) as pale-yellow oil, which solidified upon standing in vacuo at room temperature and was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For compound 144: C11H13FINO2, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]2[NH:15][C:14]3[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:13]=3[N:12]=2)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH:48]([CH:58]1[CH2:60][CH2:59]1)[CH2:49][C:50]([NH:52][C:53]1[NH:54][CH:55]=[CH:56][N:57]=1)=[O:51]>>[CH:58]1([CH:48]([NH:47][C:20]([C:18]2[CH:17]=[CH:16][C:14]3[NH:15][C:11]([C:3]4[N:2]=[CH:1][C:10]5[C:5]([CH:4]=4)=[CH:6][CH:7]=[CH:8][CH:9]=5)=[N:12][C:13]=3[CH:19]=2)=[O:21])[CH2:49][C:50](=[O:51])[NH:52][C:53]2[NH:54][CH:55]=[CH:56][N:57]=2)[CH2:60][CH2:59]1
Reactant: O=C(O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1
Reactant: NC(CC(=O)Nc1ncc[nH]1)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(CC(NC(=O)c1ccc2[nH]c(-c3cc4ccccc4cn3)nc2c1)C1CC1)Nc1ncc[nH]1
Yield: 4.3 %

Procedure:
289 mg (1 mmol) of 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid (289 mg, 1 mmol) was reacted with 380 mg (1 mmol) of HBTU and 3-amino-3-cyclopropyl-N-(1H-imidazol-2-yl)-propionamide (230 mg, 1 mmol) as described in general procedure A. A solid precipitated from the solution and was collected by filtration, washed with H2O and Et2O, to give 2-isoquinolin-3-yl-1H-benzoimidazole-5-carboxylic acid [1-cyclopropyl-2-(1H-imidazol-2-ylcarbamoyl)-ethyl]-amide (20 mg, 4%). LCMS: 466 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H), 8.56 (s, 1H), 8.09-7.34 (m, 9H), 6.39 (s, 2H), 3.71 (t, 1H), 2.44 (m, 2H), 0.81 (m, 1H), 0.10 (m, 4H) ppm.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([N+:11]([O-])=O)=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(O)C.O>[Zn].C(O)(=O)C>[Br:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:14][CH3:15])[C:10]([NH2:11])=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: CCc1nn2c(Br)cccc2c1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CCc1nn2c(Br)cccc2c1N
Temperature: 65 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a suspension of 7-bromo-2-ethyl-3-nitropyrazolo[1,5-a]pyridine (1.78 g) in a mixed solution of ethanol (100 mL), water (50 mL) and acetic acid (10 mL) was added zinc powder (1.78 g) at room temperature and the reaction mixture was stirred for 1 hour at 65° C. The reaction mixture was filtered through celite to remove insoluble residue and the filtrate was evaporated under reduced pressure. Water was added to the obtained residue and extraction was performed with ethyl acetate, and after washing the organic extract with water, saturated aqueous sodium bicarbonate and brine, the organic extract was dried over anhydrous magnesium sulfate and filtered, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (60 g) and the title compound (1.16 g) was obtained as a dark green oil from the ethyl acetate:n-hexane (4:1) fraction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1.Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][C:25]=1[Cl:26])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: NCCCN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Yield: 73.2 %

Procedure:
The product from Step (a) (2 g) was dissolved in dioxane (100 ml) and 6N HCl (100 ml) was added. After 18 hours at room temperature the solvent was evaporated and the resultant solid was dissolved in aqueous NaOH (2M) to pH 11. The solution was extracted with ethyl acetate, the organic phase was dried (MgSO4) and evaporated to leave the title compound as an oil (1.1 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5](F)=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][C:11]2[CH:19]=[C:18]([C:20]3[CH:28]=[CH:27][CH:26]=[C:25]4[C:21]=3[CH:22]=[CH:23][NH:24]4)[CH:17]=[C:16]3[C:12]=2[CH:13]=[N:14][NH:15]3)=[O:9])[C:5]([N:31]([CH3:32])[CH3:30])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1nc(Cl)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)c1ccc(Cl)nc1C(=O)Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Temperature: 160 °C
Yield: 201.8 %

Procedure:
6-Chloro-3-fluoro-N-[6-(1H-indol-4-yl)-1H-indazol-4-yl]-2-pyridinecarboxamide (188 mg, 0.46 mmol) was placed in a microwave vial and dissolved in THF (4 ml). Dimethylamine (0.463 ml, 0.93 mmol) and DIPEA (0.485 ml) were added and the mixture was heated at 160° C. for 1 h under microwave irradiation. The solvent was removed in vacuo and the yellow residue was dissolved in DCM (10 ml) and washed with water (10 ml). The DCM was removed in vacuo and the solid was dried in vacuo on a high vacuum line to afford the title compound (400 mg) as a yellow solid.
Reaction SMILES: [OH-].[K+].F[C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25]>CS(C)=O>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:16]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:17]=1
Reactant: O=C(c1ccccc1)c1ccccc1F
Reactant: Oc1ccccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(c1ccccc1)c1ccc(Oc2ccccc2F)cc1
Yield: 87 %

Procedure:
All the components (301 g of 46 percent aqueous KOH, 501 g of fluorobenzophenone, 800 mL of DMSO, and 269 g of fluorophenol), plus 5 mole percent BHT (25 g) were mixed together under a nitrogen atmosphere and distillation of water was carried out at a maximum temperature of 80° C. Reaction continued at 70° C. for a total of 12 hr. Purification by lights distillation gave an 87 percent yield of 4-(2-fluoro-phenoxy)benzophenone.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[C:6]=1[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31].[O:32]1[CH:37]=[CH:36][CH2:35][CH2:34][CH2:33]1>O1CCCC1.FC(F)(F)C(O)=O>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][C:6]1[C:7]([NH:11][S:12]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[CH2:22])=[CH:19][CH:20]=2)(=[O:13])=[O:14])=[N:8][CH:9]=[N:10][C:5]=1[O:4][CH2:3][CH2:2][O:1][CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37][O:32]1
Reactant: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCO)c2Cc2ccccc2OC)cc1
Reactant: C1=COCCC1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(OCCOC3CCCCO3)c2Cc2ccccc2OC)cc1

Procedure:
A solution of 110 mg of N-[6-(2-hydroxyethoxy)-5-(o-methoxybenzyl)-4-pyrimidinyl]-p-vinylbenzenesulfonamide in 3 ml of absolute tetrahydrofuran was treated with 0.3 ml of 3,4-dihydro-2H-pyran and 4 drops of trifluoroacetic acid. After boiling under reflux overnight, the solvent was distilled under reduced pressure and the residue was chromatographed on silica gel with methylene chloride/ethyl acetate (9:1). There were obtained 100 mg of rac-N-[5-(o-methoxybenzyl)-6-[2-[(tetrahydro-2H-pyran-2-yl)oxy]ethoxy]-4-pyrimidinyl]-p-vinylbenzenesulfonamide as a white resin, MS: 460 (M--SO2 +H); 430 (M--SO2 +OCH3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27](Br)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:37]4[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2]
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(Br)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccc(C(F)(F)F)cc4)cc3)oc2C)cc1

Procedure:
To a 25 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methyl propionic acid ethyl ester (0.410 mmoles, 200 mg) (see Ex. 2, Part B), 4-trifluoromethylphenyl boronic acid (0.451 mmoles), toluene (5 mL), ethanol (5 mL), and sodium carbonate (0.819 mmoles, 0.410 mL of a 2M solution). This mixture was vacuum degassed and nitrogen was added in at a positive pressure. Pd(PPh3)4 (catalytic, spatula tip) was added and the reaction was heated to reflux for 3 h. Distilled water was added to the mixture. Subsequently, this was extracted with ethyl acetate and washed with brine. The organic layer was collected, filtered over a thin pad of silica gel, and concentrated in-vacuo. The crude mixture was then purified by chromatography on silica gel affording 2-(4-{2-[2-(4′-trifluoromethylbiphenyl-4-yl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:49][CH:50]2[CH2:54][CH2:53][CH2:52][CH2:51]2)[C:40]([NH:42][C:43]2[CH:47]=[CH:46][N:45]([CH3:48])[N:44]=2)=[O:41])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[C:55]([O:59][C:60](=[O:68])CN1C=CC(N)=N1)([CH3:58])([CH3:57])[CH3:56].N1C=CC=CC=1>C(Cl)Cl.O>[C:55]([O:59][C:60](=[O:68])[CH2:48][N:45]1[CH:46]=[CH:47][C:43]([NH:42][C:40](=[O:41])[C@@H:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:29]([Cl:28])[CH:30]=2)[CH2:49][CH:50]2[CH2:51][CH2:52][CH2:53][CH2:54]2)=[N:44]1)([CH3:58])([CH3:57])[CH3:56]
Reactant: Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Reactant: CC(C)(C)OC(=O)Cn1ccc(N)n1
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)OC(=O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Yield: 55.8 %

Procedure:
Triphenylphosphine (1.66 g, 6.33 mmol) was dissolved in methylene chloride (40 mL) and cooled to 0° C. To this solution was added N-bromosuccinimide (1.27 g, 7.17 mmol) and was stirred at 0° C. until it was completely dissolved and became light purple in color. The 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in PCT WO 2004/052869 A1, Example 1, 1.40 g, 4.22 mmol) was then added and it was stirred at 0° C. for 20 min and then warmed to 25° C. and stirred for 30 min. After such time, (3-amino-pyrazol-1-yl)-acetic acid tert-butyl ester (833 mg, 4.22 mmol) and pyridine (1.03 mL, 6.33 mmol) were added and it was stirred at 25° C. for 16 h. The reaction was then diluted with water (30 mL) and then extracted with methylene chloride (3×15 mL). The organic layers were then combined and dried over magnesium sulfate, filtered and concentrated in vacuo. Flash column chromatography (Merck silica gel 60, 40-63 μm; 50% ethyl acetate/hexanes) followed by reverse phase preparative HPLC purification (Column: Thomson C18 ODSA, 5 micron, 50×21.2 mm ID; 30% acetonitrile/water to 100% acetonitrile/water; 30 mL/min flow rate for 15 min run) afforded {3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-acetic acid tert-butyl ester (1.20 g, 56%) as a white solid: ESI-LRMS m/e calcd for C24H32ClN3O5S [M+] 509.2, found 510.1 [M+H+].
Reaction SMILES: IC1CCCCC1.C[O:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]>CN(C)C=O>[OH:9][C:10]1[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:11]=1[C:12]([OH:14])=[O:13]
Reactant: COc1ccc(C(F)(F)F)cc1C(=O)O
Agent: IC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(O)c1cc(C(F)(F)F)ccc1O

Procedure:
Iodocyclohexane (29.4 ml, 227 mmol) was added to a solution of 2-(methyloxy)-5-(trifluoromethyl)benzoic acid (5 g, 22.71 mmol) in N,N-dimethylformamide (25 ml), and the mixture was heated under reflux for 4 hours. After cooling, the reaction was evaporated under reduced pressure on a buchi. The residue was triturated with cyclohexane, and the solid obtained was filtered, washed with cyclohexane and dried in air under vacuum. 4.2 g
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[C:6]3([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1.[Cl:18][C:19]1[C:20]([N:25]2[CH:29]=[C:28]([CH:30]=O)[C:27]([CH3:32])=[N:26]2)=[N:21][CH:22]=[CH:23][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(O)(=O)C.ClCCl>[Cl:1][C:2]1[S:17][C:5]2[C:6]3([O:7][CH2:8][C:9]([F:11])([F:10])[C:4]=2[CH:3]=1)[CH2:12][CH2:13][N:14]([CH2:30][C:28]1[C:27]([CH3:32])=[N:26][N:25]([C:20]2[C:19]([Cl:18])=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:29]=1)[CH2:15][CH2:16]3
Reactant: FC1(F)COC2(CCNCC2)c2sc(Cl)cc21
Reactant: Cc1nn(-c2ncccc2Cl)cc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1nn(-c2ncccc2Cl)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a solution of 2′-chloro-4′,4′-difluoro-4′,5′-dihydrospiro[piperidine-4,7′-thieno[2,3-c]pyran] (0.2 g, 0.71 mmol) in 1,2-dichloroethane (5 mL) are added 1-(3-chloro-2-pyridyl)-3-methyl-pyrazole-4-carbaldehyde (0.19 g, 0.86 mmol) and a few drops of acetic acid. The reaction mixture is stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.315 g, 1.43 mmol) is added and stirred at room temperature for 14 hours. After completion, the reaction mixture is diluted with dichloromethane and washed with saturated sodium bicarbonate solution and brine. The organic phase is dried over sodium sulfate and concentrated in vacuo. The crude mixture is purified by HPLC to yield 0.195 g (56%) of 2-chloro-1′-[[1-(3-chloro-2-pyridyl)-3-methyl-pyrazol-4-yl]methyl]-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]. MS (m/z): 485 (M+1).
Reaction SMILES: [H-].[Na+].[I-].[Cl:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][N+](C)(C)C)=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1>C(O)C#C>[Cl:4][C:5]1[CH:27]=[CH:26][CH:25]=[CH:24][C:6]=1[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][O:8][CH2:7][C:6]#[CH:5])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1nc2c(OCc3ccccc3Cl)cccn2c1C[N+](C)(C)C
Agent: C#CCO
Agent: [H-]
Agent: [I-]
Product: C#CCOCc1c(C)nc2c(OCc3ccccc3Cl)cccn12
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.6 %

Procedure:
To a solution of sodium hydride (60% in mineral oil dispersion, 0.186 g) in 2-propynyl alcohol (8 ml) was added 8-(2-chlorobenzyloxy)-3-trimethylammoniomethyl-2-methylimidazo[1,2-a]pyridine iodide (2 g) and the mixture was heated at 90°-95° C. with stirring for 1 hour. After being cooled, the mixture was poured into ice-water and the resulting precipitate was collected by filtration and dissolved in methylene chloride. The solution was treated successively with silica gel (1 g) and activated charcoal and evaporated in vacuo. The crystalline residue was recrystallized from a mixture of methylene chloride and n-hexane to give 8-(2-chlorobenzyloxy)-3-(2-propynyloxymethyl)-2-methylimidazo[1,2-a]pyridine (0.9 g).
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:19]=[CH:18][C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:9]([CH3:20])[CH:8]=1)(C)C.C(=O)([O-])[O-].[K+].[K+]>CO>[C:6]([C:7]1[CH:19]=[CH:18][C:10]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][O:13]2)=[C:9]([CH3:20])[CH:8]=1)#[CH:5]
Reactant: Cc1cc(C#C[Si](C)(C)C)ccc1OC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(OC2CCCCO2)c(C)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 91 %

Procedure:
In a flask equipped with a stirrer and a thermometer, 11.87 g of 2-(4-(trimethylsilylethynyl)-2-methylphenoxy)perhydro-2H-pyrane prepared in Step 2-2 and 0.13 g of potassium carbonate were suspended in 50 g of methanol under a nitrogen atmosphere, stirred at room temperature for 7 hours, and concentrated at 60° C. under a pressure of 20 Torr. The concentrate was purified through silica gel chromatography using a 20/1 (by volume) mixture of hexane/ethylacetate mixed with 0.1 wt % triethyl amine as an eluting solvent, to thereby obtain 8.10 g of 2-(4-ethynyl-2-methylphenoxy)perhydro-2H-pyrane at 91% yield.