Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[CH3:12][S:13][CH2:14][CH2:15][NH2:16].C(N(CC)C(C)C)(C)C>CN1CCCC1=O.C(OCC)(=O)C>[CH3:11][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[NH:16][CH2:15][CH2:14][S:13][CH3:12]
Reactant: Cc1cccc([N+](=O)[O-])c1Cl
Reactant: CSCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CSCCNc1c(C)cccc1[N+](=O)[O-]
Temperature: 220 °C
Yield: 157.4 %

Procedure:
A mixture of 2-chloro-3-nitrotoluene (1.3 g, 7.3 mmol), 2-(methylthio)ethylamine (1.4 mL, 15 mmol) and N,N-diisopropylethylamine (5.0 mL, 29 mmol) in 1-methyl-2-pyrrolidinone (3.7 mL) was heated to 220° C. by microwave for 1 h. The mixture was diluted with ethyl acetate (0.10 L) and washed with water (50 mL×2), brine (50 mL), dried over sodium sulfate, filtered and concentrated to give a crude material. The another batch starting from 1.3 g of 2-chloro-3-nitrotoluene was combined to this crude material and the combined crude products were purified by column chromatography on silica gel eluting with hexane/ethyl acetate (3/1) to afford 2.6 g (77%) of the title compound.
Reaction SMILES: S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])(C1C=CC(C)=CC=1)(=O)=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=[C:32]([CH2:34][OH:35])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:35][CH2:34][C:32]1[CH:33]=[C:28]([NH:27][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:29]=[C:30]([CH2:36][OH:37])[CH:31]=1
Reactant: Nc1cc(CO)cc(CO)c1
Reactant: COC(=O)CCOCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CCOCCOCCOCCNc1cc(CO)cc(CO)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 25.7 %

Procedure:
To a mixture of methyl 3-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)propanoate (263a) (250 mg, 0.640 mmol) and (5-amino-1,3-phenylene)dimethanol (26)(108 mg, 0.704 mmol) in anhydrous DMF (1.4 ml) was added potassium carbonate (133 mg, 0.960 mmol). The reaction stirred for 18 hours at 80° C. and then was allowed to cool to room temperature. The mixture was quenched with water and extracted two times with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% Methanol/methylene chloride) yielded methyl 3-(2-(2-(2-(3,5-bis(hydroxymethyl)phenylamino)ethoxy)ethoxy)ethoxy)propanoate (264a) (61 mg, 25%); 1H NMR (400 Hz, CDCl3): δ 6.58 (s, 1H), 6.47 (s, 2H), 4.49 (s, 4H), 3.67 (t, J=6.4 Hz, 2H), 3.62 (s, 3H), 3.64-3.54 (m, 10H), 3.21 (t, J=5.2 Hz, 2H), 2.51 (t, J=6.4 Hz, 2H); MS (m/z), found 394.3 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C)C=O.O.CCOCC>[CH2:29]([O:28][C:26]([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:1])=[C:3]1[N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)CCCCCCCBr
Reactant: Cc1c(-n2ccnc2)[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)CCCCCCCn1c(-n2ccnc2)c(C)c2ccccc21

Procedure:
3-Methyl-2-(1-imidazolyl)indole (0.78 g) in dimethylformamide (8 ml) is added dropwise to a suspension of sodium hydride (50% dispersion in mineral oil, 0.20 g) in dimethylformamide (8 ml) stirred under nitrogen at 5°-10°. The resulting solution is stirred at 5°-10° for 1/2 hour. A solution of ethyl 8-bromooctanoate (1.00 g) in dimethylformamide (5 ml) is added dropwise. The reaction mixture is stirred at 5°-10° for 1/2 hour and then overnight at room temperature. The mixture is diluted with water (50 ml) and extracted into methylene chloride (3×25 ml). The extract is washed with water and saturated aqueous sodium chloride solution, dried over MgSO4, filtered, and concentrated in vacuo to give a two-phase oil. This oil is dissolved in ether (50 ml) and the solution is washed with water (5×25 ml) to remove dimethylformamide. The ether layer is dried over MgSO4, filtered, and concentrated in vacuo to give 1-(7-ethoxycarbonylheptyl)-2-(1-imidazolyl)-3-methylindole a viscous oil; NMR (CDCl3): δ 4.12 (q, 2H), 3.82 (t, 2H), 2.20 (s, 3H), 1.23 (t, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1.[O:13]=[CH:14]C(Cl)(Cl)Cl.C(Cl)(Cl)Cl>>[CH:14]([NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]2[CH:12]=1)=[O:13]
Reactant: NCCc1cn2ccccc2n1
Reactant: O=CC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=CNCCc1cn2ccccc2n1

Procedure:
To a stirred solution of 2-(2-aminoethyl)imidazo [1,2-a] pyridine in chloroform chloral was added dropwise and stirring continued at room temperature for an hour. A solid precipitate was filtered off and recrystallised to give 2-(2-formamidoethyl)imidazo [1,2-a]pyridine. The 2-(2-formamidoethyl)imidazo [1,2-a]pyridine was gradually added to a slurry of lithium aluminium hydride in anhydrous tetrahydrofuran and the resultant suspension heated under reflux for 3 hours. By extracting the reaction mixture with dilute hydrochloric acid there was isolated 2-(2-methylaminoethyl)imidazo [1,2-a]pyridine dihydrochloride.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH2:7][OH:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1.[F:16][C:17]([C:20]1[CH:25]=[C:24](O)[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])(F)[CH3:18].FC(C1C=C(O)C=CC=1CCC(OCC)=O)C>>[Cl:1][C:2]1[C:6]([CH2:7][O:8][C:24]2[CH:23]=[CH:22][C:21]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[C:20]([CH:17]([F:16])[CH3:18])[CH:25]=2)=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[S:4][N:3]=1
Reactant: CCOC(=O)CCc1ccc(O)cc1C(C)(F)F
Reactant: Cc1ccc(-c2snc(Cl)c2CO)cc1
Agent: CCOC(=O)CCc1ccc(O)cc1C(C)F
Product: Cc1ccc(-c2snc(Cl)c2COc2ccc(CCC(=O)O)c(C(C)F)c2)cc1

Procedure:
The two title compounds were prepared according to the procedure described in Example 127, following Steps 6-7, coupling [3-chloro-5-(4-methylphenyl)-1,2-thiazol-4-yl]methanol with a mixture of ethyl 3-[2-(1,1-difluoroethyl)-4-hydroxyphenyl]propanoate (255g) and ethyl 3-[2-(1-fluoroethyl)-4-hydroxyphenyl]propanoate (255h). Upon hydrolysis and purification, the desired products were each isolated as an off-white solid.
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:6][SH:7].[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16]Br)[CH3:13].O>C(O)C>[CH2:12]([O:14][CH:15]([O:18][CH2:19][CH3:20])[CH2:16][S:7][CH2:6][C:5]([O:9][CH2:10][CH3:11])=[O:8])[CH3:13]
Reactant: CCOC(=O)CS
Reactant: CCOC(CBr)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSCC(OCC)OCC
Yield: 58.5 %

Procedure:
Sodium ethoxide (2.83 g) is added to a solution of ethyl thioglycolate (5.00 g) and bromoacetaldehyde diethylacetal (8.20 g) in ethanol (150 ml), and the mixture is refluxed for three hours. The reaction mixture is allowed to stand at room temperature, water is added to the mixture, and the whole is extracted with diethyl ether. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (5.75 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][C:12]2([CH2:22][OH:23])[CH2:21][CH2:20][C:15]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:13]2)=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:24]([O-])([O-])OCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O>[N:11]1([C:12]2([CH2:22][OH:23])[CH2:21][CH2:20][C:15]3([O:16][CH2:17][CH2:18][O:19]3)[CH2:14][CH2:13]2)[C:3]2=[C:4]3[S:10][CH:9]=[CH:8][C:5]3=[N:6][CH:7]=[C:2]2[N:1]=[CH:24]1
Reactant: Nc1cnc2ccsc2c1NC1(CO)CCC2(CC1)OCCO2
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: OCC1(n2cnc3cnc4ccsc4c32)CCC2(CC1)OCCO2
Temperature: 85 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of {8-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-1,4-dioxaspiro[4.5]dec-8-yl}methanol (90.0 mg, 0.268 mmol), ethyl orthoformate (112 μL, 0.671 mmol), and p-toluenesulfonic acid monohydrate (5.1 mg, 0.027 mmol) in toluene (3.0 mL) was stirred at 85° C. overnight. The mixture was diluted with EtOAc, then washed with sat. sodium bicarbonate and brine. The organic layer was dried (Na2SO4), filtered and concentrated to give 50 mg (50%) of the desired product. LCMS calculated for C17H20N3O3S (M+H)+: m/z=346.1. Found: 346.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1>>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)=[CH:40][CH:39]=1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3ccc(Cl)cc3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 4-chlorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: [C:1]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(OCC1C=CC=CC=1)=O.[C:19]([O:24][CH2:25][C@@H:26]1[O:28]C1)(=[O:23])CCC>O1CCCC1>[F:18][C:14]1[CH:13]=[C:12]([N:11]2[CH2:1][C@H:25]([CH2:26][OH:28])[O:24][C:19]2=[O:23])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Nc1cccc(F)c1)OCc1ccccc1
Reactant: CCCC(=O)OC[C@H]1CO1
Solvent: C1CCOC1
Product: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reaction time: 8 h

Procedure:
A mixture of N-(carbobenzyloxy)-3-fluoroaniline (1.000 g, 4.08 mmol) in dry tetrahydrofuran (10 ml) is cooled with a dry ice/acetone bath to about -78° and then nbutyllithium (1.87 ml of a 1.6M mixture in hexanes, 2.91 mmol) is added. (R)-glycidyl butyrate (0.420 g or 0.413 ml, 2.91 mmol) is then added via syringe and the cooling bath allowed to dissipate overnight, with the reaction mixture reaching 20°-25°. The reaction mixture is quenched by the careful addition of saturated aqueous ammonium chloride, the entire mixture transferred to a separatory funnel with dichloromethane washings, and the mixture extracted with dichloromethane. The combined organic extracts are dried over sodium sulfate, filtered and concentrated under reduced pressure to give a concentrate which is purified by chromatography over silica gel, eluting with acetonitrile/chloroform (10/90) containing 1% methanol, to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].[C:20]([O-])(=[O:22])C.[Na+]>C(O)CO>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[NH:9][C:20](=[O:22])[N:16]([C:15]3[CH:17]=[CH:18][CH:19]=[C:13]([Cl:12])[CH:14]=3)[C:2]=2[CH:7]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CC(=O)[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: OCCO
Product: O=c1[nH]c2ccc(Cl)cc2n1-c1cccc(Cl)c1

Procedure:
A mixture of 50 g of 2,4-dichloro-1-nitrobenzene, 40 ml of 3-chloroaniline and 43 g of anhydrous sodium acetate in 220 ml of ethylene glycol is heated at reflux for 72 hours. After cooling, the precipitate formed is filtered off and washed with water. 39 g of the expected product are obtained after crystallization from iso ether, mp=112° C.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:15][C:12]1[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][C:11]=1[C:1](=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5]
Reactant: Fc1ccc(Cl)cc1
Reactant: O=C1C=CC(=O)O1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(O)/C=C/C(=O)c1cc(Cl)ccc1F
Reaction time: 8 h

Procedure:
Finely pulverized maleic anhydride (3.0 g) is added portionwise to a mixture of 1-chloro-4-fluorobenzene (24.6 g) and anhydrous aluminium chloride (11.56 g). A gas bubbler is attached to the top of the condenser and the mixture is heated in an oil bath at 80°-85° C. for 2 hours at which time little hydrogen chloride gas evolution is evident. The mixture is cooled and the excess 1-chloro-4-fluorobenzene is recovered by distillation at water aspirator pressure. The resultant mixture is quenched with ice and then steam distilled to remove the last traces of the 1-chloro-4-fluorobenzene. Concentrated hydrochloric acid (10 mL) is added to the cooled mixture and the resultant solid collected by filtration (9.2 g). This material is taken up in boiling benzene (50 mL), treated with decolorizing charcoal and filtered through a celite bed. On standing overnight, the yellow solid is collected by filtration (2.45 g). A second recrystallization from benzene (40 mL) leads to 4-(2'-fluoro-5'-chlorophenyl)-4-oxo-2E-butenoic acid (2.1 g) as pure regioisomer.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([NH:7][C:8](=[O:16])OC2C=CC=CC=2)[CH:4]=[C:3]2[CH2:17][CH2:18][CH2:19][C:2]=12.[CH3:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]2[C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=[C:29]([C:35]([F:38])([F:37])[F:36])[N:28]=2)[CH2:23][CH2:22]1>CN(C=O)C.CN(C1C=CN=CC=1)C>[N:1]1[CH:6]=[C:5]([NH:7][C:8]([NH:34][CH2:33][C:32]2[C:27]([N:24]3[CH2:25][CH2:26][CH:21]([CH3:20])[CH2:22][CH2:23]3)=[N:28][C:29]([C:35]([F:38])([F:36])[F:37])=[CH:30][CH:31]=2)=[O:16])[CH:4]=[C:3]2[CH2:17][CH2:18][CH2:19][C:2]=12
Reactant: O=C(Nc1cnc2c(c1)CCC2)Oc1ccccc1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2cnc3c(c2)CCC3)CC1
Temperature: 50 °C
Yield: 77.4 %

Procedure:
To a solution of phenyl 6,7-dihydro-5H-cyclopenta[b]pyridin-3-ylcarbamate (E) (80 mg, 0.31 mmol) in DMF was added DMAP (38 mg, 0.31 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (F) (90 mg, 0.33 mmol) at room temperature. The reaction mixture was heated to 50° C. for 14 h. TLC showed complete consumption of starting material. The reaction mixture was diluted with water and extracted with EtOAc. The organic part was washed with water and brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude was purified by column chromatography to give pure 1-(6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound I) (104 mg, 76%).
Reaction SMILES: C(O[P:4]([C:9]1[C:13]([P:14]([O:19][CH2:20][CH3:21])([O:16]CC)=O)=[C:12](I)[S:11][C:10]=1I)([O:6][CH2:7][CH3:8])=[O:5])C.[Cu]C#N.C([Sn](CCCC)(CCCC)[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)CCC.[F-].[K+]>>[CH2:20]([O:19][P:14](=[C:13]1[C:9](=[P:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][S:11][CH:12]1[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=[O:16])[CH3:21]
Reactant: CCOP(=O)(OCC)c1c(I)sc(I)c1P(=O)(OCC)OCC
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Product: CCO[P+]([O-])=C1CSC(c2cccs2)C1=[P+]([O-])OCC
Temperature: 70 °C
Reaction time: 13 h

Procedure:
3,4-bis(diethoxyphosphoryl)-2,5-diiodothiophene obtained in Example 7, commercially available tetrakistriphenylphosphine palladium (0.10 equivalent) and copper(I) cyanide (commercial product) in amounts indicated in Table 8 were dissolved in different types of solvents indicated in Table 8, to which 2-tributylstannylthiophene (2.2 equivalents) was added at room temperature. Thereafter, the reaction mixture was heated to 70° C. and stirred for 6 to 20 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution was added, followed by stirring for 2 hours. Thereafter, the solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting product was purified with a silica gel column (ethyl acetate:methanol=15:1).
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[N:9]2[CH:22]=1)=O)C.[OH-:23].[Na+].Cl.[CH3:26][OH:27]>C(Cl)Cl>[C:26]([CH2:4][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14][CH2:15][CH2:16][NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[N:9]2[CH:22]=1)([OH:27])=[O:23]
Reactant: [OH-]
Reactant: CO
Reactant: CCOC(=O)c1cn2c(SCCNS(C)(=O)=O)cccc2n1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)NCCSc1cccc2nc(CC(=O)O)cn12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 51.1 %

Procedure:
To a solution of 2-ethoxycarbonyl-5-[2-(methylsulfonylamino)ethylthio]imidazo[1,2-a]pyridine (1.65 g, 4.62 mmoles) in methanol (5 ml) was added 1N NaOH (6.93 ml, 6.93 mmoles) and the mixture was stirred at room temperature for 2.5 hours. After the reaction mixture was washed with methylene chloride, 1N HCl (17.39 ml, 17.39 mmoles) was added thereto and the solvent was distilled off. Water was added to the residue and the resulting solid was washed with water and dried to obtain 777 mg of the desired product (51.1%, colorless solid).
Reaction SMILES: [C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][C:15]2=[O:23])=[CH:9][C:8]=1[CH3:40])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[Cl:49][C:50]1[N:55]=[C:54](Cl)[CH:53]=[CH:52][N:51]=1.O>C1COCC1.C(OCC)C>[C:1]([Si:5]([CH3:42])([CH3:41])[O:6][C:7]1[C:8]([CH3:40])=[CH:9][C:10]([C:14]2([C:24]3[CH:29]=[C:28]([CH3:30])[C:27]([O:31][Si:32]([C:35]([CH3:36])([CH3:38])[CH3:37])([CH3:33])[CH3:34])=[C:26]([CH3:39])[CH:25]=3)[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:52]3[CH:53]=[CH:54][N:55]=[C:50]([Cl:49])[N:51]=3)[C:15]2=[O:23])=[CH:11][C:12]=1[CH3:13])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)Nc3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Reactant: Clc1ccnc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: Cc1cc(C2(c3cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c3)C(=O)N(c3ccnc(Cl)n3)c3ccccc32)cc(C)c1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 46.9 %

Procedure:
Under an N2 atmosphere, dissolve 3,3-Bis-[4-(tert-butyl-dimethyl-silanyloxy)-3,5-dimethyl-phenyl]-1,3-dihydro-indol-2-one (0.519 g, 0.862 mmol) in dry THF (2 mL). Cool the reaction to 0° C. Add a solution of potassium t-butoxide (1.0 M) in THF (0.95 mL). Allow the reaction to stir at 0° C. for 10 minutes. Add 2,4-dichloro-pyrmidine (0.141 g, 0.948 mmol), and remove the ice bath. Heat the reaction to 55° C. and stir overnight. Dilute the reaction with water (200 mL) and diethyl ether (200 mL). Separate the layers and wash the aqueous layer with diethyl ether (100 mL). Combine the organic layers. Dry the organic layer with sodium sulfate and concentrate in vacuo. Purify the crude oil by flash column chromatography. Elute the column with 20% ethyl acetate in hexanes to give 0.289 g (47%) of the title compound: 1H NMR(DMSO-d6); δ8.60 (d, 1H), 8.41 (d, 1H), 8.28 (d, 1H), 7.41-7.38 (m, 1H), 7.25-7.22 (m, 1H), 7.17-7.14 (m, 1H), 6.78 (s, 4H), 2.11 (s, 12H), 1.00 (s, 18H), 0.15 (s, 6H), 0.15 (s, 6H).
Reaction SMILES: [C@H:1]1([NH:11][C:12]([C@H:14]2[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[CH2:15]2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:30]([NH:37][C@H:38]([C:42](O)=[O:43])[CH:39]([CH3:41])[CH3:40])([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[C:33]([O:32][C:30]([NH:37][C@@H:38]([CH:39]([CH3:41])[CH3:40])[C:42]([N:19]1[CH2:18][CH2:17][N:16]([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:15][C@H:14]1[C:12]([NH:11][C@H:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1)=[O:13])=[O:43])=[O:31])([CH3:36])([CH3:35])[CH3:34]
Reactant: O=C(N[C@@H]1CCCc2ccccc21)[C@@H]1CN(C(=O)OCc2ccccc2)CCN1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCN(C(=O)OCc2ccccc2)C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21
Yield: 63.5 %

Procedure:
The deprotected piperazine 3 (16.20 g, 41.2 mmol) is coupled with BOC-L-valine (8.95 g, 41.2 mmol) using DIEA (36.0 mL, 0.21 mol), HBTU (17.19 g, 45.3 mmol) and HOBt (6.12 g, 45.3 mmol) in DMF (700 mL) under the same conditions as in step 1 above. Purification is carried out by flash chromatography on silica gel (CH2Cl2 as eluent initially, followed by 10% Et2O/CH2Cl2 to elute the desired product). The desired coupled product 4 is isolated as a white foam (15.51 g, 64% yield): 1H NMR δ (CDCl3) 6.99-7.64 (m, 9H), 5.99-6.34 (br m, 1H), 2.68-5.26 (br m, 11H), 1.51-2.15 (br m, 6H), 1.42 (s, 9H), 1.15 (s, 3H), 0.64-1.02 (br m, 5H); LCMS (APCl+) 594.2 (MH+), 537.9 (MH+-tBu), 493.7 (MH+-BOC, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]([O:16][C:17]2[C:22]([CH2:23]C=C)=[CH:21][CH:20]=[CH:19][C:18]=2[C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])[CH:14]=[CH2:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>ClCCl.C(OCC)(=O)C.C(O)C.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1CCC(P(C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:14][CH2:15][CH2:23][C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([C:26]4[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=4[Cl:33])[C:17]=3[O:16]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C=CCc1cccc(-c2c(Cl)cccc2Cl)c1O[C@H](C=C)COS(=O)(=O)c1ccc(C)cc1
Reactant: [H][H]
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: O=[Pt]=O
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCCc3cccc(-c4c(Cl)cccc4Cl)c3O2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.4 %

Procedure:
To a solution of (2R)-2-[(3-allyl-2′,6′-dichlorobiphenyl-2-yl)oxy]but-3-en-1-yl 4-methylbenzenesulfonate (702 mg, 1.394 mmol) in anhydrous dichloromethane (35 mL) at room temperature under nitrogen was added benzylidene-bis(tricyclohexylphosphine)dichlororuthenium (114 mg, 0.1394 mmol) and the reaction mixture stirred at room temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure to afford a brown syrup. The crude product was dissolved in ethyl acetate (7 mL) and the solution added to a suspension of platinum (IV) oxide (32 mg, 0.139 mmol) in absolute ethanol (21 mL). The mixture was then hydrogenated at 12 psi of hydrogen for 1 hour. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure to afford a brown syrup. Purification by flash chromatography using a solvent gradient of 3 to 10% ethyl acetate in hexane afforded 0.615 g (92%) of [(2R)-9-(2,6-dichlorophenyl)-2,3,4,5-tetrahydro-1-benzoxepin-2-yl]methyl 4-methylbenzenesulfonate as a yellow solid. MS (ESI) m/z 477 ([M+H]+).