Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](I)=[C:11]([N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])C(OCC(C)C)=O)[O:10][N:9]=1)(=O)C.[CH2:35]1[O:43][C:42]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=2[O:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[O:36]1[C:37]2[CH:38]=[CH:39][C:40]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][O:10][C:11]=3[NH:14][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[CH:41][C:42]=2[O:43][CH2:35]1
Reactant: OB(O)c1ccc2c(c1)OCO2
Reactant: CC(=O)OCCOc1noc(N(C(=O)OCC(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCO)c2-c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a stirring solution of 2-({5-[{[4-(tert-butyl)phenyl]sulfonyl}(isobutoxycarbonyl)amino]-4-iodo-3-isoxazolyl}oxy)ethyl acetate (Preparation 22) (2.41 g) in dioxane (25 ml) was added (3,4-methylenedioxyphenyl)boronic acid (0.72 g) followed by cesium carbonate (5.15 g) and water (3 ml). The reaction mixture was purged with nitrogen three times, after which time tetrakis(triphenylphosphine)palladium(0) (140 mg). The reaction mixture was heated to reflux for about 2 hours. Ethanol (50 ml) and sodium hydroxide (2M, 50 ml) were added to the reaction mixture and then this was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the solid residue was partitioned between saturated ammonium chloride solution (100 ml) and ethyl acetate (100 ml). The organics were washed with brine (50 ml), dried over sodium sulfate and concentrated under reduced pressure to yield the crude material as a brown oil. The crude material was purified by column chromatography (100 g silica, crude loaded with dichloromethane (10 ml)) using a gradient elution of hexane (50% to 0%) and ethyl acetate (50% to 100%) and also with methanol (5% in ethyl acetate) to yield the product as a light brown foam (770 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:26])=O>CN(C=O)C>[Cl:26][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCOc1ccncc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCOc1ccncc1

Procedure:
5-Methoxy-2-nitro-4-(2-(4-pyridyloxy)ethoxy)benzamide (2.15 g, 6.4 mmol) and 10% palladium-on-charcoal catalyst (100 mg) were suspended in methanol (400 ml) and placed under hydrogen at atmospheric pressure. The reaction mixture was heated at 40° C. for 1 hour, cooled to ambient temperature, filtered through diatomaceous earth and the solvent was removed by evaporation. The precipitate was slurried with ether and collected by filtration to give 2-amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide as a cream solid (1.95 g, 99%). 2-Amino-5-methoxy-4-(2-(4-pyridyloxy)ethoxy)benzamide (1.95 g, 6.4 mmol) and formamide (10 ml) were heated at 190-200° C. for 1 hour. The reaction mixture was allowed to cool to 50° C. as the product precipitated out. Water (50 ml) was added and the solid was collected by filtration, washed with more water and ether and dried under vacuum to give 6-methoxy-7-(2-(4-pyridyloxy)ethoxy)-3,4-dihydroquinazolin-4-one (0.99 g, 49%) as a cream solid. The 6-methoxy-7-(2-(4-pyridyioxy)ethoxy)-3,4-dihydroquinazolin-4-one (312 mg, 1 mmol) was heated at reflux in thionyl chloride (10 ml) and DMF (5 drops) for 1 hour, then evaporated to dryness and partitioned between a saturated solution of sodium hydrogen carbonate and methylene chloride. The methylene chloride phase was dried by filtration through a phase separator paper and the solvent was removed by evaporation to give crude 4-chloro-6-methoxy-7-(2-(4-pyridyloxy)ethoxy)quinazoline which was used without further purification.
Reaction SMILES: [C:1]([C:4](C(OC(C)(C)C)=O)([CH2:16][CH2:17][CH2:18][CH:19]([O:27][C:28](=[O:30])[CH3:29])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2].C(C(C(OC(C)(C)C)=O)(CCCC(OC(=O)C)CCCCC)CCCCCCC(OCC)=O)(=O)C>>[C:1]([CH:4]([CH2:16][CH2:17][CH2:18][CH:19]([O:27][C:28](=[O:30])[CH3:29])[C:20]([CH3:26])([CH3:25])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:3])[CH3:2]
Reactant: CCCCC(C)(C)C(CCCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OC(C)(C)C)OC(C)=O
Agent: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(C)=O)C(=O)OC(C)(C)C)OC(C)=O
Product: CCCCC(C)(C)C(CCCC(CCCCCCC(=O)OCC)C(C)=O)OC(C)=O

Procedure:
This compound is prepared as described in Example 1, Step C except that ethyl 8-acetyl-8-tertbutoxycarbonyl-12-acetoxy-13,13-dimethylheptadecanoate is substituted for ethyl 8-acetyl-8-tert-butoxycarbonyl-12-acetoxyheptadecanoate. The product, a viscous yellowish oil, is purified by chromatography on silica gel with chloroform as eluant.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:23]=[CH:22][C:11]2[C:12](=[O:21])[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[O:15][C:10]=2[CH:9]=1.[C:24](=[O:27])([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[O:21]=[C:12]1[C:11]2[CH:22]=[CH:23][C:24]([O:27][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]3[CH:23]=[CH:22][C:11]4[C:12](=[O:21])[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:10]=4[CH:9]=3)=[CH:9][C:10]=2[O:15][CH:14]=[CH:13]1
Reactant: CCOC(=O)c1cc(=O)c2ccc(OCCCCCBr)cc2o1
Reactant: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)c1cc(=O)c2ccc(OCCCCCOc3ccc4c(=O)ccoc4c3)cc2o1

Procedure:
A mixture of 4.6 parts of 7-(5-bromopentyloxy)4-oxo-4H-1-benzopyran-2-carboxylic acid, ethyl ester, 2 parts of ethyl 7hydroxychromone-2-carboxylate,1,8 parts of potassium carbonate, a few potassium iodide crystals and 80 parts by volume of dry acetone was refluxed on a steam bath for 20 hr. The cooled mixture was filtered and the filtrate evaporated down to give an oil which when treated with petroleum ether (40°-60°), solidified to give 4.0 parts of crude product. Crystallisation from ethanol gave 2.9 parts of 7-[5-(4-oxo-4H-1-benzopyran-7-yloxy)pentyloxy]-4-oxo-4H-1-benzopyran-2-carboxylic acid; ethyl ester, m.p. 113°-116°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][F:14])[C:6](=[O:15])[CH2:5]2.[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]1[CH2:26][O:25]1)([CH3:19])([CH3:18])[CH3:17].FC(F)(F)S([O-])(=O)=O.[Li+]>C(#N)C.C(OCC)(=O)C>[C:16]([O:20][C:21](=[O:27])[NH:22][CH2:23][C@H:24]([OH:25])[CH2:26][NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:12][CH2:13][F:14])[C:6](=[O:15])[CH2:5]2)([CH3:18])([CH3:17])[CH3:19]
Reactant: Nc1cc(F)c2c(c1)CC(=O)N2CCF
Reactant: CC(C)(C)OC(=O)NC[C@H]1CO1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC[C@H](O)CNc1cc(F)c2c(c1)CC(=O)N2CCF

Procedure:
5-Amino-7-fluoro-1-(2-fluoro-ethyl)-1,3-dihydro-indol-2-one (0.39 g, 1.84 mmol), (S)-oxiranylmethyl-carbamic acid tert-butyl ester (0.319 g, 1.84 mmol) and lithium trifluoromethanesulfonate (0.283 g, 1.84 mmol) in acetonitrile (4 ml) are heated at 90° C. for 6 hours. The reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (Na2SO4) and evaporated. Final purification by flash chromatography (70% Ethyl acetate/hexane) gives the title compound as a yellow-brown foamy solid. HPLC r.t. 3.92 min; MS for C18H25F2N3O4 m/z 386.1 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([CH2:24][C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:41]1CCCC1>>[CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([CH:24]([OH:41])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)Cc1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: COC(=O)C(O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)acetate (2.3 g, 5.46 mmol) in Tetrahydrofuran (THF) (30 mL) was treated with LiHMDS (8.45 mL, 8.45 mmol) at −78° C. and then stirred for 1 hour. A solution of (2R,8aS)-(+)-(Camphorsulfonyl)oxaziridine (2.421 g, 10.56 mmol) in Tetrahydrofuran (THF) (20 mL) was added, the mixture was warmed to 0° C. and then stirred for 20 minutes. The mixture was quenched with HCl (1M) and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4 and concentrated. The residue was purified on silica gel (0-100% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-hydroxyacetate (3.3 g, 4.53 mmol, 82% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.28 (s, 9H) 7.01-7.07 (m, 1H) 5.93-5.99 (m, 1H) 5.85-5.92 (m, 1H) 5.77-5.84 (m, 1H) 5.20-5.27 (m, 1H) 3.79 (s, 3H) 3.58 (s, 3H); LCMS (m/z) ES+=437 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[CH2:9]([N:16]1[C:20]([CH:21]=[O:22])=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([N:16]1[C:20]([CH:21]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:22])=[CH:19][N:18]=[CH:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1cncn1Cc1ccccc1
Product: OC(c1ccc(F)cc1)c1cncn1Cc1ccccc1
Yield: 94 %

Procedure:
Grignard reaction of 4-bromofluorobenzene and 1-benzyl-5-imidazolecarbaldehyde is performed analogously to Example 7 a). The product is crystallized as hydrochloride salt from ethylacetate. Yield 94%.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C.Br[C:31]1[CH:32]=[CH:33][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[N:35][CH:36]=1.[CH2:44]([O:46][C:47](=[O:50])[CH:48]=[CH2:49])[CH3:45]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:44]([O:46][C:47](=[O:50])[CH:48]=[CH:49][C:31]1[CH:36]=[N:35][C:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])=[CH:33][CH:32]=1)[CH3:45]
Reactant: C=CC(=O)OCC
Reactant: Fc1ccccc1-c1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1ccc(-c2ccccc2F)nc1
Temperature: 125 °C
Reaction time: 20 h

Procedure:
Under nitrogen, 0.755 g (3.38 mmol) of palladium acetate, 2.05 g (6.75 mmol) of tri(ortho-tolyl)phosphine and 97.8 ml (0.708 mol) of triethylamine were added to a solution of 34.0 g (0.135 mol) of 5-bromo-2-(2-fluoro-phenyl) -pyridine in 2.2 l of acetonitrile. Then 23.38 ml (0.216 mol) of acrylic acid ethyl ester were added, and the mixture was shaken in an autoclave at 125° C. for 20 h. After cooling, the mixture was poured onto ice/water, the mixture stirred at 5 to 10° C. for 1 h, and the precipitated product was collected by filtration and purified by chromatography (silica gel, n-heptane/ethyl acetate 3:1). Yield: 24.3 g.
Reaction SMILES: [F:1][CH:2]([F:22])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([CH:20]=[O:21])=[CH:6][CH:5]=1.[Mn]([O-])(=O)(=O)=[O:24].[K+]>CC(C)=O.O>[F:22][CH:2]([F:1])[O:3][C:4]1[C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[C:8]=2[C:7]([C:20]([OH:24])=[O:21])=[CH:6][CH:5]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O=Cc1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)c1ccc(OC(F)F)c2oc3ccc([N+](=O)[O-])cc3c12
Temperature: 65 °C
Yield: 64.5 %

Procedure:
4-difluoromethoxy-8-nitro-1-formyl dibenzo[b,d]furan (150 mg, 0.48 mmol) in acetone (20 ml) and water (5 ml) was heated to 60-70° C. for 10 min. To the above solution was added dropwise a solution of potassium permanganate (150 mg, 0.973 mmol) in water (5 ml) for 10 min. The reaction was heated to 60-70° C. for 30 min., and filtered hot through celite bed. Acidification of the filterate resulted in a precipitate which on filteration and washing with water yielded 4-difluoromethoxy-8-nitro-dibenzo[b,d]furan-1-carboxylic acid (100 mg) as white solid; mp: >270° C.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])=[N:4][CH:3]=1.ClC1C=C2C(N=CC=C2)=C2C=1C=CC=N2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:37]1[CH:42]=[CH:41][C:40]([S:43][CH3:44])=[CH:39][CH:38]=1.[OH-].[NH4+].O>CN1CCCC1=O>[CH3:1][C:2]1[S:6]/[C:5](=[N:7]\[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:9])/[N:4]([C:37]2[CH:42]=[CH:41][C:40]([S:43][CH3:44])=[CH:39][CH:38]=2)[CH:3]=1
Reactant: CSc1ccc(Br)cc1
Reactant: Cc1cnc(NC(=O)N2CCCC2)s1
Agent: Clc1cc2cccnc2c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CSc1ccc(-n2cc(C)s/c2=N\C(=O)N2CCCC2)cc1
Temperature: 120 °C

Procedure:
To a 4 mL vial equipped with a septum cap and stir bar was added N-(5-methyl-1,3-thiazol-2-yl)pyrrolidine-1-carboxamide (50 mg, 0.24 mmol), copper(I) trifluoromethanesulfonate benzene complex (23.8 mg, 0.05 mmol), 5-chloro-1,10-phenanthroline (20.3 mg, 0.09 mmol) and cesium carbonate (84.8 mg, 0.26 mmol). The mixture was placed under a nitrogen atmosphere. (4-Bromophenyl)(methyl)sulfane (0.28 mmol) in 1-methyl-2-pyrrolidinone (1.0 mL) was added to the mixture. The reaction mixture was heated at 120° C. for overnight. A solution of concentrated ammonium hydroxide/water (1:2, 1 mL) was added and the mixture was filtered and solvent removed under reduced pressure. The residue was purified by reverse phase HPLC (C8, gradient 10-100% acetonitrile/water/0.1% trifluoroacetic acid).
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)=[O:10].[F-].[K+]>C(Cl)(Cl)Cl>[CH2:3]([O:2][P:1]([CH:9]([OH:10])[C:11]1[CH:12]=[CH:13][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:16]=1)([O:5][CH2:6][CH3:7])=[O:8])[CH3:4]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CCOP([O-])OCC
Agent: [F-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CCOP(=O)(OCC)C(O)c1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diethyl phosphite (16 mL) was added to methyl 4-formylbenzenecarboxylate (10.2 g) and potassium fluoride (18.0 g), and stirred at room temperature for 30 minutes. The reaction liquid was diluted with chloroform (200 mL) added thereto, and filtrated through Celite. The solvent was evaporated off under reduced pressure from the filtrate, and the resulting solid was washed with diethyl ether to obtain the entitled compound (14.1 g) as a colorless solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]=[C:11]=[O:12].[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][OH:19]>>[Cl:1][CH2:2][C:3]1[C:8]([CH3:9])=[CH:7][CH:6]=[CH:5][C:4]=1[NH:10][C:11](=[O:12])[O:19][CH2:18][C:14]1[S:13][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cccc(N=C=O)c1CCl
Reactant: OCc1cccs1
Product: Cc1cccc(NC(=O)OCc2cccs2)c1CCl
Temperature: 25 °C

Procedure:
2-Chloromethyl-1-isocyanato-3-methylbenzene (2.5 g) and thiophenemethanol (1.57 g) are combined and stirred at RT. When crystallization commences, petroleum ether 50/70 (20 ml) is added and the suspension is stirred for 16 h at RT. After filtration and washing with diethyl ether, 2.57 g (63%) of the title compound are obtained as a solid of m.p. 111-114° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:10][NH:9][N:8]=2)=[CH:4][CH:3]=1.[CH:18]1(B(O)O)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[NH4+]>ClC(Cl)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[CH:18]1([N:9]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[N:8]2)[CH2:20][CH2:19]1
Reactant: OB(O)C1CC1
Reactant: Clc1ccc(-c2n[nH]cc2-c2ccncc2)s1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(Cl)Cl
Product: Clc1ccc(-c2nn(C3CC3)cc2-c2ccncc2)s1
Temperature: 70 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
To a suspension of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine (0.57 mmol), cyclopropylboronic acid (1.14 mmol) and sodium carbonate (1.14 mmol) in 2 mL of dichloroethane, was added a suspension of copper acetate (0.57 mmol) and 2,2′-bipyridyn (0.57 mmol) in 4 mL of hot dichloroethane. The mixture was warmed up to 70° C. and stirred for 3 h under air. The resulting mixture was cooled to room temperature, and a saturated ammonium chloride solution was added, followed by water. The organic layer was separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried with MgSO4, and concentrated under reduced pressure. The residue was purified by chromatography on basic alumina (heptane/ethyl acetate 20:1 to 10:1) to afford 43 mg (24% yield) of 4-[1-cyclopropyl-3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]pyridine.
Reaction SMILES: CSC.B.[CH3:5][O:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[CH2:9][NH:10][C@H:11]1[C@@H:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[NH:15][C:14](=O)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].Cl.CCOCC>O1CCCC1.C(Cl)Cl.C(Cl)(Cl)Cl.C(O)C.CO>[CH3:5][O:6][C:7]1[CH:27]=[CH:26][CH:25]=[CH:24][C:8]=1[CH2:9][NH:10][C@H:11]1[CH2:12][CH2:13][CH2:14][NH:15][C@H:16]1[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1ccccc1CN[C@@H]1CCC(=O)N[C@@H]1c1ccccc1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccccc1CN[C@H]1CCCN[C@H]1c1ccccc1
Yield: 120 %

Procedure:
Borane dimethylsulfide in tetrahydrofuran (2M, 158 ml, 315 mmole) was added to a solution of cis-5-(2-methoxybenzylamino)-2-oxo-6-phenylpiperidine (19.6 g, 63.0 mmole) in tetrahydrofuran (500 ml) under nitrogen and the reaction mixture was heated at reflux for 18 hours. At the end of this period, the reaction mixture was cooled and the excess borane dimethylsulfide was cautiously decomposed by dropwise addition of methanol. The contents of the reaction mixture were then concentrated under vacuum. Ethanol (500 ml) and powdered potassium carbonate (17.5 g, 126 mmole) were added to the residue and the reaction mixture was heated at reflux (18 hours). Then the reaction mixture was concentrated under vacuum and the residue was extracted with methylene chloride (4×250 ml) and dried (anhydrous magnesium sulfate). The organic solvents were removed under vacuum to afford a residue which was dissolved in a minimum amount of methylene chloride. To this solution was added excess hydrochloric acid/ether, thus precipitating the dihydrochloride salt of cis-3-(2-methoxybenzylamino)-2-phenylpiperidine, which was isolated by filtration. This was heated at reflux in chloroform (400 ml) for 3 hours and filtered to give the essentially pure hydrochloride salt of the title compound (22.4 gms, m.p. 245° C., 96%), which was crystallized from a mixture of hot methanol-ethanol to afford a white crystalline solid (19.2 gms, 83%).
Reaction SMILES: [CH:1]1([C:4](=[O:26])[CH:5]([C:13](=[O:25])[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=2[F:24])C(OC(C)(C)C)=O)[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:26])[CH2:5][C:13]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=2[F:24])=[O:25])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1F)C(=O)C1CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=O)CC(=O)C2CC2)c(F)c1
Yield: 95.3 %

Procedure:
A mixture of t-butyl 3-cyclopropyl-2-(2-fluoro-4-methylsulphonylbenzoyl)-3-oxopropionate (10.5 g) and p-toluenesulphonic acid (2.0 g) in toluene was stirred and heated at reflux for 4 hours. The mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-cyclopropyl-1-(2-fluoro-4-methylsulphonylphenyl)-propan-l,3-dione (7.4 g) as a red gum, NMR (CDCl3); 0.9-1.3 (m,4H), 1.8-2.1 (m, 1H), 3.1 (s,3H), 6.3 (s, 1H), 7.5-8.0 (m,3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5](=[O:11])[CH2:6][C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.C(NC1C=CC(S([N:33]=[N+:34]=[N-])(=O)=O)=CC=1)(=O)C>C(#N)C>[CH3:10][O:9][C:7](=[O:8])[C:6](=[N+:33]=[N-:34])[C:5](=[O:11])[CH2:4][C:3]([O:2][CH3:1])=[O:12]
Reactant: COC(=O)CC(=O)CC(=O)OC
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)CC(=O)C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-ketoglutaric acid dimethyl ester 15.0 g, triethylamine 9.6 g and acetonitrile 300 ml is portionwise added 4-acetylaminobenzensulfonylazide 20.7 g at 0° C. The mixture is stirred at room temperature for 30 minutes. After removal of the precipitate by filtration the filtrate is concentrated in vacuo. The residue is diluted with a mixture of hexane and diethyl ether (1:1). The insoluble materials are removed by filtration and the filtrate is concentrated in vacuo. The residue is purified with column chromatography (silica gel 225 g, solvent; hexane:ethyl acetate=5:1→3:1) to give 2-diazo-3-ketoglutaric acid dimethyl ester as a pale yellow oil, 16.03 g.
Reaction SMILES: C(OC([NH:8][C:9]1([C:42]([OH:44])=[O:43])[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[C:24]4[S:28][C:27]([NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:25]=4[CH:35]=3)=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.[ClH:45].O1CCOCC1>O1CCOCC1>[ClH:45].[NH2:8][C:9]1([C:42]([OH:44])=[O:43])[CH2:10][CH2:11][N:12]([C:15]2[N:16]=[CH:17][C:18]([C:21]3[CH:22]=[C:23]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=4)[C:24]4[S:28][C:27]([NH:29][C:30]([NH:32][CH2:33][CH3:34])=[O:31])=[N:26][C:25]=4[CH:35]=3)=[CH:19][N:20]=2)[CH2:13][CH2:14]1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(NC(=O)OC(C)(C)C)(C(=O)O)CC4)nc3)cc(-c3ccccn3)c2s1
Agent: Cl
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(N)(C(=O)O)CC4)nc3)cc(-c3ccccn3)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cold solution of 4-((tert-butoxycarbonyl)amino)-1-(5-(2-(3-ethylureido)-7-(pyridin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylic acid (0.02 g, 0.03 mmol) in 1,4-dioxane (2.0 mL) was added HCl-dioxane (4.0 M, 1.0 mL) solution and the reaction mixture was left to stir at rt for 30 min. After completion (by TLC), the solvent was evaporated to obtain a brownish solid material that was finally triturated with ether to afford Compound 128 (0.01 g) as a hydrochloride salt. 1H NMR (DMSO-d6): δ 1.11 (t, J=7.20 Hz, 3H), 1.87 (m, 2H), 2.11 (m, 2H), 3.19 (m, 2H), 3.40 (m, 2H), 3.93 (m, 2H), 4.12 (m, 2H), 6.99 (br s, 1H), 7.45 (m, 1H), 7.95 (br s, 2H), 8.25 (s, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.62 (s, 2H), 8.80 (d, J=4.0 Hz, 1H), 8.97 (s, 1H) and 10.65 (br s, 1H). LCMS: 519.30 [M+H]+