Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][C:3]=1[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH2:24]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:17][CH:16]=1.[F-].[K+].C(O)(C(F)(F)[F:41])=O>C(#N)C.O>[F:41][CH2:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][NH:13][C:3]2[O:4][C:5]3[C:10]([C:11](=[O:12])[C:2]=2[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:16][CH:17]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OCCCCc2ccc(CNc3oc4ccccc4c(=O)c3C)cc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1c(NCc2ccc(CCCCF)cc2)oc2ccccc2c1=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 2 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-{4-[(3-methyl-4-oxo-4H-chromen-2-ylamino)-methyl]-phenyl}-butyl ester (24 mg, 0.049 mmol) in ACN (1.1 mL) was added K222 (37 mg, 0.098 mmol) followed by KF (6 mg, 0.098 mmol). The reaction stirred in a 90° C. oil bath for 30 minutes under nitrogen atmosphere, monitored by LC-MS. The reaction was then cooled to room temperature and injected directly onto the preparative HPLC column chromatography (Luna, 10 u, C18, 250×21.2 mm 10 micro, 60% of water in 90% acetonitrile in water with 0.1% TFA as the modifier in both mobile phases). The desired fractions were collected and neutralized to pH 7.6, then lyophilized. The material was re-purified by flash column chromatography (3:1 Hexane:ethyl acetate) to obtain the desired product as a solid (0.3 mg, <2% yield). 1H NMR (600 MHz, CDCl3/DMSO-d6): δ 8.03 (m, 1H), 7.35 (m, 1H), 7.16 (m, 4H), 7.07 (m, 2H), 4.52 (m, 2H), 4.35 (m, 1H), 4.27 (m, 1H), 2.58 (m, 2H), 1.75 (s, 3H), 1.24 (m, 4H).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([CH:8]1[CH2:13][N:12]([CH3:14])[CH2:11][CH2:10][NH:9]1)=[O:7])C.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1F)([O-:17])=[O:16]>O.C(O)C>[CH3:14][N:12]1[CH2:11][CH2:10][N:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])[CH:8]([C:6]([OH:5])=[O:7])[CH2:13]1
Reactant: CCOC(=O)C1CN(C)CCN1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CN1CCN(c2ccccc2[N+](=O)[O-])C(C(=O)O)C1

Procedure:
A solution of 6.6 g. (0.164 mole) of sodium hydroxide, 28.2 g. (0.165 mole) of ethyl-4-methylpiperazine-2-carboxylate, 20 ml. of water and 200 ml. of ethanol is refluxed for 3 hours. This solution is then added under nitrogen to a hot stirred solution of o-nitrofluorobenzene in 300 ml. of ethanol and 30 ml. of water. The resultant solution is refluxed for 48 hours, cooled and filtered to give 12.8 g. of yellow product, m.p. 222°-225°. Concentration of the mother liquors to ~100 ml. and adjusting the pH to 6 yields an additional 6.6 g. of product. Further concentration of mother liquors gives yet another 3 g. of product. Total yield is 22.4 g., 51.5%. The analytical sample had m.p. 234° dec.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]([O:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])=[C:7]([CH:10]=1)[C:8]#[N:9])=[O:2].B1([O-])O[O:17]1.O.O.O.O.[Na+]>C(O)(=O)C>[C:8]([C:7]1[CH:10]=[C:3]([CH:4]=[CH:5][C:6]=1[O:11][C@@H:12]([CH3:15])[CH2:13][CH3:14])[C:1]([OH:17])=[O:2])#[N:9]
Reactant: [O-]B1OO1
Reactant: CC[C@H](C)Oc1ccc(C=O)cc1C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC[C@H](C)Oc1ccc(C(=O)O)cc1C#N
Temperature: 50 °C
Yield: 103.5 %

Procedure:
To a solution of 5-formyl-2-{[(1S)-1-methylpropyl]oxy}benzonitrile (D35) (220 mg, 1.08 mmol) in acetic acid (20 ml) was added sodium perborate tetrahydrate (334 mg, 2.17 mmol), the reaction mixture was heated at 50° C. over the weekend. The reaction mixture was concentrated in-vacuo. Water (˜50 ml) was added, EtOAc (˜30 ml) was added and the layers partitioned, the aq layer was extracted twice more with EtOAc (˜30 ml) and the combined organics were evaporated to dryness under reduced pressure to give the title compound (245 mg) as an off white solid. δH (d6-DMSO, 400 MHz): 8.17 (2H, apparent d), 7.39 (1H, s), 4.68-4.74 (1H, m), 1.55-1.76 (2H, m), 1.31 (3H, d), 0.95 (3H, t). MS (ES): C12H13NO2 requires 219; found 220 (MH+).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)[C:10]([S:11][CH2:12][C:13]2[O:14][CH:15]=[CH:16][CH:17]=2)=[C:9]([OH:18])[C:8](=[O:19])[O:7]1)=O)C.[Li+].[BH4-].O.Cl>O1CCCC1>[O:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][S:11][C:10]1[C:6]([CH2:20][S:21][CH2:22][C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)([CH2:4][OH:3])[O:7][C:8](=[O:19])[C:9]=1[OH:18]
Reactant: CCOC(=O)C1(CSCc2ccco2)OC(=O)C(O)=C1SCc1ccco1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C1OC(CO)(CSCc2ccco2)C(SCc2ccco2)=C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
To a solution of 4-hydroxy-5-oxo-3-(2-furanylmethylsulfanyl)-2-[(2-furanylmethylsulfanyl)-methyl]-2,5-dihydrofuran-2-carboxylic acid ethyl ester (0.5 g, 1.219 mmol) in anhydrous tetrahydrofuran (THF, 30 mL) was added a THF solution of LiBH4 (2 mL, 4 mmol) at 0-5° C. under argon atmosphere. The mixture was stirred overnight at room temperature and water (1 mL) was slowly added. The mixture was stirred for 5 min and concentrated hydrochloric acid (1 mL) was added. The solution was mixed with water (150 mL) and extracted with methylene chloride (2×100 mL). The combined organic solution was washed with water (50 mL), dried and evaporated. The residue was purified by column chromatography, eluted with a mixed solvent of hexane and ethyl acetate (3:1 to 2:1, v/v) affording 55.6 mg of 4-(furan-2-ylmethylsulfanyl)-5-(furan-2-ylmethylsulfanylmethyl)-3-hydroxy-5-hydroxymethyl-5H-furan-2-one as a cream oil. 1H NMR (CD3OD, 300.16 MHz) δ (ppm): 7.45-7.42 (m, 2H), 6.35-6.22 (m, 4H), 4.50-3.71 (m, 5H), 3.48 (d, J=12.2 Hz, 1H), 2.97 (d, J=14.8 Hz, 1H) and 2.64 (d, J=14.8 Hz, 1H). 13C NMR (CD3OD, 75.48 MHz) δ (ppm): 167.70, 151.21, 150.45, 143.03, 142.38, 142.19, 125.61, 110.33, 110.00, 108.44, 107.81, 88.79, 64.19, 34.07, 28.87 and 26.83. MS (ESI, rel. int.) m/z: 369 (M+H+, 3), 391 (M+Na+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.S(O)(O)(=O)=O.[CH3:18][C@H:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH:27][C@@H:19]([CH3:18])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](N)Cc1ccccc1
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(CN[C@@H](C)Cc2ccccc2)cc1OC
Reaction time: 16 h
Yield: 65.7 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (1.06 g, 6.4 mmol), (S)-1-methyl-2-phenylethylamine sulfate (1.18 g, 6.4 mmol) and triethylamine (0.89 ml, 6.4 mmol) in 1,2-dichloroethane (50 ml) was stirred at room temperature under argon for 15 min. Sodium triacetoxyborohydride (2.97 g, 14 mmol) was added over 5 min. then stirring was continued for a further 16 h. The reaction mixture was diluted with MDC (50 ml) then washed with saturated aqueous K2CO3. The aqueous phase was extracted with MDC and the combined organics washed with brine. The organic phase was dried (MgSO4) and the solvent removed in vacuo. The residue was chromatographed (silica gel, 0–100% EtOAc-pentane) to afford the title compound as a colourless oil (1.20 g, 67%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.C([Li])CCC.[I:15]I>O1CCCC1>[I:15][C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1
Reactant: c1ccc2occc2c1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Ic1cc2ccccc2o1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a solution of benzofuran (3.0 g, 25.4 mmol) in tetrahydrofuran (36 mL) at about −78° C. was added a 2.5M solution of n-butyllithium in hexanes (10.2 mL, 25.4 mmol). The solution was allowed to warm to about −10° C. and was stirred for about 2 hours. Iodine (6.41 g, 25.4 mmol) was added gradually and the mixture was stirred at about −10° C. for about 30 min. The solution was allowed to warm to room temperature, was quenched by the addition of aqueous ammonium chloride, and was extracted with diethyl ether. The combined organic extracts were washed with aqueous sodium bisulfite and brine, dried (MgSO4), filtered and concentrated under vacuum. The resulting oil was distilled (b.p. 90° C./1.05 mm Hg) to provide Example 651. 1H NMR (300 MHz, CDCl3): δ 6.93 (s, 1H), 7.20 (m, 2H), 7.48 (m, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[NH:21][C:16]4=[N:17][CH:18]=[CH:19][N:20]=[C:15]4[CH:14]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[OH-].[K+].[O:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31]Cl)[CH2:26][CH2:25]1>O>[N:27]1([CH2:30][CH2:31][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:12]=[CH:11][C:10]([C:13]4[NH:21][C:16]5=[N:17][CH:18]=[CH:19][N:20]=[C:15]5[CH:14]=4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)[CH2:28][CH2:29][O:24][CH2:25][CH2:26]1
Reactant: c1cnc2[nH]c(-c3ccc(N4CCNCC4)cc3)cc2n1
Reactant: ClCCN1CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1cnc2[nH]c(-c3ccc(N4CCN(CCN5CCOCC5)CC4)cc3)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 6-(4-piperazin-1-ylphenyl)-5H-pyrrolo[2,3-b]pyrazine (Example 49) and water (5 mL) was treated with potassium hydroxide (71 mg) and after complete solution this mixture was then treated with morpholinoethyl chloride (59 mg) and the resulting slurry was stirred at room temperature overnight. The reaction mixture was treated with water (100 mL). and then extracted three times with ethyl acetate (100 mL). The combined extracts were washed with brine and then evaporated. The residual orange solid was treated with ethyl acetate and methanol and this solution was then acidified by addition of hydrochloric acid (2N) in methanol and then concentrated on a steam bath to give after treatment with ethyl acetate and dichloromethane the title compound (55 mg) as an orange solid. LC-MS: Method A: RT=2.09 minutes, 393 (MH+).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[C:8]([O-:11])(=O)[CH3:9].[Na+].O>C(O)C>[CH2:6]([N:1]1[C:8]([OH:11])=[CH:9][C:4]([CH3:5])=[C:3]([C:2]#[N:1])[C:2]1=[O:7])[CH2:5][CH2:4][CH3:3]
Reactant: O=c1cccc[nH]1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCn1c(O)cc(C)c(C#N)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 239.9 %

Procedure:
To a mixture of 1.0 grams (4.85 mmol) of the pyridone and 6.6 grams (48.5 mmol, 10 eq) of sodium acetate in 50 mL of ethanol was added 1.27 grams (4.85 mmol, 1 eq) of 4-diazo-N,N'-diethylaniline tetrafluoroborate. The reaction mixture turned blue immediately upon addition of the diazo compound. The mixture was stirred at room temperature for two hours and 50 mL of water was added. The blue solid was collected and washed with water and dried. This material was recrystallized from approximately 200 mL of ethanol to give 1.2 grams (65% yield) of the desired product. This material decomposes at 180°-185° C. with effervescence.
Reaction SMILES: C([Li])(C)(C)C.[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Br:31]C(F)(F)C(F)(F)Br>CCCCC.CCOCC>[C:6]([O:10][C:11]([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[C:14]1[Br:31])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)n1cc(CCOC2CCCCO2)c2ccccc21
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)OC(=O)n1c(Br)c(CCOC2CCCCO2)c2ccccc21
Temperature: 25 °C

Procedure:
tert-Butyllithium (28.1 ml of a 1.7 mol solution in pentane) was added slowly to a stirred solution of 1-tert-butoxycarbonyl-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-1H-indole (15.0 g) in dry ether at −78° C. under a dry nitrogen atmosphere. During the addition the temperature was maintained below −65° C. The reaction was stirred at −78° C. for 45 min at which time 1,2-dibromotetrafluoroethane (6.24 ml) was added. The reaction mixture was then allowed to warm to room temperature over 18 h, after which time it was quenched with water (100 ml) and extracted into ether (250 ml). The organic layer was separated, washed with water (250 ml) and brine (250 ml), dried over MgSO4, filtered and the solvent removed under reduced pressure to give an orange oil. Purification by flash chromatography (SiO2; n-hexane/ethyl acetate 10:1) afforded the product as a pale yellow oil (7.12 g); 1H (250 MHz, CDCl3) δ1.50-2.00 (6H, br m), 1.61 (9H, s), 3.05 (2H, t, J=7.5 Hz), 3.43 (1H, m), 3.56 (1H, m), 3.74 (1H, m), 3.91 (1H, m), 4.61 (1H, t, J=2.5 Hz), 7.26 (2H, m), 7.54 (1H, d, J=5.0 Hz) and 8.07 (1H, d, J=5.0 Hz).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH3:9])=[O:7])=[CH:2]1.[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19]Cl>>[Cl:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([Cl:18])=[CH:13][C:12]=1[S:19][C:5]1[NH:1][CH:2]=[C:3]([C:6]([O:8][CH3:9])=[O:7])[CH:4]=1
Reactant: ClSc1cc(Cl)c(Cl)cc1Cl
Reactant: COC(=O)c1cc[nH]c1
Product: COC(=O)c1c[nH]c(Sc2cc(Cl)c(Cl)cc2Cl)c1
Yield: 32.7 %

Procedure:
By the procedure of Example 23, methyl pyrrole-3-carboxylate (2.5 g., 20 mmoles) was reacted with 2,4,5-trichlorobenzenesulfenyl chloride (4.95 g., 20 mmoles) to yield crude product (6.0 g.) as a foam. The crude was chromatographed on 300 g. of silica gel with 200 ml. fractions of the ethyl acetate-1/hexane-7 eluant collected. Fractions 6 to 12 were combined and evaporated to yield methyl 5-(2,4,5-trichlorophenylthio)pyrrole-3-carboxylate (2.2 g., m.p. 165°-175° C.).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=2)[C:12]#[N:13])=[CH:5][N:6]=1.[C:16]([Si:20]([CH3:41])([CH3:40])[O:21][CH:22]1[C:30]2[C:25](=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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>[Si:20]([O:21][CH:22]1[C:30]2[C:25](=[C:26]([C:2]3[S:3][C:4]([C:7]4[CH:8]=[CH:9][C:10]([F:15])=[C:11]([CH:14]=4)[C:12]#[N:13])=[CH:5][N:6]=3)[CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:41])[CH3:40]
Reactant: N#Cc1cc(-c2cnc(Br)s2)ccc1F
Reactant: CC1(C)OB(c2cccc3c2CCC3O[Si](C)(C)C(C)(C)C)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)OC1CCc2c(-c3ncc(-c4ccc(F)c(C#N)c4)s3)cccc21
Temperature: 85 °C
Yield: 32 %

Procedure:
Prepared using General Procedure 1. To 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4 (0.100 g, 0.35 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy) silane IND INT-8 (0.143 g, 0.38 mmol) and sodium carbonate (0.112 g, 1.1 mmol) in dioxane (1.8 mL) and H2O (0.2 mL) was added tetrakis(triphenylphosphine)palladium (0.041 g, 0.035 mmol). The solution was degassed with N2 and the reaction mixture heated at 85° C. for 6 h. Upon cooling, the reaction mixture was diluted with brine and washed with DCM (3×100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (30% EA/Hexanes) to produce 0.05 g (32%) of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-fluorobenzo-nitrile as a white solid. LCMS-ESI (m/z) calculated for C25H27FN2OSSi: 450.6; found 451.1 [M+H] +, tR=4.84 min (Method 3).
Reaction SMILES: Br[C:2]1[N:18]=[C:5]2[CH:6]=[C:7]([NH:10]C(=O)OC(C)(C)C)[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1.C(OCC)(=O)C.O.[ClH:31].C(OCC)(=O)C>>[ClH:31].[N:19]1([C:2]2[N:18]=[C:5]3[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][N:4]3[N:3]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: CC(C)(C)OC(=O)Nc1ccn2nc(Br)nc2c1
Reactant: C1CCNC1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccn2nc(N3CCCC3)nc2c1
Temperature: 150 °C

Procedure:
The tert-butyl (2-bromo-[1,2,4]triazolo[1,5-a]pyridin-7-yl)carbamate (75 mg) obtained in (Example 3.15) <Step 4> and pyrrolidine (1 ml) were stirred under microwave heating at 150° C. for 1 hour. Thereafter, ethyl acetate (10 ml) and water (3 ml) were added to the reaction solution. An organic layer was separated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. Thereafter, potassium hydroxide (134 mg) was added to an ethanol (2 ml) solution of the obtained residue, and the obtained mixture was then heated to reflux for 16 hours. Thereafter, the solvent was distilled away under reduced pressure, and potassium hydroxide (134 mg) was added to an ethylene glycol (2 ml) solution of the obtained residue, followed by heating the obtained mixture at 155° C. for 2 hours. The solvent was distilled away under reduced pressure, and ethyl acetate (10 ml) and water (3 ml) were then added to the obtained residue. An organic layer was separated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the obtained residue was then purified by silica gel column chromatography (silica gel: eluent; heptane:ethyl acetate=50:50-0:100) to obtain a crude product. The obtained crude product was dissolved in 4 N hydrochloric acid-ethyl acetate (1 ml), and the precipitated solid was then collected by filtration, so as to obtain the title compound (16 mg) in the form of a yellow solid.
Reaction SMILES: C1(O)CCCC1.[H-].[Na+].[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:20][CH:21]3[CH2:26][CH2:25]O[CH2:23][CH2:22]3)[C:18]=2[N:19]=1>CN(C=O)C.O>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]2[N:14]=[CH:15][N:16]=[C:17]([O:20][CH:21]3[CH2:26][CH2:25][CH2:23][CH2:22]3)[C:18]=2[N:19]=1
Reactant: Clc1ccc2ncnc(OC3CCOCC3)c2n1
Agent: OC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2ncnc(OC3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a solution of cyclopentanol (0.050 ml, 0.550 mmol) in DMF (2.500 ml) was added NaH (0.026 g, 55% dispersion in mineral oil, 0.600 mmol) at 0° C. The reaction mixture was stirred for 30 min at room temperature, 4,6-dichloropyrido[3,2-d]pyrimidine (Intermediate 1, step D) (0.1 g, 0.500 mmol) was added to the mixture at 0° C. After being stirred for 2 hours at room temperature, the reaction mixture was diluted with water, and extracted with EtOAc. The organic layers were dried over MgSO4 filtered and concentrated in vacuo. The residue was purified by column chromatography on SiO2 (Hex:EtOAc=5:1) to give 6-chloro-4-(cyclopentyloxy)pyrido[3,2-d]pyrimidine (0.04 g, 32%) as a yellow solid. 1H-NMR (CDCl3, Varian 400 MHz): δ 1.63-1.74 (2H, m), 1.86-1.96 (2H, m), 1.99-2.07 (2H, m), 2.12-2.20 (2H, m), 5.72-5.77 (1H, m), 7.72 (1H, d, J=8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.83 (1H, s).
Reaction SMILES: N1C=CC=N1.[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=1.S(Cl)([Cl:18])=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([C:13]([Cl:18])=[O:15])[CH:10]=[CH:9][N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccnc(Cl)c1
Agent: c1cn[nH]c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)c1ccnc(Cl)c1

Procedure:
Scheme III shows the synthesis of a pyrazole, compound 13, analogs of compound 5 in which the pyridine 10 ring bears a chlorine atom at position 2. 2-Chloropyridine-4-carboxylic acid, compound 9, is treated with thionyl chloride in a solvent such as toluene, and heated to reflux to give 2-chloropyridine-4-carboxylic acid chloride, compound 10, which is then converted to methyl 2-chloroisonicotinate, compound 11. Compound 11 is treated with a ketone 2 in the presence of a base such as sodium methoxide in a solvent such as tetrahydrofuran, at temperatures ranging from 25° C. up to reflux to provide a diketone, compound 12. Treatment of the diketone, compound 12, with an arylhydrazine derivative 4 in ethanol or other suitable solvent at a temperature ranging up to reflux, provides pyrazole compound 13. When R2 of ketone 2 is hydrido, then R2 of 13 is hydrido.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[N:10]([O-])=O.[Na+].O.O.Cl[Sn]Cl>Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][NH2:10])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: Cc1ccc(N)cc1Cl
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(NN)cc1Cl
Yield: 68412.6 %

Procedure:
The title compound was prepared according to the procedure described in step-1 of Intermediate-61 by using 3-chloro-4-methylaniline (6.0 g, 0.0420 mmol), NaNO2 (8.56 g, 0.050 mmol), SnCl2.2H2O (23.7 g, 0.105 mmol) and conc. HCl (100 mL) to afford 4.5 g of the desired product.
Reaction SMILES: [CH3:1][N:2]([CH:29]1[CH2:34][C:33]([CH3:36])([CH3:35])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]1)[C:3]1[N:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[CH:17][N:18](COCC[Si](C)(C)C)[CH:19]=3)=[CH:11][C:10]=2[OH:28])=[CH:5][CH:4]=1.C(Cl)Cl.Cl.B(Br)(Br)Br>CCO>[NH:18]1[CH:19]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3[N:7]=[N:8][C:3]([N:2]([CH3:1])[CH:29]4[CH2:34][C:33]([CH3:35])([CH3:36])[NH:32][C:31]([CH3:38])([CH3:37])[CH2:30]4)=[CH:4][CH:5]=3)=[C:10]([OH:28])[CH:11]=2)[N:16]=[CH:17]1
Reactant: CN(c1ccc(-c2ccc(-c3cn(COCC[Si](C)(C)C)cn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CN(c1ccc(-c2ccc(-c3c[nH]cn3)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Temperature: 110 °C
Yield: 5.5 %

Procedure:
To a microwave vial containing 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)phenol (mixture from previous step, 50 mg, 0.09 mmol) in EtOH (1.0 mL)/DCM (1.0 mL) and conc. HCl (8.5 μL) was added BBr3 (0.46 mL, 0.46 mmol). The vial was purged with N2 (2×) and the reaction mixture was heated at 110° C. in a microwave reactor for 30 min. The reaction mixture was filtered through celite (pre-packed filter funnel) with a MeOH wash. The filtrate was acidified to pH 3 using 1N HCl and purified by catch and release using SiliaBond Propylsulfonic Acid® (1 g, MeOH as eluent and a 2 N ammonia solution in MeOH to release the material). After evaporation, the material was purified via reverse phase HPLC to afford 5-(1H-imidazol-4-yl)-2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)phenol (2 mg). MS: 407.4 [M+H+]. LCMS Rt=0.40 min [Method Q]; 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.01 (d, J=9.60 Hz, 1H), 7.57-7.74 (m, 2H), 7.39 (s, 1H), 7.14-7.30 (m, 3H), 4.98 (br. s., 1H), 2.92 (s, 3H), 1.62 (d, J=13.14 Hz, 2H), 1.52 (t, J=12.38 Hz, 2H), 1.32 (s, 6H), 1.16 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12](CC(F)=O)[CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1.C(OC(N1CCC(N)CC1)=O)(C)(C)C.CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:36])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[CH3:35])[C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1ccc(F)cc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 88.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.1 g, 0.18 mmol) prepared in example 57a was reacted with 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.50 mmol), N-methylmorpholine (0.1 g, 0.99 mmol) and 4-dimethylaminopyridine (2 mg, 0.017 mmol) in tetrahydrofuran to give racemic (2′R,3R,4′S)-1′-[1-tert-butoxycarbonyl-piperidin-4-yl)aminocarbonyl-methyl]-6-chloro-4′-(3-chlorophenyl)-2′-(5-fluoro-2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.075 g, 58.6%).