Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:21])OC3C=CC=CC=3)=[CH:8][CH:7]=2)[CH2:5][O:4][CH2:3]1.Cl.[C:23]([C:27]1[CH:31]=[C:30]([CH2:32][NH2:33])[N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[N:28]=1)([CH3:26])([CH3:25])[CH3:24]>CC#N>[C:23]([C:27]1[CH:31]=[C:30]([CH2:32][NH:33][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:2]3([OH:1])[CH2:3][O:4][CH2:5]3)=[CH:11][CH:10]=2)=[O:21])[N:29]([C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[CH:35]=2)[N:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: O=C(Nc1ccc(C2(O)COC2)cc1)Oc1ccccc1
Reactant: CC(C)(C)c1cc(CN)n(-c2cccc(Cl)c2)n1
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)c1cc(CNC(=O)Nc2ccc(C3(O)COC3)cc2)n(-c2cccc(Cl)c2)n1
Yield: 61.3 %

Procedure:
To a stirred solution of phenyl 4-(3-hydroxyoxetan-3-yl)phenylcarbamate (synthesis described for example A108) (97 mg, 0.34 mmol, 1.02 eq) and (3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methanamine hydrochloride (100 mg, 0.33 mmol, 1.0 eq) in MeCN (8 mL) was added TEA (0.185 mL, 1.33 mmol, 4.0 eq) at RT and the mixture stirred at reflux overnight. The solvents were evaporated and the crude product was purified by CC (EtOAc/cyclohexane 3:2 as eluent) to get 1-((3-tert-butyl-1-(3-chlorophenyl)-1H-pyrazol-5-yl)methyl)-3-(4-(3-hydroxyoxetan-3-yl)phenyl)urea (92 mg; 61%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH2:8].[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27]([C:30](=O)[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1>>[F:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[CH2:20][C:21]1[N:25]2[N:26]=[C:27](/[C:30](=[N:8]/[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)/[CH3:31])[CH:28]=[CH:29][C:24]2=[N:23][CH:22]=1
Reactant: NNc1ccccn1
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\Nc1ccccn1)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 48 %

Procedure:
The title compound was prepared from pyridin-2-yl-hydrazine and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]ethanone in analogy to the synthesis of example 1 in 48% yield as a white solid. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.27 (s, 1H), 8.86 (dd, 1H), 8.31 (d, 1H), 8.19 (d, 1H), 7.97 (m, 3H), 7.78 (d, 1H), 7.70 (t, 1H), 7.65 (s, 1H), 7.47 (q, 1H), 7.40 (d, 1H), 6.87 (dd, 1H), 4.58 (s, 2H), 2.36 (s, 3H). LCMS (method A): [MH]+=412, tR=4.78 min.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16]Cl.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccccn1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.9 %

Procedure:
To an N,N-dimethylformamide (250 mL) solution of 4-hydroxybenzaldehyde (20 g, 164 mmol) and 2-picolyl chloride (27 g, 165 mmol) was added potassium carbonate (68 g, 492 mmol), which was stirred for 3 days at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (29 g, 83%). The title compound was not purified but used for the next reaction.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](O)=[O:12])=[CH:9][CH:8]=1)[CH3:2].S(Cl)([Cl:18])=O>O1CCOCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([Cl:18])=[O:12])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCOCCOc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCOCCOc1ccc(C(=O)Cl)cc1

Procedure:
A mixture of 7.2 g. of p-ethoxyethoxy benzoic acid, 50 ml. of dioxane and 12.2 g. of thionyl chloride was refluxed at 70° to 80° C. for 2 hours. After the reaction, excess of thionyl chloride and the solvent were recovered by a rotary evaporator to obtain a crude p-ethoxyethoxybenzoic chloride as a residue. The crude p-ethoxyethoxybenzoic acid chloride was dissolved in 70 ml. of acetone and then, a mixture of 6.6 g. of 2,3-dichloroaniline and 4.1 g. of triethylamine was added dropwise with stirring at room temperature during 30 minutes. After the addition, the mixture was stirred at the same temperature for 2 hours. After the reaction, the reaction mixture was poured into 300 ml. of 2% hydrochloric acid and the resulting precipitate was separated by a filtration. The resulting crude product was recrystallized from toluene to obtain 9.0 g. of 4-(2-ethoxyethoxy)-N-(2,3-dichlorophenyl)-benzamide. The yield was 74.4 g. The compound had a melting point of 121.2° to 122° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1([CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]1)[CH2:6][C:5]2=[O:23].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:23]=[C:5]1[C:4]2[C:20](=[CH:21][CH:22]=[C:2]([C:30]3[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=3)[C:24]#[N:25])[CH:3]=2)[O:19][C:7]2([CH2:12][CH2:11][CH:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)[CH2:6]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C1CC2(CCC(c3ccccc3)CC2)Oc2ccc(Br)cc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1cccc(-c2ccc3c(c2)C(=O)CC2(CCC(c4ccccc4)CC2)O3)c1
Temperature: 95 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
In a 50 mL round bottom flask was placed 6-bromo-4′-phenylspiro[chroman-2,1′-cyclohexan]-4-one (300 mg, 0.811 mmol), 3-cyanobenzeneboronic acid (155 mg, 1.06 mmol), PdCl2(PPh3)2 (57 mg, 0.08 mmol) and cesium carbonate (661 mg, 2.03 mmol). This solid mixture was dissolved in a Dioxane/water mixture (8 mL, 6:1 ratio, respectively). The solution was purged with a N2 stream for 30 seconds. A condenser was attached to the flask and the reaction was allowed to stir at 95° C. for 1 hour. At this time, the mixture was filtered through a Celite plug. The plug was rinsed with dichloromethane (20 mL) and water (20 mL). The phases in the filtrate were separated. The aqueous phase was back-extracted with dichloromethane twice (5 mL/each). The combined organic phases were dried over MgSO4, filtered and concentrated under reduce pressure. The crude material was purified by flash chromatography (ISCO, 12 g SiO2 cartridge, ethyl acetate/hexanes as the eluents). The corresponding fractions were combined and concentrated under reduce pressure yielding 3-(4-oxo-4′-phenylspiro[chroman-2,1′-cyclohexane]-6-yl)benzonitrile (173 mg, 0.440 mmol, 58% yield) as a light yellow oil.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].[OH-].[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([S:17]([O-:19])=[O:18])[CH:13]=[C:14]([Cl:16])[CH:15]=1.Br[C:21]1[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=1>O.CN(C)C=O>[Cl:16][C:14]1[CH:13]=[C:12]([S:17]([C:21]2[S:22][C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)(=[O:19])=[O:18])[CH:11]=[C:10]([Cl:9])[CH:15]=1
Reactant: O=S([O-])c1cc(Cl)cc(Cl)c1
Reactant: FC(F)(F)c1nnc(Br)s1
Agent: O=S([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc(Cl)cc(Cl)c1)c1nnc(C(F)(F)F)s1
Yield: 70 %

Procedure:
A solution of 75.6 g (0.6 mole) of analytically pure sodium sulfite in 300 ml of water was pre-warmed to 60°-70° C in a beaker. 122.8 g (0.5 mole) of 3,5-dichlorobenzenesulfochloride, and a solution of 40 g (1 mole) of sodium hydroxide in 200 ml of water were synchronously added dropwise from two dropping funnels in such a way that the pH value (measured with an electrode in the reaction solution) was always between 7 and 9; during the addition the mixture was stirred magnetically. The saline solution of the 3,5-dichlorobenzenesulfinate (about 600 ml) was then diluted with 1.8 liters of dimethylformamide and after adding 116.5 g (0.5 mole) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole the whole was stirred for 15 hours at 50° C. The sulfone was precipitated completely by adding ice water and was recrystallized from ethanol. 121 g (70% of theory) of 2-(3',5'-dichlorophenylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 123° C were obtained.
Reaction SMILES: CCN(C(C)C)C(C)C.F[C:11]1[C:12]([CH3:31])=[N:13][C:14]2[C:19]([N:20]=1)=[C:18]([C:21]1[NH:29][C:28]3[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=3[CH:22]=1)[CH:17]=[CH:16][CH:15]=2.[NH2:32][CH:33]1[CH2:37][CH2:36][S:35](=[O:39])(=[O:38])[CH2:34]1>CS(C)=O>[O:38]=[S:35]1(=[O:39])[CH2:36][CH2:37][CH:33]([NH:32][C:11]2[C:12]([CH3:31])=[N:13][C:14]3[C:19]([N:20]=2)=[C:18]([C:21]2[NH:29][C:28]4[CH2:27][CH2:26][NH:25][C:24](=[O:30])[C:23]=4[CH:22]=2)[CH:17]=[CH:16][CH:15]=3)[CH2:34]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC1CCS(=O)(=O)C1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using DIPEA (141 μl, 0.803 mmol), 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), (±) 3-amino-tetrahydrothiophene 1,1-dioxide (54.7 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(3-(((±)-1,1-dioxidotetrahydro-3-thiophenyl)amino)-2-methyl-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 11.52-11.67 (m, 1H), 7.80-7.88 (m, 1H), 7.59-7.69 (m, 1H), 7.34-7.41 (m, 1H), 7.25-7.33 (m, 1H), 6.98-7.07 (m, 1H), 6.85-6.98 (m, 1H), 4.91-5.02 (m, 1H), 3.61-3.72 (m, 2H), 3.39-3.49 (m, 3H), 3.21-3.28 (m, 1H), 2.87-2.97 (m, 2H), 2.65-2.74 (m, 1H), 2.55-2.60 (m, 3H), 2.25-2.40 (m, 1H). m/z (ESI, +ve) 412.1 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.Br[CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][O:18]1>>[O:18]1[CH2:19][CH2:20][CH2:21][CH2:22][CH:17]1[CH2:16][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: BrCC1CCCCO1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Product: CC1(C)OB(c2cnn(CC3CCCCO3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared from pyrazole-4-boronic acid pinacol ester and 2-(bromomethyl)tetrahydro-2H-pyran according to Method AC (stirred in a sealed vial at r.t. for 16 h, then heating to 80° C. for 4 h before addition of further 2-(bromomethyl)-tetrahydro-2H-pyran, and heating to 80° C. for a further 2 days) and was isolated as a brown gum (75%). LCMS (ES+) 293 (M+H)+, RT 3.41 minutes (Method 1).
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9].[CH2:10]1[CH2:14][O:13][CH2:12][CH2:11]1>>[C:4]1([CH3:9])[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:12]1([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])[CH2:11][CH2:10][CH2:14][O:13]1
Reactant: Cc1ccccc1Br
Reactant: C1CCOC1
Agent: [Mg]
Product: Cc1ccccc1C1(c2ccccc2C)CCCO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of magnesium turnings (33 g) in dry THF (150 mL) was added 2-bromotoluene (4 mL). The reaction mixture was heated to reflux and an exotermic reaction started. The heating mantle was removed and 2-bromotoluene (137 mL) in dry THF (500 mL) was added dropwise over an hour at reflux temperature (exotermic reaction). The resulting reaction mixture was boiled under reflux for additionally 1.5 hrs. The mixture was cooled to room temperature and excess Mg was filtered off in an inert atmosphere. A solution of 4-chlorobutyric acid methylester (56.4 g) in dry THF (200 mL) was added dropwise at 20° C. The reaction mixture was stirred at room temperature for additionally 1 hr and was then poured into an aqueous solution of NH4Cl and ice. The organic phase was worked-up according to the standard workup procedures. After evaporation of the organic solvent the residue was suspended in a mixture of n-heptane/ethyl acetate=4/1. Filtration of the resulting crystals afforded 2,2-di-(2-tolyl)-tetrahydrofuran 33a (32.5 g). 1H NMR (CDCl3) δ 1.96 (s,6H), 1.96-2.10 (m,2H), 2.57 (t,2H), 4.02 (t,2H), 7.00-7.07 (m,2H), 7.07-7.23 (m,4H), 7.57-7.65 (m,2H)
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][C:9]2[CH:26]=[CH:25][C:12]([O:13][CH2:14][C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])=[CH:11][CH:10]=2)=[CH:27][CH:28]=1)(=[O:39])=[O:38]
Reactant: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(O)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1COc1ccc(CCOc2ccc(OS(C)(=O)=O)cc2)cc1
Temperature: -20 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
Methyl 2-({4-[2-(4-hydroxyphenoxy)ethyl]phenoxy}methyl)benzoate (0.547 g, 1.45 mmol) was dissolved in dichloromethane (10 ml) and the solution was cooled to −20° C. Triethylamine (0.22 g, 2.17 mmol) was added dropwise followed by the dropwise addition of methylsulfonyl chloride (0.18 g, 1.59 mmol). The ice bath was removed and the mixture was stirred overnight at room temperature. Excess of triethylamine was removed by addition of diethyl ether (5 ml) and filtering off the precipitate. The organic phase was washed with three portions of brine (10 ml) and dried (MgSO4). The solvent was removed by evaporation, the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.317 g of methyl 2-{[4-(2-{4-[(methylsulfonyl)oxy]phenoxy}ethyl)phenoxy]methyl}benzoate (yield 48%).
Reaction SMILES: FC1C([O:8][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:28]=[CH:27][C:26]([S:29](=[O:32])(=[O:31])[NH2:30])=[CH:25][CH:24]=2)=O)=C(F)C(F)=C(F)C=1F.[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1>>[N:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH:44][C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[N:21][NH:22][C:23]2[CH:24]=[CH:25][C:26]([S:29](=[O:31])(=[O:32])[NH2:30])=[CH:27][CH:28]=2)=[O:8])=[CH:39][CH:38]=1
Reactant: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)Oc4c(F)c(F)c(F)c(F)c4F)cc32)cc1
Reactant: NCc1ccncc1
Product: NS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc(C(=O)NCc4ccncc4)cc32)cc1

Procedure:
The title compound was prepared from 2-oxo-3[(4-sulfamoyl-phenyl)-hydrazono]-2,3-dihydro-1H-indole-5-carboxylic acid pentafluorophenyl ester and (4-pyridyl)methylamine according to Procedure K: mp 211–215° C.; Anal. Calcd for C21H18N6O4S.¾H2O: C, 54.36; H, 4.24; N, 18.11. Found: C, 54.41; H, 4.20; N, 18.12.
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH:16]=O)=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:18].[NH2:19][OH:20]>C(O)C>[ClH:18].[C:1]1([C:7]2[C:15]([CH:16]=[N:19][OH:20])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1c(-c2ccccc2)nn2ccccc12
Agent: Cl
Solvent: CCO
Product: ON=Cc1c(-c2ccccc2)nn2ccccc12
Yield: 45.5 %

Procedure:
A mixture of 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde (0.5 g) and hydroxylamine hydrochloride (0 17 g) in ethanol (5 ml) was refluxed for 1.5 hours and evaporated in vacuo. The residue was triturated with ethyl acetate and recrystallized from a mixture of ethanol and ethyl acetate to give 2-phenylpyrazolo[1,5-a]pyridine-3-carbaldehyde oxime hydrochloride (0.28 g).
Reaction SMILES: Cl.[OH:2][C@@H:3]([CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:26][CH2:25][CH:24]([NH:27][CH3:28])[CH2:23][CH2:22]4)[C:10]=3[C:9]1=2)[C:4]([NH2:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:36][C:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:38]>CN(C)C=O.O>[OH:2][C@@H:3]([CH2:7][C@H:8]1[CH2:19][CH2:18][C:17]2[S:16][C:15]3[N:14]=[CH:13][N:12]=[C:11]([O:20][CH:21]4[CH2:22][CH2:23][CH:24]([N:27]([CH3:28])[CH2:36][C:37](=[O:38])[N:39]5[CH2:43][CH2:42][CH2:41][CH2:40]5)[CH2:25][CH2:26]4)[C:10]=3[C:9]1=2)[C:4]([NH2:6])=[O:5]
Reactant: O=C(CCl)N1CCCC1
Reactant: CNC1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(=O)N1CCCC1)C1CCC(Oc2ncnc3sc4c(c23)[C@@H](C[C@H](O)C(N)=O)CC4)CC1

Procedure:
Into a 50-mL round-bottom flask, a solution of (2S)-2-hydroxy-3-[(3R)-12-[[4-(methylamino)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide hydrochloride (110 mg, 0.26 mmol, 1.00 equiv), potassium carbonate (179 mg, 1.30 mmol, 5.03 equiv) and 2-chloro-1-(pyrrolidin-1-yl)ethan-1-one (152 mg, 1.03 mmol, 4.00 equiv) in N,N-dimethylformamide (6 mL) was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 4×20 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The crude product was purified by flash preparative HPLC under the following conditions (IntelFlash-1): column: silica gel; mobile phase; Detector, UV 254 nm. This resulted in (2S)-2-hydroxy-3-[(3R)-12-[(4-[methyl[2-oxo-2-(pyrrolidin-1-yl)ethyl]amino]cyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]propanamide (63.8 mg, 49%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 8.47 (s, 1H), 5.28 (m, 1H), 4.17-4.14 (m, 1H), 3.59-3.32 (m, 7H), 3.15-2.98 (m, 2H), 2.76-2.70 (m, 2H), 2.52-2.33 (m, 7H), 2.04-1.89 (m, 6H), 1.74-1.53 (m, 5H). MS: m/z 502 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[O:7][C:6]([CH:8]=[C:9]2[S:13]C(=S)N[C:10]2=[O:15])=[CH:5][CH:4]=1.[OH-:18].[Na+]>O>[SH:13][C:9](=[CH:8][C:6]1[O:7][C:3]([C:2]([F:17])([F:16])[F:1])=[CH:4][CH:5]=1)[C:10]([OH:18])=[O:15]
Reactant: O=C1NC(=S)SC1=Cc1ccc(C(F)(F)F)o1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C(S)=Cc1ccc(C(F)(F)F)o1
Temperature: 25 °C
Yield: 60 %

Procedure:
1.58 g of the above 5-(5-trifluoromethyl-2-furylmethylene)rhodanine, 23 ml of 1 N sodium hydroxide solution and 25 ml of water are stirred under nitrogen at room temperature for 10 hours. After cooling with an ice bath and acidification with concentrated hydrochloric acid to pH 1.5, the resulting slurry is filtered to yield a slightly brown precipitate which is washed with 50 ml of water by stirring at room temperature under nitrogen and filtered to yield 0.8 g of slightly brown crystals (yield 60%) of α-mercapto-β-(5-trifluoromethyl-2-furyl)-acrylic acid. M.P. 158° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.Br.[H][H]>CCOC(C)=O.CC(O)=O.[Pd]>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CCC=Cc1cccc(Br)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(O)CCCCc1cccc(Br)c1
Yield: 77.8 %

Procedure:
To a solution of 5-(3-Bromo-phenyl)-pent-4-enoic acid (4 g, 16 mmol) in EtOAc (150 mL) was added Pd/C (400 mg) and a solution of 40% HBr in AcOH (0.5 mL). The mixture was stirred at rt under 1 atm of hydrogen for 1 h. The reaction mixture was filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography using a solvent system of 5:1 petroleum ether/EtOAc to give 5-(3-Bromo-phenyl)-pentanoic acid (3.2 g, 80%). 1H-NMR (400 MHz, CDCl3) δ ppm 7.3-7.4 (m, 2H), 7.05-7.15 (m, 2H), 2.55 (s, 2H), 2.35 (s, 2H), 1.7 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:32]=[CH:33][C:34]=3[CH3:35])[C:22]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39].[NH2:40][CH2:41][CH2:42][N:43]([CH3:51])[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:40][CH2:41][CH2:42][N:43]([CH3:51])[C:44](=[O:50])[O:45][C:46]([CH3:47])([CH3:48])[CH3:49])[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH:32]=[CH:33][C:34]=3[CH3:35])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:39]
Reactant: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(S(C)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(CCN)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: Cc1ccc(C(=O)Nc2ccc(F)cc2)cc1-c1nc(NCCN(C)C(=O)OC(C)(C)C)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 102.9 %

Procedure:
To a solution of 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-N-(4-fluorophenyl)-4-methylbenzamide (50 mg, 0.09 mmol) in DCM (5 mL) was added 1,1-dimethylethyl (2-aminoethyl)-methylcarbamate (0.09 mL, 0.5 mmol). The resultant mixture was stirred at room temperature overnight. The mixture was concentrated under vacuo. Flash chromatography (90% CH2Cl2/7% MeOH/3% NH4OH) then provide the title compound (61 mg, 100%). LC-MS (ES) m/z 659 (M+H)+; 1H-NMR (CDCl3) δ 1.39 (s, 9H), 1.70 (br, 1H), 2.32 (s, 3H), 2.65 (s, 2H), 2.82 (s, 2H), 3.22 (s, 3H), 3.60 (br, 1H), 6.34 (d, 1H), 7.03 (m, 4H), 7.34 (m, 1H), 7.48 (m, 2H), 7.64 (m, 1H), 7.84 (m, 2H), 8.14 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:27])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([N:27]([S:29]([CH3:28])(=[O:31])=[O:30])[S:29]([CH3:28])(=[O:31])=[O:30])[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2nc3ccc(N)cc3nc2-c2ccc(OC)cc2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(-c2nc3ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc3nc2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2,3-bis(4-methoxyphenyl)quinoxalin-6-amine (123.2 mg, 0.35 mmol, 1.00 equiv) in dichloromethane (20 mL) was added methanesulfonyl chloride (47.2 mg, 0.41 mmol, 1.20 equiv) and triethylamine (174.3 mg, 1.73 mmol, 5.00 equiv). The resulting solution was stirred for 1.5 h at room temperature. The resulting mixture was concentrated in vacuo, resulting in 179.55 mg (81%) of N-(2,3-bis(4-methoxyphenyl)quinoxalin-6-yl)-N-(methylsulfonyl)methanesulfonamide as a brown solid.