Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][C@@H:23]3[N:29]([CH:30]=2)[C:28](=[O:31])[C:27]2[CH:32]=[C:33]([O:74][CH3:75])[C:34]([O:36][CH2:37][CH2:38][CH2:39][O:40][C:41]4[C:71]([O:72][CH3:73])=[CH:70][C:44]5[C:45](=[O:69])[N:46]6[CH:61]=[C:60](S(C(F)(F)F)(=O)=O)[CH2:59][C@H:47]6[C:48](=[O:58])[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:43]=5[CH:42]=4)=[CH:35][C:26]=2[N:25]([CH2:76][O:77][CH2:78][CH2:79][Si:80]([CH3:83])([CH3:82])[CH3:81])[C:24]3=[O:84])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.O>[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:60]2[CH2:59][C@@H:47]3[N:46]([CH:61]=2)[C:45](=[O:69])[C:44]2[CH:70]=[C:71]([O:72][CH3:73])[C:41]([O:40][CH2:39][CH2:38][CH2:37][O:36][C:34]4[C:33]([O:74][CH3:75])=[CH:32][C:27]5[C:28](=[O:31])[N:29]6[CH:30]=[C:21]([C:18]7[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=7)[CH2:22][C@H:23]6[C:24](=[O:84])[N:25]([CH2:76][O:77][CH2:78][CH2:79][Si:80]([CH3:81])([CH3:82])[CH3:83])[C:26]=5[CH:35]=4)=[CH:42][C:43]=2[N:49]([CH2:50][O:51][CH2:52][CH2:53][Si:54]([CH3:57])([CH3:56])[CH3:55])[C:48]3=[O:58])=[CH:6][CH:5]=1
Reactant: NCc1ccc(B(O)O)cc1
Reactant: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(S(=O)(=O)C(F)(F)F)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C2=CN3C(=O)c4cc(OC)c(OCCCOc5cc6c(cc5OC)C(=O)N5C=C(c7ccc(CN)cc7)C[C@H]5C(=O)N6COCC[Si](C)(C)C)cc4N(COCC[Si](C)(C)C)C(=O)[C@@H]3C2)cc1
Temperature: 30 °C
Reaction time: 8 h
Yield: 59.5 %

Procedure:
Solid 4-aminomethylbenzeneboronic acid hydrochloride (0.111 g, 0.59 mmol) was added to a solution of 17 (0.394 g, 0.37 mmol), sodium carbonate (175 mg, 1.654 mmol) and palladium tetrakis triphenylphosphine (28.0 mg, 0.024 mmol) in toluene (10 mL), ethanol (5 mL) and water (5 mL). The reaction mixture was allowed to stir overnight at 30° C. The following day the reaction mixture was heated for a further 3 hours at 70° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulphate. Excess solvent was removed by rotary evaporation under reduced pressure and the resulting residue was subjected to flash column chromatography (silica gel; gradient elution EtOAc/hexane 2/9815/85). Removal of excess eluent from selected fractions afforded the desired product (0.230 mg, 0.22 mmol, 61%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26].CCN(C(C)C)C(C)C>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26])(=[O:5])=[O:4]
Reactant: O=C1OCCC1CCCCO
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1OCCC1CCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 22.6 %

Procedure:
Trifluoromethanesulfonic anhydride (0.64 mL, 3.8 mmol) was added dropwise to a 0° C. solution of 3-(4-hydroxybutyl)-dihydrofuran-2(3H)-one (0.50 g, 3.2 mmol) and DIEA (0.94 mL, 5.4 mmol) in CH2Cl2 (15 mL). After stirring at 0° C. for 1.5 hours, the reaction was diluted with CH2Cl2 and washed sequentially with water, 1 M HCl, and water. The organics were dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed (1:2 EtOAc/hexanes) to afford the product as a colorless oil (0.21 g, 23%).
Reaction SMILES: [CH2:1]([O:3][P:4]([O-:8])[O:5][CH2:6][CH3:7])[CH3:2].[CH2:9]([O:11][C:12]([N:14]=[C:15]=[O:16])=[O:13])[CH3:10]>C(N(CC)CC)C.C(Cl)Cl>[CH2:1]([O:3][P:4]([C:15]([NH:14][C:12](=[O:13])[O:11][CH2:9][CH3:10])=[O:16])([O:5][CH2:6][CH3:7])=[O:8])[CH3:2]
Reactant: CCOP([O-])OCC
Reactant: CCOC(=O)N=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)NC(=O)P(=O)(OCC)OCC

Procedure:
To a solution of 11.0 parts of diethylphosphite in 175 parts of methylene chloride and 4 drops of triethyl amine was added 10.0 parts of ethoxycarbonyl isocyanate. The solution was refluxed for 3 hours. Removing the solvent under reduced pressure left 18.5 parts of colorless oil which partially crystallized. The crystals were washed with cyclohexane to give 7.3 parts of ethyl N-(diethylphosphonocarbonyl)carbamate, m.p. 57°-64°, The proton nmr spectrum was consistent with this structure. (δNH = 10.0 ppm)
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13].S([O-])([O-])=O.[Na+].[Na+].[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>>[OH:25][C:21]([CH3:24])([CH3:23])[CH2:22][O:3][N:4]1[C:9]([CH3:10])([CH3:11])[CH2:8][C:7](=[O:12])[CH2:6][C:5]1([CH3:14])[CH3:13]
Reactant: CC(C)(C)O
Reactant: CC1(C)CC(=O)CC(C)(C)N1O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(=O)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of 1-oxyl-2,2,6,6-tetramethylpiperidin-4-one and ferrous chloride in tert-butyl alcohol at 30-60° C. Excess peroxide is decomposed with aqueous sodium sulfite. The organic layer is concentrated and the residue is purified by flash chromatography to afford the desired 1-(2-hydroxy-2-methylpropoxy)-2,2,6,6-tetramethylpiperidin-4-one.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:23]=[N:24][NH:25][CH:26]=4)[N:19](S(C4C=CC=CC=4)(=O)=O)[C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:43][CH2:44][O:45][Si](C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:26]=[N:25][N:24]([CH2:43][CH2:44][OH:45])[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1cc(CCc2cnc3c(cc(-c4cn[nH]c4)n3S(=O)(=O)c3ccccc3)n2)cc(OC)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(CCc2cnc3[nH]c(-c4cnn(CCO)c4)cc3n2)cc(OC)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 14.5 %

Procedure:
To a stirred solution of 2-[2-(3,5-dimethoxyphenyl)ethyl]-5-(phenylsulfonyl)-6-(1H-pyrazol-4-yl)-5H-pyrrolo[2,3-b]pyrazine (from Example 35, Step 1, 30.0 mg, 0.0613 mmol) in acetonitrile (1 mL), cesium carbonate (20.0 mg, 0.0613 mmol) and (2-bromoethoxy) (tert-butyl)dimethylsilane (13.1 μL, 0.0613 mmol) were added sequentially at ambient temperature. The reaction mixture was then warmed up to 60° C. After 2 hours, the reaction was quenched with water, and extracted with methylene chloride. The combined organic layers were dried over MgSO4, concentrated. The residue was dissolved in methylene chloride (1.0 m)/trifluoroacetic acid (1.0 mL) at ambient temperature. After 2 hours, the volatiles were removed under vacuum and the residues were dissolved in methanol (2.0 mL). Potassium carbonate (16.9 mg, 0.122 mmol) was added and the reaction mixture was warmed up to 60° C. After 1 hour, the crude mixture was purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.05% TFA, at flow rate of 30 mL/min) to give the desired product (3.5 mg) as its TFA salt. LCMS calculated for C21H24N5O3 (M+H)+: m/z=394.2. Found: 394.2.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][C@@H:22]([OH:25])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O[N:27]1[C:35](=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]1=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:37]=[C:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35](=[O:36])[N:27]1[O:25][C@H:22]1[CH2:23][CH2:24][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:14])[CH3:15])=[O:19])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](ON2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 40.6 %

Procedure:
Diethyl azodicarboxylate (17.4 g, 100 mmol) was added to a solution of (R)-tert-butyl-3-hydroxypyrrolidin-1-carboxylate (9.40 g, 50 mmol), 2-hydroxyisoindoline-1,3-dione (8.16 g, 50 mmol) and triphenylphosphine (26.2 g, 100 mmol) in tetrahydrofuran (100 ml) at 0° C. The reaction mixture was stirred at room temperature for 17 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/petroleum ether: 5/95 to 12.5/87.5) to give (S)-tert-butyl 3-(1,3-dioxoisoin dolin-2-yloxy)pyrrolidin-1-carboxylate (6.74 g, 20%) as a white solid: LCMS: 277 [M−55]+
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][CH:11]=2)=[CH:5][C:4]=1[N+:19]([O-])=O.[CH3:22][O:23][C:24]([NH:26][C:27](=NC(OC)=O)SC)=[O:25]>CO.[Pd]>[CH3:1][N:2]1[C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10]3[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=3)=[CH:5][C:4]=2[N:19]=[C:27]1[NH:26][C:24](=[O:25])[O:23][CH3:22]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CNc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)Nc1nc2cc(Oc3ccc(N)cc3)ccc2n1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 12.3 %

Procedure:
To a mixture of N-methyl-4-(4-nitrophenoxy)-2-nitroaniline (Intermediate 8B -2.10 g, 2.27 mmol) in MeOH (100 mL) was added 5% Pd—C (catalytic amount) and stirred at room temperature under H2 atmosphere. After 7 hrs, the catalyst was removed by filtration then the solvent was evaporated off. The residual mixture was dissolved into MeOH (50 mL) and added 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.0 g, 14.5 mmol). The mixture was refluxed overnight. The solvent was removed by evaporation and sequence purification on SiO2 column chromatography gave title compound (87.3 mg, 4%): MS m/e 313 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Na+].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Br>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][N:9]2[CH2:18][CH2:17][CH2:16][CH2:15][Cl:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: ClCCCCBr
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2ccn(CCCCCl)c2c1
Temperature: 60 °C
Yield: 59.7 %

Procedure:
6-cyano-1H-indole (14.2 g, 0.10 mol) was dissolved into 200 ml of 20% wt. sodium hydroxide, 4-chlorobromobutane (34.3 g, 0.20 mol) and tetrabutyl ammonium bromide (1.0 g) were added, and mixed for 5 min. The mixture was heated to 60° C., stirred to react for 2 hours. Then the reaction solution was cooled down to ambient temperature, 100 ml of dichloromethane was added for extraction and liquid separation. To the aqueous phase, 100 of dichloromethane was added for extraction. Organic phases were mixed, washed with 100 ml of saturated saline. Liquid was separated, and organic phase was evaporated to dryness to produce oily product. Oily products were separated and purified by chromatography with neutral Al2O3 to produce 13.9 g of 6-cyano-1-(4-chlorobutyl)-1H-indole, with a yield of 60.3%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][CH2:26]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:25][CH3:26])[C:9]1[S:10][C:11]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:13]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1nc(NC(=O)OC(C)(C)C)sc1-c1ccccc1
Reactant: CCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N(CC)C(=O)OC(C)(C)C)sc1-c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 2-[(tert-butoxycarbonyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate in THF were added EtOH, PPh3, and DEAD, followed by stirring at room temperature. The reaction mixture was concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, hexane: EtOAc) to obtain ethyl 2-[(tert-butoxycarbonyl) (ethyl)amino]-5-phenyl-1,3-thiazole-4-carboxylate as a yellow oil.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]>[OH-].[Na+]>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCC[C@@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O

Procedure:
In the routine manner, H-D-Nva-OH is reacted with carbobenzoxy chloride in 2 N sodium hydroxide and the resultant compound is recrystallized from ethyl acetatepetroleum benzine. The procedure gives needles melting at 83°-84° C.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].C1(PC2C=CC=CC=2)C=CC=CC=1.[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH2:29].Cl[C:31]1[N:36]=[CH:35][C:34]([O:37][C:38]2[C:39]([CH:44]3[CH2:49][CH2:48][N:47]([C:50](=[O:52])[CH3:51])[CH2:46][CH2:45]3)=[N:40][CH:41]=[CH:42][N:43]=2)=[CH:33][CH:32]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[S:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH:29][C:31]1[N:36]=[CH:35][C:34]([O:37][C:38]2[C:39]([CH:44]3[CH2:45][CH2:46][N:47]([C:50](=[O:52])[CH3:51])[CH2:48][CH2:49]3)=[N:40][CH:41]=[CH:42][N:43]=2)=[CH:33][CH:32]=1
Reactant: CC(=O)N1CCC(c2nccnc2Oc2ccc(Cl)nc2)CC1
Reactant: Nc1nc2ccccc2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3nc4ccccc4s3)nc2)CC1
Temperature: 100 °C

Procedure:
To a mixture of tris(dibenzylideneacetone)dipalladium(0) (0.021 g, 0.023 mmol), Na2CO3 (0.081 g, 0.76 mmol), 9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine (0.040 g, 0.069 mmol), benzo[d]thiazol-2-amine (0.110 g, 0.732 mmol), and 1-(4-(3-(6-chloropyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone (0.182 g, 0.547 mmol) was added PhMe (3 mL). The reaction mixture was degassed and heated to 100° C. for 40 h. The reaction mixture was diluted with EtOAc and the organic phase was washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (10% to 80% EtOAc (10% MeOH) in hexanes) gave 1-(4-(3-(6-(benzo[d]thiazol-2-ylamino)pyridin-3-yloxy)pyrazin-2-yl)piperidin-1-yl)ethanone as a white solid. MS (ESI, pos. ion) m/z: 447.2 (M+1). IC50 (uM) ++.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][S:38][C:39]1[N:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:43]=[N:44][C:39]([S:38][CH3:37])=[CH:40][CH:41]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CSc1ccc(B(O)O)cn1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CSc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 87.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.5 g, 0.96 mmol), 6-methylsulfanyl-pyridine-3-boronic acid (370 mg, 2.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (67.4 mg, 0.096 mmol) in dioxane (6 mL) was added an aqueous sodium carbonate solution (2 M, 0.96 mL, 1.92 mmol). The resulting mixture was subjected to microwave irradiation for 3 h at 100° C. The mixture was diluted with ethyl acetate (80 mL), washed with a saturated aqueous sodium bicarbonate solution (2×20 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash column chromatography (QingDao silica gel, 200-300 mesh, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methylsulfanyl-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (400 mg, 88%) as a light yellow solid: LC/MS m/e calcd for C26H25N3O2S2 [M+H]+ 476.64, observed 476.0.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=[C:13]3[CH:12]=[C:11]2[C:23]([C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=2)=[CH:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl-].[Na+].O>[CH:25]1([CH:24]=[C:23]([C:11]2[NH:10][C:14]3=[N:15][CH:16]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:18]=[C:13]3[CH:12]=2)[C:30]2[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:32][CH:31]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cc(C(F)(F)F)cnc3[nH]2)cc1
Yield: 93 %

Procedure:
A mixture of 1-benzenesulfonyl-2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (270 mg, 0.47 mmol) and a solution of tetrabutylammonium fluoride in tetrahydrofuran (1 M, 9.4 mL, 9.4 mmol) was stirred for 12 h at room temperature. The mixture was poured into brine (15 mL), extracted with ethyl acetate (2×50 mL), washed with a saturated aqueous ammonium chloride solution (3×20 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-vinyl]-5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine (190 mg, 93%) as a solid which was used in the next step without purification: LC/MS m/e calcd for C22H21F3N2O2S [M+H]+ 435.48, observed 434.8.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]3[C:12]([N:13]=[C:14]([CH3:15])[C:5]2=[C:4]([CH3:17])[N:3]=1)=[CH:11][CH:10]=[C:9]([F:16])[CH:8]=3.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>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>[F:16][C:9]1[CH:8]=[C:7]2[C:12]([N:13]=[C:14]([CH3:15])[C:5]3[N:6]2[C:2]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:30])([F:29])[F:18])=[N:3][C:4]=3[CH3:17])=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1C(F)(F)F
Reactant: Cc1nc(Br)n2c1c(C)nc1ccc(F)cc12
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: [K+]
Product: Cc1nc(-c2ccccc2C(F)(F)F)n2c1c(C)nc1ccc(F)cc12
Yield: 49 %

Procedure:
Following the general Suzuki coupling procedure, reaction of bromide 5A (75 mg, 0.25 mmol), 2-trifluoromethylphenylboronic acid (58 mg, 0.30 mmol), K2CO3 (105 mg, 0.75 mmol) and Pd(PPh3)4 (5.8 mg, 0.005 mmol) provided the coupling product as a white powder (44 mg, 49% yield). EIMS 360.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)[N:3]=1.[F:16][C:17]([F:29])([F:28])[O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>[Pd]>[F:16][C:17]([F:28])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=3)[N:3]=2)=[CH:21][CH:20]=1
Reactant: O=Cc1ccc(-c2nccc(Cl)n2)cc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: [Pd]
Product: O=Cc1ccc(-c2nccc(-c3ccc(OC(F)(F)F)cc3)n2)cc1

Procedure:
The compound was prepared by palladium-catalyzed arylation of the product of Step 1 with 4-trifluoromethoxyphenyl boronic acid: 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 1H), 8.91 (d, J=4.2 Hz, 1H), 8.63 (d, J=8.5 Hz, 2H), 8.37 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.8 Hz, 2H), 7.67 (d, J=5.4 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H); EIMS m/z 344 (M+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17](Cl)[N:16]=1>[Cu]I.CN(C)C=O>[CH3:22][O:21][C:19]1[CH:18]=[C:17]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)[N:16]=[C:15]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[CH:4]=2)[CH:20]=1
Reactant: COc1cc(Cl)nc(Cl)c1
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Oc2cccc(C(F)(F)F)c2)nc(Oc2cccc(C(F)(F)F)c2)c1

Procedure:
To meta-trifluoromethyl phenol (2.5 g, 0.0028×5.5 mol), 15 ml of dimethylformamide was added, followed by the addition of sodium hydride (0.45 g (ca.60% in mineral oil), 0.0028×4.0 mol) and CuI (0.25 g, 0.0028×0.47 mol). To thus formed mixture was added 2,6-dichloro-4-methoxy-pyridine (0.5 g, 0.0028 mol), and the resultant solution was refluxed for about 8 hours.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[O:10][CH3:11].C([Li])CCC.CON(C)[C:20]([C:22]1[C:23]([NH2:31])=[N:24][C:25]([S:28][CH2:29][CH3:30])=[N:26][CH:27]=1)=[O:21]>CCCCC.O1CCCC1.O1CCCC1>[NH2:31][C:23]1[C:22]([C:20]([C:2]2[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=2[O:10][CH3:11])=[O:21])=[CH:27][N:26]=[C:25]([S:28][CH2:29][CH3:30])[N:24]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cc(F)c(F)cc1Br
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCSc1ncc(C(=O)c2cc(F)c(F)cc2OC)c(N)n1
Temperature: -72 °C
Reaction time: 0.17 h

Procedure:
A solution of 2-bromo-4,5-difluoro-anisole (1.95 g, 8.75 mmol, Astatech) in a mixture of pentane/tetrahydrofuran (5 mL/17 mL) was cooled to −72° C. and treated with n-butyl lithium (2.5 M in hexane, 3.6 mL, 9.0 mmol). After stirring for 10 minutes, a solution of 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (0.78 g, 3.21 mmol, Example 1) in tetrahydrofuran (3 mL) was added. The temperature was slowly raised to −35° C. for ˜2 hours. The reaction was quenched at −35° C. with 5% aqueous ammonium chloride solution and the mixture was diluted with ethyl acetate/hexane (100 mL). The organic phase was separated, washed with 1:1 water/saturated aqueous sodium chloride solution and dried (Na2SO4). The residue after solvent removal was purified by HPLC chromatography (Waters Prep 500 eluting with 35% ethyl acetate/hexane) to give, in approximately 1:1 ratio, the two positional isomers (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone identical to material prepared in Example 102, and (4-Amino-2-ethylsulfanyl-pyrimidin-5-yl)-(4,5-difluoro-2-methoxy-phenyl)-methanone as a white solid after evaporation. HRMS, observed: 326.0772; Calcd for M+: 326.0770.