Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:33]=[CH:32][C:10]([CH2:11][N:12]([CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[N:3]=1.CC(C)([O-])C.[K+].[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47](Cl)(=[O:49])=[O:48])=[CH:43][CH:42]=1>C1COCC1>[CH3:40][C:41]1[CH:46]=[CH:45][C:44]([S:47]([NH:1][C:2]2[O:6][N:5]=[C:4]([C:7]3[CH:8]=[CH:9][C:10]([CH2:11][N:12]([CH2:24][C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[C:13](=[O:23])[C:14]4[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=4)=[CH:32][CH:33]=3)[N:3]=2)(=[O:49])=[O:48])=[CH:43][CH:42]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccc(-c2noc(N)n2)cc1)C(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)Nc2nc(-c3ccc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc([N+](=O)[O-])cc4)cc3)no2)cc1
Yield: 10 %

Procedure:
Prepared using General Procedure 10. To a stirring solution of tert-butyl 2-(N-(4-(5-amino-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-67 (150 mg, 0.331 mmol) in THF (3 mL) was added potassium tert-butoxide (599 μL, 0.992 mmol) at room temperature. After 15 mins a solution of 4-methylbenzene-1-sulfonyl chloride (63.1 mg, 0.331 mmol) in THF (1 mL) was added. After 1 h the reaction mixture quenched with 1 M HCl (30 mL) and then extracted with EA (50 mL). The organic layer was concentrated in vacuo and purified by chromatography (EA/hexanes) to provide 20 mg (10%) of tert-butyl 2-(N-(4-(5-(4-methylphenylsulfonamido)-1,2,4-oxadiazol-3-yl)benzyl)-4-nitrobenzamido)acetate INT-68. LCMS-ESI (m/z) calculated for C29H29N5O8S: 607; found 608 [M+H]+, tR=2.50 min (Method 10).
Reaction SMILES: C(C1C=CC(CN)=CC=1)=C.[C:11]1([P:17]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C-:18]2[CH:22]=[C:21]([C:23]([CH3:33])([CH2:25]C[CH:27]3OCCC[O:28]3)[CH3:24])[CH:20]=[C:19]2[P:34]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:53]([C:57]1[CH:58]=[C:59]([P:75]([C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[C:76]2[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=2)[C-:60]([P:62]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:61]=1)([CH3:56])([CH3:55])[CH3:54].[Fe+2:88].Cl>C1COCC1>[C:63]1([P:62]([C:69]2[CH:74]=[CH:73][CH:72]=[CH:71][CH:70]=2)[C-:60]2[CH:61]=[C:57]([C:53]([CH3:56])([CH2:54][CH:27]=[O:28])[CH3:55])[CH:58]=[C:59]2[P:75]([C:76]2[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:82]2[CH:87]=[CH:86][CH:85]=[CH:84][CH:83]=2)[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.[C:23]([C:21]1[CH:20]=[C:19]([P:34]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C-:18]([P:17]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:22]=1)([CH3:33])([CH3:24])[CH3:25].[Fe+2:88]
Reactant: CC(C)(CCC1OCCCO1)c1cc(P(c2ccccc2)c2ccccc2)[c-](P(c2ccccc2)c2ccccc2)c1
Agent: [Fe+2]
Agent: C=Cc1ccc(CN)cc1
Agent: CC(C)(C)c1cc(P(c2ccccc2)c2ccccc2)[c-](P(c2ccccc2)c2ccccc2)c1
Solvent: C1CCOC1
Product: CC(C)(CC=O)c1cc(P(c2ccccc2)c2ccccc2)[c-](P(c2ccccc2)c2ccccc2)c1
Reaction time: 0.17 h
Yield: 96.2 %

Procedure:
For the deprotection leading to the actual compound of formula (9), with E=(CH2)3 and GF=4-vinyl-benzylamine, a solution of 1,1′,2,2′-tetrakis(diphenyl-phosphino)-4-[4-(1,3-dioxan-2-yl)-2-methylbut-2-yl]-4′-tert-butylferrocene (0.1 g, 88 μmol) in 20 ml of THF is admixed with 5 ml of 2N hydrochloric acid solution. The solution is placed under microwave radiation (125 W) according to the following program: temperature rise 10° C./min to 120° C., then plateau at 120° C. for 10 min. After cooling, the reaction mixture is concentrated under vacuum, diluted with 20 ml of water, and extracted with 2 times 25 ml of CH2Cl2. The organic phase is dried over MgSO4 and concentrated under reduced pressure. The crude product obtained is purified by chromatography on silica gel (eluent AcOEt/heptane 1:4) to give 90 mg (ρ=90%) of 1,1′,2,2′-tetrakis(diphenylphosphino)-4-(4-oxo-2-methylbut-2-yl)-4′-tert-butylferrocene in the form of a red powder, for which the 31P NMR spectrum preserves, as expected, the ABCD spin system appearance, with slightly modified chemical shifts.
Reaction SMILES: [C@H:1]1([CH2:11]O)[CH2:6][CH2:5][C@H:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O>C1C=CC=CC=1>[Br:32][CH2:11][C@H:1]1[CH2:6][CH2:5][C@H:4]([C:7]([OH:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: CC(C)(O)[C@H]1CC[C@H](CO)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC(C)(O)[C@H]1CC[C@H](CBr)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1.994 grams (11.57 mmol) of trans-p-menthane-7,8diol (for preparation, see: Ohloff, G.; Giersch, W. Helv. Chim. Acta., 1980, 63, 76), 3.035 grams (11.57 mmol) of triphenylphosphine, and 20 mL of benzene was chilled in an ice bath and treated portionwise with 2.060 grams (11.57 mmol) of N-bromosuccinimide. The ice bath was removed and the mixture was stirred for 16 hours at room temperature. The mixture was diluted with 50 mL of hexane and the solids were removed by filtering sequentially through celite and filter paper. The filtrate was washed with 0.5 Na2S2O3 solution (2×100 mL), 1 N sodium hydroxide solution (1×50 mL), brine (1×50 mL), dried (Na2SO4), and evaporated. The residue was diluted with hexane and filtered to remove triphenylphospineoxide. The residue was purified by flash chromatography using a 10-50% EtOAc-hexane eluant to give 3.382 grams (88%) of the title compound an oil. 1H NMR (CDCl3) d 0.93-1.28 (6H, m), 1.15 (6H, s), 1.58 (1H, br s), 1.83-2.00 (4H, m), 3.27 (2H, d, J=7 Hz).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=2)=[N:13][CH:14]=1.[Cl:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][C:35]=1[Cl:36]>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:29][C:30]1[CH:31]=[C:32]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:18][CH:17]=3)=[N:13][CH:14]=2)[CH:33]=[CH:34][C:35]=1[Cl:36]
Reactant: CCOC(=O)CCc1ccc(Oc2ccc(N)cn2)cc1
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCc1ccc(Oc2ccc(Nc3ccc(Cl)c(Cl)c3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (1.2 mL, 8.4 mmol) was added to a suspension of ethyl 3-(4-(5-aminopyridin-2-yloxy)phenyl)propionate (1.2 g, 4.2 mmol), 3,4-dichlorophenylboronic acid (1.6 g, 8.4 mmol), anhydrous copper acetate (0.762 g, 4.2 mmol) and molecular sieves 4A (5 g) in dichloromethane (24 mL), and the resulting reaction solution was stirred overnight at room temperature. After the resulting solution was filtered through Celite, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1), to thereby yield 1.5 g of the title compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N>>[CH2:3]1[CH2:4][CH2:5][CH2:6][CH:1]([CH2:7][CH2:8][CH2:9][NH:10][S:17]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(=[O:19])=[O:18])[CH2:2]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCCCc1ccccc1
Agent: N
Product: O=S(=O)(NCCCC1CCCCC1)c1ccccc1

Procedure:
The title compound was prepared according to example 1063A (replacing phenethylamine with 3-phenylpropylarnine, and example 1063B, replacing p-toluenesulfonyl chloride with benzenesulfonyl chloride to afford a colorless oil. MS (DCI/NH3) m/e 299 (M+NH4)+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])[N:6]=1.Br[CH2:24][CH2:25][CH:26]1[O:30][CH2:29][CH2:28][O:27]1.Cl>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:12][O:11][C:9]1[CH:10]=[C:5]([O:4][CH3:3])[N:6]=[C:7]([O:13][C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([O:18][CH2:24][CH2:25][CH:26]2[O:30][CH2:29][CH2:28][O:27]2)=[O:17])[N:8]=1
Reactant: BrCCC1OCCO1
Reactant: COc1cc(OC)nc(Oc2ccccc2C(=O)O)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc(OC)nc(Oc2ccccc2C(=O)OCCC2OCCO2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
10 Milliliters of N,N-dimethylformamide in which 0.22 g of 60% sodium hydride in oil has been suspended was mixed with 5 ml of N,N-dimethylformamide solution of 1.38 g of 2-(4,6-dimethoxypyrimidin-2-yl)oxy benzoic acid. After stirring the mixture at room temperature for 30 minutes, 10 ml of N,N-dimethylformamide solution of 1.81 g of 2-(2-bromoethyl)-1,3-dioxolane was added thereto. The resulting solution was stirred at 100° to 110° C. for 2 hours. The reaction solution was allowed to cool, poured into diluted hydrochloric acid, and extracted with ethyl acetate. The organic layer separated from the aqueous layer was washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue obtained was subjected to silica gel column chromatography (mfd. by Merck & Co., Inc., solvent: chloroform) to obtain 1.20 g of 2-(1,3-dioxolan-2-yl)ethyl 2-(4,6-dimethoxypyrimidin-2-yl)oxybenzoate [present compound (V-2)].
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Br[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>CS(C)=O.[Cu]>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([S:1][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Cc1ccc(S)cc1
Agent: [Cu]
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(Sc2ccc(C(=O)O)cc2)cc1
Temperature: 210 °C
Reaction time: 16 h
Yield: 72 %

Procedure:
A mixture of 6.0 g of 4-mercapto-toluene and 9.2 g of potassium t-butoxide is stirred at room temperature under a nitrogen atmosphere in 50 ml of dimethylsulfoxide for 10 minutes followed by the addition of 11.5 g of 4-bromobenzoic acid and 0.2 g of copper metal. The reaction mixture is stirred at 210° C. for 16 hours. The reaction mixture is poured over crushed ice and filtered through diatomaceous earth. The filtrate is acidified with HCl until pH 2. The resulting solid is collected, washed with water and 60 ml of petroleum ether to give 8.5 g of the desired product, m.p. 105°-107° C., M+H=245.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][N:14]([C@H](C3C=CC=CC=3)C)[CH2:13]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[C].[Pd]>[C:1]([O:5][C:6]([NH:8][C:9]1([C@@H:12]2[CH2:16][CH2:15][NH:14][CH2:13]2)[CH2:10][CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](c1ccccc1)N1CC[C@@H](C2(NC(=O)OC(C)(C)C)CC2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1([C@@H]2CCNC2)CC1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
3-(R)-[1-(tert-butoxycarbonylamino)cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidine (270 mg, 0.817 mmol) was dissolved in ethanol (15 ml), and after adding a 10% palladium carbon catalyst (water content: 52.0%; 270 mg), it was stirred at 40° C. for 3 hours under a hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtering (ethanol washing), the filtrate was concentrated under a reduced pressure, and as a result, 185 mg (quantitative) of the title compound was obtained in the form of a colorless syrup.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[C:11]([CH3:35])([CH3:34])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[O:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[C:26](OCC)=[O:27])C.C(OCC)(=O)C.S(=O)(=O)(O)O>C(OC)(C)(C)C.O>[CH3:34][C:11]([CH3:35])([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]([OH:33])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][OH:27])[CH2:10][OH:9]
Reactant: CCOC(=O)C(C)(C)CCCCCCC(=O)CCCCCCC(C)(C)C(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(CO)CCCCCCC(O)CCCCCCC(C)(C)CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Under N2-atmosphere, methyl tert-butyl ether (MTBE, 80 mL) was added to lithium aluminum hydride (0.67 g, 17.60 mmol) and the suspension was stirred under cooling with an ice-water bath (0° C.). A solution of 2,2,16,16-tetramethyl-9-oxoheptadecanedioic acid diethyl ester (3.0 g, 7.04 mmol) in MTBE (20 mL) was added dropwise, followed by additional MTBE (40 mL). After 2 h at 0° C., the reaction mixture was carefully quenched by addition of ethyl acetate (8 mL, 80 mmol) and allowed to warm to room temperature overnight. The mixture was cooled with an ice-water bath and carefully hydrolyzed by addition of crushed ice (15 g) and water (15 mL). The pH was adjusted to 1 by addition of 2 N sulfuric acid (28 mL) and the solution was stirred at room temperature for 15 min. The layers were separated and the aqueous layer was extracted with MTBE (40 mL). The combined organic layers were washed with deionized water (50 mL), saturated NaHCO3 solution (40 mL), brine (40 mL), dried over MgSO4, concentrated in vacuo and dried in high vacuo to yield a crude product (2.65 g). The crude product was purified by recrystallization from hot CH2Cl2 (20 mL), which was cooled to room temperature and then kept at −5° C. The crystals were filtered, washed with ice-cold CH2Cl2 (20 mL) and dried in high vacuo. This process was repeated to furnish 2,2,16,16-tetramethylheptadecane-1,9,17-triol (1.59 g, 65%) as a white solid. Mp 75-77° C. 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 3.57 (m, 1H), 3.30 (s, 4H), 1.72 (br, 2H), 1.50-1.16 (m, 25H), 0.85 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 72.09, 38.79, 37.61, 35.21, 30.70, 29.85, 25.78, 24.06, 23.92. HRMS (LSIMS, gly): Calcd for C21H45O3 (MH+): 345.3369. found: 345.3364. HPLC: 95% pure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][CH:15]=[CH2:16])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.Cl[CH2:18][C:19]1[N:23]([CH2:24][C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:32])[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CO>[CH2:14]([N:9]1[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[N:12][N:11]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[C:26]([Cl:32])=[CH:27][CH:28]=[CH:29][C:30]=3[Cl:31])[CH:22]=[N:21][CH:20]=2)[C:10]1=[O:13])[CH:15]=[CH2:16]
Reactant: C=CCn1c(-c2ccc(Cl)cc2)n[nH]c1=O
Reactant: ClCc1cncn1Cc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCn1c(-c2ccc(Cl)cc2)nn(Cc2cncn2Cc2c(Cl)cccc2Cl)c1=O
Temperature: 80 °C
Reaction time: 16 h

Procedure:
41 mg (0.17 mmol) of the compound from Example 12A were dissolved in 2 ml of DMF, and 48 mg (0.17 mmol) of the compound from Example 40A and 85 mg (0.26 mmol) of cesium carbonate were added. The mixture was stirred at 80° C. for 16 h. After cooling to RT, the reaction mixture was diluted with 1 ml of methanol and directly purified chromatographically [Method 19]. This gave 4 mg (5% of theory) of the target compound.
Reaction SMILES: Cl.[N:2]1([C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[CH2:18]([S:21](Cl)(=[O:23])=[O:22])[CH2:19][CH3:20].[OH-].[Na+]>CCN(C(C)C)C(C)C.C(Cl)Cl>[N:2]1([C:8]([C:10]2([C:16]#[N:17])[CH2:15][CH2:14][N:13]([S:21]([CH2:18][CH2:19][CH3:20])(=[O:23])=[O:22])[CH2:12][CH2:11]2)=[O:9])[CH2:3][CH2:4][O:5][CH2:6][CH2:7]1
Reactant: CCCS(=O)(=O)Cl
Reactant: N#CC1(C(=O)N2CCOCC2)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCS(=O)(=O)N1CCC(C#N)(C(=O)N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(morpholin-4-ylcarbonyl)piperidine-4-carbonitrile hydrochloride (I-3) (10.40 g, 40 mmole) in DIEA-DCM (1:4, 200 mL) was added n-C3H7SO2Cl (6.28 g, 44 mmole) at 0° C. The resultant mixture was stirred for 1 h at 0° C. After this time, LCMS indicated that the reaction was complete. 2N NaOH (60 mL) was added to the reaction. The resultant reaction mixture was stirred for 1 h at rt. After this time, the DCM layer was separated. The aqueous solution was extracted with DCM (3×150 mL). The combined DCM solution was washed with brine, dried over MgSO4, filtered, and concentrated to afford the title compound (I-4) which was pure enough for next step reaction. Analytical LCMS: single peak (214 nm), 2.406 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[OH:20])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]([O:12][C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=2[O:20][C:22]2[S:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[CH2:11]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2Oc2nc3ccccc3s2)C1
Temperature: 135 °C
Yield: 83.2 %

Procedure:
A mixture of 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (0.5 mmol), 2-chloro-benzothiazole (0.5 mmol), and K2CO3 (1 mmol) in CH3CN (3 mL) was heated at 120-150° C. via Microwave for 1 h. The mixture was cooled down and separated through PTLC providing 3-[2-(benzothiazol-2-yloxy)-5-chloro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (180 mg). The ester was re-dissolved into CH2Cl2 (20 mL), and CF3COOH (3 mL) was added. The mixture was stirred at 25° C. for 4 h. After concentration, the title compound was obtained (192 mg). MS (ESI): mass calcd. for C16H13ClN2O2S, 332.0; m/z found, 333.1 [M+H]+. 1H NMR (MeOD): 7.23-7.07 (m, 4H), 6.92-6.81 (m, 3H), 5.14-5.08 (m, 1H), 4.51 (dd, J=12.5, 6.6 Hz, 2H), 4.23 (dd, J=12.5, 5.0 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([OH:19])=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:22][CH3:23])[CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([S:31](=[O:33])(=[O:32])[NH2:34])[CH:26]=3)=[O:19])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:4]([O:22][CH3:23])[CH:3]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COc1cc(F)ccc1Oc1nc2ccccc2nc1C(=O)Nc1cccc(S(N)(=O)=O)c1
Yield: 37.1 %

Procedure:
A solution of 3-(4-fluoro-2-methoxy-phenoxy)quinoxaline-2-carboxylic acid (47.1 mg, 0.15 mmol), 3-aminobenzenesulfonamide (31.0 mg, 0.18 mmol), HATU (62.7 mg, 0.16 mmol) and N-methylmorpholine (32.98 μL, 0.30 mmol) in DMF (0.5 mL) was stirred at 50° C. for 30 min. Purification was by reverse phase HPLC using a gradient of 1-99% ACN in Water (HCl modifier). The fractions containing the product were evaporated to dryness. The residue was then taken up in ethyl acetate and water and the pH of the solution was adjusted to −8 with a saturated solution of NaHCO3 in water (˜3 drops). The layers separated and the aqueous layer was extracted with ethyl acetate (3×). All organic were combined, evaporated and purification by silica gel column chromatography using a gradient of ethyl acetate in hexanes (5 to 70%) gave 3-(4-fluoro-2-methoxy-phenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (2) (26.10 mg, 37%) as a white solid. ESI-MS m/z calc. 468.09, found 469.3 (M+1)+; Retention time: 1.49 minutes (3 minutes run). 1H NMR (400 MHz, DMSO) δ 11.27 (s, 1H), 8.42 (s, 1H), 8.18 (d, J=8.0 Hz, 1H), 7.97-7.87 (m, 1H), 7.86-7.71 (m, 3H), 7.68-7.56 (m, 2H), 7.44 (s, 2H), 7.34 (dd, J=8.7, 5.9 Hz, 1H), 7.16 (dd, J=10.8, 2.9 Hz, 1H), 6.88 (ddd, J=8.6, 2.9 Hz, 1H), 3.71 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:13]=1)#[CH:11].CCN(CC)CC>C1COCC1.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.[Cu]Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([C:10]#[C:11][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:17][CH:16]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C#Cc1ccc(CCCCCC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A mixture of 4-bromobenzaldehyde (5.00 g, 27.0 mmol), 1-ethynyl-4-hexylbenzene (6.29 g, 33.4 mmol), Et3N (4.70 mL, 33.4 mmol), bis(triphenylphosphine)palladium chloride (950 mg, 1.35 mmol) and triphenylphosphine (180 mg, 0.68 mmol) in anhydrous THF (100 mL) was stirred at rt for 30 min under inert atmosphere. Then copper(I) bromide (82 mg, 0.43 mmol) was added and the resulting mixture was stirred overnight at rt. The solvent was evaporated off. The residue was dissolved in Et2O (100 mL), washed with water (50 mL), dried over MgSO4 and the solvent was removed under reduced pressure. The resulting brown solid was triturated in hexane (25 mL), filtered off and washed with hexane to give the title compound as a beige solid (7.73 g, 91%). HPLC (Condition A), Rt: 5.88 min (HPLC purity: 91.9%).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10](Cl)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:28]3[C:23](=[N:24][CH:25]=[N:26][C:27]=3[NH2:29])[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:21]=2)=[CH:16][C:15]=1[O:37][CH3:38]>ClCCl.N1C=CC=CC=1>[NH2:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]2[N:22]([CH:30]3[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]3)[N:21]=[C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:10]([C@@H:8]4[CH2:9][C@H:7]4[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:11])=[C:15]([O:37][CH3:38])[CH:16]=3)[C:28]=12
Reactant: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 88.7 %

Procedure:
trans-2-Phenyl-1-cyclopropanecarbonyl chloride (31 mg, 0.170 mmol) in dichloromethane (0.3 mL) was added to a solution of 3-(4-amino-3-methoxyphenyl)-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (60 mg, 0.17 mmol) in pyridine (1.2 mL) at 0° C. After 5 minutes, the ice-water bath was removed and the reaction mixture was stirred at room temperature for 1 hours then, more trans-2-Phenyl-1-cyclopropanecarbonyl chloride (15 mg, 0.083 mmol) was added. After 2 hours, the solvent was evaporated and the residue was purified by flash column chromatography using dichloromethane/methanol (95:5 to 70:30) as mobile phase to give N1-{4-[4-Amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}-trans-2-phenyl-1-cyclopropanecarboxamide (75 mg, 89%). 1H NMR (CDCl3) δ 1.42 (m, 1H), 1.77 (m, 1H), 1.85 (m, 1H), 2.03 (m, 1H), 2.24 (m, 2H), 2.37 (s, 3H), 2.46 (m, 2H), 2.62 (m, 1H), 3.05 (m, 2H), 3.96 (s, 3H), 4.77 (m, 1H), 5.69 (s, 2H), 7.24 (m, 7H), 8.11 (s, 1H), 8.35 (m, 1H), 8.45 (d, J=8.38 Hz, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=498.3, Rt=1.84 min.