Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2].[N:51]1(C(OC(C)(C)C)=O)[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>C(Cl)Cl>[C:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:51]3[CH2:57][CH2:56][CH2:55][NH:54][CH2:53][CH2:52]3)[CH:10]=2)=[CH:7][C:6]([CH2:17][NH:18][C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:22]=2)=[O:20])=[CH:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C#N)c(-c3cccc(CN4CCCNCC4)c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.1 %

Procedure:
N-[(6-Cyano-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (108 mg, 0.000161 mol) in DCM (4 mL) and 1,1-dimethylethyl hexahydro-1H-1,4-diazepine-1-carboxylate (47 mg, 0.00023 mol) were mixed with sodium triacetoxyborohydride (68.3 mg, 0.00032 mol) and AcOH (11.6 mg, 11 μL). This solution was stirred overnight at room temperature. LC-MS showed that the reaction was complete. The reaction was quenched with sat. aq. NaHCO3, then extracted with DCM (2×). Combined extracts were washed with sat. aq. NaCl, dried (Na2SO4) and concentrated to a glassy foam (238.7 mg). The glassy foam was taken up in DCM (10 mL) containing 25% TFA and allowed to stand at room temperature for 3 h. LC-MS showed the reaction to be complete. Solvent was stripped off. Purification was carried out on Gilson instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic layers were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of DCM and transferred to a vial and pumped down to afford the title compound as a chalky solid [73 mg (60%)]. LC-MS m/z 754.3 (M+H)+.
Reaction SMILES: CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[O:17]1[C:22]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:21][CH2:20][CH2:19][CH2:18]1.Cl>C(Cl)Cl.CO>[CH:22]1([O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: C1CCC2(CC1)OCCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Solvent: CO
Solvent: ClCCl
Product: OCCCOC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.8 %

Procedure:
14.0 ml (14.0 mmol) of a 1M hexane solution of diisobutylaluminum hydride were added dropwise over a period of 5 minutes to a solution of 1.01 g (647 mmol) of 1,5-dioxaspiro[5.5]-undecane in 5 ml of methylene chloride, and the resulting mixture was stirred for 1 hour at room temperature. At the end of this time, the reaction mixture was ice-cooled and 20 ml of methanol were added dropwise over a period of 5 minutes in order to stop the reaction. The mixture was stirred for 20 minutes at room temperature, and then 2N aqueous hydrochloric acid was added to dissolve the precipitate. The mixture was then extracted with diethyl ether. The extract was washed with water, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. The organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 25 g of silica gel, using a 3:1 by volume mixture of diethyl ether and hexane as the eluent, to give 774 mg (yield 76%) of the title alcohol derivative as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7](B2OC(C)(C)C(C)(C)O2)[CH:8]=1)[NH2:5].Br[C:19]1[S:23][CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[Na+].[Na+].N#N>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:19]2[S:23][CH:22]=[N:21][CH:20]=2)[CH:8]=1)[NH2:5]
Reactant: Brc1cncs1
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(N)cc(-c2cncs2)c1
Temperature: 100 °C

Procedure:
3-Methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (20.98 g, 90 mmol), 5-bromothiazole (8.85 mL, 99 mmol), and sodium carbonate (90 mL, 180 mmol) were combined in a flask. 2-Methyl-THF (326 mL) was added and the flask was degassed with N2 for 1.5 h before 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (3.67 g, 4.50 mmol) was added. The reaction was heated to 100° C. overnight and was then cooled to room temperature. The reaction mixture was filtered though a pad of Celite, washing with ethyl acetate. The layers were separated and the aqueous layer was back-extracted with ethyl acetate, dried over Na2SO4, and concentrated. The residue was purified by chromatography (0-40% ethyl acetate in hexanes). 3-Methyl-5-(1,3-thiazol-5-yl)aniline was isolated as a yellowish brown solid (15.33 g, 81 mmol, 90%). MS ESI: [M+H]+ m/z 191.1. 1H NMR (500 MHz, CDCl3) δ 8.71 (s, 1H), 8.02 (s, 1H), 6.80 (s, 1H), 6.71 (s, 1H), 6.50 (s, 1H), 3.71 (s, 2H), 1.79 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[C:6]([O:13][CH3:14])[CH:7]=[CH:8][CH:9]=2)[O:4]1.[CH:15]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][O:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[O:4][CH:3]([CH2:2][NH:1][C:22]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:23])[CH2:12][CH2:11]2
Reactant: COc1cccc2c1OC(CN)CC2
Reactant: O=C(Cl)C1CCCCCC1
Product: COc1cccc2c1OC(CNC(=O)C1CCCCCC1)CC2

Procedure:
The title compound is prepared analogously to the instructions of Example XII from 2-aminomethyl-8-methoxychroman and cycloheptanecarbonyl chloride, and is further reacted directly.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]#[N:20].[N-:21]=[N+:22]=[N-:23].[Na+].[Cl-].[NH4+]>CN(C)C=O>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[NH:7][C:2](=[O:1])[C:3]([C:19]2[NH:23][N:22]=[N:21][N:20]=2)=[CH:4][N:5]=1)[CH:16]([CH3:17])[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)COc1ccccc1-c1ncc(C#N)c(=O)[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)COc1ccccc1-c1ncc(-c2nnn[nH]2)c(=O)[nH]1
Yield: 54.9 %

Procedure:
A mixture of 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)-pyrimidine-5-carbonitrile (3.78 g., 0.014 mole), sodium azide (1.0 g., 0.0154 mole), and ammonium chloride (0.824 g., 0.0154 mole) in N,N-dimethylformamide was heated at 125° for 19 hours stirring. The solvent was removed under reduced pressure. The residue was treated with water (40 ml.). The mixture was acidified with 6N hydrochloric acid with stirring. The mixture was filtered and the collected solid recrystallized from glacial acetic acid to give the title compound (2.4 g., 55% yield), m.p. 230°-231°.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2>>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH:17]=[CH:16]2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1ccc2[nH]ccc2c1
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(F)ccc32)cc1
Yield: 100 %

Procedure:
The title compound was prepared from toluene-4-sulfonyl chloride and 5-fluoro-1H-indole, according to Method A, described above. Yield 100%; mp 106-108° C.; 1H NMR (CDCl3) δ 8.13-8.19 (dd, J=4, 8 Hz, 1H), 7.96 (d, J=8 Hz, 2H), 7.82 (d, J=4 Hz, 1H), 7.40-7.48 (m, 3H), 7.25-77.38 (m,1H), 6.83 (d, J=4 Hz, 1H), 2.55 (s, 3H); 13C NMR (CDCl3) δ 161.9, 158.1, 145.6, 135.4, 132.2, 132.1, 131.6, 130.3, 128.5, 127.2, 115.0, 114.9, 113.2, 112.8, 109.4, 109.3, 107.5, 107.1, 21.9.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(=O)[CH2:12][CH2:11][CH2:10][CH2:9]1.C[Si]([C:18]#[N:19])(C)C>C(O)(=O)C>[C:2]1([NH:1][C:8]2([C:18]#[N:19])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCC1
Reactant: Nc1ccccc1
Reactant: C[Si](C)(C)C#N
Solvent: CC(=O)O
Product: N#CC1(Nc2ccccc2)CCCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
2.9 ml (31.8 mmol) of aniline (starting product 2) are added to a solution of 2.6 ml (29.4 mmol) of cyclopentanone (starting product 3) in 30 ml of acetic acid at 0° C. The solution is stirred for 15 minutes and 4 ml (30 mmol) of trimethylsilyl cyanide are added. The reaction medium is stirred for one night at room temperature and then gently poured into an ice-cold ammonium hydroxide solution while keeping the pH basic and extracted with dichloromethane. The organic phases are collected and washed with water. They are dried over sodium sulfate. The solvents are evaporated and then the residue is chromatographed on silica gel (heptane/ethyl acetate 90/10, v/v). 5 g of 1-phenylaminocyclopentanecarbonitrile are obtained in the form of a clear brown oil. Yield=91%.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5](Cl)=[O:6])[CH2:2][CH3:3].[CH3:11][S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH2:9][CH3:10])[C:5]([N:17]1[CH:18]=[N:19][C:15]([S:12]([CH3:11])(=[O:14])=[O:13])=[N:16]1)=[O:6])[CH2:2][CH3:3]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CS(=O)(=O)c1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(CCC)C(=O)n1cnc(S(C)(=O)=O)n1

Procedure:
Dipropylcarbamoyl chloride (5.5 g.) was added to a solution of 4.4 g. 3-methylsulphonyl-1,2,4-triazole and 6 ml. dry triethylamine in 25 ml. dry tetrahydrofuran and the resulting mixture refluxed for 2.5 hours under anhydrous conditions. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate poured with stirring into 150 ml. ice-cold 0.1N aqueous sodium hydroxide. The precipitated product was collected by filtration, washed with ice-cold water, dried, and crystallized twice from toluene to give 1-dipropylcarbamoyl-3-methylsulphonyl-1,2,4-triazole, m.p. 94°C. Elemental analysis satisfactory.
Reaction SMILES: C(N(CC)CC)C.Cl.[C:9]([NH:13][NH2:14])([CH3:12])([CH3:11])[CH3:10].[CH3:15][O:16][C:17](=[O:28])[C:18]([C:23]([CH:25]1[CH2:27][CH2:26]1)=O)=[CH:19]N(C)C>C(O)C>[CH3:15][O:16][C:17]([C:18]1[CH:19]=[N:14][N:13]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:23]=1[CH:25]1[CH2:27][CH2:26]1)=[O:28]
Reactant: CC(C)(C)NN
Reactant: COC(=O)C(=CN(C)C)C(=O)C1CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1C1CC1
Yield: 36.3 %

Procedure:
Triethylamine (4.8 mL, 34.2 mmol) and tert-butyl hydrazine hydrochloride (1.4 g, 11.4 mmol) were added sequentially to a solution of crude 2-cyclopropanecarbonyl-3-dimethylamino-acrylic acid methyl ester (2.4 g, 11.4 mmol) in ethanol (24 mL). The resulting suspension was mixed well and divided equally into two 25 mL Personal Chemistry Microwave Process Tubes (Biotage AB, Sweden). The tubes were sealed with a septum and submitted to 150 W microwave irradiation using a Personal Chemistry Microwave Synthesis System (Biotage AB, Sweden) at 160° C. for 30 minutes. The reaction mixtures in the two tubes were combined and ethanol was evaporated under reduced pressure. The remaining mixture was partitioned between dichloromethane and water, and the water phase was extracted three times with dichloromethane. The organic phases were combined, concentrated in vacuo, and purified by silica chromatography eluting with a gradient of 10-20% ethyl acetate/hexanes, then 20% ethyl acetate/hexanes to give 1-tert-butyl-5-cyclopropyl-1H-pyrazole-4-carboxylic acid methyl ester (921 mg, 36%). LRMS m/z calcd for C12H18N2O2 (M+H) 223.1, found 223.1.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[NH2:23])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2].C1N=CN([C:30](N2C=NC=C2)=[O:31])C=1>C1COCC1.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([N:15]1[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:30]1=[O:31])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)C[C@H](CCc1ccccc1)Nc1cc(C)ccc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C[C@H](CCc1ccccc1)n1c(=O)[nH]c2ccc(C)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.9 %

Procedure:
To a solution of (S)-3-(2-Amino-5-methyl-phenylamino)-5-phenyl-pentanoic acid ethyl ester (0.84 g, 2.6 mmol) in THF (15 mL) was added CDI (0.50 g, 3.1 mmol). The reaction mixture was stirred at room temperature for 16 h. When the reaction was complete, the reaction mixture was diluted with CH2Cl2 and washed with water. The organic phase was dried over Na2SO4 and concentrated to afford 0.75 g of the desired product as a dark brown solid. The resulting residue was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([NH2:13])=[O:12])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][C:17]([CH:20]=O)([CH3:19])[CH3:18].[NH:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:22]1([CH:20]([NH:13][C:11](=[O:12])[C:10]2[CH:9]=[CH:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:15][CH:14]=2)[C:17]([CH3:18])([CH3:19])[CH3:16])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[N:24]=[N:23]1
Reactant: NC(=O)c1ccc(-c2ccccc2)cc1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(C)(C)C(NC(=O)c1ccc(-c2ccccc2)cc1)n1nnc2ccccc21

Procedure:
4-Phenylbenzamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:27])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:4]1([CH2:1][C:2](=[O:27])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH2:18][CH2:19][CH3:20]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CCCC)CCc2cc(OC)ccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CCCCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-allyl-2-butyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (931 mg, 3.4 mmol) in acetonitrile (10 mL) was treated with benzoquinone (553 mg, 5.12 mmol), palladium(II) acetate (155 mg, 0.69 mmol), water (0.50 mL, 28 mmol), and perchloric acid (70%, ˜0.14 mL, 1.6 mmol). The resulting mixture was stirred overnight at room temperature. The mixture was partitioned between CH2Cl2 (200 mL) and water (100 mL) and the aqueous phase was back-extracted with CH2Cl2 (2×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue (1.17 g) was purified by Biotage™ (Charlottesville, Va.) flash chromatography on a 40S (4×7 cm) silica gel column, eluting with 10:1 to 5:1 hexane-EtOAc. The product-containing fractions were evaporated under vacuum to afford 2-butyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [F:1][C:2]1([F:10])[CH2:6][CH2:5][CH:4]([C:7]([NH2:9])=[O:8])[CH2:3]1.Cl[C:12]([S:14]Cl)=[O:13]>>[F:1][C:2]1([F:10])[CH2:6][CH2:5][CH:4]([C:7]2[O:8][C:12](=[O:13])[S:14][N:9]=2)[CH2:3]1
Reactant: O=C(Cl)SCl
Reactant: NC(=O)C1CCC(F)(F)C1
Product: O=c1oc(C2CCC(F)(F)C2)ns1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask, was placed 3,3-difluorocyclopentane-1-carboxamide (1.5 g, 10.06 mmol, 1.00 equiv), tol (30 mL), chloro(chlorosulfanyl)methanone (2.6 g, 19.85 mmol, 1.97 equiv). The resulting solution was stirred for overnight at 100° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/10-1/30). This resulted in 300 mg of 5-(3,3-difluorocyclopentyl)-2H-1,3,4-oxathiazol-2-one as brown oil.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)#[N:2].I[C:14]1[C:22]2[C:17](=[N:18][CH:19]=[N:20][C:21]=2[NH2:23])[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=1.C([O-])([O-])=O.[Na+].[Na+]>CCO.COCCOC.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>[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([CH:24]([CH3:26])[CH3:25])[N:15]=[C:14]([C:7]3[CH:8]=[CH:9][C:4]([CH2:3][C:1]#[N:2])=[CH:5][CH:6]=3)[C:22]=12
Reactant: CC(C)n1nc(I)c2c(N)ncnc21
Reactant: N#CCc1ccc(B(O)O)cc1
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: CCO
Solvent: COCCOC
Product: CC(C)n1nc(-c2ccc(CC#N)cc2)c2c(N)ncnc21
Temperature: 80 °C

Procedure:
A solution of (4-Cyanomethylphenyl)boronic acid (18 mg, 0.11 mmol) in EtOH (3.3 mL) was added to a solution of 3-iodo-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 0.10 mmol) in DME (12 mL). Pd(PPh3)4 (30 mg, 0.03 mmol) and saturated Na2CO3 (1.9 mL) were added and the reaction was heated to 80° C. under an argon atmosphere overnight. After cooling, the reaction was extracted with saturated NaCl and CH2Cl2. Organic phases were combined, concentrated in vacuo and purified by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA45. ESI-MS (M+H)+ m/z calcd 293.1, found 293.1.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:23])=[O:22])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2)=O.[H-].C([Al+]CC(C)C)C(C)C.C(OCC)(=O)C.Cl>O1CCCC1>[OH:2][CH2:3][C:5]1[S:6][CH:7]=[C:8]2[C:13]=1[C:12](=[O:14])[N:11]([C:15]1[CH:20]=[C:19]([S:21]([N:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)(=[O:22])=[O:23])[CH:18]=[CH:17][C:16]=1[Cl:34])[C:10](=[O:35])[NH:9]2
Reactant: COC(=O)c1scc2[nH]c(=O)n(-c3cc(S(=O)(=O)N4CCCc5ccccc54)ccc3Cl)c(=O)c12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]c2csc(CO)c2c(=O)n1-c1cc(S(=O)(=O)N2CCCc3ccccc32)ccc1Cl
Reaction time: 1 h
Yield: 58.1 %

Procedure:
To a solution of 5-methoxycarbonyl-3-[2-chloro-5-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl]thieno[3,4-d]-pyrimidine-2,4(1H,3H)-dione (0.2 g) in tetrahydrofuran (4 mL) was added diisobutylaluminum hydride (1.01 mol/L toluene solution, 1.5 mL) under ice-cooling, and the mixture was stirred for 1 hour. To the reaction mixture was added ethyl acetate, and the mixture was stirred for 10minutes. To the mixture was added 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.11 g).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][CH:6]=[CH:7][N:8]=1.Br[CH2:10][CH2:11][O:12][CH3:13].O>CN(C=O)C>[CH3:13][O:12][CH2:11][CH2:10][N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[CH3:3]
Reactant: Cc1ncc[nH]1
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCn1ccnc1C
Reaction time: 0.25 h
Yield: 33.3 %

Procedure:
NaH (60%, 620 mg) was added to a solution of 2-methyl-1H-imidazole (1.06 g, 12.95 mmol) in DMF (8 mL). After stirring for 15 minutes, 1-bromo-2-methoxyethane (2.16 g, 15.54 mmol) in DMF (1 mL) was added. The resulting solution was stirred at 80° C. under microwave irradiation for 60 minutes. Water (1 mL) was added and all solvents were removed by high vacuum. EtOAc was added to the residue, stirred for 15 minutes, filtered and concentrated in vacuo to afford the title compound as a colourless oil (604 mg, 33%) that was used directly in the next step.
Reaction SMILES: [OH:1][CH:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:24][CH2:23][C@H:22]([CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1.C(O)(C(F)(F)F)=O>ClCCl>[OH:1][CH:2]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:3][CH2:4][C:5]1[S:9][C:8]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[CH2:20][CH2:21][C@H:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)=[O:12])=[N:7][N:6]=1
Reactant: CC(C)(C)OC(=O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(O)c4ccccc4)s3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(C(=O)Nc3nnc(CCC(O)c4ccccc4)s3)cc2)CC1

Procedure:
0.146 g of tert-butyl trans-(4-{4-[5-(3-hydroxy-3-phenylpropyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetate (0.27 mmol, 1 eq.) is placed in 2 mL of dichloromethane with stirring. 0.4 mL of TFA (5.45 mmol, 20 eq.) is added. After stirring for 4 hours, the reaction medium is evaporated and the residue is chromatographed on silica gel, eluting with a gradient of methanol in dichloromethane ranging from 1% to 10%. The fractions of interest are concentrated, and triturated with ethyl acetate and methanol. 0.020 g of trans-(4-{4-[5-(3-hydroxy-3-phenylpropyl)[1.3.4]thiadiazol-2-ylcarbamoyl]phenyl}cyclohexyl)acetic acid is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][CH:7]=1.[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30]O)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH2:30][O:17][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH2:1])[CH:3]=1)([C:9]([F:10])([F:11])[F:12])[C:13]([F:14])([F:15])[F:16])=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: Nc1cccc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COC(c1cccc(N)c1)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 2-(3-amino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol (1.30 g), (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.04 g), PPh3 (2.64 g) and molecular sieves 4 Å in THF (100 mL) was added DEAD (1.55 mL) slowly. The reaction was stirred at RT for 4 h and at reflux for overnight. After filtration to remove solids, the filtrate was concentrated and the residue was taken into Et2O. The organic phase was washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated to give a crude compound as very viscous brown oil, which was purified by chromatography through silica gel (500 g, 30% to 50% EtOAc in hexanes) to afford (S)-2-[1-(3-amino-phenyl)-2,2,2-trifluoro-1-trifluoromethyl-ethoxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown oil.