Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[S:13]([O-:16])(=[O:15])=[O:14])([O-:3])=[O:2].C(=O)([O-])[O-].[Ag+2:21].CCCCCC.C(OCC)(=O)C>C(#N)C.O>[N+:1]([C:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]=1[S:13]([O-:16])(=[O:14])=[O:15])([O-:3])=[O:2].[Ag+:21]
Reactant: [Ag+2]
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1c(S(=O)(=O)[O-])sc2ccccc12
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: [Ag+]
Reaction time: 216 h

Procedure:
To a solution of mono nitro-benzothiophene-2-sulfonate (0.5177 g, 1.86 mmol) in 50 mL of acetonitrile and 1 mL of water was added silver carbonate (0.6169 g, 2.24 mmol) in portions in darkness. The resulting suspension was stirred overnight for 9 days, until no starting material is shown on the thin layer chromatography with an eluent of hexane/ethyl acetate (1:4). The mixture was filtered through half an inch of Celite° and the solid was washed with 3×40 mL acetonitrile. The organic filtrate was combined and organic solvent was removed via rotary evaporator to dryness and thus afforded 0.668 g of viscous solid with a yield of 98.2%. The resulting compound was not purified for further reactions.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][Br:38])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCCc1ccccc1
Reaction time: 2 h
Yield: 87.6 %

Procedure:
To a solution of 4-phenyl-1-butanol (5.00 g, 33.3 mmol) and CH2Cl2 (250 mL) at 0° C. was added triphenylphosphine (13.1 g, 50.0 mmol) followed by NBS (8.90 g, 50.0 mmol). After stirring at this temperature for 2 h, the mixture was quenched with H2O (50 mL) and extracted with CH2Cl2 (150 mL) The organic layer was washed with brine (40 mL) and dried (Na2SO4). After concentration, the residue was flushed through two quick columns of silica gel using 2% EtOAc/petroleum ether as an eluant to afford 4-phenylbutyl bromide (6.22 g, 88%) as an intermediate.
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[OH:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: COc1ccc(CONC(=O)C(CC(C)C)CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide (220 mg) in dichloromethane (4 ml) was added trifluoroacetic acid (200 μl) and triethylsilane (145 μl). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue was purified on silica gel (eluant:dichloromethane-ether-methanol (8.0:20:0.5) to dichloromethane-methanol (80:20) to give the title compound (88 mg, 56%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](I)[CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:13].[CH3:14][N:15](C)C=O>ClCCl.O.[C-]#N.[Zn+2].[C-]#N.[Pd]>[NH2:13][C:5]1[C:4]2[C:9](=[C:10]([C:14]#[N:15])[CH:11]=[C:2]([Cl:1])[CH:3]=2)[N:8]=[CH:7][N:6]=1
Reactant: Nc1ncnc2c(I)cc(Cl)cc12
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc2c(N)ncnc12
Temperature: 110 °C
Reaction time: 8 h

Procedure:
To an 8 mL screw-cap vial was added 6-chloro-8-iodo-quinazolin-4-amine (450 mg, 1.47 mmol), dimethylformamide (2 mL), zinc cyanide (0.65 equiv., 1.0 mmol, 115 mg), and palladium tetra is(triphenylphosphine), (0.1 equiv., 0.15 mmol), 179 mg). The reaction was capped and shaken at 110° C. overnight. The reaction was cooled to room temperature, diluted with 3 mL of dichloromethane, and 2 mL of water was added. The precipitate that followed was collected by filtration, and washed with water, then dichloromethane yielding 240 mg of 4-amino-6-chloro-quinazoline-8-carbonitrile as a light yellow solid. 1H NMR (400 MHz, DMSO) δ 8.72-8.67 (d, J=2.2 Hz, 1H), 8.54-8.50 (s, 1H), 8.50-8.46 (d, J=2.1 Hz, 1H), 8.29-8.22 (bs, 2H). LCMS M/Z (M+H)=205.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=1.C(O)C>[Zn].C(O)(=O)C>[CH:12]([NH:11][C:4]1[C:5]2[C:6](=[CH:8][S:9][CH:10]=2)[N:7]=[CH:2][N:3]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Nc1nc(Cl)nc2cscc12
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Nc1ncnc2cscc12
Reaction time: 36 h

Procedure:
15 g of zinc powder are introduced into a solution of 3.9 g (0.017 moles) of 2-chloro-4-isopropylamino-thieno[3,4-d]pyrimidine in 150 ml. of absolute ethyl alcohol. 25 ml. of glacial acetic acid are then added drop by drop wilst agitating. When the addition is completed, the agitation is continued for a further 36 hours at ordinary temperature. The reaction mixture is filtered over hyflocel and the filtrate is poured into 700 ml. of iced water. The pH of the solution is adjusted to 8 with sodium hydroxide and it is extracted several times with ether. The ether phase is washed with water to pH 7, it is dried over sodium sulfate and it is then evaporated to dryness. 1.9 g of 4-isopropylamino-thieno[3,4-d]pyrimidine, still containing a little of the initial product, are obtained. After chromatographic separation and recrystallization from ethyl acetate, one obtains 0.8 g (25% of theory) of the purified product which melts at 230°C with decomposition.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([OH:30])(=[O:29])=[O:28])=[O:17])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C@@H:18]2[CH2:24][CH2:23][C@@H:22]3[CH2:25][N:19]2[C:20](=[O:31])[N:21]3[O:26][S:27]([OH:30])(=[O:29])=[O:28])=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OS(=O)(=O)O)cc1

Procedure:
To a mixture of the product of step 3 (34.8 mg, 0.074 mmol) in dry dichloromethane (3 mL) at 0° C. under nitrogen was added trifluoroacetic acid (1.0 mL, 13 mmol). All solids dissolved immediately upon addition of trifluoroacetic acid. the solution was stirred for 1.5 ours at which time LC-MS analysis showed reaction complete. The reaction was concentrated under vacuum and the residue was triturated with ether to remove excess trifluoroacetic acid and organic impurities. The resulting sticky solid was dried under vacuum and stored in the freezer overnight. The crude product was purified by HPLC on a Phenomenex Synergi Polar-RP 80A column to afford the impure title compound as a white solid after lyophilization. The solid was triturated with acetonitrile (3×) to afford the pure title compound as a white solid. LC-MS (negative ionization) m/e 369 (M−H); LC-MS (positive ionization) m/e 354 (M+H—NH3); 1H NMR (600 MHz, D2O; unreferenced) (δ, ppm) 7.53 (2H, d, J=8.5 Hz), 7.46 (2H, d, J=8.5 Hz), 4.23 (2H, br s), 4.11 (2H, s), 3.39 (1H, d, 3=12 Hz), 3.18 (1H, d, J=12 Hz), 2.27-2.31 (1H, m), 2.09-2.14 (1H, m), 1.90-2.00 (1H, m), 1.813-1.89 (1H, m).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8]Br)=[CH:3][CH:2]=1.[S-:16][C:17]#[N:18].[K+]>CO>[C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][S:16][C:17]#[N:18])=[CH:3][CH:2]=1
Reactant: N#C[S-]
Reactant: BrCCc1ccc(-c2ccccc2)cc1
Agent: [K+]
Solvent: CO
Product: N#CSCCc1ccc(-c2ccccc2)cc1
Yield: 74.6 %

Procedure:
Bromine (1.5 ml) was added dropwise to an acetonitrile (60 ml) solution of triphenylphosphine (5 g). After stirring for 5 minutes, an acetonitrile solution (30 ml) of 2-(4-biphenylyl)ethanol (5 g) was added to the reaction mixture. The reaction mixture was stirred at room temperature for one hour and concentrated. Diethyl ether was added to the residue. The supernatant was collected, then dried and concentrated. The residue was purified by silica gel column chromatography (eluent: IPE) to obtain 2-(4-bipenylyl)ethylbromide(6 g). 2-(4-Bipenylyl)ethyl bromide (6 g) was dissolved in methanol (100 ml), which was stirred at 70° C. for 48 hours together with potassium thiocyanate (4.0 g). The reaction mixture was concentrated, and the residue was extracted with ethyl acetate. The organic layer was washed with water, then dried and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain the entitled compound (4.1 g).
Reaction SMILES: [C:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH2:20][CH2:19]2)=[O:17])=[O:9])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2]>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:20][CH2:19]2)=[O:17])=[O:9])=[CH:33][CH:34]=1)(=[NH:2])[NH2:3]
Reactant: CC(C)(C)OC(=O)COC1CCN(C(=O)C2CCCCN2C(=O)c2ccc(C(=N)N)cc2)CC1
Solvent: ClCCl
Product: N=C(N)c1ccc(C(=O)N2CCCCC2C(=O)N2CCC(OCC(=O)O)CC2)cc1

Procedure:
A solution of 700 mg of t-butyl [[1-[[1-(p-amidinobenzoyl)-2-piperidinyl]carbonyl]-4-piperidinyl]oxy]acetate in 20ml of dichloromethane and 20 ml of trfluoroacetic acid is stirred at room temperature for 3 hours and evaporated. The residue is dissolved in ethanol and treated with ether. Suction filtration and drying of the precipitate and chromatography on silica gel (RP-18, water/THF 9:1) gives 111 mg of [[1 -[[1 -(p-amidino-benzoyl)-2-piperidinyl]carbonyl]-4-piperidinyl]oxyacetic acid. M.p. 233°-234° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:3]=1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:38]1[CH2:42]OC[CH2:39]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[C:3]=1[CH:23]([CH2:39][CH2:38][CH3:42])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCCI
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)c(Cl)c1)CCCC3
Yield: 80.9 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(3,4-dichlorophenyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]acetate (0.190 g; 0.46 mmol), LHMDS 1N in THF (0.5 mL; 0.5 mmol), 1-iodopropane (0.067 mL; 0.69 mmol) in DMF (1.8 mL) for 18 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (2-30%) in heptane furnished 0.172 g (82%) of the title compound as a yellow oil.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Br:5][C:6]1[CH:7]=[C:8]2[C:12](=[N:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.[CH2:15]([S:18]([NH:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26])(=[O:20])=[O:19])[CH2:16][CH3:17].O>C(Cl)Cl>[Br:5][C:6]1[CH:7]=[C:8]2[C:9]([C:25]([C:24]3[CH:23]=[C:22]([NH:21][S:18]([CH2:15][CH2:16][CH3:17])(=[O:20])=[O:19])[CH:30]=[CH:29][CH:28]=3)=[O:26])=[CH:10][NH:11][C:12]2=[N:13][CH:14]=1
Reactant: CCCS(=O)(=O)Nc1cccc(C(=O)Cl)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(=O)c2c[nH]c3ncc(Br)cc23)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To aluminum trichloride (4.8 g, 36.0 mmol) in methylene chloride (70.0 mL), under an atmosphere of nitrogen, was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (67, 797 mg, 4.04 mmol) dissolved in methylene chloride (5.0 mL). The reaction was stirred at room temperature for 30 minutes, followed by addition of 3-(propane-1-sulfonylamino)-benzoyl chloride (77, 1.10 g, 4.20 mmol) dissolved in methylene dichloride (4.0 mL). The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (P-1116, 300.0 mg). MS (ESI) [M−H+]−=420.1, 422.1.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][CH2:10][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])(=[O:3])[CH3:2].[C:32](OCC)(=O)C.CCCCCC>C(Cl)(Cl)Cl>[OH:3][C:1]([C:4]1[C:12]2[O:11][CH2:10][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:8]=2[C:7]([CH3:22])=[C:6]([NH:23][C:24](=[O:30])[CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]=1[CH3:31])([CH3:32])[CH3:2]
Reactant: CC(=O)c1c(C)c(NC(=O)CC(C)(C)C)c(C)c2c1OC[C@@H]2c1ccc(C(C)C)cc1
Reactant: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c(C(C)(C)O)c2c1[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 82 %

Procedure:
Using (+)-N-((3R)-7-acetyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 38, the title compound was synthesized in the same manner as in Example 22. Yield: 82%. Melting point: 141-142° C. (ethyl acetate-hexane). [α]D20=+40.8° (c=0.46, chloroform).
Reaction SMILES: [H-].[Na+].C([N:11]1[CH2:28][CH2:27][CH:15]2[N:16]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]=4[CH:14]2[CH2:13][CH2:12]1)[CH:19]([OH:26])[CH2:18][CH2:17]3)(=O)C1C=CC=CC=1.I[CH3:30]>CN(C=O)C>[CH3:30][O:26][CH:19]1[C:20]2[C:25]3=[C:24]([CH:14]4[CH2:13][CH2:12][NH:11][CH2:28][CH2:27][CH:15]4[N:16]3[CH2:17][CH2:18]1)[CH:23]=[CH:22][CH:21]=2
Reactant: O=C(c1ccccc1)N1CCC2c3cccc4c3N(CCC4O)C2CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1CCN2c3c1cccc3C1CCNCCC12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.8 %

Procedure:
NaH (60% dispersion in mineral oil, 0.50g, 1.2 mmol) was added to a solution of 10-benzoyl-5,6,8,9,10,11,12,12a-octahydro-4H,7aH-azepino[4′,5′:4,5]pyrrolo[3,2,1-ij]quinoline-4-ol (0.20 g, 0.58 mmol) in DMF (5.0 mL) at 0° C. under N2. After 30 min, iodomethane (0.040 mL, 0.64 mmol) was added. The reaction was quenched with saturated aqueous NH4Cl after 1 h and then allowed to warm to room temperature prior to extracting with EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, decanted, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography with EtOAc/heptanes (2:1) to give 0.16 g (79%) of the title compound as a beige foam. 1H NMR (CDCl3) δ 7.46-7.30, 6.94, 4.51, 4.22-4.03, 4.01-3.79, 3.65-3.41, 3.29, 3.12, 3.04, 2.90, 2.82, 2.34, 2.08; IR (drift) 1631, 1493, 1477, 1459, 1422, 1370, 1359, 1324, 1292, 1267, 1098, 1085, 786, 748, 706 cm−1; HRMS (FAB) calcd for C23H24N2O2+H 361.1916, found 361.1913.
Reaction SMILES: C(O[C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:6])(C)C.[CH3:31][NH2:32]>>[CH3:31][NH:32][C:5]([CH:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(=[O:13])=[O:14])=[O:6]
Reactant: CC(C)OC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reactant: CN
Product: CNC(=O)C1CCCN1S(=O)(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Reaction time: 8 h

Procedure:
0.57 g of 1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid isopropyl ester ( ) was stirred in 20 mL methyl amine (40% wt in water) at 100° C. in a sealed tube for 5 days. The methyl amine was allowed to evaporate and the residual aqueous solution was left to stand overnight uncapped. The following morning, a white precipitate was present, which was collected by vacuum filtration. The precipitate was washed with water and hexanes. The original aqueous solution was then extracted twice with ethyl, acetate. The organic layer was then dried over sodium sulfate and concentrated in vacuo to afford more product. 0.31 g of the title compound was collected as a white solid; mp 137-139° C.; 1H NMR (CDCl3) δ 1.52-1.72 (m, 5H), 1.81 (t, J=5.82 Hz, 4H), 2.15-2.20 (m, 1H), 2.86 (d, J=4.95 Hz, 3H), 3.08-3.55 (m, 1H), 3.49-3.55 (m, 4H), 4.00 (s, 4H), 6.89-6.94 (m, 2H), 6.99-7.01 (m, 1H), 7.61-7.73 (m, 2H); MS (ES) m/z 410.0 (MH+); HRMS for C19H27N3O5S: 410.1740
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CCNC1
Solvent: CC#N
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCC1

Procedure:
A solution of 4-bromobenzenesulphonyl chloride (0.5 g) and pyrrolidine (0.284 g) in acetonitrile (5 ml) were stirred at RT for 48 h then partitioned between ethylacetate and water. The organics were separated, washed with water, dried and evaporated under reduced pressure. The residue was triturated with isohexane and filtered, yield 0.5 g.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=2[C:11]#[N:12])[C:5]([Cl:18])=[CH:4][N:3]=1.[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:18][C:5]1[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:7][C:2]([NH:25][C:23]2[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH3:19])[CH:24]=2)=[N:3][CH:4]=1
Reactant: N#Cc1cc(F)ccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1cc(N)n(C(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(F)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Yield: 12.8 %

Procedure:
To a solution of 2-[(2,5-dichloro-4-pyridinyl)amino]-5-fluorobenzonitrile (7.09 g, 25.1 mmol) and 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (3.5 g, 25.1 mmol) in 1,4-dioxane (100 mL) was added cesium carbonate (24.58 g, 75 mmol) and the reaction mixture was degassed. DPEPhos (1.083 g, 2.012 mmol) was added followed by palladium acetate (0.226 g, 1.006 mmol) and the reaction mixture was heated to reflux overnight. The suspension was then filtered. The dioxane was evaporated off. The solid was purified by flash column chromatography on silica gel (10% DCM: EtOAC). Fractions were collected and evaporated. The yellow oil was dissolved in diethyl ether, sonicated and filtered. 2-[(5-Chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]-5-fluorobenzonitrile (1.3 g, 3.21 mmol, 12.76% yield) was isolated as a white solid; 1H NMR (400 MHz, METHANOL-d4) ppm 1.35 (d, J=6.82 Hz, 6 H) 2.20 (s, 3 H) 4.43 (quin, J=6.69 Hz, 1 H) 5.82 (s, 1 H) 5.89 (s, 1 H) 7.47-7.57 (m, 2 H) 7.61-7.74 (m, 1 H) 7.88 (s, 1 H); HPLC Rt=2.40 min, MS (ESI): 385.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C[N:26]1CCOCC1.[OH-].[NH4+]>C1COCC1.[Cl-].[Na+].O>[NH2:26][C:10]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)C(C)(C)C
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(N)=O)C(C)(C)C
Temperature: -15 °C
Reaction time: 0.25 h
Yield: 93.2 %

Procedure:
A stirred solution of Example 22A (1.81 g, 7.83 mmol) in THF (20 mL) at−40° C. was treated with isobutyl chloroformate (1.01 mL, 7.83 mmol) followed by N-methylmorpholine (0.860 mL, 7.83 mmol). After 15 minutes, the milky white reaction mixture was treated dropwise with ammonium hydroxide (6.0 mL of 30% reagent, 15.0 mmol), the reaction flask was warmed to −15° C., stirred for 45 minutes, treated with brine (20 mL), and the clear homogeneous mixture was extracted with ethyl acetate (2×40 mL). The organic portions were combined, washed with aqueous KHSO4 solution (15 mL), aqueous NaHCO3 solution (15 mL), and brine (15 mL), and dried (MgSO4). Filtration and removal of solvent provided 1.68 g of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9](Br)[N:8]([CH2:22][CH2:23][C@@H:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH:25]=[CH2:26])[C:4]=2[N:5]=[CH:6][N:7]=1.C12BC(CCC1)CCC2.[OH-].[Na+]>C1COCC1.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>[NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:9]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[CH2:23][CH2:22][N:8]3[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C=C[C@@H](CCn1c(Br)c(-c2cnc3ccccc3c2)c2c(N)ncnc21)NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CCc2c(-c3cnc4ccccc4c3)c3c(N)ncnc3n2CC1
Reaction time: 1 h
Yield: 52 %

Procedure:
(R)-tert-Butyl (5-(4-amino-6-bromo-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pent-1-en-3-yl)carbamate (994 mg) obtained in Step 7 was added to a solution of 9-borabicyclo[3.3.1]nonane in 0.5 M THF (22.8 ml) at room temperature. The mixture was stirred at the same temperature for 1 hour, and a 4 N aqueous sodium hydroxide solution (5.7 ml) was carefully added thereto. After nitrogen purging, the mixture was heated to have an internal temperature of 55° C. Tetrakis(triphenylphosphine)palladium (275 mg) was added thereto, and the mixture was stirred at an internal temperature of 66° C. for 15 hours. After cooling the reaction mixture, the organic layer was separated, and toluene (7.7 ml) and a 20% aqueous ammonium chloride solution (5 ml) were added thereto. The organic layer was separated, washed with a 20% saline solution, and SH silica gel (produced by Fuji Silysia, 1 g) was added thereto. The mixture was stirred at an internal temperature 68° C. for 1 hour, and SH silica gel (produced by Fuji Silysia, 1 g) was added thereto. The mixture was stirred at an internal temperature of 68° C. for 1 hour. After cooling, the silica gel was filtered off, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate/methanol) to obtain the title compound as a yellow solid (439 mg).