Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:14]([Br:15])=[CH:13][N:12]=[C:11]3[NH:16][CH:17]=[C:18]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[C:10]=23)[CH2:4]1.C(OC)(OC)OC.CCN(C(C)C)C(C)C.[CH:44]1([CH:47]=O)[CH2:46][CH2:45]1.[BH4-].[Na+]>CO.O>[ClH:1].[Br:15][C:14]1[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([NH:2][CH2:47][CH:44]3[CH2:46][CH2:45]3)[CH2:4]2)=[C:10]2[C:18]([NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=3)=[CH:17][NH:16][C:11]2=[N:12][CH:13]=1
Reactant: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4cccnc4)c23)C1
Reactant: O=CC1CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: COC(OC)OC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NCC4CC4)C3)c12)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70.6 %

Procedure:
(R)—N-(4-(3-Aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride (0.075 g, 0.14 mmol, Example 1A), trimethyl orthoformate (0.32 mL, 2.9 mmol), and DIEA (0.100 mL, 0.57 mmol; d 0.742) were placed in MeOH (3 mL). Cyclopropanecarbaldehyde (0.022 mL, 0.29 mmol) was then added, and the reaction was stirred at room temperature for 18 hours. NaBH4 (0.014 g, 0.36 mmol) was then added, and the reaction was stirred for 1 hour. The reaction was then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by reverse phase HPLC (0-50% ACN in water, Gilson system). The purified product was then dissolved in DCM (with minimal MeOH to aid solubility) and added dropwise to a stirring solution of 1M HCl in ether. The resulting solid was filtered, dried and collected to give (R)—N-(5-bromo-4-(3-(cyclopropylmethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide hydrochloride salt (0.050 g, 60% yield). 1H NMR (400 MHz, D2O) δ 8.98-8.98 (m, 1H), 8.65-8.64 (m, 1H), 8.52-8.50 (m, 1H), 8.12 (s, 1H), 7.74-7.71 (m, 1H), 7.27 (s, 1H), 3.54-3.51 (m, 1H), 3.18-3.04 (m, 3H), 2.97-2.92 (m, 1H), 2.69-2.55 (m, 2H), 1.82-1.78 (m, 1H), 1.55-1.52 (m, 1H), 1.40-1.30 (m, 1H), 1.21-1.17 (m, 1H), 0.74-0.68 (m, 1H), 0.36-0.32 (m, 2H), 0.05-0.00 (m, 2H); LCMS (APCI+) m/z 469, 471 (M+H)+.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]5[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:22][CH:21]=4)[CH3:19])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]4[C:27]([C:32]#[N:33])=[CH:28][CH:29]=[CH:30][CH:31]=4)=[CH:22][CH:21]=3)[CH3:19])=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]3[N:37]=[CH:38][CH:39]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1c(C(C)c2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 4′-{1-[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]ethyl}biphenyl-2-carbonitrile (0.37 g) in tetrahydrofuran (4 mL) was added 3M hydrochloric acid (4 mL), and the mixture was stirred at 60° C. for 3 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 1 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (3 mL)-tetrahydrofuran (3 mL). Thereto was added sodium borohydride (0.026 g) at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.33 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[CH:9][N:10]=[C:4]2[CH:3]=1.[CH3:11][NH:12][C:13]([C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1)=[O:14].O.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[N:10]1[CH:9]=[CH:8][N:5]2[CH:6]=[CH:7][C:2]([C:19]3[CH:20]=[C:15]([CH:16]=[CH:17][CH:18]=3)[C:13]([NH:12][CH3:11])=[O:14])=[CH:3][C:4]=12
Reactant: CNC(=O)c1cccc(B(O)O)c1
Reactant: Brc1ccn2ccnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CNC(=O)c1cccc(-c2ccn3ccnc3c2)c1

Procedure:
7-Bromo-imidazo-[1,2-a]-pyridine (1 eq, 0.5 mmol, 100 mg) and (3-methylamino carbonylphenyl)boronic acid (1.1 eq, 0.558 mmol, 99.9 mg) are dissolved in DME (3 ml) and water (0.8 ml) and Na2CO3 (3 eq, 1.52 mmol, 161 mg) is added. PdCl2(PPh3)2 (0.05 eq, 0.025 mmol, 17.8 mg) is then added and the reaction mixture is heated using microwave radiation at 120° C. for 10 min. At the completion of this time the solvent is removed in vacuo and the reaction mixture is purified by flash column chromatography eluting with 9:1 DCM/MeOH to yield 3-imidazo[1,2-a]pyridine-7-yl-N-methyl-benzamide as a brown solid; [M+H]+=252
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([CH3:22])([CH3:21])[CH:5]2O.FC(F)(F)C(O)=O>C([SiH](CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1)[C:6]([CH3:22])([CH3:21])[CH2:5]2
Reactant: CC1(C)C(O)c2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a mixture of 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (14.3 g, 43 mmol) and triethylsilane (20 mL) at 25° C. was added trifluoroacetic acid (5 mL) dropwise. The resulting mixture was stirred at 25° C. for 1 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with saturated aqueous sodium bicarbonate solution (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Purification on flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company)(10% ethyl acetate/hexanes) to afford 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (10.5 g, 77%) as a white solid: LC/MS m/e calcd for C17H17ClN2O2 (M+H)+: 317.79, observed: 317.0.
Reaction SMILES: C(Cl)Cl.C(=[N:11][N:12]1[CH2:16][CH2:15][N:14]([C@@:17]2([C:35]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=3)=[O:36])[S:23][C@H:22]3[N:19]([C:20](=[O:34])[C@H:21]3[NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18]2)[C:13]1=[O:48])C1C=CC=CC=1.[N+](C1C=C([N+]([O-])=O)C=CC=1NN)([O-])=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[NH2:11][N:12]1[CH2:16][CH2:15][N:14]([C@@:17]2([C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=3)=[O:36])[S:23][C@H:22]3[N:19]([C:20](=[O:34])[C@H:21]3[NH:24][C:25](=[O:33])[CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:18]2)[C:13]1=[O:48]
Reactant: O=C(Cc1ccccc1)N[C@@H]1C(=O)N2C[C@@](C(=O)OCc3ccc([N+](=O)[O-])cc3)(N3CCN(N=Cc4ccccc4)C3=O)S[C@H]12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NNc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: NN1CCN([C@]2(C(=O)OCc3ccc([N+](=O)[O-])cc3)CN3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3S2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
In a mixed solvent consisting of 30 ml of methylene chloride and 15 ml of methanol was dissolved 3.00 g of (3R,5R,6R)-3-(3-benzylideneamino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0]heptane. To the solution were added 1.89 g of 2,4-dinitrophenylhydrazine and 850 mg of p-toluenesulfonic acid monohydrate in this order. The mixture was stirred at room temperature for 1.5 hours. Then, the insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was mixed with a mixed solvent consisting of 30 ml of methylene chloride and 7 ml of methanol. The insolubles were removed by filtration. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluant: chloroform/methanol=100/1 to 25/1) to obtain 1.56 g (yield: 60.5%) of (3R,5R,6R)-3-(3-amino-2-oxoimidazolidin-1-yl)-3-(p-nitrobenzyloxycarbonyl)-7-oxo-6-phenylacetamido-4-thia-1-azabicyclo[3.2.0] heptane.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=O)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl.[CH3:24][NH:25][CH3:26].C([BH3-])#N.[Na+].C(=O)([O-])O.[Na+]>CO.O1CCCC1>[CH3:24][N:25]([CH3:26])[CH2:21][CH:20]=[CH:19][C:11]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[NH:9][CH:10]=1
Reactant: CNC
Reactant: O=CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 56.1 %

Procedure:
700 mg (2.38 mmol) of 3-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrol-4-yl]acrylaldehyde [prepared as described in step 66 (i) above] and 1.95 g (23.8 mmol) of dimethylamine hydrochloride were dissolved in 110 ml of a 1:1 by volume mixture of methanol and tetrahydrofuran, after which 226 mg (3.59 mmol) of sodium cyanotrihydridoborate were added to the solution. The resulting mixture was stirred at room temperature for 19 hours. At the end of this time, the reaction mixture was added to a saturated aqueous solution of sodium hydrogencarbonate and then this was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The residue thus obtained was purified by chromatography on a silica gel column using a 20:1:1 by volume mixture of ethyl acetate, methanol and isopropylamine as the eluant to give 429 mg (yield 56%) of the title compound as a white powder.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1.[H-].[Na+].C1C[O:37]CC1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:37])[C:15]=2[C:14]([C:24]#[N:25])=[C:13]([N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:12]=1
Reactant: C1CCOC1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1Cc1ccccc1-2
Agent: [H-]
Agent: [Na+]
Product: N#Cc1c(N2CCCCC2)cc(-c2ccc3ccccc3c2)c2c1C(=O)c1ccccc1-2
Temperature: 2.5 °C

Procedure:
A solution of 4-(naphthalen-2-yl)-2-(piperidin-1-yl)-9H-fluorene-1-carbonitrile (400 mg) in THF was added sodium hydride (32 mg) and was stirred at 0-5° C. for less than five minutes. After completion, the reaction solvent was evaporated under vacuum and the crude solid obtained was quenched with ice water and subsequently neutralized by dilute HCL. The precipitate thus obtained was filtered and purified on a silica gel column using ethyl acetate-hexane as eluent. Light red solid; mp 182-184° C.; ESIMS 415 (M++1); IR (KBr) 2213 (CN), 1695 cm−1 (CO).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15](CC3C=CC(OC)=CC=3)[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:31]#[N:32])=[CH:4][N:3]=1.[CH3:33][O:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:36]=1B(O)O>>[C:31]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([S:12]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][N:17]=3)(=[O:13])=[O:14])[CH:7]=2)[C:2]([C:36]2[CH:37]=[CH:38][C:39]([C:41]([F:44])([F:43])[F:42])=[CH:40][C:35]=2[O:34][CH3:33])=[N:3][CH:4]=1)#[N:32]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc3c(Cl)ncc(C#N)c3c2)cc1
Reactant: COc1cc(C(F)(F)F)ccc1B(O)O
Product: COc1cc(C(F)(F)F)ccc1-c1ncc(C#N)c2cc(S(=O)(=O)Nc3ccncn3)ccc12

Procedure:
The title compound was prepared in an analogous manner to that of Example 228, except that 1-chloro-4-cyano-N-(4-methoxybenzyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide and (2-methoxy-4-(trifluoromethyl)phenyl)boronic acid were used as the coupling partners. The final compound was purified via column chromatography (12 g silica gel column, gradient elution 50 to 100% EtOAc:Heptane) to afford 4-cyano-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=9.30 (s, 1H), 8.68-8.51 (m, 2H), 8.14 (d, J=9.6 Hz, 1H), 7.91 (d, J=8.7 Hz, 1H), 7.67-7.60 (m, 1H), 7.59-7.49 (m, 2H), 3.76 (s, 3H). m/z (ESI) 486.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](OB(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Reactant: COc1cccc(OB(O)O)c1
Product: COc1cccc(-c2ccc(S(=O)(=O)n3cccc3)s2)c1
Yield: 93 %

Procedure:
N-[5-(3-methoxyphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 32C from 3-methoxyphenylboric acid and N-(5-bromothiophene-2-sulfonyl)pyrrole in 93% yield. This was purified by recrystallization using hexane/ethyl acetate as solvent.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=O)[CH2:16][CH2:15][S:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O=P(Cl)(Cl)Cl>C(#N)C.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH3:11])=[CH:8][C:7]2[C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=3)=[N:18][C@@H:17]3[CH2:16][CH2:15][S:14][CH2:13][C@@H:12]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc([C@H]2CSCC[C@H]2NC(=O)c2ccc(C(=O)OC)cc2)ccc1OC
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCSC[C@H]21

Procedure:
To a suspension of methyl 4-{[(3R,4R)-3-(3-ethoxy-4-methoxyphenyl)tetrahydro-2H-thiopyran-4-yl]carbamoyl}benzoate (20.5 g; compound C12) and potassium carbonate (6.6 g) in ACN (400 ml) is slowly added a solution of POCl3 (13.2 ml) in CAN (50 ml) at 0° C. Subsequently the mixture is heated under reflux for 17 h. The reaction is quenched by addition of water (300 ml) at RT and the pH value is adjusted to pH 7.6 by addition of a 40% aqueous sodium hydroxide solution. The acetonitrile is removed in vacuo and diethyl ether is added to the suspension. The pH is adjusted to pH 8.6 by further addition of a 40% aqueous sodium hydroxide solution and a saturated solution of sodium hydrogen carbonate. After extraction the organic phase is separated, washed with water and dried over sodium sulfate. Filtration and evaporation of the solvent give a solid that is purified by flash chromatography (silica gel, eluation gradient: n-hexane/isopropyl acetate, 19/1 to 12/8 (v/v)) to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:5]1[CH:10]=[CH:9][C:8]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[CH:7][CH:6]=1)=[O:12])[CH3:2]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A mixture of 4-bromobenzoic acid ethyl ester (2.7 mL, 16.5 mmol), 4-methoxy phenylboronic acid (2.5 g, 16.5 mmol) and sodium carbonate (7.7 g, 72.6 mmol) in toluene:ethanol:water (75 mL:37 mL:37 mL) was flushed with nitrogen for 1 hour. After addition of the tetrakis(triphenylphosphine) palladium (0) catalyst (0.95 g, 0.82 mmol), the reaction was heated at 100° C. overnight. After cooling, the mixture was filtered through Celite which was then washed with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a brown solid. Purification of the residue by flash chromatography with a solvent gradient from 25% to 50% of dichloromethane in hexane provided the title compound (4.05 g, 95.8%) as a pale yellow solid, m.p. 101-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]=[O:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH2:20][OH:21])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2C=O)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2CO)CC1
Yield: 95 %

Procedure:
A solution of 1.15 g (3.96 mmol) of 1-t-butoxycarbonyl-4-(2-formyl-phenyl)-piperazine in 10 mL of MeOH was treated with 0.15 g (3.96 mmol) of NaBH4. After 2 h the reaction was quenched by adding 1.2N HCl and the mixture was extracted with EtOAc. The EtOAc solution was washed with water, brine and dried. The filtrate was concentrated to yield 1.1 g (95%) of 1-t-butoxycarbonyl-4-(2-hydroxymethyl-phenyl)-piperazine as a white foam which was used without purification.
Reaction SMILES: [N:1]1[C:11]2[NH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])=[O:22].O>CC(N(C)C)=O>[O:22]=[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:29])[CH2:20][N:6]1[C:7](=[O:16])[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[NH:10][C:11]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1Nc2cccnc2Nc2ccccc21
Reactant: Cc1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccccc1C(=O)CN1C(=O)c2ccccc2Nc2ncccc21
Temperature: 0 °C

Procedure:
5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.0 g, 1 eq.) was suspended in dimethylacetamide (DMA) (30 mL). The reaction was cooled to 0° C. and sodium hydride (60% in mineral oil) (380 mg, 2.0 eq.) was added. The reaction was warmed to room temperature and stirred until gas evolution ceased. The reaction was cooled to 0° C. and 2-bromo-1-(o-tolyl)ethanone (1.2 g, 1.2 eq.) was added. The reaction was stirred at 50° C. overnight. The reaction was poured onto 80 mL water and extracted with dichloromethane (2×100 mL). The organic extracts were combined, washed with water (2×100 mL), brine (2×100 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product, 5-(2-oxo-2-(o-tolyl)ethyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (0.65 g) was used without purification. LCMS: 344 [M+H].
Reaction SMILES: [C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH2:7]([CH:8]1[O:20][CH:9]1[CH2:10][OH:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC/C=C/Cc1ccccc1
Solvent: ClCCl
Product: OCC1OC1Cc1ccccc1
Reaction time: 8 h
Yield: 86.7 %

Procedure:
To a solution of allylic alcohol 7 (5.0 g, 33.7 mmol) in dry CH2Cl2 (60 mL) at 0° C. was added m-chloroperbenzoic acid (8.7 g, 50.6 mmol) in small portions. The resulting solution was stirred for 8 h until complete consumption of starting materials (the progress of the reaction was monitored by TLC). The reaction mixture was quenched with water and the aqueous layer was extracted with CH2Cl2 (3×30 mL). The organic layer was washed with aq. 10% solution of NaHCO3 (15 mL). The combined organic layer was dried over anhydrous Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography over silica gel using petroleum ether/EtOAc (4:1) to give the corresponding epoxide 8 (4.8 g, 88%) as a viscous gum. IR: (CHCl3, cm−1): νmax 700, 991, 1028, 1055, 1106, 1452, 2921, 3404; 1H NMR (200 MHz, CDCl3): δ 2.88-2.99 (m, 3H), 3.17-3.23 (m, 1H), 3.57-3.72 (m, 1H), 3.85-3.95 (m, 1H), 7.18-7.34 (m, 5H); 13C NMR (50 MHz, CDCl3): δ 34.2, 67.1, 78.9, 87.5, 125.5, 127.5, 128.4, 140.8; Anal. Calcd for C10H12O2: C, 73.15; H, 7.37. Found: C, 73.25; H, 7.47%.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([OH:21])=O)[N:11]=[C:12]([C:13]3[NH:14][CH:15]=[CH:16][N:17]=3)[C:5]=12.Cl.Cl.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][C:26]=1[O:37][CH3:38].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC(=CC1=2)Cl)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH2:18][C:19]([N:34]3[CH2:33][CH2:32][N:31]([C:28]4[CH:29]=[CH:30][C:25]([Cl:24])=[C:26]([O:37][CH3:38])[CH:27]=4)[CH2:36][CH2:35]3)=[O:21])[N:11]=[C:12]([C:13]3[NH:17][CH:16]=[CH:15][N:14]=3)[C:5]=12
Reactant: COc1cc(N2CCNCC2)ccc1Cl
Reactant: Nc1ncnc2c1c(-c1ncc[nH]1)nn2CC(=O)O
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)Cn3nc(-c4ncc[nH]4)c4c(N)ncnc43)CC2)ccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
[4-Amino-3-(1H-imidazol-2-yl)pyrazolo[3,4-d]pyrimidin-1-yl]acetic acid dihydrochloride (79 g, 0.238 mol) and 1-(4-chloro-3-methoxyphenyl)piperazine dihydrochloride (71.3 g, 0.238 mol) were suspended in anhydrous DMF (793 mL) and cooled in an ice bath. N,N-diisopropylethylamine (290 mL, 1.67 mol) was added and the mixture was stirred at room temperature until all solids dissolved to form a brown solution. HCTU (113.23 g, 0.273 mol) was added in portions over 10 min while maintaining the internal temperature below 20° C. After 3 h, the reaction mixture was poured slowly into a flask of vigorously stirred ice water (6 L) to give a suspension, which was stirred for 1 h, filtered, and washed with saturated NaHCO3 (500 mL×2) and water (500 mL×2). The solid was purified by trituration in refluxing MeCN (2×500 mL) to provide 2-[4-amino-3-(1H-imidazol-2-yl)-pyrazolo[3,4-d]pyrimidin-1-yl]-1-[4-(4-chloro-3-methoxyphenyl)piperazin-1-yl]ethanone (90.5 g, 81% yield, >98% pure by LC-MS). 1H NMR (400 MHz, d6-DMSO) δ 13.0 (s, 1H), 10.14 (d, 1H, J=3.7 Hz), 8.16 (s, 1H), 7.95 (d, 1H, d, J=3.7 Hz), 7.25 (dd, 1H, J=1.03 and 1.36 Hz), 7.20 (d, 1H, J=8.8 Hz), 7.16 (s, 1H), 6.70 (d, 1H, J=2.4 Hz), 6.52 (dd, 1H, J=2.4 and 8.8 Hz), 5.37 (s, 2H), 3.83 (s, 3H), 3.74 (t, 2H, J=4.8 Hz), 3.58 (t, 2H, J=4.8 Hz), 3.28 (t, 2H, J=4.8 Hz), 3.17 (t, 2H, J=4.8 Hz). 13C NMR (100.6 MHz, d6-DMSO) δ 165.3, 159.0, 157.3, 155.7, 155.5, 151.6, 141.2, 136.6, 130.3, 128.7, 119.0, 111.9, 109.0, 101.9, 98.0, 56.7, 49.4, 48.9, 48.8, 44.7, 42.1; IR (KBr) 3219, 2937, 1682, 1638, 1594, 1567 cm−1; MS (ES) m/z 468.1 (M+H+). Anal. Calcd for C21H22N9O2Cl-0.85 H2O: C, 52.20; H, 4.94; N, 26.09; Cl, 7.34. Found: C, 51.92; H, 4.68; N, 26.44; Cl, 7.18.