Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.BrC1C(N2CCN([CH:52]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])CC2)=C([N+]([O-])=O)C(N)=NC=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>C(O)C.CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23]([CH:52]([C:54]3[CH:55]=[N:56][CH:57]=[CH:58][CH:59]=3)[CH3:53])[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(c1cccnc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CC(c1cccnc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 16 h
Yield: 13 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-3-yl)ethyl)piperazin-1-yl)pyridin-2-amine (300 mg, 0.73 mmol), DMF (4.4 mL), ethanol (0.6 mL), 1M Na2S2O4 (3 eq, 2.19 mmol, 2.19 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.1 eq, 0.81 mmol, 121 mg). After 16 h, concentration in vacuo and column chromatography (EtOAc-DCM-MeOH, 50:50:2) gave the product (49 mg, 13%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 1.39 (d, J=6.6 Hz, 3H, CHCH3), 2.51-2.67 (2 m, 4H, piperazine N(CH2)2), 3.00 (s, 6H, N(CH3)2), 3.58-3.66 (m, 5H, piperazine N(CH2)2 & CHCH3), 6.81 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 7.39 (dd, J=7.6, 4.8 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.00 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.13 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.48 (d, br, J=4.4 Hz, 1H, pyridine H-6), 8.58 (br s, 1H, pyridine H-2), 13.11 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[Cl:23][C:24]1[CH:36]=[CH:35][C:27]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Br)=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][O:28][C:27]3[CH:26]=[CH:25][C:24]([Cl:23])=[CH:36][CH:35]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: Clc1ccc(OCCCCCBr)cc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCOc2ccc(Cl)cc2)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.3 g) as starting compound and 5-(4-chlorophenoxy)-pentyl bromide (1.0 g) were reacted and treated in the same manner as in Example 168 to give 4-amino-5-chloro-N-((1-(5-(4-chlorophenoxy)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25](Cl)(=[O:27])=[O:26])([O-:15])=[O:14].N1C=CC=CC=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[N+:13]([C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[CH:18][C:17]=1[S:25]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)(=[O:27])=[O:26])([O-:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COC(=O)c1ccc(CNS(=O)(=O)c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A solution of methyl 4-(aminomethyl)benzoate (1.00 g, 4.96 mmol), 2,4-dinitrobenzenesulfonyl chloride (1.39 g, 5.21 mmol), DCM (16.5 mL) and pyridine (481 uL, 5.95 mmol) was treated with Hunig's base (2.17 mL, 12.4 mmol) and stirred for 2 h. The reaction was concentrated, taken into EtOAc and washed with 2M aq. HCl 2×, water, brine, dried (MgSO4) and concentrated to afford a brown oil used crude in the next reaction. MS: cal'd 396 (MH+), exp 396 (MH+).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([NH2:18])[C:7]([NH2:17])=[CH:8][C:9]=1[N:10]1[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11]1.[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][C:21]=1[N:34]=[C:35]=S.CCN(C(C)C)C(C)C>CC#N>[Cl:19][C:20]1[CH:33]=[CH:32][C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:22][C:21]=1[NH:34][C:35]1[NH:18][C:6]2[CH:5]=[C:4]([Cl:3])[C:9]([N:10]3[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11]3)=[CH:8][C:7]=2[N:17]=1
Reactant: Nc1cc(Cl)c(N2CCC(F)(F)C2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(N4CCC(F)(F)C4)c(Cl)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Chloro-5-(3,3-difluoropyrrolidin-1-yl)benzene-1,2-diamine dihydrochloride (340 mg, 1.1 mmol) was added to N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (300 mg, 1.1 mmol) in MeCN (10 mL) and stirred at rt overnight. After addition of DIPEA (0.41 μL, 2.3 mmol) the reaction mixture was stirred at rt for 4.5 h. The mixture was concentrated. The crude was purified by chromatography to give the sub-title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19](OC(N1CC[C@@H](OS(C2C=CC(C)=CC=2)(=O)=O)C1)=O)(C)(C)C.C[C@H]1CCCCN1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:18][C@@H:14]2[CH3:19])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: C[C@H]1CCCCN1
Product: C[C@H]1CCCCN1[C@H]1CCN(C(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared in a manner substantially the same as intermediate (2R,3′S)-2-Methyl-[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester by condensing 3-(3R)-(toluene-4-sulfonyloxy)-pyrrolidine-1-carboxylic acid tert-butyl ester (5 g) with (S)-2-Methyl-piperidine to get 1.50 g (38% yield) of the product as a beige oil.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:1]1
Reactant: OCC(S)CS
Reactant: COC(=O)CCC(=O)c1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)CCC1(c2ccccc2)OCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-dimercapto-1-propanol (2.3 g, 0.019 mol), methyl 3-benzoylpropionate from Example 67 (3.7 g, 0.019 mol) and boron trifluoride etherate (0.5 ml) in methylene chloride (50 ml). The crude product was chromatographed on silica gel using 1% acetone/toluene as eluent to give 1.0 g (31%) of product.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[O:18]=[C:19]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(O)CCC>[O:18]=[C:19]([N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:23][CH2:22]1
Reactant: Nc1cc(Cl)ncn1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CC(=O)N3CCCC3)CC2)ncn1
Temperature: 150 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.50 g, 3.86 mmol) and diisopropylethylamine (0.499 g, 3.86 mmol) were suspended in n-butanol and then 1-(2-oxo-2-pyrrolidin-1-ylethyl)piperazine 17-1 (0.762 g, 3.86 mmol) was added. The reaction was stirred at 150° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and air dried. 1H-NMR (CD3OD): 7.96 ppm (s, 1H); 5.72 ppm (s, 1H); 3.55 ppm (m, 6H); 3.44 ppm (t, 2H); 3.24 ppm (s, 2H); 2.60 ppm (t, 2H); 1.98 ppm (m, 2H); 1.88 ppm (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[NH:13][C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:5][CH:4]=1.Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:27][CH2:26][CH2:25][N:24]([CH3:29])[CH3:23])[C:12]3[CH:18]=[CH:19][CH:20]=[CH:21][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)CCCCl
Reactant: COc1ccc([C@@H]2Sc3ccccc3NC(=O)[C@@H]2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCCN(C)C)C(=O)[C@@H]2O)cc1
Yield: 85.5 %

Procedure:
3.01 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-2,3-dihydro-1,5-benzothiazepin-4(5H)-one and 1.74 g of 3-(dimethylamino)propyl chloride hydrochloride are dissolved in 30 ml of acetone, and 3.04 g of potassium carbonate are added thereto. The mixture is refluxed overnight under stirring. After the reaction, the mixture is condensed under reduced pressure, and the residue is dissolved in ethyl acetate and water. The ethyl acetate layer is collected, dried and then evaporated to remove solvent. 3.3 g of (+)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[3-(dimethylamino)-propyl]-2,3-dihydro-1,5-benzothiazepin-4(5H)-one are thereby obtained as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 g, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate (0.90 g, 0.0065 mole), and dimethylsulfate (0.76 g, 0.006 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.13 g, yield: 89.6%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:32]=[CH:31][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][NH:21][CH2:20]4)[CH2:14][CH2:13]3)[C:9]2=[O:30])=[CH:5][CH:4]=1.[N:33]1([C:39]([Cl:41])=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[ClH:41].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:12][CH2:11][C:10]3([CH2:17][CH2:16][N:15]([CH2:18][C@@H:19]4[C@@H:23]([C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:22][N:21]([C:39]([N:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:40])[CH2:20]4)[CH2:14][CH2:13]3)[C:9]2=[O:30])=[CH:31][CH:32]=1
Reactant: COc1ccc(CN2CCC3(CCN(C[C@H]4CNC[C@@H]4c4ccccc4)CC3)C2=O)cc1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(CN2CCC3(CCN(C[C@H]4CN(C(=O)N5CCOCC5)C[C@@H]4c4ccccc4)CC3)C2=O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.7 %

Procedure:
To a solution of 2-(4-methoxy-benzyl)-8-((3R,4S)-4-phenyl-pyrrolidin-3-ylmethyl)-2,8-diaza-spiro[4.5]decan-1-one (60 μmol) in anhydrous DCM (1 mL) was added 4-morpholinecarbonyl chloride (21 μL, 180 μmol). The reaction mixture was stirred overnight at room temperature. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and the aqueous layer washed with DCM (3×2 mL). The organic layer was then concentrated in vacuo and purified by semi-preparative HPLC (Method D) and lyophilized to give Compound 157 as a colorless solid (6.2 mg, 19%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:12](=[O:13])[C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[S:9][CH2:8][C:7]1=[O:18].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1N1CCNCC1.O1[CH2:36][CH2:35]OCC1>>[N:21]1[CH:22]=[CH:23][CH:24]=[N:19][C:20]=1[CH:36]1[CH2:35][CH2:7][N:6]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:12](=[O:13])[C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[S:9][CH2:8][C:7]2=[O:18])[CH2:5][CH2:4]1
Reactant: c1cnc(N2CCNCC2)nc1
Reactant: O=C1CSc2ccccc2C(=O)N1CCCCBr
Reactant: C1COCCO1
Product: O=C1CSc2ccccc2C(=O)N1CCCCN1CCC(c2ncccn2)CC1
Yield: 52 %

Procedure:
To a solution of 53.8 of the compound of Example 13 dissolved in 10 ml of dioxane was added 84.3 mg (3 equivalents) of 1-(2-pyrimidinyl)piperazine, and the mixture heated under reflux for 6 hours. The reaction treatment and purification were conducted in the same manner as in Example 17 to obtain 35.2 mg of the desired compound (yield 52%). The maleate was obtained by converting the product to maleate in a conventional manner, followed by recrystallization from methylene chloride-ether.
Reaction SMILES: [C:1]1([CH:7]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([O:10][C@@H:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[CH:34]=[CH:33][O:32][N:31]=1)=[O:28]>CCOC(C)=O.C(#N)C>[Cl-:25].[O:32]1[CH:33]=[CH:34][C:30]([NH:29][C:27](=[O:28])[CH2:26][N+:13]23[CH2:18][CH2:17][CH:16]([CH2:15][CH2:14]2)[C@@H:11]([O:10][C:8](=[O:9])[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12]3)=[N:31]1
Reactant: O=C(CCl)Nc1ccon1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCC1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCCC1)C2)Nc1ccon1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 30 h
Yield: 37.5 %

Procedure:
To a solution of (R)-quinuclidin-3-yl 2-phenyl-2-(piperidin-1-yl)acetate (100 mg, 0.30 mmol) in EtOAc (2 ml) and acetonitrile (1 ml), was added 2-chloro-N-(isoxazol-3-yl)acetamide (58.7 mg, 0.36 mmol). The reaction was stirred at room temperature for 30 hours and then the solvents were evaporated. Purification by flash chromatography (DCM/MeOH=9/1) followed by trituration with Et2O afforded the title compound (55 mg, 36.9% yield) as an off-white solid.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[CH2:24]1[O:26][CH:25]1[CH2:27][OH:28]>C(#N)C>[Si:10]([O:28][CH2:27][CH:25]([OH:26])[CH2:24][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: c1c[nH]cn1
Reactant: OCC1CO1
Solvent: CC#N
Product: CC(C)(C)[Si](OCC(O)Cn1ccnc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.4 %

Procedure:
Add 1H-imidazole (19.72 g; 6.2 equiv; 289.67 mmoles) followed by tert-butylchlorodiphenylsilane (12.00 mL; 1.0 equiv; 46.28 mmoles) to a solution of freshly distilled glycidol (5.0 mL; 1.62 equiv; 75.05 mmoles) in acetonitrile (50 mL). Stir the solution at ambient temperature for 30 minutes, then heat to reflux for 4 hours. Allow the mixture to cool to ambient temperature and concentrate the reaction mixture, then pour the residue into dichloromethane/2M sodium bicarbonate (1:1, 400 mL). Separate the layers and further extract the aqueous layer with dichloromethane (2×). Dry the combined organic extracts over magnesium sulfate, filter, and concentrate to afford crude product. Purification by column chromatography affords the desired 1-[tert-butyl(diphenyl)silyl]oxy-3-imidazol-1-yl-propan-2-ol (8.87 g; 50%). MS (m/z): 381(M+1).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([N:12]2[CH2:15][CH:14]([NH:16][C:17](=[O:34])[CH2:18][NH:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[C:26]([C:29]([F:32])([F:31])[F:30])[CH:27]=4)[N:22]([CH3:33])[N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)=[O:5])C.O.O.[OH-].[Li+]>C1COCC1.CO>[CH3:33][N:22]1[C:23]2[C:28](=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[C:20]([NH:19][CH2:18][C:17]([NH:16][CH:14]2[CH2:13][N:12]([CH:9]3[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]3)[CH2:15]2)=[O:34])=[N:21]1
Reactant: CCOC(=O)C1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(NCC(=O)NC2CN(C3CCC(C(=O)O)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
4-{3-[2-(1-Methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetylamino]-azetidin-1-yl}-cyclohexane carboxylic acid ethyl ester (from Example 32, 350 mg, 0.773 mmol) in THF (2 mL), MeOH (2 mL) and distilled water (2 mL) was treated with lithium hydroxide monohydrate (87 mg, 1.93 mmol) at room temperature for 1 hour. The reaction mixture was acidified to pH=5 and extracted with DCM:IPA (3:1) solvent three times. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to give the title compound as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28]C#N)[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].O=C1COC2N=C(C3C=CC(C4(NC(=O)OC(C)(C)C)CCC4)=CC=3)C(C3C=CC=CC=3)=CC=2N1.[F:75]CCI>>[C:1]([O:5][C:6](=[O:39])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:27][CH2:28][F:75])[C:25](=[O:31])[CH2:24][O:23][C:22]=4[N:32]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCC#N)C(=O)CO4)cc2)CCC1
Reactant: FCCI
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CCF)C(=O)CO4)cc2)CCC1

Procedure:
Following the procedure for tert-butyl(1-(4-(1-(2-cyanoethyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate, tert-butyl 1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutylcarbamate (100 mg, 0.212 mmol) was reacted with 1-fluoro-2-iodoethane (111 mg, 0.636 mmol) to afford the title compound (85 mg. 1H NMR (500 MHz, CDCl3): 7.45 (1H, s), 7.24-7.31 (7H, m), 7.17-7.20 (2H, m,), 5.01 (1H, s), 4.94 (2H, s), 4.80 (1H, t), 4.70 (1H, t), 4.27 (1H, t), 4.22 (1H, t), 2.44-2.49 (4H, m), 2.06 (1H, m), 1.86 (1H, m), 1.2-1.43 (9H, br).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].Cl.[C:6]1([C@H:16]([NH:18][C@H:19]2[CH2:23][CH2:22][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[CH2:20]2)[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[OH:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([N:21]2[CH2:22][CH2:23][C@H:19]([NH:18][C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[CH2:20]2)=[CH:25][CH:26]=1
Reactant: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)O)cc2)C1)c1cccc2ccccc12
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](N[C@H]1CCN(c2ccc(C(=O)NCCO)cc2)C1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.5 %

Procedure:
To a mixed solution of 7.7 mg of 2-aminoethanol and 50 mg of 4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzoic acid hydrochloride (the compound obtained in Example 3.001) dissolved in 8 ml of dimethylformamide were added 22.2 mg of 1-hydroxybenzotriazole, 70 μl of triethylamine and 31.4 mg of EDC hydrochloride, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was evaporated, a saturated aqueous sodium bicarbonate solution and chloroform were added to the residue, and the mixture was stirred and the liquids were separated. The organic layer was dried and concentrated, and the residue was purified by NH thin layer silica gel chromatography (chloroform:methanol=39:1) and thin layer silica gel chromatography (chloroform:methanol=9:1) to give 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide. (2) To a solution of 22.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]-benzamide dissolved in 1 ml of methylene chloride was added dropwise 3 ml of a solution of 4M hydrochloric acid in dioxane, and the mixture was stirred for a while. The reaction mixture was evaporated; and, to the residue was added tert-butanol to dissolve the same, and freeze-dried to obtain 25.6 mg of N-(2-hydroxyethyl)-4-[(S)-3-[(R)-1-(naphthalen-1-yl)ethylamino]pyrrolidin-1-yl]benzamide hydrochloride (the following Table A3, Example 3.017).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:6][CH:5]([C:7]2[C:8]([O:28][CH3:29])=[C:9]([CH:15]([N:17]3[C:21]4=[N:22][CH:23]=[N:24][C:25]([NH2:26])=[C:20]4[C:19]([CH3:27])=[N:18]3)[CH3:16])[CH:10]=[C:11]([Cl:14])[C:12]=2[CH3:13])[CH2:4]1.C(N(CC)CC)C.Br[C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>C(#N)C>[NH2:26][C:25]1[N:24]=[CH:23][N:22]=[C:21]2[N:17]([CH:15]([C:9]3[C:8]([O:28][CH3:29])=[C:7]([CH:5]4[CH2:4][N:3]([C@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[CH2:6]4)[C:12]([CH3:13])=[C:11]([Cl:14])[CH:10]=3)[CH3:16])[N:18]=[C:19]([CH3:27])[C:20]=12
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1C1CNC1
Reactant: COC(=O)[C@H](C)Br
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)N1CC(c2c(C)c(Cl)cc(C(C)n3nc(C)c4c(N)ncnc43)c2OC)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.6 %

Procedure:
To a solution of 1-[1-(3-azetidin-3-yl-5-chloro-2-methoxy-4-methylphenyl)ethyl]-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine hydrochloride (20.1 mg, 0.0475 mmol, chiral intermediate from Example 1, Step 7) in acetonitrile (1 mL) was added triethylamine (23 μL, 0.17 mmol) and methyl (2S)-2-bromopropanoate (9.5 mg, 0.057 mmol). The reaction solution was stirred at room temperature for 4 h. The solvent was removed to give the desired product (6.2 mg, 28%). LCMS calculated for C23H30ClN6O3 (M+H)+: m/z=473.2; Found:473.3