Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[NH:10][CH2:9][S:8][CH2:7]1)=[O:5].Cl.[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16]>>[Cl:12][C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([N:10]1[CH:6]([C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:7][S:8][CH2:9]1)=[O:16]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCOC(=O)C1CSCN1
Agent: Cl
Product: CCOC(=O)C1CSCN1C(=O)c1cccnc1Cl
Yield: 77.5 %

Procedure:
Ethyl N-(2-chloronicotinoyl)thiazolidine-4-carboxylate is prepared as described in Example 5, from 23 g of ethyl L-thiazolidine-4-carboxylate hydrochloride and 20.4 g of 2-chloronicotinoyl chloride. 27 g of ethyl N-(2-chloronicotinoyl)thiazolidine-4-carboxylate are thus obtained in the form of a yellow oil, employed crude.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9].O>CN(C)C=O>[CH2:7]([C:10]1[N:14]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:29][N:3]=[N:2][N:1]=3)=[CH:20][CH:21]=2)[C:13]2[CH:30]=[C:31]([C:35]3[N:39]([CH3:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=3)[CH:32]=[C:33]([CH3:34])[C:12]=2[N:11]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
4.3 g (66 mMol) of sodium azide and 3.5 g (66 mMol) of ammonium chloride are added to a solution of 1.60 g (3.3 mMol) of 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-2-cyano-biphenyl in 50 ml of dimethylformamide and the mixture is stirred for 24 hours at 140° C. Then water is added and the precipitate is removed by suction filtering. The crude product thus obtained is purified by chromatography over silica gel (300 g of silica gel, methylene chloride +6% ethanol).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29].CO.Cl>C[O-].[Na+].O>[OH:15][C:14]1[C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=[N:6][C:5]=1[C:3]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4]
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Reactant: NCCCCC(=O)O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(O)CCCCNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Yield: 79.4 %

Procedure:
A mixture of 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (100 mg, 0.34 mmol) and 5-amino-valeric acid (597 mg, 5.1 mmol) in 0.5 N NaOMe in MeOH solution (6.8 mL, 3.4 mmol) was heated to reflux overnight. Reaction mixture was diluted with water (100 mL) and acidified by 1 N HCl solution to pH=3-4. Precipitate was collected and rinsed with water. It was dried in vacuo to provide the title compound (102 mg, 0.27 mmol) in 80% yield. LC-MS ESI−: 379.07 (M−1)−.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13]Br)=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20].[OH2:21]>CS(C)=O.[Cu-]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH2:13][OH:21])=[CH:11][C:10]([C:15]([F:18])([F:17])[F:16])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: O
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2CBr)ccc1F
Agent: O=[Cu-]
Solvent: CS(C)=O
Product: N#Cc1cc(-n2nc(C(F)(F)F)cc2CO)ccc1F
Temperature: 60 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-bromomethylpyrazole (0.6 g, 1.72 mmol) in DMSO (10 mL) was added copper (I) oxide (0.52 g, 3.62 mmol) and water (3 mL). The reaction was stirred at 60° C. overnight. The next day the reaction mixture was filtered through Celite®. The filtrate was partitioned between ethyl acetate and water. The organic was washed three times with water, brine, dried over sodium sulfate, filtered and concentrated to leave 1-(4-fluoro-3-cyanophenyl)-3-trifluoromethyl-5-hydroxymethyl pyrazole (0.45 g, 92% yield) as pure compound: MS (CI): 286 (M+H)+ (100%).
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([C:11](=[O:42])[NH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:20]3[N:27]([CH3:28])[N:26]=[C:25]([CH3:29])[C:21]=3[N:22]=[CH:23][N:24]=2)[CH:16]=[C:15]([C:30]#[C:31][C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[N:37]([CH3:41])[N:36]=[CH:35]3)[N:14]=1)[CH3:10])C)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:28][N:27]1[C:20]2[C:19]([C:17]3[CH:16]=[C:15]([C:30]#[C:31][C:32]4[CH:33]=[C:34]5[C:38](=[CH:39][CH:40]=4)[N:37]([CH3:41])[N:36]=[CH:35]5)[N:14]=[C:13]([NH:12][C:11](=[O:42])[CH:9]([NH:7][CH3:6])[CH3:10])[CH:18]=3)=[N:24][CH:23]=[N:22][C:21]=2[C:25]([CH3:29])=[N:26]1
Reactant: Cc1nn(C)c2c(-c3cc(C#Cc4ccc5c(cnn5C)c4)nc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)c3)ncnc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)Nc1cc(-c2ncnc3c(C)nn(C)c23)cc(C#Cc2ccc3c(cnn3C)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl-N-{1-[(4-{1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7-yl}-6-[2-(1-methyl-1H-indazol-5-yl)ethynyl]pyridin-2-yl)carbamoyl]ethyl}-N-methylcarbamate H1 (246 mg, 0.42 mmol), DCM (5 ml) and TFA (1 ml) is stirred at RT for 1 h. 50 ml of a saturated aqueous sodium hydrogencarbonate solution is added and the mixture extracted with DCM. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 99 mg (49%). HPLC-MS: M+H=480; tR=1.16 min (METHOD—1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCC[Si](C)(C)C)[C:19](=[O:29])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](I)[CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:9]1[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]1)[NH:20][C:19]2=[O:29]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(I)cc3c(=O)n2COCC[Si](C)(C)C)c1
Reactant: OB(O)c1ccccc1Cl
Product: O=C(O)c1cnn(-c2nc3ccc(-c4ccccc4Cl)cc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 69, steps C-E, using 1-[6-iodo-4-oxo-3-(2-trimethylsilanyl-ethoxymethyl)-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Example 69 product from step B) and 2-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (600 MHz, DMSO-d6): 12.99 (s, 2H), 8.98 (d, J=0.6 Hz, 1H), 8.27 (s, 1H), 8.13 (d, J=2.1 Hz, 1H), 7.91 (dd, J=8.4, 2.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.64-7.61 (m, 1H), 7.55-7.52 (m, 1H), 7.47 (pd, J=7.4, 1.8 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3.[C:24]([N:28]=[C:29]=[O:30])([CH3:27])([CH3:26])[CH3:25].N12CCCN=C1CCCCC2>C1C=CC=CC=1>[C:24]([NH:28][C:29]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([N:13]([CH3:23])[C:14](=[O:22])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)N=C=O
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(CO)CC[C@H]4[C@@H]3CC[C@@H]12
Solvent: c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)C(COC(=O)NC(C)(C)C)CC[C@H]4[C@@H]3CC[C@@H]12
Reaction time: 48 h

Procedure:
To a stirred solution of 17-(hydroxymethyl)-4-methyl-5α-4-azaandrostan-3-one (0.048 g, 0.15 mM) in dried benzene (5 mL) was added at room temperature t-butylisocyanate (0.03 mL, 0.23 mM) followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.023 mL, 0.15 mM). After stirring for two days, the volatiles were removed in vacuo and the residue flash chromatographed on silica gel using ethyl acetate as eluant to give the title compound as a white solid. MS M+1 calculated for C25 H42N2O3, mw=418.55; observed m/e 419.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1N)([CH3:3])[CH3:2].N([O-])=[O:15].[Na+].O>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[OH:15])([CH3:3])[CH3:2]
Reactant: O=N[O-]
Reactant: CC(C)c1cc([N+](=O)[O-])ccc1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C)c1cc([N+](=O)[O-])ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.4 %

Procedure:
2-Isopropyl-4-nitro-phenylamine (2.5 g, 13.9 mmol) was dissolved in 10% sulfuric acid (25 mL) and to this was added sodium nitrite (1.64 g, 23.8 mmol) in portions over 15 min at 0° C. The diazotized solution was added to boiling water and stirred for 15 min. the mixture was cooled to r.t. and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to afford 2-isopropyl-4-nitro phenol (2 g, 80%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].Br[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][N:12]=1.CC1(C)CCCC(C)(C)N1>CN(C=O)C.CCOC(C)=O>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:7]2[CH2:8][CH2:9][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]2)=[N:12][CH:13]=1)#[N:16]
Reactant: COC(=O)C1CCNC1
Reactant: N#Cc1ccc(Br)nc1
Agent: CC1(C)CCCC(C)(C)N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(c2ccc(C#N)cn2)C1
Temperature: 130 °C
Yield: 50.9 %

Procedure:
Pyrrolidine-3-carboxylic acid methyl ester (100 mg, 0.77 mmol) was dissolved in dry DMF (0.5 MI) in a shield tube. 6-Bromonicotinonitrile (140 mg, 077 mmol) was added to the reaction mixture, followed by 2,2,6,6-tetramethylpiperadine (110 mg, 0.77 mmol) and the mixture was heated to 130° C. for 3 h, cooled to room temperature, and diluted with EtOAc. The organic layer was washed with H2O and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 15-18% EtOAc in petroleum ether) to afford methyl 1-(5-cyanopyridin-2-yl)pyrrolidine-3-carboxylate (90 mg, yield 70%). 1H NMR (300 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 7.62-7.59 (dd, J=8.9 Hz, J=2.3 Hz, 1H), 6.36 (d, J=9.0 Hz, 1H), 3.78-3.77 (m, 2H), 3.75 (s, 3H), 3.67 (m, 1H), 3.56-3.52 (m, 1H), 3.28-3.23 (t, J=7.1 Hz, 1H), 2.37-2.30 (q, J=7.1 Hz, 2H). MS (ESI) m/z: Calculated for C12H13N3O2: 231.10. found: 232.2 (M+H)+
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[C:4](OC)=O.CC([N:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25](=[O:27])C)=[CH:21][CH:20]=1)[C:16](=[O:18])[O-:17])(C)C>CN(C=O)C>[CH3:21][C:22]([O:17][C:16]([NH:15][C:19]1[CH:20]=[CH:21][C:22](/[C:25](/[OH:27])=[CH:4]/[C:3]([O:9][CH3:10])=[O:8])=[CH:23][CH:24]=1)=[O:18])([CH3:25])[CH3:23]
Reactant: CC(=O)c1ccc(N(C(=O)[O-])C(C)(C)C)cc1
Reactant: COC(=O)C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)/C=C(\O)c1ccc(NC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Yield: 111.3 %

Procedure:
NaH (60% dispersion, 2.22 g, 55.5 mmol) was added to a solution of dimethyl oxalate (2.73 g, 23.1 mmol) and 1,1-dimethylethyl(4-acetylphenyl)carbamate (N-BOC-4-aminoacetophenone, 5.44 g, 23.1 mmol) in anhydrous DMF (50 mL) at 0° C. The reaction mixture was allowed to warm to room temperature overnight and quenched with saturated aqueous NH4Cl and neutralized with 1M HCl. The reaction was diluted with ethyl acetate (80 mL) and the organic layer washed successively with saturated aqueous NaHCO3 and brine. The organic phase was separated and dried over Na2SO4, filtered, concentrated in vacuo and triturated with chloroform to provide the condensation product (3.77 g, 53.1% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCC2CCCC2Nc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCC2CCCC2Nc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Reaction time: 14 h
Yield: 69.6 %

Procedure:
Methyl 4-[2-[N-(4-chlorophenyl)amino]cyclopentan-1-ylmethoxy]benzoate (2.57 g) was dissolved in methanol (40 ml) and thereto was added a solution of sodium hydroxide (0.86 g) in water (8 ml), and the mixture was heated with stirring at 60° C. for 14 hours. The reaction mixture was cooled and thereto was added conc. hydrochloric acid (1.87 ml), then, the mixture was concentrated under reduced pressure. The residue was washed with water and about 50 % aqueous methanol was added thereto, and the mixture was heated. The mixture was allowed to stand, and the resulting crystal was collected by filtration to give the desired product (1.72 g). mp. 153°-156° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)(=[O:8])=[O:9])[CH:11]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)c2ccccc2)c1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2cccc(S(=O)(=O)c3ccccc3)c2)cc1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(phenylsulfonyl)benzoic acid and 4-methoxyaniline as the starting materials.
Reaction SMILES: C[N:2]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1N1CCCCC1C)[C:3](=O)C1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[C:35]([O:42][CH3:43])[CH:34]=1>CCCCCCC.CCOC(C)=O>[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:24]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[NH:2][CH3:3])=[C:35]([O:42][CH3:43])[CH:34]=1
Reactant: CC1CCCCN1c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CNc1cnccc1-c1ccc(F)cc1OC

Procedure:
The title compound was prepared in analogy to example 72, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate b) and 4-fluoro-2-methoxyphenylboronic acid (CAS 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 20:80) for the chromatographic purification. Light yellow oil (85%). MS (ESI): m/z=233.108 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>C(O)C>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[N:24]=[CH:23][C:22]([C:25](=[NH:42])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cn1)n2C)c1ccccn1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cn1)n2C)c1ccccn1

Procedure:
Prepared analogously to Example 25d from 1-Methyl-2-[N-(3-cyanopyridin-6-yl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C@H:7]([NH:19][C:20](=[O:23])[CH2:21][NH2:22])[C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([Br:18])[CH:9]=1)[CH3:3].[C:25]([O-:28])(O)=[O:26].[Na+]>O1CCOCC1>[CH2:2]([O:4][C:5](=[O:24])[CH2:6][C@@H:7]([C:8]1[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:11]=[C:10]([Br:18])[CH:9]=1)[NH:19][C:20](=[O:23])[CH2:21][NH:22][C:25]([O:28][C:8]([CH3:13])([CH3:9])[CH3:7])=[O:26])[CH3:3]
Reactant: CCOC(=O)C[C@H](NC(=O)CN)c1cc(Br)cc(C(C)(C)C)c1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C[C@H](NC(=O)CNC(=O)OC(C)(C)C)c1cc(Br)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of the product from example H (2 gm, 5.204 mmol) in 1,4-Dioxane (20 ml) was added saturated aq. NaHCO3 solution (2.5 ml) and stirred for 5 min at RT. Boc-anhydride (1.36 ml, 6.245 mmol) was then added to it at 0 C and the reaction mixture was allowed to stir at room temperature for 2 hrs. Reaction mixture was concentrated, dissolved in EtOAc (60 ml) and washed with water (60 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude which was purified by silica gel (100-200 mesh) column chromatography eluting with 10% EtOAc to afford the desired compound (1.7 g) as a colorless liquid.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][C:6](=[O:10])[CH2:5]1)([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:14][C:15]1[N:16]([CH3:41])[C:17]2[C:22]([N:23]=1)=[C:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[N:20]=[C:19]([N:30]1[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]1[CH2:39][CH3:40])[N:18]=2>CN(C=O)C>[CH2:39]([C:31]1[N:30]([C:19]2[N:18]=[C:17]3[C:22]([N:23]=[C:15]([CH2:14][N:7]4[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][C:6]4=[O:10])[N:16]3[CH3:41])=[C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:20]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1)[CH3:40]
Reactant: CC(C)N1CCNC(=O)C1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)C)CC3=O)n(C)c2n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 12.1 %

Procedure:
To a solution 4-isopropylpiperazin-2-one (56 mg, 0.35 mmol) in DMF (3 mL) at 0° C. was added sodium hydride (18 mg, 0.45 mmol, 60% dispersion in mineral oil) and the resulting mixture stirred for 30 min before the addition of a solution of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine (200 mg, 0.44 mmol) in DMF (2 mL). The resulting mixture was stirred at r.t. for 72 h, then partitioned between DCM and H2O. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) followed by reverse phase HPLC (Phenomenex Gemini 5 μm C18, 20 mM triethylamine in water on a gradient acetonitrile 30-70%) affording 711 as a white solid (22 mg, 15%). LCMS: RT 2.43 min, [M+H]+518.2. 1H NMR (DMSO, 400 MHz): δ 8.01-8.01 (1 H, m), 7.63-7.62 (1 H, m), 7.25-7.24 (2 H, m), 4.83 (2 H, s), 4.26 (4 H, brd s), 3.77 (4 H, t, J=4.61 Hz), 3.74 (3 H, s), 3.31 (2 H, m), 3.26 (2 H, q, J=7.45 Hz), 3.15 (2 H, s), 2.69-2.68 (3 H, m), 1.33 (3 H, t, J=7.44 Hz), 0.98 (6 H, d, J=6.50 Hz)
Reaction SMILES: [CH3:1][N:2]([CH2:13][CH:14]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:6]=2[N:7]=1.[CH:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(Cl)Cl>C(Cl)Cl.CO>[CH:20]1([C:26]2[CH:27]=[CH:28][C:29]([C:30]([NH:12][C:9]3[CH:10]=[CH:11][C:5]4[O:4][C:3]([N:2]([CH3:1])[CH2:13][CH:14]5[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15]5)=[N:7][C:6]=4[CH:8]=3)=[O:31])=[CH:33][CH:34]=2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CN1CCC(CN(C)c2nc3cc(N)ccc3o2)C1
Reactant: O=C(O)c1ccc(C2CCCCC2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CN1CCC(CN(C)c2nc3cc(NC(=O)c4ccc(C5CCCCC5)cc4)ccc3o2)C1
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Combine rac-N2-methyl-N2-(1-methyl-pyrrolidin-3-ylmethyl)-benzooxazole-2,5-diamine (0.150 g, 0.576 mmol), 4-cyclohexyl-benzoic acid (0.177 g, 0.864 mmol), HATU (0.219 g, 0.576 mmol), polystyrene-bound diisopropylamine (1.44 g, loading: 2.0 to 3.5 mmol/g), and CH2Cl2 (20 mL). Shake the mixture overnight at room temperature. Add HATU (0.219 g, 0.576 mmol) and shake for 21 h at room temperature. Dilute with 1:1 CH2Cl2/MeOH, wash with 10M NaOH (equal volume), dry over Na2SO4, filter, and concentrate in vacuo. Subject the mixture to silica gel flash column chromatography (2×12 g columns, 5% 2M NH3 in MeOH/CH2Cl2, then ramping to 10% after 10 min) to yield the desired product as a colorless oil (0.103 g, 40%). Subject the product to chiral preparative chromatography [Chiralpak AD-H column, (8×32 cm), eluting with 70/30 3 Å ethanol/ACN w/0.2% dimethylethylamine; Flow rate=350 mL/min] to yield isomer 1 (0.039 g). mass spectrum (m/e): 447.3 (M+1). 1H NMR (400 MHz, CDCl3): δ 7.83 (s, 1H), 7.80-7.76 (m, 2H), 7.48 (d, J=2.0 Hz, 1H), 7.35 (dd, J=8.6, 1.8 Hz, 1H), 7.31-7.27 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 3.61-3.46 (m, 2H), 3.19 (s, 3H), 2.77-2.51 (m, 6H), 2.42-2.37 (m, 1H), 2.37 (s, 3H), 2.07-1.97 (m, 1H), 1.91-1.80 (m, 4H), 1.76 (d, J=12.8 Hz, 1H), 1.61-1.52 (m, 1H), 1.48-1.22 (m, 4H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)=[CH:30][CH:29]=4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:42]C1C=CC(COC2C=CC(COC(=O)OC(Cl)C)=CC=2)=CC=1.C(N1CCNCC1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[F:42][C:39]1[CH:38]=[CH:37][C:36]([CH2:35][O:34][C:31]2[CH:30]=[CH:29][C:28]([CH2:27][O:26][C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]4[C:11]5[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=5[C:5]5[C:13]4=[CH:1][CH:2]=[CH:3][CH:4]=5)=[O:17])[CH2:23][CH2:22]3)=[O:25])=[CH:33][CH:32]=2)=[CH:41][CH:40]=1
Reactant: CC(Cl)OC(=O)OCc1ccc(OCc2ccc(F)cc2)cc1
Reactant: O=C(OCc1ccc(OCc2ccccc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1
Agent: O=C(OCC1c2ccccc2-c2ccccc21)N1CCNCC1
Product: O=C(OCc1ccc(OCc2ccc(F)cc2)cc1)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1

Procedure:
Prepared in analogy to piperazine-1,4-dicarboxylic acid 4-benzyloxy-benzyl ester 9H-fluoren-9-ylmethyl ester (Example 41) from (RS)-carbonic acid 1-chloro-ethyl ester 4-(4-fluoro-benzyloxy)-benzyl ester) and N-Fmoc-piperazine: yellow solid. 1H-NMR (CDCl3): 3.3–3.6 m, 8H; 4.23 t, J=6 Hz, 1H; 4.48 d, J=6 Hz, 2H; 5.03 s, 2H; 5.08 s, 2H; 6.95 d, J=8.5 Hz, 2H, 7.08 t, J=8.5 Hz, 2H, 7.25–7.46 m, 8H, 7.55 d, J=7 Hz, 2H and 7.77 d, J=7 Hz, 2H.