Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([OH:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:2]1([CH2:10][CH2:9][CH:8]=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: O=CCCc1ccccc1
Temperature: 100 °C
Yield: 27 %

Procedure:
0.1 g Palladium acetate, 10.2 g iodobenzene, 4.4 g allyl alcohol and 6.0 g triethylamine were heated while stirring under nitrogen to 100° C. After one hour the iodobenzene was 97% reacted and there was produced 27% 3-phenylpropanal and 13% hydratropic aldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([Mg]Br)[CH:6]=[CH:7][CH:8]=1.C[O:12][C:13](=[O:20])[C:14](=[O:19])[CH:15]=[C:16]([CH3:18])[CH3:17].C[Si](C)(C)Cl.Cl>O1CCCC1.[Cu].C(OCC)(=O)C.CN1CCCN(C)C1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:16]([CH3:18])([CH3:17])[CH2:15][C:14](=[O:19])[C:13]([OH:20])=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(=O)C=C(C)C
Reactant: COc1cccc([Mg]Br)c1
Agent: [Cu]
Agent: C[Si](C)(C)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCCN(C)C1=O
Product: COc1cccc(C(C)(C)CC(=O)C(=O)O)c1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
4.2 ml of a 0.6 m solution of 3-methoxyphenylmagnesium bromide in tetrahydrofuran is mixed at −70° C. with 257 mg of copper bromidedimethylsulfide complex and then stirred at −40° C. for 20 minutes. It is cooled again to −70° C., and 0.33 ml of 1,3-dimethyl-tetrahydro-2-1H-pyrimidinone and a mixture of 400 mg of 4-methyl-2-oxo-3-pentenoic acid methyl ester (Liebigs Annalen [Liebigs Annals] 1974, 477) and 0.71 ml of trimethylchlorosilane in 3.5 ml of tetrahydrofuran are slowly added. It is stirred for one hour at −70° C. and then heated to room temperature. Then, 2N hydrochloric acid and ethyl acetate are added, the ethyl acetate phase is separated, it is concentrated by evaporation, and the residue is dissolved in 5 ml of dichloromethane. After 200 mg of tetrabutylammonium fluoride is added, it is left at room temperature for one hour, then washed with water, and the dichloromethane phase is dried (Na2SO4) and concentrated by evaporation. After chroma-tography on silica gel with hexane/ethyl acetate (97:3), 63 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid-methyl ester, which is mixed with 1 ml of potassium hydroxide in methanol (10%), is obtained. After 45 minutes, it is concentrated by evaporation, the residue is dissolved in water and extracted with diethyl ether. The aqueous phase is then acidified with 6N hydrochloric acid and extracted with diethyl ether. The diethyl ether phase is dried (Na2SO4) and concen-trated by evaporation. 50 mg of 4-(3-methoxyphenyl)-4-methyl-2-oxo-valeric acid is obtained.
Reaction SMILES: [CH3:1][I:2].[N:3]1([CH2:10][CH2:11][CH:12]([C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[OH:26])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1>C(Cl)Cl>[I-:2].[OH:26][C:20]1[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:19]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][CH2:10][N+:3]1([CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: CI
Reactant: Cc1ccc(O)c(C(CCN2CCCCCC2)c2ccccc2)c1
Solvent: ClCCl
Product: Cc1ccc(O)c(C(CC[N+]2(C)CCCCCC2)c2ccccc2)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl iodide (10 equivalents) was added to a solution of the free base 2-(3-azepan-1-yl-1-phenylpropyl)-4-methylphenol of Example 30 (0.3 g, 1.02 mmol) in CH2Cl2 (2 mL). The reaction mixture was stirred overnight at room temperature. The solution was concentrated to initiate precipitation of the resulting quaternary ammonium salt. The white precipitate was filtered out, washed with diethyl ether and dried under vacuum to give a quaternized salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][NH2:20])[CH2:14][CH2:13]1)[CH:6]=[CH:5]2.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23].C(N(CC)C(C)C)(C)C.C(OC(C)C)(C)C>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:13][CH2:14][CH:15]([CH2:18][CH2:19][NH:20][C:22](=[O:23])[O:24][C:25]3[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=3)[CH2:16][CH2:17]1)[CH:6]=[CH:5]2
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1
Solvent: CC(C)OC(C)C
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCC1CCN(c2ccc3cc(Cl)ccc3n2)CC1)Oc1ccc([N+](=O)[O-])cc1

Procedure:
The process is performed according to the method described in Example 1 (step 1.5.). Starting with 5.00 g (17.25 mmol) of 2-[1-(6-chloroquinolin-2-yl)piperidin-4-yl]ethylamine, prepared in step 6.3., 3.825 g (18.98 mmol) of 4-nitrophenyl chloroformate, 4.46 g (34.51 mmol) of N,N-diisopropylethylamine and 0.105 p (0.86 mmol) of N,N-dimethylaminopyridine, and after triturating from a mixture of diisopropyl ether and hexane, 7.8 g of pure product are obtained in the form of a white powder.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[CH2:14]([N:6]1[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@@H]1CNCCN1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CN(Cc2ccccc2)CCN1
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of (R)-2-methylpiperazine (10 g, 100 mmol) in ethanol at room temperature was added K2CO3 (27.6 g, 200 mmol). The reaction mixture was cooled to 0° C., benzyl bromide (15.3 g, 89.5 mmol) was added and the reaction mixture was heated to 60° C. and stirred for 8 h. The reaction mixture was allowed to cool to room temperature, filtered through a filtration funnel and the filtrate was concentrated under reduced pressure to remove ethanol. The residue was washed with water and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel (100-200 mesh) column chromatography eluting with 5% methanol in chloroform to afford pure 12.0 g of (R)-1-benzyl-3-methylpiperazine.
Reaction SMILES: [OH:1][C@H:2]([C@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:7]1=[O:23])[C:3]([OH:5])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[NH:32][O:33][C:34](=[O:36])[N:35]=2)=[CH:27][CH:26]=1.NC1C=C2C(=CC=1)C(N(C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=NC=C2>CN(C=O)C>[OH:1][C@H:2]([C@H:6]1[O:11][CH2:10][CH2:9][N:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=2)[C:7]1=[O:23])[C:3]([NH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[NH:35][C:34](=[O:36])[O:33][N:32]=2)=[CH:29][CH:30]=1)=[O:5]
Reactant: Nc1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: O=C(O)[C@H](O)[C@H]1OCCN(c2ccc(OC(F)(F)F)cc2)C1=O
Agent: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nccc2cc(N)ccc12
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H](O)[C@H]1OCCN(c2ccc(OC(F)(F)F)cc2)C1=O

Procedure:
According to the Step 1-3 in synthetic method for EXAMPLE 1, compound 55-6 (0.3 g) and 3-(4-aminophenyl)-1,2,4-oxadiazol-5(2H)-one with DMF were used instead of 1-2 and 6-amino-1-bis(tert-butoxycarbonyl)aminoisoquinoline to obtain compound 56-1 (26 mg) as a colorless amorphous solid.
Reaction SMILES: [Br:1]Br.[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)(=[O:5])[CH3:4]>C(O)(=O)C.O>[C:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:9][C:8]=1[Br:1])(=[O:5])[CH3:4]
Reactant: CC(=O)Nc1ccc(CC(=O)O)cc1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(CC(=O)O)cc1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 55.1 %

Procedure:
102.2 g (0.64 mole) of bromine are added dropwise at room temperature, with stirring, to a suspension of 100 g (0.52 mole) of 4-acetamidophenylacetic acid in 1 liter of glacial acetic acid; during this dropwise addition, a solution forms intermittently. Subsequently, heating to 60° C. is effected for 12 hours, followed by cooling to room temperature, diluting with 2 liters of water and extracting three times with diethyl ether. The organic phase is washed with sodium hydrogen sulfite solution and water, dried and concentrated to dryness. The residue is recrystallized from acetonitrile to yield 78 g (55.3% of theory) of 4-acetamido-3-bromophenylacetic acid (m.p. 157° to 159° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1.[N+:13]([O-])([OH:15])=[O:14]>S(=O)(=O)(O)O>[Cl:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:12])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)cc1F
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1cc([N+](=O)[O-])c(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4'-chloro-2'-fluoroacetanilide (51 g, 0.272 mol) in concentrated sulfuric acid (100 mL) is cooled to 0° C., treated with nitric acid (90% real, 14 mL, 0.300 mol) over 45 minutes, stirred for 10 minutes, and poured onto ice. The resultant aqueous mixture is filtered to obtain a tan solid which is washed with water, dried overnight, and recrystallized from a chloroform/hexanes (17:1) solution to give the title product as a yellow solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[N:16]1[CH:20]=[N:19][C:18]([CH3:21])=[N:17]1.C(N(C(C)C)CC)(C)C.[Cl:31][C:32]1[N:33]=[C:34](Cl)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1>C(#N)C>[Cl:31][C:32]1[N:33]=[C:34]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[N:16]2[CH:20]=[N:19][C:18]([CH3:21])=[N:17]2)[C:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:36]=2[N:37]=1
Reactant: CNCCCOc1cc([N+](=O)[O-])ccc1-n1cnc(C)n1
Reactant: Clc1nc(Cl)c2c(n1)C(c1ccccc1)CC2
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCCCN(C)c2nc(Cl)nc3c2CCC3c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a solution of N-methyl-3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propan-1-amine (Preparation L, 1.20 g, 4.15 mmol) in acetonitrile (50 mL) was added diisopropylethylamine (0.731 g, 5.66 mmol) followed by 2,4-dichloro-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation R, 1 g, 3.77 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was taken up in dichloromethane (10 mL) and silica (2 g). The resultant slurry of the compound on silica was subjected to flash chromatography using a Teledyne Isco instrument (12 g RediSep silica column, 50% ethyl acetate in pet-ether) to get 2-chloro-N-methyl-N-(3-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)propyl)-7-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (1.2 g, 61.2%) as a light yellow solid. LC-MS (M+H)+=518.2. 1H NMR (400 MHz, CDCl3) δ ppm 8.95 (1H, s), 8.05-7.93 (3H, m), 7.30-7.11 (5H, m), 4.35-4.31 (2H, m), 4.18-4.14 (1H, m), 3.87-3.70 (2H, s), 3.28 (3H, s), 3.21-3.07 (2H, m), 2.54-2.50 (1H, m), 2.27-2.24 (2H, m), 2.01-1.98 (1H, m).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=4)=[O:23])=[CH:19]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]>[Ni].C1COCC1.N.CO>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][C:18]([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][NH2:32])=[C:27]([C:33]([F:36])([F:34])[F:35])[CH:26]=4)=[O:23])=[CH:19]3)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(C#N)c(C(F)(F)F)c4)cc3c2)ccn1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(CN)c(C(F)(F)F)c4)cc3c2)ccn1
Reaction time: 18 h
Yield: 27.6 %

Procedure:
A slurry of 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-[4-cyano-3-(trifluoromethyl)-phenyl]-2-naphthamide (I-157) (163 mg, 0.33 mmol) and Raney Nickel (2800 slurry in water, 50% v/v, approx 8 mg) in THF (5 mL) and 7.0 M ammonia in MeOH (5 mL), was allowed to stir under an atmosphere of hydrogen for 18 h. After this time, additional Raney Nickel was added and hydrogenation continued for a further 18 h. The reaction mixture was filtered through Celite and washed with THF and MeOH. The filtrate was concentrated and purified by column chromatography. The product was dissolved in MeOH and 2M HCl in Et2O was added. The solvents were evaporated to give 7-{[2-(acetylamino)pyridin-4-yl]oxy}-N-[4-(aminomethyl)-3-(trifluoromethyl)phenyl]-2-naphthamide (I-151) as an off-white solid (45 mg, 23%). 1H NMR (400 MHz, d6-DMSO): δ 11.27 (s, 1H), 10.97 (s, 1H), 8.67 (s, 1H), 8.63 (br.s, 2H), 8.36 (d, 1H), 8.28 (d, 1H), 8.24-8.16 (m, 3H), 8.09-8.06 (m, 1H), 7.93 (d, 1H), 7.55 (dd, 1H), 7.45 (d, 1H), 6.96 (dd, 1H), 4.15-4.11 (m, 2H), and 2.08 (s, 3H). LCMS: (FA) ES+ 495.4.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].[CH2:5]([Br:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.CCOCC>C(Cl)(Cl)Cl>[BrH:12].[CH2:5]([S:3][C:1](=[NH:4])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: CC(N)=S
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: Br
Product: CC(=N)SCc1ccccc1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a solution of thioacetamide (0.478 g, 6.36 mmol) in CHCl3 (16 mL) was added benzyl bromide (0.76 mL, 6.39 mmol) and the resultant solution was heated to reflux for 2 hours. The mixture was cooled to room temperature. Ether (50 mL) was added and the mixture was cooled in an ice-water bath to precipitate a white solid. The supernatant solution was decanted and the solid was washed with ether (2×50 mL). The solid was dried under vacuum to provide 1.44 g (92%) of S-benzylthioacetimidate hydrobromide as a white solid. 1H NMR (DMSO-d6) δ 2.63 (s, 3H), 4.61 (s, 2H), 7.34–7.46 (m, 5H), 11.89 (br s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([C@H:12]([CH:17]([CH3:19])C)C(OC)=O)[C:8]2=[O:11])=[CH:4][CH:3]=1.Cl.NCCC[C:25]([O:27][CH3:28])=[O:26]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][N:7]([CH2:12][CH2:17][CH2:19][C:25]([O:27][CH3:28])=[O:26])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2ccc(Br)cc2C1=O
Reactant: COC(=O)CCCN
Agent: Cl
Product: COC(=O)CCCN1Cc2ccc(Br)cc2C1=O

Procedure:
The compound of example 347 was prepared analogous to compound of example 329 by reaction of the compound of example 328 and methyl 4-aminobutanoate hydrochloride.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1)([O-])=O.C(OC(=O)C)C>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][C:11]2=[O:14])=[CH:6][CH:5]=1
Reactant: O=C1NCCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1ccc2c(c1)C(=O)NCC2
Reaction time: 3.5 h
Yield: 105.2 %

Procedure:
10% Pd/C (100 mg) was added to a solution of 7-nitro-3,4-dihydro-2H-isoquinolin-1-one (I-24a: 900 mg, 4.6875 mmol) in methanol (20 mL) at room temperature under nitrogen atmosphere. The resulting mixture was hydrogenated at room temperature for 3.5 hours. The reaction was monitored by TLC (100% ethylacetate). The reaction mixture was filtered; the filtrate was concentrated and dried to afford 800 mg of the crude product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:4](Cl)=[O:5].[NH3:28].C1[CH2:33][O:32]CC1>CO>[NH2:28][C:4](=[O:5])[C@@H:3]([NH:7][C:8]([C:10]1[N:11]=[C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][C:14]=12)=[O:9])[C:2]([CH3:27])([CH3:26])[CH3:1].[CH:33]([O-:32])=[O:5]
Reactant: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(=O)Cl)C(C)(C)C)c2C1
Reactant: C1CCOC1
Reactant: N
Solvent: CO
Product: CN1CCn2c(-c3ccccc3)nc(C(=O)N[C@H](C(N)=O)C(C)(C)C)c2C1
Product: O=C[O-]
Reaction time: 2 h
Yield: 15 %

Procedure:
Intermediate 23A (0.11 g, 0.3 mmol) was dissolved in THF (2 mL) and 7M ammonia solution in methanol was added. The resulting mixture was stirred for 2 h, the solvent was evaporated and the residue was purified by prep LC/MS using 5-95% gradient acetonitrile/water with 0.1% formic acid to give Compound 285 as a formate salt (20 mg, 15%). 1H-NMR (400 MHz, CD3OD) δ: 1.11 (s, 9H), 2.59 (s, 3H), 2.93 (m, 2H), 4.09 (m, 2H), 4.21 (m, 2H), 4.40 (m, 1H), 7.51 (m, 3H), 7.72 (m, 2H), 8.31 (s, 1H); LCMS (+ESI) m/z 370.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.[C:22]([O-:25])([O-])=[O:23].[K+].[K+].[CH3:28][C:29](C)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][C@@H:28]([CH3:29])[C:22]([OH:25])=[O:23])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Reactant: CC(C)=O
Agent: [K+]
Product: C[C@H](Oc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1)C(=O)O
Yield: 46 %

Procedure:
(5-Bromo-2-hydroxyphenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone (100 mg, 0.29 mmol), (R)-(+)-bromoacetic acid (44 mg, 0.29 mmol) ethyl 2-bromopropionate and K2CO3 (80 mg, 0.58 mmol) in acetone was stirred at room temperature for 16 h. The reaction mixture was concentrated and the residue was partitioned between EtOAc and dilute HCl (pH˜1). The organic phase was dried (Na2SO4) and concentrated, and the residue was purified by flash chromatography (EtOAc:heptane, 1:1) to yield 55 mg (46%) of the title compound: Chiral HPLC (Column: Ciracel OD (0.46 cm×24 cm); Eluent: isocratic, 85% hexane+15% 2-propanol+0.1% TFA; Flow 0.5 mL/min) Rt 15.7 min, >90% e.e. (Racemic material eluates with baseline separation of enantiomers: Rt 15.7 and 16.7 min.) MS and NMR spectra correspond to racemic material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([OH:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1.C(N(CC)CC)C.O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:6](=[O:11])[CH2:7][CH2:8][C:9]=2[CH:10]=1
Reactant: OC1CCc2cc(Cl)cnc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: O=C1CCc2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ol (570 mg, 3.36 mmol) in dimethylsulphoxide (17.7 ml) was treated at room temperature with triethylamine (2.81 ml, 20.2 mmol) followed by sulfur trioxide-pyridine complex (1.6 g, 10.1 mmol). The solution was stirred at room temperature for 1 hour. After completion, the reaction mixture was treated with water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, then evaporated leaving a dark red liquid. The crude material was purified by flash chromatography on silica gel using a gradient of heptane/ethyl acetate=70:30 to 30:70 as the eluent. The 3-chloro-5,6-dihydro-[1]pyrindin-7-one was obtained as a pink solid (472 mg, 84%); (calculated) C8H6ClNO [167.60]; (found) [M+H]+=168.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:16]([NH:18][C:19]2[N:27]=[CH:26][N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][NH:23]3)[CH3:17])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:37](Cl)(=[O:39])[CH3:38]>C1COCC1.C(Cl)Cl>[N:27]1[C:19]([NH:18][C@H:16]([C:8]2[N:7]([CH:4]3[CH2:5][CH2:6][N:1]([C:37](=[O:39])[CH3:38])[CH2:2][CH2:3]3)[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)[CH3:17])=[C:20]2[C:24]([NH:23][CH:22]=[N:21]2)=[N:25][CH:26]=1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccccc2n1C1CCNCC1
Reactant: CC(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(n2c([C@H](C)Nc3ncnc4[nH]cnc34)nc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.5 %

Procedure:
To a stirred suspension of [(S)-1-(1-piperidin-4-yl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine 113 (46 mg, 0.127 mmol) and DIPEA (26 μL, 0.152 mmol) in anhydrous THF (3 mL) and anhydrous DCM (1 mL) was added acetyl chloride (9 μL, 0.127 mmol). Stirring at RT was continued for 3 h then volatiles were removed under reduced pressure and the resulting residue was partitioned between EtOAc and water. The aqueous layer was further washed with DCM and the organic layers were then washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residues were combined, purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 20 min gradient 5-70% 0.1% HCO2H in acetonitrile/water) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated under reduced pressure affording 115 as a white solid (10 mg, 19%). LCMS: RT 2.13 min [M+H]+ 405.1. 1H NMR (CDCl3, 400 MHz): δ 8.35 (1H, s), 7.88 (1H, s), 7.78-7.70 (1H, m), 7.49-7.42 (1H, m), 7.28-7.20 (3H, m), 6.05 (1H, s), 4.98-4.82 (1.5H, m), 4.71-4.61 (0.5H, m), 4.09-3.99 (0.5H, m), 3.90-3.78 (0.5H, m), 3.42-3.37 (0.5H, m), 3.32-3.18 (0.5H, m), 2.88-2.37 (1H, m), 2.20-2.10 (4H, m), 2.06-1.96 (1H, m), 1.90-1.69 (5H, m). Signals split due to presence of rotamers
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1.O.CCOCC>N1C=CC=CC=1>[C:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][S:22]([C:19]2[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=2)(=[O:24])=[O:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCC/C=C/c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: O
Solvent: CCOCC
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCC/C=C/Cc2ccccc2)cc1
Temperature: 10 °C
Reaction time: 5 h
Yield: 91.2 %

Procedure:
To a solution of 7.5 g of (E)-8-phenyl-7-octen-1-ol dissolved in 60 ml of pyridine, 9.1 g of p-toluenesulfonyl chloride was added at 0° C. After stirring at 10° C. for 5 hours, 10 ml of water was added and the mixture was stirred for 30 minutes, followed by addition of 200 ml of ether. The mixture was washed with 10% aqueous hydrochloric acid, water and saturated saline water. The organic layer was dried, and the solvent was removed under reduced pressure. The pale yellow oily product obtained was purified by silica gel column chromatography (solvent: hexane-ethyl acetate=5:1) to give 12 g of (E)-1-phenyl-8-p-toluenesulfonyloxy-2-octene as an oily product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7](O)=[O:8])([O-:3])=[O:2].C(Cl)(=O)C([Cl:16])=O.CN(C=O)C>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([Cl:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
To a suspension of 3-nitrobenzoic acid (934 mg, 5.64 mmol) in benzene (15 mL) was added oxalyl chloride (0.6 mL, 6.77 mmol) and DMF (7 mL), respectively. The resulting mixture was stirred at room temperature until a clear solution was formed. The solvent was removed under reduced pressure and crude acid chloride was used in the next reaction without further purification.