Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[C:8](C(O)=O)=[N:9][C:10]([Cl:14])=[C:11]([Cl:13])[N:12]=1.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:14][C:10]1[N:9]=[C:8]([N+:18]([O-:20])=[O:19])[C:7]([NH2:6])=[N:12][C:11]=1[Cl:13]
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(Cl)c(Cl)nc1C(=O)O
Agent: O=S(=O)(O)O
Product: Nc1nc(Cl)c(Cl)nc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a 450 ml concentrated sulfuric acid cooled to 10 is added 50.0 g (0.2 m) 3-amino-5,6-dichloropyrazine carboxylic acid. To this solution cooled to 0°-5°, is added a cold solution of 15 ml fuming sulfuric acid in 15 ml fuming nitric acid dropwise over 15 minutes. The reaction mixture is stirred at 0°-5° for 2 hours and then at ambient temperature for 2 hours. The reaction mixture is the poured onto ice and the yellow solid is collected. This solid is taken up in ethyl acetate, and then washed twice with saturated sodium carbonate solution and then the solution is filtered through a pad of silica gel. The resulting solution is evaporated in vacuo to afford 35 g of 5,6-dichloro-3-nitropyrazinamine, m.p. 169°-170°.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20]Br)[CH:9]=[CH:8][C:7]=1[C:22]([F:25])([F:24])[F:23])[CH3:2].[CH3:27][C@@H:28]1[C@H:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[O:31][C:30](=[O:39])[NH:29]1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[CH2:20][N:29]2[C@H:28]([CH3:27])[C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:31][C:30]2=[O:39])[CH:9]=[CH:8][C:7]=1[C:22]([F:23])([F:25])[F:24])[CH3:2]
Reactant: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CBr)ccc1C(F)(F)F
Reactant: C[C@H]1NC(=O)O[C@H]1c1ccccc1
Product: CCOC(=O)Cc1cc(Oc2ccc(Br)cc2CN2C(=O)O[C@@H](c3ccccc3)[C@H]2C)ccc1C(F)(F)F

Procedure:
Prepared according to the procedure described in Example 24, Step 7, using the following starting materials: [5-(4-bromo-2-bromomethyl-phenoxy)-2-trifluoromethyl-phenyl]-acetic acid ethyl ester and (4R,5S)-4-methyl-5-phenyl-2-oxazolidinone.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].I[CH2:24][CH2:25][OH:26]>C(#N)C>[F:1][C:2]1[C:7]([CH:8]2[CH2:9][CH2:10][N:11]([CH2:24][CH2:25][OH:26])[CH2:12][CH2:13]2)=[CH:6][CH:5]=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: OCCI
Reactant: CC(=O)c1cccc(C2CCNCC2)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cccc(C2CCN(CCO)CC2)c1F

Procedure:
Preparation according to Example 1: 1-(2-fluoro-3-piperidin-4-ylphenyl)ethanone (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethanol (0.01 g). MS m/z (rel. intensity, 70 eV) 265 (M+, 1), 235 (16), 234 (bp), 133 (5), 109 (5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:37]=[CH:36][C:17]([O:18][CH2:19][C:20]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=4[Cl:35])([OH:27])[CH2:21][N:22]4[CH:26]=[N:25][CH:24]=[N:23]4)=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:44][C:45]([F:52])([F:51])[CH2:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[Cl:35][C:29]1[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:28]=1[C:20]([OH:27])([CH2:19][O:18][C:17]1[CH:36]=[CH:37][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][S:47]([CH2:46][C:45]([F:52])([F:51])[F:44])(=[O:49])=[O:48])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: O=S(=O)(Cl)CC(F)(F)F
Reactant: Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(CC(F)(F)F)Nc1ccc(N2CCN(c3ccc(OCC(O)(Cn4cncn4)c4ccc(Cl)cc4Cl)cc3)CC2)cc1

Procedure:
To a solution of 3-(4-[4-(4-aminophenyl)piperazin-1-yl]phenoxy)-2-(2,4-dichlorophenyl)-1-(1H-1,2,4-triazol-1-yl)propan-2-ol (see Preparation 1) (0.2 g, 0.37 mmole) and pyridine (0.06 g, 0.75 mmole) in methylene chloride (20 ml) at 0° was added, dropwise, a solution of 2,2,2-trifluoroethanesulphonyl chloride (0.095 g, 0.52 mmole) in methylene chloride (1 ml) and the resulting mixture was stirred for 0.5 hour. The reaction was quenched by the addition of aqueous citric acid, the resulting organic phase separated, washed with water and dried over magnesium sulphate. After concentration under reduced pressure the residue was purified by flash chromatography on silica gel eluting with ethyl acetate (80):hexane (20) to yield, after collection and evaporation of appropriate fractions, the desired product as a foam, m.p. 74°-75° (0.159 g, 62%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2([NH:27]C(=O)OC(C)(C)C)[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[ClH:35]>C(Cl)Cl.CCOCC>[ClH:35].[NH2:27][C:23]1([C:20]2[CH:21]=[CH:22][C:17]([C:3]3[C:2](=[O:1])[C:10]4[C:5]([C:4]=3[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:18][CH:19]=2)[CH2:26][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C3=C(c4ccccc4)c4ccccc4C3=O)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: NC1(c2ccc(C3=C(c4ccccc4)c4ccccc4C3=O)cc2)CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of tert-butyl 1-(4-(1-oxo-3-phenyl-1H-inden-2-yl)phenyl)cyclobutylcarbamate (6 mg, 0.0133 mmol) in DCM (1.0 mL) was added 2 M HCl in ether (2.0 mL). The reaction mixture was stirred at RT for 24 h and concentrated in vacuo to give the title compound (3 mg, 64%). 1H NMR (500 MHz, CD3OD): 7.65-7.10 (m, 13H), 2.75-2.60 (m, 2H), 2.55-2.45 (m, 2H), 2.20-2.05 (m, 1H), 1.95-1.80 (m, 1H). LCMS (Method I): [M+H]+=353.
Reaction SMILES: P(Br)(Br)[Br:2].[N+:5]([C:8]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10]O)([O-:7])=[O:6].O>C(Cl)Cl>[N+:5]([C:8]1[C:15]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:14][CH:13]=[CH:12][C:9]=1[CH2:10][Br:2])([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1c(CO)cccc1Oc1ccccc1Cl
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1c(CBr)cccc1Oc1ccccc1Cl
Temperature: 0 °C

Procedure:
A solution of Phosphorus tribromide (1.72 ml) in methylene chloride (15 ml) was added dropwise to a solution of 2-nitro-3-(2-chlorophenoxy)benzyl alcohol (9.6 g) in methylene chloride (80 ml) at -10° C., and the mixture was stirred at 0° C. for an hour. To the reaction mixture was added water (50 ml), and the methylene chloride layer was separated, washed with aqueous sodium bicarbonate and saline, dried and then evaporated in vacuo. The oily residue was subjected to column chromatography on silica gel (110 g) and eluted with a mixture of n-hexane and benzene (2:1). The eluate was evaporated in vacuo, and the residue was recrystallized from a mixture of benzene and n-hexane to give 2-nitro-3-(2-chlorophenoxy)benzyl bromide (2.7 g). mp 68°-70° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)[CH3:2].C(OC)(=O)[CH2:15][C:16](OC)=[O:17].C[O-].[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][C:11](=[O:13])[CH:12]=[C:16]([OH:17])[CH2:15]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: COC(=O)CC(=O)OC
Reactant: CCc1ccc(C=CC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(C2CC(=O)C=C(O)C2)cc1
Temperature: 25 °C

Procedure:
144 g (0.83 mol) of 4-(4-ethylphenyl)-3-buten-2-one dissolved in a small amount of methanol is dripped into 109 g (0.83 mol) of dimethyl malonate and 45 g (0.83 mol) of sodium methylate in 40 ml of methanol. The mixture is stirred at reflux for 3 hours and for 10 hours at room temperature. The methanol is distilled off, and the residue is taken up in 2 liters of 10% strength potassium hydroxide solution and stirred for 8 hours at room temperature. At 60° C., the mixture is acidified to pH 1 with concentrated hydrochloric acid. The mixture is stirred for a further 2 hours and suction filtered, and the precipitate is dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16][CH:17]([C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH3:18])[CH:6]=[CH:7][C:8](OCC)=[O:9].[H-].C([Al+]CC(C)C)C(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:7]/[CH2:8][OH:9])[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([C:19]1[N:20]=[C:21]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:22][C:23]=1[CH3:24])[CH3:18]
Reactant: CCOC(=O)C=Cc1ccc(OC(C)c2nc(-c3ccccc3)oc2C)c(OC)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: COc1cc(/C=C/CO)ccc1OC(C)c1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Reference Example 24, ethyl 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]cinnamate was subjected to reduction reaction with diisobutylaluminum hydride to yield (E)-3-[3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]-2-propen-1-ol.
Reaction SMILES: C(S[C:9](=[O:49])[CH:10]([CH:18]1[CH:25]=[CH:24][CH2:23][CH:22]([CH:26]([NH:39]C(OC(C)(C)C)=O)[CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34]C(C)(C)C)=[CH:30][CH:29]=2)[O:21][Si](C)(C)[O:19]1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.N1C=CC=CC=1.[Li+].[OH-:57].OO>C1COCC1>[NH2:39][CH:26]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=1)[CH:22]([OH:21])[CH2:23]/[CH:24]=[CH:25]\[CH:18]([OH:19])[CH:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:9]([OH:57])=[O:49]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(OC(C)(C)C)cc1)C1CC=CC(C(Cc2ccccc2)C(=O)SCc2ccccc2)O[Si](C)(C)O1
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NC(Cc1ccc(O)cc1)C(O)C/C=C\C(O)C(Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Compounds 8 were silyl deprotected in parallel with HF/pyridine in THF at 0° C. for 30 minutes according to the reported procedure. The products were purified by flash chromatography (4:1 hexanes:EtOAc to 1:1 hexanes:EtOAc) to give the desilylated products in the following yields: (S,S,S,R) 83%, (S,S,R,R) 67%, (S,R,R,R) 85%, (S,R,S,R) 81%. To hydrolyze the thioester to the free acid, these products were dissolved in THF (40 ml/mmole) in parallel, and a 1:1 mixture of 0.2 N LiOH (aq, 4 eq.) and 30% H2O2 (aq) was added to each. The reactions were stirred at room temperature for 3 hours, then cooled to 0° and quenched with 2N NaHSO3 (aq, 5 mL per ml 30% H2O2). The reactions were extracted with EtOAc, washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to give clean 15 in the following yields: (S,S,S,R)-15 100%, (S,S,R,R)-15 96%, (S,R,R,R)-15 100%, (S,R,S,R)-15 100%.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=O.Cl.[NH2:29][OH:30].N1C=CC=CC=1>C(O)C>[F:27][C:5]1[N:6]([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:3]([CH:1]=[N:29][OH:30])[N:4]=1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1
Reaction time: 18 h

Procedure:
To a stirred mixture of 4-formyl-2-fluoro-1-triphenylmethylimidazole (0.356 g.) and hydroxylamine hydrochloride (0.035 g.) in ethanol (4 ml.) was added pyridine (0.2 ml.). Stirring was continued at ambient temperature for 18 hours and the precipitated solid was filtered to give 2-fluoro-4-hydroxyiminomethyl-1-triphenylmethylimidazole, m.p. 147°-149°. Further amounts of product could be isolated from the mother liquors.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]([OH:11])[O:5][CH2:6][CH:7]([CH2:9][CH3:10])[CH:8]=1)[CH3:2].[H][H]>[Ni].O>[CH2:1]([CH:3]([CH2:8][CH:7]([CH2:9][CH3:10])[CH2:6][OH:5])[CH2:4][OH:11])[CH3:2]
Reactant: CCC1=CC(CC)COC1O
Reactant: [H][H]
Agent: [Ni]
Solvent: O
Product: CCC(CO)CC(CC)CO

Procedure:
3,5-Diethyl-5,6-dihydro-2H-2-pyranol obtained in Example 3 (5 g) was put into a 100-ml autoclave together with 0.25 g of Raney nickel and 0.5 ml of water, followed by stirring at 120° C. for 5 hours at a hydrogen pressure of 30 kg/cm2. After the catalyst was filtered off from the reaction mixture, water was distilled under reduced pressure to obtain 2,4-diethyl-1,5-pentanediol quantitatively.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:13]3[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=3[N:7]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Yield: 49.3 %

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.FC(F)(F)C(O)=O.[CH3:31][S:32]([N:35]1[CH2:40][CH2:39][CH:38]([NH2:41])[CH2:37][CH2:36]1)(=[O:34])=[O:33]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[C:12]([F:18])[C:11]=2[CH3:19])=[O:9])=[CH:6][N:5]=[C:4]([NH:41][CH:38]2[CH2:39][CH2:40][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)ccc(F)c2C)c(N)n1
Reactant: CS(=O)(=O)N1CCC(N)CC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)c(C)c1C(=O)c1cnc(NC2CCN(S(C)(=O)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(3-fluoro-6-methoxy-2-methyl-phenyl)-methanone (Example 350) and 1-methanesulfonyl-piperidin-4-ylamine; compound with trifluoroacetic acid (Example 162) to give [4-amino-2-(1-methanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(3-fluoro-6-methoxy-2-methyl-phenyl)-methanone. MS (M+H)+, 438
Reaction SMILES: [C:1]([OH:6])(=O)[C@H:2]([CH3:4])[OH:3].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.[CH:37]1([CH2:40][N:41]2[C:49]([N:50]3[CH2:55][CH2:54][NH:53][C@@H:52]([CH3:56])[CH2:51]3)=[N:48][C:47]3[C:42]2=[N:43][C:44]([C:63]2[CH:64]=[N:65][C:66]([NH2:69])=[N:67][CH:68]=2)=[N:45][C:46]=3[N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[CH2:39][CH2:38]1>C(Cl)Cl.CO.CN(C)C=O>[NH2:69][C:66]1[N:65]=[CH:64][C:63]([C:44]2[N:43]=[C:42]3[C:47]([N:48]=[C:49]([N:50]4[CH2:55][CH2:54][N:53]([C:1](=[O:6])[C@@H:2]([OH:3])[CH3:4])[C@@H:52]([CH3:56])[CH2:51]4)[N:41]3[CH2:40][CH:37]3[CH2:39][CH2:38]3)=[C:46]([N:57]3[CH2:62][CH2:61][O:60][CH2:59][CH2:58]3)[N:45]=2)=[CH:68][N:67]=1
Reactant: C[C@H](O)C(=O)O
Reactant: C[C@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)CCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](O)C(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC2CC2)C[C@@H]1C
Reaction time: 20 h
Yield: 66 %

Procedure:
L-Lactic acid (27.1 μl, 0.31 mmol), 1-hydroxybenzotriazole monohydrate (39.3 mg, 0.26 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (73.8 mg, 0.38 mmol), and triethylamine (53.6 μl, 0.38 mmol) were added to an N,N-dimethylformamide solution (2.0 ml) of 5-{9-(cyclopropylmethyl)-8-[(3S)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (115.6 mg, 0.26 mmol) at room temperature. The resulting mixture was stirred for 20 hours followed by the addition of L-lactic acid (27.1 μl, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (73.8 mg, 0.38 mmol), and triethylamine (53.6 μl, 0.38 mmol) and the resulting mixture was stirred for 3 days. L-Lactic acid (27.1 μl, 0.31 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (73.8 mg, 0.38 mmol), and triethylamine (53.6 μl, 0.38 mmol) were further added, the resulting mixture was stirred for 2 days, and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (double development with methylene chloride:methanol=15:1) to give the title compound (89.7 mg, 67%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[N:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)([CH3:23])[CH3:22]>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:20])[N:7]([CH2:17][CH:18]=[CH2:19])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:30]([C:27]2[CH:28]=[CH:29][C:24]([CH:21]([CH3:23])[CH3:22])=[CH:25][CH:26]=2)(=[O:32])=[O:31])=[CH:12][CH:11]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=CCN(CCc1ccc(N)cc1)C(=O)OC(C)(C)C
Solvent: c1ccncc1
Product: C=CCN(CCc1ccc(NS(=O)(=O)c2ccc(C(C)C)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 646.9 %

Procedure:
To a solution of allyl-[2-(4-amino-phenyl)ethyl]-carbamic acid tert-butyl ester (1.86 g, 6.74 mmol) in pyridine (25 ml) at 0° C. was added 4-isopropyl-benzenesulfonyl chloride (1.47 g, 6.74 mmol) and the mixture was stirred at 0° C. for 1 h. After concentration in vacuo the residue was partitioned between ethyl acetate and saturated aqueous NaHCO3. The organic layer was washed with water, dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The residue was purified by column chromatography (n-heptane/ethyl acetate, 2/1) to give the product as a yellow resin (1.35 g, 43.6 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[N:7]([CH3:16])[CH2:8][CH:9]([CH2:13][CH2:14]Cl)[CH2:10][C:11]=2[N:12]=1.[NH:18]1[CH2:21][CH2:20][CH2:19]1.[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24]>>[C:22]([OH:27])(=[O:26])[C:23]([OH:25])=[O:24].[N:18]1([CH2:14][CH2:13][CH:9]2[CH2:8][N:7]([CH3:16])[C:6](=[O:17])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[N:12][C:11]=3[CH2:10]2)[CH2:21][CH2:20][CH2:19]1
Reactant: C1CNC1
Reactant: CN1CC(CCCl)Cc2nc(Cl)ccc2C1=O
Agent: O=C(O)C(=O)O
Product: CN1CC(CCN2CCC2)Cc2nc(Cl)ccc2C1=O

Procedure:
Following the procedure of Example 21, 2-chloro-8-(2-chloroethyl)-6,7,8,9-tetrahydro-6-methyl-5H-pyrido[3,2-c]azepin-5-one and azetidine are reacted and the free base of the title is isolated and reacted with oxalic acid.
Reaction SMILES: CN.[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[O:13])[NH:10]2)=[CH:6][C:5]=1[C:14]([OH:16])=O.F[B-](F)(F)F.[N:22]1(OC(N(C)C)=[N+](C)C)[C:26]2C=CC=CC=2N=N1.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][C:9](=[O:13])[NH:10]2)=[CH:6][C:5]=1[C:14]([NH:22][CH3:26])=[O:16]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C1Cc2cc(C(=O)O)c(Br)cc2N1
Agent: CN
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2c(cc1Br)NC(=O)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 48.4 %

Procedure:
Methylamine (0.75 mL, 2.0 M in tetrahydrofuran) was added to a stirred solution of 6-bromo-2-oxoindoline-5-carboxylic acid (0.246 g, 0.96 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.369 g, 1.15 mmol), 1-hydroxybenzotriazole hydrate (0.176 g, 1.15 mmol), and diisopropylethylamine (0.55 mL, 3.16 mmol) in dry N,N-dimethylformamide (4 mL) under an atmosphere of nitrogen. The resulting mixture was stirred at room temperature for 1.5 h. An aqueous solution of sodium bicarbonate was added and the solvent was evaporated. The resulting residue was purified on a silica gel column using dichloromethane/methanol, (9:1), as the eluent to give 0.125 g (48% yield) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 7.27 (s, 1H), 7.11 (s, 1H), 3.20 (m, 2H), 3.09 (s, 3H); MS (ES) m/z 269 and 271 (M++1).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@H:3]1[O:11][C:12]1[C:13]2[N:14]([C:18]([N:22]=O)=[C:19]([CH3:21])[N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(O)(=O)C.C(=O)([O-])O.[Na+]>[Zn].O>[NH2:22][C:18]1[N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C@@H:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@H:2]3[OH:1])[C:13]2=[N:20][C:19]=1[CH3:21]
Reactant: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1N=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc2c(O[C@@H]3c4ccccc4C[C@H]3O)cccn2c1N

Procedure:
0.5 g of 8-(2-(trans)-hydroxy-2,3-dihydro-1-indenyloxy)-2-methyl-3-nitroso-imidazo[1,2-a]pyridine is dissolved in a mixture consisting of 10 ml glacial acetic acid and 3 ml water and 0.5 g commercial zinc powder is added at 0° C. waterbath temperature. After one hour the solution is diluted with 100 ml icewater adjusted to pH 8 with saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The combined extracts are dried over potassium carbonate. After removal of the solvent in vacuo, the mixture is purified over silica gel (methylene chloride/methanol=98/02). After recrystallization from ethanol the title compound of 125°-127° C. is obtained.