Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.ClC1N=CC=CN=1.Br[C:37]1[CH:42]=[CH:41][N:40]=[C:39]([O:43][C:44]2C=CC(NC3N=C(N)C=C(C4C=CC=CC=4)N=3)=CC=2)[CH:38]=1.COC[C@@H]1CCCN1>>[CH3:44][O:43][CH2:39][C@@H:38]1[CH2:37][CH2:42][CH2:41][N:40]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:19]=[C:18]([NH2:28])[N:17]=3)=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Nc1cc(-c2ccccc2)nc(Nc2ccc(Oc3cc(Br)ccn3)cc2)n1
Reactant: Nc1nc(Nc2ccc(Oc3cc(Br)ccn3)cc2)cc(-c2ccccc2)n1
Agent: COC[C@@H]1CCCN1
Agent: Clc1ncccn1
Product: COC[C@@H]1CCCN1c1ccnc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)c1
Temperature: 108 °C
Reaction time: 24 h
Yield: 40 %

Procedure:
N4-{4-[(4-Bromopyridin-2-yl)oxy]phenyl}-6-phenylpyrimidine-2,4-diamine (75 mg, 0.17 mmol, was prepared by the method of Example 1 using and Intermediates 2T and 1A as starting materials. N-[4-(4-bromo-pyridin-2-yloxy)-phenyl]-6-phenyl-pyrimidine-2,4-diamine, was then combined with (S)-(+)-2-(methoxymethyl)pyrrolidine (99.5 mg, 0.86 mmol) in a 5-mL reaction flask and heated at 108° C. with stirring for 24 h. TLC and LC-MS indicated that the reaction was complete. After cooling to rt, the reaction mixture was extracted with EtOAc and washed with 1N aqueous sodium hydroxide solution (2×) and H2O (3×). The organic layer was dried and concentrated to give 75 mg of the crude product. The residue was purified by Prep-TLC (CH3OH:EtOAc=2:8) to obtain 32 mg (40%) of the title product as a yellowish oil. 1H NMR (CD3OD) δ 7.82 (m, 2H), 7.70 (m, 3H), 7.41 (m, 3H), 7.04 (d, 2H), 6.41 (m, 2H), 5.94 (s, 1H), 3.86 (s, 1H), 3.38 (m, 2H), 3.30 (m, 3H), 3.18 (m, 1H), 2.01 (m, 4H), 1.30 (m, 1H); MS ES 469 (M+H)+, calcd 469, RT=1.9 min; TLC (EtOAc) Rf=0.2.
Reaction SMILES: [CH3:1][N:2]([S:31]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)(=[O:33])=[O:32])[C:3]1[CH:4]=[C:5]([O:24][CH2:25][C:26](OCC)=[O:27])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2.[BH4-].[Li+].Cl.C(=O)([O-])O.[Na+]>O1CCCC1>[OH:27][CH2:26][CH2:25][O:24][C:5]1[CH:6]=[C:7]2[C:11](=[C:3]([N:2]([CH3:1])[S:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)(=[O:32])=[O:33])[CH:4]=1)[NH:10][C:9]([C:12]1[S:13][CH:14]([CH2:17][N:18]3[CH2:23][CH2:22][S:21][CH2:20][CH2:19]3)[CH2:15][N:16]=1)=[CH:8]2
Reactant: CCOC(=O)COc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=NCC(CN4CCSCC4)S3)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: C1CCOC1
Product: CN(c1cc(OCCO)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 55.2 %

Procedure:
To a solution of ethyl ({7-[methyl(pyridin-2-ylsulfonyl)amino]-2-[5-(thiomorpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-5-yl}oxy)acetate (400 mg) in tetrahydrofuran (5 mL) was added lithium borohydride (18 mg) under ice-cooling, and the mixture was stirred at room temperature for 3 days. 1N Hydrochloric acid was added under ice-cooling, and the mixture was basified with saturated aqueous sodium hydrogencarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure: The residue was crystallized from ethyl acetate to give the title compound (205 mg, yield 55%) as a colorless solid. melting point 160-162° C.
Reaction SMILES: C(O[C:4]1[C:5](=[O:18])[C:6](=[O:17])[C:7]=1[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])C.[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([NH:23][C:4]1[C:5](=[O:18])[C:6](=[O:17])[C:7]=1[NH:8][C:9]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=1[OH:16])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOc1c(Nc2c(C)cccc2O)c(=O)c1=O
Reactant: CC(C)(C)N
Solvent: ClCCl
Product: Cc1cccc(O)c1Nc1c(NC(C)(C)C)c(=O)c1=O
Reaction time: 168 h

Procedure:
3-Ethoxy-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione (0.4 g, 1.62mmol) in t-butylamine (4.8mL) and dichloromethane (4.8mL) was allowed to stand at room temperature for 7 days. The slurry was filtered, rinsed with ethyl acetate, and dried. Chromatography with 10% methanol in dichloromethane, followed by trituration with 5% ethyl acetate in hexane gave 3-tert-butylamino-4-(2-hydroxy-6-methyl-phenylamino)-cyclobut-3-ene-1,2-dione, 0.18 g (0.66 mmol, 41%).
Reaction SMILES: [O-]CC.[K+].[C:5]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH3:17][C:18]([CH3:20])=O.C(Br)C>CN(C)C=O>[C:18](=[C:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:5]([O:14][CH2:15][CH3:16])=[O:13])([CH3:20])[CH3:17]
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: CC(C)=O
Agent: CC[O-]
Agent: [K+]
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C(=O)OCC)=C(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
52.5 mmol of potassium ethoxide were suspended in 100 mL of N,N-dimethylformamide in a 250 mL round bottom flask. To this slurry, heated up to 60° C., a mixture of 50 mmol of diethyl succinate and 57.5 mmol of acetone was added dropwise in 10 minutes. The course of the reaction was detected by GC. After 60 minutes the reaction was completed with a conversion of 97.2% (determined by GC). Then 87.5 mmol of ethyl bromide were added to the reaction mixture at 60° C. The slurry was stirred for 60 minutes at 60° C. The reaction was complete, giving the product isomers with a yield of 95% (determined by GC).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[F:15][C:16]1[C:17]([CH3:27])=[C:18]([CH:24]=[CH:25][CH:26]=1)[CH:19]=[CH:20][C:21](O)=O>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:21](/[CH:20]=[CH:19]/[C:18]3[CH:24]=[CH:25][CH:26]=[C:16]([F:15])[C:17]=3[CH3:27])=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: Cc1c(F)cccc1C=CC(=O)O
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Product: CCn1c(=O)c2[nH]c(/C=C/c3cccc(F)c3C)nc2n(CC)c1=O
Yield: 50.5 %

Procedure:
Substantially the same procedure as in Example 7 was repeated using 2.50 g (12.6 mmol) of 5,6-diamino-1,3-diethyluracil and 2.50 g (13.9 mmol) of 3-fluoro-2-methylcinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane to give 2.18 g (yield 51%) of Compound 171 as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OS(C(F)(F)F)(=O)=O)=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH:37](NC(C)C)(C)[CH3:38]>CN(C=O)C.[Cu]I.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:37]#[CH:38])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2ccc(F)cc2)c1OS(=O)(=O)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: C#Cc1c(C(=O)OCC)ncc2c1ccn2Cc1ccc(F)cc1
Temperature: 90 °C
Reaction time: 18 h

Procedure:
To a solution of 1-(4-fluoro-benzyl)-4-trifluoromethanesulfonyloxy-1H-pyrrolo[2,3-c]pyridine -5-carboxylic acid ethyl ester (2.0 g, 4.48 mmol) in DMF (4.5 mL) and diisopropylamine (4.5 mL) was added trimethylsilylalkyne (4.4 mL, 31.4 mmol), copper (I) iodide (68 mg, 0.36 mmol), and bis(triphenylphosphine) palladium (II) chloride (126 mg, 0.18 mmol). The reaction was vacuum degassed with nitrogen three times, and then heated in a pre-heated oil bath at 90° C. After thirty minutes, the reaction was cooled to room temperature and diluted with 20 mL of ethyl acetate. The solution was filtered through a silica plug (15 mm×10 mm), and concentrated. The resulting oil was dissolved in EtOH (25 mL), and potassium carbonate (1.24 g, 9 mmol) was added. The reaction was stirred for 18 hours at room temperature, and then the solids were removed by filtration. The solvent was removed by rotary evaporation, and the resulting residue was dissolved in CH2Cl2 (80 mL). The organic layer was washed with 2×50 mL of water, and then 50 mL of saturated NaCl. After drying the organic liquid over MgSO4, the solids were removed by filtration and then the solvent was removed by rotary evaporation to give the desired product. Yield 0.927 g, 64%. MS (APCI): Calc: 322, Found: (M+H) 323.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)O1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH:31]1[C:32]2[C:28](=[C:27]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([CH:11]=[O:12])=[CH:8][C:6]=4[N:7]=3)[CH:35]=[CH:34][CH:33]=2)[CH:29]=[N:30]1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Yield: 75.8 %

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (66) (100 mg, 0.35 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole (70) (95 mg, 0.39 mmol) and sodium carbonate (112 mg) were suspended in toluene (2.5 mL), ethanol (1.5 mL) and water (0.7 mL). To this was added bis(triphenylphosphine)palladium(II) chloride (13.5 mg) and the reaction vessel was flushed with argon. The reaction mixture was microwaved at 120° C. for 1 hour and then partitioned between dichloromethane and water, the organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting residue was purified using flash chromatography to yield the title compound 71 (97 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[S:15][CH2:16][CH:17]([CH3:19])[CH3:18])=O.COC1C=CC(/C=[C:35]2/[C:36]([NH:38][C:39]([S:41]/2)=[NH:40])=[O:37])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:40][C:39]1[S:41]/[C:35](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[S:15][CH2:16][CH:17]([CH3:19])[CH3:18])/[C:36](=[O:37])[N:38]=1
Reactant: CC(C)CSc1c(C#N)cnc2ccc(C=O)cc12
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CSc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-isobutylsulfanyl-quinoline-3-carbonitrile (example 65b), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 369 (MH+).
Reaction SMILES: [ClH:1].[Cl:2][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1.[CH3:17][N:18](C)C=O.CN.N>ClC(Cl)Cl.CO>[ClH:2].[ClH:1].[CH3:17][NH:18][CH2:3][C:4]1[N:8]([CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:7]=[N:6][CH:5]=1
Reactant: CN(C)C=O
Reactant: CC(c1ccccc1)n1cncc1CCl
Agent: CN
Agent: Cl
Agent: N
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CNCc1cncn1C(C)c1ccccc1
Yield: 44.5 %

Procedure:
Through a stirred mixture of 3 parts of 5-(chloromethyl)-1-(1-phenylethyl)-1H-imidazole monohydrochloride and 45 parts of N,N-dimethylformamide were bubbled 3 equivalents of gaseous methanamine at room temperature during a 1 hour-period: exothermic reaction, the temperature rose to 50° C. The reaction mixture was taken up in trichloromethane and methanol, previously saturated with ammonia, was added. The formed precipitate was filtered off and the filtrate was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in 2-propanol. The salt was filtered off, washed with 2-propanol, dried and crystallized from 2-propanol, yielding 1.6 parts (44.5%) of (±)-N-methyl-1-(1-phenylethyl)-1H-imidazole-5-methanamine dihydrochloride.monohydrate; mp. 109° C. (compound 8.38).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:8]=[N:7]2.C([Sn](CCCC)(CCCC)[C:24]([O:26]CC)=[CH2:25])CCC.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[C:13]1([NH:12][C:9]2[CH:8]=[N:7][C:6]3[C:11]([N:10]=2)=[C:2]([C:24](=[O:26])[CH3:25])[CH:3]=[CH:4][CH:5]=3)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1cccc2ncc(Nc3ccccc3)nc12
Agent: [Cu]I
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: CC(=O)c1cccc2ncc(Nc3ccccc3)nc12
Temperature: 160 °C
Yield: 78 %

Procedure:
A mixture of 8-chloro-N-phenylquinoxalin-2-amine (0.65 g, 2.54 mmol), tributyl(1-ethoxyvinyl)stannane (1.288 ml, 3.81 mmol, Aldrich), Pd2(dba)3 (0.582 g, 0.636 mmol), XPhos (Strem, Newburyport, Mass.; 0.303 g, 0.636 mmol), copper(I) iodide (0.097 g, 0.508 mmol), and cesium fluoride (0.772 g, 5.08 mmol) in dioxane (12.71 ml) was heated in a microwave (Biotage Initiator) for 20 min at 160° C. Purification by silica gel (100% hexanes to 30% EtOAc/hexanes) provided 1-(3-(phenylamino)quinoxalin-5-yl)ethanone (180b, 78% yield) as a yellow oil. MS (ESI, pos. ion) m/z: 264.2 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[C:10]([NH2:29])=[N:11][CH:12]=[C:13]([C@@H:15]2[CH2:20][CH2:19][CH2:18][C@H:17]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16]2)[N:14]=1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:8][C:9]1[C:10]([NH:29][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:11][CH:12]=[C:13]([CH:15]2[CH2:20][CH2:19][CH2:18][CH:17]([O:21][Si:22]([C:25]([CH3:27])([CH3:26])[CH3:28])([CH3:23])[CH3:24])[CH2:16]2)[N:14]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCC[C@@H](c2cnc(N)c(Br)n2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)Nc1ncc(C2CCCC(O[Si](C)(C)C(C)(C)C)C2)nc1Br
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Pivaloyl chloride (71.5 μL, 0.569 mmol) was added dropwise to a stirred, cooled (0° C.) mixture of (+/−)-3-bromo-5-((1R,3S)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-amine (110 mg, 0.285 mmol) and TEA (159 μL, 1.139 mmol) in CH2Cl2 (949 μL). The red mixture was stirred at 0° C. for 1 h, then at room temperature for 2 h. EtOAc and Sat NaHCO3 was added and stirred well. Organic layer was separated and the aqueous layer was extracted well with EtOAc. Combined EtOAc layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with EtOAc/heptane to give (+/−)-N-(3-bromo-5-(3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide 97 mg in 72.4% yield. LCMS (m/z): 472.3 (MH+), 1.19 min.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:16]=2)=[N:7]1)C>C(O)C.S(=O)(=O)(O)O>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][N:15]2[CH:16]=[C:12]([C:8]3[CH:9]=[C:10]4[NH:11][CH:4]=[CH:5][N:6]4[N:7]=3)[CH:13]=[N:14]2)=[CH:19][CH:20]=1
Reactant: CCOC(Cn1nc(-c2cnn(Cc3ccc(OC)cc3)c2)cc1N)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc(Cn2cc(-c3cc4[nH]ccn4n3)cn2)cc1

Procedure:
In a microwave oven (Biotage Initiator, with Dynamic Field Tuning), 155 mg (0.40 mmol) of the compound of Example 2A in 0.4 ml of ethanol and 0.2 ml of 2 M sulphuric acid were heated at 120° C. for 15 min. The reaction was then purified directly by preparative HPLC (Method 11). The product fractions were concentrated and the residue was dried under high vacuum. This gave 54 mg (46% of theory) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[O:7])=[CH:4][CH:3]=1.[N+](=[CH2:18])=[N-]>O1CCCC1>[CH3:18][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])=[O:7])=[CH:14][CH:15]=1
Reactant: O=C1CCCN1C(=O)c1ccc(O)cc1
Reactant: C=[N+]=[N-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)N2CCCC2=O)cc1

Procedure:
150 mg. of 1-(p-hydroxybenzoyl)-2-pyrrolidinone are dissolved in 7 ml. of absolute tetrahydrofuran and then etheric diazomethane solution is added. The solvents are distilled off, the residue is triturated with diethyl ether and the mixture is filtered. There is obtained 1-(p-methoxybenzoyl)-2-pyrrolidinone which melts at 117.5°-119° C. after sublimation.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([N:10]=1)=[C:8]([N:11]1[CH2:16][CH2:15][O:14][CH2:13][C@H:12]1[CH3:17])[N:7]=[C:6]([Cl:18])[N:5]=2.[F-].[Cs+].[NH:21]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25](B(O)O)[C:24]=2[CH:23]=[CH:22]1>CC#N.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([C:25]3[CH:26]=[CH:27][CH:28]=[C:29]4[C:24]=3[CH:23]=[CH:22][NH:21]4)[NH:3]2)=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][C@H:12]2[CH3:17])[N:7]=1
Reactant: OB(O)c1cccc2[nH]ccc12
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(Br)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CC#N
Product: C[C@@H]1COCCN1c1nc(Cl)nc2[nH]c(-c3cccc4[nH]ccc34)nc12
Yield: 63.7 %

Procedure:
In a sealed tube, to a solution of 8-bromo-2-chloro-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (495 mg, 1.49 mmol) in CH3CN/H2O (11/1.1 mL) was added cesium fluoride (452 mg, 2.98 mmol), indole-4-boronic acid (266 mg, 1.64 mmol), and tetrakis(triphenylphosphine)palladium (172 mg, 0.15 mmol). Then the reaction was conducted under microwave irradiation at 160° C. for 30 min. The solvents were removed under reduced pressure and the crude was purified by flash column chromatography (20-100% EtOAc/cyclohexane gradient) to provide 2-chloro-8-(1H-indol-4-yl)-6-((R)-3-methyl-morpholin-4-yl)-9H-purine (350 mg, 63.8%) as a pale yellow solid. LC-MS at 254 nm; [M+H] 369.2; Rt 1.00 min; (LCMS method 1). (400 MHz, DMSO-d6): 13.59 (s, 1H), 11.41 (s, 1H), 7.73 (dd, 1H), 7.58-7.49 (m, 2H), 7.38-7.20 (m, 2H), 5.14 (s, 1H), 4.05-4.01 (m, 1H), 3.79-3.88 (m, 1H), 3.69-3.79 (m, 1H), 3.57 (s, 1H), 3.60 (s, 1H), 1.41 (d, 3H)
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[CH:16]=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:23]O.C([O-])=O.[Na+].O>C(O)=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]3[CH2:20][CH2:19][CH2:18][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]#[N:23])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
35.7 g (118 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde are heated to boiling under reflux for 6 hours together with 9.52 g (137 mmol) of hydroxylamine hydrochloride and 14.6 g (214 mmol) of sodium formate in 178 ml of formic acid. The solution obtained is then poured into 2.5 l of water; the precipitated product is filtered off under suction and rinsed with water. After recrystallization from methylene chloride/ethyl acetate there is obtained (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carbonitrile of melting point 236°-237°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[C@H:13]([CH3:29])[NH:14][CH:15]([C:25]([O:27]C)=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:4])([CH3:3])[CH3:2]>CO.O>[C:1]([O:5][C:6](=[O:31])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:30])[C@H:13]([CH3:29])[NH:14][CH:15]([C:25]([OH:27])=[O:26])[CH2:16][CH2:17][C:18](=[O:24])[C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C(CCC(=O)c1cccs1)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: O
Solvent: CO
Product: C[C@H](NC(CCC(=O)c1cccs1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Aqueous N-sodium hydroxide solution (4.7 ml.) was added to a solution of N-[1-methoxycarbonyl-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester (Example 32; 2.0 g.) in a mixture of methanol (3 ml.) and water (1.5 ml.) and the mixture was stirred at laboratory temperature for 16 hours and then evaporated to dryness under reduced pressure. The residue was partitioned between water and ethyl acetate and the aqueous layer was separated, acidified to pH 5 with aqueous N-hydrochloric acid and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated to dryness, and there was thus obtained as an oil N-[1-carboxy-4-oxo-4-(2-thienyl)butyl]-L-alanyl-L-proline t-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][C:9]3=2)[NH:4][CH:3]=1.[H-].[Na+].[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:26]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CN(C=O)C>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[O:15][CH2:14][CH2:13][NH:12][CH2:11][C:9]3=2)[N:4]([S:31]([C:27]2[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]cc(Cl)c3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1cccnc1)n1cc(Cl)c2c3c(ccc21)OCCNC3
Temperature: 50 °C

Procedure:
Pyridine-3-sulfonyl chloride hydrochloride (20 mg, 0.093 mmol) was dissolved in a mixture of dichloromethane and aqueous saturated NaHCO3 and the organic layer was dried (MgSO4) and evaporated to give pyridine-3-sulfonyl chloride. tert-Butyl 10-chloro-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 20, 10 mg, 0.031 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% in mineral oil, 2.5 mg, 0.062 mmol) was added. The mixture was stirred for 10 minutes before pyridine-3-sulfonyl chloride (0.093 mmol) in DMF (1 mL) was added. The reaction mixture was stirred at room temperature for 10 minutes before TFA (2 mL) was added and the mixture was heated at 50° C. overnight. The reaction mixture was evaporated and the crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (2.6 mg) in the form of the trifluoroacetate salt. MS m/z 364 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>>[CH2:1]([C:3]1[N:4]([CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH3:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH3:2]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: COCCOCCCl
Product: CCc1nc2ccccc2n1CCOCCOC
Yield: 77 %

Procedure:
2-Ethyl-1-[2-(2-methoxyethoxy)ethyl]-1H-benzimidazole was synthesized as in Synthesis Example 1 except that an equimolar amount of 2-ethylbenzimidazole was used instead of benzimidazole and an equimolar amount of 2-chloroethyl 2-methoxyethyl ether was used instead of 2-chloroethyl methyl ether. Yield 77%.