Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[C:12]([CH3:27])=[N:13][N:14]([CH3:26])[C:15]=1[O:16][C:17]1[C:22]([F:23])=[CH:21][C:20](N)=[CH:19][C:18]=1[F:25].N(OC(C)(C)C)=O.[ClH:35]>C(#N)C.[Cu]Cl>[Cl:35][C:20]1[CH:21]=[C:22]([F:23])[C:17]([O:16][C:15]2[N:14]([CH3:26])[N:13]=[C:12]([CH3:27])[C:11]=2[C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=2[F:10])=[C:18]([F:25])[CH:19]=1
Reactant: COc1cc(F)c(-c2c(C)nn(C)c2Oc2c(F)cc(N)cc2F)c(F)c1
Reactant: Cl
Agent: Cl[Cu]
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: COc1cc(F)c(-c2c(C)nn(C)c2Oc2c(F)cc(Cl)cc2F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Copper(I) chloride (56 mg, 0.42 mmol) was added to a solution of 4-[[4-(2,6-difluoro-4-methoxyphenyl)-1,3-dimethyl-1H-pyrazol-5-yl]oxy]-3,5-difluorobenzenamine (prepared analogous to Synthesis Example 9) (132 mg, 0.346 mmol) in acetonitrile (5 mL). The stirred mixture was cooled using an ice-water bath, and tert-butyl nitrite (90% technical grade, 72 μL) was added dropwise. The reaction mixture was allowed to warm slowly to ambient temperature and stirred at room temperature overnight, and then it was heated at reflux for 1 h. Hydrochloric acid (1 N, 5 mL) was added, and the mixture was extracted with ethyl acetate (˜20 mL). The organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified by column chromatography through silica gel eluted with 20% ethyl acetate in hexane to give the title product, a compound of the present invention, as a viscous oil (45 mg).
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3Cl)[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[C:7](=[O:18])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCN
Reactant: O=C1c2cccc(Cl)c2C(=O)c2c(Cl)cccc21
Solvent: O
Product: CN(C)CCNc1cccc2c1C(=O)c1c(NCCN(C)C)cccc1C2=O
Temperature: 25 °C

Procedure:
A mixture of 1,8-dichloroanthraquinone (5.5 g, 20 mmol) and N,N-dimethylethylenediamine (40 mL) was refluxed for 18 h. The mixture was cooled to room temperature and diluted with water to precipitate the title compound which was recrystallised from methanol to afford Compound 6 (4.5 g). The structure of Compound 6 is given below:
Reaction SMILES: [N:1]#[C:2]Br.[NH:4]1[CH2:8][CH2:7][N:6]=[C:5]1[C:9]1[C:14]([NH2:15])=[C:13]([O:16][CH3:17])[C:12]([O:18][CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:11][CH:10]=1>C(Cl)Cl>[CH3:17][O:16][C:13]1[C:14]2[N:15]=[C:2]([NH2:1])[N:4]3[CH2:8][CH2:7][N:6]=[C:5]3[C:9]=2[CH:10]=[CH:11][C:12]=1[O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: N#CBr
Reactant: COc1c(OCCCN2CCOCC2)ccc(C2=NCCN2)c1N
Solvent: ClCCl
Product: COc1c(OCCCN2CCOCC2)ccc2c1N=C(N)N1CCN=C21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyanogen bromide (10.9 g, 102.9 mmol) was added to a mixture of 6-(4,5-dihydro-1H-imidazol-2-yl)-2-methoxy-3-(3-morpholin-4-ylpropoxy)aniline (17.2 g, 51.4 mmol) and TEA (15.6 g, 154.3 mmol) in DCM (200 mL) precooled to 0° C. After 1 h the reaction mixture was concentrated under reduced pressure and the resulting residue stirred with EtOAc (300 mL) overnight at rt. The resulting slurry was filtered to generate the title compound contaminated with triethylamine hydrobromide (26.2 g, 71%): HPLC MS RT=0.17 min, MH+=360.2.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:13])[NH:8][C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36]>COCCOC>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:13])[N:8]([CH2:33][C:34](=[O:39])[C:35]([CH3:38])([CH3:37])[CH3:36])[C:9]([CH3:12])=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc(C)[nH]c1=O
Reactant: CC(C)(C)C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COCCOC
Product: CCOC(=O)c1cnc(C)n(CC(=O)C(C)(C)C)c1=O
Temperature: 25 °C

Procedure:
To a suspension of 5-ethoxycarbonyl-2-methylpyrimid-4-one (2.7 g, 14.75 mmol.) in DME (20 ml), tetrabutylammonium fluoride (22 ml, 22.0 mmol.) was added. The solution was stirred at room temperature until solids dissolved, then 1-bromopinacolone (2.2 ml, 1.1 eq., 16.22 mmol) was added. The solution was stirred overnight and concentrated to a brown oil. The crude mixture was purified by silica gel column chromatography (hexane/ethyl acetate, 100/0 to 0/100). A less polar O-alkylated by-product was eluted first (1.8 g) and then the desired N-alkylated product (1.1 g); MS (281, M+H)+. NMR (CDCl3, δ): 8.57 (1H, s) , 5.06(1H, s), 4.35(2H, q), 2.42 (3H, s), 1.34 (3H, t), 1.30 (9H,s).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([OH:10])=O)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[C:16]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:18])[CH3:17].CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:12]=[CH:11][C:5](/[CH:6]=[CH:7]/[C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:16](=[O:18])[CH3:17])[CH2:20][CH2:21]2)=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C(O)/C=C/c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(C(=O)/C=C/c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a stirred solution of trans-4-chloro-3-nitrocinnamic acid (1.50 g, 6.59 mmol) and 1-acetylpiperazine (0.89 g, 6.94 mmol) in 20 mL of DMF at room temperature was added EDAC (1.4 g, 7.30 mmol). The mixture was then stirred at room temperature for 2 hours. TLC indicated the complete consumption of the acid. Water was then added to quench the reaction and to precipitate out the product. Cinnamide was then collected through filtration and washed with cold water. The light yellow product was dried in vacuum oven overnight at 40° C. to give 2.04 g (6.03 mmol, 91.6%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:20]([N:21]([C:23](=[O:36])[CH2:24][N:25]2C(=O)C3=CC=CC=C3C2=O)[CH3:22])=[CH:19][CH:18]=[C:17]([Cl:37])[C:3]=1[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH3:15])[N:11]([CH3:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1.O.NN>C(O)C>[NH2:25][CH2:24][C:23]([N:21]([C:20]1[C:2]([Cl:1])=[C:3]([C:17]([Cl:37])=[CH:18][CH:19]=1)[CH2:4][O:5][C:6]1[C:14]2[N:13]=[C:12]([CH3:15])[N:11]([CH3:16])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[CH3:22])=[O:36]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN4C(=O)c5ccccc5C4=O)c3Cl)cccc2n1C
Agent: NN
Solvent: CCO
Solvent: O
Product: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)cccc2n1C
Yield: 97.7 %

Procedure:
A mixture of 4-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-1,2-dimethyl-1H-benzimidazole (405 mg), hydrazine monohydrate (75.4 mg) and ethanol (4.0 ml) was refluxed for 30 minutes. After cooling, the resulting precipitate was filtered off, and the filtrate was concentrated in vacuo to give 4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (300 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4](Cl)[N:3]=1.[NH3:14]>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH3:12])=[C:4]([NH2:14])[N:3]=1
Reactant: CCn1cnc2c(Cl)nc(Cl)nc21
Reactant: N
Product: CCn1cnc2c(N)nc(Cl)nc21
Reaction time: 20 h

Procedure:
A solution of 2,6-dichloro-9-ethylpurine (2.7 g, 12.4 mmol), a compound of formula (2), in liquid ammonia (20 mL) was sealed in a stainless steel tube and set aside at room temperature for 20 hours. The solvent was removed in vacuo and the residue was purified by flash chromatography on a silica gel column eluting with EtOAc-cyclohexane (65:35) to give 2-chloro-9-ethyl-9H-purin-6-ylamine, a compound of formula (3) (2.28 g, 93%) as a chromatographically pure solid: mp 258–262° C.; 1H NMR (Me2SO-d6) δ 1.39 (t, 3H, J=7.3 Hz, CH2CH3), 4.13 (q, 2H, J=7.3 Hz, CH2CH3), 7.74 (s, 2H, NH2), 8.18 (s, 1H, H-8). Anal. (C7H7ClN5) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][NH:23][CH2:24][CH:25]=3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10].C(OC([N:33]1[CH2:37][CH2:36][CH2:35][C@@H:34]1[C:38](O)=[O:39])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C@H:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]3[CH2:21][CH2:22][N:23]([C:38]([C@H:34]4[CH2:35][CH2:36][CH2:37][NH:33]4)=[O:39])[CH2:24][CH:25]=3)[CH:18]=2)[CH:13]=[N:12]1)[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCNCC3)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](c1ccc(Cl)cc1Cl)n1ncc2ccc(C3=CCN(C(=O)[C@H]4CCCN4)CC3)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a stirred solution of (R)-1-(1-(2,4-dichlorophenyl)ethyl)-6-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole (0.038 g, 0.10 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.044 g, 0.20 mmol) in dichloromethane (1 mL) was added HATU (0.078 g, 0.20 mmol) and Et3N (0.10 mL g, 0.72 mmol). The reaction mixture was stirred at room temperature for 30 min, followed by dilution with dichloromethane. The mixture was washed with deionized water, and the aqueous layer was extracted with dichloromethane (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (0.037 g, 0.065 mmol, 65%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH2:21][N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[S:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1>[OH-].[Na+]>[C:1]([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[S:33][CH:32]=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Reactant: NN1CCN(Cc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)NN1CCN(Cc2cccs2)CC1
Reaction time: 6 h
Yield: 63.9 %

Procedure:
4-Acetylamino-5-chloro-2-methoxybenzoic acid (3.67 g, 0.015 mole) was treated with thionyl chloride (30 ml) at 50° for 1/2 hour. The mixture was evaporated in vacuo and the residue azeotroped twice with anhydrous toluene (100 ml), redissolved in hot anhydrous toluene (150 ml) and filtered. Triethylamine (2 ml) was added to the filtrate followed by N-amino-N'-2-thenylpiperazine (2.70 g, 0.0137 mole) and the reaction left for 6 hours at room temperature. The mixture was basified with 10% sodium hydroxide (10 ml) and the toluene layer separated, dried over K2CO3 and evaporated in vacuo to yield 4-acetylamino-5-chloro-2-methoxy-N-[1-(2-thenyl)-4-piperazinyl]-benzamide (3.7 g, 64%) as colourless microcrystals, m.p. 178°-181° C. (ex EtOAc-light petroleum 40°-60°).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8](Br)[CH:9]=1)=[O:4].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[SH:22]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([N+:11]([O-:13])=[O:12])=[C:8]([S:22][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[O:15][CH3:14])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])s1
Reactant: COc1ccccc1S
Product: COC(=O)c1cc(Sc2ccccc2OC)c([N+](=O)[O-])s1

Procedure:
The procedure as in Example 20: step a was followed using 4-bromo-5-nitro-thiophene-2-carboxylic acid methyl ester ((Example 114, step c) 200 mg, 0.75 mmol) and 2-methoxy-benzenethiol (109 μL, 1.25 mmol, Aldrich Chemical Company) to isolate 4-(2-methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester. 4-(2-Methoxy-phenylsulfanyl)-5-nitro-thiophene-2-carboxylic acid methyl ester (200 mg, 0.61 mmol) was then treated with TiCl3 (20% aq. HCl solution, 5 mL, 6.1 mmol) in THF (6 mL). The reaction was stirred for 20 minutes at rt. The reaction mixture was concentrated in vacuo and then dissolved into EtOAc. The organic layer was washed several times with saturated NaHCO3. The combined organic layers were dried over sodium sulfate. Removal of the solvents in vacuo yielded 5-amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step e was followed using 5-amino-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (160 mg, 0.54 mmol), t-butylnitrite (96 μL, 0.81 mmol), and copper(II) bromide (112.6 mg, 0.65 mmol) resulting in 5-bromo-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step b was followed using 5-bromo-4-(2-methoxy-phenylsulfanyl)-thiophene-2-carboxylic acid methyl ester (18 mg, 0.05 mmol) and m-CPBA (32 mg, 0.25 mmol) resulting in 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester. The procedure as in Example 20: step f was followed using 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (45 mg, 11 mmol) and dimethyl aluminum amide (1M, 0.57 mL, 0.55 mmol) resulting in the title compound 5-bromo-4-(2-methoxy-benzenesulfonyl)-thiophene-2-carboxamidine (4 mg, 13%). 1H-NMR (CD3OD): δ: 8.30 (s, 1H), 8.12–8.14 (d of d, J=6.1, 1.8 Hz, 1H), 7.70–7.74 (m, 1H), 7.16–7.24 (m, 2H), 3.79 (s, 3H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[N:17]=[CH:18][N:19]4C3CCCCO3)[CH2:12][CH3:13])[N:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]=2[CH:36]=1>O1CCOCC1.CO>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:14][C:15]3[N:23]=[CH:22][N:21]=[C:20]4[C:16]=3[NH:17][CH:18]=[N:19]4)[CH2:12][CH3:13])[N:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:7]=2[CH:36]=1
Reactant: CC[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)cc2n1-c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98.7 %

Procedure:
HCl (0.22 mL of a 4M solution in dioxane) was added to a solution of [(S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propyl]-[9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (82 mg, 0.17 mmol) in MeOH (2 mL) and the reaction was stirred at RT for 10 min. The reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 360 (65 mg, quant.) as a white solid. LCMS (Method K): RT 3.58 min [M+H]+ 388.1. 1H NMR (CD3OD, 400 MHz): δ 8.06 (1H, s), 8.04 (1H, br s), 7.61 (1H, dd, J=8.8, 4.6 Hz), 7.57-7.43 (5H, m), 7.02 (1H, ddd, J=9.6, 8.8, 2.7 Hz), 6.76 (1H, dd, J=8.7, 2.7 Hz), 5.44 (1H, br s), 2.14 (1H, dqd, J=14.8, 7.4, 6.5 Hz), 2.05 (1H, dqd, J=14.8, 7.4, 6.5 Hz), 0.95 (3H, t, J=7.4 Hz)
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1.ClS([N:35]=[C:36]=[O:37])(=O)=O.O>C(#N)C>[C:36]([O:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1)(=[O:37])[NH2:35]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CO)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: O
Solvent: CC#N
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(COC(N)=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2S,4R)-2-[2-(hydroxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.1 g) in acetonitrile (50 ml) was added chlorosulfonyl isocyanate (0.48 ml) at 0°-5° C. and the mixture was stirred at ambient temperature for 1 hour. Water (3 ml) was added to the solution at the same temperature and the mixture was stirred for 20 hours. After the solvent was removed, the residue was dissolved in ethyl acetate, and washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S,4R)-2-[2-(carbamoyloxymethyl)thiazol-4-yl]-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (2.2 g).
Reaction SMILES: Br[CH:2]([C:4]1[O:5][C:6](=[O:29])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)(=[O:22])=[O:21])[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].[NH:30]1[C:34]2=[N:35][CH:36]=[N:37][C:38]([NH2:39])=[C:33]2[CH:32]=[N:31]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:39][C:38]1[N:37]=[CH:36][N:35]=[C:34]2[N:30]([CH:2]([C:4]3[O:5][C:6](=[O:29])[C:7]4[C:12]([C:13]=3[C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([S:20]([N:23]5[CH2:28][CH2:27][O:26][CH2:25][CH2:24]5)(=[O:22])=[O:21])[CH:15]=3)=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH3:3])[N:31]=[CH:32][C:33]=12
Reactant: CC(Br)c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: Nc1ncnc2[nH]ncc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(c1oc(=O)c2ccccc2c1-c1cccc(S(=O)(=O)N2CCOCC2)c1)n1ncc2c(N)ncnc21
Yield: 53.9 %

Procedure:
The title compound was made in a similar way as that of the compound of example 15, 3-(1-bromoethyl)-4-(3-(morpholinosulfonyl)phenyl)-1H-isochromen-1-one (intermediate C9, 90 mg, 0.188 mmol), 1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.8 mg, 0.376 mmol) and K2CO3 (52 mg, 0.376 mmol) in DMF (1 ml) at 80° C. for 2 hrs to give the title compound (54 mg, 54%).
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH2:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1>>[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:22][CH:23]=2)[CH:18]=[CH:17]1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1ccc2cc(CN)ccc21
Product: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(ccn3C)c2)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (1-methyl-1H-indol-5-yl)methanamine.
Reaction SMILES: [ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@H:29]2[N:33](C(OC(C)(C)C)=O)[C:32]([CH3:42])([CH3:41])[CH2:31][CH2:30]2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][C@@H:24]([OH:28])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][C:4]=1[F:43]>C(Cl)Cl>[ClH:1].[ClH:1].[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([C@@H:29]2[CH2:30][CH2:31][C:32]([CH3:42])([CH3:41])[NH:33]2)[C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][C@@H:24]([OH:28])[C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][C:4]=1[F:43]
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4C(=O)OC(C)(C)C)CC3)c21
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)[C@@H](c4ccc(Br)c(F)c4)[C@@H]4CCC(C)(C)N4)CC3)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.9 %

Procedure:
4.0M HCl in dioxanes (1.5 mL) was added to a solution of (S)-tert-butyl 5-((S)-1-(4-bromo-3-fluorophenyl)-2-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-2-oxoethyl)-2,2-dimethylpyrrolidine-1-carboxylate (0.012 g, 0.0186 mmol) in DCM (5 mL). This solution was stirred at room temperature overnight, and then the solvent was removed to yield (S)-2-(4-bromo-3-fluorophenyl)-2-((S)-5,5-dimethylpyrrolidin-2-yl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)ethanone dihydrochloride (0.00367 g, 0.00593 mmol, 31.9% yield). HPLC, 254 nm=1.99 minutes, 96.93% purity, LCMS (APCI+) 548.3 m/z [M+H]+; Retention time=2.56 minutes, 1H NMR (400 MHz, CD3OD) 8.59 (s, 1H), 7.71 (t, J=7.418 Hz, 1H), 7.39 (dd, J1=1.562 Hz, J2=9.761 Hz, 1H), 7.22 (d, J=7.418 Hz, 1H), 5.30 (t, J=7.809 Hz, 1H), 4.53 (d, J=9.371 Hz, 1H), 3.81-3.65 (m, 6H), 2.30 (dd, J1=7.809 Hz, J2=12.884 Hz, 1H), 2.21-2.15 (m, 1H), 2.02-1.85 (m, 4H), 1.55 (s, 3H), 1.45 (s, 3H), 1.19 (d, J=7.028 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:24][C:25](=[O:33])[CH:26]([NH:31][CH3:32])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:43]([O:46][CH2:47][CH2:48]Br)(=[O:45])[CH3:44]>C1COCC1>[CH2:47]([O:46][C:43](=[O:45])[CH2:44][N:31]([CH:26]([C:25](=[O:33])[NH:24][CH:16]([C:17](=[O:23])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)[CH2:27][CH:28]([CH3:30])[CH3:29])[CH3:32])[CH3:48]
Reactant: CC(=O)OCCBr
Reactant: CNC(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CN(C)C(CC(C)C)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
A mixture of [S-(R*,R*)]-4-methyl-2-methylamino-pentanoic acid [2-(4-benzyloxy-phenyl)-1-tert-butylcarbamoyl-ethyl]-amide (0.55 mmol), diisopropyl ethylamine (1.65 mmol), 2-bromoethyl acetate (0.8 mmol), and anhydrous THF (6 mL) was stirred at 25° C. for 6 hours. The precipitate was filtered off. The reaction mixture was concentrated and purified by column chromatography on silica gel eluting with 10% acetone/methylene chloride to give the titled compound (84% yield).
Reaction SMILES: I.CS[C:4](=[NH:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH2:23].C(O)C.[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:4]([NH2:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CSC(=N)Nc1ccccc1N1CCCCC1
Reactant: COCCN
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CO
Product: COCCNC(N)=Nc1ccccc1N1CCCCC1

Procedure:
A mixture of 2-methyl-1-(2-piperidino)phenyl]-2-thiopseudourea hydroiodide (7.5 g prepared as described in Preparative Procedure G), 2-methoxyethylamine (2 ml) and ethanol (40 ml was stirred at ambient residue which was dissolved in methanol and treated with fumaric acid to give 1-(2-methoxyethyl)-2-(2-piperidinophenyl)guanidine hemifumarate (m.p. 218°-220° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:22][CH3:23])[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=1.CN(C)C=O.[H-].[Na+].[CH2:31](I)[CH2:32][CH3:33]>O>[CH2:22]([N:3]1[C:4](=[O:21])[C:5]2[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[CH:9][N:8]([CH3:20])[C:6]=2[N:7]=[C:2]1[NH:1][CH2:31][CH2:32][CH3:33])[CH3:23]
Reactant: CCCI
Reactant: CCn1c(N)nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNc1nc2c(c(-c3c(C)cc(C)cc3C)cn2C)c(=O)n1CC
Reaction time: 0.5 h
Yield: 27.3 %

Procedure:
To a solution of 2-amino-3-ethyl-5-mesityl-7-methyl-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one (80 mg, 0.26 mmol) and N,N-dimethylformamide (3 ml) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C. and stirred for 0.5 hour. After stirring at room temperature for 0.5 hour, to the mixture was added a solution of n-PrI (170 mg, 1.0 mmol) and N,N-dimethylformamide (2 ml) at 0° C. and stirred for 0.5 hour. After stirring at 50° C. for 3 hours, the mixture was cooled and diluted with water (20 ml) and extracted with ethyl acetate (50 ml×2). The extracts were combined, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with hexane/ethyl acetate (20:1) to give 25 mg (25%) of the title compound.