Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:14][C:15]([CH3:19])=[N:16]2)=[CH:11][C:10]=1[F:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1cc(Cl)c2cc(F)c(OCc3ccccc3)cc2n1
Product: Cc1cc(N2CCCC2)c2cc(F)c(OCc3ccccc3)cc2n1
Temperature: 80 °C
Yield: 46.4 %

Procedure:
A mixture of 3.1 g of (10.9 mmol) of 7-benzyloxy-4-chloro-6-fluoro-2-methyl-quinoline and 18.1 ml (21.8 mmol) pyrrolidine was heated at 80° C. (oil bath temperature) under an argon atmosphere for 6 h. The reaction mixture was concentrated in vacuo, the residue taken up in methylene chloride, which was washed with water, saturated NaCl solution and then dried over magnesium sulphate. The solvent was removed in vacuo, the residue purified by flash chromatography on silica gel with CH2Cl2/MeOH (100:0 to 90:10 over 1 h) as eluent. Combination of the purified fractions and concentration in vacuo gave 1.7 g (46.2%) of the 7-benzyloxy-6-fluoro-2-methyl-4-pyrrolidin-1-yl-quinoline as a brown crystalline solid. ISP mass spectrum, m/e: 337.4 (M+1 calculated for C21H21FN2O: 337).
Reaction SMILES: Cl[C:2]1C=C(C=C[CH:11]=1)C(OO)=O.C(S[C:15]1[CH:20]=[C:19]([S:21][C:22]([F:25])([F:24])[F:23])[CH:18]=[CH:17][C:16]=1[C:26]1[N:41]([CH3:42])[C:29]2=[N:30][CH:31]=[C:32]([C:34]([F:40])([F:39])[C:35]([F:38])([F:37])[F:36])[CH:33]=[C:28]2[N:27]=1)C.C(=O)(O)[O-].[Na+].[S:48]([O-:52])([O-])(=[O:50])=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:2]([S:48]([C:15]1[CH:20]=[C:19]([S:21][C:22]([F:23])([F:25])[F:24])[CH:18]=[CH:17][C:16]=1[C:26]1[N:41]([CH3:42])[C:29]2=[N:30][CH:31]=[C:32]([C:34]([F:40])([F:39])[C:35]([F:36])([F:37])[F:38])[CH:33]=[C:28]2[N:27]=1)(=[O:52])=[O:50])[CH3:11]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S([O-])([O-])=S
Reactant: CCSc1cc(SC(F)(F)F)ccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCS(=O)(=O)c1cc(SC(F)(F)F)ccc1-c1nc2cc(C(F)(F)C(F)(F)F)cnc2n1C
Reaction time: 2 h

Procedure:
0.19 g of 3-chloroperoxybenzoic acid (purity of 65% or more) was added to a mixture of 0.19 g of 2-(2-ethylsulfanyl-4-trifluoromethylsulfanylphenyl)3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine and 3 ml of chloroform under ice cooling, and then the mixture was stirred under ice cooling for 2 hours. A saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium thiosulfate solution were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The resulting residue was applied to a silica gel column chromatography to obtain 0.22 g of 2-(2-ethylsulfonyl-4-trifluoromethylsulfanylphenyl)3-methyl-6-pentafluoroethyl-3H-imidazo[4,5-b]pyridine (hereinafter, referred to as Compound 10).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]2[CH:12]=[CH:13][C:14]([O:26][CH3:27])=[C:15]([NH:17][C:18](CCCC(O)=O)=[O:19])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2].[C:32]1(=O)[O:37][C:35](=[O:36])[CH2:34][CH2:33]1>>[CH3:32][CH2:33][N:9]([CH:6]([CH3:5])[CH3:7])[CH:10]([CH3:11])[CH3:28].[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:28]([O:30][CH3:31])=[O:29])[C:11]2[CH:12]=[CH:13][C:14]([O:26][CH3:27])=[C:15]([NH:17][C:18](=[O:19])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CCC(=O)O1
Reactant: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCCC(=O)O)c1
Product: CCN(C(C)C)C(C)C
Product: COC(=O)C(Nc1ccc(C#N)cc1)c1ccc(OC)c(NC(=O)CCC(=O)O)c1

Procedure:
In analogy to Example 70.4-6, from the methyl (RS)-(3-amino-4-methoxy-phenyl)-(4-cyano-phenylamino)-acetate described in Example 70.3, succinic anhydride and Hünig's base there was obtained (RS)-N-{5-[(4-cyano-phenylamino)-methoxycarbonyl-methyl]-2-methoxy-phenyl}-succinamidic acid, which was subsequently converted via (RS)-N-{5-[carboxy-(4-cyano-phenylamino)-methyl]-2-methoxy-phenyl}-succinamidic acid into (RS)-(E)- and/or -(Z)-N-(5-{carboxy-[4-(N-hydroxycarbamimidoyl)-phenylamino]-methyl}-2-methoxy-phenyl)-succinamidic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([OH:16])=[N:6][C:7]=1[NH:8][C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[C:17](OC)(OC)(OC)[CH3:18]>>[CH3:17][C:18]1[N:8]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:7]2=[N:6][C:5]([OH:16])=[CH:4][CH:3]=[C:2]2[N:1]=1
Reactant: COC(C)(OC)OC
Reactant: CC1(Nc2nc(O)ccc2N)CCCCC1
Product: Cc1nc2ccc(O)nc2n1C1(C)CCCCC1

Procedure:
From 5-amino-6-(1-methylcyclohexylamino)pyridin-2-ol and trimethyl orthoacetate, prepared in a similar manner as the one described in Example 1.127, Step D, the title compound was obtained. LCMS m/z=246.10 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ ppm 1.52-1.58 (m, 1H), 1.67-1.78 (m, 5H), 1.90 (s, 3H), 2.48-2.52 (m, 2H), 2.75-2.82 (m, 2H), 3.02 (s, 3H), 6.91 (d, J=8.8 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]#[N:24])=[C:21]([CH3:25])[NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[C:21]([CH3:25])[C:22]([C:23]#[N:24])=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Reactant: Cc1[nH]nc(N)c1C#N
Product: Cc1nn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc2c1C#N
Yield: 65.9 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and commercially available 3-amino-4-cyano-5-methyl-pyrazole (122 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (222 mg, 66%). MS (ISP) 337.1 [(M+H)+]; mp 238° C.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][CH:10]([N:12]([CH2:23][CH2:24][C:25]2[C:33]3[S:32][C:31](=[O:34])[NH:30][C:29]=3[C:28]([OH:35])=[CH:27][CH:26]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>C(Cl)Cl>[C:48]([N:8]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:9][CH:10]([N:12]([CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11])(=[O:51])[CH:49]=[CH2:50]
Reactant: CC(CNC1CCCCCC1)N(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)N(CC(C)N(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzyl [2-(cycloheptylamino)-1-methylethyl][2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate (0.46 g) in CH2Cl2 (10 mL) was added triethylamine (0.773 mL) and trimethylsilyl chloride (0.586 mL) and the mixture was stirred for 1 h at room temperature. The reaction mixture was cooled in ice and acryloyl chloride (0.0976 mL) was added. The mixture was allowed to warm slowly to RT, diluted with CH2Cl2 and washed with 2M HCl and brine. Drying and evaporation afforded an orange foam (470 mg), which was used directly in the next step.
Reaction SMILES: [C:1]1([S:7][CH:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[CH:9]2[C:16]([O:18][CH:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.S(Cl)(Cl)(=O)=O>C(Cl)Cl>[C:1]1([S:7][C:8]2[CH2:14][CH:13]3[CH:10]([C:11](=[O:15])[CH2:12]3)[C:9]=2[C:16]([O:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CC2CC(Sc3ccccc3)C(C(=O)OC(c3ccccc3)c3ccccc3)C12
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(Sc2ccccc2)CC2CC(=O)C12

Procedure:
A 500 mL, 3-neck flask fitted with an argon inlet, septum cap, thermometer, and stir bar was charged with 7.2 g of 3-phenylthio-7-oxobicyclo[3.2.0]heptan-2-carboxylic acid, diphenylmethyl ester, prepared by the procedure of Paragraph A, dissolved in 200 mL of methylene chloride. To this rapidly stirred solution at -65° was added 5.7 mL of pyridine in one portion, then 1.85 mL of sulfonyl chloride dropwise, slowly. This solution was stirred between -60° and -55° C. for 30 min and then it was poured onto water. The organic phase was washed again with water, then with brine dried over sodium sulfate and evaporated to dryness. The two major components of this mixture was separated on a Waters prep LC/System 500 liquid chromatograph by elution on 2 silica gel cartridges with methylene chloride. The second major component to be eluted was 3-phenylthio-7-oxobicyclo[3.2.0]hept-2-en-2-carboxylic acid, diphenylmether ester, 3.46 g (48.3%) as a colorless solid: NMR (220 MHz; CDCl3): δ 2.27 (1 H, dd, J=17, 3.5), 2.6-3.0 (3H, m), 3.18 (1H, ddd, J=17, 8, 4), 4.57 (1H, m), 6.84 (1H, s), and 7.0-7.5 (15H, m). The analytical sample, mp 148° to 150°, was prepared by recrystallization from benzene-ether.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5]Br.[C:7]([NH:12][NH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N:12]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][N:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)NNC(=O)OCC
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)N1CCCCN1C(=O)OCC
Temperature: 25 °C
Yield: 69.4 %

Procedure:
1,4-Dibromobutane (81.4 mL, 0,682 mol) is added over hour to a mixture of 1,2-dicarbethoxyhydrazine (100 g, 0.568 mol) and potassium carbonate (158 g, 1.14 mol) in acetonitrile (600 mL). The resultant reaction mixture is refluxed for 6 hours, cooled to room temperature, and filtered. The filtrate is concentrated in vacuo to obtain a yellow liquid which is distilled under reduced pressure to give the title product as a colorless liquid (90.8 g, bp 115°-120° C. at 0.9 mm Hg).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15]COCCOC)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl.CO>[F:1][C:2]1[C:3]([NH:22][C:23]2[CH:24]=[C:25]([NH:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH:26]=[CH:27][CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(OCOCCOC)cc3)ncc2F)c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: C=CC(=O)Nc1cccc(Nc2nc(Nc3ccc(O)cc3)ncc2F)c1
Yield: 6.9 %

Procedure:
In a 25 mL 3-neck RBF equipped with a rubber septum, N-(3-((5-fluoro-2-((4-((2-methoxyethoxy)methoxy)phenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide (0.180 g) was taken and TFA (1.0 mL) was added drop wise at room temperature under stirring. The reaction mixture was further stirred for 30 min. Completion of reaction was monitored by TLC using CHCl3:MeOH (9.5:0.5). After completion, the reaction mixture was quenched in water. The aqueous solution was basified with saturated sodium bicarbonate solution. The product was extracted into DCM, washed with water and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was treated with DBU and 75 mg of product was collected. This was further purified by preparative TLC using CHCl3: MeOH (9.5:0.5) as a mobile phase to give 10 mg of N-(3-((5-fluoro-2-((4-hydroxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)acrylamide. M+1=365.9 1H NMR: DMSO-d6 (400 MHz) 5.73-5.76 (dd, 1H, J=2, 8), 6.23-6.28 (dd, 1H, J=2, 18.8), 6.48-6.55 (m, 1H), 6.59.6.61 (d, 2H, J=8.8), 7.22-7.261 (t, 1H, J=8.16), 7.40-7.51 (m, 4H), 8.03-8.04 (d, 2H, J=3.6), 8.426 (s, 1H), 8.902 (s, 1H), 9.331 (s, 1H), 10.26 (s, 1H).
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]3)[CH2:4][CH2:3][CH2:2]1.[O:19]1C=CC(CO)=C1.C(OC(C1NC2C(C=1)=C(O)C=CC=2)=O)C>>[O:19]1[CH:4]=[CH:3][CH:2]=[C:1]1[CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[NH:11]2
Reactant: O=C(O)c1cc2c(OCC3CCC3)cccc2[nH]1
Reactant: OCc1ccoc1
Agent: CCOC(=O)c1cc2c(O)cccc2[nH]1
Product: O=C(O)c1cc2c(OCc3ccco3)cccc2[nH]1

Procedure:
4-(Furan-3-ylmethoxy)-1H-indole-2-carboxylic acid (16c) is synthesized analogous to 16a from furan-3-yl-methanol and 4-hydroxy-1H-indole-2-carboxylic acid ethyl ester.
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[O:13])[C:9]([OH:23])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[SH:24][CH2:25][C:26]([OH:28])=[O:27].C(N(CC)CC)C.Cl>COCCOCCOC>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:12]([C:10]2[C:9]([OH:23])=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[C:2]([S:24][CH2:25][C:26]([OH:28])=[O:27])[N:11]=2)=[O:13])=[CH:17][CH:18]=1
Reactant: O=C(O)CS
Reactant: O=C(NCc1ccc(F)cc1)c1nc(Br)c2cccnc2c1O
Agent: Cl
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: O=C(O)CSc1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 130 °C
Reaction time: 18 h

Procedure:
A mixture of 5-bromo-N-(4-fluorobenzyl)-8-hydroxy-[1,6]naphthyridine-7-carboxamide (0.40 g, 1.05 mmol), mercaptoacetic acid (0.11 mL, 1.60 mmol), triethylamine (0.59 mL, 4.2 mmol) in diglyme (2.5 mL) was heated with stirring at 130° C. under an atmosphere of nitrogen for 18 hours. The product mixture was treated with 1 M aq HCl at 0° C. The resulting yellow solid was filtered, washed with diethyl ether to provide the title acid.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])(=O)C.CO.[OH-].[Na+]>CCCCCC>[CH2:5]([OH:4])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCC=CCCCCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCCC
Product: CCCCC=CCCCCO
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
A portion of the 5-decenyl acetate can be removed and converted to the corresponding alcohol according to the following procedure and the scale can be adjusted as necessary. 15.0 g (67 mmol) of the 5-decenyl acetate, 35 mL of methanol and 34 mL of 2 M sodium hydroxide are added to a 250 mL round-bottomed flask. This mixture is stirred for three hours at room temperature. After three hours the hydrolysis is complete, 10 mL of hexane is then added and the solution is washed with 10 mL of 1 M HCl, 10 mL of NaHCO3-saturated water and 10 mL of brine. The organic phase is dried with sodium sulfate and filtered, and the hexane is removed under reduced pressure to yield 9.4 g of 5-decenol. GC analysis shows the isometric ratio of the 5-decenol to be conserved.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]1[N:12]([CH3:28])[C:13](=[O:27])[C:14]2[N:15]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:16]=[N:17][C:18]=2[N:19]=1)[CH:4]1[CH2:9]CCC[CH2:5]1.[CH3:29]O>>[OH:1][CH2:2][CH:3]([NH:10][C:11]1[N:12]([CH3:28])[C:13](=[O:27])[C:14]2[N:15]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:16]([CH3:29])=[N:17][C:18]=2[N:19]=1)[CH:4]([CH3:9])[CH3:5]
Reactant: CO
Reactant: Cn1c(N[C@H](CO)C2CCCCC2)nc2ncn(Cc3ccccc3)c2c1=O
Product: Cc1nc2nc(NC(CO)C(C)C)n(C)c(=O)c2n1Cc1ccccc1

Procedure:
5A28 2-[2-hydroxy-1 (S)-(cyclohexyl)ethylamino]-1-methyl-7-(phenylmethyl)purin-6-one, solid, [α]D23.5 =+12.1° (CH3OH)
Reaction SMILES: [N:1]1([C:8]2[CH:9]=[C:10]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].O>ClCCl>[CH3:31][S:32]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:9]=[C:10]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH:11]=[CH:12][CH:13]=2)[CH2:2][CH2:3]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(-c2cccc(N3CCCNCC3)c2)nc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1c(-c2cccc(N3CCCN(S(C)(=O)=O)CC3)c2)nc2ccccc21
Yield: 56.5 %

Procedure:
To a solution of 2-(3-[1,4]Diazepan-1-ylphenyl)-1-methyl-1H-benzoimidazole (0.18 g, 0.46 mmol) and triethylamine (0.32 mL, 2.30 mmol) in dichloromethane (4 mL), was added methanesulfonyl chloride (0.04 mL, 0.55 mmol). After 16 h stirring at room temperature water (1 mL) was added, the organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The resulting crude was purified by flash chromatography (eluent:EtOAc) to obtain 0.10 g (54%) of the title compound.
Reaction SMILES: [NH:1]([C:5]([O:7][CH2:8][CH:9]([NH:22]C(OC(C)(C)C)=O)[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:6])[C:2]([NH2:4])=[O:3].CC(O)C.Cl>CO.C(Cl)(Cl)Cl>[ClH:21].[NH2:22][CH:9]([CH2:8][O:7][C:5]([NH:1][C:2]([NH2:4])=[O:3])=[O:6])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1
Reactant: CC(C)(C)OC(=O)NC(COC(=O)NC(N)=O)COc1noc2ccc(Cl)cc12
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CC(C)O
Product: NC(=O)NC(=O)OCC(N)COc1noc2ccc(Cl)cc12

Procedure:
3-(3-Ureidocarbonyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole is suspended in 10 ml of methanol and 5 ml of chloroform, and 12.8 ml of a 2-propanol solution (7.5N) of hydrogen chloride is added, after which they are subjected to reaction at 20°-25° C. overnight. The crystals precipitated are collected by filtration, to obtain 0.62 g of colorless, crystalline 3-(2-amino-3-ureidocarbonyloxypropoxy)-5-chloro-1,2-benzisoxazole hydrochloride having a melting point of 203°-204° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C@@H:9]1[CH2:15][CH2:14][C@@H:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[C:17]=2[F:23])[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:10]1=[O:29].Cl[C:31](OC1C=CC([N+]([O-])=O)=CC=1)=[O:32].Cl.[NH:44]1[CH2:49][CH2:48][CH:47]([N:50]2[C:58]3[C:53](=[N:54][CH:55]=[N:56][CH:57]=3)[NH:52][C:51]2=[O:59])[CH2:46][CH2:45]1>O1CCCC1>[F:23][C:17]1[C:18]([F:22])=[CH:19][CH:20]=[CH:21][C:16]=1[C@H:13]1[CH2:12][N:11]([CH2:24][C:25]([F:28])([F:26])[F:27])[C:10](=[O:29])[C@H:9]([NH:8][C:31]([N:44]2[CH2:49][CH2:48][CH:47]([N:50]3[C:58]4[C:53](=[N:54][CH:55]=[N:56][CH:57]=4)[NH:52][C:51]3=[O:59])[CH2:46][CH2:45]2)=[O:32])[CH2:15][CH2:14]1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O
Reactant: O=c1[nH]c2ncncc2n1C1CCNCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CC(F)(F)F)C1=O)N1CCC(n2c(=O)[nH]c3ncncc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Triethylamine (0.030 mL, 0.215 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one (80 mg, 0.248 mmol) and 4-nitrophenyl chloroformate (44 mg, 0.218 mmol) in tetrahydrofuran (3 mL) at 0° C. After 0.5 h, 7-piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride (73 mg, 0.248 mmol) and triethylamine (0.120 mL, 0.860 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (114 mg). MS 567.2123 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[C:17]1=[O:31])[CH3:13])(=[O:11])=[O:10].[CH2:32](N)[CH2:33][NH2:34].[S]>O>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([N:12]([CH2:14][CH2:15][N:16]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:29]3[NH:34][CH2:33][CH2:32][N:30]=3)=[CH:27][CH:28]=2)[C:17]1=[O:31])[CH3:13])(=[O:10])=[O:11]
Reactant: CN(CCN1CCN(CCc2ccc(C#N)cc2)C1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: NCCN
Agent: [S]
Solvent: O
Product: CN(CCN1CCN(CCc2ccc(C3=NCCN3)cc2)C1=O)S(=O)(=O)c1cccc(Cl)c1Cl
Product: Cl

Procedure:
A solution of 137 mg (0.29 mmol) of 2,3-dichloro-N-(2-{3-[2-(4-cyanophenyl)ethyl]-2-oxoimidazolidin-1-yl}ethyl)-N-methylbenzenesulphonamide, 2 ml of ethylenediamine and 4.6 mg (0.14 mmol) of sulphur was stirred at 100° C. for two hours. Water was then added, and the mixture was extracted with ethyl acetate. The organic extracts were washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated. The crude product obtained in this manner was purified by column chromatography on silica gel (mobile phase: dichloromethane/methanol/NH3 13:1:0.1 to 8:1:0.1). Using etheral hydrochloric acid, the product was then converted into the hydrochloride and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[C:18]([NH2:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][N:14]=1.[Cl:24][C:25]1[C:30]([C:31](O)=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:27][CH:26]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:24][C:25]1[C:30]([C:31]([NH:23][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]3[C:17]=2[N:16]=[CH:15][N:14]=[C:13]3[NH:12][C:3]2[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=2[F:1])=[O:32])=[C:29]([F:34])[C:28]([CH2:35][NH:36][C:37](=[O:42])[C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:27][CH:26]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(Nc3cc(C(F)(F)F)ccc3F)ncnc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cc(C(F)(F)F)ccc4F)ncnc23)c1F
Yield: 6.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2-fluoro-5-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-14, 100 mg, 0.31 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 178 mg, 0.62 mmol), oxalyl chloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (120 mg, 0.93 mmol) in CH2Cl2 (5 mL) to afford 12 mg of the title product. 1H NMR (300 MHz, CDCl3): δ 9.92 (s, 1H), 9.15 (d, 1H), 9.08 (d, 1H), 8.79 (s, 1H), 7.83 (s, 1H), 7.66 (m, 2H), 7.40 (m, 2H), 4.50 (d, 2H), 1.23 (s, 9H); MS (m/z): 592.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)[N:28]=2)=[CH:19]1
Reactant: Cc1ccc(N)cc1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1ccc(Nc2nccc(-c3c[nH]c4ncccc34)n2)cc1
Yield: 43.1 %

Procedure:
Using the procedure of example 1, p-toluidine (87 mg) was reacted with compound 1f (100 mg) to provide compound 10 (35 mg, 43%). 1H NMR (400 MHz, CD3OD) δ 8.82 (d, J=8.0 Hz, 1H), 8.28 (m, 2H), 8.13 (s, 1H), 7.62 (s, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 7.12 (d, J=5.2 Hz, 1H), 2.38 (s, 3H). MS (ESI) m/z: 302 (M+H)+.