Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[O:13][C@H:12]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[C@@H:7]([O:8][C:9](=[O:11])[CH3:10])[C@H:6]1[Cl:19])(=O)C.[BrH:20]>ClCCl.C(O)(=O)C>[C:9]([O:8][C@@H:7]1[C@@H:12]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:13][CH:5]([Br:20])[C@@H:6]1[Cl:19])(=[O:11])[CH3:10]
Reactant: CC(=O)OC[C@H]1OC(OC(C)=O)[C@H](Cl)[C@@H]1OC(C)=O
Reactant: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1OC(Br)[C@H](Cl)[C@@H]1OC(C)=O

Procedure:
3,5-Di-O-acetyl-2-chloro-2-deoxy-α,β-D-ribofuranosyl acetate (the compound described by J. P. Schaumberg et al., in "J. Org. Chem.," 50, pp. 1651-1656, 1985) represented by the following formula (N) ##STR52## where Ac is acetyl group is dissolved in dichloromethane. To the resulting solution is added 30% hydrogen bromide in acetic acid to effect the reaction at room temperature overnight. The resulting reaction solution is concentrated and the remaining acetic acid is removed by azeotropic distillation with toluene, to yield 3,5-di-O-acetyl-2-chloro-2-deoxy-α,β-D-ribofuranosyl bromide [compound (O)] as a syrup.
Reaction SMILES: C1(=O)[N:5]([C@H:6]2[C@@H:9](/[CH:10]=[CH:11]/[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]([Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[C:7]2=[O:25])C(=O)C2=CC=CC=C12.CNN>C(COC)OC>[NH2:5][C@H:6]1[C@@H:9](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([Si:18]([C:21]([CH3:23])([CH3:22])[CH3:24])([CH3:20])[CH3:19])[C:7]1=[O:25]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N2C(=O)c3ccccc3C2=O)[C@H]1/C=C/c1ccccc1
Agent: CNN
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](N)[C@H]1/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 5 ml of dimethoxyethane is suspended 440 mg of cis-3-phthalimido-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine and after addition of 0.26 ml of methylhydrazine, the mixture is stirred at room temperature for 30 minutes. The solvent is then distilled off under reduced pressure and the residue is dissolved by addition of 5 ml of methylene chloride and allowed to stand overnight. The precipitate is filtered off and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (6:4)] to give an oil of cis-3-amino-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine. This oil is dissolved in 10 ml of tetrahydrofuran and under ice-cooling and stirring, 0.2 ml of triethylamine is added, followed by addition of 0.212 g of 2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetyl chloride hydrochloride. The mixture is stirred under ice-cooling for 10 minutes and then at room temperature for 30 minutes, after which the reaction mixture is shaken with ethyl acetate and water. The ethyl acetate layer is taken, washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The solvent is then distilled off under reduced pressure and the residue is purified by silica gel column chromatography [eluent: chloroform-ethyl acetate (7:3)] and crystallized from ether to give cis-[2-(2-chloroacetamido-4-thiazolyl)-2-methoxyiminoacetamido]-4-(E)-styryl-1-(tert-butyldimethylsilyl)-2-oxoazetidine (syn-isomer), melting at 228°-231° C. (decomp.).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([OH:14])=O)=[CH:2]1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][C:12]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[O:14])=[CH:2]1
Reactant: O=C(O)CCc1c[nH]c2ccccc12
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCc1c[nH]c2ccccc12)N1CCCC1

Procedure:
681 mg (3.60 mmol) 3-(1H-indol-3-yl)-propionic acid, 0.3 mL (3.60 mmol) pyrrolidine, 1.13 g (3.50 mmol) TBTU and 0.98 mL (7.00 mmol) triethylamine in 5.0 mL DMF were stirred overnight at RT. The mixture was purified by preparative HPLC. The product fractions were combined and evaporated down i. vac.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]([NH:16][C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>C(#N)C>[C:35]1([C:33](=[O:34])[CH2:32][N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([N:16]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17](=[O:24])[C@H:18]([C@H:20]([CH2:22][CH3:23])[CH3:21])[NH2:19])=[O:5])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC[C@H](C)[C@H](N)C(=O)N(Cc1ccccc1)C(=O)[C@@H]1CCCN1CC(=O)c1ccccc1
Yield: 93.9 %

Procedure:
Using the procedure described in example 5, treatment of L-proline-L-isoleucine benzylamide (361 mg, 1.14 mmol), with cesium carbonate (0.74 g, 2.28 mmol), and 2-bromoacetophenone (1.134 g, 5.69 mmol, 5.0 eq) in acetonitrile (12 mL), provided 466 mg (94%) of L-isoleucine, N-[1-(2-phenyl-2-oxoethyl)-L-prolyl] benzylamide as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]([O-:11])[C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])O)[OH:6])[OH:4].[Na+].[O:13]=[C:14]([O-])[C@@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16].[Na+]>[Ni]>[C:2]1(=[O:1])[O:11][C@H:7]([CH2:9][OH:10])[C@@H:5]([OH:6])[C@H:3]1[OH:4].[CH2:14]([OH:13])[C@@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16]
Reactant: O=C([O-])[C@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C([O-])[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Ni]
Agent: [Na+]
Product: O=C1O[C@H](CO)[C@@H](O)[C@H]1O
Product: OC[C@@H](O)[C@@H](O)[C@@H](O)CO

Procedure:
According to this example the dissolution of the nickel catalyst was prevented by lowering the acidity of the reaction solution with an addition of alkali. The hydrogenation proceeded smoothly and the yield of pentitols was close to the maximum value of 75% in this case. The salts of pentonic acids, of course, did not undergo hydrogenation. On the contrary, sodium D-arabinonate was partly isomerized to sodium D-ribonate, and the subsequent hydrogenation of D-ribono-1,4-lactone resulted in enhanced formation of ribitol. In spite of the isomerization of the starting material, the control of pH can be applied in the production of xylitol from D-arabinonic acid as both arabinitol and ribitol yield xylitol in the second isomerization step. On the contrary, the control of pH can not be applied when L-xylonic acid is to be converted to xylitol.
Reaction SMILES: P(Cl)(Cl)Cl.P(Cl)(Cl)(Cl)(Cl)Cl.[C:11]([O:14][C:15](=O)[CH3:16])(=[O:13])[CH3:12]>C(O)(=O)C>[C:11]([O:14][CH2:15][CH:15]([O:14][C:11](=[O:13])[CH3:12])[CH3:16])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClP(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCC(C)OC(C)=O

Procedure:
2 g phosphorus trichloride and 2 g phosphorus pentachloride were dissolved with 2 g cupric chloride in 500 ml glacial acetic acid and 50 ml acetic anhydride and then further treated a described in Example 4. 5.2 g propylene glycol diacetate were obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([CH:10]=[CH:11][N:12]3[CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl[C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19]>C(Cl)Cl>[N:1]1([C:6]2[CH:14]=[C:13]3[C:9]([C:10]([C:17](=[O:22])[C:18]([O:20][CH3:21])=[O:19])=[CH:11][N:12]3[CH3:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: COC(=O)C(=O)Cl
Reactant: Cn1ccc2ccc(-n3ccnc3)cc21
Solvent: ClCCl
Product: COC(=O)C(=O)c1cn(C)c2cc(-n3ccnc3)ccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 116.1 %

Procedure:
6-Imidazol-1-yl-1-methyl-1H-indole (0.90 g, 4.56 mmol ) was dissolved in CH2Cl2 (2 mL) and cooled at 0° C. Methyl chlorooxoacetate (1.3 mL, 14 mmol) was added. Stirring was continued for 2 h at 0° C. and more methyl chlorooxoacetate (0.4 mL, 4.3 mmol) was added. After an additional 2 h, the solvent was removed. The residual solid was taken up in ether, filtered and washed well with ether to give crude methyl (6-imidazol-1-yl-1-methyl-1H-indol-3-yl)glyoxylate (1.50 g).
Reaction SMILES: [CH3:1][Si:2]([CH3:8])([CH3:7])[O:3][CH2:4][C:5]#[CH:6].C([Mg]Br)C.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C.O>[OH:13][C:14]1([C:6]#[C:5][CH2:4][O:3][Si:2]([CH3:8])([CH3:7])[CH3:1])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: C#CCO[Si](C)(C)C
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(O)(C#CCO[Si](C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Trimethyl(2-propynyloxy)silane (11.54 ml, 9.62 g, 75 mmol) was added dropwise to a stirred, cooled (−5° C.) solution of ethyl magnesium bromide (1M in tetrahydrofuran, 75 ml, 75 mmol) in tetrahydrofuran (150 ml), maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 90 minutes. The mixture was cooled to −5° C. and 1,1-dimethylethyl 4-oxo-1-piperidinecarboxylate (15.0 g, 75 mmol) was added slowly, maintaining the internal temperature below 0° C. The mixture was stirred at 0° C. for 3 hours then at room temperature for 96 hours. Saturated aqueous ammonium chloride (300 ml), water (100 ml) and ethyl acetate (300 ml) were added and the layers were separated. The aqueous layer was extracted with ethyl acetate (200 ml) and the combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (24.4 g, 100%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1[CH3:20].[CH2:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1.C(O)(C)C.C(OC(C)C)(C)C>>[CH3:20][C:7]1[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:9][CH:10]=[CH:11][C:6]=1[S:5][CH2:4][CH2:3][CH2:2][CH:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24][CH2:23][NH:22]1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: c1ccc2c(c1)CCNC2
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Product: Cc1c(SCCCC2NCCc3ccccc32)ccnc1CSc1ccncc1
Yield: 36 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1,2,3,4-tetrahydroisoquinoline, chromatography on silica gel and subsequent crystallization from isopropanol/diisopropyl ether gives the title compound; m.p. 190-192° C.; yield 36% of theory.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)=[O:43])=[O:39])=[N:11][C:12]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][N:30]=4)=[CH:25][CH:24]=3)[CH2:19][CH2:18]2)=[N:13][C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:52](OC(=O)C)(=[O:54])[CH3:53].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl.N1C=CC=CC=1>[C:52]([O:37][CH:35]([C:32]1[CH:33]=[CH:34][C:29]([C:26]2[CH:27]=[CH:28][C:23]([N:20]3[CH2:19][CH2:18][CH:17]([CH2:16][C:12]4[N:11]=[C:10]([C:38]([NH:40][CH2:41][C:42]([O:44][CH2:45][C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)=[O:43])=[O:39])[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[C:14]([CH3:15])[N:13]=4)[CH2:22][CH2:21]3)=[CH:24][CH:25]=2)=[N:30][CH:31]=1)[CH3:36])(=[O:54])[CH3:53]
Reactant: Cc1nc(CC2CCN(c3ccc(-c4ccc(C(C)O)cn4)cc3)CC2)nc(C(=O)NCC(=O)OCc2ccccc2)c1OCc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(C)c1ccc(-c2ccc(N3CCC(Cc4nc(C)c(OCc5ccccc5)c(C(=O)NCC(=O)OCc5ccccc5)n4)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.6 %

Procedure:
Benzyl [({5-(benzyloxy)-2-[(1-{4-[5-(1-hydroxyethyl)pyridin-2-yl]phenyl}piperidin-4-yl)methyl]-6-methylpyrimidin-4-yl}carbonyl)amino]acetate (0.24 g, 0.35 mmol) obtained in Example 12-(3) was dissolved in dichloromethane (30 mL), and acetic anhydride (0.050 mL, 0.52 mmol) and triethylamine (1.8 mL) were added, followed by stirring at room temperature for 12 hours. Acetic anhydride (1.8 mL) and pyridine (0.90 mL) were added to the reaction solution, followed by stirring for further 12 hours, and subsequently a saturated aqueous sodium hydrogencarbonate solution was added, followed by extraction with ethyl acetate. After the organic layer was concentrated under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (0.12 g, 0.17 mmol) as a yellow oil (yield 48%).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].[C:24](=[O:27])([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH3:36])[CH2:35]O[CH2:33]1>C(#N)C>[F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][CH2:13][C:14]3=[O:19])=[C:6]([O:20][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][O:27][CH3:24])[C:5]=1[O:21][CH3:22]
Reactant: CC1(CBr)COC1
Reactant: O=C([O-])[O-]
Reactant: COc1c(OC(F)F)ccc(-c2cccc3c2CCC3=O)c1O
Agent: [K+]
Solvent: CC#N
Product: COCC(C)(C)COc1c(-c2cccc3c2CCC3=O)ccc(OC(F)F)c1OC
Temperature: 80 °C
Yield: 25.4 %

Procedure:
To a stirring solution of 4-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (75 mg, 0.234 mmol) in acetonitrile (10 mL) was added potassium carbonate (96.8 mg, 0.702 mmol) and 3-bromomethyl-3-methyl-oxetane (115 mg, 0.702 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-20% ethyl acetate in pet ether) to afford title compound as a solid (25 mg, 26%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[N:15]=[C:14]3[C:10]([N:11]=[CH:12][N:13]3[C@@H:16]3[CH2:20][C@H:19]([N:21]4[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]4)[C@@H:18]([OH:28])[C@H:17]3[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:8]=2)[CH2:3]1.Cl.C1(C(C2C=CC=CC=2)CNC2N=C(N3CC[C@@H](N[C:70](NCC4C=CC=CN=4)=[O:71])C3)N=C3C=2N=CN3[C@@H]2C[C@H](N3N=NC(CC)=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[NH2:100][CH2:101][C:102]1[CH:107]=[CH:106][N:105]=[CH:104][CH:103]=1>>[C:33]1([CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:31][NH:30][C:9]2[N:8]=[C:7]([N:4]3[CH2:5][CH2:6][C@@H:2]([NH:1][C:70]([NH:100][CH2:101][C:102]4[CH:107]=[CH:106][N:105]=[CH:104][CH:103]=4)=[O:71])[CH2:3]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][CH3:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: NCc1ccncc1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](N)C5)nc43)[C@H](O)[C@@H]2O)c1
Reactant: CCc1nnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccccn6)C5)nc43)[C@H](O)[C@@H]2O)n1
Agent: Cl
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)NCc6ccncc6)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-((R)-3-amino-pyrrolidin-1-yl)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol. (Example 110) using a procedure analogous to that of 1-((R)-1-{6-(2,2-diphenyl-ethylamino)-9-[(1R,2S,3R,4S)-4-(5-ethyl-tetrazol-2-yl)-2,3-dihydroxy-cyclopentyl]-9H-purin-2-yl}-pyrrolidin-3-yl)-3-pyridin-2-ylmethyl-urea hydrochloride (Example 113) by replacing 2-aminomethyl pyridine with 4-aminomethylpyridine. The compound is partitioned between DCM and saturated NaHCO3(aq). The organics are dried (MgSO4), filtered and reduced in vacuo to yield the title compound. MS (ES+) m/e 728.22 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12]Cl)[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCNCC
Reactant: CCOC(=O)c1c(CCl)nc2ccc(Cl)cc2c1-c1ccccc1
Product: CCOC(=O)c1c(CN(CC)CC)nc2ccc(Cl)cc2c1-c1ccccc1

Procedure:
According to the same manner as that described in Example 33, ethyl 6-chloro-2-chloromethyl-4-phenylquinoline-3-carboxylate was reacted with diethylamine to give ethyl 6-chloro-2-(N,N-diethylaminomethyl)-4-phenylquinoline-3-carboxylate. This compound was recrystallized from ethanol. Colorless prisms, mp. 107°-108° C.
Reaction SMILES: [C:1]([C:3](=[CH:17][NH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([I:27])[CH:20]=1)[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=O)#[N:2].CO.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:16][C:8]1[CH:9]=[C:10]([Cl:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=1[NH:6][C:4]1[C:24]2[C:19](=[CH:20][C:21]([I:27])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][C:3]=1[C:1]#[N:2]
Reactant: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(I)c2)c(Cl)cc1Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CO
Product: COc1cc(Nc2c(C#N)cnc3cc(I)c(OC)cc23)c(Cl)cc1Cl
Reaction time: 24 h
Yield: 28.8 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)-3-[(3-iodo-4-methoxyphenyl)amino]prop-2-enamide (720 mg, 1.39 mmol) in 40 mL of acetonitrile was added 0.2 mL of methanol. The mixture was heated to reflux and phosphorous oxychloride (1.24 mL, 13.9 mmol) was added dropwise, via syringe. This solution was heated at reflux overnight. After 24 hours, the mixture was cooled in an ice-bath and the solid was collected by filtration, washed with cold acetonitrile (40 mL) and then suspended in tetrahydrofuran (100 mL). To both the acetonitrile filtrate and the tetrahydrofuran suspension were added concentrated ammonium hydroxide (2×50 mL) and the mixtures were stirred for 1 hour. Water (2×800 ml) was added and stirring was continued for 2 hours. The resulting solids were combined, washed with hot water and dried under reduced pressure at ˜40° C., overnight, to provide 200 mg (29%) of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-iodo-6-methoxy-3-quinolinecarbonitrile, as yellow solid, mp 253-254° C.; 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 4.00 (s, 3H), 7.33(s, 1H), 7.74(s, 1H), 7.86 (s, 1H), 8.39 (s, 1H), 8.43 (s, 1H), 9.61 (s, 1H); MS (ES) m/z 500.0, 502.1 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[C:8]([NH2:10])=[O:9].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.C([O-])(O)=O.[Na+]>CO.O.CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[C:8]([NH2:10])=[O:9])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: NC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)[C@@H]1CCCC[C@@H]1Nc1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of (±)-cis-2-aminocyclohexanecarboxamide (28 mg, 0.20 mmol), 2,4,5-trichloropyrimidine (37 mg, 0.20 mmol, 1 equiv.) and NaHCO3 (17 mg, 0.20 mmol, 1 equiv.) in a mixture of MeOH (1.0 mL) and H2O (0.5 mL) is stirred at room temperature for 12 h. The reaction is diluted with EtOAc and washed with water (2×), dried over Na2SO4 and concentrated in vacuo to generate the product (±)-cis-2-(2,5-dichloropyrimidin-4-ylamino)cyclohexanecarboxamide; ESMS m/z 289.1 (M+H+).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:7][CH:8]=[CH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.Cl>CCCCC>[Br:1][C:9](=[CH:8][O:7][CH2:3][CH2:4][CH2:5][CH3:6])[C:10](=[O:15])[C:11]([F:13])([F:14])[F:12]
Reactant: CCCCOC=CC(=O)C(F)(F)F
Reactant: BrBr
Agent: Cl
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: CCCCOC=C(Br)C(=O)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h

Procedure:
8.0 g (0.05 mole) of bromine, dissolved in 100 ml pentane, are added dropwise to a solution of 9.75 g (0.05 mol) of 4-n-butoxy-1,1,1-trifluorobut-3-en-2-one in 50 ml of pentane cooled to -20° C. After stirring for 1 hour at -20° C., a solution of 6.0 g (0.06 mole) of triethylamine in 100 ml pentane is added dropwise at the same temperature. After being allowed to stand overnight at 25° C., the mixture is poured into ice water and acidified by means of 1N hydrochloric acid and the phases are separated. Conventional work-up gives 12.1 g of almost homogeneous crude 3-bromo-4-n-butoxy-1,1,1-trifluorobut-3-en-2-one, which is freed from the small amount of impurities by distillation under reduced pressure. Boiling point 113°-115° C./16 mbar, nD20 =1.4640.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH:8]=1)(=O)=O.[N:48]1[CH:53]=[C:52](B(O)O)[CH:51]=[N:50][CH:49]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:44][O:43][C:40]1[C:39]([CH3:45])=[CH:38][N:37]=[C:36]([CH2:35][N:33]2[N:34]=[C:9]3[CH:8]=[C:7]([C:52]4[CH:53]=[N:48][CH:49]=[N:50][CH:51]=4)[C:16]4[CH2:15][S:14][N:13]=[C:12]([N:17]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[C:11]([C:10]=43)=[N:32]2)[C:41]=1[CH3:42]
Reactant: OB(O)c1cncnc1
Reactant: COc1c(C)cnc(Cn2nc3cc(OS(=O)(=O)C(F)(F)F)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(C)cnc(Cn2nc3cc(-c4cncnc4)c4c-3c(n2)C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSC4)c1C
Temperature: 40 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
4-[Bis(tert-butoxycarbonyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7-dihydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-8-yl trifluoromethanesulfonate (50 mg) was dissolved in 1,4-dioxane (4 ml). Pyrimidine-5-boronic acid (13 mg), a 2 N sodium carbonate solution (2 ml) and bis(triphenylphosphine)palladium (II) dichloride (5 mg) were added and the mixture was stirred at 40° C. for two hours. Water was placed into the reaction solution, followed by extraction with ethyl acetate. The resulting organic layer was sequentially washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform-methanol) to obtain the title compound as an oil (45 mg).