Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][C:5]=1[OH:21].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:6][C:5]=1[O:21][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Reactant: BrCc1ccccc1
Product: CCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Yield: 81 %

Procedure:
The reaction of 5-(decyloxy)-2-hydroxybenzoic acid methyl ester with benzyl bromide under conditions described in Example 59 gave 5-(decyloxy)-2-(phenylmethoxy)benzoic acid methyl ester (81% yield, mp 32°-34°).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:8]([N:10]([O:22][CH3:23])[C:11]([C:13]2[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=2)=[O:12])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[Cl:31].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([N:10]([O:22][CH3:23])[C:11]([C:13]3[C:14]([CH:19]([F:21])[F:20])=[N:15][N:16]([CH3:18])[CH:17]=3)=[O:12])[CH3:9])[CH:3]=2)[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Product: CON(C(=O)c1cn(C)nc1C(F)F)C(C)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
To a stirred solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3-iodo-phenyl)-ethyl]-methoxy-amide (0.2 g, 0.46 mmol), prepared as described in example P2, in a mixture of ethanol (12 ml) and water (4 ml) was added, 3,4-dichloro-phenyl boronic acid (0.096 g, 0.5 mmol) followed by palladium acetate (0.052 g, 0.23 mmol) and potassium carbonate (0.19 g, 1.38 mmol). It was stirred for 18 hours at ambient temperature. Reaction mass was filtered on celite bed then diluted with water and extracted in ethyl acetate (3×60 ml), washed with water, brine and dried over anhydrous sodium sulfate). The crude mass was purified by column chromatography using 36% Ethyl acetate in hexane to yield 0.12 g (60% of theory) of 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid [1-(3′,4′-dichloro-biphenyl-3-yl)-ethyl]-methoxy-amide in form of a solid. Mp 162-164° C.
Reaction SMILES: [C:1]([S:4][C:5]([CH3:19])([CH3:18])[CH:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(Cl)CCl.[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([S:4][C:5]([CH3:19])([CH3:18])[CH:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([O:9][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)SC(C)(C)C(NC(=O)OC(C)(C)C)C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-(acetylthio)-2-(tert-butoxycarbonylamino)-3-methylbutanoic acid (693 mg, 2.38 mmol) was dissolved in DCM (10 ml). DMAP (73 mg, 0.59 mmol), EDC (342 mg, 1.79 mmol), and (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (500 mg, 1.19 mmol) were added, and the mixture stirred for 4 hours at RT. The reaction mixture was diluted with DCM and washed with NaHCO3 sat. sol. (10 ml), HCl 1N, brine, dried over Na2SO4 and evaporated under vacuum to give 1.06 g. Crude compound was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[CH2:21][NH:22][CH2:23][CH2:24]C(C)C)([CH3:4])([CH3:3])[CH3:2].C(C=O)=O.[NH4+:45].[OH-].Cl>CCO>[C:1]([C:5]1[C:6]([O:39][CH3:40])=[C:7]([CH:28]=[C:29]([N:31]2[CH:36]=[CH:35][C:34](=[O:37])[NH:33][C:32]2=[O:38])[CH:30]=1)/[CH:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=1[C:21]1[NH:45][CH:24]=[CH:23][N:22]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CNCCC(C)C)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: [NH4+]
Agent: Cl
Agent: O=CC=O
Agent: [OH-]
Solvent: CCO
Product: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2-c2ncc[nH]2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 50 %

Procedure:
To a solution of the product from Example 30, Part A (50 mg, 0.10 mmol) in EtOH (2 ml) was added glyoxal (57 uL, 0.50 mmol) and concentrated aqueous NH4OH (70 uL, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 h. To the mixture was added 1 N aq. HCl until pH=7, and the mixture was partitioned between H2O (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using 5% MeOH in CH2Cl2 as the eluent to give the title compound (27 mg, 50%). 1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1 H) 11.40 (d, J=1.84 Hz, 1 H) 9.98 (s, 1 H) 7.89 (d, J=8.82 Hz, 1 H) 7.66-7.76 (m, 2 H) 7.38 (t, J=2.21 Hz, 2 H) 7.23-7.31 (m, 2 H) 7.06-7.21 (m, 3 H) 5.63 (dd, J=8.09, 1.84 Hz, 1 H) 3.78 (s, 3 H) 3.07 (s, 3 H) 1.37 (s, 9 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18](O)=[O:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][CH:18]=[O:19])[CH2:10][C@H:9]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: O=CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](OC=O)CN1C(=O)OC(C)(C)C
Yield: 65.6 %

Procedure:
To a solution of (2S,4R)-1-t-butoxycarbonyl-4-hydroxy-2-methoxycarbonylpyrrolidine (7.36 g: 30 mmole) in tetrahydrofuran (30 ml), formic acid (1.36 ml: 36 mmole), triphenylphosphine (9.44 g: 36 mmole) and diethyl azodicarboxylate (5.67 ml: 36 mmole) are successively added in a nitrogen atmosphere under ice cooling. The mixture is stirred to react for 40 minutes at the same temperature to give (2S,4S)-1-t-butoxycarbonyl-4-formyloxy-2-methoxycarbonylpyrrolidine (5.38 g). Yield: 66%. Colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[C:17]([O:19][CH2:20][O:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(CCN(C)C)C.[Li]CCCC.ClCC[I:39]>C1COCC1.CCCCCC.O.[Au]>[C:1]([O:5][C:6]([NH:8][C:9]1[C:18]([I:39])=[C:17]([O:19][CH2:20][O:21][CH3:22])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCOc1cc(NC(=O)OC(C)(C)C)cc2ccccc12
Reactant: ClCCI
Agent: [Au]
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COCOc1c(I)c(NC(=O)OC(C)(C)C)cc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.8 %

Procedure:
A solution of 23 (0.435 g 1.43 mmol) in 5.7 mL anhydrous THF was cooled to −25° C. and treated with TMEDA (0.758 mL, 5.0 mmol) followed by n-BuLi (2.29 mL of a 2.5 M solution in hexane, 5.0 mmol) in a slow dropwise manner. The resulting gold solution was stirred for 2 h at −25° C. The reaction mixture was treated with 1-chloro-2-iodoethane (0.37 mL, 5.0 mmol) and stirred for 15 min at 25° C. The reaction was diluted with H2O (40 mL), extracted with Et2O (3×20 mL), and the combined organic extracts were washed with saturated aqueous NaCl, dried Na2SO4) and concentrated under reduced pressure. Flash chromatography (SiO2, 2.5×15 cm, 0-7% EtOAc/hexane gradient) yielded 24 (490 mg, 80%) as a yellow oil: 1H NMR (CDCl3, 400 MHz) δ 8.35 (s, 1H), 8.03 (d, J=12.8 Hz, 1H), 7.78 (d, J=12.5 Hz, 1H), 7.42 (m, 2H), 7.14 (br s, 1H), 5.20 (s, 2H), 3.74 (s, 3H), 1.56 (s, 9H); 13C NMR (CDCl3, 100 MHz) δ 154.7, 152.6, 135.1, 134.8, 127.6, 127.4, 125.1, 125.0, 122.2, 113.0, 100.5, 87.7, 81.1, 58.5, 28.4; IR (film) νmax 3391, 2977, 2933, 1732, 1524, 1367, 1340, 1276, 1228, 1157 cm−1; FABHRMS (NBA/NaI) m/z 430.0507 (C17H20INO4+H+ requires 430.0515).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=O)=[O:4].[CH3:23][S:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]([C:5]1[N:30]([CH2:29][C:28]2[CH:31]=[CH:32][C:25]([S:24][CH3:23])=[CH:26][CH:27]=2)[C:7](=[O:6])[C:9]2[C:14]([C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:13][C:12]([Br:22])=[CH:11][CH:10]=2)=[O:4]
Reactant: CSc1ccc(CN)cc1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(SC)cc1

Procedure:
The present compound was synthesized by a method similar to that in Example 83 and using 6-bromo-4-phenyl-3-isocoumarincarboxylic acid methyl ester and 4-(methylthio)benzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][CH:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(C(C)C)CC)(C)C.ClCl>CS(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:6])[C:11]([NH:13][CH:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CNCCNC1
Reactant: CC(NC(=O)c1ccc(C(=O)O)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(NC(=O)c1ccc(C(=O)N2CCCNCC2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1d from 2-chloro-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, 1,4-diazepan, PFTU, and diisopropylethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.69 minutes; C22H23Cl2N5O2 (460.36); mass spectrum: (M−H)−=459/461/463 (chlorine isotope).
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][C:37]=1[I:38])[CH:33]=O)[CH2:26][CH2:27][CH3:28]>C1(C)C=CC=CC=1>[CH2:25]([O:29][C:30]1[CH:31]=[C:32](/[CH:33]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:35]=[CH:36][C:37]=1[I:38])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCOc1cc(C=O)ccc1I
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCOc1cc(/C=C/C(=O)OC)ccc1I
Yield: 87.2 %

Procedure:
65.08 g (0.195 mol, 2 eq) of methyl (triphenylphosphoranylidene)acetate are added to a solution of 29.60 g (0.097 mol, 1 eq) of 3-butoxy-4-iodobenzaldehyde in 360 ml of toluene. The reaction mixture is refluxed for 2 hours. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (50/50 heptane/dichloromethane). 30.47 g of methyl(E)-3-(3-butoxy-4-iodophenyl)acrylate are obtained in the form of pale yellow crystals. Yield=87%.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[F:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=1.FC1C=C(F)C=CC=1C=O>ClCC(Cl)(Cl)Cl>[F:5][C:6]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:7]=1[C:8]([C:25]1[C:26]([CH3:30])=[N:27][N:28]([CH3:29])[C:24]=1[C:18]1[CH:19]=[CH:20][C:21]([F:23])=[CH:22][C:17]=1[F:16])=[O:9]
Reactant: Cc1cc(-c2ccc(F)cc2F)n(C)n1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: ClCC(Cl)(Cl)Cl
Agent: O=Cc1ccc(F)cc1F
Agent: [Al+3]
Product: Cc1nn(C)c(-c2ccc(F)cc2F)c1C(=O)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of aluminum chloride (380 mg, 2.88 mmol) in tetrachloroethane (10 mL) at about 0° C. was added 2,4-difluorobenzoyl chloride (0.36 mL, 2.88 mmol). The reaction mixture was stirred for about 30 minutes, and then a mixture of 5-(2,4-difluorophenyl)-1,3-dimethyl-1H-pyrazole (prepared by the method analogous to Example 4, Steps A-B starting with 2,4-difluorobenzaldehyde) in tetrachloroethane (0.5 mL) was added. The reaction mixture was allowed to warm to room temperature, stirred for 1 h, and then heated at reflux for 24 h. The reaction mixture was cooled to room temperature, poured over a mixture of ice/hydrochloric acid and extracted with dichloromethane (3×). The combined organic layers were washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by MPLC (50% ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a solid (0.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([O:14]CC)=O)[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:14])[C:6]3[CH2:17][CH2:18][N:19]([CH3:21])[CH2:20][C:5]=3[C:4]=2[CH:3]=1
Reactant: NC1CCCCC1
Reactant: CCOC(=O)Cn1c2c(c3cc(Cl)ccc31)CN(C)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)NC2CCCCC2)C1
Temperature: 80 °C
Yield: 2 %

Procedure:
A solution of ethyl 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetate (500 mg, 1.63 mmol) in oxalyl chloride (2.0 g, 16.33 mmol) was stirred at 25° C. for 3 h. After completion of the reaction (monitored by LCMS), cyclohexyl amine (1.0 ml, excess) was added to it and the reaction mixture heated at 80° C. for 3 h. The reaction mixture was concentrated and basified with aqueous saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was concentrated to dryness and the resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml) to obtain 10 mg (yield: 2.0%) of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)-N-cyclohexylacetamide as TFA salt. 1H NMR (DMSO) 10.0 (bs, 1H), 8.30 (d, 1H), 7.60 (s, 1H), 7.5 (d, 1H), 7.21 (d, 1H), 4.80 (m, 2H), 4.6 (m, 1H), 4.30 (m, 1H), 3.80 (m, 1H), 3.41 (m, 2H), 3.10 (bs, 2H), 3.0 (s, 3H), 1.80-1.20 (m, 10H).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH2:18][N:19](C(OC(C)(C)C)=O)[CH3:20])[NH:13][C:12]4=[N:28][NH:29][CH:30]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:15]([C:16]#[N:17])=[C:14]([CH2:18][NH:19][CH3:20])[NH:13][C:12]4=[N:28][NH:29][CH:30]=[C:11]34)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CN(CC1=C(C#N)C(c2cccc3nonc23)c2c[nH]nc2N1)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNCC1=C(C#N)C(c2cccc3nonc23)c2c[nH]nc2N1

Procedure:
4-(2,1,3-Benzoxadiazol-4-yl)-6-((N-t-butoxycarbonyl-N-methylamino)methyl)-5-cyano-4,7-dihydro-2H-pyrazolo[3,4-b]-pyridine (0.6 g) was added to trifluoroacetic acid (10 mL) at 0° C. and the mixture was stirred for an hour. The solvent was evaporated under reduced pressure and the residue was crystallized by ethanol, and the precipitated crystals were collected by filtration to give the title compound (0.1 g) as yellow crystals.
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.C(N(CC)CC)C.[CH2:27]([O:34][C@@H:35]1[CH2:39][CH2:38][CH2:37][C@H:36]1[NH2:40])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(O)C>[C:28]1([CH2:27][O:34][C@@H:35]2[CH2:39][CH2:38][CH2:37][C@H:36]2[NH:40][C:5]2[N:6]=[CH:1][N:2]=[C:3]3[C:4]=2[N:8]=[CH:9][N:10]3[CH:11]2[C@H:12]([OH:19])[C@H:13]([OH:18])[C@@H:14]([CH2:16][OH:17])[O:15]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: N[C@@H]1CCC[C@H]1OCc1ccccc1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: CCO
Product: OC[C@H]1OC(n2cnc3c(N[C@@H]4CCC[C@H]4OCc4ccccc4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
To a solution of 6-chloropurine riboside (10.0 g, 35 mmol) in ethanol (350 mL) was added triethylamine (10.0 mL, 100 mmol) and (1R,2R)-2-(benzyloxy)-cyclopentylamine (5.2 g, 52 mmol). The mixture was refluxed for 24 hours, during which the reaction went from a suspension to a clear solution. The ethanol was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water (100 mL:200 mL). The organic layer was separated and the aqueous layer washed with ethyl acetate (2×75 mL). The combined organic layers were dried (sodium sulfate), and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and product precipitated by addition of hexane, to afford 2-(6-{[(1R,2R)-2-(phenylmethoxy)cyclopentyl]amino}purin-9-yl)(4S,3R,5R)-5-(hydroxymethyl)oxolane-3,4-diol as a white solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([N:9]2[C@@H:16]3[C@@H:11]([CH2:12][CH2:13][NH:14][CH2:15]3)[CH2:10]2)[N:4]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38](O)=[O:39].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[F:35][C:36]1[CH:44]=[CH:43][CH:42]=[C:41]([N:45]2[N:49]=[CH:48][CH:47]=[N:46]2)[C:37]=1[C:38]([N:14]1[CH2:13][CH2:12][C@@H:11]2[C@@H:16]([N:9]([C:5]3[N:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:8]=[CH:7][N:6]=3)[CH2:10]2)[CH2:15]1)=[O:39]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: FC(F)(F)c1ccnc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC[C@H]2CN(c3nccc(C(F)(F)F)n3)[C@H]2C1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(4-(trifluoromethyl)pyrimidin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 27) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. For C20H17F4N7O, 447.40; m/z found 448.0 [M+H]+.
Reaction SMILES: C[C@@H]1[O:7][C@@H](O[C@@H:9]2[C:14]3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4[C:18](O)=[C:13]3[CH2:12][C@@:11](O)(C(CO)=O)[CH2:10]2)C[C@H](N)[C@@H]1O.Cl.C[C@@H]1O[C@@H](O[C@@H]2C3=C(O)C4C(=O)C5C(=CC=CC=5OC)C(=O)C=4[C:58]([OH:59])=[C:53]3[CH2:52][C@@:51]([OH:77])([C:73]([CH2:75][OH:76])=[O:74])C2)C[C@H](N)[C@@H]1O.C#CCCCC#C.[OH2:87]>CS(C)=O>[CH:14]#[C:9][CH2:10][CH2:11][CH2:12][C:13]#[CH:18].[O:87]=[C:75]1[O:76][C@H:52]([C@H:53]([CH2:58][OH:59])[OH:7])[C:51]([OH:77])=[C:73]1[OH:74]
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Reactant: O
Agent: C#CCCCC#C
Agent: Cl
Solvent: CS(C)=O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
100 mg of product 1 are dissolved in 1.1 ml of distilled water; a solution of 140 μl of 1,6-Heptadiyne in 9.86 ml of DMSO are prepared separately, whereas 23.2 mg of doxorubicin hydrochloride are dissolved in 0.5 ml of distilled water. The solution of hyaluronic acid is mixed with that of doxorubicin and with 0.2 ml of that of 1,6-Heptadiyne; 0.1 ml of an aqueous solution obtained with 50 mg of CuSO4.5H2O in 1 ml of H2O and 0.1 ml of an aqueous solution of 20 mg of ascorbic acid are then added. The mixture is stirred vortically for a few minutes. The rapidly formed gel (see FIG. 28) incorporates the doxorubicin hydrochloride inside.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:14][C:15]3[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=3)[N:3]=2)=[CH:24][CH:23]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(F)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-fluoro-phenylboronic acid to give [1-(4-fluoro-phenyl)-6-methoxy-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 345(MH+).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1I)[CH2:15][N:16]([CH3:20])[CH2:17][CH:18]=[CH2:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5].C([Li])CCC.CCCCCC.[CH2:38]([Sn:42](Cl)([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH3:46])[CH2:39][CH2:40][CH3:41].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]([F:26])([F:25])[C:3]([C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[Sn:42]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:38][CH2:39][CH2:40][CH3:41])[CH2:15][N:16]([CH3:20])[CH2:17][CH:18]=[CH2:19])([O:8][CH2:9][O:10][CH3:11])[C:4]([F:7])([F:6])[F:5]
Reactant: C=CCN(C)Cc1ccc(I)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=CCN(C)Cc1ccc([Sn](CCCC)(CCCC)CCCC)c(C(OCOC)(C(F)(F)F)C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Compound 12 (470 mg, 945 μmol) was dissolved in freshly distilled THF (5 mL) under nitrogen atmosphere and cooled to −78° C. n-butyllithium 1.6M in hexane solution (886 μL, 1.42 mmol) was then added and the mixture stirred 30 min at −78° C. Tributyltin chloride (462 mg, 1.42 mmol) in solution in THF (2 mL) was added and the mixture let to warm to room temperature overnight. A 0.1M ammonium chloride solution (5 mL) was added to the reactionnal mixture. The organic layer was isolated and the aqueous layer was extracted with dichloromethane (2×5 mL). The organic layers were combined and dried over sodium sulfate. After solvent evaporation under reduced pressure, the residue was purified over silica gel with heptane/acetone (98/2) as eluant to give 524 mg (794 μmol, 84% yield) of a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.C[CH2:14][N:15](C(C)C)C(C)C.CN>CN(C=O)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([CH:3]=1)[NH:15][CH3:14]
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Solvent: CN(C)C=O
Product: CNc1cc(Cl)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-chloro 2,5-difluoro nitrobenzene (2.0 g, 0.010 mol) in DMF (15 ml) was added DIPEA (4.5 ml, 0.026 mol) followed by MeNH2 (5 ml, 0.010 mol, 2M in THF) and the resulting solution was stirred at room temperature for 12 h. The reaction was quenched with H2O and extracted with EtOAc (3×30 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to get crude product which was purified column chromatography to get the title compound 5-chloro-4-fluoro-N-methyl-2-nitroaniline as a yellow solid, 1H NMR (400 MHz, DMSO-d6), δ: 8.20 (s, 1H), 8.09 (d, J=10 Hz, 1H), 7.22-7.20 (d, J=6.4 Hz, 1H), 2.95 (s, 3H). MS (M+1): 205.12