Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][CH:11]=[C:10]2[C:6]=1/[C:7](=[CH:18]/[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25])/[C:8](=[O:17])[NH:9]2.[Cl-].[NH4+]>O.CO.[Zn]>[NH2:14][C:13]1[C:5]([C:4]#[C:3][CH2:2][OH:1])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:17])/[C:7]/2=[CH:18]\[C:19]1[NH:20][CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(C#CCO)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(C#CCO)c21

Procedure:
Using Method L above, (Z)-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (63 mg, 0.19 mmol) (from Example 30 above) was reduced with zinc (0.11 g, 1.67 mmol) and ammonium chloride (22.4 mg, 0.42 mmol) in 10% water in methanol (10 mL) with heating at reflux for 2 h to give (Z)-5-amino-1,3-dihydro-4-(3-hydroxy-1-propynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H -indol-2-one. (Yield 18 mg, 40%).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[CH:14]=[CH2:15].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH:14]=[CH2:13]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C=CCOc1ccc(C(=O)O)cc1

Procedure:
The reaction of ethyl 4-hydroxybenzoate and allyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 4-Allyloxy-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.56 (s, —CO2H); 7.83 (d-like, J=8.0, 2 arom. H); 6.97 (d-like, J=8.0, 2 arom. H); 5.99 (m, —CH═CH2); 5.38, 5.24 (2 d-like, —CH═CH2); 4.59 (d-like, CH2—CH═CH2); 13C-NMR (100 MHz, d6-DMSO): 166.92 (—C═O); 161.72; 133.17; 131.28 (2 arom. C); 123.04; 117.80; 114.42 (2 arom. C); 68.34.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:3][CH2:2]1.Br[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50]>>[CH:1]1([N:4]([CH2:5][C:6]2[CH:7]=[C:8]([CH:42]=[CH:43][CH:44]=2)[C:9]([NH:11][C:12]2[S:13][C:14]3[CH2:41][CH2:40][CH2:39][CH2:38][C:15]=3[C:16]=2[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=3)=[CH:22][CH:21]=2)=[O:18])=[O:10])[CH2:46][CH2:47][CH2:48][C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccc(CCc2ccc(NC(=O)c3c(NC(=O)c4cccc(CNC5CC5)c4)sc4c3CCCC4)cc2)cc1
Product: CCOC(=O)CCCN(Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1)C1CC1
Yield: 56.4 %

Procedure:
By using 300 mg of methyl 4-{2-[4-({[2-({3-[(cyclopropylamino)methyl]benzoyl}amino)-4,5,6,7-tetrahydro-1-benzothiophen-3-yl]carbonyl}amino)phenyl]ethyl}benzoate and 289 mg of ethyl 4-bromobutyrate, the reaction similar to Preparation Example 30 was performed, thereby obtaining 201 mg of methyl 4-(2-{4-[({2-[(3-{[cyclopropyl(4-ethoxy-4-oxobutyl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[C:12]([F:18])[CH:11]=1.FC1C=CC(C(C2C=CC(C(F)(F)F)=CC=2)O)=CC=1>>[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]([C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=2)[OH:15])=[C:12]([F:18])[CH:11]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: Fc1ccc(Br)cc1
Agent: OC(c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Product: OC(c1ccc(F)cc1)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 4.60 g (26.28 mmol) of 4-bromofluorobenzene and 5.00 g (31.53 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 80A. 4.45 g (66% of theory) of the title compound were obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([OH:15])=[O:14])=[CH:7]2)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[CH3:27][C:28]([CH3:31])([O-])[CH3:29].[K+]>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13]([O:15][C:28]([CH3:31])([CH3:29])[CH3:27])=[O:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)[O-]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Temperature: 30 °C
Reaction time: 0.67 h
Yield: 59.9 %

Procedure:
To a stirred solution of 9 (12.8 g, 61.2 mmol) in dry THF (200 mL) under argon was added oxalyl chloride (12.0 mL, 137.5 mmol) followed by DMF (0.1 mL), which caused a vigorous evolution of gas. After 40 min, the reaction mixture was evaporated to dryness. The resulting solid was re-dissolved in THF (150 mL), cooled to ˜30° C., and stirred under argon. A solution of potassium t-butoxide (1.0 M in THF, 140 mL, 140 mmol) was then added dropwise over 45 min, and stirring was continued for an additional 45 min. The reaction was quenched with 600 mL of water, neutralized with few drops of a 10% aqueous solution of H3PO4 and extracted with ethyl acetate (3×400 mL). The organic extracts were washed with saturated aqueous NaHCO3, water, and then dried over magnesium sulfate, filtered, concentrated and crystallized with ethanol/hexane to afford compound 10 (9.62 g, 85% yield). Rf=0.35 (1:5 Ethyl acetate/Hexane); 1H NMR (CDCl3), 11.63 (s, 1H), 8.66 (dd, 1H, J=0.5, 1.3Hz), 8.20 (dd, 1H, J=0.5, 9.0 Hz), 7.48 (dd, 1H, J=0.5, 9.1 Hz), 7.28 (dd, 1H, J=0.9, 11.1 Hz), 1.63 (s, 9H); 13C NMR 160.39, 142.12, 138.11, 132.10, 126.78, 120.22, 119.83, 111.98, 109.82, 82.91, 28.26; MS m/z 285.43 (M+Na)+.
Reaction SMILES: [CH3:1][Li].[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:14])=[CH:11][C:10](=[O:15])[CH2:9]1>O1CCCC1.C(OCC)C.[Cu]I>[CH3:3][O:4][C:5]([CH3:17])([CH3:16])[CH2:6][CH2:7][CH:8]1[CH2:13][C:12]([CH3:1])([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1
Reactant: [Li]C
Reactant: COC(C)(C)CCC1CC(=O)C=C(C)C1
Agent: [Cu]I
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(C)(C)CCC1CC(=O)CC(C)(C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of copper(I) iodide (6.0 g, 0.032 mol) in tetrahydrofuran (120 mL) cooled to 0° C. was added a methyllithium solution (45 mL of a 1.4M solution in diethyl ether, 0.063 mol). After stirring 0.5 hour, 3-(3-methoxy-3-methylbutyl)-5-methylcyclohex-5-en-1-one (2.0 g, 0.0095 mL) in tetrahydrofuran (80 mL) was slowly added. After stirring 2.5 hours, the mixture was added to ice cold dilute hydrochloric acid. Subsequent workup yielded 3-(3-methoxy-3-methylbutyl)-5,5-dimethylcyclohexan-1-one, bp0.5 125°-130° C. (1.3 g); NMR (CDCl3)δ0.9(s,3H), 1.1(s,3H), 1.1(s,6H), 1.2-1.6(m,6H), 1.6-2.5(m,5H), 3.2(s,3H); IR(neat) 2960, 1715, 1365, 1085 cm-1. MS(m/e) 41, 55, 73, 138, 161, 211, 212.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[N:32]1([S:38](Cl)(=[O:40])=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)N1CCOCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (50 mg, 0.120 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. morpholine-4-sulfonyl chloride (24 mg, 0.130 mmol) and pyridine (11 uL, 0.130 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 59 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)morpholine-4-sulfonamide (percentage yield: 86%), was obtained.
Reaction SMILES: C1(S([CH:10]([F:27])/[C:11](=[N:19]\S(C(C)(C)C)(=O)=O)/[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)(=O)=O)C=CC=CC=1.OP([O-])([O-])=O.[Na+].[Na+].[ClH:35].O1CCOCC1>CO>[ClH:35].[Br:18][C:14]1[CH:13]=[C:12]([C@H:11]([NH2:19])[CH2:10][F:27])[CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)S(=O)(=O)/N=C(/c1cccc(Br)c1)C(F)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: N[C@H](CF)c1cccc(Br)c1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-methyl-propane-2-sulfonic acid [2-benzenesulfonyl-1-(3-bromo-phenyl)-2-fluoro-eth-(Z)-ylidene]-amide (1.74 g, 3.76 mmol) and sodium phosphate dibasic (4.27 g, 30.1 mmol) in methanol (50 mL), cooled to −20° C., was added Na/Hg amalgam (6.92 g, 30.1 mmol). The reaction mixture was stirred for 1 h at −20° C., followed by filtration. To the filtrate was added a 4N HCl solution in dioxane (9.41 mL, 37.6 mmol), followed by stirring for 30 min at 25° C. After evaporation of volatiles, Et2O was added to the residue and the resulting precipitate was filtered off. The title compound thus obtained was used in the next reaction step without further purification. MS (LC/MS): 218/220 [M+H]+; tR (HPLC conditions f): 1.05 min.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]([CH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][N:16](CC2C=CC=CC=2)[CH2:15]1)C)C1C=CC=CC=1>O.C(O)C.[C].[Pd]>[ClH:1].[ClH:1].[CH3:3][NH:10][CH2:12][CH2:13][CH:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: CN(CCC1CN(Cc2ccccc2)CCO1)Cc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CNCCC1CNCCO1

Procedure:
The solvent is concentrated under reduced pressure and the residue is treated with 25% hydrochloric acid-ethanol in ethanol to give 2-[2-(N-benzyl-N-methylamino)ethyl]-4-benzylmorpholine dihydrochloride as white crystals, melting at 256°-258° C. with decomposition. The obtained hydrochloride compound (5.25 g) is subjected to catalytic reduction with 1 g of 10% palladium-carbon in 50 ml of water and 200 ml of ethanol. After absorbing the theoretical volume of the hydrogen, the catalyst is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with ethanol to give 2-(2-methylaminoethyl)morpholine dihydrochloride, melting at 179°-181° C. with decomposition.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.COC1C=CC([Mg]Br)=CC=1.O=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:23]1[C:37]([O:39]CC)=[O:38]>C1COCC1.CCOCC.CCOCC>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([CH:22]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]2[C:37]([OH:39])=[O:38])=[CH:4][CH:5]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1=O
Reactant: COc1ccc(Br)cc1
Agent: COc1ccc([Mg]Br)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2c3ccccc3C(c3ccccc3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Ethyl (1RS)[1-Hydroxy-1-(4methoxyphenyl)1-3-phenylindene-2-carboxylate. To dry magnesium turnings (0.88 g, 36 mmol) under an argon atmosphere was added, portionwise, a solution of p-bromoanisole (4.5 ml, 36 mmol) in 5% THF/Et2O (37 ml). The resulting p-methoxyphenyl magnesium bromide solution was added to a solution of ethyl 1-oxo-3-phenylindene-2-carboxylate (5.0 g, 18 mmol) in Et2O (300 ml) under an argon atmosphere at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 10 min. The mixture was partitioned between 3M HCl (100 ml) and EtOAc (200 ml). The organic extract was washed successively with H2O, aqueous NaHCO3, H2O and saturated aqueous NaCl and dried (Na2SO4). The solvent was removed in vacuo to provide a yellow oil which was treated with Et2O/hexanes. The solid which formed was collected by filtration (3.47 g). The filtrate was concentrated under reduced pressure and purified by flash chromatography. The material which was isolated was treated with Et2O/ hexanes, and the additional solid which formed (1.76 g, 75% total yield) was collected by filtration to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][NH2:18])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20](O)(=[O:26])/[CH:21]=[CH:22]\[C:23](O)=[O:24].C(N=C=NC(C)C)(C)C.C(OCC)(=O)C>O1CCCC1>[C:1]([O:5][C:6]([C:8]1[C:16]2[CH2:15][CH:14]([CH2:17][N:18]3[C:23](=[O:24])[CH:22]=[CH:21][C:20]3=[O:26])[O:13][CH2:12][C:11]=2[S:10][C:9]=1[NH2:19])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN)OC2
Reactant: O=C(O)/C=C\C(=O)O
Agent: CC(C)N=C=NC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c(N)sc2c1CC(CN1C(=O)C=CC1=O)OC2
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a solution of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester (0.53 g, 1.86 mmol, prepared as described in Example 17) in tetrahydrofuran (10 ml) was added, maleic acid (0.24 g, 2.05 mmol) and diisopropylcarbodiimide (0.58 ml, 3.72 mmol). The reaction mixture was heated to reflux for 3 h. and then allowed to cool to room temperature over an 18 hours period. The solvent was stripped off in vacuo and the residue diluted into ethyl acetate (50 ml). The organic phase was washed with saturated sodium bicarbonate (2×50 ml), 1% hydrochloric acid (2×20 ml), brine (3×50 ml), dried (MgSO4), filtered, and the solvent evaporated in vacuo affording an oil which was subjected to flash chromatography using a mixture of ethyl acetate/hexanes (6:4) as eluent. Pure fractions (Rf=0.25) were collected and the solvent evaporated in vacuo to give 0.60 g (90%) of 2-amino-5-(2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl)-4,7-dihydro-5H-thieno[2,3-c]pyran-3-carboxylic acid tert-butyl ester as an oil.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:76][CH:77]1[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:76][CH:77]5[CH2:82][CH2:81][N:80]([CH3:83])[CH2:79][CH2:78]5)=[O:28])=[CH:24][C:23]=4[CH2:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 47.4 %

Procedure:
To a mixture of 0.040 g (0.0899 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-benzoic acid (I-194) and 6 mL of dimethylformamide was added 0.0182 g (0.135 mmole) of 1-hydroxybenzotriazole, 0.0520 g (0.135 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.060 g (0.463 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0153 g (0.134 mmole) of 4-amino-1-methylpiperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0231 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethyl-N-(1-methyl-piperidin-4-yl)-benzamide (I-195) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11](=[O:13])[CH3:12])[NH:8][C:5]2=[N:6][CH:7]=1.[CH:14]([C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=1)[C:19]([NH:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:20])=O.[BH3-]C#N.[Na+]>CO.CC(O)=O>[C:11]([C:9]1[NH:8][C:5]2=[N:6][CH:7]=[C:2]([NH:1][CH2:14][C:16]3[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=3)[C:19]([NH:21][C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[O:20])[CH:3]=[C:4]2[CH:10]=1)(=[O:13])[CH3:12]
Reactant: O=Cc1cccc(C(=O)Nc2cccnc2)c1
Reactant: CC(=O)c1cc2cc(N)cnc2[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(=O)c1cc2cc(NCc3cccc(C(=O)Nc4cccnc4)c3)cnc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(5-Amino-1H-pyrrolo[2,3-b]pyridin-2-yl)-ethanone (1 eq) and 3-Formyl-N-pyridin-3-yl-benzamide (1.1 eq) were stirred in a mixture of MeOH/AcOH (10/1; 0.06M) for 2 h. Then NaBH3CN (1.2 eq) was slowly added and the mixture was stirred under argon at RT overnight. The reaction was quenched by addition of saturated NaHCO3 solution until neutrality. MeOH and acetic acid were evaporated. The crude was filtered and washed with water and Et2O before being purified on reverse phase (H2O 1% TFA/MeCN 1% TFA 100/0, 0/100). MeCN was evaporated. The product was suspended in H2O and basified with saturated NaHCO3 solution until pH=8-9. The aqueous layer was extracted three times with AcOEt. The organic layer was dried over Na2SO4, filtered and concentrated to give the expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([C:17]([CH:19]([CH3:21])[CH3:20])=[CH2:18])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1.[CH3:36][S:37]([O-:39])=[O:38].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:22][C@H:23]4[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]4)[C:15]([CH:17]([CH2:18][S:37]([CH3:36])(=[O:39])=[O:38])[CH:19]([CH3:20])[CH3:21])=[N:16][C:12]=3[CH:11]=[C:10]([C:30]3[NH:34][C:33](=[O:35])[O:32][N:31]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: C=C(c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1)C(C)C
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)C(CS(C)(=O)=O)c1nc2cc(-c3noc(=O)[nH]3)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 60 °C

Procedure:
To a stirred solution of 3-{4-(5-chloropyridin-3-yl)-2-(3-methylbut-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (synthesized in a manner similar to Example 9.1; 20 mg, 0.046 mmol) in dry ethanol (0.7 mL) was added sodium methanesulfinate (47 mg, 0.46 mmol) followed by acetic acid (27 μL, 0.046 mmol). The reaction mixture was heated to 60° C. for 12 h. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue obtained was purified by reverse phase prep-HPLC (Kromasil C18, water/MeOH+0.1% TFA) to give 3-[4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-2-{2-methyl-1-[(methylsulfonyl)methyl]propyl}-3H-imidazo[4,5-c]pyridin-6-yl]-1,2,4-oxadiazol-5(4H)-one (TFA salt, racemate). 1H NMR (400 MHz, DMSO-d6): δ 12.90 (br s, 1H), 8.86 (s, 1H), 8.85 (s, 1H), δ 8.43 (s, 1H), 8.24 (s, 1H), 4.07-3.96 (m, 2H), 3.84-3.79 (m, 1H), 3.67-3.64 (m, 2H), 3.02 (s, 3H), 2.21-2.16 (m, 1H), 1.39 (d, J=11.6 Hz, 2H), 1.22-1.15 (m, 2H), 1.04 (d, J=6.7 Hz, 3H), 0.83 (d, J=6.7 Hz, 3H), 0.70 (d, J=6.5 Hz, 3H), 0.78-0.41 (m, 6H). MS ES/APCl calc'd. for C27H33ClN6O4S [M+H]+ 573. found 573.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[CH:7][CH:6]=1)=[O:3].[Cl:22][C:23]1[CH:24]=[C:25]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[K+].[Br-]>>[F:19][C:18]([F:21])([F:20])[C:15]1[CH:16]=[CH:17][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]3[CH2:29][CH2:28][N:27]([CH2:26][C:25]4[CH:33]=[CH:34][C:35]([Cl:36])=[C:23]([Cl:22])[CH:24]=4)[CH2:32][CH2:31]3)=[O:3])=[CH:6][CH:7]=2)=[N:13][CH:14]=1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: Clc1ccc(CN2CCNCC2)cc1Cl
Agent: [Br-]
Agent: [K+]
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCN(Cc2ccc(Cl)c(Cl)c2)CC1

Procedure:
The hydrochloride of the title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate and 1-(3,4-dichloro-benzyl)-piperazine, yield 86%. White crystals, m.p. 229–230° C.; IR (KBr): ν 1717 (C═O) cm−1.
Reaction SMILES: [CH:1](=[N:8]/[OH:9])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:10][C:2]1([CH:7]=[CH:6][CH:5]=[CH:4][CH2:3]1)/[CH:1]=[N:8]/[OH:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C/c1ccccc1
Solvent: ClCCl
Solvent: O
Product: O/N=C/C1(Cl)C=CC=CC1
Yield: 83.8 %

Procedure:
After dissolving (E)-benzaldehyde oxime (3.0 g, 25 mmol) in CH2Cl2 (30 ml), N-chlorosuccinimide (3.4 g, 25 mmol) was slowly added at 0° C. After stirring reaction solution for 2 hours, the reaction was completed by adding water (20 ml), and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde oxime (3.30 g, 85%) was obtained by separating the residue with silica gel column chromatography. After dissolving the (E)- and (Z)-oxime mixtures (1.5 g, 9.64 mmol) in CH2Cl2 (30 ml), benzoylchloride (1.45 ml, 12.53 mmol) was slowly added at 0° C. under the presence of triethylamine (1.75 ml, 12.53 mmol). After stirring reaction solution for 1 hour, the reaction was quenched by 1 N hydrochloric acid, and the reaction solution was extracted with dichloromethane. A pure compound of (E)-1-chloro-benzaldehyde O-benzoyloxime (15) (1.9 g, 76%) was obtained by separating the residue with silica gel column chromatography.