Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:22]([O-:24])=[O:23])[C:19]([O-:21])=[O:20])=[O:15])=[CH:6][CH:5]=1.[OH-].[Li+].C(O)(C(F)(F)F)=O>O.C(#N)C>[NH2:1][N:2]=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:25])[CH2:12][CH2:13][C:14]([NH:16][CH2:17][CH:18]([C:19]([OH:21])=[O:20])[C:22]([OH:24])=[O:23])=[O:15])=[CH:6][CH:5]=1
Reactant: NN=Cc1ccc(NC(=O)CCC(=O)NCC(C(=O)[O-])C(=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NN=Cc1ccc(NC(=O)CCC(=O)NCC(C(=O)O)C(=O)O)cc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Dimethyl [[[4-[[4-(aminoiminomethyl)phenyl]amino]-1,4-dioxobutyl]aminomethyl]propanedioate prepared in Example 23, Step 2 (500 mg) was added to water/acetonitrile (20 ml) followed by lithium hydroxide (100 mg) at 25° C. The mixture was stirred for 30 min. The course of the reaction was monitored by RPHPLC. After satisfactory product was formed the reaction was neutralized with TFA and purified by reverse phase chromatography (0.5% TFA water/acetonitrile) to result in 350 mg of a white solid: 1H NMR (d6 -DMSO) δ2.41 (m, 2H), 2.57 (m, 2H), 3.35 (m, 1H), 3.47 (m, 2H), 7.79 (s, 4H), 8.1 (t, 1H, J=6.1 Hz), 7.78 (s, 4H), 8.02 (m, 1H), 8.87 (bs, 2H), 9.15 (bs, 2H), 10.39 (s, 1H); MS (FAB) m/z 350 (MH+).
Reaction SMILES: Br.[C:2]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:23][CH2:24][CH2:25]Cl.[C:27]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)#[N:28]>CN(C=O)C>[C:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:23][CH2:24][CH2:25][O:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]#[N:28])=[CH:30][CH:31]=2)[CH2:12][CH2:11]1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: ClCCCBr
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCCCN2CCC(C(=O)c3ccccc3)CC2)cc1
Reaction time: 8 h
Yield: 77.8 %

Procedure:
4-Benzoylpiperdine hydrobromide (2.70 g, 10 mmol) was combined with K2CO3 (6.9 g, 50 mmol) in DMF (˜40 mL), followed by 1-bromo-3-chloropropane (1.55 g, 10 mmol). The reaction progress was monitored by LC-MS and upon completion of the reaction (˜2 h) 4-cyanophenol (1.3 g, 11 mmol) was added and the reaction allowed to stir overnight. The mixture was poured onto water and extracted with ethyl acetate, washed with brine and dried over Na2SO4. The volatiles were removed under reduced pressure and the crude mixture purified on silica gel (0-100% EtOAc in hexanes) to give 2.71 g (78% yield over 2 steps) of 4-(3-(4-benzoylpiperidin-1-yl)propoxy)benzonitrile: LC-MS (>98%) m/z=349.2 [M+H].
Reaction SMILES: C[CH2:2][N:3](CC)[CH2:4]C.[CH3:8][N:9](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)[CH3:10].[B-](F)(F)(F)F.[O:30]1[C:34]2([CH2:39][CH2:38][CH:37]([CH2:40][C:41]([OH:43])=O)[CH2:36][CH2:35]2)[O:33][CH2:32][CH2:31]1.CNC>CN(C=O)C.C1COCC1>[CH3:2][N:3]([CH3:4])[C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][C:34]2([O:33][CH2:32][CH2:31][O:30]2)[CH2:35][CH2:36]1.[CH3:8][N:9]([CH3:10])[C:41](=[O:43])[CH2:40][CH:37]1[CH2:38][CH2:39][C:34](=[O:33])[CH2:35][CH2:36]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)CC1CCC2(CC1)OCCO2
Reactant: CCN(CC)CC
Agent: CNC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)CC1CCC(=O)CC1
Product: CN(C)C(=O)CC1CCC2(CC1)OCCO2
Reaction time: 0.5 h

Procedure:
NEt3 (2.0 ml) and TBTU (2.56 g) are added to a solution of 2-(1,4-dioxaspiro[4.5]decan-8-yl)acetic acid (1.45 g; see J. Med. Chem. 1998, 41(5), 760) in DMF (50 ml) and the mixture is stirred for 30 min. 2 M Dimethylamine in THF (7.24 ml) is added. The reaction mixture is stirred for one hour and the solvent is removed under reduced pressure. The residue is dissolved in EtOAc and washed with water and aqueous citric acid (10%, 2×). The organic layer is dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure. The crude product is purified using reverse phase HPLC (Varian C18 Microsorb) eluting with a gradient of 10-100% acetonitrile in water containing 0.2% trifluoroacetic acid to give N,N-dimethyl-2-(1,4-dioxaspiro[4.5]decan-8-yl)acetamide (400 mg) and N,N-dimethyl-2-(4-oxocyclohexyl)acetamide (420 mg).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@H:14]([CH2:15][CH3:16])[CH2:13][C:12](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:11]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O.O>C1COCC1>[CH2:15]([C@H:14]1[C@@H:10]([CH2:9][OH:8])[CH2:11][C:12](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:13]1)[CH3:16]
Reactant: CCOC(=O)C=C1C[C@@H](CC)[C@@H](CO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C1C[C@@H](CC)[C@@H](CO)C1
Reaction time: 6 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 2-((3S,4R)-3-((tert-butyldimethylsilyloxy)methyl)-4-ethylcyclopentylidene)acetate (1.00 g, 3.06 mmol) in THF (20 mL) was added TBAF (1M in THF, 4.59 mL, 4.59 mmol). After 6 h, EtOAc and water were added. The organic layer was separated, concd in vacuo and purified by chromatography on silica gel eluting with EtOAc/heptane to provide ethyl 2-((3R,4S)-3-ethyl-4-(hydroxymethyl)cyclopentylidene)acetate (0.620 g, 95%) as an oil. LC/MS (Table 1, Method a) Rt=1.96, 2.08 min; MS m/z: 213 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH2:10][C:11]1[C:15]([Br:16])=[C:14]([CH3:17])[O:13][N:12]=1>N1C=CC=CC=1>[Br:16][C:15]1[C:11]([NH:10][S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])=[N:12][O:13][C:14]=1[CH3:17]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1onc(N)c1Br
Solvent: c1ccncc1
Product: Cc1onc(NS(=O)(=O)c2cccs2)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
Thiophene-2-sulfonyl chloride (183 mg, 1 mmol) was added to a solution of 3-amino-4-bromo-5-methylisoxazole (177 mg,1 mmol) in dry pyridine (0.5 ml). The reaction mixture was stirred at room temperature for 3 h. Pyridine was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. The organic layer was washed with 1N HCl (3×10 ml), brine (10 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvents left an oily residue which was solidified at -20° C. and then purified by recrystallization from ethyl acetate/hexanes, to give the pure product (51 % yield) as a tan solid, m.p. 156-158° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH:30]=O>>[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:30][NH:1][C:4]1[C:5]2[CH:6]=[CH:7][C:8]([NH:25][C:24]3[C:18]4[O:17][C:16]([CH3:15])=[CH:20][C:19]=4[CH:21]=[CH:22][CH:23]=3)=[N:9][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1cc2cccc(N)c2o1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: Cc1cc2cccc(Nc3ccc4c(NCc5cc(F)cc(F)c5)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=416.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and 3,5-difluorobenzaldehyde as described in example 26.
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C:47]3[C@H:38]([C@H:39]4[C@@:43]([CH2:45][CH:46]=3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)[CH2:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:36]1[CH2:37][CH2:38][C@H:39]2[C@H:40]3[C:47](=[CH:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:35]=[CH:34][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:50][C:49]=1[CH2:42][CH2:41]3
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C[C@]12CC=C3c4ccc(OC5CCCCO5)cc4CC[C@H]3[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 42.6 %

Procedure:
A solution of 3.85 g of difluoromethyldiphenylphosphine oxide in 107 ml of tetrahydrofuran is slowly mixed with 7.6 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 2.14 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),9(11)-tetraen-17-one in 42 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is diluted with ethyl acetate and water, suctioned off on Celite, rewashed with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 1.0 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),9(11)-tetraene is obtained as a colorless oil, [α]D22 +52.6° (c=0.5% in pyridine).
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)[CH:12]=1.O.O.O.C([O-])(=O)C.[Na+]>ClCCCl.O>[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]([CH:3]=[O:4])=[CH:18]2)[CH:12]=1
Reactant: c1cncc(-n2ccc3ccccc32)c1
Reactant: CN(C)C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1cn(-c2cccnc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2.12 ml of N,N-dimethylformamide in 20 ml of 1,2-dichloroethane is cooled to 0° and 3.1 ml of phosphorus oxychloride is added dropwise. The reaction is stirred for 10 minutes at 15° and recooled to 0° before a solution of 4.85 g of N-(3-pyridyl)indole in 10 ml of 1,2-dichloroethane is added. After 2 hours at 5°, the reaction mixture is refluxed for 15 minutes, cooled to room temperature and a solution of 18.75 g of sodium acetate trihydrate in 25 ml of water is added. After an additional 15 minutes at reflux, the organic phase is separated, washed with sodium bicarbonate and water, and dried over magnesium sulfate. Filtration, evaporation and recrystallization of the residue from methylene chloride-methanol yields N-(3-pyridyl)-indole-3-carboxaldehyde, m.p. 148°-150°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17]>O1CCCC1.C(O)C>[NH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[C:16]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1)=[O:17]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccccc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To an ice-cold solution of 28 ml (134 mmol) of 4-amino-1-(phenylmethyl)piperidine in 200 ml of tetrahydrofuran were added, batchwise, 21.9 g (134 mmol) of isatoic acid anhydride. The resulting suspension was stirred for 2½ hours at room temperature and 2½ hours at reflux temperature, then freed from solvent. The residue was dissolved in 100 ml of hot ethanol, the resulting solution was filtered whilst hot after the addition of 5 g of activated charcoal. The crystal mass precipitated after cooling was suction filtered, washed with diisopropylether and dried in vacuo at 50° C. 28.3 g of colourless crystals were obtained. A further 5.1 g of a product of the same quality were isolated from the combined mother liquors. Total yield: 33.4 g (80.6% of theory).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[C:4]([NH2:15])[CH:3]=1.[CH:16]1(/[CH:22]=[CH:23]/[C:24](Cl)=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1>>[CH:16]1(/[CH:22]=[CH:23]/[C:24]2[N:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[C:5]3[CH:13]=[CH:14][C:2]([F:1])=[CH:3][C:4]=3[N:15]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Nc1cc(F)ccc1Nc1ccccn1
Reactant: O=C(Cl)/C=C/C1CCCCC1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Product: Fc1ccc2c(c1)nc(/C=C/C1CCCCC1)n2-c1ccccn1

Procedure:
The titled compound was prepared from 4-fluoro-2-amino-N-(2-pyridyl)aniline and (E)-3-Cyclohexylacryloyl chloride according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). MW: 321.40; mp: 109.1-110.1° C.; 1H-NMR (CDCl3) δ: 8.76-8.72 (1H, m), 7.97 (1H, ddd, J=7.7, 7.7, 2.0 Hz), 7.47-7.40 (3H, m), 7.34 (1H, dd, J=9.0, 4.8 Hz), 7.11 (1H, dd, J=15.7, 7.1 Hz), 6.97 (1H, ddd, J=9.0,9.0,2.5 Hz), 6.38 (1H, dd, J=15.7, 1.3 Hz), 2.27-2.10 (1H, m), 1.84-1.57 (5H, m), 1.37-1.09 (5H, m).
Reaction SMILES: CC(C)[N:3]=C=NC(C)C.[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH:43](C(OC(C)(C)C)=O)[C@H:44]([C:49]([OH:51])=O)[CH2:45][CH:46]([CH3:48])[CH3:47].C1(C)C=CC(S([O-])(=O)=O)=CC=1.CN(C)C1C=C[NH+]=CC=1>C(Cl)Cl.CN(C=O)C>[CH3:10][C:11]1[C:16]([NH:17][C:18]([C:20]2[S:24][C:23]([NH:25][C:26]3[CH:27]=[C:28]([N:33]4[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][OH:41])[CH2:35][CH2:34]4)[N:29]=[C:30]([CH3:32])[N:31]=3)=[N:22][CH:21]=2)=[O:19])=[C:15]([Cl:42])[CH:14]=[CH:13][CH:12]=1.[NH2:43][C@H:44]([C:49]([NH2:3])=[O:51])[CH2:45][CH:46]([CH3:48])[CH3:47]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)N=C=NC(C)C
Agent: CN(C)c1cc[nH+]cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cc1nc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)cc(N2CCN(CCO)CC2)n1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
DIC (302 mg, 2.4 mmol) was added with stirring to a DMF (4 mL) solution of dasatinib (196 mg, 0.4 mmol), Boc-Leu-OH (111 mg, 0.48 mmol), and DPTS (124 mg, 0.4 mmol). The resulting mixture was stirred at room temperature for five hours. After this period, DCM (100 mL) was added to the reaction mixture which was allowed to stir for an additional 20 minutes. The resulting mixture was transferred into a separatory funnel and washed with 5% NaCl (100 mL×3). The organic phase was dried over Na2SO4 and the solvent removed under reduced pressure. The resulting residue was purified by column chromatography (biotage: DCM/CH3OH, CH3OH, 5-10%, 25 CV). The obtained solid was dissolved in 5.0 mL of TFA/DCM (2:3) and the solution was stirred at room temperature for one hour. TFA and DCM were removed under reduced pressure. The residue was dissolved in 150 mL of DCM and the resulting solution was washed with 5% Na2CO3 and 5% NaCl. The desired product was obtained (146 mg, yield: 61%) as a white solid; 1H NMR (500 MHz, CD3OD). δ 0.98 (m, 6H), 1.46 (m, 1H), 1.60 (m, 1H), 1.80 (m, 1H), 2.33 (s, 3H), 2.48 (s, 3H), 2.62 (t, 4H), 2.74 (t, 2H), 3.50 (m, 1H), 3.65 (t, 4H), 4.33 (m, 2H), 6.02 (s, 1H), 7.25 (m, 2H), 7.36 (d, 1H), 8.15 (s, 1H); LC-MS (m/z) calcd., 600.2, found 601.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:14])[C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11])[CH:5]=O.CC(O)C.[CH3:19][C:20](=[O:25])[CH2:21][C:22](=[O:24])[CH3:23].N1CCCCC1>C(O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:21]([C:20](=[O:25])[CH3:19])[C:22](=[O:24])[CH3:23])[CH:7]=[C:8]([Cl:14])[C:9]=1[S:10]([CH3:13])(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1c(Cl)cc(C=O)cc1Cl
Reactant: CC(=O)CC(C)=O
Solvent: CC(C)O
Solvent: O=CO
Solvent: C1CCNCC1
Product: CC(=O)C(=Cc1cc(Cl)c(S(C)(=O)=O)c(Cl)c1)C(C)=O
Temperature: 23.5 °C
Reaction time: 63 h

Procedure:
3,5-Dichloro-4-(methylsulfonyl)benzaldehyde (1.5 g), 2-propanol (20 mL), 2,4-pentanedione (1.6 mL), formic acid (44 mL) and piperidine (114 mL) were mixed and stirred at 22-25° C. for 63 h. The product was filtered, washed with 2-propanol and dried (yield 1.0 g, melting point 134-136° C.). 1H-NMR(400 MHz, DMSO-d6 d=2.29 (s, 3H), 2.46 (s, 3H), 3.48 (s, 3H), 7.67 (s, 2 H), 7.71 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:53][C:54]1[N:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:55]=1[C:56](O)=[O:57].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:53][C:54]1[N:62]=[CH:61][CH:60]=[C:59]([CH3:63])[C:55]=1[C:56]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][O:30][CH3:31])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5])=[O:57]
Reactant: Cc1ccnc(Cl)c1C(=O)O
Reactant: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Cl)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.1 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amine (0.065 g, 0.15 mmol), EDCI (0.033 g, 0.17 mmol) and HOBT (0.023 g, 0.17 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-chloro-4-methyl-nicotinic acid (0.029 g, 0.17 mmol) followed by DIPEA (54 μL, 0.31 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 88:10:2, v/v/v) afforded 2-chloro-N-((R)-3-{4-[[4-(2-methoxy-ethoxy)-phenyl]-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.068 g, 76%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d, 3H, J=6.0 Hz), 1.06 (m, 1H), 1.25 (m, 1H), 1.58 (m, 2H), 1.82 (m, 3H), 2.11 (br t, 1H), 2.35 (s, 6H), 2.50 (br t, 1H), 2.75-2.89 (m, 3H), 3.21-3.33 (m, 2H), 3.42 (s, 3H), 3.69 (t, 2H, J=4.5 Hz), 3.82 (m, 1H), 3.90 (m, 2H), 4.01 (t, 2H, J=4.5 Hz), 6.59 (d, 2H, J=9.0 Hz), 6.72 (d, 2H, J=9.0 Hz), 6.96 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.99 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=3.0 Hz), 8.38 (br s, 1H). ES-MS m/z 580 (M+H). Anal. Calcd. for C32H42N5O3Cl.0.4 CH2Cl2: C, 63.37; H, 7.02; N, 11.40. Found: C, 63.28; H, 7.16; N, 11.60.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:23]([O-])=O)=[C:6]([CH:22]=1)[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:23][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: [H][H]
Reactant: CCOC(=O)c1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2cc(F)ccc2N)sc2ccccc12
Yield: 52.7 %

Procedure:
Ethyl 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carboxylate (50.7 g) was dissolved in ethyl acetate (1000 ml) and 10% palladium-carbon (8.0 g) was added. The mixture was stirred with hydrogen (60 kg/cm2) at 55° C. for 5 hr. The reaction mixture was cooled and the catalyst was filtered off. The filtrate was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform) to give ethyl 2-(2-amino-5-fluoroanilino)benzo[b]thiophene-3-carboxylate (24.5 g).
Reaction SMILES: Cl([O-])=O.[Na+].S(=O)(=O)(O)N.[CH2:10]([O:17][C:18]1[C:19]([CH:36]=[O:37])=[N:20][CH:21]=[C:22]([C:34]=1[OH:35])[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)=[O:24])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH2:38]>O1CCCC1>[CH2:10]([O:17][C:18]1[C:19]([C:36]([OH:38])=[O:37])=[N:20][CH:21]=[C:22]([C:23](=[O:24])[NH:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:34]=1[OH:35])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ncc(C(=O)NCc2ccc(F)cc2)c(O)c1OCc1ccccc1
Reactant: O
Agent: NS(=O)(=O)O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: C1CCOC1
Product: O=C(NCc1ccc(F)cc1)c1cnc(C(=O)O)c(OCc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To an aqueous solution (105 ml) of sodium chlorite (7.13 g, 78.8 mmol), and sulfamic acid (7.65 g, 78.8 mmol) was added a solution of the compound 12 (15.0 g, 39.4 mmol) in tetrahydrofuran (630 ml) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. After water (2500 ml) was added to the reaction solution, precipitated crystals were filtered. Washing with diethyl ether afforded 3-benzyloxy-5-(4-fluoro-benzylcarbamoyl)-4-hydroxy-pyridine-2-carboxylic acid 13 (1.4.0 g, 90%) as a colorless crystal.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)#[CH:2].C(O)=[O:27]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]3[CH:15]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH2:24][CH3:25])[CH2:20][CH2:19]4)[S:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1)(=[O:27])[CH3:2]
Reactant: O=CO
Reactant: C#Cc1ccc(-c2cc3sc(N4CCN(CC)CC4)cc3cn2)cc1
Product: CCN1CCN(c2cc3cnc(-c4ccc(C(C)=O)cc4)cc3s2)CC1

Procedure:
6-(4-Ethynylphenyl)-(4-ethylpiperazin-1-yl)thieno[3,2-c]pyridine (0.59 g) was reacted in formic acid (15 ml) at 100° C. for 12 hr. The reaction solutionwas evaporated, basified with an aqueous solution of potassium carbonate, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried and concentrated. The resulting residue was purified by NH-silica gel column chromatography (ethyl acetate/hexane system), to give 0.37 g of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:17]([C:23]([F:26])([F:25])[F:24])([C:19]([F:22])([F:21])[F:20])[OH:18])[NH:7][C:8]=1[C:9]1[CH:14]=[CH:13][C:12](SC)=[CH:11][CH:10]=1)[CH3:3].O[O:28][S:29]([O-:31])=O.[K+].S(OOS([O-])(=O)=O)(O)(=O)=O.[K+].[CH3:44]O>>[CH3:1][CH:2]([C:4]1[N:5]=[C:6]([C:17]([C:23]([F:26])([F:24])[F:25])([C:19]([F:20])([F:21])[F:22])[OH:18])[NH:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([S:29]([CH3:44])(=[O:31])=[O:28])=[CH:13][CH:14]=1)[CH3:3]
Reactant: O=S([O-])OO
Reactant: CO
Reactant: CSc1ccc(-c2[nH]c(C(O)(C(F)(F)F)C(F)(F)F)nc2C(C)C)cc1
Agent: O=S(=O)([O-])OOS(=O)(=O)O
Agent: [K+]
Product: CC(C)c1nc(C(O)(C(F)(F)F)C(F)(F)F)[nH]c1-c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4.0 g (0.01 mole) of 4-(1-methylethyl)-5-(4-methylthiophenyl)-α,α-bis(trifluoromethyl)-1H-imidazole-2-methanol, 16.06 g (0.026 mole) of Oxone® (potassium hydrogen persulfate) and 115 ml of methanol was stirred at room temperature overnight. The inorganic solid was filtered off, and the filtrate was evaporated. The residue was partitioned between ethyl acetate and water. The layers were separated and the organic layer was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The product was recrystallized from dichloroethane affording 3.33 g (77%) of the title compound as a white solid, m.p. 182°-184° C.