Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11].CCCCCCC.C(OC(C)C)(C)C>[Pd].O1CCCC1.O>[ClH:1].[CH3:2][C:3]1[NH:7][CH:6]=[N:5][C:4]=1[CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: Cc1[nH]cnc1/C=C/C(=O)O
Agent: [Pd]
Agent: Cl
Solvent: CCCCCCC
Solvent: O
Solvent: CC(C)OC(C)C
Product: Cc1[nH]cnc1CCC(=O)O
Reaction time: 19 h
Yield: 155.5 %

Procedure:
60 mg of palladium-on-charcoal at 10% are added to a solution of 387 mg (1.1 mmol) of (E)-3-(5-methyl-1H-imidazol-4-yl)acrylic acid hydrochloride in a 1/1 tetrahydrofuran/water mixture. The reaction medium is placed under a hydrogen atmosphere and stirred for 19 h, and then filtered through celite. The filtrate is concentrated under vacuum. The residue obtained is taken up in a heptane/diisopropyl ether mixture with stirring for 2 h. The white precipitate formed is filtered off and then dried. 326 mg of 3-(5-methyl-1H-imidazol-4-yl)propanoic acid hydrochloride are obtained in the form of a white solid with a yield of 83%.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:6][CH:5]([CH2:24][OH:25])[CH:4]1[CH3:26])[CH3:2].[CH2:27]([CH:29]1[CH:34]([C:35]2[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=2)[C:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)=[CH:32][CH:31]([CH2:50][OH:51])[CH:30]1[CH3:52])[CH3:28]>C(Cl)Cl.C(OCC)(=O)C.O.Cl[Ti](Cl)(Cl)Cl>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[C:7]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[CH2:6][CH:5]([CH2:24][OH:25])[CH:4]1[CH3:26])[CH3:2].[CH2:27]([CH:29]1[CH:30]([CH3:52])[CH:31]([CH2:50][OH:51])[CH2:32][CH:33]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[CH:34]1[C:35]1[CH:36]=[CH:37][C:38]([OH:41])=[CH:39][CH:40]=1)[CH3:28]
Reactant: CCC1C(c2ccc(O)cc2)C(c2ccc(OC)cc2)=CC(CO)C1C
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CCC1C(c2ccc(O)cc2)=C(c2ccc(OC)cc2)CC(CO)C1C
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC1C(C)C(CO)CC(c2ccc(OC)cc2)C1c1ccc(O)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
To the above mixture of 4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]-phenol and 4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-2-enyl]-phenol (380 mg) in DCM (10 mL) at −10° C. was added TiCl4 (0.180 mL) and the mixture was stirred for 3 h at −10° C. The reaction mixture was diluted with ethyl acetate/H2O (200/100 mL). The organic layer was dried and purified on SiO2 to yield two products 4-[6-ethyl-4-hydroxymethyl-2-(4-methoxy-phenyl)-5-methyl-cyclohex-1-enyl]-phenol and 4-[2-ethyl-4-hydroxymethyl-6-(4-methoxy-phenyl)-3-methyl-cyclohexyl]-phenol.
Reaction SMILES: C1C=CC(CC(N)CO)=CC=1.[CH2:12]([C@@H:19]1[N:25]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:24](=[O:34])[C@@H:23]([NH:35][C@@H:36]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:22][S:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([C@@H]1N(CC(OC(C)(C)C)=O)C(=O)[C@@H](N[C@H](C(OCC)=O)CCC2C=CC=CC=2)CSC1)C1C=CC=CC=1>>[CH2:12]([C@@H:19]1[N:25]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[O:28])[C:24](=[O:34])[C@@H:23]([NH:35][CH:36]([C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH2:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:22][S:21][CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)N[C@H]1CSC[C@H](Cc2ccccc2)N(CC(=O)OC(C)(C)C)C1=O
Agent: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC[C@H](Cc2ccccc2)N(CC(=O)OC(C)(C)C)C1=O
Agent: NC(CO)Cc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)N[C@H]1CSC[C@H](Cc2ccccc2)N(CC(=O)OC(C)(C)C)C1=O

Procedure:
The procedure described in steps (a) to (h) of Example 1 was repeated, except that L-2-amino-3-phenyl-1-propanol was used as the starting material. Two isomers (derived from the asymmetric carbon atom to which the phenethyl group is attached), that is t-butyl α-{3(S)-benzyl-6(R)-[1(R)-ethoxycarbonyl-3-phenylpropylamino]-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer A) and t-butyl α-{3(S)-benzyl-6(R)-[1(S)-ethoxycarbonyl-3-phenylpropylamino]-5-oxoperhydro-1,4-thiazepin-4-yl}acetate (isomer B) were obtained as oils.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].[CH3:19][S:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1)(=[O:22])=[O:21].[I-].[Na+]>CN(C=O)C>[Cl:14][C:10]1[N:9]=[C:8]2[N:7]([CH2:27][C:26]3[CH:25]=[CH:24][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:30][CH:29]=3)[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]2=[CH:12][CH:11]=1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.045 g, 0.19 mmol) in DMF (1.5 ml) under an inert atmosphere of Argon is added sodium hydride (0.008 g of a 60% dispersion in mineral oil, 0.21 mmol). After stirring at 0° C. for 30 minutes, the reaction mixture is stirred at room temperature for two hours and then re-cooled to 0° C. 4-Methylsulphonylbenzyl bromide (0.076 g, 0.3 mmol) in DMF (1.5 ml) is added followed by sodium iodide (0.076 g, 0.30 mmol) and the resulting solution is stirred at room temperature overnight. The reaction mixture is poured onto water (20 ml) and extracted with 1:1 ethyl acetate/diethyl ether. The organic portions are washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the titled product. (MH+ 407)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[CH:19]=[CH:18][CH:17]=[C:15]([NH2:16])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1cccc(Br)c1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: N#Cc1cccc(-c2cccc(N)c2)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
3-cyanophenyl boronic acid (0.131 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in dioxane (2 mL) in a flame-dried, round-bottom flask. K3PO4 (1.27M, 0.778 mL, 0.99 mmol), PCy3 (0.004 g, 0.014 mmol), and Pd2(dba)3 (0.005 g, 0.006 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.085 g in 75% yield.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=3[F:30])[C:16]=2[NH:31][S:32]([CH:35]2[CH2:37][CH2:36]2)(=[O:34])=[O:33])[CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[OH-].[Na+]>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[O:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[C:17]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])[C:16]=1[NH:31][S:32]([CH:35]1[CH2:36][CH2:37]1)(=[O:33])=[O:34]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Oc2cc(F)cc(Nc3ccc(I)cc3F)c2NS(=O)(=O)C2CC2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.3 %

Procedure:
1.19 g of tert-butyl(3-{2-[(cyclopropylsulfonyl)amino]-5-fluoro-3-[(2-fluoro-4-iodophenyl)amino]phenoxy}phenyl)carbamate (1.8 mmol, 1 eq.) were dissolved in 15 mL DCM, treated with 2 mL TFA and stirred at rt for 6 h. The reaction mixture was cooled to 0° C. and adjusted with 1N Sodium hydroxide to pH 10. The layers were separated, the aqueous layer was reextracted with DCM. The combined organic layers were dried, filtered and concentrated in vacuo to yield 776 mg of the crude product (77% yield), which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=[O:9])[CH2:7][CH3:8])[CH3:2].[CH3:11][CH2:12][O-].[Na+].C(I)C>CCO>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([CH2:11][CH3:12])[C:6](=[O:9])[CH2:7][CH3:8])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)CC(=O)CC
Agent: [Na+]
Solvent: CCO
Solvent: CCI
Product: CCOC(=O)C(CC)C(=O)CC
Temperature: 80 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a solution of 3-oxo-pentanoic acid ethyl ester (5.19 g, 36 mmol) in anhydrous EtOH (40 mL) was added NaOEt (21% wt. in EtOH, 11.7 mL, 36 mmol). he reaction mixture was heated to 80° C. Ethyl iodide (6.18 g, 39.6 mmol) was added dropwise at 80° C. Stirring was continued at 80° C. for 16 hours. The reaction mixture was concentrated and loaded onto a silica gel column and eluted with 1-2% EtOAc/heptane to give 4.38 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=O>C(O)(=O)C>[C:8]([C:7]1[C:2]2[N:1]=[C:12]([CH:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17][CH2:16][N:15]3[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:25])[NH:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)(=[O:10])[NH2:9]
Reactant: NC(=O)c1cccc(NC(=O)C2c3ccccc3CCN2C(=O)OCc2ccccc2)c1N
Solvent: CC(=O)O
Product: NC(=O)c1cccc2[nH]c(C3c4ccccc4CCN3C(=O)OCc3ccccc3)nc12
Reaction time: 8 h

Procedure:
Step-2: A solution of benzyl 1-((2-amino-3-carbamoylphenyl)carbamoyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (425 mg, 0.956 mmol) in acetic acid (5 ml) was heated to 80° C. and stirred overnight. The reaction mixture was concentrated, neutralized with aq. NaHCO3 and extracted with DCM. The DCM layer was washed with brine, dried over anhydrous sodium sulfate and evaporated. Purification of the crude product over silica gel column using ethyl acetate/hexane mixture (1:1) as eluent afforded benzyl 1-(4-carbamoyl-1H-benzo[d]imidazol-2-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylate. MS (ES+): m/z 427.2 [M+H]+
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:13][C:14]([CH3:19])([CH2:17][OH:18])[CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH2:6]([N:13]1[C:14]([CH2:17][OH:18])([CH3:19])[CH2:15][O:16][CH2:2][C:3]1=[O:4])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(Cl)CCl
Reactant: CC(CO)(CO)NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(CO)COCC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Chloroacetyl chloride (14.0 ml) was added dropwise to a mixture of 2-benzylamino-2-methyl-1,3-propanediol (28.5 g), potassium carbonate (30.3 g) in dichloromethane (150 ml) and water (150 ml) at 0° C., and the whole was stirred at room temperature for 2 hours. The mixture was extracted with dichloromethane and the extract was washed successively with water, 1N hydrochloric acid and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was dissolved in tert-butanol (400 ml) and the solution was added potassium tert-butoxide (16.38 g) portionwisely and the whole was refluxed for 30 minutes. After cooling, the solvent was removed by evaporation and ethyl acetate and water were added thereto. The organic layer was separated, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give 4-benzyl-5-hydroxymethyl-5-methyl-3-morpholinone (10.89 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].O[CH2:11][CH:12]([CH2:14]O)O.[N+](C1C=C(S([O-])(=O)=O)C=CC=1)([O-])=O.[Na+].S(=O)(=O)(O)O>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]2[C:8]=1[CH:11]=[CH:12][CH:14]=[N:7]2
Reactant: Nc1cc(Br)ccc1F
Reactant: OCC(O)CO
Agent: O=S(=O)(O)O
Agent: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: [Na+]
Product: Fc1ccc(Br)c2cccnc12
Temperature: 140 °C

Procedure:
5-Bromo-2-fluoroaniline (1.0 g, 5.3 mmol) was mixed with glycerol (2.0 mL, 27 mmol), sodium 3-nitrobenzene sulfonate (1.2 g, 5.3 mmol) and concentrated sulfuric acid (8 mL), then the mixture was heated to 140° C. for 2 hours. The inital suspension became a dark brown solution. The mixture was allowed to cool to room temperature. The solution was made basic with 5N NaOH (30 mL), then extracted with EtOAc. The combined organic phase was washed with water then saturated NaCl (aq), dried over MgSO4, filtered, then concentrated to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3): δ 9.00 (d, J=4.2 Hz, H); 8.54 (d, J=8.6 Hz, 1H); 7.77 (dd, J=8.3, 4.5 Hz, 1H); 7.59 (dd, J=8.6, 4.2 Hz, 1H); 7.32 (dd, J=9.9, 8.3 Hz, 1H). LC4 1.81 min. (M+H)=226.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:12]=1[CH2:13][N:14]1[CH2:17][CH2:16][CH:15]1C(OC(C)(C)C)=O.[O:33]1CCCC1>>[CH3:9][O:10][C:11]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[C:12]=1[CH2:13][N:14]1[CH2:17][CH2:16][C:15]1=[O:33]
Reactant: C1CCOC1
Reactant: COc1cc(OC)c(CN2CCC2C(=O)OC(C)(C)C)c(OC)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COc1cc(OC)c(CN2CCC2=O)c(OC)c1
Reaction time: 1 h
Yield: 56 %

Procedure:
In a 50 ml round bottom 3-neck flask was prepared a solution of 1.2 mmol lithium diisopropylamide in ca. 10 ml tetrahydrofuran. To this clear, practically colorless solution cooled to -78°, was added 0.34 g (1 mmol) N-(2,4,6-trimethoxybenzyl)-2-carbo-tert-butoxyazetidine dissolved in 3 ml tetrahydrofuran. After stirring for 1 hour at this temperature, the golden-orange solution was silylated and photooxygenated in the usual manner. The resulting pink solution was then concentrated in vacuo and the residue applied to a 10×2 cm silica gel (Woelm) column. Elution with chloroform gave 0.14 g (56%) of pale yellow liquid, which by NMR analysis was greater than 90% pure: IR (liquid film) cm-1 1745, 1600, 1230, 1210, 1150, 1060, 1050, 950, 820; NMR (CDCl3) delta 6.09 (2H, s), 4.36 (2H, s), 3.79 (6H, s), 3.75 (3H, s), 2.98 (2H, t, J=4 Hz), 2.74 (2H, t, J=4 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>N1C=CC=CC=1.O1CCCC1.O>[C:16]([C:15]1[CH:18]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][S:20]([CH3:19])(=[O:22])=[O:21])[CH:3]=2)[CH:12]=[N:13][CH:14]=1)#[N:17]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.8 %

Procedure:
Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.2 g, 0.8 mmol) in anhydrous pyridine. Add a solution of methanesulfonyl chloride (0.1 g, 0.88 mmol) in tetrahydrofuran to the reaction and stir overnight at room temperature. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 95:5 to 80:20 dichloromethane:ethyl acetate), to give the title compound as a tan solid (50 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17](F)[CH:16]=3)[S:12][C:11]=2[C:22]2[N:26]=[CH:25][N:24](C3CCCCO3)[N:23]=2)[OH:9])=[CH:4][CH:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34].C(N(CC)C(C)C)(C)C.CS(C)=O.O1CCOCC1.Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[C:10]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH:36][CH2:35][CH2:33][OH:34])[CH:16]=3)[S:12][C:11]=2[C:22]2[NH:26][CH:25]=[N:24][N:23]=2)=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)c1cc(-c2ccnc(F)c2)sc1-c1ncn(C2CCCCO2)n1
Reactant: NCCO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1COCCO1
Product: OCCNc1cc(-c2cc(C(O)c3ccc(Cl)cc3)c(-c3nnc[nH]3)s2)ccn1
Temperature: 200 °C
Yield: 24.2 %

Procedure:
A mixture of (4-chlorophenyl){5-(2-fluoropyridin-4-yl)-2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanol (80.0 mg, 0.170 mmol), ethanolamine (0.104 g, 1.70 mmol) and N,N-diisopropylethylamine (0.118 mL, 0.679 mmol) in dimethylsulfoxide (0.5 mL, 7 mmol) was heated at 200° C. for 1 h under argon. The reaction mixture was cooled, diluted with water and extracted with butanol. The butanol layer was collected and evaporated to a residue which was purified by chromatography (SiO2, elution with 0-20% MeOH in DCM) to afford the intermediate. The intermediate in 1,4-dioxane (1.0 mL, 13 mmol) and conc HCl (1.0 mL, 12 mmol) was stirred at rt for 1 h. The solvent was evaporated and the residue was purified by chromatography (SiO2, elution with 0-70% (MeOH/DCM/NH4OH, 13/85/2) in DCM) to afford 2-({4-[4-[(4-chlorophenyl)(hydroxy)methyl]-5-(4H-1,2,4-triazol-3-yl)-2-thienyl]pyridin-2-yl}amino)ethanol (17.6 mg, 24.2%). LCMS: (AA) ES+ 428.2, 430.0; 1H NMR (400 MHz, d6-DMSO) δ: 14.66-14.13 (m, 1H), 8.68 (s, 1H), 7.94 (d, J=5.30 Hz, 1H), 7.58-7.48 (m, 3H), 7.38-7.30 (m, 2H), 6.81-6.68 (m, 3H), 6.60 (s, 1H), 4.72 (s, 1H), 3.57-3.45 (m, 2H), 3.34 (d, J=5.88 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].S(O)(O)(=O)=O.[NH2:36][C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[CH:41][CH:42]=1.C(OCC)(=O)C>O.O1CCOCC1>[NH2:36][C:37]1[CH:42]=[C:41]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:14]2[CH2:15][CH2:16][N:17]([S:20]([CH2:23][CH3:24])(=[O:22])=[O:21])[CH2:18][CH2:19]2)[CH:40]=[CH:39][CH:38]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(N)c4)cc23)CC1
Yield: 36.2 %

Procedure:
To a CEM microwave tube was added 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (40 mg, 0.0965 mmol), potassium carbonate (80 mg, 0.578 mmol) and (3-aminophenyl)boronic acid sulfate (145 mg, 0.386 mmol). The mixture was taken up in water (1.2 mL) and dioxane (2.8 mL), and chloro-2-(dimethylaminormethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(II) (1 mg, 0.002 mmol) was added. The mixture was then reacted in a CEM microwave for 10 min at 150° C. Ethyl acetate (2 mL) was added and the layers were separated. The aqueous layer was washed with ethyl acetate (1×2 mL). The organic layers were pooled, concentrated under a stream of nitrogen, and taken up in dimethyl sulfoxide (0.89 mL) and trifluoroacetic acid (0.15 mL). This solution of crude product was purified on an Agilent MDAP eluting with a linear gradient of 30% CH3CN/H2O (0.1% TFA) to 70% CH3CN/H2O (0.1% TFA) at 20 mL/min over 9 min. To the HPLC fraction containing product was added a solution of saturated K2CO3 (1 mL), a 1 M solution of sodium hydroxide (1 mL), and ethyl acetate (2 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×2 mL). The organic layers were pooled, filtered through a plug of magnesium sulfate, and concentrated under a stream of nitrogen to give 14.9 mg of the title compound (36%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[C:12]([O:14][CH:15]([CH2:17][CH3:18])[CH3:16])[CH:11]=[CH:10][C:9]=1[OH:19].[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>CN(C)C=O>[CH:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]([O:19][CH2:20][C:21]2[CH:28]=[CH:27][C:24]([CH3:25])=[CH:23][CH:22]=2)=[C:8]([Cl:7])[CH:13]=1)([CH2:17][CH3:18])[CH3:16]
Reactant: Cc1ccc(CCl)cc1
Reactant: CCC(C)Oc1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC(C)Oc1ccc(OCc2ccc(C)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
A mixture of 0.30 g of potassium carbonate, 0.40 g of 2-chloro-4-sec-butoxyphenol, 0.28 g of p-methylbenzyl chloride and 15 ml of N,N-dimethylformamide was stirred at room temperature overnight. The reaction mixture was poured into ice-water and extracted twice with 100 ml of ethyl acetate. The extracts were combined together, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 0.50 g of 1-sec-butoxy-3-chloro-4-(4-methylbenzyloxy)benzene. Yield, 82%. nD18.9 1.5557.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:13][CH3:14])=[O:7]
Reactant: O=C(O)CCCCBr
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCCCBr

Procedure:
A! Starting from 5-bromopentanoic acid (50 g, 0.276 mole) and thionyl chloride (39 ml, 0.552 mole) in absolute ethanol (500 ml) and following the procedure of Example 13,A!, there were obtained 62.7 g of ethyl 5-bromopentanoate (quantitative yield) which was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)([CH2:14][CH2:15][OH:16])[CH2:9]1)=[O:7].C(N(CC)C(C)C)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([O:30][CH3:31])[C:27]=1[O:28][CH3:29])[C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)([CH2:14][CH2:15][O:16][S:42]([CH3:41])(=[O:44])=[O:43])[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCCC(CCO)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)N2CCCC(CCOS(C)(=O)=O)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidine (0.61 g, 1.3 mmol) and N,N-diisopropylethylamine (0.37 g, 2.86 mmol) in anhydrous dichloromethane (12 mL). Cool the reaction mixture to 0° C. with an ice bath. Slowly add methanesulfonyl chloride (0.19 g, 1.7 mmol). After 3.5 hours, dilute the reaction mixture with dichloromethane and extract with 1M hydrochloric acid and with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain the title compound: Rf=0.60 (silica gel, 1/1 ethyl acetate/hexane).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([Cl:14])=[C:8]([NH:10][C:11](=[O:13])[CH3:12])[CH:9]=1)(=[O:3])[CH3:2].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[Cl:14][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[CH:17][N:18]([CH3:20])[CH3:19])=[CH:9][C:8]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: COC(OC)N(C)C
Reactant: CC(=O)Nc1cc(C(C)=O)ccc1Cl
Product: CC(=O)Nc1cc(C(=O)C=CN(C)C)ccc1Cl
Yield: 80.5 %

Procedure:
4.46 g (21.1 mmol) of N-(5-acetyl-2-chloro-phenyl)-acetamide were dissolved in 10.4 ml (9.34 g) (78.39 mmol) of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 6.5 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was crystallized from ethyl acetate. 4.53 g of N-[2-chloro-5-(3-dimethylamino-acryloyl)-phenyl]-acetamide as a yellowish-white solid were obtained (yield 80.5%).