Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13](OC)(=[O:19])[C:14]#[C:15][CH2:16][CH2:17][CH3:18]>C1COCC1>[O:19]=[C:13]([CH2:14][CH2:15][CH2:16][C:17]#[CH:18])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCC#CC(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C#CCCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl hexynoate (1.26 g, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH:CH2Cl2=2:98) to give the product (370 mg) with colorless oil in 17% yield. 1HNMR (CDCl3, ppm) δ 1.80 (t, J=7.0 Hz, 2H), 1.95 (s, 1H), 2.24 (dt, J=2.9 and 7.0 Hz, 2H), 2.73 (t, J=7.0 Hz, 2H), 3.06 (d, J=22.7 Hz, 2H), 3.77 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([OH:11])=O)=[CH:5][CH:4]=1.P(Cl)(OCC)(OCC)=O.C(N(CC)CC)C.[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][NH:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([CH3:42])[CH2:38][CH2:37]1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:31][N:32]([CH3:43])[CH2:33][CH2:34][N:35]([C@H:36]1[CH2:37][CH2:38][C@H:39]([CH3:42])[CH2:40][CH2:41]1)[C:9](=[O:11])[CH:8]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:14])=[CH:13][CH:12]=1
Reactant: CN(C)c1ccc(C=CC(=O)O)cc1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CCN(C(=O)C=Cc1ccc(N(C)C)cc1)[C@H]1CC[C@H](C)CC1

Procedure:
Using 2.0 g of 4-dimethylaminocinnamic acid, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.1 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-dimethylaminocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[CH:23]=[C:22](Br)[C:21]([C:25]#[N:26])=[CH:20][C:19]=3[F:27])[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[NH2:29][C:30]1[S:34][N:33]=[C:32]([CH3:35])[CH:31]=1.C([O-])([O-])=O.[K+].[K+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CS(C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@@H:13]([NH:17][C:18]3[CH:23]=[C:22]([NH:29][C:30]4[S:34][N:33]=[C:32]([CH3:35])[CH:31]=4)[C:21]([C:25]#[N:26])=[CH:20][C:19]=3[F:27])[C:14]([NH2:16])=[O:15])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(N)sn1
Reactant: N#Cc1cc(F)c(N[C@H](Cc2ccc(-n3ccnc3)cc2)C(N)=O)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](Cc3ccc(-n4ccnc4)cc3)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h
Yield: 14.2 %

Procedure:
A mixture of (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(5-bromo-4-cyano-2-fluorophenylamino)propanamide (59 mg, 0.137 mmol), 5-amino-3-methylisothiazole hydrochloride (35 mg, 0.232 mmol), K2CO3 (60 mg, 0.434 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (15 mg, 0.066 mmol) in dioxane (2 mL) and DMSO (0.3 mL) was degassed with argon, then was stirred at 120 C for 18 h. The mixture was purified by HPLC to give (R)-3-(4-(1H-imidazol-1-yl)phenyl)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)propanamide (9 mg).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=4)=[C:11]3[CH:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[NH:8]1[C:12]2=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]3[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=3)=[C:11]2[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2ncc3c(Oc4ccc(N)cc4)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(Oc2ccnc3[nH]ncc23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
4-[1-(4-Methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy]aniline (263 mg) was dissolved in TFA (7.5 mL). The resulting mixture was stirred at 60° C. for 2 hours and concentrated under reduced pressure. The residue was diluted with dichloromethane and then washed with a sodium bicarbonate solution and saturated brine. The organic layer was separated and concentrated under reduced pressure. The residue was suspended in ether, and the precipitate was collected by filtration to give 4-(1H-pyrazolo[3,4-b]pyridin-4-yloxy)aniline (151 mg, yield: 88%) as a light-brown powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)[C:5]([CH:23]2[CH2:25][CH2:24]2)=[CH:4][N:3]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]2>C(O)CCC.C(O)(C(F)(F)F)=O>[NH2:15][CH2:14][CH:11]1[CH2:10][CH2:9][N:8]([C:6]2[C:5]([CH:23]3[CH2:24][CH2:25]3)=[CH:4][N:3]=[C:2]([NH:26][C:27]3[CH:28]=[C:29]4[C:34](=[CH:35][CH:36]=3)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]4)[N:7]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2nc(Cl)ncc2C2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCO
Product: NCC1CCN(c2nc(Nc3ccc4c(c3)CCC(=O)N4)ncc2C2CC2)CC1
Temperature: 140 °C
Reaction time: 20 h
Yield: 15.1 %

Procedure:
A solution of tert-butyl (1-(2-chloro-5-cyclopropylpyrimidin-4-yl)piperidin-4-yl)methylcarbamate (99 mg, 0.27 mmol) and 6-amino-3,4-dihydroquinolin-2(1H)-one (50 mg, 0.30 mmol) in nBuOH (3 mL) was stirred at 116° C. for 20 h. It was then stirred at 140° C. for another 20 h. It was concentrated in vacuo. The residue was purified by HPLC to give a powder, which was then dissolved in TFA (3 mL). After being stirred at room temperature for 20 h, TFA was removed in vacuo. The residue was purified by HPLC to give the titled compound (16 mg). MS 393.5 (M+H); UV 208.9, 264.5 nm
Reaction SMILES: [F:1][C:2]1[C:21]([NH:22][C:23]([NH:25]C2C=CN=C(C)C=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])C)=[O:12])[CH2:7][CH2:6]1.Cl.CCN(CC)CC.[CH:41]1[C:46]([N+:47]([O-])=O)=[CH:45][CH:44]=[C:43]([Cl-]C([O-])=O)[CH:42]=1.OC1C[CH2:59][O:58][CH2:57]C1.[H-].[Na+].C(=O)([O-])N>CO.C(Cl)Cl>[F:1][C:2]1[C:21]([NH:22][C:23]([NH:25][C:43]2[CH:42]=[N:47][C:46]([CH3:41])=[CH:45][CH:44]=2)=[O:24])=[CH:20][CH:19]=[CH:18][C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][CH:14]2[CH2:16][CH2:59][O:58][CH2:57][CH2:17]2)=[O:12])[CH2:7][CH2:6]1
Reactant: OC1CCOCC1
Reactant: Cc1cc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC(C)(C)C)CC3)c2F)ccn1
Agent: Cl
Agent: NC(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)Nc2cccc(CN3CCN(C(=O)OC4CCOCC4)CC3)c2F)cn1
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
To a solution of tert-butyl 4-(2-fluoro-3-(3-(2-methylpyridin-4-yl)ureido)benzyl)piperazine-1-carboxylate (1.0 g, 2.26 mmol, 1.0 equiv) in MeOH (10 mL) was added HCl (4N in dioxane, 10 mL, 40 mmol, 17.7 equiv). The mixture was stirred for 30 min, and the solvent was then removed in vacuo. The residue was suspended in dry DCM (20 mL) and Et3N (1.64 mL, 11.79 mmol, 5.2 equiv). To the resulting mixture was added 4-nitrophenylchloroformate (500 mg, 2.49 mmol, 1.1 equiv). The resulting solution was stirred for 30 min, diluted with DCM, washed with aq NH4Cl and brine and concentrated in vacuo. The resulting residue was divided into three equal portions for subsequent derivitization. To a solution of 4-hydroxytetrahydropyran (190 μL, 2 mmol, 2.65 equiv) was added NaH (120 mg of 60% dispersion in mineral oil, 3.0 mmol, 4 equiv) after stirring for 10 minutes, the activated carbamate was added to the reaction mixture, and the reaction was stirred at room temperature overnight. The excess NaH was quenched by the careful addition of water, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed repeatedly with water and once with brine, dried over sodium sulfate, and concentrated in vacuo. Purification by preparative reverse phase HPLC provided tetrahydro-2H-pyran-4-yl 4-(2-fluoro-3-(3-(6-methylpyridin-3-yl)ureido)benzyl)piperazine-1-carboxylate (140 mg, 39%). LCMS m/z (APCI)=472.2 (M+H).
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:22][N:23]1[CH2:28][CH2:27][C:26](=[C:29]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[CH:33]=[CH:32][C:31]3[CH:40]=[CH:41][CH:42]=[CH:43][C:30]2=3)[CH2:25][CH2:24]1)[C:13]([NH:15][CH2:16][C:17]([O:19]CC)=[O:18])=[O:14])=O)C1C=CC=CC=1.[OH-].[Na+].Cl>C(O)C>[NH2:11][C@@H:12]([CH2:22][N:23]1[CH2:24][CH2:25][C:26](=[C:29]2[C:30]3[CH:43]=[CH:42][CH:41]=[CH:40][C:31]=3[CH:32]=[CH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]2=3)[CH2:27][CH2:28]1)[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: CCOC(=O)CNC(=O)[C@H](CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N[C@@H](CN1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl α-{(S)-2-benzyloxycarbonylamino-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidin-1-yl]propionylamino}acetate(1 g, 1.7 mmol) in 20 ml ethanol was added 20 ml of 1N NaOH solution. The mixture was stirred at room temperature for 3 hours and acidified with conc. HCl. The mixture was stirred at room temperature for another hour. After neutrallization with NaHCO3, the white precipitate was collected by filtration and dried in vacuum. Recrystallization from methanol afforded the title compound as a white crystalline. Yield: 0.5 g (69%).
Reaction SMILES: C([SiH2][O:6][C:7](C)(C)[C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]2([CH3:24])[CH3:23])[CH:11]=[N:10][CH:9]=1)(C)(C)C.Cl.O1CCOCC1>>[OH:6][CH2:7][C:8]1[N:12]([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:22])[C:14]2([CH3:24])[CH3:23])[CH:11]=[N:10][CH:9]=1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cncn1C1c2ccccc2C(=O)C1(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)C(=O)c2ccccc2C1n1cncc1CO
Reaction time: 2 h

Procedure:
To 3-[5-(tert-butyl-dimethyl-silanyloxymethyl)-imidazol-1-yl]-2,2-dimethyl-indan-1-one (370 mg, 1 mmol) is added 4N HCl in 1,4-dioxane (20 mL, 0.80 mmol). The reaction is permitted to stir for 2 hours, at which time it is quenched with saturated aqueous NaHCO3 and diluted with ethyl acetate. The layers are separated and the aqueous layer is extracted twice with ethyl acetate. The combined organic layers are dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (methanol-dichloromethane, 0:1 to 1:20) to furnish 3-(5-Hydroxymethyl-imidazol-1-yl)-2,2-dimethyl-indan-1-one; HRMS: (ESI) m/z 257.1295 [(M+H)+: Calcd for C15H17N2O2: 257.1290]; 1H NMR (400 MHz, CDCl3) δ ppm 0.87 (s, 3 H), 1.46 (s, 3 H), 4.69-4.97 (m, 2 H), 5.93 (s, 1 H), 7.16 (s, 1 H), 7.19 (s, 1 H), 7.54 (d, J=7.6 Hz, 1 H), 7.65 (t, J=7.5 Hz, 1 H), 7.72-7.82 (m, 1 H), 7.93 (d, J=7.6 Hz, 1 H).
Reaction SMILES: [Br:1][C:2]([Cl:13])([C:9]([F:12])([F:11])[F:10])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[C:14](OC)([O:18][CH3:19])([O:16][CH3:17])[CH3:15].C(O)(=O)C(C)C>>[Br:1][C:2]([Cl:13])([C:9]([F:10])([F:11])[F:12])[CH:3]([O:8][C:14]([O:18][CH3:19])([O:16][CH3:17])[CH3:15])[CH:4]=[C:5]([CH3:7])[CH3:6]
Reactant: COC(C)(OC)OC
Reactant: CC(C)=CC(O)C(Cl)(Br)C(F)(F)F
Solvent: CC(C)C(=O)O
Product: COC(C)(OC)OC(C=C(C)C)C(Cl)(Br)C(F)(F)F
Temperature: 111 °C

Procedure:
5-Bromo-5-chloro-4-hydroxy-2-methyl-6,6,6-trifluorohex-2-ene (10.0 g), trimethyl orthoacetate (48.0 g) and isobutyric acid (0.29 g) were charged to a round-bottomed flask fitted with: nitrogen inlet/bubbler, thermometer and Dean and Stark received packed with 5 A molecular seives. The mixture was heated with agitation to reflux and distillates collected until reaction mass temperature increased to 111° C. (ca. 1 hr). Once the reaction was complete, the residual trimethyl orthoacetate was removed by distillation under vacuum (ca. 50° C. @50 mmHg) to give the product, 5-bromo-5-chloro-4-(1,1-dimethoxyethoxy)-2-methyl-6,6,6-trifluorohex-2-ene, as an orange oil (10.9 g, 85% yield).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([OH:6])=[O:5].[OH-].[K+].Cl[CH2:16][C:17]([NH2:19])=[O:18].O1CCOCCOCCOCCOCCOCC1>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([O:6][CH2:16][C:17]([NH2:19])=[O:18])=[O:5]
Reactant: O=C(O)c1c(Cl)ccc(Cl)c1Cl
Reactant: NC(=O)CCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: NC(=O)COC(=O)c1c(Cl)ccc(Cl)c1Cl

Procedure:
This compound was prepared in the manner of Example I, using 15.0 grams (0.066 mole) of 2,3,6-trichlorobenzoic acid, 4.4 grams (0.066 mole) of potassium hydroxide, 6.2 grams (0.066 mole) of 2-chloroacetamide, and 1.8 grams of 1,4,7,10,13,16-hexaoxacyclooctadecane in 300 ml of dry toluene and 200 ml of dimethylformamide. The crude product was purified by liquid chromatography, followed by recrystallization from ethyl acetate. The yield was 0.9 gram of (aminocarbonyl)methyl 2,3,6-trichlorobenzoate; mp 158°-160°. The ir and the nmr spectra were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17](O)=[O:18])[CH2:15][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([CH:32]2[NH:36][C:35](=[O:37])[NH:34][C:33]2=[O:38])[CH2:28][CH2:27]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]([CH2:21][C:22]([F:24])([F:25])[F:23])[C:13](=[O:20])[C@H:14]([CH2:16][C:17]([N:26]3[CH2:27][CH2:28][CH:29]([CH:32]4[NH:36][C:35](=[O:37])[NH:34][C:33]4=[O:38])[CH2:30][CH2:31]3)=[O:18])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)C(C2CCNCC2)N1
Reactant: O=C(O)C[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2CN(CC(F)(F)F)C1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)C(C2CCN(C(=O)C[C@@H]3Cc4cc(Cl)c5[nH]ncc5c4CN(CC(F)(F)F)C3=O)CC2)N1
Reaction time: 2 h
Yield: 41.7 %

Procedure:
To a solution of (S)-2-(4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetic acid (50 mg, 0.133 mmol) in DMF (2.0 mL) was added 5-(piperidin-4-yl)imidazolidine-2,4-dione (37 mg, 0.2 mmol) followed by 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (47 mg, 0.15 mmol) and triethylamine (1.0 mL). After 2 h, the solvent was removed under reduced pressure and the crude product was purified by Prep HPLC to give 5-(1-(2-((S)-4-chloro-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetyl)piperidin-4-yl)imidazolidine-2,4-dione (30 mg) in 42% yield. 1H NMR (500 MHz, CD3OD): in δ 8.27 (s, 1H), 7.21 (s, 1H), 5.54 (d, J=17 Hz, 1H), 4.82 (d, J=17 Hz, 1H), 4.69-4.54 (m, 2H), 4.18-3.95 (m, 4H), 3.30-2.96 (m, 4H), 2.71-2.62 (m, 1H), 2.58-2.48 (m, 1H), 2.21-2.12 (m, 1H), 1.91-1.84 (m, 2H), 1.66-1.31 (m, 2H); MS (ESI) 541 (M+H); Rf=2.05.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[O:28]=[C:29]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([S:39](Cl)(=[O:41])=[O:40])[CH:35]=2)[NH:30]1>C(Cl)Cl.C1COCC1>[O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:39]([C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29](=[O:28])[C:37]2=[O:38])(=[O:40])=[O:41])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Nc2ccc(S(=O)(=O)Cl)cc2C1=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1ccccc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.6 %

Procedure:
To a solution of 9 (1.46 g, 5.2 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (5 mL) at 0° C. The mixture was stirred at 0° C. for 15 min. After evaporation of the solvent in vacuo, CH2Cl2 (15 mL) and triethylamine (2 mL) were added, then a solution of 6 (1.44 g, 5.9 mmol) in THF (25 mL) was added at 0° C. The reaction mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, then ethyl acetate (150 mL) was added, washed with water (50 mL×2) and saturated NaCl (50 mL), and dried over Na2SO4. After evaporation of the ethyl acetate, the crude product was purified with ether to afford 1.7 g (84%) of 10 as a yellow solid, mp 204.5-205.9° C. 1H NMR (300 MHz, CDCl3) δ 8.94 (s, 1H), 7.77 (dd, J=8.25 Hz, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.02 (t, J=8.7 Hz, 2H), 6.84 (d, J=8.1 Hz, 1H), 6.69 (t, J=7.2 Hz, 1H), 6.63 (d, J=7.8 Hz, 2H), 3.89 (m, 1H), 3.75-3.66 (m, 2H), 3.23 (m, 1H), 2.96 (m, 1H), 1.72 (m, 2H), 1.54-1.42 (m, 2H). LRMS (FAB) m/e: 387.1 (M+H, 100). Anal. Calcd for C19.N2O5S: C, 59.06, H, 4.70; N, 7.25. Found: C, 58.99, H, 4.74, N, 7.11.
Reaction SMILES: C(O[C:4]([CH:6]1[C:12](=O)[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH:7]1[CH3:21])=[O:5])C.[NH2:22][C:23]1[CH:27]=[CH:26][NH:25][N:24]=1>C(O)(=O)C>[C:17]([O:16][C:14]([N:9]1[CH2:8][CH:7]([CH3:21])[C:6]2=[C:4]([OH:5])[N:24]3[C:23]([N:22]=[C:12]2[CH2:11][CH2:10]1)=[CH:27][CH:26]=[N:25]3)=[O:15])([CH3:18])([CH3:19])[CH3:20]
Reactant: Nc1cc[nH]n1
Reactant: CCOC(=O)C1C(=O)CCN(C(=O)OC(C)(C)C)CC1C
Solvent: CC(=O)O
Product: CC1CN(C(=O)OC(C)(C)C)CCc2nc3ccnn3c(O)c21
Temperature: 80 °C

Procedure:
To a solution of 1.95 g (6.23 mmol) 3-methyl-5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester in 10 mL acetic acid was added 0.52 g (6.23 mmol) 3-aminopyrazole and the reaction mixture was heated at 80° C. for 3 hours. After the reaction was cooled at room temperature, the solvent was evaporated and the product purified by column chromatography (silica, DCM/MeOH 95:5).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[F:17][C:18]1[CH:23]=[C:22](F)[CH:21]=[CH:20][C:19]=1[S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH3:29][N:28]([CH3:30])[S:25]([C:19]1[CH:20]=[CH:21][C:22]([O:1][C:2]2[C:7]3[CH:8]=[C:9]([CH3:11])[O:10][C:6]=3[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=2)=[CH:23][C:18]=1[F:17])(=[O:27])=[O:26]
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CN(C)S(=O)(=O)c1ccc(F)cc1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(=O)(=O)N(C)C)c(F)c2)c2cc(C)oc2c1
Temperature: 100 °C
Yield: 88.9 %

Procedure:
A mixture of ethyl 4-hydroxy-2-methyl-1-benzofuran-6-carboxylate (500 mg, 2.27 mmol), 2,4-difluoro-N,N-dimethylbenzenesulfonamide (553 mg, 2.75 mmol), Cs2CO3 (1.1 g, 4.12 mmol) and CuI (100 mg, 1 mmol) in DMF (20 mL) was heated to 100° C. for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layers was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via gradient silica gel column chromatography using EtOAc/Hex (10/90 to 30/70) to afford the desired compound (850 mg, 91%) as a white solid. 1 H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.41 (t, J=7.16 Hz, 3 H) 2.48 (s, 3 H) 2.78-2.94 (m, 6 H) 4.40 (q, J=7.10 Hz, 2 H) 6.24 (s, 1 H) 6.66-6.94 (m, 2 H) 7.65 (s, 1 H) 7.79 (t, J=8.38 Hz, 1 H) 8.04 (s, 1 H); MS (ESI, pos): 422.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=1[CH2:18][CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:37]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)[CH:38]([CH3:40])[CH3:39]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:44]2[CH2:45][CH2:46][N:41]([CH2:37][CH:38]([CH3:40])[CH3:39])[CH2:42][CH2:43]2)=[O:15])=[CH:11][C:10]=1[CH2:18][CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CN1CCNCC1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccccc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(=O)N2CCN(CC(C)C)CC2)ccc1OCc1ccccc1
Reaction time: 0.67 h
Yield: 100.2 %

Procedure:
4-benzyloxy-3-isobutylbenzoic acid (4.94 g) was dissolved in a mixture of chloroform (60 ml) and triethylamine (4.83 ml). To this mixture, diphenylphosphinic chloride (3.66 ml) was added while being cooled with ice. After being stirred for 40 minutes, the mixture, with 1-isobutylpiperazine (2.48 g) added thereto, was stirred for 1.5 hours at room temperature. The reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. Thus obtained residue was purified by silica gel column chromatography (chloroform: methanol=50:1), thereby yielding 7.11 g of the aimed compound.
Reaction SMILES: [CH3:1][N:2](C(=O)C)[C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[K+]>C(O)C.O>[CH3:1][NH:2][C:3]1[S:7][C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][C:5]=2[C:4]=1[C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(=O)N(C)c1sc2c(c1C(=O)c1ccccc1)CCCC2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CNc1sc2c(c1C(=O)c1ccccc1)CCCC2
Temperature: 95 °C

Procedure:
To solution of 5.0 g of N-methyl-2-acetylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene in 120 ml of ethanol, is added 2.7 g of potassium hydroxide in 60 ml of water. The mixture is heated at 95°C for 4 hours, evaporated under reduced pressure to a residue. Water is added to the residue and extracted with chloroform. The chloroform extracts are washed with water, dried over sodium sulfate, then evaporated under reduced pressure to give crystals, which are recrystallized from ethanol to give 2-methylamino-3-benzoyl-4,5,6,7-tetrahydrobenzo[b]thiophene as crystals having a melting point of 127.5° - 129.5°C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8](=[O:25])[CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:25])[CH2:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:23])([F:24])[F:22])=[CH:16][CH:15]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCC(=O)c1cccc(F)c1)Nc1ccc(OC(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C(CCC(O)c1cccc(F)c1)Nc1ccc(OC(F)(F)F)cc1
Yield: 65.9 %

Procedure:
Stir 4-(3-fluoro-phenyl)-N-(4-trifluoromethoxy-phenyl)-4-oxo-butyramide (3.0 g, 8.5 mmol) in ethanol (70 mL) at room temperature. Add sodium borohydride (650 mg, 17.2 mmol) portionwise and stir at room temperature until TLC indicates that no starting material remains. Add acetone to quench excess borohydride, concentrate the reaction mixture under reduced pressure, redissolve in ethyl acetate and wash with brine. Dry over anhydrous magnesium sulfate, evaporate under reduced pressure to give the titled compound (2.0 g, 67% yield) MS (m/z): 358(M+1).