Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1.CC1C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1>O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)=[CH:16][CH:15]=1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N1CCC(=Nc2ccc(Cl)cc2)CC1

Procedure:
A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 159.5 parts of 4-chlorobenzenamine, 1520 parts of anhydrous methylbenzene and a few crystals of 4-methylbenzenesulfonic acid is stirred and refluxed for 7 hours. (The reaction vessel is provided with a reflux-condensor and water-separator). The methylbenzene is evaporated and the oily residue is distilled in vacuo, yielding 192 parts of oily ethyl 4-[(4-chlorophenyl)imino]-1-piperidinecarboxylate; bp. 171°-176° C. at 0.4 mm. pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2=[N:15][N:16]([CH3:18])[CH2:17][N:13]2[C:12]2[S:19](=[O:22])[CH2:20][CH2:21][C:11]=2[CH2:10][N:9]=1.[H-].[Na+].[CH3:25]I>CN(C)C=O.CCOCC>[CH3:25][CH:20]1[S:19](=[O:22])[C:12]2[N:13]3[CH2:17][N:16]([CH3:18])[N:15]=[C:14]3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]=2[CH2:21]1
Reactant: CI
Reactant: CN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1CC2=C(N3CN(C)N=C3C(c3ccccc3Cl)=NC2)S1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
1 g of 6-o-chlorophenyl-8-methyl-1,2-dihydro-4H-s-triazolo[3,4-c]-thieno[2,3-e][1,4]diazepin-1-one is dissolved in 25 ml of dimethylformamide, and 0.09 g of sodium hydride (50% in mineral oil) is added, and the resulting mixture is heated at 60° C on a water bath with stirring for 30 minutes. After cooling to room temperature, a solution of 0.6 g of methyl iodide in 5 ml of ether is added dropwise, and the whole mixture is stirred at room temperature for 7 hours. Then the reaction mixture is poured into ice water, the precipitated crystals are filtered off, and the filtrate is extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate, and the chloroform is removed under reduced pressure. The residue is recrystallized from a mixture of ligroin and ethanol to give the title compound as white crystals, melting at 199°-200° C.
Reaction SMILES: [S:1]=[C:2]1[NH:6][C:5]2[CH:7]=[C:8]([C:11]#[N:12])[CH:9]=[CH:10][C:4]=2[S:3]1.[CH3:13]CN(CC)CC.CI>CCO>[CH3:13][S:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[CH:7][C:5]=2[N:6]=1
Reactant: CCN(CC)CC
Reactant: N#Cc1ccc2sc(=S)[nH]c2c1
Solvent: CI
Solvent: CCO
Product: CSc1nc2cc(C#N)ccc2s1
Yield: 97.3 %

Procedure:
To a solution of 2-thioxo-2,3-dihydrobenzothiazole-5-carbonitrile (260 mg, 1.35 mmol) in EtOH (10.8 mL) was added Et3N (137 mg, 1.35 mmol) and methyliodide (192 mg, 1.35 mmol). The mixture was heated at reflux for 1 h. The volatiles were evaporated and the residue was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to give 2-methylsulfanylbenzothiazole-5-carbonitrile 271 mg (97%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH2:18]O)[N:9]=[N:8]1.Cl.Cl.[OH:31][NH2:32].O>CS(C)=O>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([CH:18]=[N:32][OH:31])[N:9]=[N:8]1
Reactant: NO
Reactant: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: ON=Cc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Reaction time: 6 h

Procedure:
Add 3 eq sulfur trioxide pyridine complex (Aldrich) to a solution of [1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazol-4-yl]-methanol in DMSO, then add 10 eq TEA. Stir for 6 hours, pour into 15 ml 1N HCl and extract with EtOAc (2×20 ml). Remove solvent and dissolve the crude aldehyde in MeOH. Add 1.5 eq of hydroxyl amine hydrochloride and stir for 6 hours. Pour into 50 ml water and extract with EtOAc. Purify via radial chromatography 1:1 hexanes:EtOAc to give the title compound. MS (IS) 416.1 (M+1). Rf=0.16 (1:1 hexanes:EtOAc).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[C:23]([NH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:25])[CH3:24]>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[CH:12]([O:11][N:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:31]3[CH:32]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:28]=[CH:29][CH:30]=3)[CH:3]=2)[CH:8]=[CH:9]1)[CH3:13]
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Product: CC(=O)Nc1cccc(-c2cnc3ccn(OC(C)c4c(Cl)ccc(F)c4Cl)c3c2)c1

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [3-(acetylamino)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CCOC(C)=O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH2:2][CH2:3][CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[CH:29][CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(OCc3ccccc3)cc2)CC1
Temperature: 25 °C
Yield: 72.7 %

Procedure:
A solution/suspension of tert-butyl 4-(2-bromoethyl)piperidine-1-carboxylate (1.22 g, 4.18 mmol), 4-(benzyloxy)phenol (1.01 g, 5.04 mmol, 1.20 equiv.), K2CO3 (830 mg, 6.01 mmol, 1.40 equiv.) and KI (75 mg, 0.45 mmol, 0.11 equiv.) in acetone was heated to reflux under N2 overnight. After cooling to room temperature, the mixture was diluted with 100 mL of EtOAc, and the solids were filtered off. The filtrate was concentrated under vacuum, and the residue was applied onto a silica gel column, which was eluted with ethyl acetate/petroleum ether (1:5) to afford the product (1.25 g, 73%) as a white solid. 1H NMR (CDCl3, 300 MHz) δ 7.43-7.29 (m, 5H), 6.90 (d, 2H, J=6.6 Hz), 5.01 (s, 2H), 4.08 (d, 2H, J=7.2 Hz), 3.95 (t, 1H, J=4.2 Hz), 2.70 (t, 2H, J=9.6 Hz), 1.71-1.69 (m, 5H), 1.45 (s, 9H), 1.20-1.15 (m, 2H). LC-MS (ESI) m/z 434 (M+Na+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O-:27])=[O:26])[CH2:10][CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:13][N+:14]([O-])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CCO>[C:1]([O:5][C:6]([N:8]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@@H:9]([C:25]([O:27][CH2:12][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:26])[CH2:10][CH2:11][CH:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[Cl:24])[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(C[N+](=O)[O-])c1cccc(Cl)c1Cl)C(=O)[O-]
Reactant: [H][H]
Solvent: CCO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CCC(CN)c1cccc(Cl)c1Cl)C(=O)OCc1ccccc1
Yield: 182.1 %

Procedure:
To an EtOH rinsed (4×5 mL) slurry of Raney Ni (1 mL) was added a solution of benzyl (5R or S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D-norleucinate (0.52 g, 0.85 mmol) in EtOH (5 mL). This slurry was hydrogenated under a balloon of hydrogen for 2 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (0.45 g). MS 581 (M+1).
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([CH:14]=[O:15])=[CH:3][CH:2]=1.[BH4-].[Na+].O>C(O)C>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([CH2:14][OH:15])=[CH:3][CH:2]=1
Reactant: O=Cc1cccc2c1oc1ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
1 g (5.1 mmol) of Dibenzofuran-4-carboxaldehyde is dissolved in 5 ml of ethanol. 0.24 g of NaBH4 is then added portionwise to the stirred solution during a period 20 minutes. The solution is maintained under stirring at room temperature for 2 hours, following which the solvent is evaporated. The residue obtained is treated with water, and aqueous layer is then extracted with ether. Evaporation of the organic phase yielded 0.90 g of Dibenzofuran-4-ylmethanol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=1[C:37]1[C:41]([CH2:42]O)=[C:40]([CH:44]([CH3:46])[CH3:45])[O:39][N:38]=1>ClCCl>[Cl:9][C:3]1[CH:4]=[C:5]([O:8][CH2:42][C:41]2[C:37]([C:31]3[C:30]([Cl:29])=[CH:35][CH:34]=[CH:33][C:32]=3[Cl:36])=[N:38][O:39][C:40]=2[CH:44]([CH3:46])[CH3:45])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CO
Reactant: Nc1ccc(O)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(N)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-amino-3-chlorophenol (1.14 g, 7.9 mmol), triphenylphosphine (2.08 g, 7.9 mmol), [3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methanol (2.27 g, 7.9 mmol) in dichloromethane (20 mL) was treated with diisopropylazidodicarboxylate (1.57 mL, 7.9 mmol) dropwise. After stirring at ambient temperature for 16 h, the material was chromatographed on silica gel eluting with dichloromethane. Yield=1.73 g (53%) of 2-chloro-4-{[3-(2,6-dichlorophenyl)-5-isopropylisoxazol-4-yl]methoxy}aniline.
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18]C(=O)OC(C)(C)C)[N:14]=[CH:15]3)=[C:10]([CH3:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1.FC(F)(F)C(O)=O>ClCCCl>[F:1][C:2]1[C:3]([CH3:27])=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[C:10]([CH3:26])[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Cc1c(F)cncc1-c1cc2cnc(NC(=O)OC(C)(C)C)cc2c(C)n1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(F)cncc1-c1cc2cnc(N)cc2c(C)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
A suspension of tert-butyl 7-(5-fluoro-4-methylpyridin-3-yl)-5-methyl-2,6-naphthyridin-3-ylcarbamate (110 mg, 0.30 mmol) in 1,2-dichloroethane (2 mL) was treated with trifluoroacetic acid (0.23 mL, 3.0 mmol), and the mixture was stirred at 40° C. for 2 hours. The mixture was concentrated in vacuo and then diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate solution (10 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford the title compound as a bright yellow solid (80 mg, 99%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.[CH3:18][C:19]1C=CC(S(O)(=O)=O)=C[CH:24]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[C:19]([CH3:24])([CH3:18])[O:8][C:5]2=[CH:6][CH:7]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC1(C)Oc2ccc(Br)cc2-c2[nH]c3ccccc3c21
Temperature: 150 °C
Yield: 391.7 %

Procedure:
To the solution of 4-bromo-2-(1H-indol-2-yl)phenol (200 mg, 0.69 mmol) in acetone (5 mL) was added PTSA (26 mg, 0.14 mmol), it was stirred at 150° C. in a sealed tube. Then the solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 2-bromo-6,6-dimethyl-6,11-dihydrochromeno[4,3-b]indole (180 mg, yield: 79.3%). MS (M+H)+: 327/329.
Reaction SMILES: C(OC([N:6]=[C:7]=[S:8])=O)C.C(O[C:12]([C:14]1[NH:15][CH:16]=[CH:17][C:18]=1[NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH2:28][CH3:29])[N:22]=1)=[O:13])C.CC[O-].[Na+].C(O)C>C(Cl)Cl>[CH2:28]([O:27][C:23]1[N:22]=[C:21]([CH2:20][N:19]2[C:18]3[CH:17]=[CH:16][NH:15][C:14]=3[C:12](=[O:13])[NH:6][C:7]2=[S:8])[CH:26]=[CH:25][CH:24]=1)[CH3:29]
Reactant: CCOC(=O)c1[nH]ccc1NCc1cccc(OCC)n1
Reactant: CCOC(=O)N=C=S
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOc1cccc(Cn2c(=S)[nH]c(=O)c3[nH]ccc32)n1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 15.3 %

Procedure:
Ethoxycarbonyl isothiocyanate (0.12 g, 0.90 mmol) was added to 3-[(6-ethoxy-pyridin-2-ylmethyl)-amino]-1H-pyrrole-2-carboxylic acid ethyl ester (0.24 g, 0.82 mmol) in CH2Cl2 (5 mL) and the solution was stirred at ambient temperature for 35 minutes. The solvent was evaporated and 0.4M NaOEt in ethanol (3 mL, 1.2 mmol) was added to the residue and the mixture was refluxed for 1 h. More NaOEt (0.4M in ethanol, 1.5 mL, 0.6 mmol) was added and the solution was refluxed for another 1.5 h. The solvent was evaporated, the residue was dissolved in water and the pH adjusted to neutral pH with 1M HCl. The resulting solid was collected, washed, and dried to give crude product. This material was purified by preparative HPLC to yield the title compound (38 mg, 15%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[C:27]([C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[CH:33][C:34]([CH2:35][NH:36][C:3]2[C:4]3[CH2:10][CH2:9][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:7][CH2:6][C:5]=3[CH:17]=[CH:18][C:2]=2[Cl:1])=[CH:37][CH:38]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CN)cc1
Product: CC(C)(C)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1
Yield: 78.1 %

Procedure:
Use a method similar to the General Procedure 5-1 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (300 mg, 0.7 mmol) with 4-(tert-butyl)benzyl amine (375 4, 2.1 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (95:5) followed by SCX chromatography to give 6-(4-tert-butylbenzylamino)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a colorless oil (240 mg, 78%). MS (ES+) m/z: 439 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[S:5][CH:6]=1.C(O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[N:3]=[C:4]([N:7]3[CH2:12][CH2:11][CH2:10][CH2:9][C:8]3=[O:13])[S:5][CH:6]=2)=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1CCCCN1c1nc(Br)cs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=C1CCCCN1c1nc(-c2ccc(Cl)cc2)cs1
Temperature: 100 °C
Yield: 71.3 %

Procedure:
To a solution of 1-(4-bromothiazol-2-yl)piperidin-2-one (Step-1 of compound 10, 1.0 g, 3.83 mmol) in a mixture of toluene:ethanol (10 ml: 30 ml) were added (4-chlorophenyl) boronic acid (0.72 g, 4.60 mmol) and potassium carbonate (1.06 g, 7.66 mmol) at 25° C. in a tube, the nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was added tetrakis(triphenylphosphine)palladium(0) (0.44 g, 0.38 mmol) under nitrogen the tube was sealed. The reaction mixture was heated at 100° C. for 10 hr with stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite. The residue was washed with ethyl acetate (2×30 ml). The filtrate was concentrated under reduced pressure to obtain a crude product; which was purified by flash column chromatography using 10% ethyl acetate in hexanes as an eluent to obtain the title compound (0.80 g, 71.4%). MS: m/z 293 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]1([CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:26]=[CH:25][CH:24]=[CH:23][C:17]=2[O:18][CH2:19][CH:20]2[CH2:22][O:21]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(#N)C>[N:1]1([CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:17]2[CH:23]=[CH:24][CH:25]=[CH:26][C:16]=2[CH2:15][CH2:14][CH2:13][CH2:12][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: c1ccc(CCCCc2ccccc2OCC2CO2)cc1
Solvent: CC#N
Product: OC(COc1ccccc1CCCCc1ccccc1)Cn1ccnc1
Yield: 82.4 %

Procedure:
940 mg of imidazole were added to a solution of 780 mg of 2-[2-(4-phenylbutyl)phenoxymethyl]oxirane [prepared as described in Example 1(a)] in 25 ml of acetonitrile, and the resulting mixture was heated under reflux for 24 hours. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 798 mg (yield 82%) of the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:16])[CH:8]=[CH:7][C:6]([C:9]([NH:11][CH2:12][C:13](=[O:15])[CH3:14])=[O:10])=[CH:5][CH:4]=1.I[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>CN(C)C=O>[C:13]([CH:12]([NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH3:16])=[CH:8][CH:7]=1)=[O:10])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:15])[CH3:14]
Reactant: CC(=O)CNC(=O)c1ccc(C)cc1
Reactant: CCOC(=O)CCCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCC(NC(=O)c1ccc(C)cc1)C(C)=O
Yield: 65.6 %

Procedure:
A suspension (100 ml) of 60% sodium hydride (2.64 g) in N,N-dimethylformamide was cooled to −18° C. with an ice-sodium chloride bath, and 31 ml of a solution of 12.62 g of 1-(p-toluoylamino)-2-propanone in N,N-dimethylformamide was added dropwise slowly. After 1-hour-stirring, 31 ml of a solution of 16.21 g of ethyl 6-iodohexanoate in N,N-dimethylformamide was added dropwise slowly. The ice-bath was removed and the mixture was stirred for 18 hours at room temperature. After addition of ice-cold water, the reaction solution was extracted with ethyl acetate, washed with water and brine sequentially, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (Wakogel® C-200, n-hexane:ethyl acetate=3:1) to provide 13.13 g of the objective compound as yellow oil.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:38](Cl)(=[O:40])[CH3:39]>O1CCCC1>[C:38]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][NH:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[NH:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]2[NH:26][CH:27]=[CH:28][C:21]=12)=[O:13])(=[O:40])[CH3:39]
Reactant: O=C(NCCNCc1ccccc1)c1sccc1Nc1ccnc2[nH]ccc12
Reactant: CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)N(CCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12)Cc1ccccc1
Yield: 24 %

Procedure:
A solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-benzylamino-ethyl)-amide (95 mg, 0.24 mmol), diisopropylethylamine (84 uL, 0.49 mmol) and acetyl chloride (25 uL, 0.37 mmol) in tetrahydrofuran (2.0 mL) was stirred at room temperature for 18 h. The solution was concentrated in vacuo then purified by ISCO Companion (silica, 10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(acetyl-benzyl-amino)-ethyl]-amide (25 mg, 24%). LCMS (ESI) 434 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (1H, br. s.) 10.16-10.43 (1H, m) 8.15 (0H, t, J=5.00 Hz) 8.02 (1H, t, J=2.71 Hz) 7.72-7.86 (1H, m) 7.44-7.54 (1H, m) 7.13-7.39 (6H, m) 6.83 (1H, dd, J=12.23, 5.49 Hz) 6.36-6.50 (1H, m) 4.49-4.61 (2H, m) 3.34-3.50 (4H, m) 1.91-2.19 (3H, m)
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[C:7]([OH:10])[C:6]([CH3:11])=[CH:5][C:3]=1[OH:4].O[CH:13]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]>CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.C1(C)C=CC=CC=1>[CH3:11][C:6]1[C:7](=[O:10])[C:8]([CH3:9])=[C:2]([CH3:1])[C:3](=[O:4])[C:5]=1[CH:13]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19]
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: COc1ccc(C(O)CCCCC(=O)O)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: Cc1ccccc1
Product: COc1ccc(C(CCCCC(=O)O)C2=C(C)C(=O)C(C)=C(C)C2=O)cc1
Temperature: 70 °C
Yield: 68.8 %

Procedure:
D-Camphor-10-sulfonic acid (0.1 g) was added to a toluene solution (60 ml) of 2,3,5-trimethylhydroquinone (3.1 g, 0.02 mole) and 6-hydroxy-6-(4-methoxyphenyl)hexanoic acid (5.0 g, 0.021 mole), and the mixture was heated at 70° C. for 20 hours, with stirring. The reaction solution was evaporated under reduced pressure, and tetrahydrofuran (50 ml) was added to dissolve the residue, followed by adding furthermore a 10% aqueous solution of ferric chloride and stirring at room temperature for 10 minutes. The reaction product was extracted with ethyl acetate, and the organic layer was washed with water, dried and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column, and elution was performed with isopropyl ether to give 6-(3,5,6-trimethyl-1,4-benzoquinon-2-yl)-6-(4-methoxyphenyl)hexanoic acid (5.1 g, 76%). Its typical physical properties and nuclear magnetic resonance spectrum data are shown in Table 1. By following the procedure of this Example, the Compound Nos. 23 to 34 and 68 were prepared.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]([CH3:17])[CH:10]1[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1.CO>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N:9]([CH3:17])[CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[C:2]=1[F:1])=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(N(C)c2cccc(N)c2F)CC1
Solvent: C1COCCO1
Solvent: CO
Product: CN1CCC(N(C)c2cccc(NC(=O)c3ccc(F)cc3Cl)c2F)CC1
Yield: 100 %

Procedure:
Heat 2-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 22, 44 mg) with 2-chloro-4-fluorobenzoyl chloride (40 mg) in 1,4-dioxane (5 mL) at reflux for 2 hr. Dilute the reaction mixture with methanol (5 mL) and load on a SCX column (10 g). After wash with methanol, elute the product with 2 M NH3 in methanol, evaporate to give 73 mg of the title compound: mass spectrum (electric spray) m/z=394 (M+1); 1H NMR (CDCl3): 8.29 (br d, 1H), 7.94 (t, 1H), 7.81 (dd, 1H), 7.18 (dd, 1H), 7.05 (m, 2H), 6.77 (ddd, 1H), 3.15 (m, 1H), 2.72 (s, 3H), 2.26 (s, 3H), 1.96 (m, 2H), 1.83 (m, 2H), 1.70 (m, 2H).