Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl.C(OCC)(=O)C>[CH2:16]([NH:6][C:5]1[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(F)cc1
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Fc1ccc(NCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
A solution of 4-fluoroaniline (1.50 g, 13.5 mmol)and triethylamine (2.26 mL, 16.2 mmol) in dichloromethane (7 mL) was cooled to 0° C., and the solution was added dropwise with benzyl bromide (1.61 mL, 13.5 mmol). After stirring at room temperature for 1 hour, the reaction mixture was diluted with ethyl acetate and washed three times with water and then with brine, and dried over Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated, the residue was purified by silica gel chromatography (ethyl acetate/hexane) to obtain the title compound (yield: 46%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.[CH2:11]([O:13][C:14](OCC)(OCC)OCC)[CH3:12]>C(OC(C)C)(C)C>[CH2:11]([O:13][C:14]1[NH:1][C:2]2=[N:3][C:4]([CH3:10])=[CH:5][C:6]([CH3:9])=[C:7]2[N:8]=1)[CH3:12]
Reactant: Cc1cc(C)c(N)c(N)n1
Reactant: CCOC(OCC)(OCC)OCC
Solvent: CC(C)OC(C)C
Product: CCOc1nc2c(C)cc(C)nc2[nH]1
Temperature: 155 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
2,3-Diamino-4,6-dimethylpyridine (U.S. Pat. No. 5,332,744; 2.70 g, 19.7 mmol) and tetraethoxymethane (16.5 mL, 78.7 mmol) were mixed, and the mixture was stirred at 155° C. for 2 hr. The mixture was cooled to room temperature, and diisopropyl ether (30 mL) was added. The precipitated solid was collected by filtration to give the title compound (2.42 g, 64%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.C([O-])(=O)C.[Na+].C(O)(=O)C.F[P-](F)(F)(F)(F)F.ClC1C=CC([N+:37]#N)=CC=1>O.C(O)C.O.[Zn]>[Cl:8][C:6]1[C:5]([NH2:37])=[C:4]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CC(C)(C)Cc1cc(Cl)nc(N)n1
Reactant: N#[N+]c1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)Cc1nc(N)nc(Cl)c1N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-amino-4-chloro-6-neopentylpyrimidine (1 mmol), sodium acetate (14 mmol), acetic acid (86 mmol), and 4-chlorobenzene-diazonium hexafluorophosphate (1.15 mmol) in water was stirred at 25° C. for 12 h. Extraction and evaporation gave a yellow solid which was treated with zinc dust (10 mmol) and acetic acid (5.54 mmol) in EtOH-H2O at 80° C. for 1 h. Extraction and chromatography gave 4-chloro-2,5-diamino-6-neopentyl-pyrimidine as a yellow solid. TLC: Rf=0.25, 50% EtOAc-hexane.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([O:13][C:14]([F:17])([F:16])[F:15])[C:10]([C:18]2[N:19]=[N:20][C:21]([NH:24][CH:25]3[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:34])([CH3:33])[CH2:26]3)=[CH:22][CH:23]=2)=[C:9]([OH:35])[CH:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:46]2[CH:47]=[N:48][NH:49][CH:50]=2)O1>>[NH:48]1[CH:47]=[C:46]([C:7]2[CH:12]=[C:11]([O:13][C:14]([F:15])([F:17])[F:16])[C:10]([C:18]3[N:19]=[N:20][C:21]([NH:24][CH:25]4[CH2:30][C:29]([CH3:32])([CH3:31])[NH:28][C:27]([CH3:33])([CH3:34])[CH2:26]4)=[CH:22][CH:23]=3)=[C:9]([OH:35])[CH:8]=2)[CH:50]=[N:49]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC1(C)CC(Nc2ccc(-c3c(O)cc(OS(=O)(=O)C(F)(F)F)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Product: CC1(C)CC(Nc2ccc(-c3c(O)cc(-c4cn[nH]c4)cc3OC(F)(F)F)nn2)CC(C)(C)N1
Yield: 45 %

Procedure:
3-Hydroxy-4-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(trifluoromethoxy)phenyl trifluoromethanesulfonate (32 mg, 0.043 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (16.68 mg, 0.086 mmol) were reacted according to GENERAL METHOD 1-5 for Suzuki coupling. 5-(1H-Pyrazol-4-yl)-2-(6-((2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-3-(trifluoromethoxy)phenol was obtained as a yellow solid after HPLC purification. The product was converted to the HCl salt by addition of 1 M aqueous HCl (0.1 mL, 2.3 equivalents) followed by lyophilization (10 mg, 45% yield). LCMS Rt=0.48 min [Method Q], MS (M+1)=477.3. 1H NMR (METHANOL-d4) δ 8.17 (s, 2H), 8.05 (d, J=9.6 Hz, 1H), 7.68 (d, J=9.6 Hz, 1H), 7.22-7.30 (m, 2H), 4.49 (t, J=12.1 Hz, 1H), 2.33 (dd, J=13.6, 3.5 Hz, 2H), 1.70 (t, J=12.9 Hz, 2H), 1.61 (s, 6H), 1.54 (s, 6H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3].[CH3:14][N:15]([CH:17](OC)OC)[CH3:16]>CN(C=O)C>[CH3:14][N:15]([CH:17]=[CH:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][CH3:13])[CH:5]=1)=[O:3])[CH3:16]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(C(C)=O)cc1OC
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)C=CN(C)C)cc1OC
Temperature: 150 °C
Reaction time: 35 h
Yield: 77.4 %

Procedure:
A mixture of 3,4-dimethoxy acetophenone 11 (5 g, 27.47 mmol) and DMF-DMA (3.9 g, 111.1 mmol) in DMF (10 mL) was heated to 150° C. under an atmosphere of N2. After stirring for 35 h 150° C., the reaction mixture was concentrated in vacuo. The resulting residue was triturated with diethylether and dried under high vacuum to afford compound 12 (5.0 g, 77%) as a yellow solid. TLC Rf=0.5 (CHCl3-MeOH, 9:1); 1H NMR (CDCl3) δ 7.8 (d, J=12.2 Hz, 1H), 7.56-7.51 (m, 3H), 6.86 (d, J=8.1 Hz, 1H), 5.71 (d, J=12.2 Hz, 1H), 3.95 (s, 3H), 3.92 (s, 3H), 3.03 (br, 6H); MS (ES) m/z 236 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.[C:24]1([CH:32]=O)[C:25]([CH:30]=[O:31])=[CH:26][CH:27]=[CH:28][CH:29]=1>C(O)(=O)C>[O:31]=[C:30]1[C:25]2[C:24](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:32][N:1]1[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Reactant: O=Cc1ccccc1C=O
Solvent: CC(=O)O
Product: O=C(Nc1cn2cc(Oc3cccc(N4Cc5ccccc5C4=O)c3)ccc2n1)C1CC1
Temperature: 100 °C
Reaction time: 13 h
Yield: 17.7 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (19.7 mg, 0.064 mmol), benzene-1,2-dicarbaldehyde (10.7 mg, 0.080 mmol) and acetic acid (4.0 mL) was stirred at 100° C. for 13 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The mixture was washed with aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (4.8 mg, 18%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:17]([OH:19])=O)[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[C:21]1([CH2:27][CH2:28][CH2:29][CH:30]([NH2:40])[CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:34]1([CH2:33][CH2:32][CH2:31][CH:30]([NH:40][C:17](=[O:19])[C@H:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:29][CH2:28][CH2:27][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NC(CCCc1ccccc1)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
N-tert-Butoxycarbonyl-3-(3-pyridyl)-alanine (1.00 g; 3.76 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1,7-Diphenyl-4-aminoheptane hydrochloride (1) (1.37 g; 4.51 mmol), N,N-diisopropylethylamine (1.55 g; 12.0 mmol) and PyBOP (2.34 g; 4.51 mmol) are added sequentially. The reaction is stirred for 2.5 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (60%→80% ethyl acetate in hexanes) affording the desired product (84) as a solid. ESMS:MH+ 516.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-])=O)[C:13]([CH2:25][OH:26])=[N:12][C:11]=2[CH:27]([CH3:29])[CH3:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[H][H]>C(OCC)(=O)C.[Pt]>[NH2:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:14]1[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:27]([CH3:29])[CH3:28])[N:12]=[C:13]1[CH2:25][OH:26]
Reactant: [H][H]
Reactant: CC(C)c1nc(CO)n(Cc2ccccc2[N+](=O)[O-])c1Sc1cc(Cl)cc(Cl)c1
Agent: [Pt]
Solvent: CCOC(C)=O
Product: CC(C)c1nc(CO)n(Cc2ccccc2N)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
In ethyl acetate was dissolved 170 mg of 5-(3,5-dichlorophenylthio)-2-hydroxymethyl-4-isopropyl-1-(o-nitrobenzyl)-1H-imidazole (103c), platinum sulfided carbon was added. After replacement with hydrogen atomosphere, catalytic hydrogenation was performed at atmospheric pressure at room temperature. After 1 hour, the mixture was filtered through Celite, and the Filtrate was distilled off under reduced pressure. To the residue, diethyl ether was added, the precipitated crystals were collected by filteration, and 77 mg of Compound I-119 was obtained (yield 49%).
Reaction SMILES: C1(S([N:10]2[CH:21]=[CH:20][C:19]3[C:11]2=[N:12][CH:13]=[C:14]2[C:18]=3[N:17]([CH:22]3[CH2:27][CH2:26][C:25]([CH2:29][OH:30])([OH:28])[CH2:24][CH2:23]3)[N:16]=[N:15]2)(=O)=O)C=CC=CC=1.[OH-].[Na+].Cl>CO.O>[OH:30][CH2:29][C:25]1([OH:28])[CH2:24][CH2:23][CH:22]([N:17]2[C:18]3[C:14](=[CH:13][N:12]=[C:11]4[C:19]=3[CH:20]=[CH:21][NH:10]4)[N:15]=[N:16]2)[CH2:27][CH2:26]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2c1ncc1nnn(C3CCC(O)(CO)CC3)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: OCC1(O)CCC(n2nnc3cnc4[nH]ccc4c32)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11.8 %

Procedure:
To a solution of 4-(6-Benzenesulfonyl-6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-1-hydroxymethyl-cyclohexanol (200 mg, 0.47 mmol) in methanol (25 mL) was added a solution of sodium hydroxide (46.8 mg, 1.17 mmol) in water (5 mL), then the reaction mixture was stirred at 60° C. for 3 hours and neutralized with dilute hydrochloride acid until pH=7. The reaction mixture was purified by a reverse-phase preparatory HPLC (Column: Waters Xbridge C18 150*30 mm*5 um, 0% to 25%: acetonitrile+0.05% NH4OH in water, 10 min, 25 mL/min) to give 15.9 mg (39%) of 1-Hydroxymethyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol, LCMS (Method K, ESI): RT=0.873 min, m+H=288.0; 1H NMR (400 MHz, DMSO-d6) δ: 8.97 (s, 1H), 7.57 (d, 1H), 6.96 (d, 1H), 5.14-5.07 (m, 1H), 4.62-4.57 (m, 1H), 4.31-4.25 (m, 1H), 3.52 (s, 3H), 2.25-2.18 (m, 2H), 2.18-2.15 (m, 2H), 1.93-1.90 (m, 2H), 1.62-1.51 (m, 2H); and 19.3 mg (39%) of 1-Hydroxymethyl-4-(6H-1,2,3,5,6-pentaaza-as-indacen-1-yl)-cyclohexanol, LCMS (Method K, ESI): RT=0.889 min, m+H=288.1; 1H NMR (400 MHz, DMSO-d6) δ: 12.32 (s, 1H), 8.96 (s, 1H), 7.57 (s, 1H), 7.17 (s, 1H), 5.01-4.98 (m, 1H), 4.67 (d, 1H), 4.38 (d, 2H), 2.54-2.46 (m, 2H), 1.88-1.63 (m, 6H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:14][CH:15]=2)[N:10]=[CH:9][C:8]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)=O.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:7]2[C:16]3[C:11](=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][C:8]=2[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:28])=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: O=C(c1ccccc1)c1cnc2c(C(F)(F)F)cccc2c1OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)cc1
Yield: 81 %

Procedure:
A solution of 3-benzoyl-8-(trifluoromethyl)quinolin-4-yl trifluoromethanesulfonate (1.8 g, 4 mmol), 4-methoxyphenylboronic acid(1.0 g, 6.5 mmol), and K3PO4(3.0 g) in dioxane (50 ml) was heated to reflux. After, 4 hr, the reaction was cooled, filtered, concentrated to give an oil which was purified by column chromatography (eluent 10% EtOAc/Hex) to give a white solid (1.3 g Yield=81%); MS (ESI) m/z 408 ([M+H]+;
Reaction SMILES: [Si]([O:18][CH2:19][C@@H:20]([N:51]([CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])[S:52]([C:55]1[CH:60]=[CH:59][C:58]([N+:61]([O-:63])=[O:62])=[CH:57][CH:56]=1)(=[O:54])=[O:53])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[OH:18][CH2:19][C@@H:20]([N:51]([CH2:64][CH2:65][CH:66]([CH3:68])[CH3:67])[S:52]([C:55]1[CH:56]=[CH:57][C:58]([N+:61]([O-:63])=[O:62])=[CH:59][CH:60]=1)(=[O:53])=[O:54])[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30](=[O:50])[C@H:31]([CH:37]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[NH:32][C:33]([O:35][CH3:36])=[O:34]
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H](CO)N(CCC(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(c1ccccc1)c1ccccc1
Yield: 69750.3 %

Procedure:
A solution of N-{2-[(3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-{(3-methylbutyl)[(4-nitrophenyl)sulfonyl]amino}butyl]phenyl}-Nα-(methoxycarbonyl)-β-phenyl-L-phenyl alaninamide (10, 141.3 mg, 0.148 mmol) in THF (1.5 ml) stirred at 0° C. in a plastic vial, was treated with a 70% solution of HF in pyridine (1.5 mL, 5.8 mmol), the plastic bottle was capped and the final mixture stirred at room temperature for 4 h. Diluted with EtOAc, washed with water followed by saturated NaHCO3, dried over MgSO4, filtered and concentrated. Purification made by passage through a chromatographic cartridge of silicagel (12 g) eluted with 20% to 60% EtOAc in hexane to give 74 g (69% yield) of title compound as white foam. MS: m/z=717.3 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][O:13][CH3:14])[CH:6]=1.[Li]CCCC.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[CH2:20]([C:6]1[C:7]([O:11][CH2:12][O:13][CH3:14])=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH2:3][O:2][CH3:1])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCOc1cccc(OCOC)c1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(OCOC)c1Cc1ccccc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
A solution of 12 (500 mg, 2.52 mmol) in anhydrous THF (2.02 mL) was added dropwise to a solution of nBuLi (2.5 M in hexanes, 1.51 mL, 3.78 mmol) in anhydrous THF (1.65 mL) at room temperature. After one hour, the solution was cooled to −40° C. and benzyl bromide (1.22 mL, 10.10 mmol) was added. The resulting solution was warmed to room temperature over 12 hours, and the reaction was quenched by the addition of saturated aqueous NH4Cl. Water (5 mL) was added and the solution was extracted with CH2Cl2 (3×10 mL). Combined organic fractions were dried (Na2SO4), filtered, and concentrated. The residue was purified via column chromatography (SiO2, 4:1; Hexane:EtOAc) to afford 13 as a yellow oil (214 mg, 30%): 1H NMR (CDCl3, 500 MHz) 7.17 (d, J=7.9 Hz, 2H), 7.17-7.12 (m, 2H), 7.06-7.02 (m, 2H), 6.71 (d, J=8.3 Hz, 2H), 5.09 (s, 4H), 4.00 (s, 2H), 3.29 (s, 6H); 13C NMR (CDCl3, 125 MHz) 155.9 (2C), 141.6, 128.5 (2C), 128.0 (2C), 127.5, 125.4, 119.4, 107.7 (2C), 94.3 (2C), 56.0 (2C), 29.1; IR (film) νmax 2953, 2930, 1595, 1470, 1452, 1254, 1153, 1097, 1043, 941, 922, 727, 698 cm−1; HRMS (ESI+) m/z: [M+Na]+ calcd for C17H20O4, 311.1259; found, 311.1201.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[O:9]=[C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=[CH:12]O1.Cl.CN(C)CCCN=C=NCC.O>CN(C=O)C.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:12]=[CH:13][CH:14]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:10]2=[O:9])=[CH:4][CH:3]=1
Reactant: Nc1ccc(F)cc1
Reactant: COC(=O)c1cccoc1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-fluoroaniline (6.5 g, 58.4 mmol) in DMF (30 mL) at ice bath temperature was added methyl 2-oxo-2H-pyran-3-carboxylate (9.0 g, 58.4 mmol). The resulting mixture was stirred for 15 min cold and was then warmed to ambient temp for 3 hours. N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI—HCl) (13.5 g, 70.0 mmol) and DMAP (1.43 g, 11.7 mmol) were added and the resulting mixture was stirred at ambient temp overnight. The reaction mixture was poured into water (300 mL), extracted with ethyl acetate (3×100 mL), washed with brine, dried over anhydrous Na2SO4 and concentrated in vacuo to obtain methyl 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate. This crude product was used for the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH:8]=2)[NH:3]1.[F:26][C:27]1[CH:32]=[CH:31][C:30](I)=[CH:29][CH:28]=1.CN[C@@H]1CCCC[C@H]1NC.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.[Cu](I)I>[F:26][C:27]1[CH:32]=[CH:31][C:30]([N:3]2[C:4]3[C:9](=[CH:8][C:7]([O:12][CH:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]4)=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCC(=O)N3)CC1
Reactant: Fc1ccc(I)cc1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCC(=O)N3c2ccc(F)cc2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A suspension of tert-butyl 4-(2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)piperidine-1-carboxylate prepared in Example 7-(1) (3.0 g), 1-fluoro-4-iodobenzene (2.9 g), rac-trans-N,N′-dimethylcyclohexane-1,2-diamine (1.2 g), copper iodide (0.41 g) and cesium carbonate (5.6 g) in toluene (8.0 mL) was stirred at 100° C. for 4 hours. The reaction mixture was cooled to room temperature, diluted with toluene and filtered to remove insoluble materials. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=7/3 to 1/4) to give the titled compound (3.8 g, 99%) as a colorless amorphous substance.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Br)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]2[C:26]([CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:25][S:24][C:23]=2[CH:33]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:30]3[CH2:31][CH2:32][CH:27]([C:26]4[C:22]5[CH:21]=[CH:20][C:19]([F:18])=[CH:33][C:23]=5[S:24][CH:25]=4)[CH2:28][CH2:29]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCC(c3csc4cc(F)ccc34)CC2)C1
Temperature: 90 °C
Reaction time: 22 h
Yield: 50.4 %

Procedure:
A mixture of 210 mg of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine, 200 mg of 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride, 250 mg of potassium carbonate and 140 mg of potassium iodide in 5 ml of dimethylformamide and 5 ml of toluene was stirred at 90° C. for 22 hours and concentrated in vacuo. To the residue were added ethyl acetate and water, and separated. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on a silica gel to give 160 mg of 6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH:7]=O.[CH3:13][NH2:14].[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:3]2[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=2[S:5][C:6]=1[CH2:7][NH:14][CH3:13]
Reactant: CN
Reactant: O=Cc1sc2ccccc2c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CNCc1sc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To 3-chloro-benzo[b]thiophene-2-carbaldehyde (1.9 g, 9.5 mmol) was added a solution of 2 M methylamine in methanol (32 mL) and the resulting mixture was stirred overnight at room temperature. The mixture was concentrated under reduced pressure and the residue taken up in ethanol (32 mL). The solution was cooled to 0° C., NaBH4 (0.54 g, 14 mmol) was added in one portion and stirring continued overnight. The mixture was concentrated under reduced pressure and the residue solvated in 1 M NaOH (200 mL). The mixture was extracted with diethyl ether (3×150 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate 1:1) gave the title compound (1.62 g, 80%) as a pale yellow oil which crystallized under vacuum: 1H NMR (300 MHz, CDCl3) δ 7.70 (m, 2H), 7.45 (m, 2H), 4.08 (s, 2H), 2.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[C:6]([O:10][CH3:11])[C:5]([O:12][CH3:13])=[C:4]([O:14]C)[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]>C(#N)C.O>[Cl:1][C:2]1[C:7](=[O:8])[C:6]([O:10][CH3:11])=[C:5]([O:12][CH3:13])[C:4](=[O:14])[C:3]=1/[CH:16]=[C:17](\[CH3:21])/[C:18]([OH:20])=[O:19]
Reactant: COc1c(Cl)c(/C=C(\C)C(=O)O)c(OC)c(OC)c1OC
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C(/C=C(\C)C(=O)O)=C(Cl)C1=O
Reaction time: 0.5 h
Yield: 23.3 %

Procedure:
Following a modified procedure of Flader et al.,22 22 (0.124 g, 0.391 mmol) was dissolved in acetonitrile (10.0 mL) at room temperature, then ceric ammonium nitrate (0.970 g, 1.77 mmol) dissolved in water (8.0 ml) was added at room temperature. The reaction was stirred for 30 minutes and then extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, filtered, and condensed. The red oil was then purified by either flash column chromatography (1:1 Et2O:hexanes 0.5% AcOH) or recrystallization from Et2O/hexanes to afford 23 (0.026 g, 0.091 mmol, 22%) as a red solid.
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([S:7][CH2:8][C:9](=O)[CH3:10])=[CH:3][CH:2]=1>ClC1C=CC=CC=1>[CH3:10][C:9]1[C:3]2[CH:2]=[C:1]([CH3:12])[CH:6]=[CH:5][C:4]=2[S:7][CH:8]=1
Reactant: CC(=O)CSc1ccc(C)cc1
Solvent: Clc1ccccc1
Product: Cc1ccc2scc(C)c2c1
Temperature: 25 °C
Yield: 112.9 %

Procedure:
A solution of 10 mL of polyphosphoric acid (PPA) in chlorobenzene (200 mL) was heated to reflux. To this solution 1-(p-tolylsulfanyl)-propan-2-one 5.0 g (20.3 mmol) was added in portions within 20 minutes. The resulting mixture was refluxed for 18 h and then cooled to room temperature. The organic phase was separated and concentrated under reduced pressure. The oily residue was purified by flash chromatography on silica gel (90:10 hexane/EtOAc) to give 3.72 g (81%) the title compound.