Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.[CH:18]([N:21]1[C:30]2[N:29]=[C:28]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C:41](O)=[O:42])=[C:36]4[C:40]=3[O:39][CH2:38][CH2:37]4)[N:27]=[CH:26][C:25]=2[N:24]([CH3:44])[C:23](=[O:45])[C@@H:22]1[CH2:46][CH3:47])([CH3:20])[CH3:19].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N>ClCCl>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C@@H:11]3[CH2:16][CH2:15][C@H:14]([NH:17][C:41]([C:35]4[CH:34]=[CH:33][C:32]([NH:31][C:28]5[N:27]=[CH:26][C:25]6[N:24]([CH3:44])[C:23](=[O:45])[C@H:22]([CH2:46][CH3:47])[N:21]([CH:18]([CH3:19])[CH3:20])[C:30]=6[N:29]=5)=[C:40]5[O:39][CH2:38][CH2:37][C:36]=45)=[O:42])[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[CH2:2][CH2:3]1
Reactant: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C(C)C
Reactant: N[C@H]1CC[C@@H](N2CCN(CC3CC3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)N[C@H]4CC[C@@H](N5CCN(CC6CC6)CC5)CC4)c4c3OCC4)nc2N1C(C)C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
(cis)-4-[4-(Cyclopropylmethyl)piperazin-1-yl]cyclohexanamine 12e (577 mg, 2.43 mmol), the crude compound 7-[[(7S)-8-isopropyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 43e (1 g, 2.43 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (780 mg, 2.43 mmol) and diisopropylethylamine (690 mg, 5.35 mmol) were dissolved in 60 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting mixture was added with 50 mL of aqueous ammonia and extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated brine (50 mL×3), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound N-[(cis)-4-[4-(cyclopropylmethyl)piperazin-1-yl]cyclohexyl]-7-[[(7S)-7-ethyl-8-isopropyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxamide 43 (1.12 g, yield: 74.6%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[N:52]1[CH:57]=[CH:56][CH:55]=[C:54]([CH2:58][NH2:59])[CH:53]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([NH:59][CH2:58][C:54]3[CH:53]=[N:52][CH:57]=[CH:56][CH:55]=3)=[O:21])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.2 %

Procedure:
To a solution of 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid (0.20 g, 0.67 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added 1-hydroxybenzotriazole (0.23 g, 1.73 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (0.17 g, 0.87 mmol), N,N-diisopropylethylamine (0.15 mL, 0.87 mmol) and pyridin-3-ylmethanamine (0.081 mL, 0.80 mmol). The reaction mixture was stirred at ambient temperature for 18 hours, diluted with ethyl acetate (15 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The obtained solid was washed with 5% ethyl acetate in hexanes and dried in air to afford the title compound as a white solid (0.16 g, 60%): mp 212-213° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 8.53 (br s, 1H), 7.98-7.95 (m, 1H), 7.73-7.66 (m, 1H), 7.43-7.22 (m, 6H), 6.28 (t, J=5.6 Hz, 1H), 5.55 (s, 2H), 4.61 (d, J=5.6 Hz, 2H), 2.67 (s, 3H); MS (ES+) m/z 391.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][CH2:28]OS(C)(=O)=O)[CH:22]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:28][CH2:27][C:23]2[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Reactant: CS(=O)(=O)OCCc1cccnc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1CCc1cccnc1
Yield: 63.2 %

Procedure:
Using General Procedure A: A solution of 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (0.219 g, 0.82 mmol), methanesulfonic acid 2-pyridin-3-yl-ethyl ester (approx. 3 mmol), KI (15 mg), and DIPEA (0.25 mL, 1.44 mmol) in DMF (3 mL was heated at 80° C. for 17 hours. Purification of the crude material by column chromatography on silica gel (CH2Cl2—CH3OH—NH4OH, 94:4:2) followed by radial chromatography on silica gel (1 mm plate, CH2Cl2—CH3OH—NH4OH, 50:1:1) provided 193 mg (63%) of COMPOUND 92 as a colorless oil. 1H NMR (CDCl3) δ 1.61-1.70 (m, 4H), 2.00-2.22 (m, 4H), 2.51 (s, 6H), 2.51-2.55 (m, 2H), 4.14-4.18 (m, 2H), 6.55-6.60 (m, 1H), 6.85 (dd, 1H, J=7.5, 4.8 Hz), 7.09-7.12 (m, 2H), 7.42 (d, 2H, J=6.9 Hz), 7.54-7.60 (m, 1H), 8.18 (dd, 1H, J=4.8, 1.5 Hz), 8.42-8.46 (m, 2H); 13C NMR (CDCl3) δ 17.59, 22.43, 24.32, 26.23, 28.85, 30.67, 47.26, 51.85, 63.52, 70.06, 121.05, 121.87, 131.24, 134.51, 137.16, 138.57, 145.34, 145.73, 148.78, 158.55; ES-MS m/z 373 (M+H). Anal. Calcd. for C24H28N4.0.3 H2O: C, 76.28; H, 7.63; N, 14.83. Found: C, 76.14; H, 7.78; N, 14.82.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[Br:8].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Br:8])[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Br)c(F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccc1Br
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3-Fluoro-4-bromotoluene (5.0 g, 27 mmol) in carbon tetrachloride (50 mL) was treated with N-bromosuccinimide (7.0 g, 40 mmol, 1.5 eq) and heated to 80° C. Benzoyl peroxide (65 mg, 0.27 mmol, 0.01 eq.) was added and heating was continued for 1 h. The reaction was then cooled to ambient temperature and filtered, and the filtercake was washed sparingly with chloroform. The filtrate was washed with water and brine, dried over Na2SO4, and concentrated to give crude 3-fluoro-4-bromobenzyl bromide as a clear oil which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([OH:28])=O)[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11].[CH3:30][N:31]([CH3:38])[CH:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH3:29])[C:10]([C:12]1[S:21][C:20]2[C:19]3[CH:22]=[C:23]([C:26]([N:35]4[CH2:36][CH2:37][CH:32]([N:31]([CH3:38])[CH3:30])[CH2:33][CH2:34]4)=[O:28])[CH:24]=[CH:25][C:18]=3[O:17][CH2:16][CH2:15][C:14]=2[CH:13]=1)=[O:11]
Reactant: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)O)ccc1OCC2)c1ccc(Cl)cc1Cl
Reactant: CN(C)C1CCNCC1
Product: CN(C(=O)c1cc2c(s1)-c1cc(C(=O)N3CCC(N(C)C)CC3)ccc1OCC2)c1ccc(Cl)cc1Cl

Procedure:
2-[(2,4-Dichloro-phenyl)-methyl-carbamoyl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid and 4-(dimethylamino)piperidine were reacted by General Procedure B to give 247. NMR: (CDCl3): 1.45-1.62 (2H, br m), 1.88-2.01 (2H, br, m), 2.39 (6H, s, Me), 2.50-2.61 (1H, br m), 2.82-3.10 (2H, br m), 3.07-3.09 (2H, m), 3.38 (3H, s, Me), 3.80-4.01 (1H, br m), 4.26-4.29 (2H, m), 4.58-4.79 (1H, br m), 6.85 (1H, s, Ar), 7.02 (1H, d, J 8.3, Ar), 7.25 (1H, dd, J 8.2 and 2.0, Ar), 7.28-7.32 (1H, m, Ar), 7.37-7.39 (1H, m, Ar), 7.55 (1H, s, Ar) and 7.60 (1H, s, Ar). MS: (ESI+) MH+=558.14
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[N:19]=[CH:20][N:21]=[C:22]3[S:39][C:25]4[C:26]5[C:30]([CH2:31][CH2:32][C:24]=4[C:23]=23)=[N:29][N:28]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH:27]=5)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[Cl:40][CH2:41][C:42](Cl)=[O:43].C(N(CC)CC)C>C(Cl)Cl.O>[Cl:40][CH2:41][C:42]([N:36]1[CH2:37][CH2:38][CH:33]([N:28]2[CH:27]=[C:26]3[C:30]([CH2:31][CH2:32][C:24]4[C:23]5=[C:18]([NH:17][C:4]6[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]7[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=7)=[C:2]([Cl:1])[CH:3]=6)[N:19]=[CH:20][N:21]=[C:22]5[S:39][C:25]=43)=[N:29]2)[CH2:34][CH2:35]1)=[O:43]
Reactant: O=C(Cl)CCl
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4sc5c(c34)CCc3nn(C4CCNCC4)cc3-5)cc2Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)N1CCC(n2cc3c(n2)CCc2c-3sc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a suspension of N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-2-piperidin-4-yl-4,5-dihydro-2H-pyrimido[5′,4′:4,5]thieno[2,3-e]indazol-6-amine 500 mg (0.89 mmol, 1 eq) in DCM (10 mL) was added chloroacetyl chloride (100 mg, 0.89 mmol, 1 eq) and triethylamine (90 mg, 0.89 mmol, 1 eq). It was stirred at rt for 3 h after which time it was diluted with water. It was then was extracted 3 times with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to yield the desired product (400 mg, 70%). 1H-NMR (DMSO-d6) δ 8.45 (broad, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.74 (d, 1H), 7.5 (dd, 1H), 7.44 (m, 1H), 7.29 (m, 2H), 7.20 (m, 2H), 5.23 (s, 2H), 4.45 (m, 4H), 3.93 (m, 1H), 3.38 (t, 2H), 3.24 (m, 1H), 2.92 (t, 2H), 2.83 (m, 1H), 2.08 (m, 2H), 1.97 (m, 1H), 1.80 (m, 1H). LCMS RT=3.68 min; [M+H]+=637.4.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:13]3[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=3[N:7]=[C:6]([CH3:16])[C:5]=2[C:4](=[O:17])[NH:3]1.Cl[CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH3:16][C:6]1[C:5]2[C:4](=[O:17])[N:3]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:2](=[O:1])[C:14]=2[C:13]2[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: Cc1ccc2nc(C)c3c(c2c1)C(=O)NC3=O
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(C)c3c(c2c1)C(=O)N(CCN1CCOCC1)C3=O

Procedure:
A mixture of 5 g (0.022 mole) of 1,3-dioxo-4,8-dimethyl-2H-pyrrolo[3,4-c]quinoline (vii) (also known as 2,6-dimethyl quinoline 3,4-dicarboximide), 4.65 g (0.025 mole) of N-(2-chloroethyl) morpholine, 6.9 g (0.05 mole) K2CO3, and 50 ml of dry DMF was stirred and heated at 50° for 18 hours. The dark mixture was poured into H2O with stirring and the solids filtered; yield, 6 g after drying in vacuo.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][NH:15][CH2:14][CH2:13][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1.Cl[C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=2)[CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C.O>C(O)CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH:11]3[CH2:16][N:15]([C:25]4[C:34]5[C:29](=[CH:30][CH:31]=[C:32]([O:35][CH3:36])[CH:33]=5)[CH:28]=[CH:27][N:26]=4)[CH2:14][CH2:13][N:12]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1Cc1ccc2c(c1)OCO2
Reactant: COc1ccc2ccnc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: OCCO
Solvent: O
Product: COc1ccc2ccnc(N3CCN(C(=O)OC(C)(C)C)C(Cc4ccc5c(c4)OCO5)C3)c2c1
Yield: 44 %

Procedure:
A mixture of 320 mg of 2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazine as synthesized in the above step, 200 mg of 1-chloro-7-methoxyisoquinoline and 100 mg of triethylamine was stirred in 2 ml of ethylene glycol at 150° C. for 18 hours. After addition of water, the solution was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography (ethyl acetate:n-hexane=1:1) to provide 210 mg (44%) of 1-(2-benzo[1,3]dioxol-5-ylmethyl-1-tert-butoxycarbonylpiperazin-4-yl)-7-methoxyisoquinoline.
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([O-:3])=[O:2].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.[C:27]([O:31][C:32](=[O:40])[N:33]([CH:35]([CH3:39])[CH2:36][CH2:37]Br)[CH3:34])([CH3:30])([CH3:29])[CH3:28]>O1CCCC1>[C:27]([O:31][C:32](=[O:40])[N:33]([CH3:34])[CH:35]([CH3:39])[CH2:36][CH2:37][CH:4]([N+:1]([O-:3])=[O:2])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:29])([CH3:30])[CH3:28]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: CC(CCBr)N(C)C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC(CCC(c1ccccc1)[N+](=O)[O-])N(C)C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 0.75 h
Yield: 28.1 %

Procedure:
To a −78° C. solution of 304 mg (2.219 mmol) nitromethyl-benzene (CAS: 622-42-4) in 5 ml tetrahydrofuran over mol-sieve and 1.29 ml HMPA, was added dropwise 2.91 ml (4.654 mmol) n-BuLi (1.6 M in hexane). After 45 minutes at −78° C., a solution of 590.7 mg (2.219 mmol) (3-bromo-1-methyl-propyl)-methyl-carbamic acid tert-butyl ester in 1.5 ml tetrahydrofuran over mol-sieve was added dropwise. After 1 hour at −78° C., the reaction mixture was allowed to warm up slowly, during 2 hours, to −15° C. The mixture was then cooled again to −78° C. and quenched with 0.75 ml of acetic acid, then with 13 ml saturated ammonium chloride. Back to room temperature, the aqueous phase was extracted two times with ethylacetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified on silica (Eluent: heptane/ethyl acetate 0 to 10%) to provide 201 mg (28%) of the title compound as a colorless oil. MS (m/e): 323.3 (M+H).
Reaction SMILES: [CH2:1]([C:3]1([C:11](Cl)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:10])[CH3:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CCOCC>[CH2:1]([C:3]1([C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[CH3:10])[CH3:2]
Reactant: CCC1(C(=O)Cl)CCCCCC1C
Reactant: C1COCCN1
Solvent: CCOCC
Product: CCC1(C(=O)N2CCOCC2)CCCCCC1C

Procedure:
1-Ethyl-2-methylcycloheptanecarbonyl chloride (1.5 g, 0.007 mole) in ether (10 ml.) was added slowly to a solution of morpholine (0.02 mole) in ether (10 ml.). The mixture was washed with dilute hydrochloric acid, dilute sodium bicarbonate and then with water. The ether layer was dried and distilled to give N-(1-ethyl-2-methylcycloheptanecarbonyl) morpholine bp. 145°-7°/0.35 mm.
Reaction SMILES: CS([O:5][C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]([F:15])([F:14])[CH3:13])[CH2:8][CH2:7]1)(=O)=O.O[C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([CH2:27][N:28]1[CH2:31][CH:30]([C:32]([O:34]C)=[O:33])[CH2:29]1)[CH:21]=[CH:20]2.C([O-])([O-])=O.[Cs+].[Cs+].Cl>C(O)(C)(C)C.CC(=O)CC>[F:14][C:12]([C@H:9]1[CH2:10][CH2:11][C@H:6]([O:5][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[CH:23]=[C:22]([CH2:27][N:28]2[CH2:29][CH:30]([C:32]([OH:34])=[O:33])[CH2:31]2)[CH:21]=[CH:20]3)[CH2:7][CH2:8]1)([F:15])[CH3:13]
Reactant: COC(=O)C1CN(Cc2ccc3cc(O)ccc3c2)C1
Reactant: CC(F)(F)[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: CC(C)(C)O
Product: CC(F)(F)[C@H]1CC[C@H](Oc2ccc3cc(CN4CC(C(=O)O)C4)ccc3c2)CC1
Temperature: 110 °C
Reaction time: 16 h

Procedure:
(trans)-4-(1,1-difluoroethyl)cyclohexyl methanesulfonate (WO 2010051030) (0.98 mmol, 236 mg, 1.0 eq.), methyl 1-((6-hydroxynaphthalen-2-yl)methyl)azetidine-3-carboxylate (1.17 mmol, 317 mg, 1.2 mmol) and Cs2CO3 (4.41 mmol, 1.4 g, 4.5 eq.) were dissolved in t-butanol (4 mL) and 2-butanone (2 mL). The mixture was stirred at 110° C. for 16 h. 1 M aq. HCl solution was added to the mixture to adjust pH=6. Then the mixture was extracted with EtOAc. The organic layer was purified by silica gel column chromatography using DCM/CH3OH (10/1) as eluent to give product (7 mg, 1.8%) as a white solid. ESI-MS (M+1)+: 404.1. HPLC: 89.46%. 1H NMR (400 MHz, CD3OD) δ: 7.89 (s, 1H), 7.86-7.81 (m, 2H), 7.46 (dd, 1H), 7.31 (s, 1H), 7.19 (dd, 1H), 4.47 (s, 2H), 4.43-4.41 (m, 1H), 4.21 (d, 4H), 3.45-3.41 (m, 1H), 2.32-2.30 (m, 2H), 2.02-1.99 (m, 2H), 1.64-1.54 (m, 3H), 1.51-1.45 (m, 3H), 1.36-1.28 (m, 2H).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C1(N(C)C)C=CC=CC=1.C([O:21][CH2:22][C@@H:23]([NH:39][S:40]([C:43]1[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([Cl:50])[CH:44]=1)(=[O:42])=[O:41])[C:24]1[N:28]([CH2:29][CH3:30])[C:27]([O:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)=[N:26][N:25]=1)C1C=CC=CC=1.CCOC(C)=O>C(Cl)Cl>[Cl:50][C:45]1[CH:44]=[C:43]([S:40]([NH:39][C@@H:23]([C:24]2[N:28]([CH2:29][CH3:30])[C:27]([O:31][C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)=[N:26][N:25]=2)[CH2:22][OH:21])(=[O:41])=[O:42])[CH:48]=[CH:47][C:46]=1[Cl:49]
Reactant: CCn1c(Oc2ccc(F)cc2)nnc1[C@@H](COCc1ccccc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: CCn1c(Oc2ccc(F)cc2)nnc1[C@@H](CO)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
AlCl3 (49 mg) and PhNMe2 (148 mg) were added to a solution of the compound (69 mg) of Example 23 in CH2Cl2 (2.0 ml), and the mixture was stirred at room temperature for one hour. Then, AcOEt was added, and the mixture was washed with 1N hydrochloric acid and thereafter with saturated aqueous sodium chloride. The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to remove the solvent. Then, the resulting crude product was purified by column chromatography (OH SiO2, AcOEt/hexane=2/1) to give 54 mg of the titled compound (Compound 696) as a colorless powder.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[N:10](CC2C=CC(OC)=CC=2)[C:9]1=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce].[NH4+].C(OCC)(=O)C>C(#N)C.O>[CH2:1]([N:8]1[C:12]([CH3:14])([CH3:13])[C:11](=[O:15])[NH:10][C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN2C(=O)N(Cc3ccccc3)C(C)(C)C2=O)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC1(C)C(=O)NC(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
A solution of 3-benzyl-1-(4′-methoxybenzyl)-2,5-dioxo-4,4-dimethylimidazolidine (3.9 g, 11.54 mmol) in acetonitrile (100 mL) was treated with a solution of ammonium cerium nitrate (31 g, 57.7 mmol) in 65 mL of water, stirred at 25° C. for 15 minute, then diluted the reaction with ethyl acetate and partitioned between ethyl acetate and brine. The organic layer was dried, filtered, and concentrated. Purification by recrystalization with ethyl acetate/hexane provided 1.58 g (7.25 mmol, 63%) of title compound as white solid. MS (DCI/NH3) m/e 236 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[CH3:17][N:18]([CH3:28])[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](Cl)=[O:23].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([C:22](=[O:23])[C:21]2[CH:25]=[CH:26][CH:27]=[C:19]([N:18]([CH3:17])[CH3:28])[CH:20]=2)[CH2:15][CH:16]=1
Reactant: CN(C)c1cccc(C(=O)Cl)c1
Reactant: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)N2CC=C(c3c[nH]c4ccc(Cl)cc34)CC2)c1
Yield: 95 %

Procedure:
A mixture of 5-chloro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.53 g, 2.3 mmol) (Eur. J. Med. Chem., 1987, 22, 33-43) and 3-(dimethylamino)benzoyl chloride (0.5 g, 2.3 mmol) (Chem. Pharm. Bull., 1980, 28, 2045-2051) in tetrahydrofuran was stirred and treated with triethylamine (0.64 mL, 2 eq). The mixture was stirred for 2 h, treated with aqueous sodium bicarbonate (50 mL) and extracted with ethyl acetate. The organic phase was washed with brine and dried (Na2SO4) to give the title compound (0.83 g).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+].C(Cl)[Cl:38]>>[ClH:38].[ClH:38].[CH3:1][C:2]1[C:3]2[CH:24]=[CH:23][CH:22]=[CH:21][C:4]=2[S:5][C:6]=1[CH2:7][N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: Cc1c(CN2CCN(C(=O)OC(C)(C)C)CC2)sc2ccccc12
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCNCC2)sc2ccccc12
Product: Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The title A compound, t-butyl 4-((3-methylbenzo[b]thiophen-2-yl)methyl)piperazine-1-carboxylate is dissolved in dry DCM (50 mL), and 5 equiv. of TFA are added at 0° C. The reaction mixture is stirred at RT for 3 h. After the solvent is evaporated in vacuo, the residue is trituated in Et2O, and the precipitate that forms is collected by filtration, washed with EtOH and dried in a vacuum oven at 40° C. overnight to give a hygroscopic solid. The solid is treated with sodium bicarbonate solution, and extracted with EtOAc. The organic layer is evaporated in vacuo, and the residue is dissolved in Et2O and treated with a solution of hydrochloric acid in Et2O. The precipitated solid is collected by filtration and dried to give 1-((3-methylbenzo [b]thiophen-2-yl)methyl)piperazine dihydrochloride: LC/MS (M+1=247.1). 1H NMR (DMSO-d6, 200 MHz) δ 2.48 (s, 3H), 3.39 (m, 4H), 3.54 (m, 4H), 4.63 (s, 2H), 7.45 (m, 2H), 7.84 (d, 1H, J=7.2 Hz), 7.95 (d, 1H, J=7.2 Hz), 9.52 (br s, NH). Anal. calculated for (C14H18N2S 2HCl): C, 52.66; H, 6.31; Cl, 22.21; N, 8.77; S, 10.04. Found: C, 52.70; H, 6.58; N, 8.77; S, 9.70.
Reaction SMILES: C[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.[CH3:10][N:11]1[CH:15]2[CH2:16][C:17]([CH2:19][CH:12]1[CH2:13][CH2:14]2)=O.[CH3:20]O>C1(C)C=CC=CC=1.ClCCl>[CH3:20][CH:19]1[C@H:12]2[N:11]([CH3:10])[C@H:15]([CH2:14][CH2:13]2)[C:16](=[N:7][CH2:6][C:5]2[CH:4]=[CH:3][CH:2]=[CH:9][CH:8]=2)[CH2:17]1
Reactant: CO
Reactant: CN1C2CCC1CC(=O)C2
Reactant: Cc1ccc(CN)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC1CC(=NCc2ccccc2)[C@H]2CC[C@@H]1N2C

Procedure:
4-Methylbenzylamine (1.21 g, 10 mmol) and Tropinone (1.39 g, 10 mmol) were placed in 100 ml flask and dissolved in 50 ml toluene. Mixture was heated to reflux for 3 hrs and water was removed using a Dean/Stark water-separator. Crude product was concentrated on Rotavapor (40° C.) giving 47AKU-38. TLC (10% methanol in dichloromethane): Rf=0.3. 1H-NMR (400 MHz, CDCl3, isomers): 7.20-7.09 (4H, m); 4.47 (1H, m); 3.81 (1H, s); 3.42 (1H, m); 3.31 (1H, m); 2.77-2.56 (2H, m); 2.47 and 2.41 (3H, 2s); 2.33 and 2.31 (3H, 2s); 2.27-1.97 (4H, m); 1.69-1.54 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:32]([O-:34])=[O:33])[CH:28]=3)[NH:23][C:22]2=[O:35])[CH2:17][CH2:16]1.[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39]Br>>[Cl:36][C:37]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:45])[C:38]=1[CH2:39][N:23]1[C:24]2[C:29](=[CH:28][C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=2)[C:30](=[O:31])[N:21]([CH:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)[C:22]1=[O:35]
Reactant: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Reactant: Clc1cccc(Cl)c1CBr
Product: COc1cc2ncnc(N3CCC(n4c(=O)c5cc([N+](=O)[O-])ccc5n(Cc5c(Cl)cccc5Cl)c4=O)CC3)c2cc1OC
Yield: 29 %

Procedure:
The procedure similar to that described in Example 1 was repeated, except that 300 mg (0.63 mmol) of Compound 24 was used and 2,6-dichlorobenzyl bromide was used in place of methyl iodide. As a result, 117.1 mg (yield: 29%) of Compound 10 was obtained as pale yellow crystals.