Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N12CCCN=C1CCCCC2.CS(O[CH:17]1[CH2:23][CH:22]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]2)[CH:18]1[C:32]([O:34][CH3:35])=[O:33])(=O)=O>CN(C=O)C>[CH:19]12[N:24]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH:22]([CH2:21][CH2:20]1)[CH2:23][CH:17]=[C:18]2[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)C1C(OS(C)(=O)=O)CC2CCC1N2C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C1=CCC2CCC1N2C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 64 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (8.05 g, 53 mmol) was added into a solution of 8-tert-butyl 2-methyl 3-(methylsulfonyloxy)-8-azabicyclo[3.2.1]octane-2,8-dicarboxylate (5.29 mmol) in DMF at room temperature and the reaction solution was heated at 100° C. for 16 h. The resulting solution was concentrated and purified using flash chromatography (0-60% ethyl acetate in hexane) to give the titled compound (905 mg, yield 64% for three steps).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([CH:17]=1)[CH:15]=[CH:14][CH:13]=[CH:12]2.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([C:17]=1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)=[O:26])[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc2ccccn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc2ccccn2c1C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 74.8 %

Procedure:
4.54 ml (32.52 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 3.56 g (27.14 mmoles) of 2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 5.53 g (29.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 18 h at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 5.69 g of a yellow solid are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=O.[NH2:11][OH:12].Cl>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[N:11][OH:12]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(Cl)c(Cl)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
3,4-Dichlorobenzaldehyde (1 eq) and hydroxylamine.HCl (4 eq) were suspended in pyridine (10 vol) in a sealed tube. The reaction mixture was stirred at 50° C. overnight under an atmosphere of N2. The reaction mixture was concentrated in vacuo before the addition of EtOAc (10 vol) and 2M citric acid solution (5 vol). The organic layer was separated and washed with citric acid (2×5 vol) and saturated aqueous NaCl solution (5 vol). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield required 3,4-dichloro-benzaldehyde oxime.
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].Cl[CH:25]([O:27][C:28]([CH:30]1[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH:30]1([C:28]([O:27][CH:25]([O:14][C:4]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=3[S:11](=[O:13])(=[O:12])[N:2]([CH3:1])[C:3]=2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=2)=[O:16])[CH3:26])=[O:29])[CH2:32][CH2:31]1
Reactant: CC(Cl)OC(=O)C1CC1
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Product: CC(OC(=O)C1CC1)OC1=C(C(=O)Nc2ccccn2)N(C)S(=O)(=O)c2ccccc21

Procedure:
By the procedure of Example 6, piroxicam (3.00 g, 9.1 mmol) and cyclopropanecarboxylic acid alpha-chloroethyl ester (4.03 g, 27.2 mmol) were converted to title product, 3.51 g white foam (7.0 mmol, 87.3%) which gave 1.90 g white crystals from toluene; mp 176°-177° C.; IR (KBr) 1735, 1680 cm-1 ; 1H NMR (CDCl3) delta 0.70-0.97 (m, 4H), 1.37-1.50 (m, 1H), 1.72 (d, J=6 Hz, 3H), 3.11 (s, 3H), 6.40 (q, J=6 Hz, 1H), 7.07-7.17 (m, 1H), 7.63.7.97 (m, 5H), 8.29-8.42 (m, 2H), 9.54 (br s, 1H); precise mass calcd for C21H22N3O6S m/e (P+ +H) 444.1235, found 444.1013.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.Cl.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]2[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH:19]=[CH:20][CH:21]=1.C(N(CC)CC)C>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:24]1[CH2:25][CH2:26][CH2:27][CH:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([O:15][CH3:14])[CH:17]=2)[CH2:23]1
Reactant: BrCC1COc2ccccc2O1
Reactant: COc1cccc(C2CCCNC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1cccc(C2CCCN(CC3COc4ccccc4O3)C2)c1
Temperature: 145 °C
Yield: 31.3 %

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (36 mg, 0.16 mmol), 3-(3-methoxyphenyl)piperidine HCl (36 mg, 0.16 mmol) and triethylamine (40 mg, 0.39 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 140-150° C. for 300 min. After evaporation to dryness, the crude product was purified by flash chromatography using a gradient of heptane and EtOAc as eluent to give 17 mg of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[Cl:33][C:34]1[CH:44]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:42]=[CH:41][C:35]=1[O:36][CH2:37][C:38]([OH:40])=O.[Cl:49][C:50]1[CH:51]=[C:52]([NH:64][CH3:65])[CH:53]=[CH:54][C:55]=1[O:56][CH2:57][CH2:58][N:59]([CH2:62][CH3:63])[CH2:60][CH3:61].C(N(C(C)C)C(C)C)C>C1COCC1>[Cl:49][C:50]1[CH:51]=[C:52]([N:64]([CH3:65])[C:38](=[O:40])[CH2:37][O:36][C:35]2[CH:41]=[CH:42][C:43]([C:45]([F:48])([F:47])[F:46])=[CH:44][C:34]=2[Cl:33])[CH:53]=[CH:54][C:55]=1[O:56][CH2:57][CH2:58][N:59]([CH2:62][CH3:63])[CH2:60][CH3:61]
Reactant: CCN(CC)CCOc1ccc(NC)cc1Cl
Reactant: O=C(O)COc1ccc(C(F)(F)F)cc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCOc1ccc(N(C)C(=O)COc2ccc(C(F)(F)F)cc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h

Procedure:
293 mg (0.911 mmol) of TBTU and 123 mg (0.911 mmol) of HOBT were added to a suspension of 231 mg (0.911 mmol) of (2-chloro-4-trifluoromethyl-phenoxy)-acetic acid (intermediate product Z2b) in 5 mL abs. THF and the mixture was stirred for 10 minutes at RT. 180 mg (0.701 mmol) of [3-chloro-4-(2-diethylamino-ethoxy)-phenyl]-methyl-amine and 0.18 mL (1.051 mmol) of ethyl-diisopropylamine were added, the mixture was stirred for 16 hours at RT and evaporated down i. vac. The residue was purified by column chromatography (silica gel, silica gel, dichloromethane/MeOH/conc. aqueous ammonia 85:15:1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[CH2:10][CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+].O>S(=O)(=O)(O)O>[CH2:10]([C:3]1[C:4]([F:9])=[C:5]([N+:12]([O-:14])=[O:13])[CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:11]
Reactant: CCc1c(F)ccc(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: CCc1c(F)c(F)cc([N+](=O)[O-])c1F
Yield: 81.6 %

Procedure:
2,3,6-Trifluoro-1-ethylbenzene (1.09 g) is dissolved in conc. sulfuric acid (5.5 ml), and thereto is added with stirring a mixture of potassium nitrate (0.83 g) in conc. sulfuric acid (4 ml) at room temperature, and the mixture is stirred at the same temperature for one hour. The reaction mixture is poured into cold water (100 ml) and is extracted with diethyl ether. The ether layer is washed with aqueous saturated sodium chloride and dried over magnesium sulfate and then concentrated under reduced pressure to give 3-ethyl-2,4,5-trifluoro-nitrobenzene (1.14 g), as yellow oil.
Reaction SMILES: CO[C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][C:11](=[O:23])[N:12]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:24]#[N:25])[N:6]=1)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>>[CH2:16]([N:12]1[C:13]2[C:8](=[C:7]([C:24]#[N:25])[N:6]=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[C:14]=2[OH:15])[CH:9]=[CH:10][C:11]1=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1nc(C#N)c2ccc(=O)n(Cc3ccccc3)c2c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c1ccc(=O)n2Cc1ccccc1
Temperature: 25 °C
Yield: 66.1 %

Procedure:
A mixture of 1-benzyl-5-cyano-8-hydroxy-2-oxo-1,2-dihydro-[1,6]naphthyridine-7-carboxylic acid methyl ester (20 mg, 0.060 mmol), glycine (448 mg, 6.0 mmol) and NaOMe solution (9.6 mL, 4.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH about 2. The organic layer was dried over MgSO4 and concentrated. The residue was taken up in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2 with 4 M HCl, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a pale pink solid. MS: (−) m/z 377.31 (M−1).
Reaction SMILES: [C:1]([C:5]1[NH:6][C:7](=[O:21])[C:8]2([N:20]=1)[CH2:16][C:15]1[C:10](=[CH:11][CH:12]=[C:13]([N+:17]([O-])=O)[CH:14]=1)[CH2:9]2)([CH3:4])([CH3:3])[CH3:2].CC(C)(C)C(NC1(C(N)=O)CC2C(=CC=C([N+]([O-])=O)C=2)C1)=O.[OH-].[Na+].[NH4+].[Cl-]>CCO>[NH2:17][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8]1([C:7](=[O:21])[NH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:20]1)[CH2:16]2
Reactant: CC(C)(C)C1=NC2(Cc3ccc([N+](=O)[O-])cc3C2)C(=O)N1
Agent: CC(C)(C)C(=O)NC1(C(N)=O)Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)(C)C1=NC2(Cc3ccc(N)cc3C2)C(=O)N1

Procedure:
(±)-2-tert-Butyl-5′-nitro-1′,3′-dihydrospiro[imidazole-4,2′-inden]-5(1H)-one A solution of (±)-2-[(2,2-dimethylpropanoyl)amino]-5-nitroindane-2-carboxamide from Step A (23.0 mg, 0.075 mmol) and 5N NaOH (0.075 mL, 0.38 mmol) in EtOH (5 mL) was heated to reflux for 3.5 h. The reaction mixture was poured onto saturated NH4Cl (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the title compound. MS: m/z=288 (M+1).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[C:8]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:7]=1)[C:3](=O)[CH3:4].[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:2]2[S:19][C:18]([NH2:20])=[N:17][C:3]=2[CH3:4])=[CH:7][C:8]=1[S:13]([CH3:16])(=[O:15])=[O:14]
Reactant: NC(N)=S
Reactant: CC(=O)C(Br)c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: CCO
Product: Cc1nc(N)sc1-c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
1-bromo-1-(4-chloro-3-methanesulfonyl-phenyl)-propan-2-one (480 mg 1.5 mmol) and thiourea (114 mg 1.5 mmol) were combined in ethanol (12 ml) and heated to 70° C. for 2 hours. The reaction mixture was allowed to cool to room temperature and the solid product was collected by filtration and dried under vacuum to yield 5-(4-chloro-3-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine as an off-white solid (375 mg). 1H NMR (400 MHz DMSO-d6) δ 9.4 (br s, 2H), 8.0 (d, 1H), 7.9 (d, 1H), 7.8 (dd, 1H), 3.4 (s, 3H), 2.3 (s, 3H).
Reaction SMILES: [CH2:1]([N:9]1[C:17]([C:18](OC)=[O:19])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:22])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:9]1[C:17]([CH2:18][OH:19])=[N:16][C:15]2[C:10]1=[N:11][CH:12]=[N:13][C:14]=2[NH2:22])[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1nc2c(N)ncnc2n1CCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1ncnc2c1nc(CO)n2CCc1ccccc1

Procedure:
A solution of N9-phenethyl-8-methoxycarbonyladenine (1 mmol) in tetrahydrofuran was treated with lithium aluminum hydride (1 mmol) at 0° C. for 1 h. Extraction and chromatography gave N9-phenethyl-8-hydroxymethyl-adenine as a white solid. TLC: Rf=0.31, 10% MeOH—CH2Cl2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](I)=[C:6]([O:11][CH2:12][C:13]([CH3:15])=[CH2:14])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[C:13]([CH2:15][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)([CH3:14])[CH2:12][O:11][C:6]=2[CH:5]=1)=[O:16]
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1I
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)OCC2(C)Cc1ccccc1
Temperature: 115 °C
Reaction time: 3 h
Yield: 95.1 %

Procedure:
To a solution of 4-Iodo-3-(2-methyl-allyloxy)-benzoic acid methyl ester (455 mg, 1.37 mmol) obtained in Example 4(A), in DMF (15 mL) were added Potassium carbonate (379 mg, 2.74 mmol), Tetrabutylammonium chloride (380 mg, 1.37 mmol), Palladium acetate (25.6 mg, 0.136 mmol) in DMF (5 mL) and Phenylboronic acid (200 mg, 1.64 mmol). The resulting mixture was stirred for 3 h at 115° C., cooled to room temperature, filtered over silica, washed with water, dried over MgSO4 and concentrated. Column chromatography (silica gel, heptane/CH2Cl2: 4/6) afforded 368 mg (95%) of the title compound as a slightly brown oil which crystallize. Mp: 52° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:15][CH2:14][C@:13]1([F:16])[C:12](=O)[N:11]([C@@H:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:19])[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)C.O.C(N(CC)CC)C>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:15][CH2:14][C@@:13]1([F:16])[CH2:12][N:11]([C@@H:18]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH3:19])[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(NC(=O)OC(C)(C)C)CC[C@]2(F)C1=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: C[C@H](c1ccccc1)N1C[C@]2(F)CC[C@@]2(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
A 1.16 M solution of a borane-tetrahydrofuran complex in tetrahydrofuran (6.0 mL) was added dropwise to a solution of (1R,5R)-1-(tert-butoxycarbonylamino)-5-fluoro-4-oxo-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.2.0]heptane (811 mg, 2.33 mmol) in tetrahydrofuran (6.0 mL) at 0° C. over five minutes. The mixture was heated to room temperature, stirred for five hours, and then cooled to −10° C. A mixture of ethanol (9.0 mL)-water (1.0 mL) was carefully added dropwise. After addition of triethylamine (3.0 mL) dropwise, the mixture was heated to reflux for one hour. The reaction solution was concentrated, and the precipitated white solid was removed by filtration through Celite. The filtrate was concentrated, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give 530 mg (68%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[O:11]=[C:8]1[CH2:7][C:6]2[C:10](=[C:2]([NH:1][C:12](=[O:14])[CH3:13])[CH:3]=[CH:4][CH:5]=2)[NH:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1NC(=O)C2
Product: CC(=O)Nc1cccc2c1NC(=O)C2
Yield: 79.8 %

Procedure:
According to the method described in example A48a, 7-aminoindolin-2-one (80 mg, 0.54) was reacted with acetic anhydride (66 mg, 0.65 mmol) to give the title compound as a white solid (82 mg, 80%). 1H NMR (400 MHz, CD3OD) δ 7.13 (d, 2H, J=8 Hz), 6.99 (t, 1H, J=8 Hz), 3.57 (s, 2H), 2.16 (s, 3H). MS ESI [M+H]+, calcd for [C10H10N2O2+H]+ 191.08; found m/z 191.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:2]1.Cl.[Cl:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH2:24][CH:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:17].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH:23]([C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:22]3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COc1ccc(C2CCCN(CCCCl)C2)cc1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C2CCCN(CCCN3CCC(c4c[nH]c5ccccc45)CC3)C2)cc1
Yield: 98.3 %

Procedure:
To a suspended solution of 4-(3-indolyl)piperidine (48 mg, 0.24 mmol) and 1-(3-chloropropyl)-3-(4-methoxyphenyl)piperidine hydrochloride (61 mg, 0.2 mmol) in acetonitrile (13 mL) was added potassium carbonate (111 mg, 0.8 mmol), and the resulting mixture was refluxed for 12 hours. After the precipitated salt was filtered off, the filtrate was concentrated, and the resulting crude product was purified by column chromatography on a silica gel (eluent; chloroform:ammonia-saturated chloroform=10:1→3:1→1:2) to afford a free form (92 mg) of the title compound as a colorless viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then freeze-dried to afford the title compound (81 mg, yield: 80%) as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].CN(C=O)C.O1CCOCC1.[Br:23][CH2:24][C:25](Br)=[O:26]>O>[Cl:11][C:7]1[C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:1][C:25](=[O:26])[CH2:24][Br:23])[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: O=C(Br)CBr
Solvent: O
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 30 %

Procedure:
A solution of 2-amino-6-chlorobenzoic acid (10 g, 0.06 mol), anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) was cooled to 0° C. in 300 mL 3-necked flask fitted with a magnetic stirrer and constant additional funnel. Bromoacetyl bromide was added dropwise over a 20-25 min period keeping the internal temperature between 0° to 1° C. After the addition was completed, the solution was allowed to warm to room temperature and stirring was continued for 20 h. The reaction mixture was cooled in an ice-bath and diluted with water (150 mL) The resulting yellow crystalline product was filtered, washed sequentially with 5% HBr solution (50 mL), water (50 mL), and then dried in vacuum oven (20 h, 40-45° C.) to afford 5 g (30%) of the title compound, mp 133-135° C. (decomp.); 1H NMR (CD3OD) δ 7.70 (d, 1H, J=8), 7.43 (t, 1H, J=8.4), 7.35 (d, 1H, J=8), 4.05 (s, 2H); 13C NMR (CD3OD) δ 168.19, 167.84, 137.24, 133.31, 132.85, 132.08, 128.78, 128.21, 124.20, 29.21; MS (EI, m/z) 293 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21].N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:16][C:17]3[CH:18]=[C:19]([CH:25]=[CH:26][CH:27]=3)[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Br)cc12
Reactant: CCOC(=O)c1cccc(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(NS(=O)(=O)c2sc3ccc(Br)cc3c2C)c1
Yield: 35.9 %

Procedure:
A solution of 5-bromo-3-methyl-benzothiophene-2-sulfonyl chloride (Intermediate 10) (1.00 g, 3.26 mmol), ethyl 3-aminobenzoate (550 mg, 3.33.mmol) and pyridine (3 mL) in CH2Cl2 (150 mL) was stirred at room temperature overnight. The reaction was diluted with CH2Cl2, washed with water and aqueous HCl, dried and concentrated. The residue was purified on silica, using CH2Cl2 as eluent, resulting in 532 mg (36%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.34 (t, J=7.09 Hz, 3 H) 2.44 (s, 3 H) 4.34 (q, J=7.09 Hz, 2 H) 6.85 (s, 1H) 7.36 (dd, J=8.03, 7.62 Hz, 1 H) 7.43 (ddd, J=8.03, 2.26, 1.25 Hz, 1 H) 7.57 (dd, J=8.66, 1.88 Hz, 1 H) 7.65 (dd, J=8.66, 0.50 Hz, 1 H) 7.72 (dd, J=2.26, 1.63 Hz, 1 H) 7.84 (ddd, J=7.62, 1.63, 1.25 Hz, 1 H) 7.87 (dd, J=1.88, 0.50 Hz, 1 H). MS (ESI+) m/z 454 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]([NH2:8])=O)=[CH:4][N:3]=1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][CH:12]([CH3:14])[CH3:13])[C:5]([C:6]#[N:8])=[CH:4][N:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1C#N
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-4-(isopropylamino)nicotinamide (17) (2.5 g, 11.7 mmol) in DMF (10 mL), cyanuric chloride (11.7 mmol, 1 equiv.) was added at 0° C. and stirred for 2 h. The reaction mixture was quenched with ice-cool water and extracted twice using EtOAc. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The crude material was purified by column chromatography, silica gel (60-120 mesh) and EtOAc:pet Ether as eluent to furnish 6-chloro-4-(isopropylamino)nicotinonitrile. 1H NMR: 400 MHz, CDCl3: δ 1.32 (d, J=6.40 Hz, 6H), 3.69-3.79 (m, 1H), 4.91 (bs, 1H), 6.57 (s, 1H), 8.23 (s, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:24][CH:16]([C:17]4[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(N(CC)CC)C>CN1CCCC1=O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]2[CH:16]3[CH2:24][C:9]([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:26]5[N:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:3][CH2:4]4)([C:10]4[C:15]3=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:22]=2[CH:21]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reactant: Clc1ncccn1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: Clc1ccc2c(c1)C1(CN3CCC(Nc4ncccn4)CC3)CC2c2ccccc21

Procedure:
4-amino-1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)piperidine (0.500 g, 1.48 mmol, prepared as described in Example 7b) was heated to 100° C. for 5 hours in 1.5 mL N-methylpyrrolidinone with 2-chloropyrimidine (0.212 g, 1.85 mmol, commercial grade purified by extraction into petroleum ether) and triethylamine (0.300 g, 29.6 mmol) under a nitrogen atmosphere. Aqueous method (3 mL, 50% v/v) was added to the warm (50° C.) reaction mixture to give a white precipitate. The solid was collected by filtration and washed with fresh aqueous methanol (5 mL, 50% v/v) to give the title compound as a white solid. The solid was dissolved in methanolic hydrogen chloride, evaporated to dryness on a rotary evaporator, redissolved in a minimum volume of fresh methanol (2 mL) and added at a slow dropwise rate to rapidly stirring ethyl ether (80 mL) to precipitate the hydrochloride salt as a white solid (0.414 g, 0.99 mmol, 67%), mp 212°-214° C.; MS(CI) 417 (M+H); NMR (250 MHz, DMSO-d6): 10.17(br s, 1H), 8.38-8.33(m, 2H), 7.67(br m, 1H), 7.52-7.49(m, 1H, 7.38-7.31(m, 3H), 7.05-6.96(m, 3H), 6.70-6.63(m, 1H), 4.47(s, 1H), 4.35-4.29(m, 2H), 4.16(br m, 1H), 3.57-3.36(m, 4H), 2.76(m, 2H), 2.12-1.90 (m, 4H).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.C1C(=O)N([Cl:19])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Cl:19][C:3]1[C:4]2[C:5]([C:10]#[N:11])=[CH:6][CH:7]=[CH:8][C:9]=2[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cccc2[nH]ccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cccc2[nH]cc(Cl)c12
Temperature: 25 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
To 1H-indole-4-carbonitrile (514.0 mg, 3.61 mmol) in anhydrous DMF (2.8 mL) at 0° C. was added dropwise NCS (517.3 mg, 3.80 mmol) dissolved in DMF (8.5 mL). The reaction mixture was slowly warmed to RT. After stirring for 20 h, the mixture was diluted with EtOAc. The organic layer was washed with satd. aq. NaHCO3 solution, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with heptane:EtOAc to afford 3-chloro-1H-indole-4-carbonitrile as a white solid (630 mg, 98.7%). MS (ESI) m/z: 177.1 [M+1]+. 1H NMR (400 MHz, DMSO) 11.99 (br s, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.78 (d, J=8.2 Hz, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.37-7.26 (m, 1H).