Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:20]([O-:22])=O)[C:8]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[CH2:16][CH2:15][CH2:14]3)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[C:37](=[O:38])[N:26]2[CH:27]([C:32]3[NH:36][N:35]=[N:34][N:33]=3)[C:28]([CH3:31])([CH3:30])[S:29][C@H:25]12>>[CH2:15]1[C:14]2[C:13](=[CH:12][C:11]([O:10][C:8]([CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:20]([NH:23][CH:24]3[C:37](=[O:38])[N:26]4[CH:27]([C:32]5[NH:33][N:34]=[N:35][N:36]=5)[C:28]([CH3:30])([CH3:31])[S:29][C@H:25]34)=[O:22])=[O:9])=[CH:19][CH:18]=2)[CH2:17][CH2:16]1
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Reactant: O=C([O-])C(C(=O)Oc1ccc2c(c1)CCC2)c1ccccc1
Product: CC1(C)S[C@@H]2C(NC(=O)C(C(=O)Oc3ccc4c(c3)CCC4)c3ccccc3)C(=O)N2C1c1nnn[nH]1
Yield: 63 %

Procedure:
(2.0 mmole) of 5-indanyl 2-phenylmalonate with 480 mg. (2.0 mmole) of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam, according to the procedure of Example CXLVII affords 680 mg. (63% yield) of 6-(2-[5-indanyloxycarbonyl]-2-phenylacetamido)-2,2-dimethyl-3-(5-tetrazolyl)penam as its sodium salt. The infrared spectrum (KBr disc) of the product shows absorption bands at 1780 cm-1 (β-lactam), 1705 cm-1 (ester), 1680 cm-1 (amide I) and 1565 cm-1 (amide II). The NMR spectrum (D2O) shows absorption bands at 7.80-6.80 ppm (multiplet, aromatic hydrogens), 5.70 ppm (multiplet, C-5 and C-6 hydrogens), 5.25 ppm (doublet, C-3 hydrogen), 2.60-2.00 ppm (multiplet, C-1 and C-3 indanyl hydrogens), 2.00-1.80 ppm (multiplet, C-2 indanyl hydrogens), 1.35 ppm (doublet, C-2 methyl hydrogens) and 0.90 ppm (doublet C-2 methyl hydrogens).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:20]4[CH:21]=[CH:22][C:23]5[N:24](S(C6C=CC=CC=6)(=O)=O)[C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][C:28]([N:33]4[C:45]5[CH:44]=[CH:43][C:42]([C:46]7[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=7)=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)=[CH:27][CH:26]=6)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl>CS(C)=O.O>[C:46]1([C:42]2[CH:43]=[CH:44][C:45]3[N:33]([C:28]4[CH:27]=[CH:26][C:25]5[NH:24][C:23]6[C:31]([C:30]=5[CH:29]=4)=[CH:32][C:20]([N:11]4[C:10]5[CH:9]=[CH:8][C:7]([C:1]7[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=7)=[CH:19][C:18]=5[C:17]5[C:12]4=[CH:13][CH:14]=[CH:15][CH:16]=5)=[CH:21][CH:22]=6)[C:34]4[C:39]([C:40]=3[CH:41]=2)=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: O=S(=O)(c1ccccc1)n1c2ccc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)cc2c2cc(-n3c4ccccc4c4cc(-c5ccccc5)ccc43)ccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(-c2ccc3c(c2)c2ccccc2n3-c2ccc3[nH]c4ccc(-n5c6ccccc6c6cc(-c7ccccc7)ccc65)cc4c3c2)cc1
Temperature: 25 °C

Procedure:
97 g (123 mmol) of 3,3″-bis(phenyl)-9′-[(phenyl)sulfonyl]-9,3′:6′,9″-ter-9H-carbazole and 48 g (856 mmol) of potassium hydroxide in 65 ml of dimethyl sulfoxide and 21 ml of water are heated under reflux for 1 h. The mixture is subsequently cooled to room temperature and neutralised using 1 M HCl solution. The mixture is then extracted with dichloromethane. The solvent is evaporated in vacuo, and the residue is purified by chromatography (heptane/ethyl acetate 10:1). Yield: 64.8 g (100 mmol), 80%.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[CH:2]=1.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].C([O-])(=O)C.[NH4+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:14][C:15]([OH:17])=[O:16])[CH:2]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1cnc2ccccc2c1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CCc1cnc2ccccc2c1
Temperature: 25 °C
Yield: 56 %

Procedure:
A solution containing quinoline-3-carboxaldehyde 4-1 (5 g, 31.8 mmol), malonic acid (3.6 g, 35.0 mmol), and ammonium acetate (5.0 g, 63.6 mmol) in anhydrous ethanol (125 mL) was heated at reflux for 12 h. After cooling to room temperature, the resulting white solid was collected by filtration and washed with cold ethanol (150 mL) and then dried under vacuum to provide 4-2 as a white solid (3.84 g, 17.8 mmol, 56%). 1H NMR (300 MHz, D2O):δ 8.91 (d, J=2 Hz 1H), 8.21 (d, J=2 Hz, 1H), 8.12 (d, J=8 Hz, 1H), 7.84 (d, J=7 Hz, 1H), 7.72 (t, J=7 Hz, H), 7.54 (t, J=7 Hz, 1,H), 4.72 (m, 1H), 2.73 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]=[C:11]([CH3:13])[C:10]([C:14]([OH:16])=O)=[CH:9][N:8]=2)[CH:2]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH2:36])(=[O:31])=[O:30]>CN(C=O)C>[CH3:27][NH:28][S:29]([C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][CH:39]=1)[CH2:35][NH:36][C:14]([C:10]1[C:11]([CH3:13])=[N:12][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[N:8][CH:9]=1)=[O:16])(=[O:30])=[O:31]
Reactant: CNS(=O)(=O)c1cccc(CN)c1
Reactant: Cc1nc(-c2cccnc2)ncc1C(=O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccnc3)nc2C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 45 %

Procedure:
A mixture of 2-(3-pyridyl)-4-methylpyrimidine-5-carboxylic acid (215 mg, 1 mmol, prepared according to the general procedure described in Example 42, steps 1 and 2) and O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (380 mg, 1 mmol) in dry DMF (12 mL) is treated with of diisopropylethylamine (0.18 mL) and stirred at room temperature for 30 min. 3-Methylsulfamoylbenzylamine hydrochloride (355 mg, 1.5 mmol) is added and the mixture is stirred at room temperature for 24 hours. The solvent is removed and the residue partitioned between EtOAc and saturated NaHCO3. The organic phase is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by column chromatography eluting with 2% MeOH in EtOAc to afford 2-(3-pyridyl)-4-methyl-pyrimidine-5-carboxylic-acid-3-methylsulfamoyl-benzylamide (180 mg, 45%) as a solid. MS: 398 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.43 (s, 3H), 2.65 (s, 3H), 4.60 (d, 2H), 7.57-7.71 (m, 4H), 7.79 (s, 1H), 8.68-8.72 (d, 1H), 8.72-8.78 (d, 1H), 8.93 (s, 1H), 9.34 (t, 1H), 9.53 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][NH:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:35]=[CH:34][C:33]5[O:32][CH2:31][O:30][C:29]=5[CH:28]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[Cl:45])[CH:40]=O>CO>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[Cl:45])[CH:40]=[N:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][NH:16][CH2:17][C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:35]=[CH:34][C:33]5[O:32][CH2:31][O:30][C:29]=5[CH:28]=4)[CH2:22][CH2:21]3)=[O:19])=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccc(CNCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Solvent: CO
Product: O=C(CNCc1ccc(Oc2ccc(N=Cc3ccc(Cl)c(Cl)c3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1

Procedure:
2-{[(4-(5-aminopyridin-2-yloxy)phenyl]methylamino}-1-(4-piperonylpiperazin-1-yl)ethanone (7.80 g, 16.4 mmol) was dissolved in methanol (400 mL), and to the resulting solution was added 3,4-dichlorobenzaldehyde (2.87 g, 16.4 mmol). This solution was refluxed for 16 hours. The resulting reaction solution was concentrated under reduced pressure, to thereby yield 10.4 g of the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:24][CH2:25][N:26]=[C:27]=[O:28].[Cl-].[NH4+]>ClCCl>[O:28]=[C:27]1[NH:26][CH2:25][CH2:24][N:2]1[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C=NCCCl
Reactant: COC(=O)Cc1cccc(N)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Cc1cccc(N2CCNC2=O)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Methyl (3-aminophenyl)acetate hydrochloride was suspended in dichloromethane (7 vol) under nitrogen. Diisopropylethylamine (1.04 vol) was added at 20° C. over 30 minutes, and the reaction mixture was stirred for 30 minutes at 20° C. 2-Chloroethyl isocyanate (0.44 vol) was added dropwise at 20° C. over 100 minutes. The reaction mixture was stirred at 20° C. for three hours. A saturated solution of ammonium chloride (5 vol) was added dropwise over 10 mins and the resultant mixture was stirred for ten minutes. The organic phase was separated and washed with water (5 vol). Tetrahydrofuran (2×3 vol) was added and the mixture was concentrated to 2 vol. Dry tetrahydrofuran (5 vol) was added, and the mixture was concentrated to 2 vol. Dry THF (3 vol) was added, under nitrogen at 20° C. The reaction mixture was cooled to 0° C., and potassium tert-butoxide (0.56 wt) was added portion-wise in 5 stages, allowing 20 minutes between two subsequent additions. The reaction mixture was stirred at 20° C. for one hour. Hydrochloric acid (0.5N, 2 vol) was added dropwise over 20 minutes. Ethyl acetate (10 vol) was added and the organic phase was separated. The organic layer was washed with aqueous sodium hydrogencarboante solution (4%, 2 vol) and brine (2 vol), and the organic layer was then evaporated to dryness under vacuum to give the title compound (overall yield: 90% w/w).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[C:7]([N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ncc[nH]1
Solvent: C1CCOC1
Product: Cc1nccn1C(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 0.17 h

Procedure:
8.2 g (0.1 mol) of 2-methylimidazole (a pale yellow solid, 99% pure, m.p. 143°-144° C.) and 50 ml of tetrahydrofuran are placed in a flask. Over a 20 minute period, there is added gradually, with stirring, a solution of 7.0 g (0.05 mol) of benzoyl chloride in 25 ml of tetrahydrofuran. During this period the temperature of the contents of the flask, initially room temperature, rises owing to the exothermic reaction; the temperature of the contents of the flask is maintained at 40° C. by cooling. Stirring is continued, at 40° C., for 10 minutes. Then the mixture is refluxed (at 70° C.) for one hour. An oily layer separates. The mixture is cooled to solidify the oily material and the resulting precipitate is removed by filtration. After removal of tetrahydrofuran by evaporation under vacuum there remains 7.7 g of paste-like crude N-benzoyl 2-methylimidazole.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=1)(=[O:25])=[O:24]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][N:12]([C:31]([C:30]4[CH:29]=[CH:28][C:27]([NH:26][S:23]([C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=5)(=[O:25])=[O:24])=[CH:35][CH:34]=4)=[O:32])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(NS(=O)(=O)c2ccccn2)cc1
Reactant: Clc1ccc2nc(N3CCNCC3)oc2c1
Product: O=C(c1ccc(NS(=O)(=O)c2ccccn2)cc1)N1CCN(c2nc3ccc(Cl)cc3o2)CC1

Procedure:
Compound 14 is prepared using synthesis method 2 using intermediates 3b and 5c (yield: 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2([CH2:36][C:37]([NH2:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[C:26]([Cl:40])=[CH:25][N:24]=1>>[Cl:40][C:26]1[C:27]([NH:29][C:30]2([CH2:36][C:37]([NH2:39])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: NC(=O)CC1(Nc2nc(Cl)ncc2Cl)CCCCC1
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(NC4(CC(N)=O)CCCCC4)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-[1-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-acetamide in an analogous manner to Example 61e. Product isolated as a pale yellow foam (0.064 g, 49%). MP: 71-83° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 7.92 (s, 1H), 7.84 (s, 1H), 7.14 (s, 1H), 6.64 (s, 1H), 5.40 (br s, 1H), 5.24 (s, 1H), 5.05 (br s, 1H), 3.85 (s, 3H), 3.57-3.51 (m, 2H), 3.47-3.41 (m, 2H), 3.32 (s, 6H), 3.06-2.98 (m, 1H), 2.90 (s, 2H), 2.87-2.77 (m, 8H), 2.37-2.29 (m, 2H), 1.71-1.29 (m, 8H). MS: 561.29 (MH)+.
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14]>CN(C1C=CN=CC=1)C.C1COCC1>[Br:10][C:11]1[CH:12]=[C:13]([NH:14][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:15]=[CH:16][CH:17]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C(Cl)C1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Br)c1)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Cyclohexanecarbonyl chloride (0.74 g, 6.97 mmol) was added to a mixture of 3-bromoaniline (1.0 g, 5.8 mmol), TEA (1.07 mL, 7.55 mmol) and DMAP (cat.) in THF with stirring at 0° C. over 10 min. Stirring was continued for another 30 min and quenched with saturated NaHCO3. The product was extracted with ethyl acetate. Combined organic layers were concentrated under reduced pressure to give a residue which was triturated with pentane to give N-(3-bromophenyl)cyclohexanecarboxamide as an off-white solid. Yield (1.3 g, 79%); 1H NMR (400 MHz, DMSO-d6) δ 9.96 (s, 1H), 7.97 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.26-7.18 (m, 2H), 2.33-2.26 (m, 1H), 1.76 (t, J=14.0 Hz, 4H), 1.65 (d, J=10.4 Hz, 1H), 1.43-1.34 (m, 2H), 1.30-1.12 (m, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].O=[C:12]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:13][C:14](OC)=[O:15]>>[OH:15][C:14]1[N:1]([C:3]2[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=2)[N:2]=[C:12]([CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=1
Reactant: COC(=O)CC(=O)COc1ccccc1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(COc3ccccc3)cc2O)c1
Yield: 58 %

Procedure:
The title compound was prepared in 58% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and methyl 3-oxo-4-phenoxybutanoate according to the procedure for the preparation of Example 3, part A. [M+H] Calc'd for C16H12N4O2, 293. Found, 293.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][C:6]1[C:7](=[O:8])[N:2]([CH3:1])[C:3]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:4][CH:5]=1
Reactant: Cn1c(Nc2ccccc2)nccc1=O
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cn1c(Nc2ccccc2)ncc(Br)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
To a solution of 3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.104 g, 0.517 mmol) in CHCl3 (5 mL)/MeOH (1 mL) at 0° C. was added bromine (0.027 mL, 0.517 mmol). The reaction mixture was stirred for 30 minutes at room temperature and then quenched with 10% aqueous sodium bisulfite solution. The reaction mixture was partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield the desired product (0.145 g; 100%) as a white solid that was used without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 7.94 (s, 1H), 7.47 (m, 2H), 7.34 (t, J=7.4 Hz, 2H), 7.14 (t, J=7.4 Hz, 1H), 3.53 (s, 3H). LRMS (ESI pos) m/e 280, 282 (M+1, Br pattern).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1.Cl.[CH3:16][N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1>OS(O)(=O)=O.O1CCOCC1>[CH3:16][N:17]1[CH2:22][CH2:21][C:20]2[NH:11][C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:14])([F:13])[F:2])=[CH:10][C:9]=3[C:19]=2[CH2:18]1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccc(OC(F)(F)F)cc3c2C1
Temperature: 80 °C
Reaction time: 6 h
Yield: 76.2 %

Procedure:
(4-(Trifluoromethoxy)phenyl)hydrazine hydrochloride (1 g, 4.37 mmol) was dissolved in 7% H2SO4 in 1,4-dioxane (50 mL), 1-methylpiperidin-4-one hydrochloride (0.65 g, 4.37 mmol) was added and stirred at 80° C. for 6 h. Reaction was monitored by TLC & LCMS. After completion of the reaction, reaction mixture was concentrated under vacuum and slowly quenched with aq. NaHCO3 solution, extracted with EtOAc. Organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure and purified by column chromatography to afford 0.9 g of 2-methyl-8-(trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CDCl3, free base) δ (ppm) 7.9 (bs, 1H), 7.3-7.2 (m, 2H), 7.1-6.9 (d, 1H), 3.7 (s, 2H), 2.9-2.8 (m, 4H), 2.6 (s, 3H).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Br[CH:25]([O:27][CH2:28][CH3:29])[CH3:26].[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:26][CH2:25][O:27][CH2:28][CH3:29])=[C:18]([F:23])[N:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCOC(C)Br
Reactant: CCCCCCCCOc1ccc(-c2ccc(O)c(F)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ccc(OCCOCC)c(F)n2)cc1

Procedure:
A mixture of 0.1 mol of 2C, 0.1 mol of 1-bromoethoxyethane, 0.1 mol of sodium hydroxide, 20 ml of ethanol and 50 ml of water is heated at the boil for 2 hours. The mixture is cooled, dilute hydrochloric acid is added, and the aqueous phase is extracted with dichloromethane. The solvent is removed under reduced pressure, and the residue is purified by column chromatography, giving the product 2-(4-octyloxyphenyl)-5-(2-ethoxyethoxy)-6-fluoropyridine.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12]([CH2:20][C:21]3[S:25][C:24]([NH:26][CH2:27][C:28]4[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=4)=[N:23][C:22]=3[Cl:35])=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[Cl:35][C:22]1[N:23]=[C:24]([NH:26][CH2:27][C:28]2[CH:29]=[N:30][CH:31]=[C:32]([F:34])[CH:33]=2)[S:25][C:21]=1[CH2:20][C:12]1[C:13]2[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=2)[NH:10][CH:11]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(Cc2sc(NCc3cncc(F)c3)nc2Cl)c2cc(Cl)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cncc(CNc2nc(Cl)c(Cc3c[nH]c4ncc(Cl)cc34)s2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To [5-(1-benzenesulfonyl-5-chloro-1H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-yl]-(5-fluoro-pyridin-3-ylmethyl)-amine (595, 0.030 g, 0.055 mmol) in tetrahydrofuran (6.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.034 g, 0.11 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0231, 1.5 mg, 6.7%). MS (ESI) [M+H+]+=408.1.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)[CH2:19][CH2:18]3)=[O:16])[C:12]([CH3:28])=[CH:11][C:10]=2[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([C:15]([N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH2:19][CH2:18]2)=[O:16])[C:12]([CH3:28])=[CH:11][C:10]=1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1
Reactant: COc1ccc(CNc2nc(C(=O)N3CCC(N4CCCC4)CC3)c(C)cc2-c2cccc(C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(N)nc1C(=O)N1CCC(N2CCCC2)CC1
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a solution of 1.48 g (2.7 mmol) of [6-(4-methoxy-benzylamino)-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 6) in 75 ml of CH2Cl2 was added 12.2 ml=18.2 g (160 mmol) of trifluoroacetic acid and the reaction mixture was subsequently heated up to reflux. After two hours, it was poured into crashed ice, the pH was adjusted to 8-9 with sodium carbonate solution and it was extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 98:2 to 3:1) to give 1.04 g (90%) of the title compound as light yellow foam. MS: 433.3 (MH+).
Reaction SMILES: [CH:1]1([C:16]([OH:18])=O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH:2]1[C:13](O)=[O:14].[OH-].[NH4+:20]>>[CH:1]12[C:16](=[O:18])[NH:20][C:13](=[O:14])[CH:2]1[C:3]1[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]2=3)[CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)C1c2cccc3cccc(c23)C1C(=O)O
Reactant: [NH4+]
Agent: [OH-]
Product: O=C1NC(=O)C2c3cccc4cccc(c34)C12
Temperature: 200 °C

Procedure:
5.5 Parts of acenaphthene-1,2-dicarboxylic acid is heated in an oil bath with an excess of concentrated ammonium hydroxide. After most of the excess of ammonium hydroxide has distilled off, the temperature of the oil bath is raised to 200° C. and it is maintained at that temperature for 45 minutes. The residual material is sublimed under vacuum (0.05-0.1 mm.) using an oil bath at 280° C. The resultant solid is recrystallized from ethanol to give acenaphthene-1,2-dicarboximide melting at about 242°-246° C.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[CH:11]=[CH:12][CH:13]=[C:8]3[C:9]=2[C:4](=[CH:5][CH:6]=[CH:7]3)[N:3]1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(Cl)([Cl:23])(=O)=O.[Cl-]>C(O)(=O)C>[Cl:23][C:7]1[C:8]2[C:9]3[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:2](=[O:1])[C:10]=3[CH:11]=[CH:12][CH:13]=2
Reactant: CCOC(=O)CN1C(=O)c2cccc3cccc1c23
Reactant: O=S(=O)(Cl)Cl
Agent: [Cl-]
Solvent: CC(=O)O
Product: CCOC(=O)CN1C(=O)c2cccc3c(Cl)ccc1c23
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 2-oxo-benz[cd]indole-1(2H)acetic acid, ethyl ester (17 g, 0.067 mole, described in Example 3) in glacial acetic acid (67 mL) was added sulfuryl chloride (9 g, 5.4 ml, 0.067 mol) dropwise at room temperature over a period of 50 min with mechanical stirring. The solid initially disappeared after a few milliliters of the chloride were added. Towards the end of additon, the product started to precipitate. The reaction mixture was stirred at room temperature for an additional 30 min and then at 94° C. for 2 hr. After cooling to room temperature the mixture was poured into water (200 mL). The precipitate was filtered, dried (18.3 g), and crystallized from boiling ethanol (360 mL) to give the title compound: mp 138°-140° C.; Anal. Calcd for C15H12ClNO3 : C, 62.19% H, 4.18% N, 4.83% and Found: C, 61.98% H, 4.08% N, 4.82%; IR (CHCl3) 1745 and 1710 cm-1 ; UV max (methanol) 339 (ε3690), 322 (2530), 279 (6030), 258 (18,680) and 214 nm (32,760); NMR (CDCl3)δ 1.25 (t, 3H), 4.2 (q, 2H), 4.65 (s, 2H), and 7.5 (m, 5H).