Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:16])[C:12]([F:15])([F:14])[F:13])([O-:3])=[O:2].[N+:17](C1C=CC(OC(F)C(F)(F)F)=CC=1)([O-:19])=[O:18]>S(=O)(=O)(O)O.[N+]([O-])(O)=O>[N+:1]([C:4]1[CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=[CH:6][C:5]=1[O:10][CH:11]([F:16])[C:12]([F:14])([F:15])[F:13])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])c1ccccc1OC(F)C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O=[N+]([O-])O
Product: O=[N+]([O-])c1ccc(OC(F)C(F)(F)F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6 g (0.025 moles) of 2-nitrotetrafluoroethoxybenzene or 4-nitrotetrafluoroethoxybenzene are dissolved in 20 ml concentrated sulfuric acid (density, d=1.84 g/ml) and nitrated at 5°-10° C. with a mixture of 1.2 ml nitric acid (d=1.5 g/ml) and 5 ml sulfuric acid (d=1.84 g/ml). After the addition of the nitrating acid, the aforesaid preparation is allowed to heat at room temperature. The preparation, after being left to stand overnight, is then poured onto ice water. The precipitated oil is separated by means of decanting and the aqueous phase is extracted three times with 50 ml ether. The ether extracts and the oil are then combined, washed with sodium bicarbonate solution so as to be acid-free and dried over calcium chloride. After distilling the solvent, 6.6 g (93% of the theoretical yield) dinitro compound (from the 2-nitrotetrafluoroethoxybenzene) or 6.7 g (94% of the theoretical yield) dinitrotetrafluoroethoxybenzene (from the 4-nitrotetrafluoroethoxybenzene) is obtained. The dinitro compound was further processed directly in the following step without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH:8][C@H:9]([C:17]([NH:19][CH2:20][C:21]([NH:23][CH2:24][C:25]([OH:27])=O)=[O:22])=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].[N:28]1([CH2:34][CH2:35][NH:36][C:37](=[O:49])[C@@H:38]([NH2:48])[CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][CH2:35][NH:36][C:37](=[O:49])[C@@H:38]([NH:48][C:25](=[O:27])[CH2:24][NH:23][C:21](=[O:22])[CH2:20][NH:19][C:17](=[O:18])[C@H:9]([CH2:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[CH2:39][CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: O=C(O)CNC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccco1
Reactant: N[C@@H](CCCN1CCCCC1)C(=O)NCCN1CCCCC1
Product: O=C(CNC(=O)[C@H](CC1CCCCC1)NC(=O)c1ccco1)NCC(=O)N[C@@H](CCCN1CCCCC1)C(=O)NCCN1CCCCC1
Yield: 57.3 %

Procedure:
In the same way as example 1, from 2-furoyl-L-phenylalanyl-glycyl-glycine (23.7 mg, 0.063 mmol) and (S)-2-amino-5-(1-piperidinyl)pentanoic acid N-[2-(1-piperidinyl)ethyl]amide (16.7 mg, 0.054 mmol) synthesized in the same way as reference example 1, (S)-2-[(2-furoyl)-β-cyclohexyl-L-alanyl-glycyl-glycyl-amino]-5-(1-piperidinyl)pentanoic acid [2-(1-piperidinyl)ethyl]amide (20.8 mg) was obtained as a colorless oily material (yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)O[C:10](=[O:11])[C:5]=2[CH:4]=1.[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CN(C=O)C>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([Br:15])=[CH:17][CH:18]=1)=[O:11]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: Nc1ccc(Br)cc1
Solvent: CN(C)C=O
Product: COc1ccc(N)c(C(=O)Nc2ccc(Br)cc2)c1

Procedure:
A solution of 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (0.800 g, 4.10 mmol) and 4-bromoaniline (0.750 g, 4.30 mmol) in anhydrous DMF (10 mL) was stirred at 115° C. for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated, backwashed with brine (50 mL), and concentrated. The residue was purified by column chromatography (SiO2, hexane/ethyl acetate=1:1) to give 2-amino-N-(4-bromo-phenyl)-5-methoxy-benzamide. Yield: 0.240 g (18%).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[C:16]([O:17]COC)=[CH:15][C:14]([O:21]COC)=[CH:13][C:12]=2[CH2:25][C:26]([O:28]C)=[O:27])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.N1C=CC=CC=1.[OH-].[Na+].Cl>ClCCl.CO>[C:1]([NH:4][CH2:5][C:6]1[O:10][C:9]([C:11]2[C:16]([OH:17])=[CH:15][C:14]([OH:21])=[CH:13][C:12]=2[CH2:25][C:26]([OH:28])=[O:27])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: COCOc1cc(CC(=O)OC)c(-c2ccc(CNC(C)=O)o2)c(OCOC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)NCc1ccc(-c2c(O)cc(O)cc2CC(=O)O)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
Methyl 2-[5-(N-acetylaminomethyl)furan-2-yl]-3,5-bis(methoxymethoxy)phenylacetate (45 mg, 0.15 mmol) obtained in Example 264 was dissolved in dichloromethane (1.0 mL), and acetic anhydride (0.20 mL, 2.12 mmol) and pyridine (0.20 mL, 2.5 mmol) were added thereto and stirred at room temperature for 3 hours. Methanol (5.0 mL) was added to the reaction solution, then stirred for 0.5 hours, and concentrated under reduced pressure. The resulting residue was dissolved in acetonitrile (1.0 mL), and aqueous 4 mol/L sodium hydroxide solution (1.0 mL, 4.0 mmol) was added thereto and stirred at 40° C. for 4 hours. 3 mol/L hydrochloric acid (3.0 mL) was added to the reaction solution, and concentrated under reduced pressure, and the resulting residue was purified through HP-20 (Mitsubishi Chemical Industry; water to acetonitrile/water=1/4) to obtain Compound 266 (23 mg, 23%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([NH:11][C:12]2[C:17]3[C:18](=[O:21])[NH:19][CH2:20][C:16]=3[CH:15]=[C:14]([NH:22][C@@H:23]3[CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:28]C(=O)OC(C)(C)C)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Cl>CC(O)=O>[NH2:28][C@H:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[NH:22][C:14]1[N:13]=[C:12]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=2)[C:17]2[C:18](=[O:21])[NH:19][CH2:20][C:16]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1Nc1cc2c(c(Nc3cccc(S(C)(=O)=O)c3)n1)C(=O)NC2
Agent: Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1cccc(Nc2nc(N[C@@H]3CCC[C@@H]3N)cc3c2C(=O)NC3)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.3 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(4-(3-(methylsulfonyl)phenylamino)-3-oxo-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclopentylcarbamate (16.5 mg, 0.329 mmol) and HCl (1 mL, 32.9 mmol) in HOAc (2 mL) was stirred at RT for 3 h. The mixture was concentrated under reduced pressure and the residue was recrystallized from EtOH-H2O to give the title compound (9.6 mg, 67%). 1H-NMR (DMSO-d6) δ ppm 1.63-1.79 (m, 4H), 20.3-2.06 (m, 1H), 2.19-2.20 (m, 1H), 3.32 (s, 3H), 3.74 (br s, 1H), 4.23-4.28 (m, 2H), 4.45 (br s, 1H), 6.22 (s, 1H), 7.34-7.35 (m, 1H), 7.51-7.58 (m, 3H), 7.73 (br s, 3H), 8.13 (s, 1H), 8.82 (s, 1H), 9.26 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1.CS(O[CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])(=O)=O>>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:29])[N:19]([CH:23]5[CH2:28][CH2:27][N:26]([CH2:41][CH2:42][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:25][CH2:24]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:32]([F:35])([F:34])[F:33])[CH:3]=1
Reactant: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1C1CCNCC1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Product: CS(=O)(=O)CCN1CCC(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-{1-[2-(methylsulfonyl)ethyl]piperidin-4-yl}-1,3-thiazolidine-2,4-dione was prepared from (5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-piperidin-4-yl-1,3-thiazolidine-2,4-dione (Example 113) and 2-(methylsulfonyl)ethyl methanesulfonate (prepared following General the methods described in PCT Int, Appl. 2006047277) following General Procedure S.
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[CH3:13])[CH3:2]>CO.[Pd]>[CH2:14]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[CH3:13])[CH3:15]
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cc1C
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1ccc(N)cc1C
Yield: 83.4 %

Procedure:
A solution of diethyl-(2-methyl-4-nitro-phenyl)-amine (340 mg, 1.634 mmol) in methanol (10 ml) was hydrogenated over 10% Pd—C (50 mg) at room temperature and atmospheric pressure until no more gas absorption occurred. The reaction mixture was filtered over celite and the filtrate concentrated to dryness to give N1,N1-Diethyl-2-methyl-benzene-1,4-diamine (243 mg, 46.5%) as oil.
Reaction SMILES: Cl.[CH3:2][NH:3][N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1.C(N(CC)CC)C.[C:20]1([N:26]=[C:27]=[S:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O.CCOCC>[CH3:2][N:3]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)[C:27]([NH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[S:28]
Reactant: CNN1Cc2ccccc2C1
Reactant: S=C=Nc1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: CN(C(=S)Nc1ccccc1)N1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 1.12 g (0.006 mole) of N-methylamino dihydroisoindole hydrochloride in 10 ml of dimethylformamide was added 1 ml of triethylamine followed by 0.82 g (0.006 mole) of phenylisothiocyanate. The reaction mixture was allowed to stir at room temperature overnight. Water (25 ml) was added and the resulting gummy solid was extracted with ethyl acetate. After drying and filtering, evaporation gave a thick oil which solidified upon adding a small amount of ether and scratching. There was obtained 1.4 g of the desired product, mp: 121°-125° dec. The IR and NMR were consistent with the proposed structure.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[F:10][C:11]([F:23])([F:22])[C:12]1[CH:21]=[CH:20][C:15]([C:16](=O)[CH2:17]Br)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[O:8][CH:17]=[C:16]([C:15]2[CH:20]=[CH:21][C:12]([C:11]([F:10])([F:22])[F:23])=[CH:13][CH:14]=2)[N:9]=1
Reactant: NC(=O)c1sccc1Cl
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2coc(-c3sccc3Cl)n2)cc1
Temperature: 150 °C
Yield: 6 %

Procedure:
3-Chloro-thiophene-2-carboxamide (0.145 g, 0.898 mmol) and 4-trifluoromethyl-phenacyl bromide (0.200 g, 0.749 mmol) were placed in a sealed tube and heated at 150° C. for 4 h. The reaction mixture was quenched with ethyl acetate and the residue was purified by column chromatography (gradient 100:1, 20:1 hexane:dichloromethane). The product was further purified by preparative-TLC (100:1, hexane:dichloromethane) to yield 0.0148 g (5.0%) of the title compound as a white solid. 1H NMR (Acetone-d6): 8.58 (s, 1H), 8.01 (d, J=8.1 Hz, 2H), 7.71 (t, 3H), 7.10 (d, J=5.1 Hz, 1H), 7.08 (d, J=5.7 Hz, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([N:16]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([NH:29][C:30](=[O:57])[CH:31]([S:47]CC3C=CC(OC)=CC=3)[CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[C:44](=[O:45])[C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[C:37]3=[O:46])[C:17]2=[O:58])[C:9]([O:11]C(C)(C)C)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>ClCCl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:1]1([CH2:7][CH:8]([N:16]2[CH2:22][CH2:21][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH:18]([NH:29][C:30](=[O:57])[CH:31]([SH:47])[CH2:32][CH2:33][CH2:34][CH2:35][N:36]3[C:37](=[O:46])[C:38]4[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=4)[C:44]3=[O:45])[C:17]2=[O:58])[C:9]([OH:11])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(CSC(CCCCN2C(=O)c3ccccc3C2=O)C(=O)NC2CC(c3ccccc3)CCN(C(Cc3ccccc3)C(=O)OC(C)(C)C)C2=O)cc1
Agent: CC(=O)[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)(Cl)Cl
Solvent: COc1ccccc1
Solvent: ClCCl
Product: O=C(NC1CC(c2ccccc2)CCN(C(Cc2ccccc2)C(=O)O)C1=O)C(S)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine N-[hexahydro-1-[1-(phenylmethyl)-1-t-butoxycarbonylmethyl]-2-oxo-5-phenyl-1H-azepin-3-yl]-1,3-dihydro-a-(p-methoxybenzylthio)-1,3-dioxo-2H-isoindole-2-hexanamide (0.16 g, 0.20 mmol), mercury (II) acetate (0.084 g, 0.26 mmol), and anisole (0.23 mL, 2.1 mmol) in dichloromethane (6.6 mL). Cool in an ice bath and degas by repeatedly cycles of vacuum and filling the vessel with nitrogen gas. Add trifluoroacetic acid (2.5 mL). After 1 hour, warm to ambient temperature. After 3 hours, purge with hydrogen sulfide (gas) for about 10 minutes. Filter and evaporate in vacuo to give a residue. Repeatedly, combine the residue and carbon tetrachloride and evaporate in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[N:17][C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1=NNc2ccc(NC(=O)OCc3ccccc3)cc2C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(NC(=O)OCc3ccccc3)ccc2nn1

Procedure:
A solution of ethyl 6-(benzyloxycarbonylamino)-1,4-dihydrocinnolin-3-yl carboxylate in ethyl acetate (obtained as described below) was heated to reflux temperature and manganese dioxide (20 g.) was added. The mixture was heated under reflux for 30 minutes, filtered, and the filtrate evaporated in vacuo to approximately 25 ml. Petroleum ether (b.p. 60°-80° C.; 75 ml.) was added and the mixture filtered to give, as solid residue, ethyl 6-(benzyloxycarbonylamino)cinnolin-3-yl carboxylate, m.p. 205° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=2)[C:18]([O:26][CH2:27][CH3:28])=[C:17]([C:29](O)=[O:30])[C:16]=1[C:32](O)=[O:33])[CH3:13]>CN1C(=O)CCC1.CCOC(C)=O>[CH2:27]([O:26][C:18]1[C:17]2[C:29](=[O:30])[N:1]([C:2]3[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=3)[C:32](=[O:33])[C:16]=2[C:15]([O:14][CH2:12][CH3:13])=[C:24]2[CH:23]=[CH:22][C:21]([F:25])=[CH:20][C:19]=12)[CH3:28]
Reactant: CCOc1c(C(=O)O)c(C(=O)O)c(OCC)c2cc(F)ccc12
Reactant: Nc1ccc(CC(=O)O)cc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCOc1c2c(c(OCC)c3cc(F)ccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2=O
Temperature: 180 °C
Yield: 44 %

Procedure:
4-Aminophenylacetic acid (418 mg, 2.77 mmol) was added to 1,4-bis(ethyloxy)-6-fluoro-2,3-naphthalenedicarboxylic acid (810 mg, 2.5 mmol) and powdered molecular sieves (4 Å, 200 mg) in NMP (4.5 ml) and heated in a microwave at 180° C. for 10 minutes. The reaction mixture was cooled and diluted with EtOAc, filtered through celite, washed with water, brine, dried over magnesium sulphate and concentrated in vacuo to yield a yellow solid. This was recrystallised from methanol (˜50 ml) and the white solid filtered, washed with methanol and dried in vacuo in an oven to give the title compound as a white solid (490 mg, 1.1 mmol). The filtrate was concentrated in vacuo and the yellow oil purified by reverse phase chromatography eluting with acetonitrile:water (1:20-1:0) to give the title compound as a white solid (107 mg, 0.24 mmol).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]([OH:12])[CH2:9][CH2:10][OH:11])=[CH:6][CH:5]=[CH:4][N:3]=1.C(O[K])(C)(C)C>CC(O)(C)C>[O:11]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=[C:7]2[CH:8]([OH:12])[CH2:9][CH2:10]1
Reactant: OCCC(O)c1cccnc1Br
Agent: CC(C)(C)O[K]
Solvent: CC(C)(C)O
Product: OC1CCOc2ncccc21
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
A mixture of 1-(2-bromopyridin-3-yl)propane-1,3-diol (40.9 mmol) (Bioorg. Med. Chem. Lett., 20(9), 2938-2941, 2010) and tBuOK (123 mmol) in 164 mL tBuOH was stirred for 90 min at 80° C. The reaction mixture was then concentrated in vacuo, taken up in H2O and extracted with EtOAc and DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using DCM/MeOH (1-5%) gives the desired product as brown oil;
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[CH:11][C:10]=1[O:20][C@@H:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:22][N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(C)(C)C.[ClH:35]>O1CCOCC1>[ClH:35].[ClH:35].[NH2:7][CH2:8][C:9]1[C:10]([O:20][C@@H:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:22][N:23]2[CH:27]=[CH:26][N:25]=[CH:24]2)=[CH:11][CH:12]=[C:13]2[C:18]=1[CH2:17][CH2:16][CH2:15][C:14]2=[O:19]
Reactant: CC(C)(C)OC(=O)NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: Cl
Solvent: C1COCCO1
Product: NCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reaction time: 0.25 h

Procedure:
[2-((S)-2-Imidazol-1-yl-1-phenyl-ethoxy)-5-oxo-5,6,7,8-tetrahydro-naphthalen-1-ylmethyl]-carbamic acid tert-butyl ester (0.830 g, 1.80 mmol) was dissolved in dioxane (10 mL) and 4M HCl in dioxane (4 mL) was added. After 15 minutes, a white precipitate formed. The precipitate was collected by filtration, washed with Et2O and dried in a vacuum oven to give the title compound as a white fluffy solid (0.761 g, 1.75 mmol, 97%). The structure was confirmed by NMR, mass spectrometry and elemental analysis. MS m/z 362 (M++H).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([NH:16][C:17](=[O:25])[C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[CH3:28][CH:29]1[CH2:34][NH:33][CH2:32][CH2:31][NH:30]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:26]=[CH:27][C:2]([N:33]3[CH2:32][CH2:31][NH:30][CH:29]([CH3:28])[CH2:34]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[NH:16][C:17](=[O:25])[C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(F)cc2)c1)c1ccc(Cl)nc1
Reactant: CC1CNCCN1
Product: CC1CN(c2ccc(C(=O)Nc3ccc(Cl)c(NC(=O)c4ccc(F)cc4)c3)cn2)CCN1

Procedure:
6-chloro-N-(4-chloro-3-(4-fluorobenzamido)phenyl)nicotinamide (0.18 mmol) was used in general procedure 3 with 2-methylpiperazin (0.54 mmol). The product was purified by RP-HPLC to give N-(4-chloro-3-(4-fluorobenzamido)phenyl)-6-(3-methylpiperazin-1-yl)nicotinamide. MS (Q1) 468.3 (M)+
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]([O:17]CC)=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[C:1]([N:9]1[CH2:14][CH2:13][CH2:12][C:11]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]([OH:17])=[O:16])[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCCN(C(=O)c2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(c1ccccc1)N1CCCC(Cc2ccccc2)(C(=O)O)C1
Yield: 55.7 %

Procedure:
Ethyl 1-benzoyl-3-benzylpiperidine-3-carboxylate (6.308 g; 18 mmol) was hydrolyzed with 1 N aq NaOH (220 mL) in ethanol (110 mL) for 20 h at rt. The ethanol was removed by rotary evaporation and the aqueous layer was extracted once with CH2Cl2. The pH of the aqueous layer was adjusted to pH=3-4 with 1 N aq HCl and extracted with CH2Cl2 (3×). The organic phase was dried over anhydrous Na2SO4, filtered and evaporated to give 1-benzoyl-3-benzylpiperidine-3-carboxylic acid (3.24 g, 55.7%). 1H NMR (CD3OD, 400 MHZ): δ=1.12 (m, 3H), 1.50˜1.72 (m, 4H), 2.18 (m, 1H), 2.75 (d, 1H), 3.05 (m, 1H), 3.16 (m, 1H), 4.08 (m, 2H), 7.08 (m, 2H), 7.22 (m, 3H), 7.48 (m, 5H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[O:9][CH2:10][CH2:11]Br.[Li]CCCC>C1COCC1.CCCCCC>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[CH2:11][CH2:10][O:9][C:3]=2[CH:4]=1
Reactant: BrCCOc1cc(Br)ccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Brc1ccc2c(c1)OCC2
Temperature: -78 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
1,4-dibromo-2-(2-bromoethoxy)benzene (136) (922 mg, 2.57 mmol) was dissolved in 25 ml dry THF. After cooled down to −78° C., a solution of 2.5M n-BuLi (1.23 ml, 1.2q) in hexane was added dropwise. The reaction mixture was stirred at −78° C. for 4 h before poured into ice-water. After extracted twice with ethyl acetate, the org. phase was washed with brine, dried over sodium sulfate and then concentrated to give 504 mg (purity ca 80%) 6-bromo-2,3-dihydrobenzo[b]furan (137) as dark brow oil which was used directly for further reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][C:21]=2[N+:26]([O-:28])=[O:27])=[O:7])=[CH:9][CH:10]=1
Reactant: Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)nc1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 4-benzyloxy-2-nitroaniline and was obtained as a yellow solid as described in Example 1. 1H NMR (CDCl3): 11.13 (bs, 1H), 9.00 (d, J=3.0, 1H), 8.83 (d, J=9.3, 1H), 8.23-8.20 (m, 1H), 7.85 (d, J=3.0, 1H), 7.53-7.46 (m, 1H), 7.44-7.37 (m, 6H), 5.15 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][NH:11]1>>[Br:1][C:2]1[C:3]([N:14]2[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:9])[CH2:15]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: C[C@H]1CNCCN1
Product: C[C@H]1CN(c2ncccc2Br)CCN1

Procedure:
A mixture of 3-bromo-2-chloropyridine (0.76 g, 4 mmol, Aldrich) and (S)-(+)-2-methylpiperazine (0.6 g. 6 mmol, Aldrich) reacted under the conditions of Example 3c to give the title compound as a light-brown solid. MS (ESI, pos. ion) m/z: 256 (M+1).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Cl:8][C:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19].C(O)(=O)C>CCCCCC.CO>[Cl:8][C:9]1[C:14]([C:15]([O:17][CH3:1])=[O:16])=[CH:13][CH:12]=[CH:11][C:10]=1[N+:18]([O-:20])=[O:19]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl

Procedure:
A solution of trimethylsilyldiazomethane in hexane (2 M) was added dropwise to a solution of 2.01 g 2-chloro-3-carboxy-nitrobenzene in 20 mL methanol at room temperature until no further gas evolution occurred. Acetic acid was then added to quench excess trimethylsilyldiazomethane. The reaction mixture was evaporated under vacuum and the residue was dried in an oven overnight. The 2-chloro-3-methoxycarbonylnitrobenzene obtained was pure enough for the following reaction.