Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](I)=[CH:4][N:3]=1.[Si]([C:13]#[CH:14])(C)(C)C.C(=O)([O-])[O-].[K+].[K+].C>O.[Cu]I.CO.C(N(CC)CC)C.C(#N)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:13]#[CH:14])=[CH:4][N:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(I)cn1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: C#Cc1cnc(N)nc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 1 L round bottom flask was placed the 2-amino-5-iodopyrimidine (8.0 g, 36.2 mmol), acetonitrile (300 mL), triethylamine (30 mL), TMS acetylene (7.68 g, 78.2 mmol), palladium dichloro-bis-triphenylphosphine (1.26 g, 1.8 mmol), and copper(I) iodide (0.342 g, 1.8 mmol). The vessel was filled with argon gas and allowed to stir at room temperature for 3 hours. The solvent was evaporated and the crude was taken up in methanol (400 mL). Then excess potassium carbonate (10 eq) was added, and the mixture was stirred at room temperature for 1.5 hours. Activated charcoal was added and the mixture was filtered through celite. The filtrate was concentrated under reduced pressure to afford a tan solid, which was added to a solution of 10% methanol in water (200 mL). The resulting precipitate was isolated by filtration, dried in a vacuum oven to constant mass and afforded the title compound as a tan solid. MS m/z=120 [M+H]+. Calc'd for C6H5N3: 119.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][O:14][CH2:13][C:12]1=[O:17])[C:5]([OH:7])=O.[Br:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH2:30])[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[Br:18][C:19]1[CH:32]=[CH:31][C:22]2[NH:23][C:24]([C@@H:26]([NH:30][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][C:12]4=[O:17])=[C:2]([CH3:1])[CH:3]=3)[CH2:27][O:28][CH3:29])=[N:25][C:21]=2[CH:20]=1
Reactant: COC[C@H](N)c1nc2cc(Br)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1N1CCOCC1=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC[C@H](NC(=O)c1ccc(N2CCOCC2=O)c(C)c1)c1nc2cc(Br)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-methyl-4-(morpholin-3-on-4-yl)-benzoic acid, (1R)-1-(5-bromo-1H-benzimidazol-2-yl)-2-methoxy-ethylamine, TBTU and DIPEA in THF with subsequent purification by chromatography on silica gel.
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([CH3:9])([CH3:8])[C:4]([O:6][CH3:7])=[O:5])(=[O:30])=[O:29]
Reactant: COC(=O)C(C)(C)C(O)CCCCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C(C)(C)C(CCCCc1ccccc1)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Methyl 3-hydroxy-2,2-dimethyl-7-phenylheptanoate (10 g, 38 mmol) and triethylamine (6.3 mL, 45 mmol) are dissolved in CH2Cl2 (50 mL) and cooled to 0° C. Methanesulfonyl chloride (3.2 mL, 42 mmol) is added and the reaction is allowed to stir at room temperature for 1 hour. The reaction mixture is then washed with NaHCO3 (2×40 mL), 1 N HCl (40 mL) and brine (40 mL). The solution is dried over MgSO4 and the solvent removed in vacuo to yield methyl 3-methanesulfonyloxy-2,2-dimethyl-7-phenylheptanoate (11.2 g, 86%). 1H NMR (300 MHz, CDCl3) δ 7.30-7.25 (m, 2H), 7.19-7.15 (m, 3H), 4.99 (dd, J=9.2, 2.0 Hz,1H), 3.69 (s, 3H), 2.93 (s, 3H), 2.62 (t, J=7.4 Hz, 2H), 1.71-1.38 (m, 6H), 1.27 (s, 3H), 1.18 (s, 3H); MS (FAB) m/e 343 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH:15]C(=O)OC(C)(C)C)[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[CH2:11][N:10]1[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[C@@H:14]([NH2:15])[CH2:13][C@@H:12]([N:23]2[CH2:30][C:29]3[CH:28]=[N:27][NH:26][C:25]=3[CH2:24]2)[CH2:11][N:10]1[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn[nH]c3C2)CN(Cc2ccccc2)[C@@H]1c1cc(F)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1C[C@@H](N2Cc3cn[nH]c3C2)CN(Cc2ccccc2)[C@@H]1c1cc(F)ccc1F

Procedure:
The product from Step E was treated with 2 ml, TFA in CH2Cl2 (2 mL) for 1 h. 1H NMR (500 MHz, CD3OD): δ 7.68 (br, 1H); 7.50 (m, 6H); 7.30 (m, 2H); 7.12 (br, 1H); 4.71 (br, 4H); 3.91 (br, 2H); 3.87 (br, 2H); 3.80 (br, 1H); 3.41 (br, 1H); 3.31 (br, 1H); 3.22 (br, 1H); 2.52 (m, 1H); 2.31 (m, 1H); LC-MS: 410.08 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([N+:9]([O-:11])=[O:10])[CH:5]=[C:4]([Cl:12])[CH:3]=1.[C:13](OCC)(=[O:15])C>>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]2[O:8][C:13](=[O:15])[NH:1][C:2]=2[CH:3]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc(Cl)cc([N+](=O)[O-])c1O
Product: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Temperature: 22.5 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
188.6 g (1 mole) of 6-amino-4-chloro-2-nitrophenol prepared according to Example 1c was suspended in 1000 ml of ethyl acetate under mild nitrogen purge and the optional present water was removed by azeotropic distillation of 250 ml of the solvent. The mixture was cooled to 20-25° C. and 224 g of carbonyldiimidazole was added as a slurry in 650 ml of ethyl acetate. An additional 100 ml of ethyl acetate was added and the mixture was vigorously stirred during two hours, without the application of cooling. 1000 ml of water was added and the mixture was stirred for 15 minutes. 1450-1500 ml of ethyl acetate was distilled off at about 200 mBar and about 50° C. The mixture was cooled to 0-5° C., 225 ml of 36% HCl was added and the mixture ws cooled again to 0-5° C. and stirred at this temperature for 15 minutes. The solid was filtered off, washed with 400 ml of 1N HCl, washed twice with 500 ml of cold water and once with 500 ml of cold water/ethanol (4/1), and dried at 50° C. and 100 mbar under a gentle nitrogen stream till dry. Yield about 99%.
Reaction SMILES: [O:1]1CCCO[CH:2]1[C:7]1[C:15]2[O:14][CH:13]=[CH:12][C:11]=2[CH:10]=[C:9]([N:16]2[CH:20]=[C:19]([Si](C)(C)C)[N:18]=[N:17]2)[CH:8]=1>[OH-].[K+].O.CO>[N:16]1([C:9]2[CH:8]=[C:7]([CH:2]=[O:1])[C:15]3[O:14][CH:13]=[CH:12][C:11]=3[CH:10]=2)[CH:20]=[CH:19][N:18]=[N:17]1
Reactant: C[Si](C)(C)c1cn(-c2cc(C3OCCCO3)c3occc3c2)nn1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=Cc1cc(-n2ccnn2)cc2ccoc12
Reaction time: 0.5 h

Procedure:
A solution of 1-(7-[1,3]dioxan-2-yl-benzofuran-5-yl)-4-trimethylsilanyl-1H-[1,2,3]triazole (180 mg) in potassium hydroxide (0.1 g), water (10 ml) and methanol (10 ml) was stirred for 18 h at room temperature. The solvent was removed, diluted with water (10 ml) and extracted with dichloromethane (3×15 ml). The organic extracts were washed with water (10 ml), dried, and evaporated. The residual oil was dissolved in hydrochloric acid (2M; 10 ml) and tetrahydrofuran (10 ml) and stirred at 70° for 30 min. The solution was cooled, basified with 1M sodium carbonate solution and extracted with dichloromethane (3×20 ml). The combined extracts were dried, and evaporated to give the title compound as a pale cream coloured solid (74 mg).
Reaction SMILES: C[O:2][C:3](=[O:41])[C@H:4]([CH2:37][CH2:38][S:39][CH3:40])[NH:5][C:6](=[O:36])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:19][CH:20]([CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH3:21])[S:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][C:8]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH3:35].O.[OH-].[Li+:44]>>[Li+:44].[CH2:15]([S:14][CH:13]([O:19][CH:20]([CH2:22][CH:23]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1)[CH3:21])[C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][C@H:4]([C:3]([O-:41])=[O:2])[CH2:37][CH2:38][S:39][CH3:40])=[O:36])=[C:8]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])[CH:9]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCSC(OC(C)CC1CCCCC1)c1ccc(C(=O)N[C@@H](CCSC)C(=O)OC)c(-c2ccccc2C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCCSC(OC(C)CC1CCCCC1)c1ccc(C(=O)N[C@@H](CCSC)C(=O)[O-])c(-c2ccccc2C)c1

Procedure:
The product from Example 1312C (242 mg, 0.4 mmol) was allowed to react with lithium hydroxide monohydrate (18 mg, 0.42 mmol) in a manner similar to that described in Example 608E to afford the title compound. 1H NMR (DMSO-d6, 300 MHz) δ0.73-0.93 (m, 2H), 0.82 (t, J=7 Hz, 3H), 1.02-1.74 (m, 20H), 1.77-2.02 (m, 6H), 2.15 (m, 1H), 2.59 (dd, J=6.5, 13 Hz, 1H), 2.72 (dd, J=4.5, 13 Hz, 1H), 3.55-3.73 (m, 2H), 4.51 (d, J=12.5 Hz, 1H), 4.65 (d, J=12.5 Hz, 1H), 6.95 (m, 1H), 7.10-7.25 (m, 4H), 7.37 (d, J=7.5 Hz,1H), 7.53 (d, J=8 Hz, 1H); MS (APCI(−)) m/z: (M−H)− 584; Anal. Calcd for C33H46LiNO4S2.0.85 H2O: C, 65.29; H, 7.92; N, 2.31. Found: C, 65.29; H, 7.45; N, 2.15.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=[O:21])[N:7]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>C1(C)C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[N:7]1[C:8]2[C:3](=[C:2]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=2)[CH2:4][CH2:5][C:6]1=[O:21]
Reactant: OB(O)c1ccccc1Cl
Reactant: COc1cc(Br)c2c(c1)N(c1ccccc1Cl)C(=O)CC2
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc(-c2ccccc2Cl)c2c(c1)N(c1ccccc1Cl)C(=O)CC2
Reaction time: 0.03 h
Yield: 86.8 %

Procedure:
5-Bromo-1-(2-chlorophenyl)-7-methoxy-3,4-dihydro-2(1H)-quinolinone (2.10 g, 5.728 mmol), and 2-chlorophenylboronic acid (1.77 g, 11.32 mmol) were dissolved in toluene (40 ml)-ethanol (15 ml), and 1M aqueous sodium carbonate (15 ml) added. Nitrogen gas was passed through the mixture for 2 min., then tetrakis(triphenylphosphine)-palladium(0) (0.3 g) added, and the mixture stirred under reflux under nitrogen for 3.5 h. The organic phase was separated, dried (Na2SO4), and evaporated in vacuo and the residue purified by flash chromatography over silica (70 g) eluting with cyclohexane-ethyl acetate gradient to afford the title compound as a white solid (1.98 g, 87%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]2)[CH:26]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][C:20]([NH:22][NH2:23])=O)=[CH:10][CH:9]=1)=[O:6].[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>O1CCCC1>[CH2:34]([N:36]1[C:37](=[O:38])[NH:23][N:22]=[C:20]1[CH2:19][O:18][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:24]=[C:25]([N:27]3[CH2:32][CH2:31][CH:30]([CH3:33])[CH2:29][CH2:28]3)[CH:26]=[C:2]([F:1])[CH:3]=2)=[CH:9][CH:10]=1)[CH3:35]
Reactant: CCN=C=O
Reactant: CC1CCN(c2cc(F)cc(C(=O)Nc3ccc(OCC(=O)NN)c4ccccc34)c2)CC1
Solvent: C1CCOC1
Product: CCn1c(COc2ccc(NC(=O)c3cc(F)cc(N4CCC(C)CC4)c3)c3ccccc23)n[nH]c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.7 %

Procedure:
To a solution of 3-fluoro-N-(4-hydrazinocarbonylmethoxy-naphthalen-1-yl)-5-(4-methyl-piperidin-1-yl)-benzamide (0.35 g, 0.77 mmol) in tetrahydrofuran (10 ml) is added ethylisocyanate (60 mg, 1.1 eq). The mixture is stirred at room temperature for 15 hours before being evaporated to dryness to give the urea intermediate as a solid (0.34 g). MS: 522 (M+1). Urea intermediate (0.1 g, 0.19 mmol) in 5% NaOH (2 ml) is heated at 100° C. for five hours. The mixture is then extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated to dryness. The residue is purified by column chromatography on silica gel eluted with ethyl acetate then ethyl acetate containing a few drops of ammonium hydroxide to give N-[4-(4-ethyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-ylmethoxy)-naphthalen-1-yl]-3-fluoro-5-(4-methyl-piperidin-1-yl)-benzamide as a white solid (21 mg). Mp: 240-241° C. 1H NMR (300 MHz, DMSO-d6) δ 11.88 (s, 1H), 10.27 (s, 1H), 8.16 (d, J=5.1 Hz, 1H), 7.88 (d, J=4.5 Hz, 1H), 7.57-6.95 (m, 7H), 5.27 (s, 2H), 3.78 (m, 4H), 2.77 (t, J=11.4 Hz, 2H) 1.68 (m, 3H), 1.20 (brs, 6H), 0.95 (brs, 3H). MS: 504 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:21])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)Nc2cccc(C3CC(C)(C)c4cc(Cl)ccc4N3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and 4-methyl-benzenesulfonyl chloride (103 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/Ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-4-methyl-benzenesulfonamide (133 mg, yield: 46%) as yellow solid. MS (ESI+APCI) M+1=441.1.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3]O.[NH2:7][C:8](C)(CO)[CH2:9][OH:10].N(CCO)(CCO)CCO>>[OH:10][CH2:9][CH2:8][NH:7][CH2:3][C:2]([CH3:6])([NH2:1])[CH3:5]
Reactant: CC(N)(CO)CO
Reactant: CC(C)(N)CO
Solvent: OCCN(CCO)CCO
Product: CC(C)(N)CNCCO

Procedure:
Neutralization with 2-amino-2-methyl-1-propanol or 2-amino-2-methyl-1-3-propandiol or triethanolamine is preferred.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]([F:26])([F:25])[F:24])=[N:4][N:5]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.BrN1C(=[O:33])CCC1=O>C(Cl)(Cl)(Cl)Cl.C1C=CC=CC=1>[OH:33][CH2:1][C:2]1[C:3]([C:23]([F:26])([F:24])[F:25])=[N:4][N:5]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(C(F)(F)F)nn(-c2ccc(S(N)(=O)=O)cc2)c1-c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(CO)c2-c2ccccc2)cc1

Procedure:
To a solution of 4-[4-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide prepared in Example 201 (500 mg, 1.3 mmol) in carbon tetrachloride (9 mL) and benzene (4 mL) was added N-bromosuccinimide (285 mg, 1.6 mmol). The mixture was irradiated with a sunlamp for 3.5 hours. The reaction mixture was partitioned between dichloromethane and water and the organic solution was dried and concentrated to give the desired product, 412 mg (69%).
Reaction SMILES: [F:1][C:2]1[C:21](F)=[CH:20][C:5]2=[N:6][C:7]3[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=3[CH:13]=[C:4]2[CH:3]=1.CS(O)(=O)=O.CS(O)(=O)=O.[NH2:33][C:34]1([CH3:38])[CH2:37][NH:36][CH2:35]1>>[NH2:33][C:34]1([CH3:38])[CH2:37][N:36]([C:21]2[C:2]([F:1])=[CH:3][C:4]3[C:5]([CH:20]=2)=[N:6][C:7]2[N:8]([O:18][CH3:19])[CH:9]=[C:10]([C:15]([OH:17])=[O:16])[C:11](=[O:14])[C:12]=2[CH:13]=3)[CH2:35]1
Reactant: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(F)cc3nc21
Reactant: CC1(N)CNC1
Agent: CS(=O)(=O)O
Product: COn1cc(C(=O)O)c(=O)c2cc3cc(F)c(N4CC(C)(N)C4)cc3nc21
Yield: 68.3 %

Procedure:
8-(3-Amino-3-methyl-1-azetidinyl)-7-fluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid was prepared under the conditions of Example 15, but starting with 1.53 g of 7,8-difluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3carboxylic acid and 2.22 g of 3-amino-3-methylazetidine dimethane-sulphonate. 1.27 g of 8-(3-amino-3-methyl-1-azetidinyl)-7-fluoro-1-methoxy-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxylic acid are obtained in the form of a yellow solid, which decomposes at 346° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C@@:10]23[CH2:19][C:18](=[O:20])[CH2:17][CH2:16][C@H:15]2[CH2:14][NH:13][CH2:12][CH2:11]3)[CH:7]=[CH:8][CH:9]=1.[CH2:21](Br)[CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:21]([N:13]1[CH2:12][CH2:11][C@@:10]2([C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH3:2])[CH:5]=3)[C@@H:15]([CH2:16][CH2:17][C:18](=[O:20])[CH2:19]2)[CH2:14]1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCBr
Reactant: COc1cccc([C@]23CCNC[C@@H]2CCC(=O)C3)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Yield: 24.9 %

Procedure:
0.71 g (2.55 mmol) of (±)-trans-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8, 8a-decahydroisoquinoline hydrochloride, 0.37 g (2.68 mmol) of butyl bromide, 0.53 g of potassium carbonate and a catalytical amount of potassium iodide in 15 ml of DMF were reacted as described in preparation 20, yielding 0.2 g of the title compound which was used as such in the subsequent step.
Reaction SMILES: [OH:1][C@H:2]([C:38]1[CH:47]=[CH:46][C:45]([OH:48])=[C:44]2[C:39]=1[CH:40]=[CH:41][C:42](=[O:49])[NH:43]2)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]2[CH2:37][CH2:36][C:24]3([O:29][CH2:28][CH2:27][N:26](C(=O)C(F)(F)F)[CH2:25]3)[CH2:23][CH2:22]2)[CH:15]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(=O)([O-])[O-].[K+].[K+]>CO.O>[O:29]1[C:24]2([CH2:36][CH2:37][N:21]([CH2:20][C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:12][N:4]([CH2:3][C@H:2]([OH:1])[C:38]3[CH:47]=[CH:46][C:45]([OH:48])=[C:44]4[C:39]=3[CH:40]=[CH:41][C:42](=[O:49])[NH:43]4)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:22][CH2:23]2)[CH2:25][NH:26][CH2:27][CH2:28]1
Reactant: CC(C)(C)OC(=O)N(CCc1cccc(CN2CCC3(CC2)CN(C(=O)C(F)(F)F)CCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1cccc(CN2CCC3(CC2)CNCCO3)c1)C[C@H](O)c1ccc(O)c2[nH]c(=O)ccc12

Procedure:
A solution of (R)-tert-butyl 2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl(3-((4-(2,2,2-trifluoroacetyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethyl)carbamate (example 12, step g) (0.100 g) in methanol (5.0 mL) was treated with a solution of potassium carbonate (0.035 g) in water (5.0 mL) and the resultant mixture stirred at 20° C. for 5 hours. The methanol was evaporated off under a stream of nitrogen and further water (5.0 mL) was added. The solution was acidified by addition of acetic acid and then passed through a 10 g cartridge of C18 silica. The cartridge was washed with water and then flushed with methanol to bring off the product. The solvent was evaporated off under reduced pressure to yield 0.090 g of the acetic acid salt. This solid was dissolved in methanol (2 mL) and passed through 0.700 g of VARIAN Bond Elut NH2 resin and the solvent was evaporated off under reduced pressure to afford the subtitled compound. Yield 0.074 g.
Reaction SMILES: [N+:1]([C:4]1[N:5]([CH2:9][C:10]#[CH:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]=[N+:19]=[N-:20])(=[O:14])[CH3:13].CCN(C(C)C)C(C)C>C1COCC1.[Cu]I>[C:12]([O:15][CH:16]([CH2:21][O:22][S:23]([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)(=[O:25])=[O:24])[CH2:17][N:18]1[CH:11]=[C:10]([CH2:9][N:5]2[CH:6]=[CH:7][N:8]=[C:4]2[N+:1]([O-:3])=[O:2])[N:20]=[N:19]1)(=[O:14])[CH3:13]
Reactant: C#CCn1ccnc1[N+](=O)[O-]
Reactant: CC(=O)OC(CN=[N+]=[N-])COS(=O)(=O)c1ccc(C)cc1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)OC(COS(=O)(=O)c1ccc(C)cc1)Cn1cc(Cn2ccnc2[N+](=O)[O-])nn1
Reaction time: 8 h
Yield: 81.6 %

Procedure:
To a solution of 2-nitro-1-(prop-2-ynyl)-1H-imidazole (0.2 gm, 1.32 mmol) and 1-azido-3-(tosyloxy)propan-2-yl acetate (0.41 gm, 1.32 mmol) in THF (2.5 mL), was treated with CuI (0.025 gm, 0.132 mmol) and DIPEA (0.3 mL, 1.46 mmol) at room temperature. After stirring the reaction mixture for overnight, silica was added, solvent evaporated under reduced pressure and purified by chromatography on silica gel (MeOH/CH2Cl2, 1/10) to give the 1-(4-((2-nitro-1H-imidazol-1-yl)methyl)-1H-1,2,3-triazol-1-yl)-3-(tosyloxy)propan-2-yl acetate (0.5 gm, 81%) as white solid. 1H NMR (CDCl3, 400 MHz) δ: 7.76-7.78 (m, 3H), 7.35-7.39 (m, 3H), 7.15 (br, 1H), 5.68 (d, J=5.6 Hz, 2H), 5.27-5.32 (m, 1H), 4.56-4.67 (m, 2H), 4.19 (dd, J=4.0, 11.2 Hz, 1H), 4.08 (dd, J=4.0, 11.2 Hz, 1H), 2.46 (s, 3H), 1.97 (s, 3H); Mass Spec (lo-res): Calc'd for C18H20N6O7S: 464.11. found: 465.1 (M+H+).
Reaction SMILES: C(C1C=CC(OCC2N=C(CC3C=CC(C(O)=O)=CC=3)ON=2)=C(Cl)C=1O)(=O)C.C([O:31][C:32](=[O:58])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][C:40]2[O:44][N:43]=[C:42]([CH2:45][O:46][C:47]3[CH:52]=[CH:51][C:50]([C:53](=[O:55])[CH3:54])=[C:49]([OH:56])[C:48]=3[Cl:57])[N:41]=2)[CH:34]=1)C>>[C:53]([C:50]1[CH:51]=[CH:52][C:47]([O:46][CH2:45][C:42]2[N:41]=[C:40]([CH2:39][C:35]3[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=3)[C:32]([OH:58])=[O:31])[O:44][N:43]=2)=[C:48]([Cl:57])[C:49]=1[OH:56])(=[O:55])[CH3:54]
Reactant: CCOC(=O)c1cccc(Cc2nc(COc3ccc(C(C)=O)c(O)c3Cl)no2)c1
Agent: CC(=O)c1ccc(OCc2noc(Cc3ccc(C(=O)O)cc3)n2)c(Cl)c1O
Product: CC(=O)c1ccc(OCc2noc(Cc3cccc(C(=O)O)c3)n2)c(Cl)c1O

Procedure:
The title compound is prepared essentially as described for 4-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid, employing 3-[3-(4-acetyl-2-chloro-3-hydroxy-phenoxymethyl)-[1,2,4]oxadiazol-5-ylmethyl]-benzoic acid ethyl ester. 1H NMR (DMSO-d6) δ 13.06 (s, 1H), 12.99 (s, 1H), 7.91 (m, 2H), 7.83 (m, 1H), 7.58 (m, 1H), 7.46 (dd, 1H), 6.89 (d, 1H), 5.49 (s, 2H), 4.48 (s, 2H), 2.59 (s, 3H). LC-MS (m/e): 401 (M−1).