Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C([N:31]([CH2:34]C)CC)C>C1COCC1>[CH3:17][O:18][N:31]([CH3:34])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CCN(CC)CC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a stirred solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol). The mixture was stirred for 1 h under ice-water bath. A suspension of triethylamine (207 mL, 1.41 mol) and N, O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC showed the reaction was complete. The solvent was evaporated, and the residue was dissolved in CH2Cl2 (1.2 L) and washed successively with 0.5 N hydrochloride solution, saturated solution of sodium carbonate and brine, dried over anhydrous sodium sulfate and evaporated to give crude compound (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 g, 91%), which was used in the next step directly without purification. 1H NMR (400 MHz, CDCl3): 4.05-4.19 (m, 2H), 3.72 (s, 3H), 3.17 (s, 3H), 2.75-2.85 (m, 2H), 2.65 (t, 1H), 1.90 (d, 1H), 1.60-1.78 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].[Mg].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH:11]=[O:12].S(=O)(=O)(O)O>C(OCC)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:11]([OH:12])[CH:2]([CH3:4])[CH3:3])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: CC(C)Br
Reactant: COc1ccc(C=O)cc1OC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: COc1ccc(C(O)C(C)C)cc1OC
Temperature: 0 °C
Yield: 99.6 %

Procedure:
An isopropyl magnesium bromide ether solution prepared by using 5.6 g of 2-bromopropane, 0.94 g of magnesium and 30 ml of diethyl ether, was dropwise added to a mixture comprising 5.0 g of 3,4-dimethoxybenzaldehyde and 50 ml of diethyl ether, followed by a reaction for 15 hours under reflux. The reaction mixture was put into ice water, and dilute sulfuric acid was added, followed by stirring. Then, the mixture was extracted with methylene chloride, followed by washing with water. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain 6.3 g of oily 1-(3′,4′-dimethoxyphenyl)-2-methylpropanol.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:3]2[C:2]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:10]3[C:5]([N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7](=[O:13])[N:8]([CH3:12])[C:9]3=[O:11])=[CH:4]2)=[CH:24][CH:23]=1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Cl)n(Cc3ccc(-c4ccccn4)cc3)cc21
Reactant: Nc1ccccc1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(Nc3ccccc3)n(Cc3ccc(-c4ccccn4)cc3)cc21
Temperature: 150 °C
Yield: 46 %

Procedure:
Crude 5-chloro-1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (0.032 mmol) is placed in a Biotage microwave tube, and then aniline (0.2 mL) is added. The mixture is heated at 150° C. for an hour, and then purified by a semi-preparative HPLC to give 7 mg of pure product (overall yield:46%). MS (ESI) m/z 480.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH2:4][C:5](C)([C:24]([O:26][CH3:27])=[O:25])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH:18]=[CH:19][Si](C)(C)C)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].[CH:29](Cl)(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl>[CH3:29][C:4]1[C:5]2([C:24]([O:26][CH3:27])=[O:25])[CH:6]3[CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:2]([CH3:1])([CH2:19][CH:18]2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]3=2)[N:3]=1
Reactant: COC(=O)C1=C(C)NCC(C)(C(=O)OC)C1c1ccccc1C=C[Si](C)(C)C
Reactant: ClC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Product: COC(=O)C1C2c3ccccc3C3CC1(C)N=C(C)C32C(=O)OC
Reaction time: 3 h

Procedure:
To the Compound 1b (1.0 mmol) in Chloroform (10 ml) was added titanium tetrachloride (1.1 mmol) under nitrogen at ambient temperature. After 3 hours, the solvent was removed in vacuo and the residue flash chromatographed on silica gel eluted with hexane:diethyl ether (1:2) to afford the desired product. The β-isomer was a white solid (Rf =0.4, m.p. 104.5°-105.5° C.). The α-isomer was a white solid (Rf =0.3, m.p. 160°-161.5° C.).
Reaction SMILES: [F-].[K+].[F:3][C:4]([F:19])([F:18])[C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[C:6]=1[C:7]([OH:9])=[O:8].Br[CH2:21][C:22](CBr)=[O:23].[C:26]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:44]([NH:46][C@H:47]([C:52]([OH:54])=[O:53])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:45])[CH3:43])=[O:40])[CH:36]([CH3:38])[CH3:37])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH3:21][C:22]([O:8][C:7](=[O:9])[C:6]1[C:5]([C:4]([F:18])([F:19])[F:3])=[CH:13][CH:12]=[CH:11][C:10]=1[C:14]([F:15])([F:17])[F:16])=[O:23].[C:26]([NH:34][C@H:35]([C:39]([NH:41][C@H:42]([C:44]([NH:46][C@H:47]([C:52]([OH:54])=[O:53])[CH2:48][CH2:49][CH2:50][CH3:51])=[O:45])[CH3:43])=[O:40])[CH:36]([CH3:37])[CH3:38])(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C(CBr)CBr
Reactant: O=C(O)c1c(C(F)(F)F)cccc1C(F)(F)F
Agent: CCCC[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C)C(=O)O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OC(=O)c1c(C(F)(F)F)cccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A mixture of potassium fluoride (0.1 mmol, 6 mg) and 2,6-bis(trifluoromethyl)benzoic acid (0.066 mmol, 17 mg) in dry DMF (500 μl) was stirred over molecular sieves at room temperature for 5 minutes. A solution of N-benzoyl-L-valyl-L-alanyl-L-norleucine bromomethyl ketone (0.033 mmol), 16 mg) in dry DMF (500 μl) was added and the reaction mixture stirred for 1 hour. The reaction mixture was passed through a short silica plug and washed with 5% methanol in dichloromethane. Solvent was removed under vacuum and the residue purified using prep. HPLC. Freeze drying afforded (6.4 mg) as a white lyophilisate. Electrospray MS m/z 660 [MH+ ]. ##STR6##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:29][C:28]([F:30])([F:31])[O:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: [O-]B([O-])Oc1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)C1=Cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
Under argon atmosphere, A mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-trifluoromethoxyphenyl borate (0.55 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 20 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give pale yellow crystals of methyl 7-(4-trifluoromethoxyphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (638.5 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[N:16][C:17]([NH2:20])=[N:18][CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][N:23]=1.C1COCC1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>CS(C)=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[N:18][C:17]([NH:20][C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[C:25]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)=[N:24][N:23]=4)=[N:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1
Reactant: COc1cnc2c(Nc3cnc(N)nc3)ccnc2c1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1cnc2c(Nc3cnc(Nc4nnc(-c5ccccc5)c5ccccc45)nc3)ccnc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N5-(7-methoxy-1,5-naphthyridin-4-yl)pyrimidine-2,5-diamine (90 mg, 335 μmol), 1-chloro-4-phenylphthalazine (97 mg, 403 μmol), THF (1677 μl, 335 μmol), and LiHMDS (1006 μl, 1006 μmol) were added into a pressure tube. The mixture was stirred at RT for 10 min. A red solution was formed. The tube was placed in a preheated oil bath at 100° C. After 1 h, LCMS showed complete conversion of SM to product. The reaction was cooled to rt. Hexane was added to induce the product to precipitate out of the reaction mixture. The resulting red solid was filtered with an aid of hexane. LCMS confirmed that the solid was the product. The product was purified by performing a column chromatography on silica gel using 60:40 CH2Cl2:(90:10:1 CH2Cl2:MeOH:NH4OH). Yellow solid was obtained. LCMS confirmed product. HPLC showed 96% pure. 1H NMR showed rotamers. Note: this cmpd was slightly soluble in DMSO at rt. MS Calcd for C27H20N8O: [M]+=472. Found: [M+H]+=473.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:19]3=[C:20]4[C:10](=[CH:11][CH:12]=[C:13]([CH3:21])[C:14]4=[CH:15][CH:16]=[C:17]3[CH:18]=1)[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].CO.[Br-:24].[Br-].[Br-].C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.C([N+](C)(C)C)C1C=CC=CC=1.O>ClCCl>[Br:24][C:11]1[C:10]2[C:20]3=[C:19]4[C:7](=[CH:8][CH:9]=2)[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:18]=[C:17]4[CH:16]=[CH:15][C:14]3=[C:13]([CH3:21])[CH:12]=1
Reactant: Cc1ccc2ccc3cc(C(C)(C)C)cc4ccc1c2c34
Reactant: [Br-]
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: Cc1cc(Br)c2ccc3cc(C(C)(C)C)cc4ccc1c2c43
Temperature: 25 °C
Reaction time: 4 h
Yield: 155.4 %

Procedure:
Next, a mixed solution of 3 g of 7-t-butyl-1-methylpyrene, 130 ml of dichloromethane and 43 ml of methanol was cooled to 0° C. under a nitrogen gas stream and then 4.3 g of benzyltrimethylammonium tribromide dissolved in 5 ml of dichloromethane was added dropwise. This mixed solution was stirred at room temperature for 4 hours and 50 ml of water was poured into the solution, followed by extraction with 50 ml of dichloromethane. The organic layer was washed twice with 50 ml of water, dried over magnesium sulfate and then evaporated. The concentrate was purified by silica gel column chromatography and then vacuum-dried to obtain 3.4 g of 1-bromo-7-t-butyl-3-methylpyrene.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:39].CO>O1CCCC1>[ClH:39].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:32][O:33][CH2:34][CH2:35][N:36]=[N+:37]=[N-:38])[C:10]([NH:12][CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: [N-]=[N+]=NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: [N-]=[N+]=NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.6 %

Procedure:
A mixture of 7-[2-(2-formamidothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer, 0.9 g.), conc. hydrochloric acid (0.2 g.), methanol (10 ml.) and tetrahydrofuran (4 ml.) was stirred at room temperature for 5 hours. After concentrating the resultant solution in vacuo, the residue was pulverized with a mixture of disopropyl ether and ethyl acetate (30 ml. 5:1 v/v). The precipitates were collected by filtration, washed with diisopropyl ether and dried to give 7-[2-(2-aminothiazol-4-yl)-2-(2-azidoethoxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 0.8 g.).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15]Br.O>CN(C=O)C>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCCBr)cc1
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
A solution of 4-hydroxybenzaldehyde (3.7 g, 30 mmol) in DMF (10 ml) was added cautiously to a stirred solution of sodium hydride (60% in oil, 1.44 g) in DMF (80 ml). After 30 min., 1,3-dibromopropane (9.2 ml, 90 mmol) in DMF (10 ml) was added dropwise, the mixture stirred for 16 h, poured into water, extracted twice with ethyl acetate, and the combined extracts washed with water and saturated aqueous sodium chloride, dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica, eluting with 25% diethyl ether in hexane, to afford 4-(3-bromopropyloxy)benzaldehyde (3.85 g). M+ 205; 360 MHz 1H n.m.r (CDCl3) 7.85 (2H, d, J 7.0 Hz), 7.01 (2H, d, J 7.0 Hz), 4.20 (2H, t, J 5.8 Hz), 3.62 (2H, t, J 6.4 Hz), 2.36 (2H, pentet, J 6.1 Hz).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH2:42][C@@H:43]([OH:46])[CH2:44][NH2:45])=[CH:30][CH:29]=1>>[CH:28]1[C:40]2[NH:39][C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:32]=2[C:31]([O:41][CH2:42][C@@H:43]([OH:46])[CH2:44][NH:45][CH:2]2[CH2:3][CH2:4][N:5]([C:8]3[CH:13]=[CH:12][C:11]([NH:14][S:15]([C:18]4[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:27])[CH3:26])=[CH:22][CH:23]=4)(=[O:16])=[O:17])=[CH:10][CH:9]=3)[CH2:6][CH2:7]2)=[CH:30][CH:29]=1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(=O)CC3)cc2)cc1
Reactant: NC[C@H](O)COc1cccc2[nH]c3ccccc3c12
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2ccc(N3CCC(NC[C@H](O)COc4cccc5[nH]c6ccccc6c45)CC3)cc2)cc1

Procedure:
The title compound was prepared from N-{4-[4-(4-oxo-piperidin-1-yl)-phenylsulfamoyl]-phenyl}-acetamide (which was obtained in Example 216) and (2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamine (Berridge et al., Int. J. Radial. Appl. Instrum., 1992, 563) according to the procedure of Example 255 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.55–1.75 (m, 2 H), 2.00–2.15 (m, 2 H), 2.06 (s, 3 H), 2.50–2.70 (m, 2 H), 3.00–3.50 (m, 3 H), 3.60–3.70 (m, 2 H), 4.10–4.25 (m, 2 H), 4.35–4.50 (m, 1 H), 5.97 (brs, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 6.80 (d, J=8.0 Hz, 2 H), 6.88 (d, J=8.0Hz, 2 H), 7.10–7.50 (m, 5 H), 7.59 (d, J=8.7 Hz, 2 H), 7.69 (d, J=8.7 Hz, 2 H), 8.22 (d, J=7.8 Hz, 1 H), 9.71 (s, 1 H), 10.40 (s, 1 H), 11.32 (s, 1 H); MS (ES) m/z: 627.9 (MH+); HRMS Calcd. for C34H38N5O5S (MH+): 628.2594. Found: 628.2593.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11])=[O:4].[C:12](=[O:15])([O-])[O-].[Cs+].[Cs+].C(Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C=O)C>[CH2:12]([O:15][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH3:2])=[C:6]([CH3:11])[CH:7]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C([O-])[O-]
Reactant: BrCc1ccccc1
Reactant: Cc1ccccc1C(=O)CO
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Hydroxy-2′-methylacetophenone (5.508 g, 0.037 mol) in DMF (10 mL) is added cesium carbonate (23.8 g, 0.073 mol). The reaction is stirred at room temperature for 10 minutes. Benzyl bromide (4.36 mL, 0.037 mol) is added and after 1 hour at room temperature, the reaction is concentrated under reduced pressure. The residue is dissolved in ethyl acetate and water. The layers are separated and the organic phase is washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the title compound. ES/MS m/e 241.0 (M+1)
Reaction SMILES: [C:1]([NH:7][C@H:8]([C:13]([OH:15])=[O:14])[CH2:9][C:10]([OH:12])=O)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C(OC(=O)C)(=O)C.[O-2].[Mg+2].C(OC(C)C)(=O)C>C(O)(=O)C>[C:1]([NH:7][C@@H:8]1[C:13](=[O:14])[O:15][C:10](=[O:12])[CH2:9]1)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4]
Reactant: CC(=O)CC(=O)N[C@@H](CC(=O)O)C(=O)O
Agent: [Mg+2]
Agent: [O-2]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)C
Solvent: CC(=O)OC(C)=O
Product: CC(=O)CC(=O)N[C@H]1CC(=O)OC1=O

Procedure:
Reaction of 22.8 parts N-acetoacetyl-L-aspartic acid with 11.25 parts acetic anhydride, 0.059 parts magnesium oxide, and 2.1 parts by volume glacial acetic acid in 32 parts by volume isopropyl acetate at 45°-50° C. for 100 minutes as described above in Example 6-H above afforded 19.5 parts N-acetoacetyl-L-aspartic anhydride.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([O:16][CH3:17])[CH:9]=2)=[N:6][CH:7]=1.[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH:19]=[CH2:20].CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([C:5]2[N:6]=[CH:7][C:2](/[CH:20]=[CH:19]/[C:18]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[CH:3][CH:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2ccc(Br)cn2)cc1OC
Reactant: C=CC(=O)OC(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2ccc(/C=C/C(=O)OC(C)(C)C)cn2)cc1OC
Reaction time: 18 h
Yield: 82.4 %

Procedure:
To a degassed solution of bromide 37 (0.47 g, 1.6 mmol), tert-butyl acrylate 38 (1.12 mL, 7.7 mmol), POT (0.34 g, 1.1 mmol) and Hunig's base (1.11 mL, 6.4 mmol) in DMF (8 mL) was added tris(dibenzylideneacetone)dipalladium (0) (0.124 g, 0.16 mmol). The solution was placed in a preheated oil bath at 120° C., stirred for 18 h and concentrated. Flash chromatography purification of the residue (eluent: 3:1 hexane:AcOEt) afforded title compound 39 (0.45 g, 83% yield).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][NH:8][S:9]([C:12]2[S:16][C:15]([C:17]3[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=3[CH3:26])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH2:4][O:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][NH:8][S:9]([C:12]1[S:16][C:15]([C:17]2[S:21][C:20]([NH:22][C:23](=[O:25])[CH3:24])=[N:19][C:18]=2[CH3:26])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC3COC(C)(C)O3)s2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCC(O)CO)s2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
N-[5-(5-{[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]aminosulfonyl}-2-thienyl)-4-methyl-1,3-thiazol-2-yl]acetamide (14) (48 mg; 0.11 mmol; 1 eq), is dissolved in DCM (5 ml). Trifluoroacetic acid (0.2 ml) is added and reaction mixture stirred at room temperature for 30 minutes. The solvents are evaporated and the crude product purified directly by preparative HPLC, affording Compound (17) as a white-off solid (7 mg; 16%). M− (ESI): 390.2; M+ (ESI): 392.2. HPLC (method A), Rt: 2.13 min (purity: 83.5%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:10]=[C:11]([NH:15][C:16]([C:18]3[N:22]([CH3:23])[N:21]=[C:20]([CH3:24])[CH:19]=3)=[O:17])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.N1C=CC=CC=1>O>[CH3:23][N:22]1[C:18]([C:16]([NH:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:5]3[CH:6]=[N:7][C:2]([NH:1][S:31]([C:28]4[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=4)(=[O:33])=[O:32])=[CH:3][CH:4]=3)[CH:10]=2)=[O:17])=[CH:19][C:20]([CH3:24])=[N:21]1
Reactant: Cc1cc(C(=O)Nc2cccc(Oc3ccc(N)nc3)c2)n(C)n1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Oc3cccc(NC(=O)c4cc(C)nn4C)c3)cn2)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 102 %

Procedure:
A mixture of N-{3-[(6-aminopyridin-3-yl)oxy]phenyl}-1,3-dimethyl-1H-pyrazole-5-carboxamide (750 mg, 2.32 mmol), p-toluenesulfonyl chloride (486 mg, 2.55 mmol) and pyridine (6 mL) was stirred at 80° C. for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure and dried to give the title compound (1.13 g, 99%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Br:12]N1C(=O)CCC1=O.O>C(O)(=O)C>[Br:12][C:8]1[CH:7]=[CH:6][C:4]([NH2:5])=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[Cl:1]
Reactant: Nc1cccc(Cl)c1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(Br)c(Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 66.9 %

Procedure:
3-Chloro-2-nitroaniline (5.00 g, 29.0 mmol) was dissolved in glacial acetic Acid (258 mL). N-Bromosuccinimide (5.06 g, 28.4 mmol) was added and the resulting mixture was refluxed for 1 hour. The reaction was cooled to room temperature and poured into water to give a precipitate that was filtered, rinsed with water and dried to constant weight to give the title compound (4.78 g, 67%). 1H NMR (400 MHz, CDCL3) δ ppm 7.46 (d, J=9.0, 1H), 6.64 (d, J=9.0, 1H), 4.74 (s, 2H).
Reaction SMILES: C1(B(O)O)C=CC=CC=1.[CH3:10][N:11]([CH3:35])[C:12]1[C:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:16][C:15]([C:24]2[N:25]=[C:26](O)[C:27]3[CH:28]=[CH:29][CH:30]=[N:31][C:32]=3[CH:33]=2)=[CH:14][CH:13]=1.[NH2:36][CH2:37][CH2:38][CH2:39][NH2:40]>>[NH2:36][CH2:37][CH2:38][CH2:39][NH:40][C:26]1[N:25]=[C:24]([C:15]2[CH:16]=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]([N:11]([CH3:35])[CH3:10])=[CH:13][CH:14]=2)[CH:33]=[C:32]2[C:27]=1[CH:28]=[CH:29][CH:30]=[N:31]2
Reactant: NCCCN
Reactant: CN(C)c1ccc(-c2cc3ncccc3c(O)n2)cc1-c1ccccc1
Agent: OB(O)c1ccccc1
Product: CN(C)c1ccc(-c2cc3ncccc3c(NCCCN)n2)cc1-c1ccccc1

Procedure:
Treatment of the above intermediate with 2-methylnicotinic acid according to Method A (Example 1) provided the corresponding [1,6]napthyridin-5-ol. Treatment of this with phenylboronic acid using the procedure described in Example 5 provided 7-(6-dimethylamino-biphenyl-3-yl)-[1,6]naphthyridin-5-ol. Conversion to the 5-chloro intermediate using Method B, followed by treatment of this with 1,3-diaminopropane by the procedure described in Method C (Example 3) provided the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.82 (dd, 1H), 8.16 (d, 1H), 8.04 (dd, 1H), 8.00 (d, 1H), 7.63 (dd, 2H), 7.52 (s, 1H), 7.41 (t, 2H), 7.29 (t, 1H), 7.19 (dd, 1H), 7.08 (d, 1H), 3.84 (t, 2H), 3.00 (t, 2H), 2.58 (s, 6H), 1.99 (t, 2H); MS (m/e) calculated for C25H27N5 397, found 398.3 (M+H).