Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]3[O:39][C:40]([CH3:43])=[N:41][N:42]=3)=[CH:34][CH:33]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25].CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:58][O:59][CH2:60][C@H:61](O)[CH3:62]>C1(C)C=CC=CC=1>[CH3:58][O:59][CH2:60][C@@H:61]([O:20][C:21]1[CH:22]=[C:23]([CH:28]=[C:29]([O:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[O:39][C:40]([CH3:43])=[N:41][N:42]=3)=[CH:36][CH:37]=2)[CH:30]=1)[C:24]([O:26][CH3:27])=[O:25])[CH3:62]
Reactant: COC[C@@H](C)O
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(-c3nnc(C)o3)cc2)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC[C@H](C)Oc1cc(Oc2ccc(-c3nnc(C)o3)cc2)cc(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 3 h
Yield: 237.6 %

Procedure:
Triphenyl phosphine (21 g, 80 mmol, 2.8 equiv.) was added to a stirring solution of Methyl 3-hydroxy-5-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy)benzoate (Intermediate 7) (9.3 g, 28.52 mmol, 1 equiv.) in toluene (100 mL) under nitrogen atmosphere at room temperature. The mixture was heated to 90° C. for 30 min. A mixture of Diisopropylazadicarboxylate (DIAD) (11.52 g, 57 mmol, 2 equiv.) and (R)-(−)-1-Methoxy-propan-2-ol (3.8 g, 42.8 mmol, 1.5 equiv.) in toluenene (50 mL) was added to the above reaction mixture at 90° C. and the reaction mixture was stirred for 3 h at 100° C. The completion of the reaction was monitored by TLC. After completion, the reaction mixture was concentrated under vacuum and purified by column chromatography to get (5)-Methyl 3-[(1-methoxypropan-2-yl)oxy]-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (Intermediate 8) as thick liquid (27 g). Sodium hydroxide (3.43 g, 85.92 mmol, 3 equiv.) in water (55 mL) was added to a stirring solution of (9-Methyl 3-[(1-methoxypropan-2-yl)oxy]-5-[4-(5-methyl-1,3,4-oxadiazol-2-yl)phenoxy]benzoate (crude) (Intermediate 8) in methanol (110 mL) in round bottomed flask. The reaction mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC. After completion, methanol was removed under vacuum and water was added. The reaction mixture was filtered. Filtrate was washed with ethyl acetate. The aqueous layer was acidified and extracted with DCM twice. The combined organic layer was washed with water, brine and dried over anhydrous sodium sulphate, filtered and concentrated in vacuum to furnish title acid as thick liquid (9.5 g).
Reaction SMILES: Cl[C:2]1[C:3]([F:22])=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]2=[O:21].[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3=[O:21])[CH2:34][CH2:35]1)=[O:29])([CH3:26])([CH3:24])[CH3:25].[C:23]([O:27][C:28]([N:30]1[CH2:31][CH:32]=[C:33]([C:2]2[C:3]([F:22])=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:21])[CH2:34][CH2:35]1)=[O:29])([CH3:24])([CH3:25])[CH3:26]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(Cl)c(F)cn2c1=O
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)cn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(C3=CCN(C(=O)OC(C)(C)C)CC3)c(F)cn2c1=O

Procedure:
Ethyl 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.32 mmol) and tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (124.5 mg, 0.40 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded quantitatively the title compound as a yellow solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[NH4+].[Cl-].[N:7]1[CH:8]=[CH:9][N:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=12>CN(C=O)C.CCOCC>[N:1]1[NH:2][N:3]=[N:17][C:16]=1[C:13]1[CH:14]=[CH:15][N:10]2[CH:9]=[CH:8][N:7]=[C:11]2[CH:12]=1
Reactant: N#Cc1ccn2ccnc2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: c1cn2ccc(-c3nn[nH]n3)cc2n1
Temperature: 80 °C
Yield: 330 %

Procedure:
Sodium azide (97 mg, 1.45 mmol) was added to a stirred mixture of NH4Cl (82 mg, 1.53 mmol) and imidazo[1,2-a]pyridine-7-carbonitrile (200 mg, 1.4 mmol) in dry DMF (5 ml) at RT under N2. The reaction was stirred and heated at 80° C. in a sealed vial for 10 hours. [3 identical reactions were run in parallel] After cooling to RT the reaction mixtures were combined and diluted with Et2O. The solid was collected by filtration and dried to give the title compound (860 mg) as a light brown solid. [presumably contains NaCl] 1H NMR (400 MHz, DMSO-d6): 8.55 (1H, dd), 8.02 (1H, s), 7.94 (1H, s), 7.57 (1H, d), 7.54 (1H, dd).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[N:6]=[C:5]2[CH2:16][CH2:17][CH2:18][C:4]=12.Cl.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:7]2[N:6]=[C:5]3[CH2:16][CH2:17][CH2:18][C:4]3=[C:3]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23][CH2:22]3)[CH:8]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: N[C@H]1CC[C@H](CO)CC1
Reactant: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Agent: Cl
Product: OC[C@H]1CC[C@H](Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)CC1

Procedure:
Following general procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride (0.093 g, 0.31 mmol) was reacted with trans-(4-aminocyclohexyl)methanol hydrochloride (0.077 g, 0.47 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.011 g, 9%) as a light yellow solid. MW=393.35. 1H NMR (DMSO-d6, 500 MHz) δ 13.44 (s, 1H), 7.99-7.96 (m, 1H), 7.83 (d, J=7.5 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.55 (br s, 1H), 7.10 (s, 1H), 4.45-4.43 (m, 1H), 3.84-3.80 (m, 1H), 3.28-3.23 (m, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H); 1.92-1.90 (m, 2H), 1.79-1.77 (m, 2H), 1.45-1.34 (m, 3H), 1.16-1.10 (m, 2H); APCI MS m/z 357 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13].[C-:14]#[N:15].[Na+]>CO.O>[C:14]([CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[F:13])#[N:15]
Reactant: [C-]#N
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(CC#N)c(F)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 56.7 %

Procedure:
To a solution of methyl 4-(bromomethyl)-3-fluorobenzoate (18 g, 73 mmol) in MeOH (150 ml) was added the solution of NaCN (7.2 g, 146 mmol) in H2O (40 ml). The mixture was stirred at 65° C. for 5 hours. Most of MeOH was evaporated and additional water was added and extracted by EtOAc (200 ml×3), dried with anhydrous Na2SO4, filtered and evaporated to give the crude product. Purification by column chromatography (PE/EtOAc=50/1 to 10/1) gave the product (8 g, 63.8%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[C:4]([Cl:11])[CH:3]=1.[CH2:12](P(CCCC)CCCC)CCC.C[Mg]Br.Cl>C1COCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[O:7])[CH3:12])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CCCCP(CCCC)CCCC
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Br)cc1Cl
Temperature: -22 °C
Reaction time: 0.67 h

Procedure:
5 g of crude 4-bromo-2-chlorobenzoyl chloride (from step 1) are dissolved in 120 ml anhydrous THF. 45.6 ml of tributylphosphine is added dropwise at −22° C., and after 20 minutes 141 ml of methyl magnesium bromide is added dropwise and the reaction mixture is stirred for 40 minutes at −22° C. The reaction mixture is poured into 1N aqueous HCl solution and the aqueous layer is extracted with ethyl acetate (3×). The combined organic layers are washed with a saturated solution of sodium chloride, dried over MgSO4 and evaporated to dryness under reduced pressure. The remaining residue is purified by flash chromatography (n-hexane/ethyl acetate, 9/1 (v/v)) to yield the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH2:9][CH2:10][CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1>[CH3:21][O:22][C:23]1[C:28]([CH2:29][N:14]2[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9][C:8]3[CH:17]=[CH:18][CH:19]=[CH:20][C:7]=3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:16][CH2:15]2)=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: c1ccc(-c2ccccc2CCC2CCNCC2)cc1
Reactant: COc1ncccc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1ncccc1CN1CCC(CCc2ccccc2-c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.8 %

Procedure:
181 mg of 4-(2-phenylphenethyl)piperidine synthesized from the corresponding raw material in the same manner as in the above-mentioned process, 150 mg of 2-methoxy-3-pyridinecarboxaldehyde and 226 mg of sodium triacetoxy borohydride were suspended in 5 ml of tetrahydrofuran, and the mixture was stirred for 20 hours at room temperature. The reaction mixture was basified by adding a 1N aqueous sodium hydroxide thereto, and then extracted with ethyl acetate. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the crude product was purified by NH form silica gel column chromatography (ethyl acetate:hexane=1:19), to give 213 mg of the title compound as a colorless oil.
Reaction SMILES: Cl.[F:2][C:3]([CH3:7])([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.[N:15]([C@H:18]([C@H:28]1[CH2:30][O:29]1)[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)=[N+:16]=[N-:17]>CC(O)C>[N:15]([C@@H:18]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[C@H:28]([OH:29])[CH2:30][NH:5][CH2:4][C:3]([F:2])([CH3:7])[CH3:6])=[N+:16]=[N-:17]
Reactant: COc1ccc(C[C@H](N=[N+]=[N-])[C@H]2CO2)cc1
Reactant: CC(C)(F)CN
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1ccc(C[C@H](N=[N+]=[N-])[C@H](O)CNCC(C)(C)F)cc1
Temperature: 60 °C
Yield: 50 %

Procedure:
To a solution of 2-fluoro-2-methylpropan-1-amine-HCl (2.0 eq) and triethyl amine (4.0 eq) in iPrOH was added an iPrOH solution of (S)-2-((S)-1-azido-2-(4-methoxyphenyl)ethyl)oxirane. The mixture was heated at 60° C. for 6 h. Upon completion the reaction mixture was concentrated then dissolved in ethyl acetate and washed with H2O. The organic layer was combined washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by flash chromatography. 50% yield. 1H NMR (400 MHz, Chloroform-d) δ 7.4 (d, J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 3.80 (s, 3H), 3.64-3.57 (m, 2H), 2.96-2.88 (m, 2H), 2.78-2.68 (m, 4H), 1.42 (d, J=3.1 Hz, 3H), 1.37 (d, J=3.1 Hz, 3H).
Reaction SMILES: C(OC([N:8]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)[N:21]([CH2:36][C:37](=[O:42])[NH:38][CH:39]([CH3:41])[CH3:40])[C:20]3=[O:43])[CH2:10][CH:9]1[CH3:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([C:22]2[N:21]([CH2:36][C:37]([NH:38][CH:39]([CH3:41])[CH3:40])=[O:42])[C:20](=[O:43])[C:19]3[C:24](=[CH:25][CH:26]=[C:17]([N:11]4[CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][NH:8][CH:9]([CH3:44])[CH2:10]4)[CH:18]=3)[N:23]=2)=[CH:28][C:29]=1[O:34][CH3:35]
Reactant: COc1cc(-c2nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)CC(C)(C)C4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Solvent: CO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nc3ccc(N4CC(C)NCC(C)(C)C4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[2-(4-Fluoro-3-methoxyphenyl)-3-(isopropylcarbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2,6,6-trimethylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (120 mg, 0.197 mmol) was dissolved in DCM (6 mL) and TFA (3 mL) added. The reaction was stirred at room temperature for 4 h. Product mixture was poured directly onto an SCX cartridge and product eluted with 2N NH3/MeOH. Solvent was evaporated under reduced pressure to afford a red solid. Product was diluted with MeOH (20 mL) and heated at reflux temperature with activated carbon. The mixture was filtered through a celite pad, solvent evaporated under reduced pressure and the resultant product recrystallised from ethanol:heptane. This afforded 2-[2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a) (74 mg, 0.145 mmol, 74%). Data for 2-[2-(4-fluoro-3-methoxyphenyl)-4-oxo-6-(3,6,6-trimethylperhydro-1,4-diazepin-1-yl)-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a): MS (ESI) m/z: 510 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([OH:14])[CH:3]=1.F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1.C(OCC)C>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][C@@H:7]([CH3:11])[C:8]([OH:10])=[O:9])=[C:4]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH:3]=1
Reactant: C[C@H](Oc1ccc(Cl)cc1O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOCC
Product: C[C@H](Oc1ccc(Cl)cc1Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Temperature: 90 °C

Procedure:
To a solution of (2S)-2-(4-chloro-2-hydroxyphenoxy)-propanoic acid (0.216 g) and 1-fluoro-4-nitro-benzene (0.127 g) in NMP (3 ml) was added potassium carbonate (0.276 g) and the reaction heated at 90° C. for 2 h. After cooling to RT, water and diethylether were added. The aqueous layer was separated and extracted again with diethylether. The aqueous layer was isolated, acidified to pH 2 and extracted with diethylether. This later extract was dried and evaporated under reduced pressure. The residue was purified by chromatography on silica eluting with 30-50% ethylactate/isohexane+1% AcOH, yield 0.2 g
Reaction SMILES: [NH2:1]OS(O)(=O)=O.[NH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1.[OH-].[K+]>O>[NH2:1][N:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[NH2:7]
Reactant: NOS(=O)(=O)O
Reactant: Nc1nc2ccccc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nc1nc2ccccc2n1N
Reaction time: 0.5 h

Procedure:
Hydroxylamine O-sulphonic acid (tech. 23.25 g, 205 mmol) was added to a stirred solution of 2-aminobenzimidazole (25 g, 187.5 mmol) dissolved in water (600 ml) containing potassium hydroxide (24.6 g, 438 mmol) at 23° C. After a few moments a white solid began to precipitate. The mixture was stirred for 30 mins and the product collected by filtration, washed with water and dried in air at ambient temperature, 10.75 g. On standing overnight a second crop, 5.8 g was obtained. The total yield of product was 16.55 g, 60%, mp. 252°-254° C., (lit. 255°-259° C.). Spectroscopic analysis was consistent with the product but indicated a small amount of the starting material was also present. This was used without further purification (note 1).
Reaction SMILES: Br[CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3.[N-:19]=[N+:20]=[N-:21].[Na+].CN(C)C=O>C(Cl)(Cl)Cl>[N:19]([CH2:2][CH:3]1[O:18][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[C:9]([CH3:17])=[CH:8]3)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CBr)O3
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Cc1cc2c3c(cc(C)c2[nH]c1=O)CC(CN=[N+]=[N-])O3
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.7 %

Procedure:
To 2-Bromomethyl-5,8-dimethyl-2,3,6,7-tetrahydrofuro[2,3-f]quinoline-7-one (3.36 g, 10.9 mmol) and sodium azide (5.1 g, 78.5 mmol), dimethylformamide (73.2 ml) were added, and stirred for 1 hour in a bath at 100° C. After cooling, the mixture was condensed, and the resultant residue was dissolved in chloroform, which was washed with water and dried. After condensation, the precipitated crystals were subjected to recrystallization (chloroform-ether) to obtain 2.76 g of the title compound as colorless crystals (93.8%).
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][CH2:14][C:15]([NH:17][OH:18])=[NH:16])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:27])=O)=[CH:23][CH:22]=1>>[ClH:27].[CH:1]1([N:6]2[CH2:7][CH2:8][CH:9]([CH2:12][CH2:13][CH2:14][C:15]3[N:16]=[C:25]([C:24]4[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=4)[O:18][N:17]=3)[CH2:10][CH2:11]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: N=C(CCCC1CCN(C2CCCC2)CC1)NO
Product: COc1ccc(-c2nc(CCCC3CCN(C4CCCC4)CC3)no2)cc1
Product: Cl

Procedure:
The title compound was prepared by a similar procedure to that described in Example 3, starting from 4-(1-cyclopentylpiperidin-4-yl)-N-hydroxybutyramidine and 4-methoxybenzoyl chloride.
Reaction SMILES: [C:1]([N:9]=[C:10]=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>C(Cl)Cl>[C:1]([NH:9][C:10](=[O:11])[NH:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C=NC(=O)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)NC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.7 %

Procedure:
To a solution of benzoylisocyanate (4.8 g, 32.6 mmol) in CH2Cl2 (180 mL) at 0° C. was added 4-amino-1-N-boc-piperidine (6.0 g, 30 mmol). The reaction mixture was stirred at room temperature for 4 h and concentrated. The residue was treated with Et2O (100 mL). The precipitate was filtered and washed with Et2O to yield 5.70 g (55%) of the title compound as a white solid. LC/MS: m/z (ES+) 337 (M+H)+.
Reaction SMILES: [OH-].[Na+].O1CCCC1.C([O:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18]C=C(O)[CH:21]=2)[N:16]=[C:15]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:14]=1)=[O:12])C.[C:30]([O:33][C:34](=[O:36])[CH3:35])(=O)[CH3:31]>ClCCl>[C:34]([O:33][C:30]1[CH:21]=[C:22]2[C:17](=[CH:18][CH:31]=1)[N:16]=[C:15]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:14]=[C:13]2[C:11]([OH:12])=[O:10])(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2ccc(O)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc2nc(-c3ccccc3)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
An aqueous sodium hydroxide solution (0.3184 g/30.0 mL) was added to a tetrahydrofuran (30.0 mL) solution of 6-hydroxy-2-phenyl-4-quinolinecarboxylic acid ethyl ester (1.1120 g, 3.79 mmol) obtained above, and the mixture was stirred at room temperature for 3 hours. To the reaction solution, dichloromethane (30.0 mL) and acetic anhydride (2.0 mL) were added. The mixture was washed with water and saturated saline and dried over anhydrous sodium sulfate, and then, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain the title compound (1.0903 mg, 3.55 mmol) as a pale yellow powder.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:14]([NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[NH2:1][C@H:2]([C:14]([NH:16][C@H:17]([C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])[CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1.[F:42][C:43]([F:48])([F:47])[C:44]([O-:46])=[O:45]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: N[C@@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Product: O=C([O-])C(F)(F)F

Procedure:
Boc-L-Asp(OBzl)-L-Phe-OBzl (9.91 g) was dissolved in a mixture of trifluoroacetic acid (50 ml) and dichloromethane (50 ml). The resultant solution was stored at room temperature for 2 hr. The reaction mixture was evaporated to dryness to yield a residue which was triturated with ether, collected, washed thoroughly with ether and dried under high vacuum to yield L-Asp(OBzl)-L-Phe-OBzl, trifluoroacetate salt (8.36 g) as a white solid: NMR (CDCl3) δ2.88 (2H, m), 3.07 (2H, m), 4.33 (1H, m), 4.78 (1H, m), 5.02 (2H, s), 5.06 (2H, q), 6.20 (3H, v. br), 7.04 (2H, m), 7.26 (13H, m), 7.65 (1H, d); m/Z 461 (M +H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][CH:4]=1.[OH-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O>[CH2:15]([O:9][C:8](=[O:10])[C:7]1[CH:11]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[O:12][CH2:8][C:7]1[CH:11]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1ccc(O)c(C(=O)O)c1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(OCc2ccccc2)c(C(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A solution of 5-methoxysalicylic acid (33.6 g., 0.2 mol) in 300 ml. of hexamethylphosphorustriamide is treated successively with 16 g. of sodium hydroxide in 40 ml. of water and 68.4 g. (0.4 mol) of benzyl bromide. The resulting solution is stirred 14 hours at room temperature, poured into water and extracted with diethyl ether. The ether solution is dried and evaporated to a yellow oil which solidified on standing. Recrystallization from benzenehexane gives the desired 2-benzyloxy-5-methoxy benzoic acid benzyl ester.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][N:4]=1.[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][C:14]([C:15](O)=[O:16])=[C:13]([F:21])[CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.Br>CN(C=O)C.O>[Cl:10][C:11]1[C:19]([Cl:20])=[CH:18][C:14]([C:15]([NH:9][C:7]2[CH:6]=[CH:5][NH:4][C:3](=[O:2])[CH:8]=2)=[O:16])=[C:13]([F:21])[CH:12]=1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1F
Reactant: COc1cc(N)ccn1
Agent: Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(Nc1cc[nH]c(=O)c1)c1cc(Cl)c(Cl)cc1F
Temperature: 95 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
A solution of 2-methoxypyridin-4-amine (186.2 mg, 1.5 mmol), 4,5-dichloro-2-fluoro-benzoic acid (285.1 mg, 1.36 mmol), HATU (622.4 mg, 1.64 mmol) and N-methylmorpholine (299.9 μL, 2.73 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with ethyl acetate (3×). The organics were combined, washed with water (3×), brine and dried over Na2SO4, filtered through a short plug of silica and evaporated to dryness. The material was taken up in HBr (in acetic acid) (6.689 mL of 33% w/v, 27.28 mmol) and stirred at 95° C. for 16 h. The solution was cooled to room temperature, filtered and solid product washed with water (2×) and then ether (2×) and dried under vacuum to give 4,5-dichloro-2-fluoro-N-(2-oxo-1H-pyridin-4-yl)benzamide (250 mg, 61%) as an off white solid. ESI-MS m/z calc. 299.99, found 301.3 (M+1)+; Retention time: 1.16 minutes (3 minutes run).