Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([C:8](O)=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:25][NH:26][O:27][CH3:28].C(OCC)(=O)C>CN(C)C=O.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.O>[F:1][C:2]1[C:7]([C:8]([N:26]([O:27][CH3:28])[CH3:25])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][N:3]=1
Reactant: CNOC
Reactant: O=C(O)c1cc(F)cnc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1cc(F)cnc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a solution of 2,5-difluoropyridine-3-carboxylic acid (3.00 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.34 g), 1-hydroxybenzotriazole (127 mg), and N,O-dimethylhydroxylamine hydrochloride (1.93 g) in N,N-dimethylformamide (30 ml), diisopropylethylamine (7.42 ml) was added, and the mixture was stirred overnight at room temperature. Ethyl acetate and water were added to the reaction solution to separate the aqueous and organic layers. The aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain the title compound (2.42 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:16][C@H:12]2[O:13][CH2:14][CH2:15][C@@:11]2([C:17]([OH:19])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][C:26]=1[CH2:35][NH2:36])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][C:26]=1[CH2:35][NH:36][C:17]([C@:11]12[CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:16][C@H:12]1[O:13][CH2:14][CH2:15]2)=[O:19])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)Oc1ccc(C(F)(F)F)cc1CN
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)O)C1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2OCC[C@@]2(C(=O)NCc2cc(C(F)(F)F)ccc2OC(C)(C)C)C1

Procedure:
The product of Step A was prepared from the reaction of the product of Example 23, Step E and (2-(tert-butoxy)-5-(trifluoromethyl)phenyl)methanamine prepared according to procedures in ACS Med. Chem. Letters 2010, 1, 14 following the procedure from Example 1, Step C. Calculated for C25H35F3N2O5: 523.2 (M+23). found: 523.2.
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[Cl:16][C:17]1[CH:22]=[N:21][CH:20]=[C:19]([Cl:23])[N:18]=1.[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]=[O:28].Cl>O1CCCC1.C(=O)(O)[O-].[Na+].C(O)C>[Cl:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH:27]([C:20]1[C:19]([Cl:23])=[N:18][C:17]([Cl:16])=[CH:22][N:21]=1)[OH:28]
Reactant: O=Cc1ccccc1Cl
Reactant: Clc1cncc(Cl)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: C1CCOC1
Product: OC(c1ccccc1Cl)c1ncc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
To a −20° C. solution of n-butyllithium (2.5 M in hexane, Aldrich, 26.5 mmol) in dry tetrahydrofuran (200 mL) under argon was added 2,2,6,6-tetramethylpiperidine (Aldrich, 11.5 mL, 66.5 mmol, 1.22 eq). The resulting solution was warmed to 0° C. over 0.5 hour period. The solution was then cooled to −78° C., and a solution of 2,6-dichloropyrazine (Aldrich, 8.24 g, 55.3 mmol, 1.0 eq) in tetrahydrofuran was slowly added via a syringe. After addition was complete, the resulting mixture was stirred at −78° C. for an additional 1 hour after which 2-chlorobenzaldehyde (Aldrich, 9.3 mL, 83 mmole, 1.5 eq) was added drop wise via a syringe. The reaction mixture was stirred for an additional 1 hour, quenched with hydrochloric acid (18 mL, 220 mmol, 4 eq)/ethanol (75 mL)/tetrahydrofuran (90 mL) mixture, and then warmed to room temperature. The reaction mixture was diluted with aqueous saturated sodium bicarbonate solution and extracted with ether. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered, and concentrated to give a crude oil which was purified via chromatography using dichloromethane/hexanes (1:1) as the eluent to give (2-chlorophenyl)-(3,5-dichloropyrazin-2-yl)methanol (12.8 g, 44 mmol, 80% yield). Mass spec, M+1=290.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:36][O:37][CH3:38])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[CH2:13][S:14][C:15]([S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:16]3[C:20]([O:22]C(C)(C)C)=[O:21])=[O:9])[N:6]=1>C(O)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:36][O:37][CH3:38])[C:8]([NH:10][CH:11]2[C:18](=[O:19])[N:17]3[CH:12]2[CH2:13][S:14][C:15]([S:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[C:16]3[C:20]([OH:22])=[O:21])=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(C)(C)C)=C(Sc3ccc(OC)cc3)SCC12)c1csc(N)n1
Solvent: O=CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Sc3ccc(OC)cc3)SCC12)c1csc(N)n1
Temperature: 50 °C

Procedure:
100 mg of the product of Step C dissolved in 2 ml of 66% formic acid were heated to 50° C. for 3 hours with stirring and was concentrated to dryness under reduced pressure. The residue was taken up in acetonitrile and the solvent was evaporated. The crude product was crystallized from ether and was then dissolved in methylene chloride with 10% of methanol. The solution was treated with active charcoal, then filtered and the filtrate was concentrated to dryness. The residue obtained was crystallized from ether to obtain 80 mg of syn isomer of racemic 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-3-(4-methoxyphenylthio)-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid melting at 185°-190° C. (with decomposition).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].CN(C)C(=N)N(C)C.[C:25]([O:29][C:30](N=[N+]=[N-])=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C)C=O>[C:25]([O:29][C:30]([NH:2][CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: NC(CCCC(=O)O)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N=[N+]=[N-]
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(CCCC(=O)O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of crude 5-amino-6-phenylhexanoic acid hydrochloride (0.235 g, 0.97 mmoles) prepared as described in Example 1 and tetramethylguanidine (0.438 g, 2.90 mmoles) in dimethylformamide (6.60 mls) is treated with t-butoxycarbonylazide (0.276 g, 1.93 mmoles) in dimethylformamide (3.00 mls) and the solution stirred for 48 hours at room temperature. The dimethylformamide is evaporated and the product partitioned between ethyl acetate and 1 M citric acid. Extraction of the organic phase with 3% aqueous ammonia followed by acidification and extraction affords 5-t-butoxycarbonylamino-6-phenylhexanoic acid, which is further purified by preparative t.l.c. using benzene-dioxane-acetic acid (95:25:4 v/v/v) for development. Elution with ethyl acetate affords the pure acid as a white solid (0.180 g, 53% based on 5-phenyl-4-phthalimidopentanoic acid). Crystallisation from ethyl acetate/petrol (60°-80° C.) gives the acid in the form of a white powder, m.p. 94.5°-96.5° C.; τ(CDCl3): -0.67 (1H, s,D2O-exchangeable), 2.82 (5H,s), 5.58 br (1H, D2O-exchangeable) 6.28 br (1H), 7.28 (2H,d, J=6.5Hz), 7.68 (2H multiplet), 8.05-8.90 (10H, complex); νmax (CHCl3): 2600 (very broad) 1710, 1500 cm-1.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([OH:25])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1.FC(F)(F)S(O[CH2:32][C:33]([F:36])([F:35])[F:34])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:17]2[CH:18]=[C:19]([O:25][CH2:32][C:33]([F:36])([F:35])[F:34])[C:20](=[O:24])[N:21]([CH3:23])[CH:22]=2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(O)c(=O)n(C)c2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccc(OCC2CC2)c(-c2cc(OCC(F)(F)F)c(=O)n(C)c2)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
A mixture of 5-[2-(cyclopropylmethoxy)-5-ethylsulfonylphenyl]-3-hydroxy-1-methylpyridin-2-one (50 mg, 0.14 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (33 mg, 0.14 mmol), Cs2CO3 (134.48 mg, 0.42 mmol) in DMF (2 mL) was stirred at 20° C. for 2 h After the mixture was filtered, the filtrate was concentrated in vacuo. The residue was purified by prep-HPLC to give the title compound (29 mg, 47%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.84 (m, 1H), 7.77 (m, 1H), 7.41 (m, 2H), 7.04 (m, 1H), 4.58 (m, 2H), 3.95 (m, 2H), 3.70 (s, 3H), 3.14 (m, 2H), 1.33-1.27 (m, 4H), 0.72-0.69 (m, 2H), 0.39-0.35 (m, 2H). LCMS (M+H)+=446.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[N:10][C:11]([CH3:18])=[C:12]([CH3:17])[CH:13]=2)[N:8]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=2)[CH:7]=1)=[O:5])C.[OH-].[Li+].O>CO>[CH3:17][C:12]1[CH:13]=[C:14]2[C:9](=[N:10][C:11]=1[CH3:18])[N:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=1)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16]
Reactant: CCOC(=O)c1cn(Cc2cccc(C)n2)c2nc(C)c(C)cc2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cccc(Cn2cc(C(=O)O)c(=O)c3cc(C)c(C)nc32)n1
Yield: 85.6 %

Procedure:
Experimental conditions analogous to those described for Step 4 of Example 60 were used with 1.60 g (4.55 mmol) of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid ethyl ester, 0.33 g (13.66 mmol) of lithium hydroxide, 100 mL of water and 50 mL of methanol to afford 1.26 g of 6,7-Dimethyl-1-(6-methyl-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]([NH2:19])=[C:17]([OH:20])[C:16]([Br:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23].[C:24]([O:27][C:28]([C:31](Cl)=O)([CH3:30])[CH3:29])(=[O:26])[CH3:25].C(N(CC)CC)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:18]3[N:19]=[C:29]([C:28]([O:27][C:24]([CH3:25])=[O:26])([CH3:31])[CH3:30])[O:20][C:17]=3[C:16]([Br:21])=[CH:15][C:14]=2[F:22])[C:3]1=[O:23]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2c(F)cc(Br)c(O)c2N)c1=O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: CC(=O)OC(C)(C)c1nc2c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc(Br)c2o1
Temperature: 25 °C
Yield: 109 %

Procedure:
A stirred solution of 0.50 gram (0.0013 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.21 gram (0.0013 mole) of 1-chlorocarbonyl-1-methylethyl acetate, 0.14 gram (0.0014 mole) of triethylamine, and 0.16 gram (0.0006 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene was heated at 150 ° C. for about 18 hours. The reaction mixture was then cooled to ambient temperature and taken up in ethyl acetate. The solution was washed with water and an aqueous solution saturated with sodium chloride; then it was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 0.72 gram of Compound 104. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@@:13]1([Cl:17])[CH2:12][N:11]([C@@H](C1C=CC=CC=1)C)[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([NH:8][C@@:9]12[CH2:16][CH2:15][CH2:14][C@@:13]1([Cl:17])[CH2:12][NH:11][CH2:10]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](c1ccccc1)N1C[C@]2(Cl)CCC[C@@]2(NC(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@]12CCC[C@@]1(Cl)CNC2
Temperature: 40 °C
Reaction time: 19 h

Procedure:
Under hydrogen atmosphere, a mixture of (1R,5R)-1-(tert-butoxycarbonylamino)-5-chloro-3-[(1R)-1-phenylethyl]-3-azabicyclo[3.3.0]octane (63.0 mg, 0.173 mmol), 10% Pd—C (50 wt %, M, 32 mg) in methanol (6 mL) was stirred for 4 hours at room temperature and for 19 hours at 40° C. After removing catalyst by filtration, the filtrate was distilled off under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=O>>[Cl:25][C:23]1[CH:24]=[C:16]2[C:17]([C:18](=[O:20])[N:12]([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:11])=[O:10])[C:13](=[O:14])[NH:15]2)=[CH:21][CH:22]=1
Reactant: COc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Product: COc1ccc(S(=O)(=O)n2c(=O)[nH]c3cc(Cl)ccc3c2=O)cc1
Yield: 47.8 %

Procedure:
1.14 g (5.35 mmol) of 4-methoxybenzenesulfonylisocyanate and 938 mg (5.35 mmol) of 2-amino-4-chlorobenzoic acid were treated in the same way as in Example 1 to obtain 938 mg of the above-identified compound (yield 64.3%). Properties: colorless crystal, Melting point: >200° C. (decomposition), PMR (δppm, DMSO-d6):3.88 (3H,s), 7.12 (1H,s), 7.17-7.23 (3H,m), 7.85 (1H,d), 8.10 (2H,d), 11.68 (1H,br).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58]([NH2:62])[CH:59]=[CH:60][CH:61]=2)[CH:51]=1>CN(C=O)C>[N:50]1[CH:55]=[CH:54][CH:53]=[C:52]([C:56]2[CH:57]=[C:58]([NH:62][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:59]=[CH:60][CH:61]=2)[CH:51]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: Nc1cccc(-c2cccnc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cccnc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 83.6 %

Procedure:
DIEA (43.5 μL, 0.25 mmol) was added to 8-methoxy-3-carboxy-coumarin (50.0 mg, 0.23 mmol) and HATU (95.0 mg, 0.25 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-pyridin-3-yl-phenylamine (38.7 mg, 0.23 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 71.6 mg of product in 84% yield: LCMS (ESI) m/z 373 (MH+).
Reaction SMILES: [CH2:1]([N:3]([C:23]1[CH:28]=[C:27]([O:29]C)[CH:26]=[CH:25][C:24]=1[CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([O:41]C)[CH:37]=2)[CH2:32]1)[C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:18][CH:17]3[N:19]([CH3:20])[CH:14]([CH2:15][CH2:16]3)[CH2:13]2)=[C:7]([F:21])[CH:6]=1)[CH3:2].C(N(CC1C=CC(OC2CC3N(C)C(CC3)C2)=C(F)C=1)C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)C>>[CH2:1]([N:3]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]2[CH2:13][CH:14]3[N:19]([CH3:20])[CH:17]([CH2:16][CH2:15]3)[CH2:18]2)=[C:7]([F:21])[CH:6]=1)[C:23]1[CH:28]=[C:27]([OH:29])[CH:26]=[CH:25][C:24]=1[CH:31]1[CH2:40][CH2:39][C:38]2[CH:37]=[C:36]([OH:41])[CH:35]=[CH:34][C:33]=2[CH2:32]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(OC2CC3CCC(C2)N3C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)c(F)c1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Product: CCN(Cc1ccc(OC2CC3CCC(C2)N3C)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from N-ethyl-3-fluoro-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)benzamide according to an analogous synthetic method to Example 337, ethyl[3-fluoro-4-(8-methyl-8-azabicyclo[3.2.1]oct-3-yloxy)benzyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (123 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (108 mg).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:37]1([C:41](Cl)=[O:42])[CH2:40][CH2:39][CH2:38]1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][C:41]([CH:37]4[CH2:40][CH2:39][CH2:38]4)=[O:42])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: O=C(Cl)C1CCC1
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1)C1CCC1
Reaction time: 0.17 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (150 mg, 0.38 mmol) in DCM (4 mL) at room temperature was added triethylamine (56 μL, 0.40 mmol) followed by cyclobutanecarbonyl chloride (43 μL, 0.38 mmol) and the solution stirred for 10 minutes. The solution was then loaded directly onto a pre-wetted Biotage 25M column for flash chromatography and eluted with 2-8% MeOH/DCM to yield the title compound as a white solid, 138 mg, 76%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.43-8.56 (2 H, m), 7.60-7.70 (3 H, m), 7.24-7.35 (2 H, m), 7.09-7.21 (2 H, m), 6.51 (1 H, s), 5.09-5.31 (2 H, m), 4.13 (1 H, d, J=13.39 Hz), 3.93 (2 H, s), 3.70-3.88 (2 H, m), 3.15 (1 H, t, J=11.37 Hz), 2.89-3.04 (1 H, m), 2.69-2.82 (1 H, m), 2.03-2.17 (2 H, m), 1.93-2.03 (2 H, m), 1.81-1.92 (1 H, m), 1.66-1.80 (3 H, m,) 1.29-1.48 (1 H, m), 1.13-1.27 (1 H, m); m/z (APCI+) for C27H30N5O2F 476.2 (M+H)+.
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][NH:5][CH3:6].C(N(CC)CC)C.Cl[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>C(Cl)Cl>[CH2:18]([O:17][C:15]([N:4]([CH3:3])[NH:5][CH3:6])=[O:16])[CH:19]([CH3:21])[CH3:20]
Reactant: CNNC
Reactant: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNN(C)C(=O)OCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of N,N'-dimethylhydrazine dihydrochloride (940 mg) and triethylamine (2.15 g) in methylene chloride (30 ml) which was cooled to 0° C., was added isobutyl chloroformate (970 mg). The mixture was stirred at 0° C. for 1 hour. After evaporation of the solvent, the residue was dissolved in ethyl acetate (50 ml) and the solution was washed with 1M sodium bicarbonate solution and water successively, and dried over sodium sulfate. The solvent was evaporated to give N-isobutoxycarbonyl-N,N'-dimethylhydrazine (922 mg) as an oil.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=CC(S(O)(=O)=O)=CC=2O)[CH:5]=[C:4]([S:17]([OH:20])(=[O:19])=[O:18])[CH:3]=1.[N:21]1C(F)=NC(F)=NC=1F.C(=O)([O-])[O-].[Na+].[Na+].NC1C=CC=C2C=1C=CC(S(O)(=O)=O)=C2.N([O-])=O.[Na+]>O.Cl>[NH2:21][C:5]1[CH:6]=[CH:11][CH:2]=[CH:3][C:4]=1[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: Fc1nc(F)nc(F)n1
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Agent: Cl
Agent: Nc1cccc2cc(S(=O)(=O)O)ccc12
Agent: O=C([O-])[O-]
Solvent: O
Product: Nc1ccccc1S(=O)(=O)O

Procedure:
34.1 g of 1-amino-8-hydroxynaphthalene-3,6-disulphonic acid are dissolved in 400 ml of water at pH 5.5. After cooling the solution to 0°-5°, 9.2 ml of cyanuric fluoride are added dropwise in the course of 10 minutes, and during this the pH value in the solution is kept at 4.0-4.5 by adding 20% strength sodium carbonate solution dropwise. The solution is subsequently stirred at this pH value and at 0°-5° for 1/2 an hour and 24.5 g of 5-aminonaphthalene-2-sulphonic acid are then added. The ph value of the solution kept at 5.5-6.0 with sodium carbonate solution and the temperature is gradually increased to 20° in the course of 2 hours. After the condensation reaction has ended, the mixture is again cooled to 0°-10° and the suspension of a diazonium compound which has been obtained from 18.4 g of 2-aminobenzenesulphonic acid in 200 ml of water and 30 ml of concentrated hydrochloric acid with 54 ml of 2N sodium nitrite solution in the manner shown in the Example is now added.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[C:19]([CH2:22][CH2:23][N:24]1[C:28]([SH:29])=[N:27][N:26]=[N:25]1)([OH:21])=[O:20].B(F)(F)F.CCOCC>C(#N)C>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:29][C:28]3[N:24]([CH2:23][CH2:22][C:19]([OH:21])=[O:20])[N:25]=[N:26][N:27]=3)[CH2:15][S:14][C@H:9]12
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(O)CCn1nnnc1S
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3CCC(=O)O)CS[C@H]12
Yield: 80.1 %

Procedure:
7-aminocephalosporanic acid (38.4 g) and 1-(2-carboxyethyl)-1H-tetrazole-5-thiol (20.0 g) were reacted in the presence of boron trifluoride etherate (80.0 g) and dry acetonitrile (200 ml) to give 7-amino-3-[1-(2-carboxyethyl)-1H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylic acid (35.52 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([CH:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15][O:14][C:13]4[CH:22]=[CH:23][C:24]([Br:26])=[CH:25][C:12]3=4)[CH2:7][CH2:6]2)[O:4]CC1.C(O)C>Cl>[O:4]=[C:5]1[CH2:10][CH2:9][N:8]([CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][O:14][C:13]3[CH:22]=[CH:23][C:24]([Br:26])=[CH:25][C:12]2=3)[CH2:7][CH2:6]1
Reactant: Brc1ccc2c(c1)C(N1CCC3(CC1)OCCO3)c1ccccc1CO2
Agent: Cl
Solvent: CCO
Product: O=C1CCN(C2c3ccccc3COc3ccc(Br)cc32)CC1
Yield: 100 %

Procedure:
Step 2): A suspension of 11-(1,4-dioxa-8-azaspiro[4,5]decane-8-yl)-2-bromo-6,11-dihydrodibenz[b,e]oxepin (5.5 g, 13.2 mmol) in 4N HCl was heated at 60°-70° C. for 30 minutes. Then ethanol was added to the mixture. The mixture was heated at 60°-70° C. for 1.5 hours. After ethanol was evaporated, the reaction mixture was made alkaline with 50% NaOH solution, then extracted with ethyl acetate and chloroform. The organic layer was washed with water, dried (MgSO4) and concentrated to give 11-(4-oxopiperidin-1-yl)-2-bromo-6,11-dihydrodibenz[b,e]oxepin (100%): mp 196°-200° C.
Reaction SMILES: C[CH2:2][CH:3]([C:14]([OH:16])=[O:15])[C:4]1[CH:5]=[CH:6][C:7](CC(C)C)=[CH:8][CH:9]=1>C1C=CC=CC=1>[C:4]1([CH:3]([CH3:2])[C:14]([OH:16])=[O:15])[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCC(C(=O)O)c1ccc(CC(C)C)cc1
Solvent: c1ccccc1
Product: CC(C(=O)O)c1ccccc1

Procedure:
The above examples are directed specifically to the production of ibuprofen, 2-(4-isobutylphenyl)propionic acid. However, the procedures and limits described in those examples are also illustrative of the application of the process to the production of other related acids of the class previously defined. Thus, by substituting cyclohexylbenzene for the isobutylbenzene starting material in Example 1 and proceeding as described in Examples 1-4, the product of the process is 2-(4-cyclohexylphenyl)propionic acid which is obtained in similar purity and yield. In the same way, when ethyl chloride is used in place of methyl chloride in the alkylation step of Example 3 and the procedures of Examples 3 and 4 are otherwise repeated, the final product is butibufen, 2-(4-isobutylphenyl)butyric acid, also obtained in good purity and yield as described. Similarly, using benzene in place of isobutylbenzene as a starting material in this process, a good yield of pure 2-phenylpropionic acid is produced. Likewise, tert-butylbenzene as the starting benzene reactant produces 2-(4-tert-butylphenyl)propionic acid, 1,1-diethylpropylbenzene produces 2-(4-(1,1-diethylpropyl)phenyl)propionic acid, and isopropylbenzene produces 2-(4-isopropylphenyl)propionic acid. In the same way, the appropriate alkylbenzene reactant and alkylating halide produce the compounds 2-(4-cyclopentylphenyl)propionic acid, 2-(4-(1-methylcyclohexyl)phenyl)propionic acid, 2-(4-tert-butylphenyl)butyric acid, 2-(4-isopentylphenyl)butyric acid, and 2-(4-cyclohexylphenyl)butyric acid.