Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][NH:11][C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1.[CH2:18](I)[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:13][CH2:12][N:11]([CH2:18][CH3:19])[C:10]2=[CH:14][N+:15]([O-:17])=[O:16])=[CH:4][N:3]=1
Reactant: CCI
Reactant: O=[N+]([O-])C=C1NCCC1Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(Cc2ccc(Cl)nc2)C1=C[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 0.5 g of 3-(2-chloropyrid-5-yl-methyl)-2-nitromethylidene-pyrrolidine, 0.3 g of ethyl iodide and 0.27 g of potassium carbonate in 3 ml of dimethylformamide is stirred at room temperature for 18 hours. The reaction mixture is poured onto water and extracted with diethyl ether. The ether phase is dried over magnesium sulfate and concentrated by evaporation in vacuo. The residue is chromatographed on silica gel with ethyl acetate/hexane (2:1). The title compound having a melting point of 129-131° C. (compound 5.5) is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][CH:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]2[OH:29])[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:12]([O:16][C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=2[N+:8]([O-:10])=[O:9])[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC2C(=CC=CC2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2c(cccc2Oc2cc(Cl)ccc2[N+](=O)[O-])C1
Temperature: 60 °C
Reaction time: 24 h
Yield: 97.7 %

Procedure:
A mixture of 4-chloro-2-fluoronitrobenzene (1.93 g, 11 mmols), 2-tert-butoxycarbonyl-5-hydroxy-tetrahydroisoquinoline (2.74 g, 11 mmols), potassium carbonate (1.53 g, 11 mmols) and N,N-dimethylformamide (20 ml) was stirred at 60° C. for 24 hours. The reaction mixture was cooled, then poured into water, and extracted with ethyl acetate. The extract was washed with water, and then dried with anhydrous magnesium sulfate, and the solvent was evaporated away. The residue was purified through silica gel column chromatography to give an oil of 2-tert-butoxycarbonyl-5-(5-chloro-2-nitrophenoxy)-1,2,3,4-tetrahydroisoquinoline (4.35 g, 97.7%).
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([S:10][CH2:11][C:12]#[C:13][CH2:14][C:15]#[C:16][CH2:17][C:18]#[CH:19])=[CH:8][CH:7]=1.[CH2:22]([O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31]I)[CH3:23].S(=O)(=O)(O)O>CCOCC.O1CCCC1>[CH2:22]([O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]#[C:30][CH2:31][C:19]#[C:18][CH2:17][C:16]#[C:15][CH2:14][C:13]#[C:12][CH2:11][S:10][C:9]1[CH:20]=[CH:21][C:6]([CH3:5])=[CH:7][CH:8]=1)[CH3:23]
Reactant: C#CCC#CCC#CCSc1ccc(C)cc1
Reactant: CCOC(=O)CCCC#CCI
Agent: CC[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CCCC#CCC#CCC#CCC#CCSc1ccc(C)cc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
12.03 ml (6.077 g, 0.0455 mol) of 3.8N ethylmagnesium bromide in ether was added dropwise to a solution of 9.65 g (0.0379 mol) of 9-(p-methylthiophenoxy)-1,4,7-nonatriyne in 80 ml of anhydrous tetrahydrofuran. The temperature was maintained at -10° C. The reaction mixture was stirred for 1 hour further at 0° C., allowed to warm to room temperature, and then 374 mg of cuprous cyanide were added. The mixture was stirred for 20 additional minutes, heated to 40° C. and then treated with 13.83 g (49.38 mmol) of 7-iodo-5-heptynoic acid ethyl ester in 30 ml of anhydrous tetrahydrofuran.The resulting mixture was stirred for 3 additional hours at 40° C., then poured on to 300 ml of 1N sulfuric acid and ice. After extraction with ether (3×150 ml), the combined extract was concentrated to a small volume and washed several times with Versene solution and water, dried and evaporated in vacuo. The crude material was purified by column chromatography on 125 g of silica gel, using hexane:ethyl acetate (95:5) as eluant, to obtain 16-(p-methylthiophenoxy)-hexadeca-5,8,11,14-tetraynoic acid ethyl ester, as an oil. The product was stored in dry ice.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: OCc1ccc(Cl)c(O)c1
Product: OCc1ccc(Cl)c(OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-chloro-5-(hydroxymethyl)phenol and 4-(bromomethyl)-1-fluorobenzene according to the procedure for the preparation of Example 117, part A. 1H NMR (400 MHz, CDCl3): δ 1.71 (1H, t, J=6.0 Hz), 4.65 (2H, d, J=6.4 Hz), 5.12 (2H, s), 6.88-6.90 (1H, m), 7.02 (1H, d, J=2.0 Hz), 7.05-7.10 (2H, m), 7.35 (1H, d, J=8.0 Hz), 7.43-7.46 (2H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=3[C:17]#N)[CH:10]=[N:9]2)=[C:5]([CH3:23])[O:4][N:3]=1.Cl.C[OH:26]>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[CH2:14][C:15]4[C:16](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]3=[O:26])[CH:10]=[N:9]2)=[C:5]([CH3:23])[O:4][N:3]=1
Reactant: Cc1noc(C)c1Cn1cc(NCc2ccccc2C#N)cn1
Reactant: CO
Agent: Cl
Product: Cc1noc(C)c1Cn1cc(N2Cc3ccccc3C2=O)cn1
Yield: 50 %

Procedure:
2-((1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-ylamino)methyl)benzonitrile (example 9-2) (30 mg, 0.14 mmol) was stirred in a mixture of MeOH/2N aqueous NaOH (5 mL) at 100° C. for 30 minutes in the microwave reactor. The reaction was acidified with 1N aqueous HCl (100 mL) and extracted with ethyl acetate (3×, 70 mL). The combined organic extracts were dried over sodium sulfate and concentrated. The residue was dissolved in MeOH (3 mL) and purified by reversed phase HPLC in 2-1.5 mL aliquots (5 to 95% acetonitrile in H2O: 16 minute gradient). The pure fractions were combined and concentrated to afford 2-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)isoindolin-1-one (21 mg, 50%) as a pure white solid. 1H NMR (DMSO-d6, 400 MHz): δ2.15 (s, 3H), 2.41 (s, 3H), 4.81 (s, 2H), 5.17 (s, 2H), 7.48-7.50 (m, 1H), 7.51-7.52 (m, 2H), 7.72 (d, J=7.2 Hz, 1H), 7.75 (s, 1H), 8.20 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 11 μM.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:7]=2[O:6][N:5]=1)[CH3:2].[OH:13]S(O)(=O)=O.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>C(O)(=O)C.C(OCC)C>[CH2:1]([O:3][C:4]1[C:8]2[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:7]=2[O:6][N:5]=1)[CH3:2]
Reactant: CCOc1noc2c1CCCC2
Reactant: O=S(=O)(O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCOc1noc2c1C(=O)CCC2
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
To a solution of 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazole 1a (35 g) in glacial acetic acid (500 mL) at 10° C. was added concentrated H2SO4 (29 mL). A solution of sodium dichromate (71 g) in glacial acetic acid (300 mL) kept at 40-45° C. was added dropwise during one hour at 20-25° C. The mixture was stirred for another 3 hours at 25-30° C. The reaction mixture was poured onto ice and diethyl ether (3 L). pH was adjusted to >10 by addition of concentrated aqueous NaOH. The organic phase was separated and worked up. The remaining crude title compound was purified by column chromatography on silica gel (eluted with ethyl acetate/heptane 1:1). Pure 3-ethoxy-4,5,6,7-tetrahydro-1,2-benzisoxazol-4-one was washed with diisopropyl ether and dried. Yield 27 g. Mp 98-99° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28](OC2C=CC([N+]([O-])=O)=CC=2)=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13].C(N(CC)CC)C>ClCCl>[CH3:10][O:11][C:12]([C:14]1[C@H:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[N:18]([C:28]([NH:8][CH2:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:9])=[O:29])[C:17](=[O:40])[NH:16][C:15]=1[CH2:41][O:42][CH3:43])=[O:13]
Reactant: COCC1=C(C(=O)OC)[C@H](c2ccc(F)c(F)c2)N(C(=O)Oc2ccc([N+](=O)[O-])cc2)C(=O)N1
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)N1C(=O)NC(COC)=C(C(=O)OC)[C@@H]1c1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
β-Alanine ethyl ester hydrochloride (87 mg, 0.57 mmol), (+)-5-methyoxycarbonyl-4-methoxymethyl-1,2,3,6-tetrahydro-2-oxo-6 (S)-(3,4-difluorophenyl)-1-[(4-nitrophenyloxy)-carbonyl]pyrimidine (as described in Section I.A.(c)) (227 mg, 0.48 mmol), and triethylamine (209 mL, 1.50 mmol) were combined in 5 mL of dichloromethane. The yellow mixture was stirred at ambient temperature for 1 hour, then evaporated to dryness. The resulting oil was purified by “flash” chromatography (5.02, 98:2:0.2 of dichloromethane: methanol:ammonium hydroxide). The product fractions were evaporated to dryness to give the title compound as a clear oil.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:5]([O:6][CH3:7])[C:4]=1[Cl:11].[F:12][C:13]1[CH:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15](Cl)=[O:16].[Al+3].[Cl-].[Cl-].[Cl-].O>ClC(Cl)C>[Cl:11][C:4]1[C:3]([OH:2])=[C:10]([CH:9]=[CH:8][C:5]=1[O:6][CH3:7])[C:15]([C:14]1[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=1[F:12])=[O:16]
Reactant: COc1cccc(OC)c1Cl
Reactant: O=C(Cl)c1ccccc1F
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CC(Cl)Cl
Product: COc1ccc(C(=O)c2ccccc2F)c(O)c1Cl

Procedure:
2-chlororesorcinol dimethyl ether (22.0 g) and o-fluorobenzoyl chloride (20.2 g) are dissolved in 250 ml of dichloroethane, chilled in an ice bath and treated with AlCl3 (18.6 g). Fifteen minutes after the addition is complete, the reaction is heated to reflux for 30 minutes. It is poured into H2O and extracted with ethylacetate. Evaporation and trituration with hexane gives 3-chloro-2'-fluoro-2-hydroxy-4-methoxybenzophenone, mp 132°-133° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:19][CH:20]1[O:24][C:23](=[O:25])[NH:22][CH2:21]1>CN(C)C=O>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([O:1][CH2:19][CH:20]3[O:24][C:23](=[O:25])[NH:22][CH2:21]3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:5]1
Reactant: O=C1NCC(CCl)O1
Reactant: O=C1CCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1NCC(COc2cccc3c2CCC3=O)O1
Temperature: 200 °C
Reaction time: 0.08 h

Procedure:
A mixture of 4-hydroxy-1-indanone (500 mg, 3.37 mmol), cesium carbonate (2.0 g, 6.14 mmol) and 5-chloromethyl-2-oxazolidinone (503 mg, 3.71 mmol) in N,N-dimethylformamide (5 mL) was stirred under nitrogen in a heavy walled process vial in a microwave synthesizer at about 200° C. for about 5 minutes. The reaction mixture was cooled, concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using dichloromethane/methanol (50:1) as the mobile phase to provide the desired product. MS (ESI): m/z 248 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:20])C(O)=O)=[CH:12][CH:11]=1)([O-:3])=[O:2].[N+](C1C=CC=CC=1C1C=CC=CC=1)([O-])=[O:22].C(Cl)(=O)C>>[C:16]([C:13]1[CH:14]=[CH:15][C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:11][CH:12]=1)(=[O:22])[CH3:20]
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1
Reactant: O=[N+]([O-])c1ccccc1-c1ccccc1
Solvent: CC(=O)Cl
Product: CC(=O)c1ccc(-c2ccccc2[N+](=O)[O-])cc1

Procedure:
The 2-(2'-nitro-4-biphenylyl)propionic acid is readily prepared in the following manner: 2-nitrobiphenyl is acylated with acetyl chloride, giving 4-acetyl-2'-nitrobiphenyl. This is converted with chloroacetonitrile under alkaline conditions to the intermediate isomeric 2-methyl-2-[4-(2'-nitrophenyl)]glycidonitriles which, when treated with lithium perchlorate and then base, is isomerized to methyl 2-(2'-nitro-4-biphenylyl)propionate. Saponificiation of the latter gives the desired 2-(2'-nitro-4-biphenylyl)propionic acid. The esters are readily converted to the acid and the acid to the esters by conventional means.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)C.C(=O)=O.C([N-]C(C)C)(C)C.[Li+].[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:38])([F:37])[F:36])[C:29]#[N:30]>O1CCCC1>[F:25][C:26]1[CH:27]=[C:28]([C:29]2[N:30]=[C:4]([OH:6])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[CH:1]=2)[CH:31]=[CH:32][C:33]=1[O:34][C:35]([F:37])([F:38])[F:36]
Reactant: N#Cc1ccc(OC(F)(F)F)c(F)c1
Reactant: Cc1ncccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: Oc1nc(-c2ccc(OC(F)(F)F)c(F)c2)cc2ncccc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
300 mg 2-methyl-nicotinic acid was suspended in 10 mL of tetrahydrofuran, and cooled to −70° C. with a bath of ethanol/dry ice. 3.3 mL lithium diisopropylamide (2.0 M in tetrahydrofuran/n-heptane/ethylbenzene) was added dropwise over 10 min and the mixture was stirred for 1.5 h at 0° C. After this time, it was cooled again to −70° C. and 0.9 g 3-fluoro-4-trifluoromethoxy-benzonitrile (4.1) was added quickly. Then the reaction mixture was stirred for 2 h at −70° C. and then warmed overnight to ambient temperature. The solvent was distilled off, diluted with ethyl acetate, 10 mL phosphate buffer and 5 mL 2N aqueous hydrochloric acid solution (pH 6-7). The formed precipitate was collected and dried. The resulting liquid phase was separated and the water phase extracted twice with ethyl acetate. The organic phase was dried over magnesium sulfate, concentrated and the residue suspended in ether and ethyl acetate. The precipitate was collected, dried and combined with the first precipitate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11](F)=[N:12][CH:13]=1.[NH2:22][NH2:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:10][C:11]([NH:22][NH2:23])=[N:12][CH:13]=1
Reactant: NN
Reactant: Fc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Solvent: c1ccncc1
Product: NNc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
To a suspension of 5-(2-chlorophenyl)-4-(4-chlorophenyl)-2-fluoropyridine (0.32 g, 1 mmol) in pyridine (4 mL) at room temperature was added anhydrous hydrazine (1 mL). The resulting mixture was stirred at 90° C. for 1 hour. Analysis by HPLC/MS indicated the reaction was complete. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue was added water, and the resulting suspension was extracted with EtOAc (50 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure to yield 0.28 g of the title compound (85%) as a white foam. HPLC/MS: retention time=3.03 min, [M+H]+=330.1.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)C[CH2:62][CH2:61][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54]CSC)=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].FC(F)(F)C(O)=O.[CH:78](S)(S)[CH3:79].[CH3:82][S:83][CH3:84]>>[NH:1]1[CH2:79][CH2:78][CH2:62][CH2:61][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:82][S:83][CH3:84])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH2:32][C:33]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSC
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Reactant: CC(S)S
Solvent: O=C(O)C(F)(F)F
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
BocPro-DTrp-Phe-DTrp-Leu-MetNH2 (2.45 mmole.) was added to a solution of trifluoroacetic acid (18 ml.), dimethylsulfide (20 ml.) and ethanedithiol (1.8 ml.) with cooling to 0° C. The mixture was allowed to warm to room temperature, stirred for one hour, and stripped of volatiles. The residue was washed with hexane, then with ether, then purified by reverse phase high pressure liquid chromatography on octadecylsilated silica gel using methanol-water (75:25) containing ammonium acetate (0.2%) as eluant. Conversion of the product to the phosphate salt by ion exchange and lyophilization afforded HPro-DTrp-Phe-DTrp-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt hydrate (2:7) in 62% yield (1.63 g.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:31])=[C:15]([N:19]4[CH2:22][C:21]([CH3:30])([NH:23]C(=O)C(F)(F)F)[CH2:20]4)[C:16]=3[F:18])[C:11](=[O:32])[C:10]([C:33]([OH:35])=[O:34])=[CH:9]2)=[CH:4][CH:3]=1.O>[OH-].[Na+]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([F:31])=[C:15]([N:19]4[CH2:22][C:21]([NH2:23])([CH3:30])[CH2:20]4)[C:16]=3[F:18])[C:11](=[O:32])[C:10]([C:33]([OH:35])=[O:34])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: CC1(NC(=O)C(F)(F)F)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(N)CN(c2c(F)cc3c(=O)c(C(=O)O)cn(-c4ccc(F)cc4)c3c2F)C1

Procedure:
A solution of 1.25 g (2.5 mmoles) of 1-(4-fluorophenyl)-6,8-difluoro-7-(3-amino-3-trifluoroacetamido-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (example 19), in 8 ml of 1N sodium hydroxide and 10 ml of water is heated under reflux for 3 hours. It is cooled, filtered, and acetic acid is added. After filtering and washing with water and cold ethanol, 0.8 g (72%) of 1-(4-fluorophenyl)-6,8-difluoro-7-(3-amino-3-methyl-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid are obtained, melting at 272°-7° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Br:4][C:5]1[CH:6]=[C:7](F)[CH:8]=[C:9]([Br:21])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O>[Br:4][C:5]1[CH:6]=[C:7]([O:2][CH3:1])[CH:8]=[C:9]([Br:21])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(Oc2c(Br)cc(F)cc2Br)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(Oc2ccc([N+](=O)[O-])cc2)c(Br)c1
Temperature: 100 °C
Yield: 52.4 %

Procedure:
Sodium methylate (2.2 g) was added to a solution of 3,5-dibromo-4-(4-nitrophenoxy)fluorobenzene (10 g) and dimethylformamide (25 mL). The reaction mixture was heated at 100° C. for 15 minutes. After cooling down to room temperature, concentration and purification on column (silica gel, ethyl acetate/petrolium ether, 1:9), 5.4 g of 3,5-dibromo-4-(4-nitrophenoxy)anisole was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2].[NH2:24][CH2:25][CH:26]1[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]1>>[C:1]([C:3]1[CH:4]=[C:5]([CH:21]([CH3:23])[CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:19]=[CH:18][C:14]([C:15]([NH:24][CH2:25][CH:26]4[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OC(C)(C)C)C4)cc3)oc12

Procedure:
The title compound was prepared from 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoic acid (INTERMEDIATE 36) and tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate by a procedure analogous to that described in EXAMPLE 1. Mass spectrum (ESI) 489.3 (M+1).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[F:7][C:8]([F:19])([F:18])[C:9]1[CH:17]=[CH:16][C:12]([C:13](Cl)=O)=[CH:11][CH:10]=1>ClCCl>[CH3:5][C:2]1([CH3:6])[CH2:3][O:4][C:13]([C:12]2[CH:11]=[CH:10][C:9]([C:8]([F:7])([F:18])[F:19])=[CH:17][CH:16]=2)=[N:1]1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(N)CO
Solvent: ClCCl
Product: CC1(C)COC(c2ccc(C(F)(F)F)cc2)=N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-amino-2-methyl-1-propanol (21.4 g) in dichloromethane (100 ml) at 0C was added dropwise a solution of 4-(trifluoromethyl)benzoyl chloride (25 g). The mixture was stirred at room temperature for 16 hours, washed with 2M HCl then sodium bicarbonate solution, dried (MgSO4) and evaporated. The residue was dissolved in dichloromethane (100 ml) and treated with thionyl chloride (14 ml) at 0C. The mixture was stirred at room temperature for 2 hours and evaporated. The residue was partitioned between ethyl acetate and aqueous potassium hydroxide. The organic phase was dried (MgSO4) and evaporated. Yield 14.57 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][N:13]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH2:7][CH2:8][CH2:9][S:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1c2ccccc2C(=O)N1CCSCCCc1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCSCCCc1ccccc1

Procedure:
The product of Example A (33.0 g, 100.6 mmol) was refluxed in ethanol (1 L) in the presence of hydrazine hydrate (20.2 g, 402.4 mmol) for 4.5 hours. The reaction mixture was cooled and filtered. The solid was washed with ethanol. The filtrate and solid were combined and stripped at reduced pressure. The resulting mass was repeatedly triturated with diethyl ether. The ether fractions were combined, filtered, and stripped at reduced pressure to give the title compound as a yellow oil.
Reaction SMILES: COC(=O)[CH2:4][N:5]([S:29]([C:32]1[CH:37]=[CH:36][C:35]([O:38]CC2C=CC=CC=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:6]([C:20]12[O:27][CH2:26][C:23]([CH3:28])([CH2:24][O:25]1)[CH2:22][O:21]2)[CH:7]([NH:9][C:10]([O:12]CC1C=CC=CC=1)=O)[CH3:8].C(N(CC)CC)C.[H][H]>C(O)C.[Pd]>[OH:38][C:35]1[CH:34]=[CH:33][C:32]([S:29]([N:5]2[CH:6]([C:20]34[O:27][CH2:26][C:23]([CH3:28])([CH2:22][O:21]3)[CH2:24][O:25]4)[CH:7]([CH3:8])[NH:9][C:10](=[O:12])[CH2:4]2)(=[O:31])=[O:30])=[CH:37][CH:36]=1
Reactant: COC(=O)CN(C(C(C)NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1NC(=O)CN(S(=O)(=O)c2ccc(O)cc2)C1C12OCC(C)(CO1)CO2
Yield: 75.3 %

Procedure:
A solution of {(4-benzyloxy-benzenesulfonyl)-[2-benzyloxycarbonylamino-1-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-propyl]-amino}-acetic acid methyl ester (compound of formula LIII, 1.3 g, 2.0 mmol) in 75 ml of ethanol was treated with triethylamine (0.28 ml, 0.20 g, 2.0 mmol) and 0.2 g of 10% palladium on carbon. After stirring for about 2 hours under 1 atmosphere of hydrogen, the mixture was filtered through a pad of Celite® and concentrated in vacuo. The residue was dissolved in 10 ml of toluene, diluted with 3 ml of methanol and was refluxed for about 1.5 hours. Concentration of the mixture in vacuo afforded 0.6 g of 4-(4-hydroxy-benzenesulfonyl)-6-methyl-5-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazin-2-one (compound of formula LIV). A compound of the formula LI can be converted to a compound of the formula LIII by the method of Step 42 that, in turn, can be converted to a compound of Formula I according to the procedure of Step 43.