Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:10][C:11]1[CH:27]=[CH:26][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([S:22]([NH:8][C:7]3[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:9])[CH:6]=3)(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)cnc1Br
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Br)cnc1Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2,5-dibromo-3-aminopyridine (0.51 g, 2.0 mmol) and 4-(4-chloro-phenoxy)-benzenesulfonyl chloride (0.76 g, 2.0 mmol) in dry CH2Cl2 (10 mL) was added pyridine (1 mL) at 0 C. The resulting mixture was allowed to warm to room temperature and stirred until TCL showed the completion of the reaction. The reaction mixture was diluted with CH2Cl2 and washed with aqueous HCl solution. After the pyridine was neutralized, the organics were washed with water, brine and dried over anhydrous Na2SO4. The filtration (Celite) and concentration under vacuo gave a crude material, which was purified by silica column (30% EtOAc/hexanes). MS: 516, 518 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:11]3[C:16]([F:17])=[C:15]([F:18])[CH:14]=[C:13]([F:19])[C:12]=3[F:20])[N:9]=[CH:10][C:3]=12.[O:21]1CC[O:23][BH:22]1.C([O-])(=O)C.[K+].C(Cl)Cl>CS(C)=O>[F:20][C:12]1[C:13]([F:19])=[CH:14][C:15]([F:18])=[C:16]([F:17])[C:11]=1[N:8]1[C:4]2=[N:5][CH:6]=[CH:7][C:2]([B:22]([OH:23])[OH:21])=[C:3]2[CH:10]=[N:9]1
Reactant: B1OCCO1
Reactant: Fc1cc(F)c(F)c(-n2ncc3c(I)ccnc32)c1F
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: OB(O)c1ccnc2c1cnn2-c1c(F)c(F)cc(F)c1F
Temperature: 105 °C

Procedure:
To a 48 mL pressure bottle under N2 was added the compound from Intermediate 69A (1.1 g, 2.8 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane (1.17 g, 4.61 mmol), potassium acetate (1.15 g, 11.72 mmol), and anhydrous DMSO (8 mL). Argon was bubbled into the reaction mixture for 5 min and then PdCl2(dppf).CH2Cl2 (71 mg, 0.097 mmol) was added. The reaction mixture was flushed with argon, securely capped, and heated at 105° C. for 75 min. After adding 30 mg more palladium catalyst and 60 mg more 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane, the reaction mixture was heated at 115° C. in an oil bath for an additional 75 min to give the desired intermediate. LC/MS (Condition B): ret. T=3.2 min, (M+H)+ 312.03.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH2:9][CH2:10][CH3:11])[CH:8]=1)[CH2:2][CH3:3].[CH2:17]=O>>[CH2:1]([C:4]1[NH:5][C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:7]([CH2:9][CH2:10][CH3:11])[C:8]=1[CH3:17])[CH2:2][CH3:3]
Reactant: C=O
Reactant: CCCc1cc(CCC)c(C(=O)OCC)[nH]1
Product: CCCc1[nH]c(C(=O)OCC)c(CCC)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2,4-di-n-propyl-5-carbethoxypyrrole and paraformaldehyde, was extracted with ether then sublimed (65° C. 1 × 10-4 mm), m.p. 78°-80° C. (17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[N+:13]([O-])=O)[C:6]([O:8][CH3:9])=[O:7].[H][H]>CO.C1COCC1.[C].[Pd]>[NH2:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc(N)c(OC)c1
Temperature: 25 °C
Yield: 104.1 %

Procedure:
10% palladium-carbon (containing 50% water, 15 g) was added to a solution of methyl 3-methoxy-4-nitrobenzoate (150 g) in methanol (600 mL) and THF (300 mL), and the reaction solution was stirred at a hydrogen pressure of 0.9 MPa at 50° C. to 64° C. for 6.5 hours. The reaction solution was left to cool to room temperature and then filtered through celite. The resulting filtrate was concentrated under reduced pressure to obtain 134 g of the title compound. The property values corresponded to the reported values (CAS #41608-64-4).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5](Br)=[CH:6][N:7]=1.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([SH:16])[N:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:2][C:3]1[S:4][C:5]([S:16][C:12]2[N:11]=[C:10]([NH2:9])[CH:15]=[CH:14][N:13]=2)=[CH:6][N:7]=1
Reactant: Nc1ccnc(S)n1
Reactant: Nc1ncc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1ccnc(Sc2cnc(N)s2)n1
Temperature: 90 °C
Yield: 54.3 %

Procedure:
A mixture of 2-amino-5-bromothiazole hydrochloride (2.2 g), 4-amino-2-mercaptopyrimidine (2.2 g) and potassium carbonate (6.5 g) in N,N-dimethylformamide (100 ml) was heated at 90° C. for 2.5 hours with stirring. The reaction mixture was concentrated under reduced pressure and water was added to this residue. The solution was extracted with a mixture of tetrahydrofuran and ethyl acetate (1:1), washed with aqueous saturated sodium chloride and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subjected to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give solid. The solid was triturated with ethanol to give 2-amino-5-(4-aminopyrimidin-2-ylthio)thiazole (1.25 g, yield: 55.6%).
Reaction SMILES: [CH3:1][C:2]1([OH:29])[CH2:7][CH2:6][CH:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:3]1.[CH3:30]I>>[CH3:1][C:2]1([O:29][CH3:30])[CH2:7][CH2:6][CH:5]([CH3:8])[CH:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]([CH3:27])[C:22](=[O:28])[CH:21]=[CH:20]4)[CH:10]=2)[CH2:3]1
Reactant: CI
Reactant: CC1CCC(C)(O)CC1c1cccc(OCc2ccc3c(ccc(=O)n3C)c2)c1
Product: COC1(C)CCC(C)C(c2cccc(OCc3ccc4c(ccc(=O)n4C)c3)c2)C1
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 2, (1SR,3RS,4SR)-1,4-dimethyl-1-hydroxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane was reacted with methyl iodide to give (1SR,3RS,4SR)-1,4-dimethyl-1-methoxy-3-[3-(1-methyl-2-oxo-1,2-dihydroquinolin-6-ylmethoxy)phenyl]cyclohexane as an oil in 58% yield.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][N:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].CO>C1COCC1>[O:11]=[C:6]1[N:7]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:8]=[CH:9][C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: CCOC(=O)CI
Reactant: Oc1nccc2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)Cn1ccc2ncccc2c1=O
Temperature: 100 °C
Yield: 95 %

Procedure:
1,6-naphthyridin-5-ol (1.00 g, 6.8 mmol), ethyl iodoacetate (1.6 ml, 14 mmol) and cesium carbonate (4.5 g, 14 mmol) were dissolved in 25 mL of THF then stirred and heated at 100° C. for 2 h until the reaction was complete. The reaction was concentrated and purified via MPLC using a gradient to 90% DCM: 10% MeOH to afford ethyl 2-(5-oxo-1,6-naphthyridin-6(5H)-yl)acetate (1.5 g, 94% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:14]=[CH:13][C:9]([CH2:10][CH2:11][OH:12])=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(=O)([O-])O.[Na+]>ClCCl>[S:16]([O:12][CH2:11][CH2:10][C:9]1[CH:13]=[CH:14][C:6]([N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:7][CH:8]=1)(=[O:18])(=[O:17])[CH3:15]
Reactant: OCCc1ccc(N2CCCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)OCCc1ccc(N2CCCC2)cc1
Reaction time: 8 h

Procedure:
4-Pyrrolidinophenethyl alcohol (16.41 g, 85.9 mmol) was dissolved in dichloromethane (150 ml). Dissopropylethylamine (19.0 ml, 108 ml) and methanesulfonyl chloride (8.40 ml, 108 mmol) were added to the obtained solution at 0° C., and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (7:3) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 4-pyrrolidinophenethyl mesylate in the form of a white solid (21.14 g, 80%).
Reaction SMILES: [CH2:1]([N:3]([CH2:10][CH3:11])[C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7])[CH3:2].CC(O[Na])=O.O.[Cl-].[C:19]1([N+:25]#[N:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:10]([N:3]([CH2:1][CH3:2])[C:4](=[O:9])[C:5](=[N:26][NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6](=[O:8])[CH3:7])[CH3:11]
Reactant: N#[N+]c1ccccc1
Reactant: CCN(CC)C(=O)CC(C)=O
Agent: CC(=O)O[Na]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)C(=NNc1ccccc1)C(C)=O
Temperature: 10 °C

Procedure:
15.7 g (0.1 mol) of N,N-diethyl-3-oxobutyramide were mixed with 12 g (0.14 mol) of CH3COONa, 20 ml of water and 75 ml of ethanol. The solution obtained was cooled to 10° C. and 0.1 mol of freshly prepared solution of phenyldiazonium chloride [Organic Reactions, R. Adams Ed; Wiley, New York, 10, 32-33, (1951-1959)] were added dropwise. The precipitated solid was filtered, dried in vacuo yielding 22.6 g of the title compound. M.p.=63°-65° C.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al].Cl[CH:21](Cl)[CH2:22][Si:23]([Cl:26])([Cl:25])[Cl:24]>C(=S)=S.CCCCCC>[Cl:24][Si:23]([CH2:22][CH:21]1[C:12]2[CH:11]=[CH:10][C:9]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:8][C:7]=2[C:1]2[C:2]1=[CH:3][CH:4]=[CH:5][CH:6]=2)([Cl:26])[Cl:25]
Reactant: ClC(Cl)C[Si](Cl)(Cl)Cl
Reactant: c1ccc(-c2cccc(-c3ccccc3)c2)cc1
Agent: [Al]
Solvent: CCCCCC
Solvent: S=C=S
Product: Cl[Si](Cl)(Cl)CC1c2ccccc2-c2cc(-c3ccccc3)ccc21
Yield: 15 %

Procedure:
In the same apparatus and procedures as Example 1 above, 5.0 g (21.7 mmol) of meta-terphenyl and 0.47 g (17.4 mmol) of aluminum foil were alkylated in CS2 (50 ml) solution with (2,2-dichloroethyl)-trichlorosilane 6.68 g (21.7 mmol) under dry nitrogen atmospheric pressure for 24 hr at reflux temperature. Freshly distilled hexane (100 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic solution. After hexane and CS2 were distilled, recrystallization from ether yielded 1.27 g of 9-(trichlorosilyl)methyl-3-phenylfluorene (yield; 15%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:7]=12.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20](Cl)(=[O:22])=[O:21].CN(C)C(=O)C>C(OCC)(=O)C>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[S:20]([NH:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[NH:8][C:7]=12)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1cc2ccnc(N)c2[nH]1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2ccnc(NS(=O)(=O)c3cccs3)c2[nH]1
Yield: 1.5 %

Procedure:
A mixed solution of methyl 7-amino-1H-pyrrolo[2,3-c]pyridine-2-carboxylate (0.40 g), thiophene-2-sulfonyl chloride (0.48 g) and N,N-dimethylacetamide (20 ml) was stirred at 120° C. for 18 hr. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=2:8-1:1) to give the title compound (10.5 mg, yield 1.5%) as pale-yellow crystals. melting point 159-160° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[C:11]1([S:17](Cl)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:10][O:9][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[NH:1][S:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:19])=[O:18])=[O:8]
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccccc1
Yield: 92.4 %

Procedure:
Methyl 3-aminothiophene-2-carboxylate (3.14 g, 20 mmol) was dissolved in pyridine (10 mL) at room temperature. The flask was sealed with a septum and a nitrogen inlet. The solution was treated slowly with a benzenesulfonyl chloride (2.5 mL, 19.5 mmol). The reaction was followed by thin layer chromatography. The reaction was diluted with ethyl acetate and washing with 2N HCl. The organic layer was washed with saturated, aqueous sodium chloride solution and dried over sodium sulfate. The solution was decanted and evaporated under reduced pressure to give 3-benzenesulfonylaminothiophene-2-carboxylic acid methyl ester (5.36 g, 90%), which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[Cl:25][C:26]1[CH:31]=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42].Cl>ClCCl.CO>[ClH:25].[Cl:25][C:26]1[CH:31]=[C:30]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([N:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]2)[CH:29]=[C:28]([Cl:41])[C:27]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](N(C)C)CC1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](N(C)C)CC1

Procedure:
Following general procedure F, 1-(6-bromo-4-(trans-4-(dimethylamino)cyclohexylamino)quinolin-3-yl)ethanone (4.48 g, 11.0 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (3.65 g, 13.0 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (2:1, 325 mL) after which HCl (115 mL, 1.25 M in methanol) was added to from a solution. The solution was concentrated to ˜100 mL and the resultant solid was filtered, washed with dichloromethane, and dried to obtain desired product (4.2 g, 70% over two steps) as a yellow solid: 1H NMR (500 MHz, MeOD) δ 9.13 (s, 1H), 8.48 (br s, 1H), 8.30 (dd, J=8.8, 1.8 Hz, 1H), 8.01 (d, J=8.7 Hz, 1H), 7.77 (s, 2H), 4.62 (br s, 1H), 3.50-3.46 (m, 1H), 2.91 (s, 6H), 2.75 (s, 3H), 2.58-2.54 (m, 2H), 2.35-2.29 (m, 2H), 1.92-1.82 (m, 4H); ESI MS m/z 472 [C25H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=6.41 min.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][OH:17])[NH:10]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:8][C:9]1([CH3:19])[C:14](=[O:15])[O:13][CH2:12][C:11]([CH3:18])([CH2:16][O:17][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[NH:10]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CC1(CO)COC(=O)C(C)(C)N1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(COC(=O)C(C)(C)C)COC(=O)C(C)(C)N1
Reaction time: 16 h

Procedure:
A solution of 2.63 g (0.021 mol) of pivaloyl chloride is added dropwise to a solution of 3.5 g (0.02 mol) of 3,3,5-trimethyl-5-hydroxymethylmorpholin-2-one (prepared in accordance with J. T. Lai.: Synthesis 122 (1984)) and 0.1 g of 4-dimethylaminopyridine in 20 ml of dichloromethane at 15° C. After stirring for 16 hours, another 0.75 ml of pivaloyl chloride is added and the reaction mixture is stirred for 24 hours.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]([CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:22]2=[O:28])[S:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1.Cl>ClCCl>[O:28]=[C:22]1[CH:21]([N:7]([CH2:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][C:40]([CH:37]3[CH2:39][CH2:38]3)=[O:41])=[CH:3][CH:4]=2)[S:8]([C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH2:27][CH2:26][CH2:25][CH2:24][NH:23]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(CN(C2CCCCNC2=O)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1)C1CC1
Yield: 14 %

Procedure:
Rac-4-trifluoromethyl-benzenesulfonic acid (4-amino-benzyl)-(2-oxo-azepan-3-yl)-amide (75 mg, 0.17 mmol) is dissolved in dichloromethane (2 ml), then pyridine (80 mg, 1 mmol) and cyclopropanecarbonyl chloride (21 mg, 0.2 mmol) were added. After shaking the mixture at room temperature for 1 hour hydrochloric acid (5 ml, 0.1M) was added. The organic layer was separated evaporated and the residue was redissolved in 1 ml of dimethylformamide for preparative HPLC separation (RP—C18, eluent acetonitrile/water) to yield 12 mg (14% of the final product). MS: m/e=510.4 (MH+), 527.2 (M+NH4+).
Reaction SMILES: [CH2:1]([C@H:7]1[C@H:10]([CH2:11][C@H:12]([OH:24])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:9][C:8]1=[O:25])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:45]([NH:47][C@H:48]([C:53](O)=[O:54])[CH2:49][CH:50]([CH3:52])[CH3:51])=[O:46].N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([C@@H:7]1[C:8](=[O:25])[O:9][C@H:10]1[CH2:11][C@@H:12]([O:24][C:53](=[O:54])[C@H:48]([CH2:49][CH:50]([CH3:52])[CH3:51])[NH:47][CH:45]=[O:46])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCC[C@@H](O)C[C@@H]1OC(=O)[C@H]1CCCCCC
Reactant: CC(C)C[C@H](NC=O)C(=O)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCC[C@@H](C[C@@H]1OC(=O)[C@H]1CCCCCC)OC(=O)[C@H](CC(C)C)NC=O
Reaction time: 8 h
Yield: 26.5 %

Procedure:
To a solution of 100 mg of rac-3-hexyl -4-(2-hydroxy-tridecyl)-2-oxetanone(2R,3S,4S:2S,3R,4R) or of 100 mg of (3S,4S)-3-hexyl-4-[(R)-2-hydroxytridecyl]-2-oxetanone, 74 mg of triphenylphosphine and 45 mg of N-formyl-L-leucine in 2 ml of THF are added dropwise while stirring 44.3 μl of diethyl azodicarboxylate. After stirring overnight the organic phase is evaporated in vacuo and the residue is purified by chromatography on silica gel with toluene-ethyl acetate (9:1). There are obtained 20 or 37 mg of N-formyl-L-leucine (S)-1-[[(2S,3S)-3-hexyl-4-oxo-2-oxetanyl]methyl]dodecyl ester, [α]D20 =-33° C. (c=0.36, CHCL3).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([O:25]C)=[O:24])=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:20](=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:19]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 11.7 %

Procedure:
In a manner similar to that described in Example 3, 4-nitro-benzoyl chloride (0.062 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.010 g of 4-[4-(4-nitro-benzoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+343.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH2:25])[C:17]=1[F:26])(=[O:12])[CH3:11].[F:27][C:28]([F:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[C:10]([O:13][CH2:14][CH2:15][C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[C:18]([NH:25][C:29](=[O:30])[C:28]([F:27])([F:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:17]=1[F:26])(=[O:12])[CH3:11]
Reactant: O=C(Cl)C(F)(F)c1ccccc1
Reactant: CC(=O)OCCc1c([N+](=O)[O-])ccc(N)c1F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCCc1c([N+](=O)[O-])ccc(NC(=O)C(F)(F)c2ccccc2)c1F
Reaction time: 24 h
Yield: 92.1 %

Procedure:
To a solution of DIEA (1.49 mL, 8.55 mmol) and 2-(3-amino-2-fluoro-6-nitrophenyl)ethyl acetate (690 mg, 2.85 mmol), as prepared in the preceding step, in DCM (6 mL) was added a solution of 2,2-difluoro-2-phenylacetyl chloride (0.99 g, 5.20 mmol), as prepared according to the procedure of step 3 of Example 1, in DCM (3 mL). After stirring for 24 hours, the mixture was concentrated, and partitioned between DCM and H2O. The organic layer was separated, and the aqueous layer extracted with DCM. The organic layers were combined, washed with H2O and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with EtOAc/DCM (0, 2.5, and 5%) to give the title compound (1.04 g, 92% yield) as an orange oil. 1H-NMR (400 MHz, CDCl3) δ 8.49-8.43 (m, 2H), 7.87 (d, J=9.2 Hz, 1H), 6.68 (d, J=7.1 Hz, 2H), 7.55-7.49 (m, 3H), 4.35 (t, J=6.4 Hz, 2H), 3.37 (dt, J=6.3, 2.3 Hz, 2H), 2.01 (s, 3H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=1[F:16])[CH2:26]2
Reactant: Fc1ccc2c(c1)CNC2
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: Nc1c(F)c(N2Cc3ccc(F)cc3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 71.3 %

Procedure:
268 mg of 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 137 mg of 5-fluoroisoindoline, 274 mg of DBU, and 2 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 266 mg of the target compound.
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.Br[C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])[CH:15]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Brc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(-c2cccnc2)c1
Yield: 83.7 %

Procedure:
To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 3-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g of 3-(pyridin-3-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][OH:15]>>[CH3:14][O:15][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: CO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Br
Product: COc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
An argon filled Schlenk flask was charged with 25.77 g (104 mmol) of 2-bromo-1,3-dinitrobenzene, 150 mL of absolute methanol was added and the reaction mixture was chilled in an ice bath. 2.4 g (104 mmol) of Na was added, and the resulting reaction mixture was purged with argon until all Na was dissolved and stirred at RT over night. The solvent was removed, the residue was re-suspended in acetone and filtered through Celite to remove NaBr. The solvent was removed, and the crude product was recrystallized from iPrOH. Yield: 19.8 g (90%). 1H NMR (CDCl3): δ 8.05 (d, JHH=8.2 Hz, 2H, Ar), 7.38 (t, JHH=8.2 Hz, 1H, Ar), 4.07 (s, 3H, OCH3) ppm.