Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:13])[CH2:11][CH3:12])[N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.Cl[C:22]1[N:30]=[CH:29][N:28]=[C:27]2[C:23]=1[N:24]=[CH:25][N:26]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:13][C:22]3[N:30]=[CH:29][N:28]=[C:27]4[C:23]=3[NH:24][CH:25]=[N:26]4)[CH2:11][CH3:12])[N:7]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[CH:20]=1
Reactant: CC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](Nc1ncnc2nc[nH]c12)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 21 %

Procedure:
A mixture of (S)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)propylamine from Example 28 (42 mg, 0.16 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (37 mg, 0.16 mmol) and DIPEA (0.14 mL, 0.8 mmol) in n-butanol (1 mL) was stirred in a sealed vial for 16 h at 90° C. After cooling to RT, the crude reaction mixture was loaded into an Isolute® SCX-2 which was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording 160 as a white solid (13 mg, 21%). LCMS: RT 3.61 min [M+H]+ 388.1. 1H NMR (DMSO, 400 MHz): δ 8.22-8.03 (2H, m), 7.80 (1H, s), 7.71-7.43 (6H, m), 7.09 (1H, t, J=9.42 Hz), 6.85 (1H, d, J=8.93 Hz), 5.38 (1H, s), 2.08-1.88 (2H, m), 0.83 (3H, t, J=7.34 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[CH2:10]([NH:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[C:7]([Br:9])[CH:6]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(Br)cc(Br)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Brc1cc(Br)cc(NCc2ccccc2)c1
Yield: 69.5 %

Procedure:
The same procedure as described above was used in a scale up reaction where 3,5-dibromoaniline (273) (3.85 g, 15.35 mmol), benzaldehyde (274) (1.61 g, 15.35 mmol), Na(OAc)3BH (6.47 g, 30.7 mmol), AcOH (1.11 g, 18.42 mmol) and DCE (38 mL) were used. After 3 h reaction and purification (flash chromatography), benzyl-(3,5-dibromo-phenyl)-amine (275) (3.64 g, 10.67 mmol) was obtained in 69.6% isolated yield.
Reaction SMILES: [Na].[Br:2][C:3]1[NH:4][C:5]([Br:9])=[C:6]([Br:8])[N:7]=1.[H-].[Na+].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18]Br>CN(C)C=O.O>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH2:18][N:4]1[C:5]([Br:9])=[C:6]([Br:8])[N:7]=[C:3]1[Br:2]
Reactant: BrCCCCOCBr
Reactant: Brc1nc(Br)c(Br)[nH]1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: BrCCCCOCn1c(Br)nc(Br)c1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.3 %

Procedure:
To a solution of a sodium salt, prepared from 1.22 g of 2,4,5-tribromoimidazole and 0.16 g of 60% oil-based sodium hydride, in 5 ml of N,N-dimethylformamide was added dropwise 1.23 g of 4-bromobutoxymethyl bromide at room temperature. After stirring at room temperature for 3 hours, 50 ml of water was added to the reaction mixture which was then extracted with three 30-ml portions of ether. The ether layer was dried over magnesium sulfate and concentrated. The oily product obtained was purified by column chromatography on silica gel to obtain 0.74 g of 1-(4-bromobutoxymethyl)-2,4,5-tribromoimidazole.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]23[CH2:18][CH2:17][C:14]([NH:19]C(=O)OC(C)(C)C)([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>O.C(Cl)Cl>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([C:11]23[CH2:18][CH2:17][C:14]([NH2:19])([CH2:15][CH2:16]2)[CH2:13][CH2:12]3)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: CC(C)(C)OC(=O)NC12CCC(c3ccc(S(C)(=O)=O)cc3)(CC1)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C23CCC(N)(CC2)CC3)cc1
Yield: 95.9 %

Procedure:
To a 100 mL round-bottomed flask equipped with magnetic stirring was added tert-butyl 4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-ylcarbamate (170 mg, 448 μmol), 2 mL of CH2Cl2, ca. 5 drops of water, and trifluoroacetic acid (2 mL, 27 mmol). The reaction mixture was stirred at ambient temperature for 3.5 h, after which time the mixture was concentrated in vacuo. NaOH (ca. 50 mL of a 1M aq. solution) was added to the mixture, and the aqueous layer was extracted with CH2Cl2 (3×15 mL). The organic layers were combined, dried over K2CO3, filtered, and concentrated in vacuo to give 4-(4-(methylsulfonyl)phenyl)bicyclo[2.2.2]octan-1-amine (mass=120 mg, Mass Spec. m/z+ion=280.2) The crude reaction product was taken onto the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:12]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:12][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1ccc(Br)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.6 %

Procedure:
To a solution of 5-bromo-2-methyl-benzoic acid (9.9 g, 46 mmol) in DMF (100 mL) was added K2CO3 (7.6 g, 55 mmol) and CH3I (20 g, 140 mmol) slowly. After stirring at room temperature for 4 h, the solvent was removed under vacuum. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed under vacuum to afford 5-bromo-2-methylbenzoic acid methyl ester (8.6 g, 82%), which was used in next step without further purification. 1H NMR (300 MHz, CDCl3) δ 8.04 (d, J=2.1, 1H), 7.50 (dd, J=8.1, 2.1, 1H), 7.12 (d, J=8.1, 1H), 3.89 (s, 3H), 2.53 (s, 3H).
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5].[CH2:9]([N:16]=[C:17]=[O:18])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.C(OCC)(=O)C>[CH2:9]([NH:16][C:17](=[O:18])[NH:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4]([OH:6])=[O:5])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(N)CC(=O)O
Reactant: O=C=NCc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.9 %

Procedure:
To a solution of 3-amino-3-methylbutanoic acid (5.86 g, 34.2 mmol) in THF was added benzyl isocyanate (5.87 ml, 47.5 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (100 ml) and washed with water (100 ml) and brine (100 ml). Then the organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo. The crude residue was subjected to silica gel column chromatography (eluent: chloroform:methanol=95:5) to obtain the title compound (5.73 g, 67%).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:22])[CH2:7][NH:8][C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([F:21])([F:20])[F:19])[CH:16]=3)[NH:11][N:10]=2)[CH2:2]1.O=[C:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1>>[F:21][C:18]([F:20])([F:19])[C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[NH:8][CH2:7][C:6]([NH:5][CH:3]1[CH2:2][N:1]([CH:24]2[CH2:25][CH2:26][CH:27]([C:30]3[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH2:39])=[O:38])=[CH:32][CH:31]=3)[CH2:28][CH2:29]2)[CH2:4]1)=[O:22]
Reactant: NC(=O)Cc1ccc(C2CCC(=O)CC2)cc1
Reactant: O=C(CNc1n[nH]c2ccc(C(F)(F)F)cc12)NC1CNC1
Product: NC(=O)Cc1ccc(C2CCC(N3CC(NC(=O)CNc4n[nH]c5ccc(C(F)(F)F)cc45)C3)CC2)cc1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide (as prepared in Example 41, Step A) and 2-[4-(4-oxo-cyclohexyl)-phenyl]-acetamide using the procedure described in Step E of Example 1.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2F)(=[O:18])=[O:17])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].C(N(CC)CC)C.[CH3:33][N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][CH2:40][NH2:41]>C(#N)C>[CH2:1]([O:3][C:4]1[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[C:9]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:41][CH2:40][CH2:39][CH:35]2[CH2:36][CH2:37][CH2:38][N:34]2[CH3:33])(=[O:18])=[O:17])[C:5]=1[C:6]([OH:8])=[O:7])[CH3:2]
Reactant: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2F)c1C(=O)O
Reactant: CN1CCCC1CCN
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1c(CC)ccc(NS(=O)(=O)c2ccccc2NCCC2CCCN2C)c1C(=O)O

Procedure:
A solution of Example 385I (120 mg, 0.33 mmol), triethylamine (0.24 mL) and N-methyl-2-(2′-aminoethyl)pyrrolidine (217 mg, 1.7 mmol) in acetonitrile (3 mL) was heated to 120° C. in a sealed vial for 2 days, concentrated, and purified using a reverse phase HPLC, giving the desired product, 79 mg, 50.3%. 1H NMR (DMSO-d6) δ 1.08 (t, 3H), 1.28 (t, 3H), 1.60-1.70 (m, 1H), 1.80-2.00 (m, 3H), 2.12-2.30 (m, 2H), 2.53 (q, 2H), 2.68 (s, 3H), 2.90-3.04 (m, 1H), 3.20-3.32 (m, 3H), 3.50-3.60 (m, 1H), 3.90 (q, 2H), 5.98 (br s, 1H), 6.60 (d, 1H), 6.68 (t, 1H), 6.85 (d, 1H), 7.15 (d, 1H), 7.40 (t, 1H), 7.58 (d, 1H), 9.68 (s, 1H), 10.48 (br s, 1H); MS (ESI(+)) m/e 476 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[NH:12][CH2:11][CH:10](COS(C3C=CC(C)=CC=3)(=O)=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][NH:26]1.[C:35](=O)([O-])[O-].[K+].[K+]>ClC1C=CC=CC=1>[C:1]1([C:7]2[N:12]([CH3:35])[CH2:11][CH:10]([N:26]3[CH2:27][CH2:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:25]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: c1ccc2c(c1)CCNC2
Reactant: Cc1ccc(S(=O)(=O)OCC2CNC(c3ccccc3)=NO2)cc1
Agent: [K+]
Solvent: Clc1ccccc1
Product: CN1CC(N2CCc3ccccc3C2)ON=C1c1ccccc1

Procedure:
To 3.46 g. of 3-phenyl-6-tosyloxymethyl-5,6-dihydro-4H-1,2,4-oxadiazine 1.33 g. of 1,2,3,4-tetrahydro-isoquinoline, 1.38 g. of anhydrous potassium carbonate and 30 ml. of chlorobenzene are added. The reaction mixture is refluxed for 2 hours, whereupon it is decolored and filtered while hot. Upon cooling 1.95 g. of 3-phenyl-6-(1,2,3,4-tetrahydro-2-isoquinolyl)-methyl-5,6-dihydro-4H-1,2,4-oxadiazine are obtained in crystalline form. The product has the same properties as the product of Example 4. Melting point: 187° to 189° C.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C[O:15]S([O-])(=O)=O.CC1C=CC=C2C=1N=C1C(C=CC=C1)=[NH+]2.C(O)(=O)C.O.NN>O.[Ni]>[OH:15][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][C:7]=1[OH:10])[CH2:3][C@@H:2]([C:11]([OH:13])=[O:12])[NH2:1]
Reactant: COS(=O)(=O)[O-]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Agent: [Ni]
Agent: Cc1cccc2[nH+]c3ccccc3nc12
Agent: NN
Solvent: O
Solvent: CC(=O)O
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Yield: 1139.3 %

Procedure:
1.8 g of tyrosine, 0.15 g of 9-methylphenazinium methylsulphate are placed into a reactor, dissolved in 1,000 ml of water. The resulting solution is acidified with acetic acid to the reaction medium pH of 4.5 and added with 30 ml of hydrazine hydrate and 5 g of Raney nickel. After filtering-off nickel, the resulting reaction mixture is evaporated to dryness under the pressure of 20 mm Hg, the residue is dissolved in 20 ml of methanol and the mixture is chromatographically separated into alumina and the desired product by eluting with a mixture consisting of n-propanol and a 34% aqueous ammonia taken in the ratio of 70:3. 1.1 g of 3,4-dihydroxyphenylalanine is thus obtained; the yield is 61% as calculated for the starting compound, m.p. of the product is 271°-272° C. The composition, in percent, is as follows:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[C:27]([C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:32]=[C:33]([NH:34][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[NH:1][S:23]([C:18]3[CH:17]=[C:16]([F:15])[CH:21]=[C:20]([F:22])[CH:19]=3)(=[O:25])=[O:24])[N:9]=2)[CH:35]=[CH:36][CH:37]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Product: CC(C)(C)c1cccc(Nc2ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n2)c1

Procedure:
The title compound, MS: m/e=468.3 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and 3-tert.butyl-aniline.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCC(Br)C(=O)OCC
Product: CCCCCCCCC(Oc1ccc(C(=O)CCC)cc1)C(=O)OCC
Yield: 85 %

Procedure:
1-[4-Hydroxyphenyl]-1-butanone (328 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Butyrylphenoxy]decanoate (616 mg, 85%) as a clear, colourless oil. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.64 (dd, J=5.7, 6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.85-1.99 (m, 2H), 1.65-1.75 (m, 2H), 1.39-1.44 (m, 2H), 1.22-1.34 (m, 10H), 1.20 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.04, 171.39, 161.80, 130.98, 130.48 (2C), 114.74 (2C), 76.68, 61.55, 40.37, 32.85, 32.01, 29.53, 29.37 (2C), 25.33, 22.84, 18.11, 14.34, 14.29, 14.10. The resulting ester (616 mg, 1.70 mmol) was saponified with lithium hydroxide (203 mg, 8.5 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Butyrylphenoxy]decanoic Acid (166 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 10.06 (br s, 1H), 7.91 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.70 (dd, J=5.9, 6.4 Hz, 1H), 2.87 (t, J=7.3 Hz, 2H), 1.96-2.02 (m, 2H), 1.68-1.77 (m, 2H), 1.44-1.59 (m, 2H), 1.24-1.37 (m, 10H), 0.97 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.95, 176.56, 161.74, 131.03, 130.73 (2C), 114.82 (2C), 76.16, 40.47, 32.79, 32.03, 29.53, 29.39, 29.37, 25.38, 22.86, 18.26, 14.31, 14.12. The acid (166 mg, 0.5 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Butyrylphenoxy]decanoate (149 mg, 85%) as a white solid. mp 262-278° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 4.70 (dd, J=6.1, 6.5 Hz, 1H), 2.90 (t, J=7.3 Hz, 2H), 1.88-1.93 (m, 2H), 1.67 (tq, J=7.4, 7.4 Hz, 2H), 1.41-1.57 (m, 2H), 1.20-1.35 (m, 10H), 0.95 (t, J=7.4 Hz, 3H), 0.83 (t, J=6.9 Hz, 3H); 13C NMR (101 MHz, CD3OD): δ 201.82, 178.07, 163.36, 130.53 (2C), 129.54, 114.83 (2C), 79.46, 39.99, 33.11, 31.80, 29.40, 29.27, 29.15, 25.72, 22.54, 18.30, 14.46, 14.15; LRMS (ESI): m/z 713 (M2H+), 669 (2M−2Na++3H+), 335 (M−Na++2H+); HPLC: 3 min.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Li]CCCC.[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][N:17]=1.[C:23](=[O:25])=[O:24]>C1COCC1.CCCCCC>[Cl:15][C:16]1[N:17]=[CH:18][CH:19]=[C:20]([Cl:22])[C:21]=1[C:23]([OH:25])=[O:24]
Reactant: O=C=O
Reactant: Clc1ccnc(Cl)c1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(O)c1c(Cl)ccnc1Cl
Reaction time: 0.67 h
Yield: 82 %

Procedure:
To a stirring solution of diisopropyl ethyl amine (11.1 ml, 81.08 mmol) in THF (50 ml) was added dropwise a solution of BuLi (1.46 M, 43.3 ml, 73.65 mmol) in hexane below −65° C. and the mixture was stirred for 40 minutes. To this solution was added dropwise 2,4-dichloropyridine (10 g, 67.57 mmol) in THF (15 mL) at −78° C. and stirred for 30 minutes. Carbon dioxide generated from freshly crushed dry ice was passed through CaCl2 guard tube and then charged into the reaction mixture for 10 minutes and the reaction mixture was slowly allowed to come to room temperature. The solvent was evaporated under reduced pressure and dissolved in a minimum volume of water. The aqueous layer was washed with water and acidified to pH 4 with conc. HCl. It was then extracted with ethyl acetate, the organic layer was washed with brine and dried over sodium sulfate. The organic solvent was removed under reduced pressure to provide 2,4-dichloronicotinic acid (10.6 g, 82%) as off white solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2I)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1>>[NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:25]2[CH:24]=[CH:23][C:22]3[O:21][CH2:20][O:28][C:27]=3[CH:26]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(I)C1=O
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: CC1(C)OC(c2ccc(S(N)(=O)=O)cc2)=C(c2ccc3c(c2)OCO3)C1=O
Yield: 33.8 %

Procedure:
120 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-iodo-3(2H)-furanone was reacted with 100 mg of 3,4-(methylenedioxy)benzeneboronic acid by following a procedure similar to Step 4 of Example 22 to yield 40 mg of 5-{4-(aminosulfonyl)phenyl}-2,2-dimethyl-4-{3,4-(methylenedioxy)phenyl}-3(2H)-furanone as a solid. mp: 178-179° C. NMR: δ1.56 (s, 6H), 4.89 (br s, 2H), 5.99 (s, 2H), 6.74 (m, 2H), 6.83 (m, 1H), 7.82 (d, J=9.0 Hz, 2H), 7.92 (d, J=9.0 Hz, 2H). IR (cm−1): 3237, 1682, 1338, 1245, 1164.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[H][H]>O1CCCC1.[Ni]>[CH3:1][S:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:12]
Reactant: CSCCOc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CSCCOc1ccccc1N

Procedure:
33.9 g of he oil obtained under (a) are hydrogenated in 100 ml of absolute tetrahydrofuran, with the addition of 13.6 g of Raney nickel, under normal pressure (hydrogen absorption=10.6 liters). After the catalyst has been filtered off, the filtrate is concentrated by evaporation, and then purified by means of chromatography (silica gel; hexane/ethyl acetate as eluant).
Reaction SMILES: C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[Pb+3].[F:22][CH:23]([F:38])[CH2:24][N:25]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][N:33]=2)[C:28](=[O:35])[CH2:27][S:26]1(=[O:37])=[O:36].[C:39](Cl)(=[O:43])[CH:40]([CH3:42])[CH3:41]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1.ClCCl.Cl>[Cl:13][C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[C:27]1[S:26](=[O:36])(=[O:37])[N:25]([CH2:24][CH:23]([F:22])[F:38])[C:34]2[C:29]([C:28]=1[O:35][C:39](=[O:43])[CH:40]([CH3:42])[CH3:41])=[N:30][CH:31]=[CH:32][N:33]=2
Reactant: CC(C)C(=O)Cl
Reactant: Cc1ccc([Pb+3])c(Cl)c1
Reactant: O=C1CS(=O)(=O)N(CC(F)F)c2nccnc21
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(C2=C(OC(=O)C(C)C)c3nccnc3N(CC(F)F)S2(=O)=O)c(Cl)c1
Temperature: 25 °C

Procedure:
A mixture of 2-chloro-4-methyl-phenyl lead triacetate (0.153 g), 1-(2,2-difluoro-ethyl)-2,2-dioxo-2,3-dihydro-1H-2-λ-6-thia-1,5,8-triaza-naphthalen-4-one (Example 9.4) (0.070 g) and 4-dimethylaminopyridine (“DMAP”) (0.169 g) in anhydrous chloroform (2 ml) and toluene (1 ml) under a nitrogen atmosphere was heated to reflux for four hours. Isobutyryl chloride (53 μl) was added and the reaction mixture heated to reflux for a further two hours. The reaction mixture was then allowed to cool to ambient temperature and diluted with dichloromethane and aqueous hydrochloric acid (2M). The solids were removed by filtration and the filtrate was separated. The aqueous layer was extracted with further dichloromethane. The combined organic extracts were concentrated. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane 1:6) to give Compound No. C136 of Table C (0.019 g).
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=O)[C:6]=1[CH2:13][CH2:14][CH3:15])[CH:2]([CH3:4])[CH3:3].[CH2:16]([C:20]1[C:21]([C:28]([OH:30])=O)=[N:22][O:23][C:24]=1[CH2:25][CH2:26][CH3:27])[CH:17]([CH3:19])[CH3:18].O/[N:32]=[C:33](/[C:35]1[CH:52]=[CH:51][C:38]([CH2:39][N:40]2[CH2:43][CH:42]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:41]2)=[CH:37][CH:36]=1)\[NH2:34].C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>CN(C=O)C>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([C:10]2[O:12][N:34]=[C:33]([C:35]3[CH:36]=[CH:37][C:38]([CH2:39][N:40]4[CH2:41][CH:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:43]4)=[CH:51][CH:52]=3)[N:32]=2)[C:6]=1[CH2:13][CH2:14][CH3:15])[CH:2]([CH3:3])[CH3:4].[CH2:16]([C:20]1[C:21]([C:28]2[O:30][N:34]=[C:33]([C:35]3[CH:36]=[CH:37][C:38]([CH2:39][N:40]4[CH2:41][CH:42]([C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])[CH2:43]4)=[CH:51][CH:52]=3)[N:32]=2)=[N:22][O:23][C:24]=1[CH2:25][CH2:26][CH3:27])[CH:17]([CH3:18])[CH3:19]
Reactant: CCCc1c(C(=O)O)noc1CC(C)C
Reactant: CC(C)(C)OC(=O)C1CN(Cc2ccc(/C(N)=N/O)cc2)C1
Reactant: CCCc1onc(C(=O)O)c1CC(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCCc1c(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)noc1CC(C)C
Product: CCCc1onc(-c2nc(-c3ccc(CN4CC(C(=O)OC(C)(C)C)C4)cc3)no2)c1CC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.6 %
Yield: 66.6 %

Procedure:
A mixture of 5-isobutyl-4-propylisoxazole-3-carboxylic acid, and 4-isobutyl-5-propylisoxazole-3-carboxylic acid (42.26 mg, 0.2 mmol), (Z)-tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)benzyl)azetidine-3-carboxylate (61.1 mg, 0.200 mmol), HOBt (38.3 mg, 0.250 mmol), diisopropylethylamine (0.070 mL, 0.400 mmol) and EDC (47.9 mg, 0.250 mmol) in DMF (1 mL) was stirred at rt for 18 hr. DMF (1 mL) was added and the reaction mixture was warmed to 50° C. for 8 hr. The reaction mixture was partitioned between EtOAc (30 ml) and saturated sodium bicarbonate solution (30 ml). The organic layer was washed with water (2×30 ml) and brine (30 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an oil that was chromatographed on a 4 gm Isco silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford a mixture of tert-butyl 1-(4-(5-(5-isobutyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (32 mg, 0.067 mmol, 66.6% yield) and tert-butyl 1-(4-(5-(4-isobutyl-5-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)benzyl)azetidine-3-carboxylate (32 mg, 0.067 mmol, 66.6% yield) as a colorless oil. HPLC retention time=1.89 minutes (YMC Combi 4.6×30 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.1 TFA a 2 minute gradient.