Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3]C(Cl)=O)C.[Cl:7][C:8]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([C:19]([NH:21][OH:22])=[NH:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:7][C:8]1[CH:28]=[C:27]([O:29][CH2:30][CH:31]=[C:32]([Cl:34])[Cl:33])[CH:26]=[C:25]([Cl:35])[C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]2[NH:20][C:1](=[O:3])[O:22][N:21]=2)=[CH:23][CH:24]=1
Reactant: CCOC(=O)Cl
Reactant: N=C(NO)c1ccc(OCCCOc2c(Cl)cc(OCC=C(Cl)Cl)cc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=c1[nH]c(-c2ccc(OCCCOc3c(Cl)cc(OCC=C(Cl)Cl)cc3Cl)cc2)no1
Reaction time: 3 h

Procedure:
90 mg of chloroformic acid ethyl ester in 1 ml of acetone are added dropwise at 5° C. to 400 mg of 4-{3-[2,6-dichloro-4-(3,3-dichloro-allyloxy)-phenoxy]-propoxy}-N-hydroxy-benzamidine and 127 mg of potassium carbonate in 3 ml of acetone. After 3 hours at 0-5° C., the reaction mixture is poured onto water and extracted with dichloromethane. Concentration of the organic phase and purification over silica gel yield the title compound (compound 1.15).
Reaction SMILES: Br[C:2]1[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[N:4][N:5]([CH3:17])[C:6]=1[CH2:7][CH2:8][O:9][Si:10]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].[CH3:26][C:27]1[C:31](B(O)O)=[C:30]([CH3:35])[O:29][N:28]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Si:10]([O:9][CH2:8][CH2:7][C:6]1[N:5]([CH3:17])[N:4]=[C:3]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:2]=1[C:31]1[C:27]([CH3:26])=[N:28][O:29][C:30]=1[CH3:35])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2Br)cc1
Reactant: Cc1noc(C)c1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2nn(C)c(CCO[Si](C)(C)C(C)(C)C)c2-c2c(C)noc2C)cc1
Yield: 23.6 %

Procedure:
A mixture of 4-bromo-5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1-H-pyrazole (140 mg, 0.33 mmol), 3,5-dimethylisoxazol-4-ylboronic acid (92.8 mg, 0.66 mmol), K2CO3 (328 mg, 2.37 mmol) and Pd(PPh3)4 (19.0 mg, 0.02 mmol) in DME (1 mL) and water (1 mL) was flushed with argon and irradiated in the microwave at 140° C. for 20 min. Full conversion was not achieved. The mixture was filtered to remove palladium black. Irradiation in the microwave was continued until full conversion was achieved. Altogether 3,5-dimethylisoxazol-4-ylboronic acid (233 mg, 1.66 mmol) and Pd(PPh3)4 (57.0 mg, 0.06 mmol) were used and three irradiations were run. Water was added and the crude mixture was extracted with EtOAc. Purification on silica gel gave 4-(5-(2-(tert-butyldimethylsilyloxy)ethyl)-3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-4-yl)-3,5-dimethylisoxazole (34.4 mg, 0.078 mmol, 24%).
Reaction SMILES: [C:1](=[O:9])([O:6][CH2:7][CH3:8])[O:2][CH:3](Cl)[CH3:4].[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O-:23])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11].[K+].[I-].[Na+]>CN(C=O)C>[C:10]([NH:13][C:14]1[C:15]([I:29])=[C:16]([C:25]([NH:27][CH3:28])=[O:26])[C:17]([I:24])=[C:18]([C:21]([O:23][CH:3]([O:2][C:1]([O:6][CH2:7][CH3:8])=[O:9])[CH3:4])=[O:22])[C:19]=1[I:20])(=[O:12])[CH3:11]
Reactant: CCOC(=O)OC(C)Cl
Reactant: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)[O-])c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)NC)c1I
Temperature: 50 °C
Reaction time: 24 h

Procedure:
1-Chloroethyl ethyl carbonate (1.67 g, 11.0 mmol) was added dropwise at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-methylaminocarbonyl)-2,4,6-triiodobenzenecarboxylate (6.52 g, 10.0 mmol) and sodium iodide (150 Mg, 1.0 mmol) in dry DMF (50 ml). After stirring at 50° C. for 24 hours the solvent was removed at reduced pressure. The residue was dissolved in chloroform and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After drying with magnesium sulfate and filtration, the solvent was removed at reduced pressure to give the title compound. Yield: (2.2 g, 38%). Purity by HPLC: 98%. 1H-NMR (DMSO-d6 ): delta=1.24 (t, J=7 Hz, CH3); 1.63 (d, J=6 Hz, CH3); 2.03 (s, CH3CO); 2.75 (d, J=3 Hz, NCH3); 4.21 (q, J=7 Hz, CH2): 6.93 (q, J=6 Hz, CH); 8.4-8.7 (m, NHMe); 10.03 ppm (s, NHAc).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:13]([N:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:12]=[CH:11][C:3]=1[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][C:24]1=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>O1CCOCC1>[CH3:21][N:18]1[CH2:19][CH2:20][N:15]([C:13]2[CH:12]=[CH:11][C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[C:2]([NH:1][CH:26]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[CH:14]=2)[CH2:16][CH2:17]1
Reactant: CN1CCCCC1=O
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(Nc2cc(N3CCN(C)CC3)ccc2C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 26 h
Yield: 51 %

Procedure:
tert-Butyl 2-amino-4-(4-methylpiperazin-1-yl)benzoate (1.5 g, 5.15 mmol) was dissolved in dry dioxane (25 mL) under a nitrogen atmosphere. N-methylpiperidone (0.72 g, 6.18 mmol, 1.2 eq) was added, followed by trifluoroacetic acid (1.03 mL, 13.39 mmol, 2.6 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq). The mixture was stirred at room temperature for 26 hours. During this time extra portions of N-methylpiperidone (0.5 mL, 0.75 eq) and sodium triacetoxyborohydride (1.72 g, 7.73 mmol, 1.5 eq) were added. A saturated aqueous solution of NaHCO3 was then added and the reaction mixture was concentrated under reduced pressure. 10% ammonium hydroxide was added until pH 10 and the aqueous phase was extracted with dichloromethane. The organic phase was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. After purification by chromatography over silica gel (DCM/MeOH/NH3 7% in MeOH 90:8:2) 1.025 g of title compound were obtained as off-white solid (51% yield).
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8](S(C)(=O)=O)=[N:9][CH:10]=1.[CH2:30]([S:32]([NH2:35])(=[O:34])=[O:33])[CH3:31]>>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:6]([C:15]2[CH:16]=[C:17]([O:23][CH3:24])[C:18](=[O:22])[N:19]([CH3:21])[CH:20]=2)=[N:7][C:8]([NH:35][S:32]([CH2:30][CH3:31])(=[O:34])=[O:33])=[N:9][CH:10]=1
Reactant: COc1cc(-c2nc(S(C)(=O)=O)ncc2Oc2ccc(F)cc2F)cn(C)c1=O
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)Nc1ncc(Oc2ccc(F)cc2F)c(-c2cc(OC)c(=O)n(C)c2)n1

Procedure:
The title compound of Example 150 was treated with EtSO2NH2 instead of MeSO2NH2 in a manner similar to Example 152, step 6 to give the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.35 (d, J=2.0 Hz, 1H), 8.18 (s, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.25-7.22 (m, 1H), 7.12-7.07 (m, 1H), 7.04-7.01 (m, 1H), 3.93 (s, 3H), 3.70 (s, 3H), 3.38 (s, 3H). LCMS: 423.9 (M+1)+
Reaction SMILES: COC(OC)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:45][O:46][CH:47]([O:50][CH3:51])[CH2:48]Br.[CH3:52][CH:53]([CH3:60])[CH2:54][C:55](=O)[C:56]([OH:58])=[O:57]>>[CH3:45][O:46][CH:47]([O:50][CH3:51])[CH2:48][CH:55]([CH2:54][CH:53]([CH3:60])[CH3:52])[C:56]([OH:58])=[O:57]
Reactant: COC(CBr)OC
Reactant: CC(C)CC(=O)C(=O)O
Agent: COC(C=P(c1ccccc1)(c1ccccc1)c1ccccc1)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COC(CC(CC(C)C)C(=O)O)OC

Procedure:
Alternatively, for those compounds wherein n=1 and R1 is H, the compounds can be prepared by condensing the ylide 1,1-dimethoxy-2-(triphenylphosphoranylidene)ethane prepared from triphenylphosphine and 1,1-dimethoxy-2-bromoethane with 4-methyl-2-oxopentanoic acid. The product is then hydrogenated to obtain 4,4-dimethoxy-2-isobutylbutanoic acid which is coupled to the moiety R3NHCHR4COX to obtain 4,4-dimethoxy-2-isobutylbutanoyl-NR3CHR4COX. Treatment with aqueous acid yields the aldehyde 2-isobutyl-4-oxobutanoyl-NR3CHR4COX. The oxime is prepared by reaction with hydroxylamine and reduced to the corresponding N-substituted hydroxylamine. Acylation of both the hydroxaminol oxygen and nitrogen followed by hydrolysis of the O-acyl group provides the N-acyl reverse hydroxymates. (Summers, J. B., et al., J Med Chem (1988) 31:1960-1964.)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=O)[C:11]3[CH2:14][CH2:15][CH2:16][C:10]=3[NH:9]2)=[C:4]([F:17])[CH:3]=1.P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:17])[N:9]=[C:10]2[CH2:16][CH2:15][CH2:14][C:11]=12
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1c2c([nH]n1-c1ccc(Cl)cc1F)CCC2
Product: Fc1cc(Cl)ccc1-n1nc2c(c1Cl)CCC2

Procedure:
By reacting 2-(4-chloro-2-fluorophenyl)-1,4,5,6-tetrahydrocyclopentapyrazol-3(2H)-one with phosphorous oxychloride according to the procedure of Example 1(d), 3-chloro-2-(4-chloro-2-fluorophenyl)-2,4,5,6-tetrahydrocyclopentapyrazole (m.p. 102°-104°) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:35]C(=O)OC(C)(C)C)[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:16])[CH3:17])=[CH:13][N:14]=1)[NH2:35]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(NC(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(N)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A solution of tert-butyl 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorophenylcarbamate (200 mg) in DCM (1 mL) was treated with TFA (1 mL) with stirring. After 1 h, the solution was concentrated under reduced pressure, diluted with DCE (5 mL). The organic layer was washed with water, satd NaHCO3 and brine, then dried (MgSO4) and concentrated to afford the title compound (152 mg, 90%). 1H NMR (400 MHz, MeOD) δ 7.40 (s, 1H), 7.36 (d, J=9.1 Hz, 1H), 6.93 (d, J=8.4, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.68-6.61 (m, 2H), 6.53 (s, 1H), 6.40-6.27 (m, 3H), 4.01 (s, 2H), 3.76 (s, 3H), 1.58 (s, 6H); MS (EI) m/z 534 (MH+).
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[CH2:14]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([NH:35][C:36]2[S:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][NH:46][CH3:47])=[N:39][N:40]=2)(=[O:34])=[O:33])=[CH:28][CH:27]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C([O-])(O)=O.[Na+]>CO>[CH2:14]([C:26]1[CH:27]=[CH:28][C:29]([S:32]([NH:35][C:36]2[S:37][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]([CH3:47])[C:2]3[C:10]4[C:6](=[N:7][O:8][N:9]=4)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=3)=[N:39][N:40]=2)(=[O:33])=[O:34])=[CH:30][CH:31]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Reactant: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCNC)s2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nnc(CCCCCN(C)c3ccc([N+](=O)[O-])c4nonc34)s2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
4-Chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl) (18 mg, 0.085 mmol) was dissolved in methanol (1 mL). After the addition of 4-dodecyl-N-(5-(5-(methylamino)pentyl)-1,3,4-thiadiazol-2-yl)benzenesulfonamide (43 mg, 0.085 mmol) and NaHCO3 (7 mg, 0.085 mmol) in methanol (2 mL), the solution was stirred for 2 h at 40° C. The reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on silica gel 60 (70-230 mesh) eluted with CH2Cl2:MeOH 49:1. Product 137 was obtained in 53% yield (30 mg, 0.045 mmol), mp 102-104° C. 1H NMR (300 MHz, CDCl3) δ 0.87 (t, 3, J=7.2 Hz), 1.25 (m, 18), 1.51-1.57 (m, 4), 1.79-1.85 (m, 4), 2.63 (t, 2, J=6.6 Hz), 2.84 (t, 2, J=7.5 Hz), 3.45 (s, 3), 4.14 (s, 2), 6.11 (d, 1, J=9.3 Hz), 7.27 (d, 2, J=8.1 Hz), 7.79 (d, 2, J=8.4 Hz), 8.44 (d, 1, J=9.0 Hz); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.6, 25.7, 27.7, 29.2, 29.3, 29.4, 29.5, 29.6, 30.4, 31.1, 31.9, 35.9, 55.6, 101.2, 126.5, 128.9, 135.4, 138.3, 145.3, 148.5, 154.7, 158.3, 163.8, 167.9; HRMS (ESI+, m/z) calculated for C32H46N7O5S2 672.3002. observed 672.2996 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)([OH:3])=O.Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.[CH3:41][NH:42][C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1>ClCCl>[CH3:41][N:42]([C@H:43]1[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH2:46][CH2:45][CH2:44]1)[C:1]([C:4]1[N:5]=[C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[O:7][CH:8]=1)=[O:3]
Reactant: CN[C@@H]1CCCc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C(=O)c1coc(C2CCN(C(=O)OC(C)(C)C)CC2)n1)[C@@H]1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40.5 %

Procedure:
A mixture of 1-(1,1-dimethylethyl) 4-(4-carboxy-2-oxazolyl)-1-piperidinecarboxylate (600 mg, 2.02 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (425.57 mg, 2.22 mmol) and N-methylmorpholine (224.55 mg, 2.22 mmol) in 4 mL dichloromethane was stirred for 15 minutes at room temperature. To the reaction mixture was added 424 mg (2.63 mmol) of (1R)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using 25-75% of ethyl acetate in hexanes as eluant to give 360 mg of the title compound as an oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[Cl-].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]1[C:3]([C:4]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=2)=[N:23][N:22]=[N:21]1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnnc1-c1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
N-Methyl-4-nitro-benzamide (2.25 g, 12.5 mmol, 1 eq.) and PCl5 (2.60 g, 12.5 mmol, 1 eq.) were melted together under house vacuum connected to a NaOH trap behind a safety shield. Melting occurred at 100° C. Heated at 130° C. for 1 hour then purified by kugelrohr distillation at 0.1 mmHg at 130° C. CAUTION: THE EXPLOSIVE PROPERTIES OF THIS COMPOUND ARE UNKNOWN). The iminoyl chloride (12.5 mmol 1 eq.) in DMF 10 ml was added to NaN3 in 10 ml of DMF at 25° C. and stirred overnight. Worked up by adding EtOAc then rinsing 3× with H20. The organic layer was dried over MgSO4, then stripped to obtain yellow solids which were purified over silica gel in 3:1 hexanes/EtOAc to 100% EtOAc. Obtained 1.21 g of yellow solids as product. NMR (300 MHz, CDCl3) δ 8.46 (d, 2H, J=7 Hz), 8.02 (d, 2H, J=7 Hz),4.27 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][O:26][CH3:27]>CN(C=O)C.O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]([CH2:25][O:26][CH3:27])[C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCN(c1nccs1)S(=O)(=O)c1ccc(C#N)cc1
Reaction time: 4 h
Yield: 82 %

Procedure:
To a suspension of 4-cyano-N-thiazol-2-yl-benzenesulfonamide (10 mmol) and potassium carbonate (15 mmol) in DMF (30 mL) was added chloro-methoxy-methane (10 mmol) and the mixture was stirred for 4 h. The reaction mixture was diluted with water (30 mL) and the resulting mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography to give 4-cyano-N-methoxymethyl-N-thiazol-2-yl-benzenesulfonamide (8.2 mmol) as a white solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:12]=[C:11]2[N:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:15]=[CH:16][C:10]2=[N:9][CH:8]=1)(=O)=O.[Br-:29]>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:29][C:7]1[N:12]=[C:11]2[N:13]=[C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[CH:15]=[CH:16][C:10]2=[N:9][CH:8]=1
Reactant: [Br-]
Reactant: COc1ccc(COc2ccc3ncc(OS(=O)(=O)C(F)(F)F)nc3n2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COc1ccc(COc2ccc3ncc(Br)nc3n2)cc1
Temperature: 85 °C
Yield: 102.6 %

Procedure:
6-({[4-(Methyloxy)phenyl]methyl}oxy)pyrido[2,3-b]pyrazin-3-yl trifluoromethanesulfonate (1.39 g, 3.35 mmol) was dissolved in dry toluene (100 mL) under argon and tetrabutylammonium bromide (2.16 g, 6.7 mmol) was added. The reaction was heated at 85° C. for 4 h; 1.08 g of tetrabutylammonium bromide were added and the reaction was heated at 90° C. for another 6 h; 0.54 g of bromide were added and the reaction was heated for 3 h. The reaction was cooled to rt, the toluene was evaporated, the residue was partitioned between water (200 mL) and diethyl ether (400 mL). The layers were separated and the aqueous was extracted with diethyl ether (2×300 mL). The organic phases were combined and washed with water (300 mL) then dried and evaporated to afford the title compound (1.19 g, 100%).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[F:13][C:14]([F:41])([F:40])[C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:39]=[CH:38][C:23]([O:24][CH:25]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:19]=1.Cl.[NH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47].ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>ClCCl>[F:40][C:14]([F:13])([F:41])[C:15]1[N:16]=[CH:17][N:18]([C:20]2[CH:39]=[CH:38][C:23]([O:24][CH:25]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([NH:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:35])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:22][CH:21]=2)[CH:19]=1
Reactant: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)O)cc1
Reactant: COC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCC(Oc1ccc(-n2cnc(C(F)(F)F)c2)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (40 mg, 0.21 mmol) was added to a room temperature solution of (+/−)-4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzoic acid (80 mg, 0.20 mmol), methyl 3-aminopropanoate hydrochloride (28 mg, 0.20 mmol), 1-hydroxy-7-azabenzotriazole (30 mg, 0.22 mmol), and triethylamine (31 μL, 0.22 mmol) in dichloromethane (2 mL). The solution was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (20 mL) and washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give (+/−)-methyl 3-(4-(1-(4-(4-(trifluoromethyl)-1H-imidazol-1-yl)phenoxy)butyl)benzamido)propanoate (89 mg, 90%). 1H NMR (400 MHz, CDCl3, δ): 7.74-7.70 (m, 2H), 7.69-7.66 (s, 1H), 7.44-7.41 (m, 1H), 7.40-7.36 (m, 2H), 7.18-7.13 (m, 2H), 6.91-6.86 (m, 2H), 6.83-6.75 (m, 1H), 5.16-5.12 (m, 1H), 3.72-3.66 (m, 5H), 2.66-2.60 (m, 2H), 2.06-1.93 (m, 1H), 1.86-1.74 (m, 1H), 1.55-1.35 (m, 2H), 0.99-0.91 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3]1([CH2:11]Br)[CH2:8][O:7]C(C)(C)[O:5][CH2:4]1.C(=O)(O)[O-].[Na+].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CS(C)=O>[OH:7][CH2:8][C:3]1([CH2:4][OH:5])[CH2:2][N:25]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:11]1
Reactant: NCc1ccccc1
Reactant: CC1(C)OCC(CBr)(CBr)CO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: OCC1(CO)CN(Cc2ccccc2)C1
Temperature: 135 °C
Reaction time: 1.5 h

Procedure:
A mixture of 30.2 g of 5,5-bis(bromomethyl)-2,2-dimethyl-1,3-dioxane (0.1 mol), 24.0 g of sodium bicarbonate and 50 ml of dimethyl sulfoxide was heated to 135° C. A solution of 10.7 g of benzylamine in 50 ml of DMSO was then added dropwise with stirring over 1.5 hours. After addition was complete, the mixture was stirred for 2.5 hours at 135° C. After cooling, 100 ml of DMSO and 20 ml of water were added and the solution was extracted with pentane. The extract was washed with water and then shaken with 5% (w/w) sulfuric acid in order to extract the basic 3,3-bis(hydroxymethyl)-1-benzylazetidine acetone acetal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].Br[CH:22]([CH2:27][O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:29]([O:28][CH2:27][CH:22]([N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=1)[C:23]([O:25][CH3:26])=[O:24])([CH3:32])([CH3:31])[CH3:30]
Reactant: COC(=O)C(Br)COC(C)(C)C
Reactant: CCOc1ccc(S(=O)(=O)Nc2ccc(C)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(COC(C)(C)C)C(=O)OC)cc1
Temperature: 60 °C
Yield: 26.3 %

Procedure:
The crude N-aryl-benzenesulfonamide building block XIII, e.g. 4-ethoxy-N-(4-methylphenyl)benzenesulfonamide (388 mg, 1.33 mmol, preparation described in example 1, step a)), was dissolved in DMF (5 mL). Intermediate XI with R3═CH2OtBu, e.g. methyl 2-bromo-3-tert-butoxypropanoate (478 mg, 2 mmol) and potassium carbonate (368 mg, 2.66 mmol) were added. The mixture was heated overnight at 60° C. Solvents were evaporated. The crude residue was suspended in ethyl acetate (10 mL) and was washed with 1N HCl solution (7 mL) and with brine (7 mL). Organic phase was dried over MgSO4, fitrated and evaporated. The crude mixture was purified by flash chromatography, using a 8:2 mixture cyclohexane/ethyl acetate as eluent. The desired product, e.g. methyl 3-tert-butoxy-2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (157 mg, 26.3%) was isolated as a light yellow oil, in 96.4% purity by HPLC (MaxPlot detection between 230 and 400 nm).