Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[H-].[Na+].[CH3:29][O:30][CH2:31]Cl.O>CN(C)C=O>[CH3:29][O:30][CH2:31][O:1][C:2]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:4][C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)C(=O)C(=O)OCc1ccccc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(CC(=O)OC(C)(C)C)=C(OCOC)C(=O)OCc1ccccc1
Reaction time: 0.75 h
Yield: 86.5 %

Procedure:
992 mg of 1-benzyl 3-tert-butyl 2-ethyl 1-oxo-1,2,3-propanetricarboxylate in 10 ml of dimethylformamide was stirred together with 131 mg of 60% oily sodium hydride at room temperature for 1 hour. After addition of 273 mg of chloromethyl methyl ether, the reaction solution was stirred for another 45 minutes, then poured into water and extracted with ethyl ether. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [hexane/ethyl acetate=5/1] to give 962 mg of the title compound as a colorless oily substance.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:12][CH3:13])[C:9]=2[OH:11])[C:4](=O)[O:3]1.[NH2:15][NH2:16]>C(O)C>[OH:11][C:9]1[C:8]([O:12][CH3:13])=[CH:7][CH:6]=[C:5]2[C:10]=1[CH:2]=[N:15][NH:16][C:4]2=[O:3]
Reactant: NN
Reactant: COc1ccc2c(c1O)C(O)OC2=O
Solvent: CCO
Product: COc1ccc2c(=O)[nH]ncc2c1O
Yield: 72 %

Procedure:
A solution of 3,4-dihydroxy-5-methoxy-3H-isobenzofuran-1-one (6.63 g, 34 mmoles), prepared as described in example 57, in ethanol (60 ml) was added with 98% hydrazine (8.5 ml). The mixture was heated to clarity and after 5 minutes a precipitate formed and was filtered and treated with 1N HCl. The mother liquors were concentrated more times and the resultant solid fractions joined to give 4.65 g of the title compound (yield: 72%).
Reaction SMILES: [131I][131I].[CH3:3][C:4]1[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[N:6][NH:7][N:8]=1.[CH3:14][O:15][CH2:16][CH2:17]Br>>[CH3:14][O:15][CH2:16][CH2:17][N:7]1[N:6]=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([CH3:3])=[N:8]1
Reactant: COCCBr
Reactant: CCOC(=O)c1n[nH]nc1C
Agent: [131I][131I]
Product: CCOC(=O)c1nn(CCOC)nc1C
Yield: 54 %

Procedure:
The title compound was synthesized as described for Intermediate example I-131 in 54% yield starting from ethyl 5-methyl-2H-1,2,3-triazole-4-carboxylate and 2-bromoethyl methyl ether; 1H NMR (400 MHz, CDCl3) δ ppm 4.58 (t, 2 H), 4.42 (q, 2 H), 3.90 (t, 2 H), 3.35 (s, 3 H), 2.49-2.56 (m, 3 H), 1.34-1.46 (m, 3 H); MS (ESI) m/z 214[M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:11][C:10](=O)[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:15][C:16](=[O:37])[CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:14]>ClCCl>[CH2:13]([O:15][C:16](=[O:37])[CH:17]=[C:10]1[CH2:11][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH2:9]1)[CH3:14]
Reactant: O=C1CC(c2cccc(Br)c2)C1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C=C1CC(c2cccc(Br)c2)C1
Yield: 89 %

Procedure:
3-(3-Bromo-phenyl)-cyclobutanone (2.03 g 9.02 mmol) and Triphenyl-phosphoranylidene acetic acid ethyl ester (15.72 gms 45.12 mmol) were dissolved in dichloromethane (30 mL) inside a CEM 80 ml microwave vessel. The solution was irradiated in a CEM Discover™ microwave instrument for 30 minutes at 120° C. Pressure reached a maximum of 180 PSI. The product was purified by column chromatography (isocratic; 10% diethyl ether in hexanes) to give 2.37 gm of an oil (89%) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.20 (t, J=7.1 Hz, 3H) 2.89-3.00 (m, 1H) 3.03-3.11 (m, 1H) 3.16-3.27 (m, 1H) 3.46-3.57 (m, 1H) 3.63 (q, J=8.0 Hz, 1H) 4.08 (q, J=7.0 Hz, 2H) 5.71 (q, J=2.9 Hz, 1H) 7.25-7.35 (m, 2H) 7.39-7.43 (m, 1H) 7.48-7.52 (m, 1H); MS (APPI) m/z 295 [M+H]·+.
Reaction SMILES: N.[Na].C1([P:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)C=CC=CC=1.Cl[C:23]1[NH:24][C:25](=[O:33])[C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>O1CCCC1>[C:16]1([P:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:23]2[NH:24][C:25](=[O:33])[C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=c1[nH]c(Cl)cc2ccccc12
Agent: N
Agent: [Na]
Solvent: C1CCOC1
Product: O=c1[nH]c(P(c2ccccc2)c2ccccc2)cc2ccccc12
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
At −78° C., 130 ml of ammonia were condensed in and 2.10 g of sodium (91.3 mmol) were dissolved therein within 5 min. The dark blue solution was admixed with 11.70 g of triphenylphosphine (44.6 mmol) in portions and stirred at −78° C. for 2 h. After 100 ml of dry tetrahydrofuran had been added, the cold bath was removed and the ammonia evaporated off within 2 h. After the orange-colored solution had been warmed to room temperature, it was admixed with 4.0 g (22.3 mmol) of 3-chloroisoquinolin-1(2H)-one from example 16.4 in portions and heated to 60° C. for 20 h. After the mixture had been cooled, it was admixed with 50 ml of dist. H2O, and the aqueous phase was extracted three times with 100 ml each time of dichloromethane, and the combined organic phases were dried over MgSO4 and concentrated under reduced pressure. The resulting solid was digested with dichloromethane, filtered off and dried. The filtrate was concentrated and the resulting solid again digested with dichloromethane, filtered off and dried. The solids were combined. 4.47 g (13.6 mmol, 60.9%) of 3-(diphenyl-phosphino)isoquinolin-1(2H)-one were obtained. The filtrate was concentrated under reduced pressure and the resulting solid purified by column chromatography (5:1 dichloromethane/ethyl acetate). A further 0.216 g (0.66 mmol, 2.9%) of 3-(diphenylphosphino)isoquinolin-1(2H)-one was obtained.
Reaction SMILES: [C:1]([CH:5]1[CH2:17][CH2:16][C:8]2([O:12][N:11]=[C:10]([C:13]([OH:15])=O)[CH2:9]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH:22]=[CH:21][N:20]=[C:19]1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][C:8]2([O:12][N:11]=[C:10]([C:13]([N:26]3[CH2:27][CH2:28][N:23]([C:19]4[S:18][CH:22]=[CH:21][N:20]=4)[CH2:24][CH2:25]3)=[O:15])[CH2:9]2)[CH2:16][CH2:17]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)C1CCC2(CC1)CC(C(=O)O)=NO2
Reactant: c1csc(N2CCNCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)C1CCC2(CC1)CC(C(=O)N1CCN(c3nccs3)CC1)=NO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound 8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-ene-3-carboxylic acid (120 mg, 0.51 mmol), 1-thiazol-2-ylpiperazine (110 mg, 0.51 mmol), 4-methylmorpholine (101 mg, 1.02 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (288 mg, 0.65 mmol) (HBTU) were dissolved in DMF (10 ml) and stirred overnight under a nitrogen atmosphere at RT. The solvent was removed under vacuum, the residue taken up in EtOAc and sat. aq. NaHCO3 solution and the phases were separated. The aqueous phase was extracted several times with EtOAc and the combined organic phases were washed with sat. aq. NaCl solution, dried over magnesium sulphate and the solvent was removed under vacuum. After purification by column chromatography (silica gel, hexane/EtOAc 3:1), the desired product (8-tert-butyl-1-oxa-2-azaspiro[4.5]dec-2-en-3-yl)-(4-thiazol-2-ylpiperazin-1-yl)methanone was obtained as a trans isomer (50 mg, 26% of the theoretical amount) and as a cis isomer (100 mg, 51% of the theoretical amount).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([OH:12])[CH2:8][CH2:7]1)=[O:5].[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:31](O)=[O:32])=[CH:25]2>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C@H:3]([NH:2][C:31]([C:26]2[NH:27][C:28]3[C:24]([CH:25]=2)=[CH:23][C:22]([F:21])=[CH:30][CH:29]=3)=[O:32])[C:4]([N:6]2[CH2:7][CH2:8][CH:9]([OH:12])[CH2:10][CH2:11]2)=[O:5])=[CH:19][CH:18]=1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1)c1cc2cc(F)ccc2[nH]1

Procedure:
(S)-2-Amino-3-(4-fluoro-phenyl)-1-(4-hydroxy-piperidin-1-yl)-propan-1-one hydrochloride (0.5 mmol) and 5-fluoro-1H-indole-2-carboxylic acid (0.5 mmol) were coupled according to Procedure A. The crude product was triturated once with 1:1 ether-hexanes and once with hexanes. The resulting solid was boiled in ethyl acetate, the resulting suspension filtered, and the collected solid dried. Yield 103 mg, 48%; HPLC (60/40) 3.69 minutes (95%); PBMS 428 (MH+, 100%);
Reaction SMILES: [N:1]1([C:5]2[S:6][C@H:7]3[O:13][C@H:12]([CH2:14][OH:15])[C@@H:11]([OH:16])[C@H:10]([OH:17])[C@H:8]3[N:9]=2)[CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>CN(C=O)C>[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([O:15][CH2:14][C@H:12]2[O:13][C@H:7]3[C@H:8]([N:9]=[C:5]([N:1]4[CH2:4][CH2:3][CH2:2]4)[S:6]3)[C@@H:10]([OH:17])[C@@H:11]2[OH:16])(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: OC[C@H]1O[C@@H]2SC(N3CCC3)=N[C@@H]2[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H]3SC(N4CCC4)=N[C@@H]3[C@@H](O)[C@@H]2O)cc1
Yield: 12.7 %

Procedure:
A solution of (3aR,5R,6S,7R,7aR)-2-(azetidin-1-yl)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol (5.0 g, 19 mmol) and triethylamine (3.88 g, 38 mmol) in DMF (50 mL) was treated with 4-methylbenzene-1-sulfonyl chloride (4.4 g, 23 mmol) overnight at room temperature. The reaction mixture was quenched by water (100 mL), extracted with dichloromethane (3×80 mL), washed with brine (3×50 mL), dried over anhydrous magnesium sulfate, and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 1%-5% methanol in dichloromethane to give crude compound 4 as a light yellow solid (1.0 g). This material was employed in the next step without further purification. (ES, m/z) [M+H]+ 415.0.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[NH2:8])=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cnccc2N)cc1
Reaction time: 6.5 h
Yield: 76.3 %

Procedure:
A solution of N4-(tert-butyloxycarbonyl)-N3-(4-methoxybenzoyl)-3,4-pyridinediamine (600 mg, 1.75 mmol) in methylene chloride (8 mL) was treated with trifluoroacetic acid (1.35 mL, 17.5 mmol). After 6.5 h, the mixture was concentrated and the residue dissolved in water and treated with 5 N aqueous sodium hydroxide. The resulting precipitate was collected by filtration yielding 325 mg (76%) of the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[C:13]1([SH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:13]1([S:19][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Reactant: Sc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(Sc2ccccc2)c2ccccc12
Yield: 83.3 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (2.1 g, 12 mmol), thiophenol (2.6 g, 23 mmol), and K2CO3 (2.4 g, 17 mmol) in DMF (40 mL) was microwaved at 125° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, concentrated, and triturated with Et2O to give the title compound (2.5 g, 10 mmol): 1H NMR (400 MHz, DMSO-d6) δ 12.88 (s, 1H), 8.28 (dd, J=7.8, 1.1, 1H), 8.06-7.99 (m, 1H), 7.98-7.92 (m, 1H), 7.92-7.85 (m, 1H), 7.44 (d, J=1.2, 2H), 7.38 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[C:9](=[O:11])[CH:10]=1.[CH3:28][C:29]1([CH3:41])[O:33][C@H:32]([CH2:34][N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH2:31][O:30]1>>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:13]([NH:40][C:37]2[CH:38]=[CH:39][N:35]([CH2:34][C@@H:32]3[CH2:31][O:30][C:29]([CH3:41])([CH3:28])[O:33]3)[N:36]=2)=[O:14])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCOCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 32) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as an off-white solid as a mixture of diastereomers (0.60 g, 53%); ES+-HRMS m/e calcd for C27H31N5O6F2 [M+H+] 560.2315 found 560.2319. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.13-1.29 (m, 2H), 1.25 (s, 3H), 1.30, 1.31 (2×s, 3H), 1.35-1.59 (m, 3H), 1.84-1.94 (m, 1H), 2.15-2.26 (m, 1H), 3.09-3.27 (m, 2H), 3.70-3.85 (m, 3H), 3.97-4.18 (m, 3H), 4.31-4.40 (m, 1H), 5.54 (dd, J=11.1, 4.0 Hz, 1H), 6.04 (d, J=2.7 Hz, 1H), 6.39 (d, J=2.1 Hz, 1H), 7.34-7.43 (m, 2H), 7.43-7.53 (m, 1H), 7.60 (br s, 1H), 8.29 (d, J=2.7 Hz, 1H), 10.86, 10.87 (2×s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CN(C=O)C.C(OCC)(=O)C>[N:13]([CH2:2][C:3]([C:5]1[CH:6]=[C:7]([OH:12])[C:8](=[CH:10][CH:11]=1)[OH:9])=[O:4])=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(CCl)c1ccc(O)c(O)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=NCC(=O)c1ccc(O)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.6 %

Procedure:
To the solution of 4-chloroacetylcatechol (25 g) in DMF (200 ml) was added sodium azide (10.5 g), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with water and dried over anhydrous magnesium sulfate. After the solvent was evaporated, the solids thus obtained was washed with a solution of n-hexane:ether=5:1 to give 23.2 g of 4-azidoacetylcatechol (yield, 90%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[CH3:11][S:12]([C:15]1[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=1)(=[NH:14])=[O:13].Cl.CN(C)CCCN=C=NCC.CCOC(C)=O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:6]([C:7]([N:14]=[S:12]([C:15]2[CH:16]=[C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:18]=[CH:19][CH:20]=2)([CH3:11])=[O:13])=[O:9])[CH:5]=[N:4][CH:3]=1
Reactant: COC(=O)Cc1cccc(S(C)(=N)=O)c1
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1cccc(S(C)(=O)=NC(=O)c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
To a solution of 5-bromonicotinic acid (648 mg, 3.21 mmol), methyl [3-(S-methylsulfonimidoyl)phenyl]acetate (802 mg, 3.53 mmol), and catalytic DMAP in 15.0 ml DMF at room temperature was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (738 mg, 3.85 mmol). The reaction was stirred 1 hour at room temperature then added to EtOAc. The EtOAc solution was washed with dilute brine, NaHCO3 solution, brine, dilute HCl/brine mixture, brine/NaHCO3 solution, dried with anhydrous Na2SO4 and rotary evaporated. The oil was chromatographed eluting with CHCl3/EtOAc to give viscous clear oil (994 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:5]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[Si](Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>C(#N)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:26][N:25]=[N:24]2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=2)[CH:5]=1
Reactant: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(Cl)cn2)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-c2ccc(Cl)cn2)cc(-n2nnnc2C(C)C)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 90.1 %

Procedure:
3-(5-Chloro-pyridin-2-yl)-5-isobutyrylamino-benzoic acid methyl ester (1.90 g, 5.71 mmol) was dissolved in acetonitrile, and NaN3 (3.71 g, 5.71 mmol) and SiCl4 (1.64 mL, 14.28 mmol) were added. The reaction mixture was stirred at 60° C. for 18 hours, then cooled and poured in to cold saturated aqueous NaHCO3. The resulting mixture was extracted with EtOAc, and the combined organic layers were dried (MgSO4), filtered and concentrated under reduced pressure to give 1.84 g of 3-(5-chloro-pyridin-2-yl)-5-(5-isopropyl-tetrazol-1-yl)-benzoic acid methyl ester, MS (M+H)=358.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2].C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:16])=[O:8])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C(=O)O)ccc1C#N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C(=O)Cl)ccc1C#N
Reaction time: 3 h

Procedure:
The crude product of 4-cyano-3-methylbenzoic acid (1.0 g) was suspended in dichloromethane. To the mixture, oxalyl chloride (1.2 g) and an catalytic amount of N,N-dimethylformamide (2 to 3 drops) were added under ice cooling. After adjusting to room temperature, the reaction solution was stirred for three hours. The solvent was distilled off under reduced pressure to obtain 4-cyano-3-methylbenzoyl chloride as a crude product (1.0 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:6]=O.Cl.[NH2:15][OH:16]>CCO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH:6]=[N:15][OH:16]
Reactant: COc1cc(C=O)ccc1[N+](=O)[O-]
Reactant: NO
Agent: Cl
Solvent: O
Solvent: CCO
Product: COc1cc(C=NO)ccc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To 3-methoxy-4-nitrobenzaldehyde (53.5 g, 295.5 mmol)) in EtOH (285 ml) was slowly added a solution of hydroxylamine hydrochloride (30.8 g, 443 mmol) in water (50 ml). The reaction mixture was stirred overnight, poured into ice-cold water, and the formed precipitate was collected by filtration to furnish 44 g of 3-methoxy-4-nitrobenzaldehyde oxime. The filtrate was extracted with DCM, and the organic phase was washed with water and brine, dried over sodium sulfate, and concentrated to furnish additional 8.2 g of the title product. 1H NMR (CDCl3) δ: 8.13 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.51 (s, 1H), 7.35 (s, 1H), 7.18 (dd, J=8.4, 1.4 Hz, 1H), 4.01 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27]([Cl:39])[C:28]=1[C:29]1[C:33]([CH2:34]O)=[C:32]([CH:36]([CH3:38])[CH3:37])[O:31][N:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[Cl:39][C:27]1[CH:26]=[N:25][CH:24]=[C:23]([Cl:22])[C:28]=1[C:29]1[C:33]([CH2:34][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:15](=[CH:16][CH:17]=3)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]4)=[CH:4][CH:3]=2)=[C:32]([CH:36]([CH3:37])[CH3:38])[O:31][N:30]=1
Reactant: CC(C)c1onc(-c2c(Cl)cncc2Cl)c1CO
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cncc5Cl)noc4C(C)C)cc3)ccc2n1
Temperature: 100 °C
Yield: 50.7 %

Procedure:
Methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (100 mg, 0.36 mmol), [3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methanol (103 mg, 0.36 mmol), triphenyl phosphine (94 mg, 0.36 mmol), diisopropyl azodicarboxylate (0.07 mL, 0.36 mmol) and dichloromethane (3.6 mL) were placed in a microwave reaction tube, sealed and heated in a microwave reactor to 100° C. for 10 minutes. The solution was concentrated then slurried in a 3:7 mixture of acetone: hexane. The resulting off-white solid was purified by chromatography (silica gel, 3:7 acetone:hexanes) to provide methyl 6-[4-({[3-(3,5-dichloro-4-pyridinyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (0.10 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 8.81 (s, 2H), 8.55 (d, J=9 Hz, 1H), 8.29 (d, J=2 Hz, 1H), 8.18-8.10 (m, 3H), 7.74 (d, J=9 Hz, 2H), 6.89 (d, J=9 Hz, 2H), 4.97 (s, 2H), 3.94 (s, 3H), 3.49 (septet, 7 Hz, 1H), 1.34 (d, J=7 Hz, 6H). ESI-LCMS m/z 548 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH2:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[C:26]([O:29][C:30]1[C:31](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:32](Cl)=[O:33])(=[O:28])[CH3:27]>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:16])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([NH:15][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][C:30]=1[O:29][C:26](=[O:28])[CH3:27])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: CCOC(=O)c1cc2cc(N)ccc2n1C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3OC(C)=O)ccc2n1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-amino-1-methyl-indole-2-carboxylic acid ethyl ester (12.86 g, 58.92 mM) and diisopropylethylamine (20.5 mL, 117.84 mM) in CH2Cl2 at 0° C. was added a solution of acetyl salicyloyl chloride in CH2Cl2 over 30 minutes. After the addition was complete the cooling bath was removed and the mixture was allowed to warm to room temperature and stirred at that temperature for 2 hours. The mixture was transferred to a separatory funnel and the solution was washed with 1N HCl (150 mL) and aqueous NaHCO3. The organic fraction was dried over MgSO4 and filtered. The solvent was removed under reduced pressure to provide the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([S:15]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:17])=[O:16])=[CH:10][CH:9]=[CH:8]2)(=O)C.C(O)CC.[ClH:30]>O>[ClH:30].[NH2:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11]([S:15]([NH:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)(=[O:17])=[O:16])=[CH:10][CH:9]=[CH:8]2
Reactant: CC(=O)Nc1ccc2c(S(=O)(=O)NCc3ccccc3)cccc2c1
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Nc1ccc2c(S(=O)(=O)NCc3ccccc3)cccc2c1
Temperature: 25 °C
Yield: 63.8 %

Procedure:
6-Acetylamino-N-benzylnaphthalene-1-sulfonamide (compound No. 7-1; 188 mg, 0.530 mmol) was suspended to a mixed solvent of 1-propanol (3.0 ml) and water (1.5 ml). Concentrated hydrochloric acid (1.5 ml) was added to the suspension and the mixture was refluxed for 1 hour. After cooling to room temperature, the separated crystal was collected and washed with 1-propanol and isopropyl ether to give the title compound as a light yellow crystal (118 mg, 63.8%).