Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:11]([O-])=O.[Na+].[C:15]([O:21][CH2:22][CH3:23])(=[O:20])[CH2:16][C:17]([CH3:19])=[O:18].C([O-])(=O)C.[Na+]>O.Cl.C(O)C>[CH2:22]([O:21][C:15](=[O:20])[C:16](=[N:11][NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:17](=[O:18])[CH3:19])[CH3:23]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(=NNc1ccc([N+](=O)[O-])cc1)C(C)=O
Temperature: -2 °C
Yield: 94491.6 %

Procedure:
A suspension of 4-nitroaniline (41.43 g, 0.3 mmol) in water (150 ml) and 37% hydrochloric acid (75 ml) was heated to dissolution. The cooled suspension of hydrochloride salt was treated with sodium nitrite (20.7 g) at -5° C. at a rate which maintained the reaction temperature at -2° C. The diazonium salt solution was added to a solution of ethyl acetoacetate (39 g, 0.3 mmol) in ethanol (225 ml) and ice water (1.5 L) containing sodium acetate (75 g, 0.9 mmol). The mixture thickened and sufficient water was added to permit agitation for 3.5 hours. The mixture was filtered, the filter cake washed with water, and crystallized from ethanol to yield the title compound, (79.16 g), m.p. 128° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C[O:25]CC1.B1C2CCCC1CCC2.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:21]3[CH:16]([CH2:17][CH:18]=[CH:19][CH:20]=3)[C:15](=[O:25])[CH2:14]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(C=Cc3ccccc32)CC1
Reactant: C1CCOC1
Agent: O=[Cr](=O)([O-])Cl
Agent: B1C2CCCC1CCC2
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)C1CC=CC=C12
Temperature: 70 °C
Yield: 47 %

Procedure:
To a solution of 661 mg (2.31 mmol) of 1'-(t-butyloxycarbonyl)spiro[1H-indene-1,4'-piperidine][prepared by the method of Chambers, et al, J. Med. Chem., 1992, 35, 2036]in 5.0 ml of THF was added 5.8 ml (1.0 M THF, 2.9 mmol) of 9-BBN. The reaction mixture was heated at 70° C. until TLC analysis indicated that the starting material was consumed. The solution was concentrated and the residue was dissolved in dichloromethane. The solution was cooled to 0° C. and 4.1 g (19.2 mmol) of PCC was added slowly over 15 minutes. The reaction mixture was warmed to room temperature and then to reflux for 30 minutes. The solution was then diluted with ether and filtered through a pad of a mixture of celite and florisil. Purification by flash chromotgraphy (silica gel, hexane/ethyl acetate, 4:1) gave 326 mg (47%) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[C:14]([CH:16]=[CH2:17])[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:12]([F:23])[CH:11]=1)[CH3:9])(C)(C)C.C1(C)C=CC=CC=1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH:8]([C:10]1[CH:15]=[C:14]([CH:16]=[CH2:17])[C:13]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[C:12]([F:23])[CH:11]=1)[CH3:9]
Reactant: C=Cc1cc(C(C)NC(=O)OC(C)(C)C)cc(F)c1NS(C)(=O)=O
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: C=Cc1cc(C(C)N)cc(F)c1NS(C)(=O)=O
Reaction time: 12 h
Yield: 134.2 %

Procedure:
[1-(3-fluoro-4-methanesulfonylamino-5-vinyl phenyl)ethyl]carbamic acid tert-butyl ester (0.06 mmol, 20.2 mg) was dissolved in methylene chloride, 5˜6 drops of CF3COOH were added. A reaction mixture was stirred for 12 hr. A toluene was added. The reaction mixture was concentrated in vacuo to yield brownish syrup (20.8 mg, 100.0%).
Reaction SMILES: [OH:1][Li].O.OO.C([C@@H]1COC(=O)N1C(=O)[C@H:20]([C@H:32]1[N:36]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:35]([CH3:45])([CH3:44])[CH2:34][CH2:33]1)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[F:31])C1C=CC=CC=1.[O-]S([O-])=O.[Na+].[Na+].C1[CH2:57][O:56]CC1.O>C1COCC1>[C:40]([O:39][C:37]([N:36]1[C:35]([CH3:44])([CH3:45])[CH2:34][CH2:33][C@H:32]1[C@H:20]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:23][C:22]=1[F:31])[C:57]([OH:56])=[O:1])=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(C(F)(F)F)cc2F)CCC1(C)C
Reactant: [Li]O
Reactant: C1CCOC1
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(C(F)(F)F)cc2F)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
To a solution of LiOH—H2O (0.3177 g, 7.570 mmol) in THF/water (2:1, 240 mL) was added 30% H2O2(0.91 mL, 9.46 mmol) and the soln stirred at RT for 10 min. The solution was cooled to 0° C. and a solution of 320 (2.19 g, 3.785 mmol) in THF (10 mL) was added. The reaction was stirred at 0° C. for 2 h then warmed to RT and stirred overnight. The reaction was then cooled to 0° C. and treated with 1M Na2SO3 (10 mL) and stirred for 10 min then warmed to RT and stirred for 10 min. The reaction was concentrated and extracted with EtOAc (2×20 mL). The aqueous phase was acidified with H2SO4 to pH ca. I-2 and extracted with DCM (2×20 mL). The organic extracts were concentrated and the crude product purified C18 preparative MPLC (Analogix 200 g C18 column) to afford 1.321 g (83.2%) of (S)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)acetic acid (322).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH:16][CH2:17][C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:13]1[CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[CH:1]=[N:2][CH:3]=[CH:4]3)[O:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CNc1cc(-c2ccc3cnccc3c2)on1)Cc1ccc(C(F)(F)F)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N[C@H](CNc1cc(-c2ccc3cnccc3c2)on1)Cc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of tert-butyl(S)-1-(5-(isoquinolin-6-yl)isoxazol-3-ylamino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (0.027 g, 0.053 mmol) in 5 mL of DCM was added TFA (0.50 mL, 6.5 mmol). The mixture was stirred for 30 minutes and diluted with 20 mL of EtOAc. The mixture was washed twice with 10 mL of 10% aqueous Na2CO3 and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 10% MeOH/DCM) afforded N-((S)-2-amino-3-(4-(trifluoromethyl)phenyl)propyl)-5-(isoquinolin-6-yl)isoxazol-3-amine (0.013 g, 60% yield) as a clear oil. MS m/z: 413 (M+1); 1H NMR (400 MHz, CD3OD) δ ppm 9.26 (s, 1H), 8.48 (d, J=5.8 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J=8.6 Hz, 1H), 8.01 (dd, J=1.3 Hz, 8.6 Hz, 1H), 7.90 (d, J=5.9 Hz, 1H), 7.62 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 6.52 (s, 1H), 3.45-3.25 (m, 2H), 3.34 (s, 2H), 3.18 (dd, J=7.4 Hz, 13.5 Hz, 1H), 3.00 (dd, J=5.5 Hz, 13.5 Hz, 1H), 2.75 (dd, J=7.9 Hz, 13.5 Hz, 1H), 2.22 (dt, 1.8 Hz, 6.7 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:16]([Br:17])=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)=[O:5].[C:18](=O)(OC(Cl)(Cl)Cl)[O:19]C(Cl)(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>C(Cl)Cl>[Br:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:3]2[C:2]=1[NH:1][C:18](=[O:19])[N:6]([CH:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)[C:4]2=[O:5]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1c(Br)cccc1C(=O)NC1CCOCC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c(Br)cccc2c(=O)n1C1CCOCC1
Temperature: 90 °C

Procedure:
A solution of 2-amino-3-bromo-N-(tetrahydro-2H-pyran-4-yl)benzamide (515a, 1.54 g, 5.15 mmol), bis(trichloromethyl) carbonate (0.764 g, 2.57 mmol), and triethylamine (3.59 mL, 25.7 mmol) in DCM (51.5 mL) was refluxed for 16 h. Toluene (50 mL) was added to the clear solution; this mixture was partially concentrated to remove the DCM. More bis(trichloromethyl) carbonate (0.764 g, 2.57 mmol) was added, and the yellow solution was heated to 90° C. for 1 h. The reaction mixture was concentrated to give 8-bromo-3-(tetrahydro-2H-pyran-4-yl)quinazoline-2,4(1H,3H)-dione (515b) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.56-1.62 (m, 2H) 2.87 (qd, J=12.39, 4.69 Hz, 2H) 3.52 (td, J=12.03, 1.76 Hz, 2H) 4.10 (dd, J=11.54, 4.69 Hz, 2H) 5.11 (tt, J=12.18, 3.96 Hz, 1H) 7.11 (t, J=8.02 Hz, 1H) 7.79 (dd, J=7.82, 1.17 Hz, 1H) 8.09 (s, 1H) 8.11 (s, 1H). MS (ESI, pos. ion) m/z: 325.0/326.9 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]2[CH2:22][O:21]2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([NH2:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1.C(O)(C)C.C(O)(=O)C(C(C(O)=O)O)O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15](=[O:19])[NH:16]2)=[C:11]([CH:20]([OH:21])[CH2:22][NH:35][C:32]([CH3:34])([CH3:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2c(C3CO3)cc(OCc3ccccc3)cc2[nH]1
Reactant: COc1ccc(CC(C)(C)N)cc1
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: COc1ccc(CC(C)(C)NCC(O)c2cc(OCc3ccccc3)cc3[nH]c(=O)ccc23)cc1

Procedure:
150 mg (0.51 mmol) 7-benzyloxy-5-oxiranyl-1H-quinolin-2-one and 208 mg (1.2 mmol) 2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamine are combined with 1 mL isopropanol and irradiated with microwaves for a total of 1 hour at 135° C. Then the reaction mixture is combined with ethyl acetate and 0.5 molar tartaric acid, whereupon a precipitate is formed. The organic phase is discarded and the solid and the aqueous phase are extracted with dichloromethane/methanol. The combined organic phases are evaporated down and combined with 8 mL ethyl acetate. The insoluble solid is suction filtered and dried. Yield: 130 mg (54%).
Reaction SMILES: [OH-].[Na+].CO.C1(C)C=CC=CC=1.C([S:15][CH2:16][C:17]([N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[CH:20]([CH3:25])[CH2:21][N+:22]([O-])=[O:23])=[O:18])(=O)C>O>[N:22](=[C:21]1[CH:20]([CH3:25])[N:19]([CH2:26][CH2:27][CH2:28][CH3:29])[C:17](=[O:18])[CH2:16][S:15]1)[OH:23]
Reactant: CCCCN(C(=O)CSC(C)=O)C(C)C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCN1C(=O)CSC(=NO)C1C

Procedure:
A solution of 6.8 g of sodium hydroxide, 125 ml of methanol, and 125 ml of toluene was charged to a flask and stirred vigorously while adding 33 g. of 2-(acetylthio)-N-butyl-N(1-nitro-2-propyl) acetamide over a 5-minute period of 30°-40° C. The reaction mixture was stirred at 40° C for 5 hours; then stirred overnight at room temperature. The mixture was stripped of solvents under reduced pressure. The solid residue was dissolved in 500 ml of cold water and the mixture was filtered and the filtrate was acidified with conc. hydrochloric acid. The resulting mixture was extracted three times with methylene chloride and the methylene chloride layer was dried with MgSO4. The methylene chloride was stripped from product under reduced pressure. The oily residue crystallized over night. This crude reaction product was recrystallized from 60/40 xylene-hexane mixture to yield 12 g of 2-oximino-3-methyl-4-butyltetrahydro-1,4-thiazin-5-one, m.p. 118°-120° C. An nmr spectrum supported the proposed structure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:6][CH:7]=1.O.[O-:17][C:18]#[N:19].[K+].C(O)(=O)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:18]([NH2:19])=[O:17])=[N:6][CH:7]=1
Reactant: CCOC(=O)CNCc1ccc(Br)cn1
Reactant: N#C[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CN(Cc1ccc(Br)cn1)C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 84.2 %

Procedure:
Ethyl 2-((5-bromopyridin-2-yl)methylamino)acetate (9J1) (41.6 mmol, 11.37 g) was dissolved in dioxane (80 ml) and water (80 ml) and potassium cyanate (62.4 mmol, 5.07 g) added. After 10 min, acetic acid (133 mmol, 8.00 g) was added and the reaction mixture stirred at room temperature under nitrogen overnight. The reaction mixture was quenched with saturated sodium bicarbonate (to pH 8-9) and then extracted with dichloromethane (3×). The organic layers were combined, washed with water, brine and dried using a hydrophobic frit, then concentrated under reduced pressure to give ethyl 2-(1-((5-bromopyridin-2-yl)methyl)ureido)acetate (9J2) 11.08 g (84%) which was used without further purification. 1H NMR (400 MHz, CDCl3) 8.61 (d, 1H) 7.84 (dd 1H) 7.39 (d, 1H) 5.35 (bs, 2H) 4.51 (s, 2H) 4.17 (q, 2H) 4.11 (s, 2H) 1.25 (t, 3H)
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:16]1[C:21]([OH:23])=[O:22]>CO>[ClH:3].[CH3:5][O:22][C:21]([C@@H:16]1[CH2:17][CH2:18][CH2:19][CH2:20][NH:15]1)=[O:23]
Reactant: O=C(O)[C@@H]1CCCCN1
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)[C@@H]1CCCCN1
Product: Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (161 ml) was added dropwise to a suspension of (2S)-2-piperidinecarboxylic acid L-tartrate (60 g) [see Preparation 1] in methanol (800 ml) at 0° C. The reaction mixture was stirred for 18 hours at room temperature after which time the solvent was removed under reduced pressure and the product azeotroped with toluene, precipitated out using methanol and filtered to afford (2S)-2-(methoxycarbonyl)piperidine hydrochloride (37.7 g) as a white solid.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)#N.[Cl-].[NH4+].C([O:25]CC)C>>[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1)(=[O:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCOCC
Reactant: CCCCCCCCCCBr
Reactant: N#Cc1ccccn1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Product: CCCCCCCCCCC(=O)c1ccccn1
Yield: 58.3 %

Procedure:
To 100 ml of anhydrous ether was added 3.60 g of magnesium for Grignard reaction, and to the mixture was added while stirring 36.5 g of 1-bromodecane. After the magnesium was completely dissolved, a diethyl ether solution of 15.6 g (0.15 mol) of 2-cyanopyridine was added dropwise, and the mixture was refluxed for 7 hours. After cooling, saturated ammonium chloride solution was added, the diethyl ether layer was separated, and the aqueous layer was further extracted with diethyl ether. The ether layers were combined, washed with water, and then dried over anhydrous sodium sulfate. After concentration under a reduced pressure, the residue was purified by separation according to silica gel column chromatography (ethyl acetate:hexane=1:9) to obtain 21.6 g of the desired product (yield 58.3%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)=[C:2]=[S:3].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[H-].[Na+].O>C1COCC1>[N:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=[O:11])=[O:12])=[CH:8][CH:9]=1)=[C:2]=[S:3]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)NS(=O)(=O)c1ccc(N=C=S)cc1
Reaction time: 1 h
Yield: 80 %

Procedure:
4-Isothiocyanato-benzenesulfonamide (750 mg, 3.5 mmol), and tert-butyldimethylsilyl chloride (528 mg, 3.5 mmol) stirred in dry THF (20 mL) at 0° C. Sodium hydride (210 mg, 60% in mineral oil, 5.25 mmol) was added, and the reaction stirred for 1 h before it was poured over H2O (50 mL) and extracted with ether (2×50 mL). Organics were washed with brine (25 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography gave 920 mg (80%) of 4-isothiocyanato-N-(TBDMS)-benzenesulfonamide as a white solid. 1H NMR (300 MHz, CDCl3) δ7.86 (d, 2H, J=6.9 Hz), 7.31 (d, 2 H, J=6.9 Hz), 4.40 (s, 1H), 0.90 (s, 9H), 0.22 (s, 6H). Anal. (C13H20N2O2S2Si) C, H, N, S. Calculated C=47.53; H=6.14; N=8.53; S=19.52; found C=47.47; H=6.25; N=8.46; S=19.49.
Reaction SMILES: F[CH:2](F)[C:3]1[CH:7]=[C:6]([O:8][C:9]2[N:10]=[N:11][CH:12]=[C:13]([O:15][CH3:16])[CH:14]=2)[N:5]([CH3:17])[N:4]=1.ClCCl.[Cl-].[Al+3].[Cl-].[Cl-].[OH2:26]>>[CH3:16][O:15][C:13]1[CH:14]=[C:9]([O:8][C:6]2[N:5]([CH3:17])[N:4]=[C:3]([CH:2]=[O:26])[CH:7]=2)[N:10]=[N:11][CH:12]=1
Reactant: COc1cnnc(Oc2cc(C(F)F)nn2C)c1
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cnnc(Oc2cc(C=O)nn2C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 12 %

Procedure:
3-[[3-(Difluoromethyl)-1-methyl-1H-pyrazol-5-yl]oxy]-5-methoxypyridazine (Compound No. 45, 4.5 g, 0.017 mole) and dichloromethane (80 mL) were stirred and cooled with a water bath while aluminum chloride (4.3 g, 0.031 mole, (note: this aluminum chloride was old and wet) was added and the mixture was then stirred at room temperature for 5 hours. The mixture was poured into cold water and the aqueous phase washed three times with dichloromethane. The pH of the aqueous phase was adjusted to 4, using 10% sodium hydroxide; and the product was extracted with ethyl acetate. The extracts were dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel to give 5-[(5-methoxy-3-pyridazinyl)oxy]-1-methyl-1H-pyrazole-3-carboxaldehyde (0.50 g, 12% yield) as white solid.
Reaction SMILES: C[O-].[Na+].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])=[CH:7][C:6]=1[O:16][CH3:17].[CH2:18](Br)[C:19]#[CH:20]>CO>[CH3:17][O:16][C:6]1[CH:7]=[C:8]([CH2:11][CH2:12][NH:13][CH:14]=[O:15])[CH:9]=[CH:10][C:5]=1[O:4][CH2:20][C:19]#[CH:18]
Reactant: C#CCBr
Reactant: COc1cc(CCNC=O)ccc1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C#CCOc1ccc(CCNC=O)cc1OC

Procedure:
Sodium methoxide (32 ml of a 5.4 M solution in methanol, 0.17 mol) is added to a solution of N-[2-(4-hydroxy-3-methoxy-phenyl)-ethyl]-formamide (32 g, 0.16 mol) in methanol (400 ml). Propargyl bromide (20 g, 0.17 mol) is added and the mixture is refluxed for 4 hours. After evaporation the residue is taken up in ethyl acetate (400 ml) and washed with water (2×200 ml). The organic layer is dried over magnesium sulfate and evaporated. The residue is submitted to flash-chromatography to give the N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-formamide. 1H-NMR (300 MHz, CDCl3, δ(ppm)): 2.44 (t, 1H, C≡CH), 2.73 (t, 2H, CH2CH2), 3.51 (t, 2H, CH2CH2), 3.82 (s, 3H, OCH3), 4.69 (m, 2H, OCH2), 5.53(bs, 1H, NH), 6.62–6.95 (m, 3H, CH arom.), 8.09 (s, 1H, CHO).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[O:12][CH3:13])[N:8]([CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=O)[C:5]2=[O:18].C1C=CC(OP(Cl)(OC2C=CC=CC=2)=O)=CC=1.C(N(CC)CC)C.[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=1>C(Cl)Cl>[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH2:48][NH:49][C:15]([C:6]2[C:5](=[O:18])[C:4]3[C:9](=[N:10][C:11]([O:12][CH3:13])=[C:2]([I:1])[CH:3]=3)[N:8]([CH3:14])[CH:7]=2)=[O:17])=[CH:46][CH:45]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: COc1nc2c(cc1I)c(=O)c(C(=O)O)cn2C
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1nc2c(cc1I)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 2 h
Yield: 29 %

Procedure:
6-Iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid (1.50 g) is dissolved in CH2Cl2 (0.5 L). To this is added diphenyl chloridophosphate (1.5 mL) and triethyl amine (1.7 mL). The resulting mixture is stirred at room temperature for 2 h, followed by the addition of 4-chlorobenzyl amine (1.2 mL). The reaction is stirred for additional 3 h, then washed with 1N HCl, 1N NaOH, brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc 4/1, 1/1, CH2Cl2/MeOH 19/1) and the product is then triturated with MeOH to afford 592 mg (29%) of N-(4-chlorobenzyl)-6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide. Physical characteristics are as follows: 1H NMR (CDCl3) δ10.20, 9.01, 8.81, 7.32-7.27, 4.62, 4.13, 3.96; 13C NMR (CDCl3) δ175.24, 164.41, 162.95, 159.66, 148.69, 147.78, 147.69, 137.26, 132.85, 128.93, 128.69, 118.76, 113.68, 55.77, 42.58, 39.12; IR (diffuse reflectance) 2296, 1908, 1665, 1613, 1593, 1570, 1544, 1507, 1491, 1460, 1447, 1386, 1286, 1278, 809, cm−1; MS (FAB) m/z 484 (MH+), 486, 485, 484, 344, 343, 217, 133, 127, 125, 55; Anal. calcd for C18H15ClIN3O3: C, 44.70; H, 3.13; N, 8.69. Found: C, 44.38; H, 3.17; N, 8.62.
Reaction SMILES: Cl/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([SH:28])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([S:28]/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3]/[C:4]([O:6][CH3:7])=[O:5])[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: COC(=O)/C=C(/Cl)CCCCc1ccccc1
Reactant: COc1ccc(S)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COC(=O)/C=C(\CCCCc1ccccc1)Sc1ccc(OC)c(OC)c1
Yield: 30.4 %

Procedure:
A mixture of methyl (E)-3-chloro-7-phenyl-2-heptenoate (1.3 g, 5.1 mmol), 3,4-dimethoxythiophenol (0.86 g, 5.1 mmol) and potassium carbonate (0.7 g, 5.1 mmol) in methanol (50 mL) is heated under reflux for 3 hours. The mixture is filtered and the filtrate is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed (4:1 hexane:ethyl acetate) to obtain methyl (E)-3-[(3,4-dimethoxyphenyl)thio]-7-phenyl-2-heptenoate (0.6 g, 31% ). A small amount is recrystallized from hexane to give m.p. 53-5° C. Anal.(C22H26O4S) C, H: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.68-1.82 (m, 4H), 2.60-2.70 (m, 2H) 2.80-2.92 (m, 2H), 3.57 (s, 3H), 3.86 (s,3H), 3.90 (s, 3H), 5.12 (s, 1H), 6.82-6.92 (m, 2H), 6.98-7.08 (m, 1H), 7.13-7.31 (m, 5H); MS (EI) m/e 386 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:25])[C:12]([C:16](=O)[C:17]2[CH:22]=[CH:21]C(Cl)=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5].C[S-:27].[Na+].[C:29](O)(=O)[CH3:30]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH2:9][C:10]1[N:11]([CH3:25])[C:12]([C:16](=[S:27])[C:17]2[CH:22]=[CH:21][C:29]([CH3:30])=[CH:19][CH:18]=2)=[C:13]([CH3:15])[CH:14]=1)[NH2:5]
Reactant: CC(=O)O
Reactant: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccc(Cl)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)c2c(C)cc(Cc3ccc(N)cc3F)n2C)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 55 %

Procedure:
3-Fluoro-4-[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (2.0 g, 5.6 mmol) was dissolved in degassed DMF. Sodium thiomethoxide (1.5 g, 22.4 mmol) was added and the mixture stirred at room temperature under argon for 24 h. The reaction was poured into ice-water, acidified with acetic acid to pH 3 and extracted with ethyl acetate. The organic extracts were washed with water, and brine, and dried over magnesium sulfate. The solvent was removed in vacuo and the crude product was purified on a silica gel column (methylene chloride-methanol-acetone, 96:2:2) to give 3-fluoro-4-[5-(4-methylthiobenzoyl)-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (1.13 g, 55%) as a solid, mp 199.1-199.7° C.