Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23]([O:25]CC)=O)=[N:21][N:22]=2)[N:19]=1.[CH2:31]1COCC1.C[Mg]Cl>O.C(Cl)Cl.[Cl-].[NH4+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[CH2:30][CH2:29][CH2:28][N:12]2[C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([C:23](=[O:25])[CH3:31])=[N:21][N:22]=2)[N:19]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4n3CCC4)nn12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
A 100 mL round bottom flask was charged with ethyl 6-(2-(2,4-difluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-a]imidazol-3-yl)-[1,2,4]triazolo[4,3-b]pyridazine-3-carboxylate (3.04 g, 7.41 mmol). THF (37.0 mL) was added and the mixture was stirred at ambient temperature for about 15 min. The slurry was cooled to about −40° C. and a solution of methylmagnesium chloride (3 M in THF, 9.88 mL, 29.6 mmol) was added slowly while keeping the internal temperature between about −30° C. and −40° C. After about 15 min the mixture was cooled to about −55° C. followed by the slow addition of saturated ammonium chloride solution (about 10 mL). The mixture was then warmed to ambient temperature and diluted with water (50 mL), DCM (75 mL), and saturated aqueous ammonium chloride solution (50 mL). The layers were separated and the aqueous solution was extracted with DCM (2×100 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (2.74 g, 97%): LC/MS (Table 1, Method h) Rt=1.22 min; MS m/z: 381.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C:3]#[C:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([F:14])=[CH:7][C:6]=1[NH:15]C(=O)CCC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>CN(C=O)C>[C:2]([C:3]1[NH:15][C:6]2[C:5]([CH:4]=1)=[CH:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([F:14])[CH:7]=2)([CH3:22])([CH3:21])[CH3:1]
Reactant: CCCC(=O)Nc1cc(F)c([N+](=O)[O-])cc1C#CC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc([N+](=O)[O-])c(F)cc2[nH]1
Yield: 64.8 %

Procedure:
A solution of N-(2-(3,3-dimethylbut-1-ynyl)-5-fluoro-4-nitrophenyl)butyramide (3.0 g, 9.8 mmol) and TBAF (4.5 g, 17.2 mmol) in DMF (25 mL) was heated at 100° C. overnight. The mixture was poured into water and then extracted with EtOAc (80 mL×3). The combined extracts were washed with water (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated under reduced pressure to dryness. The residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give compound 2-tert-butyl-6-fluoro-5-nitro-1H-indole (1.5 g, 65%). 1H-NMR (400 MHz, CDCl3) δ 8.30 (d, J=7.2 Hz, 1H), 7.12 (d, J=11.6 Hz, 1H), 6.35 (d, J=1.2 Hz, 1H), 1.40 (s, 9H).
Reaction SMILES: [C:1]([C:3](=[CH:8][CH:9]([CH3:11])[CH3:10])[CH2:4][C:5]([O-:7])=[O:6])#[N:2].C([NH3+])(C)(C)C.[OH-].[K+].C(O)(=O)C>O>[CH3:11][CH:9]([CH2:8][C@H:3]([CH2:1][NH2:2])[CH2:4][C:5]([OH:7])=[O:6])[CH3:10]
Reactant: CC(C)C=C(C#N)CC(=O)[O-]
Agent: CC(C)(C)[NH3+]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 65 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
An argon-purged 600 mL pressure reactor is charged tert-butyl ammonium 3-cyano-5-methylhex-3-enoate (prepared as described in Example 1A 36 g, 159.1 mmol) and [(R,R)MeDUPHOS]Rh(COD)BF4 (0.054 g, 0.0894 mmol). The reactor is pressure purged with argon (3×50 psi). To a 1000 mL reactor is charged 360 mL of methanol. The methanol is pressure purged with argon (3×50 psi). The methanol is then charged to the reactor containing the substrate and catalyst. The solution is pressure purged with argon (3×50 psi), and then the reactor is pressurized to 50 psi with hydrogen and stirred overnight at 27° C. to 33° C. The hydrogen pressure is released, and the solution purged with argon. The solution is transferred into a vessel containing a solution of potassium hydroxide (91%, 10.3 g, 167 mmol) in 90 mL of water. The solution is concentrated to about 180 mL in vacuo. The concentrated solution is transferred to a 600 mL pressure reactor containing sponge nickel A-7000 (12.0 g, 50% water wet). The solution is purged with argon (3×50 psi), and then the reactor is pressured to 50 psi with hydrogen and stirred overnight. The hydrogen pressure is released. The solution is purged with argon and filtered. The filter cake is washed with 90 mL of methanol. The filtrate is concentrated in vacuo to remove the methanol, and 72 mL of isopropyl alcohol is charged. The solution is heated to 65° C. Glacial acetic acid (9.4 mL, 171 mmol) is charged, and the solution is heated to 73° C. The solution is quickly cooled to 50° C., then slowly cooled to room temperature. The slurry is cooled to 0° C. to 5° C. for 3.5 hours. The slurry is filtered, and the cake is washed with isopropyl alcohol. The solid is dried under vacuum at 45° C. to give 18.4 g (73%) of pregabalin as a white solid (99.89% S).
Reaction SMILES: [C@H:1]12[CH2:26][C@H:4]([N:5]([CH2:7][C:8]3[N:12]([C:13]4[CH:14]=[C:15]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=4)[C:16]([NH2:18])=O)[N:11]=[N:10][N:9]=3)[CH2:6]1)[CH2:3][O:2]2.C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C@H:1]12[CH2:26][C@H:4]([N:5]([CH2:7][C:8]3[N:12]([C:13]4[CH:14]=[C:15]([CH:19]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:21]=4)[C:16]#[N:18])[N:11]=[N:10][N:9]=3)[CH2:6]1)[CH2:3][O:2]2
Reactant: NC(=O)c1cc(-n2nnnc2CN2C[C@@H]3C[C@H]2CO3)cc(C(F)(F)F)c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(-n2nnnc2CN2C[C@@H]3C[C@H]2CO3)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 37.8 %

Procedure:
To a solution of 3-{5-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]hept-5-ylmethyl]-1H-tetrazol-1-yl}-5-(trifluoromethyl)benzamide (Intermediate 32, 100 mg, 0.272 mmol) and triethylamine (0.076 ml, 0.543 mmol) in dichloromethane (5 ml) was added trifluoroacetic anhydride (0.038 ml, 0.272 mmol). The reaction was stirred at room temperature for 4 hours before the addition of trifluoroacetic anhydride (0.038 ml, 0.272 mmol). The reaction was stirred at room temperature for a further three hours. The reaction was partitioned between DCM (5 mL) and water (5 mL). The organic layer was collected via a hydrophobic frit and the solvent removed. The residue was purified by silica chromatography (Biotage SP4, eluting a gradient from 20-80% EtOAc in iso-hexane). The compound was further purified by high pH MDAP to yield the title compound as a white solid (36 mg)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12]1([CH2:18][CH2:19][CH2:20][C:21](OC)=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC[O-].[Na+].CC(O)=O.O>C(O)C>[Cl:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[C:21]([CH2:20][CH2:19][CH2:18][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:6]=[C:4]2[OH:5]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: COC(=O)CCCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Oc1nc(CCCc2ccccc2)nc2ccc(Cl)cc12
Temperature: 25 °C
Yield: 22.8 %

Procedure:
Preparation D8, Step 1: 2-Amino-5-chlorobenzamide (Avocado) (0.50 g, 2.93 mmol, 1 eq.), methyl 4-phenylbutyrate (3.14 g, 17.6 mmol, 6 eq.), NaOEt in ethanol (3.09 M, 5.69 mL, 17.6 mmol, 6 eq.) and ethanol (20 mL) were refluxed overnight. Cooled to 25° C. Added 10 mL of 10% HOAc/H2O. Solids formed which were filtered, the solids rinsed with 5 mL H2O, then dissolved in 20 mL of EtOAc/THF. Dried and stripped in vacuo followed by purification over silica gel in 3:1 to 1:1 Hexanes/EtOAc to give 6-chloro-2-(3-phenyl-propyl)-quinazolin-4-ol as a tan solid (200 mg). MS found: (M+H)+=299.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13]1[S:17][C:16]([N:18]2[CH2:22][C@H:21]3[CH2:23][N:24](C(OC(C)(C)C)=O)[CH2:25][C@H:20]3[CH2:19]2)=[N:15][N:14]=1.Cl>O1CCOCC1>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13]1[S:17][C:16]([N:18]2[CH2:19][C@@H:20]3[C@@H:21]([CH2:23][NH:24][CH2:25]3)[CH2:22]2)=[N:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3nnc(-c4ccc(-c5cn[nH]c5)cc4Cl)s3)C[C@@H]2C1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1cc(-c2cn[nH]c2)ccc1-c1nnc(N2C[C@H]3CNC[C@H]3C2)s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (3aR,6aS)-tert-butyl 5-(5-(2-chloro-4-(1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazol-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (10 mg, 0.021 mmol) in 1,4-dioxane (2 mL) was treated with 4M HCl in dioxane (1 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give the title compound (2 mg, MS: 373.1 [M+H+], LCMS Rt=0.44 min (LCMS method D); 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.99 (br. s., 2H), 7.92 (d, J=8.59 Hz, 1H), 7.71 (d, J=2.02 Hz, 1H), 7.53-7.60 (m, 1H), 3.68 (dd, J=10.86, 7.83 Hz, 2H), 3.36 (dd, J=10.86, 3.28 Hz, 2H), 3.03-3.11 (m, 2H), 2.97-3.03 (m, 2H), 2.75 (dd, J=11.12, 3.03 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[C:12]([F:14])[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]=1[O:18][CH3:19].C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:14][C:12]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:10][C:9]([O:18][CH3:19])=[C:8]([N:4]2[CH:5]=[N:6][C:2]([CH3:1])=[N:3]2)[CH:13]=1
Reactant: Cc1nc[nH]n1
Reactant: COc1cc([N+](=O)[O-])c(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc([N+](=O)[O-])c(F)cc1-n1cnc(C)n1
Temperature: 80 °C
Yield: 18.6 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (2.20 g, 26.4 mmol), 1,5-difluoro-2-methoxy-4-nitrobenzene (5.00 g, 26.4 mmol), and potassium carbonate (3.65 g, 26.4 mmol) in anhydrous DMSO (50 mL) was heated at 80° C. for 24 h. The reaction mixture was allowed to cool to rt and was poured into 500 mL of water/10 mL brine solution. The aqueous mixture was extracted with EtOAc (2×250 mL). The combined organic extracts were washed with water (500 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 1-(5-fluoro-2-methoxy-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (1.24 g, 18% yield). LC-MS (M+H)+=253.2. 1H NMR (500 MHz, CDCl3) δ ppm 8.95 (s, 1H) 8.00 (d, J=11.60 Hz, 1H) 7.80 (d, J=6.10 Hz, 1H) 4.09 (s, 3H) 2.50 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].S([O:20][CH2:21][C:22]1([CH:28]=O)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(C)(=O)=O.C(N(CC)CC)C.Cl>COCCOCCOC>[C:4]([C:3]1[CH:12]=[CH:13][CH:14]=[CH:15][C:2]=1[S:1][CH2:28][C:22]1([CH:21]=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CS(=O)(=O)OCC1(C=O)CCCCC1
Reactant: O=C(c1ccccc1)c1ccccc1S
Agent: Cl
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: O=CC1(CSc2ccccc2C(=O)c2ccccc2)CCCCC1
Yield: 18.1 %

Procedure:
A mixture of 69 g (0.303 mole) of 2-mercaptobenzophenone, 82 g (0.303 mole) of mesylate 55, 32 g of triethylamine, and 150 ml of diglyme was stirred and held at reflux for 24 h. The mixture was cooled, poured into dil. HCl and extracted with methylene chloride. The organic layer was washed with 10% NaOH, water, brine, and dried over sodium sulfate and concentrated under vacuum to remove excess diglyme. This was purified by silica gel flush column (5% EtOAc:Hexane) and gave 18.6 g (75.9%) of yellow oil. Proton NMR and mass spectra were consistent with the product.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][C:5]([S:20](=[O:34])(=[O:33])[NH:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N+:41]([O-])=O)[CH:36]=1.[Cl-].[NH4+]>CO.[Fe]>[NH2:41][C:37]1[CH:36]=[C:35]([C:3]2[CH:4]=[C:5]([S:20](=[O:34])(=[O:33])[NH:21][C:22](=[O:32])[CH2:23][CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:6]=[C:7]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][C:15]([C:17]([NH2:19])=[NH:18])=[CH:16][C:10]=4[N:9]=3)[C:2]=2[OH:1])[CH:40]=[CH:39][CH:38]=1
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCCc4ccccc4)cc(-c4cccc([N+](=O)[O-])c4)c3O)nc2c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: N=C(N)c1ccc2[nH]c(-c3cc(S(=O)(=O)NC(=O)CCCc4ccccc4)cc(-c4cccc(N)c4)c3O)nc2c1
Yield: 29.9 %

Procedure:
2-[2-Hydroxy-3′-nitro-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.063 g, 0.1 mmol), prepared as in Example 10 was dissolved in methanol (3 mL) and saturated aqueous ammonium chloride (1 mL) was added to the solution. The mixture was heated with iron powder (1 g) for 5-10 minutes, filtered through celite and concentrated under reduced pressure. Product was purified from the residue by reverse phase HPLC (acetonitrile gradient) to give 2-[3′-amino-2-hydroxy-5-(4-phenyl-butyrylsulfamoyl)-biphenyl-3-yl]-1H-benzoimidazole-5-carboxamidine (0.017 g). MS: found (M+H+) 569.3, (M−H+) 567.4, calc. 568.19.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH2:20][N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([CH2:18][OH:19])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:6]([N:13]1[CH2:17][CH2:16][C:15]([CH2:20][N:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)([CH2:18][O:19][S:1]([CH3:4])(=[O:3])=[O:2])[CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCC1(CN(Cc2ccccc2)Cc2ccccc2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
Mesyl chloride (2.7 ml) was added to a solution of 1-benzyl-3-(dibenzylaminomethyl)-3-hydroxymethylpyrrolidine (7.88 g) and triethylamine (5.5 ml) in chloroform (80 ml) under ice-cooling, and the mixture was stirred for 30 minutes under ice-cooling. The reaction mixture was sequentially washed with an aqueous solution of sodium hydrogencarbonate and water, dried, concentrated and purified by silica gel column chromatography to give 6.97 g of the object compound as an oil.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]([O:11][CH3:12])=[O:10].[CH3:13][C:14]([NH:16][CH:17]1[C:27]2[CH:28]=[C:29]([OH:32])[CH:30]=[CH:31][C:26]=2[C:25]2[C:20](=[CH:21][C:22]([O:37][CH3:38])=[C:23]([O:35][CH3:36])[C:24]=2[O:33][CH3:34])[CH2:19][CH2:18]1)=[O:15]>C1COCC1>[C:9](=[O:10])([O:11][CH3:12])[O:32][C:29]1[CH:30]=[CH:31][C:26]2[C:25]3[C:24]([O:33][CH3:34])=[C:23]([O:35][CH3:36])[C:22]([O:37][CH3:38])=[CH:21][C:20]=3[CH2:19][CH2:18][C@H:17]([NH:16][C:14](=[O:15])[CH3:13])[C:27]=2[CH:28]=1
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: COC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Oc1ccc2c(c1)[C@@H](NC(C)=O)CCc1cc(OC)c(OC)c(OC)c1-2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
Triethylamine (70 μl; 0.5 mmol) and methyl chloroformate (39 μl; 0.5 mmol) were added to a solution of N-acetyl-colchicinol (0.178 g; 0.5 mmol) in THF (3 ml). The mixture was stirred at ambient temperature for 90 minutes. After removal of the insoluble material by filtration the residue was purified by flash chromatography eluting with dichloromethane/ethanol (98/2) to give (5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl methyl carbonate.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Br:12])=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([C@@H:16]1[C@H:21]2[CH2:22][C@H:18]([CH2:19][CH2:20]2)[N:17]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=O.CC(O)=O.[OH-].[Na+]>C(OCC)(=O)C>[Br:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]1[NH:1][C:14]([C@@H:16]3[C@H:21]4[CH2:22][C@H:18]([CH2:19][CH2:20]4)[N:17]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[N:13][C:3]=1[CH:4]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1C(=O)Nc1ccc2cc(Br)ccc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1
Temperature: 50 °C
Reaction time: 14 h
Yield: 93.3 %

Procedure:
(1S,3S,4R)-tert-butyl 3-(1-amino-6-bromonaphthalen-2-ylcarbamoyl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (2.01 g, 4.36 mmol) was suspended in AcOH (8.73 mL, 152.7 mmol) and placed in a preheated 50° C. oil bath. The suspension was let stir at 50° C. for 4 hours and at room temperature for 14 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and aqueous NaOH (6M, 25.4 mL, 152.7 mmol) was added slowly with stirring. The layers were separated and the aqueous layer was back extracted with ethyl acetate twice. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The resulting oil was purified by normal phase chromatography (30-55-100% ethyl acetate (5% MeOH) in hexanes) to give (1S,3S,4R)-tert-butyl 3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.8 g, 93%). LCMS-ESI+: calc'd for C22H24BrN3O2: 441.11 (M+); Found: 442.7 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].CN(C)[CH:34]=[O:35]>>[CH2:1]([O:8][C:9]1[C:13]([CH:34]=[O:35])=[C:12]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[N:11]([CH:22]([CH3:24])[CH3:23])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cc(OCc3ccccc3)nn2C(C)C)cc1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2c(C=O)c(OCc3ccccc3)nn2C(C)C)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 3-benzyloxy-1-isopropyl-5-(4-methoxyphenyl)-1H-pyrazole (0.40 g) in N,N-dimethylformamide (1.5 mL) was added phosphorus oxychloride (0.23 g) at 80° C. and the mixture was stirred at 80° C. for 1 hour. After cooling to room temperature, a sodium hydroxide aqueous solution (1 mol/L, 5 mL) was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the title compound (0.42 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:12][C:13](=O)[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].BrBr.C(O)C.[NH:21]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[S:28])=[N:22]1>O1CCOCC1.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[S:28][C:27]([NH:26][C:23]3[CH:24]=[CH:25][NH:21][N:22]=3)=[N:29][C:13]=2[CH3:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CC(=O)Cc1ccc(S(C)(=O)=O)c(F)c1
Reactant: NC(=S)Nc1cc[nH]n1
Agent: BrBr
Solvent: CCO
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cc1nc(Nc2cc[nH]n2)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Temperature: 10 °C
Reaction time: 0.25 h

Procedure:
1-(3-Fluoro-4-methanesulfonyl-phenyl)-propan-2-one (68c) (6.0 g, 26 mmol) is dissolved in dioxan (50 ml) and the solution is cooled to 10° C. at which point the mixture is semi frozen. A solution of bromine (0.9 ml, 17 mmol) in chloroform (2 ml) is added slowly over 30 minutes and the mixture is stirred for an additional 15 minutes in a semi frozen state. The mixture is then allowed to warm to room temperature and the solvent is removed to give a red oil. Ethanol (70 ml) and (1H-pyrazol-3-yl)-thiourea (35a) (3.2 g, 22 mmol) are added and the reaction is stirred at 60° C. for 30 minutes. The solution is allowed to cool to room temperature whereupon the product crystallises. Filtration affords the titled compound.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1)#[CH:2].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>C(Cl)Cl>[CH3:21][S:18]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([C:1]#[CH:2])=[CH:4][CH:5]=1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: C#Cc1ccc(CO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#Cc1ccc(COS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 4-ethynylbenzyl alcohol (5.0 g, 37.8 mmol) in CH2Cl2 (50 mL) and triethylamine (Et3N) (14.4 mL, 104.0 mmol) was added mesyl chloride (8.04 mL, 104.0 mmol) at 0° C. and the reaction was allowed to warm to room temperature. Stirring continued for 2 h under argon during which TLC revealed a quantitative conversion into a higher Rf product. Ice cold water was added into the reaction mixture and extracted with Et2O (200 ml). The organic layer was washed with 1N HCL (70 ml), H2O (100 ml), aqueous NaHCO3 (70 ml), and finally H2O (100 ml); and then dried over Na2SO4. Solvent was evaporated off and dried in vacuo to give 7.0 g of compound 3 as brownish oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:24]=C(Cl)C=C[C:3]=1[CH2:4][NH:5][C:6]([C:8]1[C:9](=[O:20])[NH:10][N:11]=[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:13]=1)=[O:7].O=C1C(C(O)=O)=CC(C2C=CN=CC=2)=NN1.C(Cl)(=O)C(Cl)=O.C(N)CCC>C(N(CC)CC)C.CN(C)C=O.ClCCl>[O:20]=[C:9]1[C:8]([C:6]([NH:5][CH2:4][CH2:3][CH2:2][CH3:24])=[O:7])=[CH:13][C:12]([C:14]2[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=2)=[N:11][NH:10]1
Reactant: O=C(NCc1ccc(Cl)cc1Cl)c1cc(-c2ccncc2)n[nH]c1=O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc(-c2ccncc2)n[nH]c1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCCN
Product: CCCCNC(=O)c1cc(-c2ccncc2)n[nH]c1=O

Procedure:
Working as in example 2 for the preparation of N-(2,4-dichlorobenzyl)-3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxamide, but starting with 0.3 g of 3-oxo-6-pyridin-4-yl-2,3-dihydropyridazine-4-carboxylic acid, 10 cm3 of dichloromethane, 0.02 cm3 of dimethylformamide, 0.12 cm3 of oxalyl chloride, 0.15 cm3 of n-butylamine and 0.19 cm3 of triethylamine, and after purification by chromatography on silica gel (particle size 40-63 μm, under an argon pressure of 150 kPa), eluting with a mixture of dichloromethane and methanol (97.5/2.5 by volume), 0.23 g of 3-oxo-6-pyridin-4-yl-N-(n-butyl)-2,3-dihydropyridazine-4-carboxamide was obtained in the form of a white solid melting at 209° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([CH:15]([OH:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(C)=O.O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10]([O:24][CH3:25])=[CH:11][C:12]([C:18]2[N:22]=[C:21]([CH3:23])[O:20][N:19]=2)=[C:13]([C:15](=[O:17])[CH3:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2noc(C)n2)c(C(C)O)cc1OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1cc(-c2noc(C)n2)c(C(C)=O)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.6 %

Procedure:
To a mixture of 1-[5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]ethanol (reference example 6-2) (467 mg), triethylamine (0.956 mL) and dimethyl sulfoxide (6 mL) was added a mixture of pyridine sulfur trioxide complex (655 mg) and dimethyl sulfoxide (2 mL). After stirring at room temperature for 2 hours, water and ethyl acetate were added to the mixture. The separated organic layer was washed with 2 mol/L hydrochloric acid and brine successively, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 25%-34% ethyl acetate/hexane, gradient elution) to give the title compound (365 mg).