Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>ClCCl>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:35]([CH3:34])(=[O:37])=[O:36])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) in dichloromethane (1.5 ml) was added at room temperature triethylamine (113 mg, 156 μl, 1.12 mmol) and methanesulfonyl chloride (42.8 mg, 29 μl, 374 μmol). The mixture was allowed to stir at room temperature for 18 h, and was afterwards evaporated. The crude material was further purified by flash chromatography on silica gel (dichloromethane/MeOH/NH4OH 150:10:1) and trituration with dichloromethane (1 ml) and heptane (5 mL) for 30 min to yield the title compound as an off-white solid (96 mg, 95%), MS (ISP) m/z=407.4 [(M+H)+], mp 152° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10](Cl)=[O:11].[CH3:18][C:19]1[NH:20][CH:21]=[C:22]([CH3:24])[CH:23]=1>ClCCl.C(OCC)(=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:10]([C:21]2[NH:20][C:19]([CH3:18])=[CH:23][C:22]=2[CH3:24])=[O:11])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: Cc1c[nH]c(C)c1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2[nH]c(C)cc2C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
Aluminum chloride (1.7 g, 12.75 mmol) in dichloromethane (100 mL) was added to the 3,4-dimethoxybenzoyl chloride (2.0 g, 10 mmol) at room temperature, followed by a solution of 2,4-dimethylpyrrole (1.5 g, 15.8 mmol) in dichloromethane (5 mL). The mixture was then stirred at room temperature for overnight. The reaction was diluted with ethyl acetate, washed with brine, dried and concentrated. The residue was chromatographed eluting with ethyl acetate and hexane to give 1 g (39%) of (3,4-dimethoxy-phenyl)-(3,5-dimethyl-1H-pyrrol-2-yl)-methanone as a solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]1[O:17][CH2:18][O:19][C:11]=1[CH:10]=2)=[O:5])C.[OH-].[K+]>C(O)C>[OH:16][C:15]1[C:14]2[C:9](=[CH:10][C:11]3[O:19][CH2:18][O:17][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1cnc2cc3c(cc2c1O)OCO3
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc2cc3c(cc2c1O)OCO3
Reaction time: 20 h

Procedure:
4-Hydroxy-6,7-methylenedioxy-3-quinolinecarboxylic acid ethyl ester (45.0 g, 0.172 mol) was added to a solution of KOH (16.8 g, 0.258 mol) in ethanol (500 mL) and the mixture was heated to reflux with stirring for 20 hours. The reaction flask was then cooled and ethanol was evaporated under reduced pressure. Then 800 mL of water were added with stirring to fully dissolve the potassium salt, and the solution was filtered to remove any impurities. Concentrated HCl was added to bring the mixture to pH 1, and the free acid was filtered off and dried under vacuum, to give 33.9 g as a beige solid, in 84%; mp>300° C. (lit.221 mp>290° C.); 1H NMR (DMSO-d6) δ 6.27 (s, 2H), 7.30 (s, 1H), 7.55 (s, 1H), 8.72 (s, 1H); 13C NMR (DMSO-d6) δ 98.5, 101.8, 103.8, 107.9, 120.8, 137.9, 143.5, 148.1, 153.7, 167.4, 177.4.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17])([O-:3])=[O:2].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:31](O)[CH3:32]>>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:13][CH2:14][C:15]([F:19])([F:20])[C:16]([O:18][CH2:31][CH3:32])=[O:17])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)C(F)(F)CNc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
To a solution of 3-[(2,6-dinitrophenyl)amino]-2,2-difluoropropanoic acid (3.52 g, 12.09 mmol) in ethanol (30.0 mL) was added sulfuric acid (4 mL) at 0° C. The reaction mixture was stirred at 100° C. for 1 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and the solvent was removed. The residue was extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-20% ethyl acetate/n-hexane gradient mixture to give the title compound as a yellow oil (2.94 g, 9.210 mmol, 76%).
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=1[CH2:6]2.[Cl-].[NH+]1C=CC=CC=1>>[OH:2][C:3]1[C:4]([CH3:20])=[C:5]2[C:16](=[CH:17][C:18]=1[CH3:19])[C:8]1[NH:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=3[C:7]=1[CH2:6]2
Reactant: COc1c(C)cc2c(c1C)Cc1c-2[nH]c2ccccc12
Agent: [Cl-]
Agent: c1cc[nH+]cc1
Product: Cc1cc2c(c(C)c1O)Cc1c-2[nH]c2ccccc12
Temperature: 200 °C

Procedure:
5,10-Dihydro-2-methoxy-1,3-dimethylindeno[1,2-b]indole (2.4 g, 9.1 mmol) and pyridinium chloride (5.8 g) were mixed and heated to 200° C. for 30 minutes. The reaction mixture was cooled, and partitioned between ethyl acetate and water. The organic phase was washed three times with 2 M hydrochloric acid, and then three times with water, and then dried (MgSO4). The solvent was removed in vacuo, and the residue purified by column chromatography to give the title compound as colourless prisms. Yield: 1.5 g (66%). M.p. 190° C. (from dichloromethane). 1H NMR (DMSO-d6) δ: 2.25 (3H,s,), 2.26 (3H,s,), 3,50 (2H, s,), 6.9-7.5 (5H, m,), 8.16 (1H, br,), 11.33 (1H, br,).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:15](=[O:24])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH2:7][C@@H:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]([NH:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-(Benzylcarbamoyl-phenyl-methyl)carbamic acid tert-butyl ester (0.85 g, 2.50 mmol) was dissolved in HCl/dioxane (10 mL, 4.0M). The mixture was stirred at room temperature overnight. The volatiles were removed under reduced pressure to provide the desired product in quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]([SH:14])[NH:12][N:13]=2)[CH:6]=[CH:7][CH:8]=1.Cl[CH2:22][CH:23]=[O:24]>C1COCC1.O.C(OC(=O)C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:11]3[S:14][CH2:22][CH:23]([OH:24])[N:12]3[N:13]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2n[nH]c(S)c2-c2ccncc2)c1
Reactant: O=CCCl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cccc(-c2nn3c(c2-c2ccncc2)SCC3O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
5-(3-Methoxy-phenyl)-4-pyridin-4-yl-2H-pyrazole-3-thiol prepared as described in Example 8 (115 mg, 0.406 mmol) was dissolved in a 1:1 THF/water mixture (3 mL). A 55% aqueous solution of chloroacetaldehyde (0.071 mL, 0.609 mmol, 1.5 eq) was added and the mixture was stirred at room temperature for 2 hours. It was then diluted with ethylacetate and washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to dryness to give 123 mg (93%) of crude product, which was used without further purification in the following step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([N+:16]([O-])=O)[CH:15]=1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.Cl>[Fe].CO>[F:1][C:2]1[CH:15]=[C:14]([NH2:16])[CH:13]=[C:4]([O:5][CH:6]2[CH2:7][CH2:8][N:9]([CH3:12])[CH2:10][CH2:11]2)[CH:3]=1
Reactant: CN1CCC(Oc2cc(F)cc([N+](=O)[O-])c2)CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Product: CN1CCC(Oc2cc(N)cc(F)c2)CC1
Temperature: 25 °C
Reaction time: 32 h
Yield: 55.6 %

Procedure:
Combine 4-(3-fluoro-5-nitro-phenoxy)-1-methyl-piperidine (preparation 16, 2.75 g, 10.82 mmol), iron dust (2.0 g, 35.69 mmol), methanol (150 mL) and 1M aqueous hydrochloric acid solution (3.25 mL, 3.25 mmol), stir and heat at reflux. After 32 hr., cool to ambient temperature, filter through celite and concentrate to an oil. Partition between ethyl acetate (100 mL) and 1M aqueous sodium hydroxide solution (50 mL), separate the organic layer, dry over sodium sulfate, filter and concentrate. Purify residue by silica gel flash chromatography eluting with 10% (2M NH3/methanol)/methylene dichloride to give the title compound (1.35 g, 56%). 1H NMR (CDCl3): 6.0 (m, 3H), 4.2 (m, 1H), 3.7 (bs, 2H), 2.7 (m, 2H), 2.3 (m, 5H), 2.0 (m, 2H), 1.8 (m, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16]>CN(C)C(=O)C>[N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[N:3][CH:2]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Nc1ccncn1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1ccncn1)OCC(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of pyrimidine-4-amine (1.00 g, 10.5 mmol) and pyridine (2.55 ml, 31.5 mmol) in N,N-dimethylacetamide (50 ml) was added 2,2,2-trichloroethyl chloroformate (2.55 ml, 31.5 mmol) with ice-cooling, and the mixture was stirred for 1 hour with ice-cooling. The reaction mixture was poured into ice-water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate and the desired product (1.97 g, 69.4%) as a solid was collected by filtration.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[C:10]([C:9]1[CH:12]=[CH:13][C:6]([N:1]2[C:5]([B:22]([OH:27])[OH:23])=[CH:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)#[N:11]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: N#Cc1ccc(-n2cccn2)cc1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(-n2nccc2B(O)O)cc1
Reaction time: 1 h

Procedure:
4-(1H-Pyrazol-1-yl)benzonitrile (Eur. J. Org. Chem. 2004, 695-709) (1.5 g, 8.87 mmol) in dry THF (50 ml) under argon was stirred at −78° C. whilst lithium diisopropylamide (1.8M solution in THF/hexane/ethyl benzene; 5.2 ml, 9.32 mmol) was added dropwise during 20 min. Stirring and cooling were continued for 1 h, triisopropyl borate (8 ml, 34.5 mmol) was added dropwise during 30 min and then the temperature was allowed to rise overnight to RT. The pH of the reaction mixture was adjusted to 5 with 1M HCl and the mixture was then concentrated to a minimum volume and extracted with ethyl acetate (200 ml) and brine (3×100 ml). The organic phase was collected, dried (Na2SO4), filtered and evaporated to a brown solid (1.32 g) which was used in the next step without further purification.
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40]Cl>C(OCC)(=O)C>[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18]2)=[CH:28][CH:29]=1
Reactant: Oc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CCOc1ccc(CCN2CCC(N3CCc4ccccc43)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 42.6 %

Procedure:
N,N-Dimethylformamide (2.5 ml) was added to 1-[1-(4-hydroxyphenethyl)piperidin-4-yl]indoline (0.1 g), potassium carbonate (0.081 g) and 2-dimethylaminoethyl chloride hydrochloride (0.078 g) followed by stirring at 80° C. overnight (12 hr). After allowing to cool, the resultant mixture was mixed with ethyl acetate (200 ml) and the layers were separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system) to give the title compound (0.052 g) as a brown oil (yield: 27.0%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].C(N(C(C)C)CC)(C)C.[C:32](Cl)(=[O:34])[CH3:33]>ClCCl>[C:32]([O:1][CH2:2][CH:3]1[CH2:8][CH:7]([O:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])(=[O:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CCC(OC2CCCCO2)CC1CO
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC1CC(OC2CCCCO2)CCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 53 %

Procedure:
To a solution of the product of step F (1.0 g, 3.7 mmol) in dichloromethane (20 mL) at 0° C. was added diisopropylethylamine (1.0 mL, 5.7 mmol) followed by acetyl chloride (0.32 mL, 4.4 mmol). The solution was stirred for 10 min at 0° C. followed by 45 min at ambient temperature. The reaction mixture was washed with NaHCO3 solution (3×15 mL) then NaCl solution (2×10 mL) and dried over Na2SO4. The mixture was filtered and the filtrate concentrated in vacuo to afford the crude product which was purified by flash column chromatography (SiO2, 19:1 to 4:1, hexanes/ethyl acetate) to give tert-butyl 2-(acetoxymethyl)-4-((tetrahydro-2H-pyran-2-yl)oxy)piperidine-1-carboxylate (701 mg, 68%) as a colorless oil: 1H NMR (CDCl3, 300 MHz) δ 4.69-4.51 (m, 3H), 4.22-3.83 (m, 5H), 3.53-3.48 (m, 3H), 3.23-3.18 (m, 1H), 2.05-2.03 (m, 3H), 1.84-1.55 (m, 7H), 1.41 (s, 9H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]1([C:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)Cl)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.C(#N)C>[C:6]1([C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: C1CCNC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCCC2)cc1
Yield: 39.2 %

Procedure:
Pyrrolidine (0.26 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.), triphenylchloromethane (1.02 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.), and potassium carbonate (0.51 g, 3.66 mmol) (Wako Pure Chemical Industries, Ltd.) were added to acetonitrile (30 mL) (Wako Pure Chemical Industries, Ltd.), and the mixture was refluxed for 5 hours. A saturated aqueous solution of sodium hydrogen carbonate (Wako Pure Chemical Industries, Ltd.) was added to the reaction solution, and mixture was extracted with ethyl acetate (Wako Pure Chemical Industries, Ltd.). The organic layer was dried with anhydrous sodium sulfate (Wako Pure Chemical Industries, Ltd.), and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane (Wako Pure Chemical Industries, Ltd.):ethyl acetate (Wako Pure Chemical Industries, Ltd.)=9:1 as an eluent)), to thereby obtain the title compound (0.45 g, 80% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[S:11])[CH:3]=1.S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:8][C:6]1[N:5]2[S:11][C:10](=[N:12][S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:14])=[O:15])[N:9]=[C:4]2[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=S)Nc2cc(C)cc(C)n2)cc1
Solvent: ClC(Cl)Cl
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ccc(S(=O)(=O)N=c2nc3cc(C)cc(C)n3s2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.3 %

Procedure:
To a mixture of 1-(4,6-dimethyl-2-pyridyl)-3-(4-methylphenyl)sulfonyl-2-thiourea (2.90 g) and chloroform (50 ml), sulfuryl chloride (1.28 g) was added. After being stirred at room temperature for 15 minutes, the mixture was refiuxed with heating for 30 minutes. The reaction mixture was concentrated, and the resulting crystal was collected by filtration and suspended in water. After pH adjustment to 7 by the addition of saturated aqueous sodium bicarbonate, the suspension was stirred at room temperature for 1 hour. The separating crystal was collected by filtration and recrystallized from chloroform-methanol to yield 5, 7-dimethyl-2-(4-methylphenyl) sulfonylimino-2H-[1,2,4]thiadiazolo[2,3- a]pyridine (2.40 g, yield 83%) as a colorless needle.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7]Br)[C:3](Cl)=[O:4].[F:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:13].CCN(CC)CC.[H-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][CH:2]1[CH2:6][CH2:7][N:13]([C:12]2[CH:14]=[CH:15][C:16]([CH3:17])=[C:10]([F:9])[CH:11]=2)[C:3]1=[O:4]
Reactant: Cc1ccc(N)cc1F
Reactant: O=C(Cl)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(N2CCC(Br)C2=O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
To a solution of 2,4-dibromobutanoyl chloride (10 g, 38 mmol) in 100 mL of DCM at 0° C. under nitrogen was added 3-fluoro-4-methylaniline (5.21 g, 42 mmol) followed by Et3N (6.3 mL, 45 mmol). The mixture was stirred at rt for 2 h, then concentrated in vacuo. The residue was dissolved in diethyl ether, then hexanes was added and a solid precipitated. The solid was removed by filtration and discarded. The filtrate was then concentrated in vacuo to give a dry residue. To a solution of this residue in 100 mL DMF at 0° C. under nitrogen was slowly added 60% NaH (1.82 g, 45 mmol). The mixture was stirred and allowed to warm up to rt over 30 min. The reaction mixture was slowly poured into 400 mL of icewater and allowed to stand overnight. A solid formed, and was filtered off and dried, then purified via silica gel chromatography eluting with 0-50% ethyl acetate/hexanes to give racemic 3-bromo-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one (5.6 g, 20.6 mmol). LCMS (method U) RT 3.41 min, m/z 273.97 (M+H+). 1H NMR (500 MHz, chloroform-d) δ 7.50 (dd, J=11.7, 2.2 Hz, 1H), 7.31-7.27 (m, 1H), 7.23-7.17 (m, 1H), 4.60 (dd, J=7.0, 2.9 Hz, 1H), 4.03 (ddd, J=9.8, 7.9, 6.8 Hz, 1H), 3.82 (ddd, J=10.0, 7.7, 2.7 Hz, 1H), 2.75 (dq, J=14.6, 7.5 Hz, 1H), 2.48 (ddt, J=14.3, 6.7, 2.7 Hz, 1H), 2.28 (d, J=1.7 Hz, 3H).
Reaction SMILES: C[O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]([CH:18]([CH3:20])[CH3:19])[N:10]=2)=[CH:5][CH:4]=1.Cl>CO>[CH3:20][CH:18]([N:11]1[C:12]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9]([C:6]2[CH:5]=[CH:4][C:3]([OH:2])=[N:8][CH:7]=2)=[N:10]1)[CH3:19]
Reactant: COc1ccc(-c2nn(C(C)C)c3cccnc23)cn1
Agent: Cl
Solvent: CO
Product: CC(C)n1nc(-c2ccc(O)nc2)c2ncccc21
Yield: 80.2 %

Procedure:
A mixture of 3-(6-methoxypyridin-3-yl)-1-(1-methylethyl)-1H-pyrazolo[4,3-b]pyridine (100 mg), MeOH (10 mL) and concentrated HCl (3 mL) was stirred at reflux for 24 h and then evaporated. The residue was treated with saturated NaHCO3 aqueous solution and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was suspended in IPE and collected by filtration to give the title compound (76 mg).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]1([CH3:23])[CH:12]=[CH:11][C:10]([N:13]=[C:14]=[N:15][C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1>CN(C=O)C>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([NH:15][C:14]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:13][C:10]2[CH:9]=[CH:8][C:7]([CH3:23])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc(N=C=Nc2ccc(C)cc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(N=C(Nc2ccc(C)cc2)N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
1.2 mmol of piperazine was dissolved in 10 ml of DMF and 1.0 mmol of 1,3-di-p-tolylcarbodiimide was added. After 0.5 hour of stirring at room temperature, a small precipitation was filtered off, and washed twice with 1 ml of DMF. The filtrates were collected and kept at room temperature overnight. 50 ml of water was added to the solution. A precipitated oil was separated by centrifugation. The residual oil was dissolved in 10 ml of methanol and 0.2 ml of conc. HCl was added. The methanol solution was concentrated to 2 ml and purified by gel filtration on Sephadex LH-20 in methanol. Yield=52%.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=2[F:19])=[CH:10][CH:11]=1)=[O:5])C.[OH-].[Na+]>CO>[F:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([F:18])[C:12]=1[C:9]1[N:8]=[CH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=1
Reactant: CCOC(=O)c1ccc(-c2c(F)cccc2F)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2c(F)cccc2F)nc1
Yield: 63 %

Procedure:
Combine the mixture as obtained above (0.225 g, 1.04 mmol) with hexamethylditin (0.375 g, 1.15 mmol), Pd(OAc)2 (21 mg, 0.09 mmol), and triphenylphosphine (25 mg, 0.09 mmol) in toluene (5 mL). Purge with N2 and stir at 80° C. for 18 hours. Cool reaction to room temperature. Add a solution of 1-bromo-2,6-difluorobenzene (250 mg, 1.29 mmol) in toluene (1 mL) followed by Pd(OAc)2 (21 mg, 0.09 mmol) and triphenylphosphine (25 mg, 0.09 mmol). Purge with N2 and stir at 80° C. for an additional 18 hours. Cool reaction to room temperature. Evaporate the solvent and purify by column chromatography (silica, 10% ethyl acetate in hexane) to give 50 mg (20% yield) of 6-(2,6-difluorophenyl)pyridine-3-carboxylic acid ethyl ester. Hydrolyze the ester with 1 N sodium hydroxide solution (0.22 mL, 0.22 mmol) in methanol (3 mL) at room temperature for 3 days. Remove the volatiles under vacuum and combine the residue with 1 N hydrochloric acid solution. Collect the white solid by filtration, wash with water, and dry under vacuum to give 30 mg (63% yield) of the title compound. MS (m/e): 235.9 (MH+).
Reaction SMILES: CC(C)(OC([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[O:20][N:19]=[C:18]([CH3:21])[N:17]=2)=[CH:11][CH:10]=1)=O)C.[ClH:23]>>[ClH:23].[CH3:21][C:18]1[N:17]=[C:16]([CH2:15][C:12]2[CH:13]=[CH:14][C:9]([CH2:8][NH2:7])=[CH:10][CH:11]=2)[O:20][N:19]=1
Reactant: Cc1noc(Cc2ccc(CNC(=O)OC(C)(C)C)cc2)n1
Agent: Cl
Product: Cc1noc(Cc2ccc(CN)cc2)n1
Yield: 56 %

Procedure:
Prepared analogously to Example 65i) by treating 5-[[4-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]phenyl]methyl]-3-methyl-1,2,4-oxadiazole with methanolic hydrogen chloride solution in a yield of 56% of theory.