Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:26])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([C:21](=[O:25])[N:22]([CH3:23])[CH3:24])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:26])[CH:5]=1
Reactant: [H][H]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2ccc(C(=O)N(C)C)cc2C1=O
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(C(=O)N(C)C)cc2C1=O

Procedure:
The mixture of 6.5 g of N-(4-nitro-o-tolyl)-4-dimethylcarbamoylphthalimide, 3.0 g of Raney nickel and 270 ml of ethyl acetate is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, the filtrate evaporated, the residue washed with hot ethanol and dried, to yield the N-(4-amino-o-tolyl)-4-dimethylcarbamoylphthalimide melting at 214°-217°.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=O)#[N:2].C1(P(=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1C=CC=CC=1>[CH2:34]([O:33][C:31](=[O:32])[CH:30]=[CH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH3:35]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#CCCCCCCC=O
Solvent: c1ccccc1
Product: CCOC(=O)C=CCCCCCCC#N
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The mixture of 14 g of 7-cyanoheptanal, 38 g of ethyl triphenylphosphoranylidene-acetate and 100 ml of benzene is refluxed for 15 hours and evaporated. The residue is triturated with diethyl ether, filtered and the filtrate evaporated. The residue is allowed to stand overnight in the refrigerator, triturated with the minimum amount of diethyl ether, the suspension filtered, the filtrate evaporated, the residue distilled and the fraction boiling at 130°-138°/0.1 mm Hg collected, to yield the 9-cyano-2-nonenoic acid ethyl ester of the formula
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:14][CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.Cl[CH2:35][C:36](Cl)=[O:37].[OH-].[K+]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[CH:16][CH:17]=2)[O:11][CH2:35][C:36]1=[O:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CCCCCCCCOc1ccc(C(O)CNCc2ccccc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCOc1ccc(C2CN(Cc3ccccc3)C(=O)CO2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
To a solution of 2-benzylamino-1-(4-octyloxy-phenyl)-ethanol (22.50 g; 63.3 mmol) and Et3N (9.7 mL; 69.6 mmol) in CH2Cl2 (500 mL) was added dropwise a solution of chloroacetyl chloride (5.5 mL; 69.6 mmol) in CH2Cl2 (25 mL), at 0° C. After 1 hour at 0° C. the reaction mixture was quenched with 1M aqueous HCl (200 mL). The layers were separated and the organic layer washed with a 5% aqueous NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The residue was dissolved in 2-propanol (250 mL) and KOH (4.26 g; 76 mmol) was added. The resulting mixture was stirred at RT for 1 hour and subsequently concentrated in vacuo. The crude product was partitioned between EtOAc and 0.5 M aqueous HCl. The layers were separated and the organic layer was washed with 5% aqueous NaHCO3 solution, dried (Na2SO4) and evaporated in vacuo to afford 4-benzyl-6-(4-octyloxy-phenyl)-morpholin-3-one (22.30 g) which was used as such in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[N+:10]([O-])([O-:12])=[O:11].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:10]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[C:4]=1[OH:9])([O-:12])=[O:11]
Reactant: O=[N+]([O-])[O-]
Reactant: N#Cc1ccccc1O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 42.7 %

Procedure:
2-Cyanophenol (4.72 g, 40 mmol) was dissolved in methylene chloride(80 ml) followed by the addition of sodium nitrate (3.76 g, 44 mmol). The addition of sulfuric acid (40 ml/3M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hrs, the reaction mixture was diluted with methylene chloride and extracted with water. The organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product (2.8 g, 42%). 1H NMR (CD3COCD3): δ 8.47 (d, 1H), 8.15 (d, 1H), 7.30 (t, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@H:11]([C:13]1[C:14]([N:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]2)=[N:15][CH:16]=[N:17][C:18]=1Cl)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1>[CH2:1]([O:8][C:9](=[O:33])[CH2:10][C@H:11]([C:13]1[C:18]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])=[N:17][CH:16]=[N:15][C:14]=1[N:20]1[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]1)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](CC(=O)OCc1ccccc1)c1c(Cl)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1CCOC1
Product: CC(C)OC(=O)c1ncnc(N2CCN(C(=O)OC(C)(C)C)CC2)c1[C@H](C)CC(=O)OCc1ccccc1
Temperature: 37.5 °C

Procedure:
(R)-tert-butyl 4-(5-(4-(benzyloxy)-4-oxobutan-2-yl)-6-chloropyrimidin-4-yl)piperazine-1-carboxylate (1710 g) was dissolved in THF (4.0 L) and placed in a nitrogen-purged 5 gallon autoclave. Isopropanol (6.0 L) was added. The reaction mixture was sparged with nitrogen gas 5 times (25 psi), and the autoclave was heated to 35-40° C. A slurry of palladium acetate (81 g) and dppp (163 g) in isopropanol (2.0 L) was added at 40-45° C. and stirred. The reaction mixture was sparged with nitrogen gas 3 times (25 psi) and stirred for 20 minutes at 40-45° C. to dissolve the solids. A slurry of potassium carbonate, 325 mesh (299 g) in isopropanol (2.0 L) was added at 40-45° C. with stirring. The reaction mixture was sparged with nitrogen gas 5 times (25 psi), then sparged with carbon monoxide gas 5 times (40 psi). The autoclave was sparged with carbon monoxide gas to 55 psi. The reaction mixture was stirred at 50° C. and 55 psi (carbon monoxide gas) for a minimum of 50 hours and monitored by TLC and HPLC. The reaction mixture was cooled to room temperature and transferred into a filtration bottle. Silica gel (400 g) and Celite® (400 g) were added, and the reaction mixture was stirred open to air for 2 hours. The reaction mixture was filtered using a silica gel pad (1000 g) in a scintered funnel (D×H, 8×14 inches) and washed with ethyl acetate (4-5 L) and concentrated under vacuum to yield the product as viscous dark brown oil (contains residual dppp[O]2. Yield=1900 g (˜100%, contains residual dppp[O]2), structure confirmed by 1H-NMR (CDCl3).
Reaction SMILES: [Br:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH:3]1[OH:13].OS(O)(=O)=O.C(O)(C)C>CC(C)=O.O>[Br:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][C:3]1=[O:13]
Reactant: CCOC(=O)C1CCC(Br)C(O)C1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)O
Solvent: CC(C)=O
Product: CCOC(=O)C1CCC(Br)C(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 4-bromo-3-hydroxycyclohexanecarboxylate (15.06 g) in acetone (300 mL) at 0° C. was added CrO3 (12.0 g, 120 mmol), and 2 N H2SO4 (60 mL). The mixture was stirred at room temperature for 30 min. Isopropanol (15 mL) was added and the reaction was stirred for 20 min. The volume was reduced under vacuum then diluted with water and extracted with ethyl acetate. The organic layer was washed with water, then brine, was dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica gel (10% EtOAc in hexane) afforded 6.7 g of tide compound.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:15])=O>C(OCC)(=O)C>[Cl:15][C:8]1[CH:7]=[N:6][C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1cnc2ccc(F)cc2n1
Solvent: CCOC(C)=O
Product: Fc1ccc2ncc(Cl)nc2c1
Yield: 86.4 %

Procedure:
A mixture of 7-fluoro-quinoxalin-2-ol (2.60 g, 15.84 mmol, 1.0 eq) and phosphorus oxychloride (50 mL, 536.4 mmol, 34.0 eq) is refluxed for 1 hour, then concentrated, diluted with water (60 mL), basified to pH 7 by adding saturated sodium hydrogen carbonate aqueous solution, and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a crude that is purified by column chromatography (silica gel, eluent: ethyl acetate:petroleum ether, 1:20, v/v) to afford 2-chloro-7-fluoro-quinoxaline as a white solid (2.50 g, 84% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH:16]1[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17]1.CCOCC>CO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([N:16]3[CH2:20][CH2:19][C@@H:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: COc1ccc(N2CCC(=O)CC2)cc1
Solvent: CCOCC
Solvent: CO
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)cc1
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 1-(4-methoxyphenyl)piperidin-4-one (5.65 g, 27.6 mmol) and (R)-tert-butyl pyrrolidin-3-ylcarbamate (5.65 g, 30.3 mmol) in MeOH (200 mL) was added STAB (10.49 g, 49.5 mmol) in small portions. The reaction mixture was stirred overnight, then was concentrated to 1/10 of the original volume. NaOH (100 mL, 1N aqueous) and CH2Cl2 (100 mL) were added and the organic layer was washed with brine, dried over Mg2SO4, filtered and concentrated. Upon the addition of ether, tert-butyl {(3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-yl}carbamate (6.98 g, yield 67.5%) precipitated as a white solid. The resulting solid was dissolved in CH2Cl2 (50 mL) to which was added 4N HCl/dioxane (50 mL). After 2 h at room temperature, ether was added until (3R)-1-[1-(4-methoxyphenyl)piperidin-4-yl]pyrrolidin-3-amine precipitated (as the HCl salt) from the solution, and was collected by filtration as a white solid (6.40 g, 52% over 2 steps).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:3]=1[CH2:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][CH2:11][NH:10][C:9]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:10]1[C:9]2[CH:14]=[C:5]([CH2:4][C:3]3[CH:15]=[C:16]([I:19])[CH:17]=[CH:18][C:2]=3[Br:1])[CH:6]=[CH:7][C:8]=2[O:13][CH2:12][CH2:11]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Brc1ccc(I)cc1Cc1ccc2c(c1)NCCO2
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1ccc(I)cc1Cc1ccc2c(c1)N(Cc1ccccc1)CCO2
Temperature: 50 °C
Yield: 92.3 %

Procedure:
To a stirred solution of 6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (9.4 g, 21.86 mmol) in DMF (50 mL) was added potassium carbonate (6.04 g, 43.71 mmol), benzyl bromide (3.2 mL, 26.23 mmol) and the mixture was heated to 50° C. overnight. The reaction mixture was cooled to room temperature, quenched by the addition of water (100 mL), then extracted with ethyl acetate (3×50 mL). The organic layers were combined then washed with water (50 mL), brine (50 mL), dried over sodium sulfate, and concentrated to a residue which was purified by silica gel column chromatography to furnish 4-benzyl-6-(2-bromo-5-iodo-benzyl)-3,4-dihydro-2H-benzo[1,4]oxazine (10.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH:21]=[O:22])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C(=O)([O-])O.[Na+]>CO.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[O:13][C:14]4[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][C:15]=4[CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: OCc1ccc2oc(-c3ccc4ccc(Cl)cc4n3)cc2c1
Reaction time: 2 h
Yield: 87.5 %

Procedure:
To a cooled solution of 7-chloro-2-(5-formylbenzofuran-2-yl)quinoline (0.92 g) in a mixture of methanol (20 ml) and chloroform (10 ml) was added sodium borohydride (0.40 g) in small portions. After being stirred at the same temperature for 2 hours, the resulting mixture was treated with diluted hydrochloric acid and adjusted to be basic with aqueous sodium hydrogen carbonate. The resulting precipitates were collected by filtration, Washed with water and dried to give 7-chloro-2-(5-hydroxymethylbenzofuran-2-yl)quinoline (0.81 g).
Reaction SMILES: Cl.ClCCN1CCCC1.ClC1C=CC(N[C:16]2[C:25]3[C:20](=[CH:21][C:22](O)=[C:23](OC)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=C(F)C=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=[N:17][CH:18]=1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: Cl
Agent: ClCCN1CCCC1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1ccc2ncncc2c1
Temperature: 100 °C
Yield: 30.5 %

Procedure:
1-(2-Chloroethyl)pyrrolidine hydrochloride (200 mg, 1.2 mmol) was added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (403 mg, 1.26 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (650 mg, 4.7 mmol) in DMF (4 ml). The mixture was heated to 100° C. and further portions of 1-(2-chloroethyl)pyrrolidine hydrochloride (800 mg in total) were added periodically over 4 hours while the reaction mixture was maintained at 100° C. The reaction was then allowed to cool and volatiles were removed by evaporation. The residue was partitioned between methylene chloride and water, separated and the organic phase passed through phase separating paper. Column chromatography eluting with methylene chloride/methanol 19/5) gave 4-(4-chloro-2-fuoroanilino)-6-methoxy-7-(pyrrolidin-1-yl)ethoxy)quinazoline (50 mg, 10%).
Reaction SMILES: [BH4-].[Na+].[I:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1.O>O1CCOCC1>[I:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCc1ccc(I)cc1
Temperature: 100 °C
Yield: 96.3 %

Procedure:
(Acheson, R. M.; Lee. G. C. M. J. Chem. Soc. Perkin Trans. I 1987, 2321-2332.) To a stirred suspension of sodium borohydride (5.68 g, 150 mmol, 2.0 equiv) in 50 mL dioxane at 0° C. was added dropwise a solution of 4-iodobenzoyl chloride (19.99 g, 75 mmol, 1.0 equiv) in 50 mL dioxane over 25 min. The resulting mixture was heated to 100° C. for 90 min under a reflux condenser then cooled to 0° C. 50 mL H2O was added cautiously under a flowing stream of nitrogen. [CAUTION: Evolves gas!] The mixture was extracted 3×125 mL CH2Cl2 and the combined organic extracts were washed with 2×H2O, 2×0.1N HCl, 2×1N NaOH, H2O, and brine, dried (MgSO4), filtered, and evaporated to yield 16.9 g of crude 4-iodobenzyl alcohol as a white solid, determined by NMR to contain 78% desired product with the remainder residual starting material and 4-iodobenzoic acid. The crude product was used without further purification. mp: 61.0-66.5° C. TLC Rf: 0.27 (3:1 hexanes/EtOAc). IR (film): 3306, 1005, 791. 1H-NMR (400 MHz, CDCl3): δ 7.69 (d, 2H, J=8.3, C4-H, C6-H), 7.12 (d, 2H, J=8.5, C3-H, C7-H), 4.66 (br d, 2H, J=:4.1, C1-H2), 1.67 (br t, 1H, C1-OH). 13C-NMR (125 MHz, CDCl3): δ 140.4, 137.6, 128.8, 93.0, 64.6. EI-MS m/z (rel int): 234 (M+, 100).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9](C)[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][O-:26].[Na+]>CN(C=O)C.CS(C)=O.CO>[OH:23][C:20]([C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([O:26][CH3:25])[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:19][CH:18]=1)([CH3:21])[CH3:22]
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: COc1cc(NC(=O)c2ccc(C(C)(C)O)cc2)nc2ccnn12
Temperature: 25 °C
Yield: 3.4 %

Procedure:
A solution of N-(7-chloropyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2D, 100 mg, 0.302 mmol) and sodium methoxide (1.2 mL from 2M solution in methanol, 0.605 mmol) in DMF (3 mL) was stirred at room temperature overnight. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC, 30-40% (MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (3.4 mg, 6%). 1H NMR (DMSO-d6) δ: 11.10 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 8.01-8.03 (m, 1H), 7.98-8.01 (m, 1H), 7.61 (d, J=6.6 Hz, 1H), 7.55 (s, 1H), 6.41 (d, J=2.3 Hz, 1H), 5.19 (s, 1H), 4.21 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 327.3 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:16])[C:6](=[O:15])[C:7]([CH3:14])=[C:8]([Cl:13])[C:9]=1[C:10](O)=[O:11])(=O)[CH3:2].O.[NH2:18][NH2:19].Cl>C1COCC1.C(OCC)(=O)C>[Cl:13][C:8]1[C:9]2[C:10](=[O:11])[NH:19][N:18]=[C:1]([CH3:2])[C:4]=2[N:5]([CH3:16])[C:6](=[O:15])[C:7]=1[CH3:14]
Reactant: NN
Reactant: CC(=O)c1c(C(=O)O)c(Cl)c(C)c(=O)n1C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(Cl)c2c(=O)[nH]nc(C)c2n(C)c1=O
Reaction time: 16 h

Procedure:
To a solution of 2-acetyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (1 equivalent) and hydrazine monohydrate (3.30 equivalents) in THF is added 1 N HCl (0.80 equivalents). After 16 hours, the reaction mixture is diluted with ethyl acetate, washed with water and brine, dried (MgSO4) and concentrated under reduced pressure. The desired product purified by trituration or flash column chromatography to afford the desired product as necessary.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])C.C[C:7]([CH3:10])([O-])[CH3:8].[K+]>C1COCC1.O>[CH2:4]=[CH:1][CH:3]=[CH:10][CH2:7][CH2:8][CH2:8][CH2:7][CH:10]=[CH:3][CH:1]=[CH2:4]
Reactant: CC(C)(C)O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC=CCCCCC=CC=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
The latter compound (2.0 g) was dissolved in 50 mL of 1:4 THF:tert-butanol and added dropwise to an ice cold solution of potassium tert-butoxide (3.00 g) in 100 mL of 1:4 THF:tert-butanol. The reaction mixture was stirred in ice for 0.5 hours and at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with pentane. The combined organic layer was washed with water. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and the solvent removed in vacuo to give an oil. Distillation gave 0.34 g (48% yield) of 1,3,9,11-dodecatetraene as established by proton and carbon-13 NMR and IR analysis.
Reaction SMILES: [CH:1]([N:4]([S:12](=[O:16])(=[O:15])[NH:13]C)[C:5](=O)OC(C)(C)C)([CH3:3])[CH3:2].Cl>>[CH:1]([N:4]([CH3:5])[S:12]([NH2:13])(=[O:16])=[O:15])([CH3:3])[CH3:2]
Reactant: CNS(=O)(=O)N(C(=O)OC(C)(C)C)C(C)C
Agent: Cl
Product: CC(C)N(C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
To a solution of chlorosulfonyl isocyanate (1.230 ml, 14.13 mmol) in DCM (10 ml) was added tert-BuOH (1.351 ml, 14.13 mmol) at 0° C. dropwise. The mixture was stirred at room temperature for 1 h and added a solution of N-methylpropan-2-amine (1.57 ml, 14.13 mmol) and TEA (2.167 ml, 15.54 mmol) in DCM (3 ml) at 0° C. The mixture was stirred at room temperature for 2 h and diluted with EtOAc, washed with cold 1N HCl, brine, dried (MgSO4), removed the solvent and purified by Biotage 40M column (EtOAc-MeOH (90-10)/hexane 5% to 100%) to afford a colorless gel (2.3 g, 64.5%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J=6.55 Hz, 6H) 1.49 (s, 9H) 2.90 (s, 3H) 4.05-4.26 (m, 1H) 7.02 (br. s., 1H). To tert-butyl N-isopropyl-N-methylsulfamoylcarbamate (2.3 g, 9.12 mmol) was added cold HCl (dioxane, 6 mL, 24.00 mmol) and stirred at room temperature for 2 h, removed the solvent to afford N-isopropyl-N-methylsulfamide as a light tan solid (1.38 g, 99%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.80 Hz, 5H) 2.72 (s, 3H) 4.16 (dt, J=13.53, 6.70 Hz, 1H) 4.43 (br. s., 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:11]([CH:24]=CC)=[C:12]([C:20]([O:22][CH3:23])=[O:21])[CH:13]=[C:14]([CH:19]=2)[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[O:29]=[O+][O-]>C(Cl)Cl.CO>[CH:24]([C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:27]=2)=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=1[C:20]([O:22][CH3:23])=[O:21])=[O:29]
Reactant: CC=Cc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c(C=O)c(C(=O)OC)c1
Temperature: 25 °C
Yield: 98 %

Procedure:
A solution of dimethyl 5-(4-(methylsulfonyl)phenoxy)-4-(prop-1-enyl)isophthalate (2.6 g, 7.8 mmol) in CH2Cl2 and methanol was cooled to −78° C. and treated with ozone until the solution appeared blue (20 min). Nitrogen was bubbled through the solution until the blue color dissipated. Dimethylsulfide (1.0 mL) was added and the cold-bath was removed allowing the reaction mixture to warm to room temperature overnight. Concentration of the solution under vacuum provided an oil, which was introduced into a silica gel column and eluted with 10-30% EtOAc in hexanes to afford the title compound (2.5 g, 98%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 3.08 (q, 3 H) 3.95 (dd, 6 H) 7.08-7.16 (m, 2 H) 7.98 (q, J=2.07 Hz, 2 H) 7.99-8.03 (m, 1 H) 8.33-8.39 (m, 1 H) 10.46 (s, 1 H); LC-MS (ERS)+ m/z=393.00 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[C:9]3[N:12]=[CH:13][N:14]=[C:8]3[CH2:7][C:6]=2[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=1)[NH2:21].Cl.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(OCCO)C>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:2]2[C:11]3[CH:10]=[C:9]4[N:12]=[CH:13][N:14]=[C:8]4[CH2:7][C:6]=3[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:22]=[CH:23][CH:24]=1
Reactant: N#Cc1cnc2c(c1Cl)C=C1N=CN=C1C2
Reactant: Nc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Product: N#Cc1cnc2c(c1Nc1cccc(Br)c1)C=C1N=CN=C1C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
A mixture of 0.2 g (0.87 mmol) of 8-chloroimidazo[4,5-g]quinoline-7-carbonitrile, 0.12 mL (1.1 mmol) of 3-bromoaniline, and 0.1 g (0.87 mmol) of pyridine hydrochloride in 5.0 mL of 2-ethoxyethanol is heated at reflux temperature for 45 minutes, then cooled to room temperature. The product mixture is poured into a saturated solution of sodium bicarbonate and stirred for 0.5 hour. The solid is collected by filtration, washed with water and dried. The solid is purified by silica gel chromatography, utilizing a gradient of methylene chloride/methanol(98:2 to 93:7) to yield 0.20 g of 8-(3-bromo-phenylamino)imidazo[4,5-g]quinoline-7-carbonitrile as pink solid, mp 286-288° C.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:12][CH:11]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:10]1)=O)(C)(C)C>CO>[ClH:1].[NH:9]1[CH2:12][CH:11]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][CH:16]=[CH:17][CH:18]=2)[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CC(c2cccnc2-c2ccccc2)C1
Agent: Cl
Solvent: CO
Product: c1ccc(-c2ncccc2C2CNC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
To a solution of 4 M HCl in MeOH (10 mL) was added 3-(2-phenyl-pyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl ester (27) (180 mg, 0.58 mmol) at 0° C. and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated under reduced pressure to give 3-azetidin-3-yl-2-phenyl-pyridine hydrochloride (28) (120 mg, yield 94%) which was used for the next step without further purification. ESI-MS (M+1): 211 calc. for C14H14N2 210.