Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Li+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:23]([C:24]([O:26]C)=[O:25])=[C:22]3[C:17]([CH:18]4[CH2:28][CH:19]4[CH2:20][O:21]3)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[C:6]([CH:29]=[CH2:30])[CH:5]=1>O1CCOCC1.O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[C:23]([C:24]([OH:26])=[O:25])=[C:22]3[C:17]([CH:18]4[CH2:28][CH:19]4[CH2:20][O:21]3)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[C:6]([CH:29]=[CH2:30])[CH:5]=1
Reactant: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21

Procedure:
Lithium hydroxide (0.101 g) was added to a solution of methyl (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 75, 0.150 g) in a mixture of dioxane (3 mL) and water (0.6 mL) and the mixture was irradiated in the microwave at 130° C. for 30 minutes. After cooling, the mixture evaporated to dryness and the residue was acidified by addition of 10% aqueous citric acid (2 mL), extracted with DCM, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of methanol and DCM with a gradient of 0-10% to give (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.0.35 g) as a glass.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18](=[O:44])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]([CH2:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=3)[N:34]=[CH:33][C:32]=2[OH:43])[CH2:28]O)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>O1CCCC1>[C:13]([O:17][C:18](=[O:44])[NH:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([CH2:26][CH:27]2[CH2:30][C:31]3[C:40]4[C:35](=[CH:36][CH:37]=[C:38]([O:41][CH3:42])[CH:39]=4)[N:34]=[CH:33][C:32]=3[O:43][CH2:28]2)[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COc1ccc2ncc(O)c(CC(CO)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc3c(c2c1)CC(C[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1)CO3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Diethyl azodicarboxylate (455 μL, 2.90 mmol, 3.0 eq) is added at 0° C. to a stirred solution of {trans-4-[3-hydroxy-2-(3-hydroxy-6-methoxy-quinolin-4-ylmethyl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester (430 mg, 0.97 mmol, 1.0 eq) in tetrahydrofuran (100 mL), followed by triphenylphosphine (761 mg, 2.90 mmol, 3.0 eq). After 2 hours stirring at room temperature, solvent is removed and the crude is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford [trans-4-(6-methoxy-3,4-dihydro-2H-1-oxa-9-aza-phenanthren-3-ylmethyl)-cyclohexyl]-carbamic acid tert-butyl ester as an off-white solid (247 mg, 60% yield).
Reaction SMILES: [N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH:29]6[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[ClH:42]>C1OCCOC1.O>[ClH:42].[N:1]1([C:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]4[C:28]5[C:23](=[CH:24][CH:25]=[C:26]([CH:29]6[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]6)[CH:27]=5)[NH:22][N:21]=4)[N:17]=[N:16]3)=[CH:11][CH:10]=2)=[O:8])[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc3[nH]nc(-c4cn(-c5ccc(C(=O)N6CCOCC6)cc5)nn4)c3c2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1ccc(-n2cc(-c3n[nH]c4ccc(C5CCNCC5)cc34)nn2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 4-(3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-1H-indazol-5-yl)piperidine-1-carboxylate (40 mg; 0.07 mmol; 1.0 eq.) in Dioxane-1,4 (3.0 mL) and water (1.0 mL) was added Hydrogen chloride (1 mL of a 4N solution in dioxane, 4.00 mmol; 56 eq.). The resulting solution was stirred at RT for 12 h. Solvent was removed under reduced pressure, the residue was redissolved in ACN and water and lyophilized to give the title compound as a yellow solid (40 mg, 100%). 1H NMR (300 MHz, DMSO) δ 13.38 (brs, 1H), 9.37 (s, 1H), 8.96 (brs, 1H), 8.76 (brs, 1H), 8.23 (s, 1H), 8.19-8.09 (m, 2H), 7.75-7.53 (m, 3H), 7.34 (dd, J=1.4, 8.7 Hz, 1H), 3.80-3.52 (m, 5H), 3.53-3.21 (m, 3H), 3.04 (d, J=5.3 Hz, 4H), 2.15-1.75 (m, 5H). HPLC (Condition A): Rt 2.44 min (purity 93.2%). MS (ES+): 458.5, MS (ESI−): 456.5.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])=[N:9]2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:21][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([F:20])[C:14]=1[C:10]1[NH:11][C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([C:27]3[CH:28]=[N:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=3)=[CH:3][CH:4]=2)[N:9]=1
Reactant: OB(O)c1ccc(C(F)(F)F)nc1
Reactant: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Temperature: 110 °C
Reaction time: 36 h
Yield: 25.5 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-(2-chloro-6-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-1, 0.100 g, 0.271 mmol) in DMSO (3.0 mL) was added [6-(trifluoromethyl)pyridin-3-yl]boronic acid (0.078 g, 0.40 mmol), K2CO3 (0.112 g, 0.81 mmol) and tetrakistriphenyl phosphine palladium (0) (0.062 g, 0.054 mmol). The reaction mass was stirred at 110° C. for 24-48 h. The reaction mass was quenched in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated. The obtained product was purified with column chromatography on silica gel eluting with 4-5% EA:DCM to afford 0.030 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.38-7.48 (m, 1H), 7.61-7.63 (m, 1H), 7.88-7.99 (m, 4H), 8.01-8.17 (m, 2H), 8.41 (d, J=7.8 Hz, 1H), 9.14 (s, 1H), 12.60 (br s, 1H). MS (m/z): 435.25 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH2:12]([S:18][CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21](=[O:34])[CH2:20]1)[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>ClCCl.CCOCC>[CH2:12]([S:18]([CH:19]1[N:22]([CH2:23][C:24](=[O:33])[CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21](=[O:34])[CH2:20]1)=[O:9])[CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCSC1CC(=O)N1CC(=O)CCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCS(=O)C1CC(=O)N1CC(=O)CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of m-chloroperbenzoic acid (2.48 g, 0.0144 mol) in dichloromethane (50 ml) was added dropwise to a stirred solution of 4-hexylthio-1-(4-phenyl-2-oxobutyl)azetidin-2-one (4.0 g, 0.012 mol) in dichloromethane (50 ml) at -60° C. Stirring was continued at -60° C. for 30 minutes then the mixture was poured into an aqueous solution of sodium hydrogen carbonate and sodium sulphite. The layers were separated and the aqueous was extracted with dichloromethane. The combined extracts were dried (MgSO4) and evaporated to give a solid which was slurried in ether, filtered, washed with ether and petrol. The solid was recrystallised from ethyl acetate to give the title compound as white crystals, 920 mg, (22%), m.p. 154-5° C.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:15]=O)=[N:6][N:7](C2CCCCO2)[CH:8]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([NH2:31])[C:21]([NH2:30])=[CH:22][C:23]=1[N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CO>[F:17][C:18]1[C:23]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:22][C:21]2[N:30]=[C:15]([C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=3)[NH:31][C:20]=2[CH:19]=1
Reactant: O=Cc1nn(C2CCCCO2)cc1[N+](=O)[O-]
Reactant: Nc1cc(F)c(N2CCOCC2)cc1N
Solvent: CO
Product: O=[N+]([O-])c1c[nH]nc1-c1nc2cc(N3CCOCC3)c(F)cc2[nH]1
Temperature: 22 °C
Reaction time: 18 h

Procedure:
530 mg of 4-nitro-1-(tetrahydropyran-2-yl)-1H-pyrazole-3-carbaldehyde (the preparation of which is described in WO 03/035065, reference example 6m page 479) are added slowly to a solution of 500 mg of 4-fluoro-5-morpholin-4-ylbenzene-1,2-diamine in 50 mL of methanol, and then 19.5 mg of ferric chloride are added. The reaction medium is stirred at 22° C. for 18 hours. After evaporation, the reaction crude is purified by flash chromatography on an Intelliflash apparatus on an Analogix RS-90 cartridge. The elution is carried out as follows: 100% cyclohexane for 20 minutes, then 20 minutes with an 80:20 cyclohexane/ethyl acetate mixture and 120 minutes with a 20:80 cyclohexane/ethyl acetate mixture. 457 mg of 6-fluoro-5-morpholin-4-yl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzimidazoleare isolated. 1H NMR (400 MHz, (CD3)2SO, δ in ppm): 1.42-1.80 (m: 3H); 1.91-2.06 (m: 2H); 2.18 (m: 1H); 3.02 (m: 4H); 3.70 (m: 1H); 3.78 (m: 4H); 4.00 (broad d J=10 Hz: 1H); 5.60 (dd, J=10 and 2 Hz: 1H); 7.18 (very broad s: 1H); 7.45 (very broad s: 1H); 9.18 (s: 1H); 12.85 (very broad s: 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][CH:6]=[C:5]2[I:12].[H-].[Na+].[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[N:7]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[CH:6]=[C:5]2[I:12]
Reactant: Fc1cc2[nH]cc(I)c2cc1F
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(F)c(F)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.4 %

Procedure:
To a solution of 5,6-difluoro-3-iodo-1H-indole (Intermediate 27; 930 mg; 3.33 mmol) in THF (20 mL) at 0° C. was added NaH (266.4 mg; 60%; 6.66 mmol) under nitrogen. The reaction mixture was stirred at r.t. for 15 minutes before a solution of benzenesulfonyl chloride (763.4 mg; 4.32 mmol) in THF (2 mL) was added dropwise. The reaction was stirred at r.t. for 12 hours, quenched with an ice-water mixture (60 mL) and extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, concentrated, and purified by a silica gel chromatography (petroleum ether/EtOAc=10/1-3/1) to afford 1.01 g (72%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:3].[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3]
Reactant: ClCc1ccccc1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
27.2 g of 4-hydroxyacetophenone is mixed with 100 ml of dimethylformamide, 25.3 g of benzyl chloride and 30.4 g of potassium carbonate. The resulting mixture is stirred in a stream of nitrogen at 100°-110° C. for 3 hours and then cooled. The cooled mixture is added to about 2 l of ice water to deposit solid. The solid is separated therefrom by filtration and then washed with water until the solid becomes neutral. The washed solid is dried and then recrystallized from 500 ml of ethanol to obtain 38.8 g of 4-benzyloxyacetophenone. Thus obtained 4-benzyloxyacetophenone has a melting point of 92.5°-93° C.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH:6]=[CH:7][CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[C:15]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[CH:19]=[CH:18][C:17]4[CH:26]=[CH:27][CH:28]=[CH:29][C:16]3=4)[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[CH:25]1[C:20]2[CH:19]=[CH:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[C:15](=[C:12]3[CH2:11][CH2:10][N:9]([CH2:8][CH:7]=[CH:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:31][CH:30]=4)[CH2:14][CH2:13]3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1ccc(C=CCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 67 %

Procedure:
This compound was prepared from 1-(4-Aminocinnamyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine (compound 5) and methanesulfonyl chloride. Yield 67.0%
Reaction SMILES: [CH2:1](Br)[CH2:2][CH3:3].[OH:5][C:6]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:7]=1[CH:8]=[O:9].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH3:15][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:6]([O:5][CH2:1][CH2:2][CH3:3])[C:7]=1[CH:8]=[O:9]
Reactant: COc1cccc(O)c1C=O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCCOc1cccc(OC)c1C=O
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Propyl bromide (1 ml) was added to a mixture of 2-hydroxy-6-methoxybenzaldehyde (0.45 g), potassium carbonate (0.83 g) and a small amount of potassium iodide in a mixed solvent of N,N-dimethylformamide (10 ml) and acetone (5 ml). After being stirred for 5 hours at 100° C., the mixture was poured into ice-water (20 ml) and extracted with ethyl acetate. The extract was washed with brine (10 ml), dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of hexane and ethyl acetate (4:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give colorless oil of 2-methoxy-6-propoxybenzaldehyde (0.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:26]=[C:25]([F:27])[C:18]([O:19][CH2:20][C:21](OC)=[O:22])=[C:17]([F:28])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH3:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:26]=[C:25]([F:27])[C:18]([O:19][CH2:20][C:21]([NH2:29])=[O:22])=[C:17]([F:28])[CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: N
Reactant: COC(=O)COc1c(F)cc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Solvent: CO
Product: NC(=O)COc1c(F)cc(SCCNS(=O)(=O)c2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Methyl 4-[2-(4-chlorophenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetate (1 g) was added to methanol (50 ml) saturated with ammonia gas, and the mixture was stirred at room temperature for 3 days. The reaction mixture was evaporated under reduced pressure, and the residue was recrystallized from methanol to give 4-[2-(4-chlorophenylsulfonylamino)ethylthio]-2,6-difluorophenoxyacetamide (Compound No. 132).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([C@@:11]23[CH2:20][C@H:15]([CH2:16][C:17](=O)[CH2:18]2)[N:14]([CH3:21])[CH2:13][C@H:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)[CH3:3].Cl.[NH2:24][OH:25]>CCO>[CH:2]([O:4][C:5]1[CH:6]=[C:7]([C:11]23[CH2:20][CH:15]([CH2:16][C:17](=[N:24][OH:25])[CH2:18]2)[N:14]([CH3:21])[CH2:13][CH:12]3[CH3:22])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:1]
Reactant: NO
Reactant: CC(C)Oc1cccc([C@]23CC(=O)C[C@@H](C2)N(C)C[C@H]3C)c1
Agent: Cl
Solvent: CCO
Product: CC(C)Oc1cccc(C23CC(=NO)CC(C2)N(C)CC3C)c1
Temperature: 25 °C
Yield: 87.5 %

Procedure:
5-(3-Isopropoxy-phenyl)-2,4-dimethyl-2-aza-bicyclo[3.3.1]nonan-7-one (2.2) (3.11 g, 13.0 mmole) and hydroxylamine hydrochloride (4.50 g, 64.8 mmol) in EtOH (absolute, 195 mL) were heated to reflux for 3 h. The reaction mixture was allowed to cool to room temperature and the ethanol was removed under reduced pressure. The crude oil was dissolved in 2 N NaOH (100 mL) and extracted with 3:1 CH2Cl2/THF (4×50 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated under reduced pressure yielding crude product. The crude product was purified by flash chromatography (neutral alumina, Brockman activity II-III) eluting with 9:1 ethyl acetate:hexane to afford the title compound (3.6 g, 88%) as an off white solid. 1H NMR (CDCl3) δ 8.47 (br, 1H), 7.23 (t, J=7.8 Hz, 1H), 7.00-6.72 (m, 3H), 4.54 (m, 1H), 3.63 (d, J=17 Hz, 1H), 3.29 (br, 1H), 2.94-2.85 (m, 2H), 2.51 (d, J=15.9 Hz, 1H), 2.44-2.40 (m, 4H), 2.05-1.87 (m, 5H), 1.33 (d, J=6.0 Hz, 6H), 0.76 (d, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[OH:18][CH2:19][C:20]([N+:25]([O-:27])=[O:26])([CH2:23]O)[CH2:21][OH:22].Cl.CN(C)CCCN=C=NCC.N(C(C)C)(C(C)C)CC>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:23][C:20]([CH2:21][OH:22])([N+:25]([O-:27])=[O:26])[CH2:19][OH:18])=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Reactant: O=[N+]([O-])C(CO)(CO)CO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc([C@H](C)C(=O)OCC(CO)(CO)[N+](=O)[O-])ccc2c1
Yield: 36.9 %

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (naproxen, 4.27 g, 18.5 mmol), 2-hydroxymethyl-2-nitro-1,3-propanediol (2.89 g, 19.1 mmol), N,N-dimethylaminopyridine (DMAP, 0.88 g, 7.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.86 g, 25.4 mmol) and NEt(i-Pr)2 (11 mL, 63.2 mmol) in acetone (100 mL) was stirred at ambient temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between 3N HCl (100 mL) and CH2Cl2 (200 mL×2). The combined organic layer was back washed with water and brine, dried over Na2SO4, filtered, concentrated and dried under vacuum. The product was separated by silica gel column chromatography eluting with ethyl acetate/hexane (gradient from 1:2 to 1:1, Rf=0.1 in 1:2) to give the title compound as a white solid (2.48 g, 39% yield). Mp 124-126° C. 1H NMR (300 MHz, 10% CD3OD/CDCl3) δ 7.73-7.64 (m, 3H), 7.37-7.33 (m, 1H), 7.17-7.12 (m, 2H), 4.44 (d, J=2.6 Hz, 2H), 3.92 (s, 3H), 3.9-3.7 (m, 5H), 3.4 (br, 2H), 1.58 (d, J=7.2 Hz, 3H), 13C NMR (75 MHz, 10% CD3OD/CDCl3) δ 174.1, 157.4, 134.5, 133.5, 129.0, 128.6, 127.0, 125.7, 118.8, 105.4, 92.4, 61.2, 60.1, 55.0, 45.0, 17.7.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][C:11]1[N:12]([C:17]2[N:22]=[CH:21][C:20]([C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=2)[C:13]([CH3:16])=[CH:14][CH:15]=1.Cl>[OH-].[Na+].CCO>[CH3:10][C:11]1[N:12]([C:17]2[N:22]=[CH:21][C:20]([C:23](=[O:25])/[CH:24]=[CH:4]/[C:3]3[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=3[OH:1])=[CH:19][CH:18]=2)[C:13]([CH3:16])=[CH:14][CH:15]=1
Reactant: O=Cc1ccccc1O
Reactant: CC(=O)c1ccc(-n2c(C)ccc2C)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C)n1-c1ccc(C(=O)/C=C/c2ccccc2O)cn1
Yield: 36 %

Procedure:
To a vigorously stirred solution of 2-hydroxybenzaldehyde in 2.5N NaOH (2.2 mL) at 0° C. was added 1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]ethanone (prepared by a method analogous to that described by Scott et al., Org. Proc. Res. And Dev., 8:587 (2004)) (0.58 g, 2.7 mmol) in EtOH (2 mL). The reaction mixture was allowed to stir and warm to rt whereupon an additional 1 mL of EtOH was added. The mixture turned a dark red color and was allowed to stir for 25 h. The reaction was neutralized by the addition of 1M HCl and the mixture was extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography to give (2E)-1-[6-(2,5-dimethyl-1H-pyrrol-1-yl)pyridin-3-yl]-3-(2-hydroxyphenyl)prop-2-en-1-one as a yellow solid (0.31 g, 36%). LCMS: (FA) ES+ 319.2 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](O)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCOC(/[N:17]=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[NH4+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1)[NH2:17]
Reactant: COc1cc(O)cc(OC)c1
Reactant: CCOC(=O)/N=N/C(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(N)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
2 g of dry 3,5-dimethoxyphenol was dissolved in 25 mL dry THF and cooled in an ice bath. To this solution was added 2.25 g of diethylazodicarboxylate (DEAD), 6 g of triphenylphosphine and 1 mL of ammonium chloride (NH4Cl). The mixture was stirred for 20 minutes. The mixture was warmed to room temperature and stirred for an additional 30 minutes. Silica gel was added to remove DEAD, triphenylphosphine, and excess ammonia, yielding 3,5-dimethoxyaniline.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][S:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>>[CH3:12][S:13][C:14]1[CH:15]=[C:16]([NH:17][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: CSc1cccc(N)c1
Product: CSc1cccc(Nc2ccccc2CC(=O)O)c1

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 3-methylmercaptoaniline to yield 2-[(3-methylmercaptophenyl)amino]phenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[N:18]=[C:17]([C:19](=O)[CH3:20])[CH:16]=[CH:15][CH:14]=1)[CH3:12].[CH3:22][C:23]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:24]=1[NH2:25]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]=[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:19](=[N:25][C:24]2[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:23]=2[CH3:22])[CH3:20])[N:18]=1)[CH3:12]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Reactant: Cc1cccc(C)c1N
Solvent: C1CCOC1
Product: CC(=Nc1c(C)cccc1C)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Yield: 67 %

Procedure:
18.80 g of 1-{6-[1-(2-chloro-4,6-dimethylphenylimino)-ethyl]pyridin-2-yl}ethanone (0.0625 mol), 15.13 g of 2,6-dimethylaniline (0.125 mol) and 20.0 g of Sicapent were heated under reflux under argon in 300 ml of tetrahydrofuran for 17 h. A further portion of Sicapent (10.0 g) was added and the mixture was heated under argon for a further 4 h and then cooled to room temperature. It was filtered and the residue on the filter was washed with 50 ml of tetrahydrofuran. The solvent was distilled off completely from the combined filtrates and the residue was stirred with 50 ml of methanol. The precipitate formed was filtered off, washed twice with methanol, stirred with 100 ml of hot methanol and then filtered. 16.92 g (0.0419 mol) of 2-[1-(2-chloro-4,6-dimethylphenylimino)ethyl]-6-[1-(2,6-dimethylphenylimino)ethyl]pyridine were obtained in a yield of 67%.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[OH:11][C:12]1[CH:21]=[C:20]2[C:15]([C:16]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:17][CH:18]=[N:19]2)=[CH:14][C:13]=1[O:29][CH3:30].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:30][O:29][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:12]=1[O:11][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[N:19]=[CH:18][N:17]=[C:16]2[O:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCCN1CCCCC1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCN1CCCCC1
Temperature: 110 °C
Yield: 84.8 %

Procedure:
1-(2-Chloroethyl)piperidine hydrochloride (0.83 g, 4.5 mmol) was added to 7-hydroxy-6-methoxy-4-phenoxyquinazoline (1.0 g, 3.73 mmol), (prepared as described for the starting material in Example 1), and potassium carbonate (2.6 g, 18.8 mmol) in DMF (30 ml), and the mixture heated at 110° C. for 2.5 hours and allowed to cool. The insolubles were removed by filtration, and the volatiles were removed from the filtrate by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) to give 6-methoxy-4-phenoxy-7-(2-piperidinoethoxy)quinazoline (1.2 g, 85%).