Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[CH2:20]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:28](=[O:36])[NH:29][C@H:30]1[CH2:34][CH2:33][N:32]([CH2:2][C:3]2[CH:12]=[C:11]3[C:6]([CH:7]=[CH:8][N:9]=[C:10]3[O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:5][CH:4]=2)[C:31]1=[O:35])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: BrCc1ccc2ccnc(Oc3ccccc3)c2c1
Reactant: O=C(N[C@H]1CCNC1=O)OCc1ccccc1
Product: O=C(N[C@H]1CCN(Cc2ccc3ccnc(Oc4ccccc4)c3c2)C1=O)OCc1ccccc1

Procedure:
The title compound is prepared as described in Example 1, Part H using 7-bromomethyl-1-phenoxyisoquinoline and [2-oxopyrrolidin-3-(S)-yl]carbamic acid benzyl ester as the starting materials. The crude product is purified by column chromatography eluting with 70% EtOAc/hexanes to afford the title product as a clear oil.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26]Br)[CH:20]=2)[O:7][C@@H:6]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:41]2[CH:46]=[CH:45][C:44]([C:47]3([CH:50]=[O:51])[CH2:49][CH2:48]3)=[CH:43][CH:42]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:41]3[CH:46]=[CH:45][C:44]([C:47]4([CH:50]=[O:51])[CH2:48][CH2:49]4)=[CH:43][CH:42]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:28][O:29][C:30](=[O:32])[CH3:31])(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2ccc(C3(C=O)CC3)cc2)OC1(C)C
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(CBr)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C4(C=O)CC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 80 °C
Yield: 30.1 %

Procedure:
To a mixture of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.0 g, 1.77 mmol, Intermediate 1), 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropane carbaldehyde (762.0 mg, 2.80 mmol), Pd(dppf)Cl2 (76 mg, 0.09 mmol) and sodium carbonate (591.0 mg, 5.58 mmol) under nitrogen atmosphere, was added DMF and H2O (9 mL, 1:1). The reaction mixture was heated at 80° C. for 1 h. After the completion of the reaction as confirmed by TLC, the solution was cooled to r.t and filtered through celite. The solvent was concentrated in vacuo. The crude compound was diluted with ethyl acetate (100 mL). The organic layer was washed with water (3×10 mL), dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by column chromatography (silica gel, 1:4 EtOAc:Pet ether) to afford the title compound (320 mg, 29%) as a white solid
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=O.[CH3:19][S:20][C:21](SC)=[CH:22][N+:23]([O-:25])=[O:24].O>C(O)(=O)C>[Cl:18][C:15]1[CH:14]=[C:4]2[C:3](=[CH:17][CH:16]=1)[N:2]=[C:21]([S:20][CH3:19])[C:22]([N+:23]([O-:25])=[O:24])=[C:5]2[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CSc1nc2ccc(Cl)cc2c(-c2ccccc2Cl)c1[N+](=O)[O-]
Temperature: 25 °C
Yield: 85.2 %

Procedure:
A solution of 2-amino-2',5-dichlorobenzophenone hydrochloride (1.6 g, 5.3 mmol) and 1,1-bis(methylthio)-2-nitroethylene (875 mg, 5.3 mmol) in 12 ml acetic acid was heated at 120° C. overnight. The reaction mixture was cooled to room temperature, 30 ml of water was added and the resulting mixture was extracted with 2×60 ml ethyl acetate. The ethyl acetate extracts were washed with 2×50 ml water, 2×50 ml saturated sodium bicarbonate solution and 50 ml brine, and then dried (anhydrous sodium sulfate), filtered and concentrated in vacuo. The residue was chromatographed on silica gel (440 g, 230-400 mesh), eluting with 85:15 hexane/ethyl acetate to yield the title compound as a yellow solid (1.65 g, 72% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[N:11]=[C:10]([O:25]C)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[NH4+].[OH-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]([C:20]4[CH:24]=[CH:23][O:22][CH:21]=4)=[O:19])[CH:16]=3)[NH:11][C:10](=[O:25])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)c2cc(C(=O)c3ccoc3)ccc2n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(c1ccoc1)c1ccc2[nH]c(=O)cc(-c3cccc(Cl)c3)c2c1
Temperature: 0 °C
Yield: 98.7 %

Procedure:
A mixture of (intermediate 25) (0.0434 mol) in THF (160 ml) and HCl 3N (160 ml) was stirred and refluxed overnight. The mixture was poured out into ice water and alkalized with a concentrated NH4OH solution. The precipitate was filtered off, washed with water and dried, yielding 15 g (98.7%) of 4-(3-chlorophenyl)-6-(3-furanylcarbonyl)-2(1H)-quinolinone (intermediate 26), melting point >250° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1.C(=O)(O)[O-].[Na+]>C(O)C>[N+:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:15]#[N:16])=[C:2]2[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1)([O-:14])=[O:13]
Reactant: Cc1cccc(N)c1
Reactant: N#Cc1cnc2ccc([N+](=O)[O-])cc2c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Nc2c(C#N)cnc3ccc([N+](=O)[O-])cc23)c1
Yield: 73.7 %

Procedure:
A mixture of 5.00 g (21.5 mmol) 4-chloro-6-nitro-3-quinolinecarbonitrile, 200 ml ethanol, and 2.75 ml (25.7 mmol) 3-toluidine was heated to reflux for 4.5 hours. Cooled and added a saturated sodium bicarbonate until pH was basic. Stripped solvents and azeotroped with ethanol. Slurried with hexane, collected, and air dried. Washed with water and dried in vacuo. Boiled in ethyl acetate, stirred with Darco and filtered. Stripped solvent and dried in vacuo to give 4.82 g of yellow-orange solid: mass spectrum (electrospray m/e): M+H=305.2.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.[H-].[Na+].Br.Br[CH2:27][C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1.C(#N)C>CN(C=O)C.O>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([S:10][C:6]3[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=3)[C:3]([OH:2])=[O:22])=[C:12]([CH3:21])[N:13]2[CH2:27][C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)=[CH:18][CH:17]=1
Reactant: BrCc1ccncc1
Reactant: COC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: Cc1c(Sc2cccc(C(=O)O)c2)c2ccc(Cl)cc2n1Cc1ccncc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-(6-Chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid methyl ester (0.050 g, 0.15 mmol) was dissolved in DMF (4 mL), cooled to ° C., and sodium hydride (60% dispersion in mineral oil, 0.015 g, 0.375 mmol) was added. After 15 minutes, 4-(bromomethyl)pyridine hydrobromide (0.057 g, 0.225 mmol) was added and the reaction stirred at room temperature for 70 minutes. The reaction was then heated to 50° C. for 2 hours then submitted to standard aqueous workup. Preparatory HPLC (10-100% ACN in H2O) afforded the title compound as a minor component.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Br.Br[CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>C(O)C>[C:3]([NH:6][C:7]([CH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: BrCc1ccncc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccncc1)(NC(C)=O)C(=O)OCC
Temperature: 20 °C
Yield: 82.9 %

Procedure:
To 750 mL of ethanol, about 9 g of sodium hydroxide is added dropwise, while stirring under an inert atmosphere. After the addition of sodium hydroxide, the temperature of reaction mixture is maintained at about 20° C., and 42 g of diethyl acetamidomalonate is slowly added then the mixture is stirred at a temperature of about 20° C. for 1 hour and 30 minutes. A suspension of 61.5 g of 4-bromomethyl-pyridine hydrobromide in 250 mL of ethanol is then quickly added and the resulting suspension is stirred at a temperature of about 20° C. for 18 hours. The reaction medium is then concentrated under reduced pressure (2 kPa) at a temperature of about 40° C. The residue is taken up in 200 mL of distilled water and is neutralized with 1N aqueous hydrochloric acid until the pH is equal to 7. The obtained suspension is cooled at a temperature of about 0° C., filtered and the insoluble material is washed with 2 times 50 mL of ice-cold water, then dried in an oven under reduced pressure (10 kPa) at a temperature of about 40° C. for 18 hours. Thus 49.4 g of diethyl 2-(acetylamino)-2-(4-pyridinylmethyl)malonate is obtained in the form of a white-pinkish solid. [Infrared spectrum CH2Cl2: 3409; 2895; 1741; 1681; 1603; 1496; 1302; 1198; 1057; 855; 557 and 524 cm−1].
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][N:10]1[C:14]([C:15]2[CH:16]=[C:17]([NH:29]C(=O)C)[CH:18]=[CH:19][C:20]=2[O:21][CH2:22][C:23]([CH3:28])([N+:25]([O-:27])=[O:26])[CH3:24])=[CH:13][CH:12]=[N:11]1.[OH-].[Na+].O>CO>[Br:1][C:13]1[CH:12]=[N:11][N:10]([CH3:9])[C:14]=1[C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[O:21][CH2:22][C:23]([CH3:28])([N+:25]([O-:27])=[O:26])[CH3:24])[NH2:29]
Reactant: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1ncc(Br)c1-c1cc(N)ccc1OCC(C)(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61 %

Procedure:
N-Bromosuccinimide (0.931 g, 5.23 mmol) was added to a suspension of N-(3-(2-Methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-nitropropoxy)phenyl)acetamide (1.58 g, 4.75 mmol) in 10 mL of methanol, and the mixture was stirred at room temperature. A clear solution was obtained within minutes. After 20 min, a solution of sodium hydroxide (1.14 g, 28.5 mmol) in water (1.00 mL, 55.5 mmol) was added, and the solution was heated to 160° C. for 0.5 hr under microwave irradiation in a heavy walled sealed tube. The solvent was evaporated under reduced pressure, and the residue was taken up in saturated sodium bicarbonate and extracted twice with dichloromethane. The extracts were combined, dried with sodium sulfate, filtered, and evaporated to dryness. The crude product was purified by flash chromatography (ethyl acetate-hexanes 1:2, then 1:1) to afford the title compound as an off-white solid (1.07 g, 61%). LCMS m/z (%)=371.0 (M+H 81Br 36%), 369.1 (M+H 79Br 30%). 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 3H), 1.50 (s, 3H), 3.63 (s, 3H), 3.81 (d, J=9.85 Hz, 1H), 4.34 (d, J=9.85 Hz, 1H), 6.72 (d, J=1.52 Hz, 1H), 6.87-6.93 (m, 2H), 7.51 (s, 1H).
Reaction SMILES: [C:1]([CH:5]1[C:11](=[O:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2].[BH4-].[Na+].[ClH:17]>CO.C(O)C>[ClH:17].[C:1]([CH:5]1[CH:11]([OH:12])[CH2:10][C@H:9]2[N:13]([CH3:14])[CH:6]1[CH2:7][CH2:8]2)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)C1C(=O)C[C@@H]2CCC1N2C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: COC(=O)C1C(O)C[C@@H]2CCC1N2C
Reaction time: 4 h

Procedure:
To a solution of (1RS,2RS)-2-carbomethoxy-3-tropanone (17 g, 85 mmol) in 750 ml methanol cooled to -35° C. was added sodium borohydride (17 g, 450 mmol) and the mixture was stirred for 4 hours, The cooled solution was quenched by slow addition of concentrated hydrochloric acid (40 ml) and the mixture was concentrated in vacuo. Water (400 ml) was added and the pH was adjusted to 3 by addition of concentrated hydrochloric acid. After having washed the water phase three times with diethyl ether pH was adjusted to 11 by addition of concentrated ammonium hydroxide and the water phase was extracted three times with methylene chloride. Concentration in vacuo yields an oil which was dissolved in ethanol and added concentrated hydrochloric acid followed by concentration in vacuo. Freeze drying the residue yielded the title compound as an amorphous product.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]#[N:13])[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[CH2:15][CH:16]1[CH2:20][CH2:19][CH2:18][O:17]1>C1(C)C=CC=CC=1>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][C:9]([CH2:15][CH:16]2[CH2:20][CH2:19][CH2:18][O:17]2)([C:12]#[N:13])[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(C#N)CC1
Reactant: BrCC1CCCO1
Solvent: Cc1ccccc1
Product: CCS(=O)(=O)N1CCC(C#N)(CC2CCCO2)CC1
Reaction time: 12 h

Procedure:
In a dry round bottom flask was placed 1-(ethylsulfonyl)-4-ethynylpiperidine (14) (6.7 g, 33.1 mmol) and anhydrous toluene (200 ml). To this was added 2-(bromomethyl)tetrahydrofuran (6.51 ml, 49.7 mmol). Solid KHMDS1.2 equiv (7.93 g, 39.7 mmol) was added in one portion at room temperature and an exotherm was observed. The solution was allowed to stir for 12 hours at which time it was quenched with saturated aq. NH4Cl solution (100 ml). To the mixture was added EtOAc (50 ml) and the solution was then extracted by dilution with 250 ml, water and 3 washes with EtOAc (75 ml each). The organic layer was washed with brine (200 ml) and dried over MgSO4. The organic solvent was removed in vacuo to give a yellow solid. The residue was purified by column chromatography on silica gel, eluting with EtOAc/Hexanes to give 1-(ethylsulfonyl)-4-(tetrahydrofuran-2-ylmethyl)piperidine-4-carbonitrile (15) as a off-white solid. MS 287 (M+1)
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN1CCCC1=O>N>[CH3:12][N:11]([CH2:10][CH2:9][C:8]1[C:14]2[C:5](=[CH:4][CH:3]=[C:2]([C:17]#[N:18])[CH:15]=2)[NH:6][CH:7]=1)[CH3:13]
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Reactant: N#C[Cu]
Agent: N
Solvent: CN1CCCC1=O
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 200 °C

Procedure:
A flask is charged with 5-bromo-dimethyltryptamin (5.34 g, 20 mmol), copper (I)cyanide (2.69 g, 30 mmol), and N-Methylpyrrolidone (20 ml). The mixture is heated at 200° C. for 9 hours under a nitrogen atmosphere and then left stirring over night. The brown mixture is poured on water to give a brown precipitate. This is suspended in ammonia (100 ml 25% solution in water), and the mixture is stirred over night. Extraction with TBME (3*100 ml), and removal of the solvent from the dried (sodium sulfate) organic layer gives the title product as a yellow solid (properties as in Reference Example 3).
Reaction SMILES: [C:1]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[CH2:18][OH:19])=[CH:12][CH:11]=1.N1C=CN=C1>ClCCl.Cl>[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[CH:16]=[CH:17]/[CH2:18][O:19][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6])=[CH:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC/C=C/c1ccc(Br)cc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC/C=C/c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.4 %

Procedure:
tert-Butyl chlorodimethylsilane (1.33 g, 19.5 mmol) was added to a stirred solution of (E)-3-(4-bromo-phenyl)-prop-2-en-1-ol (3.20 g, 15.0 mmol), and imidazole (2.72 g, 18.0 mmol) in dry dichloromethane (75 ml) and the resulting mixture stirred at room temperature for 18 h, a colourless precipitate being formed. The mixture was diluted with dichloromethane (100 ml) and 1N hydrochloric acid (100 ml). The aqueous layer was separated, further extracted with dichloromethane (2×100 ml) and the combined organic layers washed with brine, dried (MgSO4) and evaporated. The product was purified by column chromatography on silica gel (1% diethyl ether in n-heptane eluent) to give the colourless solid, (E)-[3-(4-bromo-phenyl)-allyloxy]-tert-butyldimethylsilane (4.39 g, 89%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:36])[CH3:35])=[CH:29][N:28]=2)=[C:21]([CH3:37])[N:20]=1)([O-])=O>>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:34]([CH3:35])[CH3:36])=[CH:29][N:28]=3)=[C:21]([CH3:37])[N:20]=2)=[CH:7][CH:6]=1)[CH3:1]
Reactant: Cc1nc(N[N+](=O)[O-])[nH]c(=O)c1Cc1ccc(CN(C)C)cn1
Reactant: CN(C)Cc1ccc(CSCCN)o1
Product: Cc1nc(NCCSCc2ccc(CN(C)C)o2)[nH]c(=O)c1Cc1ccc(CN(C)C)cn1

Procedure:
Reaction of 2-(5-dimethylaminomethyl-2-furanylmethylthio)ethyl amine with 2-nitroamino-5-(5-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone gives 2-[2-(5-dimethylaminomethyl-2-furanylmethylthio)ethylamino]-5-(5-dimethylaminomethyl-2-pyridylmethyl)-6-methyl-4-pyrimidone.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[C:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:33][CH:32]=[CH:31]3)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[C:34]([C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:33][CH:32]=[CH:31]4)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Reactant: CCOC(=O)c1cccc2cc(-c3ccc(O)cc3)ccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc12
Temperature: 80 °C
Yield: 55.8 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.110 g, 0.35 mmol) (from multiple batches), ethyl 6-(4-hydroxyphenyl)-1-naphthalenecarboxylate (0.102 g, 0.35 mmol), triphenylphosphine (0.092 g, 0.35 mmol) and diisopropyl azodicarboxylate (0.063 mL, 0.35 mmol) in toluene (3.5 mL) was placed in microwave reaction tube and heated to 80° C. for 1000 seconds. The solution was concentrated and purified by chromatography (silica gel, hexane to 1:4 ethyl acetate:hexanes) to provide the title compound (0.115 g, 51.6% as 0.7EtOAc). 1H NMR (DMSO-d6): δ 8.79 (d, J=9 Hz, 1H), 8.28 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.09 (d, J=7 Hz, 1H), 7.98 (dd, J=2, 9 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.60 (m, 1H), 7.42 (d, J=8 Hz, 2H), 7.25 (t, J=8 Hz, 1H), 7.14 (d, J=8 Hz, 2H), 4.98 (s, 2H), 4.40 (q, J=7 Hz, 2H), 3.35 (septet, J=7 Hz, overlapping H2O, 1H), 3.24-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.37 (t, J=7 Hz, 3H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 588 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[C:11]=[O:12]>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:11]([NH:10][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:21])[F:22])[CH:14]=2)=[O:12])=[C:4]([F:9])[CH:3]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Br)cc1F
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (3.0 g, 15.8 mmol) in THF (15 mL) was added 1-isocyanato-3-(trifluoromethyl)benzene (3.55 g, 18.9 mmol). The reaction was stirred at room temperature overnight. Solid product was present in the reaction vessel. Product was further precipitated by the addition of 1:2 ether/hexanes. The solids were collected by filtration, dried under hi vacuum and found to be clean title compound in 60% yield. 1H-NMR (DMSO-d6) δ 9.44 (s, 1H), 8.76 (d, J=1.2 Hz, 1H), 8.12 (t, J=8.7, 1H), 8.05 (s, 1H), 7.64-7.37 (m, 5H); MS [M+H]+=378.9, LCMS RT=3.92 min.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Cl[CH2:15][C:16]([CH3:18])=[CH2:17]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:17][C:16]([CH3:18])=[CH2:15])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C=C(C)CCl
Product: C=C(C)Cn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as a pale yellow oil in 86.2% yeild in a similar procedure to that described in Referential Example 9 by using but using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-chloro-2-methyl-1-propene.
Reaction SMILES: C(O)C.[OH-].[K+].[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[C:22]([Br:39])[N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([O:36]CC)=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]>O>[CH2:6]([C:10]1[N:11]([CH2:18][C:19]2[CH:27]=[CH:26][C:25]3[C:21](=[C:22]([Br:39])[N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([OH:36])=[O:35])[N:24]=3)[CH:20]=2)[C:12]([CH:16]=[O:17])=[C:13]([Cl:15])[N:14]=1)[CH2:7][CH2:8][CH3:9]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)OCC)c(Br)c2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc2nn(-c3ccccc3C(=O)O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
Ethanol (1.2 ml ), ion-exchanged water (0.3 ml ), and potassium hydroxide (28 mg) were added to 2-butyl4-chloro-1-[3-bromo-2- (2-ethoxycarbonylphenyl)-2H-indazol-5-yl]methyl-1 H-imidazole-5-carbaldehyde (101 mg, 0.186 mmol) as obtained in Example 1, and the mixture was stirred at room temperature for one day. The mixture was concentrated in an evaporator, and partitioned by ion-exchanged water (2.5 ml) and diethyl ether (5 ml). The water layer was separated and conc. hydrochloric acid was dropwise added thereto to adjust its pH to 5. The resultant solid was filtered off and washed three times with ion-exchanged water (1 ml). The solid was dried in vacuo overnight at 37° C. to give 72 mg of 2-butyl-4-chloro-1-[3-bromo-2-(2-carboxyphenyl)-2H-indazol-5-yl]methyl-1H-imidazole-5-carbaldehyde.