Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]3[CH:22]=[N:23][NH:24][CH:25]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][CH:5]=1.Cl[CH2:27][CH2:28][N:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:21]3[CH:22]=[N:23][N:24]([CH2:27][CH2:28][N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:25]=3)=[N:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])=[CH:6][CH:5]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2cn[nH]c2)c2ccc(Br)cc21
Reactant: ClCCN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1nc(-c2cnn(CCN3CCCC3)c2)c2ccc(Br)cc21
Reaction time: 0.33 h

Procedure:
Sodium hydride (17.46 mg, 0.437 mmol) was added in a single portion to a solution of 6-bromo-3-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (101 mg, 0.257 mmol) (prepared by substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in Example 1C) in DMF (10 ml) at room temperature under argon. The resulting bubbling solution was stirred for 20 minutes, then treated with 1-(2-chloroethyl)pyrrolidine (51.5 mg, 0.385 mmol) which was dissolved in 0.5 ml DMF and added dropwise via pipette. The resulting mixture was stirred at 70° C. for 3 hours, allowed to cool, and partitioned between ethyl acetate and water. The organic extract was washed with brine, dried with MgSO4, and filtered. The filtrate was concentrated and the residue was purified via silica gel chromatography eluting with 3 to 5% CH2Cl2/CH3OH to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[F:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)COc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCOc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Ethyl 2-(4-fluorophenoxy)acetate (3.12 g, 15.74 mmol) was dissolved in diethyl ether (50 ml) and cooled to about 0° C. Lithium aluminum hydride (1.792 g, 47.2 mmol) was added in portions while maintaining reaction temperature below 35° C. The reaction was allowed to stir at room temperature for one hour. The crude reaction was diluted with ether (50 mL) then cooled in an ice bath and quenched by dropwise addition of water (6.1 mL), then 2 M NaOH (12.2 mL), then water (6.1 mL). The mixture was filtered and concentrated. The crude product was purified on silica gel (4:1 heptane:EtOAc as eluant) to give 2-(4-fluoro-phenoxy)-ethanol (1.36 g, 55%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:31]1[CH2:30][CH2:29][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=3)[CH2:33][CH2:32]1)=[O:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2cc(Cl)ccc2nc1OC
Reactant: COc1cccc(N2CCNCC2)c1
Product: COc1cccc(N2CCN(C(=O)Nc3nc4cc(Cl)ccc4nc3OC)CC2)c1
Yield: 70 %

Procedure:
Ethyl N-(6-chloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methoxyphenyl)piperazine were reacted by the same way with the example 22 to obtain the titled compound (yield, 70%). 1H NMR (300 MHz, CDCl3): δ 3.22-3.30 (m, 4H), 3.76-3.80 (m, 6H), 4.08-4.14 (m, 4H), 6.46-6.57 (m, 3H), 7.20 (t, J=8.1 Hz, 1H), 7.34-7.44 (m, 1H), 7.50-7.67 (m, 1H), 7.80 (s, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[S:15]([O-:18])([O-:17])=[O:16].[Na+:19].[Na+].O>CO>[Na+:19].[C:6]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]([CH2:2][S:15]([O-:18])(=[O:17])=[O:16])=[CH:4][CH:5]=1
Reactant: BrCc1ccc(-c2ccccc2)cc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=S(=O)([O-])Cc1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Reaction time: 12 h
Yield: 50.4 %

Procedure:
A mixture of 28.69 g of 4-bromomethylbiphenyl and 29.27 g of sodium sulfite in 200 ml of a mixture of water and methanol (1:1) was stirred at 60° C. for 12 hours. After cooling to room temperature, the solvent was removed under reduced pressure and the aqueous residue was extracted twice with 100 ml of ethyl acetate. The aqueous phase was concentrated by rotary evaporation and the solid residue was stirred with 200 ml of isopropanol for 1 hour. After filtration to remove the solid constituents, the filtrate was concentrated by rotary evaporation. This gave the product (15.80 g) with a molecular weight of 270.3 g/mol (C13H11O3S.Na).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([NH:22][NH2:23])=[O:21])=[CH:18][CH:17]=1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:23][NH:22][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([O:15][C:14]([F:13])([F:27])[F:26])=[CH:25][CH:24]=1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: NNC(=O)c1ccc(OC(F)(F)F)cc1
Solvent: CC(=O)O
Product: O=C1Nc2ccc(I)cc2C1=NNC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Yield: 57 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3dione in acetic acid was added 4-(trifluoromethoxy)benzohydrazide. After stirring at 100° C., the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 135 mg of the title compound (57%) as a yellow solid in 99.7% purity by HPLC (Rt: 6.39, gradient of 10 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])[C:5]#[N:6].[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][C:26](O)=O)=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:18][CH:19]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:26]1[CH2:25][C:24]1[N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[N:21]=[CH:22][CH:23]=1)[CH3:12]
Reactant: O=C(O)Cc1ccnn1-c1cccc(F)c1
Reactant: CCNc1ccc(C#N)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirring solution of 3-amino-4-ethylaminobenzonitrile (887 mg, 5.5 mmol) and 1-(3-Fluorophenyl)-5-carboxymethylpyrazole (1.10 g, 5 mmol) in pyridine (5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol). The mixture is stirred at room temperature for 17.5 h, then concentrated. The residue is cooled in an ice bath, aqueous HCl is added with stirring, the precipitate is collected by filtration, rinsed well with water and dried. The solid is added to acetic acid (75 mL) and heated at reflux for 5.5 h. The mixture is cooled, concentrated, and purified by silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole. The product is converted to the mesylate salt in acetone. 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.89 (d, J=8.52 Hz, 1H), 7.68-7.75 (m 1H), 7.44-7.54 (m, 2H), 7.37-7.40 (m, 1H), 7.21-7.28 (m, 1H), 6.35 (d, J=1.65 Hz, 1H) 4.65 (s, 2H), 4.29 (q, J=7.14 Hz, 2H), 2.34 (s, 3H), 1.19 (t, J=7.14 Hz, 3H). LCMS 346.0 (MH+), 344.4 (MH−).
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[CH3:16][O:17][C:18]([C:20]1[C:21]2[CH:22]=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19].C([O-])(=O)C.[Na+]>C(Cl)CCl>[CH3:16][O:17][C:18]([C:20]1[C:21]2[C:22]([CH:9]=[O:10])=[CH:23][NH:24][C:25]=2[CH:26]=[CH:27][CH:28]=1)=[O:19]
Reactant: CN(C=O)c1ccccc1
Reactant: COC(=O)c1cccc2[nH]ccc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cccc2[nH]cc(C=O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of N-methylformanilide (15.6 g) and phosphorus oxychloride (17.7 g) is added ethylene dichloride (75 g ) followed by 4-indolecarboxylic acid methyl ester (17.5 g). The reaction mixture is stirred at room temperature for 1 1/2 hr., then at 45°-50°C for 30 minutes more. The mixture is now poured into a solution of 75 g of sodium acetate in 150 ml of ice-water. More ethylene dichloride is added. The layers are separated and the organic phase is washed with water, dried (Na2SO4) and evaporated under reduced pressure. The residual brown oil is passed through a silica gel column using 3% methanol in chloroform. Concentration of the eluate affords a solid which on recrystallization from benzene affords the pure title compound, mp 135°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15](Br)[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[I-:19].[Na+]>[Cu]I>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[O:13])[C:11]3[CH:14]=[C:15]([I:19])[CH:16]=[CH:17][C:10]=3[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1
Reactant: [I-]
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: [Cu]I
Agent: [Na+]
Product: O=c1c2cc(I)ccc2ccc2ncc(Cl)cc12
Reaction time: 24 h

Procedure:
A sealed tube was charged with 3-chloro-7-bromo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.0 g, 3.1 mmol), CuI (59 mg, 0.31 mmol), and sodium iodide (0.94 g, 6.2 mmol). The tube was evacuated and backfilled with argon three times. Fully degassed dioxane (8 mL) was added. The tube was sealed, placed in an oil bath at 110° C., and stirred rapidly for 24 hours. Upon completion, the reaction mixture was cooled and quenched via the addition of 20 mL of a 30% aqueous ammonia solution, poured into 80 mL of water, and extracted three times with 150mL dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via flash chromatography (silica, 0-100% ethyl acetate/hexanes) to afford the title compound. 1H NMR (600 MHz, d6-DMSO) δ 8.99 (d, 1H), 8.43 (d, 1H), 8.39 (d, 1H), 8.16 (dd, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 7.32 (d, 1H). LRMS (APCI) calc'd for (C14H8ClINO) [M+H]+, 367.9; found 367.9.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:8]2[C:9]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=3)=[N:10][CH2:11][C:12]([NH:14][NH2:15])=[N:13][C:7]=2[CH:6]=[C:5]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[CH:4]=1.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=O.C([O-])(=O)C.[Na+]>>[Cl:33][CH:34]([Cl:38])[C:35]1[N:13]2[C:7]3[CH:6]=[C:5]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:26])=[O:27])[CH:4]=[C:3]([C:2]([F:31])([F:1])[F:32])[C:8]=3[C:9]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH2:23][CH3:24])=[CH:20][CH:21]=3)=[N:10][CH2:11][C:12]2=[N:14][N:15]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCCS(=O)(=O)c1cc2c(c(C(F)(F)F)c1)C(c1ccc(OCC)cc1)=NCC(NN)=N2
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCCS(=O)(=O)c1cc2c(c(C(F)(F)F)c1)C(c1ccc(OCC)cc1)=NCc1nnc(C(Cl)Cl)n1-2

Procedure:
In the manner given in Example 1, 6-trifluoromethyl-8-propylsulfonyl-5-(p-ethoxyphenyl)-3H-1,4-benzodiazepin-2-yl hydrazine was reacted with dichloroacetyl chloride and after 1.5 hours with sodium acetate, then refluxed to give 1-(dichloromethyl)-7-trifluoromethyl-9-propylsulfonyl-6-(p-ethoxyphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[N:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Reactant: O=Cc1ccc(F)cc1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(N=Cc2ccc(F)cc2)cc1

Procedure:
A mixture of 19.60 g (115 mmol) of 4-methylsulfonylaniline, 12.19 mL (115 mmol) of 4-fluorobenzaldehyde and 590 mL of toluene was refluxed in a Dean-Stark for 2 days. The solvent was removed and the crude product obtained was directly used in the next reaction.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][CH:13]([P:21]([OH:23])[OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>[OH-].[Na+].O.O1CCOCC1>[CH2:5]([O:4][C:2]([NH:12][CH:13]([P:21]([OH:23])[OH:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC(Cc1ccccc1)P(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NC(Cc1ccccc1)P(O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
2.25 ml (14.25 mmol) of benzyl chloroformate are added dropwise, at 0° C. and within the space of 30 min., to a suspension of 1.76 g (9.5 mmol) of 1-amino-2-phenylethylphosponous acid in 15 ml of 1M NaOH, 5 ml of water and 5 ml of dioxane. During a further 2.5 h of stirring at 0° C., the pH of the mixture is maintained at 9-10 using 1M NaOH (approximately 10 ml). After removing the cooling medium, the mixture is stirred at RT overnight. The reaction solution is then washed several times with diethyl ether. The aqueous phase is adjusted to pH 2, at 0°-5° C., using 6M HCl and extracted several times with ethyl acetate. The combined extracts are washed with a saturated solution of NaCl, dried with Na2SO4, filtered and subjected to rotary evaporation i.V. A solid residue remains which is recrystallized from ether/petroleum ether.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[O:6][CH2:7][C:8]#[N:9].[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([O-:29])=[CH:27][CH:26]=1.[Na+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[CH2:23][O:24][C:25]1[CH:31]=[CH:30][C:28]([O:29][CH2:2][C:3]2[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=2)[O:6][CH2:7][C:8]#[N:9])=[CH:27][CH:26]=1
Reactant: N#CCOc1cccc(CCl)c1
Reactant: [O-]c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCOc1cccc(COc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of α-(3-chloromethylphenoxy)acetonitrile (0.025 mol), sodium 4-(2-quinolinylmethyloxy)phenoxide (0.025 mol) and anhydrous potassium carbonate (0.125 mol) in dimethylsulfoxide (50 ml) is stirred at ambient temperature for 18 hrs. The reaction is diluted with water (600 ml) and extracted with ethylacetate (3×150 ml). The ethyl acetate solution is washed with water (3×100 ml) and brine (100 ml) then dried and evaporated to give α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile. (M.P. 110°-114° C.)
Reaction SMILES: C(O)=O.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[NH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17].C[O-].[Na+].Br[CH2:22][C:23](=[O:39])[CH2:24][C@H:25]1[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]1[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34]>CO>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=[O:15])[N:10]([CH2:22][C:23](=[O:39])[CH2:24][C@H:25]3[C@H:30]([O:31][CH3:32])[CH2:29][CH2:28][CH2:27][N:26]3[C:33]([O:35][CH2:36][CH:37]=[CH2:38])=[O:34])[CH:11]=[N:12]2)=[CH:7][C:6]=1[S:16][CH3:17]
Reactant: CSc1cc2c(=O)[nH]cnc2cc1Br
Reactant: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)CBr
Agent: C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: CO
Product: C=CCOC(=O)N1CCC[C@@H](OC)[C@@H]1CC(=O)Cn1cnc2cc(Br)c(SC)cc2c1=O

Procedure:
Under a nitrogen atmosphere in a flame dried flask at room temperature and with magnetic stirring, a suspension of 0.43 g (0.00136 mol) of 7-bromo-6-methylthioquinazolin-4(3H)-one formic acid salt in 5 ml of methanol was treated with two equivalents of sodium methoxide in methanol (approximately 1N). After 15 minutes 0.53 g (0.0016 mol) of allyl trans-2-(3-bromo-2-oxopropyl)-3-methoxy-1-piperidinecarboxylate was added in one portion. After being stirred for an hour, the reaction mixture was evaporated under reduced pressure, and the residue was taken up in about 15 ml of water. The aqueous solution was extracted three times with 15 ml portions of dichloromethane. The combined extracts were dried over anhydrous sodium sulfate, filtered, and evaporated to afford the title compound: yield 0.61 g (86%). 1H-NMR(CDCl3): 1.3-2.0 ppm (multiplet, 4H, CH3OCHCH2CH2CH2N), 2.6 (singlet, 3H, CH3S), 2.8-3.0 (multiplet, 4H, COCH2CH and NCH2), 3.3 (broad singlet, 1H, CH2CHNCO), 3.4 (singlet, 3H CH3O), 4.0 (broad doublet, 1H, CHOCH3), 4.6 (broad doublet 2H, CH2CH=CH2), 4.8-5.1 (multiple peaks, 2H, NCH2CO), 5.2-5.4 (multiplet, 2H, CH2 =CH), 5.9 (octet, 1H, CH=CH2), 7.3 (singlet, 1H, aromatic H), 7.9 (singlet, 1H, aromatic H), 7.95 (singlet, 1H, N=CH--N).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH3:29][O:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([O:30][CH3:29])[CH:32]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: COc1cccc(O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(Oc2cccc(OC)c2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.8 g), 3-methoxyphenol (0.34 g), 8 M potassium hydroxide solution (0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.45 g, 51%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=O)[O:9][CH:8]2OC)([CH3:4])([CH3:3])[CH3:2].O.[NH2:19][NH2:20].O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:11](=[C:12]([F:14])[CH:13]=1)[C:10](=[O:9])[NH:20][N:19]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC1OC(=O)c2c(F)cc(C(C)(C)C)cc21
Reactant: NN
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)[nH]ncc2c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
To a solution of 101g (40 g, 168 mmol) in glacial acetic acid (360 mL) was added hydrazine monohydrate (240 mL) at 0-10° C. under N2 protection. The resulting slurry was stirred under nitrogen at 50° C. for 1.5 hours. The reaction mixture was poured into 300 mL of water with continuous stirring. The aqueous phase was extracted with DCM (2×500 mL), and the combined organic phase was dried over Na2SO4, filtered and concentrated to give a residue, which was purified by re-crystallization in DMC and Et2O to provide 101h (17 g, 37.6% over 2 steps) as an off-white solid. 1HNMR (300 MHz, CDCl3) δ 8.11 (d, J=2.7 Hz, 1H), 7.46 (m, 2H), 1.39 (s, 9H). LCMS (ESI) m/z 221 (M+H)+.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:20])=[O:19]>C1COCC1>[CH3:14][O:13][C:11](=[O:12])[C:10]1[CH:15]=[CH:16][C:7]([C:18]([OH:19])([CH3:20])[CH3:17])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: CC(C)=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)(C)O)cc1
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
6.3 ml of a 2 molar solution of isopropylmagnesium chloride in THF (12 mmol) were added dropwise to a solution of 3 g methyl 4-iodobenzoate (11.5 mmol) in 30 ml THF at a temperature of −20° C. The reaction mixture was stirred for 1.5 h at −20° C., then 1.26 ml acetone (17 mmol) were added and the mixture was allowed to warm to rt. After 30 min at ambient temperature the reaction was quenched with methanol, poured into water and extracted with EtOAc. The combined extracts were washed with brine, dried with magnesium sulfate, filtered and concentrated. Chromatographic purification (silica gel; c-hexane/EtOAc 2:1) of the remaining residue yielded 1.64 g (74%) of 4-(1-hydroxy-1-methyl-ethyl)-benzoic acid methyl ester as a colorless liquid. 1H-NMR (CDCl3, 300 MHz): δ 1.60 (s, 6H), 3.91 (s, 3H), 7.56 (d, J=9 Hz, 1H), 8.01 (d, J=9 Hz, 1H).
Reaction SMILES: F[C:2]1[CH:24]=[CH:23][C:5]([C:6]([C:8]2[N:12]3[C:13]4[C:18]([CH:19]=[CH:20][C:11]3=[C:10]([C:21]#[N:22])[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[O:7])=[CH:4][CH:3]=1.[NH:25]1[CH:29]=[CH:28][CH:27]=[N:26]1>>[C:21]([C:10]1[CH:9]=[C:8]([C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:3][CH:4]=2)[N:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:19]=[CH:20][C:11]=12)#[N:22]
Reactant: N#Cc1cc(C(=O)c2ccc(F)cc2)n2c1ccc1ccccc12
Reactant: c1cn[nH]c1
Product: N#Cc1cc(C(=O)c2ccc(-n3cccn3)cc2)n2c1ccc1ccccc12

Procedure:
The title compound was prepared as described for Example 21, using (4-fluoro-benzoyl)-pyrrolo[1,2-a]quinoline-3-carbonitrile (50 mg, 0.16 mmol) and pyrazole, and yielded 44.9 mg (78%). 1H NMR (CDCl3): 8.19 (m, 2H), 8.07 (m, 2H), 7.93 (m, 2H), 7.85 (dd, J=9.6, 1.8 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 7.71 (m, 2H), 7.58 (m, 2H), 7.44 (s, 1H), 6.56 (t, J=2.1 Hz, 1H).
Reaction SMILES: [CH3:1][C@H:2]1[C:24](=[O:25])[C:23]2[C@H:12]([C@H:13]3[C@@H:21]([CH:22]=2)[C@H:20]2[C@@H:16]([CH2:17][C@@H:18]([O:26][C@@H:27]4[O:32][C@@H:31]([CH3:33])[C@H:30]([O:34][CH3:35])[C@@H:29]([O:36][CH3:37])[C@H:28]4[O:38][CH3:39])[CH2:19]2)[CH:15]=[CH:14]3)[CH2:11][C:9](=[O:10])[O:8][C@@H:7]([CH:40]2[CH2:43][CH2:42][CH2:41]2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:44][C@@H:45]1[O:50][C@H:49]([CH3:51])[C@@H:48]([N:52]([CH3:54])[CH3:53])[CH2:47][CH2:46]1>C1(C)C=CC=CC=1.C(O)C>[CH3:1][C@H:2]1[C:24](=[O:25])[C:23]2[C@H:12]([C@H:13]3[C@@H:21]([CH:22]=2)[C@H:20]2[C@@H:16]([CH2:17][C@@H:18]([O:26][C@@H:27]4[O:32][C@@H:31]([CH3:33])[C@H:30]([O:34][CH3:35])[C@@H:29]([O:36][CH3:37])[C@H:28]4[O:38][CH3:39])[CH2:19]2)[CH2:15][CH2:14]3)[CH2:11][C:9](=[O:10])[O:8][C@@H:7]([CH:40]2[CH2:43][CH2:42][CH2:41]2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[O:44][C@@H:45]1[O:50][C@H:49]([CH3:51])[C@@H:48]([N:52]([CH3:53])[CH3:54])[CH2:47][CH2:46]1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[C@H]2C[C@H]3[C@@H]4C=C5C(=O)[C@H](C)[C@@H](O[C@H]6CC[C@H](N(C)C)[C@@H](C)O6)CCC[C@H](C6CCC6)OC(=O)C[C@H]5[C@@H]4C=C[C@@H]3C2)[C@@H]1OC
Solvent: CCO
Solvent: Cc1ccccc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](O[C@@H]2C[C@H]3CC[C@@H]4[C@@H](C=C5C(=O)[C@H](C)[C@@H](O[C@H]6CC[C@H](N(C)C)[C@@H](C)O6)CCC[C@H](C6CCC6)OC(=O)C[C@H]54)[C@@H]3C2)[C@@H]1OC
Reaction time: 16 h
Yield: 69.1 %

Procedure:
A solution of 21-desethyl-21-cyclobutyl spinosyn A (3.1 mg, 0.004 mmol) in 2 mL of toluene and 0.5 mL of ethanol was purged with a slow stream of nitrogen for 20 minutes, then 2 mg of chlorotris(triphenylphosphine) rhodium was added and the solution hydrogenated at 60° C. and 1 atm. for 16 hours. After cooling and removal of solvent, the residue was chromatographed using a 10 cm×2 cm silica gel column, eluting with 5×25 mL fractions of dichloromethane containing 0%, 2%, 3%, 4%, and 5% MeOH respectively. The product-containing fractions were combined and concentrated to give 2.1 mg of 5,6-dihydro-21-desethyl-21-cyclobutyl spinosyn A. MS M+760.