Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg]Br.[Cl-].[NH4+]>O1CCCC1>[NH2:21][CH:20]([C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]2)=[N:15][CH:16]=1)[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cn2)CC1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(N)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
900 mg of the t-butyl-4-(5-cyanopyridin-2-yl)piperazin-1-carboxylate [140-1] was dissolved in 40 mL of tetrahydrofuran, then 2.5 mL of methylmagnesium bromide (3.0M diethyl ether solution) was added under an ice-cold condition, and stirred at the same temperature for 1 hour. Thereafter, the temperature was increased back to room temperature and stirred overnight. Thereto, a saturated aqueous solution of ammonium chloride was added under an ice-cold condition, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 50 mL of methanol, then 850 mg of sodium boronhydride was added under an ice-cold condition, and the mixture was stirred at the same temperature for 2 hours and a half. The reaction mixture was added with water, and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insolubles were filtered. The filtrate was concentrated under reduced pressure, and the thus obtained residue was purified by silica gel column chromatography, to obtain 950 mg of t-butyl 4-[5-(1-aminoethyl)pyridin-2-yl]piperazin-1-carboxylate [140-2] as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH:4][CH2:13][CH:14]=[O:15]
Reactant: O=CCCl
Reactant: COCc1ccc(C)c(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCc1ccc(C)c(NCC=O)c1
Temperature: 150 °C

Procedure:
2-Methyl-5-methoxymethylaniline (0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150° C. for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[NH:13][N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1.[N+](=[CH2:26])=[N-]>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:15])[N:13]([CH3:26])[N:14]=[C:10]3[CH2:9][CH:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[F:22])[C:6]=2[CH:23]=1
Reactant: C=[N+]=[N-]
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Solvent: ClCCl
Solvent: CO
Product: Cn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1F)=CC2
Reaction time: 3 h

Procedure:
A solution of 2.65 g of 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-1H-s-triazolo[4,3-a][1]benzazepin-1-one in a mixture of 16 ml of methanol and 16 ml of methylene chloride is treated at 0° with 100 ml of ethereal diazomethane solution. After 3 hours, a further 33 ml of diazomethane solution are added and the mixture is left to stand for a further 2 hours. After evaporation of the solution, the residue is chromatographed on 80 g of silica gel while eluting with chloroform/ethanol (99:1). The crude product is recrystallized from ether/hexane. There is obtained 8-chloro-6-(2-fluorophenyl)-2,4-dihydro-2-methyl-1H-s-triazolo[4,3-a][1]benzazepin-1-one of melting point 142°-143°.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[OH:20][C@@H:17]1[CH2:18][CH2:19][N:15]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: O[C@@H]1CCNC1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@@H](O)C2)cc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 91.1 %

Procedure:
To a solution of t-butyl 4-fluorobenzoate (2.17 g, 11.0 mmol) and (R)-(+)-3-pyrrolidinol (1.00 g, 11.5 mmol) in DMSO (8 mL) was added potassium carbonate (1.53 g, 11.0 mmol). The mixture was stirred at 130° C. for 18 h and poured into stirring water (100 mL) while still hot. The resulting beige precipitate was collected by filtration and dried at 120° C. for 1.5 h to afford the title compound (2.64 g, 91% yield). 1H NMR (Acetone-d6) δ (ppm): 7.78 (d, J=9.0 Hz, 2H), 6.54 (d, J=8.8 Hz, 2H), 4.58 (bs, 1H), 4.15 (bs, 1H), 3.55 (dd, J=10.36, 4.7 Hz, 1H), 3.49 (t, J=6.8 Hz, 1H), 3.42 (td, J=9.2, 2.3 Hz, 1H), 3.28 (d, J=10.8 Hz, 1H), 2.21-2.10 (m, 1H), 2.09-2.03 (m, 1H), 1.56 (s, 9H). m/z: 520.3 (MH+).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[C:3]=1[F:23].C([Li])CCC.CN(C)[CH:31]=[O:32].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[F:23][C:3]1[C:4]2[O:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:5]=2[CH:21]=[CH:22][C:2]=1[CH:31]=[O:32]
Reactant: Fc1c(Br)ccc2c1OC(c1ccccc1)(c1ccccc1)O2
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc2c(c1F)OC(c1ccccc1)(c1ccccc1)O2
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
5-Bromo-4-fluoro-2,2-diphenyl-1,3-benzodioxol (17.3 g) are dissolved in 150 ml of tetrahydrofuran, treated at -78° C. with 29.1 ml of a 0.6M solution of n-butyllithium in n-hexane and stirred at -78° C. for 15 minutes. Thereupon, 10 ml of dimethylformamide are added, after stirring for a further 15 minutes the mixture is treated with semi-saturated, aqueous ammonium chloride solution and extracted with ethyl acetate. The organic phase is dried with magnesium sulphate and evaporated. The residue is crystallized from ethanol. After drying there are obtained 12.7 g of 4-fluoro-2,2-diphenyl-1,3-benzodioxol-5-carboxaldehyde as white crystals of m.p. 92°-94° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=1[O-])(=[O:3])[CH3:2].S(OC)(OC)(=O)=O.[C-:20]#[N:21].[K+]>CS(C)=O>[C:1]([NH:4][CH2:5][C:6]1[N:7]=[C:8]([C:20]#[N:21])[CH:9]=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: [C-]#N
Reactant: CC(=O)NCc1cccc[n+]1[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: COS(=O)(=O)OC
Product: CC(=O)NCc1cccc(C#N)n1
Reaction time: 3 h
Yield: 15.2 %

Procedure:
A mixture of 2-acetylaminomethylpyridine N-oxide (1.00 g) and dimethyl sulfate (0.63 ml) was stirred for three hours. Dimethyl sulfoxide (6 ml) and potassium cyanide (392 mg) were added to the mixture and the solution was stirred for two hours at ambient temperature. Additional potassium cyanide (392 mg) was added to the mixture and which was further stirred for two hours. After the solvent was removed by concentration, the residue was mixed with water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (15 g) by eluting with a mixture of ethyl acetate and methanol (20:1) to give 6-acetylaminomethyl-2-pyridinecarbonitrile (0.16 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:20])([F:19])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][NH:13][CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3].[CH3:21][S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:34][C@H:35]([CH3:40])[C:36]([F:39])([F:38])[F:37])=[C:29]([CH:33]=1)[C:30](O)=[O:31])(=[O:24])=[O:23]>>[CH2:2]([O:4][C:5]([C:7]1[C:8]([C:17]([F:19])([F:20])[F:18])=[N:9][C:10]2[CH2:11][CH2:12][N:13]([C:30](=[O:31])[C:29]3[CH:33]=[C:25]([S:22]([CH3:21])(=[O:23])=[O:24])[CH:26]=[CH:27][C:28]=3[O:34][C@H:35]([CH3:40])[C:36]([F:39])([F:37])[F:38])[CH2:14][C:15]=2[CH:16]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCNC2
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: CCOC(=O)c1cc2c(nc1C(F)(F)F)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1O[C@H](C)C(F)(F)F)C2

Procedure:
Prepared in analogy to example 1.1 from 2-trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine-3-carboxylic acid ethyl ester hydrochloride (CA [741736-90-3]; WO2004069162) and 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (example 2.3). MS (m/e): 569.0 (M+H+).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(OCC)(=O)CC(OCC)=O.[O-:31][CH2:32][CH3:33].[Na+]>C(O)C>[O:31]=[C:32]1[O:1][C@H:2]([C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:3][CH2:33]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(=O)CC(=O)OCC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Temperature: 45 °C
Reaction time: 5 h

Procedure:
450 g of tert-Butyl (1S)-1-[(2R)-oxiran-2-yl]-2-phenylethylcarbamate was treated with 1.1 equivalents of diethyl malonate and 1.05 equivalents of sodium ethoxide in 1200 mL of ethanol at 5° C. for 0.5 hr, then at 25° C. for 5 hrs. The reaction mixture was quenched with acetic acid till the pH of the mixture was about 6. The reaction mixture was extracted with ethyl acetate (4 L) and the isolated organic phase was washed sequentially with 25% brine (4 L), 5% NaHCO3 (5L), and 25% brine (4 L), dried over NaSO4, filtered, concentrated and chased with 2 L of methyl tert-butyl ether to dryness. The oil was dissolved in 950 mL of methyl tert-butyl ether and warmed to 45° C., added heptane (4L) and cooled to −5° C. The solid was isolated by filtration to provide tert-butyl(1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate. A mixture of the tert-butyl (1S)-1-[(2S)-5-oxotetrahydrofuran-2-yl]-2-phenylethylcarbamate (400 g, 1.028 mol), the product of Example 111-7 (321 g, 1.08 mol, 1.05 equivalents) in absolute ethanol (3.35 L) was cooled to 5° C. was treated with a solution of sodium ethoxide (77.5 g sodium ethoxide in 0.65 L of absolute ethanol, 1.05 equivalents) over 1 hour. The reaction mixture was stirred at 3° C. for 3 hours. Lithium hydroxide monohydrate (215.6 g, 5.138 mol, 5 equivalents) was added all at once and the temperature rose to 10° C. The mixture was stirred at 10° C. for 2 hours, treated with acetic acid (308.6 gm, 5.138 mol, 5 eq) and stirred at 60° C. for 17 hours. The reaction mixture was treated with distilled water (4 L) over 20 minutes while maintaining the internal temperature >55° C. The slurry was cooled slowly to 14° C. over 2.5 hours, filtered, washed with 1:1 ethanol:water (total volume=2 L), heptanes (2 L) and dried at 55° C. vacuum oven under N2 for 40 hours to give the title compound (451.9 g, 91% yield). 1H NMR (CDCl3): δ 8.65(m, 1H), 7.90(m, 2H), 7.65-7.75 (m, 2H), 7.17-7.30(m, 8H), 4.63(m, 1H), 4.32(m, 1H), 3.95(m, 1H), 3.32(m, 1H), 2.7-3.0(m, 4H), 2.10 (m, 1H), 1.74(m, 1H), 1.36 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[NH:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20].CC(N1CCCC(C(C)=O)=C1)C>>[CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[N:9]([C:19](=[O:20])[C:18]3[CH:22]=[CH:23][CH:24]=[C:16]([O:15][CH3:14])[CH:17]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:12])[CH2:3]1
Reactant: CC1(C)CC(=O)C2=C(C1)NCCC2
Reactant: COc1cccc(C(=O)Cl)c1
Agent: CC(=O)C1=CN(C(C)C)CCC1
Product: COc1cccc(C(=O)N2CCCC3=C2CC(C)(C)CC3=O)c1

Procedure:
7,7-Dimethyl-1,2,3,4,7,8-hexahydro-quinolin5(6H)-one was reacted with 3-methoxybenzoyl chloride according to the procedure of Part (b) of Example 1 to give 7,7-dimethyl-1,2,3,4, 7,8-hexahydro-1-(3-methoxybenzoyl)-quinolin-5(6H)-one (20) as a pale yellow solid.
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:20])[NH:13]2)C1C=CC=CC=1.C(O)CO.COC.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19](=[O:21])[NH2:20])[NH:13]2
Reactant: Cc1cc(OCc2ccccc2)c2cc(C(N)=O)[nH]c2c1
Reactant: [H][H]
Agent: [Pd]
Agent: COC
Solvent: CO
Solvent: OCCO
Product: Cc1cc(O)c2cc(C(N)=O)[nH]c2c1
Yield: 93 %

Procedure:
8.5 g of the thus obtained 4-benzyloxy-2-carbamoyl-6-methyl indole are hydrogenated in a composition of 100 ml methanol and 50 ml ethylene glycol-dimethyl ether during addition of 1.0 g 10% Pd/C up to the absorption of the theoretical amount of hydrogen. The catalyst is aspirated and the filtrate is evaporated in vacuum. There is obtained 5.4 (~93% of theory) 4-hydroxy-2-carbamoyl-6-methyl indole as a light yellow syrup.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9]O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[I-:13].[Cs+].B(F)(F)F.CCOCC>C(#N)C>[C:1]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][I:13])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(CO)cc1
Reactant: [I-]
Agent: FB(F)F
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOCC
Product: CC(=O)Oc1ccc(CI)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 4-acetoxybenzyl alcohol (0.332 g, 2 mmol), and cesium iodide (0.571 g, 2.2 mmol) in anhyd. acetonitrile (10 mL) under nitrogen, boron trifluoride etherate (0.28 mL, 2.2 mmol) in acetonitrile (5 mL) was introduced. After stirring overnight, the reaction mixture was poured into ice-cold water (20 mL) and the solid separated was filtered, washed with water and later with hexanes. The product was dried under high vacuum. Yield, 0.39 g, 71%; TLC, hexanes:EtOAC (4:1). 1H NMR (CDCl3): δ 2.3 (s, 3H), 4.35 (s, 2H), 7.05 (d, 2H), 7.5 (d, 2H).
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][CH:10]=1.O.FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>ClC1C=CC=CC=1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]([C:12]2[CH:13]=[CH:14][C:9]([CH3:18])=[CH:10][CH:11]=2)=[O:16])=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: Clc1ccccc1
Solvent: O
Product: COc1ccc(C(=O)c2ccc(C)cc2)cc1
Yield: 7 %

Procedure:
In like manner to Example 8, anisole and para-toluic acid were reacted together (4 hour reflux) in chlorobenzene in the presence of ytterbium (III) trifluoromethanesulfonate hydrate, to give crude 4-methoxy-4′-methylbenzophenone (0.15 g, 7% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[N:20]1([C:26]2[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(CCCN=C=N)C>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:30](=[O:31])[C:29]3[CH:28]=[CH:27][C:26]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:34][CH:33]=3)[CH:15]=[CH:14][C:13]=2[CH3:19])=[CH:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Reactant: CCOC(=O)c1ccc(-c2cc(N)ccc2C)cc1
Agent: CN(C)CCCN=C=N
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)c3ccc(N4CCOCC4)cc3)ccc2C)cc1
Yield: 88.1 %

Procedure:
5′-Amino-2′-methyl-biphenyl-4-carboxylic acid ethyl ester (2.15 g), 4-morpholin-4-yl benzoic acid (1.27 g), N-methylmorpholine (2.05 ml), 1-hydroxybenzotriazole (826 mg) and 1-ethyl-3-(3-(dimethylaminopropyl)carbodiimide hydrochloride (1.17 g) in dry DMF (30 ml) was stirred at 20 C for 18 h. Then the DMF was evaporated and the residue partitioned between water and dichloromethane. The dried extracts were evaporated and the residue purified on silica gel. Elution with 1-2% methanol in dichloromethane gave a colourless solid (2.4 g)
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12.C(N(C(C)C)C(C)C)C.[C:24]([O:28][C:29]([NH:31][CH2:32][C:33](ON1C(=O)CCC1=O)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C(Cl)Cl>[C:24]([O:28][C:29]([NH:31][CH2:32][C:33]([NH:6][C:7]1[CH:11]=[N:10][N:9]2[CH2:12][CH2:13][NH:14][C:8]=12)=[O:34])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: Nc1cnn2c1NCC2
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)Nc1cnn2c1NCC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 59.5 %

Procedure:
To a solution of 7-amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole sulfuric acid salt (1.42 g) and N-ethyldiisopropylamine (2.73 g) in methylene chloride (50 ml) was added N-[2-(tert-butoxycarbonylamino)acetoxy]succinimide (1.90 g). The mixture was stirred at room temperature for 22 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The oily residue was purified by column chromatography on silica gel eluting with 5% methanol/chloroform to give 7-[2-(tert-butoxycarbonylamino)acetyl]amino-2,3-dihydro-1H-imidazo[1,2-b]pyrazole (1.07 g) as a solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1.[Cl:17]N1C(=O)CCC1=O>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:16])[CH2:8][CH2:7][CH2:6][C:5]2[CH:9]=[C:10]([Cl:17])[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:4]=2[O:3]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)CCCc2cccc(C(=O)O)c2O1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CCCc2cc(Cl)cc(C(=O)O)c2O1
Reaction time: 48 h

Procedure:
To a solution of 3.6 g (16.4 mmol) of 2,2-dimethyl-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid in 20 ml of DMF is added 2.6 g (19.7 mmol) of N-chlorosuccinimide in one portion at room temperature. The resulting solution is stirred for 31/2 days. The reaction mixture is then diluted with ethyl acetate washed with water, and the organic layer is dried (MgSO4), filtered and concentrated to obtain 2,2-dimethyl-7-chloro-2,3,4,5-tetrahydro-1-benzoxepin-9-carboxylic acid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:23][CH2:22][C:21]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:13]=2[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: O=C(OCc1ccccc1)N1CCc2c([nH]c3ccccc23)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2c(n(Cc3ccc(F)cc3)c3ccccc23)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.9 %

Procedure:
To a stirred solution of 2-benzyloxycarbonyl-1,3,4,9-tetrahydro-2H-pyrido[3,4 b]indole (5.0 g, 16.33 mmole) in dry DMF (75 mL) at 5° C. was added 60% NaH (0.98 g, 24.5 mmole). After 10 min, 4-fluorobenzyl bromide 3,40 g, 18.0 mmole) was added and the reaction was allowed to warm to RT and stir for 12 hr. The reaction contents were poured into H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic phases were washed sequentially with H2O and brine, then were dried over Na2SO4. Concentration under reduced pressure and purification on silica (hexanes/EtOAc, 4:1) afforded the title compound (6.42 g, 95%) as a white solid: MS (ES) m/e 415 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1.[C-:12]#[N:13].[Na+].O>CN(C=O)C>[N+:9]([C:5]1[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:8]=[CH:7][CH:6]=1)([O-:11])=[O:10]
Reactant: [C-]#N
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1cccc([N+](=O)[O-])c1
Yield: 43.9 %

Procedure:
A solution of 1-(bromomethyl)-3-nitrobenzene (30 g, 0.139 mol) and NaCN (10.21 g, 0.208 mol) in DMF (150 mL) was stirred at 50° C. for 5 hrs. The mixture was poured into water and extracted with ethyl acetate. The combined organic layer were dried, concentrated and purified by silica-gel column chromatography (PE:EA 20:1˜6:1) to give compound 2-(3-nitrophenyl)acetonitrile (9.9 g, yield 44%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]1([CH3:10])[CH3:9].[O:11]=C1CC(C)(C)CC(C)=C1>>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][O:8][C:4](=[O:11])[C:3]1([CH3:10])[CH3:9]
Reactant: CC1=CC(=O)CC(C)(C)C1
Reactant: CC1CCCC(=O)C1(C)C
Product: CC1CCCOC(=O)C1(C)C

Procedure:
It is further noted that trimethylcyclohexanone can be prepared by a hydrogenation reaction of isophorone, followed by a Baeyer-Villiger reaction with a peracid to obtain trimethylcaprolactone on a commercial basis.
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:12]=2)[C:7](=[O:19])[NH:6][C:5]1=[O:20].[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1>CN(C)C=O>[CH3:21][N:22]1[CH2:23][CH2:24][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH:34]/[CH:3]=[C:4]3\[C:5](=[O:20])[NH:6][C:7](=[O:19])[C:8]4[C:13]\3=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)=[CH:10][CH:9]=4)=[CH:30][CH:29]=2)[CH2:26][CH2:27]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(-n5cccc5)cc43)cc2)CC1
Temperature: 100 °C

Procedure:
A mixture of 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione, (100 mg, 0.3727 mmol), 4-(4-methyl-piperazin-1-yl)-phenylamine (71.3 mg, 0.3727 mmol) in 1 mL of N,N-dimethylformamide is heated at 100° C. for 0.5 h. After the solvent is evaporated, ether is added to the residue. The precipitate is collected, and washed with ether to give 122 mg (77%) of light brown solid mp 239-240° C.; HRMS (ESI) m/z calcd for C25H25N5O2 428.20811. found 428.20865 (M+H)+1, Analysis for C25H25N5O2 (0.6H2O), Calcd: C, 68.51; H, 6.02; N, 15.98. Found: C, 68.67; H, 5.85; N, 15.62.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[F:20][C:21]([F:32])([C:28]([F:31])([F:30])[F:29])[C:22]([F:27])([F:26])[C:23](Cl)=[O:24]>ClCCl>[F:26][C:22]([F:27])([C:21]([F:20])([F:32])[C:28]([F:29])([F:30])[F:31])[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1)=[O:24]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Reactant: Nc1ccc(CCO)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(CCO)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.4 %

Procedure:
To a 0° C. solution of 2-[(4-amino)phenyl]ethanol (25 g), diisopropylethylamine (23.9 g) and dichloromethane (400 mL) was added heptafluorobutyryl chloride (41.8 g) dropwise over 0.5 hour. The mixture was allowed to warm gradually to room temperature and stirred for 2 hours. The precipitate was filtered off and the filtrate was diluted with ethylacetate (100 mL), washed with water (3×500 mL), dried over sodium sulfate, filtered and concentrated with a rotary evaporator. The residue was triturated with dichloromethane and collected by filtration. The combined solids were dissolved in diethyl ether and washed with water and saturated aqueous sodium chloride solutions, dried over sodium sulfate, filtered and concentrated to give 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-hydroxyethyl)phenyl]butanamide as a white solid (39.2 g).