Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[O:5]=[C:6]([CH:8]=[C:9]([CH3:11])[CH3:10])[CH3:7].[CH2:12]=[CH:13][C:14](=[CH2:16])[CH3:15]>C1C=CC=CC=1>[CH3:16][C:14]1[CH2:15][C:9]([CH3:11])([CH3:10])[CH:8]([C:6](=[O:5])[CH3:7])[CH2:12][CH:13]=1
Reactant: CC(=O)C=C(C)C
Reactant: C=CC(=C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: CC(=O)C1CC=C(C)CC1(C)C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A flask is charged with 63 g of aluminium chloride and 2160 ml of anhydrous benzene. The apparatus is filled with nitrogen and 441 g of mesityl oxide are added, whilst stirring and maintaining the temperature of the mixture at +15°. The mixture is then left for 30 minutes at this temperature, whilst stirring. 1224 g of isoprene dissolved in 1800 ml of anhydrous benzene are then added in the course of 1 hour at +15°. Reaction is then effected for 20 hours at 16° followed by 6 hours at +25°, with stirring. The contents of the flask are then transferred to a separating funnel and the product is washed twice with 500 ml of 10% hydrochloric acid, once with 500 ml of water, once with 500 ml of a 9% solution of sodium bicarbonate and twice with 500 ml of water. The benzene is distilled off on a water bath, finally, under a pressure of 30 mm of mercury. 1070 g of crude product are obtained, which are purified in a Vigreux flask under a pressure of 1 mm of mercury. 560 g of 1,5,5-trimethyl-4-acetyl-cyclohex-1-ene (76.3%) are obtained, having the following physical properties:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([O:6][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:5]
Reactant: BrCc1ccccc1
Reactant: CC(C)(CO)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a suspension of hydroxypivalic acid (3 g) and potassium carbonate (3.9 g) in N,N-dimethylformamide (25 mL) was added benzyl bromide (2.9 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (4.7 g).
Reaction SMILES: [NH2:1][C:2]1[C:6]([Br:7])=[CH:5][NH:4][N:3]=1.CN(C)[CH:10]=[C:11]([CH3:14])[CH:12]=O.C(O)C>C(O)(=O)C>[Br:7][C:6]1[CH:5]=[N:4][N:3]2[CH:12]=[C:11]([CH3:14])[CH:10]=[N:1][C:2]=12
Reactant: CC(C=O)=CN(C)C
Reactant: Nc1n[nH]cc1Br
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cnc2c(Br)cnn2c1
Yield: 71.6 %

Procedure:
3-Amino-4-bromopyrazole (0.331 g, 2.04 mmol) and 3-(dimethylamino)-2-methyl-2-propenal (0.220 g, 1.94 mmol) were dissolved in acetic acid (6.48 mL) and ethanol (9.72 mL) and the reaction stirred at room temperature for 16 h. Solvents were removed under reduced pressure. The remaining residue was taken up in dichloromethane and purified by column chromatography (20-80% EtOAc/Hex) to give the title compound (0.294 g, 1.39 mmol). LRMS (APCI) calc'd for (C7H6BrN3) [M+H]+, 212.0; found 211.9. 1H NMR (500 MHz, cdcl3) δ 8.44 (s, 2H), 8.04 (s, 1H), 2.40 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][CH2:6]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[CH2:6]2
Reactant: Cc1ccc(CBr)cc1
Reactant: COc1ccc2c(c1)CNC2=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1ccc2c(c1)CN(Cc1ccc(C)cc1)C2=O
Temperature: 70 °C
Reaction time: 4 h
Yield: 22.4 %

Procedure:
5-Methoxy-2,3-dihydroisoindol-1-one (40 mg, 0.25 mmol), Cs2CO3 (239 mg, 0.74 mmol), 1-bromomethyl-4-methylbenzene (68 mg, 0.37 mmol) in acetonitrile (4 mL) was allowed to stir at room temperature for 18 hours and at 70° C. for 4 hours. The reaction was partitioned between ethyl acetate and water and the organic layer was washed with brine and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure and the product was purified by column chromatography (30% EtOAc/Hexanes) to afford a white solid (15 mg). 1H NMR (300 MHz, CDCl3): δ 7.81 (d, 1H), 7.18 (q, 4H), 7.00 (dd, 1H), 6.87 (s, 1H), 4.75 (s, 2H), 4.21 (s, 2H), 3.87 (s, 3H), 2.34 (S, 3H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[N:4]([CH3:6])[CH3:5].[Li]C(C)(C)C.CCCCC.CN([CH:25]=[O:26])C>CCOCC>[CH3:5][N:4]([CH3:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[CH:25]=[O:26]
Reactant: Cc1cccc(Br)c1N(C)C
Reactant: CN(C)C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1cccc(C=O)c1N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Compound 150 (0.17 g, 0.81 mmol) in Et2O (5.0 mL) at −78° C. under Argon atmosphere was added dropwise a solution of 1.7M t-BuLi in pentane (1.0 mL, 1.79 mmol), and the reaction was stirred for 1 h. DMF (0.25 mL, 3.24 mmol) was added, and the cooling bath was removed. After 1h15, the reaction was cooled to 0° C., and saturated NH4Cl was added. The mixture was extracted with EtOAc, washed with brine, dried over MgSO4, and filtered. The solvent was removed, and the residue was purified by silica gel flash chromatography with EtOAc (15%) and hexanes (85%) as eluent to produce Compound 151 as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]#[N:12].[C:13]([O:16][C:17]1[CH:25]=[C:24]([NH:26][C:27]([CH3:29])=[O:28])[C:23]([Cl:30])=[CH:22][C:18]=1[C:19](Cl)=[O:20])(=[O:15])[CH3:14]>C(Cl)(Cl)Cl>[C:11]([CH2:10][NH:9][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([Cl:30])[C:24]([NH:26][C:27]([CH3:29])=[O:28])=[CH:25][C:17]=1[O:16][C:13](=[O:15])[CH3:14])#[N:12]
Reactant: N#CCN
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)Cl)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NCC#N)cc1Cl
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
104 g of triethylamine and 890 cc of chloroform were introduced into a 3 liter balloon flask provided with a sealed agitator, a reflux condenser and a thermometer. The solution obtained was cooled to 5° C. 51 g of amino acetonitrile hydrochloride was then gradually added, with the temperature being maintained at between 5° and 10° C. Thereafter over a period of 30 minutes and at a temperature of between 0° and 5° C., 143 g of 2-acetoxy 4-acetamino 5-chlorobenzoyl chloride in finely divided form was added. A dark-coloured solution resulted, which was agitated, first, for a period of 2 hours at 10° C. and, thereafter, for 2 hours at ambient temperature.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[C:13]([N:14]=1)=[CH:12][CH:11]=[C:10]([O:15][C:16]1[CH:17]=[C:18]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[CH:19]=[CH:20][C:21]=1[CH3:22])[N:9]=2)=[O:4].C(N(CC)CC)C.[CH3:43][N:44]1[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:22][C:21]1[CH:20]=[CH:19][C:18]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:26]=2)=[CH:17][C:16]=1[O:15][C:10]1[N:9]=[C:8]2[S:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:47]3[CH2:48][CH2:49][N:44]([CH3:43])[CH2:45][CH2:46]3)=[N:14][C:13]2=[CH:12][CH:11]=1
Reactant: CN1CCNCC1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CCl)sc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Oc1ccc2nc(NC(=O)CN3CCN(C)CC3)sc2n1
Temperature: 60 °C
Reaction time: 14 h
Yield: 54.7 %

Procedure:
To a solution of N-[3-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]-3-(trifluoromethyl)benzamide (218 mg, 0.419 mmol) in tetrahydrofuran (5 mL) were added triethylamine (117 μL, 0.838 mmol) and 1-methylpiperazine (93.4 μL, 0.838 mmol), and the mixture was stirred at 60° C. for 14 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to basic silica gel column chromatography (ethyl acetate/methanol=100/0→90/10), and precipitated with ethyl acetate to give the title compound (134 mg, 55%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C:5]1([NH2:9])[CH2:8][O:7][CH2:6]1.C(N(CC)CC)C.[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23](Cl)=[O:24])[CH3:19].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:18]([O:20][C:21](=[O:26])[CH2:22][C:23]([NH:9][C:5]1([CH2:4][C:3]([O:2][CH3:1])=[O:10])[CH2:8][O:7][CH2:6]1)=[O:24])[CH3:19]
Reactant: CCOC(=O)CC(=O)Cl
Reactant: COC(=O)CC1(N)COC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)NC1(CC(=O)OC)COC1
Temperature: 25 °C

Procedure:
(3-Amino-oxetan-3-yl)-acetic acid methyl ester (95 mg; 0.655 mmol) dissolved in CH2Cl2 (5 ml) and triethylamine (0.22 ml; 1.6 mmol) are cooled to −5° C. Chlorocarbonyl-acetic acid ethyl ester (0.1 ml; 0.79 mmol) is slowly added under stirring. The reaction mixture is warmed to room temperature, stirred for 20 minutes, poured on a saturated solution of NaHCO3 and extracted with CH2Cl2 three times. The organic phases are combined, dried over Na2SO4, filtered and evaporated to dryness. Chromatography (SiO2; Hexanes/acetone 4:1) yields the title compound as yellow resin. 1H-NMR (400 MHz; DMSO-d6): 8.93 (s, 1H); 4.54 (dd, 4H); 4.09 (q, 2H); 3.60 (s, 3H); 3.23 (s, 2H); 3.10 (s, 2H); 1.19 (t, 3H). MS (m/z) ES+: 260 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:7]=1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1>CC(O)C.C(OCC)(=O)C>[N:13]1([CH2:12][CH:10]([OH:11])[CH2:9][O:8][C:6]2[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[CH:14]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Brc1cncc(OCC2CO2)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: OC(COc1cncc(Br)c1)Cn1cnc2ccccc21
Yield: 49.8 %

Procedure:
A solution of Example 436A (500 mg, 2.17 mmol) and 1H-Benzoimidazole (28 mg, 2.39 mmol) in 2-propanol (10 mL) was refluxed under N2 for 2 hrs. The reaction mixture was cooled, diluted with ethyl acetate(50 mL) and washed with brine (2×25 mL). The residue was concentrated and purified by flash column chromatography on silica gel eluting with 100% ethyl acetate to 5% methanol/ethyl acetate to provide the desire product (1.08 mmol, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.[N+:27]([C:30]1[O:34][C:33]([CH:35]=O)=[CH:32][CH:31]=1)([O-:29])=[O:28]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([CH:19]3[CH2:20][CH2:21][N:22]([CH2:35][C:33]4[O:34][C:30]([N+:27]([O-:29])=[O:28])=[CH:31][CH:32]=4)[CH2:23][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCNCC2)cc1
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)C2CCN(Cc3ccc([N+](=O)[O-])o3)CC2)cc1

Procedure:
Using the general procedure described in Example 3, N1-(4-methoxybenzoyl)-N2-(piperidin-4-ylcarbonyl)-1,2-benzenediamine (0.14 mmol) was reacted with 5-nitro-2-furaldehyde to provide 30 mg of the title product as the free base. Treatment with hydrochloric acid and concentration in vacuo yielded the salt of the title compound.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8]([OH:10])[N:7]=[C:6]([NH:11][CH:12]([CH3:14])[CH3:13])[N:5]=1)[CH3:2].[OH-].[K+].COCCOCCOC.Cl[CH:27]([F:29])[F:28]>O>[F:28][CH:27]([F:29])[O:10][C:8]1[N:9]=[C:4]([NH:3][CH2:1][CH3:2])[N:5]=[C:6]([NH:11][CH:12]([CH3:13])[CH3:14])[N:7]=1
Reactant: CCNc1nc(O)nc(NC(C)C)n1
Reactant: FC(F)Cl
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOC
Solvent: O
Product: CCNc1nc(NC(C)C)nc(OC(F)F)n1
Temperature: 90 °C

Procedure:
A mixture of 200 g (1.02 moles) of 2-ethylamino-4-hydroxy-6-isopropylamino-1,3,5-triazine, 454 g (8.11 moles) of potassium hydroxide, 1150 ml of diethylene glycol dimethyl ether and 1150 ml of water was vigorously stirred, and heated to 90° C. Chlorodifluoromethane gas was blown into the reaction mixture until 2-ethylamino-4-hydroxy-6-isopropylamino-1,3,5-triazine was no longer detected by thin-layer chromatography. After the reaction, the reaction mixture was cooled to room temperature, extracted with methylene chloride. The methylene chloride layer was washed with water twice or thrice, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column. The column was eluted with n-hexane/ethyl acetate (5:1) to give 58.9 g of 2-difluoromethoxy-4-ethylamino-6-isopropylamino-1,3,5-triazine.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2]1.[S:29](N)([NH2:32])(=[O:31])=[O:30]>O1CCOCC1>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([S:29]([NH2:32])(=[O:31])=[O:30])[CH2:22][CH2:23]4)(=[O:15])=[O:16])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:2][CH2:3]1
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCNCC3)ccc2n1CC1CC1
Solvent: C1COCCO1
Product: CC(C)(C)Cc1nc2cc(S(=O)(=O)CC3CCN(S(N)(=O)=O)CC3)ccc2n1CC1CC1

Procedure:
The mixture of 1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-5-[(piperidin-4-ylmethane)sulfonyl]-1,3-benzodiazole (STEP D of Example 5, 25 mg, 0.062 mmol), sulfamide (15 mg, 0.16 mmol)and 1,4-dioxane was refluxed for 6 h. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate (20 mL) and water (30 mL). The organic layer was washed with water (20 mL) and brine (15 mL), dried over magnesium sulfate. The crude product (27 mg) was purified by prep LC-MS(“process A”).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]2[C:14](=[O:32])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([F:31])[CH:19]=3)[O:17][C:12]=2[C:11]([F:33])=[CH:10][C:9]=1[F:34].Cl.[CH3:36][NH:37][CH3:38].C(=O)([O-])[O-].[K+].[K+]>>[CH3:36][N:37]([CH3:38])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:13]2[C:14](=[O:32])[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[C:20]([F:31])[CH:19]=3)[O:17][C:12]=2[C:11]([F:33])=[CH:10][C:9]=1[F:34]
Reactant: CNC
Reactant: CC(C)(C)C(=O)Nc1ccc(-c2cc(=O)c3c(NCCCCCBr)c(F)cc(F)c3o2)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C)CCCCCNc1c(F)cc(F)c2oc(-c3ccc(NC(=O)C(C)(C)C)c(F)c3)cc(=O)c12
Yield: 74 %

Procedure:
Substantially the same manner as that in Example 130 (1) was repeated except that 1.47 g (2.73 mmol) of the above 5-(5-bromopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one was reacted with 2.22 g (27.3 mmol) of dimethylamine hydrochloride and 3.77 g (27.3 mmol) of potassium carbonate and the resulting compound was purified by silica gel column chromatography (chloroform:methanol=9:1), to give 1.02 g. of 5-(5-dimethylaminopentylamino)-6,8-difluoro-2-(3-fluoro-4-pivaloylaminophenyl)-4H-1-benzopyran-4-one (yield: 74%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[C:6]2[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:30][C:31]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=3)[C:6]3[CH:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]([CH3:20])[C:3]2=[O:21])=[O:32])[CH:27]=[CH:28][CH:29]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Cc1ccc(C2=NC(N)C(=O)N(C)c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(NC(=O)NC2N=C(c3ccc(C)cc3)c3ccccc3N(C)C2=O)c1
Reaction time: 0.33 h

Procedure:
Equimolar amounts of 3-(R,S)-amino-1,3-dihydro-1-methyl-5-(p-tolyl)-2H-1,4-benzodiazepin-2-one, 3-methoxyphenylisocyanate, and triethylamine were mixed in THF at 0° C. and stirred 20 minutes. Removal of THF in vacuo and crystallization from MeOH gave the title compound: m.p. 240°-242° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: CC(C)(C)OC(=O)/C=C/c1ccnc(C#N)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 13.6 %

Procedure:
tert-Butyl (E)-3-(2-cyano-4-pyridyl)acrylate (0.84 g, 3.2 mmol) and methyl thiosalicylate (0.74 g, 4.4 mmol) were dissolved in toluene (3 ml), and triethylamine (0.77 ml, 5.5 mmol) was added thereto. The reaction mixture was refluxed for 7 hrs and subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethyl acetate-isopropyl ether to give the titled compound (0.16 g, 17%) as white crystals.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[C:16]2[CH:17]=[C:18]([C:33]([O:35]C)=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:22][C:21]3=[O:32])[CH:7]=[C:8]([F:10])[CH:9]=1.Cl>CO.C(Cl)Cl>[F:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[C:16]2[CH:17]=[C:18]([C:33]([OH:35])=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)=[CH:22][C:21]3=[O:32])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cc([C@H]2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
An aqueous NaOH 2N (2.55 ml, 5.10 mmol) solution was added to methyl 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylate (0.79 g, 1.68 mmol) in a mixture of MeOH (9 mL) and DCM (6 mL) and the reaction mixture was stirred at room temperature overnight. The mixture was cooled to 0° C. and an aqueous HCl 2N (2.5 mL, 5.0 mmol) solution was added dropwise to the reaction mixture until pH ˜3. After dilution with water (9 mL), the reaction mixture was concentrated to half volume. The aqueous phase was extracted with DCM, the organic phase was concentrated to dryness, leading to a foam, which was triturated in EtAc, collected by filtration, washed with EtAc, diethyl ether, dried under vacuum at 50° C. to afford 8-[(2R)-1-(3,5-difluorophenyl)pyrrolidin-2-yl]-2-morpholino-4-oxo-chromene-6-carboxylic acid (0.638 g, 83%) as an off-white solid. Mass Spectrum: m/z [M+H]+=457.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[OH:28][C@@H:29]([CH2:35][CH3:36])[CH2:30][C:31](OC)=[O:32]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:31](=[O:32])[CH2:30][C@@H:29]([OH:28])[CH2:35][CH3:36])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC[C@H](O)CC(=O)OC
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC[C@H](O)CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (104 mg, 97%), MS (ISP) m/z=431.5 [(M+H)+], mp 217° C., was prepared in accordance with the general method of example 5 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and (S)-methyl 3-hydroxy-pentanoate.
Reaction SMILES: C=CCCCCCC.[C:9]([OH:24])(=O)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]CCCCCC.OO>C1(C)C=CC=CC=1>[CH2:9]1[O:24][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCCCCCCC(=O)O
Agent: OO
Solvent: Cc1ccccc1
Solvent: C=CCCCCCC
Product: CCCCCCC1CO1
Yield: 35 %

Procedure:
A mechanically stirred suspension of immobilized C. antarctica lipase (100 mg, according to example 1) in toluene (13.5 ml), 1-octene (1.5 ml, 9.54 mmol) and myristic acid (0.22 g, 0.95 mmol) was heated to 50° C. To this mixture hydrogen peroxide (0.8 ml, 60% (w/v)) was added in four equal portions after 0, 1.5, 3 and 4.5 hours (14 mmol in all). After 24 hours 35% octene oxide was formed as determined by gas chromatography.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[F:18][C:19]([F:24])([F:23])[C:20](O)=[O:21].Cl>O1CCCC1.C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:20](=[O:21])[C:19]([F:24])([F:23])[F:18])=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)CCc1cc(N)ccc1O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CCc1cc(NC(=O)C(F)(F)F)ccc1O
Reaction time: 2 h

Procedure:
t-Butyl 3-(1-hydroxy-4-aminobenzen-2-yl)propionate was disslolved in a mixture of tetrahydrofuran (100 ml) and triethylamine (7.1 ml). Anhydrous trifluoroacetic acid (6.0 ml) was added to the solution at 0° C. in an atmosphere of argon gas. The solution was stirred for 2 hr. at 0° C. The reaction solution was poured into a mixture of ice and 1N hydrochloric acid (100 ml). The reaction mixture was extracted with ethyl acetate (300 ml). The extract was washed with water, saturated aqueous solution of sodium bicarbonate, followed by brine, dried over anhydrous magnesium sulfate and evaporated. The residue was recrystallized from a mixture of ethyl acetate-n-hexane (1:5) to give the title compound having the following physical data.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][C:13]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1cccc1S(=O)(=O)NC(C)(C)C
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccn(C)c1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a solution of 2.5 g (11.5 mmol) of N-(1,1-dimethylethyl)-1-methyl- 1H-pyrrole-2-sulfonamide in 50 mL THF under nitrogen atmosphere cooled to below -70° C. was added dropwise 13 ml, (32.5 mmol) of 2.5M n-butyllithium at such a rate as to keep the temperature below -58° C. After stirring at -20° C. to -10° C. for 30 min then 1 h at 0° C., the mixture was recooled to -70° C. and treated with a solution of 1.63 g (17.3 mmol) of methyl chloroformate in 6 mL THF causing an exotherm to -57° C. The reaction mixture was stirred overnight at ambient temperature then diluted with 200 mL of ethyl acetate. This solution was washed successively with two 60 ml, portions of 1N HCl, brine, then dried (Na2SO4) and evaporated to a dark oil. The crude product was purified by chromatography on silica gel (30% ethyl acetate/70% hexanes) then collected from hexanes to afford 0.45 g of the title compound, m.p. 105°-108° C.