Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[C:8]([F:16])[CH:7]=1.O.[OH-].[Li+].CO>O1CCCC1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[C:8]([F:16])[CH:7]=1
Reactant: COC(=O)c1ccc(C2OCCO2)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2OCCO2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a solution of EXAMPLE 20C (2.0 g) in tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide monohydrate (1 g) in water (5 mL). Methanol was added until a transparent solution formed and the solution stirred at ambient temperature for 4 hours and concentrated to about 5 mL. The residue was acidified with 2N HCl to pH 2 and the mixture partitioned between ethyl acetate and water. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated to give the title compound (1.5 g, 79%). MS (DCI): m/z 213 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(=O)([O-])[OH:14].[NH4+].OO>C(#N)C.O>[O:14]1[CH2:1][CH:2]1[C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: C=Cc1ccc(S(N)(=O)=O)cc1
Agent: OO
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: NS(=O)(=O)c1ccc(C2CO2)cc1
Reaction time: 0.25 h
Yield: 26100.9 %

Procedure:
To a suspension of 4-sulfonamidostyrene (1.83 g, 0.01 mmol) and ammonium hydrogencarbonate (1.6 g, 0.02 mol) in acetonitrile/water (60 mL/30 mL) was added hydrogen peroxide (30% solution, 10 mL, 0.09). The mixture was kept in dark without stirring for 72 hours during which two portion of hydrogen peroxide (5 mL each) were introduced slowly. While HPLC showed all of the starting 4-sulfonamidostyrene was consumed, sodium thiosulfate solution (10%, 60 mL) was added slowly and stirred for 15 minutes. The mixture was extracted with dichloromethane (3×80 mL). The organic phases were combined, washed with brine and dried over magnesium sulfate. The solution was concentrated to give the crude title compound (0.52 g) as an oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Br[CH2:15][C:16]1[CH:28]=[CH:27][C:19]2[S:20][C:21]([S:23](=[O:26])(=[O:25])[NH2:24])=[CH:22][C:18]=2[CH:17]=1.O>CO>[N:1]1([CH2:15][C:16]2[CH:28]=[CH:27][C:19]3[S:20][C:21]([S:23](=[O:25])(=[O:26])[NH2:24])=[CH:22][C:18]=3[CH:17]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: NS(=O)(=O)c1cc2cc(CBr)ccc2s1
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cc2cc(CN3CCOCC3)ccc2s1
Yield: 9.6 %

Procedure:
To a stirred solution of morpholine (0.91 g, 10.5 mmol) and triethylamine (1.01 g, 10 mmol) in 20 ml of methanol was added 5-bromomethyl-2-sulfamoylbenzo[b]thiophene (3.06 g, 10 mmol) portionwise over 5 minutes at ambient temperature. Stirring was continued for 11/4 hours. The resulting suspension was cooled and filtered after an additional 1 hour to give 2.76 g. of yellow solid. Concentration of the filtrate in vacuo followed by trituration of the residue with water and filtering gave an additional 0.3 g of yellow solid. (Total crude yield was 98%). Recrystallization from nitromethane gave material with m.p. 221.5°-224° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.CCN(CC)CC.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:19]([N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[CH3:1])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18]
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.8 %

Procedure:
A mixture of 2-methylbenzimidazole (1.5 g, 11.35 mmole), Et3N (1.66 mL, 11.92 mmole), DMAP (0.20 g, 1.6 mmole), and (BOC)2O (2.60 g, 11.92 mmole) in anhydrous CH2Cl2 (15 mL) was stirred at RT for 24 hr, then was concentrated. The residue was taken up in H2O, stirred, and filtered to afford the title compound as a colorless solid (2.63 g, 100%): mp 71-72° C.
Reaction SMILES: C1C2C(=CC=CC=2)[C@@H](N)[C@H]1O.B.CCN(C1C=CC=CC=1)CC.[Cl:24][C:25]1[C:34]2[C:35](=[O:43])[O:36][C:37]3([CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:33]=2[C:32]2[C:31](=[O:44])[CH2:30][C:29]([CH3:46])([CH3:45])[CH2:28][C:27]=2[N:26]=1.CO>O1CCCC1>[Cl:24][C:25]1[C:34]2[C:35](=[O:43])[O:36][C:37]3([CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:33]=2[C:32]2[C@@H:31]([OH:44])[CH2:30][C:29]([CH3:46])([CH3:45])[CH2:28][C:27]=2[N:26]=1
Reactant: CC1(C)CC(=O)c2c(nc(Cl)c3c2C2(CCOCC2)OC3=O)C1
Agent: B
Agent: N[C@@H]1c2ccccc2C[C@@H]1O
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)c1ccccc1
Product: CC1(C)Cc2nc(Cl)c3c(c2[C@@H](O)C1)C1(CCOCC1)OC3=O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
213 mg (1R,2S)-(+)-cis-1-Amino-2-indanol are dissolved in 250 ml tetrahydrofurane and to this solution are dropwise added 3.58 ml of a borane-diethylaniline-complex. After completion of gas evolution the solution is cooled to 0° C. and 3.17 g 4-chloro-7,7-dimethyl-2′,3′,5′,6′,7,8-hexahydro-3H-spiro[furo[3,4-c]quinoline-1,4′-pyran]-3,9(6H)-dione in 250 ml tetrahydrofurane are added dropwise. The temperature is raised during 2 hours to room temperature and the mixture is stirred for 18 hours, 213 mg (1R,2S)-(+)-cis-1-Amino-2-indanol are added and stirring is continued for further 7 hours. 20 ml methanol are added dropwise and the mixture is stirred for additional 10 minutes. The mixture is partitioned between 0.1 M hydrochloric acid and ethylacetate. The aqueous phase is twice extracted with ethylacetate. The combined organic phases are dried with sodium sulphate and the solvents are evaporated in vacuo. The residue is chromatographed on silica gel (petrole ether/ethylacetate 100:0 to 0:100).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[C:13](OC)=[O:14].C(OCC)(=O)C.S(=O)(=O)(O)O>C(OCC)C.O1CCCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:18])=[C:12]([CH:17]=1)[CH2:13][OH:14]
Reactant: COC(=O)c1cc(Br)ccc1C
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.1 %

Procedure:
To a suspension of 4.2 g (0.1094 mol) of lithium aluminum hydride in 250 ml of dry diethyl ether was added dropwise a solution of 33.4 g (0.1458 mol) of methyl 5-bromo-2-methylbenzoate in 50 ml of dry diethyl ether at room temperature over 30 minutes with ice-cooling under an atmosphere of nitrogen. The mixture was stirred at room temperature for 2 hours. About 10 ml of ethyl acetate was added dropwise thereto and further about 50 ml of tetrahydrofuran was added thereto. The mixture was added to 200 ml of a 10% aqueous solution of sulfuric acid and ice, and the mixture was separated. The organic layer was washed successively with water, a saturated aqueous solution of sodium bicarbonate and saturated brine, then dried and concentrated. The residue (28.7 g) was subjected to silica gel column chromatography (eluted with n-hexane:ethyl acetate=10:1 and then 5:1) to obtain 24.36 g of 5-bromo-2-methylbenzylalcohol as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][CH:16]2[CH2:17][CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21]2)=[O:33])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCC(Nc2ccccc2Sc2ccc(Cl)cc2)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(=O)N1CCC(Nc2ccccc2S(=O)c2ccc(Cl)cc2)CC1
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of 1-{4-[2-(4-chloro-phenylsulfanyl)-phenylamino]-piperidin-1-yl}-ethanone (AMR01098, STX1832, 140 mg, 0.388 mmol) was treated with m-chloroperbenzoic acid (77%, 104.33 mg, 0.466 mmol) and stirred for 2 h, keeping the temperature between −30 and −10° C. The reaction mixture was quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using DCM/MeOH 95:5 as eluent gave 1-{4-[2-(4-chloro-benzenesulfinyl)-phenylamino]-piperidin-1-yl}-ethanone (119 mg, 81%) as an oil. LC/MS (APCI) tr=4.53 min, m/z 379.28 (39), 377.26 (M++H, 100). HPLC tr=2.38 min (98.44%) 1H NMR (270 MHz, CDCl3) δ 1.12 (1H, m, ½CH2), 1.45 (1H, m, ½CH2), 1.62 (1H, m, ½CH2), 1.95 (2H, m, CH2), 2.04, 2.07 (3H, 2s, CH3), 2.94-4.00 (5H, m, CH and 2CH2), 6.20, 6.28 (1H, 2d, J=6.9 and 7.4 Hz, NH), 4.20 (1H, m), 6.60 (1H, d, J=8.4 Hz, ArH), 6.70 (1H, m, ArH) and 7.27-7.48 (6H, m, ArH). 13C NMR (270 MHz, CDCl3) δ 21.58 (CH3), 30.89, 31.17, 31.28, 31.83, 39.23, 39.46, 43.80, 44.44 (CH2), 47.77, 48.18 (CH), 112.17, 112.44, 115.67, 115.73, 122.13, 122.58, 126.13, 126.25, 128.97, 129.04, 129.53, 129.70, 133.88, 133.93, 136.39, 136.61, 142.28, 147.47, 147.56 (ArC), and 168.96 (C═O).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:16][NH:17][C:18]([NH2:20])=[O:19]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[C:5]([C:4]1[CH:7]=[CH:8][N:9]=[C:2]([NH:20][C:18]([NH:17][CH3:16])=[O:19])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CNC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CNC(=O)Nc1cc(C#N)ccn1
Temperature: 130 °C
Yield: 68.7 %

Procedure:
A mixture of 2-chloro-isonicotinonitrile [Talik et al. Rocz. Chem.; 29; 1955; 1019, 1025.] (13.9 g, 0.1 mol), Pd2 dba3 (2.0 g, 2 mmol), Xantphos (3.6 g, 6.22 mmol), cesium carbonate (39.1 g, 120 mmol) and methylurea (37.04 g, 0.5 mol) in dioxane (800 mL), under a nitrogen atmosphere was heated for 8 hours at 130° C. (bath temperature). On cooling the reaction mixture was concentrated in vacuo. The residue was partitioned between CH2Cl2 and water. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel (gradient elution: 100% hexane to 100% EtOAc) to give 1-(4-cyano-pyridin-2-yl)-3-methyl-urea (12.1 g) as a solid; Mp. 203-204° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:10][CH2:11][CH2:12][Si:13]([Si:22]([CH3:25])([CH3:24])[CH3:23])([Si:18]([CH3:21])([CH3:20])[CH3:19])[Si:14]([CH3:17])([CH3:16])[CH3:15])(=O)C.O.[OH-].[Na+]>O1CCCC1>[CH3:17][Si:14]([Si:13]([Si:22]([CH3:25])([CH3:24])[CH3:23])([Si:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][OH:10])([CH3:15])[CH3:16]
Reactant: CC(=O)OCC[Si]([Si](C)(C)C)([Si](C)(C)C)[Si](C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)[Si](CCO)([Si](C)(C)C)[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
A solution of 3.8 g lithium aluminum hydride (LiAlH4) in 100 ml tetrahydrofuran was stirred at 5° C. in an argon atmosphere. To the solution, 33.5 g of 2-[tris(trimethylsilyl)silyl]ethyl acetate was added dropwise. After one hour of stirring at 5° C., with ice cooling, 3.8 ml of water, 3.8 ml of 15% aqueous sodium hydroxide, and 11.4 ml of water were successively added to the solution in the described order. The mixture was stirred for one hour at room temperature. The resulting precipitate was filtered off, and the tetrahydrofuran solution was dried and concentrated, obtaining 24.8 g of 2-[tris(trimethylsilyl)silyl]ethanol. This crude product was dissolved in a solvent and analyzed by gas chromatography, finding that it contained 98.2% of 2-[tris(trimethylsilyl)silyl]ethanol. This was esterified with methacryloyl chloride in the presence of triethylamine as the base as in Comparative Example 1. Subsequent extraction and vacuum distillation for purification gave 29.5 g of the end compound, 2-[tris(trimethylsilyl)silyl]ethyl methacrylate. The yield throughout the two steps was 82%.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([NH:22]N)=[O:21])[CH2:10][N:9]4[CH3:24])=[CH:5]1)([CH3:3])[CH3:2].N([O-])=O.[Na+].C(=O)(O)[O-].[Na+].[CH:34]1(N)[CH2:38][CH2:37][CH2:36][CH2:35]1>Cl.CN(C=O)C.O>[CH:34]1([NH:22][C:20]([C@@H:11]2[CH2:12][C@H:13]3[C@@H:8]([CH2:7][C:6]4[C:19]5[C:18](=[CH:17][CH:16]=[CH:15][C:14]3=5)[N:4]([CH:1]([CH3:3])[CH3:2])[CH:5]=4)[N:9]([CH3:24])[CH2:10]2)=[O:21])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: NC1CCCC1
Reactant: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)NN)CN(C)[C@@H]1C2
Agent: Cl
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)NC3CCCC3)CN(C)[C@@H]1C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 32.4 %

Procedure:
To a solution of 3.26 g (0.01 mol) of (8β)-1-isopropyl-6-methylergoline-8-hydrazide dissolved in 25 ml of hydrochloric acid and 100 ml of water at a temperature of about 5° C. was added 55 ml of a solution of 0.2N sodium nitrite dropwise over a period of about five minutes. The resulting mixture was stirred at room temperature for approximately five minutes and sufficient saturated sodium bicarbonate solution was added dropwise until the pH of the mixture was basic. The mixture was extracted with three 200 ml portions of diethyl ether. The organic extracts were combined, dried over anhydrous magnesium sulfate and filtered. To the resulting filtrate was added a solution of 2.55 g (0.03 mol) of cyclopentylamine dissolved in 50 ml of DMF. The resulting mixture was stored at a temperature of about 5° C. overnight. The solvent was decanted from the resulting oil. The oil was slurried in acetonitrile and the solvent was again decanted. The resulting solid was recrystallized from acetonitrile to provide 1.23 g of the desired compound. m/e=379.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13](=[O:26])[C:14](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(Cl)Cl>CO.[Pd]>[CH3:18][O:17][C:15](=[O:16])[CH:14]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13](=[O:26])[CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: [H][H]
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)C(=Cc1ccccc1)C(=O)OC
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)C(=O)C(Cc1ccccc1)C(=O)OC
Yield: 58.6 %

Procedure:
Dimethyl 2,4-bis(phenylmethylene)-3-oxo-glutarate (630 mg, 1.8 mmol) (C. H. Chen, et al, J. Org. Chem., 1981, 46, 2752-2757) was dissolved in about 100 mL of methanol and 250 mg of 10% palladium on carbon was added. The reaction mixture was shaken at ambient temperature under 4 atmospheres of hydrogen for about 12 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue (750 mg) was taken up in ~15 mL of methylene chloride and applied to a 1.0×45 cm column of silica gel. The column was eluted @ 5 p.s.i. with 150 mL of methylene chloride to give 374 mg (58% yield) of the title compound. The 300 MHz 1H NMR was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:14][CH3:15])[CH:3]=1.C(Cl)(=O)OCC.[NH2:22][C@H:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]1[O:34][CH3:35]>ClC(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH:22][C@H:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][C@H:24]2[O:34][CH3:35])=[O:8])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1C(=O)O
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc([N+](=O)[O-])c(Cl)cc2OC)[C@H](OC)C1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a stirred and cooled (5° C.) suspension of 81 parts of 4-chloro-2-methoxy-5-nitrobenzoic acid in 1350 parts of trichloromethane were added first 35.4 parts of N,N-diethylethanamine and then 38 parts of ethyl carbonochloridate at a temperature below 5° C. The whole was stirred for 2 hours in an ice bath. A solution of 65 parts of ethyl cis-4-amino-3-methoxy-1-piperidinecarboxylate in 1125 parts of trichloromethane was added while the temperature was kept below 10° C. Stirring was continued first for 1 hour in an ice bath and then overnight at room temperature. The mixture was washed successively once with water, twice with a sodium hydroxide solution 5% and three times with water, dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 100 parts (75%) of ethyl cis-4-[(4-chloro-2-methoxy-5-nitro-benzoyl)amino]-3-methoxy-1-piperidinecarboxylate; mp. 181.3° C. (interm. 13).
Reaction SMILES: [F:1][CH:2]([F:49])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:21]3[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:49][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH:21]3[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]3)[N:9]=2)[C:6]2[CH:43]=[CH:44][CH:45]=[C:46]([O:47][CH3:48])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN2CCOCC2)C2CCCNC2)n1

Procedure:
Reaction of tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(4-morpholinyl)propyl]amino}-1-piperidinecarboxylate with TFA in CH2Cl2 gave 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-N-(3-piperidinyl)-1,3,5-triazin-2-amine, which was treated with methanesulfonyl chloride in CH2Cl2 to give 4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-N-[1-(methylsulfonyl)-3-piperidinyl]-6-(4-morpholinyl)-N-[3-(4-morpholinyl)propyl]-1,3,5-triazin-2-amine in 78% yield.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:10](=[O:11])[CH2:9][N:8]([CH2:12][C:13]2[S:14][C:15]([C:18](=[N:24][OH:25])[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=[CH:16][CH:17]=2)[S:7]1(=[O:27])=[O:26].C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:25]/[N:24]=[C:18](/[C:15]1[S:14][C:13]([CH2:12][N:8]2[S:7](=[O:27])(=[O:26])[NH:6][C:10](=[O:11])[CH2:9]2)=[CH:17][CH:16]=1)\[CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccc(C(CCC(C)C)=NO)s3)S2(=O)=O)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)CC/C(=N\O)c1ccc(CN2CC(=O)NS2(=O)=O)s1
Reaction time: 0.25 h

Procedure:
The title E compound, 2-(2,4-dimethoxy-benzyl)-5-(5-{1-[-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (40 mg, 0.08 mmol) is stirred in equal volumes of CH2Cl2 and TFA (4 mL) at RT for 3 h. The volatiles are evaporated and the residue is stirred in equal volumes of MeCN/water (5 mL) for 15 min. The mixture is filtered through a 0.2, Acrodisc and the solvents are evaporated to dryness. The residue is triturated from hexane/Et2O (4:1) to afford 5-(5-{1-[(E)-hydroxyimino]-4-methyl-pentyl}-thiophen-2-ylmethyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one as a light pink solid: [M+1]+=346.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([OH:9])=O.[NH2:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH3:23])([CH3:22])[C:16](=[O:21])[N:17]2[CH3:20])=[CH:13][CH:12]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[C:7]([NH:10][C:11]1[CH:19]=[C:18]2[C:14]([C:15]([CH3:23])([CH3:22])[C:16](=[O:21])[N:17]2[CH3:20])=[CH:13][CH:12]=1)=[O:9]
Reactant: Cn1ccnc1C(=O)O
Reactant: CN1C(=O)C(C)(C)c2ccc(N)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)C(C)(C)c2ccc(NC(=O)c3nccn3C)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-methyl-1H-imidazole-2-carboxylic acid (99.4 mg, 788 μmol) and 6-amino-1,3,3-trimethylindolin-2-one (100 mg, 526 μmol) in DMF (3 ml) were added HATU (400 mg, 1.05 mmol) and DIPEA (347 mg, 468 μl, 2.63 mmol). The reaction mixture was stirred for 3 hours at room temperature and then poured into ethyl acetate and 1 M aqueous sodium carbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed under reduced pressure. The crude material was purified by silica gel chromatography using ethyl acetate/heptane as eluent followed by reversed phase preparative HPLC. The title compound was obtained as off-white crystals (135 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][OH:8].[OH-].[K+].O.Cl[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:14]=1[Cl:22]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C1(C)C=CC=CC=1>[Cl:22][C:14]1[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:13]=1[O:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(OCc2ccccn2)c(Cl)c1
Temperature: 60 °C
Yield: 48.3 %

Procedure:
To a mixture of pyridin-2-ylmethanol (6.82 g, 62.5 mmol), Aliquat 336 (8.08 g, 20.0 mmol), potassium hydroxide (3.51 g, 62.5 mmol) and water (40 mL) were added toluene (80 mL) and 1,2-dichloro-4-nitrobenzene (10.0 g, 52.1 mmol). The mixture was heated to 60° C. overnight with vigorous stirring. The layers were separated, and the organic layer was diluted with ethyl acetate and washed with water. The organic layer was dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with petroleum ether and tert-butyl methyl ether to yield 6.66 g (48%) of the title compound.
Reaction SMILES: C([Li])CCC.N1CCOCC1.[O:12]1[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13]1.C([Li])(CC)C.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=[O:30])=[CH:27][CH:26]=1.Cl>CCCCCC.O1CCCC1.C1CCCCC1>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]([C:16]2[O:12][CH:13]=[C:14]([CH:17]=[O:18])[CH:15]=2)[OH:30])=[CH:27][CH:26]=1
Reactant: O=Cc1ccoc1
Reactant: O=Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li]C(C)CC
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1COCCN1
Solvent: CCCCCC
Product: O=Cc1coc(C(O)c2ccc(Br)cc2)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (a 2.5M solution in hexane; 4.37 ml, 10.9 mmol) was added to a solution of morpholine (0.91 ml, 10.4 mmol) in tetrahydrofuran (30 ml) at -78° under argon. After 20 min., 3-furaldehyde (0.91 ml, 10.4 mmol) was added. After another 20 min., sec-butyl lithium (a 1.3M solution in cyclohexane; 8.4 ml, 10.9 mmol) was added dropwise and stirring continued at -78° for 4 hours before a solution of 4-bromobenzaldehyde (2.11 g, 11.4 mmol) in tetrahydrofuran (10 ml) was added. Stirring was continued overnight (17 hours) while the cooling bath was allowed to attain room temperature. The solution was poured into ice cold 10% (v/v) hydrochloric acid (30 ml) and after stirring at 0° for 10 min., the layers were separated. The aqueous phase was extracted with diethyl ether. All the organic phases were combined, dried (magnesium sulfate) and evaporated down to give an oil, which was purified by flash chromatography on silica using 40% ethyl acetate/hexane. Fractions with Rf of about 0.23 on evaporation gave the title compound as a yellow solid, m.p. 83°-4° (recrystallized from chloroform).