Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.O.[NH:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1.C(N(CC)CC)C.[CH2:17]([O:19][C:20]([CH2:22][CH2:23][C:24](Cl)=[O:25])=[O:21])[CH3:18]>C(Cl)Cl>[CH2:17]([O:19][C:20]([CH2:22][CH2:23][C:24]([N:3]1[CH2:8][CH2:7][C:6](=[O:9])[CH2:5][CH2:4]1)=[O:25])=[O:21])[CH3:18]
Reactant: O=C1CCNCC1
Reactant: CCOC(=O)CCC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCC(=O)N1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a solution of 4-piperidone monohydrate hydrochloride (7.68 g, 50 mmol) and triethylamine (21 ml) in methylene chloride (100 ml) was added 3-(ethoxycarbonyl)propionyl chloride (9.87 g, 60 mmol) at 0° C. over a period of 10 min. The mixture was stirred at room temperature for 16 h before being quenched with water (100 ml). The organic layer was separated and the aqueous layer was extracted with methylene chloride (100 ml). The combined organic layers were washed with 1M HCl (100 ml), saturated aqueous sodium bicarbonate (100 ml), and brine (100 ml), dried over sodium sulfate, and concentrated. Purification by flash chromatography (silica gel, 30% ether in hexanes) gave the desired ketone (3.80 g, 33%) as a light yellow oil. 1H NMR (500 MHz, CDCl3) δ1.27 (t, J=7.3 Hz, 3H), 2.48 (t, J=6.4Hz, 2H), 2.53 (t, J=6.4 Hz, 2H), 2.68 (s, 4H), 3.82 (t, J=6.3 Hz, 2H), 3.82 (t, J=6.3 Hz, 2H), 4.16 (q, J=7.3 Hz, 2H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CS(C)=O.C1([O:15][C:16](=O)[NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:35](=[O:37])[NH2:36])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[CH:20][C:19]=2[F:40])C=CC=CC=1.O>C(OCC)(=O)C>[F:40][C:19]1[CH:20]=[C:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:38][CH3:39])=[C:32]([C:35](=[O:37])[NH2:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][C:18]=1[NH:17][C:16]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:15]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)c2cc1C(N)=O
Reactant: NC1CC1
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1C(N)=O
Reaction time: 0.17 h

Procedure:
Cyclopropylamine (0.10 ml) was added to dimethylsulfoxide (0.8 ml), and then [4-(6-carbamoyl-7-methoxyquinolin-4-yloxy)-2-fluorophenyl]carbamic acid phenyl ester (80 mg) was dissolved therein and the mixture was stirred for 10 minutes. Water and ethyl acetate were added to the reaction solution and the precipitated crystals were filtered out to obtain the title compound (33 mg).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][NH:15][CH2:16][C:17]([CH3:20])([OH:19])[CH3:18].[OH2:21]>N1C=CC=CC=1>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([N:15]([CH2:16][C:17]([CH3:20])([OH:19])[CH3:18])[CH2:14][CH2:13][O:12][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:8])=[O:21])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: CC(C)(O)CNCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN(CC(C)(C)O)S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-Toluenesulfonyl chloride (166.1 g) was added portionwise to a stirred solution of 1-[(2-hydroxyethyl)amino]-2-methyl-2-propanol (58.0 g) in pyridine (275 ml) at 0°-10° C. The resulting solution was stirred at room temperature for 15 h and then poured into water (1 l). The mixture was extracted with dichloromethane and the organic phase was washed with hydrochloric acid (2.5M) and brine. After drying over magnesium sulfate, the solvent was removed under reduced pressure to give 1-{N-[(4-methylphenyl)sulfonyl]-N-[(4-methylphenyl)sulfonyloxyethyl]amino}-2-methyl-2-propanol (155.8 g). δ (CDCl3) 1.23 (s,6H), 2.44,2.46 (6H), 3.08 (s,2H), 3.45 (t,2H), 4.35 (t,2H) and 7.25-7.85 (m,8H).
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=2)[CH2:8][CH:7]=1.S([C:26]1[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=1)([O-])(=O)=O.[C:33](=[O:36])([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][CH2:5][C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:36][CH2:33][CH:26]3[CH2:32][CH2:31][C:29]([CH2:30][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:28][CH2:27]3)=[CH:16][CH:15]=2)[CH2:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC(C)=CCCC1=CCC(CCc2ccc(O)cc2)CC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCCCC1=CCC(COc2ccc(CCC3CC=C(CCC=C(C)C)CC3)cc2)CC1
Reaction time: 8 h

Procedure:
To a round-bottom flask equipped with a stirbar is added phenol 2G (R=4-Methyl-3-pentenyl) (5 g), tosylate 1H (R=n-pentyl) (5.95 g), cesium carbonate (7.45 g), and anhydrous dimethylforrnamide (50 mL). The reaction mixture is stirred overnight. It is then poured into 50 mL dilute HCl, and extracted with 1:1 hexanes:ethyl acetate. The combined organic layers are washed with brine and dried over potassium carbonate, and the solution is concentrated in vacuo. Filtration through silica gel using 10% ethyl acetate in hexanes gives the pure product.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)#[N:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.O>CCCCCC.O1CCCC1>[C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH:9]=[CH:8]2)#[N:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ccc3cc(C#N)ccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Sodium hydride (8.4 g, 210 mmol) was washed twice with hexane and then suspended in tetrahydrofuran (500ml). 5-Cyanoindole (20g, 140 mmol) in tetrahydrofuran (200 ml) was added dropwise. The resulting mixture was stirred at ambient temperature for 1 hour and then p-toluenesulfonyl chloride (26.7 g, 140 mmol) in tetrahydrofuran (200 ml) was added. The reaction was stirred 3 hours more followed by addition of water. The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was washed with brine, dried over calcium sulfate and concentrated. The residue was recrystallized from ether to afford 29.97 g, 72% of title product; m.p. 129°-131° C.; NMR 8.04 (d, J=8.5 Hz, 1H), 7.85 (d, J=1 Hz, 1H), 7.75 (d, J=9 Hz, 2H), 7.67 (d, J=3.5 Hz, 1H), 7.23 (m, 2H), 6.68 (d, J=3.5 Hz, 1H), 2.34 (s, 3H). IR(CHCl3 solution) 2225, 1597, 1453, 1380, 1289, 1266, 1169, 1138, 1123, 1089 (shoulder), 990. FAB HRMS calcd for C16H13N2O2S(MH+): 297.0669. Observed m/e: 297.0685.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16]([OH:25])[CH:15]=2.N1C=CC=CC=1.[O:33](S(C(F)(F)F)(=O)=O)[S:34]([C:37]([F:40])([F:39])[F:38])(=O)=[O:35].C(OCC)(=O)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:26])[O:13][C:14]2[C:19]([C:20]=1[CH2:21][CH2:22][O:23][CH3:24])=[CH:18][CH:17]=[C:16]([O:25][S:34]([C:37]([F:40])([F:39])[F:38])(=[O:35])=[O:33])[CH:15]=2
Reactant: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(O)ccc12
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCCc1c(-c2ccc(OC)cc2OC)c(=O)oc2cc(OS(=O)(=O)C(F)(F)F)ccc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-(2,4-Dimethoxy-phenyl)-7-hydroxy-4-(2-methoxy-ethyl)-chromen-2-one (1.8 g, 5.2 mmol) and pyridine (30 mL) were dissolved in CH2Cl2 (200 mL) at room temperature and the reaction mixture was cooled to 0° C., then treated with Tf2O (1.3 mL). After 1 hour, ethyl acetate (200 mL) was poured into the reaction mixture and the reaction mixture was transferred into a separation funnel. The reaction mixture was then washed with 5% sodium bicarbonate (2×250 ml), water (250 ml) and then brine. The organic layer was dried over sodium sulfate and concentrated. Flash column chromatography on silica gel eluted with 20-50% ethyl acetate in hexane yielded the title compound as a yellow solid.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]\[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:41][C:42]1([F:46])[CH2:45][NH:44][CH2:43]1>C(Cl)Cl>[F:41][C:42]1([F:46])[CH2:45][N:44]([C:4](=[O:6])/[CH:3]=[CH:2]\[I:1])[CH2:43]1
Reactant: O=C(O)/C=C\I
Reactant: FC1(F)CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(/C=C\I)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 49.8 %

Procedure:
A solution of (Z)-3-iodoacrylic acid (1a) (2.75 g, 1.0 eq.) in CH2Cl2 (25.0 mL) was cooled to 0° C. and sequentially treated with DIPEA (1.96 g, 1.1 eq), HATU (5.78 g, 1.1 eq) and 3,3-difluoroazetidine hydrochloride (1.98 g, 1.1 eq). The reaction mixture was stirred at 0° C. for 2-3 hr before being filtered, and concentrated under reduced pressure affording 3.5 g of crude compound. Purification by column chromatography (silica gel, elution with EtOAc/hexane) afforded 1.89 g of pure desired compound. Yield (49.87%). Mass: (ES+) 273.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][CH:60]([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (111.0 mg, 0.287 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. To the mixture was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 30 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 1.5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (50.0 mg, 0.111 mmol, 39).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=O)=[CH:6][CH:5]=1)[CH3:2].Cl.[NH2:29][OH:30].C(=O)([O-])O.[Na+]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[CH3:27])[CH2:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[N:29][OH:30])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([C@@H](CC(=O)c2ccnc(C)c2)c2ccccc2C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1ccc([C@@H](CC(=NO)c2ccnc(C)c2)c2ccccc2C)cc1

Procedure:
In analogy to example 132, step 6, from (R)-3-(4-ethoxy-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=375.2 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[Mg].[C:13]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)(=[O:15])[CH3:14].Cl>O1CCCC1.C(OCC)C>[OH:22][C:19]1([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=2)[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]1
Reactant: CC(=O)N1CCC(=O)CC1
Reactant: Brc1ccc2ccccc2c1
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(O)(c2ccc3ccccc3c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 43.1 %

Procedure:
2-Bromonaphthalene (24.75 g, 0.12 mol) in tetrahydrofuran (180 ml) was slowly added to magnesium (2.9 g, 0.12 mol) in tetrahydrofuran (20 ml) and the mixture stirred at room temperature for one hour. The resultant solution was slowly added to 1-acetyl-4-piperidone (16.9 g, 0.12 mol) in tetrahydrofuran (200 ml) at -78° C., and then allowed to stir to room temperature. The white suspension formed was hydrolysed with hydrochloric acid (120 ml, 1M) and the organic layer removed and concentrated in vacuo. The residue was taken up in dichloromethane, dried (MgSO4), and concentrated to leave a clear oil. Trituration of this oil with diethyl ether gave 1-(4-hydroxy-4-naphthalen-2-yl-piperidin-1-yl)ethanone (13.92 g, 43%) as a white solid; δH (CDCl3) 1.90 (4H, m, 2× piperidinyl CH2), 2.10 (2H, m, piperidinyl CH2), 2.15 (3H, s, COCH3), 3.20 (1H, m, piperidinyl H), 3.70 (1H, m, piperidinyl H), 4.60 (1H, br m, OH), 7.50 (2H, m, ArH), 7.60 (1H, dd, J 9.6, 1.6 Hz, ArH), and 7.90 (4H, m, ArH).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13](Br)=[CH:14][C:15]([Br:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.C[O-].[Na+].[C:26](O)(=[O:28])C>O>[CH2:1]([S:8][C:9]1[N:19]=[C:12]2[C:13]([O:28][CH3:26])=[CH:14][C:15]([Br:17])=[CH:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Brc1cc(Br)c2nc(SCc3ccccc3)nn2c1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1cc(Br)cn2nc(SCc3ccccc3)nc12

Procedure:
2-Benzylthio-6,8-dibromo[1,2,4]triazolo[1,5-a]pyridine (9.5 g, 23.8 mmol) was mixed with acetonitrile (50 mL) in a round bottom flask. Sodium methoxide (13.1 mL of 25 percent solution in methanol, 57.1 mmol) was added and the mixture was heated at reflux for 2 hours. Glacial acetic acid (10 mL) was added and the entire reaction mixture was poured into a mixture of ice and water (300 mL). The brown precipitate that formed was recovered by filtration and dried. This was chromatographed on silica gel eluting with a 1:1 mixture of ethyl acetate and hexane. Product-containing fractions were combined and concentrated under reduced pressure to obtain 6.58 g (80 percent of theory) of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(O[C:24](=[O:30])OC(Cl)(Cl)Cl)Cl.[CH3:32][N:33]([CH3:59])[CH2:34][CH2:35][C@@H:36]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([S:52]([NH2:55])(=[O:54])=[O:53])=[CH:48][C:47]=1[N+:56]([O-:58])=[O:57])[CH2:37][S:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH3:59][N:33]([CH3:32])[CH2:34][CH2:35][C@@H:36]([NH:45][C:46]1[CH:51]=[CH:50][C:49]([S:52]([NH:55][C:24]([N:10]2[CH2:11][CH2:12][N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:8][CH2:9]2)=[O:30])(=[O:53])=[O:54])=[CH:48][C:47]=1[N+:56]([O-:58])=[O:57])[CH2:37][S:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1[N+](=O)[O-]
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)N2CCN(c3ccccc3)CC2)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
A solution of N-phenylpiperazine (30 mg, 0.185 mmol) in dichloromethane (2 mL) was treated with triethylamine (77 μL, 0.555 mmol), cooled to 0° C., treated with triphosgene (33 mg, 0.111 mmol), warmed to room temperature, stirred for 1 hour, treated with 4-({(1R)-3-(dimethylamino)-1-[(phenylthio)methyl]propyl}amino)-3-nitrobenzenesulfonamide (prepared according to the procedure described in commonly owned U.S. patent application Ser. No. 09/957,256, filed Sep. 20, 2001, 86 mg, 0.204 mmol) and DMAP (23 mg, 0.185 mmol), stirred overnight, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 20% 2N NH3 in methanol/dichloromethaneto provide the desired product (46 mg, 41%). MS (ESI) m/e 613 (M+H)+; 1H NMR (500 MHz, CD3OD) δ 8.0-6.75 (13H, m), 4.15 (1H, m), 3.59 (2H, t), 3.39 (4H, m), 3.25 (4H, m), 3.16 (2H, t), 2.88 (6H, s), 2.35-2.15 (2H, m).
Reaction SMILES: [N+]([O-])(O)=O.[Mn]([O-])(=O)(=O)=O.[K+].[O-2:11].[Mg+2].[CH2:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:28])[C:19]=2[CH:29]=1)[CH3:14]>O>[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:27][C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20](=[O:28])[C:19]=2[CH:29]=1)(=[O:11])[CH3:14]
Reactant: CCc1ccc2oc3ncccc3c(=O)c2c1
Reactant: [O-2]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O=[N+]([O-])O
Solvent: O
Product: CC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 60 °C
Yield: 67 %

Procedure:
7.6 ml of nitric acid (specific gravity 1.38) and 7.9 g of potassium permanganate are added to a suspension of 2 g of magnesium oxide in 50 ml of water, and the mixture is heated to 60°C. To the mixture is added 4.5 g of 7-ethyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine over a period of 30 minutes with stirring, keeping the temperature at 60°-70°C. After the addition the mixture is stirred at 60°-70°C for 4.5 hours. After cooling, the reaction mixture is filtered under reduced pressure, and the residue containing manganese dioxide is extracted several times with chloroform. The chloroform layer is washed with water, dried, and the chloroform is distilled off. The residue is recrystallized from toluene to give 3.2 g of 7-acetyl-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at 195°-196°C.
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Br:13][C:9]1[CH:8]=[C:7]([C:2]([NH:1][C:27](=[O:28])[CH2:26][Cl:25])([CH2:5][OH:6])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)(CO)c1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)NC(CO)(CO)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-amino-2-(3-bromo-phenyl)-propane-1,3-diol (3.5 g, 14.22 mmol), 30 ml of THF and 30 ml of 10% aqueous Na2CO3 solution was added dropwise chloroacetyl chloride (1.472 ml, 18.5 mmol) at 0° C. over a period of 10 min. The mixture was stirred for 1 h, diluted with water and extracted with EtOAc. The organic phase was washed with 1N aqueous NaOH solution, 10% aqueous Na2CO3 solution and brine. Chromatography on silica gel (EtOAc/hexane 50-30%) gave the title compound in the form of a colourless solid. TLC (hexane/EtOAc=1:1): Rf=0.21; HPLC: RtH2=2.926 min; 1H-NMR (400 MHz, CD3OD): 7.58 (s, 1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.29 (t, 1H), 4.91 (s, 2H), 4.07 (d, 2H), 4.00 (d, 2H); MS: 322, 324, 326 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4](F)[C:3]=1[O:10][CH3:11].C[Si](C)(C)[N-:14][Si](C)(C)C.[K+].O.S(=O)(=O)(O)O.[C:28]1([CH3:34])[CH:33]=CC=C[CH:29]=1>C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([C:28]([CH3:34])([CH3:33])[C:29]#[N:14])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1c(F)ccc(C)c1Cl
Reactant: Cc1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(C(C)(C)C#N)ccc(C)c1Cl
Temperature: 27 °C
Reaction time: 456 h
Yield: 53.4 %

Procedure:
17.6 g (100.8 mmol) of 2-chloro-6-fluoro-3-methylanisole is dissolved in 880 ml of toluene. After 27.8 g (403.2 mmol) of isobutyric acid nitrile is added, 302.4 ml (151.2 mmol) of a 0.5 molar solution of potassium hexamethyl disilazide in toluene is added in drops within 40 minutes (temperature increase to 27° C.). After 19 days of stirring at room temperature, the batch is mixed with 300 ml of water and 400 ml of ethyl acetate and then acidified with 10% sulfuric acid to a pH of 4. The aqueous phase is shaken with 200 ml of ethyl acetate. The combined organic extracts are washed with water and twice with saturated NaCl solution and then dried. After spinning-in and chromatography on silica gel (mobile solvent: ethyl acetate/hexane), 12.01 g (53.4%) of the desired compound is obtained.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.C([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22]2[S:23][CH:24]=[C:25](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:26]=2)[CH2:17][CH2:16]1)C1C=CC=CC=1>ClCCl>[ClH:1].[ClH:1].[NH:15]1[CH2:16][CH2:17][CH:18]([NH:21][C:22]2[S:23][CH:24]=[C:25](/[CH:27]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:26]=2)[CH2:19][CH2:20]1
Reactant: CC(Cl)OC(=O)Cl
Reactant: CCOC(=O)/C=C/c1csc(NC2CCN(Cc3ccccc3)CC2)n1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1csc(NC2CCNCC2)n1
Product: Cl
Reaction time: 1.5 h

Procedure:
1-Chloroethyl chloroformate (1.88 mL) was added a mixture of ethyl (2E)-3-{2-[(1-benzyl-4-piperidyl)amino]-1,3-thiazol-4-yl}acrylate (2.7 g) in dichloromethane (40 mL) at ambient temperature and the mixture was stirred at same temperature for 1.5 hour. The solvent was removed by concentration. To the residue was added an EtOH (42.7 mL) and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was added 2N-ethanolic hydrogen chloride (7.3 mL) at ambient temperature and the mixture was stirred at same temperature for 20 hours. The isolated precipitate was collected by filtration to give ethyl (2E)-3-[2-(4-piperidylamino)-1,3-thiazol-4-yl]acrylate dihydrochloride (1.44 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([N:16](CC)CC)[CH3:15].ClCCN>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][CH2:14][NH2:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCN(CC)CC
Agent: NCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Yield: 26 %

Procedure:
A solution of N-tert-butoxycarbonyl-piperazin (5 g, 26.8 mmol), triethylamine (7.44 ml, 53.6 mmol), and chloroethylamine (3.11 g, 26.8 mmol) in dimethylformamide (50 ml) was stirred at room temperature for 72 hours. The reaction mixture was filtered, partitioned between H2O and ethyl acetate. The aqueous phase was lyophilized, the residue stirred with methanol and the precipitate collected by suction. The precipitate was purified by flash chromatography on silica gel (dichloromethane/methanol/aqueous ammonia=9/1/0.1) to give 1.6 g (26%) of the desired product. MS m/z: 230 ((M+H)+, 91%).