Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:16]=[CH:17][C:18]([OH:22])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:31])[F:30])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1.I[CH:33]([CH3:35])[CH3:34]>C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:20]([CH3:21])=[N:19][C:18]([O:22][CH:33]([CH3:35])[CH3:34])=[CH:17][CH:16]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:28][CH:29]([F:30])[F:31])[C:24]([F:27])([F:26])[F:25])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: Cc1nc(O)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1nc(OC(C)C)ccc1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 5-{9-chloro-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-3,4-dihydropyrimido[1,2-a]benzimidazol-1(2H)-yl}-6-methylpyridin-2-ol (30.0 mg, 0.0648 mmol) in toluene (1.0 mL) was added silver carbonate (35.7 mg, 0.130 mmol) and 2-iodopropane (32.3 μL, 0.324 mmol). The reaction mixture was stirred at room temperature for 5 hrs. The starting material wasn't consumed completely. The mixture was stirred at 50° C. for 5 hrs. After cooling the mixture was filtered through on the pad of celite. The filtrate was concentrated. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (29.3 mg, 0.0633 mmol, 98%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].[O:21]=[C:22]1[CH2:27][N:26]([CH2:28][C:29]([OH:31])=[O:30])[CH2:25][C:24](=[O:32])[O:23]1>CN(C=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:22](=[O:21])[CH2:27][N:26]([CH2:25][C:24]([OH:32])=[O:23])[CH2:28][C:29]([OH:31])=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCCC(=O)OCc1ccccc1
Reactant: O=C(O)CN1CC(=O)OC(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CN(CC(=O)O)CC(=O)NCCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To an ice bath cooled solution of benzyl 3-aminopropanoate hydrochloride (4.49 g, 20.8 mmol) in DMF (30 mL) was added K2CO3 (3.02 g, 21.84 mmol) and the resulting mixture was stirred at o° C. for 2 hr. The mixture was then filtered and the filtrate was added to an ice bath cooled solution of 2-(2,6-dioxomorpholino)acetic acid (4.47 g, 25.8 mmol) in DMF (30 mL). The resulting mixture was stirred at 0° C. for 30 min, then at rt for 2 hr. The reaction was quenched by the addition of water (30 mL) and the resulting mixture was concentrated. The residue was stirred with water (40 mL), and the resulting precipitate was collected through filtration and dried to give the title compound. 1H NMR (DMSO-d6) δ 2.53 (t, J=6.8, 2H), 3.27 (s, 2H), 3.36 (q, J=6.2, 2H), 3.42 (m, m 2H), 3.49 (s, 2H), 5.09 (s, 2H), 7.28 (m, 4H), 8.16 (m, 1H), 12.45 (br s, 2H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][OH:15])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:26][C:27]#[N:28].[Na+].[OH-].[Na+]>O>[CH3:1][C:2]1[C:3]([N:9]([CH:16]2[C:25]3[N:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH2:19][CH2:18][CH2:17]2)[CH2:10][CH2:11][CH2:12][CH2:13][N:14]([OH:15])[C:27]([NH2:28])=[O:26])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N(CCCCNO)C2CCCc3cccnc32)c(C)c1
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cnc(N(CCCCN(O)C(N)=O)C2CCCc3cccnc32)c(C)c1

Procedure:
N-{4-[(3,5-Dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-hydroxylamine (HBr salt) (180 mg, 0.25 mmol) was dissolved in H2O (2.5 mL) and treated with sodium cyanate (65 mg, 1.0 mmol) for 2 hours. 15% aqueous NaOH solution (0.1 mL) was added and the aqueous was extracted with CH2Cl2 (3×5 mL). The combined organics were then dried (Na2SO4) and concentrated under reduced pressure to afford, after radial chromatographic purification on a silica gel plate (3% NH4OH/CH3CN)N-{4-[(3,5-dimethyl-pyridin-2-yl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-N-hydroxyurea (73 mg, 73%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH:13]([N:16](C(C)C)CC)(C)[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:8][CH:14]=[CH:13][N:16]=2)=[C:4]([CH2:11][CH3:12])[CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCc1cc(Br)ccc1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCc1cc(Br)ccc1-c1ncco1
Temperature: 135 °C

Procedure:
4-Bromo-2-ethyl-benzoic acid (6.8 g, 30 mmol), diisopropylethylamine (7.8 mL, 44.7 mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 14 g, 37 mmol), and aminoacetaldehyde dimethyl ether (4 mL, 37 mmol) in 2:1 dichlormethane/dimethylformamide (120 mL) 5 h at room temperature. The solution was washed with several portions of water, then 1 N HCl(aq) and saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude light yellow oil. The residue was redissolved in Eaton's reagent (P2O5 in methanesulfonic acid, 100 mL), and the solution was heated at 135° C. under argon for 6 h. The solution was cooled to room temperature and carefully poured onto ice. The mixture was extracted with dichloromethane, and the organic layer was backwashed with saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to a crude oil. The residue was redissolved in ethyl acetate and washed with saturated sodium bicarbonate, then saturated sodium chloride, dried (Na2SO4), filtered, and concentrated in vacuo to pure brown liquid (3.16 g, 44%) 1H NMR (300 MHz, CDCl3): δ ppm 1.24 (t, J=7.54 Hz, 3H) 3.09 (q, J=7.54 Hz, 2H) 7.27 (s, 1H) 7.42 (dd, J=8.38, 1.98 Hz, 1H) 7.48 (d, J=2.07 Hz, 1H) 7.74 (s, 1H) 7.81 (d, J=8.48 Hz, 1H).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([OH:13])=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH:2]=[CH2:3]>C1(C)C=CC=CC=1.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[OH:13][C:5]1[C:4](/[CH:1]=[CH:2]/[CH3:3])=[CH:9][CH:8]=[CH:7][C:6]=1[C:10](=[O:12])[CH3:11]
Reactant: C=CCc1cccc(C(C)=O)c1O
Agent: Cl[Pd]Cl
Solvent: Cc1ccccc1
Solvent: N#Cc1ccccc1
Product: C/C=C/c1cccc(C(C)=O)c1O
Temperature: 120 °C

Procedure:
40 g (227 mmol) of 1-(3-allyl-2-hydroxyphenyl)ethanone are dissolved in 120 ml of toluene, and 2.17 g (5.6 mmol) of bis(benzonitrile)dichloropalladium(II) are added. The reaction mixture is heated at 120° C. ovemight. Cooling to room temperature is followed by filtration through kieselguhr, and the solvent is removed in vacuo. 20.9 g (95% of theory) of the title compound are obtained and are reacted without further purification in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.O.O.O.C([O-])(=O)C.[Na+].[CH3:20][C:21]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:22]=1[CH2:23]Cl.Cl>C(#N)C.O>[CH3:20][C:21]1[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][C:22]=1[CH2:23][NH:1][C:2]1[CH:3]=[C:4]([S:8]([OH:11])(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C)c(CCl)c1
Reactant: Nc1cccc(S(=O)(=O)O)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: Cc1ccc(C)c(CNc2cccc(S(=O)(=O)O)c2)c1
Reaction time: 0.33 h
Yield: 53 %

Procedure:
To a stirred slurry of 52.0 g (0.30 mole) of 3-aminobenzenesulfonic acid in 225 ml of hot (65° C.) water was added 83.0 g (0.61 mole) of sodium acetate trihydrate and 75 ml of acetonitrile. The temperature was stabilized at approximately 67°-68° C. and a solution of 30.93 g (0.20 mole) of 2,5-dimethylbenzyl chloride in 75 ml of acetonitrile added dropwise over 1 hr. The resulting orange solution was refluxed for 31/2 hrs, then acidified with 40 ml of conc. HCl while simultaneously distilling off 80 ml of acetonitrile. After placing the reaction mixture in a refrigerator a flocculent cream-colored precipitate formed which was collected by vacuum filtration, washed with water and air-dried. The collected solids were then slurried in 400 ml of boiling methanol for 20 minutes, then vacuum filtered and then dried in vacuo at about 60° C., which afforded 30.86 g (53.0% yield) of purified 3-(((2,5-dimethylphenyl)methyl)amino)benzenesulfonic acid as a white powder having a melting point greater than 275° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=O)C.O.[NH2:28][NH2:29]>CCO>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]2([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:29][NH:28][C:4]2=[O:3])[CH2:7]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NN=C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of racemic mixture of 3-benzoyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (step 1) (400 mg, 1.1 mmol) in EtOH (4 ml) was added hydrazine hydrate (166 mg, 3.3 mmol). The reaction mixture was stirred at RT for 30 min before heating in the microwave at 120° C. for 3 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was further washed with EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.[H-].[Na+].Br[CH2:17][C:18]1[C:19]([Cl:24])=[N:20][CH:21]=[CH:22][CH:23]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:24][C:19]1[C:18]([CH2:17][N:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: c1cncc(Nc2cccnc2)c1
Reactant: Clc1ncccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ncccc1CN(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.8 %

Procedure:
To a solution of N-pyridin-3-ylpyridin-3-amine (510 mg, 3 mmol) in anhydrous DMF (4.5 mL) was added 60% sodium hydride/mineral oil (169 mg, 4.2 mmol). After stirring at ambient temperature for 15 min., 3-(bromomethyl)-2-chloropyridine (677 mg, 3.28 mmol) (preparation described in U.S. Pat. No. 5,739,326) was added neat and the action was stirred for ˜2 hours. The reaction was diluted with ethyl acetate, washed with NaHCO3 solution, then water, and the organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent evaporated. The residue was purified by silica gel chromato-graphy eluting with a 20-90% acetonelhexane gradient to give the purified product which upon trituration with diethyl ether gave the title compound as a tan solid (684 mg, 77% yield). 1H-NMR (500 MHz , CDCl3): δ 8.40 (2H, d, J=2.7 Hz), 8.34 (1H, d, J=4.6 Hz), 8.30 (2H, d, J=4.6 Hz), 7.69 (1H, d, J=7.8 Hz), 7.33-7.35 (2H, br d, J=˜8.3 Hz), 7.20-7.26 (4H, m), 5.04 (2H, s). m/e (m+1): 297.0
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH2:2]1.[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27](O)=[O:28])[CH2:26][CH2:25]3)=[CH:23][C:18]=2[O:17][CH2:16]1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(#N)C>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3([C:27]([NH:14][C:8]4[CH:7]=[C:6]5[C:11](=[CH:10][CH:9]=4)[NH:12][C:13]4[CH2:1][CH2:2][CH2:3][CH2:4][C:5]5=4)=[O:28])[CH2:25][CH2:26]3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: Nc1ccc2[nH]c3c(c2c1)CCCC3
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(Nc1ccc2[nH]c3c(c2c1)CCCC3)C1(c2ccc3c(c2)OCO3)CC1
Temperature: 70 °C
Reaction time: 16 h
Yield: 70 %

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-6-amine (81.8 mg, 0.439 mmol) and 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (90.4 mg, 0.439 mmol) were dissolved in acetonitrile (3 mL) containing diisopropylethylamine (0.230 mL, 1.32 mmol) and a magnetic stir bar. O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (183 mg, 0.482 mmol) was added to the mixture and the resulting solution was allowed to stir for 16 h at 70° C. The solvent was evaporated and the crude product was then purified on 40 g of silica gel utilizing a gradient of 5-50% ethyl acetate in hexanes to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2,3,4,9-tetrahydro-1H-carbazol-6-yl)cyclopropanecarboxamide as a beige powder (0.115 g, 70%) after drying. ESI-MS calc. 374.2. found 375.3 (M+1)+. Retention time of 3.43 minutes. 1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.39 (s, 1H), 7.46 (d, J=1.8 Hz, 1H), 7.10-6.89 (m, 5H), 6.03 (s, 2H), 2.68-2.65 (m, 2H), 2.56-2.54 (m, 2H), 1.82-1.77 (m, 4H), 1.41-1.34 (m, 2H), 1.04-0.97 (m, 2H).
Reaction SMILES: [C:1](=[O:16])([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)OC1C=CC=CC=1.[NH2:17][C@H:18]([C:23]([O-:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22].C([S+]1CCCC1)CCC.Cl>C(#N)C>[O:9]([C:1]([NH:17][C@H:18]([C:23]([OH:25])=[O:24])[CH2:19][CH2:20][S:21][CH3:22])=[O:16])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CSCC[C@H](N)C(=O)[O-]
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: CCCC[S+]1CCCC1
Agent: Cl
Solvent: CC#N
Product: CSCC[C@H](NC(=O)Oc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, 428 mg (2 mmol) of diphenyl carbonate and 5 mL of acetonitrile were loaded into a round bottom flask having a volume of 100 mL, and then the mixture was stirred at room temperature. A solution prepared by dissolving 633 mg (mL) of butyltetrahydrothiophenium methionine salt in 15 mL of acetonitrile was dropped to the solution, and then the mixture was stirred for 20 minutes. After that, a 1M aqueous HCl solution was added to the reaction solution to terminate the reaction, and then the resultant was concentrated with an evaporator. Next, water was added to the concentrated product, and then the resultant was extracted with ethyl acetate. The resultant organic layer was washed with water and brine, and was then dried with sodium sulfate. After that, the dried product was concentrated with an evaporator. Thus, a crude product was obtained. Next, the crude product was purified by column chromatography. Thus, N-phenoxycarbonyl-L-methionine was obtained. An isolation amount and an isolation yield were 428.8 mg and 80%, respectively.
Reaction SMILES: O1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[N:7]1([CH2:12][C:13]2C=CC(NN)=C[CH:14]=2)C=NC=N1>O1CCOCC1.O>[NH:7]1[C:12]2[C:4](=[CH:5][CH:6]=[CH:14][CH:13]=2)[CH:3]=[CH:2]1
Reactant: NNc1ccc(Cn2cncn2)cc1
Reactant: C1=COCCC1
Solvent: C1COCCO1
Solvent: O
Product: c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 1.75 h
Yield: 37.2 %

Procedure:
3,4-Dihydro-2H-pyran (3.9 ml, 42.7 mmol) was added to a stirred solution of 4-(1,2,4-triazol-1-ylmethyl)phenyl hydrazine (EP 497,512; 4.0 g, 21.1 mmol) in dioxane/water/5N HCl (38 ml/14 ml/4.7 ml) and stirred at room temperature for 1.75 h. The solution was then refluxed for 1.5 h and the solvent removed under vaccum. The residue was taken up into CH2Cl2 and saturated aqueous K2CO3 solution. The aqueous was separated and further extracted with CH2Cl2 (×4). The combined organic extracts were dried (MgSO4) and evaporated and the residue chromatographed on silica gel eluting with CH2Cl2 /MeOH/NH3 (80:8:1) to give the title-indole (0.919 g, 17%), δ (250 MHz, CDCl3) 1.91-2.03 (2H, m, CH2), 2.84 (2H, t, J=7.9 Hz, CH2), 3.73 (2H, t, J=7.9 Hz, CH2), 5.43 (2H, s, CH2), 7.04 (1H, d, J=2.3 Hz, Ar--H), 7.11 (1H, dd, J=2.3 and 8.3 Hz, Ar--H), 7.35 (1H, d, J=8.3 Hz, Ar--H), 7.58 (1H, s, Ar--H), 7.97 (1H, s, Ar--H), 8.02 (1H, s, Ar--H), 8.18 (1H, s, NH).
Reaction SMILES: [Cl:1][CH:2]([Cl:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:12]=[C:13]=[O:14])(=[O:11])=[O:10].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=1>C(#N)C>[Cl:15][CH:2]([Cl:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([NH:12][C:13]([NH:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[N:20]=[C:19]([CH3:25])[N:18]=1)=[O:14])(=[O:11])=[O:10]
Reactant: O=C=NS(=O)(=O)c1ccccc1C(Cl)Cl
Reactant: COc1nc(C)nc(N)n1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(Cl)Cl)n1
Reaction time: 18 h

Procedure:
2-(Dichloromethyl)benzenesulfonyl isocyanate prepared from 10 mmol of sulfonamide as described in the synthesis of Example 1, was treated with acetonitrile (15 ml) and 2-amino-4-methoxy-6-methyl-1,3,5-triazine (1.40 g). The mixture was stirred for 18 hrs. and filtered. The filtrate was evaporated and recrystallized from acetone to give 0.78 g of white solid, mp. 168°-169° (dec). 1H nmr δDMSO-d6TMS 8.37-7.50 (m, featuring singlet at 8.07), 7.00-6.17 (brds), 4.00 (s), 2.48 (s). IR (nujol) featured bands at 1720 and 1590 cm-1. Mass spectrum featured 264.9367 (calc'd for C8H5Cl2NO3S 264.9367) and 140.0687 (calc'd for C5H8N4O 140.0697).
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.CN(C)P(N(C)C)(N(C)C)=O>C1COCC1>[OH:20][C:17]1([C:1]2([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]2)[CH2:18][CH2:19][O:15][CH2:16]1
Reactant: O=C1CCOC1
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#CC1(C2(O)CCOC2)CCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 44.3 %

Procedure:
To a solution of cyclobutanecarbonitrile (405 mg, 5 mmol) in THF (7 ml) was added 2.0M lithium diisopropylamide (2.5 ml, 5 mmol) dropwise at −78° C. The reaction solution was stirred at −78° C. for 40 minutes, followed by the addition of a solution of dihydrofuran-3(2H)-one (473 mg, 5.5 mmol) in hexamethylphosphoramide (268 mg, 1.5 mmol). The mixture was warmed to room temperature and stirred for 3 hours. The reaction mixture was quenched with 1N aqueous HCl solution and extracted with EtOAc (3×20 mL). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography (eluted with petroleum ether:EtOAc=20:1) to provide the title compound as a corloless oil (0.37 g, yield 44%). 1H NMR (400 MHz, CDCl3): δ 4.15-4.05 (m, 2H), 3.86 (d, J=10.0 Hz, 1H), 3.74 (d, J=9.6 Hz, 1H), 2.47-2.42 (m, 4H), 2.39-2.31 (m, 3H), 2.01-1.94 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:13][N:14]1[S:18](=[O:20])(=[O:19])[N:17]2[CH2:21][CH2:22][CH2:23][CH:16]2[C:15]1=[O:24]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([O:6][CH2:13][N:14]1[S:18](=[O:20])(=[O:19])[N:17]2[CH2:21][CH2:22][CH2:23][CH:16]2[C:15]1=[O:24])=[O:5]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: O=C1C2CCCN2S(=O)(=O)N1CCl
Solvent: CO
Product: O=C(OCN1C(=O)C2CCCN2S1(=O)=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.9 %

Procedure:
To a solution of CS2CO3 (0.47 g; 1.44 mmol) in 10 ml of methanol was added 0.55 g (2.88 mmol) of 2,6-dichlorobenzoic acid and the resulting mixture was stirred under nitrogen at room temperature for 3 hours. The above mixture was concentrated in vacuo to remove the excess methanol, the residue suspended in 10 ml of DMF and 2-chloromethyl-tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3 (2H)-one 1,1-dioxide (0.5 g; 2.6 mmol) was added. The resulting mixture was allowed to react at 90° C. for 3 hours and then cooled. The mixture was poured into ice/water, extracted with ether/ethyl acetate (3:1; 250 ml), and the organic layer was washed with water and brine, and dried. The organic layer was concentrated in vacuo and the residue was purified by silica gel flash chromatography (35% ethyl acetate in hexane) to afford 0.6 g (61%) of 2-(2,6-dichlorophenylcarbonyloxymethyl) tetrahydropyrrolo[1,2-b]-1,2,5-thiadiazol-3(2H)-one 1,1-dioxide (Formula I: Ar=2,6-Cl2 -phenyl; R1 =H; R2 and R3 together =-(CH2)3 -) as a solid, m.p. 92°-93.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH3:9].[N+]([C:13]1[CH:18]=CC=C[CH:14]=1)([O-])=O.S(=O)(=O)(O)O>C(O)C(O)CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[CH3:9])[N:8]=[CH:18][CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1ccccc1
Reactant: Cc1cc(N)ccc1Br
Agent: O=S(=O)(O)O
Solvent: OCC(O)CO
Product: Cc1cc2ncccc2cc1Br

Procedure:
A mixture of 20 g of 4-bromo-3-methyl-phenylamine, 6.6 g of ferrous sulfate, 40.8 g of propane-1,2,3-triol, 8.12 g of nitrobenzene and 23 ml of concentrated sulfuric acid were heated gently. After the first vigorous reaction, the mixture was heated to reflux for 3 h and then evaporated to remove the excess nitrobenzene. To the solution was added saturated NaHCO3 to pH 8 and the solution was filtered and extracted with dichloromethane. The dichloromethane layers were combined and dried over Na2SO4 and concentrated. The solid was purified via flash column chromatography to give yellow solid which was washed with petroleum ether to return the title compound (7.5 g, 65%). NMR (CDCl3, 300 MHz) δ 8.89 (m, 1H), 8.04 (m, 2H), 7.96 (s, 1H), 7.36 (m, 1H), 2.60 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][N:32]([CH2:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)[CH3:33].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:38]2[CH:39]=[CH:40][C:35]([CH2:34][N:32]([CH3:33])[CH3:31])=[CH:36][CH:37]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: CN(C)Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCN(c1cc(-c2ccc(CN(C)C)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 53.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (0.2 g, 0.42 mmol) and (4-((dimethylamino)methyl)phenyl)boronic acid (0.15 g, 0.505 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.16 g, 1.51 mmol) was added and the solution purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was the added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was then diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and the solvent removed under reduced pressure to afford the crude product which was purified by column chromatography over silica gel to afford the title compound (0.120 g, 53.8%). LCMS: 531.30 (M+1)+; HPLC: 94.88% (@254 nm) (Rt; 3.949; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.19 (t, 1H, J=4.4 Hz), 7.61 (d, 2H, J=8 Hz), 7.39-7.41 (m, 3H), 7.23 (s, 1H), 5.86 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.62-3.84 (m, 4H), 3.22-3.38 (m, 2H), 3.02-3.06 (m, 3H), 2.30 (bs, 6H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.64-1.67 (m, 2H), 1.51-1.53 (m, 2H), 0.83 (t, 3H, J=6.8 Hz).