Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1ccccn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: Cl[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[CH3:13][NH2:14]>C(#N)C>[CH3:13][NH:14][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: CN
Reactant: O=S(=O)(CCCl)c1ccccc1
Solvent: CC#N
Product: CNCCS(=O)(=O)c1ccccc1

Procedure:
A solution of 2-chloroethylphenyl sulfone and a large excess of methylamine (40% solution in water) in acetonitrile is stirred at room temperature overnight. The solvent is removed in vacuo and the residue is partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution is extracted with dilute sulfuric acid. The acidic extract is made basic with 50% sodium hydroxide and the basic solution is extracted with methylene chloride. The methylene chloride solution is dried over magnesium sulfate and the solvent is removed in vacuo to give the title compound.
Reaction SMILES: [Cl-:1].[OH:2][CH:3]([CH2:9]O)[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6].S(Cl)([Cl:13])=O>CN(C)C=O>[Cl-:13].[Cl:1][CH2:9][CH:3]([OH:2])[CH2:4][N+:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: C[N+](C)(C)CC(O)CO
Reactant: O=S(Cl)Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C[N+](C)(C)CC(O)CCl
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
There was suspended 9.20 g of 2,3-dihydroxypropyltrimethylammonium chloride (chemical purity: 100%) in 50 ml of dimethylformamide, and thereto 6.80 g of thionyl chloride was added at a temperature from 5° to 10° C. After stirring for 20 minutes, it was heated at 100° C. for 5 hours. Finally, after cooling the reaction mixture to room temperature, 9.85 g of 3-chloro-2-hydroxypropyltrimethylammonium chloride was obtained by evaporating the reaction mixture to dryness.
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1.N1C=CC=CC=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.C(O)C(N)(CO)CO>ClCCCl>[CH3:1][C:2]1[C:7]([NH:8][S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:6][CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][C@@H:11]([N:14]3[CH2:18][CH2:17][CH2:16][C@@H:15]3[CH3:19])[CH2:10]2)[N:3]=1
Reactant: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1N
Reactant: O=S(=O)(Cl)C1CC1
Agent: NC(CO)(CO)CO
Solvent: c1ccncc1
Solvent: ClCCCl
Product: Cc1nc(N2CC[C@@H](N3CCC[C@@H]3C)C2)ccc1NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 29.6 %

Procedure:
To a solution of 2-methyl-6-[(3R)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]pyridin-3-amine (22.7 mg, 0.09 mmol) in DCE (1 mL) was added pyridine (0.22 mL, 2.7 mmol) followed by a solution of cyclopropanesulfonyl chloride (38 mg, 0.27 mmol) in DCE (1 mL) and stirred at ambient temperature for 5 hours. To this mixture was then added trisamine resin (200 mg, 0.8 mmol, 4 mmol/g loading), stirred for 30 min, filtered and concentrated to afford a crude solid which was purified by flash column chromatography (5% 7N NH3 in MeOH/CH2Cl2) to obtain 9.7 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[F:14].Cl[Sn]Cl>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[F:14]
Reactant: COC(=O)c1cc(I)cc([N+](=O)[O-])c1F
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(I)cc(N)c1F
Temperature: 25 °C
Yield: 61.6 %

Procedure:
2-Fluoro-5-iodo-3-nitro-benzoic acid methyl ester (1.0 g, 3.08 mmol) and SnCl2 (2.33 g, 12.3 mmol) were added to 20 mL EtOAc, and the mixture was heated to reflux for two hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 20 mL saturated aqueous NaHCO3, and the aqueous mixture was extracted with EtOAc. The combined organic layers were washed with and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 560 mg (62%) of 3-amino-2-fluoro-5-iodo-benzoic acid methyl ester, MS (M+H)=296.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([NH2:19])[N:18]=3)[N:15]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:22]=1[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC>ClC(Cl)C.CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[NH2:19][C:17]1[N:18]=[C:13]2[CH:12]=[CH:11][C:10]([C:9]#[C:8][C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:24])[C:22]4[CH:26]=[C:27]([CH3:30])[CH:28]=[CH:29][C:21]=4[F:20])=[CH:3][CH:4]=3)=[N:15][N:14]2[CH:16]=1
Reactant: Cc1ccc(F)c(C(=O)O)c1
Reactant: Nc1ccc(C#Cc2ccc3nc(N)cn3n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1ccc(F)c(C(=O)Nc2ccc(C#Cc3ccc4nc(N)cn4n3)cc2)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To 6-[(4-aminophenyl)ethynyl]imidazo[1,2-b]pyridazin-2-amine, (30 mg, 0.12 mmol, 1 eq) and 2-fluoro-5-methylbenzoic acid (18.5 mg, 1 eq) in anhydrous dichloroethane (1 mL) under nitrogen atmosphere at room temperature was added 4-(dimethylamino)pyridine (2.94 mg, 0.2 eq) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (27.76 mg, 1.2 eq). After the reaction was stirred at 50° C. for 2 hours, it was diluted with chloroform, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, brine, and lastly dried with anhydrous sodium sulfate. The upper solution was decanted, concentrated, and the solid residue was subject to a gradient column chromatography (from CHCl3 to MeOH—CHCl3 1:25) to yield N-{4-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)ethynyl]phenyl}-2-fluoro-5-methylbenzamide as a yellow solid in amount of 7 mg.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:20])[CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:26].CCCCCC>O1CCCC1>[CH3:17][O:16][C:14]1[CH:15]=[C:10]([CH:9]([C:25]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[C:8]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH:11]=[C:12]([O:18][CH3:19])[CH:13]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(CC(=O)Oc2ccccc2)cc(OC)c1
Agent: O=C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(C(=O)Oc2ccccc2)C(=O)Oc2ccccc2)c1
Temperature: -70 °C
Reaction time: 2.5 h

Procedure:
To a solution of lithium bis(trimethylsilyl)amide (400 mL, 1M in tetrahydrofuran obtained commercially from Aldrich Chem. Co.) was added a solution of 3,5-dimethoxybenzeneacetic acid phenyl ester (53.1 g) in tetrahydrofuran (65 mL) dropwise over 20 min while cooling in a dry ice bath at −70° C. The resulting slurry was stirred at dry ice temperature for 45 min Phenyl chloroformate (26 mL) was added all at once followed by 50 mL of tetrahydrofuran. The resulting thick slurry was stirred for 2.5 h at 0° C. while cooling in an ice bath before quenching with diluted aqueous HCl (50 mL of conc. HCl diluted to 150 mL with water). The bulk of tetrahydrofuran was removed under vacuum and diethyl ether (550 mL) and water (80 mL) were added. The aqueous layer was separated and extracted with diethyl ether (50 mL). The combined ether layers were dried over magnesium sulfate and concentrated under vacuum to yield a crude solid which was stirred with hexane (250 mL) for 24 h. The solid was then collected by filtration, washed with hexane (100 mL), and vacuum dried to yield 62 g of the title compound. 1H NMR (CDCl3) δ 7.37 (t, 2H), 7.26 (q, 1H), 7.13 (d, 2H), 6.73 (s, 2H), 6.45 (s, 1H), 5.02 (s, 1H), 3.82 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH:11](O)[C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH2:21][N:22]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=1[Cl:35])=[O:24].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]1[N:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]2=[N:14][C:13]=1[CH2:21][N:22]([CH2:36][CH2:37][CH:38]([CH3:40])[CH3:39])[C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[C:26]=1[Cl:35])=[O:24]
Reactant: COc1ccc(OC)c(C(O)c2c(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)nc3ccccn23)c1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(OC)c(Cc2c(CN(CCC(C)C)C(=O)c3ccc(OC)c(OC)c3Cl)nc3ccccn23)c1
Temperature: 60 °C
Yield: 58.3 %

Procedure:
A solution of 58 mg (0.1 mmol) of N-({3-[(2,5-dimethoxyphenyl) hydroxymethyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide in 5 mL dichloromethane is treated with 116 mg (1.0 mmol) triethylsilane and 114 mg (1.0 mmol) trifluoroacetic acid. The solution is heated in a sealed tube at 60° C. for 18 hr and diluted with 15 mL sat. NaHCO3 and extracted with 3×10 mL dichloromethane. The combined organics are washed with 10 mL water and 10 mL brine. The resulting organic layer is dried over anhydrous MgSO4 and the solvent removed in vacuo to give the crude material. The residue is prep-plate chromatographed (9% MeOH/CH2Cl2/0.5% NH4OH) to afford 33 mg (58%) N-({3-[(2,5-dimethoxyphenyl)methyl](imidazolo[1,2-a]pyridin-2-yl)}methyl)(2-chloro-3,4-dimethoxyphenyl)-N-(3-methylbutyl)carboxamide. Mass Spec m/z (M++1) 567.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[N:14][CH:15]=2)=[CH:5][CH:4]=1)#[N:2].Br[CH2:17][C:18]1[CH:19]=[CH:20][C:21]2[C:22]([CH:26]=1)=[N:23][O:24][N:25]=2>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]3[C:22]([CH:26]=2)=[N:23][O:24][N:25]=3)[C:10]2[CH:15]=[N:14][CH:13]=[N:12][CH:11]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: BrCc1ccc2nonc2c1
Reactant: N#Cc1ccc(Nc2cncnc2)cc1
Product: N#Cc1ccc(N(Cc2ccc3nonc3c2)c2cncnc2)cc1

Procedure:
Starting compounds: 5-[N-(4-cyanophenyl) amino]pyrimidine and 5-bromomethylbenzofurazane
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([OH:22])=O)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[O:29]([NH2:31])[CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:28])=[C:14]([C:24]([NH:26][CH3:27])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][C:20]([NH:31][O:29][CH3:30])=[O:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CON
Reactant: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)O)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NOC)c1=O

Procedure:
This compound was prepared from [7-[(4-fluorophenyl)methyl]-4-hydroxy-3-[(methylamino)carbonyl]-2-oxo-1,5-naphthyridine-1(2H)-yl]acetic acid and methoxylamine employing methods similar to those described in example 558. The product was obtained as a white solid: 1H NMR (d6-DMSO) δ 11.39 (1H, br s), 9.96 (1H, br s), 8.55 (1H, s), 7.88 (1H, s), 7.36-7.31 (2H, m), 7.14-7.09 (2H, m), 4.80 (2H, s), 4.11 (2H, s), 3.52 (3H, s), 2.88 (3H, d, J=4.8 Hz); HRMS calcd for C20H19FN4O5+H+: 415.1412. Found 415.1416.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][OH:13].Cl.[N-]=[C:16]=[O:17].[K+]>O>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]2[N:9]([CH2:10][CH2:11][CH2:12][OH:13])[C:16](=[O:17])[NH:1][C:2]=2[CH:7]=1
Reactant: Nc1cc(Cl)ccc1NCCCO
Reactant: [N-]=C=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=c1[nH]c2cc(Cl)ccc2n1CCCO
Reaction time: 20 h
Yield: 32 %

Procedure:
To a stirred solution of 40 parts of 3-[(2-amino-4-chlorophenyl)amino]-1-propanol in 140 parts of water and 24 parts of a hydrochloric acid solution 10N is added dropwise a solution of 18 parts of potassium isocyanate in 40 parts of water (exothermic reaction: temperature rises to 35° C). Upon completion, stirring is continued first for 30 minutes at room temperature and further for 20 hours at reflux temperature. The reaction mixture is allowed to stirr over week-end without heating. The precipitated product is filtered of and treated with a diluted hydrochloric acid solution in 4-methyl-2-pentanone. The whole is stirred and the layers are separated. The 4-methyl-2-pentanone-phase is washed with water, dried, filtered and evaporated, yielding 18 parts (32%) of 5-chloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 148.8° C.
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:34]1[CH:38]2[CH2:39][NH:40][CH2:41][CH:37]2[CH2:36][N:35]1C(OC(C)(C)C)=O>CN(C=O)C>[CH2:34]1[CH:38]2[CH2:39][NH:40][CH2:41][CH:37]2[CH2:36][N:35]1[C:2]1[C:21]([C:22]2[CH:27]=[N:26][CH:25]=[N:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2cncnc2)c1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC3CNCC3C2)c(-c2cncnc2)c1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
To a solution of 6-chloro-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 223.1, 100 mg, 0.253 mmol) in DMF (2 mL) were added K2CO3 (105 mg, 0.760 mmol) and tert-butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (81 mg, 0.380 mmol). The RM was stirred at 110° C. for 4 h and then at 130° C. for 5 h. After removal of solvent under reduced pressure, the crude intermediate was treated with a mixture of TFA/DCM (1 mL/2 mL) at RT for 5 h. The solvent was evaporated off under reduced pressure to afford 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-5-(pyrimidin-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide, a portion of which (100 mg, 0.213 mmol) was dissolved in anhydrous THF (2 mL) and was treated with KOtBu (71.6 mg, 0.638 mmol) and 2-bromoethanol (0.1 mL, 1.435 mmol). The RM was stirred at 70° C. overnight, the solvent was evaporated off under reduced pressure and the crude material was purified by preparative HPLC. The compound was lyophilized in water/MeCN to afford the title product. UPLC-MS (Condition 3), tR=0.77 min, m/z=515.2 [M+H]+.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][N:12]=[N+]=[N-])[CH2:5][CH2:4]1)=[O:2].[H][H].[ClH:17]>[Pd].O.C(OCC)(=O)C>[ClH:17].[CH:1]([N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1)=[O:2]
Reactant: [H][H]
Reactant: [N-]=[N+]=NCCCC1CCN(C=O)CC1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: NCCCC1CCN(C=O)CC1

Procedure:
To a suspension of 10% palladium-on-carbon catalyst (3 g) in water (100 ml), a solution of N-formyl-4-(3-azidopropyl)-piperidine (19.6 g) in ethyl acetate (100 ml) was added. Hydrogen was passed through the mixture, and the pH was maintained at 3.0 by simultaneous addition of 1 N hydrochloric acid. When the consumption of acid ceased, the catalyst was filtered off, and the two layers separated. The aqueous phase was extracted twice with 25 ml portions of ethyl acetate, and thereafter evaporated to dryness in vacuo. The residue was dissolved in propanol-2, filtered, and the filtrate taken to dryness. The residue was treated with acetonitrile, and the crystals were filtered off and washed with acetonitrile followed by ether to give the title compound with m.p. 141°-143° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2S[CH2:11][CH2:10][O:9][N:8]=2)=[CH:4][CH:3]=1.[S:13]([O-:17])([O-])(=O)=[O:14].[Mg+2].ClC1C=C(C=CC=1)C(OO)=O>C=Cl.C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:13](=[O:17])(=[O:14])[CH2:11][CH2:10][O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=NOCCS2)s1
Reactant: O=S(=O)([O-])[O-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Mg+2]
Solvent: ClCCl
Product: O=S1(=O)CCON=C1c1ccc(Cl)s1
Temperature: 30 °C
Yield: 103.3 %

Procedure:
3-(5-Chloro-2-thienyl)-5,6-dihydro-1,4,2-oxathiazine (12 g, 0.055 mol) prepared in Example 1, in methylene chlorine (50 ml) and anhydrous magnesium sulphate (10 g) in suspension, was stirred while m-chloroperoxybenzoic acid (34 g, 50-60% material) in methylene chloride (250 ml), was added dropwise, to prepare a reaction mixture. The reaction mixture was allowed to warm to 30° C. and after the dropwise addition was externally heated to 35° C. for 10 hours by which time a negative starch/Kl test was obtained. Unwanted m-chlorobenzoic acid was then removed from the reaction mixture by extraction with aqueous sodium bicarbonate. The remaining reaction mixture was washed with water, dried (MgSO4) and evaporated to dryness. The resultant residue was chromatographed on 500 g silica gel eluting with methylene chloride, to produce 3-(5-chloro-2-thienyl)-5,6-dihydro-1,4,2-oxathiazine-4,4-dioxide (mp 113°-114° C., 14.3 g, Found: C 33.27, H 2.33, N 5.55; C7H6ClNO3S2 requires C 33.40, H 2.39, N 5.57).
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9](O)=[O:10]>>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C:9]([Cl:3])=[O:10]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCOc1ccc(C(=O)O)cc1Br
Product: CCCCCCCOc1ccc(C(=O)Cl)cc1Br

Procedure:
11 g of thionyl chloride was added to 14.5 g (0.046 mol) of the 3-bromo-4-n-heptyloxybenzoic acid prepared in Step II and was gently refluxed for two hours. Excess thionyl chloride was removed by distillation or vacuum distillation to yield 14.2 of 3-bromo-4-n-heptyloxybenzoyl chloride. The yield was calculated to be 92.3%.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][C:20]3=[O:30])[CH:12]=[CH:11][C:10]1=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>O1CCCC1.C(OCC)(=O)C>[OH:8][CH:9]1[CH2:18][CH2:17][CH2:16][C:15]2[N:14]=[C:13]([CH:19]3[C:27]4[C:22](=[CH:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[NH:21][C:20]3=[O:30])[CH:12]=[CH:11][C:10]1=2
Reactant: CC(C)(C)[Si](C)(C)OC1CCCc2nc(C3C(=O)Nc4ccc(C#N)cc43)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)C(c1ccc3c(n1)CCCC3O)C(=O)N2
Temperature: 0 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
A suspension of 3-(5-(tert-butyldimethylsilyloxy)-5,6,7,8-tetrahydroquinolin-2-yl)-2-oxoindoline-5-carbonitrile (26 mg, 0.062 mmol) in tetrahydrofuran (5 mL) was cooled to 0° C. To this mixture was added dropwise a 1.0M solution of TBAF in THF (0.124 ml, 0.124 mmol) resulting in a clear yellow solution. The reaction was stirred for 1 h at 0° C. and then warmed to RT. After 3 h another portion of TBAF (1.0M in THF, 0.124 ml, 0.124 mmol) was added and the reaction was stirred at RT for 16 h. The mixture was diluted with ethyl acetate and the organic layer was washed with water (2×) and brine (1×). The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness. The crude was purified by flash chromatography (silica gel, DCM/MeOH) yielding a yellow solid. Amount 11 mg. Yield 59%.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](/[C:11](/[S:25][CH3:26])=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH:30]O>C(O)(=O)C.ClCCl>[CH2:1]([C:5]1[CH:10]=[C:9](/[C:11](/[S:25]([CH3:26])=[O:30])=[CH:12]/[C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[N:8]2[N:27]=[CH:28][CH:29]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: OO
Reactant: CCCCc1cc(/C(=C/c2cc(OC)c(OC)c(OC)c2)SC)n2nccc2n1
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCCCc1cc(/C(=C/c2cc(OC)c(OC)c(OC)c2)S(C)=O)n2nccc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.50 g of the compound obtained in Example 12 was dissolved in 5 ml of acetic acid. To the solution was added 0.14 ml of 30% aqueous hydrogen peroxide solution, followed by stirring at room temperature for 4 hours. The reaction mixture was diluted with dichloromethane, washed sequentially with water, sodium bicarbonate solution and saturated saline and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:1→ethyl acetate→dichloroethane:methanol=10:1) and recrystallized from ethyl acetate-n-hexane. 0.38 g of the desired compound was obtained as crystals. The structure and melting point of the compound obtained are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([NH:15][C:16](=O)[C:17]([F:20])([F:19])[F:18])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:32])=CC=1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:32][C:16]([C:17]([F:20])([F:19])[F:18])=[N:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(NC(=O)C(F)(F)F)C(=O)c1ccc(F)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C(F)(F)F)sc1-c1ccc(F)cc1
Yield: 64 %

Procedure:
To a solution of ethyl 3-(4-fluorophenyl)-3-oxo-2-(2,2,2-trifluoroacetamido)propanoate (271 mg, 0.84 mmol) in anhydrous THF (10 mL) was added Lawesson's reagent (682 mg, 1.69 mmol) in one portion and the resulting solution was refluxed for 22 hrs under nitrogen until no starting material is detected by TLC. The solvent was removed under reduced pressure and the crude material was purified by SiO2 chromatography (80% hexanes/20% DCM to 100% DCM in a linear gradient, product elutes in 50% hexanes/50% DCM) (175 mg, 64% yield). 1HNMR (400 MHz, CDCl3): d 7.50 (m, 2H), 7.15 (t, 2H, J=8.8 Hz), 4.31 (q, 2H, J=6.8 Hz), 1.26 (t, 3H, 7.2 Hz).
Reaction SMILES: [CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[H][H]>[Pd].C(O)C>[CH2:1]([C:5]1[N:9]2[CH:10]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]4[NH:30][N:29]=[N:28][N:27]=4)=[CH:16][CH:15]=3)[CH2:11][CH2:12][CH2:13][C:8]2=[N:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CC=C2
Agent: [Pd]
Solvent: CCO
Product: CCCCc1cnc2n1C(c1ccc(-c3ccccc3-c3nnn[nH]3)cc1)CCC2

Procedure:
A suspension of bicyclic olefin imidazole (0.1 mmol, the title compound of Example 1434) and 20 mg (0,019 mmol) of 10% palladium on charcoal in 2 mL of absolute ethanol is agitated on a Parr apparatus under 50 psi of hydrogen gas at room temperature until the reaction is complete. The mixture is filtered through a pad of celite, concentrated in vacuo and purified to give the title compound of Example 1436.
Reaction SMILES: [N:1]1([NH:7][CH2:8][CH2:9][NH:10]C(=O)C)[CH:6]=[CH:5][CH:4]=[N:3][CH2:2]1.[OH-].[Na+].Cl>>[N:1]1([NH:7][CH2:8][CH2:9][NH2:10])[CH:6]=[CH:5][CH:4]=[N:3][CH2:2]1
Reactant: CC(=O)NCCNN1C=CC=NC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCNN1C=CC=NC1
Yield: 86 %

Procedure:
A solution of N-[2-[(pyrimidin-1-yl)amino]ethyl]acetamide (7.1 g, 0.039 mol) in 2.5N NaOH (47 mL, 0.118 mol) was heated under reflux for 22 hours. The mixture was cooled and the pH was adjusted to 8 with 2N HCl (38 mL). The mixture was concentrated, suspended in EtOH (100 mL) and filtered. The filtrate was concentrated to give an oily solid 4.7 g (87%).