Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:18]([NH2:20])=[O:19])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[CH:17]=1.C(N(CC)CC)C.[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[S:38][C:37]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:35]=1>C(#N)C>[Cl:8][C:9]1[C:10]([C:18]([NH2:20])=[O:19])=[C:11]2[CH2:16][N:15]([S:39]([C:37]3[S:38][C:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][N:28]=4)=[CH:35][CH:36]=3)(=[O:40])=[O:41])[CH2:14][CH2:13][N:12]2[CH:17]=1
Reactant: NC(=O)c1c(Cl)cn2c1CNCC2
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1c(Cl)cn2c1CN(S(=O)(=O)c1ccc(-c3ccccn3)s1)CC2
Temperature: 60 °C
Reaction time: 4 h
Yield: 24.7 %

Procedure:
A suspension of 7-chloro-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (156 mg, Reference Example 24) in dry acetonitrile (13 mL) was treated with dry triethylamine (0.28 mL), then with 5-(pyrid-2-yl)thiophene-2-sulfonyl chloride (127 mg). After stirring at 60° C. for 4 hours the reaction mixture was allowed to cool to room temperature and evaporated. The residue was subjected to column chromatography on silica eluting with ethyl acetate to give 7-chloro-2-(5-pyridin-2-ylthiophene-2-sulfonyl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide (51 mg) as a white solid, m.p. 213–214° C. [Elemental analysis: C, 47.99; H, 3.44; N, 12.97%; Calculated for C17H15ClN4O3S2: C, 48.28; H, 3.58; N, 13.25%].
Reaction SMILES: [C:1]1([SnH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([O:17][CH:18]=[CH2:19])(=[O:16])[CH3:15]>C1CCCCC1>[C:14]([O:17][CH2:18][CH2:19][Sn:7]([CH2:19][CH2:18][O:17][C:14](=[O:16])[CH3:15])([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)(=[O:16])[CH3:15]
Reactant: c1ccc([SnH2]c2ccccc2)cc1
Reactant: C=COC(C)=O
Solvent: C1CCCCC1
Product: CC(=O)OCC[Sn](CCOC(C)=O)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
Stoichiometric amounts of diphenyltin dihydride and vinyl acetate were placed in a Pyrex® tube containing anhydrous cyclohexane. The reactionmixture was exposed to ultraviolet radiation for 1 hour at 30° C. The solvent was then eliminated at ambient temperature under vacuum. The product was obtained quantitatively and had the following formula:
Reaction SMILES: [CH2:1]([C:4]1[CH2:5][CH:6]([OH:9])[CH2:7][CH:8]=1)[CH2:2][CH3:3].CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(Cl)=O.C(C1CC(O)CC=1C)C.[Cl:31]/[C:32](/[C:42]([F:45])([F:44])[F:43])=[CH:33]\[C@@H:34]1[C@H:36]([C:37](Cl)=[O:38])[C:35]1([CH3:41])[CH3:40]>>[Cl:31]/[C:32](/[C:42]([F:43])([F:44])[F:45])=[CH:33]\[C@@H:34]1[C@H:36]([C:37]([O:9][CH:6]2[CH2:7][CH:8]=[C:4]([CH2:1][CH2:2][CH3:3])[CH2:5]2)=[O:38])[C:35]1([CH3:41])[CH3:40]
Reactant: CCCC1=CCC(O)C1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Agent: CCC1=C(C)CC(O)C1
Product: CCCC1=CCC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 91 %

Procedure:
(RS)-3-propyl-3-cyclopenten-1-ol (500 mg) and (1RS)-cis-2,2-dimethyl-3-(2,2-dichlorovinyl)cyclopropanecarbonyl chloride (902 mg) were respectively used instead of (RS)-3-ethyl-4-methyl-3-cyclopenten-1-ol and (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride used in Example 1 above and the reaction procedures were carried out in the same manner as in Example 1 to afford 1150 mg of (RS)-3-propyl-3-cyclopentenyl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 130). Yield 91% nD24 1.5038
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[O:16][CH:13]([CH:14]=[CH2:15])[CH:4]([CH:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH:7]=O)[O:3]1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1.C(OCC)C>[CH3:1][C:2]1([CH3:17])[O:16][CH:13]([CH:14]=[CH2:15])[CH:4]([CH:5]([O:9][CH2:10][O:11][CH3:12])[CH2:6][CH:7]=[N:19][OH:20])[O:3]1
Reactant: C=CC1OC(C)(C)OC1C(CC=O)OCOC
Reactant: NO
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: C=CC1OC(C)(C)OC1C(CC=NO)OCOC
Reaction time: 8 h
Yield: 91.7 %

Procedure:
The above 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal (91.9 mg) was dissolved in 1 ml of pyridine, and 45 mg of hydroxylamine hydrochloride was added at room temperature, and stirring was conducted at room temperature for 8 hours. The reaction mixture was diluted with diethyl ether. The diluted reaction mixture was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to afford 89.5 mg of 4,5-(dimethylmethylenedioxy)-3-methoxymethoxy-6-heptenal oxime having the following properties (yield 52%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1.[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:2]([Cl:12])=[CH:3][O:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[CH2:11][Br:13]
Reactant: Cc1cccc(OC=C(Cl)Cl)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: ClC(Cl)=COc1cccc(CBr)c1
Yield: 65 %

Procedure:
3-Tolyl 2,2-dichlorovinyl ether (12.2 g) was dissolved in carbon tetrachloride (75 ml), and N-bromosuccinimide (12.0 g) and a trace of wet benzoyl peroxide added, and the mixture refluxed for 3 hours. After filtration the solvent was evaporated from the filtrate, and the residue dissolved in ether and extracted with 1% w/v sodium hydroxide solution. The ethereal solution was dried over anhydrous magnesium sulphate, the solvent removed by evaporation under reduced pressure, and the residual oil distilled to yield a fraction boiling at 150° C/0.5 mm Hg. This fraction was shown by NMR to contain about 65% of the required product together with about 30% of unchanged starting material, the remainder being a small proportion of the dibromomethyl compound.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH2:23][CH2:24][CH2:25][CH2:26][S:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[N:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3].S(=O)(=O)(O)[OH:35].B1([O-])OO1.O.O.O.O.[Na+]>CO>[N:17]1([CH2:16][CH2:15][N:14]=[S:12]([C:9]2[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:11][CH:10]=2)([CH2:23][CH2:24][CH2:25][CH2:26][S:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:35])=[O:13])[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1
Reactant: O=S(=O)(O)O
Reactant: CS(=O)(=O)Nc1ccc(S(=O)(CCCCSc2ccccc2)=NCCN2CCOCC2)cc1
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(S(=O)(CCCCS(=O)c2ccccc2)=NCCN2CCOCC2)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A cold (0° C.) solution of S-[4-(methanesulfonylamino)phenyl]-N-[2-(4-morpholinyl)ethyl]-S-[4-(phenylthio)butyl]sulfoximine in methanol is treated slowly with excess 30% sulfuric acid and then sodium perborate tetrahydrate (10 equivalents) is added. The mixture is stirred at 0° C. for 2 hrs and then at ambient temperature for 2 hrs. The methanol is removed in vacuo and the residue basified with 50% sodium hydroxide and filtered. The filter cake is washed with methylene chloride. The aqueous filtrate is extracted with methylene chloride and the extract combined with the methylene chloride used to wash the filter cake. The methylene chloride solution is washed with water, dried and concentrated to obtain the title compound.
Reaction SMILES: [CH2:1]1[CH2:5]OC[CH2:2]1.[CH2:6]([O:8][C:9](=[O:22])[CH2:10][C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH3:7].[Li+].CC([N-]C(C)C)C.C(Br)C=C>C(OCC)C>[CH2:6]([O:8][C:9](=[O:22])[CH:10]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])([CH3:13])[CH3:12])[CH2:5][CH:1]=[CH2:2])[CH3:7]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(C)(C)c1ccc(Cl)cc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCC(C(=O)OCC)C(C)(C)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
Cool a THF solution of 1.0 equivalent of 3-(2,4-Dichloro-phenyl)-3-methyl-butyric acid ethyl ester, obtained above, to −78° C., treat with LDA (2.0 eq), followed by allyl bromide (1.1 eq), warm to room temperature and stir 17 h. Quench reaction with NH4Cl, dilute with diethyl ether, wash organics with 0.1 N HCl, brine, dry over sodium sulfate, filter and evaporate. Chromatography, (silica, hexanes/EtOAc, 98:2) provides 2-[1-(2,4-dichloro-phenyl)-1-methyl-ethyl]-pent-4-enoic acid ethyl ester in 52% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][C:3]=1[S:10]([NH:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[C:15]=1[CH3:27])(=[O:12])=[O:11].[H-].[Na+].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>CN(C=O)C>[Cl:8][C:7]1[C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[C:3]([S:10]([NH:13][C:14]2[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[C:16]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[C:15]=2[CH3:27])(=[O:11])=[O:12])[CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(C)c(N2CCCC2)c(C)c1NS(=O)(=O)c1cc(Cl)cc(Cl)c1N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c(N2CCCC2)c(C)c1NS(=O)(=O)c1cc(Cl)cc(Cl)c1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.3 %

Procedure:
To a solution of 40 (69 mg, 0.16 mmol) in DMF at 0° C. was added NaH (60% in mineral oil, 14 mg, 0.35 mmol). The mixture was stirred for 10 min at 0° C. before the addition of methanesulfonyl chloride (22 mg, 0.19 mmol). The resulting mixture was then stirred at room temperature overnight. The reaction was quenched with a few drops of dilute HCl and then diluted with EtOAc (60 mL). The organic layer was washed with water (2×30 mL) and brine (30 mL) and the volatiles were removed by evaporation on a rotavap. The residue was purified on a silica gel column (15% to 30% EtOAc in hexanes) to yield the title compounds as an off-white solid (10 mg ESI [M+H+]=506.12).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:6][C:7](=[O:11])[C:8]=1OC)=[O:5])#[N:2].O.[NH2:13][NH2:14]>C(O)(C)C>[C:1]([C:3]1[C:4]([NH:6][C:7](=[O:11])[C:8]=1[NH:13][NH2:14])=[O:5])#[N:2]
Reactant: NN
Reactant: COC1=C(C#N)C(=O)NC1=O
Solvent: CC(C)O
Solvent: O
Product: N#CC1=C(NN)C(=O)NC1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
50 parts of 2-cyano-3-methoxymaleimide are introduced into a solution of 16.5 parts of hydrazine hydrate in 300 parts by volume of isopropanol, while cooling with ice, the reaction mixture is then stirred at room temperature for half an hour, and the red precipitate is filtered off under suction, washed with isopropanol and dried. 47 PG,6 parts (94% of theory) of 2-cyano-3-hydrazinomaleimide of melting point >350° C. are obtained. IR (KBr): 3120, 2200, 1670 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[OH2:9]>Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:6]([C:3]([OH:9])=[CH:2][C:8]([CH3:7])=[N:5]2)=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O
Agent: Cl
Product: Cc1cc(O)c2ccc(F)cc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 3-fluoroaniline (4.44 g, 40 mmol) and acetoacetic ester (5.20 g, 40 mmol), a catalytic amount (2 drops) of dilute hydrochloric acid was added at 25° C., within 10 minutes water began to separate and small amount of heat was generated. The reaction mixture was allowed to stand at 25° C. overnight; the reaction mixture was diluted with dichloromethane (150 mL), washed successively with 0.5 N HCl (2×50 mL), 0.5 N NaOH (2×50 mL) and water, dried over anhydrous sodium sulphate. Dichloromethane was evaporated and oily residue was added to the refluxing diphenyl ether (40 mL) over a period of 5 minutes, refluxing was continued for 1 hour after that reaction mixture was cooled at 25° C. and solid was separated by filtration, washed with diethyl ether to remove some coloring impurities. The product was obtained as yellow solid (2.3388 g, 33%, based on 3-fluoroaniline) as isomeric mixture of 5 and 7-fluoro-2-methylquinolin-4-ol, used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:15])=[C:4]([N+:12]([O-])=O)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[OH-].[Na+]>Cl>[NH2:12][C:4]1[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=[C:2]([Cl:1])[C:3]=1[F:15]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc(Cl)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc(C(F)(F)F)cc(Cl)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
5-Chloro-4-fluoro-3-nitrotrifluoromethylbenzene (50 g) was added to a cooled (5° C.) solution of stannous chloride (140 g) in concentrated agueous hydrochloric acid (187 ml). After stirring for several hours at the ambient temperature (ca 22° C.), the reaction mixture was stood overnight. After basification by the addition of sodium hydroxide, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried, and the solvent removed by evaporation under reduced pressure. The residual yellow oil was kugelrohr distilled under reduced pressure to give 3-amino-5-chloro-4-fluorotrifluoromethylbenzene (32 g):bp. 105° C./11 mm Hg; 'H NMR δ (CDCl3) 7.03 (1H, dq), 6.90 (1H, dq).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].O[C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH3:1][CH2:2][CH:3]([O:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH:23]([NH:25][C:26](=[O:28])[CH3:27])[CH3:24])=[CH:20][CH:21]=2)=[CH:12][CH:13]=1)[CH2:4][CH3:5]
Reactant: CC(=O)NC(C)Cc1ccc(C#Cc2ccc(O)cc2)cc1
Reactant: CCC(O)CC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)Oc1ccc(C#Cc2ccc(CC(C)NC(C)=O)cc2)cc1
Reaction time: 72 h

Procedure:
14.7 μl (0.14 mmol) 3-pentanol, 40 mg (0.14 mmol) N-(1-(4-((4-hydroxyphenyl)-ethynyl)phenyl)propan-2-yl)acetamide (I74.1) and 69.8 mg (0.21 mmol) polymer bound triphenylphosphine (˜3 mmol/g) are added to 1 mL THF followed by 31.4 mg (0.14 mmol) DBAD. After stirring the mixture for 2 h at r.t. further 7.5 μl (0.07 mmol) 3-pentanol and 16 mg (0.07 mmol) DBAD are added and stirring is continued for 72 h. The reaction mixture is filtered and the filtrate is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:6]2[S:15][C:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:36][S:37]([N:12]1[CH2:13][CH2:14][CH:9]([CH2:8][N:7]2[C:2](=[O:1])[CH:3]=[CH:4][C:5]3[C:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:16]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:15][C:6]2=3)[CH2:10][CH2:11]1)(=[O:39])=[O:38]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2CC2CCNCC2)c1-c1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1sc2c(ccc(=O)n2CC2CCN(S(C)(=O)=O)CC2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.2 %

Procedure:
The compound of Example 118 (104 mg, 0.26 mmol) was dissolved in DCM (5 mL) and triethylamine (73 μL) followed by methanesulphonylchloride (40 μL, 0.28 mmol) added. The reaction was allowed to stir at ambient temperature for 18 hours. The reaction was diluted with brine and extracted with DCM (×3). The organic phases were washed with saturated NaHCO3 solution and dried (MgSO4). The reaction was filtered and the solvents removed in vacuo to give the title product as a white solid (120 mg). δH (CDCl3) 7.45–7.30 (3H, m), 7.27–7.10 (3H, m), 6.43 (1H, d, J 9.4 Hz), 4.12 (2H, q, J 7.1 Hz), 4.02 (2H, d, J 7.2 Hz), 3.75 (2H, m), 2.70 (3H, s), 2.61 (2H, m), 2.20 (1H, m), 1.82 (2H, m), 1.55 (2H, m), 1.12 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.55 minutes, 475 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]3[NH:11][CH2:12][CH2:13][N:14]=3)[NH:8][C:4]=2[CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>C(O)C>[C:17]([NH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]3[NH:11][CH2:12][CH2:13][N:14]=3)[NH:8][C:4]=2[CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2nc(NC3=NCCN3)[nH]c2c1
Solvent: CCO
Product: CC(=O)Nc1ccc2nc(NC3=NCCN3)[nH]c2c1
Yield: 8.8 %

Procedure:
A mixture of 2-(5-aminobenzimidazolyl) amino-2-imidazoline (0.48g, 0.0022 mol) and acetic anhydride (0.0022 mol) in ethanol (20 ml) was heated under reflux for 2 hours. The cooled reaction mixture was evaporated in vacuo and the resulting solid dissolved in methanol. Treatment with dry hydrogen chloride gas followed by ethyl acetate gave brown microcrystals (0.33 g). Recrystallisation from methanol/ethyl acetate gave a poor recovery of slightly hydroscopic 2-(5-acetylamino-2-benzimidazolyl) amino-2-imidazoline (50 mg) as colourless microcrystals m.p. 294°C (with shrinking). EXAMPLES 43 and 44
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26](I)=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH:35]1([S:38]([NH2:41])(=[O:40])=[O:39])[CH2:37][CH2:36]1.N(CC(O)=O)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.[Cu]I>[F:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]([C:18]3[NH:23][C:22]4[CH:24]=[CH:25][C:26]([NH:41][S:38]([CH:35]5[CH2:37][CH2:36]5)(=[O:40])=[O:39])=[CH:27][C:21]=4[S:20](=[O:30])(=[O:29])[N:19]=3)=[C:14]([OH:31])[C@H:13]3[C@@H:8]2[C@H:9]2[CH2:32][C@@H:12]3[CH2:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: O=C1C(C2=NS(=O)(=O)c3cc(I)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: [Cu]I
Agent: CNCC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: O=C1C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)C4CC4)ccc3N2)=C(O)[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2N1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
(1R,2S,7R,8S)-3-(4-Fluoro-benzyl)-6-hydroxy-5-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-3-aza-tricyclo[6.2.1.02,7]undec-5-en-4-one (prepared as described in Example 19, 81 mg, 0.14 mmol), cyclopropane sulfonic acid amide (132 mg, 1.09 mmol), sarcosine (N-methyl glycine) (18 mg, 0.20 mmol), copper (I) iodide (26 mg, 0.14 mmol), and potassium phosphate (173 mg, 0.82 mmol) were combined and dissolved in N,N-dimethylformamide (4 mL). The flask was degassed and backfilled with nitrogen (3×). The reaction was stirred at 100° C. for 4 h. The mixture was allowed to cool to 25° C., diluted with ethyl acetate (20 mL), and extracted with saturated aqueous sodium bicarbonate solution (2×20 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by flash column chromatography (Teledyne Isco RediSep column; 0 to 8% methanol in dichloromethane) afforded the desired product, cyclopropane sulfonic acid {3-[(1R,2S,7R,8S)-3-(4-fluoro-benzyl)-6-hydroxy-4-oxo-3-aza-tricyclo[6.2.1.02,7]undec-5-en-5-yl]-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-7-yl}-amide (76 mg, 0.13 mmol, 96%), as a white powder. 1H NMR (400 MHz, DMSO-d6) δ: 0.85-1.68 (8H, m), 2.50-2.62 (2H, m), 2.83-2.97 (3H, m), 3.45-3.47 (1H, m), 4.56 (1H, bs), 5.17-5.20 (1H, m), 7.03-7.07 (2H, m), 7.20-7.23 (2H, m), 7.63-7.69 (2H, m), 8.01 (1H, s). LC-MS (ESI) calcd for C27H27FN4O6S2 586.14, found 587.4 [M+H+].
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[N:3]1[C:8]1[N:13]=[CH:12][C:11](/[CH:14]=[CH:15]/[C:16]([N:18]([CH3:30])[CH2:19][C:20]2[N:21]([CH3:29])[C:22]3[C:27]([CH:28]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:17])=[CH:10][CH:9]=1.[NH3:31]>>[CH3:30][N:18]([CH2:19][C:20]1[N:21]([CH3:29])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16](/[CH:15]=[CH:14]/[C:11]1[CH:10]=[CH:9][C:8]([NH:3][C:4](=[O:7])[CH2:5][CH2:6][C:2]([NH2:31])=[O:1])=[N:13][CH:12]=1)=[O:17]
Reactant: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N2C(=O)CCC2=O)nc1
Reactant: N
Product: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(NC(=O)CCC(N)=O)nc1
Temperature: 60 °C
Yield: 51.7 %

Procedure:
A mixture of (E)-3-[6-(2,5-dioxo-pyrrolidin-1-yl)pyridin-3-yl]-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide (260 mg, 0.645 mmol) and ammonia (12 mL of 0.5M solution in 1,4-dioxane, 6.0 mmol) in a sealed tube was heated to 60° C. overnight. After cooling to ambient temperature, the resulting white precipitate was collected by filtration. The resulting solid was triturated with MeOH, washed with Et2O, and dried under high vacuum at 50° C. for 2 d to give the title compound (140 mg, 52%) as a white solid and as a mixture of amide rotamers: mp 225-227° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.67-10.63 (m, 1H), 8.62-8.58 (m, 1H), 8.21-8.07 (m, 2H), 7.60-7.25 (m, 5H), 7.12 (dd, J=7.7, 7.4 Hz, 1H), 7.00 (dd, J=7.3, 6.9 Hz, 1H), 6.77 (br s, 1H), 6.42-6.17 (m, 1H), 5.05-4.85 (m, 2H), 3.72-3.68 (m, 3H), 3.12-2.99 (m, 3H), 2.64-2.60 (m, 2H), 2.40-2.36 (m, 2H); MS (ESI) m/e 420 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:3]=1.[F:26][CH:27]([F:44])[O:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[C:20]([O:19][C:18](=[O:24])[N:17]([CH2:16][C:4]1[CH:3]=[C:2]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH:27]([F:44])[F:26])=[CH:30][CH:31]=2)[N:6]([S:7]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)(=[O:9])=[O:8])[CH:5]=1)[CH3:25])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC1(C)OB(c2ccc(OC(F)F)cc2)OC1(C)C
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
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: COCCOC
Solvent: O
Product: CN(Cc1cc(-c2ccc(OC(F)F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 111.5 %

Procedure:
tert-Butyl {[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (430 mg), 2-[4-(difluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (348 mg), sodium carbonate (254 mg) and tetrakis(triphenylphosphine)palladium (174 mg) were suspended in dimethoxyethane (10 mL) and water (4 mL), and the mixture was stirred under a nitrogen atmosphere at 105° C. for 1 hr. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=4:1→2:1) to give the title compound as a pale-yellow oil (yield 550 mg, quantitative yield).