Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:14]([F:39])=[C:15]([C:19]2[N:20]=[C:21]([C:35]([CH3:38])([CH3:37])[CH3:36])[S:22][C:23]=2[C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32](O)=[O:33])[N:25]=2)[CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:10].[NH:40]1[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]1>>[CH3:37][C:35]([C:21]1[S:22][C:23]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([CH2:30][CH2:31][C:32]([N:40]3[CH2:45][CH2:44][S:43](=[O:47])(=[O:46])[CH2:42][CH2:41]3)=[O:33])[N:25]=2)=[C:19]([C:15]2[C:14]([F:39])=[C:13]([NH:12][S:9]([C:3]3[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=3[F:1])(=[O:10])=[O:11])[CH:18]=[CH:17][CH:16]=2)[N:20]=1)([CH3:38])[CH3:36]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)O)n2)s1
Reactant: O=S1(=O)CCNCC1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(CCC(=O)N3CCS(=O)(=O)CC3)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 254 using 3-{4-[4-(3-{[(2,5-difluorophenyl)sulfonyl]amino}-2-fluorophenyl)-2-(1,1-dimethylethyl)-1,3-thiazol-5-yl]-2-pyrimidinyl}propanoic acid (200 mg, 0.347 mmol) and thiomorpholine 1,1-dioxide (0.094 g, 0.694 mmol), the title compound was obtained as a white solid (108 mg, 36% yield). MS (ESI): 694 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3C2CCCCO2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(O)C>[C:30]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Yield: 100.6 %

Procedure:
To a suspension of ethyl 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl)-9H-purine-2-carboxylate (Preparation 62) (250 g, 0.530 moles) in absolute ethanol (1250 ml) under an atmosphere of nitrogen was added trifluoroacetic acid (73.5 g, 0.645 moles) and the resultant mixture was heated at 50° C. for 20 hours. The mixture was cooled and the solid was collected by filtration. The filter cake was washed with absolute ethanol (350 ml) and was then dried in vacuo at 50° C. to give the title compound (206.5 g) as a cream coloured fine powder, m.p. >200° C.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][NH:6][C:5]2=[O:10])[CH2:3][CH2:2]1.[H-].[Na+].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:16]=1[CH2:17]Br>CN(C=O)C.[Cl-].[Na+].O>[CH:1]1([N:4]2[C:8]([CH3:9])=[CH:7][N:6]([CH2:17][C:16]3[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:15]=3[C:14]([F:24])([F:13])[F:25])[C:5]2=[O:10])[CH2:3][CH2:2]1
Reactant: Fc1ccc(C(F)(F)F)c(CBr)c1
Reactant: Cc1c[nH]c(=O)n1C1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(Cc2cc(F)ccc2C(F)(F)F)c(=O)n1C1CC1
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Cyclopropyl-5-methyl-1,3-dihydro-imidazol-2-one (150 mg) was dissolved in DMF (5 mL) under argon and sodium hydride (55% in mineral oil, 71 mg) was added in one portion. The mixture was stirred until gas evolution stopped (approx. 20 minutes) and then a solution of 2-trifluoromethyl-5-fluorobenzyl bromide (307 mg) in DMF (2 mL) was added over 5 minutes. Stirring was continued for 1 hour and then the reaction mixture was poured into brine. The aqueous solution was extracted with ethyl acetate and the organic layer was separated and washed with brine. The combined organic extracts were dried over Na2SO4 and evaporated. Residual DMF was removed by co-evaporation with toluene. The crude material was purified by flash chromatography using a gradient of 20 to 50% ethyl acetate in heptane as an eluent. Fractions containing the desired product were combined and evaporated to give 3-cyclopropyl-1-(5-fluoro-2-trifluoromethyl-benzyl)-4-methyl-1,3-dihydro-imidazol-2-one as a colorless oil (201 mg). MS (ESI): 315.1 (MH+).
Reaction SMILES: [ClH:1].[CH2:2]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH2:5][CH2:4][NH:3]1.[C:21]1(NN)C=CC=CC=1>>[ClH:1].[CH3:21][C:11]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]3[CH2:5][CH2:4][NH:3][CH2:2][C:14]=3[C:13]=2[CH:12]=1
Reactant: CCOC(=O)Cn1c2c(c3ccccc31)CNCC2
Reactant: NNc1ccccc1
Agent: Cl
Product: CCOC(=O)Cn1c2c(c3cc(C)ccc31)CNCC2

Procedure:
The title compound is prepared using a procedure analogous to Intermediate 1, substituting 4-methylphenylhydrazine for phenylhydrazine in Step 1a).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=O)=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1.[S:25]1[CH2:29][C:28](=[O:30])[NH:27][C:26]1=[O:31].N1CCCCC1>CCO.CN(C=O)C>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][N:17]4[N:20]=[CH:21][C:22]([CH:23]=[C:29]5[S:25][C:26](=[O:31])[NH:27][C:28]5=[O:30])=[C:16]4[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1cccc(Nc2ccn3ncc(C=O)c3n2)c1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1nccn1-c1cccc(Nc2ccn3ncc(C=C4SC(=O)NC4=O)c3n2)c1
Temperature: 70 °C

Procedure:
To 5-(3-(2-methyl-1H-imidazol-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (48 mg, 0.151 mmol) in 0.5 mL EtOH was added 2,4-thiazolidinedione (18 mg, 0.151 mmol) and piperidine (15 μL, 0.151 mmol). The mixture was heated at 70° C. overnight. The solid formed was isolated by filtration and dissolved in DMF. Insolubilities were filtered off and the resulting filtrate purified by HPLC to yield 5-((5-(3-(2-methyl-1H-imidazol-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)thiazolidine-2,4-dione. LCMS (M+1=418)
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([N:15]2[CH:16]=[C:12]([N+:9]([O-:11])=[O:10])[N:13]=[CH:14]2)[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccnc(-n2cnc([N+](=O)[O-])c2)c1
Temperature: 130 °C
Reaction time: 21 h
Yield: 34.2 %

Procedure:
A suspension of 2-fluoro-4-methylpyridine (1.11 g), 4-nitroimidazole (1.24 g) and potassium carbonate (1.65 g) in N,N-dimethylformamide (10 ml) was stirred at 130° C. for 21 hours. After cooling, the mixture was poured into water and stirred for 30 minutes. The precipitate was collected by filtration and dried to give 1-(4-methylpyridin-2-yl)-4-nitroimidazole (698 mg).
Reaction SMILES: C(N[C@H](C(O)=O)C([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C(O)=O)(OC(C)(C)C)=O.O.OC1[C:34]2[N:33]=N[NH:31][C:30]=2[CH:29]=CC=1.C1(N=C=NC2CCCCC2)CCCCC1.CN1CC[O:54]CC1>C(OCC)(=O)C.CN(C)C=O>[C:15]1([CH2:14][NH:33][C:34](=[O:54])[C@H:30]([CH3:29])[NH2:31])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN1CCOCC1
Reactant: Oc1cccc2[nH]nnc12
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](N)C(=O)NCc1ccccc1
Reaction time: 1 h

Procedure:
To a mechanically-stirred, 18° C. solution of 37.5 g (116 mmole) of BOC-β-benzyl-(L)-aspartic acid in 270 mL ethyl acetate is added a solution of 17.75 g (116 mmole) of hydroxybenzotriazole hydrate in 25 mL of dimethylformamide. A solution of 24.5 g (119 mmole) of dicyclohexylcarbodiimide in 50 mL of ethyl acetate is then added over 30 minutes, using a water bath to keep the reaction temperature at or below 25° C. The reaction mixture is stirred for 1 hour, then a syrup of 33 g (116 mmole) of 3-cyclohexyl-(L)-alanineamide ester mono (trifluoroacetate) in 25 mL of dimethylformamide is added at 23° C., followed by dropwise addition of neat N-methylmorpholine over 2 minutes. The reaction mixture is allowed to warm to 30° C. during the N-methylmorpholine addition. The reaction mixture is stirred at ambient temperature overnight. The reaction mixture is filtered to remove dicyclohexyl urea, and the filtrate is diluted with ethyl acetate, washed twice with water, once with brine, twice saturated aqueous sodium bicarbonate, and once with 1:1 0.5N citric acid/brine. The organic phase is dried with magnesium sulfate, filtered, and diluted with heptane. The mixture is allowed to stand overnight, and the resulting crystals are collected by filtration, washed twice with heptane, and dried under vacuum to give a first crop of 37.5 g and a second crop of 9.5 g. Both crops show acceptable HPLC purity and are physically combined to afford 47 g of N-[(1,1-dimethylethoxy)carbonyl]-(L)-α-aspartyl-3-cyclohexyl-(L-alanineamide phenylmethyl ester (85 yield). MS (FAB) m/7 476 (M+H)+.
Reaction SMILES: [P:1]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])[O:2]CC.Cl[CH2:12][C:13]1[S:14][CH:15]=[CH:16][CH:17]=1>>[S:14]1[CH:15]=[CH:16][CH:17]=[C:13]1[CH2:12][P:1](=[O:2])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cccs1
Product: CCOP(=O)(Cc1cccs1)OCC
Temperature: 150 °C

Procedure:
Following the general procedure for carrying out the Arbuzov reaction (reference cite: Chem. Rev. 81, 415, 1981) 0.1 mole (17.5 ml) of triethyl phosphite and 0.1 mole (13.2 g) of 2-chloromethylthiophene were combined and heated under N2 at 150° C. for 5 hours. The reaction mixture was cooled and partitioned between 100 ml methylene chloride and 50 ml. water. The organic phase was separated, washed with saturated NaHCO3 solution, dried over magnesium sulfate and concentrated under vacuum to yield 17.5 g. crude liquid product.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17](/[CH:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]#[N:26])[CH:18]=[CH:19][CH:20]=1.[Cl-].[NH4+].[N-:29]=[N+:30]=[N-:31].[Na+]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=[CH:24][C:25]2[NH:31][N:30]=[N:29][N:26]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1oc(-c2ccccc2)nc1COc1cccc(/C=C/C=C/C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1oc(-c2ccccc2)nc1COc1cccc(C=CC=Cc2nnn[nH]2)c1

Procedure:
According to the method described for Example 1, (E,E)-5-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-2,4-pentadienenitrile was allowed to react with sodium azide -ammonium chloride to give 5-[4-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]-1,3-butadien-1-yl]tetrazole. Recrystallization from methanol gave colorless prisms, m.p.201°-202° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[C:12]([O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][C:25](=[O:27])[CH3:26])[CH:23]=1)[CH:19]=[CH2:20])(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].P(C(C)(C)C)(C(C)(C)C)C(C)(C)C>>[C:12]([O:15][C:16]1[CH:17]=[C:18](/[CH:19]=[CH:20]/[C:8]2[CH:9]=[CH:10][C:5]([O:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)[CH:21]=[C:22]([O:24][C:25](=[O:27])[CH3:26])[CH:23]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1ccc(Cl)cc1
Reactant: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)Oc1ccc(/C=C/c2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Temperature: 120 °C
Reaction time: 19 h

Procedure:
A 10 ml Schlenk tube equipped with magnetic stirrer was charged with 59 mg (0.7 mmol) of 4-acetoxychlorobenzene, 100 mg (0.84 mmol, 1.2 eq) of 3,5-diacetoxystyrene, 125 mg of cesium carbonate (0.38 mmol, 1.1 eq), 5 μl of P(t-Bu)3 (0.02 mmol, 6 mol %) and 5.57 mg (0.01 mmol, 1.5 mol %) of tris(dibenzylideneacetone)-dipalladium chloroform complex. The tube was evacuated and flushed with argon three times and 1 ml de-aerated dioxane was added under inert conditions. The reaction was carried out under stirring for 19 hours at 120° C. Work-up was conducted following the procedure of Example 5 and gave (E)-3,4′,5-triacetoxystilbene.
Reaction SMILES: [CH3:1][Mg]Cl.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13](=[O:15])[CH3:14]>>[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[C:13]([OH:15])([CH3:1])[CH3:14]
Reactant: C[Mg]Cl
Reactant: CC(=O)c1c(C)cc(C)cc1C
Product: Cc1cc(C)c(C(C)(C)O)c(C)c1

Procedure:
According to Example 2, MeMgCl (2.9 M; 0.76 mL, 2.2 mmol, 1.10 equiv) was reacted with 1-(2,4,6-trimethyl-phenyl)-ethanone (324 mg, 2.00 mmol) in the presence of LaCl3.2LiCl (0.33 M; 6.06 mL, 2.00 mmol, 1.00 equiv). Column chromatographical purification (silica; pentane:Et2O 9:1) afforded the desired product as colorless, crystalline solid, mp=106−107° C. (217 mg, 61%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]=1[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([OH:9])=[O:8])([O-:3])=[O:2].OS(O)(=O)=O.[CH3:29]O>>[CH3:29][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:11]([S:20](=[O:23])(=[O:22])[NH2:21])[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: CO
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Oc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
34 g (~0.1 mol) of 3-nitro-4-phenoxy-5-sulphamylbenzoic acid are dissolved in 150 ml of methanol and are heated to the boil. 5.4 ml of concentrated H2SO4 are then added slowly dropwise and the mixture is heated at reflux temperature for 10 hours. On cooling, 3-nitro-4-phenoxy-5-sulphamylbenzoic acid methyl ester crystallises.
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH2:17][CH:16]3[CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][C:23]=4[C:15]3=[N:14]2)=[CH:9][CH:8]=1.[H-].[Na+].[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35]Cl>O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH2:17][CH:16]3[CH2:20][S:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:35][CH2:34][CH2:33][N:32]([CH3:37])[CH3:31])=[CH:24][C:23]=4[C:15]3=[N:14]2)=[CH:9][CH:8]=1
Reactant: O=C1CC2CSc3ccc(O)cc3C2=NN1c1ccc(Cl)cc1
Reactant: CN(C)CCCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCOc1ccc2c(c1)C1=NN(c3ccc(Cl)cc3)C(=O)CC1CS2
Temperature: 25 °C
Yield: 9.3 %

Procedure:
To 50 ml of dry dimethylformamide is added 4.5 g of 2-(4-chlorophenyl)-9-hydroxy-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, and 0.7 g of 60% sodium hydride is added thereto while stirring at room temperature. After stirring at room temperature for 1 hour and addition of 2 g of 3-dimethylaminopropyl chloride, the mixture is stirred under heating at 40°-50° C. for 3 hours. After the completion of the reaction, the reaction mixture is poured into a large amount of water and the mixture is extracted with chloroform. The extract is washed with water and dried over anhydrous magnesium sulfate. Thereafter, the solvent is distilled off. The residue is subjected to column chromatography and the eluate is converted into its fumarate to give 0.52 g of 2-(4-chlorophenyl)-9-(3-dimethylaminopropoxy)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one.fumarate, as yellow crystals, m.p. 208°-210° C.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:21][CH2:20][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:17]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2.C(N(CC)CC)C.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>ClCCl>[CH3:37][S:38]([O:1][CH2:2][C@H:3]1[CH2:14][CH2:13][C:12]2[S:11][C:10]3[C:5](=[C:6]([NH:15][CH:16]4[CH2:17][CH2:18][CH:19]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:20][CH2:21]4)[N:7]=[CH:8][N:9]=3)[C:4]1=2)(=[O:40])=[O:39]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](CO)CC4)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(Nc2ncnc3sc4c(c23)[C@@H](COS(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3S)-3-(hydroxymethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate (400 mg, 0.96 mmol, 1.00 equiv) and triethylamine (0.27 mL, 2.00 equiv) in dichloromethane (20 mL) was added dropwise MsCl (164 mg, 1.43 mmol, 1.50 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 2×40 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). Purification afforded 379 mg (80%) of tert-butyl N-(4-[[(3S)-3-[(methanesulfonyloxy)methyl]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-12-yl]amino]cyclohexyl)carbamate as a light yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH3:21])[CH2:3][NH:4][S:5]([C:8]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[C:9]=1[C:10]([O:12]C)=O)(=[O:7])=[O:6].C[O-].[Na+].[CH3:25][NH:26][CH3:27]>CO>[CH3:25][N:26]([CH3:27])[C:10](=[O:12])[C:9]1[C:14]([N+:18]([O-:20])=[O:19])=[CH:15][CH:16]=[CH:17][C:8]=1[S:5]([NH:4][CH2:3][CH:2]([OH:1])[CH3:21])(=[O:6])=[O:7]
Reactant: COC(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCC(C)O
Reactant: CNC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
Methyl 2-[N-(2-hydroxy-1-propyl)aminosulfonyl]-6-nitrobenzoate (2.00g, 628 mmol) was dissolved in 60 ml of methanol. Sodium methoxide (1.0 ml of a 0.1 M solution in methanol) was added and the solution cooled and stirred in an ice-bath while a rapid stream of dimethylamine was passed into the vortex for 15 minutes. Stirring in the ice-bath then was continued for 1 hour, when the flash was removed from the bath and the reaction mixture allowed to stand at room temperature overnight. The methanol and excess dimethylamine then were evaporated under reduced pressure and the residue shaken with ethyl acetate, 80 ml; 0.2N HCl, 10 ml; and saturated NaCl, 10 ml. The ethyl acetate layer was separated, extracted with 3×15 ml of saturated NaCl and evaporated to give a clear yellow oil. After drying 23 hours in vacuo, this product weight 2.03 g. Crystallization had started after 3 days. Recrystallization from a mixture of ethyl acetate and hexane gave 1.33 g (63.9%) of product, m.p., 95.5°-97°.
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:11]([Cl:13])Cl>>[CH2:11]([Cl:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2]
Reactant: ClCCl
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=CCCCCCCCCCCl
Temperature: 50 °C

Procedure:
A one liter, three necked flask equipped with mechanical stirrer, reflux condenser, argon inlet and addition funnel was heated in an oil bath at 50° C. To the flask was added methylene chloride (400 milliliters), undecylenol (100 grams) and pyridine (55.7 grams). Thionyl chloride (78.9 grams) in methylene chloride (100 milliliters) was added dropwise under reflux over five hours. The mixture was filtered, the solvent was removed from the filtrate using a rotary evaporator, and the resultant oil was refiltered and then distilled using a packed column to yield two fractions. A fraction collected between 100° and 110° C. and about 1 millimeter of mercury was redistilled to yield 40 grams of undecylenyl chloride as an oil obtained at 80° to 85° C. at about 1 millimeter of mercury.
Reaction SMILES: [FH:1].[CH3:2][N:3]=[C:4]=[O:5].Cl[S:7][N:8]([CH3:24])[C:9](=[O:23])[O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(N(CC)CC)C>C(Cl)Cl.O>[CH2:11]([O:10][C:9]([N:8]([CH3:24])[S:7][N:3]([CH3:2])[C:4]([F:1])=[O:5])=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCOC(=O)N(C)SCl
Reactant: F
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCCCCOC(=O)N(C)SN(C)C(=O)F
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Anhydrous hydrogen fluoride (8 g, 0.4 mole) was added to 400 ml of methylene chloride at 0° C. in a polyethylene reactor. Methylisocyanate (22.8 g, 0.4 mole) was added at -5° C. to 0° C. in 0.5 hr. After stirring for 1 hr at 0° C., a solution of 125.6 g of n-dodecyl N-chlorothio-N-methylcarbamate in 100 ml of methylene chloride was added, followed by a dropwise addition of 40.5 g (0.4 mole) of triethylamine. The mixture was stirred at 0° C. for one hour and was allowed to warm to ambient temperature. Water (300 ml) was added with vigorous stirring. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate, then with water until the washings became neutral, dried over anhydrous magnesium sulfate, filtered and concentrated to give 129 g (92%) of oily N-(N'-n-Dodecyloxycarbonyl-N'-Methylaminosulfenyl)-N-methylcarbamoyl fluoride.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7](Br)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].[CH2:24]([NH2:26])[CH3:25]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:7]([NH:26][CH2:24][CH3:25])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCN
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1Br
Solvent: C1CCOC1
Product: CCNC1C(C(=O)OCC)=C(c2ccccc2)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.6 %

Procedure:
1-Bromo-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (100 mg, 0.27 mmol) obtained in Example 18 was dissolved in THF (10 mL), and 2.0 M ethylamine (0.68 mL, 1.35 mmol) in THF was added dropwise thereto. The mixture was stirred for 12 hrs at RT, and the solvent was removed under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 68 mg of the titled compound (yield: 75.6%).