Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[NH2:34][C:35]([NH2:37])=[S:36]>C(#N)C>[NH2:37][C:35]1[S:36][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:34]=1
Reactant: NC(N)=S
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1-c1ccccc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a solution of ethyl 3-phenyl-3-oxopropionate (5.0 g, 26.0 mmol) in 100 mL of acetonitrile was added hydroxy(tosyloxy)iodobenzene (11.2 g, 28.6 mmol) . The resulting suspension was stirred at 65° C. for 1 h at which time the reaction was a homogeneous solution. Thiourea (2.2 g, 28.6 mmol) was added and stirring was continued at 65° C. for 2 h. The mixture was cooled and concentrated, and the residue was taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford 4.9 g (70%) of the title compound as a yellow solid. 1H NMR (CDCl3) d 7.65 (m, 2H), 7.39 (m, 3H), 5.98 (broad s, 2H), 4.18 (q, 2H), 1.22 (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][O:27][C:28]1[C:33]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[CH:32][CH:31]=[CH:30][N:29]=1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:37]2[CH2:38][CH2:39][CH:34]([C:33]3[C:28]([O:27][CH3:26])=[N:29][CH:30]=[CH:31][CH:32]=3)[CH2:35][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: COc1ncccc1C1CCNCC1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(c2cccnc2OC)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 87.6 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.38 g) was coupled to 4-(2-methoxy-3-pyridyl)piperidine (0.60 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the desired title compound (0.26 g); mp 135-194° C. (d); MS: m/z=554(M+1); NMR(CD3OD): 1.9-2.1 (m,4), 2.6 (m,2), 2.9-3.1 (m,8), 3.6-3.8 (m,4), 3.8 (s,3), 4.0 (s,3), 4.8 (d,1, J=4), 6.7-8.1 (m,9). Analysis for C30H33Cl2N3O3.1.5 HCl-0.5 H2O: Calculated: C, 58.29; H, 5.79, N, 6.80; Found: C, 58.25; H, 5.71; N, 6.68.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(=O)([O-])[O-:6].[K+].[K+].[N+:11]([C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17])([O-:13])=[O:12]>O>[CH3:2][O:3][N:4]([C:16](=[O:17])[C:15]1[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=1[N+:11]([O-:13])=[O:12])[OH:6]
Reactant: CON
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CON(O)C(=O)c1ccccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 49.2 %

Procedure:
186 g (2.2 moles) of O-methylhydroxylamine hydrochloride, dissolved in 322 ml of water, were added dropwise at 10° C to 322 g (2.32 moles) of potassium carbonate dissolved in 276 ml of water. 340 g (1.84 moles) of 2-nitrobenzoyl chloride were added dropwise to this mixture. After stirring the batch for one hour, the residue was filtered off and was suspended in lukewarm water in order to dissolve the admixed potassium chloride. The solid constituents were again filtered off and washed with water. 192 g (53% of theory) of N-methoxy-2-nitro-benzhydroxamic acid were obtained as a slightly granular beige-colored powder of melting point 104° C (which can be recrystallized from ethyl acetate). ##STR26##
Reaction SMILES: [CH:1](=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1.[C:22](=S)=S>>[C:1]1([C:8]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)([CH3:22])[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Reactant: S=C=S
Reactant: c1c[nH]cn1
Product: CC(C(=O)c1ccccc1)(c1ccccc1)n1ccnc1
Temperature: 25 °C

Procedure:
Benzalacetophenone (4.2 g, 0.02 mol) and imidazole (1.34 g, 0.02 mol) were warmed over a flame for 30 minutes. After cooling to room temperature, the oil was treated with carbon disulphide to give, as colourless crystals, 2-phenyl-2-(imidazol-1-yl) propiophenone (compound 3) m.p. 75°-76° C.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[C:6]1Cl)[C:2]#[C:3][CH3:4].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:6]2[N:5]([CH2:1][C:2]#[C:3][CH3:4])[C:13]3[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=3[N:7]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC#CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Yield: 49.3 %

Procedure:
3-Methylxanthine (1.1 g) was dissolved in N,N-dimethylformamide (15 ml), and potassium carbonate (1.0 g) and 1-bromo-2-butyne (0.64 ml) were added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.3 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione (1.3 g) was dissolved in N,N-dimethylformamide (15 ml), and N-chlorosuccinimide (0.89 g) was added while cooling on ice. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected by filtration, and washed with ethyl acetate to give 1.1 g of 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione. The resulting 7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione (1.4 g) and 1-piperazine carboxylic acid tert-butyl ester (2.8 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, then the organic layer was washed with water and saturate brine, and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.1 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]=2[O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:50]([O:53][CH2:54]Cl)(=[O:52])[CH3:51].[I-].[Na+].C(N(CC)CC)C>CC(C)=O.CN(C=O)C>[C:50]([O:53][CH2:54][O:16][C:15](=[O:17])[C:14]1[CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:29]=2[O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:20]=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=1)(=[O:52])[CH3:51]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1
Reactant: CC(=O)OCCl
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)OCOC(C)=O)c1
Yield: 23.5 %

Procedure:
A mixture of 0.5 g (0.75 mmol) of 3-(decyloxy)-5-[[6-[2,3-bis (phenylmethoxy)phenyl]hexyl]oxy]benzoic acid, 0.25 g (2.25 mmol) of chloromethyl acetate, 0.23 g (1.5 mmol) of sodium iodide and 0.31 ml (2.25 mmol) of triethylamine in 15 ml of acetone and 5 ml of DMF was stirred at reflux under argon for 19 hours. The solvent was removed under reduced pressure, NaHCO3 solution was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to an oil which was purified by HPLC using 10% ethyl acetate-hexane to give 0.13 g of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy)phenyl]hexyl]oxy]benzoic acid (acetyloxy)methyl ester as an oil. A mixture of 0.13 g of 3-(decyloxy)-5-[[6-[2,3-bis (phenylmethoxy)phenyl]hexyl]oxy]benzoic acid (acetyloxy)methyl ester and 0.1 g of 10% palladium on carbon in 15 ml of ethyl acetate was stirred under a hydrogen atmosphere for 3.5 hours when uptake ceased. The usual workup gave 0.07 g of 3-(decyloxy)-5-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]benzoic acid (acetyloxy) methyl ester as an oil. The structure was confirmed by the nmr and mass spectra.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@H](NC(=O)CO)CC4)c[nH]c13)OCO2

Procedure:
Starting from trans-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A185) and acetic acid chlorocarbonyl-methyl ester the title compound was obtained as colorless solid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24].[Cl-].[CH3:26][O:27][C:28]([CH2:30][NH3+:31])=[O:29].CCN(CC)CC.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O>[CH3:26][O:27][C:28](=[O:29])[CH2:30][NH:31][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[C:15]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:16]=3[S:17][CH:18]=2)[C:5]1=[O:24]
Reactant: Cc1cccc2scc(Cn3c(=O)n(CCBr)c4ccccc43)c12
Reactant: COC(=O)C[NH3+]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CNCCn1c(=O)n(Cc2csc3cccc(C)c23)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.7 %

Procedure:
1-(2-Bromo-ethyl)-3-(4-methyl-benzo[b]thiophen-3-ylmethyl)-1,3-dihydro-benzimidazol-2-one (30 mg, 0.075 mmol) is dissolved in CH3CN (0.5 mL)) and Methoxycarbonylmethyl-ammonium chloride (11 mg, 0.09 mmol) and Et3N (0.025 mL, 0.18 mmol) are added. The mixture is first stirred at room temperature for 16 hr. And then 11 mg of Na2CO3 is added and the mixture is stirred at room temperature for another 48 hr. Since the reaction is not completed, another 11 mg of Methoxycarbonylmethyl-ammonium chloride, 0.025 mL of Et3N and 11 mg of Na2CO3 are added. The mixture is then heated at 80° C. for 20 hrs. Then 10 mL of water is added and the mixture is extracted with EtOAc (3×15 mL). The organic layers are combined, dried and concentrated to give crude product. Purification by flash column chromatography affords 30 mg (98%) of {2-[3-(4-Methyl-benzo[b]thiophen-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-ethylamino}-acetic acid methyl ester.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:32][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:32])[NH2:2]
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Reactant: [Li]O
Agent: OO
Solvent: CO
Solvent: O
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (600 mg, 1.36 mmol, 1.00 equiv) in methanol (8.0 mL). Then LiOH.H2O (171 mg, 4.08 mmol, 3.00 equiv) and H2O2 (30%, 1.0 mL) were added at 0° C. and the resulting solution was stirred overnight at this temperature. The reaction was then quenched by the addition of 40 mL of NaHSO3 (aq.) and extracted with 3×60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1) to afford tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (450 mg, 72%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.[CH3:35][O:36][C:37]1[CH:42]=[C:41]([O:43][C:44]([F:47])([F:46])[F:45])[CH:40]=[CH:39][C:38]=1[S:48](Cl)(=[O:50])=[O:49]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:48]([C:38]1[CH:39]=[CH:40][C:41]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:42][C:37]=1[O:36][CH3:35])(=[O:49])=[O:50])[C:6](=[O:11])[C:5]2([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34])[CH2:12][C:13](=[O:26])[N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=2)[CH2:16][CH2:15]1
Reactant: COc1ccccc1C1(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)Nc2ccc(Cl)cc21
Reactant: COc1cc(OC(F)(F)F)ccc1S(=O)(=O)Cl
Product: COc1ccccc1C1(CC(=O)N2CCN(c3ccncc3)CC2)C(=O)N(S(=O)(=O)c2ccc(OC(F)(F)F)cc2OC)c2ccc(Cl)cc21
Yield: 31.7 %

Procedure:
With 150 mg of 5-chloro-3-(2-methoxyphenyl)-3-[2-oxo-2-(4-pyridin-4-yl piperazin-1-yl)ethyl]-1,3-dihydro-2H-indol-2-one, which is the compound described in EXEMPLE 1 of Publication No. WO03/008407, and 100 mg of 2-methoxy-4-(trifluoromethoxy)benzene sulfonyl chloride as starting materials, 73 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 1.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1>>[CH:11]1([CH2:14][CH2:15][NH:16][C:17]([C:19]2[N:20]=[N:21][C:22]([N:25]3[CH2:30][CH2:29][N:28]([C:8]([CH:5]4[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7][CH2:6]4)=[O:10])[CH2:27][CH2:26]3)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Reactant: CC1CCC(C(=O)O)CC1
Product: CC1CCC(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)CC1

Procedure:
Following the procedure of Example 14, making variations only as required to use 4-methylcyclohexanecarboxylic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (43% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.09, 7.05, 3.89, 3.79, 3.64-3.70, 3.56, 2.40-2.60, 1.65-1.88, 1.50-1.62, 0.99, 0.91, 0.75, 0.48, 0.10. MS (ES+) m/z 400 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([C:14]([O:16]CC)=O)[CH2:9][S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]1([S:25][CH2:26]Cl)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([N:30](CC)CC)C>C(#N)C>[CH2:7]([CH:8]1[CH2:9][S:10](=[O:11])(=[O:12])[N:30]([CH2:26][S:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]1=[O:16])[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)CC
Reactant: ClCSc1ccccc1
Reactant: CCOC(=O)C(Cc1ccccc1)CS(=O)(=O)Cl
Solvent: CC#N
Product: O=C1C(Cc2ccccc2)CS(=O)(=O)N1CSc1ccccc1
Yield: 23 %

Procedure:
A mixture of 4-benzylisothiazolidin-3-one 1,1-dioxide 4 (0.9 g; 4 mmol), chloromethyl phenyl sulfide (0.63 g; 4 mmol) and triethylamine (0.40 g; 4 mmol) in dry acetonitrile (10 mL) was refluxed for 2 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and extracted with water (50 mL) 5% hydrochloric acid (50 mL) and 5% sodium bicarbonate (50 mL). The organic layer was dried and evaporated, leaving a crude product (0.8 g) which was purified by flash chromatography (silica gel/hexane:methylene chloride), yielding 0.32 g of 4-benzyl-2-(1-Phenylthiomethyl)isothiazolidin-3-one 1,1-dioxide. This was oxidized to compound 10 by stirring overnight with m-chloroperbenzoic acid (2.2 eq) in methylene chloride. Compound 10 was obtained by evaporating off the solvent, adding ether and collecting the precipitated product, mp 137°-8° C. (0.38 g; 90% yield). 1H NMR: δ 2.85(m, 1H), 3.3(m,2H), 3.5(m,2H), 4.87(s,2H), 7.15(dd,2H), 74.0-7.25(m,3H), 7.81-7.70(m,3H), 8.0(m,2H).
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6](=[N+]=[N-])[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[C:9]([F:14])[CH:8]=1)[CH:2]=[CH2:3]>ClCCl.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.CCCCCCCC(O)=O.[Rh].[Rh]>[F:14][C:9]1[CH:8]=[C:7]([C:6]23[CH2:3][CH:2]2[CH2:1][O:4][C:5]3=[O:17])[CH:12]=[CH:11][C:10]=1[F:13]
Reactant: C=CCOC(=O)C(=[N+]=[N-])c1ccc(F)c(F)c1
Agent: [Rh]
Solvent: ClCCl
Solvent: CCCCCCCC(=O)O
Product: O=C1OCC2CC12c1ccc(F)c(F)c1
Yield: 72.9 %

Procedure:
Diazo-(3,4-Difluoro-phenyl)acetic acid allyl ester (70 g) was dissolved in dichloromethane (1000 mL) and added slowly during 36 h via a syringe pump (alternatively it is added dropwise via an addition funnel; 30 mL pr. hour) to a refluxing solution of rhodium (II) octanoate dimer (1.17 g, 1.5 mmol) in dichloromethane (200 mL). After all diazo compound has been added, the mixture is refluxed for another 30 min, then was evaporated in vacuo and crystallised by addition of cyclohexane (200 mL). This gave 30 g crystalline. Further 15 g was isolated from the motherliq. by repeated evaporation and crystallisation giving in total 45 g 1-(3,4-Difluoro-phenyl)-3-oxa-bicyclo[3.1.0]hexan-2-one.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([O:19]C)=[O:18])=[O:13])[S:5][CH:6]=1.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([C@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([C:14]2[CH:15]=[C:16]([CH:21]=[CH:22][CH:23]=2)[C:17]([OH:19])=[O:18])=[O:13])[S:5][CH:6]=1
Reactant: COC(=O)c1cccc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1csc([C@H]2CCCN2C(=O)c2cccc(C(=O)O)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To the solution of (R)-methyl 3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoate (155 mg, 0.49 mmol) in THF (5 mL) was added 1N LiOH (2 mL) and the reaction mixture was stirred at rt for 1 h. Then the volatiles were removed on a rotavap under reduced pressure. Then reaction mixture was diluted with water, acidified with 1N HCl to pH ˜3 and extracted with ethyl acetate. Organic layer was dried and evaporated to yield 132 mg of the acid (R)-3-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid. \
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:17])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14](O)=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:28]C=2C=1.N>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3]([CH3:17])=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][CH:10]([C:14]([NH2:28])=[O:15])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1c(Br)cccc1N1CC(C(=O)O)CC1=O
Agent: N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1c(Br)cccc1N1CC(C(N)=O)CC1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 26.1 %

Procedure:
A mixture of 1-(3-bromo-2-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid (Intermediate 41-10, 100 mg, 0.335 mmol), EDC (129 mg, 0.671 mmol), HOBT (103 mg, 0.671 mmol) and 28% aqueous ammonia in THF (2 mL) was stirred at rt for 5 h. The mixture was diluted with ethyl acetate, washed with NaHCO3 (aq) and water, and dried and concentrated. The residue was purified by column chromatography (eluting with 90:10 DCM-methanol) to provide 1-(3-bromo-2-methylphenyl)-5-oxopyrrolidine-3-carboxamide as a white solid (26 mg, 26%). Mass spectrum m/z 297, 299 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]=[O:11].N12CCC(CC1)C(O)C2>>[OH:11][CH2:10][C:2](=[CH2:3])[C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: C=O
Agent: OC1CN2CCC1CC2
Product: C=C(CO)C(=O)OC(C)(C)C

Procedure:
 In a typical procedure, t-butyl acrylate (III) is reacted with paraformaldehyde in the presence of 3-quinuclidinol to provide t-butyl hydroxymethylacrylate (IV). This is first treated with thionyl chloride in the presence of triethylamine and pyridine to provide the corresponding chloromethylacrylate, which is then reacted with (S,S)-α-α′-dimethyldibenzylamine to provide an acrylate of the formula (V). This is converted to a compound of the formula (IX) by the method set out in Tet. Lett., 1993, 34(8), 1323-6. A compound of the formula (IX) is then condensed with a lysine derivative of the formula (X) by a similar procedure to that described in EP-A-0358398 for the preparation of a compound of the formula (XI). A compound of the formula (XI) is then converted to a compound of the formula (II) using a solution of trifluoroacetic acid and anisole in dichloromethane.
Reaction SMILES: C(Cl)Cl.[CH2:4]([O:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[S:21](Cl)(=[O:23])=[O:22])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:25]([O:29][C:30](=[O:37])[CH2:31][C@H:32]([NH2:36])[C:33]([NH2:35])=[O:34])([CH3:28])([CH3:27])[CH3:26].N1C=CC=CC=1>C(OCC)(=O)C>[C:25]([O:29][C:30](=[O:37])[CH2:31][C@H:32]([NH:36][S:21]([C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[O:11][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:23])=[O:22])[C:33]([NH2:35])=[O:34])([CH3:28])([CH3:26])[CH3:27]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)c(OCc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(N)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1)C(N)=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 43 %

Procedure:
To a room temperature CH2Cl2 solution (50 mL) of 2-benzyloxy-4-nitro-benzenesulfonyl chloride from Route J (2.62 g, 8.0 mmol) was added (S)-3-amino-succinamic acid tert-butyl ester (1.50 g, 8.0 mmol) and pyridine (2.60 mL). The reaction mixture was allowed to stir for 12 h at room temperature. The reaction was then diluted with ethyl acetate (200 mL) and washed with 5% citric acid and then saturated NaHCO3. The organic phase was dried (MgSO4), and then the solvent was removed under vacuum. The resulting crude product was purified using silica gel flash chromatography (40% hexanes in EtOAc). (S)-3-(2-Benzyloxy-4-nitro-benzenesulfonylamino)-succinamic acid tert-butyl ester was obtained in 43% yield (1.66 g) as an off white foam. MS (APCI) m/z 478.3 (M−1).