Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[CH:16]12[CH2:24][CH2:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH2:17]2>>[CH:20]12[CH2:23][CH2:24][CH:16]([CH2:22][CH2:21]1)[CH2:17][N:18]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:2]1[N:3]=[N:4][C:5]([CH3:15])=[C:6]3[N:14]4[C:9]([CH2:10][CH2:11][CH2:12][CH2:13]4)=[CH:8][C:7]=13)[CH2:19]2
Reactant: NCCCCN1CC2CCC(CC2)C1
Reactant: Cc1nnc(Cl)c2cc3n(c12)CCCC3
Product: Cc1nnc(NCCCCN2CC3CCC(CC3)C2)c2cc3n(c12)CCCC3

Procedure:
Following the procedure in Example 9, compound XII was allowed to react with 4-(3-azabicyclo[3.2.2]non-3-yl)butylamine to give the title compound which was converted to the dihydrochloride salt: m.p.210° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].Cl[C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl.[OH:28][CH2:29][CH:30]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]1>ClCCl>[N+:1]([C:4]1[CH:10]=[CH:9][C:8]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:7][C:5]=1[NH:6][C:17]([O:28][CH2:29][CH:30]1[CH2:33][N:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:31]1)=[O:19])([O-:3])=[O:2]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(-c2cccs2)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CC(CO)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(COC(=O)Nc2cc(-c3cccs3)ccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 166 %

Procedure:
To a solution of 2-nitro-5-(thiophen-2-yl)aniline (0.30 g, 1.36 mmol, 1 eq.) and triphosgene (0.24 g, 0.82 mmol, 0.6 eq.) in dichloromethane (7 mL) at 0° C. was added TEA (0.38 mL, 2.90 mmol, 2 eq.). The reaction was stirred at room temperature for 2 h, then cooled down to 0° C. Tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (0.31 g, 1.64 mmol, 1.2 eq.) in dichloromethane (7 mL) and TEA (0.38 mL, 2.90 mmol, 2 eq.) were added at 0° C. The reaction was warmed to room temperature and stirred for 1 h. The reaction was diluted with dichloromethane and washed with citric acid solution then brine. The organic layer was separated, dried over sodium sulfate and concentrated. The crude product was purified by column chromatography (silica gel, 25% EtOAc/hexanes) to obtain tert-butyl 3-((((2-nitro-5-(thiophen-2-yl)phenyl)carbamoyl)oxy)methyl)azetidine-1-carboxylate (0.59 g, 85% yield).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]3)=[N:19]2)=[CH:14][CH:13]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>ClCCl>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][S:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:29][CH2:30]3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2ncc(SCCN3CCC(NS(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (318 μL, 1.82 mmol, 2.5 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (237 mg, 0.73 mmol, 1.0 eq) in dichloromethane (4 mL), followed by 2-nitro-benzenesulfonyl chloride (183 mg, 0.80 mmol, 1.1 eq). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate 100%) to afford N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide as a yellow waxy solid (307 mg, 82% yield).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:26])([F:25])[C:7]1[C:16]([C:17](O)=[O:18])=[C:15]([OH:20])[C:14]2[C:9](=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:11]=[CH:12][CH:13]=2)[N:8]=1>C1C=CC=CC=1>[F:5][C:6]([F:26])([F:25])[C:7]1[C:16]([C:17]([Cl:3])=[O:18])=[C:15]([OH:20])[C:14]2[C:9](=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Solvent: c1ccccc1
Product: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O

Procedure:
9.6 ml of thionyl chloride were added with stirring to a suspension of 8.75 g of the product of Step D in 285 ml of benzene and the mixture was refluxed for 90 minutes. Then, the benzene and excess thionyl chloride was evaporated and the residue was taken up twice in anhydrous benzene to obtain 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride which was used as is for the next step.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][CH:18]([O:20][C:21](=[O:39])[NH:22][CH2:23][C@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31](Br)[CH:32]=2)[N:27]([C:35](=[O:37])[CH3:36])[C@@H:26]([CH3:38])[CH2:25]1)[CH3:19].C(=O)([O-])[O-].[K+].[K+].C(O)C>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.C1(C)C=CC=CC=1>[CH:21]([OH:39])=[O:20].[C:35]([N:27]1[C:28]2[C:33](=[CH:32][C:31]([C:11]3[CH:12]=[CH:13][C:8]([CH2:7][N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:9][CH:10]=3)=[CH:30][CH:29]=2)[C@H:24]([CH2:23][NH:22][C:21](=[O:39])[O:20][CH:18]([CH3:17])[CH3:19])[CH2:25][C@@H:26]1[CH3:38])(=[O:37])[CH3:36]
Reactant: OB(O)c1ccc(CN2CCCCC2)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](CNC(=O)OC(C)C)C[C@@H]1C
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CC(=O)N1c2ccc(-c3ccc(CN4CCCCC4)cc3)cc2[C@H](CNC(=O)OC(C)C)C[C@@H]1C
Product: O=CO
Temperature: 90 °C
Reaction time: 8 h

Procedure:
[4-(1-Piperidinylmethyl)phenyl]boronic acid (135 mg, 0.475 mmol), 1-methylethyl[(cis)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]methylcarbamate (for a preparation see Intermediate 40) (104 mg, 0.271 mmol), Tetrakis(triphenylphosphine)palladium(0) (15.68 mg, 0.014 mmol) and potassium carbonate (150 mg, 1.085 mmol) were placed in a round-bottomed flask with ethanol (1.8 mL) and Toluene (1.800 mL). The reaction mixture was stirred at 90° C. under N2 overnight. The brown reaction mixture was concentrated down and partitioned between EtOAc (10 mL) and water (10 mL). Further EtOAc (15 mL) was used to extract the product from the aqueous layer and the organics were combined, washed with saturated sodium bicarbonate solution (10 mL), dried (phase separator) and concentrated to yield a brown oil. This was purified by SP4 on a 12+M silica column using a gradient of 0.6-6% 2M methanolic ammonia in DCM. The relevant fractions were concentrated down to obtain a yellow oil (121 mg). Further purification was carried out using MDAP to give the desired compound (70 mg). LCMS (Method B): Rt=0.73, MH+=478
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:8]=2)[N:5]=[C:4]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])[CH:3]=1.[OH-].[Na+].Cl[C:31]([O:33][CH2:34][C:35]([Cl:38])([Cl:37])[Cl:36])=[O:32]>CCOC(C)=O>[Cl:36][C:35]([Cl:38])([Cl:37])[CH2:34][O:33][C:31](=[O:32])[NH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:14][CH2:15][O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][O:18]3)[CH:8]=2)[N:5]=[C:4]([C:23]([C:24]#[N:25])([CH3:27])[CH3:26])[CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C#N)c1cc(N)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(OCCOC3CCCCO3)c2)n1
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
Intermediate 20c (317 mg, 0.86 mmol) was dissolved in EtOAc (2.5 mL) and 1M NaOH solution (1.4 mL, 2.14 mmol) and cooled in an ice bath. While stirring, 2,2,2-trichloroethyl chloroformate (227 mg, μL, 1.07 mmol) was then added dropwise, and the ice bath removed. After 30 min, a further 0.65 eq. of 2,2,2-trichloroethyl chloroformate was added, and the reaction continued. After 30 min, a further 0.65 eq. of 2,2,2-trichloroethyl chloroformate was added, and the reaction continued overnight. The reaction was then partitioned between H2O and EtOAc, the organic layer was separated, and the aqueous layer extracted again with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 5-30% EtOAc in cyclohexane, to afford the title compound as a light yellow oil (375 mg, 80%). LCMS (Method 3): Rt 4.41 min, m/z 567, 569 [M+Na].
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([O:32]C(C)(C)C)=[O:31])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1>C(Cl)Cl>[CH:8]1([S:14][C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[CH:22][CH:21]=3)[N:18]=[CH:17][C:16]=2[C:30]([OH:32])=[O:31])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: COC(=O)c1ccc(-n2ncc(C(=O)OC(C)(C)C)c2SC2CCCCC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-n2ncc(C(=O)O)c2SC2CCCCC2)cc1
Temperature: 20 °C
Reaction time: 24 h
Yield: 101.5 %

Procedure:
Trifluoroacetic acid (4.72 mL, 61.46 mmol) was added to tert-butyl 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylate (Intermediate #89) (2.56 g, 6.15 mmol) in CH2Cl2 (40 mL) The resulting solution was stirred at 20° C. for 24 hours. The reaction mixture was evaporated to dryness, re-dissolved in dioxan (20 mL) and re-evaporated to dryness to afford 5-(cyclohexylthio)-1-(4-(methoxycarbonyl)phenyl)-1H-pyrazole-4-carboxylic acid (2.25 g, 100%) as a white crystalline solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Br:29][C:26]1[CH:25]=[CH:24][C:23]([C:11]2([C:21]#[N:22])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])=[CH:28][CH:27]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Br)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 54b (1.1 g, 2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-4-(4-bromo-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (1.2 g, 99%).
Reaction SMILES: B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O(C)[Li].I[C:23]1[CH:28]=[CH:27][C:26]2[O:29][CH2:30][O:31][C:25]=2[CH:24]=1>CO>[CH2:30]1[O:31][C:25]2[CH:24]=[CH:23][CH:28]=[CH:27][C:26]=2[O:29]1
Reactant: Ic1ccc2c(c1)OCO2
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Li]OC
Solvent: CO
Product: c1ccc2c(c1)OCO2

Procedure:
284 mgs (1.12 mmol) of bis(pinacolato)diboron under anaerobic conditions in dry methanol (3 ml) in a reaction tube was treated with 2 ml of a 1 M LiOMe solution in methanol. After stirring, 22 mg (0.028 mmol) of PtCl2(PPh3)2 was added followed by 258 mg (1.04 mmol) of 1-iodo-3,4-methylenedioxybenzene and a further 2 ml of methanol. At 60° C. the reaction goes to completion to form the desired product together with 3,4-methylenedioxybenzene. In DMSO the reaction rate is significantly slower than in methanol.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][CH:6]=C[C:4]=1[C:9]1[CH:34]=[CH:33][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=1)=O.[C-:35]#N.[Na+].[CH3:38][C:39]([OH:41])=[O:40]>CO.O=[Mn]=O>[CH3:35][O:40][C:39]([C:38]1[CH:6]=[CH:7][CH:8]=[CH:3][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C:14]23[C:22](=[O:23])[N:21]([C:24]4[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=4)[C:20](=[O:32])[N:19]2[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:33][CH:34]=1)=[O:41]
Reactant: [C-]#N
Reactant: CC(=O)O
Reactant: O=Cc1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: O=[Mn]=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccccc1-c1ccc(CC23CCCCN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-[4-(2-formylphenyl)benzyl]-8-(3,5-dichlorophenyl)-1,8-diazabicyclo[4.3.0]nonane-7,9-dione (0.206 g) in MeOH (20 mL) was added NaCN (0.204 g), AcOH (0.086 mL) and MnO2 (activated, 1.84 g) and the mixture was stirred overnight at room temperature. The inorganics were removed by filtration through Celite and the filtrate was evaporated. The residue was dissolved in EtOAc and washed with water, brine, dried (MgSO4), filtered, and concentrated. Purification by chromatography (Silica gel: EtOAc/hexane: 1/2) afforded the titled compound (0.161 g). It was converted to the HCl salt. MS (m/z) 545(M++Na), 523 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=O)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:31]([O:38][C:39](=[O:51])[CH2:40][NH:41][CH:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl>[CH2:31]([O:38][C:39](=[O:51])[CH2:40][N:41]([C:13](=[O:15])[C@H:9]([CH:10]([CH3:11])[CH3:12])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:42]1[CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: O=C(CNC1Cc2ccccc2C1)OCc1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(CC(=O)OCc1ccccc1)C1Cc2ccccc2C1
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of N-(tert-butoxycarbony1)-L-valine (4.35 g) and triethylamine (2.13 g) in dry CH2Cl2 (40 ml) was added isobutyl chloroformate (2.87 g) at -20° C. After being stirred at same temperature for 30 minutes, a solution of N-(2-indanyl)glycine benzyl ester (5.37 g) in dry CH2Cl2 (20 ml) was added at -20° C. The reaction mixture was stirred at -10° C. for one hour then at room temperature for 4 hours. After the reaction mixture was evaporated under reduced pressure, the residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium bicarbonate (100 ml×2). The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified with silica gel (50 g) column chromatography (CHCl3:AcOEt=10:1) to give N-(tert-butoxycarbonyl)-L-valyl-N-(2-indanyl)glycine benzyl ester (2.20 g) as an oil.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7](O)(=O)[C:8](O)=[O:9].[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.C(Cl)(=O)C>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:8]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:9])[CH3:7]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)Cl
Product: CC(=O)NC1CCN(CCNC(=O)c2nn(C(C)C)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise acetyl chloride (0.071 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature and filtered, and the filtrate was evaporated to 0.360 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.243 g colorless crystals. Mp 176° C. Mass spectrum, m+ =371. Anal (C22H31N5O6) theory C, 57.25; H, 6.77; N, 15.17; found C, 56.95; H, 6.74; N, 14.99.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.N1C=CC=CC=1.[CH2:19]([S:22](Cl)(=[O:24])=[O:23])[CH2:20][CH3:21]>C(Cl)Cl>[CH2:19]([S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:24])=[O:23])[CH2:20][CH3:21]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCCS(=O)(=O)Cl
Agent: CCOC(=O)Cc1csc(=N)[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1nc(CC(=O)OCC)cs1
Temperature: 40 °C

Procedure:
A mixture of ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-imino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (40 g.) and pyridine (200 ml.) was stirred in a stream of nitrogen gas at 40° C., and to the mixture was dropwise added a mixture of propanesulfonyl chloride (61.3 g.) and methylene chloride (100 ml.) over 2 hours, and then the mixture was stirred for 2 hours at the same temperature. After the reaction, pyridine and methylene chloride were distilled off from the reaction mixture. The residue was dissolved in ethyl acetate, and the solution was washed with water, 1/2N hydrochloric acid and water in turn and then dried. The ethyl acetate was distilled off from the solution, and the residue was washed with a mixture of ethyl acetate and diethyl ether and then dried to give ethyl 2-(2-propanesulfonylamino-1,3-thiazol-4-yl)acetate, which can be represented as ethyl 2-(2-propanesulfonylimino-2,3-dihydro-1,3-thiazol-4-yl)acetate, (16.4 g.), mp 140° to 142° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][C:16](=[O:36])[N:17]2[CH2:21][CH2:20][CH2:19][C@H:18]2[C:22](=[O:35])[NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+]>CO.O>[O:36]=[C:16]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:35])[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=1)[CH2:15][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:7]1
Reactant: CCOC(=O)c1cn(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(CC(=O)N2CCC[C@H]2C(=O)Nc2cccc(OC(F)(F)F)c2)c2ccccc12
Temperature: 80 °C
Reaction time: 0.54 h

Procedure:
To a solution of 1-{2-oxo-2-[(S)-2-(3-trifluoromethoxy-phenylcarbamoyl)-pyrrolidin-1-yl]ethyl}-1H-indole-3-carboxylic acid ethyl ester (314 mg, 0.62 mmol) in MeOH (12 mL) and water (1.2 mL) was added NaOH 1N (1.87 mL, 1.87 mmol) and the mixture was heated at 80° C. for 6 h. MeOH was concentrated, HCl 1N was added and the residue was extracted with EtOAc. The organic extracts were dried with Na2SO4, filtered and concentrated. The crude residue was purified by preparative HPLC (Interchrom C18-ODB, 10 μm, 28×250 mm, 20% CH3CN in H2O 2.5 min, then 20% to 100% CH3CN in H2O in 32.5 min, CH3CN and H2O containing 0.1% HCOOH; flow: 40 mL/min) to give after lyophilization of the purified fractions the desired compound. TLC, Rf (EtOAc)=0.05; MS (LC/MS): 498.1 [M+Na]+, 474.1 [M−H]−; tR (HPLC conditions a): 3.48 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11]O)[CH3:2].[Cl:13][C:14]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])=[CH:19][C:15]=1[C:16](Cl)=[O:17].[OH2:35]>N1C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:17][C:16](=[O:35])[C:15]1[CH:19]=[C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=2[Cl:34])[CH:21]=[CH:22][C:14]=1[Cl:13])[CH3:2]
Reactant: O=C(Cl)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CCOCCOCCOCCO
Reactant: O
Solvent: c1ccncc1
Product: CCOCCOCCOCCOC(=O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 25 °C
Yield: 63.3 %

Procedure:
In 20 ml pyridine was dissolved 2.0 g (0.0167 mol) of triethylene glycol monoethyl ether, and while stirring at room temperature, 1.8 g (0.0049 mol) of 2-chloro-5-(2-chloro-4-trifluoromethylphenoxy)benzoyl chloride was added. After 4-hour stirring, the reaction fluid was poured into 200 ml of water, and extracted with benzene. The extract was washed with a dilute aqueous solution of caustic soda and then with dilute hydrochloric acid. By concentration 1.4 g (0.0031 mol) of the intended product was obtained as a viscous oily substance, yield 63.3%, nD28 1.5175.
Reaction SMILES: Cl[C:2]1[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21]>>[N+:15]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([S:11](=[O:14])(=[O:13])[NH2:12])[C:2]=1[O:21][CH2:20][C:19]([F:23])([F:22])[F:18])[C:6]([OH:8])=[O:7])([O-:17])=[O:16]
Reactant: OCC(F)(F)F
Reactant: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1Cl
Product: NS(=O)(=O)c1cc(C(=O)O)cc([N+](=O)[O-])c1OCC(F)(F)F

Procedure:
To a solution of sodium β,β,β -trifluoroethoxide in β,β,β-trifluoroethanol (prepared by dissolving 2.1 g of sodium in 45 ml of β,β,β-trifluoroethanol), 4-chloro-3-nitro-5-sulphamyl-benzoic acid (4.2 g) was added, and the resulting solution was refluxed for 5 days. After evaporation of the reaction mixture in vacuo, water (50 ml) was added, and the aqueous solution was acidified with 4N hydrochloric acid. After standing in a refrigerator, the precipitate was collected by suction. After several recrystallizations from aqueous ethanol, the 3-nitro-5-sulphamyl-4-(β,β,β-trifluoroethoxy)-benzoic acid was obtained with a melting point of 195°-197° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13].COC(OC)N(C)C>CN(C)C=O>[N+:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]2[C:5]=1[CH:13]=[CH:1][O:2][C:3]2=[O:14])([O-:12])=[O:11]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1C
Agent: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: O=c1occc2c([N+](=O)[O-])cccc12
Yield: 54.4 %

Procedure:
16.4 g (84.03 mmol) of 2-methyl-3-nitrobenzoic acid methyl ester is stirred with 26.8 g (225.1 mmol) of N,N-dimethylformamide dimethylacetal in 85 ml of dimethylformamide for 12 hours at 130° C. The solvent is drawn off in a rotary evaporator, the residue is taken up in methyl-tert-butyl ether and washed three times with water. After washing with saturated NaCl solution, the organic phase is dried. After the desiccant is filtered off and the solvent is spun off, the remaining residue is chromatographed on silica gel (mobile solvent ethyl acetate/hexane). 8.73 g (54.4%) of the desired compound is isolated.