Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=O)[CH:9]=2)=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(F)cc2)c2ccccc2[nH]1
Product: Fc1ccc(-c2cc(Cl)nc3ccccc23)cc1

Procedure:
A mixture of 12 g of 4-(4-fluorophenyl)carbostyril and 50 ml of phosphorus oxychloride is heated under reflux for 1.5 hours and then concentrated under reduced pressure. Ice-water is added to the residue and the resulting mixture is extracted with chloroform. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is recrystallized from diethyl ether - ethanol to give 11.1 g of the title compound, m.p. 118° C.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH:10]([O:28][CH3:29])[CH2:11][N:12]1[C:17](=[O:18])[C:16]([C:19](O)=[O:20])=[CH:15][N:14]=[C:13]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(Cl)(=O)OCC(C)C.[NH2:38][OH:39]>O1CCCC1>[OH:39][NH:38][C:19]([C:16]1[C:17](=[O:18])[N:12]([CH2:11][CH:10]([O:28][CH3:29])[O:9][CH3:8])[C:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:14][CH:15]=1)=[O:20]
Reactant: NO
Reactant: COC(Cn1c(-c2ccccc2)ncc(C(=O)O)c1=O)OC
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(Cn1c(-c2ccccc2)ncc(C(=O)NO)c1=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Triethylamine (49.4 ml) was added to a solution of 1-(2,2-dimethoxyethyl)-6-oxo-2-phenyl-1,6-dihydropyrimidin-5-ylcarboxylic acid (97.3 g) in tetrahydrofuran (800 ml) in an ice bath in an argon atmosphere, and isobutyl chlorocarbonate (45.6 ml) was added dropwise thereto at 5° C. or lower, followed by stirring at the same temperature for 1 hour. To the reaction mixture was added a 50% hydroxylamine aqueous solution (422 ml), followed by stirring for 20 minutes. The reaction mixture was separated to layers. The aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined, washed with saturated saline (200 ml), and concentrated. To the residue was added toluene (200 ml), followed by concentration. The resulting crude crystals were washed with isopropyl ether (1000 ml) by heating under reflux for 10 minutes, cooled to room temperature, and crystals were collected by filtration. The collected crystals were dried in vacuo at room temperature overnight to obtain the title compound (93.3 g; yield: 91%) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[CH2:37]([N:40]([CH2:46][CH2:47][CH3:48])[C@H:41]([C:43](O)=[O:44])[CH3:42])[CH2:38][CH3:39]>C1COCC1.C(OCC)(=O)C>[CH3:42][C@H:41]([N:40]([CH2:37][CH2:38][CH3:39])[CH2:46][CH2:47][CH3:48])[C:43]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:44]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: CCCN(CCC)[C@@H](C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCN(CCC)[C@@H](C)C(=O)N1CCc2cc(OC)c([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 41.7 %

Procedure:
To a solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (0.8 g, 4.12 mmol) in THF (200 mL) was added EDC hydrochloride (2.37 g, 12.4 mmol), HOBT (1.67 g, 12.4 mmol), and N,N-dipropyl-L-alanine (2.14 g, 12.4 mmol). After stirring at rt for 5 days, the reaction was diluted with ethyl acetate (100 mL), washed with saturated NaHCO3 (200 mL) and 1M NaOH (200 mL). The organic layer was separated, adsorbed onto silica gel, and purified by column chromatography (DCM to 5% MeOH/DCM) to provide N-{(1S)-1-methyl-2-[5-(methyloxy)-6-nitro-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-N-propyl-1-propanamine (0.6 g, 42%). ESIMS (M+H)+=350.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([O:7][C:8]([CH:10]([N:19]1[C:23]([CH2:24][CH2:25][CH2:26]O)=[CH:22][N:21]=[CH:20]1)[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)=[O:9])[CH3:6]>C(Cl)Cl>[ClH:3].[Cl:3][CH2:26][CH2:25][CH2:24][C:23]1[N:19]([CH:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])[C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[CH:20]=[N:21][CH:22]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)C(c1ccc(C#N)cc1)n1cncc1CCCO
Solvent: ClCCl
Product: CCOC(=O)C(c1ccc(C#N)cc1)n1cncc1CCCCl
Product: Cl

Procedure:
To a solution of 5.75 g of thionylchloride in 80 ml of methylene chloride is added 8.4 g of 1-(α-ethoxycarbonyl-p-cyanobenzyl)-1H-imidazole-5-propanol as a solid in portions. When addition is complete, the solution is refluxed for 1.5 h, cooled in ice and filtered to obtain 5-(3-chloropropyl)-1-(α-ethoxycarbonyl-p-cyanobenzyl)-1H-imidazole hydrochloride. The salt is partitioned between methylene chloride and saturated sodium bicarbonate. The organic extracts are washed with water, dried over sodium sulfate and evaporated to yield the free base.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CC[N:27]([CH:31]([CH3:33])C)[CH:28](C)C.N1CCC1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:27]4[CH2:28][CH2:33][CH2:31]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Agent: C1CNC1
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CCC3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and azetidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.88 (1H), 6.69 (1H), 4.49 (m, 4H), 3.24 (m, 2H), 2.40 (m, 2H), 2.04 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 3H), 1.27-1.30 (m, 2H). m/z: 394 [M+H].
Reaction SMILES: [CH3:1][N:2]([CH2:22][CH2:23][OH:24])[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH3:1][N:2]([CH2:22][CH2:23][O:24][C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3](=[O:21])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]/[CH:11]=[CH:12]\[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CCO
Reactant: O=C(Cl)c1ccccc1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N(C)CCOC(=O)c1ccccc1

Procedure:
N-methyl-N-(2-benzoyloxyethyl)oleamide was prepared by the procedure of example 1 from 34 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)oleamide and 14 gms. (0.1 mole) of benzoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: CO.O.[CH3:4][C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[C:8]2[S:23][CH:24]=[CH:25][C:7]=2[C:6]=1[CH2:26][C:27]([O:29]C)=[O:28].[OH-].[K+]>CC(O)=O>[CH3:4][C:5]1[N:9]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)(=[O:11])=[O:12])[C:8]2[S:23][CH:24]=[CH:25][C:7]=2[C:6]=1[CH2:26][C:27]([OH:29])=[O:28]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(S(C)(=O)=O)cc2)c2sccc12
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Cc1c(CC(=O)O)c2ccsc2n1S(=O)(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.6 %

Procedure:
Methanol (0.5 mL) and water (0.5 mL) were added to the crude methyl 2-(5-methyl-6-(4-(methylsulfonyl)phenylsulfonyl)-6H-thieno[2,3-b]pyrrol-4-yl)acetate, followed by the addition of KOH (47.5 mg, 0.846 mmol). The mixture was stirred at ambient temperature for 1 h before adding the AcOH (0.66 mL). The reaction mixture was dried under reduced pressure (Genevac®) and the residue purified by HPLC (Table 1, Method g) to afford the title compound (0.017 g, 14.6%): LC/MS (Table 1, Method b) Rt=1.89 min; MS m/z 412 (M−H)−; 1H NMR (DMSO) δ 8.19-8.08 (m, 4H), 7.23 (d, 1H, J=5.28 Hz), 6.96 (d, 1H, J=5.28 Hz), 3.41 (s, 2H), 3.29 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=2[CH2:20][S:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH:6]=1.C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:6]=[C:7]([O:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:15][C:14]=2[CH2:20][S:21][CH2:22][C:23]([F:25])([F:26])[F:24])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: COC(=O)Cc1cc(Cl)cc(Oc2ccc(N)cc2CSCC(F)(F)F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Cc1cc(Cl)cc(Oc2ccc(NC(=O)C(C)(C)C)cc2CSCC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of {3-[4-amino-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-5-chloro-phenyl}-acetic acid methyl ester (0.058 g, 0.14 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.04 mL, 0.28 mmol), followed by pivaloyl chloride (0.02 mL, 0.17 mmol), and the reaction was stirred at room temperature for 10 minutes. After work-up with CH2Cl2 and H2O, the crude material was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.Cl.[S:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:22][NH2:23])=[CH:18][CH:17]=1)(=[O:15])(=[O:14])[NH2:13]>>[S:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:22][N:23]=[CH:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:20][CH:21]=1)(=[O:15])(=[O:14])[NH2:13]
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(C=O)cc1
Agent: Cl
Product: COc1ccc(C=NNc2ccc(S(N)(=O)=O)cc2)cc1
Yield: 62 %

Procedure:
A solution of 4-methoxybenzaldehyde (5 mmol) and 4-sulfamylphenyl-hydrazine hydrochloride was to the General Procedure. The title compound, melting point 228–231° C., was obtained in 62% yield.
Reaction SMILES: [CH2:1](/[C:3](=[CH:8]\[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)/[C:4]([O:6]C)=[O:5])[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([C:3](=[CH:8][S:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: CC/C(=C\Sc1ccccc1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCC(=CSc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
A solution of 4.39 g (19.8 mmol) of (E)-methyl 2-ethyl-3-(phenylthio)-2-propenoate and 20 ml of an aqueous 2N NaOH solution in 40 ml of ethanol was stirred at 80° C. for 2 hours and then cooled to room temperature. To the reaction mixture was added 100 ml of water and washed with t-butyl methyl ether. The aqueous layer was acidified to pH 2 with concentrated HCl and extracted with tert-butyl methyl ether. The organic layer was washed with a saturated NaCl solution, dried over anhydrous MgSO4, and concentrated to obtain 4.07 g of 2-ethyl-3-(phenylthio)-2-propenoic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH2:15][C:16]([OH:18])=[O:17])([O-:3])=[O:2].Cl.[CH3:20]O>>[N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:12])[F:13])[C:5]=1[CH2:15][C:16]([O:18][CH3:20])=[O:17])([O-:3])=[O:2]
Reactant: O=C(O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Yield: 92 %

Procedure:
[2-Nitro-4-iodo-6-(trifluoromethyl)phenyl]acetic acid (34.7 g, 96.2 mmol) was dissolved in HCl/MeOH (300 mL) and the solution was heated at reflux for 4.5 hours. The solvent was removed in vacuo and the resulting oil was dissolved in EtOAc (400 mL). The solution was washed with saturated aqueous NaHCO3 (60 mL, 100 mL and 80 mL) and then dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to yield the title compound (33.11 g, 92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([Cl:65])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:67]=[CH:66][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([Cl:65])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2ccc(F)c(Cl)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2ccc(F)c(Cl)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 52 %

Procedure:
To a solution of 100 mg (0.47 mmol) 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 7 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 150 mg (0.47 mmol) (4-tert-butyl-benzyl)-[2-(3-chloro-4-fluoro-phenyl)-ethyl]-amine in 1 ml DMF was added. After stirring for 17 h at rt, the reaction mixture was diluted with 80 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (8 g silica gel; diethylether/heptane 1:1; then 8 g silicagel DCM/heptane 70:30 to 90:10) to give 130 mg light yellow foam (52%). MS (EI) 514.1 (M)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:9]=1)(=O)[NH2:2].S(Cl)(Cl)=O.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:9]=1)#[N:2]
Reactant: COc1ccc(C(N)=O)cc1S(=O)(=O)Cl
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)cc1S(=O)(=O)Cl
Temperature: 55 °C
Reaction time: 3 h
Yield: 62.4 %

Procedure:
5-Carbamoyl-2-methoxybenzenesulfonyl chloride (150 g) was suspended in 1800 mL of ethyl acetate. After 219 mL of thionyl chloride was dropped to the stirred suspension under ice-cooling, 2.3mL of N,N-dimethylformamide was added to the mixture. After being stirred at 55° C. for 3 hours, the reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and water, and the separated organic layer was washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained crude product was recrystallized from ethyl acetate-hexane to give 86.8 g of 5-cyano-2-methoxybenzenesulfonyl chloride.
Reaction SMILES: O[Li].[OH2:3].C(OC(=O)[CH2:8][CH:9]1[N:14]2[CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=[C:13]2[C:12](=[O:21])[NH:11][CH2:10]1)C.O1CCCC1.[OH2:28]>>[N+:18]([C:16]1[CH:17]=[C:13]2[C:12](=[O:21])[NH:11][CH2:10][CH:9]([C:8]([OH:28])=[O:3])[N:14]2[CH:15]=1)([O-:20])=[O:19]
Reactant: CCOC(=O)CC1CNC(=O)c2cc([N+](=O)[O-])cn21
Reactant: O
Agent: [Li]O
Solvent: C1CCOC1
Product: O=C1NCC(C(=O)O)n2cc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
LiOH.H2O (27 mg, 1.12 mmol) was added to a solution of ethyl(7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl)acetate (V, where R1=OCH2CH3) (0.15 g, 0.56 mmol) in a mixture tetrahydrofuran-water (1:1, 9 mL) and the reaction mixture was stirred at room temperature for 3 h. The organic phase was washed with dichloromethane (2×10 mL). The aqueous phase was acidified with hydrochloric acid (1 M) to reach pH<1 and extracted with EtOAc (3×10 mL). The combined organic layers were dried over Na2SO4 and the solvent was evaporated under vacuum to obtain compound 7-nitro-1-oxo-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-4-carboxylic acid (V, where R1=OH) as an off-white solid (101 mg, 75% yield).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[C:18]([CH3:20])[C:17]([O:21]C)=[C:16]([CH3:23])[CH:15]=3)[O:11][C:9]=2[N:10]=1.B(Br)(Br)Br.C(=O)([O-])O.[Na+]>ClCCl>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[N:6]=[CH:7][C:8]2[N:13]=[C:12]([C:14]3[CH:15]=[C:16]([CH3:23])[C:17]([OH:21])=[C:18]([CH3:20])[CH:19]=3)[O:11][C:9]=2[N:10]=1
Reactant: COc1c(C)cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2nc3cnc(Oc4ccccc4F)nc3o2)cc(C)c1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.7 %

Procedure:
A solution of 510 mg of 5-(2-fluoro-phenoxy)-2-(4-methoxy-3,5-dimethyl-phenyl)-oxazolo[5,4-d]pyrimidine in 20 ml of dichloromethane was cooled to 0° C. Over a period of 10 min, 4.2 ml of a 1 M solution of boron tribromide in dichloromethane was added. The mixture was stirred at 0° C. for 1 h, and then another 2 ml of a 1 M solution of boron tribromide in dichloromethane were added. After stirring for another 1 h, 10 ml of a saturated aqueous solution of sodium hydrogencarbonate were added slowly. The aqueous layer was extracted twice with 15 ml of dichloromethane, and the combined organic layers were dried over sodium sulfate, filtered. The solvents were removed in vacuo to give 445 mg of the title compound as a white solid. LC/MS (method LC2): Rt=3.62 min; m/z=352.13 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)[C:11]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[O:12][C:11]1[C:10]([O:21][CH2:22][CH2:23][O:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][O:26]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:39]([C:36]1[CH:35]=[CH:34][C:33]([S:32][CH3:31])=[CH:38][CH:37]=1)(=[O:40])=[O:41]
Reactant: CSc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)c1cc(N)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(SC)cc2)c(Oc2cccc(OC)c2)c(OCCOC2CCCCO2)c1

Procedure:
Analogously to Example 86, by condensing methyl 3-amino-4-(3-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate with 4-methylsulphanylbenzenesulphonyl chloride there was obtained methyl 4-(3-methoxy-phenoxy)-3-(4-methylsulphanyl-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yl-oxy)-ethoxy]-benzoate and therefrom by treatment with 5.5M HCl there was obtained methyl 3-(2-hydroxy-ethoxy)-4-(3-methoxy-phenoxy)-5-(4-methylsulphanyl-benzenesulphonylamino)-benzoate.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[NH:13][C:12]2=[O:19])=[CH:7][CH:6]=1.Cl[CH2:21][C:22]([NH:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=1)=[O:23]>CN(C=O)C>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:15][C@H:14]([CH2:16][CH2:17][CH3:18])[N:13]([CH2:21][C:22]([NH:24][C:25]3[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][N:26]=3)=[O:23])[C:12]2=[O:19])=[CH:9][CH:10]=1
Reactant: O=C(CCl)Nc1cc(C(F)(F)F)ccn1
Reactant: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC[C@H]1CN(c2ccc(OC)cc2)C(=O)N1CC(=O)Nc1cc(C(F)(F)F)ccn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.9 %

Procedure:
Sodium hydride (60%, 27 mg) was added to a solution of (4S)-1-(4-methoxyphenyl)-4-propylimidazolidin-2-one (32 mg) in DMF (1.5 mL), and the mixture was stirred at room temperature for 15 min. To the mixture was added 2-chloro-N-[4-(trifluoromethyl)pyridin-2-yl]acetamide (39 mg), and the resulting mixture was stirred for 15 hr. Thereafter, the reaction mixture was subjected to filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC, and further the resulting solid was washed with isopropyl ether to afford 2-[(55)-3-(4-methoxyphenyl)-2-oxo-5-propylimidazolidin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]acetamide (19 mg).
Reaction SMILES: C(OC(=O)COC1C=CC(S([Br:16])(=O)=O)=CC=1Cl)C.C([C:21]1[CH:31]=[C:30]([S:32][CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][CH:40]=3)[O:36][C:35]=2[CH3:49])[CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([OH:27])=[O:26])C>>[Br:16][C:21]1[CH:31]=[C:30]([S:32][CH2:33][C:34]2[CH:38]=[C:37]([C:39]3[CH:44]=[CH:43][C:42]([C:45]([F:46])([F:48])[F:47])=[CH:41][CH:40]=3)[O:36][C:35]=2[CH3:49])[CH:29]=[CH:28][C:22]=1[O:23][CH2:24][C:25]([OH:27])=[O:26]
Reactant: CCc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)oc2C)ccc1OCC(=O)O
Reactant: CCOC(=O)COc1ccc(S(=O)(=O)Br)cc1Cl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)cc1CSc1ccc(OCC(=O)O)c(Br)c1

Procedure:
The title compound was prepared from ethyl[4-(bromosulfonyl)-2-chlorophenoxy]acetate (intermediate 114) by a method analogous to that used for the preparation of {2-ethyl4-[({2-methyl-5-[4-(trifluoromethyl)phenyl]-3-furyl}methyl)thio]phenoxy}acetic acid (example 145).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(OCC)C.O>[Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: C1COCCN1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: O
Product: O=S(=O)(c1ccc(CBr)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a solution of 4-bromomethylbenzenesulfonyl chloride (1.62 g, 6.01 mmol) in anhydrous diethyl ether (10 mL) at −10° C. was added a solution of morpholine (0.52 mL, 5.94 mmol) and triethylamine (0.92 mL, 6.6 mmol) in anhydrous diethyl ether (10 mL). The resulting mixture was allowed to warm up to room temperature over 1 hr, and continue stirring at r.t. overnight. The reaction mixture was then diluted with water, extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with water, brine, dried over Na2SO4, and filtered. Solvents were removed to yield an orange oil, which was purified on a 40 g silica gel column to give a white solid (1.34 g, 71% yield). 1H NMR (CD2Cl2) δ ppm: 7.75 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 4.58 (s, 2H), 3.77-3.73 (m, 2H), 3.03-2.98 (m, 2H). MS (ESI+): 320 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](Cl)=[N:8][OH:9])=[N:4][O:5][N:6]=1.[CH3:11][O:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7](=[N:8][OH:9])[NH:15][CH2:14][CH2:13][O:12][CH3:11])=[N:4][O:5][N:6]=1
Reactant: COCCN
Reactant: Nc1nonc1C(Cl)=NO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCCNC(=NO)c1nonc1N
Temperature: 2.5 °C
Yield: 118.8 %

Procedure:
4-Amino-N-hydroxy-1,2,5-oxadiazole-3-carboximidoyl chloride (200.0 g, 1.23 mol) was mixed with ethyl acetate (1.2 L). At 0-5° C. 2-methoxyethylamine [Aldrich, product #143693] (119.0 mL, 1.35 mol) was added in one portion while stirring. The reaction temperature rose to 41° C. The reaction was cooled to 0-5° C. Triethylamine (258 mL, 1.84 mol) was added. After stirring 5 min, LCMS indicated reaction completion. The reaction solution was washed with water (500 mL) and brine (500 mL), dried over sodium sulfate, and concentrated to give the desired product (294 g, 119%) as a crude dark oil. LCMS for C6H12N5O3 (M+H)+: m/z=202.3. 1H NMR (400 MHz, DMSO-d6): δ 10.65 (s, 1H), 6.27 (s, 2H), 6.10 (t, J=6.5 Hz, 1H), 3.50 (m, 2H), 3.35 (d, J=5.8 Hz, 2H), 3.08 (s, 3H).