Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OC(Cl)C)=O.C[N:9]1[CH2:31][C:14]2=[C:15]3[C:19](=[CH:20][CH:21]=[C:13]2[O:12][CH2:11][CH2:10]1)[N:18]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH:17]=[CH:16]3.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1.Cl.C(OCC)C>C(Cl)Cl>[C:25]1([S:22]([N:18]2[C:19]3[C:15](=[C:14]4[CH2:31][NH:9][CH2:10][CH2:11][O:12][C:13]4=[CH:21][CH:20]=3)[CH:16]=[CH:17]2)(=[O:24])=[O:23])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN1CCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c2C1
Agent: CC(Cl)OC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=S(=O)(c1ccccc1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 43 °C
Reaction time: 1 h
Yield: 7.6 %

Procedure:
1-Chloroethyl chloroformate (1.0 mL, 7.0 mmol) was added to a solution of 2-methyl-8-(phenylsulfonyl)-1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole (Example 5, 0.15 g, 0.44 mmol), and 1,8-bis-(dimethylamino)-naphthalene (proton sponge) (0.056 g, 0.26 mmol) in DCM (10 mL) and the mixture was stirred at 43° C. for 1 hour. 1.0 M HCl in diethylether (2.5 mL, 2.5 mmol) was added and the mixture was evaporated. The residue was dissolved in dry MeOH (10 mL) and heated at 78° C. for 30 minutes and evaporated. The residue was dissolved in DCM and washed with water, brine, and the organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (5:94:1) as the eluent to give the title compound (11 mg) as a light pink solid. MS m/z 329 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[NH:12][C:11]2[C:6]1=[N:7][C:8]([C:15]1[CH:16]=[N:17][N:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=13)=[N:9][CH:10]=2)[CH3:4].[CH3:26]N(C=O)C.CI>>[OH:1][CH2:2][C@H:3]([N:5]1[C:13](=[O:14])[N:12]([CH3:26])[C:11]2[C:6]1=[N:7][C:8]([C:15]1[CH:16]=[N:17][N:18]3[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][C:19]=13)=[N:9][CH:10]=2)[CH3:4]
Reactant: CN(C)C=O
Reactant: C[C@H](CO)n1c(=O)[nH]c2cnc(-c3cnn4ccc(C#N)cc34)nc21
Solvent: CI
Product: C[C@H](CO)n1c(=O)n(C)c2cnc(-c3cnn4ccc(C#N)cc34)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.6 %

Procedure:
To a solution of example 28 (20 mg, 0.06 mmol) in AcN (2 mL) and DMF (0.5 mL) silver (I) oxide (23 mg, 0.12 mmol) and methyl iodide (0.005 mL, 0.09 mmol) were added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was filtered through a plug of Celite® and the solvent was evaporated under reduced pressure. The crude residue was cromatographed on a silica gel flash system (ISCO Combiflash) using CH2Cl2/MeOH mixtures of increasing polarity as eluent to afford 6 mg of the desired product (29% yield).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]1([SH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:11]1([S:17][CH2:2][C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:4])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Sc1ccccc1
Solvent: c1ccncc1
Product: O=C(CSc1ccccc1)c1ccccc1
Yield: 67.7 %

Procedure:
To 300 mL of pyridine was added a-bromoacetophenone (150 g, 750 mmol) and thiophenol (83 g, 750 mmol). The mixture was heated at reflux for six hours. The pyridine was evaporated and the residue dissolved in ethyl acetate. The ethyl acetate solution was washed exhaustively with 1 N sodium hydroxide, then with 1 N hydrochloric acid, dried over magnesium sulfate, filtered, and evaporated to yield a brown oil. The product was crystallized from ethanol at 0° C. to yield 116 g of the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:43]=[C:42]([Cl:44])[C:16]([C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=3[CH3:37])=[CH:27][CH:26]=2)[C:21]([OH:23])=[O:22])=[O:18])=[C:15]([Cl:45])[CH:14]=1.O=C1CCC(=O)N1[O:53][C:54](=O)[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]1[C:77](=[O:78])[CH:76]=[CH:75][C:74]1=[O:79].CCN(C(C)C)C(C)C>>[Cl:45][C:15]1[CH:14]=[C:13]([O:12][CH2:11][CH2:10][CH2:9][NH:8][C:54](=[O:53])[CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]2[C:77](=[O:78])[CH:76]=[CH:75][C:74]2=[O:79])[CH:43]=[C:42]([Cl:44])[C:16]=1[C:17]([NH:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[C:32](=[O:41])[N:33]([CH3:40])[C:34](=[O:39])[N:35]([CH3:38])[C:36]=2[CH3:37])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22])=[O:18]
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Reactant: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCN)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cc(OCCCNC(=O)CCOCCOCCOCCOCCNC(=O)CCN4C(=O)C=CC4=O)cc3Cl)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[4-(3-aminopropoxy)-2,6-dichlorobenzoylamino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid trifluoroacetate salt (203 mg, 0.3 mmol), 3-[2-[2-[2-[[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)-propionylamino]-ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (154 mg, 0.3 mmol), and DIPEA (194 mg, 261 uL, 1.5 mmol), and after HPLC purification, resulted in an amorphous white solid (175 mg, 61%). ES(+)-HRMS m/e calcd. for C44H54Cl2N6O14 (M+H)+ 961.3148, obsd. 961.3156.
Reaction SMILES: [I-].[C:2]([C:5]1[CH:10]=[CH:9][N+:8]([CH3:11])=[CH:7][CH:6]=1)(=[O:4])[CH3:3].[Br:12]Br.C(OCC)C>Br.C(O)(=O)C>[Br-:12].[Br:12][CH2:3][C:2]([C:5]1[CH:10]=[CH:9][N+:8]([CH3:11])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(=O)c1cc[n+](C)cc1
Reactant: BrBr
Agent: Br
Agent: [I-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: C[n+]1ccc(C(=O)CBr)cc1
Product: [Br-]
Yield: 180.2 %

Procedure:
10.0 g 4-Acetyl-1-methylpyridinium iodide were dissolved in 75 ml hydrogen bromide/acetic acid at 0° C. and 8.6 g bromine dissolved in 40 ml hydrogen bromide/acetic acid were added dropwise. The reaction mixture was added to 800 ml diethylether and the precipitate was filtered, washed with diethyl ether and dried in vacuo to give 14.3 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH2:9][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([BH3-])#N.[Na+]>CO.ClCCl>[CH2:12]([N:1]1[CH2:11][CH2:10][CH2:9][C@H:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CCOC(=O)[C@H]1CCCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CCCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 23 h
Yield: 39.5 %

Procedure:
(S)-ethyl nipecotate (309.1 mg; 1.97 mmol) was dissolved in anhydrous methanol (8 ml) and commercially available benzaldehyde (200 μl; 1.97 mmol) was added, followed by sodium cyanoborohydride (234 mg; 3.72 mmol). This mixture was allowed to stir at ambient temperature for 23 hours and was then diluted with dichloromethane. The dichloromethane was washed with water, then washed with saturated sodium chloride solution, dried with anhydrous potassium carbonate, and evaporated under reduced pressure at ambient temperature. The crude product was purified by chromatography on silica eluting with 50% ethyl acetate/50% hexane, giving (S)-ethyl 1-benzyl-3-piperidinecarboxylate (192.7 mg) as a colorless oil. MS mi/z (positive ion) 248 (MH+; 100).
Reaction SMILES: O.C([O-])=O.[Na+].C(O)(=O)C.[F:10][CH:11]([F:35])[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([N+:32]([O-])=O)[CH:20]=1>[C].[Pd].CC(O)C>[NH2:32][C:21]1[CH:20]=[C:19]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[O:12][CH:11]([F:10])[F:35])[CH:31]=[CH:30][C:22]=1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2OC(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2OC(F)F)cc1N
Temperature: 25 °C
Yield: 90.8 %

Procedure:
Water (0.53 mL), sodium formate (0.13 g), acetic acid (0.13 mL), and 10% palladium-carbon (35 mg) were added to a 2-propanol (2.1 mL) solution of tert-butyl 4-(2-(difluoromethoxy)phenyl)-2-nitrobenzoate (0.18 g), followed by heating to reflux for 2 hours. The reaction mixture was cooled to room temperature, and then the insoluble substance was removed by filtration. The solvent was evaporated under reduced pressure, and ethyl acetate and a saturated aqueous solution of sodium bicarbonate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 0.15 g of tert-butyl 2-amino-4-(2-(difluoromethoxy)phenyl)benzoate as a yellow oily substance.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[NH:13][C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1.[C:31]([O-:34])([O-])=O.[Cs+].[Cs+].CN([CH:40]=[O:41])C>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[C:12](=[O:30])[N:13]([CH2:31][O:34][C:40](=[O:41])[CH2:15][CH2:11][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:14](=[O:29])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][C:21]([N+:25]([O-:27])=[O:26])=[CH:22][CH:23]=3)[N:18]([CH3:28])[CH:17]=2)=[CH:3]1
Reactant: O=C([O-])[O-]
Reactant: CN(C)C=O
Reactant: Cn1cc(C2=C(c3cn(C)c4cc([N+](=O)[O-])ccc34)C(=O)NC2=O)c2ccccc21
Agent: [Cs+]
Product: CCCCCCCCCC(=O)OCN1C(=O)C(c2cn(C)c3ccccc23)=C(c2cn(C)c3cc([N+](=O)[O-])ccc23)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
3-(1-Methyl-3-indolyl)-4-(1-methyl-6-nitro-3-indolyl)-1H-pyrrole-2,5-dione (20 mg 0.05 mmol) (See Davis U.S. Pat. No. 5,057,614) was dissolved in DMF and treated with Cs2CO3 (49 mg, 0.15 mmol) for a few minutes, the chloromethyl ester (33 mg, 0.15 mmol) prepared in step a) above was added and the reaction was stirred at room temperature for 30 minutes. Aqueous workup, followed by purification by flash chromatography yielded decanoic acid 3-(1-methyl-1H-indol-3-yl)-4-(1-methyl-6-nitro-1H-indol-3-yl)-2,5-dioxo-2,5-dihydro-pyrrol-1-ylmethyl ester (yield—58%).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][O:12][C:11]2=[O:15])[CH:7]=[C:6](Br)[CH:5]=1.[CH2:18]=[C:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[NH:25]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28](=O)[C:26]1=[O:27]>>[O:15]=[C:11]1[N:10]([C:8]2[CH:9]=[C:4]([CH:5]=[C:6]([N:25]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[C@:28]4([C:19]5([CH2:24][CH2:23][O:22][CH2:21][CH2:20]5)[CH2:18]4)[C:26]3=[O:27])[CH:7]=2)[C:3]([OH:2])=[O:17])[CH2:14][CH2:13][O:12]1
Reactant: COC(=O)c1cc(Br)cc(N2CCOC2=O)c1
Reactant: C=C1CCOCC1
Reactant: O=C1Nc2ccccc2C1=O
Product: O=C(O)c1cc(N2CCOC2=O)cc(N2C(=O)[C@]3(CC34CCOCC4)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 101 starting from methyl-3-bromo-5-(2-oxooxazolidin-3-yl)benzoate prepared as in Example 101, 4-methylene-tetrahydro-pyran, isatin (commercially available) according to Scheme 2. LC/MS m/e calcd. for C24H22N206: 434, observed (M+H)+: 434.21H NMR (400 MHz, DMSO-d6) δppm 1.72-1.80 (m, 1 H) 1.83 (d, J=4.29 Hz, 1 H) 1.91-2.01 (m, 3 H) 2.06-2.16 (m, 1 H) 3.36-3.44 (m, 1 H) 3.50-3.56 (m, 1 H) 3.58-3.65 (m, 2 H) 4.13-4.21 (m, 2 H) 4.48 (t, J=7.96 Hz, 2 H) 6.90 (d, J=8.08 Hz, 1 H) 7.07 (t, 1 H) 7.23 (t, 1 H) 7.29 (d, J=7.58 Hz, 1 H) 7.71 (s, 1H) 7.92 (s, 1 H) 8.19 (s, 1 H) 13.40 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[CH:4][C:3]=1[C:16]1[NH:20][C:19](=[O:21])[N:18]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[N:17]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:14]=[CH:15][C:2]([Cl:1])=[C:3]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=3)[N:17]=2)[CH:4]=1
Reactant: O=C(NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1
Yield: 63 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-3-(1-(3-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (0.400 g), KOH (0.200 g), water (2 mL) and THF (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:5]=1[CH:6]=O.[OH:13]S([O-])(=O)=O.[Na+].[CH2:19]1[CH2:23][O:22][CH2:21][CH2:20]1>CC(=O)OCC>[CH2:21]([O:22][C:23](=[O:13])/[CH:19]=[CH:6]/[C:5]1[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:4]=1[F:3])[CH3:20]
Reactant: C1CCOC1
Reactant: O=Cc1cc(F)ccc1F
Reactant: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 100 %

Procedure:
To an iced chilled suspension of NaH (1.13 g, 60% in oil dispersion, 28.2 mmol) in THF (32 mL) was added triethylphosphonoacetate (5.6 ml, 28.2 mmol). The reaction mixture was stirred at rt for 20 min. 2,5-difluoro-benzaldehyde (3.34 g, 23.5 mmol) was added drop wise. After 30 min, 10% aq. NaHSO4 (100 mL) was added and the mixture was diluted with EA (150 mL). The two phases were separated and the aq. layer was extracted twice with EA (2×100 mL). The combined org. layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was chromatographed over SiO2 (Hex-EA 19-1) to afford the title ester as colourless oil (5.0 g, 100% yield).
Reaction SMILES: [K].[CH3:2][O:3][CH2:4][C:5]([CH:7]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[C:8]1=[O:22])=O.Cl.[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1CCCCC1.C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:31]=[CH:30][C:28]([NH:29][C:5](=[C:7]2[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[C:8]2=[O:22])[CH2:4][O:3][CH3:2])=[CH:27][CH:26]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COCC(=O)C1CCN(C(=O)OCc2ccccc2)C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: [K]
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COCC(Nc1ccc(Cl)cc1)=C1CCN(C(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
Into a 200 mL four-mouthed flask were added benzyl 3-(2-methoxyacetyl)-2-oxopyrrolidine-1-carboxylate potassium salt (6.60 g) [mw. 329.39, 20.0 mmol], 1 mol/L aqueous hydrochloric acid solution (33 mL) and toluene (60 mL), and the mixture was stirred at room temperature for 30 min. After partitioning, the organic layer was washed with water (33 mL), and dried over magnesium sulfate. After filtration, p-chloroaniline (2.56 g) [mw. 127.57, 20.0 mmol], p-toluenesulfonic acid monohydrate (0.038 g) [mw. 190.22, 0.2 mmol] and cyclohexane (33 mL) were added. Dean-Stark trap was set, and distillation by thermal dehydration was performed for 90 min. After cooling to room temperature, 5 w/w % aqueous acetic acid solution (33 mL) was added to allow for partitioning. The organic layer was washed successively with 5 w/w % aqueous sodium bicarbonate solution (33 mL) and water (33 mL), further washed with water (33 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. To the concentrate were added methanol (q.s.) and activated carbon (1 g), and the mixture was stirred at room temperature for 30 min. After filtration, the mother liquor was concentrated under reduced pressure. The concentrate was purified by basic silica gel column (silica gel amount; 25 g, eluent:toluene, Rf=0.2), and the effective fraction was concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate (3 mL) and diisopropyl ether (30 mL). The mixture was cooled in a freezer to produce crystal core. The mixture was suspended by stirring at room temperature for 1 hr. After filtration under reduced pressure, the crystals were washed with a mixed solvent of ethyl acetate/diisopropyl ether (1/10) (10 mL), and dried at 45° C. under reduced pressure to give the object compound. Pale-yellow white crystal, 2.50 g, yield 31.2%, 1H-NMR (500 MHz, CDCl3, TMS) δ 2.78 (t, J=7.5 Hz, 2H), 3.34 (s, 3H), 3.81 (t, J=8.0 Hz, 2H), 3.99 (s, 2H), 5.29 (s, 2H), 7.03-7.05 (m, 2H), 7.25-7.44 (m, 7H), 10.50 (s, 1H). 13C-NMR (125 MHz, CDCl3, CDCl3) δ 20.95, 43.61, 58.53, 67.71, 67.96, 99.68, 123.83, 128.11, 128.25, 128.57, 129.28, 129.67, 135.81, 138.06, 149.88, 152.23, 169.93.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1OS(C)(=O)=O)(=O)[CH3:2].[CH3:16][O:17][CH2:18][CH2:19][CH2:20][NH:21][NH2:22].C([O-])(=O)C.[NH4+].O>CC1C=CC=CC=1C>[Br:10][C:7]1[CH:6]=[C:5]2[C:4]([C:1]([CH3:2])=[N:22][N:21]2[CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[CH:9][CH:8]=1
Reactant: COCCCNN
Reactant: CC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1C
Product: COCCCn1nc(C)c2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A mixture of 10.90 g methanesulfonic acid 2-acetyl-5-bromo-phenyl ester, 7.75 g of (3-methoxy-propyl)-hydrazine and 7.17 g of ammonium acetate in 100 ml of o-xylene is refluxed for 3 days with continuous separation of the water which is formed during the reaction. The reaction mixture is then cooled to room temperature and concentrated by evaporation. The title compound is obtained as an orange-yellow oil from the residue by means of flash chromatography (SiO2 60 F). Rf=0.38 (1:1 EtOAc-heptane). Rt=4.52 (gradient I).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[NH:17][N:16]=[C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(N(C(C)C)CC)(C)C.[CH3:32][O:33][CH2:34]Cl>ClCCl>[CH3:32][O:33][CH2:34][N:17]1[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:14][C:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:16]1
Reactant: COCCl
Reactant: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)[nH]n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2cc(OC)c(OC)c(OC)c2)n(COC)n1

Procedure:
Ethyl 5-(3,4,5-trimethoxyphenyl)pyrazole-3-carboxylate (1.70 g) was dissolved in dichloromethane (50 mL), and to the solution diisopropylethylamine (933 mg) was added at 0° C., and chloromethyl methyl ether (581 mg) was then added thereto. The resultant mixture was stirred at room temperature for 30 minutes under an argon atmosphere. The reaction mixture was washed with water and saturated brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:11])(=[O:10])[N:4]=1.[CH3:12][N:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[O:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:14].[NH3:27]>>[CH3:12][N:13]([CH2:15][C:16]1[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=1)[O:19][CH2:20][CH2:21][CH2:22][NH:23][C:7]1[C:3]([NH2:27])=[N:4][S:5](=[O:10])(=[O:11])[N:6]=1)[CH3:14]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: N
Reactant: COC1=NS(=O)(=O)N=C1OC
Product: CN(C)Cc1cccc(OCCCNC2=NS(=O)(=O)N=C2N)c1

Procedure:
When a methanolic suspension of 3,4-dimethoxy-1,2,5-thiadiazole 1,1-dioxide is successively treated with an equimolar amount of 3-[3-(dimethylaminomethyl)phenoxy]propylamine [prepared according to the procedure described in Belgian Pat. No. 867,106] and excess ammonia by the general procedure described in Example 35, the title compound is thereby produced.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:14])[CH:17]=[CH2:18]
Reactant: C=CCOC(=O)Cl
Reactant: NCc1ccc(C(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)NCc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 7.55 g of 4-(aminomethyl)-benzoic acid in 50 ml of 1N sodium hydroxide solution were added at 6°-8° C. over 1.5 h 6.55 g of allyl chloroformate. Stirring was continued at 0° C. for 0.5 h and the mixture was then extracted with 60 ml of diethyl ether. The organic phase was extracted with 20 ml of saturated sodium carbonate solution and the combined aqueous layers were then acidified to pH 1.8 by the addition of 12N sulfuric acid and subsequently extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was crystallized from ethyl acetate/hexane to yield 7.61 g of 4-(allyloxycarbonylaminomethyl)-benzoic acid as a white solid, m.p. 175°-177° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[C:16]([N:17]2[CH2:22][CH2:21][N:20](CC3C(OC)=CC(OC)=CC=3OC)[CH2:19][C:18]2=[O:36])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[N+:37]([O-:39])=[O:38].C1(OC)C=CC=CC=1>C(Cl)Cl>[Cl:8][C:9]1[C:16]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][C:18]2=[O:36])=[CH:15][C:12]([C:13]#[N:14])=[CH:11][C:10]=1[N+:37]([O-:39])=[O:38]
Reactant: COc1cc(OC)c(CN2CCN(c3cc(C#N)cc([N+](=O)[O-])c3Cl)C(=O)C2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(N2CCNCC2=O)c(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.6 %

Procedure:
To a solution of triphenylphosphine (263 mg, 1.002 mmol) in THF (2 mL) was added DIAD (0.195 mL, 1.002 mmol). The reaction mixture was stirred for 10 min. Then a solution of N-(2-chloro-5-cyano-3-nitrophenyl)-2-((2-hydroxyethyl)(2,4,6-trimethoxybenzyl)amino)acetamide (160 mg, 0.334 mmol) in TIIF (1.000 mL) was added drop wise. The reaction mixture was then stirred at room temperature for 3 h. LC-MS indicated the desired peak. It was diluted with EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated. Purification via silica gel chromatography (0-100% EtOAc in Hexanes, 12 g) gave 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg) as a yellow solid. TFA (1 mL) was added to the above obtained solution of 4-chloro-3-nitro-5-(2-oxo-4-(2,4,6-trimethoxybenzyl)piperazin-1-yl)benzonitrile (30 mg, 0.065 mmol) and ANISOLE (0.028 mL, 0.260 mmol) in DCM (1 mL) and the reaction mixture was stirred at room temperature for 2 h. LC-MS showed completion. Solvent was evaporated and purification via flash chromatography (0-10% MeOH in DCM, 24 g) gave 4-chloro-3-nitro-5-(2-oxopiperazin-1-yl)benzonitrile (20 mg) as a yellow oil.