Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32]CC1C=CC=CC=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+]([O-])=O)=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5]>[C].[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@H:15]1[C:16]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:25])[NH2:29])=[O:17])=[O:13])[CH3:11])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[CH3:19][C:30]([OH:32])=[O:31]
Reactant: C[C@H](NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(=O)O
Product: C[C@H](NC(=O)[C@@H](N)CC(N)=O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O

Procedure:
150 mg of Z-Asn-Ala-Pro-Arg(NO2)-OBzl was reduced in the presence of palladium-carbon in the same manner as in Example 7-(4). The resulting product was purified by high-performance liquid chromatography at 12 ml/min. (flow rate), 0 to 10% (B) 20 rain, linear gradient (A) (mobile phase), subjected to Dowex 1×2 (acetate type) treatment and freeze-dried to obtain the desired compound.
Reaction SMILES: Cl[C:2](OC1C=CC([N+]([O-])=O)=CC=1)=[O:3].[OH:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:42])([F:41])[F:40])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17]1.[CH2:43]([O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][O:56][CH2:57][CH2:58][O:59][CH2:60][CH2:61][O:62][CH2:63][CH2:64][O:65][CH2:66][CH2:67][OH:68])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.Cl>N1C=CC=CC=1>[O:21]=[C:19]1[N:18]([C:22]2[CH:31]=[C:30]3[C:25]([CH:26]=[C:27]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[C:39]([F:41])([F:40])[F:42])[NH:28][C:29]3=[O:32])=[CH:24][CH:23]=2)[CH2:17][C@@H:16]([CH2:15][O:14][C:2](=[O:3])[O:68][CH2:67][CH2:66][O:65][CH2:64][CH2:63][O:62][CH2:61][CH2:60][O:59][CH2:58][CH2:57][O:56][CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:20]1
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Reactant: O=C1O[C@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(OCCOCCOCCOCCOCCOCCOCc1ccccc1)OC[C@@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37 %

Procedure:
4-Nitrophenyl chloroformate was added to 1 mL of a solution of 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 (30 mg, 0.074 mmol) in pyridine, and the mixture was stirred at room temperature for six hours. Hexaethylene glycol monobenzyl ether (138 mg, 0.370 mmol) was added to the mixture which was then stirred at 60° C. for 14 hours. 1 N hydrochloric acid was added to the mixture, followed by extraction with ethyl acetate. The extract was washed with saturated saline and then dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (methylene chloride:methanol=50:1) to obtain 2-[2-(2-{2-[2-(2-benzyloxyethoxy)ethoxy]ethoxy}ethoxy)ethoxy]ethyl carbonate (S)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]-oxazolidin-5-ylmethyl ester (22 mg, yield: 37%) as a colorless oil. The product was deprotected by a method similar to that of Example 1-36 using a 10% Pd—C catalyst in a hydrogen atmosphere to synthesize the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.C1O[CH2:25][CH2:24]OCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+].CN1[CH2:39][CH2:38][CH2:37][N:36]([CH3:40])C1=O>[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:36]2[C:37]3[CH:38]=[CH:39][CH:25]=[CH:24][C:5]=3[C:4]3[C:40]2=[CH:6][CH:7]=[CH:2][CH:3]=3)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CN1CCCN(C)C1=O
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ccc(-n2c3ccccc3c3ccccc32)cc1
Temperature: 180 °C
Reaction time: 6 h

Procedure:
In a 300 mL three-neck flask were put 56 g (240 mmol) of 1,4-dibromobenzene, 31 g (180 mmol) of 9H-carabazole, 4.6 g (24 mmol) of copper(I) iodide, 2.1 g (8.0 mmol) of 18-crown-6-ether, 66 g (480 mmol) of potassium carbonate, and 8 mL of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidinone (abbreviation: DMPU). This mixture was stirred under a nitrogen stream at 180° C. for 6 hours. After that, this mixture was filtered. The resulting filtrate was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in that order. The organic layer was dried with magnesium sulfate. This mixture was filtered. The resulting filtrate was concentrated to give a compound, which was then purified by silica gel column chromatography (the developing solvent was a mixed solvent of a 9:1 ratio of hexane to ethyl acetate). The fraction obtained was concentrated to give a compound. This compound was recrystallized with a mixed solvent of chloroform and hexane to give the desired substance as 21 g of a light brown plate-like crystal in a yield of 35%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].C1(C)C=CC=CC=1.CC(C)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>O.CC(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([N:25]=[N+:26]=[N-:27])=[O:8]
Reactant: O=C(Cl)c1cc(F)ccc1[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NC(=O)c1cc(F)ccc1[N+](=O)[O-]

Procedure:
A solution of 5-fluoro-2-nitrobenzoyl chloride (52 g, 0.256 mol) in a toluene (50 mL) and acetone (60 mL) mixture is added dropwise to a solution of sodium azide (19.55 g, 0.301 mol) in water while maintaining the reaction mixture temperature below 30° C. The resultant solid is collected and the filtrate is extracted with ether. The organic extracts are combined, washed with water, dried over anhydrous magnesium sulfate and concentrated by blowing air over the solution to obtain additional solids. The solids are combined, slurried in an acetone/water (1:3) solution, filtered and dried to give the title product as a yellow solid.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[N:28]1([C:34]2[N:35]=[CH:36][C:37]([C:40](O)=[O:41])=[N:38][CH:39]=2)[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:40]([C:37]5[CH:36]=[N:35][C:34]([N:28]6[CH2:33][CH2:32][O:31][CH2:30][CH2:29]6)=[CH:39][N:38]=5)=[O:41])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: O=C(O)c1cnc(N2CCOCC2)cn1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1)c1cnc(N2CCOCC2)cn1

Procedure:
The title compound, white solid (114 mg, 87%), MS (ISP) m/z=522.4 [(M+H)+], mp 200.5° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and 5-morpholin-4-yl-pyrazine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH:12][C:13]([C@H:15]1[N:23]([C:24](=[O:43])[C@@H:25]([NH:29][C:30](=[O:42])[C@@H:31]([N:33](C)[C:34](=O)OC(C)(C)C)[CH3:32])[CH:26]([CH3:28])[CH3:27])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH2:16]1)=[O:14].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[NH:12][C:13]([C@H:15]1[N:23]([C:24](=[O:43])[C@@H:25]([NH:29][C:30](=[O:42])[C@@H:31]([NH:33][CH3:34])[CH3:32])[CH:26]([CH3:27])[CH3:28])[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[CH2:16]1)=[O:14]
Reactant: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)Nc1c(F)cccc1C(F)(F)F)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.8 %

Procedure:
In a 50 mL round-bottomed flask, tert-butyl (S)-1-((S)-1-((S)-2-(2-fluoro-6-(trifluoromethyl)phenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (20 mg, 32.8 μmol Eq: 1.00) was combined with DCM (1.5 mL) to give a colorless solution. TFA (500 μL, 6.49 mmol, Eq: 198) was added and the reaction mixture was stirred at rt for 30 min. The crude reaction mixture was concentrated in vacuo. The residue was taken up in DCM, washed with saturated aqueous NaHCO3, dried over Na2SO4 and concentrated in vacuo to give (S)—N-(2-fluoro-6-(trifluoromethyl)phenyl)-1-((S)-3-methyl-2-((S)-2-(methylamino)propanamido)butanoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide as a white solid (10 mg), m/z=510.
Reaction SMILES: C(OC[N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:32][C:33]#[N:34])[CH2:26][N:25]([S:27]([CH2:30][CH3:31])(=[O:29])=[O:28])[CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=O)C(C)(C)C.O.[OH-].[Li+].Cl>C(#N)C.C(O)(C)C>[N:14]1[C:13]2[NH:9][CH:10]=[CH:11][C:12]=2[C:17]([C:18]2[CH:19]=[N:20][N:21]([C:23]3([CH2:32][C:33]#[N:34])[CH2:24][N:25]([S:27]([CH2:30][CH3:31])(=[O:28])=[O:29])[CH2:26]3)[CH:22]=2)=[N:16][CH:15]=1
Reactant: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4[nH]ccc34)cn2)C1
Temperature: 47.5 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
Alternatively, a suspension of (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 10.0 g, 20.6 mmol) and lithium hydroxide monohydrate (2.59 g, 61.8 mmol) in acetonitrile (CH3CN 40 mL) and isopropyl alcohol (10 mL) was heated at 45-50° C. for 6 hours. When HPLC showed that the reaction was deemed complete, the reaction mixture was cooled to room temperature and 1M hydrochloric acid aqueous solution (41 mL) as added to adjust the pH to 6-7 at temperature below 25° C. After the acid addition, the mixture was stirred at room temperature for 1 h and the precipitates were isolated by filtration. The wet cake was washed with water (50 mL) and dried in vacuum oven at 50° C. to give crude 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (14, 6.0 g, 7.65 g theoretical, 78% yield) as off-white solids, which was found to be identical to the material prepared by Method A.
Reaction SMILES: [CH2:1]([N:3]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[C:5]([C:6]([O:8]C)=[O:7])=[C:4]1[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[CH3:2].Cl>[OH-].[Na+]>[CH2:1]([N:3]1[C:12]([CH3:13])=[CH:11][C:10](=[O:14])[C:5]([C:6]([OH:8])=[O:7])=[C:4]1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCn1c(C)cc(=O)c(C(=O)OC)c1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCn1c(C)cc(=O)c(C(=O)O)c1-c1ccc(Cl)cc1
Yield: 95.5 %

Procedure:
46.1 g of crude methyl 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinate is suspended in 600 ml of 5% aqueous NaOH solution and warmed to 80°-85°. After 11/2 hours at this temperature the reaction mixture is cooled and acidified with dilute HCl. The resulting solid precipitate is collected by filtration, yielding 42 g of 1-ethyl-6-methyl-2-(4'-chlorophenyl)-4-oxonicotinic acid, mp (methylene choride/ether)=235°-237° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12]C(C=C)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[C:14]([C:26]1[O:27][CH2:28][C@H:29]([C:31]([CH3:34])([CH3:33])C)N=1)(C1OC[C@H](C(C)(C)C)N=1)(C)C.CCCCCC.C([OH:43])C>>[CH2:26]([O:27][C:28]([C@@H:29]1[CH2:34][C@H:31]1[C:33]1[CH:12]=[CH:13][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:7][CH:8]=1)=[O:43])[CH3:14]
Reactant: CCO
Reactant: C=Cc1ccc(OC(C)(C)C)cc1
Reactant: CC(C)(C1=N[C@@H](C(C)(C)C)CO1)C1=N[C@@H](C(C)(C)C)CO1
Solvent: CCCCCC
Product: CCOC(=O)[C@@H]1C[C@H]1c1ccc(OC(C)(C)C)cc1

Procedure:
The title compound is prepared from 4-tert-butoxystyrene (4.3 g, 24.4 mmol) in a manner analogous to that described for Intermediate 4, step 1, using (S,S)-2,2′-isopropylidenebis(4-tert-butyl-2-oxazoline) (72 mg, 0.24 mmol) as the ligand (yield 6.4 g). LC (GC METHOD 1): tR=11.47 min; Mass spectrum (EI+): m/z=262 [M]+, e.e. 94% by chiral HPLC. (Column: Daicel Chiralcel OJ-H, 4.6×250 mm, 5 μm Mobile phase: hexane:ethanol 95:5, 1 mL/min, 25° C.) tR=8.94 (9.93) min
Reaction SMILES: [NH2:1][C:2]1[C:28]([Cl:29])=[CH:27][C:5]([C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][C@H:10]2[OH:26])=[O:7])=[C:4]([O:30][CH3:31])[CH:3]=1.C(N(CC)CC)C.[C:39](Cl)(=[O:41])[CH3:40]>O1CCCC1>[C:39]([O:26][C@H:10]1[C@@H:9]([NH:8][C:6](=[O:7])[C:5]2[CH:27]=[C:28]([Cl:29])[C:2]([NH2:1])=[CH:3][C:4]=2[O:30][CH3:31])[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[CH2:11]1)(=[O:41])[CH3:40]
Reactant: CC(=O)Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)N[C@H]1CCN(CCCOc2ccc(F)cc2)C[C@H]1OC(C)=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 7.5 parts of cis-4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-hydroxy-4-piperidinyl]-2-methoxybenzamide in 68 parts of tetrahydrofuran were added dropwise 2.02 parts of N,N-diethylethanamine. After cooling to 0° C., there was added dropwise a solution of 1.4 parts of acetyl chloride in 9 parts of tetrahydrofuran at a temperature below 0° C. Upon completion, stirring was continued for a while while cooling in an ice-bath. The reaction mixture was allowed to reach slowly room temperature and stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was taken up in a sodium carbonate solution in water. The product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further separated by HPLC using a mixture of trichloromethane, hexane and methanol (48:48:4 by volume) as eluent. The second fraction (B-isomer) was collected and the eluent was evaporated. The residue was suspended in petroleum ether. The product was filtered off and dried, yielding 1.7 parts of cis-4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-[3-(4-fluorophenoxy)propyl]-3-piperidinol acetate (ester); mp. 58.8° C. (compound 232).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH2:11][C:12](=O)[CH:13]([F:15])[F:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:18]1[C:23]([NH:24][NH2:25])=[CH:22][CH:21]=[C:20]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:19]=1.Cl.O>C(O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:24]([C:23]4[CH:18]=[CH:19][C:20]([S:26]([NH2:29])(=[O:28])=[O:27])=[CH:21][CH:22]=4)[N:25]=[C:12]([CH:13]([F:15])[F:14])[CH:11]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(CC(=O)C(F)F)c1ccc2c(c1)OCO2
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2ccc3c(c2)OCO3)cc1
Yield: 83.9 %

Procedure:
1-(1,3-Benzodioxol-5-yl)-4,4-difluorobutane-1,3-dione from Step 1 (2.4 g, 10 mmol) was dissolved in ethanol (100 mL). To the stirred mixture was added 4-sulfonamidophenylhydrazine hydrochloride (2.46 g, 11 mmol) and heated to reflux for 16 hours. The mixture was cooled and water was added until crystals slowly appeared. Filtration yielded a light tan solid (3.3 g, 84%): mp 214-218° C.; 1H NMR (D6 -DMSO): 7.86 (d, J=8.7 Hz, 3H), 7.51 (d, J=8.7 Hz, 2H), 7.49 (brs, 2H), 7.3-6.7 (m, 5H), 6.06(s, 2H). Anal. Calc'd for C17H13N3SO4F2 : C, 51.91; H, 3.33; N, 10.68. Found: C, 51.90; H, 3.25; N. 10.65.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[CH2:10][C@H:9]1[C:24]([OH:26])=O)=[O:7])(C)(C)C.[N:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=C=O.[S:35]1[CH:39]=[CH:38][CH:37]=[C:36]1[CH2:40][NH2:41]>>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][N:13]=[C:11]2[CH2:12][N:8]([C:6]([NH:27][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[O:7])[C@H:9]([C:24]([NH:41][CH2:40][C:36]3[S:35][CH:39]=[CH:38][CH:37]=3)=[O:26])[CH2:10]2)=[CH:21][CH:20]=1
Reactant: CCCCCN=C=O
Reactant: NCc1cccs1
Reactant: COc1ccc(CON=C2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)cc1
Product: CCCCCNC(=O)N1CC(=NOCc2ccc(OC)cc2)C[C@H]1C(=O)NCc1cccs1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-{[(4-methoxybenzyl)oxy]imino}-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 2-thienylmethylamine the title compound was obtained in 86% purity by LC/MS. MS(ESI+): m/z=473.2.
Reaction SMILES: [O:1]1[CH:6]([C:7]([OH:9])=[O:8])[CH:2]1[C:3]([OH:5])=O.[C:10]1([K])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(Cl)(=O)C(Cl)=O.Cl.CN.[CH2:26]([N:28](CC)CC)C>C(OCC)C>[CH3:26][NH:28][C:3](=[O:5])[CH:2]1[O:1][CH:6]1[C:7]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8]
Reactant: [K]c1ccccc1
Reactant: CCN(CC)CC
Reactant: O=C(O)C1OC1C(=O)O
Agent: CN
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOCC
Product: CNC(=O)C1OC1C(=O)Oc1ccccc1
Yield: 43.8 %

Procedure:
To a suspension of monophenyl potassium epoxysuccinate (1.23 g) in ethyl ether (30 ml), oxalyl chloride (0.7 g) in ethyl ether was added dropwise with stirring under ice-cooling and the mixture was stirred for an hour at room temperature. To the reaction mixture, a solution of methylamine hydrochloride (0.5 g) and triethylamine (1.5 g) in ethyl ether was added dropwise with stirring under ice-cooling, and the mixture was stirred for an additional hour at room temperature. The precipitate produced was filtered off and the filtrate was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate and concentrated to dryness. The residue was purified by silica gel column chromatography using benzene as a developer to give 0.48 g of phenyl N-methyl-2,3-epoxysuccinamate (Compound No. 84) as colorless oil.
Reaction SMILES: S(Cl)(Cl)=[O:2].[CH:5]([CH:14]1[C:16]([CH3:18])([CH3:17])[CH2:15]1)=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH2:19]([Cl:21])Cl>CN(C)C=O>[CH:5]([CH:14]1[C:16]([CH3:17])([CH3:18])[CH:15]1[C:19]([Cl:21])=[O:2])=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCC=CC1CC1(C)C
Reactant: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCC=CC1C(C(=O)Cl)C1(C)C
Yield: 89 %

Procedure:
2 drops of dimethylformamide and then 11.2 g (0.095 mol) of thionyl chloride were added to a solution of 16.8 g (0.07 mol) of 2-(1-nonen-1-yl)-3,3-dimethylcyclopropane acid in 80 ml of methylene chloride. The mixture was then boiled under reflux for 1 hour, the solvent is distilled off in vacuo and the residue was distilled in vacuo. 16 g (89% of theory) of 2-(1-nonen-1-yl)-3,3-dimethylcyclopropanecarboxylic acid chloride with a boiling point of 110°/0.5 mm Hg were obtained in this manner.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[CH:12]=[C:11]([N:13]2[CH:17]=[CH:16][N:15]=[CH:14]2)[C:10]([C:18]#[N:19])=[CH:9][C:8]=1[N+:20]([O-])=O)[CH3:2].[CH2:24]1[CH2:28][O:27]CC1.C[OH:30]>[C].[Pd]>[C:18]([C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][C:11]=1[N:13]1[CH:17]=[CH:16][N:15]=[CH:14]1)[N:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:23])[C:28](=[O:27])[C:24](=[O:30])[NH:20]2)#[N:19]
Reactant: CCOC(=O)CNc1cc(-n2ccnc2)c(C#N)cc1[N+](=O)[O-]
Reactant: CO
Reactant: C1CCOC1
Agent: [Pd]
Product: CCOC(=O)Cn1c(=O)c(=O)[nH]c2cc(C#N)c(-n3ccnc3)cc21
Yield: 50 %

Procedure:
A mixture of 2.00 g of N-[4-cyano-5-(1H-imidazol-1-yl)-2-nitrophenyl]glycine ethyl ester, 40 ml of THF, 8 ml of methanol and 200 mg of 10% palladium-carbon was stirred under a hydrogen gas atmosphere to reduce the nitro group. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Then, 50 ml of chloroform and 4.43 ml of triethylamine were added to the resulting residue, followed by the dropwise addition of 1.69 ml of ethyl chloroglyoxylate under ice-cooling. After stirring at room temperature for 20 hours, the reaction mixture was diluted with chloroform. The diluted mixture was washed with brine, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Then, 60 ml of ethanol and 0.5 ml of concentrated hydrochloric acid were added to the resulting residue, followed by heating under reflux for 3 hours. After cooling, the crystals so formed were collected by filtration and dried under reduced pressure to give 1.07 g (50%) of ethyl 2-[6-cyano-2,3-dioxo-7-(1H-imidazol-1-yl)-1,2,3,4-tetrahydroquinoxalin-1-yl]acetate.
Reaction SMILES: [CH3:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4].[S:11](Cl)(Cl)=[O:12].[CH:15]1([NH:20][P:21](=[S:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH2:19][CH2:18][CH2:17][CH2:16]1>N1C=CC=CC=1>[CH2:23]([O:22][P:21]([N:20]([CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19]1)[S:11]([CH2:1][NH:2][C:3]([O:5][N:6]=[C:7]([S:9][CH3:10])[CH3:8])=[O:4])=[O:12])([O:25][CH2:26][CH3:27])=[S:28])[CH3:24]
Reactant: O=S(Cl)Cl
Reactant: CCOP(=S)(NC1CCCC1)OCC
Reactant: CNC(=O)ON=C(C)SC
Solvent: c1ccncc1
Product: CCOP(=S)(OCC)N(C1CCCC1)S(=O)CNC(=O)ON=C(C)SC

Procedure:
Methyl N-[[[[[(diethoxyphosphinothioyl)cyclopentylamino]sulfinyl]methylamino]carbonyl]oxy]ethanimidothioate was prepared by the procedure employed in Example 9, by reaching methyl N-[[(methylamino)carbonyl]oxy]ethanimidothioate (2.43 g, 0.015 mole), thionyl chloride (1.79 g, 0.015 mole) and O,O-diethyl cyclopentylphosphoramidothioate (3.56 g, 0.015 mole) in pyridine. Recrystallization from cyclohexane afforded 1.0 g of colorless prisms of the formula below, mp 79~80°. ##STR29##
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14](=[O:26])[NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=1)=O)(C)(C)C.C(OC)(C)(C)C>O1CCOCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][NH:15][C:14]([C@@H:10]2[CH2:11][CH2:12][CH2:13][NH:9]2)=[O:26])=[CH:19][CH:20]=1
Reactant: COc1ccc(CCNC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: COC(C)(C)C
Product: COc1ccc(CCNC(=O)[C@@H]2CCCN2)cc1

Procedure:
4N HCl solution in 41 ml of dioxane is added to a fine suspension of 16.78 g of (S)-2-[2-(4-Methoxy-phenyl)-ethylcarbamoyl]-pyrrolidine-1-carboxylic acid tert-butyl ester in 40 ml of dioxane. After stirring under poor cooling with an ice-bath for 2.5 hours, solvent is evaporated, the residue obtained is cooled over night at 0° and resulting crystals are stirred with 150 ml of tert-butylmethylether, filtered and dried to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]([NH:12][CH2:13][CH2:14][CH2:15]O)=[N:9][C:8]=2[CH:17]=1)([O-:3])=[O:2].S(Cl)([Cl:20])=O>CN(C)C=O>[ClH:20].[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][C:10]3=[N:12][CH2:13][CH2:14][CH2:15][N:9]3[C:8]=2[CH:17]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2sc(NCCCO)nc2c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cl
Product: O=[N+]([O-])c1ccc2c(c1)N1CCCN=C1S2
Temperature: 120 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
To a stirred and cooled (0° C.) solution of 27.2 parts of 3-[(5-nitro-2-benzothiazolyl)amino]-1-propanol in 135 parts of N,N-dimethylformamide is added dropwise a solution of 15.7 parts of thionyl chloride in 45 parts of N,N-dimethylformamide. Upon completion, the whole is heated slowly to 120° C. and stirring at 120° C. is continued for 4 hours. The reaction mixture is cooled and the precipitated product is filtered off. It is washed with N,N-dimethylformamide and 2,2'-oxybispropane, and dried, yielding 24.4 parts (80%) of 3,4-dihydro-7-nitro-2H-pyrimido[2,1-b]benzothiazole monohydrochloride; mp. 328°-339° C.