Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C(OC([O:23][C:24]1([CH3:61])[CH:36]([OH:37])[CH:35]=[CH:34][CH:33]([CH3:38])[CH:32](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([O:51]C(OCC)C)[CH2:49][CH3:50])[O:31][C:29](=[O:30])[CH:28]=[CH:27][CH2:26][CH2:25]1)C)C>CO>[OH:23][C:24]1([CH3:61])[CH:36]([OH:37])[CH:35]=[CH:34][CH:33]([CH3:38])[CH:32](/[C:39](/[CH3:60])=[CH:40]/[CH:41]=[CH:42]/[CH:43]([CH3:59])[CH2:44][CH:45]2[O:58][CH:46]2[CH:47]([CH3:57])[CH:48]([OH:51])[CH2:49][CH3:50])[O:31][C:29](=[O:30])[CH:28]=[CH:27][CH2:26][CH2:25]1
Reactant: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)C=CCCC(C)(OC(C)OCC)C(O)C=CC1C
Agent: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)/C=C\CCC(C)(O)C(O)/C=C/C1C
Agent: CCOC(C)OC(CC)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)/C=C\CCC(C)(OC(C)OCC)C(O)/C=C/C1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Product: CCC(O)C(C)C1OC1CC(C)/C=C/C=C(\C)C1OC(=O)C=CCCC(C)(O)C(O)C=CC1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridinium p-toluenesulfonate (2 mg, 7.7 μmol) was added to a solution of (2Z,8E,12E,14E)-6,21-di(1-ethoxyethoxy)-7-hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-2,8,12,14-tetraen-11-olide (6.3 mg, 10.1 μmol) in methanol (1.5 mL), followed by stirring at room temperature for one hour. The reaction solution was evaporated, and to the resulting residue were added ethyl acetate, water and a saturated sodium bicarbonate aqueous solution. The mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous magnesium sulfate, filtered and then evaporated. The resulting residue was purified by thin layer chromatography (MERCK Silica gel 60 F254, 0.2 mm, developing solution; ethyl acetate-hexane=4:3) to obtain the title compound (3.3 mg, 68%) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:40][C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[C:20]([C:28]5[CH:33]=[CH:32][C:31]([NH:34][C:35](=[O:39])[N:36]([CH3:38])[CH3:37])=[CH:30][CH:29]=5)=[N:21][N:22]([CH2:24][CH2:25][NH:26][CH3:27])[CH:23]=4)=[C:13]3[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[OH-].[Na+].CC(O[C:47]([CH3:49])=[O:48])=O>CO.O>[CH3:37][N:36]([CH3:38])[C:35]([NH:34][C:31]1[CH:30]=[CH:29][C:28]([C:20]2[C:19]([C:18]3[CH:17]=[CH:16][N:15]=[C:14]4[NH:40][C:11]([C:7]5[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=5)=[CH:12][C:13]=34)=[CH:23][N:22]([CH2:24][CH2:25][N:26]([CH3:27])[C:47](=[O:48])[CH3:49])[N:21]=2)=[CH:33][CH:32]=1)=[O:39]
Reactant: CNCCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N(C)CCn1cc(-c2ccnc3[nH]c(-c4cccc(CN(C)C)c4)cc23)c(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Yield: 90 %

Procedure:
To N′-(4-{4-(2-{3-[(dimethylamino)methyl]phenyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1-[2-(methylamino)ethyl]-1H-pyrazol-3-yl}phenyl)-N,N-dimethylurea 3TFA (300 mg, 0.34 mMol) in MeOH (10 mL) was added with stirring at RT, aq. 1 N NaOH and Ac2O (40 uL, 0.42 mMol). After stirring for 30 min. the reaction was diluted with water, basified with aq. 1 N NaOH (0.4 mL), extracted with (9:1) CHCl3/iPrOH, dried (Na2SO4), filtered, and evaporated to dryness under vacuum. Trituration with (1:1) Et2O and petroleum ether, filtration and drying under vacuum gave the title compound (177 mg, 90%) as an off-white solid. ESMS [M+H]+: 579.7.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[C:15]([N+]([O-])=O)[C:12]=1[C:13]#[N:14])([O-:10])=[O:9]>>[CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:15]1[CH:16]=[CH:17][CH:18]=[C:11]([N+:8]([O-:10])=[O:9])[C:12]=1[C:13]#[N:14]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CSCCCCO
Product: CSCCCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 89 %

Procedure:
Prepared as in Example 197c from 4-(methylthio)butan-1-ol and 2,6-dinitrobenzonitrile in 89% yield. MS 267 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH2:41][C:42]([O:44]CC)=[O:43])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:48]=[CH:47][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31]([C:35]5[CH:36]=[C:37]([CH2:41][C:42]([OH:44])=[O:43])[CH:38]=[CH:39][CH:40]=5)[O:32][C:33]=4[CH3:34])=[C:25]([O:49][CH3:50])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(-c2nc(COc3ccc(COc4nn(-c5ccccc5)cc4/C=C/c4csc(CC)n4)cc3OC)c(C)o2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4cccc(CC(=O)O)c4)oc3C)c(OC)c2)cs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of ethyl {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetate (0.36 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at 50° C. for 1 hr. To the reaction mixture were added 1N hydrochloric acid (1 mL) and water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give {3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]phenyl}acetic acid as colorless crystals (0.29 g, 85%). Recrystallization from acetone-hexane gave pale-yellow prism crystals. melting point: 154-155° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[C:11](=[O:25])[C:12]2[S:16][C:15]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:14][CH:13]=2)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:26])[CH:11]([C:12]2[S:16][C:15]([NH:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[N:14][CH:13]=2)[OH:25])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)C(=O)Nc2ccc(F)c(F)c2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ncc(C(O)C(=O)Nc2ccc(F)c(F)c2)s1
Yield: 91.9 %

Procedure:
N-(3,4-difluorophenyl)-2-(2-tert-butoxycarbonylamino-1,3-thiazole-5-yl) (oxo)acetamide (938 mg, 2.4 mmol) in THF (50 ml) and MeOH (10 ml) was treated with sodium borohydride (93 mg, 2.4 mmol) for 30 minutes. The mixture was evaporated, the residue dissolved in ethanol (3 ml) water (25 ml) was added, and the pH adjusted to 6, more water was added, a solid was recovered, dried, recristalized in ether/petroleum ether to give title compound (850 mg, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=O)[C:10](C)(C)C)C=1C=O.O=[C:18]([CH3:34])[CH2:19][C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[O:21].C[Si](C)(C)N[Si](C)(C)C.[K]>C1COCC1.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[C:34]=1[CH:18]=[C:19]([C:20]([NH:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)=[O:21])[C:9]([CH3:10])=[N:8]2
Reactant: CC(C)(C)C(=O)Nc1nccc(Cl)c1C=O
Reactant: CC(=O)CC(=O)NCc1cccc(C(F)(F)F)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: Cc1nc2nccc(Cl)c2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.3 %

Procedure:
N-(4-Chloro-3-formylpyridin-2-yl)pivalamide (678 mg, 2.82 mmol) and 3-oxo-N-(3-(trifluoromethyl)benzyl)butanamide (2.82 mmol) was dissolved in dry THF (25 ml) and cooled to 0° C. under an atmosphere of nitrogen. Potassium hexamethyldisilazane (14 ml, 7.0 mmol, 0.5 M in toluene) was added dropwise under 15 minutes and the reaction was stirred at 0° C. for 15 minutes followed by 18 hours at room temperature. Reaction was then diluted with NH4Cl (50 ml, sat aq) and extracted with CH2Cl2 (3*30 ml). Combined organics were dried over MgSO4, filtered and evaporated. The crude product was purified by flash chromatography using CH2Cl2/CH3OH (20:1) as eluent to give 0.86 g (80%) of 5-chloro-2-methyl-N-(3-(trifluoromethyl)benzyl)-1,8-naphthyridine-3-carboxamide as a pale syrup.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.[CH2:15]1[O:25][C:24]2[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][C:17]=2[O:16]1>C(O)C>[CH2:15]1[O:25][C:24]2[CH:23]=[CH:22][C:19]([CH2:20][O:2][C:3]3[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=3)=[CH:18][C:17]=2[O:16]1
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: ClCc1ccc2c(c1)OCO2
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(OCc2ccc3c(c2)OCO3)cc1
Yield: 56.5 %

Procedure:
To a sodium alcoholate solution of 2.16 gm (94 mmol) of sodium in 100 ml ethanol were added 16.9 gm (94 mmol) of ethyl 4-hydroxyphenylacetate with agitation. Then, 16.0 gm (94 mmol) of 3,4-methylenedioxybenzyl chloride were added dropwise, and the mixture was maintained at the boiling temperature for eight hours. After evaporation, taking up of the residue in ether, washing with Na2CO3 solution and water, treating of the ether solution with activated charcoal, and evaporation, the residue was distilled at 0.13 mbar. The volatile material that was removed by distillation until a pot temperature of 240° C. was reached, amounted to 5.9 grams. The residue of 21 gm was chromatographed in a column of silica gel (granule size 0.063 to 0.200 mm, available from Merck & Co.), with methylene chloride as solvent. An amount of 16.7 gm of ethyl 4-(3,4-methylenedioxybenzyloxy)-phenylacetate (57% of theory), with a melting point of 49° to 52° C. and refractive index nD20 =1.5643, was obtained.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:8]=[CH:9][CH:10]=[CH:11][C:2]1=2.C(N(CC)CC)C.[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][C:21]=1[N+:30]([O-])=O.O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:1]2[C:2]3[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=3[CH2:4][CH2:5][CH2:6][CH2:7]2)(=[O:28])=[O:27])=[CH:22][C:21]=1[NH2:30]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1F
Reactant: c1ccc2c(c1)CCCCN2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1cc(S(=O)(=O)N2CCCCc3ccccc32)ccc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 38.9 %

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-benzo[B]azepine (0.37 g), triethylamine (0.35 mL) and 4-dimethylaminopyridine (26 mg) in methylene chloride (8 mL) was added 4-fluoro-3-nitrobenzenesulfonyl chloride (0.5 g), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7 mL). To the solution were added methanol (7 mL) and nickel(II) bromide (23 mg). To the mixture was added sodium borohydride (0.24 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=1/1) to give the title compound (0.26 g).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[C:23]([Cl:29])[C:22]=1[CH3:30])=[O:19])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[Cl:29][C:23]1[C:22]([CH3:30])=[C:21]([NH:20][C:18]([N:6]2[CH2:7][CH2:8][C@H:9]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:12])[CH3:13])[C@H:5]2[CH2:3][OH:2])=[O:19])[CH:26]=[CH:25][C:24]=1[C:27]#[N:28]
Reactant: COC(=O)[C@@H]1[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)Nc1ccc(C#N)c(Cl)c1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)N2CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]2CO)ccc(C#N)c1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
To a solution of compound 55B (300 mg, 0.66 mmol) in anhydrous THF (6.7 mL) at −25° C. was added 1 N LAH in THF (1.34 mL, 1.34 mmol) over a period of 10 min. The solution was then warmed to 0° C. and stirred for 2.0 h before quenching with H2O (0.05 mL), 15% NaOH (0.05 mL) and H2O (0.16 mL). After warming to rt, the mixture was extracted with EtOAc (2×40 mL). The combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant off-white solid was chromatographed (silica gel; EtOAc/hexane gradient) to yield the title compound (217.2 mg, 78%) as a white solid, mp 174-176° C. HPLC: 3.23 min (retention time) (Conditions: YMC S-5 C-18 (4.6×50 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=7.11 min (96.1%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 424 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O.Br[CH:34]=[C:35]([C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1)[CH3:36]>CN(C=O)C.[Cu]I>[CH3:1][N:2]1[CH:15]([CH3:16])[CH2:14][C:5]2[N:6](/[CH:34]=[C:35](/[C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)\[CH3:36])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)C(C)C3
Reactant: CC(=CBr)c1ccncc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)C(C)C2)c1ccncc1
Temperature: 140 °C

Procedure:
2,3,8-Trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (107 mg, 0.5 mmol), and potassium phosphate (414 mg, 2 mmol) were mixed in DMF and the suspension was purged with nitrogen. The suspension was heated at 140° C. for 10 min. Copper (I) iodide (9.5 mg, 0.05 mmol) and L-proline (11.5 mg, 0.1 mmol) were added followed by a solution of 4-(1-Bromoprop-1-en-2-yl)pyridine (107.83 mg, 0.55 mmol) in DMF. The contents were purged with nitrogen and heated overnight at 140° C. The contents were cooled to RT and poured into water. The precipitate obtained was filtered, dried and purified by silica gel chromatography (100-200 mesh, neutralized with aqueous ammonia) eluting with 0-4% MeOH-DCM as eluent. The compound was further purified by HPLC. 1H NMR (CDCl3, freebase) δ (ppm): 8.62 (d, 2H), 7.42 (d, 2H), 7.25 (d, 1H), 7.10 (s, 1H), 7.0 (s, 2H), 3.90 (d, 1H), 3.70 (d, 1H), 2.90 (m, 1H), 2.80 (m, 1H), 2.52 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.0 (s, 3H), 1.20 (d, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:12]=1[CH3:13])(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].C(OCC)(=O)C>CN(C=O)C>[N:20]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[S:11][C:12]=1[CH3:13])=[N+:21]=[N-:22]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc(-c2ccccc2)nc1CCOS(C)(=O)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1sc(-c2ccccc2)nc1CCN=[N+]=[N-]
Temperature: 60 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a brown solution of 2-(5-methyl-2-phenylthiazol-4-yl)ethyl methanesulfonate (200 mg, 673 μmol; prepared according to WO 2001/021602) in DMF (2.5 mL) was added sodium azide (52.5 mg, 807 μmol) at RT. The mixture was heated to 60° C. and stirred for 3 h and was then allowed to slowly cool down to RT. The reaction mixture was poured into ethyl acetate (50 mL) and the organic phase was washed with water (3×25 mL) and brine (1×25 mL). The aqueous layers were back-extracted with ethyl acetate (1×50 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to give 174 mg crude product. The product was obtained after purification by flash chromatography (using silica gel and an ethyl acetate/heptane gradient) as colorless oil (107 mg, 438 μmol, 65.1%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C:14](=[O:17])[CH2:15][CH3:16])[C:11](=[O:18])[N:10]([CH2:19][C:20]([NH:22][C:23]([CH3:35])([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=3)[CH3:24])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])[C:11](=[O:18])[N:10]([CH2:19][C:20]([NH:22][C:23]([CH3:24])([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=3)[CH3:35])=[O:21])[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCC(=O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(C)(C)c2cccc(C(F)(F)F)c2)c1=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: CCC(O)Cn1c(-c2ccc(Cl)cc2)nn(CC(=O)NC(C)(C)c2cccc(C(F)(F)F)c2)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
62 mg (0.12 mmol) of 2-[3-(4-chlorophenyl)-5-oxo-4-(2-oxobutyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]-N-{1-methyl-1-[3-(trifluoromethyl)phenyl]ethyl}-acetamide from Example 443 are dissolved in 2 ml of methanol and treated at RT with 4.7 mg (0.12 mmol) of sodium borohydride. This is stirred for 1 hr at RT. It is then treated with saturated ammonium chloride solution and extracted with 10 ml of ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated. 57 mg (92% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[CH3:23][C:24]1[S:28][C:27]([NH2:29])=[N:26][N:25]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:29][C:27]2[S:28][C:24]([CH3:23])=[N:25][N:26]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1nnc(N)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nnc(NC(=O)/C(=N/OC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)s1
Reaction time: 2 h
Yield: 45.2 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 100 mg, 0.29 mmol), 5-methyl-[1,3,4]thiadiazol-2-ylamine (37 mg, 0.32 mmol) and N,N-diisopropylethylamine (166 μL, 0.95 mmol) were combined in methylene chloride (2 mL) and cooled in an ice bath. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (121 mg, 0.32 mmol) was added and the ice bath was removed. After stirring 2 h, the reaction mixture was evaporated in vacuo. The residue was treated with saturated aqueous sodium bicarbonate solution (1 mL) and extracted with chloroform (2×3 mL). The combined organic phases were dried over sodium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 60% ethyl acetate/hexanes) to afford (E)-2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-N-(5-methyl-[1,3,4]thiadiazol-2-yl)-acetamide (58 mg, 45%) as a white solid after lyophilization from aqueous acetonitrile: LC-MS (ESI) m/e calcd for C17H19ClN4O4S [M+] 442.05, found 443 [M+H+]; H1-NMR (400 MHz, CDCl3) δ ppm 1.67 (m, 4 H, 2×CH2), 1.89 (m, 4 H, 2×CH2), 2.75 (s, 3 H, ArCH3), 3.32 (s, 3 H, SO2CH3), 4.97 (m, 1 H, OCH), 7.58 (dd, Jo=8.2, Jm=1.5 Hz, 1 H, Ar), 7.68 (d, Jm=1.5 Hz, 1 H, Ar), 8.22 (d, Jo=8.2 Hz, 1 H, Ar), 10.33 (brs, 1 H, NH).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH:18][C@H:19]([C:24](O)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[C:27]([O:31][C:32](=[O:46])[C@H:33]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[NH2:34])([CH3:30])([CH3:29])[CH3:28].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:27]([O:31][C:32](=[O:46])[C@H:33]([CH2:35][C:36]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38][CH:37]=1)[NH:34][C:24](=[O:25])[C@H:19]([CH2:20][CH:21]([CH3:22])[CH3:23])[NH:18][CH:9]([P:4]([O:3][CH2:1][CH3:2])([O:6][CH2:7][CH3:8])=[O:5])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CCOP(=O)(OCC)C(CCc1ccccc1)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1cccc2ccccc12)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 61 mg of N-(1-diethoxyphosphoryl-3-phenylpropyl) -leucine and 39 mg of 3-(α-naphthyl) -L-alanine tert-butyl ester in 1.0 ml of dichloromethane was cooled to 0° C. Then 26 mg of 1-hydroxybenzotriazole monohydrate and 34 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added to the solution which was stirred at 0° C. for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with 15 ml of dichloromethane, and the diluted solution was washed with 15 ml of a saturated aqueous solution of sodium bicarbonate and then dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was separated and purified by silica gel chromatography (hexane: ethyl acetate=1:1) to yield the title compound as two mixtures each of which are composed of two stereoisomers (42 mg of a/b mixture, 35 mg of c/d/mixture). (iv) N-[N-(3-phenylphosphonopropyl)leucyl]-3-(α-naphthyl)-L-alanine
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12][CH2:13][C:14]#[CH:15])=[CH:5][C:3]=1[NH2:4].[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]1=2.O>C(O)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([NH:12][CH2:13][C:14]#[CH:15])=[CH:5][C:3]=1[N:4]1[C:19](=[O:20])[C:18]2[CH2:22][CH2:23][CH2:24][CH2:25][C:17]=2[C:16]1=[O:21]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: C#CCNc1cc(N)c(F)cc1[N+](=O)[O-]
Solvent: O
Solvent: CC(=O)O
Product: C#CCNc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1[N+](=O)[O-]
Yield: 36.7 %

Procedure:
A mixture of 2-fluoro-4-nitro-5-(2-propynylamino)-aniline (1.41 g) and 3,4,5,6-tetrahydrophthalic anhydride (1.33 g) was suspended in acetic acid (7 ml), followed by heating under reflux for 4 hours. The reaction mixture was cooled, water was added thereto, and the resultant mixture was extracted with ethyl acetate. The extract was washed with water and an aqueous sodium bicarbonate solution, dried and concentrated to give 2-[2-fluoro-4-nitro-5-(2-propynylamino)phenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.85 g). m.p., 183.5° C.