Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH2:19])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:30]([S:33](Cl)(=[O:35])=[O:34])[CH2:31][CH3:32]>ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6](=[O:29])[NH:7][CH:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([CH2:18][NH:19][S:33]([CH2:30][CH2:31][CH3:32])(=[O:35])=[O:34])=[CH:13][CH:14]=2)[CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCc2ccc(CN)cc2C1Cc1ccc(Cl)c(Cl)c1
Reactant: CCCS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCc1ccc2c(c1)C(Cc1ccc(Cl)c(Cl)c1)C(NC(=O)OC(C)(C)C)CC2

Procedure:
tert-Butyl[7-(aminomethyl)-1-(3,4-dichlorobenzyl)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamate (120 mg, 0.276 mmol, cf. Example 38) was dissolved in dichloromethane (5 mL). 4-Dimethylaminopyridine (35 mg, 0.289 mmol) was added. After stirring at room temperature for 5 min propane-1-sulfonyl chloride (39 mg, 0.031 mmol) was added and stirring was continued over night. The reaction mixture was diluted with dichloromethane and washed successively with 0.5 N hydrochloric acid (2×2 mL) and saturated NaHCO3 (1×2 mL). The organic phase was dried (MgSO4) and concentrated in vacuo. The crude product was used for the next step without further purification. Yield: 125 mg (0.231 mmol, 84%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].S(=O)(=O)(O)[OH:13].[NH4+].[OH-]>O>[NH2:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([F:11])[C:3]=1[C:4]([NH2:5])=[O:13]
Reactant: N#Cc1c(F)ccc(F)c1N
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NC(=O)c1c(F)ccc(F)c1N
Temperature: 70 °C

Procedure:
2-Amino-3,6-difluorobenzonitrile (2.3 g, 15 mmol) was added to concentrated sulfuric acid (5 mL) in a 25 mL 2-necked flask equipped with a thermometer with good stirring. The temperature rose to around 40° C. and the mixture became homogeneous. The solution was heated to 70° C. for 2 hours, cooled to room temperature, poured over ice, neutralized with concentrated NH4OH using water and NH4OH to rinse the flask and adding ice as necessary to keep the mixture cold. The separated solid was collected by filtration, washed with water and dried to give 2-amino-3,6-difluorobenzamide, 2.2 g. A second crop of 0.24 g was collected from the cold, concentrated filtrate, 95% overall. M.P. 121-123° C., LC/MS (ESI) m/z 172, 1H NMR (300 MHz, d6-DMSO) δ 7.70 (bs, 1H), 7.63 (bs, 1H), 7.10 (m, 1H), 6.32 (m, 1H), 6.05 (bs, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8]O)[CH:5]=[C:4]([CH3:10])[N:3]=1.S(Cl)([Cl:13])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:13])[CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)cc(Cl)n1
Solvent: ClCCl
Product: Cc1cc(CCl)cc(Cl)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
(2-Chloro-6-methylpyridin-4-yl)methanol (0.212 g, 1.35 mmol) and thionyl chloride (0.12 mL, 1.62 mmol) were combined in methylene chloride (4 mL) and stirred at room temperature for 4 h. The solvents were removed and the product dried under vacuum for several hours to afford 0.24 g (quant.) as a clear oil which was used without purification. Mass spec.: 176.0 (MH)+.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)(C)C.[OH-].[K+].CC(O)=O>CO>[C:6]([C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1)#[CH:5]
Reactant: CC(=O)c1ccc(C#C[Si](C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: C#Cc1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a stirring solution of compound 1.9 (19 g, 88 mmol) in MeOH (200 mL) was added a solution of KOH (2.46 g, 44 mmol) in MeOH (20 mL) at 10° C. and the mixture was stirred at room temperature for 1 hr. AcOH was added until the pH was 7, and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL), washed with 5% aqueous NaHCO3 (100 mL), brine (100 mL), dried, and concentrated under reduced pressure to give compound 1.10 as a white solid (12 g, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.95 (d, J=8, 2H), 7.62 (d, J=8, 2H), 4.49 (s, 1H), 2.59 (s, 3H).
Reaction SMILES: P(Br)(Br)[Br:2].[C:5]1([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>O1CCOCC1.C(OCC)(=O)C>[Br:2][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCCCCCc1ccccc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: BrCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
Phosphorus tribromide (4.7 ml, 49.8 mmol) was added dropwise to a solution of 5-phenylpentan-1-ol (3 ml, 17.8 mmol) in dioxane (70 ml). The reaction mixture was stirred for 2 hours at room temperature. Another portion of phosphorus tribromide (4.7 m. 49.8 mmol) was added. The reaction mixture was stirred for 16 h at room temprature. It was cooled to 0° C. Water (60 ml) was added dropwise. The reaction mixture was diluted with ethyl acetate (100 ml). The phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 ml). The combined organic layers were washed with a saturated aqueous solution of sodium hydrogencarbonate (200 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (50 g), using ethyl acetate/heptane (1:10) as eluent, to give 1.35 g of 1-bromo-5-phenylpentane.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:13]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:12]=1)C(=O)OC(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].[Cl:44]CCl>>[ClH:44].[ClH:44].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[N:13]([S:23]([C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)(=[O:25])=[O:24])[CH:12]=1
Reactant: Cc1ccccc1-c1cc(CN(C)C(=O)OC(C)(C)C)cn1S(=O)(=O)c1cccnc1
Reactant: ClCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CNCc1cc(-c2ccccc2C)n(S(=O)(=O)c2cccnc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
By a similar operation as in Example 26 and using tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (210 mg), the title compound was obtained as colorless crystals (yield 67 mg, 34%). More specifically, tert-butyl methyl{[5-(2-methylphenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}carbamate (210 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (1 mL) was added at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction solution was basified by adding dropwise to a 6% aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=1:1→1:9) to give a free salt of the title compound as a pale-yellow oil. The obtained free salt was dissolved in ethyl acetate (5 mL), a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added, and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-ethanol to give the title compound as colorless crystals (yield 67 mg, 34%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Br[C:5]1[C:6]([I:14])=[C:7]([CH:11]=[CH:12][N:13]=1)[C:8]([OH:10])=[O:9].Cl>CO>[I:14][C:6]1[C:5]([O:2][CH3:1])=[N:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: C[O-]
Reactant: O=C(O)c1ccnc(Br)c1I
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1nccc(C(=O)O)c1I
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a 28% methanol solution (5 g) of sodium methoxide was added 2-bromo-3-iodoisonicotinic acid (880 mg), and the mixture was stirred at 80° C. for 2 hr. To the reaction mixture was added 1N hydrochloric acid under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (780 mg).
Reaction SMILES: [NH2:1][C:2]1[Se:3][C:4]([CH3:15])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]=1[C:7]#[N:8].C[N:17]([CH:19](OC)OC)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:29]=[CH:30][C:31]=1[F:32])N.[K+].[Br-]>C1(C)C=CC=CC=1.C(O)(=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([NH:8][C:7]2[C:6]3[C:5]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=4)=[C:4]([CH3:15])[Se:3][C:2]=3[N:1]=[CH:19][N:17]=2)[CH:29]=[CH:30][C:31]=1[F:32]
Reactant: COC(OC)N(C)C
Reactant: Nc1ccc(F)c(Cl)c1
Reactant: Cc1[se]c(N)c(C#N)c1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: Cc1[se]c2ncnc(Nc3ccc(F)c(Cl)c3)c2c1-c1ccccc1
Temperature: 105 °C
Reaction time: 2 h

Procedure:
To a solution of 2-amino-5-methyl-4-phenylselenophene-3-carbonitrile (1.0 g, 3.81 mmol) in toluene (30 mL) was added sequentially acetic acid (0.2 mL) and DMF-DMA (1.14 mL, 8.01 mol). The reaction mixture was stirred at 105° C. for 2 h and treated with 3-chloro-4-fluoroaniline (670 mg, 4.57 mmol) as described in example 12, gave the product as an off-white color solid, mp 166-168° C. IR (KBr) νmax 3397, 3020, 1614, 1563, 1498, 1433, 1263, 1196, 1145, 967, 904, 868, 774 cm−1; 1H NMR (400 MHz, CDCl3): δ 8.51 (1H, s), 7.59-7.62 (3H, m), 7.55 (1H, dd, J=6.4, 2.8 Hz), 7.42-7.45 (2H, m), 6.94 (1H, t, J=8.8 Hz), 6.76-6.96 (1H, m), 6.45 (1H, br s), 2.40 (3H, s); 13C NMR (100 MHz, CDCl3): δ 170.2, 154.4, 154.0 (d, J=244.0 Hz), 152.0, 139.4, 136.4 (d, J=3.0 Hz), 131.9, 130.0, 130.0, 129.6, 129.2, 121.8, 120.8 (d, J=18.0 Hz), 119.3 (d, J=7.0 Hz), 118.9, 116.3 (d, J=22.0 Hz), 16.3; LC-MS (positive ion mode): m/z 416, 418, 420 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>CS(C)=O.O>[CH3:13][O:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=[C:2]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc(F)cc(O)c1[N+](=O)[O-]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCOCC2)cc(O)c1[N+](=O)[O-]
Temperature: 100 °C
Yield: 26.2 %

Procedure:
To a stirred solution of 5-fluoro-3-methoxy-2-nitro-phenol (2.0 g, 10.6 mmol) in dimethylsulfoxide (25 ml) is added morpholine (9.2 ml, 106 mmol) at room temperature. The resulting mixture is heated at 100° C. for 2 h. After completion of reaction (monitored by TLC), the mixture is diluted with water (40 ml) and the aqueous layer is extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (30 ml), brine (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product is purified by flash column chromatography (45% ethyl acetate/hexane) to yield 3-methoxy-5-morpholin-4-yl-2-nitro-phenol (0.71 g, 2.78 mmol, 26%).
Reaction SMILES: [CH:1]1([NH:7][S:8](Cl)(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCN([C:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]=2)CC1.C(N(CC)CC)C.[O:31]1CCCC1>>[CH:1]1([NH:7][S:8]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][C:18]2=[O:31])(=[O:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: C1CCOC1
Reactant: O=S(=O)(Cl)NC1CCCCC1
Solvent: CCN(CC)CC
Product: O=C1CCCCC1S(=O)(=O)NC1CCCCC1
Reaction time: 4 h
Yield: 57.4 %

Procedure:
20.8 g (0.105 mol) of cyclohexylaminosulfonyl chloride in 60 ml of tetrahydrofuran were added dropwise, over a period of 2 hours, at -50° C., to a solution of 16.7 g (0.1 mol) of morpholinocyclohex-1-ene and 10.6 g (0.105 mol) of triethylamine in 150 ml of tetrahydrofuran, the mixture was brought to 20° C. over a period of 4 hours and filtered, the filtrate was evaporated to dryness in vacuo and the residue was chromatographed on 80 g of silica gel with methylene chloride. After crystallization from diisopropyl ether, the main fraction yielded 14.9 g (57.4%) of colorless crystals of melting point 105°-109° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:11]([CH3:24])[CH:10]=2)=[CH:4][C:3]=1[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29].[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:52]=[CH:51][C:45]([O:46][CH2:47][C:48](O)=[O:49])=[CH:44][CH:43]=2)[S:36]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:34]=[C:35]1[NH:39][C:38](=[O:40])[CH:37]([CH2:41][C:42]2[CH:43]=[CH:44][C:45]([O:46][CH2:47][C:48]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[C:13]([CH3:15])[C:12]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[C:11]([CH3:24])[CH:10]=4)=[CH:4][C:3]=3[N:25]([CH3:33])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:49])=[CH:51][CH:52]=2)[S:36]1
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)cc(C)c1NC(=O)OC(C)(C)C
Yield: 76.9 %

Procedure:
Using 1.56 g of t-butyl N-[2-amino-5-(4-t-butoxycarbonylamino-3,5-dimethylphenoxy)phenyl]-N-methylcarbamate, 1.05 g of 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid, 0.61 g of diethyl cyanophosphonate, 0.38 g of triethylamine and 30 ml of anhydrous tetrahydrofuran, reaction and purification were carried out in a similar manner to that described in Example (2-1), whereby 1.89 g of the desired compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:22])=[C:4](B2OC(C)(C)C(C)(C)O2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.Br[C:24]1[N:25]=[CH:26][S:27][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:1][C:2]1[C:3]([CH3:22])=[C:4]([C:24]2[N:25]=[CH:26][S:27][CH:28]=2)[C:5]([O:11][CH3:12])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1
Reactant: Brc1cscn1
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1cscn1
Temperature: 95 °C

Procedure:
Into a microwave vial was added 1-[5-chloro-2-methoxy-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]ethanone (0.040 g, 0.12 mmol), 4-bromo-1,3-thiazole (0.024 g, 0.15 mmol), 1 M sodium carbonate solution (0.30 mL, 0.31 mmol), 1,4-dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (8.5 mg, 0.0074 mmol). The mixture was bubbled with N2 for 5 minutes, and then heated at 95° C. overnight. The cooled reaction was purified on silica gel column (eluting with 0 to 30% EtOAc in hexanes) to give the desired product. LCMS calculated for C13H13ClNO2S (M+H)+: m/z=282.0. found: 282.0.
Reaction SMILES: N1CCCCC1.[NH:7](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:8]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[CH3:39][C@@H:40]1[O:45][C@@H:44]([O:46][C@@H:47]2[C:52]3=[C:53]([OH:70])[C:54]4[C:66](=[O:67])[C:65]5[C:60](=[CH:61][CH:62]=[CH:63][C:64]=5[O:68][CH3:69])[C:58](=[O:59])[C:55]=4[C:56]([OH:57])=[C:51]3[CH2:50][C@@:49]([OH:75])([C:71]([CH2:73][OH:74])=[O:72])[CH2:48]2)[CH2:43][C@H:42]([NH2:76])[C@@H:41]1[OH:77]>CN(C)C=O>[NH2:7][C@H:8]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[CH3:39][C@@H:40]1[O:45][C@@H:44]([O:46][C@@H:47]2[C:52]3=[C:53]([OH:70])[C:54]4[C:66](=[O:67])[C:65]5[C:60](=[CH:61][CH:62]=[CH:63][C:64]=5[O:68][CH3:69])[C:58](=[O:59])[C:55]=4[C:56]([OH:57])=[C:51]3[CH2:50][C@@:49]([OH:75])([C:71]([CH2:73][OH:74])=[O:72])[CH2:48]2)[CH2:43][C@H:42]([NH2:76])[C@@H:41]1[OH:77]
Reactant: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC[C@H]1C(=O)O
Agent: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
A solution of piperidine in dimethylformamide 50% (1.92 mL) was added to Fmoc-Val-Pro-doxorubicin (F) (29.7 mg, 0.03 mmol) and the reaction mixture was stirred at room temperature for 1 minute (the reaction colour changes form red to purple). Then, the reaction mixture was evaporated to dryness under reduced pressure and the residue thus obtained was purified by reverse phase chromatography with water/acetonitrile (70:1) to give the deprotected compound G (50% yield)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]=[N+]=[N-])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(N[C@H](C(NN)=O)CC1N=CNC=1)=O)C1C=CC=CC=1.[CH2:46]([NH:50][C:51]([C@@H:53]1[CH2:57][CH2:56][CH2:55]N1)=[O:52])[CH2:47][CH2:48][CH3:49]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([N:21]1[CH2:55][CH2:56][CH2:57][C@H:53]1[C:51]([NH:50][CH2:46][CH2:47][CH2:48][CH3:49])=[O:52])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reactant: CCCCNC(=O)[C@@H]1CCCN1
Agent: NNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCNC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
To 75 ml of an ethyl acetate solution of Nα -benzyloxycarbonyl-L-histidine azide (4) prepared from 4.85 g of Nα -benzyloxycarbonyl-L-histidine hydrazide (3) by the method of Reference example 2 was added 2.23 g of compound (31) under ice-cooling and the mixture was placed overnight in a refrigerator to complete the reaction. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. By eluting the product with chloroform-methanol-aqueous ammonia (95:5:0.5), 4.13 g of Nα -benzyloxycarbonyl-L-histidyl-N-butyl-L-prolinamide was obtained.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:4])[NH:2][NH2:3].C(OCC)(=O)NN.[C:19](Cl)([Cl:21])=[O:20]>ClCCl>[O:5]([C:1]([NH:2][NH:3][C:19]([Cl:21])=[O:20])=[O:4])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NNC(=O)Oc1ccccc1
Reactant: O=C(Cl)Cl
Agent: CCOC(=O)NN
Solvent: ClCCl
Product: O=C(Cl)NNC(=O)Oc1ccccc1

Procedure:
Example 1 was repeated but substituting phenyl carbazate (77.3, 0.57 mole) for the ethyl carbazate and using phosgene (50 ml, 0.7 mole) in dry dichloromethane. 2-Phenoxycarbonylhydrazinecarbonyl chloride was isolated as impure solid (42 g, 54%) mp 76°-80° C. decomp., whose ir spectrum was consistent with the named compound being the major component.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:16]([CH3:18])[CH3:17])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:20][O:21]CN.CCN=C=NCCC[N:32]([CH3:34])C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C@H:12]([C:13](=[O:15])[N:32]([O:21][CH3:20])[CH3:34])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COCN
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.4 %

Procedure:
To (S)-2-benzyloxycarbonylamino-3-methyl-butyric acid (7) (50.0 g, 199 mmol), N-methoxymethylamine hydrochloride (38.8 g, 398 mmol) and EDC.HCl (47.7 g, 249 mmol) in DCM (500 mL) was added DIPEA (87 mL, 497 mmol) and the reaction mixture stirred at ambient temperature for 20 h, after which time the reaction mixture was diluted with DCM (200 mL), washed with 1M HCl (aq) (3×200 mL), 1M NaOH (aq) (200 mL), sat. NaHCO3 (aq) (200 mL) and brine (300 mL). The organic layer was dried over MgSO4, filtered and the solvent removed under vacuum to give the desired compound as a colourless oil (51.2 g, 87%); (AnalpH2_MeOH—4 min) Rt 2.76 min; m/z 295 (MH)+.
Reaction SMILES: [CH2:1]([N:5]=[C:6]=[N:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH3:4].C([N:18]=[C:19]=[N:20]C1C=NC=CC=1)(C)(C)C>>[CH2:1]([NH:5][C:6]([NH:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1)=[N:20][C:19]#[N:18])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)N=C=Nc1cccnc1
Reactant: CCCCN=C=Nc1cccnc1
Product: CCCCNC(=NC#N)Nc1cccnc1

Procedure:
By following the procedure of Example 1, but substituting N-n-Butyl-N'-3-pyridylcarbodiimide for the N-tert-butyl-N'-3-pyridylcarbodiimide, the desired compound was obtained with a melting point of 96.0°-97.0° C.
Reaction SMILES: [ClH:1].Cl.[OH:3][NH:4][C:5]([NH:17][CH3:18])=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16].[CH2:19](ON)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl.Cl.Cl.ON(CCSCC1NC=NC=1C)C(N)=NCCSCC1NC=NC=1C>>[ClH:1].[ClH:1].[CH3:18][NH:17][C:5]([NH:4][O:3][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[N:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16]
Reactant: NOCc1ccccc1
Reactant: CNC(=NCCSCc1[nH]cnc1C)NO
Agent: Cc1nc[nH]c1CSCCN=C(N)N(O)CCSCc1[nH]cnc1C
Agent: Cl
Product: CNC(=NCCSCc1[nH]cnc1C)NOCc1ccccc1

Procedure:
Reaction of the isothiourea dihydrochloride of Example 1 (i) with benzyloxyamine by the procedure of Example 1 (ii) gave the title product.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=[O:13])[C:8]=2[C:17]([F:20])([F:19])[F:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[OH-].[Li+]>CO.O>[C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([OH:14])=[O:13])[C:8]=2[C:17]([F:19])([F:20])[F:18])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1noc(-c2ccccc2)c1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1noc(-c2ccccc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
To a solution of ethyl 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylate (3.6 g, 12.6 mmol) in methanol (100 mL) and water (20 mL) at room temperature was added lithium hydroxide, monohydrate (0.583 g, 13.9 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The methanol was removed under reduce pressure, and the residue was diluted with water (−100 mL). Ethyl ether (200 mL) was added, and the pH of the aqueous layer was adjusted to <1 with a 1N aqueous solution of hydrochloric acid. The mixture was transferred to a separatory funnel, and after agitation, the layers were separated. The organic layer was washed with brine (100 mL), dried over anhydrous magnesium sulfate, and concentrated to afford 5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxylic acid (3.12 g, 12.13 mmol, 96% yield) as a white, crystalline solid. The compound had an HPLC retention time=2.58 minutes (YMC-Combi 4.6×50 mm S-5 ODS column) eluting with 10-90% aqueous methanol+0.2% phosphoric acid over a 4 minute gradient. MS: (M+Na)=279.95. 1H NMR (400 MHz, CDCl3) δ ppm 7.53-7.64 (m, 3H), and 7.70 (d, J=7.5 Hz, 2H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2].N>CO.O1CCCC1.[Ni]>[CH2:1]([S:3]([C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1ccc(C#N)cc1
Agent: [Ni]
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CCS(=O)(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.9 %

Procedure:
[Step 3] To a mixture of 4-ethanesulfonylbenzonitrile (500 mg) in methanol (6 ml) and tetrahydrofuran (2 ml) was added 28% aqueous ammonia (1 ml) and then Raney nickel (500 mg) was added. Under a hydrogen pressure (0.5 Mpa), the mixture was stirred at room temperature for 2 hrs., and undesired substances were removed by filtration. The filtrate was concentrated under reduced pressure to give 4-ethanesulfonylbenzylamine (408 mg, 82%).