Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1C2C(=CC=CC=2)C=CC=1S(Cl)(=O)=O>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[N:16][CH:17]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: c1cc2[nH]cc(C3CCN4CCCC4C3)c2cn1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2cnccc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 1-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5 mL) at RT. The two enantiomers were separated by Chiral chromatography (Chiracel OD). 3-(Octahydro-7-indolizinyl)-1-(2-naphthalenesulfonyl)-5-azaindole (17.5 mg, 97.7%); from 3-(octahydro-7-indolizinyl)-1-H-5-azaindole (10 mg, 0.0415 mmol), 2-naphthalenesulfonyl chloride (15 mg, 0.072 mmol) and 1M NaN(TMS)2 (100 μL, 0.10 mmol) in THF (0.5mL) at RT.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][NH:7][CH2:8][C:9]#[CH:10].CN(C1C=CC=CN=1)C.C(OCC)(=O)C>N1C=CC=CC=1>[CH3:6][N:7]([CH2:8][C:9]#[CH:10])[S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: C#CCNC
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C#CCN(C)S(C)(=O)=O
Reaction time: 15 h

Procedure:
Methanesulfonylchloride (1.12 mL, 14.5 mmol) was added to a stirred solution of N-methylpropargylamine (1.22 mL, 14.5 mmol) and dimethylaminopyridine (35 mg, 0.30 mmol) in pyridine (10 mL) at room temperature. After aging for approximately 15 h, the reaction mixture was poured into ethyl acetate and washed successively with 1N HCl and brine. The organic phase was dried (Na2SO4), filtered and concentrated in vacuo, to afford the title compound (i-2), which was used without further purification.
Reaction SMILES: ClCCN(C1C=CC(N=C=O)=CC=1)CCCl.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.[NH:27]([CH2:31][CH2:32][OH:33])[CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][N:27]([C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)[CH2:31][CH2:32][OH:33]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C=Nc1ccc(N(CCCl)CCCl)cc1
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)cc1

Procedure:
The known compound phenylisocyanate N-mustard 19 can be prepared by following the literature procedure35,36 with modification (Scheme 3). The commercially available 4-fluoronitrobenzene (15) is reacted with diethanolamine under refluxing to give 4-[N,N-bis(2-hydroxyethyl)amino]nitrobenzene (16), which is then converted to 4-[N,N-bis(2-chloroethyl)amino]nitrobenzene (17) by treating with thionyl chloride. Catalytic hydrogenation (10% Pd/C, H2) of compound 17 in ethyl acetate affords N,N-bis(2-chloroethyl)benzene-1,4-diamine (18), which is immediately treated with HCl in ethyl acetate to yield hydrochloride salt of 18. The hydrochloride salt 18 is suspended in CHCl3 and cooled in an ice-bath. To the suspension is added triethylamine and stirred in Argon atmosphere for 5 to 10 min. and then is added dropwise triphosgene solution in CHCl3 and continuously stirred for 20 min. The reaction mixture is evaporated under reduced pressure and the residue is the triturated with THF, filtered and the filtrate containing phenylisocyanate 19, which is used directly for the next reaction without purification. Compound 18 and 19 can be used for the synthesis of the newly invented compounds.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].F[C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1>CN(C=O)C>[N+:15]([C:12]1[CH:13]=[CH:14][C:9]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[CH:10][CH:11]=1)([O-:17])=[O:16]
Reactant: OCCNCCO
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(N(CCO)CCO)cc1
Temperature: 140 °C
Reaction time: 3.5 h
Yield: 70.7 %

Procedure:
Diethanolamine (2.70 mL, 2.5 mmol) was added to 1-fluoro-4-nitrobenzene (1.0 g, 7.09 mmol) in DMF (30 mL). The resulting mixture was stirred at 140° C. for 3.5 h. The solution was cooled to room temperature and solvent was evaporated off in vacuo. The residue was dissolved in EtOAc (30 mL) and washed with water (3×10 mL) and brine (3×20 mL) and dried (MgSO4). Solvent was evaporated off in vacuo and the product was purified by flash chromatography, eluting with EtOAc to give 67 (400 mg, 25%) as a yellow solid. H1 NMR (500 MHz, CDCl3): δ=8.06 (2H, d, J=9.50 Hz, ArH), 6.87 (2H, d, J=9.50 Hz, ArH), 4.27 (2H, t, J=5.35 Hz, 2×OH), 3.83 (4H, q, J=5.55 & 5.45 Hz, 2×CH2), 3.74 (4H, t, J=5.62 Hz, 2×CH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+].I[CH2:22][CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:22][CH3:23])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCI
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CC#N
Product: CCN1CCC(O)(c2ccc(F)c(F)c2)C1
Temperature: 80 °C
Yield: 39.6 %

Procedure:
In a sealed tube a mixture of enantiomer E1 of 3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.26 g, 1.3 mmol), acetonitrile (3 mL), potassium carbonate (0.269 g, 1.95 mmol) and iodoethane (0.20 g, 1.3 mmol) was heated under microwave irradiation at 80° C. for 25 minutes. Aqueous sodium carbonate (10%, 50 mL) was added and the aqueous phase was extracted with ethyl acetate (2×50 mL), the combined organic phase was washed with brine, dried (Na2SO4) and evaporated. Purification by HPLC on Waters OBD C18, 5 μm (MeOH/33 mM NH3, 35:65 to 50:50) gave the title compound (0.117 g). [α]D=+19.4° (methanol). The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 136-137° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 10), 207, (19), 141 (20), 72 (42), 71 (bp).
Reaction SMILES: C(S)C.[Cl-].[Cl-].[Cl-].[Al+3].C[O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1>C(Cl)Cl>[OH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClCCl
Product: CCOC(=O)CN(CC(C)C)S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of ethanethiol (15 mL) and methylene chloride (15 mL) is cooled to 0° C. Aluminum trichloride (9.62 g, 72.2 mmol) is added (the solution turns green), and the reaction is warmed to room temperature. Ethyl 2-[[4-methoxybenzenesulfonyl](isobutyl)amino]acetate (4.75 g, 14.44 mmol) is added in methylene chloride (5 mL), and the reaction is stirred for 3.5 hours at room temperature. The reaction is then slowly quenched with water, and the crude reaction is partitioned between water and methylene chloride. The aqueous layer is extracted well with methylene chloride, the combined organic layers are dried (Na2SO4), and the solvent is evaporated. The product is purified by silica gel chromatography (25% to 50% ethyl acetate/hexane) to give ethyl 2-[[4-hydroxybenzenesulfonyl](isobutyl)amino]acetate.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][C@@H:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.[Ag]=O>[O:1]1[CH2:5][CH2:4][C@@H:3]([O:6][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH2:2]1
Reactant: O[C@@H]1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=[Ag]
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCOC2)cc1
Temperature: 25 °C
Yield: 85.5 %

Procedure:
To (R)-tetrahydro-furan-3-ol (2.0 g, 22.7 mmol), triethylamine (3.8 mL, 27.3 mmol), DMAP (277 mg, 2.26 mmol), and silver oxide (5.26 g, 22.7 mmol) in dry DCM (30 mL) at 0° C. under nitrogen, add portion wise with stirring p-toluenesulfonyl chloride (4.76 g, 25.0 mmol). Warm to ambient temperature overnight, filter from silver salts, and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (7:1) to give the title compound as a clear liquid (4.7 g, 85%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[C:7]1([C:13](Cl)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>CN(C=O)C>[C:13]([N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1cn[nH]c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Ic1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reaction time: 8 h

Procedure:
The title compound was prepared by combining 4-iodopyrazole (10 g, 52 mmol), triphenylmethyl chloride (14.4 g, 51.6 mmol), triethylamine (NEt3) (7.2 mL, 52 mmol), and DMF (80 mL). After stirring overnight, the mixture was poured onto ice water. The precipitated solid was collected and recrystallized to give the title compound as a solid, mp 193-194° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH:8]=1)([O-])=O.[BH4-].[Na+].O>C(O)C.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][N:16]([C:19]3[N:20]=[CH:21][CH:22]=[CH:23][N:24]=3)[CH2:17][CH2:18]2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1cnn(CCCCN2CCN(c3ncccn3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
10.2 g (43.2 mmol) of nickel(II) chloride hexahydrate are added to a solution of 7.2 g (21 mmol) of 4-nitro-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole, Example no. 7, in 60 ml of ethanol with vigorous stirring. The mixture is cooled in an ice bath and 10.2 g (81 mmol) of sodium borohydride are added slowly. The mixture is left stirring for 1 hour and, after 1 hour at room temperature, water is added, the mixture is evaporated under vacuum, the residue is acidified with concentrated hydrochloric acid and the resulting mixture is filtered, alkalinised with ammonia solution and extracted with ethyl ether. 4.4 g of 4-amino-1-{4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl}-1H-pyrazole are thereby obtained in liquid form.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH2:11]([NH2:13])[CH3:12]>C1COCC1.O>[Br:1][C:2]1[C:3]([O:9][CH3:10])=[N:4][C:5]([NH:13][CH2:11][CH3:12])=[N:6][CH:7]=1
Reactant: CCN
Reactant: COc1nc(Cl)ncc1Br
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ncc(Br)c(OC)n1
Temperature: 60 °C
Yield: 86.5 %

Procedure:
A solution of 5-bromo-2-chloro-4-methoxypyrimidine (0.6 g, 2.69 mmol) in THF (10 mL) was treated with ethylamine (2.0M in THF, 6.71 mL, 13.43 mmol) was heated at 60° C. for 1 h, cooled to RT and diluted with water. The mixture was extracted with EtOAc (2×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified by column chromatography (EtOAc/Hex) to afford 5-bromo-N-ethyl-4-methoxypyrimidin-2-amine as a white solid (0.54 g, 87%). MS (ESI) m/z: 232.03 (M+H+).
Reaction SMILES: C[Si](C)(C)[C:3]1[S:4][CH:5]=[CH:6][N:7]=1.C([Li])CCC.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.O>C1COCC1.CCOC(C)=O>[S:4]1[C:5]([C:21]2([OH:24])[CH2:22][CH2:23][C:18]3([O:25][CH2:15][CH2:16][O:17]3)[CH2:19][CH2:20]2)=[CH:6][N:7]=[CH:3]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: C[Si](C)(C)c1nccs1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2cncs2)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of 2-trimethylsilyl-thiazole (2.5 g, 15.89 mmol) in THF (20 mL) was added to a 1.6 M solution of n-butyllithium in hexanes (11.9 mL, 19.07 mmol) at −78° C. with stirring under N2. After being stirred at −78° C. for 0.5 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (2.48 g, 15.89 mmol) in THF (20 mL) was added to the solution via syringe and stirring was continued for 1 h at −78° C. Water (5 mL) and EtOAc were added, and the reaction mixture was warmed to room temperature and extracted with EtOAc three times. The combined organic layers were dried (MgSO4), filtered, and crystallized from EtOAc to yield 3.4 g (90%) of the desired product. MS (M+H)+=242.1.
Reaction SMILES: [Al](Br)(Br)Br.[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6].CCCCCC.C(OCC)(=O)C.Cl>C1C=CC=CC=1>[C:5]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[C:10]([N+:22]([O-:24])=[O:23])[CH:9]=1)(=[O:7])[CH3:6]
Reactant: COc1ccc(-c2ccc(C(C)=O)cc2[N+](=O)[O-])cc1
Agent: Br[Al](Br)Br
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc(-c2ccc(O)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of AlBr3 (12.6 g, 47.4 mmole) in benzene (45 mL) is added dropwise under nitrogen a solution of the methylether (5 g, 18.45 mmole) of Step A in benzene (12 mL) over 30 minutes. The resulting solution is stirred at room temperature for 3.5 hours. (TLC, 8:2 hexane-ethyl acetate). The mixture is cooled in an ice bath and the complex is decomposed by the dropwise addition of 6N-HCl (ca. 37 mL). The organic layer is separated and the aqueous phase is reextracted with ether (3×). The combined extracts are concentrated to a small volume and extracted again with 2.5N-NaOH (2×50 mL +1×10 mL). The basic extracts are cooled and acidified with concentrated HCl (to pH 2). The solid is collected and dried (4.27 g, 90%). It is used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3[O:14][CH:8]3[C:7]=2[CH:15]=1)#[N:2].[CH3:16][O:17][C:18]1[CH2:22][NH:21][C:20](=[O:23])[CH:19]=1.[H-].[Na+].O>C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[C@@H:9]([OH:14])[C@H:8]([N:21]3[CH2:22][C:18]([O:17][CH3:16])=[CH:19][C:20]3=[O:23])[C:7]=2[CH:15]=1)#[N:2]
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Reactant: COC1=CC(=O)NC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: COC1=CC(=O)N([C@@H]2c3cc(C#N)ccc3OC(C)(C)[C@H]2O)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 17.1 %

Procedure:
A solution of 6-cyano-3,4-dihydro-2,2-dimethyl-3,4-epoxy-2H-1-benzopyran (15 g) and 4-methoxy-3-pyrrolin-2-one (8.5 g) in dimethylsufoxide (40 ml) was stirred and sodium hydride (80% dispersion in oil, 2.2 g) was added. The mixture was stirred at room temperature for 5 hours. Water (50 ml) was slowly added, and the resulting solution extracted with ethyl acetate (2×50 ml). After drying the organic layer with sodium sulfate the solvent was removed under reduced pressure and the residual oil chromatographed on silica gel (4% methanol in methylene chloride). The product obtained was dissolved in diethylether and precipitated with pentane to afford 4 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-3-hydroxy-4-(4-methoxy-2-oxo-3-pyrrolin-1-yl)-2H-1-benzopyran, m.p. 256° C.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:1]1([NH:7][C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NC1CCCCC1
Solvent: c1ccccc1
Product: O=C(NC1CCCCC1)c1ccccc1
Yield: 84 %

Procedure:
18 g of cyclohexylamine was dissolved in 150 ml of benzene. To the resulting solution was very slowly added 20 g of benzoyl chloride with stirring at temperatures below 40° C. White crystals separated from the mixture, generating white smoke. The mixture was stirred for one hour and was then made alkaline by addition of pyridine thereto. The product was filtered with suction. Crude crystals melting at 142° C. to 144° C. were recrystallized from a mixture of methanol and ethanol (1:1 in volume), from which white needles melting at 144° C. to 145° C. separated. The yield was 84%.
Reaction SMILES: N[C@H](C(O)=O)C(C)C.[OH-].[Na+].[CH3:11][S:12]([O-:14])=[O:13].[Na+].Br[C:17]1[CH:18]=[C:19]([C:29]([NH:31][CH2:32][C:33]2[C:34](=[O:41])[NH:35][C:36]([CH3:40])=[CH:37][C:38]=2[CH3:39])=[O:30])[C:20]2[CH:21]=[N:22][N:23]([CH:26]([CH3:28])[CH3:27])[C:24]=2[CH:25]=1>O.CS(C)=O>[CH3:39][C:38]1[CH:37]=[C:36]([CH3:40])[NH:35][C:34](=[O:41])[C:33]=1[CH2:32][NH:31][C:29]([C:19]1[C:20]2[CH:21]=[N:22][N:23]([CH:26]([CH3:28])[CH3:27])[C:24]=2[CH:25]=[C:17]([S:12]([CH3:11])(=[O:14])=[O:13])[CH:18]=1)=[O:30]
Reactant: CS(=O)[O-]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc3c2cnn3C(C)C)c(=O)[nH]1
Agent: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(C)c(CNC(=O)c2cc(S(C)(=O)=O)cc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To a 10 mL microwave vial containing a stirring mixture of L-valine (8.42 mg, 0.072 mmol), NaOH (0.024 mL, 0.072 mmol), and DMSO (1.6 mL) were added sodium methanesulfinate (0.065 g, 0.539 mmol) copper(I) iodide (6.85 mg, 0.036 mmol) and 1-Ethyl-3-methylimidazoliym bromide (0.014 g, 0.072 mmol). After stirring for 15 min, 6-bromo-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-indazole-4-carboxamide (0.15 g, 0.359 mmol) was added. The reaction vial was sealed and the mixture was stirred with heating at 90° C. (heat block) for 18 h. The contents were then irradiated (microwave) at 130° C. for 2 hr. After cooling to RT, the reaction mixture was poured onto 50 mL of water and stirred. The contents were extracted with hot 30% THF/EtOAc (2×) (need to heat to break up emulsion). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: 5-75% chloroform (containing 10% 2M ammonia in methanol) and dichloromethane. The isolated product was concentrated from DCM and MTBE, and dried under hi vacuum. The title compound was collected as 75 mg (49%); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50 (d, J=6.57 Hz, 6H) 2.13 (s, 3H) 2.22 (s, 3H) 3.30 (s, 3H) 4.38 (d, J=4.80 Hz, 2H) 5.23 (quin, J=6.57 Hz, 1H) 5.90 (s, 1H) 8.02 (d, J=1.01 Hz, 1H) 8.45 (s, 1H) 8.52 (s, 1H) 8.77 (t, J=4.80 Hz, 1H) 11.56 (s, 1H); LCMS: (M+H)+=417.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C@H:13]2[CH2:17][CH:18]=[CH:19][CH2:20][C@@H:12]12>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:9][CH3:10])[C:11]([C@H:12]1[CH2:20][CH:19]=[CH:18][CH2:17][C@H:13]1[C:14]([OH:16])=[O:15])=[O:21]
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: COc1ccccc1OC
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC

Procedure:
Prepared from 1,2-dimethoxybenzene and cis-1,2,3,6-tetrahydrophthalic anhydride as described for compound A. M.p. 110°-112° C.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:27])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22]C=1.Cl.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1>>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C@H:17]([C:26]([NH:28][C@H:29]([C:37]([O:39][CH3:40])=[O:38])[CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[O:27])[CH2:18][C:19]1[CH:20]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:5]
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Yield: 67 %

Procedure:
Condensation of ZPheOH (29.2 g.) and HPheOMe (21.6 g.) by the mixed anhydride method using isobutyl chloroformate gave ZPhe-PHeOMe in 57% yield. Debenzyloxycarbonylation of ZPhe-PHeOMe (26.4 g.) by hydrogenation in acidified methanol with palladium catalyst gave HPhe-PheOMe in 86% yield. Condensation of BocProOH (6.46 g.) and HPhe-PheOMe hydrochloride (10.9 g.) by the mixed anhydride method using diphenylphosphinyl chloride gave BocPro-Phe-PheOMe in 67% yield. Hydrazinolysis of BocPro-Phe-PheOMe (9.57 g.) gave BocPro-Phe-Phe-NHNH2 in 92% yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[OH-].[K+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[CH2:12]([O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1
Temperature: 80 °C
Yield: 58 %

Procedure:
Treated a solution of 4-hydroxybenzonitrile (5.0 g, 42 mmol) in DMF (20 mL) with 2M KOH (21 mL, 42 mmol) followed by benzyl chloride (3.46 mL, 42 mmol). Heated in an oil bath at 80° C. for 2 h. Cooled to room temperature and poured onto water (100 mL). Filtered the resulting solid, washed with water (2×25 mL) and dried to obtain 4-benzyloxy-benzonitrile (5.1 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8]([OH:10])=O)[CH:6]=1)[CH3:2].O[N:23]1[C:27]2C=CC=C[C:26]=2N=N1.C(N)C>CN(C=O)C.ClCCl>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:13]=[C:12]([C:14](=[O:20])[N:15]([CH3:19])[CH2:16][CH2:17][CH3:18])[CH:11]=[C:7]([C:8](=[O:10])[NH:23][CH2:27][CH3:26])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Reactant: On1nnc2ccccc21
Agent: CCN
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCN(C)C(=O)c1cc(C(=O)NCC)cc(C(=O)OCC)c1
Yield: 98 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (146 mg, 0.5 mmol), 1-hydroxybenzotriazole (74 mg, 0.55 mmol), 1-(3-dimethylamninopropyl)-3-ethylcarbodiimide hydrochloride (110 mg, 0.55 mmol), ethylamine (2 N in THF, 0.275 mL, 0.55 mmol) in 0.75 mL DMF at room temperature overnight. Dilute with dichloromethane (15 mL) and wash with water (5 mL), 0.1 N aqueous citric acid (5 mL), saturated aqueous sodium bicarbonate (5 mL), and saturated aqueous sodium chloride (5 mL). Dry (magnesium sulfate) and concentrate to give the title compound (157 mg, 100%).
Reaction SMILES: O.[F:2][C:3]([P:9]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])(F)F)([F:8])[C:4]([F:7])([F:6])[F:5]>>[P:9]([C:3]([C:4]([F:5])([F:6])[F:7])([F:2])[F:8])([C:19]([C:20]([F:23])([F:22])[F:21])([F:25])[F:24])[C:12]([C:13]([F:16])([F:15])[F:14])([F:18])[F:17]
Reactant: FC(F)(F)C(F)(F)P(F)(F)(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Solvent: O
Product: FC(F)(F)C(F)(F)P(C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Temperature: 20 °C
Reaction time: 4 h

Procedure:
0.30 g (16.7 mmol) of water and 3.19 g (53.1 mmol) of fire-extinguishing sand as SiO2 source are added to 12.0 g (28.0 mmol) of tris(pentafluoroethyl)difluorophosphorane, (C2F5)3PF2, in a 100 ml glass round-bottomed flask and warmed (20° C. oil-bath temperature). An intensive reflux condenser is connected downstream of the flask. The suspension is stirred at 120° C. for 4 h. Complete consumption of (C2F5)3PF2 and formation of (C2F5)3P═O (72.0%) and (C2F5)2P(O)OH (28.0%) can be detected. The entire suspension is condensed at room temperature in vacuo (10−3 mbar). Clear and colourless (C2F5)3P═O (6.27 g; 15.5 mmol; 55%) can be isolated in 99% purity. Further (C2F5)3P═O can be isolated from the solid residue by extraction.