Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH2:27][CH:28]([CH3:31])[CH2:29][OH:30])[CH2:25][OH:26])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([O:23][CH:24]([CH2:25][O:26][S:41]([CH3:40])(=[O:43])=[O:42])[CH2:27][CH:28]([CH3:31])[CH2:29][O:30][S:41]([CH3:40])(=[O:43])=[O:42])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][C:6]([CH3:32])=[N:5]1)([CH3:3])[CH3:2]
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(OC(CO)CC(C)CO)cc2OCC3)n(C(C)C)n1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cn3c(n2)-c2ccc(OC(COS(C)(=O)=O)CC(C)COS(C)(=O)=O)cc2OCC3)n(C(C)C)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-4-methylpentane-1,5-diol (90 mg, 0.2038 mmol) and Et3N (85 uL, 0.6114 mmol) in DCM (10 mL) cooled at 0° C. was added methanesulfonyl chloride (40 uL, 0.51 mmol) and stirring at RT was continued for 1.5 h. The mixture was diluted with DCM, washed with a saturated solution of NaHCO3, followed by water, then dried (Na2SO4) and concentrated in vacuo affording Methanesulfonic acid 4-[2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-8-yloxy]-5-methanesulfonyloxy-2-methylpentyl ester as a colorless gum (quantitative). LCMS: RT 3.07 min [M+H]+ 598.1
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([C:13]#[N:14])[C:11]#[N:12])=[CH:4][CH:3]=1.IC1C=CC(N)=CC=1.C(#N)CC#N.O.[NH2:29][NH2:30]>>[NH2:14][C:13]1[C:10](=[N:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[C:11]([NH2:12])=[N:30][N:29]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1ccc(I)cc1
Agent: Nc1ccc(I)cc1
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1ccc(I)cc1
Yield: 70 %

Procedure:
This compound was prepared using 148 mg (0.5 mmol) of 2-[(4-iodophenyl)hydrazono]-malononitrile, which was derived from 4-iodoaniline (219 mg, 101.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 114 mg (70%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:12])=[O:11])=[CH:6][CH:5]=1)[CH3:3].[Br:13]Br>C(OCC)(=O)C>[Br:13][CH2:12][C:10]([C:7]1[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=1)=[O:11]
Reactant: CC(=O)c1ccc(C(C)C)cc1
Reactant: BrBr
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C(=O)CBr)cc1
Reaction time: 5 h
Yield: 66.2 %

Procedure:
A solution of 4-isopropylacetophenone (65 g) in ethyl acetate (250 mL) is cooled to 0° C. and treated with bromine (65 g) dropwise. The mixture is stirred for 5 h, then quenched by the addition of water (250 mL). The phases are separated, and the aqueous layer is extracted with ethyl acetate. The organic phases are washed with satd. aq. NaHCO3 and brine, combined, dried over Na2SO4, filtered and evaporated to afford the product, 2-bromo-4′-isopropylacetophenone (64 g, 66%).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[CH:14][N:15]2[CH2:18][CH3:19])=[C:11]([NH2:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O>CN(C=O)C>[CH2:1]([NH:8][C:9]1[N:17]=[C:16]2[C:12]([N:13]=[C:14]([Br:21])[N:15]2[CH2:18][CH3:19])=[C:11]([NH2:20])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCn1cnc2c(N)nc(NCc3ccccc3)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCn1c(Br)nc2c(N)nc(NCc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-benzylamino-9-ethyl-9H-purin-6-ylamine (1.0 mmol), a compound of formula (4), in 10 mL of dry DMF was added N-bromosuccinimide (267 mg, 1.5 mmol). The reaction mixture was stirred at room temperature for 1 hour. The solvent was then removed in vacuo and the residue partitioned between water and chloroform. The organic layer was washed with 1N sodium hydroxide, dried (Na2SO4), filtered, and the filtrate concentrated in vacuo. The residue was chromatographed on a silica gel column, eluting with chloroform/methanol; (98/2), to give 2-benzylamino-8-bromo-9-ethyl-9H-purin-6-ylamine as a chromatographically pure solid.
Reaction SMILES: [H+].[B-](F)(F)(F)F.[CH3:7][N:8]1[CH:12]([CH3:13])[CH2:11][CH2:10][C:9]1=[NH:14].[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[N:23]=[C:24]=[O:25]>C1C=CC=CC=1>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]=1[NH:23][C:24]([N:14]=[C:9]1[CH2:10][CH2:11][CH:12]([CH3:13])[N:8]1[CH3:7])=[O:25]
Reactant: CC1CCC(=N)N1C
Reactant: Cc1cccc(C)c1N=C=O
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: c1ccccc1
Product: Cc1cccc(C)c1NC(=O)N=C1CCC(C)N1C
Reaction time: 2 h

Procedure:
The HBF4 salt of 1,5-dimethyl-2-iminopyrrolidine (6.75 g.; 0.0337 mole) is converted to free base in benzene in the usual manner. Then 4.96 g. (0.0337 mole) of 2,6-dimethylphenylisocyanate, dissolved in anhydrous benzene, is added. The reaction mixture is stirred for 2 hours and then the solvent is evaporated in vacuo leaving a oily residue which eventually crystallizes. Recrystallization from ethyl acetate gives the product, 1-(2,6-dimethylphenyl)-3-(1,5-dimethyl-2-pyrrolidylidene)urea, m.p. 120°-122° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][OH:4].[P:6]12([S:18]P3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:7].S>>[CH3:1][CH:2]([CH3:5])[CH2:3][O:4][P:6]([SH:18])(=[S:7])[O:4][CH2:3][CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CO
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: S
Product: CC(C)COP(=S)(S)OCC(C)C
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a four-necked flask equipped with a stirrer, condenser, dropping funnel and thermometer were added 608 g (8.2 moles) of 2-methyl-1-propanol and the contents were heated to 60° C. At that temperature, 444.5 g (2.0 mole) of phosphorus pentasulfide was added portion-wise over a 3-hour period with agitation. After all of the sulfide reactant was introduced, the temperature was raised to 65° C. and held for 3 hours. The evolution of hydrogen sulfide gas was trapped by a caustic scrubber which indicates a substantially complete reaction. The reaction was then allowed to cool to ambient temperature under a nitrogen blanket and the solution was filtered through diatomaceous earth to produce a greenish fluid (927 g) as the desired phosphorodithioic acid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]([CH3:15])([CH3:14])[CH3:13])[C:5]([O:7][CH3:8])=[O:6].[C:16](B1OC(C)(C)C(C)(C)O1)([CH3:18])=[CH2:17].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1(C)C=CC=CC=1.[Cl-].[Na+].O.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>[C:12]([C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[C:16]([CH3:18])=[CH2:17])([CH3:15])([CH3:14])[CH3:13]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(C(C)(C)C)c(Br)c1
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: [Cl-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)c1cc(C(=O)OC)ccc1C(C)(C)C
Temperature: 100 °C
Reaction time: 24 h
Yield: 88 %

Procedure:
Methyl 3-bromo-4-tert-butylbenzoate (500 mg, 1.80 mmol, prepared according to the procedure of Hambley T. W. et al. Aust. J. Chem., 1990, 43, 807-814) and commercially available isopropenylboronic acid pinacol ester (0.693 mL, 3.6 mmol) were suspended in toluene (7 mL). Potassium carbonate (765 mg, 5.5 mmol) was added followed by Pd(PPh3)4 (213 mg, 0.180 mmol). The resulting mixture was heated to 100° C. and stirred for 24 hours. After cooling to room temperature, the mixture was treated with EtOAc (5 mL) and brine (5 mL). The organic layer was separated, washed twice with brine, dried with MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-10% EtOAc/hexane) to give 26.2 (378 mg, 88%) as a clear oil.
Reaction SMILES: Cl[C:2]([F:27])([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23].C(N(CC)CC)C>C(O)C>[F:27][CH:2]([F:26])[C:3]1[N:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([NH:18][CH:19]([CH3:21])[CH3:20])[C:4]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NC(C)C
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1NC(C)C
Yield: 89.8 %

Procedure:
This compound was prepared as described in Example 54: 2.7 g (0.006 mol) of product of Example 60, 0.65 g (0.006 mol) of triethylamine and 0.12 g of C (10%) in 30 ml of ethanol were reacted affording an oil residue which was kugelrohr distilled at 80 Pa. pot temperature 104° C., to give 2.07 g (89.8%) of product as a white solid; mp 53°-55° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH2:10][C:11]([O:13]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([Mg]Br)[CH3:24].[NH4+].[Cl-]>CCOCC.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][CH2:10][C:11]1([OH:13])[CH2:24][CH2:23]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC[Mg]Br
Reactant: CCOC(=O)CCN(Cc1ccccc1)Cc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Cl-]
Solvent: CCOCC
Product: OC1(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
Titanium isopropoxide (860 mg, 3.03 mmol) was added to a solution of ethyl 3-(dibenzylamino)propanoate (9.0 g, 30.3 mmol) in Et2O, cooled to 0° C., treated drop-wise with ethyl magnesium bromide (3M in Et2O, 30.3 mL) over 1 h, maintaining the temperature at 0˜4° C., then allowed to warm to RT and stirred overnight. The mixture was cooled to 0° C., treated with satd. NH4Cl, stirred at RT for 15 minutes, made basic with satd. NaHCO3 and extracted with EtoAc (2×). The combined organics were washed with brine, dried over MgSO4, concentrated and purified via silica gel chromatograph to give 1-(2-(dibenzylamino)ethyl)cyclopropanol (7.5 g, 88%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.20-7.15 (m, 8 H), 7.12-7.07 (m, 2 H), 3.45 (s, 4 H), 2.61-2.59 (m, 2 H), 1.57 (t, J=5.6 Hz, 2 H), 0.36-0.33 (m, 2 H), 0.30-0.17 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=2)=[O:11])=[CH:5][CH:4]=1.[CH2:22]([O:29][C:30]1[CH:55]=[CH:54][C:33]([CH2:34][C:35]2[NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH2:44][NH:45][CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])=[CH:43][C:37]=3[N:36]=2)=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:22]([O:29][C:30]1[CH:55]=[CH:54][C:33]([CH2:34][C:35]2[NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH2:44][N:45]([CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C:17](=[O:19])[C:16]4[CH:15]=[CH:14][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]5[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=5)=[CH:21][CH:20]=4)=[CH:43][C:37]=3[N:36]=2)=[CH:32][CH:31]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(CNCC(=O)OC(C)(C)C)ccc3[nH]2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCOc1ccc(Cc2nc3cc(CN(CC(=O)OC(C)(C)C)C(=O)c4ccc(NC(=O)Cc5ccc(OC)cc5)cc4)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a stirring solution of 4-(2-(4-methoxyphenyl)acetamido)benzoic acid (142 mg, 0.498 mmol), tert-butyl 2-(((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)amino)acetate INT-48 (221, 0.475 mmol) and TEA (206 μL, 1.42 mmol) in DMF (2 mL) was added HATU (189 mg, 0.489 mmol). After stirring at room temperature for 1 h, the reaction mixture was diluted with DCM (5 mL) and NaHCO3 (15 mL). The layers were split through a hydrophobic frit and the organics evaporated. The crude product was purified by column chromatography (EA/isohexanes) to give 313 mg (88%) of tert-butyl 2-(N-((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)-4-(2-(4-methoxyphenyl)acetamido)benzamido)acetate INT-49. LCMS-ESI (m/z) calculated for C44H52N4O6: 732; found 733[M+H]+, tR=2.09 min (Method 5).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]3[CH:19]=[C:18]([Cl:20])[S:17][C:16]=3[Cl:21])(=[O:14])=[O:13])[CH2:7][CH2:6]2)[O:4]CC1.[OH-].[Na+].[Na+].[Cl-].C(Cl)Cl>CC(C)=O.O>[O:4]=[C:5]1[CH2:6][CH2:7][CH:8]([NH:11][S:12]([C:15]2[CH:19]=[C:18]([Cl:20])[S:17][C:16]=2[Cl:21])(=[O:14])=[O:13])[CH2:9][CH2:10]1
Reactant: O=S(=O)(NC1CCC2(CC1)OCCO2)c1cc(Cl)sc1Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(NS(=O)(=O)c2cc(Cl)sc2Cl)CC1
Reaction time: 6 h
Yield: 80.5 %

Procedure:
p-TosOH×H2O 4 g (21.0 mmol) was added to a solution of 2,5-dichloro-thiophene-3-sulfonic acid-(1,4-dioxa-spiro[4.5]dec-8-yl)-amide 894 mg (2.40 mmol) in acetone (10 ml) and water (1 ml) and stirring was performed for 6 h at RT. After addition of aqueous 1M NaOH (100 ml) and aqueous saturated NaCl solution (100 ml), extraction was performed with CH2Cl2 (3×200 ml). After separation of the organic phases, drying over Na2SO4 and filtration, the solvent was removed by distillation. After purification by means of column chromatography, the product 2,5-dichloro-thiophene-3-sulfonic acid (4-oxo-cyclohexyl)-amide 634 mg (80% of theoretical) was obtained.
Reaction SMILES: [C:1]1([CH:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(O)C>[C:1]1([CH:7]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:8]2[CH2:9][CH2:10]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: c1ccc(C2NCCNCc3ccccc32)cc1
Solvent: CCO
Product: c1ccc(C2c3ccccc3CN3CCN2C3c2ccccc2)cc1
Yield: 85 %

Procedure:
A mixture of 2 g (8.4 mmol) of 1,2,3,4,5,6-hexahydro-1-phenyl-2,5-benzodiazocine and 1.0 g (9.2 mmol) of benzaldehyde in 40 mL of ethanol was refluxed for 30 min, cooled on ice and the product filtered off. There was obtained 2.33 g of 3,4-dihydro-1,11-diphenyl-2,5-methano-1H,6H-2,5-benzodiazocine, mp 175°-176°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.[CH2:24]([C:26]1[NH:27][CH:28]=[CH:29][N:30]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:24][CH3:25]
Reactant: CCc1ncc[nH]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1nccn1CCCCCCOc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Stir at room temperature for four days 2 gms. of the iodide prepared in Examples 2 or 3, 2 gms. of 2-ethylimidazole, 2.5 ml. DMF and 0.4 gm sodium hydroxide in a reaction flask. Remove the solvent and partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride and then 10% methanol to yield the title compound. MS:m/z 337 (M+) H1 -NMR-200 mHz, δH (CDCl3), 1.34 (3H,t,J 7.5 Hz), 1.3-1.65 (4H,m), 1.70-1.90 (4H,m) 2.66 (2H,q,J 7.5Hz), 3.75 (3H,s), 3.83 (2H,t,J 7Hz), 3.95 (2H,t,J 6Hz), 6.7-7.0 (5H,m).
Reaction SMILES: [H][H].[CH3:3][CH2:4][O:5][C:6]([N:8]1[CH2:13][CH:12]=[CH:11][CH2:10][N:9]1C(OCC1C=CC=CC=1)=O)=[O:7]>C(O)C.[C].[Pd]>[CH2:4]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)=[O:7])[CH3:3]
Reactant: CCOC(=O)N1CC=CCN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)N1CCCCN1

Procedure:
In a hydrogen atmosphere, 10% palladium-carbon (3.2 g) was added to the above-obtained 1,2,3,6-tetrahydropyridazine-1,2-dicarboxylic acid 1-benzyl ester 2-ethyl ester (32 g) in ethanol (100 mL), and the resultant mixture was stirred at 40° C. for 24 hours, and then cooled in air. The reaction mixture was filtered, and the solvent of the filtrate was removed under reduced pressure, and the residue was purified by distillation (boiling point 81° C./1 mmHg), to thereby give hexahydropyridazine-1-carboxylic acid ethyl ester as an oily product (5.96 g, yield from the 2 processes: 31.1%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([SH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[OH-].[K+].[Cl:13][C:14]([F:18])=[C:15]([F:17])[F:16].ClC1C(C(F)(F)CF)=CC=CC=1[N+]([O-])=S>[Hg].CC(C)=O>[Cl:13][CH:14]([F:18])[C:15]([F:17])([F:16])[S:10][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S)c1
Reactant: FC(F)=C(F)Cl
Agent: [Hg]
Agent: [K+]
Agent: [O-][N+](=S)c1cccc(C(F)(F)CF)c1Cl
Solvent: CC(C)=O
Product: O=[N+]([O-])c1cccc(SC(F)(F)C(F)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 50 g. (0.322 moles) of 3-nitrothiophenol, 46.6 g. (0.402 moles) of potassium hydroxide, 60 ml. of acetone and 59 g. (0.395 moles) of 2-chloro-1,1,2-trifluoroethylene is heated in an autoclave with stirring for 11/2 hours at 60°-70° C. The reaction mixture is cooled, decanted and the solution evaporated to dryness in vacuo. The oily residue is combined with the solids, water is added and the product extracted with methylene chloride. The extracts are washed with 2.5 N aqueous sodium hydroxide and water, dried and evaporated to dryness in vacuo affording 76.5 g. of 3(2-chloro 1,1,2-trifluoroethylthio nitrobenzene with a b.p. at 0.25 mm. of mercury of 98°-102° C. The structure is verified with nuclear magnetic resonance.
Reaction SMILES: ClC(OCC)=O.[CH:7]1([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][NH:34][C:35](=[O:41])[CH2:36][S:37][CH2:38][CH2:39]O)[CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(OCC)(=O)C>[N:16]1([CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([O:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][NH:34][C:35](=[O:41])[CH2:36][S:37][CH2:38][CH2:39][O:14][C:13]([CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[O:15])[CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)C1CCCCC1
Reactant: O=C(CSCCO)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Agent: CCOC(=O)Cl
Solvent: CCOC(C)=O
Product: O=C(CSCCOC(=O)C1CCCCC1)NC/C=C\COc1cc(CN2CCCCC2)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
0.10 ml of ethyl chloroformate was added, whilst ice-cooling, to a solution of 0.13 ml of cyclohexanecarboxylic acid in 18 ml of ethyl acetate, and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, a solution of 0.40 g of N-[4-(4-piperidinomethyl-2-pyridyloxy)-cis-2-butenyl]-2-(2-hydroxyethylthio)acetamide (prepared as described in Example 1) in 4 ml of ethyl acetate was added to the reaction mixture, whilst ice-cooling. The reaction mixture was then stirred at room temperature for 1 hour, after which it was heated under reflux for 16 hours. At the end of this time, it was concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, using a 1:9 by volume mixture of methanol and ethyl acetate as the eluent, to give 0.18 g of the title compound in a 35% yield.
Reaction SMILES: O.O.Cl.[NH2:4][C:5]1[N:14]=[C:13]([NH2:15])[C:12]2[C:7](=[N:8][CH:9]=[C:10]([CH2:16][N:17]([CH3:27])[C:18]3[CH:26]=[CH:25][C:21](C(O)=O)=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(CN(C3C=CC([C:47](O)=[O:48])=CC=3)C)N=2)N=1.O.O.C(P(=O)(OCC)OCC)#N.CCN(C(C)C)C(C)C.C(O)(=O)C.[CH2:77]([O:79][C:80](=[O:96])[C@@H:81]([O:83][P:84]([CH2:93][CH2:94][NH2:95])([O:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:85])[CH3:82])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80](=[O:96])[CH:81]([O:83][P:84]([CH2:93][CH2:94][NH:95][C:47](=[O:48])[C:21]1[CH:20]=[CH:19][C:18]([N:17]([CH2:16][C:10]2[N:11]=[C:12]3[C:7](=[N:8][CH:9]=2)[N:6]=[C:5]([NH2:4])[N:14]=[C:13]3[NH2:15])[CH3:27])=[CH:26][CH:25]=1)([O:86][C:87]1[CH:92]=[CH:91][CH:90]=[CH:89][CH:88]=1)=[O:85])[CH3:82])[CH3:78]
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](C)OP(=O)(CCN)Oc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(C)OP(=O)(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 16.4 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (60.0 mg, 158.3 μmol) in DMF (2.5 mL) were added diethyl cyanophosphonate (31.2 μL, 205.7 μmol) and DIEA (81.8 μL, 474.9 μmol). The solution was stirred at ambient temperature for 3.5 hours, when a solution of (S)-2-[(2-aminoethyl)phenoxyphosphinoyloxy]propionic acid ethyl ester mono acetic acid salt (57.1 mg, 158.3 μmol; mixture of diastereomers at phosphorus) in DMF (200 μL) was added. The solution was stirred for 1.5 additional hours, whereupon complete consumption of the starting materials was observed. The solvent was removed in vacuo and the crude material was purified by silica gel chromatography using MeOH—CH2Cl2 (10-30%). A small amount of the product (24.8 mg) was repurified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 15.8 mg (65%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.17-1.27 (m, 3H), 1.32 (d, 2H, J=7.5 Hz), 1.42 (d, 1H, J=7.5 Hz) 2.27 (m, 2H), 3.19 (s, 3H), 3.53 (m, 2H), 4.08-4.14 (m, 2H), 4.77 (s, 2H), 4.98 (m, 1H), 6.72 (br s, 1H), 6.81 (d, 2H, J=9 Hz), 7.21 (m, 3H), 7.36 (m, 2H), 7.66 (d, 2H, J=9 Hz), 8.26 (br s, 1H), 8.56 (s, 1H); 31P (121.4 MHz, DMSO-d6) δ 26.6, 27.4. MS (m/z) 609.2 [M+H]+.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14]/[N:15]=[CH:16]/[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:25]([CH2:52][CH2:53][CH2:54][CH3:55])=[CH:26][C:27]1[CH:39]=[CH:38][C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:29][C:28]=1[C:40]([N:42]1[CH2:51][CH2:50][C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43]1)=[O:41])([O-])=O>>[C:34]([O:33][C:31]([C:30]1[CH:38]=[CH:39][C:27]([C:26]2[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N:15][N:14]([C:10]3[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)[C:25]=2[CH2:52][CH2:53][CH2:54][CH3:55])=[C:28]([C:40]([N:42]2[CH2:51][CH2:50][C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[CH2:43]2)=[O:41])[CH:29]=1)=[O:32])([CH3:35])([CH3:36])[CH3:37]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1cccc(Oc2ccccc2)c1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1cccc(Oc2ccccc2)c1
Yield: 33 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(3-phenoxyphenyl)hydrazono)acetate (37 mg, 0.13 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (60 mg, 0.13 mmol) were converted to the title compound (30 mg, 33%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.08 (dd, J=8, 2 Hz, 1H), 8.04-8.02 (m, 1H), 7.44-6.78 (m, 14H), 5.02-4.98 (m, 1H), 4.41-4.35 (m, 1H), 4.31-4.26 (m, 2H), 4.16-3.98 (m, 1H), 3.58-3.28 (m, 1H), 2.81-2.50 (m, 4H), 1.61 (s, 9H), 1.28 (t, J=8 Hz, 1.5H), 1.22 (t, J=8 Hz, 1.5H), 1.13-0.88 (m, 4H), 0.63-0.59 (m, 3H); MS(ESI+) m/z 700.3 (M+H)+.