Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].Cl[C:25]1[CH:34]=[C:33]([CH3:35])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=1>CN(C)C=O>[CH3:35][C:33]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]=[C:25]([O:1][CH:2]([C:7]([O:20][CH3:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:34]=1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Cl)nc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1cc(C)c2ccccc2n1)C(OC)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 30.4 %

Procedure:
5.7 g (20 mmol) of Methyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate were dissolved in 90 ml of dimethylformamide, and 0.98 g (22 mmol) of sodium hydride (55% in oil) was added. After stirring for 15 minutes, 3.9 g (22 mmol) of 2-chloro-4-methylquinoline were added. The dark red solution was stirred at room temperature overnight, then cautiously hydrolyzed with 20 ml of water and subsequently extracted with ethyl acetate. The organic phase was washed with water, and dried over magnesium sulfate, and the solvent was removed by distillation. The residue (8.1 g) was then chromatographed on silica gel, resulting in 2.6 g of impure product as oil.
Reaction SMILES: [Br-].[CH2:2]([N+:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:16][C:17]1[NH:18][CH:19]=[C:20]([CH3:24])[C:21]=1[C:22]#[N:23].N1C(C)=CC=CC=1C>C(Cl)Cl>[Br-:15].[NH2:16][C:17]1[NH:18][C:19]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N+:9]=2[CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:20]([CH3:24])[C:21]=1[C:22]#[N:23]
Reactant: Cc1c[nH]c(N)c1C#N
Reactant: Brc1cccc[n+]1Cc1ccccc1
Agent: [Br-]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: Cc1c(-c2cccc[n+]2Cc2ccccc2)[nH]c(N)c1C#N
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
Under an argon atmosphere, 1.81 g (5.5 mmol) of N-benzyl-2-bromo-pyridinium bromide [for preparation see J. Heterocyclic Chem. 28,1083 (1991)] are added to 605.5 mg (5.0 mmol) of 2-amino-3-cyano-4-methyl-pyrrole [for preparation see Synthesis (1976), 51] in 40 ml of methylene chloride and 639 μl (5.5 mmol) of lutidine. After 5.5 hours' stirring at RT, the reaction mixture is concentrated by evaporation to approximately half its original volume. Filtering the suspension and washing with methylene chloride/ethyl acetate (1:1) and ethyl acetate/hexane (1:1) yield the title compound; 1H-NMR (300 MHz, DMSO-d6): 10.83 (s, 1H), 9.10 (d, J=7, 1H), 8.49 (t, J=7, 1H), 7.96 (m, 2H), 7.30 (m, 3H), 6.95 (m, 2H), 6.57 and 5.80 (2s, each 2H), 1.76 (s, 3H); FAB-MS: (M+H)+ =289.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[SH:8][C:9]1[C:10]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:11]=2[S:12][C:13]=1[C:14]([NH2:16])=[O:15].C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[NH2:16][C:14]([C:13]1[S:12][C:11]2[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[CH:20][C:10]=2[C:9]=1[S:8][CH2:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[O:15]
Reactant: COC(=O)C(C)Br
Reactant: COc1ccc2sc(C(N)=O)c(S)c2c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCSc1c(C(N)=O)sc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Methyl bromopropionate (75 μL, 0.69 mmol) is added to a room temperature solution of 3-mercapto-5-methoxybenzo[b]thiophene-2-carboxamide (150 mg, 0.63 mmol) in 7 mL of THF followed by NaHCO3 (334 mg, 3.15 mmol). Additional methyl bromopropionate (150 μL) and Na2CO3 (70 mg) are added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is diluted with ethyl acetate and washed with 1N HCl, water, 1N NaOH, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane followed by recrystallization from methanol: water gives methyl 3-[[2-(aminocarbonyl)-5-methoxybenzo[b]thien-3-yl]thio]propanoate in 46% yield; mp=142°-144° C.
Reaction SMILES: [H-].[Na+].I[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH:11]=[O:12].C([Li])CCC.[C:18]1(=[O:22])[CH2:21][CH2:20][CH2:19]1>O1CCCC1>[OH:22][C:18]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[NH:10][CH:11]=[O:12])[CH2:21][CH2:20][CH2:19]1
Reactant: O=C1CCC1
Reactant: O=CNc1ccccc1I
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: O=CNc1ccccc1C1(O)CCC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (65% dispersion in mineral oil, 71 mg, 1.775 mmol) was suspended in tetrahydrofuran (6 mL), and to this stirred slurry was added dropwise a solution of N-(2-iodophenyl)formamide (250 mg, 1.012 mmol) in tetrahydrofuran (4 mL). The mixture was stirred at room temperature for 20 minutes, then chilled to −78° C. To the cold suspension was added dropwise 2.5 M n-butyllithium in hexanes (0.506 ml, 1.265 mmol). The mixture was stirred at −78° C. for 30 minutes, then cyclobutanone (0.083 ml, 1.113 mmol) was added dropwise. The mixture was stirred at −78° C. for 2 hours and quenched with saturated NH4Cl (20 mL) solution and warmed to room temperature. The mixture was extracted with ethyl acetate (3×30 mL), and the combined organic layers were dried (Na2SO4), filtered, and concentrated. The product was purified by flash chromatography (Analogix, 20 to 50% ethyl acetate-hexanes over 25 min, 4 g silica cartridge, 18 mL/min) to give the title compound as a 2:1 ratio of two rotational isomers.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([F:33])=[C:16]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[C:21]=3[Cl:31])[CH:17]=1)[N:5]=2.[C:34](Cl)(=[O:37])[CH2:35][CH3:36].O>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[Cl:31][C:21]1[C:22]([C:26]2([C:29]#[N:30])[CH2:28][CH2:27]2)=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:6]2[N:5]=[C:4]3[S:3][C:2]([NH:1][C:34](=[O:37])[CH2:35][CH3:36])=[N:10][C:9]3=[CH:8][CH:7]=2)[CH:13]=[CH:14][C:15]=1[F:33])=[O:32]
Reactant: CCC(=O)Cl
Reactant: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(N)sc5n4)ccc3F)c2Cl)CC1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: CCC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4cccc(C5(C#N)CC5)c4Cl)c3)nc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-fluorophenyl}-2-chloro-3-(1-cyanocyclopropyl)benzamide (0.16 g, 0.33 mmol) and N,N-dimethylpyridine-4-amine (0.12 g, 1.00 mmol) in pyridine (2 mL) was added dropwise propionyl chloride (0.09 g, 1.00 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in methanol (5 mL), 8N aqueous sodium hydroxide solution (1 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water (50 mL), and the mixture was extracted with ethyl acetate (50 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (80 mg, 45%) as white crystals.
Reaction SMILES: C1C=C(Cl)C(S[CH:9]([CH2:19][N:20]2[CH:24]=[N:23][CH:22]=[CH:21]2)[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=C(Cl)C=1.[N+]([O-])(O)=O.[Cl:30]C1C=CC=CC=1CCC(O)CN1C=CN=C1.S(Cl)(Cl)=O>>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][CH:9]([Cl:30])[CH2:19][N:20]2[CH:21]=[CH:22][N:23]=[CH:24]2)=[CH:17][CH:16]=1
Reactant: OC(CCc1ccccc1Cl)Cn1ccnc1
Reactant: Clc1ccc(CCC(Cn2ccnc2)Sc2c(Cl)cccc2Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: O=[N+]([O-])O
Product: Clc1ccc(CCC(Cl)Cn2ccnc2)cc1

Procedure:
in the presence of sodium hydride reagent in dimethylformamide solvent. This substitution reaction takes a long time and gives the (1-[4-(4-chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) with a poor yield (51.7%). In the next step of the butoconazole nitrate synthesis (1-[4-(chlorophenyl)-2-hydroxy-n-butyl]-imidazole) (IV) is treated with thionyl chloride (which is at once a reagent and a solvent) at 65-70° C. to yield 1-[4-(4-chlorophenyl)-2-chloro-n-butyl]-imidazole of the formula (V).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]3=[CH:20][CH:21]=[N:22][N:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8].C([Sn](CCCC)(CCCC)[C:28]1[O:29][CH:30]=[CH:31][CH:32]=1)CCC>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>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:17](=[O:19])[CH2:16][CH2:15][CH2:14][C:13]=3[NH:12][C:11]3=[C:20]([C:28]4[O:29][CH:30]=[CH:31][CH:32]=4)[CH:21]=[N:22][N:10]23)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1CCCC2=C1C(c1ccc(Cl)c(Cl)c1)n1nccc1N2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O=C1CCCC2=C1C(c1ccc(Cl)c(Cl)c1)n1ncc(-c3ccco3)c1N2

Procedure:
The product from Example 6, tetrakis(triphenylphosphine)palladium(0) (0.11 g) and 2-tributylstannylfuran were processed as described in Example 51 to provide the title compound.
Reaction SMILES: [CH2:1]=O.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][CH2:24][CH2:25][N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:19][CH:18]=2)[C:13](=[O:31])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH2:27]([N:26]([CH2:29][CH3:30])[CH2:25][CH2:24][N:23]([CH3:1])[C:20]1[CH:19]=[CH:18][C:17]([N:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:12][C:13]2=[O:31])=[CH:22][CH:21]=1)[CH3:28]
Reactant: CCN(CC)CCNc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Reactant: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)CCN(C)c1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
Aqueous 37% formalin solution (100 μL) and 0.3 mol Zn[B(CN)H3]2/methanol solution (1.0 mL, 0.3 mmol, prepared from ZnCl2 and NaB(CN)H3) were added to a methanol solution (1 mL) of the compound obtained in Example 15 (7 mg, 0.018 mmol), and stirred at room temperature for 45 minutes. Aqueous 1 N sodium hydroxide solution was added to the reaction liquid, extracted with chloroform, dried with anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to obtain the entitled compound (2.8 mg, 39%).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=[C:24]([C:31]3[CH:39]=[CH:38][C:34]4[O:35][CH2:36][O:37][C:33]=4[CH:32]=3)[CH:23]=2)[C:10]=1[CH2:40][CH2:41][C:42]([O:44]CC)=[O:43])C.[OH-].[Na+]>C1COCC1.C(O)C>[O:35]1[C:34]2[CH:38]=[CH:39][C:31]([C:24]3[CH:23]=[C:22]([CH:27]=[C:26]([O:28][CH2:29][CH3:30])[CH:25]=3)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]3[C:10]([CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[C:9]([CH:14]=[CH:13][CH:12]=3)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:47])=[O:3])=[CH:32][C:33]=2[O:37][CH2:36]1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.6 %

Procedure:
To a solution of the 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (152 mg, 0.23 mmol) in THF (5 mL) and ethanol (5 mL) was added aqueous 1.0 N sodium hydroxide (5 mL) at room temperature. The resulting suspension was stirred for 5 h at room temperature at which time TLC analysis of the mixture indicated the absence of starting material. Then, the reaction mixture was concentrated and the residue was diluted with water (20 mL) and extracted with diethyl ether (30 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N hydrochloric acid and the precipitated white organic compound was extracted into ethyl acetate (2×30 mL). The combined ethyl acetate extracts were washed with brine solution (50 mL) and the organic layers were dried over anhydrous magnesium sulfate. Filtration of the drying agent and removal of the solvent afforded 4-[3-[6-(3-benzo[1,3]dioxol-5-yl-5-ethoxy-phenoxy)-hexyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (129 mg, 95%) as a off-white waxy solid: ES(+)-HRMS m/e calcd for C34H40O9 (M+H)+ 593.2745. found 593.2744.
Reaction SMILES: [N+](=[CH:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@@H:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]([CH3:15])[CH3:14])=[O:5])=[N-].[BrH:22]>CC(O)=O>[Br:22][CH2:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:21])[C@@H:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]([CH3:15])[CH3:14])=[O:5]
Reactant: Br
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-])C(C)C
Solvent: CC(=O)O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)CBr)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
A mixture of Example 173D (70 mg, 0.236 mmol) in HOAc (0.6 mL) at ambient temperature was added 48% HBr (80 μL, 0.709 mmol). Mixture was stirred at ambient temperature for 1 hour. Mixture was poured into ice/H2O and extracted with CH2Cl2 (3×75 mL). Organic was dried (Na2SO4), filtered and concentrated afford 63 mg (76%) of the title compound. MS (ESI) m/z 350 (M+H)+.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1cc([N+](=O)[O-])cnc1Br
Product: COc1cccc(-c2ncc([N+](=O)[O-])cc2C)c1
Yield: 72 %

Procedure:
Obtained (2.43 g, yield 72%) following the procedure described in Intermediate 27, starting with 2-bromo-3-methyl-5-nitropyridine (13.82 mmol, 3.0 g), 3-methoxyphenylboronic acid (13.82 mmol, 2.10 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:21]1([NH:27][C:28](=[O:31])[CH2:29]Br)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:21]1([NH:27][C:28](=[O:31])[CH2:29][N:18]2[CH2:17][CH2:16][CH:15]([C:12]3[CH:13]=[CH:14][C:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[CH:10][CH:11]=3)[CH2:20][CH2:19]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Fc1ccc(Cc2ccc(C3CCNCC3)cc2)cc1
Reactant: O=C(CBr)Nc1ccccc1
Product: O=C(CN1CCC(c2ccc(Cc3ccc(F)cc3)cc2)CC1)Nc1ccccc1

Procedure:
The compound (7) synthesized in Reference Example 7 and the compound (23) synthesized in Reference Example 23 were used to produce the above compound in the same way as Example 1.
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:22](O)=[O:23])=[CH:20][CH:19]=3)[N:11]=2)[N:6]=1.NC1N=C(N)C2C(=NC=C(CN(C3C=CC(C(O)=O)=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(O)=O.[CH2:79]([O:81][P:82]([CH2:87][CH2:88][NH2:89])(=[O:86])[O:83][CH2:84][CH3:85])[CH3:80]>CN(C=O)C>[CH2:84]([O:83][P:82]([CH2:87][CH2:88][NH:89][C:22](=[O:23])[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])[O:81][CH2:79][CH3:80])[CH3:85]
Reactant: CCOP(=O)(CCN)OCC
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)O)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCNC(=O)c1ccc(N(C)Cc2cnc3nc(N)nc(N)c3n2)cc1)OCC
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.2 %

Procedure:
To a solution of 4-[(2,4-diamino-pteridin-6-ylmethyl)-methyl-amino]-benzoic acid hemihydrochloride dihydrate (61.2 mg, 161 μmol) in DMF (2.8 mL) were added diethyl cyanophosphonate (31.8 μL, 210 μmol) and DIEA (27.8 μL, 161 μmol). The solution was stirred at ambient temperature for 4 hours, when diethyl(aminoethyl)phosphonate oxalate (43.8 mg, 161 μmol) was added. The solution was stirred for 3 additional hours, by which time complete consumption of the starting materials was observed. The reaction was worked up by removal of the solvent in vacuo and purifying the residue by silica gel chromatography using MeOH—CH2Cl2 (10-30%). The product collected from this chromatography step was sufficiently pure to be carried on to the next reaction. A small amount of the product (32 mg) was re-purified by RP HPLC on C18 column using H2O/acetonitrile (2-95%) to provide 19 mg (70%) of the pure product. 1H NMR (300 MHz, DMSO-d6) δ 1.21 (t, 6H, J=7 Hz), 1.95-2.05 (m, 2H), 3.20 (s, 3H), 3.13-3.22 (m, 2H), 3.98 (appt septet, 4H, J=7 Hz), 4.79 (s, 2H), 6.80 (d, 2H, J=9 Hz), 7.65 (d, 2H, J=9 Hz), 8.20 (br s, 1H), 8.60 (s, 1H). 31P (121.4 MHz, DMSO-d6) δ 28.9. MS (m/z) 489.2 [M+H]+, 511.2 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N:12]1[C:16](=[O:17])[C:15]([CH3:18])=[C:14]([CH3:19])[C:13]1=[O:20].C(=O)([O-])[O-].[K+].[K+].[Cl:27][CH:28]=[CH:29][CH2:30]Cl>CC(=O)CC>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH2:30][CH:29]=[CH:28][Cl:27])=[O:10])=[CH:4][C:3]=1[N:12]1[C:13](=[O:20])[C:14]([CH3:19])=[C:15]([CH3:18])[C:16]1=[O:17]
Reactant: CC1=C(C)C(=O)N(c2cc(C(=O)O)c(Cl)cc2F)C1=O
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC1=C(C)C(=O)N(c2cc(C(=O)OCC=CCl)c(Cl)cc2F)C1=O

Procedure:
A mixture of 3 g of N-(2-fluoro-4-chloro-5-carboxyphenyl)-2,3-dimethylmaleic acid imide, 4.5 g of potassium carbonate, 1 ml of 1,3-dichloropropene and 50 ml of 2-butanone is heated under reflux for 16 hours. The precipitate is separated off and the filtrate is concentrated by evaporation. 3.3 g of N-[2-fluoro-5-(3-chlorallyloxycarbonyl)-4-chlorophenyl]-2,3-dimethylmaleic acid imide are obtained in the form of an oil. Refractive index nD24 1.5640.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:31][S:32](Cl)(=[O:34])=[O:33].CCOC(C)=O>C(Cl)Cl.CCCCCCC>[CH2:1]([O:8][C:9]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:21][CH2:20][C@H:19]([O:22][S:32]([CH3:31])(=[O:34])=[O:33])[CH2:18]2)=[CH:15][CH:16]=1)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc([C@H]2CCC(O)C2)cc1)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCC(c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Temperature: 0 °C
Yield: 93.5 %

Procedure:
To a solution of [4-((S)-3-hydroxy-cyclopentyl)-phenyl]-carbamic acid benzyl ester (0.44 g, 1.4 mmol) in DCM (8 mL) was added Et3N (214 mg, 0.3 mL, 2.12 mmol, 1.5 equiv.). The solution was cooled in an ice-water bath and then de-aerated by vacuum/nitrogen exchange. To this solution was transferred a solution of methanesulfonyl chloride (242 mg, 2.12 mmol, 1.5 equiv.) in DCM (2 mL). The clear solution was stirred with the ice-water bath on all the time for 1 h. TLC (50% EtOAc in heptane) indicated that the reaction was complete. The reaction was quenched by diluting with DCM (10 mL), followed by addition of NaHCO3 aq. (5 mL). The two layers were separated and the aqueous layer was extracted with DCM (2×5 mL). The combined extracts were washed successively with NaHCO3 aq. (5 mL), brine (5 mL) and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with 5% MeOH in DCM. The filtrate was concentrated to dryness to obtain 510 mg (yield: 93%) of the title compound as an off-white wax-like solid material.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].NC1C=CC(C)=CC=1>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14]2[CH:15]=[CH:20][C:17]([CH3:16])=[CH:18][CH:19]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Cc1ccccc1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Solvent: Cc1ccc(N)cc1
Product: Cc1ccc(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Yield: 97 %

Procedure:
(RK1-1-29)I This compound was prepared according to the procedure described for compound 11a except using p-toluidine to obtain required product as a yellow solid, (256 mg, 97%). Mp=170-172° C. (lit 184-184.5° C. Bioorganic and Medicinal Chemistry 15(2), 1014-1021; 2007); 1H NMR (400 MHz, CDCl3) δ 8.27 (d, J=9.0 Hz, 2H), 7.88 (d, J=9.0 Hz, 2H), 7.08 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.2 Hz, 2H), 6.41 (bs, 1H), 2.30 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH2:4].[Li]CCCC.Cl[Si:17]([CH:20]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[C:22]([CH3:28])=[C:21]1[CH3:29])([CH3:19])[CH3:18]>C1COCC1>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH3:10])[C:3]=1[NH:4][Si:17]([CH:20]1[C:24]2[S:25][CH:26]=[CH:27][C:23]=2[C:22]([CH3:28])=[C:21]1[CH3:29])([CH3:18])[CH3:19]
Reactant: Cc1cc(C)c(N)c(Br)c1
Reactant: CC1=C(C)C([Si](C)(C)Cl)c2sccc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1=C(C)C([Si](C)(C)Nc2c(C)cc(C)cc2Br)c2sccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under and argon atmosphere, to a solution of 14.8 g (74.2 mmol) of 2-bromo-4,6-dimethylaniline in 200 ml of THF, 29.7 ml of 2.5 M (74.2 mmol) nBuLi in hexanes was added at −80° C. This mixture was warmed for ca. 1 hour to ambient temperature. Then, the resulting solution was added dropwise for ca. 1 hour while vigorously stirring to a solution of 18.0 g (74.2 mmol) of chloro(4,5-dimethyl-6H-cyclopenta[b]thien-6-yl)dimethylsilane in 100 ml of THF. The resulting mixture was stirred overnight at ambient temperature, then, evaporated to dryness. To the residue, 150 ml of toluene was added. This mixture was filtered through a glass frit (G4). The filtrate was evaporated to dryness. Fractional distillation gave a yellow liquid, bp 168-172° C./0.2 mm Hg. The product crystallizes slowly at ambient temperature. Yield 16.5 g (55%).