Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].[CH:26](N)=O>>[CH:23]1([CH2:22][O:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[C:9]2[N:8]=[C:7]3[C:12](=[N:13][CH:26]=[N:6]3)[C:11](=[O:14])[N:10]=2)[CH2:24][CH2:25]1
Reactant: NC=O
Reactant: Nc1nc(-c2ccccc2OCC2CC2)[nH]c(=O)c1N
Agent: O=S(=O)(O)O
Product: O=C1N=C(c2ccccc2OCC2CC2)N=C2N=CN=C12
Temperature: 180 °C

Procedure:
A stirred mixture of 4,5-diamino-2-(2-cyclopropylmethoxyphenyl)pyrimidin-6-one sulphate (1.48 g) and formamide (5 ml) was heated in an oil bath at 180° C. for 2 to 3 hours. The cooled mixture was filtered and the collected solid was washed with ethanol to give a crude product (1.07 g) which was recrystallised three times from ethanol to afford the title compound, 0.32 g, m.p. 259°-260° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[C:18][Si](C)(C)C)=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:24])([CH3:23])[CH2:8][CH:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:17]#[CH:18])=[C:13]([CH3:16])[CH:14]=2)[C:9]([CH3:23])([CH3:24])[CH2:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CCC(C)(C)c2cc(C#C[Si](C)(C)C)c(C)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C#Cc1cc2c(cc1C)C(C(=O)OCC)=CCC2(C)C

Procedure:
Following General Procedure F and using 4,4,7-trimethyl-6-trimethylsilanylethynyl-3,4-dihydro-naphthalene-1-carboxylic acid ethyl ester (Intermediate 184, 0.43 g, 1.3 mmol), ethanol (4 mL) and potassium carbonate (0.84 g, 6.06 mmol), the title compound was obtained (0.33 g, 95%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:8][CH:7]([N:9]2[C:13]3[N:14]=[C:15]([S:29][CH2:30][CH2:31][CH3:32])[N:16]=[C:17]([N:18]([CH:20]4[CH2:22][CH:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[C:12]=3[N:11]=[N:10]2)[CH:6]([OH:33])[CH:5]1[OH:34].C(N(CC)C(C)C)(C)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[OH:34][CH:5]1[CH:6]([OH:33])[CH:7]([N:9]2[C:13]3[N:14]=[C:15]([S:29][CH2:30][CH2:31][CH3:32])[N:16]=[C:17]([N:18]([CH:20]4[CH2:22][CH:21]4[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:19])[C:12]=3[N:11]=[N:10]2)[CH2:8][CH:4]1[CH2:3][NH:2][C:44](=[O:46])[CH3:45]
Reactant: CCCSc1nc(N(C)C2CC2c2ccccc2)c2nnn(C3CC(CN)C(O)C3O)c2n1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCSc1nc(N(C)C2CC2c2ccccc2)c2nnn(C3CC(CNC(C)=O)C(O)C3O)c2n1
Reaction time: 2 h
Yield: 59.3 %

Procedure:
A solution of the product from Example 7 (0.2 g) in dichloromethane (15 ml) was treated with N,N-diisopropylethylamine (0.11 g) followed by acetic anhydride (0.16 g) and the resultant mixture was stirred at room temperature for 4 hours. The mixture was washed with a saturated solution of aqueous sodium bicarbonate (15 ml) and the organic layer concentrated in vacuo. The residue was dissolved in a 0.1 molar solution of sodium methoxide in methanol (20 ml) and the solution allowed to stand for 2 hours at room temperature. Following concentration in vacuo the residue was acidified by careful addition of acetic acid, the mixture was again concentrated in vacuo and he residue azeotroped with toluene (3×100 ml). Purification by chromatography (SiO2 methanol:chloroform 1:24 as eluant) gave the title compound (0.12 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.NC(N)=[S:17]>C(O)C>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2](=[S:17])[CH:3]=[CH:4][NH:5]2)=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1ccc2c(Cl)ccnc2c1
Reactant: NC(N)=S
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(=S)cc[nH]c2c1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4-Chloro-7-nitroquinoline (100 mg, 0.48 mmol) and thiourea (100 mg, 1.3 mmol) were added to ethanol (50 ml) and stirred at 80° C. for 30 minutes. After allowing to cool to room temperature, ethanol was removed under reduced pressure. The residue was chromatographed by silica gel column chromatography and eluted with mixed solution of methylene chloride with methanol (19 : 1) for collection of yellow bands. The solvent was removed to obtain 7 mg (7%) of the titled yellow compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12]Br.[CH3:14][OH:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:15][CH3:14]
Reactant: COC(=O)c1ccc(Br)c(CBr)c1
Reactant: CO
Product: COCc1cc(C(=O)OC)ccc1Br
Yield: 94 %

Procedure:
A solution of methyl 4-bromo-3-(bromomethyl)benzoate obtained in step 1 (37.50 g; 121.77 mmol) in MeOH (1 125 mL) was refluxed for 4 days. After concentration, the mixture was partitioned between EtOAc (500 mL) and water (200 mL). The organic layer was washed with a 5% NaHCO3 aqueous solution (200 mL), brine (200 mL), dried over MgSO4 and concentrated affording the title compound as a beige solid (29.8 g, 94%). 1H NMR (DMSO-d6) δ 8.06-8.05 (m, 1H), 7.83 (d, J=1.23 Hz, 2H), 4.54 (m, 2H), 3.90 (s, 3H), 3.45 (s, 3H). LC/MS (Method B): 227.2 (M−H)−. HPLC (Method A) Rt 4.42 min (Purity: 93.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[OH-].[NH4+:29]>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH2:29])=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(N)=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (147 mg, 0.44 mmol) in toluene (5 mL) with N,N-dimethylformamide (2 drops) at 25° C. was treated with oxalyl chloride (0.05 mL, 0.53 mmol). The reaction was stirred at 25° C. for 30 min. At this time, the reaction was cooled to −60° C. and treated with ammonium hydroxide (0.50 mL, 3.8 mmol). The resulting suspension was allowed to warm to 25° C. and stirred at 25° C. for 1 h. At this time, the reaction was quenched by the addition of a 2N aqueous hydrochloric acid solution (1 mL) and then extracted with diethyl ether (3×25 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 65/35 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (130 mg, 89%) as a white foam: EI-HRMS m/e calcd for C5H20ClNO3S (M+) 329.0852, found 329.0852.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=[CH:13][C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1.[CH3:38]CN(CC)CC.CCOCC.C(Cl)Cl>C(Cl)(Cl)Cl.CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@@:6]12[CH2:38][C@@H:13]1[C:14]1[CH:22]=[C:21]2[C:17]([C:18](/[CH:23]=[CH:24]/[C:25]3[CH:26]=[N:27][C:28]([N:31]4[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]4)=[CH:29][CH:30]=3)=[N:19][NH:20]2)=[CH:16][CH:15]=1
Reactant: COc1ccc2c(c1)C(=Cc1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Reactant: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)[C@@]1(C[C@@H]1c1ccc3c(/C=C/c4ccc(N5CCN(C)CC5)nc4)n[nH]c3c1)C(=O)N2
Yield: 4 %

Procedure:
From two repeated batches of Example A31 using 5-methoxy-3-((3-((E)-2-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)vinyl)-1H-indazol-6-yl)methylene)indolin-2-one (combined 491 mg, 1.0 mmol), purification using flash chromatography (silica gel, 1% Et3N in CHCl3/MeOH 96:4 to 92:8), followed by trituration with 1:1 Et2O/CH2Cl2 gave the minor diastereomer title compound as a pale yellow solid (18 mg, 4%). 1H NMR (400 MHz, CDCl3 with a few drops of CD3OD) δ ppm 8.21 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.27 (d, J=17.3 Hz, 1H), 7.16 (d, J=17.3 Hz, 1H), 7.05 (d, J=8.8 Hz, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 6.67 (d, J=9.3 Hz, 1H), 6.54 (s, 1H), 3.77 (s, 3H), 3.58 (bs, 4H), 3.18-3.27 (m, 1H), 2.57 (bs, 4H), 2.40 (dd, J=8.5, 5.3 Hz, 1H), 2.35 (bs, 3H), 2.09 (dd, J=9.0, 5.0 Hz, 1H); MS ESI 507.3 [M+H]+, calcd for [C30H30N6O2+H]+ 507.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([CH:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=O)=[CH:4][CH:3]=1.Cl.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[NH:28][NH2:29]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH3:20])[N:29]=[C:10]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccccc1NN
Reactant: O=C(CC(=O)C1CCOCC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Product: COc1ccccc1-n1nc(C2CCOCC2)cc1-c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
A solution of 1-(4-chlorophenyl)ethanone (2.0 g, 12.9 mmol) in anhydrous THF was cooled in a dry ice acetone bath and treated with sodium hexamethyldisilazid (14.2 mL, 1M in THF, 14.2 mmol). The resulting solution was stirred for 1 h at −78° C. and a solution of tetrahydro-pyran-4-carbonyl chloride (1.92 g, 12.9 mmol) in THF was slowly added. The resulting solution was stirred for 30 min at −78° C., allowed to warm up to room temperature and stirred for 5 h. The reaction was quenched by adding 6N HCl and extracted with EtOAc (×3). The organic fractions were combined and washed with sat. NaCl, dried over Na2SO4 and evaporated under vacuum. The resulting residue was purified by silica column chromatography to give 2 g (58%) of 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione. 1-(4-chlorophenyl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione 1 g (3.75 mmol) was taken in absolute ethanol (20 mL) and TEA (1.4 mL, 10 mmol) was added slowly. This solution was stirred for 20 min and added drop-wise to a solution of (2-methoxyphenyl)hydrazine hydrochloride (0.7 g, 4.0 mmol) in ethanol (20 mL). This solution was heated to 60° C. and stirred for 5 h. Ethanol was removed under vacuum and the residue was taken in EtOAc and washed with water, and sat. NaCl. The solution was dried over Na2SO4 and evaporated. The residue was purified by silica column chromatography to give 5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazole.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3].[C:12]([NH:20][NH2:21])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:2]([N:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:4](=[N:21]/[NH:20][C:12](=[O:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)/[C:2]1=[O:3])[CH2:4][CH2:6][CH2:7][CH3:8]
Reactant: NNC(=O)c1ccccc1
Reactant: O=C1Nc2ccccc2C1=O
Product: CCCCCN1C(=O)/C(=N\NC(=O)c2ccccc2)c2ccccc21
Yield: 78.1 %

Procedure:
The title compound was prepared as a yellow solid, using isatin 6 and benzhydrazide according to the synthetic method D. The resulting solid was washed with ethanol. Yield: 78.1%. 1H NMR (DMSO-d6): δ 0.90 (t, J=6.5 Hz, 3H), 1.34-1.36 (m, 4H), 1.63-1.68 (m, 2H), 3.80 (t, J=7 Hz, 2H), 7.22 (t, Hz, J=7.5 Hz, 1H), 7.26 (d, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.65-7.70 (m, 3H), 7.74 (t, Hz, J=7 Hz, 1H), 7.96 (d, (d, J=7, 2H), 13.95 (br s, 1H). 13C NMR (DMSO-d6): δ 14.30 (CH3), 22.27 (CH2), 27.15 (CH2), 28.89 (CH2), 39.75 (CH2), 110.66 (CH), 119.65 (C), 121.26 (CH), 123.69 (CH), 127.88 (CH), 129.67 (CH), 132.23 (CH), 132.42 (C), 133.40 (CH), 137.80 (C), 143.43 (C═N), 161.58 (C═O), 163.36 (C═O). HRMS (ES+) calcd for C20H22N3O2 (M+H+) m/e, 336.1713; found 336.1707.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][CH2:15][C@H:8]3[C:7](=[O:16])[NH:6][C:5]=2[CH:4]=1.Cl.C([NH:20][C:21](=[O:35])[C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24](C)[CH:23]=1)C.[I-].C(C[P+](C)(C)C)#N.C(N(CC)C(C)C)(C)C>C(#N)CC>[O:16]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][CH:29]3[CH2:30][NH:31][CH2:32][CH2:33][N:28]3[C:25]3[CH:24]=[CH:23][C:22]([C:21]([NH2:20])=[O:35])=[CH:27][CH:26]=3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][CH2:15][CH:8]12
Reactant: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(C)c1
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCNCC2Cc2cnc3c(c2)NC(=O)C2CCCN32)cc1
Temperature: 105 °C
Yield: 62.7 %

Procedure:
(S)-3-(hydroxymethyl)-6a,7,8,9-tetrahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-6(5H)-one (100 mg, 0.456 mmol), N-ethyl-3-methyl-4-(piperazin-1-yl)benzamide hydrochloride (129 mg, 0.456 mmol), (cyanomethyl)trimethylphosphonium iodide (166 mg, 0.684 mmol) and N,N-diisopropylethylamine (0.398 ml, 2.281 mmol) were suspended in propiononitrile (Volume: 1.370 ml) and heated in a closed vial at 90-120° C. for 4 h. The reaction mixture became a dark brown solution. It was cooled to room temperature, concentrated in vacuo, dissolved in DMSO (2 mL) and purified using HPLC (basic, 45-95% ACN in water, basic). The fractions were concentrated in vacuo and the resulting solid was recrystallized from water-MeOH (2:1, 6 mL) and dried in vacuum to afford(S)—N-ethyl-3-methyl-4-(4-(((6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazin-3-yl)methyl)piperazin-1-yl)benzamide (128.5 mg, 0.286 mmol, 62.8% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83-2.03 (m, 3H) 2.09-2.25 (m, 1H) 2.50 (m, 4H) 2.75 (d, J=4.29 Hz, 3H) 2.96-3.14 (m, 4H) 3.35-3.45 (m, 3H) 3.53-3.65 (m, 1H) 3.93-4.05 (m, 1H) 6.98 (d, J=1.77 Hz, 1H) 7.04 (t, J=8.59 Hz, 1H) 7.51-7.67 (m, 3H) 8.27-8.38 (m, 1H) 10.44 (s, 1H). [M+H] calc'd for C25H32N6O2, 449; found, 449.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:16]=[CH:15][C:9]3=[N:10][CH:11]=[C:12]([Cl:14])[CH:13]=[C:8]3[C:7](=[O:17])[C:6]=2[CH:18]=1.FC(F)(F)C([O-])=O.[O:26]1[CH2:31][CH2:30][O:29][CH2:28][C@H:27]1[CH2:32][N:33]([CH3:38])[S:34]([NH3+:37])(=[O:36])=[O:35].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:14][C:12]1[CH:13]=[C:8]2[C:7](=[O:17])[C:6]3[CH:18]=[C:2]([NH:37][S:34]([N:33]([CH2:32][C@@H:27]4[CH2:28][O:29][CH2:30][CH2:31][O:26]4)[CH3:38])(=[O:35])=[O:36])[CH:3]=[CH:4][C:5]=3[CH:16]=[CH:15][C:9]2=[N:10][CH:11]=1
Reactant: CN(C[C@@H]1COCCO1)S([NH3+])(=O)=O
Reactant: O=c1c2cc(Br)ccc2ccc2ncc(Cl)cc12
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CN(C[C@@H]1COCCO1)S(=O)(=O)Nc1ccc2ccc3ncc(Cl)cc3c(=O)c2c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
7-bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (1.41 g, 4.41 mmol), {[((2R) 1,4-dioxan-2-ylmethyl)(methyl)amino]sulfonyl}ammonium trifluoroacetate (1.30 g, 4.01 mmol), tris(dibenzylideneacetone)dipalladium (0.183 g, 0.20 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino) xanthene (0.347 g, 0.60 mmol), and cesium carbonate (3.91 g, 12.0 mmol) were combined in a dry flask. 50 mL dry dioxane was added and argon was bubbled through the solution for five minutes. The solution was stirred and heated to 95° C. After 2 hours, the solution was concentrated in vacuo, diluted with ethyl acetate, and washed with water and brine. The organic layer was isolated, dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by silica chromatography (0-100% ethyl acetate/hexanes gradient) to afford the title compound. LRMS (APCI) calc'd for (C20H21ClN3O5S) [M+H]+, 450.1; found, 450.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][C:21](O)=[O:22])=[CH:15][CH:14]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[CH2:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3]1[C:4](=[O:25])[C:5]([CH3:24])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][C:21]([NH:34][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:22])=[CH:17][CH:18]=2)[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)O)cc2)=C(C)C1=O
Reactant: NCCc1ccccc1
Product: COC1=C(OC)C(=O)C(Cc2ccc(CCC(=O)NCCc3ccccc3)cc2)=C(C)C1=O
Yield: 24.1 %

Procedure:
3-[4-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-ylmethyl)phenyl]propionic acid (200 mg, 0.58 mmol) obtained in Example 1 and phenethylamine (91 mg, 0.75 mmol) were used, and a method similar to that described in Example 3 was employed to obtain the title compound (61 mg, 0.14 mmol, yield 24%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[O:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:14][N:13]=[CH:12]1>>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:22]([C:19]1[CH:20]=[CH:21][C:16]([C:15]3[O:11][CH:12]=[N:13][CH:14]=3)=[CH:17][CH:18]=1)(=[O:23])=[O:24])[CH:6]=[CH:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccc(-c2cnco2)cc1
Product: O=S(=O)(c1ccc(-c2cnco2)cc1)n1ccc2cc(I)ccc21

Procedure:
This compound was prepared from 5-iodo-1H-indole and 4-oxazol-5-ylbenzene-sulfonyl-chloride by the method outlined under 1.a).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][CH:9]=[O:10])=[C:6]([Cl:11])[N:5]=[C:4]([NH:12][CH:13]=[O:14])[N:3]=1.[NH2:15][O:16][CH2:17][CH2:18][CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].C(N(C(C)C)CC)(C)C>COCCOCCOC>[Cl:11][C:6]1[C:7]([NH:8][CH:9]=[O:10])=[C:2]([NH:15][O:16][CH2:17][CH2:18][CH2:19][P:20]([O:21][CH2:22][CH3:23])([O:24][CH2:25][CH3:26])=[O:27])[N:3]=[C:4]([NH:12][CH:13]=[O:14])[N:5]=1
Reactant: CCOP(=O)(CCCON)OCC
Reactant: O=CNc1nc(Cl)c(NC=O)c(Cl)n1
Solvent: COCCOCCOC
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(CCCONc1nc(NC=O)nc(Cl)c1NC=O)OCC
Temperature: 100 °C
Yield: 44.5 %

Procedure:
A mixture of 4,6-dichloro-2,5-diformamidopyrimidine (1.48 g, 6.3 mmol), diethyl 3-(aminooxy)propylphosphonate (1.33 g, 6.3 mmol), diisopropylethylamine (2.19 ml, 12.6 mmol) in diglyme (20 ml) was heated at 100° C. for 11/2 hours. After cooling, the solvent was removed under reduced pressure. The residue was chromatographed on silica gel (dichloromethane-methanol (97:3) as eluant) to give the title compound as a yellow foam (1.15 g, 58% based on recovered pyrimidine). 1H NMR: δH ((CD3)2SO+D2O) 1.21 (6H, t, J=7Hz, (OCH2CH3)2), 1.65-2.00 (4H, m, CH2CH2P), 3.85-4.05 (6H, m, N--OCH2, (OCH2CH3)2), 7.90+8.15 (1H, 5-NHCHO), 9.25 (2-NHCHO) Found: C, 38.12; H, 5.15; N, 16.25%. C13H21N5O6PCl requires: C, 38.10; H, 5.17; N, 17.09%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N.[OH-].[Na+]>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Brc1ccccn1
Reactant: Clc1ncccn1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Clc1nccc(-c2ccccn2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.1 %

Procedure:
To a solution of 2-chloropyrimidine (8.0 g, 50 mmol) in THF (100 mL) at −78° C., n-BuLi (24 mL, 60 mmol) was added dropwise under N2. After addition, the reaction solution was stirred for 30 min, a solution of 2-bromopyridine (5.75 g, 50 mmol) in THF (50 mL) was added in portions. The reaction mixture was stirred at −30° C. for 30 min and at 0° C. for 45 min., then quenched with AcOH (5 mL) and water (1 mL). A solution of DDQ (16.3 g, 80 mmol) in THF (50 mL) was added in portions and the mixture was stirred at room temperature for 45 min. TLC (petroleum:EtOAc=5:1) indicated the reaction was complete. The reaction mixture was cooled to 0° C. and 3N NaOH (142 mL) was added and stirred for 30 min. The aqueous layer was extracted with EtOAc (50 mL×3). The combined extract was dried over Na2SO4, concentrated and purified by chromatography, eluted with petroleum ether:EtOAc (10:1 to 5:1) to give title compound (4.8 g, 50%) as a light yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([OH:17])[CH2:14][CH2:13][CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10]2)[C:6]=1[CH3:7].[H-].[Na+].I[CH3:21]>CN(C)C=O.CCOCC>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH2:8][C:9]2([O:17][CH3:21])[CH2:14][CH2:13][CH2:12][C:11]([CH3:15])([CH3:16])[CH2:10]2)[C:6]=1[CH3:7]
Reactant: Cc1c(Br)cnn1CC1(O)CCCC(C)(C)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC1(Cn2ncc(Br)c2C)CCCC(C)(C)C1
Reaction time: 0.17 h

Procedure:
A solution of EXAMPLE 157B (0.62 g) was dissolved in N,N-dimethylformamide (10 mL) and treated with NaH (0.062 g, 60% in mineral oil). After 10 minutes, iodomethane (0.16 mL) was added. After 1 hour, additional sodium hydride (0.5 eq.) and iodomethane (0.5 eq.) were added and stirring was continued at room temperature for 3 hours. The reaction was diluted with ether (75 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with a gradient of 1.5% to 15% ethyl acetate/hexanes provided the title compound.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])([O-])=O.[Na+].[Na+].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O.O1CCCC1>[C:19]([NH:1][CH:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture containing 8.21 g of L-Phenylalanine, 5.565 g of Na2CO3 in 40 ml of water and 20 ml of tetrahydrofuran (THF) was stirred at room temperature. Benzoyl chloride, 7.73 g, dissolved in 20 ml of anhydrous THF, was added gradually over a period of 45 minutes with continued stirring at room temperature. Stirring was allowed to continue for an additional hour, at which time the reaction mixture was transferred to a rotary evaporator at 30° C. to remove the THF. An excess of water was then added and the reaction mixture extracted four times with ethyl acetate. The aqueous phase was then titrated to pH 2 with 3N HCl. A white crystalline precipitate formed which was recovered by filtration, washed three times with cold dilute HCl and three times with cold water, and dried in a vacuum oven over P2O5 at about 50° C. The product was recrystallized from aqueous 30 ethanol, yielding 8.37 g, m.p. 183° C.- 184° C., which migrated as a single compound on thin layer chromatography in five separate solvent systems.