Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:21]CC)(=[O:20])[C:17]([CH3:19])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][CH:10]=1)[CH:17]([CH3:19])[C:16]([OH:21])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: CCOC(=O)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
A mixture of 20 g of 2-benzoyl-cyclohexanone, 21.6 g of ethyl pyruvate and 0.2 g of p-toluenesulfonic acid is heated at 150° for 15 hours. There is removed that fraction which distills at 1 mm (Hg up to 150°) and the residue is heated for 10 hours at 230° with 5 parts by weight of pyridine hydrochloride. After cooling the raw reaction products are poured in water and extracted with ether. The residue which is obtained after evaporation of the solvent is steam distilled. The part which does not distil is extracted with ether, the ether solution is dried well over sodium sulfate and to the dried solution there is added diethylamine until a clearly alkaline pH is reached. There thus precipitates a mixture of diethylamine salts from which, through fractional crystallization with hexane-ethyl acetate there is obtained the diathylamine salt of m-benzoyl-hydratropic acid m.p. 102°-104°. The free acid is obtained therefrom with the usual techniques.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH:9]=[CH:10][C:11](Cl)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C:15]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:16]=1[C:17]([OH:19])=[O:18].C(N(CC)CC)C>O1CCCC1>[C:17]([C:16]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:15]=1[NH:14][C:11](=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:19])=[O:18]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: O=C(Cl)C=CC=Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(C=CC=Cc1ccccc1)Nc1ccc(F)cc1C(=O)O

Procedure:
Prepared analogously to Example 31 from 5-phenyl-penta-2,4-dienoic acid chloride and 2-amino-5-fluoro-benzoic acid in tetrahydrofuran with the addition of triethylamine.
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[NH:10]1[CH2:15][CH2:14][CH:13]([NH:7][CH2:6][CH2:5][NH:4][CH2:3][C:2]([NH2:1])([CH3:9])[CH3:8])[CH2:12][CH2:11]1
Reactant: CC(C)(N)CNCCN
Reactant: O=C1CCNCC1
Product: CC(C)(N)CNCCNC1CCNCC1

Procedure:
In a manner analogous to that described immediately hereinabove, by reacting N-(2-amino-2-methylpropyl)-1,2-ethanediamine with piperidin-4-one, it is reductively alkylated to yield N-(4-piperidyl)-N'-(2-amino-2-methylpropyl)-1,2-ethanediamine; and, 2,2,6,6-piperidin-4-one is reductively alkylated to yield N-(2,2,6,6-tetramethyl-4-piperidyl)-N'-(2-amino-2-methylpropyl)-1,2-ethanediamine having the structure: ##STR15##
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:11][C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].Br[CH2:28][CH2:29][CH2:30]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH2:1]([O:3][C:4]([C:5]1([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:30][CH2:29][CH2:28][N:11]1[C:12]1[CH:13]=[N:14][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([I:25])=[CH:21][CH:20]=2)=[CH:16][CH:17]=1)=[O:26])[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(Oc2ccc(I)cc2)nc1)C(=O)OCC
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(I)cc2)nc1
Temperature: 55 °C
Yield: 71.8 %

Procedure:
2-[6-(4-Iodo-phenoxy)-pyridin-3-ylamino]-malonic acid diethyl ester (4.35 grams, 9.25 mmol) was added to a flame dried flask and dissolved in dimethylformamide (90 mL). 1,3 dibromopropane (938 μL, 9.25 mmol) and cesium carbonate (6 grams, 18.5 mmol) were added and the reaction mixture was stirred for approximately 24 hours to 48 hours. The solution was filtered through celite, and then concentrated under vacuum while heating to 55° C. to remove the dimethylformamide (azeotroping with toluene). The crude product obtained was chromatographed on silica gel (ISCO MPLC purification, 40 minutes, 0-50% ethyl acetate gradient, Biotage flash 40 m column) to provide 3.39 grams (72%) of the title compound. MS m/z: ESI+ 511.1 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][C:7]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=3[Cl:28])(=[O:20])=[O:19])=[CH:13][CH:12]=2)=[N:8][C:9]=1Cl)(=O)[CH3:2].[NH2:29][NH2:30]>CC(O)C.O>[Cl:28][C:22]1[C:23]([Cl:27])=[CH:24][CH:25]=[CH:26][C:21]=1[S:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[N:8]=[C:9]3[NH:29][N:30]=[C:1]([CH3:2])[C:4]3=[N:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:20])=[O:19]
Reactant: CC(=O)c1ncc(-c2ccc(NS(=O)(=O)c3cccc(Cl)c3Cl)cc2)nc1Cl
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: Cc1n[nH]c2nc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4Cl)cc3)cnc12
Temperature: 120 °C

Procedure:
N-[4-(5-acetyl-6-chloro-pyrazin-2-yl)-phenyl]-2,3-dichloro-benzenesulfonamide (230 mg) was suspended in a mixture of 2 ml iPrOH and 2 ml 35% hydrazine in water at RT and heated to 120° C. by microwave irradiation (Biotage Initiator™ apparatus) for 20 min under stirring in a sealed vessel. The reaction mixture was left to cool to RT, quenched with a saturated aqueous sodium bicarbonate solution (10 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were dried over sodium sulfate, filtered and evaporated to afford the crude product. Purification by recrystallisation from an acetone-water mixture afforded the title compound as a pale yellow solid after drying under vacuum. Yield: 81.6 mg (38%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1.O>[F:1][C:2]1[CH:8]=[C:7]([I:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:11]([CH3:10])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(I)cc1F
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)(=O)Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.6 %

Procedure:
To a solution of 2-fluoro-4-iodoaniline (5.0 g, 21 mmol) in pyridine (30 mL) at 0° C. was added methanesulfonyl chloride (2.5 mL, 32 mmol) dropwise. The mixture was allowed to warm to ambient temperature and stirred for 3 hours. The mixture was diluted with water and extracted three times with EtOAc. The combined organic extracts were washed with water and brine, dried over Na2SO4, and concentrated. Purification by chromatography (SiO2, 33% EtOAc/Hexanes) afforded the title compound (5.0 g, 75% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.71 (dd, J=9.9, 1.9 Hz, 1H), 7.56 (ddd, J=8.4, 1.9, 1.0 Hz, 1H), 7.19 (t, J=8.4 Hz, 1H), 3.03 (s, 3H); MS (ESI; M−H) m/z 314.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH:13]([OH:26])[C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>C(O)C>[C:33]1([C:11]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH:13]([OH:26])[CH2:12]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Solvent: CCO
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: 65 °C
Yield: 88.2 %

Procedure:
A mixture of 2 g of (3aRS,4RS,5RS,7aRS)-2-benzyl-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5-diol and 50 cm3 of ethanol is heated at 65° C., while stirring; 0.65 g of 20% palladium hydroxide-on-charcoal is added and the reaction mixture is then hydrogenated at a temperature of 65° C. and under atmospheric pressure, while stirring. After a reaction time of 1 hour, the theoretical volume of hydrogen has been absorbed; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallised in 10 cm3 of isopropyl ether. 1.45 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)-perhydroisoindole-4,5-diol which melts at 230° C. are obtained.
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:23]([O:27][CH3:28])(=[O:26])[CH:24]=[CH2:25].C(N(CC)CC)C.Br[C:37]1[CH:38]=[C:39]([CH2:43][C:44]([C:46]2[O:47][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)=[O:45])[CH:40]=[CH:41][CH:42]=1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:28][O:27][C:23](=[O:26])[CH:24]=[CH:25][C:41]1[CH:42]=[CH:37][CH:38]=[C:39]([CH2:43][C:44](=[O:45])[C:46]2[O:47][C:48]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)[CH:40]=1
Reactant: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1cccc(CC(=O)c2ccc(-c3ccccc3)o2)c1
Temperature: 90 °C
Reaction time: 0.03 h

Procedure:
Tri(o-toly)phosphine (25 mg, 0.082 mmol) and palladium(II) acetate (9 mg, 0.041 mmol) in acetonitrile (1 mL) was added to a mixture of methyl acrylate (84 mg, 0.98 mmol) and triethylamine (329 mg, 3.26 mmol). Aryl bromide (25) (278 mg, 0.82 mmol) in acetonitrile (3 mL) was then added and the reaction mixture heated in a CEM Discover microwave for 45 minutes at 90° C. The solvent was concentrated in vacuo, and the crude product was purified by Flash Master Jones Chromatography using a 25 g silica cartridge eluting with 5-17% EtOAc in heptane. Yield: 222 mg, 78%; LC-MS tr 1.62 min; HPLC Purity: 100%; MS (ES+) m/z 347 (M+H)
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:19][CH3:20].[H-].[Na+].C1(C)C=CC(S(O[CH2:33][CH2:34][O:35][CH:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=O)=O)=CC=1>CN(C=O)C>[CH:36]1([O:35][CH2:34][CH2:33][O:1][C:2]2[CH:11]=[C:10]3[C:5]([C:6]([O:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:19][CH3:20])[CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: Cc1ccc(S(=O)(=O)OCCOC2CCCC2)cc1
Reactant: COc1cc2c(Oc3ccccc3)ncnc2cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccccc3)ncnc2cc1OCCOC1CCCC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
7-Hydroxy-6-methoxy-4-phenoxyquinazoline (1.11 g, 4.2 mmol), (prepared as described for the starting material in Example 16), in DMF (1 7 ml) was added to a suspension of sodium hydride (184 mg of a 60% suspension in oil, 4.6 mmol) in DMF (3 ml). The mixture was stirred until evolution of gas ceased, and then 2-cyclopentyloxyethyl 4-toluenesulphonate (1.25 g, 4.45mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at ambient temperature for 30 minutes, then heated at 60° C. for 2 hours, and then at 80° C. for a further 4 hours before being allowed to cool. The mixture was poured onto ice and extracted with methylene chloride. The combined extracts were washed with brine, passed through phase separating paper and the solvent removed by evaporation. The residue was purified by column chromatography eluting with ethyl acetate. The purified product was triturated with isohexane to give 7-(2-cyclopentyloxyethoxy)-6-methoxy-4-phenoxyquinazoline (480 mg, 28%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][C:15]([NH:17][CH:18]([CH2:22][CH2:23][CH3:24])[C:19]([OH:21])=O)=[O:16])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][C:26]1[O:27][C:28]([C:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:32])=[CH:29][N:30]=1.Cl.CN(C)C>C(Cl)Cl.C(Cl)CCl>[C:31]([C:28]1[O:27][C:26]([NH:25][C:19](=[O:21])[CH:18]([NH:17][C:15](=[O:16])[CH2:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)[CH2:22][CH2:23][CH3:24])=[N:30][CH:29]=1)(=[O:32])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: Nc1ncc(C(=O)c2ccccc2)o1
Reactant: CCCC(NC(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)O
Agent: CN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CCCC(NC(=O)Cc1cccc(Oc2ccccc2)c1)C(=O)Nc1ncc(C(=O)c2ccccc2)o1

Procedure:
A mixture of 2-[2-(3-phenoxy-phenyl)-acetylamino]-pentanoic acid (65 mg, 0.2 mmol), (2-Amino-oxazol-5-yl)-phenyl-methanone (38 mg, 0.2 mmol.), HBOT (32 mg, 0.24 mmol), EDC. HCl (58 mg, 0.3 mmol) and a trimethylamine (0.11 ml, 0.8 mmol) in methylene chloride was stirred at room temperature until disappearance of starting material. The mixture was quenched with water and extracted with methylene chloride. The organic layer was washed with dilute HCl, brine, dried over sodium sulfate and the solvent was removed at reduced pressure to provide the title compound, LC-MS M+1=498.5.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16](Cl)=[O:17].O>C(#N)C>[CH3:11][O:12][CH2:13][CH2:14][O:15][C:16](=[O:17])[NH:6][C:5]1[C:7]([CH3:9])=[CH:8][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10]
Reactant: COCCOC(=O)Cl
Reactant: Cc1cc(Br)cc(C)c1N
Solvent: CC#N
Solvent: O
Product: COCCOC(=O)Nc1c(C)cc(Br)cc1C
Temperature: 130 °C
Yield: 82.1 %

Procedure:
4-Bromo-2,6-dimethyl-aniline (2.00 g) and chloroformic acid 2-methoxyethyl ester (1.52 g) were dissolved in acetonitrile (25 mL) and heated to 130° C. for 15 minutes in a sealed microwave process vial. Water (25 mL) was added to the reaction mixture, and the product was collected by filtration and washed with water (25 mL) and heptane (25 mL) to furnish 2.48 g (82% yield) of the title compound as a white solid. LC-MS (m/z) 304 (MH+); tR=2.93, (UV, ELSD) 96%, 97%. 1H NMR (500 MHz, CDCl3): 2.36 (m, 6H), 3.40 (m, 3H), 3.60 (m, 2H), 4.35 (m, 2H), 6.55 (broad s, 1H), 7.45 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.O/[C:16](=[C:18]1\[C:19](=[O:25])[NH:20][C:21](=[O:24])[CH2:22][CH2:23]\1)/[CH3:17]>C(O)C.Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]/[C:16](=[C:18]3\[C:19](=[O:25])[NH:20][C:21](=[O:24])[CH2:22][CH2:23]\3)/[CH3:17])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: C/C(O)=C1\CCC(=O)NC1=O
Agent: Cl
Solvent: CCO
Product: C/C(Nc1ccc(N2CCN(C)CC2)cc1)=C1\CCC(=O)NC1=O
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-methyl-1-piperazinyl)-benzenamine (43 mg, 0.23 mmol) and (3Z)-3-(1-hydroxyethylidene)-piperidine-2,6-dione (35 mg, 0.23 mmol) in absolute ethanol (1.5 mL) is added concentrated ethanolic hydrogen chloride (2 drops), which caused the precipitation of a white solid. The mixture is heated in a 65° C. oil bath for 20 minutes. Then N,N-dimethylformamide (0.4 mL) is added to the mixture and the temperature of the oil bath is increased to 70° C. An additional volume of N,N-dimethylformamide (0.6 mL) is added and the temperature of the oil bath is increased to 135° C., at which setting it stirred for 30 minutes. The mixture is stirred overnight at 130° C. After cooling to room temperature, the semi-solid reaction mixture is triturated with methanol. The solid that formed is collected by filtration and washed with diethyl ether, water, and methanol to give (3Z)-3-(1-{[4-(4-methylpiperazin-1-yl)phenyl]amino}ethylidene)piperidine-2,6-dione as a light beige solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([S:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(Sc2cc(C)c(C(=O)CBr)c(C)c2)cc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1ccc(Sc2cc(C)c(-c3csc(N)n3)c(C)c2)cc1
Yield: 89.7 %

Procedure:
A reaction mixture containing 2-bromo-1-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)ethanone (1.06 g, 2.9 mmol, 1.0 equiv) and thiourea (221.5 mg, 2.9 mmol, 1.0 equiv) in EtOH (20.0 mL) was heated at reflux for 16 h. The solution was concentrated under reduced pressure, and the residue was re-dissolved in EtOAc (50 mL). The solution was washed with saturated aqueous NaHCO3 (30 mL), dried over MgSO4(s), and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (5.0% EtOAc in hexanes as eluant) to provide 4-(4-(4-methoxyphenylthio)-2,6-dimethylphenyl)thiazol-2-amine (890.9 mg, 2.6 mmol) as yellow solids in 90% yield: 1H NMR (DMSO-d6, 500 MHz) δ 7.40 (d, J=8.7 Hz, 2 H), 7.00 (d, J=8.7 Hz, 2 H), 6.86-6.87 (m, 4 H), 6.33 (s, 1 H), 3.78 (s, 3 H), 2.03 (s, 6 H); ESI-MS m/z 343.9 (M+H)+.
Reaction SMILES: [O:1]([NH2:3])[CH3:2].Cl[C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[C@@H:14]1[O:20][C@H:19]([CH2:21][OH:22])[C@@H:17]([OH:18])[C@@:15]1([CH3:23])[OH:16]>>[CH3:23][C@@:15]1([OH:16])[C@H:17]([OH:18])[C@@H:19]([CH2:21][OH:22])[O:20][C@H:14]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][CH:12]=[N:13][C:5]=2[NH:3][O:1][CH3:2]
Reactant: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(Cl)ncnc21
Reactant: CON
Product: CONc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@@]1(C)O

Procedure:
The above compound was synthesized from methoxylamine and 6-chloro-9-(2′-C-methyl-β-D-ribofuranosyl)purine as described in Example 1, Step 3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC(OC)=C2C=1C=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: Fc1cc(Br)cc2cc[nH]c12
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Product: CCOC(=O)C=C(c1ccccc1)c1cc(F)c2[nH]ccc2c1
Yield: 74 %

Procedure:
3-(7-Fluoro-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester LXXXI (215 mg, 74% yield) was prepared from 5-bromo-7-fluoroindole using the procedure described for 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:16]([CH3:18])[CH3:17])\[CH3:7])[CH3:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH:16]([CH3:18])[CH3:17])\[CH2:7][Br:20])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccccc1OC(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccccc1OC(C)C
Yield: 62.9 %

Procedure:
To a stirred mixture of (E)-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (4.90 g, 0.019 mol) in carbon tetrachloride (35 mL) under a nitrogen atmosphere was added N-bromosuccinimide (4.95 g, 0.028 mol) and benzoyl peroxide (450 mg, 0.002 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-isopropoxy-phenoxy)-but-2-enoic acid ethyl ester (4.10 g, 64%) as a yellow oil.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH2:31])=[N:6][C:7]([CH:18]3[CH2:20][CH2:19]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:3][CH2:2]1.Cl[C:33](Cl)(Cl)[C:34](=[O:36])C>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:5]([NH:21][C@@H:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C@H:23]3[NH:31][C:34](=[O:36])[CH3:33])=[N:6][C:7]([CH:18]3[CH2:19][CH2:20]3)=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=3[Cl:17])[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC(=O)C(Cl)(Cl)Cl
Reactant: N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Solvent: ClC(Cl)Cl
Product: CC(=O)N[C@@H]1Cc2ccccc2[C@H]1Nc1nc(C2CC2)c(-c2ccc(Cl)cc2Cl)nc1C1CC1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 101.3 %

Procedure:
To a solution of (1R,2R)-N1-[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]-2,3-dihydro-1H-indene-1,2-diamine (0.10 g, 0.22 mmol) in CHCl3 (1 mL) at 0° C. under N2 was added trichloroacetone (30 μL, 0.26 mmol). The mixture was allowed to slowly warn to rt for 1.5 hr. The reaction was then heated at 60° C. for 1.5 h. Cool to rt, add additional trichloroacetone (10 μL) and continue heating at 60° C. for 2 hr. The reaction was concentrated and purified by biotage MPLC (90 g column, 80% ethyl acetate/hexanes) to afford 0.11 g (55%) of N-((1R,2R)-1-{[3,6-dicyclopropyl-5-(2,4-dichlorophenyl)pyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-yl)acetamide as a solid: 1H NMR (CDCl3) δ 0.84-1.01, 1.61-1.81, 2.04, 2.80-2.86, 3.58-3.64, 4.07-4.13, 4.46, 5.56, 6.56, 7.28-7.51; MS (ESI+) for C27H26Cl2N4O m/z 493 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.CCN(S(F)(F)[F:18])CC>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:18])([CH3:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(O)c1ccc(Br)cc1
Solvent: ClCCl
Product: CC(C)(F)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(4-bromophenyl)propan-2-ol (8.3 g, 38.59 mmol) in 100 mL of CH2Cl2 was added DAST (6.1 mL, 46.31 mmol) at −78° C. The reaction was stirred to rt overnight, and quenched with 100 mL of water at 0° C. The product was extracted with EtOAc, and the extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous MgSO4, and concentrated to give 1-bromo-4-(1-fluoro-1-methylethyl)benzene, which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br)#[N:23]>CC(C)=O>[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1)#[N:23]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: N#Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#Cc1cccc(CN2CCN(c3ccc([N+](=O)[O-])cc3)CC2)c1
Reaction time: 4 h
Yield: 93.1 %

Procedure:
To a stirred solution of 1-(4-nitro-phenyl)-piperazine (35.9 g) and potassium carbonate (71.6 g) in acetone (500 mL) was added dropwise 3-cyano-benzyl bromide (34 g) at room temperature and the mixture was heated under reflux. After 4 hours, the salts were removed by filtration, washed with acetone and the filtrate was evaporated to dryness. The residue was taken in CH2Cl2 and the solution was washed with water, dried over Na2SO4, filtered and evaporated. The oily residue was crystallized from AcOEt/diisopropyl ether to give the title compound (52 g) as orange crystals.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][NH:6][C:5](=[O:9])[CH2:4]1)=[O:2].[H-].[Na+].[CH3:12]I>CN(C)C=O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH3:12])[C:5](=[O:9])[CH2:4]1)=[O:2]
Reactant: O=CN1CCNC(=O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(C=O)CC1=O

Procedure:
To a solution of 6.4 g of 1-formyl-3-oxo-piperazine in 10 ml of anhydrous dimethylformamide was added 2.7 g of a sodium hydride (purity 53%) with ice-cooling, and the resulting mixture was reacted at room temperature for 1 hour. Subsequently, the mixture was incorporated with 7.1 g of methyl iodide and reacted for 10 hours. After the reaction, the dimethylformamide was removed by reduced pressure distillation to obtain 1-formyl-4-methyl-3-oxo-piperazine. This piperazine was dissolved in 70 ml of a 50% aqueous acetone solution containing 2.2 g of sodium hydroxide, and the resulting solution was reacted at room temperature for 3 hours. Thereafter, the solvent was removed by distillation under reduced pressure, and the residue was charged into acetone to deposit insolubles. The insolubles were separated by filtration, and the acetone was removed from the filtrate by distillation under reduced pressure. Subsequently, the residue was subjected to reduced pressure distillation to obtain 5.2 g of 1-methyl-2-oxo-piperazine, b.p. 104° C/4 mmHg, yield 91%.