Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[NH:10][CH:9]=[C:8]2[C:16]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:19]2=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]2[CH:17]=1.[CH3:36]I>CN(C)C=O.O>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]([CH3:36])[CH:9]=[C:8]2[C:16]1[N:25]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])[C:19]2=[N:20][CH:21]=[CH:22][C:23]([CH3:24])=[C:18]2[CH:17]=1
Reactant: COc1cc2[nH]cc(-c3cc4c(C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(-c3cc4c(C)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Reaction time: 4 h

Procedure:
0.017 g of sodium hydride (60%) is added to a solution of 0.17 g of 2-[5,6-dimethoxy-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine in 7 cm3 of anhydrous dimethylformamide, under an inert atmosphere of argon at a temperature in the region of 20° C. After stirring for one hour at the same temperature, 0.025 cm3 of methyl iodide is added. Stirring is continued at this temperature for 4 hours. The reaction mixture is taken up in 50 cm3 of water and then extracted with 100 cm3 of ethyl acetate, and the aqueous phase is re-extracted with 2×50 cm3 of ethyl acetate. The combined organic phases are washed successively with 50 cm3 of saturated aqueous sodium chloride solution and then with 50 cm3 of distilled water. After separation of the phases by settling, the organic phase is dried over magnesium sulfate, filtered and then concentrated under reduced pressure. The residue obtained is purified on a Flash Chromabond RS 6 SiOH cartridge (3 g of silica). The elution was performed at a flow rate of 10 cm3/min with a dichloromethane/methanol mixture (95/05 by volume). The fractions containing the expected compound are combined and evaporated to give 2-[5,6-dimethoxy-1-methyl-1H-indol-3-yl]-1-(toluene-4-sulfonyl)-4-methyl-1H-pyrrolo[2,3-b]pyridine in the form of a beige-colored solid (0.130 g, 72%), the characteristics of which are as follows:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>>[CH2:13]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCc2cc(OCc3ccccc3)ccc21
Temperature: 10 °C
Yield: 79.6 %

Procedure:
The mixture of 6-hydroxy-3,4-dihydro-2H-naphthalen-1-one (30.74 g, 0.1895 mol), benzyl bromide (27.0 mL, 0.227 mol) and potassium carbonate (39.3 g, 0.284 mol) in acetone (250 mL, 3.4 mol) was heated to reflux under an atmosphere of nitrogen for 3 hours. The mixture was cooled to 10° C. with an ice bath, filtered and washed with small amount of to acetone. The filtrate was concentrated in rotavap. The resulting crystals were collected by filtration and washed with EtOAc-hexane then hexane to give a pale yellow solid product as the first crop. The mother liquid was concentrated in rotavapor and the residue was purified by chromatograph with EtOAc:hexane (0:100 to 20:80) to give the second crop of solid product (38.07 g, 80%). 1H NMR (CHLOROFORM-d) δ: 8.02 (d, J=8.6 Hz, 1H), 7.32-7.51 (m, 5H), 6.91 (dd, J=8.8, 2.3 Hz, 1H), 6.80 (s, 1H), 5.13 (s, 2H), 2.93 (t, J=6.1 Hz, 2H), 2.56-2.68 (m, 2H), 2.12 (quin, J=6.3 Hz, 2H). MS (M+1): 253.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:3]=1.[CH2:22]([CH2:24][NH2:25])[OH:23].CCN(C(C)C)C(C)C>Cl.CCCCO>[C:16]1([NH:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:25][CH2:24][CH2:22][OH:23])[CH:3]=3)=[CH:10][CH:11]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1cc(Nc2ccc(Nc3ccccc3)cc2)ncn1
Reactant: NCCO
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: OCCNc1cc(Nc2ccc(Nc3ccccc3)cc2)ncn1
Temperature: 200 °C
Yield: 32 %

Procedure:
176 mg of N1-(6-chloropyrimidin-4-yl)-N4-phenylbenzene-1,4-diamine in the form of a hydrochloride, 72 mg of ethanolamine and 153 mg of DIPEA were dissolved in 2 mL of n-BuOH and the mixture obtained was charged into a microwave vial and the vial obtained was heated to 200° C. for 60 minutes under microwave irradiation. Progress of the reaction was monitored by TLC. Upon termination of the reaction n-BuOH was evaporated and the evaporation residue was subjected to MPLC eluting the product with EtOAc. 2-(6-(4-(Phenylamino)phenylamino)pyrimidin-4-ylamino)ethan-1-ol was obtained in the form of a solid.
Reaction SMILES: [CH:1]1([NH:9][C:10]([NH2:12])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:14]1([C:18](OCC)=[O:19])[CH2:17][CH2:16][CH2:15]1>>[CH:1]1([NH:9][C:10]2[S:11][C:14]3([C:18](=[O:19])[N:12]=2)[CH2:17][CH2:16][CH2:15]3)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NC1CCCCCCC1
Reactant: CCOC(=O)C1(Br)CCC1
Product: O=C1N=C(NC2CCCCCCC2)SC12CCC2

Procedure:
Synthesis was performed from N-cyclooctylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D2.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:13]([CH:15]=[O:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[BH4-].[Na+]>C1COCC1.O>[F:1][C:2]1[CH:14]=[C:13]([CH2:15][OH:16])[CH:12]=[C:11]([O:17][CH3:18])[C:3]=1[O:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)COc1c(F)cc(C=O)cc1OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)COc1c(F)cc(CO)cc1OC
Yield: 60.9 %

Procedure:
The compound was prepared according to general procedure F with Ethyl 2-(2-fluoro-4-formyl-6-methoxyphenoxy)acetate (1.4 mmol) in THF (20 ml) and water (20 ml) and NaBH4 (1.4 mmol). 220 mg of compound were obtained. This compound was used without further purification. 1H NMR (250 MHz, CDCl3): δ 1.33 (t, J=7.1 Hz, 3H), 3.90 (s, 3H), 4.28 (q, J=7.1 Hz, 2H), 4.65 (s, 2H), 4.71 (s, 2H) 6.95 (s, 1H), 6.76 (m, 2H). MS (ESI): m/z 538.8 [2M+Na]+
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9]Br)[C:3]=1[O:11][CH3:12].[C-:13]#[N:14].[Na+]>C(O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[C:4]([CH2:9][C:13]#[N:14])[C:3]=1[O:11][CH3:12]
Reactant: [C-]#N
Reactant: COc1c(Br)cc(Br)cc1CBr
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1c(Br)cc(Br)cc1CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of the product of stage (c) (183 g) in ethanol (150 ml) was heated to reflux. A solution of sodium cyanide (25 g) in hot water (50 ml) was added which maintained gentle refluxing. The mixture was then stirred for 5 minutes, poured into ice water, and the product was filtered off, taken up in dichloromethane, washed with water, dried over magnesium sulphate and filtered. The solvent was removed to give a brown oil which slowly crystallised. Recrystallisation from petroleum ether gave the title product as colourless needles, mp 87°-88° C.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43]([C@H:45]1[CH2:49][CH2:48][C@@H:47]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:46]1)=[O:44])=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:44][C:43]([C@H:45]2[CH2:49][CH2:48][C@@H:47]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:54])[CH3:55])[CH2:46]2)=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a 0° C. solution of PPh3 (2.2 g 8.4 mmol) in dry DCM (20 mL) was added I2 (2.1 g, 8.4 mmol). After I2 was dissolved, TEA (2.4 mL, 16.8 mmol) was added quickly at rt. The reaction mixture was stirred for 15 min. tert-Butyl (1R,3S)-3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)cyclopentylcarbamate (2.1 g, 4.2 mmol) was added. The reaction mixture was stirred at rt for 1 h. The reaction mixture was concentrated and the residue was purified by silica gel column (gradient elution 0-50% EtOAc/petroleum ether) to afford the crude tert-butyl (1R,3S)-3-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)cyclopentylcarbamate (−1.7 g) as a white solid. ESI-MS (EI+, m/z): 484.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[N:13]1([C:19]2[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:16]3[CH2:17][CH2:18][N:13]([C:19]4[CH:24]=[CH:23][C:22]([S:25]([NH2:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)[CH2:14][CH2:15]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 39.6 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.500 g), 4-(piperazin-1-yl)benzenesulfonamide (Example 2, Step 2; 0.630 g), triethylamine (0.477 g), and ethylene glycol (6 mL) give 0.40 g of the title compound after chromatography on silica gel using methanol/dichloromethane (8/92) and crystallization from methanol/dichloromethane; mp 255-256° C.; IR (mineral oil) 1153, 1327, 1322, 3306, 1106 cm-1. 1H NMR (DMSOd6) δ2.60, 3.29, 3.66, 7.01, 7.06, 7.25, 7.54, 7.60, 7.84, 8.80.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:3]1.[O:23]1[CH:25]([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]1>CC(O)C>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:22])([CH3:1])[CH2:3][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:17][CH2:18][N:19]([CH2:24][CH:25]([OH:23])[CH2:26][CH2:27][CH2:28][CH3:29])[CH2:20][CH2:21]2)[CH2:5]1
Reactant: CC1(C)CC(c2ccccc2N2CCNCC2)CC(C)(C)C1
Reactant: CCCCC1CO1
Solvent: CC(C)O
Product: CCCCC(O)CN1CCN(c2ccccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.6 %

Procedure:
A mixture of 1-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine (120 mg, 0.399 mmol) produced in Example (8b), 1,2-epoxyhexane (240 mg, 2.39 mmol) and 2-propanol (0.8 mL) was stirred for 18 hours at an external temperature of 80° C. The reaction mixture was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 116 mg of 1-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-yl}hexan-2-ol as a light yellow solid. This compound (12 mg, 0.030 mmol) was dissolved in diethyl ether and a 4N solution of hydrogen chloride in ethyl acetate (0.0083 mL, 0.033 mmol) was added. The mixed solution was concentrated under reduced pressure and the obtained solid residue was washed with a diethyl ether-heptane mixed solvent and then dried under reduced pressure to give 10 mg of the title compound as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][CH2:10][C:11](Cl)=[O:12].C(N(CC)C(C)C)(C)C>ClCCl>[Cl:9][CH2:10][C:11]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[Cl:1])=[O:12]
Reactant: Nc1ccccc1Cl
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)Nc1ccccc1Cl
Temperature: 0 °C
Reaction time: 12 h

Procedure:
2-Chloroaniline (5 g) was dissolved in dichloromethane (100 ml) and chloroacetyl chloride (3.11 ml) and N,N-diisopropylethylamine (13.65 ml) were added at 0° C. under a nitrogen atmosphere. The mixture was stirred for 1 hour at 0° C. and 12 hours at room temperature, then quenched with water. The product was extracted with dichloromethane. The organic layer was washed with water, brine, dried (MgSO4) and concentrated under reduced pressure to leave the subtitle product as a beige solid. Yield 7.5 g. This was used in the next step without further purification.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[N:13]=[C:14]([NH:16][C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])[S:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:22]=1.Cl[C:24](Cl)([O:26]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[Br:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3[N:13]=[C:14]([N:16]4[C:17]([CH3:20])([CH3:21])[CH2:18][NH:19][C:24]4=[O:26])[S:15][C:11]=3[CH2:10][CH2:9][O:8][C:7]=2[CH:22]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(CN)Nc1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: Br
Solvent: C1CCOC1
Product: CC1(C)CNC(=O)N1c1nc2c(s1)CCOc1cc(Br)ccc1-2
Yield: 51 %

Procedure:
Following the Example 356, N2-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-2-methylpropane-1,2-diamine hydrobromide was reacted with triphosgene in tetrahydrofuran and purified on silicagel column eluting with 50% of ethyl acetate in heptane to give 1-(8-bromo-4,5-dihydrothiazolo[4,5-d]benzo[b]oxepin-2-yl)-5,5-dimethylimidazolidin-2-one. Yield 51%. MS(ESI+): 393.9
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=1[O:30][CH2:31][CH2:32][CH2:33]Cl.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CO.C(O)CCC>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:24]3[C:25]([Cl:29])=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])[CH2:11][CH2:10]2)=[CH:20][CH:19]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)C2CCNCC2)cc1
Reactant: ClCCCOc1c(Cl)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CCCCO
Product: Fc1ccc(C(c2ccc(F)cc2)C2CCN(CCCOc3c(Cl)cccc3Cl)CC2)cc1

Procedure:
A mixture of 4-[bis(4-fluorophenyl)methyl]piperidine (free base 6.90 g, 0.024 mole), 1,3-dichloro-2-(3-chloropropoxy)benzene (5.72 g, 0.024 mole), and potassium carbonate (5.54 g, 0.04 mole) was heated overnight at gentle reflux in 350 m l of 1-butanol containing potassium iodide (0.2 g). The reaction was concentrated to dryness. The residue was partitioned several times between chloroform and water. The chloroform layer was dried, filtered, and solvent removed to give an oil. The oil was placed in the refrigerator overnight in 50 ml of methanol. A white solid was obtained and dried in vacuo overnight at 80° C. A yield of 3.26 g (27.7%) of white, crystalline solid, m.p. 101.5°-103° C., was obtained.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH:2]=[CH2:3].[OH:13]NC(=O)OC(C)(C)C.[H-].[Na+].C(Br)C=C.ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[O:13]1[CH2:3][CH:2]1[CH2:1][O:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NO
Reactant: C=CCONC(=O)OC(C)(C)C
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: C=CCBr
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NOCC1CO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62 %

Procedure:
According to (16-1) described in Reference Example 16, 659 mg (3.80 mmol) of tert-butyl N-(allyloxy)carbamate prepared from tert-butyl N-hydroxycarbamate, sodium hydride and allyl bromide was dissolved in 10 ml of dichloromethane, and the thus prepared solution was mixed with 886 mg (4.67 mmol) of m-chloroperbenzoic acid and stirred at room temperature for 24 hours. The reaction solution was filtered, mixed with a 1 N sodium hydroxide aqueous solution and extracted with chloroform. The chloroform layer was washed with saturated brine and dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to obtain 447 mg (yield, 62%) of tert-butyl N-(2,3-epoxypropoxy)carbamate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[O:13].[CH:30]1([NH2:34])[CH2:33][CH2:32][CH2:31]1>CC(N(C)C)=O>[CH:30]1([NH:34][C:2]2[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=2[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[CH2:33][CH2:32][CH2:31]1
Reactant: CS(=O)(=O)c1ccc(I)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Reactant: NC1CCC1
Solvent: CC(=O)N(C)C
Product: CS(=O)(=O)c1ccc(NC2CCC2)c(C(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)c1
Yield: 54 %

Procedure:
A solution of (2-Iodo-5-methanesulfonyl-phenyl)-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-methanone (compound CK, 0.05 g, 0.09 mmol) and of cyclobutylamine (0.1 ml) in dimethylacetamide was heated in a microwave oven (180 deg) for 10 min before being concentrated in vacuo. The residue was disolve in ethyl acetate, washed with water dried over sodiumsulfate, filtered and concentrated. The residue was purified by column chromatography (SiO2, 5 g, Heptane/EtOAc 0-50%) to give the title compound as a white foam (24 mg, 54%). MS (m/e): 482.5 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[CH3:28])[CH2:9]/[C:10](/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[N:11]\[OH:12])=[CH:4][CH:3]=1.[CH3:29][S:30]([NH:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)(=[O:32])=[O:31]>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([CH:8]([C:5]2[CH:4]=[CH:3][C:2]([C:37]3[CH:38]=[CH:39][C:34]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:35][CH:36]=3)=[CH:7][CH:6]=2)[CH2:9]/[C:10](=[N:11]\[OH:12])/[C:13]2[CH:14]=[CH:15][C:16](=[O:20])[N:17]([CH3:19])[CH:18]=2)=[C:22]([CH3:28])[CH:23]=1
Reactant: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(Br)cc1
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Product: Cc1cc(Cl)ccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(-c2ccc(NS(C)(=O)=O)cc2)cc1

Procedure:
The title compound was prepared in analogy to example 166, from (+)-5-{3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-[(E)-hydroxyimino]-propyl}-1-methyl-1H-pyridin-2-one (example 415) and 4-(methanesulfonylamino)phenylboronic acid (CAS RN 380430-57-9). The compound was purified by silica gel chromatography on a 20 g column using a MPLC system eluting with a gradient of dichloromethane:methanol (100:0 to 90:10). Light brown foam. MS (ESI+): m/z=550.2 ([M+H]+).
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]([CH3:30])[C:6]2[C:11]([N:12]=1)=[C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:9]=[C:8]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH2:28][CH3:29])[N:7]=2.[CH3:31][S:32]([N:35]1[CH2:40][C@@H:39]([CH3:41])[NH:38][C@@H:37]([CH3:42])[CH2:36]1)(=[O:34])=[O:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:42][C@@H:37]1[CH2:36][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:40][C@H:39]([CH3:41])[N:38]1[CH2:3][C:4]1[N:5]([CH3:30])[C:6]2[C:11]([N:12]=1)=[C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:9]=[C:8]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH2:28][CH3:29])[N:7]=2
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3[C@H](C)CN(S(C)(=O)=O)C[C@@H]3C)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine hydrobromide (200 mg, 0.37 mmol), (3S,5R)-1-methanesulfonyl-3,5-dimethylpiperazine (88 mg, 0.46 mmol) and K2CO3 (150 mg, 1.09 mmol) in DMF (1 mL) was allowed to stir at r.t. for 24 h. The reaction mixture was partitioned between EtOAc and H2O, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) followed by recrystallisation from EtOAc affording 737 (57 mg, 28%). LCMS (method I): RT 3.05 min, [M+H]+ 568.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (1 H, m), 7.76-7.75 (1 H, m), 7.26-7.25 (2 H, m), 4.34 (4 H, s), 4.18 (2 H, s), 3.87 (4 H, t, J=4.70 Hz), 3.84 (3 H, s), 3.54-3.51 (2 H, m), 3.35 (2 H, q, J=7.48 Hz), 3.29-3.23 (2 H, m), 2.80 (3 H, s), 2.68-2.66 (2 H, m), 1.45 (3 H, dd, J=7.69, 7.26 Hz), 1.17 (6 H, d, J=6.36 Hz)
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][C:20]([F:29])=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[Cl:28])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:30][NH2:31]>>[F:29][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][CH:13]([CH2:12][NH:31][CH3:30])[O:14][C:15]=2[C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:28]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3ccc(F)c(-c4ccccc4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2ccc(F)c(-c3ccccc3Cl)c2O1

Procedure:
The title compound was prepared (0.12 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[6-fluoro-7-(2-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.4 g, 0.92 mmol) and methylamine (0.55 g, 17.7 mmol). mp 170-173° C.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].C(N(CC)CC)C.[C:14]1([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([NH2:37])=[N:27][CH:28]=[C:29]([C:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=4)[N:30]=3)[N:21]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH2:1]([S:3]([N:34]1[CH2:35][CH:36]=[C:31]([C:29]2[N:30]=[C:25]([C:22]3[N:21]=[C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[O:24][N:23]=3)[C:26]([NH2:37])=[N:27][CH:28]=2)[CH2:32][CH2:33]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ncc(C2=CCNCC2)nc1-c1noc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N1CC=C(c2cnc(N)c(-c3noc(-c4ccccc4)n3)n2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
Ethanesulfonyl chloride (62.13 mg, 45.78 μL, 0.4832 mmol) and triethyl amine (122.2 mg, 168.3 μL, 1.208 mmol) were added to a solution of 3-(5-phenyl-1,2,4-oxadiazol-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-amine (129 mg, 0.4027 mmol) in dichloromethane (5 mL) at 0° C. and the resulting solution stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, and freeze-dried. The solid was taken up in dichloromethane (5 mL) and washed with saturated aqueous NaHCO3 solution (2×5 mL), dried over MgSO4 and concentrated in vacuo to leave the product (65 mg, 40% yield) 1H NMR (400 MHz, DMSO) d 1.24 (t, 3H), 2.68 (m, 2H), 3.13 (q, 2H), 3.48 (m, 2H), 3.99 (m, 2H), 6.63 (m, 1H), 7.29 (br s, 2H), 7.68 (m, 2H), 7.77 (m, 1H), 8.26 (m, 2H) and 8.52 (1H, s) ppm; MS (ES+) 412.97