Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(=O)C.[NH2:5][C:6]1[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[Cl:16][O-].[Ca+2].Cl[O-]>ClCCl>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccccc1N
Reactant: [O-]Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)ccc1N
Temperature: 0 °C
Reaction time: 6 h
Yield: 65.2 %

Procedure:
1 liter of glacial acetic acid and 10 liters of ice-water are added to a solution of 2.0 kg of methyl 2-aminobenzoate in 15 liters of dichloromethane. 1.9 kg of calcium hypochlorite are added at 10° with vigorous stirring, during which the temperature should not rise above 15°. The mixture is stirred for a further 6 hours and left to stand for 16 hours. The dichloromethane is separated off, the aqueous phase is washed with dichloromethane, and the combined organic phases are washed with a 10% Na2SO3 solution (warming!). The combined dichloromethane phases are stirred with 2 kg of silica gel, 200 g of activated carbon and 2 kg of sodium sulfate. The phases are separated, the dichloromethane is removed, 10 liters of nhexane are added, the mixture is left to stand at 0-5° for 16 hours, and the product is separated off, giving 1.6 kg of methyl 2-amino-5-chlorobenzoate (“1”).
Reaction SMILES: Cl.Cl.Cl.Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1.[H-].[Na+].Br[CH:43]([CH3:45])[CH3:44].O>CN(C)C=O>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]([N:34]2[CH2:39][CH2:38][N:37]([CH:43]([CH3:45])[CH3:44])[CH2:36][CH2:35]2)[CH2:13][N:14]2[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=[CH:26][CH:25]=3)[CH2:16][CH2:15]2)=[CH:8][CH:7]=1
Reactant: CC(C)Br
Reactant: Fc1ccc(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)N2CCNCC2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Reaction time: 0.17 h
Yield: 78.1 %

Procedure:
0.2 g of 1-[2-(4-Fluorophenyl)-2-piperazinoethyl]-4-(4-naphthalen-1-yl-butyl)piperazine tetrahydrochloride was dissolved in 0.7 ml of dimethylformamide, and 74 mg of 60% sodium hydride in oil was added with ice-cooling. The temperature was elevated to room temperature, followed by stirring for 10 minutes. To the reaction solution was added a 0.3 ml of dimethylformamide solution of 0.2 g of 2-bromopropane, followed by stirring overnight. The reaction solution was poured to water and, after extraction with ethyl acetate, the organic layer was washed with a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=1:1) to give 0.13 g of 1-[2-(4-fluorophenyl)-2-(4-isopropylpiperazino)ethyl]-4-(4-naphthalen-1-yl-butyl)piperazine as an oil.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH2:12][CH2:13][CH3:14])=[O:3].[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>>[CH2:12]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][C:2]([O:18][CH2:17][CH2:16][CH2:15][OH:19])=[O:3])[CH2:13][CH3:14]
Reactant: OCCCO
Reactant: CCCOc1ccccc1OC(=O)Cl
Product: CCCOc1ccccc1OC(=O)OCCCO

Procedure:
The reaction of 2-propoxyphenol chloroformate with 1,3-propanediol yields 1-(2-propoxyphenoxycarbonyloxy)-3-propanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH2:5][C:6]3[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:12]([OH:14])=O)[C:8](=[O:22])[C:7]=3[O:23][C:24]=2[CH:25]=[CH:26][CH:27]=1.[NH2:28][C:29]1[S:30][CH:31]=[CH:32][N:33]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.O>[CH:16]1([CH2:15][C@H:11]([N:9]2[CH2:10][C:6]3[CH2:5][C:4]4[C:3]([O:2][CH3:1])=[CH:27][CH:26]=[CH:25][C:24]=4[O:23][C:7]=3[C:8]2=[O:22])[C:12]([NH:28][C:29]2[S:30][CH:31]=[CH:32][N:33]=2)=[O:14])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)O)C1
Reactant: Nc1nccs1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1cccc2c1CC1=C(O2)C(=O)N([C@@H](CC2CCCCC2)C(=O)Nc2nccs2)C1
Yield: 27.8 %

Procedure:
A solution of (S)-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-3-cyclohexyl-propionic acid (200 mg, 0.54 mmol) (Example 7, Step 2c), commercially available 2-amino-thiazole (66 mg, 0.64 mmol), N-ethyl-N-dimethyaminopropyl carbodiimide hydrochloride (EDCI. HCl) (113 mg, 0.59 mmol), and N-hydroxybenzotriazole (HOBt) (80 mg, 0.59 mmol) in methylene chloride (10 mL) was stirred for 16 hours at 25° C. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting residue, upon silica gel flash chromatography using hexane-ethyl acetate gradient elution, afforded (S)-3-Cyclohexyl-2-(8-methoxy-3-oxo-3,9-dihydro-1H-chromeno[2,3-c]pyrrol-2-yl)-N-thiazol-2-yl-propionamide (68 mg, 27.9%), as an off white solid. 1H NMR (DMSO-d6) δ: 12.56 (br. s., 1H), 7.49 (d, J=3.4 Hz, 1H), 7.11-7.31 (m, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.68 (d, J=8.3 Hz, 1H), 5.05 (d, J=5.4 Hz, 1H), 4.36 (d, J=19.1 Hz, 1H), 4.05 (d, J=18.6 Hz, 1H), 3.82 (s, 3H), 3.55 (br. s., 2H), 1.47-1.89 (m, 7H), 0.78-1.29 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:18][C:19]1([CH3:23])[CH2:22][O:21][CH2:20]1>CS(C)=O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][O:11][CH2:18][C:19]1([CH3:23])[CH2:22][O:21][CH2:20]1)[C:12]([OH:14])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(CBr)COC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)COC1
Reaction time: 1 h
Yield: 63 %

Procedure:
To N-(tert-Butoxycarbonyl)-L-serine (1.2 g, 6.06 mmol) in anhydrous dimethyl sulfoxide (20 mL) at room temperature and under an atmosphere of nitrogen was added sodium hydride (60% in mineral oil, 363 mg, 9.1 mmol) in three portions. The reaction was stirred for 1 h after which was added 3-bromomethyl-3-methyl oxetane (obtained from Fluorochem Ltd., UK), 1 g, 6.06 mmol) and a further amount of sodium hydride (60% in mineral oil, 363 mg, 9.1 mmol). The reaction was stirred for 16 h and quenched by careful addition of water. The solution was washed with diethyl ether (1×) and acidified to pH 2 with 2 M hydrochloric acid. The solution was extracted with ethyl acetate (2×) and the combined organics washed with brine. The organic layer was dried through a hydrophobic frit and concentrated in vacuo to yield the title compound (1.1 g, 63%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 1.30 (s, 3H), 1.48 (s, 9H), 3.50, 3.53 (ABq, J=9.4 Hz, 2H), 3.77 (dd, J=9.4, 3.8 Hz, 1H), 3.98 (dd, J=9.4, 2.9 Hz, 1H), 4.37 (d, J=5.8 Hz, 2H), 4.47-4.55 (m, 1H), 4.57 (d, J=5.8 Hz, 2H), 5.47 (d, J=8.3 Hz, 1H). LCMS (m/z) 289.3 [M+H], Tr=1.67 min.
Reaction SMILES: Cl[C:2]1[C:7](Cl)=[CH:6][N:5]=[N:4][C:3]=1[OH:9].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>>[N:10]1([C:2]2[C:7]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:6][N:5]=[N:4][C:3]=2[OH:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Oc1nncc(Cl)c1Cl
Reactant: C1CCNCC1
Product: Oc1nncc(N2CCCCC2)c1N1CCCCC1
Yield: 75 %

Procedure:
4,5-Dichloro-3-hydroxypyridazine (25.0 g; 0.151 mol) was dissolved in piperidine (120 mol), under reflux condition for 24 hours. After cooling, the deposited crystal was filtered, to give 4,5-dipiperidino-3-hydroxypyridazine in white crystal (30.3 g as a yield of 75%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9].C([BH3-])#N.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([NH:9][NH:8][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C1CCOCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1-dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 2H), 1.39 (s, 9H), 1.43-1.48 (m, 1H), 1.59-1.69 (m, 2H), 2.82-2.98 (m, 1H), 3.20-3.32 (m, 2H), 3.80 (d, J=11.62 Hz, 2H), 4.36 (br. s., 1H), 8.07-8.34 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][NH:11][C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][CH2:32][CH2:33][CH:34]=O.C([BH3-])#N.[Na+].Cl>CO.C(OCC)C>[CH2:1]([O:8][C@H:9]1[C@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:12][N:11]([CH2:31][CH2:32][CH2:33][CH3:34])[C@@H:10]1[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCC=O
Reactant: c1ccc(COC[C@H]2NC[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: CCCCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(2R,3R,4R)-3,4-Dibenzyloxy-2-benzyloxymethylpyrrolidine (Compound 1) (0.7 g, 1.7 mmol) was dissolved in dry methanol. Butyric aldehyde (0.153 ml, 1.7 mmol) and sodium cyanoborohydride (0.107 g, 1.7 mmol) was added. A solution of anhydrous hydrogen chloride in diethylether (2 M) was added dropwise until pH 6. The resulting mixture was stirred for 24 hours at room temperature under a nitrogen atmosphere and evaporated in vacuo. Addition of 1M sodium hydroxide (50 ml), extraction of the product with diethylether (2×50 ml), drying of the organic phases with magnesium sulphate and evaporation of the solvent in vacuo gave the title compound as a crude oil (0.644 g). Purification of the crude product on a silica gel column (Eluent: methylene chloride/methanol (19:1)) afforded (2R,3R,4R)-3,4-dibenzyloxy-2-benzyloxy-methyl-1-butylpyrrolidine (0.243 g, yield: 30%) as an oil.
Reaction SMILES: [CH2:1](O)[C:2]#[CH:3].[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([OH:9])=[O:8].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[Br:5][C:6]([CH3:11])([CH3:10])[C:7]([O:9][CH2:3][C:2]#[CH:1])=[O:8]
Reactant: CC(C)(Br)C(=O)O
Reactant: C#CCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C#CCOC(=O)C(C)(C)Br
Reaction time: 24 h

Procedure:
Propargyl alcohol (12.8 mL, 0.218 mol) and 2-bromoisobutyric acid (36.4 g, 0.218 mol) were dissolved in methylene chloride (150 mL). The reaction mixture was cooled in an ice-water bath and a solution of dicyclohexyl carbodiimide (45.0 g, 0.22 mol) in methylene chloride (50 mL) was slowly added while stirring. A solution of 4-dimethylaminopyridine (1.5 g) in methylene chloride (50 mL) was then added over a period of 10 min. The mixture was stirred in the cooling bath for 1 h and then at room temperature for 24 h. The precipitated dicyclohexylurea was filtered and washed on the filter with methylene chloride (50 mL). The solvent was removed on a rotary evaporator and the product was distilled under vacuum. Yield: 33.0 g (0.161 mol, 74%). 1H NMR spectrum in CDCl3 (δ, ppm): 4.77 (d, 2H, CH2O), 2.51 (t, 1H, C≡CH), and 1.96 (s, 6H, (CH3)2C). IR spectrum (neat liquid, NaCl plates): 3296 cm−1 (ν≡C—H), 2131 cm−1 (νC≡C), and 1741 cm−1 (νC═O).
Reaction SMILES: [NH2:1][C@:2]12[CH2:37][CH2:36][C@@H:35]([C:38]([CH3:40])=[CH2:39])[C@@H:3]1[C@@H:4]1[C@@:17]([CH3:20])([CH2:18][CH2:19]2)[C@@:16]2([CH3:21])[C@@H:7]([C@:8]3([CH3:34])[C@@H:13]([CH2:14][CH2:15]2)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]2[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=2)=[CH:10][CH2:9]3)[CH2:6][CH2:5]1.Cl.[N:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49](O)=[O:50]>>[CH3:20][C@:17]12[C@@:16]3([CH3:21])[C@@H:7]([C@:8]4([CH3:34])[C@@H:13]([CH2:14][CH2:15]3)[C:12]([CH3:23])([CH3:22])[C:11]([C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=3)=[CH:10][CH2:9]4)[CH2:6][CH2:5][C@@H:4]1[C@H:3]1[C@H:35]([C:38]([CH3:40])=[CH2:39])[CH2:36][CH2:37][C@:2]1([NH:1][C:49](=[O:50])[CH2:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][N:42]=1)[CH2:19][CH2:18]2
Reactant: C=C(C)[C@@H]1CC[C@]2(N)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C(O)Cc1ccccn1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NC(=O)Cc3ccccn3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared from methyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-amino-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate following the general procedure described for the parallel synthesis of C-17 amides above, using 2-pyridylacetic acid hydrochloride as the reacting carboxylic acid. LCMS: m/e 649.6 (M+H)+, 4.23 min (method 3).
Reaction SMILES: N[C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.S(=O)(=O)(O)[OH:16].N([O-])=O.[Na+]>O>[OH:16][C:2]1[C:3]([C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1
Reactant: O=S(=O)(O)O
Reactant: COC(=O)c1cc2c(cc1N)OCO2
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc2c(cc1O)OCO2

Procedure:
A mixture of methyl 6-amino-1,3-benzodioxole-5-carboxylate (6.3 g, 32 mmol), concentrated sulfuric acid (7 mL) and water (35 mL) was cooled in an ice-bath and then a mixture of sodium nitrite (2.3 g, 33 mmol) and water (15 mL) was added. The mixture was diluted with 50 mL of water and added to a boiling solution of cupric sulfate pentahydrate (35 g, 140 mmol) and water (75 mL). The mixture was heated 10 minutes at boiling and then cooled in an ice-bath and extracted with diethyl ether (3×). The combined extracts were washed with water (4×) and brine (1×), dried. (K2CO3) and concentrated. The residue was purified by column chromatography eluting with hexane/ethyl acetate (98:2-97:3) to give methyl 6-hydroxy-1,3-benzodioxole-5-carboxylate (2.7 g, 14 mmol), m.p. 100°-101° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)=[O:5].[OH:18][CH2:19][CH2:20][O:21][C:22]1[C:29]([CH3:30])=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[CH3:31]>C(O)C.[Cu](Cl)Cl>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:1]=[C:26]2[C:25]2[CH:28]=[C:29]([CH3:30])[C:22]([O:21][CH2:20][CH2:19][OH:18])=[C:23]([CH3:31])[CH:24]=2)=[CH:8][CH:9]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Agent: Cl[Cu]Cl
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)cc(C)c1OCCO
Temperature: 25 °C

Procedure:
To a solution of 2-amino-N-(4-bromo-phenyl)-benzamide (3.75 g, 12.9 mmol) and 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (D) (2.50 g, 12.9 mmol) in anhydrous ethanol (75 mL) was added anhydrous copper (II) chloride (5.19 g, 38.6 mmol). The reaction mixture was stirred under reflux for 16 hours under nitrogen, then cooled to room temperature. The ethanol was evaporated under reduced pressure. The residue was taken in dichloromethane (300 mL) and the organic phase was washed with water (200 mL). The aqueous phase was then extracted with CH2Cl2 (2×200 mL). The combined organic phase was washed with brine (200 mL) and dried over anhydrous Na2SO4. The solvent was evaporated. The crude compound was purified by column chromatography (silica gel 230-400 mesh; 30-50% ethyl acetate in hexanes as eluent) to give the title compound (K) as white solid. Yield: 3.84 g (64%). MP 164-165° C. 1H-NMR (400 MHz, DMSO-d6): δ 8.33 (d, J=7.80 Hz, 1H), 7.82-7.80 (m, 2H), 7.55-7.45 (m, 3H), 7.04 (d, J=8.58 Hz, 2H), 6.98 (s, 2H), 3.94-3.90 (m, 2H), 3.82 (t, J=4.68 Hz, 2H), 2.17 (s, 6H), 2.13 (t, J=3.51 Hz, 1H). MS (ES+) m/z: 465.42 (97%) (M+1), 467.43 (100%) (M+3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15]I)[O:11][CH:12]=2)=[CH:4][CH:3]=1.[C:17]1([O:24][CH3:25])[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][CH2:14][CH2:15][O:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[O:24][CH3:25])[O:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2coc(CCCI)n2)cc1
Reactant: COc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccccc1OCCCc1nc(-c2ccc(Cl)cc2)co1
Reaction time: 0.5 h
Yield: 90 %

Procedure:
A mixture of 4-(4-chlorophenyl)-2-(3-iodopropyl)oxazole (0.5 g), guaiacol (0.19 ml), potassium carbonate (0.24 g) and N,N-dimethylformamide (5 ml) was stirred for 30 minutes at 60 ° to 65° C. and poured into water. precipitated crystals were collected by filtration to obtain 4-(4-chlorophenyl)-2-[3-(2-methoxyphenoxy) propyl]oxazole (0.445 g, 90%). Recrystallization from ether-hexane gave colorless prisms of mp 94°-95° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:7][C:6]=2[CH:19]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][N:29]=2)[CH:24]=[CH:23][N:22]=1>C(O)C>[CH3:33][C:31]1[NH:30][N:29]=[C:28]([NH:27][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[S:9][C:8]([NH:10][C:11](=[O:18])[C:12]5[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=5)=[N:7][C:6]=4[CH:19]=3)[N:26]=2)[CH:32]=1
Reactant: Nc1ccc2sc(NC(=O)c3ccccc3)nc2c1
Reactant: Cc1cc(Nc2ccnc(Cl)n2)n[nH]1
Solvent: CCO
Product: Cc1cc(Nc2ccnc(Nc3ccc4sc(NC(=O)c5ccccc5)nc4c3)n2)n[nH]1

Procedure:
N-{5-[4-(5-Methylpyrazol-3-ylamino)pyrimidin-2-ylamino]benzothiazol-2-yl}benzamide was prepared by beating a mixture of N-(5-aminobenzothiazol-2-yl)benzamide (IM 5, 35 mg, 0.13 mmol) and (2-chloropyrimidin-4-yl)-(5-methylpyrazol-3-yl)amine (IM 11, 30 mg, 0.143 mmol) in ethanol (3 mL) to 80° C. for 9 h. The precipitate was separated by filtration, washed with ethanol and dried (32 mg, 72 μmol, 56%) LC/ESI-MS: m/z=443 [M+H]+; m/z 441 [M−H]−; Rt=2.92 min.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([C@@H:9]2[NH:13][C:12](=[O:14])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.I[C:18]1[CH:31]=[CH:30][C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][C:21]2[CH:30]=[CH:31][C:18]([N:13]3[C@@H:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:15])[F:16])[CH:4]=4)[CH2:10][CH2:11][C:12]3=[O:14])=[CH:19][CH:20]=2)=[CH:24][CH:25]=1
Reactant: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1
Reactant: Clc1ccc(Oc2ccc(I)cc2)cc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 110 °C

Procedure:
To a 10 mL reaction tube fitted with a screw cap is charged with (R)-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one (90 mg, 0.39 mmol) and 1,4-dioxane (3 mL). 1-(4-iodophenoxy)-4-chlorobenzene (157 mg, 0.47 mmol) is then added, followed by copper iodide (15 mg, 0.078 mmol), N,N′-1,2-trans-dimethylcyclohexane-1,2-diamine (11.2 mg, 0.078 mmol), and K3PO4 (167 mg, 0.78 mmol). The system is degassed with argon then sealed and heated to 110° C. for 28 h. The reaction is cooled to room temperature, dissolved in ethyl acetate and washed with water and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. Purification on silica gel (0-30% ethyl acetate in hexane) gave (R)-1-[4-(4-chlorophenoxy)phenyl]-5-[3-(trifluoromethyl)phenyl]pyrrolidin-2-one as a slightly yellow oil (102 mg, 60%). 1H NMR (CDCl3) δ (ppm) 7.60-7.50 (m, 1H), 7.49-7.37 (m, 3H), 7.34-7.28 (m, 2H), 7.27-7.21 (m, 2H), 6.91-6.67 (m, 4H), 5.28 (dd, J=6.8, 5.6 Hz, 1H), 2.84-2.59 (m, 3H), 2.07-1.94 (m, 1H). HPLC-MS calculated for C23H17ClF3NO2 (M+H+) 432.09, found 432.10.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C[Al](C)C.[C:10]([O:14][C:15]([C@:17]12[C@@H:22]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C@H:21]1[CH2:20][O:19][C:18]2=[O:29])=[O:16])([CH3:13])([CH3:12])[CH3:11].Cl>ClCCl>[C:10]([O:14][C:15]([C@:17]1([C:18](=[O:29])[N:3]([O:4][CH3:5])[CH3:2])[C@@H:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:21]1[CH2:20][OH:19])=[O:16])([CH3:12])([CH3:11])[CH3:13]
Reactant: CC(C)(C)OC(=O)[C@@]12C(=O)OC[C@@H]1[C@@H]2c1ccccc1
Reactant: CNOC
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)[C@]1(C(=O)OC(C)(C)C)[C@H](CO)[C@@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 86 %

Procedure:
In a 100 mL round-bottomed flask, a solution of N,O-dimethyl hydroxylamine HCl was suspended in 20 mL of dichloromethane. After cooling to 0° C., trimethyl aluminum (2 M in toluene. 3.83 mL, 7.66 mmol) was added dropwise and the mixture was stirred at 0° C. for 45 min. A solution of the previously described (1R*,5R*,6R*)-2-oxo-6-phenyl-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid tert-butyl ester (0.3 g, 1 mmol) in 10 mL of dichloromethane was added dropwise to the cooled stirring solution. After stirring at 0° C. for 5 min, the reaction mixture was warmed to room temperature and stirred for 3 hours. After the reaction was completed, the reaction mixture was again cooled in an ice bath and acidified with 10 mL of 1N HCl, extracted with dichloromethane (×3), dried over MgSO4 and concentrated to afford 0.32 g (86%) of the desired product as a clear oil.
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].C(N(S(F)(F)[F:28])CC)C.O>C(Cl)Cl>[F:28][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution of 12.1 g (0.04 mol) of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one in 25 ml of anhydrous methylene chloride was added dropwise over a period of 15 min. to a stirred solution of 12.6 ml (0.1 mol) of diethylaminosulfur trifluoride in 300 ml of anhydrous methylene chloride cooled to -70°. The reaction mixture was allowed to warm slowly over a period of 45 min. to 5° and then poured into 500 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to give 10.9 g (90% yield) of crude product as a light yellow solid residue. Recrystallization from heptane gave 8.48 g (70% yield) of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 138°-140°; 19F nmr (CCl3D) δ -161.7 ppm (d, J = 57 Hz); 1H nmr (CCl3D) δ 3.43 ppm (s, 3H), 5.54 ppm (d, J = 57 Hz, 1H), 7.5 ppm (m, 8H).