Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[NH:24][CH:23]=[CH:22]5)[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:30]I>CN(C=O)C.ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([O:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([CH3:30])[CH:23]=[CH:22]5)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CI
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(Oc2ccc3[nH]ccc3c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc2cc(OC3CN(C(=O)N4CCCN(C5CCC5)CC4)C3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
To a stirred solution of 5-({1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}oxy)-1H-indole (30 mg, 81 μmol) in DMF (2 ml) was added NaH (4 mg of a 60% dispersion in mineral oil, 97 μmol) at room temperature in one portion. The suspension was stirred for 30 min at room temperature under a nitrogen atmosphere then cooled to 0° C. and MeI (6 μl, 97 μmol) was added. The reaction was allowed to warm to room temperature and stirred for 16 hours then diluted with dichloromethane (30 ml) and washed twice with saturated NaHCO3 (15 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by FCC (DCM/MeOH/NH3 with gradient, 98:2:1 to 90:10:1) to provide the title compound (23 mg, 74%) as light brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9](Cl)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]([NH:24][C:23]2[CH:22]=[CH:21][C:20]([N:17]3[CH2:16][CH2:15][N:14]([CH3:13])[CH2:19][CH2:18]3)=[CH:26][CH:25]=2)[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5]
Reactant: NC(=O)c1cc(F)c(Cl)nc1Cl
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc(Nc3nc(Cl)c(C(N)=O)cc3F)cc2)CC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 32.8 %

Procedure:
To a mixture of 2,6-dichloro-5-fluoronicotinamide (1 g, 4.78 mmol) and 4-(4-methylpiperazin-1-yl)aniline (1.007 g, 5.26 mmol) in THF (30 mL) was added lithium bis(trimethylsilyl)amide (16.75 mL, 16.75 mmol) portionwise at −78° C. The mixture was stirred at −78° C. for 20 min and then removed from the dry ice bath. Next, the mixture was stirred at rt for 30 min. Two isomeric products were formed. The reaction mixture was quenched with water, extracted with ethyl acetate twice, washed the combined organic with water, and concentrated. The dark brown residue was triturated with methylene chloride, to give 570 mg of 2-chloro-5-fluoro-6-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as light brown solid. The mother liquor was concentrated and triturated again with methylene chloride to give 540 mg of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as brown solid. The mother liquor was purified twice by mPLC (ISCO, 7% ammonia/methanol/methylene chloride, 40 g+12 g stacked columns) to give an additional 490 mg of 6-chloro-5-fluoro-2-(4-(4-methylpiperazin-1-yl)phenylamino)nicotinamide as brown solid.
Reaction SMILES: C[O:2][C:3]1[C:8]([CH3:9])=[CH:7][C:6]([N+:10]([O-:12])=[O:11])=[C:5]([CH3:13])[N:4]=1>Cl>[CH3:9][C:8]1[C:3]([OH:2])=[N:4][C:5]([CH3:13])=[C:6]([N+:10]([O-:12])=[O:11])[CH:7]=1
Reactant: COc1nc(C)c([N+](=O)[O-])cc1C
Agent: Cl
Product: Cc1cc([N+](=O)[O-])c(C)nc1O
Temperature: 110 °C
Yield: 91.5 %

Procedure:
A solution of 2-methoxy-3,6-dimethyl-5-nitropyridine (32.3 g, 182 mmol) in 12 N hydrochloric acid (300 mL) was heated at 100° C. for 1 h. Analysis by TLC indicated that some starting material remained, so the reaction was heated at 110° C. for an additional 45 min. The reaction mixture was cooled to room temperature and poured onto ice (400 g). When the ice had melted and the temperature of the resulting thick brown suspension was still less than 0° C., the mixture was filtered. The solid cake was washed with water (100 mL) and allowed to dry on the filter for 30 min. The solid was then resuspended in cold (−10° C.) ethanol (150 mL), filtered, washed with cold ethanol (50 mL), and air-dried on the filter for 1 h to afford 3,6-dimethyl-5-nitropyridin-2-ol (28.0 g, 94% yield) as a tan powder: mp 263° C.; 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s br, 1H), 8.03 (s, 1H), 2.61 (s, 3H), 2.01 (s, 3H); LRMS (ESI) m/e 169.3 [(M+H)+, calcd for C7H9N2O3 169.1]. Anal. calcd. for C7H8N2O3: C, 50.00; H, 4.79; N, 16.66. Found: C, 50.01; H, 4.59; N, 16.75.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH2:18][CH3:19])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:5]([CH3:11])=[N:6][C:7]=1[NH:8][CH2:9][CH3:10].[C:20](O)(=O)[CH3:21]>>[CH3:10][C:9]1[N:8]([CH2:20][CH3:21])[C:7]2=[N:6][C:5]([CH3:11])=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]([O:17][CH2:18][CH3:19])=[C:2]2[N:1]=1
Reactant: CCNc1nc(C)c(C(=O)OCC)c(OCC)c1N
Reactant: CC(=O)O
Product: CCOC(=O)c1c(C)nc2c(nc(C)n2CC)c1OCC

Procedure:
Crude 5-amino-4-ethoxy-6-ethylamino-2-methylpyridine-3-carboxylic acid, ethyl ester is refluxed in acetic acid overnight. The solvent is distilled off and the residue, 2,5-dimethyl-7-ethoxy-3-ethyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester is recrystallized from petroleum ether, m.p. 62°-65° .
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[N:12]([S:15]([O:18][C:19]1[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=1[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])(=[O:17])=[O:16])=[C:13]=[O:14]>ClCCl>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:13](=[O:14])[NH:12][S:15]([O:18][C:19]2[CH:30]=[CH:29][CH:28]=[CH:27][C:20]=2[C:21]([O:23][CH2:24][CH:25]=[CH2:26])=[O:22])(=[O:17])=[O:16])[N:7]=1
Reactant: C=CCOC(=O)c1ccccc1OS(=O)(=O)N=C=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: ClCCl
Product: C=CCOC(=O)c1ccccc1OS(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1.55 g (0.01 mole) of 2-amino-4,6-dimethoxypyrimidine are dissolved in 100 ml of dichloromethane, and 3.40 g (0.012 mole) of allyl 2-isocyanatosulfonyloxybenzoate, dissolved in 20 ml of dichloromethane, are added at 0° C. The mixture is stirred at room temperature for 18 hours and filtered off with suction, and 2.54 g (58% of theory) of allyl 2-[3-(4,6-dimethoxypyrimidin-2-yl)ureidosulfonyloxy]-benzoate of melting point 110°-112° C. are obtained.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12]>CCOCC>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11](=[NH:12])[O:6][CH:3]([CH2:4][CH3:5])[CH2:2][CH3:1]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(CC)OC(=N)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 68.8 %

Procedure:
3-Pentyl trichloroacetimidate was prepared as follows. Under an atmosphere of nitrogen, a solution of 3-pentanol (8.815 g, 100 mmol) in anhydrous Et2O (14 mL) was added dropwise to NaH (0.4 g, 10 mmol, 60% oil dispersion prewashed with hexane) suspended in Et2O (10 mL). The mixture was stirred for 10 min at room temperature, and added dropwise over a period of 20 min to a cold (−5° C.) solution of trichloroacetonitrile (15 mL, 150 mmol) in Et2O (20 mL) under an atmosphere of nitrogen. The reaction mixture was warmed to room temperature, and stirred for 2 h. After removal of solvent, the residue was triturated with MeOH/hexane (1:19, 10 mL) with vigorous stirring for 1 min to give precipitates, which were filtered off and washed with cold hexane. The filtrate was evaporated under reduced pressure to dryness, giving 3-pentyl trichloroacetimidate (16 g, 70% yield) as light brown oil. TLC (EtOAc/hexane, 1:4) Rf=0.3; 1H NMR (600 MHz, CDCl3) δ 8.17 (1 H, br s, NH), 4.89 (1 H, m, J=6.0 Hz), 1.69 (4 H, qd, J=7.4, 6.0 Hz), 0.94 (6 H, t, J=7.4 Hz); 13C NMR (150 MHz, CDCl3) δ 162.7, 92.2, 81.9, 25.7 (2×), 9.4 (2×); HRMS calcd for C7H13Cl3NO (M++H): 232.0063, found: m/z 232.0067. Under an atmosphere of nitrogen, the freshly prepared 3-pentyl trichloroacetimidate (350 mg, 1.5 mmol) and CF3SO3H (13 μL, 0.15 mmol) were added to a solution of alcohol 10a (321 mg, 1.2 mmol) in CH2Cl2 (15 mL). The reaction mixture was stirred at room temperature for 24 h, during which more imidate and CF3SO3H (350 mg and 13 μL mmol) were added 5 times every 4 h period. The reaction was quenched with aqueous NaHCO3 solution (5%). The aqueous layer was extracted with CH2Cl2 (2×). The combined organic phase was washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/hexane, 3:7) to afford the alkylation product 11a (317 mg, 78% yield). Colorless solid, mp 115-117° C.; TLC (EtOAc/hexane, 1:1) Rf=0.4; [α]D20=−48.9 (c=1.1, CHCl3); IR (neat) 2101, 1712, 1655 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.75 (1 H, s), 5.98 (1 H, d, J=7.4 Hz), 4.53 (1 H, d, J=5.0 Hz), 4.51-4.16 (3 H, m), 3.33-3.28 (2 H, m), 2.82 (1 H, dd, J=17.6, 5.6 Hz), 2.22-2.16 (1 H, m), 2.00 (3 H, s), 1.49-1.45 (4 H, m), 1.25 (3 H, t, J=7.1 Hz), 0.95-0.80 (6 H, m); 13C NMR (150 MHz, CDCl3) δ 171.1, 165.8, 137.9, 128.1, 82.0, 73.4, 61.0, 58.0, 57.2, 30.5, 26.2, 25.6, 23.5, 14.1, 9.5, 9.3; HRMS calcd for C16H27N4O4(M++H): 3390.2032, found: m/z 339.2035.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:7][C:8]1[C:9](F)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=2[CH3:40])=[C:19]([CH3:41])[CH:18]=1.O>CS(C)=O>[Cl:7][C:8]1[C:9]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]([CH3:29])[C:27](=[O:30])[N:26]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[C:25](=[O:39])[C:24]=3[CH3:40])=[C:19]([CH3:41])[CH:18]=2)=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: Fc1cnc(F)c(Cl)c1
Reactant: Cc1cc(O)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Oc2ncc(F)cc2Cl)ccc1-c1c(C)c(=O)n(COCC[Si](C)(C)C)c(=O)n1C
Temperature: 80 °C
Reaction time: 6 h

Procedure:
Cesium carbonate (476 mg, 1.46 mmol) was added to a mixture of 3-chloro-2,5-difluoropyridine (97%, 150 mg, 0.97 mmol) and C5 (366 mg, 0.972 mmol) in dimethyl sulfoxide (5 mL), and the reaction mixture was stirred at 80° C. for 6 hours. Water was added, and the mixture was extracted three times with ethyl acetate; the combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 10% to 40% ethyl acetate in heptane) provided the product as a sticky solid. Yield: 414 mg, 0.818 mmol, 84%. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=2.7 Hz, 1H), 7.64 (dd, J=7.1, 2.7 Hz, 1H), 7.09-7.15 (m, 3H), 5.51 (AB quartet, JAB=9.3 Hz, ΔνAB=3.4 Hz, 2H), 3.74-3.80 (m, 2H), 3.07 (5, 3H), 2.19 (5, 3H), 1.69 (5, 3H), 1.00-1.06 (m, 2H), 0.03 (5, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>ClCCl>[C:21]1([S:27]([NH:1][C:2]2[CH:20]=[CH:19][C:5]([C:6]([N:8]3[C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[CH2:12][CH2:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][CH:3]=2)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2)cc1)N1CCCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.50 g), phenylsulfonyl chloride (0.29 ml), triethylamine (0.32 ml) and dichloromethane (30 ml) is stirred at room temperature overnight. The reaction mixture is washed successively with water and saturated saline solution, and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from methanol/diethyl ether to give 1-(4-phenylsulfonylaminobenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (0.27 g) as colorless prisms, m.p. 178°-182.5° C.
Reaction SMILES: [CH3:1][C:2]1[NH:13][C:12]2[C:7](=[CH:8][C:9]([O:14][CH3:15])=[CH:10][CH:11]=2)[C:3]=1[CH2:4][CH2:5][NH2:6].[CH3:16][C:17](OC(C)=O)=[O:18]>C1COCC1>[CH3:1][C:2]1[NH:13][C:12]2[CH:11]=[CH:10][C:9]([O:14][CH3:15])=[CH:8][C:7]=2[C:3]=1[CH2:4][CH2:5][NH:6][C:17]([CH3:16])=[O:18]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc2[nH]c(C)c(CCN)c2c1
Solvent: C1CCOC1
Product: COc1ccc2[nH]c(C)c(CCNC(C)=O)c2c1
Reaction time: 8 h

Procedure:
To a cold solution in THF (15 mL) of the crude 2-methyl-5-methoxytryptamine, from the step above, TEA (0.7 mL) and 0.47 mL of Ac2O were added. The ice bath was removed and the solution stirred for 8 h. The solvent was evaporated in vacuo, the residue was taken up in ethyl acetate and washed with a saturated aqueous solution of NaHCO3 followed by saturated NaCl solution. The organic phase was dried (Na2SO4), concentrated under vacuum and the crude oil residue was purified by flash chromatography (silica gel; ethyl acetate-cyclohexane, 7:3) and crystallization. The overall yield of 4a was 0.541 g (44%); mp 122° C.; 1H NMR data were identical with that reported in literature (Flaugh et at., J. Med. Chem. 22, 63-67 (1979).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:24])[OH:23])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26].[C:45]([CH:47](O)[C:48](Cl)([Cl:50])[Cl:49])#[N:46]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:16][C:17]1([CH3:44])[C@@H:19](/[CH:20]=[CH:21]\[C:22](=[O:23])[O:24][C:47]([C:45]#[N:46])=[C:48]([Cl:50])[Cl:49])[C@H:18]1[C:25]([O:27][C@H:28]([C:42]#[N:43])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=1)=[O:26]
Reactant: N#CC(O)C(Cl)(Cl)Cl
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)OC(C#N)=C(Cl)Cl
Temperature: 20 °C
Reaction time: 2 h
Yield: 37.6 %

Procedure:
140 mg of 4-dimethlaminopyridine and then 1.76 g of dicyclohexylcarbodiimide were added at 0° C. to a mixture of 3.36 g (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-hydroxy-1-propenyl]-cyclopropane-carboxylate, 1.7 g of chloral cyanohydrin and 16 ml of methylene chloride and the mixture was stirred at 20° C. for 21/2 hours and was then evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with an 85-15 cyclohexane-ethyl acetate mixture to obtain 1.65 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis,Z) 2,2-dimethyl-3-[3-oxo-3-(2,2-dichloro-1-cyanovinyloxy)-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+40° (c=0.3% in chloroform).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[N:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1>C(O)(C)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:5]=[C:4]([NH2:14])[N:3]=2)=[CH:18][CH:17]=1
Reactant: Fc1ccc(S)cc1
Reactant: Nc1nc(Cl)cc(-c2ccccc2)n1
Solvent: CC(C)O
Product: Nc1nc(Sc2ccc(F)cc2)cc(-c2ccccc2)n1
Yield: 64 %

Procedure:
4-(4-Fluoro-phenylsulfanyl)-6-phenyl-pyrimidin-2-ylamine was prepared from 4-Chloro-6-phenyl-pyrimidin-2-ylamine (0.5 g, 2.44 mmol) using 4-fluorothiophenol (0.31 mg, 2.44 mmol) in iso-propanol (15 mL) at 80° C. for 6 hours. Yield: 64%.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:24]=[CH:25][C:26]=1[CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:12]=1)=[O:9].C(=O)([O-])[O-].[K+].[K+].[CH3:38][CH:39]1[O:44][CH:43]([CH3:45])[CH2:42][NH:41][CH2:40]1>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:10][C:8](=[O:9])[C:7]2[CH:24]=[CH:25][C:26]([CH2:27][S:28]([CH3:31])(=[O:30])=[O:29])=[C:5]([O:4][CH2:3][CH2:2][N:41]3[CH2:40][CH:39]([CH3:38])[O:44][CH:43]([CH3:45])[CH2:42]3)[CH:6]=2)=[CH:12][C:13]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1OCCBr
Reactant: CC1CNCC(C)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1CN(CCOc2cc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)ccc2CS(C)(=O)=O)CC(C)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
3-(2-Bromoethoxy)-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide (50 mg, 0.095 mmol) was dissolved in DMF (1.0 ml) and treated with potassium carbonate (18 mg, 0.13 mmol) and 2,6-dimethylmorpholine (14 μl, 0.11 mmol), and stirred at room temperature for 18 hours. The reaction was quenched in 5% NaOH and extracted with ethyl acetate twice. The ethyl acetate extracts were washed with water once, brine once, dried with MgSO4, and purified by reverse phase HPLC to yield 20 mg of N-(4-chloro-3-(pyridin-2-yl)phenyl)-3-(2-(2,6-dimethylmorpholino)ethoxy)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 571 (M)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:20][N:21](C)C=O>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:20]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:19])[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][CH:3]=1)#[N:21]
Reactant: CC(C)(C)OC(=O)N1CC(O)(c2ccc(Br)cc2)C1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccc(C#N)cc2)C1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
Into a 500-mL round-bottom flask, purged and maintained with an inert atmosphere of nitrogen, was placed a mixture of tert-butyl 3-(4-bromophenyl)-3-hydroxyazetidine-1-carboxylate (compound 43.1, 16.3 g, 49.7 mmol) in N,N-dimethylformamide (250 mL), zinc cyanide (8.7 g, 75 mmol) and Pd(PPh3)4 (5.77 g, 5.00 mmol). The resulting mixture was stirred for 15 h at 100° C., then cooled to room temperature. The reaction was quenched with saturated aqueous FeSO4 (500 mL) and stirred vigorously. The mixture was filtered through Celite® and the layers from the filtrate were separated. The aqueous phase was extracted with ethyl acetate (300 mL) and the combined organic layers were washed with brine (2×100 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1/100-1/3) as the eluent to yield 14 g (crude) of the title compound as a white solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11].[CH:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([SH:27])[CH:23]=[CH:24]2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.O>[CH:21]1[C:20]2[C:25](=[CH:26][CH:17]=[CH:18][CH:19]=2)[CH:24]=[CH:23][C:22]=1[S:27][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC=C(C(=O)OC)c1ccccc1CSc1ccc2ccccc2c1

Procedure:
8 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate, 4.5 g of 2-thionaphthol, 4.4 g of potassium carbonate and 100 mg of potassium iodide are refluxed for 20 hours in 200 ml of acetone. 200 ml of water is then added and extraction is carried out three times with methylene chloride. The organic phases are dried over Na2SO4 and evaporated down. The oil which remains is chromatographed on silica gel using a mixture of n-hexane and ethyl acetate. There is obtained 8.19 g of slightly yellow crystals of melting point 52°-58° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:5][CH:6]=1.Cl.[Br-:15].[K+].OO>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:15][C:7]([C:4]1[S:5][CH:6]=[C:2]([CH3:1])[N:3]=1)([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)c1nc(C)cs1
Reactant: [Br-]
Agent: Cl
Agent: OO
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(Br)c1nc(C)cs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
To a solution of ethyl 2-(4-methyl-1,3-thiazol-2-yl)propanoate (3.91 g, 19.62 mmol) in toluene (95 mL) was added hydrochloric acid (1.77 mL, 21.58 mmol). The mixture was stirred at room temperature for 10 minutes. The mixture was cooled to 0° C. and then potassium bromide (MERCK, 2.57 g, 21.58 mmol) and hydrogen peroxide (2.37 mL, 25.5 mmol) were added. Reaction mixture was stirred at 0° C. for 5 hours, at which point TLC (1:1 EtOAc-Hex) showed reaction had gone to completion. Reaction mixture was quenched with 1N Na2S2O3 (60 mL) and saturated NaHCO3 (60 mL). Organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×60 mL). Combined organics were washed with brine, dried over sodium sulfate and concentrated to give the title compound (5.02 g, 18.05 mmol, 92% yield) as a red oil. 1H-NMR (300 MHz, DMSO-d6) δ ppm: 7.41 (s, 1H), 4.23 (q, 3H), 2.33 (s, 3H), 2.28 (s, 3H), 1.20 (t, 3H). [ES+MS] m/z 278 (MH+).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:38]=[O:39].C(=O)([O-])O.[Na+]>C1COCC1>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:38]([NH:37][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:39])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN=C=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound (35 mg) obtained in Example 1 and Et3N (22 μl) in THF (2.0 ml), ethyl isocyanatoacetate (11 mg) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].CCN(C(C)C)C(C)C.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>C(#N)C>[O:26]1[CH2:27][CH2:28][N:23]([CH:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:24][CH2:25]1
Reactant: CCOC(=O)C(Br)c1ccccc1
Reactant: C1COCCN1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(c1ccccc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 112.5 %

Procedure:
Ethyl 2-bromo-2-phenylacetate (0.22 ml, 1.23 mmol) was dissolved in acetonitrile (4.0 ml) and DIPEA (0.26 ml, 1.48 mmol) and morpholine (0.13 ml, 1.481 mmol) were sequentially added. The solution was stirred at room temperature for 1.5 hours. Acetonitrile was evaporated and the residue was purified by flash chromatography (petroleum ether/EtOAc=85/15) to obtain ethyl 2-morpholino-2-phenylacetate (345 mg, quantitative yield) as a colorless oil.