Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:3]([NH2:4])[CH:2]1[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(COC1C=CC(C2C(N)C2)=C(OCC(C)C)C=1)C>>[CH2:16]1[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:5]([CH:2]3[CH:3]([NH2:4])[CH2:1]3)=[C:6]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:7]=2)[CH2:18][CH2:17]1
Reactant: NC1CC1c1ccc(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(C)COc1ccc(C2CC2N)c(OCC(C)C)c1
Product: NC1CC1c1ccc(OCC2CCCCC2)cc1OCC1CCCCC1

Procedure:
In FIG. 16, the detecting apparatus 100 selects a destination MAC address and a source MAC address from among destination MAC addresses and source MAC addresses included in the boot notification and sets the addresses in the detecting apparatus 100 (step S1601). The detecting apparatus 100 transmits a quality analyzing packet including the destination MAC address and the source MAC address (step S1602). The detecting apparatus 100 stores a result of the quality analysis in the quality analysis result table 400 (step S1603).
Reaction SMILES: CC(C)([O-])C.[K+].C[O:8][C:9](=O)[C:10]([N:12]([S:16]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:11]>CN(C=O)C>[OH:8][C:9]1[C:10](=[O:11])[N:12]([CH:13]([CH3:15])[CH3:14])[S:16](=[O:18])(=[O:17])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(=O)N(C(C)C)S(=O)(=O)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(O)=C(c2ccccc2)S1(=O)=O

Procedure:
Potassium tert-butoxide (1.5 g, 13.4 mmol) was added to a solution of crude methyl[(benzylsulfonyl)(isopropyl)amino](oxo)acetate (2.0 g, 21.6 mmol) in DMF (15 mL).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][CH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([C:12]#[N:11])=[CH:14][CH:15]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: N#Cc1ccc(CN)cc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: N#Cc1ccc(CNC(=O)c2ccc(Cl)nc2)cc1
Reaction time: 48 h
Yield: 63.8 %

Procedure:
Combined 6-chloronicotinic acid (1.0 g, 6.35 mmol), 4-(aminomethyl)benzonitrile (1.007 g, 7.62 mmol), and EDC (1.825 g, 9.52 mmol) in methylene chloride (50 mL) then added Hunig's base (2.328 mL, 13.33 mmol) and the mixture stirred at 20° C. for 2 h. More 4-(aminomethyl)benzonitrile (250 mg), EDC (750 mg) and Hunig's base (1 mL) was added and stirring continued for 2 days. The reaction was concentrated in vacuo to give a residue which was taken up in EtOAc (100 mL) and washed with saturated aqueous ammonium chloride (100 mL) and brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on an 80 g silica gel column eluted with 0 to 80% EtOAc in hexanes to give the title compound (1.1 g, 63.8% yield) as a white solid. MS m/z 272, 274 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.58 (d, J=6.1 Hz, 2H) 7.53 (d, J=8.6 Hz, 2H) 7.68 (dd, J=8.3, 0.8 Hz, 1H) 7.77-7.85 (m, 2H) 8.28 (dd, J=8.3, 2.5 Hz, 1H) 8.89 (dd, J=2.5, 0.5 Hz, 1H) 9.40 (t, J=5.7 Hz, 1H).
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH2:7]([CH:9]1[O:11][CH2:10]1)Cl.[OH-].[Na+]>CC(C)[O-].CC(C)[O-].CC(C)[O-].[Al+3].S(=O)(=O)(O)O>[CH2:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH:9]1[O:11][CH2:10]1
Reactant: CCCCCO
Reactant: ClCC1CO1
Agent: CC(C)[O-]
Agent: O=S(=O)(O)O
Agent: [Al+3]
Product: CCCCCOCC1CO1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
Amyl alcohol (660.2 g, 7.5 mole), 5.11 q of aluminum triisopropoxide (0.025 mole) and 3.35 g of 96% sulfuric acid (0.033 mole) were heated to 90° C. while stirring under a nitrogen gas atmosphere. To the reaction mixture, 462.5 g (5.0 mole) of epichlorohydrin was added dropwise over 1 hour, followed by stirring for 3 hours. It was found that the conversion ratio of the raw material epichlorohydrin was 100%, while the yield of the resulting halohydrin ether was 95%. To the reaction mixture, 1270 mL of a 4N aqueous solution of sodium hydroxide was added and the resulting mixture was stirred at 60° C. for 6 hours. After cooling to room temperature, the water layer was removed and the residue was purified by distillation under reduced pressure, whereby 657 g of amyl glycidyl ether (1,2-epoxy-4-oxanonane) was obtained (total yield: 94%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11](O)=[O:12])[CH2:6]1)=[O:4].S(C)C>C1COCC1>[OH:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)C1CCCC(C(=O)O)C1
Solvent: C1CCOC1
Solvent: CSC
Product: COC(=O)C1CCCC(CO)C1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclohexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15].CS(C)=O.Cl.[NH2:22][CH:23]([C:40]([CH3:43])([CH3:42])[CH3:41])[C:24]([N:26]1[CH2:35][CH2:34][C:33]2[C:28](=[CH:29][C:30]([O:38][CH3:39])=[C:31]([O:36][CH3:37])[CH:32]=2)[CH2:27]1)=[O:25]>C(OCC)C>[CH3:37][O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:38][CH3:39])[CH2:27][N:26]([C:24](=[O:25])[C@@H:23]([NH:22][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N+:14]([O-:16])=[O:15])[C:40]([CH3:41])([CH3:43])[CH3:42])[CH2:35][CH2:34]2
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COc1cc2c(cc1OC)CN(C(=O)C(N)C(C)(C)C)CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CS(C)=O
Product: COc1cc2c(cc1OC)CN(C(=O)[C@@H](Nc1ccccc1[N+](=O)[O-])C(C)(C)C)CC2
Temperature: 80 °C
Yield: 27 %

Procedure:
Anhydrous potassium carbonate (640 mg, 4.63 mmol) and 2-fluoronitrobenzene (820 mg, 5.81 mmol) were added to a dimethyl sulfoxide (100 ml) solution of N-(2-amino-3,3-dimethylbutyryl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.05 g, 3.42 mmol) obtained in Reference example 7, and the mixture was heated at 80° C. for 90 minutes. The reaction mixture was cooled to room temperature, diluted with a diethyl ether solution (200 ml), washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography using ethyl acetate and hexane (1:4 to 2:1) as an eluent to obtain the captioned compound (395 mg, 27%) as an orange foamy substance.
Reaction SMILES: [F:1][CH2:2][CH:3](O)[CH2:4][F:5].N1C=CC=CC=1.C(#N)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][O:38][C:39]1[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]2[CH2:43][CH2:44][NH:45][CH2:46][CH2:47][C:41]=2[CH:40]=1>>[F:1][CH2:2][CH:3]([N:45]1[CH2:46][CH2:47][C:41]2[CH:40]=[C:39]([O:38][CH3:37])[C:49]([N+:50]([O-:52])=[O:51])=[CH:48][C:42]=2[CH2:43][CH2:44]1)[CH2:4][F:5]
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Reactant: OC(CF)CF
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CC#N
Solvent: c1ccncc1
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(CF)CF)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A mixture of 1,3-difluoro-propan-2-ol (0.697 mL, 9.00 mmol) and pyridine (0.910 mL, 11.2 mmol) in acetonitrile (42.3 mL, 810 mmol) was cooled at 0° C. and trifluoromethanesulfonic anhydride (1.59 mL, 9.45 mmol) was added dropwise. The mixture was stirred for 30 minutes and then potassium carbonate (1.24 g, 9.00 mmol) and 7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.00 g, 4.50 mmol) were added. The reaction was heated at 50° C. overnight and then cooled to room temperature and concentrated under reduced pressure. The residue was taken up in DCM (75 mL) and washed with water (75 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification by silica gel chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain 3-(2-fluoro-1-fluoromethyl-ethyl)-7-methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine as a yellow amorphous solid (679 mg, 50%). LCMS (m/e) 301 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.75-4.65 (m, 2H), 4.63-4.54 (m, 2H), 3.96 (s, 3H), 3.29-3.11 (m, 1H), 2.99-2.93 (m, 2H), 2.93-2.82 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10][C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:18].OO.[OH:21]S([O-])=O.[Na+]>CO.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH2:9][S:10]([C:11]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][N+:12]=1[O-:18])=[O:21]
Reactant: Cc1ccc[n+]([O-])c1SCc1c(Cl)cccc1Cl
Reactant: O=S([O-])O
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CO
Product: Cc1ccc[n+]([O-])c1S(=O)Cc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
To 10.5 g (0.035 mole) of 2-[(2,6-dichlorophenyl)methylthio]-3-methyl-pyridine-N-oxide (See Example 28 above) dissolved in 100 ml of methanol were added a pinch of sodium tungstate and then dropwise 4.2 ml (0.4 mole) of 50% hydrogen peroxide. The temperature was maintained at 25° C. for four hours, and then a cold solution of NaHSO3 was added slowly to destroy residual H2O2. The solid was filtered and air-dried, having a melting point of 178-181° C., yield 10 g. The elemental analysis for C,H,N; the infrared spectrum, and the NMR spectrum all supported the proposed structure.
Reaction SMILES: C([O:5][NH:6][C:7]([C@:9]1([CH3:44])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]([S:38]([CH:41]([CH3:43])[CH3:42])(=[O:40])=[O:39])[CH2:10]1)=[O:8])(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][NH:6][C:7]([C@:9]1([CH3:44])[C@H:14]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=[C:29]([CH3:37])[CH:28]=3)=[CH:21][CH:20]=2)(=[O:17])=[O:18])[CH2:13][CH2:12][N:11]([S:38]([CH:41]([CH3:42])[CH3:43])(=[O:40])=[O:39])[CH2:10]1)=[O:8]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(S(=O)(=O)C(C)C)C[C@]3(C)C(=O)NOC(C)(C)C)cc2)c2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@@H]3CCN(S(=O)(=O)C(C)C)C[C@]3(C)C(=O)NO)cc2)c2ccccc2n1
Temperature: 45 °C
Reaction time: 8 h
Yield: 90.6 %

Procedure:
To 0.11 g of (3S,4R)-N-tert-butoxy-1-(isopropylsulfonyl)-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide was added 3 mL of trifluoroacetic acid and the resulting mixture was stirred at 45° C. for 8 h. The reaction mixture was then concentrated and the residue was purified by silica chromatography (silica prewashed with MeOH) eluting with a gradient of 5-20% MeOH/CH2Cl2 to afford (3S,4R)-N-hydroxy-1-(isopropylsulfonyl)-3-methyl-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]piperidine-3-carboxamide (0.091 g, 83%) as a colorless solid. MS: 591.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[CH3:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:13]1[C:14]([C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=2[O:10][CH3:11])[CH:5]=[O:6])=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Reactant: COc1ccc(C=O)cc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1ccc(C=O)cc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A mixture of 3-bromo-4-methoxybenzaldehyde (19.0 g, 88.4 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (23.8 g, 97.2 mmol) and potassium carbonate (48.8 g, 353.6 mmol) in 1,2-dimethoxyethane (500 mL) and water (40 mL) was degassed with argon for 60 minutes. Tetrakis(triphenylphosphine) palladium(0) (5.0 g, 4.3 mmol) was added and the mixture heated at reflux under argon for 16 hours. The solution was cooled to room temperature, diluted with ethyl acetate (200 mL) and washed successively with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (eluent: ethyl acetate/hexane, 1:9) to give 26.8 g of 3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-4-methoxy-benzaldehyde (90%). 1H NMR (500 MHz; CDCl3): δ 1.26 (s, 6 H); 1.32 (s, 6 H); 1.70 (s, 4 H); 2.08 (s, 3 H); 3.89 (s, 3 H); 7.06 (d, J=8.5 Hz, 1 H); 7.09 (s, 1 H); 7.16 (s, 1 H); 7.71 (d, J=2.0 Hz, 1 H); 7.88 (dd, J1=2.0 Hz, J2=8.5 Hz 1 H), 9.91 (s, 1 H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]([O:8]C)=[O:7].[OH-].[Na+:11]>>[NH:1]1[CH2:5][CH2:4][CH:3]=[C:2]1[C:6]([O-:8])=[O:7].[Na+:11]
Reactant: COC(=O)C1=CCCN1
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])C1=CCCN1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl pyrroline-2-carboxylate (2.265 g) was dissolved in 1 N NaOH(aq) (17.8 mL) and stirred at room temperature for 1 hour. The reaction mixture was lyophilized to give crude sodium pyrroline-2-carboxylate (3647-164) as a white powder. ESI-MS calculated for C5H7NO2 [MH]+: 114.1; observed: 114.2.
Reaction SMILES: [C:1]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=CC2N(O)N=NC=2C=1.O.Cl.C(N=C=NCCCN(C)C)C.Cl.[NH2:40][CH2:41][C:42]([C:44]1[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][CH:45]=1)=[O:43].C(N(CC)C(C)C)(C)C>ClCCl>[Br:50][C:47]1[CH:46]=[CH:45][C:44]([C:42](=[O:43])[CH2:41][NH:40][C:10]([C@@H:9]2[CH2:13][CH2:14][CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[O:12])=[CH:49][CH:48]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of N-Boc-L-Proline (5.16 g, 24.0 mmol) and HOBt.H2O (3.67 g, 24.0 mmol) was stirred at room temperature for 10 min and then treated with N-ethyl-N′-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl, 4.60 g, 24.0 mmol). The resulting mixture was stirred at room temperature for 30 min and then treated with a yellow solution formed by stirring 2-amino-4′-bromoacetophenone hydrochloride (5.0 g, 20.0 mmol) and N,N-diisopropylethylamine (DIPEA, 2.58 g, 20 mmol) in dichloromethane (DCM, 150 ml) at room temperature for 10 min. The resulting mixture was stirred at room temperature overnight and then filtered through Celite® to remove the precipitate. The filtrate was extracted with DCM and H2O. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified with column chromatography (ethyl acetate:hexanes=2:5) to yield pure product 1a as a yellow gel (7.39 g, 90%).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][CH2:12][CH2:13][S:14][CH:15]=1)[C:5]([O:7]CC)=[O:6]>[OH-].[Na+]>[CH3:1][O:2][N:3]=[C:4]([C:10]1[S:11][CH2:12][CH2:13][S:14][CH:15]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(=NOC)C1=CSCCS1
Agent: [Na+]
Agent: [OH-]
Product: CON=C(C(=O)O)C1=CSCCS1
Yield: 91.3 %

Procedure:
Ethyl 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetate (syn isomer) (2.47 g) was treated with 1 N aqueous solution of sodium hydroxide (20 ml.) according to similar manners to those of Examples 1 (a) (5), 2 (a) (3) and 3(a) (3) to give 2-methoxyimino-2-(2,3-dihydro-1,4-dithiin-5-yl)acetic acid (syn isomer) (2.0 g.), mp. 120° to 122° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:29][NH:30][O:31][CH3:32]>C1COCC1.C1COCC1.O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:30]([O:31][CH3:32])[CH3:29])=[O:12])=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(F)cc1
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)CCc1ccc(F)cc1
Yield: 97.8 %

Procedure:
A solution of 3-(4-fluorophenyl)propanoic acid (5.0 g, 30 mmol) in THF is cooled in an ice bath and treated with N-methyl morpholine (NMM) (3.0 g, 30 mmol), isobutylchloroformate (4.04 g, 30 mmol) and stirred for few mins. This was then treated with a solution of N,O-Dimethyl hydroxylamine hydrochloride (3.0 g, 30 mmol) in THF/water (neutralized with 3.0 g of NMM) and stirred for 30 minutes. The reaction mixture is diluted with CH2Cl2 and washed successively with 1 N NaOH, water and brine. The solvent was evaporated under vacuum to give 6.2 g of 3-(4-fluorophenyl)-N-methoxy-N-methylpropanamide as oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH:21]=O)=[CH:13][CH:12]=1)[C:5]#[N:6].C(O)(=O)C.[CH3:27][CH:28]([CH3:32])[CH2:29][CH2:30][NH2:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH2:21][NH:31][CH2:30][CH2:29][CH:28]([CH3:32])[CH3:27])=[CH:13][CH:12]=1)[C:5]#[N:6]
Reactant: CC(C)CCN
Reactant: N#Cc1ccc(Oc2ccc(C=O)c3ccccc23)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(C#N)cc2Cl)c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-chloro-4-(4-formylnaphthalen-1-yloxy)benzonitrile (Preparation 82) (800 mg, 2.60 mmol) in DCM (35 mL) was added acetic acid (0.7 mL, 7.80 mmol), 3-methylbutylamine (0.91 mL, 7.80 mmol) and NaBH(OAc)3 (1.65 g, 7.80 mmol). The reaction was stirred at rt for 16 h. The mixture was partitioned between DCM (150 mL) and saturated NaHCO3 (200 mL) and the organic phase dried (MgSO4). Solvent was removed in vacuo and the residue purified by column chromatography (EtOAc:isohexane 1:1) to give the title compound: RT=3.01 min; m/z (ES+)=379.3, 381.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:6]=1[O:12][CH3:13])=O.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH2:20]>CCO>[Br:11][C:9]1[CH:8]=[CH:7][C:6]([O:12][CH3:13])=[C:5]([C:3]2[N:20]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][N:14]3[CH:2]=2)[CH:10]=1
Reactant: Nc1ccccn1
Reactant: COc1ccc(Br)cc1C(=O)CBr
Solvent: CCO
Product: COc1ccc(Br)cc1-c1cn2ccccc2n1
Temperature: 80 °C
Reaction time: 12 h
Yield: 6.2 %

Procedure:
To a mixture of 2-bromo-1-(5-bromo-2-methoxyphenyl)ethanone (500 mg, 1.6 mmol) in EtOH (5 mL), pyridin-2-amine (153 mg, 1.6 mmol) was added. The mixture was stirred at 80° C. for 12 hours, and then cooled to 25° C. After filtrated, the solid was dried in vacuo to provide 2-(5-bromo-2-methoxyphenyl)imidazo[1,2-a]pyridine (30 mg, yield: 5%). 1H-NMR(CDCl3, 400 MHz) δ 8.54 (s, 1H), 8.18 (s, 1H), 8.12˜8.13 (m, 1H), 7.62˜7.64 (m, 1H), 7.37˜7.40 (m, 1H), 7.16˜7.21 (m, 1H), 6.86˜6.88 (m, 1H), 6.76˜6.79 (m, 1H), 3.98 (s, 3H). MS (M+H)+: 303/305.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3[CH:14]4[CH2:20][CH2:19][N:17]([CH2:18][C:8]=3[C:7]=2[CH:6]=1)[CH2:16][CH2:15]4)(=[O:4])=[O:3].[C:21]([C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[N:27][CH:28]=1)#[CH:22]>>[CH3:29][C:26]1[N:27]=[CH:28][C:23](/[CH:21]=[CH:22]\[N:10]2[C:11]3[CH:12]=[CH:13][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][C:7]=3[C:8]3[CH2:18][N:17]4[CH2:16][CH2:15][CH:14]([C:9]2=3)[CH2:20][CH2:19]4)=[CH:24][CH:25]=1
Reactant: C#Cc1ccc(C)nc1
Reactant: CS(=O)(=O)c1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Product: Cc1ccc(/C=C\n2c3c(c4cc(S(C)(=O)=O)ccc42)CN2CCC3CC2)cn1

Procedure:
The coupling of 9-(methylsulfonyl)-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (150 mg, 0.517 mmol; Example 180) and 5-ethynyl-2-methylpyridine (182 mg, 1.55 mmol; prepared as described in International Publication No. WO2005090333) was performed according to the procedure described in Example 20 to afford the title compound as the major product: 1H NMR (300 MHz, methanol-d4) δ ppm 1.70-1.82 (m, 2H), 1.88-2.01 (m, 2H), 2.40 (s, 3H), 2.96-3.24 (m, 5H), 3.10 (s, 3H), 4.32 (s, 2H), 6.91 (d, J=8 Hz, 1H), 7.00 (d, J=8 Hz, 1H), 7.09 (s, 2H), 7.32 (d, J=9 Hz, 1H), 7.61 (dd, J=9, 2 Hz, 1H), 7.87 (s, 1H), 8.04 (d, J=2 Hz, 1H); MS (DCI/NH3) m/z 408 (M+H)+.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][OH:18])=[CH:12][CH:11]=1.N1C=CN=C1>CN(C=O)C>[C:4]([Si:1]([O:18][CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1ccc(F)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyldimethylsilyl chloride (9.03 g) was added portionwise to a stirred solution of 2-(4-fluorophenyl)ethanol (7 g) and imidazole (4.08 g) in DMF (100 mL) at 20° C. The reaction mixture was stirred for 3 hours at room temperature and then partitioned between ethyl acetate and brine. The organic layer was washed twice with brine, dried, filtered and the solvent concentrated under reduced pressure. The crude product was purified by flash silica chromatography eluting with 2% ethyl acetate in isohexane. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 11.60 g.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O)#[N:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:32][C:21]1[O:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:15]=2)=[N:23][C:22]=1[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH3:31]
Reactant: N#Cc1ccccc1B(O)O
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: Cc1oc(-c2ccc(-c3ccccc3C#N)cc2)nc1CCN1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 2-Cyanobenzene boronic acid (211 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 70 mg (66%). MS (m/e) 372.2 (M+1)