Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[O:18][C:17](=[O:19])[NH:16][N:15]=3)[CH2:10][CH2:9]2)=[C:4]([F:20])[CH:3]=1.[N+:21]([C:24]1[O:28][C:27]([CH:29]=O)=[CH:26][CH:25]=1)([O-:23])=[O:22]>CC(O)=O.CO>[F:20][C:4]1[CH:3]=[C:2](/[N:1]=[CH:29]/[C:27]2[O:28][C:24]([N+:21]([O-:23])=[O:22])=[CH:25][CH:26]=2)[CH:7]=[CH:6][C:5]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:18][C:17](=[O:19])[NH:16][N:15]=2)[CH2:10][CH2:9]1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: Nc1ccc(N2CCC(c3n[nH]c(=O)o3)CC2)c(F)c1
Solvent: CO
Solvent: CC(=O)O
Product: O=c1[nH]nc(C2CCN(c3ccc(/N=C/c4ccc([N+](=O)[O-])o4)cc3F)CC2)o1
Yield: 81 %

Procedure:
5-[1-(4-Amino-2-fluorophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (7e, 0.28 g, 1 mml) on reacting with 5-nitro2-furaldehyde in the presence of catalytic amount of CH3COOH (3 drops) in methanol at 0° C. for 10 h and the obtained solid is filtered, washed with water and recrystallized in ethanol to obtain product 5-[1-(2-fluoro-4-[(E)-1-(5-nitro-2-furyl)methylidene]aminophenyl)-4-piperidyl]-2,3-dihydro-1,3,4-oxadiazol-2-one (9e, 324 mg, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].Cl.[NH2:28][OH:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:28][OH:29])=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: NO
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Agent: Cl
Product: O=C(NO)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1

Procedure:
75 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to hydroxylamine hydrochloride via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-hydroxyterephthalamide. MS (Q1) 403 (M)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34]([O:36][C:37](=[O:43])[CH2:38][CH2:39][CH2:40][CH2:41]Br)[CH3:35]>>[CH2:1]([N:8]([CH2:19][C:20]1[CH:33]=[CH:32][C:23]([O:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:41][CH2:40][CH2:39][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:43])=[CH:29][CH:30]=2)=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH3:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(N(Cc2ccccc2)Cc2ccc(Oc3ccc(O)cc3)cc2)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CCCCBr
Product: CCOC(=O)CCCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc([N+](=O)[O-])c3C)cc2)cc1

Procedure:
The product from Example 60E and ethyl-5-bromovalerate was processed as described in Example 116A to provide the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:17])[F:16])[C:11]([CH3:18])=[N:10]2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].Br[CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:19])[C:5]([N:9]2[C:13](=[O:14])[N:12]([CH:15]([F:16])[F:17])[C:11]([CH3:18])=[N:10]2)=[CH:6][C:7]=1[O:8][CH:23]([CH3:28])[C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)C(C)Br
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2F)c(=O)n1C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(-n2nc(C)n(C(F)F)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.5 %

Procedure:
To a stirred mixture of 1.5 g (0.0051 mole) of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 0.12 g (0.0051 mole) of sodium hydride in 50 mL of N,N-dimethylformamide was added 0.85 g (0.0051 mole) of methyl 2-bromopropionate. After complete addition the reaction mixture was heated at reflux for two hours, then cooled to room temperature and stirred for approximately 18 hours. The solvent was removed by evaporation under reduced pressure leaving a residue. This residue was partitioned between diethyl ether and water. The organic phase was washed with an aqueous 10% sodium hydroxide solution. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.5 g of methyl 2-[2-chloro-4-fluoro-5-(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate as an oil, Compound 3.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])O.O>C(O)C>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:22]1[O:23][C@H:14]([CH2:13][OH:12])[C@@H:16]([OH:17])[C@H:18]([OH:19])[C@H:20]1[OH:21]
Reactant: Fc1ccc2c(c1Cl)CCN2
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: O
Solvent: CCO
Product: OC[C@H]1O[C@@H](N2CCc3c2ccc(F)c3Cl)[C@H](O)[C@@H](O)[C@@H]1O
Yield: 94.2 %

Procedure:
A mixture of 4-chloro-5-fluoroindoline (584 mg) and D-glucose (1.04 g) in ethyl alcohol (20 ml)-H2O (3 ml) was refluxed for 1.5 days. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0-85:15) to give 4-chloro-5-fluoro-1-(β-D-glucopyranosyl)indoline (1.07 g) as a colorless foam. APCI-Mass m/Z 334/336 (M+H). 1H-NMR (DMSO-d6) δ 3.02 (m, 3H), 3.20-3.45 (m, 4H), 3.57 (m, 2H), 3.71 (m, 1H), 4.35 (t, J=5.8 Hz, —H), 4.60 (d, J=8.3 Hz, 1H), 4.93 (d, J=5.1 Hz, 1H), 5.04 (d, J=4.0 Hz, 1H), 5.07 (d, J=4.3 Hz, 1H), 6.51 (dd, J=8.6, 3.6 Hz, 1H), 7.00 (t, J=9.1 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:35][CH2:34][CH2:33][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[CH:20]([OH:32])[CH2:21][S:22]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:35][CH2:34][CH2:33][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][C@H:16]1[C:20](=[O:32])[CH2:21][S:22]([C:24]1[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=1)=[O:23])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(S(=O)CC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: COc1ccc(S(=O)CC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Yield: 72.7 %

Procedure:
(2S)-1-(N-Benzyloxycarbonyl-L-prolyl)-2-[1-hydroxy-2-(4methoxyphenylsulfinyl)ethyl]pyrrolidine (901 mg) was subjected to DMSO-DCC oxidation as in Example 1-D) to give 652 mg of the title compound (See Table 2).
Reaction SMILES: [C:1]1(=[O:19])[N:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]12.[Br:20]Br.S(=O)(O)[O-].[Na+].C(=O)(O)[O-].[Na+]>O>[Br:20][CH:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:4](=[O:14])[C:3]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:2]2[C:1]1=[O:19])[C:11]([OH:13])=[O:12]
Reactant: BrBr
Reactant: O=C(O)CCCCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)C(Br)CCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
Combine 6-phthalimidohexanoic acid (12.7 g, 48 mmol) and dry red phosphorous (1.95 g, 63 mmol). Cool in an ice bath and add bromine (12.7 mL, 246 mmol) dropwise. Warm to room temperature and then heat to 80° C. After 3 hours, cool the reaction mixture to ambient temperature, pour into water (300 mL) containing sodium bisulfite, and neutralize using solid sodium bicarbonate and extract with diethyl ether (about 150 mL). Acidify the aqueous layer with concentrated hydrochloric acid to give a solid. Collect the solid by filtration and dry to give the title compound (15 g, 91.5% yield, 73.2% for both steps).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.[F:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:4]2[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:20][CH:19]=1
Reactant: Oc1ccc(F)cc1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2ccc(F)cc2)cc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
The compound prepared in Example 34 (4.73 g) was dissolved in DMF (40 mL), added with 4-fluorophenol (2.34 g) and potassium phosphate (5.32 g) and stirred overnight at 80° C. The reaction solution was diluted with ethyl acetate, sequentially washed with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulphate before distillation of the solvent. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=9:1→1:1) to give the titled compound (4.81 g) having the following physical properties.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:17]=[CH:16][CH:15]=[CH:14][C:8]=2[C:9]([O:11][CH2:12]C)=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(C(CC)CNC1N=CC=CC=1C(OCC)=[O:26])C>>[CH:1]1([N:6]2[C:7]3[N:17]=[CH:16][CH:15]=[CH:14][C:8]=3[C:9](=[O:10])[O:11][C:12]2=[O:26])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cccnc1NCC(CC)CC
Reactant: CCOC(=O)c1cccnc1NC1CCCC1
Product: O=c1oc(=O)n(C2CCCC2)c2ncccc12

Procedure:
The title compound was prepared according to the procedure of Example 3B substituting the product of Example 68A for the product of Example 3A (0.130 g, 56%). MS (ESI+) m/z 221.08 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 1.66 (m, 1H), 1.99 (m, 4H), 2.21 (m, 2H), 5.79 (m, 1H), 7.25 (dd, J=8.09, 4.78 Hz, 1H), 8.42 (dd, J=7.72, 2.21 Hz, 1H), 8.70 (dd, J=4.78, 1.84 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].Br[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.O>[C:28]([C:27]1[CH:26]=[C:25]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:9][CH2:10]3)[CH:16]=2)[CH:32]=[CH:31][CH:30]=1)#[N:29]
Reactant: N#Cc1cccc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cccc(C#N)c3)c2)CC1
Temperature: 150 °C
Yield: 77.5 %

Procedure:
A mixture of {3-[(4-{[(1,1-dimethylethyl)oxy]carbonyl}-1-piperazinyl)methyl]phenyl}boronic acid (1 g), 3-bromobenzonitrile (0.56 g), potassium carbonate (1.725 g) and tetrakis triphenylphosphine palladium (180 mg) in dioxan/water (3:1, 4 mL) was sealed in a tube and heated at 150° C. for 15 minutes in a microwave vessel. After cooling to room temperature, the reaction mixture was then diluted with water (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organic phases were dried (MgSO4) and concentrated under vacuum. The resulting crude residue was further purified by flash column chromatography on silica (100 g) to give the title compound (0.9 g) (purity ca 75%). LC/MS: m/z, 378 (M+H), 2.57 min.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][C:14]([F:18])([F:17])[CH2:13][CH2:12]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([OH:34])=O)[CH2:27]3)(=[O:25])=[O:24])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:36]([NH2:38])[CH3:37].C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:12][CH2:13][C:14]([F:18])([F:17])[CH2:15][CH2:16]2)[C:8]2[CH:19]=[CH:20][C:21]([S:23]([N:26]3[CH2:31][CH2:30][O:29][CH:28]([C:32]([NH:38][CH2:36][CH3:37])=[O:34])[CH2:27]3)(=[O:24])=[O:25])=[CH:22][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)N3CCOC(C(=O)O)C3)ccc2n1CC1CCC(F)(F)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)C1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCC(F)(F)CC2)CCO1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
4-({2-tert-butyl-1-[(4,4-difluorocyclohexyl)methyl]-1H-benzimidazol-5-yl}sulfonyl)morpholine-2-carboxylic acid (500 mg, 1 mmol) (see following steps B and C for preparation) was dissolved in DMF (10 mL). Ethylamine hydrochloride (122 mg, 1.5 mmol) and N,N-diisopropylethylamine (1 mL, 5 mmol) were added and the reaction mixture was cooled down to 0° C. HATU (456 mg, 1.2 mmol) was added portionwise and the reaction was stirred overnight at room temperature. The reaction was concentrated, extracted with EtOAc and washed with sodium bicarbonate, water then brine and dried over anhydrous sodium sulfate. The crude product was purified by LCMS using high pH column 40-70% acetonitrile gradient to give 200 mg (40%) as white solid racemic mixture of the title compound. The two enantiomers were separated on a chiral OD 5 microns column using 20% ethanol/hexane. Example 112 (isomer-1): 1H NMR (400 MHz, METHANOL-D4) δ 1.04 (t, J=7.23 Hz, 3 H), 1.46-1.56 (m, 2 H), 1.57 (s, 9 H), 1.61-1.70 (m, 3 H), 1.70-1.81 (m, 1 H), 1.98-2.08 (m, 2 H), 2.12-2.23 (m, 1 H), 2.39 (m, 1 H), 2.74 (q, J=7.23 Hz, 2 H), 3.17 (dd, J=7.23, 3.91 Hz, 2 H), 3.68 (m, 1 H), 3.87-3.94 (m, 1 H), 4.01 (dd, J=10.45, 2.83 Hz, 2 H), 4.40 (d, J=7.62 Hz, 2 H), 7.64 (dd, J=8.59, 1.56 Hz, 1 H), 7.77 (d, J=8.59 Hz, 1 H), 8.03 (d, J=1.76 Hz, 1 H); MS (APPI) (M+H)+=527.3; Anal. Calc. for C21H29F2N3O3S+4.9C2HO2F3+5.0H2O+2.7 CH3CN: C, 39.47; H, 4.14; N, 6.31. Found: C, 39.48; H, 4.14; N, 6.30.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:2]1=[O:21].Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[O:21]=[C:2]1[C:3]2([CH2:13][O:12][C:11]3[CH:14]=[C:15]4[C:19](=[CH:20][C:10]2=3)[CH2:18][CH2:17][O:16]4)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Temperature: 25 °C
Yield: 62.9 %

Procedure:
A mixture of 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]2′(1′H)-one (0.28 g, 1.00 mmol), ethyl 2-bromoacetate (0.17 g, 1.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in acetone (20.0 mL) was stirred at reflux for 5 hours. After cooling down to ambient temperature, the mixture was filtered. The filtrate was evaporated under reduced pressure and the residue was subjected to column chromatography to give the title compound (0.23 g, 63%) as a white solid: MS (ES+) m/z 366.4 (M+1).
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:9][CH:8]=1>>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14](=[O:16])[CH3:15])=[CH:11][C:12]=1[S:2]([Cl:1])(=[O:5])=[O:3]
Reactant: CC(=O)Cc1ccc(F)cc1
Reactant: O=S(=O)(O)Cl
Product: CC(=O)Cc1ccc(F)c(S(=O)(=O)Cl)c1
Temperature: 25 °C

Procedure:
To chlorosulfonic acid (25 ml, excess) cooled at −10° C. is added dropwise 4-fluorophenyl acetone (1.0 g, 6.57 mmol). The temperature is kept below 0° C. throughout the addition. The reaction mixture is then left to warm up to room temperature overnight. The reaction mixture is poured carefully onto ice (1500 ml). Once ice is melted, the aqueous layer is extracted with DCM (3×250 ml). The combined organic layers are dried over MgSO4, filtered and concentrated to afford the titled compound as an off-white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:7]=1[Cl:15].[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:15][C:7]1[CH:8]=[CH:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1
Reactant: O=[N+]([O-])c1ccc(Cl)c(OCCCBr)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCCN2CCN(c3ccccc3)CC2)c1
Reaction time: 18 h
Yield: 78 %

Procedure:
To the compound 26a (2.1 g, 7.1 mmol) in DMF (9 mL) was added N-phenyl piperazine (1.16 g, 7.1 mmol) and potassium carbonate (1.28 g, 9.23 mmol). The mixture was stirred for 18 hrs. at room temperature. Water (10 mL) was added to the reaction mixture and extracted with ethyl acetate (3×20 mL). The combined extracts were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash column chromatography to get the title compound 26b in 78% yield as yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N:8]2[CH:11]=[CH:12][N:13]=[C:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[N:20]=[C:19]([C:21]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=2[C:23]#[N:24])[CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[CH:10]=[CH:9][N:8]2[C:11]([C:15]3[N:20]=[C:19]([C:21]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=4[C:23]#[N:24])[CH:18]=[CH:17][CH:16]=3)=[CH:12][N:13]=[C:7]2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccn2ccnc2n1
Reactant: N#Cc1cc(F)ccc1-c1cccc(Br)n1
Product: CC(C)(C)c1ccn2c(-c3cccc(-c4ccc(F)cc4C#N)n3)cnc2n1
Yield: 63 %

Procedure:
7-tert-Butylimidazo[1,2-α]pyrimidine was coupled with 2-(6-bromopyridin-2-yl)-5-fluorobenzonitrile as described in Example 27 to give 2-[6-(7-tert-butylimidazo[1,2-α]pyrimidin-3-yl)pyridin-2-yl]-5-fluorobenzonitrile (0.235 g, 63%) as a white powder: δH (360 MHz, CDCl3) 1.43 (9H, s), 7.05 (1H, d, J 7), 7.37-7.73 (6H, m), 7.81 (1H, s), 7.85 (1H, dd, J 8 and 1), 8.75 (1H, d, J 7); m/z (ES+) 371 (M++H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][OH:7].[H-].[Na+].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[C:18](F)[C:15]=1[C:16]#[N:17]>CN(C)C=O>[F:13][C:14]1[CH:21]=[CH:20][C:19]([O:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: N#Cc1c(F)cccc1F
Reactant: COc1cccc(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(F)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a solution of 3-methoxybenzyl alcohol (1.0 g, 7.2 mmol) in dimethylformamide was added to a cooled (0° C.) slurry of sodium hydride (0.32 g, 7.91 mmol) in dimethylformamide under nitrogen atmosphere. The reaction mixture was slowly warmed to room temperature, stirred for 1 hour. Again, cooled (0° C.), then a solution of 2,6-difluorobenzonitrile (1.0 g, 7.2 mmol) in dimethylfomamide was added, stirred overnight at room temperature. The reaction mixture was poured on crushed ice-water, stirred, filtered and dried to afford 1.6 g of 2-fluoro-5-(3-methoxybenzyloxy)benzonitrile.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[C:6]2[C:7]([CH2:11][OH:12])=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.N1C=CN=C1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C=O)C>[Si:21]([O:12][CH2:11][C:7]1[C:6]2[N:5]([N:4]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:13]=2)[CH:10]=[CH:9][CH:8]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: OCc1cccn2nc(C(F)(F)F)cc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccn2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 43.3 %

Procedure:
The compound of Example 64 (5.17 g, crude product) was dissolved in DMF (100 mL). To this solution, imidazole (4.89 g) and t-butyldimethylsilyl chloride (4.33 g) were added and the mixture was stirred at room temperature for 1.5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. Evaporation of the solvent and subsequent purification by silica gel column chromatography (hexane:ethyl acetate=9:1) afforded the title compound as a yellow oil (3.42 g).
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:8][N:9]=1)(=O)C.Cl>C(O)(=O)C>[NH2:4][C:5]1[S:6][C:7]([S:10][C:11]2[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=2)=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Agent: Cl
Solvent: CC(=O)O
Product: Nc1ncc(Sc2ccc([N+](=O)[O-])cc2)s1
Yield: 75.8 %

Procedure:
A mixture of 2-acetylamino-5-(4-nitrophenylthio)thiazole (4.0 g) in a mixture of acetic acid (30 ml) and aqueous 6N hydrochloric acid (9 ml) was refluxed for 3 hours with stirring. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. The solution was adjusted to pH 8.5 using aqueous sodium bicarbonate. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(4-nitrophenylthio)thiazole (2.6 g, yield: 76.5%).
Reaction SMILES: CS([C@H:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=O)=O.[Cl-].[C-:31]#[N:32].[K+]>C(Cl)(Cl)(Cl)Cl.O>[C:31]([CH:5]1[NH:8][C:7](=[O:9])[C@H:6]1[NH:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:32]
Reactant: [C-]#N
Reactant: CS(=O)(=O)[C@H]1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: N#CC1NC(=O)[C@H]1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 72.2 %

Procedure:
In 120 ml of carbon tetrachloride are dissolved 12.2 g of (3R,4R)-4-methylsulfonyl-3-tritylamino-2-azetidinone and 2.44 g of tri-n-octlymethylammonium chloride and, under stirring, a solution of 2.15 g of potassium cyanide in 30 ml of water is added. The mixture is stirred vigorously at the same temperature for 15 minutes and the organic layer is separated, while the aqueous layer is extracted with chloroform. The organic layers are combined, washed with water and treated in the same manner as (1) of Example 13 to give 7.66 g of (3S,4RS)-4-cyano-3-tritylamino-2-azetidinone.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])#[N:2].Cl[C:24]([O:26][CH3:27])=[O:25]>>[C:1]([CH:3]([C:4]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:24]([O:26][CH3:27])=[O:25])#[N:2]
Reactant: COC(=O)Cl
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1CC#N
Product: COC(=O)C(C#N)c1c(OC)cc(C)c2c1ccn2C(=O)OC(C)(C)C

Procedure:
The title compound was synthesized from tert-Butyl 4-(cyanomethyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate (Example 155-B) using the same procedure as in Example 148-A using methyl chloroformate in the place of methyl bromoacetate. MS (ESI+) m/z 359.4 (M+H).