Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])=[CH:19][CH:18]=2)=[C:12]([CH:15]=1)[C:13]#[N:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:33])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([C:8]1[CH:15]=[C:12]([C:13]([NH2:14])=[O:33])[C:11]2[NH:16][C:17]3[C:22]([C:10]=2[CH:9]=1)=[CH:21][C:20]([C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24])=[CH:19][CH:18]=3)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: N#Cc1cc(Cc2ccccc2)ccc1Nc1ccc(C(=O)N2CCOCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: NC(=O)c1cc(Cc2ccccc2)cc2c1[nH]c1ccc(C(=O)N3CCOCC3)cc12
Temperature: 130 °C

Procedure:
A 5-ml microwave vial was loaded with 5-benzyl-2-(4-(morpholine-4-carbonyl)phenylamino)benzonitrile (42 mg, 0.080 mmol), acetic acid (4 mL) and palladium acetate (45.1 mg, 0.201 mmol). The flask was sealed and heated to 130° C. for 13 hours. The reaction mixture was filtered through a 0.45 um Nylon filter and concentrated in vacuum. The crude was filtered through a layer of BIOTAGE® Si-propylthiol resin (0.8 g in a 6 ml cartridge, to remove Pd) and rinsed with methanol. The pale yellow eluent was concentrated and purified by prep HPLC to give 7.0 mg 3-benzyl-6-(morpholine-4-carbonyl)-9H-carbazole-1-carboxamide. MS (ESI) m/e−412, m/e+=414 consistent with [M−H]− and [M+H]+ resp. HPLC retention time 9.14 min. (Sunfire C18 3.5 μm, 4.6×150 mm column, 15 min gradient, 10-100% B, 1 mL/min. Solvent A: 5% CH3CN—95% H2O—0.1% TFA; Solvent B: 95% CH3CN—5% H2O—0.1% TFA). 1H NMR (CD3OD) δ ppm 8.18 (m, 2H), 7.87 (s, 1H), 7.65 (b, 1H), 7.52 (b, 1H), 7.30 (m, 4H), 7.20 (b, 1H), 4.21 (s, 2H), 3.90-3.50 (b, 8H).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][CH:29]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(=O)c1ccc(OCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1ccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)cc1
Yield: 47.7 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.27 g, 14.8 mmol), K2CO3 (3 g), 1-[4-(3-bromopropoxy)phenyl]ethanone (4.5 g, 17.5 mmol) in acetonitrile (60 ml) was heated at reflux for 4 hours. The solvent was removed. The residue was dissolved in dichloromethane (300 ml) and washed with water and brine, then dried over MgSO4. The crude product from the evaporated solution was purified by flash chromatography (SiO2, 60 g; eluted with 1% methanol in dichloromethane, 1 liter). The purest fractions were combined and gave 2.8 g, 48% of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy)phenyl]ethanone, m.p.=111-112° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([NH:17][C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:21]([O:23][CH3:24])=[O:22])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1.[C:30]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[S:12][C:13]([C:15]([N:17]([C:18]4[CH:19]=[C:20]([CH:25]=[CH:26][C:27]=4[Cl:28])[C:21]([O:23][CH3:24])=[O:22])[CH3:30])=[O:16])=[CH:14][C:10]=3[CH2:9][CH2:8][O:7][C:6]=2[CH:29]=1
Reactant: COC(=O)c1ccc(Cl)c(NC(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cl)c(N(C)C(=O)c2cc3c(s2)-c2ccc(Br)cc2OCC3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To a solution of methyl 3-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (32 g, 65 mmol) and Cs2CO3 (42.4 g, 130 mmol) in DMF (500 mL) was added CH3I (12 mL, 195 mmol). The reaction mixture was stirred at room temperature overnight. Then it was concentrated to remove the DMF, and water was added into the mixture. The resulting precipitate was filtrated, washed by water, and dried to give methyl 3-(8-bromo-N-methyl-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxamido)-4-chlorobenzoate (31 g, 94%)1H NMR (CDCl3, 400 MHz): δ8.07-7.08 (m, 6H, ArH), 6.81 (s, 1H, ═CH), 4.22 (t, J=5.2 Hz, 2H, CH2), 3.94 (s, 3H, OCH3), 3.40 (s, 3H, NCH3), 3.01 (t, J=5.2 Hz, 2H, CH2)
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].COS(OC)(=O)=O>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: COS(=O)(=O)OC
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.6 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 9, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate 0.90 g, 0.0065 mole), and dimethylsulfate (0.76 g, 0.006 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and then the resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.13 g, yield: 89.6%) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]([OH:8])=O)[C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([N:22]2[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]2)=[C:18]([CH:21]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:21]=[C:14]([NH:13][C:6]([C:4]2[C:3]3[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=3[S:1][CH:5]=2)=[O:8])[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:27][CH2:26][CH:25]([OH:28])[CH2:24][CH2:23]1)#[N:20]
Reactant: N#Cc1cc(N)ccc1N1CCC(O)CC1
Reactant: O=C(O)c1csc2c1CCCC2
Product: N#Cc1cc(NC(=O)c2csc3c2CCCC3)ccc1N1CCC(O)CC1
Yield: 52.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 6 using 4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid (1.2 g) and 5-amino-2-(4-hydroxypiperidin-1-yl)benzonitrile (1.3 g), the title compound (1.2 g) was obtained. melting point: 172-173° C.
Reaction SMILES: [CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)[C:19](Cl)=[O:20]>C(Cl)CCl>[CH:1]([C:4]1[O:8][C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([N:15]=[C:19]=[O:20])=[O:14])=[CH:11][CH:10]=2)=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc(-c2ccc(C(N)=O)cc2)o1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Product: CC(C)c1nnc(-c2ccc(C(=O)N=C=O)cc2)o1

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-8 by using 4-(5-isopropyl-1,3,4-oxadiazol-2-yl)benzamide (0.200 g), oxalyl chloride (0.012 mL) and EDC (15 mL) to afford 0.150 g of the desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=O)[CH3:16].C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[C:1]([O:5][C:6](=[O:14])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:21][C:20]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:18]([O:17][CH2:15][CH3:16])[CH:19]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: CCOc1cc(C=O)ccc1OC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(CN2CCC(NC(=O)OC(C)(C)C)CC2)ccc1OC
Temperature: 100 °C
Yield: 53 %

Procedure:
A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10.0 g, 50.0 mmol, 1.0 equiv), 3-ethoxy-4-methoxy-benzaldehyde (10.8 g, 60.0 mmol, 1.2 equiv; commercially available) and acetic acid (11.4 mL, 12.01 g, 200.0 mmol, 4.0 equiv) in ethanol (40 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (6.27 g, 100.0 mmol, 2.0 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 5 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate to yield 9.71 g (53%) of the title compound as a white solid. MS (ISP): 365.3 [M+H]+.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])(O)=O.[Na+]>CC(C)=O>[C:1]1([N:7]2[CH2:12][CH2:11][N:10]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCl
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)CN1CCN(c2ccccc2)CC1

Procedure:
Synthesized according to General Procedure B: 1-phenylpiperazine (5{30}, 1 mL, 6.55 mmol, 1 equiv.), ethyl chloroacetate (0.77 mL, 7.20 mmol, 1.1 equiv.), NaHCO3 (0.69 g, 8.18 mmol, 1.25 equiv.), acetone (13.1 mL). Purification with flash column chromatography on silica gel (1:1 hexanes:EtOAc) afforded 6{30} (1.50 g, 93%) as a light yellow liquid. 1H-NMR (500 MHz, CDCl3): δ 7.20 (dd, 2H, J=7.0, 8.5 Hz), 6.87 (dd, 2H, J=1.0, 9.0 Hz), 6.80 (t, 1H, J=7.0 Hz), 4.15 (q, 2H, J=7.0 Hz), 3.20 (s, 2H), 3.19 (t, 4H, J=5.0 Hz), 2.68 (t, 4H, J=5.0 Hz), 1.23 (t, 3H, J=7.0 Hz). 13C-NMR (125 MHz, CDCl3): δ 169.6, 150.8, 128.6, 119.2, 115.6, 60.1, 58.9, 52.5, 48.5, 13.8.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([OH:16])[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C1C=CC=CC=1>[C:1]([C:5]1[S:9][C:8]([N:10]2[CH:15]([O:16][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)[CH2:14][CH2:13][N:12]([CH3:17])[C:11]2=[O:18])=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC(O)N(c2nnc(C(C)(C)C)s2)C1=O
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)OC2CCN(C)C(=O)N2c2nnc(C(C)(C)C)s2)cc1

Procedure:
Tetrahydro-1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3 -methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 4-Methoxybenzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-t-butyl-1,3,4 -thiadiazol-2-yl)-3-methyl-6-(4-methoxybenzoyloxy)-2(1 H)-pyrimidinone.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N.Cl>>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: COc1ccccc1NN
Agent: Cl
Product: COc1ccccc1-n1nccc1-c1nn(-c2ccccc2)ccc1=O
Yield: 61 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2-methoxy-phenylhydrazine×HCl according to the method described for Example 1 in 61% yield. MS: M=345.1 (M+H)+
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[CH:21][CH:20]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32]([O:34]C)=[O:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][CH3:31])=[CH:23][CH:24]=3)=[CH:18][C:13]=2[CH:12]=[C:11]([C:32]([OH:34])=[O:33])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
In methanol (10 ml) and THF (10 ml) was dissolved methyl 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.27 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature overnight and concentrated, which was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 1-benzyl-7-[4-(2-propoxyethoxy)phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.16 g) as yellow crystals.
Reaction SMILES: [C:1]([C@H:5]([NH:9][NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([O:34][CH3:35])[C:32]=1[CH3:33])[C:27](Cl)=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:1]([C@H:5]([N:9]([C:27](=[O:28])[C:26]1[CH:30]=[C:31]([O:34][CH3:35])[C:32]([CH3:33])=[C:24]([O:23][CH3:22])[CH:25]=1)[NH:10][C:11](=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[C:13]=1[CH3:20])[CH2:6][CH2:7][CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCC[C@@H](NNC(=O)c1cccc(OC)c1C)C(C)(C)C
Reactant: COc1cc(C(=O)Cl)cc(OC)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCC[C@@H](N(NC(=O)c1cccc(OC)c1C)C(=O)c1cc(OC)c(C)c(OC)c1)C(C)(C)C
Temperature: 25 °C

Procedure:
(R)-3-methoxy-2-methyl-benzoic acid N′-(1-tert-butyl-butyl)-hydrazide (100 mg, 0.34 mmol) and 3,5-dimethoxy-4-methyl-benzoyl chloride (90 mg, 0.41 mmol) were dissolved in 1 mL methylene chloride. 1.5 eq. of ca. 25% K2CO3 was added, and the reaction mixture was stirred at room temperature and monitored by TLC. Upon completion, the phases were separated, adding additional CH2Cl2 and/or water as needed to aid manipulation. The CH2Cl2 phase was dried over MgSO4 or Na2SO4, and solvent was removed in vacuo to provide an oily solid. This was triturated with 1:1 hexane:ether and allowed to dry in air to yield (R)-3,5-Dimethoxy-4-methyl-benzoic acid N-(1-tert-butyl-butyl)-N′-(3-methoxy-2-methyl-benzoyl)-hydrazide. Rf=0.29 (2:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) δ 7.1 (t, 1H), 7.0 (s, NH 1H), 6.9 (d, 1H), 6.7 (s, 2H), 6.3 (d, 1H), 4.78 (m, 1H), 3.95 (s, 3H), 3.85 (2 s, 6H), 2.2 (s, 3H), 2.05 (m, 1H), 1.95 (s, 3H), 1.8 (m, 1H), 1.6 (m, 2H), 1.2+1.1+1.05 (3 s, 9H), 1.05 (m, 3H); HRMS (ESI) m/z calcd for C27H39N2O5 [M+H]+ 471.2859, found 471.2850, calcd for C27H38NaN2O5 [M+Na]+ 493.2670, found 493.2678.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[CH:2]=1.[F:9][C:10]([F:18])([F:17])[C:11]([C:13]([F:16])([F:15])[F:14])=[O:12]>[Cl-].[Al+3].[Cl-].[Cl-].Cl>[F:9][C:10]([F:18])([F:17])[C:11]([C:6]1[CH:5]=[CH:4][C:3]([CH3:7])=[CH:2][C:1]=1[CH3:8])([OH:12])[C:13]([F:16])([F:15])[F:14]
Reactant: Cc1cccc(C)c1
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)c(C)c1
Reaction time: 1 h
Yield: 89 %

Procedure:
A 1 L reactor was charged under nitrogen with 100.0 g (0.94 mol) of m-xylene and 6.3 g (0.047 mol/0.05 eq) of aluminum chloride, followed by adjusting the inside temperature to 10° C. Then, 164.2 g (0.99 mol/1.05 eq) of hexafluoroacetone was introduced in a temperature range of 10-25° C. After the introduction, stirring was conducted at room temperature for 1 hr. Then, 100 mL of 10% hydrochloric acid was added. The resulting aqueous layer was extracted two times with 40 mL of chloroform. The resulting organic layers were combined together, followed by removing water with anhydrous magnesium sulfate, filtration, concentration, and vacuum distillation, thereby obtaining 227.6 g of 4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]-1,3-dimethylbenzene represented by the following formula. Upon this, purity was 95%, and yield was 84%.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:11][C@@H:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@@H](N)C1

Procedure:
(R)-3-(Benzyloxycarbonylamino)-N-(t-butoxycarbonyl)-pyrrolidine (300 mg) was dissolved in ethanol (5 ml). Palladium on charcoal 10% (20 mg) was added. The reaction was degassed three times and put under hydrogen atmosphere (1 bar). The reaction was over after 2 hours. The solvent was removed, the residue was taken up in ethyl acetate (5 ml) and filtered through a silica gel pad. The silica was washed with ethyl acetate (50 ml). The organic phases were evaporated. The desired (R)-3-Amino-N-(t-butoxycarbonyl)-pyrrolidine was obtained as a colorless oil in a quantitative yield (175 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[F:15][CH:16]([F:34])[N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:18]1=[O:33].[H-].[Na+]>CN(C=O)C.CO>[F:34][CH:16]([F:15])[N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:28][CH:27]=2)[C:18]1=[O:33]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: O=c1n(-c2ccc(O)cc2)c2ncccc2n1C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: Cn1c(Oc2ccc(-n3c(=O)n(C(F)F)c4cccnc43)cc2)nc2cccnc21
Temperature: 180 °C
Yield: 28.7 %

Procedure:
3-Methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (90 mg) was added to a solution of 1-(difluoromethyl)-3-(4-hydroxyphenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (124 mg) and NaH (25.6 mg) in DMF (3 mL) at 100° C. The mixture was heated at 180° C. for 1 h under microwave irradiation. The reaction mixture was diluted with MeOH and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-50% EtOAc in hexane) to give 1-(difluoromethyl)-3-{4-[(3-methyl-3H-imidazo[4,5-b]pyridin-2-yl)oxy]phenyl}-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (50 mg) as white crystals.
Reaction SMILES: [C@@H:1]12[N:8]([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:10]([O:12]CC)=O.[Si](Cl)(C)(C)[CH3:16].[Li]C>C1COCC1>[C:10]([C:2]1[C@@H:1]2[N:8]([CH3:9])[C@H:5]([CH2:4][CH:3]=1)[CH2:6][CH2:7]2)(=[O:12])[CH3:16]
Reactant: CCOC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Reactant: C[Si](C)(C)Cl
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(=O)C1=CC[C@@H]2CC[C@H]1N2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a mixture, of ethyl trop-2-ene-2-carboxylate (3.43 g, 0.019 mol) and Me3SiCl (10.32 g, 0.095 mol) in THF (70 mL) cooled to -100° C., MeLi (1.4 M, 7.07 mL, 0.0239 mol) was added dropwise. After warming up to room temperature, the reaction mixture was stirred for 16 hours. Excess Me3SiCl and THF was evaporated off and the resulting residue was stirred with EtOH (6 mL) followed by water (6 mL). The mixture was then made acidic (6N HCl) and extracted with ether. The aqueous layer was made basic (solid K2CO3) and extracted with chloroform, dried (K2CO3) and concentrated to give 3.14 g (81%) of 2-acetyltrop-2-ene as an oil: IR (neat) 1670 (COCH3);
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[SH:19][C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)(O)[O-].[Na+].Cl>O.CC(C)=O>[NH2:13][CH:10]1[C:11](=[O:12])[N:8]2[C:7]([C:16]([OH:18])=[O:17])=[C:6]([CH2:5][S:19][C:20]3[S:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH2:15][S:14][C@H:9]12
Reactant: Sc1nc2ccccc2s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: NC1C(=O)N2C(C(=O)O)=C(CSc3nc4ccccc4s3)CS[C@H]12
Yield: 58.1 %

Procedure:
To a mixture of 7-aminocephalosporanic acid (23.1 g., purity 86.4%) and 2-mercaptobenzothiazole (14.7 g.) in water (800 ml.), sodium bicarbonate (13.5 g.) was added portionwise with stirring, and acetone (250 ml.) was added thereto. The mixture was stirred at 73° C. for 4.5 hours, cooled below 20° C. and adjusted to pH 3.4 with 6N hydrochloric acid. The precipitating crystals were collected by filtration, washed with water and acetone in turn and dried under reduced pressure to give 7-amino-3-(benzothiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (18.7 g.).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].[C-:14]#[N:15].[Na+].Cl>C(O)C.O>[C:14]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4])#[N:15]
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 0 °C

Procedure:
To a solution of 2-bromo-4′-nitroacetophenone (30 g, 0.123 mol) in ethanol (200 mL) at 0° C. was added a solution of NaCN (18 g, 0.368 mol) in H2O (60 mL) dropwise over 1 h. Upon completion of the addition, the mixture was stirred at 0° C. for an additional hour and then diluted with H2O (200 mL). The solution was treated with 1N aq. HCl solution, to a pH of 2, and extracted with CH2Cl2 (2×500 ML). The combined organic layers were dried over Na2SO4 and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel eluting with 1:1 hexane/EtOAc to obtain 2-cyano-4′nitroacetophenone as an orange solid.
Reaction SMILES: [N:1]1[C:10]2[CH2:9][CH2:8][CH:7]([C:11]([O:13][CH3:14])=[O:12])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.CS(C)=O>C(Cl)(Cl)Cl>[CH3:14][O:13][C:11]([CH:7]1[CH2:8][CH2:9][C:10]2[N+:1]([O-:23])=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:6]1)=[O:12]
Reactant: COC(=O)C1CCc2ncccc2C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CS(C)=O
Product: COC(=O)C1CCc2c(ccc[n+]2[O-])C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122.8 %

Procedure:
A 1-L flask was charged with methyl 5,6,7,8-tetrahydroquinoline-6-carboxylate (12.53 g, 65.52 mmol), chloroform (400 mL) and m-chloroperbenzoic acid (22.6 g, 91.7 mmol). The resulting solution was stirred at room temperature for 1 hour then dimethyl sulfoxide (2.8 mL, 39 mmol) was added to quench any remaining m-chloroperbenzoic acid and stirred at room temperature for 30 minutes. The mixture was poured into 2M Na2CO3 (400 mL). The aqueous layer was extracted with CHCl3 (3×200 mL), dried (Na2SO4), filtered and concentrated to afford a white solid (16.67 g). Chromatography on silica (0-15% MeOH in DCM) produced an off white solid (13.90 g, greater than theoretical), which was carried forward without additional purification. m/z=208.3 (M+H)+. NMR (400 MHz, CDCl3) δ 8.16 (d with fine str., J=5.8 Hz, 1H), 7.10-7.03 (m, 2H), 3.74 (s, 3H), 3.20 (app dt, J=13.9, 5.6 Hz, 1H), 3.11-2.99 (m, 2H), 2.93-2.82 (m, 1H), 2.79-2.71 (m, 1H), 2.39-2.30 (m, 1H), 2.05-1.92 (m, 1H).