Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[CH3:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH:7]1N.C([O-])(=O)C>O1CCOCC1>[CH3:5][CH:6]1[CH2:11][CH:10]([CH3:12])[CH2:9][CH2:8][CH:7]1[NH:1][C:2](=[O:3])[NH2:4]
Reactant: NC(N)=O
Reactant: CC1CCC(N)C(C)C1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC1CCC(NC(N)=O)C(C)C1

Procedure:
8.2 g of N-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-urea.(melting point 171°-173°C) are suspended in 150 ml of dioxane and heated under reflux for 1 hour after addition of 3.75 g of 2.4-dimethyl-cyclohexyl-amine-acetate. Then the solvent is distilled off in vacuo and water is added to the residue. The crystals obtained of N-[4-(β-<2-methoxy5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-(2.4-dimethylcyclohexyl)-urea are recrystallized from methanol/dimethyl formamide and melt at 200°-201°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[S:5][CH:6]=1.[CH2:9]([Mg]Br)[CH3:10]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]([OH:8])[CH2:9][CH3:10])[S:5][CH:6]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 g (157 mmol) of 4-bromo-2-thiophenecarboxaldehyde are dissolved in 200 mL of anhydrous THF. 104 mL (312 mmol) of 3.0 M ethylmagnesium bromide are added slowly and the medium is stirred for 2 hours at room temperature. After the usual treatment, an orange-coloured oil is obtained (m=33.5 g; Y=96%).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:3].CS(O[CH:17]1[CH2:20][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:18]1)(=O)=O>>[CH3:3][N:2]([CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH:17]2[CH2:18][N:19]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20]2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CN(C)Cc1ccc(O)cc1
Product: CN(C)Cc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)cc1
Yield: 87 %

Procedure:
Using a similar protocol as described in Example 29C employing 4-((dimethylamino)methyl)phenol (8.4 g, 55.5 mmol) and tert-butyl 3-(methylsulfonyloxy)azetidine-1-carboxylate (16.8 g, 66.7 mmol) as starting materials afforded 14.8 g (75%) of 33A as an oil. 1H NMR (500 MHz, CDCl3): δ 1.40 (s, 9H), 2.55 (s, 6H), 3.90 (s, 2H), 4.00 (m, 2H), 4.30 (m, 2H), 4.85 (m, 1H), 6.75 (d, 2H), 7.35 (d, 2H), MS (APCI+) m/z 307 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: COc1cccc(/C(=C\C=C\C(=O)O)c2ccccc2)c1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.5 %

Procedure:
As in Example 115, (2E,4Z)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (2.85 g) and 4-nitrophenol (1.56 g) in dichloromethane (35 mL) was treated with 1,3-dicyclohexylcarbodiimide (2.1 g) and the mixture was stirred at room temperature for 75 minutes. The usual work up furnished 3.5 g of crude product which was crystallized from 2-propanol to give 3.0 g of (2E,4Z)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 155°-157° C. Anal. Calculated for C24H19NO5 : C, 71.81; H, 4.77; N, 3.49 Found: C, 72.09; H, 5.03; N, 3.55.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[C:20]([Cl:27])[C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([O:18]C)=[C:9]([S:11]([CH2:14][CH:15]2[CH2:17][CH2:16]2)(=[O:13])=[O:12])[CH:10]=1.B(Br)(Br)Br.O>C(Cl)Cl>[CH:15]1([CH2:14][S:11]([C:9]2[CH:10]=[C:5]([O:4][C:3]3[C:2]([Cl:1])=[CH:23][C:22]([N+:24]([O-:26])=[O:25])=[CH:21][C:20]=3[Cl:27])[CH:6]=[CH:7][C:8]=2[OH:18])(=[O:12])=[O:13])[CH2:16][CH2:17]1
Reactant: COc1ccc(Oc2c(Cl)cc([N+](=O)[O-])cc2Cl)cc1S(=O)(=O)CC1CC1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Cl)c(Oc2ccc(O)c(S(=O)(=O)CC3CC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.1 %

Procedure:
To a solution of 5-(2,6-dichloro-4-nitro-phenoxy)-2-methoxy-(cyclopropyl-methane-sulfonyl)-benzene (160 mg, 0.37 mmol) in CH2Cl2 (3 mL) was added boron tribromide (1M in CH2Cl2, 0.74 mL, 0.74 mmol). The resulting mixture was stirred at room temperature for 2 h and water (15 mL) was added. After stirring at room temperature for 1 h, the solution was extracted with EtOAc (3×20 mL). The combined organic extracts were dried and concentrated. The residue was purified by preparative TLC (100% CH2Cl2) to afford the title compound of Step D (76 mg). MS (APCI−) Calc.: 417.0, Found: 416.2 (M−1).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:5]([CH2:26][CH3:27])[C:6]([N:8]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[CH3:25])(=[O:17])=[O:16])=[N:9]1)=[O:7])[CH3:4].O>CO>[CH2:26]([N:5]([CH2:3][CH3:4])[C:6]([N:8]1[CH:12]=[C:11]([CH2:13][OH:14])[C:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[CH3:25])(=[O:17])=[O:16])=[N:9]1)=[O:7])[CH3:27]
Reactant: CCN(CC)C(=O)n1cc(C=O)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)n1cc(CO)c(S(=O)(=O)c2cccc(Cl)c2C)n1
Reaction time: 0.5 h

Procedure:
11 mg of sodium borohydride were added at 0° C. to a solution of 112 mg of 1-(diethylcarbamoyl)-3-(2-methyl-3-chlorophenylsulfonyl)-4-formylpyrazole [prepared as described in Example 9(3)] in 3.5 ml of methanol, and the resulting mixture was stirred for 30 minutes. At the end of this time, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated by evaporation under reduced pressure. The concentrate was purified by column chromatography through silica gel, eluted with a 5:1 by volume mixture of hexane and ethyl acetate, to afford 114 mg (a quantitative yield) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[I-].[K+]>C(N(C(C)C)CC)(C)C.C(OCC)C>[F:1][C:2]([F:6])([F:5])[CH2:3][NH:4][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CBr
Reactant: NCC(F)(F)F
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCOC(=O)CNCC(F)(F)F
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
2,2,2-trifluoroethylamine (2.0 g) was added to a suspension of ethyl bromoacetate (2.3 mL), potassium iodide (0.34 g) in diisopropylethylamine (3.3 mL) and the mixture was stirred at RT for 5.5 h. The mixture was diluted with diethyl ether (30 mL), stirred at RT for 30 mins. The suspension was filtered and concentrated under reduced pressure. The sub-title compound (2.6 g) was obtained as a yellow oil; 1H NMR (300 MHz, CDCl3); 4.19 (2H, q), 3.50 (2H, s), 3.22 (2H, q), 1.26 (3H, t).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6](Cl)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[I-].[Na+].[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)(C)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]([N:18]2[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCNC1
Reactant: Clc1ccc(C(Cl)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)O
Product: Clc1ccc(C(c2ccccc2)N2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-chlorobenzhydryl chloride (5.32 g, 22.4 mmol), isopropanol (80 ml) and sodium iodide (3.41 g, 22.8 mmol) was stirred at room temperature for 30 minutes. Thereto was added homopiperazine (11.2 g, 112 mmol), and the mixture was stirred at 95° C. for 18 hours. The solvent was distilled off, and the concentrate was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated. The thus-obtained crude product was used for the next reaction without purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:11]3=[C:12]4[CH:18]=[CH:17][NH:16][C:13]4=[N:14][CH:15]=[C:10]3[NH:9][N:8]=2)[CH2:2]1.Cl[C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CCO>[C:7]1([CH:3]2[CH2:4][CH2:5][CH2:6][N:1]([C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][N:21]=3)[CH2:2]2)[C:11]2=[C:12]3[CH:18]=[CH:17][NH:16][C:13]3=[N:14][CH:15]=[C:10]2[NH:9][N:8]=1
Reactant: c1cc2c(ncc3[nH]nc(C4CCCNC4)c32)[nH]1
Reactant: N#Cc1ccc(Cl)nc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)nc1
Temperature: 120 °C
Yield: 5.4 %

Procedure:
A mixture of 1-(piperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.16 g, 0.65 mmol, Example #26, Step E) and 6-chloronicotinonitrile (0.090 g, 0.65 mmol) with DIEA (0.37 mL, 2.12 mmol) in EtOH (3 mL) was heated at about 120° C. for about 15 min in a microwave reactor. The crude material was purified by RP-HPLC (Table 2, Method h) to give 6-(3-(3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridin-1-yl)piperidin-1-yl)nicotinonitrile (0.012 g, 6%): LC/MS (Table 2, Method a) Rt=1.96 min; m/z: 344 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([O:16][CH3:17])[C:13]([OH:15])=O)[CH:8]=2)[O:3]1.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=1>>[C:20]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:13](=[O:15])[CH:12]([C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[O:3][C:2]([CH3:1])([CH3:18])[CH2:11][CH2:10]3)[O:16][CH3:17])=[CH:23][CH:22]=1)#[N:19]
Reactant: COC(C(=O)O)c1ccc2c(c1)CCC(C)(C)O2
Reactant: N#Cc1ccc(CN)cc1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc2c(c1)CCC(C)(C)O2

Procedure:
(RS)-(2,2-Dimethyl-chroman-6-yl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure C to give (RS)-N-(4-cyano-benzyl)-2-(2,2-dimethyl-chroman-6-yl)-2-methoxy-acetamide. Off-white semi-solid. MS 365.2 ([M+H]+)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[CH:16])[CH:6]=1)=[O:4].[I:19][C:20]1[CH:25]=[CH:24][C:23](I)=[CH:22][CH:21]=1>CN(C=O)C.[Cu]I>[F:18][C:2]([F:1])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]#[C:16][C:23]2[CH:24]=[CH:25][C:20]([I:19])=[CH:21][CH:22]=2)[CH:6]=1)=[O:4]
Reactant: C#CCn1cc(C(=O)C(F)(F)F)c2ccccc21
Reactant: Ic1ccc(I)cc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: O=C(c1cn(CC#Cc2ccc(I)cc2)c2ccccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.8 %

Procedure:
A mixture of product of Step B (0.25 g, 1 mmol), 1,4 di-iodobenzene (0.4 g, 1.2 mmol) Cl2Pd(PPh3)2 (0.06 g) and catalytic amount of CuI in a mixture of DMF:DIPEA (10 ml: 0.5 ml) at room temperature was degassed under reduced pressure and saturated with N2. This was stirred overnight at room temperature, quenched with NaHCO3 solution and diluted to 50 ml with EtOAc. The organic layer was separated and washed with H2O, dried over MgSO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the title compound (0.28 g, 51%), as light yellow solid. 1H-NMR (CDCl3) 8.43-8.40 (b, 1H); 8.12 (b, 1H); 7.66 (t, 2H, J=8.36 Hz); 7.55-7.51 (m, 1H); 7.44-7.38 (m, 2H); 7.14 (d, 2H, J=8.30 Hz); 5.16 (s, 2H).
Reaction SMILES: [Mg].[CH:2]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:9]([C:17]([O:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[O:18])(=[O:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cl-].[NH4+]>C1COCC1.O>[CH:2]1([C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([OH:16])[C:17]([O:19][C:20]([CH3:24])([CH3:23])[C:21]#[CH:22])=[O:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: BrC1CCCCC1
Reactant: C#CC(C)(C)OC(=O)C(=O)c1ccccc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C#CC(C)(C)OC(=O)C(O)(c1ccccc1)C1CCCCC1
Reaction time: 18 h

Procedure:
A Grignard reagent, prepared from 3.38 g magnesium and 2.27 g cyclohexyl bromide in anhydrous THF in the usual way, was added dropwise under a nitrogen gas stream to a solution of 1,1-dimethyl-2-propynyl benzoylformate in anyhdrous THF under ice cooling, and stirring was continued for 18 hours under cooling with water. A solution of 7.5 g ammonium chloride in 30 ml water was then added under ice cooling. The separated organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The oily residue was purified by silica gel column chromatography (Wako Gel C-200; 1:15 mixture of ethyl acetate and n-hexane), giving 17.6 g of the objective compound as oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[S:14]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15]1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>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.O>[S:14]1[CH:18]=[CH:17][C:16]([C:2]2[CH:3]=[C:4]([N:8]3[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:15]1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cc(-c2ccsc2)cc(N2CCNCC2)c1
Temperature: 25 °C
Yield: 83.8 %

Procedure:
A mixed solution of 1-(3-bromophenyl)-piperazine (300 mg, 1.24 mmol), 3-thienylboronic acid (239 mg, 1.87 mmol), tetrakis(triphenylphosphine)palladium (173 mg, 0.149 mmol), 2N aqueous solution of sodium carbonate (4.98 ml, 9.95 mmol), and toluene (12 ml) was stirred at 95° C. for 15 hours under a nitrogen atmosphere. After cooling to room temperature, water was poured into the reaction solution, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduce pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate) to give the titled compound 254 mg (83.5%) as an oil.
Reaction SMILES: [CH2:1]([S:3]([C:5]1[CH:12]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:10]=[C:9]([CH3:19])[C:6]=1[C:7]#[N:8])=[O:4])[CH3:2].[OH-:20].[Na+]>C(O)C.O>[CH2:1]([S:3]([C:5]1[CH:12]=[C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[CH:10]=[C:9]([CH3:19])[C:6]=1[C:7]([NH2:8])=[O:20])=[O:4])[CH3:2]
Reactant: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C#N
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCS(=O)c1cc(N2CCOCC2)cc(C)c1C(N)=O
Temperature: 80 °C
Yield: 36 %

Procedure:
To a stirred solution of 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzonitrile (0.78 g, 2.81 mmol) in ethanol (8.5 ml) is added a 5M solution of sodium hydroxide (8.5 ml) and the mixture is heated at 80° C. for 16 h. After completion of the reaction (monitored by TLC) the reaction mixture is concentrated to get a residue, which is diluted with water (10 ml) and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (10 ml), brine (10 ml), dried over anhydrous sodium sulfate and evaporated to get the crude product which is purified by column chromatography (alumina, 5% methanol/dichloromethane) to yield 2-(ethylsulfinyl)-6-methyl-4-morpholin-4-yl-benzamide (0.30 g, 1.01 mmol, 36%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([OH:29])=O)[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:34][C@@H:35]1[C:60](=[O:61])[N:37]2[C:38]([C:44]([O:46][CH:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])=[C:39]([CH2:42][Cl:43])[CH2:40][S:41][C@H:36]12.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH3:32])/[C:27]([NH:34][C@@H:35]2[C:60](=[O:61])[N:37]3[C:38]([C:44]([O:46][CH:47]([C:48]4[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:45])=[C:39]([CH2:42][Cl:43])[CH2:40][S:41][C@H:36]23)=[O:29])[N:25]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C

Procedure:
To 25 ml of N,N-dimethylformamide were added 1.3 g (3 mmol) of (Z)-2-(2-tritylaminothiazol-4-yl)-2-methoxyiminoacetic acid and 1.35 (3 mmol) of diphenylmethyl 7 β-amino-3-chloromethyl-ceph-3-em-4-carboxylate hydrochloride. The mixture was cooled to 0° C., and 0.53 g (3.9 mmol) of N-hydroxybenzotriazole hydrate and then 0.80 g (3.9 mmol) of N,N-dicyclohexylcarbodiimide were added thereto.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([N:12]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([C:26]([F:29])([F:28])[F:27])[CH:20]=2)(=[O:18])=[O:17])COC)=[CH:10][C:9]([CH3:30])=[CH:8][N:7]=1)=[O:5].I[C:33]1[C:34]2[CH:41]=[CH:40][N:39](COCC[Si](C)(C)C)[C:35]=2[N:36]=[CH:37][N:38]=1.CO.Cl>C1COCC1.C([Mg]Cl)(C)C>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([S:16]([NH:12][C:11]2[C:6]([C:4]([C:33]3[C:34]4[CH:41]=[CH:40][NH:39][C:35]=4[N:36]=[CH:37][N:38]=3)=[O:5])=[N:7][CH:8]=[C:9]([CH3:30])[CH:10]=2)(=[O:18])=[O:17])=[CH:20][C:21]=1[C:26]([F:29])([F:27])[F:28]
Reactant: C[Si](C)(C)CCOCn1ccc2c(I)ncnc21
Reactant: COCN(c1cc(C)cnc1C(=O)N(C)OC)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(C(=O)c2ncnc3[nH]ccc23)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1

Procedure:
Prepared from 200 mg (0.42 mmol) of 3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-5-methyl-pyridine-2-carboxylic acid methoxy-methyl-amide, 202 mg (0.50 mmol) of 90% 4-iodo-7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine dissolved in 2 mL THF with 0.25 mL of 2 M isopropylmagnesium chloride solution in THF added. All of the resulting intermediate ketone was used in the second step with 2 mL methanol and 2 mL 6N hydrochloric acid mixture to give after purification 29 mg of the final product as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]([OH:14])=O)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:15][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[O:14])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: Nc1ccccc1
Product: COc1cccc2cc(C(=O)Nc3ccccc3)oc12

Procedure:
Substantially the same procedure as in Example 219 was repeated using a starting material, 7-methoxybenzofuran-2-carboxylic acid, and aniline to give N-phenyl-7-methoxybenzofuran-2-carboxamide (Compound 249a). Successively, it was formylated to give N-phenyl-4-formyl-7-methoxybenzofuran-2-carboxamide (Compound 249b), then compound 249b was reacted with methylamine hydrochloride to give compound 249 as a white solid.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[O:21]1CCOCC1>>[C:14]1([P:7](=[O:21])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C1COCCO1
Agent: Cl
Product: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Intermediate 2 (25.72 g, 40 mmol) was suspended in a solution of triphenylphosphine (10.94 g, 41.7 mmol) and 5% aqueous hydrochloric acid (2 mL) in 1,4-dioxane (200 mL). Stirring at room temperature in a stoppered flask for 2 h produced a solution of the product 3 and triphenylphosphine oxide. The reaction was worked up with ether and brine giving a solid from which 3 was extracted with hexanes at room temperature. The yield of 3 was 26.58 g (82.4 mmol, 103%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.Cl.[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][NH:27][CH2:26]1>>[NH2:23][CH2:24][CH:25]1[C:29](=[N:30][O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28][N:27]([C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:16])[CH2:26]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)ON=C1CNCC1CN
Agent: Cl
Product: CC(C)(C)ON=C1CN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1CN
Temperature: 25 °C
Yield: 67.3 %

Procedure:
141 mg (0.5 mmole) of 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and 143 mg (0.55 mmole) of 3-aminomethyl-4-t-butyloxyiminopyrrolidine dihydrochloride were refluxed for 2.5 hours under heating according to the same manner as Example 89 and cooled down to room temperature. Then, the resulting product was then separated and purified with preparative HPLC to obtain. 151 mg (Yield: 67%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[F:10].[NH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:15][CH2:16]2)=[CH:4][C:3]=1[F:10]
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: O=Cc1ccc(Cl)c(F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)c(F)c2)CC1
Reaction time: 24 h
Yield: 105.2 %

Procedure:
4-Chloro-3-fluorobenzaldehyde (0.793 g) and tert-butyl 4-piperidinylcarbamate (1.00 g) were stirred under nitrogen in dried tetrahydrofuran (25 ml). Sodium triacetoxyborohydride (1.266 g) was then added and left for 24 hours. Saturated sodium hydrogen carbonate was added to the reaction, with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave tert-butyl 1-(4-chloro-3-fluorobenzyl)-4-piperidinylcarbamate (1.80 g) as a white solid.