Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[B-](F)(F)F.[F:6][CH2:7][CH2:8][C:9]1C=CC=C[C:10]=1[C:11](=N)[O-].[C:18]1([C@H:24]([NH2:33])[C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH2:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClCCl.C(N([CH2:42][CH3:43])CC)C>CCCCCC.O>[F:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:42]=1[C:43]1[NH:33][C@@H:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:26]=1
Reactant: N=C([O-])c1ccccc1CCF
Reactant: CCN(CC)CC
Reactant: N[C@@H](c1ccccc1)[C@@H](N)c1ccccc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: Fc1ccccc1C1=N[C@@H](c2ccccc2)[C@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 77.4 %

Procedure:
To a 100 ml flask was charged 5.00 g imidate 7 (19.6 mmol, 1 eq.), 4.16 g (S,S)-1, 2-diphenylethylenediamine (19.6 mmol, 1 eq.), 50 ml dichloromethane, and 6.3 ml triethylamine (45.3 mmol, 2.3 eq.) in the order given. After stirring 4 hours at ambient temperature, the reaction mixture was poured into 50 ml water, the phases separated, and the aq. phase reextracted with dichloromethane. The combined methylene chloride layers were washed with 2% aq. ammonium chloride, dried with magnesium sulfate, filtered, and the filtrate evaporated in vacuo to give an oil. This oil was dissolved in 25 ml boiling hexane, cooled to 0°, filtered and air dried to give 4.80 g of 2-(2′-fluorophenyl)-(4S,5S)-diphenyl4,5-dihydroimidazole 8 (78%) as a colorless solid. M.p. 122-124° C.; MS (ES+): MH+317; 19F NMR (CDCl3)δ: −113.6 ppm.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[C:18]([CH:19]=[CH2:20])=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[Cl:12][C:13]1[C:18]([CH:19]2[CH2:20][O:9]2)=[CH:17][C:16]([C:21]#[N:22])=[CH:15][C:14]=1[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27]
Reactant: C=Cc1cc(C#N)cc(NC(=O)OC(C)(C)C)c1Cl
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CO2)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
Added m-CPBA 50% (1.92 gm, 5.56 mmol) in portions to an ice-cooled solution of tert-butyl (2-chloro-5-cyano-3-vinylphenyl)carbamate (Example 399A)(517 mg, 1.86 mmol) in DCM (30 mL). The bath was removed and the reaction was left stirring at room temperature overnight. Added additional 50% MCPBA (0.6 gm) and left stirring overnight. Added 20 mL of 0.5 M NaHCO3 solution and left stirring for 4 hr. The aqueous phase was separated and washed with DCM. The combined organic phases were washed three times with 1 N Na2CO3 solution. After drying with sodium sulfate, the solvents were removed to leave crude tert-butyl (2-chloro-5-cyano-3-(oxiran-2-yl)phenyl)carbamate (516 mg, 94% yield). This was dissolved in a mixture of DCE (12 mi) and MeOH (6 mL) in a microwave vial. Ethanolamine (2.12 mL, 35.0 mmol) was added and the vial was sealed and heated at 60° C. overnight. The solvent was removed and the residue was taken up in DCM and washed with water (2×) and brine. After drying with sodium sulfate, the solvent was removed and radial silica gel chromatography eluting with DCM containing 0 to 14% MeOH and then 10% 2N NH3 in MeOH afforded tert-butyl (2-chloro-5-cyano-3-(1-hydroxy-2-((2-hydroxyethyl)amino)ethyl)phenyl)carbamate (337 mg).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([N:30]=[C:31]=[O:32])[CH:25]=1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:31](=[O:32])[NH:30][C:26]2[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:22])([F:34])[F:33])[CH:25]=2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: O=C1c2ccccc2SCCC1CO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(C(F)(F)F)c1)OCC1CCSc2ccccc2C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (256 mg, 1.23 mmol) in 15 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.19 ml, 1.4 mmol) and α,α,α-trifluoro-m-tolyl isocyanate (345 μl, 2.46 mmol). The mixture was stirred at room temperature for 2 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 180 mg (37%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]3[C:14]4[NH:15][C:16]5[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=5[C:22](=[O:23])[C:13]=4[CH2:12][N:11]3[CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:9][C:4]=2O[CH2:2]1.[CH:31]1C=C(Cl)C=C(C(OO)=O)C=1.CO.C(Cl)Cl>C(Cl)Cl.CN(C=O)C>[CH2:24]([N:11]1[CH:12]=[C:13]2[C:14]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[C:22]2=[O:23])=[C:10]1[C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:31][C:4]=2[CH:9]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=c1c2c([nH]c3ccccc13)C(c1ccc3c(c1)OCO3)N(Cc1ccccc1)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: O=c1c2ccccc2[nH]c2c(-c3ccc4c(c3)CCO4)n(Cc3ccccc3)cc12

Procedure:
3-Benzo[1,3]dioxol-5-yl-2-benzyl-1,2,3,4-tetrahydro-pyrrolo[3,4-b]quinolin-9-one, prepared as in WO 01/87882, Example 3, page 45, (39.6 mg, 0.1 mmol) in a mixture of CH2Cl2 (4 mL) and DMF (1 mL) was stirred with a solution of mCPBA (26 mg, 0.15 mmol) in CH2Cl2 (2 mL) at room temperature for 72 h. The product was isolated by preparative TLC (2.5% MeOH/CH2Cl2, Rf=0.72) to yield the title compound as a yellow solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[C:19](=[O:25])[CH:18]([CH2:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH2:17]2.C([O-])(=O)C.[Na+].C(=O)C1C=CC=CC=1>[Pd].CO>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[CH2:17][CH:18]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30]([CH2:11][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:29][CH2:28]3)[C:19](=[O:25])[C:20]2=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc2c(cc1OC)C(=O)C(CC1CCNCC1)C2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=Cc1ccccc1
Product: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Temperature: 25 °C
Reaction time: 10 h
Yield: 370.4 %

Procedure:
0.22 g of 2,3-dihydro-5,6-dimethoxy-2-((piperidin-4-yl)methyl)inden-1-one p-toluenesulfonic acid salt, and 0.10 g of sodium acetate were added to 60 mL of anhydrous methanol. 100 milligrams of 10% Pd/C were also added. The reaction mixture was stirred at room temperature with H2 being supplied at 1 atmosphere for 10 hours. 55 milligrams of benzaldehyde were added in equal portions at 0 hrs, 2 hrs, 4 hrs, 6 hrs and 8 hrs. Solids were filtered off. The filtrate was concentrated. 30 mL of 5% aqueous Na2CO3 solution were added, and the resulting mixture was extracted with 3×30 mL of ethyl acetate. The extracts were combined, washed with 15 mL of aqueous Na2CO3 solution and 15 mL of aqueous NaCl solution, and dried over anhydrous MgSO4. After solids were filtered off, solvent was removed in vacuo to afford 0.67 g of product as oil. Purification on silica gel column chromatography afforded 0.11 g of title compound in 62% yield.
Reaction SMILES: C(O)(=O)C.[NH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:16])[C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6]1.CN(C)C=O.I[CH2:23][CH:24]1[CH2:28][C:27]2[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=2[O:25]1.[ClH:33]>C(N(CC)CC)C>[ClH:33].[O:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[CH2:28][CH:24]1[CH2:23][N:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH3:16])[C:12](=[O:15])[CH2:13][CH3:14])[CH2:7][CH2:6]1
Reactant: CCC(=O)N(C)C1CCNCC1
Reactant: ICC1Cc2ccccc2O1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCC(=O)N(C)C1CCN(CC2Cc3ccccc3O2)CC1
Yield: 30 %

Procedure:
5.1 g of N-piperid-4-yl-N-methylpropionamide acetate, 90 ml of dimethylformamide and 6.3 ml of triethylamine are introduced into a 250 ml three-necked flask. 6.6 g of 2,3-dihydro-2-iodomethylbenzofuran are poured onto the mixture which is heated to 60°-65° C. This temperature is maintained for 15 hours. The reaction mixture is evaporated to dryness and the residue is taken up in ethyl acetate and extracted with 150 ml of N hydrochloric acid. The aqueous phase is rendered alkaline with sodium hydroxide in the presence of ethyl acetate. The organic phase is washed with water and dried over magnesium sulphate. The solvent is evaporated to yield a base in the form of a brown oil, which is converted into a salt with 3.8N ethereal hydrogen chloride to yield the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([NH:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.O.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>[CH3:20][NH:19][C:17]([C:15]1[CH:14]=[CH:13][C:12]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:22]4[S:21][CH:25]=[CH:24][CH:23]=4)[CH:3]=3)[CH:9]=[N:10][C:11]=2[CH:16]=1)=[O:18]
Reactant: CNC(=O)c1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: OB(O)c1cccs1
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: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc2c(c1)ncn2-c1cccc(-c2cccs2)c1

Procedure:
To a solution of 1-(3-bromophenyl)-N-methyl-1H-benzimidazole-5-carboxamide (20 mg, 0.06 mmol) and thiophene-2-boronic acid (9.0 mg. 0.073 mmol) in anhydrous DMF (0.6 mL) was added Pd(PPh3)4 (3.5 mg, 0.003 mmol) followed by a solution of Na2CO3 (19 mg, 0.18 mmol) in water (0.16 mL). The reaction was irradiated in the microwave for 10 min (200 W, 150° C.). After cooling, the reaction mixture was filtered through Celite and washed with EtOAc (15 mL). The combined organic layer was washed with saturated aqueous NaHCO3 solution (10 mL) followed by saturated aqueous solution brine (3×10 mL), dried (MgSO4) and evaporated to dryness. The crude product was purified by solid-phase extraction (Isolute SAX, followed by Isolute SCX), giving N-methyl-1-(3-thien-2-ylphenyl)-1H-benzimidazole-5-carboxamide as an off-white solid; 1H NMR (400 MHz, MeOH-d4): δ 8.57 (s, 1H), 8.27 (d, J=2 Hz, 1H), 7.89-7.86 (m, 2H), 7.78 (d, J=7.8 Hz, 1H), 7.66-7.62 (m, 2H), 7.52-7.54 (m, 2H), 7.45 (d, J=5.1 Hz, 1H), 7.12 (dd, J=3.5 Hz, 1.5 Hz, 1H), 2.97 (s, 3H); MS (ES+): m/z 333.9 (100%) [MH+].
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][NH:27][CH2:28][CH:29]([OH:37])[C:30]1[CH:31]=[CH:32][C:33]([OH:36])=[CH:34][CH:35]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:27]([CH2:28][CH:29]([OH:37])[C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[CH3:26])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:24][CH:25]=1
Reactant: CNCC(O)c1ccc(O)cc1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccc(O)cc2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (48 mg, 0.12 mmol), synephrine (Aldrich, 30 mg, 0.18 mmol) and diisopropylethylamine (31 μL, 0.18 mmol) in dry DMF (2.0 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 3 hours at that temperature. After cooling to room temperature, the solution was diluted with water (5 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (10 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (49 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]([Cl:17])([Cl:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:11]=1)[C:6](Cl)=[O:7].[CH3:18][N:19](C)CC1C=CC=CC=1.C#N.[C-]#N.[K+]>C(Cl)Cl.O>[Cl:1][C:2]([Cl:17])([Cl:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:11]=1)[C:6]([C:18]#[N:19])=[O:7]
Reactant: CN(C)Cc1ccccc1
Reactant: O=C(Cl)c1cc(C(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)c1
Agent: C#N
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N#CC(=O)c1cc(C(Cl)(Cl)Cl)cc(C(Cl)(Cl)Cl)c1

Procedure:
78 g of 3,5-bis-(trichloromethyl)-benzoyl chloride and 0.4 g of dimethylbenzylamine are dissolved in 500 ml of methylene chloride and, at -15° C., first a solution of 10 ml of hydrogen cyanide in 50 ml of methylene chloride and then a solution of 12.4 g of potassium cyanide in 20 ml of water are added dropwise. After 11/2 hours, the mixture is dried by means of sodium sulfate stirred in, the inorganic salts are filtered off with suction and the solvent is stripped off in vacuo. On addition of ether, 14 g (18% of theoretical) of dimeric 3,5-bis-(trichloromethyl)-benzoyl cyanide crystallize out from the remaining viscous residue. The remaining monomeric product is purified by double distillation in a bulb tube.
Reaction SMILES: [CH:1]1([NH:4][NH2:5])[CH2:3][CH2:2]1.[C:6]([O:12][CH2:13][CH3:14])(=O)[O:7]COC.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>CCO>[CH:1]1([N:4]2[C:16]([CH3:17])=[CH:15][C:20]([C:6]([O:12][CH2:13][CH3:14])=[O:7])=[N:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)OCOC
Reactant: Cc1ccccc1
Reactant: NNC1CC1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(C2CC2)n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a stirred solution of cyclopropylhydrazine (Step 17.2) (4.90 g, 45.1 mmol) in toluene (30 mL) and EtOH (30 mL) was added ethyl 2,4-dioxavalerate (6.34 mL, 45.1 mmol). The reaction mixture was stirred for 1 hr at 100° C., quenched with a saturated aq. NaHCO3 solution, and extracted with EtOAc. The organic layers were combined and washed with a saturated aq. NaHCO3 solution, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (hexane/EtOAc 2.5-30%) to afford the title product (3.74 g, 19.26 mmol, 43% yield). tR: 3.84 min (HPLC 1); tR: 0.84 min (LC-MS 2); ESI-MS: 195 [M+H]+ (LC-MS 2); Rf=0.50 (hexane/EtOAc 1:1).
Reaction SMILES: [O:1](C(C)(C)C)[K].[N+:7]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])#[C-:8].[CH3:15][C:16]([CH3:22])([CH:19]([CH3:21])[CH3:20])[CH:17]=O.CCOCC>O.CC(O)=O>[CH2:13]([O:12][C:10](=[O:11])[C:9]([NH:7][CH:8]=[O:1])=[CH:15][C:16]([CH3:22])([CH3:17])[CH:19]([CH3:21])[CH3:20])[CH3:14]
Reactant: CC(C)C(C)(C)C=O
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: CC(C)(C)O[K]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(=CC(C)(C)C(C)C)NC=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 65.1 %

Procedure:
A clean and dry 250 mL round-bottom flask was equipped with a stir bar and flushed with Ar. Dry THF was added (40 mL) followed by addition of a 1.0 M solution of KO-t-Bu (32.2 mL, 32.2 mmol, 1.05 equiv). The solution was cooled to −78° C. in a dry-ice/acetone bath. Ethyl isocyanoacetate (3.35 mL, 30.7 mmol, 1.0 equiv) was added dropwise over a 10 min period. The resulting mixture was stirred an additional 5 min followed by addition, via syringe, of 2,2,3-trimethyl-butanal (3.5 g, 30.7 mmol, 1.0 equiv). The cold-bath was removed and resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted by addition of a mix of 125 mL Et2O, 20 g ice, 2 mL AcOH. After the ice melted, 50 mL of water was added and the layers were mixed and separated. The organic layer was washed with 1×50 mL sat. NaHCO3 and dried over Na2SO4. The organic layer was decanted and concentrated. The crude enamide was purified by flash chromatography on silica gel using CH2Cl2 to 4% MeOH in CH2Cl2 to provide 2-formylamino-4,4,5-trimethyl-hex-2-enoic acid ethyl ester as a thick oil (4.54 g); MS: 228 (M+1).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1.[OH-:26].[K+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:9]2[CH2:14][CH2:13][C:12](=[O:26])[CH2:11][CH2:10]2)=[O:22])=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: O=C1CCCCN1
Reactant: [OH-]
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(C(=O)c2ccc(Cl)cc2)CC1
Temperature: -10 °C
Reaction time: 16 h

Procedure:
Triethylamine (4.4 g, 43.0 mmol) and a catalytic amount of DMAP were added to a solution of piperidone hydrochloride (3.0 g, 19.5 mmol) in CH2Cl2 (20 ml). After cooling to −10° C., 4-chlorobenzoyl chloride (3.8 g, 21.5 mmol) dissolved in CH2Cl2 (10 ml) was slowly added and the mixture was stirred at RT for 16 h. 5M potassium hydroxide solution (20 ml) was added to the suspension, the organic phase was separated off and the aqueous phase was extracted with CH2Cl2 (3×10 ml). After drying of the combined organic phases over Na2SO4, filtration and removal of the solvent, the product 1-(4-chlorobenzoyl)piperidin-4-one was obtained in a yield of 4.4 g (95%).
Reaction SMILES: C(Cl)(Cl)=O.[CH:5]([NH:7][C@@H:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18][CH:19]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=O.N1C=CC=CC=1>C(Cl)Cl>[N+:7]([C@@H:8]1[C:32](=[O:33])[N:10]2[C:11]([C:16]([O:18][CH:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)#[C-:5]
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Agent: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: [C-]#[N+][C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C)CS[C@H]12
Yield: 81.5 %

Procedure:
A solution of phosgene (3.27 g., 33 mmole) in methylene chloride (ca. 25 ml.) at =20° was added to a stirred solution of diphenylmethyl (6R, 7R)-7-formamido-3-methyl-ceph-3-em-4- carboxylate (prepared as described in Belgian Pat. No. 761,897) (12.24 g., 30 mmole) in methylene chloride (500 ml.) containing pyridine (12 ml., 150 mmole), at -20°. The solution was washed with water (2 × 250 ml.) and the organic layers combined with the methylene chloride backwash (250 ml.) of the aqueous layers, dried, and evaporated to a brown foam, which was then dissolved in ethyl acetate (100 to 150 ml.). This solution was added to petroleum-ether (b.p. 40° to 60°) to precipitate the product, which was isolated by filtration and dried to give the title compound as a pale-pink solid (9.539 g., 24.4 mmole, 81.5%); m.p. 117° - 118°; [α]D ± 0°; λmax. 252.5 nm (ε 7,030); λinf. 257,263.5 nm (ε 6,960; 6,480); νmax. 2150 (C=N), 1795 (azetidin-2-one), 1722 (CO2R), 1498, 752 and 735 cm.-1 ( [C6H5 ]2CH); τ 2.40 to 2.80 (m,[C6H5 ]2CH), 3.04 (s,[C6H5 ]2CH), 4.88 (d, J 4.5 Hz, C7 -H), 5.10 (d, J 4.5 Hz, C6 -H), 6.69 (s, C2 -H2), 7.81 (s, C 3 -CH3). (Found: C, 67.2; H, 4.8; N, 6.9; S, 8.1; C22H18N2O3S (390.4) requires: C, 67.6; H, 4.6; N, 7.2; S, 8.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[O:10][C:11]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:19][CH:18]=2)=[C:12]([C:14]([NH2:16])=[O:15])[N:13]=1.[CH3:29][N:30]=[C:31]=[O:32]>C(Cl)Cl>[C:14]([C:12]1[N:13]=[C:9]([C:3]2[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[O:10][C:11]=1[C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:24][CH2:25][N:26]([C:31]([NH:30][CH3:29])=[O:32])[CH2:27][CH2:28]2)=[CH:21][CH:22]=1)(=[O:15])[NH2:16]
Reactant: CN=C=O
Reactant: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Product: CNC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.7 %

Procedure:
To a suspension of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.029 g, 0.075 mmol) in DCM (3 mL) was added methyl isocyanate (8 uL, 0.136 mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo to afford 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)phenyl)-N-methylpiperazine-1-carboxamide (0.026 g, 0.059 mmol, 79%) as a yellow solid. 1H NMR (DMSO) 2.85 (3H, d), 3.34 (4H, m), 3.56 (4H, m), 4.46 (1H, br. q), 5.49 (1H, br. s), 6.95 (2H, d), 7.07 (2H, t), 7.20 (1H, br. s), 7.46 (1H, m), 8.32 (2H, d). LCMS (2) Rt: 2.43 min; m/z (ES+) 442.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[NH:8][CH:9]=[CH:10][C:6]=2[C:5]([C:11]([OH:13])=O)=[CH:4][N:3]=1.Cl.[CH:15]1([CH2:19][NH2:20])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][NH:20][C:11]([C:5]2[C:6]3[CH:10]=[CH:9][NH:8][C:7]=3[C:2]([Cl:1])=[N:3][CH:4]=2)=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: NCC1CCC1
Reactant: O=C(O)c1cnc(Cl)c2[nH]ccc12
Agent: Cl
Product: O=C(NCC1CCC1)c1cnc(Cl)c2[nH]ccc12

Procedure:
Prepared in a similar manner to Example 19 (e) from 7-chloro-1H-pyrrolo[2,3-c]pyridine-4-carboxylic acid using cyclobutylmethylamine hydrochloride (46 mg) instead of tetrahydro-pyran-4-ylmethylamine to give the title compound (39 mg).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:23]([C:24](=[O:27])[NH:25][CH3:26])=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)[O:21][C:5]2=[N:6][C:7]=1[N:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:9]([CH3:12])(=[O:11])=[O:10].[C:35]1([CH3:41])C=CC=C[CH:36]=1>>[CH:41]1([C:2]2[CH:3]=[C:4]3[C:23]([C:24](=[O:27])[NH:25][CH3:26])=[C:22]([C:28]4[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=4)[O:21][C:5]3=[N:6][C:7]=2[N:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:9]([CH3:12])(=[O:11])=[O:10])[CH2:35][CH2:36]1
Reactant: Cc1ccccc1
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(I)cc12
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCCCC(=O)OC)S(C)(=O)=O)c(C3CC3)cc12
Yield: 67 %

Procedure:
The methyl 5-(N-(5-iodo-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)pentanoate (35 mg, 0.058 mmol) was suspended/dissolved in 1 mL toluene and added to 2. 1 was added to 2. The biphasic mixture was degassed for 5 min, then microwaved at 122° C. for 10 min. The mixture was then heated again at the same temperature for another 2×10 min. HPLC purification yielded methyl 5-(N-(5-cyclopropyl-3-(methylcarbamoyl)-2-p-tolylfuro[2,3-b]pyridin-6-yl)methylsulfonamido)pentanoate (20 mg, 0.039 mmol, 67%) MS-ES [M+H]+=513.9, LC RT=1.60 min, Method A.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH:12][CH2:13][CH3:14])[N:8]=[CH:7][N:6]=[C:5]2[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[S:30])[NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16]1.N1C=CC=C[CH:32]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Na+]>CN(C)C=O.O>[CH2:23]([NH:22][C:21]([N:18]1[CH2:19][CH2:20][N:15]([C:5]2[C:4]3[CH:3]=[C:2]4[N:1]=[CH:32][N:12]([CH2:13][CH3:14])[C:11]4=[CH:10][C:9]=3[N:8]=[CH:7][N:6]=2)[CH2:16][CH2:17]1)=[S:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccncc1
Reactant: CCNc1cc2ncnc(N3CCN(C(=S)NCc4ccccc4)CC3)c2cc1N
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCn1cnc2cc3c(N4CCN(C(=S)NCc5ccccc5)CC4)ncnc3cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 55 %

Procedure:
To a solution of 504.4 mg (1.20 mmol) of 4-(6-amino-7-ethylamino-4-quinazolinyl)-N-benzyl-1-piperazinethiocarboxamide obtained in Example 461 in 10 ml of dimethylformamide were added 0.29 ml (3.60 mmol) of pyridine and 0.13 ml (1.49 mmol) of oxalyl chloride under ice-cooling, followed by overnight stirring at room temperature in an atmosphere of argon. Then, the resulting mixture was heated at 80° C. with stirring for 5 hours. The reaction mixture was allowed to cool to room temperature and then poured into water, and sodium chloride was added thereto. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel chromatography to give the desired compound as colorless crystals.