Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=O)[CH3:4].[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]=1>C(O)C>[CH3:4][C:3]1[N:6]=[C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][N:8]2[CH:2]=1
Reactant: CC(=O)CCl
Reactant: COc1ccc(N)nc1
Solvent: CCO
Product: COc1ccc2nc(C)cn2c1
Yield: 54 %

Procedure:
0.74 g (8.04 mW of chloroacetone is added to a solution of 0.5 g (mM) of 2-amino-5-methoxypyridine in 17 ml of ethanol. The mixture is refluxed for 20 hours and then concentrated under reduced pressure. Ethyl acetate is added to the evaporation residue and the organic phase is washed with a saturated aqueous solution of sodium bicarbonate and then with a saturated solution of sodium chloride. The organic phase is subsequently dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The evaporation residue is purified by NH2 (amino group)-grafted silica gel chromatography, elution being carried out with a toluene/isopropyl alcohol mixture (99/1; v/v). The expected product is obtained in the form of an orange oil with a yield of 54%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[C:6](=[C:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:25])(=O)C.[N:26]1([CH2:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>>[N:26]1([CH2:32][C:33]2[CH:34]=[CH:35][C:36]([NH:37]/[C:17](=[C:6]3\[C:5](=[O:25])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([F:15])([F:14])[F:16])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:38][CH:39]=2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Nc1ccc(CN2CCCCC2)cc1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccc(C(F)(F)F)cc21
Product: O=C1Nc2cc(C(F)(F)F)ccc2/C1=C(/Nc1ccc(CN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-6-trifluoromethyl-2-indolinone and 4-(piperidin-1-yl-methyl)-aniline
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9](C=O)[NH:8][C:7]=1[CH2:19][CH2:20][NH:21]C(OC(C)(C)C)=O)=[O:5])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:9][NH:8][C:7]=1[CH2:19][CH2:20][NH2:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCNC(=O)OC(C)(C)C)[nH]c(C=O)c1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccccc2)c[nH]c1CCN
Reaction time: 3 h

Procedure:
A stirred solution of 2-(2-tert-butoxycarbonylamino-ethyl)-5-formyl-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.120 g, 3 mmol) in dichloromethane (32 ml) was added dropwise slowly with trifluoroacetic acid (3.2 ml) at room temperature. Upon completion of the addition, the mixture was stirred for 3 hours, and concentrated to give 2-(2-amino-ethyl)-4-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester which was used as such.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:11][C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.I[CH2:15][CH3:16].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[N:11]([CH2:15][CH3:16])[C:10]([CH3:13])([CH3:12])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: CCI
Reactant: CC1(C)Cn2c(cc(Cl)nc2=O)N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCN1c2cc(Cl)nc(=O)n2CC1(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
To a solution of 7-chloro-2,2-dimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (100 mg, 0.501 mmol) and iodoethane (94.0 mg, 0.601 mmol) in acetonitrile (4 mL) was added Cs2CO3 (326 mg, 1.00 mmol). The reaction mixture was stirred at 90° C. for 1 h, filtered and concentrated to afford the crude product (110 mg) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([CH:31]=3)[C:28](O)=[O:29])=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.CN.[CH3:35][N:36](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([C:28]([NH:36][CH3:35])=[O:29])[CH:31]=3)=[O:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:18])([F:17])[F:19])=[CH:6][CH:7]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Agent: CN
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1cncc(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
5-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylcarbamoyl]-nicotinic acid (120 mg, 260 μmol) and methylamine hydrochloride (140 mg, 2.6 mmol) were dissolved in DMF (3 mL). TBTU (125 mg, 390 μmol) and DIPEA (672 mg, 908 μl, 5.2 mmol) were added. The reaction mixture was stirred at room temperature for 20 h. The crude reaction mixture was concentrated in vacuo and purified by flash chromatography (silica gel, 10 g, 0% to 100% ethyl acetate in heptane) to deliver 34 mg (28%) of the title compound as white solid; LC-MS (UV peak area/ESI) 99.5%, 465.0928 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([NH:13][C:14](=O)[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:29])=O>>[CH2:1]([NH:8][C:9]1[CH:18]=[C:17]2[C:12]([N:13]=[C:14]([Cl:29])[C:15]3[N:16]2[CH:19]=[CH:20][N:21]=3)=[CH:11][C:10]=1[C:23]([F:26])([F:25])[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(NCc3ccccc3)cc2n2ccnc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1NCc1ccccc1
Yield: 47 %

Procedure:
A solution of 8-(benzylamino)-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (72 mg; 0.2 mmol; 1 eq) and N,N′-dimethylaniline (0.2 ml) in phosphoryl chloride (2 ml) is stirred at 135° C. under argon for 2 h. Concentration, partition (ice water/ethyl acetate), extraction of the aqueous phase (ethyl acetate), reunion of the organic phases, drying (magnesium sulfate), concentration and purification by prep CCM on silicagel (dichloromethane/methanol 90:10) affords the title product (35 mg; 0.093 mmol; 47%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:30]=[CH:29][C:24]2[NH:25][C:26](=[O:28])[O:27][C:23]=2[CH:22]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:30]=[CH:29][C:24]4[NH:25][C:26](=[O:28])[O:27][C:23]=4[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1ccc2[nH]c(=O)oc2c1
Solvent: CCOCC
Product: O=C(Nc1ccc2[nH]c(=O)oc2c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 6-amino-3H-benzoxazol-2-one [J. Chem. Soc.,321. (1938)] according to the method described in Example 1c. Melting Point: 224-227° C. (diethylether)
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:27][C:28](=[CH2:36])[CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>C(O)C>[CH3:36][C:28](=[CH2:27])[CH2:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[N:20][C:6]2=3)=[O:4])[CH2:32][CH2:31]1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Reactant: C=C(C)CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C=C(C)CN1CCN(CC(=O)N2c3ccccc3C(=O)Nc3cccnc32)CC1

Procedure:
8.62 gm of 11-chloroacetyl-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one, 3.5 gm of sodium carbonate and 4.6 gm of 1-(2-methyl-allyl)-piperazine were refluxed in 100 ml of absolute ethanol for 2 hours. Then, the reaction mixture was suction-filtered while still hot, and the filtrate was evaporated to a volume of 40 ml and cooled. The precipitated crystals were recrystallized from ethanol in the presence of activated charcoal, yielding 75% of theory of the compound of the formula ##STR9## which had a melting point of 205°-207° C.
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[CH:23](OCC)(OCC)OCC>>[N:10]1([CH2:9][CH:8]([CH3:15])[CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:19][CH:18]=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=3)[N:1]=[CH:23]2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CC(CNC(=O)c1cc([N+](=O)[O-])ccc1N)Cn1ccnc1
Reactant: CCOC(OCC)OCC
Product: CC(Cn1ccnc1)Cn1cnc2ccc([N+](=O)[O-])cc2c1=O

Procedure:
A mixture of 3.03 g of 2-amino-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]-5-nitrobenzamide and 10 ml of triethyl orthoformate is heated at reflux temperature for 20 hours and concentrated to obtain the above compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([OH:10])[CH2:8][OH:9].[Cl:11][C:12]1[N:17]=[C:16](S(C)(=O)=O)[CH:15]=[CH:14][N:13]=1>CN(C=O)C.CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([O:9][CH2:8][CH2:7][OH:10])[CH:15]=[CH:14][N:13]=1
Reactant: CS(=O)(=O)c1ccnc(Cl)n1
Reactant: OCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: OCCOc1ccnc(Cl)n1
Reaction time: 0.25 h

Procedure:
Potassium carbonate (0.89 g, 6.45 mmol) was added at room temperature to an oven-dried, nitrogen cooled flask containing a suspension of ethylene glycol (1.3 mL, 23.4 mmol) in DMF (29 mL) and the mixture was then stirred for 15 minutes. 2-Chloro-4-(methylsulfonyl)pyrimidine (1.13 g, 5.86 mmol) was then added. The solution was stirred for 1.5 h at room temperature, then diluted with EtOAc (30 mL) and washed with 1:1 water:brine (3×50 mL). The organic extracts were dried over sodium sulfate, filtered, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (0 to 100% EtOAc/hexanes) to afford 2-[(2-chloropyrimidin-4-yl)oxy]ethanol as a pale yellow solid. MS ESI calcd. for C6H8ClN2O2 [M+H]+ 175. found 175.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:11]=2[N+:17]([O-])=O)=[N:6][CH:7]=1.[Cl-].[NH4+]>C(O)C.O>[NH2:17][C:11]1[C:12]([OH:16])=[CH:13][CH:14]=[CH:15][C:10]=1[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)=[O:20]
Reactant: O=C(Nc1ccc(Br)cn1)c1cccc(O)c1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1c(O)cccc1C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Yield: 6 %

Procedure:
N-(5-Bromo-2-pyridyl)-3-hydroxy-2-nitrobenzamide (7.71 g) was suspended in 50 ml of ethanol and 22 ml of distilled water, then 12.7 g of reduced iron and 2.45 g of ammonium chloride were added thereto and the mixture was heated to reflux for 6 hours. After it was cooled down to room temperature, insoluble matter was filtered and washed with chloroform. The filtrate was concentrated in vacuo, a saturated aqueous solution of sodium hydrogen carbonate was added thereto, the mixture was extracted with chloroform and the extract was washed with a saturated saline solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated in vacuo to give 0.42 g of 2-amino-N-(5-bromo-2-pyridyl)-3-hydroxybenzamide. Then N,N-dimethylformamide was added to the insoluble matter obtained by filtration of the reaction solution, the mixture was filtered and the filtrate was concentrated in vacuo. Water was added to the resulting residue and the resulting precipitate was collected by filtration and dried in vacuo to give additional 3.28 g of the above compound. Although this contained impurities therein, it was not purified but used for the next reaction as it was.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2.[Cu][C:20]#[N:21]>CN(C=O)C.[Cu]I>[C:20]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:5]2)#[N:21]
Reactant: N#C[Cu]
Reactant: CCOC(=O)CCc1cc2cc(Br)cc(F)c2[nH]1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc2cc(C#N)cc(F)c2[nH]1
Yield: 74.3 %

Procedure:
To a suspension of ethyl 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoate (D161) (650 mg), copper(I) iodide (394 mg) in DMF (5 mL) was added copper(I) cyanide (741 mg). The reaction vessel was sealed and heated in Biotage Initiator using initial very high to 200° C. for an hour. After cooling the reaction, the precipitate was filtered, and the filtrate was diluted with EtOAc (30 mL). The organic phase was washed with brine (25 mL), water (25 mL×2). The organic layer was dried over sodium sulphate and the crude product was purified by column chromatography to give ethyl 3-(5-cyano-7-fluoro-1H-indol-2-yl)propanoate (D162) (400 mg) as a yellow solid. MS (ES): C14H13FN2O2 requires 260; found 261.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1)[NH2:5].[O:23]=[C:24]1[N:28]([CH:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH2:27][CH2:26][N:25]1[C:35](Cl)=[O:36].O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:22])=[C:4]([NH:5][C:35]([N:25]2[CH2:26][CH2:27][N:28]([CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[C:24]2=[O:23])=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=2)[CH:11]=1
Reactant: O=C(Cl)N1CCN(C2CCOCC2)C1=O
Reactant: Cn1cc(-c2cc(Oc3ccc(N)c(F)c3Cl)ccn2)cn1
Solvent: O
Solvent: ClCCl
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)N4CCN(C5CCOCC5)C4=O)c(F)c3Cl)ccn2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
A mixture of 3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.250 g, 0.784 mmol) and TEA (0.150 mL, 1.076 mmol) in DCM (5 mL) was treated drop-wise with a solution of Example B2 (0.219 g, 0.941 mmol) in DCM (5 mL), warmed to RT and stirred overnight. The mixture was treated with water, extracted with DCM (3×) and the combined organics were dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with MeCN, sonicated and the resulting solid collected via filtration to afford N-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide (242 mg, 60%). 1H NMR (400 MHz, DMSO-d6): δ 10.86 (s, 1 H), 8.36 (d, J=5.7 Hz, 1 H), 8.26 (s, 1 H), 8.18 (t, J=8.9 Hz, 1 H), 7.97 (s, 1 H), 7.25-7.20 (m, 2 H), 6.65 (dd, J=5.7, 2.4 Hz, 1 H), 3.90 (m, 3 H), 3.84 (s, 3 H), 3.81 (m, 2 H), 3.47 (m, 2 H), 3.38 (m, 2 H), 1.77-1.65 (m, 2 H), 1.59 (m, 2H); MS (ESI) m/z: (M+H+): 515.1.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].[Cl:16][C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]=[C:23]=[O:24])=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][C:3]=1[CH2:4][N:5]([CH2:6][CH3:7])[C:23]([NH:22][CH2:21][C:20]1[CH:25]=[CH:26][C:17]([Cl:16])=[CH:18][CH:19]=1)=[O:24]
Reactant: O=C=NCc1ccc(Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)NCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 95, Step 1, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and 4-chlorobenzyl isocyanate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:15]([CH3:17])[CH3:16])=[C:11]([CH2:13]I)[N:12]=1.[C-:18]#[N:19].[Na+].O>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]([CH:15]([CH3:17])[CH3:16])=[C:11]([CH2:13][C:18]#[N:19])[N:12]=1
Reactant: [C-]#N
Reactant: CC(C)c1oc(-c2ccccc2Cl)nc1CI
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)c1oc(-c2ccccc2Cl)nc1CC#N
Temperature: 25 °C
Yield: 8.7 %

Procedure:
In acetone (2 mL) was dissolved 2-(2-chlorophenyl)-4-iodomethyl-5-isopropyloxazole (590 mg, 1.63 mmol). Sodium cyanide (88 mg, 1.63 mmol) was added, and the resulting mixture was heated under reflux for 22 hours. The reaction mixture was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed successively with water and a saturated brine, dried over sodium sulfate, filtered and concentrated. The resulting residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate=5/1), to obtain the desired compound (37 mg, 82%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10].[C:11](Cl)(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C1(C)C=CC=CC=1>[C:11]([N:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:10])(=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=C1CCCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCC(=O)N1CCCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride [5.14 g (50% oil dispersion); 0.107 mol] in 100 ml of dry toluene was added to a 500 ml, 3-necked flask fitted with a mechanical stirrer. Azacycloheptan-2-one (10.07 g; 0.089 mol) was dissolved in 50 ml of dry toluene with slight warming and added to the sodium hydride suspension dropwise at room temperature. The suspension was stirred at room temperature for 1 hour. n-Dodecanoyl chloride (19.39 g; 0.089 mol) in 10 ml of dry toluene was added dropwise to the mixture and after the addition was complete, the mixture was stirred overnight at room temperature. The mixture was then washed with water, and the organic layer separated, dried with MgSO4, and concentrated. The resulting yellow oil was distilled 160° C./0.35 mm to yield 1-n-dodecanoylazacycloheptan-2-one as clear oil.
Reaction SMILES: C([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][NH:30]C(OC(C)(C)C)=O)[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:38]>CO>[ClH:20].[ClH:38].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:26][O:27][CH2:28][CH2:29][NH2:30])[C:10]([NH:12][CH:13]2[C:24](=[O:25])[N:15]3[C:16]([C:21]([OH:23])=[O:22])=[C:17]([Cl:20])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CC(C)(C)OC(=O)NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(NC=O)n1
Agent: Cl
Solvent: CO
Product: NCCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(Cl)CS[C@H]12)c1csc(N)n1
Yield: 187.2 %

Procedure:
7-[2-(2-Formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid (syn isomer, 1.3 g.), conc.hydrochloric acid (1.2 g.) and methanol (20 ml.) were treated in similar manner to that of Example 11-(3) to give 7-[2-(2-aminothiazol-4-yl)-2-(2-aminoethoxyimino)acetamido]-3-chloro-3-cephem-4-carboxylic acid dihydrochloride (syn isomer, 1.1 g.).
Reaction SMILES: [CH2:1]([C:16]1[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:25]([OH:27])=[O:26])[C:23]=2[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl.O.[CH2:30](O)[CH3:31]>>[CH2:1]([C:16]1[NH:17][C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH2:30][CH3:31])=[O:26])[C:23]=2[CH:24]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1cc2c(C(=O)O)cccc2[nH]1
Reactant: CCO
Agent: Cl
Solvent: O
Product: CCCCCCCCCCCCCCCc1cc2c(C(=O)OCC)cccc2[nH]1

Procedure:
A solution of 2-(n-pentadecyl)indole-4-carboxylic acid (15 g) in ethanol (100 ml) containing a solution of hydrogen chloride gas in ethanol (100 ml, of strength 35% w/v) was refluxed for 6 hours. After cooling, the solution was poured into water and the solid was collected and was recrystallised from methanol to give ethyl 2-(n-pentadecyl)indole-4-carboxylate (12.4 g), in the form of a pale yellow solid, m.p. 42°-45° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1.C(Cl)(=O)C.[I-:17].[Na+]>C(#N)C>[I:17][C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([CH3:12])[N:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: COC(=O)c1c(Cl)ccnc1C
Agent: [Na+]
Solvent: CC#N
Solvent: CC(=O)Cl
Product: COC(=O)c1c(I)ccnc1C
Temperature: 80 °C
Yield: 22.4 %

Procedure:
To a solution of methyl 4-chloro-2-methylnicotinate (6.00 g, 32.3 mmol) in acetonitrile (80 mL) was added acetyl chloride (3.45 mL, 48.5 mmol) followed by sodium iodide (48.5 g, 323 mmol). The reaction mixture was heated at 80° C. for 16 hrs. The reaction mixture was evaporated to dryness and the residue was adjusted to pH 6 by adding saturated potassium carbonate solution. The product was extracted with dichloromethane (250 mL). The organic phase was washed with brine (2×100 mL), dried over Na2SO4, and concentrated under reduced pressure to afford methyl 4-iodo-2-methylnicotinate (2.00 g, 7.22 mmol, 22% crude yield) as colorless semisolid which was carried on without further purifications. LC/MS (ESI) m/e 278.0 [(M+H)+, calcd for C8H9INO2 278.0]; LC/MS retention time (method C): tR=2.13 min.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1>C(#N)C>[CH3:9][O:10][C:11](=[O:20])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=1[I:1]
Reactant: COC(=O)Nc1ccc(Br)cc1
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: COC(=O)Nc1ccc(Br)cc1I
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
133 g (0.591 mol) N-iodosuccinimide and 5.0 mL (8.60 g, 0.0573 mol) trifuoromethanesulfonic acid were added to a solution of 130.0 g (0.5651 mol) of (4-bromo-phenyl)-carbamic acid methyl ester in 660 mL acetonitrile. The mixture was stirred at room temperature for 18 h. The precipitate was collected by filtration washed with 160 mL ice-cold acetonitrile and dried to constant weight to yield 187.0 g (92%) of the title compound as white crystals melting at 129.4-130.0° C.
Reaction SMILES: O.NN.[Br:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:12]=1)[C:8]#[N:9].Cl>CCO>[NH2:14][CH2:13][C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([Br:4])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc(Br)cc(CN2C(=O)c3ccccc3C2=O)c1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: N#Cc1cc(Br)cc(CN)c1

Procedure:
Hydrazine hydrate (85%, 1.31 g) was added to a suspension of 3-bromo-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]benzonitrile (3.50 g, 10.3 mmol) in EtOH (60 mL). The mixture was refluxed for 3 h. Then, at room temperature, 2 N HCl (20 mL) was added (pH=3), and the mixture was filtered and the solid was rinsed with water (20 mL×2). The filtrate was evaporated to about 50 mL and filtered again. After addition of NaHCO3 (pH=9), the filtrate was extracted with CH2Cl2 (50 mL×3). The combined extracts were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. It was recrystallized from MeOH-Et2O yielding the product (1.40 g, 55%) as colorless fine needles. 1H NMR (400 MHz, D2O): δ 7.92 (m, 1H), 7.84 (m, 1H), 7.69 (m, 1H), 4.11 (s, 2H); 13C NMR (400 MHz, D2O): δ 137.1, 135.9, 135.8, 131.7, 123.0, 117.7, 113.8, 42.0; MS: m/z 209.0 (M+-HCl); HPLC: retention time: 9.313 min; purity: 98.4%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[CH2:10][CH2:11]O)[CH2:2][CH3:3].S(Cl)([Cl:15])=O>ClCCl>[Cl:15][CH2:11][CH2:10][CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][N:4]1[CH2:1][CH2:2][CH3:3]
Reactant: CCCN1CCCCC1CCO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCN1CCCCC1CCCl

Procedure:
To a solution of 2-(1-propyl-piperidin-2-yl)-ethanol (0.150 g, 0.875 mmol) in dichloromethane (5 mL) was added thionyl chloride (1.0 mL, 13.70 mmol) at room temperature and the reaction mixture was refluxed for 3 h. The solvent and excess thionyl chloride was removed under reduced pressure. The product was dissolved in dichloromethane and evaporated to dryness. The product was used for the next step without further purifications. GC-MS m/z 189.00