Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:21]([OH:23])=[O:22])=[C:6]([CH:9]([S:15][C:16]3[NH:20][N:19]=[N:18][N:17]=3)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])[CH2:7][S:8][C@H:3]12.C(Cl)Cl.[C:29](OC(=N)N(C(C)C)C(C)C)([CH3:32])([CH3:31])[CH3:30]>C1C=CC=CC=1>[C:29]([O:22][C:21]([C:5]1[N:4]2[C:24](=[O:25])[CH:2]([NH2:1])[C@H:3]2[S:8][CH2:7][C:6]=1[CH:9]([S:15][C:16]1[NH:17][N:18]=[N:19][N:20]=1)[CH2:10][CH2:11][C:12](=[O:14])[NH2:13])=[O:23])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)N(C(=N)OC(C)(C)C)C(C)C
Reactant: NC(=O)CCC(Sc1nnn[nH]1)C1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C1=C(C(CCC(N)=O)Sc2nnn[nH]2)CS[C@@H]2C(N)C(=O)N12

Procedure:
To a suspension of 19.3 g. (0.05 mol.) of 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4-carboxylic acid in 500 ml. of dry methylene chloride is added in one portion 30.0 g. (0.15 mol.) of O-t-butyldiisopropylpseudourea in 50 ml. of methylene chloride and the mixture is stirred at ambient temperature for 24 hours. The precipitate is removed by filtration and the filtrate is evaporated to give a residue which is taken up in 200 ml. of benzene and filtured again. The filtrate is extracted with three 100 ml. portions of cold 1 N hydrochloric acid. The aqueous extracts are layered with ethyl acetate and the pH is adjusted to 7.5 by addition of solid sodium bicarbonate. The organic layer is separated and the aqueous phase is extracted with two 150 ml. portions of ethyl acetate. The combined extracts are dried (MgSO4), filtered and evaporated to dryness to give 7-amino-3-[1-(2-carbamoylethyl)tetrazol-5-ylthiomethyl]-3-cephem-4 -carboxylic acid t-butyl ester.
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:33])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:33])[C:5]([C:3]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NCCC(=O)O
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(O)CCNC(=O)c1ncc2c(cc(-c3ccc(C(F)(F)F)cc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-2-oxo-3-(4-trifluoromethyl-phenyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (30 mg, 0.066 mmol), β-alanine (589 mg, 6.6 mmol) and NaOMe solution (10.6 mL, 5.3 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined, dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (5-50% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound as a light yellow solid. MS: (+) m/z 512.34 (M+1).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.Cl.[NH2:11][C:12]1[CH:13]=[C:14]([CH:21]=[CH:22][C:23]=1[CH3:24])[C:15]([NH:17][CH:18]1[CH2:20][CH2:19]1)=[O:16]>>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:11][C:12]2[CH:13]=[C:14]([C:15](=[O:16])[NH:17][CH:18]3[CH2:20][CH2:19]3)[CH:21]=[CH:22][C:23]=2[CH3:24])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N
Reactant: O=C(O)c1ccc(Br)s1
Agent: Cl
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(Br)s1

Procedure:
Compound a was prepared by coupling 5-bromothiophene-2-carboxylic acid with 3-amino-N-cyclopropyl-4-methylbenzamide hydrochloride (prepared as described in WO04071440) using the method described in Example 2. HPLC Ret time=3.16 min. LCMS [M+H]+ 379.15.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27](OCC)=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:41][CH2:40][CH2:39][C:38]1=[O:42]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:32])=[C:14]([C:27]([NH:33][CH2:34][CH2:35][CH2:36][N:37]4[CH2:41][CH2:40][CH2:39][C:38]4=[O:42])=[O:28])[C:15](=[O:26])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: NCCCN1CCCC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(C)(=O)=O)c1=O
Product: CS(=O)(=O)CCCn1c(=O)c(C(=O)NCCCN2CCCC2=O)c(O)c2ncc(Cc3ccc(F)cc3)cc21

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[3-(methylsulfonyl)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 1-(3-aminopropyl)-2-pyrrolidinone employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.23 (t, J=5.5 Hz, 1 H), 8.55 (s, 1 H), 7.65 (s, 1 H), 7.20 (dd, J=8.5, 5.4 Hz, 2 H), 7.00 (t, J=8.8 Hz, 2 H), 4.39 (t, J=7.7 Hz, 2 H), 4.11 (s, 2 H), 3.46-3.35 (m, 6 H), 3.13 (t, J=7.1 Hz, 2 H), 2.94 (s, 3 H), 2.39 (t, J=8.2 Hz, 2 H), 2.19 (m, 2 H), 2.03 (m, 2 H), 1.85 (m, 2 H); HRMS C27H31FN4O6S (M+H)+ calcd 559.1948, found 559.2055.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[C:13]=2[F:20])=[CH:8][C:7]=1[F:21])[CH2:2][CH2:3][CH3:4].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH2:46]([CH:49]1[CH2:54][CH2:53][CH:52]([CH:55]2[CH2:60][CH2:59][CH:58]([C:61](O)=[O:62])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1)[CH2:47][CH3:48]>C1(C)C=CC=CC=1>[CH2:46]([CH:49]1[CH2:54][CH2:53][CH:52]([CH:55]2[CH2:60][CH2:59][CH:58]([C:61]([O:18][C:15]3[CH:16]=[CH:17][C:12]([C:9]4[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[C:7]([F:21])[CH:8]=4)=[C:13]([F:20])[C:14]=3[F:19])=[O:62])[CH2:57][CH2:56]2)[CH2:51][CH2:50]1)[CH2:47][CH3:48]
Reactant: CCCC1CCC(C2CCC(C(=O)O)CC2)CC1
Reactant: CCCCOc1ccc(-c2ccc(O)c(F)c2F)cc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(-c2ccc(OC(=O)C3CCC(C4CCC(CCC)CC4)CC3)c(F)c2F)cc1F
Reaction time: 16 h
Yield: 66.9 %

Procedure:
4′-Butoxy-2,3,3′-trifluorobiphenyl-4-ol (T-11) (2.00 g) prepared in Example 8, dicyclohexylcarbodiimide (DCC) (1.46 g) and dimethylaminopyridine (DMAP) (0.08 g) were dissolved in toluene (100 ml), and 4′-propylbicyclohexane-4-carboxylic acid (1.70 g) was added, and then the stirring was continued at room temperature for another 16 hours. After the completion of the reaction, the reaction mixture was filtered and the filtrate was extracted with toluene. The organic layer was washed with a 1N—HCl aqueous solution, a 1N-aqueous sodium hydroxide solution, a saturated aqueous solution of sodium hydrogencarbonate, water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave pale brown solids. Silica gel chromatography (heptane:ethyl acetate=20:1 by volume) and recrystallization (heptane:toluene=4:1 by volume) gave 4′-butoxy-2,3,3′-trifluorobiphenyl-4-yl 4′-propylbicyclohexane-4-carboxylate (1-8-14) as colorless powders (2.39 g) in 67% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.Cl.[NH2:14]O.C([O-])(=O)C.[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:14][C:6]=2[CH:12]=1
Reactant: Cc1ccc2c(c1)C(=O)CCS2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)NC(=O)CCS2
Reaction time: 1 h
Yield: 23.7 %

Procedure:
6-Methyl-2,3-dihydro-4H-1-benzothiopyran-4-one (2g, 10.9 mmol) was dissolved in 80% ethanol (73 mL) and to this was added hydroxylamine hydrochloride (840 mg, 12.05 mmol) and sodium acetate (990 mg, 12.03 mmol). This mixture was heated at reflux for 3 hours. Water (150 mL) was added and then extracted with dichloromethane (3×100 mL), washed with brine (75 mL), water (75 mL), dried (sodium sulfate) and concentrated to residue. The residue was taken up in polyphosphoric acid (10 mL) and heated at reflux for 1 hour. Ice chips were added and water was added (100 mL) this was stirred for 1 hour. A solid formed and was filtered and purified by flashcolumn chromatography on 20 g of silica gel, eluting with (50%, 60%, and 70%) ethyl acetate in hexanes to give 7-methyl-2,3,4,5-tetrahydrobenzo[b]1,4-thiazepin-4-one (500 mg, 30%). 1H NMR (CDCl3, 300 MHz): δ7.87 (s-broad, 1H), 7.47 (d, 1H, J=7.7 Hz), 6.98 (d, 1H, J=8.1 Hz), 6.91 (s, 1H), 3.42 (t, 2H, J=6.9 Hz), 2.62 (t, 2H, J=6.9 Hz), 2.35 (s, 3H) ppm.
Reaction SMILES: [NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CN(C=O)C.O>[NH2:1][C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:3]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(N)cc1F
Reactant: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])c(N)cc1-n1ccnc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In 5 ml of DMF were dissolved 1 g of 4-amino-2-fluoro-5-nitrobenzonitrile and 1.1 g of imidazole, and the mixture was stirred at 100° C. for 1 hour. The reaction mixture was then diluted with water and the resulting crystals were recovered by filtration to provide 1.2 g of 4-amino-2-(1-imidazolyl)-5-nitrobenzonitrile. Physicochemical properties:
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:23][CH2:22]2)[CH2:10]1)=O)(C)(C)C.[C:44]1([CH2:50]C(Cl)=O)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>>[CH2:50]([C:6]([NH:8][C@H:9]1[CH2:13][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([N:27]([C:31]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=3)=[O:32])[CH2:28][CH:29]=[CH2:30])[CH2:25][CH2:26]2)[CH2:10]1)=[O:5])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)OC(C)(C)C)C[C@@H]2c2ccccc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Product: C=CCN(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CCN(C[C@H]2C[C@@H](NC(=O)Cc3ccccc3)C[C@@H]2c2ccccc2)CC1

Procedure:
Using essentially the same procedure as in Example 16, Step A and B but substituting 1-(S)-((t-butoxycarbonyl)amino)-3-(S)-((4-(N-(4-nitrobenzyloxycarbonyl)-N-(allyl)amino)piperidin-1-yl)methyl)-4-(S)-phenylcyclopentane from Example 33 in Step A and phenylacetyl chloride in Step B, the title compound was prepared.
Reaction SMILES: [O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([CH2:15][C:16](O)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[O:1]=[C:2]1[C:11]2=[N:12][N:13]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:14]([CH2:15][C:16]([N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)=[O:17])=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1c2c(nn1-c1ccccc1)c(=O)[nH]c1ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2c3c(nn2-c2ccccc2)c(=O)[nH]c2ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A mixture of (4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetic acid (1.50 g, 4.70 mmol), N-Boc piperazine (0.96 g, 5.17 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.35 g, 7.05 mmol), 1-hydroxybenzotriazole (0.95 g, 7.05 mmol) and 20 mL of DMF was stirred at ambient temperature overnight. The mixture was concentrated under reduced pressure. The residue was triturated with acetonitrile, isolated by filtration, and dried to afford 1.96 g of tert-butyl 4-[(4-oxo-2-phenyl-4,5-dihydro-2H-pyrazolo[3,4-c]quinolin-1-yl)acetyl]piperazine-1-carboxylate as a pale yellow solid.
Reaction SMILES: Br[C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[C:10]([O-:13])(=[S:12])[CH3:11].[K+]>C(#N)C>[C:10]([S:12][C@H:2]([C@@H:6]([CH3:9])[CH2:7][CH3:8])[C:3]([OH:5])=[O:4])(=[O:13])[CH3:11]
Reactant: CC[C@H](C)[C@@H](Br)C(=O)O
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC#N
Product: CC[C@H](C)[C@@H](SC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
2.11 g (10.8 mmol) of (2R,3S)-2-bromo-3-methylpentanoic acid obtained in the Synthesis Example C-1 was dissolved in 43 ml of acetonitrile and 1.42 g of potassium thioacetate was added thereto at 0° C. The mixture was stirred at0° C. for 30 minutes and then at room temperature for 5 hours. After filtering off the insoluble matters, the filtrate was concentrated. To the residue were added ether and a saturated aqueous solution of sodium hydrogencarbonate, followed by separation. The aqueous phase was acidified by adding a 2N aqueous solution of hydrochloric acid at a low temperature and then extracted with ether. The ether phase was washed with a saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated. Thus, 1.68 g of the title compound was obtained as a colorless oil (yield 82%).
Reaction SMILES: [O:1]=[C:2]1[NH:8][CH2:7][CH2:6][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:4][CH2:3]1.Br[CH:15]([CH2:23][CH3:24])[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17].[H-].[Na+]>C(#N)C>[C:19]([O:18][C:16]([CH:15]([N:8]1[C:2](=[O:1])[CH2:3][CH2:4][CH:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:7]1)[CH2:23][CH3:24])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOC(=O)C1CCNC(=O)CC1
Reactant: CCC(Br)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)C1CCC(=O)N(C(CC)C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 94.4 %

Procedure:
In a 150 ml three necked flask fitted with reflux condenser, magnetic stirrer and dropping funnel under inert atmosphere, 5.09 g (27.5 mmoles, 1 eq) of ethyl 7-oxo-4-azepanecarboxylate 28 and 12.27 g (55 mmoles, 2 eq) of tert-butyl 2-bromobutanoate were dissolved in 70 ml of acetonitrile. The temperature was raised to 50° C. and 1.32 g (55 mmoles, 2 eq) of sodium hydride were added portionwise (exothermicl). The mixture was stirred one more hour at 50° C. and concentrated to dryness, the residue was poured on ice/water and neutralised with solid ammonium chloride. The mixture was extracted three times with CH2Cl2, the combined organic phases were dried over magnesium sulfate, filtered and concentrated to dryness. The residue was purified by PrepLC (1 kg SiO2, CH2Cl2/MTBE, 85/15) to give 8.5 g of pure diester 29, 69% yield.
Reaction SMILES: N([O-])=O.[Na+].[Cl:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]([F:13])[C:7]=1N.C(OCC)C.[ClH:20]>O.[Cu]Cl>[Cl:20][C:7]1[C:6]([Cl:5])=[C:11]([CH3:12])[CH:10]=[CH:9][C:8]=1[F:13]
Reactant: Cc1ccc(F)c(N)c1Cl
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(F)c(Cl)c1Cl
Temperature: -5 °C
Reaction time: 0.08 h

Procedure:
Sodium nitrite (0.172 g, 2.5 mmol) was added to a stirred solution of 2-chloro-6-fluoro-3-methyl-phenylamine (0.400 g, 2.5 mmol) in water (20 ml) and 37% aqueous hydrogen chloride (5 ml) at −5° C. The mixture was stirred at −5° C. for 5 minutes and then added in one pot to a solution of copper (I) chloride (0.742 g, 7.5 mmol) in 37% aqueous hydrogen chloride (5 ml) whilst maintaining the temperature at −5 to 0° C. The reaction mixture was heated to 38° C. and stirred for 1 hr then the mixture was cooled and diethyl ether (20 ml) was added. The organic phase was separated and washed with 1N aqueous hydrogen chloride and then with water. The organic layer was then dried over sodium sulphate and concentrated in vacuo. The crude residue was purified by flash silica column chromatography, eluting with petroleum ether, to give 2,3-dichloro-1-fluoro-4-methylbenzene (0.090 g, 0.5 mmol) as a white solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:31][C:32]1[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>C(#N)C>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[N:18]([C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[CH3:31])[C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3C)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1.5 h
Yield: 38.3 %

Procedure:
500 mg of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry acetonitrile, and the resulting solution was cooled with ice. To the solution was added 710 mg of 2-methylbenzoyl chloride, and the mixture was allowed to stand at room temperature for 90 minutes. The same procuedre as in Example 1 gave 260 mg (yield: 38.4%) of 2'-deoxy-3',5'-di-O-acetyl-5-fluoro-3-(2-methylbenzoyl)uridine as crystals having a melting point of 108° to 109° C. This was identical with the crystals obtained in Examples 1 by the mixed examination.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:24]2)=[N:21][CH:22]=1>>[C:12]([C:6]1[CH:7]=[N:8][C:9]2[C:4]([C:5]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:24]3)=[N:21][CH:22]=1)=[CH:3][C:2]([Br:1])=[CH:11][CH:10]=2)(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cn2)C1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Product: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 45.6 %

Procedure:
Following General procedure C, 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (284 mg, 1 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)pyrrolidin-3-ylcarbamate (439 mg, 1.5 mmol) to afford the desired product (240 mg, 46%) as a yellow solid: ESI MS ink 526 [C25H28BrN5O3+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>CN(C)C=O.C(OCC)(=O)C>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1)#[N:7]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
To a solution of 4-hydroxy-benzonitrile (1 g, 8.395 mmol) in dimethylformamide (10 mL) were added potassium carbonate (2.321 g, 16.79 mmol) and ethyl bromoacetate (1.117 mL, 10.07 mmol), respectively. The reaction mixture was stirred at room temperature for 23 h. It was taken in ethyl acetate and diethyl ether (1:1 ratio), and the solid was filtered off. The filtrate was washed with water, brine and dried over anhydrous sodium sulfate. The solid was then filtered off, and the filtrate was concentrated in vacuo to afford ethyl (4-cyano-phenoxy)-acetate. It was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12](Cl)(=[O:18])/[CH:13]=[CH:14]/[C:15](Cl)=[O:16].Cl>C(=S)=S>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]([CH:13]=[CH:14][C:15](=[O:16])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[O:18])=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: O=C(C=CC(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 0 °C
Yield: 96 %

Procedure:
To a solution of fluorobenzene (0.52 mols, 50 g, 48.83 mL) in carbon disulfide (500 mL) was added aluminium chloride (0.651 mmol, 86.8 g). The resulting suspension was gently refluxed under an atmosphere of nitrogen. Fumaryl chloride (0.26 mols, 28.2 mL) was added over a period of 15-20 minutes. The resulting dark orange reaction mixture was refluxed for 18 h and the residue was poured into crushed ice (1 Kg) and concentrated hydrochloric acid (15.0 mL). The semi-solid was filtered off, washed with ether and ethanol, digested in ethanol, and recrystallized from ethyl acetate/ethanol to give pale yellow needles of compound 1 in 96% yield, m.p. 115°-116° C. 1H NMR: 7.14-7.18 (t, 2H, Jmeta =1.9 Hz, C6H4), 7.96 (s, 2H, CH=CH), 8.05-8.12 (q, 6H, J=2.2 Hz, C6H4); ms m/e (Cl with NH3 ), 290(NH3 +H+M), 273(M+1), 272(M); HRMS m/e calcd for C16H10O2F2 273.0727, found 273.0727.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]([F:13])[C:5]([F:12])=[C:6]([C:10]#[N:11])[C:7]=1[C:8]#[N:9].[F:15][C:16]1[C:21]([OH:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([OH:25])[C:17]=1[F:26].[Na].[Na]>CN(C=O)C>[C:8]([C:7]1[C:2]([F:1])=[C:3]([C:4]([F:13])=[C:5]([F:12])[C:6]=1[C:10]#[N:11])[O:22][C:21]1[C:16]([F:15])=[C:17]([F:26])[C:18]([O:25][C:3]2[C:4]([F:13])=[C:5]([F:12])[C:6]([C:10]#[N:11])=[C:7]([C:8]#[N:9])[C:2]=2[F:1])=[C:19]([F:24])[C:20]=1[F:23])#[N:9]
Reactant: N#Cc1c(F)c(F)c(F)c(F)c1C#N
Reactant: Oc1c(F)c(F)c(O)c(F)c1F
Agent: [Na]
Solvent: CN(C)C=O
Product: N#Cc1c(F)c(F)c(Oc2c(F)c(F)c(Oc3c(F)c(F)c(C#N)c(C#N)c3F)c(F)c2F)c(F)c1C#N
Reaction time: 0.33 h
Yield: 53.9 %

Procedure:
In an Erlenmeyer flask were charged 40.0 g (0.2 mol) of tetrafluorophthalonitrile and 0.1 liter of DMF. The flask containing the mixture was immersed in an ice-water bath to keep the mixture at 0° to 5° C. To the mixture was added portionwise in 10 minutes 11.3 g (0.05 mol) of disodium tetrafluorohydroquinone. The resulting mixture was stirred at that temperature for 20 minutes and then at room temperature for 30 minutes. Thereafter, the reaction mixture was treated in the same manner as in Example 16 and the product was identified in the same manner as in Example 16. Thus 14.6 g of 1,4-bis(3,4-dicyanotrifluorophenoxy)tetrafluorobenzene was obtained in a yield of 54 %.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH2:4]Br.[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[C:21](=[C:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]=2[CH:28]=1.C(N(CC)CC)C>C1COCC1>[CH3:1][O:2][C:3](=[O:6])[CH2:4][N:25]1[CH2:24][CH2:23][C:22](=[C:21]2[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:28]=[C:8]([Cl:7])[CH:9]=[CH:10][C:11]2=3)[CH2:27][CH2:26]1
Reactant: COC(=O)CBr
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)CN1CCC(=C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Reaction time: 18 h
Yield: 89.2 %

Procedure:
Methylbromoacetate (0.17 ml, 1.77 mmol) was added dropwise to a solution of 4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidine (0.50 g, 1.61 mmol) and triethylamine (0.45 ml, 3.22 mmol) in THF (15 ml) under an inert atmosphere. The reaction was left to stir for 18 hours. THF was removed under reduced pressure and the product purified by column chromatography on silica gel, eluting with 5% methanol/DCM. Product containing fractions were combined and solvent removed under reduced pressure to yield methyl-[4-{8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene}-piperidin-1-yl]acetate as an orange solid (550 mg, 90%).