Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[N:9]([CH3:18])[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5].[NH:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>C(O)(C)C>[ClH:1].[CH3:18][N:9]1[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:6]([C:4](=[O:5])[CH2:3][CH2:2][N:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]1=2
Reactant: CN1C(=O)c2ccccc2N(C(=O)CCCl)c2ccccc21
Reactant: C1CCNC1
Solvent: CC(C)O
Product: CN1C(=O)c2ccccc2N(C(=O)CCN2CCCC2)c2ccccc21
Product: Cl

Procedure:
4.5 gm (0.015 mol) of 5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 2.6 gm (0.0375 mol) of pyrrolidine were refluxed for 2 hours in 45 ml of isopropanol. The reaction mixture was worked up as described in Example 1.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.C1(P([N:26]=[N+:27]=[N-:28])(C2C=CC=CC=2)=O)C=CC=CC=1.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:38]=1[CH2:39]O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>C1(C)C=CC=CC=1>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][C:38]=1[CH2:39][N:26]=[N+:27]=[N-:28])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: OCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: Cc1ccccc1
Product: [N-]=[N+]=NCc1cc(C(F)(F)F)ccc1OCc1ccccc1
Reaction time: 3 h
Yield: 84.1 %

Procedure:
DBU (1 mL, 6.62 mmol) and diphenyl phosphoryl azide (1.6 mL, 7.5 mmol) were added to a solution of 2-benzyloxy-5-trifluoromethyl-benzyl alcohol (1.24 g, 4.41 mmol) in anhydrous toluene (10 mL) at room temperature. After 3 hours, water was added and the mixture extracted with ethyl acetate (3×). The combined organic layers were washed with 1N HCl (1×), brine (1×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (3% ethyl acetate/hexanes) to afford 1.14 grams of the title compound as a colorless oil (84%). MS 280 (M−N2)+. 1H NMR (400 MHz, CDCl3) δ 7.6-7.3 (m, 7H); 7.01 (d, 1H, J=9.1 Hz); 5.18 (s, 2H); 4.42 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[Cl:12].[NH:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1>>[Cl:12][C:3]1[C:4]([C:8]([F:11])([F:10])[F:9])=[CH:5][CH:6]=[CH:7][C:2]=1[N:13]1[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:14]1
Reactant: FC(F)(F)c1cccc(Br)c1Cl
Reactant: CCOC(=O)CCC1CCNC1
Product: CCOC(=O)CCC1CCN(c2cccc(C(F)(F)F)c2Cl)C1
Yield: 13 %

Procedure:
The title compound (895 mg, yield 13%) was obtained from 1-bromo-2-chloro-3-(trifluoromethyl)benzene and ethyl 3-(pyrrolidin-3-yl)propanoate obtained in Reference Example 12 by a method similar to that in Reference Example 1.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([C@H:15]1[O:19][C:18](=[O:20])[CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:16]1)([CH3:14])([CH3:13])[CH3:12].[C:27]1(=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C1COCC1>[C:11]([C@H:15]1[O:19][C:18](=[O:20])[C@@:17]([C:27]2([OH:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:16]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C1CCCCC1
Reactant: CC(C)(C)[C@H]1OC(=O)C(c2ccccc2)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1OC(=O)[C@](c2ccccc2)(C2(O)CCCCC2)O1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 1 M lithium bis(trimethylsilyl)amide in hexanes (1 litre, 1 mol) is added dropwise (R)-2-tert-butyl-5-phenyl-[1,3]dioxolan-4-one (170 g, 0.77 mol) in THF (1.1 litre) over 90 minutes ensuring the temperature does not exceed −70° C. After stirring at −78° C. for 1 hour, cyclohexanone (112 ml, 1.1 mol) is added dropwise over 15 minutes and then stirring continued at −78° C. for another hour. The reaction is quenched by addition of 10% aqueous ammonium chloride solution (170 ml) and after warming to −20° C., a further 2 litres of 10% aqueous ammonium chloride solution is added. The aqueous portion is separated and extracted with EtOAc (500 ml). The organic portions are combined, dried over MgSO4 and concentrated in vacuo. The resulting crude product is slurried in heptane for 20 minutes and then filtered and dried in vacuo to afford the titled compound as a white solid.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:13]([CH2:21][CH:22]=[O:23])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:11]=[CH2:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:24]([O:28][CH3:29])(=[O:27])[CH:25]=[CH2:26].N12CCC(CC1)CC2>O.CO.C(OCC)(=O)C>[C:16]([O:15][C:14]([N:13]([C@@H:10]([CH:11]=[CH2:12])[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[CH2:21][CH:22]([OH:23])[C:25](=[CH2:26])[C:24]([O:28][CH3:29])=[O:27])=[O:20])([CH3:19])([CH3:18])[CH3:17]
Reactant: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC=O)C(=O)OC(C)(C)C
Reactant: C=CC(=O)OC
Agent: C1CN2CCC1CC2
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(O)C(=C)C(=O)OC)C(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 79.6 %

Procedure:
To a stirred solution of (S)-tert-butyl 1-(tert-butyldimethylsilyloxy)but-3-en-2-yl(2-oxoethyl)carbamate (Intermediate 99, 16.1 g, 46.8 mmol), methyl acrylate (6.3 mL, 70 mmol), and methanol (about 2 mL), under nitrogen at ambient temperature, was added Quinuclidine (2.1 g, 19 mmol) as a solid. The mixture was then stirred for 1 day; analysis by TLC (15% ethyl acetate in hexanes) indicated incomplete conversion of starting material. Another 0.8 eq of quinuclidine was added every 24 hours; another 0.75 eq methyl acrylate and 1 mL methanol were added every two days. After 6 days total, the reaction was diluted with water and extracted with ethyl acetate. TLC indicated that only one extraction with about 250 mL ethyl acetate was needed to bring all the crude product into the organic layer, which was then washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. Normal-phase chromatography (5-30% ethyl acetate in hexanes, 220-g column, 35 minutes) afforded the desired compound (16 g, 80%, pale oil) as a mixture of diastereomers, with about 10 mol % of starting aldehyde present according to proton NMR analysis. The material was taken forward in this state.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[N:13]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:18][CH:17]=1.[H-].[Na+]>CO.CCOC(C)=O>[CH2:1]([C:5]1([CH2:5][CH2:1][CH2:2][CH3:3])[N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:18][CH:17]=2)[C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:7]=2[NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnccc2[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCC1(CCCC)Nc2ccncc2N1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
2-butyl-3-[(2'-tert-butoxycarbonylbiphen-4-yl)methyl]-2-butyl-3H-imidazo[4,5-c]pyridine was prepared according to the procedure described in Example 1, Part A from 2-butylimidazo[4,5-c]pyridine (220 mg, 1.25 mmol), tert-butyl 4'-bromomethylbiphenyl-2-carboxylate (414 mg, 1.19 mmol), and NaH (1.88 mmol). Yield: 25 mg (5%) thick oil; Rf: 0.45 (SiO2 tlc, 1% MeOH/EtOAc); 1H NMR (250 MHz, CDCl3) δ 8.66 (s 1H), 8.42 (d, 1H, J=5.6 Hz), 7.78 (dd, 1H, J=7.5 1.4 Hz), 7.66 (d, 1H, J=5.5 Hz), 7.52-7.35 (m, 2H) 7.31-7.24 (m, 3H), 7.10 (d, 2H, J=8 Hz), 5.46 (s, 2H), 2.92 (t, 2H, J=7.5 Hz), 1.97- 1.80 (m, 2H), 1.55-1.39 (m, 2H), 1.21 (s, 9H), 0.96 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:9]/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=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:13][C:12](=[O:14])/[CH:11]=[CH:10]/[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)[C:15]2[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: Cc1ccc(C(=C/C=C/C(=O)O)c2ccc(C)cc2)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(C)cc2)cc1
Reaction time: 0.5 h
Yield: 85.5 %

Procedure:
As in Example 115, (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid (7.25 g) and 4-nitrophenol (4.4 g) in dichloromethane (60 mL) was treated with 1.3-dicyclohexylcarbodiimide (5.36 g). The mixture was stirred at 0°-5° C. for 30 minutes and then at room temperature for 18 hours. After the usual work up. the ester was crystallized from 2-propanol to yield 8.9 g of (E)-5,5-bis(4-methylphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 153.5°-154.5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:18]OS(C)(=O)=O)[CH2:7]1.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@H:8]([CH2:18][NH:31][CH3:30])[CH2:7]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C[C@H]1COS(C)(=O)=O
Reactant: CN
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC[C@@H]1C[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 (10 volume equivalents) and once with brine (10 volume equivalents). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 119% mass balance; the material was used without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.O>C(#N)C>[O:21]1[CH2:22][CH2:23][N:18]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=2)[CH2:19][CH2:20]1
Reactant: OB(O)c1ccc(CBr)cc1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: OB(O)c1ccc(CN2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
To a mixture of (4-(bromomethyl)phenyl)boronic acid (500 mg) and potassium carbonate (643 mg) in acetonitrile (10 mL) was added morpholine (0.304 mL), and the mixture was stirred at room temperature for 60 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained solid was washed with diisopropyl ether and ethyl acetate to give the title compound (449 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.C([Li])CCC.[B:14]([O:23]C(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>CCCCCC.O1CCCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([O:15][B:14]([OH:23])[OH:19])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(OB(O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73.4 %

Procedure:
To a mixture of 4-bromotoluene (743 mmol) and 500 ml of tetrahydrofuran (THF) was added dropwise 500 ml of a solution of n-butyl lithium (corresponding to 780 mmol) in hexane at −78° C. in 1.6 hours, and stirred at the same temperature for 1.5 hours. To this solution was added dropwise 200 ml of a solution of triisopropyl borate (1,486 mmol) in THF, the solution was gradually warmed up to room temperature, and then the solution was stirred overnight. After 750 ml of 7.3% hydrochloric acid was added and stirred for 30 min, the reaction solution was extracted twice with diethyl ether, washed thrice with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was recrystallized from about 1,000 ml of toluene to give a white solid of 4-methylphenyl boric acid (545 mmol).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[C:5]([C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.O[C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[C@H:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:22][CH2:21]3)[C:5]([C:13]([F:16])([F:14])[F:15])=[CH:4][CH:3]=1
Reactant: OCCCNc1nc(Cl)ccc1C(F)(F)F
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCCNc3nc(Cl)ccc3C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
To a solution of 3-{[6-chloro-3-(trifluoromethyl)-2-pyridinyl]amino}-1-propanol (Example 302) (0.63 g, 2.45 mmol) and ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 0.45 g, 2.05 mmol) in THF (6.80 mL) was added triphenylphosphine (0.70 g, 2.66 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (0.68 g, 2.66 mmol) under argon. The golden yellow mixture was stirred at rt for 18 h, and then concentrated under reduced pressure. The product (0.58 g, 62%) was isolated after column chromatography (2:1 hexanes/EtOAc). 1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.02 (d, 1H), 6.76 (d, 1H), 6.69 (dd, 1H), 6.60 (d, 1H), 6.48 (b, 1H), 4.15 (q, 2H), 4.04 (t, 2H), 3.65 (q, 2H), 3.46 (qt, 1H), 2.92-2.68 (m, 3H), 2.42-2.30 (m, 2H), 2.08 (qt, 2H), 1.78-1.68 (m, 1H), 1.27 (t, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=2)[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]1>[Br-].[Zn+2].[Br-]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:23][CH:24]=2)[CH2:17][CH2:16][NH:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CCCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1
Agent: [Br-]
Agent: [Zn+2]
Product: c1ccc(CCCc2ccc(C3CCNCC3OCc3ccc4ccccc4c3)cn2)cc1

Procedure:
In an analogous manner to that described in Example 125 (h), from tert-butyl (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-6-(3-phenyl-propyl)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate by cleavage of the BOC group by means of anhydrous zinc bromide there was obtained (3'RS,4'RS)-3'-(naphthalen-2-ylmethoxy)-6-(3-phenyl-propyl)-1',2',3',4',5',6'-hexahydro-[3,4']bipyridine in the form of an amorphous, colourless foam; MS: 437 (M+H)+.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([CH3:49])=[C:44]([NH2:50])[N:43]=1>C(Cl)(Cl)Cl.CO>[NH2:41][C:42]1[N:43]=[C:44]([N:50]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:45]([CH3:49])=[CH:46][C:47]=1[F:48]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: Cc1cc(F)c(N)nc1N
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(N)c(F)cc2C)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 85 °C
Reaction time: 0.67 h

Procedure:
To 1 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 280 mg of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added all of 2,6-diamino-3-fluoro-5-methylpyridine as described above together with 2 ml of methanol and 4 ml of chloroform. After allowing to stand at room temperature for 40 minutes, the solution was concentrated under reduced pressure. To the residue were added 600 mg of anhydrous potassium carbonate and 1 ml of N,N-dimethylformamide, and the mixture was stirred at 85° C. for 15 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added 0.5 ml of ethanol, and the mixture was allowed to stand overnight. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 171 mg of the title compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[C:13](=O)([O-:15])[O-:14].[K+].[K+].C(=O)=O>>[F:1][C:2]1[CH:11]=[C:10]([C:13]([OH:15])=[O:14])[C:9]([OH:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(F)c2cccnc12
Agent: O=C=O
Agent: [K+]
Product: O=C(O)c1cc(F)c2cccnc2c1O
Temperature: 170 °C
Yield: 43.8 %

Procedure:
5-Fluoro-8-hydroxyquinoline (3.00 g) and potassium carbonate (7.62 g) are mixed together in a stainless steel bomb and heated to 170° C. under 800 p.s.i. CO2 for 7 days. The reaction is cooled and the resulting solid is partitioned between 800 mL water and 400 mL EtOAc in a separatory funnel. The aqueous layer is washed with EtOAc (3×400 mL). The aqueous layer is then acidified to pH 4.5 with conc. HCl and cooled. The resulting solid is collected, washed with water and dried. The crude product is triturated with i-PrOH and dried to yield 1.67 g of the title product as a brown solid.
Reaction SMILES: COC(C[C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:28](=[O:41])[N:10]2[C:11]=1[C:12]([O:14]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:13])=O.[C:42]1([O:48][CH3:49])C=CC=C[CH:43]=1.FC(F)(F)C(O)=[O:53].C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:49][O:48][C:42]([CH2:43][CH:7]1[CH:6]=[C:11]([C:12]([OH:14])=[O:13])[N:10]2[C:28](=[O:41])[C@@H:29]([NH:30][C:31](=[O:40])[CH2:32][O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@H:9]2[S:8]1)=[O:53]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccccc1
Reactant: COC(=O)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)CC1C=C(C(=O)O)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2S1

Procedure:
1.72 g (3 mmols) of diphenylmethyl 3-(methoxycarbonylmethyl)-7β-phenoxyacetylamino-3-cephem-4-carboxylate in 21 ml of methylene chloride are stirred with 1.62 ml (5 equivalents) of anisole and 9.3 ml (40 equivalents) of trifluoroacetic acid for 30 minutes in an ice bath, 100 ml of cold toluene are added and the mixture is evaporated in a rotary evaporator. The residue is digested with ether and the precipitate which has formed is filtered off, washed with ether and dried. A crude product is obtained and is chromatographed on 10 g of silica gel, which had been deactivated by the addition of 5% of water. Elution with methylene chloride and 20-30% of ethyl acetate gives amorphous 3-(methoxycarbonylmethyl-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid, which according to thin layer chromatography is a single compound; Rf 0.38 (on silica gel; using n-butanol:acetic acid:water, 67:10:23); UV spectrum (in ethanol): λmax =262, 267 and 274; IR spectrum (in methylene chloride): bands at 2.94, 5.58,5.74, 5.88, 6.11, 6.24, 6.59 and 6.69μ.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[N+:22]([CH3:25])([O-:24])=[O:23].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]([NH:11][C:12](=[O:13])[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([CH2:25][N+:22]([O-:24])=[O:23])=[O:6]
Reactant: C[N+](=O)[O-]
Reactant: Cc1ccccc1CC(=O)Nc1ccc(C(=O)O)c(Cl)c1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1CC(=O)Nc1ccc(C(=O)C[N+](=O)[O-])c(Cl)c1

Procedure:
This compound was obtained by carrying out the procedure as in Example 42 starting with 19 g (62.5 mmol) of 2-chloro-4-[(2-methylbenzyl)carbonylamino]benzoic acid obtained in step a), 3.18 g of nitromethane, 11 g (67.6 mmol) of diethyl cyanophosphonate, 16.8 g (167 mmol) of triethylamine in 205 ml of DMF dried over a molecular sieve. After chromatography on a silica column (eluent: dichloromethane-methanol 95:5) and recrystallization from a hexane-ethyl acetate mixture, 0.2 g (Yield=1) of a pale yellow powder is obtained.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18]C(O)=[C:16]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)=[O:22])[CH:15]=1.Cl>O1CCCC1.N1C=CC=CC=1>[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[CH:19]=[CH:18][C:5]2[O:4][C:2](=[O:3])[N:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][CH:25]=3)[C:21](=[O:22])[C:16]=2[CH:15]=1
Reactant: O=C(Nc1ccc(C(F)(F)F)cc1)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: COC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=c1oc2ccc(-c3ccc(F)cc3F)cc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 11 %

Procedure:
A solution of methyl chloroformate (1.2 mL, 12 mmol) was added drop wised to a stirred solution of compound 7 (1.56 g, 4 mmol) in dry anhydrous tetrahydrofuran/pyridine (30 mL) at 0° C. The mixture was refluxed for 3 h. After 10 h stirring at room temperature, the pH value of the mixture was adjusted to pH=6 by 5% HCl(aq). The mixture was cooled to obtain crystalline compound on an ice bath for 2-3 h. After cooling, precipitated crystals were filtered off and washed with diluted HCl and water. The crude product was purified by crystallization from hot ethanol to afford compound 19.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([OH:9])=[O:8].[CH2:10]([Li])CCC.IC.Cl>O1CCCC1.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:10])[S:4][C:3]=1[C:7]([OH:9])=[O:8]
Reactant: [Li]CCCC
Reactant: Cc1ccsc1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Solvent: CI
Solvent: O
Product: Cc1cc(C)c(C(=O)O)s1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Methyl-2-thiophenecarboxylic acid (7.11 g) was dissolved in tetrahydrofuran (100 ml), and the mixture was cooled to -78° C. n-Butyllithium (1.6M in hexane, 69 ml) was slowly added dropwise. The mixture was stirred at -78° C. for 1 hour, and iodomethane (6.2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred at room temperature for 15 hours, poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3,5-dimethyl-2-thiophenecarboxylic acid (4.97 g) as crystals.