Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[O:7])=[CH:13][CH:14]=1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCC(=O)c1ccc(F)cc1

Procedure:
A solution of 3-(p-fluorobenzoyl)propionic acid (58.8 g.) in anhydrous methanol (250 ml.) was treated with concentrated sulphuric acid (3.2 ml.) and the mixture heated at reflux temperature for 10 hours. It was then concentrated to a volume of 100 ml., cooled and diluted with ice-water. The resultant solid was collected and crystallised from ligroin to yield the ester (59.7 g.), m.p. 48°-50°C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][N:10]2[C@@H:18]3[C@@H:13]([C:14]4[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[C:15]=4[CH2:16][CH2:17]3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:24]([N:26]([CH2:29]C)[CH2:27]C)C.CC(N(C)Cl)=[O:33].O>C1(C)C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH3:24][N:26]([CH3:29])[C:27](=[O:33])[O:23][C:19]1[C:15]2[CH2:16][CH2:17][C@H:18]3[C@H:13]([CH2:12][CH2:11][N:10]3[CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[C:14]=2[CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCN1CCOCC1
Reactant: CC(=O)N(C)Cl
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Cc1ccccc1
Product: CN(C)C(=O)Oc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCN1CCOCC1
Yield: 88.7 %

Procedure:
3.37 g (0.01065 mol) of rac-cis-2,3,3a,4,5,9b-hexahydro-3-(3-morpholin-4-yl-propyl)-1H-benzo[e]indol-6-ol were dissolved in 60 ml of toluene. 2.155 g (2.97 ml, 0.0214 mol) of triethyl-amine and 130 mg (1065 mmol, 0.1 eq.) of 4-dimethylaminopyridine were added thereto in succession and then 1.96 ml (0.0213 mol) of dimethyl chloroformamide were added dropwise thereto. The mixture was boiled under reflux for 2 hours, then cooled, poured into water and extracted with toluene. The organic phase was washed with water, dried with Na2SO4, filtered and concentrated. By chromatography of the residue over silica gel with methanol there were obtained 3.66 g (89%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-3-(3-morpholin-4-yl-propyl)-1H-benzo[e]indol-6-yl dimethylcarbamate.
Reaction SMILES: C([Li])CCC.[C:6]1([CH2:12][CH2:13][CH2:14][C:15]#[CH:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:17][O:18][C:19]1[CH2:26][CH2:25][C:22]2([O:24][CH2:23]2)[C:21](=[O:27])[CH:20]=1.[Cl-].[NH4+]>C(OCC)C.C1(C)C=CC=CC=1>[OH:27][C:21]1([CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:20]=[C:19]([O:18][CH3:17])[CH2:26][CH2:25][C:22]21[O:24][CH2:23]2
Reactant: C#CCCCc1ccccc1
Reactant: COC1=CC(=O)C2(CC1)CO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC1=CC(O)(C=CCCCc2ccccc2)C2(CC1)CO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 103.7 %

Procedure:
74 ml (0.118 mol) of n-butyllithium (1.6 molar in hexane) are added dropwise, under a nitrogen atmosphere, to a solution, cooled to -78° C., of 25 ml (0.157 mol) of 5-phenylpentyne in 400 ml of anhydrous diethyl ether. The whole is stirred at -78° C. for 15 minutes and then at 0° C. for 75 minutes. There is then added dropwise to that solution a solution, cooled to -78° C., of 6-methoxy-1-oxa-spiro[2.5]oct-5-en-4-one (11 g; 71.33 mmol) in 80 ml of anhydrous toluene. After 1 hour's stirring at -78° C., the reaction mixture is poured into an aqueous 10% ammonium chloride solution (1000 ml). Conventional treatment of the organic phase yields 22 g (74 mmol) of 4-hydroxy-6-methoxy-4-(5-phenylpenten-1-yl)-1-oxa-spiro[2.5]octene (2 isomers) in the form of an oily residue which is used in the following step without being purified. Hydrogenation of a solution of 22 g (74 mmol) of that mixture of isomers in 610 ml of benzene in the presence of 10 g of Lindlar catalyst for a period of 7 hours results, after filtration and evaporation, in 22 g (73 mmol) of 4-hydroxy-6methoxy-4-(5-phenylpentyl)-1-oxa-spiro[2.5]oct-5-ene in the form of an oily residue which is used in the following step without being purified.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:29]([O:31]CC4C=CC(OC)=CC=4)=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([CH2:25][C:26](=[O:28])[NH2:27])([CH2:23][CH3:24])[CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C1(OC)C=CC=CC=1>[F:44][C:45]([F:50])([F:49])[C:46]([O-:48])=[O:47].[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:41](=[O:42])[N:13]3[C:14]([C:29]([OH:31])=[O:30])=[C:15](/[CH:18]=[CH:19]/[CH2:20][N+:21]([CH2:25][C:26](=[O:28])[NH2:27])([CH2:23][CH3:24])[CH3:22])[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC[N+](C)(C/C=C/C1=C(C(=O)OCc2ccc(OC)cc2)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1)CC(N)=O
Reactant: O=C(O)C(F)(F)F
Agent: [I-]
Solvent: COc1ccccc1
Product: CC[N+](C)(C/C=C/C1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1)CC(N)=O
Product: O=C([O-])C(F)(F)F

Procedure:
In a manner similar to Example 5, the compound (23 g) of Example 11 was suspended in anisole (130 ml), followed by an addition of trifluoroacetic acid (140 ml) to obtain the target product (15.9 g).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1>C(Cl)Cl>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH2:6][CH2:5][N:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[N:3]=2)=[CH:16][CH:15]=1
Reactant: ClC1=NN(c2ccccc2)CC1
Reactant: Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: Clc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Yield: 36.9 %

Procedure:
3-Chloro-4,5-dihydro-1-phenylpyrazole (1.8 g) and 4-chloroaniline (3.8 g) were fused under N2 at 140° for 20 minutes. The melt was cooled and the solid dissolved in CH2Cl2, washed with 1% HCl (×3), water, dried (Na2SO4), then absorbed into silica and column chromatographed using first 1:1 petrol: ether and then ether to give the title product as a yellow powder (1.0 g), (37%), m.p. 144°-7°.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([O:30][CH3:31])[CH:24]=2)[CH:19]=[CH:18][N:17]=1>C(#N)C>[NH2:15][C:16]1[CH:21]=[C:20]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[S:11])=[C:25]([O:30][CH3:31])[CH:24]=2)[CH:19]=[CH:18][N:17]=1
Reactant: N#C[S-]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc(Oc2ccnc(N)c2)ccc1N
Agent: [K+]
Solvent: CC#N
Product: COc1cc(Oc2ccnc(N)c2)ccc1NC(=S)NC(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39 %

Procedure:
2-Phenylacetyl chloride (0.198 ml) was dissolved in acetonitrile (10 ml) under a nitrogen atmosphere, and then potassium thiocyanate (292 mg) was added at 60° C., followed by stirring at the same temperature for 3.5 hrs. The reaction mixture was cooled down to room temperature, and then 2-amino-4-(4-amino-3-methoxyphenoxy)pyridine (231.3 mg) was added thereto, followed by further stirring for 2 hrs. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with water and brine in this order, and dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=9:1) to provide the titled compound (158 mg, 39%) as pale brown powder.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][N:6]1[C:10]2=[CH:11][N:12]=[CH:13][CH:14]=[C:9]2[C:8](N2CCCCC2)=[CH:7]1)[CH3:2].[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32]Cl>>[CH3:21][O:22][C:23](=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH2:31][CH2:32][N:12]1[CH2:13][CH2:14][CH:9]([C:8]2[C:9]3[C:10](=[CH:11][N:12]=[CH:13][CH:14]=3)[N:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])[CH:7]=2)[CH2:10][CH2:11]1
Reactant: CCOCCn1cc(N2CCCCC2)c2ccncc21
Reactant: COC(=O)c1ccccc1OCCCl
Product: CCOCCn1cc(C2CCN(CCOc3ccccc3C(=O)OC)CC2)c2ccncc21
Yield: 52.1 %

Procedure:
This compound was prepared following the procedure described in example 4, part E, starting with 0.46 g (1.7 mmol) of 1-(2-ethoxyethyl)-3-piperidin yl-1H-pyrrolo[2,3-c]pyridine and 0.44 g (2.0 mmol) of 2-(2-chloroethoxy)-benzoic acid methyl ester. After standard work-up and purification, 0.2 g (21% yield) of 2-(2-{4-[1-(2-ethoxyethyl)-1H-pyrrolo[2,3-c]pyridin-3-yl]-piperidin-1-yl}-ethoxy)benzoic acid methyl ester were obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:17]2[C:18]([CH3:23])=[N:19][NH:20][C:21]=2[NH2:22])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[CH:28]=O.FC(F)(F)C(O)=O>CO>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]([C:28]2[C:9]3[CH:10]=[C:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:7][C:8]=3[C:17]3[C:18]([CH3:23])=[N:19][NH:20][C:21]=3[N:22]=2)[CH:30]=[CH:31][C:32]=1[OH:33]
Reactant: O=Cc1ccc(O)c(Cl)c1
Reactant: COCCOc1ccc(-c2c(C)n[nH]c2N)cc1OCCOC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: COCCOc1cc2c(-c3ccc(O)c(Cl)c3)nc3[nH]nc(C)c3c2cc1OCCOC
Product: Cl
Temperature: 70 °C
Yield: 47.2 %

Procedure:
A mixture of 4-(3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-methyl-1H-pyrazol-5-amine (114 mg, 0.36 mmol), 3-chloro-4-hydroxybenzaldehyde (117 mg, 0.75 mmol) and trifluoroacetic acid (3 mL) was heated at 70° C. for 18 hours. Then the reaction mixture was concentrated, dissolved in 10 mL of N,N-dimethylformamide and purified by preparatory HPLC (Shimadzu LC-8A HPLC, Waters Xterra C18 30 mm×100 mm column, acetonitrile-water-trifluoroacetic eluent). After concentration then lyophillization of the pure fractions a yellow powder was obtained. It was dissolved in 4 mL of 1:1 methanol: 4M hydrogen chloride in dioxane, and evaporated to dryness (repeated three times) to give 2-chloro-4-(1-methyl-7,8-bis{[2-(methyloxy)ethyl]oxy}-3H-pyrazolo[3,4-c]isoquinolin-5-yl)phenol hydrochloride salt (84 mg, 0.17 mmol, 47% yield) 1H NMR (400 MHz, d6-DMSO): 10.65 (b, 1H), 7.68-7.67 (b, 2H), 7.53-7.48 (m, 2H), 7.16-7.14 (d, 1H), 4.45-4.43 (m, 2H), 4.09-4.07 (m, 2H), 3.80-3.78 (m, 2H), 3.68-3.66 (m, 2H), 3.36 (s, 3H), 3.30 (s, 3H), 2.81 (s, 3H); MS (EI) for C23H24ClN3O5: 458 (MH+).
Reaction SMILES: O.CO[CH:4](OC)[CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[CH3:16]>ClC1C=CC=CC=1>[CH3:16][C:8]1[C:7]2[O:6][CH:5]=[CH:4][C:12]=2[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][CH:9]=1
Reactant: COC(COc1cc([N+](=O)[O-])ccc1C)OC
Solvent: Clc1ccccc1
Solvent: O
Product: Cc1ccc([N+](=O)[O-])c2ccoc12
Temperature: 25 °C
Yield: 38 %

Procedure:
Add Amberlyst® 15 ion-exchange resin (36 g) to chlorobenzene (700 mL), and heat the mixture to reflux and azeotrope out water, to dry the resin. Dissolve 2-(2,2-dimethoxyethoxy)-1-methyl-4-nitrobenzene (34.8 g, 144 mmol) in chlorobenzene (125 mL), and add this mixture dropwise to the stirring, refluxing reaction mixture under nitrogen over a 15 minute period. Continue refluxing for 1.5 hours, then cool to room temperature. Filter to remove the resin and concentrate under reduced pressure. Dissolve the residue in hexane and diethyl ether (1:1), then wash with 0.5M aqueous sodium hydroxide and aqueous saturated sodium chloride. Dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Chromatography on flash silica using hexane and ethyl acetate (9:1) and precipitation from hexane and toluene (1:1) yielded 9.7 g (42%) of the title compound as a yellow solid (42%). 1H NMR (400 MHz, DMSO-d6) δ 8.36 (d, 1 H, J=2.0 Hz), 8.12 (d, 1 H, J=8.4 Hz), 7.44 (d, 1 H, J=2.4 Hz), 7.38 (d, 1 H, J=8.8 Hz), 2.59 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][NH:6][CH2:7][CH:8]([O:11][CH3:12])[O:9][CH3:10].N1C=CC=CC=1.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1>ClCCl>[F:1][C:2]1[C:3]([CH3:17])=[C:4]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:5][N:6]([S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)(=[O:32])=[O:31])[CH2:7][CH:8]([O:9][CH3:10])[O:11][CH3:12]
Reactant: COC(CNCc1ccc(F)c(F)c1C)OC
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(CN(Cc1ccc(F)c(F)c1C)S(=O)(=O)c1ccc(C)cc1)OC
Temperature: 25 °C
Yield: 110.9 %

Procedure:
3,4-Difluoro-2-methylbenzyl-2,2-dimethoxyethylamine (23, 37.8 g) was dissolved in dichloromethane (100 mL). Pyridine (42 mL) was added. At 0° C. a solution of p-toluenesulphonyl chloride (36.8 g, 193 mmol) in dichloromethane was added dropwise. The reaction was allowed to warm to room temperature and stirring continued until the conversion was complete. For workup, the reaction mixture was diluted with dichloromethane (100 mL) and extracted twice with 1.5M hydrochloric acid, twice with sodium bicarbonate solution and once with brine. The organic layer was dried over magnesium sulphate, evaporated to dryness to give crude product as an orange oil (68.3 g). This was used without further purification.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=1.C(Cl)Cl>ClC1C=CC=CC=1Cl>[Br:26][C:27]1[CH:28]=[C:29]([CH2:33][C:34]([C:23]2[O:22][C:21]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:25][CH:24]=2)=[O:35])[CH:30]=[CH:31][CH:32]=1
Reactant: c1ccc(-c2ccco2)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Solvent: ClCCl
Product: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C

Procedure:
Phosphorous pentoxide (2.02 g, 14.20 mmol) suspended in 1,2-dichlorobenzene (60 mL) was added to a mixture of 2-phenyl-furan (23) (500 mg, 2.84 mmol) and 3-bromophenylacetic acid (24) (1.34 g, 6.25 mmol). The reaction mixture was heated to 80° C. for 2 hours and then cooled to ambient temperature. DCM was added, the organic layer washed with water and partially reduced in vacuo. The crude product was purified by Flash Master Jones Chromatography using a 50 g silica cartridge and first eluting with heptane to remove excess 1,2-dichlorobenzene, then 5-10% EtOAc in heptane to give the title compound. Yield: 278 mg, 38%; LC-MS tr 1.73 min; HPLC Purity: 100%; MS (ES+) m/z 341, 343 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[C:15]([CH3:22])[CH:14]=1.BrC1C=CC(C(NC2C=CC=C(C(C)(C)C)C=2)=O)=CC=1F>>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:6]=2)=[O:18])=[C:15]([CH3:22])[CH:14]=1
Reactant: CC(C)(C)c1cccc(N)c1
Reactant: Cc1cc(Br)ccc1C(=O)O
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(Br)c(F)c2)c1
Product: Cc1cc(Br)ccc1C(=O)Nc1cccc(C(C)(C)C)c1

Procedure:
4-Bromo-N-(3-tert-butyl-phenyl)-2-methyl-benzamide was synthesized from 3-tert-butyl-phenylamine and 4-bromo-2-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-bromo-N-(3-tert-butyl-phenyl)-3-fluoro-benzamide above. LCMS calcd for C18H20BrNO (m/e) 345, obsd 346 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[C:23]([C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)#[N:24].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:22]=[C:20]1[NH:19][C:16]2=[N:17][CH:18]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=[C:15]2[C:21]1=[CH:29][C:28]1[CH:31]=[CH:32][C:25]([C:23]#[N:24])=[CH:26][CH:27]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: COc1cc(-c2cnc3c(c2)CC(=O)N3)cc(OC)c1OC
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(-c2cnc3c(c2)C(=Cc2ccc(C#N)cc2)C(=O)N3)cc(OC)c1OC
Yield: 53.6 %

Procedure:
A mixture of 5-(3,4,5-trimethoxy-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one (Intermediate BY, 42 mg, 0.14 mmol), 4-cyanobenzaldehyde (22 mg, 0.168 mmol), triethylamine (22 μl, 0.168 mmol) and molecular sieves 4 Å (100 mg) in toluene (2 ml) was reacted at 80° C. for 1 d. The mixture was partitioned between DCM and water, the aqueous phase extracted with DCM, combined organic phases dried, evaporated and purified by silica gel chromatography (0-5% MeOH:DCM) to obtain 31 mg (54%) of the title compound as a mixture of (E)- and (Z)-isomers.
Reaction SMILES: O=O.[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>>[Br:3][C:4]1[CH:5]=[C:6]([O:10][CH2:13][CH:12]=[CH2:11])[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(Br)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: O=O
Agent: [K+]
Product: C=CCOc1cccc(Br)c1

Procedure:
The compounds of this invention in which X is oxygen are available as in the foregoing, but using a 5-substituted 3-chromanone. This molecule can be produced by a sequence of reactions beginning with m-bromophenol. Briefly, m-bromophenol is treated with allyl bromide in the presence of potassium carbonate to produce allyl 3-bromophenyl ether. The ether is converted to 2-allyl-3-bromophenol upon heating it in the presence of N,N-dimethylaniline. The phenol, upon reaction with ethyl chloroacetate, is converted to the ethyl ester of 2-allyl-3-(carboxymethoxy)bromobenzene. Upon oxidation using ozone followed by reductive work up, the allyl group is converted to a formylmethyl substituent which is then further oxidized using Jones' Reagent to the carboxymethyl substituent, the resulting product being the ethyl ester of (2-carboxymethyl-3-bromo)phenoxyacetic acid. The carboxylic acid group of this compound is esterified with t-butyl acetate and concentrated H2SO4 to form the ethyl ester of 3-bromo-2-(carbo-t-butoxymethyl)phenoxyacetic acid. In the presence of potassium t-butoxide, the diester is cyclized to form 4-t-butoxy-carbonyl-5-bromo-3-chromanone. Upon stirring at room temperature in the presence of acid, the latter is converted to 5-bromo-3-chromanone.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[F:2])[N:13]=1
Reactant: Fc1ccccc1C[Zn+]
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: Fc1ccccc1Cc1cccc(Br)n1
Temperature: 68 °C

Procedure:
A solution of 2-fluoro-benzylzinc bromide was added to 2,6-dibromo-pyridine (1.25 g, 5.27 mmol) then tetrakis(triphenylphosphine)palladium(0) (0.122 g, 0.106 mmol) was added and the reaction was heated to 68° C. for 4 hours. After cooling, silica gel was added to the reaction and it was concentrated to near-dryness. The silica gel was loaded onto a column of silica gel for purification to afford thet title compound.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])=[C:15]([CH2:19][S:20][C:21]4[NH:25][N:24]=[N:23][N:22]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:44](Br)[C:45]#[CH:46].C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:7][C:8]([NH:10][CH:11]2[C:42](=[O:43])[N:13]3[C:14]([C:26]([O:28][CH:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)=[O:27])=[C:15]([CH2:19][S:20][C:21]4[N:22]=[N:23][N:24]([CH2:46][C:45]#[CH:44])[N:25]=4)[CH2:16][S:17](=[O:18])[C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CSc3nnn[nH]3)CS(=O)[C@H]12
Reactant: C#CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCn1nnc(SCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)Cc4ccccc4)[C@H]3S(=O)C2)n1
Temperature: 0 °C
Yield: 19.7 %

Procedure:
A mixture of benzhydryl 7-(2-phenylacetamido)-3-(1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylate-1-oxide (78.0 g) in N,N-dimethylformamide (780 ml) was stirred to give a homogeneous solution and thereto were added 2-propynyl bromide (30.2 g) and triethylamine (38.5 g). The resulting solution was stirred for 22.3 hours at room temperature. The reaction mixture was added to ice-water (1.5 l) and the mixture was extracted with ethyl acetate (×2). The extract was washed with water (×4), dried over magnesium sulfate, treated with activated charcoal and then evaporated. The residue was pulverized in isopropyl ether, collected by filtration, washed with isopropyl ether and then dried. The obtained product (60.61 g) was subjected to column chromatography on silica gel (1.5 kg), using benzene and ethyl acetate (2:1) as an eluent. Fractions containing 2-(2-propynyl)-2H-tetrazolyl isomer, which were firstly eluted, were collected and then evaporated. The residue was pulverized in a mixture of isopropyl ether and n-hexane to give benzhydryl 7-(2-phenylacetamido)-3-[2-(2-propynyl)-2H-tetrazol-5-yl]thiomethyl-3-cephem-4-carboxylate-1-oxide (16.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:27].[F:35][C:36]1[CH:58]=[CH:57][C:39]([CH2:40][N:41]2[C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=3[N:43]=[C:42]2[NH:50][CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)=[CH:38][CH:37]=1.C(N(CC)C(C)C)(C)C.C(N(CC)CC)C>C(#N)C>[CH3:34][O:33][C:29]1[CH:28]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:30]=1[O:31][CH3:32])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:54]2[CH2:55][CH2:56][CH:51]([NH:50][C:42]3[N:41]([CH2:40][C:39]4[CH:57]=[CH:58][C:36]([F:35])=[CH:37][CH:38]=4)[C:45]4[CH:46]=[CH:47][CH:48]=[CH:49][C:44]=4[N:43]=3)[CH2:52][CH2:53]2)([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:8]1=[O:27]
Reactant: Fc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)cc1
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc(CN2CCC(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)(Cc3ccc(F)cc3)C2=O)cc(OC)c1OC
Reaction time: 12 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzyl)-3-(4-fluorophenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine (0.42 g, 1.3 mmol) and (1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine (0.64 g, 1.3 mmol), and N,N-diisopropylethylamine (0.32 g, 2.5 mmol) in acetonitrile (10 mL). Heat to reflux. After 12 hours, cool and partition the reaction mixture between dichloromethane and water. Separate the layers and extract the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on a short column of silica gel eluting with 2% triethylamine/10% methanol/ethyl acetate to give a residue. Partition the residue between dichloromethane and brine. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to give the title compound: Rf=0.19 (silica gel, 2% triethylamine/10% methanol/ethyl acetate).