Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)=[O:8].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][OH:27])[CH:22]=[N:23][C:24]=1Cl>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:18][C:19]1[C:24]([C:12]2[CH:13]=[CH:14][C:9]([CH:7]=[O:8])=[CH:10][CH:11]=2)=[N:23][CH:22]=[C:21]([CH2:26][OH:27])[CH:20]=1
Reactant: OCc1cnc(Cl)c(Cl)c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2ncc(CO)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.8 %

Procedure:
2.68 g of sodium carbonate (25.3 mmol), 1.15 g of 4-formylphenylboronic acid (7.66 mmol), and 0.27 g of Pd(PPh3)4 were added to 1.5 g of (5,6-dichloropyridin-3-yl)methanol (8.43 mmol) dissolved in 30 mL of 1,2-dimethoxyethane and 30 mL of distilled water, and refluxed under heating and stirring for 18 hours. The mixture was cooled to room temperature, and concentrated under about 50% reduced pressure to extract the aqueous layer with ethyl acetate. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (eluting solvent: chloroform/methanol=10/1) to obtain 1.40 g of 4-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)benzaldehyde (yield 74%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B1C2CCCC1CCC2.[OH:32]O.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][OH:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: OCC[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Dissolve (S)-1,4-dibenzyl-2-vinylpiperazine (16.2 g, 55.5 mmol) in tetrahydrofuran (370 mL), add 9-BBN (0.56 L of a 0.5 M solution in tetrahydrofuran) via addition funnel, stir at room temperature overnight. Cool to 0° C. and treat with 30% aqueous hydrogen peroxide (195 mL), followed by 3N aqueous sodium hydroxide (195 mL). Allow to reach room temperature and stir for 24 h. Pour into separatory funnel, separate organic layer and remove solvent in vacuo. Take up residue in dichloromethane, add water and recombine with aqueous layer from before. Pour into separatory funnel, separate organic layer and extract aqueous layer with several portions of dichloromethane. Combine all organic layers, remove solvent in vacuo. Take up residue in 1 L of methanol, add 185 g of SCX resin. Filter slurry through Büchner funnel, washing well with methanol. To elute product, wash cake thoroughly with 50% 7N ammonia-methanol in dichloromethane. Concentrate filtrate in vacuo to obtain the title compound (16.6 g, 96%) as a thick brownish oil: mass spectrum (APCI): m/z=311.2 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].O.[N+:20]([O-])([OH:22])=[O:21]>C(Cl)Cl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[C:3]([CH3:18])=[C:4]([C:14]([OH:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=1)[C:5]([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: Cc1c(F)ccc(O)c1C(=O)Oc1ccccc1
Reactant: O=[N+]([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: O
Solvent: ClCCl
Product: Cc1c(F)cc([N+](=O)[O-])c(O)c1C(=O)Oc1ccccc1
Temperature: 26 °C
Reaction time: 20 h
Yield: 109.3 %

Procedure:
A 30 L 4-neck flask equipped with mechanical stirrer, thermometer and addition funnel was charged with a solution of compound 63 (1100 g, 4.47 mol) in CH2Cl2 (8.0 L) followed by water (8.1 L) and tetrabutyl ammonium bromide (144 g, 0.45 mol). Aqueous HNO3 (591 mL, 68 w %, 8.94 mol) was added to the stirred two-phase reaction mixture at 24˜27° C. over 3 min and the mixture was stirred at 24-28° C. for 20 h. The two layers were separated and the aqueous layer was extracted with CH2Cl2 (4×1.0 L). The organic layers were then combined and successively washed with water (3×1.0 L) and brine (2×2 L). The organic layer was dried over Na2SO4 and filtered and concentrated under reduce pressure to give 1423 g (>100%) of compound 64 as dark brown solid.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.Cl[S:18]([C:21]1[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:20])=[O:19]>C(OCC)(=O)C>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][S:18]([CH:21]1[C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][C:24]([CH3:27])([CH3:28])[CH2:25][CH2:26]1)(=[O:20])=[O:19]
Reactant: Nc1ccc(F)cc1F
Reactant: CCOC(=O)C1=C(S(=O)(=O)Cl)CCC(C)(C)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=CC(C)(C)CCC1S(=O)(=O)Nc1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.7 %

Procedure:
2,4-Difluoroaniline (1.51 g) was dissolved in ethyl acetate (33 ml) and the resultant solution was admixed with triethylamine (2.51 ml) with ice-cooling, and then treated dropwise with a solution of ethyl 2-chlorosulfonyl-5,5-dimethyl-1-cyclohexene-1-carboxylate (2.53 g) obtained in Reference Example 18 in ethyl acetate (17 ml). The reaction mixture was stirred under nitrogen flow at 0° C. for 30 minutes then at room temperature for 64.5 hours. The reaction mixture was diluted with ethyl acetate, and washed successively with water (120 ml), 0.5 N HCl (120 ml), water (120 ml×2) and saturated brine (120 ml). The ethyl acetate layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/9→1/7). A desired fraction was concentrated under reduced pressure, and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield ethyl 6-[N-(2,4-difluorophenyl)sulfamoyl]-3,3-dimethyl-1-cyclohexene-1-carboxylate (Compound 83; 0.83 g) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13]O)[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:26]=[N+:27]=[N-:28])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: COc1c(F)cc(CCCO)cc1F
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Product: COc1c(F)cc(CCCN=[N+]=[N-])cc1F
Yield: 94.1 %

Procedure:
3-(3,5-Difluoro-4-methoxyphenyl)propanol (0.073 mol), tosyl chloride (0.146 mol) and sodium azide (0.146 mol) were reacted substantially as described in Example 7E above to obtain 15.6 g (95%) yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:19][C:20]1[S:21][C:22]([C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:23][N:24]=1.[C:30]1([CH3:40])[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1.O>N1C(C)=CC=CC=1C>[CH3:40][C:30]1[CH:35]=[CH:34][C:33]([S:36]([O:18][CH2:17][C@@H:10]2[C@@H:11]([OH:16])[C@H:12]([OH:15])[C@@H:13]([OH:14])[C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:19][C:20]4[S:21][C:22]([C:25]5[O:26][CH:27]=[CH:28][CH:29]=5)=[CH:23][N:24]=4)[CH:4]=3)[O:9]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ncc(-c4ccco4)s3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@@H](c3ccc(Cl)c(Cc4ncc(-c5ccco5)s4)c3)[C@H](O)[C@@H](O)[C@@H]2O)cc1
Yield: 76.3 %

Procedure:
The solution of alcohol 89 (1.0 g, 2.28 mmol) and p-toluenesulfonyl chloride (2.3 g, 11.8 mmol) in 2,6-lutidine (22.8 mL) was stirred at room temperature for 15 h. H2O (150 mL) was added to the reaction mixture and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification by silica gel column chromatography provided desired toluenesulfonate 90 (1.03 g, 78%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1.Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([C:34]([F:37])([F:36])[F:35])=[CH:31][CH:32]=2)[N:27]=[CH:26][CH:25]=1>>[Br:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:24]4[C:33]5[C:28](=[CH:29][C:30]([C:34]([F:37])([F:35])[F:36])=[CH:31][CH:32]=5)[N:27]=[CH:26][CH:25]=4)=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Reactant: Nc1ccc(CN2CCN(c3cc(Br)cc(Br)c3)CC2)cc1
Product: FC(F)(F)c1ccc2c(Nc3ccc(CN4CCN(c5cc(Br)cc(Br)c5)CC4)cc3)ccnc2c1

Procedure:
In the manner given in Example 1C, 1-(3,5-dibromophenyl)-4-[(4-aminophenyl)methyl]piperazine and 4-chloro-7-(trifluoromethyl)quinoline are reacted together at reflux to give 4-[[4-[[4-(3,5-dibromophenyl)-1-piperazinyl]methyl]phenyl]amino]-7-(trifluoromethyl)quinoline.
Reaction SMILES: [Na+].[Cl-].O[C:4]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:5]=1[C@@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])[C:10]([O:16]C)=[CH:11][CH:12]=2)[O:7]1.C[OH:29]>>[CH3:21][C:20]([CH3:22])=[CH:19][CH2:18][C:9]1[C:10]([OH:16])=[CH:11][CH:12]=[C:13]([C:14](/[CH:15]=[CH:6]/[C:5]2[CH:23]=[CH:24][C:25]([OH:27])=[CH:26][CH:4]=2)=[O:29])[C:8]=1[OH:7]
Reactant: COc1ccc2c(c1CC=C(C)C)O[C@H](c1ccc(O)cc1O)CC2
Reactant: CO
Agent: [Cl-]
Agent: [Na+]
Product: CC(C)=CCc1c(O)ccc(C(=O)/C=C/c2ccc(O)cc2)c1O

Procedure:
Yellow powder; mp 75-76° C.; UV (MeOH) λmax (log ε) 368 (4.09), 206 (4.08) nm; IR (NaCl) γmax 3395, 2921, 1635 cm−1; 1H NMR (CD3OD, 500 MHz) δ 1.63 (3H, s, H-5″), 1.77 (3H, s, H-4″), 3.34 (2H, d, J=7.2 Hz, H-1″), 5.26 (1H, m, H-2″), 6.53 (1H, d, J=8.8 Hz, H-5′), 6.92 (2H, d, J=8.5 Hz, H-3), 7.72 (2H, d, J=8.4 Hz, H-2), 7.74 (1H, d, J=15.2 Hz, H-1), 7.82 (1H, d, J=15.3 Hz, H-β), 7.96 (H, d, J=8.9 Hz, H-6′); 13C NMR (CD3OD, 125 MHz) δ 17.9 (C-4″), 22.2 (C-1″), 25.8 (C-5″), 107.9 (C-5′), 114.4 (C-1′), 116.0 (C-3′), 116.7 (C-3), 118.5 (C-α), 123.2 (C-2″), 127.6 (C-1), 130.3 (C-6′), 131.5 (C-3″), 131.7 (C-2), 144.9 (C-β), 160.9 (C-4), 162.6 (C-4′), 164.7 (C-2′), 192.5 (CO); EIMS m/z 324 (M+, 100), 281 (83), 269 (22), 176 (22) 161 (36), 149 (96), 120 (31).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]=[CH:7][C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])=[C:5]2[OH:24].[C:25](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH3:12])[N:8]([CH3:25])[CH:7]=[C:6]([C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=[O:14])[C:5]2=[O:24]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2cc1Br
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cc1nc2c(cc1Br)c(=O)c(C(=O)NCc1ccc(Cl)cc1)cn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.8 %

Procedure:
To a solution of 6-bromo-N-(4-chlorobenzyl)-4-hydroxy-7-methyl[1,8]naphthyridine-3-carboxamide (0.400 g, 0.98 mmol) and potassium carbonate (0.54 g, 3.92 mmol) in 5 mL DMF at room temperature is added dropwise methyl iodide (0.167 g, 1.18 mmol). The mixture is stirred at room temperature for 30 min then diluted with water. The resulting solid is filtered, washed with water and dried. The crude product is triturated with EtOAc/hexanes to yield 0.358 g (85%) of the desired product as a white solid. Physical characteristics are as follows: m.p. 266-268° C.; 1H NMR (CDCl3) δ 10.18, 8.92, 8.83, 7.30, 4.65, 4.03, 2.82; Anal. Calcd for C18H15BrClN3O2: C, 51.39; H, 3.59; N, 9.99; Found: C, 51.02; H, 3.57; N, 9.94.
Reaction SMILES: Cl.[O:2]([CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[Cl:19][S:20]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH2:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[O:11])=[CH:4][CH:5]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(COc1ccccc1)Nc1ccccn1
Agent: Cl
Solvent: ClCCl
Product: O=C(COc1ccc(S(=O)(=O)Cl)cc1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.32 g of 2-(phenoxyacetyl)aminopyridine HCl salt (5 mmole) was resuspended in 10 ml of dichloromethane and 2 ml of chlorosulfonic acid was added in ice-bath to give clear solution. The solution was stirred at room temperature for 3 hr. The reaction mixture was added to ice-water with good stirring to give white solids. The solids were filtered, washed with acetonitrile, and dried in vacuo. 0.65 g of solid was obtained. M. P. 170-175° C. (decomposition)
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>C(Cl)Cl.O.C1COCC1.CCN(CC)CC>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: CC(O)c1ccc(F)nc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(c1ccc(F)nc1)N1CCOCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
To a stirred solution of 1-(6-fluoropyridin-3-yl)ethanol (2.30 g, 16.3 mmol) and Et3N (4.52 mL, 32.6 mmol) in DCM (50 mL) in 500 mL round-bottomed flask, methanesulfonyl chloride (Aldrich, 1.30 mL, 16.8 mmol) was added dropwise at 0° C. The mixture was stirred at 0° C. for 30 min. Water (50 mL) was added and the layers were separated. The aqueous phase was extracted with DCM (2×30 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to afford cloudy viscous pale yellow oil. To this intermediate, DCM (40 mL), Et3N (9 mL) and morpholine (5.68 mL, 65.2 mmol) were added and the mixture was stirred at room temperature overnight. THF (5 mL) was added and the stirring was resumed. After overnight stirring, water (60 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2×60 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (100 g, eluent: iPrOH in CHCl3 0% to 5%) to give 4-(1-(6-fluoropyridin-3-yl)ethyl)morpholine (2.92 g, 85% yield) as a pale yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.12 (s, 1H) 7.79 (td, J=8.12, 2.35 Hz, 1H) 6.90 (dd, J=8.41, 2.93 Hz, 1H) 3.68 (t, J=4.60 Hz, 4H) 3.36-3.44 (m, 1H) 2.44-2.56 (m, 2H) 2.30-2.40 (m, 2H) 1.35 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion): 211.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([Br:14])=CC=2)=[CH:4][CH:3]=1.[Mg].[Cl-].[Cl-].C(C1C=C(C(C)(C)C)C=CC=1OP(O)O)(C)(C)C>O1CCCC1.O1CCCC1.CCCCCCC>[Br:14][C:11]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:8]=[CH:13][CH:12]=1
Reactant: Brc1ccc(-c2ccc(Br)cc2)cc1
Agent: CC(C)(C)c1ccc(OP(O)O)c(C(C)(C)C)c1
Agent: [Cl-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Brc1cccc2ccccc12
Yield: 200 %

Procedure:
4,4'-Biphenylene-bis- (1-naphthyl-phosphinous acid 2,4-di-tert-butylphenyl ester): in deviation from the general instructions, 200 mmol (=62.4 g) of 4,4'-dibromobiphenyl were subjected to a Grignard reaction with 600 mmol (=14.6 g) of magnesium filings in 600 ml of tetrahydrofuran under the action of ultrasound (40 kHz), and the product was then reacted with 400 mmol (=122.9 g) of phosphorous acid 2,4-di-tert-butylphenyl ester-dichloride in 700 ml of tetrahydrofuran/heptane=1/6. The Grignard reagent obtained from 82.8 g (400 mmol) of 1-bromonaphthalene was added dropwise to the resulting suspension. The mixture was filtered and the filtrate was concentrated in vacuo to give 175 g of yellow resin having a content of 76% of the above compound 31P-NMR: δ(CDCl103.7 ppm]. Pale yellow crystals of melting point 255° C. crystallized from acetone.
Reaction SMILES: C(OC1C=CC(C([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][C:19](=O)[C:20]2[CH:25]=[CH:24][C:23]([O:26]CCC)=[CH:22][CH:21]=2)=O)=CC=1)CC.C(OC1C=CC(C(Cl)=O)=CC=1)CC.C1(N)C=CC=CC=1N.Cl.C(=O)(O)[O-].[Na+]>>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:18]=2)=[CH:21][CH:22]=1
Reactant: CCCOc1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc(OCCC)cc2)cc1
Agent: CCCOc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: Nc1ccccc1N
Product: Oc1ccc(-c2nc3ccccc3[nH]2)cc1
Yield: 76 %

Procedure:
N,N'-Bis(p-propoxybenzoyl)-o-phenylenediamine (m.p. 196° C.) [prepared in 86% yield from p-propoxybenzoyl chloride and o-phenylenediamine was heated (200° C.) for four hours with concentrated hydrochloric acid. Mixture was cooled, neutralized with sodium bicarbonate and filtered. Recrystallization from ethanol gave 2-(p-hydroxyphenyl)benzimidazole (Yield 76%, m.p. 286°-288° C.). A well stirred mixture of 2-(p-hydroxyphenyl)benzimidazole (0.1 mole), iodoethane (0.1 mole) and sodium bicarbonate (0.12 mole) in 200 ml of acetone was refluxed overnight, filtered and the acetone removed on the steam bath. The isolated 2-(p-hydroxyphenyl)-1-methylbenzimidazole was reacted with 4-(2-bromoethoxy)-2-hydroxybenzophenone as in Example 1 to produce 4-{2-[4-(1-ethyl-2-benzimidazolyl)phenoxy]ethoxy}-2-hydroxybenzophenone.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.[Zn]>[OH:14][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCC=O
Reactant: CCOC(=O)CBr
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: CCCCCC(O)CC(=O)OCC
Temperature: 83 °C

Procedure:
7.64 g (0.117 mol) of zinc pretreated as described in Reference Example 1 were suspended in 50 ml of toluene, the mixture was heated to 83° C., the heat source was subsequently removed and a mixture of 11.4 ml (0.103 mol) of ethyl bromoacetate and 11.23 ml (0.0935 mol) of hexanal was added dropwise over a period of 30 minutes. After a brief induction phase, rigorous foaming and heating of the reaction mixture to 110° C. was observed. After all the mixture had been added, the resulting suspension was cooled to 8° C. by means of an ice/water mixture, after which 15 ml of 50% strength sulfuric acid was added dropwise at such a rate that the temperature of the suspension did not exceed 35° C. After phase separation, the organic phase was washed twice with 15 ml of water and dried over sodium sulfate. After filtration and removal of all volatile constituents on a rotary evaporator at 50° C./5 torr, the residue obtained was distilled in an oil pump vacuum at 2.5 torr. The fraction comprising ethyl 3-hydroxyoctanoate went over at 88-93° C. Yield: 12.25 g (70%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li][C:11](C)([CH3:13])[CH3:12]>C1COCC1>[CH2:12]([C:5]1[S:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=1)[CH2:11][CH3:13]
Reactant: c1ccc2sccc2c1
Reactant: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CCCc1cc2ccccc2s1

Procedure:
2-n-Propylbenzo[b]thiophene was prepared by the method of Example 40A with benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7 M, 9.7 mmoles, 5.7 ml), n-bromopropane (9.7 mmoles, 0.88 ml) and THF (20 ml). 1.11 g (85%) of a light yellow liquid was isolated.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:18])[CH:4]=1)=[O:2].C(N(CC)CC)C.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>CN(C=O)C.C(OCC)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:31][O:30][C:26](=[O:29])[CH:27]=[CH:28][C:6]1[C:7]([CH3:9])=[CH:8][C:3]([CH:1]=[O:2])=[CH:4][C:5]=1[CH3:18]
Reactant: C=CC(=O)OC
Reactant: Cc1cc(C=O)cc(C)c1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1c(C)cc(C=O)cc1C
Temperature: 115 °C
Reaction time: 5 h
Yield: 79.6 %

Procedure:
To a stirred solution of trifluoro-methanesulfonic acid 4-formyl-2,6-dimethyl-phenyl ester (4.7 g, 16.7 mmol) in dry DMF (75 mL) under argon is sequentially added at rt triethylamine (3.4 g, 33.3 mmol), methyl acrylate (14.3 g, 167 mmol), 1,3-bis-(diphenylphosphino)-propane (378 mg, 0.92 mmol) and Pd(OAc)2 (187 mg, 0.83 mmol). The mixture is heated to 115° C. and stirred for 5 h. The mixture is diluted with diethyl ether (350 mL) and washed twice with aq. 1 N HCl and once with sat. aq. NaHCO3. The organic extract is dried over MgSO4, filtered and evaporated. The residue is purified by CC on silica gel eluting with heptane:EA 5:1 to give 3-(4-formyl-2,6-dimethyl-phenyl)-acrylic acid methyl ester (2.9 g) as a slightly yellow solid; LC-MS: tR=0.96 min.
Reaction SMILES: CCOCC.Cl.Cl[C:8]1[C:14]2[CH:15]=[CH:16][C:17]([C:19]([O:21][CH3:22])=[O:20])=[CH:18][C:13]=2[S:12][C:11]2[CH:23]=[CH:24][CH:25]=[CH:26][C:10]=2[N:9]=1>C(Cl)Cl>[CH:15]1[C:14]2[CH:8]=[N:9][C:10]3[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=3[S:12][C:13]=2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2
Temperature: 25 °C

Procedure:
Stir at room temperature a mixture of 4.27 gm. (22.54 mmole) of stannous chloride in 200 ml. of dry ether while passing dry hydrogen chloride through the mixture to saturation. Dissolve 3.42 gm. (11.27 mmole) of the 11-chloro ester of Example 6 in 35 ml. of methylene chloride and add this solution to the stannous chloride solution over a 10 minute period. Pass dry hydrogen chloride through the mixture for 30 minutes and decant the supernatant liquid. Wash the residue by decantation with dry ether. Filter and wash with dry ether. Shake the solids for 2 minutes in a mixture of 25 ml. of 5 N aqueous sodium hydroxide and 25 ml. of methylene chloride. Separate the organic layer and extract the aqueous layer with 25 ml. of methylene chloride. Wash the combined extracts with water, separate the organic layer and dry over magnesium sulfate. Evaporate to a residue. Recrystallize from acetonitrile to obtain the title product, (m.p. 103.5°-109.5° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Br:9][C:10]1[CH:11]=[CH:12][C:13]2[O:22][CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([C:23](Cl)=[O:24])[S:16][C:15]=3[C:14]=2[CH:26]=1.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:23]([C:17]1[S:16][C:15]2[C:14]3[CH:26]=[C:10]([Br:9])[CH:11]=[CH:12][C:13]=3[O:22][CH2:21][CH2:20][C:19]=2[CH:18]=1)=[O:24]
Reactant: O=C(Cl)c1cc2c(s1)-c1cc(Br)ccc1OCC2
Reactant: Nc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1Cl)c1cc2c(s1)-c1cc(Br)ccc1OCC2

Procedure:
Reaction of 2-chloroaniline with 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carbonyl chloride (prepared from the corresponding carboxylic acid using oxalyl chloride with catalytic N,N-dimethylformamide) yielded 9-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-2-carboxylic acid (2-chloro-phenyl)-amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([F:9])[CH:3]=1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[C:13]([F:19])[CH:12]=1.ClC1C=CC(C(C2C=CC(OC)=CC=2)O)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:15]([C:14]2[CH:17]=[CH:18][C:11]([Cl:10])=[CH:12][C:13]=2[F:19])[OH:16])=[C:4]([F:9])[CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1F
Reactant: Fc1cc(Cl)ccc1Br
Agent: COc1ccc(C(O)c2ccc(Cl)cc2)cc1
Product: OC(c1ccc(Cl)cc1F)c1ccc(Cl)cc1F

Procedure:
The title compound was prepared starting from 5.00 g (23.87 mmol) of 4-chloro-2-fluorobromobenzene and 4.54 g (28.65 mmol) of 4-chloro-2-fluorobenzaldehyde in analogy to the synthesis of the compound from Example 175A. A difference was that a preliminary separation by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate gradient) was carried out before the purification of the crude product by preparative HPLC. 1.79 g (26% of theory) of the title compound were obtained.