Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:21]([C:23]1[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=1[CH3:34])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:21][C:23]4[NH:27][C:26]([CH3:28])=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:24]=4[CH3:34])[C:17](=[O:19])[N:16]([CH3:20])[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1C(=O)Cc2c(Nc3ccc(F)c(Cl)c3)ncnc21
Reactant: Cc1[nH]c(C=O)c(C)c1CCC(=O)O
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1[nH]c(C=C2C(=O)N(C)c3ncnc(Nc4ccc(F)c(Cl)c4)c32)c(C)c1CCC(=O)O
Yield: 22.5 %

Procedure:
4-(3-Chloro-4-fluoro-phenylamino)-7-methyl-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (100 mg, 0.34 mmol) was condensed with 3-(5-formyl-2,4-dimethyl-1H-pyrrol-3-yl)-propionic acid (80 mg, 0.41 mmol) and piperidine (2 drops) in ethanol (3 mL) at 80° C. for 2 hours to give 36 mg (23%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.15 (br s, 1H, NH), 12.07 (br s, 1H, COOH), 9.18 (s, 1H), 8.33 (s, 1H), 7.71 (m, 1H), 7.40 (s, 1H), 7.30-7.39 (m, 2H), 3.32 (s, 3H, CH3), 2.63 (m, 2H, CH), 2.35 (m, 2H, CH2), 2.33 (s, 3H, CH3), 2.13 (s, 3H, CH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:17][C:18](=O)[CH2:19][CH:20]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[CH2:21][C:22]([OH:24])=[O:23])([O-])=O.Cl.[C:34]([O-])(O)=O.[Na+].C(OCC)(=O)C>CO.Cl.[Fe]>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:20]([CH2:19][C:18]2[NH:1][C:4]3[CH:9]=[C:8]([O:10][C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH:7]=[CH:6][C:5]=3[N:17]=2)[CH2:21][C:22]([O:24][CH3:34])=[O:23])=[CH:26][CH:27]=1
Reactant: O=C(O)CC(CC(=O)Nc1ccc(Oc2ccccc2)cc1[N+](=O)[O-])c1ccc(Cl)cc1
Reactant: O=C([O-])O
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC(Cc1nc2ccc(Oc3ccccc3)cc2[nH]1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(2-Nitro-4-phenoxyphenyl)-3-(4-chlorophenyl)glutaramic acid (0.72 g) is dissolved in methanol (8 ml). Iron powder (0.88 g) is added and the suspension is heated to reflux. Conc. HCl (10 drops) was added carefully and refluxing was continued for 1 h. Then further conc. HCl (4 ml) was added and the greenish-yellow solution was stirred at reflux for additional 20 h. After cooling to rt the solution was poured into a mixture of sat. NaHCO3 solution (60 ml) and ethyl acetate (50 ml). The inorganic precipitates were removed by suction filtration and subsequently washed with ethyl acetate. From the filtrate the organic layer was separated and the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were dried (sodium sulfate), concentrated and dried in vacuo. The residue (0.61 g of brownish oil) was purified by flash chromatography (dichloromethane/2% methanol/1% triethyl amine) on silica gel to give methyl 3-(4-chlorophenyl)-4-(5-phenoxy-2-benzimidazolyl)butanoate (0.46 g) as a colourless solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH:6]=[C:5]2[NH:19][CH3:20].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN1CCCC1=O.O.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)[CH:6]=[C:5]3[NH:19][CH3:20])[CH:25]=[C:26]([Cl:28])[CH:27]=1
Reactant: CNc1cc(-c2cccc(F)c2)nc2ccc(Br)cc12
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: O
Solvent: CN1CCCC1=O
Product: CNc1cc(-c2cccc(F)c2)nc2ccc(-c3cc(Cl)cc(Cl)c3)cc12
Temperature: 80 °C

Procedure:
To 0.4 g. (1.2 mmole) of N-[6-bromo-2-(3-fluorophenyl)4-quinolinyl]-N-methylamine was added 0.275 g. (1.45 mmole) of 3,5-dichlorophenylboronic acid and a catalytic amount of tris(dibenzylideneacetone)dipalladium (0), 0.0109 g. (0.012 mmole). The mixture was dissolved in 7 mL of N-methyl-2-pyrrolidinone. Sodium carbonate, 0.105 g. (1.45 mmole) was dissolved in a minimal amount of water and added in one portion to the N-methyl-2-pyrrolidinone reaction solution. The mixture was heated to 80° C. for 10 hours. After cooling to room temperature, the mixture was diluted to 10 mL total volume with methanol and filtered through a silica plug. The title compound was isolated by reverse phase HPLC on a 2 inch Dynamax phenyl column using a solvent gradient from 85:15 methanol:water to 100% methanol, yield 0.320 g. (67%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CC#N>[CH2:11]([NH:18][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)c1cnccc1Cl
Solvent: CC#N
Product: O=C(O)c1cnccc1NCc1ccccc1
Temperature: 80 °C

Procedure:
A mixture of 4-chloronicotinic acid (300 mg, 1.90 mmol) and benzylamine (408 mg, 3.81 mmol) in MeCN (3 mL) was stirred and heated in the microwave (80° C., 200 W) for 1 h. The solution obtained was partitioned between water and EtOAc. The precipitate formed was filtered off, washed with water, EtOAc and dried in vacuo. 4-(benzylamino)nicotinic acid was obtained as a colourless solid (147 mg, 34%). ESI-MS [M+H]+=229.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26](C)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[NH3:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[C:11]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH2:30])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CC(C)CCc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O
Product: CC(C)CCc1c(-c2ccc(S(N)(=O)=O)cc2)cnn(-c2cccc(Cl)c2)c1=O

Procedure:
The title compound was prepared according to the method of Example 384, substituting 2-(3-chlorophenyl)-4-(3-methylbutyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 366) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 0.0756 g, 16%). mp 167-170° C. 1H NMR (300 MHz, DMSO d6) δ 0.78 (d, J=6 Hz, 6H), 1.47 (5H, obstructed by hexanes), 7.51-7.65 (m, 4H), 7.68 (m, 2H), 7.75 (m, 1H), 7.98 (m, 2H), 8.03 (s, 1H), 8.60 (bs, 1H). MS (DCI/NH3) m/z 432 (M+H)+, 449 (M+NH4)+. Anal. calc. for C21H22ClN3O3S (0.25H2O): C, 57.79; H, 5.19; N, 9.62. Found: C, 57.78; H, 5.02; N, 9.40.
Reaction SMILES: N1C=CN=CC=1C1C=CN=[C:9]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][CH:16]=2)N=1.[NH:24]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)[C:25]([NH2:27])=N.CN(/C=C/C(C1C=NC=CN=1)=O)C.CN(C)/C=C/C(C1C=NC=CC=1)=O>>[N:13]1[CH:14]=[CH:15][CH:16]=[C:17]([C:18]2[CH:22]=[CH:23][N:27]=[C:25]([NH:24][C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)[CH:19]=2)[CH:9]=1
Reactant: O=C(O)c1ccc(CNc2nccc(-c3cnccn3)n2)cc1
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Agent: CN(C)/C=C/C(=O)c1cccnc1
Agent: CN(C)/C=C/C(=O)c1cnccn1
Product: O=C(O)c1ccc(Nc2cc(-c3cccnc3)ccn2)cc1

Procedure:
Title compound was prepared according to the procedure described for the synthesis of compound 25a (scheme 6, step 3) replacing the guanindine 24 by 4-guanidinobenzoic acid (344) (Zlatoidsky P., Maliar T. Eur. J. Med. Chem Chim. Ther.; 1996, 31, 895-900) and (E)-3-(dimethylamino)-1-(pyrazin-2-yl)-prop-2-en-1-one (23a) by (E)-3-(dimethylamino)-1-(pyridin-3-yl)prop-2-en-1-one (345) (Zimmermann J., Buchdunger E., et al. Bioorg. Med. Chem. Lett., 1996, 6, 1221-1226). Yield of the product 28%. MS (m/z): 292.29 (calc) 293.1 (MH+) (found).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11](OS(C(F)(F)F)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]([O:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O)=[O:28])([CH3:25])([CH3:24])[CH3:23].[Cl-].[Li+].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([N:29]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:27](=[O:28])[O:26][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
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: [Cl-]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(N(C(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 25 °C

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (100 mg) was added to a degassed mixture of 1-t-butoxycarbonyl-4-trifluoromethanesulfonyloxy-1,2,3,6-tetrahydropyridine (5.0 g), 2-(t-butoxycarbonylamino)phenylboronic acid (Tetrahedron Lett. 1993, 28, 5093) (4.99 g), lithium chloride (1.94 g) and aqueous sodium carbonate (2N, 21 mL) in 1,2-dimethoxyethane (100 mL). The resulting solution was heated under reflux for 3 h., cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and aqueous sodium carbonate (2M) and the organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by MPLC on silica gel, eluting with EtOAc/Hexane (5:95) to give the title compound as a waxy solid (2.7 g), δH (CDCl3) 1.43 (18H, s), 2.29 (2H, m), 3.57 (2H, t, J 8.0 Hz), 4.00 (2H, m), 5.64 (1H, br s), 6.46 (1H, br s), 6.92-6.96 (2H, m), 7.15-7.19 (1H, m), 7.87 (1H, m).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[NH:11][C:10]3[CH:12]=[C:13]([O:16][C:17]4[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=4)[CH:14]=[CH:15][C:9]=3[N:8]=2)=[O:5])[CH2:3][CH2:2]1>FC(F)(F)C(O)=O>[NH2:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[O:16][C:13]1[CH:14]=[CH:15][C:9]2[N:8]=[C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])[NH:11][C:10]=2[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)[nH]c3c2)c1
Temperature: 25 °C
Yield: 88.6 %

Procedure:
tert-Butyl [3-({2-[(cyclopropylcarbonyl)amino]-1H-benzimidazol-6-yl}oxy)phenyl]carbamate (1.58 g, 3.88 mmol) was suspended in trifluoroacetic acid (50 mL), and the reaction mixture was heated under reflux for 1 hr. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. The residue was diluted with ethyl acetate (200 mL), and washed with 0.1N hydrochloric acid (100 mL) and saturated aqueous sodium hydrogencarbonate solution (100 mL), successively. The collected aqueous layer was extracted with ethyl acetate (100 mL×2). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from methanol to give the title compound (1.06 g, 88%) as pale-brown crystals.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CC(C)([O-])C.[K+].F[C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[C:26]([F:29])([F:28])[F:27]>C1COCC1>[CH2:1]([O:9][C:17]1[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][C:18]=1[C:26]([F:27])([F:29])[F:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CCCCCCCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCOc1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 110.5 %

Procedure:
A 12 L round bottom flask was inerted and charged with 1-octanol (103 g, 0.793 mol, 1 equiv), THF (2 L), 1 M potassium tert-butoxide (2 L, 2.5 equiv) and heated to 65° C. and held for 45 minutes. The reaction was charged over 1 hour with 4-fluoro-3-trifluoromethyl benzoic acid (165 g, 0.793 mol) while maintaining the temperature at 64 to 67° C. After 2 hours, the reaction mixture was sampled. The sample was concentrated, quenched into 1 N HCl, extracted with ethyl acetate, removed the ethyl acetate, diluted with acetonitrile and injected in to the HPLC. The reaction was complete. The reaction mixture was stirred overnight at 18 to 23° C. The mixture was cooled to 5 to 10° C. and cautiously quenched with water (1.6 L). The quench was exothermic and the temperature was maintained at T<10° C. The resulting mixture was concentrated under vacuum until no noticeable THF was coming off. The resulting aqueous mixture was acidified to pH 1 to 2 using 6 N HCl (400 mL). The mixture was extracted with MTBE (2×2.5 L). The MTBE phases were combined, washed with brine (2 L), dried with magnesium sulfate, filtered over Celite, concentrated to afford the title product (279 g, 111% yield, 95.6% AUC by HPLC) as a tan solid.
Reaction SMILES: C(O[C:4]([NH:6]/[C:7](/[C:14]([F:17])([F:16])[F:15])=[CH:8]\[C:9]([O:11]CC)=O)=[O:5])C.[NH2:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][N:25]=[C:24]([C:27]3[CH:28]=[C:29]([CH3:35])[C:30]([O:33][CH3:34])=[CH:31][CH:32]=3)[C:23]=2[CH:36]=1.N12CCCN=C1CCCCC2>C1(C)C(C)=CC=CC=1>[CH3:34][O:33][C:30]1[C:29]([CH3:35])=[CH:28][C:27]([C:24]2[C:23]3[CH:36]=[C:19]([N:18]4[C:9](=[O:11])[CH:8]=[C:7]([C:14]([F:15])([F:16])[F:17])[NH:6][C:4]4=[O:5])[CH:20]=[CH:21][C:22]=3[S:26][N:25]=2)=[CH:32][CH:31]=1
Reactant: CCOC(=O)/C=C(\NC(=O)OCC)C(F)(F)F
Reactant: COc1ccc(-c2nsc3ccc(N)cc23)cc1C
Solvent: Cc1ccccc1C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nsc3ccc(-n4c(=O)cc(C(F)(F)F)[nH]c4=O)cc23)cc1C
Yield: 72 %

Procedure:
A mixture of ethyl 3-[(ethoxycarbonyl)amino]-4,4,4-trifluorocrotonate, (Z)-(2.04 g, 8 mmol), 5-amino-3-(6-methoxy-m-tolyl)-1,2-benzisothiazole (2.59 g, 9.6 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU, 1.46 g, 9.6 mmol) in xylene (15 mL) is heated at 110° C. for 6 hours, cooled, and quenched with ethyl acetate and water. The resultant mixture is extracted with ethyl acetate. The organic extracts are combined, washed with aqueous 2 N hydrochloric acid, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a foam. Flash chromatography of the foam using silica gel and a 3:7 ethyl acetate/hexanes solution gives the title product as a solid (2.5 g, 72% yield) which is identified by 1H and 19F NMR spectral analyses.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C[O-].[Na+].[I-].[K+].Br[CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]>CO.C1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH:16]([C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[CH:23][CH:22]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: C[O-]
Agent: [I-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Solvent: CO
Product: COC(=O)C(Oc1ccc(Cl)c(Cl)c1)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To a solution of 4.08 g of 3,4-dichlorophenol, 1.188 g of sodium methoxide, and 50 mg of potassium iodide in 40 ml of methanol is added 7.11 g of methyl α-bromo-α-[p-(p-chlorophenoxy)phenyl]acetate in 10 ml of benzene. The mixture is maintained at reflux overnight and then poured into 100 ml of water. The product is extracted with ether and the extracts are washed with 5% NaOH, water and brine and dried (MgSO4). Evaporation of the solvent yields an oil which is chromatographed on 100 g of silica gel (benzene 400 ml) to yield a yellow oil.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][N:20]=[N:19][C:18]=1Cl)=[O:16])[CH3:13]>O1CCOCC1>[CH2:12]([O:14][C:15]([C:17]1[CH:22]=[CH:21][N:20]=[N:19][C:18]=1[N:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH:2]([OH:1])[CH2:10][OH:11])[CH2:5][CH2:6]1)=[O:16])[CH3:13]
Reactant: CCOC(=O)c1ccnnc1Cl
Reactant: OCC(O)CN1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)c1ccnnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 10.2 of 1-(2,3-dihydroxypropyl)piperazine and 5.9 g of 3-chloropyridazine-4-carboxylic acid ethyl ester in 100 ml dioxane were refluxed for one hour. Then it was settled, the solvent evaporated till dryness, and the residue dissolved in chloroform and washed with a small amount of water. The organic phase was made anhydrous, evaporated to dryness and the residue, purified on a column eluting with chloroform:methanol (9:1), gave 2.4 g of 3-[4-(2,3-dihydroxypropyl)piperazin-1-yl]pyridazine-4-carboxylic acid ethyl ester as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH2:10]([NH2:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:16][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccccc1Br
Reactant: CCCCCCN
Product: CCCCCCNc1ccccc1OC
Yield: 88.8 %

Procedure:
Using the general procedure, 2-bromoanisole (125 μL, 1.0 mmol) was coupled with n-hexylamine (198 μL, 1.5 mmol) at 100° C. for 22 h. Purification of the crude product by column chromatography on silica gel using hexane/ethyl acetate (30:1) as eluent afforded the desired product as a colorless liquid (184 mg, 89% yield). Rf=0.4 (hexane/ethyl acetate=20:1).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.Br[C:28]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=1.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C)C=O.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:34][C:33]1[C:28]([C:16]2[CH:15]=[C:10]([CH:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:29][CH:30]=[CH:31][CH:32]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(-c2ccc(C)cn2)c1
Reactant: Fc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CC(C)NC(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2ncccc2F)c1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.80 g, 2.27 mmol) in N,N-dimethylformamide (6.8 mL) and water (2.3 mL) were added 2-bromo-3-fluoropyridine (0.44 g, 2.49 mmol), palladium acetate (25.4 mg, 0.11 mmol), 3,3′,3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (0.19 g, 0.34 mmol) and diisopropylamine (0.81 mL, 5.66 mmol). The reaction mixture was heated to 80° C. After 18 h, the mixture was cooled to ambient temperature and the solid was filtered off. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. MS 323.0 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]2C(COS(C3C=CC(C)=CC=3)(=O)=O)[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1.[C:29]([O-:32])(=O)[CH3:30].[Na+].[OH-].[K+]>C(O)(=O)C.CO>[Br:1][C:2]1[CH:28]=[CH:27][C:5]2[C:29]([OH:32])=[CH:30][C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2c3ccccc3C=Cc3cc(Br)ccc32)cc1
Reactant: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: OC1=Cc2ccccc2C=Cc2cc(Br)ccc21
Yield: 47.7 %

Procedure:
To a solution of 2-bromo-5-p-toluenesulphonyloxymethyl-dibenzo[a,d]cycloheptene (8.1 g) in glacial acetic acid (75 ml) was added anhydrous sodium acetate (2.9 g). The reaction mixture was refluxed for 24 h then the solvent removed under vacuum to leave a residue which was partitioned between dichloromethane (3×100 ml) and water (100 ml). The combined organic layers were dried (Na2SO4) , filtered and concentrated in vacuo to leave a residue which was dissolved in 75% aqueous methanol (100 ml) and treated with potassium hydroxide (4 g). After 14 h the reaction mixture was concentrated in vacuo and the residue partitioned between water (50 ml) and diethyl ether (3×50 ml). The combined organic layers were dried (Na2SO4) , filtered and concentrated in vacuo. Chromatography of the residue on flash silica with 10% ethyl acetate in hexane as eluent gave the less polar isomer, 2-bromo-5-hydroxy-dibenzo[a,e]cyclooctene (2.54 g, m.p. 148°-151° C.). δ (360 MHz, CDCl3) 3.26 (1H, dd, J=13.9 and 9.9 Hz, CHAHB --CHOH), 3.46 (1H, dd, J=13.9 and 6.2 Hz, CHAHB --CHOH), 5.24 (1H, dd, J=9.9 and 6.2 Hz, CHOH), 6.76 (1H, d, J=12.1 Hz, CHC =CHD), 6.87 (1H, d, J=12.1 Hz, CHC =CHD), 7.09-7.35 (7H, m, ArH), m/e 302 and 300 (M+); and as an oil the more polar isomer 2-bromo-6-hydroxy-dibenzo[a,e]cyclooctene (1.04 g), 67 (360 MHz, CDCl3) 3.25 (1H, dd, J=13.8 and 10.0 Hz CHAHB --CHOH), 3.40 (1H, dd, J=13.8 and 6.4 Hz, CHAHB --CHOH), 5.26 (1H, dd, J =10.0 and 6.4 Hz, CHAHB --CHOH), 6.75 (1H, d, J=12.1 Hz, CHC =CHD), 6.90 (1H, d, J=12.1 Hz, CHC =CHD), 7.08-7.45 (7H, m, ArH). m/e 302 and 300 (M+).
Reaction SMILES: [I:1][CH2:2][C:3]1[N:4]=C(C2C=CC(C)=CC=2)O[C:7]=1[C:8]1C=CC=CC=1.C/C(/C(C)=O)=N\O.[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[O:35])=[CH:32][CH:31]=1>>[I:1][CH2:2][C:3]1[N:4]=[C:34]([C:33]2[CH:36]=[CH:37][C:30]([C:29]([F:38])([F:39])[F:28])=[CH:31][CH:32]=2)[O:35][C:7]=1[CH3:8]
Reactant: Cc1ccc(-c2nc(CI)c(-c3ccccc3)o2)cc1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)/C(C)=N/O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CI

Procedure:
Analogously to the building block synthesis of 4-iodomethyl-5-phenyl-2-p-tolyloxazole, diacetylmonoxime and 4-trifluoromethylbenzaldehyde gave 4-iodomethyl-5-methyl-2-(4-trifluoromethylphenyl)oxazole.