Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[C:12]1([CH2:18][CH2:19][CH:20]=O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:12]1([CH2:18][CH2:19][CH2:20][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCCc1ccccc1
Reactant: NCCCCCn1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: c1ccc(CCCNCCCCCn2ccnc2)cc1
Temperature: 5 °C

Procedure:
A mixture of 1-(5-aminopentyl)imidazole (3.48 g), 3-phenylpropionaldehyde (3.08 g), p-toluenesulphonic acid (0.1 g) and toluene (90 ml) was boiled under reflux whilst removing the water formed using a Dean & Stark apparatus under nitrogen for 2 hours. The mixture was evaporated to dryness under reduced pressure to give an oil which was dissolved in IMS (100 ml) and cooled to 5° C. under nitrogen. Sodium borohydride (0.87 g) was added to the solution with stirring. The mixture was allowed to warm to 20° C. and stirred at this temperature for 16 hours. The solvent was removed under reduced pressure. The residue was dissolved in water and acidified to pH 2 with 2M hydrochloric acid. The solution was then basified with 2M sodium hydroxide solution (100 ml) and extracted with ethyl acetate to give an oil. The oil was distilled under high vacuum b.p. 250° C. at 0.04 mbar. The distillate was purified by flash column chromatography on silica using ethyl acetate/methanol/triethylamine (80:10:10) as the mobile phase to give N-(3-phenylpropyl)-5-imidazol-1-ylpentylamine 0.75 hydrate.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O-:26])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].[C:32]([O:38][CH2:39]I)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:29]/[OH:30])/[C:8]([NH:10][CH:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:39][O:38][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[S:25])=[C:15]([CH2:18][CH:19]4[O:23][CH2:22][CH2:21][CH2:20]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(/C(=N/O)C(=O)NC2C(=O)N3C(C([O-])=S)=C(CC4CCCO4)CS[C@H]23)cs1
Reactant: CC(C)(C)C(=O)OCI
Agent: [Na+]
Product: CC(C)(C)C(=O)OCOC(=S)C1=C(CC2CCCO2)CS[C@@H]2C(NC(=O)/C(=N\O)c3csc(N)n3)C(=O)N12
Yield: 25.3 %

Procedure:
Sodium 7-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-tetrahydrofurfurylthio-3-cephem-4-carboxylate (50 mg) was reacted with iodomethyl pivalate (36 mg) and post-treated in the same manner as in Example 4, yielding the titled compound (15 mg; 25%) as colorless crystals.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][CH:13]([NH2:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Cl:21][C:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31](O)=[O:32])=[CH:28][CH:29]=2)[NH:24][CH:23]=1>>[Cl:21][C:22]1[C:30]2[C:25](=[CH:26][C:27]([C:31]([NH:20][CH:13]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:12][CH2:11][CH2:10][N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]3)=[O:32])=[CH:28][CH:29]=2)[NH:24][CH:23]=1
Reactant: O=C(O)c1ccc2c(Cl)c[nH]c2c1
Reactant: CC(C)N1CCN(CCCC(N)c2ccccc2)CC1
Product: CC(C)N1CCN(CCCC(NC(=O)c2ccc3c(Cl)c[nH]c3c2)c2ccccc2)CC1

Procedure:
Using coupling method A, crude 4-(4-isopropylpiperazin-1-yl)-1-phenylbutylamine (530 mg, 1.9 mmol) and 3-chloro-indole-6-carboxylic acid (376 mg, 1.9 mmol) afforded, after purification (SiO2: 10:10:1 hexane:EtOAc:isopropyl-amine), 184 mg (21%) of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C@@H:7]([OH:10])[CH2:8][OH:9])[CH2:3][CH2:2]1.N1C(C)=CC=CC=1C.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[NH4+].[Cl-]>C(Cl)Cl>[Si:19]([O:9][CH2:8][C@@H:7]([CH:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)[OH:10])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC[C@H](O)C1CCOCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)(C)[Si](C)(C)OC[C@H](O)C1CCOCC1
Temperature: 25 °C
Yield: 78 %

Procedure:
A solution of (1R)-1-tetrahydro-2H-pyran-4-ylethane-1,2-diol (2.40 g, 16.2 mmol) in 60 mL of CH2Cl2 was cooled to 0° C. under N2. 2,6-Lutidine (3.77 mL, 32.4 mmol) and tert-butyldimethylsilyl chloride (2.57 g, 17.0 mmol) were added and the reaction mixture was stirred and allowed to warm to ambient temperature overnight. The reaction mixture was treated with saturated aqueous NH4Cl solution and the layers were separated. The organic portion was washed successively with aqueous 3.5% NaH2PO4 solution (2×), H2O and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Chromatography (SiO2, 20% ethyl acetate/hexanes) gave 3.29 g of (1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethanol as a colorless oil.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].C([O-])([O-])=O.[Na+].[Na+]>O.[Fe]>[NH2:15][C:12]1[CH:13]=[CH:14][C:6]([Br:5])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Br
Agent: [Fe]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Glacial acetic acid (75 mL) was added dropwise with stirring, at 40-50° C. to a mixture of compound of example 150 (15 g, 57.62 mmol) and iron dust (15 g, 0.267 mol) in water (120 mL). The reaction mixture was stirred vigorously at 25° C. for 1 h. It was poured into water (200 mL), basified using saturated aqueous Na2CO3 solution and extracted with EtOAc (3×250 mL). The organic extract was washed, dried (anhydrous Na2SO4) and concentrated to obtain 5-amino-2-bromobenzoic acid which was then converted into title compound as follows.
Reaction SMILES: O(CC(C)CCCC(C)=CC[Br:27])[Si](C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:30]([O:37][CH2:38][CH:39]([CH3:48])[CH2:40][CH2:41][CH2:42][C:43]([CH3:47])(O)[CH:44]=[CH2:45])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][CH2:38][CH:39]([CH3:48])[CH2:40][CH2:41][CH2:42][C:43]([CH3:47])=[CH:44][CH2:45][Br:27])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(=CCBr)CCCC(C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: C=CC(C)(O)CCCC(C)COCc1ccccc1
Product: CC(=CCBr)CCCC(C)COCc1ccccc1
Yield: 90 %

Procedure:
Following the procedure for the synthesis of 8-t-butyldiphenylsiloxy-1-bromo-3,7-dimethyl-oct-2-ene, treatment of 8-benzyloxy-3,7-dimethyl-1-octen-3-ol (0.605 g) gives 8-benzyloxy-1-bromo-3,7-dimethyl-oct-2-ene (0.675 mg, 90% yield, 7:3 E:Z).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:25]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([NH:32][CH3:33])[N:27]=4)=[CH:24][CH:23]=[CH:22][N:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:39]1[S:40][CH:41]=[CH:42][N:43]=1)CCC>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>[CH3:33][NH:32][C:28]1[N:27]=[C:26]([C:25]2[C:20]([O:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:39]5[S:40][CH:41]=[CH:42][N:43]=5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:31]=[CH:30][N:29]=1
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(Cl)c4ccccc34)cc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CNc1nccc(-c2cccnc2Oc2ccc(Nc3nnc(-c4nccs4)c4ccccc34)cc2)n1
Temperature: 110 °C

Procedure:
A resealable pressure tube, purged with argon, was charged with 4-chloro-N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)phthalazin-1-amine (150 mg, 0.329 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.033 mmol), and 2-(tributylstannyl)thiazole (0.207 mL, 0.658 mmol). This mixture was purged with argon for 10 minutes, followed by addition of toluene (1.6 ml, 0.2 M). Tube was sealed and mixture heated to 110° C. overnight. Next day LC/MS shows completion of reaction. The reaction was stopped, cooled to RT and concentrated under reduced pressure to a brown residue. This residue was purified by Gilson reverse phase chromatography (10% to 90% CH3CN/H2O/0.1% TFA). The product-containing fractions were combined, basified by addition of aq. NaHCO3 and extracted with ethyl acetate. The organic portion was dried with Na2SO4, filtered, and concentrated to afford pure N-(4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(thiazol-2-yl)phthalazin-1-amine as a yellow solid. MS m/z=505 [M+H]+. Calc'd for C27H20N8OS: 504.57.
Reaction SMILES: [S:1]1[CH:5]=[N:4][N:3]=[C:2]1[NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][N:29]([C:7]([NH:6][C:2]4[S:1][CH:5]=[N:4][N:3]=4)=[O:14])[CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1nncs1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1nncs1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 18 h
Yield: 53.1 %

Procedure:
A mixture of 2,2,2-trichloroethyl 1,3,4-thiadiazol-2-ylcarbamate (247 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.7 ml) was stirred at 70° C. for 18 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and tetrahydrofuran to obtain the desired product (161 mg, 53.2%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([NH2:31])=[O:30])[CH:9]=2)[C:5](I)=[CH:4][N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][C:38]([C:41]([N:43]2[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]2)=[O:42])=[CH:37][CH:36]=1)#[CH:34]>C(#N)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[N:12]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[CH3:28])=[C:10]([C:29]([NH2:31])=[O:30])[CH:9]=2)[C:5]([C:34]#[C:33][C:35]2[CH:36]=[CH:37][C:38]([C:41]([N:43]3[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]3)=[O:42])=[CH:39][CH:40]=2)=[CH:4][N:3]=1
Reactant: C#Cc1ccc(C(=O)N2CCN(C)CC2)cc1
Reactant: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2I)n1COCC[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Product: Cc1ccc(Cl)cc1-c1c(C(N)=O)cc(-c2nc(N)ncc2C#Cc2ccc(C(=O)N3CCN(C)CC3)cc2)n1COCC[Si](C)(C)C
Temperature: 80 °C
Yield: 79.8 %

Procedure:
To a degassed solution of 5-(2-amino-5-iodopyrimidin-4-yl)-2-(5-chloro-2-methylphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-3-carboxamide (140 mg, 0.24 mmol), (4-ethynylphenyl)(4-methylpiperazin-1-yl)methanone (98 mg, 0.43 mmol) and TEA (0.335 mL, 2.4 mmol) in dry ACN (2.5 mL) were added copper iodide (2.5 mg, 0.012 mmol) and Pd(PPh3)2Cl2 (8.4 mg, 0.012 mmol). The mixture was heated at 80° C. for 2 h, then the solvent was evaporated. The crude was purified by flash chromatography on silica gel (DCM/MeOH/7N NH3 in MeOH 95/4/1) to afford the title compound (131 mg, 80%).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=2[N:6]=1.Cl[C:13]1[C:18]([Cl:19])=[CH:17][C:16]([N+:20]([O-:22])=[O:21])=[CH:15][C:14]=1[C:23](=[O:25])[CH3:24].[H-].[Na+]>CN(C=O)C>[Cl:19][C:18]1[C:13]([S:1][C:2]2[S:3][C:4]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=3[N:6]=2)=[C:14]([C:23](=[O:25])[CH3:24])[CH:15]=[C:16]([N+:20]([O-:22])=[O:21])[CH:17]=1
Reactant: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Cl
Reactant: Cc1ccc2sc(S)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc([N+](=O)[O-])cc(Cl)c1Sc1nc2cc(C)ccc2s1
Yield: 97.3 %

Procedure:
The title compound was prepared using the method of example 258, starting with 5-methyl-benzothiazole-2-thiol (245) (1.90 g, 10.5 mmol), 1-(2,3-dichloro-5-nitro-phenyl)-ethanone (248) (2.45 g, 10.5 mmol) and NaH (Aldrich, 60% suspension, 420 mg, 10.5 mmol) in DMF (20 mL). Compound 264 (3.87 g, 98%) was obtained as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][Br:5].[CH3:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:17]=[C:16]([CH3:18])[C:15](O)=[C:14]([CH3:20])[CH:13]=2)=[N:8]1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O.CCOCC>[CH3:6][N:7]1[N:11]=[N:10][C:9]([C:12]2[CH:13]=[C:14]([CH3:20])[C:15]([O:1][CH2:2][CH2:3][CH2:4][Br:5])=[C:16]([CH3:18])[CH:17]=2)=[N:8]1
Reactant: OCCCBr
Reactant: Cc1cc(-c2nnn(C)n2)cc(C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(-c2nnn(C)n2)cc(C)c1OCCCBr
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82 %

Procedure:
A mixture of (3-hydroxypropyl)-bromide (2.17 ml, 24 mmol), 4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenol (5.1 g, 25 mmol), and DEAD (4.18 g, 24 mmol) was dissolved in 50 ml of THF at 0° C. To the above solution was added dropwise triphenylphosphine (6.3 g, 24 mmol) at 0° C. and the mixture was allowed to stir at 0° C. for 0.5 h. The mixture was diluted with 500 ml of water and 100 ml of ether, and the aqueous layere was extracted with ether (2×400 ml). The combined organic layer was dried over sodium sulfate, and concentrated in vacuo. The residue was dissolved in 800 ml of ether, and the organic layer was washed with 10% NaOH solution (3×50 ml), dried over sodium sulfate, and concentrated in vacuo. The residue was purified by silica column chromatography (7 cm column, ethyl acetate/hexane, 1/5) followed by recrystallization from methylene chloride/hexane to afford 6.4 g (82%) of 3-[4-(2-methyl-tetrazol-5-yl)-2,6-dimethylphenoxyl]-propylbromide, as a light yellow oil.
Reaction SMILES: [N:1]1([C@H:8]2[CH2:11][C@H:10]([C:12]3[S:13][C:14]4[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=CC2N=C([C@H]3[CH2:33][C@H:32]([N:34]4[CH2:38][CH2:37][CH2:36][C@H:35]4[CH3:39])C3)SC=2C=1.CC1C(B2OC(C)(C)C(C)(C)O2)=CC=C(C)N=1.N1C=C(B(O)O)C=NC=1>>[N:1]1([C@H:8]2[CH2:11][C@H:10]([C:12]3[S:13][C:14]4[CH:20]=[C:19]([C:38]5[C:32]([CH3:33])=[N:34][C:35]([CH3:39])=[CH:36][CH:37]=5)[CH:18]=[CH:17][C:15]=4[N:16]=3)[CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: Brc1ccc2nc([C@H]3C[C@H](N4CCCCCC4)C3)sc2c1
Agent: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C)n1
Agent: OB(O)c1cncnc1
Product: Cc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCCCC5)C4)sc3c2)c(C)n1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, except for substituting the product of Example 71A for the product of Example 1E, and substituting Example 2A (2,6-dimethyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine) for pyrimidine-5-boronic acid. 1H NMR (500 MHz, CDCl3) δ ppm 8.02 (d, J=8.54 Hz, 1H) 7.76 (d, J=1.53 Hz, 1H) 7.46 (d, J=7.63 Hz, 1H) 7.39 (dd, J=8.24, 1.83 Hz, 1H) 7.07 (d, J=7.63 Hz, 1H) 3.78-3.86 (m, 1H) 3.32-3.43 (m, 1H) 2.59 (s, 6H) 2.45-2.56 (m, 8H) 1.58-1.73 (m, 8H). MS: (M+H)+=392.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8]1[C:15]([Cl:16])=[N:14][C:12](Cl)=[N:11][C:9]=1[Cl:10].[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:10][C:9]1[N:8]=[C:15]([Cl:16])[N:14]=[C:12]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1
Reactant: Oc1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Clc1nc(Cl)nc(Oc2ccccc2)n1
Yield: 45 %

Procedure:
2,4-Dichloro-6-phenoxy-s-triazine (C) was prepared in 45% yield via the condensation of one equivalent of phenol with cyanuric chloride in chloroform at 50° which also contained one equivalent of sodium hydroxide. The product C, obtained as a white crystalline solid (mp. 110°-112°), was condensed in a second step with B in a manner similar to that described in Example 6. During the course of the reaction a solid appeared which was filtered, air-dried and identified as 7.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5].C[Si](Cl)(C)C.C(N(CC)CC)C.[Br:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32](Cl)=[O:33].[OH-].[Na+].Cl>C(Cl)Cl>[Br:29][C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:5])=[O:33]
Reactant: Nc1ccccc1C(=O)NCCCC(=O)O
Reactant: O=C(Cl)c1ccccc1Br
Agent: C[Si](C)(C)Cl
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)CCCNC(=O)c1ccccc1NC(=O)c1ccccc1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of 2.00 g (9.01 mmol) of 4-(2-aminobenzoylamino)butanoic acid in 20 mL of dry methylene chloride, add 8.36 g (77.00 mmol) of trimethylsilyl chloride and allow the reaction to reflux for 5 hours. Then place the flask in an ice bath and add 1.17 g (11.55 mmol) of triethylamine and a solution of 1.68 g (7.70 mmol) of 2-bromobenzoyl chloride dissolved in 5 mL of dry methylene chloride. Allow the reaction to stir for 30 minutes in an ice bath and 24 hours at room temperature. Eliminate the solvent at low pressure, add 30 ml of 10% NaOH to the crude product and continue stirring the mixture until the oil has completely disappeared. Immediately acidify with concentrated HCl, filter the resulting solid and wash several times with water and with ether. Finally, purify by recrystallization (EtOH/H2O). This yields 1.95 g (63%) of 4-[2-(2-bromobenzoylamino)benzoylamino] butanoic acid as a cream-coloured solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7](Cl)=[O:8].[CH2:19]([CH2:21][NH2:22])[OH:20]>>[NH2:1][C:2]1[C:3]([I:18])=[C:4]([CH2:13][O:14][C:15](=[O:17])[CH3:16])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([NH:22][CH2:21][CH2:19][OH:20])=[O:8]
Reactant: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)Cl)c1I
Reactant: NCCO
Product: CC(=O)OCc1c(I)c(N)c(I)c(C(=O)NCCO)c1I

Procedure:
5-Amino-3-acetoxymethyl-2,4,6-triiodobenzoyl chloride was reacted with ethanolamine according to the general procedure in Example 24g. The yield of isolated product was 98%.
Reaction SMILES: CO[C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][CH2:22][CH3:23])(=[O:20])=[O:19])[N:15]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[C:14]=2[CH:31]=1.[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH2:38]>>[CH3:33][O:34][CH2:35][CH2:36][CH2:37][NH:38][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]2[N:17]=[C:16]([S:18]([CH2:21][CH2:22][CH3:23])(=[O:19])=[O:20])[N:15]([C:24]3[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=3)[C:14]=2[CH:31]=1
Reactant: CCCS(=O)(=O)c1nc2ccc(OCCCCCC(=O)OC)cc2n1-c1ccc(C)cc1
Reactant: COCCCN
Product: CCCS(=O)(=O)c1nc2ccc(OCCCCCC(=O)NCCCOC)cc2n1-c1ccc(C)cc1

Procedure:
100 mg of 6-[[1-(4-methylphenyl)-2-propanesulfonyl-1H-benzimidazol-6-yl]oxy]hexanoic acid methyl ester was reacted with 3-methoxypropylamine according to general operating instructions 4. 105 mg was obtained.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C1C=CC=CC=1.[Na].[Br:15][C:16]1[CH:34]=[CH:33][C:19]([O:20][C:21]2[CH:32]=[CH:31][C:24]([O:25][CH:26]([CH3:30])[C:27](Cl)=[O:28])=[CH:23][CH:22]=2)=[C:18]([F:35])[CH:17]=1>CCOCC.O>[C:4]([CH:3]([C:27](=[O:28])[CH:26]([O:25][C:24]1[CH:31]=[CH:32][C:21]([O:20][C:19]2[CH:33]=[CH:34][C:16]([Br:15])=[CH:17][C:18]=2[F:35])=[CH:22][CH:23]=1)[CH3:30])[C:2](=[O:7])[CH3:1])(=[O:6])[CH3:5]
Reactant: CC(Oc1ccc(Oc2ccc(Br)cc2F)cc1)C(=O)Cl
Reactant: CC(=O)CC(C)=O
Agent: [Na]
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: O
Product: CC(=O)C(C(C)=O)C(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A mixture of 1.7 g (17 mmol) of 2,4-pentanedione, 30 ml of benzene and 0.26 g (11.3 mmol) of sodium was warmed at reflux for 3 hours. The reaction mixture was cooled to room temperature and a solution of 10 mmol of 2-(4-(4-bromo-2-fluorophenoxy)phenoxy)propanoyl chloride was added dropwise. The resulting mixture was warmed at reflux for 2.5 hours, stirred at room temperature overnight and poured into water and ether. The organic layer was separated, dried over MgSO4 and evaporated to dryness. The residue was purified by prep LC, eluting with 4:1 hexane:acetone. The product was taken up in ether and extracted with two portions of 1% aqueous NaOH. The combined aqueous layers were made acidic with aqueous HCl and extracted with ether. The ether layer was evaporated to dryness and the residue again purified by prep LC, eluting with 85:15 hexane:acetone. This gave a yellow oil which was thoroughly dried to leave 0.70 g product. Calc for C20H18BrFO5 : C, 54.93, H, 4.15. Found: C, 54.13, H, 4.30.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:17]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7])[CH3:4].[N+:30](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O.O>CN(C)C=O>[NH2:30][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:20][CH:21]=1)[C:6]([O:5][CH2:3][CH3:4])=[O:7]
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CCCCCCCCc1ccc(CCC(C(=O)OCC)C(=O)OCC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCc1ccc(CCC(N)(C(=O)OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 133.8 %

Procedure:
60% Sodium hydride (0.38 g) was suspended in dry dimethylformamide (30 ml) and ethyl 2-ethoxycarbonyl-4-(4-octylphenyl)butyrate (3.0 g) was added thereto. The mixture was stirred at room temperature for 2 hours. O-(2,4-Dinitrophenyl)hydroxylamine (1.14 g) was added thereto and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into cool water and extracted with toluene. The extract was washed with aqueous sodium chloride and dried over magnesium sulfate. The solvent was distilled away under reduced pressure to give 3 g of the subject compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[CH3:13][C@@H:14]1[CH2:18][CH2:17][N:16]([C@@H:19]([CH3:30])[CH2:20][O:21][C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH2:15]1.N1CCCC1>CO>[CH3:9][O:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][CH:26]([C:25]1[CH:28]=[CH:29][C:22]([O:21][CH2:20][C@@H:19]([N:16]3[CH2:17][CH2:18][C@@H:14]([CH3:13])[CH2:15]3)[CH3:30])=[CH:23][CH:24]=1)[CH2:11][C:10]2=[O:12]
Reactant: C[C@@H]1CCN([C@@H](C)COc2ccc(C=O)cc2)C1
Reactant: COc1ccc(O)c(C(C)=O)c1
Solvent: CO
Solvent: C1CCNC1
Product: COc1ccc2c(c1)C(=O)CC(c1ccc(OC[C@H](C)N3CC[C@@H](C)C3)cc1)O2
Temperature: 50 °C
Yield: 18 %

Procedure:
A mixture of 1-(2-hydroxy-5-methoxyphenyl)ethanone (1 g, 6 mmol), 4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)benzaldehyde (1.5 g, 6.08 mmol), and pyrrolidine (0.12 mL, 1.5 mmol) in methanol (12 mL) was heated at 50° C. for two days. After cooling, the solvent was removed and the residue was purified by silica gel chromatography to afford 427 mg of 6-methoxy-2-(4-((S)-2-((R)-3-methylpyrrolidin-1-yl)propoxy)phenyl)chroman-4-one as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 7.45 (d, 2H), 7.22-7.18 (m, 2H), 7.03 (d, 1H), 6.98 (d, 2H), 5.52 (dd, 1H), 4.04 (m, 1H), 3.83 (m, 1H), 3.80 (s, 3H), 3.24 (dd, 1H), 2.87 (m, 1H), 2.76 (dd, 1H), 2.67 (m, 2H), 2.58 (m, 1H), 2.11 (m, 2H), 1.91 (m, 1H), 1.22 (m, 1H), 1.13 (d, 3H), 0.97 (d, 3H).