Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.N[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:4]=1[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].Cl.[CH3:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[N:23]=[C:22]([SH:28])[N:21]=1.[OH-].[Na+]>O>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:3]([S:28][C:22]2[N:21]=[C:20]([O:19][CH3:18])[CH:25]=[C:24]([O:26][CH3:27])[N:23]=2)[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COc1cc(OC)nc(S)n1
Reactant: Nc1cccc(Cl)c1C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 22.9 %

Procedure:
5.0 g of 2-amino-6-chlorobenzoic acid hydrochloride was converted to a diazonium salt with 2.3 g of sodium nitrite and concentrated hydrochloric acid. Then, this diazonium salt was gradually dropwise added to a solution comprising 4.8 g of 4,6-dimethoxy-2-mercaptopyrimidine, 2.4 g of sodium hydroxide and 40 ml of water at 0° C. After completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours to complete the reaction. Concentrated hydrochloric acid was added to the reaction solution, and then, the mixture was extracted with ethyl acetate. The extract was dried, and then the solvent was distilled off under reduced pressure. The residue thereby obtained was purified by column chromatography to obtain 1.8 g of 2-chloro-6-[(4,6-dimethoxypyrimidin-2-yl)thio]benzoic acid as ocher powder. Melting point: 148°-151° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:50])[C:19]([C:25]3[N:26]=[C:27]([NH:30]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH:23]=[CH2:24])[C:15](=[O:51])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(O)=O>O>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18](=[O:50])[C:19]([C:25]3[N:26]=[C:27]([NH2:30])[S:28][CH:29]=3)=[N:20][O:21][CH2:22][CH:23]=[CH2:24])[C:15](=[O:51])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: O=CO
Solvent: O
Product: C=CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(COC(C)=O)CS[C@H]12)c1csc(N)n1
Temperature: 60 °C
Yield: 29.6 %

Procedure:
A mixture of 610 mg of the product of Example 8 and 3 ml of 50% aqueous formic acid was heated at 60° C. for 15 minutes and 4 ml of water were added. The mixture was stirred and vacuum filtered. The filtrate was rinsed with water and concentrated to dryness under reduced pressure. The residue was taken up in water and was effloresced. The mixture was vacuum filtered and the product was rinsed to obtain 120 mg of 3-acetoxymethyl-7-[2-(2-amino-4-thiazolyl)-2-(2-propenyl) oxyiminoacetamido]-ceph-3-eme-4-carboxylic acid with a melting point of about 160° C. and a syn configuration.
Reaction SMILES: [Br:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=O)[C:4]=2[CH:3]=1.[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1>S(Cl)(Cl)=O>[Br:1][C:2]1[C:13]([O:14][CH3:15])=[CH:12][C:5]2[S:6][CH:7]=[C:8]([C:9]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[O:11])[C:4]=2[CH:3]=1
Reactant: Nc1cccnc1
Reactant: COc1cc2scc(C(=O)O)c2cc1Br
Solvent: O=S(Cl)Cl
Product: COc1cc2scc(C(=O)Nc3cccnc3)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.3 %

Procedure:
5-Bromo-6-methoxybenzo[b]thiophene-3-carboxylic acid (D5) (0.36 g, 0.0013 mole) and thionyl chloride (20 ml) were heated under reflux for 1 hour, after which the reaction mixture was cooled to ambient temperature and evaporated in vacuo. The resulting acid chloride was dissolved in dry dichloromethane (30 ml) and acetonitrile (10 ml) under argon. 3-Aminopyridine (0.12 g, 0.0013 mole) was added and the reaction mixture stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the resulting solid basified with 10% sodium hydroxide solution, extracted into dichloromethane, dried (Na2SO4) and evaporated in vacuo. The resulting solid was recrystallised from ethyl acetate/methanol to afford the title compound (0.11 g, 23%) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](Cl)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:17]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:12][C:11]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.1 %

Procedure:
5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl chloride (0.200 g) was added to a solution of 3-fluoro-5-trifluoromethyl-phenylamine (0.105 g) and N,N-diisopropylethylamine (0.102 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×15 mL) and basic (dilute NaHCO3, 2×15 mL) workup followed by washing with brine (saturated NaCl, 2×15 mL), drying over MgSO4, and concentration. The crude compound was triturated with hexanes/ethyl ether (1:1) to afford the title compound (0.069 g, 24% yield). 1H NMR (CDCl3) δ 7.69 (d, 1H, J=0.02 Hz), 7.68 (s, 1H), 7.67 (d, 2H, J=0.017 Hz), 7.53 (s, 1H), 7.47 (d, 2H, J=0.017 Hz), 7.16 (d, 1H, J=0.02 Hz), 7.02 (s, 1H). ES-MS negative Q1 (m/z) 451.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19])[C:8]([O:10]C(C)(C)C)=[O:9])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:17]=1[C:18]([NH2:20])=[O:19])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)OC(C)(C)C)ccc1C(N)=O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1cc(C(=O)O)ccc1C(N)=O
Yield: 95.8 %

Procedure:
A solution of 1,1-dimethylethyl 3-(acetylamino)-4-(aminocarbonyl)benzoate (110 mg, 0.47 mmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 15 minutes, concentrated, and the residue was rinsed with hexane (3×3 mL) and dried in vacuo to give 3-(acetylamino)-4-(aminocarbonyl)benzoic acid (100 mg, 97% yield), MS (EI) for C10H10N2O4: 223 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([O:22]CC)=[O:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+]>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([C:20]([OH:22])=[O:21])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(Cl)c2)c(-c2cccc(Cl)c2)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2cccc(Cl)c2)c(-c2cccc(Cl)c2)o1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
760 mg (2.10 mmol) of the compound from Example 14A are provided in 20 ml of dioxane, and 20 ml of a 2N aqueous lithium hydroxide solution are added at room temperature. The mixture is stirred at 50° C. for two hours and subsequently concentrated. A 1N aqueous HCl solution is then added until an acidic pH is established, the mixture is extracted with dichloromethane and the organic phase is dried over magnesium sulfate, filtered and concentrated. 401 mg (57% of theory) of the title compound are obtained.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:18]3[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:20][CH:12]2[CH2:13]4)[CH2:17]3)=[O:9])[CH2:4]1.Cl[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>>[CH:25]([O:24][C:22]([NH:2][C@@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH:11]2[CH:12]3[CH2:13][CH:14]4[CH2:15][CH:16]([CH2:17][CH:18]2[CH2:19]4)[CH2:20]3)=[O:9])[CH2:4]1)=[O:23])([CH3:27])[CH3:26]
Reactant: CC(C)OC(=O)Cl
Reactant: N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1
Agent: Cl
Product: CC(C)OC(=O)N[C@@H]1CCN(C(=O)OC2C3CC4CC(C3)CC2C4)C1

Procedure:
The title compound was prepared from (R)-2-adamantyl 3-aminopyrrolidine-1-carboxylate HCl salt and isopropyl chloroformate following a procedure analogous to that described in Example 3 Step 2. LC-MS Method 1 tR=1.98 min, m/z=351; 1H NMR (CDCl3) 1.24 (d, 6H), 1.57 (d, 2H), 1.70-2.00 (13H), 2.18 (m, 1H), 3.16 (1H), 3.49 (m, 2H), 3.69 (m, 1H), 4.24 (m, 1H), 4.74 (1H), 4.82 (s, 1H), 4.93 (m, 1H)
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CN(C=O)C>O>[C:1]([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:11]=2[C:12]=1[CH3:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(O)c12
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1cccc2oc(C(=O)OC(C)(C)C)c(C)c12
Reaction time: 8 h
Yield: 90 %

Procedure:
To a round bottom flask with a stir bar was added 4-hydroxy-3-methyl-benzofuran-2 carboxylic acid t-butyl ester (1 mmol), ethyl 2-bromoacetate (1.1 eq.) potassium carbonate (5 equiv.), and 10 mL of DMF. The reaction mixture was stirred overnight and then slowly added dropwise to water (10 mL) with stirring. The resulting mixture was extracted with ethyl acetate (2×20 mL), brine (20 mL), dried over magenesium sulfate. Filtration and evaporation of the solvent gave 4-ethoxycarbonylmethoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester as a thick oil in 90% yield.
Reaction SMILES: FC1C=NC2C(N=1)=C([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)C=CC=2.Cl.CC1(N)CC1.CCN(C(C)C)C(C)C>>[NH:20]1[C:19]2[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=2[CH:13]=[CH:12]1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ncc(F)nc34)cc21
Agent: CC1(N)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1NCCc2[nH]ccc21
Temperature: 100 °C
Yield: 21 %

Procedure:
Prepared similarly to that described in Example 210 using 2-(3-fluoroquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 210i; 72 mg, 0.255 mmol), 1-methylcyclopropanamine hydrochloride (54.9 mg, 0.510 mmol, ChemBridge, San Diego, Calif.), and DIPEA (223 μl, 1.275 mmol), heating at 100° C. for 1 h. Purification by silica gel (100% DCM to 4% MeOH/DCM) provided 2434(1-methylcyclopropyl)amino)-quinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (21% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.89 (s, 4H) 1.54 (s, 3H) 2.93 (t, J=6.85 Hz, 2H) 3.46 (td, J=6.85, 2.35 Hz, 2H) 6.99 (br. s., 1H) 7.15 (d, J=1.56 Hz, 1H) 7.37 (t, J=7.82 Hz, 1H) 7.63 (dd, J=8.02, 0.98 Hz, 1H) 8.05 (dd, J=7.63, 1.17 Hz, 1H) 8.33 (s, 2H) 12.89 (br. s., 1H). MS (ESI, pos. ion) m/z: 334.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30](O)=[O:31]>>[Cl:24][C:25]1[CH:26]=[CH:27][C:28]([O:34][CH3:35])=[C:29]([CH:33]=1)[C:30]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:31]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: COc1ccc(Cl)cc1C(=O)O
Product: COc1ccc(Cl)cc1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(C)sc1-c1cccc(C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 5-Chloro-2-methoxy-benzoic acid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]1[S:23][CH2:22][C:21]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[NH:20]1)[CH3:2].[CH:28]1(Br)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH2:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]=[C:19]1[S:23][CH2:22][C:21]2([CH2:27][CH2:26][CH2:25][CH2:24]2)[N:20]1[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH3:2]
Reactant: BrC1CCCC1
Reactant: CCc1cc([N+](=O)[O-])ccc1-c1ccccc1N=C1NC2(CCCC2)CS1
Product: CCc1cc([N+](=O)[O-])ccc1-c1ccccc1N=C1SCC2(CCCC2)N1C1CCCC1

Procedure:
2-Ethylaniline was protected as 2-ethylacetanilide according to Method A2a, Step 1. The acetamide was converted to 2-ethyl-4-nitroaniline, then deprotected according to Method A2a, Step 2. The aniline was converted to 2-ethyl-4-nitrophenyl isothiocyanate according to Method A2a, Step 3. 1-Hydroxymethylcyclopentanamine was prepared according to Method B1c. The 2-hydroxyethylamine was converted to 1-chloromethylcyclopentanamine HCl salt according to Method B7e. 1-Chloromethylcyclopentanamine HCl salt was reacted with 2-ethyl-4-nitrophenyl isothiocyanate according to Method C1e to give 2-(2-ethyl-4-nitrophenylphenylimino)-3-thia-1-azaspiro[4.4]nonane. The thiazolidine was reacted with cyclopentyl bromide according to Method D2b to give 2-(2-ethyl-4-nitrophenylphenylimino)-1-cyclopentyl-3-thia-1-azaspiro[4.4]nonane.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])#[CH:9].Cl[C:15]1[N:16]=[N:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1>C(#N)C.C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].[Cu]I>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([C:18]2[N:17]=[N:16][C:15]([C:9]#[C:8][Si:10]([CH3:13])([CH3:12])[CH3:11])=[CH:20][CH:19]=2)=[CH:26][CH:25]=1
Reactant: Clc1ccc(-c2ccc(Cl)nn2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(Cl)cc2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under an argon atmosphere 3.48 mL (25.0 mmol) triethylamine and 2.08 mL (15.0 mmol) ethynyl-trimethyl-silane are added successively to a solution of 2.25 g (10.0 mmol) 3-chloro-6-(4-chloro-phenyl)-pyridazine in 50 mL acetonitrile and 20 mL THF. Then 292 mg (0.40 mmol) Pd(dppf)Cl2 and 76 mg (0.40 mmol) CuI are added. The reaction solution is stirred overnight at RT. The solvent is eliminated i.vac. and further purification is carried out by column chromatography on silica gel (PE/EtOAc 1:1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[C:15](O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]1
Reactant: CC(=O)O
Reactant: Clc1cccc(C2CCNCC2)c1Cl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(c2cccc(Cl)c2Cl)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 4-(2,3-dichlorophenyl)piperidine (20 mg, 0.064 mmol), 1,2-dichloroethane (1 ml), glacial acetic acid (4 mg, 0.064 mmol), paraformaldehyde (2 mg, 0.066 mmol) and sodium triacetoxyborohydride (20 mg, 0.092 mmol) was stirred 15 h at ambient temperature. MS m/z (rel. intensity, 70 eV) 244 (M+, 68), 243 (54), 242 (bp), 208 (61), 115 (29).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH2:16])[CH3:15].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH2:13][CH:14]([NH:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1)[CH3:15]
Reactant: Cc1ccc(C=O)o1
Reactant: CC(N)COc1ccc2ccccc2c1Cl
Product: Cc1ccc(CNC(C)COc2ccc3ccccc3c2Cl)o1
Yield: 69 %

Procedure:
Prepared from 1-[(1-chloronaphthalen-2-yl)oxy]propan-2-amine and 5-methylfuran-2-carbaldehyde in 69% yield as a pale yellow oil.
Reaction SMILES: [NH2-].[Na+].Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][NH2:12])=[CH:7][CH:6]=1.Br[CH2:14][C:15]1[N:16]=[C:17]([CH3:20])[S:18][CH:19]=1>O1CCCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:14][C:15]2[N:16]=[C:17]([CH3:20])[S:18][CH:19]=2)[NH2:12])=[CH:7][CH:6]=1
Reactant: NNc1ccc(F)cc1
Reactant: Cc1nc(CBr)cs1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(CN(N)c2ccc(F)cc2)cs1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
A flask containing tetrahydrofuran (2.0 mL) was charged with sodium amide (152 mg, 3.69 mmol; Aldrich) and chilled to 0° C. (4-Fluorophenyl)hydrazine hydrochloride (400 mg, 2.46 mmol; Aldrich) was added in portions. After 5 minutes, the solid had completely dissolved and the ice bath was removed. Stirring was continued for 1 hour, then the solution was chilled again in an ice bath and 4-(bromomethyl)-2-methylthiazole (473 mg, 2.46 mmol; Aldrich) was added dropwise. After 30 minutes, the ice bath was removed and the reaction was heated to 50° C. overnight. The mixture was diluted with water (5 mL) and extracted with dichloromethane (2×10 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title product which was carried on without further purification: LC/MS (DCI/NH3) m/z 221 (M+H−NH3)+.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([O:12][CH:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:14]([O:16]C)=[O:15])[CH:3]=1.[OH-].[K+]>O1CCOCC1.O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([O:12][CH:13]([C:18]([O:31][CH3:32])([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:14]([OH:16])=[O:15])[CH:3]=1
Reactant: COC(=O)C(Oc1cc(C)c2ccccc2n1)C(OC)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COC(c1ccccc1)(c1ccccc1)C(Oc1cc(C)c2ccccc2n1)C(=O)O
Temperature: 60 °C
Reaction time: 20 h
Yield: 57.6 %

Procedure:
1.8 g (4.2 mmol) of methyl 2-(4-methyl-2-quinolinyloxy)-3-meth-oxy-3,3-diphenylpropionate were dissolved in 25 ml of dioxane, 8.4 ml of 1N KOH solution were added, and the mixture was stirred at 60° C. for 20 hours. The solution was diluted with 300 ml of water and extracted with ethyl acetate to remove unreacted ester and impurities. The aqueous phase was then adjusted to pH 1-2 with dilute hydrochloric acid and was extracted with ethyl acetate. Drying over magnesium sulfate and removal of the solvent by distillation resulted in 1.0 g of a foam. This was dissolved in a little ethyl acetate and left to stand at room temperature overnight, during which 265 mg of the product separated out as white crystals. Repetition of this procedure with the mother liquor afforded a further 166 mg of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.C([O-])(=O)C.[K+].C([O:23][N:24]=[C:25]1[C:33]2([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:32]2[C:27](=[CH:28][CH:29]=[C:30](Br)[CH:31]=2)[NH:26]1)C1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd]Cl>[OH:23][N:24]=[C:25]1[C:33]2([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([C:4]3[CH:5]=[C:6]([CH:7]=[C:2]([F:1])[CH:3]=3)[C:8]#[N:9])[CH:31]=2)[NH:26]1
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: N#Cc1cc(F)cc(-c2ccc3c(c2)C2(CCCCC2)C(=NO)N3)c1
Temperature: 80 °C
Yield: 66 %

Procedure:
To a solution of 3-fluoro-5-cyano-bromobenzene (0.4 g, 2.0 mmol) in dry DMF (10 ml) was added diboron pinacolate ester (0.63 g, 2.5 mmol), potassium acetate (0.65 g, 6.7 mmol) and PdCl2 (dppf) (0.2. g) and the reaction was heated to 80° C. under a nitrogen atmosphere. After 8 h. from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (0.2 g, 0.5 mmol), PdCl2 (dppf) (0.05 g) and sodium carbonate (1.30 g, 12.5 mmol) were added and heating at 80° C. was continued. After 8 h. the reaction was cooled and partitioned between water and ethyl acetate, the organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography (SiO2, EtOAc:hexane 1:20) to give the desired product (0.14 g, 0.33 mmol, 66%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[F:18][C:19]([F:31])([F:30])[S:20]([C:23]1[CH:28]=[CH:27][C:26](Cl)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:30][C:19]([F:18])([F:31])[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:1][C:2]2[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=2)[O:5][C:6]2[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=2)=[CH:25][CH:24]=1)(=[O:21])=[O:22]
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Reactant: O=C(O)c1ccc(Oc2cccc(O)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)c1ccc(Oc2cccc(Oc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)cc1
Temperature: 100 °C

Procedure:
A mixture of 4-(3-hydroxyphenoxy)benzoic acid (100 mg, 0.434 mmol), 4-(trifluoromethylsulfonyl)chlorobenzene (106 mg, 1 equiv.) and potassium carbonate (240 mg, 4 equiv.) in DMF was heated to 100° C. overnight. The reaction was poured into water, extracted with EtOAc, washed the organic layer with water, brine, dried and concentrated. The residue was column chromatographed to give 4-[3-(4-trifluoromethanesulfonyl-phenoxy)-phenoxy]-benzoic acid. 1HNMR (300 MHz, DMSO-d6) δ 8.09 (d, J=8.97 Hz, 2H), 7.95 (d, J=8.94 Hz, 2H), 7.56 (t, J=8.54 Hz, 1H), 7.33 (d, J=8.94 Hz, 2H), 7.10 (d, J=8.97 Hz, 2H), 7.04-7.11 (m, 3H). MS-EI m/z 438 [M+].
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1)[CH2:11][C:12]([OH:14])=[O:13].[N:22]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[C:23]=[S:24]>CC#N.CCN(C(C)C)C(C)C>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:23]([NH:22][C:25]1[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH2:34])=[CH:29][CH:30]=1)=[S:24])[CH2:11][C:12]([OH:14])=[O:13]
Reactant: NS(=O)(=O)c1ccc(N=C=S)cc1
Reactant: NCCCCCCCCN(CC(=O)O)Cc1ccccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: NS(=O)(=O)c1ccc(NC(=S)NCCCCCCCCN(CC(=O)O)Cc2ccccn2)cc1

Procedure:
2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid. A solution of tert-butyl 2-((8-(tert-butoxycarbonylamino)octyl)(pyridin-2-ylmethyl)amino)acetate (0.449 g, 1.0 mmol) in DCM (4 mL) and TFA (4.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to afford 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid. A solution of the above product 2-((8-aminooctyl)(pyridin-2-ylmethyl)amino)acetic acid, 4-isothiocyanatobenzenesulfonamide (0.278 g, 1.3 mmol) in CH3CN (40 mL) and DIPEA (3.0 mL) was stirred at 50° C. under nitrogen for 48 h. The solvent was evaporated under reduced pressure to give a crude product, which was purified by Amberchrom™ eluting with acetonitrile/water to give 2-((pyridin-2-ylmethyl)(8-(3-(4-sulfamoylphenyl)thioureido)octyl)amino)acetic acid (0.500 g) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.65 (d, J=4.4 Hz, 1H), 8.11 (s, 1H), 7.94 (td, J=7.6, 1.6 Hz, 1H), 7.70 (d, J=8.8 Hz, 2H), 7.63 (d, J=8.8 Hz, 2H), 7.57 (d, J=7.6 Hz, 1H), 7.50-7.47 (m, 1H), 7.26 (s, 2H), 4.53 (s, 2H), 4.14 (s, 2H), 3.44-3.40 (m, 2H), 3.14-3.08 (m, 2H), 1.64-1.24 (m, 1 H); ESMS m/z: 508.3 (M+H)+.