Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1.[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:19]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[O:16]=[S:2]1(=[O:1])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:8]=[CH:9][C:10]([C:11]([N:29]2[CH2:30][CH2:31][N:26]([C:19]3[C:20]([CH3:25])=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:27][CH2:28]2)=[O:13])=[CH:14][CH:15]=1
Reactant: Cc1cc(C)c(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3)CC2)c(C)c1
Yield: 23 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)benzoic acid (253 mg) described in Preparation Example 16 and 1-(2,4,6-trimethylphenyl)piperazine (215 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (103 mg) was obtained.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[NH:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][C:14]([CH2:19][C:20]([OH:22])=O)=[CH:13][CH:12]=2.ClC(OCC)=O.[CH3:29][NH:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@H:32]1[N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>O1CCCC1>[N:37]1([C@@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]2[N:30]([CH3:29])[C:20](=[O:22])[CH2:19][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([CH3:8])=[C:17]3[CH3:18])[CH2:38][CH2:39][CH2:40][CH2:41]1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: Cc1[nH]c2ccc(CC(=O)O)cc2c1C
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1[nH]c2ccc(CC(=O)N(C)[C@@H]3CCCC[C@H]3N3CCCC3)cc2c1C
Reaction time: 0.08 h
Yield: 55.5 %

Procedure:
Triethylamine (139 μl, 1 mmol) was added to a solution of 2,3-dimethyl-1H-indole-5-acetic acid (203 mg, 1 mmol) in tetrahydrofuran (10 ml) at -15° C., with vigorous stirring. Ethyl chloroformate (96 μl, 1 mmol) was added, and the mixture stirred for five minutes. A solution of trans-(±)-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine (182 mg, 1 mmol) in tetrahydrofuran (2 ml) was added, and stirring continued for 30 minutes at -15° C., then 30 minutes at room temperature. The reaction was evaporated to small volume, the residue taken into ethyl acetate (50 ml), and washed with saturated sodium bicarbonate solution (3×50 ml). The organic extract was dried (MgSO4), evaporated under reduced pressure and recrystallized from ethyl acetate to yield the amide (204 mg, 56%); VmaxC=0 1615 cm-1.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[C:7]([C:13]([OH:15])=[O:14])=[CH:6]1.[I:16]N1C(=O)CCC1=O>C(O)(C(F)(F)F)=O.ClCCl.O>[I:16][C:9]1[C:8](=[O:12])[C:7]([C:13]([OH:15])=[O:14])=[CH:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[C:10]=1[CH3:11]
Reactant: O=C1CCC(=O)N1I
Reactant: COCCn1cc(C(=O)O)c(=O)cc1C
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COCCn1cc(C(=O)O)c(=O)c(I)c1C

Procedure:
A solution 1-(2-methoxy-ethyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (150 mg, 0.71 mmol) and N-iodosuccinimide (200 mg, 0.89 mmol) in TFA (1 mL) and dichloromethane (1 mL) is stirred for 5 days at room temperature. The reaction mixture is diluted with water and extracted with dichloromethane. The organic layer is evaporate under reduced pressure. ESI mass spectrum: [M+H]+=338; Retention time HPLC: 0.95 min (Z002_005).
Reaction SMILES: [OH:1][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:3].[BrH:13].[Ag:14].[N+]([O-])([O-])=O.[Ag+]>C(OCCCC)(=O)C>[O-:3][C:2]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:1].[Ag+:14].[Ag:14][Br:13]
Reactant: Br
Reactant: [Ag]
Reactant: CCCCCCCCCC(=O)O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCCCOC(C)=O
Product: Br[Ag]
Product: CCCCCCCCCC(=O)[O-]
Temperature: 5 °C

Procedure:
Into a solution of 8.6 g of capric acid in 100 ml of butyl acetate was emulsified 20 ml of a 2.5%, by weight, aqueous solution of hydrogen bromide while stirring with a stirrer at 5° C. To this emulsion was added 50 ml of an aqueous silver ammine complex solution containing 8.5 g of silver nitrate (which solution had been previously cooled to 5° C) over a period of 30 seconds to allow the capric acid, the hydrogen bromide and the silver ion to react simultaneously to form silver caprate and silver bromide simultaneously. After being allowed to stand, the mixture separated into a water phase and butyl acetate phase containing silver bromide and silver caprate. The water phase was removed and the butyl acetate phase was dispersed into 120 g of a 15%, by weight, solution of polyvinyl butyral in isopropanol. To the resulting silver salt-polymer dispersion, the following components were added in succession at 40° C at intervals of 5 minutes.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH3:23])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([O:17]C(C)(C)C)=[O:16])=[C:7]1[CH3:22])[CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][CH:3]([CH3:23])[CH:4]([N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([C:15]([OH:17])=[O:16])=[C:7]1[CH3:22])[CH3:5]
Reactant: COC(C)C(C)n1c(C)c(C(=O)OC(C)(C)C)c2cccnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(C)C(C)n1c(C)c(C(=O)O)c2cccnc21
Temperature: 27 °C
Reaction time: 1.5 h

Procedure:
To the pre-cooled solution of tert-butyl 1-(3-methoxybutan-2-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxylate (3.0 g, 9.42 mmol) in CH2Cl2 (20 mL) was added trifluoroacetic acid (20 mL) dropwise. The solution was stirred at 27° C. for 1.5 hours. The solvent was removed under vacuum at 27° C. The residue was used for next step without purified. LCMS (M+H+) m/z: calcd 263.30. found 262.9.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][NH:9]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:19]1[C:28]2[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=2)[N:22]=[CH:21][N:20]=1>CC(O)C>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH3:32])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[CH:5][CH:4]=1
Reactant: Clc1ccc2c(c1)NCC2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCc4ccc(Cl)cc43)c2cc1OC

Procedure:
To 6-chloroindoline hydrochloride (1 00 mg, 0.526 mmol) and pyridine (0.957 mmol, 77 μL) in dry i-PrOH (8 mL) was added 4-chloro-6,7-dimethoxyquinazoline (107 mg, 0.478 mmol). The mixture was refluxed for 2 hours under an atmosphere of dry N2(g) and then the solvent was removed in vacuo. The residue was partitioned between CHCl3 and 1M NaOH, and the organic phase was washed with brine, dried over Na2SO4(g) and concentrated in vacuo. The residue (171 mg) was purified by flash chromatography on silica using 80%EtOAc/CH2 Cl2 to yield 4-(6-chloro-2,3-dihydro-indol-1-yl)-6,7-dimethoxy-quinazoline as its free base (148 mg) (M.P. 229°-230° C.; LC-MS: 342 (MH+); anal. RP18-HPLC RT: 4.38 min.).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[S:12]1[CH2:17][CH2:16][CH:15]([N:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[NH:20][C:19]2=[O:27])[CH2:14][CH2:13]1>CN(C=O)C>[O:27]=[C:19]1[N:20]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:18]1[CH:15]1[CH2:16][CH2:17][S:12][CH2:13][CH2:14]1
Reactant: O=c1[nH]c2ccccc2n1C1CCSCC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(=O)n(C2CCSCC2)c2ccccc21
Reaction time: 1 h

Procedure:
Sodium hydride (68.3 mg of a 60% dispersion in mineral oil, 1.71 mmol) followed by tert-butyl bromoacetate (0.189 mL, 1.28 mmol) was added to a solution of 1-tetrahydro-2H-thiopyran-4-yl-1,3-dihydro-2H-benzimidazol-2-one from Step B (200 mg, 0.854 mmol) in DMF (5 mL). After 1 h, the reaction was quenched with H2O (10 mL) and extracted with CH2Cl2 (10 mL). The organic layer was washed with saturated NaHCO3 (5 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography, eluting with a gradient of hexane:EtOAc-100:0 to 50:50, gave the title compound. MS: m/z=349 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[S:7][C:8]2[C:14](I)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:9]=2[N:10]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:24]1[O:25][CH2:26][CH2:27][O:28][CH:29]=1)CCC.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>O1CCOCC1.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]>[CH2:1]([O:3][C:4](=[O:18])[NH:5][C:6]1[S:7][C:8]2[C:14]([C:24]3[O:25][CH2:26][CH2:27][O:28][CH:29]=3)=[CH:13][CH:12]=[C:11]([O:16][CH3:17])[C:9]=2[N:10]=1)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=COCCO1
Reactant: CCOC(=O)Nc1nc2c(OC)ccc(I)c2s1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Product: CCOC(=O)Nc1nc2c(OC)ccc(C3=COCCO3)c2s1
Temperature: 100 °C
Yield: 90.1 %

Procedure:
To a stirred solution of 5.0 g (13.2 mmol) (7-iodo-4-methoxy-benzothiazol-2-yl)-carbamic acid ethyl ester in 60 ml dioxane were added 6.94 g (18.5 mmol) tributyl-(5,6-dihydro-[1,4]dioxin-2-yl)-stannane, 456 mg (0.79 mmol) bis(dibenzylideneacetone)palladium and 491 mg (2.12 mmol) trifurylphosphine. The mixture was heated at 100° C. for 3 h, then cooled to room temperature and concentrated in vacuo. Flash chromatography (5/95 acetone/dichloromethane) afforded 4.00 g (90%) [7-(5,6-dihydro-[1,4]dioxin-2-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid ethyl ester as a light yellow foam. ES-MS m/e (%): 337 (M+H+, 100).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SC)=[N:18][C:17]3=[O:23])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[C:34]([O:38][C:39](=[O:45])[NH:40][CH:41]1[CH2:44][NH:43][CH2:42]1)([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39](=[O:45])[NH:40][CH:41]1[CH2:44][N:43]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:33])[F:32])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:42]1)([CH3:37])([CH3:35])[CH3:36].[NH2:40][CH:41]1[CH2:44][N:43]([C:19]2[S:20][C:16](=[CH:15][C:11]3[CH:10]=[C:9]4[C:14](=[CH:13][CH:12]=3)[N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([C:28]([F:31])([F:30])[F:29])=[CH:27][C:3]=3[C:2]([F:1])([F:32])[F:33])[N:7]=[CH:8]4)[C:17](=[O:23])[N:18]=2)[CH2:42]1
Reactant: CSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Product: CC(C)(C)OC(=O)NC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1
Product: NC1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)C1

Procedure:
(1-{5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-azetidin-3-yl)-carbamic acid tert-butyl ester was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazol-4-one and azetidin-3-yl-carbamic acid tert-butyl ester following General Procedure C. The compound was used directly following General Procedure H to provide 2-(3-Amino-azetidin-1-yl)-5-[1-(2,4-bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-thiazol-4-one.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].[C:7](Cl)([Cl:9])=[O:8].C(N(CC)CC)C.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>O1CCCC1.C(Cl)Cl>[O:6]=[C:2]1[N:3]([C:7]([Cl:9])=[O:8])[CH2:4][CH2:5][O:1]1
Reactant: O=C(Cl)Cl
Reactant: O=C1NCCO1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)N1CCOC1=O

Procedure:
In a similar manner to that of Example 1-9), 2-oxo-3-oxazolidinecarbonyl chloride, which was prepared from 2-oxazolidinone (1.04 g), phosgene (0.018 mole) and triethylamine (3.0 g) in tetrahydrofuran was treated with a solution of 7-(D-2-phenylglycinamido)-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (3.0 g) and bis(trimethylsilyl) acetamide (4.8 g) in methylene chloride (60 ml). The reaction mixture was worked up in a similar manner to that of Example 1--1) to give powder (1.92 g). This powder was dissolved into acetone and water was added thereto. The resultant mixture was concentrated, and a precipitated solid was collected by filtration to give powder (1.55 g) of 7-[D-2-(2-oxo-3-oxazolidinecarboxamido)-2-phenylacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid, mp 165° to 170° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.N1C=CC=CC=1.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19]>C(Cl)Cl>[O:11]=[C:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:23]([CH2:22][O:21][C:18](=[O:20])[CH3:19])=[O:24])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CC(=O)OCC(=O)Cl
Reactant: Nc1ccc2c(c1)CCC2=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCC(=O)Nc1ccc2c(c1)CCC2=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a solution of 5-Amino-indan-1-one (commercially available, 100 mg, 0.679 mmol, 1 eq.) in DCM (5 mL) is added pyridine (0.066 mL, 0.815 mmol, 1.2 eq.). The resulting solution is cooled to 0° C. followed by the addition of acetoxy acetyl chloride (0.073 mL, 0.679 mmol, 1 eq.). After stirring at 0° C. for 15 min., the reaction is warmed to 25° C. and stirred for 12 h. The reaction is diluted with DCM and sequentially washed with 1 N HCl (aq) and saturated aqueous NaHCO3. The resulting organic solution is dried over Na2SO4. After concentration, the residue is purified by silica gel chromatography (1:6 hexanes/EtOAc) to give Acetic acid (1-oxo-indan-5-ylcarbamoyl)-methyl ester as an off-white solid (136 mg, 81% yield). [MS: (ES+) 248.1 (M+1)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].OS(O)(=O)=O.C([O-])([O-])=O.[Na+].[Na+].[CH3:23][CH2:24]O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH2:23][CH3:24])=[O:10]
Reactant: O=C(O)Cc1ccccc1Cl
Reactant: CCO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)Cc1ccccc1Cl
Yield: 97 %

Procedure:
A mixture of 2-(2-chlorophenyl)acetic acid (10 g, 58.6 mmol) in EtOH (Volume: 152 ml) was treated with H2SO4 (1.719 ml, 32.2 mmol). The result mixture was refluxed overnight. The heat was removed, and the reaction mixture was concentrated. The resulting oil was dissolved in EtOAc and CAREFULLY treated with aqueous Na2CO3 (3.47 g, 32.8 mmol) (CAUTION: Gas evolution) until the solution remained basic and no further gas evolution was seen. The EtOAc layer was then removed and the aqueous layer was again extracted two times with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4 and concentrated in vacuo to obtain ethyl 2-(2-chlorophenyl)acetate (11.32 g, 57.0 mmol, 97% yield). LC-MS (M+H)+=199.1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[S:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C(COC)OC.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.O>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([C:14]2[CH:15]=[CH:16][S:12][CH:13]=2)=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: OB(O)c1ccsc1
Reactant: COc1ccc(Br)cc1C=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: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc(-c2ccsc2)cc1C=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 81.6 %

Procedure:
Under nitrogen atmosphere, to a solution of 5-bromo-2-methoxybenzaldehyde (350 mg) in dimethoxyethane (3.5 ml) were added 3-thiopheneboronic acid (417 mg), tetrakis(triphenylphosphine)palladium (0) (282 mg), and 2M sodium carbonate (4.9 ml) at room temperature. After being heated at 80° C. with stirring for 5 hours, the reaction mixture was poured into mixed solvents of ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (6 g) using a mixed solvent of hexane and ethyl acetate (10:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give 2-methoxy-5-(3-thienyl)benzaldehyde (290 mg) as yellowish oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=[C:5]2[CH3:14].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)([O-:17])=[O:16].CC1(C)C=C(C)C2C(=CC=C(OS(C(F)(F)F)(=O)=O)C=2)N1.C1C(=O)N(Br)C(=O)C1.[CH2:56]([SH:59])[CH:57]=[CH2:58]>>[CH2:56]([S:59][CH2:14][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])[CH:3]=2)[NH:8][C:7]([CH3:13])([CH3:12])[CH:6]=1)[CH:57]=[CH2:58]
Reactant: CC1=CC(C)(C)Nc2ccc(Br)cc21
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Reactant: C=CCS
Agent: CC1=CC(C)(C)Nc2ccc(OS(=O)(=O)C(F)(F)F)cc21
Agent: O=C1CCC(=O)N1Br
Product: C=CCSCC1=CC(C)(C)Nc2ccc(-c3ccccc3[N+](=O)[O-])cc21

Procedure:
6-Bromo-2,2,4-trimethyl-1,2-dihydroquinoline was coupled with 2-nitrophenylboronic acid using the procedure described in Example 7 for trifluoromethanesulfonic acid 2,2,4-trimethyl-1,2-dihydroquinolin-6-yl ester. The resulting intermediate was brominated with NBS, followed by the coupling reaction with allyl mercaptan as described in Example 7, to provide 15 mg of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([CH2:8][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=O)=O)=[CH:4][CH:3]=1.[S:20]([C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>C(O)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[N:28]([C:27]3[CH:29]=[CH:30][C:24]([S:20](=[O:23])(=[O:22])[NH2:21])=[CH:25][CH:26]=3)[CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: O=CC(CC(=O)c1ccc(F)cc1)c1ccccc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1ccc(-n2cc(-c3ccccc3)cc2-c2ccc(F)cc2)cc1
Yield: 71.3 %

Procedure:
0.32 g (1.25 mmol) of 3-(4-fluorobenzoyl)-2-phenylpropionaldehyde [prepared as described in step (i) above] and 0.26 g (1.5 mmol) of 4-sulfamoylaniline were dissolved in 20 ml of acetic acid, and the mixture was heated under reflux for 4 hours. The solvent was then removed by distillation under reduced pressure and water was added to the residue, which was then extracted with ethyl acetate. The organic extract was washed with water and dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was applied to a silica gel chromatography column and eluted with a 3:2 by volume mixture of hexane and ethyl acetate, to give 0.35 g (yield 60%) of the title compound as a slightly yellow powder, melting at 192-194° C.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[C:21]1([CH:27](C)[C:28]([O:30][CH3:31])=[O:29])C=CC=CC=1.[CH:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(=S)=S>[C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:33]1[CH:38]=[CH:37][C:36]([CH2:21][CH2:27][C:28]([O:30][CH3:31])=[O:29])=[CH:35][CH:34]=1)=[O:12])(=[O:3])[CH3:2]
Reactant: c1ccccc1
Reactant: COC(=O)C(C)c1ccccc1
Reactant: CC(=O)NCCCCCC(=O)O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: S=C=S
Product: COC(=O)CCc1ccc(C(=O)CCCCCNC(C)=O)cc1

Procedure:
Eight hundred milligrams of ε-N-acetylaminocaproyl chloride obtained by reacting ε-N-acetylaminocaproic acid with thionyl chloride in benzene was suspended in 20 ml of carbon disulfide. With vigorous stirring under ice cooling, 1.3 g of aluminum chloride was added. A solution of 550 mg of methyl phenylpropionate in 5 ml of carbon disulfide was added, and the mixture was stirred for 4 hours under reflux. After the reaction, the carbon disulfide layer was separated by decantation. A small amount of ice water was carefully added to the residue to decompose the excess of aluminum chloride. An aqueous solution of sodium hydroxide was added to the resulting aqueous solution to dissolve the resulting aluminum hydroxide. It was extracted three times with chloroform. The chloroform layer was washed with water and dried over anhydrous sodium sulfate. The chloroform was distilled off under reduced pressure to give 900 mg of a white oily substance. The product had the following NMR spectrum and identified as the title compound.
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH3:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2[CH:39]=[CH:38][O:37][CH:36]=2)=[O:34])=[CH:28][C:27]=1B1OC(C)(C)C(C)(C)O1>>[O:37]1[CH:38]=[CH:39][C:35]([C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([CH3:25])=[C:31]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:30]=2)=[O:34])=[CH:36]1
Reactant: Cc1ccc(NC(=O)c2ccoc2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(NC(=O)c2ccoc2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-[5-(Fur-3-ylcarbonylamino)-2-methyl-phenyl]-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-[4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3-furamide (Intermediate 13) using General Method B. LCMS: retention time 2.53 min, MH+ 510. NMR: δH [2H6]-DMSO 11.64, (1H, b), 10.02, (1H, s), 9.23, (1H, s), 8.38, (2H, m), 8.31, (1H, d), 7.86, (1H, s), 7.80, (1H, s), 7.76, (2H, m), 7.38-7.29, (3H, m), 7.11, (1H, t), 7.01, (1H, s), 3.77, (2H, s), 2.66-2.20, (11H, m), 2.16, (3H, s).
Reaction SMILES: Cl.[OH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]2[C:21]([I:22])=[CH:20][C:13]([CH2:14][C@@H:15]([C:17]([OH:19])=[O:18])[NH2:16])=[CH:12][C:11]=2[I:23])=[CH:5][CH:4]=1.N[C@H:25](C(O)=O)CC1C=C(I)C(OC2C=C(I)C(O)=C(I)C=2)=C(I)C=1.C([O-])(O)=O.[Na+]>CO>[CH3:25][O:18][C:17](=[O:19])[C@H:15]([CH2:14][C:13]1[CH:12]=[C:11]([I:23])[C:10]([O:9][C:6]2[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)=[C:21]([I:22])[CH:20]=1)[NH2:16]
Reactant: N[C@@H](Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1)C(=O)O
Reactant: N[C@@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1cc(I)c(Oc2ccc(O)cc2)c(I)c1
Temperature: 20 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
A 6 M solution of HCl in MeOH (8 mL; 48 mmol) was added to a suspension of O-(4-hydroxyphenyl)-3,5-diiodo-L-tyrosine (2.12 g; 5 mmol) (prepared according to: Chalmers J. R., Dickson G. T., Elks J. and Hems D. A., “The Synthesis of Thyroxine and Related Substances”, Part V., J. Chem. Soc., 3424-3433, 1949) in MeOH (12 mL). The resulting solution was left under stirring for 4 days at 20° C. Then an NaHCO3 aqueous saturated solution was added until pH 7, to obtain a precipitate which was filtered. After concentration of the solution, a second amount of precipitate was obtained. The two samples were combined and dried (50° C.; 1.3 kPa), to, give the desired product (2 g; 3.7 mmol). Yield 87%.
Reaction SMILES: [CH2:1]([OH:3])C.C([O-])=O.[NH4+].C(O)=O.[CH2:11]([OH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Pd].O>[C:12]1([CH:11]([OH:18])[CH2:1][OH:3])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1ccccc1
Reactant: CCO
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: O=CO
Product: OCC(O)c1ccccc1
Temperature: 80 °C
Reaction time: 0.42 h
Yield: 60 %

Procedure:
Pd/C (5 mol %) is weighed into a reaction flask. A solvent mixture consisting of ethanol and water (4:1) and ammonium formate (30 mol %) is added, the reaction flask is capped with a rubber septa and the mixture is heated (80° C.) for 2 minutes. Formic acid (3 equivalents) and then benzyl alcohol are added by syringe. The reaction is run for 10-40 minutes and the reaction is quenched with brine. The product is extracted by DCM and the organic phase is dried by Na2SO4. The product 1-phenyl-2-propanol was analyzed by 1H NMR and produced in 60% yield.