Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=2)[N:14]=[CH:13][N:12]=1>CC(O)C>[N:1]1([C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=3)[N:14]=[CH:13][N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc2c(c1)CCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4ccccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 2, this product was prepared in 94% yield from indoline (2 eq.) and 4-chloro-6,7-dimethoxyquinazoline (1.0 eq) in i-PrOH. (M.P. 162°-163° C.; LC-MS: 308 (MH+); anal. RP18-HPLC RT: 4.11 min.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[CH:22][C:21]3[C:20](=O)[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:26][OH:27]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:23]=[CH:22][C:21]3[C:20](=[N:26][OH:27])[CH2:19][CH2:18][CH2:17][C:16]=3[N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Agent: Cl
Solvent: CO
Product: ON=C1CCCc2nc(N3CCN(Cc4ccccc4)CC3)ncc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Added to 30 ml of methanol were 2.6 g (8.07 mmol, Referential Example 48) of 2-(4-benzylpiperazino)-5-oxo-5,6,7,8-tetrahydroquinazoline and 0.67 g (9.64 mmol) of hydroxylamine hydrochloride. The resultant mixture was heated with stirring at 60° C. for 2 hours. The reaction mixture was cooled to 20° C. and the resultant precipitate was collected by filtration, thereby obtaining 2.85 g of white solid (yield: 95%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:19]=[CH:18][C:17]3[N:16]4[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]4=[CH:14][C:13]=3[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[C@H]1CCCN1>>[CH3:2][C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[CH:18][C:17]2[N:16]3[CH2:20][CH2:21][NH:22][C:23](=[O:24])[C:15]3=[CH:14][C:13]=2[CH:12]=1
Reactant: O=C1NCCn2c1cc1cc(OCCCN3CCCCC3)ccc12
Agent: C[C@H]1CCCN1
Product: C[C@H]1CCCN1CCCOc1ccc2c(c1)cc1n2CCNC1=O
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 2, from 8-(3-chloro-propoxy)-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (example 2, intermediate) and (S)-2-methylpyrrolidine (commercially available), to give the desired product as a white solid (10%).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:12])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][N:8]=[CH:7][CH:6]=2.[H][H]>CO.[Pd].[Pd].[C]>[CH3:1][CH:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[N:8][CH:9]=2)[NH:4][C:3]1=[O:12]
Reactant: Cc1nc2cnccc2[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC1Nc2cnccc2NC1=O
Yield: 79.7 %

Procedure:
3-Methyl-1,4,6-triazanaphthalen-2(1H)-one (J. W. Clark-Lewis, R. P. Singh J. Chem. Soc. 1962, 3162) (3.1 g, 0.02 mol) was hydrogenated in 300 ml of methanol with palladium catalysis (10% Pd/carbon) under 1 atm of hydrogen. After hydrogen uptake ceased, the catalyst was filtered off with suction, the solvent was removed, and the residue was stirred with diethyl ether and filtered off with suction. 2.6 g (82%) of the desired product of melting point 230° C. (dec.) were obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.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]>[Cl:17][C:15]1[CH:14]=[CH:13][C:12]([C:2]2[CH:7]=[CH:6][N+:5]([O-:8])=[CH:4][CH:3]=2)=[C:11]([O:10][CH3:9])[CH:16]=1
Reactant: COc1cc(Cl)ccc1B(O)O
Reactant: [O-][n+]1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc(Cl)ccc1-c1cc[n+]([O-])cc1
Temperature: 120 °C
Reaction time: 0.33 h
Yield: 74.2 %

Procedure:
4-Chloropyridine-N-oxide (500 mg, 3.85 mmol), 2-methoxy-4-chlorophenylboronic acid (862 mg, 4.63 mmol) and K2CO3 (1.59 g, 11.55 mmol) were suspended in DMSO (5 mL) and PdCl2(dppf) (314 mg, 0.385 mmol) was added. The reaction mixture was placed under vacuum for 20 min and flushed with N2. This process was repeated, and the reaction mixture was heated at 120° C. for 3 h. The reaction mixture was cooled to 25° C. and partitioned between methylene chloride and 5% lithium chloride. The aqueous phase was removed, and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (ISCO 40 g column, methylene chloride/MeOH 100:0 to 90:10) provided the title compound (673 mg, 74%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 8.21 (dd, J=5.4, 1.8 Hz, 2H), 7.47 (dd, J=5.6, 1.6 Hz, 2H), 7.26 (d, J=8.2 Hz, 1H), 7.06 (dd, J=8.3, 2.4 Hz, 1H), 7.00 (d, J=1.7 Hz, 1H), 3.87 (s, 3H); ESI MS m/z 235 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[C:34]([O:38][C:39](=[O:43])[C@H:40]([CH3:42])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:41][C@H:40]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:43])[CH3:42])=[O:19])=[C:5]2[OH:23]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 66.5 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (610 mg, 1811 μmol, prepared in Example 1 A-C) was dissolved in 1,4-dioxane (1811 μL) and N-ethyl-N-isopropylpropan-2-amine (947 μL, 5434 μmol). L-Alanine t-butyl ester hydrochloride (494 mg, 2717 μmol) was added, and the reaction mixture was heated to 80° C. for 24 hours. The reaction mixture was then cooled to ambient temperature, diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 50 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (525 mg) as an oil after flash chromatography. MS (m/z)=436 (M+H)+.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([CH3:12])[N:5]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=O>CO>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]2[CH:13]=[CH:10][C:9]3[CH:8]=[N:7][C:6]([CH3:12])=[N:5][C:4]=3[N:3]=2)=[CH:17][CH:18]=1
Reactant: Cc1ncc(C=O)c(N)n1
Reactant: CC(=O)c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncc2ccc(-c3ccc(F)cc3)nc2n1
Temperature: 20 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
15 ml of 40% strength by weight aqueous potassium hydroxide solution were slowly added to a suspension of 30.1 g (0.22 mol) of 4-amino-5-formyl-2-methylpyrimidine and 31.7 g (0.23 mol) of 4-fluoroacetophenone in 395 ml of methanol at 20°-25° C., a homogeneous solution being formed. After the mixture had been stirred for 20 hours at about 20° C., the solid formed was isolated and was recrystallized from ethanol. Yield: 50%; mp.>200° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>O1CCCC1>[Cl:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(Cl)c1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 3-chlorophenyl isocyanate (0.148 ml, 1.22 mmol) at room temperature, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 100 mg (30.9%) of the desired product as a solid.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+]>C1COCC1.CO.O>[CH2:11]([O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:18])=[O:2])=[CH:9][CH:8]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)cc1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 92.9 %

Procedure:
4-Benzyloxy-benzoic acid methyl ester (8.0 g, 0.033 mol) was dissolved in THF:methanol:water (3:2:1, 80 ml) and NaOH (1.98 g, 0.05 mol) was added to the reaction mixture and stirred at 50-55° C. for 3 hours. Solvents were removed and residue was diluted with water, washed with hexane and acidified with dil HCl to obtain 4-benzyloxy-benzoic acid (7.0 g, 92%) as a white solid.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.B.CSC.CO>O1CCCC1>[CH:9]1[C:8]2[CH2:2][NH:3][C:4]3[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=3[S:6][C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: O=C1Nc2ccccc2Sc2ccccc21
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc2c(c1)CNc1ccccc1S2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 3.3 g of 10,11-dihydro-11-oxodibenz[b,f][1,4]thiazepine in 25 ml of tetrahydrofuran is added 4.0 ml of 10 molar borane-dimethylsulfide in tetrahydrofuran. The mixture is stirred at room temperature for 18 hours, 50 ml of anhydrous methanol added and the solvent removed. An additional 30 ml of methanol is added and the solvent removed to give white crystals. A sample is purified by chromatography on silica gel with hexane-chloroform-ethyl acetate (2:1:1) as solvent to give white crystals, m.p. 145°-148° C.
Reaction SMILES: Cl.[CH2:2]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH2:16])[C:6]1=[O:7])[CH:3]=[CH2:4].[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[NH:23][C:22]([C:27](O)=[O:28])=[CH:21]2.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(C(C)C)CC)(C)C>O1CCCC1>[CH2:2]([N:5]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C@H:8]([NH:16][C:27]([C:22]2[NH:23][C:24]3[C:20]([CH:21]=2)=[CH:19][C:18]([Cl:17])=[CH:26][CH:25]=3)=[O:28])[C:6]1=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCN1C(=O)[C@@H](N)Cc2ccccc21
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CCN1C(=O)[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reaction time: 16 h
Yield: 53.7 %

Procedure:
(S)-1-allyl-3-amino-3,4-dihydrocarbostyril hydrochloride (7.6 mg) was added to a mixture of tetrahydrofuran (4 mL), 5-chloroindole-2-carboxylic acid (6.9 mg), 1-hydroxy-7-azabenzotriazole (5.5 mg), and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.7 mg) at room temperature. Diisopropylethylamine (12 mg) was added, and the resulting yellow suspension was stirred under argon for 16 h, during which a solution formed. The solution was evaporated under vacuum and the residue was directly purified by reverse phase preparative HPLC to provide the title compound (6.5 mg). HPLC/MS [M+H]+, 380; HPLC/MS [M+Na]+, 402.
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.C=O.[OH:12][PH:13]([OH:15])=[O:14].P(Cl)(Cl)Cl>>[P:13]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:15])([OH:14])=[O:12]
Reactant: CC(=O)N(C)CC(=O)O
Reactant: O=[PH](O)O
Agent: C=O
Solvent: ClP(Cl)Cl
Product: CN(CC(=O)O)CP(=O)(O)O

Procedure:
As depicted, the carboxymethylation step of Reaction Scheme 12 is the same as the carboxymethylation step of Reaction Schemes 10 and 11. In Reaction Scheme 12, however, N-acetylsarcosine XX is reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized in the presence of a platinum catalyst and oxygen to Glyphosate I and acetic acid. The acetic acid is then reacted with methylamine to yield the N-methylacetamide starting material.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:12]=[CH:11][N:10]([C:13]2[CH:18]=[CH:17][C:16](Cl)=[CH:15][N:14]=2)[CH:9]=1)=[O:7])(C)(C)C.[CH:20]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCC[CH2:21]1.C(B1OC(C)(C)C(C)(C)O1)=C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH2:20]([C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH:11]=[CH:12][C:8]([C:6]([OH:5])=[O:7])=[CH:9]2)=[N:14][CH:15]=1)[CH3:21]
Reactant: CC(C)(C)OC(=O)c1ccn(-c2ccc(Cl)cn2)c1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: C=CB1OC(C)(C)C(C)(C)O1
Agent: CC(=O)[O-]
Solvent: O
Product: CCc1ccc(-n2ccc(C(=O)O)c2)nc1
Temperature: 100 °C
Reaction time: 8.5 h
Yield: 197.6 %

Procedure:
Tetrehydrofuran (7.2 ml) was added to 1-(5-chloropyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (1.0 g) described in Reference Example 55(1), palladium (II) acetate (80 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (147 mg), vinylboronic acid pinacol ester (860 μl) and tripotassium phosphate (1.9 g) and stirred at 100° C. for 8.5 hours. Water was added to the reaction solution and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. 1,4-Dioxane (15 ml) and 10% palladium-carbon (containing ca. 50% water; 200 mg) was added to the resulting residue and the mixture was stirred under hydrogen atmosphere at room temperature for six hours. The reaction solution was filtered through Celite and the filtrate was concentrated in vacuo. The residue was purified with silica gel column chromatography (n-hexane/ethyl acetate). To the resulting residue was added Dichloromethane (10 ml) and trifluoroacetic acid (3 ml) and the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction solution and the precipitated solid was washed with water. The resulting solid was dissolved in ethyl acetate, extracted with 4N aqueous solution of sodium hydroxide and the aqueous layer was acidified by the addition of 1N hydrochloric acid aqueous solution and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo to give the titled compound (153 mg) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:35])[CH3:34])[C:29]([O:31]C)=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[Li+].[OH-].Cl>C1COCC1.O>[C:1]([C:5]1[CH:37]=[CH:36][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:26]=[C:25]4[C:21]([CH2:22][N:23]([C@@H:28]([CH:33]([CH3:34])[CH3:35])[C:29]([OH:31])=[O:30])[C:24]4=[O:27])=[CH:20][CH:19]=3)=[N:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 403 (80 mg, 0.160 mmol) was taken in THF (4 mL) and MeOH (1 mL) and to this reaction mixture, 1N LiOH (33.59 mg, 0.800 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: S(Cl)([Cl:3])=O.[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1>C(Cl)Cl.CN(C=O)C>[I:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:3])=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
Thionyl chloride (36.0 g, 302 mmol) was added to a suspension of 4-iodobenzoic acid (50.0 g, 202 mmol) in anhydrous DCM (300 ml) followed by a few drops of DMF and the reaction mixture was stirred overnight at r.t. Upon completion, reaction flask was concentrated under reduced pressure to yield 51.6 g (96.0% yield) of crude 4-iodobenzoyl chloride that was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]CC)=[O:9])[N:5]=[C:4]([C:13](=O)[CH2:14]Br)[CH:3]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[C:23]([NH2:25])=[S:24])[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([C:23]2[S:24][CH:14]=[C:13]([C:4]3[CH:3]=[C:2]([NH2:1])[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]=3)[N:25]=2)[CH:26]=[CH:27][C:28]=1[O:29][CH2:30][CH3:31])[CH3:18]
Reactant: CCOc1ccc(C(N)=S)cc1OCC
Reactant: CCOC(=O)c1cc(N)cc(C(=O)CBr)n1
Product: CCOc1ccc(-c2nc(-c3cc(N)cc(C(=O)O)n3)cs2)cc1OCC

Procedure:
A reaction was conducted in the same manner as in Example 1, by using 4-amino-6-ethoxycarbonyl-2-(α-bromoacetyl)pyridine and 3,4-diethoxythiobenzamide. Then, hydrolysis was conducted in the same manner as in Example 2 to obtain 2-(3,4-diethoxyphenyl)-4-(4-amino-6-carboxy-2-pyridyl)thiazole.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([Li])(C)(C)C.CCCCC.[CH2:24]1[O:26][CH2:25]1.Cl>C(OCC)C.O>[C:4]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=[C:2]([CH2:24][CH2:25][OH:26])[CH:3]=1
Reactant: C1CO1
Reactant: Brc1cccc(-c2ccccc2)c1
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CCCCC
Product: OCCc1cccc(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromobiphenyl (18 g, 77 mmol) in diethyl ether (150 ml) under N2 cooled to -78° C. was added 1.6M t-butyl lithium in pentane (100 ml, 0.16 mole) via cannula over a 15 minute period. The solution was stirred 30 minutes at -78° C., ethylene oxide (9 g, 0.2 mole added and the reaction mixture allowed to warm to room temperature over a 1 hour period. The solution was boiled briefly to drive off excess ethylene oxide, transferred to a separatory funnel, a small volume of water added, and neutralized with concentrated HCl. The organic solution was dried (MgSO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:4) to give 2-(3-biphenylyl)ethanol (10.5 g). 1H NMR (CDCl3, 60 MHz) δ: 2.81 (t, J=7 Hz, 2H, CH2), 3.76 (t, J=7 Hz, 2H, CH2), 6.95-7.70 (m, 9H, Ar).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[N:19]=[C:20]([CH2:23][C:24]([OH:26])=O)[S:21][CH:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:60]1[CH2:65][CH2:64][CH:63]([CH2:66][NH2:67])[CH2:62][CH2:61]1>CN(C=O)C.O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[N:19]=[C:20]([CH2:23][C:24]([NH:67][CH2:66][CH:63]3[CH2:64][CH2:65][O:60][CH2:61][CH2:62]3)=[O:26])[S:21][CH:22]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NCC1CCOCC1
Reactant: COc1ccc(-c2c(-c3csc(CC(=O)O)n3)cnn2C(C)(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2c(-c3csc(CC(=O)NCC4CCOCC4)n3)cnn2C(C)(C)C)cc1
Yield: 17.3 %

Procedure:
A solution of the compound (54 mg, 0.15 mmol) obtained in step 7, HATU (66.3 mg, 0.17 mmol), DIEA (0.030 mL, 0.17 mmol) and (tetrahydro-2H-pyran-4-yl)methanamine (0.020 mL, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 3 days. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, aqueous sodium hydrogen carbonate solution and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 80→100% ethyl acetate/hexane) to give the title compound (12 mg, 0.026 mmol, 18%)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[Li]CCCC.CCCCCC.[CH:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CCOCC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[OH:31])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10]
Reactant: FC(F)(F)c1cc(I)ccc1Br
Reactant: O=Cc1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: CCOCC
Product: OC(c1ccccc1)c1ccc(Br)c(C(F)(F)F)c1
Reaction time: 0.25 h
Yield: 76 %

Procedure:
To a solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (246 mg, 0.701 mmol) in 1.4 mL of Et2O (C=0.5M) was added dropwise a 1.6M solution of BuLi in hexane (460 μL, 1.05 eq) at −78° C. After 15 min of stirring, benzaldehyde (86 μL, 1.2 eq) was slowly added. The mixture was stirred for 4 h at −75° C. and then, hydrolyzed with water and with a 1M HCl solution to acidify. The layers were separated. The aqueous layer was extracted with DCM (3×10 mL). The combined organics were washed with brine, dried over MgSO4, filtered and solvents were removed in vacuo. The crude residue was purified by silica gel flash chromatography (cyclohexane/AcOEt 93:7 to 90:10) to afford the desired product in 76% yield (176 mg) as an uncoloured oil. 1H NMR (300 MHz, CDCl3) δ 7.76 (d, J=2.2 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.41-7.27 (m, 6H), 5.81 (s, 1H), 2.36 (s, OH); 13C NMR (75 MHz, CDCl3) δ 143.5 (C), 142.8 (C), 135.1 (d, J=2.0 Hz, CH), 131.0 (CH), 130.2 (q, J=31.3 Hz, C), 129.0 (CH), 128.5 (CH), 126.7 (CH), 125.9 (q, J=5.4 Hz, CH), 123.0 (q, J=273.6 Hz, C), 118.9 (q, J=2.0 Hz, C), 75.4 (CH); MS (ESI) m/z: 313.0, 315.0 [M-OH, 79Br, 81Br]+; 348.0, 350.0 [M+NH4, 79Br, 81Br]+; 680.0 [2M+NH4, 79Br, 81Br]+.
Reaction SMILES: [OH:1][C:2]([CH2:34][CH2:35][CH3:36])([CH2:31][CH2:32][CH3:33])[CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([C@@H:11]([O:26][Si](C)(C)C)[C@@H:12]([CH3:25])[CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O>CCO>[OH:26][C@H:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([CH2:4][CH2:3][C:2]([OH:1])([CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32][CH3:33])[CH:6]=1)[C@@H:12]([CH3:25])[CH2:13][N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]1=[O:24]
Reactant: CCCC(O)(CCC)CCc1cccc([C@@H](O[Si](C)(C)C)[C@@H](C)CN2C(=O)c3ccccc3C2=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: CCCC(O)(CCC)CCc1cccc([C@@H](O)[C@@H](C)CN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C

Procedure:
To a solution of 2-((2S,3S)-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methyl-3-(trimethylsilyloxy)propyl)isoindoline-1,3-dione in EtOH is added trifluoroacetic acid. The reaction mixture is stirred at room temperature then concentrated under reduced pressure, re-evaporated with EtOAc then with hexane to give 2-((2S,3S)-3-hydroxy-3-(3-(3-hydroxy-3-propylhexyl)phenyl)-2-methylpropyl)isoindoline-1,3-dione.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][CH2:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[CH:15]=2)=[CH:10][C:9]=1[CH3:21].FC(F)(F)C(O)=O>>[CH3:20][C:16]1[CH:15]=[C:14]([C:11]2[CH:12]=[N:13][C:8]([CH2:7][NH2:6])=[C:9]([CH3:21])[CH:10]=2)[CH:19]=[CH:18][N:17]=1
Reactant: COc1ccc(CNCc2ncc(-c3ccnc(C)c3)cc2C)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cnc(CN)c(C)c2)ccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the reaction vessel containing N-(2,4-dimethoxybenzyl)-1-(2′,5-dimethyl-3,4′-bipyridin-6-yl)methanamine 81-4 (0.54 g, 1.5 mmol) was added trifluoroacetic acid (2 mL). The reaction was stirred at room temperature for 2 hours. TFA was removed by rotary evaporation to give crude (2′,5-dimethyl-3,4′-bipyridin-6-yl)methanamine 81-5. MS m/z 214.2 (M+1).