Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8].[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O)=[O:10].C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Cl:8])=[O:10]
Reactant: Clc1ccccc1Br
Reactant: O=Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1ccccc1-c1ccccc1Cl

Procedure:
To a solution of 2-bromochlorobenzene (0.12 mL, 1 mmol) and 2-formylbenzeneboronic acid (0.17 g, 1.1 mmol) in toluene (9 mL) were added 2M aq. sodium carbonate (1.2 mL) followed by (Ph3P)4Pd (0.34 g, 0.3 mmol). The resulting reaction mixture was refluxed for 3 h, cooled and diluted ethyl acetate. The organic phase was washed with water, saturated aq. sodium bicarbonate, brine and dried over sodium sulfate. The filtrate was concentrated in vacuo and the residue obtained was purified by chromatography (hexane:ethyl acetate; 4:1) to yield the title product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[C:16]([O:19][CH2:20][CH:21]2[CH2:24][CH2:23][CH2:22]2)[CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:3][CH2:2]1.[C@H:25]1([CH2:35]O)[C@@H:34]2[N:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1>>[C@H:25]1([CH2:35][N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]3[NH:11][C:12]4[C:17]([CH:18]=3)=[C:16]([O:19][CH2:20][CH:21]3[CH2:24][CH2:23][CH2:22]3)[CH:15]=[CH:14][CH:13]=4)=[O:9])[CH2:3][CH2:2]2)[C@@H:34]2[N:29]([CH2:30][CH2:31][CH2:32][CH2:33]2)[CH2:28][CH2:27][CH2:26]1
Reactant: OC[C@@H]1CCCN2CCCC[C@H]12
Reactant: O=C(NC1CCNCC1)c1cc2c(OCC3CCC3)cccc2[nH]1
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCC3CCC3)cccc2[nH]1

Procedure:
This compound is synthesized from 4-cyclobutylmethoxy-1H-indole-2-carboxylic acid piperidin-4-ylamide, 162 (preparation see below) and (1R,9aR)-1-(octahydro-quinolizin-1-yl)-methanol analogously to the method described in example 127.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5](C(O)=O)[CH2:4][CH2:3]1.CN(C)C=O.S(Cl)(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[C:24]([C:31]([OH:33])=[O:32])=[CH:23]2.C(N(CC)CC)C.Cl[Si](C)(C)C>ClCCl>[O:30]=[C:25]1[C:24]([C:31]([OH:33])=[O:32])=[CH:23][C:22]2[C:27](=[CH:28][CH:29]=[C:20]([NH:19][CH:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)[CH:21]=2)[NH:26]1
Reactant: Nc1ccc2[nH]c(=O)c(C(=O)O)cc2c1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1CCC(Nc2ccc3[nH]c(=O)c(C(=O)O)cc3c2)N1
Temperature: 25 °C
Yield: 60.9 %

Procedure:
A mixture of 2.32 g (18 mmol) 5-oxo-L-proline, 1.39 ml (18 mmol) dimethylformamide, and 45 ml of dichloromethane is stirred at 0°-5° and 1.32 ml (18 mmol) of thionyl chloride is added. The reaction mixture is stirred at 0°-5° for 1 hour. A mixture of 2.45 g (12 mmol) of 6-amino-1,2-dihydro-2-oxo-3-quinolinecarboxylic acid, 100 ml of dichloromethane, 5.04 ml (36 mmol) triethylamine and 4.57 ml (36 mmol) chlorotrimethylsilane is stirred at room temperature for 40 min and then is cooled to 0°-5°. The solution of the acid chloride complex is added to the silylated quinoline acid and is stirred with cooling for 4 hours and at room temperature overnight. The reaction mixture is evaporated to dryness, and the residue is treated with methanol and filtered to give 2.1 g of 1,2-dihydro-2-oxo-6-[(5-oxo-2-pyrrolidinyl)amino]3-quinolinecarboxylic acid. mp>300°
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Br:15][C:16]1[CH:17]=[N:18][C:19]2[C:20]3[N:28]([CH2:29][CH2:30][CH2:31][OH:32])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:21]=3[CH:22]=[N:23][C:24]=2[CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:57]1[C:61](=[O:62])[C:60]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:59]2[C:58]1=[O:67]>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:17]=[N:18][C:19]2[C:20]3[N:28]([CH2:29][CH2:30][CH2:31][O:32][N:57]4[C:61](=[O:62])[C:60]5[C:59](=[CH:66][CH:65]=[CH:64][CH:63]=5)[C:58]4=[O:67])[C:27]([CH2:33][O:34][CH2:35][CH3:36])=[N:26][C:21]=3[CH:22]=[N:23][C:24]=2[CH:25]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOCc1nc2cnc3cc(Br)cnc3c2n1CCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOCc1nc2cnc3cc(Br)cnc3c2n1CCCON1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Diisopropyl azodicarboxylate (6.47 mL, 32.9 mmol) was added dropwise over ten minutes to a stirred solution of 3-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propan-1-ol (10.0 g, 27.4 mmol), triphenylphosphine (8.62 g, 32.9 mmol), and N-hydroxyphthalimide (5.36 g, 32.9 mmol) in DMF (110 mL) at 0° C. The reaction was allowed to warm to room temperature and was stirred overnight. The solvent was removed under reduced pressure to afford a solid that was slurried in ethyl acetate, isolated by filtration, washed with ethyl acetate, and dried under vacuum to yield 11.45 g of 2-{3-[7-bromo-2-(ethoxymethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl]propoxy}-1H-isoindole-1,3(2H)-dione as a pink solid.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH:8]([OH:10])[CH3:9].[Cr](O)(O)(=O)=O>CCOCC>[CH3:9][C:8]([CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[CH3:1])=[O:10]
Reactant: CC(O)[C@@H]1CCCC[C@H]1C
Agent: O=[Cr](=O)(O)O
Solvent: CCOCC
Product: CC(=O)C1CCCCC1C
Temperature: 10 °C
Reaction time: 1 h

Procedure:
A solution of 13.2 g. (0.0928 moles) cis/trans-1-(2-methylcyclohexyl)-1-ethanol in 50 ml. of ether was chilled in an ice bath and 50 ml. 2 N chromic acid solution (BROWN GARG-Reagent) was added dropwise, with stirring, at such a rate as to maintain the temperature at about 10° C. After the addition was complete, the ice bath was removed and the stirring was continued at ambient temperature for one hour.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][NH:16][CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1.[CH2:21]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[CH:30][C:31]#[N:32]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[N:15][N:16]([C:22]4([CH2:30][C:31]#[N:32])[CH2:23][C:24]5([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)[CH2:21]4)[CH:17]=3)[N:10]3[CH:18]=[CH:19][N:20]=[C:9]3[CH:8]=2)[CH:4]=[N:3]1
Reactant: N#CC=C1CC2(CCCCC2)C1
Reactant: Cn1cc(-c2cc3nccn3c(-c3cn[nH]c3)n2)cn1
Product: Cn1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CC5(CCCCC5)C4)c3)n2)cn1
Yield: 37.3 %

Procedure:
This was prepared from 7-(1-methyl-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (100 mg; 0.377 mmol) and 2-(spiro[3.5]nonan-2-ylidene)acetonitrile (91 mg; 0.565 mmol) using the procedure described in Example 148, Step D to give the desired product (60 mg). MS (apci) m/z=427.2 (M+H).
Reaction SMILES: [C:1]([OH:14])(=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>O>[C:15]([O:13][C:1](=[O:14])[C:2]1[CH:3]=[C:4]([O:5][CH3:6])[C:7]([OH:8])=[C:9]([O:10][CH3:11])[CH:12]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)O)cc(OC)c1O
Solvent: O
Product: COc1cc(C(=O)OC(C)=O)cc(OC)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
A suspension of syringic acid 81 (10.0 g, 50.5 mmol) in acetic anhydride (30.0 g, 27.7 mL, 294.1 mmol) was warmed gently until a clear solution was obtained. Fused sodium acetate (0.5 g, 6.10 mmol) was added to the solution which was allowed to stir for 16 hours at room temperature. The solution was poured into water (100 mL) and stirred thoroughly to ensure hydrolysis of any excess anhydride. Crude O-Acetyl-syringic acid was recrystallized from water to afford the product as an off-white powder (11.2 g, 46.7 mmol). H1 NMR (270 MHz, CDCl3) δ 7.36 (s, 2H), 5.94 (br s, 1H), 3.87 (s, 6H), 2.35 (s, 3H). HRMS calcd for 240.0634, found 240.0637.
Reaction SMILES: C(OC([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11](Cl)=[CH:10][CH:9]=2)=O)C.[H-].[Na+].C1(S(Cl)(=O)=O)C=CC=CC=1.O>CN(C=O)C>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:14]=[CH:6]1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: O=S(=O)(Cl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2[nH]ccc2c1
Yield: 90 %

Procedure:
To a stirred and cooled (0° C.) solution of ethyl-5-chloroindole-2-carboxylate (1.052 g, 4.70 mmol) in DMF (25 mL) under N2, was added NaH (60% in oil, 230 mg, 5.64 mmol) portionwise. After the end of gas evolution, phenylsulfonyl chloride (0.72 mL, 5.64 mmol) was added. The reaction mixture was stirred for 1H (TLC monitoring, eluant dichloromethane). A little amount of water was added carefully and DMF was evaporated. Crude residue was dissolved in EtOAc and washed with water and brine. After drying and evaporation of solvents the compound was purified by chromatography on silica gel (eluant:cyclohexane/EtOAc 9/1 to 7/3) to afford protected indole (1.547 g, 90% yield. Off-white solid; 1H NMR (d6-DMSO) δ 1.30 (t, J=7.2 Hz, 3H), 4.35 (q, J=7.2 Hz, 2H), 7.37 (s, 1H), 7.53 (dd, J=2.2 and 9.1 Hz), 7.62-7.77 (m, 3H), 7.80 (d, J=2.2 Hz, 1H), 7.99 (m, 2H), 8.06 (d, J=9.1 Hz); MS (ESI, E1+) m/z=364 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([F:10])[CH:3]=1.[CH3:11][Mg]Br.CO.[BH4-].[Na+]>C1COCC1.C(OCC)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([NH2:7])[CH3:11])=[C:4]([F:10])[CH:3]=1
Reactant: C[Mg]Br
Reactant: N#Cc1ccc(Br)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOCC
Product: CC(N)c1ccc(Br)cc1F
Temperature: 0 °C
Reaction time: 6 h
Yield: 44 %

Procedure:
To a solution of 12 g of 4-bromo-2-fluorobenzonitrile (60 mM) in THF (120 ml) were added 75 ml (150 mM) of a 2 M solution of methylmagnesium bromide in diethyl ether at 0° C. The reaction mixture was stirred at 0° C. for 6 h. Then 200 ml of methanol were added gradually to the reaction mixture. Subsequently, 5.7 g (150 mM) of sodium borohydride were added in portions, and the mixture was stirred at room temperature for 16 h. Thereafter, the reaction mixture was concentrated under reduced pressure, and 200 ml of water were added. The pH was adjusted to pH=˜1 with 2 M HCl, and the aqueous solution was extracted with chloroform. Subsequently, the pH was adjusted to pH=˜9 with 2M NaOH, and extraction was effected with chloroform (2×100 ml). The combined chloroform extracts were dried, and the solvent was removed under reduced pressure. 7.3 g (44%) of 1-(4-bromo-2-fluorophenyl)ethanamine were obtained as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([N+:10]([O-])=O)=[C:6]([CH:9]=1)[CH:7]=[O:8]>C(Cl)Cl.C1COCC1.[Pt]>[NH2:10][C:5]1[CH:4]=[C:3]([F:13])[C:2]([Br:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Agent: [Pt]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Nc1cc(F)c(Br)cc1C=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a suspension of Pt/C (10%, 1.5 g, 0.77 mmol) in DCM (200 mL) and THF (50 mL) was added 5-bromo-4-fluoro-2-nitrobenzaldehyde (9.0 g, 36.3 mmol). The mixture was purged with H2 gas, and was stirred under an atmosphere of H2 gas at ambient temperature for 24 h. The reaction mixture was filtered through celite rinsing with DCM. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (600 mL) eluting with 15% EtOAc/hexane to afford 2-amino-5-bromo-4-fluorobenzaldehyde.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])=O.[NH2:12][C@H:13]([C:19]([OH:21])=[O:20])[CH2:14][CH2:15][C:16](=[O:18])[NH2:17].[BH4-].[Na+].Cl>C(O)C.[OH-].[Na+]>[C:16]([CH2:15][CH2:14][C@H:13]([NH:12][CH2:1][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6])[C:19]([OH:21])=[O:20])(=[O:18])[NH2:17]
Reactant: O=Cc1ccccc1C(=O)O
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CC[C@H](NCc1ccccc1C(=O)O)C(=O)O
Temperature: 20 °C
Reaction time: 1 h

Procedure:
A suspension of 1.65 g 2-formylbenzoic acid in 5 ml ethanol and 5 ml 2 M sodium hydroxide solution was added to a solution of 1.46 g L-glutamine in 5 ml of a 2 M aqueous sodium hydroxide solution. After stirring for 1 h at 20° C., the mixture was cooled to 0° C. and 0.25 g sodium borohydride were added in portions over 15 min with vigorous stirring. After 90 min a further 0.33 g 2-formyl benzoic acid and 0.05 g sodium borohydride were added. After stirring for 16 h at 20° C., the reaction mixture was acidified with conc. hydrochloric acid to pH 2 and cooled to 0° C. The precipitate formed was separated off, washed with acetone and dried in vacuo. 0.87 g (31% of theoretical) of the title compound remained in the form of crystals, which melted at 132-133° C.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[S:33][N:32]=1)=[O:30]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([C:31]3[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[S:33][N:32]=3)=[O:30])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C(CCCCCBr)c1nsc2ccccc12
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCC(=O)c2nsc3ccccc23)CC1

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride as starting compound and 6-bromo-1-(3-benzisothiazolyl)-1-hexanone are reacted and treated in the same manner as in Example 199 to give 4-amino-5-chloro-2-methoxy-N-((1-(6-(3-benzisothiazolyl)-6-oxohexyl)piperidin-4-yl)methyl)benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=2)=[S:10])=[CH:4][CH:3]=1.[Br:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30](Cl)=[O:31].C(N(CC)CC)C>C(Cl)Cl>[C:19]([C:16]1[CH:15]=[CH:14][C:13]([C:12]([NH:11][C:9](=[S:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][Br:24])=[CH:3][CH:4]=2)=[O:23])=[CH:18][CH:17]=1)([CH3:20])([CH3:22])[CH3:21]
Reactant: O=C(Cl)CCCCCBr
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCBr)cc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Thiourea 4 (200 mg, 0.61 mmol, 1 equiv.) was stirred in CH2Cl2 (10 mL) under N2 atmosphere. 6-Bromohexanoyl chloride (195.8 mg, 0.92 mmol, 1.5 equiv.) was added, followed by triethylamine (85 μL, 0.61 mmol, 1 equiv.). The beige suspension was stirred at rt for 1.5 h and diluted with CH2Cl2 (10 mL). The organic solution was washed with 1 M aqueous hydrochloric acid (1×10 mL), 10% aqueous sodium hydroxide (1×50 mL), and saturated brine (1×10 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The resulting brown foam was purified by flash chromatography on silica (50% ethyl acetate/petroleum ether) to give 6-bromo-hexanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (166 mg, 55%) as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]2[CH:10]=[C:11]([O:15][CH3:16])[C:12]([OH:14])=[CH:13][C:7]=2[C:6]=1[Cl:17])=[O:4].[OH-].[Na+]>CO>[Cl:17][C:6]1[C:7]2[CH:13]=[C:12]([OH:14])[C:11]([O:15][CH3:16])=[CH:10][C:8]=2[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc2cc(OC)c(O)cc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2sc(C(=O)O)c(Cl)c2cc1O

Procedure:
3-Chloro-5-hydroxy-6-methoxy-benzo[b]thiophene-2-carboxylic acid methyl ester (0.5 g) was dissolved in methanol (10 ml) and 5M sodium hydroxide (10 ml) added to. The solution refluxed for two hours. Methanol was evaporated and the resultant solution was acidified with 2M hydrochloric acid. The resultant solid was dried under vacuum. The product was used for the next step without any purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:21]1([CH3:29])[CH:26]=[CH:25][C:24]([CH:27]=O)=[CH:23][CH:22]=1.Cl>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[C:10]=1[C:16](=[O:18])[CH:17]=[CH:29][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: CC(=O)c1c(O)cccc1OCc1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(C=CC(=O)c2c(O)cccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of 2′-benzyloxy-6′-hydroxyacetophenone (0.5 g) in ethanol (10 mL)-water (3 mL) was added potassium hydroxide (1.39 g), and the mixture was stirred at room temperature for 10 minutes. To the reaction mixture was added p-tolualdehyde (0.37 mL), and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid (12.5 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give the title compound (0.69 g).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][Sb-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[F:9][Sb-:10]([F:15])([F:14])([F:13])([F:12])[F:11].[CH2:1]([N+:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: c1ccncc1
Agent: F[Sb-](F)(F)(F)(F)F
Solvent: CC#N
Product: c1ccc(C[n+]2ccccc2)cc1
Yield: 40 %

Procedure:
10.81 g (0.1 mol) of benzyl alcohol and 31.58 g (0.1 mol) of pyridine hexafluoroantimonate were dissolved in 80 g of acetonitrile and allowed to react at 80° C. for 8 hours. After the completion of the reaction, the mixture was concentrated, and the precipitated white solid was washed with ether and dried to give N-benzylpyridinium hexafluoroantimonate. Yield: 40%.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([C:10]2[N:11]=[C:12]([NH2:15])[S:13][CH:14]=2)=[C:5]([CH3:16])[CH:4]=1.C(N(CC)CC)C.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:17][N:2]([CH3:1])[C:3]1[CH:4]=[C:5]([CH3:16])[C:6]([C:10]2[N:11]=[C:12]([NH:15][C:26](=[O:33])[C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)[S:13][CH:14]=2)=[C:7]([CH3:9])[CH:8]=1
Reactant: O=C(Cl)c1ccncc1
Reactant: Cc1cc(N(C)C)cc(C)c1-c1csc(N)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(N(C)C)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a solution of 4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazol-2-amine (1-4, 0.50 g, 2.0 mmol) in CH2Cl2 (5.1 mL) was added triethylamine (0.61 g, 6.1 mmol) followed by isonicotinoyl chloride hydrochloride (0.54 g, 3.0 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with hot water. The resultant precipitate was filtered and dried under vacuum to give N-{4-(4-(dimethylamino)-2,6-dimethylphenyl)thiazol-2-yl}isonicotinamide (1, 0.55 g) as yellow solids in 77% yield: 1H NMR (500 MHz, CDCl3) δ 8.64 (d, J=5.5 Hz, 2 H), 7.55 (d, J=5.5 Hz, 2 H), 6.74 (s, 1 H), 6.12 (s, 2 H), 2.89 (s, 6 H), 1.91 (s, 6 H). ESI-MS: m/z 352.6 (M+H)+.
Reaction SMILES: CC1(C)[O:6][C@@H:5]([CH2:7][O:8][NH:9][C:10]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[NH:21][C:22]2[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=2[F:29])=[O:11])[CH2:4][O:3]1.Cl>CO.C1COCC1.CCOC(C)=O>[OH:6][C@H:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[S:14][C:13]=1[NH:21][C:22]1[CH:27]=[CH:26][C:25]([I:28])=[CH:24][C:23]=1[F:29])=[O:11]
Reactant: CC1(C)OC[C@H](CONC(=O)c2c(Nc3ccc(I)cc3F)sc3ncccc23)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(NOC[C@H](O)CO)c1c(Nc2ccc(I)cc2F)sc2ncccc12
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of Example 22 (125 mg, 0.23 mmol) in methanol (5 mL) and THF (5 mL) was treated with 10% aq. HCl (5 mL). The reaction mixture was stirred for 3.5 h at r.t., then diluted with EtOAc (25 mL). The organic solution was washed with sat. brine (2×25 mL), then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white powder, which was washed with EtOAc, then hexanes, and dried under suction (76 mg, 66%). δH (DMSO-d6) 11.31 (1H, s), 10.33 (1H, s), 8.34-8.33 (1H, m), 8.12-8.09 (1H, m), 7.79-7.76 (1H, m), 7.63-7.60 (1H, m), 7.45-7.40 (2H, m), 4.89-4.88 (1H, m), 4.62-4.59 (1H, m), 3.99-3.97 (1H, m), 3.85-3.80 (2H, m), 3.43 (2H, m). LCMS RT 3.38 minutes, (ES−) 502 (M−H)−, (ES+) 504 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]([C:37]([OH:39])=[O:38])[NH:19][C:20]([O:22][CH2:23][CH:24]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][C@@H:18]([C:37]([OH:39])=[O:38])[NH:19][C:20]([O:22][CH2:23][CH:24]2[C:36]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])(=[O:11])=[O:12])=[CH:8][CH:9]=1
Reactant: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(S(=O)(=O)NCCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 95 %

Procedure:
The product obtained from example 3 (553 mg, 1.00 mmol) was dissolved in EtOAc (10 mL) and then hydrogenated using 10% Pd on charcoal as catalyst at atmospheric pressure for 2 h. The catalyst was filtered off and the filtrate was evaporated in vacuo to yield the title compound in 95% yield.
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1B(O)O>>[Br:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:15]1[C:13]2=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]2[N:17]=[CH:16]1
Reactant: OB(O)c1ccccc1Br
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: Oc1ccc2ncn(-c3ccccc3Br)c2n1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 2-bromophenylboronic acid, prepared in a similar manner as the one described in Example 1.26, the title compound was obtained. LCMS m/z=289.9[M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 6.59 (d, J=8.6 Hz, 1H), 7.52 (td, J1=7.9 Hz, J2=1.8 Hz, 1H), 7.61 (td, J1=7.5 Hz, J2=1.4 Hz, 1H), 7.67 (dd, J1=7.8, J2=1.7 Hz, 1H), 7.89 (dd, J1=8.0, J2=1.3 Hz, 1H), 8.01 (d, J=8.6 Hz, 1H), 8.28 (s, 1H), 10.86 (s, 1H).