Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[CH2:10]([OH:24])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[H-].[Na+].CC1C=CC(C)=CC=1>O.C(O)(=O)C>[CH2:10]([O:24][C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(Br)o1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccc(C)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1

Procedure:
A mixture of 57.2 (0.300 mole) of 5-bromo-2-furoic acid, 102.0 g (0.45 mole) of tetradecanol, 18.0 g (0.750 mole) of sodium hydride and 2 liters of p-xylene are heated to reflux for 48 hours. The mixture is allowed to cool, then is acidified with acetic acid and diluted with 2 liters of water. The organic layer is separated, dried, evaporated to dryness, and the residue recrystallized from hexane to give 5-tetradecyloxy-2-furoic acid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:6]([C:19]([OH:21])=O)=[CH:5]2.[NH2:22][C:23]1[CH:24]=[N:25][C:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)=[CH:27][CH:28]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[N:29]1([C:26]2[N:25]=[CH:24][C:23]([NH:22][C:19]([C:6]3[N:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:8]4[C:4]([CH:5]=3)=[CH:3][C:2]([I:1])=[CH:10][CH:9]=4)=[O:21])=[CH:28][CH:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(O)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Reactant: Nc1ccc(N2CCCC2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(N2CCCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Yield: 70.6 %

Procedure:
The compound was prepared according to a process similar to that described in stage 5.4, by reacting 0.3 g (0.76 mmol) of 5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxylic acid, prepared according to the protocol described in stage 8.2, with 148 mg (0.91 mmol) of 3-amino-6-(pyrrolidin-1-yl)pyridine in the presence of 145 mg (0.76 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC) and of 105 mg (0.76 mmol) of 1-hydroxybenzotriazole (HOBT) in 5 ml of dimethylformamide. 290 mg of the expected product are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[N:43]12[CH2:50][CH2:49][CH:46]([CH2:47][CH2:48]1)[C@@H:45](O)[CH2:44]2>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:9]([O:11][C@@H:45]2[CH:46]3[CH2:49][CH2:50][N:43]([CH2:48][CH2:47]3)[CH2:44]2)=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(c1ccc(Cl)cc1)N1CCCCC1
Reactant: O[C@H]1CN2CCC1CC2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(c1ccc(Cl)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.4 %

Procedure:
2-(4-Chlorophenyl)-2-(piperidin-1-yl)acetic acid (190 mg, 0.75 mmol), DCC (309 mg, 1.50 mmol), and HOBT (229 mg, 1.50 mmol) were dissolved in dry THF (8 ml). (R)-quinuclidin-3-ol (286 mg, 2.25 mmol) was added and the reaction was stirred at room temperature for 16 hours. THF was evaporated and the residue was dissolved in EtOAc and washed with 1M NaHCO3, water and brine. The organic layer was separated, dried over Na2SO4, filtered and evaporated. The crude compound was purified by flash chromatography (DCM/MeOH/NH4OH=9 5/5/0.1) to obtain (R)-quinuclidin-3-yl 2-(4-chlorophenyl)-2-(piperidin-1-yl)acetate (167 mg, 61.5% yield) as a colorless oil.
Reaction SMILES: [H-].[Na+].C(=O)=O.CO.[Br:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[N:13][CH:14]=1.Br[CH2:19][CH2:20][O:21][CH2:22][CH2:23]Br>C1COCC1>[Br:8][C:9]1[CH:10]=[C:11]([C:15]2([C:16]#[N:17])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[CH:12]=[N:13][CH:14]=1
Reactant: N#CCc1cncc(Br)c1
Reactant: BrCCOCCBr
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N#CC1(c2cncc(Br)c2)CCOCC1
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
Under argon, NaH (60% in mineral oil, 0.497 g, 12.4 mmol) is added into THF (10 mL). The reaction mixture is cooled on a bath of dry ice/CH3OH. A solution of (5-bromo-pyridin-3-yl)-acetonitrile (1.0 g, 5.0 mmol) and 2-bromoethyl ether (0.719 mL, 5.15 mmol) in THF (4.5 mL) is added dropwise. The reaction is stirred for 30 min. The dry ice/MeOH bath is removed and the mixture is stirred at room temperature for 14 hrs. The reaction is quenched by slow addition of MeOH (5 mL). The mixture is then concentrated. The resulting crude product is purified by normal phase chromatography using 0-3% MeOH in DCM as the gradient to afford 4-(5-bromo-pyridin-3-yl)-tetrahydro-pyran-4-carbonitrile (1.07 g, 79% yield).
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH2:12].C(N(CC)CC)C.O>O1CCOCC1>[CH3:8][O:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[NH:12][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: COc1ccccc1N
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccccc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Pivaloyl chloride (120 g, 1 mol) was added dropwise at ambient temperature to a stirred solution of 2-methoxyaniline (123 g, 1 mol) and triethylamine (111 g, 1.1 mol) in 1,4-dioxane (1200 ml), the mixture was stirred at ambient temperature for 2 hours, then it was poured into water (3000 ml). The product was extracted into ethyl acetate (3×300 ml), then the combined extracts were dried (MgSO4) and the solvents were removed in vacuo to give N-(2-methoxyphenyl)pivalamide (198 g; 96%) as a low-melting solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]([C:16]#[C:17][C:18](OC)=[O:19])=[O:15]>>[F:11][C:8]([F:9])([F:10])[C:5]1[CH:6]=[C:7]2[C:2](=[CH:3][CH:4]=1)[NH:1][C:16]([C:14]([O:13][CH3:12])=[O:15])=[CH:17][C:18]2=[O:19]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C#CC(=O)OC
Product: COC(=O)c1cc(=O)c2cc(C(F)(F)F)ccc2[nH]1
Yield: 2.7 %

Procedure:
Using the method described in Example 18a with 4-aminobenzotrifluoride (20 g) and dimethylacetylene dicarboxylate (17.5 g) as reagents gave methyl 6-trifluoromethyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.91 g), m.p. 289°-291° C., δ (360 MHz, DMSO-d6) 3.98 (3H, s, CH3), 6.74 (1H, s, 3-H), 8.02 (1H, dd, 7-H), 8.13 (1H, d, 8-H), 8.33 (1H, s, 5-H) and 12.40 (1H, s, NH).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH2:34][CH2:35]O)=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:17][C:16]([O:30][CH3:31])=[C:15]([O:32][CH3:33])[CH:14]=2)=[O:9])[CH3:6].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:5]([O:7][C:8]([C:10]1[C:11]([CH2:34][CH2:35][Br:2])=[N:12][C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([O:28][CH3:29])[CH:21]=1)=[CH:17][C:16]([O:30][CH3:31])=[C:15]([O:32][CH3:33])[CH:14]=2)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1c(CCO)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)c1c(CCBr)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Phosphorus tribromide (PBr3) (1.0 g) was added drop by drop to a solution of 6,7-dimethoxy-4-(3,4-dimethoxyphenyl)-2-(2-hydroxyethyl)quinoline-3-carboxylic acid ethyl ester (1.7 g) in benzene (50 ml) at room temperature. After stirring at 80° C. for 1 hour, the reaction mixture was poured over ice water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with chloroform. The chloroform layer was washed with water and then dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with chloroform-ethyl acetate (1:1, v/v) to yield 2-(2-bromoethyl)-6,7-dimethoxy-4-(3,4-dimethoxyphenyl)quinoline-3-carboxylic acid ethyl ester (0.49 g, 26%), which was then recrystallized from ethyl acetate-hexane to yield a colorless prismatic crystal having a melting point of 132° to 133° C.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]>>[CH:1](=[O:3])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:9][CH2:8][CH:7]=[CH:6][CH:5]=[CH2:4]
Reactant: CCCCCCC
Reactant: O=CO
Product: C=CC=CCCCCCCCCCC=O
Yield: 94 %

Procedure:
The Grignard solution is then added to a mixture of 1,4-pentadien-3-yl isobutyrate ester (114 g, 0.740 mol) and LiCuBr2 reagent (1 M/THF, 86 mL) at a rate that maintains the reaction temperature between 25-30° C., with cooling as necessary. The mixture is stirred for 15 minutes then quenched with aqueous citric acid solution (1 L). The layers are separated and the organic portion is washed with water (2×) and dilute sodium hydroxide solution (until pH basic). The crude organic portion is then stripped of solvent and distilled to afford 56.2 g of the 11,13-tetradecadienal DEA product (b.p. 150° C., 0.1 mm Hg, Yld. 27%, m/z 282), which is subsequently deprotected at room temperature with formic acid in heptane to give 11,13-tetradecadienal (40.0 g, Yld. 94%, E/Z 76:24).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10]Br)=[CH:6][C:5]=1[O:12][C:13](=[O:15])[CH3:14].C([O-])=[O:18].[Na+]>CCO.CS(C)=O.O.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:18])=[CH:6][C:5]=1[O:12][C:13](=[O:15])[CH3:14]
Reactant: O=C[O-]
Reactant: COC(=O)c1ccc(CBr)cc1OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc(CO)cc1OC(C)=O
Temperature: 100 °C
Yield: 49.5 %

Procedure:
A solution containing 2-acetoxy-4-(bromomethyl) benzoic acid methyl ester (1.34g, 4.67 mmol, RN 13339-10-1) and sodium formate (0.795 g, 11.7 mmol) In EtOH:DMSO:H2O (2:2:1, 93 mL) was heated at 100° C. for 16 h. The reaction was cooled to ambient temperature, diluted with 10% CH2Cl2 /EtOAc (100 mL), washed with brine (3×), dried (Na2SO4) and concentrated. The crude product was purified on Biotage KP-Sil eluting with 20% acetone/hexane to give 0.518 g (49%) of the title compound as a clear oil. 1H NMR (DMSO-d6) δ 2.28 (s, 3H), 3.80 (s, 3H), 4.57 (d, 2H), 5.45 (br, t, 1H), 7.16 (s, 1H), 7.33 (d, 1H), 7.91 (d, 1H).
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][CH:15]2[CH:10]([CH:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH:13]=[CH:14]2)[CH2:9]1)C1C=CC=CC=1>CO.[Pd]>[CH2:9]1[CH:10]2[CH:15]([CH2:14][CH2:13][CH2:12][CH:11]2[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:16][CH2:17][NH:8]1
Reactant: CCOC(=O)C1CC=CC2CCN(Cc3ccccc3)CC21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C1CCCC2CCNCC21
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A solution of ethyl (4aRS,8SR,8aSR)-2-benzyl-1,2,3,4,4a,7,8,8a-octahydroisoquinoline-8-carboxylate (440 mg, 1.47 mmol) in methanol (10 mL) was treated with 10% palladium on charcoal (20 mg) and stirred for 16 hours under an atmosphere of hydrogen. The mixture was filtered, and the filtrate was concentrated to provide a colorless oil (305 mg, 98%). 1H NMR (300 MHz, CDCl3) δ4.09 (q, J=7 Hz, 2H), 3.07 (m, 1H), 2.94 (dd, J=12, 4 Hz, 1H), 2.60 (m, 2H), 2.25 (J=12, 11 Hz, 1H), 2.0-1.7 (m, 3H), 1.6-1.2 (m, 6H), 1.91 (t, J=7 Hz, 3H), 1.10 (m, 2H). Mass spec (ES+) m/z 212.4 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:16]=[C:17]([C:27]2[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O-:14])=[O:13].C(N(CC)CC)C.O>ClCCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:24]2[CH2:25][CH2:26][N:21]([C:20]3[CH:19]=[CH:18][C:17]([C:27]4[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=4)=[CH:16][C:15]=3[N+:12]([O-:14])=[O:13])[CH2:22][CH2:23]2)=[O:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3ccc(C4=NNC(=O)CC4C)cc3[N+](=O)[O-])CC2)cc1
Temperature: 25 °C

Procedure:
0.70 g (4.1 mmol) of 4-methoxybenzoyl chloride is added to a slurry of 1.0 g (3.15 mmol) of 6-[3-nitro-4-(1-piperazinyl)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 1.14 ml (8.2 mmol) of triethylamine in 40 ml of 1,2-dichloroethane and the reaction mixture is boiled under reflux for 0.5 h. It is then cooled to room temperature, 50 ml of water are added, and the organic phase is separated off.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:32][CH:33]1[CH:37]([OH:38])[CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]1.O>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:32][CH:33]2[CH:37]([OH:38])[CH2:36][N:35]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:34]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(O)C1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O)C(NC(=O)c2ccc(Cl)s2)C1
Reaction time: 0.5 h

Procedure:
201 mg (1.2 mmol) 5-chlorothiophene-2-carboxylic acid and 436 mg (1.4 mmol) TBTU are suspended in 5 ml DCM and combined with 260 μl (1.9 mmol) TEA. The mixture is stirred for 30 minutes and then a solution of 250 mg (1.2 mmol) tert. Butyl (3SR,4SR)-3-amino-4-hydroxy-pyrrolidine-1-carboxylate in 5 ml DCM is added and the mixture is stirred for 16 hours at RT. Then the reaction mixture is poured into water and extracted with DCM. The organic phase is washed with sat. sodium chloride solution and, after being mixed with activated charcoal, dried on sodium sulphate. The mixture is filtered and the filtrate is evaporated to dryness. The residue thus obtained is purified by column chromatography (silica gel, eluant DCM/MeOH 10:1).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:30](Cl)=[O:31])[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[N:15]=2)=[C:7]([O:33][CH2:34][CH3:35])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:36]1([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[C:45]([O:44][C:42]([N:36]1[CH2:41][CH2:40][N:39]([C:30]([N:12]2[C@H:13]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C@H:14]([C:16]3[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=3)[N:15]=[C:11]2[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][C:7]=2[O:33][CH2:34][CH3:35])=[O:31])[CH2:38][CH2:37]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
4-[(4S,5R)-2-(4-tert-Butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester was prepared from (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 11) and tert-butyl piperazine-1-carboxylate in an analogous manner as described in example 25. LR-MS: 679.4 [(M+H)+]
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[S:25][C:24](=N)[NH:23][C:22]3=[O:27])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].Cl.C([OH:31])C>>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]3[S:25][C:24](=[O:31])[NH:23][C:22]3=[O:27])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2SC(=N)NC2=O)cc1
Reactant: CCO
Agent: Cl
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C2SC(=O)NC2=O)cc1

Procedure:
To a suspension of 5-[4-[(2-ethyl-5,7-dimethylimidazo[4,5-b]pyridin-3-yl)methyl]phenyl]-2-iminothiazolidin-4-one (6.23 g) in ethanol was added concentrated hydrochloric acid (20 ml) to give a solution, which was stirred under reflux for 24 hrs. After the reaction, the mixture was concentrated under reduced pressure and the residue was dissolved in ethyl acetate-water, and the solution was neutralized with aqueous sodium bicarbonate. After partitioning and extraction, the extracted organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated and concentrated, and the precipitated object compound (5.32 g) was collected by filtration melting point: 221-222° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[C:6]([C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[C:17]([OH:24])=[C:16]3[OH:25])[N:12]=1)=[O:7].B.[Na]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]([C:8]2[S:9][CH:10]=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18](=[O:23])[C:17]([OH:24])=[C:16]4[OH:25])[N:12]=2)[OH:7])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1ccc(C(=O)c2nc(-c3ccc4[nH]c(=O)c(O)c(O)c4c3)cs2)cc1OC
Agent: B
Agent: [Na]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(O)c2nc(-c3ccc4[nH]c(=O)c(O)c(O)c4c3)cs2)cc1OC
Reaction time: 1 h
Yield: 51.8 %

Procedure:
In 6 ml of chloroform was dissolved 100 mg of 2-(3,4-dimethoxybenzoyl)-4-(3,4-dihydroxycarbostyril-6-yl)thiazole. Thereto was added sodium boron hydride at room temperature, and the mixture was stirred for 1 hour at the same temperature. The solvent was distilled off. The residue was extracted with chloroform. The extract was water-washed, dried and then subjected to solvent removal by distilation. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=99/1) and then recrystallized from ethyl acetate to obtain 52 mg of 2-[1-(3,4-dimethoxyphenyl)-1-hydroxymethyl]-4-(3,4-dihydroxycarbostyril-6-yl)thiazole as light brown prismatic crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[CH:5][N:6]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(Cl)(Cl)Cl.CN(C)C=O>[NH2:1][C:2]1[S:3][C:4]([S:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[O:22])=[CH:5][N:6]=1
Reactant: Nc1ncc(Sc2ccncc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: Nc1ncc(S(=O)c2ccncc2)s1
Yield: 58.1 %

Procedure:
To a mixture of 2-amino-5-(4-pyridylthio)thiazole (4.0 g) in a mixture of chloroform (300 ml) and N,N-dimethylformamide (10 ml) was added dropwise the solution of 3-chloroperbenzoic acid (4.5 g) in chloroform (100 ml) at 5° C. with stirring. The mixture was stirred at 5° C. for 26 hours under ice cooling. The reaction mixture was washed with aqueous sodium bicarbonate and water and dried over magnesium sulfate. The solvent was concentrated under reduced pressure to give solid. The solid was subject to column chromatography on silica gel (silica gel 60, 70-230 mesh; Merck: 250 g) and eluted with a mixture of chloroform and methanol (10:1). The fractions containing the objective compound were combined and concentrated under reduced pressure to give 2-amino-5-(4-pyridylsulfinyl)thiazole (2.5 g, yield: 58.1%). mp: 193°-195° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[N:22]=3)[CH:16]=2)=[CH:11][C:10]=1[O:31][CH3:32])C1C=CC=CC=1.Br.C(O)(=O)C>ClCCl>[CH3:32][O:31][C:10]1[CH:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:28])[F:29])[N:22]=3)[CH:16]=2)[CH:13]=[CH:14][C:9]=1[OH:8]
Reactant: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc(-c2cccc(-c3cccc(C(F)(F)F)n3)c2)ccc1O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(4′-(benzyloxy)-3′-methoxybiphenyl-3-yl)-6-(trifluoromethyl)pyridine (1.061 g, 2.44 mmol) in dichloromethane (20 mL) cooled in an ice-water bath was added a 30% solution of hydrogen bromide in acetic acid (4 mL, 20 mmol) dropwise. The resulting solution was allowed to stir at room temperature for six hours then poured onto ice-water (100 mL). The phases were separated and the aqueous phase was extracted with dichloromethane (10 mL). The combined organic layers were washed with water and brine, then dried over anhydrous sodium sulphate and filtered. Evaporation of the solvent left a brown oil that was chromatographed over silica gel (petroleum ether/ethyl acetate, 4:1) to give 3-methoxy-3′-(6-(trifluoromethyl)pyridin-2-yl)biphenyl-4-ol as a clear oil, 0.547 g (65%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[OH:19][NH:20][C:21]([CH:23]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:26][CH2:25][N:24]1[S:39]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([F:57])[CH:55]=3)[N:50](S(CC[Si](C)(C)C)(=O)=O)[CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])=[O:40])=[O:22].C(O)(=O)C>O1CCCC1>[OH:19][NH:20][C:21]([CH:23]1[CH2:28][N:27]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:26][CH2:25][N:24]1[S:39]([N:42]1[CH2:47][CH2:46][CH:45]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[C:54]([F:57])[CH:55]=3)[NH:50][CH:49]=2)[CH2:44][CH2:43]1)(=[O:41])=[O:40])=[O:22]
Reactant: C[Si](C)(C)CCS(=O)(=O)n1cc(C2CCN(S(=O)(=O)N3CCN(C(=O)OCc4ccccc4)CC3C(=O)NO)CC2)c2cc(F)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=C(NO)C1CN(C(=O)OCc2ccccc2)CCN1S(=O)(=O)N1CCC(c2c[nH]c3ccc(F)cc23)CC1
Temperature: 45 °C
Yield: 71 %

Procedure:
Tetrabutylammonium fluoride (0.194 ml, 1M solution in tetrahydrofuran) was added to a solution of N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoro-1-(2-trimethylsilylethanesulfonyl)-indol-3-yl]-piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (0.067 mg, 0.093 mmol), [prepared as described in Step 7 above] in tetrahydrofuran (1.6 ml). The reaction mixture was heated at 45° C. for approx. 20 min., and then quenched with glacial acetic acid (0.011 ml, 0.194 mmol). The reaction mixture was concentrated and the residue was chromatographed by preparatory TLC (10% methanol/methylene chloride) to give N-hydroxy-4-benzyloxycarbonyl-1-{4-[5-fluoroindol-3-yl]piperidine-1-sulfonyl}piperazine-2-(RS)-carboxamide (71%), mp 85.7-89.7° C.