Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1.[C:23]([C:26]1[CH:36]=[CH:35][C:29]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:28]([O:37][CH3:38])[CH:27]=1)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)([OH:9])[CH:10]2[CH2:11][CH2:12][N:13]([CH2:33][CH2:32][CH2:31][O:30][C:29]3[CH:35]=[CH:36][C:26]([C:23](=[O:25])[CH3:24])=[CH:27][C:28]=3[O:37][CH3:38])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCNCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A mixture of 5.0 g (0.0165 mole) of α,α-bis(p-fluorophenyl)-4-piperidinemethanol, 4.0 g (0.0165 mole) of 3-(p-acetyl-o-methoxyphenoxy)propyl chloride and 1.4 g (0.0165 mole) of sodium bicarbonate in 60 ml of dimethylformamide was stirred and heated at 80° C. for two hours. The temperature was raised to 100° C. for one hour. After cooling, the reaction mixture was filtered and the dimethylformamide was removed at reduced pressure. The residual oil which crystallized on standing in ether was dissolved in benzene and placed on a Florisil® column. Using a gradient elution of acetone-benzene, 1.8 g (21.4%) of product was obtained from the column, m.p. 141.5°-143° C. (See Ex. 12, U.S. Pat. No. 3,956,296).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9].C([Li])CCC.C([O:20][B:21](OC(C)C)[O:22]C(C)C)(C)C.Cl>C1COCC1.CCCCCC>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[B:21]([OH:22])[OH:20]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)c1ccccc1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OB(O)c1ccccc1C(F)(F)F
Temperature: 10 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 58.8 g (0.261 mol) of 1-bromo-2-(trifluoromethyl)benzene in 250 mL of THF under Ar was added 110 mL (0.275 mol) of 2.5M n-butyllithium in hexane over 35 minutes, keeping the temperature between 0-5° C. The reaction mixture was allowed to warm to 10° C. Triisopropylborate (95 mL, 0.313 mol) was added, keeping the temperature below 35° C. After 1 hour, the reaction mixture was cooled, 1N HCl (425 mL) was added, and the mixture was stirred overnight. The mixture was extracted with 100 mL of ether three times, and the combined organic extracts were extracted with 100 mL of 1N NaOH three times. The aqueous extracts were acidified to pH 1 with 6N HCl, and then extracted with 100 mL ether three times. The combined ether extracts were dried over MgSO4, and the solvents evaporated in vacuo to give 46.1 g (93%) of the desired compound as a light yellow oil. 1H NMR (CDCl3) δ: 7.77 (d, 1H); 7.72 (d, 1H); 7.56 (m, 2H); 4.87 (br s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1B(O)O.Br[C:14]1[C:15]([CH3:24])=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:14]1[C:15]([CH3:24])=[CH:16][C:17]([C:20]([O:22][CH3:23])=[O:21])=[N:18][CH:19]=1
Reactant: COc1ccc(B(O)O)c(F)c1
Reactant: COC(=O)c1cc(C)c(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)cc2F)cn1
Reaction time: 0.03 h

Procedure:
(2-Fluoro-4-methoxyphenyl)boronic acid (177 mg, 1.043 mmol), methyl 5-bromo-4-methylpyridine-2-carboxylate (200 mg, 0.869 mmol), 1,1bis(di-tert-butylphosphino)ferrocene palladium dichloride (89 mg, 0.130 mmol), cesium carbonate (623 mg, 1.913 mmol) and THF (5 mL) were sealed in a microwave vessel and subject to microwave irradiation at 140° C. for 20 min. The reaction crude was combined with the crude from an identical probe reaction (44.3 mg scale). Volatiles were removed under reduced pressure. The resulting pot residue was purified by preparative HPLC (reverse phase, Kromasil® 100-5C18, 100×21.1 mm) eluting with acetonitrile/water+0.1% TFA (30% to 100% organic in 10 min, then to 100% for 2 min, 20 mL/min). Related fractions were pooled and evaporated under reduced pressure to afford a dark solid. This solid was further purified by flash chromatography (SiO2, Biotage SNAP Cartridge, silica gel, KP-Sil, 50 g cartridge). The column was eluted with an EtOAc/hexanes mixture (0% to 100%). Related fractions were pooled and evaporated to afford a light yellow oil as the titled compound. LCMS calc.=275.10. found=276.11 (M+H)+.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([OH:30])[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:18][CH:17]=1.[CH2:31]([O:33][CH2:34]OCC)[CH3:32]>ClCCl.C(OCC)C>[CH2:31]([O:33][CH2:34][O:30][C@H:22]([C:19]1[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=1)[CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH3:32]
Reactant: CCOCOCC
Reactant: COC(=O)CCC[C@H](O)c1ccc(F)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Solvent: CCOCC
Product: CCOCO[C@@H](CCCC(=O)OC)c1ccc(F)cc1
Temperature: 29 °C
Yield: 113.9 %

Procedure:
40.6 g of phosphorus pentoxide are added to a vigorously stirred solution of 10.5 g (42.7 mmol) of methyl 5-(4-fluorophenyl)-5-(S)-hydroxypentanoate with a purity of 92% area % (Example 1) in 220 ml of dichloromethane and 152 ml (1200 mmol) of 99% pure diethoxymethane in a 4-neck flask with mechanical stirrer, the internal temperature rising from initially 23° C. to 30° C. There is initial formation of a white suspension whose particles quickly agglomerate and form a viscous mass which partly adheres to the bottom of the flask and changes color via yellow to brown. HPLC analysis (system as in Example 5) shows complete conversion of the precursor (tret9.8 min.) into the product (tret 13.4 min.) after only 5 min. The reaction mixture is stirred at 29° C. without external heating (i.e. continuing exothermic reaction) for 0.5 h, but the only effect of this was to increase an impurity (tret 13.2 min.). The reaction mixture is cooled to +10° C. in an ice bath, and 100 g of ice are added to the mixture. The viscous solid mass dissolves only slowly even with vigorous stirring. The mixture is transferred into a separating funnel and diluted with 200 ml of diethyl ether. The organic phase is separated off, and the aqueous phase is extracted again with 100 ml of diethyl ether. The combined extracts are washed with 100 ml of saturated aqueous sodium bicarbonate solution and with 100 ml of saturated aqueous sodium chloride solution, and then concentrated in vacuo, and the residue is dried under HV. 13.83 g of brown oil are obtained. The crude product has a GC purity of 84 area %. It is distilled through a silvered 15 cm vacuum-jacketed Vigreux column under HV (0.005 mbar). After a fore-run (1 g, b.p. 33-88° C., colorless mobile oil), the product distills (9.5 g, b.p. 102-103° C., colorless oil) at a bath temperature of 160-170° C., and 3 g of higher-boiling impurity remain as bottom product. Yield: 9.5 g (33.4 mmol), 78% of theory.
Reaction SMILES: Br[C:2]1[C:3]([O:19][CH3:20])=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[CH:6]=[C:5]2[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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>[F:11][C:9]1[CH:10]=[C:2]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:3]([O:19][CH3:20])=[C:4]2[C:8]=1[N:7]([CH3:12])[CH:6]=[C:5]2[CH2:13][C:14]([N:16]([CH3:18])[CH3:17])=[O:15]
Reactant: COc1c(Br)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Reactant: OB(O)c1ccccc1
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COc1c(-c2ccccc2)cc(F)c2c1c(CC(=O)N(C)C)cn2C
Yield: 81 %

Procedure:
To the solution of 8-11 (200 mg, 0.58 mmol) in dioxane (10 mL) was added phenylboronic acid (86 mg, 0.70 mmol), Pd(PPh3)4 (68 mg, 0.06 mmol), and Cs2CO3 (760 mg, 2.3 mmol) under nitrogen atmosphere. The reaction mixture was refluxed overnight, poured into water and extracted with ethyl acetate (20 mL×3). The separated organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (elution with petroleum ether:ethyl acetate=1:1) to afford 8-12 (160 mg, 81%) as white solid. LCMS: calc 340.4 and found 341.1 [MH]+.
Reaction SMILES: [CH2:1]([NH:6][C:7]1[N:8]=[CH:9][NH:10][C:11]=1[C:12]1[NH:16][N:15]=[CH:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C1N=CN([C:22](N2C=NC=C2)=[O:23])C=1>O1CCOCC1>[CH2:1]([N:6]1[C:7]2[N:8]=[CH:9][NH:10][C:11]=2[C:12]2=[N:13][CH:14]=[N:15][N:16]2[C:22]1=[O:23])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCCCNc1nc[nH]c1-c1ncn[nH]1
Solvent: C1COCCO1
Product: CCCCCn1c(=O)n2ncnc2c2[nH]cnc21
Temperature: 110 °C
Reaction time: 2 h
Yield: 5.1 %

Procedure:
A mixture of N-pentyl-5-(1H-1,2,4-triazol-5-yl)-1H-imidazol-4-amine (0.52 g, 2.4 mmol) and N,N-carbonyldiimidazole (0.57 g, 3.5 mmol) in 1,4-dioxane (10 mL) was stirred at 110° C. for 2 hours. The solvent was removed under reduced pressure, and the residue was purified by preparative LCMS to yield the desire product (30 mg, 5% yield). LCMS calculated for C11H15N6O (M+H): 247.1. found: 247.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)[CH2:32][C:33]1[CH:34]=[N:35][C:36]([O:39][CH2:40][CH2:41][O:42][CH3:43])=[CH:37][CH:38]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: COCCOc1ccc(CO)cn1
Product: COCCOc1ccc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1
Yield: 63.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 142 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.2 g) and 3-hydroxymethyl-6-(2-methoxyethoxy)pyridine (0.55 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-{[6-(2-methoxyethoxy)pyridin-3-yl]methyl}-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.07 g) was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([I:12])[NH:8][C:7]=1[CH3:13])=[O:5])[CH3:2].[CH3:14]OS(C1C=CC(C)=CC=1)(=O)=O.CC(C)([O-])C.[Na+]>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH3:11])=[C:9]([I:12])[N:8]([CH3:14])[C:7]=1[CH3:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(C)[nH]c(I)c1C
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)c(I)n(C)c1C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
5-Iodo-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6d (4.1 g, 13.99 mmol) was dissolved in 80 mL of tetrahydrofuran followed by addition of 4-methyl-benzenesulfonic acid methyl ester (2.73 g, 14.69 mmol) and sodium tert-butoxide (2.02 g, 20.99 mmol). Upon completion of the addition, the reaction mixture was stirred for 0.5 hours and monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was washed with tetrahydrofuran. The filtrate was concentrated under reduced pressure to obtain the title compound 5-iodo-1,2,4-trimethyl-1H-pyrrole-3-carboxylic acid ethyl ester 6e (3.8 g, yield 88.6%) as a grey solid.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([Cl:22])[CH:21]=1.C(N(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12](=[O:14])[CH2:13][C:23]([C:18]3[CH:19]=[C:20]([Cl:22])[CH:21]=[C:16]([Cl:15])[CH:17]=3)([OH:28])[C:24]([F:27])([F:26])[F:25])=[CH:10][CH:11]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)c1ccc(-n2ccnc2)cc1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCCCN(CCCC)CCCC
Product: O=C(CC(O)(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(-n2ccnc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
0.50 g (2.69 mmol) of 1-(4-(1H-imidazol-1-yl)phenyl)ethanone, 0.65 g (2.69 mmol) of 3′,5′-dichloro-2,2,2-trifluoroacetophenone, 1.31 g of toluene and 0.15 g (0.81 mmol) of tributylamine were fed and the mixture was stirred for 8 hours at 60° C. After leaving the reaction mixture for one night at room temperature, the solid was filtered under reduced pressure to obtain 0.94 g of 1-(4-(1H-imidazol-1-yl)phenyl)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one as a white solid (yield 85.7%).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7](=[O:31])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([NH:19][C:20]2[CH:21]=[N:22][C:23]3[C:28]([CH:29]=2)=[CH:27][CH:26]=[CH:25][C:24]=3C)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[OH-].[Na+].[CH2:35]1COCC1.CO>>[CH3:17][CH:16]([CH3:18])[CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:32])=[O:31])=[CH:9][CH:10]=1)[NH:19][C:20]1[CH:21]=[N:22][C:23]2[C:28]([CH:29]=1)=[CH:27][CH:26]=[C:25]([CH3:35])[CH:24]=2
Reactant: C1CCOC1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Nc2cnc3c(C)cccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc2cc(NC(CC(C)C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a mixture of 3-{4-[3-Methyl-1-(8-methyl-quinolin-3-ylamino)-butyl]-benzoylamino}-propionic acid methyl ester (12) (49 mg, 0.11 mM) in 1:1 mixture of THF/MeOH (1 mL) was added 1N NaOH solution (0.283 mL, 0.283 mM). The reaction mixture was stirred at RT for 1 h. The reaction mixture was concentrated to remove organic solvent. The aqueous solution was diluted with DCM (5 mL), acidified by 1N HCl solution to pH=3-4. The organic solution was separated and the aqueous solution was extracted with 10% i-PrOH-DCM (3×5 mL). The combined organic solution were dried (Na2SO4) and concentrated to give a yellow solid product (˜78%). 1H NMR (500 MHz, DMSO-d6) δ ppm 0.93 (d, J=6.59 Hz, 3H) 0.98 (d, J=6.59 Hz, 3 H) 1.53-1.60 (m, 1 H) 1.70 (dt, J=13.72, 6.68 Hz, 1 H) 1.76-1.83 (m, 1 H) 2.43 (s, 3 H) 2.47 (t, J=7.07 Hz, 2 H) 3.35-3.46 (m, 2 H) 4.65 (t, 1 H) 7.23 (br. s., 1 H) 7.37 (d, J=8.54 Hz, 1 H) 7.41 (br. s., 1 H) 7.54 (d, J=8.29 Hz, 2 H) 7.59-7.67 (m, 2 H) 7.76 (d, J=8.29 Hz, 2 H) 8.43 (t, J=5.49 Hz, 1 H) 8.61 (d, J=2.68 Hz, 1 H), one proton was exchanged. LC-MS: m/z 420.2 (M+1).
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:9]([C:16]#[N:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:16]([CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])#[N:17]
Reactant: N#CCc1ccccc1
Reactant: CCCCCBr
Agent: [Na+]
Agent: [OH-]
Product: CCCCCC(C#N)c1ccccc1
Yield: 82 %

Procedure:
Hexadecyltributyl phosphonium hectorite (0.050 mmol) was mixed with 2.0 ml of 50 wt % of aqueous sodium hydroxide, 1-bromopentane (5.0 mmol) and benzyl cyanide 95.0 mmol). After reaction at 50° C. for 2 hr, the emulsion was broken by centrifugation and 1-cyano-1-phenyl hexane was obtained in 82.0% yield.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O>[CH:2]([C:6]1[S:7][CH:8]=[CH:9][C:10]=1[S:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[O:1]
Reactant: COC(=O)CSc1ccsc1C1OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)CSc1ccsc1C=O

Procedure:
2,3-Dibromothiophene (1) is converted to 3-Bromothiophene-2-carboxaldehyde (2) through a series of reactions with n-butyl lithium yielding 2-litho-3-bromothiophene, followed by N-formylpiperidine and 3N HCl. This 3-bromothiophene-2-carboxaldehyde (2) is then placed in toluene solution containing ethylene glycol to which is added pyridinium tosylate yielding 3-bromo-2-(2-dioxolanyl)thiophene (3). This 3-bromo-2-(2-dioxolanyl)thiophene (3) is then reacted with n-butyllithium followed by sulfur, then by methyl bromoacetate, to yield methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4). This methyl 3-[2-(2-dioxolanyl)thiophene-3-yl]-3-thiapropionate (4) is next dissolved in acetone and p-toluenesulfonic acid monohydrate is added in catalytic amount yielding methyl 3-(2-formylthiophene-3-yl)-3-thiapropionate (5). This methyl 3-(2-formylthiophene-3-yl)3-thiapropionate (5) is then treated in solution with piperidinium acetate yielding methyl thieno[3,2-b]thiophene-2-carboxylate (6). This methyl thieno[3,2-b]thiophene-2-carboxylate (6) is then placed in solution with lithium aluminum hydride yielding 2-hydroxymethylthieno[3,2-b]-thiophene (7). This 2-hydroxymethylthieno[3,2-b]-thiophene (7) is then added to a suspension of pyridinium chlorochromate in methylene chloride and yields thieno[3,2-b]thiophene-2-carboxaldehyde (8). This thieno[3,2-b]thiophene-2-carboxaldehyde (8) is then mixed with ethylene glycol, pyridinium tosylate and benzene yielding 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9). This 2-(2-dioxolanyl)thieno[3,2-b]thiophene (9) is then reacted with n-butyllithium after which SO2 is bubbled onto the surface and N-chlorosuccinimide and NH4OH are added separately at the appropriate time. This series of steps yields 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10). This 5-(2-dioxolanyl)thieno[3,2-b]thiophene-2-sulfonamide (10) may then be reacted with p-toluenesulfonic acid monohydrate in acetone to yield 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11). The 5-formylthieno[3,2-b]thiophene-2-sulfonamide (11) is then reacted with an appropriate amine yielding the intermediate iminium salt (12) which may then be reduced with NaBH4 or NaCNBH3 to give the desired 5-substituted thieno[3,2-b]thiophene-2-sulfonamide.
Reaction SMILES: C([O:5][C:6](=[O:27])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([F:26])[CH:20]=2)=[O:18])=[CH:11][CH:10]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[F:26][C:21]1[CH:20]=[C:19]([C:17](=[O:18])[CH:16]=[CH:15][C:12]2[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:27])=[O:5])=[CH:10][CH:11]=2)[CH:24]=[CH:23][C:22]=1[F:25]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C=Cc1ccc(C=CC(=O)c2ccc(F)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 113.6 %

Procedure:
3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid tert-butyl ester (210 mg, 0.56 mmol) was dissolved in DCM (5 ml) and trifluoroacetic acid was added (2 ml). The reaction was stirred at room temperature for 12 h. The solvent was evaporated under vacuo giving 200 mg of 3-{4-[3-(3,4-difluoro-phenyl)-3-oxo-propenyl]-phenyl}-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:17]2[CH:18]=[C:19]([OH:23])[CH:20]=[CH:21][CH:22]=2)=[N:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16].[CH3:24][O:25]C1C=CC=CC=1NC1N=C(C2C=C(O)C=CC=2)C=CC=1[N+]([O-])=O>C(O)(=O)C.[Fe]>[OH:23][C:19]1[CH:18]=[C:17]([C:5]2[N:6]=[C:7]3[N:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[O:15][CH3:16])[C:24](=[O:25])[NH:1][C:2]3=[CH:3][CH:4]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)ccc1N
Reactant: COc1ccccc1Nc1nc(-c2cccc(O)c2)ccc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccccc1-n1c(=O)[nH]c2ccc(-c3cccc(O)c3)nc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
3-(5-Amino-6-(2-methoxyphenylamino)pyridin-2-yl)phenol. 3-(6-(2-Methoxyphenyl-amino)-5-nitropyridin-2-yl)phenol (1.48 g, 4.39 mmol) was dissolved in glacial acetic acid (120 mL). Iron powder (0.489 g, 8.78 mmol) was then added and the solution heated to 80° C. The reaction was monitored via thin layer chromatography for starting material consumption. After 2 h, the solution was cooled and filtered through celite and condensed under reduced pressure. The resultant oil was partitioned between sodium bicarbonate solution and ethyl acetate (3×). The organics were combined, dried over magnesium sulfate, filtered and solvent removed under reduced pressure to afford the title compound (1.15 g, 85%). MS (ESI) m/z 308.4 [M+1]+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:6]=1)=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.[OH-].[K+]>O.O1CCOCC1>[CH3:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:16]1[CH:17]=[CH:18][C:13]([O:12][CH2:11][C:7]2[N:6]=[C:5]([C:3]([OH:2])=[O:4])[CH:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)n1
Reactant: COCc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COCc1ccccc1-c1ccc(OCc2cccc(C(=O)O)n2)cc1
Reaction time: 1 h

Procedure:
A first stock solution was prepared consisting of 6-(4-iodo-phenoxymethyl)-pyridine-2-carboxylic acid methyl ester (of intermediate 5; 1.77 g, 4.8 mmol), bis(tri -cyclohexyl-phosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 168 mg, 0.25 mmol), and dioxane (approximately 100 mL). A second stock solution was prepared consisting of potassium carbonate (1.99 g, 14.4 mmol) and water (approximately 10 mL). The solutions were sonicated and degassed by bubbling nitrogen gas through them. 4 mL of the first stock solution and 0.4 mL of the second stock solution were added to a reaction tube containing 2-methoxymethyl-phenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK; 100 mg, 0.6 mmol). The mixture was heated in a microwave oven at 170 degrees for 25 min, and then 1 M KOH solution (1 equivalent) was added and the reaction mixture was heated in the microwave for 10 minutes at 120 degrees, for 10 minutes at 130 degrees, and at 170 degrees for one hour. The reaction mixture was then filtered through a silica column (1 g) and washed with dimethylacetamide (2×1 mL). The solvent was evaporated to give 6-(2′-methoxymethyl-biphenyl-4-yloxymethyl)-pyridine-2-carboxylic acid. Mass spectrum MH+=350.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([OH:22])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:26][C:27]([O:31][CH3:32])([O:29][CH3:30])[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:26][C:27]([O:31][CH3:32])([O:29][CH3:30])[CH3:28])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(C)(CBr)OC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](O)c2cccc(Cl)c2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(C)(CO[C@@H](c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)OC
Temperature: 80 °C

Procedure:
A mixture of (R)-tert-butyl 3-((R)-(3-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (0.2234 g, 0.68 mmol), 60% NaH (1.460 g, 36.5 mmol), and 1-bromo-2,2-dimethoxypropane (7.760 g, 42.4 mmol) in THF (20 mL) was heated at 80° C. for 3 d and then cooled to rt. The reaction mixture was then quenched with water, extracted with ethyl acetate (3×), and dried over Na2SO4. After the solvent was evaporated under reduced pressure, the crude product (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2,2-dimethoxypropoxy)methyl)piperidine-1-carboxylate was directly used in the next step without further purification.