Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[N:14]1([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O1CCOCC1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:17]1[CH2:18][CH2:19][N:14]([C:20]([C:22]2[CH:23]=[C:24]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27](=[O:32])[CH2:26][CH2:25]3)=[O:21])[CH2:15][CH2:16]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC

Procedure:
1.8 Grams of 3,4-dimethoxybenzoic acid and 2.75 g of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were added to a mixed solvent of 20 ml of dioxane with 20 ml of methylene chloride. Under the condition that the outside of reaction vessel was ince-cooled with stirring, a solution of 2.1 g of N,N-dicyclohexylcarbodiimide being dissolved in 5 ml of methylene chloride by keeping its temperature to 10°-20° C. was added dropwise thereto and stirred at the same temperature for 3.5 hours. The crystals formed in the reaction mixture were removed by filtration, and the mother liquor was concentrated under a reduced pressure. The residue thus obtained was dissolved in 100 ml of methylene chloride and the organic layer was washed with 5%-hydrochloric acid aqueous solution, 5%-sodium hydrogen-carbonate aqueous solution and water in this order, then the organic layer was dried with anhydrous sodium sulfate. The solvent was removed by distillation under a reduced pressure and the residue thus obtained was recrystallized from chloroform-ethanol to obtain 0.9 g of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=[O:12])[CH:2]=1.[BH4-].[Na+]>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][OH:12])[CH:2]=1
Reactant: O=Cc1cnc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.8 %

Procedure:
To a solution of 3.14 g (20 mmol) of 3-quinolinecarboxaldehyde in 60 mL of methanol was added portionwise 0.95 g (25 mmol) of sodium borohydride at 0° C. The reaction mixture was then stirred at room temperature for 2 hours. Excess sodium borohydride was quenched with acetic acid and the reaction mixture was evaporated in vacuo. The residue was dissolved in dilute aqueous sodium bicarbonate and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated in vacuo to give an oil. The oil was chromatographed on silica gel, using first 3:2 chloroform/ethyl acetate and then ethyl acetate as eluents, to afford 2.35 g (79.5%) of the title compound of the structural formula ##STR82## The product was characterized as follows: TLC Rf =0.30 (ethyl acetate); IR (neat) ν 3120, 1580, 1500, 1060 cm-1 ; NMR (CDCl3) δ 8.73 (1H, d, J=2 Hz), 8.07 (1H, s), 8.02 (1H, d, J=7 Hz), 7.8-7.3 (3H, m), 4.82 (2H, s).
Reaction SMILES: [CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)([CH3:3])[CH3:2].Br[C:20]1[S:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.O.CO>[CH:1]([Si:4]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[N:5]1[CH:9]=[CH:8][C:7]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)=[CH:6]1)([CH3:3])[CH3:2]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: c1ccccc1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(-c2nccs2)c1
Temperature: 90 °C

Procedure:
A solution of 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acid (0.274 g, 0.46 mmol, based on presumed 45% yield of previous step), 2-bromo-1,3-thiazole (0.206 g, 1.2 mmol), potassium carbonate (0.1736, 1.2 mmol), tetrakis(triphenlyphosphine)palladium(0) (0.040 g, 0.035 mmol) in mixed solvent of benzene/water/methanol (10 mL/1 mL/1 mL), was degassed for 5 minutes, then refluxed at 90° C. for overnight. The reaction mixture was quenched with H2O (30 mL), then extracted with EtOAc (3×30 mL) and the combined organic extracts washed with brine. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude purified by liquid chromatography on silica gel using an ISCO single channel system (Hexane/EtOAc=9/1 to 1/9) to afford 2-[1-(triisopropylsilyl)-1H-pyrrol-3-yl]-1,3-thiazole as a yellow oil.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[C:7]([NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[N+]([C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([C:26]#[N:27])[C:24]=1[C:31]#[N:32])([O-])=O>CS(C)=O.CC#N.C1C=CC=CC=1>[C:31](#[N:32])[C:24]1[C:25](=[CH:28][CH:29]=[CH:30][CH:23]=1)[C:26]#[N:27].[C:31](#[N:32])[C:24]1[C:25](=[CH:28][CH:29]=[CH:30][CH:23]=1)[C:26]#[N:27].[C:7]([NH:14][CH:15]([CH2:16][OH:17])[CH2:18][OH:19])([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: CC(C)(C)OC(=O)NC(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Solvent: c1ccccc1
Product: N#Cc1ccccc1C#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Finely ground K2CO3 (4.32 g, 31.2 mmol, 4 equiv.) was added to N-Boc-serinol (1.45 g, 7.8 mmol, 1 equiv.) in 20 mL DMSO under argon; then 3-nitrophthalonitrile (3.38 g, 19.5 mmol, 2.5 equiv.) was added. The reaction mixture first turned pink, and then orange upon addition of the 3-nitrophthalonitrile. The reaction mixture was stirred at room temperature and monitored periodically by TLC (9:1 benzene:CH3CN). After 72 h, the reaction mixture was partitioned between EtOAc and water. The two layers were separated, and the aqueous layer was extracted 3 times with 50 mL EtOAc. The organic layer from the original partitioning was added to the organic extract. This mixture was then washed twice with 50 mL of saturated NaHCO3, and twice with 50 mL of water, and was then dried over Na2SO4. The solvent was removed at reduced pressure, and the resulting crude orange solid was recrystallized from methanol/water to give 2.43 g (70% yield) of a slightly pink/tan solid. [Rf: 0.25 (9:1 benzene:CH3CN); melting point 167-169° C.; 1H NMR (200 MHz, CD3CN) δ 7.85-7.4 (m, 6H, ArH), 5.76 (br s, 1H, NH), 4.39 (s, 5H, (—CH2)2CH—), 1.42 (s, 9H, C(CH3)3).]
Reaction SMILES: S(Cl)(Cl)=O.C(OC(OCC)CN)C.S(=O)(=O)(O)O.[N+]([C:22]1[CH:29]=[CH:28][CH:27]=[C:24]([C:25]#[N:26])[C:23]=1[C:30]#[N:31])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O.[Zn].CC(N(C)C)=O.C(O)C.C(OCC)(=O)C.C(#N)C.C1(C)C=CC=CC=1>[C:30](#[N:31])[C:23]1[C:24](=[CH:27][CH:28]=[CH:29][CH:22]=1)[C:25]#[N:26]
Reactant: N#Cc1cccc([N+](=O)[O-])c1C#N
Agent: CCOC(CN)OCC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: O=S(Cl)Cl
Solvent: CC(=O)N(C)C
Solvent: CC#N
Product: N#Cc1ccccc1C#N

Procedure:
Toluene (100 ml) and dimethylacetamide (0.25 mol) were added to Compound B (17.5 g, 0.114 mol), and then to the resultant mixture was added dropwise thionyl chloride (25 ml) under reflux over 10 minutes. The mixture was refluxed under heating for additional 1 hour, and then concentrated under reduced pressure, to thereby obtain a viscous liquid. Separately, dimethylacetamide (10 ml) and acetonitrile (100 ml) were added to diethoxyethylamine (38.0 g, 0.235 mol), and to the resultant mixture the aforesaid viscous liquid was added dropwise over 15 minutes under stirring at 10° C. to 15° C. The mixture was stirred for additional 30 minutes, and was poured into water (100 ml) and ethyl acetate (100 ml), to thereby separate the ethyl acetate layer. The ethyl acetate layer was washed twice with water (100 ml). The ethyl acetate layer was dried with magnesium sulfate, and ethyl acetate was distilled off under reduced pressure, to thereby obtain a pale yellow viscous liquid of C. To this pale yellow viscous liquid of C, were added water (50 ml), ethanol (200 ml), and zinc powder (12 g), and to the resultant mixture was added, dropwise, a solution containing sulfuric acid (10 ml) diluted with water (40 ml) under reflux by heating, over 20 minutes. The mixture was stirred under heating for additional 30 minutes, and then cooled, and an insoluble substance was separated through filtration. To the thus-obtained solution, were added a saturated brine (50 ml) and ethyl acetate (100 ml), to thereby separate the ethyl acetate layer. The ethyl acetate layer was washed twice with water (100 ml). The ethyl acetate layer was dried with magnesium sulfate, and then the ethyl acetate was distilled off under reduced pressure, to thereby obtain a pale yellow viscous liquid of D. Separately, 3-nitrophthalonitrile (19.7 g, 0.113 mol), dimethylacetamide (70 ml), and potassium carbonate (15 g, 0.108 mol) were stirred at 20° C. to 25° C. under a stream of nitrogen, and to the resultant mixture was added the aforesaid pale yellow viscous liquid of D over 10 minutes. The mixture was stirred for additional 30 minute, and was then poured into water (300 ml) under stirring. The thus-precipitated crystals were filtered, and sufficiently washed with water. The thus-obtained crystals were recrystallized from methanol (70 ml). The precipitated crystals were filtered, washed with cold methanol (30 ml), and dried, to thereby obtain white crystals of Phthalonitrile compound 140 (35.0 g, yield 72.6%).
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[CH:10][CH:9]=1
Reactant: Ic1cccs1
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(-c2cccs2)cc1
Yield: 86.1 %

Procedure:
2-iodothiophene (1.05 g, 5 mmol) was dissolved in 6 mL of mixed solution (dimethyl ether and water, v:v=2:1), followed by addition of 4-fluorophenylboronic acid 9a (700 mg, 5 mmol), potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenyl phosphine)palladium (173 mg, 0.15 mmol). The mixture was microwaved for 30 minutes at 100° C. Thereafter, the reaction mixture was extracted with ethyl acetate (20 mL×3) after 10 mL water were added. The organic extract was washed with saturated sodium chloride solution (20 mL) and combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system C to obtain the title compound 2-(4-fluorophenyl)thiophene 9b (767 mg, white solid), yield: 86.1%.
Reaction SMILES: [C:1]1([CH3:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(B(O)O)C=CC=CC=1.ClC1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][N:25]=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.O>[N+:30]([C:27]1[CH:28]=[CH:29][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:25][CH:26]=1)([O-:32])=[O:31]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
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: OB(O)c1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Yield: 66 %

Procedure:
A mixture of toluene (15 mL) and water (5 mL) was degassed with argon for 5 minutes. Sodium carbonate (0.802 g, 0.00454 mole) was then added and the mixture was degassed with argon for 5 minutes. Phenylboronic acid (0.587 g, 0.00454 mole) and 2-chloro-5-nitro-pyridine (0.6 g, 0.0037 8 mole) were then added and the resulting mixture was degassed with argon for 5 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.878 g, 0.00076 mole) was added and the mixture was degassed with argon for 5 minutes. The resulting mixture was then heated to reflux for 3 hours. The mixture was diluted with ethyl acetate, and the organic layer was washed with water followed by brine solution. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by column chromatography using silica gel 60-120 mesh (5% ethyl acetate in hexane) afforded 0.5 g (66%) of 5-nitro-2-phenyl-pyridine. LCMS purity: 201 (M+1)+, 98.2%, 1H NMR (DMSO-d6): δ 9.5 (s, 1H), 8.55 (dd, 1H), 8.1 (m, 2H), 7.9 (d, 1H), 7.55 (m, 3H). To a stirred solution of 5-nitro-2-phenyl-pyridine (0.5 g, 0.0025 mole) in THF (10 mL) was added ammonium chloride (1.1 g, 0.020 mole) dissolved in water (15 mL). Methanol (5 mL) was then added, resulting in a clear solution. Zinc powder (1.3 g, 0.020 mole) was then added portionwise and the resulting mixture was stirred for 1 hour. The mixture was filtered through a bed of celite and the filtrate was concentrated under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over Na2SO4, and evaporated under reduced pressure to afford 0.35 g (82%) of 6-phenyl-pyridin-3-ylamine. LCMS purity: 171.08 (M+1)+, 87.9%, 1H NMR (DMSO-d6): δ 8.12 (d, 1H), 8.0 (d, 2H), 7.72 (d, 1H), 7.48 (t, 2H), 7.36 (t, 1H), 7.1 (dd, 1H), 5.6 (s, 2).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[NH:3].[CH3:5][C:6]1[CH:15]=[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:12][C:7]=1[C:8](OC)=[O:9].O>CO>[NH2:3][C:2]([NH2:4])=[N:1][C:8](=[O:9])[C:7]1[CH:12]=[C:13]([S:21]([CH3:24])(=[O:23])=[O:22])[C:14]([N:16]2[CH:20]=[CH:19][CH:18]=[CH:17]2)=[CH:15][C:6]=1[CH3:5]
Reactant: COC(=O)c1cc(S(C)(=O)=O)c(-n2cccc2)cc1C
Reactant: N=C(N)N
Solvent: CO
Solvent: O
Product: Cc1cc(-n2cccc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Yield: 66 %

Procedure:
A solution of 694 g of guanidine and 310 g of methyl 2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzoate in 3 l of methanol is stirred for 3 h at 50°. Then, water is added to the reaction mixture, and the crude product which forms as a result is filtered off and recrystallized from methanol. This gives N-diaminomethylene-2-methyl-4-(1-pyrrolyl)-5-methylsulfonylbenzamide in a yield of 66%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](I)[O:9][C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].[NH2:31][C:32]1[C:33]([CH3:38])=[CH:34][CH:35]=[CH:36][CH:37]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:33]1([CH3:38])[C:32]([NH:31][C:8]2[O:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]4)=[CH:13][CH:12]=3)=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:7]=2)=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cc1ccccc1N
Reactant: CCOC(=O)c1nc(I)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1nc(Nc2ccccc2C)oc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 150 °C
Yield: 54.5 %

Procedure:
A mixture of tert-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1-carboxylate (0.06 g, 0.11 mmol), o-toluidine (0.061 m, 0.57 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.005 g, 0.005 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (0.011 g, 0.02 mmol) and potassium carbonate (0.063 g, 0.46 mmol) in DMF (1.5 ml) was degassed and heated in the microwave at 150° C. for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water (×2). The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 10-90% EtOAc in hexane as gradient to afford tert-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.030 g, 0.06 mmol, 52%). LCMS (1) Rt: 2.63 min; m/z (ES+) 507.
Reaction SMILES: [CH2:1]([C:5]12[CH2:12][S:11][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])([S:9][CH2:10]1)[O:7][CH2:6]2)[CH2:2][CH2:3]C.C(C12CSC(CCCCC#C)(SC1)OC2)(C)(C)C.C(C12CSC(CCCCC#C)(SC1)OC2)C(C)C.C(C12SCC(C3C=CC=CC=3)(CS1)CO2)CCCC#C.C1(CC23CSC(CCCCC#C)(SC2)OC3)CC1.C(C(CO)(CS)CS)CCC.C(C(CO)(CS)CS)(C)(C)C.C(C(CO)(CS)CS)C(C)C.OCC(C1C=CC=CC=1)(CS)CS.C1(CC(CO)(CS)CS)CC1>>[CH2:13]([C:8]12[S:9][CH2:10][C:5]([CH2:1][CH2:2][CH3:3])([CH2:12][S:11]1)[CH2:6][O:7]2)[CH2:14][CH2:15][CH2:16][C:17]#[CH:18]
Reactant: C#CCCCCC12OCC(CCCC)(CS1)CS2
Agent: C#CCCCCC12OCC(C(C)(C)C)(CS1)CS2
Agent: C#CCCCCC12OCC(CC(C)C)(CS1)CS2
Agent: C#CCCCCC12OCC(CC3CC3)(CS1)CS2
Product: C#CCCCCC12OCC(CCC)(CS1)CS2

Procedure:
In an analogous manner 4-n-butyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane, 4-t-butyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane, 4-i-butyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane, 1-(hex-5-ynyl)-4-phenyl-2-oxa-6,7-dithiabicyclo[2.2.2]octane and 4-cyclopropylmethyl-1-(hex-5-ynyl)-2-oxa-6,7-dithiabicyclo[2.2.2]octane were prepared from trimethyl orthohept-6-ynoate and 2-n-butyl-2-hydroxymethylpropan-1,3-dithiol, 2-t-butyl-2-hydroxymethylpropan-1,3-dithiol, 2-i-butyl-2-hydroxymethylpropan-1,3-dithiol, 2-hydroxymethyl-2-phenylpropan-1,3-dithiol and 2-cyclopropylmethyl-2-hydroxymethylpropan-1,3-dithiol respectively.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1>C(O)C>[OH:10][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Solvent: CCO
Product: O=Cc1cccc(CO)c1

Procedure:
To a solution of isophtalaldehyde (8 g) in ethanol (80 mL) at room temperature was added NaBH portion wise, until about 50% reaction by TLC. The reaction mixture was quenched with 25% ammonium acetate, extracted with ethyl acetate, which was washed with brine (2x), dried over sodium sulfate, filtered and evaporated to dryness. Purification of the residue by flash chromatography using 50% ether in hexane afforded the pure title compound.
Reaction SMILES: [CH:1](=[O:10])[C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=1.CCO.[BH4-].[Na+].CCOC(C)=O>C1COCC1>[OH:10][CH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=Cc1cccc(CO)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
Isophthalaldehyde (150 g, 1.1 mole) was dissolved in THF (1 L) and EtOH (1 L) at 0° C. NaBH4 (11.0 g, 291 mmol) was added portionwise and the mixture stirred 1 hour at 0° C. Addition of 25% aq. NH4OAc and extraction with EtOAc (2×) followed by purification by flash chromatography (20% to 40% EtOAc in hexanes) yielded 60 g of 3-(hydroxymethyl)benzaldehyde.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:3]=1.N1C=CC=C(CC(O)=O)C=1>>[NH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][C:9]([OH:11])=[O:10])[CH2:3]1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Product: O=C(O)CC1CCCNC1
Yield: 80.5 %

Procedure:
3-Pyridylacetic acid hydrochloride (13 grams) (74.9 mmoles) was hydrogenated as described in Preparative Example 15 to give a mixture of unreacted 3-pyridylacetic acid and the title compound (76:24) (8.63 grams, MH+ 144).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH2:10][CH2:11][CH2:12][CH2:13][OH:14]>O>[OH:14][CH2:13][CH2:12][CH2:11][NH:10][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: N#Cc1ccc(F)cc1
Solvent: O
Product: N#Cc1ccc(NCCCO)cc1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
A mixture of 4-fluorobenzonitrile (12.0 g, 99.1 mmol) and 3-amino-1-propanol (59.6 g, 793 mmol) was stirred at 80° C. under an inert atmosphere for 3 hours before water (150 mL) was added. The mixture was allowed to cool to rt, and was then extracted with diethyl ether. The organic layer was separated, dried (Na2SO4), filtered and concentrated in vacuo to yield 17 g (97%) of the title compound as an oil that crystallised upon standing.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].OS(O)(=O)=O.[CH3:17]O>>[OH:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:17])=[O:6]
Reactant: Cc1c(O)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(O)c1C
Yield: 65.6 %

Procedure:
A solution of 17.98 g (0.118 mol) of 3-hydroxy-2-methylbenzoic acid in 200 mL of MeOH was treated with 2.0 mL of conc. H2SO4 and heated at reflux overnight. The solution was concentrated under reduced pressure and diluted with H2O. The product was collected and recrystallized from MeOH/H2O to give 12.85 g (65.6% yield) of a tan solid, mp 74-75° C. The structure was confirmed by NMR and mass spectroscopy. MS m/z 167 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:17])([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:6][CH:5]=1)([O-])=O.C([O-])=O.[K+]>CCO.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]([CH3:16])([CH3:17])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(C)(C)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(C)(C)c1ccc(N)cc1
Temperature: 45 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
A solution of ethyl 2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 3.8 mmol) in EtOH (10 mL) was treated with 10% Pd—C (80 mg) and heated to 45° C. A solution of potassium formate (4.10 g, 48.8 mmol) in H2O (11 mL) was added over a period of 15 min. The reaction mixture was stirred at 65° C. for 2 h and then treated with additional 300 mg of Pd/C. The reaction was stirred for 1.5 h and then filtered through Celite. The solvent volume was reduced by approximately 50% under reduced pressure and extracted with EtOAc. The organic layers were dried over Na2SO4 and the solvent was removed under reduced pressure to yield ethyl 2-(4-aminophenyl)-2-methylpropanoate (G-1) (670 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 7.14 (d, J=8.5 Hz, 2H), 6.65 (d, J=8.6 Hz, 2H), 4.10 (q, J=7.1 Hz, 2H), 1.53 (s, 6H), 1.18 (t, J=7.1 Hz, 3H).
Reaction SMILES: C([O-])(=O)C1C=CC=CC=1.[CH3:10][C:11]1([CH3:41])[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[C:17]2[CH:16]=[C:15]([C:28]#[C:29][C:30]3[CH:40]=[CH:39][C:33]([C:34]([O:36]CC)=[O:35])=[CH:32][CH:31]=3)[CH:14]=[CH:13][C:12]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:10][C:11]1([CH3:41])[CH2:20][CH:19]=[C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=2)[C:17]2[CH:16]=[C:15]([C:28]#[C:29][C:30]3[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:39][CH:40]=3)[CH:14]=[CH:13][C:12]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cccc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: O=C([O-])c1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cccc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-1(5,6-dihydro-5,5-dimethyl-8-(3-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 2) 30.0 mg (0.071 mmol) in 3 ml of EtOH and 2 ml of THF was added 28.0 mg (0.70 mmol, 0.7 ml) of NaOH (1.0 M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.5 Hz), 7.59 (2H, d, J=8.5 Hz), 7.46 (2H, s), 7.32-7.13 (4H, m), 7.10 (1H, s), 6.98 (1H, t, J=4.5 Hz), 2.34 (3H, s), 2.31 (2H, d, J=4.5 Hz), 1.30 (6H, s).