Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Ge](F)(F)(F)F.ClC(Cl)(Cl)C(Cl)(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-].[Cl:18][C:19]([Cl:25])(Cl)[C:20]([F:23])([F:22])[F:21].[Cl:26][C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29]>C(Cl)(F)(F)C(Cl)(Cl)F>[C:20]([F:23])([F:22])([F:21])[C:19]([Cl:25])([Cl:18])[F:29].[C:28]([F:31])([F:30])([F:29])[C:27]([Cl:26])([F:33])[F:32]
Reactant: FC(F)(F)C(Cl)(Cl)Cl
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: FC(F)(F)C(F)(F)Cl
Agent: F[Ge](F)(F)F
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: FC(F)(F)C(F)(Cl)Cl
Yield: 73 %

Procedure:
In the reactor 101, GeF4 and hexachloroethane in the reaction feed contact the catalyst (e.g., AlCl3) held in the catalyst bed. The reactor 101 can be at a temperature of about 220° to about 375° C. and at a pressure of about 500 to 800 psig (i.e., about 3.45 MPa to about 5.52 MPa). In one embodiment, the inventor has observed that hexachloroethane and GeF4 in the reaction feed can react to form CFC-113 with high yield and good selectivity at a reaction temperature of about 310° C. and a molar ratio of hexachloroethane to GeF4 of about 1:1.67. Other potential fluorination products can include 1,1,1-trichloro-2,2,2-trifluoroethane (CFC-113a), 1,2-dichloro-1,2,2,2-tetrafluoroethane (CFC-114a), 1-chloro-1,1,2,2,2-pentafluoroethane (CFC-115), and/or other fluorine-substituted chloroethanes. In another embodiment, the inventor has observed that hexachloroethane and GeF4 in the reaction feed can react to form CFC-114a (about 73%) and CFC-115 (about 27%) at a reaction temperature of about 340° C. and a molar ratio of hexachloroethane to GeF4 of about 1:2.75.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[C:24]([Br:30])[CH:23]=2)[C:10]=1[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])C.[OH-].[Na+]>C(O)C.CCOC(C)=O>[Br:30][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=1)[O:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:11]1[C:10]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(CO)c2)c1CCC(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 89.2 %

Procedure:
To a solution of 4-[3-[6-(3-Bromo-5-hydroxymethyl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.0 g, 1.68 mmol) in hot ethanol (40 mL) was added aqueous 2.0 N sodium hydroxide (10 mL). The resulting solution was heated to 60° C. and stirred for 4 h. Then, the reaction mixture was cooled down and diluted with EtOAc, washed with 10% aq. HCl and brine. The combined ethyl acetate extracts were dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure to afford 805 mg (89%) of title compound as a light yellow oil. HR-ES(+) calcd for C26H33O7Br [M+Na]+ 559.1302, observed 559.1299.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=2[NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH2:3][CH2:2]1.[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:12][C:10]1[CH:9]=[CH:8][C:7]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])=[C:6]([O:5][CH2:4][CH:1]2[CH2:3][CH2:2]2)[CH:11]=1
Reactant: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1OCC1CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)Nc1ccc(N)cc1OCC1CC1
Yield: 91.4 %

Procedure:
A mixture of N-(2-(cyclopropylmethoxy)-4-nitrophenyl)methanesulfonamide (0.830 g, 2.90 mmol), iron (0.971 g, 17.39 mmol), and NH4Cl (0.099 g, 1.848 mmol) in EtOH (15 ml) and water (6 ml) was heated to reflux for 30 minutes. The hot reaction mixture was filtered and the filtrate was evaporated. The residue was portioned between EtOAc and water; the organic phase was washed with brine and dried over Na2SO4. The solvent was removed affording N-(4-amino-2-(cyclopropylmethoxy)phenyl)-methanesulfonamide (0.679 g, 2.65 mmol, 91% yield, MS/ESI+ 256.9 [MH]+).
Reaction SMILES: [CH3:1][NH:2][S:3](/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH:21]=CCN1C)(=[O:5])=[O:4].[ClH:24]>CN(C=O)C.O.[Pd]=O>[ClH:24].[CH3:1][NH:2][S:3]([CH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:17]1[CH2:22][CH2:21][N:13]([CH3:14])[CH2:12][CH2:11]1)(=[O:4])=[O:5]
Reactant: CNS(=O)(=O)/C=C/c1ccc2[nH]cc(C3CC=CCN3C)c2c1
Agent: O=[Pd]
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CNS(=O)(=O)CCc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Reaction time: 20.5 h

Procedure:
A mixture of (E)-N-methyl-2-[3-(1,2,3,6-tetrahydro-1-methylpyridinyl)-1H-indol-5-yl]-ethenesulphonamide (10 kg) and 10% palladium oxide on charcoal (10 kg, 50% wet paste, added as two charges) in DMF (50L), water (35L) and 2N hydrochloric acid (15.75L) was hydrogenated at atmospheric pressure over 20.5 h. The catalyst was removed by filtration. The filter cake was washed with water (40L). The filtrate was concentrated in vacuo to approximately 30L and cooled to 18°. Ethyl acetate (70L) was added over 1 h and the resulting suspension cooled to 5° and aged for 1 h. The product was collected by filtration, washed with ethyl acetate (20L) and dried in vacuo at 40°-50° overnight (8.87 kg, 79.0% of theory). A portion (0.2 kg) of the solid was recrystallised from hot IMS/water (4:1) (1L) and obtained as fine, off-white crystals (0.143 kg), 71.7% of theory).
Reaction SMILES: [CH2:1]([N:5]([C:8]1[C:13]([CH3:14])=[C:12](Cl)[N:11]=[C:10]([CH3:16])[N:9]=1)[CH2:6][CH3:7])[CH2:2][CH2:3][CH3:4].[CH3:17][C:18]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:19]=1[NH2:20].C(N(C(C)C)CC)(C)C>>[CH2:1]([N:5]([CH2:6][CH3:7])[C:8]1[C:13]([CH3:14])=[C:12]([NH:20][C:19]2[C:21]([CH3:26])=[CH:22][C:23]([CH3:25])=[CH:24][C:18]=2[CH3:17])[N:11]=[C:10]([CH3:16])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CC)c1nc(C)nc(Cl)c1C
Reactant: Cc1cc(C)c(N)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CC)c1nc(C)nc(Nc2c(C)cc(C)cc2C)c1C
Temperature: 220 °C
Yield: 103.1 %

Procedure:
A mixture of butyl-(6-chloro-2,5-dimethyl-pyrimidin-4-yl)-ethylamine (398 mg, 1.65 mmol), 2,4,6-trimethylaniline (4.04 g, 30 mmol) and diisopropyl-ethyl-amine (200 mg, 1.55 mmol) was heated at 210 to 230° C. overnight. The mixture was quenched with water and dilute hydrogen chloride, and extracted with ethyl acetate. The organic layer was neutralized with saturated potassium carbonate, washed with brine, dried and concentrated to give a dark oil. The oil was distilled to give 579 mg of dark oil which was then purified through silica gel column chromatography using 1:1 hexane to chloroform as eluent to give 327 mg of the compound as a yellow solid. 1H NMR (CDCl3) δ 0.92 (t, 3H), 1.14 (t, 3H), 1.2-1.4 (m, 2H), 1.45-1.60 (m, 2H), 1.85 (s, 3H), 2.16 (s, 6H), 2.30 (s, 3H), 2.33 (s, 3H), 3.2-3.4 (m, 4H), 5.8 (brs, 1H), 6.90 (s, 2H) ppm.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:13](CC2C=CC(OC)=CC=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=2)[N:7]=1.[OH:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([NH:36]C(=O)OC(C)(C)C)[CH2:32][CH2:31]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1([C-]2C(C3C=CC=CC=3)=C(C3C=CC=CC=3)C(C3C=CC=CC=3)=C2C2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[Fe+2]>[NH2:36][C@H:33]1[CH2:34][CH2:35][C@H:30]([O:29][C:2]2[CH:3]=[C:4]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:5]3[N:6]([C:8]([C:11]#[N:12])=[CH:9][N:10]=3)[N:7]=2)[CH2:31][CH2:32]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3c(C#N)cnc23)cc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: N#Cc1cnc2c(Nc3ccccc3)cc(O[C@H]3CC[C@H](N)CC3)nn12
Temperature: 105 °C

Procedure:
A mixture of 6-chloro-3-cyano-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (20 mg, 0.05 mmol) from 1b, tert-butyl(trans)-4-hydroxycyclohexylcarbamate (22 mg, 0.1 mmol), palladium(II) acetate (1.1 mg, 0.005 mmol), 1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (7.5, 0.01 mmol) and cesium carbonate (100 mg) was suspended in anhydrous dioxane (1 mL) in a Teflon lined septum capped vial. The vessel was purged with argon and heated at 105° C. for 48 h. LCMS shows that product (m/z, M+1, 569.4) is present (˜25% conversion) along with starting materials. The reaction is cooled and filtered thru a plug of celite and the celite pad rinsed with ˜5 ml of ethyl acetate. The solvents are removed in vacuo and the resulting oil suspended in 1 mL of TFA and heated at 50° C. of 2 h. The reaction showed complete removal of the p-methoxybenzyl protecting group. TFA is removed under a stream of air and the resulting mixture taken up in MeOH (2 mL) and purified by preparative HPLC to yield 2.2 mg of the titled compound as a TFA salt. MS m/e 349 (M+1); 1H NMR (MeOH, δ) 8.1 (1H, s), 7.48 (2H, t, J=8 Hz), 7.39 (2H, d, J=8 Hz), 7.27 (1H, t, J=8 Hz), 6.21 (1H, s), 5.00 1H, m), 3.21 (1H, m), 2.38 (2H, m), 2.15, 2H, m), 1.62 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([OH:17])=O)[CH:7]=[CH:6]2.S(Cl)([Cl:20])=O>CN(C)C=O.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[C:8]([C:15]([Cl:20])=[O:17])[CH:7]=[CH:6]2
Reactant: COc1cc2ccc(C(=O)O)cc2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: COc1cc2ccc(C(=O)Cl)cc2cc1OC

Procedure:
To a solution containing 15.0 g. of 6,7-dimethoxy-2-naphthoic acid and one drop of dimethylformamide in 200 ml. of benzene was added 25 ml. of thionyl chloride. After heating one hour under reflux the mixture was evaporated to dryness in vacuo. Additional benzene was added and evaporation repeated to give 6,7-dimethoxy-2-naphthoyl chloride which was used directly in the preparation of 6,7-dimethoxy-2-naphthamide as described hereinabove in Example 113.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].O=O.[C:8](=[S:10])=[S:9]>C([O-])(=O)C.[Mn+2].C([O-])(=O)C>[CH2:1]([N:3]([CH2:4][CH3:5])[C:8](=[S:10])[S:9][S:9][C:8](=[S:10])[N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[CH3:2]
Reactant: S=C=S
Reactant: CCNCC
Agent: [Mn+2]
Agent: CC(=O)[O-]
Agent: O=O
Product: CCN(CC)C(=S)SSC(=S)N(CC)CC
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
Diethylamine (150 g, 2.05 moles) and manganese acetate catalyst (30 mg, 0.12 mmole) were charged into a 1 liter reactor at room temperature. The reactor was evacuated to 0.6×105 Pa (0.6 bar) and carbon disulfide (87.5 g, 1.15 moles) was dosed in 20 min while increasing the temperature to 60° C. The reactor was pressurized to 3×105 (3 bar) with pure oxygen and the stirring speed was raised to 1400 rpm. Carbon disulfide dosing was started again at a dosing rate of 2 moles per mole oxygen reacted, i.e. 68.5 g (0.90 mole) in 280 min. The reaction was stopped when the oxygen flow fell below 1 ml/min. After removal of the reaction water formed by evaporation, 295 g of tetraethyl thiuram disulfide were obtained (yield: 97.2 wt %) with a purity of 96.7 wt % (as determine d by the H2S titration method).
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1)([O-])=O.C([Br:20])(=O)C>C(O)(=O)C>[Br:20][C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N+:7]([O-:10])=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(-c2ccccn2)c1
Reactant: CC(=O)Br
Solvent: CC(=O)O
Product: [O-][n+]1ccc(Br)cc1-c1ccccn1
Yield: 95 %

Procedure:
To 4-nitro-2,2′-bipyridyl-N-oxide (Wenkert, D.; Woodward, R. B. J. Org. chem. 48,283 (1983)) (5 g) dissolved in 30 mL acetic acid in a 100 ml round bottom flask was added 16 mL acetyl bromide. The yellow mixture was refluxed for 1.5 h and then rotovaporated to dryness. The resulting light yellow solid was sufficiently pure enough for the next step without further purification. Yield: 95%
Reaction SMILES: C([O:8][C@@H:9]([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:10][C@@H:11]([F:20])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C1C=CC=CC=1>[Pd].CO>[F:20][C@H:11]([CH2:10][C@@H:9]([OH:8])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][C:13]([O:15][C:16]([CH3:18])([CH3:19])[CH3:17])=[O:14]
Reactant: CCCC[C@@H](C[C@@H](F)CC(=O)OC(C)(C)C)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCCC[C@H](O)C[C@@H](F)CC(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 64.3 %

Procedure:
In a 200 ml flask were charged 60 ml of methanol, 3.18 g of 10% palladium-on-carbon, and 10.6 g of t-butyl (3R,5S)-5-benzyloxy-3-fluorononanoate obtained in Step 4, and hydrogenolysis was conducted at room temperature for 8 hours. The catalyst was removed by filtration, and the filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography to obtain 5.0 g (64.2%) of the titled compound.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[CH:19][CH:18]=1.[C:33](O)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]>CN(C)C1C=CN=CC=1.ClCCl>[C:33]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:24][C:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:26][CH:27]=2)=[CH:19][CH:18]=1)(=[O:39])/[CH:34]=[CH:35]/[CH2:36][CH2:37][CH3:38]
Reactant: CCCCCc1ccc(-c2ccc(O)cc2)s1
Reactant: CCC/C=C/C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCC/C=C/C(=O)Oc1ccc(-c2ccc(CCCCC)s2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.7 %

Procedure:
Dicyclohexylcarbodiimide (0.2 g) was added to a solution of 2-(4-hydroxyphenyl)-5-pentylthiophene (0.25 g), (E)-hex-2-enoic acid, (0.1 g) 4-(dimethyiamino)pyridine (0.05 g) and dichloromethane (20 cm3) at 0° C. under an atmosphere of nitrogen. The reaction mixture was stirred overnight at room temperature, filtered to remove inorganic material and the filtrate evaporated down. The residue was purified by column chromatography on silica gel using hexane/ethyl acetate (9/1 v/v) as eluent and recrystallisation from hexane to yield 0.17 g of 2-(4-[(E)-hex-2-enoyloxy]phenyl)-5-pentylthiophene, K 47° C., [N 46° C.], I.
Reaction SMILES: [N:1]1([CH2:6][C@H:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[CH2:10][CH2:9][C@H:8]2[C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.B(Br)(Br)Br.[Na]>ClCCl>[OH:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[C@H:7]([CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C@H:8]([C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=1)[CH2:9][CH2:10]2
Reactant: COc1ccc([C@@H]2CCc3cc(OC)ccc3[C@@H]2Cn2ccnc2)cc1
Agent: BrB(Br)Br
Agent: [Na]
Solvent: ClCCl
Product: Oc1ccc([C@@H]2CCc3cc(O)ccc3[C@@H]2Cn2ccnc2)cc1
Reaction time: 48 h

Procedure:
A solution of (1R*,2R*)-1,2,3,4-tetrahydro-1-(1H-imidazol-1-ylmethyl)-6-methoxy-2-(4-methoxyphenyl)naphthalene, (prepared as described in Example 1), in dichloromethane (20 ml) was stirred in an argon atmosphere and cooled in an acetone/solid carbon dioxide bath while a 1M solution of boron tribromide was added dropwise over 5 minutes. The mixture was kept at -20° for 48 h, then poured into a mixture of saturated sodium bicaronate solution (30 ml) and stirred vigorously for 2 h. The solid thus obtained was filtered off, washed with water (100 ml) then dichloromethane (100 ml) and dried in a desiccator under reduced pressure to give (1R*,2R*)-1,2,3,4-tetrahydro-6-hydroxy-2-(4-hydroxyphenyl)-1-(1H-imidazol-1-ylmethyl)naphthalene, m.p. 238°.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([CH2:28][OH:29])[N:19]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:29][CH2:28][C:20]2[N:19]=[CH:18][C:27]3[C:22]([CH:21]=2)=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:5]([C:11]#[N:12])=[C:4]([N:13]2[CH:17]=[CH:16][CH:15]=[N:14]2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-n2cccn2)c1C#N
Reactant: OCc1cc2ccccc2cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: N#Cc1c(OCc2cc3ccccc3cn2)nc(N)nc1-n1cccn1

Procedure:
From 2-amino-4-methanesulfinyl-6-pyrazol-1-yl-pyrimidine-5-carbonitrile, isoquinolin-3-yl-methanol and DBU in DME. ES-MS m/e (%): 366 (M+Na+, 60), 344 (M+H+, 100).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([F:29])[C:6](=[O:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1.[BH4-].[Na+].O.Cl>O1CCCC1.CO.C(OCC)(=O)C>[OH:1][C@@H:2]1[CH2:25][CH2:24][C@@:23]2([CH3:26])[C@H:4]([C@@H:5]([F:29])[C@H:6]([OH:28])[C@@H:7]3[C@@H:22]2[CH2:21][CH2:20][C@@:19]2([CH3:27])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:18])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:3]1
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3C(=O)[C@H](F)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)[C@H](F)[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 38.2 %

Procedure:
A solution of 3α-hydroxy-6α-fluoro-7-keto-5β-cholanoic acid (0.42 g, 1.02 mmoles) in tetrahydrofuran (44 ml) was added with sodium borohydride (0.165 g, 4.36 mmoles) in methanol (11 ml) and the resulting mixture was left to react for one hour under magnetic stirring. Then the reaction mixture was diluted with ethyl acetate (20 ml), added with water (20 ml) and acidified with 10% hydrochloric acid (10 ml). The organic phase was separated, the aqueous phase was extracted with methylene chloride (3×20 ml); the combined organic phases were washed with brine (1×30 ml) and dried over sodium sulfate. After evaporating the solvent, the residue (0.42 g) was subjected to flash chromatography on silica, eluting with methylene chloride/methanol 98:2, to obtain 0.03 g of the starting product and 0.16 g of the title product (41%), the structure of which was confirmed by 1H-NMR, 13C-NMR, 19F-NMR and mass spectroscopies. mp 198-201° C.; IR (CHCl3) 1725 (C=O); 1H-NMR (200 MHz, CDCl3 +CD3OD) 0.7 (s, 3H, 18-CH3), 0.9-0.95 (m, 6H, 19-CH3, 21-CH3), 3.38 (m, 1H, 6-H), 3.7 (m, 2H, 3H, 7-H); 13C-NMR (200 MHz, CDCl3 +CD3OD) 75.43 C3, 79.199 C7, 95.45 C6. 176.24 (--COOH); 19F-NMR(CDCl3 +CD3OD) inner standard C6F6, φ-5.4; m/z 391 (9.18%), 390 (34.28%), 354.4 (2.64%). C24H39OF4.
Reaction SMILES: C([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])(C)(C)C.Br[C:21]1[CH:22]=[C:23]([S:27]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)(=[O:29])=[O:28])[CH:24]=[N:25][CH:26]=1>>[C:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:19])=[C:10]([C:17]#[C:18][C:21]2[CH:26]=[N:25][CH:24]=[C:23]([S:27]([N:30]3[CH2:31][CH2:32][O:33][CH2:34][CH2:35]3)(=[O:29])=[O:28])[CH:22]=2)[CH:11]=1)#[N:16]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: O=S(=O)(c1cncc(Br)c1)N1CCOCC1
Product: N#Cc1ccc(OCC(=O)O)c(C#Cc2cncc(S(=O)(=O)N3CCOCC3)c2)c1

Procedure:
Following the general method as outlined in Example 35, starting from tert-butyl(4-cyano-2-ethynyl phenoxy)acetate (Intermediate 46) and 4-[(5-bromopyridin-3-yl)sulfonyl]morpholine (Apollo), the title compound was obtained as an off-white solid.
Reaction SMILES: [CH2:1]([O:6][C:7](=[O:20])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH2:16][C:17]#[C:18][CH3:19])=[O:13])CC#CC.O(CC)CC>C1(C)C=CC=CC=1>[O:6]1[CH2:1][CH2:19][C:18]#[C:17][CH2:16][CH2:15][O:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:20]
Reactant: CC#CCCOC(=O)CCCCC(=O)OCCC#CC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: O=C1CCCCC(=O)OCCC#CCCO1
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.9 %

Procedure:
In a dry 100 mL Schlenk-tube, which has been flooded with argon, adipic acid dipent-3-inyl ester (135 mg, 485 μmol), complex 23a.OEt2 (10.5 mg, 9.67 μmol, 2 mol %) and molecular sieve (970 mg, 5 Å, powder) were suspended in 24.2 mL of toluene. The reaction solution was stirred for 24 h at room temperature, was filtered for the processing over a short silica gel column, the filtrate was concentrated and the residue was purified by means of column chromatography (SiO2, hexane/EtOAc, 20:1). One obtains 1,8-dioxacyclotetradec-11-in-2,7-dione (100 mg, 92%) as colorless solid. M.p.=109-110° C.; 1H NMR (400 MHz, CD2Cl2): δ=4.13-4.06 (m, 4H), 2.53-2.47 (m, 4H), 2.39-2.30 (m, 4H), 1.76-1.67 (m, 4H); 13C NMR (100 MHz, CD2Cl2): δ=173.2 (2×C), 78.2 (2×C), 62.8 (2×CH2), 35.2 (2×CH2), 25.4 (2×CH2), 19.4 (2×CH2); IR (film): v=2995, 2954, 2937, 2918, 2901, 2872, 1721, 1458, 1425, 1384, 1341, 1272, 1236, 1167, 1140, 1080, 1065, 1021, 981, 931, 843, 124, 699 cm−1; MS (EI) m/z (%): 129 (3), 111 (8), 78 (100), 66 (20), 55 (15), 41 (8); HRMS (ESI): m/z: calculated for C12H16O4+Na: 247.0941; found: 247.0938.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C(NCC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:45](#[N:51])[CH2:46][CH2:47][CH2:48][C:49]#[CH:50]>CN(C=O)C.[Cu]I>[C:45]([CH2:46][CH2:47][CH2:48][C:49]#[C:50][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([OH:17])=[C:14]([C:18]#[N:19])[C:13](=[O:20])[NH:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1)#[N:51]
Reactant: C#CCCCC#N
Reactant: N#Cc1c(O)c2c(-c3ccc(I)cc3)csc2[nH]c1=O
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: N#CCCCC#Cc1ccc(-c2csc3[nH]c(=O)c(C#N)c(O)c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4-iodo-phenyl)-4-hydroxy-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (60 mg, 0.15 mmol) in 1.5 mL DMF was added diethylamine (0.16 mL, 1.5 mmol), followed by copper(I) iodide (trace), Pd(PPh3)Cl2 (3.5 mg, 0.005 mmol), and triphenylphosphine (12 mg, 0.04 mmol). The resulting mixture was stirred at rt for 5 min, after which hex-5-ynenitrile (50 μL, 0.5 mmol) was added. The reaction was then heated to 90° C. using microwave reactor for 20 min, filtered, concentrated and purified by reverse phase HPLC to give the titled compound. MS (ESI) m/e 358 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.82–1.91 (m, 2H), 2.56 (t, J=7.12 Hz, 2H), 2.65 (t, J=7.12 Hz, 2H), 6.67 (s, 1H), 7.31 (d, J=8.48 Hz, 2H) 7.43 (d, J=8.48, 2H), 10.80 (s, 1H).
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][OH:10])[N:6]=[C:5]([CH2:11][OH:12])[N:4]=1.N1C=CC=CC=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.O>C(Cl)Cl>[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25]([CH2:2][C:3]2[N:8]=[C:7]([CH2:9][OH:10])[N:6]=[C:5]([CH2:11][OH:12])[N:4]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCc1nc(CO)nc(CO)n1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cc2nc(CO)nc(CO)n2)cc1
Reaction time: 8 h

Procedure:
2,4,6-Trihydroxymethyl-s-triazine (1 eq.) is dissolved in an excess of pyridine. p-Toluenesulfonylchloride (0.6 eq.) in CH2Cl2 is added and the reaction mixture is stirred overnight. The solvent volume is reduced to a slurry to which water and dichloromethane are added and the resulting mixture is extracted with CH2Cl2. The combined CH2Cl2 layers are dried (MgSO4) and concentrated to an oil. The oil is purified by silica gel flash column chromatography to give the title compound.