Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3(O)[CH2:25][CH2:24][C:23]([N:32]([CH3:34])[CH3:33])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:22][CH2:21]3)=[CH:19][C:14]=2[O:13][CH2:12]1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C.[OH-].[Na+]>ClCCl.O=O>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]3([C:3]4[NH:4][C:5]5[C:10]([C:2]=4[CH3:1])=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH2:21][CH2:22][C:23]([N:32]([CH3:34])[CH3:33])([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:24][CH2:25]3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: CN(C)C1(c2ccccc2)CCC(O)(c2ccc3c(c2)OCO3)CC1
Reactant: Cc1c[nH]c2ccccc12
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C2(c3ccc4c(c3)OCO4)CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-methyl-1H-indole (393 mg, 3 mmol) and the more polar 1-(benzo[d][1,3]dioxol-5-yl)-4-(dimethylamino)-4-phenylcyclohexanol (679 mg, 2 mmol) were dissolved in absolute dichloromethane (50 ml) with the exclusion of oxygen, mixed with trifluoromethane sulphonic acid trimethylsilyl ester (581 μl, 3 mmol) and stirred for 16 h at room temperature. For work up the batch was mixed with 5N NaOH (50 ml) and stirred for 1 h at room temperature. The aqueous phase was separated and extracted with dichloromethane (3×25 ml). The combined organic phases were dried over Na2SO4 and then concentrated to low volume. A raw product was isolated that was purified by chromatography [silica gel 60 (50 g); ethyl acetate (1000 ml)]. The product was obtained as a white solid with a yield of 545 mg (60%) and a melting point of 235-238° C. This concerned one of two possible diastereoisomers.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[B-](F)(F)(F)[CH:11]=[CH2:12].[K+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([CH:11]=[CH2:12])[N:3]=[C:4]([CH3:9])[N:5]=1
Reactant: C=C[B-](F)(F)F
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Product: C=Cc1cc(Cl)nc(C)n1
Temperature: 100 °C

Procedure:
In the reaction vessel 4,6-dichloro-2-methylpyrimidine (26.3 g, 161 mmol, 1.0 eq), potassium trifluoro(vinyl)borate (0.905 g, 4.03 mmol) cesium carbonate (97 g, 299 mmol, 2.0 eq) and butyldi-1-adamantylphosphine (2.89 g, 8.06 mmol 0.054 eq) were combined. This mixture was then evacuated and backfilled with nitrogen (3 times). Toluene (452 ml) and water (45 mL) were added to this flask. This mixture was purged with nitrogen for 20 min, then palladium acetate (0.905 g, 4.03 mmol, 0.027 eq) was added. Continue purged for 10 min, then heated at 100° C. for 2 h. The mixture was cooled, diluted with EtOAc (200 mL), washed with water (×200 mL), dried, filtered and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes) to give 4-chloro-2-methyl-6-vinylpyrimidine (4-1) as a white solid.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=1.[F:19][C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:36]=[N:37][C:38]([NH2:41])=[N:39][CH:40]=1>>[F:19][C:20]1[CH:25]=[C:24]([C:2]2[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=2[O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=2)[CH:23]=[CH:22][C:21]=1[C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[N:37][CH:36]=1
Reactant: FC(F)(F)c1nccc(Oc2ccccc2Br)n1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ccnc(C(F)(F)F)n3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 4-(2-bromophenoxy)-2-(trifluoromethyl)pyrimidine and 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine. MS (ESI): mass calcd. for C21H13F4N5O, 427.11; m/z found, 428.1 [M+H]+. 1H NMR (500 MHz, DMSO-d6) δ 8.78 (d, J=5.7, 1H), 8.37 (m, 2H), 7.57 (dd, J=7.5, 1.8, 1H), 7.48 (m, 3H), 7.39 (dd, J=8.0, 1.3, 1H), 7.33-7.22 (m, 3H), 6.85 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH2:17][CH2:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)[C:7]=1[CH2:8][CH3:9])[CH3:2].BrBr>C(O)(=O)C>[CH2:1]([C:3]1[N:4]=[CH:5][N:6]([C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:17]=[CH:18][C:19](=[O:22])[NH:20][N:21]=3)=[CH:12][CH:11]=2)[C:7]=1[CH2:8][CH3:9])[CH3:2]
Reactant: CCc1ncn(-c2ccc(C3=NNC(=O)CC3)cc2)c1CC
Agent: BrBr
Solvent: CC(=O)O
Product: CCc1ncn(-c2ccc(-c3ccc(=O)[nH]n3)cc2)c1CC

Procedure:
Similarly, reaction of 4,5-dihydro-6-[4-(4,5-diethyl-1H-imidazol-1-yl)phenyl]-3(2H)-pyridazinone with bromine in acetic acid as described in this Example gives 6-[4-(4,5-diethyl-1H-imidazol-1-yl)phenyl)-3(2H)-pyridazinone (13g).
Reaction SMILES: C1(NC2CCCCC2)CCCCC1.[C:14]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].S(Cl)([Cl:29])=O>ClCCl.C(OCC)C>[C:14]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([Cl:29])=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1
Temperature: 25 °C

Procedure:
1.1 ml (5.6 mmol) of dicyclohexylamine are added to 1 g (5.6 mmol) of 4-acetoxybenzoic acid placed in 10 ml of dichloromethane, and the solution is stirred at room temperature for minutes. 400 μl (5.6 mmol) of thionyl chloride are added and this mixture is stirred at room temperature for 2 hours. The reaction medium is diluted with ethyl ether. The precipitate is filtered off and rinsed with ethyl ether. Concentration of the filtrate gives the 4-acetoxybenzoyl chloride.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.[H][H]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([N:22]3[CH2:27][CH2:26][C@:25]([CH2:34][C:35]([OH:38])([CH3:37])[CH3:36])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:24][C:23]3=[O:39])[CH3:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: [H][H]
Reactant: C[C@@H](c1ccc(C2=CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: [Pd]
Solvent: CO
Product: C[C@@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
A mixture of 4-(4-{(S)-1-[(S)-6-(2-hydroxy-2-methyl-propyl)-2-oxo-6-phenyl-[1,3]oxazinan-3-yl]ethyl}-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (0.34 g) and 10% palladium on carbon (60 mg) in methanol (10 mL) was shaken in hydrogen atmosphere (50 psi) for 4 h. Then, the catalyst was separated by filtration and the filtrate was concentrated to yield the title compound.
Reaction SMILES: CN(C)[C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][NH:14][C@@H:15]([CH3:25])[C@H:16]([OH:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:8][C:7]=1[N:26]([CH3:28])[CH3:27].Cl.[OH-:32].[Na+]>>[CH3:28][N:26]([CH3:27])[C:7]1[CH:8]=[C:9]([CH2:12][CH2:13][NH:14][C@@H:15]([CH3:25])[C@H:16]([OH:24])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:10]=[CH:11][C:6]=1[O:5][CH2:4][C:3]([OH:29])=[O:32]
Reactant: C[C@H](NCCc1ccc(OCC(=O)N(C)C)c(N(C)C)c1)[C@H](O)c1ccc(O)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Product: C[C@H](NCCc1ccc(OCC(=O)O)c(N(C)C)c1)[C@H](O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
N,N-Dimethyl-2-[2-dimethylamino-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetamide (503 mg) was dissolved in 1N aqueous sodium hydroxide solution (6.0 ml), and the solution was stirred for 20 hours at room temperature. 1N Hydrochloric acid (6.0 ml) was added to the stirred reaction mixture under ice-cooling, and direct purification of the resulting mixture by medium pressure liquid column chromatography on ion exchange resin (Nippon Rensui Co. Ltd., DIAION® HP-20) (eluent:water/methanol=1/0 to 1/1) gave 2-[2-dimethylamino-4-[2-[[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl]phenoxy]acetic acid (330 mg).
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][Si](C)(C)C)=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>CO>[C:14]([C:11]1[CH:12]=[CH:13][C:8]([C:5]2([N:4]([CH2:20][CH2:21][CH3:22])[CH2:1][CH2:2][CH3:3])[CH2:6][CH2:7]2)=[CH:9][CH:10]=1)#[CH:15]
Reactant: CCCN(CCC)C1(c2ccc(C#C[Si](C)(C)C)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C2(N(CCC)CCC)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure E; dipropyl-[1-(4-trimethylsilanylethynylphenyl)-cyclopropyl]-amine (Intermediate 122, 45.0 mg, 0.14 mmols) in methanol (5 mL) was treated with potassium carbonate (50.0 mg, 0.37 mmol) and stirred overnight at ambient temperature. The crude alkyne (34 mg, 100%) was used directly in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.Cl[CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].[OH-].[Na+]>CC(C)=O.ClC(Cl)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][S:13]([CH:12]=[CH2:11])(=[O:15])=[O:14])=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: O=S(=O)(Cl)CCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CC(Cl)Cl
Solvent: O
Product: C=CS(=O)(=O)Oc1ccc(Cl)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred mixture of 4-chloro-2-methylphenol (24.7 g, 173 mmol) in acetone (10 ml), dichloroethane (25 ml) and water (45 ml) at 0-5° C. was added drop wise simultaneously 2-chloro-1-ethane sulfonyl chloride (28.2 g, 173 mmol) and a solution of 25% sodium hydroxide (60 g) during approximately one hour. The mixture was stirred for one hour at Sand for one hour at room temperature. Water was added and the mixture was extracted twice with DCM. The organic phase was dried with sodium sulphate, filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with hexane-ethyl acetate which gave the title compound (33.4 g, 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:15]2[C:6]([CH3:21])([C:7]3[C:8](=[O:20])[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11](=[O:16])[C:12]=3[CH2:13][CH2:14]2)[CH2:5][CH2:4][C:3]=1[C:22]([OH:24])=[O:23]>C(OCC)(=O)C.[C].[Pd]>[OH:20][C:8]1[CH:9]=[C:10]([CH:17]([CH3:19])[CH3:18])[C:11]([OH:16])=[C:12]2[C:7]=1[C:6]1([CH3:21])[CH:15]([CH2:14][CH2:13]2)[C:2]([CH3:1])=[C:3]([C:22]([OH:24])=[O:23])[CH2:4][CH2:5]1
Reactant: CC1=C(C(=O)O)CCC2(C)C3=C(CCC12)C(=O)C(C(C)C)=CC3=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)CCC2(C)c3c(O)cc(C(C)C)c(O)c3CCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 Milligrams of 3,4,4a,5,8,9,10,10a-octahydro-1,4a-dimethyl-7-(1-methylethyl)-5,8-dioxo-2-phenanthrenecarboxylic acid was dissolved in 10 ml of ethyl acetate. Thereto was added, as a catalyst, 3 ml of an ethyl acetate suspension containing 15 mg of 10% palladium-carbon. The container inside was purged with hydrogen gas, and the contents were stirred at room temperature for 3 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain 135 mg of 3,4,4a,9,10,10a-hexahydro-5,8-dihydroxy-1,4a-dimethyl-7-(1-methylethyl)-2-phenanthrenecarboxylic acid.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CO.[OH-].[Na+]>CN(C=O)C.O>[NH:24](/[C:13](=[C:6]1\[C:5](=[O:23])[NH:4][C:12]2[C:7]\1=[CH:8][CH:9]=[CH:10][CH:11]=2)/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Reactant: Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=C1Nc2ccccc2/C1=C(/Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
450 mg (1.5 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 0.41 ml of (4.5 mmol) of aniline are stirred in 7 ml of DMF for 90 minutes at 120° C. After cooling to ambient temperature 7 ml of methanol and 3 ml of 1N sodium hydroxide solution are added. The mixture is stirred for 20 minutes, then diluted with water, the crystalline reaction product is suction filtered and dried.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1/[CH:9]=[CH:10]/[C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26]([NH2:29])(=[O:28])=[O:27])=[CH:19][C:13]=2[N:12]=1>[Pd].CO>[F:31][C:2]([F:1])([F:30])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]1[NH:15][C:14]2[CH:16]=[CH:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[S:26]([NH2:29])(=[O:27])=[O:28])=[CH:19][C:13]=2[N:12]=1
Reactant: NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(/C=C/c3ccccc3C(F)(F)F)nc2c1
Agent: [Pd]
Solvent: CO
Product: NS(=O)(=O)c1ccccc1-c1ccc2[nH]c(CCc3ccccc3C(F)(F)F)nc2c1
Reaction time: 1 h

Procedure:
A mixture of (E)-2-{2-[2-(2-trifluoromethyl-phenyl)-vinyl]-1H-benzimidazol-5-yl}-benzenesulfonamide Cpd 364 (0.020 g, 0.045 mmol) and 10% palladium on charcoal (0.005 g, 0.0045 mmol) in 2 mL MeOH was hydrogenated under H2 gas (1 atm) for 1 hour. The catalyst was removed by filtration, the filtrate was concentrated to dryness, and the residue was purified by chromatography (silica gel, MeOH:CH2Cl2=10:1) to give the title compound as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=1.2 and 7.6 Hz) 7.74-7.53 (m, 4H) 7.60-7.56 (m, 2H) 7.51-7.40 (m, 4H) 3.41 (m, 4H) MS (ESI, pos. ion) m/z: 446.5 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8](O)(=O)[CH:9](C(C(O)=O)O)[OH:10]>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9](=[O:10])[CH3:8])[CH2:4][CH2:3]1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: CN1CCNCC1
Product: CC(=O)N1CCN(C)CC1
Yield: 38 %

Procedure:
2-(2,3-Dihydro-2-oxo-3-phenyl-5-benzofuranyl)-1-(4-methylpiperazinyl-1-oxoethane was prepared according to the process described in Example 3, but using 4-methylpiperazine in Stage C. The latter compound was dissolved in a solution of DL-tartaric acid to form the corresponding salt, and then recrystallized in ethyl ether.
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([O:9][C:10]([NH:12][C@H:13]([C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:14][C:15]2[CH:27]=[CH:26][C:18]([O:19][CH2:20][CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[O:11])[CH2:2]1.C([N:51](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N>CN(C=O)C.CO>[NH2:51][C:23](=[O:24])[CH2:22][CH2:21][CH2:20][O:19][C:18]1[CH:26]=[CH:27][C:15]([CH2:14][C@H:13]([NH:12][C:10](=[O:11])[O:9][C@@H:3]2[C@H:4]3[C@H:5]([O:6][CH2:7][CH2:8]3)[O:1][CH2:2]2)[C@H:28]([OH:47])[CH2:29][N:30]([S:35]([C:38]2[CH:46]=[CH:45][C:41]3[O:42][CH2:43][O:44][C:40]=3[CH:39]=2)(=[O:37])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[CH:16][CH:17]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(=O)O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCCC(N)=O)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43.9 %

Procedure:
A solution of 25 mg (0.037 mmol) of 4-(4-{(2S,3R)-2-({[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yloxy]carbonyl}amino)-4-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-3-hydroxybutyl}phenoxy)butanoic acid and 19 μL (0.11 mmol) of N,N-diisopropylethylamine in 1 mL of anhydrous DMF was treated with 28 mg (0.074 mmol) of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU). The resulting solution was stirred at RT for 15 minutes and was then treated with 0.5 mL of 2M NH3 in MeOH. After 20 minutes TLC indicated the reaction to be complete. The solution was concentrated to dryness at reduced pressure and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 11 mg (44%) of the desired compound as a white powder. 1H NMR (CDCl3): 7.30 (d, 1H), 7.14 (s, 1H), 7.07 (d, 2H), 6.85 (d, 2H), 6.75 (d, 2H), 6.05 (s, 2H), 5.60 (d, 1H), 5.56-5.34 (m, 2H), 4.97 (m, 2H), 3.94 (m, 3H), 3.78 (m, 3H), 3.66 (m, 2H), 3.09 (m, 1H), 3.00-2.64 (m, 7H), 2.40 (t, 2H), 2.08 (m, 2H), 1.80 (m, 1H), 1.61 (m, 1H), 1.48 (m, 1H), 0.90 (d, 3H), 0.82 (d, 3H). MS(ESI): 678(M+H).
Reaction SMILES: [Na+].[CH2:2]([C:8]1[S:12][C:11](OB(O)[O-])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=2)=[C:20]([F:35])[CH:19]=1.C(=O)([O-])O.[Na+]>C1COCC1.O.CC(OC)(C)C.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:35][C:20]1[CH:19]=[C:18]([C:11]2[S:12][C:8]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[CH:9][CH:10]=2)[CH:23]=[CH:22][C:21]=1[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:26][CH:25]=1
Reactant: CCCCCCc1ccc(OB([O-])O)s1
Reactant: CCCCCc1ccc(-c2ccc(Br)cc2F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: COC(C)(C)C
Product: CCCCCCc1ccc(-c2ccc(-c3ccc(CCCCC)cc3)c(F)c2)s1

Procedure:
A mixture of 3.30 g (13.1 mmol) of 5-hexylthiophen-2-ylhydroxyboronic acid sodium salt, 4.20 g (13.1 mmol) of 4-bromo-2-fluoro-4′-pentylbiphenyl, 2.2 g (26.2 mmol) of sodium hydrogencarbonate and 0.70 g (0.61 mmol) of tetrakis(triphenylphosphine)palladium(0) in THF/water (1:1) is refluxed for 6 h. The mixture is diluted with MTBE, and the organic phase is separated off. The aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is evaporated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane). The further purification is carried out by recrystallisation from methanol/-pentane (5:1). 2-(2-Fluoro-4′-pentylbiphenyl-4-yl)-5-hexylthiophene is obtained as a colourless solid having an m.p. of 44° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1
Reactant: O=C(O)c1ccc(-c2ccccc2C(F)(F)F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(-c2ccccc2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2'-trifluoromethylphenyl)benzoic acid (1.525 g, 5.728 mmol) in THF (25 mL) at 0° C. was added 1.0 M lithium aluminum hydride in tetrahydrofuran (12.0 mL, 12.0 mmol) over 10 minutes. The reaction was allowed to stir at ambient temperature for 3 hours, cooled to 0° C., and quenched by dropwise addition of water (0.5 mL), 4 N aq. NaOH (0.5 mL), and water (1.5 mL). The reaction was filtered through a pad of Celite and the filtrate evaporated in vacuo. The residue was chromatographed (Silica gel, 20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH2:2][CH3:3].[I:11]I>C(O)C.O>[I:11][C:6]1[N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[C:9]([OH:10])=[CH:8][CH:7]=1
Reactant: II
Reactant: CCCc1ncccc1O
Solvent: CCO
Solvent: O
Product: CCCc1nc(I)ccc1O
Reaction time: 2 h
Yield: 60.1 %

Procedure:
2-Propylpyridin-3-ol (2.42 g, 17.7 mmol) was dissolved in ethanol (40 mL) and water (10 mL). Iodine (4.71 g, 18.6 mmol) was added thereto under ice-cold conditions, and stirred for 2 hours. Then, the mixture was stirred at room temperature for 4 hours. After completion of the reaction, ethanol was concentrated in vacuo and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate), and 6-iodo-2-propylpyridin-3-ol (2.80 g, yield 60%) was obtained as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14](Br)[C:13]([C:17]#[N:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:20]1[O:28][C:27]2[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=2[O:21]1.C(=O)([O-])[O-].[Na+].[Na+].Cl>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.CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[C:14]([C:25]3[CH:24]=[CH:23][C:22]4[O:21][CH2:20][O:28][C:27]=4[CH:26]=3)[C:13]([C:17]#[N:18])=[N:12]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(-n2cc(Br)c(C#N)n2)cc1
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(-c3ccc4c(c3)OCO4)c(C#N)n2)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 26.1 %

Procedure:
A suspension of 4-(4-bromo-3-cyanopyrazole-1-yl)benzoic acid ethyl ester (0.17 g), (3,4-methylenedioxyphenyl)boronic acid (0.11 g), tetrakis(triphenylphosphine)palladium (0.12 g) and sodium carbonate (0.17 g) in a mixed solvent of water (0.5 mL) and N,N-dimethylformamide (5 mL) was stirred at 70° C. for 12 hours. To this reaction mixture was added dilute hydrochloric acid, and this mixture was extracted with ethyl acetate. This organic layer was washed with brine, dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate/n-hexane=1/5) to give the title compound (0.05 g).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15]>C(Cl)(Cl)Cl>[CH2:14]([N:16]([CH2:17][CH3:18])[C:4](=[O:6])[C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[N:10][C:2]=1[CH3:1])[CH3:15]
Reactant: CCNCC
Reactant: Cc1ncc([N+](=O)[O-])cc1C(=O)O
Solvent: ClC(Cl)Cl
Product: CCN(CC)C(=O)c1cc([N+](=O)[O-])cnc1C

Procedure:
In dry chloroform were dissolved 0.3 g of 2-methyl-5-nitronicotinic acid and 1.5 ml of diethylamine. After addition of 10 g of phosphorous pentaoxide, the mixture was stirred with heating at 55° - 60° C. for 3 hours. After cooling, the chloroform portion was separated and evaporated under reduced pressure. The residue was, after addition of water, neutralized with sodium hydrogen carbonate and extracted with ethyl acetate. The extract was concentrated and purified on a silica gel column to give 0.25 g of a colorless oil.