Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[ClH:21]>CO.O1CCOCC1.[Pt]=O>[ClH:21].[F:19][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[CH2:10][C@@H:11]([C:12]([O:14][CH3:15])=[O:13])[CH2:16][CH2:17][NH:18]2)=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CCN[C@@H](c2ccc(C(F)(F)F)cc2)C1
Reaction time: 2 h

Procedure:
Methyl 2-[4-(trifluoromethyl)phenyl]isonicotinate (5 g) was dissolved in MeOH (180 ml) and HCl in dioxane (4.5 ml, 4N). To this solution was added platinum oxide (500 mg) and the mixture was hydrogenated at 30 psi for 2 h. The mixture was filtered through Hyflo® to remove the catalyst and the solution was evaporated and azeotroped with toluene to yield the product as a white crystalline solid (5 g). 1H NMR (400 MHz, CDCl3) δ: 1.95-2.03 (1H, m), 2.09-2.17 (1H, m), 2.33 (1H, d, J 14.5), 2.44 (1H, d, J 14.2), 2.95-3.02 (1H, m), 3.35-3.39 (1H, m), 3.60-3.64 (1H, m), 3.75 (3H, s), 4.51 (1H, dd, J 2.7, 12.6), 7.74 (2H, d, J 8.2), 7.83 (2H, d, J 8.2); M/Z (ES+) 288 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[S:25](Cl)(Cl)=O.[CH:29]1[CH:34]=CC=C[CH:30]=1>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[N:14]=[C:13]2[O:23][CH3:24])=[CH:7][C:3]=1[C:4]([O:6][CH:29]1[CH2:34][S:25][CH2:30]1)=[O:5]
Reactant: c1ccccc1
Reactant: O=S(Cl)Cl
Reactant: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)O)c(Cl)cc1F
Solvent: CN(C)C=O
Product: COc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC2CSC2)c(Cl)cc1F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
3.4 g of 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H) pyrimidinyl]-benzoic acid are heated at reflux temperature for 3 hours in 25 ml of benzene and 3.4 ml of thionyl chloride together with 2 drops of dimethylformamide. The reaction mixture is subsequently evaporated to dryness and dissolved in 20 ml of dioxan. This solution, which consists mainly of the acid chloride of the above-mentioned benzoic acid and the solvent, is added dropwise to a solution of 1.0 g of 3-thietanol and 1.3 g of pyridine in 20 ml of dioxan. The reaction mixture is then stirred at room temperature for 3.5 hours, treated with 400 ml of water and extracted twice with 400 ml of ethyl acetate each time. The combined organic phases are washed twice with 200 ml of 1N hydrochloric acid each time and once with 200 ml of saturated sodium chloride solution, dried over anhydrous magnesium sulphate and evaporated. The residue is purified by chromatography on silica gel with diethyl ether/n-hexane (1:2). In this manner there is obtained thietan-3-yl 2-chloro-4-fluoro-5-[2-methoxy-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-benzoate as a colourless oil, 1H-NMR(CDCl3, 400 MHz): 3.37-3.44 (m,2H), 3.57-3.66 (m,2H), 4.03 (s,3H), 5.85 (quintet, 1H), 6.63 (s,1H), 7.42 (d,1H), 7.88 (d,1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:35]([O-])=O)[C:9]=1[C:10]#[C:11][CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6]>C(O)C.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:35][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([OH:34])([CH2:18][C:19]1([CH3:33])[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:27]=2)[O:22][CH2:21][CH2:20]1)[C:14]([F:17])([F:15])[F:16])[C:5]#[N:6]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(S(C)(=O)=O)cc21)C(F)(F)F
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
A mixture of 200 mg (0.4 mmol) of 3-methyl-5-nitro-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile and 375 mg (6.7 mmol) of iron powder in 4 mL of ethanol and 2 mL of acetic acid was warmed at 90° C. After 2 hours, the mixture was cooled and diluted with 50 mL of ethyl acetate and filtered through CELITE® filter aid. The filtrate was washed with three portions of saturated aqueous sodium bicarbonate, dried over sodium sulfate, and concentrated in vacuo to afford 130 mg (68%) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-hydroxy-4-(6-methanesulfonyl-4-methylchroman-4-ylmethyl)pent-1-ynyl]benzonitrile as a brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH2:14][CH:15]([OH:17])[CH3:16].ClCCl>C(O)CCC.O>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH2:14][CH:15]([OH:17])[CH3:16])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CC(O)CN
Solvent: CCCCO
Solvent: O
Solvent: ClCCl
Product: CC(O)CNc1ccnc2cc(Cl)ccc12
Temperature: 25 °C

Procedure:
A mixture of 20 g of 4,7-dichloroquinoline and 16 g of 1-amino-2-propanol in 60 ml of butanol was stirred at reflux until the reaction was complete (6 hours). The reaction mixture was cooled down to room temperature and diluted with water. The organics were exracted into dichloromethane (3×300 ml). Drying over anhydrous magnesium sulfate and evaporation of solvents resulted in an oil which crystallized upon standing. The crystals were isolated by filtration and washed with ether to yield a solid which was recrystallized from isopropanol. The resultant crystals had a melting point of 168°-169.5° C. and the yield was 15 g.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[CH3:21][S:22](Cl)(=[O:24])=[O:23].CCN(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:21][S:22]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2N)CC1
Solvent: c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Yield: 72.1 %

Procedure:
tert-Butyl 4-{2-[(methylsulfonyl)amino]phenyl}-piperazinecarboxylate was prepared following the procedure for Preparation III using, tert-butyl 4-(2-aminophenyl)piperazinecarboxylate (4.4 g, 16 mmol), methanesulfonyl chloride (1.4 mL, 18 mmol) and DIEA (instead of pyridine) (3.1 mL, 18 mmol). The crude material was purified by flash chromatography (SiO2, 4:1 hexane:EtOAc) and concentrated in vacuo to afford the desired compound (4.1 g). MS (ESI, pos. ion) m/z: 356 (M+H), (ESI, neg. ion) m/z: 354 (M−H). Calc'd for C16H25N3O4S: 355.16.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][CH2:5][CH2:6][NH2:7].[OH-:11].[Na+].C(=O)(O)[O-].[Na+].F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>O.C(O)C>[N+:25]([C:22]1[CH:23]=[CH:24][C:19]([NH:1][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:26])=[O:11])=[CH:21][CH:20]=2)[C:8]([OH:10])=[O:9])=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: [OH-]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(O)C(CCCCNc1ccc([N+](=O)[O-])cc1)Nc1ccc([N+](=O)[O-])cc1
Yield: 88 %

Procedure:
5 g (34.2 mmol) of L-lysine are dissolved in 100 ml of water in the presence of 1.4 g (1 eq.) of sodium hydroxide and 8.6 g (3 eq.) of sodium bicarbonate, in a 250 ml three-necked flask equipped with a condenser and a thermometer. A solution of 10.8 ml (3 eq.) of 4-fluoronitrobenzene in 60 ml of ethanol is poured onto the mixture, which is brought to reflux (85°-90° C.) for 5 days. The cooled mixture is extracted with ethyl ether. The aqueous phase is acidified to pH ˜3 with 5 N hydrochloric acid. A gum-like precipitate forms and is extracted with dichloromethane in the presence of a small amount of methanol. The organic phase is washed with water until neutrality is reached, dried over sodium sulphate, and then evaporated to give an orange-coloured oil which crystallizes in the presence of ethyl ether. 11.7 g of a yellow crystalline product are obtained, i.e. an 88% yield.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:38])=[C:15]([CH2:20][NH:21][C:22]([C:24]3[N:28](COCC[Si](C)(C)C)[CH:27]=[N:26][C:25]=3[Cl:37])=[O:23])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4].C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([C:5]1[CH:6]=[C:7]([O:12][C:13]2[C:14]([F:38])=[C:15]([CH2:20][NH:21][C:22]([C:24]3[NH:28][CH:27]=[N:26][C:25]=3[Cl:37])=[O:23])[CH:16]=[CH:17][C:18]=2[Cl:19])[CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a solution of N-({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (148 mg, 0.246 mmol) in DCM (5 ml) was added TFA (3.0 ml) and the reaction mixture was stirred at rt for 2 hours. The reaction mixture was neutralized with saturated sodium bicarbonate, diluted with EtOAc, and the organic layer was separated. The solvent was evaporated and the crude material was purified via silica gel chromatography to give N-({3-[(3-butyl-5-chlorophenyl)oxy]-4-chloro-2-fluorophenyl}methyl)-4-chloro-1H-imidazole-5-carboxamide (94 mg, 0.200 mmol, 81% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.69 (s, 1H), 7.24-7.37 (m, 2H), 6.90 (s, 1H), 6.56-6.66 (m, 2H), 4.62 (s, 2H), 2.53 (t, 2H), 1.51 (qd, 2H), 1.20-1.35 (m, 2H), 0.88 (t, 3H). LC-MS (ES+) m/z 469.93, [M+H].
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:11][C:10](C=O)=[CH:9][CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:1]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[CH2:2]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methyltriphenylphosphonium bromide (5.10 g, 14.27 mmol) in THF (26 mL) was slowly added potassium tert-butoxide (1M solution in THF, 14.27 mL) over ˜20 min at 0° C. The reaction mixture was allowed to warm up to room temperature and stirred for 10 min. The mixture was cooled to 0° C. and a solution of 4-biphenylcarbaldehyde (2.0 g, 10.98 mmol) in THF (9 mL) was added over 20 min. The reaction mixture was allowed to warm up to room temperature and stirred for ˜19 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved/suspended in DCM and filtered through a silica pad and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 80 g, EtOAc/heptane] to provide vinylbiphenyl (1.845 g) as a white solid. LCMS Rt 0.79 min.
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC.[CH:40]1[C:52]2[CH:51]([CH2:53][O:54][C:55]([N:57]3[CH2:66][CH2:65][C:64]4[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=4)[C@H:58]3[C:67]([OH:69])=O)=[O:56])[C:50]3[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=3)[C:44]=2[CH:43]=[CH:42][CH:41]=1>C(O)C.C(Cl)Cl.O.C(Cl)Cl>[CH3:1][N:4]([CH3:5])[C:67]([C@@H:58]1[C:59]2[C:64](=[CH:63][CH:62]=[CH:61][CH:60]=2)[CH2:65][CH2:66][N:57]1[C:55]([O:54][CH2:53][CH:51]1[C:52]2[CH:40]=[CH:41][CH:42]=[CH:43][C:44]=2[C:45]2[C:50]1=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:56])=[O:69]
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)[C@@H]1c2ccccc2CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CN(C)C(=O)[C@@H]1c2ccccc2CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h
Yield: 84.7 %

Procedure:
1.61 g of diisopropylethylamine, 5.53 g of BOP and then 5 ml of a 5.6M solution of dimethylamine in ethanol are added to a solution of 5 g of (1S)-2-(9-fluorenylmethoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-1-carboxylic acid (commercial) in 100 ml of DCM and the mixture is left stirring for 3 hours at AT. The reaction mixture is taken up in a water/DCM mixture, after separation by settling the organic phase is washed with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (70/30, v/v) mixture. 4.5 g of the expected product are obtained in the form of an oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[F:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[F:20])[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2F)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-fluorobenzoic acid (29 mg, 0.21 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water. The resulting precipitate was dried to afford 87 mg (94%) of N-biphenyl-4-yl-3-[4-(2-fluoro-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 446.18 (M+1)+ 93.2%, 1H NMR: (CDCl3): δ 9.7 (d, 1H), 7.6 (m, 6H), 7.44 (t, 4H), 7.34 (t, 1H), 7.22 (m, 1H), 7.14 (t, 1H), 3.86 (m, 6H), 3.54 (d, 2H), 3.4 (bs, 2H).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:29][CH2:30][CH3:31])[CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.C(O)C.O>[CH2:30]([O:29][CH:4]([CH2:5][C:6]1[C:14]2[O:13][CH:12]=[CH:11][C:10]=2[C:9]([O:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:8][CH:7]=1)[C:3]([OH:32])=[O:2])[CH3:31]
Reactant: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c2ccoc12)C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 35 %

Procedure:
Potassium carbonate (37 mg, 300 μmol, 1.4 eq.) and potassium iodide (4 mg, 30 μmol, 0.1 eq.) were added to a solution of [rac]-2-ethoxy-3-(4-hydroxy-benzofuran-7-yl)-propionic acid methyl ester (50 mg, 189 μmol) and 4-chloromethyl-5-methyl-2-phenyl-oxazole (39 mg, 189 μmol, 1 eq.) in N,N-dimethylformamide (0.5 ml). The mixture was shaken at 80° C. for 12 h, filtered off and the filtrate evaporated in vacuo to give [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester. Crude [rac]-2-ethoxy-3-[4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-benzofuran-7-yl]-propionic acid methyl ester was dissolved in a 2:1:1 mixture of THF/ethanol/water. Lithium hydroxide (40 mg, 945 μmol, 5 eq.) was added and the solution was shaken at ambient temperature for 12 h. Acidification with 25% aqueous hydrochloric acid and evaporation of the solvent in vacuo were followed by purification through a preparative HPLC column to give the title compound (28 mg, 66 μmol, 35%) as white solid.
Reaction SMILES: Br[CH:2]1[CH:11]([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:9]=2)[O:4][C:3]1([CH3:20])[CH3:19].O1CCOCC1.[OH-].[Na+]>O>[CH3:19][C:3]1([CH3:20])[CH:2]2[O:12][CH:11]2[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])[CH:9]=2)[O:4]1
Reactant: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2C(O)C1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)Oc2ccc(C(=O)C(F)(F)F)cc2C2OC21
Temperature: 20 °C
Reaction time: 20 h
Yield: 89.5 %

Procedure:
A mixture containing 2.9 g of 3-bromo-2,2-dimethyl-4-hydroxy-6-trifluoroacetylchromane, prepared in the previous step, 25 ml of dioxane, 0.5 g of sodium hydroxide pellets and 5 ml of water is stirred at 20° C. for 20 hours. After concentration under vacuum at 40° C., the residue is treated 4 times with 100 ml of ethyl ether and the extracts are then dried and concentrated under vacuum to give 2 g of a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O.C(OC(C)C)(C)C>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([S:10]([CH3:13])(=[NH:12])=[O:11])=[CH:8][CH:9]=1
Reactant: CS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(C)OC(C)C
Product: CS(=N)(=O)c1ccc(N)cc1

Procedure:
A solution of 2.45 g (12.2 mmol) of (RS)—S-(4-nitrophenyl)-S-methyl sulfoximide in 150 ml of ethanol is hydrogenated at room temperature with use of 0.80 g of Pd/C (10%×50% H2O) under a hydrogen atmosphere at normal pressure over 4 hours. The hydrogen absorption is 920 ml. The batch is filtered and concentrated by evaporation. The residue that is obtained is digested with diisopropyl ether. 1.90 g (11.2 mmol, corresponding to 92% of theory) is obtained.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].Br[C:17]#[C:18][CH3:19].P(O)(O)([O-])=O.[Na+]>O1CCCC1>[CH2:19]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[C:3]1[C:2]([F:1])([F:12])[F:13])[C:18]#[CH:17]
Reactant: FC(F)(F)c1cc2ccccc2[nH]1
Reactant: CC#CBr
Agent: O=P([O-])(O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCn1c(C(F)(F)F)cc2ccccc21
Reaction time: 0.03 h

Procedure:
8.57 g of 2-trifluoromethyl-1H-indole described in J. Org. Chem. (1983) 48-3233 and 10 ml of tetrahydrofuran were mixed together under an inert atmosphere at +5° C. and after 15 minutes, 2.4 g of sodium hydride in oil were added. After 2 minutes, 4.5 ml of 2-bromo-propyne were introduced and the resulting mixture was stirred for 30 minutes at +5° C., then for one hour at 25° C. Another 4.5 ml of bromo-propyne were added and the mixture was stirred for 4 hours and then poured into an iced solution of monosodium phosphate and extracted with ethyl ether. The extracts were concentrated to dryness by distillation under reduced pressure and the residue was chromatographed over silica and eluted with a mixture of hexane and ethyl acetate (95/5) to obtain 8.88 g of 1-(2-propynyl)-2-trifluoromethyl-(1H)-indole melting at 59° C.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH2:2][CH2:3][CH3:4].[C:16]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([NH:5][C:6]1[CH:11]=[C:10]([O:26][C:23]2[CH:24]=[CH:25][C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:21][CH:22]=2)[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1cc(Oc2ccc(C(C)(C)C)cc2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 10 h

Procedure:
A mixture of 2-n-butylamino-4-fluoronitrobenzene (10 mmol), 4-t-butylphenol (13 mmol), solid K2CO3 (30 mmol) and DMF (30 mL) was heated with stirring at 90° C. for 10 h. The reaction was quenched by cold H2O (50 mL), and the resulting mixture was extracted with EtOAc (3×100 mL). The combined EtOAc extracts were washed with brine (2×50 mL) and dried (anhydrous Na2SO4). The solvent was removed in vacuo, and the crude products were purified by silica gel column chromatography (eluting with 10% EtOAc in hexane), giving 2-n-butylamino-4-(4-t-butylphenoxy)nitrobenzene.
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:47])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:46])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:45])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:44])[CH2:22][CH2:23][C:24](=[O:43])[CH:25]([CH3:42])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:41])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])=[CH:3][CH2:4][OH:5].[CH3:48][C:49](OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=[O:50].CCOCC>N1C=CC=CC=1>[C:49]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:47])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:46])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:45])[CH2:18][CH2:19][CH:20]=[C:21]([CH3:44])[CH2:22][CH2:23][C:24](=[O:43])[CH:25]([CH3:42])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:41])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:40])[CH2:34][CH2:35][CH:36]=[C:37]([CH3:39])[CH3:38])(=[O:50])[CH3:48]
Reactant: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)C(=O)CCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC(=O)C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 0 °C
Reaction time: 5 h

Procedure:
To a solution of 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-on-1-ol 6.5 g) in pyridine (1 g), acetic anhdyride (3.0 g) is added, and the resulting mixture is allowed to stand at room temperature for 5 hours. The reaction mixture is poured into ice water and shaken with ether. The ether layer is washed with water, dried and evaporated. The residual material (6.5 g) is chromatographed on silica gel (70 g) using benzene to give 1-acetoxy-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-one (6.1 g). A solution of this compound in ethanol (6 ml) is dropwise added to a solution of sodium borohydride (0.1 g) in ethanol (10 ml) while cooling with ice, and stirring is continued for 3 hours. The reaction mixture is poured into an aqueous saturated solution of ammonium chloride and extracted with ether. The ether extract is washed with water, dried and concentrated. The residual material (4.8 g) is treated as in Example 1 (5) a) to give 1-acetoxy-3,7,11,15,19,23,27,31, 35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen- 22-ol (2.1 g) as a fraction (1) and 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaene-1,22-diol (0.9 g) as a fraction (2). The latter is treated with acetic anhydride as above to give 1-acetoxy-3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,26,30,34-hexatriacontaoctaen-22-ol (0.82 g).