Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[C:27]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH:11]([C:13]2[CH:14]=[N:15][C:16]([O:21][CH2:22][C:23]([F:25])([F:26])[F:24])=[C:17]([O:19][CH3:20])[CH:18]=2)[CH3:12])=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)Cl
Reactant: COc1cc(C(C)NC(=O)c2ccnc(N)n2)cnc1OCC(F)(F)F
Product: COc1cc(C(C)NC(=O)c2ccnc(NC(C)=O)n2)cnc1OCC(F)(F)F

Procedure:
The title compound is prepared from 2-amino-N-(1-(5-methoxy-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)ethyl)pyrimidine-4-carboxamide (15 mg, 0.04 mmol, Step-1, single enantiomer) and acetyl chloride (10 mg, 0.12 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].I[CH2:13][CH3:14].Cl>CS(C)=O>[CH2:13]([O:10][C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[CH:7][C:8]=1[F:11])[CH:4]=[O:5])[CH3:14]
Reactant: CCI
Reactant: O=Cc1ccc(F)c(O)c1O
Agent: Cl
Solvent: CS(C)=O
Product: CCOc1c(F)ccc(C=O)c1O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of 2,3-dihydroxy-4-fluorobenzaldehyde (3.0 g, 19.23 mmol) in DMSO (100 mL), NaOBu-t (3.692 g, 38.46 mmol) was added in portions at room temperature and stirred for 15 min. Then iodoethane was added dropwise at room temperature and stirred for 18 h. The reaction mixture was poured onto crushed ice (200 mL) and acidified with 2.5 M HCl to pH 3.0. The product was extracted with ethyl acetate (2×100 mL), concentrated and the product was chromatographed on a column of silica gel (Hex:EtOAc=95:5) to give the title compound as a crystalline solid (2.3 g, 65%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 11.36 (s, 1H), 9.83 (s, 1H), 7.39-7.19 (m, 1H), 6.77 (t, J=9.2 Hz, 1H), 4.22 (q, J=7.0 Hz, 2H), 1.40 (t, J=7.0 Hz, 3H); MS (ESI) m/z=183 (M+1, positive).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C@H:15]([C:33](=[O:35])[NH2:34])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(C)(C)C>ClCCl>[NH2:14][C@@H:15]([CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:32])[CH2:22][CH2:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:33]([NH2:34])=[O:35]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)CCC(=O)c1ccccc1)C(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)[C@@H](N)CCCCNC(=O)CCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.8 %

Procedure:
Trifluoroacetic acid (25 ml) was added to a solution of [(1S)-1-carbamoyl-5-(4-oxo-4-phenylbutyrylamino)pentyl]carbamic acid tert-butyl ester (0.56 g, 1.38 mmol) in dichloromethane (25 ml). The reaction mixture was stirred for 1 h at room temperature. The solvent was removed. The crude product was purified by HPLC on a RP-18 column, using a gradient of 20-45% acetonitrile in water, containing 0.1% of trifluoracetic acid as buffer to give 92 mg of the title compound with a purity of approx. 85%, which was used for the further experiments.
Reaction SMILES: C1C(C=O)=CC=C(C=O)C=1.C(O)(O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:26]1[CH:30]=[CH:29][O:28][CH:27]1[C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1.[CH2:39]([N:43]1[C:47](=[O:48])[CH2:46][NH:45][C:44]1=[O:49])[CH2:40][CH2:41][CH3:42]>C1C=CC=CC=1.O>[CH2:39]([N:43]1[C:47](=[O:48])[C:46](=[CH:35][C:34]2[CH:37]=[CH:38][C:31]([CH:27]3[O:28][CH:29]=[CH:30][O:26]3)=[CH:32][CH:33]=2)[NH:45][C:44]1=[O:49])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCN1C(=O)CNC1=O
Reactant: O=Cc1ccc(C2OC=CO2)cc1
Agent: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=Cc1ccc(C=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCN1C(=O)NC(=Cc2ccc(C3OC=CO3)cc2)C1=O

Procedure:
Terephthaldialdehyde (67 g; 0.5 mole), ethanediol (31 g, 0.5 mole) and p-toluenesulphonic acid (0.5 g) in benzene (400 ml.) were boiled under reflux for 2 hours, with the removal of the water formed via a Dean and Stark separator. After cooling, the mixture was washed with dilute sodium bicarbonate solution (100 ml, 2% W/V), then saturated sodium chloride solution (2×100 ml.) and dried over magnesium sulphate. After filtration, the benzene solution was evaporated in vacuo to give a straw-coloured oil containing ca 70% of the desired aldehyde, viz: 4-(1,3-dioxol-2-yl)-benzaldehyde, which was reacted with 3-n-butylhydantoin as in Example 1.
Reaction SMILES: N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)C(C)C.C([S:24][CH2:25][CH:26]([CH3:41])[C:27]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28])(=O)C>>[SH:24][CH2:25][CH:26]([CH3:41])[C:27]([NH:29][C@H:30]([C:38]([OH:40])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:28]
Reactant: CC(=O)SCC(C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Product: CC(CS)C(=O)N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
By substituting L-phenylalanine for the L-valine in the procedure of Example 22, and then treating the product by the procedure of Example 23, N-(3-actylthio-2-methylpropanoyl)-L-phenylalanine and N-(3-mercapto-2-methylpropanoyl)-L-phenylaline are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([C:31](OC)=[O:32])[CH2:20][CH2:21][N:22]2[CH2:29][CH2:28][C:25]3([CH2:27][CH2:26]3)[C@H:24]([OH:30])[CH2:23]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][C:15](=[O:18])[N:14]([C@H:19]([CH2:31][OH:32])[CH2:20][CH2:21][N:22]2[CH2:29][CH2:28][C:25]3([CH2:26][CH2:27]3)[C@H:24]([OH:30])[CH2:23]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(C(=O)OCc2ccccc2)CCC1=O
Agent: [BH4-]
Agent: [Li+]
Product: O=C(OCc1ccccc1)N1CCC(=O)N([C@H](CO)CCN2CCC3(CC3)[C@H](O)C2)CC1

Procedure:
In analogy to the procedure described in example 2, 4-[(S)-3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-1-methoxycarbonyl-propyl]-5-oxo-[1,4]diazepane-1-carboxylic acid benzyl ester (intermediate 8H) and lithium borohydride gave the title compound in quantitative yield as a white foam. MS; 446.3 (MH+).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:16].[NH3:17]>C(O)C.C(Cl)(Cl)Cl>[ClH:16].[CH2:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[C:11]([NH2:17])=[NH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: N#Cc1cccc(Cc2ccccc2)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: N=C(N)c1cccc(Cc2ccccc2)c1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
3-Benzylbenzonitrile (83.45 g.; prepared as described by C. R. Hauser, W. Q. Beard and F. N. Jones, J. Org. Chem., 1961, 26, 4790) was dissolved in a mixture of anhydrous ethanol (52 ml.) and anhydrous chloroform (390 ml.). The solution was saturated with anhydrous hydrogen chloride at 0° C. and kept at 0° C. for 3 days. The solvent was evaporated in vacuo and the residue triturated with anhydrous diethyl ether. The solid obtained (78 g.) was treated with saturated anhydrous ethanolic ammonia (600 ml.), and the mixture maintained at 0° C. for 3 days. A small amount of ammonium chloride was filtered off and the filtrate was evaporated in vacuo. The gummy residue was triturated with anhydrous diethyl ether to give a solid, which was filtered off and extracted with hot water. The extract was filtered and evaporated to dryness in vacuo. The resulting residue was recrystallised from a mixture of ethanol and diethyl ether (with the aid of charcoal) to give 3-benzylbenzamidine hydrochloride (30.1 g.), m.p. 170°-180° C.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:21]([F:24])([F:23])[F:22])([OH:20])[C:16]([F:19])([F:18])[F:17])[CH:12]=[C:11]([C:25]([C:31]([F:34])([F:33])[F:32])([OH:30])[C:26]([F:29])([F:28])[F:27])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[H-].[CH:40]([C:43]1[CH:48]=[CH:47][C:46]([S:49](Cl)(=[O:51])=[O:50])=[CH:45][CH:44]=1)([CH3:42])[CH3:41]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:35])([F:36])[C:3]([C:9]1[CH:14]=[C:13]([C:15]([C:16]([F:18])([F:17])[F:19])([O:20][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:21]([F:22])([F:23])[F:24])[CH:12]=[C:11]([C:25]([C:31]([F:32])([F:33])[F:34])([O:30][S:49]([C:46]2[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=2)(=[O:51])=[O:50])[C:26]([F:29])([F:28])[F:27])[CH:10]=1)([O:8][S:49]([C:46]1[CH:47]=[CH:48][C:43]([CH:40]([CH3:42])[CH3:41])=[CH:44][CH:45]=1)(=[O:51])=[O:50])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: OC(c1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C(O)(C(F)(F)F)C(F)(F)F)c1)(C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(S(=O)(=O)OC(c2cc(C(OS(=O)(=O)c3ccc(C(C)C)cc3)(C(F)(F)F)C(F)(F)F)cc(C(OS(=O)(=O)c3ccc(C(C)C)cc3)(C(F)(F)F)C(F)(F)F)c2)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 5 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
4.5 g (7.88 mmol) of 1,3,5-tris-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)-benzene were dissolved in 40 ml of dry DMF, and 0.95 g (31.5 mmol) of sodium hydride was added while flushing with nitrogen. After dissolution of the hydride, 6.56 g (30 mmol) of 4-isopropylbenzenesulfonyl chloride were added at 0 to 5° C. Slight evolution of heat was observed. The mixture was stirred for 20 hours at 5° C., ethyl acetate was added and the mixture was washed with water, dried, filtered and evaporated down. 9.6 g of crude product were obtained, and said crude product was eluted over a silica gel column with a 1:1 mixture of methylene chloride/hexane. The third fraction obtained was freed from the solvent and gave 6.8 g of 1,3,5-tris-[2,2,2-trifluoro-1-(4-isopropylbenzenesulfonyloxy)-1-trifluoromethylethyl]-benzene. M.p. 105° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:21])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:6]([C:8]([C:10]2[CH:11]=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)=[O:9])[CH:7]=1
Reactant: O=C(c1cnn(-c2ccccc2)c1)c1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Br)cc1C(=O)c1cnn(-c2ccccc2)c1
Yield: 100 %

Procedure:
Prepared from (5-bromo-2-hydroxy-phenyl)-(1-phenyl-1H-pyrazol-4-yl)ketone and ethyl bromoacetate according to GP2 to give 215 mg (100%) white crystals. The product was used without further purification: LC/MS (an 10p8): Rt 6.15 min, m/z 429 [M+H]+; 1H NMR (CDCl3): δ 1.26 (t, J=7.1 Hz, 3H), 4.24 (q, J=7.1 Hz, 2H), 4.64 (s, 2H), 6.72 (d, J=8.9 Hz, 1H), 7.34 (m, 1H), 7.46 (m, 2H), 7.53 (dd, J=8.9, 2.5 Hz, 1H), 7.59 (d, J=2.5 Hz, 1H), 7.73-7.78 (m, 2H), 8.17 (s, 1H), 8.58 (s, 1H); 13C NMR (CDCl3): δ14.3, 61.9, 65.5, 114.0, 114.5, 119.8, 125.3, 127.7, 129.8, 131.8, 132.3, 132.7, 134.6, 139.6, 142.7, 154.1, 168.5, 186.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][CH:10]=O)=[CH:4][CH:3]=1.[CH2:19]([NH:26][CH2:27][CH2:28][C:29]1[N:34]=[CH:33][CH:32]=[CH:31][N:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH2:19]([N:26]([CH2:27][CH2:28][C:29]1[N:30]=[CH:31][CH:32]=[CH:33][N:34]=1)[CH2:10][CH2:9][CH:8]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=CCC(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: c1ccc(CNCCc2ncccn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Fc1ccc(C(CCN(CCc2ncccn2)Cc2ccccc2)c2ccc(F)cc2)cc1

Procedure:
To a solution of 3,3-bis(4-fluorophenyl)propanal (0.908 g, 3.69 mmol) in DCE (12 mL) at room temperature was added N-benzyl-2-(pyrimidin-2-yl)ethanamine (0.704 g, 3.30 mmol), acetic acid (0.208 g, 3.46 mmol) (0.20 mL). and NaBH(OAc)3 (0.834 g, 3.94 mmol) The reaction mixture was stirred at room temperature for 3 h, quenched with 5 M NaOH (1×), diluted with EtOAc, washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 40% to 70% EtOAc in hexanes) gave N-benzyl-3,3-bis(4-fluorophenyl)-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(Cl)[CH2:9]Cl)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.[K].[H-].C([Al+]CC(C)C)C(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([SiH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:9][N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Si](Cl)(CCl)c2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Agent: CC(C)C[Al+]CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Fc1ccc([SiH](Cn2ccnc2)c2ccc(F)cc2)cc1
Temperature: -70 °C

Procedure:
To a solution of 3.0 g (9.9 mmol) of bis(4-fluorophenyl)chlorochloromethylsilane and 50 mg of tetrabutylammonium hydrogen sulfate in 10 ml of toluene is added 2.2 g (20.5 mmol) of potassium imidazole. The resulting exotherm is controlled by cooling with ice-water. Th solution is heated at reflux for 5 hours and then was cooled to -70° C. A solution of 10.5 ml (10.5 mmol) of diisobutylaluminum hydride (1.0 molar) in tetrahydrofuran is then added dropwise, and the reaction is warmed to room temperature and quenched by dropwise addition of saturated aqueous ammonium chloride. The solution is diluted with methylene chloride and washed three times with water and once with brine. Drying over magnesium sulfate and removal of solvent gives a viscous oil which is triturated with ether to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1Br.[OH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>[OH-].[Na+]>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[N:12]1[CH2:13][CH2:14][CH:9]([OH:8])[CH2:10][CH2:11]1
Reactant: Cn1ccnc1Br
Reactant: OC1CCNCC1
Agent: [Na+]
Agent: [OH-]
Product: Cn1ccnc1N1CCC(O)CC1
Temperature: 140 °C
Reaction time: 16 h

Procedure:
A mixture of N-methyl-2-bromoimidazole (7.3 g, 45.3 mmol) and 4-hydroxypiperidine (11.4 g, 113 mmol, 2.5 eq) was stirred at 140° C. for 16 h. After cooling to room temperature, the reaction mixture was diluted with 10% aq. NaOH solution to pH 12. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layers were washed with water (20 mL) followed by brine (20 mL), dried over sodium sulfate, filtered, and evaporated under vacuum. The solid residue was purified by column chromatography by eluting with 5% to 20% methanol in dichloromethane to yield the title compound as yellow solid. 1H NMR (CDCl3, 300 MHz): δ=6.64 (d, J=0.9 Hz, 1H), 6.75 (d, J=0.9 Hz, 1H), 3.85-3.84 (m, 1H), 3.47 (s, 3H), 3.24-3.22 (m, 2H), 2.94-2.92 (m, 2H), 2.01-1.98 (m, 2H), 1.71-1.69 (m, 2H). MS (ES+): m/z=182.28 (100) [MH+]. HPLC: tR=0.74 & 1.13 min (verypolar—5 min, ZQ3).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(N)C1C=CC=CC=1.[CH3:18][C:19]([CH3:23])([CH3:22])[CH:20]=[CH2:21].Cl>C1COCC1>[CH3:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH2:21][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: C=CC(C)(C)C
Reactant: CC(=O)c1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: NCc1ccccc1
Product: CC(=O)c1ccccc1CCC(C)(C)C
Temperature: 150 °C
Yield: 95.5 %

Procedure:
In a 500 ml pressure reactor, acetophenone 26 mg (0.22 mmol), benzylamine 12 mg (0.11 mmol), tristriphenylphosphine rhodium (I) chloride 10.0 mg (0.011 mmol) and 3,3-dimethyl-1-butene 91 mg (1.1 mmol) were placed. While the reactor was stopped with a stopper, the reactants were heated at 150° C. for 6 hours with stirring. After completion of the on, a reactant mixture was dissolved in THF 3 ml and added with 1 N HCl soln. 10 ml, followed by hydrolysis with stirring for 12 hours at room temperature. After the mixture was two or three times extracted with Et2O and CH2Cl2, the organic layer was dried over MgSO4 and then filtered, and the solvent was evaporated under reduced pressure. The reactant mixture of the organic layer was purified by column chromatography on silica gel (5:2 hexane:ethyl acetate) to obtain 2-(3,3-dimethylbutyl)phenyl-1-ethanone 42 mg (0.21 mmol). Yield: 95%. Under the same conditions, various olefins were employed, and the results are given in Table 7, below.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]([C:23]#[N:24])=[CH:13][CH:12]=2)[CH:8]=[N:7][CH:6]=1.CC([O-])(C)C.[K+].C1COCC1>C1COCC1>[CH2:6]1[CH:5]2[CH2:4][CH2:3][CH2:2][CH:10]([C:11]3[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][C:14]([C:23]#[N:24])=[CH:13][CH:12]=3)[N:9]2[CH:8]=[N:7]1
Reactant: N#Cc1ccc(Cn2cncc2CCCCl)c(-c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: N#Cc1ccc(C2CCCC3CN=CN32)c(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-[5-(3-chloropropyl)imidazol-1-ylmethyl]biphenyl-3-carbonitrile (1.0 g, 3.0 mmol) in THF (16 mL) at 0° C. is added t-BuOK/THF (1.0 M, 6 mL, 6.0 mmol). The mixture is warmed up to ambient temperature and stirred for 2 h. The reaction mixture is quenched by saturated aqueous NH4Cl and partitioned between CH2Cl2 and brine. The organic layer is washed by brine, dried over anhydrous Na2SO4 and concentrated to give the crude oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 300 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.50-1.66 (m, 1 H), 1.73-1.83 (m, 1 H), 1.83-1.95 (m, 1 H), 1.95-2.16 (m, 1 H), 2.68-2.95 (m, 2 H), 5.28 (dd, J=8.5, 5.2 Hz, 1 H), 6.83 (s, 1 H), 7.01-7.15 (m, 2 H), 7.27-7.35 (m, 2 H), 7.43-7.54 (m, 3 H), 7.58 (s, 1 H), 7.62 (d, J=8.3 Hz, 1 H). Resolution of the enantiomers of the title compound is achieved by Chiral HPLC using the ChiralPak AD column with a 20% IPA/Hexane mobile phase.
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:16]([F:19])([F:18])[F:17])[CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[OH-].[Na+]>CO>[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[S:7][CH2:6][CH2:5][C@H:4]([NH:14][CH:15]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:16]([F:19])([F:17])[F:18])[C:3]([OH:27])=[O:2]
Reactant: COC(=O)[C@H](CCSc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@H](CCSc1ccccn1)NC(c1ccc(F)cc1)C(F)(F)F
Reaction time: 2 h

Procedure:
4-(Pyridin-2-ylsulfanyl)-2(S)-[2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino]butyric acid methyl ester was dissolved in methanol (2 mL) and 1N NaOH (1.2 mL) was added. After stirring for 2 h, methanol was removed and the aqueous layer was acidified to pH 5. After extracting with ethyl acetate the organic layer was dried and concentrated to give 4-(pyridin-2-ylsulfanyl)-2(S)-[2,2,2-trifluoro-1-(4-fluorophenyl)ethylamino]butyric acid as an oil which was then converted to the title compound as described above. MS (485.5 M+1)
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)=[O:7])(O)=[O:2].S(Cl)([Cl:25])=O>C(OCC)C>[Cl:25][C:1]([CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([C:16]2([OH:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:15])=[CH:10][CH:9]=1)=[O:7])=[O:2]
Reactant: O=C(O)CCC(=O)c1ccc(C(=O)C2(O)CCCCC2)cc1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)CCC(=O)c1ccc(C(=O)C2(O)CCCCC2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
A 250-ml round-bottomed flask fitted with a condenser was charged with 12.0 g of 1-hydroxycyclohexyl 4-(2-carboxyethyl)carbonylphenyl ketone (0.04 mole), 5.95 g (0.05 mole) of thionyl chloride (Aldrich Chemical Co., Milwaukee, Wis.), and 50 ml of diethyl ether. The resulting reaction mixture was stirred at 30° C. for 30 minutes, after which time the solvent was removed under reduced pressure. The residue, a white solid, was maintained at 0.01 Torr for 30 minutes to remove residual solvent and excess thionyl chloride, leaving 12.1 g (94 percent) of 1-hydroxycyclohexyl 4-(2-chloroformylethyl)carbonylphenyl ketone.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]([F:26])([F:25])[S:15]([C:18]1[CH:23]=[CH:22][C:21](Cl)=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][C:21]2[CH:22]=[CH:23][C:18]([S:15]([C:14]([F:26])([F:25])[F:13])(=[O:17])=[O:16])=[CH:19][CH:20]=2)[CH:11]=[C:10]([O:12][C:21]2[CH:20]=[CH:19][C:18]([S:15]([C:14]([F:25])([F:13])[F:26])(=[O:17])=[O:16])=[CH:23][CH:22]=2)[CH:9]=1
Reactant: COC(=O)c1cc(O)cc(O)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc(Oc2ccc(S(=O)(=O)C(F)(F)F)cc2)c1

Procedure:
A mixture of methyl 3,5-dihydroxybenzoate (100 mg, 0.595 mmol), 4-(trifluoromethylsulfonyl)chlorobenzene (291 mg, 1.189 mmol) and potassium carbonate (330 mg, 2.379 mmol) was heated in DMF to give 3,5-bis-(4-trifluoromethanesulfonyl-phenoxy)-benzoic acid methyl ester. It was then hydrolysed with potassium hydroxide (25 mg) in THF (10 mL) and water (10 mL) to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 8.11 (d, J=9.2 Hz, 4H), 7.57 (d, J=2.11 Hz, 2H), 7.39 (d, J=9.2 Hz, 4H), 7.39 (m, 1H).
Reaction SMILES: [CH:1]([C@H:4]1[CH2:8][O:7][C:6](/[CH:9]=[C:10](\[CH3:27])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[N:5]1)(C)C.C(C/C(/C)=C/CC/C(/C)=C/CC(Cl)=O)/C=C(/CCC=C(C)C)\C>>[CH3:1][C@H:4]1[CH2:8][O:7][C:6](/[CH:9]=[C:10](\[CH3:27])/[CH2:11][CH2:12]/[CH:13]=[C:14](\[CH3:26])/[CH2:15][CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][CH:21]=[C:22]([CH3:24])[CH3:23])=[N:5]1
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C1=N[C@@H](C(C)C)CO1
Agent: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/CC(=O)Cl
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C(C)=C/C1=N[C@@H](C)CO1
Yield: 11 %

Procedure:
Similar to the preparation of 27a, the reaction of 25 with 26b afforded the desired compound 27b (12 mg, 11%) as oil. TLC Rf: 0.35 (20% EtOAc/petroleum ether); 1H NMR (400 MHz, CDCl3): δ 5.11-5.08 (m, 2H), 4.33-4.31 (m, 1H), 3.76-3.77 (m, 1H), 2.14-1.94 (m, 12H), 1.72-1.41 (m, 16H), 1.28-1.19 (m, 5H). LCMS: MS (m/z): 344.30 (M+H); ret. time: 5.23 min.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[NH2:9].[CH3:10][O:11][C:12]1[C:17](B(O)O)=[CH:16][CH:15]=[CH:14][N:13]=1>>[Cl:8][C:6]1[N:5]=[N:4][C:3]([NH2:9])=[C:2]([C:17]2[C:12]([O:11][CH3:10])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: COc1ncccc1B(O)O
Product: COc1ncccc1-c1cc(Cl)nnc1N

Procedure:
The title compound was prepared in analogy to example 1, intermediate b, from 4-bromo-6-chloropyridazin-3-amine (CAS RN 446273-59-2) and 2-methoxypyridine-3-boronic acid (CAS RN 163105-90-6) after a reaction time of 18 hours. Brown solid (49%). MS (ESI+): m/z=237.054 ([M+H]+).