Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[K+]>C(O)C>[CH:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OC1CCCc2ccccc21
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Tris(triphenylphosphine)ruthenium (II) chloride (1.9 mg, 2 μmol, 0.5 mol %) and a chiral ligand (M=Ru, R=i-Pr, Ar=C6H5—, 1.3 μmol, 0.33 mol %) were dissolved in ethanol (3 mL) under nitrogen atmosphere, and then heated and stirred for 1 h at 80° C. After the mixture was cooled to room temperature, 1-tetralone (0.4 mmol), ethanol (2 mL) and a solution of potassium hydroxide in ethanol (0.4 mL, 0.2 M) were added thereto. Thereafter, the reaction system was placed in an autoclave, and stirred for 48 h under H2 (10 atm) at 0° C. The solvent was removed under reduced pressure, and the resultants were separated by column chromatography (silica gel column; eluent: ethyl acetate/petroleum ether=1/5). Accordingly, pure 1,2,3,4-tetrahydro-1-naphthol was obtained and the ee value (ee=99.7%) was measured by GC analysis.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6].Cl[C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1.O>CN(C=O)C>[CH2:3]([N:7]([C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=1)[S:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNS(=O)(=O)c1ccccc1
Reactant: Cn1c(Cl)nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCN(c1nc2ccccc2n1C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.029 g, 0.0012 mol, 1.1 equiv) was suspended in DMF (5 mL). N-Butyl-benzenesulfonamide (0.256 g, 0.222 mL, 0.0012 mol. 1.2 equiv) was then added and stirred at room temperature for 10 minutes. To the resulting mixture was then added the 2-chloro-N-methyl benzimidazole, (0.166 g, 0.001 mol). The resulting mixture was heated to 50° C. and stirred overnight (16 hours). The resulting mixture was then poured into water (15 mL) and stirred for 1 hour. The resulting solution was extracted with DCM (20 mL) and the organic layer was separated. The organic layer was washed with 1N NaOH (20 mL), and brine (20 mL), then dried over Na2SO4 and evaporated under reduced pressure. The resulting residue was purified by reverse phase HPLC (eluent 60-80% acetonitrile) to yield the title compound as a yellowish solid. MS 343.4
Reaction SMILES: [CH2:1]([C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:17]([Mg]Br)[CH:18]=[CH2:19]>C1COCC1>[CH2:1]([C:9]1[CH:10]=[CH:11][C:12]([CH:13]([OH:14])[CH2:19][CH:18]=[CH2:17])=[CH:15][CH:16]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc(C=O)cc1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(CCCCCCCC)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
4-octylbenzaldehyde (10.0 g, 45.8 mmol) (Aldrich) was dissolved in THF (229 ml) under nitrogen. The reaction was cooled to about 0-5° C. in an ice bath. A solution of allylmagnesium bromide (48.1 ml, 48.1 mmol) (Aldrich) was added slowly and the reaction stirred for about 2 h. The reaction was quenched by the addition of saturated ammonium chloride followed by addition of ethyl acetate. The layers were separated and the aqueous extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, filtered, and evaporated to an off-white oil. The residue was dissolved in ether and dried over sodium sulfate and filtered. The solvents were removed under reduced pressure to provide 1-(4-octylphenyl)but-3-en-1-ol (11.54 g, 44.3 mmol, 97% yield) as a light yellow oil: LC/MS (method f) Rt=2.90 min.; MS m/z: 243.21 (M-water)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH:3]([N+:10]([O-])=O)[CH:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[H][H]>C(O)(C)C.C(O)(=O)C.[Pd]>[NH2:10][CH:3]([CH:2]([CH3:13])[CH3:1])[CH:4]([OH:9])[C:5]([F:6])([F:7])[F:8]
Reactant: [H][H]
Reactant: CC(C)C(C(O)C(F)(F)F)[N+](=O)[O-]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(C)C(N)C(O)C(F)(F)F
Temperature: 5 °C

Procedure:
A solution of 4-methyl-3-nitro-1,1,1-trifluoro-2-pentanol (17.1 g) in isopropanol (115 ml) and acetic acid (0.43 ml) was hydrogenated over 10% palladium on carbon (2.4 g) at 3.5 barg pressure until uptake of hydrogen was complete. The catalyst was removed by filtration through diatomaceous earth and the filter cake washed with isopropanol. The filtrate was evaporated under vacuum until no further isopropanol distilled and the residue dissolved in acetonitrile (40 ml). A solution of oxalic acid (3.94 g) in acetonitrile (80 ml) was added with stirring and the mixture cooled to 5° C. The product which crystallised was collected by filtration, washed with cold acetonitrile and dried at 50° C. to give 3-amino-4-methyl-1,1,1-trifluoro-2-pentanol as its oxalate salt (9.08 g). ##STR4##
Reaction SMILES: [CH2:1]([N:8]([C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1I)[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>[N+](CC)(CC)(CC)CC.[Cl-].CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([N:8]1[C:9]2([CH:10]=[CH:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14]2)[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(N(Cc2ccccc2)C(=O)c2ccccc2I)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC[N+](CC)(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1C=CC2(CC1)c1ccccc1C(=O)N2Cc1ccccc1
Temperature: 110 °C

Procedure:
A mixture of tert-butyl 4-[benzyl(2-iodobenzoyl)amino]-3,6-dihydropyridine-1(2H)-carboxylate (4.63 mmol), Pd(OAc)2 (73 mg, 0.32 mmol, 7 mol %), PPh3 (170 mg, 0.65 mmol, 14 mol %), K2CO3 (959 mg, 6.95 mmol) and Et4NCl (537 mg, 3.24 mmol) in CH3CN (30 ml) is degassed by Argon for 15 min then heated at 110° C. in a sealed tube overnight. Water (40 ml) is added, the layers are separated and the aqueous layer is extracted with EtOAc (40 ml). The combined extracts are washed with brine (40 ml), dried over Na2SO4 and evaporated. The residue is purified by flash column to give the title compound as a light yellow oil.
Reaction SMILES: Cl.Br[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[CH:9]([C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[CH:9]([C:12]1[CH:17]=[CH:16][C:15]([C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)=[CH:14][CH:13]=1)([CH3:11])[CH3:10]
Reactant: Brc1ccncc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(C)c1ccc(-c2ccncc2)cc1

Procedure:
Part A. A solution of 4-bromopyridine hydrochloride (1.0 g, 6.3 mmol) in acetonitrile-water (50 mL/20 mL) is treated with 4-isopropylbenzeneboronic acid (1.04 g, 6.3 mmol) and sodium carbonate (2.1 g, 25.2 mmol). The mixture is degassed twice, and a catalytic quantity of tetrakis(triphenylphosphine)palladium is added. The mixture is heated to reflux for 12 h., then cooled and poured into water (50 mL). The mixture is filtered and extracted with ethyl acetate (3×50 mL). The extracts are combined, washed with brine, dried over magnesium sulfate, filtered and evaporated to afford 1.01 g of sufficiently pure product, 4-(4-isopropyl-phenyl)-pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([S:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[S:9])=[CH:4][CH:3]=1.[N+](=[CH2:21])=[N-]>C(OCC)C>[CH3:21][O:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][S:10][C:8](=[S:9])[NH:7][CH2:6][C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)CCCSC(=S)NCc1ccc(Cl)cc1
Solvent: CCOCC
Product: COC(=O)CCCSC(=S)NCc1ccc(Cl)cc1

Procedure:
1.5 G. of 4-{[(p-chlorobenzyl)thiocarbamoyl]thio}-butyric acid were dissolved in 30 ml. of diethyl ether and treated with an excess of an ethereal diazomethane solution. The resulting solution was evaporated. The residue was recrystallized from cyclohexane, and 1.2 g. of 4-{[(p-chlorobenzyl)thiocarbamoyl]thio}-butyric acid methyl ester having a melting point of 60°-62° C. were obtained.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.[F:16][C:17]([F:28])([F:27])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CN(C)C=O>[F:16][C:17]([F:27])([F:28])[O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:3]2[C:4](=[O:15])[C:5]3[C@@H:6]4[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]4)[C:10]=3[N:2]2[CH3:1])=[CH:21][CH:20]=1
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: CN(C)C=O
Product: Cn1c2c(c(=O)n1Cc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 100 °C
Yield: 60.2 %

Procedure:
A mixture of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 100 mg, 0.49 mmol) and 4-trifluoromethoxy-benzyl bromide (77 μL, 0.48 mmol) in N,N-dimethylformamide (5 mL) was heated at 100° C. overnight. The reaction mixture was evaporated and the residue was purified using a Biotage 40S system, eluting with 0-1% methanol/chloroform, followed by drying under high vacuum to give (4S,7R)-2-(4-trifluoromethoxy-benzyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (110 mg, 60%) as a light yellow oil. APCI-MS (M+H) 381.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([OH:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[H-]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:25]([O:24][CH:19]([CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])=[CH:17][CH:16]=1)[C:20]([O:22][CH3:23])=[O:21])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COC(=O)C(O)Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Product: COC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)OCc1ccccc1

Procedure:
In a similar manner to that described in Reference example 1(c), a reaction was carried out using methyl 3-[4-(2-t-butoxycarbonylaminoethoxy)phenyl]-2-hydroxypropionate (398 mg), which is obtained in a similar manner to that described in Reference example 39(a), benzylbromide (0.28 ml), hydride (55% suspension in oil, 168 mg) and tetrabutylammonium iodide (43 mg) and the reaction mixture was treated to afford the desired compound (133 mg) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:11]=1[CH2:12][O:13][C:14]1[CH:19]=[C:18]([CH3:20])[N:17]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=2[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16](=[O:32])[CH:15]=1.CN1CCOCC1.Cl[C:46]([O:48][CH3:49])=[O:47]>CC(N(C)C)=O>[F:37][C:35]1[CH:34]=[CH:33][C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[C:23]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:24]([O:26][CH3:27])=[O:25])[C:16](=[O:32])[CH:15]=2)=[C:10]([CH2:9][NH:8][C:46]([O:48][CH3:49])=[O:47])[CH:36]=1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)cc(OCc3ccc(F)cc3CN)cc2=O)c1
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)OC)ccc2C)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled (0° C.) solution of methyl 3-[4-{[2-(aminomethyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate trifluoroacetate (from Step 2) (0.50 g, 0.95 mmol) in DMA (4 mL) was added 4-methylmorpholine (0.21 mL, 1.9 mmol) and methyl chloroformate (0.08 mL, 1.0 mmol). Reaction was stirred at RT for 1 h. Solvent removed by distillation. Crude product purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (30 mL) and extracted in DCM (3×25 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to a white solid, dried in vacuo (0.36 g, 81%). 1H NMR (CD3OD/400 MHz) δ8.03 (m, 1H), 7.77 (s, 1H), 7.53 (d, 1H, J=7.6 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.89 (s, 3H), 3.65 (s, 3H), 2.12 (s, 3H), 1.89 (s, 3H). ESHRMS m/z 469.1767 (M+H calculated for C25H26FN2O6 requires 469.1769).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])(=[O:6])[CH2:4][CH3:5]>C(OCC)C>[Br:1][CH:4]([CH3:5])[C:3]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:6]
Reactant: CCC(=O)c1cccc(C(=O)OC)c1
Reactant: BrBr
Solvent: CCOCC
Product: COC(=O)c1cccc(C(=O)C(C)Br)c1
Reaction time: 0.17 h

Procedure:
Bromine (4.6 ml) was dropped at 20-30° C. over 20 min. to a solution of methyl 3-propionyl-benzoate (17.24 g) in diethyl ether (0.15 L). Stirring was continued for 10 min. and the reaction mixture was then evaporated in vacuum to give methyl 3-(2-bromo-propionyl)-benzoate (25.5 g) as a yellow oil.
Reaction SMILES: C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.F[B-](F)(F)F.C1(C(N)C2CCCCC2)CCCCC1.[C:33]([O:37][CH3:38])(=[O:36])[CH:34]=[CH2:35].FC(F)(F)S(O[C:45]1[C:50]([N+:51]([O-:53])=[O:52])=[CH:49][C:48]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)=[CH:47][C:46]=1[C:62](=[O:64])[CH3:63])(=O)=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCOCC1.CCOCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:62]([C:46]1[CH:47]=[C:48]([O:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:49]=[C:50]([N+:51]([O-:53])=[O:52])[C:45]=1[CH:35]=[CH:34][C:33]([O:37][CH3:38])=[O:36])(=[O:64])[CH3:63]
Reactant: C=CC(=O)OC
Reactant: CC(=O)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CCOCC
Product: COC(=O)C=Cc1c(C(C)=O)cc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
100 g of molecular sieve (4 Å), tris(dibenzylideneacetone)dipalladium (5.88 g, 6.42 mmol), tri-tert-butylphosphonium-tetrafluoroborate (3.50 g, 12.06 mmol), dicyclohexylmethylamine (81.2 mL, 0.371 mol), dried tetrabutylammonium iodide (105.8 g, 0.286 mol), and methyl acrylate (32.6 mL, 0.362 mol) are added to a solution of 2-acetyl-4-benzyloxy-6-nitrophenyl trifluoromethanesulfonate (100.0 g, 0.238 mol) in dioxane (360 mL) under a nitrogen atmosphere. The reaction mixture is stirred for 2 hours at 80° C., diluted with ether (2 L) and combined with 500 g silica gel. The suspension is stirred for 10 minutes, filtered, and the silica gel is washed several times with ether (4×600 mL). The combined organic phases are washed with 1 M aqueous hydrochloric acid (300 mL), sodium bicarbonate solution, and sodium chloride solution, dried with sodium sulfate, and evaporated down. The oily crude product is recrystallized from hot ethanol (0.75 L). The precipitate is filtered off, washed with ethanol (2×50 mL) and dried at 40° C. Yield: 32.2 g (38%); mass spectroscopy: [M+H]+=356.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[C:9]([F:10])=[CH:8][C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[C:6]([CH3:16])[CH:5]=1)[CH3:3].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH2:25][CH:24]([C:29](O)=[O:30])[CH2:23][CH2:22]2.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CN(C)C=O>[F:10][C:9]1[CH:8]=[C:7]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[C:6]([CH3:16])=[CH:5][C:4]=1[CH:2]([NH:1][C:29]([CH:24]1[CH2:23][CH2:22][C:21]2[C:26](=[CH:27][CH:28]=[C:19]([O:18][CH3:17])[CH:20]=2)[CH2:25]1)=[O:30])[CH3:3]
Reactant: Cc1cc(C(C)N)c(F)cc1NS(C)(=O)=O
Reactant: COc1ccc2c(c1)CCC(C(=O)O)C2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCC(C(=O)NC(C)c1cc(C)c(NS(C)(=O)=O)cc1F)C2
Temperature: 50 °C
Yield: 36.3 %

Procedure:
In a 20 ml vial, N-[4-(1-amino-ethyl)-5-fluoro-2-methyl-phenyl]-methanesulfonamide (100 mg, 0.4 mmol), 6-methoxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (100 mg, 0.49 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (380 mg, 1.0 mmol) were dissolved in N,N-dimethylformamide (8 mL). N,N-Diisopropylethylamine (400 uL, 2.0 mmol) was added while stirring. The reaction was heated for 1 hour at 50° C. After cooling the reaction to room temperature, saturated NaHCO3 solution (20 ml) was poured into the vial and extracted with DCM (3×30 ml). The combined organics was washed once with brine (40 ml), dried over NaSO4, filtered and concentrated. Purification by HPLC yielded a solid (63.1 mg, 30%). m/z=435.2 (M+1). 1H-NMR (400 MHz, DMSO-d6) δ 9.24 (s, 1H), 8.34 (t, 1H, J=7.60 Hz), 7.21 (d, 1H, J=8.67 Hz), 7.06 (d, 1H, J=11.56 Hz), 7.00-6.97 (m, 1H), 6.68-6.62 (m, 2H), 5.11-5.06 (m, 1H), 3.68 (s, 3H), 3.00 (d, 31-1, J=0.97 Hz), 2.77-2.68 (m, 4H), 2.57-2.51 (m, 1H), 2.25 (s, 3H), 1.95-1.88 (m, 1H), 1.70-1.54 (m, 1H), 1.33 (d, 3H, J=7.13 Hz).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH2:17][C:16](=[NH:18])[N:15]([C:19]2[C:24]([CH:25]([CH3:27])[CH3:26])=[CH:23][CH:22]=[CH:21][C:20]=2[CH:28]([CH3:30])[CH3:29])[CH2:14]1)([CH3:3])[CH3:2].[Cl-:31].[Cl-].[Cl-].[CH:34]1([Ti+3:39])[CH:38]=[CH:37][CH:36]=[CH:35]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl-:31].[Cl-:31].[CH:34]1([Ti+2:39])[CH:38]=[CH:37][CH:36]=[CH:35]1.[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[CH2:17][C:16](=[NH:18])[N:15]([C:19]2[C:20]([CH:28]([CH3:30])[CH3:29])=[CH:21][CH:22]=[CH:23][C:24]=2[CH:25]([CH3:27])[CH3:26])[CH2:14]1)([CH3:3])[CH3:2]
Reactant: [Ti+3]C1C=CC=C1
Agent: CC(C)c1cccc(C(C)C)c1N1CC(=N)N(c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: [Ti+2]C1C=CC=C1
Temperature: 4 °C
Reaction time: 1 h

Procedure:
To a suspension of 1,3-bis(2,6-diisopropylphenyl)-iminoimidazoline (2.03 g, 5.0 mmol) and cyclopentadienyltitanium trichloride (1.10 g, 5.0 mmol) in toluene (30 mL) was added triethylamine (0.8 mL, 5,7 mmol) at ambient temperature. After stiriring for 1 hour, the thick yellow-orange suspension was diluted with toluene (50 mL) and ligroin (120 mL). The suspension was heated to reflux and filtered hot. Cooling to approx. 4° C. afforded yellow crystals, which were filtered and washed with cold ligroin to give 1.34 g (46% yield) of NMR pure 1,3-bis(2,6-diisopropylphenyl)-iminoimidazoline cyclopentadienyl titanium dichloride.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]([CH:11]2[CH2:15][CH2:14][CH2:13][S:12]2)=[O:10])=[CH:6][CH:5]=1.C(OCC)(=O)C.O>O1CCCC1.CO>[CH3:3][C:4]1[O:8][C:7]([CH:9]([CH:11]2[CH2:15][CH2:14][CH2:13][S:12]2)[OH:10])=[CH:6][CH:5]=1
Reactant: Cc1ccc(C(=O)C2CCCS2)o1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C(O)C2CCCS2)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 101.6 %

Procedure:
6.69 g (0.18 mol; 1.20 eq) of sodium borohydride were added in small portions to a solution of 30.24 g (0.15 mol; 1.0 eq) of (5-methylfuran-2-yl)-(tetrahydrothiophen-2-yl)methanone in 300 ml of tetrahydrofuran and 50 ml of methanol cooled to 0° C. The reaction medium was stirred at ambient temperature for 3 hours. The reaction medium was poured into 400 ml of ethyl acetate and then 200 ml of water were added. The aqueous phase was extracted with ethyl acetate and then the organic phases were combined, washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and evaporated. 30.22 g of (5-methylfuran-2-yl)-(tetrahydrothiophen-2-yl)methanol were obtained. Quantitative yield.
Reaction SMILES: [C:1]([CH:5]([CH2:8][OH:9])[CH2:6][OH:7])([CH3:4])([CH3:3])[CH3:2].[C:10]1([CH3:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:16]([O:7][CH2:6][CH:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:8][OH:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)(C)C(CO)CO
Reactant: Cc1ccccc1
Product: CC(C)(C)C(CO)COCc1ccccc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-t-butylpropane-1,3-diol (11.0 g.) (E.L. Eliel et al J. Amer Chem Soc. 1968, 90, 3444) was stirred in dry toluene (200 ml), at 20° C. Sodium hydride (2.4 g., 80% dispersion in oil), previously washed with hexane, was added carefully to the stirred mixture. The mixture was stirred at 120° C. for 30 minutes and cooled. Benzyl bromide (9.5 ml) was added dropwise and the mixture heated at 130°, with stirring for 6 hours. The mixture was cooled, water was added and the mixture extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on silica, eluting with 1:4 diethyl ether: hexane. 2-Benzyloxymethyl-3,3-dimethyl-butan-1-ol (8.0 g) was obtained as a colourless
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]2)=[CH:13][CH:12]=1
Reactant: OCCC1CCNCC1
Reactant: O=Cc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCCC1CCN(Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(2-hydroxyethyl)piperidine (21.5 g), 4-fluorobenzaldehyde (17.5 ml) and p-toluene sulfonic acid (3 mg) in benzene (200 ml) was refluxed with separating water as the benzene azeotrope. After 2 hours, the mixture was evaporated in vacuo. The residue was dissolved in methanol (200 ml) and sodium borohydride (6.3 g) was added thereto at 5° C. After stirring at ambient temperature for 1 hour, the mixture was evaporated in vacuo. 4N Hydrochloric acid (200 ml) was added to the residue and washed with ethyl acetate. The aqueous layer was made basic to pH 10 with potassium carbonate and extracted with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate, and evaporated in vacuo to give 1-(4-fluorobenzyl)-4-(2-hydroxyethyl)piperidine (32.0 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:45]=[CH:44][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([O:39]C(C)(C)C)=[O:38])=[O:33])=[CH:30][CH:29]=3)[CH3:27])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[N:16][C:17]4[C:22]([CH:23]=3)=[CH:21][CH:20]=[C:19]([O:24][CH3:25])[CH:18]=4)[N:11]([C@H:26]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([NH:34][CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:44][CH:45]=3)[CH3:27])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)OC(C)(C)C)cc3)cnc2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2cc(-c3cc(-c4cc(Cl)cc(Cl)c4)nn3[C@@H](C)c3ccc(C(=O)NCCC(=O)O)cc3)cnc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of the intermediate from step I (64 mg) in CH2Cl2(2 mL) was added TFA (2 mL). After the reaction was stirred at room temperature for 30 minutes it was concentrated in vacuo and azeotroped with toluene (3×). The resulting light yellow solid was dissolved in 1,4-dioxane and lyophilized overnight to afford the product as a white solid. 1H NMR (DMSO, 500 MHz) 8.8 (d, J=1.6 Hz, 1H), 8.45 (t, J=5.5 Hz, 1H), 8.38 (s, 1H), 7.94 (s, 2H), 7.92 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.0 Hz, 2H), 7.58 (s, 1H), 7.45 (d, J=2.1 Hz, 1H), 7.37 (dd, J=2.3, 8.7 Hz, 1H), 7.28 (s, 1H), 7.2 (d, J=8.0 Hz, 2H), 5.8 (q, J=6.9 Hz, 1H), 3.95 (s, 3H), 3.41 (q, J=6.9 Hz, 2H), 2.45 (t, J=7.1 Hz, 2H), 1.93 (d, J=6.9 Hz, 3H). LC-MS: 3.53 min; (M+H)=588.9.