Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5][C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12].[OH:19]O>C(O)(=O)C>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][S:5]([C:6]1[C:7](=[O:14])[O:8][C:9]([CH3:13])=[CH:10][C:11]=1[OH:12])=[O:19]
Reactant: Cc1cc(O)c(SCc2ccccc2F)c(=O)o1
Reactant: OO
Solvent: CC(=O)O
Product: Cc1cc(O)c(S(=O)Cc2ccccc2F)c(=O)o1

Procedure:
3-(o-Fluorobenzylthio)-4-hydroxy-6-methyl-2-pyrone (13.8 g., 0.0519 mole) and 30% hydrogen peroxide (5.9 g., 0.0519 mole) were mixed with glacial acetic acid (100 ml.) with stirring. After ten days the peroxide had been consumed, and the solution was diluted with water. The resulting mixture was extracted with methylene chloride. The extract was dried (MgSO4) and evaporated to dryness, leaving 13.3 g. (91 percent) of a colored solid. Recrystallization from a mixed hexane-benzene solution gave the pure product as a white solid, m.p. 115°-116°C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([Si:13]([C:16]#[CH:17])([CH3:15])[CH3:14])([CH3:12])([CH3:11])[CH3:10].CCOC(C)=O>C1COCC1.C(N(CC)CC)C.[Cu]I>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:17]#[C:16][Si:13]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:15])[CH3:14])=[N:3][CH:4]=1
Reactant: C#C[Si](C)(C)C(C)(C)C
Reactant: Brc1ccc(Br)nc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)C#Cc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under an argon atmosphere 0.80 g (4.20 mmol) of CuI and 2.90 g (4.13 mmol) of bis(triphenylphosphane)palladium (II) chloride were added to a solution of 49.90 g (201.0 mmol) of 2,5-dibromopyridine and 43.0 mL (225.6 mmol) of tert-butylethynyldimethylsilane in 500 mL of dry THF and 120 mL of triethylamine at −7° C. and the mixture was stirred for 30 minutes at 0° C. The reaction mixture was stirred for a further 3.5 hours at RT, then filtered and the filtrate was evaporated down in vacuo. The residue was dissolved in 1 L of EtOAc, the organic phase was washed with water and saturated NaCl solution, dried over sodium sulfate, and evaporated down in vacuo. The crude product was reacted further without purification. Yield: 59.5 g (quant. yield); C13H18BrNSi (M=296.278); calc.: molpeak (M+H)+: 296/298 (Br); found: molpeak (M+H)+: 296/298 (Br); Rf value: 0.75 (silica gel, cyc/EtOAc 8:1).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O1[CH2:22][CH2:21][NH:20]C1=O>>[CH:11]1[C:12]2[C:7](=[CH:6][C:5]3[C:14]([C:13]=2[O:15][CH2:22][CH2:21][NH2:20])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C1c2ccccc2Cc2ccccc21
Reactant: O=C1NCCO1
Agent: [K+]
Agent: [OH-]
Product: NCCOc1c2ccccc2cc2ccccc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 35.2 %

Procedure:
ExxonMobil™ Aromatic 100 solvent vvas added into a 3-neck round bottom flask containing anthrone (10 g, 51.5 mmol) at room temperature. Potassium hydroxide pellets (0.33 g, 5.15 mmol) and 2-oxazolidinone (7.62 g, 87.5 mmol) were added, and the reaction mixture was heated to reflux and stirred for 2.5 h under nitrogen. The reaction mixture was cooled to room temperature, decanted, and filtered. The solvent was evaporated in vacuo to give 4.3 g (35%) of the desired amine. The crude reaction mixture could be further purified by flash column chromatography. 1H NMR (DMSO-d6, 400 MHz) δ 8.38-8.31 (m, 3H), 8.08-8.02 (m, 2H), 7.56-7.47 (m, 4H), 4.13 (dd, 2H, J=5.58, 5.58 Hz), 3.15 (dd, 2H, J=5.60, 5.60 Hz), 2.91 (bs, 2H). 13C NMR (DMSO-d6, 400 MHz) δ 150.7, 132.8, 128.4, 125.6, 125.4, 124.1, 122.1, 121.9, 78.2, 42.1.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:12][C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[C:10]=1Cl)=[O:5])C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl>CCOC(C)=O>[F:24][C:23]([F:25])([F:26])[C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=1)[CH2:12][N:9]1[C:10]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[C:6]([C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:5])[N:7]=[N:8]1
Reactant: CCOC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1Cl
Reactant: C1COCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1N1CCOCC1)N1CCOCC1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-chloro-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester in morpholine (20 eq). Stir at 70° C. overnight then increase temp to 80° C. and continue stirring for another 60 hours. Cool to RT, pour into separatory funnel with EtOAc and 1N HCl. Separate layers and wash organic layer with 1N HCl and then with brine. Dry over MgSO4, filter, and concentrate. Purify via silica gel chromatography using a gradient of 1:1 to 1:5 hexanes:EtOAc to give the desired product. MS (IS) 494.2 (M+1). Rf=0.16 (1:1 Hexanes:EtOAc)
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[N:7]([C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:8][CH:9]1[CH:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[Na+].Cl[C:40]([O:42][C:43]1[CH:52]=[CH:51][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:45][CH:44]=1)=[O:41]>C1COCC1.O>[C:1]([O:5][C:6]([N:7]([CH2:8][CH:9]1[CH:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][N:11]([C:40]([O:42][C:43]2[CH:44]=[CH:45][C:46]([C:47]([O:49][CH3:50])=[O:48])=[CH:51][CH:52]=2)=[O:41])[CH2:10]1)[C@@H:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[CH3:22])=[O:33])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CNCCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(OC(=O)N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.9 %

Procedure:
To a solution of 238 mg of the crude tert-butyl[(1R)-1-(1-naphthyl)ethyl][(4-phenylpiperidin-3-yl)methyl]carbamate in 3 mL of THF was added 200 mg of sodium hydrogen carbonate while suspending it in 2 mL of water. The reaction mixture was added 170 mg of methyl 4-[(chlorocarbonyl)oxy]benzoate (Fluka). After stirring at room temperature overnight, the mixed solution was extracted with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4-(methoxycarbonyl)phenyl 3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidine-1-carboxylate (353 mg, colorless foamy substance) as a crude product. ESI+: 623
Reaction SMILES: [C:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:19]([CH2:20][CH2:21][C@:4]12[CH3:5])[C@:17]1([CH3:18])[C@H:12]([CH2:13][C@H:14]([O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)#[CH:2].I[C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1.[NH4+].[Cl-].C(OCC)(=O)C>N1CCCC1.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.[Cu]I>[Si:23]([O:22][C@@H:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C@@H:12]([CH2:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH2:7][CH2:8][C@@H:3]2[C:1]#[C:2][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=2)[CH2:13]1)([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C#C[C@H]2CC[C@H]3[C@@H]4CC[C@H]5C[C@H](O[Si](c6ccccc6)(c6ccccc6)C(C)(C)C)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 17β-ethynyl-3α-(t-butyidiphenylsilyloxy)-5α-androstane (120 mg, 0.23 mmol) in pyrrolidine (2 mL) was added to a mixture of tetrakis triphenylposphine palladium (0) (13.28 mg, 0.0115 mmol) and CuI (4.4 mg, 0.023 mmol) in pyrrolidine (1 mL). To the resulting mixture was added 4-iodotoluene (150 mg, 0.69 mmol) and was stirred at RT for 24 h. Addition of saturated aqueous NH4Cl solution followed by ethyl acetate. Extraction of the organic layer with water and brine and drying (Na2SO4) followed by evaporation of the solvent in vacuo and subsequent purification of the residue with flash column chromatography using petroleum ether/acetone 80/20 as eluent afforded the desired compound named above.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].O>CCOCC>[CH3:11][Sn:12]([CH3:14])([CH3:13])[C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: C[Sn](C)(C)c1ccco1
Temperature: -30 °C
Yield: 96.3 %

Procedure:
To a solution of 6.8 g furan in 100 ml dry ether at 0° C. under nitrogen was added 10.5 ml 9.5M n-butyllithium. The reaction mixture was heated at reflux for 15 min., then cooled to -30° C. and 19.9 g trimethyltin chloride was added. The reaction mixture was allowed to warm to room temperature and then poured into water. The ether layer was separated, washed with water and passed through an alumina column, eluting with hexane. Removal of the solvent provided 22.2 g (96%) 2-(trimethylstannyl)furan as a pale-yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:44]=[CH:43][C:6]([CH2:7][N:8]2[C:16]3[CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[CH:12][C:11]=3[C:10]3[N:25]=[C:26]([C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:9]2=3)=[CH:5][CH:4]=1.[CH3:45][C@H:46]1[O:51][C@@H:50]([CH3:52])[CH2:49][NH:48][CH2:47]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C2C=CC=CC=2)C=CC=CC=1P(C(C)(C)C)C(C)(C)C>CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:45][C@H:46]1[CH2:47][N:48]([C:14]2[CH:13]=[CH:12][C:11]3[C:10]4[N:25]=[C:26]([C:33]5[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:40])[F:41])[CH:34]=5)[CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[C:9]=4[N:8]([CH2:7][C:6]4[CH:43]=[CH:44][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[C:16]=3[CH:15]=2)[CH2:49][C@@H:50]([CH3:52])[O:51]1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c3ccc(OS(=O)(=O)C(F)(F)F)cc3n(Cc3ccc(OC)cc3)c12
Reactant: C[C@@H]1CNC[C@H](C)O1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Product: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3n(Cc3ccc(OC)cc3)c12
Temperature: 80 °C
Yield: 56.3 %

Procedure:
A microwave vial containing a mixture of methyl 5-(4-methoxybenzyl)-2-(3-(trifluoromethyl)phenyl)-7-(trifluoromethylsulfonyloxy)-5H-pyrido[3,2-b]indole-4-carboxylate (51 mg, 0.08 mmol), cis-2,6-dimethylmorpholine (9.8 μL, 0.080 mmol), powdered potassium phosphate, tribasic (51 mg, 0.240 mmol), biphenyl-2-yldi-tert-butylphosphine (11 mg, 0.036 mmol), and Pd(OAc)2 (2.7 mg, 0.012 mmol) was flushed with nitrogen. DME (160 μL) was added and the vial was sealed and heated at 80° C. for 24 hr. The reaction was then partitioned between EtOAc and water and the organic phase was washed with brine and dried with sodium sulfate. The solvent was removed and the residue was chromatographed (step gradient elution with hexane containing 50 to 100% DCM) to afford methyl 7-((2S,6R)-2,6-dimethylmorpholino)-5-(4-methoxybenzyl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (27 mg, 0.045 mmol, 56% yield) as a yellow oil. MS (ESI) m/z 604.40 (M+H). 1H NMR (500 MHz, chloroform-d) δ ppm 8.40 (1H, s), 8.28-8.35 (2H, m), 7.88 (1H, s), 7.56-7.65 (2H, m), 7.03 (1H, dd, J=8.70, 1.98 Hz), 6.89 (2H, d, J=8.55 Hz), 6.81 (1H, d, J=1.83 Hz), 6.72-6.77 (2H, m), 5.66 (2H, s), 3.80-3.89 (2H, m), 3.80 (3H, s), 3.72 (3H, s), 3.54-3.62 (2H, m), 2.54 (2H, m), 1.28 (6H, d, J=6.1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[C:22]2[C:27](=O)[O:26][C:24](=[O:25])[C:23]2=[CH:29][CH:30]=1>CC#N>[Cl:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:29][CH:30]=1)[C:24](=[O:25])[N:1]([CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12][CH:11]=3)[CH2:4][CH2:3]1)[C:27]2=[O:26]
Reactant: O=C1OC(=O)c2cc(Cl)ccc21
Reactant: NC1CCN(CCc2c[nH]c3ccccc23)CC1
Solvent: CC#N
Product: O=C1c2ccc(Cl)cc2C(=O)N1C1CCN(CCc2c[nH]c3ccccc23)CC1
Yield: 43.5 %

Procedure:
4-Amino-1-[2-(indol-3-yl)ethyl]piperidine (3.86 g, 15.9 mmol) was dissolved in warm methyl cyanide (50 cm3) and a solution of 4-chlorophthalic anhydride (2.9 g, 15.9 mmol) in methyl cyanide (20 cm3) was added dropwise with stirring, to precipitate a solid. The suspension was stirred at room temperature overnight then cooled briefly in ice and the solid collected. This crude material was heated in acetic anhydride (70 cm3) for 21/2 hours then the solvent was evaporated. The residue was dissolved in methanol, to destroy excess acetic anhydride, then the methanol was evaporated. The residue was dissolved in very dilute aqueous acetic acid and the solution was basified by addition of conc. ammonia to precipitate a gum. The supernatant layer was decanted and the gum triturated with boiling ethanol and cooled in ice to give crystals of the title compound (2.82 g, 43.6%), m.p. 188°-190° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:25]([CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1)=O.CCCCCC>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:25][CH2:27][CH:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[CH:33][C:34]=2[O:38][CH3:39])[CH2:29]1
Reactant: BrC(Br)(Br)Br
Reactant: COc1cccc2c1CCC(CC=O)C2
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: COc1cccc2c1CCC(CC=C(Br)Br)C2
Reaction time: 0.17 h

Procedure:
To a solution of carbon tetrabromide (19.5 g) in methylene chloride (50 ml) was added triphenylphosphine (30.8 g) at 0° C., and the mixture was stirred for 10 min. To the mixture was added a solution of 2-formylmethyl-5-methoxy-1,2,3,4-tetrahydronaphthalene (4.09 g; the compound prepared by method described in the specification of the Japanese Patent Application No. 3-130467) in methylene chloride (25 ml) at 0° C. The mixture was stirred for 30 min at 0° C. To the mixture was gradually added n-hexane, and filtrated to remove triphenylphosphineoxide. The filtrate was washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=24:1) to give the title compound (6.42 g) having the following physical data.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>ClCCl>[CH3:24][S:25]([OH:27])(=[O:9])=[O:26].[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][OH:13])[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Agent: O=c1[nH]c2cc(Cl)c(Cl)cc2n1CCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred mixture of 31.2 parts of 3-[(2-amino-4,5-dichlorophenyl)amino]-1-propanol hydrochloride in 200 parts of water is added dropwise, during a 15 minutes-period, a solution of 10.6 parts of potassium cyanate in 50 parts of water at a temperature between 15° and 20° C. Upon completion, stirring is continued first for 20 minutes at room temperature and further for 20 hours at reflux. The reaction mixture is allowed to cool over week-end to room temperature. The precipitated product is filtered off and boiled in trichloromethane. The undissolved part is filtered off and boiled in 4-methyl-2-pentanone. After cooling, the product is filtered off and dried, yielding 14.5 parts (48% ) of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one; mp. 174.7° C. To a stirred mixture of 13.3 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one, 8 parts of N,N-diethylethanamine and 260 parts of dichloromethane are added dropwise 7.4 parts of methanesulfonyl chloride. Upon completion, stirring is continued for one hour at reflux temperature. The reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is shaken with acidified water and 4-methyl-2-pentanone. The whole is filtered (the filtrate is set aside) and the filter-cake is dried, yielding a first fraction of 6.2 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate. The 4-methyl-2-pentanone-phase is separated from the filtrate, dried, filtered and evaporated, yielding a second fraction of 8 parts of 5,6-dichloro-1,3-dihydro-1-(3-hydroxypropyl)-2H-benzimidazol-2-one methanesulfonate as an oily residue.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH2:5][CH:6]2[C:11]([CH3:13])([CH3:12])[O:10][C:9](=[O:14])[NH:8][C:7]=12.[Br:15]Br>C(O)(=O)C>[Br:15][C:4]1[CH2:5][CH:6]2[C:11]([CH3:12])([CH3:13])[O:10][C:9](=[O:14])[NH:8][C:7]2=[C:2]([F:1])[CH:3]=1
Reactant: CC1(C)OC(=O)NC2=C(F)C=CCC21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC1(C)OC(=O)NC2=C(F)C=C(Br)CC21
Reaction time: 0.17 h
Yield: 82.8 %

Procedure:
To a solution of 8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one (0.15 g, 0.77 mmol) in acetic acid (5 mL) was added dropwise a solution of bromine (0.37 g, 2.31 mmol) in acetic acid (5 mL) under nitrogen at rt. After stirred for 10 minutes, the mixture was concentrated and the residue obtained was purified by a silica gel column (hexane:ethyl acetate/4:1) to afford 6-bromo-8-fluoro-4,4-dimethyl-dihydro-benzo[d][1,3]oxazin-2-one as an off-white solid (0.176 g, 84%) which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@H:26]([OH:37])[C:27]1[CH:32]=[CH:31][C:30]([Sn](C)(C)C)=[CH:29][CH:28]=1)=[O:23]>CN(C=O)C.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]>[Cl:20][CH:21]([Cl:40])[C:22]([NH:24][C@H:25]([CH2:38][F:39])[C@@H:26]([C:27]1[CH:28]=[CH:29][C:30]([C:16]2[CH:17]=[CH:18][C:13]([CH:9]3[CH2:10][CH2:11][CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:14][CH:15]=2)=[CH:31][CH:32]=1)[OH:37])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)cc1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)cc2)cc1
Temperature: 80 °C
Yield: 29.9 %

Procedure:
A mixture of commercially available 2-(4-Bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (500 mg, 1.53 mmol), 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(trimethylstannyl)phenyl)propan-2-yl)acetamide (679 mg, 1.53 mmol, 1 eq.), P(2-fur)3 (72 mg, 0.31 mmol, 0.2 eq.) and Pd2(dba)3 (142 mg, 0.153 mmol, 0.1 eq.) are dissolved in DMF (8 mL, 0.2 M) and de-oxygenated. The mixture is heated to 80° C. for 16 hours. Reaction is concentrated under vacuum to a syrup and purified on a 24 g silica column eluting from 0-100% EtOAc/heptane) to give the title compound 240 mg.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.Cl.O.[C:15]([OH:19])(=[O:18])[CH:16]=O>O>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][N:10]=[CH:16][C:15]([OH:19])=[O:18])=[CH:7][CH:8]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Product: O=C(O)C=NNc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a mixture of 5.0 g of 4-(trifluoromethyl)phenylhydrazine (28.4 mmol), 31 ml of water and 3.1 ml of concentrated hydrochloric acid was added 2.9 g of glyoxylic acid-hydrate (31.4 mmol), and the mixture was stirred for one hour at room temperature. The precipitates thus separated out was collected by filtration, washed with water and dried over phosphorus pentoxide to give 6.26 g of 4-(trifluoromethyl)phenylhydrazonoacetic acid (95%) as a pale yellow powder.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11](C2C(=O)N(CC(C)C)N=C(C3C=CC(C)=C(F)C=3)C=2C)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47]OS(C)(=O)=O)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1.CN1CCNCC1>>[F:34][C:35]1[CH:63]=[CH:62][C:38]([CH2:39][N:40]2[C:45](=[O:46])[C:44]([CH2:47][N:11]3[CH2:12][CH2:13][N:8]([CH3:6])[CH2:9][CH2:10]3)=[CH:43][C:42]([C:53]3[CH:58]=[CH:57][C:56]([O:59][CH3:60])=[C:55]([F:61])[CH:54]=3)=[N:41]2)=[CH:37][CH:36]=1
Reactant: Cc1ccc(-c2nn(CC(C)C)c(=O)c(N3CCN(C(=O)OC(C)(C)C)CC3)c2C)cc1F
Reactant: COc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Agent: CN1CCNCC1
Product: COc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(Cc3ccc(F)cc3)n2)cc1F
Yield: 45.8 %

Procedure:
Following the procedure of Example 1 (10), 2-(4-fluorobenzyl)-6-(3-fluoro-4-methoxyphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and 1-methylpiprazine were reacted to yield the title compound as a slightly-brown crystalline powder (yield: 45.8%).
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:10](=[O:11])[CH2:9][CH2:8][CH:7]1[CH2:12][C:13](OC)=[O:14].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:5]([C@H:6]1[CH:10]([OH:11])[CH2:9][CH2:8][C@@H:7]1[CH2:12][CH2:13][OH:14])[CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCC1C(=O)CCC1CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC[C@H]1C(O)CC[C@@H]1CCO

Procedure:
This compound was prepared in a way similar to that described in Example 2, by reacting methyl dihydrojasmonate in tetrahydrofuran with lithium aluminium hydride at 50° C. for 4 hours.