Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Br)[C:28]#[CH:29].[Cl-].[NH4+]>C(OCC)C.C(#N)C>[Cl:1][C:2]1[C:7]([O:8][CH2:29][C:28]#[CH:27])=[CH:6][C:5]([N:9]2[C:17](=[O:18])[C:12]3=[CH:13][CH2:14][CH2:15][CH2:16][N:11]3[C:10]2=[O:19])=[C:4]([F:20])[CH:3]=1
Reactant: C#CCBr
Reactant: O=C1C2=CCCCN2C(=O)N1c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: C#CCOc1cc(N2C(=O)C3=CCCCN3C2=O)c(F)cc1Cl
Yield: 54.1 %

Procedure:
An acetonitrile (15 mL) solution of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.82 g, 2.76 mmol), potassium carbonate (0.29 g, 2.07 mmol) and propargylbromide (0.27 mL, 3.04 mmol) was stirred fir 4.5 hours under reflux. A saturated ammonium chloride solution (15 mL) and diethyl ether (15 mL) were added to the resulting mixture, and the organic layer was separated and then the aqueous layer was extracted with diethyl ether (15 mL×2 times). The organic layer combined was washed with a saturated sodium chloride solution (20 mL) and dried over anhydrous magnesium sulfate. After removal of magnesium sulfate by filtration, the filtrate was evaporated to give crude product, which was purified by silica gel column (Wakogel C-200, ethyl acetate/hexane=1/2) to obtain a pale yellow solid of 2-(4-chloro-2-fluoro-5-propargyloxyphenyl)-5,6-dihydroimidazo [1,5-a] pyridine-1,3[2H, 7H]-dione (0.50 g, yield:56.6%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=3[F:24])=[C:12]([C:25]3[C:29]([CH3:31])([CH3:30])[CH2:28][CH2:27][CH:26]=3)[CH:11]=2)[CH:3]=1.[Br-].[CH2:33]([O:35][C:36](=[O:40])[CH2:37][CH2:38][Zn+])[CH3:34]>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].CC(P(C(C)(C)C)[C]1[CH][CH][CH][CH]1)(C)C.C1C=CC([C]2[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C](C3C=CC=CC=3)[C]2C2C=CC=CC=2)=CC=1.[Fe].C1COCC1>[CH3:30][C:29]1([CH3:31])[C:25]([C:12]2[CH:11]=[C:10]([CH2:9][O:8][C:4]3[CH:3]=[C:2]([CH2:38][CH2:37][C:36]([O:35][CH2:33][CH3:34])=[O:40])[CH:7]=[CH:6][N:5]=3)[CH:15]=[CH:14][C:13]=2[C:16]2[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=2[F:24])=[CH:26][CH2:27][CH2:28]1
Reactant: COc1ccc(F)c(-c2ccc(COc3cc(Br)ccn3)cc2C2=CCCC2(C)C)c1
Reactant: CCOC(=O)CC[Zn+]
Agent: [Fe]
Agent: [Pd]
Agent: CC(C)(C)P([C]1[CH][CH][CH][CH]1)C(C)(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccnc(OCc2ccc(-c3cc(OC)ccc3F)c(C3=CCCC3(C)C)c2)c1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 78 %

Procedure:
To a sealed tube containing 95.A (0.1059 g, 0.22 mmol), bis(dibenzylideneacetone)palladium (0.0068 g, 0.012 mmol), and CTC-Q-Phos (commercially available from Strem Chemicals) (0.0079 g, 0.011 mmol) was added dry THF (2.1 mL). After 5 minutes, 3-ethoxy-3-oxopropylzinc bromide, 0.5 M solution in THF (0.9 mL, 0.45 mmol) was added dropwise. After 1 hour, the mixture was heated to 80° C. and monitored with TLC and LC-MS. After 16.5 hours, the reaction was cooled to room temperature, and then the organic solvent was removed under reduced pressure. The solid was filtered off, and the solvent was concentrated. The residue was purified by silica gel flash chromatography (0-40% EtOAc/hexane) to afford 95.B (86.2 mg, 78% yield). 1H NMR (500 MHz) (CDCl3) δ ppm 8.10 (1H, d, J=5.4 Hz), 7.41 (1H, dd, J=7.9, 1.8 Hz), 7.33 (2H, dd, J=4.6, 1.5 Hz), 6.98 (1H, m), 6.81 (3H, m), 6.70 (1H, s), 5.52 (1H, t, J=2.0 Hz), 5.42 (2H, s), 4.15 (2H, q, J=7.1 Hz), 3.76 (3H, s), 2.93 (2H, t, J=7.7 Hz), 2.66 (2H, m), 2.25 (2H, td, J=7.0, 2.4 Hz), 1.66 (2H, t, J=7.0 Hz), 1.25 (3H, t, J=7.1 Hz), 0.86 (6H, s).
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[CH2:31]([O:34][CH2:35][CH:36]1[CH2:41][CH2:40][C:39](=O)[CH2:38][CH2:37]1)[CH:32]=[CH2:33]>>[CH2:31]([O:34][CH2:35][CH:36]1[CH2:41][CH2:40][CH:39]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:38][CH2:37]1)[CH:32]=[CH2:33]
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Reactant: C=CCOCC1CCC(=O)CC1
Solvent: O=C(O)C(F)(F)F
Product: C=CCOCC1CCC(N2CC(NC(=O)CNc3nn(C)c4ccc(C(F)(F)F)cc34)C2)CC1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 18, Step D) and 4-allyloxymethyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[I:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[C:3](=[O:13])[N:20]([CH2:19][C:18]1[CH:21]=[CH:22][CH:23]=[C:16]([O:15][CH3:14])[CH:17]=1)[CH2:11]2
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: COc1cccc(CN)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(CN2Cc3cccc(I)c3C2=O)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 27.3 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.107 g, 0.3 mmol), 3-methoxy-benzylamine (0.052 mL, 0.4 mmol), and K2CO3 (0.138 g, 1.0 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-iodo-2-(3-methoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.031 g, 27%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.78 (s, 3H), 4.16 (s, 2H), 4.74 (s, 2H), 6.79 (m, 3H), 7.14-7.38 (m, 3H), 7.91 (d, 1H). GC-MS: m/z 379 (M)+.
Reaction SMILES: OC(C(F)(F)F)=O.[N:8]1([C:14]2[CH:15]=[N:16][CH:17]=[N:18][CH:19]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[N:18]1[CH:19]=[C:14]([N:8]2[CH2:13][CH2:12][N:11]([C:30]([C:29]3[CH:33]=[CH:34][CH:35]=[C:27]([C:24]4[N:23]=[C:22]([C:21]([F:36])([F:20])[F:37])[O:26][N:25]=4)[CH:28]=3)=[O:31])[CH2:10][CH2:9]2)[CH:15]=[N:16][CH:17]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: c1ncc(N2CCNCC2)cn1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccc(-c2noc(C(F)(F)F)n2)c1)N1CCN(c2cncnc2)CC1
Yield: 32 %

Procedure:
This compound was synthesized from 5-(piperazin-1-yl)pyrimidine TFA salt and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (50 mg, yield 32%). 1H NMR (400 MHz, MeOD) δ 8.61 (s, 1H), 8.52 (s, 2H), 8.29-8.26 (dt, J=6.7 Hz, 1.9 Hz, 1H), 8.23 (m, 1H), 7.76-7.71 (m, 2H), 3.99-3.83 (m, 2H), 3.69 (m, 2H), 3.49 (m, 2H), 3.44-3.36 (m, 2H). MS (ESI) m/z: Calculated for C18H15F3N6O2: 404.12. found: 405.2 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:11])[CH2:8][CH2:9][CH3:10].[C:12]1([CH2:18][CH2:19][N:20]2[C:24](Br)=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]([N:31]([CH2:69][CH2:70][CH3:71])[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[N:49]([C:50]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:48]=[N:47][N:46]=4)=[CH:35][CH:34]=3)=[N:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>[Cu]=O>[C:12]1([CH2:18][CH2:19][N:20]2[C:24]([NH:11][CH2:7][CH2:8][CH2:9][CH3:10])=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]([N:31]([CH2:69][CH2:70][CH3:71])[CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[N:49]([C:50]([C:63]5[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=5)([C:57]5[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=5)[C:51]5[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=5)[N:48]=[N:47][N:46]=4)=[CH:35][CH:34]=3)=[N:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCCCN
Reactant: CCCN(Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1)c1nn(CCc2ccccc2)c(Br)c1C(=O)OCC
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCNc1c(C(=O)OCC)c(N(CCC)Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)nn1CCc1ccccc1

Procedure:
30 mg of reduced copper, 20 mg of copper(II) oxide, 83 mg of potassium carbonate and 5 ml of n-butylamine were added to 216 mg of N-[1-(2-phenylethyl)-5-bromo-4-ethoxycarbonylpyrazol-3-yl]-N-[(2'-(N-triphenylmethyl-(1H-tetrazol-5-yl))biphenyl-4-yl)methyl]-n-propylamine, and heated under reflux for 14 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane-ethyl acetate=7:1) to obtain 92 mg of the intended compound as a pale yellow, amorphous solid.
Reaction SMILES: N(CCO)CCO.CCOCC.[C:13]([CH2:21][C:22]([OH:24])=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+]([O-])([O-])=O.[Ag+:29]>O>[C:13]([CH2:21][C:22]([O-:24])=[O:23])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Ag+:29]
Reactant: O=C(O)CC(=O)c1ccccc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCOCC
Solvent: O
Solvent: OCCNCCO
Product: O=C([O-])CC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 97.1 %

Procedure:
Diethanolamine (0.33 g) was dissolved in water (5 mL), and to this was added an ether solution (20 mL) containing benzoylacetic acid (0.54 g). Next, the mixture was stirred at 15° C. while an aqueous solution (5 mL) containing silver nitrate (0.51 g) was added dropwise, and this further was stirred for 15 minutes. The pale yellow precipitate that settled was filtered off, yielding silver benzoylacetate (yield 0.79 g). FIG. 4 shows the infrared absorption spectrum (IR) of the silver benzoylacetate that was obtained. IR:1687 cm−1, 1540 cm−1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH:9]1[C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:27]=[N+:28]=[N-:29].[Na+].O.CCCCCC.C(OCC)(=O)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([N:27]=[N+:28]=[N-:29])[CH2:10][CH:9]1[C:18]([CH3:26])([CH3:25])[O:19][SiH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)CC1C(C)(C)O[SiH2]C(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC(N=[N+]=[N-])CC1C(C)(C)O[SiH2]C(C)(C)C
Temperature: 60 °C

Procedure:
The 4-methanesulfonyloxy-2-(t-butyl-dimethyl-silanyloxymethyl)-pyrrolidine-1-carboxylic acid t-butyl ester (220.94 mg, 0.54 mmol) was taken up in dry DMF under argon and sodium azide (175.31 mg, 2.70 mmol) was added. The reaction was then heated to 60° C. for 48 h. The reaction was poured into water and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were washed with sat NaHCO3 and brine then dried over MgSO4. The solution was filtered and the solvent removed under reduced pressure. The product was isolated by flash chromatography. (5:1 hexane-ethyl acetate) Yield 184.83 mg. C16H32N4O3Si MS m/e=357.3 (M+H).
Reaction SMILES: CN(C=O)C.[S:6]([Cl:10])(Cl)(=[O:8])=[O:7].[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][CH:16]=1>>[CH3:11][C:12]1[O:13][C:14]([CH3:17])=[CH:15][C:16]=1[S:6]([Cl:10])(=[O:8])=[O:7]
Reactant: O=S(=O)(Cl)Cl
Reactant: Cc1ccc(C)o1
Solvent: CN(C)C=O
Product: Cc1cc(S(=O)(=O)Cl)c(C)o1

Procedure:
2,5-dimethyl-furan-3-sulfonylchloride was prepared by the method of Example 40B with DMF (28 mmoles, 2.2 ml), sulfurylchloride (24 mmoles, 1.9 ml) and 2,5-dimethyl-furan (14 mmoles, 1.5 ml). Flash chromatography (5% ethyl acetate/hexanes) provided 0.61 g (22%) of a yellow liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)N.[CH2:9]([N:11](CC)CC)[CH3:10].S(OCC)(OCC)(=O)=O.O>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:9][NH2:11])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Br)c1
Reactant: CCN(CC)CC
Agent: CCOS(=O)(=O)OCC
Solvent: O
Solvent: CCOCC
Product: NCCc1cccc(Br)c1
Reaction time: 192 h

Procedure:
5 g (29.1 mmol) of 3-bromoaniline in 500 ml of ether are introduced into a round-bottomed flask under a stream of nitrogen. 4.5 ml (32 mmol) of triethylamine and 15.2 ml (117 mmol) of diethyl sulfate are added. The medium is refluxed for 24 hours and then left for 8 days at room temperature. It is then poured into water and extracted with ether. The organic phase is washed with saturated aqueous sodium chloride solution and is then dried over magnesium sulfate, filtered and evaporated. The residue is purified by chromatography on a column of silica eluted with a heptane/ethyl acetate mixture (95/5) and 2.5 g (43%) of the expected product are obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[C:12]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:5][CH:4]=1)[CH3:2].[BH4-].[Na+]>C(O)C>[CH2:18]([O:17][C:12]1[C:11]([CH:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=2)[OH:10])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCc1ccc(C(=O)c2cccnc2OCc2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCc1ccc(C(O)c2cccnc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The above 2-benzyloxy-3-pyridyl 4-ethylphenyl ketone (1.69 g) was dissolved in ethanol (15 ml), and thereto was added sodium borohydride (403 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed with water and successively with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give crude 2-benzyloxy-3-pyridyl-4-ethylphenylmethanol as colorless oil, which was used in the subsequent step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:8][CH2:7]1.[OH-].[Na+]>CO.O>[O:19]([C:16]1[CH:15]=[CH:14][C:13]([O:12][CH:9]2[CH2:10][CH2:11][N:6]([CH2:5][CH2:4][C:3]([OH:26])=[O:2])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCN1CCC(Oc2ccc(Oc3ccccc3)cc2)CC1
Temperature: 50 °C
Yield: 113.5 %

Procedure:
To a solution of the product (143 mg, 0.4 mmol) from step 1 in 4:1 mixture of MeOH/water (2 mL) was added 2M solution of NaOH (241 uL, 0.48 mmol). Reaction mixture was heated at 50° C. for 16 h. Solvent was removed in vacuo, residue was washed with water, dissolved in MeOH and filtered. Filtrate was concentrated to give the product as white solid (155 mg, 100%): MS; m/z 342.5 (M+H); 1H NMR (400 MHz, DMSO-d6); δ 1.99 (br, 2H), 2.17-2.21 (m, 2H), 2.84-2.88 (m, 2H), 3.25-3.32 (m, 7H), 6.92-7.10 (m, 7H), 7.33-7.37 (m, 2H); HPLC (UV); 93%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=1.[CH:16]1[C:28]2[N:27]([CH2:29][CH2:30]O)[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:25]1[C:26]2[N:27]([CH2:29][CH2:30][O:1][C:2]3[CH:3]=[C:4]([S:8][C:9]([CH3:15])([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][CH:7]=3)[C:28]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]=2[CH:22]=[CH:23][CH:24]=1
Reactant: OCCn1c2ccccc2c2ccccc21
Reactant: COC(=O)C(C)(C)Sc1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Sc1cccc(OCCn2c3ccccc3c3ccccc32)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
The title product was prepared according to the procedure described in Method B starting from methyl 2-(3-hydroxyphenylthio)iso-butyrate (prepared as described in example 1) (0.609 g, 2.7 mmol), 9H-carbazol-9-ethanol (0.570 g, 2.7 mmol), DIAD (0.708 g, 3.5 mmol), and triphenylphosphine (0.917 g, 3.5 mmol) added piecemeal in small portions, keeping the temperature below 30° C., in 14 mL of anhydrous THF. The reaction was left under magnetic stirring for 18 hours at room temperature. After this period, the solvent was evaporated and the residue purified by silica gel chromatography using hexane/AcOEt 9/1 as eluent. 0.510 g of product were obtained (yield: 45%); Mp: 101-103° C.; TLC: silica gel, eluent hexane/AcOEt 8/2, Fr: 0.38; 1H NMR (CDCl3, 300 MHz) δ: 8.05 (d, 2H), 7.50 (m, 4H), 7.15 (m, 2H), 7.08 (t, 1H), 7.00 (d, 1H), 6.90 (s, 1H), 6.80 (m, 1H), 4.75 (t, 2H), 4.35 (t, 2H), 3.60 (s, 3H), 1.40 (s, 6H); HPLC: Column: Symmetry—C18, (5 μm) 4.6×150 mm, T: room temperature, mobile phase CH3CN/H2O 65/35 (v/v), pH: as is, flow rate: 0.80 mL/min, 205 nm UV detector, retention time 11.45 min; E.A. conforming for C25H25NO3S.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([O:17][C:18]3[C:27]4[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[CH:12][CH:13]=2)[CH:8]=1)(=O)=O.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(C(C2C=CC=CC=2)=[NH:93])C=CC=CC=1.Cl>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:29][O:28][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][C:24]=1[O:30][CH3:31])[N:21]=[CH:20][CH:19]=[C:18]2[O:17][C:11]1[CH:10]=[C:15]2[C:14]([CH:9]=[CH:8][C:7]([NH2:93])=[CH:16]2)=[CH:13][CH:12]=1
Reactant: COc1cc2nccc(Oc3ccc4ccc(OS(=O)(=O)C(F)(F)F)cc4c3)c2cc1OC
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-yl trifluoromethanesulfonate (0.825 g, 1.72 mmol) in THF (30 mL), was added Pd(OAc)2 (0.039, 0.17 mmol), followed by BINAP (0.1187 g, 0.19 mmol) and Cs2CO3 (0.784 g, 2.41 mmol). Diphenylmethanimine was added and the mixture was stirred at 65° C. for 16 h. The reaction was cooled to RT, treated with 1N HCl (12 mL) and stirred for 4 h. The mixture was diluted with water and extracted with EtOAc 3×. The aqueous extract was treated with NH4OH until pH=12. This was extracted with EtOAc 3×. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was taken on directly without purification. MS (ESI, pos. ion) m/z: 347.4 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[P:23]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:24])#[N:2].OO.C(=O)([O-])[O-:40].[K+].[K+]>CS(C)=O.O>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[P:23]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:24])(=[O:40])[NH2:2]
Reactant: N#Cc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Reaction time: 15 h
Yield: 98.6 %

Procedure:
9.99 g (20.8 mmol) of (+)-2-cyano-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (4a)), synthesized according to the known method (Tetrahedron 50, 4293, (1994)), was weighed and added into a four neck flask, which was equipped with a thermometer, a cooling tube and a dropping funnel with an equalizer. 100 ml of Dimethylsulfoxide was added into the flask. 50 ml of 30 percent aqueous solution of hydrogen peroxide was added at 0° C. followed by the addition of potassium carbonate (57.6 g) and sonication for 25 minutes. Thereafter, 43 ml of water was added and 43 ml of dimethylsulfoxide was then added, followed by sonication to the resultant mixture for 30 minutes, which was then stirred for 15 hours. The resultant mixture was extracted with 300 ml of ethyl acetate, and the extract was washed with 100 ml of saturated aqueous solution of ammonium chloride and 200 ml of brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was purified using a silica gel column chromatography (eluent: ethyl acetate) to obtain 10.2 gram of the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C)=[CH:4][C:3]=1[F:21]>C(O)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)=[CH:4][C:3]=1[F:21]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccc(Br)c(F)c1
Solvent: O=CO
Product: Fc1cc(C2=NCCC2)ccc1Br
Yield: 81.9 %

Procedure:
A solution of tert-butyl 4-(4-bromo-3-fluorophenyl)-4-oxobutylcarbamate (23 g, 64.07 mmol) in formic acid (290 mL) was heated at 40° C. for 5 hours. The reaction mixture was cooled, concentrated and the residue was partitioned between ethyl acetate and aqueous sodium hydroxide. The organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel, using a gradient of 20-60% ethyl acetate in petroleum ether to give 5-(4-bromo-3-fluorophenyl)-3,4-dihydro-2H-pyrrole (12.7 g, yield 82%). LC-MS (ESI) m/z: 242 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:21][CH3:22])[C:19]=1[CH3:20])[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15]C)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:22][O:21][C:18]1[CH:17]=[C:5]([C:6]2[O:15][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=2)[CH:4]=[C:3]([O:2][CH3:1])[C:19]=1[CH3:20]
Reactant: COc1ccccc1NC(=O)c1cc(OC)c(C)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(-c2nc3ccccc3o2)cc(OC)c1C
Temperature: 25 °C

Procedure:
A mixture of 3,5-dimethoxy-N-(2-methoxyphenyl)-4-methylbenzamide (1.29 g, 4.49 mmol), toluene (22 mL), p-toluenesulfonic acid monohydrate (5.9 g, 31 mmol) and molecular sieves was refluxed until no starting material was observed by TLC. Cooled mixture to rt and filtered, washing with warm chloroform. Removal of solvent from filtrate afforded a yellow solid. Purification of crude solid by flash chromatography on silica gel using 1:3 EtOAc:hexanes gave the desired intermediate, 2-(3,5-dimethoxy-4-methylphenyl)-1,3-benzoxazole, as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18](Br)=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[CH3:23])=[CH:19][CH:20]=[CH:21][C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(Br)cccc3O2)cc1
Reactant: Cc1ccccc1B(O)O
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(cccc3-c3ccccc3C)O2)cc1
Yield: 68.6 %

Procedure:
Treatment of (±)-(4-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 5.21 mmol), 2-methylphenyl boronic acid (1.06 g, 7.82 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.205 g, 0.261 mmol), and potassium carbonate (1.80 g, 13.04 mmol) generally according to the procedure described for Intermediate 37 provided 1.41 g (69%) of (±)-[4-(2-methylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.42 (silica, ethyl acetate:hexanes 1:4); Anal. calcd. for C23H22O4S: C, 70.03; H, 5.62. Found: C, 69.70; H, 5.45.