Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:18])([F:17])[F:16])=[CH:4][C:3]=1[CH2:19][CH2:20][C:21]([CH3:24])([OH:23])[CH3:22].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[O:58]1[C:62]2([CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]2)[CH2:61][C:60]([C:68](O)=[O:69])=[N:59]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]([CH2:19][CH2:20][C:21]([OH:23])([CH3:24])[CH3:22])=[CH:4][C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([F:16])([F:17])[F:18])=[CH:6][C:7]=1[NH:8][C:68]([C:60]1[CH2:61][C:62]2([CH2:63][CH2:64][CH2:65][CH2:66][CH2:67]2)[O:58][N:59]=1)=[O:69]
Reactant: O=C(O)C1=NOC2(CCCCC2)C1
Reactant: CC(C)(O)CCc1cc(-c2ccccc2C(F)(F)F)cc(N)c1N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(O)CCc1cc(-c2ccccc2C(F)(F)F)cc(NC(=O)C2=NOC3(CCCCC3)C2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
4-(4,5-Diamino-2′-trifluoromethyl-biphenyl-3-yl)-2-methyl-butan-2-ol (57.5 mg, 0.170 mmol, as prepared in the previous step) was placed in a 50 mL round-bottom flask equipped with a magnetic stir bar. DCM (15 mL), PyBrOP (95.0 mg, 0.204 mmol), and DIPEA (36.0 μL, 0.204 mmol) were added via syringe. 1-Oxa-2-aza-spiro[4.5]dec-2-ene-3-carboxylic acid (31.0 mg, 0.170 mmol, as prepared in Example 1, step B) in DCM (10 mL) was placed in an addition funnel and added dropwise over 2 h. After completion of the addition, the mixture was stirred at rt for 2 h. The solvent was removed under reduced pressure. The residue was chromatographed on a 40-g pre-packed SiO2 column eluting with EtOAc/heptane, 0:1 to 3:7, v/v over 20 min, yielding 34.4 mg (40%) of the title compound. Mass Spectrum (LCMS, ESI pos.) Calcd. for C27H32F3N3O3: 504.2 (M+H). Found 504.1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([N:18]=[C:19]=[S:20])[CH:13]=[CH:14][C:15]=2[CH3:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([NH2:24])[CH2:22][NH2:23]>C(Cl)Cl>[NH2:23][CH2:22][CH2:21][NH:24][C:19](=[S:20])[NH:18][C:12]1[CH:13]=[CH:14][C:15]([CH3:17])=[C:16]2[C:11]=1[CH2:10][CH2:9][N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7]
Reactant: Cc1ccc(N=C=S)c2c1N(C(=O)OC(C)(C)C)CC2
Reactant: NCCN
Solvent: ClCCl
Product: Cc1ccc(NC(=S)NCCN)c2c1N(C(=O)OC(C)(C)C)CC2
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of 1-t-butoxycarbonyl-2,3-dihydro-4-isothiocyanato-7-methylindole (1.70 g; 5.86 mmol) in methylene chloride (10 mL) is slowly added to a solution of ethylenediamine (1.76 g, 29.3 mmol) in methylene chloride (10 mL). After 30 minutes, the solution is washed with four 50-mL portions of aqueous potassium carbonate, dried over anhydrous potassium carbonate, filtered and rotary evaporated to yield an off-white solid. The crude residue is purified via silica gel column chromatography using 10% methanol (ammonium hydroxide treated)/methylene chloride as the eluent. The appropriate fractions are combined and the solvents removed by rotary evaporation to yield 1.92 g of 4-[N'-(2-aminoethyl)thioureido]-1-t-butoxycarbonyl-2,3-dihydro-7-methylindole as a white solid (94% yield).
Reaction SMILES: N#N.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.C(N(CC)CC)C.[C:20](Cl)(=[O:22])[CH3:21]>CN(C)C1C=CN=CC=1>[C:20]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1)(=[O:22])[CH3:21]
Reactant: Nc1ccc([N+](=O)[O-])cn1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 1.5 %

Procedure:
To a N2 covered suspension of 3.0 g (21.6 mmol) of 2-amino-5-nitropyridine in 12 ml of CH2C12 was added 9.9 ml (71.2 mmol) of triethylamine followed by 0.13 g (1.1 mmol) of 4-dimethylaminopyridine. The mixture was cooled in an ice bath and there was added 5.06 ml (71.2 mmol) of acetyl chloride dropwise over 18 minutes. The ice bath was removed and after stirring at room temperature for 18 hours, the reaction mixture was diluted with CH2Cl2 and washed once with 20 ml of 1M aqueous K2CO3. The aqueous layer was separated and extracted twice with CH2Cl2. The combined organic fractions were dried over MgSO4 and concentrated in vacuo. The residue was chromatographed over silica gel (20% EtOAc: hexane) and recrystallized from CH3CN to yield 0.653 g, m.p. 196.5°-198° C. (16.7%), 0.157 g, m.p. 183°-193° C. (4.0%) and 0.057 g, m.p. 191°-196° C (1.5%) of the titled product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C.C(N(CC)CC)C.CCOC(C)=O.CCCCCC>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1)[CH3:13]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C/C=C/c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 40 h
Yield: 101.6 %

Procedure:
Under a nitrogen atmosphere, a mixture of 4-bromo-1,2-dichlorobenzene (1.81 g, 8.03 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (1.60 g, 8.03 mmol), prepared as previously described, palladium(II) acetate (18.0 mg, 0.08 mmol), tri-o-tolylphosphine (97.7 mg, 0.32 mmol), triethylamine (2.5 mL, 17.94 mmol) and anhydrous acetonitrile (5 mL) was stirred and heated under reflux at 80-90° C. (oil bath temperature) for 18 h. TLC analysis on silica gel eluting with EtOAc-hexane (3:1, v/v) indicated an incomplete reaction. Therefore, additional palladium(II) acetate (18.0 mg), tri-o-tolylphosphine (92 mg), triethylamine (2.5 mL) and anhydrous acetonitrile (5 mL) were added and heating was continued at 60° C. for an additional 40 h. The resulting mixture, an oily brown semi-solid, was cooled to ambient temperature, diluted with water (25 mL), and extracted with CH2Cl2 (3×25 mL). The combined CH2Cl2 extracts were dried (Na2SO4), filtered, concentrated by rotary evaporation, and the residue was dried under high vacuum to produce a dark-brown oil (2.81 g). The crude product was purified by column chromatography on silica gel (132 g), eluting with ethyl acetate-hexane (15:85, v/v). Selected fractions containing the product (Rf 0.34) were combined, concentrated by rotary evaporation and the residue was vacuum dried to give 1.38 g (50.0%) of a light-yellow oil.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=1)O)C1C=CC=CC=1.Cl>CO.[OH-].[Pd+2].[OH-]>[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[OH:8])=[CH:18][CH:19]=1)([CH3:25])[CH3:24]
Reactant: CC(C)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: CC(C)c1ccc(Cc2ccccc2O)cc1
Reaction time: 15 h
Yield: 73.1 %

Procedure:
To a solution of (2-benzyloxyphenyl)-(4-isopropylphenyl)methanol (2.63 g, 7.92 mmol) in methanol (50 mL), a 20% palladium hydroxide catalyst (263 mg) was added and furthermore 2N—HCl (0.4 mL) was added thereto, and the mixture solution was stirred under a hydrogen atmosphere for 15 hours, and then the catalyst was filtered off. The solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (1.31 g, 73%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][S:8](/[CH:11]=[CH:12]/[C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])(=[O:10])=[O:9])=[CH:5][C:4]=1[N+:27]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].O>CC(C)=O.O>[CH3:24][O:23][C:14]1[CH:15]=[C:16]([O:21][CH3:22])[CH:17]=[C:18]([O:19][CH3:20])[C:13]=1/[CH:12]=[CH:11]/[S:8]([CH2:7][C:6]1[CH:25]=[CH:26][C:3]([O:2][CH3:1])=[C:4]([NH2:27])[CH:5]=1)(=[O:10])=[O:9]
Reactant: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c([N+](=O)[O-])c2)c(OC)c1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1cc(OC)c(/C=C/S(=O)(=O)Cc2ccc(OC)c(N)c2)c(OC)c1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-((E)-2-(4-methoxy-3-nitrobenzylsulfonyl)vinyl)-1,3,5-trimethoxybenzene (13 mmol) in acetone-water (10:5, 25 mL) was heated to 50° C. After 30 min, sodium hydrosulfite (Na2S2O4, 26.3 mmol) was added slowly, and the mixture was heated at reflux (50° C.) for 1 h. The heated mixture was then cooled to room temperature (25° C.) and water (25 mL) was added. A solid precipitate formed and was separated by filtration. The filtered product was washed with aqueous sodium bicarbonate. The product was distributed between water and ethyl acetate. The ethyl acetate layer was separated and dried over anhydrous sodium sulfate. The ethyl acetate was removed under reduced pressure and the crude product obtained thereby was recrystallized from 2-propanol to yield the desired (E)-5-((2,4,6-trimethoxystyrylsulfonyl)methyl)-2-methoxybenzenamine product. m.p. 148-150° C.
Reaction SMILES: [NH2:1][C@:2]12[C:8]([CH3:10])([CH3:9])[C@H:5]([CH2:6][CH2:7]1)[CH2:4][C:3]2=[O:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([NH:1][C@:2]23[C:8]([CH3:9])([CH3:10])[C@H:5]([CH2:6][CH2:7]2)[CH2:4][C:3]3=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(N)C(=O)C2
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)[C@@H]2CC[C@@]1(Nc1ccccc1)C(=O)C2
Temperature: 40 °C
Reaction time: 25 h
Yield: 16 %

Procedure:
To a solution of (1S,4R)-1-amino-7,7-Dimethyl-bicyclo[2.2.1]heptan-2-one (compound 1) (1.0 g, 6.5 mmol) and phenyl boronic acid (2.0 equivant) in methylene chloride (43 mL, 0.15 M) was added copper acetate Cu(OAc)2 (1.0 equivant) and triethylamine (2.0 equivant). The reaction mixture was stirred for 25 h at 40° C., then filtered with Celite and washed with ethyl acetate. The combined organic extracts were purified by column chromatography with EA/hexane (1/8) as eluent to give white solid (0.23 g, 16%). 1H NMR (400 MHz, CDCl3) δ7.15-7.08 (m, 2H), 6.81-6.73 (m, 3H), 4.13 (br, 1H), 2.49-2.35 (m, 2H), 2.16-2.01 (m, 3H), 1.52-1.40 (m, 2H), 1.21 (s, 3H), 0.90 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH:27]=O)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O.C(Cl)Cl>[Cl:1][C:2]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:3]=1[CH2:4][NH:5][C:6](=[O:29])[N:7]([CH:9]([CH2:25][CH2:26][CH2:27][N:39]1[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]1)[CH2:10][O:11][C:12](=[O:24])[NH:13][C:14]1[N:15]=[CH:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH3:8]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(CCC=O)COC(=O)Nc1cc2ccccc2cn1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(CCCC(COC(=O)Nc2cc3ccccc3cn2)N(C)C(=O)NCc2cccc(F)c2Cl)CC1
Temperature: 25 °C

Procedure:
To a solution of isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-oxo-pentyl ester (2.37 g crude mixture, 4.92 mmol) in anhydrous DCE (5 mL) and AcOH 1 (1 mL) was added N-methyl piperazine (0.573 mL, 5.16 mmol) at RT After 3 h of stirring at RT, sodium triacetoxyborohydride (4.17 g, 19.7 mmol) was added in one portion followed by 10 mL DCE. The mixture was stirred for 2 h at RT, the diluted in CH2Cl2 and washed with aq. NaHCO3 and brine. After drying the solution over Na2SO4, the reaction mixture was concentrated and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and H2O with a TFA Buffer. The purified fractions were concentrated, redissolved in EtOAc and washed with saturated aq. NaHCO3. Removal of the solvent afforded isoquinolin-3-yl-carbamic acid 2-[3-(2-chloro-3-fluoro-benzyl)-1-methyl-ureido]-5-(4-methyl-piperazin-1-yl)-pentyl ester as the free base (1.43 g, 51%) LRMS (M+H+) m/z 571.3.
Reaction SMILES: [Si:1]([O:18][CH:19]([C:21]1[N:22]=[N:23][NH:24][CH:25]=1)[CH3:20])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:52]=[C:51]([O:53][CH3:54])[CH:50]=[CH:49][C:29]=1[CH2:30][N:31]1[C:34](=[O:35])[C@@H:33]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:32]1[CH2:47]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Si:1]([O:18][CH:19]([C:21]1[CH:25]=[N:24][N:23]([CH2:47][C@@H:32]2[C@H:33]([NH:36][C:37](=[O:46])[O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34](=[O:35])[N:31]2[CH2:30][C:29]2[CH:49]=[CH:50][C:51]([O:53][CH3:54])=[CH:52][C:28]=2[O:27][CH3:26])[N:22]=1)[CH3:20])([C:14]([CH3:15])([CH3:16])[CH3:17])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CO)c(OC)c1
Reactant: CC(O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)c1c[nH]nn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2ncc(C(C)O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.6 %

Procedure:
To a solution of 4-(1-((tert-butyldiphenylsilyl)oxy)ethyl)-1H-1,2,3-triazole (2.42 g, 6.88 mmol), benzyl ((2S,3S)-1-(2,4-dimethoxybenzyl)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)carbamate (2.76 g, 6.88 mmol), and PPh3 (2.17 mg, 8.26 mmol) in THF (35 ml) at 0° C. was added DIAD (1.60 ml, 8.26 mmol) dropwise. The reaction was stirred at room temperature for 5 h then concentrated in vacuo. Purification of the crude residue via silica gel chromatography (EtOAc-Heptane, 30-60%) afforded the title compound (4.32 g, 85%) as a solid. LCMS: Rt=1.12 min, m/z=734 (M+1) Method 2m_acidic.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6](Br)[CH:7]=1.[Cu][C:11]#[N:12]>CN1CCCC1=O>[Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([C:11]#[N:12])[CH:7]=1
Reactant: Cc1cc(Br)cc(Br)c1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: Cc1cc(Br)cc(C#N)c1
Temperature: 200 °C
Reaction time: 1.5 h
Yield: 21 %

Procedure:
To a solution of 3,5-dibromotoluene (10.00 g) in 1-methyl-2-pyrrolidone (70 ml) was added copper (I) cyanide (5.20) and the mixture was stirred at 200° C. for 1.5 hours. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The extract was washed with 1M hydrochloric acid, water and brine, dried over anhydrous magnesium sulfate and then concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=9/1 as an eluant to give the desired compound (1.70 g, yield 21%).
Reaction SMILES: [F:1][C@H:2]1[CH2:4][C@H:3]1[NH:5][CH:6]=[C:7]([C:13](=[O:25])[C:14]1[C:19]([CH3:20])=[C:18]([F:21])[C:17]([F:22])=[C:16]([F:23])[C:15]=1F)[C:8]([O:10][CH2:11][CH3:12])=[O:9].[H-].[Na+]>O1CCOCC1>[F:1][C@H:2]1[CH2:4][C@H:3]1[N:5]1[C:15]2[C:14](=[C:19]([CH3:20])[C:18]([F:21])=[C:17]([F:22])[C:16]=2[F:23])[C:13](=[O:25])[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6]1
Reactant: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1c(C)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
In 10 ml of anhydrous dioxane was dissolved 1.15 g of ethyl 3-[(1R,2S)-2-fluorocyclopropylamino]-2-(2,3,4,5-tetrafluoro-6-methylbenzoyl)acrylate, and 190 mg of 60% sodium hydride in oil was added thereto, followed by stirring at room temperature for 30 minutes. The dioxane was concentrated to about half the volume, and the concentrate was added to 25 ml of 1N hydrochloric acid under cooling with ice. The crystals precipitated were collected by filtration, washed with diethyl ether, and dried to yield 1.05 g of the titled compound as a yellow crystal.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]([CH2:11][S+:12]([O-:24])[C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:22][CH3:23])=[CH:19][C:20]=3[N:21]=2)=[C:6]([CH3:10])[C:7]=1[O:8][CH3:9].C1(C(C2C=CC=CC=2)(O)[C@H](C2C=CC=CC=2)O)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S@@:12]([C:13]2[NH:21][C:20]3[CH:19]=[C:18]([O:22][CH3:23])[CH:17]=[CH:16][C:15]=3[N:14]=2)=[O:24])=[N:4][CH:3]=1
Reactant: COc1ccc2[nH]c([S+]([O-])Cc3ncc(C)c(OC)c3C)nc2c1
Agent: O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc2nc([S@@](=O)Cc3ncc(C)c(OC)c3C)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of omeprazole (250 mg, 0.72 mmol) and (S)-1,1,2-triphenyl-1,2-ethanediol (315 mg, 1.08 mmol) was dissolved in a minimum volume of toluene (11 ml) at 90° C. On dissolution, the solution was cooled to ambient temperature slowly with vigorous stirring, and on reaching this temperature was stirred for a further 1 h. The precipitate was filtered, was washed with toluene (2×3 ml) and was dried in vacuo to afford (S)-omeprazole.2[(S)-1,1,2-triphenyl-1,2-ethanediol] inclusion complex (291 mg, 87%, 95% e.e.) as an off-white powder.
Reaction SMILES: [CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]=[C:2]2[C:16]([O:18][CH3:19])=[O:17]>CO>[CH:1]12[N:8]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1=CCC2CCC1N2C(=O)OC(C)(C)C
Solvent: CO
Product: COC(=O)C1CCC2CCC1N2C(=O)OC(C)(C)C
Reaction time: 16 h
Yield: 94.8 %

Procedure:
8-tert-butyl 2-methyl 8-azabicyclo[3.2.1]oct-2-ene-2,8-dicarboxylate (880 mg, 3.29 mmol) was dissolved in methanol (15 ml). The reaction flask was flushed with argon and 5% palladium hydroxide on carbon (88 mg) was added. The flask was degassed under vacuum. Hydrogen gas is then added via balloon. The reaction is stirred under hydrogen atmosphere for 16 hours. The reaction was then filtered through celite, and concentrated to give the titled compound (840 mg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](O)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:27]2[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]2)=[O:21])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: CN1CCNCC1
Reactant: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCC(COC)n1cc(C(=O)N2CCN(C)CC2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.4 %

Procedure:
To a solution of 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate 78, 300 mg, 0.72 mmol) and 1-methylpiperazine (100 mg, 1.00 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (HOBT) (110 mg, 0.72 mmol) and N-methylmorpholine (290 mg, 2.87 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC HCl) (234 mg, 1.29 mmol) was added. The resulting reaction mixture was stirred at room temperature over night. The reaction mixture was quenched with 2N hydrochloric acid (30 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered and concentrated under vacuum to afford 1-(1,3-dimethoxypropan-2-yl)-6-iodo-3-[(4-methylpiperazin-1-yl)carbonyl]quinolin-4(1H)-one 300 mg (80%) as thick oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:5][CH2:8][CH3:9])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Oc1ccc(-c2ccc(O)cc2)cc1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCOc1ccc(-c2ccc(OCCCCCCCC)cc2)cc1
Yield: 170 %

Procedure:
56 g of 4,4′-dihydroxybiphenyl was dissolved in 500 g ethanol. To this solution was added 40 g of potassium hydroxide, and the mixture was reacted. Next, this solution was heated, and 128 g of 1-bromooctane was dropped at 70° C., and subsequently, the mixture was reacted at 70° C. for 7 hours. The reaction was performed under a nitrogen atmosphere. After the reaction, this solution was cooled, and the generated precipitate was filtrated to recover. Next, this precipitate was washed with 500 ml of methanol, then, washed with a mixed solvent of methanol 500 ml/ion exchanged water 300 ml, and further, washed with a mixed solvent of acetone 500 ml/ion exchanged water 300 ml. This precipitate was dried under reduced pressure, to obtain 105 g of 4,4′-dioctyloxybiphenyl represented by the following structural formula:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O>CO.[Cl-].[Na+].O>[CH2:5]([O:11][C:10]1[CH:9]=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[F:1])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: O=C(O)c1ccc(O)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(OCc2ccccc2)c(F)c1
Temperature: 70 °C
Yield: 184.1 %

Procedure:
To a solution of 3-fluoro-4-hydroxybenzoic acid (25.0 g) in methanol (150 mL) was added sulfuric acid (20.0 mL), and the mixture was heated under reflux for 1 day. To the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To a solution of the obtained residue in DMF (200 mL) were added potassium carbonate (33.2 g) and benzyl bromide (21.0 mL), and the mixture was stirred with heating at 70° C. for 30 min. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, and washed with saturated brine. The obtained organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. To a solution of the obtained residue in a mixed solvent of THF (100 mL) and methanol (100 mL) was added 2 M aqueous sodium hydroxide solution (160 mL), and the mixture was stirred with heating at 50° C. for 2 hr. The reaction mixture was allowed to cool to room temperature, and neutralized with 6 M hydrochloric acid, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained solid was washed with ethyl acetate to give the title compound (36.3 g).