Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13](O)=[CH:12][C:11]3=[O:22])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH:23]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([N:10]3[CH:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[C:13]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:12][C:11]3=[O:22])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC1CCCCC1
Reactant: O=C1C=C(O)C(c2ccccc2)N1c1ccc2[nH]cnc2c1
Product: O=C1C=C(NC2CCCCC2)C(c2ccccc2)N1c1ccc2[nH]cnc2c1

Procedure:
The compound was synthesized starting from 1-(1H-benzo[d]imidazol-5-yl)-4-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one (0.120 g, 0.366 mmol) and cyclohexylamine (0.59 ml, 5.13 mmol) according to method 7 described above.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].CC1C=CC(S(O[CH2:23][C@@H:24]2[CH2:26][O:25]2)(=O)=O)=CC=1>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][CH2:23][C@@H:24]1[CH2:26][O:25]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OC[C@@H]2CO2)cc1F
Temperature: 0 °C
Reaction time: 8 h
Yield: 51.1 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 13.0 g of 3,4-difluorophenol and 200 ml of N,N-dimethylformamide, there were added 4.8 g of a dispersion of sodium hydride in mineral oil (50%) and, after stirring for 1 hour, a solution of 22.8 g of (S)-(oxiranylmethyl) 4-methylbenzenesulfonate (ester) in some N,N-dimethylformamide. Stirring at room temperature was continued overnight. The reaction mixture was poured into ice-water and the product was extracted with methylbenzene. The extract was washed with NaCl (dil.) and water and was then dried, filtered and evaporated. The residue was distilled (13.3 Pa, 55° C.), yielding 9.5 g (51.0%) of (S)-[(3,4-difluorophenoxy)methyl]oxirane (interm. 1 ).
Reaction SMILES: [K].CCOCC.[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=O)[CH2:14][CH2:13][CH2:12]2.[N:20](OCCCC)=[O:21]>C(O)(C)(C)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[N:20][OH:21])[CH2:14][CH2:13][CH2:12]2
Reactant: CCCCON=O
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [K]
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: COc1ccc2c(c1)CCCC2=NO
Reaction time: 0.5 h
Yield: 12 %

Procedure:
In 60 ml of refluxing t-butanol was dissolved 3.84 g (0.0985 mole) of potassium. Ether (150 ml) was added followed by 15.87 g (0.09 mole) of 6-methoxy-1-tetralone. Butyl nitrite (11.1 g, 0.0932 mole) was added dropwise with stirring over a period of 30 minutes. The insoluble salts were filtered and washed with ether. They were slurried with 180 ml of water and then 15 ml of Concentrated HCl was added. The initially formed oil solidified. The solid was filtered and washed with water. Recrystallization of the still damp product from 250 ml of ethanol gave 8.86 g. Concentration of the filtrate to 1/3 volume gave 2.06 g additional material. Total yield 10.92 g (59%). A second recrystallization gave an analytical sample, mp 168°-171° dec.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[CH:21][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:15][C:11]=2[C:10]=1[CH2:23][CH2:24][CH3:25])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:8][C:9]1[CH:22]=[CH:21][C:12]2[CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[O:15][C:11]=2[C:10]=1[CH2:23][CH2:24][CH3:25]
Reactant: [H][H]
Reactant: CCCc1c(OCc2ccccc2)ccc2cc(C(=O)OCC)oc12
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc2cc(C(=O)OCC)oc12

Procedure:
The ester product of step (d) was dissolved in ethyl acetate and reduced under hydrogen with palladium/charcoal catalyst until uptake of hydrogen was complete. The solution was filtered and evaporated to leave ethyl 6-hydroxy-7-propylbenzofuran-2-carboxylate (2.8 g) as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)[C:3]=1[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:33])[CH2:27][CH2:28][CH2:29][N:30]=[C:31]=[O:32]>O1CCCC1>[C:16]([C:3]1[C:4]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:5][S:6][C:2]=1[NH:1][C:31]([NH:30][CH2:29][CH2:28][CH2:27][C:26]([O:25][CH3:24])=[O:33])=[O:32])#[N:17]
Reactant: COC(=O)CCCN=C=O
Reactant: N#Cc1c(-c2ccc([N+](=O)[O-])cc2)nsc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)CCCNC(=O)Nc1snc(-c2ccc([N+](=O)[O-])cc2)c1C#N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
A solution of 5-amino-3-(4-nitrophenyl)isothiazole-4-carbonitrile (25.0 g, 0.101 mol) in tetrahydrofuran (300 mL) dimethylsulfoxide (40 mL) at ambient temperature was treated with potassium carbonate (35.0 g, 0.25 mol). The resulting mixture was stirred at ambient temperature for 15 min. The reaction mixture was treated with 4-isocyanato-butyric acid methyl ester (21.8 g, 0.15 mol) at ambient temperature. The mixture was stirred at ambient temperature overnight. The reaction mixture was filtered through celite and filtrate concentrated in vacuo. The residue was dissolved EtOAc (600 mL) and washed with water and brine then dried (sodium sulfate), filtered, solvent concentrated in vacuo. The crude residue was purified by column chromatography (20% ethyl acetate in dichloromethane) to give the title compound as a light brown solid (31.5 g, 78%).
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH2:12][C:13]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]([F:33])([F:32])[F:31])=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:23])[N:3]=1.[NH:34]1[CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:36]=[N:35]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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>[CH3:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:16]=1[N:15]=[C:14]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]([F:33])([F:32])[F:31])[C:13]([CH2:12][N:4]1[C:5]3=[N:6][CH:7]=[N:8][C:9]([NH2:11])=[C:10]3[C:2]([C:37]3[CH:38]=[N:34][NH:35][CH:36]=3)=[N:3]1)=[CH:22]2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(-c4cn[nH]c4)c4c(N)ncnc43)c(-c3ccccc3C(F)(F)F)nc12

Procedure:
Prepared according to Procedure J using 3-iodo-1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.1000 g, 0.178 mmol, 1 eq), pyrazole-4-boronic acid pinacol ester (0.0693 g, 0.357 mmol, 2.0 eq), tetrakis(triphenylphosphine)palladium(0) (0.0206 g, 0.0178 mmol, 10 mol %), and sodium carbonate (2M aq. sol, 0.535 mL, 1.07 mmol, 6 eq) in DMF (1 mL). After purification, 1-((8-methyl-2-(2-(trifluoromethyl)phenyl)quinolin-3-yl)methyl)-3-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained as white solid. The white solid was suspended in CH2Cl2 and filtered to give the desired product as white solid [PI3Kδ IC50=8 nM]. 1H NMR (DMSO-d6) δ ppm 13.17 (1 H, s), 8.22 (1 H, s), 7.97-8.08 (2 H, m), 7.71-7.90 (3 H, m), 7.56-7.66 (3 H, m), 7.52 (1 H, dd, J=7.8, 7.0 Hz), 7.35-7.44 (1H, m), 6.82 (2 H, br. s.), 5.42-5.55 (2 H, m), 2.60 (3 H, s). Mass Spectrum (ESI) m/e=501.1 (M+1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10](=O)[CH2:11][C:12](=O)[C:13]([F:16])([F:15])[F:14].Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[N:30]([C:27]2[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=2)[N:31]=[C:12]([C:13]([F:16])([F:15])[F:14])[CH:11]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)(F)F)c1nc2ccccc2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2nc3ccccc3s2)cc1
Yield: 44 %

Procedure:
The product obtained in Example 7.1), 1-(benzothiazol-2-yl)-4,4,4-trifluorobutane-1,3-dione, was treated with 4-sulfamoylphenylhydrazine hydrochloride in the same manner as in Example 9 to give 4-[5-(benzothiazol-2-yl)-3-trifluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide (yield, 44%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:26][N:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[N:6]=[N:7][C:2]([N:29]5[CH2:30][CH2:31][N:27]([CH3:26])[C:28]5=[O:32])=[CH:3][CH:4]=4)=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Cl)nn2)CC1
Reactant: CN1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCN(C)C3=O)nn2)CC1
Yield: 43.7 %

Procedure:
Using (6-chloropyridazin-3-yl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (179 mg) described in Preparation Example 233 and 1-methylimidazolidin-2-one (50 mg) and by the reaction and treatment in the same manner as in Example 536, the title compound (92 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1.[OH-].[Na+].[CH3:25][C:26]1([O:29][CH2:28]1)[CH3:27]>C1COCC1.O.CCOC(C)=O>[F:1][C:2]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:25][C:26]([CH3:28])([OH:29])[CH3:27])=[CH:12][CH:13]=2)[N:8]=[CH:7][CH:6]=1
Reactant: CC1(C)CO1
Reactant: O=[N+]([O-])c1ccc(Oc2ccnc3cc(O)ccc23)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2c1
Temperature: 45 °C
Reaction time: 10 h
Yield: 42.4 %

Procedure:
To a solution of 4-(2-fluoro-4-nitrophenoxy)quinolin-7-ol (60 g, 0.2 mol) in THF/H2O (1 L, THF/H2O=1:1, v/v) was added NaOH (24 g, 0.6 mol) at room temperature, followed by isobutylene oxide (144 g, 2 mol). The reaction was stirred at 45° C. for 10 hours, and then diluted with EtOAc (1 L). The resulted solution was washed with 1 M NaOH aqueous solution (500 mL×4). The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The residue was washed with 500 mL of petroleum ether, and collected through filtration to give the title compound as a light yellow solid (31.6 g, 42.5%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([OH:13])(=[O:12])=[O:11].[OH-].[Na+:15]>>[CH2:2]=[CH:3][C:4]1[C:5]([S:10]([O-:13])(=[O:12])=[O:11])=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:15]
Reactant: O=S(=O)(O)c1ccccc1CCBr
Agent: [Na+]
Agent: [OH-]
Product: C=Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Next, 2-(2-bromoethyl)benzenesulfonic acid (10 g) was slowly added dropwise to a 1-mol/L aqueous solution of sodium hydroxide (100 mL), and the whole was stirred for 1 hour at room temperature. After that, the resultant was refluxed for 4 hours, and was then subjected to a dehydrobromination reaction, whereby sodium o-styrenesulfonate was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[C:33]([CH3:35])([CH3:34])[CH2:32][CH2:31][C:30](=[O:36])[NH:29][C:28]=2[CH:37]=1>>[Cl:22][C:5]1[C:6]([NH:8][C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[N:16]([CH3:21])[CH2:17][CH2:18][C:19]#[N:20])=[N:7][C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[C:33]([CH3:34])([CH3:35])[CH2:32][CH2:31][C:30](=[O:36])[NH:29][C:28]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: CN(CCC#N)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCC(=O)Nc2cc(N)ccc21
Product: CN(CCC#N)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3(C)C)ncc1Cl

Procedure:
3-({2-[5-Chloro-2-(5,5-dimethyl-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-3-fluoro-phenyl}-methyl-amino)-propionitrile was prepared from 3-{[2-(2,5-Dichloro-pyrimidin-4-ylamino)-3-fluoro-phenyl]-methyl-amino}-propionitrile and 8-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one in an analogous manner to Example 1221d. Product isolated a white lyophilate (27 mg, 36%). HPLC purity 99%, LCMS 510.15 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 12.03 (s, 1H), 7.94 (s, 1H), 7.70 (s, 1H), 7.53-7.49 (m, 1H), 7.30-7.26 (m, 2H), 7.18-7.13 (m, 2H), 7.07-7.03 (m, 2H), 3.29 (t, J=6.3 Hz, 2H), 2.74 (s, 3H), 2.53 (t, J=6.3 Hz, 2H), 2.37 (t, J=6.2 Hz, 2H), 2.10 (t, J=7.0 Hz, 2H), 1.36 (s, 6H).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:24][CH2:23][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:10][CH2:9]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[Li]>>[OH:1][C:2]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:14][NH:13][C:12]2=[O:22])[CH2:23][CH2:24]1
Reactant: O=C1CCCCC1N1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: [Li]c1ccccn1
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCCC1(O)c1ccccn1)CC2

Procedure:
The title compound was prepared from rac-8-(2-oxo-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one and 2-pyridyl-lithium in analogy of the procedure described for the synthesis of (rac,cis)-8-(2-hydroxy-2-phenyl-cyclohexyl)-1-(3-methyl-butyl)-1,3,8-triaza-spiro[4.5]decan-4-one (Example 73e). (rac,cis) 8-(2-Hydroxy-2-pyridin-2-yl-cyclohexyl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one was obtained as off-white solid, MS (ISP): 407.4 MH+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>Cl.CC(OC)(C)C>[N:20]1([CH2:19][CH2:18][CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][CH:3]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCCN1CCCC1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Product: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 51.6 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (2 g, 9.86 mmol), 1-(3-chloro-propyl)-pyrrolidine (2.33 g, 15.78 mmol), DMF (40 ml) and K2CO3 (5.45 g, 39.44 mmol) were reacted together according to general procedure E. The crude reaction product was diluted with 2M HCl solution (200 ml) and washed with ethyl acetate (3×50 ml). The aqueous phase was basified to pH 14 with 2M NaOH (200 ml) and extracted with ethyl acetate (4×50 ml). The combined organic extracts were dried over MgSO4, filtered, washed with ethyl acetate and concentrated in vacuo to give a white solid. The solid was slurried in TBME (15 ml) and heptane (15 ml), filtered, washed with heptane (8 ml) and dried on the filter for 2 hours to give the title compound as a white solid (1.6 g, 53%). 1H NMR (400 MHz, DMSO-d6) δ7.43 (d, 2H), 6.99 (d, 2H), 4.08-3.94 (m, 4H), 3.64 (dt, 2H), 2.57-2.47 (m, 2H), 2.46-2.36 (m, 4H), 2.12-1.94 (m, 4H), 1.87 (p, 2H), 1.73-1.62 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24]C2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=3[F:50])[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1(CO)[CH2:51][OH:52])C1C=CC=CC=1.F[C:56](F)(F)[C:57](O)=O>ClCCl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:57]2[CH:56]=[CH:51][CH:10]=[CH:9][CH:14]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:11][C@@:10]1([CH2:51][OH:52])[CH2:32][O:31]2)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(Cc2cc([C@]3(OC)OC(CO)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(F)c1F
Solvent: ClCCl
Product: COc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Reaction time: 1.5 h
Yield: 149.6 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 2n (500 mg, 0.66 mmol) was dissolved in 10 mL dichloromethane, followed by dropwise addition of trifluoroacetic acid (0.2 mL, 2.62 mmol). The reaction mixture was stirred for 1.5 hours. Thereafter, the reaction mixture was washed with 10 mL saturated sodium bicarbonate solution and the organic extract was combined, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography with elution system B to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 2p (360 mg, white solid), with yield: 75.3%. MS m/z (ESI): 746.2 [M+18].
Reaction SMILES: C([O:24][C@@H:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26])(=O)CCCCCCCCCCCCCCCCCCCCC.C(OCC)(=O)CCCCCCCCCCCCCCCCCCCCC>CC(C)=O>[C:27]1([C@H:25]([OH:24])[CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O[C@H](C)c1ccccc1
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC
Solvent: CC(C)=O
Product: C[C@@H](O)c1ccccc1
Temperature: 5 °C
Yield: 88 %

Procedure:
Interesterification was carried out by using 1 g of Lipase QL, 40 g of (R,S)-1-phenylethanol, and 60 g of ethyl behenate under the same conditions as in Example 6 at 95° C. for a period of 20 hours. The water content of the reaction system was 0.03% by weight, and 95% of the lipase particles had a particle size of 20 to 40 μm. Gas chromatography of the reaction mixture revealed that 47 mol % of (R,S)-1-phenylethanol had been converted to 1-phenylethyl behenate. The reaction mixture was treated in the same manner as in Example 6 and subjected to simple distillation at 85° C. and 5 mmHg to give (S)-(-)-1-phenylethanol (yield: 97%; chemical purity: 99.9%; optical purity: 88.9% ee). On the other hand, the residue, i.e., a mixture of (R)-(+)-1-phenylethyl behenate and unreacted ethyl behenate was alkali-hydrolyzed in the same manner as in Example 1, and 1000 ml of acetone was added to the reaction mixture, followed by cooling to 5° C. The precipitated behenic acid was removed by filtration to obtain (R)-(+)-1-phenylethanol (yield: 88%; chemical purity: 99.9%; optical purity: 98.5% ee).
Reaction SMILES: C([C:4]1[C:12]2[C:7](=[C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]3=[CH:10][CH:11]=2)[N:6]([CH:17]2[CH2:22][CH:21]=[C:20]([S:23]([NH2:26])(=[O:25])=[O:24])[CH:19]=[CH:18]2)[N:5]=1)(O)=O.[C:27](OCC)(=[O:29])C>>[CH3:27][O:29][C:14]1[CH:15]=[CH:16][C:8]2[C:9]([CH:13]=1)=[CH:10][CH:11]=[C:12]1[C:7]=2[N:6]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([NH2:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)[N:5]=[CH:4]1
Reactant: NS(=O)(=O)C1=CCC(n2nc(C(=O)O)c3ccc4ccccc4c32)C=C1
Reactant: CCOC(C)=O
Product: COc1ccc2c(ccc3cnn(-c4ccc(S(N)(=O)=O)cc4)c32)c1
Temperature: 295 °C
Yield: 20 %

Procedure:
4,5-Dihydro-4- [3-(carboxy)-1H-benz[g]indazol-1-yl]benzenesulfonamide from Step 3 (1.00 g, 2.5 mmol) was placed in a round bottomed flask and heated to 295° C. for 0.5 hour. The residue was dissolved in a small amount of ethyl acetate and purified by flash chromatography, eluting with 40% ethyl acetate in hexane to give 4-[7-methoxy-1H-benz[g]indazol-1-yl]benzenesulfonamide as a white solid (200 mg, 20%): 1H NMR (CD3OD): 8.28 (1H, s), 8.18 (2H, d, J=8.66 Hz), 7.81 (1H, s), 7.77 (2H, d, J=8.66 Hz), 7.59 (1H, d, J=8.86 Hz), 7.52 (1H, d, J=9.27 Hz), 7.46 (1H, d, J=2.62 Hz), 7.0 (1H, dd, J=9.27, 2.62 Hz), 3.91 (3H, s) . Mass spectrum M+H =354. Elemental analysis Calc'd. for C18H15N3O3S: C, 61.18; H, 4.28; N, 11.89; S, 9.07. Found: C, 60.93; H, 4.23; N, 11.73; S, 8.93.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].Cl.[CH3:6][O:7][C:8](=[O:23])[CH:9]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH2:10][NH2:11].C(N(CC)CC)C>C1COCC1>[CH3:6][O:7][C:8](=[O:23])[CH:9]([NH:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH2:10][NH:11][CH2:3][C:2]#[CH:1]
Reactant: C#CCBr
Reactant: COC(=O)C(CN)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCNCC(NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Propargyl bromide (1.6 mL, 14.4 mmol) is added to a solution of 3-amino-2-benzyloxycarbonylamino-propionic acid methyl ester hydrochloride (4.0 g, 13.9 mmol) and triethylamine (4.1 mL, 29.4 mmol) in THF (46 mL). The resulting mixture is heated to 50° C. and stirred overnight then cooled to RT and concentrated in vacuo. The crude residue is diluted with methylene chloride, washed with saturated NaHCO3 and brine then the organic layer is dried over MgSO4, filtered and concentrated in vacuo. The crude material (4.0 g) is taken on to the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ7.25-7.30 (m, 5H), 5.75 (bs, 1H), 5.20 (s, 2H), 4.45 (bs, 1H), 3.80 (s, 3H), 3.75 (m, 1H), 3.31 (s, 2H), 3.08 (dd, 1H), 2.98 (dd, 1H), 2.20 (t, 1H). EI MS, [M+H]+=291.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]3[N:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][N:14]=3)[CH2:9][CH2:8]2)[C:3]1=[O:21].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:69]1[CH:74]=[C:73]([CH3:75])[C:72]([S:76]([CH3:79])(=[O:78])=[O:77])=[CH:71][C:70]=1[F:80].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:19]([C:16]1[CH:15]=[N:14][C:13]([N:10]2[CH2:11][CH2:12][CH:7]([N:4]3[CH2:5][CH2:6][C@H:2]([NH:1][C:69]4[CH:74]=[C:73]([CH3:75])[C:72]([S:76]([CH3:79])(=[O:78])=[O:77])=[CH:71][C:70]=4[F:80])[C:3]3=[O:21])[CH2:8][CH2:9]2)=[N:18][CH:17]=1)[CH3:20]
Reactant: Cc1cc(Br)c(F)cc1S(C)(=O)=O
Reactant: CCc1cnc(N2CCC(N3CC[C@H](N)C3=O)CC2)nc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCc1cnc(N2CCC(N3CC[C@H](Nc4cc(C)c(S(C)(=O)=O)cc4F)C3=O)CC2)nc1
Reaction time: 8 h
Yield: 23.8 %

Procedure:
(S)-3-Amino-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)pyrrolidin-2-one (Example 34, Steps A-D; 152 mg, 0.525 mmol) was dissolved in toluene (5 mL). 2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (32.7 mg, 0.0525 mmol), 1-bromo-2-fluoro-5-methyl-4-(methylsulfonyl)benzene (Preparation B; 281 mg, 1.05 mmol) and Cs2CO3 (205 mg, 0.630 mmol) were added and nitrogen bubbled through for 5 minutes. Pd2 dba3 (24.0 mg, 0.0263 mmol) was added and the reaction plunged into a 95° C. oil bath and stirred under nitrogen overnight. The reaction was cooled, concentrated, dissolved in small amount of CH2Cl2, solids filtered away and filtrate purified over silica gel (90% EtOAc in hexanes) to afford (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-5-methyl-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (59.3 mg, 0.125 mmol, 24% yield) as a tan solid. Mass spectrum (apci) m/z=476.3.