Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:38]=[CH:37][C:33]([C:34]([OH:36])=O)=[CH:32][C:31]=5F)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[CH3:51][N:52]1[CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:8]([CH2:7][C:6]2[CH:49]=[CH:50][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:30]5[CH:31]=[CH:32][C:33]([C:34]([N:55]6[CH2:56][CH2:57][N:52]([CH3:51])[CH2:53][CH2:54]6)=[O:36])=[CH:37][CH:38]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:46][CH:45]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)O)cc3F)cn2)cc1
Reactant: CN1CCNCC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)N4CCN(C)CC4)cc3)cn2)cc1

Procedure:
Using 4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-3-fluoro-benzoic acid (65.6 mg, 0.0968 mmol) obtained in Step A in Example 1-D-21 and N-methylpiperazine (20.9 μl, 0.194 mmol) instead of 1-pyridin-3-yl-piperazine, amidation was carried out in the same manner as Step B in Example 1-D-21, a crude product of {4-[4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone was obtained as a yellow solid (85.0 mg), and then the PMB groups and BOC group were removed according to the above Deprotection method 3, to obtain the desired compound (D-140) as a yellow powder (25.0 mg, 50%).
Reaction SMILES: [Na].C(OCC)(=O)[CH2:3][C:4](OCC)=[O:5].[C:13]([C:16]1[CH2:20][CH2:19][CH2:18][C:17]=1[CH3:21])(=[O:15])[CH3:14]>>[CH3:21][C:17]12[CH2:18][CH2:19][CH2:20][CH:16]1[C:13](=[O:15])[CH2:14][C:4](=[O:5])[CH2:3]2
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(=O)C1=C(C)CCC1
Agent: [Na]
Product: CC12CCCC1C(=O)CC(=O)C2

Procedure:
Following the procedure of Example 5, the sodium salt of diethyl malonate (161.0 mmol) and 1-acetyl-2-methyl-1-cyclopentene (20.0 g, 161.0 mmol) are reacted together to give 7a-methyl-2,3,7,7a-tetrahydro-1H-indene-4,6(5H)-dione, which is then reacted with 4-chloro-2-nitrobenzoyl chloride (1 equiv.) to give 4-(4-chloro-2-nitrobenzoyloxy)-7a -methyl-2,3,7,7a-tetraydro-1H-inden-6-one and 6-(4-chloro-2-nitrobenzoyloxy)-7a-methyl-2,3,7,7a-tetrahydro-1H-inden-4-one.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20]O)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[C:22]([F:25])([F:24])[F:23])[CH:2]([CH3:4])[CH3:3].[NH:26]1[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]1.CCN(CC)CC.[BH3-]C#N.[Na+]>O1CCOCC1.O=[Mn]=O>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[CH:19]=[C:18]([CH2:20][N:26]4[CH2:29][CH:28]([C:30]([OH:32])=[O:31])[CH2:27]4)[CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][C:6]=1[C:22]([F:24])([F:25])[F:23])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc3ccc(CO)cc3o2)cc1C(F)(F)F
Reactant: O=C(O)C1CNC1
Agent: O=[Mn]=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)Cc1ccc(-c2nc3ccc(CN4CC(C(=O)O)C4)cc3o2)cc1C(F)(F)F
Temperature: 50 °C

Procedure:
To a solution of [2-(4-isobutyl-3-trifluoromethyl-phenyl)-benzooxazol-6-yl]-methanol (1 eq) in dioxane (0.2 M) is treated with MnO2 (10 eq). The resulting mixture is refluxed for 20 minutes and filtered through celite. After concentration, the residue is redissolved in MeOH (0.2 M) and is added azetidine-3-carboxylic acid (2 eq) and Et3N (1.8 eq). The resulting mixture is heated at 50° C. for 1 hour. After cooling to room temperature, NaBH3CN (3 eq) is added in portions. The final compound is purified by preparative LCMS. 1H NMR (400 MHz, CD3OD) δ 8.49 (s, 1H), 8.38 (d, J=8.4 Hz, 1H), 7.88 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.66 (d, J=8.4 Hz, 1H), 7.52 (d, J=8.4 Hz, 1H), 4.57 (s, 2H), 4.34 (m, 4H), 3.70 (m, 1H), 2.76 (d, J=6.8 Hz, 2H), 2.03 (m, 1H), 0.95 (d, J=7.2 Hz, 6H). MS: (ES+): 433.2 (M+1)+.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CO>[C:1]1([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C1(c2ccccc2)CC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2)CC1
Yield: 147.5 %

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH3OH (200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was refluxed overnight. The solvent was evaporated under reduced pressure to give crude product, which was dissolved into EtOAc. The EtOAc layer was washed with aq. sat, NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 1-phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 3.63 (s, 3H), 1.63-1.60 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:17]([F:19])[F:18])=[C:6](/[CH:8]=[CH:9]/[C:10]([O:12]C(C)(C)C)=[O:11])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:17]([F:18])[F:19])=[C:6](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: CC(C)(C)OC(=O)/C=C/c1cc(Cl)ccc1C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)/C=C/c1cc(Cl)ccc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.1 %

Procedure:
To a solution of Intermediate 14B (232 mg, 0.804 mmol) in DCM (2.0 mL) was added TFA (2.0 mL, 26.0 mmol). The reaction was stirred under argon at rt. After 1 h, the solvent was removed and residue was dried to give Intermediate 14 (191 mg, 100%) as tan solid. 1H NMR (400 MHz, MeOD) δ 7.99 (dt, J=15.8, 1.5 Hz, 1H), 7.83 (s, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.55-7.48 (m, 1H), 7.01 (t, J=54.6 Hz, 1H), 6.51 (d, J=15.8 Hz, 1H). 19F NMR (376 MHz, MEOD) δ −111.67 (s, 2F) ppm. MS (ESI) m/z: 233.1 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([O:21]CC)=[O:20])[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[OH-].[Na+]>CO>[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:17]=[C:18]([CH:24]=[CH:25][CH:26]=3)[C:19]([OH:21])=[O:20])[CH2:14][CH2:15]2)[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 85.6 %

Procedure:
The compound (2.00 g) prepared in step (b) was dissolved in a mixed solvent composed of tetrahydrofuran (20 ml) and methanol (10 ml), and a 1 mol/l aqueous sodium hydroxide solution (10 ml) was added to the solution. The mixture was then stirred at 65° C. for one hr. The solvent was removed from the reaction solution by distillation under the reduced pressure. Water (30 ml) was then added to the residue, and the mixture was adjusted to pH 4 by the addition of 1 mol/l hydrochloric acid. The resultant precipitate was collected by filtration, and was then dried to give 1.60 g (85.6%) of 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzoic acid.
Reaction SMILES: [F:1][C:2]([F:17])([S:13](F)(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6].[OH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([O:31][CH3:32])=[O:30].C(N(CC)CC)C.C1(C)C=CC=CC=1>O1CCCC1>[F:1][C:2]([F:17])([S:13]([O:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:15])=[O:14])[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[C:5]([F:8])([F:7])[F:6]
Reactant: COC(=O)c1c(O)ccc2ccccc12
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)ccc2ccccc12
Temperature: 0 °C
Reaction time: 64 h

Procedure:
Perfluoro-1-butanesulfonyl fluoride (19 mL, 106 mmol, 1 eq) was added to a solution of methyl 2-hydroxy-1-naphthoate (21.25 g, 105 mmol, 1 eq) and triethylamine (15 mL, 108 mmol, 1 eq) in tetrahydrofuran (150 mL) maintained at an internal temperature about 0° C., under nitrogen. Once the addition was complete, the mixture was allowed to warm to ambient temperature and stirred for 64 hours. Toluene (150 mL) was added causing some precipitation. The solids were removed by filtration through Celiteä and washed with toluene (20 mL). The organic solutions were combined and washed with 2 N HCl (aq) (2×50 mL), water (100 mL), saturated aqueous sodium carbonate solution (100 mL) and brine (100 mL). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. Yield 48.79 g, 95%
Reaction SMILES: [H-].[Na+].[C:3]([NH:7][C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH2:4][CH3:5].I[CH3:22].O>CN(C)C=O>[CH3:22][N:7]([C:8]1[CH:20]=[CH:19][C:11]([CH:12]=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:10][CH:9]=1)[C:3](=[O:6])[CH2:4][CH3:5]
Reactant: CI
Reactant: CCOC(=O)C=Cc1ccc(NC(=O)CC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(N(C)C(=O)CC)cc1
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a suspension of sodium hydride (60% active, 31 mg) in dimethylformamide (1 ml) was added a solution of ethyl 4-propionamidocinnamate (160 mg) in dimethylformamide (2 ml) at ambient temperature under nitrogen atmosphere. The mixture was stirred for 1 hour at same temperature, and a solution of iodomethane (111 mg) in dimethylformamide (2 ml) was added thereto. The reaction mixture was stirred at same temperature for 2 hours, poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl 4-(N-methylpropionamido)cinnamate (168 mg) as an oil.
Reaction SMILES: [C:1]1(=[O:24])[N:5]([CH2:6][C:7](=O)[CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=O)[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]12.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].C([O-])(=O)C.[Na+]>C(O)(=O)CC>[CH3:26][O:27][C:28]([CH2:29][N:30]1[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]1[CH2:6][N:5]1[C:4](=[O:19])[C:3]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:2]2[C:1]1=[O:24])=[O:31]
Reactant: O=C(CCC(=O)c1ccccc1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CN
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCC(=O)O
Product: COC(=O)Cn1c(CN2C(=O)c3ccccc3C2=O)ccc1-c1ccccc1

Procedure:
9.6 g (0.03 mol) of 5-phthalimido-1-phenyl-1,4-pentanedione, 5.0 g (0.04 mol) of glycine methyl ester hydrochloride and 3.2 g (0.04 mol) of anhydrous sodium acetate are stirred in 80 ml of propionic acid at 60° C. for 20 hours. Purification is by column chromatography. Solid phase: "Silica-Woelm", particle size 0.1 to 0.2 mm; manufacturer: Messrs. Woelm, Eschwege, Germany; mobile phase: methylene chloride.
Reaction SMILES: C([Mg]Cl)(C)(C)C.[Cl:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]([Si:19]([CH3:22])([CH3:21])[CH3:20])[C:9]=1[C:10]([NH:12][CH2:13][CH3:14])=[O:11].[CH3:23][O:24][CH2:25]Cl>C1COCC1>[Cl:7][C:8]1[CH:18]=[CH:17][CH:16]=[C:15]([Si:19]([CH3:21])([CH3:20])[CH3:22])[C:9]=1[C:10]([N:12]([CH2:13][CH3:14])[CH2:23][O:24][CH3:25])=[O:11]
Reactant: COCCl
Reactant: CCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCN(COC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.4 %

Procedure:
A 2M THF solution of tert-butylmagnesium chloride (2.5 mL, 5 mmol) was added to an ice water cooled solution of the compound of Example 45 (1.28 g, 5 mmol) in THF (25 mL). Chloromethyl methyl ether (0.44 g, 5.5 mmol) was then added and the reaction mixture was stirred at ambient temperature for 1 h and then partitioned between water and ethyl acetate. The organic solution was dried (MgSO4), concentrated, and purified by RC with 1:9 ethyl acetate/hexanes to afford 0.80 g of the title compound as a colorless oil, a 53% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][NH2:39])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.N1([P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:37][CH2:38][NH:39][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH:22]=[CH:23][C:24]=1[O:25][CH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COc1cc(CCN)ccc1OCc1cccc2ccccc12
Agent: CN(C)[P+](N(C)C)(N(C)C)n1nnc2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)NCCc1ccc(OCc2cccc3ccccc23)c(OC)c1

Procedure:
13.9 g of (2S,3S)-2-(tert-butoxycarbonyl-amino)-3-methyl-valeric acid (BOC-L-isoleucine) and 18.5 g of 2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethylamine are stirred at room temperature for two hours together with 25 g of (benzotriazol-1-yl)-tris(dimethylamino)-phosphonium hexafluorophosphate and 155 ml of diisopropylethylamine in 300 ml of dimethylformamide. The reaction mixture is then introduced into 800 ml of water. Extraction is carried out twice using 800 ml of ethyl acetate each time. The organic phases are washed twice using 250 ml of 2N hydrochloric acid each time, twice using 250 ml of 2N potassium hydrogen carbonate solution each time and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated, yielding (2S,3S)-2-(tert-butoxy-carbonyl-amino)-3-methyl-valeric acid N-{2-[3-methoxy-4-(naphthalen-1-ylmethoxy)-phenyl]-ethyl}-amide in the form of a yellowish oil, which can be purified by chromatography on silica gel.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:9]([C:14]([O:16][CH2:17]C)=[O:15])=[CH:10][CH2:11][CH2:12][C:13]=3[C:5]=2[CH:4]=[CH:3][NH:2]1.[H-].[Na+].[CH2:21](I)[CH3:22]>CN(C=O)C>[CH2:21]([CH:12]1[CH2:11][CH:10]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[C:8]2[NH:7][C:6]3[CH2:1][NH:2][CH:3]=[CH:4][C:5]=3[C:13]1=2)[CH3:22]
Reactant: CCI
Reactant: CCOC(=O)C1=CCCc2c1[nH]c1c2C=CNC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CC=C(C(=O)OC)c2[nH]c3c(c21)C=CNC3
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 72.2 %

Procedure:
Ethyl 1,2,5,6-tetrahydropyrido[3,4-b]indole-8-carboxylate (0.62 g, 2.68 mmol) was dissolved in DMF (10 mL) and cooled to 0° C. Sodium hydride (60% suspension in mineral oil, 0.16 g, 6.7 mmol) was added and the mixture stirred for 45 min prior to addition of ethyl iodide (0.50 g, 3.22 mmol). The mixture was stirred for 15 hours, then quenched with water and extracted with ethyl acetate. The organic layer was then removed and the crude was redissolved in acetonitrile and then washed with hexane to remove the mineral oil. The acetonitrile layer was evaporated to afford 0.5 g of title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1S([O-])(=O)=O.[Na+].[OH-:16].[Na+]>O>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:16]
Reactant: [OH-]
Reactant: O=S(=O)([O-])c1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Product: Oc1ccc2ccccc2c1
Yield: 95.3 %

Procedure:
Sodium naphthalene-2-sulfonate and a hydrogenated triphenyl mixture were sent to a mixing tank 1 at a rate of 230 kg/hr and 825 kg/hr, respectively, and mixed with stirring. In a dispersing tank 2, 200 kg/hr of a 50% aqueous solution of sodium hydroxide was added to form a dispersed mixture. The dispersed mixture was dehydrated in a dehydrating tank 3, and sent to a reservoir 4. From the reservoir 4, a mixture consisting of sodium naphthalene-2-sulfonate, sodium hydroxide and the hydrogenated triphenyl mixture was sent to a reaction tank 5 at a rate of 1155 kg/hr, and continuously reacted at 310° C. in a nitrogen stream with a residence time of 6 hours. After the reaction, the reaction mixture was cooled in a heat exchanger 6, and sent to a water mixing tank 7 where it was mixed with 1200 liters/hr of water. Then, the reaction medium layer was separated in a separating tank 8, and the aqueous layer was mixed with 3.1 kg/hr of activated carbon in a mixing tank 9. Then, the activated carbon was removed in a filtration device 10. The residue was precipitated with dilute sulfuric acid in an acid precipitation tank 11, and separated by a centrifugal separator 12 to give 137.2 g (yield 95.3%) of 2-naphthol hourly.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([CH3:18])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:22][CH2:23][CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]([CH2:22][CH2:23][CH3:24])[N:11]=[C:12]3[C:17]=2[CH:16]=[CH:15][CH:14]=[C:13]3[CH3:18])=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(C)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc2c(C)cccc2c1-c1ccc(OC)cc1
Yield: 10 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-methyl-1H-indazole (0.115 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.014 g). Used as is in the next step.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:24][C:25]1[N:30]=[C:29]([O:31][C@H:32]([CH3:37])[C:33]([CH3:36])([OH:35])[CH3:34])[C:28]([I:38])=[CH:27][N:26]=1>C(Cl)Cl>[Cl:24][C:25]1[N:30]=[C:29]([O:31][C@H:32]([CH3:37])[C:33]([CH3:34])([O:35][CH:6]2[CH2:5][CH2:4][CH2:3][CH2:2][O:1]2)[CH3:36])[C:28]([I:38])=[CH:27][N:26]=1
Reactant: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)O
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C[C@@H](Oc1nc(Cl)ncc1I)C(C)(C)OC1CCCCO1
Temperature: 25 °C
Reaction time: 22 h
Yield: 89 %

Procedure:
2.64 ml (29.0 mmol) dihydropyran and 0.36 g (1.5 mmol) pyridinium tosylate were added to a solution of 4.96 g (14.5 mmol) (R)-3-(2-chloro-5-iodo-pyrimidin-4-yloxy)-2-methyl-butan-2-ol in 30 ml DCM and stirred for 22 hours at room temperature. The mixture was diluted with DCM and washed with saturated sodium hydrogencarbonate solution. The organic phase was dried (Na2SO4), filtered and concentrated by evaporation. The residue obtained was purified chromatographically (hexane/ethyl acetate 4:1). 5.50 g (12.9 mmol; yield: 89%) of the mixture of diastereomers was obtained.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:27][SH:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:28][CH2:27][C:26]([O:30][CH2:31][CH3:32])=[O:29])=[N:21][CH:20]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)c2ccc(Cl)nc2)CC1
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CSc1ccc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
A mixture of 1-(2-tert-butylphenyl)-4-[(6-chloropyridin-3-yl)carbonyl]piperazine obtained in Example 18 (590 mg), ethyl thioglycolate (361 mg), potassium carbonate (691 mg), and N,N-dimethylformamide (10 mL) was stirred at 80° C. for 2 h. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography (silica gel, 50:50-0:100 hexane/ethyl acetate) to provide the title compound (430 mg, 59%) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N12CCCN=C1CCCCC2.O>C(#N)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:14]([O:19][CH3:20])[CH:13]=2)=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2
Reactant: COc1cc(-c2ccc(N)c3c2CNC3=O)ccc1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CC#N
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(-c2ccc(N)c3c2CNC3=O)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.3 h
Yield: 71.8 %

Procedure:
7-Amino-4-(4-hydroxy-3-methoxyphenyl)isoindolinone (50.0 mg, 0.185 mmol) was dissolved in acetonitrile (2.5 mL), and the solution was added with tert-butyldimethylsilyl chloride (33.5 mg, 0.222 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.033 mL, 0.22 mmol), followed by stirring at room temperature for 1.3 hours. The mixture was added with tert-butyldimethylsilyl chloride (33.5 mg, 0.222 mmol) and DBU (0.033 mL, 0.22 mmol), followed by further stirring for 1 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by preparative thin-layer chromatography (chloroform/acetonitrile=2/1) to obtain 7-amino-4-(4-tert-butyldimethylsilyloxy-3-methoxyphenyl)isoindolinone (51.1 mg, yield 72%).
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([CH3:23])[C:17]([CH3:25])([CH3:24])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:10]([N:14]([CH:15]1[CH2:16][C:17]([CH3:25])([CH3:24])[N:18]([CH3:23])[C:19]([CH3:21])([CH3:22])[CH2:20]1)[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1)[CH2:11][CH2:12][CH3:13]
Reactant: CC1(C)COP(Cl)OC1
Reactant: CCCCNC1CC(C)(C)N(C)C(C)(C)C1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C1CC(C)(C)N(C)C(C)(C)C1)P1OCC(C)(C)CO1

Procedure:
18.4 g of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added dropwise, at room temperature, with stirring, to a solution of 19.7 g (0.1 mol) of 4-butylamino1,2,2,6,6-pentamethylpiperidine in 100 ml of triethylamine. After heating at the reflux temperature for 15 hours, the mixture is diluted with toluene and the precipitated hydrochloride is filtered off. Evaporation of the filtrate gives 2-[N-butyl(1,2,2,6,6-pentamethyl-4-piperidyl)amino]-5,5-dimethyl-1,3,2-dioxaphosphorinane as an oil which boils at 120° under 40 Pa (Compound No. 1).