Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:19]C(=O)C)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1C[O:26][CH2:25]C1>>[OH:26][CH2:25][CH:1]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH2:19][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc(C[Mg]Br)cc1
Reactant: C1CCOC1
Reactant: CC(=O)CCc1ccccc1
Product: COc1ccc(C(CO)CCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
An 0.5M solution of 4-anisyl magnesium bromide in THF (66.7 mL. 33.3 mmol) was added dropwise to an ice-water cooled solution of benzyl acetone (5.0 mL, 33.3 mmol) in THF. The resulting reaction was allowed to warm to room temperature, and after 1h was partitioned between aqueous ammonium chloride and ether. The organic phase was dried over magnesium sulfate, concentrated, and purified by chromatography over silica gel eluted with 1:5 ethyl acetate/hexanes to afford 6.2 g of 4-(1-hydroxy-4-phenyl-2-butyl) anisole as a clear oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.C([O-])([O-])=O.[Na+].[Na+].[C:21]1([CH3:27])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH2:28](O)[CH3:29].O>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>[C:21]1([C:27]2[C:28]3[C:29](=[CH:4][CH:3]=[CH:2][CH:14]=3)[C:13]([C:2]3[CH:3]=[CH:4][C:5]4[NH:6][C:7]5[C:12]([C:13]=4[CH:14]=3)=[CH:11][CH:10]=[CH:9][CH:8]=5)=[C:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=[CH:7]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCO
Reactant: Brc1ccc2[nH]c3ccccc3c2c1
Reactant: Cc1ccccc1
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: O
Product: c1ccc(-c2c3ccccc3c(-c3ccc4[nH]c5ccccc5c4c3)c3ccccc23)cc1
Temperature: 120 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
3-bromocarbazole (2.54 g, 10.320 mmol), 9-phenyl-boronic acid (3.69 g, 12.384 mmol), Na2CO3 (2.2 g, 20.64 mmol), Pd(PPh3)4 (1.19 g, 1.032 mmol) were put in a 250 mL two-neck flask and dissolved in toluene/ethanol/H2O. The solution was refluxed and stirred at 120° C. for 12 hours. After completion of the reaction, the solution was extracted with methylenechloride/H2O and distilled under reduced pressure to remove the solvent. The resultant was columned with a solution of n-hexane and methylenechloride (4:1) and was re-crystallized in a solution of methylene chloride and petroleum ether such that the white solid compound was obtained, (2.60 g, yield: 60%).
Reaction SMILES: [NH2:1][C@@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(Cl)([Cl:15])=O.[CH3:17]O>>[ClH:15].[CH3:17][O:11][C:10](=[O:12])[C@@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1]
Reactant: N[C@H](Cc1ccccc1)C(=O)O
Reactant: CO
Reactant: O=S(Cl)Cl
Product: COC(=O)[C@H](N)Cc1ccccc1
Product: Cl
Yield: 97 %

Procedure:
(D)-Phenylalanine (25.0 g) was dissolved in 450 mL of methanol and 22 mL thionyl chloride were slowly added at −20° C. The mixture was refluxed for 1 h, followed by evaporation of the volatiles to give 31.2 g (97%) of the title compound as a white solid. M.p. 155-163° C.
Reaction SMILES: C[O:2][C:3](=[O:33])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([S:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)(=[O:24])=[O:23])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[OH-].[Na+]>CO.C1COCC1>[CH3:32][O:31][C:28]1[CH:27]=[CH:26][C:25]([S:22]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[C:5]2[C:6]([CH3:11])=[CH:7][C:8]([CH3:10])=[CH:9][C:4]=2[C:3]([OH:33])=[O:2])(=[O:24])=[O:23])=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc(C)cc(C)c1N(Cc1cccc(OC)c1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)(=O)N(Cc2cccc(OC)c2)c2c(C)cc(C)cc2C(=O)O)cc1
Yield: 70.4 %

Procedure:
To a solution of 0.610 g (1.3 mmol) of the product of Example 103 in 6.5 mL methanol and 6.5 mL of THF was added 6.5 mL of 1N NaOH solution. The reaction mixture was refluxed for 18 hr and the organics were removed in vacuo. The resulting mixture was diluted with water, acidified with 3N HCl and extracted with EtOAc. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was triturated with ether and filtered to provide 0.417 g (79%) of the desired carboxylic acid as a white solid. Electrospray Mass Spec 456.3(M+H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]([S:15][CH2:16][C:17]([OH:19])=O)[N:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:33][C:34]([CH:36]1[CH2:38][CH2:37]1)=[NH:35]>CN(C=O)C>[CH2:8]([C:7]1[C:2]([NH2:1])=[N:3][C:4]([S:15][CH2:16][C:17]2[O:19][N:35]=[C:34]([CH:36]3[CH2:38][CH2:37]3)[N:33]=2)=[N:5][CH:6]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: Nc1nc(SCC(=O)O)ncc1Cc1ccccc1
Reactant: N=C(NO)C1CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1nc(SCc2nc(C3CC3)no2)ncc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 8.4 %

Procedure:
A solution of (4-amino-5-benzyl-pyrimidin-2-ylsulfanyl)-acetic acid (0.35 mg, 1.27 mmol) as prepared according to the method described in example 22, and 1,1′-carbonyl-diimidazole (0.31 g, 1.91 mmol) in DMF (8 ml) was stirred at room temperature for 3 h and subsequently N-hydroxy-cyclopropanecarboxamidine (0.19 g, 1.91 mmol) was added. The reaction mixture was stirred at 80° C. for 20 h and evaporated. Acetic acid (10 ml) was added and the stirred mixture was heated under reflux conditions for 2 h. Aqueous work-up, column chromatography on silica gel (ethyl acetate/hexane 3:2) and crystallization from ethyl acetate/hexane yielded the title compound (36 mg, 9%) as an off-white solid, m.p. 94° C. and MS: m/e=340.3 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[N:4][N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[F:45][C:46]1[CH:47]=[C:48]([CH:50]=[CH:51][C:52]=1[O:53][C:54]1[CH:59]=[CH:58][N:57]=[C:56]2[N:60]([CH2:70][C:71]3[CH:76]=[CH:75][C:74]([O:77][CH3:78])=[CH:73][CH:72]=3)[N:61]=[C:62]([N:63]3[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]3)[C:55]=12)[NH2:49]>C(Cl)Cl.C(Cl)Cl.CN(C=O)C>[CH3:78][O:77][C:74]1[CH:73]=[CH:72][C:71]([CH2:70][N:60]2[C:56]3=[N:57][CH:58]=[CH:59][C:54]([O:53][C:52]4[CH:51]=[CH:50][C:48]([NH:49][C:8]([C:7]5[C:2](=[O:1])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=6)[N:4]=[CH:5][CH:6]=5)=[O:10])=[CH:47][C:46]=4[F:45])=[C:55]3[C:62]([N:63]3[CH2:68][CH2:67][N:66]([CH3:69])[CH2:65][CH2:64]3)=[N:61]2)=[CH:76][CH:75]=1
Reactant: O=C(O)c1ccnn(-c2ccccn2)c1=O
Reactant: COc1ccc(Cn2nc(N3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COc1ccc(Cn2nc(N3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccccn6)c5=O)cc4F)ccnc32)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
3-Oxo-2-(pyridin-2-yl)-2,3-dihydropyridazine-4-carboxylic acid (0.0282 g, 0.130 mmol; prepared as in Example 141, Steps A-C) was dissolved in 5 mL of CH2Cl2 and cooled to 0° C. HOBt (0.0351 g, 0.259 mmol), EDCI (0.0497 g, 0.259 mmol), and NMM (0.0333 ml, 0.303 mmol) were added and the reaction mixture was stirred under N2(g) for 15 minutes. 4-(1-(4-Methoxybenzyl)-3-(4-methylpiperazin-1-yl)-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-3-fluorobenzenamine (0.020 g, 0.0432 mmol; prepared according to Example 86, Step A) in 2 mL of 1:1 CH2Cl2/DMF was added and the reaction was stirred at ambient temperature for 5 hours. The mixture was partitioned between EtOAc and aqueous NaHCO3. The organic layer washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (Flash 5 g) eluting with 3% MeOH/CH2Cl2 to afford the desired product as yellow semi-solid. Yield: 25.8 mg, 86%. LRMS (APCI pos) m/e 662 (M+H).
Reaction SMILES: [C:1]([O:13][CH3:14])(=[O:12])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.C(O)[CH2:16][CH2:17][OH:18].[La].CC(C)(C)/C(/O)=[CH:24]/[C:25](C(C)(C)C)=[O:26].CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.CC(C)(C)/C(/O)=C/C(C(C)(C)C)=O.[La]>>[C:6]([O:8][CH2:9][CH2:16][CH2:17][OH:18])(=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([C:1]([O:13][CH2:14][CH2:24][CH2:25][OH:26])=[O:12])=[CH:3][CH:4]=1
Reactant: CC(C)(C)C(=O)/C=C(\O)C(C)(C)C
Reactant: OCCCO
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: [La]
Product: O=C(OCCCO)c1ccc(C(=O)OCCCO)cc1

Procedure:
This example demonstrates the transesterification reaction of dimethyl terephthalate with 1,3-propanediol using lanthanum t-butylacetylacetonate (otherwise known as tris(2,2,6,6-tetramethyl-3,5-heptanedionato)lanthanum or La(t-Bu-acac)3) as the transesterification catalyst (100 ppm La based on final polymer) to form bis(3-hydroxypropyl) terephthalate.
Reaction SMILES: C(O[C:4](=[O:26])[C:5]([N:7]([C:14]1[C:19]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:17]=[CH:16][C:15]=1[CH:23]([CH3:25])[CH3:24])C1C=CC=CC=1)=[O:6])C.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:20]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:23]([CH3:24])[CH3:25])[C:14]=1[NH:7][C:5](=[O:6])[C:4]([NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[OH:34])=[O:26])([CH3:21])[CH3:22]
Reactant: Nc1ccccc1O
Reactant: CCOC(=O)C(=O)N(c1ccccc1)c1c(C(C)C)cccc1C(C)C
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C(=O)Nc1ccccc1O
Yield: 85 %

Procedure:
N-(2,6-Diisopropylphenyl)-oxanilic acid ethyl ester (2.78 g, 10 mmol, 1 eq) and 2-aminophenol (1.31 g, 12 mmol, 1.2 eq) were dissolved in toluene (50 ml), forming a suspension. To this suspension was added triethylamine (2.78 ml, 20 mmol, 2 eq). The suspension was then heated to reflux, causing the solids to dissolve. After heating at reflux overnight, the product precipitated. At this point, ethyl acetate was added until the precipitate redissolved. The solution was then washed with 2 M HCl solution (2×100 ml). The aqueous layer was then washed with ethyl acetate, and the combined organic layers were washed with brine (100 ml), and dried over MgSO4. The solvent was then removed under reduced pressure, leaving a yellowish solid. The yellowish solid was then recrystallized from toluene, producing a product, white crystalline solid (2.9 g, 8.5 mmol, 85% yield). 1H NMR (300 MHz, CDCl3) δ 9.67 (s, 1H), 8.84 (s, 1H), 8.12 (s, 1H), 7.50 (dd, J=8.25, 1.8 Hz 1H), 7.37 (t, J=7.2 Hz, 1H), 7.23 (d, J=7.5 Hz, 1H), 7.16 (dt, J=7.7, 1.5 Hz, 1H), 6.95 (comp m, 2H), 3.03 (septet, J=6.6 Hz, 2H), 1.22 (d, J=6.9, 12H); 13C NMR (75 MHz, CDCl3) δ 158.9, 158.2, 148.2, 146.1, 129.4, 127.9, 124.2, 124.0, 122.3, 121.2, 119.1, 29.2, 23.9. Anal. Calcd for C20H24N2O3: C, 70.56; H, 7.11; N, 8.23; O, 14.10. Found: C, 34.90; H, 4.64; N, 5.79.
Reaction SMILES: [C:1]([C:3]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][CH2:9]2)[N:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:4]=1)#[CH:2].Cl[C:23]1[CH:32]=[N:31][C:30]2[C:25](=[CH:26][C:27]([Cl:33])=[CH:28][CH:29]=2)[N:24]=1.C(N(CC)CC)C>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:33][C:27]1[CH:26]=[C:25]2[C:30]([N:31]=[CH:32][C:23]([C:2]#[C:1][C:3]3[N:7]=[C:6]([N:8]4[CH2:12][CH2:11][CH2:10][CH2:9]4)[N:5]([CH2:13][C:14]4[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=4)[N:4]=3)=[N:24]2)=[CH:29][CH:28]=1
Reactant: Clc1ccc2ncc(Cl)nc2c1
Reactant: C#Cc1nc(N2CCCC2)n(Cc2ccc(OC)cc2)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2nc(C#Cc3cnc4ccc(Cl)cc4n3)nc2N2CCCC2)cc1
Yield: 49.1 %

Procedure:
A mixture of 3-ethynyl-1-(4-methoxybenzyl)-5-(pyrrolidin-1-yl)-1H-1,2,4-triazole (115 mg, 407 μmol, Eq: 1.00), 2,7-dichloroquinoxaline (89.2 mg, 448 μmol, Eq: 1.1) and triethylamine (61.8 mg, 85.2 μl, 611 μmol, Eq: 1.5) in tetrahydrofuran (3 ml) was purged with argon, then copper (I) iodide (3.1 mg, 16.3 μmol, Eq: 0.04), bis(triphenylphosphine)palladium(II) chloride (11.4 mg, 16.3 μmol, Eq: 0.04) and triphenylphosphine (4.27 mg, 16.3 μmol, Eq: 0.04) were added, the vessel was capped and heated for 18 hours to 75° C. The crude material was applied on silica gel and purified by flash chromatography to give 7-Chloro-2-[1-(4-methoxy-benzyl)-5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylethynyl]-quinoxaline (89 mg, 49.1%) as yellow solid. MS: m/z=445.4 (M+H+)
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[C:11]([CH3:16])[C:10]=2[CH3:17])[CH2:4][O:3]1.C(OC(=O)C)(=[O:21])C>>[CH3:1][C:2]1([CH3:18])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([CH2:16][OH:21])[C:10]=2[CH3:17])[CH2:4][O:3]1
Reactant: Cc1c(OC[C@@H]2COC(C)(C)O2)cc[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Product: Cc1c(OC[C@@H]2COC(C)(C)O2)ccnc1CO
Temperature: 80 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
The 4-(((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-2,3-dimethylpyridine1-oxide (10.5 g, 41.5 mmol) obtained in the step (14a) was mixed with acetic anhydride (20 ml). The mixture was stirred at 80° C. for one hour. After cooled to room temperature, the reaction mixture was concentrated under reduced pressure. To the residue, methanol (40 ml) and a 5N aqueous sodium hydroxide solution (20 ml) were added and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was partitioned between a saturated saline solution and ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated and the residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/methanol) to obtain the title compound (3.77 g, yield: 41.9%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[CH2:22][C:23]#[N:24]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:22][C:23]#[N:24])#[N:2]
Reactant: N#Cc1cccc(O)c1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCOc1cccc(C#N)c1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
The compound 3-cyanophenoxyacetonitrile was prepared by heating 20.0 g of 3-cyanophenol, 30.1 g of anhydrous potassium carbonate and 30 ml of dimethylformamide with stirring in a 250 ml round-bottomed three-necked flask to 70° C. and then 12.7 g of chloroacetonitrile was added dropwise over a 15 minute period with cooling. The temperature of the mixture was held at 70°-80° C. for three hours, after which time the reaction mixture was poured into approximately 700 ml of ice and water which resulted in crystal formation. The crystals were separated by filtering and then washed thoroughly with water. After drying in a vacuum oven, a tan solid 3-cyanophenoxyacetonitrile was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[CH:8]2)(=[O:4])=[O:3].[OH-].[K+].[I:16]I.O>CS(C)=O>[I:16][C:8]1[C:7]2[C:11](=[CH:12][CH:13]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[NH:10][N:9]=1
Reactant: CS(=O)(=O)c1ccc2[nH]ncc2c1
Reactant: II
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
To a solution of 5-(methylsulfonyl)-1H-indazole (430 mg, 2.19 mmol) in DMSO (10 mL) at 0° C., were added KOH (0.4 g, 6.57 mmol) and I2 (1.2 g, 4.38 mmol) successively, then the reaction mixture was stirred at room temperature for 3 hours. Water (40 mL) was added, product extracted with EtOAc (3×30 mL), organics combined dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with petroleum ether/EtOAc=20:1) to give 3-iodo-5-(methylsulfonyl)-1H-indazole (410 mg, 59.9%) as an off-white solid. LCMS: (M+H)+=323; 1H NMR (300 MHz, DMSO): δ 7.98-7.95 (m, 4H), 3.27 (s, 3H).
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:6]=1)=[O:4].[NH:16]1[CH2:20][CH2:19][NH:18][C:17]1=[S:21]>>[BrH:1].[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([OH:4])[CH2:2][S:21][C:17]3=[N:16][CH2:20][CH2:19][N:18]23)=[CH:6][C:7]=1[S:12](=[O:15])(=[O:14])[NH2:13]
Reactant: S=C1NCCN1
Reactant: NS(=O)(=O)c1cc(C(=O)CBr)ccc1Cl
Product: Br
Product: NS(=O)(=O)c1cc(C2(O)CSC3=NCCN32)ccc1Cl

Procedure:
6.2 g of 2-bromo-4'-chloro-3'-sulfamoylacetophenone and 2 g of ground 2-imidazolidine-thione were reacted according to the prescription given in Example 12 and the crystalline precipitate was filtered off. Colorless solid body: decomposition beginning at 100° C., γC=N 1590 cm-1.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22]Cl>O1CCCC1>[CH2:15]([O:14][C:9](=[O:13])[C:10]([CH3:12])([CH3:11])[CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([O:18][CH3:17])[CH:20]=1)[CH3:16]
Reactant: CCOC(=O)C(C)C
Reactant: COc1cccc(CCl)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 106.4 %

Procedure:
Lithium diisopropylamide (2 M in tetrahydrofuran, 2.71 mL, 5.42 mmol) was added to a mixture of ethyl isobutyrate (600 mg, 5.17 mmol) in tetrahydrofuran (60 mL) at −78° C. and stirred at this temperature for 1 hour. 3-Methoxybenzyl chloride (1.15 g, 7.34 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for another 1 hour and then at room temperature overnight. The mixture was quenched by water and extracted with ethyl acetate. The combined organic fractions were washed with water, dried over sodium sulfate and concentrated under vacuum to give ethyl-3-(3-methoxyphenyl)-2,2-dimethylpropanoate (1.3 g) as a yellow oil, which was used in the next step without further purification.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13](/[CH:14]=[CH:15]/[C:16]([CH3:18])=[O:17])[C:12]([CH3:20])([CH3:19])[CH2:11][CH2:10][CH:9]=1.[H][H]>CC(O)C>[CH3:7][C:8]1[CH:13](/[CH:14]=[CH:15]/[CH:16]([OH:17])[CH3:18])[C:12]([CH3:19])([CH3:20])[CH2:11][CH2:10][CH:9]=1
Reactant: CC(=O)/C=C/C1C(C)=CCCC1(C)C
Reactant: [H][H]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1=CCCC(C)(C)C1/C=C/C(C)O
Yield: 100 %

Procedure:
Under a nitrogen atmosphere, 64 mg of RuCl2 [(S)-DM-BINAP][(S)-DAIPEN], 720 mg of K2CO3, 100 mL of IPA, and 20 g of α-ionone as a racemic form were mixed. After deaeration, the obtained mixture was subjected to an asymmetric hydrogenation at 30° C. and a hydrogen pressure of 3 MPa for 21 hours. The reaction pressure was returned to the constant pressure. It was confirmed by GC that the raw material disappeared, and a post-treatment was then carried out by a conventional method, to give 20.2 g of desired optically active α-ionol (100% yield; 90% e.e.; 0% d.e.).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:21])[C:7]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:23][O-:24].[Na+]>CO>[ClH:1].[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]([CH3:21])[C:7]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)(=[O:14])=[O:13])=[N:8]2)=[C:4]([O:24][CH3:23])[N:3]=1
Reactant: C[O-]
Reactant: Cn1c(NS(=O)(=O)c2ccccc2)nc2nc(Cl)nc(Cl)c21
Agent: [Na+]
Solvent: CO
Product: COc1nc(Cl)nc2nc(NS(=O)(=O)c3ccccc3)n(C)c12
Product: Cl
Yield: 81 %

Procedure:
3.00 g (8.00 mmol) of the sulfonamide prepared in Example 1 and 2.90 g (16.0 mmol) of 30% strength sodium methylate solution were stirred in 50 ml of methanol for 12 hours at room temperature, and then evaporated down in a rotary evaporator. Stirring the residue in H2O and acidifying with dilute HCl gave 2.30 g (81%) of the desired product in the form of colorless crystals (active ingredient 1.002).
Reaction SMILES: Cl.[C:2]([NH:6][CH2:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:12]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:11]=1)=[O:9])([CH3:5])([CH3:4])[CH3:3].[BH4-].[Na+].[CH3:31][S:32](O)(=[O:34])=[O:33]>CO>[CH3:31][S:32]([O:9][CH:8]([CH2:7][NH:6][C:2]([CH3:5])([CH3:3])[CH3:4])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[C:12]([CH2:24][O:25][C:26](=[O:28])[CH3:27])[CH:11]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)O
Reactant: CC(=O)OCc1cc(C(=O)CNC(C)(C)C)ccc1Oc1ccccc1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)OCc1cc(C(CNC(C)(C)C)OS(C)(=O)=O)ccc1Oc1ccccc1C

Procedure:
Proceeding in a manner similar to that described above in part B of Example 151, 22 g. of 3-(acetoxymethyl)-4-(o-toluyloxy)phenyl tert-butylaminomethyl ketone hydrochloride was reduced in anhydrous methyl alcohol with 1.13 g. of sodium borohydride and the reduction product was treated with methanesulfonic acid to yield 3-(acetoxymethyl)-4-(o-toluyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol methanesulfonate as a white solid which melted at 116-118° C.(uncorr.).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:14](=[O:15])[CH2:13][CH2:12][Cl:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCl
Reactant: CC(C)(C)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl benzene (31 ml, 200 mmol) and 3-chloro-propionyl chloride (19 ml, 200 mmol) in methylene chloride (75 ml) was added dropwise to a suspension of aluminum chloride (29.33 g, 220 mmol) in methylene chloride (300 ml) at 0° C. The reaction mixture was allowed to warm to ambient temperature, stirred for 16 hours, and quenched with water dropwise. The reaction mixture was washed with water, dried with magnesium sulfate, and the filtrate was evaporated under reduced pressure to provide the title compound which was used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Product: O=Cc1cn(S(=O)(=O)c2ccc(F)cc2)c2ccccc12

Procedure:
The same procedures used in Example 17 were repeated except for using 870 mg of indole-3-carbaldehyde and 4-fluorobenzenesulfonyl chloride instead of the benzenesulfonyl chloride used in Example 17 to give 1.73 g of 1-(4-fluorobenzenesulfonyl)indole-3-carbaldehyde as brown crystals. The yield thereof was found to be 95%.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])(=[O:4])=[O:3].CS(N[CH2:21][CH2:22]CCCCC(OCC)=O)=O.[C:32]([O:35][CH:36]([CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[CH2:37][CH2:38][CH2:39]N(CCCCCCC(OCC)=O)S(C)=O)(=[O:34])[CH3:33]>>[CH2:21]([CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:39]/[CH:38]=[CH:37]/[CH:36]([O:35][C:32](=[O:34])[CH3:33])[CH2:55][CH2:56][CH2:57][CH2:58][CH3:59])[S:2]([CH3:1])(=[O:3])=[O:4])[C:12]([OH:14])=[O:13])[CH3:22]
Reactant: CCOC(=O)CCCCCCNS(C)(=O)=O
Reactant: CCCCCC(CCCN(CCCCCCC(=O)OCC)S(C)=O)OC(C)=O
Reactant: CCOC(=O)CCCCCCNS(C)=O
Product: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1 except that, in Step A, the ethyl 7-(methanesulfonamido)heptanoate is replaced by an equimolar amount of ethyl 7-(methanesulfinamido)heptanoate (Example T). The product of Step A is thus ethyl 7-[N-(4-acetoxynonyl)methanesulfinamido]heptanoate. The subsequent step yields 7-[N-(4-hydroxynonyl)methanesulfinamido]heptanoic acid (B).