Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C[S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([N:29]3[CH2:32][CH:31]([N:33]4[CH:37]=[N:36][CH:35]=[N:34]4)[CH2:30]3)=[O:28])[CH2:10]2)=CC=1.FC(F)(F)C(O)=O.FC(F)(F)S(O)(=O)=O>C1(OC)C=CC=CC=1>[SH:8][C@@H:9]1[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:11]([C:27]([N:29]2[CH2:30][CH:31]([N:33]3[CH:37]=[N:36][CH:35]=[N:34]3)[CH2:32]2)=[O:28])[CH2:10]1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC(n4cncn4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC(n2cncn2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 130 %

Procedure:
858 mg of (2S, 4S)-4-(4-methoxybenzylthio)-2-[3-(1-1,2,4-triazolyl)-1-azetidinylcarbonyl)-1-(4-nitrobenzyloxycarbonyl)pyrrolidine [prepared as described in step (a) above] were suspended in 1.7 ml of anisole, and 8.4 ml of trifluoroacetic acid and 0.27 ml of trifluoromethanesulfonic acid were added to the resulting suspension, whilst ice-cooling, after which the mixture was stirred at 0° C. for 30 minutes and then at room temperature for 30 minutes. At the end of this time, the solvent was removed by evaporation under reduced pressure, and the residue was washed with hexane to remove anisole. The mixture was then mixed with diethyl ether to wash the mixture further. The resulting compound was mixed with 100 ml of ethyl acetate and with 30 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The organic layer was then dried over anhydrous magnesium sulfate, and the residue was filtered and concentrated by evaporation under reduced pressure, to give 873 mg of the title compound, as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][NH:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: NCc1ccccn1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CNCc3ccccn3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 2-(aminomethyl)pyridine (0.010 mL, 0.097 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[(pyridin-2-ylmethyl)amino methyl]indol-2-yl)isoindolinone.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.[C:18]([C:20]1[N:24]([CH3:25])[C:23](B(O)O)=[CH:22][CH:21]=1)#[N:19].[F-].[K+]>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].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[C:18]([C:20]1[N:24]([CH3:25])[C:23]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=2)=[CH:22][CH:21]=1)#[N:19]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CCNS(=O)(=O)c1ccc(Br)cc1C(F)(F)F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1C(F)(F)F
Reaction time: 16 h
Yield: 45 %

Procedure:
According to general procedure B, 4-bromo-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (186 mg, 0.56 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (100 mg, 0.67 mmol), potassium fluoride (107 mg, 1.85 mmol), and tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.4 mL) was added. Tri-t-butylphosphine (83 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethyl-2-(trifluoromethyl)benzenesulfonamide (90 mg, 45%) was provided after purification. MS (ESI) m/z 357. HPLC purity 100.0% at 210-370 nm, 10.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]2[N:11]3[N:12]=[CH:13][CH:14]=[C:10]3[N:9]=[C:8]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:7]=2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)Cl.CN([CH:32]=[O:33])C>>[CH:2]1([NH:5][C:6]2[N:11]3[N:12]=[CH:13][C:14]([CH:32]=[O:33])=[C:10]3[N:9]=[C:8]([NH:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)[CH:7]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3nccc3n2)cc1
Reactant: CN(C)C=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Temperature: 0 °C
Reaction time: 5 h
Yield: 64 %

Procedure:
4-(7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile hydrochloride (205 mg, 0.62 mmol) was dissolved in anhydrous DMF (1 mL) and the solution was cooled to 0° C. by an external ice bath. POCl3 (115 μL, 1.25 mmol) was added dropwise keeping the internal temperature <5° C. After addition, the ice bath was removed. After 5 h, the solution was poured into H2O (20 mL) and the pH was adjusted to 11 by the addition of 6N NaOH. The solution was allowed to stir for 1 h, and the precipitate was filtered off. The crude product was triturated with EtOH (7 mL), filtered, and dried under high vacuum (1 mmHg) to provide 4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (129 mg, 64%) as an orange solid. LCMS (ES): >90% pure, m/z 319 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][NH:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:16][CH:15]=2)=[N:11][CH:12]=1.[CH:45](=O)[CH3:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][C:43]=1[Cl:44])[CH2:5][N:6]([CH2:45][CH3:46])[C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][CH2:22][C:23]([N:25]3[CH2:30][CH2:29][N:28]([CH2:31][C:32]4[CH:40]=[CH:39][C:38]5[O:37][CH2:36][O:35][C:34]=5[CH:33]=4)[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:19]=2)=[N:11][CH:12]=1
Reactant: O=C(CNCc1ccc(Oc2ccc(NCc3ccc(Cl)c(Cl)c3)cn2)cc1)N1CCN(Cc2ccc3c(c2)OCO3)CC1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(Cc1ccc(Cl)c(Cl)c1)c1ccc(Oc2ccc(CNCC(=O)N3CCN(Cc4ccc5c(c4)OCO5)CC3)cc2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-({4-[5-(3,4-dichlorobenzylamino)pyridin-2-yloxy]phenyl}methylamino)-1-(4-piperonylpiperazin-1-yl)ethanone (1.59 g, 2.5 mmol) was dissolved in dichloroethane (80 mL). To this solution were added acetoaldehyde (1.40 mL, 25.0 mmol) and sodium triacetyloxy borohydride (1.59 mL, 7.5 mmol) under ice cooling. To the resulting solution was added dropwise acetic acid (0.43 mL, 7.5 mmol), and this solution was stirred at room temperature for 16 hours. The resulting reaction solution was washed with a saturated sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was then purified by silica gel column chromatography (chloroform:methanol=50:1). The obtained solid was recrystallized from ethanol, to thereby yield 0.65 g of the title compound.
Reaction SMILES: NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(OCC3C=CC(C4SC(N5CCC6C(=C(C(=O)N(C7SC8C=CC=CC=8N=7)COCC[Si](C)(C)C)C=CC=6)C5)=NC=4C(OCC)=O)=CC=3)=CC=2)C=1C#N.NC1N(C(OC(C)(C)C)=O)N=C(C2C=CC(O)=CC=2)C=1C#N.[S:92]1[C:96]2[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=2[N:94]=[C:93]1[N:101]([CH2:127][O:128][CH2:129][CH2:130][Si:131]([CH3:134])([CH3:133])[CH3:132])[C:102]([C:104]1[CH:105]=[CH:106][CH:107]=[C:108]2[C:113]=1[CH2:112][N:111]([C:114]1[S:115][C:116]([CH2:123][CH2:124][CH2:125][OH:126])=[C:117]([C:119]([O:121][CH3:122])=[O:120])[N:118]=1)[CH2:110][CH2:109]2)=[O:103].[NH2:135][C:136]1[S:137][CH:138]=[C:139]([C:143]2[CH:148]=[CH:147][C:146](O)=[CH:145][CH:144]=2)[C:140]=1[C:141]#[N:142]>>[NH2:135][C:136]1[S:137][CH:138]=[C:139]([C:143]2[CH:148]=[CH:147][C:146]([O:126][CH2:125][CH2:124][CH2:123][C:116]3[S:115][C:114]([N:111]4[CH2:110][CH2:109][C:108]5[C:113](=[C:104]([C:102](=[O:103])[N:101]([C:93]6[S:92][C:96]7[CH:97]=[CH:98][CH:99]=[CH:100][C:95]=7[N:94]=6)[CH2:127][O:128][CH2:129][CH2:130][Si:131]([CH3:134])([CH3:133])[CH3:132])[CH:105]=[CH:106][CH:107]=5)[CH2:112]4)=[N:118][C:117]=3[C:119]([O:121][CH3:122])=[O:120])=[CH:145][CH:144]=2)[C:140]=1[C:141]#[N:142]
Reactant: N#Cc1c(-c2ccc(O)cc2)csc1N
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCO
Agent: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Product: COC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1CCCOc1ccc(-c2csc(N)c2C#N)cc1

Procedure:
Compound 47G was prepared in a similar manner to the synthesis of compound 35A by substituting compound 34B and compound 31F with compound 47F and compound 47C, respectively: MS (ESI(+)): m/z 838 (M+H).
Reaction SMILES: C([NH:4][CH:5]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[C:10]=1[O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:6]([OH:8])=[O:7])(=O)C.C(N(CC)CC)C.C1C=NC2N(O)N=NC=2C=1.[F:50][CH:51]([F:55])[C:52](O)=[O:53].CCN=C=NCCCN(C)C>C(Cl)Cl.CCOC(C)=O>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[CH2:25][O:24][C:10]1[C:11]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[CH:12][CH:13]=[CH:14][C:9]=1[CH:5]([NH:4][C:52](=[O:53])[CH:51]([F:55])[F:50])[C:6]([OH:8])=[O:7]
Reactant: CC(=O)NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl
Reactant: O=C(O)C(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(C(=O)O)c1cccc(OCc2ccccc2Cl)c1OCc1ccccc1Cl)C(F)F
Reaction time: 16 h
Yield: 64 %

Procedure:
To a stirred solution of Example 13 Part A compound (222 mg, 0.45 mmol) under argon at room temperature in CH2Cl2 (2.5 mL) was added triethylamine (85 μL, 0.6 mmol), HOAt (69 mg, 0.5 mmol) and difluoroacetic acid (48 mg, 0.5 mmol) was added EDAC (96 mg, 0.5 mmol). After 16 h, the reaction mixture was diluted with EtOAc, washed once with 10% citric acid, dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel provided the title compound as a colorless oil, 156 mg (64% yield). LC/MS gave the correct molecular ion [(M+H)+=538] for the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=[O:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CO.[BH4-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([OH:21])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1ccc(CC(=O)c2cc(OC)cc(OC)c2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(CC(O)c2cc(OC)cc(OC)c2)cc1
Reaction time: 1 h

Procedure:
5 g of precipitated 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanone (1.74 mmol) prepared according to Example 4 are introduced into 75 ml of methanol and 62.5 ml of THF in a 250 ml three-necked round-bottomed flask. 0.78 g of sodium borohydride (1.1 eq.) is added at ambient temperature over approximately 1 h. The reaction medium is kept stirred for 1 h and concentrated and the residue is taken up in 50 ml of a water/methanol (50/50 by volume) mixture. The precipitate obtained is filtered off and washed on the filter with 25 ml of water/methanol (50/50 by volume). 5 g of a white precipitate are recovered, which precipitate, by NMR, corresponds to the expected 1-(3,5-dimethoxyphenyl)-2-(4-methoxyphenyl)ethanol, i.e. a virtually quantitative yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.C[O:36][C:37](=[O:47])[C:38]1[CH:43]=[C:42](Br)[CH:41]=[C:40]([Cl:45])[C:39]=1[OH:46].C(=O)(O)[O-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(OCC)(=O)C.C(#N)C>[Cl:45][C:40]1[C:39]([OH:46])=[C:38]([CH:43]=[C:42]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:12]3=[N:13][CH:14]=2)[CH:41]=1)[C:37]([OH:36])=[O:47]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: COC(=O)c1cc(Br)cc(Cl)c1O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Temperature: 75 °C
Yield: 55.4 %

Procedure:
400 mg (0.83 mmol) of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine, 265 mg (1.00 mmol) of 5-bromo-3-chloro-2-hydroxy-benzoic acid methyl ester and 34 mg (41 μmol) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct were placed in a vial. 8 mL of acetonitrile and 8 mL of a saturated aqueous solution of sodium bicarbonate were added. The vial was closed and the mixture heated to 75° C. for 17 h. The crude mixture was distributed between ethyl acetate and 10% aqueous citric acid. The aqueous layer was extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulfate and evaporated. The crude was purified by flash chromatography on silica gel using a gradient of ethyl acetate containing 15% of methanol in hexanes to afford 241 mg (0.46 mmol, 55%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid as a brown oil. 1H NMR (500 MHz, DMSO-d6) δ 8.89 (d, 1H), 8.36 (d, 1H), 8.12 (d, 1H), 8.07 (d, 1H), 7.64 (dd, 1H), 7.50 (ddd, 1H), 7.24 (d(d), 1H), 7.11 (ddd, 1H), 5.85 (s, 2H), 3.84 (s, 3H), 3.70 (t, 2H), 0.86 (t, 2H), −0.08 (s, 9H), MS: m/z 526.1 (M+H+), 548.1 (M+Na+).
Reaction SMILES: C([O:4][C@H:5]1[CH2:29][CH2:28][C@@:27]2([CH3:30])[C@@H:7]([CH2:8][C:9](=[O:32])[C:10]3[C@H:11]4[C@:23]([CH3:31])([CH2:24][CH2:25][C:26]=32)[C@@H:14]([C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]4)[CH2:6]1)(=O)C.Cl.O>C(O)C.[OH-].[Na+]>[O:32]=[C:9]1[CH2:8][C@@H:7]2[C@:27]([CH3:30])([CH2:28][CH2:29][C@H:5]([OH:4])[CH2:6]2)[C:26]2[CH2:25][CH2:24][C@@:23]3([CH3:31])[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@H:15]([CH3:22])[CH2:16][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])[C:10]1=2
Reactant: CC(=O)O[C@H]1CC[C@]2(C)C3=C(C(=O)C[C@H]2C1)[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2C3=C(CC[C@]12C)[C@@]1(C)CC[C@H](O)C[C@@H]1CC3=O
Temperature: 25 °C
Yield: 43.8 %

Procedure:
0.50 g of 3β-acetoxy-7-oxo-5α-cholest-8-ene (Fieser, L F J Am Chem Soc (1953) 4395) was refluxed in a mixture of 30 ml of ethanol and 20 ml of 1 M aqueous sodium hydroxide for 1 hour. After cooling to room temperature, 23 ml of 1M hydrochloric acid and 100 ml of water were added. After cooling on an ice bath, the precipitate was filtered off, washed with water and dried to give 0.435 g of the crude compound which was purified by chromatography on silica gel (methylene chloride/methanol, 40:1 (w/w)) and crystallized from methanol/water to give 0.198 g of the title compound. Melting point: 115-117° C. The 1H-NMR spectrum (CDCl3,d) showed characteristic signals at: 0.59 (s,3H); 1.18 (s,3H); 3.64 (m,1H). The 13C-NMR spectrum (CDCl3, 100.6 MHz) showed characteristic signals at: 69.5; 132.8; 164.8; 198.6.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[C]=[O:18].B(F)(F)F>C(OCC)(=O)C.CC(C)=O>[CH3:9][C:1]1[CH:2]=[CH:3][C:4]([C:7]([OH:18])=[O:8])=[CH:5][CH:6]=1
Reactant: [C]=O
Reactant: Cc1ccc(C=O)cc1
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)O)cc1

Procedure:
As described above, p-tolualdehyde, starting material of the present invention, is synthesized through reaction of toluene with carbon monoxide in the presence of a catalyst of HF--BF3 or HCl--AlCl3, and the resulting crude p-tolualdehyde is in a form of complex with the catalyst. After passage through the ordinary step of decomposing the complex, the crude p-tolualdehyde is purified to a purity of about 99% by distillation. Th resulting p-tolualdehyde has a sufficient quality as an industrial raw material for the ordinary reaction processes other than the process of the present invention. That is, even if the resulting p-tolualdehyde as such is autooxidized with air under pressure in a solvent of acetone or ethyl acetate in the absence of catalyst, a long induction period is required for the start of reaction, and even if the reaction is started, a sufficient reaction rate cannot be obtained. Even with a sufficient time, the per-p-toluic acid yield is low, and thus the resulting p-tolualdehyde of purity of about 99% is not industrially preferable as the starting material for the present invention.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12]3=[N:13][N:14]=[N:15][N:11]3[CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1.[CH3:17][O:18]C1C=C2C(=CC=1C=O)N1N=NN=C1CC2>>[CH3:1][O:2][C:3]1[C:4]([CH:17]=[O:18])=[CH:5][C:6]2[C:12]3=[N:13][N:14]=[N:15][N:11]3[CH2:10][CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: COc1ccc2c(c1)CCCn1nnnc1-2
Reactant: COc1cc2c(cc1C=O)-n1nnnc1CC2
Product: COc1cc2c(cc1C=O)-c1nnnn1CCC2

Procedure:
This compound was prepared from Compound 9 in the same manner of Compound 2.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][CH:4]=1)#[N:2].[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[CH:25])[CH3:21]>CCCCCCC.CCOC(C)=O>[CH2:20]([N:22]([CH2:26][CH3:27])[CH2:23][C:24]#[C:25][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)[CH3:21]
Reactant: C#CCN(CC)CC
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C#N)cc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1ccc(C#N)cc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 4-cyano-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 6:4; yield (95.4 mg, 90%); 1H NMR δ (CDCl3): 7.58 (d, J=8.65 Hz, 2H), 7.49 (d, J=8.63 Hz, 2H), 3.64 (s, 2H), 2.61 (q, J=7.16 Hz, 4H), 1.11 (t, J=7.15 Hz, 6H); LCMS m/z: 212.
Reaction SMILES: ClC1C=CC(C2C=CC(CO)=CC=2)=CC=1C(F)(F)F.C[O:21][C:22](=[O:51])[CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([C:46]([F:49])([F:48])[F:47])[CH:40]=3)=[CH:35][CH:34]=2)=[CH:27][C:26]=1[CH3:50]>>[Cl:45][C:42]1[CH:43]=[CH:44][C:39]([C:36]2[CH:37]=[CH:38][C:33]([CH2:32][S:31][C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:23][C:22]([OH:51])=[O:21])=[C:26]([CH3:50])[CH:27]=3)=[CH:34][CH:35]=2)=[CH:40][C:41]=1[C:46]([F:49])([F:47])[F:48]
Reactant: COC(=O)COc1ccc(SCc2ccc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2)cc1C
Agent: OCc1ccc(-c2ccc(Cl)c(C(F)(F)F)c2)cc1
Product: Cc1cc(SCc2ccc(-c3ccc(Cl)c(C(F)(F)F)c3)cc2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in the manner analogous to Example 3B using 6A. MS m/z 305 (M). Step 3. Preparation of [4-(4′-Chloro-3′-trifluoromethyl-biphenyl-4-ylmethylsulfanyl)-2-methyl-phenoxy]-acetic acid methyl ester (Compound 6C)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1>C(O)C.C(O)(=O)C.[Pt]=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1

Procedure:
A mixture of platinum oxide (1.0 g) in ethanol (37.5 ml) and glacial acetic acid (12.5 ml) was treated under nitrogen with 4-(6-fluoroindol-3-yl)-1,2,5,6-tetrahydropyridine (20 g, 92.6 mmol) in ethanol (187.5 ml) and glacial acetic acid (62.5 ml). The nitrogen was evacuated and hydrogen was admitted. The reaction mixture was then hydrogenated at 60 psi until the reaction was complete by tlc. The catalyst was removed by filtration and the solvent evaporated in vacuo to give a yellow solid which after drying at 60C in vacuo weighed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:29][CH2:30][CH2:31][OH:32].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:29][CH2:30][CH2:31][OH:32])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccccc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.5 %

Procedure:
5-[(2,5-Difluorophenyl) (phenylsulfonyl)methyl]-4-meth ylpyridine-2-carboxylic acid (90 mg, 0.22 mmol), 2-aminoethanol (27 μl, 0.45 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (64 mg, 0.34 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol), and triethylamine (92 μl, 0.66 mmol) were dissolved in methylene chloride (15 ml), and the resulting solution was stirred overnight at room temperature. Water was added to the reaction mixture, and the resulting mixture was extracted twice with methylene chloride. The combined organic layer was dried over anhydrous sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative thin-layer chromatography (developed with 5% methanol/methylene chloride, eluted with 30% methanol/methylene chloride), to obtain the title compound (30 mg, 0.067 mmol, 30%) as a white amorphous substance.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[NH2:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][CH:26]=1)[CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[NH:15][N:14]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([NH:8][C:9]1[CH:26]=[CH:25][CH:24]=[C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[NH:15][N:14]=2)[CH:10]=1)=[O:6]
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: O=C(Cl)CCCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(CCCCl)Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Chlorobutyryl chloride (5.42 g, 38.4 mmol) was added dropwise at ambient temperature to a stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (8 g, 32 mmol; prepared in a manner similar to that described above), triethylamine (5.35 ml, 38.4 mmol) and 1,4-dioxane (40 ml), the mixture was stirred at ambient temperature for 1 hour, then it was poured into ice-water (100 ml). The resulting solid was collected by filtration, washed with water (30 ml) and dried in vacuo to give 4-chloro-N-[3-(4-oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]butyramide (12.34 g) as an off-white solid, m.pt. 180–184° C.