Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]([C:9]2[S:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+].C([BH3-])#N.[Na+]>O1CCCC1.[Ti](Cl)(Cl)(Cl)Cl.C(O)(=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:28][CH:29]=2)[C:9]2[S:17][C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]=2[CH3:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)C2CCCCC2)sc2ncccc12
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [BH3-]C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 64.1 %

Procedure:
To a mixture of cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methanone (1.00 g) synthesized above, methyl 4-aminobenzoate (642 mg), triethylamine (4.31 mL) and methylene chloride (20 mL) was added titanium (IV) chloride (508 μL) at 0° C., and the mixture was stirred at room temperature for 1.5 days under argon atmosphere. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give a dark brown solid. To a solution (20 mL) of the obtained solid in tetrahydrofuran were added acetic acid (442 μL) and sodium cyanoborohydride (485 mg), and the mixture was stirred at room temperature for 1.5 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (975 mg, 64%) as a pale-brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([O:27]CC4C=CC=CC=4)[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]>Cl.O1CCOCC1>[CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH2:20])[C:14]3=[C:13]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(OCc4ccccc4)c3)c3c(N)nccn32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@H]1CC[C@H](c2nc(-c3cccc(O)c3)c3c(N)nccn32)CC1
Temperature: 25 °C

Procedure:
A solution of trans-4-[8-Amino-1-(3-benzyloxy-phenyl)-imidazo[1,5-a]pyrazin-3-yl]-cyclohexanecarboxylic acid methyl ester (50 mg, 0.110 mmol) in 4M HCl in dioxane (2 mL) was heated to 75° C. in a oil-bath for ˜2 h. The reaction mixture was allowed to cool to rt, the dioxane was decanted off and the reaction mixture was quenched with 7N NH3 in MeOH solution (˜2 mL). This crude mixture was concentrated in vacuo resulting in 79 mg of an off-white solid (containing NH4Cl salts). The crude material was purified by flash silica chromatography (10% 7N NH3 in MeOH in CHCl3) resulting in an off-white solid; 1H NMR (DMSO-d6, 400 MHz) δ 1.51-1.78 (m, 4H), 1.95-2.08 (m, 4H), 2.38-2.48 (m, 1H), 3.07-3.20 (m, 1H), 3.63 (s, 3H), 6.06 (brs, 2H), 6.76-6.89 (m, 1H), 6.95-7.05 (m, 3H), 7.29 (t, 1H, J=7.8 Hz), 7.65 (d, 1H, J=5.1 Hz), 9.62 (brs, 1H); MS (ES+): m/z 367.26 [MH+].
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([OH:20])=O)[N:9]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:28]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:32]2C=CC=CC=2N=N1.Cl.CN.CCN(CC)CC>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:28][CH3:32])=[O:20])[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1cc2ccccc2c(-c2ccc(I)cc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
A mixture of 1-(4-iodophenyl)-3-isoquinolinecarboxylic acid (0.2073 g, 0.55 mmol), BOP (0.2447 g, 0.55 mmol), Methylamine hydrochloride (0.096 g, 1.42 mmol), and Et3N (0.25 mL, 1.80 mmol) in DMF (8 mL) was stirred under Ar at room temperature. After stirring for 1 h , additional Et3N (0.2 ml,) was added in one portion. The mixture was stirred under Ar for 7 h, then quenched by adding H2O (8 mL). The resulting mixture was extracted with CH2Cl2 (3×20 mL). The combined organic layers were dried (Na2SO4), then filtered. The filtrate was concentrated in vacuo. The residue was purified on column chromatography (SiO2, 35% ethyl acetate in hexane, 0.1% Et3N), thereby affording the title compound as a white solid (0.1724, 81%). mp 163-164 ° C. 1H NMR (CDCl3) d 3.07, 3.09 (two s, total 3 H, N-methyl), 7.46 (d, J=8.4 Hz, 2 H, aromatic), 7.64 (t, J=7.2 Hz, 1 H, aromatic), 7.77 (t, J=6.9 Hz, 1 H, aromatic), 7.92 (d, J=8.4 Hz, 2 H, aromatic), 8.07 (t, J=7.8 Hz, 2 H, aromatic), 8.24 (br s, 1 H, NH), 8.02 (s, 1 H, aromatic). 13C NMR (CDC13) d 26.05 (q,N-methyl), 95.14 (s, C--I), 119.54 (d, aromatic), 127.02 (d, aromatic), 128.58 (d, aromatic), 128.75 (di aromatic), 130.60 (d, aromatic), 131.43 (d, aromatic), 131.56 (aromatic), 137.02 (s, aromatic), 137.40 (d, aromatic), 138.28 (s, aromatic), 142.58 (s, aromatic), 158.09 (s, aromatic), 165.12 (s, CO). HRMS calcd. for C17H13IN2O: 388.0073. Found: 388.0077.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]2=[O:24])[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:9].Cl[C:26]1[C:31]([Cl:32])=[CH:30][C:29]([Cl:33])=[CH:28][N:27]=1>>[Cl:32][C:31]1[C:26]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:7]3[CH:6]=[CH:5][C:4]([N:16]4[C@H:20]([CH2:21][O:22][CH3:23])[CH2:19][O:18][C:17]4=[O:24])=[CH:3][C:2]=3[F:1])=[O:9])[CH2:11][CH2:12]2)=[N:27][CH:28]=[C:29]([Cl:33])[CH:30]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCNCC2)c(F)c1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(Cl)cc3Cl)CC2)c(F)c1
Yield: 59.5 %

Procedure:
By reaction and treatment in the same manner as in Example 147 and using (R)-3-[3-fluoro-4-(piperazine-1-carbonyl)phenyl]-4-methoxymethyloxazolidin-2-one (875 mg) described in Preparation Example 158 and 2,3,5-trichloropyridine (945 mg), the title compound (746 mg) was obtained. MS(ESI)m/z:483(M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)[C:3]#[N:4].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[S:25])=[CH:22][CH:21]=1>>[C:3]([C:2]([NH:1][C:24](=[S:25])[C:23]1[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:29])[F:30])=[CH:28][CH:27]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([Cl:16])[CH:11]=[C:12]2[Cl:15])=[N:7]1)#[N:4]
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2c(Cl)cc(Cl)cc2n1
Product: CC(C#N)(Cn1cc2c(Cl)cc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(4,6-dichloro-2H-indazol-2-yl)-2-methylpropionitrile (20 mg, described in Example 134) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (34 mg, 97%). MS (ES): M/Z [M+H]=473. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.82 (d, 1H), 4.93 (d, 1H), 7.15 (d, J=0.9 Hz, 1H), 7.60 (s, 1H), 7.79 (d, 2H), 7.88 (d, 2H), 8.22 (s, 1H) and 8.32 (s, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[OH:14])[CH:7]=[CH:6]2.N1CCC(C(C2C=CC3C(=CC=C(Cl)C=3)C=2)=O)CC1.Cl[CH2:41][CH2:42][CH2:43][CH:44]([C:46]1[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=1)[OH:45].ClCCCC(C1C=CC(F)=CC=1)=O>>[F:52][C:49]1[CH:48]=[CH:47][C:46]([CH:44]([OH:45])[CH2:43][CH2:42][CH2:41][N:18]2[CH2:19][CH2:20][CH:15]([CH:13]([C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][CH:12]=[C:3]([Cl:2])[CH:4]=4)[CH:9]=3)[OH:14])[CH2:16][CH2:17]2)=[CH:51][CH:50]=1
Reactant: OC(CCCCl)c1ccc(F)cc1
Reactant: OC(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Agent: Cl
Agent: O=C(CCCCl)c1ccc(F)cc1
Agent: O=C(c1ccc2cc(Cl)ccc2c1)C1CCNCC1
Product: OC(CCCN1CCC(C(O)c2ccc3cc(Cl)ccc3c2)CC1)c1ccc(F)cc1

Procedure:
When in the procedure of Example 25, α-(6-chloro-2-naphthyl)-4-piperidinemethanol hydrochloride is substituted for 6-chloro-2-naphthyl 4-piperidyl ketone and 4-chloro-1-(4-fluorophenyl)butanol substituted for 4-chloro-1-(4-fluorophenyl)-1-butanone, α-(4-fluorophenyl)-4-[(6-chloro-2-naphthyl)hydroxymethyl]-1-piperidinebutanol is produced.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[C:39]([O:43][C:44](=[O:49])[NH:45][CH2:46][CH2:47]O)([CH3:42])([CH3:41])[CH3:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:39]([O:43][C:44]([NH:45][CH2:46][CH2:47][O:23][C:22](=[O:24])[CH2:21][O:20][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])=[CH:26][CH:25]=1)=[O:49])([CH3:42])([CH3:41])[CH3:40]
Reactant: O=C(O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1
Reaction time: 16 h
Yield: 48.3 %

Procedure:
[4-(4-Benzyloxycarbonylaminobutyl)phenoxy]acetic acid 48 (240 mg, 0.67 mmol) was dissolved in anhydrous CH2Cl2 (6 mL). To the solution was added DMAP (98 mg, 0.80 mmol), followed by EDC.HCl (154 mg, 0.81 mmol). The reaction mixture was stirred at room temperature for 15 min. (2-Hydroxyethyl)carbamic acid tert-butyl ester (0.21 mL, 1.34 mmol) was then added and the stirring was continued for 16 h. Solvent was removed by rotary evaporation. The residue was subjected to flash silica gel column chromatography eluting with ethyl acetate/dichloromethane (1:20, 1:15, and 1:10, v/v) to give the desired ester 44a as a colorless oil (162 mg, 48% yield). 1H NMR (300 MHz, CDCl3) δ 1.35-1.65 (m, 4H), 1.44 (s, 9H), 2.45-2.58 (m, 2H), 3.10-3.22 (m, 2H), 3.25-3.42 (m, 2), 4.18-4.28 (m, 2H), 4.62 (s, 2H), 4.70 (br s, 1H), 4.84 (br s, 1H), 5.08 (s, 2H), 6.81 (d, 2H), 7.07 (d, 2H), 7.25-7.38 (m, 5H). m/z (ESI) 501 [C27H36N2O7+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13]2[N:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-])=O)=[CH:15][N:14]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]>[Pd]>[NH2:21][C:16]1[C:17]([NH:19][CH3:20])=[N:18][C:13]([NH:12][C:9]2[CH:8]=[CH:7][C:6]([C:4]([N:3]([CH2:24][CH3:25])[CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)=[N:14][CH:15]=1
Reactant: CCN(CC)C(=O)c1ccc(Nc2ncc([N+](=O)[O-])c(NC)n2)cc1
Agent: [Pd]
Product: CCN(CC)C(=O)c1ccc(Nc2ncc(N)c(NC)n2)cc1

Procedure:
Hydrogenation of 2-[[4-(diethylaminocarbonyl)phenyl]amino]-4-(methylamino)-5-nitropyrimidine (from Example 2(3) above) over Pd/C gave the title compound as a solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)[CH:4]=1.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[ClH:2].[Cl:15][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cccc(-c2cc(Cl)ccn2)c1
Reactant: Nc1ccc(CCO)cc1
Agent: Cl
Product: OCCc1ccc(Nc2ccnc(-c3cccc(Cl)c3)c2)cc1
Yield: 64.8 %

Procedure:
Following general procedure A2, 4-chloro-2-(3-chlorophenyl)pyridine hydrochloride (0.114 g, 0.44 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.072 g, 0.53 mmol), followed by formation of the hydrochloride salt to afford the title compound (0.103 g, 65%) as a light yellow solid. MW=361.27. 1H NMR (DMSO-d6, 500 MHz) δ 14.08 (s, 1H), 10.70 (s, 1H), 8.28 (d, J=7.0 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.79 (d, J=7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.37-7.28 (m, 5H), 7.13-7.08 (m, 1H), 3.64 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H); APCI MS m/z 325 [M+H]+.
Reaction SMILES: [SH:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.I[CH2:8][CH2:9][CH2:10][CH2:11]I>C(O)C>[N:4]1[CH:3]=[C:2]([S:1][CH2:8][CH2:9][CH2:10][CH2:11][S:1][C:2]2[NH:6][N:5]=[N:4][CH:3]=2)[NH:6][N:5]=1
Reactant: Sc1cnn[nH]1
Reactant: ICCCCI
Solvent: CCO
Product: c1nn[nH]c1SCCCCSc1cnn[nH]1
Yield: 70.2 %

Procedure:
20 mmole of 5-mercapto-1H-1,2,3-triazole (sodium salt) was dissolved in 20 ml of ethanol in stirring. 10 mmole of 1,4-diiodobutane was added dropwise to the solution of 5-mercapto-1H-1,2,3-triazole (sodium salt), and stirred overnight. After the solvent was evaporated in vacuum, the residual was washed with 50 ml pure H2O for three times, and then with 50 ml hexane for 3 times. At last, the residual was dried in oven at 60° C. for 24 hours. 1.8 g product was obtained as white solid. Yield: 70%. 1H NMR (DMSO): δ (ppm) 7.86 (2H, s), 2.85 (4H, m), and 1.66 (4H, m).
Reaction SMILES: [CH:1]1([NH:7][C:8](=S)[NH:9][NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12][CH:13]([C:19]([CH3:21])=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].Cl>C(O)C>[ClH:12].[CH:1]1([NH:7][C:8]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:19]([CH3:21])[NH:10][N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NC1CCCCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NC2CCCCC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 34.7 g (0.2 mole) of 4-cyclohexyl-3-thiosemicarbazide and 32.9 g (0.2 mole) of ethyl 2-chloroacetoacetate in 350 mL of absolute ethanol was stirred under nitrogen atmosphere at ambient temperature for 2 hr, treated with 100 mL of 2N ethanolic hydrogen chloride and heated at reflux for 2 hr. The hot reaction mixture was filtered to remove an amorphous solid. The product persistently crystallized in the filter. The product was recrystallized from acetone and recovered by decating off hot acetone solvent and washing the residue with cold acetone to give 27 g of large, off-white crystals, mp 178°-182° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:17])[C:11]=3[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=1[CH3:31]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=4[CH3:31])=[C:11]3[C:10]([CH3:18])=[N:9]2)=[CH:19][CH:20]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: COc1ccc(Cn2nc(C)c3c(O)ccnc32)cc1
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc([N+](=O)[O-])cc4C)ccnc32)cc1
Yield: 47.5 %

Procedure:
Prepared from 1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-ol (0.150 g, 0.557 mmol; prepared as in Example 5, Step B) and 1-fluoro-2-methyl-4-nitrobenzene (0.0864 g, 0.557 mmol) according to the procedure of Example 13, Step A. The crude product was purified by Biotage 40S column eluting with 3:1 hexane/EtOAc then EtOAc to obtain the product (107 mg, 48%) as a off white solid. 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=5.5 Hz, 1H), 8.25 (m, 1H), 8.15 (m, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=9.0 Hz, 1H), 6.84 (d, J=8.6 Hz, 2H), 6.18 (d, J=5.5 Hz, 1H), 5.57 (s, 2H), 3.77 (s, 3H), 2.64 (s, 3H), 2.36 (s, 3H). LRMS (esi pos) m/e 405 (M+1).
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][CH:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15]2=[O:21])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[OH:8][C:9]1[CH:23]=[CH:22][C:12]([CH2:13][CH:14]2[O:18][C:17]([CH3:20])([CH3:19])[O:16][C:15]2=[O:21])=[CH:11][CH:10]=1
Reactant: CC1(C)OC(=O)C(Cc2ccc(OCc3ccccc3)cc2)O1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C(Cc2ccc(O)cc2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105 %

Procedure:
A mixture of 5-(4-benzyloxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (1.0 g, 3.20 mmol) and 10% Pd/C (0.75 g) in EtOAc (40 mL) was purged with N2 then H2 and then stirred under a H2 balloon atmosphere for 3 h at room temperature. Upon reaction completion, Na2SO4 was added and the mixture filtered through hyflo. The solvent was removed in vacuo to afford 0.747 g (100%) 5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one. 1H NMR (500 MHz, CDCl3) δ 7.11 (d, 2H, J=8.31 Hz), 6.76 (d, 2H, J=8.31 Hz), 4.92 (bs, 1H), 4.61 (dd, 1H, J=6.36 Hz, J=4.40 Hz), 3.11 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 2.98 (dd, 1H, J=14.67 Hz, J=4.40 Hz), 1.50 (s, 3H), 1.36 (s, 3H); MS (ES−) Calc'd for C12H13O4 (M−1) 221. Found m/z 221 (100%).
Reaction SMILES: [N:1]([C@H:4]1[C@@H:7]([CH2:8][O:9][CH2:10][C:11]([OH:13])=[O:12])[NH:6][C:5]1=[O:14])=[N+:2]=[N-:3].[C:15]1([C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N+]=[N-])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CC(C)=O>[C:15]1([CH:21]([O:12][C:11](=[O:13])[CH2:10][O:9][CH2:8][C@H:7]2[NH:6][C:5](=[O:14])[C@H:4]2[N:1]=[N+:2]=[N-:3])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1COCC(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(C)=O
Product: [N-]=[N+]=N[C@@H]1C(=O)N[C@@H]1COCC(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of (±)-(cis)-[(3-azido-2-oxo-4-azetidinyl)methoxy]acetic acid (0.880 g, 4.42 mmole) was treated with a solution of diphenyl diazomethane (858 mg, 4.42 mmole) in acetone (12 ml). The reaction was stirred at room temperature for nineteen hours and then combined with another run (621 mg acid, 3.12 mmole). The solvent was removed in vacuo and ethyl acetate was added and evaporated. The residue was dissolved in ethyl acetate (70 ml), dried (sodium sulfate), filtered, and concentrated to 2.6 g of a heavy yellow-red oil. The crude product was chromatographed on silica gel (230-400 mesh, 100 g) with 50% hexane-ethyl acetate. Concentration of the appropriate fractions and removal of solvents produced a heavy oil which was triturated with ether to produce a white solid which was filtered and dried to yield 1.34 g of the title compound. An additional 463 mg was obtained from the mother liquor. The total yield was 1.804 g.
Reaction SMILES: C(O[C@:5]1([C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH2:13]1)[C:6](=[O:12])[CH2:7][O:8][C:9](=[O:11])[CH3:10])(=O)C.C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[C:9]([O:8][CH2:7][C:6](=[O:12])[C:5]1[C@:29]2([CH3:30])[C@H:15]([C@H:16]3[C@H:26]([C@@H:27]([OH:31])[CH2:28]2)[C@:24]2([CH3:25])[C:19](=[CH:20][C:21](=[O:32])[CH:22]=[CH:23]2)[CH2:18][CH2:17]3)[CH2:14][CH:13]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OCC(=O)[C@@]1(OC(C)=O)CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@]12C
Yield: 80.9 %

Procedure:
One gram of 17α,21-diacetoxy-11β-hydroxy-1,4- pregnadiene-3,20-dione is treated analogously to Example 1 in "Dowtherm" for 50 minutes at 250° C. and worked up. Recrystallization from isopropyl ether yields 700 mg of 21-acetoxy-11β-hydroxy-1,4,16-pregnatriene-3,20-dione (81% of theory).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:3]1.[Cl:21]Cl>C(O)(=O)C>[CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([Cl:21])[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:12]=2)=[N:3]1
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nn1C
Reactant: ClCl
Solvent: CC(=O)O
Product: COC(=O)c1c(Cl)c(-c2cccc(C(F)(F)F)c2)nn1C
Reaction time: 4 h

Procedure:
A solution was prepared by dissolving 5.2 g. of methyl 1-methyl-3-(3-trifluoromethylphenyl)pyrazole-5-carboxylate in 200 ml. of glacial acetic acid. The solution was heated to refluxing temperature while gaseous chlorine was passed into the mixture. After about four hours, the addition of chlorine was stopped and the reaction mixture poured over ice. The consequent aqueous mixture was extracted with two 150 ml. portions of chloroform and the chloroform extracts separated, combined and dried. Removal of the chloroform in vacuo yielded as a residue methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-chloropyrazole-5-carboxylate formed in the above reaction. The residue was dissolved in ethyl acetate and the ethyl acetate solution washed with saturated aqueous sodium bicarbonate. The ethyl acetate solution was then dried with phase separation paper. Removal of the solvent in vacuo left a residue which was dissolved in hexane and chromatographed over grade 62 silica. The chromatogram was developed with chloroform/hexane mixtures as the eluant. Use of 100% chloroform as the eluant yielded a small amount of a rapidly moving material which was not the desired product. The desired product, methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-chloropyrazole carboxylate, was next eluted. Fractions containing this material were combined and the chloroform removed in vacuo. Recrystallization of the residue (weight 1.5 g.) from hexane yielded methyl 1-methyl-3-(3-trifluoromethylphenyl)-4-chloropyrazole-5-carboxylate; melting point=97° -8° C. The compound has the following elemental analysis.
Reaction SMILES: N1C=CN=C1.C(O[C:10]1[CH:30]=[CH:29][C:13]([C:14]2[CH2:15][O:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[C:19](OC(=O)C)[C:18]=3C)=[CH:12][CH:11]=1)(=O)C>C(O)C>[O:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:14]([C:13]2[CH:29]=[CH:30][CH:10]=[CH:11][CH:12]=2)[CH2:15]1
Reactant: CC(=O)Oc1ccc(C2=Cc3ccc(OC(C)=O)c(C)c3OC2)cc1
Agent: c1c[nH]cn1
Solvent: CCO
Product: C1=C(c2ccccc2)COc2ccccc21
Reaction time: 8 h

Procedure:
Imidazole (0.6 g) was added to a suspension of 4′,7-diacetoxy-8-methylisoflav-3-ene (0.25 g, 0.7 mmol) in absolute ethanol (5.0 ml) and the mixture was refluxed for 45 min under argon. The solution was concentrated under reduced pressure and the product was precipitated by addition of distilled water (10 ml). The mixture was left overnight in the fridge and filtered to yield isoflav-3-ene. The crude product was recrystallised from methanol/benzene to yield 8-methylisoflav-3-ene-4′,7-diol (0.13 g, 68%). m.p. 190-93° C. 1H NMR (CDCl3+d6-DMSO): δ 1.94 (s, 3H, CH3), 4.98 (s, 2H, H2), 6.32 (d, 1H, J 7.9 Hz, H6), 6.58 (bs, 1H, H4), 6.67 (bd, 1H, H5), 6.72 (d, 2H, J 8.7 Hz, ArH), 7.21 (bd, 2H, ArH). Mass spectrum: m/z 255 (M+1, 16%); 254 (M, 79); 253 (100); 161 (32).