Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:31]=[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[NH2:33]>>[OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([O:22][C:23]([F:24])([F:26])[F:25])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:27]3[O:28][N:33]=[C:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:31]=3)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1
Reactant: NC(=NO)c1ccccc1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(-c3ccccc3)no2)C1

Procedure:
100 mg (0.24 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 63A) and 49 mg (0.36 mmol, 1.5 eq.) of N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 58 mg (47% of theory)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH:15]=[C:16]2[C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.[Pt]>[C:1]([O:4][C@@H:5]1[C@@:25]2([CH3:26])[C:9](=[CH:10][CH2:11][C@@H:12]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:27])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[C@H:17]([CH3:20])[CH2:18][OH:19])[CH2:8][C@@H:7]([O:28][C:29](=[O:31])[CH3:30])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC[C@@H]3[C@H](CC[C@]4(C)C([C@H](C)CO)=CC[C@@H]34)[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CC(=O)O[C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CO)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Yield: 86.2 %

Procedure:
To a solution of 860 mg (2.0 mmol) of (20S)-20-methylpregna-5,16-diene-1α,3β,21-triol 1,3-diacetate in 50 ml of absolute ethanol was added 89 mg of 5% platinum on charcoal. The suspension was stirred under a hydrogen atmosphere at 23° until (2 hr.) the hydrogen uptake was 48 ml (theory 48.8 ml). The catalyst was removed by filtration (several filtrations were necessary to remove colloidal charcoal) through diatomaceous earth and was washed several times with methylene chloride. The filtrate was evaporated under reduced pressure, and the residue, 835 mg (97%), was recrystallized from 20 ml of hexane (cooled to -5°) to yield 746 mg (86%) of (20S)-20-methylpregn-5-ene-1α,3β,21-triol 1,3-diacetate as white crystals, mp 133.5°-134.5°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12.[F:18][C:19]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:20]=1[O:21]C1C=CN=C2C=C(C(N(C)C)=O)SC=12>>[F:18][C:19]1[CH:39]=[C:38]([N+:40]([O-:42])=[O:41])[CH:37]=[CH:36][C:20]=1[O:21][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[O:12])[S:10][C:3]=12
Reactant: CN(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CCCC1
Product: O=C(c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1)N1CCCC1
Yield: 93 %

Procedure:
Starting from (7-chlorothieno[3,2-b]pyridin-2-yl)(pyrrolidin-1-yl)methanone (139, scheme 26) and following the procedure described above for the synthesis of compound 6 (scheme 1, example 1), title compound 193 was obtained in (93% yield). LRMS (M+1) 387.4 (100%).
Reaction SMILES: CN(C)C(N1CC=C(C2NC3N=CN=C(C4C=CC=C(NC(=O)C5C=CC(C(O)(C)C)=CC=5F)C=4C(C4C=CC=CC=4)(C4C=CC=CC=4)O[SiH2]C(C)(C)C)C=3C=2)CC1)=O.[C:60]([O:64][C:65]([N:67]1[CH2:72][CH:71]=[C:70]([C:73]2[NH:90][C:76]3[N:77]=[CH:78][N:79]=[C:80]([C:81]4[CH:86]=[C:85]([F:87])[CH:84]=[C:83]([NH2:88])[C:82]=4[CH3:89])[C:75]=3[CH:74]=2)[CH2:69][CH2:68]1)=[O:66])([CH3:63])([CH3:62])[CH3:61].FC1C=C(C(O)(C)C)C=CC=1C(O)=O.[F:105][S:106]([F:119])([F:118])([F:117])([F:116])[C:107]1[CH:115]=[CH:114][C:110]([C:111](O)=[O:112])=[CH:109][CH:108]=1>>[C:60]([O:64][C:65]([N:67]1[CH2:68][CH:69]=[C:70]([C:73]2[NH:90][C:76]3[N:77]=[CH:78][N:79]=[C:80]([C:81]4[CH:86]=[C:85]([F:87])[CH:84]=[C:83]([NH:88][C:111](=[O:112])[C:110]5[CH:114]=[CH:115][C:107]([S:106]([F:119])([F:105])([F:116])([F:117])[F:118])=[CH:108][CH:109]=5)[C:82]=4[CH3:89])[C:75]=3[CH:74]=2)[CH2:71][CH2:72]1)=[O:66])([CH3:63])([CH3:62])[CH3:61]
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12
Agent: CC(C)(O)c1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(=O)N1CC=C(c2cc3c(-c4cccc(NC(=O)c5ccc(C(C)(C)O)cc5F)c4C(O[SiH2]C(C)(C)C)(c4ccccc4)c4ccccc4)ncnc3[nH]2)CC1
Product: Cc1c(NC(=O)c2ccc(S(F)(F)(F)(F)F)cc2)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)OC(C)(C)C)CC3)cc12

Procedure:
Intermediate 23 was prepared analogue to Intermediate 9 by replacing Intermediate 7 with Intermediate 20 and Intermediate 8 with 4-(pentafluoro-sulfanyl)-benzoic acid.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([NH:11][C:12](=[O:27])[C@H:13]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:14][C:15](=[O:19])[C:16](=O)[CH3:17])[CH:9]=[CH2:10]>>[CH2:8]([N:11]1[C:16](=[CH2:17])[C:15](=[O:19])[NH:14][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:12]1=[O:27])[CH:9]=[CH2:10]
Reactant: C=CCNC(=O)[C@H](Cc1ccccc1)NC(=O)C(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C=CCN1C(=C)C(=O)N[C@@H](Cc2ccccc2)C1=O

Procedure:
The effect of the amount of TFA acid catalyst was evaluated. (S)-1-Allyl-3-benzyl-6-methylenepiperazine-2,5-dione was prepared by reacting N-2-oxo-propanoyl-L-phenylalanine allylamide with various amounts of trifluoroacetic acid for 24 hours. Enantiomeric excess of the product was determined by chiral HPLC using a CHIRALCEL OD column eluted with n-Hexane:Ethanol (5:1). The TFA amounts, product yields, and enantiometric excess presented in Table 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[O:8])([O-:3])=[O:2].[CH:12](O)([OH:14])[CH3:13]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]2[O:14][CH2:12][CH2:13][O:8]2)[CH:9]=[CH:10][CH:11]=1)([O-:3])=[O:2]
Reactant: CC(O)O
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(C2OCCO2)c1

Procedure:
Protection of the aldehyde was performed following reported procedures. (Borchardt, R. T.; Huber, J. A.; Houston, M. J. Med. Chem. 1982, 25, 258.; Brasili, L.; Sorbi, C.; Franchini, S.; Manicardi, M.; Angeli, P.; Marucci, G.; Leonarke, A.; Poggesi, E. J. Med. Chem. 2003, 46, 1504) 3-Nitrobenzaldehyde (4.0 g, 26.4 mmol) was dissolved in toluene (200 mL). Following this, ethanediol (3.0 mL, 53 mmol, 2.0 eq) was added to the solution and the resulting mixture was refluxed overnight with a Dean-Stark trap. The reflux mixture was then extracted with saturated NaHCO3 (2×75 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The residue was then purified by flash column chromatography (30% EtOAc/hexanes) to afford 3-nitrophenyl-1,3-dioxolane as a clear yellow oil that solidified upon standing. (5.09 g, 98%, Rf=0.7 40% EtOAc/hexanes). 1H-NMR (400 MHz, CDCl3, δ): 4.0-4.2 (m, 4H), 5.87 (s, 1H), 7.55 (t, 1H, J=7.93 Hz), 7.79 (d, 1H, J=7.7 Hz), 8.21 (dd, 1H, J1=1.2 Hz, J2=8.2 Hz), 8.34 (s, 1H). 13C-NMR (100 MHz, CDCl3, δ): 148.4, 140.5, 132.8, 129.6, 124.1, 121.8, 102.3, 65.6.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:17]([OH:27])[C@H:18]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@@H:19]1[OH:20]>O1CCCC1>[C:1]([O:26][CH2:25][C@H:23]1[O:24][C@H:18]([CH2:17][OH:27])[C@@H:19]([OH:20])[C@@H:21]1[OH:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(OC[C@H]1O[C@H](CO)[C@@H](O)[C@@H]1O)c1ccccc1
Temperature: 25 °C

Procedure:
7.9 g. (6.5 ml., 56.3 mmol.) of benzoyl chloride and 5.7 g. (8.02 ml., 56.3 mmol.) of triethylamine were added to a suspension of 8.4 g. (51.2 mmol.) of 2,5-anhydro-D-mannitol in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for 5 hrs., allowed to cool to room temperature and evaporated at room temperature and 200 ml. of chloroform is added to the residue. The solids were removed by filtration and washed with chloroform and the chloroform filtrate and washings were combined and evaporated at reduced pressure. The residue was filtered through 200 ml. of silica gel utilizing chloroform and 5% methanol/chloroform to elute the dibenzoate and 5% methanol/chloroform and 10% methanol/chloroform to elute the monobenzoate. The fractions containing the monobenzoate (as indicated by thin layer chromatography) were combined and evaporated at reduced pressure to an uncrystallizable, very thick oil. The oil was distilled in a Kugelrohr apparatus at 135°-145° C. and 40μ. to obtain a thick, pale yellow oil (2.50 g.) [α]D =+46.191° (methanol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH2:17]([NH2:22])[CH2:18][CH:19]([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH2:13][NH:22][CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CC(C)CCN
Reactant: O=Cc1ccc(Oc2ccc(Br)cn2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)CCNCc1ccc(Oc2ccc(Br)cn2)cc1

Procedure:
As shown in scheme 7, 4-Hydroxybenzaldehyde is treated with potassium carbonate and 2,5-dibromopyridine in DMAC to afford 4-(5-bromo-pyridin-2-yloxy)-benzaldehyde (35). The aldehyde 35 is combined with isoamylamine, sodium triacetoxyborohydride, acetic acid, and dichloromethane to yield the reductive amination product [4-(5-bromo-pyridin-2-yloxy)-benzyl]-(3-methyl-butyl)-amine (36). The resulting aryl bromide 36 is treated with acetamide, copper iodide, and 1,2 diaminocyclohexane in dioxane to yield the target compound 37.
Reaction SMILES: [C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]([OH:26])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:12][CH:11]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2].[C:33](C1C=CC(OCC2C=CC(C(OC)C3C=C(C=CC=3)C#N)=CC=2)=C(CCC)C=1O)(=O)C>>[C:1]([C:4]1[CH:28]=[CH:27][C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH:16]([O:26][CH3:33])[C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=[O:21])=[CH:14][CH:15]=2)=[C:6]([CH2:29][CH2:30][CH3:31])[C:5]=1[OH:32])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCc2ccc(C(O)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O
Reactant: CCCc1c(OCc2ccc(C(OC)c3cccc(C#N)c3)cc2)ccc(C(C)=O)c1O
Product: CCCc1c(OCc2ccc(C(OC)c3cccc(C(=O)O)c3)cc2)ccc(C(C)=O)c1O

Procedure:
The title compound is prepared essentially as described for 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-hydroxy-methyl}-benzoic acid employing 3-{[4-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-methoxy-methyl}-benzonitrile to give a white solid, 82%. 1H NMR (DMSO-d6) δ 13.00 (bs, 1H), 12.85 (s, 1H), 7.96 (s, 1H), 7.79-7.85 (m, 2H), 7.63 (d, 1H), 7.40-7.48 (m, 5H), 6.72 (d, 1H), 5.50 (s, 1H), 5.24 (s, 2H), 3.30 (s, 3H), 2.58-2.61 (m, 5H), 1.44-1.52 (m, 2H), 0.84-0.88 (m, 3H). LCMS M+1 449.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH:14]2[C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:22]=3)[C@@H:14]3[CH2:15][CH2:16][CH2:17][N:13]3[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)cc1OC
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1ccc([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)cc1OC
Yield: 77 %

Procedure:
1-(3,4-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.30 g (77%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.5 [M+H]+. 1H NMR (MeOH-d4): 7.40 (m, 1H), 7.35 (d, J=2.0, 1H), 7.17 (m, 1H), 6.96 (m, 1H), 6.91 (d, J=7.6, 1H), 6.81 (d, J=8.5, 1H), 6.76 (m, 1H), 3.91 (m, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.40 (m, 3H), 2.40 (m, 6H), 2.28 (m, 1H), 2.11 (m, 1H), 1.91 (m, 3H), 2.75 (m, 1H), 2.62 (m, 1H), 1.54 (m, 4H), 1.41 (m, 2H).
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C([Li])CCC.[C:30](=[O:32])=[O:31].Cl>O1CCCC1.O>[CH2:1]([O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][C:21]([C:30]([OH:32])=[O:31])=[CH:20][CH:19]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1ccc(-c2ncc(-c3ccc(Br)cc3)s2)cc1
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCCCCOc1ccc(-c2ncc(-c3ccc(C(=O)O)cc3)s2)cc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
A solution of 2-(4-pentyloxyphenyl)-5-(4-bromophenyl)thiazole (2.3 g) in dry tetrahydrofuran (60 ml) was cooled to −60° C., and a solution of n-butyllithium (1.66M in n-hexane, 4.46 ml) was added slowly to maintain the reaction temperature at −60° C. After stirring for 1 hour, a solution of n-butyllithium (1.66M in n-hexane, 1.0 ml) was additionally added. The reaction mixture was allowed to warm to −40° C. After stirring for 30 minutes, dry-ice (5 g) was added. The reaction mixture was allowed to warm to room temperature over 30 minutes. To the reaction mixture was added water (25 ml) and 0.5N-hydrochloric acid (100 ml), then extracted with dichloromethane (500 ml). The organic layer was washed with brine, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. The solids were slurried in acetonitrile, and collected by filtration to give 4-[2-(4-pentyloxyphenyl)thiazol-5-yl]benzoic acid (1.70 g).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:26][C:16]3=[C:17]4[C:22](=[CH:23][CH:24]=[C:15]3[O:14][CH2:13]2)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]4)(=O)=O)=CC=1.[S:28]1[C:32]([C:33]2[CH2:34][CH2:35][NH:36][CH2:37][CH:38]=2)=[CH:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2>CS(C)=O>[S:28]1[C:32]([C:33]2[CH2:34][CH2:35][N:36]([CH2:11][CH:12]3[O:26][C:16]4=[C:17]5[C:22](=[CH:23][CH:24]=[C:15]4[O:14][CH2:13]3)[N:21]=[C:20]([CH3:25])[CH:19]=[CH:18]5)[CH2:37][CH:38]=2)=[CH:31][C:30]2[CH:39]=[CH:40][CH:41]=[CH:42][C:29]1=2
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)ccc4c3O2)cc1
Reactant: C1=C(c2cc3ccccc3s2)CCNC1
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CC=C(c2cc4ccccc4s2)CC1)O3
Temperature: 90 °C
Reaction time: 18 h
Yield: 137.8 %

Procedure:
To a mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl 4-toluenesulfonate (0.638 g, 1.66 mmol) and 4-benzo[b]thiophen-2-yl-1,2,3,6-tetrahydro-pyridine (0.46 g, 2.1 mmol) was added 12 mL of dimethylsulfoxide. The mixture was stirred at 90° C. for 18 hours. The solvent was evaporated under reduced pressure. The residue was partitioned between 500 mL each of methylene chloride and saturated aqueous sodium bicarbonate. The methylene chloride layer was washed with water twice and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave 0.98 g of oil. This was chromatographed on silica gel with a gradient of ethyl acetate and hexane. The product fractions were collected and concentrated in vacuum to give 0.39 g of the title compound as nearly pure, light yellow oil. This was triturated with ethanol to give 0.2563 g of the S enantiomer of the title compound as a light yellow solid, m.p. 174-176° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])[N:5]=[C:4]([CH:15]([CH3:17])[CH3:16])[C:3]=1[C:18]([NH2:20])=[O:19].[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O-])=O)=[CH:24][CH:23]=1.[O-]CC.[Na+]>C(O)C>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([CH3:13])[C:7]=1[N:6]1[C:2]2=[N:1][C:29]([CH2:28][C:25]3[CH:26]=[CH:27][C:22]([NH2:21])=[CH:23][CH:24]=3)=[N:20][C:18](=[O:19])[C:3]2=[C:4]([CH:15]([CH3:17])[CH3:16])[NH:5]1
Reactant: Nc1ccc(CC(=O)[O-])cc1
Reactant: Cc1cccc(Cl)c1-n1nc(C(C)C)c(C(N)=O)c1N
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Cl)c1-n1[nH]c(C(C)C)c2c(=O)nc(Cc3ccc(N)cc3)nc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.9 %

Procedure:
Part D: To a stirred solution of 1.4 g (4.8 mmol) 5-amino-3-isopropyl-1-(2-chloro-6-methyl-phenyl)pyrazole-4-carboxamide in 100 mL absolute ethanol was added 5.14 g (28.8 mmol) of 4-amino-phenylacetate followed by 10.7 mL (28.8 mmol) of 2.66 M sodium ethoxide in ethanol. The solution was stirred 18 h at reflux and the heating mantle was then removed. The reaction was treated with water and 10% aq. HOAc, cooled to ambient temperature, and filtered. The solid purified by column chromatography on silica gel using 1:1 hexanes-EtOAc as eluant to afford 743 mg (38%) of 1-(2-chloro-6-methylphenyl)-3-isopropyl-6-(4-aminobenzyl)-pyrazolo[3,4-d]pyrimidin-4-one, mp 206-207° C. Mass Spec. (CI+): 408 (M+H)+.
Reaction SMILES: [C:1]1(=[O:28])[N:5]([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:9][CH:8]=2)[C:4](=[O:23])[C:3]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:2]12.CO.[ClH:31].C[CH2:33][O:34]CC>C(Cl)(Cl)Cl>[ClH:31].[C:4]1(=[O:23])[N:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][C:15]3[CH:22]=[CH:21][C:18]([C:19](=[NH:20])[O:34][CH3:33])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[C:1](=[O:28])[C:2]2=[CH:27][CH:26]=[CH:25][CH:24]=[C:3]12
Reactant: N#Cc1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Reactant: CCOCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=N)c1ccc(CCc2ccc(CN3C(=O)c4ccccc4C3=O)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 6 g of 4-[2-(4-phthalimidomethylphenyl)ethyl]benzonitrile in 300 ml of chloroform, was added at room temperature slowly dropwise 50 ml of anhydrous methanol saturated with anhydrous hydrogen chloride. The mixture was stirred at room temperature for 15 hours. The reaction mixture was stripped of the solvent under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 6 g of methyl 4-[2-(4-phthalimidomethylphenyl)ethyl]benzimidate hydrochloride; m.p. 238°-240° C.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C:12]1[CH:19]=[CH:18][C:16]([OH:17])=[C:14]([OH:15])[CH:13]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>C(Cl)(Cl)Cl>[C:22]([O:15][C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][NH:9][C:1]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)=[O:8])[CH:19]=[CH:18][C:16]=1[O:17][C:22](=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20])(=[O:23])[C:21]([CH3:26])([CH3:25])[CH3:20]
Reactant: O=C(NCCc1ccc(O)c(O)c1)c1cccnc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1OC(=O)C(C)(C)C

Procedure:
To a suspension of 5.16 g (0.02 mol) finely powdered nicotinoyldopamine in 100 ml chloroform, 7.23 g (0.06 mol) trimethylacetyl chloride were added under stirring. The mixture was refluxed for 6 hrs and then filtered. The filtrate was washed with water free of chloride ions, then washed once with a 5% solution of NaHCO3, then with water. The chloroform was evaporated and the residue was chromatographed by using a silica gel G column and 2% methanol in chloroform as the eluent. The first fraction was collected and evaporated and the residue was crystallized from ether/petroleum ether. Yield, 6.2 g (73%) of a white crystalline solid, m.p. 112°-114° C., NMR (CDCl3) δ 9.06 (bs, 1H, C2 pyridine proton), 8.73 (bd, 1H, C6 pyridine proton), 8.30-8.13 (m, 1H, C4 pyridine proton), 7.46-7.10 (m, 5H, C6H3 +C5 pyridine proton+CONH), 3.66 (q, 2H, J=6.25 Hz, --N--CH2), 3.0 (t, 2H, J=6 Hz, --CH2), 1.41 (s, 18H, 2--C(CH3)3). Anal. Calcd for C24H30N2O5 : C, 67.58; H, 7.09; N, 6.56. Found: C, 67.61; H, 7.10; N, 6.54.
Reaction SMILES: B(F)(F)F.[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8](N)[CH:7]=1.N(OC(C)(C)C)=O.[I:24]I>C1COCC1.CCOCC>[Br:5][C:6]1[C:14]2[S:13][C:12]([NH2:15])=[N:11][C:10]=2[CH:9]=[C:8]([I:24])[CH:7]=1
Reactant: Nc1cc(Br)c2sc(N)nc2c1
Reactant: II
Agent: CC(C)(C)ON=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: Nc1nc2cc(I)cc(Br)c2s1
Temperature: -2.5 °C
Reaction time: 0.67 h

Procedure:
To THF (6 L) at −78° C. under N2 was added BF3-etherate (50% assay, 708 mL, 2.81 mol) followed by a slow addition of a solution of iv (275 g, 1.02 mol) in THF (500 mL) over 20 min. Tert-butyl nitrite (548 L, 4.61 mol) was then added to the solution at −78° C. and the mixture was stirred at the same temperature for 40 min and then warmed to −5-0° C. Et2O was added (at −5-0° C.) and the mixture stirred for 20 min. The solid was filtered and taken in acetone at 0° C. followed by sequential addition of KI (510 g, 3.07 mol) and iodine (519 g, 2.04 mol) and the mixture stirred at 0° C. for 30 min. The reaction was quenched with saturated solution of sodium metabisulfite and extracted with EtOAc (3×5 L). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo at 45° C. The residue was purified over basic alumina (30-35% EtOAc-hexane) to obtain v (235 g, 65%). 1H NMR (DMSO-d6, 400 MHz): δ 7.50 (d, J=1.20 Hz, 1H), 7.63 (d, J=1.20 Hz, 1H) and 7.91 (br s, 2H). MS: 354.90 [M+H]+.
Reaction SMILES: Br[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#[N:15])[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+]>CN(C)C=O>[C:2]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([C:14]#[N:15])[C:10](=[O:16])[C:9]=2[CH:17]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(Br)c1ccc2occ(C#N)c(=O)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)c1ccc2occ(C#N)c(=O)c2c1
Yield: 74 %

Procedure:
A mixture of 6-(1-bromo-1-methylethyl)-4-oxo-4H-1-benzopyran-3-carbonitrile (2.0 g), sodium acetate (575 mg) and dimethylformamide (20 ml) was heated for one hour, which was then concentrated. The concentrate was dissolved in chloroform. The solution was washed with water and dried (sodium sulfate), followed by removing chloroform by evaporation. The residue was subjected to a silica-gel (100 g) column chromatography, eluting with chloroform-acetone-formic acid (20:1:0.1). The initial eluate was recrystallized from ethanol to give colorless crystals (1.07 g) of 6-isopropenyl-4-oxo-4H-1-benzopyran-3-carbonitrile, m.p. 142°-144° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([C@@](O)([C@@H](O)[C@H](O)[C@H](O)CO)C(N)=O)=[CH:16][CH:15]=1.ClC(OC1C=CC([N+:43]([O-])=O)=CC=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[C:18]([NH2:43])[CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc([C@](O)(C(N)=O)[C@@H](O)[C@H](O)[C@H](O)CO)cc2)C1
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(N)c2)C1

Procedure:
1.54 g (5.0 mmol) of enantiomer B of intermediate 1 were reacted with 1.1 equivalents of 4-nitrophenyl chloroformate in a similar manner to the method described in Example 6, intermediate 1 to obtain 1.87 g of the title compound.