Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[C:7]([NH:13][NH:14][C:15](=O)[CH2:16][C:17]2[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][N:18]=2)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].P(Cl)(Cl)(Cl)=O>>[Br:1][C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[O:5][C:6]1[C:7]2[N:8]([C:15]([CH2:16][C:17]3[C:25]4[C:20](=[N:21][CH:22]=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[N:14][N:13]=2)[CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(NNC(=O)Cc2n[nH]c3ncccc23)c1Oc1cc(Cl)cc(Br)c1
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccn2c(Cc3n[nH]c4ncccc34)nnc2c1Oc1cc(Cl)cc(Br)c1
Temperature: 120 °C

Procedure:
A mixture of N′-[3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-yl]-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)acetohydrazide (44 mg, 0.090 mmol) in phosphorus oxychloride (250 μL, 2.6 mmol) was heated to 120° C. for 35 minutes, after which the excess reagent was removed in vacuo and the residue partitioned between saturated aqueous NaHCO3 (20 mL) and CH2Cl2 (2×20 mL). The combined extracts were concentrated in vacuo and the residue was purified on a Luna column (10μ, C18, 250×21.2 cm) eluting with 5-95% ACN/water with 0.1% TFA) to give the title compound. LRMS (M+1)=470.7.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=O.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:13][O:12][C:8]1[CH:9]=[CH:10][C:11]2[C:2]3[C:3]([C:14](=[O:16])[N:25]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[N:26]=3)=[CH:4][NH:5][C:6]=2[CH:7]=1
Reactant: CCOC(=O)c1cnc2cc(OC)ccc2c1Cl
Reactant: NNc1ccccc1
Product: COc1ccc2c3nn(-c4ccccc4)c(=O)c-3c[nH]c2c1

Procedure:
The title compound was prepared following the procedure described in Step 3 using 3e and phenyl hydrazine. 1H NMR (DMSO-d6) δ (ppm): 3.86 (3H, s), 7.10 (3H, m), 7.38 (2H, dd, J=8.24, 7.42 Hz), 8.09 (3H, m), 8.65 (1H, d, J=6.04 Hz). m/z 292.3 (MH+).
Reaction SMILES: CN1CCCC1=[O:7].[Cl:8][C:9]1[C:10]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:11]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:12]2=[N:13][C:14]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Cl:8][C:9]1[C:10]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)=[C:11]2[C:29]3[CH2:30][CH2:31][S:32](=[O:7])[CH2:33][C:28]=3[S:27][C:12]2=[N:13][C:14]=1[CH2:15][N:16]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]1=[O:26]
Reactant: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Reactant: CN1CCCC1=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCS(=O)C4)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To N-methylpyrrolidone (140.56 L) was added 2-{[3-chloro-4-(4-methoxyphenyl)-5,8-dihydro-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridin-2-yl]methyl}-1H-isoindole-1,3(2H)-dione (14.056 kg) and the mixture was dissolved by heating at about 40° C. Then, vanadium (IV) oxyacetylacetone (49.09 g) was added thereto and the 30% hydrogen peroxide was added dropwise, while maintaining at 20 to 23° C. The mixture was stirred at the same temperature for 1 hour and then cooled to 3° C., followed by adding dropwise 0.5 N sodium thiosulfate (5 L) and then water (281.14 L). The mixture was stirred for 1 hour under ice-cooling. The crystals deposited was filtered off, dried and dissolved in N-methylpyrrolidone (135.65 L). Active carbon (678 g) was added and the mixture was stirred at room temperature for 30 minutes. The active carbon was filtered off and washed with N-methylpyrrolidone (13.565 L). The filtrate and washings were combined and to the mixture was added dropwise isopropyl ether (298.43 L). The crystals deposited were filtered off, washed with isopropyl ether (67.83 L×2) to obtain the titled compound (9.56 kg, 64.3%). 1H-NMR (CDCl)δ: 2.01–2.19 (1H, m), 2.54–2.73 (2H, m), 3.00–3.07 (1H, m), 3.89 (3H, s), 3.95 (1H, d, J=16.9 Hz), 4.05 (1H, d, J=16.9 Hz), 5.20 (2H, s), 6.99–7.03 (2H, m), 7.16–7.20 (2H, m), 7.76–7.80 (2H, m), 7.91–7.95 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH:41]1([C@H:44]([NH:51][CH3:52])[CH2:45][N:46]2[CH2:50][CH2:49][CH2:48][CH2:47]2)[CH2:43][CH2:42]1.[OH-].[K+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([N:51]([C@@H:44]([CH:41]1[CH2:43][CH2:42]1)[CH2:45][N:46]1[CH2:47][CH2:48][CH2:49][CH2:50]1)[CH3:52])=[O:7]
Reactant: CN[C@H](CN1CCCC1)C1CC1
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [K+]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C(=O)c1ccc(F)c(Cl)c1)[C@H](CN1CCCC1)C1CC1
Reaction time: 0.17 h
Yield: 54.1 %

Procedure:
3-Chloro-4-fluorobenzoic acid (0.156 g, 0.89 mmol), TBTU (0.334 g, 1.04 mmol) and NMM (0.204 mL, 1.86 mmol) was mixed in DCM (10 mL). After 10 min at rt was (S)-1-cyclopropyl-N-methyl-2-(pyrrolidin-1-yl)ethanamine (Compound M3) (0.125 g, 0.74 mmol) added. The resultant mixture was stirred at rt for 48 h. To the mixture was 1.4 N KOH (5 mL) added. The organic phase was isolated, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (130 mg, 54%). Mixture of rotamers: 1H NMR (600 MHz, DMSO-d6) δ 0.03, 0.16-0.62, 0.95, 1.50-1.74, 2.14-2.41, 2.47-2.51, 2.65-3.06, 3.84, 7.29, 7.46. Total no of protons: 22. HRMS (M+H)+: calculated 325.1483. found 325.1475.
Reaction SMILES: [CH2:1]([C:5]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:9]2[CH2:10][N:11]([C:14](=[O:26])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:23]([O-])=O)[CH2:12][CH2:13][C:8]=2[C:7](=[O:27])[O:6]1)[CH:2]([CH3:4])[CH3:3]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][C:14]([N:11]1[CH2:12][CH2:13][C:8]2[C:7](=[O:27])[O:6][C:5]([CH2:1][CH:2]([CH3:3])[CH3:4])([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:9]=2[CH2:10]1)=[O:26]
Reactant: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)/C=C/c1ccccc1[N+](=O)[O-])CC2
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)CC1(c2ccccc2)OC(=O)C2=C1CN(C(=O)CCc1ccccc1N)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
To a solution of (E)-3-isobutyl-5-(3-(2-nitrophenyl)acryloyl)-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (90 mg, 0.20 mmol) in ethanol/ethyl acetate/(3:1, 20 mL) was added Pd/C (10%, 20 mg). The reaction mixture was stirred vigorously under an atmosphere of H2(g) at room temperature for 1 h. The mixture was filtered through a pad of diatomaceous earth, the filtrate concentrated in vacuo, and the residue purified by column chromatography (4 g, SiO2, 0 to 50% ethyl acetate in hexanes) to provide 5-(3-(2-aminophenyl)propanoyl)-3-isobutyl-3-phenyl-4,5,6,7-tetrahydrofuro[3,4-c]pyridin-1(3H)-one (54 mg, 64%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.82-0.98 (m, 6H), 1.59-1.71 (m, 1H), 1.73-1.87 (m, 1H), 2.18-2.37 (m, 2H), 2.72 (d, J=6.78 Hz, 2H), 2.87 (d, J=6.78 Hz, 2H), 3.22-3.33 (m, 1H), 3.46-3.66 (m, 2H), 3.77-3.89 (m, 2H), 3.92-4.04 (m, 1H), 4.60-4.74 (m, 1H), 6.59-6.64 (m, 2H), 6.96-7.07 (m, 2H), 7.28-7.44 (m, 5H); MS m/z 419 (M+H)+.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][C:24]([NH2:26])=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.B>O1CCCC1>[CH2:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][N:2]1[C:12]1[CH:21]=[C:20]([CH2:22][CH2:23][CH2:24][NH2:26])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: NC(=O)CCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Agent: B
Solvent: C1CCOC1
Product: NCCCc1cc(N2CCCc3ccccc3C2)nc2ccccc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 20.8 %

Procedure:
To the mixture of 3-[2-(1,3,4,5-tetrahydro-2H-2-benzazepin-2-yl)quinolin-4-yl]propanamide (50 mg, 0.145 mmol) in tetrahydrofuran (5 mL) was added a tetrahydrofuran solution of borane (1.5 mL, 1.5 mmol) at 0° C., followed by stirring at 70° C. for 4 hours. After being quenched with methanol (5 mL) at 0° C., the resulting mixture was concentrated in vacuo to give a residue which was purified by flash column (ethyl acetate/hexane, 3:7) to afford 10 mg of product as a white solid. MS obsd. (ESI+) [(M+H)+] 332. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.79 (d, J=7.2 Hz, 1 H), 7.57-7.52 (m, 2 H), 7.47-7.43 (m, 1 H), 7.18-7.04 (m, 5 H), 5.24 (brs, 2 H), 4.85 (s, 2 H), 4.14 (brs, 2 H), 3.03 (brs, 2 H), 2.93 (t, J=7.2 Hz, 2 H), 1.89-1.82 (m, 4 H).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@:4](NC(OC(C)(C)C)=O)(CCN1CCCCC1)[CH2:5][CH2:6][CH2:7][CH2:8]B1OC(C)(C)C(C)(C)O1.[ClH:35]>O>[ClH:35].[ClH:35].[C:3]([OH:34])(=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: COC(=O)[C@@](CCCCB1OC(C)(C)C(C)(C)O1)(CCN1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: O
Product: CCCCCC(=O)O
Temperature: 25 °C
Yield: 53 %

Procedure:
(R)-2-Amino-6-borono-2-[2-piperidin-1-yl)-ethyl]-hexanoic acid dihydrochloride is prepared in a manner analogous to that set forth in Example 1, except piperidinyl is used as the amine in step 7. The final step is as follows: a solution of (R)-2-tert-butoxycarbonylamino-2-(2-piperidin-1-yl-ethyl)-6-(4,4,5,5-tetramethyl-[1,3,2]-dioxa-borolan-2-yl)-hexanoic acid methyl ester (182 mg) in 6 N hydrochloric acid (5 mL) was stirred at 95° C. overnight. After cooling to room temperature, the reaction mixture was transferred to a separatory funnel, diluted with deionized water (5 mL) and washed with dichloromethane (3×). The aqueous layer was frozen in liquid nitrogen and lyophilized to give (R)-2-amino-6-borono-2-[2-piperidin-1-yl)-ethyl]-hexanoic acid dihydrochloride as a colorless foam (72 mg, 53%); 1H NMR (D2O, 300 MHz) δ 3.34 (d, J=11.5 Hz, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.77 (t, J=12 Hz, 2H), 2.19 (t, J=8.5 Hz, 2H), 1.76 (m, 4H), 1.55 (m, 3H), 1.23 (m, 4H), 1.06 (m, 1H) and 0.59 (t, J=7.5 Hz, 2H).
Reaction SMILES: [O:1]([C:8]1[CH:21]=[CH:20][C:19]2[C:18](=[O:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10]=2[CH:9]=1)C1C=CC=CC=1.O(C1C=CC(C(C2C=CC=CC=2C(O)=O)=O)=CC=1)C1C=CC=CC=1.O(C1(S([O-])(=O)=O)C=CC2C(=O)C3C(=CC=CC=3)C(=O)C=2C1S([O-])(=O)=O)C1C=CC=CC=1.[Na+].[Na+]>>[OH:1][C:8]1[CH:21]=[CH:20][C:19]2[C:18](=[O:22])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:23])[C:10]=2[CH:9]=1
Reactant: O=C1c2ccccc2C(=O)c2cc(Oc3ccccc3)ccc21
Agent: O=C(O)c1ccccc1C(=O)c1ccc(Oc2ccccc2)cc1
Agent: O=C1C2=C(C(=O)c3ccccc31)C(S(=O)(=O)[O-])C(Oc1ccccc1)(S(=O)(=O)[O-])C=C2
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)c2cc(O)ccc21

Procedure:
2-phenoxyanthraquinonedisulfonic acid formed as an intermediate product in the course of preparing 2-phenoxyanthraquinonepolysulfonic acid from 2-phenoxyanthraquinone or 2-(p-phenoxybenzoyl) benzoic acid was confirmed, by way of a proton-NMR-absorption spectrum thereof, as having such a structure that the two sulfonic acid groups are bonded, as shown in the reaction formulas (1), to o- and p-positions of the phenoxy group in the 2-phenoxyanthraquinone. FIG. 3 shows a proton-NMR-absorption spectrum (solvent: dimethylacetamide; measuring temp.: room temperature) of sodium 2-phenoxyanthraquinonedisulfonate. This spectrum shows that in the compound of the formula (VII): ##STR11## absorption of proton f is detected in 8.44 ppm (1H), absorption of protons c, h in 8.04-8.3 ppm (3H), absorption of protons e, g in 7.83-8.02 ppm (3H), absorption of proton a in 7.61 ppm (1H), absorption of proton b in 7.42 ppm (1H) and absorption of proton d in 7.1 ppm (1H). It is confirmed therefore that 2-phenoxyanthraquinonedisulfonic acid has the structure shown by the formula (VII). The structure of the formula (VII) is supported also by the fact that when this 2-phenoxyanthraquinonedisulfonic acid is treated under heating with a 5% aqueous solution of sodium hydroxide, the phenoxy group of this compound is split off to afford 2-hydroxyanthraquinone.
Reaction SMILES: [F:1][C:2]([F:26])([C:22]([F:25])([F:24])[F:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21].CCN(CC)CC.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[F:1][C:2]([F:26])([C:22]([F:23])([F:24])[F:25])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][S:35]([CH3:34])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Into a clean flame dried 250 mL RBF under current of N2, was added 10.10 g (26 mmol) of 55. To this was added 100 mL of DCM and 5.5 mL (39 mmol) of Et3N. The reaction mixture was then cooled in an ice-water bath and 2.3 mL (29 mmol) of MsCl was added and stirred for 12 h at room temperature. The reaction was then diluted with 200 mL of DCM and washed successively with sat. aq. NaHCO3 (1×), H2O (2×), brine (1×), dried over MgSO4, filtered and the solvent evaporated under vacuum. The residue was then purified using combiflash (120 g silica column) with hexane/ethyl acetate as eluent to furnish 10.15 g (84%) of target product 56 as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=1.[CH:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2B2OC(C)(C)C(C)(C)O2)[CH2:12][CH2:11]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N#N>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CC(=O)OCC.C(Cl)Cl>[CH:10]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][C:16]=2[C:2]2[CH:3]=[C:4]([CH3:9])[C:5](=[O:8])[NH:6][CH:7]=2)[CH2:11][CH2:12]1
Reactant: Cc1cc(Br)c[nH]c1=O
Reactant: CC1(C)OB(c2cc(S(C)(=O)=O)ccc2OCC2CC2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(-c2cc(S(C)(=O)=O)ccc2OCC2CC2)c[nH]c1=O
Temperature: 70 °C
Yield: 58.8 %

Procedure:
5-bromo-3-methyl-1H-pyridin-2-one (950 mg, 5.05 mmol), the title compound of Example 90, step 1 (2.93 g, 5.95 mmol), Pd(dppf)Cl2 (365 mg, 0.5 mmol) and K3PO4 (2.14 g, 10.1 mmol) in dioxane (30 mL) and water (5 mL) was purged with N2 and heated at 70° C. for 12 h. Silica gel chromatography (PE:DCM:EA=3:0:1 to 0:1:3) gave impure title compound (990 mg) as a yellow solid which was used directly in the next step. 1H NMR (CDCl3, 400 MHz) δ 12.57 (brs, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.65 (s, 1H), 7.03 (d, J=8.8 Hz, 1H), 3.96 (d, J=7.2 Hz, 1H), 3.07 (s, 3H), 2.24 (s, 3H), 1.40-1.25 (m, 1H), 0.67-0.65 (m, 2H), 0.37-0.36 (m, 2H). LCMS: 334.1 (M+1)+
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[N:15]=[C:14](Cl)[CH:13]=[C:12]([CH3:17])[N:11]=1.O.O.O.C([O-])(=O)C.[Na+].[OH-].[Na+]>O>[C:1]1([N:7]([C:14]2[CH:13]=[C:12]([CH3:17])[N:11]=[C:10]([NH2:9])[N:15]=2)[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: NNc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N(N)c2ccccc2)nc(N)n1

Procedure:
A mixture of phenylhydrazine (66ml.), 2-amino-4-chloro-6-methylpyrimidine (86g.), and sodium acetate trihydrate (120g.) in water (2 1.) was heated under reflux for 16 hours. The mixture was cooled, and adjusted to pH 9.0 by the addition of 40% w/v aqueous sodium hydroxide. The resulting precipitate was collected by filtration, and washed successively with water (2 1.) and ethanol (200ml.). The solid was crystallised from ethanol to give N-phenyl-N-(2-amino-6-methylpyrimidin-4-yl)hydrazine, m.p. 173°-174° C.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[S:14][C:15]([C:19]([O:21]CC)=[O:20])=[C:16]([CH3:18])[N:17]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6]C=CC=1.C1(CN2C=C(C3SC(C(OCC)=O)=C(C)N=3)N=N2)CC1>>[CH:2]1([CH2:1][N:8]2[CH:12]=[C:11]([C:13]3[S:14][C:15]([C:19]([OH:21])=[O:20])=[C:16]([CH3:18])[N:17]=3)[N:10]=[N:9]2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1sc(-c2cn(Cc3ccccc3)nn2)nc1C
Agent: CCOC(=O)c1sc(-c2cn(CC3CC3)nn2)nc1C
Product: Cc1nc(-c2cn(CC3CC3)nn2)sc1C(=O)O
Yield: 99 %

Procedure:
Following the procedure as described in Example 3, making variations as necessary to replace ethyl 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate with ethyl 2-(1-(cyclopropylmethyl)-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained as a white solid in 99% yield: MS (ES−) m/z 263.2 (M−1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[C:20](Cl)[N:21]=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1C(=O)C[CH2:44][CH2:43]1.C([Mg]Cl)C>C1COCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[C:24]3[C:19](=[C:20]([CH2:43][CH3:44])[N:21]=[CH:22][CH:23]=3)[N:18]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:17]=2[O:32][C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(F)cc1Oc1c(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c2ccnc(Cl)c2n1-c1ccccc1
Reactant: CN1CCCC1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCc1nccc2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Oc3cc(F)ccc3C)n(-c3ccccc3)c12
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 45.1 %

Procedure:
A mixture of the compound of example 38, step 6, (65 mg, 115 μmol), iron(III) acetylacetonate (2.03 mg, 5.7 μmol) and NMP (102.6 mg, 1.04 mmol) in THF (5 ml) was cooled to 0° C. Ethylmagnesium chloride (115 μl, 230 μmol, 2 M in THF) was added and the resulting solution was stirred for 5 min. The brown mixture was quenched with water and extracted with EA. The organic layers were dried over sodium sulfate and concentrated. The residue was purified by silica gel chromatography (EA/HEP) to give 29 mg of the title compound.
Reaction SMILES: [C:1]([O-])(=O)[CH2:2][C:3]([CH2:8][C:9]([O-])=O)([C:5]([O-])=O)O.[CH2:14](O)[C:15](N)([CH2:18]O)[CH2:16]O.OP([O-])(O)=O.OP([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl-].[Cl-].[K+].[K+]>>[CH3:14][C:15]([CH3:18])=[CH:16][CH2:1][CH2:2]/[C:3](/[CH3:5])=[CH:8]/[CH2:9][CH2:14]/[C:15](/[CH3:18])=[CH:16]/[CH2:1][CH2:9]/[CH:8]=[C:3](\[CH3:5])/[CH2:2][CH2:1]/[CH:16]=[C:15](\[CH3:18])/[CH2:14][CH2:9][CH:8]=[C:3]([CH3:5])[CH3:2]
Reactant: NC(CO)(CO)CO
Reactant: O=C([O-])CC(O)(CC(=O)[O-])C(=O)[O-]
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Cl-]
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CC/C=C(\C)CC/C=C(\C)CCC=C(C)C
Reaction time: 0.01 h

Procedure:
10 Baboons were divided into two groups (five baboons per group) and administered the formulations specified in Table 1. For Group 1, equal parts of the adjuvant MF59-0, and p24gag/sf2 (in a citrate/Tris buffer) were combined to yield a total of 0.7 ml. The composition was gently mixed and 500 p1 (to yield 100 μg p24gag/sf2/dose) of vaccine was injected intramuscularly (IM) in the thigh muscle. For Group 2, 1.5 ml of 2× phosphate buffered saline (PBS) was added to 46.8 mg of the PLG-entrapped p24gag/sf2 formulation produced in Example 1. The material was vortexed for about 30 seconds until all beads were in suspension. 1.5 ml of MF59-0 was added to the resuspended beads to yield a total of 3 ml. The composition was gently mixed and 500 μl (to yield 100 μg p24gag/sf2/dose) of vaccine was injected IM in the thigh muscle.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([C:24](=[O:26])[CH3:25])[CH:3]=1.[BH4-].[Na+]>CO>[Cl:1][C:2]1[C:7]([C:8]#[CH:9])=[C:6](/[N:10]=[N:11]/[N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:4]([CH:24]([OH:26])[CH3:25])[CH:3]=1
Reactant: C#Cc1c(Cl)cc(C(C)=O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C#Cc1c(Cl)cc(C(C)O)c(-c2cccc(F)c2)c1/N=N/N(CC)CC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-{4-chloro-6-[(1E)-3,3-diethyltriaz-1-en-1-yl]-5-ethynyl-3′-fluorobiphenyl-2-yl}ethanone (2.3 g, 6.1 mmol) in methanol (38 mL) at 0° C. was treated with sodium borohydride (0.46 g, 12 mmol) in two portions and stirred at 0° C. for 30 minutes. The reaction mixture was quenched with water at 0° C., poured into saturated sodium bicarbonate (50 mL), and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (quantitative). This material was used without further purification. LCMS for C20H22ClFN3O (M+H)+: m/z=374.1; Found: 373.9.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2OS(C(F)(F)F)(=O)=O.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>C1(C)C=CC=CC=1.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[O:8][C:7]([CH3:15])([CH3:14])[CH:6]=[C:5]2[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc2c(cc1Br)C(OS(=O)(=O)C(F)(F)F)=CC(C)(C)O2
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: [Cl-]
Solvent: Cc1ccccc1
Product: COc1cc2c(cc1Br)C(c1ccccc1)=CC(C)(C)O2
Temperature: 90 °C
Reaction time: 12 h

Procedure:
A solution of trifluoro-methanesulfonic acid 6-bromo-7-methoxy-2,2-dimethyl-2H-chromen-4-yl ester (Compound 7, 2.14 g, 5.30 mmol) in 35 mL of anhydrous toluene was first degassed by bubbling with argon for 15 min. Phenylboronic acid (650 mg, 5.30 mmol), potassium carbonate (1.47 g, 10.6 mmol), lithium chloride (632 mg, 14.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (270 mg, 0.53 mmol) were added. After stirring at 90° C. for 12 h, the mixture was cooled to room temperature and quenched with water. The product was extracted with ethyl acetate. The organic layer was washed with water, brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo and purified by column chromatography (silica gel, 5% ethyl acetate in hexane) to give the title compound as a foam.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[O:19]1[C:24]2[CH:25]=[CH:26][C:27](N)=[CH:28][C:23]=2[O:22][CH2:21][CH2:20]1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[O:19]1[CH2:20][CH2:21][O:22][C:23]2[CH:28]=[C:27]([NH:13][C:12]3[C:11]4[C:10](=[CH:9][CH:8]=[C:6]5[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]5=4)[N:14]=[CH:15][N:16]=3)[CH:26]=[CH:25][C:24]1=2
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc2c(c1)OCCO2
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc5c(c4)OCCO5)c3c2s1
Yield: 33 %

Procedure:
Prepared from VII and 1,4-benzodioxan-6-amine. Flash chromatography eluent (DCM-EtOAc, 8:2). Yield: 33%; yellow solid; mp 180-190° C.; IR (KBr) νmax/cm−1 3055, 2978, 2932, 2875, 2230, 1709, 1638, 1609, 1578, 1496, 1460, 1376, 1299, 1281, 1239, 1200, 1151, 1063, 916, 885, 814; 1H NMR (300 MHz, DMSO-d6) δ 8.37 (d, 1H, J=8.4 Hz), 7.85 (m, 1H), 7.76 (m, 1H), 6.88 (d, 1H, J=8.4 Hz), 6.56 (m, 2H), 4.25 (s, 4H); HRMS calcd for C18H12N5O2S (M+H+): 362.0712, found 362.0696.