Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCCCCC.C1COCC1.C1(CO[CH2:20][C:21]2(O)[CH2:27][O:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]2)CC1.Br[C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[N:38]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC.C(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH3:43][C:39]1[N:38]=[C:37]([CH2:20][CH:21]2[CH2:27][O:26][CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[CH2:22]2)[CH:42]=[CH:41][CH:40]=1
Reactant: Cc1cccc(Br)n1
Reactant: CC(C)(C)OC(=O)N1CCOCC(O)(COCC2CC2)C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCCCC
Solvent: ClCCl
Product: Cc1cccc(CC2COCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.5M 9-Borobicyclo[3.3.1]nonane in THF (415 mL, 0.21 mol, 1.1 eq) was added under stirring in a stream of argon at room temperature to tert-butyl 6-[(cyclopropylmethoxy)methyl]-6-hydroxy-1,4-oxazepane-4-carboxylate (Preparation 80, 40 g, 0.19 mol, 1 eq). The reaction mixture was stirred at room temperature for 2 h. After this, the catalyst palladium (0) tetrakis(triphenylphosphine) (4 g, 0.003 mol, 0.02 eq) and 2-bromo-6-methylpyridine (36 g, 0.21 mmol, 1.1 eq) were added to the mixture, and the latter was stirred for 15 min. Then 3M potassium carbonate solution (125 mL, 0.38 mol, 2 eq) was added, and the reaction mixture was refluxed for 3 h. The mixture was cooled, diluted with hexane (300 mL) and DCM (100 mL). The organic layer was separated, washed with water (2×100 mL), and with the saturated sodium chloride solution. The combined aqueous layer was extracted with ethyl acetate/hexane (3:1) mixture (2×200 mL). The organic layers were sequentially filtered through silica (25 g; 63-100 μm) and sodium sulphate (50 g) and evaporated. The residue was subjected to chromatography (carbon tetrachloride/chloroform/isopropanol 100:0:0→90:10:0→70:30:0→50:50:0→30:70:0→0:100:0→0:99:1→0:98:2→0:97:3→0:95:5→0:93:7→0:92:8→0:90:10) on silica (500 g; 63-100 μm). The fractions, containing the product, were collected and evaporated to give title compound as a light oil in (42.5 g, 0.14 mol, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C2C(=CC=1)OC(C1C=CC=CC=1)=CC2=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][C:16]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:15][C:14]3=[O:27])=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1cc(-c2ccccc2)oc2ccc(O)cc12
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Product: O=c1cc(-c2ccccc2)oc2ccc(Oc3ccc([N+](=O)[O-])cn3)cc12

Procedure:
6-(5-Nitropyridin-2-yloxy)-2-phenylchromen-4-one was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 500 mg of 6-hydroxyflavone. The product was recrystallised from a mixture of 2-propanol and acetone. 1H NMR (300 MHz, d6-DMSO) δ: 9.04 (d, 1H, J 2.9 Hz), 8.67 (dd, 1H, J 9.0, 2.9 Hz), 8.16-8.13 (m, 2H), 7.95 (d, 1H, J 9.0 Hz), 7.82 (d, 1H, J 2.9 Hz), 7.63 (dd, 1H, J 9.1, 2.9 Hz), 7.64-7.61 (m, 3H), 7.38 (d, 1H, J 9.1 Hz), 7.09 (s, 1H).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[NH2:6][CH:7]1[NH:12][C:11]([NH2:13])=[CH:10][C:9](=O)[NH:8]1>>[Cl:3][C:9]1[N:8]=[C:7]([NH2:6])[N:12]=[C:11]([NH2:13])[CH:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: NC1=CC(=O)NC(N)N1
Product: Nc1cc(Cl)nc(N)n1

Procedure:
To 500 mL of freshly distilled POCl3 at a temperature of 80-90° C. is added 100 g of 2,4-diamino-6-oxo-dihydropyrimidine (Aldrich, Milwaukee, Wis., USA). The mixture is distilled under reflux until, after approximately 2 hours, the mixture has completely dissolved. The residual POCl3 is suctioned off using vacuum and the remaining syrup is dripped slowly onto ice. The highly acidic solution is carefully neutralized by cooling it using concentrated sodium aluminate solution, and in the final stage with solid sodium carbonate. When completed the total volume of solution is approximately 1800 mL. Upon cooling a yellowish precipitate is separated out which is suctioned off and dried in a vacuum desiccator. The end product which contains mostly non-organic-salts is boiled three times, each time with 1 liter of acetone to which active charcoal is added. The extracts are cooled and the resulting clear precipitate is collected. Evaporation of the filtrates yields an additional fraction.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:36])[C@@H:15]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:27][CH:26]=2)[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][O:38][C:39]1[CH:49]=[CH:48][C:42](/[CH:43]=[CH:44]/[C:45](O)=[O:46])=[CH:41][CH:40]=1>>[CH2:16]([C@H:15]([N:23]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:29][CH:30]=1)[C:45](=[O:46])[CH:44]=[CH:43][C:42]1[CH:48]=[CH:49][C:39]([O:38][CH3:37])=[CH:40][CH:41]=1)[C:14]([N:11]1[CH2:10][CH2:9][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]1)=[O:36])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCCc1ccc(CN[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(OC)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 47.8 %

Procedure:
Acylation of 1-(4-benzyl-piperazin-1-yl)-(S)-2-(4-pentyl-benzylamino)-3-phenyl-propan-1-one (43.5 mg, 0.09 mmol) according to the procedure described for the preparation of Example 1 with trans-4-methoxy-cinnamic acid (17.6 mg, 0.099 mmol) gave 27.7 mg (48%) of N—[(S)-1-benzyl-2-(4-benzyl-piperazin-1-yl)-2-oxo-ethyl]-3-(4-methoxy-phenyl)-N-(4-pentyl-benzyl)-acrylamide. LC-MS: tR=1.00 min; [M+H]+=644.50.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([OH:5])=[O:4].[CH3:9]O.Cl>>[NH2:1][C@H:2]([CH2:6][CH:7]=[CH2:8])[C:3]([O:5][CH3:9])=[O:4]
Reactant: CO
Reactant: C=CC[C@@H](N)C(=O)O
Agent: Cl
Product: C=CC[C@@H](N)C(=O)OC
Yield: 98 %

Procedure:
A solution of (R)-2-aminopent-4-enoic acid (18d) (5 g, 43.5 mmol) in MeOH.HCl (2.4M, 50 mL) was stirred at 70° C. overnight. The mixture was concentrated under reduced pressure to give compound 18e (5.5 g, 98% yield), which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([OH:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]([O:27][S:29]([CH3:28])(=[O:31])=[O:30])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(O)CCCCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CCCCC1CCN(C(=O)OCc2ccccc2)CC1)OS(C)(=O)=O

Procedure:
In pyridine (30 ml) is dissolved R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (7 g), and methanesulfonyl chloride (2.9 ml) is added dropwise, with stirring, under ice-cooling over the period of 5 minutes. The mixture is stirred under ice-cooling for 1.5 hours, and water (5 ml) is added dropwise to the mixture. The reaction mixture is stirred for 30 minutes, diluted with ethyl acetate (300 ml) and washed with 1N hydrochloric acid, saturated sodium hydrogencarbonate solution and water. The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate (8.2 g) as a pale yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:55])[C:5]([CH2:17][O:18][C:19](=[O:54])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([O:46]CC2C=CC=CC=2)[CH:22]=1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]>CO.[C].[Pd]>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:17][O:18][C:19](=[O:54])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C:30]2[C:31]([C:36]3[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:45])[F:44])=[CH:40][CH:41]=3)=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:29])=[C:23]([OH:46])[CH:22]=1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:55])[CH3:10]
Reactant: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(OCc2ccccc2)c1)(C(=O)OCC)c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(COC(=O)Cc1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(O)c1)(C(=O)OCC)c1ccccc1
Reaction time: 2 h

Procedure:
2-(2-{3-Benzyloxy-4-[(4′-trifluoromethyl-biphenyl-2-carbonyl)amino]phenyl}acetoxymethyl)-2-phenylmalonic acid diethyl ester (Reference Example 2-4) (0.310 g) was dissolved in methanol, and palladium carbon (0.04 g) was added thereto. The mixture was hydrogenated at normal pressure for 2 hours. The reaction solution was filtered through a Celite, and the filtrate was concentrated to give the title compound as a colorless non-crystalline substance (0.245 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35](F)[CH:36]=3)[C:31](=[O:40])[N:30]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:29]2=[O:49])[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:37]3[C:32](=[CH:33][C:34]([F:39])=[C:35]([N:11]4[CH2:12][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]4)[CH:36]=3)[C:31](=[O:40])[N:30]([O:41][CH2:42][C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:29]2=[O:49])[CH:25]=[CH:26][CH:27]=1
Reactant: O=c1c2cc(F)c(F)cc2n(-c2cccc(F)c2)c(=O)n1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2cc3c(cc2F)c(=O)n(OCc2ccccc2)c(=O)n3-c2cccc(F)c2)C1
Yield: 85.2 %

Procedure:
Using General Method 4, the reaction of 3-t-butoxycarbonylamino-pyrrolidine (0.266 g, 1.43 mmol), triethylamine (0.2 mL, 1.43 mmol), and 1-(3-fluorophenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example G-1, 0.19 g, 0.48 mmol) provided 0.231 g of the title compound as a solid.
Reaction SMILES: [NH2:1][OH:2].Cl.C[O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1>CO>[OH:2][NH:1][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:20][C:21]1[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: COC(=O)CCCCN(Cc1ncccc1C)Cc1ncccc1C
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cccnc1CN(CCCCC(=O)NO)Cc1ncccc1C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
To a mixture of Na metal (1—mg, 4.91 mmol) in MeOH (5 mL) was added NH2OH—HCl (204 mg, 2.94 mmol) followed by a solution of 5-[Bis-(3-methyl-pyridin-2-ylmethyl)-amino]-pentanoic acid methyl ester (126 mg, 0.37 mmol) in MeOH (7 mL) and the reaction stirred 1.5 h. An additional amount of Na (134 mg, 5.83 mmol) and NH2OH—HCl (208 mg, 2.99 mmol) was then added and the mixture stirred another 40 min then quenched with water (2-3 mL). The mixture was concentrated and diluted with H2O (10 mL), saturated aqueous NaHCO3 (to pH 10) and CHCl3 (25 mL) and stirred vigorously overnight. The layers were separated and the aqueous was extracted with CHCl3 (2×15 mL). The combined organic extracts were dried (Na2SO4), concentrated and purified by radial chromatography on silica gel (1 mm plate, CH2Cl2/MeOH/NH4OH, 50:1:1 then 25:1:1 then 10:1:1) to give COMPOUND 172 (47 mg, 37%) as a white solid: 1H NMR (CDCl3) δ 1.54-1.58 (m, 4H), 2.11 (s, 6H), 2.12-2.15 (m, 2H), 2.52-2.55 (m, 2H), 3.71 (s, 4H), 7.12 (dd, 2H, J=9, 6 Hz), 7.42 (d, 2H, J=9 Hz), 8.36 (d, 2H, J=6 Hz). 13C NMR (CDCl3) δ 17.91, 21.92, 23.16, 31.68, 52.73, 57.23, 122.58, 133.61, 138.43, 145.52, 156.61, 170.55. ES-MS m/z 343 (M+H). Anal. Calcd. for C19H26N4O2.1.3CH3OH: C, 63.48; H, 8.19; N, 14.59. Found: C, 63.66; H, 8.03; N, 14.33.
Reaction SMILES: [H][H].[CH2:3]([N:10](CC1C=CC=CC=1)[C:11]1[N:12]=[CH:13][CH:14]=[C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:21])[NH:17][C:16]=12)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>[Pd].C(O)C>[CH2:3]([NH:10][C:11]1[N:12]=[CH:13][CH:14]=[C:15]2[CH:19]=[C:18]([C:20]([NH:22][CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)=[O:21])[NH:17][C:16]=12)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(NCc1ccncc1)c1cc2ccnc(N(Cc3ccccc3)Cc3ccccc3)c2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O=C(NCc1ccncc1)c1cc2ccnc(NCc3ccccc3)c2[nH]1
Yield: 24.6 %

Procedure:
Hydrogen (1 atm, balloon) was applied to a slurry of 7-(dibenzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (Example 41) (69 mg, 0.15 mmol), 10% palladium on carbon (wet, 100 mg) and HCl (saturated solution in 2-propanol, 5 M, 0.5 mL) in ethanol (4.5 mL) at room temperature for 3 h. The slurry was filtered to remove the catalyst, and the filtrate was concentrated in vacuo. The residue was partitioned between ethyl acetate and aqueous sodium hydrogen carbonate. The two layers were separated. The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 2:1 to 1:2 hexanes/ethyl acetate). Recrystallization from hexanes/ethyl acetate gave 7-(benzylamino)-N-(4-pyridinylmethyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide (13.2 mg, 24%) as colorless crystals: Rf 0.42 (silica gel, 20:80 methanol/ethyl acetate); mp 199-200° C. (recrystallized from hexanes/ethyl acetate); 1H NMR (300 MHz, CD3OD) δ4.63 (2H, s), 4.69 (2H, s), 6.91 (1H, d, J=6.0 Hz), 7.05 (1H, s), 7.22-7.43 (7H, m), 7.55 (1H, d, J=6.0 Hz), 8.48 (2H, d, J=6.0 Hz); ESI MS m/z 358 [C21H19N5O+H]+; HPLC (Method A) >99% (AUC), tR=13.2 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[N:18][C:17]([NH2:20])=[C:16]([C:21]([OH:23])=[O:22])[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si](C=[N+]=[N-])(C)C>C1C=CC=CC=1.CO>[CH3:24][O:22][C:21]([C:16]1[N:15]=[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)[CH:19]=[N:18][C:17]=1[NH2:20])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cnc(N)c(C(=O)O)n2)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cnc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4-tert-butyl ester (510 mg, 1.6 mmol; see Example 16 (e) above) in benzene (4 mL) and methanol (4 mL) was added a solution of trimethylsilyldiazomethane (2 M in hexane, 2 mL). The reaction was stirred at room temperature for overnight. The solvent was then removed in vacuo and the residue was purified by flash chromatography using ethyl acetate/hexanes (40:60) as eluant to afford 5′-amino-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4,6′-dicarboxylic acid 4-tert-butyl ester 6′-methyl ester as a yellow solid (520 mg, 96%). 1H NMR (300 MHz, CDCl3) δ1.49 (s, 9H), 3.40 (s, 4H), 3.59 (s, 4H), 3.95 (s, 3H), 8.01 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 28.41, 46.30, 52.52, 80.05, 119.69, 135.58, 148.24, 150.00, 154.70, 167.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:7][O:6][C:5]([CH2:14][S:15][CH2:16][C:17]([O:19]CC)=[O:18])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1([CH3:22])[CH2:7][O:6][C:5]([CH2:14][S:15][CH2:16][C:17]([OH:19])=[O:18])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:4][CH2:3]1
Reactant: CCOC(=O)CSCC1(c2ccccc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)COC(CSCC(=O)O)(c2ccccc2)OC1
Temperature: 0 °C
Reaction time: 19 h
Yield: 96.4 %

Procedure:
Ethyl {[(5,5-dimethyl-2-phenyl-1,3-dioxan-2-yl)methyl]thio}acetate (11.2 g, 34.3 mmol) was dissolved in THF (150 ml) and cooled to 0° C. LiOH (2.88 g, 68.7 mmol) in water (40 ml) was added and the mixture was stirred for 19 h. The solvents were evaporated. The crude-product was extracted between water and diethyl ether. The aqueous layer was acidified to a pH of 6 using 2M HCl and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to give 9.8 g (96%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.3 (s, 2H), 3.5 (s, 4H), 7.3-7.6 (m, 5H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1.[CH2:13]([Mg]Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>C1COCC1.C1(P(C2C=CC=CC=2)C([Ni]Cl)CCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][N:6]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCC[Mg]Br
Reactant: Brc1nnc(-c2ccccc2)s1
Agent: Cl[Ni]C(CCP(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCCc1nnc(-c2ccccc2)s1
Reaction time: 4 h

Procedure:
2-Bromo-5-phenyl-1,3,4-thiadiazole (2.9 g, 12 mmol) is added to a 1-octylmagnesium bromide solution (4.6 g, 24 mmol) in THF (80 ml) under a protective-gas atmosphere, and 1,3-bis(diphenylphosphino)propylnickel(II) chloride (0.15 mmol), dissolved in . . . , is then added dropwise at -5° C. The mixture is subsequently stirred at this temperature for 4 hours. After acidification by means of hydrochloric acid (pH=2), the organic phase is separated off and evaporated. The crude product is recrystallized from acetonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[NH2:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[NH2:23])[C:16]([O:18][CH3:19])=[O:17].N1C=CC=CC=1>CC#N>[NH2:23][C:22]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=1[NH:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1ccc(N)c(NC(=O)c2ccc(OC)cc2)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
A solution of 4-methoxybenzoyl chloride (1.03 g, 6.02 mmol) in CH3CN (6 ml) was added drop wise to a solution of methyl 3,4-diaminobenzoate (106) (1.00 g, 6.02 mmol) and pyridine (0.49 ml, 6.02 mmol) in CH3CN (25 ml) at 0° C. The reaction mixture was stirred for 3 h at 0° C. and the solvent was evaporated. Ethyl acetate was added and the organic layer was washed successively with saturated solutions of NH4Cl, NaHCO3 and NaCl, dried over MgSO4, filtered and concentrated. After purification by flash chromatography on silica gel (eluent 1-3% MeOH in DCM), 1.03 g (56%) of compound 107 was obtained as a off white solid. 1H NMR: (DMSO) δ(ppm): 9.51 (s, 1H), 7.96 (d, J=8.8 Hz, 2H), 7.75 (d, J=2.0 Hz, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.03 (d, J=9.0 Hz, 2H), 6.75 (d, J=8.4 Hz, 1H), 5.80 (s, 2H), 3.83 (s, 3H), 3.75 (s, 3H). MS: (calc.) 300.1; (obt.) 301.1 (MH)+.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[CH:28]([C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH3:44])[C:35]3[C:40]([S:41][C:42]=2[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3)=O>CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:28][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH3:44])[C:35]3[C:40]([S:41][C:42]=2[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3
Reactant: CN1c2ccccc2Sc2cc(C=O)ccc21
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CN1c2ccccc2Sc2cc(C=C(Br)Br)ccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.4 %

Procedure:
In an atmosphere of argon, carbon tetrabromide (8.29 g, 25 mmol) and zinc powder (1.63 g, 25 mmol) were added in that order to a mixture of triphenylphosphine (6.56 g, 25 mmol) and dichloromethane (75 ml), and the mixture was stirred at room temperature for 23 hours. A dichloromethane (25 ml) solution of 3-formyl-10-methylphenothiazine (3.02 g, 12.5 mmol) was added and the mixture was again stirred for 7 hours. The reaction mixture was diluted with hexane and the insoluble matter was removed by filtration. The reaction product was extracted from the insoluble matter three times with hexane (about 60° C.), and the thus collected organic layers were combined and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:dichloromethane:hexane=10:10:80) to give the title compound (3.15 g, 7.93 mmol, 63%) as yellow crystals.
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2SC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:23]([CH2:25][NH2:26])[OH:24]>CN(C=O)C>[C:1]1([S:7]([C:10]2[C:15](=[NH:16])[N:14]3[CH:17]=[CH:18][CH:19]=[CH:20][C:13]3=[N:12][C:11]=2[NH:26][CH2:25][CH2:23][OH:24])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCO
Reactant: CSc1nc2ccccn2c(=N)c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: N=c1c(S(=O)(=O)c2ccccc2)c(NCCO)nc2ccccn12
Temperature: 55 °C
Yield: 10 %

Procedure:
To a one dram vial was added 20 mg (0.0604 mmol) of 3-(benzenesulfonyl)-2-methylsulfanyl-pyrido[1,2-a]pyrimidin-4-ylideneamine and 1.1 equivalents of ethanolamine in 750 ml of DMF. The vial was fitted with a TEFLON® lined cap and heated to 55° C. over night. The resulting product was then purified on a reverse phase preparative HPLC (XTerra™ MS C18 5.0 mM, MeOH/H2O as the eluent) to give 23 mg of the title compound as a brown solid; 10% yield.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH3:14]O>>[CH3:14][O:4][C:3](=[O:5])[C:2]([CH3:1])=[CH:6][CH2:7][CH3:8]
Reactant: CO
Reactant: CCC=C(C)C(=O)O
Agent: O=S(=O)(O)O
Product: CCC=C(C)C(=O)OC
Temperature: 20 °C
Yield: 91 %

Procedure:
A mixture of 2-methylpent-2-enoic acid (5.0 g, 44 mmol) and sulfuric acid (0.5 mL) in methanol (250 mL) was heated at reflux for 16 hours. The solution was allowed to cool down to 20° C. and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with saturated aqueous sodium hydrogen carbonate (2×50 mL), distilled water (50 mL), then with brine (50 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to give the title compound (5.1 g, 91%) as a colourless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:10]2)=[CH:6][CH:5]=1)([O-])=O>[Pd].O1CCCC1>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]([O:8][CH:9]2[CH2:12][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:10]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc([N+](=O)[O-])cc2)C1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Oc2ccc(N)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Tert-butyl 3-(4-nitrophenoxy)azetidine-1-carboxylate (1 g, 3.40 mmol) and tetrahydrofuran (20 ml) were added to 5% palladium on carbon (wet, 0.200 g, 1.879 mmol) in a 250 mL SS pressure bottle and the mixture was stirred for 1 hour at 30 psi and room temperature. The mixture was filtered through a nylon membrane and the fitrate was concentrated to give the title compound.