Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[N:5]1[C:9]([CH3:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:17])[N:7]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[C:6]1=[O:30])(=O)C.Cl.F[C:33](F)(F)[C:34]([OH:36])=[O:35].ClCCl>>[CH3:16][C:9]1([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:5]([CH2:33][C:34]([OH:36])=[O:35])[C:6](=[O:30])[N:7]([C:18]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=[CH:22][CH:21]=2)=[O:19])[C:8]1=[O:17]
Reactant: CC(=O)ON1C(=O)N(C(=O)c2cccc3ccccc23)C(=O)C1(C)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tert-butyl (5-methyl-3-naphthylcarbonyl-2,4-dioxo-5-phenylimidazolidinyl acetate (400 mg) was dissolved in a 20% trifluoroacetic acid/dichloromethane solution (10 mL), and the mixture was stirred at room temperature overnight. After 0.5N hydrochloric acid was added, and the solution was extracted twice using chloroform (100 mL). The resulting organic layer was washed with a saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was distilled off. Further recrystallization from IPE afforded 276 mg of white crystals.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[C:9]([Cl:28])[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=1.B(OC)(OC)[O:30]C.Cl>CCCCCC.O1CCCC1>[Cl:28][C:9]1[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:15][CH:14]=2)=[N:11][CH:12]=[C:7]([OH:30])[CH:8]=1
Reactant: COB(OC)OC
Reactant: CCCCCCCCOc1ccc(-c2ncc(Br)cc2Cl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCCCOc1ccc(-c2ncc(O)cc2Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
18.9 ml (30.30 mmol) of 1.6M n-BuLi solution in n-hexane are added dropwise at 0° C. to 4.50 g (12.10 mmol) of 5-bromo-3-chloro-2-(4-octyloxyphenyl)pyridine and 2.7 ml (24.20 mmol) of trimethyl borate in 70 ml of tetrahydrofuran, and the mixture is stirred at 0° C. for 0.5 hour. The mixture is subsequently acidified by means of dilute hydrochloric acid and partitioned between aqueous sodium chloride solution and ether, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated. The dry residue is dissolved in 100 ml of tetrahydrofuran and refluxed for 2 hours with 5 ml of 35% strength hydrogen peroxide. After the mixture has been cooled to 0° C., 6.3 g of Na2SO3 in 45 ml of water are added dropwise, and the mixture is stirred at room temperature for a quarter of an hour. The mixture is subsequently partitioned between ether and aqueous sodium chloride solution, the organic phase is washed with sodium chloride solution, dried over sodium sulfate and filtered, and the filtrate is evaporated to dryness. Chromatographic purification (silica gel, dichloromethane:ethyl acetate=4:1) gives 2.35 g of 3-chloro-5-hydroxy-2-(4-octyloxyphenyl)pyridine. ##STR18## m.p.: 128°-129.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([NH2:16])=[CH:15][C:8]=23)=[CH:4][CH:3]=1.[CH3:19][N:20]=[C:21]=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([NH:16][C:21]([NH:20][CH3:19])=[S:22])=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Reactant: CN=C=S
Solvent: c1ccncc1
Product: CNC(=S)Nc1cc2c(Oc3ccc(Cl)cc3)cncc2s1
Temperature: 100 °C
Yield: 58 %

Procedure:
A solution of obtained amine from Example 263 (150 mg, 0.542 mmol) in 5 mL of pyridine was treated with methyl isothiocyanate (198 mg, 2.71 mmol). The solution heated to 100° C. under a nitrogen atmosphere for 5 days. All volatiles were removed under reduced pressure. The resulting product was purified by flash column chromatography on silica gel eluting with chloroformn/NH4OH, affording 110 mg (58.1%) of the title compound.
Reaction SMILES: C1(C)C=CC(S([CH2:10][N+:11]#[C-:12])(=O)=O)=CC=1.[CH3:14][CH:15]([CH3:22])/[CH:16]=[CH:17]/[C:18]([O:20][CH3:21])=[O:19].CC(C)([O-])C.[K+]>>[CH:15]([C:16]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:10][NH:11][CH:12]=1)([CH3:22])[CH3:14]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)/C=C/C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: COC(=O)c1c[nH]cc1C(C)C
Yield: 53.8 %

Procedure:
Using p-toluenesulfonylmethyl isocyanide (7.6 g), methyl (2E)-4-methylpent-2-enoate (5.0 g) and potassium tert-butoxide (5.25 g), a procedure as in Reference Example 39 was performed to give the title compound as a pale-yellow oil (yield 3.5 g, 54%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH:29]([OH:31])[CH3:30]>>[OH:31][CH:29]([CH3:30])[CH2:28][NH:27][C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][S:23](=[O:26])[CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([NH:12][CH2:13][C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)[C:6]=2[N:7]=1
Reactant: CC(O)CN
Reactant: O=S1CCN(c2nc(Cl)nc3c(NCc4cccnc4)ncnc23)CC1
Product: CC(O)CNc1nc(N2CCS(=O)CC2)c2ncnc(NCc3cccnc3)c2n1

Procedure:
This compound was prepared analogous to Example 2 from 2-chloro-4-(1-oxido-thiomorpholino)-8-(3-picolyl-amino)pyrimido[5,4-d]pyrimidine (melting point: 227°-229° C.) and 1-amino-2-propanol.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([S:16][CH2:17][CH2:18][CH3:19])[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=1.[O:20]1CCOCC1>O>[CH2:17]([S:16][C:14]1[C:13]2[C:4](=[C:5]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[CH:8][CH:7]=[N:6]3)[N:3]=[C:2]([CH:1]=[O:20])[CH:15]=1)[CH2:18][CH3:19]
Reactant: C1COCCO1
Reactant: CCCSc1cc(C)nc2c1ccc1cccnc12
Solvent: O
Product: CCCSc1cc(C=O)nc2c1ccc1cccnc12
Yield: 27 %

Procedure:
A solution of SeO2 (0.98 g, 8.8 mmol) in a mixture of dioxane (50 mL) and water (2 mL) was heated to reflux in a two-neck 250 mL round-bottomed flask. A solution of 2-methyl-4-propylsulfanyl-[1,10]phenanthroline (0.95 g, 3.5 mmol) in hot dioxane (50 mL) was added through an addition funnel over a period of 30 minutes and the reaction mixture was refluxed for additional 1 hour. The reaction mixture was filtered while hot and the residue rinsed with more hot dioxane (20 mL) and filtered. The filtrates were combined and evaporated in vacuo and the residue was treated with methylene chloride (100 mL) and a 10% K2CO3 aqueous solution (100 mL). The aqueous layer was extracted several times with methylene chloride (3×100 mL) and the combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by flash chromatography (neutral Al2O3, MeOH/DCM, 1:50 to 1:15) to afford the pure product as a brown solid (0.27 g, 27%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[O:28][CH2:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[C:20](=[O:29])[C:19]=3[CH:30]=1)[CH:6]=[CH:5]2.[BH4-].[Na+]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]3[O:28][CH2:27][C:22]4=[N:23][CH:24]=[CH:25][CH:26]=[C:21]4[CH:20]([OH:29])[C:19]=3[CH:30]=1)[CH:6]=[CH:5]2
Reactant: O=C1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2OCc2ncccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OC1c2cc(OCc3ccc4cc(F)c(F)cc4n3)ccc2OCc2ncccc21

Procedure:
A suspension of 5.4 g (13.35 mmol) of the product of step 5 in 90 ml of THF and 30 ml of methanol is stirred with external ice bath cooling. There are added, 0.55 g (14.4 mmol) of sodium borohydride in little portions. Once the addition is finished the reaction is stirred for 1 hour, evaporated and 100 ml of water are added. The system is stirred for 30′ and the solid is filtered and thoroughly washed with water. Once dried, the solid weights 5.3 g (97
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[NH2:22][CH2:23][CH:24]([C:26]1[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=1)[OH:25]>>[O:18]=[C:16]1[NH:15][C:14](=[O:19])[C:13](=[CH:12][C:11]2[CH:20]=[CH:21][C:8]([N:3]3[CH2:4][CH2:5][CH:6]([NH:22][CH2:23][CH:24]([C:26]4[CH:27]=[CH:28][C:29]([OH:37])=[C:30]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH:31]=4)[OH:25])[CH2:7][CH2:2]3)=[CH:9][CH:10]=2)[S:17]1
Reactant: CS(=O)(=O)Nc1cc(C(O)CN)ccc1O
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Product: CS(=O)(=O)Nc1cc(C(O)CNC2CCN(c3ccc(C=C4SC(=O)NC4=O)cc3)CC2)ccc1O

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide (which was obtained in Example 9) according to the procedure of Example 73 as a pale yellowish solid; mp>200° C. (decomposed); 1H NMR (300 MHz, DMSO-d6), δ 1.45–1.60 (m, 2 H), 1.90–2.05 (m, 2 H), 2.70–3.50 (m, 5 H), 2.94 (s, 3 H), 3.88 (brd, J=9.9 Hz, 2 H), 4.67 (dd, J=7.2, 2.1 Hz, 1 H), 6.87 (d, J=6.3 Hz, 1 H), 7.00 (d, J=6.8 Hz, 2 H), 7.06 (dd, J=6.3, 1.5 Hz, 1 H), 7.23 (d, J=1.5 Hz, 1 H), 7.33 (s, 1 H), 7.38 (d, J=6.8 Hz, 2 H); MS (ES) m/z: 533.0 (MH+); HRMS Calcd. for C24H29N4O6S2 (MH+): 533.1529. Found: 533.1544.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:8][C:9]([N:17]1[CH2:18][CH2:19][CH:14]([CH2:13][OH:12])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(OCc1ccccc1)N1CCC(CO)CC1
Reaction time: 3 h
Yield: 42.5 %

Procedure:
A solution of benzylchloroformate (17 g, 100 mmol) in 50 mL of 2-butanone was added dropwise to a stirred mixture of 4-hydroxymethylpiperidine (10.3 g, 100 mol) and potassium carbonate (13.8 g, 100 mmol) in 300 mL of 2-butanone. When the addition was complete the stirring was continued for an additional 3 hours. The solids formed were filtered and the filtrate concentrated in vacuo. Pure product was obtained by flash chromatography (hexane-ethyl acetate, 2:1) to give 10.6 g of product as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[H-].[Na+].[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1.O>CN(C=O)C>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:3]2[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]2[CH3:1])=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1cc[nH]c1C
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccn(Cc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (106.26 g, 0.694 mol) (prepared by the method of: Wee, A. G. H.; Shu, A. Y. L.; Djerassi, C. J. Org. Chem. 1984, 49, 3327-3336) in anhydrous DMF (1.0 L), under nitrogen, was added sodium hydride (60% in oil, 30.5 g, 0.763 mol, 1.1eq.) in 5 portions over 1 hour. When gas evolution ceased, 4-fluorobenzyl bromide (131.13 g, 0.694 mol) in anhydrous DMF (0.2 L) was added via pressure equalized addition funnel over 45 minutes. The mixture was allowed to stir at room temperature for 16 hours after the addition was complete, then was poured into water (1.4 L) in a 4 L separatory funnel. The mixture was extracted with diethyl ether (5×1.0 L) and the combined organic phases were washed with brine (3.0 L) and dried (Na2SO4). Filtration, rinsing of the filter cake with diethyl ether (0.5 L) and concentration in vacuo (approx. 20 Torr) gave the crude product and DMF. Residual DMF was removed on a cold finger trap rotary evaporator at full pump vacuum in a 40° C. water bath to give the crude benzylate pyrrole as an orange oil. The crude product was purified by chromatography on a column of silica gel (125 mm OD, 1 kg 230-400 mesh, packed with hexanes-EtOAc 95:5) eluted with hexanes:EtOAc (95:5, 2.0 L) and hexanes:EtOAc (90:10, 8.0 L) while collecting 500 mL fractions, using the flash technique. Fractions 4-18 were combined to afford ethyl 1-(4-fluorobenzyl)-2-methyl-1H-pyrrole-3-carboxylate (172.3 g, 95%) as a clear, pale yellow, viscous liquid. TLC (Merck, hexanes:EtOAc 85:15, UV-+, cerium molybdate-+): Rf=0.26; LCMS (Eclipse XDB-C8, 0.8mL/min, gradient 80:20 to 5:95 H2O (+0.1% HOAc):CH3CN—5 minutes, APCl, +mode): RT-3.711 min, m/e=262.1 (base), 263.2 (30); 1H-NMR (300 MHz, CDCl3): δ=1.33 (t, J=7.06 Hz, 3H), 2.43 (s, 3H), 4.26 (q, J=7.06 Hz, 2H), 5.00 (s, 2H), 6.52 (d, J=3.20 Hz, 1H), 6.58 (d, J=3.20 Hz, 1 H), 6.92-7.04 (m, 4H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][O:12][N:11]=2)=[CH:6][CH:5]=1.O.[OH-].[Li+]>C1COCC1.O>[Cl:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][O:12][N:11]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1conc1-c1ccc(CCCl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1conc1-c1ccc(CCCl)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 99.9 %

Procedure:
Methyl 3-(4-(2-chloroethyl)phenyl)isoxazole-4-carboxylate (1.46 g, 5.49 mmol) was dissolved in THF-water (2:1, 30 ml), lithium hydroxide monohydrate (922 mg, 21.97 mmol) was added, and the mixture was stirred at room temperature for 6 hours. THF was evaporated under reduced pressure, 2N hydrochloric acid was added to weak-acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.38 g, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][CH2:11][CH2:12]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][O:10][CH3:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COCCOc1ccc(Br)cc1
Reaction time: 1 h
Yield: 83.1 %

Procedure:
4-Bromophenol (8.65 g; 0.05 mol), 2-methoxyethanol (1.1 eq.; 0.055 mol; 4.36 ml) and triphenylphosphine (1.1 eq.; 0.055 mol; 14.4 g) are dissolved in 210 ml of toluene. The reaction medium is brought to 54° C. and diisopropyl azodicarboxylate (1.0 eq.; 0.05 mol; 10.1 g) dissolved in 21 ml of toluene is added dropwise. The reaction medium is left at 54° C. for one hour and then overnight at room temperature, and is then evaporated to dryness. The crude product is purified by flash chromatography on silica on a gradient of heptane comprising 0-100% DCM to give 9.6 g of the expected product in the form of an oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19](O)=[O:20])=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:53]([N:55]1[N:59]=[N:58][C:57]([CH2:60][N:61]2[C:66]3[CH:67]=[C:68]([C:70]4[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=4)[S:69][C:65]=3[C:64](=[O:76])[N:63]([CH:77]3[CH2:82][CH2:81][NH:80][CH2:79][CH2:78]3)[C:62]2=[O:83])=[N:56]1)[CH3:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[C:18]([C:19]([N:80]4[CH2:81][CH2:82][CH:77]([N:63]5[C:64](=[O:76])[C:65]6[S:69][C:68]([C:70]7[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=7)=[CH:67][C:66]=6[N:61]([CH2:60][C:57]6[N:58]=[N:59][N:55]([CH2:53][CH3:54])[N:56]=6)[C:62]5=[O:83])[CH2:78][CH2:79]4)=[O:20])[CH:22]=[CH:23][CH:24]=3)=[N:9][C@@H:8]3[CH2:25][CH2:26][S:27][CH2:28][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)O)c1)=N[C@@H]1CCSC[C@H]21
Reactant: CCn1nnc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1cc2c(cc1OC)C(c1cccc(C(=O)N3CCC(n4c(=O)c5sc(-c6ccccc6)cc5n(Cc5nnn(CC)n5)c4=O)CC3)c1)=N[C@@H]1CCSC[C@H]21

Procedure:
In analogy to the procedure described for example 14 3-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoic acid (120 mg; compound C8) is reacted with HBTU (120 mg), 1-[(2-ethyl-2H-tetrazol-5-yl)methyl]-6-phenyl-3-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2,4(1H,3H)-dione (132 mg; compound B39) and DIPEA (0.16 ml) in DCM (10 ml). After purification by flash column chromatography (silica gel, eluent: EtOAc) the title compound is obtained as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([CH:6]=[CH:7][C:8](O)=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:17].O.C([O-])(O)=O.[Na+]>CCOC(C)=O>[Cl:17][C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[C:11]([O:12][CH3:13])[C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1c(Cl)ccc2ccc(O)nc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1c(Cl)ccc2ccc(Cl)nc12

Procedure:
7-Chloro-8-methoxy-2-quinolinol (4b) (2.85 g, 13.6 mmol) was mixed with POCl3 (6 mL) and allowed to reflux for 1.5 hours. To the concentrated contents, H2O and AcOEt were added followed by NaHCO3 to neutralize the mixture. The water layer was extracted with AcOEt, washed with saturated NaCl and dried with MgSO4. The product was filtered through silica gel using CHCl3 and recrystalized from CHCl3-hexanes to afford the desired product as off white crystals (2.53 g, 82% yield): mp 103-104 □C; 1H NMR (400 MHz, CDCl3) 8.07 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.19 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2cccnc2)CC1
Reactant: CC1(C(=O)Cl)CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2cccnc2)NC(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-3-ylmethyl-ethylamine (326 mg.; 1 mmol, from Example 3) in dichloromethane (15 mL) at 0° C. was added triethylamine (0.28 mL; 2 mmol) and 1-methyl-1-cyclohexanecarbonyl chloride (160 mg.; 1 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, washed sequentially with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (5% methanol/chloroform) to yield the free base of the title compound as a clear oil (132 mg.; 29%). Treatment with an equimolar amount of fumaric acid in ethanol afforded the fumarate salt as an off-white amorphous solid, m.p. 150–152° C.; MS (+) FAB, [M+H]+ @ m/z 451, [M+Na]+ @ m/z 473; 1H NMR, 400 MHz, DMSO-d6. Analysis for C27H38N4O2.C4H4O4.0.5H2O Calculated: C, 64.68; H, 7.53; N, 9.73 Found: C, 64.89; H, 7.18; N, 9.64.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)[CH:13]=1)[C:8]([OH:10])=O)=[O:4].[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl>[OH:19][CH:20]1[CH2:25][CH2:24][N:23]([C:8]([C:7]2[CH:6]=[C:5]([CH:13]=[C:12]([N:14]3[CH:18]=[CH:17][CH:16]=[CH:15]3)[CH:11]=2)[C:3]([O:2][CH3:1])=[O:4])=[O:10])[CH2:22][CH2:21]1
Reactant: COC(=O)c1cc(C(=O)O)cc(-n2cccc2)c1
Reactant: OC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COC(=O)c1cc(C(=O)N2CCC(O)CC2)cc(-n2cccc2)c1
Temperature: 25 °C
Reaction time: 30 h
Yield: 89.2 %

Procedure:
To a mixture of 3-methoxycarbonyl-5-(pyrrol-1-yl)-benzoic acid (3.0 g), 4-hydroxypiperidine (1.23 g) and 1-hydroxybenzotriazole (1.81 g) in dichloromethane (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (2.57 g) under ice cooling, and the solution was stirred for 30 hours at room temperature. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate and a saturated aqueous sodium hydrogencarbonate solution under stirring. The organic layer was successively washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (50:1). The fractions containing the desired product were collected and evaporated in vacuo to afford methyl 3-[(4-hydroxypiperidin-1-yl)carbonyl]-5-(pyrrol-1-yl)benzoate (3.56 g).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[F:20][C:21]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)=[CH:25][C:22]=1[CH:23]=O>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:23][C:22]2[CH:25]=[C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:27]=[CH:28][C:21]=2[F:20])[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: O=Cc1cc(-c2ccccn2)ccc1F
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1cc(-c2ccccn2)ccc1F

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-fluoro-5-(pyridin-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.66 min.; [M+H]+: 420.83 g/mol.
Reaction SMILES: CN([CH:4]=[C:5]1[CH2:11][C:10](=[O:12])[NH:9][C:8]2[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=2[C:6]1=O)C.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:29][C:30]([NH2:32])=[NH:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:29][C:30]2[N:32]=[CH:4][C:5]3[CH2:11][C:10](=[O:12])[NH:9][C:8]4[CH:13]=[C:14]([CH3:17])[CH:15]=[CH:16][C:7]=4[C:6]=3[N:31]=2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Cc1ccc2c(c1)NC(=O)CC(=CN(C)C)C2=O
Reactant: COc1ccc(NC(=N)N)cc1OC
Product: COc1ccc(Nc2ncc3c(n2)-c2ccc(C)cc2NC(=O)C3)cc1OC

Procedure:
In a manner similar to method I, 4-((dimethylamino)methylene)-8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-g) and 1-(3,4-dimethoxyphenyl)guanidine were converted to I-42 (57%): HRMS Calcd. for C21H20N4O3: 377.1613, Found 377.1613.
Reaction SMILES: [K].[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27]>>[OH:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: OCCCCCCI
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(O)cc2)cc1
Agent: [K]
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(OCCCCCCO)cc2)cc1

Procedure:
Employing the procedure of Example I(A), 14 g (0.05M) of the potassium salt of 4-hydroxy-4'-nitrostilbene and 14 g (0.06M) of 6-iodo-1-hexanol are reacted. The resultant product is recrystallized from toluene, m.p. 154°-157° C.