Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22](Cl)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:32][C:33]1([F:37])[CH2:36][NH:35][CH2:34]1.C(=O)(O)[O-].[Na+].CS(C)=O>CCOC(C)=O>[F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][CH:23]=[C:22]([N:35]4[CH2:36][C:33]([F:37])([F:32])[CH2:34]4)[N:21]=3)[C@H:14]2[CH3:28])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(Cl)ccc1Br
Reactant: FC1(F)CNC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ccc1Br
Temperature: 150 °C
Reaction time: 16 h

Procedure:
A reaction vessel was charged with (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[(3-bromo-6-chloropyridin-2-yl)methyl]-4-methyl-1,3-oxazolidin-2-one (50 mg, 0.097 mmol), 3,3-difluoroazetidine hydrochloride (125 mg, 0.966 mmol) and sodium bicarbonate (162 mg, 1.932 mmol). DMSO (2 mL) was added. The reaction was heated to 150° C. under an atmosphere of N2. After 16 hours, the reaction was cooled to r.t., diluted with EtOAc (40 mL), and washed with water and brine (10 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 80% EtOAc/hexanes afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[3-bromo-6-(3,3-difluoroazetidin-1-yl)pyridin-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one contaminated with a minor impurity. This material was used in subsequent reactions without further purification. LCMS=575.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.89 (s, 1H), 7.78 (s, 2H), 7.63 (d, J=8.7 Hz, 1H), 6.24 (d, J=8.7 Hz, 1H), 5.75 (d, J=8.4 Hz, 1H), 4.87 (d, J=17.1 Hz, 1H), 4.23-4.40 (m, 6H), 0.79 (d, J=7.6 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19].[Br:20]Br.[K+].[Br-]>ClCCl>[Br:20][C:11]1[S:12][C:4]2[CH:3]([N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3=[O:19])[CH:2]([OH:1])[C:7]([CH3:8])([CH3:9])[O:6][C:5]=2[CH:10]=1
Reactant: BrBr
Reactant: CC1(C)Oc2ccsc2C(N2CCCCC2=O)C1O
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: CC1(C)Oc2cc(Br)sc2C(N2CCCCC2=O)C1O

Procedure:
The title compound was prepared as described in Example 4 starting with 5,6-dihydro-6-hydroxy-5,5-dimethyl-7-(2-oxopiperidin-1-yl)-7H-thieno[3,2-b]pyran (1.4 g, 5.0 mmol) and bromine (0.27 mL, 5.2 mmol) in dichloromethane (30 mL). Purification by flash chromatography using 1% methanol in dichloromethane as the eluant and recrystallization from dichloromethane/hexanes gave the product, 3.87 g (78%), as a colorless solid: mp 200°-202° C.; IR (KBr): 3442, 2942, 1616, 1571 and 1488 cm-1 ; MS: m/z 360 (MH+); 1H NMR (CDCl3): δ1.29(s, 3H), 1.46(s, 3H), 1.82(m, 4H), 2.51(m, 2H), 3.12(m, 1H), 3.27(m, 1H), 3.46(d, J=5.0 Hz, 1H, exchanges with D2O), 3.78(d, d, J=9.0 Hz, J=5.0 Hz, 1H, simplifies to d, J=9.0 Hz, with D2O), 5.74(d, J=9.0 Hz, 1H) and 7.58(s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[F:11][C:12]([F:17])([F:16])[C:13](N)=[NH:14].FC(F)(F)C(O)=O>CCO>[F:11][C:12]([F:17])([F:16])[C:13]1[NH:14][C:7](=[O:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1
Reactant: N=C(N)C(F)(F)F
Reactant: COC(=O)c1sccc1N
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(C(F)(F)F)nc2ccsc12
Temperature: 150 °C
Yield: 27.7 %

Procedure:
To a stirring solution of methyl 3-aminothiophene-2-carboxylate (45a, 1.57, 10.0 mmol) in EtOH (10 mL) was added trifluoroacetamidine (2.24 g, 2 eq) and trifluoroacetic acid (1.54 ml, 2 eq). The resulting mixture was heated to 150° C. for 1 hour in microwave reactor. The reaction mixture was cool and filtered to provide 2-(trifluoromethyl)thieno[3,2-d]pyrimidine-4(3H)-one 45b as a solid (0.61 g). 1H NMR (400 MHz, MeOD) δ ppm: 7.49 (d, J=5.29 Hz, 2H), 8.18 (d, J=5.29 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:29]([O:31][CH2:32][CH3:33])=[CH2:30])CCC>CN(C=O)C.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>[CH2:32]([O:31][C:29]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]([CH3:23])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:30])[CH3:33]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(OCC)c1ccc2ncc(C(C)c3cc4cnn(C)c4cc3F)n2n1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 64.5 %

Procedure:
To a solution of 6-chloro-3-(1-(6-fluoro-1-methyl-1H-indazol-5-yl)ethyl)imidazo[1,2-b]pyridazine (900 mg, 1.910 mmol) in DMF (8 mL) was added Pd(Ph3P)4 (221 mg, 0.191 mmol). The mixture was stirred for 20 min, and tributyl(1-ethoxyvinyl)stannane (784 mg, 2.102 mmol) was added. The resulting mixture was heated at 100° C. until LC-MS showed the reaction was complete. The reaction mixture was filtered through celite and the solid was washed with ether. The combined filtrate was washed with water, dried over Na2SO4, and concentrated. The residue was purified by column chromatography with gradient hexane:EtOAc to give 450 mg (52%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]([O-:29])(=[S:28])[CH3:27].[K+].O>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:10][S:28][C:26](=[O:29])[CH3:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CC(C)C)NC(=O)OC(C)(C)C)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)SC[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 90.4 %

Procedure:
To 1.00 g of toluene-4-sulfonic acid (S)-2-tert-butoxycarbonylamino-4-methyl-pentyl ester in 10 ml DMF were added 308 mg of potassium thioacetate. After 24 h at room temperature, the reaction was poured unto water, the pH was then adjusted to 9 and the mixture was extracted with ethyl acetate twice. The combined organic phases were washed with brine until neutral, dried over sodium sulphate and concentrated in vacuo. 0.67 g (90%) of Thioacetic acid S—((S)-2-tert-butoxycarbonylamino-4-methyl-pentyl)ester were obtained.
Reaction SMILES: COC(=O)C1C(C)=CC(C2C=CC=C(C(F)(F)F)C=2)=NC=1OC.Cl[C:25]1[N:30]=[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])[C:28]([CH3:44])=[CH:27][C:26]=1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=1.CC1(C)C(C)(C)OB([C:63]2[CH:64]=[N:65][NH:66][CH:67]=2)O1>>[CH3:44][C:28]1[C:29]([C:31]([N:33]2[CH2:38][CH2:37][CH:36]([N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[CH2:35][CH2:34]2)=[O:32])=[N:30][C:25]([C:63]2[CH:64]=[N:65][NH:66][CH:67]=2)=[C:26]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([C:51]([F:54])([F:53])[F:52])[CH:46]=2)[CH:27]=1
Reactant: Cc1cc(-c2cccc(C(F)(F)F)c2)c(Cl)nc1C(=O)N1CCC(N2CCCC2)CC1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1OC
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)c(-c2cn[nH]c2)nc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for the preparation of intermediate 5C, [6-chloro-3-methyl-5-(3-trifluoromethyl-phenyl)-pyridin-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 3) was reacted with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give the title compound as colorless amorphous solid. MS: 484.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:33]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=1)[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3]([C:9](=[N:24][O:25][CH:33]([C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)[CH3:34])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(Br)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(ON=C(CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.2 %

Procedure:
To a suspension of 200 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 211 mg of potassium carbonate in 2 ml of N,N-dimethylformamide, 155 mg of 1-(1-bromoethyl)-4-fluorobenzene was added, and the mixture was stirred at room temperature for 18 hours. After completion of the reaction, the reaction mixture was mixed with 3 ml of water and extracted with ethyl acetate (3 ml×2), the resulting organic layers were combined, washed with water (3 ml×1) and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 5:95 to 50:50) as the eluent to obtain 171 mg of the desired product as a pale yellow resinous substance.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:4])=[O:3].[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:7](=[O:9])[C:6]3[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: CS(=O)(=O)c1ccccc1C(=O)O
Product: CC(C)CCNC(=O)c1ccc(N2CCN(C(=O)c3ccccc3S(C)(=O)=O)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2-methanesulfonylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (97% yield). 1H NMR (400 MHz, CDCl3) δ 8.11, 8.03, 7.85, 7.74-7.62, 7.38, 4.32-3.33, 3.27, 1.73-1.62, 1.52-1.46, 0.94. MS (ES+) m/z 484.3 (M+1).
Reaction SMILES: [OH-].[Na+].O.NN.[Br:6][C:7]1[CH:8]=[C:9]([Cl:17])[C:10]([OH:16])=[C:11]([C:13](=O)[CH3:14])[CH:12]=1>C(O)COCCOCCO>[Br:6][C:7]1[CH:12]=[C:11]([CH2:13][CH3:14])[C:10]([OH:16])=[C:9]([Cl:17])[CH:8]=1
Reactant: CC(=O)c1cc(Br)cc(Cl)c1O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: CCc1cc(Br)cc(Cl)c1O
Temperature: 160 °C
Yield: 82.8 %

Procedure:
Sodium hydroxide (1.2 g, 30 mmol) and hydrazine monohydrate (1.75 mL, 36 mmol) were added to a solution of 5′-bromo-3′-chloro-2′-hydroxyacetophenone (3 g, 12 mmol) dissolved in triethylene glycol (15 mL). The reaction mixture was heated to 160° C. for 72 hours and then partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated. The residue was purified by flash silica gel chromatography (0% to 10% EtOAc in hexanes) to give the title compound (2.34 g, 83%). 1H NMR (400 MHz, CDCl3): δ 1.22 (t, J=7.6 Hz, 3 H), 2.65 (q, J=7.6 Hz, 2 H), 5.55 (s, 1 H), 7.17 (s, 1 H), 7.31 (s, 1 H).
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(CC)CC.[N:37]([CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[C:38]=[O:39].C(=O)([O-])O.[Na+]>C1COCC1>[F:29][C:3]([F:2])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][N:12]([C:38]([NH:37][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42])=[O:39])[CH2:11][C@H:10]1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)CN=C=O
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the compound (35 mg) obtained in Example 1 and Et3N (22 μl) in THF (2.0 ml), ethyl isocyanatoacetate (11 mg) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, an aqueous saturated sodium hydrogen carbonate solution was added, and then the product was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and then the solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC to obtain the title compound.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.Br.C(O)(=O)C>O>[OH:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1
Reactant: COc1ccc(Oc2cccc(C(=O)O)c2)cc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cccc(Oc2ccc(O)cc2)c1
Temperature: 25 °C

Procedure:
A mixture of 73 g of 3-(4-methoxyphenoxy)benzoic acid, 300 ml of 48% hydrobromic acid, and 600 ml of acetic acid was heated at reflux for 48 hours. The reaction mixture was allowed to cool to ambient temperature, poured into cold water, and extracted with ethyl acetate. The organic extracts were dried and concentrated in vacuo. The residue was crystallized from ethyl/hexane providing 39.41 g of the desired subtitle intermediate, m.p. 172°-174° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10]O)=[CH:3][CH:2]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][Cl:14])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCCc1ccncc1
Solvent: ClC(Cl)Cl
Product: ClCCCCc1ccncc1
Temperature: 25 °C

Procedure:
A solution of 4-(4-pyridinyl)-1-butanol (Mayer J. M. and Testa, B., -Helv. Chim. Acta 65, pages 1868-1884 (1982) (4.20 g, 27.7 mmol) in 30 mL of chloroform is cooled to 0° C. and treated with thionyl chloride (6.60 g, 55.54 mmol) in 30 mL of chloroform. The reaction is allowed to warm to room temperature over 15 hours. The volatiles are removed in vacuo. The residue is cooled to 0° C. and treated with 50 mL of cold 10% sodium hydroxide solution and the mixture is extracted with three 100-mL portions of chloroform. The combined organic extracts are dried over sodium sulfate and the solvents are removed under reduced pressure to give 4.25 g of 4-(4-pyridinyl)-1-butylchloride as a brown oil.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[N:11][C:10]([O:16][CH3:17])=[CH:9][CH:8]=2.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[CH2:18]([O:25][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[N:11][C:10]([O:16][CH3:17])=[CH:9][CH:8]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2ncc(Cl)c(C#N)c2n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(OCc3ccccc3)c(C#N)c2n1
Temperature: -30 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
Sodium hydride (70 mg, 1.73 mmol, 2.0 eq) is added at −30° C. to a stirred solution of 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile (190 mg, 0.87 mmol, 1.0 eq) and benzyl alcohol (187 mg, 1.73 mmol, 2.0 eq) in tetrahydrofuran (12 mL). After 2 hours stirring at −30° C., the reaction mixture is concentrated and extracted with ethyl acetate (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-carbonitrile as a light yellow solid (160 mg, 64% yield).
Reaction SMILES: CN(C=O)C.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:29][CH2:28][N:27]([C:30]4[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=4)[CH2:26][CH2:25]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15].Cl[CH2:38][C:39]1[CH:44]=[CH:43][N+:42]([O-:45])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]2[N:21]=[C:20]([C:22]([N:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]([O:36][CH2:38][C:39]5[CH:44]=[CH:43][N+:42]([O-:45])=[CH:41][CH:40]=5)=[CH:34][CH:35]=4)[CH2:28][CH2:29]3)=[O:23])[CH:19]=[CH:18][CH:17]=2)[CH:11]=[CH:12][C:13]=1[O:14][CH3:15]
Reactant: [O-][n+]1ccc(CCl)cc1
Reactant: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(O)cc4)CC3)n2)cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(-c2cccc(C(=O)N3CCN(c4ccc(OCc5cc[n+]([O-])cc5)cc4)CC3)n2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
To a DMF (10 ml) solution of 1.50 g of 4-{4-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]piperazin-1-yl}phenol were added 1.00 g of 4-chloromethylpyridine-N-oxide and 3.00 g of cesium carbonate, followed by 30 minutes of stirring at room temperature. After warmed to 60° C., the mixture was further stirred for 30 minutes. Then, 1.00 g of 4-chloromethylpyridine-N-oxide and 1.50 g of cesium carbonate were added thereto and the whole was stirred at 60° C. for 1 hour. After cooling to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate, and thereafter, the solvent was evaporated. The residue was purified by silica gel column chromatography (chloroform-methanol) and then recrystallization was carried out from ethanol to obtain 440 mg of 1-[6-(3,4-dimethoxyphenyl)pyridine-2-carbonyl]-4-[4-(1-oxido-4-pyridylmethoxy)phenyl]piperazine as pale yellow crystals.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15].ClCCl.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(N(CC)CC)C>[CH3:19][S:20]([OH:22])(=[O:1])=[O:21].[OH:1][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[NH:7][C:6]1=[O:15]
Reactant: CS(=O)(=O)Cl
Agent: Cc1ccc2c(c1)[nH]c(=O)n2CCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Reaction time: 1 h

Procedure:
To a stirred solution of 18.5 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one in 325 parts of dichloromethane are added 11.9 parts of N,N-diethylethanamine. Then there are added dropwise (slowly) 11.5 parts of methanesulfonyl chloride. Upon completion, stirring is continued for 1 hour at reflux temperature. After cooling, the reaction mixture is washed with water, dried, filtered and evaporated. The solid residue is crystallized from 4-methyl-2-pentanone, yielding 15 parts (58%) of 1,3-dihydro-1-(3-hydroxypropyl)-5-methyl-2H-benzimidazol-2-one methanesulfonate; mp. 125° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[C:12]1[NH:13][C:14]2[C:19]([C:20]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2.[H][H]>[Pd].CO.O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][CH2:11][C:12]1[NH:13][C:14]2[C:19]([C:20]=1[S:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: [H][H]
Reactant: C(=C/c1[nH]c2ccccc2c1Sc1ccccc1)\c1nc2ccccc2o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: c1ccc(Sc2c(CCc3nc4ccccc4o3)[nH]c3ccccc23)cc1

Procedure:
A solution of trans-2-(2-benzoxazol-2-ylethenyl)-3-phenylthioindole (0.420 g, 1.14 mmol) in 1:1 methanol/tetrahydrofuran (250 mL) was stirred under 1 atmosphere of hydrogen in the presence of 10% palladium on charcoal (100 mg). Additional catalyst was added as needed to drive the reaction to completion. The catalyst was removed by filtration, and the filtrate concentrated in vacuo. The resulting solid was triturated with 10% ethyl acetate in hexane and collected by filtration to afford the title compound, mp 192°-193° C. Anal. calc. for C23H18N2OS: C, 72.80; H, 5.04; N, 7.38. Found: C, 72.78; H, 4.95; N, 7.45.
Reaction SMILES: [CH3:1][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:16]1[NH:17][CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:3].CN1CCOCC1.Br[CH2:36][C:37](=[O:40])[CH2:38][CH3:39]>CN(C=O)C>[CH3:3][C:2]([CH3:27])([O:4][C:5]([NH:7][C@H:8]([C:16]1[N:17]([CH2:36][C:37](=[O:40])[CH2:38][CH3:39])[CH:18]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6])[CH3:1]
Reactant: CCC(=O)CBr
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nc(-c2ccccc2)c[nH]1
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC(=O)Cn1cc(-c2ccccc2)nc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a solution of 2-[1(S)-{(1,1-dimethylethoxy)carbonylamino}-2-phenylethyl]4-phenyl-1H-imidazole (100 mg, 1 eq) in DMF (2 mL) were successively added morpholinomethyl polystyrene resin (Novabiochem, loading: 3.51 mmol/g, 159 mg, 2 eq) and 1-bromo-2-butanone (28 mL, 2 eq). After about 18 hours of stirring at about 20° C., 2 mL DMF were added to the reaction mixture followed by aminomethylpolystyrene resin (Novabiochem, loading: 1.73 mmol/g, 319 mg). The mixture was stirred overnight at 20° C. and filtered. The filtrate was concentrated under reduced pressure and then purified by a rapid filtration on a silica gel pad (Alltech silica cartridges) with ethylacetate as eluent to yield 107 mg (90% yield) of the title compound. NMR (1H, 400 MHz, CDCl3) δ: 7.80-6.98 (m, 11H, arom. H), 5.45 (d, 1H, NH), 4.80 (m, 1H, CH), 4.40 (AB, J=18 Hz, NCH2CO), 3.33 (m, 2H, CH2Ph), 2.25 (m, 2H, CH2CH3), 1.0 (t, 3H, CH3). LC/MS: calculated MW=433.5, m/z=434.2 (M+H), m/z=432.2 (M−H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([NH2:9])[N:3]=1.C(O)(=O)C.[N:14]([O-])=[O:15].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([OH:8])[C:5]([N:14]=[O:15])=[C:4]([NH2:9])[N:3]=1
Reactant: Nc1cc(O)nc(N)n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1nc(N)c(N=O)c(O)n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
To a solution of 2,6-diamino-4-hydroxypyrimidine (12.9 g, 102.2 mmoles) in 200 ml of a 10% acetic acid solution in water at 80° C. was added dropwise a solution of NaNO2 (7.05 g, 102.2 mmoles) in 20 ml water. A pink precipitate was formed, which was further stirred for 1 hour at 80° C. The reaction mixture was cooled down in the refrigerator overnight. The precipitate was filtered off and dried over P2O5, providing the title compound as a pink powder (15.43 g, yield: 97%). The spectral data are in accordance with literature data (Landauer et al. in J. Chem. Soc. (1953) 3721–3722).