Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[CH:9][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1.Cl[CH:17]([CH3:19])[CH3:18].ClC1N=CC2C(C(=O)C)=CN(C3CCCC3)C=2N=1>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:17]([CH3:19])[CH3:18])=[CH:9][N:8]([CH:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)[C:6]=2[N:7]=1
Reactant: Clc1ncc2ccn(C3CCCC3)c2n1
Reactant: CC(C)Cl
Agent: CC(=O)c1cn(C2CCCC2)c2nc(Cl)ncc12
Product: CC(C)c1cn(C2CCCC2)c2nc(Cl)ncc12

Procedure:
2-Chloro-7-cyclopentyl-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidine is prepared from 2-chloro-7-(cyclopentyl)-7H-pyrrolo[2,3-d]pyrimidine and 2-chloropropane using a method similar to that for the preparation of 1-(2-Chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-ethanone given in Example 325.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([CH3:20])[CH2:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]([CH2:14][C:15]([O:17]CC)=[O:16])([CH:12]=[CH2:13])[CH2:5]1.O.Cl>CO>[CH3:3][C:4]1([CH3:20])[CH2:9][C:8]([CH3:10])([CH3:11])[CH2:7][C:6]([CH2:14][C:15]([OH:17])=[O:16])([CH:12]=[CH2:13])[CH2:5]1
Reactant: C=CC1(CC(=O)OCC)CC(C)(C)CC(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=CC1(CC(=O)O)CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
A solution of NaOH (1.03 g, 25.8 mmol) and acetate 16 (1.3 g, 5.15 mmol) in methanol (26 ml) was refluxed for 3 h. The mixture was cooled to room temperature and poured into water (100 ml). The aqueous phase was acidified by conc. aqueous HCl and extracted with hexane (330 ml). The combined organic phases were washed with brine and dried over CaCl2, filtered and evaporated. The residue was purified by flash chromatography on silica gel (light petroleum ether-ethyl acetate, 10:1) to give 17 (0.7 g, 71%) as a colorless solid with m.p. 92-94° C. 1H-NMR (CDCl3, TMS): 0.92 (6H, s, 3,5-CH3); 1.02 (6H, s, 3,5-CH3); 1.00-1.30 (4H, m, 4-CH2 and 2,6-CH); 1.90 (2H, d, 14 Hz, 2,6-CH); 2.27 (2H, s, CH2C═O); 5.11 and 5.13 (total 2H, both d, 11 and 18 Hz, ═CH2); 5.99 (1H, dd, 18 and 11 Hz, ═CH) and 10.80 ppm (1H, br s, COOH).
Reaction SMILES: C(OC([NH:11][C@H:12]([C:16]([O:18][CH2:19][CH:20]([O:40][CH2:41][N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][C:43]1=[O:49])[CH2:21][O:22][C:23](=[O:39])[C@H:24]([CH:36]([CH3:38])[CH3:37])[NH:25]C(OCC1C=CC=CC=1)=O)=[O:17])[CH:13]([CH3:15])[CH3:14])=O)C1C=CC=CC=1.C1CC=CCC=1>[Pd].C(O)(=O)C>[NH2:25][C@H:24]([C:23]([O:22][CH2:21][CH:20]([O:40][CH2:41][N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[N:44][C:43]1=[O:49])[CH2:19][O:18][C:16](=[O:17])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH2:11])=[O:39])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OCn1ccc(N)nc1=O
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CC(=O)O
Product: CC(C)[C@H](N)C(=O)OCC(COC(=O)[C@@H](N)C(C)C)OCn1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cool mixture of 3.44 g of 2-((4-amino-1,2-dihydro-2-oxo-1-pyrimidinyl)methoxy)-1,3-propanediyl bis(N-((benzyloxy)carbonyl)-L-valinate) and 7 g of 10% palladium catalyst in acetic acid was slowly added 8.65 mL of 1,4-cyclohexadiene. The mixture was allowed to stir at room temperature for 18 h. The reaction mixture was filtered through a pad of Celite. The filtrate was then concentrated and dried in the lyophilizer for 48 h. The resulting beige foam was scraped off affording 2.38 g (68%, as the acetic acid salt) of the title compound. The elemental analysis (showing 2M of acetic acid and 1M of water) UV, 1H, 13C-NMR spectra were consistent with the title structure.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=2)[CH:10]=[N:9][CH:8]=1)(=O)=O.[C:28]([N:31]1[CH2:36][CH2:35][C:34]([C:38]2[CH:43]=[CH:42][C:41](B3OC(C)(C)C(C)(C)O3)=[CH:40][CH:39]=2)([OH:37])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]>>[C:28]([N:31]1[CH2:36][CH2:35][C:34]([C:38]2[CH:43]=[CH:42][C:41]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH:15]=4)[CH:10]=[N:9][CH:8]=3)=[CH:40][CH:39]=2)([OH:37])[CH2:33][CH2:32]1)(=[O:30])[CH3:29]
Reactant: C[Si](C)(C)CCOC(=O)c1ccc2cncc(OS(=O)(=O)C(F)(F)F)c2c1
Reactant: CC(=O)N1CCC(O)(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CC(=O)N1CCC(O)(c2ccc(-c3cncc4ccc(C(=O)OCC[Si](C)(C)C)cc34)cc2)CC1
Yield: 99.9 %

Procedure:
Using 2-(trimethylsilyl)ethyl 4-{[(trifluoromethyl)sulfonyl]oxy}isoquinoline-6-carboxylate (800 mg, 1.90 mmol) and 1-acetyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperidin-4-ol (983 mg, 2.85 mmol) synthesized in Reference Example 10, the desired title compound (931 mg, yield 100%) was obtained by the same method as in Reference Example 4 (4a).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[SH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.[CH:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:15]1([C:14]2[S:13][C:12]3[C:11]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:5]=[CH:4][C:3]=3[N:2]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cnc2ccccc2c1S
Agent: Cl
Solvent: CCO
Product: c1ccc(-c2nc3cnc4ccccc4c3s2)cc1

Procedure:
A mixture of 20.52 g (0.1 mole) of 3-amino-4-mercapto-quinoline-hydrochloride, 10.61 g (0.1 mole) of freshly distilled benzaldehyde and 200 ml of ethanol is refluxed for 2 hours, whereupon air is bubbled through the reaction mixture for several days. The precipitated crystals are filtered and recrystallized from ethanol. Thus 13.5 g of 2-phenyl-thiazolo[4,5-c]quinoline are obtained. The melting point of this product is identical with that of the compound prepared according to Example 5.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].C[Si](C#N)(C)C.[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([S:23](Cl)(=[O:25])=[O:24])=[C:18]([CH3:27])[C:17]=1[CH3:28].CO>C(#N)C>[CH3:14][O:15][C:16]1[CH:21]=[C:20]([CH3:22])[C:19]([S:23]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])(=[O:24])=[O:25])=[C:18]([CH3:27])[C:17]=1[CH3:28]
Reactant: N[C@H](CO)C(=O)O
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Agent: C[Si](C)(C)C#N
Solvent: CO
Solvent: CC#N
Product: COc1cc(C)c(S(=O)(=O)N[C@H](CO)C(=O)O)c(C)c1C
Temperature: 80 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a suspension of D-serine (6.95 g, 66.1 mmol) in acetonitrile (100 mL) was added trimethylsilyl cyanide (40 mL, 298 mmol) and the resulting solution was heated to 80° C. After 1 h, 4-methoxy-2,3,6-trimethylbenzenesulfonyl chloride (17.3 g, 69.4 mmol) was added and the heating was continued. After 12 h, the reaction mixture was cooled to room temperature. Methanol (15 mL) was added, and the organics were removed in vacuo. The residue was diluted with diethyl ether (300 mL) and after cooling the reaction mixture to 0° C., the pH was adjusted to 8 with 6 N aqueous sodium hydroxide solution. The organic layer was collected and the aqueous layer was extracted with diethyl ether. The aqueous layer was adjusted to pH 4 and again extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford 2(R)-(4-methoxy-2,3,6-trimethylbenzene-sulfonylamino)-3-hydroxypropionic acid (20.5 g) as a brown foam which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:31]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:25])[F:26])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1cccc(C(F)(F)F)c1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 3-trifluoromethylphenylboronic acid (105 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate. (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 7-trifluoromethyl-4-(3-trifluoromethyl-phenyl)-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: [P:1]([OH:4])([OH:3])[OH:2].Cl.[NH:6]1[CH:10]=[C:9]([CH2:11][C:12]([OH:14])=O)[N:8]=[CH:7]1.P(Cl)(Cl)Cl>ClC1C=CC=CC=1>[OH:14][C:12]([P:1]([OH:4])(=[O:2])[OH:3])([P:1]([OH:4])(=[O:3])[OH:2])[CH2:11][C:9]1[N:8]=[CH:7][NH:6][CH:10]=1
Reactant: OP(O)O
Reactant: O=C(O)Cc1c[nH]cn1
Agent: Cl
Solvent: ClP(Cl)Cl
Solvent: Clc1ccccc1
Product: O=P(O)(O)C(O)(Cc1c[nH]cn1)P(=O)(O)O
Temperature: 110 °C
Reaction time: 0.17 h

Procedure:
3 g. Phosphorous acid are added to 3.5 g. imidazol4-ylacetic acid hydrochloride (m.p. 198-200° C.) in 40 ml. chlorobenzene. The reaction mixture is stirred for 10 minutes at 110° C., cooled and 9 g. phosphorus trichloride slowly added dropwise thereto. The reaction mixture is heated for 16 hours to 110° C., cooled, the chlorobenzene is decanted off from an orange-coloured syrup and the residue is mixed with 50 ml. 6N hydrochloric acid. The suspension is heated under reflux for 5 hours, cooled, mixed with charcoal and filtered off with suction. The filtrate is evaporated, dried and boiled up with acetone for 2 hours. The residue (4.3 g.) is dissolved in water, the solution is adjusted with 2N aqueous sodium hydroxide solution to a pH of 5, mixed with methanol and the precipitate obtained is filtered off with suction. There are obtained 1.2 g. (about 16.9% of theory) of the desired product; m.p.>290° C. The compound is obtained as the monosodium salt containing 2 moles of water of crystallisation (Mrel =0.37).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=O)[CH3:10].[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1/[C:9](=[N:27]/[NH:26][C:24](=[O:25])[C:23]1[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]2[CH2:16][CH2:17][O:12][CH2:13][CH2:14]2)(=[O:19])=[O:20])[CH:22]=1)/[CH3:10]
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CC(=O)c1cc(Cl)ccc1Cl
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cc(Cl)ccc1Cl
Temperature: 120 °C

Procedure:
1-(2,5-Dichlorophenyl)ethanone (20 mg, 0.106 mmol) and 3-(morpholinosulfonyl)benzohydrazide (30.2 mg, 0.106 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography affording the title compound in a 10 mg yield. 1H NMR (400 MHz, CDCl3): δ 8.29 (m, 1H), 8.09 (m, 1H), 7.81 (m, 1H), 7.57 (m, 1H), 7.40 (m, 1H), 7.26 (m, 2H), 3.52 (m, 4H), 2.91 (m, 4H), 2.28 (s, 3H). ESI-MS: 456.1 [M+H]+.
Reaction SMILES: [CH:1]([CH:3]=O)=[O:2].[CH2:5]([NH:12][N:13]=[CH:14][C:15](=[O:17])[CH3:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.CO>[CH2:5]([N:12]1[CH:16]=[C:15]([OH:17])[C:14]([C:1](=[O:2])[CH3:3])=[N:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)C=NNCc1ccccc1
Reactant: O=CC=O
Solvent: CO
Solvent: O
Product: CC(=O)c1nn(Cc2ccccc2)cc1O
Temperature: 25 °C
Yield: 33 %

Procedure:
To a 40% aqueous solution of glyoxal (8.28 g, 6.55 mL, 57.1 mmol) was added a slurry of 2-oxopropanal benzylhydrazone (10.1 g, 57.1 mmol) in water (250 mL) and methanol (25 mL). The resulting mixture was heated at reflux for 3 hours before cooling to room temperature. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated. The crude material was purified by CombiFlash (120 g column, 0-100% EtOAc/heptane gradient) to provide 1-(1-benzyl-4-hydroxy-1H-pyrazol-3-yl)ethanone (4.07 g, 33%).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22]>C(OCC)C>[CH2:19]([NH:23][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCN
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCC(=O)NCCCC

Procedure:
An amount of 137.4 g of palmitoyl chloride in 100 ml of ethyl ether was added, under stirring at room temperature, to 80.5 g of n-butylamine in 700 ml of ethyl ether. Stirring was continued under gentle reflux for one hour. The precipitate was filtered off and thoroughly washed with water. The reaction product was recrystallized from ethanol giving 148.4 g of the title compound, melting point 74°-76° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:11]([CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:10])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: CNC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(Cc1ccc(Cl)nc1)C1CCCC1
Temperature: 80 °C
Yield: 77.2 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (318 mg, 1.96 mmole) in 4 mL of dry acetonitrile is 395 mg (3.92 mmol) of N-methylcyclopentylamine followed by 270 mg (1.96 mmol) of potassium carbonate. The reaction is heated at 80° C. for 20 h. After cooling, the reaction mixture is quenched with 5 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 340 mg (77% yield) of (6-Chloro-pyridin-3-ylmethyl)-cyclopentyl-methyl-amine. Diagnostic 1H NMR (400 MHz, CDCl3) 1.40–1.90 (m, 4H), 2.15 (s, 3H), 2.78–2.89 (m, 1H), 3.56 (s, 2H), 7.29 (d, 1H, J=8.3 Hz), 7.70–7.80 (m, 1H), 8.28 (d, 1H, J=2.1 Hz); MS 225.3 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1F)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([N:8]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[NH:34][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1F)C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1NCc1ccccc1)C(=O)OC(C)(C)C
Yield: 71 %

Procedure:
Using the compound obtained in Example 263 as a starting material and also using benzylamine as a reagent, the same procedure of Example 264 gave the titled compound (yield, 71%).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23]O)=[N:20][C:19]([O:25][CH3:26])=[CH:18][CH:17]=2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH2:5]([O:12][C:13]1[C:22]([CH2:23][Br:2])=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([O:25][CH3:26])=[N:20]2)=[N:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2ncc(OCc3ccccc3)c(CO)c2n1
Reactant: BrP(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2ncc(OCc3ccccc3)c(CBr)c2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.5 %

Procedure:
Phosphorus tribromide (32 μL, 0.34 mmol, 2.0 eq) is added at room temperature to a stirred solution of (3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-yl)-methanol (50 mg, 0.17 mmol, 1.0 eq) in dichloromethane (5 mL). After 1 hour stirring at room temperature, pH of the reaction mixture is adjusted to 7 by the addition of a sodium carbonate aqueous solution. The resulting solution is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to afford 7-benzyloxy-8-bromomethyl-2-methoxy-[1,5]naphthyridine as a white solid (62 mg, 99% yield).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][Cl:18])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7].[ClH:37].[CH3:38][C:39]1([CH3:45])[CH2:44][O:43][CH2:42][CH2:41][NH:40]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:18].[ClH:37].[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14]/[CH:15]=[CH:16]/[CH2:17][N:40]2[CH2:41][CH2:42][O:43][CH2:44][C:39]2([CH3:45])[CH3:38])[CH2:10][C@H:9]1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22]([CH3:27])[CH:21]=1)=[O:7]
Reactant: CC1(C)COCCN1
Reactant: Cc1ccc(C[C@@H]2CN(C/C=C/CCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C[C@@H]2CN(C/C=C/CN3CCOCC3(C)C)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reaction time: 6 h
Yield: 64 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-[(E)-4-chloro-2-butenyl]-2-(3,4-dimethylbenzyl)piperazine (450 mg), 3,3-dimethylmorpholine hydrochloride (130 mg) and powdered potassium carbonate (350 mg) in dry acetonitrile (5 ml) was heated at reflux temperature for 3 hours. Additional potassium carbonate (350 mg) and 3,3-dimethylmorpholine hydrochloride (130 mg) were added and then the resulting mixture was further heated at reflux temperature. After 6 hours, the reaction mixture was cooled and then filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using a mixture of dichloromethane and methanol (50:1). The obtained product was dissolved in ethyl acetate and treated with 4N hydrogen chloride in ethyl acetate solution to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-[(E)-4-(3,3-dimethylmorpholino)-2-butenyl]piperazine dihydrochloride (370 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[C:10]([C:12]2[S:13][C:14]([O:18][CH3:19])=[C:15]([CH3:17])[N:16]=2)[CH:9]=[CH:8][C:6]=1[NH2:7])(=[O:4])=[O:3].[H-].[Na+].Cl[S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][C:33]([F:35])=[CH:34][C:28]=2[C:27]=1[CH3:36])(=[O:25])=[O:24].Cl>CC(N(C)C)=O.C1COCC1>[F:35][C:33]1[CH:32]=[CH:31][C:29]2[S:30][C:26]([S:23]([NH:7][C:6]3[CH:8]=[CH:9][C:10]([C:12]4[S:13][C:14]([O:18][CH3:19])=[C:15]([CH3:17])[N:16]=4)=[CH:11][C:5]=3[S:2]([CH3:1])(=[O:3])=[O:4])(=[O:24])=[O:25])=[C:27]([CH3:36])[C:28]=2[CH:34]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(F)cc12
Reactant: COc1sc(-c2ccc(N)c(S(C)(=O)=O)c2)nc1C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Product: COc1sc(-c2ccc(NS(=O)(=O)c3sc4ccc(F)cc4c3C)c(S(C)(=O)=O)c2)nc1C
Temperature: -25 °C
Reaction time: 0.17 h
Yield: 70.5 %

Procedure:
Under an argon atmosphere, 41 mg of 2-methanesulfonyl-4-(5-methoxy-4-methylthiazol-2-yl)aniline was dissolved into a mixed solution of 3 mL of THF and 3 mL of dimethylacetamide. The solution was cooled to −25° C. and 15 mg of sodium hydride (oily, 60%) was added thereto, followed by 10 minutes of stirring at the same temperature. Further, 44 mg of 2-chlorosulfonyl-5-fluoro-3-methylbenzo[b]thiophene was added and the whole was stirred for 2 hours at the same temperature, followed by termination of the reaction with 1 mol/L hydrochloric acid. After the reaction mixture was warmed to room temperature, the mixture was extracted with ethyl acetate-toluene (2/1) and the organic layer was washed with water and saturated brine, successively. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed by evaporation under reduced pressure and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 51 mg of the title compound as light yellow powder.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.N12CCCN=C1CCCCC2.P(Cl)(Cl)(OC1C=CC=CC=1)=O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Br)ccc1C(N)=O
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cc(Br)ccc1C#N
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 53.4 %

Procedure:
A solution of 4-bromo-2-methoxybenzamide (508 mg, 2.21 mmol) in anhydrous DCM (10 mL) was cooled to 0° C. and then treated with 1,8-diazabicyclo(5.4.0)undec-7-ene (0.991 mL, 6.62 mmol). The mixture was stirred at 0° C. for 15 min, and then treated with phenyl dichlorophosphate (0.660 mL, 4.42 mmol) over 2 min. The reaction was stirred at 0° C. for 10 min, and then warmed to RT where it stirred for 1 h. After this time, the mixture was partitioned between DCM (10 mL) and saturated NH4Cl (20 mL). The aqueous phase was extracted with DCM. The combined extracts were dried (MgSO4) and concentrated to give the crude product, which was purified by flash chromatography (12 g SiO2 column; 0-30% EtOAc/Hex gradient) to give 4-bromo-2-methoxybenzonitrile (250 mg, 1.18 mmol, 53% yield) as a white solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.40 (1H, s), 7.16 (1H, s), 7.12 (1H, s), 3.91 (3H, s).
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:14]1([CH:21]=[CH:20][CH:19]=[C:17]([OH:18])[CH:16]=1)[OH:15]>CN(C)C=O>[Si:6]([O:15][C:14]1[CH:16]=[C:17]([OH:18])[CH:19]=[CH:20][CH:21]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: Oc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc(O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 48.1 %

Procedure:
Imidazole (4.3 g, 62 mmol) and t-butyldimethylsilylchloride (5.5 g, 36 mmol) were added to a solution of resorcinol (2.8 g, 25 mmol) and dimethylformamide (100 mL) in a 250 mL round bottom flask under a nitrogen atmosphere at room temperature. The solution was heated in a 60° C. oil bath and allowed to stir for 2 hours. The resulting mixture was cooled to room temperature. The reaction was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (3×200 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (40 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 2.7 g (48%) of 3-((t-butyldimethylsilyl)oxy)phenol.