Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH:10]([OH:12])[CH3:11])=[CH:4][CH:3]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.C(OCC)C>CN(C)C=O.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH:10]([O:12][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)C(Cc1ccc(Br)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
1.54 g of (2RS,3RS)-4-(4-bromophenyl)-3-(4-chlorophenyl)-2-butanol (prepared in the same manner as in Reference Example 1) was dissolved in 45 ml of dimethylformamide, and 1.4 g of tert-butyldimethylsilyl chloride and 1.2 g of imidazole were added thereto, followed by stirring at room temperature for one hour. Ethyl ether and water were added to the reaction solution for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=15/1) to obtain 2.02 g (yield: 99%) of (2RS,3SR)-4-(4-bromophenyl)-2-(tert-butyldimethylsilyloxy)-3-(4-chlorophenyl)butane.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][C:6]([C:8]([OH:10])=[O:9])=[CH:5]1.O1CCCC1.Cl>[Zn].O>[CH3:1][C:2]([CH3:12])([CH3:11])[CH2:3][CH:4]1[CH2:7][CH:6]([C:8]([OH:10])=[O:9])[CH2:5]1
Reactant: CC(C)(C)CC1C=C(C(=O)O)C1
Agent: Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)CC1CC(C(=O)O)C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
3-(2,2-dimethylpropyl)-1-cyclobutenecarboxylic acid (10 g), tetrahydrofuran (100 mL) and 6 N hydrochloric acid (100 mL) were mixed. To the mixture was added zinc (30 g) at ice temperature. The mixture was stirred at 70° C. overnight. After an addition of 6 N hydrochloric acid and water the mixture was filtered. The filtrate was extracted with ethyl acetate (150 mL, 100 mL). The organic layer was washed with brine (100 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo to give the title compound (11.6 g) as a crude product.
Reaction SMILES: C([O:3][C:4](=[O:43])[CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[OH-].[K+]>CCO>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:33]2[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:17]2)[CH:15]=1)[C:4]([OH:43])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4ccccc4c3)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc4ccccc4c3)C2)c1
Temperature: 78 °C

Procedure:
To compound 46a, 4-Methyl-2-[5-(1-naphthalen-2-ylmethyl-piperidin-3-yl)-4′-trifluoromethyl-biphenyl-3-yl]-pentanoic acid ethyl ester (48.4 mg, 0.082mmol) in EtOH (4.1 ml) was added 2M KOH (0.41 ml, 0.82 mmol). The reaction was heated to 78° C. for 1.5 hour, cooled to room temperature, and concentrated in vacuo. Purification via Gilson HPLC, salt exchange with 1N HCl (aqueous) gave the product as a white lyophilate, (27 mg, 56%). 1HNMR (300 MHz, MeOD) δ ppm 0.88-0.96 (m, 7 H) 1.41-1.52 (m, J=6.59, 6.59, 6.59, 6.59 Hz, 1 H) 1.61-1.70 (m, J=7.06, 6.74, 6.74, 2.45 Hz, 1 H) 1.89-2.02 (m, 3 H) 2.04-2.14 (m, 2 H) 3.08-3.05 (m, 3 H) 3.52-3.67 (m, 2 H) 3.75 (t, J=7.91 Hz, 1 H) 4.47-4.61 (m, 2 H) 7.32 (s, 1 H) 7.49-7.64 (m, 5 H) 7.77 (q, J=8.29 Hz, 4 H) 7.91-8.02 (m, 3 H) 8.07 (s, 1 H), Calcd for C32H32F7NO2 (M+H) 559.66, Found 560.4.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:30]=[CH:29][C:14]4[N:15]=[C:16]([N:18]5[C@@H:22]6[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]6[O:20]C5(C)C)[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1.C(Cl)Cl>C(O)(C(F)(F)F)=O>[N:1]1[CH:9]=[C:8]2[C:4]([N:5]([CH2:10][C:11]3[CH:30]=[CH:29][C:14]4[N:15]=[C:16]([NH:18][C@@H:22]5[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]5[OH:20])[S:17][C:13]=4[CH:12]=3)[CH:6]=[N:7]2)=[N:3][CH:2]=1
Reactant: CC1(C)O[C@@H]2CCCC[C@H]2N1c1nc2ccc(Cn3cnc4cncnc43)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cncnc43)cc2s1
Yield: 3.7 %

Procedure:
A solution of (3aR,7aR)-3-(6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)-2,2-dimethyloctahydrobenzo[d]oxazole (220 mg, 0.5 mmol) from Step 7 of this Example in TFA (5 mL) and CH2Cl2 (5 mL) was stirred for 2 h at rt. The mixture was concentrated under reduced pressure and the residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((9H-purin-9-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (7 mg, 4%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 9.17 (s, 1H), 8.96 (s, 1H), 8.74 (s, 1H), 8.01 (d, J=7.5 Hz, 1H), 7.68 (d, J=1.1 Hz, 1H), 7.17-7.36 (m, 2H), 5.50 (s, 2H), 4.78 (d, J=4.5 Hz, 1H), 3.52 (m, 1H), 3.33 (m, 1H), 2.03 (m, 1H), 1.87 (m, 1H), 1.57-1.67 (m, 2H), 1.11-1.34 (m, 4H). LCMS (ESI) m/z 381 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:20]=[N:19][C:14]3[O:15][CH2:16][CH2:17][NH:18][C:13]=3[CH:12]=2)=[CH:3][N:2]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C.Cl>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:18]2[CH2:17][CH2:16][O:15][C:14]3[N:19]=[CH:20][C:11]([C:4]4[C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=[N:2][CH:3]=4)=[CH:12][C:13]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1ccc2c(-c3cnc4c(c3)NCCO4)cncc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cncc5ccccc45)cc32)cc1Br
Reaction time: 3 h
Yield: 23.3 %

Procedure:
Under nitrogen atmosphere, in a 10 ml flask, 7-isoquinolin-4-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (22.6 mg, 0.085 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (42.2 mg, 0.129 mmol) were dissolved in dichloromethane (1.0 ml). After cooling to 0□, triethylamine (0.06 ml, 0.429 mmol) was added thereto at room temperature for 3 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane, and the combined organic layer was dried over anhydrous magnesium sulfate (MgSO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on amine silica eluting with a solvent of ethyl acetate and n-hexane. The fractions containing the product were collected and evaporated to obtain white solid (11.0 mg, 23%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C@@H:20]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH2:21]Br)=[C:13]2[C:18]=1[NH:17][C:16](=[O:19])[CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C)C=O.O>[N:33]([CH2:21][C@@H:20]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:18]2[C:13]=1[CH:14]=[CH:15][C:16](=[O:19])[NH:17]2)[O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])=[N+:34]=[N-:35]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN=[N+]=[N-])c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 25 °C
Yield: 78.3 %

Procedure:
(R)-8-(Benzyloxy)-5-(2-bromo-1-(tert-butyldimethylsilyloxy)ethyl)-quinolin-2(1H)-one (5.0 g, 10.2 mmol) was dissolved in dimethyl formamide (90 mL) and water (10 mL). Sodium iodide (1.7 g, 11.3 mmol) and sodium azide (0.7 g, 11.3 mmol) were added sequentially. The reaction mixture was stirred at RT until all the solid was in solution. The solution was heated at 80° C. for 40 hours then cooled to RT and diluted with water (300 mL). The aqueous layer was extracted with dichloromethane, and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated under reduced pressure. The crude residue was recrystallised from ethyl acetate and iso-hexane to afford the desired compound, (3.6 g, 78%), used without further purification in the next step.
Reaction SMILES: [OH:1][C@@H:2]([C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.O>N1C=CC=CC=1>[CH3:31][C:21]1[CH:26]=[CH:25][C:24]([S:27]([O:4][CH2:3][C@H:2]([C:5]2[CH:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[CH3:12])=[CH:7][CH:6]=2)[OH:1])(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1ccc([C@H](O)CO)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2ccc([C@H](C)NC(=O)OC(C)(C)C)cc2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
4.32 g of the compound [5-2] was dissolved in 50 mL of pyridine, and 3.66 g of p-toluenesulfonyl chloride was added thereto under an ice-cold condition. The reaction mixture was stirred overnight at 0° C., water was added thereto, and then the mixture was extracted with ethyl acetate, and the resulting organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the obtained residue was purified by silica gel column chromatography (eluent:hexane/ethyl acetate=50/50-0/100), to obtain 6.52 g of (2S)-2-(4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-hydroxyethyl 4-methylbenzenesulfonate [5-3] (hereinafter, referred to as the compound [5-3]) as a colorless amorphous.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[N:20]=[C:12]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([I:17])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[I:17][C:16]1[N:11]2[N:10]=[C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)[N:20]=[C:12]2[C:13]([O:18][CH3:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1(c2nc3c(OC)ccc(I)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(I)n2nc(C3(C(=O)O)CC3)nc12
Reaction time: 15 h

Procedure:
1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester (compound 305) (0.06 g, 0.16 mmol) was suspended in 1,4-dioxan (1.4 mL) and LiOH (0.01 g, 0.23 mmol) in H2O (0.23 mL) was added. The suspension was stirred for 15 h. The mixture was concentrated in vacuo. H2O and 4N HCL (0.085 mL) was added. Brine was added and the aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as a slightly coloured solid.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CC(C)=O>[CH:1]1([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Solvent: CC(C)=O
Product: C1CCC(NC2CCCCC2)CC1
Temperature: 20 °C
Yield: 157.9 %

Procedure:
Sodium azide (52.2 g, 0.803 mol) was added to water (200 mL) in a 2 L three-neck flask fitted with a mechanical stirrer and a reflux condenser. A gas outlet tube from the condenser was connected to the sidearm of a 4 L filter flask containing bleach (3 L) in order to destroy the methanethiol evolved during the reaction. A rubber stopper was placed lightly on the top of the filter flask, and the stirred bleach was cooled in an ice bath. Compound 3 (185 g, 0.730 mol) and isopropanol (400 mL) were added to the NaN3 solution, and the thick slurry stirred and slowly heated to reflux. A clear solution was obtained and the evolution of gaseous methanethiol become vigorous before reflux was reached. The heating was discontinued for several minutes to allow the rate of methanethiol evolution to diminish. The solution was then gently refluxed for 1.5 h, after which the light yellow solution was cooled to room temperature. To the solution was added 50% aqueous NaOH solution (73 g, 0.91 mol), raising the solution temperature to 55° C. After 10 min the light orange solution was cooled to 10° C. The solution was acidified with concentrated hydrochloric acid (140 mL); the resulting pH was 3. Another 10 mL of concentrated hydrochloric acid was added, and the separated oil was extracted with dichloromethane (400 and 2×100 mL). The extract was dried (MgSO4), filtered, and evaporated in vacuo to give an oil (170 g). The oil was dissolved in acetone (450 mL) and cooled in an ice bath to 20° C. Cyclohexyl amine (145 g, 1.46 mol) was added with stirring; a precipitate quickly formed. After cooling 0.5 h the solid was filtered and washed with acetone to give the bis-cyclohexylamine salt (4) (209 g, 66%), mp 205° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)C.C1(C)C=CC=CC=1>C(=O)([O-])[O-].[Na+].[Na+].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.O>[C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]([CH:8]2[C:12]3[C:13]([CH3:19])=[CH:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c2c(c1C)OCC2c1ccc(Br)cc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1cc(C)c2c(c1C)OCC2c1ccc(-c2ccccc2)cc1
Yield: 76 %

Procedure:
A mixed solution of 3-(4-bromophenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran obtained in Reference Example 236 (1.0 g, 3.15 mmol), phenylboronic acid (500 mg, 4.10 mmol), tetrakis(triphenylphosphine)palladium(0) (73 mg, 0.063 mmol) in 2 N sodium carbonate aqueous solution (4 mL)-ethanol (4 mL)-toluene (15 mL) was reacted under argon atmosphere at 80° C. for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, was dried over anhydrous sodium sulfate, and then was concentrated under reduced pressure to obtain the residue, which was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain (3-biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran 750 mg (yield 76%). Using this compound, 873 mg of the title compound was synthesized in the same manner as in Reference Example 23. Yield 93%. Melting point: 153-154° C. (methanol).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][N:27]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:22][CH:21]=1)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].CN.CO>>[C:1]([O:5][C:6](=[O:38])[N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][NH2:27])=[CH:24][CH:25]=1)[CH2:8][CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][CH3:15])[CH2:16][CH2:17][CH3:18])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCCN(CCC)CCCCN(Cc1ccc(CN2C(=O)c3ccccc3C2=O)cc1)C(=O)OC(C)(C)C
Agent: CN
Solvent: CO
Product: CCCN(CCC)CCCCN(Cc1ccc(CN)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 124.7 %

Procedure:
The compound (70.0 mg) obtained in Example 25-3 was added with a 40% methylamine/methanol solution (3.0 ml) and then stirred at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was then added with a 1 mol/l sodium hydroxide aqueous solution and chloroform to extract the aqueous layer therefrom with chloroform. The extract was dried with anhydrous sodium sulfate, and the solvent was distilled off, thereby obtaining the subject compound (65.5 mg) as a colorless viscous liquid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]=[C:14]([N:16]3[CH2:22][CH:21]4[O:23][CH:18]([CH2:19][CH2:20]4)[CH2:17]3)[N:13]=[C:12]([N:24]3[CH2:30][CH:29]4[O:31][CH:26]([CH2:27][CH2:28]4)[CH2:25]3)[CH:11]=2)=[CH:6][CH:5]=1)([O-])=O.C(NC1C=CC=CC=1)C>C(O)C.[Pd]>[CH:18]12[O:23][CH:21]([CH2:20][CH2:19]1)[CH2:22][N:16]([C:14]1[N:15]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=3)[CH:11]=[C:12]([N:24]3[CH2:25][CH:26]4[O:31][CH:29]([CH2:28][CH2:27]4)[CH2:30]3)[N:13]=1)[CH2:17]2
Reactant: O=[N+]([O-])c1ccc(-c2cc(N3CC4CCC(C3)O4)nc(N3CC4CCC(C3)O4)n2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCNc1ccccc1
Product: Nc1ccc(-c2cc(N3CC4CCC(C3)O4)nc(N3CC4CCC(C3)O4)n2)cc1
Reaction time: 16 h

Procedure:
In a 250 mL round-bottomed flask was placed 3,3′-(6-(4-nitrophenyl)pyrimidine-2,4-diyl)bis(8-oxa-3-azabicyclo[3.2.1]octane) (22, 89 mg, 0.21 mmol) in ethanol (3 ml). A catalytic amount of Pd on charcoal (wet) was added and the mixture was stirred under a hydrogen atmosphere for 16 hours. The mixture was filtered over Celite™, rinsed with dichloromethane and concentrated to give a quantitative yield of the title compound along with an impurity (the N-ethyl aniline product). The crude mixture was reacted in the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]=[C:6]([F:9])[CH:7]=[O:8].[Na].C1(S)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH2:4]/[CH:5]=[C:6](\[F:9])/[CH:7]=[O:8]
Reactant: O=CC(F)=CCCCCl
Agent: Sc1ccccc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C/C(F)=C/CCCCl

Procedure:
2.35 Grams of 6-chloro-2-fluoro-2-hexenal (E form : Z form =6.8 : 1) was dissolved in 20 ml of dry toluene, and after adding 10 mg of the sodium salt of thiophenol, the resulting solution was heated under reflux for 25 hours with stirring. Thereafter, 10 ml of water was added to the reaction solution, and the toluene layer was separated. The aqueous layer was extracted twice with ether, and the ether extracts were combined with the above toluene layer. This mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 2.35 g of (Z)-6-chloro-2-fluoro-2-hexenal.
Reaction SMILES: C([O:4]C1C=C(C=CC=1Cl)N)C=C.C1(=O)OC(=O)C2=CC=CC=C12.[CH2:24]([C:27]1[C:32]([OH:33])=[C:31]([Cl:34])[CH:30]=[CH:29][C:28]=1[N:35]1[C:39](=[O:40])[C:38]2[CH2:41][CH2:42][CH2:43][CH2:44][C:37]=2[C:36]1=[O:45])[CH:25]=[CH2:26]>>[Cl:34][C:31]1[C:32]2[O:33][CH:25]([CH2:26][OH:4])[CH2:24][C:27]=2[C:28]([N:35]2[C:39](=[O:40])[C:38]3=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]3[C:36]2=[O:45])=[CH:29][CH:30]=1
Reactant: C=CCOc1cc(N)ccc1Cl
Reactant: C=CCc1c(N2C(=O)C3=C(CCCC3)C2=O)ccc(Cl)c1O
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1c1ccc(Cl)c2c1CC(CO)O2

Procedure:
The title compound was prepared, as a white solid, m.p.: 181°-183° C., from 3B and phthalic anhydride in three steps, according to the procedures described for preparing Example 4 from 3D.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[N:3]=1.[S-2:19].[Na+].[Na+].O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])[C:5]([CH:9]=[O:10])=[C:6]([SH:19])[N:7]=1
Reactant: Cc1ccc(-c2nc(N)nc(Cl)c2C=O)c(C)c1
Reactant: [S-2]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc(N)nc(S)c2C=O)c(C)c1
Reaction time: 1 h

Procedure:
2-Amino-4-chloro-6-(2,4-dimethylphenyl)-pyrimidine-5-carbaldehyde was added to a suspension of sodium sulphide (5 eq.) in DMF and the mixture stirred for ˜60 mins, to give a yellow suspension. The suspension was poured into water, and the solution filtered. The filtrate was acidified with acetic acid, to give a yellow precipitate. The solids were removed by filtration and washed with water and hexane, dried in vacuo, to give a yellow powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:11]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([C:24]1[N:33]=[C:32]([C:34]([O:36]C)=[O:35])[C:31]([O:38][S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[N:29]2)[CH3:23])(=[O:21])=[O:20])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Li+].Cl>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:11]=1[C:12]([NH:14][CH2:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([C:24]1[N:33]=[C:32]([C:34]([OH:36])=[O:35])[C:31]([O:38][S:39]([C:42]2[CH:48]=[CH:47][C:45]([CH3:46])=[CH:44][CH:43]=2)(=[O:41])=[O:40])=[C:30]2[C:25]=1[CH:26]=[CH:27][CH:28]=[N:29]2)[CH3:23])(=[O:20])=[O:21])=[O:13])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(N(C)S(=O)(=O)CCCCNC(=O)c2cc(F)ccc2CNC(=O)OC(C)(C)C)c2cccnc2c1OS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Oc2c(C(=O)O)nc(N(C)S(=O)(=O)CCCCNC(=O)c3cc(F)ccc3CNC(=O)OC(C)(C)C)c3cccnc23)cc1
Yield: 41 %

Procedure:
To a solution of methyl 5-(4-(2-((tert-butoxycarbonylamino)methyl)-5-fluorobenzamido)-N-methylbutylsulfonamido)-8-(tosyloxy)-1,6-naphthyridine-7-carboxylate (Example 3.3; 2.75 mmol) in a 1:1 mixture of THF and water (5.5 mL) was added lithium hydroxide (4.13 mmol) at room temperature. After the reaction was finished, ethyl acetate and water were added. The aquous layer was treated with HCl 1N until pH=5-6. The aqueous layer was extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated, to obtain the target material in 41% yield.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5].[C:12]([C:15]1[S:16][C:17]([CH3:20])=[CH:18][CH:19]=1)(=O)[CH3:13].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:20][C:17]1[S:16][C:15]([C:12](=[N:5][C:4]2[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=2[C:2]([F:10])([F:11])[F:1])[CH3:13])=[CH:19][CH:18]=1
Reactant: Nc1ccccc1C(F)(F)F
Reactant: CC(=O)c1ccc(C)s1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=Nc1ccccc1C(F)(F)F)c1ccc(C)s1
Yield: 87.5 %

Procedure:
A solution of 2-(trifluoromethyl)aniline (4.0 q, 25 mmol), 2-acetyl-5-methylthiophene (4.4 g, 31 mmol), and p-toluenesulfonic acid (50 mg) in toluene (30 mL) was heated under reflux with azeotropic removal of water for 10 hours. Then the mixture was concentrated on a rotary evaporator, and the oily residue was distilled under reduced pressure to give 6.2 g (88%) of ketimine 12q as an oil (bp 128°-130° C./0.3 mm Hg).