Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=2)=[O:5])[CH2:3][CH2:2]1.[CH3:16][Si](C)(C)N[Si](C)(C)C.[Li].IC.[Cl-].[NH4+]>O1CCCC1>[CH3:16][C:1]1([C:4]([C:6]2[CH:7]=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][CH:15]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: COC(=O)c1ccc(C(=O)C2CC2)cc1
Agent: [Cl-]
Agent: [Li]
Agent: [NH4+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)C2(C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 8 %

Procedure:
To a solution of methyl 4-(cyclopropylcarbonyl)benzoate (500 mg, 2.45 mmol) in tetrahydrofuran (12 mL) was added dropwise a solution of 1 mol/L lithium hexamethyldisilazane in tetrahydrofuran (3.0 mL, 3.00 mmol) at −78° C. under argon atmosphere, and the mixture was stirred for 15 minutes. To the mixture was added dropwise iodomethane (200 μL, 3.21 mmol) at the same temperature, and the reaction solution was slowly warmed to room temperature and stirred overnight. To the reaction solution was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate three times. The organic layer was combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→97:3) to give methyl 4-[(1-methylcyclopropyl)carbonyl]benzoate (45 mg, 8%) as a colorless oil.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([OH:30])=O)=[CH:24][CH:23]=2)=[O:21])=[N:4][N:3]=[N:2]1.Cl.C[N:35](C)C=O>N.O>[NH:4]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]([C:22]2[CH:32]=[CH:31][C:25]([O:26][CH2:27][C:28]([NH2:35])=[O:30])=[CH:24][CH:23]=2)=[O:21])=[N:1][N:2]=[N:3]1
Reactant: O=C(O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: N
Solvent: O
Product: NC(=O)COc1ccc(C(=O)Nc2ccccc2Sc2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 6 ml of N,N-dimethylformamide was dissolved 0.63 g of 4-[2-[2-(1H-tetrazol-5-yl)phenylthio]phenylcarbamoyl]phenoxyacetic acid (prepared in Example 6) followed by addition of 0.24 g of N,N'-carbonyldiimidazole. The mixture was stirred at room temperature for 1 hour, and then it was poured in 28% aqueous ammonia and stirred for 1 hour. The reaction mixture was diluted with water and, then, acidified with concentrated hydrochloric acid, and the crystals separated out therefrom were collected by filtration and washed with water. The crude crystals thus obtained were recrystallized from N,N-dimethyl-formamide-ethanol to give 0.52 g of the title compound as white crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH3:34])([N:17]2[CH2:22][CH2:21][CH:20]([NH:23][C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[CH:29]4)[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)=[O:10].Cl[CH2:36][C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1.CC1C=CC=C(C)C=1C(N1CCC(C)(N2CCC(=O)CC2)CC1)=O.CN1C2C(=CC=CC=2N)C=C1>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]([N:11]1[CH2:12][CH2:13][C:14]([CH3:34])([N:17]2[CH2:22][CH2:21][CH:20]([N:23]([C:24]3[CH:25]=[CH:26][CH:27]=[C:28]4[C:32]=3[N:31]([CH3:33])[CH:30]=[CH:29]4)[CH2:36][C:37]3[N:38]=[C:39]([CH3:42])[S:40][CH:41]=3)[CH2:19][CH2:18]2)[CH2:15][CH2:16]1)=[O:10]
Reactant: Cc1nc(CCl)cs1
Reactant: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(Nc3cccc4ccn(C)c34)CC2)CC1
Agent: Cc1cccc(C)c1C(=O)N1CCC(C)(N2CCC(=O)CC2)CC1
Agent: Cn1ccc2cccc(N)c21
Product: Cc1nc(CN(c2cccc3ccn(C)c23)C2CCN(C3(C)CCN(C(=O)c4c(C)cccc4C)CC3)CC2)cs1

Procedure:
It is prepared from (2,6-dimethyl-phenyl)-[4′-methyl-4-(1-methyl-1H-indol-7-ylamino)-[1,4′]bipiperidinyl-1′-yl]-methanone and 4-chloromethyl-2-methyl-thiazole using a procedure as described for Example 52 of PCT/EP02/03871. MS/ESI 570 [M+H]+. (2,6-Dimethyl-phenyl)-[4′-methyl-4-(1-methyl-1H-indol-7-ylamino)-[1,4′]bipiperidinyl-1′-yl]-methanone used as starting material may be prepared from 1′-(2,6-dimethyl-benzoyl)-4′-methyl-[1,4′]bipiperidinyl-4-one and 1-methyl-1H-indol-7-ylamine using a procedure as described in Example 51e of PCT/EP02/03871. MS/ESI 459 [M+H]+. 1′-(2,6-Dimethyl-benzoyl)-4′-methyl-[1,4′]bipiperidinyl-4-one may be prepared using a procedure as described in Example 51a-d of PCT/EP02/03871. MS/ESI 329 [M+H]+.
Reaction SMILES: C(O)(=O)C.[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][NH:14][O:15][CH3:16])[CH:9]=[N:10][C:11]=1[Cl:12].[CH2:17]1[C:22](=[O:23])[O:21][CH2:20][C:18]1=O.O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([CH2:13][N:14]([O:15][CH3:16])[C:18]2[CH2:20][O:21][C:22](=[O:23])[CH:17]=2)[CH:9]=[N:10][C:11]=1[Cl:12]
Reactant: O=C1COC(=O)C1
Reactant: CONCc1cnc(Cl)c(Cl)c1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CON(Cc1cnc(Cl)c(Cl)c1)C1=CC(=O)OC1
Yield: 61 %

Procedure:
120 μl (2.04 mmol) of acetic acid and 422 mg (2.04 mmol) of 1-(5,6-dichloropyridin-3-yl)-N-methoxymethanamine (III-3) are added to 224 mg (2.24 mmol) of tetronic acid in 50 ml of toluene, and the mixture is heated under reflux on a water separator for 3 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in ethyl acetate and the mixture is washed successively twice with 1 N aqueous hydrochloric acid, twice with 1 N aqueous sodium hydroxide solution and saturated sodium chloride solution and dried over sodium sulphate. Concentration of the organic phase under reduced pressure and purification of the residue by recrystallization from ethyl acetate gives 360 mg (59% of theory) of 4-[[(5,6-dichloropyridin-3-yl)methyl](methoxy)amino]furan-2(5H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]#[N:10])=[CH:4][CH:3]=1.C1COCC1.CN(C=O)C.[BH4-].[Na+]>O.C(Cl)Cl.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CC(=Cc1ccco1)c1ccc(Cl)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: C1CCOC1
Product: N#CC(Cc1ccco1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 90.4 %

Procedure:
To a flask under a nitrogen atmosphere was added 9.24 g. (0.04 mole) of 2-(4-chlorophenyl)-3-(2-furyl)acrylonitrile in 55 ml. of a 10 to 1 mixture of THF and DMF. While stirring at room temperature, 1.44 g. (0.04 mole) of sodium borohydride in 25 ml. of ethanol was added and the resulting mixture stirred for an additional 18 hours. A mixture of 175 ml. of 6 to 1 methylene chloride and water was added to the reaction while stirring at room temperature. The methylene chloride solution was washed with 10% aqueous hydrochloric acid, dried, and concentrated to give 8.24 g. (90.4% yield) of 2-(4-chlorophenyl)-3-(2-furyl)propionitrile as a thick oil.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[OH:11])=[O:3].C([O-])([O-])=O.[K+].[K+].[Br:18][CH2:19][CH2:20]Br>CC(=O)CC>[Br:10][C:8]1[CH:7]=[CH:6][C:5]([O:11][CH2:20][CH2:19][Br:18])=[C:4]([C:2](=[O:3])[CH3:1])[CH:9]=1
Reactant: CC(=O)c1cc(Br)ccc1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc(Br)ccc1OCCBr
Yield: 69.9 %

Procedure:
To a stirred solution of 5-bromo-2-hydroxyacetophenone (15.29 g; 71 mmol) in 2-butanone (150 ml) was added K2CO3 (21 g; 152 mmol) then 1,2-dibromoethane (30 ml; 350 mmol). The reaction mixture was heated at reflux temperature overnight (17 h), cooled, filtered (acetone washing) and the solvent evaporated. The residue was treated with a mixture of Et2O/EtOAc (4:1; 250 ml) and the resulting solid removed by filtration. The filtrate was washed with 2M NaOH (150 ml), dried (MgSO4) and concentrated to give 1-[5-bromo-2-(2-bromo-ethoxy)-phenyl]-ethanone as an off-white crystalline solid (15.99 g). This solid was dissolved in anhydrous THF (300 ml), cooled to 0° C. and treated with NaH (2.11 g of a 60 wt % suspension in mineral oil; 53 mmol). The reaction mixture was carefully heated to reflux and heating continued overnight (17 h). The reaction mixture was cooled, quenched with 2M HCl (50 ml) and partitioned between brine (300 ml) and EtOAc (200 ml). The organic layer was dried (MgSO4), concentrated and purified by ISCO (hexanes/EtOAc) to give 7-bromo-3,4-dihydro-2H-benzo[b]oxepin-5-one as a pale yellow oil (9.84 g; 57%). δH (400 MHz, CDCl3) 2.24 (quintet, J=6.8, 2H), 2.91 (t, J=6.8, 2H), 4.25 (t, J=6.8, 2H), 6.98 (d, J=8.8, 1H), 7.52 (dd, J=8.8 and 2.8, 1H), 7.90 (d, J=2.8, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>ClCCl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(CC(=O)O)cc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 4-methylphenylacetic acid (1.50 g, 10.0 mmol) in dried dichloromethane was added nitric acid (fuming, 1.5 mL) dropwise. The mixture was stirred at room temperature for 2 hours, then quenched with water and extracted with ethyl acetate. The extracts were washed with water twice and brine, dried over magnesium sulfate, filtered, and concentrated to provide the title compound (1.66 g, 85% yield): 1H NMR (CDCl3) 7.91 (d, 1H), 7.42 (dd, 1H), 7.31 (d, 1H), 3.71 (s, 2H), 2.58 (s, 3H); ES-MS m/z 196 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][N:11]=[C:30]=[O:31])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)Cl
Reactant: NCCc1cccc(C(F)(F)F)c1
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C=NCCc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-(3-trifluoromethylphenyl)ethylamine (5.65 mmol) at 0° C. was added solid Proton sponge (5.65 mmol) then a 20% solution of phosgene in toluene (5.65 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated. 1H-NMR (CDCl3): 7.5 ppm (m, 4H); 3.6 ppm (t, 2H); 2.95 ppm (t, 2H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][C:14]([OH:17])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][CH:19]([N:21]1[N:25]=[N:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C@H:32](O)[CH3:33])[CH2:28][CH2:27]2)=[N:22]1)[CH3:20]>>[CH3:20][CH:19]([N:21]1[N:25]=[N:24][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C@@H:32]([O:17][C:14]3[CH:13]=[N:12][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:16][N:15]=3)[CH3:33])[CH2:28][CH2:27]2)=[N:22]1)[CH3:18]
Reactant: CC(C)n1nnc(N2CCC([C@@H](C)O)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2cnc(O)cn2)cc1
Product: CC(C)n1nnc(N2CCC([C@H](C)Oc3cnc(-c4ccc(S(C)(=O)=O)cc4)cn3)CC2)n1
Yield: 58 %

Procedure:
The title compound (145 mg, 58%) was prepared from 5-[4-(methylsulfonyl)phenyl]-2-pyrazinol (and tautomers thereof) (prepared as in Example 145, Steps 1-2, 125 mg, 0.5 m mol) and (1R)-1-{1-[2-(1-methylethyl)-2H-tetrazol-5-yl]-4-piperidinyl}ethanol (prepared as in Example 190, Step 3, 120 mg, 0.5 mmol) in a manner similar to Example 190, Step 4. Enantiomeric excess was not determined. 1H NMR (400 MHz, DMSO-d6): 8.91 (d, 1H, J=1.4 Hz), 8.41 (d, 1H, J=1.4 Hz), 8.34-8.26 (m, 2H), 8.07-7.99 (m, 2H), 5.13 (quint, 1H, J=6.2 Hz), 4.87 (septet, 1H, J=6.7 Hz), 4.06-3.91 (m, 2H), 3.26 (s, 3H), 2.95-2.78 (m, 2H), 1.96-1.71 (m, 3H), 1.49 (d, 6H, J=6.7 Hz), 1.45-1.35 (m, 2H), 1.32 (d, 3H, J=6.2 Hz); LRMS (ESI), m/z 472 (M+H).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:9])([CH2:7][OH:8])[CH2:5][OH:6].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1COCC1>[NH2:3][C:4]([CH3:9])([CH2:7][O:8][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][OH:6]
Reactant: CC(N)(CO)CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(N)(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 109.4 %

Procedure:
Sodium hydride (55% in dispersion in oil) (1.141 g) was added portion wise to a solution of 2-amino-2-methyl-propane-1,3-diol (2.50 g) in dry THF (35 ml) at 0° C. The reaction mixture was stirred at room temperature for 1 h. tert-Butyldiphenylsilyl chloride (6.54 g) in dry THF (10 ml) was added dropwise 0° C. and the reaction mixture was stirred for 17 hrs at room temperature. The reaction mixture was quenched with water (18 ml) and extracted thrice with ethyl ether. The two layers were separated and the organic layer was washed once with water and then dried over sodium sulphate, filtered and concentrated under reduced pressure to yield 8.94 g of 2-amino-3-(tert-butyl-diphenyl-silanyloxy)-2-methyl-propan-1-ol as a crude product which was used as such in Stage 2 described below. 1H NMR (CDCl3) δ ppm: 7.68-7.62 (4H, m); 7.47-7.37 (6H); 3.52 (2H, dd); 3.39 (2H, dd); 1.09 (9H, s); 1.02 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:45][CH:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCC(N)CC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CN1CCC(Nc2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and 1-methyl-piperidin-4-ylamine according to conditions described in general procedure C. Mp: 128-129° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.41-1.84 (m, 4 H), 2.09 (s, 3 H), 2.66 (bs, 2 H), 3.26-3.80 (m, 3 H), 3.27 (t, J=4.7 Hz, 4 H), 3.76 (t, J=4.7 Hz, 4H), 6.32 (s, 1 H), 7.05 (d, J=12.4 Hz, 2 H), 7.27 (d, J=8.4 Hz, 1 H), 7.40 (d, J=8.0 Hz, 1 H), 7.47 (s, 1 H), 7.55-7.60 (m, 3H), 7.82 (d, J=8.0 Hz, 1 H), 8.00 (d, J=7.7 Hz, 1 H), 8.23 (bs, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@:14]([OH:20])([C@H:17]([OH:19])[CH3:18])[CH2:15][OH:16].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[F:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[C@:14]([OH:20])([C@H:17]([O:19][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:18])[CH2:15][O:16][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@](O)(CO)c1cccc(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: C[C@@H](OS(C)(=O)=O)[C@](O)(COS(C)(=O)=O)c1cccc(F)c1F
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
5.71 g (50 mmol) of methanesulfonyl chloride were added to a solution of 3.51 g (16.1 mmol) of (2R,3 R)-2-(2,3-difluorophenyl)-1,2,3-butanetriol [obtained as described in Step 7(ii) above] in 18 ml of pyridine at 0° C. After stirring the resulting mixture for 0.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the product was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and then washed with aqueous sodium chloride solution and then concentrated under reduced pressure. The resulting residue was purified by chromatography on a silica gel (100 g) column using a 1:1 mixture of ethyl acetate and hexane as the eluant to afford 5.04g (yield 84%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[OH:32])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:43]>C(O)C>[Na+:43].[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[OH:32])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: O=C(O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2O)nc1

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 3 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (182 mg). The resulting 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid (184 mg) is dissolved in ethanol (5 ml), and thereto is added 1N-aqueous sodium hydroxide solution (305 μl), and concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-hydroxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (184 mg). MS (m/z): 598 [M+H]+
Reaction SMILES: C([Mg])=C.ClC1CCCCCCCCCCC1=O.Cl.[OH-].[Na+].[CH:21]([C@@:23]12[O:35][C@@H:34]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH2:22]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.O1CCCC1>[CH:21]([C@@:23]12[O:35][C@H:34]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[CH2:22]
Reactant: C=C[C@]12CCCCCCCCCC[C@H]1O2
Agent: C=C[Mg]
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C[C@]12CCCCCCCCCC[C@@H]1O2
Temperature: 95 °C
Reaction time: 6 h
Yield: 85 %

Procedure:
A four-neck flask equipped with a thermometer, stirrer and condenser tube was charged with a tetrahydrofuran solution of vinylmagnesium (1.31 mol), and toluene (600 ml) was added to the solution. At 0° C., a toluene solution of 2-chlorocyclododecanone (159 g, 0.735 mol) was added dropwise to the solution, for reaction for 1 hour. After completion of reaction, 16% hydrochloric acid (120 g) was added for hydrolysis, and the solution was separated to take out the organic layer. The organic layer was washed with 2% sodium hydroxide aqueous solution (320 ml). To the obtained toluene solution, added were 30% sodium hydroxide aqueous solution (370 g, 2.78 mol) and benzyltriethylammonium chloride (1.86 g 0.00816 mol), and the mixture was stirred for reaction at 95° C. for 6 hours. After completion of reaction, the solution was separated to take out the organic layer, and the organic layer was washed with a saline solution. The solvent was distilled away under reduced pressure, and the residue was distilled for purification under reduced pressure, to obtain 133 g of a distillate. It was analyzed by means of capillary gas chromatography and found to be a mixture containing 61% of cis-1-vinyl-13-oxabicyclo[10.1.0]tridecane and 37% of trans-1-vinyl-13-oxabicyclo[10.1.0]tridecane (yield was 85%). The distillate was partially separated by means of silica gel chromatography for isolation into trans-1-vinyl-13-oxabicyclo[10.1.0]tridecane and cis-1-vinyl-13-oxabicyclo[10.1.0]tridecane.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]#[N:16])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:13])[CH3:12])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-:35].[Na+]>>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]([C:15]([NH2:16])=[O:35])=[C:8]([CH:10]([OH:14])[CH:11]([CH3:12])[CH3:13])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C(O)C(C)C)c(C#N)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Reactant: [OH-]
Agent: [Na+]
Product: CCCCc1nc(C(O)C(C)C)c(C(N)=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Following a procedure similar to that described in Example 74(d), but using 0.34 g of 2-butyl-4-(1-hydroxy-2-methylpropyl)-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carbonitrile [prepared as described in step (c) above] in a 1N aqueous solution of sodium hydroxide, 0.24 g of the title compound was obtained as a powder, melting at 155°-157° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:17]3[C:12](=[N:13][CH:14]=[C:15]([N:18]4[CH2:21][CH:20]([N:22]5[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]5)[CH2:19]4)[CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:31])=CC=1>C(O)(C(F)(F)F)=O>[CH:28]([N:25]1[CH2:26][CH2:27][N:22]([CH:20]2[CH2:19][N:18]([C:15]3[CH:16]=[C:17]4[C:12]([CH:11]=[CH:10][C:9](=[O:31])[NH:8]4)=[N:13][CH:14]=3)[CH2:21]2)[CH2:23][CH2:24]1)([CH3:30])[CH3:29]
Reactant: COc1ccc(Cn2c(=O)ccc3ncc(N4CC(N5CCN(C(C)C)CC5)C4)cc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N1CCN(C2CN(c3cnc4ccc(=O)[nH]c4c3)C2)CC1
Temperature: 25 °C
Yield: 95.5 %

Procedure:
1-(4-methoxybenzyl)-7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-8) (5.6 g, 12.5 mmol, 1.0 eq) was dissolved in TFA (100 mL) and the resulting mixture was stirred at reflux for 16 h. The reaction was complete based on TLC analysis. The mixture was cooled to RT and concentrated in vacuo to remove TFA. The resulting suspension was diluted with water (200 mL) and neutralized with sodium carbonate to adjust the pH value to 8-9 while keeping the temperature below 0° C. The resulting mixture was stirred at RT for 30 min. The solid was collected by filtration, rinsed with water (2×50 mL) and dried in vacuo to afford the desired product 7-(3-(4-isopropylpiperazin-1-yl)azetidin-1-yl)-1,5-naphthyridin-2(1H)-one (C-9) (3.91 g, 95.7% yield) as a white solid. ESI-MS m/z: 328.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:26])C=1>C(Cl)Cl>[C:13]([O:12][C:11]([NH:10][CH2:9][CH2:8][C:4]1[CH:5]=[N+:6]([O-:26])[CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:17])([CH3:14])([CH3:16])[CH3:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCc1cncc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1cc(Cl)c[n+]([O-])c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl (2-(5-chloropyridin-3-yl)ethyl)carbamate (93 mg, 0.36 mmol) in DCM (4 mL) was added 3-chloroperbenzoic acid (85%, 94.8 mg, 0.54 mmol) at 0° C. The resulting reaction mixture was stirred at room temperature for 1.5 h. The reaction was quenched with aqueous solution of sodium thiosulfate and extracted with DCM. The combined organic layers were washed with aqueous solution of potassium carbonate and brine, dried over sodium sulfate and concentrate to give a crude product, which was used directly in the next step without further purification (90 mg, crude). MS (ESI) m/z 273.1 [M+H]+.