Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@@H:8]([NH:17][C:18](=[O:24])[O:19]C(C)(C)C)[C@H:9](O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O>FC(F)(F)C(O)=O>[Br:1][C:2]1[N:7]=[C:6]([C@@H:8]2[C@@H:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:24][C:18](=[O:19])[NH:17]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](c1cccc(Br)n1)[C@H](O)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1N[C@H](c2cccc(Br)n2)[C@@H](c2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(±)-tert-Butyl (1R,2R)-1-(6-bromopyridin-2-yl)-2-hydroxy-2-phenylethylcarbamate (1.1 g, 1.40 mmol) was dissolved in trifluoroacetic acid (25% in dichloromethane, 25 mL) and stirred at room temperature for 1 h. The reaction was concentrated, dissolved in methanol, and loaded onto a strong cation exchange cartridge. The cartridge was flushed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated. The resulting residue was suspended in tetrahydrofuran (25 mL), cooled to 0° C., and treated with carbonyldiimidazole (580 mg, 3.58 mmol) in a single portion. The resulting suspension was stirred at 0° C. for 5 min. The ice bath was removed and stirring continued for 1 h. The reaction was treated with an additional portion of carbonyldiimidazole (90 mg) and stirred at room temperature for 2 h. The reaction was quenched by addition of 2M ammonia in methanol and concentrated. The resulting residue was purified by column chromatography (25%-->50% EtOAc/Hex) to give nearly pure product. The material was further purified by trituration of the solid with diethyl ether. 1H-NMR (CDCl3, 500 MHz) δ 7.65 (dd, J=7.6, 7.6, 1H), 7.52 (d, J=7.6, 1H), 7.37-7.50 (m, 6H), 6.83 (bs, 1H), 5.63 (d, J=5.5, 1H), 4.92 (d, J=5.5, 1H). 13C-NMR (CDCl3, 126 MHz) δ 159.9, 159.2, 142.6, 139.7, 138.2, 129.13, 129.08, 128.2, 125.8, 119.6, 83.6, 64.4. Mass spec.: 319.1 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]([OH:11])=O)=[CH:7][C:6]([C:12]([NH2:14])=[O:13])=[CH:5][CH:4]=1.[F:15][C:16]([F:26])([F:25])[O:17][C:18]1[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=1[NH2:20]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12]([NH2:14])=[O:13])=[CH:7][C:8]=1[C:9]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=1[O:17][C:16]([F:15])([F:25])[F:26])=[O:11]
Reactant: Nc1ccccc1OC(F)(F)F
Reactant: COc1ccc(C(N)=O)cc1C(=O)O
Product: COc1ccc(C(N)=O)cc1C(=O)Nc1ccccc1OC(F)(F)F

Procedure:
The captioned compound was synthesized from 6-methoxyisophthalamic acid and 2-trifluoromethoxyaniline by the same procedure as in the manufacturing method described in step C of Example 1-3-1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][N:4]=1.Br[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[C:26](=[O:30])[N:25]([C:31]1[CH:32]=[N:33][N:34]([CH2:36][C:37]#[N:38])[CH:35]=1)[CH2:24]2.C(=O)([O-])[O-].[Cs+].[Cs+].CCOC(C)=O.O>CS(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:10][O:9][C:8]1[CH:7]=[C:6]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([C:31]2[CH:32]=[N:33][N:34]([CH2:36][C:37]#[N:38])[CH:35]=2)[CH2:24]3)[CH:5]=[N:4][C:3]=1[O:2][CH3:1]
Reactant: N#CCn1cc(N2Cc3cc(Br)ccc3C2=O)cn1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cnc1OC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(-c2ccc3c(c2)CN(c2cnn(CC#N)c2)C3=O)cnc1OC
Temperature: 100 °C

Procedure:
As shown in step 5-iii of Scheme 5, 2,3-dimethoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [Compound 2021, 376 mg, 1.42 mmol; prepared by reacting 5-bromo-2,3-dimethoxypyridine with 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane], 2-[4-(5-bromo-1-oxo-isoindolin-2-yl)pyrazol-1-yl]acetonitrile (450 mg, 1.42 mmol), and cesium carbonate (925 mg, 2.84 mmol) were taken up in DMSO (7.5 mL) in a sealable tube. Nitrogen gas was bubbled through the solution for 5 minutes, dppfPdCl2 (141 mg, 0.17 mmol) added, and the vessel sealed. The reaction mixture was heated to 100° C. for 50 min. After cooling, the mixture was poured into EtOAc/H2O, the resulting dark solid material filtered off, and the organics passed through a plug of florisil. The filtrate was concentrated to a solid under reduced pressure, the residue was suspended in MeOH, and the solid collected by filtration to give 2-[4-[5-(5,6-dimethoxy-3-pyridyl)-1-oxo-isoindolin-2-yl]pyrazol-1-yl]acetonitrile as a solid (Compound 3, 323 mg, 57% yield): ESMS (M+H) 376.28; 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.99 (s, 1H), 7.95 (s, 1H), 7.84 (m, 2H), 7.64 (d, J=1.7 Hz, 1H), 5.55 (s, 2H), 4.93 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[CH:29]1([CH2:32][O:33][C:34]2[N:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH2:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:29]1([CH2:32][O:33][C:34]2[N:39]=[CH:38][C:37]([C:2]3[C:7](=[O:8])[N:6]([CH2:9][C:10]4[CH:15]=[CH:14][C:13]([C:16]5[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=5)=[CH:12][CH:11]=4)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=3[CH2:27][CH3:28])=[CH:36][CH:35]=2)[CH2:30][CH2:31]1
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc(OCC2CC2)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCc1nc(CC)c(-c2ccc(OCC3CC3)nc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 86.5 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.5 g), [6-(cyclopropylmethoxy)pyridin-3-yl]boronic acid (0.38 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution (5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.5 g, 86%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.[C:15](=O)([O:24]N1C(=O)CCC1=O)[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O.CC#N>[CH2:17]([O:16][C:15]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(N)C(=O)O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-amino-2-methyl-propanoic acid (10 g, 96.97 mmol) in water (75 mL) was added triethylamine (13.48 mL, 96.97 mmol) followed by the dropwise addition of a solution of benzyl (2,5-dioxopyrrolidin-1-yl) carbonate (24.17 g, 96.97 mmol) in MeCN (30 mL). The pH was monitored during the addition and afterwards was adjusted with triethylamine (1.5 mL) from pH 7 to 8. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated by removal of MeCN. To the aqueous was added saturated aqueous sodium bicarbonate (2 mL) which gave a suspension. This was filtered and the solid kept to one side. The filtrate was extracted with ether (three times). The aqueous phase was acidified to pH 3 with approximately 1 M aqueous potassium bisulphate and then extracted into EtOAc (three times). The combined EtOAc extracts were dried over magnesium sulphate, filtered and evaporated to yield 2-(benzyloxycarbonylamino)-2-methyl-propanoic acid (D24) as a waxy white solid, 18.001 g;
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]1[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:17]=1.[F-].[K+].[C:26]([O:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])[CH2:27][OH:28].O>O1CCOCC1>[CH2:31]([O:30][C:26]([CH2:27][O:28][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([C:12]2[C:13](=[O:23])[N:14]([CH3:22])[C:15]([C:18]([F:20])([F:21])[F:19])=[CH:16][N:17]=2)=[C:2]([F:1])[CH:7]=1)=[O:29])[CH2:32][CH2:33][CH3:34]
Reactant: CCCCOC(=O)CO
Reactant: Cn1c(C(F)(F)F)cnc(-c2cc([N+](=O)[O-])c(F)cc2F)c1=O
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCCCOC(=O)COc1cc(F)c(-c2ncc(C(F)(F)F)n(C)c2=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 82.4 %

Procedure:
Then, 7.61 g of 3-(2,4-difluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-16) was dissolved in 10 ml of 1,4-dioxane, to which 5.28 g of potassium fluoride and 9.0 g of butyl glycolate were added, and the mixture was heated under reflux for 1.5 hours. After completion of the reaction, the reaction mixture was left cooling to room temperature. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 8.37 g (yield, 82%) of 3-[4-(butoxycarbonylmethoxy)-2-fluoro5-nitrophenyl]-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (the present compound depicted below; m.p., 109.5° C.). ##STR40##
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][C:6]([O-])=[O:7].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[NH2:2][C@H:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH2:5][CH2:6][OH:7]
Reactant: N[C@@H](CCC(=O)[O-])c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N[C@@H](CCCO)c1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 5.8 %

Procedure:
(S)-4-Amino-4-phenylbutyric acid sodium salt (1.48 g) was added in portions to a suspension of lithium aluminum hydride (1.00 g) in THF (100 ml). The mixture was stirred at 50° C. for 4 hours and then admixed successively with water (1 ml), 6 N NaOH solution (3 ml) and again with water (3 ml), and filtered. The filtrate was concentrated and the residue was purified by column chromatography. This gave the product (70 mg) with a molecular weight of 165.2 g/mol (C10H15NO); MS (ESI): m/e=166 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][N:3]=1.[CH3:11][CH:12]1[CH2:24][C:16]2[N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[S:19][C:15]=2[C:14](=[O:25])[CH2:13]1>>[F:1][C:2]1[N:3]=[CH:4][C:5]([C:8]([CH:13]2[CH:12]([CH3:11])[CH2:24][C:16]3[N:17]=[C:18]([NH:20][C:21](=[O:23])[CH3:22])[S:19][C:15]=3[C:14]2=[O:25])=[O:9])=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1ccc(F)nc1
Reactant: CC(=O)Nc1nc2c(s1)C(=O)CC(C)C2
Product: CC(=O)Nc1nc2c(s1)C(=O)C(C(=O)c1ccc(F)nc1)C(C)C2

Procedure:
A-16 is prepared via general procedure A1 starting from 2-fluoropyridine-5-carbonyl chloride (4.27 g, 26.8 mmol) and N-(5-methyl-7-oxo-4,5,6,7-tetrahydro-benzothiazol-2-yl)-acetamide (A-06) (5.00 g, 22.3 mmol). Yield: 6.20 g. HPLC-MS: tR=0.93 min, (M+H)+=348.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:13]>>[CH2:12]([C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10])[CH3:13]
Reactant: CCc1ccccc1N
Reactant: O=C(O)Cc1ccccc1Br
Product: CCc1ccccc1Nc1ccccc1CC(=O)O

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2-ethylaniline to yield 2-[(2-ethylphenyl)amino]phenylacetic acid.
Reaction SMILES: Br[C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:13]([O-:15])=[O:14])=[CH:7][CH:6]=1)=[O:4].[OH-:24].[Na+].O>COCCOC>[OH:24][C:2]([CH3:23])([CH3:22])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)c1ccc(C(CC(=O)[O-])c2ccccc2)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(O)C(=O)c1ccc(C(CC(=O)O)c2ccccc2)cc1
Yield: 85.9 %

Procedure:
A mixture of 64.0 g (0.164 mol) of 3-[4-(2-bromo-2-methylpropionyl)phenyl]-3-phenylpropanoate, 13.2 g (0.328 mol) of sodium hydroxide, 70 ml of water, and 300 ml of 1,2-dimethoxyethane is heated at reflux for 16 hours. The reaction is concentrated, and then acidified with 25 ml of 1.5 N hydrochloric acid solution. Ethyl acetate (200 ml) is added, and the organic layer is washed with distilled water, dried over sodium sulfate, and concentrated. The crude product is passed through a pad of silica gel with ethyl acetate as the eluent to give 44 g (86% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:20]=[C:21](/[CH3:25])\[C:22]([OH:24])=[O:23])[C:6]2[C:11]([C:12]=1[O:13]COC)=[C:10]([CH2:17][CH2:18][CH3:19])[CH:9]=[CH:8][CH:7]=2.O>CC(C)=O.Cl>[OH:13][C:12]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH2:17][CH2:18][CH3:19])[C:5](/[CH:20]=[C:21](/[CH3:25])\[C:22]([OH:24])=[O:23])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(OCOC)c12
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: CCCc1cccc2c(/C=C(/C)C(=O)O)cc(OC)c(O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.6 %

Procedure:
2.2 g of (Z)-3-(3-methoxy-4-methoxymethoxy-5-propyl-1-naphthyl)-2-methylpropenoic acid was dissolved in 40 ml of acetone, to which 2.5 ml of concentrated hydrochloric acid was added under light-shielding conditions, followed by stirring in a stream of nitrogen at room temperature for 2 hours. The reaction mixture was poured into water, and the resultant crystals were filtered, washed with hexane and dried in vacuo to obtain 1.7 g of the titled compound as yellow crystals.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@@H:28]([CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@H](C=C(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](C=C(C)C)CC(=O)O)cc3)ccc2C(C)(C)C)c1
Reaction time: 15 h
Yield: 61.1 %

Procedure:
To a stirred solution of 14.4 (0.048 g, 0.10 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). Stirring was continued for 15 hours. The resulting reaction was concentrated in vacuo. 1N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 14 (30 mg, 64% yield) as a colorless oil. MS ESI (neg.) m/e: 489.2 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[CH3:10][S:11]([C:14]1[CH:19]=[CH:18][C:17](F)=[C:16]([Cl:21])[CH:15]=1)(=[O:13])=[O:12]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([O:9][C:17]2[CH:18]=[CH:19][C:14]([S:11]([CH3:10])(=[O:13])=[O:12])=[CH:15][C:16]=2[Cl:21])[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: Nc1ccc(Cl)cc1O
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)ccc2N)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 3 step viii) using 4-chloro-2-hydroxyaniline and the product from example 3 step vii). Yield 3.0 g.
Reaction SMILES: ClC1N=C(C)N([CH2:8][C:9]2[S:24][C:12]3[N:13]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:14](=[O:19])[N:15]([CH3:18])[C:16](=[O:17])[C:11]=3[C:10]=2[C:25]([N:27]2[CH2:31][C@H:30]([OH:32])[CH2:29][O:28]2)=[O:26])C=1Cl.[NH:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][N:41]=2)[CH:36]=[CH:35]1>>[OH:32][C@@H:30]1[CH2:29][O:28][N:27]([C:25]([C:10]2[C:11]3[C:16](=[O:17])[N:15]([CH3:18])[C:14](=[O:19])[N:13]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:12]=3[S:24][C:9]=2[CH2:8][N:34]2[C:42]3=[N:41][CH:40]=[CH:39][CH:38]=[C:37]3[CH:36]=[CH:35]2)=[O:26])[CH2:31]1
Reactant: Cc1nc(Cl)c(Cl)n1Cc1sc2c(c1C(=O)N1C[C@H](O)CO1)c(=O)n(C)c(=O)n2CC(C)C
Reactant: c1cnc2[nH]ccc2c1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)N3C[C@H](O)CO3)c(Cn3ccc4cccnc43)sc21

Procedure:
The subtitle compound was prepared using the procedure described in example 3 part c) from the product of example 3 part b) and 7-azaindole. MS (APCI) 427 [M+H]+. δ 1HCDCl3 0.85 (3H,s), 0.92 (3H,s), 2.15-2.25 (1H,m), 3.38 (3H,s), 3.66 (3H,d), 4.03 (3H,s), 4.97 (s,2H), 5.61 (2H,s), 6.49-6.91 (1H,d), 7.06-7.14 (1H,m), 7.38 (1H,d), 7.91 -7.95 (1H,m) and 8.31-8.37 (1H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:15].Br.[C:17]1([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+]>O.CC(C)CC(=O)C>[C:23]([CH:25]1[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][C:4]2[C:9](=[O:10])[N:8]3[CH:11]=[CH:12][CH:13]=[CH:14][C:7]3=[N:6][C:5]=2[CH3:15])[CH2:27][CH2:26]1)(=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(c1ccccc1)C1CCNCC1
Reactant: Cc1nc2ccccn2c(=O)c1CCCl
Agent: Br
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: Cc1nc2ccccn2c(=O)c1CCN1CCC(C(=O)c2ccccc2)CC1

Procedure:
A mixture of 5.6 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one, 6 parts of phenyl(4-piperidinyl)-methanone hydrobromide, 8 parts of sodium carbonate, 0.1 parts of potassium iodide and 240 parts of 4-methyl-2-pentanone is stirred and refluxed for 24 hours using a water-separator. The reaction mixture is filtered hot over Hyflo and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from a mixture of ethanol and 1,1'-oxybisethane, yielding 6 parts of 3-[2-(4-benzoyl-1-piperidinyl)ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 122.2° C.
Reaction SMILES: [NH2:1]/[C:2](=[N:19]\[O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[C:25]([C:36]([F:39])([F:38])[F:37])[CH:24]=1)=O)/[C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH3:10])=[CH:5][CH:4]=1>C1(C)C=CC=CC=1>[CH3:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]2[O:20][N:19]=[C:2]([C:3]3[CH:4]=[CH:5][C:6]([C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH3:10])=[CH:7][CH:8]=3)[N:1]=2)=[CH:24][C:25]=1[C:36]([F:39])([F:37])[F:38]
Reactant: Cc1ccccc1-c1ccc(C(=O)O/N=C(\N)c2ccc([C@@H](C)NC(=O)OC(C)(C)C)cc2)cc1C(F)(F)F
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc([C@@H](C)NC(=O)OC(C)(C)C)cc3)no2)cc1C(F)(F)F
Temperature: 100 °C
Yield: 116 %

Procedure:
In a round bottom flask (500 ml), put under nitrogen atmosphere, tert-butyl [(1R)-1-(4-{(Z)-amino[({[2′-methyl-2-(trifluoromethyl)biphenyl-4-yl]carbonyl}oxy)imino]methyl}phenyl)ethyl]carbamate (17 g; 31.39 mmol; 1.0 eq.) was suspended in toluene (170 ml), and then heated at 100° C. After one night, the reaction mixture was concentrated under reduced pressure to give the title compound as a pale yellow oil (19.06 g, quantitative yield). This compound was used in the next step without further purification. LC/MS (Method B): 582.4 (M+AcO)−. HPLC (Method A) Rt 6.57 min (Purity: 99.1%)
Reaction SMILES: [CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[OH:17])[CH:2]([CH2:4][OH:5])[OH:3].C(=O)([O-])O.[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O>[CH2:1]([O:6][C:7]1[C@@H:12]([C@H:13]([CH2:15][OH:16])[OH:14])[O:11][C:9](=[O:10])[C:8]=1[O:17][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:2]([CH2:4][OH:5])[OH:3]
Reactant: CCCCCCCCBr
Reactant: O=C1O[C@H]([C@@H](O)CO)C(OCC(O)CO)=C1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCOC1=C(OCC(O)CO)[C@@H]([C@@H](O)CO)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
Under an argon atmosphere, 3-O-glyceryl ascorbic acid (54.1 g) obtained in Example 1 was stirred in DMSO (200 mL), and further, sodium hydrogen carbonate (18.5 g) was added and the mixture was stirred at room temperature for 30 minutes. Thereafter, octyl bromide (63.7 g) was added and the mixture was heated up to 100° C. and stirred for 3 hours, followed by extraction with ethyl acetate. Then, the extracted liquid was dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and 131 g of the resultant residue was subjected to silica gel column chromatography. Elution was performed with chloroform/methanol/water(volume ratio:10/3/0.4), and concentration was performed under reduced pressure to obtain 3-O-glyceryl-2-O-octyl ascorbic acid (48.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(N2CCN(C)CC2)c1
Reaction time: 4 h

Procedure:
A microwave vessel charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (0.05 g, 0.11 mmol), 1-methylpiperazine (33.1 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in 1-butanol (1.5 mL) was irradiated at 200° C. After 4 hours, the reaction was cooled, evaporated to dryness and the residue was purified with reverse phase liquid chromatography to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([NH:14]C(=NC)SC)#[N:13]>C(#N)C>[CH3:1][C:2]1[NH:3][CH:4]=[N:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][N:11]=[C:12]([NH2:14])[NH2:13]
Reactant: CN=C(NC#N)SC
Reactant: Cc1nc[nH]c1CSCCN
Solvent: CC#N
Product: Cc1[nH]cnc1CSCCN=C(N)N

Procedure:
A solution of 4-methyl-5-[(2-aminoethyl)-thiomethyl]imidazole (17.0 g.) and N-cyano-N',S-dimethylisothiourea (11.2 g.) in acetonitrile (500 ml.) was heated under reflux for 24 hours. Following concentration, the residue was chromatographed on a column of silica gel with acetonitrile as eluant and the product obtained was finally recrystallized from acetonitrile-ether to yield N-cyano-N'-methyl-N"-[2-((5-methyl-4-imidazolyl)methylthioethyl]guanidine, m.p. 141°-142°.