Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3([CH2:18][NH2:19])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:20][C:21]([F:37])([F:36])[C:22]1[O:26][N:25]=[C:24]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[N:23]=1>>[C:1]1([C:7]2[S:8][CH:9]=[C:10]([C:12]3([CH2:18][NH:19][C:30](=[O:31])[C:29]4[CH:33]=[CH:34][CH:35]=[C:27]([C:24]5[N:23]=[C:22]([C:21]([F:37])([F:36])[F:20])[O:26][N:25]=5)[CH:28]=4)[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCC1(c2csc(-c3ccccc3)n2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2csc(-c3ccccc3)n2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 45 %

Procedure:
This compound was synthesized from (4-(2-phenylthiazol-4-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (85 mg, yield 45%). 1H NMR (400 MHz, DMSO-d6) δ 8.56 (t, J=6.2 Hz, 1H), 8.41 (m, 1H), 8.18 (d, J=7.8 Hz, 1H), 8.05 (d, J=7.6 Hz, 1H), 7.91-7.89 (m, 2H), 7.69-7.65 (t, J=7.8 Hz, 1H), 7.53 (s, 1H), 7.46-7.43 (dd, J=4.8 Hz, 1.9 Hz, 3H), 3.79-3.76 (m, 2H), 3.54-3.52 (d, J=6.2 Hz, 2H), 3.37 (m, 2H), 2.26-2.22 (d, J=13.8 Hz, 2H), 1.89-1.84 (m, 2H). MS (ESI) m/z: Calculated for C24H21F3N4O3S: 514.13. found: 515.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[C:17]1(C)C=CC=C[CH:18]=1>C(O)C>[CH2:17]([O:10][C:9]([C:3]1[C:2]([Br:1])=[CH:7][CH:6]=[C:5]([Cl:8])[N:4]=1)=[O:11])[CH3:18]
Reactant: O=C(O)c1nc(Cl)ccc1Br
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOC(=O)c1nc(Cl)ccc1Br

Procedure:
To a solution of 3-bromo-6-chloropicolinic acid (21, 8.0 g, 33.83 mmols) in a mixture of toluene (80 mL) and ethanol (40 mL) was added sulfuric acid (0.66 mL, 6.76 mmols). The reaction mixture was refluxed for 16 h, then allowed to cool, and partitioned between CHCl3 (200 mL) and saturated aq. NaHCO3 (250 mL). The aqueous layer was extracted with CHCl3 (2×100 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated to give crude product which was purified by column chromatography (Silica gel 10% EtOAc in hexane) to yield title compound 22 (9.0 g, quantitative) as transparent oil. 1H NMR 400 MHz (DMSO-d6) δ: 8.31 (d, J=8.6 Hz, 1H), 7.68 (d, 1H, J=8.2 Hz), 4.39 (q, J=7.0 Hz, 2H), 1.33 (t, J=7.2 Hz, 3H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:26])([F:25])[F:24])[CH:17]=3)[CH2:13][CH:12]([C:27](O)=[O:28])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.[F:30][C:31]1[CH:32]=[C:33]([C:37](=[N:39]O)[NH2:38])[CH:34]=[CH:35][CH:36]=1>>[F:30][C:31]1[CH:32]=[C:33]([C:37]2[N:39]=[C:27]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18]([C:23]([F:25])([F:24])[F:26])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:28][N:38]=2)[CH:34]=[CH:35][CH:36]=1
Reactant: NC(=NO)c1cccc(F)c1
Reactant: Cc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F
Product: Cc1ccc(C2CC(c3nc(-c4cccc(F)c4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1C(F)(F)F

Procedure:
100 mg (0.24 mmol) of the compound from Example 163A and 55 mg (0.36 mmol) of 3-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 2. Yield: 71 mg (55% of theory).
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12].C1C=CC=CC=1>O>[C:11]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][CH2:9][CH:7]([OH:8])[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=1)([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1ccc(CCN)cc1
Reactant: O=CC(=O)c1ccccc1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CCNCC(O)c2ccccc2)cc1
Reaction time: 2 h

Procedure:
Phenyl glyoxal (0.8 g) and 2-(4-carbomethoxyphenyl)ethanamine (1.1 g) were heated in refluxing benzene (100 ml) under a Dean and stark head until the theoretical amount of water had been collected. The solvent was replaced with methanol and sodium borohydride (2.0 g) was added portionwise with ice cooling. The mixture was stirred for 2 hours, the solvent was evaporated and the residue was partitioned between water and ethyl acetate. The dried organic extract was evaporated and crystallised from benzene/hexane, mp 105°-106°. (CDCl3) 6.80-7.60 (8H, m), 6.18 (3H, s), 5.34 (1H, m), 2.94 (2H, d, J=8 Hz), 2.77 (5H, m), 2.09 (2H, d, J=8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:12])[C:8](Br)=[CH:9][N:10]=1)=[O:5])[CH3:2].[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15]>CCN(CC)CC.C1COCC1.[Cu]I.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[N:7]([CH3:12])[C:8]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[CH:9][N:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc(Br)n1C
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1ncc(C#C[Si](C)(C)C)n1C
Temperature: 70 °C
Reaction time: 12 h
Yield: 24.1 %

Procedure:
To a solution of 800 mg (3.43 mmol) of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid ethyl ester in Et3N (10 mL) and THF (10 mL) was added 33 mg (0.17 mmol) of CuI and 120 mg (0.10 mmol) of Pd(PPh3)4. Trimethylsilylacetylene (0.48 mL, 3.4 mmol) was then added and the reaction was heated at 70° C. under N2. After 12 h, the mixture was cooled and filtered though a pad of celite, and then concentrated and chromatographed (0-50% EtOAc in hexanes) to give 1-methyl-5-trimethylsilanylethynyl-1H-imidazole-2-carboxylic acid ethyl ester as a brown oil (205 mg).
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C\C(C)c1cccc(C)c1)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: Cc1cccc([C@H](C)[C@@H]2C[C@@]2(C)CO)c1
Temperature: -25 °C
Reaction time: 0.25 h
Yield: 45 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 6.92 g, 8.4 mmol) was placed into a 100-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −25° C. Chloroiodomethane (2.96 g, 16.8 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −20 and −25° C. After completion of the dropwise addition, the mixture was stirred at −10 to −20° C. for 15 minutes, and then cooled to −25° C. At the same temperature, (E)-2-methyl-4-(3-methylphenyl)pent-2-en-1-ol (0.80 g, 4.2 mmol) was added dropwise over a period of 20 minutes. After completion of the dropwise addition, the stirring was continued at −10 to −25° C. for 20 minutes. Next, a 20% aqueous sulfuric acid solution (3.1 ml) was added. After stirring for 10 minutes, the aqueous layer was separated, and the organic layer was washed twice with water (10 ml). The solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1). [(1R*,2S*)-1-Methyl-2-((R*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.38 g, 1.9 mmol, 45% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-(3-methylphenyl)ethyl)cyclopropyl]methanol (0.014 g, 0.069 mmol, yield 1.6%) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=4)[S:18][C:12]=3[C:11]2=[O:27])=[CH:6][C:5]=1[O:28][CH3:29].O.[OH-].[Li+].Cl>O1CCOCC1.O>[CH3:29][O:28][C:5]1[CH:6]=[C:7]([N:10]2[CH2:15][CH2:14][C:13]3[CH:16]=[C:17]([C:19]4[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=4)[S:18][C:12]=3[C:11]2=[O:27])[CH:8]=[CH:9][C:4]=1[C:3]([OH:30])=[O:2]
Reactant: COC(=O)c1ccc(N2CCc3cc(-c4ccc(OC)cc4)sc3C2=O)cc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3c(s2)C(=O)N(c2ccc(C(=O)O)c(OC)c2)CC3)cc1

Procedure:
Dissolve 2-methoxy-4-[2-(4-methoxy-phenyl)-7-oxo-4,7-dihydro-5H-thieno[2,3-c]pyridin-6-yl]-benzoic acid methyl ester (0.2274 g, 0.54 mmol) in dioxane (10 mL) and add lithium hydroxide monohydrate (124 mg, 2.69 mmol) followed by water (5 mL). Stir the reaction at RT overnight, dilute with water (10 mL), and acidify with 1 N HCl. Collect the solid by filtration and wash with water (2×10 mL) and Et2O (2×10 mL). Dry the solid in a vacuum oven to give 0.145 g (66%). LC-MS/ES m/z 410.3 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4].[CH2:9]([C:15](=[CH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:16]=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[OH:17][CH:16]([C:15](=[CH:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]([CH3:1])([CH2:6][CH2:7][CH3:8])[C:3]([OH:5])=[O:4]
Reactant: CCCC(C)C(=O)O
Reactant: CCCCCCC(C=O)=Cc1ccccc1
Product: CCCCCCC(=Cc1ccccc1)C(O)C(C)(CCC)C(=O)O

Procedure:
The reaction of 5.8 g (0.05 mole) 2-methylvaleric acid with 10.8 (0.05 mole) of α-hexylcinnamaldehyde was conducted in the manner described in Example III, Method B. The product was isolated as a viscous yellow oil. NMR spectra confirmed the title structure.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[NH:10][C@H:11]([CH:21]([CH3:23])[CH3:22])[C:12]([NH:14][CH2:15][CH:16](OC)OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O.C([O-])([O-])=O.[Na+].[Na+]>>[CH:21]([C@@H:11]1[C:12](=[O:13])[NH:14][CH:15]=[CH:16][N:10]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])([CH3:22])[CH3:23]
Reactant: COC(CNC(=O)[C@H](NC(=O)OCc1ccccc1)C(C)C)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)[C@@H]1C(=O)NC=CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.4 %

Procedure:
(R)-benzyl(1-((2,2-dimethoxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (335 g, 0.99 mol) was added in portions to a cooled TFA-H2O (temperature <5° C., VTFA/VH2O=7/3, 2 L), and the solution was stirred at rt for 12 h. The solution was added slowly into stirring cooled sat. aq. Na2CO3 (2.5 L) to keep the pH>8. The mixture was extracted with EtOAc (5×2 L). The combined organic layers were washed with brine (2 L), dried over anhydrous Na2SO4, filtered and evaporated in vacuo to give (R)-benzyl 2-isopropyl-3-oxo-3,4-dihydropyrazine-1(2H)-carboxylate as a white solid (259 g, 95.4%), which was used for next step without further purification. LC-MS m/z 274.9 [M+H]+. 1H NMR (CD3OD 300 MHz): δ7.36-7.34 (m, 5H), 6.33-6.30 (m, 1H), 5.79-5.68 (m, 1H), 5.26-5.13 (m, 2H), 4.38-4.29 (m, 1H), 2.01-1.96 (m, 1H), 1.00-0.84 (m, 6H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH2:7].Cl[CH:9]([C:15](=O)[CH3:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl>C(O)C.CCOCC>[CH2:13]([O:12][C:10]([C:9]1[N:1]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]2=[N:7][C:15]=1[CH3:16])=[O:11])[CH3:14]
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: Nc1cnccn1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc2cnccn12
Yield: 57.9 %

Procedure:
A solution of pyrazin-2-amine (3.6 g, 37.9 mmol) and ethyl 2-chloro-3-oxobutanoate (5.24 ml, 37.9 mmol) in ethanol (30 ml) was heated at reflux for 9 hours. A 1N solution of HCl in ether was added and the mixture was concentrated under reduced pressure. The residue was triturated with 3×50 ml acetonitrile and filtered to yield crude 2-Methyl-imidazo[1,2-a]pyrazine-3-carboxylic acid ethyl ester (4.5 g, 58%) as an amorphous solid which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=O)[C:4]([CH3:9])([CH3:8])[CH2:5][O:6]C.[C:11](#[N:13])[CH3:12].[H-].[Na+].Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:6])[CH2:12][C:11]#[N:13]
Reactant: COCC(C)(C)C(=O)OC
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COCC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 90.7 %

Procedure:
A solution of 1.74 g (12 mmol) of 3-methoxy-2,2-dimethyl-propionic acid methyl ester and 0.9 mL (17 mmol) of acetonitrile in toluene (5 mL) is added dropwise to the refluxing suspension of 0.67 g (17 mmol) of sodium hydride (60% in mineral oil) in toluene (5 mL). After the addition, the reaction mixture is stirred at reflux for 3 h. After this time, the reaction mixture is cooled to room temperature and neutralized to pH˜6-7 by adding 1M aqueous HCl solution. The aqueous layer is extracted with ethyl acetate (3×20 mL). The organic layers are combined, washed with brine (1.5 L), dried over Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to yield 1.69 g of 5-methoxy-4,4-dimethyl-3-oxo-pentanenitrile as a brown oil, which is used in the next step without further purification. Yield: 91%; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.1 (6H, s), 3.2 (3H, s), 3.3 (sH, s), 4.2 (2H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].CCN(CC)CC.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[C:17]([O:9][C:3]1[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=1[F:1])(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccc(F)c(O)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(F)c(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
To a solution of 4-fluoro-3-hydroxytoluene (3.784 g, 30 mmol)) in CH2Cl2 (50 mL) was added NEt3 (5 mL) and the mixture stirred at room temperature for 0.5 h. Benzoyl chloride (4.22 mL, 30 mmol) was then added and the reaction stirred at room temperature for 18 h. The reaction was concentrated in vacuo and the residue redissolved in Et2O (200 mL), washed with water (100 mL), 2N NaOH (2×30 mL) and brine (20 mL). The ethereal layer was dried (Na2SO4) and concentrated in vacuo to give 3-benzoyloxy-4-fluorotoluene as a white solid (6.601 g, 96%), which was used without futher purification. δH (400 MHz, CDCl3) 2.36 (s, 3H), 7.01-7.12 (m, 3H), 7.49-7.55 (m, 2H), 7.63-7.68 (m, 1H), 8.19-8.23 (m, 2H); LRMS (FAB+) m/z (rel. intensity) 231.1 (100, [M+H]+)
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH2:8]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:25](Cl)=[O:26])[CH:22]=2)[CH2:17]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].Cl>O.O1CCOCC1>[CH2:8]([CH:16]1[CH2:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([C:25]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:26])[CH:22]=2)[CH2:17]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: NCC(=O)O
Reactant: CCCCCCCCC1Cc2ccc(C(=O)Cl)cc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCCCC1Cc2ccc(C(=O)NCC(=O)O)cc2C1
Yield: 66.5 %

Procedure:
1.10 g (14.7 mM) of glycine, 0.29 (7.25 mM) of NaOH, 5.8 ml of distilled water were placed in a 100 ml-three necked flask and dissolved to prepare a solution. To the solution, 5.8 ml of dioxane was added, followed by stirring or a ice-common salt bath. To the mixture, a solution of 0.29 g (7.25 mM) of NaOH in 2.5 ml of distilled water and a solution of 2.14 g (7.29 mM) of 2-octylindan-5-carbonyl chloride in 10 ml of dioxane were gradually added dropwise at the same time at -1° to 3° C. by means of a dropping funnel, respectively, followed by stirring for 30 minutes at 1°-2° C. After the reaction, 0.87 ml of concentrated HCl was added to the reaction mixture to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by drying and recrystallization from methanol to obtain 1.61 g of N-(2-octylindan-5-carbonyl)glycin (Yield: 66.6%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]1[C:14](C)=[N:15][N:16]=[C:9]1[CH:8]=[C:7]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([O-:3])=[O:2].I([O-])(=O)(=O)=[O:25].[Na+]>[Ru](=O)=O>[N+:1]([C:4]1[CH:13]=[CH:12][C:11]([N:10]2[CH:14]=[N:15][N:16]=[C:9]2[CH3:8])=[C:6]([CH:5]=1)[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:25])([O-:3])=[O:2]
Reactant: Cc1nnc2cc(-c3ccccc3)c3cc([N+](=O)[O-])ccc3n12
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Product: Cc1nncn1-c1ccc([N+](=O)[O-])cc1C(=O)c1ccccc1

Procedure:
In the manner given in Example 3, 7-nitro-1-methyl-5-phenyl-s-triazolo[4,3-a]quinoline is oxidized at low temperature with sodium periodate and ruthenium dioxide to give 5-nitro-2-(3-methyl- 4H-1,2,4-triazol-4-yl)-benzophenone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][N:9]=[C:10]([C:15](=[O:19])[CH2:16][O:17][CH3:18])[C:11]([O:13][CH3:14])=[O:12].[CH3:20]OC(OC)N(C)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH:20]=[C:16]([O:17][CH3:18])[C:15](=[O:19])[C:10]([C:11]([O:13][CH3:14])=[O:12])=[N:9]1
Reactant: COCC(=O)C(=NNc1ccccc1F)C(=O)OC
Reactant: COC(OC)N(C)C
Product: COC(=O)c1nn(-c2ccccc2F)cc(OC)c1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
A solution of methyl 2-[(2-fluorophenyl)hydrazono]-4-methoxy-3-oxobutanoate (5.02 g, 18.7 mmol) in N,N-dimethylformamide dimethyl acetal (35 mL) was refluxed for 1 h. After cooling to room temperature, the precipitate was collected by filtration and washed with hexane/AcOEt (2/1) to give the title compound (4.70 g, 90% yield) as off-white crystals: mp 155-157° C.; 1H NMR (300 MHz, CDCl3): δ ppm 3.91 (3H, s), 3.97 (3H, s), 7.29-7.36 (2H, m), 7.44-7.51 (1H, m), 7.65 (1H, dt, J=1.9, 7.9 Hz), 7.77 (1H, d, J=2.3 Hz). Anal. Calcd for C13H11FN2O4: C, 56.12; H, 3.98; N, 10.07. Found: C, 56.17; H, 3.97; N, 10.25.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23]Cl)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].[CH3:33][N:34]1[CH2:39][CH2:38][CH2:37][CH:36]2[CH2:40][NH:41][CH2:42][CH:35]12>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:25][CH3:26])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:41]4[CH2:40][CH:36]5[CH:35]([N:34]([CH3:33])[CH2:39][CH2:38][CH2:37]5)[CH2:42]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCCC2CNCC21
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCCN(C)C2C1
Temperature: 80 °C
Reaction time: 7 h
Yield: 31.7 %

Procedure:
A mixture of N-(3-chloro-4-fluorophenyl)-6-(3-chloropropoxy)-7-methoxyquinazolin-4-amine (1.50 g), K2CO3 (5.00 g) and 1-methyloctahydro-1H-pyrrolo[3,4-b]pyridine (0.90 g) in 25 mL of DMF was stirred at 80° C. for 7 h, poured into 50 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (0.60 g, 35.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 501.1 (M+1); 1H NMR (400 MHz, d6-DMSO) δ: 1.52-1.62 (m, 4H), 1.97-2.00 (m, 3H), 2.07-2.09 (m, 2H), 2.08-2.11 (m, 4H), 2.51-2.56 (m, 1H), 2.57-2.61 (m, 2H), 2.88-2.92 (m, 2H), 3.94 (s, 3H), 4.18 (t, J=8.6 Hz, 2H), 7.19 (s, 1H), 7.44 (t, J=10.4 Hz, 1H), 7.82 (s, 2H), 8.13 (t, J=6.8 Hz, 1H), 8.50 (s, 1H) ppm.
Reaction SMILES: [C:1]([Cl:5])(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1([C:14]2[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=2)CO)[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.CN(P(N(C)C)(N(C)C)=O)C>C1COCC1>[CH3:6][O:7][C:8]1([C:14]2[CH:21]=[C:20]([CH:19]=[CH:16][CH:15]=2)[CH2:1][Cl:5])[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC1(c2cccc(CO)c2)CCOCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: COC1(c2cccc(CCl)c2)CCOCC1
Reaction time: 0.17 h
Yield: 75.5 %

Procedure:
Carbon tetrachloride (30.3 g, 198 mmol) was added dropwise over 20 minutes to a solution of 3-(4-methxytetrahydropyran-4-yl)benzyl alcohol from Step 4 (29.3 g, 132 mmol) and HMPA (32.2 g, 198 mmol) in THF (400 mL) at 0°-5° C. The mixture was stirred for 10 minutes and then concentrated. Excess Et2O was added and the mixture filtered through a celite pad. The filtrate was concentrated and chromatographed on silica gel using 20% EtOAc in hexane as eluent to obtain 24 g (81%) of the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:26])C=O>C(C1CCNCC1)C1C=CC=CC=1.C(O)C>[CH2:6]([CH:9]1[CH2:14][CH2:26][N:23]([CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:10][CH:11]=2)[CH2:22][CH2:10]1)[C:5]1[CH:20]=[CH:21][CH:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=O
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Agent: c1ccc(CC2CCNCC2)cc1
Solvent: CCO
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-benzylpiperidine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=461.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.Cl.C(OCC)(=[O:12])C>C(O)C>[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([OH:8])=[O:12])[CH:5]=[CH:6]1
Reactant: O=C1NC2C=CC1C2
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CCO
Product: N[C@H]1C=C[C@@H](C(=O)O)C1
Temperature: 25 °C
Yield: 61.2 %

Procedure:
To 4.58 g (42 mmol) of (±)-2-azabicyclo[2.2.1]hept-5-en-3-one, 190 ml of 1N hydrochloric acid was added, and the mixture was refluxed for 2 hours with heating. The solvent was evaporated, and the resulting white crystals were washed with 30 ml of acetone, followed by drying to give 6.59 g of crude crystals of the subject (+)ACP acid. This crude crystals were dissolved in ethanol (20 ml) with heating, and thereafter ethyl acetate (85 ml) was added to the resulting solution, followed by cooling to room temperature. The crystals thus deposited were filtrated to give 4.26 g (25.7 mmol; yield: 61.2%) of the subject (+)ACP acid (melting point: 169-172° C.).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23]/[N:24]=[C:25](/[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)\[CH2:26][C:27]([O:29]CC)=[O:28])=[CH:20][CH:19]=1.O.Cl>O1CCCC1>[CH3:4][C:5]1[O:9][C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:7][C:6]=1[CH2:16][O:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][O:23][N:24]=[C:25]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[CH:20][CH:19]=1
Reactant: CCOC(=O)C/C(=N\OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CON=C(CC(=O)O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
Lithium hydroxide monohydrate (402 mg) was added to a solution of ethyl E-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionate (1.16 g) in tetrahydrofuran (60 ml)-water (40 ml) and stirred at room temperature for 18 hours. Dilute hydrochloric acid was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized to obtain 3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]-3-phenylpropionic acid (1.08 g, yield 99%) as colorless crystals. m.p. 107-108° C.