Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].CC[O:13][C:14]([CH2:16][C:17]([C:19]([F:22])([F:21])[F:20])=O)=O>O>[OH:13][C:14]1[N:6]2[N:5]=[CH:4][C:3]([C:7]([O:9][CH3:10])=[O:8])=[C:2]2[N:1]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=1
Reactant: COC(=O)c1cn[nH]c1N
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Solvent: O
Product: COC(=O)c1cnn2c(O)cc(C(F)(F)F)nc12
Reaction time: 16 h

Procedure:
A mixture of 11.5 g of methyl 5-aminopyrazole-4-carboxylate, 16 ml of ethyl ω,ω,ω-trifluoroacetoacetate and 150 g of polyphosphoric acid was heated to 100° while stirring for 16 hours. After cooling to 20°, cold water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with 1N aqueous hydrochloric acid and aqueous saturated sodium chloride solution and then dried over Na2SO4. The solvent was evaporated in a vacuum and the residue was taken up in ether. The solid product was filtered off under suction and recrystallized from 2-propanol. There was obtained an isomer of the product, namely methyl 7-hydroxy-5-(trifluoromethyl)pyrazolo-[1,5-a]pyrimidine-3-carboxylate of m.p. 216-217°. The product enriched in the mother liquors was crystallized from ethyl acetate. There was obtained methyl 5-hydroxy-7-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate of m.p. 149-150°.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:10](=[NH:23])([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.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([O:5][C:3](=[O:4])[CH2:2][N:23]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
In a 50-mL round-bottom flask equipped with a water-jacketed condensor and magnetic stirring bar, a mixture of t-butyl chloroacetate (10 g, 66.4 mmole), benzophenone imine (8.02 g, 44.3 mmole), and anhydrous potassium carbonate (9.18 g, 66.4 mmole) was stirred overnight at 110° C. Using a course Buchner funnel, the solid inorganic salts were removed from the solution by filtration and the solids were washed with ethyl acetate (2×25 mL). The combined filtrates were diluted with ethyl acetate to a total volume of 100 mL. The organic mixture was washed with water (3×100 mL), dried (Na2SO4), filtered, and the solvent was removed in vacuo. The crude residue was recrystallized with hexanes to afford white crystals (5.24 g, 40%): m.p. 114–115° C. (Lit. m.p. 111–112° C.).3 1H-NMR (CDCl3) δ 1.46 (s, 9H), 4.12 (s, 2H), 7.18 (m, 2H), 7.34 (m, 3H), 7.45 (m, 3H), 7.66 (m, 2H). 13C-NMR (CDCl3) δ 28.13, 56.37, 80.99, 127.74, 128.01, 128.27, 128.61, 128.73, 128.76, 130.05, 130.34, 132.39, 136.25, 139.45, 169.82, 171.48
Reaction SMILES: Cl[C:2](Cl)(Cl)[C@H:3]1[O:8][C:7](=[O:9])[C@H:6]([CH3:10])[C@@H:5]([CH3:11])[O:4]1.S(=O)(=O)(O)O.[CH3:19]C(O)C>O>[CH3:10][C@H:6]([C@H:5]([OH:4])[CH3:11])[C:7]([O:8][CH:3]([CH3:19])[CH3:2])=[O:9]
Reactant: C[C@H]1O[C@@H](C(Cl)(Cl)Cl)OC(=O)[C@@H]1C
Reactant: CC(C)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)OC(=O)[C@H](C)[C@@H](C)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1.0 g of (2R, 5R, 6R)-2-trichloromethyl-5,6-dimethyl-1,3-dioxan-4-one obtained by procedures similar to (1)-(4) of Example 1 were added 0.1 ml of concentrated sulfuric acid and 10 ml of 2-propanol and stirred at room temperature for one hour, and 20 ml of water was added to effect ether extraction. After drying the ether phase over anhydrous sodium sulfate, the ether was distilled off and the residue was subjected to distillation to give 0.4 g of isopropyl (2R, 3R)-2-methyl-3-hydroxybutanoate. The NMR chart is shown in FIG. 6. ##STR31##
Reaction SMILES: [C:1]1([CH:7]([CH2:20][N:21]2CCCC2)[CH2:8][N:9]2[C:17](=O)[C:16]3[C:11](=CC=CC=3)[C:10]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]([CH2:8][N:9]2[CH2:17][CH2:16][CH2:11][CH2:10]2)[CH2:20][NH2:21])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CC(CN1CCCC1)c1ccccc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCC(CN1CCCC1)c1ccccc1

Procedure:
A solution of 2-(2-phenyl-3-pyrrolidin-1-yl propyl)isoindole-1,3-dione (3 mmol) and hydrazine monohydrate (6 mmol) in ethanol (10 mL) is refluxed for 3.5 h. The reaction mixture is cooled and filtered through celite. The filtrate is concentrated in vacuo to give the title compound, which is directly used for the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[NH:11][CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]2=[O:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(Cc2cccc(Cl)c2Cl)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c[nH]c2ccc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 250 °C
Yield: 67.6 %

Procedure:
4-(2,3-Dichlorobenzyl)phenylamine (10.0 g, 39.7 mmol) obtained in Step 2 was dissolved in toluene (100 ml) and diethyl ethoxymethylenemalonate (8.8 ml, 43.7 mmol) was added. The mixture was heated under reflux for 3 hrs. The reaction solution was concentrated under reduced pressure, and diphenyl ether (100 ml) was added to dissolve the residue. The mixture was stirred with heating at 250° C. for 3 hrs. After allowing the mixture to cool, n-hexane was added to the reaction solution and the precipitate was collected by filtration, washed with chloroform and vacuum-dried to give an object product (10.1 g, yield 68%) as a pale-yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C(N(CC)CC)C.[C:17]([O:24][CH2:25]Cl)(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>CN(C)C=O>[C:17]([O:24][CH2:25][N:6]1[CH:7]=[C:2]([F:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8])(=[O:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCC(=O)OCCl
Reactant: O=c1[nH]cc(F)c(=O)[nH]1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCC(=O)OCn1cc(F)c(=O)[nH]c1=O
Yield: 40.5 %

Procedure:
Using a reactor similar to that used in Example 1, 3.90 g (0.03 mol) of 5-fluorouracil was dissolved in 50 ml of dimethylformamide. Then, 3.0 g of triethylamine was added to this solution. To the mixture was added dropwise 4.73 g (0.0287 mol) of caproyloxymethyl chloride. The mixture was reacted for 3 hours at 50° C. After completion of the reaction, the reaction liquid was filtered to remove the precipitated triethylamine hydrochloride and then the dimethylformamide was removed by distillation from the filtrate. Next, 50 ml of chloroform was added to the residue and the mixture was stirred and filtered to remove insoluble unreacted 5-fluorouracil. The chloroform phase was washed with water and then dried. By removing the chloroform by distillation, 3.0 g of 1-caproyloxymethyl-5-fluorouracil was obtained as white crystals having a melting point of 95°~96° C. in a yield of 38.7%.
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)(=[O:6])[CH3:5]>N1C=CC=CC=1.C(Cl)Cl>[CH3:2][NH:3][S:14]([C:11]1[CH:12]=[CH:13][C:8]([NH:7][C:4](=[O:6])[CH3:5])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(NC(C)=O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 71.2 %

Procedure:
To a solution of methylamine hydrochloride (1.4 g) in pyridine (5 ml) was added 4-acetamidobenzenesulfonyl chloride (2.3 g), and the mixture was stirred at 50° C. for 2 hours. The residue obtained by an evaporation of pyridine under a reduced pressure was dissolved in methylene chloride (50 ml), washed with water, 1N hydrochloric acid, and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Evaporation of the solvent under a reduced pressure gave N-methyl-4-(acetamido)benzenesulfonamide (1.6 g).
Reaction SMILES: Cl[C:2]1[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)[N:3]=1.Cl.[O:17]1[CH2:22][CH2:21][NH:20][C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3.C(N(CC)CC)C>O1CCCC1>[O:17]1[CH2:22][CH2:21][N:20]([C:2]2[N:7]([CH3:8])[C:6](=[O:9])[CH:5]=[C:4]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][N:11]=3)[N:3]=2)[C@@H:19]2[CH2:23][CH2:24][C:25]3[C:30]([C@@H:18]12)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: c1ccc2c(c1)CC[C@H]1NCCO[C@H]21
Reactant: Cn1c(Cl)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCO[C@@H]3c4ccccc4CC[C@H]32)nc(-c2ccncn2)cc1=O
Yield: 17 %

Procedure:
A solution of 2-chloro-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (0.25 g, 1.12 mmol), (4aRS,10bRS)-trans-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazine hydrochloride (0.3 g, 1.33 mmol) and triethylamine (0.4 g, 3.95 mmol) in tetrahydrofuran (15 ml) was stirred for 48 hours at 100° C. The mixture was partitioned between water and chloroform, and the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to give 2-((4aRS,10bRS)-trans-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-4-yl)-3-methyl-6-(pyrimidin-4-yl)-3H-pyrimidin-4-one (72 mg, 0.19 mmol, 16%) as pale white crystals.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH2:32]([N:35]=[C:36]=[O:37])[CH:33]=[CH2:34]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:36]([NH:35][CH2:32][CH:33]=[CH2:34])=[O:37])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: C=CCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: C=CCNC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and allyl isocyanate (22 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (68 mg, 61%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15].[C:16]([O-])(=[O:18])[CH3:17].[Na+].C(OC(=O)C)(=O)C>C(O)(=O)C>[C:16]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[O:13][C:12](=[O:14])[NH:11][C:10]1=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)[O-]
Reactant: Nc1ccccc1C1OC(=O)NC1=O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccccc1C1OC(=O)NC1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
5-(2-Aminophenyl)oxazolidine-2,4-dione hydrochloride (1 g., 4.37 mmoles) was taken into 15 ml. of glacial acetic acid. Sodium acetate (358 mg., 4.37 mmoles) was added and then, in a dropwise manner, acetic anhydride (449 mg., 0.41 ml., 4.37 mmoles). The reaction mixture was stirred at room temperature for 16 hours, poured into 50 ml. of water and extracted with three portions of ethyl acetate. The combined extracts were washed with two portions of water and then one of brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo solids (0.72 g.). Recrystallization from ethyl acetate gave purified 5-(2-acetamidophenyl)oxazolidine-2,4-dione in two crops [0.26 g., m.p. 197°-198° C.; m/e 234].
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=2)[N:10]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2ccc3ccccc3n2)c2ccc(C)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)c(C(=O)O)cn2-c1ccc2ccccc2n1
Yield: 116.4 %

Procedure:
0.342 g (8.15 mmol) of lithium hydroxide monohydrate and 45 cm3 of water are added at 25° C. to 0.86 g (2.7 mmol) of 3-methoxycarbonyl-5-methyl-1-(quinol-2-yl)-1H-indole dissolved in 45 cm3 of tetrahydrofuran. After stirring at reflux for 19 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 20 cm3 of water and then triturated with 8.2 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 0.95 g of 3-carboxy-5-methyl-1-(quinol-2-yl)-1H-indole is obtained in the form of a white solid. Mass spectrum (EI): m/e 302 (M+·).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[C:9](=[O:21])[C:8]=1[Br:22])(=O)=O.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=[CH2:31])=[CH:28][CH:27]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:22][C:8]1[C:9](=[O:21])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)[CH:11]=[CH:12][C:7]=1/[CH:31]=[CH:30]/[C:29]1[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=1
Reactant: O=c1c(Br)c(OS(=O)(=O)C(F)(F)F)ccn1Cc1cccc(F)c1
Reactant: C=Cc1ccc(F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1c(Br)c(/C=C/c2ccc(F)cc2)ccn1Cc1cccc(F)c1
Temperature: 65 °C
Yield: 6.5 %

Procedure:
A mixture of 3-bromo-1-(3-fluorobenzyl)-2-oxo-1,2-dihydropyridin-4-yl trifluoromethanesulfonate (1.0 g, 0.0023 mol), and 4-fluorostyrene (0.33 mL, 0.0028 mol) in degassed DMF (10 0 ml) containing diisopropyl ethyl amine (0.37 g, 0.0029 mol) was treated with PdCl2(PPh3)2 (0.32 g, 0.46 mmol) and heated at 65° C. under argon atmosphere for 16 h. DMF was distilled in vacuo, and the residue was purified by flash chromatography (EtOAc/hexane 1:4 v/v) to afford a yellow substance which was further purified by reverse-phase HPLC using 10-90% acetonitrile/water gradient (30 min), at flow rate of 100 mL/min. The appropriate fractions were combined, concentrated to a small volume (20 mL), added EtOAc (25 mL) and washed successively with satd. sod. bicarbonate, water, and dried (Na2SO4). ELOAc was removed under reduced pressure and residue was dried in vacuo to afford the title compound (0.06 g, 6%) as yellow powder: 1H NMR (CD3OD/400 MHz) δ 7.68 (m, 3H), 7.39 (m, 3H), 7.2-7.0 (m, 5H), 6.82 (d, 1H, J=7.2 Hz), and 5 22 (s, 2H); 19F NMR (CD3OD/400 MHz) δ −113.9 (m) and −115 (m); ES-HRMS m/z 402.0305 (M+HC20H15NOF2Br, requires 402.0300).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=2)[CH3:11])=[O:8])=[C:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:3]=1.[Li+].[OH-]>C1COCC1.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=2)[CH3:11])=[O:8])=[C:4]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=2)[CH:3]=1
Reactant: COC(=O)c1ccc(C(C)NC(=O)c2sc(Cl)cc2Cc2cccc(Cl)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(NC(=O)c1sc(Cl)cc1Cc1cccc(Cl)c1)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of methyl 4-[1-({[5-chloro-3-(3-chlorobenzyl)-2-thienyl]carbonyl}amino)ethyl]benzoate from Example 1, Step 10 (81.0 mg, 0.181 mmol) and LiOH (0.9 mL, 1M in water) in THF (1.5 mL) and methanol (1.5 mL) was stirred overnight at r.t. and concentrated. The residue was diluted with 1N HCl and extracted with EtOAc. The organic layer was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to give the desired product as a white solid. MS (−ESI): m/z 432.0 (M−1)−.
Reaction SMILES: [CH2:1]([N:8]([CH3:21])[C:9](=[O:20])[C@@H:10]([NH:12]C(=O)OC(C)(C)C)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:12][C@@H:10]([CH3:11])[C:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:21])=[O:20]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](N)C(=O)N(C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 85 %

Procedure:
To an ice-cold solution of (S)-tert-butyl 1-(benzyl(methyl)amino)-1-oxopropan-2-ylcarbamate (26.3 g, 0.090 mol) in CH2Cl2 (100 mL) was added TFA(100 mL) drop wise. The reaction mixture was warmed to ambient temperature. After 18.5 h, the reaction mixture was concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (250 mL) and saturated NaHCO3 (250 mL). The aqueous layer was separated and basified to pH=9-10 with 1 N NaOH and extracted again with CH2Cl2 (100 mL). The combined organic layers were washed with saturated NaHCO3 (100 mL), H2O (100 mL), brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to give (S)-2-amino-N-benzyl-N-methylpropanamide (14.7 g, 85%) as an amber oil. 1H NMR consistent.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([NH2:36])=[O:35])=[O:31])[C@@H:20]([CH3:29])[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:47]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:48]([C:59]([NH:61][CH2:62][C:63]([OH:65])=O)=[O:60])[C@@H:49]([CH3:58])[O:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1>>[NH:47]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[C@H:48]([C:59]([NH:61][CH2:62][C:63]([NH:1][C@H:2]([C:12]([NH:14][CH2:15][C:16]([NH:18][C@H:19]([C:30]([N:32]1[CH2:39][CH2:38][CH2:37][C@H:33]1[C:34]([NH2:36])=[O:35])=[O:31])[C@@H:20]([CH3:29])[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:65])=[O:60])[C@@H:49]([CH3:58])[O:50][CH2:51][C:52]1[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=1
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: C[C@@H](OCc1ccccc1)[C@H](NC(=O)CNC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(N)=O
Product: C[C@@H](OCc1ccccc1)[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)N[C@@H](COCc1ccccc1)C(=O)NCC(=O)N[C@H](C(=O)N1CCC[C@H]1C(N)=O)[C@@H](C)OCc1ccccc1
Yield: 77.7 %

Procedure:
By using 30.00 g of Boc-Ser(Bzl)-Gly-Thr(Bzl)-Pro-NH2 and 19.60 g of Boc-Thr(Bzl)-Gly-OH, and the same procedure as in Reference Example 15 was repeated to obtain 32.36 g (yield: 77.7%) of the above-mentioned objective product.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8])(=O)=O.[CH3:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[NH:27]1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[N:27]1[CH2:6][CH:7]([N:9]1[C:22]2[CH:21]=[C:20]([C:23]#[N:24])[CH:19]=[CH:18][C:17]=2[S:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH3:8]
Reactant: CC1CCC(C)N1
Reactant: CC(COS(C)(=O)=O)N1c2ccccc2Sc2ccc(C#N)cc21
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(CN1C(C)CCC1C)N1c2ccccc2Sc2ccc(C#N)cc21
Reaction time: 2 h
Yield: 19.8 %

Procedure:
A solution of 2-(2-cyano-10-phenothiazinyl)-1-propyl methanesulphonate (5 g) and (2RS,5RS)-2,5-dimethylpyrrolidine (5 g) in toluene (50 cc) is heated for 4 days to a temperature in the region of 100° C. After cooling, the reaction mixture is diluted with ethyl acetate (200 cc) and extracted successively with N aqueous hydrochloric acid solution (50 cc and 2×25 cc). The combined aqueous phases are alkalinized with 10N aqueous sodium hydroxide solution to pH 13, and extracted successively with ethyl ether (200 cc and 50 cc). The combined organic phases are dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residual yellow gum (2.8 g) is purified by chromatography on a column (height: 30 cm; diameter: 2 cm) of silica gel (0.2-0.063 mm), eluting with a mixture (80:20 by volume) (500 cc) of cyclohexane and ethyl acetate and collecting 30-cc fractions. The combined fractions 5 to 11 are concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The viscous yellow residue (2.4 g) is dissolved in isopropyl ether (15 cc) under reflux. The solution is cooled and then kept for 2 hours at a temperature in the region of 5° C. The crystals formed are drained, washed with isopropyl ether (2 cc) and dried under reduced pressure (5 mm Hg; 0.68 kPa) at 40° C. 10-((2RS)-1-[(2RS,5RS)-2,5-dimethyl-1-pyrrolidinyl]-2-propyl}-2-phenothiazine carbonitrile (1 g) is thereby obtained in the form of pale yellow crystals, m.p. 105° C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:8]([CH2:9][OH:10])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:11][OH:12].[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14]>CN(C=O)C>[Si:17]([O:12][CH2:11][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH2:9][OH:10])[N:3]=1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(CO)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 60% NaH (1.45 g, 35.9 mmol) in DMF (60 mL), which was stirred and cooled with ice, was added a solution of 2,6-pyridinedimethanol (5.00 g, 35.9 mmol) in DMF (30 mL), and stirred for 1 hour at a room temperature under Ar atmosphere. To the mixture was added a solution of tert-butyldimethylchlorosilane (6.54 g, 43.3 mmol) in DMF (40 mL), and stirred for additional 12 hours. TLC was used to confirm there was no starting material in the reaction mixture. Then, the mixture was subjected to extraction with EtOAc and 10% NaHCO3 aq. The organic layer was washed with sat. NaClaq., dried over anhydrous Na2SO4, and evaporated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Hex:EtOAc=5:1) to give 2-[(tert-butyldimethylsilyloxy)methyl]-6-hydroxymethylpyridine (1) (4.46 g, 49%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[NH:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[C:35](O)=[O:36])[CH:28]=[CH:27]1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:35]([C:33]4[CH:32]=[CH:31][CH:30]=[C:29]5[C:34]=4[NH:26][CH:27]=[CH:28]5)=[O:36])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1cccc2cc[nH]c12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5cc[nH]c45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and 1H-indole-7-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.