Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1CCCCC1>[C:11]1([NH:10]/[C:2](/[CH2:8][CH3:9])=[CH:3]\[C:4]([O:6][CH3:7])=[O:5])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: C1CCCCC1
Product: CC/C(=C/C(=O)OC)Nc1ccccc1
Yield: 72.2 %

Procedure:
A mixture of methyl 3-oxovalerate (5.21 g, 40.0 mmol), aniline (3.66 mL, 40.0 mmol), p-toluenesulfonic acid monohydrate (533 mg, 2.80 mmol) and cyclohexane (25 mL) was stirred with heating under reflux for 2 hr. The mixture was concentrated under reduced pressure, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluate, hexane:ethyl acetate=98:2→94:6) to give the title compound (5.93 g, 72%) as a colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13]>C1(C)C=CC=CC=1>[CH3:21][O:20][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[C:17]=1[O:18][CH3:19])[C:12]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:13]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Product: COc1cc(C(=O)N2CCOCC2)cc(OC)c1OC
Reaction time: 3 h
Yield: 86 %

Procedure:
Morpholine (0.8 mL) was slowly added to a solution composed of toluene (10 mL) and 3,4,5-trimethoxybenzoyl chloride (1.1 g). The reaction was accompanied by evolution of heat and precipitation of morpholine hydrochloride. After 3 hours, the solution was filtered and concentrated in vacuo to afford a white solid which was recrystallized from ethanol to afford colorless needles (1.2 g, 86%): m.p. 119.8-120.7° C., lit3c m.p. 120-121° C.; EIMS m/z 281 (M+), 266, 195; 1H NMR δ 6.63 (2H, s, H2,6), 3.87 (6H, s, OCH3×2), 3.86 (3H, s, OCH3), 3.70 (8H, bs, CH2×4).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][CH:12]=[O:13])[CH3:10].C[Si](C)(C)[C:23]([F:26])([F:25])[F:24].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@:9]([NH:14][S@@:15]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:16])([CH2:11][C@H:12]([OH:13])[C:23]([F:26])([F:25])[F:24])[CH3:10]
Reactant: CC(C)(C)[S@@](=O)N[C@@](C)(CC=O)c1cccc(F)c1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](C)(C[C@H](O)C(F)(F)F)c1cccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 24.7 %

Procedure:
To a cooled solution of (R)-N-((S)-2-(2-chloro-3-fluorophenyl)-4-oxobutan-2-yl)-2-methylpropane-2-sulfinamide (5.8 g, 18.14 mmol) in tetrahydrofuran (80 mL) at −78° C. was added trimethyl(trifluoromethyl)silane (26.8 mL, 181 mmol). After stirred for 20 min, tetrabutylammonium fluoride, 1.0M solution in THF (27.2 mL, 27.2 mmol) was added dropwise. After 3 h, the reaction was quenched with 1N HCl (30 ml), and then the cooling bath was removed. The reaction mixture was diluted with water (60 mL) and EtOAc (60 mL), and warmed to ambient temperature. The solution was extracted with EtOAc twice. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with MTBE (15 mL). The resulted solid was filtered and washed with DCM. The filtrate was concentrated in vacuo and purified by silica gel column (240 g, 0-100% EtOA/hexane in 25 min) to afford additional product. The solids were combined to give (R)-N-((2S,4S)-2-(2-chloro-3-fluorophenyl)-5,5,5-trifluoro-4-hydroxypentan-2-yl)-2-methylpropane-2-sulfinamide (1.75 g, 25% yield). MS m/z=390 [M+H]+. Calculated for C15H20ClF4NO2S: 389.8.
Reaction SMILES: ClC1C=CC=C(Cl)C=1[N:9]1[C:13]2=[N:14][C:15](CC3C=CC(CC(OCC)=O)=CC=3)=[N:16][C:17](=[O:18])[C:12]2=[C:11](C(C)C)[NH:10]1.C1COCC1.[OH-].[Li+]>O>[N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17](=[O:18])[C:12]2=[CH:11][N:10]=1
Reactant: CCOC(=O)Cc1ccc(Cc2nc3n(-c4c(Cl)cccc4Cl)[nH]c(C(C)C)c-3c(=O)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C1N=CN=C2N=NC=C12
Yield: 313.8 %

Procedure:
The ester, 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-(carbethoxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.20 g, 2.4 mmol) was stirred at RT overnight with THF (50 mL), water (15 mL) and 1 N lithium hydroxide (7.20 mL). The solution was evaporated to near dryness, diluted with 1 N hydrochloric acid, vigorously stirred and the solid was collected by filtration and dried under high vacuum to give 1-(2,6-dichlorophenyl)-3-isopropyl-6-(4-carboxymethyl)benzyl)pyrazolo[3,4-d]pyrimidin-4-one (1.01 g, 89% yield) as a white solid, mp 212-214° C. Mass Spec.: 471 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]1[S:18][C:17]([CH:19]([OH:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1.[OH-].[Na+].O>CS(C)=O>[OH:25][CH:19]([C:17]1[S:18][C:14]([CH2:13][O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:15][CH:16]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCC(O)c1ccc(CBr)s1
Reactant: Oc1ccnc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCC(O)c1ccc(COc2ccnc3ccccc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a well-stirred solution of 4-hydroxyquinoline (2 g, 0.014 mol) and 5-bromomethyl-2-(1-hydroxyhexyl)thiophene (3.82 g, 0.014 mol) in DMSO (50 ml) was added a 2N solution of sodium hydroxide (8 ml, 0.016 mol). The mixture became warm immediately. This clear solution was stirred overnight at room temperature, and then was poured into water (200 ml). The aqueous solution was extracted thoroughly with ethyl acetate (4×30 ml). The organic extract was washed with water and brine, and then dried over MgSO4. All volatiles were removed, and the crude product was purified chromatographically (silica gel; 15% ethyl acetate in hexane) to yield 2.1 g (44%) of the pure product.
Reaction SMILES: C(S([C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([N:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)[N:13]=[C:12]([N:27]2[CH2:32][CH2:31][N:30]3[CH:33]=[CH:34][N:35]=[C:29]3[CH2:28]2)[N:11]=1)=O)C1C=CC=CC=1.[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41].C(N(CC)CC)C>CN(C)C(=O)C>[Cl:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH:41][C:10]1[C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([N:20]2[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]2)[N:13]=[C:12]([N:27]2[CH2:32][CH2:31][N:30]3[CH:33]=[CH:34][N:35]=[C:29]3[CH2:28]2)[N:11]=1
Reactant: COc1ccc(CN)cc1Cl
Reactant: COC(=O)c1c(N2CCC(O)CC2)nc(N2CCn3ccnc3C2)nc1S(=O)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1c(NCc2ccc(OC)c(Cl)c2)nc(N2CCn3ccnc3C2)nc1N1CCC(O)CC1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A mixture of 4-benzylsulfinyl-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine (prepared in the above (6)) 83 mg, 3-chloro-4-methoxybenzylamine 86 mg, triethylamine 51 mg and N,N-dimethylacetoamide 3 ml is stirred at 110° C. for 1 hour. The reaction mixture is diluted with ice water and extracted with ethyl acetate. The organic layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; ethyl acetate→ethyl acetate:methanol=15:1→10:1) and crystallized from a mixture of methanol, ethyl acetate and isopropyl ether to give 4-(3-chloro-4-methoxybenzylamino)-5-methoxycarbonyl-6-(4-hydroxypiperidin-1-yl)-2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrimidine as a colorless crystalline powder 43 mg. mp 192–194° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CN(C=O)C.[Cl:20][C:21]1[CH:42]=[CH:41][C:24]([CH2:25][O:26][C:27]2[CH:40]=[CH:39][CH:38]=[CH:37][C:28]=2[C:29]([N:32]2[CH:36]=[CH:35][N:34]=[CH:33]2)=[N:30][OH:31])=[CH:23][CH:22]=1>CCOCC>[CH2:7]([O:31][N:30]=[C:29]([N:32]1[CH:36]=[CH:35][N:34]=[CH:33]1)[C:28]1[CH:37]=[CH:38][CH:39]=[CH:40][C:27]=1[O:26][CH2:25][C:24]1[CH:41]=[CH:42][C:21]([Cl:20])=[CH:22][CH:23]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCc1ccccc1
Reactant: ON=C(c1ccccc1OCc1ccc(Cl)cc1)n1ccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Clc1ccc(COc2ccccc2C(=NOCc2ccccc2)n2ccnc2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.3 %

Procedure:
Potassium carbonate (0.21 g), benzyl chloride (0.15 g) and DMF (2 ml) were added to 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde oxime (0.33 g), and the mixture was stirred at 60° C. for 2 hours. After completion of the reaction, ether (100 ml) was added, and the mixture was extracted with brine (80 ml) twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was purified by silica gel chromatography to give 2-(4-chlorobenzyloxy)-α-(1-imidazolyl)benzaldehyde O-benzyloxime (0.38 g) as colorless crystals. mp. 94°-95.5° C.
Reaction SMILES: [CH:1]1([N:4]([CH:26]2[CH2:28][CH2:27]2)[C:5]([C:7]2[N:23]([CH2:24][CH3:25])[C:10]3=[N:11][C:12]([NH:19][C:20]([NH2:22])=[S:21])=[C:13]4[N:17]=[CH:16][N:15]([CH3:18])[C:14]4=[C:9]3[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.CO[CH:31](OC)[N:32](C)C.C1(C)C=C(C)C=C(C)C=1S(ON)(=O)=O>O>[S:21]1[C:20]([NH:19][C:12]2[N:11]=[C:10]3[N:23]([CH2:24][CH3:25])[C:7]([C:5]([N:4]([CH:1]4[CH2:2][CH2:3]4)[CH:26]4[CH2:27][CH2:28]4)=[O:6])=[CH:8][C:9]3=[C:14]3[N:15]([CH3:18])[CH:16]=[N:17][C:13]=23)=[N:22][CH:31]=[N:32]1
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(NC(N)=S)nc21
Reactant: COC(OC)N(C)C
Agent: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Solvent: O
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(Nc3ncns3)nc21
Temperature: 50 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
A mixture of N,N-dicyclopropyl-6-ethyl-1-methyl-4-thioureido-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (example 2B, 30 mg, 0.075 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamine (1 g, 8.39 mmol) was heated at 50° C. for 2 h. Excess 1,1-dimethoxy-N,N-dimethylmethanamine was evaporated in vacuo and the crude example was dissolved in dichloromethane (1 mL) and O-(mesitylsulfonyl)hydroxylamine (24.4 mg, 0.113 mmol) was added. The reaction mixture was stirred at room temperature for 3 h. Water was added and the layers were separated. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give 4-(1,2,4-thiadiazol-5-ylamino)-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (7 mg, 19.20% yield) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[CH:10]1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C)cn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
6-(Methoxycarbonyl)-3-methylindole (0.57 g) is dissolved in N,N-dimethylformamide (10 ml), to which is added sodium hydride (60% oily, 0.145 g) With cooling with ice. Then, 2,4-dichlorobenzyl chloride (0.707 g) is added thereto, and stirred at room temperature for 1.5 hours. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous magnesium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-3-methylindole (72) (0.83 g).
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]2[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:8][C:6]=2[N:7]=1.[C:23]1([NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH2:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(#N)C>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:30][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:12][C:9]2[CH:10]=[CH:11][C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][C:6]=3[CH:8]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccccc1N
Reactant: CNc1nc2cc(NCc3ccc(C(=O)O)cc3)ccc2s1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1nc2cc(NCc3ccc(C(=O)Nc4ccccc4N)cc3)ccc2s1
Reaction time: 8 h
Yield: 35 %

Procedure:
A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-phenylenediamine (376 mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23 mmol; 1.27 eq) was dissolved in acetonitrile (15 mL), treated with triethylamine (3 mL) and stirred overnight. The reaction mixture was quenched with methanol, concentrated and purified by chromatographic column on silica gel (40% EtOAc in DCM) and the obtained material crystallized from DCM to give 358 mg (0.88 mmol; 35% yield) of pure compound 456. 1H-NMR (300 MHz; DMSO-d6) δ (ppm): 9.57 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.66 (d, J=4.8 Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9 Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J=7.5 Hz, 1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (dd, J=1.8, 8.3 Hz, 1H), 6.27 (t, J=5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.8 Hz, 3H). LRMS: calc: 403.5008. found: 404.2(M+NH) and 202.6 (M+2H)/2.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]([OH:15])[C:10](=[NH:14])[O:11]CC)[CH:6]=[CH:7][CH:8]=1.[O:16]1CCC[CH2:17]1>C1(C)C=CC=CC=1>[Cl:2][C:3]1[CH:4]=[C:5]([CH:9]2[O:15][C:17](=[O:16])[NH:11][C:10]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: CCOC(=N)C(O)c1cccc(Cl)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C1NC(=O)C(c2cccc(Cl)c2)O1

Procedure:
By the procedure of Example 3, ethyl 1-(3-chlorophenyl)-1-hydroxymethanecarboximidate hydrochloride (9 g., 38 moles) in 250 ml. of tetrahydrofuran was converted to toluene recrystallized 5-(3-chlorophenyl)oxazolidine-2,4-dione (4.5 g., 56%, m.p. 142°-144° C.).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br>>[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: Fc1cc(F)cc(CBr)c1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2cc(F)cc(F)c2)c1
Yield: 49.2 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 3,5-difluorobenzyl bromide were reacted by the same way with the example 1 to obtain the titled compound (205 mg, yield: 49.2%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[O:8])[O:4][N:3]=1.[F-].[Cs+].C[Si](C)(C)[C:13]([F:16])([F:15])[F:14].Cl>C1COCC1.O>[F:14][C:13]([F:16])([F:15])[CH:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)[OH:8]
Reactant: Cc1cc(C=O)on1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C(O)C(F)(F)F)on1
Temperature: -5 °C

Procedure:
A mixture of 0.1 g (0.9 mmol) 3-Methyl-isoxazole-5-carbaldehyde and 14 mg (0.09 mmol) CsF and THF is cooled to −5° C. 540 μl (1.1 mmol) trimethyl(trifluormethyl)-silane 2 M in THF is added dropwise and after 30 min the mixture is allowed to reach RT. After cooling with ice and addition of 5 ml 1 N aq. HCl, the mixture is stirred at RT over night, diluted with water and extracted with DCM. The combined organic layers are dried and evaporated giving rise to 2,2,2-trifluoro-1-(3-methylisoxazol-5-yl)ethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:32]([CH3:34])[CH3:33])[C:20]([O:22]CC1C=CC(OC)=CC=1)=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][C@@H:19]([CH:32]([CH3:34])[CH3:33])[C:20]([OH:22])=[O:21])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(COC(=O)[C@@H](OC(=O)[C@@H](NC(=O)OCc2ccccc2)C(C)C)C(C)C)cc1
Solvent: ClCCl
Solvent: CCO
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O[C@H](C(=O)O)C(C)C

Procedure:
4-methoxybenzyl 2-(N-benzyloxycarbonyl-L-valyloxy)-3-methyl-(S)-(+)-butyrate was de-esterified by the method described in Example A-I-1, step c. The title compound (3.41 g) was obtained after silica gel column chromatography (2, 10, 20% ethanol in dichloromethane). Rf (2% MeOH/CHCl3) 0.45. The compound may be activated and esterified directly to a drug or further modified as described below:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33]1(N)[CH2:35][CH2:34]1.C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH:33]3[CH2:35][CH2:34]3)=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Reactant: NC1CC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NC2CC2)C1
Yield: 78 %

Procedure:
Following general method 7, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and cyclopropylamine, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-50% ethyl acetate in DCM) afforded the title compound as a glass (64 mg, 78%); LCMS (method B): RT=3.70 min, M+H+=486.
Reaction SMILES: [CH3:1][C:2]([O:4][F:5])=[O:3].FC(C[C@H]([C@@H]([C@@H](CO)O)O)O)=O.[O:18]([F:20])[F:19].[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([Sn](C)(C)C)=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22]>C(Cl)(Cl)(Cl)F.C(Cl)Cl>[CH2:21]([O:23][C:24](=[O:56])[C@H:25]([CH2:29][C:30]1[C:35]([F:5])=[CH:34][C:33]([O:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[C:32]([O:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH:31]=1)[NH:26][CH:27]=[O:28])[CH3:22].[CH3:1][C:2]([O:4][F:5])=[O:3].[O:18]([F:20])[F:19]
Reactant: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1[Sn](C)(C)C)NC=O
Agent: CC(=O)OF
Agent: FOF
Agent: O=C(F)C[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: FC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(OC(=O)OC(C)(C)C)c(OC(=O)OC(C)(C)C)cc1F)NC=O

Procedure:
The electrophilic fluorinating agent, CH3COOF (prepared from 200 μmol) of F2 in 1% He, (Bida, G. T., Satyamurthy, N. and Barrio, J. R. (1984) The synthesis of 2- 18F!fluoro-2-deoxy-D-glucose using glycals: A reexamination. J. Nucl. Med. 25, 1327) F2 (1% in He, 200 μmol) or OF2 (1% in He, 200 μmol), was bubbled into a solution of trimethyltin derivative 6 (0.123 g, 200 μmol) in Freon-11 (CFCl3) (20 mL) at room temperature over a period of 30 min. The reaction mixture was diluted with methylene chloride (25 mL) and the organic phase was washed with 1M Na2S2O5 (2×20 mL), water (2×20 mL) and dried (MgSO4). Evaporation of solvents gave a yellow syrup which was chromatographed (silica gel, diethyl ether) to yield a colorless viscous oil 9 (41 mg, 43% in the case of CH3COOF), (65 mg, 69% for F2), 7(62 mg, 66% for OF2).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[C:15]2[N:16](COCC[Si](C)(C)C)[C:17]([CH3:30])=[C:18]3[C:23]=2[CH:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:20][C:19]3=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C([O-])(=O)C.[K+]>ClCCl>[CH:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[C:15]2[NH:16][C:17]([CH3:30])=[C:18]3[C:23]=2[CH:22]=[C:21]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:20][C:19]3=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)c1cc2c(-c3cc(F)ccc3OC3CCCCC3)n(COCC[Si](C)(C)C)c(C)c2c(=O)[nH]1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(-c3cc(F)ccc3OC3CCCCC3)[nH]c(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.5 %

Procedure:
To a solution of Example 48a (0.020 g, 0.037 mmol) in dichloromethane was added TFA (2.84 μL, 0.037 mmol). The reaction mixture was stirred at ambient temperature for 1 hour and then concentrated by rotary evaporation. The residue was concentrated down from toluene (2×) then taken up in methanol/tetrahydrofuran. Potassium acetate (0.145 g, 1.474 mmol) was added, and the reaction mixture was heated at reflux for 2 hours. The reaction mixture was concentrated by rotary evaporation. The residue was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude material was purified by flash chromatography (silica gel, 20-80% ethyl acetate in hexanes) to give the title compound (0.010 g, 66% yield). 1H NMR (300 MHz, DMSO-d6) δ 12.01 (s, 1 H), 9.29 (s, 1 H), 7.18 (s, 1 H), 6.93-7.09 (m, 3 H), 4.15-4.21 (m, 1 H), 4.12 (q, J=7.12 Hz, 2 H), 2.49 (s, 3 H), 1.69-1.75 (m, 2 H), 1.38-1.45 (m, 2 H), 1.20-1.33 (m, 2 H), 1.13 (t, J=7.02 Hz, 3 H), 1.07-1.18 (m, 4 H). MS (ESI+) m/z 413.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:25]=[C:24]3[C:19]([CH:20]=[CH:21][C:22]([C:26](O)=[O:27])=[CH:23]3)=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:29][C:30]1[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][C:31]=1[C:37]([F:40])([F:39])[F:38].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[Cl:29][C:30]1[CH:36]=[CH:35][C:33]([NH:34][C:26]([C:22]2[CH:23]=[C:24]3[C:19]([CH:18]=[CH:17][C:16]([O:15][C:13]4[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[CH:14]=4)=[CH:25]3)=[CH:20][CH:21]=2)=[O:27])=[CH:32][C:31]=1[C:37]([F:38])([F:39])[F:40]
Reactant: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)O)cc3c2)ccn1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(Oc2ccc3ccc(C(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)cc3c2)ccn1
Reaction time: 18 h
Yield: 81.8 %

Procedure:
To a solution of 7-({2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}oxy)-2-naphthoic acid (350 mg, 0.92 mmol) in DCM (9.0 mL), was added 4-chloro-3-(trifluoromethyl)aniline (198.0 mg, 1.0 mmol); EDCl (194 mg, 1.0 mmol) and DMAP (124 mg, 1.0 mmol). The mixture was allowed to stir for 18 h then diluted with EtOAc and washed with water and then brine. The organic phase was dried (Na2SO4) and evaporated, and the residue was triturated with DCM/EtOAc/MeOH to yield the title compound as a white solid (420 mg, 81.8%). LCMS: (FA) ES+ 558.1, ES− 556.1.