Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:12]([OH:14])=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:27]([O:30][CH2:31][CH3:32])(=[O:29])[CH3:28].[Li+].CC([N-]C(C)C)C>C1COCC1>[C:1]([NH:9][CH:10]([CH3:11])[C:12](=[O:14])[CH2:28][C:27]([O:30][CH2:31][CH3:32])=[O:29])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: CCOC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.4 %

Procedure:
In the first flask, N-benzoylalanine (2 g, 10.35 mmol) was dissolved in THF (20 mL), and carbonyl diimidazole (CDI) (1.84 g, 11.39 mmol) was added. The resulting mixture was stirred 1 hour at rt and cooled down to −78° C. Into a second flask, ethyl acetate (3.83 g, 43.48 mmol) in THF (40 mL) was cooled down to −78° C. and LDA (24.3 mL, 48.51 mmol, 2 M in THF) pre-cooled to −78° C. was added. The resulting solution was stirred 30 minutes at −78° C., and the lithium enolate generated was cannulated into the first flask. The resulting white slurry was stirred 30 minutes at −78° C. and warmed up to −10° C. The reaction was quenched with a saturated aqueous solution of NH4Cl. Phases were separated and the organics were dried over MgSO4 and solvents removed under reduced pressure. The crude product was carried to the next step without purification. This gave ethyl 4-(benzoylamino)-3-oxopentanoate (2.6 g, 95.5% yield) as a white solid. ES-MS m/z 263.4 ((MH)+); HPLC RT (min.) 1.53; 1H NMR (Acetone-d6) δ 8.13 (s br, 1H), 7.93-7.91 (m, 2H), 7.58-7.43 (m, 3H), 4.72 (m, 1H), 4.19-4.01 (q, 2H), 3.67 (s, 2H), 1.47 (d, 3H), 1.15 (t, 3H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=1)[NH2:2].[Cl:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH2:19][C:20](OCC)=[O:21])[CH:15]=[CH:16][CH:17]=1>>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:19]=[C:20]([OH:21])[N:1]([C:3]3[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][N:4]=3)[N:2]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)c1cccc(Cl)c1
Reactant: N#Cc1ccnc(NN)c1
Product: N#Cc1ccnc(-n2nc(-c3cccc(Cl)c3)cc2O)c1
Yield: 53 %

Procedure:
The title compound was prepared in 53% yield from 2-hydrazinylpyridine-4-carbonitrile (PREPARATION 2) and ethyl 3-(3-chlorophenyl)-3-oxopropanoate according to the procedure for the preparation of Example 158, part A.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:11][C:9](=[O:10])[C:8]([CH2:12][C:13]3[C:22](=[O:23])[O:21][C:20]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:14]=3O)=[C:7](O)[C:5]=2[CH:6]=1.[C:26]1([CH3:36])[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>ClCCl.C(N(CC)CC)C>[CH2:12]([C:8]1[C:9](=[O:10])[O:11][C:4]2[C:3]([C:7]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:13]1[C:22](=[O:23])[O:21][C:20]2[C:15]([C:14]=1[S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH3:36])=[CH:27][CH:28]=1)(=[O:34])=[O:33])=[CH:16][CH:17]=[CH:18][CH:19]=2
Reactant: O=c1oc2ccccc2c(O)c1Cc1c(O)c2ccccc2oc1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2c(Cc3c(S(=O)(=O)c4ccc(C)cc4)c4ccccc4oc3=O)c(=O)oc3ccccc23)cc1

Procedure:
To a solution of dicumarol (10 mmol) and p-toluenesulfonyl chloride (1.0 eq.) in dichloromethane (20 ml), triethylamine was added at room temperature under air atmosphere. After the reaction was complete, as monitored by TLC, the reaction mixture was evaporated and the residue was purified by flash chromatography (silica gel) to afford the product, 3,3′-methylenebis[4-tosylcoumarin].
Reaction SMILES: [I-].[Na+].Br[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1.[CH2:41]([NH2:43])[CH3:42]>O1CCOCC1.C(Cl)(Cl)Cl>[CH2:41]([NH:43][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14](=[O:20])[N:13]([CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[C:12]1[C:30]3[CH:31]=[C:32]4[O:40][CH2:39][O:38][C:33]4=[CH:34][C:35]=3[C:36](=[O:37])[C:11]2=1)[CH3:42]
Reactant: COc1cc2c(=O)n(CCCN3CCOCC3)c3c(c2cc1OCCCBr)C(=O)c1cc2c(cc1-3)OCO2
Reactant: CCN
Agent: [I-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: CCNCCCOc1cc2c3c(n(CCCN4CCOCC4)c(=O)c2cc1OC)-c1cc2c(cc1C3=O)OCO2
Yield: 48.2 %

Procedure:
Sodium iodide (0.060 g, 0.408 mmol) and compound 19 (0.020 g, 0.034 mmol) were diluted with dioxane (8 mL), and ethylamine (0.020 mL, 0.408 mmol, 70 wt. % solution in water) was added dropwise. The mixture was stirred at reflux for 26 h. The mixture was diluted to a volume of 200 mL with CHCl3, washed with H2O (2×50 mL) and saturated aq NaCl (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography (SiO2, ˜40 g), eluting with a gradient of 0.5% MeOH in CHCl3, to yield the product 24 as a solid (0.009 g, 46%): mp 187-188° C. (dec). IR (film) 1648, 1553, 1392, 1254, 1116, 1033, 785 cm−1; 1H NMR (CDCl3) δ 7.53 (s, 1H), 7.24 (s, 1H), 6.90 (s, 1H), 6.60 (s, 1H), 5.89 (s, 2H), 4.06 (s, 2H), 3.85 (s, 6H), 3.72 (s, 3H), 3.49-3.38 (m, 4H), 3.19-3.12 (m, 9H), 2.25-2.19 (m, 4H); ESIMS m/z 550 (MH+); HRESIMS m/z 550.2553 (MH+), calcd for C30H36N3O7 550.2553; HPLC purity: 98.36% (C-18 reverse phase, MeOH—H2O, 80:20).
Reaction SMILES: [Cl:1][SiH:2]([CH3:4])[CH3:3].[C:5]([CH2:7][C:8]([O:10][CH2:11][C:12]#[CH:13])=[O:9])#[N:6]>C1(C)C=CC=CC=1.[Pt]>[C:5]([CH2:7][C:8]([O:10][CH2:11][CH:12]=[CH:13][Si:2]([Cl:1])([CH3:4])[CH3:3])=[O:9])#[N:6]
Reactant: C[SiH](C)Cl
Reactant: C#CCOC(=O)CC#N
Agent: [Pt]
Solvent: Cc1ccccc1
Product: C[Si](C)(Cl)C=CCOC(=O)CC#N
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Chlorodimethylsilane (29.59 g, 0.313 mol) was added dropwise at 80° C. to a solution of 35.0 g (0.284 mol) propargyl cyanoacetate, 0.1 g of a solution of 1,3 divinyl- 1,1,3,3-tetramethyldisiloxane/Pt(0) complex containing 5 wt % platinum in xylenes (Karstedt catalyst) and 50 ml toluene under a nitrogen blanket. The reaction was stirred 3 hours at 80° C. after the addition. An IR spectrum confirmed disappearance of Sill at 2160 cm-1. After removing low-boiling volatiles by rotary evaporation, the crude product was purified by vacuum distillation. Upon removal of a small forecut at 80° C. at 0.1 mm Hg, the product distilled at 100°-115° C. at 0.1 m Hg. Yield: 47.1 g (76%) of a clear, greenish tinged liquid. Its structure was confirmed to be cyanoacetoxypropenylchlorodimethylsilane by IR and proton NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([OH:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:25][N:26]1[C:30](=[O:31])[C:29]2[C:32]([CH:37]([CH3:39])[CH3:38])=[CH:33][C:34]([OH:36])=[CH:35][C:28]=2[S:27]1(=[O:41])=[O:40]>CO>[CH:37]([C:32]1[C:29]2[C:30](=[O:31])[N:26]([CH2:25][O:13][C:12]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[N:9]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:11]=3)[S:27](=[O:41])(=[O:40])[C:28]=2[CH:35]=[C:34]([OH:36])[CH:33]=1)([CH3:39])[CH3:38]
Reactant: Oc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1
Reactant: CC(C)c1cc(O)cc2c1C(=O)N(CBr)S2(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Product: CC(C)c1cc(O)cc2c1C(=O)N(COc1cc(C(F)(F)F)nn1-c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
A mixture of 1-(4-chlorophenyl)-3-trifluoromethyl-5-hydroxypyrazole (8.4 g; 32 mmol) and Cs2CO3 (5.22 g; 16 mmol) in methanol (140 ml) was stirred at room temperature for 1.5 hours. The solvent was concentrated in vacuo, and the residue was dried in vacuo overnight. To the above residue was added 133 ml of DMF, cooled to 0° C., and 2-bromomethyl-4-isopropyl-6-hydroxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (5.33 g, 16 mmol) and the resulting mixture was stirred at room temperature for 24 hours and poured into ice/water. The resulting solid was filtered, the solid was dissolved in ether (700 ml), the organic layer was washed with brine (2×200 ml), and concentrated in vacuo. The residue was purified by column chromatography (silica gel; 14-75% ethyl acetate/hexane) and recrystallized from methanol to afford 4.54 g (55%) of 4-isopropyl-6-hydroxy-2-[1-(4-chlorophenyl)-3-trifluoromethylpyrazol-5-yl-oxymethyl]-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (Formula I: R1 =4-Cl--Ph; R2 =CH3 ; R3 =H; R4 =CH(CH3)2 ; R5 =6-OH) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([C:23](=[O:28])[NH:24][CH:25]([CH3:27])[CH3:26])=[CH:18][N:17]=1>C1COCC1>[NH:1]([C:20]1[C:19]([C:23](=[O:28])[NH:24][CH:25]([CH3:26])[CH3:27])=[CH:18][N:17]=[C:16]([Cl:15])[N:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CC(C)NC(=O)c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)NC(=O)c1cnc(Cl)nc1Nc1ccccc1
Temperature: -10 °C
Reaction time: 48 h
Yield: 36.5 %

Procedure:
A solution of aniline (0.292 ml, 3.2 mmol) and triethylamine (0.447 ml, 3.21 mmol) in THF (5 ml) was added dropwise over 10 minutes to a solution of 2,4-dichloro-5-(N-isopropylcarbamoyl)pyrimidine (Method 10, 0.75 g, 3.2 mmol) in distilled THF (8 ml) at −10° C. under nitrogen. The solution was stirred at −10° C. for 1 hour and at room temperature for 2 days. Insoluble material was removed by filtration and the filtrate was diluted with ethyl acetate (20 ml). The solution was washed with water (20 ml) and saturated sodium chloride (20 ml), and then dried. Volatile material was removed by evaporation and the residue was recrystallized from DCM to give the product as a white solid (0.34 g), which was used without characterisation.
Reaction SMILES: [C:1]([Si:5]([O:18][CH2:19][C@@H:20]([N:22]=[C:23]=[O:24])[CH3:21])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[N:31]=[C:30](Cl)[C:29]([CH:33]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[CH3:34])=[CH:28][N:27]=1.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[C:1]([Si:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[O:18][CH2:19][C@@H:20]([N:22]1[C:28]2=[N:27][C:26]([Cl:25])=[N:31][CH:30]=[C:29]2[CH:33]([CH3:34])[N:35]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:23]1=[O:24])[CH3:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N=C=O
Reactant: COc1ccc(NC(C)c2cnc(Cl)nc2Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(N2C(=O)N([C@@H](C)CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3nc(Cl)ncc3C2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-Butyl-2-isocyanato-propoxy-diphenylsilane (generated in situ from 0.440 g, 1.20 mmol, of (S)-(+)-3-(tert-butyl-diphenyl-silanyloxy)-2-methylpropionic acid) (from Example 13b supra) in hot toluene (2 mL; 120° C.) was treated with a solution of (±)-[1-(2,4-dichloro-pyrimidin-5-yl)-ethyl]-(4-methoxy-phenyl)-amine (0.35 g; 1.10 mmol) (from Example 1d supra) in toluene (2 mL). The resulting solution was kept at 120° C. for 30 minutes, then cooled to room temperature and concentrated. The residue was dissolved in anhydrous tetrahydrofuran (4 mL) and cooled in an ice-brine bath. Potassium tert-butoxide (1.0 M in tetrahydrofuran; 1.2 mL; 1.20 mmol) (Aldrich) was added dropwise and stirring continued in the cold for 15 minutes. The mixture was filtered through a bed of silica gel and eluted with ethyl acetate. Further purification with flash chromatography (Biotage 40 M; 25:75 ethyl acetate-hexanes) gave 1-[2-(tert-butyl-diphenyl-silanyloxy)-1-(S)-methyl-ethyl]-7-chloro-3-(4-methoxy-phenyl)-4-methyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one as a mixture of diastereomers. (Yield 0.31 g; 46%). No separation of diastereomers was seen at this time.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25](=[O:30])[CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(Cl)cc2)CC1
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Cc4ccc(Cl)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from [4-(4-chloro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 33b) and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 195° C. (isopropanol-diethyl ether)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([OH:21])([C:14]1[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=1)[C:10]([F:13])([F:12])[F:11].Br[CH2:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1.[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:33]([O:32][C:30](=[O:31])[C:29]1[CH:35]=[CH:36][C:26]([CH2:25][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([OH:21])([C:14]3[CH:19]=[N:18][C:17]([CH3:20])=[CH:16][N:15]=3)[C:10]([F:13])([F:11])[F:12])=[C:2]([Cl:1])[CH:3]=2)=[CH:27][CH:28]=1)[CH3:34]
Reactant: CCOC(=O)c1ccc(CBr)cc1
Reactant: Cc1cnc(C(O)(C(C)c2ccc(O)cc2Cl)C(F)(F)F)cn1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(COc2ccc(C(C)C(O)(c3cnc(C)cn3)C(F)(F)F)c(Cl)c2)cc1
Temperature: 60 °C
Reaction time: 17 h
Yield: 74.7 %

Procedure:
To a solution of 3-chloro-4-[3,3,3-trifluoro-2-hydroxy-1-methyl-2-(5-methyl-pyrazin-2-yl)-propyl]-phenol (120 mg, 0.35 mmol) in acetone (3 ml) were added ethyl 4-(bromomethyl)benzoate (197 mg, 0.78 mmol), potassium iodide (9 mg, 0.05 mmol) and potassium carbonate (108 mg, 0.78 mmol). The mixture was stirred for 17 h at 60° C. The reaction mixture was concentrated. Water and EtOAc were added and the mixture was extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated. The product was purified by flash chromatography (20 g silica gel, heptane/EtOAc 9:1) to give title compound as colorless viscous oil (133 mg). MS (m/e, ISP neg. ion)=507.1 [M−H+].
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].[BH4-].[Na+]>CCCCCC>[CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:6]=1[CH2:7][OH:8])([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([N+](=O)[O-])cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCC
Product: CC(C)Oc1ccc([N+](=O)[O-])cc1CO
Temperature: 40 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To 8A (210 mg, 1.0 mmol) in hexane (10 mL) was added sodium borohydride (1 mg, 0.30 mmol) and silica gel (0.50 g). The mixture was degassed with Ar for 3 min, then stirred at 40° C. for 3 h under Ar. The reaction was filtered, concentrated and purified via silica gel chromatography (0-20% ethyl acetate/hexane) to provide 8B (195 mg, 92%). LC-MS: 212.19 (M+H)+.
Reaction SMILES: [OH:1][C:2]1([C:7]#N)[CH2:6][CH:5]=[CH:4][CH2:3]1.C[OH:10].Cl.C([O:14][CH2:15]C)C>>[OH:1][C:2]1([C:7]([O:14][CH3:15])=[O:10])[CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: CCOCC
Reactant: CO
Reactant: N#CC1(O)CC=CC1
Agent: Cl
Product: COC(=O)C1(O)CC=CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 150 mg. of 1-hydroxy-3-cyclopentene-1-carbonitrile in 10 ml. of anhydrous methanol and 5 ml. of anhydrous diethyl ether is cooled in an ice-bath. The solution is saturated with gaseous hydrogen chloride, then allowed to warm to room temperature and finally set aside overnight. The solution is then concentrated in vacuo to a solid, which is dissolved in approximately 10 ml. of water. After 23/4 hours an aliquot is removed and extracted with methylene chloride. The extract is dried using sodium sulfate, and it is concentrated in vacuo giving methyl 1-hydroxy-3-cyclopentene-1-carboxylate as a yellowish oil. The infrared spectrum of the product (in CDCl3) shows an absorption at 1730 cm-1, confirming the presence of an ester function. The nmr spectrum of the product (in CDCl3) shows absorptions at 5.7 ppm (singlet, olefinic hydrogens), 3.8 ppm (singlet, methyl hydrogens) and 3.3-2.2 ppm (singlet superimposed on a quartet, hydroxy group and methylene hydrogens). The remainder of the aqueous solution is worked up analogously to give a further quantity of product. The combined yield is 65.8 mg.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=3[CH:29]=2)=[O:18])=[C:12]([Cl:31])[CH:11]=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]([CH3:30])[C:17]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25](=[O:27])[N:24]([CH3:28])[C:23]=3[CH:29]=2)([OH:18])[C:2]([F:4])([F:3])[F:1])=[C:12]([Cl:31])[CH:11]=1
Reactant: CC(C(=O)c1ccc2oc(=O)n(C)c2c1)c1ccc(Br)cc1Cl
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2oc(=O)n(C)c2c1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
Trifluoromethyltrimethylsilane (2M in THF, 1.13 mL) was added at 0° C. to a solution of 5-[2-(4-bromo-2-chloro-phenyl)-propionyl]-3-methyl-3H-benzooxazol-2-one (404 mg) in THF (8 mL) followed by the addition of tetrabutylammonium fluoride trihydrate (65 mg). Stirring was continued for 2 hours at 0° C. More tetrabutylammonium fluoride (1M in THF, 0.82 mL) was added to the reaction mixture and stirring was continued for 1 hour at 0° C. The reaction mixture was poured into ice/water and extracted two times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2:MeOH=100:0 to 96:4) to give the title compound as a colorless foam (320 mg, 67%). MS (m/e)=466.1 [M+H+].
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][NH:8][CH2:9][CH2:10][OH:11]>>[CH3:7][N:8]([CH2:9][CH2:10][OH:11])[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: Brc1nccs1
Reactant: CNCCO
Product: CN(CCO)c1nccs1

Procedure:
The title compound was prepared as an oil from 2-bromothiazole (15 g) and 2-methylaminoethanol (45 ml) by an analogous procedure to that described in Preparation 7
Reaction SMILES: [C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)=[C:16]([CH3:28])[NH:15][N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH:36]([CH3:38])[CH3:37].O>CN(C)C=O>[C@@H:1]1([O:12][C:13]2[C:17]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH:25]4[CH2:27][CH2:26]4)=[CH:23][CH:24]=3)=[C:16]([CH3:28])[N:15]([CH:36]([CH3:38])[CH3:37])[N:14]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: Cc1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(C2CC2)cc1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cc2ccc(C3CC3)cc2)c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)nn1C(C)C
Reaction time: 0.58 h

Procedure:
To a suspension of 3-(β-D-glucopyranosyloxy)-5-methyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (56 mg) and cesium carbonate (23 mg) in N,N-dimethylformamide (1.5 mL) was added 2-iodopropane (0.043 mL) at 8° C., and the mixture was stirred for 35 minutes. To the reaction mixture was added water, and the mixture was purified by solid phase extraction on ODS (washing solvent: distilled water, eluent: methanol). The obtained crude product was purified by preparative thin layer chromatography on silica gel (developing solvent: dichloromethane/methanol=7/1) to give 3-(β-D-glucopyranosyloxy)-5-methyl-1-isopropyl-4-[(4-cyclopropylphenyl)methyl]-1H-pyrazole (45 mg).
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][CH:5]1[C:10](OC)([O:11]C)[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>O.C(O)(C(F)(F)F)=O>[F:1][CH2:2][CH2:3][O:4][CH:5]1[C:10](=[O:11])[CH2:9][CH2:8][N:7]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:6]1
Reactant: COC1(OC)CCN(C(=O)OC(C)(C)C)CC1OCCF
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCC(=O)C(OCCF)C1
Yield: 97.5 %

Procedure:
The same operation as in Example (90b) was performed using tert-butyl 3-(2-fluoroethoxy)-4,4-dimethoxypiperidine-1-carboxylate obtained in Example (123a) (6.5 g, 21.2 mmol), a water/TFA mixed solution (1/1, 20 mL) and di-tert-butyl dicarbonate (6.54 g, 30 mol). The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 5/1, 2/1, 1/1) to obtain 5.4 g of the title compound as a light brown oily substance (98%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Reactant: COC(=O)[C@@H](N)Cc1ccc(Cl)c(Br)c1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Br)c1)C(=O)O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3-bromo-4-chloro-phenyl)-propionic acid was prepared from 3-bromo-4-chloro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoic acid as in EXAMPLE 1, Part C. Hydrolysis of the methyl ester as in EXAMPLE 2, Part E, provided the title compound. HPLC: RT=10.07 min. MS (ESI−): mass calcd. for C22H15BrCl2N4O5S2, 630.32; m/z found, 629/631 [M−H]−. 1H NMR (400 MHz, CDCl3): 11.35 (s, 1H), 8.36 (d, J=7.0, 1H), 8.20 (d, J=8.8, 1H), 7.76-7.69 (m, 2H), 7.41 (d, J=1.7, 1H), 7.36 (d, J=8.2, 1H), 7.17 (d, J=8.5, 1H), 7.05 (dd, J=8.2, 1.8, 1H), 6.91 (dd, J=8.4, 1.8, 1H), 6.53 (d, J=7.1, 1H), 5.04-4.95 (m, 1H), 3.36-3.15 (m, 2H).