Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH:1](=[O:4])([OH:3])[OH:2].[CH2:5]([C:7]([CH2:38][CH3:39])([CH:9]([S:34]C(=O)C)[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:6].C[O-].[Na+].C(=O)=O.O>CO>[PH:1](=[O:2])([OH:4])[OH:3].[CH2:38]([C:7]([CH2:5][CH3:6])([CH:9]([SH:34])[C:10]1[N:14]=[CH:13][N:12]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:11]=1)[CH3:8])[CH3:39]
Reactant: CCC(C)(CC)C(SC(C)=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[O-]
Agent: O=C=O
Agent: O=[PH](O)O
Solvent: O
Solvent: CO
Product: CCC(C)(CC)C(S)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 53.3 %

Procedure:
A solution of diethyl 3-acetylthio-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.71 g, prepared as described in Example 37) in methanol (20 ml) was added dropwise, under nitrogen, to a stirred solution of sodium methoxide (from 0.06 g sodium) in methanol (10 ml), whilst maintaining the temperature below 5° C. The mixture was allowed to attain room temperature and to stand for twenty hours, neutralized with solid carbon dioxide, poured into water and extracted with ethyl acetate. The extracts were washed with water and brine, dried over magnesium sulphate and evaporated under reduced pressure. The residue was chromatographed on silica, using dichloromethane-ethanol (49:1) as eluant, to give diethyl 3-mercapto-3(1-trityl-1,2,4-triazol-3-yl)propane phosphonate (0.35 g) as a colourless gum. NMR (CDCl3): δ1.3(6H,dt), 1.7-2.0(2H,m), 2.2-2.4(2H,m), 4.0(4H,m), 4.1(1H,m), 7.1(6H,m), 7.3(9H,m), 7.9(1H,s). M/S: M+ 521.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:26][CH2:27][O:28][C:29]([CH3:31])=[O:30].N1(C(=O)CC2CCC(C(OCC)=O)CC2)C=CN=C1>C1COCC1>[CH2:27]([O:28][C:29](=[O:30])[CH2:31][C:13](=[O:15])[CH2:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]1)[CH3:26]
Reactant: CCOC(=O)C1CCC(CC(=O)O)CC1
Reactant: CCOC(C)=O
Agent: CCOC(=O)C1CCC(CC(=O)n2ccnc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC1CCC(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a 100 mL round-bottom vessel was charged 2-(4-(ethoxycarbonyl)cyclohexyl)acetic acid (Int-4c, 4.03 g, 18.79 mmol) and THF (20 mL). To this solution was added N,N′-carbonyldiimidazole (3.66 g, 22.55 mmol). The resulting solution was allowed to stir 18 hours at room temperature. After 18 hours, in a separate 250 mL round-bottom vessel, 80 mL THF was added and the flask was flushed with argon. This solution was cooled to −78° C. in dry ice/IPA bath. To this solution was added LiHMDS (1.0 M in THF, 39.46 mmol, 39.46 mL). To the resulting solution was added dropwise dry EtOAc (40.4 mmol, 3.95 mL). This solution was allowed to stir at −78° C. for one hour. After one hour, the solution of crude ethyl 4-(2-(1H-imidazol-1-yl)-2-oxoethyl)cyclohexanecarboxylate (Int-4d) in THF was added dropwise. This solution was allowed to gradually warm to room temperature and the reaction was stirred overnight. After 18 hours, the reaction was quenched with saturated NH4Cl(aq) and extracted with Et2O (x3). The combined organics were dried over Na2SO4 and the residue was purified via silica gel chromatography to yield the title compound as clear oil. Yield=2.33 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[CH:25]1([C:28](Cl)=[O:29])[CH2:27][CH2:26]1.C(N(CC)CC)C>O1CCCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[N:11]=2)=[CH:3][C:2]=1[NH:1][C:28]([CH:25]1[CH2:27][CH2:26]1)=[O:29]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1cn2nc(Oc3ccc(Cl)c(NC(=O)C4CC4)c3)ccc2n1)C1CC1
Yield: 87.1 %

Procedure:
Using N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.435 mmol), cyclopropanecarbonyl chloride (71.8 mg, 0.652 mmol), triethylamine (132 mg, 1.30 mmol) and tetrahydrofuran (17 mL) as starting materials and in the same manner as in Example 96, the title compound (156 mg, 87%) was obtained as a white powder.
Reaction SMILES: C(Cl)CCl.[NH:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:6]([C:8]([NH:10][CH2:11][C:12]([OH:14])=O)=[O:9])[CH3:7].[NH2:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:6]([C:8]([NH:10][CH2:11][C:12]([NH:22][CH2:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:14])=[O:9])[CH3:7]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
One equivalent of 0.39 g (2 mmol) EDC (Aldrich) is added into a stirred solution of 0.5 g (2 mmol) of Boc Ala-Gly-OH (12), 0.4 g of (2 mmol) of Gly-OBzl (Sigma), 0.27 g of HOBT (Aldrich), and 0.2 ml of NMM in 100 ml of DCM at ice bath temperature. The reaction mixture is stirred for 3 h at 0° C. and 22 h at ambient temperature. The reaction mixture is concentrated using a rotary evaporator, and the residue is dissolved in 100 ml of ethyl acetate. The ethyl acetate solution is extracted with 10% NaHCO3 and water. The organic layer is dried over anhydrous Na2SO4 and isolated by decantation. Then, the ethyl acetate is evaporated to furnish the Boc-Ala-Gly-Gly-OBzl (13) as a yellow oil which is confirmed by MS and NMR. 1H-NMR (CDCl3): 1.28 (3H, d, J=7.2 Hz), 1.31 (9H, s), 3.85-4.15 (5H, m), 5.06 (2H, s), 5.45 (1H, br), 7.25 (5H, br), 7.41 (1H, br). FABMS: 394 (M+1).
Reaction SMILES: C[O:2][C:3]1(OC)[CH2:8][CH2:7][C:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:12]=2)([CH2:9][OH:10])[CH2:5][CH2:4]1.Cl>CCOCC>[CH:20]1([O:19][C:13]2[CH:12]=[C:11]([C:6]3([CH2:9][OH:10])[CH2:5][CH2:4][C:3](=[O:2])[CH2:8][CH2:7]3)[CH:16]=[CH:15][C:14]=2[O:17][CH3:18])[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COc1ccc(C2(CO)CCC(OC)(OC)CC2)cc1OC1CCCC1
Agent: Cl
Solvent: CCOCC
Product: COc1ccc(C2(CO)CCC(=O)CC2)cc1OC1CCCC1

Procedure:
4-(3-Cyclopentyloxy-4-methoxyphenyl)-4-(hydroxymethyl)-cyclohexan-1-one dimethyl ketal (0.15 g, 0.41 mmol) in ether (2 mL) was treated with 1N hydrochloric acid (2 mL) and the mixture was stirred vigorously and gently heated for 10 min. The mixture was extracted with ether, the combined organic extracts were washed with 5% aqueous sodium carbonate, dried (potassium carbonate) and the solvent was removed in vacuo. Purification by flash chromatography, eluting with 25% ethyl acetate/chloroform, provided a wax (0.06 g, 56%). Analysis Calc. for C19H26O4 : C 71.67, H 8.23; found: C 71.81, H 8.19.
Reaction SMILES: C[Si](C)(C)CCOC[N:7]1[C:11]([CH2:12][C:13]([O:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=3)[C@@:19]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])([F:30])[C:18]2=[O:40])=[O:14])=[N:10][N:9]=[N:8]1>CC#N.O>[NH:10]1[C:11]([CH2:12][C:13]([O:15][CH2:16][N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=3)[C@@:19]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:32]=3[O:38][CH3:39])([F:30])[C:18]2=[O:40])=[O:14])=[N:7][N:8]=[N:9]1
Reactant: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)Cc2nnnn2COCC[Si](C)(C)C)c2cc(C(F)(F)F)ccc21
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cl)cc1[C@]1(F)C(=O)N(COC(=O)Cc2nnn[nH]2)c2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
(S)-(3-(5-chloro-2-methoxyphenyl)-3-fluoro-2-oxo-6-(trifluoromethyl)indolin-1-yl)methyl 2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-tetrazol-5-yl)acetate (XIII1; n=1) (0.24 g, 0.38 mmol) was dissolved in CH3CN (20 mL), treated with aqueous HF (1 mL, 48% in H2O), and stirred at rt. until the starting material was completely consumed (as judged by HPLC). The mixture was neutralized with aqueous NaHCO3, and the CH3CN removed under reduced pressure. The aqueous layer was extracted with EtOAc, and the organic layer was then dried over MgSO4, filtered and concentrated. The isolated white solid was lyophilized to afford the title compund (0.14 g, 71% yield). 1H NMR (500 MHz, DMSO): δ 3.45 (s, 3 H), 5.79 (s, 2 H), 5.87 (d, J=10.96 Hz, 1 H), 5.91 (s, 2 H), 7.07 (d, J=8.85 Hz, 1 H), 7.47 (s, 2 H), 7.52 (dd, J=2.44, 8.85 Hz, 1 H), 7.72 (s, 2 H). LRMS: 500 (M). HRMS Calculated 498.8000 (M−H) found 498.8003.
Reaction SMILES: [OH-].[Na+].S(O)(O)(=O)=O.[CH3:8][S:9][C:10](=[NH:12])[NH2:11].CC(OC)(C)C.C1COCC1.[NH2:24][C:25]1[C:26]([C:33](OC(C)=CC(=O)NC(C)(C)C)=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1>O>[NH2:24][C:25]1[C:26]([C:33]([NH:12][C:10]([S:9][CH3:8])=[NH:11])=[O:34])=[N:27][C:28]([Cl:32])=[C:29]([NH2:31])[N:30]=1
Reactant: CC(=CC(=O)NC(C)(C)C)OC(=O)c1nc(Cl)c(N)nc1N
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N

Procedure:
To NaOH (1 mol/l in water; 9.2 ml; 9.2 mmol) is added S-methylisothiourea sulphate (1.78 g; 6.1 mmol). The mixture is stirred until complete solution is achieved. TBME/THF (1:1; 30 ml) and then 1-(tert-butylcarbamoyl)prop-1-en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate (example 2) (2.00 g; 6.10 mmol) are added and the mixture is stirred at r.t. over night, then water (6 ml) is added. The precipitate formed is filtered off with suction, washed successively with water, methanol and then with diethyl ether and then dried at 50° C. (C7H9ClN6OS).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1C(=O)N([Br:21])C(=O)C1.C(=O)([O-])[O-].[Na+].[Na+]>>[Br:21][C:11]1[S:10][C:9]([C:7]2[S:8][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1
Reactant: CCCc1ccc(-c2cccs2)s1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCc1ccc(-c2ccc(Br)s2)s1
Temperature: 0 °C

Procedure:
Next, 8 g (0.038 mol, 1 eq) of the obtained 5-propyl-2,2′-bithiophene was introduced into a three-necked flask, and this was flushed with Ar. To this, 100 ml of THF was added, stirred and cooled to 0° C. To this, 7.4 g (0.042 mol, 1.1 eq) of NBS was added directly. Then, the temperature was returned to the room temperature, and stirred for 12 hours. To this, 10% sodium carbonate aqueous solution was added, this was extracted with diethyl ether, water washed until pH is 7, and dehydrated with Na2SO4. After removing Na2SO4 by filtration, the solvent was removed. This was purified by silica gel chromatography, and specified substance of 5-bromo-5′-propyl-2,2′-bithiophene (3 in the chemical reaction formula) was obtained. Yielding quantity was around 8.8 g, and yielding percentage was around 80%.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:24]1([CH:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:32]Br)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[C:24]1([CH:30]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:31][CH2:32][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=3)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCCC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(N2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 68.3 %

Procedure:
The compound (1.60 g) prepared in step (a) was dissolved in N,N-dimethylformamide (20 ml). Potassium carbonate (2.79 g) and 3,3-diphenylpropyl bromide (2.82 g) were added to the solution. The mixture was stirred at 70° C. for 8 hr. The reaction solution was extracted with ethyl acetate, followed by washing with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:ethyl acetate=5:1) to give 2.00 g (71.3%) of ethyl 3-[4-(3,3-diphenyl-1-propyl)piperazin-1-yl]benzoate.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([CH3:13])[C:10]([OH:12])=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[NH2:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:34])[CH3:33])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23].C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[CH2:7]([O:6][P:4]([CH:9]([CH3:13])[C:10]([NH:14][CH2:15][C:16]1[CH:17]=[C:18]([CH2:24][CH:25]([O:31][CH:32]([CH3:33])[CH3:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])=[O:12])([O:3][CH2:1][CH3:2])=[O:5])[CH3:8]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CN)c1)OC(C)C
Reactant: CCOP(=O)(OCC)C(C)C(=O)O
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)C(C)P(=O)(OCC)OCC)c1)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
643 mg of 2-diethylphosphonopropionic acid and 973 mg of ethyl 3-[3-(aminomethyl)-4-methoxyphenyl]-2-isopropoxypropionate were dissolved in 10 ml N,N-dimethylformamide, and 470 μl diethyl cyanophosphonate and 1.07 ml triethylamine were successively added thereto. The mixture was stirred overnight at room temperature, and the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated, to give 1.310 g of ethyl 3-[3-([2-(diethoxyphosphoryl)propanoyl]aminomethyl)-4-methoxyphenyl]-2-isopropoxypropionate.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[CH:3][CH:2]=1.[C:15]([CH:17]1[CH2:19][NH:18]1)#[N:16].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]([NH:9][CH2:10][C:11]([N:18]2[CH2:19][CH:17]2[C:15]#[N:16])=[O:13])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(C(=O)NCC(=O)O)cc1
Reactant: N#CC1CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)NCC(=O)N2CC2C#N)cc1

Procedure:
In a manner analogous to Example 10, from 0.96 g. p-toluoylglycine (m.p. 161°-162° C.) and 0.34 g. 2-cyanoaziridine in 10 ml. tetrahydrofuran, after the addition of 1.08 g. dicyclohexylcarbodiimide at 10°-15° C., stirring for 30 minutes at 10°-15° C. and for 2 hours at ambient temperature and after filtering off with suction 1.1 g. dicyclohexylurea (m.p. 228° C.) and evaporation of the filtrate in a vacuum, there is obtained the desired compound in crude form. This is dissolved in ethyl acetate, the solution is shaken up with a saturated aqueous solution of sodium bicarbonate and the organic phase is dried and evaporated. The evaporation residue is repeatedly triturated with diethyl ether to give 0.95 g. 1-(4-methylbenzamidoacetyl)-2-cyanoaziridine; m.p. 92°-94° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:25]=[C:24]2[C:20](/[C:21](=[CH:27]/[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=3[F:35])/[C:22](=[O:26])[NH:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.N12CCCN=C1CCCCC2>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[NH:8][CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:21]2([C:20]3[C:24](=[CH:25][C:17]([Cl:16])=[CH:18][CH:19]=3)[NH:23][C:22]2=[O:26])[CH:27]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=1[F:35])=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/c1cccc(Cl)c1F
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [3,3-dimethyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester (3.37 g, 15.8 mmol) prepared in Example 1 and E/Z-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-1,3-dihydro-indol-2-one (4 g, 13 mmol) prepared in Example 2 in dichloromethane (100 mL) were added triethylamine (6.6 mL, 47.4 mmol) and AgF (2 g, 15.8 mmol). The mixture was stirred at room temperature for 18 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and brine. The organic layer was separated, washed with water, dried over MgSO4, and concentrated. The residue was dissolved into t-butanol (30 mL), and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, Fluka) (7.2 g, 47.4 mmol) was added. The reaction mixture was heated at 120° C. for 2 h. The mixture was then cooled to room temperature and concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:3, 1:2) to give as rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester a white foam (2.7 g, 33%)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=[O:21])[CH2:11][N:12]2[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]2=[O:20])=[CH:4][CH:3]=1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10](=[O:21])[CH2:11][N:12]3[C:16](=[O:17])[C:15]([CH3:19])([CH3:18])[NH:14][C:13]3=[O:20])=[CH:4][CH:3]=2)=[CH:29][CH:28]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCOc1ccc(B(O)O)cc1
Reactant: CC1(C)NC(=O)N(CC(=O)CSc2ccc(Br)cc2)C1=O
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCCCOc1ccc(-c2ccc(SCC(=O)CN3C(=O)NC(C)(C)C3=O)cc2)cc1
Temperature: 90 °C
Yield: 78.1 %

Procedure:
A solution of Example 46A (700 mg, 1.89 mmol) in DME (20 mL) at room temperature was treated with 4-n-butoxybenzeneboronic acid (549 mg, 2.83 mmol), tetrakis-(triphenylphosphine)-palladium (218 mg, 0.189 mmol) and 1M sodium carbonate (3.54 mL, 3.54 mmol), the reaction vessel was sealed and heated at 90° C. for 6 hours, diluted with ethyl acetate, washed with sequentially saturated ammonium chloride solution, water and brine, dried (Na2SO4), filtered, concentrated and purified on silica gel with 30 to 50% ethyl acetate/dichloromethane to provide 650 mg (78%) of the desired product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][O:9][Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1>C([O-])([O-])=O.[Na+].[Na+].C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[Si:10]([C:23]([CH3:26])([CH3:25])[CH3:24])([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
Reactant: CC(C)(C)[Si](OCc1cccc(Br)n1)(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OCc1cccc(-c2ccccc2)n1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 2-bromo-6-(tert-butyldiphenylsiloxy)methylpyridine (1 g; WO 94/00444), benzeneboric acid (400 mg) and tetrakis (triphenylphosphine) palladium (200 mg) in 2M Na2CO3 (25 mL) and THF (100 mL) was refluxed for 16 h. The THF was evaporated and the residue was extracted with EtOAc. The organics were dried (MgSO4), concentrated and chromatographed (silica gel; hexane/ethyl acetate (20:1)) to provide the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:5][C:6](=O)[C:7]=1[Cl:8])=[O:4].[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1>O>[F:10][C:11]1[CH:17]=[CH:16][C:14]([N:15]2[C:3](=[O:4])[C:2]([Cl:1])=[C:7]([Cl:8])[C:6]2=[O:5])=[CH:13][CH:12]=1
Reactant: O=C1OC(=O)C(Cl)=C1Cl
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 99.2 %

Procedure:
10g (0.06 mol) of 2,3-dichloromaleic anhydride was dissolved in 200 ml of water. Then to the resulting solution 5.55g (0.05 mol) of 4-fluoroaniline was added dropwise over a period of 5 min. at room temperature under agitation. The mixture was then allowed to react for 2 hours at reflux temperatures. Upon cooling the reaction mixture, precipitated crystal was separated by filtration to obtain 12.9g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 240°-243° C (not corrected) at a yield of 99.2%. An anaylsis by gas chromatography showed the product had a purity of 99.3%.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([OH:15])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:17][C:2]([F:1])([F:16])[C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:15][CH2:21][CH2:20][CH2:19][Br:18])=[C:11]([CH2:12][CH2:13][CH3:14])[C:6]=2[O:5][N:4]=1
Reactant: CCCc1c(O)ccc2c(C(F)(F)F)noc12
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12

Procedure:
A solution of 3-trifluoromethyl-7-propyl-6-hydroxybenzisoxazole (2.5 grams) in 2-butanone (30 mL) was treated with 1,3-dibromopropane (4.8 mL) and potassium carbonate (5.0 grams). The mixture was refluxed for 4 hours. The reaction mixture was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once with water, then dried over magnesium sulfate. The organic was filtered and evaporated to an oil which was flitered through a silica gel plug using methylene chloride and hexane (1:2) to give 3-trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole. A solution of 3-chloro-4-dimethylcarbamoylthio-phenylacetic acid methyl ester (0.33 grams) in dry methanol (3.5 mL) was treated with a solution of sodium methoxide in methanol (25 wt %; 0.341 mL). The solution was refluxed for 2 hours. HPLC analysis showed the disappearance of the carbamate. The solution was allowed to cool to 50° C. 3-trifluoromethyl-7-propyl-6-(3-bromopropyloxy)-benzisoxazole (0.31 grams) was added and the solution stirred for 1 hour. The reaction was partitioned between isopropyl acetate and pH 4 buffer. The organic was washed once more with pH 4 buffer, then water. The organic was dried over magnesium sulfate, filtered and concentrated to an oil. The oil was applied to a silica gel column packed with hexane/methylene chloride (2:1). The column was eluted with this mobile phase until the product began to appear in the eluant. The mobile phase was switched to 100% methylene chloride and elution continued until all the product was recovered.