Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:17][C:18]1C=CC(CC(O)=O)=C[CH:19]=1.C(Cl)(=O)C>N1C=CC=CC=1>[C:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1)(=[O:17])[CH3:19]
Reactant: O=C(O)C1(c2ccc(O)cc2)CCCCC1
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: c1ccncc1
Solvent: CC(=O)Cl
Product: CC(=O)Oc1ccc(C2(C(=O)O)CCCCC2)cc1
Reaction time: 0.25 h
Yield: 23.6 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)cyclohexanecarboxylic acid (10) (1.264 g crude material, obtained from 1.000 g (6.57 mmol) of 9) in pyridine (5 ml) under argon atmosphere at 0° C. acetyl chloride (0.541 g, 7.61 mmol) slowly (ca. over 10 minutes) was added and the mixture was stirred for 15 minutes at this temperature. The ice bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours, then the content was poured into ice water (30 ml) and the pH of the medium was brought to 1-2 by adding conc.HCl. The mixture was extracted with ethyl acetate (2×40 ml), the organic extract was washed successively with water (30 ml), brine (15 ml), and dried (Na2SO4). The solvent was evaporated, the residue was dissolved in toluene and chromatographed on silica gel (100 g) with petroleum ether-dioxane-acetic acid (8:2:0.1) as eluent affording the title compound (0.406 g, 23.5% based on 9) as a white solid. 1H NMR (CDCl3, HMDSO) δ: 1.06-1.98 (8H, m); 2.28 (3H, s); 2.30-2.63 (2H, m); 7.09 (2H, d, J=8.6 Hz); 7.46 (2H, d, J=8.6 Hz); 10.49 (1H, br s).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C@@H:4]([CH3:21])[C:5](=[O:20])N[C@H](C1SC=CN=1)CC1C=CC=CC=1.FC(F)(F)C(O)=[O:37]>ClCCl>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:21])[C:5]([OH:20])=[O:37])=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C(O)C(F)(F)F
Reactant: CO[C@H]([C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nccs1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
Synthesis of (2R,3R)-3-methoxy-2-methyl-N-[(1S)-2-phenyl-1-(1,3-thiazol-2-yl)ethyl]-3-[(2S)-pyrrolidin-2-yl]propanamide, trifluoroacetic acid salt (#19). According to general procedure B, from #16 (607 mg, 1.28 mmol, 1 eq.), dichloromethane (10 mL, 0.13 M) and trifluoroacetic acid (2 mL) was synthesized #19 (640 mg, quantitative), which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 8.96-9.07 (br m, 1H), 8.89 (d, J=8.8 Hz, 1H), 7.87-8.00 (br m, 1H), 7.80 (d, J=3.2 Hz, 1H), 7.66 (d, J=3.3 Hz, 1H), 7.28-7.34 (m, 4H), 7.20-7.27 (m, 1H), 5.43 (ddd, J=11.3, 8.6, 4.2 Hz, 1H), 3.42-3.50 (m, 2H), 3.36 (s, 3H), 3.04-3.14 (br m, 1H), 2.99 (dd, J=14.2, 11.5 Hz, 1H), 2.92-3.02 (m, 1H), 2.78-2.88 (br m, 1H), 2.34-2.42 (m, 1H), 1.73-1.84 (br m, 1H), 1.55-1.68 (m, 1H), 1.38-1.53 (m, 2H), 1.15 (d, J=6.9 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[NH2:29][C:20]1[C:19]2[N:18]=[C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:16]([CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:10])[C:28]=2[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:21]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: NCCCCn1c(-c2ccccc2)nc2c(N)nc3ccccc3c21
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Nc1nc2ccccc2c2c1nc(-c1ccccc1)n2CCCCNC(=O)Nc1ccc(F)cc1
Temperature: 25 °C
Yield: 47 %

Procedure:
A solution of 4-fluorophenylisocyanate (0.137 g, 1.0 mmol) in chloroform (5 mL) was added at ambient temperature to a solution of 1-(4-aminobutyl)-2-phenyl-1H-imidazo[4,5-c]quinolin-4-amine (0.331 g, 1.0 mmol) in a mixture of chloroform (25 mL) and pyridine (5 mL). The reaction mixture was maintained at ambient temperature over the weekend. The reaction was quenched with ethanol. The resulting pale yellow precipitate (identified as the bis-adduct) was isolated by filtration. The filtrate was concentrated under vacuum to provide an off-white solid. This material was purified by flash chromatography (silica gel, eluting with 10% methanol in dichloromethane). The pure fractions were combined and concentrated under vacuum to provide 0.22 g of N-[4-(4-amino-2-phenyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-N′-(4-fluorophenyl)urea as a white solid, m.p. 145-150° C. Mass spec M+1=469.2. Analysis: C27H25FN6O: %C, 69.21; %H, 5.37; %N, 17.94; Found: %C, 66.70; %H, 5.33; %N, 17.03.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:9][CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[N:12]=1.[Br:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.CN(CCN(C)C)C>ClCCl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([N:9]2[CH:10]=[C:11]([C:13]([F:16])([F:14])[F:15])[N:12]=[C:8]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])=[CH:20][CH:19]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: FC(F)(F)c1c[nH]c(-c2ccccc2Cl)n1
Agent: CN(C)CCN(C)C
Solvent: ClCCl
Product: FC(F)(F)c1cn(-c2ccc(Br)cc2)c(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 25.1 %

Procedure:
2-(2-Chloro-phenyl)-4-trifluoromethyl-1H-imidazole (370 mg, 1.5 mmol), 4-bromo-phenylboronic acid (600 mg, 3 mmol), and [Cu(OH).TMEDA]2Cl2 (140 mg, 03 mmol) were mixed with 6 mL dry dichloromethane, and stirred at room temperature under atmosphere of dioxygen for 2 days. The reaction mixture was diluted with dichloromethane and filtered through celite. The filtrate was concentrated under vacuum, and the residue was purified by chromatography on silica gel (Hexane/EtOAc 8/2) to give a solid (151 mg, 25% yield). 1H-NMR (400 MHz, CDCl3): δ 7.02 (d, 2H), 734 (m, 3H), 7.47 (ol, 2H), 7.53 (dd, 1H), 7.56 (dd, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH2:23]([S:25][CH2:26]CO)[CH3:24]>[Na]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[CH:20]=[CH:19][C:11]([O:12][CH:13]([CH3:18])[C:14]([O:16][CH2:17][CH2:26][S:25][CH2:23][CH3:24])=[O:15])=[CH:10][CH:9]=2)=[CH:21][CH:22]=1
Reactant: CCSCCO
Reactant: COC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Agent: [Na]
Product: CCSCCOC(=O)C(C)Oc1ccc(COc2ccc(Cl)cc2)cc1
Temperature: 100 °C
Yield: 76.1 %

Procedure:
A mixture consisting of 6.4 gm of methyl 2-[4-(4-chlorophenoxy-methyl)-phenoxy]-propionate and 2.12 gm of 2-ethylmercapto-ethanol was heated to 100° C. on an oil bath, 0.02 gm of sodium was added to the hot mixture, and it was then heated at 150° C. for five hours, the pressure being periodically reduced to 150 mm Hg. Thereafter, the reaction product was isolated as an oil, yielding 6.0 gm (76% of theory) of the ester named in the heading.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([C:6]1[C:7](F)=[CH:8][C:9]([O:17][CH2:18][CH3:19])=[C:10]([CH:16]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12])(=[O:5])=[O:4].[CH3:22][NH:23][CH3:24]>CN(C)C=O.O>[CH3:22][N:23]([CH3:24])[C:7]1[C:6]([S:3](=[O:5])(=[O:4])[N:2]([CH3:21])[CH3:1])=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:9]([O:17][CH2:18][CH3:19])[CH:8]=1
Reactant: CNC
Reactant: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(F)cc1OCC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(S(=O)(=O)N(C)C)c(N(C)C)cc1OCC
Temperature: 50 °C
Yield: 95.3 %

Procedure:
Ethyl 5-dimethylsulfamoyl-2-ethoxy-4-fluoro-benzoate (1.02 g, 3.20 mmol) was taken up in 5 mL of anhydrous dimethylformamide. Dimethylamine (8.0 mL, 15.9 mmol) was added and the reaction mixture was heated at 50° C. for 16 h. The reaction was allowed to cool to room temperature and diluted with water. The product was extracted three times with methylene chloride. The combined organics extracts were washed with brine, dried over magnesium sulfate and concentrated to give ethyl 4-dimethylamino-5-dimethylsulfamoyl-2-ethoxy-benzoate as a tan solid (1.05 g, 95%). LC-MS: 345.3 [(M+H)+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.CCN(CC)CC.[C:19](Cl)(=[O:24])[CH2:20][CH:21]([CH3:23])[CH3:22]>C(Cl)Cl>[CH3:22][CH:21]([CH3:23])[CH2:20][C:19]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)=[O:24]
Reactant: CC(C)CC(=O)Cl
Reactant: CCOC(=O)[C@H]1CCCNC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H]1CCCN(C(=O)CC(C)C)C1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
Ethyl (S)-Piperidine-3-carboxylate (25 g, 159.02 mmol) in anhydrous DCM (500 mL) was cooled down to 0° C. and treated with Et3N. A solution of isovaleryl chloride (23.27 mL, 190.08 mmol, 1.2 eq.) in anhydrous DCM (200 mL) was added dropwise at 0° C. The resulting reaction mixture was kept on the cooling bath and allowed to warm up slowly to room temperature. After 6 hrs the reaction was washed subsequently with aqueous HCl solution (2M), saturated NaHCO3, brine, dried over Na2SO4, filtered, concentrated under vacuum and purified by filtration over a short silica gel column using EtOAc as solvent. The solvent was removed under vacuum to yield the desired product as pale yellow oil (37.4 g, 154.97 mmol, 97.5%) that was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6, 20° C.) δ 0.88 (pseudo d, J=6.4 Hz, 6H), 1.13-1.23 (m, 3H), 1.26-1.45 (m, 1H), 1.47-1.75 (m, 2H), 1.82-2.03 (m, 2H), 2.10-2.28 (m, 2H), 2.28-2.39 (m, 0.5H), 2.45-2.56 (m, 0.5H), 2.84 (dd, J=10.0, 12.8 Hz, 0.5H), 2.97-3.11 (m, 1H), 3.38 (dd, J=8.8, 13.6 Hz, 0.5H), 3.63-3.83 (m, 1.5H), 4.00-4.14 (m, 2H), 4.26-4.36 (dm, 0.5H). MS 242 (MH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2I.C([Mg]Cl)(C)C.[CH2:19]([Sn:23]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])Cl)[CH2:20][CH2:21][CH3:22]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[N:7]([CH3:12])[N:6]=[C:5]2[Sn:23]([CH2:25][CH2:26][CH2:27][CH3:28])([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cn1nc(I)c2cc(Cl)c(Cl)cc21
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(Cl)c(Cl)cc12
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5,6-dichloro-3-iodo-1-methyl-1H-indazole (150 mg, 0.44 mmol) in THF (3 mL) at −10° C. (ice/acetone) was slowly added isopropylmagnesium chloride (2.0 M in THF, 0.26 mL, 0.52 mmol). The bright yellow heterogeneous reaction mixture was stirred at −10° C. for 15 min then tributylchlorostannane (0.14 mL, 0.52 mmol) was added dropwise. Stirring was continued at −10° C. for 30 min then at room temperature for 1 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organics were dried over MgSO4 and concentrated to afford 5,6-dichloro-1-methyl-3-tributylstannanyl-1H-indazole as a pale yellow oil which was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([O:11]COC)=[CH:9][N:10]=1)[CH:6]=[O:7].Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[OH:11][C:8]1[C:5]([CH:6]=[O:7])=[CH:4][C:3]([O:2][CH3:1])=[N:10][CH:9]=1
Reactant: COCOc1cnc(OC)cc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(O)cn1
Temperature: 50 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
To a solution of 2-methoxy-5-(methoxymethoxy)isonicotinaldehyde (33.5 g, 0.17 mol, 1 eq.) in THF (150 mL) was added HCl (3 N, 250 mL, 4.4 eq.). The reaction was stirred at 50° C. for 1 h, cooled to rt, and diluted with water (500 mL). The mixture was neutralized to pH 7-8 with solid K2CO3. The pale yellow solid was collected, washed with water, and dried to give 5-hydroxy-2-methoxyisonicotinaldehyde (17.9 g, 74.6%) as a pale yellow solid. 1H NMR (400 MHz; DMSO) δ=10.31 (s, 1H), 8.03 (s, 1H), 6.89 (s, 1H), 3.80 (s, 3H). LRMS (M+H+) m/z 154.0.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].[Cl:43][C:44]1[C:45]([CH2:50]Cl)=[N:46][CH:47]=[CH:48][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[N:35]=[N:34][N:33]([CH2:50][C:45]3[C:44]([Cl:43])=[CH:49][CH:48]=[CH:47][N:46]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: ClCc1ncccc1Cl
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Product: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nnn(Cc3ncccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-chloro-2-(chloromethyl)pyridine and isolated as light-brown gum. MS (m/e): 400.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH2:7][C:6]1=[O:17])=[O:4].[Li+].[CH3:19][CH:20]([N-]C(C)C)[CH3:21].C(Br)C=C>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:15][CH3:16])[CH2:8][CH:7]([CH2:21][CH:20]=[CH2:19])[C:6]1=[O:17])=[O:4]
Reactant: COC(=O)C1C(=O)CCc2cccc(OC)c21
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1Cc2cccc(OC)c2C(C(=O)OC)C1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
A solution of 10.2 g (43.5 mmol) 1,2,3,4-tetrahydro-8-methoxy-2-oxo-1-naphthalene carboxylic acid methyl ester in 108 mL of THF in a three-neck, round-bottomed flask, equipped with a dropping funnel, was added dropwise 63.8 mL (95.7 mmol) of LDA (1.5M in cyclohexane) at -30° C. to -40° C. under a nitrogen atmosphere. The solution was allowed to warm to 0° C. and 6.0 mL (69.6 mmol) of allylbromide was added. After stirring the mixture for one hour at room temperature, TLC analysis showed no starting material remaining. The reaction was quenched with 3N hydrochloric acid to pH 2-3 and extracted with ethyl acetate (2×1 L). The combined organic layers were washed with brine, dried (MgSO4), filtered, and concentrated in vacuo. The resulting oil was purified by liquid chromatography on 800 g silica gel 60 (230-400 m), eluting with hexane-acetone (3:1), and collecting 40 mL fractions. Fractions 36-63 gave 10.3 g (87%) of pure title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)=O>N1C=CC=CC=1>[CH2:8]([NH:15][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(C)=CC(=O)O
Reactant: NCc1ccccc1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: CC(C)(CC(=O)O)NCc1ccccc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 41.6 %

Procedure:
3-Methylcrotonic acid (12.0 g) was dissolved in pyridine (40 ml), and benzyl amine (12.8 g) was added thereto, and the mixture was stirred for 3 hours at 120° C. The reaction mixture was cooled to room temperature, and after acetone was added to the resulting suspension, crystals were collected by filtration and washed. The crystals were dried under reduced pressure to give 3-benzylamino-3-methylbutanoic acid (10.3 g, Y.:42%) as colorless crystals.
Reaction SMILES: [O:1]=[O+][O-].C1(C=[CH:11][C@@H:12]2[N:15]([Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:14](=[O:23])[C@H:13]2[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])C=CC=CC=1>C(Cl)Cl>[CH:11]([C@@H:12]1[N:15]([Si:16]([C:19]([CH3:20])([CH3:22])[CH3:21])([CH3:17])[CH3:18])[C:14](=[O:23])[C@H:13]1[CH2:24][CH2:25][CH2:26][NH:27][C:28]([NH:40][C:41]([O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:42])=[N:29][C:30]([O:32][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:31])=[O:1]
Reactant: O=[O+][O-]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)N1C(=O)[C@@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)[C@@H]1C=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Ozone was passed through a -78° C. CH2Cl2 (650 mL) solution of compound 4a (55 g, 84 mmol) until a blue color was maintained. Excess ozone was purged with N2. Dimethyl sulfide (60 mL) was added. The solution was allowed to warm to room temperature and to stand for 48 h. The solution was concentrated to afford the title compound which was not further purified but used directly in step B.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](I)=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1B(O)O.O>COCCOC>[F:15][C:16]1[C:21]([F:22])=[C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:19]=[CH:18][C:17]=1[C:5]1[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1
Reactant: CCCCCCCCOc1ccc(B(O)O)c(F)c1F
Reactant: Brc1cnc(I)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCCCCCCCOc1ccc(-c2ncc(Br)cn2)c(F)c1F
Yield: 55.5 %

Procedure:
--To a degassed mixture of 5-bromo-2-iodopyrimidine 2 (4.0 g, 14.0 mmol) tetrakis(triphenylphosphine)palladium (323 mg, 0.28 mmol), DME (30 ml), and aqueous 2M sodium carbonate (50 ml) was added 2,3-difluoro-4-octyloxyphenylboronic acid 3 (4.42 g, 15.4 mmol) dropwise in DME (10 ml) under an atmosphere of nitrogen. The mixture was heated under reflux overnight; water was added to the mixture and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (twice) and the combined organic solutions were washed with brine and dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (5% to 10% ethyl acetate-light petroleum; the crude material was preloaded onto silica in dichloromethane) to give the phenylpyrimidine 4 (3.1 g, 55%) (from methanol), m.p. 74.6° C.; νmax /cm-1 (KBr) 2920, 2850, 1625, 1475, 1420, 1310 and 1090; δ0.91(1H, t, Me), 1.2-1.55(10H, m), 1.85 (2H, quint, OCH2CH2), 4.11 (2H, t, OCH2), 6.82 (1H, ddd, 5'-H), 7.83 (1H, ddd, 6'-H) and 8.86 (2H, s, 4- and 6-H); m/z 288 (M+ -C8H16), 286 (M+ -C8H16), 178 and 155.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:17])([F:16])[F:15])[N:5]=[C:4]([NH2:18])[CH:3]=1.OS(O)(=O)=O.[N+:24]([O-])([OH:26])=[O:25]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([F:15])([F:16])[F:17])[N:5]=[C:4]([NH2:18])[C:3]=1[N+:24]([O-:26])=[O:25]
Reactant: O=[N+]([O-])O
Reactant: Nc1cc(Cl)cc(-c2ccccc2C(F)(F)F)n1
Agent: O=S(=O)(O)O
Product: Nc1nc(-c2ccccc2C(F)(F)F)cc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Chloro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (617.5 mg, 2.27 mmol, prepared as described in STEP A above) was cooled to 0° C. and treated slowly with H2SO4 (10 mL). The mixture was stirred at 0° C. for 1 h. Nitric acid (133 μL, 2.94 mmol) was added slowly, and the mixture continued to stir at 0° C. for an additional 1.5 h. Ice (50 mL) was added. A precipitate formed and was filtered, dissolved in DCM (70 mL), and washed with saturated aqueous NaHCO3 (70 mL). The aqueous layer was extracted with DCM (30 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The residue was purified on a 40-g SEPRA Si 35 SPE column (Flow rate=20 mL/min; Eluent=EtOAc-hexanes, 1:19 for 15 min, then 1:19 to 1:3 over 40 min) to yield 4-chloro-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine as a yellow solid. The basic mother liquor and acidic filtrate were carefully combined, made basic with 1 N aqueous NaOH, and extracted twice with DCM (100 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to yield additional product. 1H-NMR (400 MHz, CDCl3) δ: 7.76-7.90 (m, 1H), 7.55-7.71 (m, 2H), 7.46 (d, J=7.3 Hz, 1H), 6.93 (s, 1H), 6.11 (br. s., 2H). Mass Spectrum (LCMS, APCI pos.): Calculated for C12H7N3O2ClF3: 318.0 (M+H). Measured: 318.0.
Reaction SMILES: [C:1]([C@H:4]([C@@H:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([NH:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([CH2:24][CH2:25][N:26]([CH3:28])[CH3:27])[C:19]1=[O:29])=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(O)=[O:2].[CH2:34]([O:41][NH2:42])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C)C=O.C(OCC)(=O)C.Cl.C(N=C=NCCCN(C)C)C>[CH2:34]([O:41][NH:42][C:1]([C@H:4]([C@@H:14]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]([NH:17][N:18]1[C:22](=[O:23])[CH2:21][N:20]([CH2:24][CH2:25][N:26]([CH3:27])[CH3:28])[C:19]1=[O:29])=[O:16])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:2])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: NOCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CN(CCN(C)C)C1=O)[C@H](CCCc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A solution of 0.151 g of 2(R)-[1(S)-(carboxy)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide and 0.157 g of O-benzylhydroxylamine in 0.25 ml of dimethylformamide was treated with 0.054 mg of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride and stirred at room temperature for 4 hours. The mixture was diluted with ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give a residue which was purified by flash column chromatography on silica gel, using methanol/dichloromethane (5:95) for the elution, to give 0.061 g of 2(R)-[1(S)-(benzyloxycarbamoyl)-4-phenylbutyl]-N-[3-[2-(dimethylamino)ethyl]-2,5-dioxo-1-imidazolidinyl]-4-methylvaleramide in the form of a white foam.
Reaction SMILES: C(Br)C.[Mg].[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[C:10]#[CH:11].[Cl:12][CH2:13][C:14]([C:16]1([Cl:19])[CH2:18][CH2:17]1)=[O:15].[Cl-].[NH4+]>C(OCC)C>[Cl:12][CH2:13][C:14]([C:16]1([Cl:19])[CH2:18][CH2:17]1)([OH:15])[C:11]#[C:10][C:6]1[S:5][CH:9]=[CH:8][CH:7]=1
Reactant: C#Cc1cccs1
Reactant: O=C(CCl)C1(Cl)CC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCBr
Product: OC(C#Cc1cccs1)(CCl)C1(Cl)CC1
Temperature: 25 °C
Yield: 97.3 %

Procedure:
22.2 g (0.203 mole) of ethyl bromide are slowly added to 4.9 g (0.203 mole) of magnesium turnings in 100 ml of diethyl ether. After completion of the addition, the reaction mixture is heated under reflux for 30 minutes and then cooled to room temperature, and a solution of 20 g (0.185 mole) of 2-thienylethine in 50 ml of diethyl ether is subsequently added dropwise with stirring. The mixture is heated under reflux for 1 hour and again cooled to room temperature. 28.3 g (0.185 mole) of 1-chloro-cyclopropyl chloromethyl ketone are added dropwise with stirring and the mixture is then heated under reflux for a further 2 hours. After cooling to room temperature, the reaction mixture is poured into a saturated aqueous ammonium chloride solution and the mixture is extracted three times with diethyl ether. The combined organic phases are washed once with water, dried over sodium sulphate and concentrated under reduced pressure. 47.0 g (97% of theory) of 1-chloro-2-(1-chlorocyclopropyl)-4-(thiophen-2-yl)-but-3-in-2-ol are obtained in this way in the form of an oil which is reacted further without additional purification.