Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NCC)C.[C:6]([O:10][C:11](=[O:41])[CH2:12][C@H:13]([NH:23]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:9])([CH3:8])[CH3:7]>CN(C)C=O>[C:6]([O:10][C:11](=[O:41])[CH2:12][C@H:13]([NH2:23])[C:14]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)=[O:15])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N1CCC(O)CC1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C[C@H](N)C(=O)N1CCC(O)CC1
Reaction time: 1 h

Procedure:
Diethylamine (1.0 mmol) was added to (S)-3-(9H-fluoren-9-ylmethoxycarbonyl-amino)4-(4-hydroxy-piperidin-1-yl)4-oxo-butyric acid tert-butyl ester in dimethylformamide (5 ml) at 25° C. After 1 hour, the reaction mixture was concentrated, the residue suspended in 1:1 ether/dichloromethane, filtered and concentrated. The residue was purified by chromatography on silica gel eluted with 1-50% ethanol in dichloromethane containing 0.5% ammonium hydroxide. Yield 217 mg, 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.CCO[C:10]([CH3:12])=O>>[N:1]1[CH:12]=[CH:10][CH:5]=[CH:6][C:2]=1[C:5]1[CH:6]=[C:2]([NH2:1])[NH:3][N:4]=1
Reactant: CCOC(C)=O
Reactant: Nc1cc[nH]n1
Product: Nc1cc(-c2ccccn2)n[nH]1
Temperature: 80 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
The product was prepared according to general procedure for aminopyrazole synthesis (route A2). The crude product was dissolved in EtOAc, washed with NaHCO3, dried and evaporated. NMR analysis showed that a major portion of the crude mixture was still in the opened form: the mixture was then dissolved in CH3COOH and heated at 80° C. overnight, to allow for ring closure of the opened form. The product was then recovered as the acylated form, which was de-acylated stirring with HCl 6N at 60° C. overnight obtaining the title product (0.816 g, yield 60%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH2:8][C:9]#[C:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].I[CH3:24].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:22])[N:7]([CH3:24])[CH2:8][C:9]#[C:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([F:20])([F:21])[F:19])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC#Cc1ccc(OC(F)(F)F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CC#Cc1ccc(OC(F)(F)F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 50 %

Procedure:
[3-(4-Trifluoromethoxy-phenyl)-prop-2-ynyl]-carbamic acid tert-butyl ester (500 mg, 1.6 mmol) was added to an ice cold solution of iodomethane (100 μl, 1.7 mmol) and sodium hydride (73 mg, 1.7 mmol; 55% suspension in mineral oil) in DMF (5 ml). The reaction mixture was stirred for 5 h at ambient temperature, cooled to 0° C. and carefully quenched with saturated aqueous ammonium chloride solution. Ice water/ethyl acetate 1/1 were added, the layers were separated and the aqueous layer was extracted two times with ethyl acetate. The combined extracts were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, heptane/AcOEt) to give 258 mg (0.8 mmol, 49%) of the title compound as yellow oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:12]=2)[N:6]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)[C:4]=1[C:34]#[N:35].[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(N(CC)CC)C>[NH2:2][C:3]1[N:8]=[C:7]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][N:18]3[CH2:19][CH2:20][N:21]([C:36](=[O:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[CH2:22][CH2:23]3)[N:12]=2)[N:6]=[C:5]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][CH:25]=2)[C:4]=1[C:34]#[N:35]
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN4CCNCC4)n3)nc(N)c2C#N)cc1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(-c2nc(SCc3cccc(CN4CCN(C(=O)c5ccccc5)CC4)n3)nc(N)c2C#N)cc1
Yield: 90.3 %

Procedure:
The compound of Example 18 (292 mg), benzoic acid (61 mg) and triethylamine (0.2 mL) was dissolved in 3 mL of DMF, to the above solution, 80 mg of HOBt was added under stirring at ice temperature. After stirring the mixture at the same temperature for 15 minutes, thereto 115 mg of WSC was added, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated to dryness under reduced pressure, and ice-water was added to the resulting residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (methylene chloride-methanol-triethylamine=300:10:1) to give 261 mg of N-(4-{6-amino-2-[6-(4-benzoylpiperazin-1-ylmethyl)pyridin-2-ylmethylsulfanyl]-5-cyanopyrimidin-4-yl}phenyl)acetamide as a white powder.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1)=O)(C)(C)C.Cl>ClCCl.C(O)C>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:26]4[CH:30]=[CH:29][N:28]=[N:27]4)[O:22][C:21]3=[O:31])=[CH:16][C:15]=2[F:32])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(5R)-3-(4-((3S)-3-(t-Butoxycarbonyl)aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)oxazolidin-2-one (1.55 g, 3.47 mM), was dissolved in dichloromethane (8 ml), and treated with a solution of hydrogen chloride in ethanol (3.8M, 40 ml). After stirring 2 hours at ambient temperature, the mixture was evaporated to dryness to give product as a hydrochloride of sufficient quality to require no purification (1.64 g).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]([NH:7][NH:8]C(OC(C)(C)C)=O)=[O:6].[ClH:18]>O1CCOCC1>[ClH:18].[F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]([NH:7][NH2:8])=[O:6]
Reactant: CC(C)(C)OC(=O)NNC(=O)NCC(F)(F)F
Agent: Cl
Solvent: C1COCCO1
Product: NNC(=O)NCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 109 %

Procedure:
To a stirred solution of tert-butyl 2-((2,2,2-trifluoroethyl)carbamoyl)hydrazinecarboxylate (1.62 g, 6.30 mmol) in anhydrous dioxane (10.0 mL) was added HCl (4M in dioxane, 2-3 mL). The reaction mixture was stirred at ambient temperature for 18 h, then heated at reflux for 2-3 h. The reaction mixture was allowed to cool to ambient temperature and then evaporated to afford the title compound as a white solid (1.33 g, 109%): 1H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 3H), 9.25 (s, 1H), 7.72 (t, J=6.5 Hz, 1H), 3.91 (qd, J=9.7, 6.5 Hz, 2H); 19F NMR (376 MHz, DMSO-d6) δ −71.41; ESIMS m/z 156 ([M−H]−). This material is used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[O:6][N:5]=[C:4]([S:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][C:18]([F:21])([F:20])[F:19])(=[O:9])=[O:8])[CH2:3]1.C(N1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2)C(C)C.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:56])(=O)=O)=CC=1>C(#N)C>[F:56][CH:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][C:18]([F:21])([F:19])[F:20])[S:7]([C:4]1[CH2:3][C:2]([CH3:22])([CH3:1])[O:6][N:5]=1)(=[O:8])=[O:9]
Reactant: CC1(C)CC(S(=O)(=O)Cc2ccccc2OC(F)(F)F)=NO1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: CC(C)CN1CCN2CCN(CC(C)C)P1N(CC(C)C)CC2
Solvent: CC#N
Product: CC1(C)CC(S(=O)(=O)C(F)c2ccccc2OC(F)(F)F)=NO1
Yield: 69.2 %

Procedure:
5,5-Dimethyl-3-(2-trifluoromethoxy-phenylmethanesulfonyl)-4,5-dihydroisoxazole (0.2 g, 0.59 mmol) was dissolved in acetonitrile (5 ml) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3.3.3]undecane (Verkade's base) (0.44 ml, 1.24 mmol) was added dropwise at room temperature. After 5 minutes N-fluorobenzene-sulfonimide (NFSI) (393 mg, 1.24 mmol) was added in one portion. After 10 minutes the reaction was quenched by addition of water (10 ml). The mixture was acidified by addition of aqueous hydrochloric acid (2M) and extracted several times with ethyl acetate (3×10 ml). The combined organic phases were washed with saturated aqueous sodium hydrogencarbonate solution and with water, dried over magnesium sulfate and concentrated. The crude product was purified by chromatography on silica gel (eluent: ethyl acetate/hexane) to give the product (Compound No. 1.68 of Table 27) as colourless oil (145 mg, 69% yield).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1)(=O)C.Cl>CO>[OH:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[N:7]=1
Reactant: CC(=O)OCc1cccc(C)n1
Agent: Cl
Solvent: CO
Product: Cc1cccc(CO)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.7 %

Procedure:
2-Acetoxymethyl-6-methylpyridine (5 g) was added to saturated hydrochloric acid in methanol (250 ml, prepared by adding 25 ml of acetyl chloride to 225 ml of methanol). The reaction mixture was stirred at room temperature for 18 hours. The solvent was removed under vacuum and the residue was dissolved in dichloromethane (100 ml) and washed with 2N sodium hydroxide solution (3×50 ml). The combined organic layers were washed with brine (1×200 ml), then dried (MgSO4), filtered and evaporated to give the required product as an oil (2.6 g). 1H NMR (250 MHz, CDCl3) δ 2.54 (3H, s), 3.80 (1H, bs), 4.72 (2H, s), 7.04 (2H, d, J=7.7Hz), 7.57 (1H, t, J=7.7Hz).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][Se]C2C=CC=CC=2[N+]([O-])=O)[N:7]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:5])[CH3:2].N1C=CC=CC=1.OO>C(Cl)Cl>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH:8]([CH:11]=[CH2:12])[N:7]1[C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CCC(CC[Se]c2ccccc2[N+](=O)[O-])N1C(=O)OC(C)(C)C
Agent: OO
Solvent: ClCCl
Solvent: c1ccncc1
Product: C=CC1CC[C@@H](C(=O)OCC)N1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A solution of 576 mg of selenyl ether 171 (1.22 mmol) in 15 ml of anhydrous CH2Cl2 was cooled to 0° C., added with 0.4 ml of pyridine and 0.8 ml H2O2 (30%) and stirred overnight. The intensely orange-colored solution was subsequently concentrated and purified using silica gel column chromatography (CH2Cl2) to obtain 312 mg of vinylproline 172 (1.16 mmol, 95%) as a yellowish oil.
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH2:21][OH:22])[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].Cl.[CH2:26]([O:28][NH2:29])[CH3:27]>>[CH2:26]([O:28][N:29]=[C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[C:15]([CH2:21][OH:22])[C:14]=2[CH3:23])[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH3:27]
Reactant: CCON
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)cc(C)c(CO)c2C)CC1=O
Agent: Cl
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)cc(C)c(CO)c2C)CC1=O

Procedure:
2-[1-(Ethoxyimino)butyl]-3-hydroxy-5-(3-hydroxymethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one (51) was prepared from 2-butyryl-3-hydroxy-5-(3-hydroxymethyl-2,4,6-trimethylphenyl)cyclohex-2-en-1-one and ethoxyamine hydrochloride following essentially the same procedure as that described in Example 1, part (iv).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:40])([C:30]([F:39])([F:38])[C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][C:17]([F:29])([F:28])[C:18]([F:27])([F:26])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21].[CH2:41]([C:48](Cl)=O)[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47].[H-].[H-].[H-].[H-].[Li+].[Al+3]>O.C1COCC1.CCCCCC>[F:8][C:9]([F:40])([C:30]([F:38])([F:39])[C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[CH2:10][CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][C:17]([F:28])([F:29])[C:18]([F:26])([F:27])[C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[CH2:48][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCNCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCCCCCCC(=O)Cl
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCN(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A 250-ml flask was charged with triethylamine (4.2 g, 42 mmol), bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)amine (18.4 g, 34.3 mmol), and 30 ml THF. To the mixture was added C7H15COCl (6.0 g, 37 mmol) slowly at RT. The resulting mixture was stirred at RT for 1 h. Hexane (100 ml) and water (50 ml) were added to the flask. The mixture was then stirred at RT for 10 min. The bottom layer was isolated and extracted with hexane (50 ml). The extract from this was combined with the top layer and washed with HCl (1 N), water, KOH (aq. 5%) and water until pH=7, dried over Na2SO4, and concentrated to give a residue. The residue was pumped on full vacuum at 140° C. for 2 h to give a yellow oil, 17.6 g. A 250-ml 3-necked flask equipped with a stir bar, condenser, nitrogen inlet and an addition funnel was charged with LiAlH4 (3.0 g) ard 10 ml THF. To the mixture was added a THF (50 ml) solution of the above ye low oil dropwise at 5° C. The resulting mixture was refluxed for 2 hours. After being cooled, the mixture was carefully treated with water (10 ml) to decompose excess LiAlH4. Another 50 ml of water were added and the mixture was filtered. The slurry gel was washed with hexane (3×50 ml). The combined filtrate and hexane washings were separated into two layers. The top layer was washed with water, dried over Na2SO4, concentrated to give a residue which was distilled to afford di(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)octylamine, 15.6 g, yield 70%, bp 159° C./270 Pa absolute. 19F NMR (CDCl3) -81.7 (tt, J=10, 3 Hz, 6F), -115.1 (m, 4F), -125.2 (m, 4F), -126.7 (m, 4F) ppm. 1H NMR (CDCl3) 0.88 (t, J=7 Hz, 3H), 1.27 (m, 10H), 1.39 (m, 2H), 1.71 (m, 4H), 2.38 (t, J=7 Hz, 2H), 2.46 (t,J=7 Hz, 4H) ppm. 13C NMR (CDCl3) 14.0, 18.4, 22.7, 27.2, 27.5, 28.7 (t, J=22 Hz), 29.3, 29.6, 31.9, 53.0, 53.9, 108-123 (m) ppm. MS (m/e) 550 (M+ -C7H15, 100%), 402 (83%), 304 (78%), 290 (25%), 169 (2.0%), 119 (4.8%), 71 (10%) 69 (29%), 57 (35%). Anal. Calcd. for C22H29F18N: C, 40.67; H, 4.50; F, 52.66; N, 2.16. Found: C,40.58; H,4.54 F,53.02; N, 2.09.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[Cl:42][C:43]1[N:47]([CH3:48])[N:46]=[C:45]([CH3:49])[C:44]=1[S:50](Cl)(=[O:52])=[O:51]>C(#N)C>[CH3:48][N:47]1[C:43]([Cl:42])=[C:44]([S:50]([O:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])(=[O:52])=[O:51])[C:45]([CH3:49])=[N:46]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: Cc1nn(C)c(Cl)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1nn(C)c(Cl)c1S(=O)(=O)Oc1ccc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c1CNC2=O
Yield: 29 %

Procedure:
In a similar manner to Step 1 of Example 233, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0292 g, 0.0633 mmol) was dissolved in acetonitrile (0.650 mL), and the solution was treated with triethylamine (0.0540 mL, 0.390 mmol) and 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride (0.0447 g, 0.195 mmol) to obtain 4-(1,3-dimethyl-5-chloro-1H-pyrazol-4-ylsulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0120 g, yield 29%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:33](=[O:35])=[O:34]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]2[CH:26]=[CH:25][C:24]([C:33]([OH:35])=[O:34])=[CH:23][CH:22]=2)([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(Br)cc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cl)cc2)(c2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
Under nitrogen, a solution of 4-(4-bromo-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester* (888 mg, 1.97 mmol) in THF (5 mL) was cooled to −78° C. A solution of n-butyllithium (1.5 mL, 1.6M in hexanes) was added dropwise and the mixture maintained at this temperature for 25 minutes. Carbon dioxide gas (generated from dry ice and dried by passage through a column of calcium chloride pellets) was bubbled through the anion solution for 80 minutes then the mixture was allowed to warm to room temperature. The solvents were removed in vacuo then the residue was partitioned between 1N hydrochloric acid and diethyl ether. The organic phase was separated, dried (MgSO4), filtered and concentrated. The combined aqueous phases were further extracted with ethyl acetate, this extract also being dried (MgSO4), filtered, combined with the ethereal extract and concentrated to afford 4-(4-carboxy-phenyl)-4-(4-chloro-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (889 mg); LCMS (PS-A2) Rt 3.52 min [M−tBu+H]+ 360. * This starting material can be made by the method described in Example 14A followed by Example 48A
Reaction SMILES: Br[C:2]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:3]=1[CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8].[Li]CCCC.[B:27](OC(C)C)([O:32]C(C)C)[O:28]C(C)C.Cl>C1COCC1>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:2]([B:27]([OH:32])[OH:28])=[C:3]([CH2:4][O:5][Si:6]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[CH:7]([CH3:9])[CH3:8])[CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: -78 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
[(2-bromo-5-methoxybenzyl)oxy](triisopropyl)silane (1 eq.) was dissolved in anhydrous THF (0.43M solution) and the solution was cooled to −78° C. A solution of n-BuLi (1.6M in hexanes, 1.05 eq.) was added and the resulting mixture was left stirring for 1 h at −78° C. Then triisopropyl borate (50% in THF, 1.3 eq.) was added dropwise and the mixture was allowed to warm to RT overnight. 1N HCl was added and the resulting mixture was left stirring at RT for 30 min. THF was removed in vacuo and replaced with Et2O. The organic phase was washed with water and with brine, then dried over Na2SO4 and evaporated in vacuo. The product was obtained as a colorless oil (64% yield, 65% pure) which was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>CCCCCC.C(OCC)C.O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([Cl:20])=[CH:34][CH:33]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[OH:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccc(Cl)cc1
Reactant: c1ccc(COCn2ccnc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccc(Cl)cc1)c1nccn1COCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 11.8 g. of 1-[(benzyloxy)methyl]imidazole in 100 ml. of anhydrous tetrahydrofuran and 50 ml. of anhydrous diethyl ether a solution of 38 ml. of a 20% butyllithium suspension in hexane dissolved in 75 ml. of anhydrous diethyl ether was added drop-wise with stirring at room temperature. Thereafter a solution of 14.6 g. of 4-chlorobenzophenone in 100 ml. of anhydrous tetrahydrofuran and 50 ml. of anhydrous diethyl ether was added drop-wise at room temperature. The mixture was kept for three hours and then extracted with a dilute acid solution. The acidic aqueous layer was made alkaline with 2 N sodium hydroxide solution and extracted with diethyl ether. Part of the ether was removed by evaporation and the residue washed with water. The ether solution was again concentrated and the desired compound crystallised from a mixture of toluene and petroleum ether (boiling range 28°-40° C.). Melting point of the product was 114.5°-117° C.
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:8]([C:9]([OH:11])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.CN(C)[CH2:17][CH2:18][CH2:19]N=C=N.O.ON1C2C=CC=CC=2N=N1.C(O)CC>CN(C)C=O.O>[C:1]([C:4]1[CH:12]=[C:8]([C:9]([O:11][CH2:17][CH2:18][CH3:19])=[O:10])[C:7]([OH:13])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CN(C)CCCN=C=N
Reactant: CC(=O)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCCO
Product: CCCOC(=O)c1cc(C(C)=O)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.5 %

Procedure:
5-Acetylsalicylic acid (360 mg), 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (458 mg), 1-hydroxybenzotriazole hydrate (36.7 mg), and propanol (2 ml) were dissolved in N,N-dimethylformamide to prepare a solution which was then stirred at room temperature overnight. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give propyl 5-acetylsalicylate (202 mg, yield 45%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=4[CH3:24])=[C:14]([CH3:25])[O:13][C:12]=23)[N:3]=1.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=4[CH3:24])=[C:14]([CH3:25])[O:13][C:12]=23)[N:3]=1
Reactant: COc1ccc(-c2c(C)oc3c(-n4nc(C)nc4C)c(C)nn23)c(C)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(O)cc4C)c(C)oc23)n1
Reaction time: 0.5 h

Procedure:
7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-3-(4-methoxy-2-methyl-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Intermediate C) (100 mg, 0.285 mmol) was dissolved in dry DCM (5 ml). The mixture was placed under an atmosphere of flushed with N2 and treated with boron tribromide (1.423 ml, 1.423 mmol) dropwise at RT. After approximately 30 mins, the reaction was quenched by careful addition of H2O. The mixture was transferred to a separating funnel and extracted with DCM (50 ml). The organic portion was separated and washed with 1M HCl, 1M NaOH, brine, dried (MgSO4) and evaporated in vacuo to give a brown solid. Trituration with EtOAc afforded the title compound as an off white solid. LC-MS Rt 1.02 mins; MS m/z 338.2 [M+H]+; Method=2minLC—30_v002. 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, 1H), 6.8 (s, 1H), 6.75 (d, 1H), 2.35 (s, 3H), 2.30 (s, 6H), 2.2 (s, 3H), 2.15 (s, 3H).