Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:16]2[C:7](=[C:8]([OH:17])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[C:16]2[C:7](=[C:8]([O:17][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCCBr
Reactant: COc1cccc2c(O)c3ccccc3nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1c2ccccc2nc2c(OC)cccc12
Temperature: 120 °C
Yield: 31.8 %

Procedure:
4-methoxyacridin-9-ol (2.0 g, 8.88 mmol), 1-bromooctane (2.17 g, 11.24 mmol), and potassium carbonate (7.91 g, 57.2 mmol) was mixed in N,N-dimethylformamide and heated at 120° C. for 8 h and the potassium carbonate was filtered off. The reaction mixture was quenched with water and extracted two times with ether and the combined organic phases was then washed once with 1M HCl, two times with water, and evaporated to obtain a yellow solid. The solid was recrystallised in methanol to give 4-methoxy-9-(octyloxy)acridine (0.95 g, 2.82 mmol) as yellow crystals. 1H-NMR (CDCl3, δ): 0.881 (t, 3H), 1.2-1.4 (m, 10H), 1.924 (m, 2H), 3.985 (s, 3H), 4.507 (t, 2H), 7.2-7.3 (m, 3H), 7.621 (d, 1H), 7.707 (m, 1H), 8.181 (m, 1H), 8.498 (m, 1H) MS MALDI-TOF (m/z): 337.146
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F-].C([N+](C[CH2:21][CH2:22][CH3:23])(CCCC)CCCC)CCC.[CH2:24](OCC)C>>[CH:21]1([CH2:2][C:3](=[CH2:24])[CH2:4][CH2:5][OH:1])[CH2:22][CH2:23]1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C1CCOC1
Reactant: CCOCC
Agent: [F-]
Product: C=C(CCO)CC1CC1

Procedure:
A 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (6.44 ml, 6.44 mmol) was added to a solution of 2.13 g (5.85 mmol) of the title compound in step (v) of Example XA1 in diethyl ether (5 ml), and the mixture was stirred at room temperature for 10 min. Tetrahydrofuran (5 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 2 hr. An aqueous ammonium chloride solution was added thereto, and the mixture was extracted with diethyl ether. The organic layer was washed with brine, was dried over anhydrous sodium sulfate and was then filtered. The filtrate was concentrated at a low temperature under the reduced pressure, and the residue was purified by distillation to give 545.4 mg (yield 74%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].S(Cl)([Cl:17])=O>>[CH3:1][NH:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:17])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: CNc1ccc(C(=O)O)cc1[N+](=O)[O-]
Product: CNc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
4-Methylamino-3-nitro-benzoyl chloride (4.3 g) was prepared starting from 4-methylamino-3-nitro-benzoic acid (4 g) in thionyl chloride (20 mL). The reaction was heated to 80° C. for 8 h. The solvent was evaporated to isolate pure compound without any further purification.
Reaction SMILES: [C:1]([C:3](=[C:25]1[CH2:29][CH2:28][CH2:27][O:26]1)[C:4]1[C:5]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]([CH:14]([F:16])[F:15])=[N:8][C:9]=1[C:10]([F:13])([F:12])[F:11])#[N:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].FC(F)(F)S([Cl:45])(=O)=O.Cl>C(OCC)(=O)C.C1COCC1>[F:15][CH:14]([F:16])[C:7]1[C:6]([C:17]([O:19][CH3:20])=[O:18])=[C:5]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:4]([C:3](=[C:25]2[CH:29]([Cl:45])[CH2:28][CH2:27][O:26]2)[C:1]#[N:2])=[C:9]([C:10]([F:12])([F:11])[F:13])[N:8]=1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2CCCO2)c1CC(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C(F)F)nc(C(F)(F)F)c(C(C#N)=C2OCCC2Cl)c1CC(C)C
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 25.9 %

Procedure:
A 100 mL round-bottomed flask was charged with 1.2 g (2.9 mmol) of the compound of Example 2 and 30 mL anhydrous THF and cooled to -70° C. Then 2.9 mL sodium bis(trimethylsilyl)amide (1.0 M solution in THF) was added. After 5 minutes, 0.48 g (2.9 mmol) trifluoromethanesulfonyl chloride was added. To the reaction mixture was added 0.25 g additional trifluoromethanesulfonyl chloride. The reaction mixture was poured into dilute HCl and extracted with ethyl ether. The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give 1.3 g of crude product. Chromatography using 15% ethyl acetate in hexanes yielded 0.34 g of the desired product, as a yellow oil, a 27% yield. nD25 1.4860.
Reaction SMILES: ClCCl.Cl[CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7].[CH2:23]([SH:25])[CH3:24].C(N(CC)CC)C>O>[CH2:23]([S:25][CH:5]([NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19](=[O:21])[CH3:20])[C:6]([Cl:9])([Cl:8])[Cl:7])[CH3:24]
Reactant: CCS
Reactant: CC(=O)Oc1ccccc1C(=O)NC(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCSC(NC(=O)c1ccccc1OC(C)=O)C(Cl)(Cl)Cl
Yield: 90.3 %

Procedure:
50 ml of dichloromethane was added to 7.9 g of N-(1,2,2,2-tetrachloroethyl)-2-acetoxybenzamide. 1.3 g of ethyl mercaptan was add to the solution under stirring and then 2.0 g of triethylamine was added dropwise thereto at 10°-15° C. After effecting the reaction at room temperature for one hour, water was added thereto and the solution was allowed to stand. Then the dichloromethane layer was separated out, dried with unhydrous sodium sulfate and concentrated to obtain 7.0 g of N-(1-ethylthio-2,2,2-trichloroethyl)-2-acetoxybenzamide as white crystals.
Reaction SMILES: [N+:1]([C:4]1[C:13](Cl)=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2].[CH3:15][NH:16][CH3:17]>>[N+:1]([C:4]1[C:13]([N:16]([CH3:17])[CH3:15])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1c(Cl)ccc2ncccc12
Reactant: CNC
Product: CN(C)c1ccc2ncccc2c1[N+](=O)[O-]

Procedure:
5-Nitro-6-chloroquinoline, prepared as described by Manske & Kulka, Organic Reactions, Vol. VII, 59 (1953) and Campbell et al., J. Am. Chem. Soc., 68, 1559 (1946), was allowed to react with dimethylamine to yield 5-nitro-6-dimethylaminoquinoline. This material was converted to the title compound by the procedure described in Example 33.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].N[C:6]1[CH:7]=[C:8]([CH2:21][OH:22])[CH:9]=[C:10]([C:12]([CH3:20])([CH3:19])[O:13][SiH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:11]=1.[CH2:23]=O>CO.[Cl-].[Zn+2].[Cl-]>[C:15]([SiH2:14][O:13][C:12]([CH3:20])([CH3:19])[C:10]1[CH:9]=[C:8]([CH2:21][OH:22])[CH:7]=[C:6]([N:2]([CH3:1])[CH3:23])[CH:11]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1cc(N)cc(CO)c1
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: CO
Product: CN(C)c1cc(CO)cc(C(C)(C)O[SiH2]C(C)(C)C)c1
Yield: 82 %

Procedure:
Sodium cyanoborohydride (470 mg, 7.48 mmol) was added to a magnetically stirred solution of [3-amino-5-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-methanol (1.0 g, 3.74 mmol) in methanol (30 mL). The reaction vessel was capped with a septum and pierced with a needle. In a separate flask, parafomaldehyde (449 mg, 15.0 mmol) was heated with heat gun and the gas cannulated into the reaction vessel with a stream of nitrogen. After all the paraformaldehyde was added, a solution of zinc chloride (510 mg, 3.74 mmol) in methanol (8 mL) was added dropwise. Gas evolution was observed. After the addition was complete, TLC indicated that the starting material had been consumed. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with 1% aqueous ammonium hydroxide and then with brine. The solution was dried over sodium sulfate, filtered, concentrated, and purified by silica gel chromatography, eluting with 10-60% ethyl acetate/hexanes to give [3-(tert-butyl-dimethyl-silanyloxymethyl)-5-dimethylamino-phenyl]-methanol (906 mg, 82% yield) as a viscous oil.
Reaction SMILES: COC1C=CC=CC=1C1NC(=O)C2C(=CC=CC=2)N=1.[NH2:20][C:21]1[CH:29]=[C:28]2[O:30][CH2:31][O:32][C:27]2=[CH:26][C:22]=1[C:23]([NH2:25])=[O:24].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH:38]=O>>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:38]2[NH:25][C:23](=[O:24])[C:22]3[C:21](=[CH:29][C:28]4[O:30][CH2:31][O:32][C:27]=4[CH:26]=3)[N:20]=2)[CH:40]=[CH:41][CH:42]=1
Reactant: NC(=O)c1cc2c(cc1N)OCO2
Reactant: COc1cccc(C=O)c1
Agent: COc1ccccc1-c1nc2ccccc2c(=O)[nH]1
Product: COc1cccc(-c2nc3cc4c(cc3c(=O)[nH]2)OCO4)c1
Yield: 6.1 %

Procedure:
According to the preparation of 42, 16 (1.0 g, 5.5 mmol) and 3-methoxybenzaldehyde (34) (0.7 g, 5.5 mmol) were used to afford 54 (0.1 g, 8.8%) as pale yellow needles.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:30])=[C:4]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([OH:26])[C:18]=2[CH2:27][CH2:28][CH3:29])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].C(=O)(O)[O-].[Na+].[CH2:36](I)[CH3:37]>CN(C)C=O>[CH2:36]([O:22][C:21](=[O:23])[C:20]1[CH:24]=[CH:25][C:17]([O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:4]2[CH:5]=[C:6]([CH3:9])[C:7]([OH:8])=[C:2]([OH:1])[C:3]=2[CH3:30])=[C:18]([CH2:27][CH2:28][CH3:29])[C:19]=1[OH:26])[CH3:37]
Reactant: CCI
Reactant: CCCc1c(OCCCCCCc2cc(C)c(O)c(O)c2C)ccc(C(=O)O)c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCCCCc2cc(C)c(O)c(O)c2C)ccc(C(=O)OCC)c1O
Reaction time: 10 h
Yield: 67 %

Procedure:
A mixture of 0.170 g (1.68 mmole) of 4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid, 0.157 g (1.87 mmole) of sodium bicarbonate and 1.4 mL (16.8 mmole) of ethyl iodide in 10 mL of dimethylformamide was stirred at 50° for 10 hours. Workup as in Example 160 gave an oil which was purified by chromatography on 20 g of silica gel. Elution with 25% ethyl acetate-hexane gave the product which was recrystallized from hexane to give 0.50 g, mp 61°-64°, (67% yield) of 4-[6-(3,4-dihydroxy-2,5-dimethylphenyl)hexyloxy]-2-hydroxy-3-propylbenzoic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][C:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:13][CH:14]=3)[NH:9][C:8]=2[CH2:28][C:29]([CH3:35])([CH3:34])[C:30]([O:32][CH3:33])=[O:31])=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[K].[C:48]1([S:54](Cl)(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>C1COCC1.CN(P(N(C)C)(N(C)C)=O)C.C1(C)C=CC=CC=1>[C:48]1([S:54]([N:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)[CH:11]=3)[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:37][CH:36]=3)=[C:8]2[CH2:28][C:29]([CH3:34])([CH3:35])[C:30]([O:32][CH3:33])=[O:31])(=[O:56])=[O:55])[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COC(=O)C(C)(C)Cc1[nH]c2cc(OCc3ccc4ccccc4n3)ccc2c1Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [K]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)Cc1c(Cc2ccc(Cl)cc2)c2ccc(OCc3ccc4ccccc4n3)cc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-[3-(4-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate (Step D, Example 37) (208 mg) in dry THF (5 mL) and HMPA (0.5 mL) at -78° C. was added 0.58M potassium hexamethyldisilazane in toluene (0.77 mL) and the solution then stirred at -78° C. for 15 minutes. Then freshly distilled benzenesulfonyl chloride (0.062 mL) was added and stirred at -78° C. for 2.5 hours. The reaction mixture was quenched with 25% aq. NH4OAc, extracted with EtOAc, dried over Na2SO4 and evaporated to give crude product. Chromatography of the residue in a column of flash silica gel (eluting with EtOAc-hexane 25:75) afforded the title product as an oil.
Reaction SMILES: Br[C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:16]1[CH2:20]OC[CH2:17]1.C([Mg]Cl)(C)C>[Ni].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH:16]([C:2]1[C:3]([CH3:15])=[C:4]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)[CH:5]=[CH:6][CH:7]=1)([CH3:20])[CH3:17]
Reactant: C1CCOC1
Reactant: Cc1c(Br)cccc1C1=NC(C)(C)CO1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Product: Cc1c(C2=NC(C)(C)CO2)cccc1C(C)C
Temperature: 15 °C

Procedure:
A dry 3-neck 250 mL round bottom flask equipped with magnetic stirring and held under a nitrogen atmosphere was charged with 5.0 g 2-(3-bromo-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole, 60 mL anhydrous THF, and 100 mg Ni(dppp)Cl2. The mixture was cooled to 15° C., and isopropyl magnesium chloride (11 mL, 2M in ethyl ether) was added. A mild exotherm took place, and the mixture darkened slightly. The reaction was stirred overnight at room temperature, at which point 1H NMR indicated 50% completion. Addition of ca 75 mg Ni(dppp)Cl2 and reflux for 3 hours resulted in no further progression of the reaction. The mixture was cooled to 15° C., and an additional 13 mL of isopropyl magnesium chloride (2M in ethyl ether) and 100 mg of nickel catalyst were added and the mixture was stirred overnight at room temperature. The reaction was quenched with saturated aqueous NH4Cl, the organic layer was removed, the aqueous layer was extracted, and the organic phases were combined and dried. The solvent was removed in vacuo to yield 3.84 g crude product as a yellow oil. Column chromatography on silica gel using 4:1 hexanes: ether as eluant yielded 0.79 g of 2-(3-isopropyl-2-methyl-phenyl)-4,4-dimethyl-4,5-dihydro-oxazole as a colorless oil. 1H NMR (CDCl3, 200 MHz), δ (ppm): 7.5 (d, 1H), 7.37 (d, 1H), 7.22 (t, 1H), 4.13 (s, 2H), 3.23 (m, 1H), 2.5 (s, 3H), 1.45 (s, 6H), 1.22 (d, 6H). The oxazoline was suspended in 34 mL of 6N HCl and refluxed in an oil bath for 6 hours. The mixture was cooled and extracted with CH2Cl2. The extract was dried over Na2SO4 and evaporated to yield 0.76 g of 3-isopropyl-2-methyl-benzoic acid, suitably pure for the next step. 1H NMR (CDCl3, 300 MHz), δ (ppm): 7.8 (d, 1H), 7.48 (d, 1H), 7.3 (t, 1H), 3.3 (m, 1H), 2.55 (s, 3H), 1.2 (d, 6H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].NCCC1C2C(=CC=CC=2)NC=1.[Cl:18][CH2:19][CH2:20][CH2:21][C:22](Cl)=[O:23]>>[Cl:18][CH2:19][CH2:20][CH2:21][C:22]([N:3]([O:4][CH3:5])[CH3:2])=[O:23]
Reactant: CNOC
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: NCCc1c[nH]c2ccccc12
Product: CON(C)C(=O)CCCCl
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a solution of 4-chlorobutyryl chloride (10.0 g in 200 mL of dry methylene chloride) was added 10.4 g of N,O-dimethylhydroxylamine hydrochloride. The mixture was stirred under nitrogen and maintained below 25° C. by cooling in an ice bath as necessary while triethylamine 5 (29.1 mL)was added dropwise over about 20 minutes, resulting in precipitation. After 1.5 hours at room temperature, the mixture was concentrated in vacuo. The residue was partitioned between 100 mL of diethyl ether and 100 mL of saturated aqueous sodium bicarbonate solution. The organic layer was washed with an additional 100 mL of saturated sodium bicarbonate, and the aqueous fractions were back-extracted with ether. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo to give 10.5 g (90%) of an oil, which had satisfactory purity by 1H NMR (CDCl3). Mass spectrum (PB-NH3 / CI): m/e=166 (M+H).
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])[C:10]=1[CH3:11])=[O:5])C.[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2.[OH-].[K+]>N1CCCCC1.C(O)C>[C:14]([CH2:13][CH2:12][C:9]1[C:10]([CH3:11])=[C:6]([C:4]([OH:3])=[O:5])[NH:7][C:8]=1[CH:19]=[C:25]1[C:24]2[C:28](=[CH:29][CH:30]=[C:22]([Br:21])[CH:23]=2)[NH:27][C:26]1=[O:31])([OH:16])=[O:15]
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Reactant: O=C1Cc2cc(Br)ccc2N1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(C(=O)O)[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c1CCC(=O)O
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.1 %

Procedure:
A mixture of 5-formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 5-bromo-2-oxindole (220 mg), and piperidine (2 drops) in ethanol (2 mL) was stirred at 90° C. for 2 hours. Potassium hydroxide (537 mg) was added and the temperature was increased to 95° C. for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved into water and acidified with 2 N hydrochloric acid to pH 2. The precipitate that formed was filtered, washed with water and dried in a vacuum oven overnight to give 411 mg (98%) of 4-(2-carboxyethyl)-3-methyl-5-(5-bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[O:12][C:13]2[C:18]([C:19](=[O:21])[CH:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(=O)C>O1CCCC1>[CH2:1]([N:8]([CH2:10][CH:11]1[CH2:20][C:19](=[O:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[O:12]1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)Cc1cc(=O)c2ccccc2o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)CC1CC(=O)c2ccccc2O1
Temperature: -78 °C
Reaction time: 4 h
Yield: 31.2 %

Procedure:
A stirred solution of 2-(N-benzyl-N-methylaminomethyl)chromone (15.6 g) in dry tetrahydrofuran (400 ml) at -78° C., was treated with a suspension of LiAlH4 (3.2 g) in dry tetrahydrofuran (50 ml) and the resulting mixture was stirred at -78° C. for 4 hours before being acidified with glacial acetic acid and allowed to stand at room temperature for 17 hours. The mixture was then filtered and the filtrate was evaporated, dissolved in chloroform and washed with water. The dried, evaporated organic extracts gave an oil which was chromatographed on alumina eluting with ether to give the title compound as a yellow oil (4.9 g).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=[O:5])#[N:2].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])CO)[CH3:8].[CH3:16]S(O)(=O)=O>>[C:1]([CH2:3][C:4]([O:6][CH:9]([CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5])#[N:2]
Reactant: CCCCC(CC)CO
Reactant: N#CCC(=O)O
Reactant: CS(=O)(=O)O
Product: CCCCCC(CC)OC(=O)CC#N
Temperature: 130 °C

Procedure:
Cyanoacetic acid (85.5 g; 1.0 mol), 2-ethylhexanol (172 g; 1.32 mol) and methanesulfonic acid (0.47 g; 0.005 mol) were introduced into a 500 ml flask under a nitrogen atmosphere. The reaction vessel was equipped with a distillation column that is provided with means for recycling the alkanol distillate to the flask. The mixture was heated slowly to a maximum of 130° C. while gradually reducing the pressure to about 15 mm of Hg. Water was continuously removed from the distillates (bp 68-80° C./100 mm Hg) and the organic layer (2-ethylhexanol) was returned to the flask until the reaction was complete. After distilling off the unreacted 2-ethylhexanol, the ethylhexyl cyanoacetate (bp 146° C./5 mm Hg) was isolated as a clear liquid. The average yield was 194 g (98.1% of theoretical) having a purity of 99.5% (GC assay).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([OH:15])[CH:11]=[CH:12][C:13]=2[CH3:14])[CH:5]=[C:4]([Cl:16])[N:3]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])(=O)=O>ClCCl>[Si:31]([O:15][C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[C:8]([C:6]2[CH:5]=[C:4]([Cl:16])[N:3]=[C:2]([NH2:1])[N:7]=2)[CH:9]=1)([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32]
Reactant: Cc1ccc(O)cc1-c1cc(Cl)nc(N)n1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1-c1cc(Cl)nc(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
3-(2-amino-6-chloropyrimidin-4-yl)-4-methylphenol (2.12 g, 9.00 mmol) obtained in Step 4 above was placed in a reaction vessel, and then dichloromethane (60 ml) was added thereto. The mixture was cooled to 0° C. 2,6-Lutidine (1.25 ml, 10.7 mmol) and tert-butyldimethylsilyl trifluoromethanesulfonate (2.27 ml, 9.88 mmol) were sequentially added to the solution. The mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 minutes. The resulting reaction solution was diluted with dichloromethane (150 ml), and sequentially washed with a saturated aqueous sodium bicarbonate solution (150 ml), water (150 ml), and a saturated aqueous sodium chloride solution (150 ml). The dichloromethane solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=9:1 to 6:1) to yield 4-[5-(tert-butyldimethylsilanyloxy)-2-methylphenyl]-6-chloropyrimidin-2-ylamine (Compound 1-5) (2.41 g, 77%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[NH2:19][CH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([CH3:29])[C:21]1=[O:30].N1C2C(=CC=CC=2)CC1=O>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([C:20]2([NH2:19])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]2=[O:30])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: CN1C(=O)C(N)c2ccccc21
Agent: Cl
Agent: O=C1Cc2ccccc2N1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(C)c2ccccc21

Procedure:
Following General Procedure I above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-amino-1-methyl-2-indolinone monohydrochloride (Example 5-J), the title compound, as a ˜1:1 diastereomeric mixture at C3 of the indolinone, was prepared as a white solid having a decomposition point of 215-220° C. Purification was by flash chromatography eluting with 3:1 CH2Cl2/EtOAc gradient to straight EtOAc followed by recrystalization from CHCl3. Rf=0.16 and 0.22 (EtOAc).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)=[O:4].[OH2:15]>C(#N)C>[F:12][C:11]([F:14])([F:13])[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][OH:15])[CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Reactant: O
Solvent: CC#N
Product: O=C(CO)c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2-bromo-1-[3-(trifluoromethyl)phenyl]ethanone (1 g) in acetonitrile (2.5 mL) and water (10 mL) is treated under microwave irradiation (125° C., 50 min). The same experiment is repeated five times. All the vials are collected, extracted with DCM, dried over magnesium sulfate and concentrated under vacuum to give the desired compound.