Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:18])/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16].N1C=CC=CC=1.[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>O1CCCC1.O>[CH3:18][N:2]([CH:3]=[C:4]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=1[N+:15]([O-:17])=[O:16])[C:25](=[O:29])[CH2:26][CH2:27][CH3:28])[CH3:1]
Reactant: COC(=O)c1ccc(/C=C/N(C)C)c([N+](=O)[O-])c1
Reactant: CCCC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCC(=O)C(=CN(C)C)c1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a stirred mixture of methyl (E)-4-[2-(dimethylamino)vinyl]-3-nitrobenzoate (500 mg), which was prepared by the method of Brown et al. described in Journal of Medicinal Chemistry, vol. 35, page 2419 (1992), and pyridine (0.16 ml) in tetrahydrofuran (3 ml) was added butyryl chloride (0.21 ml) at 20° C. The reaction mixture was stirred at 40° C. for 24 hours and 50° C. for 4 hours. After cooled to 20° C., the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of ethyl acetate and hexane (1:1) to give methyl 4-(1-dimethylaminomethylene-2-oxopentyl)-3-nitrobenzoate (426 mg) as colorless amorphous.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1.Cl[C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][N:22]2C1CCCCO1.CCN(C(C)C)C(C)C>C(O)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH:10]([NH:12][C:18]3[N:26]=[CH:25][N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][NH:22]4)[CH3:11])[N:7]([CH:13]([CH3:15])[CH3:14])[C:6]=2[CH:16]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CC(C)n1c([C@H](C)N)nc2ccc(F)cc21
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C(C)C
Temperature: 100 °C
Yield: 27 %

Procedure:
(S)-1-(6-Fluoro-1-isopropyl-1H-benzoimidazol-2-yl)ethylamine (0.5 g, 2.26 mmol) was dissolved in n-butanol (5 mL) and 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.54 g, 2.26 mmol) and DIPEA (2 mL, 11.3 mmol) added. The resultant dark red solution was heated to 100° C. overnight. The mixture was allowed to cool to RT and was concentrated in vacuo. The residue was purified by column chromatography (silica gel, gradient 0-10% MeOH in DCM) to afford 379 as a pale red solid (207 mg, 27%). LCMS (Method K): RT 2.68 min [M+H]+ 340.1 1H NMR (DMSO-d6, 400 MHz): δ 8.24 (1H, s), 8.15 (1H, s), 8.00-7.90 (1H, m), 7.64-7.55 (2H, m), 7.02 (1H, td, J=9.31, 2.40 Hz), 5.96-5.77 (1H, m), 4.98-4.85 (1H, m), 1.67 (3H, d, J=6.71 Hz), 1.57 (3H, d, J=6.91 Hz), 1.46 (3H, d, J=6.78 Hz)
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)=[CH:22][CH:21]=3)[C:18](=[O:34])[CH2:17][CH2:16]2)=[CH:11][C:10]=1[C:35]([F:38])([F:37])[F:36].Cl>CN(C=O)C>[Cl:33][C:30]1[CH:29]=[CH:28][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([N:19]3[CH:15]([C:12]4[CH:13]=[CH:14][CH:9]=[C:10]([C:35]([F:36])([F:37])[F:38])[CH:11]=4)[CH2:16][CH2:17][C:18]3=[O:34])=[CH:21][CH:22]=2)=[CH:32][CH:31]=1
Reactant: Nc1ccc(C2CCC(=O)N2c2ccc(Oc3ccc(Cl)cc3)cc2)cc1C(F)(F)F
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CN(C)C=O
Product: O=C1CCC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 65 °C
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
A solution of t-butyl nitrite (4.62 mg, 0.045 mmol) in DMF (0.2 mL) is heated to 65° C. while 5-(4-amino-3-trifluoromethyl-phenyl)-1-[4-(4-chloro-phenoxy)-phenyl]-pyrrolidin-2-one (10 mg, 0.022 mmol) in DMF (0.2 mL) is added in dropwise. The resulted mixture is stirred at 65° C. for an extra 5 min and then cooled down to room temperature. The reaction mixture is treated with 2 N HCl (5 mL) and extracted with EtOAc (3×3 mL). The combined organic layers is concentrated and purified by flash column chromatography (silica gel, EtOAc/hexane 0˜50%) to provide the title compound 1-[4-(4-chloro-phenoxy)-phenyl]-5-(3-trifluoromethyl-phenyl)-pyrrolidin-2-one as colorless oil (˜7 mg, 72%). 1H NMR (CDCl3, 400 MHz) δ 7.53 (d, 1H), 7.47 (s, 1H), 7.46 (d, 1H), 7.41 (t, 1H), 7.31 (d, 2H), 7.25 (d, 2H), 6.88 (d, 2H), 6.86 (d, 2H), 5.28 (t, 1H), 2.60-2.80 (m, 3H), 1.99-2.02 (m, 1H); HPLC-MS calculated for C23H17ClF3NO2 (M+H+) 432.1, found 432.1.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([C:6]([NH:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([O:26]CC)=[O:25])[C:15]=3[CH3:29])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.O.[OH-].[Li+].O1CCCC1.CO>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[CH:31]=[CH:30][C:12]([CH2:13][C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([OH:26])=[O:25])[C:15]=3[CH3:29])=[CH:11][CH:10]=2)=[O:7])=[CH:32][CH:33]=1
Reactant: CCOC(=O)Cn1c(C)c(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(NC(=O)c3ccc(Cl)cc3)cc2)c2ccccc2n1CC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.9 %

Procedure:
Into a dry reaction vessel, ethyl 2-[3-[4-(4-chlorobenzamido)benzyl]-2-methyl-1H-indol-1-yl]acetate (580 mg, 1.26 mmol), lithium hydroxide monohydrate (159 mg, 3.79 mmol), 10 mL tetrahydrofuran, 10 mL methanol, 10 mL water were weighed, and stirred at room temperature for 1 h. The reaction was monitored to be complete by TLC. The solvent was rotate evaporated. It was adjusted to pH=3-4 with 2 N HCl solution. It was filtered, and the filter cake was washed with 20 mL methanol to obtain the product as a white solid 523 mg, at a yield of 95.9%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([N+:22]([O-])=O)=[CH:17][C:16]=2[C:25](=[O:27])[NH2:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([NH2:22])=[CH:17][C:16]=2[C:25](=[O:27])[NH2:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc([N+](=O)[O-])cc(C(N)=O)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)cc(C(N)=O)c1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.4 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-carbamoyl-5-methylnitrobenzene (3.9 g) in methanol (100 ml) was added palladium on carbon (0.5 g) and the mixture was stirred under a hydrogen atmosphere at room temperature for 1.5 hours. The reaction mixture was filtered and the filtrate concentrated in vacuo to give the desired compound (3.5 g, yield 97%) as a dark green amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10]2)=[C:5]([CH2:20][CH3:21])[CH:4]=1)#[CH:2].[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:13]([O:12][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:29]3[CH:30]=[CH:31][C:26]([CH2:25][C:24]([O:23][CH3:22])=[O:33])=[CH:27][CH:28]=3)=[CH:4][C:5]=2[CH2:20][CH3:21])[CH2:11][CH2:10]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(C2(OCc3ccccc3)CC2)c(CC)c1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CCc1cc(C#Cc2ccc(CC(=O)OC)cc2)ccc1C1(OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.5 %

Procedure:
Using General Procedure F; 1-ethynyl-4-(1-benzyloxycyclopropyl)-3-ethyl-benzene (Intermediate 90, 107.0 mg, 0.39 mmol) and methyl-(4-iodophenyl)-acetate (Reagent B, 110.0 mg, 0.39 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (25.0 mg, 0.13 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)palladium(II) (91 mg, 0.13 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-4% EtOAc-hexanes) afforded 130.0 mg (79%) of the title compound as a pale-yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C1COCC1.CO>[CH3:19][O:16][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C
Reaction time: 6 h

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (0.52 g) was dissolved in THF: MeOH (2:1, 10 mL) and 2 eq of TMSCHN2 (2M sln in hex) was added at RT and stirred for 6 h. All volatiles were removed in vacuum by rotavap and the residue was dried in vacuum to give 2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid methyl ester (0.52 g). This was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) 3.83 (s, 3H), 2.65 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[CH:3]=1.[OH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1)[O:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:19][CH:20]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1ccc(Oc2cc(Cl)cc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Yield: 92.7 %

Procedure:
The product from Example 193a (1.06 g, 5.2 mmol), N-(4-hydroxyphenyl)acetamide (0.70 g, 4.5 mmol) and K2CO3 (0.79 g, 5.7 mmol) in DMF (14 ml) was heated at 110° C. for 6 hours. The reaction mixture was cooled to room temperature, diluted with H2O and then extracted with EtOAc. The extract washed with H2O and brine, dried over MgSO4, filtered and concentrated under vacuum giving the crude title compound as a pale brown crystal, which was purified by washing with i-Pr2O to give the desired product as pale brown crystal (1.28 g, 92%).
Reaction SMILES: [C:1]1([P:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:8]2[CH2:12][NH:11][C@H:10]([CH2:13][P:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCOCC1.[C:40]1([P:46](Cl)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1(C)C=CC=CC=1>[C:1]1([P:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:8]2[CH2:12][N:11]([P:46]([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:47])[C@H:10]([CH2:13][P:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(P(C[C@@H]2C[C@H](P(c3ccccc3)c3ccccc3)CN2)c2ccccc2)cc1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CN1CCOCC1
Solvent: Cc1ccccc1
Product: O=P(c1ccccc1)(c1ccccc1)N1C[C@@H](P(c2ccccc2)c2ccccc2)C[C@H]1CP(c1ccccc1)c1ccccc1
Reaction time: 7 h
Yield: 76.8 %

Procedure:
1.01 g (2.23 mmol) of (2S,4S)-4-diphenylphosphino-2-diphenylphosphinomethylpyrrolidine, 1.46 ml (13.38 mmol) of N-methylmorpholine and 30 ml of toluene were placed in a 500 ml sulphonation flask which was provided with a stirrer, thermometer, dropping funnel and argon gasification. While stirring there was then added dropwise thereto at room temperature within 10 minutes a solution of 0.79 g (3.35 mmol) of diphenylphosphinyl chloride in 10 ml of toluene. The reaction was finished after 7 hours. The mixture was then filtered through a sintered glass suction filter and the filtrate was evaporated on a rotary evaporator at 60° C./17 mbar. The residue (2.2 g) was taken up in 30 ml of diethyl ether and treated with 30 ml of 3N hydrochloric acid. The ether phase was then separated and the aqueous phase was extracted a further twice with 30 ml of diethyl ether each time. The extracts were dried over sodium sulphate, filtered off and concentrated on a rotary evaporator at 60° C./17 mbar. For purification the residue (1.57 g) was chromatographed over 140 g of Kieselgel 60 (0.063 to 0.20 mm granular size). A mixture of benzene/ethyl acetate/ethanol (8:2:1) was used as the eluant. After evaporation of the solvent and drying for 16 hours/1 mbar, there was obtained 1.12 g (76.8%) of pure (2S,4S)-4-(diphenylphosphino)-2-[(diphenylphosphino)methyl]-1-(diphenylphosphinyl)-pyrrolidine. Melting point: sintering from 65° C., clear melting at 130° C. [α]D20 =-21.4° (c=0.5 in benzene).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)=[CH:5][CH:4]=1.C(N(CC)CC)C.S(O)(=O)(=O)C.[CH2:31]([O:38][C:39]([C@H:41]1[CH2:46][CH2:45][C@@H:44]([NH2:47])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:31]([O:38][C:39]([C@H:41]1[CH2:46][CH2:45][C@@H:44]([NH:47][C:10]([C:9]2[C:8]([O:7][C:6]3[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:18][CH:17]=3)=[N:16][CH:15]=[CH:14][CH:13]=2)=[O:12])[CH2:43][CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: N[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1
Reactant: CSc1ccc(Oc2ncccc2C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CSc1ccc(Oc2ncccc2C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.7 %

Procedure:
2-(4-methylsulfanyl-phenoxy)-nicotinic acid (3.0 g, 11.5 mmol) was dissolved in dimethylformamide (60 ml) and triethylamine (4.8 ml, 34.4 mmol) was added followed by cis-4-Amino-cyclohexanecarboxylic acid benzyl ester mesylate (4.66 g, 11.5 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (2.42 g, 12.6 mmol) and 1-hydroxybenzotriazole (1.71 g, 12.6 mmol). The reaction was stirred under nitrogen at room temperature for 18 h and the solvent was removed under reduced pressure. The residue was partitioned between sat. sodium bicarbonate solution (50 ml) and ethyl acetate (50 ml) and the aqueous phase was extracted with ethyl acetate (3×100 ml). The combined organic extracts were washed with water (25 ml), brine (25 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with ethyl acetate:pentane (1:1, by volume) to give cis-4-{[2-(4-methylsulfanyl-phenoxy)-pyridine-3-carbonyl]-amino}-cyclohexanecarboxylic acid benzyl ester (4.75 g) as a white solid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH:3]([NH:10][C@H:11]([C:16]([O:18]C)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.CO>[F:1][C:2]([F:20])([F:21])[CH:3]([NH:10][C@H:11]([C:16]([OH:18])=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(c1ccccc1)C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C[C@H](NC(c1ccccc1)C(F)(F)F)C(=O)O
Reaction time: 8 h

Procedure:
To a room temperature solution of methyl N-(2,2,2-trifluoro-1-phenylethyl)-L-leucinate (150 mg, 0.50 mmol) in 2:1 THF/MeOH was added 1M LiOH. The mixture was stirred overnight and concentrated. The residue was partitioned between ethyl acetate and pH 3.5 phosphate buffer. The organic phase was washed with brine, dried over MgSO4 and concentrated to give N-(2,2,2-trifluoro-1-phenylethyl)-L-leucine.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[O:5][CH2:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:10][C:11]=1[CH3:12])(C)C.[F-].C([N+](CC)(CC)CC)C>O1CCCC1>[CH3:12][C:11]1[CH:10]=[C:9]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=2)[S:8][C:7]=1[CH2:6][OH:5]
Reactant: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO[Si](C(C)C)(C(C)C)C(C)C
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccc(OC(F)(F)F)cc2)sc1CO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of triisopropyl({3-methyl-5-[4-(trifluoromethoxy)phenyl]thien-2-yl}methoxy)silane (intermediate 117, 0.97 g) in tetrahydrofuran (30 ml) was treated with tetraethylammonium fluoride (0.392 g) and the reaction mixture stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue purified by flash column chromatography using cyclohexane:ethyl acetate (2:1) as eluent to give the title compound.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=2[Cl:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1>>[ClH:15].[Cl:15][C:9]1[CH:10]=[C:11]([CH:12]=[CH:13][C:8]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:14][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: Nc1ccc(Oc2ccccc2)c(Cl)c1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Product: COc1cc2ncnc(Nc3ccc(Oc4ccccc4)c(Cl)c3)c2cc1OC
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reaction mixture was heated to reflux for 16 hours, 4-amino-2-chlorophenyl phenyl ether was reacted with 4-chloro-6,7-dimethoxyquinazoline hydrochloride to give 4-(3-chloro-4-phenoxyanilino)-6,7-dimethoxyquinazoline hydrochloride salt in 56% Yield, m.p. 260°-265° C.;
Reaction SMILES: [ClH:1].[C:2]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])#[N:3].[CH2:10]([OH:12])[CH3:11]>C(OCC)(=O)C>[ClH:1].[CH2:10]([O:12][C:2](=[NH:3])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:11]
Reactant: CCO
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=N)CC(=O)OCC
Yield: 90 %

Procedure:
Anhydrous hydrogen chloride (2.0 mol) is added to a mixture of ethyl cyanoacetate (1.0 mol) and ethanol (1.1 mol) in ethyl acetate (1 L) at 0° C. over a period of three hours. The mixture is then stirred at 5°-10° C. for ten additional hours. Removal of the solvent under reduced pressure gives the intermediate ethyl 3-ethoxy-3-iminopropanoate hydrochloride in a yield of about 90%. The appropriate o-aminophenol (1.0 mol) is added with vigorous stirring below 15° C. to a solution of ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.0 mol) in methanol and allowed to react for ten hours at less than 20° C. After removal of the methanol, the residue is extracted with acetone and the extract is concentrated and diluted with cold 2-propanol to precipitate the ethyl 2-benzoxazolylacetate intermediate (m.p. 50°-53° C.) which is collected by filtration in a yield of 85%. A mixture of the ethyl 2-benzoxazolylacetate (1.0 mol), a benzaldehyde compound (1.0 mol), piperidine (10 ml) and acetic acid (2.5 ml) in toluene (1 L) is refluxed with agitation for four hours while removing the water of reaction. The reaction mixture is then cooled and filtered to obtain the product. This general procedure may be used to prepare the following compounds:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1>CCO>[Cl:1][C:2]1[N:7]=[C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=C(O)[C@@H]1CCCNC1
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(c2ccnc(Cl)n2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 21 %

Procedure:
To a solution of 2,4-dichloropyrimidine (2.307, 15.49 mmol) and TEA (2.15 mL, 15.49 mmol) in EtOH (19.36 mL) at −10° C. was added (R)-piperidine-3-carboxylic acid (Sigma Aldrich, 2 g, 15.49 mmol). The reaction was allowed to slowly warm to room temperature while stirring. After 20 hours, the reaction was concentrated. The residue was adsorbed onto a plug of silica gel and purified by chromatography through a 100 g silica gel column, eluting with 2% to 10% MeOH in DCM followed by 20% to 50% 5:45:50 folic acid:EtOH:DCM, to provide M4.1 as a white solid in 21% yield. 1H NMR (400 MHz, CD3OD) δ ppm 1.51-1.63 (m, 1H) 1.76-1.91 (m, 2H) 2.09 (dd, J=8.71, 4.40 Hz, 1H) 2.51-2.60 (m, 1H) 3.33-3.51 (m, 3H) 4.01 (br. s., 1H) 6.74 (d, J=6.46 Hz, 1H) 7.96 (d, J=6.26 Hz, 1H); ESI-MS M+H 241.9.
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[C:12]([CH3:19])=[C:13]([NH2:18])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][CH2:8]2)=[CH:3][CH:2]=1.C([O:29][CH2:30][CH3:31])(=O)C>>[C:1]1([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][C:4]([CH:7]2[C:11]3[C:12]([CH3:19])=[C:13]([NH:18][C:30](=[O:29])[CH2:31][C:1]([CH3:20])([CH3:6])[CH3:2])[C:14]([CH3:17])=[C:15]([CH3:16])[C:10]=3[O:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(-c3ccccc3)cc1)CO2
Reactant: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(-c3ccccc3)cc1)CO2
Yield: 71 %

Procedure:
Using 3-(biphenyl-4-yl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 309, the title compound was synthesized in the same manner as in Example 1. Yield: 71%. Melting point: 218-219° C. (ethyl acetate).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[NH:12][C:11]([CH3:23])=[C:10]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25].[O-][Mn](=O)(=O)=O.[K+]>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]2[CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=[C:13]2[N:12]=[C:11]([CH3:23])[C:10]=1[C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25]
Reactant: CCOC(=O)c1cn2c(n1)NC(C)=C(C(=O)OC(C)(C)C)C2c1ccc(Cl)cc1Cl
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1cn2c(-c3ccc(Cl)cc3Cl)c(C(=O)OC(C)(C)C)c(C)nc2n1
Reaction time: 1 h
Yield: 56.6 %

Procedure:
To a stirred solution of 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-2,6-dicarboxylate (191 mg, 0.42 mmol) in acetone (5 mL) was added KMnO4 (66 mg, 0.42 mmol). After 1 h, the reaction was filtered through celite and concentrated under reduced pressure. The resulting residue was diluted with CH2Cl2 and extracted with H2O (2×). The organic layer was dried over MgSO4, concentrated under reduced pressure and recrystallized from EtOAc to obtain 6-tert-butyl 2-ethyl 5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2,6-dicarboxylate (107 mg, 57%) as white crystals.
Reaction SMILES: Br[C:2]1[C:6](=[O:7])[C:5]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([C:3]2[O:4][C:5]3([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)[C:6](=[O:7])[C:2]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(C2=C(Br)C(=O)C3(CCCCC3)O2)cc1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccccc3)C(=O)C3(CCCCC3)O2)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 49.4 %

Procedure:
To 102 mg of 3-bromo-2-{4-(methylsulfonyl)phenyl}-1-oxa-spiro[4,5]dec-2-en-4-one dissolved in 3 ml toluene and 15 ml ethanol, were added 16 mg of tetrakis(triphenylphosphin)palladium(0), 3 ml of 2 M aqueous sodium carbonate and 35 mg of benzeneboronic acid. The reaction mixture was stirred at 90° C. for 12 hours. The reaction mixture was then purified by a procedure similar to the procedure in Step 6 of Example 53 to afford 50 mg of 2-{4-(methylsulfonyl)phenyl}-3-phenyl-1-oxa-spiro[4,5]dec-2-en-4-one as a solid. mp: 126-127° C. NMR: δ1.77-1.85 (m, 10H), 3.06 (s, 3H), 7.27 (m, 2H), 7.35 (m, 3H), 7.83 (d, J=8.1 Hz, 2H), 7.94 (d. J=8.1 Hz, 2H). IR (cm−1): 2936, 1693, 1621, 1404, 1318, 1147, 1129, 730.