Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][OH:16])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CN(C1C=CC=CN=1)C.[C:44](OC(=O)C)(=[O:46])[CH3:45]>ClCCl>[C:1]([O:5][C:6]([CH:8]1[CH:14]([CH2:15][O:16][C:44](=[O:46])[CH3:45])[CH2:13][CH2:12][CH2:11][CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)(=[O:19])=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(CO)C2C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(S(=O)(=O)N2CCCCC(COC(C)=O)C2C(=O)OC(C)(C)C)cc1
Temperature: 0 °C

Procedure:
To a solution of 3-Hydroxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester (0.5 g, 1.25 mmoL) in 6.3 mL dichlormethane was added triethylamine (0.19 mL, 1.38 mmoL) and dimethylaminopyridine (15 mg, 0.125 mmoL). This solution was cooled to 0° C. and acetic anhydride (0.18 ml, 1.88 mmoL) was added in at once. After 5 minutes the reaction was diluted with dichloromethane and washed sequentially with 0.5N HCl, water, and brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure to yield 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid tert-butyl ester; MS: (M+H)+ =442, (M+NH4)+ =459.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.[C:12]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=CC=C[CH:13]=1.CC(O)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH:12]([CH3:17])[CH3:13])[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 77.6 %

Procedure:
5-Fluoro-2-nitrophenol (48 g) was dissolved in dry tetrahydrofuran (THF) (300 mL). Triphenylphosphine (88 g) and 2-propanol (47 mL) were added, and the resulting mixture was cooled to 0° C. Diisopropylazodicarboxylate (66 mL) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred over night. The solvent was evaporated in vacuo and the resulting mixture was filtered through silica (heptane/ethyl acetate 1:1). The solvent was evaporated in vacuo and the resulting mixture was recrystallised from heptane/ethyl acetate (1:1). The organic phase was separated from the crystalline solid by filtration, the solvent was evaporated in vacuo, and the remaining product was purified by flash chromatography (silica gel, heptane/ethyl acetate 9:1), yielding the title compound as colourless oil (47.2 g, 78%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=[CH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CCCC)CCCC)CCC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC(C)=CC=1>[C:2]1([CH:1]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccc(C)cc1
Solvent: CCCCN(CCCC)CCCC
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 120 °C
Yield: 89 %

Procedure:
7.05 g (0.05 mol) of benzoyl chloride, 6.5 g (0.0625 mol) of styrene, 8.65 g (0.05 mol) of tri-n-butylamine, 0.1122 g (0.0005 mol) of palladium acetate and 100 ml of p-xylene are introduced into a 250 ml flask and heated to 120° C., with stirring. A slight evolution of gas is observed. After the mixture has been stirred for 2 hours at 120° C., it is cooled and extracted by shaking with 2×25 ml portions of 2 N hydrochloric acid, and the organic phase is dried with magnesium sulfate. The p-xylene is distilled off and the residue is recrystallised from ethanol. 8.0 g (0.0445 mol) of stilbene are obtained as a colourless, crystalline compound, corresponding to a yield of 89% of theory; melting point 125° C.
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=O)[CH3:2].[OH-].[Na+].Br[CH2:14][CH2:15][CH2:16][CH2:17]C=C.Cl>CO.CCOC(C)=O>[CH2:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])[CH2:2][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCBr
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: C=CCCCCSC[C@@H](C)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.62 g (10 mmol) (S)-3-acetylsulfanyl-2-methyl-propionic acid in 20 ml MeOH is treated with 7.5 ml 4N NaOH and 1.63 g (10 mmol) 6-bromo-hex-1-ene. After being stirred for 1 h at rt the mixture is diluted with 50 ml EtOAc and acidified with 25 ml 1N HCl. The organic phase is washed with brine, dried with sodium sulfate and concentrated in vacuo to yield (S)-3-hex-5-enylsulfanyl-2-methyl-propionic acid as an oil which is used without purification for the next step.
Reaction SMILES: C(Cl)(Cl)Cl.CCCCCC.C1CO[C:13]2([C:19]3[CH:20]=[CH:21][C:22]([CH2:24][C:25](N)=[O:26])=[CH:23][C:18]=3[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]2=3)[O:12]1.CC(C)=[O:36].CCCCCC>>[CH:21]1[C:20]2[CH:17]=[CH:16][C:15]3[CH:28]=[CH:29][CH:30]=[CH:31][C:14]=3[C:13](=[O:12])[C:19]=2[CH:18]=[CH:23][C:22]=1[CH2:24][C:25]([OH:36])=[O:26]
Reactant: CC(C)=O
Reactant: NC(=O)Cc1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: O=C(O)Cc1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
11.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is refluxed for 2 hours in 70 ml. of acetic acid and 105 ml. of concentrated hydrochloric acid. The mixture is cooled and diluted, then extracted with ether. The ethereal solution is extracted with aqueous sodium carbonate and the extract acidified and extracted with ethyl acetate to afford a 70% yield of 2-(5H-dibenzo[a,d] cyclohepten-5-on-2-yl)propionic acid., m.p. (chloroform-hexane) 138°-139°C.; m.p. (acetone-hexane) 113°-115°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetic acid, m.p. (acetone-hexane) 148°-149.5°C.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Li])CCC.[CH3:15][C:16]1[CH:20]([Si:21](Cl)([CH3:23])[CH3:22])[C:19]([CH3:25])=[C:18]([CH3:26])[C:17]=1[CH3:27]>C(OCC)C>[CH2:1]([N:5]([C:20]1([SiH:21]([CH3:23])[CH3:22])[C:19]([CH3:25])=[C:18]([CH3:26])[C:17]([CH3:27])=[C:16]1[CH3:15])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCCC
Reactant: CC1=C(C)C([Si](C)(C)Cl)C(C)=C1C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCN(CCCC)C1([SiH](C)C)C(C)=C(C)C(C)=C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
A 250 ml roundboftom flask equipped with a condenser, stirrer, thermometer and dropping funnel with nitrogen inlet was charged with 50 ml diethyl ether in which di-n-butylamine (3.8 g, 27 mmol) was dissolved. The solution was cooled to 0° C. and n-butyllithium (26 mmol, 1.6 M in hexane) was added; the solution was stirred for 2 hours at 2° C. and 30 minutes ar room temperature. The solution was then cooled to -90° C. and tetramethylcyclopentadienyl-dimethylsilylchloride (5.7 g, 27 mmol) was added in one portion. The mixture was then stirred for 16 hours allowing the temperature of the reaction mixture to rise to room temperature. A precipitate was filtered off and the solvent was evaporated. The remaining residue was distilled at sub-atmospheric pressure (2.7 mbar) at 130° C. to obtain di-n-butylamino-dimethylsilyl-tetramethylcyclopentadiene (3.4 g). The product was characterized by GC, GC-MS, 13C and 1H NMR.
Reaction SMILES: [CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=2[O:2]1.[CH:13]([NH:16][OH:17])([CH3:15])[CH3:14]>>[CH2:1]1[CH2:12][O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[N+:16]([CH:13]([CH3:15])[CH3:14])[O-:17])=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: CC(C)NO
Product: CC(C)[N+]([O-])=Cc1ccc2c(c1)OCCO2

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-ethylenedioxybenzaldehyde and N-isopropylhydroxylamine. The crude produce was purified by column chromatography over silica gel using ethyl acetate as the eluant. The title compound was isolated in 53% yield as a solid, m.p. 108.8° C. (Rf=0.31 on a silica gel plate using EtOAc as the eluant).
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].I[C:13]1[C:18]([O:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)=[CH:17][CH:16]=[C:15]([CH3:34])[N:14]=1.[OH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1>O>[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[CH:22][CH:21]=[C:20]2[O:19][C:18]1[C:13]([C:39]2[CH:40]=[CH:41][C:36]([OH:35])=[CH:37][CH:38]=2)=[N:14][C:15]([CH3:34])=[CH:16][CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Reactant: OB(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccc(O)cc3)c2cc1OC
Temperature: 70 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
N,N-Dimethylformamide (1 ml) and a 2 M aqueous potassium carbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 4-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 70° C. overnight. The reaction solution was cooled to room temperature, water was then added thereto, 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 by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (34 mg, yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[I:25][C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][C@@H](O)CO)=[CH:28][CH:27]=1>CN(C=O)C>[I:25][C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][C@@H:1]2[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]2)=[CH:28][CH:27]=1
Reactant: COC(C)(C)OC
Reactant: OC[C@H](O)COc1ccc(I)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(I)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethoxypropane (1.94 ml, 15.8 mmol) and PPTS (0.079 mg, 0.32 mmol) are added to a solution of (S)-3-(4-Iodo-phenoxy)-propane-1,2-diol (0.93 g, 3.16 mmol) in DMF (20 ml), and the resulting solution is left to stir at room temperature overnight. The solvent is removed in vacuo and the residue is purified by chromatography (SiO2, EtOAc:Iso-hexane) to afford (R)-4-(4-Iodo-phenoxymethyl)-2,2-dimethyl-[1,3]dioxolane as a colourless oil.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)([CH3:3])[CH3:2].[BH4-].[Na+].C([OH:15])C>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([OH:15])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)N1CCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a cold solution of 1-isopropylpiperidone (purchased at Chemie Brunschwig AG, 100 g, 1.0 eq.) in ethanol (500 mL) was added sodium borohydride (19.3 g, 0.7 eq.) in small portions. The reaction mixture was allowed to warm up to room temperature and was stirred overnight. After concentrating the mixture in vacuo, ice water (1 kg), sodium hydroxide aqueous solution (28% in mass, 0.5 L) and dichloromethane (1 L) were added. The mixture was stirred vigorously for 4 h and the aqueous layer was extracted with dichloromethane. Combined organic layers were washed with brine, dried over sodium sulfate, filtered and purified by fractionated vacuum distillation (20 mbar). One fraction (boiling point 95° C. at 20 mBar) was isolated to yield 61.3 g (60%) of the desired product as colorless oil. MS (m/e): 144.5 (MH+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][C:3]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OC)CC3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COC1(c2ccc(C#Cc3ccc(C(=O)O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-(1-methoxycyclopropyl)-phenylethynyl]-benzoate (Compound 67, 110.0 mg, 0.34 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (160.0 mg, 4.0 mmols, 2.0 mL of a 2N aqueous solution) and stirred overnight at room temperature. Work-up afforded 85.0 mg (86%) of the title compound as an orange solid.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:20]=[C:21]2[C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:25]=3[NH:24][C:23](=[O:31])[N:22]2[CH:32]=1.C(N(CC)CC)C>CN(C=O)C>[C:2]([N:28]1[CH2:29][CH2:30][C:25]2[NH:24][C:23](=[O:31])[N:22]3[CH:32]=[C:19]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=4[F:12])[N:20]=[C:21]3[C:26]=2[CH2:27]1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=c1[nH]c2c(c3nc(-c4ccccc4F)cn13)CNCC2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1CCc2[nH]c(=O)n3cc(-c4ccccc4F)nc3c2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Benzyl chloroformate (57 uL, 0.4 mmol) was added to a solution of 2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e] pyrimidin-5(6H)-one (124 mg, 0.4 mmol) and triethylamine (74 uL, 0.5 mmol) in DMF (1 mL) at room temperature. The reaction mixture was stirred for 1 hour, then poured into ice water. The precipitate was collected, washed with 95% ethanol and ether, and subsequently dried to give 9-Carbobenzyloxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]pyrido[3,4-e]pyrimidin-5(6H)-one (Compound 44). Recrystallization from aqueous ethanol afforded Compound 41 as an off-white solid. m.p. 250° C. (d).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.O.[NH2:17][NH2:18]>N1C=CC=CC=1>[N:17](=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:2]=1[OH:1])[NH2:18]
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NN=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
A solution of 2-hydroxy-4-morpholin-4-yl-benzaldehyde (0.135 g, 0.65 mmol) in pyridine (5 mL) was treated with hydrazine hydrate (33 mg, 0.65 mmol) and stirred for 3 h at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the product as a pale yellow solid (96 mg, 67%)
Reaction SMILES: [CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:3](=[O:6])[CH:4]=[CH2:5].Br[C:21]1[CH:22]=[C:23]2[C:28](=[N:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25][CH2:24]2.CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][N:2]([CH2:7][C:8]1[C:16]2[C:11](=[C:12]([CH3:17])[CH:13]=[CH:14][CH:15]=2)[N:10]([CH3:18])[C:9]=1[CH3:19])[C:3](=[O:6])/[CH:4]=[CH:5]/[C:21]1[CH:30]=[N:29][C:28]2[NH:27][C:26](=[O:31])[CH2:25][CH2:24][C:23]=2[CH:22]=1
Reactant: C=CC(=O)N(C)Cc1c(C)n(C)c2c(C)cccc12
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Product: Cc1cccc2c(CN(C)C(=O)/C=C/c3cnc4c(c3)CCC(=O)N4)c(C)n(C)c12
Temperature: 25 °C
Yield: 24.8 %

Procedure:
A mixture of N-methyl-N-(1,2,7-trimethyl-1H-indol-3-ylmethyl)acrylamide (256 mg, 1 mmole) and 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (227 mg, 1 mmole) in propionitrile (20 mL) was treated with DIEA (0.3 mL), Pd(OAc)2 (29 mg, 0.13 mmole), and tri-o-tolylphosphine (50 mg, 0.16 mmole). The reaction was heated at reflux under argon for 10 h, then was cooled to RT and filtered through supercel. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel to afford the title compound (100 mg, 25%) as an off-white solid: MS (ES) m/e 403.2 (M+H)+. Anal. Calcd for C24H26N4O2.2.75 H2O: C, 63.77; H, 7.02; N, 12.39. Found: C, 63.81; H, 7.25; N, 11.90.
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8]O.N1C=CC=CC=1.P(Br)(Br)[Br:21]>C(OCC)C>[CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][Br:21]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCc1cccc(CO)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)=CCc1cccc(CBr)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
130 mg of the resulting alcohol compound was dissolved in 20 ml of ethyl ether, and 2 ml of pyridine and 270 mg of phosphorus tribromide were added. The mixture was stirred for 1 hour under ice cooling. The reaction mixture was poured into ice water, and ethyl ether was added. The mixture was worked up in a customary manner to give 109 mg (yield 62%) of the captioned compound as a pale yellow oil.
Reaction SMILES: C[Al](C)C.[NH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[Si:11]([O:18][CH2:19][C:20]1[N:21]=[C:22]([Cl:30])[S:23][C:24]=1[C:25](OCC)=[O:26])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].Cl>C(Cl)Cl>[Si:11]([O:18][CH2:19][C:20]1[N:21]=[C:22]([Cl:30])[S:23][C:24]=1[C:25]([N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:26])([C:14]([CH3:17])([CH3:15])[CH3:16])([CH3:13])[CH3:12]
Reactant: CCOC(=O)c1sc(Cl)nc1CO[Si](C)(C)C(C)(C)C
Reactant: C1COCCN1
Agent: C[Al](C)C
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)sc1C(=O)N1CCOCC1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
A solution of 2N Me3Al in hexanes (0.91 ml, 1.82 mmol) was added slowly to a solution of 0.16 ml (1.8 mmol) of morpholine in 4 ml CH2Cl2. After stirring for 15 min, a solution of 0.5 g (1.5 mmol) of ethyl 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-chloro-1,3-thiazole-5-carboxylate (Intermediate 218) in 4 ml CH2Cl2 was added. The solution was heated at 80° C. in a microwave reactor for 1 hour before pouring into dilute aqueous HCl. The mixture was extracted 3 times with CH2Cl2, which was washed with brine, dried (MgSO4) and concentrated. The residue was purified by silica gel chromatography (100% CH2Cl2 followed by gradient elution to 30% EtOAc in CH2Cl2 to give 315 mg of product. MS (ES) (MH+): 377 for C15H25ClN2O3SSi; NMR (d6-DMSO): 0.1 (s, 6H), 0.9 (s, 9H), 3.6 (m, 4H), 3.7 (m, 4H), 4.1 (q, 2H), 4.75 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:11])[C:9]=1F)[CH:5]=[O:6].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=1[F:20]>>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:9]2[C:8]([F:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[F:1])=[CH:15][C:14]=1[F:20]
Reactant: Oc1ccc(Cl)c(F)c1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Product: O=Cc1cc(F)c(Oc2ccc(Cl)c(F)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4,5-trifluorobenzaldehyde (1.0 g, 6.25 mmol),)4-chloro-3-fluorophenol.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1)([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:40])[C:29]([O:32][C:33]1[CH:34]=[CH:35][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:37][CH:38]=1)([CH3:31])[CH3:30])[CH3:26]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1
Yield: 73.1 %

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 125 mg (0.56 mmol) 2-(4-hydroxy-phenoxy)-2-methyl-propionic acid ethyl ester [Newman, Melvin S.; Cella, James A. Monoalkylation of hydroquinone. Journal of Organic Chemistry (1974), 39(2), p 214–15] and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 223 mg of pure 2-{4-[4-Cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-phenoxy}-2-methyl-propionic acid ethyl ester was isolated.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[O:11]C(=O)[NH:9][CH:8]2[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:26])([F:25])[CH:22]([F:24])[F:23])[CH:15]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O>C(O)C.[Cl-].[Na+].O>[NH2:9][CH:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:25])([F:26])[CH:22]([F:23])[F:24])[CH:15]=1)[CH:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)[OH:11]
Reactant: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(Cl)s2)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Cl)s1

Procedure:
(4RS,5RS)-5-(5-Chloro-2-thienyl)-4-[3-(1,1,2,2-tetrafluoroethoxy)benzyl]-1,3-oxazolidin-2-one (8.480 g, 20.69 mmol) and sodium hydroxide (3.31 g, 82.8 mmol) were heated in ethanol (40 ml)-water (3 ml) under reflux for 4 hrs. The reaction solution was diluted with brine, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel (APS type) column chromatography (hexane/ethyl acetate=3/1-ethyl acetate) to give the objective substance.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[Cl-].[Al+3].[Cl-].[Cl-].[N+:15]([C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22])([O-:17])=[O:16].O>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([CH:7]=[CH:8][C:1]=1[O:9][CH3:10])[C:21]([C:20]1[CH:24]=[CH:25][CH:26]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)=[O:22]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Reactant: COc1ccccc1OC
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)c2cccc([N+](=O)[O-])c2)cc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.5 %

Procedure:
To a stirred ice bath cooled solution of veratrole (2.55 mL, 20 mmol) in methylene chloride (30 mL) under nitrogen was added aluminum chloride (2.93 g, 22 mmol). A slight exotherm resulted. To the resulting mixture was added 3-nitrobenzoyl chloride (3.8 g, 20 mmol) in 30 mL of methylene chloride. The reaction was then allowed to warm to room temperature and followed by heating to refluxed. After 5 hours at reflux the reaction mixture was allowed to cool to room temperature and stirred for 72 hours. The reaction mixture was then poured into 100 mL of iced water and stirred for 20 minutes. This mixture was extracted with CH2Cl2 (3×60 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford the crude product as a green solid. The crude product was purified by flash column chromatography (silica gel, CH2Cl2) to afford 2.21 g (39%) of the product as a yellow solid: mp 133-135° C.; 1H NMR (CDCl3) δ 8.64-8.56 (m, 1 H), 8.49-8.39 (m, 1 H), 8.10-8.05 (m, 1 H), 7.76-7.65 (m, 1H), 7.55-7.47 (m, 1 H), 7.36-7.29 (m, 1 H), 7.00-6.87 (m, 1 H), 3.99 (s, 3 H), 3.97 (s, 3 H); 13C NMR (CDCl3) δ 192.8, 153.8, 149.4, 147.9, 139.7, 135.2, 129.5, 128.9, 126.2, 125.6, 124.4, 11.8, 110.0, 56.2, 56.1; Anal. Calcd for C15H13NO5. Theoretical: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.74; H, 4.59; N, 4.89.