Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ON1C2C=CC=CC=2N=N1.Cl.[CH3:12][O:13][C:14](=[O:27])[C@H:15]([CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)[NH2:16].CN1CCOCC1.Cl.[CH3:36][N:37]([CH3:54])[C:38]1([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:43][CH2:42][CH:41]([CH2:44][C:45](O)=[O:46])[CH2:40][CH2:39]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:12][O:13][C:14](=[O:27])[C@@H:15]([NH:16][C:45](=[O:46])[CH2:44][CH:41]1[CH2:40][CH2:39][C:38]([N:37]([CH3:54])[CH3:36])([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:43][CH2:42]1)[CH2:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: CN(C)C1(c2ccccc2)CCC(CC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CC1CCC(c2ccccc2)(N(C)C)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 20.4 %

Procedure:
1-Hydroxybenzotriazole (546 mg, 4.0 mmol), L-tryptophan methyl ester hydrochloride (509 mg, 2.0 mmol) and N-methylmorpholine (0.666 ml, 6.0 mmol) were added to a solution of (4-dimethylamino-4-phenylcyclohexyl)acetic acid hydrochloride (596 mg, 2.0 mmol) in dry dimethylformamide under argon. Dicyclohexylcarbodiimide (834 mg, 4.0 mmol) was added at 0° C. and the mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the solid which had precipitated out (1.1 g), which comprised a mixture of dicyclohexylurea and the hydrochloride of the amide. The filtrate was added to a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). The filtrate of the mixture was extracted by shaking with methylene chloride (3×50 ml) and, after drying, the organic phase was concentrated. An oily crude product was thereby obtained (660 mg), from which it was possible to obtain the product (188 mg) after purification by chromatography on silica gel with EA/methanol (4:1). The substance mixture which had precipitated out at the start of the working up was taken up in methylene chloride and saturated sodium bicarbonate solution. The aqueous phase was extracted with methylene chloride. The organic phase was concentrated (517 mg) and separated by chromatography with EA/methanol (4:1), it being possible for a further fraction of the amide (357 mg) to be isolated. The total yield of the product was 59% (545 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8]/[C:9](/[C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)=[N:10]\[O:11][CH3:12])=[CH:5][CH:4]=1.O[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])=[C:26]([O:36][CH3:37])[CH:25]=1>>[C:17]([C:16]1[CH:15]=[CH:14][C:13](/[C:9](=[N:10]/[O:11][CH3:12])/[CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][O:1][C:24]3[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[C:26]([O:36][CH3:37])[CH:25]=3)=[CH:22][CH:21]=2)=[CH:20][CH:19]=1)#[N:18]
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc(C#N)cc1
Reactant: COC(=O)CCc1ccc(O)cc1OC
Product: CO/N=C(\COc1ccc(COc2ccc(CCC(=O)O)c(OC)c2)cc1)c1ccc(C#N)cc1
Yield: 71.5 %

Procedure:
Compound 43 was synthesized from 4-{(1Z)-2-[4-(hydroxymethyl)-phenoxy]-N-methoxyethanimidoyl}benzonitrile (0.563 g, 1.9 mmol) and methyl 3-(4-hydroxy-2-methoxyphenyl)propanoate (0.4 g, 1.9 mmol) by following the procedure described in scheme 18 (0.27 g, yield: 71.5%); Purity: 94.96%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[F:19][C:20]([F:25])([F:24])[CH2:21][NH:22][NH2:23]>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[C:12]([C:11]2[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=2[OH:9])[N:22]([CH2:21][C:20]([F:25])([F:24])[F:19])[N:23]=1
Reactant: NNCC(F)(F)F
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Solvent: CCO
Product: Oc1ccccc1-c1nc(-c2ccccc2O)n(CC(F)(F)F)n1

Procedure:
1.38 g of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one boiled under reflux for 0.5 h with 1.6 ml of 2,2,2-trifluorethylhydrazine in 20 ml of ethanol. The mixture is cooled, poured onto water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate and concentrated on a rotary evaporator. The residue is crystallized from methanol/water. After drying, 3,5-bis(2-hydroxyphenyl)-1-(2,2,2-trifluoroethyl)-1H-[1,2,4]triazole remains as colorless crystals of m.p. 154-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15].[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>O1CCCC1.C1(C)C=CC=CC=1>[Cl:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:3]=1[O:14][CH3:15]
Reactant: OCCCCCCCCCl
Reactant: COC(=O)/C=C/c1ccc(O)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1ccc(OCCCCCCCCCl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 90.4 %

Procedure:
20.0 g (96.06 mmol) methyl(2E)-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate, 16.6 g (100.9 mmol) 8-chlor-1-octanol and 27.7 g (105.7 mmol) of triphenylphosphine were dissolved in 400 ml of tetrahydrofurane. The colourless solution was subsequently cooled to 0° C. and 46.0 g (105.7 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene was added dropwise thereto over a period of 25 minutes. The mixture was subsequently allowed to react for 4 hours at 0° C. The reaction mixture reduced in volume by evaporation. The resulting residue was added to a mixture of methanol and water (3:2) and was then extracted with a mixture of tert.-butyl-methylether:hexane 1:1. The tert.-butyl-methylether:hexane phase was washed repeatedly with water, dried over magnesium sulfate, filtered and concentrated by rotary evaporation. The crude product was recrystallised from 2-propanol yielded 30.8 g (90%) methyl(2E)-3-{4-[(8-chloroctyl)oxy]-3-methoxyphenyl}-2-propenoate as white crystals.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:22][C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:15](=[O:16])[N:14]([CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CCl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2NC1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COc2ccccc2N(CC(=O)OCc2ccccc2)C1=O
Reaction time: 15 h
Yield: 62.1 %

Procedure:
In 150 ml of N,N-dimethylformamide is dissolved 12.3 g of 3(S)-tert-butoxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one, and 8.7 g of benzyl chloroacetate, 8.7 g of anhydrous potassium carbonate and 1 g of potassium iodide are added to the solution. After stirring for 15 hours, the mixture is poured in ice-cooled water. The deposited material is collected by filtration, washed with water and recrystallized from ethyl acetate-hexane to give 11.7 g of benzyl 3(S)-tert-butoxycarbonylamino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate as colorless prisms, melting at 122°-124° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][N:11]3[CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][CH2:27][F:28]>CN(C)C=O>[F:28][CH2:27][CH2:26][CH2:25][O:16][C:13]1[CH:14]=[CH:15][C:10]2[N:11]([CH:17]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)[N:9]=2)[CH:12]=1
Reactant: Oc1ccc(-c2cn3cc(O)ccc3n2)cc1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Oc1ccc(-c2cn3cc(OCCCF)ccc3n2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 0 %

Procedure:
560 mg (corresponding to 2.48 mmol) of 2-(4′-hydroxyphenyl)-6-hydroxyimidazo[1,2-a]pyridine was dissolved in 21 mL of N,N-dimethylformamide, and 1.37 g (corresponding to 9.90 mmol) of potassium carbonate and 349 mg (corresponding to 2.48 mmol) of 1-bromo-3-fluoropropane were added thereto. The solution was stirred at room temperature for 24 hours. The reaction solution was concentrated under reduced pressure, and then supplemented with 10 mL of chloroform and 10 mL of methanol to obtain slurry. The slurry was filtered and filtrate was concentrated. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform/methanol=20/1), to obtain 151 mg (corresponding to 0.527 μmol) of 6-(3′-fluoropropoxy)-2-(4′-hydroxyphenyl)imidazo[1,2-a]pyridine (FIG. 5, Step 7).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH2:12][O:13][CH3:14])[CH:6]=1)=[O:4].Br.[C:16]1([CH2:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([CH2:2][N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[OH:4])=[CH:6][C:7]=1[CH2:12][O:13][CH3:14]
Reactant: c1ccc(CCCOCCCCCCNCc2ccccc2)cc1
Reactant: COCc1cc(C(=O)CBr)ccc1O
Agent: Br
Solvent: ClCCl
Product: COCc1cc(C(O)CN(CCCCCCOCCCc2ccccc2)Cc2ccccc2)ccc1O
Yield: 18.3 %

Procedure:
A solution of 2-bromo-1-[4-hydroxy-3-(methoxymethyl)phenyl]ethanone (700 mg), N-[6-(3-phenylpropoxy)hexyl]benzenemethanamine hydrobromide (1.1 g) and DEA (0.95 ml) in dichloromethane (10 ml) was kept at room temperature overnight. ER (50 ml) was added and the suspension was washed twice with water, brine, dried and concentrated to an oil which was dissolved in ethanol (20 ml) and treated with sodium (400 mg). The solution was stirred and refluxed refluxed overnight, water (30 ml) was added and the mixture was extracted with ER (3×25 ml). The organic extracts were washed with brine, dried and concentrated to a red oil which was purified by FCC eluting with System E (80:20:1→66:33:1) to give the title compound as an oil (250 mg), t.l.c. (System E 66:37:1) Rf 0.22.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](Cl)=[N:7][C:6]([NH:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1)=[CH:5]2.[CH:20]([OH:23])([CH3:22])[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:23][CH:20]([CH3:22])[CH3:21])=[N:7][C:6]([NH:13][C:14]1[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=1)=[CH:5]2
Reactant: CC(C)O
Reactant: Cc1cc(Nc2cc3cc(Br)ccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(Br)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 376 was used, starting from (6-Bromo-1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropanol to give (6-Bromo-1-isopropoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 361 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[CH:6]1([Mg]Cl)[CH:10]=[CH:9][CH:8]=[CH:7]1>>[CH2:2]=[CH:3][CH:4]([C:7]1[CH2:6][CH:10]=[CH:9][CH:8]=1)[CH3:5]
Reactant: C=CCCBr
Reactant: Cl[Mg]C1C=CC=C1
Product: C=CC(C)C1=CC=CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 4-bromo-1-butene (100 g of 97 wt %, 0.719 mol) was added cyclopentadienyl magnesium chloride (800 mL of 1 M solution in THF, 0.8 mol) at 0° C. in 50 minutes. After stifling for an additional 15 minutes at 0° C., the mixture was warmed to room temperature. After stirring overnight, the reaction was quenched with a mixture of ice and water. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at room temperature gave a brown liquid (94.2 g, crude buten-3-ylcyclopentadiene). To the crude buten-3-ylcyclopentadiene (94.2 g) dissolved in THF (500 mL) was added n-BuLi (70 mL of 10 M in hexanes, 0.7 mol) at −78° C. The mixture was warmed up to room temperature and stirred overnight. The anion solution was added to benzophenone (133.8 g, 0.735 mol) dissolved in THF (400 mL) at 0° C. in 35 minutes. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with a mixture of ice and 10% HCl aqueous solution. The mixture was extracted with pentane. The organic layer was washed with water and dried over anhydrous sodium sulfate. Removal of the solvent under vacuum at 40° C. gave a dark red viscous oil. The oil was dissolved in heptane and filtered through silica gel. The product was collected by washing the silica gel with 5-10% CH2Cl2 in heptane. Removal of the solvent gave the desired product (152 g, 74.4% yield based on 4-bromo-1-butene) as a dark red viscous oil.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:15]=[C:16](B2OC(C)(C)C(C)(C)O2)[CH:17]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(=[O:4])=[O:3].Br[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[F:35].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[F:34][C:31]1[CH:30]=[C:29]([F:35])[CH:28]=[CH:33][C:32]=1[C:16]1[CH:17]=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=[C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH:15]=1
Reactant: Fc1ccc(Br)c(F)c1
Reactant: CC(C)(C)OC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(S(C)(=O)=O)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)cc(S(C)(=O)=O)c1
Temperature: 120 °C
Yield: 63.3 %

Procedure:
The mixture of tert-butyl 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.125 g, 0.33 mmol), 1-bromo-2,4-difluorobenzene (36.9 μL, 0.33 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (6.68 mg, 8.2 μmol) and cesium carbonate (0.32 g, 0.98 mmol) was purged with nitrogen. A degas solution of THF (1.6 mL) and water (1.6 mL) was added. The mixture was heated in a microwave reactor at 120° C. for 15 min. The mixture was filtered with Celite. Water was added and the mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→70% hexanes/ethyl acetate) gave the title compound (77 mg).
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([O:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[CH:13]=[CH:14][C:15]=2[C@@H:19]([O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:52])[CH3:51])[CH2:20][N:21]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=2)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.[H][H]>CO.[Pd]>[NH2:46][C:43]1[CH:44]=[CH:45][C:40]([CH2:39][CH2:38][CH2:37][CH2:36][O:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][N:21]([CH2:20][C@@H:19]([C:15]2[CH:14]=[CH:13][C:12]([O:57][C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])=[C:11]3[C:16]=2[CH:17]=[CH:18][C:9]([O:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N:10]3)[O:49][Si:50]([C:53]([CH3:56])([CH3:55])[CH3:54])([CH3:51])[CH3:52])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)Oc1ccc2c([C@H](CN(CCCCCCOCCCCc3ccc([N+](=O)[O-])cc3)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)ccc(OC(=O)OC(C)(C)C)c2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Oc1ccc2c([C@H](CN(CCCCCCOCCCCc3ccc(N)cc3)C(=O)OC(C)(C)C)O[Si](C)(C)C(C)(C)C)ccc(OC(=O)OC(C)(C)C)c2n1

Procedure:
Intermediate 41 (175 mg, 0.19 mmol) was dissolved in methanol (4 mL) and ethyl acetate (1 mL) and treated with palladium on carbon (10% w/w, wet Degussa-type, catalytic amount). The suspension was stirred under a balloon of hydrogen gas for 45 minutes. The mixture was then filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure to provide the title material. ES/MS calcd. for C48H76N3O10Si+882.5. found m/z=882.5 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([P:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:5][CH:4]=1.Br.[K+].[Br-].S([O-])([O-])=[O:31].[Na+].[Na+].CBr>>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([P:9](=[O:31])([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])=[CH:5][CH:4]=1
Reactant: COc1ccc(P(c2ccc(OC)cc2)c2cc(C)c(C)cc2C)cc1
Reactant: O=S([O-])[O-]
Agent: Br
Agent: CBr
Agent: [Br-]
Product: Cc1cc(C)c(P(=O)(c2ccc(O)cc2)c2ccc(O)cc2)cc1C
Temperature: 118 °C
Yield: 68.9 %

Procedure:
A reaction flask containing the bis(4-methoxyphenyl)-2,4,5-trimethylphenylphosphine. oxide mixture (443.7 g) was charged with 48% aq. HBr (934 mL) and KBr (59.5 g). The flask was fitted with a sodium sulfite scrubber for containment of methyl bromide. The reaction mixture was heated to reflux (118° C.) and maintained at reflux until complete based on HPLC analysis. The molten product was worked up to give 283.3 g of bis(4-hydroxyphenyl)-2,4,5-trimethylphenylphosphine oxide mixture as a cream solid (68.9% yield). The ratio of products in the mixture based on 31P NMR was 39% tris(4-hydroxyphenyl)phosphine oxide, 49% bis(4-hydroxyphenyl)-2,4,5-trimethylphenylphosphine oxide, 11% di-2,4,5-trimethylphenyl-4-hydroxyphenylphosphine oxide, and 1% tris(2,4,5-triethylphenyl)phosphine oxide.
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[CH3:18][S:19]([CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])(=[O:21])=[O:20]>>[CH3:28][C:22]([S:19]([CH3:18])(=[O:20])=[O:21])([CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: ICCc1ccc(COc2ccccc2)cc1
Product: CCOC(=O)C(C)(CCc1ccc(COc2ccccc2)cc1)S(C)(=O)=O
Yield: 105.5 %

Procedure:
1-(2-Iodoethyl)-4-(phenoxymethyl)benzene (960 mg, 2.84 mmol) and ethyl 2-(methylsulfonyl)propanoate (512 mg, 2.84 mmol) were converted to the title compound (1.17 g, 106%) containing minor solvent impurities following the general procedure of step 2 in Preparation 2 for the formation of compound (1). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22-1.31 (m, 3H) 1.68-1.75 (m, 3H) 2.16-2.27 (m, 1H) 2.45-2.59 (m, 2H) 2.69-2.85 (m, 1H) 2.89 (s, 3H) 4.21-4.33 (m, 2H) 5.01-5.09 (m, 2H) 6.94-7.01 (m, 2H) 7.21 (d, J=8.20 Hz, 1H) 7.26-7.33 (m, 4H) 7.36-7.46 (m, 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]=[C:17]([OH:19])[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([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:16]=[CH:15][N:14]=1
Reactant: O=Cc1cc(F)c(F)c(F)c1
Reactant: Oc1ccnc(Cl)c1
Product: O=Cc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D30 starting from 3,4,5-trifluorobenzaldehyde and 2-chloropyridin-4-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6](=[O:19])[CH:7]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)[CH3:2].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O.C(O)(=O)C>C1(C)C=CC=CC=1.C(OCC)(=O)C.N1CCCCC1>[CH2:1]([O:3][C:4](=[O:20])/[C:5](/[C:6]([CH:7]1[CH2:8][CH2:9][CH:10]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][CH2:12]1)=[O:19])=[CH:26]\[C:25]1[CH:28]=[CH:29][CH:30]=[C:23]([C:22]([F:21])([F:31])[F:32])[CH:24]=1)[CH3:2]
Reactant: O=Cc1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)CC(=O)C1CCC(c2ccccc2)CC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(=C\c1cccc(C(F)(F)F)c1)C(=O)C1CCC(c2ccccc2)CC1
Yield: 67.9 %

Procedure:
3-Oxo-3-(4-phenyl-cyclohexyl)-propionic acid ethyl ester (7) (11.56 g, 42.1 mmol), 3-trifluoromethylbenzaldehyde (11 g, 63.15 mmol), glacial acetic acid (7.16 mmol, 0.41 mL) and piperidine (2.1 mmol, 0.21 mL) were dissolved in toluene (250 mL) and heated under Dean and Stark conditions at reflux for 48 hours. The cooled reaction mixture was diluted with an equal volume of ethyl acetate and washed with 1M aq. HCl and brine. The organics were dried over sodium sulfate, filtered, and evaporated to afford a clear, brown oil. The residue was purified by column chromatography on silica gel (gradient: 0 to 10% tert-butyl methyl ether in cyclohexane) to afford 12.3 g (68%) of (Z)-2-(4-phenylcyclohexanecarbonyl)-3-(3-trifluoromethyl-phenyl)-acrylic acid ethyl ester. 1H NMR (400 MHz, 192191), LCMS (method C), Rt=4.77 min, (M+H)+=431.2.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:21](=[O:40])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:32]=[N:33][C:34]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][CH:36]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:37]1([C:34]2[N:33]=[CH:32][C:31]([C:27]3[CH:26]=[C:25]([C:23]4[CH2:22][C:21](=[O:40])[NH:20][C:9]5[CH:10]=[C:11]([C:16]([F:18])([F:19])[F:17])[C:12]([CH2:14][CH3:15])=[CH:13][C:8]=5[N:7]=4)[CH:30]=[CH:29][CH:28]=3)=[CH:36][CH:35]=2)[CH2:38][CH2:39]1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(C4CC4)nc3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(C4CC4)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M205) (201 mg, 0.35 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (98 mg, 62%).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][C:4]1=[O:9].Cl[CH2:11][CH2:12][O:13][C:14]1[CH:18]=[C:17]([CH3:19])[N:16]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:15]=1.O>CN(C=O)C>[CH3:19][C:17]1[N:16]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=2)[N:15]=[C:14]([O:13][CH2:12][CH2:11][N:3]2[CH2:8][CH2:7][O:6][CH2:5][C:4]2=[O:9])[CH:18]=1
Reactant: Cc1cc(OCCCl)nn1-c1ccc2ccccc2c1
Reactant: O=C1COCCN1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCCN2CCOCC2=O)nn1-c1ccc2ccccc2c1
Temperature: 2.5 °C
Reaction time: 3 h
Yield: 78.1 %

Procedure:
To a stirred suspension of sodium hydride (65 mg 60% dispersion in mineral oil, 1.63 mmol) in DMF (3 ml), cooled to 0-5° C., a solution of morpholin-3-one (91 mg, 0.91 mmol) in DMF (3 ml) was added dropwise. The mixture was stirred at room temperature for 3 hrs. Then, a solution of 3-(2-chloroethoxy)-5-methyl-1-(naphthalen-2-yl)-1H-pyrazole (200 mg, 0.7 mmol) in DMF (4 ml) was added and the mixture was heated to 50° C. for 14 hrs. The reaction mixture was cooled, water (2 ml) added dropwise, and it was evaporated to dryness in vacuum. The resulting residue was partitioned between dichloromethane and water. The organic layer was washed with water, dried over Na2SO4, filtered and evaporated giving 223 mg of crude residue, which was purified by a silica gel column chromatography (eluent: ethyl acetate) and 4-(2-(5-methyl-1-(naphthalen-2-yl)-1H-pyrazol-3-yloxy)ethyl)morpholin-3-one (192 mg, 78%) was obtained as an amorphous white solid.