Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:8][OH:9])([CH3:7])[C:4](O)=[O:5].[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:10]1([CH3:18])[CH:15]=[CH:14][C:13]([N:16]([C:4](=[O:5])[C:3]([CH2:8][OH:9])([CH2:2][OH:1])[CH3:7])[NH2:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(NN)cc1
Reactant: CC(CO)(CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccc(N(N)C(=O)C(C)(CO)CO)cc1
Reaction time: 24 h
Yield: 61.5 %

Procedure:
Sixty-five grams (0.49 m) of 2,2-bis(hydroxymethyl) propionic acid was added to a solution of p-tolylhydrazine (100 g, 0.44 m) and dicyclohexylcarbodiimide (100 g, 0.49 m) in 2,500 ml of tetrahydrofuran. The reaction mixture was stirred under a nitrogen atmosphere for 24 hours. The dicyclohexylurea was removed by filtration and the solution was concentrated under reduced pressure. The residue was recrystallized from 300 ml of isopropyl alcohol. There was obtained 71 g (68 percent) of 2,2-bishydroxymethyl propionic acid p-tolylhydrazide, m.p. 129° to 130° C. ##STR6##
Reaction SMILES: [F:1][CH:2]([C:5]1[CH:6]=[C:7]([CH:30]=[CH:31][CH:32]=1)[CH2:8][N:9]1[CH2:29][CH2:28][C:12]2([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]3[N:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[S:23][CH:24]=3)=[O:19])[CH2:13]2)[CH2:11][CH2:10]1)[CH2:3][OH:4].FC(F)(F)C(O)=O.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[F:1][CH:2]([C:5]1[CH:32]=[CH:31][CH:30]=[C:7]([CH2:8][N:9]2[CH2:29][CH2:28][C:12]3([O:17][CH2:16][CH2:15][N:14]([C:18]([C:20]4[N:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[S:23][CH:24]=4)=[O:19])[CH2:13]3)[CH2:11][CH2:10]2)[CH:6]=1)[CH:3]=[O:4]
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)CO)c4)CC3)C2)cs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(C(F)C=O)c4)CC3)C2)cs1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A solution of (9-(3-(1-fluoro-2-hydroxyethyl)benzyl)-1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)(2-isopropylthiazol-4-yl)methanone (example 39, step f) (0.213 g) in DCM (5 mL) was cooled in ice-water and treated with trifluoroacetic acid (0.053 mL) and stirred for 5 minutes. Dess-Martin periodinane (0.296 g) was added and the mixture was removed from the cooling bath and stirred at room temperature for 20 minutes. More Dess-Martin periodinane (0.295 g) was added and the mixture was stirred at room temperature for an additional 30 minutes. The reaction was then quenched by the addition of saturated sodium thiosulphate solution (5 mL), saturated sodium bicarbonate solution (5 mL) and ethyl acetate (5 mL), and the resulting two-phase mixture was stirred for 10 minutes. The mixture was then extracted twice with ethyl acetate, and the combined organic extracts washed with brine. Acetic acid (0.1 mL) was added, then the acidified extracts were dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled product as an off-white foam. Yield 0.240 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22](Cl)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.BrC1C=C(C(F)(F)F)C=CC=1N1CCOC2C=C(S(Cl)(=O)=O)C=CC1=2.ClC1C=C(C(F)(F)F)C=CC=1F.[F:63][C:64]1[C:69]([F:70])=[C:68]([F:71])[C:67]([F:72])=[C:66]([F:73])[C:65]=1[OH:74].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([O:74][C:65]3[C:64]([F:63])=[C:69]([F:70])[C:68]([F:71])=[C:67]([F:72])[C:66]=3[F:73])(=[O:23])=[O:24])[CH:20]=[CH:21][C:13]1=2
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: Fc1ccc(C(F)(F)F)cc1Cl
Agent: O=S(=O)(Cl)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
INTERMEDIATE F was prepared from 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonyl chloride (INTERMEDIATE E), which was prepared in an analogous fashion to INTERMEDIATE C, except using 2-chloro-1-fluoro-4-(trifluoromethyl)benzene instead of 2-bromo-1-fluoro-4-(trifluoromethyl)benzene in STEP 1. A 25 mL septa/cap vial under Argon was charged with INTERMEDIATE E (0.400 g, 0.970 mmol), and dissolved in DCM (3.6 mL). 2,3,4,5,6-Pentafluorophenol (PFP) (0.268 g, 1.456 mmol) was added, followed by dropwise addition of triethylamine (0.202 mL, 1.46 mmol). The reaction was stirred for 1 hour at room temperature. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 40% EtOAc:Heptane; product eluted at 30%) to afford perfluorophenyl 4-(2-chloro-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (0.543 g, 0.970 mmol) as a clear colorless oil. m/z (ESI) 391.8 (M-PFP)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[K+].[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1>CS(C)=O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: c1nc[nH]n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1cc([N+](=O)[O-])ccc1-n1cncn1
Temperature: 110 °C
Yield: 18.7 %

Procedure:
2-Chloro-5-nitroanisole (0.5 g, 2.67 mmol), potassium hydroxide (219 mg, 3.92 mmol) and 1,2,4-triazole (736 mg, 10.66 mmol) were dissolved in dimethyl sulfoxide (2.5 mL), and heated at 110° C. for 24 h. The reaction mixture was poured onto ice-water (100 mL). The solid was collected by filtration and purified by flash column chromatography CH3Cl 2% methanol to yield 110 mg of 3-Methoxy-4-(1H-1,2,4-triazol-1-yl)nitrobenzene. 3-Methoxy-4-(1H-1,2,4-triazol-1-yl)nitrobenzene (105 mg, 0.48 mmol) was dissolved in methanol (10 mL) and 10% palladium on carbon (20 mg) was added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and the solvent evaporated to yield 77 mg of 265A. HPLC method A 97% pure. Mass spectrum M+H+=191.1, 1H 400 MHz NMR (CH3OD): δ8.65 (s, 1H), 8.09 (s, 1H), 7.25 (d, 1H, J=8.56), 6.52 (d, 1H, J=2.19) 6.40-6.35 (m, 1H), 3.83 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](Br)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1I.[CH:52]1([O:55][C:56]2[CH:57]=[C:58](B3OC(C)(C)C(C)(C)O3)[CH:59]=[CH:60][C:61]=2[O:62][CH:63]([F:65])[F:64])[CH2:54][CH2:53]1.C1(B(O)O)C=CC=CC=1>>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:58]2[CH:59]=[CH:60][C:61]([O:62][CH:63]([F:65])[F:64])=[C:56]([O:55][CH:52]3[CH2:53][CH2:54]3)[CH:57]=2)=[C:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=2)[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:11]1[CH:30]=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Reactant: CCOC(=O)c1c(Cc2cccc(OC)n2)c(Br)n(COCc2ccccc2)c1C=O
Agent: C[Si](C)(C)CCOCn1c(Cl)c(I)c2c(=O)[nH]ncc21
Agent: OB(O)c1ccccc1
Product: CCOC(=O)c1c(Cc2cccc(OC)n2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Yield: 105.3 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 31 except for using 875 mg (1.80 mmol) of ethyl 1-benzyloxymethyl-5-bromo-2-formyl-4-(6-methoxy-2-pyridylmethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 42-(b) in place of 2-chloro-3-iodo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 880 mg (2.70 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in Reference example 1-(a) in place of phenylboronic acid, respectively, whereby 1.15 g of the title compound was obtained as a yellowish oil substantially quantitatively.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH:10]([C:24]1[CH:29]=[CH:28][C:27]2[O:30][CH2:31][O:32][C:26]=2[CH:25]=1)[CH2:11][C:12]([C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=O.CC(O)=O.C[N:39](C)C=O>>[O:30]1[C:27]2[CH:28]=[CH:29][C:24]([C:10]3[CH:11]=[C:12]([C:14]4[CH:23]=[CH:22][C:21]5[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=5)[CH:15]=4)[N:39]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])[CH:9]=3)=[CH:25][C:26]=2[O:32][CH2:31]1
Reactant: CN(C)C=O
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc2c(c1)OCO2)c1ccc2ccccc2c1
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc3c(c2)OCO3)cc(-c2ccc3ccccc3c2)n1
Temperature: 100 °C

Procedure:
A mixture of 1-(2-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-5-(naphthalen-2-yl)-1,5-pentanedione on Wang resin (2.7 g, 1.68 mmol), NH4OAc (1.0 g), and AcOH (1.5 mL) in dimethylformamide (40 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-(4-benzo[1,3]dioxol-5-yl-6-naphthalen-2-yl-pyridin-2-yl)-phenol; mp 195-196° C.; 1H NMR (DMSO-d6) d 6.17 (s, 2 H), 6.99 (m, 2 H), 7.17 (d, J=8.2 Hz, 1 H), 7.37 (m, 1 H), 7.63 (m, 2 H), 7.71 (dd, J=8.2, 1.9 Hz, 1 H), 7.83 (d, J=1.8 Hz, 1 H), 8.03 (m, 1 H), 8.12 (m, 2 H), 8.24 (dd, J=8.6, 1.8 Hz, 1 H), 8.35 (m, 2 H), 8.42 (d, J=1.1 Hz, 1 H), 8.74 (s, 1 H), 14.55 (s, 1 H); IR (KBr) 1605 cm−1; MS [M+H]+ m/z=418. Anal. calcd for C28H19NO3: C, 80.56; H, 4.59; N, 3.36; Found: C, 80.13; H, 4.49; N, 3.18.
Reaction SMILES: [CH3:1][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].Cl[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1.C([O-])([O-])=O.[K+].[K+]>>[CH:4]([C:3]1[C:2]([CH3:1])=[C:9]([CH:8]=[CH:7][CH:6]=1)[O:10][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][N:13]=1)=[O:5]
Reactant: Cc1c(O)cccc1C=O
Reactant: N#Cc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1c(C=O)cccc1Oc1ccc(C#N)cn1
Yield: 91.5 %

Procedure:
Using a method similar to Example 221, Step 1, using 2-methyl-3-hydroxy-benzaldehyde (see European Patent 0807621 A1) (965 mg, 6.42 mmol), 6-chloronicotinonitrile (890 mg, 6.42 mmol) and K2CO3 (1.33 g, 9.63 mmol) gives 6-(3-formyl-2-methyl-phenoxy)-nicotinonitrile (1.40 g) as a white solid. 1HNMR (CDCl3): 10.30 (s, 1H), 8.41 (s, 1H), 7.96 (d, 1H), 7.78 (d, 1H), 7.45 (t, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 2.45 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][NH:20][CH3:21].C(N(CC)CC)C>O1CCOCC1>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[CH2:19][N:20]([CH3:21])[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CNCc1ccc(Cl)cc1Cl
Reactant: O=C(CBr)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(CC(=O)c1ccccc1)Cc1ccc(Cl)cc1Cl
Temperature: 20 °C
Yield: 89.9 %

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 2-bromo-1-phenylethanone (1 g, 5.05 mmol, 1.00 equiv) in 1,4-dioxane (20 mL) and (2,4-dichlorophenyl)-N-methylmethanamine (1.1 g, 5.82 mmol, 1.15 equiv). Triethylamine (2 g, 19.80 mmol, 3.92 equiv) was added dropwise with stirring at 20° C. The resulting solution was stirred for 1 h at 20° C. in an oil bath. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50). This resulted in 1.4 g (90%) of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:8][CH:9]=1)=[O:4].C1C(=O)N([Br:33])C(=O)C1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[NH:6][C:7]([C@@H:10]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[N:8][C:9]=1[Br:33])=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cnc([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)[nH]1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1[nH]c([C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)nc1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The product from Example 114 Part A (1.2 g of 83% pure, 0.28 mmol) was dissolved in CHCl3 (20 mL) and NBS (0.93 g, 0.41 mmol) was added. The mixture was stirred at RT under N2 for 1.5 h. It was diluted with CHCl3 and washed with water and brine. It was then dried over MgSO4 and concentrated to a white solid (0.79 g). MS: 424.4/426.2 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].S([CH2:29][N+:30]#[C-:31])(C1C=CC(C)=CC=1)(=O)=O>CO>[N+:10]([C:8]1[CH:7]=[CH:6][C:3]([C:4]2[O:5][CH:31]=[N:30][CH:29]=2)=[C:2]([CH3:1])[CH:9]=1)([O-:12])=[O:11]
Reactant: Cc1cc([N+](=O)[O-])ccc1C=O
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Cc1cc([N+](=O)[O-])ccc1-c1cnco1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
2Bromo-5-nitrotoluene (1.0 g, 4.54 mmol) and vinyltributyl tin (1.59 g, 4.99 mmol) were dissolved in toluene (25 mL) under argon. Palladium dibenzylidene acetone (4.15 g, 0.455 mmol) and triphenylphosphine (488 mg, 1.86 mmol) was added and the reaction refluxed overnight. The solvent was evaporated and the residue dissolved in 200 mL of methylene chloride and washed with 10% ammonium hydroxide, water, and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography heptane-methylene chlolride 1:1) to yield 726 mg of 2-methyl-4-nitrostyrene. 2-methyl-4-nitrostyrene (700 mg, 4.5 mmol) was dissolved in methylene chloride (20 mL) and cooled to −78° C., and treated with ozone until a blue color remained, after 5 minutes the excess ozone was removed by passing a stream of oxygen through the solution. Dimethyl sulfide (1 mL) was added and the reaction mixture stirred at room temperature overnight. The solvent was evaporated and the residue purified by flash column chromatography to yield 580 mg of the 2-methyl-4-nitrobenzaldehyde. 2-Methyl-4-nitrobenzaldehyde (570 mg, 3.45 mmol) and potassium carbonate (476 mg, 3.45 mmol) were suspended in methanol. Tosylmethylisocyanide (674 mg, 3.45 mmol) was added and the reaction mixture refluxed for 3 h, cooled to room temperature and concentrated. The residue was dissolved in methylene chloride (200 mL) and the organic layer was washed with water and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to yield 710 mg (94%) of 5-(4-nitro-2-methylphenyl)oxazole. 5-(4-Nitro-2-methylphenyl)oxazole was dissolved in methanol (100 mL) and 10% palladium on carbon 200 mg was wetted with water and added. The reaction mixture was hydrogenated at 45 psi overnight. The catalyst was removed by filtration and 560 mg of 5-(4-amino-2-methylphenyl)oxazole was isolated in 92% purity by HPLC method A. Mass spectrum M+H+=175.1, 1H 400 MHz NMR (CDCl3): δ7.88 (s, 1H), 7.45 (m, 1H), 7.08 (s, 1H), 6.60 m(m, 2H), 2.38 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18]OS(C)(=O)=O)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCOS(C)(=O)=O)c2c1C
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cccc(OCCNC(C)(C)C)c2c1C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
4-(2-Methanesulfonyloxy-ethoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (20 mg) and tert-butylamine (0.3 ml) were dissolved in THF (2 ml) and stirred overnight at 60° C. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by preparative thin layer chromatography (using dichloromethane:MeOH=10:1 as a developing solvent) to afford 4-(2-tert-butylamino-ethoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (11 mg) as a colorless oil. FAB-MS: m/z 320 (MH+); 1H-NMR (CDCl3): δ 1.20 (9H, s), 1.44 (3H, t, J=7 Hz), 2.75 (3H, s), 3.08 (2H, t, J=5 Hz), 4.23 (2H, t, J=5 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, J=8 Hz), 7.11 (1H, d, J=8 Hz), 7.29 (1H, t, J=8 Hz).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([C:13]([CH3:38])([CH3:37])[C:14]([N:16]([CH3:36])[C:17]2[CH:18]=[N:19][C:20]([N:30]3CC[O:33][CH2:32][CH2:31]3)=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.I([O-])(=O)(=O)=O.[Na+].C(Cl)(Cl)(Cl)Cl.C(#N)C>O.[Ru](Cl)(Cl)Cl.ClCCl.O>[F:39][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:38])[C:14]([N:16]([C:17]2[CH:18]=[N:19][C:20]([NH:30][CH2:31][CH2:32][OH:33])=[CH:21][C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH3:36])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: Cc1ccccc1-c1cc(NCCO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 37.1 %

Procedure:
A mixture of 1.0 g (1.76 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide, 100 mg (0.48 mmol) ruthenium(III)chloride hydrate, 832 mg (3.87 mmol) sodium periodate, 3.5 ml carbon tetrachloride, 3.5 ml acetonitrile and 5.3 ml water was stirred for 4 days at room temperature. Dichloromethane was added, the organic layer was separated, washed with sodium hydrogensulfite solution and filtered over celite. To the filtrate were added 10 ml 1 N potassium hydroxide solution and 20 ml methanol. After heating the mixture for 1 h at 40° C., the solvents were removed in vacuo and the residue was purified by flash-chromatography to give 352 mg (37%) of the title compound as light brown foam.
Reaction SMILES: C([O:3][C:4](=[O:34])[C:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[C:19]([NH:21][CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[N:18]=[C:17]([O:32][CH3:33])[N:16]=2)[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>CO.C1COCC1.O>[CH3:33][O:32][C:17]1[N:16]=[C:15]([C:11]2[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=2)[O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:34])=[O:3])[CH:20]=[C:19]([NH:21][CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[N:18]=1
Reactant: CCOC(=O)C(C)(C)Oc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(CCNc2cc(-c3cccc(OC(C)(C)C(=O)O)c3)nc(OC)n2)cc1
Reaction time: 5 h
Yield: 68.6 %

Procedure:
A solution of 2-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [330 mg, 0.7 mmol, Example 22(a)] in a 2M solution of sodium hydroxide (5 mL, 10 mmol) in MeOH (4 mL), THF (2 mL) and water (4 mL) is heated to 60° C. for 30 minutes. After an additional 5 hours at room temperature, the mixture is concentrated, and diluted with water and ethyl acetate. The solution is acidified with dilute hydrochloric acid to pH, 2.0, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered, and concentrated to afford 2-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid [0.21 g, 72%, Example 23(a)]. LCMS: RT=2.47 minutes, MS: 438 (M+H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.O[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=1.[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:47]=[CH:46][C:42]([C:43]([OH:45])=[O:44])=[CH:41][CH:40]=1)(=[O:28])[CH:26]=[CH2:27]>CN(C)C1C=CN=CC=1.ClCCl>[C:25]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([O:45][C:17]2[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][CH:18]=2)=[O:44])=[CH:46][CH:47]=1)(=[O:28])[CH:26]=[CH2:27]
Reactant: O=Cc1ccc(O)cc1
Reactant: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCCCOc1ccc(C(=O)Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
3.9 g of N,N'-dicyclohexylcarbodiimide were added at 0° C. within 15 minutes while stirring to a solution of 1.9 g of 4-hydroxybenzaldehyde, 5.0 g of 4-[8-acryloyloxyoctyloxy]benzoic acid and 0.1 g of 4-(dimethylamino)pyridine in 100 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight, filtered and the filtrate was concentrated. Chromatographic purification of the residue on silica gel with cyclohexane/ethyl acetate (vol. 8:2) and two-fold recrystallization from ethyl acetate of the fractions which were pure according to thin-layer chromatography gave 5.5 g of 4-(4-[8-acryloyloxyoctyloxy]phenylcarbonyloxy)benzaldehyde; m.p. 73° C.
Reaction SMILES: C(O[C:6]([N:8](C)[C@H:9]([CH2:16][O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH2:10][CH2:11][C:12](OC)=[O:13])=O)(C)(C)C.N1C(C)=CC=CC=1C.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(Cl)Cl>[Si:18]([O:17][CH2:16][C@@H:9]([NH:8][CH3:6])[CH2:10][CH2:11][CH2:12][OH:13])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: COC(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CN[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-methyl 4-(tert-butoxycarbonyl(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentanoate (37.9 g, 109.2 mmol) in DCM (200 mL) was added 2,6-lutidine (25.3 mL, 218.4 mmol) followed by TMSOTf (29.6 mL, 163.8 mmol). The resulting solution was stirred at RT for 1 h. The solvent was removed and the remaining residue was diluted with EtOAc. The organic mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give (S)-5-(tert-butyldimethylsilyloxy)-4-(methylamino)pentan-1-ol, which was used without further purification. LRMS (M+H+) m/z 248.2.