Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([NH:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=2)=[CH:4][C:3]=1[O:19][C:20]([F:23])([F:22])[F:21].[C:24]([O:28][CH3:29])(=[O:27])[NH:25][NH2:26].O.C([O-])([O-])=O.[K+].[K+]>O=P(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:29][O:28][C:24]([NH:25][N:26]=[C:14]([NH:13][C:10]1[CH:11]=[N:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([CH3:1])=[C:3]([O:19][C:20]([F:23])([F:22])[F:21])[CH:4]=2)=[CH:8][CH:9]=1)[CH3:15])=[O:27]
Reactant: COC(=O)NN
Reactant: CC(=O)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)NN=C(C)Nc1ccc(Oc2ccc(C)c(OC(F)(F)F)c2)nc1
Temperature: 60 °C
Yield: 59.1 %

Procedure:
To a solution of N-{6-[4-methyl-3-(trifluoromethoxy)phenoxy]pyridin-3-yl}acetamide (Intermediate 32, 500 mg, 1.53 mmol) in 2.2 mL of POCl3, methyl carbazate (152 mg) was added. The resulting mixture was heated at 60° C. for 7 hrs and overnight at room temperature. After additional heating for 5 hrs, further methyl carbazate (30 mg, 0.2 equiv) was added. The mixture was cooled to 0° C. and water was cautiously added, followed by a saturated solution of K2CO3 and then solid K2CO3 until pH=8 was reached. Ethyl acetate (50 mL) was then added and phases were separated. The aqueous phase was then back-extracted with ethyl acetate (2×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to give 520 mg of crude as orange foam which was purified by silica flash-chromatography, eluant cyclohexane/ethyl acetate, gradient from 50/50 to 20/80 v/v giving the title compound (360 mg) as white foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C([Li])CCC.C([O:27][B:28](OC(C)C)[O:29]C(C)C)(C)C.Cl>O1CCCC1.CCCCCC>[CH2:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:6]=[CH:7][C:2]([B:28]([OH:29])[OH:27])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCOc1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCOc1ccc(-c2ccc(B(O)O)cc2)cc1
Temperature: -30 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-bromo-4′-n-butyloxybiphenyl (3.05 g) in tetrahydrofuran (60 ml) was added 1.55 M n-butyllithium in n-hexane (7.74 ml) at −60° C. over a period of 10 minutes. The solution was stirred at −30° C. for 1.5 hours and cooled to −60° C. To the solution was added triisopropylborate (3.46 ml) over a period of 5 minutes, and the mixture was stirred for 1.5 hours without cooling. To the solution was added 1N hydrochloric acid (20 ml) and the solution was stirred for 30 minutes and extracted with ethyl acetate. The organic layer was separated and washed with water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with n-hexane. The solid was collected by filtration and dried under reduced pressure to give 4-(4-n-Butyloxyphenyl)phenylboronic acid (2.31 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][OH:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[C:16]([Si:20]([O:10][CH2:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(F)c1F
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 75.2 %

Procedure:
To a solution of (2,3-difluoro-phenyl)-methanol (5.0 g, 35 mmol), imidazole (4.9 g, 72 mmol) and DMF (40 mL) was added tert-butyldimethylchlorosilane (5.4 g, 36 mmol). After stirring at ambient temperature for 24 hours, the mixture was partitioned between 400 mL of ether and 100 mL of water. The organic layer was washed twice with water, dried over MgSO4, filtered and concentrated in vacuo, affording 6.8 g of tert-butyl-(2,3-difluoro-benzyloxy)-dimethyl-silane as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.22 (m, 1H), 7.04 (m, 2H), 4.79 (s, 2H), 0.91 (s, 5H), 0.12 (s, 6H) ppm.
Reaction SMILES: [CH2:1]([C:5]1[C:9]([CH2:10]O)=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].S(Cl)([Cl:15])=O>C(Cl)Cl>[CH2:1]([C:5]1[C:9]([CH2:10][Cl:15])=[C:8]([CH3:12])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=S(Cl)Cl
Reactant: CCCCc1noc(C)c1CO
Solvent: ClCCl
Product: CCCCc1noc(C)c1CCl
Reaction time: 1 h
Yield: 92.4 %

Procedure:
To a solution of (3-butyl-5-methyl-isoxazol-4-yl)-methanol (1.0 g, 6 mmol) in DCM (10 mL) at 0° C. was added thionyl chloride (1.46 g, 12 mmol) and the resulting mixture stirred for 1 h and then evaporated. After 1 h the reaction mixture was concentrated to give the title compound (1.04 g, 94%) as a light brown liquid. MS: m/e=188.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=O)=[CH:21][CH:20]=1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[O:14][C:23]([C:22]2[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=2)=[N:16][N:15]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(C(F)(F)F)cc2)o1
Yield: 33 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 4-trifluoromethyl-benzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 114 mg, 33%) which was obtained as a white solid. MS: m/e=372.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH:19]1([CH:24]([C:26]2[S:30][C:29]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)=[N:28][C:27]=2[CH3:41])O)[CH2:23][CH2:22][CH2:21][CH2:20]1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:24]([CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:26]2[S:30][C:29]([C:31]3[CH:32]=[CH:33][C:34]([C:37]([F:39])([F:40])[F:38])=[CH:35][CH:36]=3)=[N:28][C:27]=2[CH3:41])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C1CCCC1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CCOC(=O)C(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CCCC2)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with [rac]-cyclopentyl-(4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield 3-(4-{cyclopentyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-2-ethoxy-propionic acid ethyl ester as a mixture of two diastereomeric racemates as colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[C:11](OC)(OC)(OC)[CH3:12]>>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]2[O:10][C:11]([CH3:12])=[N:1][C:2]=2[CH:7]=1
Reactant: COc1ccc(O)c(N)c1
Reactant: COC(C)(OC)OC
Product: COc1ccc2oc(C)nc2c1
Reaction time: 24 h

Procedure:
A solution of 2-amino-4-methoxyphenol 17 (8 g, 57.4 mmol) in trimethyl orthoacetate 18 (50 mL) was heated to reflux and allowed to stir for 24 h. The reaction was allowed to cool and the excess 18 was evaporated (in vacuo). The residue was dissolved in ethyl acetate and washed with water. The organic layer was dried over MgSO4 and treated with activated carbon Norit A. The resulting solution was filtered through Celite 521 and evaporated to yield an oil. The oil was chromatographed on silica gel (20% ethyl acetateihexanes) to yield compound 19 as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:17]([CH2:21][CH2:22][NH2:23])[N+:18]([O-:20])=[O:19].C(OC(C)C)(C)C>>[O:17]([CH2:21][CH2:22][NH:23][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[C:2]([Cl:1])[CH:3]=1)[N+:18]([O-:20])=[O:19]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1cccc(Cl)c1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1cccc(Cl)c1)NCCO[N+](=O)[O-]
Yield: 28.7 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.79 g of 3-chlorophenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate, 0.28 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([OH:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH2:39]O)[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:32][CH2:31][CH2:30]1>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:39][CH:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH2:32][CH2:31][CH2:30]3)[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: OCC1CCCc2ccccc21
Product: FC(F)(F)c1cccc2c(-c3cccc(OCC4CCCc5ccccc54)c3)c(Cc3ccccc3)cnc12

Procedure:
This compound was prepared according to the procedure of example 69, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenol and (1,2,3,4-tetrahydro naphthalen-1-yl)-methanol. MS (ESI) m/z 524.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][O:9]2)=[C:4]([F:11])[CH:3]=1.[NH2:12][CH2:13][CH2:14][OH:15].CCOC(C)=O.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:9])[CH2:10][NH:12][CH2:13][CH2:14][OH:15])=[C:4]([F:11])[CH:3]=1
Reactant: Fc1cc(Br)ccc1C1CO1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OCCNCC(O)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a stirred solution of (RS)-2-(4-bromo-2-fluorophenyl)oxirane (12.3 g) in THF (40 ml) was added 2-aminoethanol (33.9 ml) and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into EtOAc/THF (3:1) and washed with saturated brine. The organic layer was separated, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography (silica gel; gradient: 0% to 35% MeOH in dichloromethane containing a few drops of aq. NH3) to afford (RS)-1-(4-bromo-2-fluorophenyl)-2-(2-hydroxyethylamino)ethanol (12.0 g, 76%) as a brown oil. MS (ISP): 280.0 ([{81Br}M+H]−), 278.0 ([{79Br}M+H]+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN.O.O[N:26]1[C:30]2C=CC=CC=2N=N1.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[CH3:30][NH:26][C:18](=[O:20])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Temperature: 10 °C
Reaction time: 70 h
Yield: 84 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-L-tyrosine (300 g, 1.07 mol) in DMF (2 L) were successively added methylamine hydrochloride (86.4 g, 1.28 mol), 1-hydroxybenzotriazole monohydrate (163 g, 1.07 mol, hereinafter to be abbreviated as HOBt.H2O), N-methylmorpholine (258 mL, 2.35 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (245 g, 1.28 mol, hereinafter to be abbreviated as WSCI.HCl), under ice-cooling (internal temperature 10° C.). The reaction mixture was stirred for 70 hr while gradually raising the temperature to room temperature. The reaction mixture was poured into iced water (10 L), and the precipitate was collected by filtration and washed with water and ether. The obtained precipitate was recrystallized from ethyl acetate (7 L) to give the title compound (265 g, 84%) as white crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:26]#[C:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:10][C:9]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1[N+](=O)[O-]
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccccc2)cc1[N+](=O)[O-]
Yield: 97.7 %

Procedure:
Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example A1) (5.64 g, 15 mmol) and phenylacetylene (2.47 mL, 22.5 mmol) according to the general procedure F. Obtained as a yellow solid (4.96 g).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:10][C@H:9]([OH:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](O)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OCC)=O)=NC(OCC)=O>>[C:31]([O:11][C@H:9]1[CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:10]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O[C@H]1C[C@@H](c2ccccc2)C1
Reactant: O=C(O)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(O[C@H]1C[C@H](c2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred solution of cis-3-phenylcyclobutanol (Eckehard, V. D.; et al. Chem. Ber., 1993, 126, 2759., 4.6 g, 30.2 mmol), triphenylphosphine (3.3 g, 59.1 mmol) and benzoic acid (7.6 mg, 62.3 mmol) was added diethyl azodicarboxylate (DEAD) (10.9 g, 62.3 mmol) at room temperature. The resulting mixture was stirred at room temperature for 40 min, then the mixture was concentrated. The residue was dissolved in diethyl ether (100 mL) and washed with saturated aqueous sodium bicarbonate (50 mL), water (50 mL), and brine (50 mL). The organic layer was dried (Na2SO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (10:1) to afford 6.52 g (86%) of the title compound as a pale yellow oil: 1H-NMR (CDCl3) δ 7.71–7.20 (10H, m), 5.49–5.41 (1H, m), 3.82–3.72 (1H, m), 2.78–2.64 (4H, m).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=3)=[CH:13][C:11]=2[CH:12]=1)(=O)=O.[CH3:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:6][CH2:7][C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[CH:13][C:11]=3[CH:12]=2)[CH2:28][CH2:27]1
Reactant: CC1CCNCC1
Reactant: CS(=O)(=O)OCCc1cc2cc(-c3ccc(C#N)cc3)ccc2o1
Product: CC1CCN(CCc2cc3cc(-c4ccc(C#N)cc4)ccc3o2)CC1

Procedure:
The product from Example 1C and 4-methylpiperidine were processed as described in Example 1D to provide the titled compound. MS (DCI) m/z 345 (M+H)+;
Reaction SMILES: [OH:1][C@@H:2]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].[CH3:13][O:14][C:15](OC)([CH3:17])[CH3:16].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CN(C)C=O>[CH3:13][O:14][C:15]([CH3:17])([O:1][C@@H:2]1[C@H:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12])[CH3:16]
Reactant: COC(C)(C)OC
Reactant: O=C1N[C@@H](c2ccccc2)[C@H]1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: COC(C)(C)O[C@H]1C(=O)N[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of the title product of step (a) of Example 1 (79.7 mg, 0.488 mmoles), dimethoxy propane (0.3 ml, 2.44 mmol), PPTS (about 12 mg, 0.049 mmol) and dimethylformamide (2 ml) under argon were stirred for 3 hours at about 0° C. and then for 24 hours at about 4° C. The product obtained was extracted with ethyl acetate and worked up (diluted with 10 ml ethyl acetate, washed with 0.5 saturated aqueous NaHCO3; aqueous fraction extracted with 2×5 ml ethyl acetate; combined organic fractions were washed with 1×10 ml water, 10 ml saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated) to obtain quantitive yield of products, which was a 1:1.7 mixture of starting material and the title product (determined by TLC analysis).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:12](=O)[CH2:13][CH3:14])=[C:7]([CH:11]=1)[C:8](O)=[O:9].O.[NH2:17][NH2:18]>>[CH2:13]([C:12]1[C:6]2[C:7](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:8](=[O:9])[NH:18][N:17]=1)[CH3:14]
Reactant: CCC(=O)c1ccc(OC)cc1C(=O)O
Reactant: NN
Solvent: O
Product: CCc1n[nH]c(=O)c2cc(OC)ccc12

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting unpurified 5-methoxy-2-propionylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[C:5]([F:12])[CH:4]=1)#[N:2].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C.C1COCC1.Cl.[CH3:50][O:51][CH2:52][CH:53]1[CH2:58][NH:57][CH2:56][CH2:55][N:54]1[CH2:59][CH:60]([N:64]1[CH:68]=[C:67]([C:69]2[C:70]3[CH:77]=[CH:76][N:75]([CH2:78][O:79][CH2:80][CH2:81][Si:82]([CH3:85])([CH3:84])[CH3:83])[C:71]=3[N:72]=[CH:73][N:74]=2)[CH:66]=[N:65]1)[CH2:61][C:62]#[N:63]>>[C:62]([CH2:61][CH:60]([N:64]1[CH:68]=[C:67]([C:69]2[C:70]3[CH:77]=[CH:76][N:75]([CH2:78][O:79][CH2:80][CH2:81][Si:82]([CH3:84])([CH3:83])[CH3:85])[C:71]=3[N:72]=[CH:73][N:74]=2)[CH:66]=[N:65]1)[CH2:59][N:54]1[CH2:55][CH2:56][N:57]([C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[F:12])=[O:9])[CH2:58][CH:53]1[CH2:52][O:51][CH3:50])#[N:63]
Reactant: COCC1CNCCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: N#Cc1ccc(C(=O)O)c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC1CN(C(=O)c2ccc(C#N)cc2F)CCN1CC(CC#N)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 1 h

Procedure:
4-cyano-2-fluorobenzoic acid (24.2 mg, 0.146 mmol, Alfa Aesar), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium Hexafluorophosphate (51.7 mg, 0.136 mmol) and triethylamine (87.4 μL, 0.627 mmol) in THF (1.3 mL, 16 mmol) was stirred at RT for 15 min. Following this, 4-[2-(methoxymethyl)piperazin-1-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloric acid salt (0.061 g, 0.10 mmol, as a mixture of diastereomers from Step 4) was added. After 1 h, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, 0.1N NaOH and brine, dried over sodium sulfate, decanted and concentrated. The product was purified by preparative HPLC-MS, (C18 eluting with a gradient of H2O/MeCN/0.1% TFA. After removing solvent in vacuo, the residue was dissolved in saturated sodium bicarbonate and DCM. The aqueous phase was extracted with a further portion of DCM. The combined extracts were dried over sodium sulfate, decanted and concentrated under high vacuum to afford product as a mixture of diastereomers (55 mg, 80%). The diastereomers were partially separated using chiral HPLC (Phenomenex Lux Cellulose-1, 20×250 mm, 5 micron particle size, 30% ethanol in hexane, 20 mL/min, 8 mg/injection). Retention time of Peak 1: 32.84 min, retention time of peak 2: 37.30 min, retention time of peak 3: 45.74 min (contains two isomers).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:18](=[O:33])[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)[CH:23]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([N:28]5[CH:32]=[CH:31][N:30]=[CH:29]5)[CH:23]=4)[CH2:19][C:18](=[O:33])[NH:17][C:9]=3[CH:10]=2)[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1cccc(-n2ccnc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-n3ccnc3)c2)=Nc2ccc(C3CC3)cc2N1

Procedure:
Prepared from {4-cyclopropyl-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example K80) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light brown solid (41 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[CH:22]1([C:27]2[C:31]([CH2:32]O)=[C:30]([CH:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[O:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH:22]1([C:27]2[C:31]([CH2:32][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]=[C:10]5[C:15](=[CH:16][CH:17]=4)[N:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[CH:12]=[CH:11]5)=[CH:4][CH:3]=3)=[C:30]([CH:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)[O:29][N:28]=2)[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2n1
Reactant: OCc1c(C2CCCC2)noc1C1CCCC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(C5CCCC5)noc4C4CCCC4)cc3)ccc2n1
Temperature: 100 °C
Yield: 34.6 %

Procedure:
Methyl 6-(4-hydroxyphenyl)-2-quinolinecarboxylate (109 mg, 0.39 mmol), (3,5-dicyclopentyl-4-isoxazolyl)methanol (92 mg, 0.39 mmol), triphenyl phosphine (102 mg, 0.39 mmol), diisopropyl azodicarboxylate (0.075 mL, 0.39 mmol) and dichloromethane (3.9 mL) were placed in a microwave reaction tube, sealed and heated in a microwave reactor to 100° C. for 10 minutes. The solution was concentrated and the residue was purified by chromatography (silica gel, hexane to 1:1 ethyl acetate:hexanes). Fractions containing the product were combined and concentrated. The residue was recrystallized from ethyl acetate and filtered to yield methyl 6-(4-{[(3,5-dicyclopentyl-4-isoxazolyl)methyl]oxy}phenyl)-2-quinolinecarboxylate (67 mg, 35%). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, J=9 Hz, 1H), 8.33 (s, 1H), 8.19 (s, 2H), 8.12 (d, J=8 Hz, 1H), 7.84 (d, J=9 Hz, 2H), 7.17 (d, J=9 Hz, 2H), 4.98 (s, 2H), 3.94 (s, 3H), 3.41-3.37 (m, 1H), 3.16 (m, 1H), 1.98-1.94 (m, 4H), 1.76-1.56 (m, 12H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:22]=[CH:21][C:8]([O:9][CH2:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=1.[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH2:23]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:1][CH2:2][CH2:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]3[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=3[C:13]([O:15][CH3:16])=[O:14])=[CH:21][CH:22]=2)=[CH:33][CH:32]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCO)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Yield: 64.3 %

Procedure:
Methyl 2-{[4-(3-hydroxypropyl)phenoxy]methyl}benzoate (0.50 g, 1.66 mmol) and 4-(benzyloxy)phenol (0.33 g, 1.66 mmol) was added to a dry round bottomed flask and fitted with a septum Dry toluene (10 ml) was added and N2 was flushed through the mixture for 5 minutes. (Tributylphosphoranylidene)acetonitrile (0.80 g, 3.33 mmol) was added drop wise and the reaction was performed in a single node microwave oven. After removing the solvent by evaporation the crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 0.515 gram of methyl 2-[(4-{3-[4(benzyloxy)phenoxy]-propyl}phenoxy)methyl]benzoate (yield 64.1%).