Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].O>CN(C=O)C>[O:1]([C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2)[Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cccc2ncccc12
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1cccc2ncccc12
Temperature: 25 °C
Yield: 109.1 %

Procedure:
5-hydroxyquinoline (101 mg) was dissolved in DMF (5 ml) under an argon atmosphere, and the resultant solution was stirred at room temperature. Imidazole (113 mg) and t-butyldimethylsilyl chloride (162 mg) were added to the solution, and the mixture was stirred at room temperature. After disappearance of the raw materials was confirmed, water (5 ml) was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The resultant organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated. The resultant residue was purified by column chromatography (silica gel:hexane/ethyl acetate=9/1) to obtain the object compound (197 mg, yield 100%).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][CH2:17][CH2:18]O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CS(Cl)(=O)=O.Br.[C:26]1([C:32]2([C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1.C(N(CC)CC)C.CC(=O)CC.O>[CH2:41]([O:40][C:38]([C:32]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:33][CH2:34][N:35]([CH2:18][CH2:17][CH:16]=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:36][CH2:37]1)=[O:39])[CH3:42]
Reactant: CCOC(=O)C1(c2ccccc2)CCNCC1
Reactant: OCCC=C1c2ccccc2CCc2ccccc21
Agent: Br
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C1(c2ccccc2)CCN(CCC=C2c3ccccc3CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.3 %

Procedure:
To a solution of 3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propanol (3.5 g, 14 mmol) in benzene (50 ml), triethylamine (4 ml) and methanesulfonyl chloride (2.0 g, 17.4 mmol) were added and the reaction mixture was stirred at room temperature for 6 h. Water was added and the phases were separated. The organic phase was dried (MgSO4) and solvent was evaporated in vacuo to give a residue which was dissolved in 2-butanone (50 ml). Ethyl 4-phenyl-4-piperidine-carboxylate hydrobromide (4.4 g, 14 mmol) and potassium carbonate (4.4 g, 32 mmol) were added and the mixture was heated at reflux temperature for 24 h. The mixture was filtered and the solvent evaporated in vacuo. The oily residue was purified by column chromatography on silica gel (50 g) using ethyl acetate as eluent to give 5.3 g of 1-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propyl)-4-phenyl-4-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]#[N:13])=[CH:9][CH:10]=2)[O:5][C:4](=[O:14])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:2]([CH2:1][C:33]([NH:32][C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)=[O:34])=[CH:3][C:4](=[O:14])[O:5]2)=[CH:10][CH:9]=1)#[N:13]
Reactant: Cc1cc(=O)oc2cc(C#N)ccc12
Reactant: O=C=Nc1cccc(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(CC(=O)Nc3cccc(Cl)c3)cc(=O)oc2c1
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-2-oxo-2H-chromene-7-carbonitrile (673 mg, 3.6 mmol) in dry THF (30 mL) at −20° C. was added drop wise 1.0 M LiHMDS solution in THF (5.4 mL). After 30 minutes 3-chloro-1-isocyanato-benzene (222.3 mg) was added into the reaction mixture and the reaction mixture was stirred for 1 hour. The reaction mixture was then quenched with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was separated and dried over sodium sulfate, then concentrated and purified on silica gel eluted with 30%-100% ethyl acetate in hexanes to yield 2-(7-cyano-2-oxo-2H-chromen-4-yl)-N-(3-chloro-phenyl)-acetamide as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH2:19])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[C:20](O)(=[O:23])[CH2:21][CH3:22].C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:1][O:2][C:3]1[C:11]([O:12][C@@H:13]2[CH2:18][CH2:17][CH2:16][C@H:15]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])[CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2
Reactant: COc1c(O[C@@H]2CCC[C@H](N)C2)ccc2[nH]ncc12
Reactant: CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCC(=O)N[C@H]1CCC[C@@H](Oc2ccc3[nH]ncc3c2OC)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 116 %

Procedure:
Under nitrogen, the cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexanamine (100 mg, 0.383 mmol) obtained in Example 583 was suspended in N,N-dimethylformamide (2 ml), and propionic acid (31 μl, 0.421 mmol) and triethylamine (107 μl, 0.765 mmol) were added thereto, followed by adding thereto 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide mono-hydrochloride (81 mg, 0.421 mmol) and 1-hydroxybenzotriazole (57 mg, 0.421 mmol). The resulting mixture was stirred at room temperature for 24 hours. Water was added to the reaction mixture, followed by extraction with ethyl acetate (three times). The combined ethyl acetate layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the resulting concentration residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/0, 100/2) to obtain N-[cis-3-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]propanamide (141 mg, yield 116%) as light-yellow tar.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH:17]3[CH2:22][CH2:21][CH:20]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]3)[CH:12]=2)[CH:7]=1)C.[AlH4-].[Li+]>C1COCC1>[C:23]([CH:20]1[CH2:21][CH2:22][CH:17]([O:16][C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[C:6]([CH2:5][CH2:4][OH:3])[CH:15]=[CH:14]3)[CH2:18][CH2:19]1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)Cc1ccc2cc(OC3CCC(C(C)(C)C)CC3)ccc2c1
Agent: [AlH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CCO)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
To a solution of [6-(4-tert-butyl-cyclohexyloxy)-naphthalen-2-yl]-acetic acid ethyl ester (250 mg, 0.68 mmol) in THF (10 mL) was added 1.0 M of lithium tetrahydroaluminate in THF (2 mL, 2 mmol) at 0° C. After stirred at room temperature for 2 hrs, the solution was quenched with ethyl acetate (1 mL), then added Rochelle's salt aqueous (1.5 mL). The solution was stirred for 1 hr, then extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and concentrated. The resulting crude was purified via a silica gel column eluted with EtOAc in hexanes from 0 to 60% to give white precipitate (0.17 g, yield: 77%). ESI-MS: 327.20 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[C:16]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].N1C=CC=CC=1.[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38](Cl)=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[OH-].[Na+]>C1COCC1>[CH2:27]([O:34][CH2:35][CH2:36][CH2:37][C:38]1[N:6]=[C:4]([OH:5])[C:3]2[C:2](=[CH:10][C:9]([C:11]3[C:16]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:8][CH:7]=2)[N:1]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NC(=O)c1ccc(-c2ncccc2C(F)(F)F)cc1N
Reactant: O=C(Cl)CCCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Oc1nc(CCCOCc2ccccc2)nc2cc(-c3ncccc3C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 2-amino-4-(3-trifluoromethyl-pyridin-2-yl)-benzamide (3.56 mmol) and pyridine (3.91 mmol) in THF (20 ml) add 4-benzyloxy-butyryl chloride (3.91 mmol). Stir the mixture 20 minutes at room temperature, add 20 ml of 20% NaOH, stir for 60 minutes at 50° C. Concentrate, add water, filter, acidify to pH=6, collect the precipitate to obtain 2-(3-benzyloxy-propyl)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-4-ol.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:18])[C@H:5]([CH3:17])[NH:6]C(OCC1C=CC=CC=1)=O)[CH3:2].[BrH:19].CCOCC>C(O)(=O)C>[BrH:19].[CH2:1]([NH:3][C:4](=[O:18])[C@H:5]([CH3:17])[NH2:6])[CH3:2]
Reactant: CCNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCNC(=O)[C@H](C)N

Procedure:
10 g (0.04 mol) of N-benzyloxycarbonyl-L-alanine ethylamide were stirred for 1 hour in 50 ml of 4-N hydrobromic acid in acetic acid. To the solution were added 300 ml of dry ether and, after stirring for a few minutes, the white solid was allowed to settle and the ether decanted from the solid. The yield of L-alanine ethylamide hydrobromide obtained was 8.0 g (96.6%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:27])=[C:4]([C:7]([O:10]C)=[CH:8][CH:9]=1)[C:5]#[N:6].B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)[CH:17]=[CH:16][C:15]=2[F:27])=[C:4]([C:7]([OH:10])=[CH:8][CH:9]=1)[C:5]#[N:6]
Reactant: COc1ccc(F)c(NCc2cc(-c3cccc(F)c3)ccc2F)c1C#N
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(O)ccc(F)c1NCc1cc(-c2cccc(F)c2)ccc1F
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 3-fluoro-2-[[2-fluoro-5-(3-fluorophenyl)phenyl]methylamino]-6-methoxy-benzonitrile (560 mg, 1.5 mmol, 1 eq) in CH2Cl2 (30 mL) was added BBr3 (1.14 g, 4.5 mmol, 3 eq) and the reaction was stirred overnight. The mixture was then poured into water, and the aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether:EtOAc, 10:1 to 5:1) to give the title compound as a yellow oil (360 mg, 68%).
Reaction SMILES: [CH:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)(=O)C.[Pd].CO>[CH:1]1([S:6]([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)C2CCCC2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)(=O)C2CCCC2)cc1
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Intermediate 2 (13.1 g) was dissolved in acetic acid (150 ml) and hydrogenated over palladium on activated carbon (1.6 g) with stirring overnight. The mixture was filtered through Celite filter aid, and the filtrate was evaporated to give a yellow/green oil. The oil was taken up in methanol and an insoluble precipitate filtered off; the filtrate was evaporated in vacuo to give a yellow solid. Trituration with ether and filtration gave the title compound as a pale yellow solid (8.1 g).
Reaction SMILES: [C:1]1([C@@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]3([CH2:22][CH2:21][CH2:20][C@H:19]([CH2:23][NH:24][C:25]4[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=4[N+:33]([O-])=O)[C:28]#[N:29])[CH2:18]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH:38](OC)(OC)OC>[Fe].C(O)=O.CCOC(C)=O>[C:1]1([C@@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:10][C:9]3([CH2:22][CH2:21][CH2:20][C@H:19]([CH2:23][N:24]4[C:25]5[CH:26]=[C:27]([C:28]#[N:29])[CH:30]=[CH:31][C:32]=5[N:33]=[CH:38]4)[CH2:18]3)[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)OC
Reactant: N#Cc1ccc([N+](=O)[O-])c(NC[C@H]2CCCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: CO
Product: N#Cc1ccc2ncn(C[C@H]3CCCC4(C3)O[C@H](c3ccccc3)[C@@H](c3ccccc3)O4)c2c1
Temperature: 64 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
To a 3 L flask fitted with an overhead stirrer was added 3-({[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}amino)-4-nitrobenzonitrile (131 g, 279 mmol), iron (156 g, 2790 mmol), MeOH (1 L), EtOAc (1 L), trimethyl orthoformate (0.308 L, 2790 mmol) and formic acid (0.107 L, 2790 mmol). The mixture was heated to 64° C. Every 15 min an additional 2-3 eq of iron, formic acid and trimethyl orthoformate was added. After 3 h, the solution was cooled to RT and filtered through Celite and washed with EtOAc. The filtrate was concentrated to give 1-{[(2R,3R,7S)-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}-1H-benzimidazole-6-carbonitrile (125 g, 100% yield). MS (m/z) 450.2 (M+H+). The product was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][O:21]1>CN(C=O)C>[CH3:13][O:12][C:10](=[O:11])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:17][CH2:18][O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)=[CH:7][CH:6]=1
Reactant: BrCCOC1CCCCO1
Reactant: COC(=O)CCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(OCCOC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl 3-(4-hydroxyphenyl)propionate (0.1 g, 0.55 mmol) is dissolved in DMF (5 ml) and NaH (0.033 g of a 60% dispersion in mineral oil, 0.83 mmol) is added. The reaction mixture is stirred at room temperature for 15 minutes then 2-(2-bromethoxy)tetrahydro-2-H-pyran (0.109 ml, 0.72 mmol) is added and the reaction mixture is left to stir for 18 hours. Dilution with EtOAc (50 ml), washing with water (25 ml), saturated NaHCO3 (25 ml) and brine (25 ml), drying over MgSO4, and concentration in vacuo yields 3-{-4-[2-(Tetrahydro-pyran-2-yloxy)-ethoxy]-phenyl}-propionic acid methyl ester as a colourless oil; [M+H]+ 309
Reaction SMILES: II.[CH2:3](Br)[CH3:4].[CH2:6]([O:13][C@@H:14]([CH3:20])[CH:15]=[N:16][NH:17][CH:18]=[O:19])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(OC)(C)(C)C>[CH2:6]([O:13][C@H:14]([C@@H:15]([NH:16][NH:17][CH:18]=[O:19])[CH2:3][CH3:4])[CH3:20])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCBr
Reactant: C[C@@H](C=NNC=O)OCc1ccccc1
Agent: II
Solvent: COC(C)(C)C
Product: CC[C@H](NNC=O)[C@H](C)OCc1ccccc1
Temperature: 42.5 °C
Reaction time: 2 h

Procedure:
A mixture of methyl tertiary butyl ether (150 ml), Mg turnings (18 g) and I2 (0.03 g) was heated to 40-45° C. under nitrogen atmosphere and ethyl bromide (81.8 g) was added slowly to the reaction mixture for about 1 hour. The reaction mixture was further heated to 50-55° C. and methyl tertiary butyl ether (60 ml) was added to it. The reaction mixture was stirred for 2 hours at 50-55° C. and cooled 0-10° C. N,O-Bistrimethyl silyl acetamide (60.9 g) was added to a mixture of methyl tertiary butyl ether (150 ml) and (S)—N′-(2-(benzyloxy)propylidene)formohydrazide compound of formula-16 (30 g) over a period of 45 minutes at 25-30° C. and stirred for 1 hour at 25-30° C. This reaction mixture was added to the above reaction mixture at 0-10° C. under nitrogen atmosphere. Temperature of the reaction mixture was raised to 25-30 C and stirred for 8 hours at 25-30° C. After completion of reaction, the reaction mixture was quenched with 8% acetic acid in chilled water. The reaction mixture was stirred for 30 minutes at 25-30° C. and both organic and aqueous layers were separated. The organic layer was washed with 10% sodium chloride solution and followed by water. Distilled off the solvent completely to get the title compound. The obtained compound was taken into next step without isolating the compound. Yield: 48 g
Reaction SMILES: [NH2:1][C:2](=[O:25])[CH2:3][O:4][CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][C:13](O)=[O:14])[O:8][N:7]=1.CN1CCOCC1.ClC(OCC(C)C)=O.C[Si](C)(C)[O:43][NH2:44]>O1CCCC1.CO>[NH2:1][C:2](=[O:25])[CH2:3][O:4][CH2:5][C:6]1[N:10]=[C:9]([C@H:11]([CH2:16][CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:12][C:13]([NH:44][OH:43])=[O:14])[O:8][N:7]=1
Reactant: C[Si](C)(C)ON
Reactant: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)O)n1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: NC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)NO)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 32.6 %

Procedure:
A solution of (3R)-3-{3-[(2-amino-2-oxoethoxy)methyl]-1,2,4-oxadiazol-5-yl}6-cyclohexylhexanoic acid (Preparation 91) (178 mg, 0.50 mmol) and N-methylmorpholine (1001 μl, 0.91 mmol) in anhydrous tetrahydrofuran (8 ml) was cooled to 0° C., treated with isobutyl chloroformate (70 μl, 0.54 mmol) and stirred under a nitrogen atmosphere for 2.5 hours. O-(Trimethylsilyl)hydroxylamine (200 μl, 1.63 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The mixture was then treated with methanol and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The oil was purified by column chromatography on silica gel eluting with a gradient system of 98:2 (dichloromethane:methanol) gradually changing to 90:10 (dichloromethane:methanol) and then neat methanol to afford the title compound as a colourless oil (60 mg).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:24]1[CH:25]=[CH:26][C:27]([Cl:30])=[N:28][CH:29]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:15][N:14]([C:24]2[CH:29]=[N:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:13][CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: Clc1ccc(Br)cn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Cl)nc2)C[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 80 °C
Yield: 47.7 %

Procedure:
Compound 308 (361 mg, 1091 μmol), 5-bromo-2-chloropyridine (200 mg, 1039 μmol), Tris(dibenzylideneacetone)dipalladium (0) (71.4 mg, 77.9 μmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (90.2 mg, 156 μmol), and sodium t-butoxide (200 mg, 2079 μmol) were taken up in toluene (5 mL). The reaction was purged with argon and heated at 80° C. for 5 hours. The resulting solution was added to aqueous K2CO3 (10%, 30 mL) and extracted with dichloromethane+10% methanol (3×30 mL). The combined organics were dried (MgSO4) and evaporated to give an orange tar. Silica gel chromatography (gradient elution hexanes/0-20% ethyl acetate) afforded compound 309 as a pale yellow oil (219 mg, 48%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11](/[CH:15]=[CH:16]\[C:17]3[CH:22]=[C:21]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:19][N:18]=3)[CH:12]=[CH:13][CH:14]=2)[C:5]([Cl:31])=[CH:4][N:3]=1.[ClH:32]>O1CCOCC1>[ClH:1].[ClH:32].[NH2:23][C:21]1[CH:20]=[CH:19][N:18]=[C:17](/[CH:16]=[CH:15]\[C:11]2[CH:10]=[C:9]([NH:8][C:6]3[C:5]([Cl:31])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:14]=[CH:13][CH:12]=2)[CH:22]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(/C=C\c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccnc(/C=C\c2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of tert-butyl [2-((Z)-2-{3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}vinyl)pyridin-4-yl]carbamate (73.6 mg, 0.16 mmol) in 1,4-dioxane (0.50 mL) was added 4 M of hydrogen chloride in 1,4-dioxane (0.70 mL). The resultant reaction mixture was stirred at rt for 1 hour. The reaction mixture was concentrated under vacuum to give the desired product as a light yellow powder (66 mg, 95%). LCMS for C17H14Cl2N5 (M+H)+: m/z=358.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[CH:9][CH:8]=1.[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O)=[O:26])[CH3:23]>>[CH2:22]([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:21]=[CH:20][CH:19]=[C:4]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:9][CH:8]=2)[CH:3]=1)=[O:26])[CH3:23]
Reactant: CCOC(=O)c1ccccc1B(O)O
Reactant: COC(=O)CCc1ccc(OCc2cccc(Br)c2)cc1
Product: CCOC(=O)c1ccccc1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Example 272 from methyl 3-[4-[(3-bromobenzyl)oxy]phenyl]propanoate and 2-ethoxycarbonylphenylboronic acid. colorless oil (yield 12%).
Reaction SMILES: [Si:1]([O:18][C@H:19]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[Si:1]([O:18][C@H:19]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCC[C@H](C/C=C\CCCCCCCCO)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCCCCC[C@H](C/C=C\CCCCCCCC=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a solution of (R,Z)-12-(tert-butyldiphenylsilyloxy)octadec-9-en-1-ol (11.1 g, 21.2 mmol) in anhydrous dichloromethane (160 mL) was added pyridinium chlorochromate (215.6 g, 110.3 mmol) and sodium carbonate (1.1 g, 18.4 mmol). The mixture was stirred at room temperature for 3 hours then filtered through a pad of silica (eluted with 100% ethyl acetate). The filtrate was concentrated in vacuo to dryness and the residue was purified by column chromatography (gradient: 100% hexanes to 10% ethyl acetate in hexanes) to afford the title compound as a yellow oil (8.9 g, 81%).