Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].[Li]CCCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]=[C:25]([CH:35]([CH3:37])[CH3:36])[C:24]=2/[CH:38]=[CH:39]/[CH:40]=[O:41])=[CH:19][CH:18]=1.Cl.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOCC>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:26]=[C:25]([CH:35]([CH3:37])[CH3:36])[C:24]=2/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6])=[CH:19][CH:18]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1/C=C/C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(-c2ccc(F)cc2)cc(-c2ccccc2)nc1C(C)C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
Methyl acetoacetate (272 mg, 2.34 mmol) was added dropwise to a slurry of NaH (60% in mineral oil, 93.7 mg, 23.4 mmol) in dry THF (5.5 ml) at 0° C. After 15 minutes, the solution was treated with n-BuLi (1.6M in hexanes, 1.11 ml, 1.78 mmol) and stirred an additional 15 minutes. (E)-3-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-2-propenal (560 mg, 1.62 mmol) in THF (3.0 ml) was added, resulting in an orange solution. After 25 minutes, the solution was poured into a biphasic mixture Et2O (30 ml), 1N HCl (4.5 ml) and H2O (16 ml). The aqueous phase was neutralized with saturated NaHCO3 and the layers were separated. The aqueous layer was extracted again with Et2O and the combined Et2O layers were washed with brine and dried (Na2 SO4). Filtration and solvent removal afforded an oil which was chromatographed (Flash, Merck SiO2, 30% EtOAc in hexane) to give (E)-7-[4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinyl]-5-hydroxy-3-oxo-6-heptenoic acid, methyl ester (387 mg, 52%) as a light yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:30])[C:3]([N:5]([CH3:29])[C:6]1[N:15]=[C:14]([C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[O:17])[C:13]([O:27]C)=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4].B(Br)(Br)Br>C(Cl)Cl>[CH3:1][N:2]([CH3:30])[C:3]([N:5]([CH3:29])[C:6]1[N:15]=[C:14]([C:16]([NH:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[O:17])[C:13]([OH:27])=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[N:11]2)=[O:4]
Reactant: COc1c(C(=O)NCc2ccc(F)cc2)nc(N(C)C(=O)N(C)C)c2cccnc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CN(C)C(=O)N(C)c1nc(C(=O)NCc2ccc(F)cc2)c(O)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-[[(dimethylamino)carbonyl](methyl)amino]-N-(4-fluorobenzyl)-8-methoxy-1,6-naphthyridine-7-carboxamide from step 2 in CH2Cl2 (1 mL) at −78 C was added boron tribromide (0.10 mL of a 1M solution in CH2Cl2, 0.01 mmol). The reaction was allowed to warm to room temperature and stirred an additional 16 hr. The solvent was evaporated in vacuo and the residue dissolved in MeOH (2 mL) and the solvent again evaporated in vacuo. The residue was dissolved in DMF (1 mL) and purified by reverse phase HPLC. (Vydak C18, Gradient elution with Water:Acetonitrile 95:5 to 5:95 with 0.1% TFA at 30 mL/min over 15 mins). Lyophilization of the pure fractions afforded the title compound as an off white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]2[CH:10]([CH:11]2[CH2:14][N:15]([C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:25]([F:35])[CH:24]=2)[C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[O:17])[CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH:10]12[CH:11]([CH2:14][N:15]([C:23]3[CH:28]=[CH:27][C:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:25]([F:35])[CH:24]=3)[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[O:17])[CH:12]1[CH2:13][NH:8][CH2:9]2
Reactant: CC(C)(C)OC(=O)N1CC2C(C1)C2CN(C(=O)c1cccs1)c1ccc(N2CCOCC2)c(F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1cccs1)N(CC1C2CNCC21)c1ccc(N2CCOCC2)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirring solution of 6-{[(3-Fluoro-4-morpholin-4-yl-phenyl)-(thiophene-2-carbonyl)-amino]methyl}-3-aza-bicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester prepared above (640 mg, 1.28 mmol) in 6 mL of CH2Cl2 at room temperature was added 6 mL of TFA. The reaction stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, taken up in toluene and concentrated again to yield 854 mg of the desired product. 400 MHz 1H NMR (CDCl3) δ 9.06 (brs, 1H), 8.62 (brs, 1H), 7.33-7.35 (m, 1H), 7.21-7.25 (m, 1H), 6.94-7.11 (m, 2H), 6.88-6.92 (m, 1H), 6.81-6.84 (m, 1H), 3.89-3.91 (m, 4H), 3.72 (d, J=7.05 Hz, 2H), 3.39-3.46 (m, 4H), 3.16-3.18 (m, 4H), 1.77 (brs, 2H), 1.35-1.37 (m, 1H); MS (M+1) 402.1
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=1.[Br:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[Br:20][C:21]1[CH:26]=[C:25]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=3)[CH:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[N:3]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: FC(F)(F)c1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(3,4-dichloro-phenyl)-6-trifluoromethyl-pyrimidine (example A.7) (0.50 g, 1.53 mmol) and commercially available 3-bromo-benzene-boronic acid (0.40 g, 1.99 mmol) according to the general procedure IVb. Obtained as a light yellow oil (0.71 g, 83%). MS (EI) 447.7 [(M)+].
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]#[N:12])=[CH:8][CH:7]=[C:6]([N+:13]([O-:15])=[O:14])[CH:5]=2.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1.C(=O)(O)[O-].[Na+].C(=O)=O>C(O)(=O)C.O>[N+:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([C:11]#[N:12])=[C:2]([N:1]3[CH:18]=[CH:22][CH:21]=[CH:20]3)[NH:3]2)=[CH:8][CH:7]=1)([O-:15])=[O:14]
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1c(N)[nH]c2cc([N+](=O)[O-])ccc12
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1c(-n2cccc2)[nH]c2cc([N+](=O)[O-])ccc12
Temperature: 25 °C

Procedure:
A solution of 2-amino-6-nitro-1H-indole-3-carbonitrile (362 mg, 1.79 mmol) in acetic acid (5 mL) is treated with 2,5-dimethoxytetrahydrofuran (0.30 mL, 2.27 mmol), and the solution is heated to reflux for 14 h. After cooling to ambient temperature, the solution is poured into water (100 mL), and solid sodium bicarbonate is added until CO2 evolution ceased. The mixture is extracted with EtOAc (2×100 mL), and the extracts are washed with saturated brine, combined, dried over MgSO4, filtered and concentrated. The residual material is separated by silica gel chromatography (EtOAc/hexanes, 1/4) to afford 6-nitro-2-pyrrol-1-yl-1H-indole-3-carbonitrile, compound 5, as a yellow solid (232 mg, 51%).
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:31]([O-])(=[O:33])C.[Na+]>CN(C=O)C>[CH2:6]([O:13][C:14]1[CH:15]=[C:16]([CH2:20][NH:21][CH2:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:29])[CH3:28])[CH:17]=[CH:18][C:19]=1[CH:31]=[O:33])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)C(=O)OCCNCc1cccc(OCc2ccccc2)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)C(=O)OCCNCc1ccc(C=O)c(OCc2ccccc2)c1
Reaction time: 0.67 h

Procedure:
POCl3 (3.6 g, 23.4 mmol) was added to 20 ml of DMF in an ice bath. After 40 minutes, 2,2-dimethylpropionic acid 2-[(3-benzyloxyphenyl)methylamino]ethyl ester (8.0 g, 23.4 mmol) dissolved in DMF (10 ml) was added dropwise. The mixture was stirred for 16 hours. After an aqueous sodium acetate solution (20%, 100 ml) was added dropwise, the oily matter was subjected to extraction with ethyl acetate. Washing was performed with a saturated aqueous NaHCO3 solution (100 ml) and then with a saturated saline solution (100 ml). After drying over Na2SO4 and concentration, the residue was purified by silica gel chromatography to give a light yellow crystal (yield: 7.2 g (83.6%)).
Reaction SMILES: [CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([N:16]1[C@H:20]([C:21](O)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:2].[N:39]1[CH:44]=[CH:43][CH:42]=[C:41]([NH2:45])[N:40]=1.ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1>C(#N)C.C(OCC)(=O)C>[CH:1]([N:3]([CH2:12][C@@H:13]([CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:14]([N:16]1[C@H:20]([C:21]([NH:45][C:41]2[N:40]=[N:39][CH:44]=[CH:43][CH:42]=2)=[O:22])[CH2:19][CH2:18][N:17]1[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])=[O:15])[O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:2]
Reactant: Nc1cccnn1
Reactant: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)Nc2cccnn2)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
To a solution of (3S)-2-[(2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)heptanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (590 mg, 0.95 mmol), 3-pyridazinamine (100 mg, 1.05 mmol) and 2-chloro-4,6-bis(methyloxy)-1,3,5-triazine (183 mg, 1.05 mmol) in acetonitrile (30 mL) under N2 was added 4-methylmorpholine (212 mg, 2.1 mmol) dropwise. The mixture was stirred at rt overnight. TLC showed that the reaction was complete. The mixture was diluted with ethyl acetate and washed with 5% citric acid, followed by brine. The organic phase was dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (2:1) to provide the titled compound (460 mg, 79%)
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[C:35]([C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]>>[C:35]([C:38]1[CH:43]=[CH:42][C:41]([C:27]2[CH:26]=[C:25]([C:28]([F:30])([F:31])[F:29])[CH:24]=[CH:23][C:22]=2[O:21][C:16]2[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=2)[O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:34])=[O:3])=[C:8]([CH3:33])[CH:9]=2)=[CH:40][CH:39]=1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2Oc2cc(C)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)cc1
Yield: 26 %

Procedure:
The compound of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester is reacted with 4-acetyl phenyl boronic acid as in Example 38 to afford 0.056 g (26%) of the title compound. 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C32H28O5F3 549.1888, found 549.1888.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: Cc1ccccc1N=C=O
Product: Cc1ccccc1NC(=O)Nc1ccc([N+](=O)[O-])cc1O
Yield: 66.1 %

Procedure:
The urea was prepared from 2-hydroxy 4-nitro aniline (308 mg, 2 mmol) and 2-methyl phenyl isocyanate (2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (0.38 g, 53%). EI-MS m/z 288 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[Li]CCCC.[F:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=[O:18]>C1COCC1>[F:13][C:14]1[CH:15]=[C:16]([CH:17]([C:4]2[N:3]([CH3:7])[C:2]([Cl:1])=[N:6][CH:5]=2)[OH:18])[CH:19]=[CH:20][CH:21]=1
Reactant: Cn1ccnc1Cl
Reactant: O=Cc1cccc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(O)c2cccc(F)c2)cnc1Cl
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a 1-L, three-necked, round-bottomed flask equipped with a magnetic stirrer, nitrogen inlet and an addition funnel is added 2-chloro-1-methyl-1H-imidazole (1 equiv.) and THF (0.5 M). The reaction mixture is cooled to −78° C. and n-BuLi (2.5 M in hexanes, 1.05 equiv.) is added. The resulting mixture is stirred for 1 h and a solution of 3-fluorobenzaldehyde (1.05 eq) in THF (2.5 M) is then added dropwise. After the addition is complete, the cooling bath is removed and the reaction is allowed to warm to rt. The reaction mixture is quenched with satd. aq. NH4Cl, transferred to a separatory funnel, and extracted with EtOAc. The organic layer is washed with water, brine and dried over anhydrous Na2SO4. After filtration, the solvents are evaporated under reduced pressure to yield the product. The material is purified by recrystallization or column chromatography.
Reaction SMILES: C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[C:31]([C@H:34]([C@@H:46]([CH2:55][CH:56]1[CH2:60][CH2:59][CH2:58][CH2:57]1)[C:47]([N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:48])[CH2:35][N:36]1[C:40](=[O:41])[C:39]([CH3:43])([CH3:42])[N:38]([CH3:44])[C:37]1=[O:45])(O)=[O:32].Cl.[CH2:62]([O:69][NH2:70])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>C(Cl)Cl>[CH2:62]([O:69][NH:70][C:31]([C@H:34]([C@@H:46]([CH2:55][CH:56]1[CH2:57][CH2:58][CH2:59][CH2:60]1)[C:47]([N:49]1[CH2:50][CH2:51][CH2:52][CH2:53][CH2:54]1)=[O:48])[CH2:35][N:36]1[C:40](=[O:41])[C:39]([CH3:43])([CH3:42])[N:38]([CH3:44])[C:37]1=[O:45])=[O:32])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: NOCc1ccccc1
Reactant: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(C[C@H](C(=O)NOCc2ccccc2)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 0.33 h
Yield: 73.1 %

Procedure:
0.74 g of N-ethylmorpholine, 0.60 g of N-hydroxybenzotriazole hydrate and 0.75 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide were added at 0° in succession to a solution of 1.38 g of 1-[2(R)-[1(R)-carboxy-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX) from Example 5 or 6 in 13 ml of methylene chloride and the mixture was stirred at 0° for 20 min. The reaction mixture was treated with 0.45 g of N-ethylmorpholine and 0.63 g of O-benzylhydroxylamine hydrochloride and then stirred at 0° for 30 min. and at 22° for 17 hrs. The solution was diluted with 13 ml of methylene chloride, washed with sodium bicarbonate solution and dilute hydrochloric acid, dried and concentrated. The residue was crystallized from ethyl acetate/hexane and the crystallizate was dried, there being obtained 1.26 g (73%) of pure 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine, m.p. 138-140°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccnc(Br)c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Brc1cc(OCC2CC2)ccn1
Temperature: 120 °C
Yield: 69.1 %

Procedure:
To a solution of 2-bromopyridin-4-ol (1.6 g, 9.2 mmol) and (bromomethyl)cyclopropane (1.61 g, 12.0 mmol) in DMF (12 mL) in a microwave vial was added cesium carbonate (4.19 g, 12.9 mmol). The vial was sealed and heated in a microwave reactor at 120° C. for 4 h. The reaction mixture was cooled to room temperature, quenched with water and extracted with EtOAc (2×). The combined organics were washed with sat'd NaCl then dried over MgSO4 and concentrated. The residue was purified by SiO2 chromatography (20-50% EtOAc/heptane) to give 1.45 g (69%) of 2-bromo-4-cyclopropylmethoxy-pyridine as a yellow oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]1[C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([CH2:31][CH2:32][O:33][C:34]([F:37])([F:36])[F:35])[CH2:24]3)=[C:17]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:16]=[C:15]([CH3:44])[N:14]=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:12][C:13]1[C:18]([CH2:19][O:20][C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[C:26](=[O:30])[N:25]([CH2:31][CH2:32][O:33][C:34]([F:37])([F:35])[F:36])[CH2:24]3)=[C:17]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH:16]=[C:15]([CH3:44])[N+:14]=1[O-:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(-c2ccccc2)c(COc2ccc3c(c2)CN(CCOC(F)(F)F)C3=O)c(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-c2ccccc2)c(COc2ccc3c(c2)CN(CCOC(F)(F)F)C3=O)c(C)[n+]1[O-]
Reaction time: 8 h
Yield: 65.8 %

Procedure:
3-Chloroperbenzoic acid (19.3 mg, 0.112 mmol) was added to a solution of 5-((2,6-dimethyl-4-phenylpyridin-3-yl)methoxy)-2-(2-(trifluoromethoxy)-ethyl)isoindolin-1-one (40 mg, 0.074 mmol, 85% pure) in DCM. After stiffing overnight the reaction mixture was diluted with DCM, sat. aqueous NaHCO3 solution was added. Extraction with DCM, washing of the combined organic layers with water, drying over MgSO4 followed by purification by HPLC provided 2,6-dimethyl-3-((1-oxo-2-(2-(trifluoromethoxy)ethyl)-isoindolin-5-yloxy)methyl)-4-phenylpyridine 1-oxide (23 mg, 64%). ESI-MS [M+H]+=473.1.
Reaction SMILES: ClCCl.[CH3:4][O:5][CH:6]([CH3:10])[CH2:7][CH2:8][OH:9].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(OCC)(=O)C.O>[CH3:18][S:19]([O:9][CH2:8][CH2:7][CH:6]([O:5][CH3:4])[CH3:10])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: COC(C)CCO
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(C)CCOS(C)(=O)=O

Procedure:
To a dichloromethane (30 mL) mixture of 3-methoxy-1-butanol (3.12 g, 30.0 mmol) and triethylamine (4.62 mL, 33.0 mmol), was added methanesulfonyl chloride (4.62 mL, 33.0 mmol) while stirring on ice, and the mixture was stirred at room temperature for 30 minutes. To the mixture, were added water and ethyl acetate. After thoroughly shaking the mixture, the organic layer was separated, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The mixture was then filtered, and the solvent in the filtrate was then distilled off under reduced pressure.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][CH:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1[Cl:27].[NH4+].[OH-]>O1CCCC1.Cl>[NH2:1][C:2]1[C:7]2[CH2:8][CH2:9][O:10][C:6]=2[C:5]([C:11]([O:13][CH:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:12])=[CH:4][C:3]=1[Cl:27]
Reactant: CC(C)(C)OC(=O)N1CCC(OC(=O)c2cc(Cl)c(N)c3c2OCC3)CC1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(Cl)cc(C(=O)OC2CCNCC2)c2c1CCO2
Yield: 49.7 %

Procedure:
A mixture of intermediate (8) (7 g) in tetrahydrofuran (20 ml) and hydrochloric acid (20 ml) was stirred and refluxed for 2 hours. The reaction mixture was cooled and alkalized with NH4OH. The organic layer was removed by decantation and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /(CH3OH/NH3) 92/8). The pure fractions were collected and the solvent was evaporated. The residue (5.5 g) was repurified by high-performance liquid chromatography (column: 200 g Kromasil; 10 μm; 100 Å; eluent: (0.5% NH4OAc in water)/methanol 70/30). The pure fractions were collected and extracted with NH3 /CH2Cl2. The extract was evaporated. The residue was crystallized from acetonitrile. The precipitate was filtered off and dried (vacuum; 70° C.), yielding 2.60 g of 4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate (54%) (intermediate 9).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:20]([O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:35][CH2:36][CH2:37]O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Br)(Br)(Br)[Br:40].C([O-])(O)=O.[Na+]>ClCCl>[Br:40][CH2:37][CH2:36][CH2:35][S:34][C:31]1[CH:32]=[CH:33][C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:29][CH:30]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCCCSc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCSc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C

Procedure:
Triphenylphosphine (7.90 g, 30.0 mmol) was added to a solution of 3-(4-benzyloxy-phenylsulfanyl)-propan-1-ol (CAB02032, 4.12 g, 15.0 mmol) and carbon tetrabromide (4.98 g, 18.0 mmol) in dichloromethane (120 mL) at 0° C. (ice/water bath). The reaction mixture was allowed to warm up to room temperature and was stirred for another hour. The solution was transferred into a separation funnel and conc. NaHCO3-solution (50 mL) was added. The organic layer was separated, dried over sodium sulphate ad concentrated under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and hexane (100 mL) was added with stirring. The precipitated triphenylphosphine oxide was filtered off and washed with more EtOAc/hexane-mixture (1:4, 100 mL). The organic solutions were concentrated and the residue was purified by column chromatography (ethyl acetate/hexane, 1:10, Rf: 0.48). Yield: 4.96 g (98%) colourless oil, which becomes a solid after a couple of days. 1H-NMR (400 MHz, CDCl3) δ=2.07 (tt, J=7.0, 7.0 Hz, 2H), 2.95 (t, J=7.0 Hz, 2H), 3.50 (t, J=7.0 Hz, 2H), 5.04 (s, 2H, —OCH2Ph), 6.92 (d, J=9.0 Hz, 2H), 7.27-7.44 (m, 7H). 13C-NMR (100.5 MHz, CDCl3) δ=32.30, 32.50, 34.41, 70.44, 115.84, 126.15, 127.72, 128.31, 128.86, 133.65, 136.89, 158.43.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7].C(=O)(O)[O-].[Na+].[NH:27]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:28]([C:33](ON1C(=O)CCC1=O)=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31].Cl>O1CCOCC1.O>[NH:27]([C:43]([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44])[C@H:28]([C:33]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
The H-Asp(OtBu)-Leu-OH (3.02 g), sodium bicarbonate (1.68 g), and 30 mL of water were mixed to give a mixture of pH 8. Z-Leu-OSu (3.63 g) in dioxane (30 mL) was added to the mixture and was stirred at room temp for 2 h. The reaction mixture was acidified by addition of conc. HCl to pH 1.0, then was extracted with ethyl acetate (30 mL×3). The combined extracts were dried over Na2SO4, filtered, and concentrated. The crude product was dissolved in methanol and chromatographed on a column of Sephadex™ LH20 to yield Z-Leu-Asp(OtBu)-Leu-OH as a foamy solid (4.43 g).