Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CCOC(=O)C(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 10 h
Yield: 53.7 %

Procedure:
A solution of 73.5 g of 4-(4-trifluoromethylphenoxy)phenol and 49.2 g of ethyl α-chloropropionate and 100 g of potassium carbonate were added to 100 ml of methyl ethyl ketone, and the mixture was heated. With stirring, the reaction was performed for 10 hours at the reflux temperature (80° to 85° C.). Inorganic salts were separated from the reaction product by filtration. The filtrate was evaporated and dried. The resulting ester was extracted with chloroform, and washed with water. The chloroform was distilled off to afford 55 g of the final product (yield: 54%). The final product had a boiling point of 176° to 185° C./3 mmHg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([O:25]C)=[O:24].[OH-].[Na+].C(O)C.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1/[CH:17]=[CH:18]/[CH:19]([OH:28])[CH2:20][CH:21]([OH:27])[CH2:22][C:23]([OH:25])=[O:24]
Reactant: COC(=O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CC(O)CC(O)/C=C/c1c(Cl)cc(Cl)cc1OCc1ccccc1
Yield: 99 %

Procedure:
A solution of methyl (E)-7-(2,4-dichloro-6-phenylmethoxyphenyl)-3,5-dihydroxy-6-heptenoate (34.8 g, 81.8 mmole), 1 N sodium hydroxide (82 ml, 82 mmole) and ethanol (200 ml) was stirred at 25° C. for 15 min. The reaction solution was acidified with 6 N hydrochloric acid, diluted with water (400 ml) and extracted with ether (3×200 ml). The combined organic extracts were washed with brine (3×100 ml), dried over magnesium sulfate and filtered. The filtrate was evaporated in vacuo, leaving the title compound as an orange oil (33.3 g, 99%); pmr (CDCl3) δ2.47 (2H, d), 4.30 (2H, br m), 4.98 (2H, s), 7.30 (5H, s).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)[CH2:2]2.[CH:24](O)([CH3:26])[CH3:25]>>[CH:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:15][CH:14]=2)=[CH:18][CH:19]=1)([CH3:26])[CH3:25]
Reactant: CC(C)O
Reactant: Oc1ccc(Sc2ccc(OC3CN4CCC3CC4)cc2)cc1
Product: CC(C)Oc1ccc(Sc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 10A (80 mg, 0.24 mmol) was treated with isopropyl alcohol (60 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.5) as oil (80 mg, yield, 90%). 1H NMR (MeOH-d4, 300 MHz) δ 1.30 (d, J=6.1 Hz, 6H), 1.60–2.10 (m, 3H), 2.15–2.25 (m, 1H), 2.30–2.40 (m, 2H), 2,98–3.20 (m, 6H), 3.50–3.60 (m, 1H), 4.50–4.58(m, 1H), 7.70–4.78 (m, 1H), 6.87 (t, J =9.2 Hz), 4H), 7.23 (d, J=8.8 Hz, 2H), 7.24 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH3) m/z 370 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].C([O-])(=O)C.[NH4+].[N+:17]([CH2:20][CH3:21])([O-:19])=[O:18]>CC(O)=O.CCOC(C)=O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[C:20]([N+:17]([O-:19])=[O:18])[CH3:21])([O-:3])=[O:2]
Reactant: CC[N+](=O)[O-]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=Cc1ccccc1[N+](=O)[O-])[N+](=O)[O-]

Procedure:
A solution of 2-nitrobenzaldehyde (5.0 g, 33.1 mmol) and ammonium acetate (2.55 g, 33.1 mmol) in AcOH (20 mL) was treated dropwise at 20° C. with nitroethane (2.84 mL, 39.7 mmol). The resulting solution was heated under reflux for 2 h, then cooled and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution and brine, then dried over Na2SO4. Filtration and removal of the volatiles gave a residue that was purified on silica gel (gradient elution, 0-40% EtOAc/hexanes) to give the title compound as an oil. (2.3 g, 33%). LCMS (ES+) m/z 209 (M+H)+
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2F)n1
Temperature: 150 °C
Yield: 45.1 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-fluoro-5-(trifluoromethyl)benzoyl chloride (0.279 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.069 g (45% yield) of pure product: MS (ES) m/z 496 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][N:12]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:13]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([OH:28])[CH2:26][OH:27].CC1C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[CH2:18]([N:12]1[CH2:13][CH:14]2[CH2:16][C:10]3([O:27][CH2:26][CH2:25][O:28][CH:11]13)[CH2:9][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:15]2)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C1C2CN(Cc3ccccc3)CC1CN(Cc1ccccc1)C2
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3CN(Cc4ccccc4)C4OCCOC4(C3)C2)cc1

Procedure:
A solution of 3,7-dibenzyl-3,7-diazabicyclo[3.3.1]nonane-9-one (10.0 g; 29.8 mmol; Bionet), ethylene glycol (20 g) and p-TSA (12.5 g; 65.7 mmol) in toluene (200 mL) was refluxed in a Dean-Stark apparatus for 12 h. NaOH (200 mL, 2M) was added and the organic layer separated, dried and concentrated to give the sub-title compound in a quantitative yield.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([C:24]([NH2:31])([CH3:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:31][C:24]([C:21]3[N:20]=[C:19]([CH3:18])[O:23][N:22]=3)([CH3:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OC(C)CF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer A) (example 287e) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer B) (example 125b) as starting materials and isolated (52.6 mg, 71%); MS (ESI, m/z): 441.4 (M+H+).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[C:8]([O:12][C:13](=[O:29])[NH:14][C:15](=[N:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])N1C=CC=N1)([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:25]([O:24][C:22](=[O:23])[NH:21][C:15](=[N:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:29])[N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([CH3:28])([CH3:27])[CH3:26]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)N1CCC(O)CC1
Reaction time: 1 h
Yield: 62.2 %

Procedure:
4-Hydroxypiperidine (0.25 g, 2.5 mmol) and (tert-butoxycarbonylimino-pyrazol-1-yl-methyl)-carbamic acid tert-butyl ester (0.78 g, 2.2 mmol) (Drake, B. et al. Synthesis 1994, 6, 579-582) were dissolved in THF (1 mL) and stirred for 1 hour. The solvent was removed under reduced pressure and EtOAc (20 mL) was added. The organic was washed with an aqueous solution of 15% NaOH (5×15 mL), dried (Na2SO4) and concentrated under reduced pressure to afford [tert-butoxycarbonylimino-(4-hydroxy-piperidin-1-yl)-methyl]-carbamic acid tert-butyl ester as a white solid (0.47 g, 55%).
Reaction SMILES: C([O-])(=O)C.[Na+].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[Br:15]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:6][C:7]1[C:12]([Br:15])=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1
Reactant: BrBr
Reactant: COc1ccc(N)cn1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(N)c(Br)n1
Reaction time: 0.33 h
Yield: 70.8 %

Procedure:
Sodium acetate (1.6 g) was added to a solution of 5-amino-2-methoxypyridine (2.5 g) in acetic acid (15 ml). To the resulting solution bromine (3.0 g) was added dropwise, and the mixture was stirred for 20 min., and then added to a solution of sodium hydroxide (10 g) in water (100 ml). The product was extracted with ethyl acetate (50 ml), dried (anhydrous magnesium sulfate), and concentrated in vacuo. The product was purified over a silica gel column (ethyl acetate/hexane, 1:4) to give 2.7 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[C:6]([CH3:13])=[N:5]1)[CH3:3].C([Li])CCC.[I:19]I>O1CCCC1.CCCCC>[I:19][C:8]1[N:4]([CH:2]([CH3:1])[CH3:3])[N:5]=[C:6]([CH3:13])[C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cn(C(C)C)nc1C
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: COC(=O)c1c(C)nn(C(C)C)c1I
Temperature: -45 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of methyl 1-(1-methylethyl)-3-methyl-1H-pyrazole-4-carboxylate (2.00 g, 11.0 mmol) in dry tetrahydrofuran (22.0 mL) at −78° C., 2 M solution of butyllithium (6.04 mL, 12.1 mmol) in pentane was added dropwise. The reaction mixture was then warmed to −45° C. and stirred for 1 h. It was then cooled to −78° C. and a solution of iodine (3.06 g, 12.1 mmol) in THF (11.0 mL) was added. The reaction mixture was warmed to RT and stirred for 1 h. Then it was quenched with saturated NH4Cl solution and extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine and dried (MgSO4). Evaporation of solvent gave a tan solid as title compound (3.38 g, 11.0 mmol, 100% crude yield). MS m/z 309 (MH+); 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.41 (d, 6H) 2.47 (s, 3H) 3.82 (s, 3H) 4.77 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.CI.[C:11]([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH3:11])[CH:7]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1cc(Br)cnc1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-bromopyrimidin-2(1H)-one (3 g), methyliodide (1.1 mL) and K2CO3 (2.4 g) in N,N-dimethylformamide (60 mL) is stirred for 5 hours at room temperature. The mixture is filtered and the mother liquor is concentrated. The residue is partitioned between water and dichloromethane. The organic phase is washed with brine, dried (MgSO4) and concentrated to give the title compound. Yield: 385 mg; LC (method 9): tR=0.25 min; Mass spectrum (ESI+): m/z=189 [M+H]+.
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]1)=[O:16])[CH3:13])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32](O)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:32]([C@@H:31]1[CH2:35][CH2:36][CH2:37][N:30]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33])=[O:16])[CH3:13])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: C[C@H](NC(=O)[C@@H]1CCCC[NH2+]1)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
12.27 g (37.54 mmol) of the hydrochloride from example 21A and 10.50 g (48.81 mmol) of N-Boc-L-proline are dissolved in methylene chloride (30 ml) and cooled to 0° C. Subsequently, the solution is treated with 18.56 g (48.81 mmol) of HATU and 5.82 g (45.05 mmol) of ethyldiisopropylamine and stirred at 0° C. for 30 min. After further addition of 11.64 g (90.10 mmol) of ethyldiisopropylamine, the mixture is stirred at room temperature for 72 h and then evaporated. The residue is taken up using ethyl acetate and the solution is washed with aq. citric acid and aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by means of silica gel chromatography using cyclohexane/ethyl acetate 5/1. 18.25 g (99% of th.) of product are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH3:25])=[CH:20][CH:19]=1.CC([O-])=O.[Na+]>C1COCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[CH3:25])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: O=[N+]([O-])c1ccc2nc(Cl)nc(Cl)c2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(Cl)nc3ccc([N+](=O)[O-])cc23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.8 %

Procedure:
A mixture of 1.65 g (6.76 mmol) of 2,4-dichloro-6-nitro-quinazoline, 1.02 g (7.44 mmol) of (4-methoxy-phenyl)-methyl-amine, 0.6 g (7.43 mmol) of NaOAc in 6 mL of THF and 6 mL of water was stirred at ambient temperature for 18 hours. The reaction mixture extracted with EtOAc (2×15 mL) and organics were washed with NaHCO3, dried and concentrated. Isolation done by MPLC (0-30% EtOAc/hexanes as eluent) to give 1.86 g of the title compound. 1H NMR (DMSO-d6) δ 8.38-7.13 (7H), 3.84 (s, 3H), 3.59 (s, 3H); LC-MS (ESI+; 345 ([M+H]+)).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Br:8])=[CH:6][CH:7]=1.[OH-].[Na+].[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>C(OCC)(=O)C>[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1)=[O:21])([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Br)c(C(F)(F)F)c1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6-bromobenzotrifluoride (Fluka, Buchs, Switzerland; 24.0 g, 100 mmol) in ethyl acetate (240 mL) is added to a stirred aqueous solution of sodium hydroxide (110 mL of 1 M) at room temperature. This stirred solution is then treated dropwise over 30 minutes with a solution of 2-nitrobenzoyl chloride (Fluka, Buchs, Switzerland; 14.5 mL, 110 mmol) in ethyl acetate (150 mL). The resulting mixture is then stirred for 30 min at ambient temperature. The mixture is extracted with ethyl acetate (3×100 mL) and the combined extracts are sequentially washed with hydrochloric acid (2×100 mL of 2M), water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated aqueous sodium chloride (1×100 mL), dried (MgSO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by recrystallisation from ethyl acetate-hexane to give the title compound as a beige crystalline solid, m.p. 157–158° C.
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11]>C(O)(=O)C>[NH:6]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([NH2:12])=[O:11])[C:2]([NH2:3])=[O:1]
Reactant: N#C[O-]
Reactant: NC(=O)c1cccc(N)c1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1cccc(C(N)=O)c1
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
Sodium cyanate (1.3 gm, 20 mMole) in 9.0 ml or water was added over a 15 minute period to a solution of 3-aminobenzamide (1.36 gm, 10 mMole) in acetic acid at 35° C. The mixture was stirred for a further 15 minutes during which time a white precipitate formed. This was filtered off, washed with cold water and crystallized from 25% ethanol to give 1.4 gm (78%) of shiny crystals. m.p. >300° C.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O-:15])=[O:14].[Na+].[CH2:18](O)[CH3:19]>>[CH3:5][C:6]1([CH3:16])[NH:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]([O:15][CH2:18][CH3:19])=[O:14]
Reactant: CC1(C)NCC(=O)N1CC(=O)[O-]
Reactant: CCO
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CN1C(=O)CNC1(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
(1) To an ice cold solution of thionyl chloride (5 ml) in dry ethanol (50 ml) a solution of sodium 2,2-dimethyl-5-oxo-1-imidazolidineacetate (4 g) in dry ethanol (50 ml) was added dropwise. The mixture was stirred at 0° C. for 1 hour, then at room temperature overnight. After evaporation under reduced pressure, the residue was taken up with a saturated solution of sodium hydrogen carbonate and extracted with 3×100 ml of dichloromethane. The organic layer was dried and evaporated, to yield ethyl 2,2-dimethyl-5-oxo-1-imidazolidineacetate (2.57 g) as a colorless oil (Rf. 0.49, methanol/acetone 1:1; silica gel plates). Oxalate salt m.p. 109°-113° C. (ethanol/diethyl ether).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)=[CH:21][CH:22]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Clc1ccc(-c2cccc3[nH]ccc23)cc1
Temperature: 70 °C
Reaction time: 15 h
Yield: 88.7 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 4-bromochlorobenzene (2.87 g, 15 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes-EtOAc (9:1) to provide 2.02 g (89%) of the product 4-(4-chloro-phenyl)-1H-indole as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]Cl)=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:6][N:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Oc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc(Br)nc2)cc1

Procedure:
To a round-bottomed flask was added 6-bromopyridin-3-ol (5.0 g), PMBCl (4.95 g), K2CO3 (7.93 g) and DMF (20 mL). The resultant mixture was stirred at r.t. overnight. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic layers was washed with water (20 mL×2), brine (20 mL×2), and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue was recrystallized from ethyl acetate and petroleum ether to provide the subtitle compound. MS ESI+: m/z=294 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:18][C@H:17]([OH:19])[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[OH-].[Na+].[CH3:27]O>>[CH3:27][O:14][C:13](=[O:15])[C@@H:12]1[CH2:16][C@@H:17]([OH:19])[CH2:18][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CO
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1

Procedure:
To a solution of trans-1-benzyloxycarbonyl-4-hydroxy-L-proline (138 g) in methanol (1380 ml), conc. sulfuric acid (9.92 g) was added, and the resultant mixture was refluxed for 2 hours. The reaction mixture was neutralized with 1N aqueous sodium hydroxide solution, and methanol was removed therefrom. The residue was diluted with ethyl acetate, washed with aqueous sodium chloride solution and dried over magnesium sulfate. Removal of the solvent gave trans-1-benzyloxycarbonyl-4-hydroxy-L-proline methyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:23])[CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1[CH:37]=[CH:36][C:28]2[N:29]=[C:30](S(C)(=O)=O)[O:31][C:27]=2[CH:26]=1.[OH-].[Na+].Cl>ClC(Cl)C.CO>[CH3:21][C:16]([CH3:22])([CH2:15][C:14]([C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:30]3[O:31][C:27]4[CH:26]=[C:25]([CH3:24])[CH:37]=[CH:36][C:28]=4[N:29]=3)=[CH:7][CH:6]=2)=[CH:13][CH:12]=1)=[O:23])[C:17]([OH:19])=[O:18]
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(-c2ccc(N)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(Cl)Cl
Product: Cc1ccc2nc(Nc3ccc(-c4ccc(C(=O)CC(C)(C)C(=O)O)cc4)cc3)oc2c1
Temperature: 85 °C
Yield: 31.7 %

Procedure:
To a solution of methyl 4-(4′-amino-1,1′-biphenyl-4-yl)-2,2-dimethyl-4-oxobutanoate (74 mg, 0.24 mmol) in dichloroethane (3 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (50 mg, 0.24 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was redissolved in DMF (5 mL). A solution of 1 N aqueous NaOH (0.72 mL, 0.72 mmol) was added, and the mixture was heated at 65° C. overnight. A solution of 1 N aqueous HCl (0.24 mL, 0.24 mmol) and methanol (5 mL) were added to the reaction mixture and the crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford 2,2-dimethyl-4-{4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}-4-oxobutanoic acid as a white solid (32.6 mg, 32.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.00-7.50 (m, 8 H), 7.30 (d, 2 H), 7.05 (d, 1 H), 3.30 (s, 2 H), 2.50 (s, 3 H), 1.10 (s, 6 H); LC-MS ret. time 3.53 min (method 2), m/z 429.17 (MH+).