Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2CN[C:15](=O)[NH:14][CH2:13]2)=[CH:8][CH:7]=1.CI.[CH3:22][N:23]([CH:25]=[O:26])[CH3:24]>C1COCC1>[CH3:3][O:4][C:5](=[O:19])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][N:14]([CH3:15])[C:25](=[O:26])[N:23]([CH3:24])[CH2:22]2)=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C2CNC(=O)NC2)cc1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2CN(C)C(=O)N(C)C2)cc1
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of sodium hydride dispersion (60% in mineral oil (88 mg, 2.2 mmol) in THF (3 mL) is added a solution comprising of 4-(2-oxo-hexahydro-pyrimidin-5-yl)-benzoic acid methyl ester (236 mg, 1 mmol, reference example 95) and methyl iodide (300 μL, 5 mmol) in DMF (4 mL). The resulting mixture is stirred for 16 h. then quenched with water, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated to give the title compound (255 mg) as a tan solid. 1H NMR (CDCl3) δ 2.98 (s, 6H), 3.37-3.53 (m, 5H), 3.93 (s, 3H), 7.32 (d, J=8 Hz, 2H), 8.01 (d, J=8 Hz, 2H). MS (ion spray) m/z 263 (M+H)+.
Reaction SMILES: [N+]([O-])(O)=[O:2].[CH3:5][C:6]1([CH3:15])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[CH:13]=[O:14].C1(C)C=CC=CC=1>O>[CH3:15][C:6]1([CH3:5])[CH2:11][CH2:10][CH2:9][CH:8]([CH3:12])[CH:7]1[C:13]([OH:2])=[O:14]
Reactant: CC1CCCC(C)(C)C1C=O
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1CCCC(C)(C)C1C(=O)O
Temperature: 55 °C
Reaction time: 3 h
Yield: 98.9 %

Procedure:
In a 300-ml 4-necked flask equipped with a condenser, a thermometer, a dropping funnel, and a stirrer was placed 39 g of nitric acid (60% aqueous solution) and heated to 55° C. To the solution was added dropwise 93 g (0.60 mole) of 2,2,6-trimethylcyclohexanecarbaldehyde (4) composed of 35% of the trans-form and 65% of the cis-form synthesized in Synthesis Example 1-A) described above over a period of 2 hours. Thereafter, the reaction was carried out for 3 hours at the same temperature. Then, 100 g of toluene and 100 g of water were added to the reaction mixture at room temperature to wash with water and form an organic layer and an aqueous layer separately. The organic layer was washed thrice with 100 g of a saturated aqueous sodium chloride solution, and the toluene was distilled off under reduced pressure by means of an evaporator, to provide 101 g of crude 2,2,6-trimethylcyclohexanecarboxylic acid (5) composed of 35% of the trans-form and 65% of the cis-form.
Reaction SMILES: [C:1](=[O:21])([O:7][C:8]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[C:15](F)=[C:16]([F:17])[C:11]=2[O:10][N:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].CCN(C(C)C)C(C)C.[CH3:31][C@H:32]1[O:37][C@@H:36]([CH3:38])[CH2:35][NH:34][CH2:33]1>C(#N)C>[C:1](=[O:21])([O:7][CH:8]1[C:12]2[CH:13]=[C:14]([CH:19]=[O:20])[C:15]([N:34]3[CH2:33][C@H:32]([CH3:31])[O:37][C@H:36]([CH3:38])[CH2:35]3)=[C:16]([F:17])[C:11]=2[O:10][NH:9]1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(C)OC(=O)Oc1noc2c(F)c(F)c(C=O)cc12
Reactant: C[C@@H]1CNC[C@H](C)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H]1CN(c2c(C=O)cc3c(c2F)ONC3OC(=O)OC(C)(C)C)C[C@H](C)O1
Temperature: 80 °C

Procedure:
To an ice cooled and stirred solution of tert-butyl 6,7-difluoro-5-formyl-1,2-benzisoxazol-3-yl carbonate (Intermediate 531, 3.0 g, 10.0 mmol) in anhydrous acetonitrile was added DIPEA (2.56 g, 20.0 mmol) followed by cis 2,6-dimethylmorpholine (1.27 g, 11.0 mmol) and the mixture heated at 80° C. for 12 hours. It was cooled to room temperature and concentrated. The residue was dissolved in ethyl acetate, washed with water followed by brine and then dried over anhydrous sodium sulfate. It was filtered and the filtrate evaporated under reduced pressure. The residue was purified on a silica gel column using a gradient of ethyl acetate in pet.ether to give product as a solid. Yield: 2.9 g (74%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([F:16])[CH:3]=1.CS([O-])(=O)=O.[C:22]([O:27][CH3:28])(=[O:26])[CH:23]([CH3:25])O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][CH:23]([CH3:25])[C:22]([O:27][CH3:28])=[O:26])=[CH:11][CH:12]=2)=[C:4]([F:16])[CH:3]=1
Reactant: Oc1ccc(Oc2ccc(Cl)cc2F)cc1
Reactant: COC(=O)C(C)O
Agent: CS(=O)(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2F)cc1

Procedure:
A mixture of 4-(4-chloro-2-fluorophenoxy)phenol (2.23 g; 0.01 mole), the methanesulfonate of S methyl lactate (18.22 g; 0.1 mole, minimum of 90% optical purity), and potassium carbonate (1.4 g; 0.01 mole) in DMSO (75 ml) was stirred at room temperature for 18 hours. After this period, the mixture was poured into water (500 ml) then extracted into ether (3×100 ml). The ether extracts were dried (MgSO4), and the solvent evaporated. The residue was purified by preparative HPLC using 8:2 hexane-ethylacetate as the eluent. The first peak to elute (after the solvent front) was collected and the solvent evaporated. This gave 2.3 g (17%) of a light yellow oil whose 1H and 19F NMR (CDCl3) were consistent with the assigned structure. This material possessed an optical rotation of +24.68° as measured at 25° C. The refractive index was 1.5466. Attempts to measure the optical purity using the optically active NMR shift reagent tris-[3-(trifluoromethylhydroxymethylene)-d-camphorateo]europium (III) were not successful. Based upon the optical purity of the starting lactate the optical purity is estimated to be between 75 and 95%.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][C:14]([CH3:56])([CH2:46][O:47][SiH2]C(C)(C)C(C)(C)C)[C:15](=[O:45])[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([CH2:27][CH3:28])[S:26][C:20]=2[N:19]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[C:37]([C:42]#[N:43])=[CH:38][CH:39]=[CH:40][CH:41]=3)=[CH:32][CH:31]=2)[C:18]1=[O:44]>O.C(OCC)(=O)C>[CH2:27]([C:25]1[S:26][C:20]2[N:19]([CH2:29][C:30]3[CH:31]=[CH:32][C:33]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]4[NH:43][C:4](=[O:7])[O:5][N:3]=4)=[CH:34][CH:35]=3)[C:18](=[O:44])[N:17]([CH2:16][C:15](=[O:45])[C:14]([CH3:13])([CH3:56])[CH2:46][OH:47])[C:22](=[O:23])[C:21]=2[CH:24]=1)[CH3:28]
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)C(C)(C)CO[SiH2]C(C)(C)C(C)(C)C)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCc1cc2c(=O)n(CC(=O)C(C)(C)CO)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 25.6 %

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.26 g) and dimethyl sulfoxide (8 mL) was stirred at 50° C. for 30 min, 4′-{[3-(3,3-dimethyl-2-oxo-4-{[(1,1,2,2-tetramethylpropyl)silyl]oxy}butyl)-6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.92 g) was added, and the mixture was stirred at 90° C. for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in tetrahydrofuran (8 ml). N,N′-Carbonyldiimidazole (0.29 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (7 mL), tetrabutylammonium fluoride (0.51 g) was added, and the mixture was stirred at room temperature for 3 hr. To the reaction mixture were added ethyl acetate and water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.21 g, 25%).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][P:7](Cl)(Cl)=[O:8])=[CH:4][CH:3]=1.[CH:13]([Mg]Br)=[CH2:14].[Cl-].[NH4+].[CH2:19]1COC[CH2:20]1>>[F:1][C:2]1[CH:12]=[CH:11][C:5]([CH2:6][P:7](=[O:8])([CH:13]=[CH2:14])[CH:19]=[CH2:20])=[CH:4][CH:3]=1
Reactant: C=C[Mg]Br
Reactant: O=P(Cl)(Cl)Cc1ccc(F)cc1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=CP(=O)(C=C)Cc1ccc(F)cc1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
4-Fluorobenzyl phosphonic dichloride (1.71 g, 7.82 mmol) was dissolved in 10 mL of dry THF, under a nitrogen atmosphere, and chilled to −70° C. To this stirred solution was added dropwise vinyl magnesium bromide in THF (18.3 mL, 1M). The resulting solution was stirred for 30 minutes at −70° C. An aqueous solution of ammonium chloride (100 mL, 2M) was chilled to 0° C. and stirred rapidly while the cold reaction mixture was added. The product was extracted into dichloromethane and washed with saturated aqueous sodium bicarbonate, and then with water. The organic phase was dried with sodium sulfate, filtered, and concentrated by rotary evaporation to yield 1.375 g of (4-fluorophenylmethyl) divinyl phosphine oxide (6.55 mmol, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.20-7.14 (m, 2H); 7.01-6.95 (m 2H); 6.29-6.08 (m, 6H); 3.20-3.15 (d, 2H); ESMS (m/z): (M+1)+ found, 211.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.C(OC(=O)C)(=O)C.N1C=CC=CC=1>COCCOC>[CH3:1][C:2]1[CH:3]=[C:4]2[C:11](=[O:12])[O:13][C:8](=[O:10])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1cnc(C(=O)O)c(C(=O)O)c1
Solvent: c1ccncc1
Solvent: COCCOC
Solvent: CC(=O)OC(C)=O
Product: Cc1cnc2c(c1)C(=O)OC2=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 104.1 %

Procedure:
A solution of 75.0 g (0.41 m) of 5-methyl-2,3-pyridinedicarboxylic acid in 500 mL of 1,2-dimethoxyethane is treated with 125 g acetic anhydride (1.2 m) and 81 g pyridine (1.02 m). The resulting solution is stirred for 18 hours at room temperature. The solution is stripped in vacuo to leave 70.3 g (100%) of 5-methyl-2,3-pyridinedicarboxylic acid anhydride. The anhydride is dissolved in 500 mL CCl4 and is treated with 1 g AIBN and 240 g (150 mL, 1.8 m) SO2Cl2 at room temperature. The solution is heated to reflux for 2 hours. An additional 1.0 g AIBN and 80 g (50 mL 0.6 m) SO2Cl2 are added and refluxing continued for an additional 2 hours. The solution, with some suspended solids, is cooled to 15° in an icebath and filtered to leave 56.0 g (69%) of a yellow solid: 5-chloromethyl-2,3-pyridinedicarboxylic anhydride (78% by nmr) mp (softens at 90° C.) 141°-145° C. Alternatively, the product can be hydrolyzed to give 5-chloromethyl-2,3-pyridinedicarboxylic acid, mp 170°-172°, from which the anhydride can be reformed by standard methods (see Example 6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH:10](Cl)[C:11](O)([CH3:13])[CH3:12].[OH-:16].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][C:11]([CH3:13])([CH3:12])[CH:10]=[O:16]
Reactant: CC(C)(O)C(Cl)Cl
Reactant: [OH-]
Reactant: Oc1cccc(Br)c1
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C=O)Oc1cccc(Br)c1
Reaction time: 18 h

Procedure:
Cetyltrimethyl ammonium bromide (0.28 g, 0.77 mmol) was added to a solution of 3-bromophenol (6.66 g, 38.5 mmol) in 3.85M aqueous sodium hydroxide solution (10 ml), followed by a solution of 1,1-dichloro-2-hydroxy-2-methylpropane (A) (1.37 g, 9.6 mmol) in ether (20 ml). The mixture was stirred under an argon atmosphere for 18 hours then diluted with ether (50 ml), and extracted with 2M aqueous sodium hydroxide solution (4×30 ml), to remove unreacted phenol. The combined aqueous extracts were extracted with ether (50 ml), and the organic phase was washed with 2M aqueous sodium hydroxide solution (20 ml) followed by water (50 ml). The combined organic extracts were dried (MgSO4), concentrated, and purified by flash column chromatography, eluting with ethyl acetate/hexane (1:10 v/v), to give 2-(3-bromophenoxy)-2-methylpropanal (0.89 g), as an oil; NMR: 1.45(6H,s), 6.75-7.20(4H,m), 9.8(1H,s).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][NH:9]1.[C-:13]#[N:14].[K+]>O>[CH3:7][CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:1]1([C:13]#[N:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [C-]#N
Reactant: O=C1CCCC1
Reactant: CC1CCCN1
Agent: [K+]
Solvent: O
Product: CC1CCCN1C1(C#N)CCCC1
Temperature: 0 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of cyclopentanone (1.34 g, 16 mmol) and 2-methylpyrrolidine (1.36 g; 16 mmol) was cooled to 0° C. (ice bath). A solution of potassium cyanide (1.04 g, 16 mmol) in water (10 ml) was added dropwise over 10 min and the whole mixture stirred vigorously for 18 h at 20° C., and then partitioned between ethyl acetate and water. The organic layer was dried (Na2SO4) and evaporated in vacuo to afford the title compound (2.24 g; 79%). 1NMR (CDCl3) δ: 1.1 (3H, d), 1.45 (1H, m), 1.75-2.05 (9H, m), 2.13 (2H, m), 2.65 (1H, m), 3.1 (2H, m).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[Ti+4:5].[CH3:6][CH:7]([CH3:9])[O-:8].CC(C)[O-].CC(C)[O-].[C:18]([OH:22])(=[O:21])[CH:19]=[CH2:20]>>[C:18]([O-:22])(=[O:21])[CH:19]=[CH2:20].[C:18]([O-:22])(=[O:21])[CH:19]=[CH2:20].[CH:2]([O:3][Ti+2:5][O:8][CH:7]([CH3:9])[CH3:6])([CH3:4])[CH3:1]
Reactant: CC(C)[O-]
Reactant: C=CC(=O)O
Reactant: [Ti+4]
Product: C=CC(=O)[O-]
Product: CC(C)O[Ti+2]OC(C)C

Procedure:
To ice cold tetra-iso-propyltitanate (titanium (IV) isopropoxide) (9.55 g; 0.033M) in a distillation flask, acrylic acid (4.8 g; 0.066M) was added. The mixture was subjected to vacuum distillation ca. 1 mm Hg (133 Pa) at 37° C. on a rotary evaporator to remove iso-propanol ca. 4.4 g. The product is the distillation flask was 10.1 g (97% of theory) of a yellow liquid. The results of NMR spectral analysis are summarised in Table S3 below. It was not possible to obtain useful IR spectra because the product hydrolysed rapidly. These results are consistent with the product being the title compound as such but we think it probable that the product is in fact a statistical mixture of the possible acrylate products and possibly unreacted starting material, the product having the `average` composition corresponding to the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][C@H:4]([CH2:7][C@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[C:9]([OH:11])=O)[CH2:3]1.C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][CH2:35][CH2:36][OH:37])[N:30]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[OH:37][CH2:36][CH2:35][CH2:34][N:31]1[CH:32]=[CH:33][C:29]([NH:28][C:9](=[O:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH2:7][C@H:4]2[CH2:5][CH2:6][C:2](=[O:1])[CH2:3]2)=[N:30]1
Reactant: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Reactant: Nc1ccn(CCCO)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: O=C1CC[C@H](C[C@@H](C(=O)Nc2ccn(CCCO)n2)c2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.6 %

Procedure:
(R)-3-((R)-3-Oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (prepared in Example 118, 90 mg, 0.30 mmol) was dissolved in methylene chloride (3 mL) and N,N-dimethylformamide (three drops) at 25° C. under argon. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 160 μL, 0.32 mmol) which produced gas evolution and it was then stirred at 25° C. for 30 minutes after which time it was concentrated in vacuo. The residue was then dissolved in methylene chloride (3 mL) and added dropwise into a solution of 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 43 mg, 0.30 mmol), 2,6-lutidine (70 μL, 0.60 mmol) and methylene chloride (3 mL) at 0° C. It was then allowed to warm to 25° C. and stirred for 1 h. After this time, the reaction was quenched with a small amount of methanol and diluted with methylene chloride and then concentrated with silica gel (2 g) in vacuo and purified on Biotage Flash chromatography system (40S column, silica gel, 50% ethyl acetate/hexanes to 5% methanol/ethyl acetate) to afford (R)—N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionamide (63 mg, 50%) as an off white foam: [α]29589=−60.6° (c=0.16, methanol); ES-HRMS m/e calcd for C21H24N3O3F3 (M+H)+ 424.1843, observed 424.1842; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.74-2.29 (m, 10H, 5×CH2), 3.33 (m, 2H, OCH2), 3.94 (m, 1H, ArCHCO), 4.02 (t, J=6.8 Hz, 2H, NCH2), 4.55 (t, J=5.4 Hz, 1H, OH), 6.41 (d, J=2.2 Hz, 1H, Ar), 7.55 (d, J=2.2 Hz, 1H, Ar), 7.60 (m, 2H, Ar), 7.69 (brd, 1H, Ar), 7.73 (brs, 1H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[O:5])[CH3:2].C(Cl)(=O)C([Cl:23])=O.[OH-].[Na+]>C(Cl)(Cl)Cl.CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:23])=[CH:13][CH:12]=[C:11]([N+:17]([O-:19])=[O:18])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1O
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1Cl
Reaction time: 0.5 h
Yield: 93.4 %

Procedure:
4-Hydroxy-7-nitro-quinoline-3-carboxylic acid ethyl ester (15.6 g, 59.5 mmol) was suspended in chloroform (250 ml) and oxalyl chloride (20.7 ml, 30.2 g, 238 mmol) was added, followed by dimethyl formamide (0.4 ml, 0.38 g, 5.2 mmol). After heating at reflux for 2.5 h, the mixture was added to 300 ml of a 2N aqueous sodium hydroxide solution cooled in an ice/water bath. After stirring vigorously for 30 minutes, the aqueous layer was extracted with chloroform (200 ml). The combined organic phases were washed with water, brine and then dried over anhydrous magnesium sulfate. After vacuum filtration, the solution was concentrated under vacuum to provide 15.6 g of a fluffy brown solid. This solid was transferred to a Soxleht thimble and extracted with dichloromethane for 4 h employing a Soxleht extractor. Concentration of the dichloromethane solution under vacuum yielded 14.68 g of a tan solid. This solid was crystallized by dissolving in 400 ml of hot acetone and cooling to 0° C. overnight. The solid was collected by filtration, rinsing with ice-cold acetone, to yield 9.91 g of the title product as light yellow needles.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=1)[C:14]([O:16][C@H:17]([CH3:21])[C@H:18]([OH:20])[CH3:19])=[O:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].N1C=CC=CC=1>ClCCl>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:25]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:24]=1)[C:14]([O:16][C@H:17]([CH3:21])[C@H:18]([O:20][C:1](=[O:3])[CH3:2])[CH3:19])=[O:15])=[O:11])([CH3:7])([CH3:8])[CH3:6]
Reactant: C[C@@H](O)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@H](C)[C@@H](C)OC(=O)[C@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
Acetyl chloride (0.39 mL, 5.5 mmol) and (1R,2R)-2-hydroxy-1-methylpropyl(2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propanoate (32) (2.0 g, 3.6 mmol) were dissolved in 25 mL of anhydrous dichloromethane. A solution of pyridine (0.5 mL, 5.5 mmol) in dichloromethane was added dropwise at 0° C. The mixture was stirred at room temperature for 2 hours. The product was extracted with dichloromethane, washed with 5% NaHCO3, 10% citric acid, and dried over Na2SO4. After concentration and drying under vacuum, the crude product (33) (2.0 g, 95% yield) was isolated and used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3): δ 1.11 (d, J=6.4 Hz, 3H), 1.15 (d, J=6.4 Hz, 3H), 1.43 (s, 9H), 2.05 (s, 3H), 2.95 (dd, J=13.6, 6.4 Hz, 1H), 3.00 (dd, J=13.6, 6.4 Hz, 1H), 4.50 (dd, J=13.6, 6.4 Hz, 1H), 4.93 (m, 2H), 4.98 (d, 1H, NH), 5.12 (s, 4H), 6.66 (dd, J=8.0, 2.0 Hz, 1H), 6.77 (d, J=2.0 Hz, 1H), 6.84 (d, J=8.0 Hz, 1H), 7.29-7.45 (m, 10H).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]([C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][CH:10]=1)([CH:6]1[CH2:8][CH2:7]1)[CH3:5].C(OC)(=O)C1C=CC=CC=1.CO.[OH-].[K+]>O>[Br:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]([CH:6]2[CH2:7][CH2:8]2)([CH3:5])[C:3]([OH:16])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)C(C)(c1ccc(Br)cc1)C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: COC(=O)c1ccccc1
Solvent: O
Solvent: CO
Product: CC(C(=O)O)(c1ccc(Br)cc1)C1CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 115.6 %

Procedure:
A 250 mL reaction vessel equipped with a condenser is charged with a mixture (9.18 g) of 2-(4-Bromo-phenyl)-2-cyclopropyl-propionic acid methyl ester (47.2 wt %, 15.3 mmoles, 1 equiv.) and methyl benzoate (19.3 wt %, 13 mmoles). The vessel is then charged with methanol (42 mL, ACS grade), water (8 mL, DI) and finally potassium hydroxide (KOH) (13.0 g, 12.7 equiv). The solution is then heated to 60±5° C. and allowed to stir for about 1.5 to 2.5 h. The colorless solution is cooled to 25±5° C. Methanol is distilled off to a minimum volume. The resulting heterogeneous mixture is acidified (pH=1) with concentrated HCl (16 mL, 37%), then extracted with methyl tert-butyl ether twice (35 mL). To the combined organic layer is added half saturated brine (40 mL). 4 N sodium hydroxide (NaOH) aqueous is added (1.6-2.3 equiv., 6-8.8 mL). The mixture is stirred for 5 min. Then the layers are separated. The organic layer is washed with brine 20 mL once and 1 N HCl 20 mL once and separated. It is concentrated to an oil to give 2-(4-Bromo-phenyl)-2-cyclopropyl-propionic acid (4.76 g). NMR assay showed 70.48 wt %; 81.4% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[N+:22]([C:25]1[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=1)[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])([O-])=O.O.CCOC(C)=O>C(O)CCC>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:25]2[CH:26]=[C:27]([CH:37]=[CH:38][CH:39]=2)[CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(CNC(=O)OC(C)(C)C)c4)nc(Cl)nc32)cc1
Temperature: 110 °C
Reaction time: 20 h
Yield: 99.1 %

Procedure:
A mixture of 2,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.585 mmol), tert-butyl 3-nitrobenzylcarbamate (137 mg, 0.617 mmol) and TEA (0.200 mL, 1.44 mmol) in nBuOH (5 mL) was stirred at 110° C. for 20 h. Water and EtOAc were added. The organic phase was washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give tert-butyl 3-(2-chloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)benzylcarbamate (306 mg).