Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1Br)([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[O:26][CH3:27]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:17])=[C:10]([C:23]2[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[C:25]([O:26][CH3:27])[CH:24]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(Cl)cc1Br
Reactant: COc1ccc(B(O)O)cc1OC
Product: COc1ccc(-c2cc(Cl)ccc2OCC(=O)OC(C)(C)C)cc1OC

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from example 1 step (i) and 3,4-dimethoxyphenylboronic acid. Yield 0.86 g
Reaction SMILES: [CH3:1][C:2]([O:5][CH2:6][CH:7]1[O:9][CH2:8]1)([CH3:4])[CH3:3].[CH2:10]([OH:16])[CH2:11][O:12][CH2:13][CH2:14][OH:15].O>ClCCl.B(F)(F)F.CCOCC.[OH-].[Na+]>[C:2]([O:5][CH2:6][CH:7]([OH:9])[CH2:8][O:16][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15])([CH3:1])([CH3:3])[CH3:4]
Reactant: OCCOCCO
Reactant: CC(C)(C)OCC1CO1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OCC(O)COCCOCCO
Yield: 39 %

Procedure:
A solution of 100 g (0.77 mole) t-BGE in 100 ml dichloromethane was slowly added with stirring to a glass round bottom flask containing a solution of 250 g (2.4 moles) diethylene glycol and 0.5 ml boron trifluoride etherate catalyst in 150 ml dichloromethane that had first been preheated to 36° C. Over the course of addition (approximately 1.25 hr) the reaction temperature rose to about 45° C. and the dichloromethane began to reflux. The reaction was continued with stirring for about 2 hours after completion of t-BGE addition. A small quantity, approximately 1 g of sodium hydroxide and 20 ml of water were added to the reaction vessel contents. The solvent was then removed by evaporation and the product residue distilled at 0.7 mm Hg pressure. Tertiary butoxymethyl triethylene glycol (71 g, 39 percent yield) was recovered having a boiling point range from 139°-145° C. Analysis by nuclear magnetic resonance (NMR) and infrared (IR) absorption spectroscopy confirmed the product's identity.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([O:13]C)=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.Cl>[OH-].[Na+]>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]([OH:13])=[O:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC(=O)c1n[nH]c2ncc(Br)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1n[nH]c2ncc(Br)cc12
Temperature: 90 °C
Yield: 92.6 %

Procedure:
A suspension of methyl 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylate (VII) (70 mg, 0.27 mmol) in aqueous 1N NaOH solution (20 mL) was heated at 90° C. for 3 h until the solution became clear. The solution was then cooled to 0° C. and acidified with a 10% HCl solution. The solids formed were filtered, washed with cold water and dried at room temperature under vacuum to give 5-bromo-1H-pyrazolo[3,4-b]pyridine-3-carboxylic acid (VIII) as a white solid (60 mg, 0.25 mmol, 92% yield). 1H NMR (CDCl3) δ ppm 8.58 (d, J=3.01 Hz, 1 H), 8.66 (d, J=3.01 Hz, 1 H); ESIMS found for C7H4BrN3O2 m/z 242.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[C:12](OC)(=[O:16])[CH:13]([CH3:15])O.C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:11])[O:10][CH:13]([CH3:15])[C:12]=1[OH:16]
Reactant: COC(=O)C(C)O
Reactant: O=C(O)Cc1ccccc1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC1OC(=O)C(c2ccccc2F)=C1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
To 2-fluorophenylacetic acid (25 g, 0.16 mol) and methyl lactate (17 g, 0.16 mol) in THF (600 ml) was added 1,3-dicyclohexylcarbodiimide (34 g, 0.16 mol) and 4-dimethylaminopyridine (0.99 g, 8.1 mmol) at 5° C. The mixture was allowed to warm to room temperature and stirred under nitrogen overnight. The solvent was removed in vacuo, then the residue was taken up in diethyl ether (300 ml), and the resulting slurry was filtered to remove insoluble material. The filtrate was concentrated in vacuo, and the residual oil was dissolved in potassium tert-butoxide solution (162 ml of a 1.0 M solution in tert-butanol). The mixture was stirred at reflux for 16 h and was allowed to cool to room temperature. Water (300 ml) was added, and the solution was washed with diethyl ether (2×100 ml). The aqueous solution was acidified to pH 1 with 5 N hydrochloric acid. The product formed an immiscible oil, which solidified upon standing. This was collected by filtration, washed with water and dried at 50° C., yielding 3-(2-fluorophenyl)-4-hydroxy-5-methyl-5H-furan-2-one as a pale yellow solid (23.2 g). 1H NMR (400 MHz, CDCl3) δ 1.46 (3H, d, J=6.7 Hz), 5.00 (1H, q, J=6.7 Hz), 7.22 (2H, m), 7.39 (2H, m), 12.50 (1H, br s).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:37])[CH2:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:18][N:25]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][C:28]=1[O:35][CH3:36])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(-c2ccc(F)cc2)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(-c2ccc(F)cc2)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 4-bromomethyl-2-(4-fluoro-phenyl)-thiazole-5-carboxylic acid ethyl ester (2.02 g, 5.89 mmol), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (1.49 g, 5.89 mmol) and potassium carbonate (1.22 g, 8.83 mmol) in anhydrous dimethylformamide (15 mL) was stirred at room temperature for 18 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (2.39 g): MS: (+) m/z 539.22 (M+Na+).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[CH3:23][N:24]([C@@H:32]1[CH2:36][CH2:35][NH:34][CH2:33]1)[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28]>>[Br:1][C:2]1[C:3]([N:34]2[CH2:35][CH2:36][C@@H:32]([N:24]([CH3:23])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:29])[CH3:30])[CH2:33]2)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)[CH:21]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Reactant: CN(C(=O)OC(C)(C)C)[C@@H]1CCNC1
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCN(c2ncc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cc2Br)C1

Procedure:
The title compound was prepared in an analogous fashion to that in Stage 93.1 using 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2) and (R)-tert-butyl methyl(pyrrolidin-3-yl)carbamate. LC-MS (Condition 6) tR=1.59 min, m/z=559.0/561.0 [M+H]+, m/z=502.9/504.9 [M+H—H2C═C(CH3)2].
Reaction SMILES: CC(C)([O-])C.[K+].O.Cl.[OH:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=1.[NH2:21][C:22]1[C:27]([C:28]#[N:29])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:25]([C:37]#[N:38])=[C:24](SC2C=CC=CC=2)[N:23]=1.O>COCCOC>[NH2:21][C:22]1[N:23]=[C:24]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH3:20])=[O:18])[CH:12]=2)[C:25]([C:37]#[N:38])=[C:26]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:27]=1[C:28]#[N:29]
Reactant: N#Cc1c(N)nc(Sc2ccccc2)c(C#N)c1-c1ccc(F)cc1
Reactant: CNC(=O)c1cc(CO)ccn1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1cc(COc2nc(N)c(C#N)c(-c3ccc(F)cc3)c2C#N)ccn1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1.62 g (14.44 mmol) of potassium tert-butoxide were suspended in 10 ml of 1,2-dimethoxyethane. After addition of 1.44 g (8.66 mmol) of 4-(hydroxymethyl)-N-methylpyridine-2-carboxamide hydrochloride monohydrate (Example 40A) and 1.00 g (2.89 mmol) of 2-amino-4-[4-fluorophenyl]-6-(phenylsulfanyl)pyridine-3,5-dicarbonitrile (Example 38A), the mixture was stirred at 60° C. for 2 h and at RT overnight. 30 ml of water were added to the reaction mixture. The precipitate was filtered off and washed with water.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[CH3:9][C:10]([O:13][C:14]([NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)=[O:15])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].C(C1CCCCC1=O)(=O)C(C)C>CCOC(C)=O.O1CCOCC1>[Br:1][C:2]1[CH:7]=[C:6]([N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:14](=[O:15])[O:13][C:10]([CH3:11])([CH3:9])[CH3:12])[CH2:22][CH2:21]2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: CC(C)C(=O)C1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(Br)c2)CC1
Temperature: 70 °C
Reaction time: 43 h
Yield: 26.3 %

Procedure:
A mixture of 3-bromo-5-iodopyridine (600 mg, 2.113 mmol, Aldrich), 4-(n-boc-amino)-piperidine (466 mg, 2.325 mmol, Aldrich), Cut (40.3 mg, 0.211 mmol, Aldrich) and cesium carbonate (1377 mg, 4.23 mmol, Strem) was capped, degassed and backfilled with argon (3×). Dioxane (2 mL) and 2-isobutyrylcyclohexanone (0.141 mL, 0.845 mmol, Aldrich) were added, and the reaction was stirred at 70° C. After 43 h, the reaction mixture was cooled to 23° C., diluted with EtOAc (50 mL) and washed with brine (50 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluent: 15-40% EtOAc/hexane), affording tert-butyl 1-(5-bromopyridin-3-yl)piperidin-4-ylcarbamate (198 mg, 26%). MS (ESI, pos. ion) m/z: 356.0 (M+1), 358.0 (M+3).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][CH:5]([CH:7]2[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]2([CH3:14])[CH3:13])[CH:4]([CH3:15])[O:3]1>[Pd]>[CH3:1][C:2]1([CH3:16])[CH2:6][CH:5]([CH:7]2[CH2:11][CH2:10][CH:9]([CH3:12])[C:8]2([CH3:14])[CH3:13])[CH:4]([CH3:15])[O:3]1
Reactant: CC1=CCC(C2CC(C)(C)OC2C)C1(C)C
Agent: [Pd]
Product: CC1OC(C)(C)CC1C1CCC(C)C1(C)C
Yield: 100 %

Procedure:
The tetrahydrofuran mixture from Example 13, 35.5 g at 96.7% (0.154 mole) was hydrogenated at 60 psi at 40-50° C. using 0.75 g of 5% Pd on carbon. The crude product, 35.7 g, was distilled to yield 34.4 g of purified product (100% yield). BP 53° C./0.04 mmHg; 1H-NMR (300 MHz), spectra consistent with assigned structures. 13C-NMR (75 MHz), spectra consistent with assigned structures. IR (Neat), 2990, 1490, 1130, 1110 cm-1 ; MS (m/e), 209 (M+ -15), 110, 96 (Base);
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:37])[C:7](=[CH2:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:11][C@@H:12]([CH:24]([CH3:26])[CH3:25])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]>O1CCCC1.[Pd]>[CH2:1]([NH:5][C:6](=[O:37])[CH:7]([CH3:36])[CH2:8][C@H:9]([OH:35])[C@@H:10]([NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:11][C@@H:12]([CH:24]([CH3:25])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C=C(C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C)C(=O)NCCCC
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C)NC(=O)OC(C)(C)C

Procedure:
150 mg of N-tert-butoxycarbonyl-2-methylene-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(p-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (diastereoisomer I) are hydrogenated in the presence of 150 mg of 10% Pd/C in 20 ml of tetrahydrofuran for 2 hours at room temperature and under normal pressure. The reaction mixture is filtered and concentrated by evaporation. The residue is purified by means of FC (50 g of silica gel, dichloromethane/diethyl ether=8:2). The title compound is obtained in the form of a diastereoisomeric mixture: Rf (dichloromethane/diethyl ether=8:2)=0.18.
Reaction SMILES: [CH2:1]([O:17][CH2:18][CH:19]([CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[OH:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[C:39](#[N:42])[CH:40]=[CH2:41].[OH-].[Na+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH2:23]([O:22][CH2:21][CH:19]([CH2:18][O:17][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[O:20][CH2:41][CH2:40][C:39]#[N:42])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCOCC(O)COCCCCCCCCCCCCCCCC
Reactant: C=CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCCCCCCOCC(COCCCCCCCCCCCCCCCC)OCCC#N
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A mixture of 1,3-di-O-(n-hexadecyl)-glycerol (80 g., 148 mmoles), acrylonitrile (1.49 kg., 28.1 moles) and aqueous 2 N sodium hydroxide (1.2 l.) was heated to 50° C. Tetrabutylammonium hydroxide (19.2 g. of 40 wt. % aqueous solution, 29.15 mmoles) was slowly added, causing the temperature of the exothermic reaction mixture to rise to about 80° to 90° C. The reaction mixture was then stirred for 20 minutes without any external heating, followed by cooling to 20° C. and addition of water (1.0 l.). A solid material, a mixture of unreacted and cyanoethylated 1,3-di-O-(n-hexadecyl)-glycerol, was isolated and treated again with fresh acrylonitrile (1.49 kg., 28.1 moles), aqueous 2 N sodium hydroxide (1.2 l.) and tetrabutylammonium hydroxide (19.2 g. of 40 wt. % aqueous solution, 29.15 mmoles) for 20 minutes with stirring at 50° C., followed by cooling and addition of water (1.0 l.). The resulting 1,3-di-O-(n-hexadecyl)-2-O-(2-cyanoethyl)-glycerol solids were filtered, washed consecutively with water, methanol and acetonitrile, and dried [82 g., 93% yield, m.p. 45°-46° C., ir (CHCl3) 2250 cm-1, n.m.r. (CDCl3) δ 3.92 (t, 2, NCCH2CH2O--), 3.33-3.67 (m, 9, --OCH[CH2OCH2C15H31 ]2), 2.62 (t, 2, NCCH2CH2O--) and 0.75-1.58 (m, 62, aliphatic protons)].
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:24]=[CH:25][CH:26]=1>>[F:20][C:21]1[CH:22]=[C:23]([C:27]2[S:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:6]3)[C@H:2]2[CH2:7][NH:8][C:9]([C:11]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2[CH3:19])=[O:10])=[O:34])[CH:24]=[CH:25][CH:26]=1
Reactant: Cc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2c(C)nc3sccn23)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid [(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 5-(3-Fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid.
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](/[CH:29]=[CH:30]/[C:31]([O:33]CC)=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4]>C(O)C.O1CCOCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[NH:25][C:24](/[CH:29]=[CH:30]/[C:31]([O-:33])=[O:32])=[CH:23]4)[N:16]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH:12]([CH3:14])[CH3:13])#[N:4].[Na+:2]
Reactant: CCOC(=O)/C=C/c1cc2cc(-c3noc(-c4ccc(OC(C)C)c(C#N)c4)n3)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]c(/C=C/C(=O)[O-])cc4c3)no2)cc1C#N
Reaction time: 1 h

Procedure:
Aqueous NaOH solution (2 N, 2 mL) was added to a solution of ethyl (2E)-3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]-2-propenoate (D27) (20 mg) in ethanol (10 mL) and dioxane (5 mL) at RT. The resulting solution was stirred for 1 hour. Ethanol and dioxane were evaporated. The solid was filtered and washed with water. The solid was collected and dried to afford sodium (2E)-3-[5-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-2-yl]-2-propenoate (E10) (8 mg) as a pale yellow solid. δH (DMSO-d6, 400 MHz): 1.39 (6H, d), 4.99 (1H, m), 6.48 (1H, d), 6.66 (1H, s), 7.11 (1H, d), 7.46 (1H, d), 7.56 (1H, d), 7.77 (1H, d), 8.25 (1H, s), 8.42 (1H, dd) 8.51 (1H, d). MS (ES): C25H21N4O4Na requires 436; found 415.0 (M—Na++2H+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[C:32]2C=CC=CC=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.IC>C1COCC1>[C:13]1([S:19]([N:22]2[C:26]3[N:27]=[CH:28][N:29]=[C:30]([Cl:31])[C:25]=3[CH:24]=[C:23]2[CH3:32])(=[O:21])=[O:20])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2c(Cl)ncnc21
Agent: [Li]CCCC
Solvent: CI
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc2c(Cl)ncnc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To flame-dried flask under N2 was charged 0.57 ml (4.07 mmol) of diisopropylamine and 5.0 mL of dry THF. The solution was cooled to −78 OC and 1.63 mL (4.08 mmol) of a 2.5 M solution of n-butyllithium in hexanes added. The resulting mixture was brought to 0° C. and stirred for 10 minutes. After cooling the mixture again to −78° C., a solution of 1.0 g (3.40 mmol) of crude product from Method C in 10 mL of dry THF was added over a 10 minute period. The resulting mixture was stirred for 1 hour, at which time, 0.28 mL (4.50 mmol) of iodomethane were added. The reaction mixture was stirred for 2 hours, quenched with a saturated solution of NH4Cl and warmed to room temperature. The mixture was stirred for 5 minutes, diluted with water and extracted three times with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, filtered and evaporated in vacuo to obtain the title compound. LRMS: 308, 310 (M+2).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](Cl)[N:6]=1.Br.C(Cl)Cl.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][O:30][C:31]2[CH:37]=[CH:36][C:34]([NH2:35])=[CH:33][CH:32]=2)[CH2:23][CH2:22]1>CN1C(=O)CCC1>[F:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[NH:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:35][C:34]2[CH:36]=[CH:37][C:31]([O:30][CH2:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)=[CH:32][CH:33]=2)[N:6]=1
Reactant: Cc1ccc(F)c(Nc2ccnc(Cl)n2)c1
Reactant: Nc1ccc(OCCCN2CCOCC2)cc1
Agent: Br
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Cc1ccc(F)c(Nc2ccnc(Nc3ccc(OCCCN4CCOCC4)cc3)n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
4-(2-Fluoro-5-methylanilino)-2-chloropyrimidine (Reference Example A-10, 140 mg, 0.6 mmol) was dissolved in dry NMP (2 ml) and 4-(3-morpholinopropoxy)aniline.2.HBr salt (see CAS Registry No. 100800–40–6; J.Am.Chem.Soc., 76, 1954, 4396; 188 mg, 0.5 mmol) added. The mixture was stirred at ambient temperature for 5 minutes, then checked to ensure the reaction mixture was acidic (pH 1) and heated at 100° C. for 3 hours. The mixture was allowed to cool and evaporated to dryness to give an oil. Silica (2 g) and DCM (10 ml) were added and the mixture then re-evaporated to dryness and purified by chromatography on a Mega Bond Elute column (10 g) (eluting with DCM (2×25 ml), 2% NH3 in MeOH (3×25 ml), 4% NH3 in MeOH (3×25 ml), 6% NH3 in MeOH (3×25 ml), 10% NH3 in MeOH (9×25 ml)) to give the title product as a colourless oil, which was triturated with diethyl ether to give a white solid (95 mg, 46%). NMR (300 MHz): 1.8 (m, 2H), 2.2 (s, 3H), 2.4 (m, 4H), 2.4 (m, 2H), 3.6 (t, 3H), 3.9 (t, 2H), 6.2 (d, 1H), 6.8 (d, 2H), 6.9 (m, 1H), 7.1 (m, 1H), 7.5 (d, 2H), 7.8 (d, 1H), 8.0 (d, 1H), 8.9 (s, 2H); m/z: (ES+) 438.2 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:9](=[O:10])[O:8][CH2:7]2)([OH:3])=O.S(Cl)(Cl)=O.[NH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21].[Cl-]>O1CCCC1.C1(C)C=CC=CC=1.CN(C)C=O>[O:10]=[C:9]1[C:11]2[C:6](=[CH:5][C:4]([C:1]([NH:18][C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])=[O:3])=[CH:13][CH:12]=2)[CH2:7][O:8]1
Reactant: CC(C)(N)CO
Reactant: O=C(O)c1ccc2c(c1)COC2=O
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(CO)NC(=O)c1ccc2c(c1)COC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-carboxyphthalide (267 g, 1.5 mol) is added to thionyl chloride (950 mL) and then N,N-dimethylformamide (12 mL) is added dropwise. The mixture is heated at reflux for 1 hour and the thionyl chloride is destined off under reduced pressure followed by successive evaporations with toluene (2×50 mL) to give a solid residue. The crude acid chloride is then taken up with 1000 mL of tetrahydrofuran. To a solution of 2-amino-2-methyl-1-propanol (400.5 g, 4.5 mol) in tetrahydrofuran (500 mL), cooled to +5° C. chloride solution is added dropwise whilst maintaining the temperature between +5→+10° C. After the addition is completed, the cooling is removed and the mixture is stirred overnight at ambient temperature. Then the mixture is poured into deionized water (2000 mL) and the organic solvent is removed under reduced pressure at 50° C. After cooling and stirring for 2 hours, the solid product is filtered off and washed with deionized water (2×100 mL). The obtained product is dried at 70° C. for 36 hours under reduced pressure. Yield: 285.3 g (76%) of an off-white product having a purity (HPLC, peak area)=90%. 1H NMR (DMSO d-6, 500 MHz): 1.18 (3H, s), 1.32 (3H, s), 3.55 (2H, s), 5.45 (2H, s), 7.88-7.98 (3H, m), 8.07 (1H, s).
Reaction SMILES: C([O:8][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:10])C1C=CC=CC=1.ClC(OCC1C=CC=CC=1)=O.S(Cl)(C1C=[CH:34][C:32]([CH3:33])=[CH:31]C=1)(=O)=O.C(Cl)(=O)C1C(=CC=CC=1)C(Cl)=O.C(Cl)(=O)C1C=CC=CC=1>C(N(CC)CC)C>[C:32]([O:10][C:9]([NH:11][CH2:12][CH:13]=[CH2:14])=[O:8])([CH3:31])([CH3:33])[CH3:34]
Reactant: C=CCNC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(Cl)OCc1ccccc1
Agent: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: C=CCNC(=O)OC(C)(C)C

Procedure:
N-benzyloxycarbonyl allyl amine was made in the same manner by utilizing benzyl chloroformate and triethylamine at 0° C. Cbz chloride, tosyl chloride, phthaloyl chloride and benzoyl chloride can similarly be used to obtain the corresponding allyl amine.