Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
16 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.07 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxybutyl)-2-propylimidazole-5-carbonitrile [prepared as described in step (b) above] in 16 ml of ethanol, and the resulting mixture was worked up in a similar manner to that described in Example 45(c), to afford 0.82 g of the title compound as an amorphous solid.
Reaction SMILES: C[O:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].O>C1(C)C(C)=CC=CC=1>[OH:2][C:3]1[C:12]2[O:11][CH2:10][CH2:9][C:8](=[O:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCCC2=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1C
Product: O=C1CCOc2c(O)cccc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
2,3-Dihydro-8-methoxy-4H-1-benzopyran-4-one (7.59 g, 42.4 mmol) was dissolved in xylene (80 mL) followed by addition of anhydrous aluminum chloride (11.4 g, 85.5 mmol), and the mixture was stirred at 100° C. for 2 hours. After cooling, the reaction mixture was poured into iced water and extracted with ethyl acetate. The organic layer was washed with 1N-hydrochloric acid and saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from methanol-ethyl acetate-diethyl ether to provide 3.94 g of the title compound. Yield 56%.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH:11]=[CH2:12])[C:5]=1[OH:13])[CH:2]=[CH2:3].[OH-].[Na+].[P:16](Cl)([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[P:16]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])([O:13][C:5]1[C:4]([CH2:1][CH:2]=[CH2:3])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:10][CH:11]=[CH2:12])=[O:17]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C=CCc1cccc(CC=C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C=CCc1cccc(CC=C)c1OP(=O)(OCC)OCC
Reaction time: 8 h

Procedure:
2,6-Diallylphenol (3.16 gm, 0.018 mol) was diluted with toluene(50 ml) and sodium hydroxide (0.72 gm, 0.018 mol) added to the solution. The reaction flask was equipped with a Dean and Stark apparatus and refluxed for 1 hr to remove water and to form an anhydrous solution of the phenate salt. After cooling, diethyl chlorophosphate, (3.45 gm) was added and the solution stirred overnight. Filtration of the solids and evaporation of the toluene gave 2,6-diallylphenyl diethyl phosphate. MS m/z 310. (M+ calcd for C16H23PO4=310). H NMR (300 MHz, CDCl3) d 1.30–1.45 (t, 6, CH3), 3.66–3.72 (d, 4, CH2), 4.20–4.49 (m, 4, OCH2), 5.15–5.30 (m, 4, CH2 vinyl), 5.90–6.16 (m, 2, CH vinyl), 7.20 7.30 (m, 3, aromatic). Oxidation of the product as described in Example 1 gave 2,6-(2,3-epoxypropyl)phenyl diethyl phosphate. MS m/z 342 (M+ calcd for C16H23PO6=342). H NMR (300 MHz, CDCl3) d 3.65 (t, 6, CH3), 2.55–2.65 (m, 2, CH2 epoxypropyl), 2.75–2.85 (m, 2, CH2 epoxypropyl), 2.90–3.30 (m, 4, CH2 epoxypropyl), 3.40–3.55 (m, 2, CH epoxypropyl), 4.10–4.35 (m, 4, OCH2), 7.05–7.25 (m, 1, aromatic), 7.40–7.60 (m, 2, aromatic).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9]C.CS(O)(=O)=O.CSC>FC(F)(F)C(O)=O>[CH3:12][O:11][C:7]1[CH:6]=[C:5]([C@H:13]2[C@H:22]3[C:23]([O:25][CH2:26][C@@H:21]3[C@H:20]([OH:27])[C:19]3[CH:18]=[C:17]4[O:28][CH2:29][O:30][C:16]4=[CH:15][C:14]2=3)=[O:24])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[OH:9]
Reactant: COc1cc([C@@H]2c3cc4c(cc3[C@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1OC
Agent: CS(=O)(=O)O
Solvent: CSC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc([C@@H]2c3cc4c(cc3[C@@H](O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Reaction time: 9 h
Yield: 65562924 %

Procedure:
10 g (24 nmol) of podophyllotoxin are dissolved in 60 ml of trifluoroacetic acid. There are successively added 5.4 ml (72 mmol) of methanesulfonic acid. Stirring is carried out for 9 hours, 5.4 ml (72 mmol) of dimethyl sulfide are again added and stirring is carried out for 9 hours. The mixture is discharged onto ice (600 ml) and extracted with ethyl acetate (3×300 ml). The organic phases are washed with water and then with NaHCO3 solution until neutral. After drying over sodium sulfate, filtration and evaporation, there are obtained 6.3 g of 4′-demethylepipodophyllotoxin, which is used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:17][CH3:18])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([C:8](=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[CH:7]=1.[F:19][C:20]([F:32])([F:31])[C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1>[Cl:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([C:6]1[C:5]([O:15][CH3:16])=[CH:4][C:3]([O:17][CH3:18])=[C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:19])([F:31])[F:32])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[CH:7]=1)=[O:14]
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1N
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)c(C(=O)CCCCCl)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
A mixture of 1-(5-amino-2,4-dimethoxyphenyl)-5-chloro-1-pentanone (0.54 g, 2 mmol), prepared as in Example 13, 4-trifluoromethylbenzenesulfonyl chloride (0.51 g, 2.1 mmol) triethylamine (0.25 g, 2.5 mmol) and THF (approximately 50 mL) was stirred 16 hours at approximately 25° C. The mixture was concentrated and the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The organic layer was washed with water (1×) and then brine (1×), dried (K2CO3), filtered and concentrated to give N-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-4-trifluoromethylbenzenesulfonamide (0.8 g, 1.7 mmol), m.p. 150°-153° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[CH2:42][CH2:43][OH:44].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[C:3]([F:31])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:29][CH3:30])=[C:16]([CH2:19][N:20]([CH3:28])[C:21]4([C:25]([NH2:27])=[O:26])[CH2:24][N:23]([CH2:42][CH2:43][OH:44])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCCl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CNC1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1CN(C)C1(C(N)=O)CN(CCO)C1
Yield: 10.8 %

Procedure:
A solution of the hydrochloride salt of 3-[({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]azetidine-3-carboxamide (100 mg, 0.19 mmol Example 74), diisopropylethylamine (100 μl, 0.58 mmol), 2-chloroethanol (60 μl, 0.58 mmol) and potassium iodide (32 mg, 0.19 mmol) in acetonitrile (1.5 ml) was heated in a microwave at 160° C. for 20 minutes. Purification of the resulting product on preparative HPLC (standard basic condition) gave the title product (10 mg, 11%) as a white solid; 1H NMR Spectrum: (CDCl3) 2.40 (s, 3H), 2.75 (t, 2H), 3.47 (s, 2H), 3.61 (t, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 3.93 (s, 2H), 5.41 (brs, 1H), 6.79 (brs, 1H), 7.18 (m, 2H), 7.21 (s, 1H), 7.75 (brs, 1H), 7.86 (s, 1H), 8.52 (brs, 1H), 8.74 (s, 1H); Mass Spectrum: (M+H)+ 489.
Reaction SMILES: [H-].[Na+].C(COC)OC.[C:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][OH:19])([CH3:12])([CH3:11])[CH3:10].C(OCCOCCO[C:29]([F:33])=[C:30]([F:32])[F:31])C>CCCCC.C1OCCOCCOCCOCCOCCOC1>[C:9]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:29]([F:33])=[C:30]([F:32])[F:31])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOCCOCCOC(F)=C(F)F
Reactant: CC(C)(C)OCCOCCO
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCC
Solvent: COCCOC
Product: CC(C)(C)OCCOCCOC(F)=C(F)F
Temperature: 65 °C
Reaction time: 0.75 h
Yield: 63 %

Procedure:
Bu-TFVE was prepared by mixing 2.66 g of NaH (0.111 mol) and 1 g of 18-crown-6 with 135 mL of glyme under inert atmosphere at 65° C. 15.0 g (0.092 mol) of 2-(2-t-butoxyethoxy)ethanol was slowly added to the flask and stirred at 65° C. 1 h. The alkoxide was transferred to the dry 300 mL Parr reactor, stirred and heated at 65° C. for 1 h after which TFE gas was added. The pressure was maintained at ˜50-60 PSI. A very slight exotherm (˜5° C.) was initially observed. After 45 minutes, stirring was stopped and the reactor was cooled to room temperature. Excess TFE was carefully vented and the reactor contents transferred to a 500 mL Erlenmeyer flask. The mixture was diluted to 300 mL with pentane to effect complete precipitation of sodium salts. The mixture was filtered through a course frit funnel to remove sodium salts. The liquid fraction was rotary evaporated to give a clear yellow crude product. The crude product was vacuum fractionally distilled over potassium carbonate. 14.1 g (63% yield) of the desired product, 1-[2-(2-ethoxyethoxy)ethoxy]-1,2,2-trifluoroethene, was isolated at a boiling point of 26-27° C. (pressure 0.15 mmHg, >99% purity by GC). 19F NMR: δ=−123.5 (dd, 1F J=56, 104 Hz, CF), −130.3 (dd, 1F J=104, 108, CF), −135.1 (dd, 1F J=56, 108 Hz, CF); 1H NMR: δ=4.15 (m, 2H, CFOCF2), 3.75 (t, 2H, OCH2), 3.65-3.45 (m, 4H, OCH2), 1.2(s, 9H, C(CH3)3).
Reaction SMILES: [C:1]1(=[O:14])[C:9]2[CH:8]=[C:7]3[CH2:10][CH2:11][CH2:12][CH2:13][C:6]3=[CH:5][C:4]=2[CH2:3][CH2:2]1.[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.[OH-].[Na+]>C(O)C>[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[C:2]2[C:1](=[O:14])[C:9]3[CH:8]=[C:7]4[CH2:10][CH2:11][CH2:12][CH2:13][C:6]4=[CH:5][C:4]=3[CH2:3]2)=[CH:19][CH:18]=1
Reactant: O=C1CCc2cc3c(cc21)CCCC3
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)c1ccc(C=C2Cc3cc4c(cc3C2=O)CCCC4)cc1

Procedure:
A solution of 1.84 g (10 mmoles) of 2,3,5,6,7,8-hexahydro-1H-benz[f]inden-1-one (12), 1.49 g (10 mmoles) of p-dimethylaminobenzaldehyde, and 0.44 g of sodium hydroxide in 25 ml ethanol was stirred under nitrogen at 50° to 60° for 19 hr. The reaction mixture was cooled in an ice bath and the precipitated solid 2-[4-(dimethylamino)phenyl)-methylene]-2,3,5,6,7,8-hexahydro-1H-benz[f]inden-1-one was collected by filtration and washed with cold ethanol. Yield: 2.5 g (79%); m.p. 161° to 163°. λmax (EtOH): 274 nm (ε=16,700); 422 nm (36,500). Calcd for C22H23NO: C, 83.24; H, 7.30; N, 4.41. Found: C, 83.01; H, 7.73; N, 4.34.
Reaction SMILES: Br[C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH:9]=[CH2:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[C:3]([Cl:11])=[CH:4][C:5]([CH:9]=[CH2:10])=[C:6]([NH2:8])[CH:7]=1
Reactant: C=Cc1cc(Cl)c(Br)cc1N
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(Cl)c(-c2ccccc2Cl)cc1N
Temperature: 25 °C
Yield: 72.8 %

Procedure:
A mixture of 5-bromo-4-chloro-2-vinylbenzenamine (600 mg, 2.6 mmol), 2-chlorophenylboronic acid (1.25 g, 12.9 mmol), Pd(PPh3)4 (300 mg, 0.2 6 mmol), Na2CO3 (1.4 g, 13.0 mmol) in 1,4-dioxane (20 mL) and water (5 mL) was stirred at reflux under argon for 16 h. The mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=30:1) to afford the desired product (500 mg, 73.1% yield). ESI-MS m/z: 263.1[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]=[O:10])=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:12].Cl[O-].[Na+]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:12])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CC=O)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-]Cl
Product: Cc1ccc(CC(=O)O)cc1

Procedure:
In the like manner as Example 1, 26.4 g of p-methylphenylacetaldehyde as an aldehyde and 2.3 g of sulfuric acid were used. The oxidation was done by using 125 g of 12% aqueous solution of sodium hypochlorite at temperatures of -10° to -12° C., which was followed by the hydrogenation to obtain p-methylphenylacetic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]I)=[CH:4][CH:3]=1.[CH3:10][O:11][C:12](=[O:30])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH2:19][CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:22]>C(OCC)C>[CH3:10][O:11][C:12](=[O:30])[CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][N:14]1[CH2:19][CH2:20][C:21]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)[OH:22]
Reactant: COC(=O)C1CCCCN1CCC(=O)c1ccc(F)cc1
Reactant: Clc1ccc([Mg]I)cc1
Solvent: CCOCC
Product: COC(=O)C1CCCCN1CCC(O)(c1ccc(F)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Yield: 4.5 %

Procedure:
7 ml (2 mmol) of 0.28 M solution of 4-chlorophenylmagnesium iodide in diethyl ether [prepared from 1-chloro-4-iodobenzene (Aldrich) and magnesium] was added dropwise to an ice-cooled solution of 0.605 g (2 mmol) N-[3-(4-fluorophenyl)-3-oxopropyl]pipecolic acid methyl ester (from Step 1) in 12 ml anhydrous diethyl ether with stirring under nitrogen. The mixture was stirred at room temperature for 16 hours, poured onto crushed ice and extracted with dichloromethane. The combined organic extracts were washed with brine, concentrated and the residue purified by preparative silica gel TLC with 25% ethyl acetate in hexanes to give 0.037 g (yield 4.5%) N-[3-(4-chlorophenyl)-3-(4-fluorophenyl)3-hydroxypropyl]pipecolic acid methyl ester (Compound B30).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OC)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>C(O)C>[OH:16][CH2:15][C@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:14][CH2:13]1
Reactant: COC(=O)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Methyl trans-4-(tert-butoxycarbonylamino)cyclohexanecarboxylate (55.5 g, 216 mmol) was suspended in ethanol (900 ml) and THF (100 ml) and the mixture was cooled to 5° C. Granular calcium chloride (47.9 g, 431 mmol) was added portionwise to give a milky suspension. Sodium borohydride (32.6 g, 863 mmol) was added portionwise over 25 mins at 5° C. The reaction mixture (white emulsion) was stirred at 5° C. for 1 hour, the water bath was removed and then the reaction mixture was allowed to warm to room temperature and stirred at room temperature overnight. The reaction mixture was cooled to 10° C. and 5% potassium carbonate (200 ml) was added dropwise until the pH of the solution was pH11. A colourless precipitate formed which was filtered off. The solid was stirred with ethyl acetate (2000 ml) and water (500 ml). The organic layer was separated and washed with 0.5M HCl (200 ml), then washed with water (2×200 ml) and saturated brine (100 ml). The organic solution was dried over anhydrous MgSO4, filtered and evaporated to give a white solid. The solid was dried under high vacuum overnight to constant weight; [M+H]+230.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([OH:10])=[O:9])[N:3]=1.[CH:11]1(O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.P(Cl)(Cl)(Cl)=O.[OH-].[K+]>C(OCC)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[N:3]=1
Reactant: OC1CCCCC1
Reactant: Cc1nc(CC(=O)O)no1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(CC(=O)OC2CCCCC2)no1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 62 %

Procedure:
8 g (56.3 mmol) of 5-methyl-1,2,4-oxadiazol-3-yl-acetic acid were suspended in 8 g (80 mmol) of re-distilled, dry cyclohexanol and 8 g (52.2 mmol) of phosphorous oxychloride were added dropwise under anhydrous conditions over about 7 minutes to the mixture. During the addition, the mixture was heated on a steam bath and heating was continued for 45 minutes. After the reaction mixture had cooled to room temperature, 75 ml of ice-water and 50 ml of diethyl ether were added and the mixture was stirred until a clear two-layer system was obtained. The flask was placed in an ice-salt bath and solid potassium hydroxide was added until a pH of 10.5 was reached. The layers were separated and the aqueous layer was extracted three times with 40 ml portions of diethyl ether. The four ethereal extracts were combined, washed once with a small volume of ice-water and subsequently concentrated in vacuo. The 10 g of residue was distilled in vacuo to obtain 7.9 g (62% yield) of cyclohexyl 5-methyl-1,2,4-oxadiazol-3-yl-acetate with a b.p. of 120°-121° C. at 0.9-1.0 mm and a refractive index nD25 =1.4715.
Reaction SMILES: [H-].[Na+].[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][OH:27])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>O1CCCC1.C(OCC)(=O)C>[CH:3]1([CH2:9][CH2:10][CH2:11][C@@H:12]([C:21]2[O:25][N:24]=[C:23]([CH2:26][O:27][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:22]=2)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CO)no1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)COCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.8 %

Procedure:
A suspension of sodium hydride 60% suspension in mineral oil (13 mg, 0.33 mmol) in anhydrous tetrahydrofuran (1 ml) was cooled to 0° C. and treated with a solution of tert-butyl (3R)-6-cyclohexyl-3-[3-(hydroxymethyl)-1,2,4-oxadiazol-5-yl]hexanoate (Preparation 85) (105 mg, 0.30 mmol) in anhydrous tetrahydrofuran (1 ml) and stirred under a nitrogen atmosphere for 1 hour. Ethyl bromoacetate (37 μl, 0.33 mmol) was added and the mixture was stirred for 18 hours, being allowed to warm to room temperature over this time. The reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The solid was purified by column chromatography on silica gel eluting with a gradient system of pentane:ethyl acetate (99:1) to pentane:ethyl acetate (80:20) to afford the title compound as a colourless oil (84 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=O)=[C:4]([NH:15][CH3:16])[CH:3]=1.[CH2:17]([NH2:19])[CH3:18].C(=O)(O)[O-].[Na+]>CN1C(=O)CCC1>[CH2:17]([NH:19][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[CH:9][C:10](=[O:12])[N:15]2[CH3:16])=[CH:6][N:7]=1)[CH3:18]
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cc1NC
Reactant: CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCNc1cc2c(ccc(=O)n2C)cn1
Temperature: 150 °C

Procedure:
A vial was charged with (E)-ethyl 3-(6-chloro-4-(methylamino)pyridin-3-yl)acrylate (45 mg), 70% aqueous ethyl amine (1 mL) and NMP (1 mL). The vial was sealed and heated with microwave irradiation for 35 min at 150° C. Aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel (50% ethyl acetate in hexanes eluant) to provide the title compound. MS (m/z) 204.0 (M+1).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[OH-].[OH-].[Pd+2]>[CH3:21][O:20][C:16]1[CH:15]=[C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)[CH:19]=[CH:18][CH:17]=1
Reactant: [H][H]
Reactant: COc1cccc(C2CN(Cc3ccccc3)CCO2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C2CNCCO2)c1
Yield: 56.1 %

Procedure:
In a 250 mL round-bottomed flask, 4-benzyl-2-(3-methoxyphenyl)morpholine (2.3 g, 8.12 mmol) and palladium hydroxide on carbon (285 mg, 406 μmol) were combined in methanol (15 ml). The suspension was stirred at room temperature under a balloon of hydrogen overnight. The system was evacuated with argon 3 times. The reaction mixture was filtered through Celite, and the filtercake washed several times with methanol. The combined filtrate and washes were concentrated in vacuo to afford 2-(3-methoxy-phenyl)-morpholine (0.88 g, 56%) which was directly used for next step. (M+H)+=194 m/e.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])=O)[CH:7]=1.B(F)(F)F.CCOCC.C(OCC)(=O)C.C(=O)(O)[O-]>C(#N)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:20])=[C:6]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([F:18])[C:11]=2[F:19])[CH:7]=1
Reactant: COc1ccc(C(=O)c2cc(Br)ccc2Cl)c(F)c1F
Agent: FB(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCOCC
Product: COc1ccc(Cc2cc(Br)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 25.9 %

Procedure:
To a solution of (5-bromo-2-chloro-phenyl)-(2,3-difluoro-4-methoxy-phenyl)methanone 21e (5.42 g, 14.9 mmol) in acetonitrile (100 mL) were added triethyl silicane (4.8 mL, 29.87 mmol) at 15° C., followed by boron trifluoride diethyl ether (7.4 mL, 59.74 mmol). The mixture was warmed up to room temperature and stirred for 15 hours. To the reaction mixture was added ethyl acetate (4 mL). The mixture was adjusted with saturated aqueous bicarbonate to pH 7, and then partitioned. The combined organic layers were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=20/1 to give the title compound 21f as pale yellow oil (1.34 g, 25.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 347.05 [M+H]+; and 1H NMR (400 MHz, CDCl3) δ (ppm): 7.33 (m, 1H), 7.28 (m, 2H), 6.84-6.76 (m, 1H), 6.75-6.62 (m, 1H), 4.05 (s, 2H), 3.91 (s, 3H).