Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BrH:1].C([N:4]([CH2:7][CH3:8])[CH2:5][CH3:6])C.[C:9](Cl)([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Cl>C(Cl)Cl.CCCCCC.O>[CH2:12]([O:11][C:9]([N:4]1[CH2:5][C:6]2[C:8](=[CH:12][CH:13]=[C:14]([Br:1])[CH:15]=2)[CH2:7]1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Br
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCC
Solvent: O
Product: O=C(OCc1ccccc1)N1Cc2ccc(Br)cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 25 ml of 47% hydrobromic acid was suspended 5.0 g of 2-(p-toluenesulfonyl)-5-bromoisoindoline, and 4.0 g of phenol and 15 ml of propionic acid were added to the suspension, after which the resulting mixture was heated under reflux for four hours. The reaction mixture was concentrated under reduced pressure, and ethanol was added to the residue obtained, after which the resulting crystals were collected by filtration, to obtain 3.5 g of 5-bromoisoindoline hydrobromide. The hydrobromide obtained was suspended in 50 ml of methylene chloride, and 2.8 g of triethylamine was added to the suspension, after which 2.4 g of carbobenzoxy chloride was dropwise added thereto with ice-cooling. Thereafter, the resulting mixture was stirred at room temperature for one hour. The reaction mixture was added 50 ml of water and the pH was adjusted to 1 with 6N hydrochloric acid. Thereafter, the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium chloride. The solvent was then removed by distillation under reduced pressure. To the residue thus obtained was added n-hexane, and the resulting crystals were collected by filtration to obtain 3.8 g of colorless, crystalline 2-benzyloxycarbonyl-5-bromoisoindoline.
Reaction SMILES: [C:1](O)(=O)[CH3:2].[N:5]1([C:11]([S:13][CH2:14][C:15]2([CH3:41])[CH:19]([C:20]([O:22]CC(Cl)(Cl)Cl)=[O:21])[N:18]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C@H:17]3[S:16]2)=[S:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>CN(C)C=O.[Zn]>[N:5]1([C:11]([S:13][CH2:14][C:15]2([CH3:41])[CH:19]([C:20]([OH:22])=[O:21])[N:18]3[C:28](=[O:40])[CH:29]([NH:30][C:31](=[O:39])[CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[C@H:17]3[S:16]2)=[S:12])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1.[CH2:32]([NH:30][CH2:29][CH2:17][NH:18][CH2:19][C:1]1[CH:2]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)O
Reactant: CC1(CSC(=S)N2CCCCC2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CN(C)C=O
Product: CC1(CSC(=S)N2CCCCC2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)O
Product: c1ccc(CNCCNCc2ccccc2)cc1
Reaction time: 0.67 h

Procedure:
Acetic acid (1 ml) and zinc powder (0.80 g) were added to a solution of 2,2,2-trichloroethyl 2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.95 g) in dimethylformamide (5 ml) under ice-cooling and the mixture was stirred for 1 hour and 40 minutes. After the reaction, zinc powder was filtered off and the filtrate was poured into ethyl acetate. The solution was washed with 3% hydrochloric acid and then with water (four times) and dried over magnesium sulfate. After drying, the solvent was distilled off and the residue was dissolved in a small amount of methanol. To this solution was added an aqueous solution of N,N'-dibenzylethylenediamine diacetate and precipitates were collected by filtration, washed with water to give N,N'-dibenzylethylenediamine 2-piperidinothiocarbonylthiomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.30 g), mp. 100° C. (dec.).
Reaction SMILES: S(Cl)(Cl)=O.N1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[CH2:6]=[C:7]1[C:8]([CH3:9])([CH3:7])[CH2:10][CH2:9][C:8]1([CH3:10])[CH3:6]
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C=C1C(C)(C)CCC1(C)C
Reaction time: 8 h

Procedure:
30 g of1,2,2,5,5-pentamethylcyclopentanol was dissolved in 150 ml of pyridine, and 20 ml of thionyl chloride was added dropwise thereto with ice cooling. The reaction mixture was stirred overnight and subjected to filtration. Ether and water were added to the filtrate, and the resulting layers were separated. The organic layer was washed twice with 200 ml of water, and then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, whereby 10.8 g of 1-methylene-2,2,5,5-tetramethylcyclopentane was obtained (b.p. 137-140° C./ 760 mmHg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH2:9]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1ccsc1
Reactant: BrCc1ccccc1
Product: c1ccc(Cc2ccsc2)cc1
Yield: 74 %

Procedure:
3-benzylthiophene was prepared in the same manner as described in Example 32C using 3-thienylboronic acid and benzyl bromide, 74% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH:11]=[CH2:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1.C(O)(=O)C>C1COCC1.CCO>[NH2:1][C:2]1[C:7]2=[C:8]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([NH:22][C:23]4[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][N:24]=4)=[O:21])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[CH:10][N:6]2[N:5]=[CH:4][N:3]=1
Reactant: C=Cc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1

Procedure:
1-[4-(4-amino-6-vinylpyrrolo[2,1-f][1,2,4]triazin-5-yl)phenyl]-3-[4-(trifluoro-methyl)pyridin-2-yl]urea (150 mg, 0.341 mmol) was slowly dissolved in THF (100 mL) by adding acetic acid (10-20 mL). The solution was further diluted with EtOH (300 mL) and run through the H-Cube® apparatus at 20 bar, rt, 1 mL/min. The resulting solution was concentrated then washed with satd. NaHCO3. A precipitate formed and the desired product was collected by vacuum filtration to yield a tan solid. (150 mg, 99%). 1H-NMR (DMSO-d6) δ 11.89 (bs, 2H), 8.49 (d, J=5.0 Hz, 1H), 8.28 (s, 1H), 7.80 (s, 1H), 7.74 (d, J=8.8 Hz, 2H), 7.60 (s, 1H), 7.27 (m, 3H), 2.48 (q, J=7.8 Hz, 2H), 1.09 (t, J=7.5 Hz, 3H). MS [M+H]+=442.0; LCMS RT=2.95.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=2[CH:18]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][CH:12]([CH3:17])[C:11]=3[CH:18]=2)=[CH:22][CH:21]=1
Reactant: Cc1ccc(S)cc1
Reactant: CC1OC(=O)Nc2ccc(OCCCCCl)cc21
Product: Cc1ccc(SCCCCOc2ccc3c(c2)C(C)OC(=O)N3)cc1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4-methyl-4H-3,1-benzoxazin-2-one and 4-methyl-thiophenol.
Reaction SMILES: N[CH:2]([NH:10][C:11]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:12]=1C(O)=O)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:28])C=CC=CC=1.C([N:40]([CH2:43]C)CC)C>C1(C)C=CC=CC=1>[Br:20][C:18]1[CH:17]=[CH:16][C:12]2[NH:40][C:43](=[O:28])[N:10]([CH2:2][C:3]([O:5][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:4])[C:11]=2[CH:19]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)C(N)Nc1cc(Br)ccc1C(=O)O
Reactant: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccc(Br)cc21
Temperature: 100 °C

Procedure:
2-[(1-Amino-2-tert-butoxy-2-oxoethyl)amino]-4-bromobenzoic acid from Step C (2.72 g, 8.24 mmol), diphenylphosphoryl azide (2.1 mL, 9.9 mmol), and triethylamine (1.4 mL, 9.9 mmol) were dissolved in toluene (80 mL) and heated at 100° C. for 1 h. The cooled mixture was partitioned between EtOAc (200 mL) and water (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=327 (M+1).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O.C(OCC)(=O)C>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[CH2:26][CH3:27])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Temperature: 60 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Compound 67a (82 mg, 0.20 mmol) obtained in Example 67 was dissolved in tetrahydrofuran (1 mL), to the solution was added a 1 mol/L solution (2 mL) of ethyl magnesium bromide in tetrahydrofuran, and the mixture was stirred at 60° C. for 1 hour. To the reaction mixture was added water and the mixture was stirred. Ethyl acetate was added to the mixture and the organic layer was washed with water and dried over magnesium sulfate. The organic layer was concentrated and to the residue were added dichloromethane and diisopropyl ether. The deposited crystals were collected by filtration to obtain the title compound (40 mg, 58%) as a white solid.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=[C:4]([C:16]#[N:17])[CH:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.Cl.[NH2:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>O1CCOCC1>[C:16]([C:4]1[CH:3]=[C:2]([NH:50][CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[N:5]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)CN
Reactant: N#Cc1cc(O)c2cc(C(F)(F)F)ccc2n1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)CNc1cc(C#N)nc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 25 mL vial, was placed a solution of 4-hydroxy-6-(trifluoromethyl)quinoline-2-carbonitrile (238 mg, 1.00 mmol, 1.00 equiv) in dioxane (2 mL), PyBrOP (217 mg, 0.47 mmol, 1.10 equiv), triethylamine (354 mg, 3.50 mmol, 2.50 equiv) and tert-butyl 2-aminoacetate hydrochloride (217 mg, 1.30 mmol, 1.30 equiv). The reaction mixture was stirred overnight at room temperature. The reaction was then quenched by the addition of 25 mL of water. The resulting solution was extracted with 3×10 mL of ethyl acetate. The combined organic layers dried over anhydrous sodium sulfate and concentrated under vacuum. The residue purified by chromatography over a silica gel column with EtOAc/petroleum ether (1:1-1:10). The title compound was obtained as a white solid.
Reaction SMILES: CC1C=CC(C)=CC=1.[CH3:9][O:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([O:22][CH2:23][O:24][CH3:25])[CH:21]=1)[C:16](Cl)=O.[C:26]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=C)=[CH:32][CH:31]=1)(=[O:28])[CH3:27].CN1CCOCC1>[Pd].[Cl-].C(C1C=CC=C(C(C)C)C=1[NH+]1CCN(C2C(C(C)C)=CC=CC=2C(C)C)C1)(C)C.CCOC(C)=O>[C:26]([O:29][C:30]1[CH:37]=[CH:36][C:33]([CH:34]=[CH:16][C:15]2[CH:14]=[C:13]([O:12][CH2:11][O:10][CH3:9])[CH:21]=[C:20]([O:22][CH2:23][O:24][CH3:25])[CH:19]=2)=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: COCOc1cc(OCOC)cc(C(=O)Cl)c1
Reactant: C=Cc1ccc(OC(C)=O)cc1
Agent: [Pd]
Agent: CC(C)c1cccc(C(C)C)c1N1CC[NH+](c2c(C(C)C)cccc2C(C)C)C1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: Cc1ccc(C)cc1
Product: COCOc1cc(C=Cc2ccc(OC(C)=O)cc2)cc(OCOC)c1
Temperature: 120 °C
Reaction time: 3.5 h
Yield: 58.6 %

Procedure:
A 50 mL round bottom flask was charged with p-xylene (20 mL), Pd II catalyst (22.5 mg, 0.1 mmol), 1,3-bis-(2,6-diisopropylphenyl) imidazolinium chloride (42.7 mg, 0.1 mmol), 3,5-bis(methoxymethoxy)benzoyl chloride (2.42 g, 10 mmol), 4-acetoxystyrene (1.94 g, 12 mmol), and N-methyl morpholine (1.38 g, 12 mmol). The mixture was stirred at 120° C. for 3.5 h under nitrogen atmosphere. Then it was cooled to room temperature and EtOAc was added and filtered. The filtrate was washed with brine and dried over Na2SO4. Then it was filtered and purified via flash chromatography and gave the product (2.1 g, 59%) as white solid. Data are: 1H NMR (CDCl3, 300 MHz) δ 7.48 (d, 2H), 7.08-6.93 (m, 4H), 6.86 (d, 2H), 6.66 (t, 1H), 5.19 (s, 4H), 3.50 (s, 6H), 2.30 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 169.5, 158.7, 150.3, 139.5, 135.0, 128.7, 128.5, 127.6, 121.9, 108.0, 104.5, 94.6, 56.2, 21.2; HRMS (EI+) found 358.1409 M+, calcd 358.1416 for C20H22O6.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-])=O)[C:5]=1[C:6]#[N:7])([O-])=O.Cl.[OH-].[Na+]>O>[NH2:1][C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([NH2:12])[C:5]=1[C:6]#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1c(N)cccc1N
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
2,6-Dinitrobenzonitrile (10.0 grams) is added in portions to a stirred solution of stannous chloride (82.5 grams) is concentrated HCl (230 ml.) at room temperature. Stirring is continued at room temperature for 1/2 hours, then the reaction mixture is cooled to 0° and made strongly basic with 50% NaOH. The reaction mixture is diluted with water (1 l.) and extracted four times with methylenechloride (200 ml.). The combined extracts are washed once with water (200 ml.), dried over sodium sulfate, then taken to dryness under reduced pressure. Recrystallization of the crude solid (4.6 grams) from benzene-Skellysolve B gives the product (4.15 grams) melting at 91°-92°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][C:14](=[O:19])[C:15]([F:18])([F:17])[F:16])[CH2:10][C@H:9]1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:32]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([N:13]([CH3:32])[C:14](=[O:19])[C:15]([F:18])([F:16])[F:17])[CH2:10][C@H:9]1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([O:28][CH3:29])=[O:27])=[CH:30][CH:31]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(OC[C@@H]2C[C@@H](NC(=O)C(F)(F)F)CN2C(=O)OC(C)(C)C)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2C[C@@H](N(C)C(=O)C(F)(F)F)CN2C(=O)OC(C)(C)C)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
To a stirred solution of methyl 4-(trans-1-tert-butoxycarbonyl-4-trifluoroacetamido-(2S)-pyrrolidinyl)methoxybenzoate (520 mg, 1.17 mmol) in DMF (10.0 ml) was added K2CO3 (321 mg, 2.33 mmol) and MeI (330 mg, 2.33 mmol) at room temperature. The reaction mixture was stirred at 50° C. for 18 hr. Water was added to the mixture and extracted with EtOAc. The organic layer was washed with water, then dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography on silica gel with EtOAc-n-hexane (1:2, v/v) as eluent to give methyl 4-[trans-1-tert-butoxycarbonyl-4-(N-methyl-trifluoroacetamido)-(2S)-pyrrolidinyl]methoxybenzoate (390 mg, 73%) as a colorless oil. 1H-NMR (CDCl3) δ 1.46 (9H, s), 2.12–2.40 (m, 2H), 2.96 and 3.05 (each s, total 3H), 3.28–3.70 (m, 2H), 3.88 (s, 3H), 3.95–4.42 (m, 3H), 5.10–5.40 (m, 1H), 6.89–6.91 (m, 2H), 7.96–8.00 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH:14]=[CH2:15])[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8][CH2:7]1)=[O:5])C.O.[OH-].[Li+].CO>O1CCCC1.O>[CH3:12][C:9]1([CH3:13])[O:10][CH2:11][C:6]([CH:14]=[CH2:15])([C:4]([OH:5])=[O:3])[CH2:7][O:8]1
Reactant: C=CC1(C(=O)OCC)COC(C)(C)OC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CC1(C(=O)O)COC(C)(C)OC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
A solution of 2,2-dimethyl-5-vinyl-[1,3]dioxane-5-carboxylic acid ethyl ester (150 mg, 0.7 mmol) in tetrahydrofuran (3 mL) was stirred at 5° C. under nitrogen. A solution of lithium hydroxide monohydrate (59 mg, 1.4 mmol) in water (1 mL) was added and the reaction mixture was stirred at 5° C. for 30 minutes and then at room temperature for 5 hours. Methanol (0.5 mL) was added to give a clear solution and the reaction mixture was stirred at room temperature for 22 hours. The solvent was evaporated. Water (2 mL) was added to the residue and the solution was acidified to pH 2 with 2 M hydrochloric acid. Brine was added and the mixture was extracted with ethyl acetate. The organic extracts were combined, washed with brine. The organic extract was separated, washed with water (×5), and brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated to afford the title compound (117 mg, 90%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 1.44 (s, 3H), 1.49 (s, 3H), 3.91 (d, J=12.0 Hz, 2H), 4.32 (d, J=12.0 Hz, 2H), 5.30 (d, J=17.8 Hz, 1H), 5.35 (d, J=10.7 Hz, 1H), 5.76 (dd, J=17.8, 10.7 Hz, 1H). LCMS (m/z) 185.1 [M−H], Tr=1.26 min.
Reaction SMILES: [CH3:1][C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:16]2[CH:17]=[CH:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:15])=[CH:12][CH:13]=1)([C:4]([OH:6])=[O:5])[CH3:3].C(O[CH:27]([CH3:29])[CH3:28])(=O)C.C(=O)([O-])[O-].[K+].[K+].BrC(C)C>CS(C)=O>[CH3:28][CH:27]([O:5][C:4]([C:2]([O:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:13]=1)([CH3:1])[CH3:3])=[O:6])[CH3:29]
Reactant: CC(C)(Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1)C(=O)O
Reactant: CC(=O)OC(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(C)Br
Product: CC(C)OC(=O)C(C)(C)Oc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1 kg (3.14 mol) of fenofibric acid (II), 500 ml of dimethyl sulfoxide and 1 l of isopropyl acetate were charged into a jacketed 5 l reactor under nitrogen. 433.5 g (3.14 mol) of potassium carbonate were then added, with stirring at ambient temperature, and the reaction mixture was brought to 85-90° C. for 45 min. The temperature of the reaction mixture was subsequently reduced to approximately 80° C. and 354 ml (3.77 mol) of 2-bromopropane and then 100 ml of isopropyl acetate were added over a period of 50 min. The mixture was kept stirring at 85-95° C. for 5 hours and then slightly cooled to approximately 80° C. In-process monitoring showed that the degree of conversion to give fenofibrate was approximately 99.5%. The content of the reactor was hot-filtered and the salts separated on the filter were washed with 1 l of isopropyl acetate, which was combined with the filtrate. The isolated salts, which essentially comprise potassium bromide, were dried and kept for recycling. The filtrate was concentrated under reduced pressure while maintaining a bulk temperature of approximately 80° C., and of 95° C. at the end of concentrating. After removal of the solvents, 2.27 l of isopropanol and 455 ml of pure water were added. The mixture was brought to gentle reflux for 10 min and then hot-filtered. Under stirring, the filtrate was slowly cooled down to a temperature of 0° C. The crystallized fenofibrate was separated by filtration on a filtering device, washed on the filtering device with approximately 500 ml of ice-cold isopropanol and then dried under vacuum at 45-50° C. 1075 g of fenofibrate with a purity of greater than 99.5% and comprising no impurity at a level of greater than 0.05% were thus obtained (yield=94.9%).
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][CH2:8][NH:9][C:10](=[O:28])[CH2:11][NH:12][C:13](=[O:27])[CH2:14][CH2:15][CH2:16][C:17]1[N:26]=[C:25]2[C:20]([CH2:21][CH2:22][CH2:23][NH:24]2)=[CH:19][CH:18]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:24]1[C:25]2[C:20](=[CH:19][CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][C:13]([NH:12][CH2:11][C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:29])=[O:5])=[O:28])=[O:27])[N:26]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: CC(C)(C)OC(=O)CCNC(=O)CNC(=O)CCCc1ccc2c(n1)NCCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCNC(=O)CNC(=O)CCCc1ccc2c(n1)NCCC2
Temperature: 25 °C

Procedure:
Ester 19-9 (69 mg, 0.17 mmol) was dissolved in 1 mL CH2Cl2 at 0° C., 1 mL TFA was added, and the reaction was warmed to ambient temperature for 6 hr. After concentrating and azeotroping with toluene, flash chromatography (silica, 7:20:1:1 EtOAc/EtOH/H2O/NH4OH) provided 19-10 as a white solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:14])[CH2:6][CH2:5]1.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:3][CH:4]2[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][C:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:14])[CH2:6][CH2:5]2)=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: NC1CCN(CCCC(=O)c2ccccc2)CC1
Agent: Cl
Product: O=C(CCCN1CCC(NC(=O)c2ccc(Cl)cc2)CC1)c1ccccc1

Procedure:
4-Amino-1-(4-phenyl-4-oxobutyl)piperidine dihydrochloride (3.19 g.) was acylated with p-chloro-benzoyl chloride (1.75 g.) in the manner of example75. Filtration afforded the title compound as the base (3.277 g.). This wassuspended in boiling ethanol (15 ml). and ethanol/HCl added until acid. On cooling the title compound crystallised out as the hydrochloride, colourless needles (3.41 g.), m.p. 261.1°. Analysis: Found: C, 62.89; H, 6.33; N, 6.64. C22H25CIN2O2.HCl requires C, 62.69; H, 6.22; N, 6.65%.
Reaction SMILES: CC([N:5]([C@@H:9]([C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]4([CH2:31][O:32][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH2:30][CH2:29]4)=[CH:19][CH:20]=1)=[O:13])[CH2:10][CH3:11])C(=O)[O-])(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:5][C@H:9]([CH2:10][CH3:11])[C:12]([NH:14][C:15]1[CH:16]=[N:17][C:18]([O:21][C:22]2[C:27]3[C:28]4([CH2:31][O:32][C:26]=3[CH:25]=[CH:24][CH:23]=2)[CH2:30][CH2:29]4)=[CH:19][CH:20]=1)=[O:13]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1)N(C(=O)[O-])C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc3c2C2(CC2)CO3)nc1
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 1,1-dimethylethyl[(1R)-1-({[6-(spiro[1-benzofuran-3,1′-cyclopropan]-4-yloxy)-3-pyridinyl]amino}carbonyl)propyl]carbamate (Intermediate 88, 128 mg) in dry dichloromethane (3 ml) at 0° C. TFA (0.9 mL, 11.68 mmol) was slowly added and the reaction mixture was stirred for 2 hours at the same temperature. The reaction was diluted with dichloromethane (10 ml) and an aqueous saturated solution of NaHCO3 was added while the pH was allowed to reach ˜8. Two phases were separated and the aqueous layer was re-extracted with dichloromethane (10 ml). The organic layers were combined, dried over sodium sulphate, filtered and evaporated affording the title compound as a colourless oil (92 mg).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:25])[CH:21]=[CH:22][C:23]=1[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[CH3:24])[O:25][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Yield: 58 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (743 mg, 2.26 mmol), 3-amino-4-methylphenol (446 mg, 3.62 mmol), potassium carbonate (782 mg, 5.66 mmol) and N,N-dimethylformamide (5.0 mL) was stirred using a microwave synthesizer at 180° C. for 30 min. The solvent was evaporated under reduced pressure, ethyl acetate, tetrahydrofuran and water were added to the residue, and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=17/83→75/25) to give the title compound (424 mg, 58%) as a brown powder.