Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1C=C(O)C=C[CH:8]=1.C(C1C(O)=CC=C2C=1C=CN2CC(C)(C)C)C=C.[CH3:28][C:29]([CH3:61])([CH3:60])[CH2:30][N:31]1[C:39]2[C:34](=[C:35]([CH2:57][CH2:58][CH3:59])[C:36]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:46]3[CH:51]=[CH:50][C:49]([C:52]4[NH:56][N:55]=[N:54][N:53]=4)=[CH:48][CH:47]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32]1>>[CH2:57]([C:35]1[C:36]([O:40][CH2:41][C:42]2[CH:8]=[CH:3][CH:2]=[C:44]([O:45][C:46]3[CH:47]=[CH:48][C:49]([C:52]4[NH:56][N:55]=[N:54][N:53]=4)=[CH:50][CH:51]=3)[CH:43]=2)=[CH:37][CH:38]=[C:39]2[C:34]=1[CH:33]=[CH:32][N:31]2[CH2:30][C:29]([CH3:60])([CH3:61])[CH3:28])[CH:58]=[CH2:59]
Reactant: CCCc1c(OCCCCOc2ccc(-c3nnn[nH]3)cc2)ccc2c1ccn2CC(C)(C)C
Reactant: OCc1cccc(O)c1
Agent: C=CCc1c(O)ccc2c1ccn2CC(C)(C)C
Product: C=CCc1c(OCc2cccc(Oc3ccc(-c4nnn[nH]4)cc3)c2)ccc2c1ccn2CC(C)(C)C

Procedure:
A similar reaction sequence as outlined in example 28 was followed using 3-(hydroxymethyl)phenol and 4-allyl-1-(2,2-dimethylpropyl)-1H-indol-5-ol, an intermediate from example 1. 1H NMR (CDCl3, 500 MHz) δ 7.97 (d, 2H), 7.43 (t, 1H), 7.30 (d, 1H), 7.20 (br s, 1H), 7.16 (d, 1H), 7.10 (s, 1H), 7.08 (d, 2H), 7.04-7.06 (m, 1H), 6.93 (d, 1H), 6.5 (br s, 1H), 5.90-6.03 (m, 1H), 5.10 (s, 2H), 5.05 (d, 1H), 4.95 (d, 1H), 3.90 (d, 2H), 3.68 (d, 2H), 1.00 (s, 9H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26][CH2:25]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:41][N:42]([CH3:48])[C@H:43]1[CH2:47][CH2:46][NH:45][CH2:44]1>>[C:1]([C:5]1[CH:6]=[C:7]([NH:36][S:37]([CH3:40])(=[O:38])=[O:39])[C:8]([O:34][CH3:35])=[C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:33])[C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][C:17]=3[CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([C:30]([N:45]3[CH2:46][CH2:47][C@H:43]([N:42]([CH3:48])[CH3:41])[CH2:44]3)=[O:31])[CH2:28][CH2:29]2)=[O:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)O)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: CN(C)[C@H]1CCNC1
Product: COc1c(NC(=O)c2cc3cccc(CN4CCC(C(=O)N5CC[C@H](N(C)C)C5)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
1-[2-(5-tert-butyl-3-methanesulphonylamino-2-methoxy-phenylcarbamoyl)-1-methyl-1H-indol-7-ylmethyl]-piperidine-4-carboxylic acid and (S)-3-dimethylamino-pyrrolidine are used as reactants.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([O:15]C)=[O:14])=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>C1COCC1>[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]([OH:15])=[O:14])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1cn(C(C)C)c2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)n1cc(C(=O)O)c2ccccc21
Temperature: 50 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
In THF (8.0 ml) was dissolved methyl 1-isopropylindole-3-carboxylate (387.6 mg, 1.784 mmol). To the resulting solution was added 0.25N NaOH (8.0 ml). The resulting mixture was stirred at 50° C. for 18 hours. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (4.5 ml). The crystals thus precipitated were collected by filtration under reduced pressure, washed with water and dried under reduced pressure to give 1-isopropylindole-3-carboxylic acid (327.8 mg, 90%) as a pale pink amorphous substance.
Reaction SMILES: [NH2:1][C@H:2]([CH3:15])[C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([F:13])=[C:8]([Cl:14])[CH:7]=1)=[O:4].[CH:16](=O)[C:17]([CH3:20])([CH3:19])[CH3:18]>C1(C)C=CC=CC=1.CCCCCC>[C:17]([C@@H:20]1[N:5]([C:6]2[CH:7]=[C:8]([Cl:14])[C:9]([F:13])=[C:10]([Cl:12])[CH:11]=2)[C:3](=[O:4])[C@@H:2]([CH3:15])[NH:1]1)([CH3:19])([CH3:18])[CH3:16]
Reactant: CC(C)(C)C=O
Reactant: C[C@@H](N)C(=O)Nc1cc(Cl)c(F)c(Cl)c1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C[C@H]1N[C@H](C(C)(C)C)N(c2cc(Cl)c(F)c(Cl)c2)C1=O
Temperature: 50 °C
Reaction time: 22 h
Yield: 59.2 %

Procedure:
To a solution of (R)-2-amino-N-(3,5-dichloro-4-fluoro-phenyl)-propionamide (149.1 g crude, max 594 mmol) in toluene (743 mL) at 40° C., was added pivalaldehyde (67.1 mL, 618 mmol) in one portion. The reaction was stirred at 50° C. for 22 h and then all volatiles were removed in vacuo to give a viscous brown oil. Hexane (500 mL) was added and the resulting suspension was stirred at room temperature for 30 min. The mixture was filtered and the solids rinsed with cold hexane. The filtrate was concentrated in vacuo and reprocessed in a similar manner to obtain additional precipitate. The remaining filtrate was diluted with hexane until a black oil separated from the solution. The hexane layer was decanted from this black oil and concentrated in vacuo. The residue was re-dissolved in warm diethyl ether (300 mL) and stored in the freezer for 1.5 h over which time crystal growth was observed. The solids were filtered, and the filtrate reprocessed in a similar manner to obtain additional crystals. All of the collected solids were combined to give 112.2 g of (2S,5R)-2-tert-butyl-3-(3,5-dichloro-4-fluoro-phenyl)-5-methyl-imidazolidin-4-one as a tan solid. To a solution of this solid in toluene (639 mL) at 0° C. was added triethylamine (73.5 mL, 527 mmol) in one portion. Trifluoroacetic anhydride (58.6 mL, 422 mmol) was added to the reaction mixture over 1 h at a rate to keep the internal temperature below 5° C. The reaction mixture was stirred at 0° C. for 1 h and then warmed to 20° C. over 1 h. The mixture was then cooled to 10° C. and water (1.2 L) was added. The layers were separated and the organic layer was washed with water (1.2 L and then 0.6 L). The combined aqueous layers were extracted with toluene (0.6 L). The combined organic layers were dried over MgSO4 and concentrated in vacuo to give 149.4 g of the title compound as a tan solid, m/z 456.4 [M+MeCN+H]+.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:31]3[CH:32]=[CH:33][C:28]([O:27][CH3:26])=[CH:29][CH:30]=3)=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)cc1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 4-methoxyphenylmagnesium bromide. Yield: 51 mg of a white solid. LC-MSD, m/z for C23H17BrN2O3 [M+H]+=449.0, 451.0; HPLC retention time: 2.3 min.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(Nc3ccc(C(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-trifluoromethylaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=18%). MS ISN (m/e): 438.4 (100) [(M−H)−]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.60-7.45 (m, 4H), 7.44 (d, 1H), 7.20-7.10 (m, 2H), 6.95 (dxd, 1H), 6.88 (s, 1H), 6.52 (s, 1H), 6.46 (s, 1H), 6.39 (t, 2H), 3.73 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][C:20]([O:22]CC)=[O:21])[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(#N)C.Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:10][C:11]2[CH:32]=[CH:31][C:14]3[N:15]([CH:18]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:19][C:20]([OH:22])=[O:21])[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:9])=[CH:33][CH:34]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Agent: Cl
Solvent: CC#N
Product: O=C(O)CC(c1ccccc1)n1cnc2cc(NC(=O)c3ccc([N+](=O)[O-])cc3)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of ethyl 3-{5-[(4-nitrobenzoyl)amino]-1H-benzimidazol-1-yl}-3-phenylpropanoate (60 mg, 131 μmol) in a mixture of acetonitrile (10 mL) and hydrochloric acid (20 mL of a 5N solution) was stirred at room temperature for 72 hours. The resulting precipitate was collected by filtration, and air-dried to afford the title compound, [LCMS (Method A, Mobile Phase II) RT=3.84 min, MH+ 431].
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[O:17][C:16]([SH:18])=[N:15][N:14]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:1][O:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[O:17][C:16]([S:18][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[C:21]([C:20]([F:19])([F:29])[F:30])[CH:22]=4)=[N:15][N:14]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1
Reactant: COCn1ncc2cc(-c3nnc(S)o3)ccc21
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCn1ncc2cc(-c3nnc(SCc4cccc(C(F)(F)F)c4)o3)ccc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.6 %

Procedure:
A suspension of 5-[1-(methoxymethyl)-1H-indazol-5-yl]-1,3,4-oxadiazole-2-thiol (525 mg, 2.00 mmol), 3-(trifluoromethyl)benzyl chloride (0.372 mL, 2.40 mmol), and potassium carbonate (415 mg, 3.00 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 hr. The reaction mixture was poured into water, the precipitate was collected by filtration, purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (821 mg, yield 98%) as colorless crystals.
Reaction SMILES: [Br:1][CH2:2][CH:3]1[O:5][CH2:4]1.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]>CO.C(N(CC)CC)C>[Br:1][CH2:2][CH:3]([OH:5])[CH2:4][S:16][C:13]1[CH:14]=[CH:15][C:10]([C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:11][CH:12]=1
Reactant: BrCC1CO1
Reactant: CC(C)(C)c1ccc(S)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1ccc(SCC(O)CBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
To a stirred solution of 64.9 ml [103.67 g (0.758 mole)] 1-bromo-2,3-epoxypropane dissolved in 18 ml methanol/triethylamine (1:1) cooled to 5°-10° C. in a water-ice bath, 124.5 g (0.75 mole) p-tert-butylthiophenol was added dropwise. After the addition was complete (about 21/4 hours), the reaction mixture was allowed to come to room temperature and was allowed to stir at room temperature for about 2 hours. Volatiles were removed in vacuo to give 233.1 g of crude product as a viscous oil.
Reaction SMILES: Cl.[C:2]([O:6][NH2:7])([CH3:5])([CH3:4])[CH3:3].Cl.CON.Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[NH:23][C:24](=O)[CH3:25]>>[C:2]([O:6][N:7]1[C:13]2[C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:16]=[CH:15][C:14]=2[N:23]=[C:24]1[CH3:25])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)ON
Reactant: CC(=O)Nc1cnc2ccccc2c1Cl
Agent: CON
Agent: Cl
Product: Cc1nc2cnc3ccccc3c2n1OC(C)(C)C
Yield: 51.9 %

Procedure:
The method of Part B of Example 25 was followed using O-(tert-butyl)hydroxylamine hydrochloride (2.0 g, 16 mmol) in lieu of O-methylhydroxylamine hydrochloride to treat N-(4-chloroquinolin-3-yl)acetamide (3.2 g, 14.5 mmol) with the modification that the reaction was heated at reflux for three hours. Following the work-up procedure, the resulting blue oil was purified by column chromatography on silica gel (eluting with 5% methanol in dichloromethane containing 5 mL of aqueous ammonium hydroxide per liter of eluent) to provide 1.92 g of 1-tert-butoxy-2-methyl-1H-imidazo[4,5-c]quinoline as a blue oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[Na+].[N+]([C:15]1[CH:16]=C(S([O-])(=O)=O)C=[CH:19][CH:20]=1)([O-])=O.C(=O)/C=C/C>Cl>[CH3:19][C:20]1[CH:15]=[CH:16][C:3]2[C:4]([C:5]([OH:7])=[O:6])=[CH:8][CH:9]=[CH:10][C:2]=2[N:1]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)[O-])c1
Agent: C/C=C/C=O
Agent: Cl
Agent: [Na+]
Product: Cc1ccc2c(C(=O)O)cccc2n1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-aminobenzoic acid (9.0 g, 65 mmol), ferrous sulfate heptahydrate (5.2 g, 18 mmol) and 3-nitrobenzenesulfonic acid sodium salt (8.1 g, 35 mmol) in 9 M HCl (140 mL) was heated to 90° C. Crotonaldehyde (9.00 mL, 108 mmol), was then added over a 1.5 h period and the resultant mixture was allowed to stir overnight. The reaction mixture was allowed to cool for 10 min and the solid obtained was collected by filtration while warm. The solids formed from the filtrate upon further cooling were collected by filtration. The filtrate was again stirred for 30 min and a third crop of solids was collected by filtration. The combined solids were washed with water and dried under reduced pressure to afford compound 73a. Mass spectrum (LCMS, ESI pos.) Calcd. For C13H9NO2: 188.1 (M+H). found 188.2.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21](Br)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([OH:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:23]([OH:25])=[O:24])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
200 mg (0.50 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A) and 82.6 mg (0.50 mmol) of 3-carboxyphenylboronic acid are introduced into 1.5 ml of DMF. Addition of 0.78 ml of 2 M sodium carbonate solution and 20.3 mg (0.02 mmol) of PdCl2(dppf) is followed by heating at 60° C. After 18 h, a further 20.3 mg (0.02 mmol) of PdCl2(dppf) are added, and the mixture is heated at 90° C. for a further 18 h. After cooling, the reaction mixture is filtered through kieselguhr and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N-hydrochloric acid, again concentrated. Drying under high vacuum results in 103 mg (45% of theory) of the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[C:13]([C:18]([F:21])([F:20])[F:19])=[N:14][O:15][C:16]=1[CH3:17])=O)C.C(OCC)(=O)C.O>C1COCC1>[CH3:17][C:16]1[O:15][N:14]=[C:13]([C:18]([F:21])([F:20])[F:19])[C:12]=1[CH2:10][OH:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)noc1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1onc(C(F)(F)F)c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 65.7 %

Procedure:
A solution of 0.16 g (4.2 mmoles) of lithium aluminum hydride dissolved in 15 ml of THF was cooled to 0° C. Thereto was gradually added a solution of 0.93 g (4.2 mmoles) of 4-ethoxycarbonyl-5-methyl-3-trifluoromethylisoxazole dissolved in 15 ml of THF. The mixture was stirred at 0° C. for 1 hour to give rise to a reaction. After the completion of the reaction, ethyl acetate was added, followed by stirring for a while. Water was added, followed by stirring for a while. The reaction mixture was filtered under vacuum. The filtrate was extracted with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 0.5 g (yield: 60.0%) of (5-methyl-3-trifluoromethylisoxazol-4-yl)-methanol.
Reaction SMILES: [C:1]([N:4]1[C:9]2[N:10]=[C:11]([C@H:24]([NH2:26])[CH3:25])[N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[C:13](=[O:14])[C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[CH2:28][C:29]1[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:1]([N:4]1[C:9]2[N:10]=[C:11]([C@H:24]([NH:26][CH2:28][C:29]3[N:33]([CH3:34])[N:32]=[C:31]([CH3:35])[CH:30]=3)[CH3:25])[N:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=3)[C:13](=[O:14])[C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCOc1ccc(-n2c([C@@H](C)N)nc3c(c2=O)CCCN3C(C)=O)cc1
Reactant: Cc1cc(CBr)n(C)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-n2c([C@@H](C)NCc3cc(C)nn3C)nc3c(c2=O)CCCN3C(C)=O)cc1
Yield: 59.2 %

Procedure:
D4 (70 mg, 0.20 mmol), C3 (37 mg, 0.20 mmol), and potassium carbonate (30 mg, 0.22 mmol) were stirred in dimethylformamide at room temperature overnight. The reaction mixture was partitioned between 4:1 ether:dichloromethane and water. The organic layer was washed with water and brine. It was dried over magnesium sulfate, filtered, then concentrated in vacuo. Purified by chromatography (2% to 5% methanol with 0.1% ammonium hydroxide in dichloromethane), yielding 55 mg of D5.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH3:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].S(Cl)([Cl:15])=O>CN(C)C=O.CC1C=CC=CC=1>[Cl:15][CH2:2][CH2:3][N:4]([CH3:12])[C:5]([N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: O=S(Cl)Cl
Reactant: CN(CCO)C(=O)N1CCCC1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN(CCCl)C(=O)N1CCCC1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 4 parts of N-(2-hydroxyethyl)-N-methyl-1pyrrolidinecarboxamide in 22.5 parts of methylbenzene were added 2.9 parts of thionyl chloride. After the addition of a few drops of N,N-dimethylformamide, the reaction mixture was heated slowly to reflux temperature. After stirring for 2 hours at this temperature, the mixture was cooled and the whole was evaporated, yielding 4.5 parts (100%) of N-(2-chloroethyl)-N-methyl-1-pyrrolidinecarboxamide as a residue (int. 31).
Reaction SMILES: O1C2C=CC=CC=2C=C1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1.CC1C=CC(S(O[CH2:32][CH:33]2[CH2:37][C:36]3[CH:38]=[C:39]([O:46][CH3:47])[CH:40]=[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:35]=3[O:34]2)(=O)=O)=CC=1.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[N-:59]=[N+:60]=[N-:61].[Na+]>>[N:59]([CH2:32][CH:33]1[CH2:37][C:36]2[CH:38]=[C:39]([O:46][CH3:47])[CH:40]=[C:41]([C:42]([CH3:45])([CH3:44])[CH3:43])[C:35]=2[O:34]1)=[N+:60]=[N-:61]
Reactant: COc1cc2c(c(C(C)(C)C)c1)OC(COS(=O)(=O)c1ccc(C)cc1)C2
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Na+]
Product: COc1cc2c(c(C(C)(C)C)c1)OC(CN=[N+]=[N-])C2

Procedure:
Treatment of 2-tert-butyl-4-methoxyphenol and 3-tert-butyl-4-methoxyphenol (18.25 g, 0.101 mol) with potassium carbonate (55.28 g, 0.400 mol) and allyl bromide (14.69 g, 0.121 mol) followed by treatment of the resultant allyl ether in refluxing mesitylene generally according to the procedure described for Intermediate 8 provided 2-allyl-6-tert-butyl-4-methoxyphenol and 2-allyl-5-tert-butyl-4-methoxyphenol. Treatment of the phenol with 3-chloroperoxybenzoic acid (49.58 g, 0.287 mol, 77%) and potassium carbonate (33.0 g, 0.238 mol) generally according to the procedure described for Intermediate 9 gave 3.23 g (14%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methanol as a white solid. Treatment of the benzofuran with p-toluenesulfonyl chloride (2.86 g, 0.015 mol) generally according to the procedure described for Intermediate 10 afforded (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate. Treatment of the tosylate with sodium azide (1.46 g, 22.5 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.14 g, 10 wt. %) generally according to the procedure described for Example 1 afforded 1.5 g (40%) of (±)-(7-tert-butyl-5-methoxy-2,3-dihydro-1-benzofuran-2-yl)methylamine) as a white solid, hydrochloride salt. mp 174-176° C.; Anal calcd. for C14H21O2NHCl: C, 61.87; H, 8.16; N, 5.15. Found C, 61.67; H, 8.37; N, 4.93.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:35])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([O:31]C)=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:36].Cl.C(O)(=O)C>O>[CH3:1][N:2]1[C:7]([C:8]([F:10])([F:11])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[C:14]([F:35])=[CH:15][C:16]3[O:20][N:19]=[C:18]([C:21]4[CH:26]=[C:25]([O:27][CH2:28][C:29]([OH:31])=[O:30])[CH:24]=[CH:23][C:22]=4[CH3:33])[C:17]=3[CH:34]=2)[C:3]1=[O:36]
Reactant: COC(=O)COc1ccc(C)c(-c2noc3cc(F)c(-n4c(=O)cc(C(F)(F)F)n(C)c4=O)cc23)c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(OCC(=O)O)cc1-c1noc2cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 90 °C
Reaction time: 2 h
Yield: 66.1 %

Procedure:
A mixture of {{2-{5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-6-fluoro-1,2-benzisoxazol-3-yl}-p-tolyl}oxy}acetic acid, methyl ester (10.9 g, 0.0190 mol), 10% hydrochloric acid and acetic acid is stirred two hours at 90° C., cooled, poured into water and extracted with ethyl acetate. The organic layers are combined, washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to a foam. The foam is recrystallized from ethyl acetate to afford the title compound as a white solid (6.20 g, 66.2%, mp 123-126° C.).
Reaction SMILES: [OH:1][C:2]1[O:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1.[C:24]1(C)C=CC=CC=1.C[Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[CH3:24][O:1][C:2]1[O:6][N:5]([CH3:7])[C:4](=[O:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1
Reactant: COc1cccc(Oc2ccccc2-c2c(O)on(C)c2=O)c1
Reactant: Cc1ccccc1
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCCCCC
Product: COc1cccc(Oc2ccccc2-c2c(OC)on(C)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
5-Hydroxy-4-[2-(3-methoxyphenoxy)phenyl]-2-methyl-3(2H)-isoxazolone (2.5 g) was dissolved in 3 mL of methanol and 15 mL of toluene and cooled in an icebath. Trimethylsilyldiazomethane (5 mL of a 2.0M solution in hexane) was added dropwise. Gas evolution was observed. The resulting yellow solution was stirred at room temperature overnight. The solvents were removed under reduced pressure and the residue was purified by flash chromatography (1:1 hexane:ethyl acetate as eluant). The second eluting component was collected to yield 950 mg (36%) of the title compound of Step D. 1H NMR (CDCl3): δ7.51 (dd,J=1.7, 7.5Hz,1H), 7.27 (dt,J=1.7, 7.5Hz,1H), 7.17 (m,2H), 6.97 (dd,J=1, 8Hz,1H), 6.5 (m,3H), 3.92 (s,3H), 3.74 (s,3H), 3.33(s,3H).