Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:12][I:13].[Li+].[OH-].Cl>C1COCC1.O.CCOCC>[I:13][CH:12]=[CH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:14])=[O:2]
Reactant: COC(=O)CCCCCCCC=CI
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCCC=CI
Temperature: 50 °C
Reaction time: 4 h
Yield: 90.9 %

Procedure:
To a stirred solution of this 10-iodo-9-decenoate methyl ester (51.0 mg, 0.164 mmol, 1.0 eq.) in THF:H2O 3:1 (3.3 mL) was added LiOH (69.0 mg, 1.64 mmol, 10.0 eq.). The reaction was stirred at 50° C. for 4 h before diluting with Et2O (5 mL) and pouring into 1 M aqueous HCl (5 mL). The layers were separated and the aqueous layer was extracted with Et2O (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4, and concentrated in vacuo. Purification of the crude product by flash chromatography (hexanes:EtOAc 5:1→EtOAc) provided 95 as a pale yellow solid (44.0 mg, 0.149 mmol, 91%). 1H NMR indicated an E:Z ratio of 10:1.
Reaction SMILES: [N:1]([O-])=O.[Na+].O.[ClH:6].Cl.Cl.[NH2:9][C:10]1[C:15]([NH2:16])=[CH:14][CH:13]=[CH:12][C:11]=1[O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:32]>C(O)(=O)C>[ClH:6].[ClH:6].[NH:16]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([O:17][CH2:18][CH:19]([OH:33])[CH2:20][NH:21][CH2:22][CH2:23][NH:24][C:25]3[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=3[CH3:32])[C:10]=2[N:9]=[N:1]1
Reactant: O=N[O-]
Reactant: Cc1cccc(C)c1NCCNCC(O)COc1cccc(N)c1N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2[nH]nnc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.38 g. Sodium nitrite dissolved in 2.2 ml. water are added to a solution, cooled to 0° C., of 9.1 g. 2,3-diamino-1-{2-hydroxy-3-[2-(2,6-dimethylphenylamino)-ethylamino]-propoxy}-benzene trihydrochloride in 12 ml. water and 4.6 ml. glacial acetic acid. After stirring for 2 hours at ambient temperature, the reaction mixture is evaporated to dryness, the residue is taken up in chloroform and the solution is washed with 1M hydrochloric acid and water, dried and evaporated. The residue is recrystallized from ethanol-ethyl acetate, with the addition of active charcoal, to give 2.2 g. (26% of theory) of the desired compound; m.p. 230°-232° C.
Reaction SMILES: [ClH:1].O1CCOCC1.OC(C(F)(F)F)=O.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1>CO>[ClH:15].[ClH:1].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]1[O:26][C:25]([C:27]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH:30]2[CH2:42][O:43][C:44]2[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=2)=[O:28])=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(-c3ccccc3Cl)o2)C(COc2cccnc2)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(-c2ccccc2Cl)o1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 59 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-(2-chlorophenyl)furan-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate TFA salt (66.6 mg, 0.109 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 30 mg (59%) of the desired product as a white solid. LC-MS: RT=5.00 min, [M+H]+=398.1.
Reaction SMILES: [CH2:1]1[C@@H:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4][C@@H:3]([CH2:10][OH:11])[O:2]1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][C@H:3]1[O:2][CH2:1][C@@H:6]2[CH2:7][CH2:8][CH2:9][N:5]2[CH2:4]1)(=[O:22])=[O:21]
Reactant: OC[C@@H]1CN2CCC[C@H]2CO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@@H]1CN2CCC[C@H]2CO1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 80.1 %

Procedure:
(3S,8aS)-Hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethanol (1.00 g, 6.37 mmol) was dissolved in dichloromethane (10 mL) and triethylamine (2.4 mL, 17.3 mmol) was added at 0° C. followed by dropwise addition of methanesulfonyl chloride (0.93 mL, 12.0 mmol). The solution was warmed to room temperature and stirred for 1.25 h and then was concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution. The organic portion was washed with saturated sodium bicarbonate solution. The combined aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford (3S,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl methanesulfonate as an orange-brown oil (1.20 g, 5.1 mmol, 80% yield). MS (EI) for C9H17NO4S: 236 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]([NH:15][CH2:16][C:17]1[CH:33]=[CH:32][C:20]([O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:18]=1)[CH2:13][CH3:14])=[O:11].FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([CH:12]([NH:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]([CH3:30])([CH3:31])[C:23]([OH:25])=[O:24])=[CH:32][CH:33]=1)[CH2:13][CH3:14])=[O:11]
Reactant: CCC(NCc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)C(=O)Nc1ccc(C)cc1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(NCc1ccc(OC(C)(C)C(=O)O)cc1)C(=O)Nc1ccc(C)cc1C
Yield: 75.8 %

Procedure:
Similarly to the procedure of Example 1-9, 170 mg (0.374 mmol) of tert-butyl 2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methylpropionate (Example 1-7) are reacted with 0.72 ml (9.35 mmol) of trifluoroacetic acid in 3 ml of dichloromethane to give 113 mg (72%) of 2-(4-{[(1-{[(2,4-dimethylphenyl)amino]carbonyl}propyl)amino]methyl}phenoxy)-2-methyl-propionic acid.
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:18](Cl)(=[O:20])[CH3:19]>>[C:18]([C:6]1[NH:7][C:8]2[C:13]([C:5]=1[CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][CH:11]=[C:10]([C:14]([O:16][CH3:17])=[O:15])[CH:9]=2)(=[O:20])[CH3:19]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1ccc2c(CC(C)C)c[nH]c2c1
Product: COC(=O)c1ccc2c(CC(C)C)c(C(C)=O)[nH]c2c1

Procedure:
Methyl 2-acetyl-3-isobutylindole-6-carboxylate (43 mg) was prepared from methyl 3-isobutylindole-6-carboxylate (99 mg) and acetyl chloride (0.073 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[NH:11][C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])[CH3:3].[H-].[Na+].[CH3:33][N:34]([CH2:43][CH2:44][CH2:45][CH2:46][C:47](=[O:50])[CH2:48]Br)[CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.Cl>O1CCCC1.O>[CH3:3][CH:2]([O:4][C:5]([C:7]1[N:27]=[CH:26][C:10]2[N:11]([CH2:48][C:47](=[O:50])[CH2:46][CH2:45][CH2:44][CH2:43][N:34]([CH3:33])[CH2:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:12]3[C:17]([C:9]=2[C:8]=1[CH2:28][O:29][CH3:30])=[CH:16][C:15]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:14][CH:13]=3)=[O:6])[CH3:1]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(OCc4ccccc4)cc3c12
Reactant: CN(CCCCC(=O)CBr)CCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1cc(OCc3ccccc3)ccc1n2CC(=O)CCCCN(C)CCc1ccccc1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
2.63 g of 6-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methyl-ethyl)-ester (6.5 mmol) is taken up in 50 ml of dry tetrahydrofuran and mixed for deprotonation with 235 mg of 80% sodium hydride suspension in oil (7.1 mmol). It is allowed to stir for 20 more minutes at room temperature, then 2.22 g of 6-[N-methyl-N-(2-phenylethyl)-amino]-2-oxohexylbromide (7.1 mmol)--dissolved in 10 ml of tetrahydrofuran--is added. It is stirred for 12 hours at room temperature, mixed with 5 ml of 2N aqueous hydrochloric acid and diluted with water. It is then extracted with dichloromethane, the solvent is drawn off in a vacuum, and the crude product that is obtained is chromatographed on silica gel using hexane-ethyl acetate. 4.1 g of 6-benzyloxy-4-methoxymethyl-9{6-[N-methyl-N-(2-phenylethyl)-amino]-2-oxohexyl}9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained as a brownish oil.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([C:6]([O-])=O)[C:3]([O-])=O.[Na+].[Na+].[CH3:12][N:13]1[C:17](=O)[CH2:16][CH2:15][CH2:14]1.[CH3:19][N:20]([CH:22]=[O:23])[CH3:21]>>[N:13]1[C:6]2[CH2:19][NH:20][C:22](=[O:23])[CH2:3][C:2]=2[CH:9]=[CH:15][CH:14]=1.[N:13]1[C:12]2[CH2:22][NH:20][CH2:21][CH2:1][C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C(=O)[O-])C(=O)[O-]
Reactant: CN1CCCC1=O
Reactant: CN(C)C=O
Agent: [Na+]
Product: O=C1Cc2cccnc2CN1
Product: c1cnc2c(c1)CCNC2

Procedure:
7,8-Dihydro-1,7-naphthyridin-6(5H)-one of Formula I-m and 5,6,7,8-tetrahydro-1,7-naphthyridine of Formula I-n are synthesized as shown in Scheme 12. Compound LVII is reacted with 1 to 1.5 equivalents of sodium dimethylmalonate in a polar solvent such as NMP or DMF at from 50° C. to 110° C. to give diester of formula LVI. Decarboxylation of this material is accomplished by heating between 50° C. and 100° C. with 1 to 1.5 equivalents of lithium chloride in DMSO and 2 equivalents of water to give ester LV. Hydrogenolysis of LV in acetic acid with palladium on activated carbon gives lactam I-m which may be converted to compound of Formula I-n by treatment with hydride reducing agents such as borane-THF complex or lithium aluminum hydride in THF at from rt to reflux.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([Cl:12])=[N:6][CH:7]=[N:8][C:9]=1[CH2:10]Br)[CH2:2][CH3:3].[F:13][C:14]1[C:15]([C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[N:16][CH:17]=[CH:18][CH:19]=1.[C:25]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:12][C:5]1[C:4]([CH2:1][CH2:2][CH3:3])=[C:9]([CH2:10][N:24]2[CH:23]=[CH:22][N:21]=[C:20]2[C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][N:16]=2)[N:8]=[C:7]([CH3:25])[N:6]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cccnc1-c1ncc[nH]1
Reactant: CCCc1c(Cl)ncnc1CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1c(Cl)nc(C)nc1Cn1ccnc1-c1ncccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-propyl-6-bromomethyl-4-chloro-pyrimidine (1 mmol), 3-fluoro-2-(1H-imidazol-2-yl)-pyridine (163 mg, 1 mmol), and K2CO3 (552 mg, 4 mmol) in DMF (6 mL) is stirred at room temperature overnight. The solvent is removed in vacuo and EtOAc (10 mL) and water (10 mL) are added to the residue. The layers are separated and the aqueous layer is extracted with EtOAc (10 mL). The combined extracts are washed with brine (10 mL), dried (Na2SO4), and evaporated. Preparative TLC separation of the residue with 5% MeOH in CH2Cl2 provides the title compound as a white solid. 1H-NMR (CDCl3) δ: 8.65 (S, 1H), 8.24 (d, 1H), 7.53 (t, 1H), 7.32 (s, 1H), 7.27-7.22 (m, 1H), 7.12 (s, 1H), 5.87 (s, 2H), 2.76 (t, 2H), 1.68-1.54 (m, 2H), 1.01 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[CH:9][CH:10]=[CH:11][C:2]=1[NH:1][CH2:13][CH2:14][CH2:15][C:16](=[O:17])[O:18][CH2:19][CH3:20]
Reactant: CCOC(=O)CCCBr
Reactant: COC(=O)c1ccccc1N
Product: CCOC(=O)CCCNc1ccccc1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 19.2 g of methyl 2-aminobenzoate and 9.6 g of ethyl γ-bromobutyrate is heated at 80°-85° C. for 24 hours, cooled to room temperature and filtered. The solid is washed with CH2Cl2 and the filtrate washed with 1NHCl, H2O, 1NNaHCO3 and brine. The solvent is removed to give an oil. The oil is distilled and the fraction boiling at 45°-75° C. and 130°-160° C. were collected and discarded. The residue is the product (55.4 g of oil)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cccc(C2CCCN2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To a stirred solution of (RS)-2-(3-fluoro-phenyl)-pyrrolidine (0.24 g, 1.45 mmol) and triethylamine (0.40 ml, 2.87 mmol) in dichloromethane (40 ml) was added at 0° C. toluene-4-sulfonyl chloride (0.42 g, 2.20 mmol). The mixture was stirred at RT for 16 h, evaporated, dissolved in water (40 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (MgSO4) and evaporated. The crude product was purified by crystallization from ethyl acetate/hexane to give the product (0.38 g, 83%) as a white solid, m.p. 116° C. and MS: m/e=319 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]3[CH2:15][CH2:16][CH:11]2[CH2:12][CH2:13]3)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O>[Pd]>[CH:11]12[N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH2:1])=[C:5]([C:17]([F:20])([F:18])[F:19])[CH:6]=3)[CH:14]([CH2:13][CH2:12]1)[CH2:15][CH2:16]2
Reactant: O=[N+]([O-])c1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Agent: [Pd]
Product: Nc1ccc(N2C3CCC2CC3)cc1C(F)(F)F
Reaction time: 12 h
Yield: 91 %

Procedure:
A flask charged with 7-[4-nitro-3-(trifluoromethyl)phenyl]-7-azabicyclo[2.2.1]heptane (26) (7.07 g, 24.70 mmol) and 10% Pd/C (0.71 g, 6.64 mmol) was evacuated and then flushed with nitrogen. Ethanol (22 ml) was added and the reaction flask was fitted with a hydrogen balloon. After stirring vigorously for 12 h, the reaction mixture was purged with nitrogen and Pd/C was removed by filtration. The filtrate was concentrated to a dark oil under reduced pressure and the residue purified by silica gel chromatography (0-15% ethyl acetate in hexanes) to provide 447-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)aniline (3) as a purple solid (5.76 g, 91% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.95 (dd, J=2.3, 8.8 Hz, 1H), 6.79 (d, J=2.6 Hz, 1H), 6.72 (d, J=8.8 Hz, 1H), 4.89 (s, 2H), 4.09 (s, 2H), 1.61-1.59 (m, 4H) and 1.35 (d, J=6.8 Hz, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:11]=[CH:12][C:13]([CH2:21][OH:22])=[N:14][C:15]=1[O:16][CH2:17][CH:18]([CH3:20])[CH3:19].[CH:23]1([CH:26]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34](O)[CH:33]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:25][CH2:24]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[CH:23]1([CH:26]([C:32]2[CH:33]=[CH:34][CH:35]=[C:36]([O:22][CH2:21][C:13]3[CH:12]=[CH:11][C:10]([C:3]4[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=4[F:1])=[C:15]([O:16][CH2:17][CH:18]([CH3:19])[CH3:20])[N:14]=3)[CH:37]=2)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:25]1
Reactant: COC(=O)CC(c1cccc(O)c1)C1CC1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2OCC(C)C)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)CC(c1cccc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)c1)C1CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 79 %

Procedure:
Under a nitrogen atmosphere, to a solution of (5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanol (100 mg) and methyl 3-cyclopropyl-3-(3-hydroxyphenyl)propanoate (72 mg) in toluene (4.7 mL) were added 1,1′-(azodicarbonyl)dipiperidine (132 mg) and tributylphosphine (131 μL), and the mixture was stirred at room temperature for 14 hr. To the reaction mixture was added hexane/ethyl acetate (1:1), and the resulting precipitate was removed by filtration. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (131 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]3[CH2:27][O:26]3)[CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[CH3:28][N:29]([CH3:30])[CH2:27][CH:25]([C:21]1[CH:20]=[C:19]([NH:18][S:15]([C:12]2[CH:13]=[CH:14][C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[CH:24]=[CH:23][CH:22]=1)[OH:26]
Reactant: CNC
Reactant: O=S(=O)(Nc1cccc(C2CO2)c1)c1ccc(-c2ccc(F)cc2F)cc1
Solvent: CCO
Product: CN(C)CC(O)c1cccc(NS(=O)(=O)c2ccc(-c3ccc(F)cc3F)cc2)c1

Procedure:
Using a method analogous to Method D, using 2′,4′-difluoro-N-(3-(oxiran-2-yl)phenyl)biphenyl-4-sulfonamide and 33% dimethylamine in ethanol, a mixture of regioisomers was obtained. Reverse-phase HPLC was used to purify the mixture and the title compound was obtained as a pale orange powder. 1H NMR (300 MHz, CDCl3): δ 2.70 (6H, s), 3.05-3.10 (2H, m), 5.05 (1H, bd), 6.80-6.95 (2H, m), 7.00-7.22 (3H, m), 7.25-7.35 (2H, m), 7.49 (2H, d, J=8 Hz) and 7.87 (2H, d, J=8 Hz).
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][CH2:28][C:27](=O)[CH2:26]1>C(O)C>[CH3:11][O:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([O:21][CH2:22][O:23][CH3:24])[CH:18]=[CH:17][C:16]=1[CH:25]1[CH2:30][CH2:29][CH2:28][C:27](=[N:2][OH:3])[CH2:26]1
Reactant: NO
Reactant: COCOc1ccc(C2CCCC(=O)C2)c(OCOC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCOc1ccc(C2CCCC(=NO)C2)c(OCOC)c1
Reaction time: 0.75 h
Yield: 93.7 %

Procedure:
Hydroxylamine hydrochloride (71 mg), triethylamine (0.17 ml) and (±)-3-[2,4-bis(methoxymethoxy)phenyl]cyclohexanone (200 mg) were heated under reflux in ethanol (8 ml). After 0.75 hr, the reaction mixture was evaporated in vacuo and the residue was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by flash column chromatography (SiO2, ethyl acetate/petrol, 1:1 v/v) to furnish the title compound as a pale yellow oil (197 mg, 94%); m/z (ES+) 310 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[C:9](=[O:14])([O:12]C)[O:10][CH3:11]>>[CH3:11][O:10][C:9](=[O:12])[O-:14].[CH3:1][O:2][CH2:3][N+:4]1([CH3:9])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: COC(=O)OC
Reactant: COCN1CCCC1
Product: COC(=O)[O-]
Product: COC[N+]1(C)CCCC1
Yield: 60 %

Procedure:
Methoxymethylpyrrolidine (10.00 g) and 117.39 g of dimethyl carbonate were placed into an autoclave and reacted at 120° C. for 24 hours. The resulting solids were filtered off and washed with dimethyl carbonate. The solids were dried in a vacuum, giving 10.70 g of the desired product.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.Cl.[NH2:42][C:43]1[CH:48]=[C:47]([NH2:49])[C:46]([F:50])=[CH:45][N:44]=1.CN1CCCC1>C(Cl)(Cl)Cl>[NH2:42][C:43]1[CH:48]=[C:47]([NH:49][CH:4]=[C:5]([C:11](=[O:22])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=2[F:21])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:46]([F:50])=[CH:45][N:44]=1
Reactant: Nc1cc(N)c(F)cn1
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: CN1CCCC1
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(=CNc1cc(N)ncc1F)C(=O)c1cc(F)c(F)c(Cl)c1F
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
To 1.2 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.34 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.25 g of 2,4-diamino-5-fluoropyridine hydrochloride together with 0.28 g of N-methylpyrrolidine. The solution was concentrated under reduced pressure, and to the residue were added 0.52 g of anhydrous potassium carbonate and 0.8 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 15 minutes and allowed to cool. The solution was separated by adding 20 ml of chloroform and 100 ml of distilled water, and the chloroform layer was washed with 100 ml of distilled water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 14 g; eluent: chloroform:methanol, 1:0, and then, 100:1), and the fraction containing the main product was concentrated under reduced pressure. The precipitate was dispersed in ethanol, collected by filtration, and washed with ethanol and diisopropylether successively to obtain 1.06 g of the title mixture (1:1 in NMR) as a pale brown powder.
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].CCC(OO)=[O:19].C(OO)(=O)C>CC(C)=O>[C:1]([C:9]1[CH:14]=[C:13]([OH:19])[C:12](=[CH:11][CH:10]=1)[OH:15])([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3]
Reactant: CCC(=O)OO
Reactant: CC(C)(C)CC(C)(C)c1ccc(O)cc1
Agent: CC(=O)OO
Solvent: CC(C)=O
Product: CC(C)(C)CC(C)(C)c1ccc(O)c(O)c1
Yield: 61 %

Procedure:
The procedure of Example 8 was followed, except 20 ml of acetone was added as a solvent for para-tert.-octyl phenol and 4.5g (0.05 mol) of perpropionic acid in the form of about 25 weight% acetone solution was added over 20 minutes in place of peracetic acid. Consequently, the conversion of para-tert.-octyl phenol was 6.8%, 4-tert.-octyl pyrocatechol was formed in a yield of 61% based on the converted octyl phenol and the conversion of perpropionic acid was 100%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Na+].[Na+]>CCN(CC)CC>[C:12]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH2:10][CH3:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCNc1nc(N)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: CCNc1nc(Cl)cc(NC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the pyrimidine 6-2 (3.76 g, 21.8 mmol), pivaloyl chloride (10.7 mL, 87 mmol), Et3N (15.2 mL, 109 mmol) and TBF (80 mL) was stirred at room temperature for 24 hours. A further 3 mL of pivaloyl chloride and 4 mL of Et3N was added and the mixture stirred for another 24 hours. The solution was poured into saturated Na2CO3, extracted twice with EtOAc, washed with brine, dried (MgSO4) and filtered through a pad of silica gel. Removal of the solvent afforded an orange solid. Trituration with ether/hexane (˜20: 1) and filtration provided the title compound 6-3 as a white solid.