Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:32])([CH3:31])[CH2:3][CH2:4][C@:5]1([CH3:30])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[S:22][CH:23]=[C:24]([CH2:25]O)[C:19]=3[S:18](=[O:28])(=[O:27])[N:17]=2)[C:6]1=[O:29].N12CCCN=C1CCCCC2.C1(P([N:58]=[N+:59]=[N-:60])(C2C=CC=CC=2)=O)C=CC=CC=1>ClCCl>[N:58]([CH2:25][C:24]1[C:19]2[S:18](=[O:28])(=[O:27])[N:17]=[C:16]([C:7]3[C:6](=[O:29])[C@@:5]([CH2:4][CH2:3][C:2]([CH3:32])([CH3:31])[CH3:1])([CH3:30])[C:14]4[C:9]([C:8]=3[OH:15])=[CH:10][CH:11]=[CH:12][CH:13]=4)[NH:21][C:20]=2[S:22][CH:23]=1)=[N+:59]=[N-:60]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CO)csc3N2)=C(O)c2ccccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3c(CN=[N+]=[N-])csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.9 %

Procedure:
A solution of Example 185 (1 g, 2.11 mmol) in 25 mL of dichloromethane was cooled to to 0° C., treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 mL, 11.2 mmol) and diphenylphosphoryl azide (2.3 mL, 10.9 mmol), allowed to warm to room temp, stirred for 16 h, and concentrated onto silica gel. The crude material was chromatographed on silica gel with hexane, hexane/dichloromethane (1:1), followed by dichloromethane, and methanol/dichloromethane (1:99) to afford the title compound (610 mg, 59% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.39 (td, J=12.7, 3.3 Hz, 1 H), 0.72 (s, 9 H), 0.81 (td, J=13.1, 4.6 Hz, 1 H), 1.57 (s, 3 H), 2.05 (m, 1 H), 2.22 (td, J=12.6, 4.6 Hz, 1 H), 4.56 (s, 2 H), 7.29 (m, J=8.6, 8.6 Hz, 1 H), 7.54 (s, 1 H), 7.74 (m, J=4.0 Hz, 2 H), 8.13 (d, J=7.7 Hz, 1 H), 14.09 (s, 1 H); MS (APCI+) m/z 498 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:4]=[CH:5][N:6]=1.[CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:29])[CH3:28])[C:22]=1[N:30]=[C:31]=[O:32])([CH3:20])[CH3:19]>C1COCC1>[CH3:20][CH:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]([CH3:28])[CH3:29])[C:22]=1[NH:30][C:31]([NH:1][C:2]1[N:3]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[N:4]=[CH:5][N:6]=1)=[O:32])[CH3:19]
Reactant: CCCCCCCCCCCn1ncnc1N
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCn1ncnc1NC(=O)Nc1c(C(C)C)cccc1C(C)C
Temperature: 25 °C
Yield: 37.7 %

Procedure:
A solution of 3-amino-2-undecyl-1,2,4-triazole (3.0 g, 12.6 mmol) and 2,6-diisopropylphenyl isocyanate (3.9 mL, 19.2 mmol) in THF (100 mL) was heated under reflux (40 hours). The resulting solution was cooled (25° C.) and concentrated in vacuo. The resulting oil was triturated with hexane and the resulting solid was collected by filtration and recrystallized from hot hexane to yield 2.1 g (37.8%) of the title compound as a white solid; mp 146.5°-147.5° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7](Br)[CH:6]=1)(=[O:3])[CH3:2].[Li]CCCC.CCCCC.[C:23](OCC)(=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1COCC1>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:23](=[O:29])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)Nc1ccc(C)c(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCC
Product: CCOC(=O)C(=O)c1cc(NC(C)=O)ccc1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 10.5 %

Procedure:
To a solution of N-acetyl-3-bromo-4-methylaniline (1.43 g, 627 mmol) in THF (50 mL) at −78° C. is added 2M BuLi in pentane (7.83 mL, 15.66 mmol) dropwise. After a further 1 h, diethyl oxalate (4.26 mL, 31.3 mmol) is added. After stirring for 4 hours at −78° C., the reaction mixture is quenched with saturated NH4Cl solution. The mixture is partitioned between ethyl acetate and water. The layer is separated and the aqueous layer is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. The residue is purified by column chromatography (silica gel, eluting with ethyl acetate; hexanes from 1/1 to 2/1) to afford fee title compound (0.82 g, 52%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15](F)=[CH:14][C:13]=2[F:22])=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8].[C:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])(=[O:26])[CH2:24][OH:25].[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([C:12]2[C:13]([F:22])=[CH:14][C:15]([O:25][CH2:24][C:23]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26])=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=2)=[N:4][N:5]([CH3:11])[C:6]=1[C:7]([F:10])([F:9])[F:8]
Reactant: CCCCOC(=O)CO
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(F)cc2F)c(Cl)c1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCOC(=O)COc1cc(F)c(-c2nn(C)c(C(F)(F)F)c2Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 71.6 %

Procedure:
A solution of 3.4 g (0.01 mole) 4-chloro-3-(2,4-difluoro-5-nitrophenyl)-1-methyl-5-(trifluoro-methyl)-1H-pyrazole and 1.4 mL (0.011 mole) butyl glycolate in 25 mL anhydrous THF was chilled to 0° C. Maintaining the temperature below 5° C., 0.33 g (0.011 mole) NaH was added in portions. Once the addition was completed, the reaction mixture was allowed to warm to 25° C. After 3 hours the mixture was carefully quenched with water and extracted with ethyl acetate. The ethyl acetate extracts were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified chromatographically with 20% ethyl acetate/hexanes to yield 3.25 g (72%) (4-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-5-fluoro-2-nitrophenoxy)acetic acid, butyl ester as a light yellow solid; mp 65° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])=[CH:3][C:4]([OH:6])=[O:5].[F:8][C:9]1[CH:10]=[C:11]([SH:17])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].N1CCCCC1>CCOC(C)=O>[F:8][C:9]1[CH:10]=[C:11]([S:17][C:2]([CH3:7])([CH3:1])[CH2:3][C:4]([OH:6])=[O:5])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(S)cc1F
Reactant: CC(C)=CC(=O)O
Solvent: C1CCNCC1
Solvent: CCOC(C)=O
Product: COc1ccc(SC(C)(C)CC(=O)O)cc1F
Temperature: 105 °C
Yield: 101.1 %

Procedure:
A heavy-walled screw cap tube was charged with 3-methyl-2-butenoic acid (1.23 g, 12.33 mmol), 3-fluoro-4-methoxy thiophenol (Compound 200, 1.95 g, 12.33 mmol), and piperidine (314.8 mg, 3.70 mmol). This mixture was heated to 105° C. for 23 hours, cooled to room temperature and dissolved in EtOAc (100mL). The resulting solution was washed with 1M aqueous HCl, H2O, and saturated aqueous NaCl before being dried over Na2SO4. Concentration of the dry solution under reduced pressure afforded 3.22 g of a clear yellow oil which was used in the next reaction without further purification. 1H NMR (300 MHz, CDCl3) δ: 7.32 (2H, m), 6.94 (1H, t, J=8.4 Hz), 3.92 (3H, s), 2.54 (2H, s), 1.41 (6H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1B1OC(C)(C)C(C)(C)O1)[NH2:27]>>[NH2:27][C:26]1[CH:28]=[CH:29][C:30]([C:2]2[N:3]=[C:4]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][C@@H:17]3[CH3:22])[C:5]3[CH2:10][N:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8][C:6]=3[N:7]=2)=[C:24]([F:23])[CH:25]=1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Reactant: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Product: CCOC(=O)N1Cc2nc(-c3ccc(N)cc3F)nc(N3CCOC[C@@H]3C)c2C1
Yield: 45 %

Procedure:
Method as described for example 47 using (S)-ethyl 2-chloro-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate (intermediate 11) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline as starting materials. The mixture was filtered through a celite 545 pre-packed cartridge (2.5 g), washed with MeOH and the solvent removed in vacuo. The residue was purified by prep. HPLC at high pH, yielding the title compound (55 mg, 0.14 mmol, 45%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2].[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[NH2:41].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:41][C:37]4[S:36][CH:40]=[CH:39][N:38]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:5]([O:34][CH3:35])[CH:4]=1)#[N:2]
Reactant: Nc1nccs1
Reactant: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1cc(C#N)ccc1-c1nccc2cc(S(=O)(=O)Nc3nccs3)ccc12
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
A vial was charged with perfluorophenyl 1-(4-cyano-2-methoxyphenyl)isoquinoline-6-sulfonate (67.07 mg, 0.132 mmol), thiazol-2-amine (13.26 mg, 0.132 mmol), and THF (662 μl) to give a clear, colorless solution. The vial was cooled in an ice-water bath for 15 min, then lithium bis(trimethylsilyl)amide (1M in THF) (265 μl, 0.265 mmol) was added drop wise. After 20 min, the mixture was loaded onto a 5-g silica gel loading column with DCM. The column was dried under vacuum for 5 min then eluted onto a pre-equilibrated 12-g column with 0 to 10% MeOH/DCM to give 1-(4-cyano-2-methoxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (56.25 mg, 0.133 mmol, 101% yield) as an off-white foam: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.89 (br. s., 1H), 8.70 (d, J=5.7 Hz, 1H), 8.56 (d, J=1.8 Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 7.87 (dd, J=1.9, 8.8 Hz, 1H), 7.74 (d, J=1.3 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.64-7.59 (m, 1H), 7.56-7.52 (m, 1H), 7.28 (d, J=4.6 Hz, 1H), 6.88 (d, J=4.6 Hz, 1H), 3.72 (s, 3H); m/z (ESI) 423.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][NH:10][C:6]=2[CH:5]=[CH:4][NH:3]1.[H-].[Na+].Br[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24]>CN(C=O)C>[O:1]=[C:2]1[C:7]2[C:8]([C:11]3[CH:12]=[C:13]([C:16]([NH2:18])=[O:17])[S:14][CH:15]=3)=[N:9][N:10]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:6]=2[CH:5]=[CH:4][NH:3]1
Reactant: CCC(Br)CC
Reactant: NC(=O)c1cc(-c2n[nH]c3cc[nH]c(=O)c23)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)n1nc(-c2csc(C(N)=O)c2)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 4-(4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxamide (80.0 mg) obtained in Step A of Example 141 in DMF (3 mL) was added sodium hydride (60% dispersion in mineral oil, 24.6 mg), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 3-bromopentane (93.0 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was extracted with water and ethyl acetate, and the organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (51.8 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][C:8]2[O:9][C:10]3[C:17]([Cl:18])=[CH:16][C:15]([CH2:19][CH2:20][CH3:21])=[C:14]([OH:22])[C:11]=3[C:12]=2[CH3:13])=[CH:5][CH:4]=1.ClC(OCC)=O.C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[O:22][C:14]3[C:15]([CH2:19][CH2:20][CH3:21])=[CH:16][C:17]([Cl:18])=[C:10]([OH:9])[C:11]=3[C:12]=2[CH3:13])=[CH:23][CH:24]=1
Reactant: CCCc1cc(Cl)c2oc(Cc3ccc(OC)cc3)c(C)c2c1O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(Cl)c(O)c2c(C)c(Cc3ccc(OC)cc3)oc12
Yield: 100 %

Procedure:
A solution of 2-(p-methoxybenzyl)-3-methyl-4-hydroxy-5-propyl-7-chlorobenzofuran (0.10 gm, 0.29 mmoles), ethyl chloroformate (0.1 mL) and triethylamine (1.0 mL) in tetrahydrofuran (15 mL) was stirred at room temperature overnight. The volatiles were removed in vacuo. The residue was purified by chromatography on silica gel and eluted with 15% ethylacetate in hexane to yield 100 mg (91%) of 2 (p-methoxybenzyl) 3 methyl 4 ethoxycarbonyloxy 5 -5-propyl 7 chlorobenzofuran, mp. 99°-100° C.
Reaction SMILES: [OH-].[NH4+:2].Cl([O-])(=O)(=O)=O.[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:29])([CH3:28])[CH2:23][C:15]=4[O+]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1.O>C(O)(C)C>[F:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[C:14]4[C:26](=[O:27])[CH2:25][C:24]([CH3:28])([CH3:29])[CH2:23][C:15]=4[N:2]=[C:17]([CH3:22])[C:18]=3[NH:19][C:20]=2[CH:21]=1
Reactant: [NH4+]
Reactant: Cc1[o+]c2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: Cc1nc2c(c3c1[nH]c1cc(F)ccc13)C(=O)CC(C)(C)C2
Yield: 50 %

Procedure:
Aqueous ammonium hydroxide solution (3 mL) was added to a suspension of 9-fluoro-3,3,6-trimethyl-1-oxo-2,3,4,7-tetrahydro-1H-5-oxonia-7-aza-benzo[c]fluorene perchlorate of Example 3b (0.72 g, 1.88 mmol) in isopropanol (2 mL). The reaction mixture was refluxed for 1 h, cooled, and water (5 mL) was added. Aqueous ammonium hydroxide solution was added to the mixture to pH 9. The precipitate was filtered off, washed with water and dried. The crude product was dissolved in acetone, and 37% aqueous hydrochloric acid (0.2 mL) was added. The precipitate was filtered off, suspended in hot water, and the mixture was basicified with ammonium hydroxide to pH 9. The product was filtered off, washed with water, dried and crystallized from toluene to give 0.26 g (50%) of colorless crystals; m.p. 244-246° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[CH:21]=[C:22]([CH3:29])[C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[C:22]([CH3:29])=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: Cc1cc(Cl)cnc1C(=O)O
Product: Cc1cc(Cl)cnc1C(=O)Nc1ccc(F)c([C@@]2(C)N=C(N)OCC2(F)F)c1

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-chloro-3-methyl-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=413.3 [M+H]+.
Reaction SMILES: [H-].[Na+].CO.[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12](Cl)[N:13]=1)[C:9]#[N:10].C[CH2:16][O:17]C(C)=O.CCCCCC>CN1CCCC1>[Cl:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:17][CH3:16])[N:13]=1)[C:9]#[N:10]
Reactant: N#Cc1cc(Cl)nc(Cl)c1
Reactant: CCOC(C)=O
Agent: CN1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCCCCC
Product: COc1cc(C#N)cc(Cl)n1
Reaction time: 0.5 h

Procedure:
In a 25-mL, 3N round-bottomed flask equipped with thermometer pocket fitted with an nitrogen inlet and a rubber septum, NaH (0.112 g, 1.0 eq.), methanol (0.11 mL, 1.0 eq.), suspended in N-methylpyrrolidine (5 mL). The reaction mixture was stir at 25-30 C for 30 minutes. To this reaction mixture 2,6-dichloroisonicotinonitrile was added at 0-5 C. The progress of the reaction was followed by TLC analysis on silica gel with 10% EtOAc-hexane as mobile phase which shows that starting material was consumed after 2 hours staring at 0-5 C. Reaction was quenched by water, precipitate was observed that was filter by filter paper and wash with hexane to give required compound (0.51 g, crude). Reaction was stirred for 20 min with water solid was separated and compound was collected by filtration on a Buchner funnel and washed with of hexane (30 mL); Yield: 0.51 g crude 2-chloro-6-methoxyisonicotinonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12]I>C(Cl)(Cl)Cl.[Al]>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:8][CH3:12])=[N:6][CH:7]=1
Reactant: CI
Reactant: O=[N+]([O-])c1cc(Br)cnc1O
Agent: [Al]
Solvent: ClC(Cl)Cl
Product: COc1ncc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.8 %

Procedure:
In a 1 L, round-bottomed, single-necked flask equipped with a magnetic stirring bar was placed 5-bromo-3-nitropyridin-2-ol (50.0 g, 0.23 mol) in CHCl3 (500 mL) under nitrogen in the dark (wrapped in aluminum foil.) To this solution was added Ag2CO3 (75.5 g, 0.28 mol) and MeI (142.0 mL, 2.3 mol). After the mixture was stirred for 48 h at room temperature, it was filtered through a pad of Celite, washed with CH2Cl2, and concentrated. The crude mixture was purified by column chromatography (EtOAc:Hexane, 1:4) to give 24.0 g (45%) of 5-bromo-2-methoxy-3-nitropyridine (15) as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Br:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:12][C:13]1[C:20]([F:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[C:18]([F:26])=[C:17]([F:27])[C:14]=1[CH2:15]Br>CN(C=O)C>[Br:11][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:15][C:14]2[C:17]([F:27])=[C:18]([F:26])[C:19]([C:22]([F:23])([F:25])[F:24])=[C:20]([F:21])[C:13]=2[F:12])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Reactant: Fc1c(F)c(C(F)(F)F)c(F)c(F)c1CBr
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NCc2c(F)c(F)c(C(F)(F)F)c(F)c2F)ccc1Br
Yield: 74 %

Procedure:
According to the similar procedure in Synthesis Example 1, by using 5-amino-2-bromobenzoic acid (1.05 g, 6.12 mmole) which was prepared from Synthesis Example (4-1), DMF (50 ml) and 2,3,5,6-tetrafluoro-4-trifloromethylbenzyl bromide (1.16 g, 6.99 mmole), 2.02 g (76.9% yield) of 2-bromo-5-(2,3,5,6-tetrafluoro-4-trifluoromethylbenzylamino)benzoic acid was obtained as a pale yellow solid.
Reaction SMILES: C([Mg]Br)C.[CH3:5][C:6]([OH:10])([C:8]#[CH:9])[CH3:7].[CH3:11][O:12][CH2:13][C:14](=[O:16])[CH3:15].[Cl-].[NH4+]>C(OCC)C>[CH3:11][O:12][CH2:13][C:14]([CH3:15])([OH:16])[C:9]#[C:8][C:6]([CH3:7])([OH:10])[CH3:5]
Reactant: COCC(C)=O
Reactant: C#CC(C)(C)O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: COCC(C)(O)C#CC(C)(C)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a solution of anhydrous diethyl ether at 0-5° C. is added ethyl magnesium bromide (37.33 ml, 112 mmol, 3M solution in diethyl ether), then 2-methyl-3-butyn-2-ol (4.70 g, 55.87 mmol) dropwise. The mixture is allowed to warm to room temperature, followed by stirring at this temperature for 30 minutes, then at 40° C. until gas evolution ceases (approximately 1 hour). The viscous mixture is next cooled to room temperature and methoxyacetone (3.78 g, 42.90 mmol) is added dropwise, followed by heating to 40° C. for 1 hour. After cooling to room temperature the suspension is poured into a mixture of ice and saturated aqueous ammonium chloride, and the product is extracted with diethyl ether (2×50 ml) then dichloromethane (2×50 ml, 2×100 ml). The organic extracts are combined, washed with brine, dried over anhydrous magnesium sulfate then concentrated in vacuo to afford 1-methoxy-2,5-dimethylhex-3-yne-2,5-diol (6.98 g) as a clear oil.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C@H:12]([C:17]([OH:19])=[O:18])[CH2:13][C:14]([OH:16])=O>C1(C)C=CC=CC=1>[CH:1]([NH:11][C@@H:12]1[C:17](=[O:18])[O:19][C:14](=[O:16])[CH2:13]1)=[O:3]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=CN[C@H]1CC(=O)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
Into a 500 ml four-necked flask with a stirrer, a dropping funnel, a Dimroth condenser, and a thermometer, 112.5 g (1.10 mol) of acetic anhydride were introduced, and 30 g (0.65 mol) of formic acid were added dropwise thereto while stirring at room temperature. After stirring was performed at room temperature for 2 hours, 66.5 g (0.5 mol) of L-aspartic acid with an optical purity of 99.5% e.e. were added thereto, the temperature was increased to 60 to 70° C., and stirring was performed for 10 hours. The temperature was decreased to room temperature while stirring, and 80 g of toluene were further added thereto, followed by stirring. The precipitated crystal was subjected to filtration under reduced pressure and was rinsed with 10 g of toluene. The crystal was subjected to vacuum drying, and thus 60.1 g of N-formyl-L-aspartic anhydride was obtained. The chemical purity was 99%, and the optical purity was 99% e.e. or more.
Reaction SMILES: O[C@@H:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[C-:9]1([C@H:14](O)[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17].C(OC(=O)C)(=O)C.CCCCCC.[N:31]1[CH:36]=CC=C[CH:32]=1>>[CH3:32][N:31]([CH3:36])[C@@H:2]([C-:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1)[CH3:3].[C-:9]1([C@H:14]([N:31]([CH3:36])[CH3:32])[CH3:15])[CH:13]=[CH:12][CH:11]=[CH:10]1.[Fe+2:17]
Reactant: C[C@@H](O)[c-]1cccc1
Reactant: c1ccncc1
Agent: [Fe+2]
Solvent: CCCCCC
Solvent: CC(=O)OC(C)=O
Product: C[C@H]([c-]1cccc1)N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
32.7 g (about 111 mmol) of crude (R,R)-1,1'-bis(1-hydroxyethyl)ferrocene were dissolved in 30 ml of pyridine and admixed with 30 ml of acetic anhydride. After stirring for 16 hours at 25° C., the excess anhydride was hydrolysed with 200 ml of ice water and the mixture was extracted three times with 100 ml each Time of diethyl ether. The combined organic phases were washed once more with about 150 ml of water, dried over magnesium sulphate and evaporated. The residue was admixed with 200 ml of hexane and the solvent was removed on a rotary evaporator (<40° C). This procedure was repeated two more times. The resulting dark brown oil was dissolved in 200 ml of isopropyl alcohol and admixed with 120 ml of dimethylamine (50% in water). After stirring at 25° C. (16 hours), 200 ml of water were added and the pH of the reaction mixture was adjusted to 1 using 100 ml of 32% strength HCl and the aqueous phase was washed twice with 100 ml each time of diethyl ether. The aqueous phase was basified with sodium hydroxide solution (40% strength) to a pH of 12-14 and extracted three times with 100 ml each time of diethyl ether. The combined organic phases were dried over magnesium sulphate and evaporated. In order to remove isopropyl alcohol still present, the oil obtained was admixed with about 100 ml of hexane and again evaporated on a rotary evaporator. This procedure was repeated two more times. Drying in a high vacuum gave 24.1 g (66%, based on 1,1'-diacetylferrocene) of the title compound in the form of a dark brown oil. (Without hydrochloric acid treatment, the yield rises to 86%).
Reaction SMILES: C(OC([N:11]([CH2:22][CH2:23][O:24][CH2:25][CH3:26])[CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1>CO.[Pd]>[CH2:25]([O:24][CH2:23][CH2:22][NH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH3:26]
Reactant: CCOCCN(CCCC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOCCNCCCC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
In methanol (87 ml) was dissolved tert-butyl 4-[(benzyloxycarbonyl)(2-ethoxyethyl)amino]butyrate (8.7 g). To the solution was added 10% palladium/carbon (0.87 g), and the mixture was stirred for 3 hours under hydrogen atmosphere. 10% palladium/carbon was removed by filtration with Celite, and the solvent of the resulting solution was removed under reduced pressure to give tert-butyl 4-[(2-ethoxyethyl)amino]butyrate (5.5 g).