Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:2]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([CH2:13][NH:14][C:31](=[O:32])[C:30]3[CH:34]=[CH:35][CH:36]=[C:28]([C:25]4[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=4)[CH:29]=3)[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)[CH:2]=1
Reactant: NCC1(c2cccc(-c3ccccc3)c2)CCOCC1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: O=C(NCC1(c2cccc(-c3ccccc3)c2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 56 %

Procedure:
This compound was synthesized from (4-([1,1′-biphenyl]-3-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (110 mg, yield 56%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 8.23-8.21 (d, J=7.7 Hz, 1H), 7.86-7.84 (d, J=8.0 Hz, 1H), 7.58-7.55 (m, 6H), 7.45-7.37 (m, 4H), 5.85-5.82 (t, J=6.1 Hz, 1H), 3.96-3.91 (m, 2H), 3.79-3.78 (d, J=6.4 Hz, 2H), 3.74-3.69 (m, 2H), 2.27-2.22 (m, 2H), 2.10-2.04 (m, 2H). MS (ESI) m/z: Calculated for C28H24F3N3O3: 507.18. found: 508.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:16]([NH:19][CH:20]2[CH2:28][CH2:27][CH2:26][C:25]3[N:24]([CH2:29][C:30]([OH:32])=[O:31])[N:23]=[CH:22][C:21]2=3)(=[O:18])=[O:17])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1>CO.[Pd]>[F:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:7]2[N:6]=[CH:5][C:4]([S:16]([NH:19][CH:20]3[CH2:28][CH2:27][CH2:26][C:25]4[N:24]([CH2:29][C:30]([OH:32])=[O:31])[N:23]=[CH:22][C:21]3=4)(=[O:18])=[O:17])=[CH:3][CH:2]=2)=[CH:10][CH:11]=1
Reactant: O=C(O)Cn1ncc2c1CCCC2NS(=O)(=O)c1cnc(Oc2ccc(F)cc2)c(Br)c1
Agent: [Pd]
Solvent: CO
Product: O=C(O)Cn1ncc2c1CCCC2NS(=O)(=O)c1ccc(Oc2ccc(F)cc2)nc1
Yield: 29.5 %

Procedure:
A solution of {4-[5-bromo-6-(4-fluoro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetra-hydro-indazol-1-yl}-acetic acid (example 2-2a) (20 mg, 0.038 mmol) in methanol (5 mL) was hydrogenated over 10% palladium on carbon (2 mg) under 30 psi in a 50 mL parr at room temperature for 3 hours. The mixture was filtered through a glass funnel. The filtrate was concentrated in vacuo and then purified by preparative HPLC to afford {4-[6-(4-fluoro-phenoxy)-pyridine-3-sulfonylamino]-4,5,6,7-tetrahydro-indazol-1-yl}-acetic acid (5 mg, 30%) as a white solid. 1H NMR (400 MHz, CD3OD) δ ppm 8.62 (d, 1 H), 8.28 (dd, 1 H), 7.20 (m, 5 H), 6.87 (s, 1 H), 4.79 (s, 2 H), 4.42 (m, 1 H), 2.57 (m, 2 H), 2.01-1.72 (m, 4 H). MS cald. for C20H19FN4O5S 446, obsd. (ESI+) [(M+H)+] 447.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[CH2:29]1[CH2:34][O:33][CH:32]=[CH:31][CH2:30]1>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH:32]2[CH2:31][CH2:30][CH2:29][CH2:34][O:33]2)[CH:7]=[C:6]([OH:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(O)cc1F
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1c(O)cc(OC2CCCCO2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a mixture of 2-fluoro-4,6-dihydroxybenzaldehyde (3.12 g, 20.0 mmol) and PPTS (0.51 g, 2.0 mmol) in dichloromethane (100 mL) was added dropwise DHP (3.02 g, 36.0 mmol). The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by column chromatography (EtOAc/PE=1/15) on silica gel to give the title compounds as a colorless oil (3.99 g, Yield: 83.2%). MS (ESI) m/z=241 [M+H]+.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12](=[O:30])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][C:23](=O)[C:22]2([CH3:29])[CH3:28])=[CH:16][N:15]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1>[C:7]([O:11][C:12](=[O:30])[NH:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][C:22]2([CH3:29])[CH3:28])=[CH:16][N:15]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc(CN2CCNC(=O)C2(C)C)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCNCC2(C)C)cn1
Temperature: 50 °C
Reaction time: 3 h
Yield: 58 %

Procedure:
LiAlH4 (1 M in THF, 78 mL, 78 mmol, 2 equiv) was added to a solution of [5-(2,2-dimethyl-3-oxo-piperazin-1-ylmethyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (Step 109.4) (13 g, 39 mmol) in THF (150 mL) at 50° C., under an argon atmosphere. The resulting mixture was stirred for 3 h at 50° C., cooled to 0° C., quenched by addition of acetone, filtered through a pad of celite and the filtrate was concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 97.5:1.5:1) to afford 7.25 g of the title compound as a white solid. Title compound: ESI-MS: 321.3 [M+H]+; tR=1.91 min (System 1); TLC: Rf=0.11 (DCM/MeOH, 9:1).
Reaction SMILES: Cl[C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:13][CH2:14][CH3:15].[Na+]>C(O)C>[CH2:14]([O:13][C:2]1[C:3]([CH3:12])=[CH:4][C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:15]
Reactant: CC[O-]
Reactant: Cc1cc2nnc(N)n2nc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nn2c(N)nnc2cc1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
6-Chloro-7-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.005; 1 g) was dissolved in ethanol (50 ml), admixed under argon with sodium ethoxide (2.2 g) and stirred at 60° C. for 1 h. Then the mixture was dried and the residue was purified using a 40 g silica gel cartridge (0-20% dichloromethane-ethanol gradient in 40 min). The clean product fractions were combined and dried. 480 mg of the title compound were obtained.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[C:15]=3[OH:22])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[OH:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][C:25]=1B(O)O>>[OH:22][C:15]1[C:16]([O:20][CH3:21])=[CH:17][CH:18]=[CH:19][C:14]=1[C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:29]3[CH:28]=[C:27]([O:30][CH3:31])[CH:26]=[CH:25][C:24]=3[OH:23])[N:7]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(-c2cccc(-c3cccc(Br)n3)n2)c1O
Reactant: COc1ccc(O)c(B(O)O)c1
Product: COc1ccc(O)c(-c2cccc(-c3cccc(-c4cccc(OC)c4O)n3)n2)c1
Yield: 16 %

Procedure:
6-(2-Hydroxy-3-methoxyphenyl)-6′-(2-hydroxy-5-methoxyphenyl)-2,2′-bipyridine was prepared from 6-bromo-6′-(2-hydroxy-3-methoxyphenyl)-2,2′-bipyridine and 2-hydroxy-5-methoxyphenylboronic acid in 16% yield using method F; δH [2H6]-DMSO 13.72,(1H, b), 12.48,(1H, b), 8.39,(1H, d), 8.32,(1H, d), 8,27-8.14,(4H, m), 7.72,(1H, d), 7.67,(1H, s), 7.09,(1H, d), 7.04-6.90,(3H, m), 3.86,(6H, s); MS 401 (MH)+; HPLC retention time (system 1) 3.98 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[N:5]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[CH:3]=1.[CH:30]1([NH2:37])[CH2:35][CH2:34][CH2:33][CH:32]([NH2:36])[CH2:31]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([S:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)(=[O:23])=[O:22])[CH:13]=2)[N:5]=[C:6]([NH:36][CH:32]2[CH2:33][CH2:34][CH2:35][CH:30]([NH2:37])[CH2:31]2)[N:7]=1
Reactant: NC1CCCC(N)C1
Reactant: CS(=O)(=O)c1nc(Cl)cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC1CCCC(Nc2nc(Cl)cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)n2)C1

Procedure:
A mixture of Example 42b (1 g, 2.23 mmol), cyclohexane-1,3-diamine (0.509 g, 4.46 mmol) and triethylamine (0.62 mL, 4.46 mmol) in dioxane (25 mL) was heated at 60° C. for 2 hours. The reaction mixture was concentrated and used directly for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[Cl:23])[O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1.[F:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=[O:28].C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:23][C:22]1[CH:21]=[CH:20][C:4]([O:5][C:6]2[C:11]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([NH:18][CH3:19])[CH:13]=3)=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:3][C:2]=1[NH:1][C:27](=[O:28])[C:26]1[CH:30]=[C:31]([C:34]([F:35])([F:36])[F:37])[CH:32]=[CH:33][C:25]=1[F:24]
Reactant: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(N)c2)ccn1
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CNc1cc(-c2cccnc2Oc2ccc(Cl)c(NC(=O)c3cc(C(F)(F)F)ccc3F)c2)ccn1
Temperature: 75 °C
Reaction time: 48 h

Procedure:
In a sealed tube, [2-(3-Amino-4-chloro-phenoxy)-[3,4′]bipyridinyl-2′-yl]-methyl-amine (300 mg, 0.918 mmol) and 2-Fluoro-5-trifluoromethyl-benzoyl chloride (0.180 mL, 1.19 mmol) were dissolved in 2.0 mL chloroform. The solution was heated to 75° C. and stirred for 48 h. The reaction was then cooled to RT, quenched with triethylamine (0.128 mL, 0.918 mmol), and concentrated in vacuo to yield the title compound as a crude light yellow solid. MS m/z (M+H)+=517; Calc'd 516.87 for C25H17ClF4N4O2.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)=[CH:4][C:3]=1[CH3:26].[F:27][C:28]([F:33])([F:32])[C@H:29]([OH:31])[CH3:30].[H-].[Na+].O>CN(C=O)C>[CH3:26][C:3]1[CH:4]=[C:5]([C:8]2[O:12][N:11]=[C:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4[CH2:22][C:23]([NH2:25])=[O:24])[N:9]=2)[CH:6]=[CH:7][C:2]=1[O:31][C@H:29]([CH3:30])[C:28]([F:33])([F:32])[F:27]
Reactant: Cc1cc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)ccc1F
Reactant: C[C@@H](O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(-c2nc(-c3cccc4c3ccn4CC(N)=O)no2)ccc1O[C@H](C)C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 55.2 %

Procedure:
To a solution of 2-{4-[5-(4-fluoro-3-methylphenyl)-1,2,4-oxadiazol-3-yl]-1H-indol-1-yl}acetamide (100 mg) and (2R)-1,1,1-trifluoropropane-2-ol (109 mg) in DMF (3 ml) was added 60% NaH (17 mg) at 0° C., followed by stirring at 80° C. for 4 hours. The reaction solution was added with water (15 ml) to complete the reaction, filtered, and then dried. The obtained powder was purified by silica gel column chromatography (chloroform:CH3OH=100:0 to 95:5), and crystallized with diisopropyl ether to obtain 2-[4-(5-{3-methyl-4-[(1R)-2,2,2-trifluoro-1-methylethoxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-1-yl]acetamide (70 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][C:7]=1[CH:8]=O.Cl.[NH2:17][OH:18].N1C=CC=CC=1>CCO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)=[N:6][C:7]=1[CH:8]=[N:17][OH:18]
Reactant: O=Cc1nc(-c2ccccn2)ccc1F
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: ON=Cc1nc(-c2ccccn2)ccc1F

Procedure:
5-Fluoro-[2,2′]bipyridinyl-6-carbaldehyde (0.36 mmol, 73 mg), hydroxylamine hydrochloride (1.8 mmol, 125 mg), pyridine (1.6 mmol, 0.12 mL) and EtOH were heated at reflux during 2 h. The solvent was evaporated under vacuum, and H2O was added. The filtration of the white precipitate obtained provided the final product without needing any purification (Florence Mongin; Francois Trecourt; Bruno Gervais; Oliver Mongin; Guy Quequiner, J. Org. Chem., 2002, 67, 3272-3276). Yield: 47 mg (60%), white solid. 1H-NMR (DMSO): 12.0 (N—OH); 8.76 (d, 1H, J=4.4 Hz); 8.46 (dd, 1H, J1=8.5 Hz, J1=3.4 Hz); 8.40 (d, 1H, J=7.9 Hz); 8.34 (s, 1H); 8.01 (m, 2H); 7.54 (m, 1H)
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[N:10][NH:9][C:8](=[O:12])[CH:7]=1.[H-].[Na+].Br[CH:22]([CH2:32][CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:23]([NH:25][C:26]1[CH:31]=[N:30][CH:29]=[CH:28][N:27]=1)=[O:24]>O1CCCC1>[CH:33]1([CH2:32][CH:22]([N:9]2[C:8](=[O:12])[CH:7]=[C:6]([O:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]=3[C:2]([F:17])([F:1])[F:18])[CH:11]=[N:10]2)[C:23]([NH:25][C:26]2[CH:31]=[N:30][CH:29]=[CH:28][N:27]=2)=[O:24])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: O=C(Nc1cnccn1)C(Br)CC1CCCC1
Reactant: O=c1cc(Oc2ccccc2C(F)(F)F)cn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)C(CC1CCCC1)n1ncc(Oc2ccccc2C(F)(F)F)cc1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 28 %

Procedure:
A solution of 5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (63.8 mg, 0.24 mmol) in tetrahydrofuran (1.24 mL) cooled to 0° C. was treated with a 60% suspension of sodium hydride in mineral oil (12 mg, 0.2 mmol). The reaction stirred at 0° C. for 5 min and then at 25° C. for an additional 30 min. After this time, the reaction was treated with 2-bromo-3-cyclopentyl-N-pyrazin-2-yl-propionamide (81.4 mg, 0.27 mmol) in a minimal amount of tetrahydrofuran. The reaction was then warmed to 50° C., where it stirred overnight. After this time, the reaction was partitioned between water (100 mL) and methylene chloride (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (AnaLogix, 12 g, 50-75% ethyl acetate/hexanes) afforded 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethyl-phenoxy)-6H-pyridazin-1-yl]-N-pyrazin-2-yl-propionamide (31.8 mg, 27%) as a white solid; ES+-HRMS m/e calcd for C23H22N5O3F3 [M+H+] 474.1748, found 474.1746. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.10 (m, 1H), 1.23-1.75 (m, 8H), 1.98 (m, 1H), 2.30 (m, 1H), 5.58 (dd, J=4.4, J=11.0 Hz, 1H), 5.92 (d, J=2.7 Hz, 1H), 7.48-7.63 (m, 2H), 7.81 (t, J=7.1 Hz, 1H), 7.88 (d, J=7.8 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.41 (br.s., 1H), 9.21 (s, 1H), 11.25 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH:6]=[CH:7][CH2:8][NH:9][CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:15])=[O:14])=[CH:4][CH:3]=1.[CH3:28]I>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][CH2:8][N:9]([CH2:10][CH2:11][NH:12][S:13]([C:16]2[C:17]3[CH:18]=[CH:19][N:20]=[CH:21][C:22]=3[CH:23]=[CH:24][CH:25]=2)(=[O:14])=[O:15])[CH3:28])=[CH:26][CH:27]=1
Reactant: O=S(=O)(NCCNCC=Cc1ccc(Cl)cc1)c1cccc2cnccc12
Reactant: CI
Solvent: ClC(Cl)Cl
Product: CN(CC=Cc1ccc(Cl)cc1)CCNS(=O)(=O)c1cccc2cnccc12
Reaction time: 0.67 h

Procedure:
1.50 g of the product of Example 172 was dissolved in 10 ml of chloroform, to the solution was added 3 ml of methyl iodide at a room temperature, and the mixture was stirred for 40 minutes. Excess methyl iodide was immediately evaporated off under a reduced pressure, and resulting residue was purified on a silica gel column (silica gel 50 g, eluant: 5% methanol in chloroform), to obtain 720 mg of the title compound in a colorless amorphous form.
Reaction SMILES: [C:1]1([CH2:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][CH2:10][C:11](=O)[CH3:12].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>O.ClCCCl>[CH2:7]([NH:8][CH:11]([CH3:12])[CH2:10][F:9])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CF
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(CF)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of phenylmethanamine (5.63 g, 52.6 mmol) and 1-fluoropropan-2-one (4.0 g, 52.6 mmol) and DCE (50 mL) was added NaBH(OAc)3 (15.6 g, 73.6 mmol) and HOAc (3.01 mL, 52.6 mmol) and the reaction was capped and stirred at RT for 3 h. The reaction was then poured into water, and extracted with DCM. The combined organic extracts were dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by SiO2 chromatography eluting with a DCM/MeOH gradient (500:5 to 500:10) to afford 6.2 g (70.5%) of N-benzyl-1-fluoropropan-2-amine (230).
Reaction SMILES: [N+](=[C:3]([C:17](=[O:28])[C@@H:18]([C@@H:20]1[C@@H:23]([C@H:24]([OH:26])[CH3:25])[C:22](=[O:27])[NH:21]1)[CH3:19])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])=[N-]>ClCCCl.C1C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[OH:26][C@@H:24]([C@H:23]1[C:22](=[O:27])[N:21]2[C@@H:20]1[C@@H:18]([CH3:19])[C:17](=[O:28])[CH:3]2[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[O:5])[CH3:25]
Reactant: C[C@@H](O)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=O)C(=[N+]=[N-])C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: ClCCCl
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12

Procedure:
To a solution of 4-nitrobenzyl (4R)-2-diazo-4-[(2R, 3S)-3-{(1R)-1-hydroxyethyl}-4-oxoazetidin-2-yl]-3-oxopentanoate (0.5 g) in 1,2-dichloroethane (10 ml) was added rhodium(II) acetate (2 mg) under refluxing. After refluxing for 30 minutes, the reaction mixture was cooled and evaporated in vacuo to give a residue. The residue was dissolved in anhydrous benzene (10 ml) and then evaporated. This operation was repeated once again and the residue was dried in vacuo to give 4-nitrobenzyl (4R,5R,6S)-6-[(1R)-1-hydroxyethyl]-4-methyl-3,7-dioxo-1-azabicyclo[3.2.0]heptane-2-carboxylate. The compound obtained above was dissolved in anhydrous acetonitrile (10 ml) and cooled to 0° C. under an atmosphere of nitrogen. To this solution were added N,N-diisopropyl-N-ethylamine (0.27 ml) and diphenyl phosphorochloridate (0.28 ml) successively, and the solution was stirred at 0° C. for 40 minutes. To the resulting solution were added dropwise a solution of (2S,4S)-2-(difluoromethyl)thiomethyl-4-mercapto-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.54 g) in anhydrous acetonitrile (3 ml) and N,N-diisopropyl-N-ethylamine (0.29 ml) at 5° C. with stirring, and the stirring was continued at the same temperature for 2 hours. To the reaction mixture was added ethyl acetate (30 ml). The solution was washed twice with saturated aqueous sodium chloride (20 ml), dried over anhydrous magnesium sulfate and evaporated. The oily residue was chromatographed on silica gel (60 g) eluting with a mixture of dichloromethane and acetone (5:1, V/V) to give 4-nitrobenzyl (4R,5S,6S)-3-[(2S,4S)-2-(difluoromethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.58 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]([OH:26])[CH:21](OCC)O)[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=1)C1C=CC=CC=1.[NH2:27][C:28]([CH3:43])([CH3:42])[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]1=[O:41]>>[CH3:43][C:28]([NH:27][CH2:21][CH:20]([C:11]1[C:12]2[O:17][CH2:16][C:15](=[O:18])[NH:14][C:13]=2[CH:19]=[C:9]([OH:8])[CH:10]=1)[OH:26])([CH3:42])[CH2:29][CH2:30][CH2:31][N:32]1[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:33]1=[O:41]
Reactant: CCOC(O)C(O)c1cc(OCc2ccccc2)cc2c1OCC(=O)N2
Reactant: CC(C)(N)CCCn1c(=O)[nH]c2ccccc21
Product: CC(C)(CCCn1c(=O)[nH]c2ccccc21)NCC(O)c1cc(O)cc2c1OCC(=O)N2

Procedure:
Prepared according to General Method 2 from 357 mg (1 mmol) 6-benzyloxy-8-(2-ethoxy-1,2-dihydroxy-ethyl)-4H-benzo[1,4]oxazin-3-one and 233 mg (1 mmol) 1-(4-amino-4-methyl-pentyl)-1,3-dihydro-benzimidazol-2-one.
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[C:3]([I:13])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([N:17]1[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]1)=[O:9]
Reactant: COc1cc(I)c(Cl)cc1C(=O)O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(I)c(Cl)cc1C(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
To a stirred solution of 5-chloro-4-iodo-2-methoxybenzoic acid (1.55 g, 4.9 mmol) in DMF (30 mL) at RT, tert-butyl piperazine-1-carboxylate (1.02 g, 5.5 mmol), BOP (2.63 g, 25.9 mmol) and DIEA (1.92 g, 14.9 mmol) were added and the resulting mixture was stirred at RT for 1 h. The reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (1.96 g, 76% yield).
Reaction SMILES: II.[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[CH2:11])[CH:5]=1.N.[NH2:21][C:22]([NH2:24])=[O:23]>C(OCC)(=O)C.C(#N)C.[Ag]OC#N>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)[CH2:11][O:23][C:22]([NH2:24])=[N:21]2)[CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: C=C(c1cccc(Br)c1)c1cccc(OC)c1
Agent: N#CO[Ag]
Agent: II
Agent: N
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1cccc(C2(c3cccc(Br)c3)COC(N)=N2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of iodine (1.65 g, 6.7 mmol) in ethyl acetate (25 mL) was added dropwise over 25 min to a mixture of 1-bromo-3-(1-(3-methoxy-phenyl)-vinyl)-benzene (1.75 g, 6.1 mmol) and silver cyanate in acetonitrile (30 mL) and ethyl acetate (15 mL), cooled in an ice bath. After complete addition, the reaction suspension was stirred for another 15 min at room temperature when TLC indicated the complete conversion of starting material. The reaction mixture was filtered, and the filtrate concentrated to give a dark grey oil. 25 mL of aqueous ammonia (25%) was added to the oil, and the mixture was stirred and warmed to 70° C. for 30 min, then kept at room temperature overnight. LC-MS at this point indicated complete conversion of the intermediate urea to the desired aminoxazoline. The reaction suspension was filtered, the solid was refluxed in toluene (20 mL) for 10 min, filtered hot (to remove residual, undissolved silver iodide), and the filtrate was left to cool to room temperature, followed by 1 h at −10° C. The pale-yellow crystalline solid was filtered off and dried at the rotary evaporator to dive 4-(3-bromo-phenyl)-4-(3-methoxy-phenyl)-4,5-dihydro-oxazol-2-ylamine (1.2 g, 57%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:3]1[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])[C:11]1[CH:12]=[CH:13][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:15][CH:16]=1)([CH3:21])[CH3:22]
Reactant: Cc1ccc(CNc2ccc(C(C)C)cc2)c(C)c1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: Cc1ccc(CN(C(=O)Nc2c(C(C)C)cccc2C(C)C)c2ccc(C(C)C)cc2)c(C)c1
Yield: 14.1 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(2,4-dimethylphenyl)methyl](4-isopropylphenyl)amine (2.2 g) and 2,6-diisopropylphenyl isocyanate (2.7 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(2,4-dimethylphenyl)methyl]-N-(4-isopropylphenyl)urea (0.56 g) was obtained. melting point: 100° C.