Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH:8]([C:17]1[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=1)[C:9]([NH:11][C:12]1[S:13][CH:14]=[CH:15][N:16]=1)=[O:10].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH:8]([CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][C:2]2=[O:1])[C:9]([NH:11][C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[O:10])=[CH:18][CH:19]=1)(=[O:24])=[O:25]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2O)C(=O)Nc2nccs2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2=O)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 14.1 %

Procedure:
A solution of 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 26, 72.4 mg, 0.184 mmol) in methylene chloride (1.8 mL) was treated with pyridinium chlorochromate (20 wt. % on basic alumina, 237.3 mg, 0.22 mmol). The resulting reaction mixture was stirred at 25° C. for 3 h, at which time, thin layer chromatography indicated a small amount of the 3-(2-hydroxy-cyclopentyl)-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide. The reaction mixture was then treated with an additional amount of pyridinium chlorochromate (20 wt. % on basic alumina, 237.3 mg, 0.220 mmol). The reaction mixture was allowed to stir at 25° C. for 4 h and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/7 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-(2-oxo-cyclopentyl)-N-thiazol-2-yl-propionamide (10.2 mg, 14%) as a white solid: mp 228–230° C.; EI-HRMS m/e calcd for C18H20N2O4S2 (M+) 392.0865, found 392.0871.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[OH:12].[H][H]>C(OCC)(=O)C.[C].[Pd]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([F:1])=[C:3]([OH:12])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1cc(O)c(F)cc1F
Yield: 96.1 %

Procedure:
24.9 g (142 mmol) of the resulting 2,4-difluoro-5-nitrophenol was dissolved in 150 ml of ethyl acetate, 5.0 g of 10% palladium-carbon was added and the mixture was stirred at 50° to 60° C. for 27 hours under a stream of hydrogen. The reaction vessel was filled with nitrogen, the reaction solution was filtered by means of suction, the solvent was distilled off under reduced pressure, and the residue was triturated with n-hexane to give 19.8 g (96%) of 5-amino-2,4-difluorophenol.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([Cl:15])=[CH:10][C:3]=1[O:4][CH:5]([CH3:9])[C:6]([OH:8])=O.C(Cl)(=O)C(C)(C)C.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:38]([O:46][CH2:47][CH3:48])(=[O:45])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[CH2:43]([O:42][C:40](=[O:41])[CH:39]([C:6](=[O:8])[CH:5]([O:4][C:3]1[CH:10]=[C:11]([Cl:15])[C:12]([Cl:14])=[CH:13][C:2]=1[Cl:1])[CH3:9])[C:38]([O:46][CH2:47][CH3:48])=[O:45])[CH3:44]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Oc1cc(Cl)c(Cl)cc1Cl)C(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1cc(Cl)c(Cl)cc1Cl
Yield: 89.7 %

Procedure:
One proceeds in an analogous manner to Example 4 except that 27 g of 2-(2',4',5'-trichloro-phenoxy)-propionic acid are reacted first with 12 g of pivaloyl chloride and thereafter with diethyl-ethoxy-magnesium malonate prepared from 17.6 g of diethyl malonate. The reaction mixture is worked up. Thus 37 g of the desired compound are obtained in the form of pale yellow crystals, yield 91%, mp.: 62°-66° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH:27]=[CH2:28])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH2:29]([Zn]CC)C.CCCCCC.ICI>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH:27]2[CH2:29][CH2:28]2)[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: C=COC(CC)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Zn]CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: ICI
Product: CCC(OC1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-6-[1-(ethenyloxy)propyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (246 mg, 0.563 mmol) in dichloromethane (5.6 mL) was added a solution of diethyl zinc in hexane (1.0 M, 2.82 mL, 2.82 mmol) and diiodomethane (454 μL, 5.63 mmol) at 0° C. After 1.5 h, the reaction mixture was diluted with ethyl acetate, quenched with aqueous ammonium chloride, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the title compound as a pale yellow solid (233 mg, 0.517 mmol, 92%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[Cl:10][C:11]1[N:16]=[C:15](Cl)[C:14]2[CH2:18][CH2:19][CH2:20][C:13]=2[N:12]=1.[CH3:21][O:22][C:23]([C:25]1([C:29]2[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=2)[CH2:28][CH2:27][CH2:26]1)=[O:24]>C(O)C>[CH3:21][O:22][C:23]([C:25]1([C:29]2[CH:30]=[CH:31][C:32]([NH:35][C:15]3[C:14]4[CH2:18][CH2:19][CH2:20][C:13]=4[N:12]=[C:11]([Cl:10])[N:16]=3)=[CH:33][CH:34]=2)[CH2:26][CH2:27][CH2:28]1)=[O:24]
Reactant: Clc1nc(Cl)c2c(n1)CCC2
Reactant: COC(=O)C1(c2ccc(N)cc2)CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COC(=O)C1(c2ccc(Nc3nc(Cl)nc4c3CCC4)cc2)CCC1
Temperature: 10 °C
Yield: 61.8 %

Procedure:
Diisopropylethylamine (45.9 mL, 264.55 mmol) was added slowly to a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (10 g, 52.91 mmol) and 1-(4-amino-phenyl)-cyclobutanecarboxylic acid methyl ester (13.015 g, 63.49 mmol) in anhydrous ethanol (100 mL) under stirring at 10° C. Thereafter, the mixture was heated at reflux for 48 hours and then concentrated under reduced pressure. The residue was purified by chromatography (silica gel) to afford the title compound as a light yellow solid (11.7 g, 62% yield).
Reaction SMILES: [C:1]([C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]([O:18]CC)=[O:17])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[Li+]>>[C:1]([C:10]1[CH:28]=[CH:27][C:13]([O:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=1)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC(=O)c1ccc(OC(CCCCCC)C(=O)OCC)cc1
Agent: [Li+]
Agent: [OH-]
Product: CCCCCCCC(=O)c1ccc(OC(CCCCCC)C(=O)O)cc1
Yield: 84 %

Procedure:
1-[4-Hydroxyphenyl]-1-octanone (440 mg, 2.0 mmol) and ethyl (RS)-2-bromooctanoate (552 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Octanoylphenoxy]octanoate (605 mg, 78%). 1H NMR (400 MHz, CDCl3): δ 7.91 (d, J=9.0 Hz, 2H), 6.88 (d, J=9.0 Hz, 2H), 4.66 (dd, J=5.1, 7.4 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 1.88-2.02 (m, 2H), 1.70 (tt, J=7.2, 7.2 Hz, 2H), 1.41-1.56 (m, 2H), 1.25-1.37 (m, 14H), 1.23 (t, J=7.1 Hz, 3H), 0.87 (t, J=7.2 Hz, 3H), 0.86 (t, J=7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.41, 171.48, 161.81, 131.01, 130.54 (2C), 114.77 (2C), 76.75, 61.62, 38.56, 32.90, 31.94, 31.78, 29.60, 29.38, 29.07, 25.33, 24.80, 22.85, 22.75, 14.39, 14.31, 14.26. The resulting ester (605 mg, 1.6 mmol) was saponified with lithium hydroxide (186 mg, 7.8 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Octanoylphenoxy]octanoic Acid (487 mg, 87%). 1H NMR (400 MHz, CDCl3): δ 9.70 (br s, 1H), 7.89 (d, J=9.0 Hz, 2H), 6.89 (d, J=9.0 Hz, 2H), 4.69 (dd, J=5.9, 6.6 Hz, 1H), 2.87 (t, J=7.5 Hz, 2H), 1.95-2.01 (m, 2H), 1.67 (tt, J=7.2, 7.2 Hz, 2H), 1.43-1.58 (m, 2H), 1.24-1.37 (m, 14H), 0.851 (t, J=6.8 Hz, 3H), 0.849 (t, J=7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 200.38, 176.08, 161.84, 130.85, 130.78 (2C), 114.83 (2C), 76.20, 38.56, 32.79, 31.93, 31.76, 29.57, 29.35, 29.05, 25.34, 24.92, 22.84, 22.74, 14.29, 14.23. The acid (500 mg, 1.4 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Octanoylphenoxy]octanoate (404 mg, 76%) as a white solid. mp 165-170° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=8.8 Hz, 2H), 6.95 (d, J=8.8 Hz, 2H), 4.58 (dd, J=6.1, 6.3 Hz, 1H), 2.91 (t, J=7.3 Hz, 2H), 1.91-1.96 (m, 2H), 1.62-1.69 (m, 2H), 1.44-1.58 (m, 2H), 1.25-1.39 (m, 14H), 0.87-0.90 (m, 6H); 13C NMR (101 MHz, CD3OD): S 200.50, 176.40, 162.96, 130.28 (2C), 129.94, 114.71 (2C), 78.38, 38.00, 32.98, 31.79, 31.74, 29.27, 29.20, 29.05, 25.50, 24.79, 22.56, 22.51, 13.36, 13.34; LRMS (ESI): m/z 769 (M2H+), 748 (2M-Na++2H+), 363 (M-Na++2W); HPLC: 3 min.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:9]=1)[CH2:3][OH:4].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[CH3:1][C:2]([CH3:21])([CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=1)[CH:3]=[O:4]
Reactant: CC(C)(CO)COCc1cccc(Oc2ccccc2)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C=O)COCc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Yield: 48.3 %

Procedure:
A solution of 2,2-dimethyl-3-(3-phenoxybenzyloxy)-propan-1-ol (15 g) in dry dichloromethane (50 cm3) was added dropwise to a stirred suspension of pyridinium chlorochromate (18.75 g) in dichloromethane (100 cm3) whilst the reaction temperature was maintained within the range 0°-5° C. When the addition was complete, the mixture was allowed to warm to the ambient temperature (ca. 25° C.) over a period of 2 hours. After the reaction mixture had been diluted with diethyl ether, the ethereal layer was decanted and filtered through celite. The solvent was removed by evaporation and the residual oil purified by column chromatography using a silica gel column and eluting with dichloromethane as eluent, to yield 2,2-dimethyl-3-(3-phenoxybenzyloxy)propane-1-al (7.2 g) as an orange oil.
Reaction SMILES: C[O:2][C:3]1[C:4]([O:19]C)=[N:5][C:6]2[CH:7]=[C:8]([CH3:18])[C:9]3[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:10]=3[C:11]=2[N:12]=1.[ClH:21].C>>[ClH:21].[CH3:18][C:8]1[C:9]2[CH2:16][N:15]([CH3:17])[CH2:14][CH2:13][C:10]=2[C:11]2[NH:12][C:3](=[O:2])[C:4](=[O:19])[NH:5][C:6]=2[CH:7]=1
Reactant: COc1nc2cc(C)c3c(c2nc1OC)CCN(C)C3
Agent: Cl
Product: Cc1cc2[nH]c(=O)c(=O)[nH]c2c2c1CN(C)CC2
Temperature: 5 °C
Yield: 43 %

Procedure:
A solution of the product from Example 102 (0.172 g, 0.63 mmol) in 4 mL of aqueous 3N HCl solution was heated at reflux for 2 hours. The hot solution was treated with charcoal and filtered. The filtrate was cooled to 5° C. and the solid which formed was collected by filtration and dried at 90° C. under vacuum to give the title compound as a white solid (83 mg, 43% yield), mp=323-330° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[C:35]([CH3:36])=[CH:34][C:33]([C:37](O)=[O:38])=[N:32]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:37]([C:33]4[CH:34]=[C:35]([CH3:36])[N:31]([CH3:30])[N:32]=4)=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1cc(C(=O)O)nn1C
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)n(C)n2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 1,5-dimethyl-1H-pyrazole-3-carboxylic acid (21 mg, 0.15 mmol).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:18][C@H:19]1[CH2:24][C:23]2[C:25]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:26][CH:27]=[CH:28][C:22]=2[O:21][CH2:20]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:35][N:32]1[CH2:33][CH2:34][N:29]([C:25]2[C:23]3[CH2:24][C@H:19]([NH:18][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][C:10]([C:12]([F:15])([F:14])[F:13])=[CH:11][C:3]=4[C:2]([F:1])([F:17])[F:16])[CH2:20][O:21][C:22]=3[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(F)(F)F)cc2C(F)(F)F)CO3)CC1
Reaction time: 8 h
Yield: 29.9 %

Procedure:
A solution of 2,4-bis(trifluoromethyl)benzoic acid (195 mg, 0.755 mmol) in thionyl chloride (4 mL) was heated at 55° C. for 45 min. The excess of thionyl chloride was removed in vacuo, and the residue was evaporated with two portions of toluene. The acid chloride was then dissolved in anhydrous methylene chloride (5 mL) and added to a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (170 mg, 0.687 mmol) and triethylamine (144 μL, 1.03 mmol) in anhydrous methylene chloride (20 mL) with stirring. The reaction mixture was left overnight at room temperature and was washed with a 2 M NH3 solution (10 mL) followed by a portion of brine. The organic layer was dried (MgSO4), and the solvent was removed in vacuo. The residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 92:8+0.5% conc. NH3) affording 100 mg (30% yield) of the title compound as a white powder: mp 202–203° C.; [α]21D−51° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 487 (16, M+).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[NH:7][C:6]1=[O:27])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]Cl>C(OCC)(=O)C.O>[C:1]([O:4][C@H:5]1[C@H:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[S:10][C:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:8]([CH3:26])[N:7]([CH2:37][CH2:36][N:35]([CH3:39])[CH3:34])[C:6]1=[O:27])(=[O:3])[CH3:2]
Reactant: CN(C)CCCl
Reactant: COc1ccc([C@@H]2SC(c3ccccc3)=C(C)NC(=O)[C@H]2OC(C)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@@H]2SC(c3ccccc3)=C(C)N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 25 °C
Yield: 62.3 %

Procedure:
A mixture of 2.3 g (0.006 mol) of trans-rac.-6-(acetyl-oxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-2-phenyl-1,4-thiazepin-5(4H)-one, 1.0 g (0.0072 mol) of powdered potassium carbonate, and 0.8 g (0.0066 mol) of 2-dimethylaminoethyl chloride in 50 ml of ethyl acetate was stirred and heated at reflux for 2 hours, then twice an additional 0.3 g of dimethylaminoethyl chloride was added at 2 hour intervals. The mixture was heated at reflux for a total of 2 hours, then cooled to room temperature and diluted with water. The organic phase was separated, washed with brine and dried (MgSO4) and the solvent was removed under reduced pressure. The residue was crystallized from ether to give 1.7 g (70%) of trans-rac.-6-(acetyloxy)-6,7-dihydro-7-(4-methoxyphenyl)-3-methyl-4-[2-(dimethylamino)-ethyl]-2-phenyl-1,4-thiazepin-5(4H)-one, mp 119°-120°.
Reaction SMILES: [F-:1].[K+].C1OCCOCCOCCOCCOCCOC1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:30]=[C:31]([Cl:34])[C:32]=1Cl)[C:25]([O:27][CH2:28][CH3:29])=[O:26]>[Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([CH:30]=[C:31]([Cl:34])[C:32]=1[F:1])[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: [F-]
Reactant: CCOC(=O)c1cc(Cl)c(Cl)c(Cl)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Br-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(Cl)c(F)c(Cl)c1
Yield: 57.4 %

Procedure:
Into a three-necked 50 ml flask equipped with a condenser and a stirrer, 1.9 g (33 mmol) of spray-dried potassium fluoride (purchased from Laporte Industry), 1.1 g (2.5 mmol) of tetraphenyl phosphonium bromide, 0.7 g (2.5 mmol) of 18-crown-6 and 6.4 g (25 mmol) of ethyl 3,4,5-trichlorobenzoate were introduced, and the mixture was heated in an oil bath and reacted under a nitrogen atmosphere at 210° C. for 2 hours. The reactor was cooled, and the mixture was diluted with 40 ml of toluene. Inorganic salts were filtered off, and toluene was concentrated to give the residue, which was distilled under reduced pressure to obtain 3.4 g of ethyl 3,5-dichloro-4-fluorobenzoate. The yield was 57%. The physical properties are shown below.
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[NH:10][C:11]1[C:16]([C:17]2[N:25]=[CH:24][N:23]=[C:22]3[C:18]=2[N:19]=[CH:20][N:21]3[CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:15][CH:14]=[CH:13][N:12]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[C:3]([NH:10][C:11]2[C:16]([C:17]3[N:25]=[CH:24][N:23]=[C:22]4[C:18]=3[N:19]=[CH:20][N:21]4[CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[C:4]([F:9])[CH:5]=[CH:6][C:7]=1[NH:8][S:38]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)(=[O:40])=[O:39]
Reactant: Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=S(=O)(Nc1ccc(F)c(Nc2ncccc2-c2ncnc3c2ncn3C2CCCCO2)c1F)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
The 2,6-difluoro-N1-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)benzene-1,3-diamine (20 mg, 0.047 mmol) prepared at Step 9 was added and dissolved into dichloromethane solvent. benzenesulfonyl chloride (12 mg, 0.07 mmol) and pyridine (8 uL, 0.094 mmol) were added into the reaction solution and stirred at 50° C. for 2 hours. After the reaction, the reactant was washed with 1N aqueous hydrochloric acid solution and salt water. After extraction with dichloromethane, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that the target compound was obtained.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N:7][CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2].ClC1C=CC=C(C(OO)=[O:21])C=1>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[NH:4][C:5]2[C:6]([N:12]=1)=[N+:7]([O-:21])[CH:8]=[CH:9][C:10]=2[CH3:11])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCc1nc2nccc(C)c2[nH]1
Solvent: ClC(Cl)Cl
Product: CCc1nc2c([nH]1)c(C)cc[n+]2[O-]
Yield: 96.6 %

Procedure:
A solution of 2-ethyl-7-methylimidazo[4,5-b]pyridine (28 g, 174 mmol) and m-chloroperbenzoic acid (80-90%, 44.6 g) in CHCl3 (300 mL) was heated at reflux for 0.5 hours. The mixture was concentrated and purified (SiO2, 100% CH2Cl2 gradient to 30% CH2Cl2 /MeOH) to give 29.8 g of 2-ethyl-7-methylimidazo[4,5-b]pyridine-4-oxide as a solid.
Reaction SMILES: [I:1]I.N1C=CN=C1.[C:8]([O:12][C:13](=[O:38])[NH:14][C@H:15]([C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17]O)([CH3:11])([CH3:10])[CH3:9]>ClCCl>[C:8]([O:12][C:13](=[O:38])[NH:14][C@H:15]([C:19]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:16][CH2:17][I:1])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: II
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCI)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h

Procedure:
A suspension of polystyrene resin-bound triphenylphosphine (2.33 g, 3 mmol/g in dry dichloromethane (25 ml) is treated with iodine (1.56 g, 6.16 mmol) and stirred for 15 minutes under argon. Imidazole (0.477 g, 7.0 mmol) is added and the reaction mixture stirred at room temperature for a further 15 minutes. The reaction mixture is then treated with a solution of [(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-hydroxy-propyl]carbamic acid tert-butyl ester (1.24 g, 2.8 mmol) in dichloromethane (5 ml). The reaction mixture is refluxed for 2 hours under argon, then filtered through a Celite™ filter pad, washing with dichloromethane. The filtrate is washed with 5% aqueous sodium thiosulphate solution and water, dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with 1:99 methanol/dichloromethane) to afford [(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-iodo-propyl]-carbamic acid tert-butyl ester. [M-BOC] 453.9.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][NH2:11]>CO>[O:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[CH2:10][NH:11][C:3]([NH:2][CH3:1])=[O:4]
Reactant: NCc1ccco1
Reactant: CN=C=O
Solvent: CO
Product: CNC(=O)NCc1ccco1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
A solution of methyl isocyanate (34.0 g) in methanol (30 ml) was added dropwise to a solution of furan-2-ylmethylamine (57.9 g) in methanol (300 ml) at 5° to 15° C. After being stirred at room temperature for three hours, the solvent was evaporated in vacuo. The residue was treated with diisopropyl ether (400 ml) to give N-(furan-2-ylmethyl)-N'-methylurea (81.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([OH:20])=O)=[CH:8]1.C[N:22](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.N.O>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:22])=[O:20])=[CH:8]1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: O=C(O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Into a 5000-mL 4-necked round-bottom flask was placed a solution of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxylic acid (280 g, 830.51 mmol, 1.00 equiv) in N,N-dimethylformamide (2500 mL), HBTU (315 g, 830.61 mmol, 1.00 equiv), and DIEA (139 g, 1.08 mol, 1.30 equiv). The resulting solution was stirred at room temperature for 1.5 h. This was followed by the addition of amine hydrate (300 mL). The resulting solution was stirred at room temperature for 0.5 h and diluted with 2000 mL of H2O. The solids were collected by filtration, washed with 3×1000 mL of water and dried to afford 150.6 g (54%) of 9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide as a white solid. LC-MS: [M+H]+336 1H-NMR (DMSO, 300 MHz, ppm) □ 1.66-1.70 (2H, m), 3.08-3.12 (2H, m), 3.70-3.71 (1H, m), 4.88-4.94 (1H, m), 7.14 (1H, s), 7.36-7.39 (1H, m), 7.60 (1H, s), 7.83 (1H, s), 8.84-8.86 (1H, m).