Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[CH:24]=O)[CH:18]=[N:17]1.[NH2:29][C:30]([NH2:32])=[O:31].Cl>CCO>[O:16]1[CH:20]=[C:19]([C:21]2[CH:22]=[C:23]([CH:24]3[C:8]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:32][C:30](=[O:31])[NH:29]3)[CH:26]=[CH:27][CH:28]=2)[CH:18]=[N:17]1
Reactant: O=C(Cc1ccccc1)c1ccccc1
Reactant: NC(N)=O
Reactant: O=Cc1cccc(-c2cnoc2)c1
Agent: Cl
Solvent: CCO
Product: O=C1NC(c2ccccc2)=C(c2ccccc2)C(c2cccc(-c3cnoc3)c2)N1
Temperature: 85 °C
Reaction time: 14 h

Procedure:
To a solution of 1,2-diphenylethanone (46 mg, 0.233 mmol), 3-(isoxazol-4-yl)benzaldehyde (Intermediate 46) (36 mg, 0.209 mmol) and urea (48 mg, 0.627 mmol) in EtOH (10 mL) was added concentrated HCl (0.4 mL). The mixture was stirred at 85° C. for 14 h. The volatiles were removed under reduced pressure and the residue was purified by silica gel column chromatography (PE:EA=1:1) to afford Compound 91 as an off-white power (18 mg, 22.2%). 1H NMR (MeOH-d4 500 MHz): δ 8.99 (s, 1H), 8.74 (s, 1H), 7.50-7.53 (m, 2H), 7.39-7.50 (m, 2H), 7.23-7.25 (m, 5H), 7.00-7.02 (m, 2H), 6.84-6.87 (m, 2H), 5.35 (s, 1H); MS (ESI): m/z 394.1 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11](O)[CH:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(S(F)(F)[F:25])CC)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([F:25])[C@H:10]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(O)C(N2CCCC2)C1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N2CCCC2)[C@@H](F)C1
Temperature: -78 °C
Reaction time: 8 h
Yield: 89.9 %

Procedure:
Dissolve 4′-hydroxy[1,3′]bipyrrolidinyl-1′-carboxylic acid tert-butyl ester (573 mg, 2.24 mmol) in dichloromethane (15 mL) and cool the mixture to −78° C. Add diethylaminosulfur trifluoride (504 mg, 3.13 mmol) dropwise and then allow the mixture to warm to room temperature. Stir the mixture overnight. Evaporate the solution and purify by silica gel chromatography, eluting with 0-3% methanol (2N NH3)/CH2Cl2 to give 520 mg (89%) of the title compound as a yellow oil. 1H NMR(DMSO-d6): δ 1.37 (s, 9H), 1.61-1.67 (m, 4H), 2.43-2.54 (m, 4H), 2.86 (bs, 1H), 3.30-3.41 (m, 1H), 3.45-3.60 (m, 1H), 5.09-5.25 (m, 1H).
Reaction SMILES: C(Cl)(=O)C.[NH:5]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>CCO>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][N:5]2[CH2:11][CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)=[CH:15][CH:14]=1
Reactant: C1CNCCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CCO
Solvent: CC(=O)Cl
Product: Clc1ccc(CN2CCCNCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.2 %

Procedure:
Acetyl chloride (11.7 mL, 0.165 mol) was added to anhydrous EtOH (500 mL) and the mixture was stirred for 30 min at 25° C. Homopiperazine (15.0 g, 0.150 mol) was added and the mixture was heated to reflux for 4 h. 4-Chlorobenzyl chloride (13.96 g, 0.087 mol) was added and the reaction mixture was heated to reflux for 16 h before concentrating. The residue was dissolved in EtOAc (500 mL) and washed with 1N aqueous KOH (50 mL). The aqueous layer was extracted with EtOAc (200 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (double separation. SiO2, 20×7 cm, 1PrOH—H2O—NH4OH, 80:12:6 to 70:20:10 gradient elution) afforded the desired product (10.6 g, 53.4%) and the dialkylated homopiperazine (2.36 g, 16.5%). GC/MS m/e 224 (M+, C12H17N2Cl).10% CH3OH—CH2Cl2); RPLC tR=5.96 min (>85%), 220 nm (Mm (Method B): ESI/MS m/e 498.3 (MH++H, C31H35N3O3).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH3:8][O:9][C:10](=[O:26])[CH2:11]P(OCC(F)(F)F)(OCC(F)(F)F)=O>>[CH3:8][O:9][C:10](=[O:26])[CH:11]=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: O=Cc1cccs1
Product: COC(=O)C=Cc1cccs1
Yield: 74.9 %

Procedure:
Thiophene-2-carbaldehyde (4.00 g, 35.7 mmol) and [bis-(2,2,2-trifluoro-ethoxy)-phosphoryl]-acetic acid methyl ester (12.5 g, 39.3 mmol) were treated by the method outlined in Example 34, step a to afford the subtitle compound (4.5 g, yield: 75%). MS calculated for C8H8O2S+H: 169, observed: 169.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)C.[CH:13](N(C(C)C)CC)(C)C.S(OC)(OC)(=O)=O.O>C(OCC)(=O)C>[CH3:1][O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH3:13])=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CNc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.3 %

Procedure:
68.15 g (0.412 mol) of 4-aminobenzoic acid ethyl ester was suspended in 86 mL (0.5 mol) diisopropyl ethyl amine and 60.0 g (45 mL, 0.474 mol) dimethyl sulfate was added drop wise. During the addition, the temperature rose to 95° C. The reaction is allowed to continue for 1 hour at 120° C. The reaction mixture was allowed to cool down to room temperature and 300 mL of water was added. The mixture was allowed to stand over night. The precipitated residue was isolated and treated with 250 mL of ethyl acetate. The solution in ethyl acetate was extracted twice with 100 mL of water, dried over MgSO4 and evaporated under reduced pressure. 4-methylaminobenzoic acid ethyl ester was purified by preparative column chromatography on Kieselgel 60 (Aldrich), using cyclohexane/ethyl acetate 4/1 as eluent. 36.3 g 4-methylaminobenzoic acid methyl ester was isolated (m.p. 66-67° C.).
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)[Cl:2].N1C2C(=CC=CC=2)C=CC=1.O(CC([NH:27][CH:28]1[C:59](=[O:60])[N:30]2[C:31]([C:43]([O:45][CH:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)=[O:44])=[C:32]([CH:35]=[CH:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH2:33][S:34][C@H:29]12)=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.C(O)CC>[ClH:2].[NH2:27][CH:28]1[C:59](=[O:60])[N:30]2[C:31]([C:43]([O:45][CH:46]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)[C:47]3[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=3)=[O:44])=[C:32]([CH:35]=[CH:36][C:37]3[N:41]([CH3:42])[N:40]=[N:39][N:38]=3)[CH2:33][S:34][C@H:29]12
Reactant: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)COc3ccccc3)[C@H]2SC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCCO
Solvent: c1ccc2ncccc2c1
Product: Cl
Product: Cn1nnnc1C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To 15 ml of chloroform was added 1.218 g of phosphorus pentachloride, and the phosphorus pentachloride was dissolved therein by warming. To the solution maintained at 10°-20° C. was added 0.929 g of quinoline. Five minutes later, the temperature was lowered to -10°--20° C., and to the mixture was added 2.7 g of benzhydryl 7-phenoxyacetamido-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate. The mixture was then stirred for 10 minutes and at room temperature for one hour. The mixture was then cooled to 0° C., and to this was added 5.4 ml of n-propanol. The resulting mixture was stirred at room temperature for one hour and poured into ice-water. To this was further added an appropriate amount of chloroform. The precipitated crystals were collected by filtration and dried to yield 1.3 g of benzhydryl 7-amino-3-(1-methyl-1H-tetrazol-5-yl)vinyl-3-cephem-4-carboxylate hydrochloride. To the obtained hydrochloride was added a mixture of a dilute aqueous sodium hydrogencarbonate solution and ethyl acetate, and the ethyl acetate layer was separated. From the ethyl acetate layer, there was obtained the 7-amino base.
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([NH:22]C(=O)OC(C)(C)C)=[N:20][CH:21]=3)[N:13]=[C:12]3[C:8]=2[N:9]=[C:10]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[N:11]3[CH2:30][C:31]([F:34])([F:33])[F:32])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44]>C(Cl)Cl>[F:41][C:42]([F:47])([F:46])[C:43]([OH:45])=[O:44].[N:1]1([C:7]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][C:19]([NH2:22])=[N:20][CH:21]=3)[N:13]=[C:12]3[C:8]=2[N:9]=[C:10]([N:35]2[CH2:36][CH2:37][NH:38][CH2:39][CH2:40]2)[N:11]3[CH2:30][C:31]([F:32])([F:34])[F:33])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCNCC4)n(CC(F)(F)F)c3n2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
tert-Butyl {5-[6-morpholin-4-yl-8-piperazin-1-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-yl}carbamate (1.18 g, 2.09 mmol) was dissolved in methylene chloride (10 ml) followed by the addition of trifluoroacetic acid (10 ml) with ice cooling and the resulting mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure followed by the addition of toluene and evaporated again under reduced pressure to give the title compound (1.5 g, 100%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]1[S:9][C:10]2[CH:16]=[C:15]([S:17](Cl)(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=2[N:12]=1.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CN1CCOCC1>CO>[CH2:21]([NH:28][S:17]([C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:3]3[C:4]([CH3:7])=[N:5][NH:6][C:2]=3[NH2:1])[S:9][C:10]=2[CH:16]=1)(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)Cl)cc2s1
Reactant: NCc1ccccc1
Solvent: CN1CCOCC1
Solvent: CO
Product: Cc1n[nH]c(N)c1-c1nc2ccc(S(=O)(=O)NCc3ccccc3)cc2s1
Yield: 13.4 %

Procedure:
the title compound (16 mg) was prepared from crude 2-(5-amino-3-methyl-1H-pyrazol-4-yl)-benzothiazole-6-sulfonyl chloride (100 mg, 0.30 mmol), benzylamine (66 μL, 0.60 mmol) and PS-NMM (0.320 g, 0.60 mmol) in 5 mL of methanol. MS (m/z, ES+): 400.5 (M+1, 100%). Yield=13%.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[NH2:19][C:20]1[CH:21]=[C:22]([SH:26])[CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:26][C:22]2[CH:21]=[C:20]([NH2:19])[CH:25]=[CH:24][CH:23]=2)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Sc2cccc(N)c2)c([N+](=O)[O-])c1
Temperature: 10 °C

Procedure:
The product from Example 4a (1.00 g, 3.51 mmol) and 3-Amino-benzenethiol (658 mg, 5.26 mmol) were dissolved in DMF to which was added K2CO3 (848 mg, 6.14 mmol). The reaction mixture was then heated to 10° C. for 16 hrs. Reaction mixture was then cooled to room temperature, diluted with water and extracted with ethyl acetate providing the title compound (650 mg, 71%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21].[OH-].[Na+].Cl>C1COCC1.CO>[F:34][C:2]([F:1])([F:33])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21]
Reactant: COC(=O)c1ccc(NC(CCC(F)(F)F)c2ccc(-n3cc4c(n3)CCCC4)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a mixture of methyl 4-((4,4,4-trifluoro-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)butyl)amino)benzoate (8.01 g), THF (34 mL) and methanol (34 mL) was added 1M aqueous sodium hydroxide solution (68 mL), and the mixture was stirred at 50° C. overnight. To the reaction mixture was added THF (34 ml), and the mixture was stirred at 60° C. for 7 hr. The reaction mixture was neutralized with 1M hydrochloric acid (68 mL), and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a crudely purified product. This compound was used in step C without further purification.
Reaction SMILES: [NH:1]1CC[O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH2:11].ClC(Cl)(Cl)C(O)[OH:19].Cl.NO>>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][C:3](=[O:4])[CH:2]=[N:1][OH:19])[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: C1COCCN1
Reactant: Nc1ccc(F)c(Br)c1
Agent: Cl
Agent: NO
Product: O=C(C=NO)Nc1ccc(F)c(Br)c1

Procedure:
Scheme Ib provides the preparation of the compounds of the invention where R1 is F and R2 is morpholine following the synthetic route described in Scheme I. Specifically 3-bromo-4-fluoro-aniline 1b is reacted with chloral hydrate and hydroxylamine hydrochloride at about 90° C. to provide N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide 2b. In one embodiment, 3-bromo-4-fluoro-aniline 1b is reacted with about 1 equivalent of chloral hydrate and about 3 equivalents of NH2OH.HCl in the presence of Na2SO4 and hydrochloric acid. Addition of N-(3-bromo-4-fluoro-phenyl)-2-hydroxyimino-acetamide 2b to sulfuric acid at about 50° C., followed by raising the temperature of the solution to about 90° C. provided 5-fluoro-6-bromo-1H-indolin-2,3-dione 3b. Conversion of 5-fluoro-6-bromo-1H-indolin-2,3-dione 3b to 3-fluoro-4-bromo-6-amino-benzoic acid 4b was performed using hydrogen peroxide. In one embodiment, the reaction is performed at about 0° C. In another embodiment, 3-fluoro-4-bromo-6-amino-benzoic acid 4b is prepared using about 1.5 volumes of H2O2 at about 0° C. in the presence of NaOH, such as 2N NaOH. Conversion of 3-fluoro-4-bromo-6-amino-benzoic acid 4b to 6-fluoro-7-bromo-quinazolin-2,4-dione 5b may be performed using urea at about 200° C. In one embodiment, 3-fluoro-4-bromo-6-amino-benzoic acid 4b is converted to 6-fluoro-7-bromo-quinazolin-2,4-dione 5b using an excess, i.e., about 10 equivalents, of urea. Replacement of the oxo groups of 6-fluoro-7-bromo-quinazolin-2,4-dione 5b with chlorine groups may be performed using a chlorinating agent such as POCl3. In one embodiment, the reaction is performed in the presence of DIPEA at about 130° C. The resultant 2,4-dichloro-6-fluoro-7-bromo-quinazoline 6b is then reacted with morpholine at about 0° C. to provide 2-chloro-4-morpholino-6-fluoro-7-bromo-quinazoline 7c. R3-substitution of 2-chloro-4-morpholino-6-fluoro-7-bromo-quinazoline 7c may be performed using R3B(OR)2. In one embodiment, R3-substitution is performed in the presence of a catalytic amount of PdCl2(PPh3)2. In another embodiment, the reaction is performed at about 90-95° C. in the presence of Na2CO3, ethanol and H2O. The 2-position of compound 8c is then substituted with a 2-(tert-butoxycarbonyl)amino)pyrimidine using (2-(tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid to provide compound 9c. In one embodiment, the reaction is performed in the presence of a catalytic amount of PdCl2(PPh3)2. In another embodiment, the reaction is also performed in the presence of about 2 equivalents of Cs2CO3 and DMF at about 75° C. to provide compound 9c. Finally, deprotection of compound 9c is performed using TFA or HCl, such as 4N HCl in 1,4-dioxane at about 0° C. to room temperature.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][C:14]2=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH2:1]([N:8]([C:9]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:20])[C:15]=2[C:16]([F:19])=[CH:17][CH:18]=1)[S:28]([CH3:27])(=[O:30])=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCc2c(NCc3ccccc3)ccc(F)c21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CS(=O)(=O)N(Cc1ccccc1)c1ccc(F)c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Example 44C (0.40 g, 1.5 mmol) in dichloromethane (9 mL) was treated with pyridine (0.36 mL, 4.4 mmol), treated with methanesulfonyl chloride (0.13 mL, 1.6 mmol), stirred for 4 hours, treated with pyridine (0.2 mL, 2.5 mmol), treated with methanesulfonyl chloride (0.10 mL, 1.3 mmol), stirred for 16 hours,refluxed for 9 hours, cooled to ambient temperature, treated with water (25 mL) and extracted with dichloromethane (3×20 mL). The combined dichloromethane extracts were washed with brine, dried (Na2SO4) and concentrated. Purification of the residue on silica gel with 1:1 ethyl acetate:hexanes provided the desired product.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(C(C)C)CC)(C)C.[CH2:19]([O:26][C:27](Cl)=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH2:19]([O:26][C:27](=[O:28])[NH:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)c1ccsc1N
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: NC(=O)c1ccsc1NC(=O)OCc1ccccc1
Reaction time: 60 h

Procedure:
To a stirred solution of 2-aminothiophene-3-carboxamide (5 g, 35.2 mmol) in tetrahydrofuran (200 mL) under argon was added diisopropylethylamine (9.52 ml, 54.5 mmol) and benzyloxycarbonyl chloride (7.53 mL, 52.8 mmol). After stirring for 60 hours, more diisopropylethylamine (9.52 mL, 54.5 mmol) and benzyloxycarbonyl chloride (7.53 mL, 52.8 mmol) were added. After an additional 24 hours, the suspension was filtered and the resulting solution was concentrated to ˜30 mL and diluted with ethyl acetate (100 mL) The organic layer was washed sequentially with saturated aqueous sodium bicarbonate (3×40 mL), a 3:1 mixture of saturated aqueous sodium bicarbonate and water (40 mL), and brine (40 mL), dried with sodium sulfate, filtered, and concentrated. The resulting mixture of white solid and brown oil was triturated with a mixture of ethyl acetate (10 mL) and hexanes (10 mL), and then the solid was collected by filtration. Drying under vacuum afforded the title compound as a solid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([C:13]#N)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.CC(C[AlH]CC(C)C)C.CC[O:28]C(C)=O>C(Cl)Cl>[F:1][C:2]([F:16])([F:15])[C:3]1[N:8]=[CH:7][C:6]([C:9]2([CH:13]=[O:28])[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(C)=O
Reactant: N#CC1(c2ccc(C(F)(F)F)nc2)CCC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: O=CC1(c2ccc(C(F)(F)F)nc2)CCC1
Temperature: -78 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
To a solution of Example 85E (1.45 g, 6.45 mmol) in DCM (50 mL) was added dropwise a solution of DIBAL (7.74 mL, 7.74 mmol, IM in toluene) at −78° C. under nitrogen. After stirring for 3 hours at −78° C., the reaction was quenched with saturated NH4Cl (10 mL) and the resulting mixture was extracted with dichloromethane (30 mLx2). The combined organic layers were washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluting with petroleum ether:EtOAc=100:1-100:3 to provide the title compound (733 mg, 3.2 mmol, 49% yield) as colorless oil. LC-MS: m/z 230 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[C:4]([O:22][CH3:23])[CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:23][O:22][C:4]1[CH:3]=[C:2]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(Br)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2ccccc2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A 100 mL round-bottom flask was purged with and maintained under an inert atmosphere of nitrogen then charged with tert-butyl 4[(4-bromo-2-methoxyphenyl)methyl]piperazine-1-carboxylate (1.00 g, 2.60 mmol, 1.00 equiv), phenylboronic acid (0.640 g, 5.25 mmol, 2.02 equiv), Tetrakis(triphenylphosphine)palladium (0.300 g, 0.260 mmol, 0.10 equiv), potassium carbonate (1.08 g, 7.81 mmol, 3.01 equiv), dioxane (24 mL), and water (4 mL). The resulting solution was stirred overnight at 80° C. and then diluted with water (10 mL) and extracted with ethyl acetate (3×5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (3/7) to provide 0.850 g (86% yield) of tert-butyl 4-[(2-methoxy-4-phenylphenyl)methyl]piperazine-1-carboxylate as yellow oil. LCMS (ESI, m/z): 383 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[C:11](=[O:14])([O-])[O-].[K+].[K+].[CH3:17]N(C)C=O>>[C:2]([C:4]1[CH:9]=[C:8]([CH:7]=[CH:6][CH:5]=1)[O:10][CH:11]([OH:14])[CH3:17])(=[O:3])[CH3:1]
Reactant: CN(C)C=O
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Product: CC(=O)c1cccc(OC(C)O)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
Under a nitrogen atmosphere, 3-hydroxyacetophenone (4.1 g) and brominated ethanol (5.6 g) were dissolved in dimethylformamide solution (60 ml), and potassium carbonate (12.4 g) was added, and the mixture was heated under stirring at 100° C. After 3 hours, the mixture was cooled to room temperature, and the organic layer was separated by adding water and diethyl ether thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give (3-acetylphenoxy) ethanol (3.28 g, 61%) as white crystals. The product (977 mg) was dissolved in acetonitrile (18 ml), triethylamine (2.3 ml) and methanesulfonyl chloride (0.5 ml) were added, and the mixture was stirred at room temperature. After 1.5 hours, sodium iodide (4.9 g) and tert-butyl-1-piperazinecarboxylate (1.2 g) were added, and the mixture was heated under stirring at 60° C. After stirring for 4.5 hours, the organic layer was separated by adding water and ethyl acetate thereto. The resulting organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. After filtering off the drying agent, the mixture was evaporated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate system), to give tert-butyl-2-(3-acetylphenoxy)ethyl-1-piperazinecarboxylate (1.33 g) as a yellow oil. The product (1.33 g) was dissolved in methanol (10 ml), and the solution was added to a 4N hydrochloric acid-ethyl acetate solution (30 ml). The mixture was stirred at a room temperature overnight, the resulting white crystals were collected by filtration and washed with diethyl ether. The organic layer was separated by adding a 1N aqueous sodium hydroxide and dichloromethane to the crystals. The resulting organic layer was evaporated, to give the title compound (830 mg, 62%; 2 steps) as a yellow oil.