Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=CC=CC=1N[C:9](=[O:29])[CH2:10][N:11]1[CH2:16][C@H:15]([CH3:17])[N:14]([C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:27])[C@H:13]([CH3:28])[CH2:12]1.Cl.C([O:33]CC)C>ClCCl>[ClH:1].[CH3:17][C@H:15]1[N:14]([C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH3:27])[C@@H:13]([CH3:28])[CH2:12][N:11]([CH2:10][C:9]([OH:29])=[O:33])[CH2:16]1
Reactant: CCOCC
Reactant: C[C@@H]1CN(CC(=O)Nc2ccccc2Cl)C[C@H](C)N1c1ncnc2c1ncn2C
Agent: Cl
Solvent: ClCCl
Product: C[C@@H]1CN(CC(=O)O)C[C@H](C)N1c1ncnc2c1ncn2C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step (iii) (0.12 g) in dichloromethane was treated with 1M hydrogen chloride in diethyl ether (12 ml). The mixture was stirred at room temperature for 18 hours. The solvent was evaporated under reduced pressure to give the subtitle product as a pale yellow solid. Yield 0.15 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[C:16]([OH:19])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].[Br:35][CH2:36][CH2:37]CBr>CN(C)C=O>[Br:35][CH2:36][CH2:37][O:19][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][C:15]=1[O:20][CH3:21])[N:12]=[CH:11][N:10]=[C:9]2[O:8][C:6]1[CH:5]=[CH:4][C:3]([NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24])=[C:2]([Cl:1])[CH:7]=1
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(O)cc23)cc1Cl
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCBr)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea. N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl]-N′-propylurea 50 mg), potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: O1CCCCC1[O:7][NH:8][CH2:9][CH:10]=[CH:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1.[O:21]1CCC[CH2:23][CH:22]1NO.S1C=C(C(Br)C=C)C2C=CC=CC1=2.O>CN(C=O)C>[OH:7][N:8]([CH2:9][CH:10]=[CH:11][C:12]1[S:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[CH:13]=1)[C:22](=[O:21])[CH3:23]
Reactant: ONC1CCCCO1
Reactant: C(=Cc1cc2ccccc2s1)CNOC1CCCCO1
Agent: C=CC(Br)c1csc2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(O)CC=Cc1cc2ccccc2s1
Reaction time: 2 h
Yield: 66 %

Procedure:
O-Tetrahydropyranyl-3-benzo[b]thien-2-ylprop-2-enyl hydroxylamine. Tetrahydropyranylhydroxyl amine (0.51 g, 4.34 mmole) in DMF (10 mL) was added to a solution of 3-benzo[b]thienylbromoprop-2-ene (0.50 g, 1.98 mmole) in DMF (10 mL). After being allowed to stir for two hours the reaction was poured into water and extracted with ether. The organic layer was washed with NaHCO3 and brine. The organic layer was dried over MgSO4 and evaporated. The residue was chromatographed on silica gel eluting with 40% ether in hexanes to give the desired product as a yellow oil (66%).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([CH:7]1[CH2:9][CH2:8]1)=O.O.[NH2:12][NH2:13]>C(O)(=O)C>[CH:7]1([C:5]2[CH2:4][C:3](=[O:2])[NH:12][N:13]=2)[CH2:9][CH2:8]1
Reactant: NN
Reactant: COC(=O)CC(=O)C1CC1
Solvent: CC(=O)O
Solvent: O
Product: O=C1CC(C2CC2)=NN1
Temperature: 100 °C
Yield: 147 %

Procedure:
To a solution of methyl-3-cyclopropyl-3-oxopropionate (10 g) and acetic acid (28 mL) in a round bottom flask under argon was added hydrazine hydrate (2.25 g). The mixture was immersed into an oil bath and heated to 100° C. overnight. The reaction vessel was then cooled and the acetic acid was evaporated in vacuo and the remaining solid was added to 1 N aqueous sodium hydroxide solution. The resulting precipitate was collected by filtration and washed with water and cold ether to afford the desired 5-cyclopropyl-2,4-dihydro-pyrazol-3-one (8.2 g) as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[C:5](OC)=[O:6].O.[NH2:39][NH2:40]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:39][NH2:40])=[O:6])[CH:9]=[CH:10][C:11]=1[C:12]1[N:17]=[C:16]2[O:18][C:19]([CH3:30])([CH3:29])[CH2:20][CH:21]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[C:15]2=[CH:14][C:13]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1
Reactant: NN
Reactant: COC(=O)c1ccc(-c2nc3c(cc2-c2ccc(Cl)cc2)C(NC(=O)C(C)(C)C)CC(C)(C)O3)c(Cl)c1
Solvent: CO
Solvent: O
Product: CC1(C)CC(NC(=O)C(C)(C)C)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(C(=O)NN)cc3Cl)nc2O1
Temperature: 25 °C

Procedure:
A solution of the product of Step B (22 mmol) and 2.0 mL of hydrazine hydrate in 10 mL of CH3OH was refluxed for 10 h. After cooling to rt, the reaction mixture was concentrated to give the product, which was taken into the next step without further purification.
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[N+:13]([CH:16](C(OC)=O)[C:17]([O:19][CH3:20])=[O:18])([O-])=[O:14].F[P-](F)(F)(F)(F)F.C([N+]1C=CN(C)C=1)CCC>C1(C)C=CC=CC=1>[CH2:3]([C:2]1[C:16]([C:17]([O:19][CH3:20])=[O:18])=[N:13][O:14][C:1]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH2:4][CH2:5][CH3:6]
Reactant: COC(=O)C(C(=O)OC)[N+](=O)[O-]
Reactant: CCCCC#Cc1ccccc1
Agent: CCCC[n+]1ccn(C)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: Cc1ccccc1
Product: CCCCc1c(C(=O)OC)noc1-c1ccccc1
Yield: 34 %

Procedure:
A solution of hex-1-ynylbenzene (0.274 mL, 1.56 mmol), dimethyl 2-nitromalonate (0.421 mL, 3.12 mmol), 1-butyl-3-methylimidazoliumhexafluorophosphate (0.032 mL, 0.156 mmol) in toluene (6 mL) was subjected to the microwave at 170° C. for 150 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography using 5% ethyl acetate in hexane to give methyl 4-butyl-5-phenylisoxazole-3-carboxylate (0.142 g, 0.531 mmol, 34.1% yield) as a clear, colorless oil. The product was 97% pure by HPLC with a ret. time=3.11 min.−Column. CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. LC/MS M+1=260.2.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH2:9].[C:15]([O:19][C:20]([NH:22][C@@H:23]([CH:38]([CH3:40])[CH3:39])[C:24]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][C@H:27]1[C:35](O)=[O:36])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16]>N1C=CC=CC=1>[F:6][C:7]1[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[C:8]=1[NH:9][C:35]([C@@H:27]1[CH2:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:26]1[C:24](=[O:25])[C@@H:23]([NH:22][C:20](=[O:21])[O:19][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:38]([CH3:40])[CH3:39])=[O:36]
Reactant: Nc1c(F)cccc1F
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)O
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1c2ccccc2C[C@H]1C(=O)Nc1c(F)cccc1F
Temperature: 25 °C
Yield: 89.2 %

Procedure:
Phosphorus oxychloride (164 mg, 0.1 mL, 1.07 mmol, Eq: 2.16) was added dropwise to a cooled (ice-bath) solution of 2,6-difluoroaniline (264 mg, 0.22 mL, 2.04 mmol, Eq: 4.12) and (S)-1-((S)-2-(tert-butoxycarbonylamino)-3-methylbutanoyl)indoline-2-carboxylic acid (0.18 g, 497 μmol, Eq: 1.00) in pyridine (4 mL). The cooling bath was removed and the reaction was stirred at rt. After 1 h the reaction mixture was diluted with toluene (10 mL) and concentrated in vacuo. The residue was treated with water (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were washed with 0.1 M aqueous HCl (10 mL) and brine (10 mL) and then concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 12 g, 0% to 30% EtOAc in hexanes) to give tert-butyl (S)-1-((S)-2-(2,6-difluorophenylcarbamoyl)indolin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.21 g), m/z=474 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)O)cc1O
Product: CC(=O)Oc1cc(C(=O)O)ccc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 3-hydroxy-4-methylbenzoic acid (10.73 g, 70.5 mmol, Lancaster) in acetic anhydride (25 mL, 265 mmol, Aldrich) was heated at reflux for 5 hours. After cooling to room temperature, the mixture was poured into an ice-water mixture (600 mL) and stirred overnight. Solid clumps were broken up and collected by filtration. The residue was washed with water and dried in a vacuum oven to give 3-acetoxy-4-methyl-benzoic acid as a tan solid. (Yield 11.82 g). 3-Acetoxy-4-methyl-benzoic acid (1.94 g, 10 mmol) was suspended in thionyl chloride (3 mL, 40 mmol, Aldrich) and N,N-dimethyl-formamide (3 drops) and heated at reflux for 2 hours. After cooling to room temperature, the mixture was diluted with toluene (30 mL) and concentrated under reduced pressure. The resulting oil was dissolved in dichloromethane (30 mL) and added dropwise to a solution of 4-chloroaniline (1.34 g, 10.5 mmol, Aldrich) and N,N-diisopropylethylamine (1.6 g, 12.5 mmol) in dichloromethane (50 mL). After stirring for another 2 hours, the mixture was diluted with water (50 mL) and stirred for another 30 minutes. The layers were separated. The organic layer was washed with water (50 mL). Aqueous layers were back washed with dichloromethane (50 mL). Organic layers were then combined and concentrated. The residue was dissolved in mixture of tetrahydrofuran (25 mL), methanol (25 mL) and 1 N aqueous sodium hydroxide (10 mL, 10 mmol). After stirring for 16 hours, the mixture was diluted with water (100 mL) and acetic acid (5 mL) and concentrated under reduced pressure to remove most of the organic solvent. Precipitate formed was collected by filtration and washed with water, and dried to give N-(4-chloro-phenyl)-3-hydroxy-4-methyl-benzamide as off-white crystals. (Yield 2.57 g).
Reaction SMILES: O[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1.S(Cl)([Cl:25])=O.CN(C)C=O>O>[Cl:25][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[Cl:22])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1O
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)nc1Cl
Yield: 50 %

Procedure:
5.0 g of 2-hydroxy-3-nitro-6-(2-chloro-4-trifluoromethylphenoxy)pyridine prepared in Preparation Example 3, 3.55 g of thionyl chloride, and 0.2 ml of dimethylformamide were charged in a flask, and the mixture was allowed to react at 80° C. for 4 hours while stirring. After completion of the reaction, the reaction product was poured into water, followed by subjecting to purification in the same manner as in Preparation Example 2 to obtain 2.64 g of a titled compound having a melting point of 53° to 59° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.II.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][CH:9]=[C:8]([CH3:11])[CH:7]=3)[N:1]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(N)c(C(N)=O)c1
Agent: II
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc(F)cc3)[nH]c(=O)c2c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
A mixture of 2-amino-5-methylbenzamide (1.0 g, 6.7 mmol), 4-fluorobenzaldehyde (0.83 g, 6.7 mmol), iodine (2.03 g, 8.0 mmol), and potassium carbonate (1.38 g, 10 mmol) in DMF (50 mL) was stirred at 80° C. for 16 hours. The reaction mixture was cooled to 20° C. and poured into icy water. The solid was collected by filtration, washed with water, and air dried to give 2-(4-fluoro-phenyl)-6-methyl-3H-quinazolin-4-one (1.41 g, 83%). A solution of 2-(4-fluoro-phenyl)-6-methyl-3H-quinazolin-4-one (1.4 g, 5.5 mmol), NBS (0.98 g, 5.6 mmol), and benzoyl peroxide (67.0 mg, 0.276 mmol) in AcOH (150 mL) and chloroform (150 mL) was stirred at 80° C. for 5 hours with light shedding on. The reaction mixture was cooled to 20° C. and concentrated using a rotary evaporator to yield the crude bromide. A solution of the above crude bromide in DMF (20 mL) and 1,4-dioxane (100 mL) was mixed with morpholine (10 mL) and stirred at 80° C. for 4 hours. The reaction was quenched by adding water (200 mL), extracted with dichloromethane (3×100 mL), and concentrated using a rotary evaporator. The residue was further purified by column (SiO2, Hexanes/EtOAc/MeOH=4:3:1) to yield 2-4-fluoro-phenyl)-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.89 g, 48% over two steps). A solution of 2-(4-fluoro-phenyl)-6-morpholin-4-ylmethyl-3H-quinazolin-4-one (0.89 g, 2.62 mmol) in dichloromethane (100 mL) and MeOH (50 mL) was mixed with HCl in ether (8 mL, 16 mmol) and stirred for 1 hour. The reaction was concentrated using a rotary evaporator. The solid was rinsed with DCM (50 mL) and MeOH (5 mL), collected by filtration, washed with DCM-MeOH (10:1) to afford 2-(4-fluorophenyl)-6-(morpholinomethyl)quinazolin-4(3H)-one (0.82 g, 76%) as an off-white solid; MS (ES) m/z: 340 (M+1); MP 321.8-323.3° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][CH2:26][C:27]1[C:28]([F:44])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:38]#[N:39])[C:30]([Cl:33])=[CH:31][CH:32]=1.[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51](O)=[O:52].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:45][C:46]1[CH:50]=[CH:49][NH:48][C:47]=1[C:51]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([O:34][C:35]2[CH:36]=[C:37]([C:38]#[N:39])[CH:40]=[C:41]([Cl:43])[CH:42]=2)[C:28]=1[F:44])=[O:52]
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: O=C(O)c1[nH]ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[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: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]ccc3Cl)c2F)c1
Reaction time: 2 h
Yield: 26.6 %

Procedure:
HATU (0.061 g, 0.16 mmole) was added to a DMF (2 ml) solution of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-chlorobenzonitrile (0.050 g, 0.16 mmole) and 3-chloro-1H-pyrrole-2-carboxylic acid (0.023 g, 0.16 mmole) in DMF. DIPEA (0.021 g, 0.16 mmole) was added and the solution stirred for 2 h. The mixture was partitioned between EtOAc and water. The organic layer was separated and washed with 15% NaHCO3 and dried over MgSO4 and the EtOAc evaporated. The residue was purified on silica with EtOAc and Hexanes to afford the title compound (0.0187 g, 26%) as a white solid. 1H NMR (400 MHz, Acetone-d6): δ ppm 10.93 (br. s., 1H), 7.62-7.67 (m, 1H), 7.56-7.62 (m, 1H), 7.37-7.48 (m, 4H), 7.02 (t, 1H), 6.23 (t, 1H), 4.72 (d, 2H). MS: m/z 438.1 (M+1).
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH2:8]([O:15][C:16]1[CH:17]=[C:18]([CH2:23][C@H:24]([NH:29]C(OC(C)(C)C)=O)[C:25]([O:27][CH3:28])=[O:26])[CH:19]=[CH:20][C:21]=1[CH3:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[NH2:29][C@@H:24]([CH2:23][C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:17]=1)[C:25]([O:27][CH3:28])=[O:26].[C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2]
Reactant: COC(=O)[C@H](Cc1ccc(C)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)Cc1ccc(C)c(OCc2ccccc2)c1

Procedure:
To TFA (5 mL) was added to a solution of (S)-methyl 3-(3-(benzyloxy)-4-methylphenyl)-2-((tert-butoxycarbonyl)amino)propanoate (1.0 g, 2.5 mmol) in DCM (10 mL) at 0° C. with stirring. The mixture was stirred for 1 h and then concentrated to dryness. The residue was azeotroped with EtOAc (10 mL×3) to remove residual TFA and afford crude (S)-methyl 2-amino-3-(3-(benzyloxy)-4-methylphenyl)propanoate as its TFA salt.
Reaction SMILES: [N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10](=[O:33])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][C:22](=O)COC3C=CC=CC=3)[C:14]2=[O:32])O)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:38])=O>O1CCOCC1>[N+:1]([C:4]1[CH:35]=[CH:34][C:7]([CH2:8][O:9][C:10](=[O:33])[CH:11]([N:13]2[C@H:16]([S:17][C:18](=[O:20])[CH3:19])[C@@H:15]([O:21][CH3:22])[C:14]2=[O:32])[Cl:38])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)S[C@@H]1[C@@H](OC(=O)COc2ccccc2)C(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1COCCO1
Product: CO[C@H]1C(=O)N(C(Cl)C(=O)OCc2ccc([N+](=O)[O-])cc2)[C@@H]1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2 g of poly-Hunig base in 8 ml of dioxan is stirred at room temperature for 30 minutes, a solution of 962 mg of 2-[(3S,4R)-4-acetylthio-3-phenoxyacetoxy-2-oxoazetidin-1-yl]-2-hydroxyacetic acid p-nitrobenzyl ester in 10 ml of dioxan is added, then a solution of 0.38 ml of thionyl chloride in 8 ml of dioxan is added slowly. The mixture is stirred for 2 hours at room temperature, the poly-H/e,uml/u/ nig base is filtered off and the filtrate is concentrated by evaporation in vacuo. The residue is purified by chromatography over silica gel with toluene/ethyl acetate (1:1) and yields the 2-[(3S,4R)-4-acetylthio-3-methoxy-2-oxoazetidin-1-yl]-2-chloroacetic acid p-nitrobenzyl ester in crude form.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCOCC1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and morpholine in ethanol essentially as described above in Example 21. Purity by LC/MS=100%, [M+H]+=373.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][N:9]1[C:13](/[CH:14]=[C:15]2\[CH2:16][N:17]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:18][CH2:19][CH:20]\2O)=[CH:12][N:11]=[N:10]1)=[O:5])[CH3:2].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C.[C:57]([OH:60])(=[S:59])[CH3:58].[Cl-].[Na+]>CN(C)C=O>[C:57]([S:59][CH:20]1[CH2:19][CH2:18][N:17]([C:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:16]/[C:15]/1=[CH:14]\[C:13]1[N:9]([CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[N:10]=[N:11][CH:12]=1)(=[O:60])[CH3:58]
Reactant: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1O
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1nncc1/C=C1\CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCC1SC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a solution of (E)-3-({1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methylidene)-1-(triphenylmethyl)piperidin-4-ol (14.34 g) in N,N-dimethylformamide (100 ml) was added N,N-dimethylformamide dineopentyl acetal (14.90 ml). Then thioacetic acid (3.58 ml) was added to the reaction mixture under ice-cooling. The resulting mixture was stirred at room temperature for 30 minutes and then N,N-dimethylformamide dineopentyl acetal (14.90 ml) and additional thioacetic acid (3.58 ml) were supplemented, and the resulting mixture was stirred for one hour. Further N,N-dimethylformamide dineopentyl acetal (14.90 ml) and thioacetic acid (3.58 ml) were added, and the resulting mixture was stirred for 30 minutes. Still further N,N-dimethylformamide dineopentyl acetal (14.90 ml) and thioacetic acid (3.58 ml) were added, and the resulting mixture was stirred for 30 minutes. Then aqueous sodium chloride solution was added to the reaction mixture, and the product was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and the organic layer was dried over anhydrous magnesium sulfate. After evaporation of the solvent under reduced pressure, the residue was repeatedly purified for three times by silica gel chromatography using ethyl acetate and hexane (1:1 or 2:1) as the eluent to afford the less polar isomer title compound (7.45 g, yield: 47%), as a yellow foam and the more polar isomer 5-((acetylsulfanyl){1-[3-(ethoxycarbonyl)propyl]-1H-1,2,3-triazol-5-yl}methyl)-1-(triphenylmethyl)-1,2,3,6-tetrahydropyridine (5.58 g, yield: 35%) as an orange-coloured foam, respectively.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([C@H:23]1[C@@H:28]([NH2:29])[CH2:27][CH:26]=[CH:25][CH2:24]1)(=[O:22])[NH2:21]>>[C:20]([C@H:23]1[C@@H:28]([NH:29][C:17]([C:15]2[CH:16]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:12]=[N:13][CH:14]=2)=[O:19])[CH2:27][CH:26]=[CH:25][CH2:24]1)(=[O:22])[NH2:21]
Reactant: NC(=O)[C@@H]1CC=CC[C@@H]1N
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)N[C@H]3CC=CC[C@H]3C(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and ((1S,6R)-6-carbamoyl-cyclohex-3-enyl)-amine to afford the title compound. MS: m/e=381 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[C:8](=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.CSC.B.[ClH:19]>O1CCCC1>[ClH:19].[Br:1][C:2]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Oc2c(Br)cccc2NC1=O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CC1(C)CNc2cccc(Br)c2O1
Reaction time: 0.17 h
Yield: 92 %

Procedure:
8-Bromo-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one from step 2 (768.30 mg, 3.0 mmol) was dissolved in dry tetrahydrofuran (THF) and the solution was heated to reflux. 0.3 ml of 10M borane dimethyl sulfide (BH3.DMS) in THF was added drop-wise to the reaction mix, and the reaction mix was kept heated under reflux for 1 hour. A solution of 10% ethanolic HCl was then added drop-wise to the reaction mix until a white precipitate appeared, after which refluxing was continued for 10 minutes. The reaction mix was cooled, and the precipitate was removed by filtration, washed with ether, and air dried to yield 770 mg of 8-bromo-2,2-dimethyl-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (92%) as a white solid. MS: (M+H) 280.