Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[NH:10][C:9](=[O:11])[CH:8]=[CH:7][CH:6]=1.Br[CH:31]([CH3:36])[C:32]([O:34][CH3:35])=[O:33].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:15]=[C:14]([F:16])[C:13]([N:17]2[C:22](=[O:23])[CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[N:19]([CH3:28])[C:18]2=[O:29])=[CH:12][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([O:11][CH:31]([C:32]([O:34][CH3:35])=[O:33])[CH3:36])[N:10]=1
Reactant: COC(=O)C(C)Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(=O)[nH]3)c(Cl)cc2F)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2Cl)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 120.1 %

Procedure:
To a mixture of 50 mg of 6-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridone, 21 mg of methyl 2-bromopropionate and 1 ml of N,N-dimethylformamide was added 21 mg of potassium carbonate, and the mixture was stirred for 1 hour at 50° C. The solution was cooled to room temperature, poured into water, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 72 mg of 2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-6-{1-(methoxycarbonyl)ethoxy}pyridine [present compound 2-42].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[O:24]1[CH2:29][CH2:28][CH:27](O)[CH2:26][CH2:25]1>>[CH3:22][C:7]1([CH3:21])[C:8]2[NH:9][C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=3)[C:16]=2[C:17](=[O:18])[C:5]2[CH:4]=[CH:3][C:2]([O:1][CH:27]3[CH2:28][CH2:29][O:24][CH2:25][CH2:26]3)=[CH:23][C:6]1=2
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: OC1CCOCC1
Product: CC1(C)c2cc(OC3CCOCC3)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21

Procedure:
Under the same conditions as the method for synthesizing Compound A7-1, the title compound was prepared from Compound A6 and tetrahydropyran-4-ol.
Reaction SMILES: [CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:12]=2)[C:7]([CH:22]=[CH:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:6]1.[H][H]>C(O)C.[Pd]>[CH3:1][N:2]([CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:3](=[O:29])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:12]=2)[C:7]([CH2:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[CH:6]1
Reactant: CN(CCc1ccccc1)C(=O)Cn1cc(C=Cc2nnn[nH]2)c2cc(OCc3ccccc3)ccc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(CCc1ccccc1)C(=O)Cn1cc(CCc2nnn[nH]2)c2cc(OCc3ccccc3)ccc21

Procedure:
To a solution 0.2 g (0.42 mmoles) of N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-ylvinyl)indol-1-yl]acetamide in 30 ml of ethanol is added 0.08 g of 10% palladium on carbon and the mixture is shaken under 30 psi of hydrogen for 4 hours. The mixture is filtered and the filtrate concentrated in vacuo. The residue is crystallized from methylene chloride to give N-methyl-N-phenethyl-2-[5-benzyloxy-3-(2-tetrazol-5-yl)ethylindol-1-yl]acetamide.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]1[C:9]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=2[F:30])=[C:10]([C:15]([N:17]2[CH2:20][C:19](=O)[CH2:18]2)=[O:16])[CH:11]=[CH:12][C:13]=1[F:14].C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[F:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([C:15]([N:17]2[CH2:20][C:19](=[CH2:1])[CH2:18]2)=[O:16])[C:9]=1[NH:22][C:23]1[CH:28]=[CH:27][C:26]([I:29])=[CH:25][C:24]=1[F:30]
Reactant: O=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C1CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Reaction time: 15 h
Yield: 21.2 %

Procedure:
Methyl triphenylphosphonium bromide (508 mg, 1.42 mmol) was treated with potassium tert-butoxide (159 mg, 1.42 mmol) in tetrahydrofuran (5 mL) at 0° C. for 10 minutes. 1-({3,4-Difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)azetidin-3-one (270 mg, 0.605 mmol), prepared using procedures similar to those described in Example 6, was dissolved in tetrahydrofuran (2 mL) and was added to the mixture. The mixture was stirred at ambient for 15 h and then the mixture was filtered and the filtrate was partitioned between ethyl acetate and water. The aqueous portion was extracted with ethyl acetate. The combined organic portion was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Column chromatography (silica gel, 20% ethyl acetate in hexanes) gave 2,3-difluoro-N-(2-fluoro-4-iodophenyl)-6-[(3-methylideneazetidin-1-yl)carbonyl]aniline (57 mg, 0.128 mmol, 21% yield): 1H NMR (400 MHz, CDCl3): 8.56 (br s, 1H), 7.39 (dd, 1H), 7.35-7.30 (m, 1H), 7.18-7.12 (m, 1H), 6.86-6.76 (m, 1H), 6.62 (ddd, 1H), 5.14-5.00 (br, 2H), 4.74 (br d, 4H); MS (EI) for C17H2F3IN2O: 445 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][NH:17][CH3:18])[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16][N:17]([CH3:18])[S:34]([CH3:33])(=[O:36])=[O:35])[O:14][CH2:13][CH2:12][N:11]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: CNCC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CC1OCCN(C(=O)OC(C)(C)C)CC1c1ccc(Cl)c(Cl)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6SR,7RS)-6-(3,4-dichlorophenyl)-7-[(methylamino)methyl]-1,4-oxazepane-4-carboxylate (150 mg) in THF (5 mL) were successively added dropwise triethylamine (0.070 mL) and methanesulfonyl chloride (0.036 mL), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (133 mg).
Reaction SMILES: C(OC(=O)C)(=O)C.[N:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].[CH:16]([C:18]1[CH:23]=[CH:22][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][CH:19]=1)=O.[OH-].[Na+]>O>[CH3:14][C:13]1[N:8]=[C:9](/[CH:15]=[CH:16]/[C:18]2[CH:19]=[CH:20][C:21]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:23]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Cc1cccc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(/C=C/c2cccc(C)n2)cc1
Yield: 65.1 %

Procedure:
An acetic anhydride solution (100 mL) of 2,6-lutidine (65 g) and methyl 4-formylbenzenecarboxylate (20 g) was stirred overnight at 180° C. The reaction solution was poured into water with ice, and aqueous 5 N sodium hydroxide solution was added thereto until it became alkaline. The resulting mixture was extracted with ethyl acetate, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated off, and the resulting residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1 to 4/1) to obtain the entitled compound (20.1 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:24][CH2:25][CH2:26]Br.O>C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][CH2:26][CH2:25][Br:24])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(OCCBr)cc1
Reaction time: 4 h

Procedure:
A mixture of 8.6 g (39 mmol) of crude N-tertiary butoxycarbonyltyramine, 27.6 g (200 mmol) of potassium carbonate and 73.3 g (390 mmol) of 1,2-dibromoethane is heated at boiling for 4 hours while stirring. The reaction mixture is cooled, and then 200 ml of water and 400 ml of ethyl acetate are added and the organic phase is separated off. After concentration by evaporation under reduced pressure, a crystalline residue remains which, after recrystallisation from 2-propanol, yields N-tertiary butoxycarbonyl-2-[p-(2-bromoethoxy)-phenyl]-ethylamine, which has a melting point of 70°-72°.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21]C)[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH2:8]C.CC1C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=NC(C)=CN=1>>[Br:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2[OH:20])=[N:6][C:7]=1[CH3:8]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Agent: Cc1cnc(C)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Product: Cc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(C)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1R,2S)-1-[(3,6-dimethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol and making non-critical variations provided the title compound as a oil: 1H NMR (300 MHz, CDCl3) δ) 7.32–7.28, 5.58, 4.92, 4.77, 3.28, 3.07, 2.51, 2.38, 2.28; HRMS (FAB) calcd for C15H16BrN3O+H 334.0555, found 334.0557. Anal. Calcd for C15H16BrN3O: C, 53.91; H, 4.83; N, 12.57. Found: C, 53.55; H, 4.88; N, 12.27.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[NH:5][C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:1][C:2]1[S:3][C:4]2[N:5]([CH3:18])[C:6](=[O:15])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[N:14]=1
Reactant: Cc1nc2c([nH]c(=O)c3ccccc32)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc2c3ccccc3c(=O)n(C)c2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 6.48 g. (0.030 mole) of 2-methyl-thiazolo[5,4-c]isoquinoline-5(4H)-one in 64 ml of dimethylformamide was added with 1.45 g of a 50% (by weight) suspension of sodium hydride in mineral oil (0.030 mole of sodium hydride). The resulting mixture was kept at 60° C. for 2 hours and, after cooling to room temperature, was added with 2.37 ml (0.038 mole) of methyl iodide and heated for 1 hour at 60° C. After evaporating the solvent, the residue was taken up with water and the obtained solid was collected, washed with water, dried and finally crystallized from methylene chloride/methanol. Yield 4.5 (65%) of the title compound. M.p. 174-176. The compound is the N-isomer.
Reaction SMILES: Cl.[OH:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[OH-].[K+].[C:14](=S)=[S:15]>C(O)C>[CH3:11][O:10][C:8]1[CH:7]=[CH:6][C:4]2[N:5]=[C:14]([SH:15])[O:2][C:3]=2[CH:9]=1
Reactant: S=C=S
Reactant: COc1ccc(N)c(O)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2nc(S)oc2c1
Reaction time: 24 h

Procedure:
A 50 mg portion of 2-hydroxy-4-methoxyaniline hydrochloride dissolved in 15 ml of ethanol was mixed with 16 mg of potassium hydroxide. After 10 minutes of reaction, to this was added 50 ml of carbon disulfide to carry out 24 hours of heating under reflux. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 100 ml of dichloromethane, washed with water, dehydrated with magnesium sulfate and then concentrated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography (dichloromethane:methanol=30:1) to obtain 46 mg of 6-methoxy-2-mercaptobenzoxazole.
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]3([C:29]4[C:20](=[CH:21][C:22]5[O:27][CH2:26][CH2:25][O:24][C:23]=5[CH:28]=4)[O:19][CH2:18]3)[C:10]2=[O:30])=[N:4][CH:5]=[CH:6][CH:7]=1.[C-:31]#[N:32].[Na+].O>CN1CCCC1=O.O.O.O.O.O.O.[Ni](Cl)Cl>[O:30]=[C:10]1[CH:9]([CH2:8][C:3]2[C:2]([C:31]#[N:32])=[CH:7][CH:6]=[CH:5][N:4]=2)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]21[C:29]1[C:20](=[CH:21][C:22]3[O:27][CH2:26][CH2:25][O:24][C:23]=3[CH:28]=1)[O:19][CH2:18]2
Reactant: [C-]#N
Reactant: O=C1C(Cc2ncccc2Br)c2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: Cl[Ni]Cl
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1cccnc1CC1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21
Temperature: 200 °C
Yield: 289 %

Procedure:
3′-[(3-Bromopyridin-2-yl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-2′(3′H)-one (0.233 g, 0.500 mmol), nickel (II) chloride hexahydrate (0.113 g, 0.500 mmol), and sodium cyanide (0.050 g, 1.0 mmol) were combined in 1-methyl-2-pyrrolidone (1 mL) and heated at 200° C. for 30 min under microwave irradiation. The reaction mixture was allowed to cool to ambient temperature, poured into water (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (3×20 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography, and eluted with a 50% to 75% gradient of ethyl acetate in hexanes, to afford 2-[(2′-oxo-2,2′,3,3′-tetrahydrospiro[furo[2,3-g][1,4]benzodioxine-8,1′-inden]-3′-yl)methyl]pyridine-3-carbonitrile (0.593 g, 29%) as a colorless solid: mp 230-233° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.71 (dd, J=4.8, 1.4 Hz, 1H), 8.38 (dd, J=7.9, 1.5 Hz, 1H), 7.56 (dd, J=7.8, 4.9 Hz, 1H), 7.27-7.15 (m, 2H), 7.04 (d, J=7.5 Hz, 1H), 6.98 (d, J=7.9 Hz, 1H), 6.50 (s, 1H), 6.38 (s, 1H), 5.30 (s, 2H), 4.74 (ABq, 2H), 4.19-4.11 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 177.3, 158.2, 155.0, 153.1, 144.6, 143.1, 142.1, 138.2, 132.4, 129.1, 124.0, 123.4, 121.9, 116.5, 112.2, 109.8, 108.0, 99.1, 79.8, 64.7, 64.1, 57.7, 44.1; MS (ES+) m/z 412.0 (M+1).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[O:21][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([OH:26])[CH2:24][N:25]=1>ClCCCl>[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[C:20]1[O:21][CH:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]([O:26][C:8](=[O:9])[NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:24][N:25]=1
Reactant: OC1CN=C(c2ccc3ccccc3c2)OC1c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCCl
Product: O=C(Nc1ccccc1)OC1CN=C(c2ccc3ccccc3c2)OC1c1ccccc1
Temperature: 80 °C
Yield: 36.3 %

Procedure:
Phenyl isocyanate (0.7 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(2-naphthyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (1.8 g) in 1,2-dichloroethane (21 cc). The solution obtained is heated to 80° C. for 4 hours and then concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is purified by chromatography on silica (0.063-0.2 mm; 200 g) contained in a column 2.5 cm in diameter, collecting 20-cc fractions. The fractions 12 to 20, eluted with dichloromethane, are concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in acetonitrile, (5RS, 6SR)-2-(2-naphthyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (0.9 g), m.p. 163° C., is obtained.
Reaction SMILES: C([O-])(=O)C.[K+].[CH2:6]([N:8]1[C:12]([CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])=[CH:11][C:10]([C:26]#[N:27])=[N:9]1)[CH3:7].[Br:28]Br.S([O-])(O)=O.[Na+]>C(O)(=O)C.ClCCl>[Br:28][C:11]1[C:10]([C:26]#[N:27])=[N:9][N:8]([CH2:6][CH3:7])[C:12]=1[CH2:13][CH2:14][N:15]1[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]2[C:19]1=[O:20]
Reactant: CCn1nc(C#N)cc1CCN1C(=O)c2ccccc2C1=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCn1nc(C#N)c(Br)c1CCN1C(=O)c2ccccc2C1=O
Reaction time: 14 h

Procedure:
Potassium acetate (3.9 g, 39.5 mmol) was added to a solution of 1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile (7.73 g, 26.3 mmol) in acetic acid (37.5 mL) and dichloromethane (75 mL). Bromine (5.88 g, 36.8 mmol) was added, and the reaction was stirred for 14 hours. A precipitate was present. Saturated aqueous sodium hydrogensulfite was added, and the dichloromethane was removed under reduced pressure. Water (500 mL) was added with stirring, and the resulting solid was isolated by filtration, washed with water, and dried on the filter funnel to provide 4-bromo-1-ethyl-5-(2-phthalimidoethyl)-1H-pyrazole-3-carbonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[NH:12][CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Li+].I[CH3:42]>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([Cl:37])[CH:35]=2)[C:10]2([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)[CH2:14][C:13](=[O:23])[N:12]([CH3:42])[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:9]1=[O:38])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccccc1C1N(C)C(=O)CC(c2cccc(Cl)c2)C12C(=O)N(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (0.25 g, 0.45 mmol) in N,N-dimethyl-formamide (20 mL) at 0° C. was added LiH (90 mg, 11.2 mmol) (Aldrich), followed by the addition of iodomethane (0.39 g, 2.74 mmol). The reaction mixture was warmed up to room temperature and stirred at room temperature for 3 h. The mixture was diluted with ethyl acetate, and then washed with saturated NH4Cl solution. The aqueous layer was extracted with ethyl acetate and the combined organic layer was dried over MgSO4. The solvent was removed and the residue was purified by chromatography (EtOAc:hexanes=1:2) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2,3-dihydro-1′-methyl-2′-(2-methylphenyl)-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid tert-butyl ester (Yield 0.20 g, 77%).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].OC(CCCCCCCCCC)C(O)=O.OC(CCCCCCCCC)CC(O)=O>>[C:13]([OH:15])(=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH3:2]
Reactant: O=C(O)CCCCCCCCCCCO
Agent: CCCCCCCCCC(O)CC(=O)O
Agent: CCCCCCCCCCC(O)C(=O)O
Product: CCCCCCCCCCCC(=O)O

Procedure:
A product peak appeared in the presence of the peroxygenase. The elution time of the product was slightly shifted compared to 12-Hydroxydodecanoic acid, which is an iso-form of 2-hydroxy lauric acid and 3-hydroxy lauric acid. Hence, the elution time was in accordance to the expected product hydroxylated in the 2 or 3 position.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:11])=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[C:3](=[O:11])[N:4]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: COc1ccc(CBr)cc1
Product: COc1ccc(Cn2cc([N+](=O)[O-])cc(Cl)c2=O)cc1

Procedure:
The title compound was prepared in analogy to the procedure described for step W2 but using 3-chloro-2-hydroxy-5-nitropyridine and 4-methoxybenzyl bromide. The reaction was quenched with a saturated aqueous solution of sodium bicarbonate. The residue was purified by trituration in EtOAc. tR: 0.98 min (LC-MS 4); ESI-MS: 295.2 [M+H]+ (LC-MS 4).
Reaction SMILES: C([O:8][CH:9]1[CH2:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[OH:8][CH:9]1[CH2:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:10]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1(C(=O)OCC)CC(O)C1
Reaction time: 12 h

Procedure:
To a solution of diethyl 3-(benzyloxy)cyclobutane-1,1-dicarboxylate (158) (1.43 g, 4.7 mmol) in EtOH (18 mL) was added 10% palladium on carbon (143 mg) and the mixture was hydrogenated with a H2 balloon for 12 hours at room temperature. The catalyst was removed by filtration using celite, washed with ethyl acetate and EtOH and the solvent was removed under reduced pressure. The crude product was purified via column chromatography using hexanes/ethyl acetate as eluent to yield diethyl 3-hydroxycyclobutane-1,1-dicarboxylate (159). 1H NMR (400 MHz, CD2Cl2) δ 4.4-4.32 (m, 1H), 4.21 (qd, J=7.2, 2.0 Hz, 4H), 2.89-2.84 (m, 2H), 2.46-2.41 (m, 2H), 2.20 (d, J=6.4 Hz, 1H), 1.27 (t, J=7.2 Hz, 6H). MS m/z 217.1 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[F:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].CO>C1COCC1.C(OCC)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:25](=[O:26])[C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([F:21])[CH:23]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)c4cccc(F)c4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
To a suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2 mmol) in THF (30 ml) was added 3-Fluorobenzoyl chloride (0.49 ml, 4 mmol). The mixture was heated to reflux for 18 hours. The reaction was cooled to room temperature, methanol (2 ml) was added, and the mixture stirred for 1 hour. The solvent was evaporated in vacuo leaving a solid which was slurried in diethyl ether (20 ml) and filtered to give 0.69 g (96%) of product as an off-white solid: mp 260-262° C.; 1H NMR (DMSO-d6) d 11.00 (s, 1H), 10.39 (s, 1H), 8.53 (d, J=8.3 Hz, 1H), 7.94-7.50 (m, 6H), 5.15 (dd, J=5.6 and 12.7 Hz, 1H), 2.97-2.83 (m, 1H), 2.66-2.49 (m, 2H), 2.14-2.06 (m, 1H); 13C NMR (DMSO-d6) d 172.36, 169.36, 167.66, 166.39, 163.62, 136.03, 131.31, 131.12, 130.99, 126.60, 123.19, 123.15, 119.44, 119.11, 118.89, 118.42, 114.31, 113.94, 48.91, 30.77, 21.83; Anal. Calcd. For C20H14FN3O5: C, 60.76; H, 3.57; N, 10.63. Found: C, 60.88; H, 3.38; N, 10.51.