Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24](=[O:27])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1.[CH2:29]([Mg]Cl)[CH3:30].[NH4+].[Cl-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:28])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[NH:12][CH:11]3[C:24]([CH2:29][CH3:30])([OH:27])[CH2:25][CH3:26])[C:5]2=[CH:4][CH:3]=1
Reactant: CC[Mg]Cl
Reactant: CCC(=O)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(CC)C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.1 %

Procedure:
To a solution of racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-propionylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (100 mg, 0.24 mmol) prepared in example 103 in tetrahydrofuran (3 mL) at −78° C. was added a tetrahydrofuran solution of ethylmagnesium chloride (2M, 6 mL, 12 mmol). The reaction mixture was stirred at −78° C. for 0.5 h, then slowly warmed to room temperature and stirred for 2 h. The mixture was poured into saturated aqueous NH4Cl solution, and the mixture was extracted with ethyl acetate. The organic layer was separated, dried over MgSO4, concentrated. The residue was purified by chromatography (EtOAc:MeOH=10:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(1-ethyl-1-hydroxy-propyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 100 mg, 93%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:17])=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 2 h

Procedure:
To a mixture of 2-chloro-5-nitrobenzoic acid (5.0 g, 25.0 mmol) and dichloromethane (100 ml) was added oxalyl chloride (2.7 ml, 31.0 mmol) followed by N,N-dimethylformamide (5 drops). After stirring for 2 hours, the mixture was concentrated under reduced pressure to provide 2-chloro-5-nitro-benzoyl chloride.
Reaction SMILES: [CH:1]([NH:3][C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[C:7]([OH:14])=[CH:6][CH:5]=1)=[O:2].[CH3:15][N:16]=[C:17]=[O:18]>CC(C)=O.C(N(CC)CC)C>[CH3:15][NH:16][C:17](=[O:18])[O:14][C:7]1[C:8]2[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=2[C:4]([NH:3][CH:1]=[O:2])=[CH:5][CH:6]=1
Reactant: CN=C=O
Reactant: O=CNc1ccc(O)c2c1CCCC2
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)Oc1ccc(NC=O)c2c1CCCC2
Yield: 87 %

Procedure:
4-Formamido-5,6,7,8-tetrahydro-1-naphthol was dissolved in anhydrous acetone and allowed to react with an excess of methyl isocyanate in a pressure bottle at room temperature for 2 days. Triethylamine was used as a catalyst. The solvent was stripped from the product under reduced pressure and the solid residue washed thoroughly with isopropyl ether. There was obtained 4-formamido-5,6,7,8-tetrahydro-1-naphthyl N-methylcarbamate, m.p. 165°-166°, in 87% yield.
Reaction SMILES: [CH2:1]([NH:8][C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:44](OC(=O)C)(=[O:46])[CH3:45].C(N(CC)CC)C>ClC(Cl)C>[CH2:1]([N:8]([C:9]1([CH2:38][CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([OH:19])=[C:11]([C:20]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[CH:29][C:23]=3[S:22](=[O:36])(=[O:35])[N:21]=2)[C:10]1=[O:37])[C:44](=[O:46])[CH3:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)CCC1(NCc2ccccc2)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)OC(C)=O
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N(Cc1ccccc1)C1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 75 °C
Yield: 23.5 %

Procedure:
To a solution of the product of Example 74G (20 mg, 0.032 mmol) in dichloroethane (0.5 mL), acetic anhydride (5 μL, 0.048 mmol) and triethylamine (13 μL, 0.096 mmol) were added. The reaction solution was heated at 75° C. for 96 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting residue was dissolved in methanol (0.5 mL) and treated with excess of K2CO3 for 30 min. The mixture was filtered and the filtrate was concentrated in vacuo. The resulting residue was taken up in ethyl acetate (1 mL), washed with aqueous 1 N HCl, dried (Na2SO4), and concentrated in vacuo. Column chromatography on silica (1%→2%→3% methanol/dichloromethane) afforded the title compound as a brown solid (5 mg, 24%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.25-0.42 (m, 1H), 0.47 (s, 9H), 0.73-0.96 (m, 1H), 1.68-2.05 (m, 5H), 3.02 (s, 3H), 5.06 (d, J=18.02 Hz, 1H), 5.24-5.42 (m, 1H), 7.27-7.61 (m, 10H), 7.83 (d, J=6.99 Hz, 1H), 10.01 (s, 1H); MS m/z 665.2 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21](O)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:47][CH:48]1[CH2:53][CH2:52][CH2:51][NH:50][CH2:49]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:47][CH:48]1[CH2:53][CH2:52][CH2:51][N:50]([C:21]([C:16]2[NH:17][C:18]3[C:14]([CH:15]=2)=[CH:13][C:12]([C:10]([N:7]2[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]2)=[O:11])=[CH:20][CH:19]=3)=[O:22])[CH2:49]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: FC1CCCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCCC(F)C4)cc3c2)CC1

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 3-fluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide to give the desired product after purification by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/formic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.CN(C=O)C.C(N=C=NCCCN(C)C)C.[NH2:35][C:36]1[S:37][C:38]2[CH:44]=[C:43]([F:45])[CH:42]=[CH:41][C:39]=2[N:40]=1>>[F:45][C:43]1[CH:42]=[CH:41][C:39]2[N:40]=[C:36]([NH:35][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[N:18][C:10]=3[NH:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[S:37][C:38]=2[CH:44]=1
Reactant: O=C(O)c1cccnc1Nc1ccc(Cl)cc1Cl
Reactant: Nc1nc2ccc(F)cc2s1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1nc2ccc(F)cc2s1)c1cccnc1Nc1ccc(Cl)cc1Cl
Temperature: 27 °C
Reaction time: 9 h

Procedure:
Compound 13 (185 mg, 1 mmol) and 2,4-dichloro aniline (18, 92 mg, 1 mmol) was taken in ethylene glycol and refluxed at 160° C. for 5 h. Then the reaction mixture was cooled and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain Ethyl. 2-(2,4-dichloro anilino) nicotinate (25) as pure product. Ethyl 2-(2,4-dichloro anilino) nicotinate (25, 311 mg, 1 mmol) were refluxed with 2N NaOH in ethanol for 2 h. The reaction mixture was cooled and left acidified with 2N HCl white solids obtained, filtered and washed with water to give pure compound of 2-(2,4-dichlorophenylamino)nicotinic acid (32). To a stirred solution of 2-(2,4-dichlorophenylamino)nicotinic acid (32, 283 mg, 1 mmol) in dry DMF (10 mL) hydroxy benzotriazole HOBt (1.2 mmol) were added at 0° C. After 10 min 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDCI) (1.2 mmol) was added and finally 2-amino 6-fluoro benzothiazole (36, 117 mg, 0.7 mmol) were added Then the resulting mixture was stirred at room temperature (27° C.) for 8-10 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (10) was purified by column chromatography employing EtOAc/hexane as an eluent.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH2:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1)[CH:13]([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].CC(CC)=O>C(OCC)(=O)C>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[C:3]=2[CH3:11])=[CH:22][CH:23]=1)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)Cc1ccc(CBr)cc1
Reactant: Cc1c(O)ccc(C=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: Cc1c(C=O)ccc(OCc2ccc(CC(C)C)cc2)c1C
Yield: 88.2 %

Procedure:
A mixture of 4-hydroxy-2,3-dimethyl-benzaldehyde (220 mg), 4-isobutylbenzyl bromide (341 mg), potassium carbonate (1.38 g) and ethyl methyl ketone (10 ml) was refluxed for 6 hrs. After cooling, the reaction mixture was diluted with ethyl acetate, the solution was washed with dil hydrochloric acid, water, successively, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane:EtOAc=10:1) to give the title compound (383 mg) having the following physical data:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.Br[C:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][C:21]([Br:27])=[CH:20][N:19]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>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.CCO>[Br:27][C:21]1[CH:22]=[C:23]([N+:24]([O-:26])=[O:25])[C:18]([C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=2)=[N:19][CH:20]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: O=[N+]([O-])c1cc(Br)cnc1-c1ccc(O)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (300 mg, 1.36 mmol), 2,5-dibromo-3-nitropyridine (383 mg, 1.36 mmol), tetrakis(triphenylphosphine)palladium (31 mg, 0.027 mmol), Na2CO3 (4.3 mL, 2 M aqueous), 4.3 mL toluene, and 2.1 mL EtOH was vigorously stirred at 55° C. for 2 h. After cooling to rt, the volatiles were removed under reduced pressure and the residue was purified with silica chromatography (EtOAc in hexane, 5% to 35%) to afford 4-(5-bromo-3-nitropyridin-2-yl)phenol as a yellow wax (285 mg, 71%). MS (ESI) m/z [M+H]+295, 297.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15](N)=[O:16])=[CH:13][CH:12]=1.S(=O)(=O)(O)O>CCOCC>[Cl:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:16])=[CH:13][CH:12]=1
Reactant: ClCc1ccccc1
Reactant: NC(=O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Product: O=C(Cc1ccccc1)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
50.6 g of dry benzyl chloride in 200 ml of dry ether was treated with 10 g of magnesium. When the reaction was complete, 15.6 g of 4-chlorobenzamide was added in portions with stirring. When the addition was complete the mixture was stirred and refluxed for 65 hours. The cooled mixture then was poured onto 400 g of ice containing 40 g of concentrated sulphuric acid. Several extractions with ether yielded the crude product as a white solid. Recrystallization from methylated spirit gave white crystals of 4-chlorodeoxybenzoin, 1A, mp: 106°-106.5° C.
Reaction SMILES: C(Cl)(=O)[C:2](Cl)=[O:3].CN(C)C=O.[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[N:35]([CH3:37])[CH:34]=[CH:33]4)[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:22])[CH3:21]>ClCCl>[Cl:12][C:13]1[CH:14]=[C:15]([C:23]2[O:27][N:26]=[C:25]([C:28]3[CH:29]=[CH:30][CH:31]=[C:32]4[C:36]=3[N:35]([CH3:37])[CH:34]=[C:33]4[CH:2]=[O:3])[N:24]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH:20]([CH3:21])[CH3:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4ccn(C)c34)no2)cc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of oxalyl chloride (2.1 mL) in dichloromethane (125 mL) at 0° C. was added a solution of N,N-dimethylformamide (2.32 mL) in Dichloromethane (DCM) (75 mL) dropwise during 30 mins. The reaction mixture was stirred at 0° C. for another 15 minutes. A solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole (D58) (7.4 g) in Dichloromethane (100 mL) was added in one portion. the mixture was stirred and warmed to room temperature slowly. After stirred at room temperature for 5 hours, dichloromethane was evaporated off. Ethyl acetate (300 mL), water (100 mL) and concentrated HCl solution (5 mL) was added to the residue. The mixture was stirred for 30 minutes and KOH was added to adjust pH value to about 8. The organic layer was separated, washed with water and brine, then dried over MgSO4. Filtration and evaporation afforded the product 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (5.2 g). δH (CDCl3, 400 MHz): 1.47 (6H, d), 3.87 (3H, s), 4.71-4.77 (1H, m), 7.09 (1H, d), 7.44 (1H, t), 7.68 (1H, dd), 7.72 (1H, s), 7.89 (1H, dd), 8.26 (1H, d), 8.56 (1H, dd), 10.06 (1H, s). MS (ES): C21H18ClN3O3 requires 395. found 396.1 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13])=[O:6].[Br:19][CH2:20][C:21](Br)=[O:22].C(OCC)C>C(OCC)(=O)C>[CH3:1][N:2]([C:21](=[O:22])[CH2:20][Br:19])[C:3]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:4]=1[C:5](=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:13]
Reactant: O=C(Br)CBr
Reactant: CNc1ccc(Cl)cc1C(=O)c1ccccc1Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 56 g of 2-methylamino-2', 5-dichlorobenzophenone in 400 cc of ethyl acetate there are added an equal volume of ice and then 23 cc of bromoacetylbromide. After stirring overnight at room temperature, 300 cc of ethyl ether are added. The solvent layer is decanted, washed with 2 N caustic soda, and then washed with water until neutral. It is then dried over sodium sulfate, filtered, and evaporated to dryness. The residue is treated with petroleum ether and then recrystallized from ethyl acetate. In this way there are obtained 65 g of crystals; yield: 81%.
Reaction SMILES: [F:1][CH:2]([F:31])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:30]=[CH:29][C:22]4[N:23](CO)[C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)=[CH:13][N:12]=2)=[CH:6][CH:5]=1>CO.O>[F:31][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][O:18][C:19]3[CH:30]=[CH:29][C:22]4[NH:23][C:24](=[O:26])[O:25][C:21]=4[CH:20]=3)=[CH:13][N:12]=2)=[CH:8][CH:9]=1
Reactant: O=c1oc2cc(OCc3cnc(Nc4ccc(OC(F)F)cc4)nc3)ccc2n1CO
Solvent: O
Solvent: CO
Product: O=c1[nH]c2ccc(OCc3cnc(Nc4ccc(OC(F)F)cc4)nc3)cc2o1
Yield: 86.5 %

Procedure:
6-((2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)-3-(hydroxymethyl)benzo[d]oxazol-2(3H)-one (0.011 g, 0.026 mmol) was dissolved in a mixture of methanol (2 mL) and water (2 mL). The reaction mixture was sonicated for 15 min. Solvent was concentrated and the residue was lyophilized to give 6-((2-((4-(difluoromethoxy)phenyl)amino)pyrimidin-5-yl)methoxy)benzo[d]oxazol-2(3H)-one as a white solid (0.009 g, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.99 (s, 2H) 6.82 (dd, J=8.53, 2.26 Hz, 1H) 6.94-7.32 (m, 5H) 7.79 (s, 2H) 8.59 (br. s., 2H) 9.84 (s, 1H) 11.42-11.50 (m, 1H). LCMS: R.T.=0.84 min; [M+H]+=401.0.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][CH:9]([CH:14]2[CH2:16][O:15]2)[C:10]([O:12][CH3:13])=[O:11])=[O:7])=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C>CO>[F:23][C:24]1[CH:25]=[C:26]([S:30][CH2:16][CH:14]([OH:15])[CH:9]([NH:8][C:6](=[O:7])[C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][C:4]=2[C:19]([F:22])([F:21])[F:20])[C:10]([O:12][CH3:13])=[O:11])[CH:27]=[CH:28][CH:29]=1
Reactant: Fc1cccc(S)c1
Reactant: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C1CO1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C(NC(=O)c1ccc(F)cc1C(F)(F)F)C(O)CSc1cccc(F)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
480 mg (1.5 mmol) of methyl (4-fluoro-2-trifluoromethylbenzoylamino)oxiranylacetate were dissolved in methanol, and 215 mg (1.5 mmol) of 3-fluorothiophenol and 280 mg (3.8 mmol) of triethylamine were then added. The mixture was then stirred at RT for 15 h, and the solvent was then removed. This gave 760 mg of diasteromerically pure crude product which was used for the next step without further purification.
Reaction SMILES: Cl[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[C:9]1([S:15][N:2]2[C:6](=[O:7])[CH2:5][CH2:4][C:3]2=[O:8])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(=O)N1Sc1ccccc1
Reaction time: 1 h

Procedure:
To a partial solution of N-chlorosuccinimide (3.34 g, 25 mmol) in dry methylene chloride (30 mL), cooled in an ice bath and under an inert atmosphere, was added thiophenol (2.05 mL, 20 mmol) via syringe. After stirring for 1 hour, additional N-chlorosuccinimide (0.40 g, 3 mmol) was added. After 2.5 hours total, triethylamine (3.9 mL, 28 mmol) was added dropwise. Within 15 minutes the reaction mixture was diluted with methylene chloride, the solvent washed with dilute aq. HCl and the solvent then dried (Na2SO4), filtered through a pad of charcoal and evaporated. The residue was triturated with diethyl ether and the product collected by filtration to yield the title compound mp 115°-116° C. [lit. mp 115°-116° C., J. Org. Chem., 34, 51 (1969)]. This material was used as is.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([O:7]C(=O)C2C=CC=CC=2)[C@@H:5]([CH2:16][O:17]C(=O)C2C=CC=CC=2)[O:4][C@H:3]1[N:26]1[CH:33]=[C:32]([I:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28].[OH-].[Na+]>CO.O>[F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:16][OH:17])[O:4][C@@H:3]1[N:26]1[CH:33]=[C:32]([I:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28]
Reactant: O=C(OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=c1[nH]c(=O)n([C@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-5-iodouracil (4.7 g, 0.0081 mole) from Procedure 6 in 60 mL 50% MeOH/H2O is stirred at 25° C. maintained at pH 10.5 with 3N NaOH until complete dissolution of solid occurs. Progress of the hydrolysis is followed by HPLC (mobile phase=70% H2O/30% MeOH, flow rate=1 mL/min., wave length=282 nm UV detection, column=Whatman 10 ODS-3 reverse-phase 25 cm., injection volume=20 μl at ~0.5 mg/l concentration, α-IX=6.86 min., β-IX=7.98 min., and 5-iodouracil=4.5 min.). When the reaction is complete (16 hr.), 25 mL of water is added and the mixture is concentrated to approximately 30 mL. The clear aqueous concentrate is adjusted to pH 6.5 to 7.0 with 3N HCl. A solid forms, the mixture is stirred at 25° C. for 2 hrs., and at 0° to 5° C. for 5 hrs. The solid is collected by filtration, washed with 30 mL cold H2O and dried at 50° C./5 mm. The yield of product is 2.7 g (90%), mp 223°-226° [360 MHz NMR (CD3OD) 8.28, d, 1H; 6.16, dd, 1H; 5.04, m, 1H; 4.32, m, 1H; 3.95-3.7, m, 3H. Elemental analysis calculated: %C 29.05, %H 2.71, %N 7.53; Found: %C 28.86, %H 2.64, %N 7.50; IR (KBr) NH, OH 3400, 3200 cm-1 ; CO--NH--CO 1725, 1655 cm-1, C--O 1050 cm-1.]
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].[CH2:20](I)[CH3:21].C([O-])([O-])=O.[K+].[K+]>CC(O)C.Cl>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:20][CH3:21])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: CCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (0.75 g) is alkylated using ethyl iodide (0.5 ml; 5.7 mmol) and K2CO3 (1.6 g; 11.6 mmol) at 55° C. for 7 h. After aqueous work-up the crude alkylated acetamide (0.8 g; 2.74 mmol) is de-acetylated under reflux conditions in 2-propanol (3 ml) and hydrochloric acid (5 ml). After aqueous work-up the crude 5-amino-1-ethyl-3,3-dimethyl-6-nitro-1,3-dihydro-indol-2-one (0.6 g) is used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH2:21][CH3:22].[CH:23]([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][CH:26]=1)=O.[BH4-].[Na+]>C1COCC1.CO>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][CH2:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][CH2:23][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:29][CH:30]=3)[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COC(=O)Cc1ccc(C=O)cc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reaction time: 1 h

Procedure:
The product from step (vii) (55 mg) was combined with methyl (4-formylphenyl)acetate (0.0329 g) and stirred in THF (15 mL) for 16 h. Sodium borohydride (0.015 g) was added followed by MeOH (3 drops) and the reaction mixture was stirred for 1 h. The reaction mixture was diluted with MeOH and purified via RPHPLC to give the title compound. Yield 17 mg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1cccc(O)c1)OCc1ccccc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 2-(3-hydroxyphenyl)acetate (1.39 g, 5.74 mmol), ethyl 4-bromobutanoate (1.23 g, 6.3 mmol), anhydrous K2CO3 (1.98 g, 14.4 mmol) and anhydrous DMF (10 mL) was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 25% to 50% v/v) to yield ethyl 4-(3-(2-(benzyloxy)-2-oxoethyl)phenoxy)butanoate (2.05 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.17 (t, J=7.2 Hz, 3H), 1.96 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), δ 3.70 (s, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.07 (q, J=7.2 Hz, 2H), 5.11 (s, 2H), 6.83 (m, 3H), 7.20 (t, 1H), 7.20 (m, 5H).