Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10][NH2:11].CN([CH:15]=[N:16][C:17](=[O:19])[CH3:18])C>C1COCC1.CC(O)=O>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[NH:10]/[N:11]=[CH:15]/[NH:16][C:17](=[O:19])[CH3:18]
Reactant: NNc1cc(F)ccc1Br
Reactant: CC(=O)N=CN(C)C
Agent: Cl
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)N/C=N/Nc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72.2 %

Procedure:
Alternatively, to a mixture of (2-bromo-5-fluoro-phenyl)-hydrazine hydrochloride (5.9 g, 28.8 mmol) and N-((dimethylamino)methylene)acetamide (3.30 g, 28.8 mmol) in THF (30 mL) was added 5 drops of HOAc, and the mixture stirred at room temperature under nitrogen for 15 min. The mixture was concentrated in vacuo, and the residue suspended in a mixture of ether (50 mL) and hexanes (50 mL) and the resulting precipitate collected and air-dried to provide 5.7 g of the title compound as an off-white powder. A second crop gave an additional 0.3 g.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH2:13]O)[N:8]=2)[N:3]=1.[OH:15][CH2:16][C:17]([CH2:19]O)=[O:18]>>[CH3:19][C:17]([CH:16]=[O:15])=[O:18].[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH3:13])[N:8]=2)[N:3]=1
Reactant: O=C(CO)CO
Reactant: Nc1nc(N)c2nc(CO)cnc2n1
Product: CC(=O)C=O
Product: Cc1cnc2nc(N)nc(N)c2n1

Procedure:
The main disadvantage in the literature methods for the preparation of 2,4-diamino-6-hydroxymethylpteridine is the necessity to use a pure 1,3-dihydroxyacetone, free of methyl-glyoxal, which affords by condensation a considerable yield of 2,4-diamino-6-methylpteridine. Purification of 1,3-dihydroxyacetone is rather difficult, especially the final distillation under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[F:15])[CH2:10][OH:11])=[CH:4][CH:3]=1.[H-].[Na+].[F:20][C:21]([F:35])([F:34])[C:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)=[CH:23]Cl.[Cl-].[Na+]>CN(C)C=O.O>[F:20][C:21]([F:34])([F:35])[C:22]([C:25]1[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH3:33])=[CH:27][CH:26]=1)=[CH:23][O:11][CH2:10][C:9]1[CH:12]=[CH:13][C:14]([F:15])=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: OCc1ccc(F)c(Oc2ccc(Cl)cc2)c1
Reactant: CCOc1ccc(C(=CCl)C(F)(F)F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc(C(=COCc2ccc(F)c(Oc3ccc(Cl)cc3)c2)C(F)(F)F)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 64.4 %

Procedure:
A solution of 3-(4-chlorophenoxy)-4-fluorobenzyl alcohol (6.3 g) in N,N-dimethylformamide (20 cm3) was added to a stirred suspension of sodium hydride (1.2 g of a 50% dispersion in oil) in N,N-dimethylformamide. After 30 minutes, this mixture was added to a stirred solution of EZ-1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-chloroprop-2-ene (5 g) in N,N-dimethylformamide (25 cm3) at a temperature maintained at -10° C. during the addition. After 45 minutes the reaction mixture was poured into water (150cm3) and sodium chloride added. The products were extracted into diethyl ether (4×100 cm3), and the combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation under reduced pressure. The crude residue was purified by column chromatography on a silica gel support, eluted with n-hexane containing 6% by volume diethyl ether, to give 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-[3-(4-chlorophenoxy)-4-fluorobenzyloxy]prop-2-ene (6 g).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1.[CH3:12]N(C=O)C.C[Sn](C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CO.C(Cl)(Cl)Cl>[CH3:12][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[CH:5]=[C:4]([NH2:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Nc1cc(Br)c2[nH]cnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Sn](C)(C)C
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1cc(N)cc2nc[nH]c12
Temperature: 140 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
To the solution of 4-bromo-6-aminobenzimidazole (0.85 g, 6.0 mmol) in sealed tube with 10 ml of DMF was added tetramethyltin (1.7 ml, 12 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.20 g). The resulting reaction mixture was stirred for 12 h at 140° C. and concentrated in vacuo, yielding oily residue which was subjected to column chromatography (5% MeOH/CHCl3) to produce 0.28 g (45%) of the desired product.
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([O:10]C)=O)=[CH:6][CH:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[NH:3]1.[CH2:18]([NH2:21])[C:19]#[CH:20].Cl>>[O:1]=[C:2]1[C:7]([C:8]([NH:21][CH2:18][C:19]#[CH:20])=[O:10])=[CH:6][CH:5]=[C:4]([C:12]([F:17])([F:16])[CH:13]([F:15])[F:14])[NH:3]1
Reactant: COC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O
Reactant: C#CCN
Agent: Cl
Product: C#CCNC(=O)c1ccc(C(F)(F)C(F)F)[nH]c1=O

Procedure:
At room temperature, 300 mg (1.19 mmol) of methyl 2-oxo-6-(1,1,2,2-tetrafluoroethyl)-1,2-dihydropyridine-3-carboxylate were stirred in 3.3 ml (41 mmol) of propargylamine for 14 h. The pH was then adjusted to 2 by addition of 1N hydrochloric acid, and the mixture was extracted with dichloromethane. Drying and concentration of the extract gave 280 mg (85% of theory) of the product.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH3:20][NH2:21]>C1C=CC=CC=1>[ClH:1].[CH3:20][NH:21][CH2:2][C:3]1[O:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: ClCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CN
Solvent: c1ccccc1
Product: CNCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Product: Cl
Yield: 69 %

Procedure:
A solution of 22 g. 2-chloromethyl-4,5-diphenyloxazole and 12.5 g methylamine in 100 ml. anhydrous benzene was heated at 120° C for 6 hours in a sealed tube. The reaction mixture was washed with water and the separated benzene phase was distilled at 20 mm. pressure. The oily residue was dissolved in 200 ml. anhydrous ether and a flow of gas hydrogen chloride was bubbled through the resulting solution. The 2-methylaminomethyl-4,5-diphenyloxazole hydrochloride was recrystallized from absolute ethanol: 16.5 g., m.p. 207°-208° C (yield 69%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12]Cl.[NH:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(CC(C)C)=O.ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:11][CH2:12][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Reactant: COC(=O)c1ccccc1OCCCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: ClCCl
Product: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 59.7 %

Procedure:
0.14 g (0.65 mmol) of 2-(2-chloro-ethoxy)-benzoic acid methyl ester were added to a mixture of 0.1 g (0.5 mmol) of 3-piperidin-4-yl-1H-indole, 0.10 g (0.75 mmol) of potassium carbonate and 0.06 g (0.37 mmol) of potassium iodide in 1.5 mL of isobutyl methyl ketone under nitrogen atmosphere and the reaction mixture was refluxed for 18 hours. After cooling at room temperature, 1.5 mL of dichloromethane and 0.08 g (0.1 mmol) of polystyrene methyl isocyanate were added and the mixture was stirred at this temperature for 3 hours. After filtering, the solution was placed directly onto a 500 mg Varian SCX ion exchange column. The columns were washed with 5 mL of methanol and the product was eluted with 5 mL of methanol/ammonia 20:1 affording, after removal of the solvent at reduced pressure, 0.113 g (60% yield) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester as a yellow oil.
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:5][CH:4]=1)=[O:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[OH:2][CH2:1][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[C:11]#[N:12])=[CH:5][CH:4]=1
Reactant: N#Cc1cccc(Oc2ccc(C=O)cc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(CO)cc2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Dissolve 3-(4-formyl-phenoxy)-benzonitrile of Preparation 10 (0.90 g, 4.04 mmol) in methanol (15 mL) and cool to 0° C. Add sodium borohydride (0.31 g, 8.08 mmol) in three batches. After 1 hr, allow to warm to ambient temperature and stir overnight. Concentrate under reduced pressure to give a residue. Dilute with ethyl acetate (50 mL) and wash with 1N hydrochloric acid (3×100 mL). Separate layers and dry the organic layer over magnesium sulfate, filter, and concentrate to a residue. Purification by flash chromatography, using 10% ethyl acetate/hexanes to 50% ethyl acetate/hexanes as a gradient eluent gives the title product (0.83 g, 91%): 1H NMR δ (CDCl3) 7.48-7.38 (m, 4H), 7.30-7.23 (m, 2H), 7.06 (d, J=8.4 Hz, 2H), 4.75 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22]O)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:24])[CH:2]([CH3:4])[CH3:3].C(Br)(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[NH:50]1[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]1.C(N(CC)C(C)C)(C)C>>[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:17]=[CH:18][C:19]([CH2:22][N:50]4[CH2:53][CH:52]([C:54]([O:56][CH3:57])=[O:55])[CH2:51]4)=[N:20][CH:21]=3)[N:12]=2)=[CH:7][C:6]=1[CH3:24])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)C1CNC1
Reactant: Cc1cc(-c2nc(-c3ccc(CO)nc3)no2)ccc1CC(C)C
Agent: BrC(Br)(Br)Br
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CN(Cc2ccc(-c3noc(-c4ccc(CC(C)C)c(C)c4)n3)cn2)C1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 23 (23g) using {5-[5-(4-isobutyl-3-methylphenyl)-1,2,4-oxadiazol-3-yl]pyridin-2-yl}methanol (0.19 g, 0.58 mmol) that was obtained in Example 28 (28a), carbon tetrabromide (0.39 g, 1.2 mmol), triphenylphosphine (0.30 g, 1.2 mmol), methyl 3-azetidinecarboxylate hydrochloride (0.13 mg, 0.87 mmol), and N,N-diisopropylethylamine (0.30 ml, 1.7 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:1 to 2:1 or 3:1) as the eluent to afford the title compound (0.15 g) in a yield of 60% as a white crystalline solid.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1)[CH:6]=2.[BrH:22].N([O-])=O.[Na+].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29]>CC(C)=O.CO>[Br:22][CH:28]([CH2:29][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH3:21])=[CH:16][N:15]=1)[CH:6]=2)[C:27]([O:31][CH3:32])=[O:30]
Reactant: CCc1ccc(COc2ccc3cc(N)cnc3c2)nc1
Reactant: Br
Reactant: C=CC(=O)OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Product: CCc1ccc(COc2ccc3cc(CC(Br)C(=O)OC)cnc3c2)nc1
Reaction time: 0.33 h
Yield: 75.7 %

Procedure:
In a mixture of acetone/methanol (5 mL/2 mL) was dissolved 3-amino-7-(5-ethyl-2-pyridylmethoxy)quinoline (680 mg, 2.43 mmol.), and to the resulting solution was added aqueous 47% hydrogen bromide (1.73 g). To the mixture was added aqueous sodium nitrite (189 mg (2.75 mmol.)/0.3 mL) under ice-chilling for 5 minutes, and methyl acrylate (1.33 mL, 14.9 mmol.) was added to the resulting mixture after it was stirred for 20 minutes. Cuprous oxide (23 mg) was added gradually to the mixture kept at 37° C. The mixture was then stirred for one hour at the same temperature. After the completion of reaction was confirmed, the solvent was distilled off under reduced pressure. To the residue were added ethyl acetate and aqueous concentrated ammonia, so that the aqueous phase was made to pH 7. The organic portion was recovered, washed with water, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give 790 mg of the desired compound as crude residue. The crude residue was subjected to the next step without further purification.
Reaction SMILES: [C:1]([S-:3])#[N:2].[K+].N1C=CC=CC=1.[NH2:11][C:12]1[N:17]=[C:16]([S:18][C@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[CH3:20])[N:15]=[C:14]([OH:28])[CH:13]=1.BrBr>CN(C=O)C.O>[NH2:2][C:1]1[S:3][C:13]2[C:14]([OH:28])=[N:15][C:16]([S:18][C@H:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH3:20])=[N:17][C:12]=2[N:11]=1
Reactant: N#C[S-]
Reactant: C[C@H](Sc1nc(N)cc(O)n1)c1ccccc1F
Agent: BrBr
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](Sc1nc(O)c2sc(N)nc2n1)c1ccccc1F
Temperature: 0 °C
Yield: 81 %

Procedure:
KSCN (10.76 g, 110.7 mmol) and pyridine (3.9 mL, 49.2 mmol) was added to 6-amino-2-{[(1S)-1-(2-fluorophenyl)ethyl]thio}pyrimidin-4-ol (6.53 g, 24.6 mmol) in DMF (70 mL). The mixture was cooled to 0° C. and Br2 was added dropwise. After 3.5 h the reaction mixture was poured into water and the formed precipitate was collected by filtration. The solid was suspended in a mixture of DMF (75 mL) and water (15 mL) and heated to 120° C. for 8 h. The reaction mixture was poured into water and the solid was collected by filtration and dried in vacuo at 40° C. to give the title compound (6.42 g, 81% yield).
Reaction SMILES: C(OCC)C.[C:6]([C:10]1[CH:15]=[CH:14][C:13]([Mg]Br)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7].[CH:18]([C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)([CH3:20])[CH3:19]>O1CCCC1>[C:6]([C:10]1[CH:15]=[CH:14][C:13]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([CH:18]([CH3:20])[CH3:19])[CH:22]=3)[N:27]=2)=[CH:12][CH:11]=1)([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Reactant: CC(C)c1ccc2ncccc2c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)c1ccc2nc(-c3ccc(C(C)(C)C)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 40645 %

Procedure:
To a cooled (ice bath) 2M diethyl ether solution of 4-tert-butylphenylmagnesium bromide (15 ml, 0.03 mmol) was added dropwise under argon 15 ml of a tetrahydrofuran solution of 6-isopropylquinoline (5.13 g, 0.03 mol). The resulting mixture was refluxed for 5 hours, stirred at room temperature for 12 hours and quenched with water (80 ml). The yellow precipitate obtained was then filtered and washed with hexane. Crystallization in hexane:chloroform 40:1 yielded 3.7 g of pure (±)-2-(4-tert-butylphenyl)-6-isopropylquinoline (40% yield). 1H NMR(CDCl3): 8.2 (m, ArH, 4H), 7.84 (m, ArH, 1H), 7.60 (m, ArH, 4H), 3.12 (s, CH(Me)2, 1H), 1.4 (s, CH(Me)2 and C(Me)3, 15H); Mass/Cl—NH3: MH− 304.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][N:67]([CH2:70][CH2:71][O:72][Si:73]([C:76]([CH3:79])([CH3:78])[CH3:77])([CH3:75])[CH3:74])[C:66](=[O:80])[CH:65]=1>>[C:76]([Si:73]([CH3:74])([CH3:75])[O:72][CH2:71][CH2:70][N:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][C:66]1=[O:80])([CH3:77])([CH3:79])[CH3:78]
Reactant: CC(C)(C)[Si](C)(C)OCCn1ccc(N)cc1=O
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CCO[Si](C)(C)C(C)(C)C)c(=O)c2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 27, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.5 g, 0.86 mmol), was reacted with diisopropylethylamine (0.89 g, 6.9 mmol), diphenylphosphinic chloride (0.82 g, 3.5 mmol), then reacted with 4-amino-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyridin-2-one (0.23 g, 0.86 mmol) at 60° C. to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid {1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-2-oxo-1,2-dihydro-pyridin-4-yl}-amide as a off white foam (Yield 0.2 g, 32%).
Reaction SMILES: C[CH:2]([O:13][CH:14](C)C1C=C([N+]([O-])=O)C=CC=1C)[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[CH3:12].O.[S-2].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(O)C.O>[CH3:14][O:13][CH2:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[CH3:12])[NH2:9]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(C)OC(C)c1cc([N+](=O)[O-])ccc1C
Agent: O=C([O-])O
Agent: [Na+]
Agent: [S-2]
Solvent: CCO
Solvent: O
Product: COCc1cc(N)ccc1C
Yield: 184.2 %

Procedure:
Methyl-2-methyl-5-nitrobenzyl ether (11.5 g) was dissolved in 125 ml of absolute ethanol. To this was added a solution of sodium sulfide monohydrate (48.3 g) and sodium bicarbonate (16.7 g) in 75 ml of water. The resulting mixture was refluxed until tlc indicated all the starting material was gone. The mixture was then concentrated in vacuo to an oily solid. Methylene chloride was added and the mixture filtered. The methylene chloride layer was separated and dried. After removal of the drying agent, the solvent was concentrated in vacuo to give 9.3 g of a mobile orange liquid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]2.[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28](B(O)O)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH:18]1([NH:21][C:22]([C:24]2[CH:25]=[C:26]([F:34])[C:27]([CH3:33])=[C:28]([C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[CH:5]4)[CH:29]=2)=[O:23])[CH2:20][CH2:19]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B(O)O
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Br)ccc21
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: COCCOC
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Yield: 211.1 %

Procedure:
A mixture of tert-butyl 5-bromo-1H-indazole-1-carboxylate (Intermediate 1, 1.07 g), {5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}boronic acid (0.85 g), sodium carbonate (1.9 g) and tetrakis(triphenylphosphine)palladium(0) (0.42 g) in 1,2-dimethoxyethane (70 ml) was stirred at reflux under nitrogen for 20 h. The solvent was removed and the residue was partitioned between water (50 ml) and ethyl acetate (50 ml). The aqueous layer was re-extracted with ethyl acetate (3×30 ml) and the combined organic extracts were dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by column chromatography on silica eluting with cyclohexane:ethyl acetate (75:25 to 60:40) to give the title compound (3.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:8][C:7](=[O:17])[C:6]=2[CH:18]=1.Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[O:17]=[C:7]1[C:6]2[CH:18]=[C:2]([O:1][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:3]=[CH:4][C:5]=2[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=c1nc(-c2ccccn2)sc2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc2sc(-c3ccccn3)nc(=O)c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.4 %

Procedure:
A mixture of 6-hydroxy-2-(2-pyridyl)-4H-1,3-benzothiazine-4-one (0.35 g, 1.3 mmol), tert-butyl bromoacetate (0.88 g, 4.5 mmol) and potassium carbonate (0.38 g, 2.7 mmol) and DMF (10 ml) was stirred at room temperature for 12 hrs. The reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated. The residue was subjected to a silica gel column chromatography and eluted with hexane-ethyl acetate (1:1, v/v). The obtained crystals were recrystallized from tetrahydrofuran-hexane to give the titled compound (0.44 g, 87%).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:17]([C:24](=[O:28])[C:25]([OH:27])=O)=[CH:16][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:35][C:36]1[C:37]([O:51][CH3:52])=[C:38]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[CH:39]=[C:40]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:41]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[C:42]([C:40]1[CH:39]=[C:38]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])[C:37]([O:51][CH3:52])=[C:36]([NH:35][C:25](=[O:27])[C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]([O:13][C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[N:12]=3)=[CH:15][CH:16]=2)=[O:28])[CH:41]=1)([CH3:45])([CH3:43])[CH3:44]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(O)C(=O)c1ccc(Oc2ccnc(N3CCOCC3)n2)c2ccccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1c(NC(=O)C(=O)c2ccc(Oc3ccnc(N4CCOCC4)n3)c3ccccc23)cc(C(C)(C)C)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
[4-(2-Morpholin-4-yl-pyrimidin-4-yl-oxy)-naphthalen-1-yl]-oxo-acetic acid (16) obtained above (36 mg, 0.095 mmol) was dissolved in 2 mL DCM and oxalyl chloride (0.08 mL, 0.949 mmol) was added, followed by catalytic DMF. The reaction mixture was stirred at rt, after which N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methanesulfonamide (14) (26 mg, 0.096 mmol) and DIEA (0.05 mL, 0.284 mmol) were added, and stirring was continued for 12 hr. The reaction mixture was concentrated in vacuo and the residue was purified by LC/MS (10-100% AcN/H2O over 8.5 min.) Calculated mass=444. Observed mass=444.