Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH:11]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[CH:20]=[CH:19]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O>[CH:11]1([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[O:27][CH3:28])[C:20]([CH:8]=[O:9])=[CH:19]2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CN(C)C=O
Reactant: COc1cccc2ccn(CC3CCCCC3)c12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cccc2c(C=O)cn(CC3CCCCC3)c12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Phosphorous oxychloride (12 ml, 0.13 mol) was added slowly over 30 minutes to dimethylformamide (30 ml) at −10° C. The solution was allowed to warm to 0° C. over 1 h, then 1-(cyclohexyl)methyl-7-methoxy-1H-indole (prepared as in Example 26; 3.2 g, 13 mmol) was added portionwise and the solution stirred at room temperature for 16 h. The solution was cooled in an ice bath and diluted with water, then neutralised carefully with sodium bicarbonate and extracted with ethyl acetate (3×50 ml). The organic extracts were combined and the solvent removed in vacuo. The residue (3.5 g) was dissolved in aqueous sodium hydroxide solution (5 M; 100 ml) and the mixture refluxed at 100° C. for a further 16 h. The solution was cooled and extracted with ethyl acetate (3×50 ml), the organic extracts combined and the solvent removed in vacuo to afford 1-(cyclohexyl)methyl-7-methoxy-1H-indole-3-carbaldehyde (2.2 g, 8.12 mmol) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[C:7]([CH:8]=O)[C:6]([OH:11])=[CH:5][CH:4]=1)=[O:2].[F:12][C:13]([F:22])([F:21])/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:14]([C:13]([F:12])([F:22])[F:21])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][C:7]=2[CH:10]=1)=[O:2]
Reactant: O=Cc1ccc(O)c(C=O)c1
Reactant: CCOC(=O)/C=C/C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2cc(C=O)ccc2OC1C(F)(F)F
Temperature: 60 °C

Procedure:
A 50 mL round bottom flask was charged with 5-formylsalicylaldehyde (3.21 g, 21.39 mmol), ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol), dimethylformamide (15 mL) and potassium carbonate (2.95 g, 21.39 mmol) and heated to 60° C. for 12 hours. Additional ethyl 4,4,4-trifluorocrotonate (3.50 mL, 3.96 g, 23.53 mmol) was added and the reaction heated for 16 hours at 75° C. After cooling to room temperature, the reaction was partitioned between H2O and diethyl ether. The organic phase was washed with saturated NaHCO3 solution, KHSO4 solution (0.25 M), brine, treated with decolorizing carbon (warmed gently). The resulting black suspension was dried over MgSO4, vacuum filtered through diatomaceous earth, and concentrated in vacuo yielding an orange crystalline mass. This material was recrystallized from hot hexanes yielding the ester (1.51 g, 24%) as orange crystals: mp 84.3–86.2° C. 1H NMR (acetone-d6/300 MHz) 9.96 (s, 1H), 8.06 (d, 1H, J=2 Hz), 8.02 (s, 1H), 7.99 (dd, 1H, J=8.5, 2.0 Hz), 7.24 (d, 1H, J=8.5 Hz), 5.99 (q, 1H, J=7.1 Hz), 4.43–4.25 (m, 2H), 1.34 (t, 3H, J=7.3 Hz). FABLRMS m/z 301 (M+H). EIHRMS m/z 300.0605 (M+, Calc'd 300.0609). Anal. Calc'd for C14H11F3O4: C, 56.01; H, 3.69. Found: C, 56.11; H, 3.73.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:11]2[C:6]([C:7]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[O:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=32)=[CH:5][CH:4]=1.[C:23]([S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:26])([CH3:25])[CH3:24].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[C:23]([S:27]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([N:18]2[CH2:17][CH2:16][C:7]3([C:6]4=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:21])[F:22])[N:11]4[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[O:8]3)[CH2:20][CH2:19]2)=[O:35])=[CH:37][CH:38]=1)(=[O:29])=[O:28])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: FC(F)(F)c1ccc2n1-c1ccccc1OC21CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)c1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 16.5 %

Procedure:
1′-(Trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine] (172 mg, 0.559 mmol), 4-tert-butylsulfonylbenzoic acid (176 mg, 0.727 mmol), 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (150 mg, 0.783 mmol), and triethylamine (312 μL, 2.24 mmol) were combined in dichloromethane (3.4 mL). The reaction mixture was allowed to stir for 72 hours at room temperature. The reaction mixture was washed three times with a 1M solution of hydrochloric acid, followed by three washes with a saturated aqueous solution of sodium bicarbonate, followed by three washes of a saturated aqueous solution of sodium chloride. The organic layer was dried over sodium sulfate, filtered, and evaporated to dryness to yield the crude product. The crude material was purified by reverse phase preparative chromatography utilizing a gradient of 10-99% acetonitrile in water to yield (4-tert-butylsulfonylphenyl)-[1′-(trifluoromethyl)spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-yl]methanone (49 mg, 16%) as a white solid. ESI-MS m/z calc. 532.2, found 533.5 (M+1)+. Retention time: 2.10 minutes (3 min run). 1H NMR (400 MHz, DMSO) δ 7.89 (d, J=8.0 Hz, 2H), 7.73 (d, J=8.0 Hz, 2H), 7.57 (d, J=8.0 Hz, 1H), 7.35-7.25 (m, 2H), 7.25-7.16 (m, 1H), 7.03 (d, J=3.9 Hz, 1H), 6.40 (d, J=3.9 Hz, 1H), 4.53-4.37 (m, 1H), 3.57-3.14 (m, 3H), 2.17-1.78 (m, 4H), 1.26 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:18]=[CH:17][C:9]2[N:10]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[S:12][C:8]=2[C:7]=1[C:19]#[N:20].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([CH2:32][C:33](O)=[O:34])[CH:29]=[CH:30][CH:31]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:14]([NH:13][C:11]1[S:12][C:8]2[C:7]([C:19]#[N:20])=[C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:33](=[O:34])[CH2:32][C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:36])([F:24])[F:37])[CH:27]=4)[CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:17][C:9]=2[N:10]=1)(=[O:16])[CH3:15]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(=O)Nc1nc2ccc(Oc3cccc(N)c3)c(C#N)c2s1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1nc2ccc(Oc3cccc(NC(=O)Cc4cccc(C(F)(F)F)c4)c3)c(C#N)c2s1
Temperature: 85 °C
Reaction time: 12 h
Yield: 69.2 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]acetamide (141 mg, 0.436 mmol) produced in Example 12(ii), [3-(trifluoromethyl)phenyl]acetic acid (176 mg, 0.872 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (331 mg, 0.872 mmol) and pyridine (3 mL) was stirred at 85° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (5 mL), washed successively with saturated aqueous ammonium chloride solution (5 mL), saturated aqueous sodium hydrogen carbonate solution (5 ml) and saturated brine (5 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-heptane (1/1) to give the title compound (154 mg, 69%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[I:9].[CH3:10][C:11]1[C:15]([C:16](O)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1.C(Cl)CCl>>[CH3:10][C:11]1[C:15]([C:16]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:1])=[C:3]([I:9])[CH:4]=2)=[O:17])=[C:14]([CH3:19])[O:13][N:12]=1
Reactant: Cc1noc(C)c1C(=O)O
Reactant: Nc1ccc(Cl)c(I)c1
Solvent: ClCCCl
Product: Cc1noc(C)c1C(=O)Nc1ccc(Cl)c(I)c1

Procedure:
4-Chloro-3-iodoaniline (1.01 g, 4 mmol) was used in procedure E with 3,5-dimethyl-4-isoxazolecarboxylic acid (0.565 g, 4 mmol), EDC (1.32 g, 6.8 mmol), TEA (0.5 mL), DMAP-(50 mg, 0.4 mmol) at 23° C. for overnight. The crude reaction was purified by silica gel chromatography (0-15% ethyl acetate/CH2Cl2) to yield 3,5-dimethyl-N-(4-chloro-3-iodophenyl)isoxazole-4-carboxamide as a white solid.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>CS(C)=O>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccc(Cl)cc4)c3)csc12
Reactant: NCCO
Solvent: CS(C)=O
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccc(Cl)cc1
Temperature: 135 °C

Procedure:
A suspension of 3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (30 mg, 0.064 mmol) (from Example 4 supra) in methyl sulfoxide (1 mL) and ethanolamine (3 mL) (Aldrich) was heated at 135° C. for 2 hours in a microwave reactor. After cooling to room temperature, the precipitate was filtered off, washed with MeOH and dried to give 3-[3-(4-chloro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)amide as a white solid. (Yield 13.2 mg, 42.6%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:13])=[CH:5][CH:4]=1
Reactant: CSc1ccc(CO)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CSc1ccc(CCl)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
To a solution of 50.0 g (325 mMol) of 4-(methylthio)benzyl alcohol in 350 ml of toluene stirring at room temperature under nitrogen, was added 5 drops of pyridine, and then 28.4 ml (46.4 g, 390 mMol, 1.2 eqs) of thionyl chloride was added dropwise. After 3 hours, ice water was added and the mixture was stirred for 20 minutes. The mixture was transferred to a separatory funnel and shaken thoroughly. The organic layer separated and was dried over sodium sulfate, filtered, and evaporated. Distillation of the residue under reduced pressure gave (4-methylthiophenyl)chloromethane (50.54 g) as a colorless liquid: b.p. 89-95° C. (1 mm).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](Cl)=O)=[CH:5][CH:4]=1.[NH2:13][NH:14][C:15]([NH2:17])=[S:16]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[S:16][C:15]([NH2:17])=[N:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CC(=O)Cl)cc1
Reactant: NNC(N)=S
Product: COc1ccc(Cc2nnc(N)s2)cc1
Temperature: 60 °C

Procedure:
A mixture of 2-(4-methoxyphenyl)acetyl chloride (88a, 3.05 g, 16.5 mmol), and thiosemicarbazide (1.37 g, 15.0 mmol) were heated to 60° C. for 3.0 hours. The reaction mixture was then cooled to room temperature, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine and 50% NaOH(aq), dried over. MgSO4(s), and concentrated under reduced pressure to give 5-(4-methoxybenzyl)-1,3,4-thiadiazol-2-amine (88b).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:6]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19])C=C.[C:20]1(C)[CH:25]=C(C)C=C(C)[CH:21]=1>>[CH2:25]([C:10]1[CH:9]=[CH:8][C:7]([F:11])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH3:19])[C:5]=1[OH:4])[CH:20]=[CH2:21]
Reactant: Cc1cc(C)cc(C)c1
Reactant: C=CCOc1cccc(F)c1-c1ccc(Cl)cc1C
Product: C=CCc1ccc(F)c(-c2ccc(Cl)cc2C)c1O
Yield: 95 %

Procedure:
A solution of 2′-allyloxy-4-chloro-6′-fluoro-2-methylbiphenyl (2.1 g, 7.6 mmol) in mesitylene (70 mL) was refluxed for 24 h. The solvent was removed under reduced pressure. Purification by ISCO using a solvent gradient of 0 to 20% ethyl acetate in hexanes provided 2.0 g (95%) of 3-allyl-4′-chloro-6-fluoro-2′-methylbiphenyl-2-ol as a pale yellow oil.
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:15]1[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.CCOC(C)=O>[OH:20][C@H:17]1[CH2:18][CH2:19][N:15]([C:2]2[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)c1ccc(F)cc1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CC[C@H](O)C2)cc1
Temperature: 130 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a solution of tert-butyl 4-fluorobenzoate (1 g, 5.1 mmol) and (S)-pyrrolidin-3-ol (462 mg, 5.3 mmol) in DMSO (10 mL) was added powdered potassium carbonate (705 mg, 5.1 mmol). The mixture was stirred at 130° C. for 4 h and allowed to cool down to room temperature. The mixture was diluted with EtOAc (300 mL) and the solution was washed with water (2×100 mL), dried over Na2SO4, filtered and concentrated to provide title compound 157 (1.23 g, 88% yield) that was used in the next step without further purification. LRMS (ESI): (calc) 263.15 (found) 264.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:18])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.C(N(C(C)C)CC)(C)C.Cl[C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:29](=[O:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)CC(=O)Cl
Reactant: Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (112 mg, 0.459 mmol, Compound C of Example 22) in methylene chloride (4 mL) at 0° C. was added 96 μL (0.55 mmol) of diisopropylethylamine followed by 61 μL (0.48 mmol) of ethyl 3-chloro-3-oxopropanoate. The reaction was stirred at 0° C. for 1 h and was then quenched with 10 mL of saturate NaHCO3 solution. The aqueous layer was extracted with chloroform (3×15 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude product as a yellow oil that solidified on standing (180 mg). 1H NMR (CDCl3) δ 9.45 (br s, 1H), 7.89 (s, 1H), 7.71 (dd, 1H, J=2.5, 1.5 Hz), 7.68 (dd, 1H, J=11.8, 2.2 Hz), 7.18 (m, 2H), 6.93 (dd, 1H, J=4.4, 1.4 Hz), 6.78 (dd, 1H, J=4.4, 2.6 Hz), 4.19 (q, 2H, J=7.2 Hz), 3.41 (s, 2H), 1.25 (t, 3H, J=7.2 Hz); MS(ESI+) m/z 359.1 (M+H)+.
Reaction SMILES: [CH2:1]1[O:42][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[N:18]=4)[C:15]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:14]([O:39][CH3:40])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:41]=[C:3]2[O:2]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>O1CCCC1>[CH2:1]1[O:42][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:20][CH2:21][CH2:22][OH:23])[N:18]=4)[C:15]([O:31][CH2:32][C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)=[C:14]([O:39][CH3:40])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:41]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c(CCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2c(c(CCCO)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
After 2,3-(methylenedioxy)-6-[3-(t-butyldimethylsiloxy)propyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (374.4 mg, 0.644 mmol) was dissolved in tetrahydrofuran (3.2 mL), tetrabutylammonium fluoride (1M tetrahydrofuran solution, 1.9 mL) was added to the solution. The mixture was stirred overnight at room temperature. Water was added to the reaction mixture followed by extraction with methylene chloride. The organic phase was dried over anhydrous sodium sulfate and then concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride) to provide 2,3-(methylenedioxy)-6-(3-hydroxypropyl)-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (263.7 mg, yield 88%) as colorless powders.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[C:14]([O:16]C)[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[O:19]C)[C:5](=[O:21])[C:4]=2[CH:3]=1.Br>O>[NH2:1][C:2]1[CH:15]=[C:14]([OH:16])[C:13]2[C:12](=[O:18])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][C:10]=3[OH:19])[C:5](=[O:21])[C:4]=2[CH:3]=1
Reactant: COc1cccc2c1C(=O)c1c(OC)cc(N)cc1C2=O
Agent: Br
Solvent: O
Product: Nc1cc(O)c2c(c1)C(=O)c1cccc(O)c1C2=O

Procedure:
2-Amino-9,10-dihydro-4,5-dimethoxy-9,10-dioxoanthracene (1 g) was suspended in a 48% solution of hydrobromic acid in water (30 ml) and heated to reflux under an atmosphere of nitrogen for sixty hours. The red suspension turned brown. The mixture was poured into water (100 ml), creating a red precipitate which was collected by filtration. Drying in vacuo over silica gel yielded 2-amino-9,10-dihydro-4,5-dihydroxy-9,10-dioxoanthracene as a dark red powder, m.p. 250°-252° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=O.[OH-].[Na+].O.[NH2:15][NH2:16]>O>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]1[N:15]=[N:16][C:4]([C:3]2[C:7]([F:11])=[CH:8][CH:9]=[CH:10][C:2]=2[F:1])=[N:15][N:16]=1
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Fc1cccc(F)c1-c1nnc(-c2c(F)cccc2F)nn1
Temperature: 0 °C
Yield: 164.8 %

Procedure:
9.05 g of 2,6-difluorobenzoyl chloride and a solution of 2.17 g of sodium hydroxide in 7.5 ml of water are simultaneously dropped into a solution of 1.25 g of hydrazine hydrate in 25 ml of water under stirring and cooling by ice-water. After addition, the white suspension is stirred at room temperature for 2 hours. After filtration the solid product is washed with water and recrystallized from glacial acetic acid to yield 6.3 g of desired product as white crystals.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N:29]=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl.CO>[CH:12]1([NH:15][C:16]([C:18]2[CH:19]=[C:20]([F:40])[C:21]([CH3:39])=[C:22]([C:24]3[N+:29]([O-:9])=[CH:28][C:27]([C:30]([NH:32][C@H:33]([CH3:38])[C:34]([CH3:36])([CH3:35])[CH3:37])=[O:31])=[CH:26][CH:25]=3)[CH:23]=2)=[O:17])[CH2:14][CH2:13]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)(C)C)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc(C(=O)N[C@H](C)C(C)(C)C)c[n+]1[O-]
Temperature: 60 °C

Procedure:
mCPBA (57-86%, 15 mg) was added to a solution of 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide (Intermediate 10, 20 mg) in chloroform (3 ml) at 60° C. and the reaction maintained at 60° C. for 7 hrs. The reaction was allowed to cool, diluted with methanol, and passed through an aminopropyl SPE (2 g) and an SCX SPE (1.0 g). The filtrate was reduced to dryness under vacuum and the residue triturated with ether to give 6-{5-[(cyclopropylamino)carbonyl]-3-fluoro-2-methylphenyl}-N-[(1R)-1,2,2-trimethylpropyl]-3-pyridinecarboxamide 1-oxide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.CSC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Cc1ccccc1Br)NCc1ccccc1
Solvent: C1CCOC1
Solvent: CSC
Product: Brc1ccccc1CCNCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-Bromophenyl)-N-(phenylmethyl)acetamide was dissolved THF (0.2 M), followed by addition of BH3.DMS (3 eq), and the reaction was heated to reflux with stirring. After 2 hrs, the mixture was cooled to room temerature, and quenched with excess 10% HCl. The mixture was heated to reflux for 1 hr, and then cooled to room temperature. After washing with EtOAc, the aqueous phase was made alkaline with 10% sodium carbonate, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with EtOAc to afford a colorless solid. EI-MS m/z 290/292 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[CH3:20][O:21][CH2:22][CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][CH2:22][O:21][CH3:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: COCCN
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCCOC
Yield: 89 %

Procedure:
The compound prepared in Example 3 was reacted with 2-methoxy-ethylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 89%).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]([C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=2)[CH2:48][NH2:49])[CH:44]=[CH:45][CH:46]=1>>[C:1]([O:9][C@@H:10]1[C@H:14]([O:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([C:24]([NH:26][CH2:27][CH3:28])=[O:25])[O:12][C@H:11]1[N:29]1[CH:37]=[N:36][C:35]2[C:30]1=[N:31][C:32]([I:39])=[N:33][C:34]=2[NH:49][CH2:48][CH:47]([C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([Cl:40])[CH:42]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[C:52]([Cl:56])[CH:51]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC(c1cccc(Cl)c1)c1cccc(Cl)c1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(Cl)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4cccc(Cl)c4)c4cccc(Cl)c4)nc(I)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1

Procedure:
Prepared from ((2R,3R,4S,5S)-4-(benzoyloxy)-2-(6-chloro-2-iodo-9H-purin-9-yl)-5-[(ethylamino)carbonyl]-tetrahydro-3-furanyl benzoate (Preparation 47) and 2,2-bis(3-chlorophenyl)ethylamine by the same method as Preparation 48. The title compound was obtained as a yellow foam.