Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5](Br)=[CH:4][C:3]=1C(O)=O.OCCS(C1C=CC(OC2C=CC(S)=CC=2)=CC=1)(=O)=O>>[CH:9]1[C:8]2[C:7](=[O:17])[C:6]3[C:15](=[CH:2][CH:3]=[CH:4][CH:5]=3)[C:14](=[O:16])[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1c(C(=O)O)cc(Br)c2c1C(=O)c1ccccc1C2=O
Agent: O=S(=O)(CCO)c1ccc(Oc2ccc(S)cc2)cc1
Product: O=C1c2ccccc2C(=O)c2ccccc21

Procedure:
Example 19 was repeated, provided that the compounds shown in 1st and 2nd columns of the following table were used in place of the 1-amino-2-carboxy-4-bromoanthraquinone and 4-(4'-β-hydroxyethylsulfonylphenoxy)thiophenol, respectively, thereby obtaining a corresponding anthraquinone compound. A color shade obtained by dyeing cotton with the compound is as shown in a 3rd column of the table.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]#[N:11].CC(C)([O-])C.[K+]>C(O)(C)(C)C.O>[O:7]1[C:4]2([CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:9]1[C:10]#[N:11]
Reactant: O=C1CCOCC1
Reactant: N#CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)(C)O
Product: N#CC1OC12CCOCC2
Reaction time: 0.17 h

Procedure:
A mixture of tetrahydropyran-4-one (10 mL) and chloroacetonitrile (6.4 mL) in tert-butanol (10 mL) was stirred for 10 minutes. To this solution was added a solution of potassium tert-butoxide (12.11 g) in 200 mL of tert-butanol at room temperature over 40 minutes. The reaction mixture was stirred for 16 hours, diluted with water and quenched slowly with 1 N HCl. The solvent was partially removed by rotary evaporation. It was then extracted with ether (5×200 mL). The combined extracts was washed with brine, dried over MgSO4, filtered, and the filtrate was concentrated and purified by flash chromatography on silica with 3:7 to 1:1 ethyl acetate:hexanes to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.I[CH:10]([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:10]([CH3:12])[CH3:11])[CH:7]=1
Reactant: Oc1ccc(Br)cn1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1cc(Br)ccc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.6 %

Procedure:
To a solution of 5-bromopyridin-2-ol (1 g, 5.75 mmol) in DMF (10 mL) were added 2-iodopropane (4.9 g, 28.75 mmol) and K2CO3 (4 g, 28.75 mmol). The mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) extracted with EtOAc (3×25 mL), the combined organic phase was washed with brine, dried over Na2SO4, concentrated and purified by prep TLC to give 5-bromo-1-isopropylpyridin -2(1H)-one (380 mg, 31%). 1H NMR (CDCl3): 1.35 (d, 6H), 5.65-5.75 (m, 1H), 6.48 (d, 1H), 7.30 (m, 1H), 7.41 (d, 1H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[CH2:11]([NH:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:17]=2[N:18]=1)[CH3:12].C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]([N:13]([C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23][CH2:24][C:25]3[O:26][CH:27]=[CH:28][CH:29]=3)[CH:20]=[CH:19][C:17]=2[N:18]=1)[CH:1]=[O:3])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCNc1nc2ccc(CCc3ccco3)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: C1CCOC1
Product: CCN(C=O)c1nc2ccc(CCc3ccco3)cc2o1
Temperature: 50 °C
Reaction time: 0.67 h

Procedure:
A mixture of acetic anhydride (1.13 ml) and formic acid (0.45 ml) was stirred at 50° C. for 40 minutes. Tetrahydrofuran (10 ml) and 2-ethylamino-6-[2-(2-furyl)ethyl]benzoxazole (1.02 g) was added thereto and the mixture was stirred at the same temperature for further 6 hours. After cooling, the mixture was neutralized with aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was washed with water dried over magnesium sulfate and evaporated in vacuo to give 2-(N-ethylformamido)-6-[2-(2-furyl)ethyl]benzoxazole (1.18 g).
Reaction SMILES: [Na].[CH2:2]([O:4][N:5]=[C:6]([C:9]1[C:10](=O)[CH2:11][CH:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH2:20][CH2:19]3)[CH2:13][C:14]=1[OH:15])[CH2:7][CH3:8])[CH3:3].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[C:26]([C:10]1[CH2:11][CH:12]([C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[CH2:21][CH2:20][CH2:19]3)[CH2:13][C:14](=[O:15])[C:9]=1[C:6](=[N:5][O:4][CH2:2][CH3:3])[CH2:7][CH3:8])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)CCC3)CC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: [Na]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(C(=O)c2ccccc2)CC(c2ccc3c(c2)CCC3)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
The sodium salt of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(5-indanyl)cyclohex-2-en-1-one (0.95 mmole) was dissolved in acetone (50 ml) and benzoyl chloride (0.13 g; 0.95 mmole) was added dropwise over a period of 2 minutes. The mixture was stirred at room temperature for 5 minutes, then filtered and evaporated under reduced pressure to give 3-benzoyl-2-[1-(ethoxyimino)propyl]-5-(5-indanyl)cyclohex-2-en-1-one (0.31 g; 75.7%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:5]([C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=1OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH3:13])=[O:11])=[CH2:6])([CH3:4])[CH3:3].CN(C=O)C.[F:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.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>[CH3:4][C:2]([C:5]([C:7]1[CH:8]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[CH:14]=[CH:15][C:16]=1[C:32]1[CH:33]=[C:34]([O:37][CH3:38])[CH:35]=[CH:36][C:31]=1[F:30])=[CH2:6])([CH3:1])[CH3:3]
Reactant: COc1ccc(F)c(B(O)O)c1
Reactant: C=C(c1cc(C(=O)OC)ccc1OS(=O)(=O)C(F)(F)F)C(C)(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: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(c1cc(C(=O)OC)ccc1-c1cc(OC)ccc1F)C(C)(C)C
Temperature: 90 °C
Reaction time: 17 h
Yield: 19.5 %

Procedure:
To a stirred solution of 66.18E (0.550 g, 1.5 mmol) in DMF (3.0 mL, 1.5 mmol) at 23° C. was added 2-fluoro-5-methoxyphenylboronic acid (0.38 g, 2.3 mmol) (commercially available from Aldrich), potassium carbonate (0.62 g, 4.5 mmol) and then tetrakis(triphenylphosphine)palladium (0.12 g, 0.11 mmol). The mixture was heated to 90° C. and stirred for 17 hours. The resulting mixture was then cooled to room temperature, diluted with water and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield 66.18F as a colorless oil (0.100 g, 19% yield).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.C(=O)([O-])[O-].[NH4+:34].[NH4+]>C(Cl)Cl.C(O)C>[ClH:28].[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][O:10][C:11]2[CH:12]=[C:13]([O:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])(=[O:21])=[O:20])[CH:14]=[C:15]([CH3:17])[CH:16]=2)[CH:6]=[CH:7][CH:8]=1)(=[NH:34])[NH2:2]
Reactant: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(OCc2cccc(C(=N)N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-[(3-cyanophenyl) methoxy]-5-methylphenyl ester (207 mg, 0.5 mmol), as prepared in the preceding step, in methylene chloride (10 mL) was added 37% HCl in ethanol (10 mL) at 0° C. The mixture was allowed to stand at 0° C. for 3 days. The solvent was evaporated in vacuo and the residue was co-evaporated with methylene chloride several times. The residue was dissolved in ethanol (10 mL) and ammonium carbonate (192 mg, 2.0 mmol) was added at 0° C. The mixture was stirred at room temperature overnight. Methylene chloride (150 mL) was added to the mixture. The methylene chloride solution was washed with 10% K2CO3 (2×50 mL) and dried over K2CO3. The solvent was removed in vacuo, HCl in methanol (30 mL) was added, and the solvent again removed in vacuo. The residue was purified by flash chromatography (10% methanol in methylene chloride) to give the title compound as a white solid (112 mg, 48%). 1H-NMR (300 MHz, DMSO-d6) δ 2.23 (s, 3 H), 5.11 (s, 2 H), 6.54 (s, 1 H), 6.56 (s, 1 H), 6.88 (s, 1 H), 7.58 (t, 1 H, J=6.5 Hz), 7.61 (t, 1 H, J=12.2 Hz), 7.66 (d, 1 H, J=3.9 Hz), 7.73-7.95 (m, 5 H), and 9.40 (br s, 4 H). Mass spectrum (MALDI-TOF, sinapinic acid matrix) calcd. for C21H19N2O4SCl: 431.1 (M+H), 453.1 (M+Na). Found: 0 431.0, 452.9.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.CN(C=O)C.[F:14][C:15]1[CH:16]=[C:17]([CH2:21][OH:22])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:22][CH2:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([F:14])[CH:16]=2)[N:3]=1
Reactant: OCc1cccc(F)c1
Reactant: Fc1cccc(Br)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(COc2cccc(Br)n2)c1
Temperature: 95 °C
Reaction time: 6 h
Yield: 55.3 %

Procedure:
To 2-bromo-6-fluoropyridine (176 mg, 1.000 mmol) was added DMF (1.5 ml) and (3-fluorophenyl)methanol (139 mg, 1.100 mmol) and cesium carbonate (391 mg, 1.200 mmol), and the resulting mixture reaction mixture was stirred at 95° C. for 6 hr, as the progress of the reaction mixture was followed by LCMS. The reaction mixture was cooled to room temperature, diluted with 120 ml of ethyl acetate, washed with saturated sodium bicarbonate (1×), water (1×), saturated salt solution (1×), dried over sodium sulfate, filtered and concentrated to yield a crude product which was purified by silica gel chromatography using a 12 g column eluting from 0%-20% ethyl acetate with hexane. The desired fractions were combined and concentrated to constant mass, giving 156 mg of the title compound as a free base. LCMS (m/z): 282.0/284.0 (MH+), retention time=1.19 min.
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][C:18]2[N:22]([CH2:23][C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=2)[CH2:13][CH2:12]1)=[O:5].C(N(CC)CC)C.[C:44](Cl)(=O)[O:45]C(Cl)(Cl)Cl>O1CCCC1>[O:25]1[CH:26]=[CH:27][CH:28]=[C:24]1[CH2:23][N:22]1[C:21]2[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=2[N:19]=[C:18]1[CH2:17][CH:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:1][C:44]2=[O:45])[CH2:16][CH2:15]1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccccc1C(=O)NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Reaction time: 8 h
Yield: 73 %

Procedure:
To a stirred mixture of 3.88 parts of 2-amino-N-[4-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]benzamide, 2 parts of N,N-diethylethanamine and 90 parts of tetrahydrofuran were added dropwise 1.64 parts of trichloromethyl carbonochloridate. Upon completion, stirring was continued overnight. Another portion of 1.6 parts of B was added and the whole was stirred overnight. The precipitate was filtered off and the filtrate was evaporated. Water was added to the residue. The solution was treated with ammonium hydroxide; The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 3 parts (73%) of 3-[4-[4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]butyl]-2,4(1H,3H)-quinazolinedione; mp. 185.5° C. (490).
Reaction SMILES: O.O.O.O.[C:5]([O-:8])(=[O:7])[CH3:6].[Co+2:9].[C:10]([O-:13])(=[O:12])[CH3:11]>C(O)CO>[C:5]([O-:8])(=[O:7])[CH2:6][OH:12].[Co+2:9].[C:10]([O-:13])(=[O:12])[CH2:11][OH:7]
Reactant: CC(=O)[O-]
Agent: [Co+2]
Solvent: OCCO
Solvent: O
Product: O=C([O-])CO

Procedure:
A cobalt solution was obtained by dissolving cobalt acetate tetrahydrate (CoAc.4H2O, 4 g) in ethylene glycol (36 g) to produce a cobalt glycolate solution containing 10% cobalt acetate tetrahydrate. After stirring for 60 minutes, large particles dissolved, it became uniform red purple solution. A portion (9 g) of the cobalt acetate tetrahydrate solution and 1 g of a phosphoric acid solution (10% H3PO4 in ethylene glycol) were mixed in an open glass beaker. After shaking, flocculates in dark bluish purple formed in the bottom of the glass beaker. After 10 days, top 3 ml was red liquid mainly ethylene glycol, bottom 7 ml was dark purple flocculates.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[CH:7]=[C:8]([CH2:10][C:11]([OH:13])=O)[S:9][C:5]=2[CH:4]=1.[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH2:23])[CH:17]([CH3:19])[CH3:18]>>[CH2:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:24])[NH:23][C:11](=[O:13])[CH2:10][C:8]1[S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:15]=[CH:14][C:6]=2[CH:7]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc2cc(CC(=O)O)sc2c1
Reactant: CC(C)COC(=O)[C@H](C)N
Product: COc1ccc2cc(CC(=O)N[C@@H](C)C(=O)OCC(C)C)sc2c1

Procedure:
Following General Procedure I′ above, and using (6-methoxybenzothiophen-2-yl)acetic acid and alanine iso-butyl ester (prepared following General Procedure J′ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: C([BH-](CC)CC)C.[Li+].[CH2:9]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH3:22])[N:18]=[CH:17][C:16]([C:23](OCC)=[O:24])=[C:15]2[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH3:10].Cl.O>C1COCC1>[CH2:9]([O:11][C:12]1[CH:13]=[C:14]2[C:19](=[N:20][C:21]=1[CH3:22])[N:18]=[CH:17][C:16]([CH2:23][OH:24])=[C:15]2[NH:28][C:29]1[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH3:10]
Reactant: CCOC(=O)c1cnc2nc(C)c(OCC)cc2c1Nc1ccc(OC)cc1
Agent: CC[BH-](CC)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1cc2c(Nc3ccc(OC)cc3)c(CO)cnc2nc1C
Temperature: 25 °C

Procedure:
Lithium triethylborohydride (a 1M solution in THF, 47 ml) was added to a solution of ethyl 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridine-3-carboxylate (4.5 g) in THF (150 ml) with stirring under nitrogen at 0°-10° C. The mixture was allowed to warm up to ambient temperature and stirred at this temperature for 18 hours. Further lithium triethylborohydride solution (15 ml) was added and the solution stirred at ambient temperature for 4 hours. The reaction mixture was cooled to 5° C. and then 5M hydrochloric acid (5 ml) was added carefully followed by water (50 ml). The organic layer was separated and the aqueous layer extracted with ether. The aqueous layer was basified with 5M sodium hydroxide solution and extracted into ethyl acetate. The residue, obtained from the ethyl acetate extracts, was purified by flash chromatography on silica, using dichloromethane/IMS (15/1) as the mobile phase, to give 6-ethoxy-4-(4-methoxyanilino)-7-methyl-1,8-naphthyridin-3-ylmethanol, m.p. 193°-197° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>O.O1CCOCC1.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>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[C:18]([C:2]2[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
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: O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccc(-c2cccc(C(F)(F)F)c2)s1
Temperature: 80 °C
Reaction time: 12 h
Yield: 83.3 %

Procedure:
Under a nitrogen atmosphere, to a mixed solvent of ethyl 5-bromothiophene-2-carboxylate (2.4 g, 10 mmol), 3-(trifluoromethyl)phenylboronic acid (2.9 g, 15 mmol) and sodium carbonate (2.1 g, 20 mmol) in water/1,4-dioxane (v/v=1/1, 10 mL) was added tetrakistriphenylphosphinepalladium (1.1 g, 1.0 mmol), and the mixture was stirred at 80° C. for 12 hr. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was purified by column chromatography (petroleum ether/ethyl acetate=60/1) to give the title compound (2.5 g, 83%) as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][C@@H:13]([C:18]([OH:20])=[O:19])[CH2:14][C:15](=[O:17])[NH2:16])(=[O:11])=[O:10])=[CH:5][CH:4]=1.[C:21](=O)([O-])[O-].[Cs+].[Cs+].CI>CN(C)C=O.[Cl-].[NH4+]>[CH3:21][O:19][C:18](=[O:20])[C@@H:13]([CH2:14][C:15](=[O:17])[NH2:16])[NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N[C@H](CC(N)=O)C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](CC(N)=O)NS(=O)(=O)c1ccc(OC)cc1
Reaction time: 8 h

Procedure:
N-[4-methoxybenzenesulfonyl]-(D)-asparagine (10.1 g, 33.3 mmol) is dissolved in dimethylformamide (167.0 mL). Cesium carbonate (5.43 g, 16.66 mmol) is added, followed by the addition of methyl iodide (2.22 mL, 33.3 mmol), and the reaction is stirred overnight. The reaction is then diluted with saturated ammonium chloride (366.0 mL), and extracted well with ethyl acetate. The combined organic extracts are washed with brine, dried (Na2SO4), and the solvent is evaporated. The crude product is recrystallized from toluene to provide N-[4-methoxybenzenesulfonyl]-(D)-asparagine methyl ester.
Reaction SMILES: [CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6]CC)[CH3:2].C(O)C[OH:16]>C(O)(C([O-])=O)=O.C(O)(C([O-])=O)=O.O.O=[Ti].[K+].[K+]>[CH2:1]([P:3]([CH2:10][CH2:11][CH2:12][NH2:13])(=[O:9])[O:4][CH2:5][CH2:6][OH:16])[CH3:2]
Reactant: CCCCOP(=O)(CC)CCCN
Reactant: OCCO
Agent: O=[Ti]
Agent: O=C([O-])C(=O)O
Agent: [K+]
Solvent: O
Product: CCP(=O)(CCCN)OCCO
Temperature: 200 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To 414 g (2 mol) of butyl ethyl(3-aminopropyl)phosphinate (produced as in Example 14) are added 155 g (2.5 mol) of ethylene glycol and 0.4 g of potassium titanyl oxalate and the mixture is stirred at 200° C. for 2 h. Gradual evacuation is applied to distill off volatiles, leaving 374 g (96% of theory) of 2-hydroxyethyl ethyl-(3-aminopropyl)phosphinate.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[CH:25]=[C:24]([F:32])[CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35](S(C5C=CC(C)=CC=5)(=O)=O)[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[F:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[NH:17][C:18]4=[N:35][CH:34]=[CH:33][C:19]4=[C:20]([NH:21][C:22]4[CH:23]=[C:24]([F:32])[CH:25]=[C:26]([F:31])[C:27]=4[C:28]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=4)=[O:30])[N:29]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: NCc1ccc(F)cc1
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4cc(F)cc(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3cc(F)cc(F)c3C(=O)NCc3ccc(F)cc3)c3ccnc-3[nH]1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.4 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,10-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added [(4-fluorophenyl)methyl]amine (1.01 mL, 8.89 mmol). The resulting mixture was let stir at rt for 16 h at which time it was diluted with ethyl acetate and washed with a saturated ammonium chloride solution, a saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure and purified via SiO2. This lead to a yellow solid containing 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide. This crude material was dissolved in 1,4-dioxane (5 mL) and transferred to a 20 ml microwave vessel. A solution of 2 M NaOH (5 ml) was added and reaction heated in microwave at 120° C. for 8 minutes. Resulting brown solution was diluted with ethyl acetate and washed with a 10% ammonium chloride solution, saturated sodium bicarbonate solution, water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure to afford a yellow solid which was purified via chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-4,6-difluoro-N-[(4-fluorophenyl)methyl]benzamide (67 mg, 0.104 mmol) as an off white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.23 (s, 6 H), 3.06-3.18 (m, 4 H), 3.76 (s, 3 H), 4.16 (t, J=8.29 Hz, 2 H), 4.51 (d, J=5.86 Hz, 2 H), 6.17 (d, J=1.19 Hz, 1 H), 6.81-7.01 (m, 3 H), 7.13 (t, J=8.84 Hz, 2 H), 7.38 (dd, J=8.29, 5.72 Hz, 2 H), 7.78 (s, 1 H), 8.43 (d, J=11.90 Hz, 1 H), 8.51 (s, 1 H), 9.14-9.25 (m, 1 H), 10.38 (s, 1 H), 11.32 (br. s., 1 H). (ESIMS (M+H)+=645)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:17]([C:18](=O)[NH:19][CH2:20][C:21](=O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O.[OH-].[NH4+:35]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH:17]([C:18]2[NH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:35]=2)[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2CC1C(=O)NCC(=O)c1ccccc1
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2CC1c1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C

Procedure:
The product prepared in Step A above (3.55 g, 9 mmol), NH4OAc (ammonium acetate) (20.8 g, 270 mmol) and AcOH (acetic acid) (30 mL) were combined at room temperature and the reaction mixture was warmed on a steam bath for about 3 hours. The reaction mixture was then cooled to room temperature and poured into an ice slurry mix (400 g). To this mixture was added concentrated ammonium hydroxide (50 mL) and ethyl ether. The layers were separated, and the aqueous phase washed with a second portion of ethyl ether. The organic phases were combined, dried over MgSO4 filtered, and concentrated under reduced pressure to yield a brown foam. This sample was purified by preparative HPLC to yield the purified title compound as a white powder. LC indicated the sample was 96% pure at 214 nm.