Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][C:17]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27]C)=[O:26])(=[O:22])=[O:21])=[O:18])[N:10]=1.O>CS(C)=O>[CH3:7][O:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH:16][C:17]([NH:19][S:20]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([OH:27])=[O:26])(=[O:22])=[O:21])=[O:18])[N:10]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)O)n1
Yield: 51.9 %

Procedure:
A solution of 0.5 g of potassium tert-butoxide and 1.0 g of methyl 2-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]aminosulfonylbenzoate in 25 ml of dimethyl sulfoxide was stirred at ambient temperature for 3 hours. The yellow solution was then poured into 250 ml of cold water. The free carboxylic acid was precipitated by the addition of enough concentrated hydrochloric acid to reach pH 3. The crude product was filtered, washed with water and dried in vacuo. Recrystallization from acetonitrile yielded 0.5 g of the title compound, m.p. 157°-158° C. The mass spectrum of this compound exhibited the expected molecular ion at m/e=367. The infrared bands at 3300 cm-1 and 1725 cm-1 are consistent with the desired structure. The nuclear magnetic resonance spectrum showed peaks at 2.5 ppm (triazine CH3), 3.9 ppm (triazine OCH3) and 7.4-8.2 ppm (phenyl). The methyl ester peak present in the starting material was not observed in the spectrum of the product.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[N+:10]1([O-:20])[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[CH:13]=[CH:12][CH:11]=1>O>[N+:6]([C:13]1[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[N+:10]([O-:20])=[CH:11][CH:12]=1)([O-:9])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cccc2c1CCCC2
Agent: O=S(=O)(O)O
Solvent: O
Product: O=[N+]([O-])c1cc[n+]([O-])c2c1CCCC2
Temperature: 25 °C

Procedure:
A stirred mixture of sulphuric acid (200 ml) and nitric acid (200 ml) was treated with 5,6,7,8-tetrahydroquinoline N-oxide (47 g, 315 mmol), heated at 60°-80° for 3h, cooled to room temperature, poured onto ice (1 Kg), diluted with water (1 1), and extracted with dichloromethane (3×500 ml). The extracts were dried (MgSO4) and evaporated in vacuo to give the product (48 g) as an oil.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:26]([CH3:28])=[CH2:27].C(N)CN.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:28][CH:26]=[CH2:27])[CH:24]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(C)Br
Reactant: CC(C)(C)[Si](OCc1c[nH]cn1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: NCCN
Product: C=CCn1cnc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-1H-imidazole (1.000 g), 2-bromo-1-propene (1.04 mL), ethylenediamine (0.40 mL), copper iodide (0.28 g) and tripotassium phosphate (1.30 g) were suspended in dioxane (10 mL), and reacted in a microwave reactor (product name: Initiator, manufactured by Biotage, Ltd.) at 140° C. for 5 hours. The reaction solution was filtered using Celite to filter off the insolubles, followed by concentration of the mother liquor. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→100%) using silica gel column (product name: Hi-Flash column 3 L, manufactured by Yamazen Corporation) to afford the title compound (0.350 g).
Reaction SMILES: [S:1](=[O:5])(=O)([OH:3])[OH:2].[OH:6][C:7]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].ClCCl>CCOCC>[C:9]([C:8]1[CH:12]=[C:13]([S:1]([OH:3])(=[O:5])=[O:2])[CH:14]=[C:15]([OH:16])[C:7]=1[OH:6])([OH:11])=[O:10]
Reactant: O=S(=O)(O)O
Reactant: O=C(O)c1cccc(O)c1O
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)c1cc(S(=O)(=O)O)cc(O)c1O

Procedure:
Concentrated sulphuric acid (1 ml) and 2,3-dihydroxybenzoic acid (0.5 g) were heated at 60° C. for 1 hour. The mixture was cooled, taken up in ether (20 ml), poured into dichloromethane (200 ml) and cooled to give as crystals, 3-carboxy-4,5-dihydroxybenzenesulphonic acid (0.31 g); δ(DMSO-d6); 7.34(d,1H); 7.61(d,1H). To a suspension of this acid (1 g) in acetonitrile (10 ml) was added triethylamine (2.4 ml), followed by isobutyryl chloride (1.5 ml). The solution was stirred at room temperature for 1 hour, the solvent was evaporated and the residue purified by chromatography on Diaion HP 20 SS resin (aqueous methanol containing 1% acetic acid) to give 3-carboxy-4,5-di-isobutyroxybenzene sulphonic acid (1.2 g); δ(DMSO-d6): 1.19(s,6H); 1.27(s,6H); 2.90-3.15(m,2H); 7.63(d,1H); 8.04(d,1H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][C@@H:13]([C:32]([OH:34])=[O:33])[NH:14]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][O:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52]Cl)=[CH:50][CH:49]=1>CCCCCC.CCOC(C)=O>[CH3:46][O:47][C:48]1[CH:55]=[CH:54][C:51]([CH2:52][O:34][C:32](=[O:33])[CH:13]([NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])=[CH:50][CH:49]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)C(N)CCCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
Compound 2 was prepared in two steps. Into a 250 mL, flame dried three necked round bottom flask under nitrogen was placed Nε-Boc-Nα-Fmoc-L-lysine (7.0 g, 15 mmol) and 60 mL of dry DMF. To this was added cesium carbonate (7 g, 21 mmol) and 4-methoxybenzyl chloride (2.5 g, 16 mmol). The suspension was stirred at room temperature under nitrogen for 4 h, then filtered and washed with ethyl acetate. Product isolation (EtOAc, 5% Na2CO3, water, Na2SO4) followed by recrystallization from 60/40 (v/v) hexane/EtOAc gave 2 crops of a colorless solid. mp 118-120° C. TLC Rf=0.33 (70/30 Hexane/EtOAc). Yield: 8.22 g, 14 mmol, 93.43%. 1H NMR(CDCl3) δ: 7.75 (d, J=7.2 Hz, 2H), 7.55 (d, J=7.2 Hz, 2H), 7.38 (t, J=7.5 Hz, 2H), 7.32-7.20 (m, 4H), 6.85-6.80 (m, 2H), 5.4 (d, J=7.6 Hz, 1H), 5.18-5.00 (m, 2H), 4.44-4.38 (m, 3H), 4.17 (t, J=6.0 Hz 1H), 3.80-3.70 (m, 4H), 3.00 (m, 2H), 1.90-1.11 (m, 15H). ESIMS m/z: 588.40 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH3:8])[N:3]=1.[Cl:9][S:10](O)(=[O:12])=[O:11]>>[Cl:1][C:2]1[C:6]([S:10]([Cl:9])(=[O:12])=[O:11])=[CH:5][N:4]([CH2:7][CH3:8])[N:3]=1
Reactant: O=S(=O)(O)Cl
Reactant: CCn1ccc(Cl)n1
Product: CCn1cc(S(=O)(=O)Cl)c(Cl)n1
Temperature: 100 °C

Procedure:
3-Chloro-1-ethyl-1H-pyrazole (0.42 g, 3.2 mmol, the product of Step B) was added to chlorosulfonic acid (2.0 mL, 30 mmol) at room temperature and the mixture was slowly warmed to 100° C., and then heated at 100-110° C. for 2 hours. The reaction mixture was cooled, poured with stirring onto 150 mL of crushed ice, and extracted into diethyl ether (2×100 mL). The ether extracts were combined, washed with water (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to obtain 0.5 g of the title compound as an oil. 1H NMR (CDCl3) δ 8.00 (s, 1H), 4.20 (q, 2H), 1.56 (t, 3H).
Reaction SMILES: FC(F)(F)S([O:6][C:7]1[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22](OS(C(F)(F)F)(=O)=O)[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[O:19]3)[C:9]=2[N:10]=[C:11]([NH2:13])[N:12]=1)(=O)=O.[C-:42]#[N:43].[Na+].CCOC(C)=O>CN(C=O)C>[NH2:13][C:11]1[NH:12][C:7](=[O:6])[C:8]2[S:16][C:15](=[O:17])[N:14]([C@H:18]3[C@H:22]([C:42]#[N:43])[CH2:21][C@@H:20]([CH2:31][O:32][Si:33]([C:36]([CH3:38])([CH3:39])[CH3:37])([CH3:34])[CH3:35])[O:19]3)[C:9]=2[N:10]=1
Reactant: [C-]#N
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](OS(=O)(=O)C(F)(F)F)[C@H](n2c(=O)sc3c(OS(=O)(=O)C(F)(F)F)nc(N)nc32)O1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](C#N)[C@H](n2c(=O)sc3c(=O)[nH]c(N)nc32)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118 %

Procedure:
To a stirred solution of [5-amino-3-[(2R,3R,5S)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-(trifluoromethylsulfonyloxy)tetrahydrofuran-2-yl]-2-oxo-thiazolo[4,5-d]pyrimidin-7-yl] trifluoromethanesulfonate (compound 38g, crude, 120 mg, 0.2 mmol) in DMF (2 mL) was added sodium cyanide (100 mg, 2.3 mmol). After being stirred at room temperature for 2 hours, the resulting solution was diluted by EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 100 mg crude product of (2R,3S,5S)-2-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-5-[[tert-butyl(dimethyl)silyl]oxymethyl]tetrahydrofuran-3-carbonitrile (compound 38h), which was used in next step without further purification. MS obsd. (ESI+) [(M+H)+]: 424.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:12]1([N:18]=[C:19]=[S:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOCC>C(Cl)Cl>[SH:20][C:19]1[N:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:1](=[O:10])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: S=C=Nc1ccccc1
Reactant: COC(=O)c1ccccc1N
Solvent: CCOCC
Solvent: ClCCl
Product: O=c1c2ccccc2nc(S)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 500 ml, three-neck round bottom flask equipped with magnetic stirrer, 25 g (0.17 moles) methyl anthranilate in 100 ml methylene chloride was placed. Into that mixture 23.0 g (0.17 moles) phenyl isothiocyanate in 50 ml methylene chloride was dropped in. The reaction mixture was stirred overnight at ambient temperature. The reaction mixture was refluxed at 40° C. for one hour. Ether (about 50 ml) was added; a precipitate formed which was removed by suction filtration to give the above-identified product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][O:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11].[CH2:19](O)[CH3:20]>>[ClH:2].[Cl:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[CH2:5][NH:6][O:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10]([O:12][CH2:19][CH3:20])=[O:11]
Reactant: CCO
Reactant: CC(C)(CONCc1ccccc1Cl)C(=O)O
Agent: Cl
Product: CCOC(=O)C(C)(C)CONCc1ccccc1Cl
Reaction time: 8 h

Procedure:
Dry hydrogen chloride gas was passed through a stirred solution of 2-(2-chlorobenzylaminooxymethyl)-2-methylpropanoic acid (2.0 grams; 0.01 mole) in absolute ethanol (100 mL) at ambient temperature for two minutes. The reaction mixture was stirred overnight under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by passing it through a silica gel column, eluting first with methylene chloride (200 mL) and then with 95:5 methylene chloride:methanol. Appropriate fractions were combined and then concentrated under reduced pressure to afford 0.45 grams of ethyl 2-(2-chlorobenzylaminooxymethyl)-2-methylpropanoate hydrochloride as a colorless gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[Na+].[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([O-:29])(=[O:28])=[O:27])=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (1.0 g), 2-formylbenzensulfonic acid sodium salt (0.94 g) and 1,2-dichloroethane (15 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (4.3 mL), trifluoroacetic acid (1.0 mL) and 1,2-dichloroethane (10 mL), and the resulting mixture was stirred at room temperature for 6 hours. The mixture was extracted with ethyl acetate and the combined organic extract was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (0:1 to 1:9 by volume) to afford the title compound as a purple gum (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][C:10](OCC)=[O:11])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(#N)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:27]2[CH2:29][CH2:28]2)([C:15]2[C:23]3[C:18](=[C:19]([CH2:24][S:25][CH3:26])[CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[CH2:9][CH2:10][OH:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)(c1c[nH]c2c(CSC)cccc12)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: CSCc1cccc2c(C(CCO)(c3ccc(Cl)cc3)C3CC3)c[nH]c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A solution of 62 mg (0.15 mmol) of the compound from Example 105A in 0.5 ml of tetrahydrofuran was added dropwise to 0.51 ml (0.51 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 1 ml of tetrahydrofuran at RT under argon. The mixture was stirred at 60° C. for 1 h and then mixed with water and acetonitrile, and the suspension was filtered through kieselguhr. The solvents were removed in a rotary evaporator, and the residue was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 52 mg (93% of theory) of the title compound were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@H:10]([CH2:12][CH3:13])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.Cl.[CH3:34][O:35][C:36](=[O:45])[C@H:37]([CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1)[NH2:38]>C(Cl)Cl>[CH3:34][O:35][C:36](=[O:45])[C@H:37]([CH2:39][C:40]1[N:44]=[CH:43][NH:42][CH:41]=1)[NH:38][C:14](=[O:16])[C@H:9]([C@H:10]([CH2:12][CH3:13])[CH3:11])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)OC
Temperature: -70 °C
Reaction time: 0.08 h

Procedure:
23.3 of t-butoxycarbonylisoleucine is dissolved in 200 ml of methylene chloride. 33.3 ml of N-methylmorpholine is added to the solution. The solution is cooled to -70° C. 13.1 ml of isobutylchloroformate is then added. The reaction mixture is warmed up to -15° C. and stirred for 5 minutes. The reaction mixture is again cooled to -70° C. 26.0 g of histidine methyl ester dihydrochloride is added to the reaction mixture. The reaction mixture is allowed to warm to room temperature, and then is stirred for 16 hours. The reaction mixture is extracted three times with 0.5 M potassium bisulfate and once with brine. The methylene chloride solution is dried over anhydrous sodium sulfate, filtered and stripped of of solvent. The residue is dissolved in 200 ml of ethyl ether. The ether solution is added to cold rapidly stirring Skellysolve B. The white precipitate is filtered and dried to afford the product t-butoxycarbonylisoleucylhistidine methyl ester.
Reaction SMILES: [CH:1]1([NH:11][C:12]([CH:14]2[CH2:18][N:17]([C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH:16]3[CH2:24][CH2:25][N:26]([C:27](=[O:36])[CH:28]([NH2:35])[CH:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)[CH:15]23)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:37]([N:47]([CH3:53])[C@H:48]([C:50](O)=[O:51])[CH3:49])([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:38].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:40]([O:39][C:37](=[O:38])[N:47]([CH:48]([C:50](=[O:51])[NH:35][CH:28]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:27]([N:26]1[CH2:25][CH2:24][CH:16]2[N:17]([C:19]([CH:21]3[CH2:22][CH2:23]3)=[O:20])[CH2:18][CH:14]([C:12](=[O:13])[NH:11][CH:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[CH:15]12)=[O:36])[CH3:49])[CH3:53])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(C(=O)NC1CCCc3ccccc31)CN2C(=O)C1CC1)C1CCCCC1)N(C)C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A solution of 47 (330 mg, 0.67 mmol) in DCM (10 mL) was cooled to 0° C. and treated with Cbz-N(Me)Ala-OH (159 mg, 0.67 mmol), EDC (154 mg, 0.80 mmol), HOBt (109 mg, 0.80 mmol) and DIPEA (0.36 mL, 2.08 mmol), respectively. After 18 h, the solution was diluted with DCM, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated to afford 48 (454 mg) as a white foam that was used without further purification. Mass spectrum, m/z [712.9] (M+H)+.
Reaction SMILES: [C:1]1([SnH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[CH2:29])=[CH2:21].N(C(C)(C)C#N)=N[C:32](C)(C)[C:33]#N>>[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]=[CH2:29])=[CH2:21].[CH:32]([C:19]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Sn:7]([CH2:21][CH2:20][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:33]
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: c1ccc([SnH](c2ccccc2)c2ccccc2)cc1
Agent: C=Cc1ccccc1C=C
Product: C=Cc1ccccc1[Sn](CCc1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 30 h

Procedure:
To a 250 ml round bottomed flask equipped with a magnetic stir bar is added 28.0 grams of triphenyltin hydride, 33.0 grams of 91% divinylbenzene, and 0.26 gram of 2,2'-azo-bis-isobutyronitrile. The mixture is placed under a nitrogen blanket and heated to a temperature of from 40° to 45° C. Samples of the reaction mixture are periodically taken and subjected to infrared analysis. The reaction is terminated when the tin-hydrogen absorption at 1850 cm-1 in the infrared spectrum disappears. This occurs after approximately 30 hours of heating the reaction mixture. The product is then stored at 0° C. until used for the preparation of the polymer.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[C:3]1[CH3:14].[CH2:15]=O.Cl.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:15])[CH2:20][CH2:12][C:11]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:14])=[O:13]
Reactant: CC(=O)c1c(C)n(C)c2ccccc12
Reactant: CNC
Reactant: C=O
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)CCN(C)C)c2ccccc2n1C

Procedure:
A mixture of 1-(1,2-dimethyl-1H-indol-3-yl)-1-ethanone (0.9 g), paraformaldehyde (0.43 g) and dimethylamine hydrochloride (1.2 g) in ethanol (60 ml) was heated at reflux for 18 h, cooled, and the solvent evaporated in vacuo. The residue was partitioned between sodium carbonate (2N; 50 ml) and ethyl acetate (2×50 ml) and the combined organic extracts were dried and evaporated in vacuo to give an oil. This oil was chromatographed eluting with System A to give the title compound, which on standing gave crystals (0.9 g), m.p. 96°-98°.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38](O)=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:64][NH:65][CH2:66][CH2:67][CH2:68][CH2:69][OH:70].C(=O)([O-])O.[Na+]>ClCCl.C(OCC)(=O)C>[F:49][C:2]([F:48])([F:1])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:46])([F:47])[F:45])[CH:43]=1)[C:6]([N:8]1[CH2:12][C@@:11]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][C:25]3([C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[CH2:29][C@@H:28]3[O:36][CH2:37][C:38]([N:65]([CH2:66][CH2:67][CH2:68][CH2:69][OH:70])[CH3:64])=[O:39])[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[O:10][CH2:9]1)=[O:7]
Reactant: O=C(O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reactant: CNCCCCO
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(CCCCO)C(=O)CO[C@H]1Cc2ccccc2C12CCN(CC[C@@]1(c3ccc(F)cc3)CN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CO1)CC2
Reaction time: 0.25 h
Yield: 77.3 %

Procedure:
The compound (400 mg, 0.576 mmol) obtained in Example 1j was dissolved in dichloromethane (30 mL), triethylamine (0.12 mL, 1.04 mmol) and pivaloyl chloride (0.11 mL, 0.864 mmol) were added under ice cooling, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 15 minutes. Subsequently, a solution of 4-(methylamino)butan-1-ol (178 mg, 1.73 mmol) in dichloromethane (2 mL) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 10:1, v/v) to give the title compound (347 mg; yield, 77%) as a colorless oily substance.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([OH:31])=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:54][C:55]1[N:60]=[C:59]([CH2:61][CH2:62]O)[CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[ClH:13].[Cl:13][C:14]1[CH:33]=[CH:32][C:17]([NH:18][C:19]2[C:28]3[C:23](=[CH:24][C:25]([O:31][CH2:62][CH2:61][C:59]4[CH:58]=[CH:57][CH:56]=[C:55]([CH3:54])[N:60]=4)=[C:26]([O:29][CH3:30])[CH:27]=3)[N:22]=[CH:21][N:20]=2)=[C:16]([F:34])[CH:15]=1
Reactant: Cc1cccc(CCO)n1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCc1cccc(C)n1
Product: Cl
Yield: 81.6 %

Procedure:
Diethyl azodicarboxylate (236 μl, 1.5 mmol) was added dropwise to a suspension of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (160 mg, 0.5 mmol), (prepared as described for the starting material in Example 24), triphenylphosphine (393 mg, 1.5 mmol) and 2-(6-methyl-2-pyridyl)ethanol (96 mg, 0.7 mmol), (J. Chem. Soc. A, 1971, 388), in methylene chloride (6 ml) and the mixture stirred for 16 hours at ambient temperature. The mixture was poured directly on to a silica column and eluted with methylene chloride/methanol (95/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1.5 ml of a 4.5M solution) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(6-methyl-2-pyridyl)ethoxy)quinazoline hydrochloride (97 mg, 34%).