Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[H-].[Na+].Br[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1.C(OCC)(=O)C>CS(C)=O>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CN(C)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCSc1ccc(C=O)cc1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 73 %

Procedure:
2-dimethylaminoethanethiol hydrochloride (1.00 g, 7.06 mmol) was suspended in dry DMSO (20 ml) and sodium hydride (60% in mineral oil, 593 mg, 2.1 equivs) was added. The reaction mixture was left stirring for 40 mins to form Me2NCH2CH2SNa, before 4-bromobenzaldehyde (1.193 g, 1 eq) was added, and the reaction mixture was then warmed to 90° C. under nitrogen. After 1 hour at 90°-100° C. analysis by thin layer chromatography (tlc) indicated almost complete disappearance of the starting material. The reaction mixture was therefore cooled, ethyl acetate was added and the mixture washed with sodium carbonate solution and brine. The mixture was then extracted with HCl (2N), basified and re-extracted with dichloromethane, dried over magnesium sulphate and the solvent was removed in vacuo to give the title compound as a yellow oil (73%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][C:17]1[CH:31]=[C:30]2[C:20]([NH:21][CH:22]=[C:23]2[CH2:24][CH:25]([C:27]([OH:29])=[O:28])[NH2:26])=[CH:19][CH:18]=1>>[C:27]([CH:25]([NH:26][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:24][C:23]1[C:30]2[C:20](=[CH:19][CH:18]=[C:17]([CH3:16])[CH:31]=2)[NH:21][CH:22]=1)([OH:29])=[O:28]
Reactant: Cc1ccc2[nH]cc(CC(N)C(=O)O)c2c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: Cc1ccc2[nH]cc(CC(Nc3nc4ccc(Cl)cc4cc3C(=O)O)C(=O)O)c2c1
Yield: 99 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 5-methyl-DL-tryptophan to provide the title compound in 99% yield as yellow needles (recrystallization from DMF/water).
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][C:31]1[CH:32]=[C:33]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[CH:34]=[CH:35][C:36]=1[C:37](=O)[CH3:38].CCOC(C)=O.CCCCCC>C1COCC1>[CH3:8][O:9][CH:10]=[C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:40]2[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=2)=[CH:32][C:31]=1[CH3:30])[CH3:38]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC=C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a an ambient temperature suspension of potassium tert-butoxide (2.42 g, 21.56 mmol) in THF (70 mL) is added (methoxymethyl)triphenylphosphonium chloride (7.39 g, 21.56 mmol) and is stirred at room temperature for 30 min. 1-(3-methyl-4′-trifluoromethyl-biphenyl-4-yl)-ethanone (2.0 g, 7.19 mmol) is added and the reaction mixture continues to stir at room temperature. After 2 h TLC (20% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (100 mL) and water (30 mL). The aqueous layer is extracted with EtOAc (100 mL) and The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (120 g SiO2, 10% EtOAc/Hexanes) to yield the title compound (2.22 g, quant.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH:4](Cl)[C:5](=[O:8])[CH2:6][CH3:7].C1(O)C=CC=CC=1.[C:18]([C:20]1[CH:21]=[C:22]([OH:28])[CH:23]=[C:24]([C:26]#[N:27])[CH:25]=1)#[N:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.O>[CH3:1][O:2][C:3](=[O:10])[CH:4]([O:28][C:22]1[CH:21]=[C:20]([C:18]#[N:19])[CH:25]=[C:24]([C:26]#[N:27])[CH:23]=1)[C:5](=[O:8])[CH2:6][CH3:7]
Reactant: N#Cc1cc(O)cc(C#N)c1
Reactant: CCC(=O)C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Solvent: O
Product: CCC(=O)C(Oc1cc(C#N)cc(C#N)c1)C(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.6 %

Procedure:
A solution of 2-chloro-3-oxo-pentanoic acid methyl ester (20 g, 121.5 mmol) in acetone (100 ml) was added to the phenol from Preparation 3 (17.5 g, 121.5 mmol) and caesium carbonate (43.5 g, 133.6 mmol) in acetone (400 ml) under a nitrogen atmosphere. The mixture was stirred at room temperature for 15 minutes and then heated under reflux for 2.5 hours. Water was added and the solvent was evaporated under reduced pressure. The residual aqueous solution was extracted with dichloromethane (3×300 ml) and the combined organic layers were dried over magnesium sulphate and evaporated under reduced pressure. The residual orange oil was pre-adsorbed onto silica gel and then purified by chromatography on silica gel using ethyl acetate in pentane (gradient from 20:80 to 80:20) to give the title compound as a yellow solid (27 g).
Reaction SMILES: [C:1]1([C:7]2[C:15]([CH2:16][C:17](=S)[C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:23][OH:24].[OH-].[K+].C(O)C>O>[C:1]1([C:7]2[C:15]([CH2:16][C:17](=[N:23][OH:24])[C:18]([OH:20])=[O:19])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C(=S)Cc1c(-c2ccccc2)nn2ccccc12
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C(Cc1c(-c2ccccc2)nn2ccccc12)=NO
Yield: 69.8 %

Procedure:
A mixture of 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-thioxopropionic acid (3.74 g), hydroxylamine hydrochloride (2.63 g), 85% potassium hydroxide (2.50 g) and 80% aqueous ethanol (22.4 ml) was refluxed for 3 hours. After cooling, to the reaction mixture was added water (40 ml) and the resulting precipitates were filtered off. The filtrate was washed with methylene chloride (20 ml) twice, acidified with 10% aqueous hydrochloric acid (pH≈2), and extracted with ethyl acetate (20 ml) twice. The organic layer was washed with water (10 ml) and a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was removed to give 3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-2-hydroxyiminopropionic acid (2.60 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9](=[N:11][OH:12])[CH3:10].[C:13](OC(=O)C)(=[O:15])[CH3:14]>>[C:13]([O:12][N:11]=[C:9]([C:3]1[C:4]([OH:8])=[CH:5][CH:6]=[CH:7][C:2]=1[OH:1])[CH3:10])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=NO)c1c(O)cccc1O
Product: CC(=O)ON=C(C)c1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.4 %

Procedure:
To 1-(2,6-dihydroxyphenyl)ethanone oxime (Intermediate 8, 588 mg), acetic anhydride (1.97 ml, 20.8 mmol) was added and the reaction mixture was stirred at room temperature for 15 minutes. After the removal of the volatiles, water was added and the solid obtained was filtered and dried under high vacuum affording 437 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH:4]([OH:17])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:9].[H-].[Na+].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>O1CCCC1>[CH3:1][O:2][C:3](=[O:18])[CH:4]([O:17][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1)=[O:9]
Reactant: COC(=O)C(O)CCNC(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(CCNC(=O)c1ccc(Cl)cc1)OCC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 165.6 %

Procedure:
A solution of 4-(N-(4-chlorophenylcarbonyl)amino)-2-hydroxybutyric acid methyl ester (3 g) in tetrahydrofuran (15 ml) was dropped to a mixture of 60% sodium hydride (2.38 g) in tetrahydrofuran (10 ml) at −78° C. The mixture was stirred at 0° C. for 30 minutes. t-Butyl bromoacetate (0.975 g) was dropped to the mixture at −78° C. The mixture was stirred at 0° C. for 1.5 hours. To the reaction mixture, 1N hydrochloric acid was added and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-Hexane:Ethyl acetate=1:1) to give the title compound (3.194 g) having the following physical data.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>C1C=CC=CC=1.CCCCCC.C(OCC)(=O)C>[C:1]([NH:9][C@H:10]([C:14]([O:16][CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])(=[S:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Solvent: c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=S)c1ccccc1)C(C)C
Temperature: 20 °C

Procedure:
To 3.0 g. N-benzoyl-L-valine, methyl ester dissolved in 50 ml benzene was added 0.56 g. phosphorus pentasulfide in one portion at 20° C. The mixture was refluxed for about 4 hours, cooled to about 20° C. and filtered. The resulting oil which was collected was washed with methylene chloride and filtered. The combined filtrates were concentrated under vacuum to yield a yellow oil. Column chromatography with silica gel and a hexane-ethyl acetate solvent system gave 1.89 g. (59%) of a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:31])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][CH:9]2[C:28](O)=[O:29])[CH:5]=[CH:6][CH:7]=1.[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH2:42])=[CH:37][C:36]=1[O:43][CH3:44].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH3:32][O:33][C:34](=[O:45])[C:35]1[CH:40]=[CH:39][C:38]([CH2:41][NH:42][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:31])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[NH:10]2)=[O:29])=[CH:37][C:36]=1[O:43][CH3:44]
Reactant: COC(=O)c1ccc(CN)cc1OC
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1OC
Yield: 104 %

Procedure:
In a manner similar to the method described in Example 379, rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid (64 mg, 0.137 mmol) and 4-aminomethyl-2-methoxy-benzoic acid methyl ester (55 mg, 0.282 mmol) in N,N-dimethyl formamide (5 mL) were reacted with DIPEA (111.3 mg, 0.861 mmol), HOBt (38.8 mg, 0.287 mmol) and HBTU (107.6 mg, 0.284 mmol) at room temperature to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-methoxy-benzoic acid methyl ester (91.8 mg, ˜100%). HRMS (ES+) m/z Calcd C33H33Cl2F2N3O4+H [(M+H): 644.1889. Found: 644.1885.
Reaction SMILES: FC(F)(F)C([O-])=O.[NH2:8][C@@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[S:11][CH2:12][C:13](/[CH:21]=[C:22]1/[C:23](=[O:46])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][N+:31]([CH2:34][C:35](=[O:45])[NH:36][C:37]4[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([F:44])[CH:38]=4)=[CH:30][CH:29]=3)[CH2:25][CH2:26]/1)=[C:14]2[C:18]([OH:20])=[O:19].C[Si](N=C(O[Si](C)(C)C)C(F)(F)F)(C)C.[Br:62][CH2:63][C:64](Br)=[O:65].O>ClCCl.C(OCC)C>[Br:62][CH2:63][C:64]([NH:8][C@@H:9]1[C:16](=[O:17])[N:15]2[C@@H:10]1[S:11][CH2:12][C:13](/[CH:21]=[C:22]1/[C:23](=[O:46])[N:24]([CH2:27][C:28]3[CH:29]=[CH:30][N+:31]([CH2:34][C:35](=[O:45])[NH:36][C:37]4[CH:42]=[CH:41][C:40]([OH:43])=[C:39]([F:44])[CH:38]=4)=[CH:32][CH:33]=3)[CH2:25][CH2:26]/1)=[C:14]2[C:18]([O-:20])=[O:19])=[O:65]
Reactant: O=C(Br)CBr
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(/C=C3\CCN(Cc4cc[n+](CC(=O)Nc5ccc(O)c(F)c5)cc4)C3=O)CS[C@H]12
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: O=C(C[n+]1ccc(CN2CC/C(=C\C3=C(C(=O)[O-])N4C(=O)[C@@H](NC(=O)CBr)[C@H]4SC3)C2=O)cc1)Nc1ccc(O)c(F)c1
Reaction time: 3 h

Procedure:
To a suspension of 280.0 mg (0.42 mmol) (E)-(6R,7R)-7-amino-3-[1-[1-[(3-fluoro-4-hydroxy-phenylcarbamoyl)-methyl]-pyridin-1-ium-4-ylmethyl]-2-oxo-pyrrolidin-3-ylidenemethyl]-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylate trifluoroacetate in 4 ml dichloromethane were added 0.37 μl (1.40 mmol) N,O-bis-(trimethylsilyl)-trifluoroacetamide. After a clear solution had formed, 36.8 μl (0.42 mmol) bromoacetyl bromide were added and the reaction mixture was stirred for 3 h. To this solution 25.6 μl (1.42 mmol) water and 25 ml diethyl ether was added. The precipitate was filtered off and washed with diethyl ether.
Reaction SMILES: [CH:1](=[O:3])[CH3:2].[Si](O[C@H:12]1[CH2:17][CH2:16][C@H:15]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.[Bi](Br)(Br)Br.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:3][C@H:12]1[CH2:13][CH2:14][C@H:15]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:16][CH2:17]1)[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Reactant: CC=O
Agent: Br[Bi](Br)Br
Agent: CC[SiH](CC)CC
Solvent: CC#N
Product: CCO[C@H]1CC[C@H](N2C(=O)c3ccccc3C2=O)CC1
Temperature: 25 °C

Procedure:
Acetaldehyde (10 mL; 0.17 mol) in acetonitrile (50 mL) was added over 30 minutes to a solution of trans-N-(4-tert-butyldimethylsilyloxycyclohexyl)phthalimide (D63; 50.0 g; 0.14 mol), bismuth tribromide (6.7 g; 0.015 mol) and triethylsilane (27 mL; 0.18 mol) in acetonitrile (500 mL) stirred at ice bath temperature and the mixture was allowed to warm to room temperature overnight. The mixture was filtered and the resulting grey solid and filtrate were worked up separately. The filtrate was evaporated and treated with hexane to give the title compound as a white solid (16.35 g). The grey solid was washed with dichloromethane, the dichloromethane extract was evaporated and the residue was stirred with hexane (200 mL) to give a second crop of the title compound as a white solid (17.47 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.Cl.[CH3:15][NH:16][OH:17].C(=O)([O-])[O-].[Na+].[Na+].[C:24]([C:31]([O:33][CH2:34][CH3:35])=[O:32])#[C:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>O.C(O)C>[CH2:34]([O:33][C:31]([C:24]1([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[O:17][N:16]([CH3:15])[C:6]([C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][C:4]=2[S:10]([CH3:13])(=[O:12])=[O:11])=[N:7]1)=[O:32])[CH3:35]
Reactant: CNO
Reactant: CCOC(=O)C#CC(=O)OCC
Reactant: CS(=O)(=O)c1cc(F)ccc1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CC1(C(=O)OCC)N=C(c2ccc(F)cc2S(C)(=O)=O)N(C)O1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
To a stirred suspension of 4-fluoro-2-(methylsulfonyl)benzonitrile (prepared according to the procedure described in Anthonyl, N. J. et al PCT Appl. WO 02/30931, 2002) (2.2 g, 11 mmol) and N-methylhydroxylamine hydrochloride (1.66 g, 20 mmol) in 1:1 water/ethanol (40 mL) was added sodium carbonate (1.06 g, 10 mmol) in small portions and the resulting mixture stirred at 80° C. for 3 h. The reaction mixture was concentrated and the residue was re-dissolved into 1:1 water :ethanol (50 mL). To this solution was added diethyl acetylene-dicarboxylate (1.92 mL, 12 mmol) and the resulting mixture stirred for 30 min at room temperature. The reaction mixture was then taken-up into ethyl acetate (150 mL), washed successively with water and brine (50 mL each), dried (MgSO4), filtered and concentrated to give yellow oil. The crude product was purified on silica gel column (3:7 to 2:3 ethyl acetate/hexanes) to afford the title product as a white solid (2.9122 g, 64% yield). 1HNMR (500 MHz, CDCl3) δ: 7.89 (1H, dd, J=8.09, 2.59 Hz), 7.62 (1H, dd, J=8.39, 5.04 Hz), 7.40 (1H, td, J=8.24, 2.44 Hz), 4.35–4.26 (2H, m), 4.19–4.13 (2H, m), 3.40 (3H, s), 3.38 (1H, d, J=16.17 Hz), 3.15 (1H, d, J=16.17 Hz), 3.02 (3H, s), 1.36–1.30 (3H, m), 1.27–1.23 (3H, m). HRMS (ESI) calcd for C17H22FN2O7S (M+H): 417.1132; found: 417.1116.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])(O)[CH:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2].[H-].[Na+].O.C(OCC)(=O)C>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])=[C:9]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:8]=2[CH:24]=1)([O-:3])=[O:2]
Reactant: CC1(C)Oc2ccc([N+](=O)[O-])cc2C(n2ccccc2=O)C1(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(n2ccccc2=O)c2cc([N+](=O)[O-])ccc2OC1(C)C
Yield: 48.5 %

Procedure:
A solution of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-3,4-dihydro-3-hydroxy-2H-1-benzopyran (3.53 g, 0.0107 mol) in tetrahydrofuran (150 ml) was treated with sodium hydride (80%, 0.32 g). The mixture was heated at reflux for sixteen hours. Water and ethyl acetate were added to the cooled solution and the organic layer separated, dried and evaporated under reduced pressure to afford 1.62 g of 6-nitro-2,2,3-trimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 200° C.
Reaction SMILES: [CH3:1][N:2]1[O:9][CH:8]([CH3:10])[CH:7]2[CH:3]1[CH2:4][N:5](C(OCC)=O)[CH2:6]2.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][N:2]1[O:9][CH:8]([CH3:10])[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2
Reactant: CCOC(=O)N1CC2C(C)ON(C)C2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC1ON(C)C2CNCC12

Procedure:
13.2 g (61.6 mmol) of ethyl 2,4-dimethyl-3-oxa-2,7-diazabicyclo[3.3.0]octane-7-carboxylate are heated under reflux with 39 g of Ba(OH)2.8HaO in 200 ml of water overnight. K2CO3 is added, the BaCO3 is filtered off with suction and the filtrate is extracted several times with CHCl3. The extract is dried over K2CO3 and concentrated and the residue is distilled.
Reaction SMILES: [C:1]([C:5]1[C:13]([N+:14]([O-])=O)=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.C(O)C>[Fe].O>[C:1]([C:5]1[C:13]([NH2:14])=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2c(cc1[N+](=O)[O-])OCO2
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1cc2c(cc1N)OCO2
Reaction time: 2 h
Yield: 24.8 %

Procedure:
The above prepared 5-tert-Butyl-6-nitrobenzo[d][1,3]dioxole (1.1 g, 5 mmol), Fe (5.5 g, 100 mmol) and HCl (2 ml) was added into ethanol (6 ml) and water (18 ml). The mixture was stirred for 2 h at refluxed temperature. The PH was adjusted to 7-8 and the mixture was filtered and washed with methanol. The filtrate was concentrated and purified by column chromatography (petroleum ether/ethyl acetate 1%-5%) to give 6-tert-butylbenzo[d][1,3]dioxol-5-amine (240 mg, 25%) as a red solid. LCMS: 194 [M+1]+; 1H NMR (400M): (DMSO-d6) δ 1.28 (s, 9H), 4.46 (s, 2H), 5.77 (s, 2H), 6.32 (s, 1H), 6.63 (s, 1H).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]=5[O:29][C@H:30]([CH3:35])[C:31]([O:33]C)=[O:32])[N:22]=[CH:21][N:20]=4)=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[N:5]=[CH:4]1>C1COCC1.CO>[S:3]1[CH:7]=[C:6]([CH2:8][N:9]2[C:17]3[C:12](=[CH:13][C:14]([NH:18][C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][C:27]=5[O:29][C@H:30]([CH3:35])[C:31]([OH:33])=[O:32])[N:22]=[CH:21][N:20]=4)=[CH:15][CH:16]=3)[CH:11]=[N:10]2)[N:5]=[CH:4]1
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@@H](Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
Aqueous sodium hydroxide (2N, 1 ml, 2 mmol) was added to a solution of methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (480 mg, 1 mmol) in THF (3 ml) and methanol (3 ml). The mixture was stirred at room temperature for 2 hours. After evaporation of the solvents, the pH of the mixture was adjusted to 3 by addition of 2N hydrochloric acid. The precipitate formed was filtered, washed with water and dried under high vacuum to give (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoic acid (435 mg, 97%); Mass spectrum MH+ 447.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:10][C:11](=O)[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1.[CH3:26][N:27]([CH3:32])[CH2:28][CH2:29][CH2:30][NH2:31]>C(O)C>[Cl:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[CH2:8][CH:9]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=4[Cl:25])[CH2:10][C:11](=[N:31][CH2:30][CH2:29][CH2:28][N:27]([CH3:32])[CH3:26])[C:12]=3[C:13]2=[O:16])=[CH:4][CH:3]=1
Reactant: CN(C)CCCN
Reactant: O=C1CC(c2ccc(Cl)cc2Cl)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Solvent: CCO
Product: CN(C)CCCN=C1CC(c2ccc(Cl)cc2Cl)Cc2[nH]c3ccc(Cl)cc3c(=O)c21
Temperature: 0 °C

Procedure:
A mixture of 3.10 g of 7-chloro-3-(2,4-dichlorophenyl)-3,4-dihydro-1,9(2H,10H)-acridinedione and 1.6 g of N,N-dimethyl-1,3-propanediamine in 125 ml of ethanol is heated under reflux for 1.5 hrs. Approximately 65 ml of solvent is removed by distillation and the resulting turbid solution is filtered. The filtrate is diluted with 50 ml of ether and chilled to 0° C. The solid is collected and recrystallized from a mixture of dichloromethane/ethyl acetate. Dry in vacuo at 80° C. for 4 hrs gives 7-chloro-3-(2,4-dichlorophenyl)-1-[[3-(dimethylamino)propyl]imino]-1,3,4,10-tetrahydro-9(2H)acridinone; mp 168°-170° C.
Reaction SMILES: C(C1OC1)Cl.[CH2:6]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[CH:21]=[N:22][OH:23])[CH:7]1[O:9][CH2:8]1.ClN1C(=O)CCC1=O.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:6]([O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]=1[C:21]#[N+:22][O-:23])[CH:7]1[O:9][CH2:8]1
Reactant: ON=Cc1c(OCC2CO2)ccc2ccccc12
Agent: O=C1CCC(=O)N1Cl
Solvent: ClCC1CO1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: [O-][N+]#Cc1c(OCC2CO2)ccc2ccccc12
Yield: 79 %

Procedure:
As shown in Chemical Formula 2, 3.00 g (12.3 mmol) of 2-(glycidyloxy)-1-naphthoaldehyde oxime (4) was dissolved in 66 mL of chloroform in an ice bath and thereto, 1.84 g (13.5 mmol) of N-chlorosuccinimide (NCS) was added. While stirring the resultant reaction mixture, 1.63 mL (16.0 mmol) of triethylamine was added to the reaction mixture, followed by stirring the resultant reaction mixture for 6 hours to effect the reaction. Then, the reaction solution was washed with each of 50 mL of pure water and 50 mL of Brine three times, and the organic phase was dried over MgSO4, followed by concentrating the solvent under reduced pressure to obtain 2-(glycidyloxy)-1-naphthonitrile oxide B with a yield of 79%.