Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Br:11][C:12]1[CH:13]=[C:14]([N+]([O-])=O)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.O>CN(C=O)C>[Br:11][C:12]1[CH:13]=[C:14]([O:8][C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][CH:6]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1
Reactant: N#Cc1ncc(Br)cc1[N+](=O)[O-]
Reactant: Cc1ncccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1Oc1cc(Br)cnc1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2-methylpyridin-3-ol (11.8 g, 108 mmol) in DMF at 0° C. was added sodium hydride (60% dispersion in oil, 4.32 g, 108 mmol) in small portions and the reaction was warmed to ambient temperature. To this mixture was added 5-bromo-3-nitropicolinonitrile (24.6 g, 108 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was poured into water (1000 mL) and the aqueous layer extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuo to yield 5-bromo-3-(2-methylpyridin-3-yloxy)picolinonitrile (15 g, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH3:10].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C[Si]([N:31]=[N+:32]=[N-:33])(C)C>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9]([CH3:10])=[N:33][N:32]=[N:31]1
Reactant: CC(=O)Nc1ccccc1Br
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: Cc1nnnn1-c1ccccc1Br
Temperature: -5 °C
Reaction time: 0.08 h
Yield: 44 %

Procedure:
To a solution of N-(2-bromophenyl)acetamide (1.0 equiv.) in acetonitrile (0.4 M) at −5° C., was added trifluoromethanesulfonic anhydride (2.0 equiv.) dropwise and the mixture was stirred for 5 min. Trimethylsilyl azide (4.0 equiv.) was added slowly while maintaining the temperature at −5° C., then the mixture was stirred at 0° C. for 80 mins. The mixture was poured into ice-cold sodium bicarbonate solution, extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the crude residue. The residue was purified by silica gel column chromatography (16% ethyl acetate in petroleum ether) to give the desired product (44% yield) as a yellow solid. MS (ESI) m/z 239.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:3]2[S:13][C:12]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH3:28])[CH:20]=4)[CH:16]=[C:17]([CH3:18])[C:11]=3[C:4]=2[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>O1CCCC1>[CH3:28][O:27][C:21]1[CH:20]=[C:19]([C:15]2[CH:16]=[C:17]([CH3:18])[C:11]3[C:4]4[N:5]=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]([N:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[C:3]=4[S:13][C:12]=3[N:14]=2)[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCCc1nc(Cl)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: CCCc1nc(N2CCNCC2)c2sc3nc(-c4ccc(OC)c(OC)c4)cc(C)c3c2n1

Procedure:
0.42 g (1.0 mmol) 4-chloro-7-(3,4-dimethoxyphenyl)-9-methyl-2-propyl-pyrido-[3′,2′:4,5]thieno[3,2-d]pyrimidine and 0.37 g (4.3 mmol) piperazine in 8 ml tetrahydrofuran are stirred at room temperature for 4 h. Having removed the solvent, the residue is suspended in 10 ml water and sucked off. The residue is suspended in about 50 ml dichloromethane and filtrated. The filtrate is washed with a total of 30 ml water, dried on sodium sulfate and the solvent is removed. The residue is recrystallized from ethyl acetate. 0.17 g (37%) of the title substance is obtained.
Reaction SMILES: [N:1](=[C:3]([C:7](=[O:10])[CH2:8][CH3:9])[C:4](=O)[CH3:5])O.[NH2:11][CH:12](C(O)=O)[CH2:13][CH2:14][CH3:15].C(C1NC(CCC)=NC=1C)(=O)C>C(O)CCC>[CH3:5][C:4]1[N:11]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:1][C:3]=1[C:7](=[O:10])[C:8]#[CH:9]
Reactant: CCCC(N)C(=O)O
Reactant: CCC(=O)C(=NO)C(C)=O
Agent: CCCc1nc(C)c(C(C)=O)[nH]1
Solvent: CCCCO
Product: C#CC(=O)c1[nH]c(CCC)nc1C
Yield: 44.9 %

Procedure:
To 92.4 g (0.646 moles) of 3-oximino-2,4-hexanedione dissolved in 807 ml of n-butanol was added 90.75 g (0.775 moles) of d,l-norvaline. The mixture was refluxed 6.25 h, then cooled and concentrated in vacuo. The residue was taken up in ethyl acetate (500 ml), suction filtered and the filtrate washed with 10% aqueous sodium hydroxide (4×100 ml). Removal of the solvent in vacuo gave 0.29 moles (48% yield based on recovered amino acid) of 4-methyl-5-propinoyl-2-propylimidazole and 5-acetyl-4-methyl-2-propylimidazole (87:13 respectively).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH2:14])=[C:11]([CH3:15])[O:10][N:9]=2)=[CH:4][CH:3]=1.Cl[C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:18]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:25]=[CH:26][C:17]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:15])=[N:18][CH:19]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1CN
Reactant: COC(=O)c1ccc(Cl)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nc1
Temperature: 160 °C
Yield: 32.7 %

Procedure:
A mixture of C-[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-yl]-methylamine (620 mg, 3.0 mmol), methyl 6-chloronicotinate (516 mg, 3.0 mmol), N,N-diisopropyl ethyl amine (1.0 mL, 6.0 mmol) and DMSO (6 mL) was heated in the microwave to 160° C. for 2 h. The mixture was then diluted with ice-water and extracted with ethyl acetate. The combined organic extracts were then washed with brine and dried over sodium sulfate. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1 then dichloromethane:methanol 97:3) afforded the title compound (335 mg, 33%) as a white foam. MS: m/e=342.1 [M+H]+.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=1)[CH2:4][C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>O.C(#N)C>[C:34]1(=[O:43])[N:2]([CH:3]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH:10]=2)[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: CCCCOc1cc(C(N)CC(=O)OC)ccc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CCCCOc1cc(C(CC(=O)OC)N2C(=O)c3ccccc3C2=O)ccc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.1 %

Procedure:
To a stirred solution of methyl 3-amino-3-(3-butoxy-4-methoxyphenyl)propionate hydrochloride (0.95 g, 3.0 mmol) and sodium carbonate (0.32 g, 3.0 mmol) in a mixture of water (10 niL) and acetonitrile (10 mL) was added N-carbethoxyphthalimide (0.68 g, 3.0 mmol). The resulting solution was stirred for 3 hours at room temperature. The acetonitrile was removed in vacuo. To the resulting mixture was added ether (5 mL) and the mixture was stirred at room temperature overnight allowing the ether to evaporate. The resulting white solid was filtered. The solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 1.1 g (89%) of methyl 3-phthalimido-3-(3-butoxy4-methoxyphenyl)propionate as a white solid: mp 54-55° C.; 1H NMR (CDCl3) δ7.86-7.63 (m, 4H), 7.16-7.05 (m, 2H), 6.85-6.76 (m, 1H), 5.76 (dd, J=5.9, 10 Hz, 1H), 4.02 (t, J=6.7 Hz, 2H), 3.86-3.71 (m, 1H), 3.83 (s, 3H), 3.63 (s, 3H), 3.24 (dd, J=5.9, 16.5 Hz, 1H), 1.89-1.73 (m, 2H), 1.59-1.41 (m, 2H), 1.04-0.89 (m, 3H); 13C NMR (CDCl3) δ171.1, 168.1, 149.2, 148.5, 133.9, 131.8, 130.9, 123.3, 120.2, 112.7, 111.4, 68.6, 55.9, 51.9, 50.7, 35.9, 31.1, 19.2, 13.9; HPLC (Waters Nova-Pak C18 column, 3.9×150 mm, 4 micron, 1 mL/min, 240 nm, 55/45, acetonitrile/0.1% aqueous phosphoric acid) 6.5 min, 100%, Anal. Calcd. for C23H25NO6. Theoretical: C, 67.14; H, 6.12; N, 3.40. Found: C, 66.89; H, 6.15; N, 3.31.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:29])C(O)CCC2C=CC=CC=2)[CH2:14][CH2:13]1.[C:31]1([CH2:37]C(O)=O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.OC1C=CC=CC=1[C@@H](CC)C(O)=O>>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][C:10](=[O:30])[CH2:11][N:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:29])[CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:16][CH2:17]1
Reactant: O=C(O)Cc1ccccc1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)C(O)CCc2ccccc2)CC1
Agent: CC[C@@H](C(=O)O)c1ccccc1O
Product: Cc1cccc(C)c1NC(=O)CN1CCN(C(=O)Cc2ccccc2)CC1

Procedure:
Compound 14 was prepared in the manner of compound 7 substituting 2-phenylacetic acid for (R)-2-hydroxy-phenylbutyric acid in part C to afford compound 14: Mass spectrum (M+1)=366.40.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[CH:24][C:23]=2[CH3:31])=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13].O>ClCCl>[NH2:9][C:10]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:30]3[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]3)=[C:24]([Br:1])[C:23]=2[CH3:31])=[O:21])=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)c1cc(C(=O)c2c(C)cc3ccccn23)ccc1N
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(C(=O)c2c(C)c(Br)c3ccccn23)ccc1N
Reaction time: 2 h
Yield: 89.4 %

Procedure:
0.492 g (2.73 mmol) of N-bromosuccinimide is added, under an inert atmosphere at ambient temperature, to 0.812 g (2.6 mmol) of methyl 2-amino-5-[(2-methylindolizin-3-yl)carbonyl]benzoate in 17 ml of dichloromethane. The reaction medium is stirred for 2 hours and then hydrolysed with water. The aqueous phase is extracted with dichloromethane. The organic phase obtained is washed with a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, filtered, and then concentrated under reduced pressure. The solid obtained is purified by silica gel column chromatography, elution being carried out with dichloromethane. 0.9 g of a yellow solid is obtained.
Reaction SMILES: CC(C)=O.[SH:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20][Cl:21]>C(Cl)Cl>[Cl:21][CH2:20][CH2:19][S:5][C:6]1[N:7]([CH3:11])[CH:8]=[CH:9][N:10]=1
Reactant: ClCCBr
Reactant: Cn1ccnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1ccnc1SCCCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To an acetone (40 ml) solution containing 2-mercapto-1-methylimidazole (4.0 g ) and anhydrous potassium carbonate (20 g) was added dropwise, under ice-cooling, 1-bromo-2-chloroethane (5.0 ml). The mixture was stirred for 2 hours at room temperature, to which was added methylene chloride (40 ml), followed by filtration. The filtrate was concentrated under reduced pressure to give 2-(2-chloroethyl thio)-1-methylimidazole (6.2 g ) as a colorless oily substance.
Reaction SMILES: C([Mg]Br)(C)C.[C:6]([O:12][CH2:13][CH3:14])(=[O:11])[CH2:7][C:8]([O-:10])=O.[CH3:15][C:16]1[O:21][CH2:20][N:19]([C:22](C)([CH3:26])[C:23](O)=O)[C:18](=[O:28])[C:17]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[N-]1C=CN=C1>O1CCCC1.CCOCC>[CH3:15][C:16]1[O:21][CH2:20][N:19]([C:22]([CH3:26])([CH3:23])[C:8](=[O:10])[CH2:7][C:6]([O:12][CH2:13][CH3:14])=[O:11])[C:18](=[O:28])[C:17]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)O)CO1
Reactant: CCOC(=O)CC(=O)[O-]
Agent: CC(C)[Mg]Br
Agent: O=C(n1ccnc1)n1ccnc1
Agent: c1c[n-]cn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C(C)(C)N1COC(C)=C(c2ccccc2)C1=O
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
Isopropyl magnesium bromide (0.7M solution in tetrahydrofuran) was added to a solution of monoethyl malonate(1.44 g) in tetrahydrofuran at 0° C. The mixture was stirred at 20° C. for 0.5 hour and at 40° C. for 0.5 hour. 2-(2,3-Dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)2-methylpropionic acid (2 g) and carbonyldiimidazole (1.42 g) was stirred in tetrahydrofuran for 8 hours and the resulting imidazolide solution then added to the above mixture at 0° C., stirred at 20° C. for 3 hours and refluxed for 2 hours. The mixture was diluted (ether), washed (5% hydrochloric acid), dried (MgSO4),evaporated and the residue purified by column chromatography (ethyl acetate/hexane 1:2) to give ethyl 4-(2,3-dihydro-6-methyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-4-methyl-3-oxo-pentanoate (Compound 200, 1.4 g), NMR 1.25(3H, t), 1.47(6H, s), 1.94(3H, s), 3.60(2H, s), 4.15(2H, q), 5.26(2H, s), 7.2-7.4(5H, m).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[CH3:23][C@H:24]([NH2:27])[CH2:25][CH3:26]>CS(C)=O.O>[C@@H:24]([NH:27][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2)([CH2:25][CH3:26])[CH3:23]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CC[C@H](C)N
Solvent: CS(C)=O
Solvent: O
Product: CC[C@H](C)Nc1nc2cc(C(=O)OC)ccc2nc1-c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 62.9 %

Procedure:
To a solution of methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (400.0 mg, 1.26 mmol) in DMSO (3 mL) was added (S)-butan-2-amine (200 mg, 2.74 mmol). The resulting solution was stirred overnight at 90° C. and then diluted with water (50 mL), extracted with dichloromethane (5×20 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography with 2% ethyl acetate in petroleum ether to afford (S)-methyl 3-(sec-butylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate as a yellow solid (280.0 mg, 63%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C(=O)([O-])O.[Na+]>O1CCOCC1>[I:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: Clc1ncccn1
Reactant: Nc1ccc(I)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Ic1ccc(Nc2ncccn2)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 54.7 %

Procedure:
Under an argon atmosphere, 2-chloropyrimidine (16.5 g) and acetic acid (11.7 ml) were added to a solution of 4-iodoaniline (30 g) in dioxane (500 ml), and the resulting mixture was stirred for 13 hours while heating the mixture to reflux. The reaction solution was cooled to room temperature and saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extracting the resulting mixture 4 times with ethyl acetate. Organic layers were washed 3 times with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent: cyclohexane/ethyl acetate=4/1). The product was recrystallized from dichloromethane/hexane mixed solvent to obtain N-(4-iodophenyl)pyrimidin-2-amine (22.27 g). NMR (H1, CDCl3): δ 6.73(1H, t, J=4.6 Hz), 7.18 (1H, brs), 7.40-7.42 (2H, m), 7.59-7.61 (2H, m), 8.41 (2H, d, J=4.6 Hz)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20]C)=[O:19])=[N:10]2)=[CH:5][CH:4]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 63.2 %

Procedure:
To a solution of dimethyl 1-[(4-methoxy)phenyl]pyrazole-3, 5-dicarboxylate (32.7 g, 110 mmol) in 50 mL of dioxane and 100 mL of water was added concentrated sulfuric acid (1.50 mL, 28.2 mmol). The resulting solution was stirred at 100° C. for 18 h and then cooled to room temperature. The reaction was made basic with potassium carbonate and then extracted with ether to remove unreacted diester. The aqueous layer was acidified with HCl and was extracted twice with ethyl acetate. The combined organics were washed with brine, dried (MgSO4) and concentrated to afford 19.2 g (63%) of the title compound along with 5.0 g (15%) of unreacted starting material. The title compound was used without further purification. LRMS (ES-): 274.9 (M-H)-.
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[CH3:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])O.[K+]>O>[CH3:10][N:11]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: CNc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Product: CN(c1ccc(O)cc1)c1ncc([N+](=O)[O-])s1

Procedure:
A mixture of 2-bromo-5-nitrothiazole (4.18 g), 4-(N-methylamino)phenol and water (50 ml) was heated under reflux for a period of 18 hours. The cooled solution was neutralised with aqueous potassium hydrogen carbonate and extracted with diethyl ether. The organic extract was dried over anhydrous magnesium sulfate and the solvent removed by distillation under reduced pressure to give 4-[N-methyl-N-(5-nitro-2-thiazolyl)amino]phenol (2.51 g) as an oil. The pmr spectrum of the compound was consistent with the assigned structure (CDCl3 ; chemical shift δ ppm): 3.55, s, 3H; 5.85, br.s, 1H; 7.15, m, 4H; 8.20, s, 1H.
Reaction SMILES: FC(F)(F)C(O)=O.[O-:8][C:9]#[N:10].[Na+].NN.[CH3:14][C:15]1[CH:16]=[C:17]([N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[NH2:23])[CH:18]=[C:19]([CH3:21])[CH:20]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[NH2:10][C:9]([NH:23][N:22]([CH2:24][C:25]([O:27][CH3:28])=[O:26])[C:17]1[CH:16]=[C:15]([CH3:14])[CH:20]=[C:19]([CH3:21])[CH:18]=1)=[O:8]
Reactant: COC(=O)CN(N)c1cc(C)cc(C)c1
Reactant: N#C[O-]
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)CN(NC(N)=O)c1cc(C)cc(C)c1
Reaction time: 2 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (1.06 ml, 13.9 mmol) was added under nitrogen to a stirred suspension of sodium cyanate (1.00 g, 15.2 mmol) in a solution of the hydrazine (Intermediate 36; 1.00 g, 4.8 mmol) in dry toluene (30 ml). The mixture was stirred for ca. 2 h, causing formation of a viscous insoluble gum. Saturated aqueous sodium hydrogen carbonate (25 ml) was added (causing effervescence and dissolution of the gum) and the mixture was extracted with ethyl acetate (3×75 ml). The combined extracts were washed with saturated brine (50 ml) dried and evaporated to afford a light yellow solid which was triturated with hexane/ethyl acetate (1:1) to give the title compound as a white powder (0.92 g, 76%), m.p. 139°-141°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[C:14]1(=[O:24])[O:19][C:17](=[O:18])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12>C(Cl)(Cl)Cl>[C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[C:14]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:24])([OH:19])=[O:18]
Reactant: NCCSc1cccc2nccn12
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccccc1C(=O)NCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 14 h
Yield: 84.8 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.12 g, 5.8 mmoles) in chloroform (58 ml) was added phthalic anhydride (1.12 g, 7.56 mmoles) and the mixture was stirred at room temperature for 14 hours and then heated at reflux for 5 hours. The reaction mixture was cooled by standing. The crystals precipitated were filtered off, washed with chloroform and dried to obtain 1.68 g of the desired product (84.8%, colorless crystals).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C@H:10]([CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)[C:11]([NH2:13])=[O:12])=[CH:5][C:4]=1[NH:24][C:25]1[S:29][N:28]=[C:27]([CH3:30])[CH:26]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:13][C:11](=[O:12])[C@H:10]([NH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]([NH2:2])=[O:37])=[C:4]([NH:24][C:25]2[S:29][N:28]=[C:27]([CH3:30])[CH:26]=2)[CH:5]=1)[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[NH:17][CH:16]=1
Reactant: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCO
Product: Cc1cc(Nc2cc(N[C@H](Cc3c[nH]c4ccccc34)C(N)=O)ccc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(4-cyano-3-(3-methylisothiazol-5-ylamino)phenylamino)-3-(1H-indol-3-yl)propanamide (100 mg, 0.240 mmol) in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1 mL, 1.0 mmol) and aq. H2O2 (50%, 1 mL) were added. The mixture was stirred at room temperature for 1 h. HOAc (1 mL) was added. The mixture was purified by HPLC to give the titled compound (51 mg). MS 435.2 (M+H); UV 221.7, 292.8 nm.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[C:14](=O)([O:20]C(C)(C)C)[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].O.Cl>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[N:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 24.0 g of 3-bromo-5-nitro-1H-indazole and 12.2 g of 4-(dimethylamino)pyridine in 50 ml tetrahydrofuran was added dropwise 23 ml of di-tert-butyl carbonate at room temperature. After stirring at room temperature for 30 minutes, the mixture was added with water, acidified by adding diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 20.5 g of the title compound as colorless needles.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[SH:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.O>[OH:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)=[O:10])=[CH:4][C:3]=2[N+:16]([O-:18])=[O:17])=[CH:27][CH:28]=1
Reactant: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cccs1
Reactant: Oc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc(Sc2ccc(O)cc2)c([N+](=O)[O-])c1)c1cccs1
Temperature: 80 °C
Yield: 79.2 %

Procedure:
The product of Example 240a (1.50 g, 5.63 mmol) was dissolved in DMF to which K2CO3 (1.55 g, 11.27 mmol), and 4-mercapto-phenol (711 mg, 5.634 mmol) were added. The reaction mixture was then heated to 80° C. for 2 hrs. At this point the reaction mixture was cooled to room temperature and diluted with water which was then extracted with ethyl acetate to isolate the desired compound (1.66 g, 79%).