Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=1[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=2.C(N(CC)CC)C.[C:25]1([CH2:31][C:32](Cl)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(Cl)Cl>[C:25]1([CH2:31][C:32]([O:1][C:2]2[C:3]3[C:8]([CH:9]=[C:10]([O:14][CH3:15])[C:11]=2[O:12][CH3:13])=[N:7][C:6](=[O:16])[C:5](=[O:17])[N:4]=3)=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: COc1cc2c(c(O)c1OC)=NC(=O)C(=O)N=2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(c(OC(=O)Cc3ccccc3)c1OC)=NC(=O)C(=O)N=2
Temperature: 25 °C
Reaction time: 12 h
Yield: 77 %

Procedure:
To a suspension of 5-hydroxy-6,7-dimethoxy-2,3-quinoxalinedione (48) (50 mg, 0.22 mmol) in 3 mL of methylene dichloride was added 0.14 mL of triethylamine and phenylacetyl chloride (77.5 mg, 0.5 mmol, Aldrich) at 0° C. The resulting mixture was stirred at room temperature for 12 hr. The reaction mixture was then poured into ice-water (5 g). A white solid precipitated and was collected by suction filtration, washed with water (3×5 mL) and ethyl acetate (3×2 mL), and dried in vacuo, giving 60 mg (77%) of the product as a white solid; mp 298-300° C.; 1H NMR (DMSO-d6, 300 MHz) δ 3.405 (s, 3H), 3.728 (s, 3H), 4.024 (s, 2H), 6.653 (s, 1H), 7.359 (m, 5H), 11.773 (s, 1 H), 11.846 (s, 1H). EIMS m/e 356 (25, M+), 238 (100). (HPLC 100%).
Reaction SMILES: [CH:1]12[CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>C(Cl)(Cl)Cl>[CH:1]12[CH2:8][NH:7][CH2:6][CH:5]1[CH2:4][CH2:3][N:2]2[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)N1CCC2CN(C(=O)OC(C)(C)C)CC21
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC2CNCC21

Procedure:
15.2 g (53.3 mol) of 2-ethyl 7-tert.-butyl 2,7-diazabicyclo[3.3.0]octane-2,7-dicarboxylate in 100 ml of chloroform are heated under reflux for five hours with 10.5 g (55.3 mol) of para-toluenesulphoic acid. The mixture is washeds with 50 ml of 10% strength sodium hydroxide solution, the organic phase is dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[H-].[Na+].[CH2:9]([O:11][C:12](=[O:40])[CH2:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=2[CH2:32][N:33]([C:36](=[O:39])[CH2:37]Cl)[CH2:34][CH3:35])[C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:10]>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:9]([O:11][C:12](=[O:40])[CH2:13][C:14]1[CH:15]=[C:16]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:24][C:23]=2[CH2:32][N:33]([CH2:34][CH3:35])[C:36](=[O:39])[CH2:37][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[C:17]([O:20][CH3:21])=[CH:18][CH:19]=1)[CH3:10]
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCl)c1
Reactant: Cc1ncc[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)Cn2ccnc2C)c1
Reaction time: 0.25 h

Procedure:
To 2-methylimidazole (0.047 g, 0.57 mmol) in DMF (2 mL) at 0° C. was added sodium hydride (60% in mineral oil; 0.031 g, 0.78 mmol), and the reaction was stirred for 15 minutes. (2′-{[(2-Chloro-acetyl)-ethyl-amino]-methyl}-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester (0.52 mmol) was added in DMF, and the reaction was stirred at room temperature for 1.5 hours. Analytical LCMS showed that a lot of starting material remained, so tetrabutylammonium iodide (0.005 g, 0.01 mmol) was added, and the reaction was stirred for 3 hours. Analytical LCMS showed that no change had occurred, so additional sodium hydride (60% in mineral oil; 0.031 g, 0.78 mmol) was added, and the reaction was stirred overnight at room temperature. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was separated and extracted twice with EtOAc. The combined organic layers were washed three times with H2O, and then dried and concentrated to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([O:9]C)=[O:8])[CH:5]=1.N#N.CCCCCCC.CCOC(C)=O.CC(O)=O>N1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:6]([C:7]([OH:9])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccc(O)c(C(=O)OC)c1
Agent: N#N
Solvent: CC(=O)O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(O)c(C(=O)O)c1
Yield: 98.5 %

Procedure:
The compound was prepared in the manner described by Coutts, Ian G. C.; Edwards, Mark; Richards, David J. Synthesis 1981, 487. 4-Hydroxy isophthalic acid dimethyl ester (5.28 g, 25.1 mmol) was refluxed in pyridine under a flow of N2. The reaction was monitored via TLC (20:10:1, heptane/AcOEt/AcOH) which indicated reaction completion after 8 h. The majority of the pyridine was removed under vacuum, and AcOEt (100 ml) was added. The solution was washed with 0.5 M HCl (3×50 ml). The acidic washes were then extracted with AcOEt (100 ml). The two organic phases were pooled, dried (MgSO4) and concentrated to yield a white solid (4.85 g, 99%). The solid was recrystallized from toluene (200 ml) to yield white crystals (4.6 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])/[C:7](/[CH3:18])=[CH:8]/[C:9]1[O:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[CH3:17][O:16][C:14]([C:11]1[O:10][C:9]([CH2:8][CH:7]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:19])[CH3:18])=[CH:13][CH:12]=1)=[O:15]
Reactant: COC(=O)c1ccc(/C=C(\C)C(=O)OC(C)(C)C)o1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(CC(C)C(=O)OC(C)(C)C)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.3 %

Procedure:
(2E)-(5-Methoxycarbonylfuran-2-yl)-2-methylpropenoic acid tert-butyl ester (2.96 g, 11.1 mmol) was dissolved in methanol (100 mL), 10% palladium/carbon (0.3 g) was added, and the mixture was stirred at room temperature for 2 hours under a hydrogen atmosphere. After completion of the reaction, palladium/carbon was removed by celite filtration, and the solvent was evaporated under reduced pressure to give the title compound (2.72 g).
Reaction SMILES: [CH3:1][C:2]1([CH2:13][OH:14])[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.[Br:15][C:16]1[CH:17]=[N:18][C:19](Cl)=[N:20][CH:21]=1.[H-].[Na+]>CN(C=O)C>[Br:15][C:16]1[CH:17]=[N:18][C:19]([O:14][CH2:13][C:2]2([CH3:1])[O:6][C:5]3=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]3[CH2:3]2)=[N:20][CH:21]=1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ncc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2.33 h

Procedure:
A mixture of alcohol 101 (see Example 2M) (100 mg, 0.502 mmol) and 5-bromo-2-chloropyrimidine (156 mg, 0.806 mmol) in anhydrous DMF (2.5 mL) under N2 at 0° C. was treated with 60% NaH (32 mg, 0.80 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 140 min, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (10 mL), added to brine (40 mL), and extracted with CH2Cl2 (6×50 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with 0-0.25% MeOH/CH2Cl2 firstly gave foreruns, and then further elution with 0.25-0.5% MeOH/CH2Cl2 gave 2-{[(5-bromo-2-pyrimidinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (103) (reported by Ding et al., WO 2009120789A1 from 101 via a similar procedure) (163 mg, 91%) as a cream solid: mp (MeOH/CH2Cl2/hexane) 224-226° C.; 1H NMR [(CD3)2SO] δ 8.77 (s, 2H), 8.14 (s, 1H), 4.61 (s, 2H), 4.41 (d, J=11.0 Hz, 1H), 4.20 (d, J=11.1 Hz, 1H), 1.70 (s, 3H). Anal. (C11H10BrN5O4) C, H, N.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.Br[CH2:16][C:17]1[C:18]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:19]=2[S:20][CH:21]=1>>[F:26][C:24]1[CH:23]=[CH:22][C:19]2[S:20][CH:21]=[C:17]([CH2:16][N:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:14]=[C:6]3[C:4]([OH:3])=[O:5])[C:18]=2[CH:25]=1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Reactant: Fc1ccc2scc(CBr)c2c1
Product: O=C(O)c1cc2ccccc2n1Cc1csc2ccc(F)cc12

Procedure:
Using general procedure B, 1H-indole-2-carboxylic acid ethyl ester was coupled with 3-bromomethyl-5-fluoro-benzo[b]thiophene (Lit. 18) and the product obtained was hydrolyzed to give the title compound as pale yellow solid. MS: 324.0 ([M−H]−).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2OC)=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.[NH3:41]>CO.C(Cl)Cl>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[NH2:41])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Reactant: N
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: CO[C@H]1/C=C\C=C(/C)C(=O)NC2=CC(=O)C(N)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@@H]1OC(N)=O)C2=O
Solvent: ClCCl
Solvent: CO
Product: CO[C@H]1C=CC=C(C)C(=O)NC2=CC(=O)C(N)=C(C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@@H]1OC(N)=O)C2=O
Reaction time: 24 h

Procedure:
Geldanamycin (1.12 g, 2 mmol, 1 equiv) was added to anhydrous DCM (5 mL). NH3 in MeOH was added to this solution (9 mL, 100 mmol, 50 equiv) and was allowed to stir for 24 hours. At which point the reaction solution was diluted with DCM and extracted with water, followed by dilute HCl. The organic layer was collected washed with brine, dried over Na2SO4 and concentrated to yield a purple solid. This solid was recrystallized twice from acetone/heptanes to yield 0.239 of 17-amino-17-demethoxygeldanamycin.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:39](=[O:40])[N:6]2[C:7]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([N+:36]([O-:38])=[O:37])=[CH:32][CH:31]=3)=[O:27])=[C:8](OP(C3C=CC=CC=3)(C3C=CC=CC=3)=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[SH:41][C@@H:42]1[CH2:46][N:45]([C:47]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][C:54]([N+:57]([O-:59])=[O:58])=[CH:53][CH:52]=2)=[O:48])[C@H:44]([C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([N:67]([C:75]([O:77][CH2:78][C:79]3[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=3)=[O:76])[C:68](=[O:74])[CH2:69][NH:70][C:71]([NH2:73])=[NH:72])[CH2:63]2)=[O:61])[CH2:43]1>>[N+:57]([C:54]1[CH:55]=[CH:56][C:51]([CH2:50][O:49][C:47]([N:45]2[CH2:46][C@@H:42]([S:41][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:39](=[O:40])[N:6]4[C:7]=3[C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([N+:36]([O-:38])=[O:37])=[CH:34][CH:35]=3)=[O:27])[CH2:43][C@H:44]2[C:60]([N:62]2[CH2:66][CH2:65][C@H:64]([N:67]([C:75]([O:77][CH2:78][C:79]3[CH:84]=[CH:83][C:82]([N+:85]([O-:87])=[O:86])=[CH:81][CH:80]=3)=[O:76])[C:68](=[O:74])[CH2:69][NH:70][C:71]([NH2:73])=[NH:72])[CH2:63]2)=[O:61])=[O:48])=[CH:52][CH:53]=1)([O-:59])=[O:58]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@H]12
Reactant: N=C(N)NCC(=O)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)[C@H]1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](N(C(=O)CNC(=N)N)C(=O)OCc5ccc([N+](=O)[O-])cc5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Yield: 49.6 %

Procedure:
By using 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-(diphenylphosphoryloxy)-1-carbapen-2-em-3-carboxylate (697 mg) and (2S,4S)-4-mercapto-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(4-nitrobenzyloxycarbonyl)guanidinoacetylamino]pyrrolidin-1-ylcarbonyl]pyrrolidine (751 mg), reaction and purification were carried out in a similar manner to that described in Example 1-(1), whereby 4-nitrobenzyl (1R,5S,6S)-2-[(2S,4S)-1-(4-nitrobenzyloxycarbonyl)-2-[(3S)-3-[(4-nitrobenzyloxycarbonyl)guanidinoacetylamino]pyrrolidin-1-ylcarbonyl]pyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (563 mg) was obtained as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([NH2:15])=[CH:13][C:12]([C:16]#[N:17])=[N:11]1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C([O-])([O-])=O.[Na+].[Na+].C1(C)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.C(O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([NH2:15])=[CH:13][C:12]([C:16]#[N:17])=[N:11]1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(Br)cc2Cl)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#Cc1cc(N)n(-c2c(Cl)cc(-c3ccc(C(F)(F)F)cc3)cc2Cl)n1
Temperature: 20 °C

Procedure:
A mixture of 1-(2,6-dichloro-4-bromophenyl)-3-cyano-5-aminopyrazole (45 g, prepared according to procedures reported in U.S. Pat. No. 5,232,940), 4-trifluoromethylphenylboronic acid (45 g), 2M of Na2CO3 (75 mL), tris(dibenzylideneacetone)dipalladium (6.4 g), toluene and ethanol was heated at 130° C. for 25 hours. After cooling to 20° C., the mixture was poured into water and extracted with diethyl ether. The ether solutions were combined, dried, filtered and the filtrate concentrated and purified via chromatography. The desired product as a solid (30.6 g, mp 195-199° C.) was obtained.
Reaction SMILES: [C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[C:1]([C:5]1[NH:9][N:8]=[C:7]([NH:10][C:11](=[O:14])[CH2:12][CH3:13])[C:6]=1[N+:15]([O-:17])=[O:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCC(=O)Nc1n[nH]c(C(C)(C)C)c1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2 g (0.01 mole) of 5-t-butyl-3-propionylaminopyrazole as prepared in Example 5 was dissolved in 20 ml of concentrated sulfuric acid, and the solution was cooled to 0° C. 0.6 ml of fuming nitric acid was added dropwise thereto, and the mixture was allowed to react for one hour at 0° C. After completion of the reaction, the reaction solution was poured into a large amount of ice, whereby crystals were precipitated. The crystals were collected by filtration and washed with water to obtain 1 g of 5-t-butyl-4-nitro-3-propionylaminopyrazole.
Reaction SMILES: O[Li].O.[C:4]([C:8]1[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:28][CH3:29])[CH:22]=[CH:21]3)[N:9]=1)([CH3:7])([CH3:6])[CH3:5]>O.C1COCC1.CCO.Cl>[C:4]([C:8]1[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]=[C:23]([NH:28][CH3:29])[CH:22]=[CH:21]3)[N:9]=1)([CH3:7])([CH3:5])[CH3:6]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1-c1ccc2nc(NC)ccc2c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CNc1ccc2cc(-n3nc(C(C)(C)C)cc3C(=O)O)ccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
LiOH.H2O (0.143 g, 3.40 mmol) was added to a solution of ethyl 3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylate (0.240 g, 0.68 mmol) in a mixture of water/THF/EtOH (1:1:1, 9 mL). The reaction mixture was stirred overnight at RT, diluted with 3 M HCl and extracted with EtOAc and THF. The combined organics were washed with brine, dried (MgSO4) and concentrated under vacuum to obtain 3-tert-butyl-1-(2-(methylamino)quinolin-6-yl)-1H-pyrazole-5-carboxylic acid (0.22 g, 100% yield). 1H-NMR (DMSO-d6) δ 7.90 (d, J=9.2 Hz, 1H), 7.66 (d, J=2.4 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.46 (dd, J=9.2, 2.8 Hz, 1H), 7.14 (m, 1H), 6.88 (brs, 1H), 6.79 (d, J=9.2 Hz, 1H), 2.92 (d, J=4.8 Hz, 3H), 1.31 (s, 9H); MS (ESI) m/z: 325.2 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH:8]=O)[CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([NH:20][NH2:21])(=[O:19])=[O:18])=[CH:13][CH:12]=1>CO.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4](/[CH:8]=[N:21]/[NH:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:18])=[O:19])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=Cc1cc(Br)ccn1
Solvent: CO
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N/N=C/c2cc(Br)ccn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromopicolinaldehyde (2.0 g, 10.8 mmol) and 4-methylbenzenesulfonohydrazide (2.0 g, 10.8 mmol) were mixed in MeOH (20 mL) and dichloromethane (20 mL). The mixture was stirred at room temperature for 1 hour. The solvents were removed under reduced pressure to give 3.80 g (theoretical) of the title compound as a yellow solid m/z ES+ 354, 356 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)[CH:9]=[C:4]2[CH:3]=[CH:2]1.[I:21]N1C(=O)CCC1=O>CC(C)=O>[I:21][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]3[CH:11]=[C:12]([NH:16][S:17]([CH3:20])(=[O:18])=[O:19])[CH:13]=[CH:14][CH:15]=3)[CH:9]=2)[NH:1][CH:2]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]ccc3c2)c1
Solvent: CC(C)=O
Product: CS(=O)(=O)Nc1cccc(-c2cnc3[nH]cc(I)c3c2)c1
Yield: 48.4 %

Procedure:
Using similar reaction conditions as described in step i of intermediate 1, N-(3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (800 mg, 3 mmol) was iodinated with N-iodo succinimide (764 mg, 3 mmol) in acetone (5 ml) to afford 600 mg (50% yield) of the pure product. LCMS: m/z=413.4 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH3:8].[CH3:15][N:16]([CH3:25])[C:17]1[CH:22]=[C:21](F)[N:20]=[C:19](F)[CH:18]=1>>[CH3:15][N:16]([CH3:25])[C:17]1[CH:22]=[C:21]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[N:20]=[C:19]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH3:8])[CH:18]=1
Reactant: CC(c1ccccn1)c1ccccn1
Reactant: CN(C)c1cc(F)nc(F)c1
Product: CN(C)c1cc(C(C)(c2ccccn2)c2ccccn2)nc(C(C)(c2ccccn2)c2ccccn2)c1
Yield: 61 %

Procedure:
NMe2PY5Me2 was synthesized in a similar manner as that of CF3PY5Me2, using 1,1-bis(2-pyridyl)ethane and 4-dimethylamino-2,6-difluoropyridine as the precursors, and purified on a silica column eluted with CH2Cl2:MeOH:triethytamine (20:1:0.1). Yield: 61%. 1H NMR (CDCl3, 400 MHz): □ =8.44 (dd, J=4.81, 0.98 Hz, 4H), 7.28 (dt, J=7.86, 7.80, 1.89 Hz, 4H), 6.95 (ddd, J=7.41, 4.85, 0.98 Hz, 4H), 6.76 (d, J=8.05 Hz, 4H), 6.31 (s, 2H), 2.80 (s, 6H), 2.13 (s, 6H). Anal. Calcd. for C31H30N6: C, 76.52%; H, 6.21%; N, 17.27%. Found: C, 76.22%; H, 6.46%; N, 17.15%. LMS (M+) m/z calcd for [NMe2PY5Me2+H]+, 487.2610, found, 487.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.F[C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:11]=[C:12]([C:16]2[CH:17]=[CH:18][C:19]([O:22][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=[CH:20][CH:21]=2)[C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C=C(C(=O)O)c2ccc(Oc3ccc([N+](=O)[O-])cc3)cc2)cc(OC)c1

Procedure:
Compound 2 was reacted with 1-fluoro-4-nitrobenzene in the presence of NaH in DMF to give 3-(3,5-dimethoxyphenyl)-2-[4-(4-nitrophenoxy)-phenyl]-acrylic acid (32). Reduction of 32 (10 g, 24 mmol) with zinc dust (15 g, 230 mmol) in acetic acid (100 mL) was accomplished at 120° C. for 15 h, the mixture was cooled to room temperature. Water (250 mL) was slowly added to the reaction mixture. The precipitated product was filtered and washed with water (70 mL) to give crude product. The product was recrystallized from toluene. Yield (33): 9.7 g, 94%.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([O:20]CC)=[O:19]>C1COCC1.CO>[Cl:3][C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][C:25]=1[Cl:26])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:18]([OH:20])=[O:19]
Reactant: CCOC(=O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc2cc(O)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.8 %

Procedure:
Sodium hydroxide (2M, 3 ml) was added to a stirred solution of ethyl N-(3,4-dichlorobenzyl)-5-hydroxyindole-2-carboxylate (0.1 g) in THF (3 ml) and methanol (1.5 ml). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated in vacuo and the residue was dissolved in water (5 ml). The solution was acidified by the addition of aqueous hydrochloric acid (2M, 4 ml) precipitating the product as a white solid. The product was filtered, washed with water and dried in vacuo to yield the title compound (82 mg, 89%). NMR: δ 5.77 (s, 2H), 6.81 (dd, 1H), 6.89 (dd, 1H), 6.95 (d, 1H), 7.13 (s, 1H), 7.26 (d, 1H), 7.34 (d, 1H), 7.52 (d, 1H), 9.01 (s, 1H), 12.85 (s, 1H); m/z 334 (M−H+).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:16][NH:17][C:18]([NH2:20])=[S:19])[C:12](=NO)[CH3:13])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]([CH3:13])=[N:20][C:18](=[S:19])[NH:17][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(C(=NNC(N)=S)C(C)=NO)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(=S)[nH]nc1-c1ccc(N)cc1
Yield: 72.3 %

Procedure:
A solution of 4'-acetamido-2-hydroxyiminopropiophenone thiosemicarbazone (5 g) and potassium carbonate (5.2 g) in water (40 ml) was refluxed for 24 hours and treated with activated carbon. The filtrate was acidified with diluted hydrochloric acid and the crystals which formed were recovered by filtration, washed with water and dried to give 6-(4-aminophenyl)-5-methyl-1,2,4-triazin-3(2H)-thione (2.69 g).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH:19]1[CH2:21][CH2:20]1)[N:6]2[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16].[NH3:22]>C(O)C>[CH:19]1([C:5]2[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]3[C:3]([N:4]=2)=[C:2]([NH2:22])[N:10]=[CH:9][N:8]=3)[CH2:21][CH2:20]1
Reactant: N
Reactant: C[Si](C)(C)CCOCn1c(C2CC2)nc2c(Cl)ncnc21
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(C2CC2)nc2c(N)ncnc21
Temperature: 120 °C

Procedure:
In a sealed tube a stirred suspension of 2-[(6-chloro-8-cyclopropyl-purin-9-yl)methoxy]ethyl-trimethyl-silane (5, 0.8 g, 2.46 mmol) and 30% aqueous ammonia (10 mL) in ethanol (10 mL) was heated at 120° C. for 14 h. After TLC showed consumption of 5, ethanol was removed under reduced pressure and the residue was washed with water (10 mL) and diethyl ether (10 mL) to obtain 8-cyclopropyl-9-(2-trimethylsilylethoxymethyl)purin-6-amine (6) as a white solid. Yield: 703 mg, 93%; MS (ESI) m/z 306.30 [M+1]+; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.10 (s, 2H), 5.64 (s, 2H), 3.57 (m, 2H), 2.24 (m, 1H), 1.08 (m, 4H), 0.83 (m, 2H), 0.09 (s, 9H).