Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([C:33](Cl)=[O:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[O:34])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=2)=[CH:10][CH:9]=1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1cccc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(O)c1ccc(F)cc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(3-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added 1-naphthoyl chloride (282 ml, 1.87 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml) and the mixture was stirred at room temperature for 2 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (582 mg, 87%).
Reaction SMILES: Cl.[C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH2:20])[CH2:14]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:22]1[C:23]2[C:30]([CH3:31])=[CH:29][S:28][C:24]=2[N:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(O)C>[C:2]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[CH2:16][CH:15]([NH:20][C:22]1[C:23]3[C:30]([CH3:31])=[CH:29][S:28][C:24]=3[N:25]=[CH:26][N:27]=1)[CH2:14]2)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1csc2ncnc(Cl)c12
Reactant: NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1csc2ncnc(NC3Cc4ccc(OC(=O)c5ccccc5)cc4C3)c12
Yield: 48.6 %

Procedure:
Using 5-benzoyloxy-2-aminoindan hydrochloride (67 mg, 0.35 mmol), 4-chloro-5-methylthieno[2,3-d]pyrimidine (68 mg, 0.37 mmol), triethylamine (0.52 ml, 3.7 mmol), and ethanol (6 ml), a similar procedure to b) in Example 19 was carried out. The product obtained was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain the title compound (70 mg, 0.17 mmol) having the following physical properties:
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([CH3:11])=[N:8][C:7]=1[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:13]([NH2:15])=[O:14])=O)C.C[O-].[Na+]>CO>[CH2:16]([N:12]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:4](=[O:3])[NH:15][C:13]1=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)c1sc(C)nc1N(Cc1ccccc1)C(N)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1nc2c(s1)c(=O)[nH]c(=O)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
To a solution of 4-benzylamino-2-methyl-thiazole-5-carboxylic acid ethyl ester (0.40 g, 1.45 mmol) in DCM (10 mL) was added chlorosulfonyl isocyanate (140 μL, 1.59 mmol) dropwise at −78° C. The mixture was allowed to warm to RT and stirred for 30 minutes. The resulting solution was concentrated in vacuo then dissolved in acetone (5 mL), before H2O (2 mL) was added dropwise. The mixture was stirred at RT for 30 minutes, then concentrated in vacuo. The resultant oil was partitioned between EtOAc and H2O. The organic layer was isolated, washed with brine, dried (MgSO4) and concentrated in vacuo to give 4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester as a pale brown oil. To a solution of 4-(1-benzyl-ureido)-2-methyl-thiazole-5-carboxylic acid ethyl ester in MeOH (10 mL) was added a solution of sodium methoxide in MeOH (25% w/w, 1.33 mL, 5.80 mmol) and the mixture was stirred at RT for 18 h. The crude reaction mixture was concentrated in vacuo and partitioned between EtOAc and an aqueous solution of HCl (1 M). The organic layer was isolated, washed with brine, then dried (MgSO4) and concentrated in vacuo. The resultant residue was triturated with EtOAc to give the title compound as a pale yellow solid (0.25 g, 63%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH2:9]([O:11][C:12](=[O:23])[CH:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])[CH3:14])C.I[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:28][CH:27]=1.[OH-].[Na+]>C1COCC1.CO>[CH3:9][O:11][C:12](=[O:23])[C:13]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22])([CH3:14])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(CI)cc2)cc1
Reactant: CCOC(=O)C(C)Oc1ccccc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 59.9 %

Procedure:
To a solution of LDA (1.5 M in cyclohexane, 33 mL, 49.5 mmole) in THF (40 mL), at −78° C., is added dropwise a solution of 2-(2-fluoro-phenoxy)-propionic acid ethyl ester (7.70 g, 36.3 mmole) in THF (100 mL). After stirring for 30 minutes at −78° C., a solution of toluene-4-sulfonic acid 4-iodomethyl-phenyl ester (12.8 g, 33.0 mmole) is injected to the reaction mixture. The reaction is stirred at −78° C. for one hour, then warmed up to room temperature and stirred overnight. The reaction is treated with 5.0N NaOH (50 mL) in presence of methanol (200 mL). After evaporating methanol, the aqueous solution is acidified with concentrated HCl to pH=1 and is extracted with ethyl acetate (2×300 mL). The combined organic layers are dried, filtered and concentrated in vacuo. The residue is dissolved in MeOH (200 mL) and treated with concentrated sulfuric acid (2 mL) at 80° C. overnight. The reaction mixture is partitioned between ethyl acetate (500 mL) and water (500 mL), the organic layer is washed by brine (3×500 mL), dried, filtered and concentrated in vacuo. The compound is purified by chromatography (silica gel, gradient elution 0-20% ethyl acetate in hexane) to provide an oil (6.02 g, 60%), which is then resolved by chiral HPLC to generate the enantiomer as an oil (2.30 g). Mass [EI+] 322 (M+NH4)+, [EI−] 303 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH2:10][CH:11]=[CH2:12])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:14]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)C=C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][CH:11]=[CH2:12])[C:5]([O:8][CH3:9])=[C:6]([Cl:14])[N:7]=1
Reactant: C=CCC1(Cl)NC(Cl)=NC=C1OC
Reactant: COc1cnc(Cl)nc1Cl
Agent: C=CC[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=CCc1nc(Cl)nc(Cl)c1OC
Reaction time: 0.33 h
Yield: 67 %

Procedure:
2,6-Dichloro-5-methoxy-6-allyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (3.0 g, 17 mmol) was dissolved in THF (30 mL) and treated in portions with allyl magnesium bromide (17 mL of 1M allyl magnesium bromide in diethyl ether, 17 mmol). The resulting reaction was exothermic. External cooling was used to keep the temperature of the mixture below 30° C. After 20 minutes, the mixture was subjected to HPLC and GC-MS. After 45 minutes, the mixture was cooled in ice/salt and the reaction quenched with saturated ammonium chloride (30 mL) then diluted with ethyl acetate (75 mL). The organic phase was washed with saturated sodium chloride (30 mL), dried, and evaporated. The residue was dissolved in 1,4-dioxane (50 mL), treated with DDQ (3.9 g, 17 mmol), and stirred for 20 h. GC-MS showed presence of 2,6-dichloro-5-methoxy-6-allyl pyrimidine (having molar weight of 218 g/mol). The residue was washed in water and ethyl acetate and purified by column chromatography using silica with ethyl acetate and hexane. This provided the title compound (2.5 g, 67% yield): mp 61-62° C. 1H NMR (400 MHz, CDCl3) δ 6.07-5.94 (m, 1H), 5.26-5.16 (m, 2H), 3.94-3.89 (s, 3H), 3.65-3.56 (m, 2H)); EIMS m/z 218.
Reaction SMILES: [C:1]1([CH3:56])[CH:6]=[CH:5][C:4]([N:7]([C:49]2[CH:54]=[CH:53][C:52]([CH3:55])=[CH:51][CH:50]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:48]=[CH:47][C:17]([N:18]([C:33]4[CH:38]=[CH:37][C:36]([C:39]5[CH:44]=[CH:43][C:42]([O:45]C)=[CH:41][CH:40]=5)=[CH:35][CH:34]=4)[C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][C:28]([O:31]C)=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.B(Br)(Br)Br>C(Cl)Cl>[C:52]1([CH3:55])[CH:51]=[CH:50][C:49]([N:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:56])=[CH:2][CH:3]=2)[C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:15]=[CH:16][C:17]([N:18]([C:19]4[CH:24]=[CH:23][C:22]([C:25]5[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=5)=[CH:21][CH:20]=4)[C:33]4[CH:34]=[CH:35][C:36]([C:39]5[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=5)=[CH:37][CH:38]=4)=[CH:47][CH:48]=3)=[CH:12][CH:13]=2)=[CH:54][CH:53]=1
Reactant: COc1ccc(-c2ccc(N(c3ccc(-c4ccc(OC)cc4)cc3)c3ccc(-c4ccc(N(c5ccc(C)cc5)c5ccc(C)cc5)cc4)cc3)cc2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(N(c2ccc(C)cc2)c2ccc(-c3ccc(N(c4ccc(-c5ccc(O)cc5)cc4)c4ccc(-c5ccc(O)cc5)cc4)cc3)cc2)cc1
Temperature: 0 °C

Procedure:
In a reaction vessel equipped with an agitator, thermometer and a cooling pipe, 2.73 g of N,N-di-p-tolyl-N′,N′-bis(4′-methoxybiphenyl-4-yl)benzidine and 100 mL of methylene chloride were placed. While the vessel was being cooled with ice, 10 mL of a 1M methylene chloride solution of boron tribromide was delivered by drops into the vessel, and furthermore the mixture was reacted at the same temperature for three hours. Then, the reacted solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with water and separated, and it was then dried with magnesium sulfate and subjected to vacuum concentration. The residue was purified with a silica gel chromatography with a mixture of n-hexane and ethyl acetate as a solvent, where the ratio of n-hexane to ethyl acetate in the mixture was one to one. Thus, the objective product was obtained with the yield of 2.53 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:18][O:19][C:20]([O:24][Si](C)(C)C)=[C:21]([CH3:23])[CH3:22].CN(C=O)C.O>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.[F-].[Zn+2].[F-].C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:7][C@H:8]([C:10]1[CH:11]=[C:12]([C:21]([CH3:23])([CH3:22])[C:20]([O:19][CH3:18])=[O:24])[CH:13]=[CH:14][CH:15]=1)[CH3:9])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)c1cccc([C@H](C)NC(=O)OC(C)(C)C)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 1 g of tert-butyl[(1S)-1-(3-bromophenyl)ethyl]carbamate, 18 mg of bis(tri-tert-butylphosphine)palladium (0), 180 mg of zinc fluoride, 1 ml of [(1-methoxy-2-methylpropa-1-en-1-yl)oxy](trimethyl)silane, and 10 ml of DMF was stirred at 80° C. overnight and at 100° C. for 5 hours. 25 mg of bis(tri-tert-butylphosphine)palladium (0) and 0.34 ml of [(1-methoxy-2-methylpropa-1-en-1-yl)oxy](trimethyl)silane were added thereto, followed by stirring at 80° C. for 3 days. To the reaction mixture were added water and ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 281 mg of methyl 2-(3-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}phenyl)-2-methylpropanoate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[O:17][CH3:18]>>[CH3:18][O:17][C:9]1[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=1[N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Reactant: C1CNCCN1
Product: COc1ccc([N+](=O)[O-])cc1N1CCNCC1

Procedure:
1-(2-Methoxy-5-nitro-phenyl]piperazine was prepared in a manner similar to Preparation 1A except that piperazine was coupled to 2-bromo-1-methoxy-4-nitro-benzene. LRMS (ESI+): 238.4 (M+1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15]>CO.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)CN
Reactant: BrCc1cccc(Br)c1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: COC(=O)CNCc1cccc(Br)c1
Yield: 36.5 %

Procedure:
A solution of 3-bromobenzylbromide (4.3 g, 17.2 mmol) in methanol (25 ml) and triethylamine (5 ml) is treated with glycine methyl ester hydrochloride (4.3 g, 34.4 mmol) and heated to reflux for 18 hours. The solvent is removed in vacuo and the residue chromatographed over silica gel (0-2% methanol in ethyl acetate as eluant) to give 1.62 g of a yellow oil.
Reaction SMILES: CC(OC([N:8](C(OC(C)(C)C)=O)[N:9]([C:17]1[C:22]([F:23])=[C:21]([N:24]2[CH2:27][C:26](C)(N3CCCC3)C2)[N:20]=[C:19]([Cl:34])[N:18]=1)C(OC(C)(C)C)=O)=O)(C)C.[CH3:42]O>Cl.O1CCOCC1>[Cl:34][C:19]1[N:20]=[C:21]([NH:24][CH:27]([CH3:26])[CH3:42])[C:22]([F:23])=[C:17]([NH:9][NH2:8])[N:18]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(N2CC(C)(N3CCCC3)C2)c1F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)Nc1nc(Cl)nc(NN)c1F

Procedure:
A solution of tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[3-methyl-3-(1-pyrrolidinyl)-1-azetidinyl]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (0.225 g, 0.37 mmol) in MeOH (6 mL) and 4.0M HCl in dioxane (4 mL) was stirred at room temperature for 3 days. The solvent was then removed in vacuo, providing the crude 2-chloro-5-fluoro-6-hydrazino-N-(1-methylethyl)-4-pyrimidinamine, presumably as the tri-HCl salt. LCMS: (M+H)+: 301.0.
Reaction SMILES: [C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25])=[CH:15][CH:14]=2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2].[OH-].[Na+]>C1COCC1>[C:1]([C:4]1[CH:30]=[CH:29][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:28])[CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:15][CH:14]=2)=[C:6]([CH2:31][CH2:32][CH3:33])[C:5]=1[OH:34])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCCCC(=O)OC)cc2)ccc(C(C)=O)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1c(OCCCSc2ccc(C(=O)CCCCC(=O)O)cc2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The compound of Example 44, Step B (1.0 g, 2.055 mmole) was dissolved in THF (10 ml). To this solution was added 1N NaOH (4.1 ml). The reaction mixture was stirred at room temperature for two hours. Additional 1N NaOH was added and stirring continued for two hours. The THF solution was removed and the aqueous portion diluted with water and extracted with ether. The aqueous layer was acidified with concentrated HCl, extracted with chloroform, dried and evaporated. Trituration of the residue with ether/methanol afforded the title compound; m.p. 130°-132°.
Reaction SMILES: Br[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.[CH3:25][NH:26][CH3:27]>CN(C=O)C>[CH3:25][N:26]([CH3:27])[C:2]1[N:24]=[C:5]2[N:6]=[C:7]([C:16]3[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=3)[C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1
Reactant: O=Cc1ccc(-c2nc3nc(Br)nn3cc2-c2ccccc2)cc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)c1nc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To 200 mg 4-(2-bromo-6-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-5-yl)benzaldehyde (prepared as described above) in 6 mL DMF were added 0.24 mL of a dimethylamine solution (60% in water). The mixture was heated under microwave irradiation to 100° C. for 2.5 hours. The solvent was removed and the solid residue is was treated with ethyl acetate/petrolether (1:1) and stirred for 2 hours. The desired product was filtered, dried and was used without further purification.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:32])[C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:5]1.Cl.[NH2:34][OH:35]>CO.Cl>[ClH:1].[CH3:2][N:3]([CH3:32])[C@H:4]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([S:19][C:20]2[N:24]4[CH:25]=[C:26](/[C:29](=[N:34]/[OH:35])/[CH3:30])[CH:27]=[CH:28][C:23]4=[N:22][N:21]=2)=[CH:14][CH:13]=3)[CH2:5]1
Reactant: NO
Reactant: CC(=O)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Agent: Cl
Solvent: CO
Product: C/C(=N\O)c1ccc2nnc(Sc3ccc4ncc(N5CC[C@H](N(C)C)C5)cc4c3)n2c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 64.4 %

Procedure:
To a solution of (81.3) (12 mg, 0.026 mmol) and hydroxylamine hydrochloride (7.11 mg, 0.102 mmol) in MeOH (3 ml) was added 2 drops of HCl (2N) by a 1-ml syringe to reach pH about 3 and the mixture was stirred in a sealed tube at 85° C. for 3 h. The mixture was evaporated to dryness and the residue was purified by preparative acid HPLC (gradient eluent NB from 20/80 to 95/5. mobile phase A: TFA/CH3CN 0.05%; mobile phase B: TFA/H2O 0.05%). The desired fractions were collected, evaporated by BUCHI under 30 mbar at 40° C. to remove CH3CN. The remained solution was lyophilized to afford the title compound (8.1 mg, yield 65.4%).
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:5]=1[CH:6]([OH:15])[C:7]([O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])([O-:3])=[O:2].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.C1(NC2CCCCC2)CCCCC1>CC(C)=O>[S:29]([C:26]1[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=1)([O:15][CH:6]([C:7]([O:9][CH2:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:8])[C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:19][CH:18]=[CH:17][C:16]=1[N+:20]([O-:22])=[O:21])(=[O:31])=[O:30]
Reactant: CC(C)(C)COC(=O)C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: CC(C)=O
Product: Cc1ccc(S(=O)(=O)OC(C(=O)OCC(C)(C)C)c2c([N+](=O)[O-])cccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Neopentyl 2,6-dinitromandelate (1.50 g, 4.80 mmol) and p-toluenesulfonyl chloride (1.00 g, 5.28 mmol) were mixed in dry acetone (50 mL) under argon. Dicyclohexylamine (0.957 g, 5.28 mmol) was added slowly to the reaction at 0° C. The mixture was stirred at room temperature for 2 hours at which time the reaction was shown to be complete by thin-layer chromatography (tlc). The acetone was then removed by evaporation under vacuum. The residue was put through a silica gel (60-200 mesh) column using methylene chloride/hexane (1:1) as the eluant. Recrystallization from CHCl3 /petroleum ether gave a yield of 2 g (89%).
Reaction SMILES: [Li]CCCC.C[N:7]([CH3:12])[CH2:8][CH2:9]NC.N1C=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])C=1.IC>C1COCC1>[CH3:17][C:16]1[CH:9]=[CH:8][N:7]=[CH:12][C:15]=1[CH:19]=[O:20]
Reactant: O=Cc1cccnc1
Reactant: CNCCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccncc1C=O
Reaction time: 0.25 h

Procedure:
n-BuLi (1.6 M in hexanes) (2.2 mmol, 1.37 ml) was added dropwise to a stirred solution of N,N,N'-trimethylethylenediamine (2.4 mmol, 0.245 g) in THF at -78° C. A solution of 3-pyridinecarboxaldehyde (2 mmol, 0.214 g) in THF was added and the mixture stirred for 15 min before adding a further portion of n-BuLi (1.6M in hexanes) (4 mmol, 2.5 ml). After stirring for 2 h at -70° C., iodomethane was added, the mixture stirred at RT for 30 min, then poured into aqueous NaCI solution, extracted twice with Et2O, dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O) to afford the title compound as an oil.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.[C:16]1([CH:23]=[CH:22][CH:21]=[C:19]([OH:20])[CH:18]=1)[OH:17].[N+](C1C=CC=CC=1)([O-])=O.Cl>>[OH:17][C:16]1[CH:18]=[C:19]([OH:20])[CH:21]=[CH:22][C:23]=1[C:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)=[O:14]
Reactant: Oc1cccc(O)c1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc(C(=O)c2ccc(O)cc2O)cc1
Temperature: 0 °C

Procedure:
Aluminum chloride (48 gm, 0.36 moles) was added gradually, with stirring to a mixture of 31 grams (0.18 moles) of anisoyl chloride, 19.82 grams (0.18 moles) of resorcinol and 300 ml. of dry nitrobenzene during 60 minutes. Sixty hours later the reaction mixture was poured on 200 grams of ice and 100 ml. of concentrated hydrochloric acid. After removal of the nitrobenzene with steam the residual crystalline solid product was washed with water and collected. The cake was then washed with cold (-50 degrees C.) methanol to remove tarry impurities and dried.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[OH:23][CH2:24][C@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][CH2:33][CH2:34][C:35]1[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[CH:37][CH:36]=1>C(Cl)Cl>[CH:24]([C@H:25]1[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[N:26]1[CH2:32][CH2:33][CH2:34][C:35]1[S:39][C:38]([C:40]([O:42][CH3:43])=[O:41])=[CH:37][CH:36]=1)=[O:23]
Reactant: COC(=O)c1ccc(CCCN2[C@@H](CO)CCS2(=O)=O)s1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1ccc(CCCN2[C@@H](C=O)CCS2(=O)=O)s1
Reaction time: 16 h
Yield: 49.8 %

Procedure:
1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (476 mg, 1.00 mmol) was added to a solution of the alcohol 10 (312 mg, 0.94 mmol) in CH2Cl2 (3.0 mL) at 23° C. The reaction was stirred for 16 h, filtered through celite and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10% EtOAc/hex) afforded 155 mg (50%) of aldehyde 11.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl[CH2:13][C:14]1[C:15]2[N:16]([CH:20]=[CH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[CH:21]=[CH:20][N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=3)[CH:7]=[O:8])[C:15]=12
Reactant: ClCc1cccn2ccnc12
Reactant: COc1ccc(O)cc1C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccn3ccnc23)cc1C=O
Temperature: 125 °C

Procedure:
A mixture of 5-hydroxy-2-methoxybenzaldehyde (723.6 mg, 4.7 mmol), 8-(chloromethyl)-imidazol[1,2-a]pyridine (785 mg, 4.7 mmol), and K2CO3 (1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at 125° C. for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxybenzaldehyde.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11]N(C)C)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[C-]#N.[Na+].[CH3:18][N:19](C=O)C.Cl>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:18]#[N:19])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: CN(C)Cc1c[nH]c2cc(Br)ccc12
Reactant: CN(C)C=O
Agent: Cl
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1c[nH]c2cc(Br)ccc12
Temperature: 25 °C
Yield: 79 %

Procedure:
6-Bromo-N,N-dimethyl-1H-indole-3-methanamine (7.76 g, 30.6 mmol) and NaCN (1.95 g, 39.8 mmol, 1.30 eq.) were combined with DMF (40 mL) and water (40 mL). The mixture was heated to reflux for 6 hours, then cooled to rt. Aqueous 1N HCl (40 mL) was added, and the product was extracted with EtOAc. The organic layer was washed with water and dried (MgSO4). The solvent was removed in vacuo to give 5.70 g (79%) of the title compound, that was 79% pure by HPLC area, containing 14% 6-bromoindole. The material was used without purification in the subsequent step.