Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:13](=O)[CH:14](Br)[CH3:15])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.Cl.C(OCC)(=O)C>[CH2:11]([O:10][C:8]([C:6]1[N:7]=[C:3]([NH:2][CH3:1])[S:4][C:5]=1[C:13]1[N:25]=[C:22]2[CH:21]=[CH:20][C:19]([CH3:18])=[CH:24][N:23]2[C:14]=1[CH3:15])=[O:9])[CH3:12]
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1nc(NC)sc1C(=O)C(C)Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1nc(NC)sc1-c1nc2ccc(C)cn2c1C
Yield: 57.4 %

Procedure:
A solution of ethyl 2-methylamino-5-(2-bromopropionyl)-4-thiazolecarboxylate (2.2 g) and 5-methyl-2-aminopyridine (2.6 g) in acetonitrile (80 ml) was refluxed for 2 hours. The reaction mixture was evaporated to afford a residue, which was dissolved in a mixture of 5% hydrochloric acid and ethyl acetate. The separated aqueous solution was adjusted to pH 8.0 with 20% potassium carbonate and extracted with ethyl acetate. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to afford a crystalline residue, which was recrystallized from a mixture of ethyl acetate and diethyl ether to give 2-(4-ethoxycarbonyl-2-methylaminothiazol-5-yl)-3,6-dimethylimidazo[1,2-a]pyridine (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH2:9])=[O:8].[CH2:10]([C:14]1[NH:15][C:16]([Cl:21])=[C:17]([CH:19]=O)[N:18]=1)[CH2:11][CH2:12][CH3:13].[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH2:10]([C:14]1[NH:18][C:17]([CH2:19][NH:1][C:2]2[N:3]=[CH:4][NH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[C:16]([Cl:21])[N:15]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc(C=O)c(Cl)[nH]1
Reactant: NC(=O)c1[nH]cnc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCc1nc(Cl)c(CNc2nc[nH]c2C(N)=O)[nH]1
Temperature: 25 °C
Yield: 25.5 %

Procedure:
A reaction mixture of 4-amino-5-imidazolecarboxamide (0.50 g, 3.96 mmol), 2-butyl-5-chloro-1H-imidazole-4-carbaldehyde (0.89 g, 4.76 mmol), and NaCNBH3 (0.25 g, 3.96 mmol) in methanol (5 mL) was stirred at r.t. over night. Acetic acid (0.24 g, 3.96 mmol) was added and the mixture was heated at 50° C. for 5 h. The mixture was concentrated in vacuo and dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.30 g (26%) of the title compound.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]2=[O:35])[CH:25]=[CH:26][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:21][C:22]4[CH:23]=[C:24]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][C:29]5=[O:35])[CH:25]=[CH:26][CH:27]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)C(=O)C1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)C(=O)C1

Procedure:
204 a) An oven dried tube was charged with 1-iodo-3-nitro-benzene (2.60 g, 10.4 mmol), 4-methyl-piperazin-2-one (1.00 g, 8.76 mmol), copper(I) iodide (85.0 mg, 0.446 mmol), (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.14 mL, 0.89 mmol), potassium phosphate (3.75 g, 17.7 mmol) and 1,4-dioxane (10 mL). The tube was carefully evacuated and backflushed with nitrogen three times then sealed. The mixture was heated at 90° C. for 24 hours then cooled to room temperature and diluted with dichloromethane (20 mL). The mixture was filtered through a plug of diatomaceous earth and the filtrate was evaporated. The residue was purified via chromatography using an ISCO automated purification apparatus (silica gel column 40 g and 0%→4% methanol:dichloromethane). 4-Methyl-1-(3-nitro-phenyl)-piperazin-2-one was isolated as a red-brown waxy solid (1.13 g, 55%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.20 (s, 1H), 8.13 (d, J=7.5 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.57 (t, J=8.2 Hz, 1H), 3.79 (t, J=5.1 Hz, 2H), 3.31 (s, 2H), 2.83 (t, J=5.2 Hz, 2H), 2.42 (s, 3H). MS=236 (MH)+. 204 b) 1-(3-Amino-phenyl)-4-methyl-piperazin-2-one was prepared from 4-methyl-1-(3-nitro-phenyl)-piperazin-2-one (1.13 g, 4.80 mmol) in a manner analogous to Example 111a. Product isolated as an orange waxy solid (0.95 g, 96%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.17 (t, J=7.9 Hz, 1H), 6.66-6.57 (m, 3H), 3.71 (br s, 2H), 3.67 (t, J=4.7 Hz, 2H), 3.26 (s, 2H), 2.76 (t, J=4.7 Hz, 2H), 2.40 (s, 3H). MS=206 (MH)+. 204 c) 1-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-4-methyl-piperazin-2-one was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3249 mmol) and 1-(3-amino-phenyl)-4-methyl-piperazin-2-one (75.0 mg, 0.365 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (27.0 mg, 0.0494 mmol) as the ligand in a manner analogous to Example 2d. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.91 (s, 1H), 8.89 (d, J=6.6 Hz, 1H), 8.44 (d, J=8.2 Hz, 2H), 8.08 (d, J=8.0 Hz, 2H), 7.99 (d, J=7.3 Hz, 1H), 7.86 (s, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.31 (t, J=7.9 Hz, 1H), 7.19 (t, J=7.0 Hz, 1H), 6.85 (d, J=7.7 Hz, 1H), 3.68-3.63 (m, 2H), 3.29 (s, 3H), 3.13 (s, 2H), 2.77-2.72 (m, 2H), 2.31 (s, 3H). MP=234-236° C. MS=477 (MH)+.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH2:9]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[CH2:9]([C:16]1[C:21]([I:1])=[CH:20][CH:19]=[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)[N:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)C1CCN(c2cccc(Cc3ccccc3)n2)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ccc(I)c(Cc3ccccc3)n2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
Under stirring in an ice bathe, 1.25 g of N-iodosuccinimide was added little by little to a mixture of 1.2 g of 2-benzyl-6-(4-ethoxycarbonylpiperidino)pyridine and 10 ml of N,N-dimethylformamide, followed by stirring as it was overnight. Sodium sulfite was added thereto, and the mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 1-5% ethyl acetate/hexane, to give 1.42 g of the target compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:10]([F:13])([F:12])[F:11])=[C:5]([C:7]([OH:9])=O)[N:6]=1.Cl.[CH3:15][NH:16][O:17][CH3:18].CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[CH3:18][O:17][N:16]([CH3:15])[C:7]([C:5]1[N:6]=[C:2]([CH3:1])[O:3][C:4]=1[C:10]([F:13])([F:12])[F:11])=[O:9]
Reactant: CNOC
Reactant: Cc1nc(C(=O)O)c(C(F)(F)F)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1nc(C)oc1C(F)(F)F
Reaction time: 16 h
Yield: 91.7 %

Procedure:
To a solution of 2-methyl-5-trifluoromethyl-oxazole-4-carboxylic acid (500 mg, 2.56 mmole) in dichloromethane (5 ml) was subsequently treated at 22° C. with N,O-dimethylhydroxylamine hydrochloride (262 mg, 2.69 mmole), N-methylmorpholine (0.29 ml, 2.69 mmole) and EDCI.HCl (516 mg, 2.69 mmole) and stirring was continued for 16 h. The mixture was washed with 1 M aqueous HCl and H2O, the organic layer was dried and evaporated to give the title compound (559 mg) as a colorless oil which was used without further purification. MS: m/z=239.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[C:5]([Cl:15])=[O:6]
Reactant: O=C(O)c1cc(F)cc(Cl)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
3-Chloro-5-fluorobenzoic acid (400 mg, 2.3 mmol) was treated with a solution of oxalyl chloride (4.6 mL of 2.5 M in dichloromethane, 11.5 mmol) and a catalytic amount of N,N-dimethylformamide. The reaction was stirred at ambient temperature for 2.5 hours. The excess oxalyl chloride was removed in vacuo to afford 3-chloro-5-fluorobenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])=[N:10][CH:9]=1)([CH3:6])[C:3]([OH:5])=[O:4].[F:32]C1C=CC(CCBr)=CC=1.C(OC(=O)C(SC1SC(N)=NC=1)(C)C)C>>[F:32][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][N:16]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][C:2]([CH3:1])([CH3:6])[C:3]([OH:5])=[O:4])=[CH:9][N:10]=2)=[CH:20][CH:21]=1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Reactant: Fc1ccc(CCBr)cc1
Agent: CCOC(=O)C(C)(C)Sc1cnc(N)s1
Product: CC(C)(Sc1cnc(NC(=O)N(CCc2ccc(F)cc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-phenethyl-ureido]-thiazol-5-ylsulfanyl}-propionic acid using 2-(4-fluorophenyl)ethylbromide and 2-(2-amino-thiazol-5-ylsulfanyl)-2-methyl-propionic acid ethyl ester.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24]O)[CH:16]=4)[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]4[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=4[CH3:36])=[O:27])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:59].O>C(Cl)Cl>[Br:59][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]3[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=3[CH3:36])=[O:27])[C:9]3[CH:8]=[N:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:14]=3[CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCO)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCBr)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxamide (0.35 g, 0.68 mmol) in DCM (5 mL), triphenyl phosphine (0.285 g, 1.08 mmol) was added and the reaction mixture stirred at room temperature for 10 min. Finally CBr4 (0.36 g, 1.08 mmol) was added portion wise and resulting solution was stirred at room temperature for 4 h. On completion, water was added to the reaction mixture and extracted with 5% MeOH/DCM. The combined organic layer was dried over sodium sulfate and concentrated to give crude material which was purified by column chromatography over silica gel to afford 6-(3-(3-bromopropoxy)phenyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.28 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:12]C(C)([O-])C.[K+].CI>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:11])=[N:7][N:8]2[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: Clc1ccc2c(I)n[nH]c2c1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: Cn1nc(I)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1.25 h
Yield: 66 %

Procedure:
In a round-bottomed flask, 6-chloro-3-iodo-1H-indazole (167 mg, 0.57 mmol) was dissolved in THF (2 ml) and the solution was cooled to 0° C. Potassium tert-butoxide (90 mg, 0.80 mmol) was added and the reaction mixture was stirred at 0° C. for 1.25 h. Methyl iodide (0.045 ml, 0.72 mmol) was added dropwise then the ice bath was removed and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over silica gel with EtOAc/Hexanes (gradient 0-5% EtOAc) to afford 110 mg (63%) of 6-chloro-3-iodo-1-methyl-1H-indazole as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH2:19]S(C(F)(F)F)(=O)=O)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:30]([N:32]1[CH:36]=[N:35][CH:34]=[N:33]1)=C>>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([CH3:28])([CH3:27])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([CH:19]=[CH:30][N:32]3[CH:36]=[N:35][CH:34]=[N:33]3)[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(Cc1c[nH]c2c(CS(=O)(=O)C(F)(F)F)cccc12)NC(=O)OC(C)(C)C
Reactant: C=Cn1cncn1
Product: CC(C)(Cc1c[nH]c2c(C=Cn3cncn3)cccc12)NC(=O)OC(C)(C)C

Procedure:
{1,1-Dimethyl-2-[7-(2-[1,2,4]triazol-1-yl-vinyl)-1H-indol-3-yl]-ethyl}-carbamic acid tert-butyl ester is prepared from [1,1-dimethyl-2-(7-trifluoromethanesulfonyhnethyl-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester and 1-vinyl-1,2,4-triazole as described for the preparation of Amine 23 (93%). FDMS m/e=381.2 (M++1).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH:10]3[CH2:12][C:6]([C:13]([OH:15])=[O:14])([CH2:7][CH:8]1[CH2:9]3)[CH2:5]2)(=[O:3])[CH3:2].[C:16](Cl)(=O)C>CO>[C:1]([C:4]12[CH2:11][CH:10]3[CH2:12][C:6]([C:13]([O:15][CH3:16])=[O:14])([CH2:7][CH:8]1[CH2:9]3)[CH2:5]2)(=[O:3])[CH3:2]
Reactant: CC(=O)C12CC3CC1CC(C(=O)O)(C3)C2
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)C12CC3CC(C1)C(C(C)=O)(C3)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To 3-acetyltricyclo[3.3.1.03,7]nonane-1-carboxylic acid (2.4 g, 11.4 mmol) obtained in step I, in MeOH (48 mL) cooled to ice bath temperature, was added acetyl chloride (1.64 mL, 22.8 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 2 h. The volatiles were removed under reduced pressure and the crude product was purified by column chromatography to obtain methyl 3-acetyltricyclo[3.3.1.03,7]nonane-1-carboxylate (2.4 g) in 93% yield as viscous liquid. m/z (M+1) 223. IR cm−1 2953, 1728, 1698, 1461, 1234, 1078, 755. 1H NMR (CDCl3) 300 MHz δ 3.66 (s, 3H), 2.75-2.70 (m, 1H), 2.53-2.46 (m, 1H), 2.40-2.32 (m, 1H), 2.19 (s, 3H), 2.15-2.05 (m, 1H), 2.03-1.60 (m, 8H). 13C NMR (CDCl3) 75 MHz δ 210.9, 175.3, 61.4, 53.4, 51.6, 50.5, 48.0, 45.9, 45.6, 42.6, 41.9, 36.8, 35.9, 26.4.
Reaction SMILES: [N:1]1[CH:9]=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.ClC1N=CN=C2C=1NC=N2.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[C:21]1([NH:20][C:9]2[N:1]=[CH:2][N:3]=[C:4]3[C:8]=2[N:7]=[CH:6][NH:5]3)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ncc2[nH]cnc2n1
Reactant: Nc1ccccc1
Agent: Clc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(Nc2ncnc3[nH]cnc23)cc1

Procedure:
The general procedure for the synthesis of purine derivatives is depicted in FIG. 1. The initial compound 6-chloropurine (1.0 eq.) was mixed with aniline (1.20 eq.) and K2CO3 (2.5 eq.) in 50.0 ml dioxane. The resultant mixture was charged in 100 mL round bottom flask with a stirring bar. The mixture was refluxed overnight and monitored by TLC. After the reaction finished, the solvent was removed and the remaining residue was extracted by ethyl acetate. After removing the solvent, the resultant crude product was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (5%) to provide pure titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[NH2:26])[C:17]2=[O:27])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([N:16]2[C:24](=[O:25])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[N:26]([S:36]([CH3:35])(=[O:38])=[O:37])[S:36]([CH3:35])(=[O:38])=[O:37])[C:17]2=[O:27])[CH2:12][C:13](=[O:15])[CH3:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(N)c3C2=O)cc1OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(CC(C)=O)N2C(=O)c3cccc(N(S(C)(=O)=O)S(C)(=O)=O)c3C2=O)cc1OC
Temperature: 5 °C
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of 2-[1-(3,4-dimethoxyphenyl)-3-oxobutyl]-4-aminoisoindoline-1,3-dione (1.02 g, 2.77 mmol) and triethylamine (1.40 g, 13.85 mmol) in methylene chloride (40 mL) was cooled to 5° C. Methanesulfonyl chloride (1.27 g, 11.08 mmol) was added at 5-8° C. and the resulting mixture was stirred at room temperature for 2 hours. The mixture was washed with sat. Sodium bicarbonate (20 mL), 1N hydrogen chloride (20 mL), water (30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (Silica gel, methylene chloride:ethyl acetate 9:1) to give 2-[1-(3,4-dimethoxyphenyl)-3-oxobutyl]-4-[bis(methylsulfonyl)amino]isoindoline-1,3-dione (1.18 g, 81%) as a white solid: mp 194-196° C.; 1H NMR (DMSO-d6) δ 8.02-7.93 (m, 3H), 6.99-6.90 (m, 3H), 5.65 (t, J=6.7 Hz, 1H), 3.75-3.65 (m, 1H), 3.71 (s, 6H), 3.56 (s, 6H), 3.53-3.46 (m, 1H), 2.11 (s, 3H); 13C NMR (DMSO-d6) δ 205.79, 166.58, 165.78, 148.64, 148.32, 138.48, 135.86, 132.68, 131.50, 129.85, 129.15, 125.06, 119.35, 111.58, 110.91, 55.49, 55.39, 49.27, 44.52, 43.53, 43.49, 29.92; Anal. Calcd. for C22H24N2O9S2: C, 50.37; H, 4.61; N, 5.34, S, 12.23. Found: C, 50.43, H, 4.77; N, 5.16; S, 12.22.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9].O>C(OCC)C>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: CC(C)(CO)CO
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: CC1(C)COS(=O)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
Step A A mixture of 2,2-dimethyl-propane-1,3-diol (Aldrich) (5 g, 48 mmol) in anhydrous ethyl ether (100 mL) at 0° C. was added thionyl chloride (8.7 mL, 120 mmol). The reaction mixture was stirred at 0° C. for 2 h. Water was added. The organic layer was separated, the aqueous layer was then extracted with ethyl ether. The combined organic layers were washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, concentrated to give 5,5-dimethyl-[1,3,2]dioxathiane 2-oxide as a light pink oil (4.8 g, 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[CH:5][CH:4]=1.C1C=C[NH+]=CC=1.[Br:21][Br-]Br.C([O-])([O-])=O.[Na+].[Na+]>CC#N.O>[Br:21][C:11]1[NH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[N:13][C:12]=1[CH3:14]
Reactant: COc1ccc(-c2nc(C)c[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(-c2nc(C)c(Br)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
2-(p-Methoxyphenyl)-4-methylimidazole, (5.0 g, 0.0265 mole), was dissolved in CH3CN (250 ml) at the boiling point. The solution was cooled to room temperature and stirred while a solution of pyridinium bromide perbromide (7.0 g) in CH3CN (70 ml) was added dropwise. A precipitate separated as the addition was completed (30 min) and stirring was continued for 30 minutes. The mixture was poured into water (1.5 L) and the precipitated hydrobromide salt was collected. The filtrate was made basic with saturated Na2CO3 solution and the product was collected, washed with water, and dried to afford 2.45 g, m.p. 183°-187° C. The hydrobromide salt was dissolved in hot CH3CN (75 ml)-H2O (25 ml) and the solution was made basic with saturated Na2CO3 solution. A second crop of product was collected, washed with water, and dried to yield 2.2 g of 35; m.p. 179°-184° C.; 65 % combined yield. A sample of the first crop recrystallized from 50% CH3CN melted at 184°-187° C.
Reaction SMILES: Cl[C:2]1[N:3]=[N+:4]([O-:16])[C:5]2[CH:14]=[C:13]3[C:9]([CH2:10][CH:11]([CH3:15])[CH2:12]3)=[CH:8][C:6]=2[N:7]=1.[N:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CCN(CC)CC>COCCOC>[CH3:15][CH:11]1[CH2:10][C:9]2[C:13](=[CH:14][C:5]3[N+:4]([O-:16])=[N:3][C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[N:7][C:6]=3[CH:8]=2)[CH2:12]1
Reactant: CC1Cc2cc3nc(Cl)n[n+]([O-])c3cc2C1
Reactant: NCCCN1CCOCC1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: CC1Cc2cc3nc(NCCCN4CCOCC4)n[n+]([O-])c3cc2C1
Yield: 95.5 %

Procedure:
A solution of chloride 95 (367 mg, 1.6 mmol), 3-(4-morpholinyl)propylamine (0.34 mL, 2.3 mmol) and Et3N (0.33 mL, 2.3 mmol) in DME (50 mL) was stirred at reflux temperature for 8 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 98 (525 mg, 98%) as a yellow solid: mp (MeOH/DCM) 138-140° C.; 1H NMR δ 8.04 (s, 1H, H-9), 7.35 (s, 1H, H-5), 6.10 (br t, J=5.0 Hz, 1H, NH), 3.75 (br t, J=4.7 Hz, 4H, 2×CH2O), 3.56-3.61 (m, 2H, CH2N), 3.08-3.18 (m, 2H, CH2), 2.56-2.65 (m, 3H, CH, CH2), 2.44-2.52 (m, 6H, 3×CH2N), 1.83 (br p, J=6.5 Hz, 2H, CH2), 1.15 (d, J=6.1 Hz, 3H, CH3); 13C NMR δ 158.8, 154.2, 148.9, 142.8, 129.8, 120.7, 114.8, 67.0 (2), 57.3, 53.8 (2), 41.2, 40.8, 40.4, 34.9, 25.3, 20.4. Anal. calcd for C18H25N5O2: C, 63.0; H, 7.3; N, 20.4. Found: C, 63.2; H, 7.2; N, 20.4%.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][CH:8](O)[C:7]2[CH:11]=[C:12]([Cl:14])[S:13][C:6]=2[S:5]1(=[O:16])=[O:15].C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:14][C:12]1[S:13][C:6]2[S:5](=[O:16])(=[O:15])[N:4]([CH2:3][CH2:2][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH:9]=[CH:8][C:7]=2[CH:11]=1
Reactant: O=S1(=O)c2sc(Cl)cc2C(O)CN1CCBr
Reactant: C1COCCN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S1(=O)c2sc(Cl)cc2C=CN1CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of the product from Step A (0.76 g, 2.20 mmol) in tetrahydrofuran (30 mL) containing triethylamine (0.56 g, 5.5 mmol) was added methanesulfonic anhydride (0.75 g, 4.3 mmol); this mixture was stirred at room temperature for 1 hr and evaporated to dryness. The residue was dissolved in DMF (30 mL), triethylamine (1 mL) was added and the mixture heated at 150° C. for 45 min. Morpholine (3 mL, 34 mmol) was added to the reaction mixture and heating continued at the same temperature for 1 hr followed by heating at 100° C. for an additional hour. The volatiles were evaporated and the residue mixed with ethyl acetate; this mixture was washed with saturated aqueous sodium bicarbonate, dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 50% ethyl acetate/hexane to ethyl acetate) to give a viscous oil (0.42 g, 58%) which was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1.[NH3:26]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][C:18]([CH3:23])([CH3:22])[C:19]([NH2:26])=[O:20])[CH:15]=3)[N:10]([CH3:24])[C:9]=2[CH3:25])=[CH:4][CH:3]=1
Reactant: N
Reactant: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)O)ccc2n1C
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(N)=O)ccc2n1C

Procedure:
The above compound was prepared from 2-[3-(4-chlorophenyl)-1,2-dimethyl-1H-indole-5-yloxy]-2-methylpropanoic acid and a saturated solution of ammonia in absolute tetrahydrofurane using a procedure analogous to that of Example 130.