Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[N+](C1C=CC([O:26][C:27](=O)[NH:28][C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)=CC=1)([O-])=O.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:27]([N:1]2[CH2:2][CH2:3][CH:4]([C:7]3[C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[CH:9][CH:8]=3)[CH2:5][CH2:6]2)=[O:26])=[CH:30][CH:31]=1)([CH3:37])[CH3:36]
Reactant: c1ccc2c(C3CCNCC3)ccnc2c1
Reactant: CC(C)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)c1ccc(NC(=O)N2CCC(c3ccnc4ccccc34)CC2)cc1
Temperature: 100 °C
Reaction time: 14 h
Yield: 32.3 %

Procedure:
A solution of 4-piperidin-4-yl-quinoline (21.1 mg, 99.5 μmol), as prepared in the previous step, (4-isopropyl-phenyl)-carbamic acid 4-nitro-phenyl ester (33.2 mg, 111 μmol), as prepared in Example 4a, and DIEA (18 μL, 109 μmol) in DMSO (100 μL) was stirred at 100° C. for 14 h. The reaction was then allowed to cool to rt, shaken with 2 M K2CO3 (aq) (2 mL), and extracted with DCM (2×2 mL). The organic layers were combined, dried (Na2SO4), and concentrated under reduced pressure. Flash chromatography of the residue (3:4 hex/acetone) provided the title compound (12 mg, 32%). 1H-NMR (300 MHz, CDCl3) δ 8.88 (d, 1H), 8.14 (m, 2H), 7.74 (m, 1H), 7.61 (m, 1H), 7.30 (m, 2H), 7.28 (d, 1H), 7.17 (m, 2H), 6.38 (br s, 1H), 4.36-4.26 (m, 2H), 3.58 (m, 1H), 3.16 (td, 2H), 2.87 (heptet, 1H), 2.13-2.03 (m, 2H), 1.95-1.79 (m, 2H), 1.23 (d, 6H). LC/MS (ESI): calcd mass 373.2, found 374.2 (MH)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18](=O)[C:19]([CH2:24]OC)=[CH:20]N(C)C)[CH:17]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:28][C:29]([NH2:31])=[S:30].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[NH:14][CH:15]=[C:16]([C:18]2[C:19]([CH3:24])=[CH:20][N:31]=[C:29]([SH:30])[N:28]=2)[CH:17]=1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NC(N)=S
Reactant: COCC(=CN(C)C)C(=O)c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1cnc(S)nc1-c1c[nH]c(C(=O)N[C@H](CO)c2ccccc2)c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
4-(3-Dimethylamino-2-methoxymethyl-acryloyl)-1H-pyrrole-2-carboxylic acid (2-hydroxy-1-(S)-phenyl-ethyl)-amide (17.6 mmol, 6.0 g) was combined with thiourea (39 mmol, 3.0 g) and potassium carbonate (53 mmol, 7.3 g) in ethanol (50 mL) and the resulting suspension was heated at 90° C. for 24 hrs. The solvent was removed in vacuo and the resulting black solid was diluted with water and the solid was removed by filtration. The solid was washed with ethyl acetate twice and the aqueous solution was acidified to pH 5–6 with HCl (2N). The solid formed was removed by filtration and the aqueous solution was then extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. The solvent was removed under vacuum to afford the title compound as a brown solid (3.0 g, 48% yield). HPLC Method B, Rt=3.7 minutes, 1H NMR consistent with structure.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[S:11]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][NH2:22])=[CH:17][CH:16]=1)(=[O:14])(=[O:13])[NH2:12]>>[S:11]([C:15]1[CH:16]=[CH:17][C:18]([NH:21][N:22]=[CH:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:19][CH:20]=1)(=[O:14])(=[O:13])[NH2:12]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: NS(=O)(=O)c1ccc(NN=Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 4-chlorobenzaldehyde (5 mmol) and 4-sulfamylphenylhydrazine hydrochloride is subjected to the General Procedure. The title compound is isolated as described in the general procedure.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[NH3:20]>CO>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH2:20])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: N
Solvent: CO
Product: Cc1noc(C)c1COc1ccc(S(N)(=O)=O)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
4-{[(3,5-dimethyl-4-isoxazolyl)methyl]oxy}benzenesulfonyl chloride (300 mg, 0.994 mmol) was added to ammonia solution (2 mL, 92 mmol, 0.88 NH3 in water). The reaction was stirred at 20° C. for 30 minutes, then left to stand overnight. The reaction mixture was diluted with methanol (5 mL) and passed sequentially through two separate aminopropyl (NH2) solid phase extraction (SPE) cartridges eluting with methanol. The product-containing fractions were combined and evaporated in vacuo to give product as a yellow solid (196.2 mg). LCMS (2 min, formic) Rt 0.71 min, m/z (ES+) 283 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:3])[NH2:2].C(O)(=[O:13])C>OO>[C:1]([C:4]1[CH:9]=[N+:8]([O-:13])[C:7]([CH3:10])=[CH:6][N:5]=1)(=[O:3])[NH2:2]
Reactant: Cc1cnc(C(N)=O)cn1
Reactant: CC(=O)O
Agent: OO
Product: Cc1cnc(C(N)=O)c[n+]1[O-]
Temperature: 70 °C
Reaction time: 7 h

Procedure:
2-Carboxy-5-methylpyrazine (9.7 g) in dry dioxan (114 ml) and tributylamine (17.7 ml) was treated with ethyl chloroformate (7.5 ml), keeping the temperature at 0°-5° C. After ten minutes, dioxan (190 ml) saturated with ammonia was added. The mixture was stirred for 3 hours at room temperature, then dioxan was distilled off, and the residue was taken up in saturated aqueous sodium bicarbonate (20 ml). The mixture was filtered and the product washed with water to give 2-carbamoyl-5-methylpyrazine (9.2 g), m.p. 204°- 206° C. This amide (7 g) in glacial acetic acid (30 ml) and 35% hydrogen peroxide (20 ml.) was heated with stirring at 70° C for 7 hours. The reaction mixture was cooled, the product which separated was filtered and washed with water to give 2-carbamoyl-5-methylpyrazine 4-oxide (5.5 g), m.p. 206°-208° C.
Reaction SMILES: [C:1]1([C:7]2[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]3[N:11]([C:13]([CH:16]=[CH2:17])=[CH:14][N:15]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.CCO.[Pd]>[CH2:16]([C:13]1[N:11]2[CH:12]=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:8]([C:18]3[CH:25]=[CH:24][C:21]([CH:22]=[O:23])=[CH:20][CH:19]=3)=[N:9][C:10]2=[N:15][CH:14]=1)[CH3:17]
Reactant: C=Cc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1cnc2nc(-c3ccc(C=O)cc3)c(-c3ccccc3)cn12
Reaction time: 2 h

Procedure:
100 mg 4-(6-phenyl-3-vinylimidazo[1,2-a]pyrimidin-7-yl)benzaldehyde (prepared as described under example 15 are dissolved in a mixture of 5 ml THF and 5 ml EtOH. 10 mg 10% Pd/C are added and the mixture stirred under an atmosphere of hydrogen for 2 h. The mixture is filtered of celite, the solvens is evaporated and the crude product is purified by chromatography on silica gel (dichloromethane/methanol).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:16]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CS(=O)(=O)c1ccc(O)c(C(=O)O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(S(C)(=O)=O)ccc1O
Temperature: 25 °C
Yield: 71 %

Procedure:
A solution of 2-hydroxy-5-(methylsulfonyl)benzoic acid (5.80 g, 26.8 mmol, prepared using procedure in J. Chem. Soc., Perkin Trans 1 1978, 6, 633-638) in MeOH (150 ml) at 0° C. was saturated with HCl (g). The solution was warmed to r.t. and heated to reflux for 3 h. The solid which formed upon cooling was filtered and dried to afford the title compound (4.40 g, 19.1 mmol, 71%).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:27]=[CH:26][C:14]([O:15][CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:24][CH:22]([S:19]([NH:18][CH2:17][CH:16]([O:15][C:14]1[CH:26]=[CH:27][C:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:4][CH2:3][NH:2][S:36]([CH3:35])(=[O:38])=[O:37])=[CH:10][CH:9]=2)=[CH:12][CH:13]=1)[CH3:25])(=[O:21])=[O:20])[CH3:23]
Reactant: CS(=O)(=O)Cl
Reactant: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCN)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(CNS(=O)(=O)C(C)C)Oc1ccc(-c2ccc(CCNS(C)(=O)=O)cc2)cc1
Yield: 105.3 %

Procedure:
The title compound (318 mg, 100%, slow crystallizing-foam) was prepared from (2-{4-[4-(2-aminoethyl)phenyl]phenoxy}propyl)[(methylethyl)sulfonyl]amine hydrochloride (250 mg, 0.664 mmol, prepared in example 39), methylene chloride (4.5 mL, anhydrous), triethylamine (0.09 mL, 0.664 mmol), and methanesulfonyl chloride (0.05 mL, 0.664 mmol) in a manner analogous to the procedure described in Example 40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24].C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH2:37][CH2:38][OH:39]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][CH2:37][CH2:38][OH:39])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23]([NH:25][CH2:26][CH2:27][CH3:28])=[O:24]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(O)c(OC)cc23)cc1Cl
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OCCCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
N-{2-Chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (55 mg), potassium carbonate (20 mg), and 3-bromo-1-propanol (62 μl) were dissolved in N,N-dimethylformamide (4 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 25 mg (yield 40%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([Cl:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:5]=1[SH:13].[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17]Br>CN(C)C=O>[F:14][C:15]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:16]=1[CH2:17][S:13][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH3:12])=[C:9]([Cl:10])[C:4]=1[Cl:3]
Reactant: COc1ccc(S)c(Cl)c1Cl
Reactant: Fc1ccc(CBr)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(SCc2ccc(F)cc2F)c(Cl)c1Cl
Reaction time: 0.42 h

Procedure:
To 1.26 g of sodium hydride in 25 ml dimethylformamide (sieve dried) is added dropwise a solution of 10 of 2,3-dichloro-4-methoxythiophenol in 25 ml dimethylformamide. After the addition is complete, the reaction mixture is stirred for 25 mins and a solution of 10 g of 2,4-difluorobenzyl bromide in 25 ml dimethylformamide is added dropwise. After this addition is complete, the mixture is stirred for 20 mins and cautiously poured onto ice-water. The aqueous mixture is extracted with ethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed to give an oil which crystallizes with cooling and trituration with hexane. Two recrystallizations with ethyl acetate-hexane give 5.1 g of (2,3-dichloro-4-methoxyphenyl) 2,4-difluorobenzyl sulfide, mp 86°-88°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([CH2:19][C:20]1[N:21]([CH2:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)[CH:22]=[CH:23][N:24]=1)[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)(C)(C)C.Cl.CCOCC>CO>[Cl:33][C:28]1[CH:27]=[C:26]([CH:31]=[C:30]([Cl:32])[CH:29]=1)[CH2:25][N:21]1[CH:22]=[CH:23][N:24]=[C:20]1[CH2:19][N:10]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:9][CH2:8][NH2:7]
Reactant: CC(C)(C)OC(=O)NCCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
{2-[[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-(3-fluoro-benzyl)-amino]-ethyl}-carbamic acid tert-butyl ester, (see Example 6) (455 mg, 0.899 mmol) was dissolved in MeOH (7 mL) and treated with 4N HCl/ether (2 mL). The solution was stirred at ambient temperature for 4 h. then heated to 40° C. for 3 h. The solvent was evaporated in vacuo providing N1-[1-(3,5-dichloro-benzyl)-1H-imidazol-2-ylmethyl]-N1-(3-fluoro-benzyl)-ethane-1,2-diamine (341 mg, 93%). ESI MS m/z 407 [C20H21Cl2FN4+H]+.
Reaction SMILES: [CH:1]([O:4][C:5]1[NH:9][N:8]=[C:7]([NH2:10])[CH:6]=1)([CH3:3])[CH3:2].[Cl:11][C:12]1[N:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15].C(N(CC)CC)C>C1COCC1>[Cl:11][C:12]1[N:19]=[C:18]([NH:10][C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[NH:9][N:8]=2)[C:17]([F:21])=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: CC(C)Oc1cc(N)n[nH]1
Reactant: N#Cc1cc(F)c(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(Nc2nc(Cl)c(C#N)cc2F)n[nH]1
Temperature: 25 °C
Yield: 49.7 %

Procedure:
A solution of 5-isopropoxy-1H-pyrazol-3-amine (0.96 g, 6.8 mmol), 2,6-dichloro-5-fluoronicotinonitrile (1.3 g, 6.8 mmol), and triethylamine (0.9 g, 8.8 mmol) in THF (30 ml) was heated to 60° C. for 4 days, and then cooled to 25° C., at which point the product precipitated. The resulting solid was filtered and washed with hexanes (100 ml) to give the title compound (1.0 g, 50%). MS: Calcd.: 295. Found: [M+H]+ 296.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:34][CH2:35][C:36]([N:38]([CH3:46])[C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:34][CH2:35][C:36]([N:38]([C:39]2[CH:44]=[CH:43][C:42]([NH:45]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=4)/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:41][CH:40]=2)[CH3:46])=[O:37])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN(C(=O)CCN1CCCCC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CCN2CCCCC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((2-(piperidin-1-yl)-ethyl)-carbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=5:1) C32H34N4O4
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH:3]([OH:5])[CH3:4].[F:7][C:8]1[C:13]([S:14](Cl)(=[O:16])=[O:15])=[C:12]([F:18])[C:11]([F:19])=[C:10]([F:20])[C:9]=1[F:21].C([O-])(O)=O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[F:7][C:8]1[C:9]([F:21])=[C:10]([F:20])[C:11]([F:19])=[C:12]([F:18])[C:13]=1[S:14]([O:6][CH2:1][CH2:2][CH:3]([OH:5])[CH3:4])(=[O:16])=[O:15]
Reactant: CC(O)CCO
Reactant: O=S(=O)(Cl)c1c(F)c(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(O)CCOS(=O)(=O)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 40.6 %

Procedure:
To a solution of 1,3-butane diol (0.9 g, 10 mmol) and TEA (0.61 g, 6 mmol) in CH2Cl2 (4 mL) at 0° C. was added pentafluorobenzenesulfonyl chloride (0.53 g, 2 mmol) dissolved in CH2Cl2 (4 mL). The solution was stirred for 6 h over which time the solution slowly warmed to rt. Saturated aqueous NaHCO3 (25 mL) was added to the solution and the mixture was stirred at rt for 30 min. The organics were extracted with CH2Cl2 (50 mL) and washed with 0.5 M HCl (3×20 mL), saturated aqueous NaHCO3 (1×20 mL) and saturated aqueous NaCl (1×20 mL). The organics were dried over Na2SO4 and concentrated to give a crude mixture. Silica gel chromatography with ethyl acetate in hexanes yielded the desired product (0.26 g, 40%). 1H NMR (400 MHz CDCl3) δ 4.62 (m, 2H), 4.13 (m, 1H), 2.11 (m, 1H), 1.94 (m, 1H), 1.40 (d, 3H, J=6.2 Hz). Anal. Calcd. For C10H9F5O4S: C, 37.51; H, 2.83. Found: C, 37.70; H, 2.93.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[O:18]1[CH2:22][CH2:21][C@@H:20]([OH:23])[CH2:19]1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:3]2[C:2]([O:23][C@@H:20]3[CH2:21][CH2:22][O:18][CH2:19]3)=[N:7][CH:6]=[C:5]([CH:4]=2)[C:8]([OH:10])=[O:9])=[CH:12][CH:13]=1
Reactant: O[C@@H]1CCOC1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Product: O=C(O)c1cnc(O[C@@H]2CCOC2)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example CI using 6-chloro-5-(4-chlorophenyl)-3-pyridinecarboxylic acid (CAN 1012792-56-1) and (3R)-tetrahydro-3-furanol (CAN 86087-24-3) as starting materials; LC-MS (UV peak area/ESI) 88.1%, 318.1 (M−H)−.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=C(C#N)[C:10](=[O:16])[NH:11]2.C(O)C.[OH-].[Na+].[C:24]([OH:27])(=[O:26])[CH3:25]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[C:25]([C:24]([OH:27])=[O:26])[C:10](=[O:16])[NH:11]2
Reactant: CC(=O)O
Reactant: N#Cc1cc2c(-c3cccs3)nccc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc2c(-c3cccs3)nccc2[nH]c1=O

Procedure:
A mixture of 1,2-dihydro-5-(2-thienyl)-2-oxo-1,6-naphthyridine-3-carbonitrile (10.0 g), ethanol (300 ml) and 10N NaOH (300 ml) was refluxed overnight. After cooling, the reaction mixture was neutralized with acetic acid, and the precipitated crystals were separated by filtration, washed with water, isopropanol and diisopropyl ether in this order and then dried to give the title compound (Compound No. 44)(10.5 g) as pale yellow crystals. M.p. 278° C.
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.[H-].[Na+].[Br:17][C:18]1[CH:23]=[N:22][C:21](Br)=[CH:20][N:19]=1>CN(C=O)C>[Br:17][C:18]1[N:19]=[CH:20][C:21]([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:22][CH:23]=1
Reactant: CC1(CO)Cn2cc([N+](=O)[O-])nc2O1
Reactant: Brc1cnc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2cnc(Br)cn2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
A solution of alcohol 101 (see Example 2M) (350 mg, 1.76 mmol) in anhydrous DMF (7 mL) under N2 at 0° C. was treated with 60% NaH (104 mg, 2.60 mmol) and 2,5-dibromopyrazine (837 mg, 3.52 mmol), then quickly degassed and resealed under N2. After stirring at room temperature for 3 h, the reaction was cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (20 mL), added to brine (80 mL), and extracted with CH2Cl2 (6×100 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 0-2% EtOAc/CH2Cl2 gave 2-{[(5-bromo-2-pyrazinyl)oxy]methyl}-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (104) (428 mg, 68%) as a white solid: mp (MeOH/CH2Cl2/hexane) 198-200° C.; 1H NMR [(CD3)2SO] δ 8.44 (d, J=1.3 Hz, 1H), 8.16 (d, J=1.3 Hz, 1H), 8.14 (s, 1H), 4.62 (s, 2H), 4.40 (d, J=11.0 Hz, 1H), 4.19 (d, J=11.0 Hz, 1H), 1.70 (s, 3H). Anal. (C11H10BrN5O4) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=S(=O)(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A 500 mL round-bottomed flask was charged with 4-bromobenzenesulfonyl chloride (10.00 g, 39.1 mmol, Sigma-Aldrich, St. Louis, Mo.), 100 mL of benzene and aluminum chloride (6.26 g, 47.0 mmol). After stirring at room temperature for 12 h, the mixture was diluted water (100 mL) and extracted with EtOAc (2×100 mL). The organic extracts were dried (MgSO4) and concentrated to give 1-bromo-4-(phenylsulfonyl)benzene (10.50 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](O)=[CH:10][C:11]2[N:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15]C)=[O:14])=[CH:5][CH:4]=1.N>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:15][C:13](=[O:14])[C:12]3[CH:17]=[CH:18][CH:19]=[N:20][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CNC(=O)c1cccnc1C=C(O)c1ccc(OC)cc1
Agent: N
Solvent: C1COCCO1
Product: COc1ccc(-c2cc3ncccc3c(=O)[nH]2)cc1
Temperature: 170 °C
Yield: 76.1 %

Procedure:
2-[2-(4-Methoxyphenyl)-2-hydroxyethenyl]-N-methylnicotinamide (2.509 g) was added to a 29% aqueous solution of ammonia (100 ml) and dioxane (50 ml), which was then heated in a sealed tube at 170° C. overnight. After cooling as it was, the resulting insoluble matters were collected by filtration, to give the title compound as a dark green solid (1.694 g, yield; 73%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)Cl.CC(O)=O>[CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[C:13]([Br:23])=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2c(c1Br)CC1CC2CN(Cc2ccccc2)C1
Yield: 27.7 %

Procedure:
11-Benzyl-5-methoxy-11-aza-tricyclo[7.3.1.02.7]trideca-2(7),3,5-triene (300 g, 10.2 mmol) was stirred at 0° C. in CH2Cl2 (10 mL) and AcOH (5 mL) and treated with bromine (3.21 g, 20 mmol) in CH2Cl2 (10 mL) and AcOH (5 mL). After 18 hours the reaction was quenched with 20% aq. NaHSO3 soin. (100 mL). The produce was extracted with CH2Cl2 (3×40 mL) and washed with sat. aq. NaHCO3 soin. (3×50 mL). The combined organic layer was dried through a cotton plug, concentrated and chromatographed on Silica gel to provide an oil (1.05 g, 28%). (TLC 30%EtOAc/hexanes Rf 0.48). 1H NMR (CDCl3) δ 7.13 (m, 3H), 6.91 (m, 3H), 6.68 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.36 (s, 2H), 2.88-2.79 (4H), 2.67 (br d, J=9.0 Hz, 1H), 2.31 (br s, 1H), 2.28 (br s, 1H), 2.22 (br s, 1H), 1.78 (AB d, J=13.0 Hz, 2H). GCMS m/e 373,371 (M+).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[CH3:26][C:27]([CH3:30])([O-:29])[CH3:28].[K+]>O1CCCC1>[C:27]([O:29][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=1[Cl:25])[N:6]2[C:11]1[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=1)([CH3:30])([CH3:28])[CH3:26]
Reactant: Clc1ccc(-n2c(-c3ccc(Cl)cc3Cl)nc3c(Cl)ncnc32)cc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)Oc1ncnc2c1nc(-c1ccc(Cl)cc1Cl)n2-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Chloro-9-(4-chlorophenyl)-8-(2,4-dichlorophenyl)-9H-purine I-(1A-1)d, potassium tert-butoxide (20 mg, 0.15 mmol) and tetrahydrofuran (1 ml) were combined and stirred overnight at ambient temperature. The reaction mixture was concentrated to dryness and the residue was extracted into ethyl acetate from saturated aqueous NaHCO3 solution. The organic layers were combined, dried (Na2SO4), filtered, and evaporated to dryness. The crude product was purified by chromatography on a preparative TLC plate using 4% methanol/methylene chloride as the solvent to give title compound 2A-1 as a yellow oil: +ESI MS (M+1) 447.5; 1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.55 (d, J=2.1 Hz, 1H), 7.49–7.44 (m, 3H), 7.34 (d, J=9.1 Hz, 2H), 1.77 (s, 9H).