Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:18]=[C:19]1[C:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:22][CH2:21][N:20]1[CH2:36][C:37](O)=[O:38].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10][N:9]([C:37](=[O:38])[CH2:36][N:20]3[CH2:21][CH2:22][C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[C:19]3=[O:18])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCNC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpyrrolidine (Example 17A, 0.22 g, 1.00 mmol) in dichloromethane (20 mL) under nitrogen was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) followed by N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.61 mg, 0.005 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was concentrated and the residue was partitioned in ethyl acetate/water (8:2, 400 mL). The organic layer was washed with water followed by brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.16-7.40 (m, 20H), 4.14-4.25 (m, 2H), 4.09-4.12 (m, 2H), 3.38-3.61 (m, 4H), 2.75-2.87 (m, 2H), 2.49-2.63 (m, 2H); MS (DCI+) m/z 501 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[O:29][CH3:30])[CH:19]=[CH:18][N:17]=1>>[F:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[CH:21]=[CH:16][N:17]=[C:18]([NH:1][C:2]3[CH:3]=[C:4]([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=3)[CH:19]=2)=[C:23]([O:29][CH3:30])[CH:24]=1
Reactant: COc1cc(F)ccc1-c1ccnc(Cl)c1
Reactant: CN(C)S(=O)(=O)Cc1cccc(N)c1
Product: COc1cc(F)ccc1-c1ccnc(Nc2cccc(CS(=O)(=O)N(C)C)c2)c1
Temperature: 140 °C

Procedure:
The title compound G3 was prepared from 1-(3-aminophenyl)-N,N-dimethylmethanesulfonamide (400 mg, 1.87 mmol) and intermediate A2 (532 mg, 2.24 mmol) following the procedure reported for G1 by heating the reaction mixture for 2 h at 140° C. in a microwave oven. The desired product G3 was obtained by flash chromatography on silica gel (cHex/EtOAc 80:20 to 20:80) as a white solid (274 mg, 35%). 1H NMR (400 MHz, d6-DMSO, 300K) δ 2.71 (s, 6H), 3.81 (s, 3H), 4.34 (s, 2H), 6.82 (dd, J=5.3 Hz, J=1.5 Hz, 1H), 6.88 (dt, J=8.3 Hz, J=1.5 Hz, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 7.05 (dd, J=11.4 Hz, J=2.4 Hz, 1H), 7.25 (t, J=7.8 Hz, 1H), 7.38 (dd, J=8.3 Hz, J=7.0 Hz, 1H), 7.67 (s, 1H), 7.72 (d, J=8.3 Hz, 1H), 8.14 (d, J=5.3 Hz, 1H), 9.11 (s, 1H). MS (ES) C21H22FN3O3S requires: 415. found: 416 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=[CH:4][N:5]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cc(Cl)ncn2)cc1
Reactant: CC#CCO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2ccc(F)cc2)ncn1
Temperature: 25 °C
Reaction time: 9 h
Yield: 57.4 %

Procedure:
In 8 ml of N,N-dimethylformamide were dissolved 207 mg of 4-chloro-6-(4-fluorophenyl)pyrimidine and 83 mg of 2-butyn-1-ol, to which 48 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 9 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 138 mg of 4-(4-fluorophenyl)-6-(2-butynyloxy)pyrimidine (the present compound (59)).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[N:5](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:4]=1.C([SiH](CC)CC)C.C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[CH3:1][O:2][C:3]1[C:7]2[CH:8]=[N:9][C:10]([NH:12][C:13]([NH:15][C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])=[O:14])=[CH:11][C:6]=2[NH:5][N:4]=1
Reactant: COc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1n[nH]c2cc(NC(=O)N[C@H](C)c3ccccc3)ncc12

Procedure:
(R)-1-(3-Methoxy-1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea (156 mg, 0.282 mmol) and triethylsilane (0.068 mL, 0.423 mmol) were stirred in TFA (2 mL) at room temperature for 2 h. Saturated NaHCO3 was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue by flash chromatography (0-15% MeOH-EtOAc) gave (R)-1-(3-methoxy-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd. For C16H17N5O2 [M+1]+ 312. found 312. 1H NMR (500 MHz, DMSO-d6) δ 11.98 (s, 1H), 8.93 (s, 1H), 8.54 (s, 1H), 7.76 (br s, 1H), 7.48 (s, 1H), 7.35-7.31 (m, 4H), 7.25-7.20 (m, 1H), 4.88-4.83 (m, 1H), 3.96 (s, 3H), 1.39 (d, J=6.5 Hz, 3H).
Reaction SMILES: [C:1]([C:8]([NH2:39])([CH2:19][CH2:20][CH2:21][C:22]1([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)[C:9]([O:11]CC1C=CC=CC=1)=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([C:8]([NH2:39])([CH2:19][CH2:20][CH2:21][C:22]1([CH2:28][C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1)[C:9]([OH:11])=[O:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)C(N)(CCCC1(CC(=O)OCc2ccccc2)CCCCC1)C(=O)O
Yield: 97.5 %

Procedure:
The Boc-diester (I) (1.27 g, 2.36 mmol) was dissolved in dioxane (15 ml) and treated with 2.6 ml 1N sodium hydroxide solution at room temperature under argon for 4 hours. The reaction mixture was acidified (pH=2) with 3N hydrochloric acid and evaporated at reduced pressure. The residue was dissolved in ethyl acetate, washed with 3N hydrochloric acid, dried over MgSO4 and evaporated at reduced pressure. The residue was purified by flash chromatography (silica gel, 5% methanol/chloroform) to give 1.03 g of the title product: MS: MH+ =448); 1HNM (CDCl3): 7.33 (S, 5H), 5.07 (S, 2H), 5.20-4.80 (m, 1H), 4.42-4.05 (m, 1H), 2.32 (S, 2H), 1.43 (S, 9H) and 2.08-1.07 (m, 16H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]=[CH2:10])=[C:7]([CH3:11])[CH:6]=[C:5]([CH3:12])[N:4]=1>[Pd].C(O)C>[CH2:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[CH3:11])[CH3:10]
Reactant: C=Cc1c(C)cc(C)nc1OC
Agent: [Pd]
Solvent: CCO
Product: CCc1c(C)cc(C)nc1OC
Reaction time: 4 h
Yield: 39.6 %

Procedure:
A mixture of the above 2-methoxy-4,6-dimethyl-3-vinylpyridine (0.66 g, 4.05 mmol), 5% palladium on charcoal and ethyl alcohol (10 mL) is stirred under an atmosphere of hydrogen for 4 hr. The catalyst is removed by filtration through a pad of Hi-Flo and the filtrate is concentrated. The residue is purified by chromatography eluting with dichloromethane. Product containing fractions are combined and concentrated to afford 3-ethyl-2-methoxy-4,6-dimethylpyridine (265 mg, 22.4% yield for two steps). LC/MS: MS m/e=166 (M+H); RT 3.76 min; 1H NMR (CDCl3, δ ppm) 6.50 (1H, s), 3.90 (3H, s); 2.58 (2H, q), 2.38 (3H, s); 2.21 (3H, s), 1.07 (3H, t).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Br:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])C.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:22][C:18]1[CH:17]=[C:16]([CH:11]2[C:10]([CH3:23])([CH3:24])[CH2:9][C:8]3[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=3)[NH:12]2)[CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(Br)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 89.7 %

Procedure:
To a stirred mixture solution of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (15 g, 38.7 mmol) in methanol (50.0 mL) and tetrahydrofuran (50.0 mL) was added 50% sodium hydroxide in water (8.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (12.5 g, 90%) as a light yellow solid: LC/MS m/e calcd for C18H18BrNO2 (M+H)+: 361.25, observed: 360.0 & 362.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:25]=1I)[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:33]([NH:36][C:37](=[CH2:42])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:33]([NH:36][C:37](=[CH:42][C:25]1[CH:26]=[CH:27][C:28]([C:30]#[N:31])=[CH:29][C:24]=1[O:23][CH2:22][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11][C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[C:38]([O:40][CH3:41])=[O:39])(=[O:35])[CH3:34]
Reactant: C=C(NC(C)=O)C(=O)OC
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)OCc1ccccc1)COc1cc(C#N)ccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(C#N)cc1OC[C@@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)NC(C)=O

Procedure:
5.72 g (10.4 mmol) of benzyl (4R)-4-t-butoxycarbonylamino-5-(5-cyano-2-iodophenoxy)pentanoate was stirred together with 3.0 g (21 mmol) of methyl 2-acetamidoacrylate, 2.0 g (6.6 mmol) of tris(2-methylphenyl)phosphine, 270 mg (1.1 mmol) of palladium (II) acetate and 3.54 g (35 mmol) of triethylamine in 50 ml of DMF at 100° C. for 5 hours. The solvent was evaporated, and the residue was treated with ethyl acetate as the extracting solvent by an ordinary method and then purified by the silica gel chromatography (ethyl acetate/hexane) to obtain the title compound.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[NH:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:47][O:48][C:49]([NH:51][C@H:52]([C:56](O)=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][O:48][C:49]([NH:51][C@H:52]([C:56]([N:2]1[CH:3]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:4][C:5]2([CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[CH2:1]1)=[O:57])[CH:53]([CH3:54])[CH3:55])=[O:50]
Reactant: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)C1CC2(CCN(C(=O)OC(C)(C)C)CC2)CN1C(=O)[C@@H](NC(=O)OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.5 %

Procedure:
To a solution of 8-(1,1-dimethylethyl) 3-ethyl 2,8-diazaspiro[4.5]decane-3,8-dicarboxylate (131) (150 mg, 0.48 mmol), HATU (183 mg, 0.48 mmol) and N-[(methyloxy)carbonyl]-L-valine (93 mg, 0.53 mmol) in anhydrous CH2Cl2 (4 mL) was added Hunig's base (0.17 mL, 0.96 mmol) and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was concentrated in vacuo and purified by silica gel chromatography eluting with 15-80% hexanes/EtOAc to afford the title compound as a pale yellow oil (125 mg, 55% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=O)=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)Cl>[CH2:1]([C:3]1[S:19][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13]([C:16]#[N:18])=[CH:12][N:9]3[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n3cc(C#N)ccc3nc2s1
Yield: 96.3 %

Procedure:
From 1.3 g (0.0048 mol) of 2-ethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carboxamide (Example 22), 30 ml of phosphorus oxychloride and 30 ml of chloroform and refluxing on a steam bath for six hours, following the procedure of Example 27, there is obtained 1.18 g of 2-ethyl-4-oxo-4H-pyrido[1,2-a]-thieno[2,3-d]pyrimidine-7-carbonitrile; mp 223°-224° C. after recrystallization from glacial acetic acid.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[C:6]([C:9]1[O:10][C:11]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)(=O)[NH2:7]>CN(C)C=O>[C:6]([C:9]1[O:10][C:11]2[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][CH:15]=[CH:14][C:12]=2[N:13]=1)#[N:7]
Reactant: NC(=O)c1nc2cccc([N+](=O)[O-])c2o1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1nc2cccc([N+](=O)[O-])c2o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
26.14 g (17.22 mmoles) of phosphorus oxychloride is added to 100 ml dimethylformamide at 0° C. and stirred at 0° C. for 15 minutes at room temperature for 30 minutes. 6.5 g (34.45 mmoles) 2-carbamyl-7-nitrobenzoxazole is added and the mixture stirred at room temperature overnight, then poured into ice water and is allowed to stand for 1 hour at room temperature. The resulting precipitate is filtered off, redissolved in ethyl acetate, decolorized with carbon, filtered and the filtrate concentrated in vacuo to give 2-cyano-7-nitro-benzoxazole.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>C1(C)C=CC=CC=1>[CH:13]1([N:18]2[C:9](=[O:10])[C:4]3[C:5](=[CH:11][CH:12]=[C:2]([OH:1])[CH:3]=3)[C:6]2=[O:8])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCC1
Reactant: O=C1OC(=O)c2cc(O)ccc21
Solvent: Cc1ccccc1
Product: O=C1c2ccc(O)cc2C(=O)N1C1CCCC1
Yield: 80.2 %

Procedure:
4-Hydroxy-phthalic anhydride (5.4 g, 32.9 mmol), cyclopentyl amine (4.9 mL, 49.6 mmol) and 4 Å molecular sieves in toluene (136 mL) were stirred at reflux overnight. The reaction mixture was filtered and the solvent was evaporated in vacuo to obtain the product (6.1 g, 80%) as a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ 7.60 (d, J=7.8 Hz, 1H), 7.05-7.01 (m, 2H), 4.50-4.40 (m, 1H), 1.97-1.52 (m, 8H).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16].O.[NH3:18]>O1CCOCC1>[NH2:18][C:2]1[N:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][OH:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:16]
Reactant: Cn1cnc2c(Cl)nc(C#CCCO)nc21
Reactant: N
Solvent: C1COCCO1
Solvent: O
Product: Cn1cnc2c(N)nc(C#CCCO)nc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(6-chloro-9-methyl-9H-purin-2-yl)but-3-yn-1-ol (650 mg, 2.74 mmol) in dioxane (4 ml) was added 30% w/w water solution of ammonia (8 ml). The reaction mixture was stirred overnight in an autoclave at 70° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.N>C(O)C>[C:14]1([N:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[N:24]=[C:6]2[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: O=C(Cl)c1ccc(I)cc1
Agent: N
Solvent: CCO
Product: Ic1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
37.47 g (136 mmol) of 97% 4-iodobenzoyl chloride and 12.82 g (68.2 mmol) of 98% o-aminodiphenylamine were heated to 100° C., in the course of which a stirrable melt formed from 85-90° C. Once the gas evolution had ended (5 min), the melt solidified. The reaction mixture was kept at 100° C. for another 3 hours. After cooling, it was admixed with 100 ml of ethanol with stirring. The precipitate was filtered off with suction, washed with ethanol and stirred up again in 400 ml of ethanol. The suspension was heated to 75° C., which formed a solution which was adjusted to pH 8 with 29 ml of 25% ammonia. After cooling to 5-10° C., the precipitate was filtered off with suction, washed with cold ethanol and dried at 75° C. in a vacuum drying cabinet. 18.37 g (68% of theory) of light gray microcrystals having an m.p. of 178-181° C. were obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]=1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.Br[CH2:27][C:28]([NH:30][C:31]1[C:32]([S:40][CH3:41])=[N:33][C:34]([CH3:39])=[CH:35][C:36]=1[S:37][CH3:38])=[O:29]>O.C(#N)C>[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]=1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:27][C:28]([NH:30][C:31]2[C:32]([S:40][CH3:41])=[N:33][C:34]([CH3:39])=[CH:35][C:36]=2[S:37][CH3:38])=[O:29])[CH2:21][CH2:20]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reaction time: 1 h
Yield: 99 %

Procedure:
Acetonitrile (450 mL) and potassium carbonate (85.7 g, 0.62 mol) were added to 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine.3 hydrochloride (59.42 g, 0.16 mol) in water (180 mL). Subsequently, 2-bromo-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (48.19 g, 0.15 mol) was gradually added thereto, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (300 mL), followed by stirring for 1 hour. The crystals that precipitated were separated through filtration, followed by washing with a solvent mixture (600 mL) of acetonitrile and water (1:1), washing with water (200 mL), and drying through air blow at 40 to 50° C., to thereby yield 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as colorless crystals (75 g, yield: 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[F:20][C:21]1[CH:22]=[C:23]([S:28](Cl)(=[O:30])=[O:29])[CH:24]=[CH:25][C:26]=1[CH3:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:19][S:28]([C:23]2[CH:24]=[CH:25][C:26]([CH3:27])=[C:21]([F:20])[CH:22]=2)(=[O:29])=[O:30])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1F
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: Cc1ccc(S(=O)(=O)Nc2cnc(Oc3cnc4ccccc4c3)c(Cl)c2)cc1F

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 3-fluoro-4-methylbenzene-1-sulfonyl chloride.
Reaction SMILES: [N+:1]([CH2:4][C:5]1([CH2:15][C:16]([O:18]C)=O)[CH2:14][CH2:13][C:8]2([O:12][CH2:11][CH2:10][O:9]2)[CH2:7][CH2:6]1)([O-])=O>CO.[Pd]>[O:12]1[C:8]2([CH2:13][CH2:14][C:5]3([CH2:15][C:16](=[O:18])[NH:1][CH2:4]3)[CH2:6][CH2:7]2)[O:9][CH2:10][CH2:11]1
Reactant: COC(=O)CC1(C[N+](=O)[O-])CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CO
Product: O=C1CC2(CCC3(CC2)OCCO3)CN1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
To a slurry of Methyl [8-(nitromethyl)-1,4-dioxaspiro[4.5]dec-8-yl]acetate (1 g, 4.7 mmol) in Methanol (20 mL) was added Pd/C (1 g, 10%) under N2 atmosphere. The reaction mixture was stirred at room temperature under 5 kg/cm2 H2 pressure for 12 h. After completion, the reaction mixture was filtered through celite pad, washed with methanol and the filtrate was concentrated under reduced pressure to afford the title compound as a white solid (0.7 g, 70%). 1H NMR (400 MHz, DMSO-d6) δ 7.46 (s, 1H), 3.83 (s, 4H), 3.00 (s, 2H), 2.00 (s, 2H), 1.56-1.51 (m, 8H).
Reaction SMILES: NC1[C:7]([CH2:8][CH2:9][C:10]2[N:18](Br)[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[N:11]=2)=[C:6](C)[CH:5]=[CH:4]N=1.[CH2:21]([O:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+]>[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([C:16]2[CH:17]=[C:12]3[N:11]=[C:10]([CH2:9][CH2:8][C:7]4[N:11]=[C:10]([NH2:18])[CH:9]=[C:5]([CH3:4])[CH:6]=4)[NH:18][C:13]3=[N:14][CH:15]=2)[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OB(O)c1cccc(OCc2ccccc2)c1
Reactant: Cc1ccnc(N)c1CCc1nc2cccnc2n1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1cc(N)nc(CCc2nc3cc(-c4cccc(OCc5ccccc5)c4)cnc3[nH]2)c1
Yield: 122 %

Procedure:
The title compound is synthesized according to General Procedure A. 150 mg of 2-[2-(2-amino-4-methylpyridinyl)ethyl]-bromo-3H-imidazo[4,5-b]pyridine in 7.5 ml dioxane, 1.36 ml Na2CO3 solution, 116 mg of 3-benzyloxyphenylboronic acid, 20 mg of PdCl2(PCy3)2, 120° C. for 48 h, 20 ml of CH2Cl2/H2O, 220 mg of crude title compound is purified by recrystallization from 6.0 ml isopropyl alcohol to yield 120 mg of the title compound. M.p. 181° C. ESI-MS: 436.3 (MH+). TLC: Rf=0.30 (dichloromethane/methanol 10:1).
Reaction SMILES: [N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]([OH:11])=O)[CH:5]=1)([O-:3])=[O:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O[N:35]=[C:36]([C:38]1[CH:43]=[CH:42][C:41]([O:44][C:45]([F:48])([F:47])[F:46])=[CH:40][CH:39]=1)[NH2:37]>CN(C=O)C.O>[N+:1]([C:4]1[NH:8][N:7]=[C:6]([C:9]2[O:11][N:37]=[C:36]([C:38]3[CH:39]=[CH:40][C:41]([O:44][C:45]([F:46])([F:47])[F:48])=[CH:42][CH:43]=3)[N:35]=2)[CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])[nH]n1
Reactant: NC(=NO)c1ccc(OC(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)n[nH]1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mechanically stirred solution of 5-nitro-1H-pyrazole-3-carboxylic acid (1.0 g, 6.24 mmol) in dry DMF (50 mL) was added EDCl (1.20 g, 6.24 mmol), HOBT (0.84 g, 6.24 mmol) and N′-hydroxy-4-(trifluoromethoxy)benzenecarboximidamide (1.37 g, 6.24 mmol). The mixture was stirred at rt for 2 h, and then warmed to 140° C. and stirred for additional 2 h. After being cooled to rt, the mixture was diluted with water (100 mL) and extracted with ethyl acetate. The organic extract was successively washed with water and brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was removed in vacuo, and the residue was redissolved in warm acetonitrile (3 mL) to which tert-butyl methyl ether (2 mL) was added. The title compound precipitated and was obtained as a white solid after filtration, washing with tert-butyl methyl ether and drying in vacuo (1.2 g, 56%): 1H NMR (500 MHz, DMSO-d6) δ 8.20 (d, 2H), 7.58 (d, 2H), 7.34 (s, 1H); ES-MS m/z 340 (M-H)−; HPLC RT (Method J) 4.87 min.