Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@@:10]1([CH2:52][OH:53])[CH:50]=[O:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:54][Mg]Br>O1CCCC1>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C@:10]1([CH:52]([OH:53])[CH3:54])[CH2:50][OH:51])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@](C=O)(CO)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@@](CO)(C(C)O)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 30 %

Procedure:
To a solution of (2R,3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxyphenyl) methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-carbaldehyde 8a (1.38 g, 1.88 mmol) in tetrahydrofuran (30 mL) was added dropwise methylmagnesium bromide (1.9 mL, 5.63 mL) at room temperature. The mixture was stirred at room temperature for 45 min under N2 and quenched with 10 mL of saturated aqueous ammonium chloride. Most of the solvent of the mixture was removed in vacuo. The resulting mixture was extracted with ethyl acetate (10 mL×2). The combined organic layers were washed with saturated aqueous sodium chloride (5 mL×2), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=8/1 to give the title compound 8b as colourless oil (414 mg, 30.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.55 (m, 1H), 7.46 (d, 1H), 7.40 (d, 1H), 7.35-7.30 (m, 5H), 7.30-7.23 (m, 8H), 7.00 (m, 4H), 6.74 (d, 2H), 5.03 (t, 1H), 4.72 (m, 4H), 4.53 (d, 1H), 4.49 (d, 1H), 4.42 (d, 1H), 4.18 (m, 2H), 4.05 (d, 1H), 3.94 (m, 2H), 3.89 (d, 1H), 3.85-3.77 (m, 2H), 3.73 (m, 1H), 3.43 (d, 1H), 2.92 (s, 3H), 1.28 (t, 3H), 1.23 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9]O[Si](C)(C)C(C)(C)C)=[C:6](O)[N:5]=[C:4]([S:19][CH2:20][C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)[N:3]=1.N1C=CC=CC=1C.P(Cl)(Cl)([Cl:40])=O>>[Cl:40][C:6]1[C:7]2[CH2:8][CH2:9][NH:1][C:2]=2[N:3]=[C:4]([S:19][CH2:20][C:21]2[C:22]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:28]=[CH:29][CH:30]=2)[N:5]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1c(N)nc(SCc2ccc3ccccc3c2)nc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccn1
Product: Clc1nc(SCc2cccc3ccccc23)nc2c1CCN2
Temperature: 22 °C
Reaction time: 8 h

Procedure:
2-(4-amino-6-hydroxy-2-(2-naphthylmethyl)thio-5-pyrimidinyl)-1-(dimethyl-tert-butylsilyloxy)ethane (Cpd #280; 104 mg, 0.23 mmol) is treated with 2-picoline (28 μL, 0.28 mmol) and phosphorus oxychloride (0.22 ml, 2.3 mmol). The solution is heated to reflux for 2 hours, stirred overnight at 22° C. then heated again to reflux for an additional hour. The solution was cooled and ice is added. The resultant solid was filtered, washed with cold 50% ethanol, and dried under vacuum. The recovered solids, 81 mg are purified by chromatography (SiO2, 4:1 hexane/ethyl acetate): 64 mg (0.19 mmol, 85%), mp 107-110° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH2:26][CH2:27][O:28][CH3:29].[C:30]([O-:33])(=[O:32])[CH3:31].[Cs+]>CN(C=O)C>[C:30]([O:33][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[CH:24])[CH:18]=3)=[N:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:25][CH2:26][CH2:27][O:28][CH3:29])(=[O:32])[CH3:31]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCCl)c(OCCOC)cc23)c1
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC(C)=O)c(OCCOC)cc23)c1
Yield: 185.7 %

Procedure:
The title product of Example 34 (160 mg, 0.368 mmol); was treated with cesium acetate (707 mg, 3.68 mmol) in DMF (3 mL) at 120° C. under an atmosphere of N2 for 16 hours. The reaction mixture was partitioned between brine and CHCl3, and the organic extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford a residue (288 mg) which was recrystallized from ethyl acetate/hexanes. (134 mg; M.P.134°-135° C.; LC-MS: 422 (MH+); anal. RP18-HPLC RT: 4.43 min.).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[CH:19][CH:18]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.Cl.[CH2:27]([O:29][C:30](=[O:34])[CH2:31][CH2:32][NH2:33])C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:1][C:2]1[C:3]([NH:12][CH:13]([C:17]2[CH:18]=[CH:19][C:20]([C:21]([NH:33][CH2:32][CH2:31][C:30]([O:29][CH3:27])=[O:34])=[O:22])=[CH:24][CH:25]=2)[CH2:14][CH2:15][CH3:16])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(Nc1nc2ccccc2cc1C)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Intermediate 5 (31.64 g, 94.61 mmol), β-alanine ethyl ester hydrochloride (45.9 g, 284 mmol), and 1-hydroxybenzotriazole hydrate (80%, 20 wt % water, 47.9 g, 284 mmol) were suspended in dichloromethane (946 mL). Triethylamine (119 mL, 852 mmol) followed by N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (46.0 g, 237 mmol) were added, and the solution was stirred at room temperature for 10 h. The reaction mixture was washed with water (3×900 mL), then sat. aq NaCl (300 mL). The organic layer was dried over Na2SO4 and filtered, and the filtrate was concentrated under reduced pressure. Purification by silica gel flash chromatography (ethyl acetate/heptane) followed by chiral SFC (Chiralpak AD-H column, 30×250, 20% methanol/carbon dioxide eluent, 0.2% isopropylamine modifier) gave methyl(+)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate (Intermediate 6, analytical chiral SFC 4.6 min retention) and methyl(−)-3-(4-(1-((3-methylquinolin-2-yl)amino)butyl)benzamido)propanoate (Intermediate 7, analytical chiral SFC 6.5 min retention)—note that ethyl ester was converted to methyl ester during the reaction and/or purification sequence. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J=8.4 Hz, 2H), 7.64-7.58 (m, 2H), 7.55-7.48 (m, 3H), 7.44 (t, J=7.7 Hz, 1H), 7.16 (t, J=7.4 Hz, 1H), 6.76 (t, J=5.5 Hz, 1H), 5.48 (q, J=7.2 Hz, 1H), 4.78 (d, J=7.0 Hz, 1H), 3.76 (q, J=6.0 Hz, 2H), 3.70 (s, 3H), 2.64 (t, J=5.9 Hz, 2H), 2.29 (s, 3H), 2.04-1.82 (m, 2H), 1.52-1.29 (m, 2H), 0.98 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Br-].N[CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:7])[CH3:6].[Br:22]CC[CH2:25][CH2:26][N:27]1C(=O)C2=CC=CC=C2C1=O>>[Br-:22].[NH2:27][CH2:26][CH2:25][CH2:3][CH2:4][N+:5]([CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:18]([NH2:19])=[N:17][C:16]([NH2:20])=[C:15]([Cl:21])[N:14]=1)=[O:12])([CH3:6])[CH3:7]
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: C[N+](C)(CCN)CCNC(=O)c1nc(Cl)c(N)nc1N
Agent: [Br-]
Product: C[N+](C)(CCCCN)CCNC(=O)c1nc(Cl)c(N)nc1N

Procedure:
The title compound is prepared by an analogous procedure to (2-amino-ethyl)-{2-[(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-amino]-ethyl}-dimethyl-ammonium bromide (Intermediate K) by replacing N-(4-bromoethyl)-phthalimide with N-(4-bromobutyl)-phthalimide. M+ 330.
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([Cl:20])[CH:15]=1)(=[O:5])[NH2:4].O.Cl>CC(C)=O.O>[Cl:20][C:16]1[CH:15]=[C:14]([C:13]2[NH:4][C:3](=[O:5])[C:6]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[N:12]=2)[CH:19]=[CH:18][N:17]=1
Reactant: NC(=O)c1ccccc1NC(=O)c1ccnc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=c1[nH]c(-c2ccnc(Cl)c2)nc2ccccc12
Reaction time: 8 h

Procedure:
Sodium hydroxide (5M, 5 mL) was added to a suspension of N-(2-carbamoylphenyl)-2-chloroisonicotinamide (4.14 g, 15.02 mmol) in acetone/water (1/1, 100 mL). The reaction was heated to reflux and stirred overnight. The resulting solid was put into solution with water and was adjusted to pH 7 using 5M HCl. The precipitate was filtered and concentrated with toluene (3×) to give 2-(2-chloro-pyridin-4-yl)-3H-quinazolin-4-one as a light brown solid. MS (ES−): 256 (M−H)−.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][C:14](=[O:23])[C@H:15]([CH3:22])[NH:16][CH2:17][CH2:18][CH2:19][O:20][CH3:21])C>>[CH3:11][O:13][C:14](=[O:23])[C@H:15]([CH3:22])[N:16]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: CCOC(=O)[C@H](C)NCCCOC
Reactant: O=[N+]([O-])c1ccccc1Cl
Product: COCCCN(c1ccccc1[N+](=O)[O-])[C@@H](C)C(=O)OC

Procedure:
The same procedure as in Example 22 is repeated except that 2-chloronitrobenzene is used in place of 2,4-dichloronitrobenzene and that (21) is used in place of (20) to obtain (25) in the form of orange oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([O:27]CC5C=CC=CC=5)=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)[N:3]=1>CO.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[C:21]([C:25]([OH:27])=[O:26])[N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)[N:3]=1
Reactant: CC1Cc2ccc(-c3cc(C(=O)OCc4ccccc4)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: [Pd]
Solvent: CO
Product: CC1Cc2ccc(-c3cc(C(=O)O)n(C)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reaction time: 2 h

Procedure:
Pd/C (25.0 mg, 10 wt. % loading dry basis, matrix activated carbon, wet support, Degussa type E101 NE/W) was added to a solution of benzyl 4-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}-1-methyl-1H-pyrrole-2-carboxylate (0.10 g, 0.18 mmol) in methanol (2.0 mL) and then the reaction was stirred under hydrogen (balloon) for 2 h. LCMS showed the reaction was complete. The reaction mixture was filtered. The solvent was removed under reduced pressure to give the product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=462.3.
Reaction SMILES: ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.[NH2:29][CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[OH:32]>>[Cl:20][C:21]1[N:26]=[C:25]([NH:29][CH2:30][CH:31]([OH:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24]([F:28])=[CH:23][N:22]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: NCC(O)c1ccccc1
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: OC(CNc1nc(Cl)ncc1F)c1ccccc1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 2-amino-1-phenylethanol were reacted to yield 2-chloro-5-fluoro-N4-(2-hydroxy-2-phenylethyl)-4-pyrimidineamine. 1H NMR (CDCl3): δ 7.88 (d, 1H, J=3.0 Hz), 7.41-7.32 (m, 5H), 5.71 (bs, 1H), 4.97 (d, 1H, J=8.1 Hz), 3.98 (m, 1H), 3.56 (m, 1H), 2.57 (s, 1H); 19F NMR (CDCl3): −45149; LCMS: ret. time: 22.27 min.; purity: 98%; MS (m/e): 263 (M+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]12[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[C:21](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[CH3:21][N:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]12[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=C1Nc2ccc(-c3ccc[nH]3)cc2C12CCCCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: Cn1cccc1-c1ccc2c(c1)C1(CCCCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.3 %

Procedure:
A mixture of 5′-(1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′(1′H)-one (0.46 g, 1.7 mmol) and potassium carbonate (5 eq, 1.18 g, 8.6 mmol) in DMF (2 mL) at room temperature was treated with a solution of iodomethane (3 eq, 0.32 g, 5.1 mmol) in DMF (1 mL). The solution was stirred 16 h at room temperature, then poured into water (10 mL). EtOAC (15 mL) was added, the layers were separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The organic layers were combined, washed with brine (15 mL) and dried over MgSO4. The solution was filtered, concentrated in vacuo, and the residue was purified by flash Column chromatography on silica gel (eluting with 40% EtOAc/hexane) to give the subtitled compound (0.44 g, 76%) as a white powder, mp, 148-149° C. 1H NMR (DMSO-d6; 400 MHz) δ 1.50-1.62 (m, 3H), 1.62-1.82 (m, 5H), 1.83-1.94 (m, 2H), 3.11 (s, 3H), 6.08 (m, 1H), 6.42 (m, 1H), 6.79 (m, 1H), 6.97 (d, 1H, J=8.1 Hz), 7.51 (dd, 1H, J=8.1, 1.8 Hz), 7.70 (d. 1H, J=1.7 Hz ), 11.20 (br s, 1H). Anal. Caled for C18H20N2O1: C, 77.11; H, 7.19; N, 9.98. Found: C, 76.44; H, 7.21; N, 9.96.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]1([C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([OH:20])[C:18]#[CH:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1C=CC=CC=1>[CH2:1]([N:8]1[C:18]([C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[OH:20])=[CH:19][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC(O)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: OC(c1ccccc1)(c1ccccc1)c1cnnn1Cc1ccccc1

Procedure:
Benzyl azide (0.200 g, 1.50 mmol), 1,1-diphenyl-2-propyn-1-ol (0.344 g, 1.65 mmol), Cp*RuCl(PPh3)2 (12 mg, 0.015 mmol). Solvent, benzene; reaction temperature, 80° C.; reaction time, 4 hours; yield, 0.39 g (75%). The reaction was performed under air. EI-MS: m/z 342 [M+1].
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[NH:7][C:6]1=[O:19])[CH2:2][CH2:3][CH3:4].[NH:20]1[CH:24]=[C:23]([CH2:25][CH2:26][CH2:27]O)[N:22]=[CH:21]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([Cl:14])[N:10]([CH2:15][CH:16]=[CH2:17])[C:9]=2[C:8](=[O:18])[N:7]([CH2:27][CH2:26][CH2:25][C:23]2[N:22]=[CH:21][NH:20][CH:24]=2)[C:6]1=[O:19])[CH2:2][CH2:3][CH3:4]
Reactant: OCCCc1c[nH]cn1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCn1c(Cl)nc2c1c(=O)n(CCCc1c[nH]cn1)c(=O)n2CCCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.8 %

Procedure:
A solution of 3-butyl-8-chloro-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.8 g, 9.9 mmol) in anhydrous THF (60 ml) was treated with 3-(1H-imidazol-4-yl)-1-propanol (1.5 g, 12 mmol) in anhydrous THF (10 ml) and PPh3 (3.4 g, 13 mmol). DBAD (2.9 g, 13 mmol) was added in one portion and the mixture was left to stir at rt, under nitrogen for 18 h. The mixture was partitioned between EtOAc and H2O. The aqueous layer was extracted and washed with EtOAc. The organic layers were combined, washed with brine, dried (MgSO4) and concentrated. The crude product was purified by a silica SPE cartridge using a MeOH/EtOAc gradient (0.5%-7% MeOH). The product fractions were combined and concentrated by to give the title compound as a white solid (2.16 g, 55%).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:7](=[O:14])[C:8]([CH:12]=C)=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].I([O-])(=O)(=O)=[O:31].[Na+].C(#N)C.O>CC(C)=O.[Os](=O)(=O)(=O)=O>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:20][CH:21]=2)[C:7](=[O:14])[C:8]([CH:12]=[O:31])=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1c(C)nc(CCCC)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: CCCCc1nc(C)c(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 4 h
Yield: 72.2 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxo-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.91 g) and sodium periodate (2.56 g) in acetone (10 mL)-acetonitrile (10 mL)-water (10 mL) was added osmium tetroxide (0.9 g, 7% polymer-bound catalyst), and the mixture was stirred for 4 hr. The insoluble material was filtered off through celite, and the filtrate was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow oil (0.66 g, 71%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N+:24]([O-:26])=[O:25])[CH:3]=1.[O:27]1[CH2:31][CH2:30][NH:29][C:28]1=[O:32]>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:29]4[CH2:30][CH2:31][O:27][C:28]4=[O:32])=[CH:3][C:4]=3[N+:24]([O-:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: O=C1NCCO1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3[N+](=O)[O-])CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 72.6 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-nitrophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (1.5 g) described in Preparation Example 63 and oxazolidin-2-one (0.3115 g), the title compound (1.105 g) was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH2:7][CH:8]([CH3:10])[CH3:9])[O:5][C:4](=[O:11])[CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:21]1>>[OH:1][C:2]1[CH:6]([CH2:7][CH:8]([CH3:9])[CH3:10])[O:5][C:4](=[O:11])[C:3]=1[CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:21]1[NH:20][C:28]2[C:23]([C:22]=1[CH2:29][CH2:30][NH:31][C:32](=[O:34])[CH3:33])=[CH:24][CH:25]=[CH:26][CH:27]=2
Reactant: O=Cc1ccccc1
Reactant: CC(C)CC1OC(=O)C=C1O
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Product: CC(=O)NCCc1c(C(C2=C(O)C(CC(C)C)OC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5-isobutyl-5H-furan-2-one (Lit. 14) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a white solid. MS: 441.1 ([M+H]+).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:22]=[CH:21][C:8]([NH:9][CH:10]=[C:11]2[C:16](=[O:17])OC(C)(C)OC2=O)=[CH:7][C:6]=1[O:23][CH3:24])(=[O:3])[CH3:2].CCOCC>C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[C:1]([O:4][C:5]1[CH:22]=[C:21]2[C:8](=[CH:7][C:6]=1[O:23][CH3:24])[NH:9][CH:10]=[CH:11][C:16]2=[O:17])(=[O:3])[CH3:2]
Reactant: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)ccc1OC(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: CCOCC
Product: COc1cc2[nH]ccc(=O)c2cc1OC(C)=O
Temperature: 195 °C

Procedure:
A suspension of 5-((4-acetoxy-3-methoxyanilino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (11.5 g) in DOWTHERM A, (trade mark of Fluka Chemie AG), (125 ml) was heated at 195° C. for 30 minutes. After cooling, ether was added (100 ml) and the precipitate was collected by filtration. The solid was washed with ether and dried under vacuum to give 6-acetoxy-7-methoxy-1,4-dihydroquinolin-4-one which was used without further purification for the next step.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:30]=[CH:29][C:10]([O:11][CH2:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH2:22]([O:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][O:11][C:10]2[CH:29]=[CH:30][C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:8][CH:9]=2)[CH2:18][CH2:17]1)=[O:20])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(OCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.7 %

Procedure:
Methanesulphonyl chloride (1.91 g) was added to a stirred solution of the product of part (iii) (5.15 g) in pyridine (50 ml) at 0°. The solution was stirred at room temperature for 18 hours and then evaporated. The residue was treated with aqueous sodium bicarbonate solution and the mixture was extracted several times with ethyl acetate. The combined extracts were washed with water, dried (Na2SO4) and evaporated. The residue was crystallised from ethyl acetate/hexane to give the title compound, (5.17 g), m.p. 150°-151°.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([NH:16][C:17]([NH:19][CH2:20][C:21]#[CH:22])=[S:18])[CH:15]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([CH3:23])=[C:14]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH2:20][C:21]#[CH:22])[C:17]2=[S:18])[CH:15]=1
Reactant: C#CCNC(=S)Nc1cc(Cl)ccc1C
Reactant: CCOC(=O)C(=O)Cl
Solvent: ClCCl
Product: C#CCN1C(=O)C(=O)N(c2cc(Cl)ccc2C)C1=S
Temperature: 25 °C
Reaction time: 18 h
Yield: 20.5 %

Procedure:
Ethyl chlorooxoacetate (11.2 mL; 0.1 mol) was added dropwise while cooling in an ice bath to the stirring solution of N-(5-chloro-2-methylphenyl)-N′-(2-propynyl)thiourea (11.95 g; 0.05 mol) in methylene chloride (200 mL). The mixture was stirred for 18 hours at ambient temperature then evaporated to dryness. The residue was stirred in ether (200 mL) and the solids were collected by filtration and air dried to give 3.0 g 1-(5-chloro-2-methylphenyl)-3-(2-propynyl)-2-thioxo-4,5-imidazolidinedione, m.p. 162–164° C. Mass spectrum; (El, M.+) m/z 292/294. 1H-NMR (DMSO-d6; 300 MHz): δ 7.50–7.47 (m, 2H), 7.73 (d, 1H), 4.66 (q, 2H), 3.37 (t, 1H), and 2.15 ppm (s,3H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]4[CH2:36][CH2:35]4)[CH:29]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:34]3[CH2:35][CH2:36]3)[CH:29]=2)=[C:20]([C:37]([F:38])([F:39])[F:40])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3cccc(C4CC4)c3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2cccc(C3CC3)c2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 85-1 (330 mg) was dissolved in ethanol (5 ml), concentrated hydrochloric acid (1 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (168 mg) as a white powder.