Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[C:35]1([C:41]#[CH:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(NC(C)C)(C)C>C(OCC)(=O)C.[Cu]I.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[Pd]Cl>[Cl:1][C:2]1[CH:10]=[C:9]([C:42]#[C:41][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COc1cc2c(Nc3c(Cl)cc(C#Cc4ccccc4)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.1 %

Procedure:
A mixture of N-(5-chloro-7-iodo-1,3-benzodioxol-4-yl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine (0.17 g, 0.285 mmol), phenyl acetylene (0.07 ml, 0.63 mmol) and diisopropylamine (0.088 ml, 0.63 mmol) in ethyl acetate (4 ml) was cooled to −20 C under a nitrogen atmosphere. To this was added copper (I) iodide (0.016 g, 0.085 mmol) and bis(triphenylphospine)palladium (II) chloride (0.04 g, 0.057 mmol). The mixture was allowed to warm to ambient temperature and then stirred overnight. The mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography on silica eluting with a mixture of 0-10% methanol in dichloromethane gave the product as a solid (0.108 g, 66%). NMR Spectrum: (DMSOd6 at 373k+d4 acetic acid) 2.10 (m, 2H), 2.76 (t, 4H), 2.83 (t, 2H), 3.69 (t, 4H), 3.97 (s, 3H), 4.24 (t, 2H), 6.12 (s, 2H), 7.15 (s, 1H), 7.30 (s(broad), 1H), 7.42 (m, 3H), 7.54 (m, 2H), 7.95 (s, 1H), 8.63 (s(broad), 1H). Mass Spectrum: M+H+ 573 and M+H− 571.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:15][CH2:14][CH2:13][O:12]1.ClC1N=CN=C2C=1NC=N2.[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(N(C(C)C)C(C)C)C>C(O)CC>[OH:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:11]2[CH2:15][CH2:14][CH2:13][O:12]2)=[CH:29][CH:28]=1
Reactant: NCc1ccc(O)cc1
Reactant: Clc1ncnc2c1ncn2C1CCCO1
Agent: Clc1ncnc2nc[nH]c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCO
Product: Oc1ccc(CNc2ncnc3c2ncn3C2CCCO2)cc1
Yield: 80 %

Procedure:
A mixture of 10 mmol (2240 mg) of 6-chloro-9-(tetrahydrofuran-2-yl)purine (prepared from 10 mmol (1546 mg) of 6-chloropurine), 12 mmol (1478 mg) of 4-hydroxybenzylamine, and 5 ml of N-ethyldiisopropylamine was refluxed in n-propanol for 3 hours. After removal of the n-propanol by vacuum evaporation, the resulting material was treated with water and extracted into ethyl acetate. The ethyl acetate phase was evaporated and the residuum subsequently washed with 30 ml of petroleum ether. The solid residue was filtered off and the crude product crystallized from methanol. Yield 80%, white solid. TLC (EtOAc:hexane (1:1 (v:v)): single spot; HPLC: purity >98%. 1H NMR (400 MHZ, DMSO): 1.36tt (2H, Ja=7.8 Hz, Jb=2.2 Hz); 2.23m (1H); 2.32m (1H); 3.62dd (1H, Ja=10.8 Hz, Jb=3.8 Hz); 3.87dd (1H, Ja=10.8 Hz, Jb=3.8 Hz); 4.62s (2H); 6.23dd (1H, Ja=5.3 Hz, Jb=1.5 Hz); 6.71d (2H, J=8.3 Hz); 7.21d (2H, J=8.3 Hz); 8.06bs (1); 8.16s (1H); 8.28s (1H); 9.23s (1H). MS (ES): [M+H]+=312 (100).
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[C:7]1[S:11]C(=S)N[C:8]1=[O:13])([OH:3])=O.[OH-:18].[Na+].Cl>O>[C:1]1([C:4]2[C:5](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[C:7]([C:8]([OH:18])=[O:13])[S:11]1)=[O:3]
Reactant: [OH-]
Reactant: O=C1NC(=S)SC1=Cc1ccccc1C(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2ccccc2c(=O)s1

Procedure:
A mixture of 5-(o-carboxybenzylidene) rhodanine (4.68g.) and sodium hydroxide (5.0g.) in water (40ml.) was heated under reflux for 30 minutes, cooled and poured into 5N hydrochloric acid (250ml.). Filtration and recrystallization from ethanol-water gave the product as a white solid, mp. 260.5°-261° (lit mp. 261°-3°), (Found: C, 58.10; H, 2.92; S, 15.41. C10H6SO3 requires C, 58.24; H, 2.93; S, 15.55).
Reaction SMILES: FC1C=CC([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=CC=1.BrC1C=CC(CCC[C:30]([NH2:32])=[S:31])=CC=1>C(#N)C.C(O)C>[CH3:18][S:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:31][CH:30]=[N:32][CH:8]=2)=[CH:12][CH:13]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: NC(=S)CCCc1ccc(Br)cc1
Solvent: CCO
Solvent: CC#N
Product: CSc1ccc(-c2cncs2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
To a solution of 2-bromo-2-(4-fluorophenyl)-1-(4-methylthiophenyl) ethanone (Example 1, Step 3 ) (2.70 g, 7.90 mmol) in acetonitrile (90 mL) and ethanol (10 mL) in a 125 mL round bottom flask was added 4-(4-bromophenyl) thiobutyramide from Step 1, (1.4 g, 7.90 mmol) and the mixture was heated to reflux for 7 hours. The reaction was cooled to room temperature and let stand overnight. The crude product was concentrated in vacuo yielding an oil which was purified by flash chromatography (1: 1 hexane:methylene chloride) yielding 2-(3-[4-bromophenyl]propyl)-4- (4-fluorophenyl))-5-(4-methylthiophenyl)thiazole (1.4 g, 36%) as a clear colorless oil (ca. 90% purity by 1H NMR): 1H NMR (CDCl3) 3 00 mHz δ7.50-7.46 (m, 2H), 7.41 (d, J=8.46 Hz, 2H), 7.22 (d, J=8.66 Hz, 2H), 7.16 (d, J=8.66 Hz, 2H), 7.10 (d, J=8.26 Hz, 2H), 6.97 (t, J=8.86, 2H), 3.03 (t, J=7.45 Hz, 2H), 2.74 (t, J=7.45 Hz, 2H), 2.49 (s, 3H), 2.20-2.09 (m, 2H). MS (EI): m/z 529, 531 (M+) 497, 499. HRMS Δ=-2.1 mmu.
Reaction SMILES: Cl[C:2]1[C:3]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]1>CS(C)=O.O>[N:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[NH:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:3]2[C:2]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]#[N:29])[CH2:24][CH2:23]3)=[N:7][CH:6]=[CH:5][N:4]=2)=[CH:10][CH:11]=1
Reactant: Clc1nccnc1Oc1ccc(Nc2ccccn2)cc1
Reactant: N#CC1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: N#CC1CCN(c2nccnc2Oc2ccc(Nc3ccccn3)cc2)CC1
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask was placed N-(4-(3-chloropyrazin-2-yloxy)-phenyl)pyridin-2-amine (0.2376 g, 0.7954 mmol) in DMSO. Piperidine-4-carbonitrile (0.4363 g, 3.977 mmol) was added and the temperature was brought to 80° C. to stir overnight. The reaction mixture was diluted with water (10 mL) and extracted with DCM (3×10 mL). The organic extract was washed with water (3×10 mL), satd sodium chloride solution (3×10 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage™ pre-packed silica gel column (25M), eluting with a gradient of 1% to 5% methanol in DCM, to provide 1-(3-(4-(pyridin-2-ylamino)-phenoxy)pyrazin-2-yl)piperidine-4-carbonitrile. MS (ESI, pos. ion) m/z: 373.1 (M+1). IC50 (uM) 0.006048.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.CC(C)([O-])C.[K+].Cl[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1.O>CN(C)C=O>[CH3:1][O:2][CH:3]([O:11][CH3:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C:20]2[N:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:5]=1
Reactant: COC(OC)c1cccc(O)c1
Reactant: Clc1ncccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(OC)c1cccc(Oc2ncccn2)c1
Temperature: 60 °C

Procedure:
A solution of 168 mg of 3-hydroxybenzaldehyde dimethyl acetal in 2 ml of anhydrous dimethylformamide was stirred under nitrogen and 220 mg of potassium tert.butoxide were added. The mixture was heated at 60° C. for 1 hour, then cooled to room temperature and 114 mg of 2-chloropyrimidine were added in portions. The mixture was heated at 150° C. for 20 hours. After cooling 20 ml of water were added and the product was extracted with ethyl acetate. The extracts were washed with 10 ml of 1M sodium hydroxide solution and 5 ml of brine and then dried over anhydrous magnesium sulphate. After filtration and evaporation of the filtrate the residual brown gum was purified by column chromatography on silica gel using ethyl acetate/hexane (1:1) for the elution to give 3-(2-pyrimidinyloxy)-benzaldehyde dimethyl acetal as a syrup.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: COC(=O)Cc1cccc(NC(=O)c2ccc(-c3cc(Cl)cc(Cl)c3)o2)c1

Procedure:
Methyl ester (16) (100 mg, 0.30 mmol) was coupled to 3,5-dichloro-phenylboronic acid (61 mg, 0.33 mmol) using Method E. The crude compound was purified by column chromatography, eluting in 17% EtOAc in heptane to give the title compound.
Reaction SMILES: [NH2:1][CH:2]1[CH:9]2[CH2:10][C:5]3(O)[CH2:6][CH:7]([CH2:11][CH:3]1[CH2:4]3)[CH2:8]2.CCN(S(F)(F)[F:19])CC>C1(C)C=CC=CC=1>[F:19][C:5]12[CH2:10][CH:9]3[CH2:8][CH:7]([CH2:11][CH:3]([CH:2]3[NH2:1])[CH2:4]1)[CH2:6]2
Reactant: CCN(CC)S(F)(F)F
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Solvent: Cc1ccccc1
Product: NC1C2CC3CC1CC(F)(C3)C2
Temperature: 25 °C
Yield: 86.3 %

Procedure:
To the solution of 4-aminoadamantan-1-ol (800 mg, 4.79 mmol) in anhydrous toluene (6 mL) was added DAST (780 mg, 5 mmol) at 0° C. The reaction mixture was refluxed for 8 h. The mixture was cooled to rt and quenched with aq NaHCO3. The mixture was concentrated and extracted with CH2Cl2 (2×). The combined organic extracts were dried, filtered and concentrated to give 1-fluoro-4-aminoadamantane (700 mg), which was used without purification.
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH:18]2[CH2:23][CH2:22][SiH:21](Cl)[CH2:20][CH2:19]2)=[CH:12][C:11]=1[F:25]>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@H:18]2[CH2:23][CH2:22][Si@H:21]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[CH2:20][CH2:19]2)=[CH:12][C:11]=1[F:25]
Reactant: Fc1cc(OCC2CC[SiH](Cl)CC2)ccc1Cl
Reactant: CCCCCCCBr
Product: CCCCCCC[Si@H]1CC[C@H](COc2ccc(Cl)c(F)c2)CC1

Procedure:
The general procedure of Example 1 was repeated using n-heptyl bromide and 4-(4-chloro-3-fluorophenyloxymethyl)-1-chloro-1-silacyclohexane, thereby obtaining the intended product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[C:31](Cl)(=[O:34])[O:32][CH3:33].C(N(CC)CC)C>O1CCCC1>[F:26][C:25]([F:28])([F:27])[C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=1)[O:10][C:7]1[CH:8]=[CH:9][C:4]2[N:5]([CH:30]=[C:2]([NH:1][C:31](=[O:34])[O:32][CH3:33])[N:3]=2)[N:6]=1)=[O:29]
Reactant: COC(=O)Cl
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Yield: 60.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), methyl chlorocarbonate (33 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (3 mL) as starting materials and in the same manner as in Example 388, the title compound (104 mg, 61%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](N(OC)C)=[O:20])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]([Mg]Br)=[CH2:26]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:19](=[O:20])[CH:25]=[CH2:26])[CH2:10][CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
(S)-tert-Butyl 4-(tert-butoxycarbonylamino)-5-(methoxy(methyl)amino)-5-oxopentanoate (4.12 g, 12.2 mmol) was dissolved in anhydrous tetrahydrofuran (100 mL) and cooled to −70° C. under nitrogen. Vinylmagnesium bromide (37 mL, 1.0 M soln in THF, 3.0 eq) was added dropwise. The reaction stirred for 30 min at −70° C. and was then the cooling bath was removed and the reaction stirred at room temperature overnight. The mixture was colled on in an ice bath and acetic anhydride (20 mL) was added, followed by methanol (27 mL). The mixture was concentrated under pressure to a small volume and then diluted with ethyl acetate. The reaction mixture was washed successively with water and brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 1:4 ethyl acetate:hexanes to yield (S)-tert-butyl 4-(tert-butoxycarbonylamino)-5-oxohept-6-enoate (0.94 g) as a yellow oil. 1H NMR (CDCl3): 6.48-6.45 (m, 2H), 5.94 (m, 1H), 5.29 (m, 1H), 4.70 (m, 1H), 2.38-2.05 (m, 2H), 2.02 (m, 1H), 1.70 (m, 1H), 1.45 ppm (s, 18H).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH3:32])[CH:24]=2)=[CH:18][C:17]=1[CH3:34].C(O)(=O)C>CC(N(C)C)=O>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:32]=[C:31]1[C:25]1[CH:24]=[C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:34])[CH:18]=2)[N:28]=[N:27][C:26]=1[O:29][CH3:30]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1C(C)=O
Reactant: Nc1ccccc1Br
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Temperature: 140 °C

Procedure:
205 mg of 2-bromoaniline and 72 mg of anhydrous magnesium sulfate are suspended in 7 ml dimethylacetamide. 325 mg of 1-[6-(4-Hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-ethanone and 86.6 μl acetic acid are added and the reaction is degassed with argon. 330 mg of tripotassium phosphate and 61 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 5 h. The solution is poured into water and extracted with ethyl acetate. The solvent is removed under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 105 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[CH:10]=[CH:9]1.[C:14](OC(=O)C)(=[O:16])[CH3:15].CN(C1C=CC=CN=1)C.C(OCC)(=O)C>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13][C:14](=[O:16])[CH3:15])[CH:10]=[CH:9]1
Reactant: O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccccn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@@H]1C=C[C@H](OC2CCCCO2)C1
Yield: 81 %

Procedure:
Dissolve (-)-cis-4-(tetrahydro-pyran-2-yloxy)-cyclopent-2-enol (292 mg, 1.59 mmol, prepared in example 11) in pyridine (2.8 mL) and treat with acetic anhydride (0.39 mL) and dimethylaminopyridine (16 mg). Stir the reaction overnight. Concentrate the reaction under vacuum, dissolve the residue with ethyl acetate (10 mL). Wash with 0.5M hydrochloric acid that is 1/2 saturated with brine (2×10 mL), saturated sodium bicarbonate (10 mL), brine (10 mL), dry over anhydrous magnesium sulfate, filter and concentrate under vacuum. Purify the residue by chromatography (silica gel, 10 g, 1.5×4 cm column, 20% ethyl acetate/hexane) to provide the title compound (290 mg, 81%).
Reaction SMILES: [NH3:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([O:23]CC)=O)[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2>C(O)C>[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[N:10]=[C:9]1[N:16]=[C:17]([C:21]([NH2:1])=[O:23])[NH:18][C:19](=[O:20])[C:8]1=[CH:7]2
Reactant: N
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Solvent: CCO
Product: COc1cc2cc3c(=O)[nH]c(C(N)=O)nc3nc2cc1OC
Temperature: 95 °C

Procedure:
Anhydrous ammonia is bubbled into a mixture of ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg., 9.00 millimoles) in absolute ethanol (75 ml.) for 15 minutes. A clear solution formed followed after a few minutes by formation of a precipitate. The reaction mixture is transferred to a pressure bomb (Monel) and heated in a 95° C. oil bath overnight. The bomb is then cooled to room temperature and the contents removed. The bomb is washed with ethanol and the combined reaction mixture plus wash filtered to recover the product. The filter cake is washed with ethanol and then dried in air. Yield = 260 mg. (95%) M.P. 310° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH2:48])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:56][S:57](Cl)(=[O:59])=[O:58]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][NH:48][S:57]([CH3:56])(=[O:59])=[O:58])=[CH:38][CH:37]=2)[CH2:9]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCN)CCC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCNS(C)(=O)=O)CCC3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
To an ice-cooled solution of 0.250 g (0.379 mmol) (3R,4R)-3-[1-(2-amino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester [example 15(b)] and 0.049 g (0.493 mmol, 1.3 equiv.) triethylamine in 5 ml of dichloromethane was added dropwise at 0° C. 0.047 g (0.417 mmol, 1.1 equiv.) methanesulfonyl chloride. After stirring for 30 min at 0° C., the reaction mixture was poured into 50 ml of an ice/water mixture and extracted three times with 50 ml of ethyl acetate. The combined organic phases were washed twice with 25 ml of water, evaporated under reduced pressure and dried in a high vacuum. The thus obtained crude product was purified by chromatography on silica gel using a 1:2 v/v mixture of hexane and ethyl acetate as eluent to yield 0.247 g (0.335 mmol, 88.3% of theory) of (3R,4R)-3-[1-(2-methanesulfonylamino-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a light yellow oil; MS: 736 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])[CH2:19][CH2:18]3)[CH3:16])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:27][N:25]([CH3:26])[CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:17]([N:15]([CH3:16])[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)=[O:42])=[CH:30][CH:29]=3)[CH:12]=[CH:11][N:10]=2)=[O:28])[CH2:18][CH2:19]1
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(N)cc3)ccn2)CC1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(C)CCN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccccc4)cc3)ccn2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
To a solution of 3-[4-(4-aminophenoxy)pyridin-2-yl]-1-[1-(2-dimethylaminoethyl)piperidin-4-yl]-1-methylurea (96 mg) in tetrahydrofuran (10 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 2.33 ml), followed by stirring at room temperature for 2.5 hrs. A solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 0.800 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate:methanol=100:7). Fractions containing a target compound were concentrated to provide the titled compound (64.5 mg, 48%) as pale yellow powder.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9](=[O:23])[C:10]1[S:11][C:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:14]=1)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].C1COCC1.Cl>CO>[O:1]=[C:2]([CH2:8][C:9](=[O:23])[C:10]1[S:11][C:12]([CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:13][CH:14]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(=O)CC(=O)c1ccc(CCc2ccccc2)s1

Procedure:
A solution of ethyl 2,4-dioxo-4-(5-phenethylthiophen-2-yl)butanoate (125 mg, 0.378 mmol), aqueous sodium hydroxide (1.2 mL, 1M, 1.2 mmol), and THF (5 mL) in methanol (5 mL) was stirred at rt overnight. The resultant mixture was treated with aq HCl (1.3 mL. 1M), and concentrated under vacuum. The residue was partitioned between brine and dichloromethane. The organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide off-white solid. Recrystallization of the solid from a mixture dichloromethane and hexane provided the title compound. 1H NMR (CDCl3) δ 7.72 (d, J=3.1 Hz, 1H), 7.35-7.15 (m, 5H), 6.94 (s, 1H), 6.86 (d, J=3.1 Hz, 1H), 3.22 (d, J=8.1 Hz, 2H), 3.03 (d, J=8.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH:5]=[C:4]([Cl:13])[N:3]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>C(O)C>[NH2:1][C:2]1[N+:7]([O-:22])=[C:6]([NH:8][CH2:9][CH:10]([CH3:11])[CH3:12])[CH:5]=[C:4]([Cl:13])[N:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)CNc1cc(Cl)nc(N)n1
Solvent: CCO
Product: CC(C)CNc1cc(Cl)nc(N)[n+]1[O-]
Reaction time: 0.5 h
Yield: 30.2 %

Procedure:
34.70 g of 2-amino-4-isobutylamino-6-chloropyrimidine are dissolved in 250 ml of ethanol. 81.50 g of metachloroperbenzoic acid, in solution in 350 ml of ethanol, are added dropwise and while keeping the temperature of the reaction mixture at 20° C. After stirring for 2 h 30 min, the precipitate formed is filtered on sintered glass, washed with 100 ml of ethyl ether and then taken up in 100 ml of water. The pH is adjusted to 8 by addition of concentrated sodium hydroxide solution. After stirring for 1 hour, the precipitate is filtered on sintered glass, washed with 3×50 ml of water and dried under vacuum over phosphorus pentoxide at 50° C. 11.30 g of 2-amino-4-isobutylamino-6-chloropyrimidine 3-oxide are obtained.