Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28]I>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH3:28])([C:14](=[O:25])[C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Temperature: 50 °C
Yield: 57.7 %

Procedure:
To 4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester (650 mg, 1.82 mmol) in DMF (14 mL) was added to NaH (60% in mineral oil, 153 mg, 6.37 mmol) and the mixture was heated at 50° C. for 30 minutes. MeI (0.47 mL, 7.64 mmol) was added and the mixture was heated at 50° C. for an additional 3 hours to afford 4-methyl-4-(4-trifluoromethyl-benzoyl)-piperidine-1-carboxylic acid tert-butyl ester as a colourless oil (390 mg, 58%) following work-up and purification.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[C:11]2[CH2:17]O>C(Cl)(Cl)Cl>[ClH:3].[Cl:3][CH2:17][C:11]1[C:10]2[C:15](=[C:6]([F:5])[CH:7]=[CH:8][CH:9]=2)[N:14]=[C:13]([CH3:16])[CH:12]=1
Reactant: Cc1cc(CO)c2cccc(F)c2n1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCl)c2cccc(F)c2n1
Product: Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.8 %

Procedure:
At 0° C., 0.75 mL (10.4 mmol) of thionyl chloride was dropped into a solution of 1.00 g (5.23 mmol) of (8-fluoro-2-methylquinolin-4-yl)methanol obtained in the above 1) in chloroform (12 mL) and stirred for 15 hours at room temperature. The reaction mixture was removed under a reduced pressure and then, the residue was washed with ethyl acetate to obtain 1.29 g (yield 100%) of 4-chloromethyl-8-fluoro-2-methylquinoline hydrochloride (XII-124). Its physical property is shown below.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][O:12][C:13]([CH:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][C:20]#[C:21][CH2:22][OH:23])=[O:14].C(N(CC)CC)C.[Cl-].[Na+]>ClCCl>[CH3:11][O:12][C:13]([CH:15]1[CH2:17][CH:16]1[CH2:18][CH2:19][C:20]#[C:21][CH:22]=[O:23])=[O:14]
Reactant: COC(=O)C1CC1CCC#CCO
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CC1CCC#CC=O
Temperature: -40 °C
Reaction time: 0.08 h
Yield: 97.1 %

Procedure:
Oxalyl chloride (0.40 g, 3.1 mmol) was dissolved in dichloromethane, and the solution was cooled to -40° C. A solution of dimethyl sulfoxide (0.52 g, 6.2 mmol) in dichloromethane (2 ml) was added thereto over a period of 5 minutes, and the mixture was stirred for 20 minutes. A solution of 2-(5-hydroxy-3-pentynyl)cyclopropanecarboxylic acid methyl ester (0.37 g, 2 mmol) in dichloromethane (5 ml) was added thereto, and the mixture was stirred for 30 minutes. Then, triethylamine (1.7 ml, 12 mmol) was added thereto. The temperature was raised to 0° C., and a saturated sodium chloride aqueous solution was added thereto. The product was extracted with dichloromethane, dried over anhydrous magnesium sulfate and then purified by silica gel column chromatography to obtain the above identified compound (0.35 g, yield: 96%).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][CH:5]=1)([O-])=O.[NH:13]1[C:21]2C(=CC=CC=2)C(CN[C@@H](CCC2NC=C(C3C=CC=CC=3)N=2)C(OCC2C=CC=CC=2)=O)=[CH:14]1.C(N(CC)CC)C>C1COCC1>[N:10]([CH2:7][CH2:8][CH2:9][CH2:4][CH2:5][CH2:6][N:13]([CH3:21])[CH3:14])=[C:11]=[S:12]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: O=C(OCc1ccccc1)[C@H](CCc1nc(-c2ccccc2)c[nH]1)NCc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCCCCCN=C=S
Temperature: 20 °C
Reaction time: 2 h
Yield: 241.3 %

Procedure:
4-nitro-phenylisothiocyanate (43 mg; 1.2 eq.) is added to a solution of benzyl (2S)-2-[(1H-indol-3-ylmethyl)amino]-4-(4-phenyl-1H-imidazol-2-yl)butanoate (93 mg; 1 eq.) in THF (2 ml). The mixture is stirred for 2 hours at approximately 20° C. then diluted with 4 ml of THF. Aminomethylpolystyrene resin (acquired from Novabiochem, load 3.2 mmol/g, 125 mg, 2 eq.) is added, then triethylamine (200 μl). The mixture is stirred for 15 hours at approximately 20° C. then filtered on frit. The filtrate is concentrated to dryness under reduced pressure at 40° C. (a co-evaporation with dichloromethane is necessary to eliminate the excess triethylamine). Purification of the residue by flash chromatography on silica gel (eluent: ethyl acetate/heptane 9:1) yields the expected compound (90 mg; 84% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([OH:14])[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][C:7]=1[F:8].[H-].[Na+].[NH2:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([Cl:25])[N:19]=1>C1COCC1>[Cl:25][C:20]1[CH:21]=[C:22]([O:14][CH:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[C:10]([F:11])([F:12])[F:13])[N:23]=[C:18]([NH2:17])[N:19]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: OC(c1ccc(F)c(F)c1)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(Cl)cc(OC(c2ccc(F)c(F)c2)C(F)(F)F)n1
Temperature: 50 °C
Reaction time: 6 h
Yield: 87.5 %

Procedure:
1-(3,4-Difluorophenyl)-2,2,2-trifluoroethanol (0.1 g, 0.471 mmol) was treated with NaH (60% in mineral oil, 38 mg, 0.943 mmol) in dry THF (3 ml) for 30 minutes. 2-Amino-4,6-dichloropyrimidine (77 mg, 0.471 mmol) was added and the mixture was stirred at 50° C. for 6 hours. The mixture was quenched with water and extracted with methylenechloride (2×). The organics were combined, washed with water, then brine, dried over MgSO4, and concentrated to give 0.14 g of 4-chloro-6-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethoxy)-pyrimidin-2-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[C:21]([CH3:28])[CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][C:21]=2[CH3:28])=[C:8]2[CH:14]=[N:13][N:12]([CH2:15][CH3:16])[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: Cc1cc(F)ccc1B(O)O
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(cnn2CC)c1-c1ccc(F)cc1C
Temperature: 70 °C
Reaction time: 15 h
Yield: 78.6 %

Procedure:
A solution of 4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (3.6 g, 0.014 mol) in toluene (80 mL) and EtOH (40 mL) was degassed 3 times before Pd(PPh3)4 (0.49 g, 0.425 mmol), 4-fluoro-2-methylphenylboronic acid (2.62 g, 0.017 mol) and an aqueous solution of Na2CO3 (2N, 14.2 mL, 0.028 mol) were added. The reaction mixture was stirred at 70° C. for 15 hours, cooled down to RT, filtered and the volatiles evaporated under vacuo. The residue was taken up in EtOAc and washed with aqueous NaOH (1N). The organic phase was dried over Na2SO4, concentrated under vacuo, before a purification on column chromatography (SiO2, EtOAc/Heptane, 1/3) yielded 3.6 g (77%) of the title compound as a colorless oil. ES-MS m/e: 328.2 (M+H+).
Reaction SMILES: [CH:1]([Si:4]([CH:9]([CH3:11])[CH3:10])([CH:6]([CH3:8])[CH3:7])[SH:5])([CH3:3])[CH3:2].[H-].[Na+].Br[C:15]1[CH:16]=[C:17]([CH:23]=[CH:24][C:25]=1[CH3:26])[C:18]([O:20][CH2:21][CH3:22])=[O:19]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([O:20][C:18](=[O:19])[C:17]1[CH:23]=[CH:24][C:25]([CH3:26])=[C:15]([S:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:6]([CH3:8])[CH3:7])[CH:9]([CH3:11])[CH3:10])[CH:16]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(C)c(Br)c1
Reactant: CC(C)[Si](S)(C(C)C)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C)c(S[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. stirred solution of triisopropylsilanethiol (14.28 mmol, 3.07 mL) in THF was added sodium hydride (14.28 mmol, 0.57 g of a 60 wt % dispersion in mineral oil). After 30 min, the mixture was added to a solution of ethyl 3-bromo-4-methylbenzoate (10.99 mmol, 2.67 g) at room temperature, followed by tetrakis(triphenylphosphine)palladium(0) (0.55 mmol, 0.64 g). The resulting mixture was warmed to reflux and stirred for 18 hours, then cooled to room temperature and subjected to standard aqueous workup to afford the title compound which was used crude in the next step.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:36])[CH:28](Br)[CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32]>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[O:24][C:7]1[CH:6]=[N:5][N:4]([CH:28]([CH2:29][CH:30]([CH2:33][CH3:34])[CH2:31][CH3:32])[C:27]([OH:26])=[O:36])[C:3](=[O:15])[CH:2]=1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: CCC(CC)CC(Br)C(=O)OC
Reactant: Oc1c(F)cccc1F
Product: CCC(CC)CC(C(=O)O)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-4-ethyl-hexanoic acid methyl ester (Intermediate 17) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-4-ethyl-hexanoic acid as a white solid (599.8 mg, 88% for the final step); ES+-HRMS m/e calcd for C18H20N2O4F2 [M+H+] 367.1464, found 367.1462. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.77 (m, 6H), 1.00 (br s, 1H), 1.09-1.44 (m, 4H), 1.93 (ddd, J=14.2, 9.4, 4.3 Hz, 1H), 2.11 (ddd, J=14.2, 10.8, 4.0 Hz, 1H), 5.38 (dd, J=10.8, 4.0 Hz, 1H), 6.09 (d, J=2.7 Hz, 1H), 7.32-7.43 (m, 2H), 7.43-7.57 (m, 1H), 8.28 (d, J=2.7 Hz, 1H), 13.11 (br s, 1H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH2:25])[C:6](=[O:22])[CH:7]([N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH2:8]C=C)[CH2:3][CH2:2]1.CS(C)=O>C1(C)C=CC=CC=1.Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[CH:1]1([CH2:4][N:5]2[CH:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:24]=[CH:25][CH2:8][CH:7]([N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[C:6]2=[O:22])[CH2:3][CH2:2]1
Reactant: C=CCC(C(=O)N(CC1CC1)C(C=C)c1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Product: O=C1C(N2C(=O)c3ccccc3C2=O)CC=CC(c2ccccc2)N1CC1CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
To a solution of (N-(cyclopropylmethyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-N-(1-phenylprop-2-en-1-yl)pent-4-enamide (4c) (210 mg) dissolved in Toluene (25 mL) at 80° C. under N2 was added Grubbs catalyst (2nd generation) (21 mg) and the reaction mixture was stirred at 80° C. for 1 h, then cooled to RT. DMSO (0.1 mL) was added to the reaction mixture which was stirred for 2 h, then concentrated. The crude product was directly purified via flash chromatography (gradient—5%, 10% and 15% EtOAc/hexanes) to give a diastereomeric mixture (1.5:1) of the title compound (128 mg, 66%). 1H NMR (300 MHz, CDCl3) δ 0.03-0.09 (m, 1H), 0.22-0.34 (m, 2H), 0.46-0.57 (m, 1H), 0.66-0.72 (m, 0.6H), 1.03-1.09 (m, 0.4H), 2.42-2.48 (m, 1H), 2.98 (dd, 0.6H), 3.20 (dd, 0.4H), 3.55 (dd, 0.6H), 3.61-3.74 (m, 1H), 3.94 (dd, 0.4H), 5.09 (dd, 0.4H), 5.28 (bd, 0.4H), 5.57 (dd, 0.6H), 5.77(d, 0.6H), 6.00-6.08 (m, 1H), 6.26-6.35 (m, 1H), 7.35-7.48 (m, 5H), 7.65-7.88 (m, 4H). MS APCI, m/z=387 (M+1). LC/MS 2.66 min., Method A.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]([F:35])([F:34])[C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[N:15]([CH2:30][C:29]3[CH:28]=[CH:27][C:26]([C:25]([F:24])([F:34])[F:35])=[CH:33][CH:32]=3)[N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)c1sc(-n2cnn(Cc3ccc(C(F)(F)F)cc3)c2=O)nc1C
Yield: 60 %

Procedure:
To a solution of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (0.17 g, 0.68 mmol) and potassium carbonate (0.14 g, 1.03 mmol) in acetone (10 mL) was added 4-(trifluoromethyl)benzyl bromide (0.21 g, 0.89 mmol). The reaction mixture was heated to reflux for 3 hours. The solvent was removed in vacuo and the residue was washed with water and hexanes to afford the title compound in 60% yield (0.17 g): 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.50 (d, J=8.3 Hz, 2H), 5.07 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 2.67 (s, 3H), 1.35 (t, J=7.1 Hz, 3H); MS (ES+) m/z 413.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30])#[N:2]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C#N
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Yield: 49 %

Procedure:
A solution of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (295 mg, 0.83 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 22 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 140 mg (49%) of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.9 (d, 1H, J=8 Hz), 7.75 (d, 1H, J=8 Hz), 7.5-7.4 (m, 4H), 7.25 (t, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (m, 1H), and 5.85 (s, 2H). IR (KBr, cm−1) 3448, 3356, 2225, 1628, and 1600. MS (ES) m/e 340, 342.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:20])[CH3:19])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:28](I)[CH3:29]>CC(C)=O>[CH2:28]([O:1][C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[CH:17][N:18]([CH3:19])[CH3:20])[C:9]2=[O:21])[CH:5]=[CH:6][CH:7]=1)[CH3:29]
Reactant: CCI
Reactant: CN(C)C=C1C(=O)N(c2cccc(O)c2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1cccc(N2C(=O)C(=CN(C)C)c3ccccc32)c1

Procedure:
Title product of Example D1 (0.28 g, 1.0 mmole ) in 2 ml of acetone was stirred under N2 with Na2CO3 (0.21 g, 2 mmoles) for 1 hour. Ethyl iodide (2.28 ml) and 0.5 g Na2CO3 were then added. The mixture was refluxed for 11 hours, cooled, salts removed by filtration and the filtrate stripped of solvent in vacuo. The residue was chromatographed on silica gel (15 cm×3.5 cm), eluting with 1:1 ethyl acetate:hexane. The resulting oil was crystallized from toluene/pentane to yield purified title product; 51.5 mg; 17%; m.p. 99°-102°.
Reaction SMILES: [Cl-].[CH:2]1([NH2+:10][CH2:11][CH2:12]Cl)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]=[S:24]>>[Cl:14][C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]=[C:23]1[N:10]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:11][CH2:12][S:24]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: ClCC[NH2+]C1CCCCCCC1
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2C2CCCCCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclooctyl bromide according to Method B2a to give N-cyclooctyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclooctyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-cyclooctyl-1,3-thiazolidine.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.[NH2:18][CH:19]1[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]1>CN(C=O)C.O>[ClH:10].[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])[NH:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: I
Solvent: CN(C)C=O
Solvent: O
Product: Cl
Product: N=C(NC(=O)c1nc(Cl)c(N)nc1N)NC1CCNCC1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea hydroiodide (7.2 g, 18.4 mmol) and 4-amino-1-Boc-piperidine (5.5 g, 27.5 mmol) in DMF (40 mL) is stirred and heated at 50° C. for 4 hours. The mixture is diluted with water (150 mL) and sonicated for 2 hours. The resulting suspension is collected by filtration and suspended in 4 M HCl in dioxane (40 mL). MeOH (20 mL) is added and the mixture is stirred at room temperature overnight and then filtered. The solid is washed with EtOH (2×10 mL) and dried to afford the title compound. [M+H]+ 313
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([CH3:27])=[N:24][C:23]=2[CH:28]=1)[CH2:3][N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[CH2:6][CH2:5]1.FC(F)(F)C(O)=O.C(Cl)Cl>CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>[CH3:27][C:25]1[S:26][C:22]2[CH:21]=[CH:20][C:19]([O:18][CH2:17][C@H:2]([OH:1])[CH2:3][N:4]3[CH2:5][CH2:6][NH:7][CH2:8][CH2:9]3)=[CH:28][C:23]=2[N:24]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCN(C(=O)OC(C)(C)C)CC3)ccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(C)=O
Product: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 4-[(2R)-2-hydroxy-3-(2-methylbenzothiazol-5-yloxy)propyl]piperazinecarboxylate, a compound of formula (5) (2.0 g, 4.9 mmol), and 25% trifluoroacetic acid/methylene chloride (20 ml) was allowed to stir at room temperature overnight. The solvent was evaporated (in vacuo) to yield an oil. The oil was diluted with acetone (20 ml) and solid potassium carbonate was added until the foaming stopped. The resulting mixture was allowed to stir overnight. The solution was filtered through Celite 512, and the filtrate was evaporated (in vacuo), to yield an oil. The oil was placed under high vacuum overnight, to yield (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol as a clear viscous oil (3.4 g. 6.3 mmol).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2)[CH3:20].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH2:19]([O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1)[CH3:20]
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: CCOc1cccc2c1CCN2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOc1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 67.7 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 163 mg of 4-(ethoxy)indoline and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 260 mg of 2-[2-(4-ethoxy-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a white powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:4]12[CH2:13][CH:8]3[CH2:9][CH:10]([CH2:12][CH:6]([CH2:7]3)[CH2:5]1)[CH2:11]2)([OH:3])=[O:2].[C:14]([C:17]([CH3:19])=[O:18])([CH3:16])=[O:15].[OH:20]N1C(=O)C2=CC=CC=C2C1=O>C([O-])(=O)C.[Co+2].C([O-])(=O)C.C(O)(=O)C>[C:14]([C:10]12[CH2:12][CH:6]3[CH2:7][CH:8]([CH2:13][C:4]([C:1]([OH:3])=[O:2])([CH2:5]3)[CH2:11]1)[CH2:9]2)(=[O:15])[CH3:16].[C:17]([C:14]12[CH2:12][C:6]3([OH:20])[CH2:7][CH:8]([CH2:13][C:4]([C:1]([OH:3])=[O:2])([CH2:5]3)[CH2:16]1)[CH2:9]2)(=[O:18])[CH3:19]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)C(C)=O
Agent: [Co+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(=O)C12CC3CC(C1)CC(C(=O)O)(C3)C2
Product: CC(=O)C12CC3CC(O)(C1)CC(C(=O)O)(C3)C2
Temperature: 75 °C
Reaction time: 6 h
Yield: 46 %
Yield: 24 %

Procedure:
A mixture of 3 mmol of 1-carboxyadamantane, 18 mmol of biacetyl, 0.3 mmol of N-hydroxyphthalimide, 0.015 mmol of cobalt (II) acetate, and 3 ml of acetic acid was stirred at 75° C. under an oxygen atmosphere (1 atm) for 6 hours. Gas chromatographic analysis of products in the reaction mixture demonstrated that 1-carboxyadamantane was converted, at a rate of 92%, to 1-acetyl-3-carboxyadamantane (yield 46%), and 1-acetyl-3-carboxy-5-adamantanol (yield 24%).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][NH:36][CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.FC(F)(F)S(O[CH2:54][CH:55]([F:57])[F:56])(=O)=O>C(Cl)Cl>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][C@H:34]5[CH2:38][CH2:37][N:36]([CH2:54][CH:55]([F:57])[F:56])[CH2:35]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCNC1
Reactant: O=S(=O)(OCC(F)F)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1O[C@H]1CCN(CC(F)F)C1
Temperature: 40 °C
Reaction time: 1 h
Yield: 44.3 %

Procedure:
To a solution of (5)-1-(5-tert-butylisoxazol-3-yl)-3-{3-[6-methoxy-7-(pyrrolidin-3-yloxy)quinazolin-4-yloxy]phenyl}urea (0.198 g, 0.38 mmol) and N,N-diisopropylethylamine (0.5 mL) in CH2Cl2 (10 mL) was added 2,2-difluoroethyl trifluoromethanesulfonate (0.128 g. 0.6 mmol) and it was stirred at 40° C. for 1 hour. It was quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 70-85% EtOAc/hexane as eluants to afford (S)-1-(5-tert-Butylisoxazol-3-yl)-3-(3-{7-[1-(2,2-difluoroethyl)pyrrolidin-3-yloxy]-6-methoxyquinazolin-4-yloxy}phenyl)urea as solid (0.098 g, 44%). 1H NMR (300 MHz, CDCl3) δ 9.4 (s, 1H), 8.62 (s, 1H), 7.81 (s, 1H), 7.65 (t, 1H), 7.54 (s, 1H), 7.40 (t, 1H), 7.33 (m, 1H), 7.19 (s, 1H), 7.00 (d, 1H), 5.93 (tt, 1H), 5.87 (s, 1H), 5.05 (m, 1H), 4.03 (s, 3H), 3.20 (m, 1H), 3.89-3.09 (m, 4H), 2.8 (m, 1H), 2.5 (m, 1H), 2.15 (m, 1H), 1.33 (s, 9H); LC-MS (ESI) m/z 583 (M+H)+.