Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[I:12][CH2:13][S:14][C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1>C(Cl)(Cl)Cl>[I:12][CH2:13][S:14]([C:15]1[N:20]=[CH:19][C:18]([Cl:21])=[CH:17][N:16]=1)=[O:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1cnc(SCI)nc1
Solvent: ClC(Cl)Cl
Product: O=S(CI)c1ncc(Cl)cn1
Reaction time: 8 h
Yield: 24 %

Procedure:
90% m-chloroperbenzoic acid 8.4 mmol) in chloroform (8 ml) was added dropwise for 10 min with stirring to a solution of 2-(iodomethyl)thio-5-chloropyrimidine in chloroform (7 ml) at -5° C. The reaction mixture was coloured violet during the addition. The mixture was left at room temperature overnight. The chloroform solution was then extracted with 1 M K2CO3, washed with a little water, then dried (MgSO4) solution evaporated and the product subjected to thick-layer chromatography. 2-(Iodomethyl)sulfinyl-5-chloropyrimidine: yield 24%, m.p. 158° C., IR (KBr): 1050 and 1090 cm-1 (SO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]=O.[NH2:15][C:16]1[CH:20]=[CH:19][NH:18][N:17]=1.O=[C:22]([CH2:29][CH2:30][CH3:31])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH2:29][CH2:30][CH3:31])[NH:15][C:16]2=[N:17][NH:18][CH:19]=[C:20]12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: Nc1cc[nH]n1
Reactant: COc1ccc2ccccc2c1C=O
Product: CCCC1=C(C(=O)OCC)C(c2c(OC)ccc3ccccc23)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-methoxynaphthalene-1-aldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.Cl.CO>O1CCCC1.ClCCl>[OH:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(CCO)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Yield: 63 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) (280 mg, 0.45 mmol) in tetrahydrofuran (30.0 mL) was added 1N HCl (6.0 mL) at room temperature and the reaction mixture was stirred for 1 h at the same temperature (silica TLC, 5% methanol in dichloromethane, Rf=0.5). The tetrahydrofuran was removed under vacuum and the residue was diluted with water and extracted with ethyl acetate (2×25 mL). The organic layer was washed with NaHCO3 solution (10 mL), water (20 mL) and brine (20 mL). The organic layer was dried and concentrated in vacuum to get a crude mass which was purified by CombiFlash using gradient eluent of ethyl acetate and hexane mixture to get pure 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (351) (145 mg, 63%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:16](N1C=CN=C1)(N1C=CN=C1)=S.[NH:28]([C:30](=[O:50])[C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([N:40]2[CH2:45][CH2:44][CH:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:42][CH2:41]2)=[N:38][CH:39]=1)=[O:32])[NH2:29].CCN=C=NCCCN(C)C.Cl>CC(N(C)C)=O.O>[F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH:11][C:16]3[O:50][C:30]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([N:40]5[CH2:41][CH2:42][CH:43]([C:46]([O:48][CH3:49])=[O:47])[CH2:44][CH2:45]5)=[N:38][CH:39]=4)=[O:32])=[N:28][N:29]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)C1CCN(c2ccc(NC(=O)C(=O)NN)cn2)CC1
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CC(=O)N(C)C
Product: COC(=O)C1CCN(c2ccc(NC(=O)c3nnc(Nc4ccc(Oc5ccc(F)cc5)cc4)o3)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 4-(4-fluorophenoxy)aniline (190 mg, 0.93 mmol) in anhydrous DMA (4 mL) was added 1,1′-carbonothioylbis(1H-imidazole) (167 mg, 0.93 mmol) and the mixture stirred at ambient temperature for 1 hr. Methyl 1-(5-{[hydrazino(oxo)acetyl]amino}pyridin-2-yl)piperidine-4-carboxylate (250 mg, 0.78 mmol) was added and the reaction mixture was heated to 50° C. for 1 hr. EDCI.HCl (180 mg, 0.93 mmol) was added and the reaction mixture heated to 85° C. overnight and then allowed to cool to ambient temperature. Water (˜20 mL) was added and the suspension filtered, washed with ether (˜15 mL) and dried to leave the title compound as a pale yellow solid (415 mg, 0.780 mmol, 100%). 1H NMR δ 1.50-1.58 (m, 2H), 1.87-1.90 (m, 2H), 2.61-2.67 (m, 1H), 2.90-2.94 (m, 2H), 3.62 (s, 3H), 4.17 (d, 2H), 6.87-6.89 (m, 1H), 7.00-7.10 (m, 4H), 7.19-7.23 (m, 2H), 7.60-7.63 (m, 2H), 7.90-7.92 (m, 1H), 8.48 (s, 1H), 10.95 (s, 1H), 10.99 (s, 1H); MS m/e MH+ 533.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH:5]=[C:6]([CH3:8])[CH3:7])[CH3:3].[N+](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N-]>FC(F)(F)S([O-])(=O)=O.[Cu+2].FC(F)(F)S([O-])(=O)=O.C(Cl)CCC>[CH3:16][CH2:15][O:14][C:12]([CH:11]1[C:6]([CH3:8])([CH3:7])[CH:5]1[CH:4]=[C:2]([CH3:3])[CH3:1])=[O:13]
Reactant: CC(C)=CC=C(C)C
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCCCCl
Product: CCOC(=O)C1C(C=C(C)C)C1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
18.05 mg (0.05 mmol) of copper trifluoromethanesulfonate, 19.9 mg (0.055 mmol) of bis[2-[4(R)-phenyl-5,5-dimethyl-2-oxazoline]]methane and 5 ml of n-butyl chloride were charged in a 50 ml Schienk's tube wherein the atmosphere is substituted with nitrogen, followed by stirring at room temperature for 10 minutes. After 30.0 g (275 mmol) of 2,5-dimethyl-2,4-hexadiene was further added, 5.70 g (50 mmol) of ethyl diazoacetate was added dropwise at 50° C. over 2 hours. After the completion of the dropwise addition of ethyl diazoacetate, the mixture was further stirred at 50° C. for 1 hour. The amount of chrysanthemic acid ethyl ester formed was determined by gas chromatography. As a result, it was 8.43 g and the yield was 86.0% based on ethyl diazoacetate and, furthermore, the trans/cis ratio was 72/28. After 2,5-dimethyl-2,4-hexadiene (boiling point: 51° C./30 mmHg) was distilled off from the reaction mixture, 1 g of the concentrated solution was taken out. Then, 10 ml of an aqueous 1N sodium hydroxide solution and 5 ml of ethanol were added and alkali hydrolysis was performed by stirring at 100° C. for 1 hour. The resulting chrysanthemic acid was reacted with I-menthol and the formed diastereomer ester was analyzed by gas chromatography. As a result, the optical purity of the (+)-trans isomer was 60% e.e., whereas, the optical purity of the (+)-cis isomer was 27% e.e.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([NH2:16])=[C:9]3[N:8]=2)[C@@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH2:3]1.C1N=CN([C:30]([N:32]2[CH:36]=N[CH:34]=[CH:33]2)=[O:31])C=1.Cl.N1CC([OH:42])C1.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]1([F:1])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([NH:16][C:30]([N:32]4[CH2:33][CH:34]([OH:42])[CH2:36]4)=[O:31])=[C:9]3[N:8]=2)[C@@H:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH2:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OC1CNC1
Reactant: Nc1cnn2ccc(N3CC(F)(F)C[C@@H]3c3cccc(F)c3)nc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cnn2ccc(N3CC(F)(F)C[C@@H]3c3cccc(F)c3)nc12)N1CC(O)C1
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a DCM (0.7 mL) solution of (R)-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (25 mg, 0.074 mmol), was added CDI (18 mg, 0.11 mmol) at ambient temperature in one portion. After stirring two hours, azetidin-3-ol hydrochloride (16 mg, 0.15 mmol) was added in one portion, followed by addition of DIEA (0.039 mL, 0.22 mmol). The reaction was stirred overnight, then concentrated, and the residue was directly purified by reverse-phase column chromatography, eluting with 0 to 45% acetonitrile/water to yield the final product as a yellowish oil (15 mg, 48% yield). MS (apci) m/z=433.1 (M+H).
Reaction SMILES: CC1C=C2N=C(C)C=C(O)N2[N:3]=1.P(Cl)(Cl)([Cl:15])=O.CN(C)C1C=CC=CC=1.CNC.[CH3:30][C:31]1[CH:43]=[C:34]2[N:35]=[C:36]([CH3:42])[CH:37]=[C:38]([N:39]([CH3:41])[CH3:40])[N:33]2[N:32]=1>O.[C].[Pd].O.NN.C(O)C>[ClH:15].[NH2:3][C:43]1[C:31]([CH3:30])=[N:32][N:33]2[C:38]([N:39]([CH3:41])[CH3:40])=[CH:37][C:36]([CH3:42])=[N:35][C:34]=12
Reactant: Cc1cc(O)n2nc(C)cc2n1
Reactant: Cc1cc(N(C)C)n2nc(C)cc2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Pd]
Agent: CNC
Agent: NN
Solvent: CCO
Solvent: CN(C)c1ccccc1
Solvent: O
Product: Cc1cc(N(C)C)n2nc(C)c(N)c2n1
Product: Cl
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2,5-Dimethyl-7-hydroxypyrazolo[1,5-a]-pyrimidine are heated under reflux for 40 minutes with 16.6 ml. phosphorus oxychloride and 0.8 ml. N,N-dimethylaniline. Excess phosphorus oxychloride is distilled off and the residue is poured on to ice. Extraction is carried out with methylene chloride, the organic phase is washed with an aqueous solution of sodium carbonate, dried and evaporated. The residue obtained is dissolved in 28 ml. ethanol and mixed with 2 g. of a 40% solution of dimethylamine in water. The mixture is stirred for 2.5 hours at ambient temperature, evaporated and the residue chromatographed over silica gel with ethyl acetate. There is obtained 0.86 g. (46% of theory) 2,5-dimethyl-7-(N,N-dimethylamino)pyrazolo[1,5-a]pyrimidine which is nitrosated analogously to Example 3. The nitroso compound is reduced analogously to Example 8 with palladium-carbon/hydrazine hydrate. There is obtained 0.8 g. of the title compound. Rf (silica gel, chloroform/methanol/methyl ethyl ketone/glacial acetic acid/water 75:35:25:5:8 v/v/v/v/v)-0.54.
Reaction SMILES: [C:1]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:18])[CH:15]=2)[CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl[C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH2:26])=[O:25])=[CH:22][N:21]=1.C([O-])([O-])=O.[K+].[K+].CC(N(C)C)=O>C1(C)C=CC=CC=1>[C:4]([O:3][C:1](=[O:2])[NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:18][C:20]3[CH:28]=[CH:27][C:23]([C:24](=[O:25])[NH2:26])=[CH:22][N:21]=3)[CH:15]=2)[CH2:10]1)([CH3:7])([CH3:6])[CH3:5]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C

Procedure:
Combine N-Boc-5-hydroxy-2-aminoindane (2.50 g, 10.0 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol, K2CO3 (1.90 g, 14.3 mmol), DMA (25 ml) and toluene (20 ml) in a round bottom flask, equipped with Dean-Stark trap, condenser, and nitrogen inlet. Reflux the suspension for two hours before cooling to ambient temperature. Remove the solids via filtration, wash solids with EtOAc, and concentrate the filtrate/wash on a rotary evaporator. Dissolve the remaining oil in EtOAc, wash with water (2×) and brine, dry (MgSO4) and concentrate. Purify the material on silica gel (20% THF/DCM) to give [5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]-carbamic acid tert-butyl ester (870 mg) as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].IC.[C:22](=O)(O)[O-].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]([CH3:22])[C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1nc(N(C)C(=O)OC(C)(C)C)sc1C(=O)O
Temperature: 25 °C

Procedure:
To a stirred solution of 2-(tert-butoxycarbonylamino)-4-methylthiazole-5-carboxylic acid (0.13 g, 0.50 mmol) in N,N-dimethylformamide (2.5 mL) at 0° C. was added sodium hydride (0.044 g, 1.10 mmol, 60% dispersed in mineral oil). The resultant mixture was stirred at 0° C. for 40 min, followed by the dropwise addition of iodomethane (31.2 mL, 0.50 mmol). The resultant solution was allowed to warm to ambient temperature over 18 h, followed by the addition of saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography eluting with ethyl acetate/hexanes (50/50 to 100/0) to afford 2-(tert-butoxycarbonyl(methyl)amino)-4-methylthiazole-5-carboxylic acid (0.070 g, 0.26 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[NH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([O:19][CH3:20])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CC(C)=O>[CH3:33][O:32][C:30](=[O:31])[CH2:29][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:21])=[CH:13][C:14]=1[O:19][CH3:20]
Reactant: COC(=O)CBr
Reactant: COc1cc(CNC(=O)OCc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(CNC(=O)OCc2ccccc2)cc1OC
Yield: 89.9 %

Procedure:
A solution of 14 (0.287 g, 1 mmol) in acetone (20 mL) was treated with K2CO3 (0.552 g, 4 mmol) and methyl bromoacetate (0.14 mL, 1.5 mmol) and refluxed for 3 h. After cooling, the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography over silica gel using EtOAc:Hex (3:2) as eluant to give 15 as white solid (0.323 g, 90%).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].S(Cl)([Cl:9])=O.[CH2:11](O)[CH:12]([CH3:14])[CH3:13]>>[ClH:9].[CH2:11]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)CO
Reactant: O=S(Cl)Cl
Reactant: C[C@H](N)C(=O)O
Product: CC(C)COC(=O)[C@H](C)N
Product: Cl

Procedure:
A mixture of 35.64 g (0.4 mol) of (D,L)-alanine (Aldrich) (or L-alanine (Aldrich)); 44 mL (0.6 mol) of thionyl chloride (Aldrich) and 200 mL of isobutanol was refluxed for 1.5 hours and the volatiles were removed completely on a rotavapor of 90° C. under reduced pressure to give (D,L)-alanine iso-butyl ester hydrochloride (or L-alanine iso-butyl ester hydrochloride), which was pure enough to be used for further transformations.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7](C)[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9].C(N(CC)CC)C>C1COCC1>[Cl:1][CH2:2][C:3]([NH:6][CH2:7][C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])=[O:4]
Reactant: CC(N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NCC(O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A solution of 0.33 ml (0.975 g, 4.2 mmol) chloroacetyl chloride in 10 ml THF was cooled to 0° C. To this was added a solution of 0.8 g (3.98 mmol) 2-amino-1,1-diphenylpropanol and 0.6 ml (0.436 g, 4.31 mmol) triethylamine in 10 ml THF. The resulting solution was stirred at 0° C. for 2 hours before it was filtered and the residue washed with THF. The combined filtrate was concentration and the residue crystallized from ethyl acetate-hexane to afford 0.986 g (78%) of 2-(2-chloroacetylamino)-1,1-diphenylethanol, m.p. 178°-180° C.
Reaction SMILES: C1(O[C:8](=[O:28])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[F:24])[C:11]=2[C:25](=[O:27])[NH2:26])C=CC=CC=1.[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][CH2:38][NH2:39])[CH2:32][CH2:31]1>>[F:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:25]([NH2:26])=[O:27])=[C:10]([NH:9][C:8]([NH:39][CH2:38][CH2:37][CH2:36][N:33]2[CH2:32][CH2:31][N:30]([CH3:29])[CH2:35][CH2:34]2)=[O:28])[S:14][N:13]=1
Reactant: CN1CCN(CCCN)CC1
Reactant: Cc1ccc(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1ccc(COc2nsc(NC(=O)NCCCN3CCN(C)CC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2-fluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 3-(4-methyl-piperazin-1-yl)-propylamine by the procedure analogous to Example 1. MS (APCI, m/z): 465 [M+H]+.
Reaction SMILES: CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([OH:28])[CH:26]=2)[N:21]=[CH:20][N:19]=1.O[CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][N:33]1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:29][CH3:30])=[C:25]([O:28][CH:36]3[CH2:35][CH2:34][N:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:32][CH2:37]3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: COc1cc2ncnc(Cl)c2cc1O
Reactant: CC(C)(C)OC(=O)N1CCCCC1O
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Cl)c2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Di-tert-butylazodicarboxylate (9.22 g) in methylene chloride (20 ml) was added slowly to a stirred suspension of 4-chloro-6-hydroxy-7-methoxyquinazoline (5.63 g), 4 hydroxy-1-tert-butoxycarbonylpiperidine (8.06 g) and triphenylphosphine (10.5 g) in methylene chloride (100 ml) at 5° C. under an atmosphere of nitrogen. The reaction mixture was allowed to warm to room temperature for 16 hours. The reaction mixture was then evaporated under vacuum and adsorbed onto silica and the product was eluted with isohexane/ethyl acetate/triethylamine (75/24/1 followed by 70/29/1). The fractions containing the desired product were combined and evaporated under vacuum to give tert-butyl 4-[(4-chloro-7-methoxyquinazolin-6-yl)oxy]piperidine-1-carboxylate as a white solid (10.3 g); 1H NMR Spectrum: (DMSO d6) 1.40 (s, 9H), 1.56-1.69 (m, 2H), 1.93-2.04 (m, 2H), 3.20-3.31 (m, 2H), 3.60-3.70 (m, 2H), 4.00 (s, 3H), 4.89 (m, 1H), 7.45 (s, 1H), 7.50 (s, 1H), 8.86 (s, 1H); Mass Spectrum: (M+H)+ 394.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17](F)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[Cl:40]C1C=CC(N2CCNCC2)=CC=1>O1CCCC1>[Cl:40][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C)CCNC(=O)N1CCN(c2ccc(Cl)cc2)CC1
Yield: 66 %

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 4.9 g (0.03 mole) of 1,1'-carbonyldiimidazole, 2.6 g (0.03 mole) of unsym-dimethylethylenediamine, and 5.9 g (0.03 mole) of 1-(4-chlorophenyl)piperazine in a total of 200 ml of tetrahydrofuran gave an oil which solidified when triturated with petroleum ether (30°-60° C.). The collected solid was recrystallized from 2-propanol-isopropyl ether to yield 6.1 g (66%) of the title compound as a white, crystalline solid, m.p. 125°-128° C.
Reaction SMILES: [H-].[Na+].[Br-].[C:4]1(=[O:35])[N:8]([CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[C:7](=[O:30])[C:6]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:5]12.[Cl:36][C:37]1[C:55]([CH:56]=O)=[CH:54][CH:53]=[C:52]([Cl:58])[C:38]=1[CH2:39][O:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[C:48]([CH3:51])[CH:47]=[CH:46]2.O>CS(C)=O>[Cl:36][C:37]1[C:55](/[CH:56]=[CH:10]\[CH2:9][N:8]2[C:4](=[O:35])[C:5]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:6]3[C:7]2=[O:30])=[CH:54][CH:53]=[C:52]([Cl:58])[C:38]=1[CH2:39][O:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[C:48]([CH3:51])[CH:47]=[CH:46]2.[Cl:36][C:37]1[C:55](/[CH:56]=[CH:10]/[CH2:9][N:8]2[C:4](=[O:35])[C:5]3=[CH:34][CH:33]=[CH:32][CH:31]=[C:6]3[C:7]2=[O:30])=[CH:54][CH:53]=[C:52]([Cl:58])[C:38]=1[CH2:39][O:40][C:41]1[CH:42]=[CH:43][CH:44]=[C:45]2[C:50]=1[N:49]=[C:48]([CH3:51])[CH:47]=[CH:46]2
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C=O)c3Cl)c2n1
Reactant: O=C1c2ccccc2C(=O)N1CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(/C=C/CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Product: Cc1ccc2cccc(OCc3c(Cl)ccc(/C=C\CN4C(=O)c5ccccc5C4=O)c3Cl)c2n1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The mixture of 60% sodium hydride in oil (56 mg) and dimethyl sulfoxide (6 ml) was stirred at 60° C. under nitrogen atmosphere for 1 hour. To the mixture was added (2-phthalimidoethyl)triphenylphosphonium bromide (1.19 g) at ambient temperature, and the mixture was stirred for 30 minutes. To the mixture was added 8-(2,6-dichloro-3-formylbenzyloxy)-2-methylquinoline (400 mg) under water bath cooling, and the mixture was stirred overnight. To the reaction mixture was added water and extracted with chloroform. The organic layer was washed with water three times and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash silica gel chromatography eluted with n-hexane-ethyl acetate to give 8-[2,6-dichloro-3-((Z)-3-phthalimido-1-propenyl)benzyloxy]-2-methylquinoline as amorphous first and 8-[2,6-dichloro-3-((E)-3-phthalimido-1-propenyl)benzyloxy]-2-methylquinoline as amorphous second. The former was crystallized from diisopropyl ether to afford pale yellow crystals (138 mg). The latter was crystallized from diisopropyl ether to afford pale yellow crystals (192 mg).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:15])[CH:10]=3.C(=O)([O-])[O-].[K+].[K+].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]Cl)[CH:34]=1>CS(C)=O>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6]4=[C:7]([C:16](=[O:26])[C:17]([CH2:19][C:20]5[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=5)=[CH:18][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:15][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)[CH:10]=3
Reactant: ClCc1cccnc1
Reactant: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(O)cc1c32
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1c(Cc2cccnc2)cn2c3cc(Br)ccc3c3cc(OCc4cccnc4)cc1c32
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
9-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (200 mg) produced in Example 102 was suspended in dimethyl sulfoxide (8 ml). After adding potassium carbonate (204 mg), the mixture was stirred at room temperature for 30 minutes, and 3-picolylchloride (0.09 ml) was added. After stirring at room temperature for 12 hours, the reaction mixture was poured into ice water (20 ml) and the crystals precipitated were recovered by filtration. The thus obtained crude crystals were washed with water, ethanol and ether in succession and recovered by filtration to obtain the title compound (177 mg, 72%).