Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Cl:21])=[CH:10][C:9]=2[CH3:22])=[O:4].[F:24][C:25]1([F:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[Cl:21][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:22])[CH:10]=1)[N:7]=[C:6]([N:28]1[CH2:29][CH2:30][C:25]([F:31])([F:24])[CH2:26][CH2:27]1)[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC1(F)CCNCC1
Reactant: COC(=O)c1c(Cl)nc2c(C)cc(Cl)cc2c1-c1ccccc1
Product: Cc1cc(Cl)cc2c(-c3ccccc3)c(C(=O)O)c(N3CCC(F)(F)CC3)nc12

Procedure:
The title compound was prepared in analogy to example 40 step D from 2,6-dichloro-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 40 step C) and 4,4-difluoro-piperidine. Light yellow foam. MS (ESI): 417.2 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]#[N:12])=[CH:6][CH:5]=1.Br[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>O>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[C:11]#[N:12])=[CH:6][CH:5]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Brc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: N#CC(c1ccc(F)cc1)c1ccccn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28.6 %

Procedure:
A sample of sodium hydride (60%, 1.60 g, 0.04 mole) was washed with dry hexanes. After removal of hexanes a 100 ml portion of dimethyl sulfoxide was added. To this mixture was added a solution of 4-fluorophenylacetonitrile (5.41 g, 0.04 mole). The mixture was stirred 3 hrs at room temperature under nitrogen. 2-Bromopyridine (6.32 g, 0.04 mole) was added to the mixture, the reaction mixture was then stirred overnight at 65° C. The reaction mixture was poured into 1200 ml of water and the aqueous phase was extracted several times with chloroform (the chloroform layer was filtered using Celite). The combined chloroform layer was extracted with water and 5% sodium hydroxide. The chloroform layer was dried over sodium sulfate, filtered, and solvent removed to give a red oil. The oil was subjected to flash chromatography on silica gel using 10% ethylacetate-90% hexanes and 20% ethylacetate-80% hexanes for elution. Fractions of similar purity was combined and solvent removed in vacuo. The oil obtained was dried in vacuo overnight at 80° C. to give 2.43 g (28.6%) of clear oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].C([N-]C(C)C)(C)C.[Li+].[CH3:19][Si:20]([CH3:37])([CH3:36])[CH2:21][CH2:22][O:23][CH2:24][N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[CH:34]=[O:35]>O1CCCC1>[F:1][C:2]1[C:3]([O:9][CH3:10])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:34]([C:26]1[N:25]([CH2:24][O:23][CH2:22][CH2:21][Si:20]([CH3:36])([CH3:37])[CH3:19])[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=1)[OH:35]
Reactant: COc1ccc(F)cc1F
Reactant: C[Si](C)(C)CCOCn1c(C=O)nc2ccccc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(F)c(C(O)c2nc3ccccc3n2COCC[Si](C)(C)C)c1F
Temperature: 25 °C

Procedure:
To a solution of 2,4-difluoro-1-methoxybenzene (156 mg) in tetrahydrofuran (5 mL) at −78° C. is added a 2M solution of lithium diisopropylamide in THF (540 μL). After stirring for 45 min a solution of 1-(2-trimethylsilylethoxymethyl)-1H-benzimidazole-2-carbaldehyde (which can be prepared according to US2003/220341 or U.S. Pat. No. 6,476,041 for example) (300 mg) in tetrahydrofuran (5 mL) is added at −78° C. and the reaction mixture allowed to warm to room temperature. After hydrolysis with aqueous saturated ammonium chloride and extraction with ethyl acetate, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel (gradient dichloromethane/methanol from 100/0 to 95/5) to afford (2,6-difluoro-3-methoxyphenyl)[1-(2-trimethylsilylethoxymethyl)-1H-benzimidazol-2-yl]methanol.
Reaction SMILES: FC(F)(F)C1C=C(C(Cl)=O)C=CC=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][C:30]=1[F:36].[F:37][C:38]([F:51])([F:50])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1>C1(C)C=CC=CC=1.C(O)C>[F:50][C:38]([F:37])([F:51])[C:39]1[CH:40]=[C:41]([C:45]([N:47]=[C:48]=[S:49])=[O:46])[CH:42]=[CH:43][CH:44]=1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[CH:21][CH:20]=[C:19]2[O:28][C:29]1[CH:35]=[CH:34][C:32]([NH:33][C:48]([NH:47][C:45](=[O:46])[C:41]2[CH:42]=[CH:43][CH:44]=[C:39]([C:38]([F:37])([F:51])[F:50])[CH:40]=2)=[S:49])=[CH:31][C:30]=1[F:36]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1cccc(C(F)(F)F)c1
Agent: O=C(N=C=S)c1cccc(C(F)(F)F)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4cccc(C(F)(F)F)c4)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
3-(Trifluoromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 3-(trifluoromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 3-(trifluoromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 89%).
Reaction SMILES: [Cl-].[NH4+].O.[C:4]([O:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][C:20]=2[C:28]#[N:29])[CH2:15][CH2:14]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>[Fe].C(O)C>[C:4]([O:12][CH:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][C:20]=2[C:28]#[N:29])[CH2:17][CH2:18]1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1N1CCC(OC(=O)c2ccccc2)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(N)ccc1N1CCC(OC(=O)c2ccccc2)CC1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
Subsequently, ammonium chloride (3.4 g) and iron powder (18 g) were added to a mixed solvent of water (80 ml) and ethanol (240 ml), and the mixture was heated to 65° C. Thereafter, 1-(2-cyano-4-nitrophenyl)-4-piperidinyl benzoate (32.3 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (25.3 g), melting point: 154–155° C.
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5]1.[H-].[Na+].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]=[C:28]1S(C)(=O)=O.O>CN(C=O)C>[F:20][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:28]3[N:27]([CH2:26][CH2:25][O:24][CH3:23])[C:31]4=[N:32][CH:33]=[CH:34][CH:35]=[C:30]4[N:29]=3)=[CH:15][CH:14]=2)=[N:5]1
Reactant: COCCn1c(S(C)(=O)=O)nc2cccnc21
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cccnc23)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1c(Oc2ccc(-c3nn(CC(F)F)c4cccnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 29.3 %

Procedure:
To a stirred solution of 4-(1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl)phenol (50 mg) in DMF (4 mL) was added NaH (60% in oil, 4.80 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-(2-methoxyethyl)-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (52 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (24.0 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1.[CH:15](=O)[CH:16]([CH3:18])[CH3:17].[BH3-]C#N.[Na+]>CO.C(O)(=O)C>[CH2:15]([NH:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[CH2:4][CH2:3]1)[CH:16]([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Reactant: CC(C)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)[C@H](NCC(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of (R)-methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (5.23 mmol, 1 eq) in MeOH (50 ml) there were added first acetic acid (2 drops) and then, at 0° C., isobutyraldehyde (0.47 ml, 5.23 mmol, 1 eq), and stirring was carried out for 1 h at RT. The reaction mixture was cooled to 0° C. again, NaCNBH3 (821 mg, 13.07 mmol, 2.5 eq) was added, and stirring was carried out for a further 30 min at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated, and the residue was taken up in water (50 ml) and extracted with dichloromethane (2×75 ml). The combined organic phases were washed with sat. NaCl solution (2×60 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (Alox neutral, 3% MeOH in dichloromethane), the desired product was obtained. Yield: 65% (0.850 g, 33.44 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2].[CH2:19]([O:21][C:22]([C@H:24]1[CH2:29][CH2:28][C@H:27]([NH2:30])[CH2:26][CH2:25]1)=[O:23])[CH3:20]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:30][C@H:27]1[CH2:26][CH2:25][C@H:24]([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:29][CH2:28]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1Cl
Product: CCOC(=O)c1cnc2c(OC)cccc2c1N[C@H]1CC[C@H](C(=O)OCC)CC1

Procedure:
4-Chloro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.94 mmol) was treated with trans-4-amino-cyclohexanecarboxylic acid ethylester following general procedure B to afford 8-methoxy-4-(trans-4-ethoxycarbonyl-cyclohexylamino)-quinoline-3-carboxylic acid ethyl ester (207 mg). Thus obtained amino-ester (200 mg, 0.50 mmol) was subjected to reaction with 1-chloro-3-isocyanato-benzene according to general procedure C to furnish trans-4-[3-(3-chloro-phenyl)-7-methoxy-2,4-dioxo-3,4-dihydro-2H-pyrimido[5,4-c]quinolin-1-yl]-cyclohexane-carboxylic acid ethyl ester (175 mg). LCMS: m/z 508 [M+1]+.
Reaction SMILES: ClCCl.[CH3:4][C:5]1[CH:37]=[CH:36][CH:35]=[CH:34][C:6]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]2[CH2:23][CH2:22][NH:21][CH:20]([CH3:24])[CH:19]2[C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH3:38][N:39]=[C:40]=[O:41]>C(OCC)(=O)C>[CH3:38][NH:39][C:40]([N:21]1[CH2:22][CH2:23][N:18]([S:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][C:6]3[CH:34]=[CH:35][CH:36]=[CH:37][C:5]=3[CH3:4])=[CH:14][CH:13]=2)(=[O:16])=[O:17])[CH:19]([C:25]23[O:32][CH2:31][C:28]([CH3:33])([CH2:29][O:30]2)[CH2:27][O:26]3)[CH:20]1[CH3:24])=[O:41]
Reactant: Cc1ccccc1COc1ccc(S(=O)(=O)N2CCNC(C)C2C23OCC(C)(CO2)CO3)cc1
Reactant: CN=C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNC(=O)N1CCN(S(=O)(=O)c2ccc(OCc3ccccc3C)cc2)C(C23OCC(C)(CO2)CO3)C1C
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a dichloromethane (5 ml) solution of 1-[4-(2-methyl-benzyloxy)-benzenesulfonyl]-3-methyl-2-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-piperazine (compound of formula XLV, 1.78 g, 3.64 mmol) at about 0° C. was added methyl isocyanate (0.24 ml, 4.0 mmol). The reaction was allowed to stir for about 0.5 hour at about 23° C., was diluted with ethyl acetate and extracted with water. The organic layer was dried with sodium sulfate and then was concentrated to give 1.927 g of a compound of formula XLIV.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1>CCCCO>[C:12]([NH:11][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([Br:1])[C:3]=2[N:25]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]2)[NH:8][CH:9]=1)(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 78.4 %

Procedure:
N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.190 g, 0.698 mmol), DIEA (0.365 mL, 2.10 mmol), and (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.390 g, 2.10 mmol) were placed in n-BuOH (2 mL) and heated to 135° C. for 8 hours. The reaction was then cooled to room temperature and concentrated to dryness. The residue was purified by silica gel chromatography (500:18 DCM:MeOH) to give (S)-tert-butyl 1-(3-acetamido-5-bromo-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.240 g, 78% yield).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11].C(N(CC)CC)C>ClCCl>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: COC(CN)OC
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)NCC(OC)OC
Reaction time: 4 h
Yield: 65 %

Procedure:
Over a period of 4 hours, 104.5 parts of methacryloyl chloride dissolved in 105 parts of dichloromethane are added dropwise at a maximum of 15° C., while cooling with ice, to 105.14 parts of aminoacetaldehyde dimethylacetal and 101.2 parts of triethylamine in 200 parts of dichloromethane. When the reaction is complete, the dichloromethane phase is washed with 200 parts of water then with 200 parts of 1N HCl solution, and then twice with 200 parts of water. After drying with anhydrous magnesium sulfate, the dichloromethane phase is concentrated by evaporation and stabilised with 0.1% of 2,6-di-tert-butyl-p-cresol, based on the reaction product. After distillation at 90° C. 10-3 mbar, 112 g of methacrylamidoacetaldehyde dimethylacetal are obtained in the form of a colourless liquid, boiling point 92° C. 10-3 mbar (65% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][CH:4]=1)#[CH:2].Br[C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[O:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C>[F:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:24]2[CH:25]=[CH:11][CH:12]=[C:13]([C:14](=[O:15])[C:16]3[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=3)[CH:23]=2)=[CH:4][CH:5]=1
Reactant: O=C(c1ccc(F)cc1)c1cccc(Br)c1
Reactant: C#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: O=C(c1ccc(F)cc1)c1cccc(C#Cc2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
In a 250-mL three-neck, round-bottom flask equipped with a magnetic stirrer, a thermocouple, and a condenser were placed 5.00 g (0.04 Mol) of 1-ethynyl-4-fluorobenzene, 11.16 g (0.04 Mol) of 3-bromo-4′-fluorobenzophenone (from the first step), 0.1 g of triphenylphosphine, 0.05 g of cuprous iodide, 0.05 g of dichlorobis(triphenylphosphine)palladium[II], and 200 mL of de-aerated triethylamine. The reaction mixture was heated to 80° C. with stirring under argon for 4 hr and then cooled to ambient with stirring for an additional 16 hr (overnight). The reaction slurry was filtered to remove the white precipitate of triethylamine hydrobromide. The triethylamine solvent was evaporated and the solid was dissolved in dichloromethane. The resulting solution was washed with water (2×100 mL), 2% HCl (2×100 mL), brine and then dried over sodium sulfate. After filtration and removal of the solvent, the product was purified by crystallization from acetone yielding 23 g (75%)of white crystals having a melting point of 130-131° C. In an alternative experiment, during which recrystallization was carried out in toluene, the recovered pure rhombic needles of the product had a melting point of 135-136° C.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]([OH:27])[CH:24]=[CH:25][CH:26]=1>C(OCC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:27])[CH:22]=3)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccc(F)cc2)CC1
Reactant: Nc1cccc(O)c1
Solvent: CCOCC
Product: O=C(Nc1cccc(O)c1)C(=O)N1CCC(Cc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from [4-(4-fluoro-benzyl)-piperidin-1-yl]-oxo-acetic acid (Example 1b) and 3-amino-phenol (Aldrich) according to the method described in Example 1c. Melting Point: 175-179° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.C([O:14][CH:15](OCC)[C:16]([NH2:18])=[S:17])C>C(O)C>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:18]=[C:16]([CH:15]=[O:14])[S:17][CH:7]=2)=[CH:4][CH:3]=1
Reactant: CCOC(OCC)C(N)=S
Reactant: O=C(CBr)c1ccc(F)cc1
Solvent: CCO
Product: O=Cc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g (23.04 mmol) of 4-fluorophenacyl bromide and 3.76 g (23.04 mmol) of 2,2-diethoxythioacetamide in 100 ml of ethanol were stirred at room temperature for 2 h. After concentration, the residue was treated with ethyl acetate and filtered. The filtrate was concentrated and the obtained residue, which consisted of the diethyl acetal of 4-(4-fluoro-phenyl)-thiazole-2-carbaldehyde, was treated with 100 ml of acetone/water and 1 ml of 2 N hydrochloric acid. After stirring at room temperature for 2 h, the reaction mixture was evaporated. Yield: 4.22 g.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11](=[NH:15])[N:12]([OH:14])[CH3:13])[N:6]=1.C(N(CC)CC)C.Cl[C:30](OC1C=CC(F)=CC=1)=[O:31]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11]2[N:12]([CH3:13])[O:14][C:30](=[O:31])[N:15]=2)[N:6]=1
Reactant: CN(O)C(=N)/C(=N\OCc1csc(N)n1)c1ccccc1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of (2Z)-2-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}-N-hydroxy-N-methyl-2-phenylethanimidamide (5.00 g, 16.37 mmol, 1 eq.) and triethylamine (2.28 ml, 16.37 mmol, 1 eq) in DMF (100 ml) at 0° C., was added dropwise 4-fluorophenyl chloroformate (28.58 g, 16.37 mmol, 1 eq.). After stirring at 0° C. for 1 hour, the reaction was quenched by addition of water (50 ml) and extracted with EtOAc (2×150 ml). The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (5.65 g, 96% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[C:19]([OH:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]([CH3:23])[C:19](=[O:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(O)n1
Reactant: CI
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cccc(=O)n1C

Procedure:
The title compound, yellow cristalline solid, MS: m/e=325.2, 327.1 (M+H+), was prepared in accordance with the general method of example 2 from 6-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyridin-2-ol and methyl iodide, along with the O-alkylation product from which it was separated by flash chromatography (gradient: EtOAc to EtOAc/MeOH 95:5).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[NH:14][CH2:13][CH2:12][CH2:11]2.[C:18]([N:26]=C=O)(=[O:25])C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]2[C:15](=[N:16][CH:17]=1)[N:14]([C:18]([NH2:26])=[O:25])[CH2:13][CH2:12][CH2:11]2
Reactant: Cc1ccncc1-c1cnc2c(c1)CCCN2
Reactant: O=C=NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccncc1-c1cnc2c(c1)CCCN2C(N)=O
Temperature: 25 °C
Yield: 23.7 %

Procedure:
To the solution of 6-(4-Methyl-pyridin-3-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (50 mg, 0.22 mmol) in 5.0 mL of anhydrous DCM is added benzoyl isocyanate (39 mg, 0.24 mmol) and the solution is heated to reflux for 3 hrs. Then the solvent is removed in vacuo and to the residue is added 5.0 mL of EtOH. Then K2CO3 (61 mg, 44 mmol) is added and the mixture is heated to reflux for 5 hrs. After cooling down to room temperature, the solid is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in DCM, washed with water and brine. The organic layer is separated, dried over Na2SO4, filtered and concentrated. The crude product is purified by preparative HPLC to give 14 mg of the titled product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[Mg].[CH3:8][N:9]([CH3:28])[CH:10]([CH3:27])[CH2:11][C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:13]=[O:14].[Cl-].[NH4+]>C1COCC1>[CH3:28][N:9]([CH3:8])[CH:10]([CH2:11][C:12]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH:13]([OH:14])[CH2:6][CH2:5][CH2:4][CH:3]=[CH2:2])[CH3:27]
Reactant: CC(CC(C=O)(c1ccccc1)c1ccccc1)N(C)C
Reactant: C=CCCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CCCCC(O)C(CC(C)N(C)C)(c1ccccc1)c1ccccc1
Temperature: 45 °C
Reaction time: 4 h
Yield: 40 %

Procedure:
A solution of 5-bromo-1-pentene (4.8 g) in anhydrous THF was added dropwise to magnesium turnings (1 g) in THF (15 ml), under nitrogen with vigorous stirring. After the initial exothermic reaction had subsided, the mixture was stirred at 45° C. for 4 hours. A solution of 4-dimethylamino-2,2-diphenylpentanal (1.2 g), as prepared above, dissolved in THF (5 ml) was then added. The resultant mixture was stirred for 18 hours. Saturated ammonium chloride solution was added and the aqueous mixture was partitioned between water and ethyl acetate (3×). The combined organic layers were washed with brine and water (once each), and dried (MgSO4). Rotary evaporation of the solution gave a crude material which was flash-chromatographed over silica gel. Elution with chloroform (CHCl3)/methanol (20:1) yielded 0.6 g of 2-dimethylamino-4,4-diphenyl-9-decene-5-ol, as a mixture of two isomers.