Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([C:24]([NH2:26])=[O:25])=[C:11]2[CH2:16][NH:15][CH2:14][CH2:13][N:12]2[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:36]>ClCCl>[C:38]1([O:37][C:35]([N:15]2[CH2:14][CH2:13][N:12]3[C:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[C:9]([Cl:8])[C:10]([C:24](=[O:25])[NH2:26])=[C:11]3[CH2:16]2)=[O:36])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CNCC2
Reactant: O=C(Cl)Oc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)c1c(Cl)c(-c2ccccc2)n2c1CN(C(=O)Oc1ccccc1)CC2
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
A suspension of 7-chloro-6-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine-8-carboxylic acid amide trifluoroacetic acid salt (100 mg, Reference Example 1) in dry dichloromethane (5 mL) was treated with dry triethylamine (0.11 mL). The resulting solution was then cooled to −40° C. and treated with a solution of phenyl chloroformate (32 μL, redistilled) in dry dichloromethane (5 mL) whilst maintaining the temperature at 40° C. After stirring at −40° C. for a further 30 minutes the reaction mixture was allowed to warm to room temperature and then washed three times with water (20 mL). The organic phase was dried over magnesium sulfate and the solvent then removed under reduced pressure. The residue was subjected to column chromatography on silica eluting with a mixture of pentane and ethyl acetate (9:11, v/v) to give 8-carbamoyl-7-chloro-6-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazine-2-carboxylic acid phenyl ester (40 mg) as a white solid, m.p. 196–198° C. [Elemental analysis: C, 63.52; H, 4.45; N, 10.31%; Calculated for C21H18ClN3O3: C, 63.72; H, 4.58; N, 10.62%].
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[CH2:6][O:5]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC(C)=O>[CH3:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[N:22]1[CH2:23][CH2:24][N:25]([CH2:2][CH2:3][CH:4]2[CH2:6][O:5]2)[CH2:26][CH2:27]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: BrCCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1cccc(N2CCN(CCC3CO3)CC2)c1C
Temperature: 65 °C
Reaction time: 16 h
Yield: 25.8 %

Procedure:
To a mixture of 2-(2-bromoethyl)oxirane obtained in step 1 (0.70 g, 4.61 mmol) and potassium carbonate (1.91 g, 13.8 mmol) in acetone (10 ml), was added 1-(2,3-dimethylphenyl)piperazine hydrochloride (1.04 g, 4.61 mmol) at room temperature. The resulting reaction mixture was stirred at 65° C. for 16 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.31 g). The compound was used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A solution of 14.61 g. (0.079 m.) of 3-fluoro-4-nitrobenzoic acid, 200 ml. of benzene, 10 ml. of thionyl chloride, and 1 ml. of N,N-dimethylformamide was stirred overnight at room temperature under a calcium chloride drying tube. The resulting clear solution was then heated to reflux for one hour, after which time the solution was concentrated to approximately 75% of the original volume by distillation. The mixture was cooled by placing the flask in an ice bath. With additional cooling, 20 g. of aluminum chloride was added in portions through Gooch tubing over a period of about 45 minutes. The resulting dark mixture was stirred and allowed to warm to room temperature overnight. The reaction flask was again cooled in an ice bath as 300 ml. of lN hydrochloric acid was added dropwise. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water, a saturated solution of sodium bicarbonate, water, a saturated solution of sodium chloride, and then dried over magnesium sulfate. Filtration and evaporation of the solvent in vacuo provided 16.8 g. (87% yield) of the desired compound as an oil which solidified on scratching. Recrystallization from 95% ethanol afforded yellow needles, m.p. about 77°-79° C.
Reaction SMILES: [C:1]([C:3](=[C:13]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([O:6][CH2:7][CH2:8][O:9]C(=O)C)=[O:5])#[N:2]>Cl.CO>[C:1]([C:3](=[C:13]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:4]([O:6][CH2:7][CH2:8][OH:9])=[O:5])#[N:2]
Reactant: CC(=O)OCCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CO
Product: N#CC(C(=O)OCCO)=C(c1ccccc1)c1ccccc1

Procedure:
A charge of 800 ml. of methanol, 335 g. (1 mole) of 2-acetoxyethyl 2-cyano-3,3-diphenylacrylate and 10 drops of concentrated hydrochloric acid was heated at 65° C. for 18 hours. Evaporation of the solvent left 235 g. (80%) of the intermediate compound as an amber, viscous oil.
Reaction SMILES: C[Li].Br[CH2:4][CH2:5][CH:6]=[CH2:7].[Mg].I[CH2:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]#[N:18])[CH2:13][CH2:12]1.[Cl-].[NH4+]>O1CCCC1.[Cu]I>[CH2:10]([C@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]#[N:18])[CH2:13][CH2:12]1)[CH2:7][CH2:6][CH:5]=[CH2:4]
Reactant: C=CCCBr
Reactant: N#C[C@H]1CC[C@H](CI)CC1
Agent: [Cu]I
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: C=CCCC[C@H]1CC[C@H](C#N)CC1
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A suspension of 9.14 g of copper(I) iodide in 90 ml of tetrahydrofuran was treated within 5 minutes at -78° C. with 25.7 ml of 1.5M solution of methyl lithium in tetrahydrofuran using a syringe. The suspension was stirred for a further 45 minutes at -78° C., then left to warm to 0° C. and stirred for a further 3 minutes at 0° C. Thereafter, the suspension was again cooled to -78° C. and treated within 5 minutes using a steel cannula with a Grignard solution prepared from 4.56 ml of 4-bromo-1-butene and 1.1 g of magnesium in 60 ml of tetrahydrofuran. The suspension was stirred for a further 20 minutes at -78° C., then left to warm to 15° C. and stirred for a further 5 minutes at 15° C. Thereafter, the solution was again cooled to -78° C. and treated dropwise within 5 minutes with a solution of 4.8 g of trans-4-(iodomethyl)cyclohexanecarbonitrile in 30 ml of tetrahydrofuran. Thereafter, the reaction mixture was left to warm and was stirred for a further 30 minutes at 16° C. Subsequently, the reaction mixture was treated cautiously in a cooling bath with about 50 ml of ammonium chloride solution and partitioned in methylene chloride/ammonium chloride solution. The aqueous phase was extracted three times with methylene chloride. The organic phases were washed once with ammonium chloride solution and twice with water, dried over magnesium sulphate, filtered and concentrated. Chromatographic separation of the yellow, oily residue (3.4 g) on silica gel with ethyl acetate/petroleum ether (vol. 5:95) gave 2.9 g (85%) of trans-4-(4-pentenyl)cyclohexanecarbonitrile as a light yellow oil.
Reaction SMILES: [CH2:1]([OH:5])[C:2]#[C:3][CH3:4].[H-].[Na+].F[C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:26])[CH:19]([CH:23]([CH3:25])[CH3:24])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl>CN(C=O)C.O>[CH2:1]([O:5][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:18]([CH3:26])[CH:19]([CH:23]([CH3:24])[CH3:25])[C:20]([OH:22])=[O:21])(=[O:17])=[O:16])=[CH:11][CH:10]=1)[C:2]#[C:3][CH3:4]
Reactant: CC(C)C(C(=O)O)N(C)S(=O)(=O)c1ccc(F)cc1
Reactant: CC#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(C(=O)O)C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
To a solution of 3.17 mL (0.042 mol) of 2-butyn-1-ol in 60 ml of DMF at room temperature was added 1.70 g (0.040 mol) 60% sodium hydride. The resulting mixture was stirred for 0.5 h and then a solution of 2.45 g (8.478 mmol) the product of Example 11 dissolved in 20 mL of DMF was added to the reaction. The reaction mixture was then heated to reflux for 24 h, cooled to room temperature and then acidified to pH 2 with 10% HCl solution. After stirring for 1 h the resulting mixture was diluted with water and extracted with ethyl acetate. The combined organics were then dried over MgSO4, filtered and concentrated in vacuo. The, residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:2) to provide 1.67 g (58%) of the desired carboxylic acid product as a white solid identical to the product of Example 8.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[C:27]3[C:32](=[CH:33][CH:34]=2)[N:31]=[CH:30][N:29]=[C:28]3[N:35]2[CH2:40][CH2:39][N:38]([C:41]3[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=3)[C:44](O)=[O:45])[CH2:37][CH2:36]2)=[N:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:50][C:51]1[CH:57]=[CH:56][C:54]([NH2:55])=[CH:53][CH:52]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:50][C:51]1[CH:57]=[CH:56][C:54]([NH:55][C:44](=[O:45])[C:43]2[CH:47]=[CH:48][CH:49]=[C:41]([N:38]3[CH2:39][CH2:40][N:35]([C:28]4[C:27]5[C:32](=[CH:33][CH:34]=[C:25]([C:22]6[CH:23]=[CH:24][N:20]([C:1]([C:2]7[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=7)([C:8]7[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=7)[C:14]7[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=7)[N:21]=6)[CH:26]=5)[N:31]=[CH:30][N:29]=4)[CH2:36][CH2:37]3)[CH:42]=2)=[CH:53][CH:52]=1
Reactant: O=C(O)c1cccc(N2CCN(c3ncnc4ccc(-c5ccn(C(c6ccccc6)(c6ccccc6)c6ccccc6)n5)cc34)CC2)c1
Reactant: Nc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cc1)c1cccc(N2CCN(c3ncnc4ccc(-c5ccn(C(c6ccccc6)(c6ccccc6)c6ccccc6)n5)cc34)CC2)c1
Reaction time: 12 h

Procedure:
200 mg 3-{4-[6-(1-trityl-1H-pyrazolyl)-4-quinazolinyl]piperazin-1-yl} benzoic acid (compound in Example 829), 35 mg 4-fluoroaniline, 46 mg 1-hydroxybenzotriazole and 65 mg 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were dissolved in dichloromethane and stirred for about 12 hours, and the reaction solution was concentrated and purified by silica gel column chromatography to give N1-(4-fluorophenyl)-3-{4-[6-(1-trityl-1H-pyrazolyl)-4-quinazolinyl]piperazin-1-yl}benzamide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][NH:10][C:11]=2[CH3:12])[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[Si:16]([O:23][CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O.[O-]S([O-])(=O)=O.[Mg+2]>CC(N(C)C)=O>[Si:16]([O:23][CH:24]1[CH2:25][CH2:26][C:27]2([NH:1][C:2]3[CH:6]=[C:5]([C:7]4[CH:8]=[N:9][NH:10][C:11]=4[CH3:12])[S:4][C:3]=3[C:13](=[O:14])[NH:15]2)[CH2:28][CH2:29]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Reactant: Cc1[nH]ncc1-c1cc(N)c(C(N)=O)s1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)N(C)C
Product: Cc1[nH]ncc1-c1cc2c(s1)C(=O)NC1(CCC(O[Si](C)(C)C(C)(C)C)CC1)N2
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A mixture of 3-amino-5-(5-methyl-1H-pyrazol-4-yl)thiophene -2-carboxamide (100 mg, 0.450 mmol), 4-{[tert-butyl(dimethyl) silyl]oxy}cyclohexanone (0.339 mL, 1.35 mmol), CSA (10.5 mg, 0.0450 mmol), MgSO4 (108 mg, 0.900 mmol) in anhydrous DMA (1.5 mL) was stirred at 90° C. for 1 h. The mixture was partitioned between EtOAc (20 mL) and aqueous NaHCO3 (10 mL). The aqueous layer was extracted with EtOAc (5 mL). The combined organic layers were washed with brine (5 mL), dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography (Purif, silica gel, 30:70 hexane/EtOAc to EtOAc) to give 4-{[tert-butyl(dimethyl)silyl]oxy}-6′-(5-methyl-1H-pyrazol-4-yl)-1′H-spiro[cyclohexane-1,2′-thieno[3,2-d]pyrimidin]-4′(3′H)-one as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CN(C=O)C.[Pd]>[CH3:14][O:13][C:11]1[CH:12]=[C:4]([NH2:1])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7]
Reactant: COc1ccc(C(=O)O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)c(N)c1
Yield: 83.5 %

Procedure:
2-Nitro-4-methoxybenzoic acid (43.4 g, 0.22 mol) in DMF (250 ml) was hydrogenated at 55 psi in the presence of 10% palladium on carbon (5.8 g) for 2.5 hours. The reaction mixture was filtered through SUPERCELL®, the filter cake was rinsed with ethanol and then the filtrate was poured into ice/water (3.5 L). A precipitate formed which was collected by filtration, washed with water and dried in an oven at 60° C. to afford 30.7 g (84%) of 4-methoxyanthranilic acid, m.p. 176°-178° C. (dec.).
Reaction SMILES: [F:1][C:2]1[C:3]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:4][C:5]2[N:14]=[CH:13][C:12]3[N:11]([CH3:15])[CH:10]=[C:9]([C:16]([O:18]CC)=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:22]=1.[OH-].[K+]>C(O)C>[F:1][C:2]1[C:3]([N:23]2[CH2:24][CH2:25][N:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:27][CH2:28]2)=[CH:4][C:5]2[N:14]=[CH:13][C:12]3[N:11]([CH3:15])[CH:10]=[C:9]([C:16]([OH:18])=[O:17])[C:8](=[O:21])[C:7]=3[C:6]=2[CH:22]=1
Reactant: CCOC(=O)c1cn(C)c2cnc3cc(N4CCN(c5ccc(F)cc5)CC4)c(F)cc3c2c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1cc(C(=O)O)c(=O)c2c3cc(F)c(N4CCN(c5ccc(F)cc5)CC4)cc3ncc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A suspension of 0.70 g of ethyl 9-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylate in a mixture of 250 cm3 of ethanol at 40% and 4 cm3 of a 1 N aqueous potassium hydroxide solution was heated, with stirring, for 8 hours at a temperature of 80° C. After cooling to a temperature of 60° C., the light insoluble material was removed by filtration. The solution was neutralized with 4.1 cm3 of a 1 N aqueous hydrochloric acid solution; the insoluble material formed was dewatered, washed 3 times with 20 cm3 of water and twice with 20 cm3 of ethanol and dried under vacuum at 100° C. 0.56 g of 9-fluoro-8-[4-(4-fluorophenyl)piperazin-1-yl]-4-methyl-1-oxo-1,4-dihydrobenzo[f][1,7]naphthyridine-2-carboxylic acid was obtained in the form of yellow crystals, which melted at 346° C.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([Zn]CC)[CH3:10]>>[C:2]1([C@H:1]([OH:8])[CH2:9][CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Zn]CC
Reactant: O=Cc1ccccc1
Product: CC[C@@H](O)c1ccccc1

Procedure:
Reaction of benzaldehyde with diethylzinc in the presence of (R)-3,3'-bis(2",5"-dihexyloxyphenyl)-1,1'-bi-2-naphthol to give (R)-1-phenyl-1-propanol. (R)-3,3'-bis(2",5"-dihexyloxyphenyl)-1,1'-bi-2-naphthol (42 mg, 0.05 mmol) and diethylzinc (0.21 mL, 2 mmol) were added to a Schlenk flask containing toluene (10 mL, dried with Na and degassed with N2) , under nitrogen and at room temperature, to form the organozinc species. The resulting mixture was stirred at r.t. for ca. 15 min. The flask was cooled to 0° C. and benzaldehyde (0.1 mL, 1 mmol) was then added dropwise. The yellow color of the mixture faded in 4 hours, which indicated the completion of the reaction. 1N HCl was added to quench the reaction at 0° C. and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine until pH=7 and then dried over anhydrous Na2SO4. The purification by column chromatography on silica gel with EtOAc/hexanes (1:5) gave (R)-1-phenylpropanol as a colorless liquid (129 mg, 95%). HPLC analysis on a Chiracel-OD column (eluent: isopropanol/hexane=1/9; 1 mL/min) indicated an ee of 99.3%. The retention time of the (R)-isomer is 7.45 min and (S)-isomer is 8.8 min. 1H NMR (270 MHz, CDCl3): 0.90 (t, J=7.5, 3H), 1.74 (m, 2H), 2.73 (s, 1H), 4.52 (t, J=6.5, 1H), 7.23-7.38 (m, 5H).
Reaction SMILES: C([C:9]1[C:14]([OH:15])=[CH:13][N:12]=[C:11]([CH2:16][CH:17]([NH:19][CH:20]([CH3:22])[CH3:21])[CH3:18])[C:10]=1C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[ClH:31]>>[ClH:31].[ClH:31].[CH:20]([NH:19][CH:17]([CH3:18])[CH2:16][C:11]1[CH:10]=[CH:9][C:14]([OH:15])=[CH:13][N:12]=1)([CH3:22])[CH3:21]
Reactant: CC(C)NC(C)Cc1ncc(O)c(C(=O)c2ccccc2)c1C(=O)c1ccccc1
Agent: Cl
Product: CC(C)NC(C)Cc1ccc(O)cn1

Procedure:
Similarly, the mixture of 0.1 g of dibenzoyl-2-(2-isopropylaminopropyl)-5-pyridinol and 10 ml of 5 N hydrochloric acid may be refluxed for three days, cooled, filtered, evaporated and the residue triturated with acetone, to yield the 2-(2-isopropylaminopropyl)-5-pyridinol dihydrochloride melting at 199°-204°; it is identical with that obtained according to Examples 1, 3 and 8.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[N:13]=[N:12][C:11]([CH2:14][OH:15])=[N:10]1.[H-].[Na+].[CH:18]1([N:21]2[C:25](S(C)(=O)=O)=[N:24][N:23]=[C:22]2[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)[CH2:20][CH2:19]1>>[CH:18]1([N:21]2[C:25]([O:15][CH2:14][C:11]3[N:12]=[N:13][N:9]([C:3]4[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=4[F:1])[N:10]=3)=[N:24][N:23]=[C:22]2[C:30]2[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=2)[CH2:20][CH2:19]1
Reactant: Cc1ccc(F)c(-n2nnc(CO)n2)c1
Reactant: CS(=O)(=O)c1nnc(-c2ccncc2)n1C1CC1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(F)c(-n2nnc(COc3nnc(-c4ccncc4)n3C3CC3)n2)c1

Procedure:
The title compound is prepared from [2-(2-fluoro-5-methyl-phenyl)-2H-tetrazol-5-yl]-methanol (1 mmol), sodium hydride (1.5 mmol) and 4-(4-cyclopropyl-5-methanesulfonyl-4H-[1,2,4]triazol-3-yl)-pyridine (1.25 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:9]1CC1C=CC=CC=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[H][H]>CO.[OH-].[OH-].[Pd+2]>[C:1]([O:5][C:6]([C@H:8]1[CH2:11][C@@H:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)[C@H]1C[C@@H](C(=O)OC(C)(C)C)N1Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1C[C@H](C(=O)OC(C)(C)C)N1
Yield: 65.5 %

Procedure:
307 mg (884 μmol) of cis-N-benzylazetidine-2,4-dicarboxylic acid di-tert.butyl ester in 25 ml of methanol is hydrogenated in a Parr shaker over 100 mg of 20% Pd(OH)2 /C (containing 31% water) under 4 atm of hydrogen for 7.5 h. The catalyst is filtered off through a double paper filter and thoroughly washed with methanol. Evaporation and filtration over SiO2 (EtOAc/hexanes 1:1) affords 149 mg (66%) of cis-azetidine-2,4-dicarboxylic acid di-tert.butyl ester as a yellowish oil which solidifies spontaneously. mp. 47°-48.5° C. 1H NMR (CDCl3): δ4.04 (dd, 2H, J=5.5, 9), 3.2 (br., 1H), 2.97 (dt, 1H, J=12 (d), 9 (t)), 2.38 (dt, 1H, J=12 (d), 5.5 (t)), 1.48 (s, 18H). IR (neat): 3328, 2979, 2934, 1731, 1480, 1458, 1394, 1369, 1280, 1257, 1156, 1103, 1048, 1031, 892, 846, 734 cm-1.
Reaction SMILES: [CH3:1][C:2]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)([CH3:6])[C:3]([NH2:5])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[NH2:5][CH2:3][C:2]([N:7]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1)([CH3:6])[CH3:1]
Reactant: CC(C)(C(N)=O)N1CCOCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CN)N1CCOCC1
Reaction time: 2 h

Procedure:
A solution of 8.33 g of 2-methyl-2-morpholino-propionic acid amide in 50 ml of tetrahydrofuran is slowly added at room temperature to 3.33 g of lithium aluminium hydride in 85 ml of tetrahydrofuran. The reaction mixture is then stirred for a further 2 hours under reflux. The reaction mixture is cooled and then 5 ml of water, 6.67 ml of 2N sodium hydroxide and a further 5 ml of water are added in succession. The suspension is clarified by filtration and the crude title compound is obtained from the concentrated filtrate: 1H NMR (CDCl3), δ(ppm)=3.67 (4H,m), 2.52 (2H, s), 2.48 (4H, m), 1.37 (2H, bs), 0.92 (6H,s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([NH2:19])=[C:11]([O:17][CH3:18])[CH:12]=[C:13]([F:16])[C:14]=2[F:15])=[C:4]([F:20])[CH:3]=1.[C:21](N1C=CN=C1)(N1C=CN=C1)=[O:22]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3[C:14]([F:15])=[C:13]([F:16])[CH:12]=[C:11]([O:17][CH3:18])[C:10]=3[NH:19][C:21]2=[O:22])=[C:4]([F:20])[CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1cc(F)c(F)c(Nc2ccc(Br)cc2F)c1N
Product: COc1cc(F)c(F)c2c1[nH]c(=O)n2-c1ccc(Br)cc1F
Yield: 74.4 %

Procedure:
Intermediate I-8a was prepared from N2-(4-bromo-2-fluoro-phenyl)-3,4-difluoro-6-methoxy-benzene-1,2-diamine (I-6a: 12.5 g, 0.036 mol) and 1,1′-carbonyldiimidazole (14.6 g, 0.0900 mol) using procedures analogous to the preparation of Intermediate (I-7a) above to afford 10 g of the product (74% yield). H1NMR (DMSO-d6, 300 MHz): δ 11.72 (s, 1H), 7.86 (dd, 1H), 7.68-7.58 (m, 2H), 7.02-6.92 (m, 1H), 3.88 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[CH:12]([CH2:27][NH2:28])[CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[N:29]1([C:34]2[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH:33]=[CH:32][N:31]=[CH:30]1>>[Br:1][C:2]1[CH:3]=[C:4]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[CH:18]=3)[CH:12]([CH2:27][NH:28][S:40]([C:37]3[CH:38]=[CH:39][C:34]([N:29]4[CH:33]=[CH:32][N:31]=[CH:30]4)=[CH:35][CH:36]=3)(=[O:41])=[O:42])[CH2:11]2)[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(CN)C2)c1
Reactant: O=S(=O)(Cl)c1ccc(-n2ccnc2)cc1
Product: COc1cc(Br)cc(N2CCN(Cc3ccc(OC)c(OC)c3)C(CNS(=O)(=O)c3ccc(-n4ccnc4)cc3)C2)c1

Procedure:
In a manner similar to Preparation 3, react 4-(3-bromo-5-methoxyphenyl)-1-[(3,4-dimethoxyphenyl)methyl]-2-piperazinemethanamine with 4-(1H-imidazol-1-yl)benzenesulfonyl chloride to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([NH:8]C(=O)OC(C)(C)C)[CH:7]=1.Br[C:26]1[C:27]([C:33]#[N:34])=[N:28][C:29]([Cl:32])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.CCOC(C)=O.O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]2[C:27](=[C:33]([NH2:34])[N:8]=[C:6]3[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]3=2)[N:28]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(NC(=O)OC(C)(C)C)c1
Reactant: N#Cc1nc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)nc(N)c1nc(Cl)ccc12
Temperature: 25 °C

Procedure:
A solution of tert-butyl 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylcarbamate (from Example 5/Step 2) (1.0 eq.) and 3-bromo-6-chloropicolinonitrile (from Example 20/Step 2) (1.0 eq.), tetrakis(triphenyl-phosphine)palladium (5 mol %), and 2N aqueous sodium carbonate solution (2.0 eq.) in toluene/ethanol (2:1, 0.03 M) was stirred at 100° C. overnight. After cooling to ambient temperature, the reaction mixture was diluted with EtOAc and water. The two phases were separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-40% EtOAc/Hexanes to give 3-chloro-8-methylbenzo[f][1,7]naphthyridin-5-amine as a pale yellow solid.