Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:18]1[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH2:25])[N:19]=1>CN(C=O)C>[NH2:25][C:20]1[N:21]=[C:22]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:14])([CH3:12])[CH3:13])=[N:7]2)[C:23]([Cl:24])=[CH:18][N:19]=1
Reactant: CC(C)(O)c1n[nH]c2cc(I)ccc12
Reactant: Nc1ncc(Cl)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(O)c1nn(-c2nc(N)ncc2Cl)c2cc(I)ccc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-(6-iodo-1H-indazol-3-yl)propan-2-ol (300 mg, 0.99 mmol) in dry DMF (10 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (63 mg of a 60% dispersion in mineral oil, 1.59 mmol). After 20 minutes at this temperature, 4,5-dichloropyrimidin-2-amine (326 mg, 1.99 mmol) was added and the solution warmed to RT for 10 minutes, then to 65° C. for 18 hr. Following cooling to RT, the reaction mixture was re-treated with additional sodium hydride (24 mg of a 60% dispersion in mineral oil) then warmed to 75° C. under nitrogen for 6 hr. The reaction mixture was cooled to RT, quenched carefully with water (20 mL) and extracted with EtOAc (2×20 mL extractions). The organic extracts were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by silica gel flash column chromatography (4:1 to 1:1 heptane/EtOAc gradient) furnished the title compound as an off-white solid: 1H NMR (500 MHz, CDCl3) delta 1.79 (6H, s), 5.19 (2H, br. s.), 7.61 (1H, dd, J=8.35, 1.42 Hz), 7.76 (1H, d, J=8.51 Hz), 8.42 (1H, s), 8.64 (1H, d, J=0.95 Hz); LC-MS: m/z=+429.90/431.65 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][NH:22][C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:13]=[CH:14][CH:15]=1.[H-].[Na+].[CH3:35]I>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][C:10]1[CH:11]=[C:12]([C@H:16]2[CH2:20][CH2:19][C@:18]3([CH2:24][CH2:23][N:22]([CH3:35])[C:21]3=[O:25])[N:17]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H](c2cccc(OCc3ccccc3F)c2)CC[C@]12CCNC2=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CC[C@]2(CC[C@H](c3cccc(OCc4ccccc4F)c3)N2C(=O)OC(C)(C)C)C1=O
Reaction time: 0.25 h
Yield: 110 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(3-{[(2-fluorophenyl)methyl]oxy}phenyl)-6-oxo-1,7-diazaspiro[4.4]nonane-1-carboxylate (D46, 60 mg, 0.14 mmol) in DMF (1 mL) cooled at 0° C., was added NaH (8 mg of a 60% dispersion in mineral oil, 0.20 mmol) in one portion. The ice-bath was removed and the reaction mixture left under stirring for 15 min. Methyl iodide (25 μL, 0.41 mmol) was added to the mixture and after 1 h the reaction was quenched with water. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and evaporated. The crude material was purified by chromatography on silica gel using cyclohexane/ethyl acetate (7:3) affording the title compound (70 mg, quant.); Rt (HPLC): 6.03 min; MS: (ES/+) m/z: 477 [M+Na+]; C26H31FN2O4 requires 454.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[C:4]#[N:5].[ClH:11].[H][H]>O.C(O)C>[ClH:11].[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][NH2:5]
Reactant: N#Cc1c(F)cccc1F
Reactant: [H][H]
Agent: Cl
Solvent: CCO
Solvent: O
Product: NCc1c(F)cccc1F

Procedure:
A mixture of 5.00 g. of 2,6-difluorobenzonitrile and 1.0 g. of 50% water-wet 5% palladium on carbon catalyst in 100 ml. of concentrated HCl and 100 ml. of absolute ethanol is shaken at room temperature under 20 lbs. pressure of hydrogen for 48 hours. The mixture is filtered and the filtrate is diluted with 500 ml. of diethyl ether and allowed to stand. Filtration gives the desired product as colorless crystals, m.p. 197°-200° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2].B1([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)C2CCCC1CCC2.[OH-].[Na+]>[Pd].O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]2[C:14]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)=[CH:23][CH:22]=3)[CH:12]=[N:11][C:10]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(I)cc3)cnc12
Reactant: c1ccc(CB2C3CCCC2CCC3)cc1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn2c(C3CCCCC3)c(-c3ccc(Cc4ccccc4)cc3)cnc12
Reaction time: 24 h
Yield: 68.3 %

Procedure:
According to a modification of a literature procedure (Suzuki, A. et al Tetrahedron Lett. 1986, 27, 6369-6372) a mixture of 57 mg (0.12 mmol) of 7-cyclohexyl-6-(4-iodo-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester and 5 mg (0.006 mmol, 5 mol %) of Pd catalyst was placed into a carousel tube. After a vacuum and argon cycle, tetrahydrofuran (THF) (2 mL) was added, followed by 0.29 mL (0.144 mmol, 1.2 equiv) of B-Benzyl-9-BBN 0.5 M solution in THF, and 0.12 mL (0.36 mmol, 3 equiv) of 3 N NaOH solution, and the resulting mixture was heated reflux under argon overnight. Since analysis by LC-MS revealed unreacted starting material still present, 0.12 mL (0.06 mmol) of B-Benzyl-9-BBN, 5 mg (0.006 mmol, 5 mol %) of Pd catalyst, and 0.12 mL (0.36 mmol) of 3 N NaOH solution was added and heating was continued for 24 h. The reaction mixture was then diluted with ethyl acetate, washed with water, dried over sodium sulfate, passed through a small pad of Celite, and evaporated to give a brown residue (crude coupling product), which was chromatographed on silica gel (Biotage; 2% ethyl acetate in dichloromethane) to afford 36 mg (68% yield) of desired 6-(4-benzyl-phenyl)-7-cyclohexyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid ethyl ester as indicated by 1H NMR (containing traces of impurities); LC-MS—calcd for C28H29N3O2 [M++H]+: 440.23, found: 440.2.
Reaction SMILES: [CH2:1]([C:3]1([CH3:30])[N:22]([CH2:23][CH2:24][OH:25])[C:21]([CH2:27][CH3:28])([CH3:26])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]1[CH3:29])[CH3:2].C(N(CC)CC)C.[C:38](Cl)(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC=CC=1>[C:38]([O:25][CH2:24][CH2:23][N:22]1[C:21]([CH2:27][CH3:28])([CH3:26])[CH2:20][C:5]2([NH:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:6]2=[O:19])[CH:4]([CH3:29])[C:3]1([CH2:1][CH3:2])[CH3:30])(=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCO)C(C)(CC)C2C)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCN1C(=O)NC2(CC(C)(CC)N(CCOC(=O)c3ccccc3)C(C)(CC)C2C)C1=O
Yield: 49.9 %

Procedure:
To a solution of 2.5 g of the oily product obtained in Example 6 in 30 ml of benzene were added 1.2 g of triethylamine; 0.8 g of benzoyl chloride was then added dropwise with ice-cooling. The mixture was refluxed by heating for 2 hours and, after cooling, an aqueous solution of potassium carbonate was added. The mixture was extracted with benzene. The extract was washed with water, dried over anhydrous sodium sulphate and then concentrated by evaporation under reduced pressure. The resulting oily product was first purified by column chromatography on silica gel (eluent: a 10 : 0.5 by volume mixture of hexane and triethylamine) and then by recrystallization from diethyl ether, giving 1.5 g of Compound 130 as crystals melting at 123° - 124.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)[CH:5]=[CH:6][CH:7]=1.[OH:25]O>>[CH3:1][C:2]1[CH:3]=[C:4]([S:8]([CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19](=[O:24])[CH2:18][CH2:17]3)=[O:25])[CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: Cc1cccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)c1
Product: Cc1cccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)c1

Procedure:
Prepared analogous to Example 2 from 6-[4-(3-methylphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:19][C@@H:20]([CH:23]([CH3:25])[CH3:24])[CH2:21][OH:22])=[N:4][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=2[O:17][CH3:18])=[CH:6][CH:7]=1.C(C1C=CC(OC)=C(C2N=C(N[C@@H](C(C)C)[CH2:43][OH:44])C([N+]([O-])=O)=CC=2)C=1)(C)C>C(O)C.[Pd]>[OH:22][CH2:21][C@@H:20]([N:19]1[C:3]2=[N:4][C:5]([C:8]3[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:9]=3[O:17][CH3:18])=[CH:6][CH:7]=[C:2]2[NH:1][C:43]1=[O:44])[CH:23]([CH3:25])[CH3:24]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(N)c(N[C@H](CO)C(C)C)n1
Reactant: COc1ccc(C(C)C)cc1-c1ccc([N+](=O)[O-])c(N[C@H](CO)C(C)C)n1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C(C)C)cc1-c1ccc2[nH]c(=O)n([C@H](CO)C(C)C)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
(S)-2-(3-Amino-6-(5-isopropyl-2-methoxyphenyl)pyridin-2-ylamino)-3-methylbutan-1-ol. A solution of (S)-2-(6-(5-isopropyl-2-methoxyphenyl)-3-nitropyridin-2-ylamino)-3-methylbutan-1-ol (0.33 g, 0.88 mmol) in ethanol (30 mL) was purged with nitrogen for several min. Following addition of palladium on carbon (0.038 g, 0.35 mmol), the flask was evacuated and a hydrogen filled balloon was placed on the reaction. After stirring at room temperature for 18 h, the reaction was filtered and the solvent removed under reduced pressure to afford the title compound (0.30 g, 99% yield). MS (ESI) m/z 344.3 [M+1]+.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[NH3:24]>CO>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:24])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CC(=O)Nc1ccc(CCc2ccc(Cl)cc2)cc1
Reactant: N
Solvent: CO
Product: NC(=O)CC(=O)Nc1ccc(CCc2ccc(Cl)cc2)cc1
Yield: 65 %

Procedure:
Prepared in analogy to example 3 from N-{4-[2-(4-chloro-phenyl)-ethyl]-phenyl}-malonamic acid methyl ester and 7M ammonia in methanol. Yield=65%. Colorless solid. MS: m/e=317.1 (M++H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:31])([F:30])[F:29])[N:11]=2)[CH2:4][CH2:3]1.[CH2:32]([N:34]=[C:35]=[O:36])[CH3:33]>CN(C=O)C>[CH2:32]([NH:34][C:35]([NH:1][C@H:2]1[CH2:3][CH2:4][C@H:5]([CH2:8][NH:9][C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][N:13]=[C:12]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][C:28]([F:30])([F:31])[F:29])[N:11]=2)[CH2:6][CH2:7]1)=[O:36])[CH3:33]
Reactant: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of N4-[(trans-4-aminocyclohexyl)methyl]-5-nitro-N2-[2-(trifluoromethoxy)benzyl]-pyrimidine-2,4-diamine (100 mg, 0.23 mmol) in DMF (2 mL) was added ethyl isocyanate (65 mg, 0.91 mmol). The reaction mixture was stirred at room temperature for 16 h. The resulting precipitate was filtered and triturated in MeOH. The solid was dried in a vacuum oven to afford 47 mg (41%) of the title compound, m/z 512.7 [M +1]+
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([O:14][C:15](=[O:31])[CH2:16][NH:17][S:18]([C:21]1[S:22][CH:23]=[CH:24][C:25]=1[CH:26]1OCCO1)(=[O:20])=[O:19])[CH3:13].Br[CH2:33][CH2:34][CH2:35][O:36][CH3:37].[I-].[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+].C1CN2C(=NCCC2)C1>CN(C=O)C.CC(C)=O.C(OCC)(=O)C>[CH3:37][O:36][CH2:35][CH2:34][CH2:33][N:17]1[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:31])=[CH:26][C:25]2[CH:24]=[CH:23][S:22][C:21]=2[S:18]1(=[O:19])=[O:20]
Reactant: CCOC(=O)CNS(=O)(=O)c1sccc1C1OCCO1
Reactant: COCCCBr
Agent: C1CN=C2CCCN2C1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)(C)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2ccsc2S(=O)(=O)N1CCCOC
Temperature: 25 °C
Reaction time: 5 h
Yield: 54.1 %

Procedure:
A solution of potassium t-butoxide in t-butanol (1M, 15.7 mL, 15.7 mmol) was added to a solution of the product of Step A (4.80 g, 14.95 mmol) in anhydrous DMF (50 mL) at 0° C. followed by 1-bromo-3-methoxypropane (3.43 g, 22.4 mmol) and sodium iodide (0.2 g). The mixture was stirred for 5 h at ambient temperature, poured into ice water (300 mL) and extracted with ethyl acetate (2×200 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a viscous liquid which was dissolved in acetone (300 mL); p-toluenesulfonic acid (0.4 g) was added and this mixture was heated at reflux temperature for 4.5 h. A saturated aqueous solution of sodium bicarbonate (100 mL) was added to the reaction mixture and acetone was evaporated. The aqueous mixture was extracted with ethyl acetate (2×200 mL) and the combined extracts were dried (MgSO4), filtered and evaporated to give crude aldehyde which was dissolved in ethyl acetate (100 mL). DBN (0.2 g) was added and the mixture heated at reflux temperature for 2 h under nitrogen. The mixture was cooled, quenched with a 2N HCl (50 mL) and extracted with ethyl acetate (2×150 mL). The combined extracts were dried (MgSO4) and evaporated to a syrup which was purified by column chromatography (silica, 30% ethyl acetate/hexane) to give a white solid (2.68 g, 54%): mp 82°-83° C.
Reaction SMILES: C([O:8][NH:9][C:10]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[O:11])C1C=CC=CC=1>C(O)C>[OH:8][NH:9][C:10]([CH:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([OH:15])=[O:14])=[O:11]
Reactant: CC(C)CC(C(=O)O)C(=O)NOCc1ccccc1
Solvent: CCO
Product: CC(C)CC(C(=O)O)C(=O)NO
Reaction time: 16 h
Yield: 99.4 %

Procedure:
Intermediate (3c) (6.6 g, 24.7 mmol) was dissolved into 75 mL ethanol and the solution was degassed with nitrogen. To the solution was added 1.3 g (20% by weight) Pd/C (10% by weight, wet) and the reaction was degassed under hydrogen. After 16 hours, the mixture was filtered through celite and the ethanol was removed in vacuo to yield intermediate (3d) (4.3 g) as a pink oil. 1H NMR (DMSO) δ (ppm): 0.7 (m, 6H), 1.2-1.4 (m, 1H), 1.4-1.6 (m, 2H), 2.9 (t, 1H), 3.3 (quart, 1H), 8.9 (br s, 1H), 10.5 (br s, 1H).
Reaction SMILES: Cl.C([NH:5][C:6]1[C:11]2[C:12](=[O:20])[C:13]3[S:19][CH:18]=[CH:17][C:14]=3[CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1)(=O)C.C(=O)([O-])O.[Na+]>CO>[NH2:5][C:6]1[C:11]2[C:12](=[O:20])[C:13]3[S:19][CH:18]=[CH:17][C:14]=3[CH2:15][S:16][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CC(=O)Nc1cccc2c1C(=O)c1sccc1CS2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Nc1cccc2c1C(=O)c1sccc1CS2
Yield: 99 %

Procedure:
In a mixed solvent of methanol (15 ml) and concentrated hydrochloric acid (15 ml), 9-acetamido-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one obtained in Reference Example 4 (0.74 g, 2.5 mmol) was heated under reflux for one hour. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate, followed by extraction with ethyl acetate (25 ml). The organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the organic layer was concentrated under reduced pressure to give 9-amino-4,10-dihydrothieno[3,2-c][1]benzothiepin-10-one as a yellow solid (0.6 g, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH:29]([NH2:32])([CH3:31])[CH3:30]>C1COCC1>[OH:16][C@@H:15]([CH2:17][NH:32][CH:29]([CH3:31])[CH3:30])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CC(C)N
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H]1CO1
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@@H](O)CNC(C)C
Temperature: 75 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A mixture of (2S)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (250 mg, 0.66 m.mol), (prepared as described for the starting material in Example 304), and isopropylamine (1.5 ml) in THF (10 ml) was stirred at 75° C. for 18 hours under an atmosphere of nitrogen and then allowed to cool to ambient temperature. The mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica gel chromatography using gradient elution with dichloromethane/methanolic ammonia (7M) (100/0 to 90/10) to give (2S)-7-(2-hydroxy-3-(isopropylamino)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (210 mg, 73%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12].[Br:13][CH2:14][CH2:15][CH2:16]Br>C(#N)C>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11][CH3:12]
Reactant: BrCCCBr
Reactant: CSc1cc(C(C)=O)ccc1O
Solvent: CC#N
Product: CSc1cc(C(C)=O)ccc1OCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-[4-hydroxy-3-(methylmercapto)phenyl]ethanone (5.4 g; 0.03 mole), K2COO3 (4.2 g), 1,3-dibromopropane (8 g, 0.039 mole) in acetonitrile (150 ml) was heated at reflux for 3 hours and stirred at room temperature overnight. Acetonitrile was removed at reduced pressure and the residue was extracted into dichloromethane (250 ml). Insolubles were filtered off. The dichloromethane solution was concentrated. The crude product was purified on a silica gel columns (SiO2, 100 g; eluted with 3:2 hexane:dichloromethane, 1.6 l). The compound crystallized upon concentration, and the product (3.5 g, 39%) was recrystallized from ethanol (40 ml) to yield 1-[4-(3-bromopropoxy)-3-(methylmercapto)phenyl]ethanone as white needles, 2.0 g; m.p.=120°-122° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:18])=[N:4][C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]#[N:16])[N:11]([CH3:17])[N:10]=2)=[C:6]([F:8])[CH:7]=1.[Br-].[Li+].[H-].[Na+].[CH3:23]I.Cl>CN(C)C=O.COCCOC>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH3:23])[C:5]([C:9]2[C:13]([CH3:14])=[C:12]([C:15]#[N:16])[N:11]([CH3:17])[N:10]=2)=[C:6]([F:8])[CH:7]=1
Reactant: CI
Reactant: Cc1c(-c2nc(O)c(Cl)cc2F)nn(C)c1C#N
Agent: Cl
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: COCCOC
Product: Cc1c(-c2c(F)cc(Cl)c(=O)n2C)nn(C)c1C#N
Temperature: 22 °C
Reaction time: 0.17 h

Procedure:
1.54 g of 3-chloro-6-(1,4-dimethyl-5-cyano-[1H]-pyrazol-3-yl)-5-fluoropyridin-2-ol are introduced into a mixture of 20 ml of absolute 1,2-dimethoxyethane and 5 ml of absolute dimethylformamide at 22° C. With stirring, first 1.20 g of lithium bromide are added and then, 10 minutes later, in portions, 0.28 g of a 60% sodium hydride dispersion in oil. After a further 10 minutes, 0.86 ml of methyl iodide is added, after which the mixture is stirred overnight at 90° C. The mixture is then cooled to 22° C., carefully poured into dilute hydrochloric acid, and extracted with diethyl ether. The combined ethereal phases are washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo together with 4 g of silica gel. The silica gel is applied to a flash chromatography column and fractionated by means of gradient elution using n-hexane/ethyl acetate 3/1 to 1/1 (v/v). 0.68 g of the desired compound is obtained in the form of a white solid having a melting point of 190-191° C.
Reaction SMILES: CO/[N:3]=[C:4]1\[CH2:5][N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7](=O)[C:8]2\1[CH2:10][CH2:9]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C1COCC1>[C:13]1([CH2:12][N:6]2[CH2:5][CH:4]([NH2:3])[C:8]3([CH2:9][CH2:10]3)[CH2:7]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CO/N=C1\CN(Cc2ccccc2)C(=O)C12CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1CN(Cc2ccccc2)CC12CC2
Temperature: 65 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of (7Z)-5-(phenylmethyl)-5-azaspiro[2.4]heptane-4,7-dione 7-(O-methyloxime) (assumed 3.1553 g, 12.92 mmol) in THF (130 mL) was added lithium aluminum hydride (1.58 g, 41.63 mmol). The mixture was heated at 65° C. and stirred for 3 h. The mixture was then cooled to 0° C., and Na2SO4.10H2O was added. The mixture was stirred overnight, and then 1 N aq. NaOH (6 mL) was added. The mixture was vigorously stirred for 30 min, and then extracted with DCM (3×50 mL). The combined organic phase was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide racemic crude 5-(phenylmethyl)-5-azaspiro[2.4]heptan-7-amine (2.5355 g, 97% for 2 steps) as a light yellow oil. LCMS: (M+H)+: 203.1.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:5]([CH2:6][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[NH2:8])=[CH:4]1.C(N(CC)CC)C.[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:8][C@H:7]([C:9]([O:11][CH3:12])=[O:10])[CH2:6][C:5]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]([CH3:2])[CH:4]=1)=[O:32]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)Cc1cn(C)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1cn(C)c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 54.7 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 20 (4.0 g), triethylamine (2.3 mL), 2-fluorocinnamic acid (2.7 g), WSC.HCl (3.1 g), and methylene chloride (100 mL), to give the captioned compound (3.1 g, 54%) as an oily product.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[CH2:19]([N+:26](C)(C)C)[C:20]1C=CC=C[CH:21]=1>C(#N)C=C>[O:1]=[C:2]1[CH:11]=[C:10]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][CH2:20][C:19]#[N:26]
Reactant: O=c1cc(-c2ccccc2)c2ccccc2[nH]1
Reactant: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C=CC#N
Product: N#CCCn1c(=O)cc(-c2ccccc2)c2ccccc21
Reaction time: 12 h

Procedure:
6.9 g of 1,2-dihydro-2-oxo-4-phenylquinoline are suspended in 45 ml of acrylonitrile, and 3 ml of benzyltrimethylammonium hydroxide are added at 40° to 45° C. During this addition, the mixture starts to boil. After boiling for ten minutes, the acrylonitrile is largely distilled off in vacuo. The residue is heated with 300 ml of ethanol to the boiling point, undissolved material is filtered off and the filtrate is treated with active charcoal and concentrated to 200 ml. The mixture is left to stand for 12 hours and the title compound which has separated out (6.4 l g of m. 162°-165° C.) is filtered off.