Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:13][CH2:14][CH2:15][OH:16].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([O:16][CH2:15][CH2:14][CH2:13][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:5]=1[O:4][CH3:3])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: COc1cccc(CCCO)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cccc(CCCOCc2ccccc2)c1OC
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
2.50 g (62.5 mmol) NaH (60% in oil) were suspended under nitrogen in 70 ml dry THF and a solution of 7.1 g (36.2 mmol) 3-(2,3-dimethoxy-phenyl)-propan-1-ol (J. Org. Chem., 1987, 52, 1072) in 50 ml THF was added dropwise at 18° C. The resulting mixture was stirred for 30 minutes and then a solution of 6.81 g (39.8 mmol) benzylbromide in 30 ml THF was added dropwise and the mixture was stirred over night at 18° C. The reaction was quenched with 10 ml water and the organic solvent was evaporated under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate and the organic layer was washed with water and brine, dried over Na2SO4 and evaporated in vacuo. The crude product was purified by column chromatography on silica gel (ethyl acetate/n-hexane 1:40) to afford 8 g (77%) of the desired product as a colorless oil.
Reaction SMILES: C(N(CC)CC)C.[Si:8](Cl)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].C(Cl)Cl.[OH:19][CH:20]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([NH:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37])=[O:30])[CH2:21][CH2:22][OH:23]>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Si:8]([O:23][CH2:22][CH2:21][CH:20]([C@@H:24]1[CH2:28][CH2:27][CH2:26][N:25]1[C:29]([C@@H:31]1[CH2:35][CH2:34][CH2:33][N:32]1[C:36]([NH:38][CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)=[O:37])=[O:30])[OH:19])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(NCc1ccccc1)N1CCC[C@H]1C(=O)N1CCC[C@H]1C(O)CCO
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCC(O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
Triethylamine (0.5 ml), 4-dimethylaminopyridine (20 mg) and tert-butyldimethylsilyl chloride (497 mg) were added to a methylene chloride solution (6 ml) of (S)-2-[[(S)-2-(1,3-dihydroxypropyl)-1-pyrrolidinyl]carbonyl]-N-(phenylmethyl)-1-pyrrolidinecarboxamide (1.13 g), and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with chloroform, washed with saturated sodium hydrogencarbonate and saturated brine in order, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent: chloroform-methanol) to give the title compound (1.02 g).
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][O:17][CH3:18]>C1C=CC=CC=1.S([O-])(O)(=O)=O.[K+].CCOCC.O>[CH3:18][O:17][CH2:16][CH2:15][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:13]
Reactant: COCCBr
Reactant: O=C1CCCCC1
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: O
Product: COCCC1CCCCC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
Example 241 A) To a mechanically stirred mixture of KOt-Bu (87 g, 0.9 mol) in benzene (700 mL) cooled to 0° C. under an N2 atmosphere was added cyclohexanone (67 g, 0.75 mol) dropwise over 15 minutes. Ten minutes after the addition was complete, bromoethyl methylether (90 g, 0.78 mol) was added dropwise over 20 minutes. The reaction mixture was warmed to room temperature, refluxed for 7 hours, stirred at room temperature for 18 hours, and diluted with 0.5N potassium hydrogen sulfate (300 mL). The mixture was further diluted with Et2O (600 mL), 0.5N potassium hydrogen sulfate (200 mL), and water (200 mL) before the organic phase was separated. The organic layer was washed with water (200 mL) and brine (200 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude product was distilled to afford 41 g (25% yield) of 2-(2-methoxyethyl)cyclohexanone.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[N:11]([NH:22][C:23](=[O:33])[CH2:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=1)[C:10]2=[O:34])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:20]([N:17]([CH2:18][CH3:19])[C:12]1[N:11]([NH:22][C:23](=[O:33])[CH2:24][C:25]2[CH:30]=[C:29]([F:31])[CH:28]=[C:27]([F:32])[CH:26]=2)[C:10](=[O:34])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([OH:6])[CH:8]=2)[N:13]=1)[CH3:21]
Reactant: CCN(CC)c1nc2ccc(O[Si](C)(C)C(C)(C)C)cc2c(=O)n1NC(=O)Cc1cc(F)cc(F)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(O)cc2c(=O)n1NC(=O)Cc1cc(F)cc(F)c1
Reaction time: 0.5 h
Yield: 52.3 %

Procedure:
N-[6-(tert-Butyl-dimethyl-silanyloxy)-2-diethylamino-4-oxo-4H-quinazolin-3-yl]-2-(3,5-difluoro-phenyl)-acetamide (1.50 g, 2.85 mmol) was dissolved in dry THF (50 mL). Tetrabutylammonium fluoride (1 M in THF, 3.13 mL, 3.13 mmol) was added to the mixture over 10 minutes at RT. Stirring was continued for 30 minutes. The solvent was removed in vacuo and the residue was subjected to column chromatography (EtOAc/Heptane) giving the title compound (0.60 g, 54%).
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16].[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1)[CH3:28]>[Zn].CCOC(C)=O>[CH2:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:8][C:9]2[CH:10]=[C:11]([CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])[CH:12]=[CH:13][C:14]=2[N+:15]([O-:17])=[O:16])=[O:38])=[CH:32][CH:31]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])c(N)c1
Reactant: CCOc1ccc(CC(=O)Cl)cc1
Agent: [Zn]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1ccc(CC(=O)Nc2cc(CNC(=O)OC(C)(C)C)ccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
To a stirring toluene solution (100 mL) of (3-Amino-4-nitrophenyl)methyl-carbamic acid, 1,1-dimethylethyl ester (1.10 g, 4.12 mmol) were added 4-ethoxyphenylacetyl chloride (980 mg, 1.2 eq) and zinc dust (400 mg, 1.5 eq). The solution was stirred at rt overnight. Another 0.5 eq of acid chloride and zinc dust were then added and the solution was stirred at rt for another 24 h. The solution was then filtered through celite and rinsed with EtOAc. The organic phase was washed with saturated NaHCO3 solution, brine and dried over anhydrous MgSO4. The crude product was purified by flash chromatography using 2:1/hex:EtOAc on silica gel to yield the desired product [3-[[(4-Ethoxyphenyl)acetyl]amino]-4-nitrophenyl]methyl-carbamic acid, 1,1-dimethylethyl ester (1.18 g, 67% yield); 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.11 (d, J=9.2 Hz, 1H), 7.22 (m, 3H), 6.93 (d, J=9.2 Hz, 2H), 4.40 (m, 2H), 3.75 (s, 2H), 3.33 (s, 3H), 1.50 (s, 9H), 1.42 (t, J=6.8 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH2:17]([O:19][C:20]([C:22]1([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])[CH3:18].Cl.CCN(C(C)C)C(C)C>C(O)C>[CH2:17]([O:19][C:20]([C:22]1([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:23][CH2:24][N:25]([C:2]2[N:11]=[C:10]([OH:12])[C:9]3[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=3)[N:3]=2)[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: COc1cc2nc(Cl)nc(O)c2cc1OC
Reactant: CCOC(=O)C1(Cc2ccccc2)CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCOC(=O)C1(Cc2ccccc2)CCN(c2nc(O)c3cc(OC)c(OC)cc3n2)CC1
Yield: 84.2 %

Procedure:
A mixture of 1.2 g (5 mmol) 2-Chloro-6,7-dimethoxy-quinazolin-4-ol (commercially available), 2.26 g (8 mmol) 4-Benzyl-piperidine-4-carboxylic acid ethyl ester; hydrochloride and 1.93 g (15 mmol) DIPEA in 80 mL ethanol was heated to reflux for 62 h. The mixture was concentrated, the precipitate filtered off and washed with ethanol and diethyl ether. The residue was dried. 1.9 g (87%) of the title compound was isolated as white solid. MS (m/e): 452.2 (MH+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([Cl:33])[CH:8]=[C:9]2[C:14]=1[NH:13][CH:12]([C:15]1[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[CH:18]=[CH:19][CH:20]=1)[C:11]([CH3:32])([CH3:31])[CH2:10]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[C:27]([C:24]1[CH:23]=[CH:22][C:21]([C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:12]3[C:11]([CH3:31])([CH3:32])[CH2:10][C:9]4[C:14](=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]([Cl:33])[CH:8]=4)[NH:13]3)[CH:16]=2)=[CH:26][CH:25]=1)([CH3:28])([CH3:29])[CH3:30]
Reactant: COC(=O)c1cc(Cl)cc2c1NC(c1cccc(-c3ccc(C(C)(C)C)cc3)c1)C(C)(C)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(-c2cccc(C3Nc4c(cc(Cl)cc4C(=O)O)CC3(C)C)c2)cc1
Temperature: 70 °C
Reaction time: 6 h
Yield: 90 %

Procedure:
To a stirred mixture solution of 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid methyl ester (600 mg, 1.3 mmol) in methanol (5.0 mL) and tetrahydrofuran (6.0 mL) was added 50% sodium hydroxide in water (2.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 2-(4′-tert-butyl-biphenyl-3-yl)-6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (524 mg, 90%) as a white solid: LC/MS m/e calcd for C28H30ClNO2 (M+H)+: 449.01, observed: 448.1.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH3:15])([CH3:14])[C:7](=[O:13])[NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[N-:16]=[C:17]=[O:18].[K+]>C(O)(=O)C>[CH3:14][C:6]1([CH3:15])[C:5]2[C:10](=[CH:11][C:2]([NH:1][C:17]([NH2:16])=[O:18])=[CH:3][CH:4]=2)[C:9](=[O:12])[NH:8][C:7]1=[O:13]
Reactant: [N-]=C=O
Reactant: CC1(C)C(=O)NC(=O)c2cc(N)ccc21
Agent: [K+]
Solvent: CC(=O)O
Product: CC1(C)C(=O)NC(=O)c2cc(NC(N)=O)ccc21

Procedure:
1.3 g. (6.3 mMole) 7-amino-4,4-dimethylisoquinoline-1,3-dione was suspended in 30 ml. 2N acetic acid, mixed with 1.0 g. (12.5 mMole) potassium isocyanate and stirred for 6 hours at 80° C. The reaction mixture was cooled and the precipitate was filtered off with suction and washed with water. The residue was dissolved in dilute aqueous sodium hydroxide solution, the solution was neutralised with dilute hydrochloric acid, the residue was filtered off with suction and, for purification, worked up with ethanol and filtered off with suction. Yield: 0.6 g. (38.5% of theory); m.p. 260°-264° C.
Reaction SMILES: [F:1][CH:2]([F:15])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[C:10]([C:12]#[CH:13])[CH:9]=[CH:8][C:7]=1[F:14].I[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]([F:26])[F:25])=[CH:19][CH:18]=1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[F:25][CH:24]([F:26])[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]#[C:12][C:10]2[CH:9]=[CH:8][C:7]([F:14])=[C:6]([O:5][CH2:4][CH2:3][CH:2]([F:1])[F:15])[CH:11]=2)=[CH:18][CH:19]=1
Reactant: C#Cc1ccc(F)c(OCCC(F)F)c1
Reactant: FC(F)Oc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Product: Fc1ccc(C#Cc2ccc(OC(F)F)cc2)cc1OCCC(F)F
Temperature: 37.5 °C

Procedure:
To a mixture of 2-(3,3-difluoropropoxy)-4-ethynyl-1-fluorobenzene (700 mg, 3.27 mmol) from the previous step, TEA (1.82 g, 2.5 mL, 17.99 mmol), PdCl2(PPh3)2 (114 mg, 0.163 mmol), and CuI (19 mg, 0.098 mmol) was added 4-iodo(difluoromethoxy)benzene (707 mg, 2.61 mmol). The reaction mixture was heated at 35-40° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature then poured into water. The aqueous mixture was extracted with EtOAc three times and the combined organic layers were dried over Na2SO4, filtered, and concentrated onto 10 g Celite. Flash chromatography (SiO2, 1% EtOAc 99% Hexanes to 5:95 EtOAc:Hexanes) provided 738 mg, 79%, of the title compound as a light yellow oil.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][NH:12]2)=[O:8])([CH3:5])([CH3:4])[CH3:3].[C:17](OC(=O)C)(=[O:19])[CH3:18].C(N(CC)CC)C>C(Cl)Cl>[C:2]([O:6][C:7]([N:9]1[CH2:14][C@@H:13]2[CH2:15][CH2:16][C@H:10]1[CH2:11][N:12]2[C:17](=[O:19])[CH3:18])=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CC[C@H]1CN2
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1C[C@@H]2CC[C@H]1CN2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a solution of (S,S)-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester hydrochloride (645 mg, 2.59 mmol) in DCM (26 mL) was added acetic anhydride (490 μL, 5.19 mmol) and triethylamine (1.08 mL, 7.77 mmol) and the mixture was stirred (rt, 16 h). The reaction mixture was washed with water (3×8 mL) and brine (1×8 mL). The organic layer was dried, filtered and concentrated in vacuo to provide (S,S)-5-acetyl-2,5-diaza-bicyclo[2.2.2]octane-2-carboxylic acid tert-butyl ester (658 mg, 100%). This intermediate was dissolved in DCM (3.5 mL), treated with HCl (4 M in dioxane, 3.5 mL) and stirred (rt, 16 h). The dispersion was concentrated in vacuo to provide the title compound as a beige powder (494 mg, 100%). MS (ESI): mass calcd. for C8H14N2O, 154.11; m/z found, 155.2 [M+H]+. 1H NMR (500 MHz, MeOD): 4.71 (s, 0.5H), 4.25 (s, 0.5H), 3.97 (dt, J=12.1, 2.8, 0.5H), 3.87 (d, J=2.6, 1H), 3.84-3.73 (m, 1H), 3.68 (m, 1H), 3.64 (dd, J=13.8, 1.6, 0.5H), 3.54 (m, 0.5H), 3.45 (m, 1.5H), 2.12 (m, 4.5H), 2.06-1.91 (m, 2.5H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:16])[C@:4]1([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Br:27])=[CH:29][CH:30]=2)[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: BrCc1ccc(Br)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@]1(Cc2ccc(Br)cc2)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)proline methyl ester (1.30 g) in THF (20 mL) at −78° C. was added a solution of KHMDS (1.25 g) in THF (20 mL). After 45 minutes, a solution of 4-bromobenzyl bromide (1.59 g) in THF (20 mL) was added at −78° C. The reaction mixture was warmed to room temperature over 3 hours and stirred for an additional 3 hours. The mixture was diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered and concentrated. Purification by flash column chromatography (silica gel; EtOAc/hexane 1:2) afforded N-(tert-butoxycarbonyl)-2-(4-bromobenzyl)proline methyl ester (0.474 g). MS (m/z) 398 (MH+).
Reaction SMILES: [CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4].[CH2:18]([CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CC(C)=O>CC(C)=O>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[CH3:1][N:2]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:28]3[CH2:29][CH2:30][CH:25]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:26][CH2:27]3)[CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5][C:3]1=[O:4]
Reactant: CN1C(=O)CCc2c(OCC3CO3)cccc21
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: CO
Product: CN1C(=O)CCc2c(OCC(O)CN3CCC(Cc4ccccc4)CC3)cccc21
Temperature: 25 °C
Yield: 78 %

Procedure:
2.4 Grams of 1-methyl-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 2.0 g of 4-benzylpiperidine were mixed with 30 ml of methanol and the mixture was heated under refluxing condition for 3 hours. The reaction mixture was concentrated under a reduced pressure and the residue thus obtained was dissolved in 30 ml of acetone and a 5%-oxalic acid-acetone solution was added under stirring at a room temperature to adjust the pH to 4.5 and allowed to stand. The precipitates thus formed were collected by filtration, washed with acetone and recrystallized from ethanol-ether to obtain 3.9 g (yield: 78%) of 1-methyl-5-[2-hydroxy-3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril monooxalate as in the form of colorless powder. Melting point: 150°-152° C.
Reaction SMILES: S[C:2]1[N:3]=[C:4]([OH:14])[C:5]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:6]=2[N:7]=1>[Ni].CCO>[N:7]1[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]=2[C:4]([OH:14])=[N:3][CH:2]=1
Reactant: Oc1nc(S)nc2c1CCCCCC2
Agent: [Ni]
Solvent: CCO
Product: Oc1ncnc2c1CCCCCC2
Yield: 78 %

Procedure:
A mixture of 2-mercapto-5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol (1 g; 4.76 mmol) and 10 g of Raney nickel in 40 mL of abs. EtOH was refluxed for 5 hours and filtered. The filtrate was evaporated to give 5,6,7,8,9,10-hexahydrocycloocta[d]-pyrimidine-4-ol as a pale-grey solid (0.66 g; 78% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1.[CH:37]1([S:40]([NH2:43])(=[O:42])=[O:41])[CH2:39][CH2:38]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:43][S:40]([CH:37]4[CH2:39][CH2:38]4)(=[O:42])=[O:41])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]([F:35])([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])=[C:4]([CH3:36])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Reactant: NS(=O)(=O)C1CC1
Product: Cc1cc(F)ccc1Nc1c(C(=O)N2CCC(F)(c3ccccc3)CC2)cnc2c(C(=O)NS(=O)(=O)C3CC3)cnn12
Yield: 18.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(4-fluoro-2-methylphenylamino)-6-(4-fluoro-4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (95 mg, 0.19 mmol) obtained in Example 97, step 4 and cyclopropanesulfonamide (115 mg, 0.95 mmol), the title compound (21 mg, 19%) was obtained.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9]2[O:14][CH2:13][CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][O:10]2)=[CH:4][C:3]=1[F:20].[C:21]([Cu])#[N:22]>CN1C(=O)CCC1>[C:21]([C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[O:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:11][O:10]2)=[CH:4][C:3]=1[F:20])#[N:22]
Reactant: CCCCCC1COC(c2cc(F)c(Br)c(F)c2)OC1
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: CCCCC[C@H]1CO[C@H](c2cc(F)c(C#N)c(F)c2)OC1
Temperature: 25 °C

Procedure:
9.1 g (0.026 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-pentyl-1,3-dioxane, 3.5 g (0.0039 mol) of CuCN and 78 cm3 of NMP were refluxed for 2 hours on a mantle heater. The reactant was cooled to room temperature, and after adding 10 cm3 of EDA, it was poured in ice water, extracted with hexane and washed with an aqueous EDA solution and water. The hexane was removed, the residue was treated in a silica gel column with chloroform as solvent, and the chloroform was removed. The residue was recrystallized from a mixture of methanol and water to obtain 1.7 g (0.006mol) of trans-2-(4'-cyano-3',5'-difluorophenyl)-5-pentyl-1,3-dioxane. The phase transition temperature of this compound as measured using DSC was as follows. ##STR16## (where, C indicates crystal, and I shows isotropic liquid).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][C:7]1[C:8]([N:34]2[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]2)=[CH:9][C:10]([O:32][CH3:33])=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]([CH3:29])[CH:21]=3)[C:17]([C:30]#[N:31])=[CH:16][N:15]=2)[CH:12]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:30]([C:17]1[C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[CH:21]=2)=[N:19][C:14]([NH:13][C:11]2[C:10]([O:32][CH3:33])=[CH:9][C:8]([N:34]3[CH2:35][CH2:36][N:37]([CH3:40])[CH2:38][CH2:39]3)=[C:7]([NH:6][C:1](=[O:4])[CH:2]=[CH2:3])[CH:12]=2)=[N:15][CH:16]=1)#[N:31]
Reactant: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(C#N)c(-c2cn(C)c3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cc(Nc2ncc(C#N)c(-c3cn(C)c4ccccc34)n2)c(OC)cc1N1CCN(C)CC1
Reaction time: 1.5 h

Procedure:
A solution of acryloyl chloride (39 mg, 0.43 mmol) in CH2Cl2 (1 mL) was added dropwise to a stirred solution of 2-{[5-amino-2-methoxy-4-(4-methylpiperazin-1-yl)phenyl]amino}-4-(1-methylindol-3-yl)pyrimidine-5-carbonitrile (Intermediate 90, 200 mg, 0.43 mmol) and DIPEA (0.081 mL, 0.47 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/water bath. The mixture was stirred for 1.5 h and then diluted with CH2Cl2 (25 mL). This mixture was then washed with sat. NaHCO3 (50 mL). The aqueous washes were further extracted with CH2Cl2 (2×25 mL). The combined organic solutions were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 5% 7N methanolic ammonia in CH2Cl2 gave the title compound together with some residual starting material. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave a residue after concentration of the appropriate fractions in vacuo. This residue was dissolved in a small amount of CH2Cl2 and trituration with diethyl ether gave a solid that was collected by filtration and dried in vacuo to give the title compound (106 mg, 48%) as a cream solid; 1H NMR: 2.27 (3H, s), 2.57 (4H, br s), 2.92 (4H, br s), 3.74 (3H, s), 3.91 (3H, s), 5.70 (1H, d), 6.17 (1H, d), 6.63 (1H, dd), 6.90 (1H, s), 7.01 (1H, br s), 7.25 (1H, s), 7.52 (1H, d), 7.88 (1H, br s), 8.02 (1H, s), 8.48 (1H, s), 8.67 (1H, s), 9.03 (1H, s), 9.40 (1H, s); m/z: ES+ MH+ 523.27.