Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].C(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=[O:16])[CH3:15])=[C:8]([F:17])[CH:7]=1.[C:18](OCC)(=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CCOCC>[CH2:22]([O:21][C:19](=[O:20])[C:18](=[O:24])[CH2:15][C:14](=[O:16])/[CH:13]=[CH:12]/[C:9]1[CH:10]=[CH:11][C:6]([Cl:5])=[CH:7][C:8]=1[F:17])[CH3:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)/C=C/c1ccc(Cl)cc1F
Agent: [Na]
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)CC(=O)/C=C/c1ccc(Cl)cc1F
Temperature: -5 °C
Reaction time: 48 h
Yield: 86.5 %

Procedure:
Sodium pellets (2.88 g, 0.125 mol) were slowly added to absolute ethyl alcohol (EtOH, 125 mL). After the sodium had reacted, the solvent was removed under reduced pressure, and anhydrous ether (200 mL) was added. The reaction mixture was cooled to −5° C., and a solution of (E)-4-(4-chloro-2-fluorophenyl)-but-3-en-2-one (1; 24.75 g, 0.125 mol) and diethyl oxalate (21.9 g, 0.15 mol) in anhydrous ether (25 mL) was added over 30 min. After stirring 2 days (d) at room temperature, the yellow solid was filtered and washed with ether. After 1 hour (h) of drying at room temperature, the solid was partitioned between CH2Cl2 (200 mL) and 1 N sulfuric acid (H2SO4, 150 mL). The organic layer was dried (MgSO4), and the solvent was removed to give (E)-6-(4-chloro-2-fluoro-phenyl)-2,4-dioxo-hex-5-enoic acid ethyl ester (3; 32.3 g, 86%) as a yellow solid. A small sample was recrystallized from EtOH to yield yellow crystals: mp 84-85° C.; 1H NMR (400 MHz, CDCl3) δ 14.72 (s, 1H), 7.76 (d, J=16.1 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.24-7.12 (m, 2H), 6.73 (d, J=16.1 Hz, 1H), 6.53 (s, 1H), 4.38 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H); HRMS-ESI (m/z): calcd for C14H12ClFO44, 298.041. found, 298.041.
Reaction SMILES: [NH2:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:14][N:13]=[N:12][N:11]=3)[C:6]([CH3:9])([CH3:8])[S:7][C@H:3]12.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][CH2:26][C:27](O)=[O:28].[K+].[Br-]>>[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25][CH2:26][C:27]([NH:1][CH:2]1[C:15](=[O:16])[N:4]2[CH:5]([C:10]3[NH:11][N:12]=[N:13][N:14]=3)[C:6]([CH3:8])([CH3:9])[S:7][C@H:3]12)=[O:28]
Reactant: NCc1ccccc1SCC(=O)O
Reactant: CC1(C)S[C@@H]2C(N)C(=O)N2C1c1nnn[nH]1
Agent: [Br-]
Agent: [K+]
Product: CC1(C)S[C@@H]2C(NC(=O)CSc3ccccc3CN)C(=O)N2C1c1nnn[nH]1
Yield: 14 %

Procedure:
The title compound is prepared in 14% yield, as a colorless amorphous solid, by acylation of 6-amino-2,2-dimethyl-3-(5-tetrazolyl)penam with 2-(2-[aminomethyl]phenylthio)acetic acid (U.S. Pat. No. 3,766,176), using the method of Example LXXVII. IR(KBr disc): 1780 and 1665 cm-1. NMR (DMSO-d6 /D2O): 7.50 ppm (m, 4H), 5.70 ppm (d, 1H), 5.43 ppm (d, 1H), 5.19 ppm (s, 1H), 4.35 ppm (s, 2H), 3.94 ppm (s, 2H), 1.60 ppm (s, 3H), and 1.00 ppm (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[CH:4][C:3]=1[Cl:21].Cl[C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[Cl:21][C:3]1[CH:4]=[C:5]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:9]2)[CH:6]=[CH:7][C:2]=1[NH:1][C:23]1[N:28]=[CH:27][C:26]([CH:29]2[CH2:31][CH2:30]2)=[CH:25][N:24]=1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(Cl)c2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Nc3ncc(C4CC4)cn3)c(Cl)c2)C1
Temperature: 120 °C
Reaction time: 16 h
Yield: 49.8 %

Procedure:
tert-Butyl (RS)-2-(4-amino-3-chlorophenyl)morpholine-4-carboxylate (70 mg), 2-chloro-5-cyclopropylpyrimidine (45.0 mg, CAS 166740-44-9) and cesium carbonate (109 mg) were combined with dioxane (2 ml) to give a yellow suspension. The mixture was degassed by bubbling argon into the mixture for several minutes. Xantphos (7.77 mg) and tris(dibenzylideneacetone)dipalladium chloroform complex (6.95 mg) were then added. The reaction mixture was then capped and stirred at 120° C. for 16 hours. The crude reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by flash column chromatography (silica gel; gradient: 0% to 75% EtOAc in hexanes) to afford tert-butyl (RS)-2-(3-chloro-4-(5-cyclopropylpyrimidin-2-ylamino)phenyl)morpholine-4-carboxylate (48 mg, 50%) as a colourless amorphous solid. MS (ISP): 433.2 ([{37Cl}M+H]+), 431.2 ([{35Cl}M+H]+).
Reaction SMILES: [OH-].[Li+].[CH2:3]([S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([O:26]C)=[O:25])=[CH:18][CH:17]=1)(=[O:12])=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O.C1COCC1>[CH2:3]([S:10]([NH:13][CH2:14][CH2:15][C:16]1[CH:33]=[CH:32][C:19]([O:20][CH2:21][C:22]2[CH:31]=[CH:30][CH:29]=[CH:28][C:23]=2[C:24]([OH:26])=[O:25])=[CH:18][CH:17]=1)(=[O:11])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCNS(=O)(=O)Cc2ccccc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1COc1ccc(CCNS(=O)(=O)Cc2ccccc2)cc1
Yield: 61.8 %

Procedure:
Lithium hydroxide (2 mg, 0.077 mmol) in water (0.5 ml) was added into methyl 2-[(4-{2-[(benzylsulfonyl)amino]ethyl}phenoxy)methyl]benzoate (17 mg, 0.038 mmol) dissolved in THF (1 ml). The mixture was then in irradiated in a microwave oven (Smith Synthesizer) at 150° C. for 7 minutes and then evaporated to remove THF. The residue was acidified with 1% hydrochloric acid, pH˜4, and extracted with ethyl acetate (×2). The organic extracts were combined and dried with MgSO4 and then evaporated. Chromatography of the residue on a column (ISOLUTE® SI, 500 mg/3 ml) using DCM, then MeOH/DCM (0.5:99.5) as eluant gave 10 mg the desired product, yield 61%.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.CN(C)C1C=CC=CC=1.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(OCC)(=O)C>[C:21]([NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: Cc1ccnc(N)c1[N+](=O)[O-]
Reactant: CCCC(=O)Cl
Solvent: CN(C)c1ccccc1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1nccc(C)c1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of 2-amino-4-methyl-3-nitropyridine (5.0 g) and N,N-dimethylaniline (8.5 ml) was heated at 100° C. under nitrogen atmosphere. To the solution was added butyryl chloride (3.5 ml) and the mixture was stirred at 100° C. for 5 hours. After being cooled to room temperature, ethyl acetate was added to the reaction mixture. The organic layer was separated and washed successively with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was washed with n-hexane to give 2-butyrylamino-4-methyl-3-nitropyridine (7.0 g).
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[C:3]=1[CH3:15].Br.[C:17](O)(=[O:19])[CH3:18]>>[C:17]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:15])(=[O:19])[CH3:18]
Reactant: CC(=O)O
Reactant: Cc1c(O)c(=O)ccn1CCCCCO
Agent: Br
Product: CC(=O)OCCCCCn1ccc(=O)c(O)c1C
Yield: 65 %

Procedure:
3-Hydroxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one, prepared as described under Example 14, (2 g) is dissolved in glacial acetic acid containing about 1% w/v of hydrogen bromide and the solution is refluxed for 2 hours. The resultant mixture is subjected to rotary evaporation and the residue crystallised from aqueous ethanol to give 1-(5'-acetoxypentyl)-3-hydroxy-2-methylpyrid-4-one in 65% yield, m.p. 132°-133° C., νmax (nujol) 1520, 1540, 1580, 1635, 1735 cm-1 and δ(d6DMSO), 1.6 (m, 6H), 2.1 (s, 3H), 2.4 (s, 3H), 4.05 (m, 4H), 6.4 (d, 1H), 7.3 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[NH:6][N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(OCC)(=O)C>C(#N)C.O>[Br:1][C:2]1[N:6]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[N:5]=[C:4]([C:7]([F:10])([F:9])[F:8])[CH:3]=1
Reactant: FC(F)(F)c1cc(Br)[nH]n1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: COC(=O)Cn1nc(C(F)(F)F)cc1Br
Temperature: 80 °C
Yield: 31.8 %

Procedure:
To a solution of 5-bromo-3-(trifluoromethyl)-1H-pyrazole (1.0 g, 4.6 mmol) and Cs2CO3 (3.0 g, 9.3 mmol) in acetonitrile (10 mL) was added methyl 2-bromoacetate (865 mg, 5.6 mmol). The reaction was heated at 80° C. for 3 h. After the reaction was cooled to room temperature, the mixture was portioned between ethyl acetate and water. The organic layer was separated and washed with saturated aqueous NH4Cl and brine. The organic layer was then dried over Na2SO4, filtered and concentrated to afford crude product which was purified by silica gel chromatography eluting with dichloromethane/hexanes to afford methyl 2-(5-bromo-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (420 mg, 32%) as a clear oil. MS (m/z): 287.1 [M+H]+; HPLC retention time 2.93 min (2-98% acetonitrile:water with 0.05% trifluoroacetic acid).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[CH:5][CH:4]=1.[OH:26]O>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(SCCCCOc2ccc3c(c2)CCC(=O)N3)cc1
Reactant: OO
Product: COc1ccc(S(=O)CCCCOc2ccc3c(c2)CCC(=O)N3)cc1

Procedure:
Prepared analogous to Example 2 from 6-[4-(4-methoxyphenyl-mercapto)-butoxy]-3,4-dihydro-carbostyril and hydrogen peroxide.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12](=[O:26])[C:13]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=2[F:25])([CH3:16])[CH2:14][CH3:15])[S:9][CH:10]=1)C.[OH-].[Na+]>CO.O>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:13]([CH3:16])([CH2:14][CH3:15])[C:12]([NH:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:27])=[O:3])[N:7]=1)=[O:26]
Reactant: CCOC(=O)Cc1csc(NC(=O)C(C)(CC)Oc2ccc(F)cc2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCC(C)(Oc1ccc(F)cc1F)C(=O)Nc1nc(CC(=O)O)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.6 %

Procedure:
To a solution of {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid ethyl ester (0.202 g, 0.51 mmol) in MeOH (3 ml) and water (1.5 ml). NaOH (0.041 g, 1.1 mmol) was added and stirred at room temperature for 16 hrs. The organic solvent was evaporated and residue was diluted with water (2 ml) and acidified (pH˜2) with 5% HCl. The aqueous layer was extracted with ethyl acetate (2×10 ml) and organic layer was washed with saturated brine (10 ml). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to obtain crude product which was solidified by triturating with hexane to afford {2-[2-(2,4-Difluoro-phenoxy)-2-methyl-butyrylamino]-thiazol-4-yl}-acetic acid (0.158 g, 84%). 1H NMR (400 MHz, CDCl3): δ1.03 (t, J=7.6 Hz, 3H), 1.44 (s, 3H), 1.86-1.9 (m, 1H), 2.05-2.09 (m, 1H), 3.78 (s, 2H), 6.78 (s, 1H), 6.80-6.84 (m, 1H), 6.88-6.93 (m, 1H), 7.0-7.06 (m, 1H), 10.6 (s, 1H), MS (EI) m/z: 371.00 (M+1) and mp: 148-149° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.[C:16](Br)([CH3:19])([CH3:18])[CH3:17]>C1CCCCC1.ClCCl.[Ag-]=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH:10]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:2]1
Reactant: COC(=O)C(O)c1csc2ccccc12
Reactant: CC(C)(C)Br
Agent: O=[Ag-]
Solvent: C1CCCCC1
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1csc2ccccc12
Reaction time: 20 h
Yield: 18.5 %

Procedure:
A mixture of methyl 2-(1-benzothiophen-3-yl)-2-hydroxyacetate (4a) (300 mg, 1.35 mmol), silver (I) oxide (938 mg, 4.05 mmol) and tertbutylbromide (910 μL, 8.1 mmol) in a mixture of cyclohexane (5 mL) and dichloromethane (1 mL) was vigorously stirred for 20 hours under a nitrogen atmosphere. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 90/10) to afford the desired ether oxide (4b) as a white solid (70 mg, 0.25 mmol, 10%).
Reaction SMILES: [C:1]([O-:4])([O-])=[O:2].[Na+].[Na+].Br[CH:8]([C:13]1C=CC=[CH:15][CH:14]=1)[C:9](OC)=O.[CH3:19][N:20](C=O)C>>[N:20]1([CH2:19][C:1]([OH:4])=[O:2])[CH2:15][CH2:14][CH2:13][CH2:8][CH2:9]1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CN1CCCCC1

Procedure:
A mixture of intermediate (40) (0.0084 mol) and Na2CO3 (0.01 mol) in DMF (150 ml) was stirred. Methyl 2-bromo-2-phenylacetate (0.01 mol) was added dropwise. The mixture was stirred overnight. The solvent was evaporated. The residue was dissolved in DCM. The organic layer was separated, washed, dried, filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: DCM 100%). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 2.79 g of 1-piperidineacetic acid, 4-[4-[([1,1′-biphenyl]-2-ylcarbonyl)amino]phenyl]-α-phenyl-, methyl ester (intermediate 41).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1.Cl.Cl[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:11]3[CH2:16][CH2:15][N:14]([CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:13][C:12]=3[C:17](=[O:19])[O:18][C:5]=2[CH:4]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OC)CCNC3
Reactant: ClCCN1CCOCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2oc(=O)c3c(c2cc1OC)CCN(CCN1CCOCC1)C3
Temperature: 25 °C

Procedure:
A mixture of 7.85 g (0.03 m) of 1,2,3,4-tetrahydro-8,9-dimethoxy-5H-[1]benzopyrano [3,4-c]pyridin-5-one, 6.15 g (0.033 m) of N-(2-chloroethyl) morpholine HCl and 7.08 g (0.07 m) of triethylamine in 250 cc of ethanol was refluxed for 6 hr. and filtered hot. Treatment of the hot reaction solution with excess HCl 6 hr. and cooling to room temperature afforded crude product. Crystallization from 75% EtOH afforded analytical material mp. 238°-40° C.
Reaction SMILES: C([CH:3]([C:43](N)=[O:44])[C:4]([NH:6][C:7]1[CH:16]=[C:15]2[C:10]([C:11](=[O:42])[NH:12][C:13](=[O:41])[N:14]2[CH2:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:23][CH2:22]2)=[CH:9][CH:8]=1)=[O:5])C.C([OH:48])C.[OH-].[Na+]>O1CCCC1>[O:41]=[C:13]1[NH:12][C:11](=[O:42])[C:10]2[C:15](=[CH:16][C:7]([NH:6][C:4]([CH2:3][C:43]([OH:48])=[O:44])=[O:5])=[CH:8][CH:9]=2)[N:14]1[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][CH:28]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:23][CH2:22]1
Reactant: CCC(C(N)=O)C(=O)Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CC(=O)Nc1ccc2c(=O)[nH]c(=O)n(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 19 %

Procedure:
Ethyl N-[2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydro-7-quinazolinyl]malonamide (690 mg) obtained in Example 43 was dissolved in tetrahydrofuran (10.0 ml) and ethanol (10.0 ml) and then a 1N aqueous solution of sodium hydroxide (5.0 ml) was added. The reaction mixture was stirred at room temperature for 16 hours and the solvent was distilled off under reduced pressure, and the residue was made acidic with 1N hydrochloric acid, and then extracted with ethyl acetate. After the extract was washed with water and dried (Na2SO4), the solvent was distilled off under reduced pressure to give the title compound (126 mg, 19%). Recrystallization from ethyl acetate-methanol-tetrahydrofuran yielded a colorless crystal having a melting point of 230 to 232° C.
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][N:7]([CH2:16][CH:17](O)[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15].C(N(CC)CC)C>ClCCCl>[CH3:6][N:7]([CH2:16][CH:17]([Cl:5])[CH3:18])[C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(C)c1N(C)CC(C)O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1N(C)CC(C)Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
3.1 ml (4.6 g, 40 mmoles) of methanesulfonyl chloride are added dropwise, at a temperature not exceeding 20° C., to a solution of 7.0 g (36.2 mmoles) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-propanol and 5.45 ml (4.0 g, 40 mmoles) of triethyl amine in 50 ml of 1,2-dichloroethane, and the resulting mixture is stirred at room temperature for 3 hours. The mixture is washed then thrice with 30 ml of water, each, dried over anhydrous magnesium sulfate, the solvent is evaporated, and the oily residue is distilled under reduced pressure. 6.9 g (90.2%) of 1-[N-methyl-N-(2,6-dimethylphenyl)-amino]-2-chloro-propane are obtained; b.p.: 116°-118° C./133 Pa.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[C:13]([N:15]([CH2:37][CH:38]([CH3:40])[CH3:39])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:17]1)=[O:14].C(N(CC)CC)C.[CH3:48][S:49](Cl)(=[O:51])=[O:50]>C1COCC1.C(=O)(O)[O-].[Na+]>[CH3:39][CH:38]([CH3:40])[CH2:37][N:15]([C:13]([C:5]1[N:4]([CH2:3][CH2:2][O:1][S:49]([CH3:48])(=[O:51])=[O:50])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1)=[O:14])[C@H:16]1[CH2:21][C@@H:20]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[CH2:19][N:18]([C:30]([O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[O:31])[CH2:17]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCO)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl(3S, 5R)-3-[[[1-(2-hydroxyethyl)-1H-benzimidazol-2-yl]carbonyl](2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (223 mg) and triethylamine (84 μl) in THF (5 ml) was added dropwise methanesulfonyl chloride (37 μl) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, diluted with aqueous sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the object product (288 mg).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:24]=[CH:23][C:15]([C:16]([O:18][C:19](C)(C)C)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:19][O:18][C:16]([C@H:15]1[CH2:23][CH2:24][C@H:12]([O:11][C:8]2[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][CH:9]=2)[CH2:13][CH2:14]1)=[O:17]
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)OC(C)(C)C)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H]1CC[C@H](Oc2ccc(C(=O)O)cc2)CC1
Temperature: 4 °C

Procedure:
1.6 g of tert-butyl trans-4-(4-methoxycarbonylcyclohexyloxy)benzoate (4.78 mmol, 1 eq.) are placed in dichloromethane. The reaction medium is cooled to a temperature of 4° C. with stirring in an ice bath. 3 mL of trifluoroacetic acid (40.39 mmol, 8.44 eq.) are added and the ice bath is removed. After stirring for 17 hours at room temperature, the medium is concentrated, taken up in diethyl ether and filtered to give 1.0 g of trans-4-(4-methoxycarbonylcyclohexyloxy)benzoic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:15][CH2:14][C:11]2([O:13][CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:23])=[N:21][CH:22]=1>C(O)C.C(OCC)(=O)C.Cl.CCO>[Br:16][C:17]1[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH2:12][C:11]2([OH:13])[CH2:14][CH2:15][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH:22]=1
Reactant: c1ccc(CN2CCC3(CC2)CO3)cc1
Reactant: Oc1ccc(Br)cn1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=c1ccc(Br)cn1CC1(O)CCN(Cc2ccccc2)CC1
Yield: 78.5 %

Procedure:
Referring to the method 2 of Example 1, N-benzyl-1-oxa-6-azaspiro[2,5]-octane and 5-bromo-2-hydroxy-pyridine were used for preparing a free base. Melting point: 146-148° C. The product was dissolved in ethanol-ethyl acetate and salified with HCl-EtOH to obtain a hydrochloride, yield 78.5%. Melting point: 148-150° C. 1H-NMR (D2O, ppm) δ: 7.594 (1H, d, J=2.80 Hz), 7.495 (1H, dd, J1=9.52 Hz, J2=2.52 Hz), 7.24-7.34 (5H, m), 6.365 (1H, d, J=9.52 Hz), 4.112 (2H, s), 3.891 (2H, s), 3.208 (2H, d, J=13.15 Hz), 3.031 (2H, t, J1=11.20 Hz, J2=12.60 Hz), 1.742 (2H, t×d, J1=11.20 Hz, J2=3.95 Hz), 1.573 (2H, J=14.57 Hz).
Reaction SMILES: [CH3:1][Si:2]([CH3:26])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][C@H:4]1[CH2:9][C@H:8]([O:10][Si:11]([CH3:17])([CH3:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:7][C:6]([C:19]#[CH:20])(O)[CH:5]1[CH3:21].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH3:26][Si:2]([CH3:1])([C:22]([CH3:25])([CH3:24])[CH3:23])[O:3][C@H:4]1[CH2:9][C@H:8]([O:10][Si:11]([CH3:16])([CH3:17])[C:12]([CH3:13])([CH3:14])[CH3:15])[CH2:7][C:6]([C:19]#[CH:20])=[C:5]1[CH3:21]
Reactant: C#CC1(O)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1C
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C#CC1=C(C)[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
90 mg (0.23 mmol) of 10 in 8 ml of pyridine is introduced, and 50 μl of thionyl chloride is added under argon. It is stirred for 10 minutes at room temperature, poured onto ice water and extracted with ethyl acetate. The organic phase is washed with sodium bicarbonate solution and sodium chloride solution, dried on sodium sulfate, the solvent is removed and the crude product is purified by chromatography on silica gel (mobile solvent: EE:H=1:19; Rf =0.9), whereby 71 mg (0.20 mmol) of title compound 11 is obtained as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][C:18]3[NH:17][C:16]([CH3:21])=[CH:15][C:14]=3[C:13]=2[C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])[N:4]=1.[C:28]([O:31]C(=O)C)(=O)[CH3:29].[N:35]1C=CC=CC=1>>[C:28]([NH:35][C:15]1[C:14]2[C:13]([C:22]([O:24][CH2:25][CH:26]=[CH2:27])=[O:23])=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:20]=[CH:19][C:18]=2[NH:17][C:16]=1[CH3:21])(=[O:31])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccncc1
Reactant: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2[nH]c(C)cc12
Product: C=CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)ccc2[nH]c(C)c(NC(C)=O)c12
Temperature: 0 °C
Reaction time: 12 h
Yield: 87 %

Procedure:
0.5 g of allyl 5-[(4,6-dimethoxypyrimidin-2-yl)oxy]-2-methylindol-4-carboxylate was dissolved in 10 ml of pyridine, and 0.16 g of acetic anhydride was added thereto. The mixture was stirred for 12 hours. The reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and then dried over anhydrous magnesium sulfate. The residue obtained by concentration under reduced pressure, was crystallized with isopropyl ether to obtain 0.49 g (yield: 87%) of the desired compound. mp: 177°-180° C.