Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[OH:2].Cl.Cl.[CH2:5]([NH:12][C:13]([NH:15][C:16]([NH:18][C:19]([CH3:26])([CH3:25])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[NH:17])=[NH:14])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[CH3:27][C:28]([CH3:30])=[O:29]>>[C:28]([OH:2])(=[O:29])[CH3:30].[CH3:27][C:28]1([CH3:30])[N:17]=[C:16]([NH:18][C:19]([CH3:25])([CH3:26])[CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[NH:15][C:13]([NH:12][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])=[N:14]1
Reactant: CCCCCCCNC(=N)NC(=N)NC(C)(C)CC(C)(C)C
Reactant: CC(C)=O
Reactant: CO
Agent: Cl
Product: CC(=O)O
Product: CCCCCCCNC1=NC(C)(C)N=C(NC(C)(C)CC(C)(C)C)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 2.9 ml of concentrated hydrochloric acid were added to 9.0 g (25.9 mmol) of N1-heptyl-N5- (1,1,3,3-tetramethylbutyl)-biguanide hydrochloride. The mixture was refluxed for 21 hours, and the solvent was distilled off under reduced pressure. To the residue were added 100 ml of ethanol, 60 ml of water and 10.6 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium acetate and water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from methyl ethyl ketone two times to obtain 8.3 g of colorless crystals having a melting point of 98 to 101° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:11]([OH:13])=[O:12])=[N:4][C:5]([CH2:8][O:9][CH3:10])=[N:6][CH:7]=1.[C:14]([O-])([O-])=O.[Cs+].[Cs+].CI>CC(C)=O>[CH3:14][O:12][C:11]([C:3]1[C:2]([Br:1])=[CH:7][N:6]=[C:5]([CH2:8][O:9][CH3:10])[N:4]=1)=[O:13]
Reactant: COCc1ncc(Br)c(C(=O)O)n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COCc1ncc(Br)c(C(=O)OC)n1
Yield: 26.5 %

Procedure:
To a solution of 5-bromo-2-methoxymethyl-pyrimidine-4-carboxylic acid (2.5 g, 10.1 mmol) in acetone (100 ml) was added Cs2CO3 (19.8 g, 60.7 mmol) followed by methyliodide (3.8 ml, 60.7 mmol). The mixture was heated to reflux for 8 h. The reaction mixture was then filtered, and the filtrate was evaporated. The crude material was purified by silica gel chromatography using a ethyl acetate/hexane eluent to yield 700 mg (27%) of the title compound as yellow oil.
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([Cl:19])=[C:14]([CH:18]=1)[C:15]([OH:17])=O)=[O:7])(C)(C)C.Cl[C:21](N(C)C)=[C:22]([CH3:24])[CH3:23].[NH2:28][C:29]1[CH:30]=[C:31]([F:39])[C:32]([F:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35].CC1C(O)=C(C=O)C(COP(O)(O)=O)=CN=1.O>C1COCC1>[Cl:19][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6]([C:22]([CH3:21])([CH3:23])[CH3:24])=[O:7])=[CH:18][C:14]=1[C:15]([NH:28][C:29]1[CH:30]=[C:31]([F:39])[C:32]([F:38])=[C:33]([CH:37]=1)[C:34]([OH:36])=[O:35])=[O:17]
Reactant: Nc1cc(F)c(F)c(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)c(C(=O)O)c1
Reactant: CC(C)=C(Cl)N(C)C
Agent: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cc(F)c(F)c(C(=O)O)c2)c1

Procedure:
Prepared analogously to example 8 with 5-(tert-butoxycarbonylamino)methyl-2-chloro benzoic acid (0.2 g; 0.75 mmol); 1-chloro-N,N,2-trimethylpropenylamine (0.124 mL; 0.9 mmol); 5-amino-2,3-difluorobenzoic acid (0.13 g; 0.75 mmol) and TEA (0.261 mL; 0.88 mmol) in 20 mL THF. Yield: 290 mg (91%); MS: [m+H]+ 425; HPLC: Rt=1.29 min (Method MC-1)
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9]C)=O.[F:11][C:12]([F:17])([F:16])[C:13](N)=[NH:14].FC(F)(F)C(O)=O>CCO>[F:11][C:12]([F:17])([F:16])[C:13]1[NH:14][C:7](=[O:9])[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:1]=1
Reactant: COC(=O)c1sccc1N
Reactant: N=C(N)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCO
Product: O=c1[nH]c(C(F)(F)F)nc2ccsc12
Temperature: 150 °C
Yield: 27.7 %

Procedure:
To a stirring solution of methyl 3-aminothiophene-2-carboxylate (45a, 1.57, 10.0 mmol) in EtOH (10 mL) was added trifluoroacetamidine (2.24 g, 2 eq) and trifluoroacetic acid (1.54 ml, 2 eq). The resulting mixture was heated to 150° C. for 1 hour in microwave reactor. The reaction mixture was cool and filtered to provide 2-(trifluoromethyl)thieno[3,2-d]pyrimidine-4(3H)-one 45b as a solid (0.61 g). 1H NMR (400 MHz, MeOD) δ ppm: 7.49 (d, J=5.29 Hz, 2 H), 8.18 (d, J=5.29 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].O.[F:18][C:19]([F:24])([F:23])[C:20](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20]([C:19]([F:24])([F:23])[F:18])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: O=C(O)C(F)(F)F
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Solvent: O
Product: N#Cc1ccccc1-c1ccc2[nH]c(C(F)(F)F)nc2c1
Temperature: 85 °C

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (0.01 moles, 2.09 g) was dissolved in 10 ml trifluoroacetic acid and heated at 85° C. for 16 hours. The solution was poured into water and extracted with ethyl acetate. The pH was adjusted to 3.0 using 5N NaOH. The ethyl acetate was washed with brine, dried over sodium sulfate, and concentrated. The residue was chromatographed on silica gel eluted with 25 % ethyl acetate in hexane. The reaction yielded 2.05 g of 5-(2-cyanophenyl)-2-trifluoromethyl-1H-benzimidazole. (MS)
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Cl:25][CH2:26][C:27]([NH:29][C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=[O:28]>CC#N>[Cl-:25].[C:19]1([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:7][CH2:8][N+:1]([CH2:26][C:27](=[O:28])[NH:29][C:30]5[N:35]=[CH:34][CH:33]=[CH:32][N:31]=5)([CH2:6][CH2:5]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(CCl)Nc1ncccn1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2ccccc2)CCCCCC1
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3ccccc3)CCCCCC1)C2)Nc1ncccn1
Product: [Cl-]

Procedure:
1-Phenyl-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl) ester (Example 14e, 0.30 mmol) and 2-chloro-N-pyrimidin-2-yl-acetamide (Example 50a) (0.36 mmol) in MeCN (1.5 mL) were stirred together at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue purified by silica gel chromatography eluting with 0-10% MeOH/dichloromethane to give the title compound as a white solid (90) mg).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.[N:19]12[CH2:26][CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:27])[CH2:20]2.[OH-].[Na+]>O.C(OCC)C>[CH3:18][O:17][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:21]1([OH:27])[CH:22]3[CH2:25][CH2:26][N:19]([CH2:24][CH2:23]3)[CH2:20]1)[CH:16]=[CH:15]2
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: O=C1CN2CCC1CC2
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: COc1ccc2cc(C3(O)CN4CCC3CC4)ccc2c1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Butyllithium (2.5 M, 1.86 ml, 4.64 mmol) was added to a mixture of 2-bromo-6-methoxynaphthalene (1.0 g, 4.22 mmol) and diethyl ether (10 ml) at 20° C. The temperature was kept below 35° C. for 30 min. The mixture was cooled to −70° C. and 3-quinuclidinone (0.53 g, 4.22 mmol) was added at −70° C. The mixture was stirred at −70° C. for 1 h. The mixture was allowed to reach room temperature. Water (1 ml) was added followed by aqueous sodium hydroxide (1 M, 10 ml). The crystalline product was filtered and was washed with cold diethyl ether (2 ml). Yield 0.49 g (41%). Mp >330° C.
Reaction SMILES: FC(F)(F)OC1C=CC(N2C(=O)C=CS2)=CC=1.[F:18][C:19]([F:35])([F:34])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH:30]=[C:29]([Cl:33])[S:28]2)=[CH:23][CH:22]=1.S(Cl)([Cl:39])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:35][C:19]([F:18])([F:34])[O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[C:30]([Cl:39])=[C:29]([Cl:33])[S:28]2)=[CH:23][CH:22]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(Cl)sn1-c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: O=c1ccsn1-c1ccc(OC(F)(F)F)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cl)c(Cl)sn1-c1ccc(OC(F)(F)F)cc1

Procedure:
First, a mixture containing 6.4 g of 2-(4-trifluoromethoxyphenyl)-4-iso-thiazolin-3-on and 5.1 g of 2-(4-trifluoromethoxyphenyl)-5-chloro-4-isothiazolin-3-on was suspended in 100 ml of dichloromethane, after which 19 g of sulfuryl chloride was then added dropwise to the suspension at room temperature, and the resultant mixture was stirred for 12 hours. After completion of the reaction, 200 ml of a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the dichloromethane layer was separated. The aqueous layer was extracted with 150 ml of dichloromethane. The combined dichloromethane layer was washed with water, dried with magnesium sulfate, and concentrated. The concentrate was purified by column chromatography (hexane: ethyl acetate=6:1) to give 4 a of 2-(4-trifluoromethoxyphenyl)-4,5-dichloro-4-isothiazolin-3-on (compound (13); m.p., 129-130° C.).
Reaction SMILES: [SH2:1].[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17]#[N:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1>N1C=CC=CC=1.C(N(CC)CC)C>[Cl:2][C:3]1[C:8]2[C:9](=[O:20])[N:10]([CH3:19])[CH2:11][C:12]3[N:13]([CH:14]=[N:15][C:16]=3[C:17](=[S:1])[NH2:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CN1Cc2c(C#N)ncn2-c2cccc(Cl)c2C1=O
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN1Cc2c(C(N)=S)ncn2-c2cccc(Cl)c2C1=O
Reaction time: 64 h
Yield: 87 %

Procedure:
A stream of hydrogen sulphide was conducted for 1 hr. through a solution of 9.64 g (0.354 mol) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carbonitrile in 210 ml of pyridine and 2.1 ml of triethylamine. The green solution was left to stand for 64 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The solid residue was partitioned between dichloromethane and water and the suspension obtained was suction filtered. There were obtained 9.41 g (87%) of 7-chloro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-thiocarboxamide as yellow crystals. An analytical sample was obtained from the organic phase after recrystallization in methanol. Yellow crystals; m.p. 300°-302°.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=1)=[O:4].[NH2:27][C:28]([CH3:41])([CH3:40])[CH2:29][NH:30][C:31](=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1.CCOCC>[BrH:1].[CH3:41][C:28]([NH:27][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:6]=1)=[O:4])([CH3:40])[CH2:29][NH:30][C:31](=[O:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: CC(C)(N)CNC(=O)Cc1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Br
Product: CC(C)(CNC(=O)Cc1ccccc1)NCC(=O)c1ccc(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
A solution of 2-bromo-3',4'-bis(benzyloxy)acetophenone (5.24 g.) and N-(2-amino-2-methylpropyl)-2-phenylacetamide (5.5 g.) in dioxan (25 ml.) was stirred for 2 hours at room temperature. The reaction mixture was diluted with dry ether (200 ml.) and the precipitate of N-(2-amino-2-methylpropyl)-2-phenylacetamide hydrobromide was separated by filtration. The ethereal filtrate was washed with water (3×50 ml.), brine (100 ml.) dried (MgSO4) and then a fresh solution of saturated ethereal hydrogen bromide was added until the solution was just acid. After 18 hours at 0°-5° C. the precipitate which had formed was collected to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-bis(benzyloxy)acetophenone hydrobromide as a solid (6.85 g.) m.p. 155°-160° C. This hydrobromide (5.0 g.) was dissolved in absolute ethanol (300 ml.) and the solution was hydrogenated at atmospheric pressure using 10% w/w palladium-on-carbon (3.0 g.) as catalyst. When the uptake of hydrogen was complete (about 3 hours), the catalyst was removed by filtration and the ethanolic filtrate was evaporated at a temperature below 30° C. to give 2-[1,1-dimethyl-2-(2-phenylacetamido)ethyl]amino-3',4'-dihydroxyacetophenone hydrobromide as a foam (3.7 g.) which was used directly for further acylation.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][C@@H:16]([OH:18])[C@@H:15]1[CH3:19])([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.I[CH3:21].[H-].[Na+].O>C1COCC1>[CH:1]([N:14]1[CH2:17][C@@H:16]([O:18][CH3:21])[C@@H:15]1[CH3:19])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(c2ccccc2)c2ccccc2)[C@H]1C
Reaction time: 1.5 h

Procedure:
To a solution of racemic-(trans)-1-benzhydryl-2-methylazetidin-3-ol (0.198 g, 0.782 mmol) in THF (16 mL) was added iodomethane (98 μL, 1.6 mmol) and sodium hydride (0.035 g, 0.86 mmol, 60% in mineral oil). After 1.5 h, water was added and the mixture was extracted with EtOAc (3×). The combined organic phases were washed with brine, dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified via FCC (0-15% EtOAc/n-heptanes) to give the title compound. MS (ESI+) m/z 268.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:17]=[C:16]([CH3:26])[CH:15]=3)=[O:12])=[C:4]2[N:3]=1.[OH-].[NH4+:28]>>[NH2:28][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:13][C:14]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:17]=[C:16]([CH3:26])[CH:15]=3)=[O:12])=[C:4]2[N:3]=1
Reactant: Cc1cc(NC(=O)c2cnn3ccc(Cl)nc23)n(-c2cccc(Cl)c2)n1
Reactant: [NH4+]
Agent: [OH-]
Product: Cc1cc(NC(=O)c2cnn3ccc(N)nc23)n(-c2cccc(Cl)c2)n1
Temperature: 105 °C
Yield: 48 %

Procedure:
A mixture of 74% pure 5-chloro-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (55 mg, 0.14 mM, 1.0 equiv) and 3 mL of concentrated ammonium hydroxide was sealed and heated in a microwave reactor at 105° C. for 30 minutes. The reaction mixture was cooled and the precipitated product collected by filtration to give 25 mg (48%) of 5-amino-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was purified by reverse phase chromatography on C-18 with acetonitrile/water (0 to 60 gradient, 0.1% TFA) and lyophilized. LCMS (ESI) m+H=368.3 (one chlorine isotope pattern), 1H NMR (400 MHz, DMSO-d6) δ: 9.94 (s, 1H), 8.66 (d, 1H), 8.20 (s, 1H) 7.67 (s, 1H), 7.57 (d, 1H), 7.49 (dd, 1H), 7.44 (d, 1H), 6.89 (br s, 1H), 6.40 (overlapping d and s, 2H), 2.26 (s, 3H).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6](CC)[C:7]([O:9][CH2:10]C)=[O:8])(=O)[CH3:2].[CH2:14](S)[C:15]1C=C[CH:18]=[CH:17][CH:16]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O.C1C[O:44][CH2:43]C1>>[CH2:1]([S:4][CH2:5][CH:6]([O:44][CH3:43])[C:7]([O:9][CH3:10])=[O:8])[C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(CC)CSC(C)=O
Reactant: C1CCOC1
Reactant: SCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COC(=O)C(CSCc1ccccc1)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the propenoate of Step 1 (26.93 g, 0.23 mmol) in THF (20 mL) at 0° C. was added benzyl mercaptan (23.0 mL, 0.23 mol) followed by 1M THF solution of Bu4NF (20 mL). The mixture was stirred at room temperature for 1 hour. The reaction was poured into H2O and extracted with EtOAc, washed with brine, dried and concentrated to yield the title compound. Although the material is essentially pure it can be distilled under vacuum, b.p. 115°-130° C./1 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:3]=1[C:4](OC1C=CC=CC=1)=O.[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27]([O:29][CH3:30])=[O:28])[N:26]=1.CO>C1(C)C(C)=CC=CC=1>[CH3:30][O:29][C:27]([C:25]1[N:26]=[C:22]([NH:21][CH2:4][C:3]2[CH:13]=[C:14]([O:19][CH3:20])[C:15]([O:17][CH3:18])=[CH:16][C:2]=2[OH:1])[S:23][CH:24]=1)=[O:28]
Reactant: COC(=O)c1csc(N)n1
Reactant: COc1cc(O)c(C(=O)Oc2ccccc2)cc1OC
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(=O)c1csc(NCc2cc(OC)c(OC)cc2O)n1
Temperature: 140 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
In 250 mg of xylene were suspended 250 mg of phenyl 2-hydroxy-4,5-dimethoxybenzoate (3a) and 144 mg of methyl 2-amino-1,3-thiazole-4-carboxylate (4a) in a stream of argon, which was then heated to reflux (at 140° C.) for 7 hours. The reaction was not completed. After cooling, methanol was added, followed by stirring for one hour. The precipitated crystal was collected by filtration and dried under reduced pressure at 60° C. to provide 170 mg of the same compound (5a) as that of Example 4 at a yield of 55%.
Reaction SMILES: [NH2:1][C:2](=[S:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH:10]1[C:15]([C:16]([CH2:18]Br)=O)=[CH:14][CH:13]=[C:12]([F:20])[CH:11]=1.[CH3:21]CO>>[F:20][C:12]1[CH:13]=[CH:14][C:15]([C:16]2[N:1]=[C:2]([CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:21])=[O:6])[S:9][CH:18]=2)=[CH:10][CH:11]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COC(=O)CCC(N)=S
Reactant: CCO
Product: CCOC(=O)CCc1nc(-c2ccc(F)cc2)cs1
Temperature: 25 °C
Yield: 7 %

Procedure:
A mixture of methyl 4-amino-4-thioxobutanoate (0.3 g, 2.03 mmol) and 2-bromo-4-fluoroacetophenone (0.440 g, 2.03 mmol) in EtOH (10 mL) was refluxed for 3 h. The reaction mixture was cooled to room temperature and solvent was removed under reduced pressure. The organic product was extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel 60-120 mesh, eluent 8-10% EtOAc in petroleum ether) to afford ethyl 3-(4-(4-fluorophenyl)thiazol-2-yl)propanoate (0.45 g, crude containing 7% of methyl ester product), which was carried through without further purification. 1H NMR (300 MHz, CDCl3) δ 7.88-7.83 (m, 2H), 7.28 (s, 1H), 7.13-7.07 (t, J=8.8 Hz, 2H), 4.22-4.15 (q, J=7.0 Hz, 2H), 3.40-3.35 (t, J=7.3 Hz, 2H), 2.93-2.88 (t, J=7.3 Hz, 2H), 1.30-1.25 (t, J=7.1 Hz, 3H). MS (ESI) m/z: Calculated for C14H14FNO2S: 279.07. found: 280.2 (M+H)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([NH2:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([O:21]CC)=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>C(Cl)(Cl)Cl.CS(C)=O>[C:24]([O:28][C:29]([N:31]1[CH2:35][CH2:34][CH:33]([O:36][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([NH2:17])[C:10]=2[F:16])[CH2:32]1)=[O:30])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(N)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a mixture of 277 mg of ethyl 1-cyclopropyl-5-amino-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 318 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 194 mg of DBU and 3 ml of DMSO was added 74 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, the reaction mixture was diluted with chloroform and then successively washed with 10% citric acid and saturated saline. The organic layer was dried over anhydrous sodium sulfate and then concentrated to dryness. The residue was recrystallized from ethanol, whereby 120 mg of 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-5-amino-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid was obtained.
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[CH2:19]([C@H:21]1[CH2:26][NH:25][C@H:24]([CH3:27])[CH2:23][N:22]1[CH2:28][C:29]([OH:31])=[O:30])[CH3:20]>C(Cl)Cl>[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[C:4]([O:3][C:1]([N:25]1[CH2:26][C@H:21]([CH2:19][CH3:20])[N:22]([CH2:28][C:29]([OH:31])=[O:30])[CH2:23][C@H:24]1[CH3:27])=[O:8])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC[C@H]1CN[C@H](C)CN1CC(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 102.1 %

Procedure:
tert-Butyl dicarbonate (2.1 g, 9.6 mmol) and triethylamine (6.7 mL, 48.4 mmol) were added to a suspension of ((2S,5R)-2-ethyl-5-methyl-piperazin-1-yl)-acetic acid (1.8 g, 9.6 mmol) in DCM. The resulting solution was stirred at room temperature for 24 h. The solvent was removed in vacuo to give (2R,5S)-4-carboxymethyl-5-ethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester triethylamine salt (3.8 g) as a yellow gum. 1H NMR (CDCl3): 11.73-9.75 (1H, m), 4.20 (1H, s), 3.86 (1H, d), 3.34-3.07 (3H, m), 2.97 (6H, q, triethylamine), 2.77-2.65 (2H, m), 2.60 (1H, dd), 1.47-1.36 (11H, m), 1.26 (3H, d), 1.24-1.14 (9H, m, triethylamine), 0.87 (3H, t).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]=[C:8]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:7]=1)[CH2:2][CH:3]=[CH2:4].C(N(CC)CC)C.[C:29](Cl)(=[O:38])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:31]([O:30][C:29]([N:19]1[CH2:20][CH2:21][N:16]([C:8]2[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH:3]=[CH2:4])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH2:17][CH2:18]1)=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: C=CCCOc1nc(N2CCNCC2)nc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCCOc1nc(N2CCN(C(=O)OCc3ccccc3)CC2)nc2ccccc12

Procedure:
To a solution of 4-[(3-buten-1-yl)oxy]-2-(1-piperazinyl)quinazoline (23.3 g) in dry methylene chloride (200 ml) is added triethylamine (22.9 ml) with stirring under ice-cooling, and thereto is further added dropwise a solution of benzyl chlorocarbonate (12.3 ml) in dry methylene chloride (30 ml). The mixture is stirred under ice-cooling for 5 hours. The reaction mixture is diluted with chloroform, washed with water, and dried over anhydrous magnesium sulfate. The solution is evaporated to dryness under reduced pressure, and the residue is purified by medium pressure liquid column chromatography (eluent, chloroform) to give 2-[4-(benzyloxycarbonyl) piperazin-1-yl]-4-[(3-buten-1-yl)oxy]quinazoline (26.7 g) as crystals.