Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:18]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=2[CH3:27])=[C:17]([F:28])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[C:7]=2[CH:6]=1)=[O:4].CO.[OH-].[Na+]>C1COCC1>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:18]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH:10]=[N:9][C:8]=3[C:17]=2[F:28])=[C:21]([CH3:27])[CH:22]=1
Reactant: C=CCCCn1cnc2c(F)c(Nc3ccc(Br)cc3C)c(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCn1cnc2c(F)c(Nc3ccc(Br)cc3C)c(C(=O)O)cc21
Reaction time: 5 h
Yield: 100 %

Procedure:
6-(4-Bromo-2-methyl-phenylamino)-7-fluoro-3-pent-4-enyl-3H-benzoimidazole-5-carboxylic acid methyl ester 9b is dissolved in 1:1 THF:MeOH (10 mL) and 1 N NaOH solution (2.3 mL) is added. After 5 h, the organic solvents are removed under reduced pressure and the residue diluted with water and 100 mL 1:1 THF:ethyl acetate. The layers are separated and the aqueous layer extracted with ethyl acetate. The combined organic extracts are dried (Na2SO4) and concentrated under reduced pressure to afford 0.39 g (100%) clean desired product as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]([CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH2:6][CH3:7])=O.[C:11]1([NH:17][NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([NH:17][N:18]=[C:3]([O:5][CH2:6][CH3:7])[C:2](=[O:1])[CH:8]([CH3:10])[CH3:9])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C(=O)C(C)C
Solvent: Cc1ccccc1
Product: CCOC(=NNc1ccccc1)C(=O)C(C)C

Procedure:
A mixture of ethyl 2-oxo-3-methylbutanoate (23.76 g) and phenylhydrazine (25 ml) was heated at 60° C. in toluene for about one hour, during which time a slight vacuum was used in order to remove the water. After removing the solvent, the residue was chromatographed on silica gel, using a 4/1 petroleum ether/ethyl acetate mixture as eluent, in order to give the desired product in the form of a yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:24])[N:10]([O:25]CC2C=CC=CC=2)[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[Pd]>[CH2:1]([N:8]1[C:13]2[N:14]=[C:15]([N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[C:16]([F:18])=[CH:17][C:12]=2[C:11](=[O:24])[N:10]([OH:25])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=c1c2cc(F)c(N3CCCC3)nc2n(Cc2ccccc2)c(=O)n1O

Procedure:
Following the procedure of Example 32, hydrogenation of 1-benzyl-3-benzyloxy-6-fluoro-7-pyrrolidin-1-yl-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example A-3, 110 mg, 0.247 mmol) and 10% Pd/C (15 mg) in MeOH (2 mL) and ethyl acetate (3 mL) afforded 67 mg, of the title compound as a solid, mp 219-220° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:4]([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1.Cl.[NH2:24][OH:25].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[N:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[C:4]([C:7](=[N:24][OH:25])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: Cc1ccccc1-n1c(C)nnc1C(=O)Cc1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-n1c(C)nnc1C(Cc1ccccc1)=NO

Procedure:
To a suspension of 10D and hydroxylamine hydrochloride (420 mg, 6 mmol) in ethanol (5 mL), sodium hydroxide (480 mg, 12 mmol) was added. It was refluxed for two hours. The reaction was acidified with 1 N hydrochloride and extracted with ethyl acetate (50 mL twice). The organic layer was dried with Na2SO4, filtered and concentrated. The crude product was purified by flash column) to provide the desired product. MS (m/z) 307 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[Cl:8][C:5]1[S:4][C:3]([NH:2][C:16](=[O:17])[O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Cl)s1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (1.00 g, 5.80 mmol) was dissolved in methylene chloride (50 mL), and the obtained solution was then washed with a saturated aqueous solution of sodium hydrogen carbonate. The resulting solution was dried over anhydrous sodium sulfate and was then filtered. After that, pyridine (0.47 mL, 5.80 mmol) and 4-nitrophenyl chloroformate (1.18 g, 5.80 mmol) were added to the filtrate, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a solid was collected by filtration, was then washed with methylene chloride, and was then dried to obtain 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (980 mg, 56%) in the form of a white solid. t-Butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (65.1 mg, 0.184 mmol) synthesized by a method described in the known method (International Publication WO2009/089454) or a method similar thereto was dissolved in N,N′-dimethylformamide (2 mL). Thereafter, 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (55.2 mg, 0.184 mmol) and triethylamine (13 μL, 0.092 mmol) were added to the above obtained solution, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the captioned compound (60.0 mg, 64%) in the form of a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15](O)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:60][CH:61]1[CH2:66][CH2:65][CH:64]([NH2:67])[CH2:63][CH2:62]1>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([C:15]([NH:67][CH:64]3[CH2:65][CH2:66][CH:61]([CH3:60])[CH2:62][CH2:63]3)=[O:16])[CH2:9]2)[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[C:20]([F:26])[CH:19]=2)[N:3]=1
Reactant: CC1CCC(N)CC1
Reactant: C[C@@H]1CC[C@H](C(=O)O)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CCC(NC(=O)[C@H]2CC[C@@H](C)N(c3cc(-c4ccc(C#N)c(F)c4)nc(N)n3)C2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 89.2 %

Procedure:
To a solution of (3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinecarboxylic acid (170 mg, 0.478 mmol) and HATU (218 mg, 0.574 mmol) in DMF (3 mL) was added Hunig's base (0.167 mL, 0.957 mmol), and the mixture was stirred at room temperature for 5 minutes. Then 4-methylcyclohexanamine (54.2 mg, 0.478 mmol) was added, and the mixture was stirred at room temperature for 0.5 hours. LCMS showed reaction was completed. The reaction was poured onto water, and the formed solid was filtered, washed by water, and dried to give the yellow title compound (192 mg). LC-MS (ES) m/z=451 [M+H]+.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.O1CCCC1.[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=1[NH2:19]>O>[F:16][C:17]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=1[NH:19][C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2o1
Reactant: Nc1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: O
Product: Fc1ccc(Nc2nc3ccccc3o2)c(F)c1
Temperature: 25 °C

Procedure:
To a solution of 15.4 g. (0.1 mole) of 2-chlorobenzoxazole in 200 ml. of tetrahydrofuran was added dropwise a solution of 12.9 g. (0.1 mole) of 2,4-difluoroaniline in 100 ml. of tetrahydrofuran with vigorous agitation. Following the addition, the reaction mixture was heated on a steam bath under reflux for 16 hours. The reaction mixture was cooled to about 25° C., and about 500 ml. of water added thereto. The tetrahydrofuran solvent was removed by distillation under vacuum. The precipitate which formed in the aqueous medium was removed by filtration and dried. The dried precipitate was dissolved in a minimum amount of warm benzene. About 200 ml. of hexane was added to the benzene solution to effect crystallization of the reaction product. The precipitate was filtered off and dried, yielding 18.3 g. of 2-(2,4-difluoroaniline)benzoxazole having a melting point of 115°-117° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:10]2[C:14](=[O:15])[CH2:13][CH:12]([C:16](N(OC)C)=[O:17])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:22]1([Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[NH4+].[Cl-]>C1COCC1>[C:16]([CH:12]1[CH2:11][N:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=2)[C:14](=[O:15])[CH2:13]1)(=[O:17])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1ccc(N2CC(C(=O)N(C)OC)CC2=O)cc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(N2CC(C(=O)c3ccccc3)CC2=O)cc1F
Temperature: 50 °C

Procedure:
To a solution of 1-(3-fluoro-4-methoxyphenyl)-N-methoxy-N-methyl-5-oxopyrrolidine-3-carboxamide (Step 1, 2 g, 6.75 mmol) in 30 mL of THF was added 2 M phenylmagnesium chloride in THF (6.75 mL) via syringe at RT. The solution was heated to 50° C. for 2 h. The solution was poured to 50 mL of satd. NH4Cl aq. soln. The resulting mixture was extracted with 100 mL of EtOAc. The organic phase was washed with 50 mL of brine, dried over Na2SO4 and concentrated in vacuo. The crude was purified by a silica gel column chromatography (10% to 80% EtOAc/hexane) to give white solid. MS (ESI pos. ion) m/z: 314.2 (M+H). Calc'd Exact Mass for C18H16FNO3: 313.32.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:8]#[N:9])=[N:4][CH:5]=[CH:6][N:7]=1.[Cl:10][C:11]1[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](N)=[NH:18])=[CH:13][CH:12]=1.CN(C)C=O>C(O)C>[NH2:9][C:8]1[C:3]2[C:2](=[N:7][CH:6]=[CH:5][N:4]=2)[N:1]=[C:17]([CH2:16][O:15][C:14]2[CH:20]=[CH:21][C:11]([Cl:10])=[CH:12][CH:13]=2)[N:18]=1
Reactant: N=C(N)COc1ccc(Cl)cc1
Reactant: N#Cc1nccnc1N
Solvent: CCO
Solvent: CN(C)C=O
Product: Nc1nc(COc2ccc(Cl)cc2)nc2nccnc12

Procedure:
Obtained using the procedure described in section c of Example 2, starting with 10.7 g (0.089 mole) of 3-amino-2-pyrazinecarbonitrile and 24.5 g (0.133 mole) of 2-(4-chlorophenoxy)acetamidine [prepared according to C. Djerassi and C. R. Scholz, U.S. Pat. No. 2,517,468; C.A. 1951, 45, 661f] in 320 ml of absolute ethanol. Refluxing time: 7 hours. Yld: 21.5 g (84%), m.p. 246°-248° C. (N,N-dimethylformamide).
Reaction SMILES: O.[NH2:2][C:3]1[C:4](=[O:13])[N:5]([CH3:12])[C:6](=[O:11])[N:7]([CH3:10])[C:8]=1[NH2:9].[CH:14]([C:16]1[CH:26]=[CH:25][C:19]([CH:20]=[CH:21][C:22]([OH:24])=[O:23])=[CH:18][CH:17]=1)=O>[N+](C1C=CC=CC=1)([O-])=O>[CH3:12][N:5]1[C:4](=[O:13])[C:3]2[N:2]=[C:14]([C:16]3[CH:26]=[CH:25][C:19](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[NH:9][C:8]=2[N:7]([CH3:10])[C:6]1=[O:11]
Reactant: O=Cc1ccc(C=CC(=O)O)cc1
Reactant: Cn1c(N)c(N)c(=O)n(C)c1=O
Solvent: O=[N+]([O-])c1ccccc1
Solvent: O
Product: Cn1c(=O)c2nc(-c3ccc(/C=C/C(=O)O)cc3)[nH]c2n(C)c1=O

Procedure:
5,6-Diamino-1,3-dimethyluracil hydrate (5.11 g, 30.0 mmol) and 4-formylcinnamic acid (5.29 g, 30.0 mmol) were refluxed in nitrobenzene (500 mL). The nitrobenzene was allowed to distill slowly with water formed. Fresh nitrobenzene was added to keep the volume constant. After 5 hours of reflux, the mixture was cooled and the precipitate collected (8.07 g). Recrystallization from N,N-dimethylformamide-water gave the monohydrate of the title compound as a pale yellow powder, identical with that of Example 1 by 1H-NMR and elemental analysis.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]2[C:8](=[O:16])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:3].[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](N)[N:26]=[CH:25][N:24]=1.C(N(C(C)C)CC)(C)C>C(O)CCC>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:1][CH:2]([C:4]2[N:5]=[C:6]3[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[N:7]3[C:8](=[O:16])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:3])[N:26]=[CH:25][N:24]=1
Reactant: Cc1cccc2nc(C(C)N)c(-c3ccccc3)c(=O)n12
Reactant: N#Cc1c(N)ncnc1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2nc(C(C)Nc3ncnc(N)c3C#N)c(-c3ccccc3)c(=O)n12
Temperature: 120 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(1-aminoethyl)-6-methyl-3-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one (0.178 g, 0.637 mmol) and 4,6-diaminopyrimidine-5-carbonitrile (0.090 g, 0.67 mmol) in butan-1-ol (4 mL) was added diisopropylethyl amine (0.33 mL, 1.91 mmol). After stirring at 120° C. for 3 h, the solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-8% MeOH in DCM) to afford 4-amino-6-(1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethylamino)pyrimidine-5-carbonitrile as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.27 (d, J=6.65 Hz, 3 H) 2.91 (s, 3 H) 5.09 (quin, J=6.85 Hz, 1 H) 6.97 (d, J=7.04 Hz, 1 H) 7.03 (d, J=7.24 Hz, 1 H) 7.32 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.72 (dd, J=8.80, 6.85 Hz, 1 H) 7.98 (s, 1 H) Mass Spectrum (ESI) m/e=398.1 (M+1). The racemic mixture (0.210 g) was separated by chiral separation using SFC to give 2 fractions. First-eluting enantiomer on AD-H column: 4-amino-6-(((1S)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.26 (d, 3 H) 2.90 (s, 3 H) 5.09 (qd, J=6.89, 6.72 Hz, 1 H) 6.97 (d, J=6.85 Hz, 1 H) 7.04 (d, J=7.34 Hz, 1 H) 7.33 (br. s., 2 H) 7.35-7.50 (m, 6 H) 7.71 (dd, J=8.93, 6.97 Hz, 1 H) 7.97 (s, 1H) Mass Spectrum (ESI) m/e=398.1 (M+1). Second-eluting enantiomer on AD-H column: Concentration of product fractions gave a solid that was triturated in water and filtered to afford 4-amino-6-(((1R)-1-(6-methyl-4-oxo-3-phenyl-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a light yellow solid. Mass Spectrum (ESI) m/e=398.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH3:14])([CH3:13])[C:6]=2[CH:15]=1.[C:16]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[C:22]([F:24])[CH:23]=1)#[N:17]>>[CH3:13][C:7]1([CH3:14])[C:6]2[CH:15]=[C:2]([C:20]3[CH:19]=[C:18]([CH:23]=[C:22]([F:24])[CH:21]=3)[C:16]#[N:17])[CH:3]=[CH:4][C:5]=2[NH:11][C:10](=[O:12])[CH2:9][O:8]1
Reactant: CC1(C)OCC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cc(F)cc(B(O)O)c1
Product: CC1(C)OCC(=O)Nc2ccc(-c3cc(F)cc(C#N)c3)cc21

Procedure:
Prepared from 7-bromo-5,5-dimethyl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-cyano-5-fluorophenyl boronic acid generally according to the coupling procedure described in example 1. A white solid: mp 238-239° C.; 1H NMR (DMSO-d6): δ 10.1 (s, 1H), 8.14 (t, J=1.5 Hz, 1H), 7.98 (m, 1H), 7.80 (m, 1H), 7.69 (d, J=1.9 Hz, 1H), 7.64 (dd, J=8.3, 2.0 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 4.27 (s, 2H), 1.63 (s, 6H). MS m/z 309 ([M−H]−); Anal. calcd for C18H15FN2O2: C, 69.67; H, 4.87; N, 9.03. Found: C, 69.51; H, 4.63; N, 9.07
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)=[S:3].Br[CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:21]1([C:19]2[N:1]=[C:2]([CH:4]3[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]3)[S:3][CH:18]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(-c3ccccc3)cs2)CC1
Temperature: 110 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of tert-butyl 4-(aminocarbonothioyl)piperidine-1-carboxylate (1.00 g, 7.24 mmol), 2-bromoacetophenone (1.58 g, 7.96 mmol), potassium carbonate (1.00 g, 7.24 mmol) and N,N-dimethylformamide (30 ml) was stirred at 110° C. for 1.5 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:1) to obtain the desired product (1.38 g, 55.2%) as an oil.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3](OC)=[O:4].[C:11]1([NH2:18])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH2:17]>CO>[O:4]=[C:3]1[NH:18][C:11]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:17]=[C:2]1[CH2:1][C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: Nc1ccccc1N
Solvent: CO
Product: COC(=O)Cc1nc2ccccc2[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dimethyl acetylenedicarboxylate (31.2 g., 0.22 mol.) was added slowly to a solution of o-phenylenediamine (21.6 g., 0.2 mol.) in methanol (400 ml.). The reaction mixture was stirred at room temperature for three hours and then cooled in an ice bath. The yellow solid was collected and washed with cold methanol. The solid was recrystallized from tetrahydrofuran (27.7 g., m.p. 230°-232° dec.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Cl:15][CH:16]([Cl:20])[C:17](Cl)=O.Cl>>[Cl:15][CH:16]([Cl:20])[C:17]1[O:5][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([F:12])([F:13])[F:14])[C:2]=2[N:1]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: Nc1c(C(=O)O)cccc1C(F)(F)F
Agent: Cl
Product: O=c1oc(C(Cl)Cl)nc2c(C(F)(F)F)cccc12
Temperature: 50 °C
Yield: 94 %

Procedure:
A mixture of 17.44 g of 2-amino-3-trifluoromethylbenzoic acid prepared by the process of J. Med. Chem., Vol. 16 (2) (1973), p. 101-106 and 34.63 g of dichloroacetyl chloride was progressively heated with stirring and at about 50° C., a hardening of the mass with rapid gas evolution of regular hydrogen chloride occured for one hour. Towards 100° C., one observed a fluidization of the reaction mixture, an intensification of hydrogen chloride evolution and an increase in the temperature of 127° C. The heating was continued until hydrogen chloride evolution ceased to obtain a brown solution which was cooled in an ice bath with stirring. The mixture was vacuum filtered and the product was empasted with ether, then with methanol and was washed with methanol to obtain 23.82 g of 2-dichloromethyl-8-trifluoromethyl-4H-3,1-benzoxazine-4-one melting at 179° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[CH:25]=O)=[CH:19][C:17]=2[CH:18]=1.[O:27]1[CH2:31][C:30](=[O:32])[NH:29][C:28]1=[O:33]>>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][C:14]1[O:15][C:16]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][CH:25]=[C:31]3[O:27][C:28](=[O:33])[NH:29][C:30]3=[O:32])=[CH:19][C:17]=2[CH:18]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(/C=C/C=O)ccc2o1
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(C=CC=C3OC(=O)NC3=O)ccc2o1
Yield: 44 %

Procedure:
In substantially the same manner as in Example 1, (E)-3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]acrolein was allowed to react with 2,4-oxazolidinedione to give 5-[3-[2-(5-methyl-2-phenyl-4-oxazolylmethyl)benzofuran-5-yl]-2-propenylidene]-2,4-oxazolidinedione. The yield was 44%. Recrystallization from dichloromethane-methanol gave pale yellow needles, m.p.237-239° C.
Reaction SMILES: [NH2:1][O:2][CH2:3]CCC(O)=O.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1>>[NH2:1][O:2][CH2:3][CH2:12][CH2:11][CH2:10][C:9]([OH:13])=[O:14]
Reactant: NOCCCC(=O)O
Reactant: O=C1CCCO1
Product: NOCCCCC(=O)O

Procedure:
5-Aminooxyvaleric acid is prepared in the same manner using the procedure of Preparation 6 for 4-aminooxybutyric acid except that the γ-butyrolactone is replaced by σ-valerolactone.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH:17]=1)[C:11]([CH3:30])=[CH:10]2.CN(C)[CH:33]=[O:34]>>[F:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:20][CH:21]=1)[C:11]([CH3:30])=[C:10]2[CH:33]=[O:34]
Reactant: Cc1cc2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1c(C=O)c2cc(F)ccc2n1-c1ccc(OCc2ccccc2)cc1
Yield: 85 %

Procedure:
Phosphorous oxychloride (5 mL) was added to anhydrous dimethylformamide (10 mL) and the mixture allowed to stir at room temperature for 15 min whereupon a solution of 5-fluoro-1-(4-benzyloxyphenyl)-2-methyl-1H-indole (1.63 g, 4.9 mmol) in dimethylformamide (10 mL) was added and reacted according to the procedure used in Example 2a to afford a tan solid (85%): mp 219-220° C.; 1H NMR (DMSO-d6): δ 2.53 (3H, s), 5.22 (2H, s), 6.99-7.06 (2H, m), 7.27 (2H, d, J=8.9 Hz), 7.37-7.53 (7H, m), 7.86 (1H, dd, J=2.5 Hz, J=9.5 Hz); MS m/z (M+H)+ 360. Anal. for C23H18FNO2·0.5H2O: Calc'd: C, 74.99; H, 5.20; N, 3.80. Found: C, 74.91; H, 4.96; N, 3.59.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Li+].C(O)C.Cl>O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:20]3[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]4[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:36])=[O:3])=[CH:14][CH:13]=4)[N:19]=3)=[CH:25][CH:26]=2)[CH:31]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4cccnc4)cc3)oc2C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3cccnc3)cc2)nc1CCOc1ccc(OC(C)(C)C(=O)O)cc1

Procedure:
To a 20 mL round-bottomed flask equipped for magnetic stirring and fitted with a reflux condenser was added 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (0.268 mmoles), lithium hydroxide (0.535 mmoles, 0.268 mL of a 2N solution), and ethanol (5 mL). This solution was heated to reflux for 2 h. Distilled water was added to the mixture and the pH was adjusted to 3 using a 1N HCl solution. The organic layer was extracted with ethyl acetate, washed with brine, and concentrated in-vacuo. This crude oil was re-solvated in pure ethyl acetate and filtered over a pad of Celite. The filtrate was concentrated in-vacuo, and the crude oil was crystallized using acetonitrile. The crystals were collected and dried in-vacuo affording 2-(4-{2-[2-(4-pyrid-3-yl-phenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid. 1H NMR (400 MHz, CDCl3) 8.91 (1H, m), 8.61 (1H, m), 8.08 (2H, m), 7.94 (1H, m), 7.64 (2H, d), 7.45 (1H, m), 7.38 (1H, m), 6.91 (2H, m), 6.78 (2H, m), 4.20 (2H, t), 3.00 (2H, t) 2.39 (3H, s), 1.54 (6H, s).