Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9].O.Cl>C(OCC)C>[Br:5][C:6]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:7]=1[CH:8]([OH:9])[CH2:1][CH3:2]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CC[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCC(O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Add ethylmagnesium bromide (1 M in ether, 8.37 mL, 8.37 mmol) at 0° C. under nitrogen to a solution of 2-bromo-4-fluorobenzaldehyde (1 g, 4.93 mmol) in diethyl ether (15 mL). Stir the mixture for 1 h at RT. Add water slowly followed by adjusting the mixture to acidic conditions with 2 M HCl. Extract the product with chloroform/IPA (3/1). Dry over sodium sulfate. Concentrate the solution in vacuo to a yellow oil. Purify by column chromatography (30% ethyl acetate in hexane) to give the title compound as a colorless oil (1.1 g, 96%). 1H NMR (400 MHz, CD3Cl) δ 0.99 (t, J=7.2 Hz, 3H), 1.75 (m, 2H), 4.99 (m, 1H), 7.03 (m, 1H), 7.25 (m, 1H), 7.53 (m, 1H).
Reaction SMILES: [NH2-].[Na+].C1(C)C=CC=CC=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[N:19])=[CH:13][CH:12]=1.Cl[C:21]1[S:22][CH:23]=[CH:24][N:25]=1>O>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[C:18]#[N:19])=[CH:13][CH:12]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: Clc1nccs1
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: N#CC(c1ccc(Cl)cc1)c1nccs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
At 0°-5° C add a suspension of 28.5 g. of sodamide in 300 ml. of toluene to a stirred solution containing 50 g. of p-chlorphenylacetonitrile and 40 g. of 2-chlorothiazole in 400 ml. of toluene. Maintain the temperature at 20° C for 2 hrs. and finally at 60° C for 1 hr. Consecutively add 100 ml. of water and 35 ml. of acetic acid at 0°-10° C and filter the resulting mixture. Separate the toluene layer, concentrate in vacuo and distill the residue to give α-(p-chlorphenyl)-2-thiazolylacetonitrile as a mobile yellow oil, b.p. 155°-160° C/1 mm.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]=[O:14].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C1COCC1.CCOC(C)=O>[Cl:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([S:16]([CH3:15])(=[O:18])=[O:17])[CH:8]=[C:7]2[CH:13]=[O:14]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)n1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C
Yield: 58.5 %

Procedure:
NaH (0.36 gm, 12.6 mmol) was added to a solution of 2.26 gm (12.6 mmol) 5-chloro-1H-indole-3-carbaldehyde in THF cooled in an ice water bath After 20 m stirring, 1.4 g (12.6 mmol) methanesulfonyl chloride was added, and the solution was warmed to room temperature with stirring overnight. The mixture was diluted with EtOAc and washed with water and brine, dried (MgSO4) and concentrated. Normal phase chromatography (CH2Cl2 followed by gradient elution to 10% EtOAc in CH2Cl2) afforded 1.9 gm of the title compound as a white solid, 1H NMR (DMSO) δ 9.75 (s, 1H), 8.0 (s, 1H), 7.9 (s, 1H), 7.5 (d, 1H), 7.1 (d, 1H), 2.3 (s, 3H).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][NH:14][C:15](=[O:27])[N:16]2[C:19]2[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:26])=[C:11]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[CH:10]=1)([CH3:8])[CH3:7])=[O:4].[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[Cl:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:11]1[CH:10]=[C:9]([C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)([CH3:8])[CH3:7])[CH:18]=[C:17]2[C:12]=1[CH2:13][NH:14][C:15](=[O:27])[N:16]2[C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:26]
Reactant: CC(C)(NC(=O)CBr)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(NC(=O)CN1CCOCC1)c1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Temperature: 80 °C

Procedure:
To a stirred solution of 2-bromo-N-{1-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methylethyl}acetamide (30 mg, 0.05 mmol, 1 eq) in DMF (0.5 mL) was added morpholine (0.01 mL) and diisopropylethylamine (0.02 mL). The mixture was warmed to and maintained at 80° C. for 1.5 h at which time HPLC analysis indicated complete reaction. The mixture was diluted with ethyl acetate and washed 3× with dilute NaOH. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated giving N-{1-[5-(2-chlorophenyl)-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]-1-methylethyl}-2-morpholin-4-ylacetamide. Mass spectrum 587.2 (M+1); 589.2 (M+3).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:60]=[CH:59][C:58]([F:61])=[CH:57][CH:56]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][NH:29][CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1>C(#N)C>[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][C:55]3[CH:56]=[CH:57][C:58]([F:61])=[CH:59][CH:60]=3)=[CH:49][CH:48]=2)=[C:25]([CH2:27][CH2:28][N:29]([CH2:2][CH2:3][C:4]2[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=2)[CH:30]2[CH2:39][CH2:38][CH2:37][C:36]3[N:35]=[C:34]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH:33]=[CH:32][C:31]2=3)[CH:26]=1
Reactant: COC(=O)c1ccc(CCI)cc1
Reactant: CCOC(=O)c1ccc2c(n1)CCCC2NCCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(n1)CCCC2N(CCc1ccc(C(=O)OC)cc1)CCc1cc(F)ccc1OCc1ccc(CCc2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 4 h

Procedure:
305 mg (1.05 mmol) of methyl 4-(2-iodoethyl)benzoate and 56 mg (0.53 mmol) of anhydrous sodium carbonate were added to a solution of 200 mg (0.35 mmol) of ethyl 5-({2-[5-fluoro-2-({4-[2-(4-fluorophenyl)ethyl]benzyl}oxy)phenyl]ethyl}amino)-5,6,7,8-tetrahydroquinoline-2-carboxylate (Enantiomer 2, Example 143A) in 3 ml of dry acetonitrile, and the mixture was stirred in a microwave apparatus (Biotage Initiator) at 140° C. for 4 hours. The reaction solution was then cooled and purified directly by preparative HPLC (mobile phase: acetonitrile/water 9:1). This gave 75 mg (0.10 mmol, 29% of theory) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([CH2:21][C:22](O)=[O:23])#[N:20].C(OC(=O)C)(=O)C>O>[C:19]([CH2:21][C:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])=[O:23])#[N:20]
Reactant: O=C(NCc1ccccc1)NCc1ccccc1
Reactant: N#CCC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N#CCC(=O)N(Cc1ccccc1)C(=O)NCc1ccccc1

Procedure:
36.0 g (0.15 mol) of dibenzylurea, 15.3 g (0.18 mol) of cyanoacetic acid and 30.6 g (0.3 mol) of acetic anhydride are stirred at 80-85° C. for 2 hours. After cooling, the reaction mixture is stirred into 600 ml of water and the resultant precipitate is filtered off with suction and then dried to constant weight.
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:14][CH2:15][O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>>[Si:17]([O:16][CH2:15][CH2:14][N:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]1=[O:12])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=C1NCCN1c1ccccc1
Product: CC(C)(C)[Si](C)(C)OCCN1CCN(c2ccccc2)C1=O

Procedure:
By using 1-phenylimidazolidin-2-one obtained by the method described in literature (J. Org. Chem., 1951, 16, 1829) and t-butyldimethylsilyl 2-bromoethyl ether obtained by the method of Example 92a, 1-[2-(t-butyldimethylsilyloxy)ethyl]-3-phenylimidazolidin-2-one was obtained as crude product by similar procedures to those of Example 151a. By using the resulting product, the title compound was obtained as colorless solid by similar procedures to those of Example 92b (yield: 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10](Cl)=[O:11].[NH:14]1[CH:18]=[CH:17]N=N1.C(=O)([O-])[O-].[K+].[K+]>C1S(=O)(=O)CCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[O:11][CH:17]=[CH:18][N:14]=1
Reactant: c1c[nH]nn1
Reactant: COC(=O)c1ccccc1C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1-c1ncco1
Temperature: 140 °C
Yield: 18.8 %

Procedure:
A mixture of 2-Chlorocarbonyl-benzoic acid methyl ester (1.3 gram, 6.56 mmol), 1H-triazole (0.42 ml, 7.22 mmol) and potassium carbonate (2.78 g, 20 mmol) in 12 ml of tetramethylene sulfone was heated at 140° C. for half an hour. The mixture was cooled, diluted with ethyl acetate, washed with water 5 times, and dried. After concentration the crude was purified by flash column (50% ethyl acetate in hexane) to afford 250 mg of 2-Oxazol-2-yl-benzoic acid methyl ester as a light yellow liquid. MS: (M+H)/z=204.1.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.[OH-].[Na+].C(Cl)Cl>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[C:5]([Cl:16])=[CH:4][CH:3]=1.[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Brc1cccc(NCC2CCOCC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Clc1ccc(Br)nc1NCC1CCOCC1
Product: Clc1ccc(NCC2CCOCC2)nc1Br
Temperature: 33 °C
Reaction time: 120 h

Procedure:
A solution of 6-bromo-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (C, 1000 mg, 3.69 mmol) in chloroform (15 mL) was diluted with 1-chloropyrrolidine-2,5-dione (NCS, 492 mg, 3.69 mmol). The mixture then was heated in a sealed tube at about 33° C. for about 16 hr, followed by heating the reaction mixture for about 24 hr at about 37° C., and then for an additional 5 days at about 43° C. The reaction mixture then was cooled to ambient temperature, diluted with 1N aqueous sodium hydroxide solution and DCM. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SiO2, 80 g, EtOAc/heptane=5/95 2 min, 5/95 to 30/70 2-15 min, to 35/65 15-18 min, then 35%]. Fractions were combined and concentrated in vacuo yielding 6-bromo-3-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (F, 453 mg), and 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (E, ˜500 mg). (F): LCMS (m/z): 305.0[M+H]+; Retention time=1.01 min. (E): LCMS (m/z): 305.0 [M+H]+; Retention time=0.96 min.
Reaction SMILES: [O:1]1[C:3]([C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=2[F:13])([CH2:4][Cl:5])[CH2:2]1.[CH3:14][Si:15]([CH3:22])([CH3:21])N1C=NC=N1.[N:23]1([K])[CH:27]=[N:26][CH:25]=[N:24]1.C(O)(=O)C>CN(C)C=O.O>[Cl:5][CH2:4][C:3]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13])([O:1][Si:15]([CH3:22])([CH3:21])[CH3:14])[CH2:2][N:23]1[CH:27]=[N:26][CH:25]=[N:24]1
Reactant: [K]n1cncn1
Reactant: Fc1ccc(C2(CCl)CO2)c(F)c1
Reactant: C[Si](C)(C)n1cncn1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: C[Si](C)(C)OC(CCl)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
4.11 g (0.02 moles) of 1,2-epoxy-2-(2,4-difluorophenyl)-3-chloropropane are reacted with 4.23 g (0.03 moles) of 1-(trimethylsilyl)-1,2,4-triazole and 0.1 g (0.001 mole) of 1,2,4-triazol-1-yl potassium in 50 ml of dimethyl formamide at 50° C. for 2 hours. Then the reaction mixture is neutralized by glacial acetic acid, mixed with 250 ml of water at room temperature and extracted twice with 50 ml of dichloromethane each. The combined extracts are washed three times with 50 ml of water each, dried over water-free sodium sulfate and evaporated in vacuo. The residue is subjected to column chromatography by the method of Example 4 above. After crystallization from n-heptane 4.9 g (71.5%) of the title compound are obtained; m.p.: 59°-61° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:12]([CH2:16][C:17](Cl)=[O:18])([CH3:15])([CH3:14])[CH3:13].N1C=CC=CC=1>ClCCl>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:16][C:17]([NH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2)=[O:18]
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Nc1ccc2ncccc2c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC(=O)Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 82.5 %

Procedure:
Following the procedure of Example 1, Step 3, 6-nitroquinoline (2.5 g) and 5% palladium on carbon (0.10 g) in ethanol (40 mL) was hydrogenated to give 6-aminoquinoline (2.2 g). A mixture of 6-aminoquinoline (2.2 g, 15 mmol), t-butylacetyl chloride (2.2 mL, 16 mmol), and pyridine (2.5 mL, 31 mmol) in dichloromethane (40 mL) was then stirred at ambient temperature for 4 h and then extracted with 1 N HCl. The acidic layer was separated and treated with 50% NaOH until basic. The basic phase was extracted with dichloromethane. The combined extracts were dried (MgSO4) and concentrated. The crude material was triturated with hexane and the solid was collected by filtration to provide 3,3-dimethyl-N-quinolin-6-ylbutanamide (3.0 g). MS (ES) m/z 241.1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([NH2:24])[CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21].CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:24][C:16]2[CH:17]=[C:18]([O:22][CH3:23])[C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[C:5]2[N:10]=[CH:9][S:8][C:6]=2[N:7]=1
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Clc1nc(Cl)c2ncsc2n1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(Nc2nc(Cl)nc3scnc23)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.5 %

Procedure:
To a stirred solution of 5,7-dichlorothiazolo[5,4-d]pyrimidine (200 mg, 0.97 mmol) and 3,4,5-trimethoxybenzenamine (230 mg, 1.25 mmol) in 7 mL of DMSO was added DIEA (188 mg, 1.45 mmol) in one portion at room temperature. Then the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 40 mL of water, and the solid obtained was filtered, washed with water (10 mL) to give a crude product. It was purified by silica gel chromatography (silica gel 200-300 mesh, eluting with ethyl acetate) to give 5-chloro-N-(3,4,5-trimethoxyphenyl)thiazolo[5,4-d]pyrimidin-7-amine (337 mg, 98.6%) as a yellow solid. LC-MS: 353.0 [M+H]+, 726.9 [2M+H]+, tR=1.56 min.
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:29][C:30]([O:32]CC)=[O:31])[C:19]1=[O:35])[CH2:7][S:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:5])C.[OH-].[Na+].C(O)(=O)C>CO>[OH2:3].[C:4]([C@@H:6]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:29][C:30]([OH:32])=[O:31])[C:19]1=[O:35])[CH2:7][S:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C(N[C@@H](CSCCC2CCNCC2)C(=O)OCC)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O
Product: O=C(O)CN1C(=O)C(N[C@@H](CSCCC2CCNCC2)C(=O)O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.3 g of dihydrobromide of the B-isomer of ethyl 3-[1(R)-ethoxycarbonyl-2-{2-(4-piperidyl)ethylthio}ethyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate obtained in Example 5 is dissolved in 10 ml of an aqueous solution of 50% methanol, and the resulting solution is gradually added dropwise to 15.5 ml of an aqueous solution of 2N sodium hydroxide. After stirring for 2 hours at room temperature, the reaction liquid is neutralized with 6.5 ml of acetic acid. The residue obtained by concentration under reduced pressure is purified by HP-20 column chromatography (water:methanol=3:1). The solvent is evaporated under reduced pressure, and the resulting residue is lyophilized to give 440 mg of the B-isomer of 3-[1(R)-carboxy-2-{2-(4-piperidyl)ethylthio}ethyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid monohydrate as a colorless powder.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.Br[C:24]1[N:29]=[C:28](/[CH:30]=[C:31]2/[C:32](=[O:37])[NH:33][C:34](=[O:36])[S:35]/2)[CH:27]=[CH:26][CH:25]=1>CS(C)=O>[C:1]1([CH3:13])[CH:2]=[CH:3][C:4]([N:7]2[CH2:8][CH2:9][N:10]([C:24]3[N:29]=[C:28](/[CH:30]=[C:31]4/[C:32](=[O:37])[NH:33][C:34](=[O:36])[S:35]/4)[CH:27]=[CH:26][CH:25]=3)[CH2:11][CH2:12]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N2CCNCC2)cc1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1ccc(N2CCN(c3cccc(/C=C4\SC(=O)NC4=O)n3)CC2)cc1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
An 8 mL round bottomed vial was charged with 1-(p-tolyl)piperazine (56 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH2Cl2 (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH2Cl2 (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(4-(p-tolyl)piperazin-1-yl)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange solid (65 mg, 122 mg theoretical, 53%). LC-MS m/z: 382 (M+1).
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:18](=[O:26])[CH:17]=[C:16]([C:27]([F:30])([F:29])[F:28])[N:15]=1.S(Cl)([Cl:36])(=O)=O>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:11])([F:10])[F:12])=[CH:5][C:4]=1[NH:13][C:14]1[N:19]([CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[C:18](=[O:26])[C:17]([Cl:36])=[C:16]([C:27]([F:28])([F:29])[F:30])[N:15]=1
Reactant: O=c1cc(C(F)(F)F)nc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)n1C1CCCCC1
Reactant: O=S(=O)(Cl)Cl
Product: O=c1c(Cl)c(C(F)(F)F)nc(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)n1C1CCCCC1
Yield: 93 %

Procedure:
In accordance with the method of Example 25, chlorination of 2-{2,5-bis(trifluoromethyl)phenyl}amino-3-cyclohexyl-6-trifluoromethyl-4(3H)-pyrimidinone (80 mg, 0.18 mmol) was carried out using sulfuryl chloride to obtain white solid of 2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-3-cyclohexyl-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 65].
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH2:24])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[C:28]([O:31][C:32]1[C:33](=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:34](O)=[O:35])(=[O:30])[CH3:29].ON1C2C=CC=CC=2N=N1>C(#N)C.CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:34](=[O:35])[C:33]3[CH:37]=[CH:38][CH:39]=[CH:40][C:32]=3[O:31][C:28](=[O:30])[CH3:29])=[C:17]([O:25][CH3:26])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCN
Reactant: CC(=O)Oc1ccccc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CN(C)C=O
Product: COc1cc(CC(=O)NCCCc2ccc(C)c(C)c2)ccc1OCCNC(=O)c1ccccc1OC(C)=O
Yield: 62.6 %

Procedure:
0.27 g (0.66 mmol) of N-{3-(3,4-dimethylphenyl)propyl}-4-(2-aminoethoxy)-3-methoxyphenylacetamide obtained in Step 5 of Example 3, 0.17 g (0.94 mmol) of acetylsalicylic acid and 0.10 g (0.74 mmol) of 1-hydroxylbenzotriazole were dissolved in 15 ml of a mixture of acetonitrile and dimethylformamide(1:2). 0.19 g (0.92 mmol) of dicyclohexanecarbodiimide was added thereto and the resultant mixture was stirred at a room temperature for 2 days. White precipitates were removed and the remaining solution was diluted with 30 ml of dichloromethane, which was washed with water and dried. After removing the solvent under a reduced pressure, the residue was subjected to silica gel chromatography to obtain 0.22 g of the title compound (yield: 63%).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[O:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)([O-:3])=[O:2].[S:19]([O:24]C)([O:22][CH3:23])(=[O:21])=[O:20]>C(OCC)(=O)C>[CH3:23][O:22][S:19]([O-:24])(=[O:21])=[O:20].[CH3:23][N+:9]1([CH2:8][CH2:7][O:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]1
Reactant: O=[N+]([O-])c1ccccc1OCCN1CCOCC1
Reactant: COS(=O)(=O)OC
Solvent: CCOC(C)=O
Product: COS(=O)(=O)[O-]
Product: C[N+]1(CCOc2ccccc2[N+](=O)[O-])CCOCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.52 g (10 mmol) of the product from Step 5.1 was dissolved in 30 mL of ethyl acetate, 1.4 g (11 mmol) of dimethyl sulfate was added and the mixture was allowed to agitate at room temperature which caused the formation of a precipitate. After 4 hours, the mixture was filtered, and the filter cake was washed with a small amount of ethyl acetate. Drying at 40° C. under vacuum gave 2.3 g (61% of the theoretical) of a beige-colored, slightly sticky product.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.C1C=CC=CC=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=2)(O)[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:16][CH:15]=1>O>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[C:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:30][CH:31]=1
Reactant: CCOC(=O)C(C)C(O)(c1ccc(OC)cc1)c1ccc(OC)cc1
Solvent: c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C(C)=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
4.10 ml of phosphorus oxychloride were dropped at from 5° to 10° C. onto 140 ml of a benzene solution containing 7.02 g of ethyl 3,3-bis(4-methoxyphenyl)-3-hydroxy- 2-methylpropionate (prepared as described in Preparation 106) on an ice bath. The reaction solution was then stirred for 3 hours at room temperature, after which it was poured into water and then extracted with diethyl ether three times. The combined ethereal extracts were washed with a saturated aqueous solution of sodium bicarbonate, with water and with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous sodium sulfate and condensed by evaporation under reduced pressure. The residue (6.72 g) was subjected to flash column chromatography through 100 g of silica gel. 6.04 g of the title compound were obtained as an oily substance from those fractions eluted with a 95:5 by volume mixture of hexane and ethyl acetate.