Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[CH2:6])[CH3:2].C([O-])(O)=O.[Na+].[CH2:21]([SH:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:7][O:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH2:6][S:28][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:2]
Reactant: SCc1ccccc1
Reactant: C=C(COC1CCOCC1)C(=O)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(COC1CCOCC1)CSCc1ccccc1
Yield: 36.8 %

Procedure:
A suspension of 2-(tetrahydro-pyran-4-yloxymethyl)-acrylic acid ethyl ester (2.2 g, 10.2 mmol) in ethanol (100 ml) was treated with a solution of NaHCO3 (0.86 g, 10.2 mmol) in water ml (10 ml) and benzyl mercaptan (1.21 ml, 10.2 mmol) at room temperature overnight. Ethanol evaporated off under reduced pressure, crude partitioned between ethyl acetate and water, organic layer separated and purified by mplc eluting with 1:9 to 2:8 v/v ethyl acetate-heptane mixture to give the title compound as pale yellow oil (1.27 g). MS: 339 (MH+); LCMS (Protocol B) retention time 4.3 minutes.
Reaction SMILES: [NH2-:1].[Na+].C(O)(=O)CCCCCCC/C=C\CCCCCCCC.[CH3:23][CH2:24][CH2:25][CH2:26][CH:27]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)[CH2:28][CH2:29][CH2:30][CH3:31]>C1(C)C(C)=CC=CC=1>[NH2:1][C:34]1[CH:33]=[C:32]([CH:27]([CH2:26][CH2:25][CH2:24][CH3:23])[CH2:28][CH2:29][CH2:30][CH3:31])[CH:37]=[CH:36][N:35]=1
Reactant: [NH2-]
Reactant: CCCCC(CCCC)c1ccncc1
Agent: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCC(CCCC)c1ccnc(N)c1
Temperature: 173 °C
Reaction time: 8.7 h
Yield: 67.3 %

Procedure:
A mixture of 50.7 g (1.3 moles) of sodamide preformed in situ as in Example 1, 350 cc of xylene containing 0.1 cc of oleic acid, and 205 g (1 mole) of 4-(5-nonyl)pyridine was placed in a Magne Drive such as the one described in Example 2. The autoclave was closed and purged of air with nitrogen, pressurized to 10 psig with ammonia and 200 psig with nitrogen. The pressure relief valve was set at 350 psig. The mixture was heated to 173° C. at which temperature amination began. The temperature was reduced and the reaction was run at 158°-163 ° C. for 8.7 hours. Hydrogen was evolved during this time. The autoclave was cooled to room temperature, vented to atmospheric pressure and hydrolyzed with 150 cc of water. The xylene phase was separated and the bottom aqueous caustic phase was re-extracted with 25 cc of xylene. Both xylene extracts were combined and distilled to give 2-amino-4-(5-nonyl)pyridine boiling at 197°-225 ° C. at 22 mm Hg. The yield was 67.3%. This result substantially increases the yield of 2-amino-4-(5-nonyl)pyridine over that reported previously by one of the applicants, McGill, U.S. Pat. No. 4,177,349 (1979) and McGill, U.S. Pat. No. 4,267,335 (1981). In this prior work, 4-(5-nonyl)pyridine was shown to prefer to couple in the presence of sodamide, giving high yields of 4,4'-di-(5-nonyl)-2,2'-bipyridyl but only low yields of 2-amino-4-(5-nonyl)pyridine. This increased yield of 2-amino-4 (5-nonyl)pyridine is of importance because the compound has valuable biocidal properties.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]#[CH:13])[N:6]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=1)=[N+:22]=[N-:23]>>[NH2:1][C:2]1[N:3]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]2[N:23]=[N:22][N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:40])[C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])=[CH:30][CH:29]=3)[CH:13]=2)[N:6]=1
Reactant: C#CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reactant: CCCCCCc1ccc(C(=O)NCCN=[N+]=[N-])cc1
Product: CCCCCCc1ccc(C(=O)NCCn2cc(CCCCCc3cn(C(=O)OC(C)(C)C)c(N)n3)nn2)cc1

Procedure:
tert-butyl 2-amino-4-(hept-6-ynyl)-1H-imidazole-1-carboxylate (0.097 g, 0.349 mmol) was reacted with N-(2-azidoethyl)-4-hexylbenzamide (0.096 g, 0.349 mmol) following the general click procedure to give tert-butyl 2-amino-4-(5-(1-(2-(4-hexylbenzamido)ethyl)-1H-1,2,3-triazol-4-yl)pentyl)-1H-imidazole-1-carboxylate 1H NMR (300 MHz, CDCl3) δ 7.65 (d, 2H), δ 7.55 (t, 1H), δ 7.26 (s, 1H), δ 7.09 (d, 2H), δ 6.39 (s, 1H), δ 6.04 (s, 2H), δ 4.48 (t, 2H), δ 3.83 (q, 2H), δ 2.56 (q, 4H), δ 2.24 (t, 2H), δ 1.50 (m, 13H), δ 1.21 (m, 1H), δ 0.77 (t, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 168.3, 148.3, 147.3, 138.7, 131.4, 128.7, 127.4, 122.2, 106.4, 84.9, 73.9, 49.5, 40.2, 36.0, 31.8, 31.3, 29.9, 29.3, 29.1, 28.9, 28.2, 28.1, 28.0, 25.6, 22.8, 14.3 ppm; HRMS (ESI) calcd for C30H45N7O3 (M+) 551.3584. found 551.3581, which was subsequently deprotected to give N-(2-(4-(5-(2-amino-1H-imidazol-4-yl)pentyl)-1H-1,2,3-triazol-1-yl)ethyl)-4-hexylbenzamide hydrochloride (0.164 g, 96% yield). 1H NMR (400 MHz, CD3OD) δ 8.28 (s, 1H), δ 7.67 (d, 2H), δ 7.21 (d, 2H), δ 6.43 (s, 1H), δ 4.72 (s, 2H), δ 3.87 (s, 2H), δ 2.74 (s, 2H), δ 2.58 (t, 2H), δ 2.31 (t, 2H), δ 1.66 (s, 2H), δ 1.55 (s, 4H), δ 1.35 (s, 2H), δ 1.25 (s, 6H), δ 0.66 (t, 3H) ppm; 13C NMR (100 MHz, CD3OD)-δ 169.2, 159.5, 147.4, 147.3, 131.2, 108.4, 51.2, 48.5, 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 39.5, 36.5, 35.6, 31.6, 31.7, 31.2, 28.8, 28.2, 27.9, 27.7, 24.1, 23.9, 22.6, 13.3, 9.9 ppm; HRMS (ESI) calcd for C25H37N7O (M+) 451.3059. found 451.3058.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([OH:16])=[O:15].O.[OH-].[Li+:19]>CO>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O-:13])=[O:12])=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:14]([O-:16])=[O:15].[Li+:19].[Li+:19]
Reactant: O=C(O)c1ccc2cc(C(=O)O)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C([O-])c1ccc2cc(C(=O)[O-])ccc2c1

Procedure:
Lithium 2,6-naphthalenedicarboxylate was synthesized by repeating the procedure of Experimental Example 1. The starting materials used were 2,6-naphthalenedicarboxylic acid and lithium hydroxide monohydrate (LiOH.H2O). Methanol (100 mL) was added to lithium hydroxide monohydrate (0.556 g), and it was stirred. After the lithium hydroxide monohydrate was dissolved, 2,6-naphthalenedicarboxylic acid (1.0 g) was added, and it was stirred for one hour. After stirring, the solvent was removed, and the residue was dried in vacuo at 150° C. for 16 hours to yield a white powder sample.
Reaction SMILES: [CH:1]([C@:3]1([CH3:27])[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=O.[Cl-].[O:29]1[CH:33]=[N:32][C:31]([CH2:34][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:30]1>C1OC1CC>[CH3:27][C@@:3]1(/[CH:1]=[CH:34]/[C:31]2[N:32]=[CH:33][O:29][N:30]=2)[S:9][C@H:8]2[N:5]([C:6](=[O:10])[CH2:7]2)[C@H:4]1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: c1ccc([P+](Cc2ncon2)(c2ccccc2)c2ccccc2)cc1
Reactant: C[C@@]1(C=O)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1
Agent: CCC1CO1
Agent: [Cl-]
Product: C[C@@]1(/C=C/c2ncon2)S[C@@H]2CC(=O)N2[C@H]1C(=O)OC(c1ccccc1)c1ccccc1

Procedure:
1.14 g (3.0 mmol) of benzhydryl (2S,3R,5R)-3-formyl-3-methyl-7-oxo-4-thia-1-aza-bicyclo[3.2.0]heptane-2-carboxylate were dissolved in 15 ml of 1,2-butylene oxide, treated with 1.38 g (3.6 mmol) of (1,2,4-oxadiazol-3-yl)methyl-triphenylphosphonium chloride and refluxed for 10 hours. Subsequently, the mixture was filtered, the filtrate is evaporated and the residual brown oil was chromatographed over silica gel (0.040-0.063 mm particle size) with methylene chloride as the eluent.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.N([O-])=O.[Na+].O.[BrH:17]>CO>[Br:17][C:2]1[S:3][C:4]([CH3:11])=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1
Reactant: Br
Reactant: COC(=O)c1nc(N)sc1C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1nc(Br)sc1C

Procedure:
2.8 g of methyl 2-amino-5-methyl-1,3-thiazole-4-carboxylate was dissolved in 30 ml methanol and 7 ml hydrobromic acid, followed by adding dropwise an aqueous solution of 1.2 g sodium nitrite thereinto under ice-cooling. After stirring the reaction solution under ice-cooling for 30 minutes, a solution, previously heated at 60° C., of 1.3 g cuprous bromide in 7 ml hydrobromic acid was added thereto, followed by stirring at 60° C. for 1 hour. The reaction solution was ice-cooled and water was-added, followed by extracting with diethyl ether. The organic layer was extracted with brine, dried over anhydrous magnesium sulfate and evaporated, to give 0.47 g of methyl 2-bromo-5-methyl-1,3-thiazole-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][NH:19][CH2:18]1>>[CH3:16][CH:17]1[CH2:22][CH:21]([CH3:23])[CH2:20][N:19]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:18]1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CC1CNCC(C)C1
Product: Cc1ccc(-c2oncc2C(=O)N2CC(C)CC(C)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3,5-dimethylpiperidine (6.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (0.7 mg). Calcd for C18H22N2O2: 298.1681, found 298.1692.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][C:14]([O:16]C(C)(C)C)=[O:15])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:13][C:14]([OH:16])=[O:15])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCOC(=O)C(CC(=O)OC(C)(C)C)(Cc1ccc(CC)c(CC)c1)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(CC(=O)O)(Cc1ccc(CC)c(CC)c1)C(=O)OCC

Procedure:
To a solution of 20.30 g (48.27 mmol) tert. butyl 4-(3,4-diethyl-phenyl)-3,3-bis-ethoxycarbonyl-butyrate (Intermediate product 61) in 100 mL CH2Cl2 was added 40 mL TFA while cooling with ice and the mixture was refluxed for 1 hour. The reaction mixture was evaporated down i. vac., the residue was combined with water and the aqueous phase exhaustively extracted with EtOAc. The combined org. extracts were washed with sat. aqueous NaCl solution, dried over sodium sulphate and evaporated i. vac.
Reaction SMILES: N#N.[C:3]([O:7][C:8](=[O:22])[NH:9][C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[H-].[Na+].[F:25][C:26]1[CH:27]=[C:28]([C:32]2[S:36][CH:35]=[N:34][C:33]=2[C:37](Cl)=[O:38])[CH:29]=[CH:30][CH:31]=1>C1COCC1.O>[C:3]([O:7][C:8](=[O:22])[N:9]([C:37]([C:33]1[N:34]=[CH:35][S:36][C:32]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([F:25])[CH:27]=1)=[O:38])[C:10]1[N:11]=[C:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[CH3:20])[O:13][CH:14]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(=O)CCCCc1nc(NC(=O)OC(C)(C)C)co1
Reactant: O=C(Cl)c1ncsc1-c1cccc(F)c1
Agent: N#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)CCCCc1nc(N(C(=O)OC(C)(C)C)C(=O)c2ncsc2-c2cccc(F)c2)co1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [2-(5-oxo-hexyl)-oxazol-4-yl]-carbamic acid tert-butyl ester (50 mg, 0.18 mL) in THF (1.0 mL) was added to a suspension of NaH (19 mg, 0.43 mmol) in THF (0.5 mL) at 0° C. The resulting suspension was stirred at 0° C. for 5 min and at rt for 30 min. It was cooled to 0° C. and treated dropwise with a solution of the above prepared 5-(3-fluoro-phenyl)-thiazole-4-carbonyl chloride in THF (1.0 mL). The resulting suspension was stirred for 30 min at 0° C. followed by 2 h at rt. Water was then added and the aq. layer was extracted several time with EA. The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (6:4 hept-EA) gave the title compound as a yellow oil. TLC: rf (6:4 hept-EA)=0.20. LC-MS-conditions 02: tR=1.06 min, [M+H]+=487.91.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24](CC#N)[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([OH:33])(=[O:32])[CH3:31]>Cl>[CH:1]1([CH2:6][CH:7]([C:18]2[NH:29][C:21]3=[N:22][CH:23]=[C:24]([CH2:31][C:30]([OH:33])=[O:32])[CH:25]=[C:20]3[CH:19]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)O
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC#N)cnc3[nH]2)cc1
Agent: Cl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2cc3cc(CC(=O)O)cnc3[nH]2)cc1

Procedure:
A mixture of {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetonitrile (as prepared in Example 38, 140 mg, 0.34 mmol) in 36% hydrochloric acid (1 mL) and acetic acid (5 mL) was refluxed for 2 h. The mixture was concentrated in vacuo, extracted with ethyl acetate (250 mL), washed with brine, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford {2-[2-cyclopentyl-1-(4-methanesulfonyl-phenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acetic acid (150 mg, quant.) as a light yellow solid which was used in the next step without further purification: LC/MS m/e calcd for C23H2N2O4S [M+H]+ 427.54, observed 427.0.
Reaction SMILES: [NH2:1]C1C=CC(C(=O)C)=CC=1.[NH2:11][C:12]1[N:17]=[C:16](Cl)[CH:15]=[C:14]([CH3:19])[N:13]=1.Cl.[OH-].[K+]>O>[NH2:1][C:16]1[CH:15]=[C:14]([CH3:19])[N:13]=[C:12]([NH2:11])[N:17]=1
Reactant: Cc1cc(Cl)nc(N)n1
Reactant: CC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(N)nc(N)n1

Procedure:
A suspension of p-aminoacetophenone (1.35 g) and 2-amino-4-chloro-6-methylpyrimidine (1.435 g) in 20 mL water was treated with 0.85 mL conc HCl and heated at reflux for 1 hr. Addition of 20 mL 1N KOH gave a light buff solid, which was filtered out and dried to give 2.28 g acetylphenyl)amino-2-amino-6-methylpyrimidine, mp 194°-196° C. Of this, 1.21 g was treated with methyl iodide (3 mL) in dimethylformamide (15 mL) at room temperature for 42 hr. Dilution with ethyl acetate and filtration gave 1.11 g 4-(4-acetylphenyl)amino-2-amino-1,6-dimethylpyrimidinium iodide as a white powder, mp 302°-3° C.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]#[N:14])=[CH:6][CH:5]=1.Br[C:22]1[CH:23]=[N:24][CH:25]=[N:26][CH:27]=1>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:22]2[CH:23]=[N:24][CH:25]=[N:26][CH:27]=2)[C:13]#[N:14])=[CH:8][CH:9]=1
Reactant: N#CC(CCc1ccc(Cl)cc1)c1ccccc1
Reactant: Brc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(CCc1ccc(Cl)cc1)(c1ccccc1)c1cncnc1
Reaction time: 0.75 h

Procedure:
In a 250 ml. 3 neck round bottomed flask under nitrogen was charged 1.2 g of 60% NaH (1.5 eq., 0.0293 moles), washed 2 times with 15 ml. hexanes, in 40 ml. DMF. Dropwise was added 5.0 g. of 4-(4-chlorophenyl)-2-phenylbutanenitrile (1.0 eq., 0.0195 moles) in 10 ml. of DMF and was stirred for one hour at rt. This was followed by the addition of 4.67 g. of 5-bromopyrimidine (1.5 eq., 0.0293 moles) in 10 ml. of DMF to the reaction mixture which resulted in an exotherm to 35° C. After 45 min. GLC analysis showed no unreacted nitrile. The reaction was quenched by the addition of 100 ml. Water and then extracted with 250 ml. EtOAc. The organic phase Was washed with 2 times 100 ml. water, dried over MgSO4 and concentrated to give 7.3 g. of oil. 6.0 g. of crude product was purified by flash chromatography with 3:7 EtOAc/hexane to give 2.3 g. of a white solid mp. 89°-91° C. (43.1% based on chromatographic portion).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17]Br)([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][O:8][C:5]1[CH:6]=[N:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:12])([CH3:11])[CH3:10]
Reactant: Oc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCOc1ccc(Br)nc1
Temperature: 40 °C
Reaction time: 20 h
Yield: 90.3 %

Procedure:
A mixture of 6-bromopyridin-3-ol (1.50 g), tert-butyl(2-bromoethyl)carbamate (2.32 g), cesium carbonate (3.65) and N,N-dimethylformamide (30 mL) was stirred at 40° C. for 20 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.47 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:11].[CH:18]1C2N(C=NC=2)C(=S)NN=1>>[Br:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][N:7]=[C:6]2[S:11][CH3:18]
Reactant: S=c1[nH]ncc2cncn12
Reactant: S=c1[nH]ncc2c(Br)nc(-c3ccccc3)n12
Product: CSc1nncc2c(Br)nc(-c3ccccc3)n12

Procedure:
The procedure of Example 29 is repeated substituting an equimolar amount of 8-bromo-6-phenyl-imidazo[1,5-d]-as-triazine-4(3H)-thione for the imidazo[1,5-d]-as-triazine-4(3H)-thione employed in that example. There is thus obtained the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH3:11])[C:5]=1[C:12]1[NH:25][C:15]2=[CH:16][C:17]3[C:18](=[O:24])[NH:19][C:20](=[O:23])[C:21]=3[CH:22]=[C:14]2[N:13]=1.[CH3:26]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([O:10][CH3:11])[C:5]=1[C:12]1[N:13]([CH3:26])[C:14]2=[CH:22][C:21]3[C:20](=[O:23])[NH:19][C:18](=[O:24])[C:17]=3[CH:16]=[C:15]2[N:25]=1
Reactant: COc1nccc(Cl)c1-c1nc2cc3c(cc2[nH]1)C(=O)NC3=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc(Cl)c1-c1nc2cc3c(cc2n1C)C(=O)NC3=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.4 %

Procedure:
NaH (0.12 g, 3.04 mmol) was added in portions to a solution of 2-(4-chloro-2-methoxypyridin-3-yl)imidazo[4,5-f]isoindole-5,7(1H,6H)-dione (1.0 g, 3.04 mmol) in 30 mL of anhydrous DMF at 0° C. under argon. The reaction mixture was then stirred at rt for 3 h. MeI (2.16 g, 15.2 mmol) was added dropwise via a syringe at rt under argon. The resulted mixture was stirred for 6 h at rt, hydrolyzed by adding 100 mL of water. The brown precipitate was isolated, washed with water and dried under vacuum. The solid was purified by column chromatography (silica-gel, CH2Cl2/MeOH=49/1 v/v) to give a white solid product, 0.68 g, 65.4% yield. MS: 343.0 [M−H]−. 1H NMR (DMSO-d6, 500 MHz): δ 11.27 (s, 1H), 8.42 (d, 1H, J=5.5 Hz), 8.23 (s, 1H), 8.08 (s, 1H), 7.43 (d, 1H, J=5.5 Hz), 3.89 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([Br:20])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1.Cl.N1CCC(C(C2C=CC3C(=CC=CC=3)C=2)=O)CC1.[Cl:40][CH2:41][CH2:42][C:43]([C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)=[O:44].ClCCCC(C1C=CC=CC=1)=O>>[ClH:40].[Br:20][C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH2:41][CH2:42][C:43]([C:45]3[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=3)=[O:44])[CH2:3][CH2:4]2)=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(CCCl)c1ccc(Cl)cc1
Reactant: O=C(c1ccc(Br)c2ccccc12)C1CCNCC1
Agent: Cl
Agent: O=C(CCCCl)c1ccccc1
Agent: O=C(c1ccc2ccccc2c1)C1CCNCC1
Product: O=C(CCN1CCC(C(=O)c2ccc(Br)c3ccccc23)CC1)c1ccc(Cl)cc1

Procedure:
When in the procedure of Example 19, 4-bromo-1-naphthyl 4-piperidyl ketone hydrochloride is substituted for 2-naphthyl 4-piperidyl ketone hydrochloride and 3-chloro-1-(4-chlorophenyl)-1-propanone substituted for 4-chloro-1-phenyl-1-butanone, 3-[4-(4-bromo-1-naphthoyl)-1-piperidyl]-1-(4-chlorophenyl)-1-propanone hydrochloride is produced.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Reactant: COc1ccc(N)cc1
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(OC)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 48 %

Procedure:
p-Methoxyaniline (0.046 g, 0.374 mmol), triethylamine (0.038 g, 0.374 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.063 g, 0.374 mmol) were added to a methylene chloride solution (5 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.070 g, 0.187 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.043 g, 0.0897 mmol, 48%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]=[O:10].[CH2:11]([Mg]Br)[CH2:12]C>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([OH:10])[CH2:11][CH3:12]
Reactant: O=CCc1ccccc1Br
Reactant: CCC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)Cc1ccccc1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(2-bromophenyl) acetaldehyde (15 g, 75.37 mmol) in THF (100 ml) was added propyl magnesium bromide (1.0 M in THF) (15.13 g, 113.6 mmol) at 0° C. then stirred at RT for 3 h. The reaction mixture was quenched with ammonium chloride then the title compound was purified by separation methods A, E and M. (Yield 7.0 g). The enantiomer showed up at tr=13.6 min with Chiralcel OJH (4.6×250 mm) 5μ, hexane:ethanol (98:02), 1 ml/min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15](O)=[O:16])[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C([Cl:23])=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([CH3:19])=[C:14]([CH:18]=2)[C:15]([Cl:23])=[O:16])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2cccc(Cl)c2)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DMF (1 drop) was added to a suspension of 5-{[(3-chlorophenyl)methyl]oxy}-2-methylbenzoic acid from the preparation of Intermediate 85 as described above (200 mg, 0.72 mmol) and oxalyl chloride (95 ul, 1.08 mmol, 1.5 eq) in DCM (5 ml). The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was then evaporated to dryness and azeotroped with toluene (2×50 ml). The organic layer was separated, dried and evaporated in vacuo to afford the title compound as a yellow solid, 213 mgs. No further purification carried out. LCMS sample dissolved in methanol, MS (ES+) m/z 291 [M+H]+ (C16H1535ClO3), corresponding to methyl ester generated from acid chloride.