Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3](Br)(CC)[CH2:4][CH:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)C.[P:21]([O:28]CC)([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>>[C:12]1([CH:5]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][P:21](=[O:28])([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOP(OCC)OCC
Reactant: CCC(Br)(CC)CC(c1ccccc1)c1ccccc1
Product: CCOP(=O)(CCC(c1ccccc1)c1ccccc1)OCC
Reaction time: 3 h

Procedure:
Diethyl 3,3-diphenylpropylbromide (43.0 g, 0.156 mol) and triethyl phosphite (51.9 g, 0.31 mol) was heated to 150° C. for 20 hours in a flask equipped with nitrogen flow through and an air condenser. Extra triethyl phosphite (20 ml) was added and heating continued to 160° C. for 3 hours. The yellow reaction solution was distilled, collecting several fractions to give the title product as a pale yellow liquid (b.p. 162-176° C. at 0.08 mbar) that crystallised on standing.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([N:18]3C=C[N:20]=[CH:19]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:27]1(C(=NO)N)[CH2:29][CH2:28]1.O>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][N:20]=[C:19]([CH:27]4[CH2:29][CH2:28]4)[N:18]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: NC(=NO)C1CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(C4CC4)no3)c2[C@@H]2CCCN12
Reaction time: 0.33 h

Procedure:
8.10 g (22 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole are dissolved in 30 ml of N,N-dimethylformamide, whereupon the solution is treated with 2.50 g (25 mmol) of cyclopropanecarboxamidoxime and the mixture is heated to 70° for 4.5 hours. The reaction mixture is then poured into 350 ml of water, stirred for 20 minutes and the precipitated product is filtered off under suction. The residue is washed with water and dried. The above residue is dissolved in 30 ml of glacial acetic acid and stirred at 115° for 2.5 hours. The reaction mixture is subsequently evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. After evaporation of the eluate there is obtained (S)-8-chloro-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 213°-214°.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>N1C=CC=CC=1>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1nc2ccccc2s1)c1ccccc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 64.1 %

Procedure:
In a 100 ml three-necked flask equipped with magnetic stirrer, thermometer, dropping funnel and nitrogen inlet, 5.34 g (35.6 mmol) of 2-amino-benzothiazole are dissolved in 50 ml of pyridine and cooled to 3° C. using an ice bath. 5.0 g of benzoylchloride (35.6 mmol) are added dropwise within 20 minutes, keeping the temperature within the mixture below 5° C. Stirring is continued for another 15 minutes, then the mixture is poured on 500 ml of water. The white suspension is stirred for 1 hour, filtered, the white residue is washed 3 times with 100 ml of water, respectively, and dried over night at 50° C. and 30 mbar. 7.5 g crude product obtained are purified by flash-chromatography using hexane/ethylacetate 3:1 (v/v), yielding 5.8 g of the title product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH2:20][CH2:19][CH:18]([OH:21])[C:14]=3[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(N(CC)C(C)C)(C)C.[C:31](Cl)(=[O:34])[CH2:32][CH3:33].[OH-].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3[CH2:20][CH2:19][CH:18]([O:21][C:31](=[O:34])[CH2:32][CH3:33])[C:14]=3[CH:15]=[N:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9]
Reactant: OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Reactant: CCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCC(=O)OC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Temperature: 25 °C
Reaction time: 15 h
Yield: 11.2 %

Procedure:
A solution of (rac)-4-(3-fluoro-4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-ol (example 82) (24 mg, 0.081 mmol) and N,N-diisopropylethylamine (0.028 mL, 0.162 mmol) in DMF (0.2 mL) was treated with propionyl chloride (0.021 mL, 0.243 mmol) and the reaction mixture stirred at room temperature. After 15 h, another aliquot of propionyl chloride (0.021 mL, 0.243 mmol) was added, the temperature increased to 50° C. and stirring continued for 2 h. The crude reaction mixture was poured into a 1 M solution of sodium hydroxide (10 mL) and extracted with ethyl acetate (2×15 mL). The combined organic extracts were washed with a sat. solution of sodium chloride (10 mL), dried (Na2SO4), and concentrated under reduced pressure. Purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.2 mg (11%) of the title compound as a light brown solid. MS: 354.5 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][NH:26][C:8]([C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: NNc1ccc(OCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NNc1ccc(OCc2ccccc2)cc1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
To a solution of 2-chloropyridine-3-carboxylic acid (3.30 g) in DMF (50 ml) were added [4-(benzyloxy)phenyl]hydrazine (5.0 g), HOBt (3.7 g), EDCI (4.6 g) and diisopropylethylamine (9.0 g), and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (5.0 g).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:44]1([CH3:53])[CH:49]=[CH:48][C:47]([C:50](Cl)=[O:51])=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH3:17])=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]1[C:27](=[O:36])[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]1=[O:35])[C:50](=[O:51])[C:47]1[CH:48]=[CH:49][C:44]([CH3:53])=[CH:45][CH:46]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1ccc2c(c1)nc(C(NCCCN1C(=O)c3ccccc3C1=O)C(C)C)n2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(C(=O)N(CCCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(C)ccc3n2Cc2ccccc2)C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of 2-{3-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione (0.56 mmol) and triethylamine (0.58 mL, 3.36 mmol) in DCM (3 mL) at 0° C., was added p-toluoyl chloride (0.38 mL, 2.8 mmol). The reaction mixture was stirred at 0° C. for 30 min. Ethyl acetate and saturated sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layers was combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give N-[1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-methyl-benzamide (181 mg).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9](=[O:11])[N:8]=[C:7]([C:12]3[C:13](C4C=CC(OCC)=CC=4)=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=3)[NH:6][C:5]=2[C:4]([CH2:31][CH2:32][CH3:33])=[N:3]1.[OH-].[Na+].[CH3:36][N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.[C:43]([OH:55])(=[O:54])[CH2:44][C:45]([CH2:50][C:51]([OH:53])=[O:52])([C:47]([OH:49])=[O:48])[OH:46]>CC(C)=O>[CH3:33][CH2:32][CH2:31][C:4]1[C:5]2[N:6]=[C:7]([C:12]3[CH:13]=[C:14]([S:18]([N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)(=[O:19])=[O:20])[CH:15]=[CH:16][C:17]=3[O:46][CH2:45][CH3:44])[NH:8][C:9](=[O:11])[C:10]=2[N:2]([CH3:1])[N:3]=1.[CH2:50]([C:45]([OH:46])([C:47]([OH:49])=[O:48])[CH2:44][C:43]([OH:55])=[O:54])[C:51]([OH:53])=[O:52]
Reactant: CCCc1nn(C)c2c(=O)nc(-c3cccc(S(=O)(=O)Cl)c3-c3ccc(OCC)cc3)[nH]c12
Reactant: CN1CCNCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(C)CC4)ccc3OCC)nc12
Temperature: 25 °C
Yield: 72 %

Procedure:
In a 3-necked flask, 3-(4,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo(4,3-d)pyrimidin-5-yl)-(4-ethoxyphenyl)benzene sulfonyl chloride (10 g, 0.024 mol) was mixed with acetone (100 ml) and NaOH (0.974 g, 47%) at room temperature. N-methyl piperazine (2.68 g, 0.027 mol) was added dropwise to the mixture. Thereafter, the reaction was stirred for 45 mm, additional acetone (100 ml) was added, and then the mixture was heated to reflux. Citric acid (5 g, 0.024 mol) was added, and a white precipitate appeared immediately. The reaction was maintained at reflux for one hour and then allowed to cool to room temperature over 3 hours. The precipitate was collected by filtration, and dried at 50° C. under 10 mm Hg to give pure sildenafil citrate in 72% yield.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:4]=1[CH2:5][N:6]1[CH2:9][CH:8]([NH2:10])[CH2:7]1.[Cl:18][C:19]1[N:28]=[C:27](Cl)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.CCN(CC)CC>C1COCC1.CN(C1C=CN=CC=1)C>[Cl:18][C:19]1[N:28]=[C:27]([NH:10][CH:8]2[CH2:9][N:6]([CH2:5][C:4]3[C:11]([O:15][CH3:16])=[CH:12][CH:13]=[CH:14][C:3]=3[N:2]([CH3:17])[CH3:1])[CH2:7]2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1
Reactant: COc1cccc(N(C)C)c1CN1CC(N)C1
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1cccc(N(C)C)c1CN1CC(Nc2nc(Cl)nc3ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of Compound 168 (0.22 g, 0.92 mmol) in THF (10.0 mL) at 0° C. was added 2,4-dichloroquinazoline (0.22 g, 1.10 mmol), followed by Et3N (0.65 mL, 4.60 mmol) and DMAP (catalytic amount), and the reaction was allowed to warm up slowly to ambient temperature and stirred for 18 h, then quenched with 7N NH3 in MeOH. The solvent was removed, and the residue was purified by preparative thin layer chromatography with 7N NH3 in MeOH (2%), hexanes (8%) and CH2Cl2 (90%) to afford the compound EE as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:11](Cl)=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:14])=[C:7]([Cl:13])[CH:8]=2)[N:3]=1.CO[CH:17]([O:20]C)[CH2:18][NH2:19]>>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]1[CH:2]=[CH:11][N:19]=[C:18]1[C:17](=[O:20])[NH:10]2
Reactant: Clc1cc2nc(Cl)c(Cl)nc2cc1Cl
Reactant: COC(CN)OC
Product: O=c1[nH]c2cc(Cl)c(Cl)cc2n2ccnc12

Procedure:
By reacting 2,3,6,7-tetrachloroquinoxaline with aminoacetaldehyde dimethyl acetal, following a procedure that is similar to that described in example 1, there is obtained 7,8-dichloroimidazo[1,2-a]quinoxalin-4(5H)-one (m.p. >300° C.). By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylamino-7,8-dichloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=139.4° C.(onset); IR (KBr): 3247, 2961, 1589, 1556 cm-1 ; 1H-NMR (CDCl3): δ7.8 (2H,m), 7.7 (1H,s), 7.55 (1H,s), 6.2 (1H,d), 4.6 (1H,m), 2.4÷1.3 (8H,m); UV (EtOH): λmax =235, 274, 292, 304, 330, 345 nm. Elementary analysis for C15H14Cl2N4 (m.w. 321.21): calcd. C 56.09, H 4.39, N 17.44%; found C 56.13, H 4.41, N 17.52%.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:16]=[CH:17][C:18]([C:19]([N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:21])=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: C1CCNCC1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)N2CCCCC2)cn1
Yield: 75 %

Procedure:
As described for example 15, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using piperidine instead of 3-methoxypropylamine, to the title compound (91 mg, 75%) which was obtained as a yellow gum. MS: m/e=378.5 [M+H]+.
Reaction SMILES: [Li][CH3:2].[CH3:3][C:4]1[C:9]([CH3:11])([CH3:10])[C:8](=[O:12])[CH2:7][C:6]([CH3:14])([CH3:13])[C:5]=1[C:15]([O:17][CH3:18])=[O:16]>C1COCC1>[OH:12][C:8]1([CH3:2])[CH2:7][C:6]([CH3:13])([CH3:14])[C:5]([C:15]([O:17][CH3:18])=[O:16])=[C:4]([CH3:3])[C:9]1([CH3:10])[CH3:11]
Reactant: [Li]C
Reactant: COC(=O)C1=C(C)C(C)(C)C(=O)CC1(C)C
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)C(C)(C)C(C)(O)CC1(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of CeCl3 (1.51 equiv.) in THF (75 ml) was stirred at room temp for 1 hour. The suspension was cooled down to −78° C., MeLi (1.50 equiv., 1.46M in Et2O) was slowly added over 10 minutes, followed by the addition of a solution of (2a) (20.31 mmol) in THF (15 ml). After 30 minutes, the mixture was allowed to warm to 0° C. and quenched by adding NH4Cl and ice. The mixture was extracted with Et2O and the organic layers were washed with water, saturated bicarbonate solution, and brine. After drying with MgSO4, the solution was concentrated and distilled (125° C., 0.1 mbar). Yield 99%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5][NH:4][C:3]1=[O:13].[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Br:14][CH2:15][CH2:16][CH2:17][N:4]1[C:3](=[O:13])[N:2]([CH3:1])[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:5]1
Reactant: BrCCCBr
Reactant: Cn1c(-c2ccccc2)n[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccccc2)nn(CCCBr)c1=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
After dissolving 4-methyl-5-phenyl-2,4-dihydro[1,2,4]triazol-3-one (CAS 50369-39-6) (500 mg) and 1,3-dibromopropane (0.87 ml) in N,N-dimethylformamide (9 ml), sodium hydride (60% in oil) (125 mg) was added and the mixture was stirred at room temperature for 6 hours. Water was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. After filtration, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (649 mg).
Reaction SMILES: [OH:1][C:2]([CH3:18])([CH3:17])[C:3]([N:5]1[CH2:10][CH2:9][C:8](=O)[CH:7]([C:12]([O:14]CC)=O)[CH2:6]1)=[O:4].Cl.[C:20]([NH2:26])(=[NH:25])[CH2:21][CH2:22][CH2:23][CH3:24].C[O-].[Na+]>C(O)C.CO.CC(C)=O>[CH2:21]([C:20]1[NH:26][C:12](=[O:14])[C:7]2[CH2:6][N:5]([C:3](=[O:4])[C:2]([OH:1])([CH3:17])[CH3:18])[CH2:10][CH2:9][C:8]=2[N:25]=1)[CH2:22][CH2:23][CH3:24]
Reactant: CCCCC(=N)N
Reactant: CCOC(=O)C1CN(C(=O)C(C)(C)O)CCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: CO
Product: CCCCc1nc2c(c(=O)[nH]1)CN(C(=O)C(C)(C)O)CC2
Yield: 81.4 %

Procedure:
A mixture of 0.7 g of ethyl 1-(2-hydroxy-2-methyl-1-oxopropyl)-4-oxo-3-piperidinecarboxylate and 0.4 g of valeramidine hydrochloride in 8 ml of anhydrous ethyl alcohol is treated with 2.8 ml of a 1M solution of sodium methoxide in methanol. The resulting mixture is stirred and heated at reflux for one hour. The reaction mixture is allowed to cool over 30 minutes then filtered. The filtrate is evaporated to a syrup which is stirred with 50 ml of ether overnight. The ether is decanted to afford a oily solid which is dissolved in acetone and applied to thick layer silica gel plates. The plates are eluted with ethyl acetate and the major zone washed stirred with water and the water decanted. The residue is dried and chromatographed on thick layer silica gel chromatography plates using ethyl acetate as the elution solvent. The major band at Rf=0.2 is isolated by washing with acetone to afford 0.65 g of the desired product as a colorless solid, m.p. 159°-161° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Br:20]Br>C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[C:15]([O:18][CH3:19])[CH:16]=[CH:17][C:11]=3[C:10]=2[Br:20])=[CH:5][CH:4]=1
Reactant: BrBr
Reactant: COc1ccc(-c2cc3ccc(OC)cc3s2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Br)cc1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A slurry of 2-(4-methoxyphenyl)-6-methoxybenzo[b]thiophene 100 g (370 mmol) in 1 L of CHCl3 was heated to reflux then removed from the heat. A solution of 19.3 mL (370 mmol) of bromine in 170 mL of carbon tetrachloride was added dropwise as the solution slowly cooled to room temperature. The resulting mixture was concentrated to dryness in vacuo to yield 129 g of the title compound as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@H:19]1[CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]1>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@H:19]2[CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[CH2:20]2)=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: N[C@H]1CCCNC(=O)C1
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@H]1CCCNC(=O)C1

Procedure:
Following General Procedure B above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 3-(S)-amino-ε-caprolactam (Aldrich), the title compound was prepared as a solid having a melting point>225° C. The reaction was monitored by tlc on silica gel (Rf=0.36 in 1:9 methanol/dichloromethane).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O-:18])(=O)=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].S(Cl)([Cl:22])=O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([Cl:22])(=[O:18])=[O:16])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)([O-])c1ccc(OCc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
To a flask containing 4-Benzyloxy-benzenesulfonate, sodium salt (42.07 g) is added thionyl chloride (170 mL). This solution is treated with dimethyl formamide (0.5 mL) and is heated to 70° C. for 4 hours. The reaction is allowed to cool and is concentrated under reduced pressure then is diluted with ethyl acetate and washed with water (3 times) followed by three washes with saturated sodium bicarbonate and brine. The organic layer is dried over sodium sulfate and concentrated to give 4-Benzyloxy-benzenesulfonyl chloride as white solid (39.18 g).
Reaction SMILES: Cl.[CH3:2][NH2:3].[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][N:11]2[C:15]([CH:16]=O)=[CH:14][N:13]=[CH:12]2)=[CH:8][CH:7]=1)#[N:5].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOC(C)=O>ClC(Cl)C>[C:4]([C:6]1[CH:19]=[CH:18][C:9]([CH2:10][N:11]2[C:15]([CH2:16][NH:3][CH3:2])=[CH:14][N:13]=[CH:12]2)=[CH:8][CH:7]=1)#[N:5]
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1
Reactant: CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CNCc1cncn1Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of methylamine hydrochloride in 5 mL dichloroethane at 0° C. are added 4 Å sieves (0.5 g), followed by 1 mmol of the aldehyde from Step E and 1.5 mmol Na(OAc)3BH. The reaction is stirred for 10 minutes at 0° C., warmed to room temperature and stirred for 2 hours. The reaction is poured into EtOAc/ sat. NaHCO3 solution. The organic layer is washed with brine, dried (Na2 SO4), filtered, and concentrated in vacuo. The crude product is taken up in 10 mL dichloromethane and 2 mL n-propylamine, stirred at room temperature for 1 hour, concentrated in vacuo , and purified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[S:16][CH:15]=2)[N:11]([CH3:29])[N:10]=1.[Cl:30]N1C(=O)CCC1=O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[N:13]=[C:12]([C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[S:16][C:15]=2[Cl:30])[N:11]([CH3:29])[N:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1csc(-c2cccc(C(F)(F)F)c2)c1
Solvent: O
Solvent: ClCCl
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1cc(-c2cccc(C(F)(F)F)c2)sc1Cl
Temperature: 25 °C
Yield: 78.3 %

Procedure:
A solution of 3-(2-chloro-6-fluorophenyl)-1-methyl-5-[5-(3-trifluoromethylphenyl)thien-3-yl]-1H-1,2,4-triazole (0.45 g, 1 mmol) and N-chlorosuccinimide (0.15 g, 1.1 mmol) in methylene chloride/glacial acetic acid (1:1, 2 mL) was refluxed under nitrogen for 2 days, cooled to room temperature, poured into water (10 mL) and extracted with ether (3×20 mL). The combined ethereal extracts were washed with water (3×30 mL), saturated aqueous sodium bicarbonate (50 mL) and brine (30 mL), dried over magnesium sulphate and chromatographed on silica to afford the product as a white solid (0.37 g, 76%): mp 53-54° C.; 1H NMR (CDCl3) δ 7.79 (s, 1H), 7.71 (d, 2H), 7.60 (d, 1H), 7.54 (t, 1H), 7.44 (s, 1H), 7.30-7.40 (m, 2H), 7.11 (t, 1H), 4.05 (s, 3H); EI/MS 472 m/e (M+); Calcd. for C20H11Cl2F4N3S: C, 50.9; H, 2.35; N, 8.90; Found: C, 50.9; H, 2.49; N, 8.82.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[CH2:11][CH2:12][O:13][CH2:14][CH3:15].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[CH2:12]([O:13][CH2:14][CH2:15][O:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[CH:2])[CH:4]=1)[CH3:11]
Reactant: C#Cc1cccc(O)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C#Cc1cccc(OCCOCC)c1
Temperature: 90 °C
Yield: 96 %

Procedure:
3-Ethynylphenol (1.707 g, 12.45 mmol, 1.0 eq.) and 1-bromo-2-ethoxyethane (1.1 eq.) were taken up in DMF (20 mL), and Cs2CO3 (2.2 eq.) was added. The mixture was heated to 90° C. for 16 hours, and then cooled to room temperature. The mixture was diluted with water (50 mL) and EtOAc (30 mL), and the layers were separated. The organic layers were washed with water (2×50 mL) and brine (3×50 mL), and dried (MgSO4). The resulting residue was purified by chromatography (10% EtOAc/hexanes) to yield 1-(2-ethoxyethoxy)-3-ethynylbenzene as an oil (2.63 g, 96%).