Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2I)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].I[C:24]1[C:32]2[C:27](=[N:28][CH:29]=[CH:30][CH:31]=2)[NH:26][N:25]=1.C[Sn](C)C.C[Sn](C)C>O1CCOCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=2[C:24]2[C:32]3[C:27](=[N:28][CH:29]=[CH:30][CH:31]=3)[NH:26][N:25]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Ic1n[nH]c2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2I)cc1
Agent: C[Sn](C)C
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-c2n[nH]c3ncccc23)cc1
Temperature: 100 °C

Procedure:
4-tert-butyl-N-(4-chloro-2-iodo-phenyl)-benzenesulfonamide (100 mg, 0.22 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (71 mg, 0.29 mmol), bis(triphenylphosphine)Pd(II)dichloride (20 mg, 0.03 mmol), and hexamethylditin (70 μL, 0.33 mmol) were suspended in 0.7 mL of dioxane and heated to 100° C. for 24 hours in a sealed 4 mL scintillation vial. The black crude residue obtained was purified by preparative TLC to afford 4-tert-butyl-N-[4-chloro-2-(1H-pyrazolo[3,4-b]pyridin-3-yl)-phenyl]-benzenesulfonamide: MS (ES) M+H expected 441.1, found 441.0.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22]O)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].P(Br)(Br)Br.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClCCl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(CO)c3c2c1COC
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(CN4CCOCC4)c3c2c1COC
Reaction time: 8 h

Procedure:
5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (0.20 g) is dissolved in dichloromethane (5 ml). A solution of phosphorous tribromide (0.17 g) in dichloromethane (3 ml) is added drop by drop with stirring. After three hours of stirring, the mixture is cooled to +10° C. and mixed with a solution of morpholine (1.0 ml) in ethanol (5 ml) drop by drop. After standing overnight the solvent is evaporated, the residue is chromatographed on silica gel with a mixture of dichloromethane (19 parts) and ethanol (1 part) and the title compound (0.16 g) with a melting point of 195°-196° C. is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>O1CCCC1.CS(C)=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=2)[N:8]([CH3:20])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c(-c2ccnc(N)n2)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2ccnc(N)n2)n(C)c1
Reaction time: 12 h
Yield: 82.3 %

Procedure:
To a solution of 5-(2-amino-pyrimidin-4-yl)-1H-pyrrole-3-carboxylic acid ethyl ester (5.1 g, 21.96 mmol) in tetrahydrofuran (70 mL) and dimethylsulfoxide (15 mL) cooled in a ice-water bath, NaH (0.96 g, 24.15 mmol) and methyl iodide (1.5 mL, 24.15 mmol) were added. The reaction was continued at room temperature for 12 h, the tetrahydrofuran was removed under vacuo, then dichloromethane (200 mL) were added and the organic phase washed with water (100 mL). The acqueous fraction was extracted with dichloromethane (1×100 mL). The organic fractions were combined, dried over sodium sulfate, filtered, and concentered in vacuo. Purification by flash chromatography on silica gel (eluant: dichloromethane/ethanol 95/5) provided 4.45 g (82%) of the title compound as a pale yellow solid.
Reaction SMILES: [Br:1][CH2:2][C:3]([OH:5])=O.[CH3:6][O:7][Si:8]([O:15][CH3:16])([O:13][CH3:14])[CH2:9][CH2:10][CH2:11][NH2:12]>Cl.CN(C)CCCN=C=NCC.C(Cl)Cl>[CH3:6][O:7][Si:8]([O:13][CH3:14])([O:15][CH3:16])[CH2:9][CH2:10][CH2:11][NH:12][C:3](=[O:5])[CH2:2][Br:1]
Reactant: CO[Si](CCCN)(OC)OC
Reactant: O=C(O)CBr
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CO[Si](CCCNC(=O)CBr)(OC)OC
Reaction time: 2 h

Procedure:
Binder DNA oligonucleotide-derivatized porous silicon films were employed to test the selectivity and limits of detection of a contemplated sensor. For attachment of DNA, a trimethoxy-3-bromoacetamido-propylsilane linker was synthesized by reaction of bromoacetic acid with trimethoxy-(3-aminopropyl)silane in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide-hydrochloride in methylene chloride as solvent. The linker product was purified by column chromatography on silica gel. The oxidized porous silicon samples were then contacted with a toluene solution of the linker for 2 hours. The resulting linker-bound substrate was thoroughly rinsed with pure toluene and methylene chloride, and dried for about 18 hours under reduced pressure.
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1.CC(C)=O>CC(=O)CC>[CH2:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: O=S1(=O)CCCO1
Reactant: CC(C)CCN
Solvent: CC(C)=O
Solvent: CCC(C)=O
Product: CC(C)CCNCCCS(=O)(=O)O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62 %

Procedure:
Isoamylamine (4 mL, 34.5 mmol) was added to a solution of 1,3-propane sultone (4.7 g, 38 mmol) in 2-butanone (70 mL). The mixture was warmed to reflux. After 30 minutes, the mixture was too thick to stir. Acetone (15 mL) was added. The reflux was maintained for a total of 4 hours. The suspension was cooled at room temperature. The white solid was collected by filtration, rinsed with acetone (10 mL), then with ether (10 mL). Compound CH was obtained as a very light, fluffy white solid (4.48 g, 62% yield). m.p. 220° C.: decomposed. 1H NMR (500 MHz, D2O) δ 0.65 (d, J=6.3 Hz, 6H), 1.29 (q, J=7.7 Hz, 2H), 1.35-1.42 (m, J=6.6 Hz, 1H), 1.86 (qt, J=7.6 Hz, 2H), 2.74 (t, J=7.3 Hz, 2H), 2.81 (t, J=8.1 Hz, 2H), 2.93 (t, J=7.8 Hz, 2H). 13C NMR (125 MHz, D2O) δ 21.3, 21.4, 25.2, 34.2, 46.1, 46.2, 47.9
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH3:10])[C:3]=1[C:13]#[N:14].[CH:15](OCC)(OCC)[O:16][CH2:17][CH3:18].C(OC(=O)C)(=O)C>O1CCOCC1>[C:13]([C:3]1[C:4]([C:7]([CH3:12])([CH3:11])[CH2:8][CH2:9][CH3:10])=[N:5][S:6][C:2]=1[N:1]=[CH:15][O:16][CH2:17][CH3:18])#[N:14]
Reactant: CCOC(OCC)OCC
Reactant: CCCC(C)(C)c1nsc(N)c1C#N
Solvent: CC(=O)OC(C)=O
Solvent: C1COCCO1
Product: CCCC(C)(C)c1nsc(N=COCC)c1C#N
Yield: 100.3 %

Procedure:
A solution of 25 g of 5-amino-4-cyano-3-(1,1-dimethylbutyl)isothiazole and 35.6 g of triethyl orthoformate in 200 ml of dioxane was heated under reflux for two hours. To the solution was added 24.5 g of acetic anhydride and the mixture was heated under reflux an additional 20 hours. The mixture wss concentrated under reduced pressure and the residue was distilled in a short path still at 120° under 0.1 mm Hg to give 31.8 g of 4-cyano-3-(1,1-dimethylbutyl)-5-[N-(ethoxymethylene)amino] isothiazole which was dissolved in 125 ml of ethanol, without further purification. The ethanolic solution was placed in a flask equipped with a gas inlet tube and one outlet of which was closed by a small rubber balloon. Dimethylamine gas was passed into the solution until the balloon remained inflated; during the introduction of dimethylamine, the temperature of the mixture increased to 60°. The reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a mixture of diethyl ether (90 parts) and pentane (10 parts) at low temperature to give 26.5 g of N'-[4-cyano-3-(1,1-dimethylbutyl)-5-isothiazolyl]-N,N-dimethylformamidine, m.p. 65°-67°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:11][CH2:10][C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1
Reactant: Sc1ccc(Br)cc1
Reactant: C=CC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCSc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 10.4 g (55.2 mmol) of 4-bromothiophenol and 6.49 g (55.4 mmol of ethyl acrylate in 5 mL of dichloromethane was added 4.13 g (41 mmol) of triethylamine at 0° C. under argon. The resulting solution was warmed to room temperature and stirred for 12 hours. The solution was then treated with 50 mL 10% aqueous NaOH and the product extracted into 3×100 mL ether.
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].CC(OC([N:15]([C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1)C(OC(C)(C)C)=O)=O)(C)C>ClCCl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[NH2:15][C:23]1[NH:24][C:25]([C:29]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([O:40][C:41]3[CH:46]=[C:45]([C:47]#[N:48])[CH:44]=[C:43]([Cl:49])[CH:42]=3)[C:34]=2[F:50])=[O:30])=[C:26]([Br:28])[N:27]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(Br)c(C(=O)NCc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c(N)nc3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.7 %

Procedure:
TFA (3.30 μl, 0.043 mmol) was added to a solution of bis(1,1-dimethylethyl)(4-bromo-5-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-imidazol-2-yl)imidodicarbonate (0.030 g, 0.043 mmol) in dichloromethane (2 mL). The mixture was stirred at RT overnight. The solvent was evaporated and the residue was purified by reverse phase HPLC (acetonitrile:water with 0. % TFA) to give the title compound (11 mg, 41%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.02-8.12 (m, 1H), 7.80 (s, 1H), 7.46-7.53 (m, 2H), 7.44 (s, 1H), 7.35 (t, 1H), 6.61 (br. s., 2H), 4.47 (s, 2H). ES MS m/z 499.
Reaction SMILES: [CH:1]([C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1)([CH3:3])[CH3:2].Br[CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19].[I-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:18]([CH2:17][CH2:16][CH2:15][CH2:14][N:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=[C:4]1[CH:1]([CH3:3])[CH3:2])([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CC(C)c1nc2ccccc2[nH]1
Reactant: CCOC(=O)CCCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCCn1c(C(C)C)nc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Part A. Sodium hydride (1.62 g of a 50% slurry, 33.8 mmol) was washed with hexane and dried under vacuum. Dimethylformamide (50 mL) was added, followed by a solution of 2-isopropyl-1H-benzimidazole (5.41 g, 33.8 mmol) in dimethylformamide (15 mL). After stirring at ambient temperature for two hours, the mixture was treated with ethyl 5-bromovalerate (5.50 mL, 34.8 mmol) and sodium iodide (1.19 g, 7.94 mmol). The mixture was heated to 80° C. for 18 hours, then cooled and poured into ethyl acetate (200 mL). This was washed with water (4×200 mL), then brine (200 mL), and dried over anhydrous magnesium sulfate, filtered and evaporated. The product, 1-(4-carboethoxybutyl)-2-(1-methylethyl)-1H-benzimidazole, was obtained as an oil after purification by silica gel chromatography (1:2 ethyl acetate-hexane) (9.54 g, 33.1 mmol, 98%). 1H NMR (CDCl3): 7.75 (1H, dd, J= 5.6, 3.1 Hz); 7.34-7.19 (3H, m); 4.12 (2H, q, J=7.1 Hz); 1.92-1.80 (2H, m); 1.78-1.65 (2H, m); 1.45 (6H, d, J=6.6 Hz); 1.24 (3H, t, J=7.0 Hz).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]=1[Br:23]>>[Br:23][C:13]1[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:15][O:16][C:12]=1[NH:11][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])=[O:8]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1onc(-c2ccccc2)c1Br
Product: O=S(=O)(Nc1onc(-c2ccccc2)c1Br)c1ccccc1
Yield: 36 %

Procedure:
This compound was prepared from benzenesulfonyl chloride and 5-amino-4-bromo-3-phenylisoxazole according to the method in Example 25b in 36% yield. Recrystallization from methanol gave a yellow solid, m.p. 113-115° C.
Reaction SMILES: CO[C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[O:13][CH3:14].[Na].[CH2:16]([OH:18])C>O>[CH3:14][O:13][C:4]1[CH:3]=[CH:12][C:11]([O:18][CH3:16])=[C:10]2[C:5]=1[CH2:6][CH:7]=[CH:8][CH2:9]2
Reactant: CCO
Reactant: COc1ccc2ccccc2c1OC
Agent: [Na]
Solvent: O
Product: COc1ccc(OC)c2c1CC=CC2

Procedure:
The dimethoxynaphthalene compound (66.5 mmol) was dissolved in 120 ml of ethanol. The resulting mixture was heated to reflux under nitrogen, and 11.7 g (0.51 mol) of sodium were added in portions. Stirring at reflux under nitrogen was continued until all of the solid had dissolved. The mixture then was stirred for 15 minutes at room temperature then cautiously diluted with 50 ml of water. The mixture was evaporated in vacuo to remove ethanol, and the remainder was diluted with water and extracted with ether. The organic extracts were combined, dried over sodium sulfate, and evaporated in vacuo to give 11.1 g of 5,8-dimethoxy-1,4-dihydronaphthalene as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:13]Br>CCOCC>[Br:13][CH2:2][C:1]([C:4]1[CH:8]=[CH:7][S:6][CH:5]=1)=[O:3]
Reactant: BrBr
Reactant: CC(=O)c1ccsc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Product: O=C(CBr)c1ccsc1
Reaction time: 0.17 h
Yield: 85.4 %

Procedure:
3-Acetylthiophene (6.3 g, 50 mmol) was dissolved in anhydrous ether (100 ml) and aluminium chloride (catalytic amount) added. Bromine (2.55 ml, 50 mmol) was added dropwise and then stirred for 10 min. The ether was removed under reduced pressure and the residue washed with water. The crude product was recrystallised from petroleum-ether (60°-80° C.) to yield 3-bromoacetylthiophene m.p. 54°-56° C. (8.76 g, 85%), δH (CDCl3) 8.15(1H, dd, H2), 7.55(1H, dd, H4'), 7.35(1H, dd, H5').
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CO.CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Solvent: CS(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3c(Cl)cccc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.50 g, 2.2 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.41 g, 2.2 mmol). The product was isolated as a white foam. Yield 370 mg (41%). mp 85°-90° C. FDMS m/e=421 (M+ of free base). α[D]589 =+3.62 (c=1.00, methanol/dimethylsulfoxide).
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[N:9]=[CH:8][C:7]=1[C:22]#[N:23])(O)=[O:2].S(Cl)([Cl:26])=O>>[Cl:26][C:1]([CH2:4][NH:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[Cl:21])[N:9]=[CH:8][C:7]=1[C:22]#[N:23])=[O:2]
Reactant: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1NCC(=O)O
Reactant: O=S(Cl)Cl
Product: N#Cc1cnn(-c2ccc(C(F)(F)F)cc2Cl)c1NCC(=O)Cl

Procedure:
A solution of 5-carboxymethylamino-1-(2-chloro-4-trifluoromethylphenyl)-4-cyanopyrazole (4.5 g; prepared as described in Example 26) in thionyl chloride (40 ml) was heated at reflux for 1 hour. The reaction mixture was cooled and evaporated under diminished pressure to give 5-chlorocarbonylmethylamino-1-(2-chloro-4-trifluoromethylphenyl)-4-cyanopyrazole (4.72 g), in the form of a red oil, which was used immediately in b or c below:
Reaction SMILES: C([C:4]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)(=O)C.ClC1C=[C:21](C=CC=1)[C:22]([O:24]O)=[O:23]>C(Cl)Cl>[C:22]([O:24][C:4]1[CH:17]=[CH:16][C:15]2[C:10]3[C:9](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:8]=[CH:7][C:6]=2[CH:5]=1)(=[O:23])[CH3:21]
Reactant: CC(=O)c1ccc2c(ccc3ccccc32)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(ccc3ccccc32)c1
Reaction time: 93 h
Yield: 64.3 %

Procedure:
A solution of 2.2 g (10 mmol) of 2-acetylphenanthrene in 50 mL of CH2Cl2 was stirred with 3.45 g (20 mmol) of m-chloro-peroxybenzoic acid for 3 h and allowed to stand for 93 h at room temperature. The solution was washed twice with 5% KOH solution and once with H2O, was dried and the solvent removed. From MeOH there was obtained 1.52 g of the title compound, m.p. 141°-142.5°.
Reaction SMILES: [Na].[OH:2][CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=[O:6].O1CCOCC1.[C:23]([O:26]C(=O)C)(=[O:25])[CH3:24]>O>[C:23]([OH:26])(=[O:25])[CH3:24].[OH:2][CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=1)=[O:6]
Reactant: CC(=O)OC(C)=O
Agent: O=C(C=CO)c1cccc(C(F)(F)F)c1
Agent: [Na]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)O

Procedure:
A suspension of 12.0 g. of 3-hydroxy-3'-(trifluoromethyl)acrylophenone sodium salt in 75 ml. of dioxane and 10 ml. of acetic anhydride is stirred at room temperature for 2 hours and then poured into water. The precipitate is collected by filtration, dissolved in methylene chloride and then passed through a hydrous magnesium silicate column as described in Example 1, giving the desired product, m.p. 55°-5° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[C:5]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[C:5]([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C)ccc1-n1cccn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2cccn2)c(C(=O)O)n1

Procedure:
A solution of methyl 6-methyl-3-(1H-pyrazol-1-yl)-2-pyridinecarboxylate D37 (106 mg) and LiOH (17.53 mg, 0.732 mmol) in THF/water (2:1, 6 ml) was stirred overnight. The mixture was evaporated under reduced pressure; the residue was taken up in water (2 ml) and the pH was adjusted to pH=2 with 1 M HCl solution. The mixture was loaded onto a pre-conditioned C18 column (5 g, eluted with water and then MeOH). The methanol fractions were evaporated under reduced pressure to give the title compound D38 (98 mg) as a white solid.
Reaction SMILES: [SH2:1].[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(N(CC)CC)C>N1C=CC=CC=1>[Br:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[S:1]
Reactant: N#Cc1ccccc1Br
Reactant: S
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC(=S)c1ccccc1Br
Temperature: 0 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
Gaseous hydrogen sulfide was bubbled into a stirred solution of 1.82 g (10.0 mmol) of 2-bromobenzonitrile, 13 mL of triethylamine and 10 mL of pyridine. After 4 hours, the reaction mixture was poured into 200 mL of ice-water mixture. The resultant oil slowly crystallized. The precipitate was removed by filtration, washed with water (3×) and dissolved in methylene chloride. The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was evaporated under vacuum to give 1.46 g (6.76 mmol, 68%) of the product. 1H NMR (200 MHz, CDCl3): 7.24 (m, 4H), 7.52 (dt, 1H), 8.59 (dd, 1H).
Reaction SMILES: [C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH2:15])[N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:39]=[CH:38][C:34]([C:35](Cl)=[O:36])=[CH:33][CH:32]=1>ClCCl>[C:1]1([C:7]2[N:22]=[C:10]3[CH:11]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=4)[CH:13]=[C:14]([NH:15][C:35](=[O:36])[C:34]4[CH:38]=[CH:39][C:31]([C:30]([F:29])([F:40])[F:41])=[CH:32][CH:33]=4)[N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12)c1ccc(C(F)(F)F)cc1
Yield: 60.9 %

Procedure:
A mixture of 0.29 g (0.001 mol) 2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-ylamine and 1.13 ml(0.014 mol) pyridine in 30 ml dichloromethane was stirred with 0.63 g(0.003 mol) p-trifluoromethyl benzoyl chloride for 18 hours at room temperature. Then another 0.63 g(0.003 mol) p-trifluoromethyl benzoyl chloride were added and stirring was continued at reflux temperature for 48 hours. After extraction with aqueous sodium hydroxide the organic solvents were distilled off and the residue was recrystallised from methanol to yield 0.28 g(60%) N-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-4-trifluoromethyl-benzamide as white crystals. MS m/e (%): 460 (M+H+, 100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][OH:10])([CH3:4])([CH3:3])[CH3:2].C(OCC)(=O)C.O.[C:19](#[N:22])[CH:20]=[CH2:21]>>[C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][O:10][CH2:21][CH2:20][C:19]#[N:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC#N
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOCCC#N
Temperature: 50 °C

Procedure:
[2-(2-Cyano-ethoxy)-ethyl]-carbamic acid tert-butyl ester (430 mg) was prepared starting from (2-hydroxy-ethyl)-carbamic acid tert-butyl ester (320 mg) in acrylonitrile (1.5 mL). The reaction was heated to 50° C. for 1 h. The reaction was added to ethyl acetate (20 mL) and water (20 mL). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organics were dried over sodium sulfate and then filtered. The solvent was evaporated and crude compound was purified by flash chromatography using hexane:ethyl actetate gradient.
Reaction SMILES: P(Br)(Br)([Br:3])=O.O[C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1.N>>[Br:3][C:7]1[N:8]=[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]2[CH:15]=1
Reactant: O=P(Br)(Br)Br
Reactant: Oc1cn2ccccc2n1
Agent: N
Product: Brc1cn2ccccc2n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 19.9 %

Procedure:
To 44.0 g of melted phosphorus oxybromide, 12.0 g of 2-hydroxyimidazo[1,2-a]pyridine is added at 60°-85° C. and stirred for 3 hours at 90° C. The mixture is poured into 300 ml of ice water, neutralized with aqueous ammonia and then extracted with chloroform. The collected chloroform layer is dried over anhydrous sodium sulfate. Chloroform is distilled off and the residue is purified by silica gel chromatography (eluent: chloroform) to obtain 3.5 g of the title compound as a crystalline solid.
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][C:3]1=[O:18].[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=O)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C(O)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][N:2]([N:1]=[C:29]2[CH2:30][CH2:31][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:27][CH2:28]2)[C:3](=[O:18])[CH2:4]1)=[O:9])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1=O
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(=NN2CCN(C(=O)OCc3ccccc3)CC2=O)CC1

Procedure:
A solution of 1-amino-4-benzyloxycarbonyl-2-piperazinone (2.49 g) and 1-(tert-butoxycarbonyl)-4-piperidone (1.99 g) in ethanol (40 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 15 hours. The reaction mixture was concentrated to obtain a crude 4-benzyloxycarbonyl-1-[1-(tert-butoxycarbonyl)-4-piperidinylideneamino]-2-piperazinone as an oil.