Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.[CH3:14][O-:15].[Na+]>O1CCCC1.CO>[NH2:1][C:2]1[C:3]([O:15][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: Cc1ccc2nc(Cl)c(N)nc2c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COc1nc2ccc(C)cc2nc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.9 %

Procedure:
To 3-amino-2-chloro-6-methylquinoxaline (550 mg, 2.84 mmol) dissolved in tetrahydrofuran (30 ml), 25 wt % sodium methoxide (6.14 g, 28.4 mmol) in methanol was added at room temperature and stirred further at room temperature for 60 minutes. The resulting mixture was concentrated under the reduced pressure to remove the solvent. The product was extracted with dichloromethane and the organic layer was washed with water and dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (2:1) mixture and concentration gave 467 mg of the titled compound (yield, 87%).
Reaction SMILES: [H-].[Na+].[N:3]1([CH2:9][CH2:10][CH2:11][OH:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][N:15]=1>CN(C=O)C>[N:21]1([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[N:15][CH:16]=2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: Brc1ccc(CN2CCCCC2)cn1
Reactant: OCCCN1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: c1cc(OCCCN2CCCCC2)ncc1CN1CCCCC1
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (1.5 mmol) in DMF is added 3-piperidin-1-yl-propan-1-ol (1.1 mmol). After 30 min, 2-bromo-5-piperidin-1-ylmethyl-pyridine (1 mmol) is added to the mixture. After 18 h, the reaction is extracted with ethyl acetate (100 mL) and washed with 1 N NaHCO3 (50 mL) and H2O(3×50 mL). The organic layer is dried, concentrated, and chromatographed on SiO2 to provide the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[N:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(N(CCCC)CCCC)CCC.[C:39]([O:43][CH2:44][CH3:45])(=[O:42])[CH:40]=[CH2:41]>C(#N)C.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[OH:10][NH:9][CH:8]([C:11]1[C:20]([CH3:21])=[CH:19][C:18]2[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=2[CH:12]=1)[C:4]1[CH:3]=[C:2]([CH:41]=[CH:40][C:39]([O:43][CH2:44][CH3:45])=[O:42])[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc2c(cc1C(=NO)c1cccc(I)c1)C(C)(C)CCC2(C)C
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCCCN(CCCC)CCCC
Product: CCOC(=O)C=Cc1cccc(C(NO)c2cc3c(cc2C)C(C)(C)CCC3(C)C)c1

Procedure:
A solution of (3-iodophenyl)-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)methanone oxime (320 mg, 0.7 mmol), palladium diacetate (20 mg, 89 μmol), tributylamine (392 μl, 1.7 mmol) and ethyl acrylate (78 μl, 0.7 mmol) in acetonitrile (10 ml) is heated for 4 h at 80° C. The reaction medium is extracted with ethyl ether and washed with water. After drying, the organic phase is concentrated on a rotary evaporator under vacuum at 40° C. The product is purified by flash- chromatography on a column of silica.
Reaction SMILES: S(=O)(=O)(O)O.C([NH2:8])=O.[CH2:9]([O:11][CH2:12][C:13]([O:15][CH2:16][C:17](=O)[C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=O)[CH3:10].Cl>O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]2[N:8]=[C:13]([CH2:12][O:11][CH2:9][CH3:10])[O:15][CH:16]=2)=[CH:19][CH:20]=1
Reactant: NC=O
Reactant: CCOCC(=O)OCC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCOCc1nc(-c2ccc(Cl)cc2)co1
Temperature: 140 °C
Yield: 45.6 %

Procedure:
40 g (0.41 mol) of concentrated sulphuric acid were added dropwise while stirring to 150 g (3.3 mol) of formamide, the temperature of the solution being held below 10° C. by cooling with ice. 50 g (0.2 mol) of (4-chlorobenzoyl)methyl ethoxyacetate were added and the solution was stirred and heated at 140° C. for 2 hours. The mixture was cooled, poured into 2 l of water, acidified to pH 1 by the addition of concentrated hydrochloric acid and extracted once with 500 ml of toluene and then twice with 250 ml of toluene each time. The combined toluene extracts were washed with water, dried over sodium sulphate, filtered and evaporated. The residual syrup was extracted with 700 ml of hot petrol (b.p. 60°-80° C.). The solution was evaporated to dryness and the residue was redissolved in 150 ml of hot petrol (b.p. 40°-60° C.). Upon cooling in acetone/CO2 the product crystallized and was filtered off rapidly and dried to give 21.7 g (47%) of 4-(4-chlorophenyl)-2-ethoxymethyl-oxazole in the form of a soft solid of indeterminate melting point.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].CC(=CC)C.O.O.P([O-])(O)(O)=[O:26].[Na+].Cl([O-])=O.[Na+]>O.C(O)(C)(C)C>[CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:26])=[O:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(C=O)cc2)cc1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CCc1ccc(Oc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C

Procedure:
An oxidation reaction (which is the method disclosed in Tetrahedron, (1987), 43, 4767-4776) was conducted using 4-(4-ethylphenoxy)benzaldehyde (which is the compound disclosed in J. Med. Chem., (1996), 39, 3984-3997, 500 mg, 2.21 mmol). 2-Methyl-2-butene (940 μL, 8.84 mmol), sodium dihydrogen phosphate dihydrate (338 mg, 2.16 mmol), and sodium chlorite (80%, 875 mg, 7.74 mmol) were added to a mixture solution of tert-butanol (3.6 mL) and water (1.0 mL) containing 4-(4-ethylphenoxy)benzaldehyde. The resulting mixture was stirred at room temperature, and the reaction was terminated with 1 N hydrochloric acid. After the extraction with ethyl acetate, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give 622 mg of 4-(4-ethylphenoxy)benzoic acid (white powder, yield: quantitative). Then, the same reaction as in Example 9 (9b) was conducted using all this 4-(4-ethylphenoxy)benzoic acid to give 437 mg of the title compound (pale red powder, yield: 66%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH:56]1[C:64]2[C:59](=[C:60]([CH2:65][NH2:66])[CH:61]=[CH:62][CH:63]=2)[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:66][CH2:65][C:60]2[CH:61]=[CH:62][CH:63]=[C:64]3[C:59]=2[CH:58]=[N:57][NH:56]3)=[CH:8][C:9]=1[CH2:10][CH3:11])=[O:4]
Reactant: NCc1cccc2[nH]ncc12
Reactant: CCc1cc(C(=O)O)sc1C(=O)OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)OC
Temperature: 25 °C
Reaction time: 48 h
Yield: 45.4 %

Procedure:
To a solution of 3-Ethyl-thiophene-2,5-dicarboxylic acid 2-methyl ester (130 mg, 0.61 mmol) in anhydrous DMF (5 mL) was added triethylamine (0.26 mL, 1.83 mmol), HBTU (0.35 g, 0.92 mmol), HOBT (0.099 g, 0.73 mmol), and C-(1H-Indazol-4-yl)-methylamine (100 mg, 0.67 mmol). The mixture was stirred at room temperature 2 d, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-80% EtOAc in hexane to afford the desired product (0.095 g, 46% yield).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O=S(Cl)[Cl:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([Cl:16])=[O:13]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2ccccc2c1
Product: O=C(Cl)c1ccc2ccccc2c1
Yield: 100 %

Procedure:
A 100 mL round bottom flask was charged with 2-naphthoic acid (2 g, 11.6 mmol) and SOCl2 (15 mL). The solution was refluxed for 4 hours and then concentrated to yield a yellow solid which was used without further purification (2.21 g, 100% yield); 1H NMR (CDCl3) δ 8.76 (s, 1H, ArH), 8.04 (2H, ArH), 7.93 (d, 2H, ArH, J=8.9 Hz), 7.66 (m, 2H, ArH).
Reaction SMILES: Cl.[CH2:2]([N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:3]([CH3:5])[CH3:4].[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([NH:39][C@H:40]([C:48](O)=[O:49])[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:38])=[CH:32][CH:31]=1>>[CH3:4][CH:3]([CH2:2][N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[C@H:7]([C:13]([OH:15])=[O:14])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:48]([C@@H:40]([NH:39][C:37]([CH2:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=1)=[O:38])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:49])[CH3:5]
Reactant: COc1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Reactant: CC(C)CN([C@@H](CCCCN)C(=O)O)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COc1ccc(CC(=O)N[C@@H](Cc2ccccc2)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(N)cc2)cc1

Procedure:
The title compound was prepared from Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-L-lysine hydrochloride (200 mg, 0.45 mmol, example 5, step C) as described in general procedure Bc using Nα-(4-methoxyphenylacetyl)-L-phenylalanine (example 132, step A). The final product, Nα-isobutyl-Nα-(4-nitrobenzenesulfonyl)-Nε-[N′α-(4-methoxyphenylacetyl)-L-phenylalanyl]-L-lysine was subsequently hydrogenolysed following the indications of general procedure E. Purification by HPLC gave the desired material (7 mg, 4%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:11]([C:12](=[O:23])[CH:13]([NH:15]C(=O)OC(C)(C)C)[CH3:14])[N:10]=[C:9]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:8]1)=[N+:2]=[N-:3].Cl>CCO>[NH2:15][CH:13]([CH3:14])[C:12]([N:11]1[N:10]=[C:9]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=2[F:31])[S:8][C:7]1([CH2:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:23]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(N)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN=[N+]=[N-])c1ccccc1
Temperature: 23 °C
Reaction time: 4 h
Yield: 95.8 %

Procedure:
tert-Butyl 1-(2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3 (2H)-yl)-1-oxopropan-2-ylcarbamate (70 mg, 0.131 mmol) was dissolved in 7.0 mL of EtOH. HCl (0.65 mL, 0.659 mmol) was then added and the reaction stirred at 23° C. for 4 hours. The reaction was then concentrated and purified by chromatography (2-10% MeOH/DCM), yielding the product (54 mg, 95%) as a yellow oil. MS ESI (+) m/z 431 (M+1) detected; 1H NMR (400 MHz, CD3OD) δ7.69 (m, 1H), 7.53 (d, 2H, J=8 Hz), 7.42 (t, 2H, J=7 Hz), 7.34 (m, 3H), 4.91 (m, 3H), 3.21 (m, 1H), 3.17 (m, 2H), 2.68 (m, 1H), 2.19 (m, 1H), 1.99 (m, 1H), 1.73 (d, 1.5H, J=8 Hz), 1.64 (d, 1.5H, J=8 Hz).
Reaction SMILES: S(O[CH2:12][CH2:13][C:14]#[C:15][Si:16]([CH2:21][CH3:22])([CH2:19][CH3:20])[CH2:17][CH3:18])(C1C=CC(C)=CC=1)(=O)=O.[C:23](=[NH:34])([O-:33])[C:24]1[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:26](=N)[O-:27].[K+].[K+]>CN(C)C=O>[CH2:19]([Si:16]([CH2:17][CH3:18])([CH2:21][CH3:22])[C:15]#[C:14][CH2:13][CH2:12][N:34]1[C:23](=[O:33])[C:24]2[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:26]1=[O:27])[CH3:20]
Reactant: N=C([O-])c1ccccc1C(=N)[O-]
Reactant: CC[Si](C#CCCOS(=O)(=O)c1ccc(C)cc1)(CC)CC
Agent: [K+]
Solvent: CN(C)C=O
Product: CC[Si](C#CCCN1C(=O)c2ccccc2C1=O)(CC)CC

Procedure:
108 g of (4-triethylsilanylbut-3-yn-1-ol) tosylate in 50 ml of dimethylformamide are added to a suspension of 72.3 g of potassium phthalimidate in 450 ml of dimethylformamide.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=1.C([Mg]Cl)(C)C.[C:33]([Si:37]([CH3:50])([CH3:49])[N:38]1[C:42]2[N:43]=[CH:44][CH:45]=[C:46]([CH:47]=[O:48])[C:41]=2[CH:40]=[CH:39]1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1>[C:33]([Si:37]([CH3:50])([CH3:49])[N:38]1[C:42]2=[N:43][CH:44]=[CH:45][C:46]([CH:47]([OH:48])[C:2]3[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=4)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[C:4]([CH3:27])[N:3]=3)=[C:41]2[CH:40]=[CH:39]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COCN(c1cc(Cl)c(C)nc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2c(C=O)ccnc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)c(C)nc1C(O)c1ccnc2c1ccn2[Si](C)(C)C(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 145 %

Procedure:
To a solution of N-(2-Bromo-5-chloro-6-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (152.7 mg, 0.3 mmol) in 2 ml of THF under nitrogen atmosphere at 0° C. was added via syringe 2.0M isopropyl magnesium chloride (0.36 ml, 0.72 mmol). The reaction mixture was stirred for about 45 minutes and 1-(tert-Butyl-dimethyl-silanyl)-1H-pyrrolo[2,3-b]pyridine-4-carbaldehyde (54 mg, 0.21 mmol) was added and the resultant mixture was stirred for 30 minutes at 0° C. and then 2 hours at room temperature. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was separated and washed with water twice and dried. Concentration of this mixture afforded the crude product (210 mg) which was used in the next step without any further purification. MS (ES) (M++H) expect 689. found 688.9
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16]([Sn:20]([CH2:27][CH2:28][CH2:29][CH3:30])([CH2:23][CH2:24][CH2:25][CH3:26])OC)[CH2:17][CH2:18][CH3:19]>ClCCCl>[CH2:27]([Sn:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:23][CH2:24][CH2:25][CH3:26])[O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1)[CH2:28][CH2:29][CH3:30]
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)OC
Solvent: ClCCCl
Product: CCCC[Sn](CCCC)(CCCC)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 60 °C
Yield: 81 %

Procedure:
In a 50 ml dry three-neck-flask 1.5 g (7.6 mmol) of 4-hydroxy-benzophenone are suspended in 25 ml of 1,2-dichloroethane and heated to reflux under argon flow. 2.7 g (8.4 mmol) of tri-n-butylmethoxy tin are added to the solution in the course of 0.5 h. The conversion is complete according to the 1H-NMR-spectrum. The solution is concentrated and dried in high vacuum. 4.1 g of an orange oil crystallize. The crude product is dissolved at 90° C. in 20 ml of heptane. The solution is cooled and at about 60° C. brown crystals begin to form. After filtration, further cooling and freezing, the formation of crystals continues. The crystals are filtered, dried and analyzed. The structure is confirmed by 1H-NMR and 13C-NMR spectra. 3.0 g of the title product are obtained, melting at 76-82° C.
Reaction SMILES: N#N.[CH2:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[CH3:29][C:30]1[NH:31][C:32]([CH3:41])=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1>CCCCCC.CCOCC>[CH3:29][C:30]1[NH:31][C:32]([CH3:41])=[CH:33][C:34]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:20]2[CH:21]=[CH:22][C:17]([CH2:16][CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][N:10]3[CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:18][CH:19]=2)[N:36]=1
Reactant: Cc1cc(-c2ccccn2)c(C)[nH]1
Reactant: Brc1ccc(CC2CCCCN2Cc2ccccc2)cc1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1cc(-c2cccc(-c3ccc(CC4CCCCN4Cc4ccccc4)cc3)n2)c(C)[nH]1
Temperature: -70 °C
Reaction time: 0.08 h
Yield: 16.2 %

Procedure:
To a 100 mL 3N round-bottomed flask equipped with septum and N2 inlet were added 175 mg (0.509 mmol) N-benzyl-2-(4-bromobenzyl)-piperidine and 7 mL dry ether. The solution was cooled to −70° C., and 0.38 mL (0.610 mmol) of a 1.6 M solution of butyl lithium in hexane added dropwise over 1 minutes. The reaction was stirred at −70° C. for 5 min, then warmed to room temperature over 20 minutes. To the stirring reaction was then added a solution of 105 mg (0.610 mmol) 2-(2,5-dimethylpyrrolyl)-pyridine in 5 mL dry ether, and the reaction, turning dark orange, was stirred at room temperature for 4 hours then quenched with aqueous ammonium chloride solution. After extraction into ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate for 16 hours to effect air-oxidation to the pyridine, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 36 mg (16%) of an oil.
Reaction SMILES: N[C:2]1[NH:10][C:9]2[N:8]=[CH:7][N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[C:4](=[O:18])[N:3]=1.N([O-])=[O:20].[Na+]>C(O)(=O)C.O>[CH2:11]([N:6]1[C:5]2[C:4](=[O:18])[NH:3][C:2](=[O:20])[NH:10][C:9]=2[N:8]=[CH:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=N[O-]
Reactant: Nc1nc(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a mixture of 2-amino-7-benzyl-3,7-dihydro-6H-purin-6-one (25.0 g, 0.104 mol) in acetic acid (750.0 mL) and water (50.0 mL) at 55° C. was added a solution of sodium nitrite (28 g, 0.41 mol) in water (50 ml) dropwise. After the addition, the mixture was continued to stir for about 30 min until no starting material was left and then cooled to room temperature. The reaction mixture was concentrated to about ⅓ of its original volume, then diluted with 250 ml water. The precipitate formed was collected by filtration to provide the desired product (20 g, 79.7%). LCMS calculated for C12H11N4O2(M+H): 243.1. found: 243.1.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>O.C(O)C>[CH3:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[CH:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH3:3])=[CH:5][CH:6]=2)=[O:12])=[CH:16][CH:15]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: Cc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C=CC(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 3.75 h
Yield: 92.2 %

Procedure:
To a solution of 0.97 g of sodium hydroxide in 9.7 ml of water was added 27.1 ml of ethanol. A solution of 2.563 g of p-methylacetophenone in 4 ml of ethanol was added dropwise to the mixture, followed by dropwise addition of a solution of 2.30 g of p-methylbenzaldehyde in 4 ml of ethanol. The resulting mixture was stirred at room temperature for 3.75 hours, and the solid matter was filtered, washed with cold water and ethanol and thoroughly desiccated to give 4.16 g of 4,4'-dimethylchalcone.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][NH:8][C:9]([NH2:11])=[O:10].C(N(CC)CC)C.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[C:19]([N:7]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)[NH:8][C:9]([NH2:11])=[O:10])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NC(=O)NNc1ccccn1
Reactant: O=C(Cl)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: NC(=O)NN(C(=O)c1ccccc1)c1ccccn1

Procedure:
A mixture was prepared by admixing 15.22 g (0.1 mole) of 2-(2-pyridinyl)hydrazinecarboxamide with a solution of 16.2 g (0.16 m) of triethylamine in 200 ml of acetonitrile. The mixture was stirred while a solution of 21.08 g (0.15 m) of benzoyl chloride in 50 ml of acetonitrile was added. After an induction period of ~5 minutes, the mixture exothermed reaching a peak temperature of 52° C. after 10 minutes. The reaction mixture was then stirred, without heating, for 51/2 hours and then heated under reflux for 2 hours. The mixture was cooled and the crude solid 2-benzoyl-2-(2-pyridinyl)hydrazinecarboxamide product was collected by filtration. The product was washed with water and air dried and recovered in a yield of 6.1 g (24 percent of theoretical). The product was recrystallized from methanol and melted at 206° C. and upon analysis, the product was found to have carbon, hydrogen and nitrogen contents of 60.53, 4.62 and 21.47 percent, respectively, as compared with the theoretical contents of 60.92, 4.72 and 21.87 percent, respectively, calculated for the above named compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14].CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][S:25]([CH3:24])(=[O:27])=[O:26])=[CH:6][C:5]=1[NH:12][C:13](=[O:15])[CH3:14]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CO)cc1NC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(COS(C)(=O)=O)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-acetylamino-4-hydroxymethyl-benzoic acid methyl ester (4 g, 17.9 mmol) and Et3N (7.5 mL, 3.0 equiv) in DCM (100 mL) at 0° C. was added MsCl (2.1 mL, 1.5 equiv) dropwise. At the end of the addition, the mixture was stirred 1 h at 0° C. The organic phase was washed with a saturated solution of NaHCO3 and then dried (Na2SO4). The solution was concentrated in vacuo to afford the title compound as a brown paste (5.4 g, 100%) (ES-MS: m/z 302.2 [M+H]+, rt 4.58 min).
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[CH2:22]([NH2:24])[CH3:23]>C(O)C>[CH2:22]([NH:24][CH2:2][C:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][C:5](=[O:13])[C:4]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH3:23]
Reactant: CCN
Reactant: COc1ccc(C2=C(CBr)C3(CCCCC3)NC2=O)cc1
Solvent: CCO
Product: CCNCC1=C(c2ccc(OC)cc2)C(=O)NC12CCCCC2
Yield: 98 %

Procedure:
4-Bromomethyl-3-(4-methoxyphenyl)-1-azaspiro[4.5]dec-3-ene-2-one (250 mg, 0.71 mmol) was dissolved in ethanol (15 mL) and ethylamine (70% solution in water, 2 mL), the mixture was stirred overnight at room temperature and concentrated. The residue was dissolved in CH2Cl2, washed with water and extracted with 0.5 M HCl. After addition of NaOH and extraction with CH2Cl2 the organic layer was dried (Na2SO4) and evaporated to yield 0.22 g (98%)of 4-ethylaminomethyl-3-(4-methoxyphenyl)-1-azaspiro[4.5]dec-3-ene-2-one, shown below, as a solid. MS (IS): 315 [MH]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1>C1COCC1>[OH:45][C:42]1[CH:43]=[CH:44][C:39]([CH2:38][NH:37][C:2]2[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]3[CH:27]=[CH:26][C:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:17][CH:16]=3)[N:3]=2)=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: NCc1ccc(O)cc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(Nc2nc(NCc3ccc(O)cc3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Yield: 84.8 %

Procedure:
To a suspension of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (10 g, 24.71 mmol) and Hunig's Base (8.63 mL, 49.4 mmol) in THF (100 mL) was added 4-(aminomethyl)phenol (3.19 g, 25.9 mmol). The resulting mixture was refluxed for 1 hour. After cooling to rt, the solvent was removed and the crude product was purified by silica gel chromatography using 20-40-100% EtOAc/Hexanes to give tert-butyl 4-((4-((4-hydroxybenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzoate (10.3 g, 85%) as white solid.