Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=O)[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12]C(C)(C)C)=[O:11])(C)(C)C.CN1CCOCC1.[NH2:42][OH:43].Cl.[OH-].[K+]>C1COCC1.CO>[Br:33][C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([S:17]([N:8]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][C:6](=[O:5])[NH:42][OH:43])(=[O:19])=[O:18])=[CH:21][CH:22]=2)=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCOCC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CN(CC(=O)NO)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
{Carboxymethyl-[4-(4-bromo-phenoxy)-benzenesulphonyl]-amino}-acetic acid (4d) (1.90 g, 4.30 mmol) was dissolved in dry THF (50 mL). ECF (0.35 mL, 3.70 mmol), and NMM (0.40 mL, 3.70 mmol) were added and stirred for 40 min at 0° C. NH2OH×HCl (0.30 g, 4.30 mmol) and KOH (0.24 g, 4.30 mmol) were dissolved in dry MeOH (20 mL) and stirred at 0° C. for 30 min. The solids were filtered off, and the THF solution was added dropwise to the methanol filtrate and stirred for 2 h at 0° C. The reaction mixture was filtered, the solvent evaporated, and the residue dissolved in H2O (20 mL). After adjusting the pH to 1-2, the aqueous layer was extracted with EtOAc (3×30 mL). The combined organic layers were dried over MgSO4 and evaporated in vacuo to yield the pure product as white crystals. Yield: 1.80 g, 3.90 mmol, 91%. 1H NMR (D2O): δ 7.7 (d, J=8.2 Hz, 2H, ArH), 7.5 (d, J=8.8 Hz, 2H, ArH), 7.0 (d, J=8.8 Hz, 2H, ArH), 4.0 (s, 4H, CH2COOH). ESI-MS calcd for C16H15BrN2O7S 457.98 [M-H]−, obsd 459.27.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].[OH:9][C:10]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=1[CH:12]=O.[CH2:19](O)[CH3:20]>>[OH:9][C:10]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:11]=1[CH:12]1[NH:2][CH:3]([C:6]([O:8][CH2:19][CH3:20])=[O:7])[CH2:4][S:5]1
Reactant: O=Cc1cc(O)ccc1O
Reactant: CCO
Reactant: N[C@@H](CS)C(=O)O
Agent: Cl
Product: CCOC(=O)C1CSC(c2cc(O)ccc2O)N1

Procedure:
To a round bottom flask, equipped with magnetic stirrer, containing 9.25 g (50 mM) ethyl ester of L-cysteine hydrochloride in 75 mL of absolute ethanol was added 8.4 mL (48 mM) ethyldulsopropylamine. A clear solution was obtained after stirring for several minutes with a magnetic stirrer under nitrogen. To this solution was added 6.65 g (49 mM) 2,5-dihydroxybenzaldehyde in 50 mL absolute ethanol, and the reaction mixture was stirred for another 4 hrs. Evaporation to dryness produced a viscous oil, which was dissolved in 20 mL absolute ethanol and loaded on a silica gel column. Elution with ethylacetate/hexane (at molar ratios from 2:8 to 3.5:6.5) produced 5.9 g of the desired product. 1H NMR (DMSO-d6; 1:1 diastereoisomeric mixture at C2)δ; 1.21-1.25 m 3H; 2.95-3.02 m and 3.19-3.22 m, 2H; (3.5 m, 3.76 m 3.90 m and 4.25 m, 2H); 4.15 m, 2H; (5.56 d, J=11.9 Hz and 5.75 d, J=9.9 Hz, 1H); (6.45-6.48 dd, J=2.9 Hz, 8.7 Hz, 6.52-6.55 dd, J=2.9 Hz, 8.7 Hz, 6.57 d, J=8.8 Hz, 6.61 d, J=8.8 Hz 2H); 6.76 dd, J=2.8 Hz, 9.2 Hz, 1H; 8.64 s and 8.75 s, 1H; 9.01 s and 9.19 s 1H.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5](=O)[CH2:6][C:7](=O)[CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH3:2].[NH2:22][NH2:23]>CCO>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[NH:23][N:22]=1)=[O:21])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(=O)CCCO[Si](C)(C)C(C)(C)C
Reactant: NN
Solvent: CCO
Product: CCOC(=O)c1cc(CCCO[Si](C)(C)C(C)(C)C)[nH]n1
Yield: 2.1 %

Procedure:
A solution of 7-(tert-butyl-dimethyl-silanyloxy)-2,4-dioxo-heptanoic acid ethyl ester (1.627 g, 51.4 mmol) and hydrazine (17 mL, 55 mmol) in EtOH was heated at reflux for 6 h. The reaction was concentrated in vacuo. Purification by flash chromatography (6:4 hexanes:EtOAc) provided the title compound (333 mg). 1H NMR (400 MHz, CDCl3) δ6.64 (s, 1H), 4.37 (q, 2H), 3.67 (t, 2H), 2.85 (t, 2H), 1.88 (m, 2H), 1.38 (t, 3H), 0.88 (s, 9H), 0.05 (s, 6H); MS 313 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]([OH:21])=O)=[CH:4][CH:3]=1.[CH2:22](CCN)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH3:32][CH2:33][N:34]=C=NCCCN(C)C.Cl>ClCCl>[CH2:22]([N:34]([CH2:33][CH3:32])[C:19](=[O:21])[CH2:18][C:17]1[N:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]2=[N:9][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccn2c(CC(=O)O)c(-c3ccc(Cl)cc3)nc2c1
Reactant: CCN=C=NCCCN(C)C
Reactant: NCCCc1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCN(Cc1ccccc1)C(=O)Cc1c(-c2ccc(Cl)cc2)nc2cc(C)ccn12
Temperature: 25 °C
Yield: 39.9 %

Procedure:
0.9 g (0.003 mol) of 2-(4-chlorophenyl)-7-methylimidazo[1,2-a]-pyridine-3-acetic acid and 0.6 g (0.0045 mol) of N-benzylethylamine were weighed, added to 80 mL of dry dichloromethane, then added with 1.0 g (0.005 mol) of EDC hydrochloride. Stirred at room temperature and reacted for 24 h, stopped the reaction until almost completion of the reaction. Filtered to remove solid urea, concentrated, and then separated with silica gel column chromatograph to obtain a crude product which was recrystallized with acetone to obtain a pure white solid powder, 0.5 g in total, yield 39.9%. m.p. 192-193° C., ESI-MS m/z: 419[M+H]+, 1H NMR (CDCl3, 400 MHz)δ: 1.20(t, 3H, J=7.00 Hz), 2.54(s, 1.7H), 2.56(s, 1.3H), 3.38(q, 0.8H, J=7.00 Hz), 3.57(q, 1.2H, J=7.00 Hz), 4.11(s, 1H), 4.21(s, 1H), 4.59(s, 0.7H), 4.62(s, 1.3H), 7.09-7.15(m, 2H), 7.24-7.37(m, 5H), 7.46-7.56(m, 2H), 7.69-7.71(m, 1H), 8.09-8.23(m, 2H).
Reaction SMILES: [O:1]=[C:2]1[C@@H:6](OS(C)(=O)=O)[CH2:5][CH2:4][NH:3]1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH:6]3[CH2:5][CH2:4][NH:3][C:2]3=[O:1])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:18]=1
Reactant: CS(=O)(=O)O[C@H]1CCNC1=O
Reactant: O=C(c1ccc(Cl)cc1)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(Cl)cc1)C1CCN(C2CCNC2=O)CC1
Temperature: 85 °C
Yield: 30.8 %

Procedure:
A 10 mL microwave vial containing methanesulfonic acid (S)-2-oxo-pyrrolidin-3-yl ester (0.56 mmol, 100 mg) and (4-chloro-phenyl)-piperidin-4-yl-methanone (0.56 mmol, 125 mg) in DIEA (2.8 mmol, 0.5 mL) was heated to 85° C. for 105 min. The diisopropylethylamine was decanted off and flash column chromatography (silica) was performed eluting with ethyl acetate to 20% MeOH/ethyl acetate afforded the title compound (53 mg, 31% yield). MS (ESI) m/e 307.3 (M+H+), calculated 306.2; HPLC (Novapak 150×3.9 mm C18 column: mobile phase: 10-90% acetonitrile/water with 0.1% TFA, at 2 mL/min over 5 min.) retention time=2.506 min.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:28])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]=[C:14]([C:16]3[S:17][C:18]([CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[C:19]([CH3:21])[CH:20]=3)[O:13][N:12]=2)=[CH:7][CH:6]=1.[C:29](O)(=[O:32])[CH2:30][OH:31]>>[CH2:26]([N:23]([CH2:22][C:18]1[S:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][CH:3]([OH:28])[CH2:2][NH:1][C:30](=[O:31])[CH2:29][OH:32])=[CH:6][CH:7]=3)[N:15]=2)=[CH:20][C:19]=1[CH3:21])[CH2:24][CH3:25])[CH3:27]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CN)cc3)no2)cc1C
Reactant: O=C(O)CO
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CC(O)CNC(=O)CO)cc3)no2)cc1C
Yield: 54.1 %

Procedure:
The title compound (31 mg) is prepared in analogy to Example 163 starting from rac-1-amino-3-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-propan-2-ol (50 mg, 125 μmol) and glycolic acid (13 mg, 175 μmol); LC-MS: tR=0.68 min; [M+1]+=458.68. 1H NMR (CDCl3): δ1.09 (t, J=7.0 Hz, 6H), 2.23 (s, 3H), 2.62 (q, J=7.0 Hz, 4H), 2.75-2.87 (m, 2H), 3.18-3.28 (m, 1H), 3.50-3.58 (m, 1H), 3.70 (s, 2H), 3.94-4.02 (m, 1H), 4.06 (s, 2H), 7.14 (t, J=5.5 Hz, 1H), 7.33 (d, J=8.3 Hz, 2H), 7.64 (s, 1H), 8.03 (d, J=8.0 Hz, 2H).
Reaction SMILES: [CH:1]1[C:11]2[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.C(OCC)(=O)C>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([N:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[N:10]3[CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: c1ccc2c(c1)NCCc1cccn1-2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCc2cccn2-c2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 mmol of 6,7-dihydro-5H-pyrrolo[1,2-a][1,5]benzodiazepine in 30 ml of methylene chloride under argon is added 15 mmol of triethylamine followed by ice bath cooling. A solution of 11 mmol of 4-nitrobenzoyl chloride in 10 ml of methylene chloride is added dropwise. Following complete addition, the ice bath is removed and the reaction mixture stirred at room temperature for 2 hours. The volatiles are removed in vacuo to give a residue which is dissolved in ethyl acetate. The solution is washed with water, 2N citric acid, NaHCO3, and brine. The reaction mixture is dried with Na2 SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography on silica gel to give the desired product as a solid.
Reaction SMILES: S[C:2]1[S:3][C:4]2[CH:10]=CC=[CH:7][C:5]=2[N:6]=1.[C:11]1([CH3:23])[CH:16]=[CH:15][C:14]([S:17]([O:20]CC)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(O)C>[C:11]1([CH3:23])[CH:12]=[CH:13][C:14]([S:17]([O-:20])(=[O:18])=[O:19])=[CH:15][CH:16]=1.[CH2:4]([S:3][C:2]1[S:17][C:14]2[CH:13]=[CH:12][CH:11]=[CH:16][C:15]=2[N+:6]=1[CH2:5][CH3:7])[CH3:10]
Reactant: Sc1nc2ccccc2s1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCO
Product: CCSc1sc2ccccc2[n+]1CC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 150 °C

Procedure:
A mixture of 3.3 g of 2-mercaptobenzothiazole and 10.0 g of ethyl p-toluenesulfonate was heated to 150° C. to react them for 6 hours. The reaction product was cooled to 80° C. and then 30 ml of ethanol was added to it, thereby producing an ethanol solution of 2-ethylmercapto-3-ethylbenzothiazolium p-toluenesulfonate.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:18][CH2:17][N:9]2[C:10]3[C:15]([CH:16]=[C:8]2[CH2:7]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:5].[CH:20]([Mg]Cl)([CH3:22])[CH3:21].[Cl-].[NH4+]>O1CCCC1>[CH:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH:16]=[C:8]1[CH2:7][C@@H:6]([C:4]([CH:20]([CH3:22])[CH3:21])=[O:5])[CH2:18][CH2:17][N:9]12
Reactant: CC(C)[Mg]Cl
Reactant: CON(C)C(=O)[C@H]1CCn2c(cc3ccccc32)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)C(=O)[C@H]1CCn2c(cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of 10.0 g (38.7 mmol) of 6,7,8,9-tetrahydro-N-methoxy-N-methyl-pyrido[1,2-a]indole-8(S)-carboxamide in 250 ml of tetrahydrofuran was treated dropwise at 0° C. with 60 ml (120 mmol) of a 2M solution of isopropylmagnesium chloride in tetrahydrofuran. The mixture was stirred at room temperature for 18 hours and poured into 250 ml of saturated ammonium chloride solution. The aqueous phase was washed four times with 100 ml of diethyl ether each time and the combined ethereal extracts were washed with 200 ml of brine, dried over magnesium sulfate and evaporated to dryness. The product was purified by flash chromatography on silica gel using ethyl acetate/petroleum ether (1:3) for the elution to give 4.4 g of isopropyl 6,7,8,9-tetrahydropyrido[1,2-a]indol-8(S)-yl ketone as a white solid of melting point 78°-79° C.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:3]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:7][CH2:6]1)=[O:4].CCN(C(C)C)C(C)C.[C:39]([NH:46][C@H:47]1[CH2:51][CH2:50][C@@H:49]([C:52](O)=[O:53])[CH2:48]1)([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:2]([NH:1][C:52]([C@H:49]2[CH2:50][CH2:51][C@@H:47]([NH:46][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:48]2)=[O:53])[C:3]([N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[NH:17][S:18]([CH3:21])(=[O:19])=[O:20])[CH2:7][CH2:6]2)=[O:4])=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)C1
Reactant: CS(=O)(=O)Nc1ccccc1C1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3NS(C)(=O)=O)CC2)C1
Yield: 62.1 %

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step (f) using (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperidyl)propan-1-one (Example 1, Step g) (471 mg, 1.0 mmol), DIEA (Aldrich) (0.20 mL, 1.0 mmol), (−)-(1S, 3R)—N-Boc-aminocyclopentane-3-carboxylic acid (PepTech Corporation) (344 mg, 1.5 mmol), HOAT (Aldrich) (232 mg, 1.70 mmol) and EDC (Aldrich) (544 mg, 2.84 mmol) in DMF (10 mL). Purification by silica gel chromatography (100% EtOAc) provided the title compound as a white foam (402 mg). MS (ESI, pos. ion) m/z: 647 (M+1); MS (ESI, neg. ion) m/z: 645 (M−1). Calc'd for C32H43ClN4O6S: 647.23.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:19]O)[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.S(Cl)([Cl:23])=O>CCOCC>[ClH:23].[Cl:23][CH2:19][C:13]1[N:14]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[C:2]([NH2:1])[C:11]=2[N:12]=1
Reactant: CC(C)Cn1c(CO)nc2c(N)nc3ccccc3c21
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: CC(C)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (5.0 g; 0.0185 mol, Example 9) was added in small portions to vigorously stirred thionyl chloride (25 mL). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with 100 mL of ether, and the solid was filtered from the mixture and dried thoroughly. The product was pure enough for further reactions. A sample was recrystallized from ethanol to give a pure product which melted with decomposition from 279-292° C. Analysis: Calculated: C, 55.4; H, 5.6; N, 17.2. Found: C, 55.3; H, 5.5; N, 17.1.
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[Cl:7][C:8]1[C:9]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)=[N:10][NH:11][CH:12]=1.C(N(CC)CC)C.O>CN(C=O)C>[CH:1]([NH:4][C:5]([N:11]1[CH:12]=[C:8]([Cl:7])[C:9]([C:13]2[CH:14]=[C:15]([Cl:20])[CH:16]=[C:17]([Cl:19])[CH:18]=2)=[N:10]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Clc1cc(Cl)cc(-c2n[nH]cc2Cl)c1
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)NC(=O)n1cc(Cl)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 2 h
Yield: 63.1 %

Procedure:
0.95 g (0.011 mol) of isopropyl isocyanate are added, dropwise and at 0° C., to a solution of 2.55 g (0.01 mol) of 4-chloro-3-(3,5-dichlorophenyl)-1H-pyrazole and 1.55 ml (0.011 mol) of triethylamine in 20 ml of anhydrous DMF. Stirring is continued for 2 h at room temperature. The reaction mixture is poured into 100 ml of water and extracted with ethyl acetate. After drying the organic phase and concentration under vacuum, the residue is triturated with 50 ml of heptane, filtered and dried. We obtain 2.10 g of 1-isopropylaminocarbonyl-4-chloro-3-(3,5-dichlorophenyl)pyrazole, melting at 127° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22](OC)=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[CH:26][C:19]([O:20][CH2:21][C:22]([NH:32][CH2:31][CH2:30][O:29][CH3:28])=[O:23])=[CH:18][CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: COCCN
Reactant: COC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Product: COCCNC(=O)COc1ccc(C(=O)CN2CCN(c3ccncc3)CC2)cc1
Reaction time: 18 h

Procedure:
A suspension of the product of Example 1, (100 mg) in 2-methoxyethylamine (1 ml) was stirred for 18 hours. Filtration of the solid and washing with ethyl acetate gave the title compound, 70 mg, as a white crystalline solid: m.p. 142°-145° C.; NMR (d6DMSO+d4 acetic acid) δ 8.20 (2H, d), 8.00 (2H, d), 7.14 (2H, d), 7.06 (2H, d), 4.62 (2H, s), 3.72 (4H, t), 3.38 (4H, m), 3.26 (3H, s), 2.78 (4H, t); m/e 413 (M+H)+ ; calculated for C22H28N4O4 : C, 64.1; H, 6.8; N, 13.6. found: C, 63.9; H, 6.8; N, 13.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C:11]([N:13]=[C:14]([S-:16])[S-:15])#[N:12].[K+].[K+].[OH2:19]>CO>[OH:19][C:11]1[N:13]=[C:14]([S:16][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:2]=2[Cl:1])[S:15][N:12]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: N#CN=C([S-])[S-]
Reactant: O
Agent: [K+]
Solvent: CO
Product: Oc1nsc(SCc2ccc(Cl)cc2Cl)n1
Temperature: 30 °C

Procedure:
72 g of 2,4-dichlorobenzyl chloride were added at 30° C to a mixture of 69.9 g of dipotassium N-cyanodithioimidocarbonate, 50 ml of water and 300 ml of methanol and the mixture was stirred at 30° C. for one-half hour. The methanol was evaporated under reduced pressure and 900 ml of water were added to the residue. 40 ml of 30% hydrogen peroxide were slowly added and the pH was kept basic by addition of potassium hydroxide. the mixture was stirred for 17 hours, was washed with ethyl acetate and was acidified with hydrochloric acid. The mixture was vacuum filtered and the precipitate was crystallized from toluene to obtain 32 g of 3-hydroxy-5-(2,4-dichlorobenzylthio)-1,2,4-thiadiazole melting at 134° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[O:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)[CH3:13]>C(O)(=O)C.CCO>[CH2:12]([C:14]1[O:18][C:17]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: CCc1ccc(C=O)o1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(C=NNC(=O)c2ccc(O)cc2)o1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-ethyl-2-furaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by pet ether to give red solid 0.44 g, in 85% yield, mp: 60.5° C. 1H NMR (DMSO-d6) δ 11.53 (s, 1H), 10.16 (s, 1H), 8.24 (s, 1H), 7.79 (d, 2H), 6.87 (d, 2H), 6.81 (s, 1H), 2.71 (q, 2H), 1.24 (t, 3H). 13C NMR (DMSO-d6) δ 164.5, 162.1, 161.2, 149.8, 138.5, 131.5, 125.7, 116.9, 116.7, 108.9, 22.8, 13.8. Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.00; H, 5.36; N, 10.55.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[N:4][C:3]=1[CH3:10].[CH:11](=[O:20])[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>>[OH:20][CH:11]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[CH2:10][C:3]1[C:2]([CH3:1])=[N:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Cc1nc(C)c(C)nc1C
Product: COc1ccc(C(O)Cc2nc(C)c(C)nc2C)cc1
Yield: 52.1 %

Procedure:
The reaction of 13.6 grams (0.1 mole) of tetramethylpyrazine with 13.6 grams (0.1 mole) of p-anisaldehyde was conducted in the manner described in Example II. Crystallization of the recovered crude product from ether yielded 14.2 gram (52%) of white crystals, m.p. 97°-98° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11](S(C)(=O)=O)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:32]([Mg]Br)[CH2:33][CH3:34].Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:16])=[C:13]([CH3:27])[N:12]=[C:11]([CH2:32][CH2:33][CH3:34])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Cc1nc(S(C)(=O)=O)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Reactant: CCC[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)c(C(=O)NCCCc2ccccc2)c(-c2cc(Cl)cc(Cl)c2)n1
Reaction time: 1 h

Procedure:
100 mg (0.209 mmol) of 4-(3,5-dichlorophenyl)-6-methyl-2-(methylsulfonyl)-N-(3-phenylpropyl)-5-pyrimidinecarboxamide was dissolved in 3 ml of THF. 0.349 ml (0.90 mol/l, THF solution) of n-propyl magnesium bromide was added at 0° C. and stirred at the same temperature for 1 hour. 10% hydrochloric acid was added at the same temperature and stirred for 10 minutes. After the reaction mixture was diluted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: Br[C:2]1[C:3]([CH3:12])=[N:4][C:5]([O:10]C)=[C:6]([CH2:8][CH3:9])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1>[Cu](I)I>[CH2:8]([C:6]1[C:5](=[O:10])[NH:4][C:3]([CH3:12])=[C:2]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)[CH:7]=1)[CH3:9]
Reactant: CCc1cc(Br)c(C)nc1OC
Reactant: c1c[nH]nn1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1cc(-n2nccn2)c(C)[nH]c1=O
Temperature: 185 °C
Yield: 11.3 %

Procedure:
Into a microwave vial is added 3-bromo-5-ethyl-6-methoxy-2-methyl-pyridine (400 mg, 1.74 mmol), potassium carbonate (360 mg, 2.61 mmol), copper iodide (50 mg, 0.263 mmol) and 1,2,3-triazole (201 μL, 3.47 mmol). The vial is flushed with nitrogen before anhydrous dimethylformamide (4 mL) is added then sealed. The reaction is heated in the CEM Discover microwave at 185° C. for 20 min (4 bar pressure attained). LC/MS shows the reaction is incomplete. The reaction is re-microwaved to 180° C. for 20 min. Further copper iodide (50 mg) is added, the reaction flushed with nitrogen and is re-microwaved to 180° C. for 20 min. LC/MS shows the reaction is complete with the formation of 2 materials. The reaction is diluted with water and extracted with six portions of dichloromethane. The combined extracts are then dried over magnesium sulfate and evaporated to give a dark oil. The crude product is purified by flash chromatography on a 5-gram silica gel cartridge by elution with dichloromethane:ethyl acetate (3:1, increasing to 2:1 then 1:1). Fractions containing the higher Rf product are combined, the solvent evaporated and the residue is triturated twice with heptane and twice with ether to give 3-ethyl-6-methyl-5-(1,2,3-triazol-2-yl)-1H-pyridin-2-one (40 mg, 11% yield) as a white powder. LC/MS: RT: 2.19 min, MS: m/e=205 (M+H); 1H NMR (δ, ppm): 11.93 (1H, s), 8.04 (2H, s), 7.40 (1H, s), 2.41 (2H, q), 2.06 (3H, s), 1.09 (3H, t).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[N:6]=[N:5][N:4]=1.C(N(CC)CC)C.[NH:25]1[CH2:30][CH2:29][NH:28][CH2:27][C:26]1=[O:31]>C(#N)C>[F:15][C:14]([F:17])([F:16])[C:10]1[CH:9]=[C:8]([N:7]2[C:3]([CH2:2][N:28]3[CH2:29][CH2:30][NH:25][C:26](=[O:31])[CH2:27]3)=[N:4][N:5]=[N:6]2)[CH:13]=[CH:12][CH:11]=1
Reactant: O=C1CNCCN1
Reactant: FC(F)(F)c1cccc(-n2nnnc2CCl)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CN(Cc2nnnn2-c2cccc(C(F)(F)F)c2)CCN1
Temperature: 120 °C

Procedure:
To a solution of 5-(chloromethyl)-1-[3-(trifluoromethyl)phenyl]-1H-tetrazole (400 mg, 1.52 mmol, commercially available from Otava, Kiev, Ukraine) in acetonitrile (5 mL) was added triethylamine (0.637 mL, 4.57 mmol) and 2-piperazinone (168 mg, 1.675 mmol, Sigma-Aldrich). The reaction mixture was heated to 120° C. for 20 min in a microwave reactor.