Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].N([O-])=[O:11].[Na+]>C(O)(=O)C.O>[O:11]=[C:2]([C:3](=[O:4])[CH3:5])[C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=O)C(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 50 g portion of ethyl acetoacetate in 60 ml of acetic acid was stirred at 0° C. to 10° C., as a solution of 30 g of sodium nitrite in 50 ml of water was added dropwise. When addition was complete, the mixture was stirred at 0° to 10° C. for 30 minutes and then diluted with 300 ml of ice water. The mixture was stirred for 2 hours and then extracted with 500 ml of dichloromethane. The dichloromethane layer was separated, washed with two 500 ml portions of ice water, dried, filtered and evaporated in vacuo. The residual oil was stirred vigorously with 200 ml of hexane and the resulting solid collected, washed with hexane and air dried, giving 31.4 g of 2,3-dioxobutyric acid, ethyl ester, (Z)-2-oxime.
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)=[O:4].[C:11](#[N:13])[CH3:12].[H-].[Na+:15].C(OC)(C)(C)C>C1COCC1>[C:11]([CH:12]=[C:3]([C:5]1[CH:10]=[N:9][CH:8]=[CH:7][N:6]=1)[O-:4])#[N:13].[Na+:15]
Reactant: COC(=O)c1cnccn1
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: N#CC=C([O-])c1cnccn1
Reaction time: 0.5 h

Procedure:
A solution of 1.5 g (10.9 mmol) of methylpyrazine-2-carboxylate and 446 mg (10.9 mmol) of acetonitrile in 16.5 ml of THF was added dropwise to a suspension, heated under reflux, of 434 mg of sodium hydride (60% strength suspension in mineral oil) in 10 ml of THF. The reaction mixture was heated under reflux for 20 h. After cooling, 50 ml of methyl tert-butyl ether were added and the mixture was stirred for 30 minutes. The precipitate formed was filtered off with suction over a frit and dried under oil pump vacuum. This gave 1.77 g (96% of theory) of the title compound which was used without further characterization for the next step.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1.[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][O:1][C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][O:9][C:4]=2[CH:3]=1
Reactant: CI
Reactant: COC(=O)C1=COc2cc(O)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1=COc2cc(OC)ccc2O1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
Stir for 15 minutes at room temperature, under argon, a solution of 0.48 mmol of methyl 6-hydroxy-1,4-benzodioxin-2-carboxylate in 5 cm3 of N,N-dimethylformamide in the presence of 0.57 mmol of 60% sodium hydride suspended in oil, and then add 0.72 mmol of methyl iodide. After being stirred for 4 hours at room temperature, the reaction mixture is concentrated under reduced pressure and then extracted with methylene chloride. After the methylene chloride phases have been concentrated to dryness, the crude product is purified by chromatography on a silica column (eluant: petroleum ether/ethyl acetate, 80:20). Methyl 6-methoxy-1,4-benzodioxin-2-carboxylate is thereby obtained in a yield of 78%.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]#[C:11][Si](C)(C)C)=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:16].O1CCCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>O>[NH2:1][C:2]1[C:9]([C:10]#[CH:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[Br:16]
Reactant: C[Si](C)(C)C#Cc1cc(C#N)cc(Br)c1N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(C#N)cc(Br)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a mixture of 4-amino-3-bromo-5-[(trimethylsilyl)ethynyl]benzonitrile (0.80 g) and tetrahydrofuran (3.0 mL) was added a 1 M tetrabutyl ammonium fluoride-THF solution (3.0 mL) under ice-cooling, followed by stirring at room temperature for 0.5 hour. To the reaction mixture was added water under ice-cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform/hexane=30-50%) to obtain 4-amino-3-bromo-5-ethynylbenzonitrile (0.57 g).
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Br:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH2:28].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C1(C)C(C)=CC=CC=1>[Br:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH:28][C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Cc1ccc(N)c(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2ccc(C)cc2Br)nc2c(Cl)ccc(C(CC)CC)c21
Temperature: 130 °C
Reaction time: 12 h
Yield: 67.6 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 1.50 g, 4.04 mmol), 2-bromo-4-methylaniline (1.0 mL, 8.08 mmol), p-toluenesulfonic acid monohydrate (822.2 mg, 4.32 mmol) and xylene (5.0 mL) was stirred at 130° C. for 12 hr. After cooling, the reaction mixture was neutralized with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as an oil (1.42 g, 2.73 mmol, 68%).
Reaction SMILES: [ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH:18]C(OC(C)(C)C)=O)[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCOCC.CO>[ClH:1].[C:2]([O:10][C@@H:11]1[C@@H:15]([CH2:16][OH:17])[CH2:14][C@@H:13]([NH2:18])[C@@H:12]1[O:26][C:27](=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: N[C@@H]1C[C@H](CO)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2 N solution of HCl in ether (15 ml) was added in stirring solution of compound 5 (10.0 g, 21.9 mmol) in methanol at 0° C. The mixture was allowed to warm to room temperature gradually and continue stirred for 2 hr. Solvent was evaporated under reduced pressure, and the residue was treated with anhydrous ether (120 mL) to precipitate the product 6. The precipitated product was washed with ether (50 mL×2) afforded the titled compound as white solid. [α]D25−28.19°; 1H NMR (500 MHz, DMSO-d6): δ 8.40 (bs, 2H, D2O exchange, NH2), 7.88 (m, 4H), 7.64 (m, 2H), 7.45 (m, 4H), 5.48 (m, 2H), 5.07 (m, 1H), 3.96 (m, 1H), 3.61 (m, 1H), 3.52 (m, 1H), 2.47 and 2.39 (m, 1H), 1.63 (m, 1H); HR-MS Calcd. For (C20H21NO5)+ 355.1420. found 335.1293.
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[F:16][C:17]([F:23])([F:22])[C:18]([NH:20][NH2:21])=[O:19].N1C=CC=CC=1.Cl>C(OCC)C>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([NH:21][NH:20][C:18](=[O:19])[C:17]([F:23])([F:22])[F:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: NNC(=O)C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)F
Reaction time: 0.05 h

Procedure:
To 1.65 g (0.007 mole) of 4,4,4-trinitrobutyryl chloride in 15 mL of anhydrous diethyl ether stirred in a water bath at 15° C. was added 0.9 g (0.007 mole) of N-(trifluoroacetyl)hydrazine. Pyridine (0.6 mL, 0.007 mole) was added dropwise. After 3 minutes, dilute hydrochloric acid was added and the ether layer was separated and dried (Na2SO4). The volatiles were removed and the residue was stirred with water and then with CH2Cl2 to give the product N-(4,4,4-trinitrobutyryl)-N'-(trifluoroacetyl)hydrazine, 1.15 g (50%), mp 154°-156° C. Crystallization from 1,2-dichloroethane raised the melting point to 157°-159° C.; 1H NMR (acetone-d6 +D2O): 2.97 (t, 2H), 3.86 (t, 2H); IR (KBr): 3330, 3220 (NH), 1745, 1690 (C=O); 1610, 1590 (NO2); 1195 (C--F).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([SH:10])=[N:8][CH:9]=1)([O-:3])=[O:2].[OH-].[Na+].Cl.Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)=[N:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S)nc1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(SCc2ccccn2)nc1
Yield: 65.3 %

Procedure:
5-nitro-2-pyridinethiol (6.0 g) was dissolved in an aqueous solution of methanol (150 ml), and to this solution was added sodium hydroxide (4.6 g) and then, 2-(chloromethyl)pyridine hydrochloride (7.6 g), and the mixture was stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 5-nitro-2-[(2-pyridinylmethyl)sulfanyl]pyridine (6.2 g).
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH2:14][CH:15]1[CH2:17][CH2:16]1)[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH:15]1([CH2:14][CH2:13][O:12][C:6]2[N:5]=[C:4]3[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]3[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[C:8]([NH2:11])[N:7]=2)[CH2:17][CH2:16]1
Reactant: Nc1nc(OCCC2CC2)nc2c1nc(Br)n2C1CCCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCCC3CC3)nc2n1C1CCCCO1

Procedure:
A stirring suspension of 8-bromo-2-[(2-cyclopropylethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.96 g) in methanol (80 ml) was treated with 25 wt % sodium methoxide in methanol (14.29 ml) and refluxed under nitrogen for 3.5 h. After allowing to cool over 16 h the solvent was evaporated and the residue treated with saturated ammonium chloride and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried by passing through a hydrophobic frit and evaporated to give the title compound as a brown solid, yield 6.49 gm.
Reaction SMILES: [N:1]1([C:7]2[CH2:8][CH2:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1>C(O)(=O)C.C(Cl)Cl>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH2:8][CH2:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1nnc2n1N=C(N1CCNCC1)CC2
Reactant: O=Cc1ccc(F)cc1
Solvent: ClCCl
Solvent: CC(=O)O
Product: Fc1ccc(CN2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.9 %

Procedure:
(Polystyrylmethyl)trimethylammonium cyanoborohydride (4.1 mmol/g, 125 mg, 0.510 mmol) was added to 6-(piperazin-1-yl)-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (100 mg, 0.365 mmol) and 4-fluorobenzaldehyde (63 mg, 0.510 mmol) in 10% acetic acid in DCM (2.2 mL). The resulting mixture was stirred at ambient temperature for 16 hours, then the resin removed by filtration and the solvents evaporated. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-[4-(4-fluorobenzyl)piperazin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (85 mg, 61%) as a solid. 1H NMR (399.9 MHz, DMSO-d6) δ 2.44 (4H, m), 2.88 (2H, t), 3.13 (2H, t), 3.52 (6H, m), 7.16 (2H, m), 7.36 (2H, m); m/z=383 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10])[C:3]=1[NH:16][C:17]1[CH:36]=[CH:35][C:20]([C:21](OC2C(F)=C(F)C(F)=C(F)C=2F)=[O:22])=[CH:19][CH:18]=1.[BH4-].[Na+].Cl>C1COCC1.O>[F:1][C:2]1[C:3]([NH:16][C:17]2[CH:36]=[CH:35][C:20]([CH2:21][OH:22])=[CH:19][CH:18]=2)=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[C:9]([NH:11][O:12][CH2:13][CH2:14][OH:15])=[O:10]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc(Nc2c(C(=O)NOCCO)ccc(F)c2F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NOCCO)c1ccc(F)c(F)c1Nc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.7 %

Procedure:
The product of Example 17, Step C, 2,3,4,5,6-pentafluorophenyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]amino]benzoate (150 mg, 0.29 mmol) was dissolved in THF (2 mL), then added dropwise to a solution of NaBH4 (110 mg, 2.90 mmol) in water (2 mL). This mixture was stirred at room temperature for 2 hours, acidified with 1 M HCl, and diluted with water (50 mL). The resulting aqueous mixture was extracted with EtOAc (2×50 mL), then the combined EtOAc fractions washed with water (50 mL), saturated NaCl (50 mL), and dried (Na2SO4). The solvent was removed under reduced pressure and the resulting residue purified by column chromatography on flash silica (50% EtOAc/hexanes as eluant) to afford 3,4-difluoro-N-(2-hydroxyethoxy)-2-[[4-(hydroxymethyl)phenyl]amino]benzamide as a cream solid (36 mg, 37%); m.p. (EtOAc/hexanes) 73-77° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.73 (br s, 1 H), 8.68 (br s, 1 H), 7.41-7.35 (m, 1 H), 7.15 (d, J=8.5 Hz, 2 H), 7.14-7.06 (m, 1 H), 6.79 (dd, J=8.5, 2.3 Hz, 2 H), 4.99 (t, J=5.7 Hz, 1 H), 4.72 (br s, 1 H), 4.38 (d, J=5.6, 2 H), 3.80 (t, J=4.9 Hz, 2 H), 3.54 (t, J=4.9 Hz, 2 H). Anal. Calcd for C16H16F2N2O4: C, 56.8; H, 4.8; N, 8.3. Found: C, 56.3; H, 4.7; N, 8.1.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:20][CH:11](SCC2C=CC=CC=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([N:35]1[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]1=[O:37])(C)(C)C>C(=O)([O-])[O-].[Cd+2].C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:20][C@@H:11]([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([Si](C)(C)C)c(=O)[nH]c1=O
Reactant: c1ccc(COC[C@H]2SC(SCc3ccccc3)C[C@@H]2OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cd+2]
Solvent: Cc1ccccc1
Product: Cc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)S2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
A suspension of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside (22.5 g, 51.6 mmol), his TMS-thymine (46 g, 170 mmol), mercuric bromide (20.5 g, 56.7 mmol), cadmium carbonate (29.3 g, 170 mmol) and dry toluene (1L) was boiled under reflux, with stiring, for 24 hours. The hot mixture was then filtered and the solids were washed with toluene. The filtrate was successively washed with potassium iodide solution (30%) and water and then evaporated. The residue was taken up in 4:1 methanol-water, stirred for 30 minutes, the suspension filtered and the filtrate evaporated. The residue was applied to a silica gel column (hexane-ethyl acetate (1:1)) and combination of the appropriate fractions gave the title product as a clear colourless syrup. 1H NMR indicated the ratio of α- to β- anomers to be 2.8:1. Further column chromatography gave more of the separated anomers. The first compound to be eluted from the column was 3',5'-di-O-benzyl-4'-thio-thymidine as a colourless syrup. This could be crystallised from methanol to give colourless crystals m.p. 140°-142° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](Cl)=[O:5].[CH3:12][CH2:13][OH:14].N1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([O:14][CH2:13][CH3:12])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
2,6-Difluorobenzoyl chloride was diluted with CH2Cl2 (5 ml) and cooled to 0° C. A mixture of EtOH (1.2 ml, 20 mmol) and pyridine (1.6 ml, 20 mmol) was added, dropwise, over 5 minutes to the reaction mixture. The ice bath was removed after 5 minutes and the reaction mixture strirred at 25° C. for 45 min. The solvent and volatiles were evaporated under reduced pressure and the residue was partitioned between 1N HCl and EtOAc (10 ml each). The aqueous phase was separated and extracted with 2×7 ml EtOAc. The combined organic extracts was washed with NaHCO3 (10 ml), brine (7 ml), dried over MgSO4 and concentrated to give 1.562 g ethyl 2,6-difluorobenzoate as an almost colorless oil. (84% yield from steps B and C).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:13]([CH:15]([CH2:18][CH3:19])[CH2:16]O)[CH3:14]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][CH2:16][CH:15]([CH2:18][CH3:19])[CH2:13][CH3:14])=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCC(CC)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 167 g of p-nitrobenzoic acid, 204 g of 2-ethyl-1-butanol and 3.5 g of p-toluenesulfonic acid is refluxed and stirred for 2 hours, separating the formed water. After that, the alcohol excess is distilled off, then the formed product is distilled at 150° C. and 0.04 mmHg, to obtain 209 g of 2-ethylbutyl p-nitrobenzoate in form of a light yellow viscous liquid.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=O)[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C1(C)C=CC=CC=1>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[C:5](=[S:27])[N:4]=[C:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cn1c(-c2ccccc2)nc(=O)c2sccc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccc2)nc(=S)c2sccc21
Reaction time: 3 h

Procedure:
2.10 g (8.67 mmol) 1-Methyl-2-phenyl-1H-thieno(3,2-d)pyrimidine-4-one and 3.51 g (8.67 mmol) Lawesson's reagent (C14H14O2P2S4, Fluka) were dissolved in 40 ml toluene. The reaction mixture was boiled for 3 h. After evaporation the residue was further purified by column chromatography with silica, eluent dichloromethane/acetone 95/5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1.C(C1C=C2C(=CC=1)NC=C2)#N.ClCCCC(Cl)=[O:33]>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:16])[CH:13]=2)[NH:8][CH:7]=1)=[O:33]
Reactant: N#Cc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: O=C(Cl)CCCCl
Agent: N#Cc1ccc2[nH]ccc2c1
Product: N#Cc1ccc2[nH]cc(C(=O)CCCCl)c2c1

Procedure:
As per the process described in the JMC Article, 3-(4-chlorobutyl)-1H-indole-5-carbonitrile is prepared by reacting 5-cyanoindole with 4-chlorobutyryl chloride in the presence of isobutyl-AlCl2 to produce 3-(4-chlorobutyryl)-1H-indole-5-carbonitrile, which is then subjected to selective desoxygenation of the keto function with sodium bis(2-methoxyethoxy)aluminum hydride (Vitride/Red-Al) to produce the 3-(4-chlorobutyl)-1H-indole-5-carbonitrile.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:23]2[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=2)=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: CNC(=O)c1cc(Cl)ccn1
Reactant: Nc1ccc(O)cc1[N+](=O)[O-]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CNC(=O)c1cc(Oc2ccc(N)c([N+](=O)[O-])c2)ccn1
Temperature: 90 °C
Reaction time: 72 h

Procedure:
A mixture containing 4-amino-3-nitrophenol (1 eq) and potassium bis(trimethylsilyl)amide (2 eq) was stirred in dimethylformamide for 2 hours at room temperature. To this mixture was added (4-chloro(2-pyridyl))-N-methylcarboxamide (1 eq) and potassium carbonate (1.2 eq) and stirred at 90° C. for 3 days. The reaction mixture was then concentrated and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried, filtered, and concentrated in vacuum to give brown solid. Purification on silica gel (2% triethyl amine/50% ethyl acetate in hexane) gave 4-[(4-amino-3-nitrophenyl)oxy]-N-methylpyridine-2-carbox-amide as an orange solid. The product gave satisfactory NMR. HPLC, 3.39 min; MS: MH+=289.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]2=[O:16])[CH2:3][CH2:2]1.Cl[C:18]1[CH:23]=[C:22]([C:24]([C:26]2[CH:36]=[C:35]([CH3:37])[C:29]3[N:30]([CH3:34])[C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)=[O:25])[CH:21]=[CH:20][N:19]=1>CN1C(=O)CCC1.CO>[CH3:34][N:30]1[C:29]2[C:35]([CH3:37])=[CH:36][C:26]([C:24]([C:22]3[CH:21]=[CH:20][N:19]=[C:18]([N:1]4[CH2:2][CH2:3][CH:4]([N:7]5[C:15]6[C:10](=[N:11][CH:12]=[CH:13][CH:14]=6)[NH:9][C:8]5=[O:16])[CH2:5][CH2:6]4)[CH:23]=3)=[O:25])=[CH:27][C:28]=2[O:32][C:31]1=[O:33]
Reactant: Cc1cc(C(=O)c2ccnc(Cl)c2)cc2oc(=O)n(C)c12
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Solvent: CO
Solvent: CN1CCCC1=O
Product: Cc1cc(C(=O)c2ccnc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)c2)cc2oc(=O)n(C)c12

Procedure:
0.40 g (1.8 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one and 0.18 g (0.60 mmol) 6-(2-chloro-pyridine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one were stirred overnight in 3 mL NMP at 120° C. The reaction mixture was diluted with MeOH and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.