Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][Cl:6])=[O:3].[C:7]1([OH:13])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.N1C=CC=CC=1>C(Cl)Cl>[C:2](=[O:3])([O:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:4][CH2:5][Cl:6]
Reactant: O=C(Cl)OCCl
Reactant: Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCCl)Oc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 58.2 %

Procedure:
To a solution of chloromethyl chloroformate (1 g, 7.8 mmol) in DCM (40 mL) was added a mixture of phenol (0.73 g, 7.8 mmol) and pyridine (750 μL, 9.3 mmol) in DCM (10 mL) at −20° C. over 20 min. The reaction was stirred at 0° C. for 4 h, then at rt for another 1 h. The mixture was washed with 1N HCl solution (50 mL), followed by brine (50 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (v/v)=100/1) to give the title compound as colorless oil (847 mg, 58.2%). The title compound was characterized by 1H NMR as shown below:
Reaction SMILES: C1([CH:7]([C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[NH2:8])CCCCC1.F[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:9]1([N:8]([CH2:7][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH:19]=[C:18]([C:20]([F:21])([F:22])[F:23])[CH:17]=[N:16]3)=[CH:11][C:10]=2[CH3:24])[C:26]2[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: COC(=O)c1ccc(F)nc1
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1C(N)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(N(Cc2ccc(-n3cc(C(F)(F)F)cn3)cc2C)C2CCCCC2)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
To a solution of (+/−)-cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanamine (80.0 mg, 0.237 mmol) in N,N-dimethylformamide (3 mL) was added methyl 6-fluoronicotinate (55.2 mg, 0.356 mmol) and potassium carbonate (98.4 mg, 0.712 mmol). The reaction was heated to 110° C. and stirred overnight. The reaction was cooled to room temperature, diluted with water, and extracted with ethyl acetate (3×5 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography gave (+/−)-methyl 6-(cyclohexyl(2-methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methylamino)nicotinate (20 mg, 15%) as a yellow solid. 1H NMR (400 MHz, CDCl3, δ): 8.63 (s, 1H), 8.06 (s, 1H), 7.79-7.82 (m, 2H), 7.43 (s, 1H), 7.33-7.36 (m, 1H), 7.25 (d, J=8.4 Hz, 1H), 6.03 (d, J=8.8 Hz, 1H), 5.39 (d, J=6.8 Hz, 1H), 4.74 (m, 1H), 3.75 (s, 3H), 2.49 (s, 3H), 1.85-1.88 (m, 1H), 1.58-1.72 (m, 5H), 1.05-1.19 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Al](C)C.C([O:22][C:23]([C:25]1[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=[C:27]([CH3:36])[CH:26]=1)=O)C>ClCCl>[CH3:36][C:27]1[CH:26]=[C:25]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[CH2:15][N:14]4[C:10]([S:11][CH2:12][CH2:13]4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[O:22])[N:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:28]=1
Reactant: CCOC(=O)c1cc(C)nn1-c1ccccc1
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(C3CN4CCSC4=N3)c2)n(-c2ccccc2)n1
Yield: 73.6 %

Procedure:
To 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (1.43 g; 6.5 mmol) in dry dichloromethane (30 ml) under nitrogen at room temperature was added trimethylaluminium (10 ml; 25% in hexane). After 30 mins 3-methyl-1-phenylpyrazole 5-carboxylic acid ethyl ester (1.5 g, 6.5 mmol) in dry dichloromethane (5 ml) was added and the mixture heated under reflux for 24 hr. The reaction was quenched by the slow addition of hydrochloric acid (20 ml; 2 N aqueous), the resulting two phase system basified with aqueous ammonia solution (5 N) and extracted with chloroform (3×200 ml). After drying (MgSO4) the combined organic phases were concentrated in vacuo to afford an oil which was separated by column chromatography on alumina eluting with chloroform. The major band was further purified by column chromatography on silica gel (60-120 mesh) eluting with chloroform to afford the amide (1.93 g; 62%) which was converted into its hydrochloride salt by the addition of isopropanolic hydrogen chloride. Recrystallisation from ethanol afforded the pure salt (0.7 g).
Reaction SMILES: CC1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=O)O1.[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:13]=1C=O>CCN(CC)CC.C(O)=O>[Cl:11][C:12]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:13]=1[CH2:4][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O=CO
Product: O=C(O)CCc1c(Cl)cc(Cl)cc1Cl
Temperature: 120 °C
Yield: 85.4 %

Procedure:
Meldrum's acid (2.06 g, 14.32 mmoles) was added to TEAF (7.05 ml) at ambient temperature under stirring and the reaction mixture was kept under nitrogen atmosphere. After 10 min 2,4,6-trichloro benzaldehyde (3 g, 14.32 mmoles) was added to the reaction mixture. It was then refluxed at 120° C. for 3 hrs. On completion of the reaction, the mixture was cooled at ambient and was poured into ice water (50 ml). Then aq. layer was extracted with ethyl acetate (3×80 ml), the combined organic layer was washed with brine (40 ml) and dried over sodium sulphate. Organic layer was concentrated under vacuum. 3.10 g (86.0% of theory) of 3-(2,4,6-trichloro-phenyl)-propionic acid was obtained in form of a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:32]=[CH:31][C:15]([O:16][C:17]2[C:18]([C:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25](=[O:30])[CH:24]=3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:14][CH:13]=1)=[O:11]>[Pd].CCO.O1CCOCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[C:25](=[O:30])[CH2:24]3)=[N:19][CH:20]=[CH:21][N:22]=2)=[CH:31][CH:32]=1)=[O:11]
Reactant: CN1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)=CC1=O
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCO
Product: CN1CCC(c2nccnc2Oc2ccc(C(=O)c3nc4ccccc4[nH]3)cc2)CC1=O
Yield: 38.1 %

Procedure:
A solution of 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methyl-5,6-dihydropyridin-2(1H)-one (0.0687 g, 0.161 mmol) (Step 7, Example 252) in 1:1 EtOH-dioxane (8 mL) was added palladium, 10% wt. on activated carbon (0.007 g, 6.58 μmol) and hydrogenated (double-walled balloon pressure) at room temperature for 24 h. The reaction mixture was filtered via a pad of Celite, and the filtrate was concentrated in vacuo and purified via flash column chromatography (20% to 80% Teac (10% MeOH)/Hexanes) to give 4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)-1-methylpiperidin-2-one (0.0262 g, 38.0% yield) as a light yellow amorphous solid. MS (ESI, pos. ion) m/z: 428.9 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[N:26]([CH2:29][CH3:30])[N:27]=[CH:28][C:23]2=[C:22]([C:31]2[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=2)[C:21]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.O>[CH2:29]([N:26]1[C:24]2=[N:25][C:20]([CH2:19][OH:18])=[C:21]([CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:22]([C:31]3[CH:32]=[N:33][CH:34]=[C:35]([CH3:37])[CH:36]=3)=[C:23]2[CH:28]=[N:27]1)[CH3:30]
Reactant: CCOC(=O)CCc1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)CCc1c(CO)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.6 %

Procedure:
To a stirred solution of ethyl 3-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (313 mg) in THF (10 ml) was added 1N tetrabutyl ammonium fluoride in THF (0.52 ml) at 0° C. and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (3:1) then a mixture of MeOH and CHCl3 (1:50) to give ethyl 3-[1-ethyl-6-(hydroxymethyl)-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (100 mg) as a yellow oil.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.C(N(CC)C(C)C)(C)C.Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:7][C:3]1[CH:2]=[C:1]([NH:8][C:19](=[O:20])[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(N)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1cccc(NC(=O)OCc2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a stirred solution of m-phenylenediamine (5.0 g, 0.046 mol) and N,N-diisopropylethylamine (8.0 mL, 0.046 mol) in CH2Cl2 (150 mL) at 0° C. was added slowly benzyl chloroformate (6.6 mL, 0.046 mol). The mixture was stirred at 0° C. for 2 h and then warmed to rt for 2 h. Aq. NaHCO3 solution was added and the organic phase was separated, washed with brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel to give the desired product (8.0 g, 71%) as a syrup. LC-MS: 2.11 min, 243.0 (M+1).
Reaction SMILES: [C:1]1([C:7]2OC(=O)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13][O:14][C:15]([C:17]#[C:18][C:19]([O:21][CH3:22])=[O:20])=[O:16]>ClC1C=CC=CC=1>[CH3:13][O:14][C:15]([C:17]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8][S:9][C:18]=1[C:19]([O:21][CH3:22])=[O:20])=[O:16]
Reactant: O=c1oc(-c2ccccc2)ns1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccccc2)c1C(=O)OC
Reaction time: 6 h
Yield: 59.5 %

Procedure:
A solution of 5-phenyl-[1,3,4]oxathiazol-2-one (30.33 mmol) and dimethylacetylenedicarboxylate (60.67 mmol) in chlorobenzene (17.8 mL) was refluxed with stirring for 6 h before it was concentrated in vacuo. The residue was crystallized from cold MeOH to give the title compound (5.0 g) as a slightly yellow solid: MS (m/z) 278.1 (M+1).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:6]=1.[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][NH:31]2)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(C(C)C)CC)(C)C>CC#N>[C:21]([O:25][C:26]([N:28]1[CH2:33][C@@H:32]2[CH2:34][C@H:29]1[CH2:30][N:31]2[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[N:14]=2)=[CH:7][CH:6]=1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: BrCCOc1ccc(Oc2nc3ccccc3s2)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2CCOc1ccc(Oc2nc3ccccc3s2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a stirred solution of 2-[4-(2-bromo-ethoxy)-phenoxy]-benzothiazole (1.5 g, 4.3 mmol) and (S,S)-2,5-diaza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (1.0 g, 5.1 mmol) in CH3CN (20 mL) at rt was added diisopropylethylamine ((i-Pr)2NEt) (900 μL, 5.1 mmol). The resulting suspension was stirred at rt for 4 h and then heated for 65 h at 60° C. The solution was cooled to rt and then partitioned between CH2Cl2 (200 mL) and satd. aq. NaHCO3 (80 mL). The organic layer was separated, dried (Na2SO4), filtered and concentrated. Purification by silica gel flash chromatography (0% to 5% CH3OH in CH2Cl2) afforded the title compound as a yellow oil (1.8 g, 92%). MS (ESI): mass calcd. for C25H29N3O4S, 467.19; m/z found, 468.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.75 (d, J=8.0 Hz, 1H), 7.68-7.66 (m, 1H), 7.42-7.38 (m, 1H), 7.31-7.25 (m, 3H), 6.99-6.95 (m, 2H), 4.40 (br s, 0.5H), 4.27 (br s, 0.5H), 4.13-4.03 (m, 2H), 3.66-3.51 (m, 2H), 3.26-2.97 (m, 4H), 2.78 (d, J=9.5 Hz, 0.5H), 2.63 (d, J=9.7 Hz, 0.5H), 1.92-1.85 (m, 1H), 1.79-1.70 (m, 1H), 1.49 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1[CH2:27][CH2:26][CH2:25][CH2:24]1.ICCCC>CN(C)C=O.C(=O)(O)[O-].[Na+]>[CH2:24]([NH:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:25][CH2:26][CH3:27]
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cnn(C)c1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCI
Solvent: CN(C)C=O
Product: CCCCNc1c(C(=O)OCC)cnn1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To ethyl 5-amino-1-methylpyrazole-4-carboxylate (3.4476 g, 20.38 mmol) in dimethylformamide (60 mL) at 0° C. was added a solution of 1.0M sodium bis(trimethylsilyl)amide in tetrahydrofuran (20.5 mL, 20.5 mmol). After 1 hour, 1-iodobutane (2.50 mL, 22.0 mmol) was added and the reaction was stirred at ambient temperature for 20 hours. The mixture was diluted with saturated aqueous sodium bicarbonate and extracted with ethyl acetate (6×). The combined organic extracts were then washed with water (2×) and brine, dried over sodium sulfate, filtered and evaporated under reduced pressure. Chromatography of the residue on silica gel eluting with 20% ethyl acetate in hexane afforded 3.8754 g (84%) of the desired product as a oil. TLC (20% ethyl acetate/80% hexane) Rf =0.12. 1H NMR (CDCl3, 300 MHz) d 0.94 (t, 3H), 1.33 (t, 3H), 1.35-1.50 (m, 2 H), 1.53-1.65 (m, 2H), 3.25 (t, 2H), 3.77 (s, 3H), 4.25 (q, 2H), 5.60-5.80 (br, 1H), 7.62 (s, 1H). MS (DCl/NH3)m/e 226 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](=[O:20])[C:9]2[C:4](=[CH:5][C:6]3[CH2:23][CH2:22][CH2:21][C:7]=3[CH:8]=2)[N:3]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH:21]1[C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][C:6]=2[CH2:23][CH2:22]1)[N:3]=[C:2]([CH3:1])[N:11]([CH2:12][O:13][C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[C:10]3=[O:20]
Reactant: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)CCC3
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1nc2cc3c(cc2c(=O)n1COC(=O)C(C)(C)C)C(Br)CC3
Temperature: 0 °C

Procedure:
A mixture of 2-methyl-3-pivaloyloxymethyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]-quinazolin-4-one (50 g), N-bromosuccinimide (31.2 g), benzoyl peroxide (0.1 g) and carbon tetrachloride (500 ml) was stirred and heated to reflux for 90 minutes. The mixture was cooled to 0° C. The mixture was filtered and the filtrate was evaporated. The residue was triturated under diethyl ether (400 ml). The mixture was cooled to 0° C. The precipitate was isolated, washed with diethyl ether and dried. The solid so obtained was purified by column chromatography using a 1:1 mixture of hexane and ethyl acetate as eluant. There was thus obtained 6-bromo-2-methyl-3-pivaloyloxy-methyl-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-4-one (21 g), m.p. 98° C. (decomposes);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][NH:12][C:11](=[O:18])[CH:10]=2)=[C:4]([F:19])[CH:3]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C>[F:19][C:4]1[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]([CH3:22])[C:11](=[O:18])[CH:10]=1
Reactant: CI
Reactant: O=c1cc(Nc2ccc(Br)cc2F)c([N+](=O)[O-])c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc([N+](=O)[O-])c(Nc2ccc(Br)cc2F)cc1=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 87 %

Procedure:
To the yellow solution of 4-(4-bromo-2-fluorophenylamino)-5-nitropyridin-2(1H)-one (1.235 g, 3.78 mmol) dissolved in dry DMF (15 mL) at −5->0° C., was added NaH (182 mg, 4.55 mmol) (60% in oil). The color of solution turned into dark brown in 20 min at 0° C. The stirring was continued at r.t. for 40 minutes, followed by the addition of MeI (283 uL, 4.54 mmol) through a syringe at 5° C. The resulted solution was stirred at r.t. for 36 hours. The desired compound started to precipitate out of solution after 20 min of MeI addition. Water was added, and the precipitate was vacuum filtered, washed with water, and dried at 40° C. under a high vacuum for 2.5 hours. The product was used for the next reaction without further purification. (1.12 gram, 87% yield).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3].[C-]#N.[Na+].[CH3:18][O:19][CH2:20]CO>>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH2:12][CH2:18][O:19][CH3:20])=[O:10])=[CH:7][CH:6]=1)[CH:2]=[CH2:3]
Reactant: COCCO
Reactant: C=CCOc1ccc(C(=O)OC)cc1
Agent: [C-]#N
Agent: [Na+]
Product: C=CCOc1ccc(C(=O)OCCOC)cc1

Procedure:
A mixture of methyl 4-allyloxybenzoate (1.92 g), sodium cyanide (50 mg) and 2-methoxyethanol (20 ml) was heated at reflux for 24 hours. The mixture was evaporated to give an oil which was partitioned between dichloromethane and water. The organic phase was separated, washed with brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica gel using a 9:1 (v/v) mixture of pentane/ethyl acetate as eluent to give 2-methoxyethyl 4-allyloxybenzoate (1.7 g) as an oil; NMR(CDCl3): 3.44(3H,s), 3.72(2H,t), 4.44(2H,t), 4.55-4.64(2H,m), 5.27-5.48(2H,m), 5.96-6.14(1H,m), 6.93(2H,d) and 8.01(2H,d); m/z237(M+H).
Reaction SMILES: [CH3:1][C:2]([C:10]#[N:11])([CH3:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:12](OCC)C>>[CH3:1][C:2]([CH3:9])([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:10](=[NH:11])[CH3:12]
Reactant: CCCCCCC(C)(C)C#N
Reactant: CCOCC
Product: CCCCCCC(C)(C)C(C)=N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of dimethyl heptylcyanide (1.00 g, 6.53 mmol) in anhydrous diethyl ether (5 mL) was added under argon 1.6 M methyl lithium in diethyl ether (25 mL, 39.00 mmol), and the mixture was stirred for 3 hours at room temperature. After quenching with water, the mixture was extracted with diethyl ether. The extracts were dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to get a colorless oil which was pure enough to carry out for further reactions based on analytical data. (1.03 g, 94%). 1H NMR (300 MHz, CDCl3): ∂ 0.80-0.85 (m, 3H), 0.92-1.05 (m, 3H), 1.15-1.28 (m, 14H), 1.54-1.6 (m, 2H), 3.4 (s, 1H). (ESI, Pos) m/z 170.2
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl.[OH-].[K+]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH:14]=1
Reactant: Clc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Clc1ccc2[nH]cc(C3=CCNCC3)c2c1

Procedure:
A mixture of 5-chloro-1H-indole (25 g), piperidin-4-one, hydrate, hydrochloride (71 g), and potassium hydroxide (38 g) in ethanol (450 ml) was refluxed for 6 hours. After cooling inorganic salts were filtered off and ethanol evaporated in vacuo. To the remaining oil was added brine (500 ml) and ethyl acetate (2×200 ml). The organic phase was separated and worked-up as above. Yield of crude title product: 45 g (semicrystalline).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.CN(C)C=O.S[C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1>C(OCC)(=O)C>[Cl:3][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[CH:15]=[C:14]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)[N:13]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cn1c(S)nc(-c2ccncc2)cc1=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 77.2 %

Procedure:
Phosphorous oxychloride (26.11 g, 170 mmol) was added to dimethyl-formamide (180 ml) and stirred 20 min. 2-Mercapto-3-methyl-6-(4-pyridyl)-pyrimidine-4-one (24.15 g, 110 mmol) was added to the solution and stirred 5 min and then stirred at 70° C. for 2 hours. Ethyl acetate (630 ml) was added to the ice-cooled solution and precipitate was collected by filtration after stirring for 20 minutes. After drying, the precipitate was dissolved in water (400 ml) and pH was adjusted to 10 by using aqueous sodium hydroxide. The precipitate was washed with water, filtered and dried to give the title compound (18.82 g, 77%).
Reaction SMILES: [C:1](Cl)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:10]1[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=1)[C:2]1[CH:9]=[CH:8][C:5]([O:6][CH3:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:34]([OH:41])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][OH:40]>N1C=CC=CC=1>[CH3:7][O:6][C:5]1[CH:8]=[CH:9][C:2]([C:1]([O:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][OH:41])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:17]=[CH:16][C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OCCCCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: COc1ccc(C(OCCCCCCO)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 4 h
Yield: 33.3 %

Procedure:
To a solution of 3.38 g (10 mmol) of DMTr-Cl and 3.45 mL (20 mmol) of diisopropylethylamine in 50 mL of dry pyridine was added 5.91 g (50 mmol) of 1,6-hexanediol. After stirring for 4 h, the mixture was quenched with 85 mL of 5% sodium bicarbonate and extracted with 2×100 mL of methylene chloride. The organic phase was washed with 2×100 mL of water and 100 mL of brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (3.5×17 cm silica) using methylene chloride. The fractions containing pure product were combined and concentrated to give 1.40 g of 37 as a yellow syrup.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].CO.[CH2:14]([NH2:16])[CH3:15].[NH4+].[OH-]>O>[CH2:14]([NH:16][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[CH3:15]
Reactant: COC(=O)c1cccnc1Cl
Reactant: CCN
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCNc1ncccc1C(=O)OC

Procedure:
To 10 g. (0.06 mole) of methyl 2-chloronicotinate in 50 ml. of methanol was added 6.0 g. (0.13 mole) of ethylamine in 25 ml. of methanol and this was placed into an autoclave and heated on a steam bath for 4 hours. Then the reaction solution was stripped, water added, made very basic via NH4OH, extracted into CHCl3, washed with water, dried and then stripped to dryness to yield 2-ethylaminonicotinic acid, methyl ester. An HCl-salt was prepared by adding the crude residue to ethyl acetate and then adding ethereal-HCl. The product precipitated out of solution and was collected on a filter and rinsed with petroleum ether to give 7 g. of product with a m.p. of 140°-5° C.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[C:4](=[O:14])[C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][Cl:30]>CN(C)C=O>[Cl:1][C:2]1[N:7]([CH2:28][CH2:29][Cl:30])[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][Cl:13])[C:4](=[O:14])[C:3]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=c1[nH]c(Cl)c(-c2ccccc2)c(=O)n1CCCCCl
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c(-c2ccccc2)c(Cl)n(CCCl)c(=O)n1CCCCCl
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a suspension of 2.43 g (7.7 mmol) of 6-chloro-3-(4-chlorobutyl)-5-phenylpyrimidine-2,4(1H,3H)-dione and 1.70 g (12.3 mmol) of potassium carbonate in 40 ml of N,N-dimethylformamide, 1.25 ml (15 mmol) of 1-bromo-2-chloroethane was added at room temperature, followed by stirring at 60° C. for 2 hours and then at 100° C. for 3 hours. After cooling, the reaction mixture was concentrated to dryness. The residue was dissolved in dichloromethane-water; the organic layer was washed with water and dried. The oily substance obtained by distilling off the solvent was purified by column chromatography (eluent, n-hexane/ethyl acetate=5/1→2/1) to yield 1.56 g (54.5%, white powder) of the desired product.