Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]([O:16]C(=O)C)[C@H:10]2[O:11]C(=O)C)[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2([OH:46])[CH2:45][CH2:44][CH2:43][CH2:42]2)=[CH:35][CH:34]=1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]([OH:16])[C@H:10]2[OH:11])[OH:9])=[CH:4][C:3]=1[CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:41]2([OH:46])[CH2:42][CH2:43][CH2:44][CH2:45]2)=[CH:35][CH:34]=1
Reactant: CC(=O)OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#CC4(O)CCCC4)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@](O)(c2ccc(Cl)c(Cc3ccc(C#CC4(O)CCCC4)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.73 g 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-[4-(1-hydroxy-cyclopentyl-ethynyl)-benzyl]-benzene in 4 mL methanol and 2 mL tetrahydrofuran is added 5.1 mL of a 1 M solution of sodium hydroxide in water. The reaction solution is stirred at ambient temperature for 1 h and then neutralized with 1 M hydrochloric acid. The solvent is removed and brine is added to the residue. The resulting mixture is extracted with ethyl acetate and the combined organic extracts are washed with water and brine and dried over sodium sulfate. After removal of the solvent in vacuo the product is yielded.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[OH:38])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[O:39]1[CH:43]=[CH:42][CH:41]=[C:40]1[C:44](Cl)=[O:45].Cl>ClCCl>[C:8]1([C:14]([NH:27][C:28]2[S:29][CH:30]=[C:31](/[C:33](=[N:37]/[O:38][C:44]([C:40]3[O:39][CH:43]=[CH:42][CH:41]=3)=[O:45])/[C:34]([OH:36])=[O:35])[N:32]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(Cl)c1ccco1
Reactant: O=C(O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(O)/C(=N\OC(=O)c1ccco1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 39.3 %

Procedure:
Triethylamine (8.7 ml) was added to an ice-cooled suspension of 2-(2-triphenylmethylamino-4-thiazolyl)- 2-(Z-hydroxyimino)acetic acid (13 g) in 250 ml of anhydrous dichloromethane with stirring. The suspension turned to a clear, faint yellow solution. A solution of 2-furoyl chloride (3.3 g) in 20 ml of anhydrous dichloromethane was dropwise added under ice cooling, the resulting light brown solution was stirred at room temperature for one hour, the mixture was poured into 130 ml of ice-cooled 0.5N hydrochloric acid, and the formed crystals were collected by filtration and washed thrice with 30 ml dichloromethane, affording 5.2 g of the objective compound as colorless crystals.
Reaction SMILES: [CH2:1]([C:3]1([CH2:16][CH3:17])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[CH2:6][CH:5]2[NH:15][CH:4]12)[CH3:2].[BrH:18].C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(O)C>[BrH:18].[NH2:15][CH:4]1[C:3]([CH2:16][CH3:17])([CH2:1][CH3:2])[C:12]2[CH:11]=[C:10]([OH:13])[CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]1[Br:18]
Reactant: CCC1(CC)c2cc(OC)ccc2CC2NC21
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCC1(CC)c2cc(O)ccc2CC(Br)C1N
Temperature: 100 °C

Procedure:
To a flask was added 7,7-diethyl-5-methoxy-1a,2,7,7a-tetrahydro-1H-1-aza-cyclopropa[b]naphthalene (268 g, 1.16 mol) and hydrogen bromide (1.97 L, 17.38 mol), followed by tetra-N-butylammonium bromide (38 g, 0.12 mol). The reaction mixture was heated at 100° C. overnight with stirring, cooled to room temperature and then poured into stirred ethyl acetate (2.5 L). The product was isolated by filtration, the filter cake was washed with ethyl acetate (2×200 mL) and dried to yield crude product (370 g) as a purplish solid. The crude product was suspended in ethanol (1.50 L) then heated at 80° C. for 30 min. The resulting slurry was cooled to room temperature over 1 h, and filtered. The flask and filter cake with were washed with ethanol (2×100 mL) and then with ethyl acetate (100 mL) and dried overnight to yield the title compound as a solid. (275 g, ˜96% purity).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4](F)[CH:3]=1.[OH:11][C:12]1[C:13]([O:20][CH2:21][CH2:22][CH3:23])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:11][C:12]2[CH:19]=[CH:18][CH:17]=[C:14]([CH:15]=[O:16])[C:13]=2[O:20][CH2:21][CH2:22][CH3:23])[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1F
Reactant: CCCOc1c(O)cccc1C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(C=O)cccc1Oc1cc(Cl)ccc1C#N
Yield: 99.3 %

Procedure:
4-Chloro-2-fluorobenzonitrile (0.35 g, 2.2 mmol), 3-hydroxy-2-propoxybenzaldehyde (0.40 g, 2.2 mmol) and cesium carbonate (0.72 g, 2.2 mmol) were heated with stirring in dry DMF (4 mL) at 50° C. for 19 h. The reaction mixture was cooled, poured into water and extracted with ethyl acetate. The ethyl acetate layer was separated, washed with 1N sodium hydroxide solution (2×), water (1×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 4-chloro-2-(3-formyl-2-propoxyphenoxy)-benzonitrile (0.69 g, 98%) as a brown oil, which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][CH:13]([OH:15])[CH3:14].N1C=CC=CC=1.C(O)(=O)C>C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([O:15][CH:13]([CH3:14])[CH3:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)O
Solvent: COC(C)(C)C
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)OS(=O)(=O)c1ccccc1Br

Procedure:
2-Bromobenzenesulfonyl chloride (50 g, 0.19 mol) was suspended in 2-propanol (45 mL, 3 equiv.) and the slurry was cooled to less than 10° C. Pyridine (32 mL, 2 equiv.) was added in portions while maintaining the reaction temperature below 10° C. After reaction completion (ca. 3 hours), 11 mL of glacial acetic acid followed by 250 mL of methyl tert-butyl ether (MTBE) were added. The layers were separated and the rich organic layer was successively washed with 125 mL of iN aqueous hydrochloric acid and 150 mL of saturated sodium bicarbonate solutions. The rich MTBE solution was solvent exchanged into hexane (i.e., the addition of hexane with concurrent distillation of MTBE) to induce crystallization. The crystal slurry was filtered, washed and dried in vacuo at no more than 25° C., to give 48 g (87 M %, HPLC area % >99) of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[C:4]([C:28]2[CH:33]=[CH:32][C:31]([C:34]3[CH:38]=[CH:37][O:36][N:35]=3)=[CH:30][CH:29]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][O:15]C2CCCCO2)=[O:13])[CH:8]=1>O1CCOCC1>[F:2][C:3]1[C:4]([C:28]2[CH:29]=[CH:30][C:31]([C:34]3[CH:38]=[CH:37][O:36][N:35]=3)=[CH:32][CH:33]=2)=[CH:5][C:6](=[O:27])[N:7]([CH2:9][CH2:10][C@@:11]([CH3:26])([S:22]([CH3:25])(=[O:24])=[O:23])[C:12]([NH:14][OH:15])=[O:13])[CH:8]=1
Reactant: C[C@@](CCn1cc(F)c(-c2ccc(-c3ccon3)cc2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@](CCn1cc(F)c(-c2ccc(-c3ccon3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.8 %

Procedure:
A solution of 1.0 M aq HCl (15 mL) was added slowly to a solution of (2R)-4-[5-fluoro-4-(4-isoxazol-3-ylphenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (655 mg, 1.23 mmol) in 1,4-dioxane (30 mL) at rt. The reaction was allowed to stir at rt overnight. The reaction was concentrated to a crude material. Water (30 mL) was added to the crude material and the mixture was boiled for 5 minutes. The mixture was allowed to cool to rt and the solid that formed was collected via filtration and dried under high vacuum to afford the title compound as a light yellow solid (314 mg, 56.9%). MS (APCI) m/z 450.1 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.55 (s, 3H) 2.10-2.21 (m, 1H) 2.42-2.49 (m, 1H) 3.09 (s, 3H) 3.66-3.85 (m, 1H) 3.96-4.09 (m, 1H) 6.59 (d, J=7.61 Hz, 1H) 7.21 (d, J=1.56 Hz, 1H) 7.71 (dd, J=8.39, 1.76 Hz, 2H) 8.00 (d, J=8.39 Hz, 2H) 8.04 (d, J=6.44 Hz, 1H) 9.03 (d, J=1.56 Hz, 1H) 9.16-9.28 (m, 1H) 11.06 (s, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@H:3]([OH:20])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[C:24](=[O:25])([O:20][C@H:3]([CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1)[C:2]([CH3:22])([CH3:21])[CH3:1])[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[C@H](O)Cn1nccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCCl
Product: CC(C)(C)[C@@H](Cn1nccc1-c1ccc(C(F)(F)F)cc1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 90.7 %

Procedure:
To 562.0 mg (1.80 mmol) of (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol in 18 mL of 1,2-dichloroethane at room temperature was added 544.1 mg (2.70 mmol) of 4-nitrophenyl chloroformate. Then, 291.1 μL (3.60 mmol) of pyridine was added, and the solution was heated at reflux for 16 h. Saturated aqueous sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (3:7) to give 779.7 mg (91%) of 4-nitrophenyl (1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl carbonate. Rf=0.21 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.29 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 7.63 (s, 1H), 7.33 (d, J=9 Hz, 2H), 6.52 (s, 1H), 4.71 (d, J=9 Hz, 1H), 4.64 (d, J=15 Hz, 1H), 4.33 (dd, J=15 Hz, J=10 Hz, 1H), 0.89 (s, 9H); ES-LCMS m/z 478 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][N:21](COCC[Si](C)(C)C)[C:18]4=[N:19][CH:20]=3)=[N:7][N:8]2[CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]3[N:16]=[C:17]4[C:23]([C:24]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][NH:21][C:18]4=[N:19][CH:20]=3)=[N:7][N:8]2[CH2:11][CH:12]2[CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC(=O)c1c[nH]c2ncc(-c3nn(CC4CC4)c4cc(Cl)ccc34)nc12
Yield: 19.9 %

Procedure:
2-(6-Chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (99 mg, 184 μmol) was dissolved in dichloromethane and to this was added trifluoroacetic acid (1.73 g, 1.17 mL, 15.2 mmol). After 72 h the mixture was concentrated in vacuo, the residue diluted in dichloromethane, and then and re-concentrated in vacuo. Purification by chromatography (silica, Analogix 40 g cartridge, 0-5% methanol in dichloromethane, gradient over 15 min) gave 2-(6-chloro-1-(cyclopropylmethyl)-1H-indazol-3-yl)-N-isopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (15 mg, 36.7 μmol, 20.0%) as an off-white powder. MS (M+Na)+=431; 1H NMR (CDCl3) δ: 9.67 (br. s., 1H), 9.19-9.31 (m, 1H), 8.46 (d, J=8.7 Hz, 1H), 8.38 (d, J=3.0 Hz, 1H), 8.25 (d, J=7.9 Hz, 1H), 7.53 (d, J=1.1 Hz, 1H), 7.21-7.26 (m, 1H), 4.41-4.55 (m, 1H), 4.34 (d, J=7.2 Hz, 2H), 1.43 (d, J=6.4 Hz, 6H), 1.04-1.21 (m, 1H), 0.62-0.71 (m, 2H), 0.51 (q, J=4.9 Hz, 2H).
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[CH2:11]([N:15]1[C:23]([N:24]2[CH2:29][CH2:28][NH:27][C@H:26]([CH3:30])[CH2:25]2)=[N:22][C:21]2[C:16]1=[N:17][C:18]([C:37]1[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=1)=[N:19][C:20]=2[N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH:12]([CH3:14])[CH3:13].[C:44](OC(=O)C)(=[O:46])[CH3:45]>C(Cl)Cl.CO>[C:44]([N:27]1[CH2:28][CH2:29][N:24]([C:23]2[N:15]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:16]3[C:21]([N:22]=2)=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:19]=[C:18]([C:37]2[CH:42]=[N:41][C:40]([NH2:43])=[N:39][CH:38]=2)[N:17]=3)[CH2:25][C@H:26]1[CH3:30])(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)Cn1c(N2CCN[C@H](C)C2)nc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)N1CCN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(C)C)C[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
Triethylamine (79.9 μl, 0.57 mmol) was added to a methylene chloride solution (3.0 ml) of 5-{9-isobutyl-8-[(3R)-3-methylpiperazin-1-yl]-6-morpholin-4-yl-9H-purin-2-yl}pyrimidin-2-amine (108.1 mg, 0.24 mmol) at room temperature followed by the addition of acetic anhydride (27.1 μl, 0.29 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 1 hour and then the reaction mixture was poured into methylene chloride-methanol (10:1), washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (110.9 mg, 94%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[NH2:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>O1CCCC1>[F:1][C:2]1[C:3]([C:17]([NH:20][C@@H:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([OH:27])[CH2:22]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(N[C@@H]1CCC[C@H](O)C1)c1noc(-c2ccc(C(F)(F)F)cc2)c1F
Reaction time: 8 h

Procedure:
To a solution of 4-fluoro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (19 mg, 0.07 mmol), (1S,3R)-3-aminocyclohexanol (9.3 mg, 0.081 mmol), 1-hydroxybenzotriazole hydrate (9.0 mg, 0.07 mmol), and triethylamine (10 μL, 0.07 mmol) in tetrahydrofuran (1 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (15 mg. 0.081 mmol). After stirring overnight, the volatiles were removed in vacuo and the compound was purified by silica gel chromatography eluting with 5% methanol in dichloromethane to afford the title compound: (12.1 mg, 0.03 mmol). MS (ESI) m/z (M+H+): 373.2.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][NH:11][CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]([O:28][CH3:29])=[O:27]>O1CCCC1>[CH3:29][O:28][C:26](=[O:27])[N:11]([CH2:10][CH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Br:1])[CH:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(CCC)NCCc1ccc(F)cc1Br
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCC(CCC)N(CCc1ccc(F)cc1Br)C(=O)OC

Procedure:
1.045 g of N-[2-(2-bromo-4-fluorophenyl)ethyl]heptan-4-amine in solution in 15 cm3 of anhydrous tetrahydrofuran and 502 mg of potassium carbonate are stirred under an inert atmosphere at a temperature in the vicinity of 20° C. 0.28 cm3 of methyl chloroformate is introduced over 10 min using a syringe. The reaction mixture is brought to reflux over 30 h, then filtered through celite and then concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual oil is put into solution in 20 cm3 of dichloromethane. The organic phase is washed successively with 10 cm3 of an aqueous solution of hydrochloric acid (pH=2), then 3×20 cm3 of distilled water. The organic phase is then dried, then concentrated to dryness using a rotary evaporator under reduced pressure (5 kPa). The residual oil is taken up with 10 cm3 of diisopropyl ether. The solid which appears is filtered and the filtrate is concentrated to dryness using a rotary evaporator under reduced pressure (5 kPa) in order to result in 778 mg of methyl[2-(2-bromo-4-fluorophenyl)ethyl](1-propylbutyl)carbamate in the form of a beige oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18].[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:41]([CH2:40][C:38]3[N:37]=[CH:36][NH:35][CH:39]=3)=[O:42])[CH2:12][CH2:11]2)[CH:6]=[CH:5][C:4]=1[CH2:16][C:17]([N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[CH2:21][CH:20]1[C:32]([NH2:34])=[O:33])=[O:18]
Reactant: COc1cc(OC2CCNCC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Reactant: O=C(O)Cc1c[nH]cn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(OC2CCN(C(=O)Cc3c[nH]cn3)CC2)ccc1CC(=O)N1CCN(c2ccccc2C)CC1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(2-Methoxy-4-(4-piperidyloxy)phenylacetyl)-4-(2-methylphenyl) piperazine-2-carboxamide (200 mg, 0.429 mmole) and 4-imidazoleacetic acid (70 mg, 0.429 mmole) were dissolved in 4 ml of dry N,N-dimethylformamide at room temperature. To this solution was added 209 mg (0.472 mmole) of benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP). The pH of the reaction mixture was adjusted to 9 with the addition of diisopropylethylamine (DEA) in 100 μL increments. The reaction mixture was stirred at ambient temperature for 2 hr whereupon all volatiles were removed under reduced pressure. The residue was suspended in ethyl acetate and this suspension was washed with water. The organic phase and some insoluble material were combined, concentrated, and azeotropically dried with toluene. The resulting semi-solid was purified via preparative thick layer chromatography on precoated silica gel plates (85:15:1.5 chloroform-methanol-concentrated ammonium hydroxide elution) to give the title compound in homogeneous form: m.p. 120°-124° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:15][CH2:14][CH2:13][N:12]=[C:11]1[SH:16].[I:17]I.[I-].[K+]>CO.O>[IH:17].[NH:12]1[CH2:13][CH2:14][CH2:15][N:10]=[C:11]1[S:16][C:3]1[C:4]2[C:9](=[N:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: II
Reactant: SC1=NCCCN1
Reactant: c1cnc2[nH]ccc2c1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: I
Product: c1cnc2[nH]cc(SC3=NCCCN3)c2c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2.8 g 7-azaindole in 25 ml methanol and 3.5 g 1,4,5,6-tetrahydro-2-pyrimidinethiol in 50 ml methanol is added to a well-stirred solution of 7.6 g iodine and 15 g potassium iodide in 50 ml water. The mixture is stirred at room temperature for 14 hours and filtered. The precipitate is washed with water and ether and then recrystallised from water to give 3-(1,4,5,6-tetrahydro-2-pyrimidinylthio)-7-aza-indole hydriodide melting at 294°-295°.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[CH3:24][C:25]1[CH:43]=[CH:42][CH:41]=[CH:40][C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][C:31]=1[Cl:39])=[O:28]>ClCCl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:34]([C:33]3[CH:37]=[CH:38][C:30]([NH:29][C:27](=[O:28])[C:26]4[CH:40]=[CH:41][CH:42]=[CH:43][C:25]=4[CH3:24])=[C:31]([Cl:39])[CH:32]=3)=[O:35])[CH2:6][C:5]=12
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1Cl
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 106 %

Procedure:
To a mixture of 1.38 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine, 1.11 g of N,N-diisopropylethylamine in 50 ml of dichloromethane is added 2.61 g of 4-[(2-methylbenzoyl)amino]-3-chlorobenzoyl chloride in 25 ml of dichloromethane. The mixture is stirred at room temperature overnight and then washed with H2O and saturated NaHCO3. The organic layer is dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is concentrated, the residue (4.0 g) dissolved in dichloromethane and again filtered through a pad of hydrous magnesium silicate. The filtrate is evaporated to give the product as a glass (3.62 g). A 1.8 g sample of the glass is crystallized from ethyl acetate to give 1.4 g of crystals, m.p. 176°-178° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44](O)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]>C(Cl)Cl>[CH3:27][O:28][C:29]1[C:30](=[O:53])[C:31]([CH3:52])=[C:32]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:48][C:49](=[O:51])[CH3:50])=[C:43]([CH:47]=2)[C:44]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:45])[C:33](=[O:37])[C:34]=1[O:35][CH3:36]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc([N+](=O)[O-])c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.3 %

Procedure:
3-Nitroaniline (0.222 g, 1.604 mmol), triethylamine (0.162 g, 1.604 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.271 g, 1.604 mmol) were added to a methylene chloride solution (50 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (hexand:ethyl acetate=1:1) and then recrystallized from ether to obtain the titled compound (0.149 g, 0.301 mmol, 56%).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:6][C:5]([CH3:20])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1.CC1C=CC(C)=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[S:22][C:2]2=[N:3][CH:4]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Solvent: c1ccncc1
Solvent: Cc1ccc(C)cc1
Product: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A mixture of N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide (5.0 g, 17.1 mmol) and P2S5 (7.6 g, 34.2 mmol) in pyridine (50 mL) and p-xylene (200 mL) was stirred at 140° C. for 20 h. The hot solution was transferred to another flask and the solvent was removed in vacuo. The residue was purified by recrystallization from EtOH to afford 6-methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a yellow solid (3.5 g, yield: 75%).