Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([OH:31])=O)[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:32]1([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:34][CH2:33]1>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]3[CH2:26][C:25]([CH3:27])([CH3:28])[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:29]([NH:38][S:35]([CH:32]5[CH2:34][CH2:33]5)(=[O:37])=[O:36])=[O:31])[CH:23]=4)[NH:18]3)[CH:12]=2)=[CH:9][CH:10]=1)([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)cc1
Reactant: NS(=O)(=O)C1CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2cccc(C3CC(C)(C)c4cc(C(=O)NS(=O)(=O)C5CC5)ccc4N3)c2)cc1
Yield: 29.9 %

Procedure:
A mixture of 2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (120 mg, 0.29 mmol), 1-3-dimethylaminopropyl-3-ethylcarbodiimide hydrochloride (83 mg, 0.43 mmol), 4-dimethylaminopyridine (52.5 mg, 0.43 mmol), cyclopropane sulfonic acid amide (110 mg, 0.87 mmol) in dichloromethane (10 mL) was refluxed for 12 h. Removal of the solvent afforded an oil residue. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded cyclopropanesulfonic acid [2-(4′-isopropoxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carbonyl]-amide (45 mg, 30%) as a light yellow solid: MS (ESI) M+1=519.1.
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[Cl:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(Cl)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (1.02 g, 3 mmol) is initially charged in 15 ml of dimethylformamide. N-Chlorosuccinimide (0.550 g, 4 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 4 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 7:3). This gives 0.45 g of product (35.9% of theory).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=1[Cl:14].CN(C1C=CC=CC=1)[CH:17]=[O:18].S(=O)(=O)(O)O>O1CCCC1.CCOCC>[Cl:14][C:8]1[C:7]([Cl:6])=[CH:12][CH:11]=[C:10]([F:13])[C:9]=1[CH:17]=[O:18]
Reactant: CN(C=O)c1ccccc1
Reactant: Fc1ccc(Cl)c(Cl)c1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=Cc1c(F)ccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
Butyl lithium (48 ml of 1.6M in hexane, 52.3 mmoles) was added with stirring over 1.5 hours under nitrogen to a solution of 1,2-dichloro-4-fluorobenzene (7.85 g, 47.6 mmoles) in dry tetrahydrofuran (120 ml) at -68°. The solution was stirred at -68° for 2 hours and then N-methyl-N-phenylformamide (6.48 ml) in dry tetrahydrofuran (15 ml) was added over 1.5 hours. After a further 1.5 hours at -68°, the reaction mixture was poured into 10% aqueous sulphuric acid and ether. The ethereal layer was separated, washed with brine, dried (Na2SO4) and evaporated to give the desired aldehyde (8 g). M+ 196/194/192, nmr (CDCl3)δ10.5 (s,H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][C@@H:6](S(C2C=CC(C)=CC=2)(=O)=O)[CH2:5]1.C1OCCOCCOCCOCCOCCOC1.[C-:47]#[N:48].[K+]>CS(C)=O.O>[CH3:1][O:2][CH2:3][C@H:4]1[N:8]([C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])[CH2:7][C@@H:6]([C:47]#[N:48])[CH2:5]1
Reactant: COC[C@H]1C[C@H](S(=O)(=O)c2ccc(C)cc2)CN1C(=O)OCc1ccccc1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC[C@@H]1C[C@H](C#N)CN1C(=O)OCc1ccccc1
Temperature: 80 °C
Reaction time: 6 h
Yield: 69 %

Procedure:
5 (13.76 g, 0.034 mol) was dissolved in DMSO (17 mL). 18-Crown-6 (5 eq) and finely ground KCN (5 eq) were added and the reaction mixture was stirred for 6 h at 80° C. The reaction solution was diluted with H2O (17 mL) and then extracted with ethyl acetate. The organic solution was dried over MgSO4 and concentrated. The crude product was purified by column chromatography eluting with hexanes/ethyl acetate (4/1, v/v) to afford 13.76 g (69% yield) of the desired product 6 as a colorless oil.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(N(CC)CC)C>[C:15]([NH:8][C:9]1[S:10][C:11]([CH3:14])=[N:12][N:13]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1nnc(N)s1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(=O)Nc1nnc(C)s1
Yield: 89.1 %

Procedure:
To a mixture of toluene (20 ml) and triethylamine(2.63 g) was added 2-amino-5- methyl-1,3,4-thiadiazole (3.0 g) and acetic anhydride (3.2 g). The mixture was heated under reflux for 2.5 hours. After cooling, the precipitated solid was filtrated, washed with water and dried. The title compound(3.65 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([CH3:34])[CH:26]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:33])[CH3:32])=[C:27]([CH3:34])[CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CC(=O)c1ccc(O)cc1C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cc1C

Procedure:
4-[4-(4-Acetyl-3-methyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 4′-hydroxy-2′-methylacetophenone (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.97-2.06 (m, 4H), 2.33 (s, 3H), 2.67 (s, 3H), 2.94-3.04 (m, 2H), 4.04-4.10 (m, 2H), 4.98-5.04 (m, 1H), 7.29-7.31 (m, 2H), 7.96-7.98 (m, 1H), 8.29 (s, 1H), 8.55 (s, 1H). Mass spectrum MH+=452.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=2)=[O:22])[CH2:17][CH2:16]1.[H][H]>C(O)C.O.[C].[Pd]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([N:18]2[CH2:17][CH2:16][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:20][CH2:19]2)=[O:22])=[CH:25][CH:26]=1
Reactant: [H][H]
Reactant: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc([N+](=O)[O-])cc4)CC3)c2cc1OC
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(N)cc4)CC3)c2cc1OC
Yield: 29 %

Procedure:
In 50 ml of ethanol was suspended 1.5 g (3.7 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-nitrophenyl)-1-piperazinecarboxamide obtained in Example 77, and a suspension of 500 mg of 10% palladium-carbon in 10 ml of water and 10 ml of ethanol was added thereto, followed by stirring in a stream of hydrogen at room temperature for 5 hours. After the catalyst was separated by filtration using Celite, the solvent was evaporated. Then, the residue was purified by silica gel chromatography and recrystallized from ethyl acetate to give the desired compound as colorless crystals.
Reaction SMILES: [CH2:1]1[S:5][C@@H:4]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[C@H:3]2[NH:13][C:14]([NH:16][C@@H:2]12)=[O:15].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[C:50]([NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH2:66])([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>CN(C=O)C>[C:50]([NH:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][NH:66][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][C@H:4]1[C@@H:3]2[C@@H:2]([NH:16][C:14]([NH:13]2)=[O:15])[CH2:1][S:5]1)([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: CC(C)(C)OC(=O)NCCOCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[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: CC(C)(C)OC(=O)NCCOCCOCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of vitamin H (Biotin) (2.2 g, 9 mmol), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (3 g, 8 mmol), and DIPEA (1.8 mL, 10 mmol) in DMF (100 mL) was stirred for 10 minutes at room temperature before being adding dropwise to a solution of N-Boc-3,6-dioxaoctane-1,8-diamine (1.5 g, 6 mmol, 1). The reaction mixture was stirred for 1 hour at room temperature, after which the DMF was removed in vacuo to give an oily residue, which was purified by flash silica gel column chromatography (CH2Cl2/CH3OH, 25/1, v/v) to afford N-Boc-N′-biotinyl-3,6-dioxaoctane-1,8-diamine (2.0 g, 90%). 1H NMR (300 MHz, CD3OD): δ 4.5 (m, 1H), 4.3 (m, 1H), 3.6 (s, 4H), 3.54 (tt, 4H), 3.39 (t, 2H), 3.26 (t, 2H), 2.9 (dd, 1H), 2.7 (d, 1H), 2.2 (t, 2H), 1.7-1.5 (m, 8H), 1.4 (s, 9H); MALDI HRMS: m/z 497.2416 [M+Na+]. Calcd for C21H38N4NaO6S 497.2410.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[I:7][C:8]1[CH:9]=[C:10]([CH2:14][C:15]#[N:16])[CH:11]=[CH:12][CH:13]=1.Cl.[NH2:18][OH:19].CCO>O>[OH:19][NH:18][C:15](=[NH:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([I:7])[CH:9]=1
Reactant: N#CCc1cccc(I)c1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N=C(Cc1cccc(I)c1)NO
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Add sodium carbonate (2.0 g, 18.5 mmol) to a mixture of 3-iodophenylacetonitrile (4.5 g, 18.5 mmol) and hydroxylamine hydrochloride (1.3 g, 18.5 mmol) in 10:1 EtOH:H2O (11 mL) Heat the reaction mixture to 50° C. for 2 days. Cool to RT, then filter to remove the solids. Concentrate the filtrate to afford the title compound (4.94 g). LC-MS (m/e): 277 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[CH:40]=[C:39]([Sn](CCCC)(CCCC)CCCC)[S:38][N:37]=1.O>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:39]3[S:38][N:37]=[C:36]([CH3:35])[CH:40]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C)ns1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(-c2nc(N[C@@H]3CCOC[C@@H]3NC(=O)OC(C)(C)C)c(F)c3c2C(=O)N(C(=O)OC(C)(C)C)C3)sn1

Procedure:
A solution of tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (10 mg, 0.02 mmol), 3-methyl-5-(tributylstannyl)isothiazole (23.25 mg, 0.06 mmol) and tetrakis(triphenylphosphine)palladium(0) (23.07 mg, 0.02 mmol) in toluene (3 mL) was heated to 120° C. for 45 min under microwave irradiation. The reaction mixture was poured into water and extracted with EtOAc. The organic extracts were dried over anhydrous Na2SO4, filtered, and evaporated in vacuo. After removal of solvent, the resulting crude material was reconstituted in DMF and purified via preparative HPLC eluting with water (0.05% TFA) and ACN (55-80% gradient, 0.035% TFA). The collected fractions were combined and ACN was removed via rotary evaporation. The resulting aq solution was neutralized with saturated aq NaHCO3 and washed with EtOAc (2×50 mL), dried over anhydrous Na2SO4, filtered, and the organic phase stripped to dryness via rotary evaporation to give the title compound. [M+H] calc'd for C26H34FN5O6S, 564; found, 564.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH3:15][S:16](Cl)(=[O:18])=[O:17]>C(Cl)Cl.O>[NH:5]1[CH2:6][CH2:7][CH:3]([CH2:2][NH:1][S:16]([CH3:15])(=[O:18])=[O:17])[CH2:4]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)NCC1CCNC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.6 %

Procedure:
TEA (1.05 mL, 7.5 mmol) was added to a solution of (R)-3-(aminomethyl)-1-N-Boc-pyrrolidine (1 g, 5 mmol) in DCM (25 mL) at 0° C. Methanesulfonyl chloride (0.43 mL, 5.5 mmol) was then added. After stirring at 0° C. for 2 h, the reaction mixture was diluted with water. The organic phase was separated, dried (MgSO4), filtered and concentrated. The crude material was treated with 1M HCl in MeOH (25 mL) at RT and stirred at RT for 20 h. The volatiles were removed under reduced pressure to afford 0.95 g of 72 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH3:11].[OH-].[NH4+:14]>C(O)C>[NH2:14][C:5]1[N:4]=[N:3][C:2]([Cl:1])=[C:7]([CH2:8][CH2:9][CH2:10][CH3:11])[CH:6]=1
Reactant: [NH4+]
Reactant: CCCCc1cc(Cl)nnc1Cl
Agent: [OH-]
Solvent: CCO
Product: CCCCc1cc(N)nnc1Cl
Yield: 36 %

Procedure:
A mixture of 3,6-dichloro-4-n-butylpyridazine (7.1 g, 34 mmol), ethanol (70 ml) and 25% aqueous ammonium hydroxide (70 ml) was heated to 135 deg in a sealed pressure resistant reaction vessel (Parr: achieving a pressure of 90 psi) for 24 hours. After this time the mixture was cooled and concentrated under reduced pressure. The residue was partitioned between dichloromethane (250 ml) and water (250 ml) and the aqueous layer re -extracted with dichloromethane (200 ml). The combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure to give the crude product as a mixture of isomers. Purification by flash chromotography (10-100% ethyl acetate/hexane) gave 3-amino-5-n-butyl-6-chloropyridazine as a white solid (2.3 g, 36%). 1H-NMR (CDCl3) 6.55 (1H, s, 4-H), 4.98 (2H, bs, NH2), 2.57 (2H, t, Bu), 1.58 (2H, m, Bu), 1.37 (2H, m, Bu), 0.91 (3H, t, Bu)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N(CC)CC)C.CS(O[CH2:54][C:55]([F:58])([F:57])[F:56])(=O)=O>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:24]=[CH:23][C:22]([CH2:25][N:26]6[CH2:31][CH2:30][N:29]([CH2:54][C:55]([F:58])([F:57])[F:56])[CH2:28][CH2:27]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ccc4[nH]ccc4c3)c3cc(-c4ccc(CN5CCNCC5)cc4)cnc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)CN1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1

Procedure:
3-(1H-indol-5-yl)-5-(4-(piperazin-1-ylmethyl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (50 mg) was dissolved in THF (1 mL) and treated with triethylamine (13 uL), and 2,2,2-trifluoroethyl methanesulfonate (13 uL); the reaction was allowed to stir for approximately hours, diluted water and extracted with EtOAC and washed with 1 N sodium hydroxide, water and brine and evaporated. The product was suspended in MeOH and (2 mL) detosylated directly by the addition of 0.5 mL sodium hydroxide solution, heated to 50 C for one hour. The reaction was diluted with water, extracted with dichloromethane and purified by MPLC, on silica gel, eluting with methanol in dichloromethane to yield 6 mg of an analytical sample (490 M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].CS(O[CH2:17][C:18]([F:21])([F:20])[F:19])(=O)=O>CN(P(N(C)C)(N(C)C)=O)C.Cl>[F:19][C:18]([F:21])([F:20])[CH2:17][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: N#Cc1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.7 %

Procedure:
To a solution 4-cyanophenol (5.0 grams, 42.0 mmole) in HMPT (40 ml) was added sodium hydride (1.68 grams, 42.0 mmole) and stirred for 15 minutes at room temperature. Via syringe 2,2,2-trifluoroethyl methane sulphonate (8.98 grams, 50.4 mmole) was added and the mixture was stirred at 140° C. over night. The mixture was cooled to room temperature, diluted with 300 ml ice water and 50 ml 2 N hydrochloric acid and extracted with diethyl ether. The combined extracts were washed with water, 1N sodium hydroxide and brine, dried over Na2SO4, filtered, and concentrated to an oil which was purified via flash chromatography on silica using 25% diethyl ether/hexane as eluent to give an oil (2.68 g). Synthesis 727 (1980).
Reaction SMILES: I[CH2:2][CH2:3][C:4]1([CH3:19])[C:16](=[O:17])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:6]2[C:5]1=[O:18].[C:20]([O-:23])(=[S:22])[CH3:21].[K+]>CC(C)=O>[C:20]([S:22][CH2:2][CH2:3][C:4]1([CH3:19])[C:16](=[O:17])[N:7]2[CH2:8][CH:9]=[CH:10][CH:11]([C:12]([O:14][CH3:15])=[O:13])[N:6]2[C:5]1=[O:18])(=[O:23])[CH3:21]
Reactant: COC(=O)C1C=CCN2C(=O)C(C)(CCI)C(=O)N12
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C1C=CCN2C(=O)C(C)(CCSC(C)=O)C(=O)N12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 6.43 g (17 mmol) of methyl 2,3,5,8-tetrahydro-2-(2-iodoethyl)-2-methyl-1,3-dioxo-1H-pyrazolo-[1,2-a]pyridazine-5-carboxylate and 1.94 g (17 mmol) of potassium thioacetate in 150 ml of acetone was stirred at room temperature for 5 hours. The solvent was removed by evaporation and the residue was partitioned between dichloromethane and water. The organic phase was separated, dried over magnesium sulfate and evaporated to give methyl 2-(2-acetylthioethyl)-2,3,5,8-tetrahydro-2-methyl-1,3-dioxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate as a mixture of diastereomers. Chromatography on silica gel using diethyl ether for the elution gave 3.81 g (69%) of diastereomer A in the form of a colorless oil and 1.26 g (23%) of diastereomer B in the form of a colorless oil.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Cl:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:62]1([CH2:67][C:68]2[CH:75]=[CH:74][C:71]([CH:72]=O)=[CH:70][CH:69]=2)[CH:66]=[CH:65][CH:64]=[N:63]1>C(O)C.CN(C=O)C>[N:62]1([CH2:67][C:68]2[CH:75]=[CH:74][C:71]([C:72]3[NH:42][C:39]4=[N:40][CH:41]=[C:36]([Cl:35])[C:37]([N:46]5[CH2:51][CH2:50][N:49]([CH2:52][CH3:53])[CH2:48][CH2:47]5)=[C:38]4[N:43]=3)=[CH:70][CH:69]=2)[CH:66]=[CH:65][CH:64]=[N:63]1
Reactant: CCN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(Cn2cccn2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: CCN1CCN(c2c(Cl)cnc3[nH]c(-c4ccc(Cn5cccn5)cc4)nc23)CC1
Reaction time: 6 h
Yield: 24.5 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-chloro-4-(4-ethylpiperazin-1-yl)-3-nitropyridin-2-amine (25 mg, 0.087 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.26 mmol, 0.26 mL) and 4-(1H-pyrazol-1-ylmethyl)benzaldehyde (1.1 eq, 0.096 mmol, 18 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (9 mg, 24%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.06 (t, J=7.2 Hz, 3H, NCH2CH3), 2.40 (q, J=7.1 Hz, 2H, NCH2CH3), 2.58 (t, br, J=3.8 Hz, 4H, piperazine N(CH2)2), 3.70 (t, J=3.9 Hz, 4H, piperazine N(CH2)2), 5.42 (s, br, 2H, PhCH2), 6.30 (t, J=2.1 Hz, 1H, pyrazole H-4), 7.35 (d, J=8.3 Hz, 2H, phenyl H-2 & H-6), 7.49 (d, J=1.5 Hz, 1H, pyrazole H-3 or H-5), 7.86 (d, J=2.2 Hz, 1H, pyrazole H-3 or H-5), 8.10 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.13 (d, J=8.2 Hz, 2H, phenyl H-3 & H-5);
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([C:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9].[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[CH:21][N:20]=1.C(N(CC)CC)C>O1CCOCC1>[Cl:18][C:19]1[N:20]=[CH:21][N:22]=[C:23]([N:15]2[CH2:14][CH2:13][N:12]([C:10]([C:5]3[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=3)=[O:11])[CH2:17][CH2:16]2)[CH:24]=1
Reactant: Cc1ccc(C(=O)N2CCNCC2)cc1F
Reactant: Clc1cc(Cl)ncn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)N2CCN(c3cc(Cl)ncn3)CC2)cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.5 %

Procedure:
A mixture of (3-fluoro-4-methylphenyl)(piperazin-1-yl)methanone hydrochloride (434 mg, 1.67 mmol), 4,6-dichloropyrimidine (250 mg, 1.67 mmol), and triethylamine (0.94 mL, 6.71 mmol) in dioxane (10 mL) was reflexed with stirring for 4 h. After cooling to rt, the mixture was poured onto water, and the aqueous phase was extracted with EtOAc (twice). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (5:1-2:1) to give 400 mg (71% yield) of the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.Br[C:14]1C(OC)=CC=C2[C:15]=1C=CN2>>[Br:1][C:2]1[CH:3]=[C:4]([O:11][CH3:12])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:15]=[CH:14]2
Reactant: COc1ccc([N+](=O)[O-])c(Br)c1
Reactant: COc1ccc2[nH]ccc2c1Br
Product: COc1cc(Br)c2[nH]ccc2c1

Procedure:
7-Bromo-5-methoxy-1H-indole CLXXVIII was prepared from 3-bromo-4-nitro-anisole using the procedure described for preparation of 4-bromo-5-methoxyindole XLVI (Example 12).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[OH:12][C:13]1[CH:14]=[C:15]([CH:21]=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[C:15]1[CH:21]=[CH:22][CH:23]=[C:13]([O:12][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH:14]=1)[CH3:20]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(Oc2ccc(F)cc2[N+](=O)[O-])c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
2,5-Difluoronitrobenzene (5.0 g, 31.4 mmol), ethyl 3-hydroxybenzoate (5.2 g, 31.4 mmol), and K2CO3 (8.7 g, 62.8 mmol) were added to DMF (50 mL). The solution was heated to 85° C. and stirred for 16 h. The reaction was cooled. The reaction was poured into distilled water and extracted with ethyl acetate. The combined organic layers were washed with distilled water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the crude title compound. The crude product was purified by silica gel column chromatography eluting with hexanes/ethyl acetate (90:10) to give the title compound (7.0 g, 73%).