Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH2:5].[CH3:7][C@:8]12[C@@:25]3([CH3:26])[C@@H:16]([C@:17]4([CH3:30])[C@@H:22]([CH2:23][CH2:24]3)[C:21]([CH3:28])([CH3:27])[C:20](=[O:29])[CH2:19][CH2:18]4)[CH2:15][CH2:14][C@@H:13]1[C@H:12]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:11]1([C:37](Cl)=[O:38])[CH2:10][CH2:9]2>CN(C1C=CN=CC=1)C.ClCCl>[CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][NH:5][C:37]([C@:11]12[CH2:33][CH2:32][C@@H:31]([C:34]([CH3:36])=[CH2:35])[C@@H:12]1[C@@H:13]1[C@@:8]([CH3:7])([CH2:9][CH2:10]2)[C@@:25]2([CH3:26])[C@@H:16]([C@:17]3([CH3:30])[C@@H:22]([CH2:23][CH2:24]2)[C:21]([CH3:28])([CH3:27])[C:20](=[O:29])[CH2:19][CH2:18]3)[CH2:15][CH2:14]1)=[O:38]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)Cl)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CN(C)CCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reaction time: 16 h

Procedure:
To a mixture of N1,N1-dimethylethane-1,2-diamine (74.5 mg, 0.845 mmol), Hunig'sBase (0.369 mL, 2.114 mmol) and DMAP (5.16 mg, 0.042 mmol) in dichloromethane (2 mL) was added (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-9-oxo-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carbonyl chloride (200 mg, 0.423 mmol). The reaction mixture was stirred for 16 h. LCMS indicated the formation of desired product. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol and the clear solution was purified by prep HPLC to provide the title compound as a colorless oil (150 mg, 68%). LCMS: m/e 525.56 (M+H)+, 2.27 min (method 1). 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 6.89 (t, J=5.04 Hz, 1H), 4.72 (d, J=2.14 Hz, 1H), 4.58 (s, 1H), 3.59-3.34 (m, 2H), 3.12 (td, J=11.06, 4.12 Hz, 1H), 2.67 (t, J=5.80 Hz, 2H), 2.53-2.43 (m, 2H), 2.41 (s, 6H), 2.40-2.32 (m, 1H), 2.07-2.03 (m, 1H), 1.97-1.84 (m, 2H), 1.78 (dd, J=11.60, 7.93 Hz, 1H), 1.71 (dd, J=13.12, 2.44 Hz, 1H), 1.67 (s, 3H), 1.62-1.22 (m, 14H), 1.21-1.11 (m, 1H), 1.06 (s, 3H), 1.01 (s, 3H), 1.04-0.97 (m, 1H), 0.97 (s, 6H), 0.91 (s, 3H).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[O:13]1[C:17]2([CH2:22][CH2:21][CH:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1.Cl[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCCC1>[O:13]1[C:17]2([CH2:22][CH2:21][C:20]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Reactant: CCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 500 mL round-bottomed flask was charged with diisopropylamine (16 mL) and tetrahydrofuran (311 mL). The solution was cooled to −78° C. under N2 and n-BuLi (2.5 M in hexanes, 44.8 mL) was added. The reaction was stirred for 30 minutes at −78° C. and ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate (20 g) was added as a tetrahydrofuran solution (ca. 10 mL). The solution was stirred at −78° C. for 1 hour and ethyl chloroformate (9 mL) was added neat. After stirring at −78° C. for 10 minutes, the reaction was warmed to room temperature over 2 hours. The reaction was quenched with saturated aqueous NH4Cl and diluted with diethyl ether. The layers were separated, the aqueous layer was extracted with diethyl ether and the combined organics were dried (Na2SO4), filtered and concentrated by rotary evaporation. The residue was purified by regular phase flash column chromatography (Analogix, 0-65% hexanes/ethyl acetate).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]([CH3:23])([CH3:22])[CH2:20][OH:21])[CH2:15][CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:3]=1.[CH3:30][NH:31][C:32]1[NH:36][C:35]2[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=2[N:33]=1>>[CH3:22][C:19]([N:16]1[CH2:15][CH2:14][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)[N:3]=[C:2]([N:33]2[C:34]4[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=4[N:36]=[C:32]2[NH:31][CH3:30])[N:10]=3)[CH2:18][CH2:17]1)([CH3:23])[CH2:20][OH:21]
Reactant: Cn1c(CN2CCN(C(C)(C)CO)CC2)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CNc1nc2ccccc2[nH]1
Product: CNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)CO)CC3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropan-1-ol and N-methyl-1H-benzo[d]imidazol-2-amine were reacted to give 453. LCMS m/z: 535.3 (MH+)
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[Si:12]([O:19][CH2:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[OH-].[Na+]>C1COCC1.O.Cl[Pd]Cl>[Si:12]([O:19][CH2:20][C:21]1[CH:22]=[C:23]([C:3]2[CH:2]=[C:11]3[C:6](=[CH:5][CH:4]=2)[CH:7]=[CH:8][CH:9]=[CH:10]3)[CH:24]=[C:25]([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:30])[CH3:31])[CH:26]=1)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]
Reactant: Ic1cccc2ccccc12
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(CO[Si](C)(C)C(C)(C)C)cc(-c2ccc3ccccc3c2)c1
Reaction time: 24 h
Yield: 137.5 %

Procedure:
12 ml of THF/H2O was added to 0.6199 g (2.44 mmol) of iodonaphthalene, and 0.122 g (5 mol %) of PdCl2 (dppf) was added in a darkroom. 1 g (2.44 mmol) of 3,5-bis-tert-butyldimethylsilyloxymethyl Phenylboronic acid dissolved in 12 ml of THF/H2O was added, 3.66 ml (3 eq) of 2N NaOH aq was injected, the reaction was initiated in a 65° C. oil bath with light shielding, and the mixture was agitated for 24 hours. Completion of the reaction could not be confirmed because the raw material iodonaphthalene overlaps the target product in TLC (Hex only). Fluorescence was confirmed with the naked eye. This was extracted with EtOAc, and the organic layer was washed with H2O, sat. NaHCO3 aq and sat. NaCl aq, and dried by addition of anhydrous NaSO4. The solvent was distilled off under reduced pressure to obtain 1.6530 g of a mixture of the target product and iodonaphthalene.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[C:12]([CH:13]=O)[C:11]([OH:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:23]([CH:25]=[CH2:26])=[O:24].O>O1CCOCC1>[O:1]([C:8]1[CH:9]=[CH:10][C:11]2[O:16][CH2:26][C:25]([CH:23]=[O:24])=[CH:13][C:12]=2[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC=O
Reactant: O=Cc1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=CC1=Cc2cc(Oc3ccccc3)ccc2OC1

Procedure:
A mixture of 5-phenoxysalicylaldehyde (15.0 g, 70.0 mmol, see example 2d) and potassium carbonate (19.4 g, 140.0 mmol) in 250 ml of 1,4-dioxane is treated with acrolein (4.32 g, 77.0 mmol) under nitrogen. The mixture is heated at reflux for 6 hours. Water is added and the mixture is extracted with dichloromethane. The organic layer is dried (MgSO4) and evaporated. The residue is purified by flash chromatography (silica gel, 10% EtOAc/hexane) to give 6-phenoxy-2H-1-benzopyran-3-carboxaldehyde, as a fluorescent solid.
Reaction SMILES: [C:1]1([S:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17](O)=[O:18])=[CH:12][CH:11]=1>>[F:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][C:17]([C:4]2[CH:5]=[CH:6][C:1]([S:7][CH3:8])=[CH:2][CH:3]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: O=C(O)Cc1ccc(F)cc1
Reactant: CSc1ccccc1
Product: CSc1ccc(C(=O)Cc2ccc(F)cc2)cc1
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 63.2 %

Procedure:
Thioanisole (10.1 g, 81.5 mmol) and 4-fluorophenylacetic acid (10.0 g, 65 mmol) were combined in a round bottom 3-neck flask. Polyphosphoric acid (PPA) (160 g), warmed to 60° C., was added and the mixture was heated to 120°-125° C. under nitrogen with vigorous stirring for 20 minutes. Upon cooling to 40° C., ice water and ice were added with vigorous stirring. The temperature was kept below 85° C. during the quench and dissolution of PPA. After cooling to 25° C., the white solids were filtered off, washed with two portions of water and dried. Recrystallization from ethyl acetate-hexane afforded the ketone (10.7 g, 63%): mp 139°-140° C. Elemental analysis Calc'd. for C15H13FOS: C, 69.21, H, 5.03, S, 12.32. Found: C, 68.74, H, 5.09, S, 12.15.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][OH:6].[H-].[Na+].[F:9][C:10]1[C:16](F)=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1.O>O1CCCC1>[F:9][C:10]1[C:16]([O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][C:13]([NH2:14])=[C:12]([N+:18]([O-:20])=[O:19])[CH:11]=1
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: COCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(N)c([N+](=O)[O-])cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 47.5 %

Procedure:
In a 250 ml three-necked flask under an argon atmosphere, 1 g of 3-methoxy-1-propanol in 20 ml of tetrahydrofuran are cooled to 0° C. using an ice bath and then 450 mg of sodium hydride at 50% in liquid petroleum jelly are introduced in fractions. After stirring for 15 minutes at 0° C., add, over 5 minutes, a solution of 1.5 g of 4,5-difluoro-2-nitroaniline in 20 ml of tetrahydrofuran and then heat in the region of 70° C. for 1 hour 30 minutes. The reaction mixture is poured into 200 ml of water, and extracted with three times 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulphate and brought to dryness under reduced pressure. After purification by flash chromatography on silica gel (15-20 μm), eluting with a mixture of cyclohexane and ethyl acetate (80/20 by volume), in this way we obtain 1 g of 4-fluoro-5-(3-methoxypropoxy)-2-nitrophenylamine, in the form of a red solid, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [NH2:1][C:2]1([C:13]([OH:15])=[O:14])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[CH2:3]1.C(=O)([O-])[O-].[Na+].[Na+].O.[C:23](Cl)(=[O:39])[O:24][CH2:25][CH:26]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2>O1CCOCC1>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:23]([NH:1][C:2]3([C:13]([OH:15])=[O:14])[CH2:5][N:4]([C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])[CH2:3]3)=[O:39])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CC(N)(C(=O)O)C1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(NC(=O)OCC2c3ccccc3-c3ccccc32)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round bottomed flask was charged with 3-amino-1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (prepared according the procedure described in Synthesis 1991, 783-784.) (2.464 mmol), sodium carbonate (1.3 g, 12.32 mmol), a stir bar and water (70 mL). (9H-fluoren-9-yl)methyl carbonochloridate (1.9 g, 7.39 mmol) in 1,4-dioxane (50 mL) was added and the milky solution was stirred overnight at rt. The next day the reaction was poured into a separatory funnel and the aqueous solution washed with diethyl ether (repeated twice) (organic phases were discarded at this stage). The aqueous phase was acidified to pH 2-3 with 1 M HCl (a precipitate was formed) and the product was extracted with EtOAc (repeated 3 times). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The solid was used without purification in the next step. LRMS (M+Na)+: 461 m/z.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH:2]([CH3:4])[OH:3].[CH2:7](O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[C:1]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])(=[O:5])[CH:2]([CH3:4])[OH:3]
Reactant: CC(O)C(=O)O
Reactant: CCCCCCCCCCO
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCOC(=O)C(C)O
Temperature: 145 °C
Yield: 13.9 %

Procedure:
A 500 mL one neck round bottom flask equipped with a Dean Stark trap, condensor and nitrogen inlet/outlet was charged with 22.52 g (0.75 moles) lactic acid, 47.46 g (0.98 moles) decyl alcohol, 3 ml sulfuric acid and 220 mL toluene. The mixture was heated to 145° C. for 20 hours and water was collected as the reaction proceeded. The acid was neutralized by washing three times with 50 ml saturated sodium bicarbonate solution. The organic layer was collected and dried over magnesium sulfate. Decyl lactate was distilled under high vacuum to yield 24.03 g (12.4% yield) of clear colorless liquid. According to GC the product is 97.78% pure.
Reaction SMILES: Br[CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:2]([CH3:7])[C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
Methyl 2-bromopropionate (60.12 g, 0.36 mol) is added to a mixture of 4-nitrophenol (25 g, 0.18 mol) and potassium carbonate (49.75 g, 0.36 mol) in acetonitrile. The reaction mixture is refluxed for 18 hours, cooled and poured into water. The phases are separated and the aqueous phase is extracted with ethyl acetate. The organic phase and the organic extracts are combined, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a white powder, mp 79°-80° C.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[NH:5]1.Cl[C:16]1[N:21]=[CH:20][C:19]([S:22]([N:25]2[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C)C=O>[OH:3][C:4]1[NH:5][C:6]2[C:11]([C:12]=1[C:16]1[CH:17]=[CH:18][C:19]([S:22]([N:25]3[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]3)(=[O:24])=[O:23])=[CH:20][N:21]=1)=[CH:10][C:9]([C:13]#[N:14])=[CH:8][CH:7]=2
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: CN1CCN(S(=O)(=O)c2ccc(Cl)nc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(S(=O)(=O)c2ccc(-c3c(O)[nH]c4ccc(C#N)cc34)nc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 9.8 %

Procedure:
A mixture of sodium hydride (0.157 g, 3.9 mmol, 60% dispersion in oil, pre-washed with hexane) in N,N-dimethylformamide (2 mL) was added to 2-oxoindoline-5-carbonitrile (0.464 g, 2.9 mmol) in N,N-dimethylformamide (5 mL). The formed brown mixture was stirred at room temperature for 10 min and 1-[(6-chloropyridin-3-yl)sulfonyl]-4-methylpiperazine (0.255 g, 0.92 mmol; described in: Thunus L. Annuale Pharmacetiques Francisies, 1977, 35, 197-203) in N,N-dimethylformamide (3 mL) was added. The obtained red solution was heated at 150° C. for 10 min and was then allowed to reach room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between an aqueous HCl solution (2 M) and ethyl acetate. The aqueous mixture was alkalized to pH 8 by adding sodium hydrogen carbonate (s), and extracted with ethyl acetate (3×10 mL). The combined extracts were dried (Na2SO4), and the solvent was removed in vacuo. The residue was purified on a silica gel column using chloroform/methanol/conc. NH3 (aq), (84:14:2), as an eluent to afford 0.050 g. Further purification was done by preparative HPLC (Xterra column (19×300 mm) with 0.05 M NH4OAc buffer/acetonitrile, (90:10-30:70), as a eluent). Fractions containing product were collected, evaporated in vacuo, and dried at 25° C. in vacuo over night to afford 0.036 g (10% yield) of the title compound: 1H NMR (D2O, 400 MHz) δ 8.12 (s, 1H), 7.60 (d, J=10 Hz, 1H), 7.13 (s, 1H), 7.00 (dd, J=8, 2 Hz, 1H), 6.93 (d, J=9 Hz, 1H), 6.73 (dd, J=8, 2 Hz, 1H), 3.91 (d, J=13 Hz, 2H), 3.60 (d, J=11 Hz, 2H), 3.24 (app. t, J=11 Hz, 2H), 3.02 (app. t, J=12 Hz, 2H), 2.89 (s, 3H); MS (TSP) m/z 398 (M++1).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)CCC>>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: N#Cc1cccnc1Cl
Product: N#Cc1cccnc1-c1cccnc1
Yield: 84 %

Procedure:
Prepared in 84% yield from 2-chloro-3-cyanopyridine and 3-(tributylstannyl)pyridine according to the procedure described for Example 164A. MS (ESI+) m/z 182.0 (M+H)+; 1H NMR (CDCl3) δ 7.44-7.51 (m, 2H), 8.13 (dd, J=7.8, 1.7 Hz, 1H), 8.27-8.31 (m, 1H), 8.77 (d, J=4.7 Hz, 1H), 8.93 (dd, J=8.9, 1.9 Hz, 1H), 9.19 (br s, 1H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29](Cl)=[O:30])[CH:24]=1>Cl.O1CCCC1>[Cl:22][C:23]1[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:2][CH2:3][CH2:4][CH:5]2[CH2:10][CH2:9][N:8]([S:11]([NH2:14])(=[O:13])=[O:12])[CH2:7][CH2:6]2)=[O:30])[CH:24]=1
Reactant: NCCC1CCN(S(N)(=O)=O)CC1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: NS(=O)(=O)N1CCC(CCNC(=O)c2cc(Cl)ccn2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 36 %

Procedure:
To a mixture of 1.95 g. (0.008 mole) of 4-(2-aminoethyl)-1-piperidinesulfonamide hydrochloride and 2.22 ml. (0.016 mole) of triethylamine in 15 ml. of dry tetrahydrofuran, there were added 1.41 g. (0.008 mole) of 4-chloropicolinoyl chloride dissolved in 15 ml. of tetrahydrofuran. The initial addition step was slightly exothermic (~40° C.) and after completion of same, the resulting reaction mixture was stirred at ambient temperatures for a period of approximately 16 hours. At this point, the thoroughly stirred mixture was poured into 50 ml. of ice water and subsequently acidified with a few drops of 3N aqueous hydrochloric acid. The resulting crystalline precipitate was then recovered by means of suction filtration and thereafter recrystallized twice from acetonitrile to afford 0.997 g. of pure product. In this way, there was ultimately obtained a 36% of 4-[2-(4-chloropicolinamido)ethyl]-1-piperidinesulfonamide, m.p. 186°-187° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[CH3:13][NH2:14].O>O1CCCC1>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([NH:14][CH3:13])=[O:9])=[CH:4][CH:3]=1
Reactant: CN
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)COc1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-chlorophenoxyacetyl chloride (2 g) in tetrahydrofuran (40 ml) at 0° C. was added methylamine (2M, 12.2 ml). The reaction was allowed to warm to room temperature, and stirred for 1 h, before water (30 ml) added and the tetrahydrofuran removed in vacuo. The aqueous was extracted with ethyl acetate (2×50 ml), the combined organic extracts washed with brine (40 ml), dried over magnesium sulphate (1 g) and the solvent removed in vacuo to yield the title compound as a white solid (1.67 g).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.CS(O)(=O)=[O:17].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[N:31]O)[CH2:26][CH2:25]2>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=[O:17])[NH:31][CH2:26][CH2:25]2
Reactant: CS(=O)(=O)O
Reactant: COc1ccc2c(c1)CCC2=NO
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: COc1ccc2c(c1)CCNC2=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Phosphorous pentoxide (1.0 g, 7.1 mmol) is added all at once to methanesulfonic acid (10 g, 104.1 mmol) and stirred for 3 hours at room temperature. 5-Methoxy-1-indanone oxime (100 mg, 0.53 mmol) is added in portions, with each portion allowed to dissolve completely before the next is added. The stirred reaction mixture is heated at 100° for 1.5 hours. The reaction is quenched by the addition of saturated sodium bicarbonate (10 ml) and extracted with 3×5 ml dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated in vacuo to yield the 6-methoxy-1-oxo-1,2,3,4-tetrahydroisoquinoline. Treatment with boron tribromide (see example 1 ) yields 6-hydroxy-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [C:1]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[NH:17]1[C:21]([C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)=[N:20][N:19]=[N:18]1>>[NH:20]1[C:21]([C:22]2[CH:23]=[C:24]([NH:28][S:7]([C:4]3[CH:5]=[CH:6][C:1]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:2][CH:3]=3)(=[O:9])=[O:8])[CH:25]=[CH:26][CH:27]=2)=[N:17][N:18]=[N:19]1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1ccc(-c2ccccc2)cc1
Yield: 58.3 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from biphenyl-4-sulfonyl chloride (14 mg, 0.055 mmol) and [3-(1H-tetrazol-5-yl)phenyl]amine (8 mg, 0.05 mmol) giving 11 mg (60%) of the title product. MS (ESI+) calcd for C19H15N5O2S 377.094645, found 377.094375.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](COCC[Si](C)(C)C)[C:9]([CH3:11])=[CH:10][C:3]=12.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][C:9]([CH3:11])=[CH:10][C:3]=12
Reactant: Cc1cc2c(Cl)ccnc2n1COCC[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: Cc1cc2c(Cl)ccnc2[nH]1
Yield: 60.6 %

Procedure:
A mixture of 4-chloro-2-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo-[2,3-b]pyridine (296.5 mg, 1 mmol) and TBAF (5 mL, 1 M in THF, Aldrich) was refluxed overnight. The THF was removed under reduced pressure and the residue was diluted with water (5 mL). The precipitate that formed was collected, washed with water and dried (MgSO4) to afford the title compound (101 mg, 60%). 1H NMR (CD3OD) δ 7.99 (d, 1H, J=5.5 Hz), 7.06 (d, 1H, J=5.5 Hz), 6.23 (s, 1H), 2.46 (s, 3H); MS(ESI+) m/z 167 and 169 (M+H, 1 Cl)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.Cl[CH2:11][C:12]1[C:17]([CH3:18])=[C:16]([S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]2[CH:25]=[CH:26][C:27]3[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=3)[N:29]=2)[CH:15]=[CH:14][N:13]=1.[OH-].[Na+]>CC(O)C>[CH3:18][C:17]1[C:12]([CH2:11][S:9][C:5]2[N:4]=[C:3]([CH3:2])[CH:8]=[CH:7][N:6]=2)=[N:13][CH:14]=[CH:15][C:16]=1[S:19][CH2:20][CH2:21][CH2:22][S:23][C:24]1[CH:25]=[CH:26][C:27]2[N:28]([C:30]([N+:33]([O-:35])=[O:34])=[CH:31][N:32]=2)[N:29]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Cc1ccnc(S)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1ccnc(SCc2nccc(SCCCSc3ccc4ncc([N+](=O)[O-])n4n3)c2C)n1
Temperature: 0 °C

Procedure:
A suspension of 4-methyl-pyrimidine-2-thiol hydrochloride (0.46 g, 2.8 mmol) and 6-[3-(2-chloromethyl-3-methyl-pyridin-4-ylsulfanyl)-propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.03 g, 2.5 mmol) in 2-propanol (50 ml) is heated under reflux for 4 h under a nitrogen atmosphere. After cooling, the mixture is treated with ice water (100 ml), adjusted to pH 10 with 40% strength sodium hydroxide solution, and extracted with ethyl acetate. The combined extracts are washed with sodium carbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue is chromatographed (silica, toluene/dioxane 2:1) and crystallized from acetonitrile to give the title compound as a colourless solid, 0.49 g (39%). M.p. 136-8° C.