Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+].[NH2:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1.[CH3:21][O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28]Cl)=[O:24]>CC(C)=O.O>[CH3:21][O:22][C:23]([NH:25][C:26]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[C:27]=1[CH2:28][NH:9][C:10]1[C:11]2[N:12]([C:16]([CH3:20])=[C:17]([CH3:19])[N:18]=2)[CH:13]=[CH:14][CH:15]=1)=[O:24]
Reactant: Cc1nc2c(N)cccn2c1C
Reactant: COC(=O)Nc1cccc(C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Nc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 25 °C
Yield: 55.7 %

Procedure:
4.5 g of sodium iodide and 6.63 g of dry sodium carbonate are added to a solution of 4.03 g of 8-amino-2,3-dimethylimidazo[1,2-a]pyridine and 6.41 g of 2-methoxycarbonylamino-6-methyl-benzyl chloride in 400 ml of dry acetone, and the mixture is heated under reflux for 6 h. After cooling to RT, 400 ml of water are added and the acetone is distilled off in a water jet vacuum. The aqueous residue is then extracted three times with each time 200 ml of ethyl acetate. The combined organic extracts are washed with 300 ml of water, dried over magnesium sulfate and then concentrated. The residue is purified by chromatography on silica gel (toluene/dioxan=9:1 as eluent). The fractions with Rf =0.2 are concentrated and then recrystallized from diisopropyl ether. 4.71 g (56%) of the title compound of m.p. 136°-138° C. are isolated.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([O:10][CH3:11])[CH:6]=[CH:5][N:4]=1.[SH:12][C:13]1[NH:17][C:16]2[CH:18]=[C:19]3[C:23](=[CH:24][C:15]=2[N:14]=1)[C:22]([CH3:26])([CH3:25])[C:21](=[O:27])[C:20]3([CH3:29])[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][O:10][C:7]1[CH:6]=[CH:5][N:4]=[C:3]([CH2:2][S:12][C:13]2[NH:14][C:15]3[CH:24]=[C:23]4[C:19](=[CH:18][C:16]=3[N:17]=2)[C:20]([CH3:28])([CH3:29])[C:21](=[O:27])[C:22]4([CH3:26])[CH3:25])[C:8]=1[CH3:9]
Reactant: COc1ccnc(CCl)c1C
Reactant: CC1(C)C(=O)C(C)(C)c2cc3[nH]c(S)nc3cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 690 mg of 2-chloromethyl-3-methyl-4-methoxypyridine and 400 mg of 5,7-dihydro-2-mercapto-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one in 40 ml of absolute acetone was treated with 1.9 g of finely ground potassium carbonate, whereupon the mixture was stirred at room temperature under argon for 18 hours. After concentrating the mixture in vacuo the residue was chromatographed on silica gel with methylene chloride/ethyl acetate (10:1) as the elution agent, the medium pressure flash chromatography method being used and the pressure being produced with nitrogen gas. By recrystallization from ethyl acetate/ether there was obtained 5,7-dihydro-2-[[(4-methoxy-3-methyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(1H)-one of melting point 218°-220°.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13][C:14]1[CH:31]=[CH:30][C:17]([O:18][CH:19]([C:21]2[N:26]3[N:27]=[CH:28][N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)[CH3:20])=[CH:16][CH:15]=1>ClCCl>[CH3:12][S:13]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([C:21]2[N:26]3[N:27]=[CH:28][N:29]=[C:25]3[N:24]=[CH:23][CH:22]=2)[CH3:20])=[CH:30][CH:31]=1)=[O:9]
Reactant: CSc1ccc(OC(C)c2ccnc3ncnn23)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(Oc1ccc(S(C)=O)cc1)c1ccnc2ncnn12
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A solution of 3-chloroperbenzoic acid (0.63 g) in dichloromethane (30 ml) was added dropwise at -78° C. to a stirred solution of 7-{1-[4-(methylthio)phenoxy]ethyl}-1,2,4-triazolo[1,5-a]pyrimidine (0.89 g, prepared in a similar manner to that described in Example 9) in dichloromethane (30 ml). The reaction mixture was stirred at -78° C. for 2 hours, washed with a 10% aqueous solution of sodium hydrogen carbonate followed by water. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography using as eluent a mixture of dichloromethane and ethanol (in the ratio of 95:5 respectively), followed by recrystallisation from a mixture of ethyl acetate and hexane, to give 7-[1-(4-methylsulphinylphenoxy)ethyl]-1,2,4-triazolo[1,5-a]pyrimidine. Yield 0.76 g, (m.p. 89°-102° C.).
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].Br[CH:52]([CH3:62])[C:53]([NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:54].C([O-])([O-])=O.[K+].[K+].N#N>CN(C=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:62][CH2:52][C:53]([NH:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:54])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(Br)C(=O)Nc1ccccc1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc(CC)c(C(=O)OCCC(=O)Nc2ccccc2)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
To a solution/suspension of 0.66 g 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, 0.23 g 2-bromo-N-phenylpropionamide, and 0.15 g K2CO3 in 7 mL of DMF was added 0.17 g of KI. The reaction was stirred 10 minutes at room temperature, then heated in a N2 atmosphere at 70° C. overnight. The reaction was partitioned between H2O and EtOAc, and the organic extract washed with brine and dried with MgSO4. Filtration, concentration, and flash chromatography with a 10-60% EtOAc/hexanes gradient provided 0.35 g of pure product.
Reaction SMILES: [F:1][C:2]12[CH2:12][CH2:11][O:10][C:9]3[CH:13]=[CH:14][C:15]([N+:17]([O-])=O)=[CH:16][C:8]=3[C@@:7]1([CH3:20])[N:6]=[C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:4]([CH3:30])([CH3:29])[S:3]2(=[O:32])=[O:31]>CCOC(C)=O.CO.[Pd]>[NH2:17][C:15]1[CH:14]=[CH:13][C:9]2[O:10][CH2:11][CH2:12][C:2]3([F:1])[S:3](=[O:32])(=[O:31])[C:4]([CH3:30])([CH3:29])[C:5]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:6][C@:7]3([CH3:20])[C:8]=2[CH:16]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OCCC2(F)S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1=N[C@]2(C)c3cc(N)ccc3OCCC2(F)S(=O)(=O)C1(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 84.3 %

Procedure:
A round bottom flask was charged with Pd/C (0.020 g, 0.019 mmol) and put under a nitrogen atmosphere. A solution of tert-butyl ((11bR)-4a-fluoro-3,3,11b-trimethyl-10-nitro-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.090 g, 0.191 mmol) in EtOAc (477 μl) and MeOH (477 μl) was added via syringe and the flask was evacuated and filled with hydrogen. The mixture was stirred at RT under hydrogen atmosphere for 17 hours. The mixture was filtered through Celite and washed with EtOAc and the filtrate was concentrated to yield tert-butyl ((11bR)-10-amino-4a-fluoro-3,3,11b-trimethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-2-yl)carbamate (0.071 mg, 0.161 mmol, 84% yield) as a light yellow solid. LC/MS (ESI+) m/z=442.3.
Reaction SMILES: C([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][CH2:11][CH2:12][NH2:13])(OC(C)(C)C)=O.F[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21].C(Cl)Cl>C(O)C.[OH-].[Na+]>[NH2:8][C@@H:9]([CH2:10][CH2:11][CH2:12][NH:13][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[C:20]#[N:21])[C:14]([OH:16])=[O:15]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)O
Reactant: N#Cc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: N#Cc1ccccc1NCCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 2.4 %

Procedure:
A solution of 928 mg (4 mmoles) of Nα -Boc-L-ornithine and 968 mg (8 mmoles) of 2-fluorobenzonitrile in 4 mL of ethanol and 4 mL of 1N NaOH were heated at reflux for 24 hours. Another 8 mmoles each of 1N NaOH and 2-fluorobenzonitrile were then added and reflux was continued for another 24 hours. The clear solution was cooled to room temperature, and the white paste dumped into 125 mL of CH2Cl2 and extracted with 100 mL of water made basic (pH 12) with NaOH. The aqueous extract was acidified with 5N HCl, and extracted with 125 mL of CH2Cl2. The organic phase was washed with 1M HCl, dried (Na2SO4) and concentrated in vacuo to give an oil. The oil was purified by flash chromatography on silica gel, eluting with 2:1 ethyl acetate:ethanol containing 1% triethylamine. The sole fluorescent product was an oil, 132 mg (10%), with rf of 0.49 in the elution solvent. 125 mg of the oil was dissolved in 22 mL of 5:1:1 acetic acid/water/12M HCl, and stirred for 3 hours at room temperature. The sample was concentrated in vacuo, then ethanol was added and the sample again concentrated in vacuo to give a waxy solid. This was recrystallized from water to give 22.5 mg of white needles. The mother liquor yielded 67 mg of white foam on concentration. Yield (100%).: mp >265°; MS (FAB) m/e calc'd for C12H10N3O2 : 234.1243, found 234.1231; M/Z 223 (M+), 224 (M+H)+. 1H NMR (300 MHz, D2O) δ: 1.74 (m, 2H), 1.96 (m, 2H), 3.33 (t, J=6.0 Hz, 2H), 3.79 (t, J=5.8 Hz, 1H), 6.71 (t, J=7 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 7.55 (m, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH:10]([CH3:16])[CH2:9]1)C1C=CC=CC=1>CO.[H][H].[OH-].[Pd+2].[OH-]>[CH3:16][CH:10]1[CH:11]([OH:15])[CH:12]([CH3:14])[CH2:13][NH:8][CH2:9]1
Reactant: [H][H]
Reactant: CC1CN(Cc2ccccc2)CC(C)C1O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1CNCC(C)C1O

Procedure:
A mixture of 1-benzyl-3,5-dimethyl-4-hydroxypiperidine (1.0 g, 4.56 mmole) and 20% palladium hydroxide (0.3 g) in methanol (20 ml) was stirred at room temperature in hydrogen atmosphere (1 atm.) for 4 hr. Catalyst was filtered off, washed with methanol, filtrate was concentrated to dryness to give 3,5-dimethyl-4-hydroxypiperidine. Yield 0.5 g (90%), C7H15NO, m/z 130 (M+1), PMR (CDCl3): 0.9 (6H, m, 2×CH3), 1.44 (1H, m, H3), 1.7 (1H, m, H5), 2.3 (1H, m, H6), 2.46-2.84 (2H, m, H2 & H6), 2.98 (1H, m, H2), 3.3-3.7 (1H, m, H4).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]([C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)Br)=[CH:4][CH:3]=1.[CH3:20][C:21]1[S:22][CH:23]=[C:24]([C:26](=[S:28])[NH2:27])[N:25]=1>C(#N)C.C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:27]=[C:26]([C:24]3[N:25]=[C:21]([CH3:20])[S:22][CH:23]=3)[S:28][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([S:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Reactant: Cc1nc(C(N)=S)cs1
Solvent: CCO
Solvent: CC#N
Product: CSc1ccc(-c2sc(-c3csc(C)n3)nc2-c2ccc(F)cc2)cc1
Yield: 48.7 %

Procedure:
A solution of 1-(4-fluorophenyl)-2-(4-methylthiophenyl)-2-bromoethanone (9.69 g, 28.6 mmol) (Example 1, Step 3) and 2-methylthiazole-4-thiocarboxamide (3.90 g, 24.7 mmol) in 35 mL of acetonitrile and 20 mL of ethanol was heated to reflux for 1 hour. The solution was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to give a yellow solid. The crude solid was purified by flash chromatography over silica gel eluting with 1:1 hexane:ethyl acetate. The appropriate fractions were combined and the solvent removed in vacuo to provide pure 4-(4-fluorophenyl)-5-(4-methylthiophenyl)-2-[2-(methyl)-4-thiazolyl]thiazole (4.79 g; 49%): mp 132.5°-135° C. 1H NMR (CDCl3) 300 MHz 7.89 (s, 1H), 7.55 (m, 2H), 7.25 (d, J=8.5Hz, 2H), 7.17 (d, J=8.5Hz, 2H), 7.01 (t, J=8.8Hz, 2H), 2.78 (s, 3H), 2.49 (s, 3H). 19F NMR (CDCl3) -113.80 (m). Mass spectrum M+H+ =399.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8]CN2CCN(C3C(OC)=CC=CN=3)CC2C)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2.S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH3:40][O:41][C:42]1[C:43]([N:48]2[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]2)=[N:44][CH:45]=[CH:46][CH:47]=1>>[ClH:1].[S:2]1[CH:6]=[C:5]([CH2:7][CH2:8][N:51]2[CH2:52][CH2:53][N:48]([C:43]3[C:42]([O:41][CH3:40])=[CH:47][CH:46]=[CH:45][N:44]=3)[CH2:49][CH2:50]2)[C:4]2[CH:25]=[CH:26][CH:27]=[CH:28][C:3]1=2
Reactant: COc1cccnc1N1CCN(CCCc2csc3ccccc23)C(C)C1
Reactant: COc1cccnc1N1CCNCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Product: COc1cccnc1N1CCN(CCc2csc3ccccc23)CC1

Procedure:
The title compound was prepared (0.63 g, 56%, mp 208°-215° C.) in a manner analogous to the preparation of 1-[3-(benzo[b]thien-3-yl)propyl]-4-(3-methoxy-2-pyridinyl)-2-methylpiperazine hydrochloride (Example 41) by the reaction of 3-benzo[b]thieneethanol tosylate (Example 47) with 1-(3-methoxy-2-pyridinyl)piperazine.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)/[CH:10]=[CH:11]/[CH3:12].Cl.O.N>>[OH:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:3]=1[N:4]=[C:11]([CH3:12])[CH:10]=[C:9]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1O
Reactant: C/C=C/C(=O)c1ccccc1
Agent: Cl
Agent: N
Solvent: O
Product: Cc1cc(-c2ccccc2)c2cccc(O)c2n1
Yield: 55.7 %

Procedure:
A mixture of 2-hydroxyaniline (2 g), crotonoylbenzene (8.03 g) and concentrated hydrochloric acid (8 ml) was refluxed for 24 hours. The mixture was neutralized with concentrated ammonia water under ice-cooling, and extracted with chloroform. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified according to a conventional manner to give 8-hydroxy-2-methyl-4-phenylquinoline (2.4 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.C([O:15][C:16](=O)[CH2:17][NH:18][CH3:19])C.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:16](=[O:15])[CH2:17][N:18]([CH3:19])[C:10]2=[S:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)CNC
Reactant: Cc1ccc(N=C=S)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccc(N2C(=O)CN(C)C2=S)cc1Cl
Yield: 57.1 %

Procedure:
The title compound was prepared by the procedure described in Example 1 using 18.3 g of 3-chloro-4-methylphenyl-isothiocyanate, 15.3 g of sarcosine ethyl ester hydrochloride, 25 g of triethyl amine, and 300 mL of chloroform. Crystallization from ethyl acetate afforded the title compound (14.5 g) as an off-white solid, m.p. 178°-180° C. Anal. Calcd. for C11H11Cl N2O S: C, 51.87; H, 4.35; N,11.00. Found: C, 51.89; H, 4.20; N, 10.95. Mass spectrum (+FAB, [M+H]+) m/z 255/257.
Reaction SMILES: [Na+].[I-:2].CC(=O)CC.Cl[CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]2[CH2:13][CH2:12]1>CCOC(C)=O>[I:2][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:14]2[CH2:13][CH2:12]1
Reactant: ClCCN1CCn2c1nc1ccccc12
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: ICCN1CCn2c1nc1ccccc12
Reaction time: 5 h
Yield: 91.1 %

Procedure:
A mixture of NaI (1.73 g, 11.57 mmol) and 2-butanone (20 mL) was heated under reflux for 30 minutes 1-N-(2-Chloroethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (1.70 g, 7.71 mmol) and additional 2-butanone (5 mL) were added and heating was continued for 5 hours. EtOAc (50 mL) was added and the mixture was filtered. The filtrate was washed with H2O, 10% sodium bisulfite (25 mL), saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give 2.2 g (92%) of a light brown solid m.p. 101°-103° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:20]C(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[Cl:20][C:5]1[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:13])[CH3:12])=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Nc1cccc(Cl)n1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1nc(Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of N-(6-chloropyridin-2-yl)pivalamide (2.00 g, 9.40 mmol) in 25 mL THF at −78° C. was added butyllithium 2.5 M in hexanes (9.40 mL, 23.5 mmol) slowly dropwise over 2 min After 5 min, the reaction mixture was warmed to 0° C., then back to −10° C. (ice/brine) and to −20° C. (ice/salt). The reaction mixture was allowed to stir at this temp for 1.5 h. The reaction mixture was cooled to −78° C. and a solution of hexachloroethane (3.34 g, 14.1 mmol) in 7.5 mL THF was added dropwise via syringe. The bath was removed and the reaction mixture warmed to ambient temperature. The reaction mixture was partitioned between satd NH4Cl and Et2O. The organic layer was washed with water once, brine once, and the organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was dissolved in DCM and purified by silica gel chromatography, 80 g, 5-50% EA/hexanes. Product-containing fractions were combined and concentrated to give N-(3,6-dichloropyridin-2-yl)pivalamide as a solid. MS (ESI) m/z: calculated: 246.0; Observed: 247.0 (M++1).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]1[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=1)[C:37]([O:39][CH3:40])=[O:38].O>CN(C=O)C>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:22][CH:23]([CH3:24])[CH3:25])[C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:33][C:34]4[CH:35]=[C:36]([CH:41]=[CH:42][CH:43]=4)[C:37]([O:39][CH3:40])=[O:38])[CH:15]=3)[N:10]3[N:18]=[N:19][N:20]=[C:9]3[C:8]=2[N:21]=1)[CH3:2]
Reactant: CCOCc1nc2c(c3cc(O)ccc3n3nnnc23)n1CC(C)C
Reactant: COC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(c3cc(OCc4cccc(C(=O)OC)c4)ccc3n3nnnc23)n1CC(C)C
Reaction time: 8 h

Procedure:
5-(Ethoxymethyl)-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-ol, 4.0 g, 11.75 mmol was dissolved in 100 mL of DMF and stirred with potassium carbonate (3.3 g, 23.5 mmol) for 30 minutes. To this mixture was added methyl 3-(bromomethyl)benzoate (2.8 g, 12.33 mmol) and the reaction was stirred overnight. The reaction was poured into 10 volumes of water and the precipitate was sequentially filtered, dissolved in dichloromethane, dried over magnesium sulfate, filtered, and concentrated to give 6.1 g of methyl 3-{[(5-ethoxymethyl-6-(2-methylpropyl)-6H-imidazo[4,5-c]tetraazolo[1,5-α]quinolin-8-yl)oxy]methyl}benzoate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].[Cl:13]N1C(=O)CCC1=O.[OH-].[Na+]>S(=O)(=O)(O)O>[Cl:13][C:4]1[C:3]([F:12])=[C:2]([Cl:1])[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:8]=[CH:9]2
Reactant: Fc1cc2ccncc2cc1Cl
Reactant: O=C1CCC(=O)N1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Fc1c(Cl)cc2cnccc2c1Cl
Temperature: 50 °C
Reaction time: 8 h

Procedure:
5.0 g (27.5 mmol) 7-Chloro-6-fluoro-isoquinoline (150) were dissolved in 90 ml of conc. sulphuric acid. At room temperature 7.35 g (55.0 mmol) N-Chlorosuccinimide were added and the mixture was stirred at 50° C. After standing overnight at room temperature another 3 eq. N-Chlorosuccinimide were added and at the following again 5 eq. N-Chlorosuccinimide were added and the temperature was increased to 80° C. After no further conversion could be detected, the mixture was cooled to room temperature and poured on ice. The aqueous solution was brought to basic pH by adding solid NaOH. The precipitate was filtered off and washed three times with dichloromethane. After drying the organic filtrates with MgSO4 and evaporation of the solvent 1.09 g of the desired isoquinoline could be isolated. Rt=1.26 min (Method #TOP). Detected mass: 216.0/218.0 (M+H+).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[C:21]=2[F:29])[N:17]=[C:16]([C:30]([OH:32])=O)[C:15]=1[Cl:33].[O:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH:35]1[O:40][NH2:41]>C1COCC1>[NH2:13][C:14]1[CH:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([O:27][CH3:28])[C:21]=2[F:29])[N:17]=[C:16]([C:30]([NH:41][O:40][CH:35]2[CH2:36][CH2:37][CH2:38][CH2:39][O:34]2)=[O:32])[C:15]=1[Cl:33]
Reactant: NOC1CCCCO1
Reactant: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)O)n2)c1F
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)NOC3CCCCO3)n2)c1F
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
1,1′-Carbonyl diimidazole (110 mg, 0.66 mmol, 1.1 equiv) was added to a stirred suspension of 4-amino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)picolinic acid (200 mg, 0.60 mmol, 1.0 equiv) in THF (3.0 mL) at 23° C. The resulting off-white suspension was stirred at 23° C. for 30 min. O-(Tetrahydro-2H-pyran-2-yl)hydroxylamine (85 mg, 0.72 mmol, 1.2 equiv) was added and the off-white suspension was stirred at 23° C. for 18 h. The reaction mixture was concentrated by a nitrogen stream, and the residue was directly subjected to silica gel column chromatography (5% methanol in chloroform) to afford a white powder (180 mg, 69%): mp 176-179° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.66 (t, J=8 Hz, 1H), 7.42 (dd, J=2, 8 Hz, 1H), 7.20 (d, J=2 Hz, 1H), 6.75 (br s, 2H), 5.01 (m, 1H), 4.05-3.90 (m, 4H), 3.50 (m, 1H), 1.77-1.66 (m, 3H), 1.60-1.47 (m, 3H); IR (neat film) 3325 (w), 3198 (w), 2946 (m), 2873 (w), 1682 (s), 1634 (s) cm−1; ESIMS m/z 430.3 ([M+H]+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:16])[CH2:9][CH2:10][CH:11](OC)[O:12]C)[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8](=[O:16])[CH2:9][CH2:10][CH:11]=[O:12])[CH:3]=1
Reactant: COC(CCC(=O)c1cc(Br)ccn1)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=CCCC(=O)c1cc(Br)ccn1
Reaction time: 8 h

Procedure:
To a solution of 1-(4-bromo-pyridin-2-yl)-4,4-dimethoxy-butan-1-one (2) (crude from Step 2, 11 g, 38.2 mmol) in 100 of CH2Cl2 at room temperature is added trifluoroacetic acid (10.9 g, 95.4 mmol) and the reaction mixture is stirred overnight. The reaction is concentrated, the residue dissolved in ethyl acetate (150 mL) and washed with water 3 times. The organic layers are combined, dried over Na2SO4 and the solvent evaporated. The residue is purified by flash column chromatography (30% EtOAc in hexanes) to give 4-(4-bromo-pyridin-2-yl)-4-oxo-butyraldehyde (3) as an yellow oil. (4.16 g, 45%): MS ES+244.04.
Reaction SMILES: [N:1]1[N:2]=[C:3]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]2C(=O)C3=CC=CC=C3C2=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.O.NN>C(O)C>[N:1]1[N:2]=[C:3]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCSc1nnc2ccccn12
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCCCSc1nnc2ccccn12
Yield: 87.5 %

Procedure:
A mixture of N-[6-(s-triazolo[4,3-a]pyridin-3-ylthio)hexyl]phthalimide (16.5 g), hydrazine monohydrate (4.34 g) and ethanol (135 ml) was heated under reflux for 1 hour. The deposited crystals were separated by filtration, and the filtrate was concentrated under reduced pressure to obtain 6-(s-triazolo[4,3-a]pyridin-3-ylthio)hexylamine as an oil. Yield: 87.5%.