Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC)(OC)OC.[N-:8]=[N+:9]=[N-:10].[Na+].[C:12](O)(=O)C.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH:21]=[C:22]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]([F:37])([F:36])[F:35])[NH:23][C:24]2=[O:27])=[CH:19][CH:18]=1>O>[N:16]1([C:17]2[CH:26]=[C:25]3[C:20]([CH:21]=[C:22]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:35])[F:36])[NH:23][C:24]3=[O:27])=[CH:19][CH:18]=2)[CH:12]=[N:10][N:9]=[N:8]1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: O
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(-n3cnnn3)cc12
Temperature: 80 °C
Reaction time: 6 h
Yield: 83 %

Procedure:
17.5 μl (0.16 mmol) of trimethyl orthoformate and 9.8 mg (0.15 mmol) of sodium azide were added to 0.2 ml of an acetic acid solution containing the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38. The obtained mixture was stirred at 80° C. for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and water was then added to thereto, followed by extraction with ethyl acetate. The extract was washed with a saturated sodium bicarbonate aqueous solution, and was then dried over anhydrous sodium sulfate, followed by concentration. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:1), so as to obtain 29.8 mg (83%) of 7-tetrazol-1-yl-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a colorless solid.
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:10][C:9](=[S:18])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][C:22]=1[CH3:31]>CCO>[ClH:19].[CH3:31][C:22]1[CH:23]=[CH:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]=1[CH2:20][S:18][C:9]1[NH:8][C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C@H:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=1
Reactant: S=C1N[C@H](c2ccccc2)[C@H](c2ccccc2)N1
Reactant: Cc1ccc2ccccc2c1CCl
Solvent: CCO
Product: Cc1ccc2ccccc2c1CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1
Product: Cl
Temperature: 25 °C
Yield: 65.5 %

Procedure:
A mixture of intermediate 25 (200 mg, 0.786 mmol) and 1-chloromethyl-2-methyl-naphthalene (299 mg, 1.57 mmol) in abs. EtOH (2 mL) is heated at 95° C. for 24 h. The reaction mixture is cooled to RT, evaporated to dryness, and the residue suspended in Et2O. The insoluble material is filtered to give 229 mg of the product 226. 1H NMR (DMSO-d6) δ 11.40 (s, 2H), 8.36 (d, 1H), 8.10-7.80 (m, 2H), 7.80-7.30 (m, 3H), 7.30-6.75 (m, 10H), 5.90 (s, 2H), 5.30 (s, 2H), 2.62 (s, 3H); MS: m/z 409 (M++1).
Reaction SMILES: [I-].C[S+](C)C.[CH3:6][Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:16][C:17]([F:22])([F:21])[C@@H:18]1[CH2:20][O:19]1.Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C1COCC1.CN1C(=O)CCC1.CCOC(C)=O>[F:16][C:17]([F:22])([F:21])[C@@H:18]([O:19][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:20]=[CH2:6]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[S+](C)C
Agent: [I-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: C=C[C@H](OCC(=O)OC(C)(C)C)C(F)(F)F
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
To a solution of trimethylsulfonium iodide (110 g) in THF (500 mL) at −30° C. was added lithium hexamethyldisilazide (530 mL, 1N in THF) portionwise over 45 min. After stirring at −20° C. for 20 min, (S)-2-trifluoromethyloxirane (37.97 g) was added at the same temperature over 15 mins, and the mixture was allowed to warm to RT and stirred for 3 h. The slurry was then added portionwise to an ice-cold solution of tert-butyl bromoacetate (105.68 g) in NMP (200 mL). The resulting mixture was allowed to warm to RT and stir for 2 days, before dilution with EtOAc (1 L). The organic layer was washed with sodium bicarbonate (sat., aq., 4×400 mL), dried over MgSO4 and evaporated. The residue was purified by silica gel column chromatography (5% EtOAc in hexanes) to obtain the title compound (70.1 g) which was used in the subsequent step without purification. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.30 (s, 9H) 3.83-3.96 (m, 2H) 4.14-4.21 (m, 1H) 5.34-5.48 (m, 2H) 5.56-5.71 (m, 1H)
Reaction SMILES: [CH3:1][N:2]([S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:25])=[O:24])[C:3]1[CH:4]=[C:5]([O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12](O)=[O:13])=[CH:8]2.[CH2:32]([S:39][CH:40]([CH:43]([O:46][CH3:47])[O:44][CH3:45])[CH2:41][NH2:42])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[CH2:32]([S:39][CH:40]([CH:43]([O:44][CH3:45])[O:46][CH3:47])[CH2:41][NH:42][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][C:5]([O:15][CH2:16][CH2:17][CH2:18][S:19]([CH3:22])(=[O:20])=[O:21])=[CH:4][C:3]=2[N:2]([CH3:1])[S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)(=[O:24])=[O:25])=[O:13])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1ccccn1
Reactant: COC(OC)C(CN)SCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(OC)C(CNC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87 %

Procedure:
A mixture of 7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxylic acid (2.10 g), 2-(benzylthio)-3,3-dimethoxypropan-1-amine (1.30 g), 1H-1,2,3-benzotriazol-1-ol (730 mg), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (1.04 g) and N,N-dimethylformamide (50 mL) was stirred at room temperature for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogencarbonate and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (1:4-1:9, volume ratio) to give the title compound (2.70 g, yield 87%) as a colorless amorphous solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9](Cl)(=[O:11])=[O:10])=[N:7][CH:8]=1.[NH2:13][CH2:14][CH2:15][OH:16].CCN(CC)CC>C(#N)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:13][CH2:14][CH2:15][OH:16])(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cn1
Reactant: NCCO
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCO)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 4 mL vial equipped with a magnetic stir bar were combined 5-bromopyridine-2-sulfonyl chloride hydrochloride (50 mg, 0.171 mmol), 2-aminoethanol (0.015 mL, 0.256 mmol), Et3N (0.071 mL, 0.512 mmol), and acetonitrile (1 mL). The resulting yellow solution stirred at room temperature overnight. The reaction mixture was subsequently partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and the aqueous layer was back-extracted with ethyl acetate (15 mL). The combined organic layers were concentrated to give the title compound as a clear liquid, which was used without further purification (55 mg).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][NH2:22]>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:22][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[O:18][CH3:17])[N:3]=1
Reactant: COc1ccccc1CN
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: COc1ccccc1CNc1nc(Cl)nc2c1ncn2C1CCCC1

Procedure:
2-Chloro-6-[(2-methoxybenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, 2-methoxybenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([O:23][CH:24]([CH3:26])[CH3:25])[CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC=CC=1>C(Cl)Cl>[C:27]([O:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:17][C:18]=1[O:23][CH:24]([CH3:26])[CH3:25])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)Oc1cc(OCc2ccccc2)ccc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)Oc1cc(OCc2ccccc2)ccc1OC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Triethylamine (4.27 mL, 30.7 mmol) was added to a solution of 4-(benzyloxy)-2-isopropoxyphenol (2.64 g, 10.22 mmol) in dry CH2Cl2 (40.9 mL) and the resulting solution was cooled to 0° C. Benzoyl chloride (1.54 mL, 13.29 mmol) was added dropwise and the reaction was stirred at 25° C. overnight. The reaction mixture was washed with water (50 mL). The aqueous layer was separated and extracted with CH2Cl2 (2×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo to give the crude product. This was azeoptoped with toluene to afford 4-(benzyloxy)-2-isopropoxyphenyl benzoate. LCMS calc.=385.1; found=385.0 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 8.25-8.21 (2 H, m), 7.66-7.60 (1 H, m), 7.52 (2 H, t, J=7.7 Hz), 7.47 (2 H, d, J=7.5 Hz), 7.44-7.39 (2 H, m), 7.39-7.33 (1 H, m), 7.12-7.05 (1 H, m), 6.73-6.68 (1 H, m), 6.60 (1 H, dd, J=8.7, 2.8 Hz), 5.07 (2 H, s), 4.54-4.43 (1 H, m), 1.27 (6 H, t, J=6.1 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([Cl:16])[N:3]=1.[O:17]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[O:20][CH2:19][CH:18]1[C:27]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)=[O:28]>C(O)CCC>[ClH:16].[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:32]2[CH2:33][CH2:34][N:29]([C:27]([CH:18]3[O:17][C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[O:20][CH2:19]3)=[O:28])[CH2:30][CH2:31]2)[N:3]=1
Reactant: COc1cc2nc(Cl)nc(N)c2cc1OC
Reactant: O=C(C1COc2ccccc2O1)N1CCNCC1
Solvent: CCCCO
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Product: Cl
Temperature: 80 °C
Yield: 75.4 %

Procedure:
4-Amino-2-chloro-6,7-dimethoxyquinazoline (140 g.) and N-(1,4-benzodioxan-2-carbonyl)piperazine (150 g.) were stirred together under reflux in n-butanol (2 l.) for 31/2 hours. The mixture was then cooled to 80° C., the solid product collected, washed with cold n-butanol (2×250 ml.), and dried. The crude product was dissolved in hot (80° C.) dimethylformamide (530 ml.) and water (130 ml.), filtered, concentrated in vacuo to about 300 ml., then cooled and ether (1.8 l.) added. The solid so obtained was collected and washed with ether to give 4-amino-2-[4-(1,4-benzodioxan-2-carbonyl)piperazin-1-yl]-6,7-dimethoxyquinazoline hydrochloride (215 g.), m.p. 289°-290° C.
Reaction SMILES: CC(C)(OC([NH:7][CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])=O)C.Cl.O1CCOCC1>C(O)(=O)C>[ClH:31].[NH2:7][CH2:8][CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11]
Reactant: CC(C)(C)OC(=O)NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NCCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 0.25 h
Yield: 163.1 %

Procedure:
To a solution of 2.30 g (5.0 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-oxopropyl]hydrazide (7), prepared as described above in Example 7, in 8 mL of acetic acid (HOAc) was added 8 mL of 6.8 N HCl/dioxane. After 15 minutes, the solvent was removed under H2O aspirator vacuum. The resulting residue was triturated with diethyl ether (Et2O). The resulting white solid was collected on a sintered glass funnel and dried in a vacuum oven at 70° C. for 16 hours. A yield of 1.62 g (81%) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(3-amino-1-oxopropyl)hydrazide, monohydrochloride (9) was isolated. Analysis calculated for C17H17N4O3Cl.0.9 HCl.1.5 H2O: C, 48.54; H, 5.01; N, 13.32; Cl, 16.01. Found: C, 48.70; H, 4.77; N, 12.87; Cl, 16.07.
Reaction SMILES: C(Cl)(=O)CCCCCCCCCCCCCCCCCCCCC.[C:25]([OH:48])(=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]CCCC.C(Cl)(=O)C>C(Cl)(Cl)Cl>[C:25]([OH:48])(=[O:47])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CC(=O)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)O
Reaction time: 0 h

Procedure:
Acylation was performed according to the invention on Whatman n0 2 paper with behenic acid chloride, behenic acid being a fatty acid with a saturated linear chain having C22. To this end, 500 mg of behenic acid were dissolved in 100 ml of chloroform in the presence of 500 mg of acetyl chloride. At the end of 15 minutes, a sample of paper was impregnated with the chloroform solution, the solvent was allowed to evaporate and a stream of gas at 150° C. was passed over the sample for 15 seconds. The presence of an excess of acetyl chloride made it possible, by means of a transchlorination reaction, to prepare behenic acid chloride extemporaneously. The excess of acetyl chloride was then eliminated by the gas stream by virtue of its high volatility. The very short dwell time of the acetyl chloride was, moreover, not sufficient for it to react significantly with the support. It was found that behenic acid was efficiently grafted onto the paper sample while providing a hydrophobic character very significantly greater than that provided by stearic acid.
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[N:13]1([CH2:18][CH2:19][NH2:20])[CH:17]=[CH:16][N:15]=[N:14]1>>[N:13]1([CH2:18][CH2:19][NH:20][C:9]([C:5]2[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=2[CH3:8])=[O:11])[CH:17]=[CH:16][N:15]=[N:14]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Reactant: NCCn1ccnn1
Product: Cc1[nH]c(C=O)c(C)c1C(=O)NCCn1ccnn1
Yield: 97.6 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2 g, 11.96 mmol) reacted with 2-[1,2,3]triazol-1-yl-ethylamine (2.66 g, 14.36 mmol) to give 3.05 g (98%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide.
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.[NH2:12][C:13]1[CH:14]=[C:15]2[C:28](=[CH:29][CH:30]=1)[CH2:27][C:17]1([C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][C:18]1=[O:26])[CH2:16]2>CC(O)C>[O:26]=[C:18]1[NH:19][C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:25]2[C:17]21[CH2:16][C:15]1[C:28](=[CH:29][CH:30]=[C:13]([NH:12][C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[C:8]([OH:10])=[O:9])[CH:14]=1)[CH2:27]2
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)c1cccnc1F
Agent: Cl
Solvent: CC(C)O
Product: O=C(O)c1cnccc1Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C

Procedure:
0.13 g (0.92 mmol) of 2-fluoropyridine-3-carboxylic acid and 20 μL (0.08 mmol) of a 4M aqueous HCl solution were added to 0.20 g (0.78 mmol) 5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one in 5.0 mL of 2-propanol. The reaction mixture was refluxed for 2 h, then cooled to RT and the resulting solid was filtered off and dried.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][C:20]1=[O:25].C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[N:12]=[C:13]([C:16]([N:22]2[CH2:23][CH2:24][NH:19][C:20](=[O:25])[CH2:21]2)=[O:17])[S:14][CH:15]=1
Reactant: O=C1CNCCN1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCNC(=O)C3)n2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (160 mg; 0.53 mmol; 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). Piperazin-2-one (Aldrich) (63.7 mg; 0.64 mmol; 1.20 eq.) and triethylamine (0.22 ml; 1.59 mmol; 3 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (41) as a yellow powder (47.7 mg; 25%). 1H NMR (DMSO-d6, 300 MHz) δ 2.14 (s, 3H), 2.48 (s, 3H), 3.25-3.40 (m, 2H), 3.82 (m, 1H), 4.15 (m, 1H), 4.45 (m, 1H), 4.86 (m, 1H), 8.03 (s, 1H), 8.19 (br s, 1H), 12.17 (s, 1H). M− (ESI): 364.05; M+ (ESI): 365.97. HPLC (method A), Rt: 2.14 min (purity: 99.5%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:12][CH:11]=1.[CH2:32]([I:34])[CH3:33]>>[I-:34].[CH2:32]([N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][NH:8][C:9](=[O:31])[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:14][CH:15]=1)[CH3:33]
Reactant: CCI
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2ccccn2)cc1
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)NCc2cccc[n+]2CC)cc1
Product: [I-]
Temperature: 140 °C

Procedure:
A mixture of 1.0 g of product from Example 4 and 9.42 ml of ethyl iodide is heated, in a sealed dark tube, at 140° C. for 20 hours. The cooled reaction mixture is concentrated in vacuo, the residue purified by column chromatography (silica gel:10% methyl alcohol/chloroform) and recrystallized from 5% chloroform/methyl alcohol to give 0.96 g of the desired product.
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([O:43][C:44]2[CH:45]=[C:46](B3OC(C)(C)C(C)(C)O3)[CH:47]=[CH:48][C:49]=2[O:50][CH3:51])[CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:46]1[CH:47]=[CH:48][C:49]([O:50][CH3:51])=[C:44]([O:43][CH:40]2[CH2:41][CH2:42]2)[CH:45]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OC1CC1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OC1CC1
Yield: 65.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 400 mg (1.07 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 468 mg (1.61 mmol) of 2-(3-cyclopropoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 1-(e) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 322 mg of the title compound was obtained as a pale yellowish solid. (Yield: 65%)
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:22]1([CH2:28][CH2:29][C:30](Cl)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:22]1([CH2:28][CH2:29][C:30]([O:1][CH2:2][CH2:3][CH2:4][S:5][C:6]2[N:11]3[CH:12]=[CH:13][N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: OCCCSc1cccc2nccn12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)OCCCSc1cccc2nccn12
Temperature: 25 °C
Yield: 83.8 %

Procedure:
To a solution of 5-[3-(hydroxy)propylthio]imidazo[1,2-a]pyridine (1.00 g, 4.80 mmoles) and triethylamine (0.80 ml, 5.74 mmoles) in methylene chloride (25 ml) was added 3-phenylpropionyl chloride (1.01 g, 5.99 mmoles) with stirring at room temperature and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was washed with an aqueous 1N sodium hydroxide solution and dried. After the solvent was distilled off, the residue was purified by column chromatography [eluent: hexane/acetone (1:1)] to obtain 1.37 g of the desired product (84.2%, yellow oily product).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.OO.[CH3:15][NH:16][CH:17]=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:17]([NH:16][CH3:15])=[O:18])[CH:3]=1
Reactant: Clc1ccncc1
Reactant: CNC=O
Agent: O=S(=O)(O)O
Agent: OO
Product: CNC(=O)c1cc(Cl)ccn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 5.3 %

Procedure:
Caution: this is a highly hazardous, potentially explosive reaction. To a stirring solution of 4-chloropyridine (10.0 g) in N-methylformamide (250 mL) at room temp. was added conc. H2SO4 (3.55 mL) to generate an exotherm. To this mixture was added H2O2 (30% wt in H2O, 17 mL) followed by FeSO4.7H2O (0.56 g) to generate another exotherm. The resulting mixture was stirred in the dark at room temp. for 1 h, then warmed slowly over 4 h to 45° C. When bubbling had subsided, the reaction was heated at 60° C. for 16 h. The resulting opaque brown solution was diluted with H2O (700 mL) followed by a 10% NaOH solution (250 mL). The resulting mixture was extracted with EtOAc (3×500 mL). The organic phases were washed separately with a saturated NaCl solution (3×150 mL), then they were combined, dried (MgSO4) and filtered through a pad of silica gel with the aid of EtOAc. The resulting brown oil was purified by column chromatography (gradient from 50% EtOAc/50% hexane to 80% EtOAc/20% hexane). The resulting yellow oil crystallized at 0° C. over 72 h to give 4-chloro-N-methyl-2-pyridinecarboxamide (0.61 g, 5.3%): TLC (50% EtOAc/50% hexane) Rf 0.50; 1H NMR (CDCl3) δ3.04 (d, J=5.1 Hz, 3H), 7.43 (dd, J=5.4, 2.4 Hz, 1H), 7.96 (br s, 1H), 8.21 (s, 1H), 8.44 (d, J=5.1 Hz, 1H); CI-MS m/z 171 ((M+H)+). Step 1b. Synthesis of 4-chloropyridine-2-carbonyl chloride HCl salt via picolinic acid
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:18])=O>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][CH2:9][CH2:10]/[CH:11]=[CH:12]/[C:13]([Cl:18])=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)/C=C/CCC#Cc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)/C=C/CCC#Cc1ccccc1

Procedure:
7-Phenylhept-2E-en-6-ynoic acid (2 g) was dissolved in benzene (20 ml), thionyl chloride (2.5 ml) was added, and the mixture was refluxed under a nitrogen atmosphere for 45 minutes. Benzene and excess thionyl chloride were removed under reduced pressure and the residue was treated with benzene (2×4 ml), followed by evaporation, to leave a residue of 7-phenylhept-2E-en-6-ynoyl chloride. The acid chloride was dissolved in ether (20 ml), and triethylamine (1.5 ml) and isobutylamine (3 ml) were added. The mixture was stirred at room temperature for 2 hours then cooled to 0° C. The mixture was filtered and the filtrate was subjected to chromatography on silica (60 g), eluting with 100% hexane grading to 100% ether, to yield N-isobutyl-7-phenylhept-2E-en-6-ynamide mp 86°-8° C.