Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:20][C:21]([F:34])([F:33])[C:22]1[C:30]([CH2:31][OH:32])=[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]2[N:23]=1.[CH2:35]([N:42]1[CH2:47][CH2:46][N:45]([C@@H:48]([CH2:53][NH:54][C:55](=[O:63])[C:56]2[CH:61]=[CH:60][C:59](O)=[CH:58][CH:57]=2)[C:49]([O:51][CH3:52])=[O:50])[CH2:44][CH2:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH2:35]([N:42]1[CH2:43][CH2:44][N:45]([C@@H:48]([CH2:53][NH:54][C:55](=[O:63])[C:56]2[CH:57]=[CH:58][C:59]([O:32][CH2:31][C:30]3[C:22]([C:21]([F:20])([F:33])[F:34])=[N:23][N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=34)=[CH:60][CH:61]=2)[C:49]([O:51][CH3:52])=[O:50])[CH2:46][CH2:47]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: OCc1c(C(F)(F)F)nn2ccccc12
Reactant: COC(=O)[C@H](CNC(=O)c1ccc(O)cc1)N1CCN(Cc2ccccc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CNC(=O)c1ccc(OCc2c(C(F)(F)F)nn3ccccc23)cc1)N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49.5 %

Procedure:
795 mg (3.0 mmol) of triphenylphosphine and 565 mg (2.6 mmol) of (2-trifluoromethylpyrazolo[1,5-a]pyridin-3-yl)methanol are added respectively to a solution of 800 mg (2.0 mmol) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-(4-hydroxybenzoylamino)propanoate (prepared as described in example 22-5) in 8 ml of tetrahydrofuran. After stirring at ambient temperature for 30 min, 595 μl (3.0 mmol) of diisopropyl azodicarboxylate are added and the medium is stirred for 18 h at ambient temperature. After evaporating to dryness, the crude residue obtained is purified by chromatography over a silica column eluted with 100% ethyl acetate. 590 mg (49%) of methyl (S)-2-(4-benzylpiperazin-1-yl)-3-[4-(2-trifluoromethylpyrazolo[1,5-a]pyridin-3-ylmethoxy)-benzoylamino]propanoate are obtained in the form of a light-yellow solid.
Reaction SMILES: [F:1][C:2]([F:18])([C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13])[CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].N1C=CC=CC=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.Cl>O>[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31]([O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][C:2]([F:18])([F:1])[C:11]([F:16])([F:17])[C:12]([F:14])([F:15])[F:13])(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCOCCOCC(F)(F)C(F)(F)C(F)(F)F)cc1
Reaction time: 3 h
Yield: 103.2 %

Procedure:
5.0 g (17.3 mM) of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecanol and 4.8 ml of pyridine were stirred under cooling on an ice bath. To the mixture, 4.0 g (20.8 mM) of p-toluenesulfonyl chloride was added, followed by stirring for 3 hours. The reaction mixture was poured into water and acidified by hydrochloric acid, followed by extraction with ethylacetate, washing with water, drying with anhydrous sodium sulfate and distilling-off of the solvent to obtain a residue. The residue was purified by silica gel column chromatography (eluent: toluene/ethyl acetate=10/1) to obtain 7.92 g of 8,8,9,9,10,10,10-heptafluoro-3,6-dioxadecyl p-toluenesulfonate (Yield: 99.8%).
Reaction SMILES: [NH3:1].Cl[CH2:3][CH2:4][N:5]([CH2:28][CH2:29]Cl)[C:6]1[CH:26]=[C:25]([Cl:27])[C:9]2[O:10][C:11]3[C:20]([CH3:21])=[CH:19][C:18]([C:22]([OH:24])=[O:23])=[CH:17][C:12]=3[S:13](=[O:16])(=[O:15])[CH2:14][C:8]=2[CH:7]=1.[CH3:31]O>>[CH3:31][O:24][C:22]([C:18]1[CH:19]=[C:20]([CH3:21])[C:11]2[O:10][C:9]3[C:25]([Cl:27])=[CH:26][C:6]([N:5]4[CH2:4][CH2:3][NH:1][CH2:29][CH2:28]4)=[CH:7][C:8]=3[CH2:14][S:13](=[O:15])(=[O:16])[C:12]=2[CH:17]=1)=[O:23]
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCCl)CCCl)cc1CS2(=O)=O
Reactant: N
Reactant: CO
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
Aqueous ammonia solution (30%, 4 mL) was added to a solution of Example 102j (0.5 g, 1.04 mmol) in methanol (1 mL), in an atmosphere of nitrogen, sealed in a pressure reactor vessel and heated at 110° C. for 6 h. The reaction mixture was brought to room temperature, concentrated, treated with chilled water and dilute HCl to neutral pH. The solid that precipitated was filtered, washed with water and dried. It was treated with methanolic HCl solution and stirred at 70° C. for 2.5 h. The reaction mixture was cooled and the solid that separated was filtered, washed with methanol, dried and purified using flash chromatography (silica gel, MeOH/CHCl3) to obtain the title compound as an off white solid. Yield: 0.220 g (48.24%); 1H NMR (DMSO-d6): δ 2.30 (m, 4H, 2CH2), 2.70 (s, 3H, CH3), 3.10 (m, 4H, 2CH2), 3.95 (s, 3H, OCH3), 5.10 (s, 2H, CH2), 7.10 (s, 1H, Ar), 7.20 (s, 1H, Ar), 8.05 (s, 1H, Ar) 8.20 (s, 1H, Ar): MS: m/e (ES+) 422 (M+1).
Reaction SMILES: [Ca:1].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Mg+2:7]>>[OH-:3].[Mg+2:7].[OH-:3].[S:2]([O-:6])([O-:5])(=[O:4])=[O:3].[Ca+2:1]
Reactant: [Ca]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: [Ca+2]
Product: [OH-]

Procedure:
It should be noted that the fly ash had residual basicity as basic calcium and reacted with the magnesium sulfate in the liquor to produce magnesium hydroxide and calcium sulfate.
Reaction SMILES: C[Si](C)(C)[O:3][C@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[OH:3][C@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1O
Yield: 89.8 %

Procedure:
tert-Butyl N-[(1S,2S)-2-trimethylsilyloxycyclopentyl]carbamate (15.5 g, 56.7 mmol) and tetrabutylammonium fluoride (85.0 mL, 85.0 mmol) in THF (113 mL) are stirred at room temperature for 1 h. Water (50 mL) is added and the mixture is concentrated in vacuo to remove the THF. The resulting mixture is extracted with EtOAc (3×75 mL). The combined organic portions are washed with brine (2×30 mL), dried over sodium sulfate, filtered, and concentrated to give 14.7 g of crude product as a yellow oil. The material is purified on silica gel (330 g) using 25% EtOAc/hexanes to give the title compound as a white solid (10.25 g, 90%). LC-ES/MS m/z 224 (M+Na).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=1)(=[O:23])=[O:22].O>CN(C)C(=O)C>[N:15]1[CH:20]=[CH:19][CH:18]=[N:17][C:16]=1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(S(=O)(=O)c2ncccn2)cc1
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1ccc(S(=O)(=O)c2ncccn2)cc1)C(F)(F)F
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a stirred, cooled (-20° C.) solution of 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (1.01 g, 6.4 mmol) in N,N-dimethylacetamide (10 mL) was added thionyl chloride (0.76 g, 6.4 mmol) and the mixture stirred at -10° to -15° C. for one hour. 4-(2-Pyrimidylsulfonyl)benzenamine (1.00 g, 4.2 mmol) was added in one portion to the orange solution and the mixture stirred at room temperature overnight. The brown mixture was poured into water and extracted with ethyl acetate (2×50 mL). The combined organic portions were washed with water, dried (MgSO4), filtered, and the solvent distilled to yield a tan solid. Flash chromatography of the solid (eluted with 10% v/v ethyl acetate in methylene chloride) and evaporation of the eluent yielded the title propanamide (1.05 g, 66%) as a white solid; mp 187°-190° C. 1H-NMR (300 MHz, d6 -DMSO): 1.60 (s, 3H, CH3), 7.59 (s, 1H, OH), 7.79 (t, 1H, J=4.9 Hz, aromatic), 7.96 (d, 2H, J=8.9 Hz, aromatic), 8.06 (d, 2H, J=8.9 Hz, aromatic), 9.02 (d, 2H, J=4.8 Hz, aromatic), 10.49 (s, 1H, NH). MS (CI, CH4): 376 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1.[CH3:13][N:14](C)C=O>>[C:13]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7]([CH3:11])([CH3:10])[C:6]=2[CH:12]=1)#[N:14]
Reactant: CC1(C)COc2ccc(Br)cc21
Reactant: CN(C)C=O
Product: CC1(C)COc2ccc(C#N)cc21

Procedure:
5-Bromo-2,3-dihydro-3,3-dimethylbenzofuran (15 g, 0.066 mole) was heated under reflux with cuprous cyanide (7.2 g. 0.08 mole) in dimethyl formamide (15 ml) as in Example 2. Work up yielded, after recrystallisation from petroleum ether (bp 60°-80° C.) with charcoaling, 5.7 g of product, mp 72°-75° C.
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.C(N(CC)CC)C.C(O[C:25]1([CH:37]=[CH:36][CH:35]=[CH:34][CH2:33]1)[CH:26]=[N:27][C:28](=O)[CH2:29][CH2:30][CH3:31])C>C(Cl)(Cl)Cl>[C:2]1([N:8]2[C:28]([CH2:29][CH2:30][CH3:31])=[N:27][C:26]([C:25]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC(=O)N=CC1(OCC)C=CC=CC1
Reactant: NNc1ccccc1
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCc1nc(-c2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29 %

Procedure:
First, 14 g of phenyl hydrazine hydrochloride and 200 ml, of carbon tetrachloride were put into a 500-mL three-neck flask, 30 mL of triethylamine (Et3N) was added dropwise to the mixture little by little, and the mixture was stirred at room temperature for 1 hour. After a predetermined time elapsed, 17 g of N-(1-ethoxybenzylidene)butyramide obtained in Step 1 of Synthesis Example 1 was added to this mixture, and the mixture was stirred at room temperature for 24 hours. After the stirring, this mixture was dissolved in chloroform and washed with water and saturated saline. After the washing, anhydrous magnesium sulfate was added to the organic layer for drying. This mixture was gravity-filtered, and the obtained filtrate was concentrated to give an oily substance. This oily substance was purified by silica gel column chromatography. As the developing solvent, toluene was used. The obtained fraction was concentrated, so that 1,3-diphenyl-5-propyl-1H-1,2,4-triazole (abbreviation: HPrp3tz1-Ph) was obtained (a red oily substance, 29% yield). The synthesis scheme of Step 1 is shown in (C-1) below.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].CO[C:11](=[O:29])[C:12]1[CH:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[C:15](Cl)=[N:14][CH:13]=1.[NH2:30][CH2:31][C@@:32]([CH3:37])([CH:34]1[CH2:36][CH2:35]1)[OH:33]>>[CH:34]1([C@:32]([OH:33])([CH3:37])[CH2:31][NH:30][C:11](=[O:29])[C:12]2[CH:17]=[C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]([F:25])([F:26])[F:27])=[CH:22][CH:23]=3)[C:15]([CH2:2][CH2:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)=[N:14][CH:13]=2)[CH2:36][CH2:35]1
Reactant: C#Cc1ccccn1
Reactant: C[C@](O)(CN)C1CC1
Reactant: COC(=O)c1cnc(Cl)c(-c2ccc(C(F)(F)F)cc2)c1
Product: C[C@](O)(CNC(=O)c1cnc(CCc2ccccn2)c(-c2ccc(C(F)(F)F)cc2)c1)C1CC1

Procedure:
The title compound was synthesized in analogy to the procedure described for the preparation of Example 140, using 2-ethynyl-pyridine (CAN 1945-84-2), 6-chloro-5-(4-trifluoromethyl-phenyl)-nicotinic acid methyl ester, and (R)-α-(aminomethyl)-α-methyl-cyclopropanemethanol as starting materials, LC at 215 nm; Rt 3.30: 98%, m/z (ES+): 470.5 (M+H).
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Cl:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][C:25]3[CH:30]=[C:29]([Cl:31])[C:28]([C:32]([F:35])([F:34])[F:33])=[C:27]([Cl:36])[CH:26]=3)[CH:19]=2)[CH:14]=[C:13]([Cl:37])[C:12]=1[C:38]([F:41])([F:40])[F:39]>ClCCCl>[Cl:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[CH:23]=[CH:22][C:21]([N+:6]([O-:9])=[O:7])=[C:20]([O:24][C:25]3[CH:26]=[C:27]([Cl:36])[C:28]([C:32]([F:33])([F:34])[F:35])=[C:29]([Cl:31])[CH:30]=3)[CH:19]=2)[CH:14]=[C:13]([Cl:37])[C:12]=1[C:38]([F:41])([F:40])[F:39]
Reactant: O=[N+]([O-])O
Reactant: FC(F)(F)c1c(Cl)cc(Oc2cccc(Oc3cc(Cl)c(C(F)(F)F)c(Cl)c3)c2)cc1Cl
Agent: O=S(=O)(O)O
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)c(C(F)(F)F)c(Cl)c2)cc1Oc1cc(Cl)c(C(F)(F)F)c(Cl)c1
Temperature: 0 °C

Procedure:
A cooled mixture of concentrated sulfuric acid (6.5 ml.) and nitric acid (4.4 ml.) is added with stirring to an ice cold solution of 1,3-bis(2,6-dichloro-α,α,α-trifluoro-p-tolyloxy)-benzene (11.1 g. 0.021 mol) in 1,2-dichloroethane (30 ml.). After thirty minutes at room temperature, the phases are allowed to separate and the organic phase washed twice with water. Benzene (200 ml.) is added and the solution washed twice with dilute sodium carbonate solution, dried, filtered through activated silica gel (~25 g.), and the solvents removed. The residual crystals are triturated with pentane, filtered, and dried to obtain 1,3-bis(2,6-dichloro-α,α,α-trifluoro-p-tolyloxy)-4-nitrobenzene (9.9 g., 82%) m.p. 137.5°-140.5° C., 90% pure.
Reaction SMILES: O[CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:5]CO.S(Cl)([Cl:17])=O.C(=O)([O-])O.[Na+].[CH2:24]([Cl:26])Cl>>[Cl:17][CH2:2][CH2:3][N:4]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[CH2:5][CH2:24][Cl:26]
Reactant: ClCCl
Reactant: OCCN(CCO)c1ccc(F)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Fc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N,N-bis(2-hydroxyethyl)-4-fluorophenylamine (9.2 g) in methylene chloride (92 ml) was added dropwise thionyl chloride (7.1 ml) over 10 min under ice-cooling. The mixture was stirred at room temperature for 1 hr and the reaction mixture was further refluxed for 1.5 hr. The mixture was poured into aqueous sodium hydrogencarbonate to make it alkaline and the organic layer was separated. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=10:1) to give the title compound (4.88 g) as an organge oil.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33]Br.O>O1CCCC1>[F:28][C:29]([F:43])([F:42])[C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1)[CH2:33][N:2]([CH3:1])[C:3](=[O:17])[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:16]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CNC(=O)c1ccncc1-c1ccccc1C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccccc1-c1cnccc1C(=O)N(C)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.3 %

Procedure:
To a solution of 226 mg (1 mmol) N-methyl-3-o-tolyl-isonicotinamide in 10 ml tetrahydrofuran were added dropwise 1.3 ml (1.3 mmol) 1M potassium hexamethyldisilazide solution in tetrahydrofuran at room temperature. The white suspension was stirred for 30 min at room temperature and 0.18 ml (1 mmol) 3,5-bis(trifluoromethyl)benzyl bromide were added at the same temperature. The light brown suspension was stirred for 1 h and water was added. The aqueous layer was separated and washed with ethyl acetate. The combined organic layers were washed twice with brine, dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 440 mg (97%) of the title compound as a light brown oil.
Reaction SMILES: [NH2:1][C:2]1[S:20][C:5]2[CH2:6][N:7](C(OCC3C=CC=CC=3)=O)[CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Br.CCCCCC.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[S:20][C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:21](=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Nc1sc2c(c1C(=O)c1ccccc1)CCN(C(=O)OCc1ccccc1)C2
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: O
Solvent: CC(=O)O
Product: Nc1sc2c(c1C(=O)c1ccccc1)CCNC2

Procedure:
To a cooled and stirred suspension of protected 2-amino-3-benzoyl-6-benzyloxycarbonyl4,5,6,7-tetrahydrothieno[2,3-c]pyridine (0.01 mol) in acetic acid (2 mL), as prepared in Example 7, was added a solution of HBr (33%) in acetic acid (10 mL). After stirring at room temperature for 4 h (TLC control), n-hexane was added and the resulting suspension was evaporated under vacuum to give a solid which was dissolved in water (10 mL) and neutralized with NaOH (5% solution). The precipitated solid was chromatographed on a silica gel column eluting with an ethyl acetate and petroleum ether mixture to give 2-amino-3-benzoyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>N1C=CC=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]([CH3:9])[S:17]([C:14]2[CH:15]=[CH:16][C:11]([Cl:10])=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=2)(=[O:18])=[O:19])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CNC1CCN(C)CC1
Solvent: c1ccncc1
Product: CN1CCC(N(C)S(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)CC1
Reaction time: 2 h

Procedure:
To a solution of 2.2 ml (15 mMol) of 1-methyl-4-methylamino-piperidine in 60 ml pyridine, 3.8 g (15 mMol) of 4-chloro-3-nitro-benzenesulphonic acid chloride were added, in batches, whilst cooling with ice. The mixture was then stirred for two hours with cooling, then evaporated to dryness, the residue was mixed with about 50 ml of water and made alkaline with concentrated ammonia whilst stirring vigorously. The crude product precipitated was suction filtered and purified by column chromatography (250 g silica gel, eluant: dichloromethane with 1.5% ethanol). Yield: 1.6 g (31% of theory), C13H18ClN3O4S (347.8) Rf value: 0.19 (silica gel; dichloromethane/ethanol=19:1)
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9].[CH2:10](Br)[C:11]#[CH:12]>CCCCCC.C1(C)C=CC=CC=1>[CH2:12]([N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C:4]1=[O:9])[C:11]#[CH:10]
Reactant: C#CCBr
Reactant: O=C1CCCCN1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: C#CCN1CCCCC1=O
Temperature: 15 °C
Reaction time: 19 h

Procedure:
Sodium hydride (5.76 g of 50% dispersion in oil, 0.12 mole) was washed three times with hexane and suspended in 645 ml of toluene. 2-Piperidone (11.88 g, 0.12 mole) in 100 ml of toluene was added to the well stirred sodium hydride suspension and heated to reflux for 2 hours. The reaction mixture was cooled to 15° C. and 2-propynyl bromide (14.28 g, 0.12 mole) in 55 ml of toluene added over 30 minutes. The mixture was then stirred at room temperature for 19 hours, filtered and mother liquor evaporated to yield a first batch of 1-(2-propynyl)-2-piperidone as an oil (7.87 g of about 55% purity by pnmr assay).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[C:17]([O:25][CH3:26])[CH:16]=2)[N:10]=1.[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32](=[N:34]O)[NH2:33])=[CH:30][CH:29]=1.[H-].[Na+]>C1COCC1>[Cl:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]2[N:34]=[C:19]([C:18]3[CH:23]=[CH:24][C:15]([N:11]4[C:12](=[O:14])[NH:13][C:9]([C:3]5[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=5[Cl:8])=[N:10]4)=[CH:16][C:17]=3[O:25][CH3:26])[O:21][N:33]=2)=[CH:30][CH:29]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(-n2nc(-c3c(Cl)cccc3Cl)[nH]c2=O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Yield: 11.7 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-(3-(2,6-dichlorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl)-2-methoxybenzoate (Intermediate-21, 0.100 g, 0.25 mmol), 4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.064 g, 0.38 mmol), sodium hydride (0.020 g, 0.50 mmol) and dry THF (5.0 mL) at RT to afford 0.015 g of desired product. 1H NMR (DMSO-d6): δ 4.00 (s, 3H), 7.66-7.72 (m, 5H), 7.81 (d, J=8.7 Hz, 1H), 7.89 (s, 1H), 8.10 (d, J=8.4 Hz, 2H), 8.22 (d, J=9.0 Hz, 1H), 12.82 (br s, 1H); MS (m/z): 515.84 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([O:29]CC)=O)[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:32][C:33]1[CH:38]=[CH:37][C:36]([CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)=[CH:35][CH:34]=1>>[C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][N:12]2[C:17]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[Cl:26])=[C:16]([C:27]([N:42]3[CH2:43][CH2:44][CH:39]([C:36]4[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=4)[CH2:40][CH2:41]3)=[O:29])[CH:15]=[N:14][C:13]=12)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(S(=O)(=O)NC(C)(C)C)cnn2c1Nc1ccc(F)cc1Cl
Reactant: Fc1ccc(C2CCNCC2)cc1
Product: CC(C)(C)NS(=O)(=O)c1cnn2c(Nc3ccc(F)cc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 61.4 %

Procedure:
Using ethyl 3-(N-tert-butylsulfamoyl)-7-(2-chloro-4-fluorophenylamino)pyrazolo[1,5-a]pyrimidine-6-carboxylate (4.98 g, 10.60 mmol) obtained in step 3 and 4-(4-fluorophenyl)piperidine (1.43 g, 7.97 mmol) instead of 4-phenylpiperidine, and in the same manner as in Example 1 step 4, the title compound (2.95 g, 93%) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11]O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([N:17]([CH2:20][CH3:21])CC)C.S([Cl:26])([CH3:25])(=O)=O>C(Cl)Cl>[ClH:26].[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([O:9][CH2:10][CH2:11][NH:17][CH:20]([CH3:21])[CH3:25])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CCN(CC)CC
Reactant: CS(=O)(=O)Cl
Reactant: CS(=O)(=O)c1ccc(OCCO)cc1
Solvent: ClCCl
Product: CC(C)NCCOc1ccc(S(C)(=O)=O)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.5 %

Procedure:
To a solution 20.5 g (0.095 mole) of 2-[4-(methylsulfonyl)phenoxy]ethanol (from preparation 36) and 12.25 g (0.12 mole) of triethylamine in a mixture of 200 ml of benene and 500 ml of methylene chloride was slowly added a solution of 14.31 g (0.125 mole) of mesyl chloride in methylene chloride, and the solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride solution was dried over magnesium sulfate, the solvent was removed in vacuo, and the residue was partitioned between methylene chloride and dilute sodium hydroxide. The methylene chloride phase was extracted with dilute sulfuric acid. The acidic extract was made basic with 50% sodium hydroxide, and the basic solution was extracted with methylene chloride. The methylene chloride solution was dried over magnesum sulfate and the solvent was removed in vacuo to give 17.45 g (62.7%) of the free base of the product as a solid. Part of this was converted to the hydrochloride salt, and the salt was recrystallized from mthanol/diethyl ether to give the product as a white, crystalline solid, m.p. 182°-184° C.
Reaction SMILES: Cl.[N+:2]([CH:5]=[C:6]([S:16][CH3:17])[NH:7][CH2:8][CH:9](OCC)OCC)([O-:4])=[O:3].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:17][S:16][C:6]1[NH:7][CH:8]=[CH:9][C:5]=1[N+:2]([O-:4])=[O:3]
Reactant: CCOC(CNC(=C[N+](=O)[O-])SC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: CSc1[nH]ccc1[N+](=O)[O-]
Yield: 53.7 %

Procedure:
Dry hydrogen chloride was passed through a stirred solution of 1-nitro-2-methylthio-2-(2,2-diethoxyethylamino)-ethylene (9.7 g, 0.04 mol) in dry ether (250 ml) at 5°-10° for 3 hours. The resulting mixture was basified by pouring it into potassium carbonate solution (300 ml). The mixture was filtered to give a yellow solid, and the aqueous phase of the filtrate was separated and extracted with ether (2×150 ml). The combined ether solutions were evaporated to a residue. This residue and the solid filtered off earlier were recrystallised from acetone-chloroform to give 2-methylthio-3-nitropyrrole (3.4 g, 54%) m.p. 212°-213°.