Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:22])[C:12]3[CH:19]=[C:18]([CH2:20]Cl)[S:17][C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:34]1([CH2:40][C@H:41]2[CH2:46][O:45][CH2:44][CH2:43][NH:42]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(Cl)Cl>CN(C=O)C>[CH2:40]([C@H:41]1[CH2:46][O:45][CH2:44][CH2:43][N:42]1[CH2:20][C:18]1[S:17][C:13]2[N:14]([CH3:16])[CH:15]=[C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:23]=[CH:24][C:2]([Cl:1])=[CH:3][CH:4]=3)=[O:9])[C:11](=[O:22])[C:12]=2[CH:19]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc(C[C@H]2COCCN2)cc1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)sc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CN3CCOC[C@@H]3Cc3ccccc3)sc21
Temperature: 90 °C
Yield: 58.4 %

Procedure:
N-(4-Chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxamide (Preparation 1, 100 mg) and diisopropylethylamine (0.13 mL) is added to a mixture of (S)-3-(phenylmethyl)morpholine (93 mg, prepared as described by Shawe, T. T. Syn. Comm. 1997,27,1777-1782) in DMF (5 mL). The mixture is heated at 90° C. for 3 hours. After cooling to room temperature, the solution is poured into CH2Cl2 (125 mL) and washed with water (2×100 mL). The organic layer is dried (Na2SO4) and the solution filtered. Evaporation of the solvent gives a residue which is purified by column chromatography (methanol/CH2Cl2, 0-6%) to obtain 80 mg of the title compound. Physical characteristics. 1H NMR (400 MHz, DMSO-d6) δ 10.61, 8.71, 7.41-7.20, 4.54, 4.20, 3.96, 3.91, 3.59, 3.41, 3.20, 2.89, 2.82-2.66, 2.40; MS (ESI+) m/z 522 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[CH:13][N:12]=[C:11](CCN)[N:10]=1.Cl[C:24]1[N:29]=[C:28]([NH:30][CH3:31])[C:27]([N+:32]([O-:34])=[O:33])=[CH:26][CH:25]=1.CO[C:37]1[N:42]=C(NCCN)C=C[C:38]=1[N+:47]([O-])=O>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:14]([C:15]2[NH:16][CH:17]=[CH:18][N:19]=2)=[CH:13][N:12]=[C:11]([NH:42][CH2:37][CH2:38][NH:47][C:24]2[CH:25]=[CH:26][C:27]([N+:32]([O-:34])=[O:33])=[C:28]([NH:30][CH3:31])[N:29]=2)[N:10]=1
Reactant: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: COc1nc(NCCN)ccc1[N+](=O)[O-]
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Product: CNc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]

Procedure:
[4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl](2-{[6-(methylamino)-5-nitro(2-pyridyl)]amino}ethyl)amine was prepared from [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methylamino-3-nitro-pyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{(2-[(6-methoxy-5-nitro(2-pyridyl))amino]-ethyl}amine.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:12]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:6][C:5]1([CH3:27])[CH3:26])(=[O:3])[CH3:2].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH2:16][NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=3[F:28])=[O:18])=[CH:11][CH:12]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:6][C:5]1([CH3:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: NCc1ccc(F)cc1F
Reactant: CC(=O)N1c2ccc(NC(=O)CBr)cc2C(C)(c2ccccc2)CC1(C)C
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)CNCc3ccc(F)cc3F)cc2C(C)(c2ccccc2)CC1(C)C
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 2,4-difluorobenzylamine (6.0 mg) and N,N-diisopropylethylamine (10 μl) in dioxane (2 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silicagel in dichloromethane/methanol=1/095/5 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@@H:9]([CH3:47])[C:10]([NH:12][C@@H:13]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:14]([N:16]1[C@H:25]([C:26](=[O:38])[NH:27][C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:39]([O:41]C)=[O:40])=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].CCOC(C)=O.Cl>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@@H:9]([CH3:47])[C:10]([NH:12][C@@H:13]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:14]([N:16]1[C@H:25]([C:26](=[O:38])[NH:27][C@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH2:31][CH2:30][CH2:29]2)[CH2:24][C:23]2[C:18](=[CH:19][C:20]([C:39]([OH:41])=[O:40])=[CH:21][CH:22]=2)[CH2:17]1)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(c1)CN(C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)(C)C)[C@H](C(=O)N[C@@H]1CCCc3ccccc31)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1Cc2cc(C(=O)O)ccc2C[C@H]1C(=O)N[C@@H]1CCCc2ccccc21)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To a solution of (S)-methyl 2-((S)-2-((S)-2-((tert-butoxycarbonyl)(methyl)amino)propanamido)-3,3-dimethylbutanoyl)-3-(((R)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamoyl)-1,2,3,4-tetrahydroisoquinoline-7-carboxylate (1.34 g, 2.02 mmol) in THF (13.5 mL) and MeOH (6.7 mL) was added NaOH(aq.) (3N, 3.4 mL, 10.1 mmol). After 3 h, the reaction mixture was poured into a sep funnel containing EtOAc and 1N HCl. The aqueous layer was extracted with EtOAc (3×), and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to afford the title compound (1.25 g, 1.93 mmol, 95%) as a light yellow foam, which was used without further purification. MS (ESI+) m/z 649.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([CH2:22][CH2:23]Br)=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[OH2:2].[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH2:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH2:23][CH2:22][C:21]3[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:26][CH:25]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CCBr)cc1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Product: O
Product: O=[N+]([O-])c1ccc(CCN2CCc3ccc([N+](=O)[O-])cc3CC2)cc1

Procedure:
The title compound was prepared similarly to Preparation 2 by the reaction of 7-nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.5 g) and 4-nitrophenethyl bromide (0.6 g), which, after 18 hours reflux, gave the title compound as an oil, yield 0.29 g.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=[C:3]1[C:12]([OH:14])=O.C(N(CC)CC)C.ClC(OC)=O.[CH2:27]([NH2:30])[CH2:28][CH3:29]>C(Cl)(Cl)Cl>[CH2:27]([NH:30][C:12]([C:3]1[C:2](=[O:1])[N:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)=[O:14])[CH2:28][CH3:29]
Reactant: CCCN
Reactant: O=C(O)c1cnc2ccccn2c1=O
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCNC(=O)c1cnc2ccccn2c1=O
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
A mixture containing 7.2 g (0.0378 mol) of 4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 6.2 g (0.044 mol) of triethylamine in 240 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 3.25 ml (0.044 mol) of methyl chloroformate dissolved in 20 ml of chloroform is dropped to the above mixture at -20° C. during 20 minutes. After stirring for 5 minutes, 2.6 g (0.04 mol) of n-propylamine dissolved in 80 ml of chloroform are dropped at -18° C. during 60 minutes. The reaction mixture is stirred for 1 hour at the same temperature, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 70 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 70 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 7.1 g (77.5%) of the named compound as light yellow crystals after recrystallization from ethanol, m.p.: 120°-122° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1.CC1C=CC(S([O-])=O)=CC=1.[Na+].[H-].[Na+]>C1COCC1.O>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([CH:8]([C:9]#[N:10])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=1
Reactant: N#CCc1ccc(F)cc1
Reactant: Clc1ccc(Cl)nc1
Agent: Cc1ccc(S(=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(c1ccc(F)cc1)c1ccc(Cl)cn1
Yield: 96.8 %

Procedure:
Under argon atmosphere, to a mixture of 4-fluorophenylacetonitrile (9.13 g), 2-chloro-5-chloropyridine (10.0 g.) and sodium 4-methylphenylsulfinate (24.1 g) in THF (280 ml) was added sodium hydride (5.41 g, 60%) at 0° C., and the mixture was heated to reflux for 20 hours. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure, and the obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:4), to give 5-chloro-2-(α-cyano-4-fluorobenzyl)pyridine (16.14 g) as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][CH:28]([C:31]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)[OH:32])[CH2:27][CH2:26]1>CN(C)C=O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([NH:1][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[OH:32])[CH2:27][CH2:26]2)=[CH:7][CH:6]=1)[CH3:13]
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1CCN(CCCCl)CC1
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 4.18 g (0.02 mole) of ethyl p-nitrophenylacetate in 200 mL of ethanol is subjected to catalytic hydrogenation. The mixture is filtered to remove the catalyst and the filtrate is concentrated to obtain quantitative yield of ethyl 4-aminophenylacetate. To an agitated solution of the ethyl 4-aminophenylacetate and 2.02 g (0.02 mole) of triethylamine in 50 ml of dimethylformamide is added dropwise a solution of 7.58 g (0.020 mole) of 1-(3-chloropropyl)-α,α-bis(4-fluorophenyl)-4-piperidinemethanol in 20 ml of dimethylformamide. After stirring at ambient temperature for 4 hr the reaction mixture is heated at 70° C. for 4 hr. The reaction mixture is concentrated and the crude product partitioned between methylene chloride and water. The methylene chloride solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated to yield the title compound.
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[OH-].[Na+].C(Cl)Cl.[Cl:17][C:18]([Cl:23])([CH3:22])[C:19](Cl)=[O:20]>O>[Cl:17][C:18]([Cl:23])([CH3:22])[C:19]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:20]
Reactant: CC(Cl)(Cl)C(=O)Cl
Reactant: CC1NCCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC1c2ccccc2CCN1C(=O)C(C)(Cl)Cl

Procedure:
A reaction vessel was chrged with 2 g 1-methyl-1,2,3,4-tetrahydroisoquinoline, 10 ml 10% sodium hydroxide and 50 ml methylene chloride. With this mixture stirred, 3 ml 2,2-dichloropropionyl chloride was added dropwise to the mixture. The mixture was stirred for 20 minutes, then water was added. The organic extract was dried with magnesium sulfate, stripped of solvent and subjected to Kugelrohr distillation (170° C. @ 0.25 mm Hg) to provide 2.7 g of a yellow oil product having the elemental analysis reported in Table I.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[F:11][C:12]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:13]=1[NH2:14].[Br:20][C:21]1[CH:22]=[C:23]([C:27](F)=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]>C1COCC1.CCOC(C)=O>[Br:20][C:21]1[CH:22]=[C:23]([C:27]([NH:14][C:13]2[CH:15]=[CH:16][C:17]([I:19])=[CH:18][C:12]=2[F:11])=[CH:28][N:29]=1)[C:24]([OH:26])=[O:25]
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1cc(Br)ncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)ncc1Nc1ccc(I)cc1F
Temperature: -78 °C
Yield: 59.3 %

Procedure:
Lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (11.9 ml, 1.00 M, 11.82 mmol) was added to a solution of 2-fluoro-4-iodoaniline (1.40 g, 5.91 mmol) at −78° C. The pale green colored solution was stirred for 1½ h at −78° C. Then, lithium 1,1,1,3,3,3-hexamethyldisilazan-2-ide (5.45 ml, 1.00 M, 5.45 mmol) was added followed by 2-bromo-5-fluoroisonicotinic acid (1.00 g, 4.55 mmol) in THF (5 ml). The dark colored homogeneous mixture was warmed to room temperature and stirred overnight. The crude was diluted with EtOAc (300 ml). Then, it washed with dilute HCl solution (20 ml), H2O (20 ml), dried and purified on Flashmaster II using a 100 g cartridge to obtain 1.18 g (59%) of 2-Bromo-5-(2-fluoro-4-iodo-phenylamino)-isonicotinic acid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[ClH:32]>ClCCl.O1CCOCC1>[ClH:32].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][N:16]=2)[CH2:12][CH2:13]1.[ClH:32]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(C(F)(F)F)cn2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(NC2CCNCC2)nc1

Procedure:
4-(5-Trifluoromethyl-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (460 mg; 1.33 mmol, prepared in accordance with Example 49) is dissolved in dichloromethane (6 mL) and trifluoroacetic acid (1 mL) is added under stirring. After 30 minutes reaction time, the solution is concentrated under reduced pressure and the residue obtained is co-evaporated with dichloromethane (5 mL). The product isolated is dissolved in dioxane (2 mL) and a 4N solution of hydrochloric acid in dioxane (3 mL) is added. The precipitate formed is filtered, rapidly rinsed with a small amount of dioxane and is dried under high vacuum to afford the desired product as hydrochloride (352 mg; 1.25 mmol).
Reaction SMILES: [O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]C)=O)[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4].O.[NH2:26][NH2:27]>C(O)C>[O:1]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:26][NH2:27])=[O:23])[C@@H:2]1[O:10][C@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@H:5]([OH:6])[C@H:3]1[OH:4]
Reactant: NN
Reactant: COC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Solvent: CCO
Solvent: O
Product: NNC(=O)CCCCCCCCO[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 92 %

Procedure:
Compoud 1 (1 g) was dissolved in a mixture of ethanol (5 ml) and 85% hydrazine hydrate (2 ml). After 24 h the solvent was evaporated and residual traces of hydrazine removed by co-evaporation with toluene to give 8-hydrazinocarbonyloctyl β-D-galactopyranoside as a white solid which was recrystallized from ethanol, mp 194°, [α]D18 -2.16° (c 1.1, water), 92% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:21][CH2:20]1.O>CC(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:28][CH2:27][CH2:26][CH2:25][N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CN1CCN(CCCN)CC1
Solvent: CC(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCCNc2cc(Cl)ncn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.9 %

Procedure:
To a solution of 4,6-dichloro-pyrimidine (1.5 g, 10 mmol) and DIPEA (1.55 g, 12 mmol) in iPrOH (50 mL) was added a solution of 3-(4-methyl-piperazin-1-yl)-propylamine (1.73 g, 11 mmol) at room temperature. The resulting mixture was stirred at room temperature for 2 hours. Water was added and the mixture was extracted with DCM. The combined extracts were washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the title compound (1.4 g, 51%), which was used directly in the next step without further purification. MS (ESI): 270 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][NH2:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20].[C:21](OCC)(OCC)(OCC)[CH3:22]>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[C:21]([CH3:22])=[N:13][N:12]=[C:7]1[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:20]
Reactant: NNc1cc(-c2ccccc2Cl)c2cc(F)ccc2n1
Reactant: CCOC(C)(OCC)OCC
Solvent: Cc1ccccc1C
Product: Cc1nnc2cc(-c3ccccc3Cl)c3cc(F)ccc3n12

Procedure:
In the manner given in Example 2, 6-fluoro-4-(o-chlorophenyl)-2-hydrazinoquinoline and triethyl orthoacetate are refluxed in xylene to give 7-fluoro-1-methyl-5-(o-chlorophenyl)-s-triazolo[4,3-a]quinoline.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[F:15][C:16]([F:26])([F:25])[C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:22][CH2:21][C:20]1[CH:19]=[CH:18][C:17]([C:16]([F:15])([F:25])[F:26])=[CH:24][CH:23]=1)#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: N#CNC(=NCc1ccc(C(F)(F)F)cc1)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.4 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 4(trifluoromethyl)benzylamine (0.51 g, 2.9 mmol) was added. The mixture was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the concentrated residue thus obtained was crystallized from diethyl ether to give the title compound (0.53 g, 1.7 mmol, yield: 66%) as colorless crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[N:27][CH:28]=1)[CH2:2][CH2:3][CH3:4].[N+](=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[N-].C(OCC)(=O)C.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+3].C([O-])(=O)C.C([O-])(=O)C>[CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]([C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:16][CH2:15]2)[C:7](=[O:21])[C:6]=1[CH2:22][C:23]1[CH:28]=[N:27][C:26]([C:29]2[CH:36]=[CH:35][CH:34]=[CH:33][C:30]=2[C:31]#[N:32])=[CH:25][CH:24]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh+3]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCc1c(Cc2ccc(-c3ccccc3C#N)nc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Reaction time: 5 h

Procedure:
To a solution of 2-(5-{[7-butyl-4-(trans-4-hydroxycyclohexyl)-5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}pyridin-2-yl)benzonitrile (0.48 g) and rhodium acetate (dimer, 0.044 g) in toluene (5 mL) was added dropwise ethyl diazoacetate (0.52 mL), and the mixture was stirred for 5 hr. Ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.26 g, 47%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33].CCO.[OH-].[NH4+:38]>O>[NH2:38][C:2]1[N:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([OH:32])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:33]
Reactant: O=S(=O)(c1cnc(Cl)c(F)c1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ncc(S(=O)(=O)N2CCN(c3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1F
Temperature: 125 °C
Yield: 53.7 %

Procedure:
A 100-mL pressure vessel was charged with 2-(4-(4-((6-chloro-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.725 g, 1.389 mmol), 5 mL of EtOH, and concentrated ammonium hydroxide (10 mL, 257 mmol). The vessel was sealed and the mixture was heated to 125° C. for 18 h. After that time, the mixture was diluted with water and extracted with CH2Cl2 (3×100 mL). The combined extracts were dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel (0 to 70% EtOAc in hexanes) and to give 2-(4-(4-((6-amino-5-fluoro-3-pyridinyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.375 g) as a white solid. 1H NMR (400 MHz, CD3OD) δ=8.18 (d, J=1.4 Hz, 1H), 7.62 (dd, J=1.9, 10.5 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.01 (d, J=9.0 Hz, 2H), 3.35-3.29 (m, 4H), 3.19-3.14 (m, 4H). m/z (ESI, +ve ion) 503.1 (M+H)+. GK-GKRP IC50 (Binding)=0.163 μM; GK-GKRP EC50 (LC MS/MS-2)=0.299 μM.
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:8][CH2:9][CH2:10]1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2c(c1)NCCO2
Reaction time: 5 h

Procedure:
To a solution of dichloromethane (10 mL) containing N-(tertbutoxycarbonyl)-2,3-dihydro-benzo[1,4]oxazine (0.438, 1.86 mmol) at 0° C. was added slowly trifluoroacetic acid (1.0 mL, 7.44 mmol). The reaction mixture was stirred at this temperature during 5 h, then the solvent was removed in vaccuo. The crude product was dissolved in EtOAc (15 mL) and washed successively with 10% Na2CO3 solution and water. The organic layer was dried over MgSO4 and the solvent was removed under reduce pressure. The title compound was obtained pure as brown oil (0.245 g, 98%). Rf=0.31 (petrol/ether 5/5); LCMS m/z 136 ([M+1]+); 1H NMR (300 MHz, CDCl3): δ 3.43 (4H, m); 3.54 (1H, s); 4.27 (4H, m); 6.60-6.82 (4H, m); 13C NMR (75 MHz, CDCl3) δ 43.4; 67.7; 118.1; 119.2; 121.3; 123.7; 136.1; 146.6. IR (film): 3375; 1498; 741 cm−1.