Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)=[CH:5][CH:4]=1.[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=O)[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1>C(O)C.N1CCCCC1>[CH3:19][C@H:20]1[NH:25][C@@H:24]([CH3:26])[CH2:23][N:22]([C:27]([C:29]2[C:30]([CH3:37])=[C:31]([CH:35]=[C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[CH:17][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)[NH:13][C:12]3=[O:18])[NH:32][C:33]=2[CH3:34])=[O:28])[CH2:21]1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)N1C[C@@H](C)N[C@@H](C)C1
Reactant: COc1ccc(-c2cccc3c2CC(=O)N3)cc1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1ccc(-c2cccc3c2C(=Cc2[nH]c(C)c(C(=O)N4C[C@@H](C)N[C@@H](C)C4)c2C)C(=O)N3)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 72.6 %

Procedure:
To a solution of 4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 4-[(cis)-3,5-dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (68.5 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 3-[4-[(cis)-3,5-Dimethyl-piperazine-1-carbonyl)-3,5-dimethyl-1H-pyrrol-2-ylmethylene]4-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a yellow solid (88 mg, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][N:16]3C(=O)C4C(=CC=CC=4)C3=O)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].O.NN.O>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][NH2:16])[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C1c2ccccc2C(=O)N1CCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: NCCn1ccc(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
To a stirred solution of 2-(2-(3-(3,4-dichlorophenyl)-1H-pyrazol-1-yl)ethyl)-isoindoline-1,3-dione (155 mg, 0.40 mmol) in EtOH (4.0 ml) was added hydrazine hydrate (0.194 ml, 4.0 mmol). The reaction mixture was refluxed for 1 h and left to cool down to RT. Water (20 ml) was added and the mixture was extracted with DCM (3×20 ml). Combined organic phases were dried over Na2SO4 and evaporated to yield quantitative amount of the title compound (102 mg, 100%). Product was used in the next step without analysis.
Reaction SMILES: [C@@H:1]1([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:21])[CH:19]=3)[N:14]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[CH:13]=2)[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+].[CH2:38](Br)[CH3:39].[Cl-].[Na+]>C(#N)C>[CH2:38]([O:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:14]2[C:15]3[C:20](=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)[C:12]([C@@H:1]3[O:9][C@H:8]([CH2:10][OH:11])[C@@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]3[OH:3])=[CH:13]2)=[CH:28][CH:27]=1)[CH3:39]
Reactant: Cc1ccc2c(c1)c([C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)cn2Cc1ccc(O)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOc1ccc(Cn2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cc(C)ccc32)cc1
Temperature: 40 °C
Reaction time: 72 h
Yield: 39.2 %

Procedure:
To a mixture of 3-(β-D-glucopyranosyl)-1-(4-hydroxy-benzyl)-5-methyl-1H-indole (50 mg), cesium carbonate (82 mg) and sodium iodide (19 mg) in acetonitrile (1 mL) was added ethyl bromide (41 mg), and the mixture was stirred at 40° C. for 3 days. The reaction mixture was poured into 15% aqueous sodium chloride solution, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (21 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[N:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16]([C@H:18]2[CH2:20][C@@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:13][OH:14])=[CH:8][CH:7]=1)[CH3:4].[CH3:27]I>CN(C=O)C.[Cl-].[Na+].O>[CH2:3]([O:5][C:6]1[N:11]=[CH:10][C:9]([C@@H:12]([NH:15][C:16]([C@H:18]2[CH2:20][C@@H:19]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])[CH2:13][O:14][CH3:27])=[CH:8][CH:7]=1)[CH3:4]
Reactant: CCOc1ccc([C@H](CO)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccc([C@H](COC)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Reaction time: 0.5 h

Procedure:
NaH (60% suspension in mineral oil) (2.06 g, 51.5 mmol) was suspended in DMF and the reaction vessel was cooled in an ice bath. (1S,2S)-2-Phenyl-cyclopropanecarboxylic acid [(R)-1-(6-ethoxy-pyridin-3-yl)-2-hydroxy-ethyl]-amide (Compound 33) (15 g, 48 mmol) was dissolved in DMF (50 ml) and added drop wise to the sodium hydride suspension at 5-8 C over 20 minutes. The solution was stirred 30 minutes. Methyl iodide (3.30 ml, 53.0 mmol) dissolved in DMF (25 ml) was added drop wise at 5-12 C over 10 minutes and the mixture was stirred at 7-8 C for 30 minutes. The mixture was added to a brine solution and extracted with EtOAc. The organic layer was washed with more brine, dried (MgSO4) filtered and the solvent was evaporated off. The crude product was purified by silica gel chromatography (eluent EtOAc in heptanes 4:1). The fractions that contained the product was collected and the solvent was removed in vac. The residue was redissolved in THF (50 ml) EtOAc (100 ml) and heptanes (25 ml). The mixture was concentrated until 40 ml remained and cooled in ice. A white solid precipitated and was collected by filtration. Yield: 6.75 g (43%) of Compound 46. LC-MS (m/z) 341.2 (MH+). tR=0.64 min (method B).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:18]=1)=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:17][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][NH2:1])[N:6]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CC(C)Cn1c(CN=[N+]=[N-])nc2c(N)nc3ccccc3c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c(CN)nc2c(N)nc3ccccc3c21

Procedure:
2-Azidomethyl-1(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine (3.2 g, 0.0108 mol, Example 11) was added to ethanol (300 mL) and 5% Pd/C (about 1 g) was added to the mixture. The mixture was hydrogenated on a Parr apparatus until hydrogen uptake stopped. Hydrogen was removed and the mixture was flushed with hydrogen to regenerate the catalyst. Hydrogenation was resumed. This procedure was repeated until no more hydrogen was absorbed. The catalyst was filtered from the mixture and the filtrate was evaporated. The residue was recrystallized several times from ethanol to give yellowish crystals m.p. 287°-291° C. Analysis: Calculated: C, 66.9; H, 7.1; N, 26.0. Found: C, 66.5; H, 7.2; N, 25.1.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:14])[CH2:12][CH3:13]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8](=[NH:9])[O:14][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1
Reactant: CCCO
Reactant: N#Cc1ccc(N)nc1
Agent: Cl
Product: CCCOC(=N)c1ccc(N)nc1
Temperature: 0 °C
Reaction time: 21 h

Procedure:
After 6-amino-3-cyanopyridine (1.0 g, 8.4 mmol) was dissolved in 1-propanol (50 ml) and hydrogen chloride gas was passed into the solution at a temperature of 0°-10° C. for 30 minutes, the reactor was tight sealed for stirring the mixture at 0° C. for 21 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and a saturated aqueous sodium hydrogen carbonate solution (50 ml) was added to the concentrated mixture to adjust the pH to alkaline. The mixture was extracted with chloroform (50 ml×3). The chloroform layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a crude product of propyl 6-amino-3-pyridinecarboximidate (1.56 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH:27]=1)[CH2:7][NH:8][C:9]([C@H:11]1[N:15]([C:16](=[O:26])[C@@H:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[OH:18])[N:14]=[CH:13][CH2:12]1)=[O:10].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40]>ClCCl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:28]2[CH:32]=[N:31][N:30]=[N:29]2)=[C:6]([CH2:7][NH:8][C:9]([C@H:11]2[N:15]([C:16](=[O:26])[C@H:17]([O:18][C:39](=[O:41])[CH3:40])[C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[N:14]=[CH:13][CH2:12]2)=[O:10])[CH:27]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NCc1cc(Cl)ccc1-n1cnnn1)[C@@H]1CC=NN1C(=O)[C@H](O)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)O[C@@H](C(=O)N1N=CC[C@H]1C(=O)NCc1cc(Cl)ccc1-n1cnnn1)c1ccc(F)cc1
Reaction time: 4 h
Yield: 90.7 %

Procedure:
To (5S)—N-[5-chloro-2-(1H-tetrazol-1-yl)benzyl]-1-[(2R)-2-(4-fluorophenyl)-2-hydroxyacetyl]-4,5-dihydro-1H-pyrazole-5-carboxamide (Example 1) (483 mg, 1.05 mmol) in dichloromethane (10 mL) was added pyridine (2 mL) and acetic anhydride (100 μL, 1.06 mmol). The mixture was stirred for 4 h. Another portion of acetic anhydride (600 μL, 6.34 mmol) and DMAP (23 mg, 0.19 mmol) was added and the mixture was stirred for another 15 h. The solvents were removed by evaporation and the residue was purified by HPLC (MeCN gradient 0 to 100% in aqueous 0.1 M NH4OAc buffer containing 5% MeCN, C8 column: 50×300 mm). The relevant fractions were collected, combined and freeze dried to give the title compound (476 mg, 90%) as a solid material.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].Cl[C:25]1[N:30]=[CH:29][N:28]=[C:27]([NH2:31])[C:26]=1[O:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:25]4[N:30]=[CH:29][N:28]=[C:27]([NH2:31])[C:26]=4[O:32][CH3:33])[CH2:16][CH2:15]3)[N:11]([CH3:13])[CH:12]=2)=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: COc1c(N)ncnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(C(F)(F)F)c3)cn2C)CC1
Temperature: 150 °C
Yield: 22 %

Procedure:
A mixture of 4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1h-imidazol-2-yl]-piperidine (40.00 mg; 0.12 mmol; 1.0 eq.), 6-chloro-5-methoxypyrimidin-4-amine (20.48 mg; 0.13 mmol; 1.05 eq.), potassium carbonate (33.78 mg; 0.24 mmol; 2.0 eq.) in DMSO (1.00 ml) in a microwave vial was heated at 150° C. for 2 h. LC-MS show ˜40% conversion and product eluted closely to the amine starting material. The reaction mixture was workup and the crude was purified by reverse phase pre-HPLC (Waters, acetonitrile/0.1% TFA in water) to yield desired product in 22% yield. LC-MS: (M+1=451, obsd.=451).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[CH:11]([OH:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([Cl:25])[CH:24]=1)[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C:11](=[O:21])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1
Reactant: COc1cccc(CC(O)c2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COc1cccc(CC(=O)c2nccn2Cc2cc(Cl)cc(Cl)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of 1-[1-(3,5-Dichloro-benzyl)-1H-imidazol-2-yl]-2-(3-methoxy-phenyl)-ethanol (40 mg, 0.11 mmol) in CH2Cl2 (1 mL) at 0° C. was added Dess-Martin periodinane (54 mg, 0.13 mmol). The mixture was stirred at ambient temperature for 2 h and then purified directly by column chromatography (silica gel, 8:1 to 4:1 hexane/EtOAc) to provide the title compound (19 mg, 48%) as an off-white solid: ESI MS m/z 375 [C19H16Cl2N2O2+H]+.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][CH2:6][CH:7]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1)[C:8]([O:10]CC)=[O:9].C(O)C.O>C1COCC1.C(OCC)C>[C:8]([CH:7]([CH:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1)[CH2:6][CH2:5][CH2:4][Cl:3])([OH:10])=[O:9]
Reactant: CCOC(=O)C(CCCCl)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(CCCCl)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 77.3 %

Procedure:
A 5 N sodium hydroxide solution (3 ml) was added to a solution of tert-butyl 4-(4-chloro-1-ethoxycarbonyl-butan-1-yl)piperidine-1-carboxylate (1.76 g) in THF (5 ml)-ethanol (15 ml), and the reaction solution was stirred at room temperature for four days. Water and diethyl ether were added to the reaction solution, and the aqueous layer was separated. The aqueous layer was washed with diethyl ether again. Then, 5 N hydrochloric acid (3 ml) and ethyl acetate were added to the aqueous layer, and the organic layer was separated. The ethyl acetate extraction layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to obtain crude tert-butyl 4-(1-carboxy-4-chlorobutan-1-yl)piperidine-1-carboxylate (1.25 g).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11]C)=[O:10])[CH2:5][CH2:4]1.Cl>O>[ClH:1].[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1
Reactant: COC(=O)[C@H]1CC[C@@H](N)CC1
Agent: Cl
Solvent: O
Product: N[C@H]1CC[C@@H](C(=O)O)CC1

Procedure:
Dissolve cis-4-amino-cyclohexanecarboxylic acid, methyl ester hydrochloride (1.5 g) in water (5 mL) and add concentrated hydrochloric acid (5 mL). Reflux under an argon atmosphere for 12 hours and evaporate the solvent in vacuo to give cis-4-amino-cyclohexanecarboxylic acid hydrochloride.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>ClCCl>[NH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12]([C:25]([C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])=[O:26])[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1cccc(C2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Nc1cccc(C2CCN(C(=O)c3c(Cl)cccc3Cl)CC2)c1
Temperature: 0 °C
Reaction time: 6 h
Yield: 46.9 %

Procedure:
To an ice-cooled solution of 4-(3-aminophenyl)-piperidine hydrochloride (250.2 mg, 1.0 mmol) and triethylamine (1 mL) in dichloromethane (6 mL) is added 2,6-dichlorobenzoic chloride (0.15 mL, 1.0 mmol). The reaction mixture is stirred at 0° C. for 6 hours. After removal of solvent, the residue is purified on a silica gel chromatography with ethyl acetate-hexanes to provide a white solid (163.9 mg, 46.9% yield, ES+(m/z) 349.1 [M+H]).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([OH:14])=[O:13])=[CH:8][C:7]=2[CH:18]=1.S(Cl)(Cl)=O.[CH2:25]([C:32]1[CH:36]=[CH:35][NH:34][C:33]=1[CH2:37]O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C.C1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:20][C:2]([F:19])([F:1])[C:3]1[CH:4]=[CH:5][C:6]2[S:10][C:9]([CH:11]([CH:15]([CH3:17])[CH3:16])[C:12]([O:14][CH2:37][C:33]3[NH:34][CH:35]=[CH:36][C:32]=3[CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:13])=[CH:8][C:7]=2[CH:18]=1
Reactant: OCc1[nH]ccc1Cc1ccccc1
Reactant: CC(C)C(C(=O)O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(C)C(C(=O)OCc1[nH]ccc1Cc1ccccc1)c1cc2cc(C(F)(F)F)ccc2s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(5-trifluoromethyl-2-benzothienyl)-3-methylbutanoic acid (3.95 mmol), thionyl chloride (0.342 ml, 4.74 mmol) and DMF (several drops) in 50 ml benzene is stirred at RT for 2 days. The solvent and excess thionyl chloride are evaporated under reduced pressure. The resulting acid chloride is dissolved in 50 ml benzene, and 3-benzylpyrrolylmethyl alcohol (3.95 mmol) and 0.482 g 4-dimethylaminopyridine (3.95 mmol) are added. The mixture is left at 25° for 18 hours and then heated under reflux for 2 hours. The mixture is then poured into water and extracted with ether. The organic phase is washed with dilute HCL, sat. NaHCO3, water and brine, dried and solvent removed under vacuum to yield 3-benzylpyrrolylmethyl 2-(5-trifluoromethyl-2-benzothienyl)-3-methylbutanoate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[OH:26][CH2:27][CH2:28][N:29]([CH2:39][CH2:40][OH:41])[S:30]([C:33]1[S:34][C:35](Cl)=[CH:36][CH:37]=1)(=[O:32])=[O:31]>>[OH:26][CH2:27][CH2:28][N:29]([CH2:39][CH2:40][OH:41])[S:30]([C:33]1[S:34][C:35]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:36][CH:37]=1)(=[O:32])=[O:31]
Reactant: O=S(=O)(c1ccc(Cl)s1)N(CCO)CCO
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: O=S(=O)(c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1)N(CCO)CCO

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (178 mg, 0.5 mmol) and 5-chloro-thiophene-2-sulfonic acid bis-(2-hydroxy-ethyl)-amide (example B.40) (143 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (60 mg, 20%). MS (ISP) 622.0 [(M+NH4)+]; mp 137° C.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[K+].C[O:7][C:8]([C@H:10]1[C@H:15]([CH3:16])[O:14][C@@H:13]([CH3:17])[CH2:12][N:11]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][C:31]([OH:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=O.Cl>CO>[OH:3][NH:2][C:8]([C@H:10]1[C@H:15]([CH3:16])[O:14][C@@H:13]([CH3:17])[CH2:12][N:11]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]#[C:30][C:31]([OH:34])([CH3:33])[CH3:32])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:7]
Reactant: NO
Reactant: COC(=O)[C@H]1[C@H](C)O[C@@H](C)CN1S(=O)(=O)c1ccc(OCC#CC(C)(C)O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: C[C@@H]1O[C@@H](C)CN(S(=O)(=O)c2ccc(OCC#CC(C)(C)O)cc2)[C@H]1C(=O)NO
Temperature: 85 °C
Reaction time: 0.25 h
Yield: 21.2 %

Procedure:
Hydroxylamine hydrochloride (2.76 g, 39.7 mmol) was dissolved in methanol (14 mL) by heating to 85° C. This solution was added to a solution of potassium hydroxide (3.31 g, 59.0 mmol) in methanol (8.3 mL) and the resulting white slurry stirred for 15 minutes. The white precipitate was removed by filtration and the filtrate was added to a flask containing (2S,3R,6S)-4-[4-(4-hydroxy-4-methyl-pent-2-ynyloxy)-benzenesulfonyl]-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester (258 mg, 0.607 mmol) and the reaction was stirred at room temperature for 1.5 hours. 1 N hydrochloric acid (20 mL) was then added drop wise and the methanol was removed in vacuo. The aqueous residue was extracted with ethyl acetate (3×50 mL) and the combined organic fractions were washed with brine ( 30 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo. The resulting white solid was chromatographed on a Biotage column® (40s) eluting with ethyl acetate and hexanes (7:1, the column was pretreated with 0.5% triethyl amine in above solvent system) to yield the title compound (54.8 mg, 21%, 2 steps). MS: Calculated for C19H26N2O7S (M+H): 427.16 and (M−H): 425.14. Found: 427.0 and 425.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C.ClCCl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@H](OS(C)(=O)=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In a mixture of ethyl acetate (2 ml) and dichloromethane (0.5 ml) was dissolved (2S,3S)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (58 mg). To the solution were added, under ice-cooling, triethylamine (66 μl) and methanesulfonyl chloride (37 μl). The mixture was stirred for two hours at room temperature. To the reaction mixture was added ethyl acetate (30 ml), which was washed with water, dried (anhydrous magnesium sulfate) and concentrated to afford (2S,3S)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H -1,2,4-triazol-1-yl)-2-butanol as an oily product . This product was dissolved in methanol (2 ml), to which was added, under ice-cooling, 28% sodium methyl ate (116 μl), and the mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added dichloromethane (30 ml), which was washed with water and dried (anhydrous magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was purified by means of a silica gel chromatography (eluent: ethyl acetate-dichloromethane=4:1 ), followed by crystallization from hexane to afford (2S,3R)-2-(2,4-difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyl oxirane (42 mg) as colorless needles. m.p. 89°-90° C. [α]D23 =+7.8° (c=1.0 in MeOH)
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[O:10][C:9]([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:8]1)(C)(C)C.[CH3:28][N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:31][CH2:30]1>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[C:18]([C:9]2[O:10][C:11]3[C:16]([C:7](=[N:6][OH:5])[CH:8]=2)=[CH:15][CH:14]=[C:13]([NH:38][CH2:37][CH2:36][CH2:35][N:32]2[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]2)[CH:12]=3)[N:19]=1
Reactant: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2cc(Br)ccc12
Reactant: CN1CCN(CCCN)CC1
Product: CN1CCN(CCCNc2ccc3c(=NO)cc(-c4cc5ccccc5cn4)oc3c2)CC1

Procedure:
2-isoquinolin-3-yl-7-[3-(4-methyl-piperazin-1-yl)-propylamino]-chromen-4-one oxime was prepared in 19% overall yield using the method described in examples 45, starting from 7-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (example 2B) and 3-(4-methyl-piperazin-1-yl)-propylamine. The title compound was isolated as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26]>CC(C)=O>[Cl:1][C:2]1[C:3]([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH:24]([CH3:29])[C:25]([O:27][CH3:28])=[O:26])=[CH:12][CH:11]=2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: COC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1

Procedure:
The above phenol (1.3 g 5.08 mm), K2CO3 (1.05 g), methyl α-bromopropionate (0.85 ml, 1.5 eq) and acetone (20 ml) is refluxed for 8 hours. The mixture is then filtered and the filtrate concentrated to give oily methyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate.