Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2]Br.[CH3:4][C:5]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]([CH3:12])[C:6]=1[NH:13][CH2:14][CH2:15][NH2:16]>C(O)C>[CH3:12][C:7]1[CH:8]=[C:9]([CH3:11])[CH:10]=[C:5]([CH3:4])[C:6]=1[N:13]1[CH2:14][CH2:15][N:16]=[C:2]1[NH2:1]
Reactant: Cc1cc(C)c(NCCN)c(C)c1
Reactant: N#CBr
Solvent: CCO
Product: Cc1cc(C)c(N2CCN=C2N)c(C)c1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
A solution of cyanogen bromide (1.8 g, 18.5 mmol) in anhydrous ethanol (3 mL) was added at 0° C. to a solution of N1-(2,4,6-trimethyl-phenyl)-ethane-1,2-diamine (3.0 g, 16.9 mmol) in anhydrous ethanol (9 mL) under nitrogen. The reaction mixture was warmed up to room temperature for 10 min, then was heated at 155° C. for 40 min with a flow of nitrogen to remove ethanol. Upon cooling to r.t., the resulting solids were transferred to a separatory funnel via dichloromethane (70 mL), and washed sequentially with 1 N sodium hydroxide (2×35 mL), water and brine. The organic layer was dried over anhydrous sodium sulfate and solvents were removed in vacuo to afford the title compound as a pale white solid (3.08 g, 90% yield). The solids were used for the next step without further purification. 1H NMR (CDCl3, 300 MHz) δ 6.70 (s, 2H), 3.46 (s, 4H), 2.06 (s, 3H), 1.99 (s, 6H); 13C NMR (CDCl3, 75 MHz) δ 160.1, 138.2, 137.8, 132.2, 129.5, 48.8, 43.5, 20.8, 17.5. LC/MS: tR=0.99 min., (MH+)=204.12.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[C:9](C(O)=O)[C:8]([Cl:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CN(C)C=O>>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([Cl:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=C(O)c1cc(Cl)c(C(=O)O)c([N+](=O)[O-])c1Cl
Solvent: CN(C)C=O
Product: O=C(O)c1cc(Cl)cc([N+](=O)[O-])c1Cl

Procedure:
0.0008 moles of 2,5-dichloro-3-nitro-terephthalic acid were refluxed for 1 hour in 0.334 moles of dimethyl formamide (DMF), after which time the reaction mixture was flash evaporated to remove most of the DMF. To the residue was added 60 ml of water with agitation, and an orange precipitate formed which was filtered off and washed. The precipitate was dissolved in approximately 50 ml of saturated sodium bicarbonate solution, refiltered and then extracted with chloroform. The aqueous phase was acidified with 10% hydrochloric acid to complete precipitation, and the resulting precipitate was filtered, washed and dried to give an 85% crude yield of 2,5-dichloro-3-nitro-benzoic acid. Subsequent GLC analysis showed it to be 95.8% pure; thus, the yield of the process was 79.5% of theoretical.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]([NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:28][OH:29]>C(O)C>[Si:1]([O:8][CH2:9][CH:10]([NH:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]1[CH:12]=[CH:13][C:14]([C:17](=[N:28][OH:29])[NH2:18])=[CH:15][CH:16]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C#N)cc1
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)CNC(CO[Si](C)(C)C(C)(C)C)c1ccc(C(N)=NO)cc1
Yield: 105.2 %

Procedure:
A solution of tert-butyl 2-(2-(tert-butyldimethylsilyloxy)-1-(4-cyanophenyl)ethylamino)acetate (0.496 g; 1.27 mmol) and 50% aqueous hydroxylamine (0.389 mL; 6.49 mmol) in ethanol (5 mL) was heated at 70° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo to afford the title compound (0.566 g, 100%). 1H NMR (CDCl3, 400 MHz) δ 7.59 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.0 Hz, 2H), 7.00 (br s, 1H), 4.84 (br s, 2H), 3.84-3.81 (m, 1H), 3.68-3.57 (m, 2H), 3.25 (d, J=17.2 Hz, 1H), 3.08 (d, J=16.8 Hz, 1H), 2.60 (br s, 1H), 1.44 (s, 9H), 0.88 (s, 9H), 0.03 (s, 3H), 0.01 (s, 3H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cc2cc(N3CCCCC3)ccc2o1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=Cc1ccc(-c2cc3cc(N4CCCCC4)ccc3o2)cc1
Yield: 30.8 %

Procedure:
A mixture of 5-(piperidin-1-yl)benzofuran-2-ylboronic acid (90 mg, 0.367 mmol), 4-bromobenzaldehyde (62 mg, 0.330 mmol), triethylamine (1.0 mL, 7.3 mmol) and bis(triphenylphosphine)palladium(II) chloride (12.8 mg, 0.02 mmol) in ethanol (9 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system yielding the title compound (31 mg, 28% yield). ESI-MS: 306.4 (M+H)+, 1H NMR (400 MHz, CDCl3) δ 10.02 (s, 1H), 7.95 (dd, 4H), 7.42 (d, 1H), 7.11 (m, 2H), 7.07 (dd, 1H), 3.13 (t, 4H), 1.78-1.74 (m, 4H), 1.62-1.56 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([C:11]2(O)[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[OH:1][C:2]1[CH:9]=[C:8]([OH:10])[C:7]([CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=3)[C:12]2=[O:29])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(CN2C(=O)C(O)(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(CN2C(=O)C(c3cc(C#N)c(O)cc3O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a stirred suspension of 2,4-dihydroxy-5-[3-hydroxy-1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (10.3 g, 25.5 mmol) and triethylsilane (12.3 mL, 77.0 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (10.0 mL, 129 mmol). The reaction mixture was stirred at ambient temperature for 18 h and concentrated in vacuo. The residue was triturated in hexanes to afford 2,4-dihydroxy-5-[1-(4-methoxybenzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]benzonitrile (9.70 g, 98%): mp 162-163° C. (hexanes); 1H NMR (300 MHz, CDCl3) δ 10.84 (s, 1H), 10.47 (s, 1H), 7.39 (s, 1H), 7.28 (d, J=9.0 Hz, 2H), 7.13-7.08 (m, 1H), 6.93-6.78 (m, 5H), 6.43 (s, 1H), 5.72 (s, 1H), 4.92-4.73 (m, 3H), 3.69 (s, 3H); MS (ES+) m/z 386.9 (M+1).
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[CH3:2].[Cl:11][C:12]([O:15]C(Cl)=O)(Cl)Cl>C(OCC)(=O)C>[CH:4]1([N:3]([CH2:1][CH3:2])[C:12]([Cl:11])=[O:15])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCNC1CCCCCC1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CCN(C(=O)Cl)C1CCCCCC1
Yield: 56.4 %

Procedure:
N-ethylcycloheptylamine (21.15 g) was added with ice bath cooling to a mixture consisting of trichloromethylchloroformate (29.7 g) end ethyl acetate (300 ml). Thereafter, the temperature was gradually elevated and heated with refluxing for 6 hours. After distilling off the solvent, the obtained oil was distilled under reduced pressure to obtain N-cycloheptyl -N-ethylcarbamoyl chloride (17.20 g). b.p. 125°-128° C./4.0 mbar.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][CH2:4][NH:5][CH2:6][C:7]1[S:11][C:10](B(O)O)=[CH:9][CH:8]=1.Br[C:17]1[CH:18]=[C:19]2[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:29]1[CH2:34][CH2:33][N:32]([S:35]([CH2:38][CH3:39])(=[O:37])=[O:36])[CH2:31][CH2:30]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:38]([S:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:20]2[C:19]3[C:23](=[C:24]([C:26]([NH2:28])=[O:27])[CH:25]=[C:17]([C:10]4[S:11][C:7]([CH2:6][NH:5][CH2:4][CH2:3][CH:2]([CH3:15])[CH3:1])=[CH:8][CH:9]=4)[CH:18]=3)[NH:22][CH:21]=2)[CH2:34][CH2:33]1)(=[O:37])=[O:36])[CH3:39]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CC(C)CCNCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNCCC(C)C)s4)cc23)CC1
Yield: 37 %

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), (3-methylbutyl)amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 46 mg of crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid. The crude (5-{[(3-methylbutyl)amino]methyl}-2-thienyl)boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 38.3 mg of the title compound (37%).
Reaction SMILES: [ClH:1].[C:2]([CH2:5][CH2:6][C:7]([OH:9])=O)(=[NH:4])[NH2:3].S(Cl)([Cl:12])=O>>[ClH:12].[C:2]([CH2:5][CH2:6][C:7]([Cl:1])=[O:9])(=[NH:4])[NH2:3]
Reactant: N=C(N)CCC(=O)O
Reactant: O=S(Cl)Cl
Agent: Cl
Product: N=C(N)CCC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.52 g. (0.01 mole) of 3-amidinopropionic acid hydrochloride in 18 ml. of thionyl chloride is allowed to stir at room temperature overnight. The excess solvent - reactant is then removed under reduced pressure and the product is isolated as a yellow gum, which crystallizes on standing, 1.5 g.
Reaction SMILES: [Si:1](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24]([CH3:31])[C:21]=1[CH2:22][OH:23].N1C=CN=C1>CN(C)C=O>[Si:1]([O:23][CH2:22][C:21]1[C:24]([CH3:31])=[CH:25][CH:26]=[C:27]([N+:28]([O-:30])=[O:29])[C:20]=1[CH3:19])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(C)c1CO
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])c(C)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 109.5 %

Procedure:
To a solution of tert-butyldiphenylsilyl chloride (30.7 g) in dimethylformamide (90 ml) was added 2,6-dimethyl-3-nitrobenzyl alcohol (18.4 g), and imidazole (8.99 g) was added thereto under ice-cooling. The mixture was stirred for 15 minutes at the same temperature and then for 3 hours at ambient temperature. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (46.67 g) as pale yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>C(Cl)Cl>[CH2:8]([NH:9][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([C:20]([F:19])([F:30])[F:31])=[CH:22][CH:23]=1)[CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
To a solution of phenylethylamine (14.0 g, 14.6 mL, 115.5 mmol) and diea (20.1 mL, 115.5 mmol) in DCM (500 mL) at 0° C. was added 4-(trifluoromethyl)benzoyl chloride (17.2 mL, 115.5 mmol) dropwise. After addition, the reaction mixture was then stirred at 0° C. and warmed up itself to RT overnight. An off-white solid precipitation was observed. The off-white solid was collected by filtration. The solid was then washed with DCM (2×50 mL), and dried under vacuum to give 31.8 g of the title compound as a white solid. MS (ESI, positive ion) m/z: 294 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.N1C=CC=CC=1.Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16]>CC#N>[C:18]1([O:17][C:15](=[O:16])[NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Nc1cccnc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CC#N
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a solution consisting of pyridin-3-yl amine (9.49 g, 101 mmol) and pyridine (8.77 g, 111 mmol) in CH3CN (80 mL) at 0° C. was added phenyl chloroformate (15.8 g, 101 mmol) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was quenched with H2O (200 mL) and the resulting precipitate was filtered and dried under vacuum to provide the title compound as a tan solid (17.34 g, 80%). MS (ESI+): calcd for C12H10N2O2 m/z 214.07, found 215.3 (M+H)+. 1H NMR (500 MHz, d6-DMSO): 10.46 (s, 1H), 8.69 (d, J=2.4 Hz, 1H), 8.27 (dd, J=4.7, 1.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.37 (dd, J=8.4, 4.7 Hz, 1H), 7.31-7.22 (m, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[N+:11]([CH:14]=[C:15](SC)[S:16][CH3:17])([O-:13])=[O:12]>C(#N)C>[N+:11]([CH:14]=[C:15]([S:16][CH3:17])[NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)([O-:13])=[O:12]
Reactant: NCCCCc1c[nH]cn1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CC#N
Product: CSC(=C[N+](=O)[O-])NCCCCc1c[nH]cn1

Procedure:
A solution of 4-(4-aminobutyl)imidazole (from the dihydrobromide 3.6 g) and 1-nitro-2,2-bis-methylthioethylene (2.0 g) in acetonitrile (50 ml) is set aside at room temperature for 3 days. The produce is chromatographed on a column of silica gel with elution by ethyl acetate to give 1-nitro-2-methylthio-2-[4-(4-imidazolyl)butylamino]ethylene. Reaction of this methylthio compound with hydrazine hydrate in the procedure of Example 3 results in the production of 1-nitro-2-[4-(4-imidazolyl)butylamino]-2-hydrazinoethylene.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]([OH:14])=O)=[O:5])[CH3:2].S(Cl)([Cl:17])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[N:9][N:8]([CH3:11])[C:7]=1[C:12]([Cl:17])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Reactant: O=S(Cl)Cl
Product: CCOC(=O)c1cnn(C)c1C(=O)Cl
Yield: 110.7 %

Procedure:
A mixture of 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-ethyl ester (6.00 g) and thionyl chloride (82.8 g) was refluxed for 4 h. Excess thionyl chloride was removed under educed pressure; the obtained crude product (7.26 g, assumed purity ˜60%, 66%) was used in the next step without further purification.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]1([C:21]([OH:23])=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.C1(C)C(S(O)(=O)=O)=CC=CC=1.C([O:39][C:40](=[O:51])[C@H:41]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1)[NH2:42])(C)(C)C.C(N1CCOCC1)C>ClCCl.CN(C)C=O>[CH:16]1([C:21]([NH:42][C@H:41]([C:40]([OH:51])=[O:39])[CH2:43][C:44]2[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(Cl)cc1
Reactant: O=C(O)C1CCCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N[C@@H](Cc1ccc(Cl)cc1)C(=O)O)C1CCCC1
Temperature: 0 °C

Procedure:
A cool solution of 15 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to a solution of 15 mmoles of cyclopentanecarboxylic acid in dichloromethane at -5° C. 15 mmoles of 4-chloro-phenylalanine t-butyl ester toluenesulfonate salt in dimethylformamide (DMF), which is neutralized with N-ethyl morpholine, is then added. The reaction mixture is stirred at 0° C. initially and then at room temperature until the reaction is completed as judged by TLC. Dicyclohexylurea is removed by filtration and 50 ml of ethyl acetate is added to the filtrate. The organic phase is washed until neutral, dried over anhydrous MgSO4 and filtered. The solvent is removed with a rotary evaporator. The residue is crystallized from isopropanol and hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH2:18][CH3:19])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C([O-])COc1ccc(Cl)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)COc1ccc(Cl)cc1
Reaction time: 96 h
Yield: 93 %

Procedure:
A solution of 4-chlorophenoxyacetate acid (Aldrich) (18.62 g, 99.8 mmoles) and concentrated sulfuric acid (Fisher) (2.5 mL) in ethanol (170 mL) was refluxed with stirring under a Drierite tube for 96 hours. The reaction solution was cooled in an ice-bath, and the volatiles were removed by spin evaporation in vacuo to a volume of about 100 mL. The liquid was dissolved in dichloromethane (225 mL) and washed with a solution of 5% aqueous sodium bicarbonate (4×100 mL) and finally with brine (1×50 mL). The solution was dried over sodium sulfate and spin evaporated in vacuo to give 19.97 g (93% yield) of ethyl 4-chlorophenoxyacetate as an amber liquid.
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>[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: C[C@@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[C@@H](OS(C)(=O)=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In ethyl acetate (40 ml) was dissolved (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (2.5 g). To the solution were added, under ice-cooling, triethylamine (1.82 ml) and methanesulfonyl chloride (1.51 g). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl acetate (40 ml), which was washed with water and dried (anhydrous magnesium sulfate), followed by concentration to give (2S,3R)-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 (40 ml), to which was added, under ice-cooling, a 28% methanol solution of sodium methylate (2.04 g). The mixture was stirred for 30 minutes at room temperature, then the reaction mixture was concentrated under reduced pressure. To the concentrate was added ethyl acetate (100 ml), which was washed with water, followed by drying (anhydrous magnesium sulfate). The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent: ethyl acetate-dichloromethane=4:1) to give (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1.62 g) as a colorless oily product. This product became a colorless solid in a freezer. m.p. 41°-43° C. [α]D23 =+5.8° (c=1.0 in methanol)
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[O:10][CH3:11].[N:13]([C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([S:24](Cl)(=[O:26])=[O:25])=[C:18]([F:28])[C:17]=1[F:29])=[N+:14]=[N-:15]>CO>[N:13]([C:16]1[C:21]([F:22])=[C:20]([F:23])[C:19]([S:24]([NH:7][C:6]2[CH:8]=[CH:9][C:3]([N:2]([CH3:12])[CH3:1])=[C:4]([O:10][CH3:11])[CH:5]=2)(=[O:26])=[O:25])=[C:18]([F:28])[C:17]=1[F:29])=[N+:14]=[N-:15]
Reactant: COc1cc(N)ccc1N(C)C
Reactant: [N-]=[N+]=Nc1c(F)c(F)c(S(=O)(=O)Cl)c(F)c1F
Solvent: CO
Product: COc1cc(NS(=O)(=O)c2c(F)c(F)c(N=[N+]=[N-])c(F)c2F)ccc1N(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Dimethylamino-3-methoxyaniline (1.66 g, 10 mmol) is added to a solution of 4-azido-2,3,5,6-tetrafluorophenylsulfonyl chloride (3.47 g, 12 mmol) in MeOH (20 ml) at ambient temperature. After stirring at room temperature for 15 min, the reaction mixture is concentrated under reduced pressure and the residue is taken up in ethyl acetate and filtered through a pad of silica gel. Concentration of the filtrate, followed by chromatography, provides the title compound.
Reaction SMILES: C([Li])CCC.[OH:6][CH2:7][CH2:8][C:9]#[N:10].[C:11]12([CH2:22][C:21](=[O:23])[O:20][C:18](=[O:19])[CH2:17]1)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2>C1COCC1>[C:9]([CH2:8][CH2:7][O:6][C:21]([CH2:22][C:11]1([CH2:17][C:18]([OH:20])=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:23])#[N:10]
Reactant: N#CCCO
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCCOC(=O)CC1(CC(=O)O)CCCCC1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
8.2 mL of 1.6M butyllithium was added to a −78° C. solution of 3-hydroxy-propionitrile (13.19 mmol) in 50 mL of THF. The reaction mixture was warmed to 30° C. and stirred for 30 minutes. Then, a solution of 1,1-cyclohexanediacetic anhydride (10.99 mmol) in 10 mL of THF was added dropwise. The reaction mixture was warmed to room temperature over a period of one hour and stirred at room temperature with monitoring by TLC. When the reaction was judged complete, the reaction mixture was quenched with saturated ammonium chloride solution and THF was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate, washed with brine and dried over Na2SO4. After concentration in vacuo the residue was purified on silica gel (5% methanol in dichloromethane) to afford 2.64 g (95%) of the title compound. 1H NMR (CDCl3): δ 4.28 (2H, t, J=6.4 Hz); 2.71 (2H, t, J=6.4 Hz); 2.61 (4H, m); 1.52-1.42 (10H, m).
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:6]=1)(=[O:4])=[O:3].C1([O:26][C:27](=O)[NH:28][C:29]2[N:34]=[C:33]([O:35][CH3:36])[CH:32]=[C:31]([O:37][CH3:38])[N:30]=2)C=CC=CC=1.N12CCCN=C1CCCCC2.Cl>C(#N)C>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([O:37][CH3:38])[N:30]=[C:29]([NH:28][C:27]([NH:1][S:2]([C:5]2[C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][N:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:6]=2)(=[O:3])=[O:4])=[O:26])[N:34]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: COC(=O)c1cn(-c2ccccn2)nc1S(N)(=O)=O
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cn(-c2ccccn2)nc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
280 mg of Methyl 3-(aminosulfonyl)-1-(2-pyridin-yl)-1H-pyrazole-4-carboxylate and phenyl(4,6-dimethoxy-2-pyrimidinyl)carbamate were dissolved in 10 mL of acetonitrile. 1,8-Diazabicyclo[5.4.0]undec-7-ene, 0.15 mL, was added, and the reaction was stirred one hour. The solution was diluted with 30 mL of ice-water and made acidic with concentrated hydrochloric acid. The solid that separated was collected to afford 260 mg of the title compound melting 183°-188° C.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][CH2:29][O:30][CH3:31]>C(#N)C>[F:1][C:2]1[C:7]([S:8]([C:11]([F:14])([F:13])[F:12])(=[O:9])=[O:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:15]1[CH2:20][CH2:19][N:18]([CH2:28][CH2:29][O:30][CH3:31])[CH2:17][CH2:16]1
Reactant: COCCBr
Reactant: O=S(=O)(c1cccc(C2CCNCC2)c1F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCCN1CCC(c2cccc(S(=O)(=O)C(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 1: 4-{2-fluoro-3-[(trifluoromethyl)sulfonyl]phenyl}-piperidine (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 1-bromo-2-methoxyethane (0.01 g). MS m/z (rel. intensity, 70 eV) 369 (M+, 1), 325 (15), 324 (bp), 191 (37), 133 (14).