Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.Cl[CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[I-].[K+].[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:42][O:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: ClCOCc1ccccc1
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [I-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)C(COCc1ccccc1)c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Temperature: 25 °C
Reaction time: 19 h
Yield: 24.2 %

Procedure:
To a solution of methyl [2-methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.175 g; 0.5 mmol) in dry DMF (2 mL) at −10° C. was added LHMDS 1N in THF (0.55 mL; 0.55 mmol), chloromethylbenzylether (0.138 mL; 1 mmol) and potassium iodide (0.166 g; 1 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 19 h. A saturated solution of ammonium chloride (4 ml) was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphatesulphate and concentrated under reduced pressure. The crude material was purified by flash-chromatography on silica gel using a gradient of ethyl acetate (5 to 40%) in heptane to furnish 0.057 g (24%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.S(Cl)([Cl:16])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Cl:16]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Reactant: O=S(Cl)Cl
Product: FC(F)(F)c1ccc(Br)c(CCl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [2-bromo-5-(trifluoromethyl)phenyl]methanol (4.4 g, 17 mmol) was added thionyl chloride (5 mL) and the resulting mixture was stirred at room temperature for 1 h. Evaporation in vacuo gave the crude product as an oil. 1H NMR (CDCl3) δ 7.77 (d, J=8.3 Hz, 1H), 7.73 (d, J=2.0 Hz, 1H), 7.53 (dd, J=8.5, 2.2 Hz, 1H), 5.66 (d, J=12.7 Hz, 1H), 5.46 (d, J=12.2 Hz).
Reaction SMILES: [C:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:22][CH3:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:24]([OH:27])(=[O:26])[CH3:25].C(Cl)Cl.CCOCC>CO.[Pd]>[C:24]([OH:27])(=[O:26])[CH3:25].[C:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH2:22][CH3:23])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC[C@H]1CN(Cc2ccccc2)[C@H](C)CN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[C@H]1CN[C@H](C)CN1C(=O)OC(C)(C)C
Reaction time: 24 h

Procedure:
A mixture of 1-Boc-2(S)-ethyl-4-benzyl-5(R)-methylpiperazine (A36; 13.6 g, 43 mmol), glacial acetic acid (2.5 mL) and 10% Pd/C (4.5 g) in methanol (150 mL) was shaken under H2 atmosphere (50 psi) for 24 h. The mixture was filtered through Celite® and the filter cake was washed copiously with EtOAc (˜500 mL). The combined filtrates were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to afford a clear colorless oil. Further co-evaporation with CH2Cl2 (200 mL) and Et2O (2×200 mL) gave the desired 1-Boc-2(S)-ethyl-5(R)-methylpiperazine acetic acid salt 34 (9.7 g) as a viscous oil.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH:6]=[CH:7][C:8]1[S:9][C:10]([CH3:13])=[N:11][N:12]=1.[Cl-].[Na+].[O:20]1[CH2:24]C[CH2:22][CH2:21]1>CN(P(N(C)C)(N(C)C)=O)C>[CH3:13][C:10]1[S:9][C:8]([CH:7]=[CH:6][C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3][CH2:22][CH:21]2[O:20][CH2:24]2)=[N:12][N:11]=1
Reactant: C1CCOC1
Reactant: Cc1nnc(C=Cc2ccccc2O)s1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Cc1nnc(C=Cc2ccccc2OCC2CO2)s1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3.72 g (0.085 mole) of 55% strength sodium hydride in paraffin oil are suspended in 150 ml of absolute tetrahydrofuran and 18.6 g (0.085 mole) of 2-(2-hydroxystyryl)-5-methyl-1,3,4-thiadiazole in 200 ml of absolute hexamethylphosphotriamide are then added dropwise in the course of 1.5 hours at from 0° to 3° C. Stirring is continued at room temperature for 1 hour, after which 11.7 g (0.085 mole) of dibromohydrin are added dropwise. The solution is left to stand at room temperature for 16 hours, after which it is poured onto 1.5 liters of ice water and 0.5 liter of saturated sodium chloride solution. The precipitated solid is filtered off and recrystallized from acetone. 11.8 g (51% of theory) of yellow crystals, of melting point 134°-135° C. are obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[C:14]([OH:16])=O)[CH3:2].[CH2:17]([O:19][C:20]([C:22]1([NH2:31])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:17]([O:19][C:20]([C:22]1([NH:31][C:14]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:12]=[CH:13][C:4]=2[O:3][CH2:1][CH3:2])=[O:16])[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23]1)=[O:21])[CH3:18]
Reactant: CCOc1ccc2ccccc2c1C(=O)O
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2c(OCC)ccc3ccccc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
To a solution of 2-ethoxy-naphthalene-1-carboxylic acid (335 mg, 1.55 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (318 mg, 1.55 mmol), HATU (886 mg, 2.33 mmol) in anhydrous DMF (8 mL) is added DIPEA (385 μL, 2.33 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (40 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (45) as white solid (420 mg, 67%).
Reaction SMILES: Br[C:2]1[CH:3]([CH3:8])N(N)[O:5][CH:6]=1.[H-].[Na+].CC1OC(C)=CC=1[S:17]([Cl:20])(=[O:19])=[O:18]>>[O:5]1[CH:6]=[CH:2][CH:3]=[C:8]1[S:17]([Cl:20])(=[O:19])=[O:18]
Reactant: CC1C(Br)=CON1N
Reactant: Cc1cc(S(=O)(=O)Cl)c(C)o1
Agent: [H-]
Agent: [Na+]
Product: O=S(=O)(Cl)c1ccco1

Procedure:
Furan-2-sulfonyl chloride was prepared by the method of Example 1 with 4-bromo-3-methyl-2-aminoisoxazole (0.354 g, 2.0 mmol), NaH (60% oil dispersion) (200 g, 5.0 mmol) and 2,5-dimethylfuran 3-sulfonyl chloride (0.467 g, 2.4 mmol). Flash chromatography (5% CH3OH/CHCl3) and recrystallization from CHCl3 /hexane provided 0.21 4 g (32% yield) of light brown crystals (m.p. 85.5°-87° C.).
Reaction SMILES: [C:1](#[N:3])[CH3:2].CCCCCC.C([Li])CCC.Cl[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[N:17]=1.O>O1CCCC1>[Cl:22][C:18]1[N:17]=[C:16]([CH2:2][C:1]#[N:3])[CH:21]=[CH:20][CH:19]=1
Reactant: Clc1cccc(Cl)n1
Reactant: CC#N
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: N#CCc1cccc(Cl)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of acetonitrile (2.77 mL) in tetrahydrofuran (80 mL) was added dropwise n-butyl lithium hexane solution (1.6 M, 29.6 mL) at −78° C., and the reaction mixture was stirred at −78° C. for 1 hr under argon atmosphere. A solution of 2,6-dichloropyridine (2.0 g) in tetrahydrofuran (10 mL) was added dropwise thereto at −78° C., and the reaction mixture was stirred at −78° C. for 2 hr under argon atmosphere, and allowed to be warmed to room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.91 g).
Reaction SMILES: O.NN.C([O:7][C@H:8]1[C@H:12]([O:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:11]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:10][C@@H:9]1[N:32]1[CH:39]=[C:38]([F:40])[C:36](=[O:37])[NH:35][C:33]1=[O:34])(=O)C.CC(C)=O>C(O)(=O)C.N1C=CC=CC=1>[C:14]([O:13][C@@H:12]1[C@H:11]([CH2:22][O:23][C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:10][C@H:9]([N:32]2[CH:39]=[C:38]([F:40])[C:36](=[O:37])[NH:35][C:33]2=[O:34])[C@H:8]1[OH:7])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(=O)O[C@H]1[C@H](OC(=O)c2ccccc2)[C@H](COC(=O)c2ccccc2)O[C@@H]1n1cc(F)c(=O)[nH]c1=O
Agent: NN
Solvent: CC(=O)O
Solvent: O
Solvent: c1ccncc1
Product: O=C(OC[C@@H]1O[C@H](n2cc(F)c(=O)[nH]c2=O)[C@@H](O)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
Hydrazine hydrate (2.80 mL, 57.4 mmol) was added to a solution of 1-(2-O-acetyl-3,5-di-O-benzoyl-β-L-xylofuranosyl)-5-fluorouracil 2 (9.80 g, 19.1 mmol) in acetic acid (35 mL) and pyridine (150 mL). The resulting solution was stirred overnight at room temperature. Acetone (50 mL) was added and the mixture was stirred during 2 h. The reaction mixture was concentrated to a small volume and partitioned between ethyl acetate (200 mL) and water (200 mL). Layers were separated and the organic phase was washed with a saturated aqueous sodium hydrogen carbonate solution (2×200 mL), and finally with water (2×200 mL). The organic phase was dried over sodium sulphate, then evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (0-5%) in methylene chloride] to give pure 3 (7.82 g, 87%), which was crystallized from methylene chloride; mp=93-97° C.; UV (ethanol): λmax=227 nm (ε=22800) 267 nm (ε=8200), λmin=249 nm (ε=5900); 1H-NMR (DMSO-d6): δ11.9 (br s, 1H, NH), 8.06 (d, 1H, H-6, J6-F5=6.9 Hz), 8.0-7.4 (m, 10H, 2 C6H5CO), 6.35 (d, 1H, OH-2′, JOH-2′=3.8 Hz), 5.77 (d, 1H, H-1′, J1′-2′=3.3 Hz), 5.43 (dd, 1H, H-3′, J3′-2′=3.1 Hz and J3′-4′=1.9 Hz) 4.8-4.6 (m, 3H, H-4′, H-5′ and H-5″), 4.43 (t, 1H H-2′, J=2.3 Hz); MS: FAB>0 (matrix GT) m/z 941 (2M+H)+, 471 (M+H)+, 341 (S)+, 131 (BH2)+, 105 (C6H5CO)+; FAB<0 (matrix GT) m/z 939 (2M−H)−, 469 (M−H)−, 129 (B)−, 121 (C6H5CO2); [α]D20=−110 (c, 1.55 DMSO).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C@H:20](O)[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32]C4CCCCO4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43]([OH:45])=[O:44]>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([C@H:20]([S:40][C:41]([CH3:47])([CH3:46])[CH2:42][C:43]([OH:45])=[O:44])[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([OH:32])([CH3:30])[CH3:31])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(S)CC(=O)O
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@@H](O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Product: CC(C)(CC(=O)O)S[C@H](CCc1ccccc1C(C)(C)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1

Procedure:
The title compound was prepared using the enantiomer of the alcohol of Example 6, Step 8, and 3-mercapto-3-methylbutanoic acid, following Method J.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([SH:10])[CH2:8][CH3:9].[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24](Cl)[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15].O>CN(C)C=O>[CH2:11]([N:16]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[C:24]([S:10][CH2:7][CH2:8][CH3:9])[C:18]=2[S:17]1(=[O:27])=[O:26])[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCN1Cc2cccc(Cl)c2S1(=O)=O
Reactant: CCCS
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCN1Cc2cccc(SCCC)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5.0 g of potassium-t-butoxide in 40 ml of dry dimethylformamide was added 4.0 ml of propyl mercaptan at -5° to 0° C. under an inert atmosphere followed by 11.0 g of 2-pentyl-7-chloro-2,3-dihydro-1,2-benzisothiazole-1,1-dioxide. The mixture was stirred at room temperature for 16 hours, poured into water and extracted with n-butyl chloride. The extract was washed with water and brine, dried over MgSO4 and concentrated to give 10.3 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][OH:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9].[Cl:30][C:31]1[CH:38]=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:29])=[C:5]([C:23]([O:25][CH:26]([CH3:27])[CH3:28])=[O:24])[CH:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21](=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[CH:38][C:31]=3[Cl:30])=[O:22])[CH:16]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])=[O:9]
Reactant: O=Cc1ccccc1Cl
Reactant: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(NO)c1
Agent: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc(/[N+]([O-])=C/c2ccccc2Cl)c1
Product: COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc([N+]([O-])=Cc2ccccc2Cl)c1

Procedure:
The reaction of hydroxylamine 55 (1.97 g, 5 mmol) with 2-chlorobenzaldehyde (61) (0.70 g, 5 mmol) afforded, after workup, a light yellow oil. The crude product was purified by flash chromatography with 3:5 ethyl acetate/petroleum ether as the eluant to obtain 2.11 g (4.0 mmol, 80%) of 72 as a light yellow gum: IR (CH2Cl2) 3440, 2940, 1690, 1623, 1590, 1550, 1470, 1295, 1202, 1100; 1H NMR (CDCl3) δ 1.10 (d, J=6.2 Hz, 3H), 1.22 (d, J=6.2 Hz, 3H), 2.25 (s, 6H), 3.30 (s, 3H), 3.54 (t, J=4.8 Hz, 2H), 4.16 (m, 2H), 4.93 (septet, J=6.2 Hz, 1H), 5.07 (s, 1H), 6.87 (s, 1H), 7.27-9.45 (m, 9H); 13C NMR (CDCl3) δ 19.69, 19.84, 22.49, 22.72, 40.43, 59.36, 63.40, 67.70, 71.18, 103.32, 104.11, 120.08, 122.09, 127.76, 128.94, 129.04, 129.76, 130.22, 130.94, 131.28, 132.16, 134.30, 145.57, 146.32, 149.83, 150.49, 167.51, 167.99. Anal. Calcd for C28H31N2O6Cl: C, 63.81; H, 5.88. Found: C, 63.51; H, 6.02.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[CH2:3][C:4](=[O:8])[C:5]([OH:7])=O.O.ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([N:35]2[CH2:40][CH2:39][CH:38]([CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[CH2:37][CH2:36]2)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>C(Cl)Cl>[CH3:9][CH:2]([CH3:1])[CH2:3][C:4](=[O:8])[C:5]([N:44]1[CH2:43][CH2:42][CH:41]([CH:38]2[CH2:37][CH2:36][N:35]([C:32]3[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:33]=3)[CH2:40][CH2:39]2)[CH2:46][CH2:45]1)=[O:7]
Reactant: CS(=O)(=O)c1ccc(N2CCC(C3CCNCC3)CC2)cc1
Reactant: CC(C)CC(=O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)CC(=O)C(=O)N1CCC(C2CCN(c3ccc(S(C)(=O)=O)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 4-methyl-2-oxovaleric acid (8.07 mg; 0.062 mmol) was treated sequentially with 1-hydroxybenzotriazole hydrate (11.4 mg; 0.0741 mmol), EDC (14.3 mg; 0.074 mmol) and 1 1-[4-(methylsulfonyl)phenyl]-4,4′-bipiperidine (20.0.0 mg; 0.062 mmol) and stirred at ambient temperature for 18 h. The reaction was diluted with CH2Cl2(10 mL) and washed with water (15 mL). The organic phase was then dried over Na2SO4, filtered and concentrated in. vac to a residue. The crude product was purified by preparative HPLC reserve phase and eluted with acetonitrile/water+0.1% TFA. The title compound was isolated.
Reaction SMILES: [NH2:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C@H:3]([OH:14])[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].C(N(CC)CC)C.[Cl:30][CH2:31][C:32](Cl)=[O:33].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCCCCC>[Cl:30][CH2:31][C:32]([NH:1][CH:2]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C@H:3]([OH:14])[CH2:4][CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:9])=[O:33]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H](O)C(N)c1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)CCl
Agent: CN(C)c1ccncc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC[C@@H](O)C(NC(=O)CCl)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 76.2 %

Procedure:
3.60 g (9.88 mmole) of 1-amino-4-t-butyldimethylsilyloxy-(2R)-(3,4-dichlorophenyl)-2-butanol [prepared as described in Example 1(e)], 1.64 ml (11.8 mmole) of triethylamine and 121 mg (0.99 mmole) of 4-dimethylaminopyridine were dissolved in 100 ml of methylene chloride, and 0.94 ml (11.8 mmole) of chloroacetyl chloride were added dropwise, whilst ice-cooling. The mixture was then stirred at the same temperature for 2 hours. At the end of this time, 100 ml of methylene chloride were added to the reaction mixture, and the resulting mixture was washed with ice-cooled 10% w/v aqueous hydrochloric acid, with a saturated aqueous solution of sodium hydrogencarbonate and with a saturated aqueous solution of sodium chloride, in that order. It was then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the resulting residue was purified by silica gel flash column chromatography, using a gradient elution method, with mixtures of ethyl acetate and hexane ranging from 1:5 to 1:2 by volume as the eluent, to obtain 3.32 g (yield 76%) of the title compound as a colorless oil.
Reaction SMILES: ClC1N=C(C2SC(C(C)C)=NC=2C2C=C(NS(C3C(F)=CC=CC=3F)(=O)=O)C=CC=2)C=CN=1.[CH3:34][C:35]([C:38]1[S:39][C:40]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][N:52]=2)=[C:41]([C:43]2[C:44]([F:50])=[C:45]([CH:47]=[CH:48][CH:49]=2)[NH2:46])[N:42]=1)([CH3:37])[CH3:36].[F:57][C:58]1[CH:59]=[C:60]([S:64](Cl)(=[O:66])=[O:65])[CH:61]=[CH:62][CH:63]=1>>[CH3:37][C:35]([C:38]1[S:39][C:40]([C:51]2[CH:56]=[CH:55][N:54]=[CH:53][N:52]=2)=[C:41]([C:43]2[C:44]([F:50])=[C:45]([NH:46][S:64]([C:60]3[CH:61]=[CH:62][CH:63]=[C:58]([F:57])[CH:59]=3)(=[O:66])=[O:65])[CH:47]=[CH:48][CH:49]=2)[N:42]=1)([CH3:34])[CH3:36]
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccncn2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Agent: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccncn2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 3-[2-(1,1-dimethylethyl)-5-(4-pyrimidinyl)-1,3-thiazol-4-yl]-2-fluoroaniline (70 mg, 0.213 mmol) and 3-fluorobenzenesulfonyl chloride (124 mg, 0.639 mmol), the title compound was obtained as a solid (76 mg, 73% yield). MS (ESI): 488 [M+H]+.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.I[C:60]1[CH:65]=[CH:64][C:63]([O:66][C:67]([F:70])([F:69])[F:68])=[CH:62][CH:61]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:60]2[CH:61]=[CH:62][C:63]([O:66][C:67]([F:68])([F:69])[F:70])=[CH:64][CH:65]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: FC(F)(F)Oc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-iodo-4-(trifluoromethoxy)benzene.
Reaction SMILES: [CH3:1][C:2]([CH3:12])([C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[C:3]([O:5][CH3:6])=[O:4].[CH3:13][O-:14].[Na+]>CO>[OH:14][CH2:13][C:8]([CH3:10])([CH3:9])[C:7](=[O:11])[C:2]([CH3:1])([CH3:12])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)C(=O)C(C)C
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(C)(C)C(=O)C(C)(C)CO

Procedure:
A mixture of 172 g. (1.0 mole) methyl 2,2,4-trimethyl-3-ketovalerate, 5.4 g. (0.10 mole) sodium methoxide and 33 g. (0.36 mole) paraformalde in 250 ml. methanol is heated at reflux for eight hours. The mixture is quenched by addition of water, neutralized with hydrochloric acid, extracted with ethyl ether, washed with water, brine and solvent evaporated. The residue is purified by vacuum distillation or chromatography on silica gel to provide the purified product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([N+:15]([O-])=O)[C:9]=1[F:18])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[F:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1c(F)ccc([N+](=O)[O-])c1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1c(F)ccc(N)c1F
Reaction time: 15 h
Yield: 86 %

Procedure:
After dissolving the tert-butyl-2,6-difluoro-3-nitrophenylcarbamate (1 g, 3.6 mmol) prepared at Step 2 in methanol solvent, palladium carbon (100 mg) was added and stirred under hydrogen pressure for 15 hours. After completing the reaction, filtering through celite, vacuum concentrating, and refining by means of column chromatography, 0.76 mg of the target compound, tert-butyl-3-amino-2,6-difluorophenylcarbamate (percentage yield: 86%), was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:14][O:15][C:16]([C:18]1[NH:19][CH:20]=[CH:21][CH:22]=1)=[O:17]>ClCCl>[CH3:14][O:15][C:16]([C:18]1[NH:19][CH:20]=[C:21]([S:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)(=[O:8])=[O:7])[CH:22]=1)=[O:17]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)c1ccc[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)c2cccs2)c[nH]1
Reaction time: 24 h

Procedure:
To a solution of thiophene-2-sulfonyl chloride in dichloromethane was added aluminum chloride at 0-5° C., 1H-pyrrole-2-carboxylic acid methyl ester in dichloromethane was added slowly. Reaction mixture was stirred from room temperature to 60° C. for 24 hrs. On completion of reaction; reaction mixture was poured over crushed ice and extracted with dichloromethane, organic layer was washed with 1 N NaOH solution and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-(thiophene-2-sulfonyl)-1H-pyrrole-2-carboxylic acid methyl ester (D1-I).
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11](O)=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.ClC([N:20](C)C)=C(C)C>C(Cl)Cl>[SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([NH2:20])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: CC(C)=C(Cl)N(C)C
Reactant: Cc1cc(S)n2ncc(C(=O)O)c2n1
Solvent: ClCCl
Product: Cc1cc(S)n2ncc(C(N)=O)c2n1

Procedure:
A suspension of 105 g of 7-mercapto-5-methylpyrazolo-[1,5-a]pyrimidine-3-carboxylic acid in 400 ml of methylene chloride was treated with 6.3 ml of 1-chloro-N,N,2-trimethyl-1-propenamine and treated in an ultrasound bath until the majority has passed into solution. The mixture was suction filtered over a glass fiber filter, and ammonia was conducted into the clear filtrate at 20°. A crystalline precipitate formed which was filtered off under suction, dried and subsequently triturated in 100 ml of H2O for 5 minutes. The insoluble material was filtered off and the filtrate was concentrated in a vacuum to half of the volume. Upon allowing to stand at 0°, there was obtained 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide as the ammonium salt in the form of white crystals.