Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH:17]([CH3:19])[CH3:18])[C:3]([NH:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]2[O:12][CH2:13][O:14][C:10]=2[CH:9]=1)=[O:4].Cl[C:21]1[S:25][N:24]=[C:23]([N:26]2[CH:30]=[CH:29][N:28]=[CH:27]2)[N:22]=1>CS(C)=O.C(N(CC)CC)C.[Cl-].[Na+].O>[O:12]1[C:11]2[CH:15]=[CH:16][C:8]([CH2:7][CH2:6][NH:5][C:3](=[O:4])[C@H:2]([NH:1][C:21]3[S:25][N:24]=[C:23]([N:26]4[CH:30]=[CH:29][N:28]=[CH:27]4)[N:22]=3)[CH:17]([CH3:19])[CH3:18])=[CH:9][C:10]=2[O:14][CH2:13]1
Reactant: CC(C)C(N)C(=O)NCCc1ccc2c(c1)OCO2
Reactant: Clc1nc(-n2ccnc2)ns1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC(C)[C@@H](Nc1nc(-n2ccnc2)ns1)C(=O)NCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 9.7 %

Procedure:
2-Amino-N-(2-benzo[1,3]dioxol-5-yl-ethyl)-3-methyl-butyramide (135 mg, 0.51 mmol) was dissolved in DMSO (2 mL) and triethylamine (150 μL). Next, the 5-chloro-3-imidazol-1-yl-[1,2,4]thiadiazole (95.1 mg, 0.51 mmol) was added to the reaction vessel and it was stirred at room temperature for 16 hours. After this period, a portion of brine (50 mL) was added and the mixture was transferred to a separatory funnel and extracted with ethyl acetate (75 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The crude material was purified by Flash Chromatography (0-50% ACN/DCM gradient) to afford 20.4 mg of pure product, N-(2-benzo[1,3]dioxol-5-yl-ethyl)-2-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-ylamino)-3-methyl-butyramide. [M+H]+ 414.84; 1H NMR (400 MHz, CDCl3) δ 8.52 (s, 1H), 7.71 (s, 1H), 6.99 (s, 1H), 6.62-6.52 (m, 3H), 5.82-5.80 (m, 2H), 4.0 (Br s, 1H), 3.64-3.47 (m, 3H), 2.76-2.72 (m, 2H), 2.30-2.29 (m, 1H), 1.03-1.01 (m, 6H).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[S:9][CH:10]=1.C(O)(=O)C.O>O1CCCC1>[CH:2]([C:6]1[CH:7]=[C:8](/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])[S:9][CH:10]=1)=[O:1]
Reactant: COC(=O)/C=C/c1cc(C2OCCO2)cs1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C/c1cc(C=O)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of methyl (2E)-3-[4-(1,3-dioxolan-2-yl)thiophen-2-yl]acrylate (3.050 g, 12.69 mmol) in tetrahydrofuran (10 ml) were added acetic acid (30 ml) and water (10 ml), and the mixture was stirred at 50° C. for 2 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure, and water (30 ml) was added to the residue. The mixture was extracted 3 times with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated to about 50 ml under reduced pressure, and hexane (200 ml) was added. The mixture was concentrated again to about 50 ml under reduced pressure, and the precipitate was collected by filtration, washed 3 times with hexane, and dried under reduced pressure to give methyl (2E)-3-(4-formylthiophen-2-yl)acrylate (2.213 g, 11.28 mmol, 88.9%) as a white solid.
Reaction SMILES: [C:1](=[S:3])=[S:2].[NH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[N:6]=1.[C:13](#N)[CH3:14]>C(N(CC)CC)C>[CH2:11]([C:7]1[N:6]=[C:5]([NH:4][C:1](=[S:3])[S-:2])[CH:10]=[CH:9][CH:8]=1)[CH3:12].[CH2:13]([NH+:6]([CH2:5][CH3:10])[CH2:7][CH3:11])[CH3:14]
Reactant: S=C=S
Reactant: CCc1cccc(N)n1
Reactant: CC#N
Solvent: CCN(CC)CC
Product: CC[NH+](CC)CC
Product: CCc1cccc(NC(=S)[S-])n1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
A solution of carbon disulphide (17.5 cc) in anhydrous acetonitrile (19.5 cc) is added, at 25° C., to a solution of 2-amino-6-ethylpyridine (27.0 g) in anhydrous triethylamine (60 cc). After stirring for 20 hours at 20° C., anhydrous diethyl ether(250 cc) is added. After cooling for 1 hour at 2° C., the resulting crystals are filtered off, washed three times with anhydrous diethyl ether (total 240 cc) and dried under reduced pressure (20 mm Hg) at 20° C. Triethylammonium 6-ethylpyrid-2-yldithiocarbamate (42.0 g), melting at 75° C., is thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH2:27][CH3:28])=[C:20]([C:22](OCC)=[O:23])[CH3:21])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[Na]>C(O)(C)C.CN(C)C=O>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]2[C:22](=[O:23])[C:20]([CH3:21])=[C:19]([CH2:27][CH3:28])[NH:18][C:16]2=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=C(CC)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: CCc1[nH]c(=O)n(-c2cc(C(=O)OC(C)C)c(Cl)cc2F)c(=O)c1C

Procedure:
using isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-ethyl-1-propenyl]ureido}-benzoate with sodium isopropylate in an isopropanol/dimethylformamide mixture there is obtained isopropyl 2-chloro-4-fluoro-5-[3,6-dihydro-4-ethyl-5-methyl-2,6-dioxo-1(2H)-pyrimidinyl]-benzoate, m.p. 192°-194° C.,
Reaction SMILES: N(C(N1CCCCC1)=O)=N[C:3](N1CCCCC1)=O.[OH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH2:29][CH:30]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:31]([O:33][CH3:34])=[O:32])=[CH:23]2.OC[CH2:44][CH2:45][NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1.C(P(CCCC)CCCC)CCC>O1CCCC1>[CH2:35]([CH:30]([CH2:29][C:24]1[NH:25][C:26]2[C:22]([CH:23]=1)=[CH:21][C:20]([O:19][CH2:3][CH:45]([NH:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][N:48]=1)[CH3:44])=[CH:28][CH:27]=2)[C:31]([O:33][CH3:34])=[O:32])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: OCCCNc1ccccn1
Reactant: COC(=O)C(Cc1ccccc1)Cc1cc2cc(O)ccc2[nH]1
Reactant: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Product: COC(=O)C(Cc1ccccc1)Cc1cc2cc(OCC(C)Nc3ccccn3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (0.18 g, 0.7 mmol) was added to a solution of methyl 3-(5-hydoxylindolyl)-2-benzylpropanoate (0.12 g, 0.39 mmol), as prepared in the preceding step, 2-(3-hydroxypropyl)aminopyridine (0.07 g, 0.47 mmol), as prepared instep b of Example 1, and tri-n-butylphosphine (0.14 g, 0.7 mmol) in tetrahydrofuran (6.0 mL). After stirring at ambient temperature overnight (16 h), the reaction was concentrated in vacuo and the residue purified by flash chromatography on silica gel (10%–50% ethyl acetate in hexane) to give the title compound as a yellow oil (0.064 g, 38%). 1H-NMR (400 MHz, CDCl3) δ 8.08 (br s, 1H), 7.40 (m, 1H), 7.37 (m, 1H), 7.22 (m, 2H), 7.00 (m, 3H), 6.84 (dd, J=8.9, 2.4 Hz, 1H), 6.54 (m, 1H), 6.40 (d, J=8.4 Hz, 2H), 6.36 (d, J=3.1 Hz, 1H), 4.77 (br s, 1H), 4.40 (m, 1H), 4.17 (m, 3H), 3.52 (m, 5H), 3.24 (m, 1H), 3.08 (m, 1H), 2.76 (m, 1H), 2.11 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[NH:7][C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]2[N:33]=[C:32]([CH2:34][CH2:35][CH2:36]O)[O:31][N:30]=2)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:57]1[CH:62]=[CH:61][C:60]([CH2:63][O:64][C:65](/[N:67]=[N:68]/[C:69]([O:71][CH2:72][C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])=[O:66])=[CH:59][CH:58]=1>C1COCC1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH2:36][CH2:35][CH2:34][C:32]3[O:31][N:30]=[C:29]([CH2:28][C:25]4[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=4)[N:33]=3)[C:6](=[O:15])[N:5]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:4]=2[N:3]=1.[CH:76]1[CH:75]=[CH:74][C:73]([CH2:72][O:71][C:69](/[N:68]=[N:67]/[C:65]([O:64][CH2:63][C:60]2[CH:61]=[CH:62][CH:57]=[CH:58][CH:59]=2)=[O:66])=[O:70])=[CH:78][CH:77]=1
Reactant: OCCCc1nc(Cc2ccc(Cl)cc2)no1
Reactant: C=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2CCCCC
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n(CCCc2nc(Cc3ccc(Cl)cc3)no2)c(=O)c2[nH]c(Cl)nc21
Reaction time: 18 h

Procedure:
To a solution of 8-chloro-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.10 g, 0.34 mmol), 3-{3-[(4-chlorophenyl)methyl]-1,2,4-oxadiazol-5-yl}-1-propanol (0.086 g, 0.34 mmol) and triphenylphosphine (0.186 g, 0.69 mmol) in THF (5 ml) was added dibenzylazodicarboxylate (0.204 g, 0.68 mmol) and the solution stirred for 18 h. The solution was then concentrated and the residues chromatographed over silica (20 g, SPE) eluting with DCM initially then DCM/Et2O mixtures to yield the title compound contaminated with dibenzylazodicarboxylate by-products (0.18 g). Material used crude in deprotection step.
Reaction SMILES: CO.O.[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[N:14]1[C:18](=[O:19])[NH:17][C:16]([CH:20]([C:37]2[C:38]([F:49])=[C:39]3[C:44](=[C:45]([O:47][CH3:48])[CH:46]=2)[O:43][CH2:42][CH2:41][CH2:40]3)[NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[N:32]=C(C(F)(F)F)O[N:29]=3)=[CH:24][CH:23]=2)=[N:15]1)=[O:8])[CH3:5]>[Fe].C(O)(=O)C>[CH2:4]([O:6][C:7]([C:9]1[CH:10]=[N:11][NH:12][C:13]=1[N:14]1[C:18](=[O:19])[NH:17][C:16]([CH:20]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[NH:29])[NH2:32])=[CH:24][CH:23]=2)[C:37]2[C:38]([F:49])=[C:39]3[C:44](=[C:45]([O:47][CH3:48])[CH:46]=2)[O:43][CH2:42][CH2:41][CH2:40]3)=[N:15]1)=[O:8])[CH3:5]
Reactant: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(C(=N)N)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 34.8 %

Procedure:
Iron powder (64 mg) was added to 6 ml of a methanol:water:acetic acid=1:1:1 mixed solvent solution containing 74 mg of 5-(3-{(5-fluoro-8-methoxychroman-6-yl)-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylamino]methyl}-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. The resulting mixture was stirred at 60° C. for 20 hours under a nitrogen atmosphere. After filtration, the reaction mixture was purified by reverse-phase high performance liquid chromatography (acetonitrile-water, 0.1% acetic acid) to give 22 mg of 5-{3-[(4-carbamimidoylphenylamino)-(5-fluoro-8-methoxychroman-6-yl)methyl]-5-oxo-4,5-dihydro-[1,2,4]triazol-1-yl}-1H-pyrazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[OH:5][CH2:6][C:7]([C@H:9]([C@@H:11]([C@@H:13]([CH2:15][OH:16])O)[OH:12])[OH:10])=[O:8].[Sb](Cl)(Cl)(Cl)(Cl)Cl.N1C=C[CH:26]=[CH:25][CH:24]=1>>[CH3:1][C:2]1([CH3:4])[O:12][C@@H:11]2[C@@H:13]([CH2:15][O:16][C@@:7]3([CH2:6][OH:5])[O:8][C:25]([CH3:26])([CH3:24])[O:10][C@H:9]32)[O:3]1
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(C)=O
Reactant: c1ccncc1
Agent: Cl[Sb](Cl)(Cl)(Cl)Cl
Product: CC1(C)O[C@@H]2[C@@H](CO[C@@]3(CO)OC(C)(C)O[C@@H]23)O1
Temperature: 60 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To 200 ml of acetone were added 10.0 g of D-fructose and 89.7 mg of antimony pentachloride, and the mixture was refluxed with stirring in a water bath of 60° C. for 8 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the condenser. After completion of the reaction, a small amount of pyridine was added to the reaction mixture, and the acetone was distilled off under reduced pressure. The residue was dissolved in benzene, and the benzene solution was washed with aqueous sodium bicarbonate and water successively, and then dried over anhydrous magnesium sulfate. The benzene was distilled off to give 12.09 g (83.7%) of 2,3:4,5-di-O-isopropylidene-β-D-fructopyranose. The compound, when recrystallized from n-hexane, showed m.p. 96°-98° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([PH:11](=[O:15])[O:12][CH2:13][CH3:14])([O:8][CH2:9][CH3:10])[CH3:7])[CH3:4].Cl[CH:17]([F:19])[F:18]>O1CCCC1>[CH2:9]([O:8][C:6]([P:11]([CH:17]([F:19])[F:18])(=[O:15])[O:12][CH2:13][CH3:14])([O:5][CH2:3][CH3:4])[CH3:7])[CH3:10]
Reactant: FC(F)Cl
Reactant: CCO[PH](=O)C(C)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(C)(OCC)P(=O)(OCC)C(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 15.8 g of sodium hydride (dispersion in oil) in 500 ml of tetrahydrofuran are added dropwise 67 g (300 mMol) of ethyl 1,1-diethoxyethylphosphinate at such a rate so that the temperature, exceed 25° C. This mixture is stirred for one hour at room temperature, then cooled to -10° C. and 77.8 g (900 mMol) of chlorodifluoromethane are introduced. Stirring is continued for another 2 hours at room temperature, then 100 ml of ice-cold water are added. The mixture is extracted three times with dichloromethane and the combined extracts dried over magnesium sulphate. Removal of the solvent in vacuo gives ethyl 1,1-diethoxyethyl(difluoromethyl)phosphinate as a viscous oil, Rf=0.44 (CH2Cl2 /CH3COOH, 9+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[N:6]1(C(OC(C)(C)C)=O)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:1][S:2]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCNCC1
Temperature: -20 °C

Procedure:
Methanesulphonyl chloride (18.3 mL, 0.236 mol) was added dropwise to a solution of tert-butyl piperazine-1-carboxylate (40 g, 0.214 mol) and triethylamine (60 mL, 0.43 mol) in CH2Cl2 (300 mL) in argon under stirring at −20° C. The mixture was stirred at room temperature for 1 h, and water (100 mL) was added. The layers were separated, and the water layer was extracted with chloroform (2×200 mL). The organic fraction were washed with the 1 N NaHSO4 solution (100 mL), the saturated NaHCO3 solution (100 mL), dried over Na2SO4, filtered through SiO2 (50 g, 40-63 μm), and evaporated to dryness. The residue (white crystals) was dissolved in isopropanol (200 mL), concentrated HCl (35 mL) was added, and the mixture was refluxed for 1 h and evaporated. Chloroform (200 mL), the saturated K2CO3 solution (50 mL), and water (50 mL) were added to the residue under stirring. The organic layer was separated, and the water layer was extracted with chloroform (2×100 mL). The organic layers were dried over Na2SO4, filtered through SiO2 (50 g, 40-63 μm), and evaporated to dryness. The residue (white crystals) was dried to give the title compound in 94% (33 g) yield. LCMS data: M+H 165.0 (Calculated for C5H12N2O2S 164.23), 97.2%, r.t. 0.913 min. 1H-NMR data (dmso-d6): 2.99 (m, 4H), 2.83 (s, 3H), 2.74 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH:9]([C:12]#[N:13])[C:10]#[N:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18].Cl>CN(C)C=O>[CH2:18]([C:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([C:12]#[N:13])[C:10]#[N:11])[CH:17]=[CH2:16]
Reactant: C=CCBr
Reactant: N#CC(C#N)Cc1ccc(Cl)nc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC(C#N)(C#N)Cc1ccc(Cl)nc1

Procedure:
((6-Chloro-3-pyridyl)methyl)malononitrile (58 mg) was dissolved in N,N-dimethylformamide (2 ml), and sodium hydride (60% in oil, 14 mg) was added to the solution with stirring under ice-cooling. Then allyl bromide (0.13 ml) was added dropwise thereto, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 10% hydrochloric acid, and extracted with diethyl ether. The organic layer was washed successively with 10% hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was subjected to silica gel column chromatography to give 26 mg of 2-allyl-2-((6-Chloro-3-pyridyl)methyl)malononitrile represented by the following formula (hereinafter referred to as the present invention compound (1)).
Reaction SMILES: [K+].[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH-:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3].[O-:15][Mn](=O)(=O)=O.[K+].Cl>O>[OH:15][C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(O)c1ccc(S(N)(=O)=O)nc1
Temperature: 25 °C

Procedure:
To a solution of 5-isopropyl-pyridine-2-sulfonamide potassium salt (synthesis described in EP 799 209) in water (10 ml) were added 1.2 g of KMnO4 at RT and the mixture was then refluxed for 30 minutes. The mixture was cooled to RT, acidified with diluted HCl and the product was extracted into AcOEt. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to give (5-(1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide as yellow oil. El mass spectrum, m/e 216 (M calculated for: C8H12N2O3S 216).
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([C:33]#[CH:34])[CH:22]=1.Br[C:36]1[CH:41]=[C:40]([S:42]([CH2:44][CH2:45][CH3:46])=[O:43])[CH:39]=[CH:38][C:37]=1[CH3:47]>>[Cl:20][C:21]1[CH:32]=[CH:31][C:24]([O:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[C:23]([C:33]#[C:34][C:36]2[CH:41]=[C:40]([S:42]([CH2:44][CH2:45][CH3:46])=[O:43])[CH:39]=[CH:38][C:37]=2[CH3:47])[CH:22]=1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC
Reactant: CCCS(=O)c1ccc(C)c(Br)c1
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCS(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)OC)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from methyl (4-chloro-2-ethynylphenoxy)acetate (Intermediate 220) and 2-bromo-1-methyl-4-(propylsulfinyl)benzene (Intermediate 219), the title compound was obtained as a yellow oil after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Li+].[OH-].[Cl:3][C:4]1[CH:5]=[C:6]([C:41]#[N:42])[C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[C@@H:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][CH:18]=3)[CH2:14][CH2:15][CH3:16])[C:8]=2[CH:40]=1.C(O)(=O)C>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([C:41]#[N:42])[C:7]2[S:11][CH:10]=[C:9]([CH:12]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)[C@@H:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][CH:18]=3)[CH2:14][CH2:15][CH3:16])[C:8]=2[CH:40]=1
Reactant: CCC[C@H](c1ccc(C(=O)NCCC(=O)OCC)cc1)C(c1ccc(Cl)cc1)c1csc2c(C#N)cc(Cl)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCC[C@H](c1ccc(C(=O)NCCC(=O)O)cc1)C(c1ccc(Cl)cc1)c1csc2c(C#N)cc(Cl)cc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of LiOH (2.0 M in water, 4.5 mL, 9.0 mmol) was added to a solution of ethyl N-(4-{(1S)-1-[(5-chloro-7-cyano-1-benzothien-3-yl)(4-chlorophenyl)methyl]butyl}benzoyl)-β-alaninate (0.100 g, 0.168 mmol) in THF (9.0 mL). The mixture was stirred at room temperature for four hours then acidified with acetic acid and extracted with ethyl acetate. The organics were dried over Na2SO4, filtered, then concentrated. The resulting residue was purified by reverse-phase HPLC eluting with 20-100% acetonitrile/water containing 0.1% TFA. Following lyophilization, the material was further purified by silica gel chromatography eluting with 5% MeOH in DCM containing 0.5% acetic acid to afford the title compound as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.77 (br s, 1H); 7.60 (d, J=5 Hz, 2H); 7.52 (br s, 1H); 7.42 (br s, 1H); 7.31-7.35 (m, 4H); 7.25 (d, J=7 Hz, 2H); 6.78 (br s, 1H); 4.49 (d, J=11 Hz, 1H); 3.67 (br s, 2H); 3.44-3.47 (m, 1H); 2.66 (br, 2H); 1.45-1.53 (m, 2H); 0.98-1.05 (m, 2H); 0.73 (t, J=7 Hz, 3H). LC1: 3.97 min. (M+H)+ 565.
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[N:30]1([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1>>[ClH:20].[ClH:20].[N:30]1([CH:35]2[CH2:40][CH2:39][N:38]([CH2:19][CH2:18][O:17][C:14]3[CH:15]=[C:16]4[C:11](=[CH:12][CH:13]=3)[O:10][C:9]([C:21]3[N:26]=[CH:25][N:24]5[CH:27]=[CH:28][CH:29]=[C:23]5[CH:22]=3)=[CH:8][C:7]4=[N:6][OH:5])[CH2:37][CH2:36]2)[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: C1CCN(C2CCNCC2)C1
Product: Cl
Product: ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCN3CCC(N4CCCC4)CC3)cc12

Procedure:
6-[2-(4-pyrrolidin-1-yl-piperidin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, dihydrochloride was prepared in 90% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 4-(1-pyrrolidinyl)piperidine.
Reaction SMILES: [C:1]([O-:4])([O-:3])=O.[C:5]([O-:8])([O-])=[O:6].OO.OO.OO.[Na+].[Na+].[Na+].[Na+].[F:19][C:20]([F:31])([C:27]([F:30])([F:29])[F:28])[C:21]([F:26])([F:25])C(Cl)=O>C(Cl)(F)(F)C(Cl)(Cl)F>[F:31][C:20]([F:19])([C:27]([F:28])([F:29])[F:30])[C:21]([F:25])([F:26])[C:1]([O:4][O:8][C:5](=[O:6])[C:21]([F:26])([F:25])[C:20]([F:31])([F:19])[C:27]([F:30])([F:29])[F:28])=[O:3]
Reactant: O=C([O-])[O-]
Reactant: O=C(Cl)C(F)(F)C(F)(F)C(F)(F)F
Agent: OO
Agent: [Na+]
Solvent: FC(F)(Cl)C(F)(Cl)Cl
Product: O=C(OOC(=O)C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 3.3 h
Yield: 37 %

Procedure:
A round-bottom flask is charged with 50 ml of CFC-113 and 2.0 g of sodium percarbonate (13 mmoles or 19 mmoles of H2O2 equivalent). After chilling the contents of the flask to 0° C., 3.73 ml of heptafluorobutyryl chloride (25 mmoles) is added and the resulting slurry is stirred magnetically for 3.3 hours. The reaction mixture is filtered through a pad of Drierite® on glass wool, washing through with fresh CFC-113, an operation assumed to remove any unreacted percarbonate and any free H2O2. The filtrate, now measuring 45 ml in volume, is found to be 0.10 M in peroxide for a 37% yield based on starting heptafluorobutyryl chloride. In order to make sure that all of the sodium percarbonate and hydrogen peroxide has been removed by filtration through Drierite®, the peroxide solution is washed three times with 45–50 ml of water. On retitration, the solution is found to still be 0.10 M in peroxide.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:18]=[C:17]([C:19]([O:21]C(C)(C)C)=[O:20])[CH:16]=[C:15]([NH:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([NH:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[N:14]=3)=[CH:11][CH:12]=2)=[CH:33][CH:34]=1.[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([C:13]3[N:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[C:15]([NH:26][C@@H:27]([CH3:32])[C:28]([O:30][CH3:31])=[O:29])[N:14]=3)=[CH:11][CH:12]=2)=[CH:33][CH:34]=1
Reactant: COC(=O)[C@H](C)Nc1cc(C(=O)OC(C)(C)C)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](C)Nc1cc(C(=O)O)nc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Reaction time: 72 h

Procedure:
To a solution of the (S)-tert-butyl 2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylate (0.312 g, 0.667 mmol) in DCM (10 mL) was added TFA (5 mL, 67 mmol). After stirring for 3 days the reaction was evaporated in vacuo and the residue triturated with hexanes, filtered and dried under a stream of nitrogen to give (S)-2-(4-(4-fluorophenoxy)phenyl)-6-((1-methoxy-1-oxopropan-2-yl)amino)pyrimidine-4-carboxylic acid as the trifluoroacetic acid salt as a cream-colored powder (0.326 g, 0.620 mmol, 93%). 1H NMR (400 MHz, DMSO-d6): 8.36-8.26 (3H, m), 7.32-7.24 (2H, m), 7.20-7.13 (2H, m), 7.10-7.03 (3H, m), 4.60-4.52 (1H, m), 3.64 (3H, s), 1.45 (3H, d, J=7.2 Hz). LC/MS: m/z=412.1 [M+H]+.