Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=O)[C:15]([OH:17])=[O:16])=[CH:11][S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:19][N:20]1[CH2:24][CH2:23][N:22]([CH3:25])[C:21]1=[O:26]>C(O)C>[C:1]([O:5][C:6]([N:8]=[C:9]1[NH:13][C:12]([C:14](=[N:19][N:20]2[CH2:24][CH2:23][N:22]([CH3:25])[C:21]2=[O:26])[C:15]([OH:17])=[O:16])=[CH:11][S:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N=c1[nH]c(C(=O)C(=O)O)cs1
Reactant: CN1CCN(N)C1=O
Solvent: CCO
Product: CN1CCN(N=C(C(=O)O)c2csc(=NC(=O)OC(C)(C)C)[nH]2)C1=O
Reaction time: 8 h

Procedure:
13.1 g of 2-(2-tert.-butoxycarbonylimino-4-thiazolin-4-yl)-glyoxylic acid are dissolved in 160 ml of ethanol by warming for a short time. 5.5 g of 1-amino-2-oxo-3-methyl-imidazolidine are added to this solution at 20° C. After standing overnight, the reaction mixture is evaporated in a rotary evaporator, the residue is treated with water and the precipitate is filtered off. Excess NaHCO3 solution is added to this precipitate and the undissolved material is filtered off. The filtrate is acidified and the precipitate which separates out is filtered off, washed with water and dried.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[N:10][N:11]([CH3:13])[N:12]=2)=[N+:6]([O-:22])[CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cn1nnc(-c2ccc(Br)cn2)n1
Solvent: ClCCCl
Product: Cn1nnc(-c2ccc(Br)c[n+]2[O-])n1
Temperature: 80 °C

Procedure:
5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine (175 mg, 0.73 mM) and 3-chloroperbenzoic acid (wet, 70%: 0.50 g, 2.05 mM) were dissolved in 1,2-dichloroethane (5 ml) and heated at 80° C. for 1.5 hours. The mixture was submitted directly to silica gel chromatography, eluting with 25% acetonitrile in dichloromethane. 5-Bromo-2-(2-methyl-2H-tetrazol-5-yl)pyridine 1-oxide was thus obtained as a white solid (165 mg). This material was homogeneous by tlc analysis and was used in the subsequent step without further characterization or purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11](Br)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([NH2:20])(=[S:19])[CH3:18].C(N(CC)CC)C>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[S:19][C:17]([CH3:18])=[N:20][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(N)=S
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(Br)CC1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc2c(s1)CCN(C(=O)OC(C)(C)C)CC2

Procedure:
The title compound was prepared by the following reaction sequence: i) treatment of the 5-bromo-azepan-4-one hydrobromide (1:1) [Ger. Offen. (1989), DE 38207751] with di-t-butyldicarbonate in dioxane/aq. sodium hydrogen carbonate solution to yield the 4-bromo-5-oxo-azepane-1-carboxylic acid tert-butyl ester; ii) treatment of the 4-bromo-5-oxo-azepane-1-carboxylic acid tert-butyl ester with thioacetamide in ethanol in the presence of triethylamine at reflux to give the 2-methyl-4,5,7,8-tetrahydro-thiazolo[4,5-d]azepine-6-carboxylic acid tert-butyl ester; iii) conversion of the 2-methyl-4,5,7,8-tetrahydro-thiazolo[5-d]azepine-6-carboxylic acid tert-butyl ester into the 2-methyl-5,6,7,8-tetrahydro-4H-thiazolo[4,5-d]azepine by removal of the tert-butyloxycarbonyl function with hydrogen chloride (aqueous, 37%) in methanol at room temperature.
Reaction SMILES: [C:1]1(=[O:11])[N:5]([CH2:6][C:7]([OH:9])=[O:8])[C:4](=[O:10])[CH:3]=[CH:2]1.O[N:13]1[C:17](=[O:18])[CH2:16][CH2:15][C:14]1=[O:19].C1(N=C=NC2CCCCC2)CCCCC1>COCCOCCOC>[CH2:16]1[C:17](=[O:18])[N:13]([O:8][C:7]([CH2:6][N:5]2[C:4](=[O:10])[CH:3]=[CH:2][C:1]2=[O:11])=[O:9])[C:14](=[O:19])[CH2:15]1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)CN1C(=O)C=CC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: COCCOCCOC
Product: O=C(CN1C(=O)C=CC1=O)ON1C(=O)CCC1=O
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Maleimidoacetic acid (155 mg, 1.0 mmol) in 5 ml of diglyme was treated at 0° C. with N-hydroxysuccinimide (127 mg, 1.1 mmol) and dicyclohexylcarbodiimide (227 mg, 1.1 mmol). After 1 hour at 0° C. and 3 hours at room temperature, the reaction mixture was filtered and evaporated to dryness to yield 0.25 g of crude maleimidoacetic acid N-succinimidyl ester.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23]C1N=C(F)N=C(F)N=1.N1C=CC=CC=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:11][N:12]([CH:21]=[O:22])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]([F:23])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Fc1nc(F)nc(F)n1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (as prepared in Scheme 1; also described in WO 2009061879) (5.2 g, 17.03 mmol) dissolved in dichloromethane (DCM) (75 mL) was added 2,4,6-trifluoro-1,3,5-triazine (1.5 mL, 17.9 mmol) followed by pyridine (1.51 mL, 18.7 mmol). The reaction mixture was stirred at 25° C. for 2 h, and then the reaction mixture was diluted with DCM (100 mL) and washed (1×50 mL) with 5% citric acid followed by 50 mL of sat. NaHCO3. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl fluoride as a pale yellow oil. LC-MS (ES) m/e 306.8 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[CH3:21][C:22]1[C:26](B(O)O)=[C:25]([CH3:30])[O:24][N:23]=1>>[CH3:21][C:22]1[C:26]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:20])[CH3:1])=[C:25]([CH3:30])[O:24][N:23]=1
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(C)(C)CC2=O

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3,5-dimethylisoxazole-4-boronic acid according to the coupling procedure described in example 21. MS m/z 256; HRMS: calcd for C16H17NO2+H+, 256.13321; found (ESI, [M+H]+), 256.1343.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:26]>C(Cl)Cl>[F:26][C:10](=[O:11])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:13]1[CH:17]=[CH:16][S:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccsc1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)F)c1ccsc1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To (R)-2-(tert-butoxycarbonylamino)-2-(thiophen-3-yl)acetic acid in CH2Cl2 cooled to −10° C. was added pyridine and cyanuric fluoride. The solution was stirred for 1 hour at −10° C., quenched with ice and extracted with CH2Cl2 and ice cold water, dried (Na2SO4), filtered and evaporated to give (R)-tert-butyl 2-fluoro-2 oxo-1-(thiophen-3-yl)ethylcarbamate.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][C:27]1[O:28][C:29]([C:32]2[CH:37]=[CH:36][C:35]([NH2:38])=[CH:34][CH:33]=2)=[CH:30][N:31]=1.[CH2:39]([C:46]1[CH:51]=[C:50]([CH3:52])[N:49]=[C:48](Cl)[N:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.O>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:39]([C:46]1[CH:51]=[C:50]([CH3:52])[N:49]=[C:48]([NH:38][C:35]2[CH:36]=[CH:37][C:32]([C:29]3[O:28][C:27]([CH3:26])=[N:31][CH:30]=3)=[CH:33][CH:34]=2)[N:47]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: Cc1cc(Cc2ccccc2)nc(Cl)n1
Reactant: Cc1ncc(-c2ccc(N)cc2)o1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(-c3cnc(C)o3)cc2)n1
Yield: 60.4 %

Procedure:
Palladium(II) acetate (9.3 mg, 0.041 mmol) and 2-(dicyclohexylphosphino)biphenyl (30 mg, 0.083 mmol) were stirred in dioxane (1.5 mL) for 15 minutes at room temperature under an atmosphere of nitrogen. Sodium tert.-butylate (76 mg, 0.78 mmol), 4-(2-methyl-oxazol-5-yl)phenylamine (90 mg, 0.52 mmol, CAS 89260-50-4) dissolved in dioxane (0.7 mL) and 4-benzyl-2-chloro-6-methyl-pyrimidine (124 mg, 0.57 mmol) were added. The reaction was heated for 30 minutes to 200° C. in a microwave oven. Water was added and the reaction was extracted twice with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane and then methylenechloride/methanol (19:1 v/v) as eluent to yield the title compound as a yellow solid (112 mg, 61%). MS ISP (m/e): 357.2 (100) [(M+H)+]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.69 (d, 2H), 7.53 (d, 2H), 7.26-7.35 (m, 4H), 7.11-7.12 (m, 2H), 6.45 (s, 1H), 3.97 (s, 2H), 2.52 (s, 3H), 2.36 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=3)[S:8][C:4]=2[CH:3]=1.[CH3:17]OS(OC)(=O)=O.[I-:24].[K+]>O>[I-:24].[CH3:17][N+:12]1[CH:11]=[CH:10][C:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([Cl:1])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[CH:14][CH:13]=1
Reactant: COS(=O)(=O)OC
Reactant: Clc1ccc2nc(-c3ccncc3)sc2c1
Agent: [I-]
Agent: [K+]
Solvent: O
Product: C[n+]1ccc(-c2nc3ccc(Cl)cc3s2)cc1

Procedure:
10 parts of the compound obtained in example 6 and 7 parts of dimethylsulfate are stirred at 100° C. for 30 minutes. At room temperature, 100 parts of water and 12 parts of potassium iodide are added and the product filtered. The product is washed with water and dried to yield 11 parts of 1-methyl-4-(6-chlor-benzothiazol-2-yl)pyridinium iodide.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:12][C:13]([OH:15])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:16][C@H:17]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:18]1>>[F:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][CH2:22][N:19]2[CH2:20][CH2:21][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:18]2)=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1ccccc1C1CCCC1
Reactant: N[C@H]1CCN(CCc2ccc(F)cc2)C1
Product: O=C(Cc1ccccc1C1CCCC1)N[C@H]1CCN(CCc2ccc(F)cc2)C1

Procedure:
2-Cyclopentylphenylacetic acid and (S)-3-amino-1-(2-(4-fluorophenyl)ethyl)pyrrolidine were reacted under the same conditions as in Example 23 to give N-((S)-1-(2-(4-fluorophenyl)ethyl)pyrrolidin-3-yl)-2-cyclopentylphenylacetamide.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])(=O)[CH2:2][CH3:3].Cl.[CH2:31]([O:33][NH2:34])[CH3:32].C([O-])(=O)C.[Na+].O>C(Cl)Cl.C(O)C>[CH2:31]([O:33][N:34]=[C:1]([C:5]1[C:6](=[O:29])[CH2:7][CH:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=3)[CH:13]=2)[CH2:9][C:10]=1[OH:11])[CH2:2][CH3:3])[CH3:32]
Reactant: CCC(=O)C1=C(O)CC(c2cccc(Oc3cccc(S(C)(=O)=O)c3)c2)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2cccc(Oc3cccc(S(C)(=O)=O)c3)c2)CC1=O
Reaction time: 24 h

Procedure:
A solution of 3.5 g (8.5 mmol) of 2-propionyl-3-hydroxy-5-(3-(3-(methylsulfonyl)phenoxy)phenyl)-cyclohex-2-en-1-one in 10 mL of methylene chloride and 20 mL of absolute ethanol was treated with 1.0 g (1.0 mmol) of ethoxyamine hydrochloride and 0.9 g (1.0 mmol) of anhydrous sodium acetate. After stirring for 24 hours, the mixture was poured into 100 mL of water and extracted thrice with 20 mL portions of methylene chloride. The combined extracts were dried over MgSO4, filtered and passed through a short column of silica gel, eluting with about 200 mL of methylene chloride. Evaporation of the eluent afforded the above named product as a light yellow oil. The product was recovered in a yield of 3.0 g (77 percent of theoretical). 1H NMR (CDCl3) δ1.08-1.49 (m, 6H, both --CH2CH3 's), 2.60-3.65 (m includes s at 3.05 for CH3SO2 --, 10H), 4.12 (q, J=7Hz, 2H, --OCH2), 6.85-7.85 (m, 8H, aromatics), 14.9 (broad s, 1H, enol H) (Compound 1).
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:17](Cl)(=[O:21])[CH:18]([CH3:20])[CH3:19]>N1C=CC=CC=1>[C:17]([O:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4])(=[O:21])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc2nc(NC(=O)CO)sc2c1
Solvent: c1ccncc1
Product: COc1ccc2nc(NC(=O)COC(=O)C(C)C)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Hydroxyacetylamino)-6-methoxybenzothiazole (1.2 g) prepared in Example 3 is dissolved in pyridine (50 ml) and thereto is added dropwise isobutyryl chloride (0.6 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off, washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (1.2 g) having the following physical properties.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][CH3:12].[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>Cl.CCOCC>[O:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[O:13][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: C1=COCCC1
Reactant: CCCOc1ccc(O)cc1OC
Agent: Cl
Solvent: CCOCC
Product: CCCOc1ccc(OC2CCCCO2)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Methoxy-4-n-propoxyphenol (19.62 g, 0.108 M) was added in portions to a stirred mixture of dihydropyran (15.7 ml) and concentrated hydrochloric acid (3 drops) under nitrogen such that the temperature did not rise above 50° C. The solution was then stirred at room temperature (3 hr). The reaction mixture was diluted with ether and washed with water, 2 N sodium hydroxide solution, water, dried (sodium sulphate) and evaporated to give 3-methoxy-4-n-propoxyphenol tetrahydropyranyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.CCN(C(C)C)C(C)C.[CH3:20][N:21]=[C:22]=[O:23]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:22]([NH:21][CH3:20])=[O:23])[CH2:6][CH2:5]2
Reactant: CN=C=O
Reactant: Brc1ccc2c(c1)CCN2
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNC(=O)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 72.6 %

Procedure:
To a solution of 5-bromoindoline (1.0 g, 5.05 mmol) and DIEA (1.9 mL, 11.11 mmol) in THF (40 mL) was added methylisocyanate (346 mg, 6.06 mmol). The reaction was maintained at room temperature for 4 h. The resulting precipitate was filtered and dried under vacuum to afford 5-bromo-N-methylindoline-1-carboxamide (935 mg, 72% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (d, J=8.78 Hz, 1H), 7.17-7.31 (m, 2 H), 6.60 (d, J=4.27 Hz, 1H), 3.85 (t, J=8.78 Hz, 2H), 3.10 (t, J=8.66 Hz, 2H), 2.65 (d, J=4.27 Hz, 3H); MS (EI) m/z=255.1[M+1]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc(-c2ccnn2C)c(Cl)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nccc1-c1cc(C(=O)O)sc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a 250 mL round-bottomed flask was added methyl 5-chloro-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (4.4 g, 17.14 mmol) and sodium hydroxide (28.6 ml, 171 mmol) in tetrahydrofuran (THF) (50 ml) and MeOH (50 mL). The reaction solution was stirred at RT for 12 h and then made acidic (pH ˜2) with 2.5 M HCl and extracted with DCM. The organic layer was separated, dried (Na2SO4) and concentrated to an off-white solid (4.2 g, 94%) which was used directly without further purification: LCMS (ES) m/z 243 (M+H)+.
Reaction SMILES: C([Li])CCC.S1C=CC=C1.[S].Br[CH2:13][CH2:14][C:15]([OH:17])=[O:16].C([O-])([O-])=O.[K+].[K+].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[SH:29]>CCCCCC.CCOCC.O>[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29][CH2:13][CH2:14][C:15]([OH:17])=[O:16]
Reactant: Sc1cccs1
Reactant: O=C(O)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: O=C(O)CCSc1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
n-Butyl lithium (180 g, 2.81 mol) in hexane (1.6M solution) was added to a solution of thiophene (200 ml, 2.5 mol) in 1500 ml ether under N2 while keeping the temperature between 25°-30° C. The mixture was stirred at room temperature for 1 hour then heated at reflux for 2 hours, cooled to -60° C. and sulfur (80.15 g, 2.5 mol) added. The mixture was stirred at -60° to -70° C. for 45 minutes, allowed to warm to -10° C. then cooled to -20° C. and H2O (500 ml) added slowly. The layers were separated and the aqueous layer added to a solution of 3-bromopropionic acid (382.5 g, 2.5 mol) in 250 ml H2O which was neutralized by the addition of K2CO3 (172.8 g, 1.25 mol) prior to the addition of the thiophenethiol. The organic layer was washed with H2O (500 ml and 100 ml) and the aqueous washes were added to the solution of the 3-bromopropionic acid (slight exotherm). The reaction mixture was stirred at room temperature for 18 hours then heated on the steam bath for 1 hour. After cooling to room temperature the mixture was extracted with ether (2×250 ml), cooled in an ice bath and acidified to pH 1.0 with 6NHCl. The acidified, aqueous mixture was extracted with ether (500 ml then 2×375 ml). The ether extracts were combined, washed with H2O (2×250 ml) and dried over Na2SO4. Evaporation of the solvent yielded 410.2 g of crude product, which was distilled in vacuo. The fraction boiling at 154°-164° C. at 0.9 mm Hg was collected yielding 346.8 g (73.7%) of product.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:17][CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[CH2:11]2)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:20]=1[C:21](O)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)[C:20]=1[C:21]([N:14]1[CH2:13][CH:12]2[CH:16]([CH2:17][N:10]([C:7]3[N:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][N:6]=3)[CH2:11]2)[CH2:15]1)=[O:22]
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Reactant: O=[N+]([O-])c1cnc(N2CC3CNCC3C2)nc1
Product: O=C(c1c(F)cccc1-n1nccn1)N1CC2CN(c3ncc([N+](=O)[O-])cn3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15, utilizing Intermediate 46 and Intermediate 12. MS (ESI): mass calculated for C19H17FN8O3, 424.14; m/z found 425.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 9.10 (ddd, J=9.9, 5.7, 3.3, 2H), 7.90-7.79 (m, 2H), 7.74 (d, J=6.6, 1H), 7.55-7.44 (m, 1H), 7.22-7.10 (m, 1H), 4.13-3.60 (m, 7H), 3.40-3.07 (m, 3H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3]1[O:5][CH2:4]1.C([Li])CCC.[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([C:18](N(OC)C)=[O:19])=[C:16]([O:26][CH3:27])[C:15]=1[F:28].C(OCC)C>C1COCC1.CCCCCC>[Cl:13][C:14]1[CH:25]=[CH:24][C:17]([C:18]([C:3]2([C:2]([F:7])([F:6])[F:1])[CH2:4][O:5]2)=[O:19])=[C:16]([O:26][CH3:27])[C:15]=1[F:28]
Reactant: FC(F)(F)C1CO1
Reactant: COc1c(C(=O)N(C)OC)ccc(Cl)c1F
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(C(=O)C2(C(F)(F)F)CO2)ccc(Cl)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
0.44 ml (5.1 mmol) 1,1,1-trifluoro-2,3-epoxypropane in 7.5 ml THF and 2.2 ml hexane are cooled to −100° C. and 2.03 ml of a 2.5 M n-butyl lithium solution (5.1 mmol) in hexane are added over 15 minutes while the temperature does not exceed −95° C. 10 minutes after complete addition 0.57 g (2.3 mmol) 4-chloro-3-fluoro-2,N-dimethoxy-N-methylbenzamid in 10 ml THF are added over 15 minutes while the temperature does not exceed −95° C. After 3 hours at −100° C. 2.3 ml diethyl ether is added and the reaction mixture is warmed to room temperature over 14 hours. The reaction is quenched by addition of saturated ammonium chloride solution. The phases were separated and the aqueous layer is extracted twice with diethyl ether, the combined organic phases washed with brine, dried over sodium sulphate and then evaporated to yield 570 mg of (4-chloro-3-fluoro-2-methoxyphenyl)[2-(trifluoromethyl)oxiranyl]methanone. 1H-NMR (CDCl3); δ=2.99 (dq, 1H), 3.37 (d, 1H), 4.14 (d, 3H), 7.18 (m, 1H), 7.19 (m, 1H).
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C[O-].[K+].[C:18](OC)(=[O:24])[CH2:19][C:20](OC)=[O:21]>CO>[OH:24][C:18]1[N:10]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([C:3]([F:13])([F:14])[F:2])=[CH:5][CH:6]=2)[NH:9][C:20](=[O:21])[CH:19]=1
Reactant: COC(=O)CC(=O)OC
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: O=c1cc(O)nc(-c2ccc(C(F)(F)F)cc2)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Trifluormethylbenzamidine hydrochloride (22.4 g, 0.1 mol, from example 41) is added to a solution of potassium methylate (0.22 mol) in anhydrous methyl alcohol (65 mL) and stirred for 15 minutes at ambient temperature. Dimethyl malonate (12.6 mL, 0.11 mol) is added and the mixture is heated to reflux for 4 hours. After cooling, the resulting suspension is diluted with methyl alcohol (50 mL).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C(O)=O)[CH2:13][O:14][C:15]([C@@H:17]1[CH2:21][C@@H:20]([CH3:22])[CH2:19][N:18]1[C:23](=[O:49])[C@@H:24]([NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[C:35]([C@@H:37]1[CH2:41][CH2:40][CH2:39][N:38]1[C:42](OC(C)(C)C)=[O:43])=[O:36])=[O:28])[CH3:25])=[O:16])=[O:10])C1C=CC=CC=1.F[C:54]1[C:59](O)=[C:58](F)[C:57](F)=[C:56](F)[C:55]=1F.C(Cl)CCl>ClCCl>[CH3:22][C@H:20]1[CH2:19][N:18]2[C@H:17]([C:15](=[O:16])[O:14][CH2:13][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[C:42](=[O:43])[N:38]3[C@H:37]([C:35](=[O:36])[N:30]4[C@H:29]([C:27](=[O:28])[NH:26][C@@H:24]([CH3:25])[C:23]2=[O:49])[CH2:34][CH2:33][CH2:32][CH2:31]4)[CH2:41][CH2:40][CH2:39]3)[CH2:21]1
Reactant: C[C@@H]1C[C@@H](C(=O)OC[C@H](NC(=O)OCc2ccccc2)C(=O)O)N(C(=O)[C@H](C)NC(=O)[C@@H]2CCCCN2C(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)C1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@@H]1C[C@H]2C(=O)OC[C@H](NC(=O)OCc3ccccc3)C(=O)N3CCC[C@H]3C(=O)N3CCCC[C@H]3C(=O)N[C@@H](C)C(=O)N2C1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
3.95 g (5.41 mm ol) of the acid from example 25A and 3.98 g (21.65 mmol) of pentafluorophenol are dissolved in dichloromethane (13 ml) and cooled to −20° C. under argon. 1.14 g (5.95 mmol) of EDC are added, and the reaction mixture is stirred overnight with slow warming to RT. The reaction solution is concentrated to dryness and the residue is treated at 0° C. with 4N hydrogen chloride solution in dioxane (80 ml). The mixture is stirred for 3 h and the solvent is subsequently removed in vacuo. The residue is dissolved in dichloromethane (about 900 ml) and slowly added dropwise at RT to a vigorously stirred two-phase mixture of 1N aqueous sodium hydrogencarbonate solution (700 ml) and dichloromethane (1200 ml). The reaction mixture is stirred overnight. The phases are separated, the aqueous phase is extracted three times with dichloromethane and the combined organic phases are dried over sodium sulfate, filtered and concentrated to dryness. The residue (2.7 g of yellow hard foam) is purified by chromatography in 3 portions by means of preparative RP-HPLC using acetonitrile/water (gradient). 1.98 g (60% of th.) of the product are obtained.