Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([C:29]([N:31]([CH3:33])[CH3:32])=O)[CH2:28][CH2:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C:26]4([CH2:29][N:31]([CH3:32])[CH3:33])[CH2:27][CH2:28]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(C(=O)N(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ccnc2cc1OCC1(CN(C)C)CC1
Yield: 64.4 %

Procedure:
The product of Example 11 (80 mg) was stirred with LAH (2 eq) in THF (10 ml) at 0° C. for 10 minutes. The reaction was refluxed for 45 minutes and quenched with water. The solution was evaporated and purified with silica gel column to give the titled product (50 mg). Mass: (M+1), 450
Reaction SMILES: [OH-].[Na+].C(OC([N:8]1[CH2:13][CH2:12][C:11](=[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)C.C(=O)(O)N>O.C(O)C>[C:15]1([C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)N1CCC(=C(c2ccccc2)c2ccccc2)CC1
Agent: NC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc(C(=C2CCNCC2)c2ccccc2)cc1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
Sodium hydroxide (15.85 g, 396 mmol) in water (30 mL) was added to the carbamate 1-ethoxycarbonyl 4-(diphenylmethylidene)piperidine 19 (11.47 g, 35.7 mmol) dissolved in ethanol (150 mL). The mixture was heated at reflux overnight. The reaction mixture was cooled to room temperature was then partitioned between water (100 mL) and ethyl acetate (150 mL). The mixture was stirred to dissolve the solid and the layers were separated. The organic layer was washed with brine (100 mL) and the separate aqueous layers were extracted with ethyl acetate (100 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The yellow oil was dried by high vacuum to give 6.7 g (75%) of 20 as a yellow-white waxy solid. 1H NMR was used to confirm the structure of the product. (Amine 22 was similarly prepared.)
Reaction SMILES: C([Li])CCC.[NH:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>CCCCCC.O1CCCC1>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11])(=[O:23])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C1CCCN1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCCN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: -10 °C
Reaction time: 0.42 h
Yield: 58 %

Procedure:
15.6 cm3 of a 1.6M solution of butyllithium in hexane is added to 2.13 g of 2-pyrrolidinone in solution in 80 cm3 of tetrahydrofuran, cooled to -10° C., maintaining the temperature between -5° C. and +5° C. After agitation at -5° C. for 25 minutes, 6.12 g of beta-naphthalene-sulphonyl chloride is added, without exceeding 0° C. The whole is then left to return to ambient temperature. The solvent is evaporated off under reduced pressure, the residue is taken up in ethyl acetate, and the lithium chloride is filtered off and after evaporating under reduced pressure, the residue is taken up in water and filtered. Finally after crystallization from isopropanol, 4 g of expected product is obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15](OC(C)(C)C)=[O:16])C(OC)=O.C(O)=O>C1(C)C=CC=CC=1.C(O)CCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]1[NH:11][C:12](=[O:22])[CH2:13][NH:14][C:15]1=[O:16]
Reactant: COC(=O)C(NC(=O)CNC(=O)OC(C)(C)C)c1cccs1
Solvent: CCCCO
Solvent: O=CO
Solvent: Cc1ccccc1
Product: O=C1CNC(=O)C(c2cccs2)N1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of 6.4 g of methyl 2-thienyl-N-(tert.-butoxycarbonylaminoacetyl)aminoacetate and 200 ml of formic acid is stirred at room temperature for 15 h. The volatile fractions are stripped off in vacuo, and the residue is heated to boiling in a mixture of 80 ml of toluene and 300 ml of butanol under reflux for 3 h. The solvents are then removed in a rotary evaporator, and the residue is recrystallized from methanol.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].[NH2:11][C:12]1[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]2[N:24]=[C:23]([C:25](=O)[CH3:26])[CH:22]=[N:21][C:20]=2[NH:28][C:29]2[CH:30]=[N:31][C:32]([O:36][CH3:37])=[C:33]([F:35])[CH:34]=2)[CH:13]=1.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.N.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[F:35][C:33]1[CH:34]=[C:29]([NH:28][C:20]2[C:19]([C:14]3[N:15]=[C:16]([CH3:18])[N:17]=[C:12]([NH2:11])[CH:13]=3)=[N:24][C:23]([CH:25]([N:8]3[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:6][CH2:7]3)[CH3:26])=[CH:22][N:21]=2)[CH:30]=[N:31][C:32]=1[O:36][CH3:37]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: COc1ncc(Nc2ncc(C(C)=O)nc2-c2cc(N)nc(C)n2)cc1F
Agent: [Ti+4]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1ncc(Nc2ncc(C(C)N3CCN(S(C)(=O)=O)CC3)nc2-c2cc(N)nc(C)n2)cc1F
Temperature: 75 °C
Reaction time: 25 h
Yield: 22.6 %

Procedure:
A mixture of 1-(methylsulfonyl)piperazine (13.34 mg, 0.081 mmol, Apollo), 1-(6-(6-amino-2-methylpyrimidin-4-yl)-5-(5-fluoro-6-methoxypyridin-3-ylamino)pyrazin-2-yl)ethanone (15 mg, 0.041 mmol) and titanium(iv) isopropoxide (0.048 mL, 0.162 mmol, Aldrich, St. Louis, Mo.) in tetrahydrofuran (0.5 mL) was stirred at 75° C. for 25 h. The mixture was cooled down to 20° C. and CH2Cl2 (1 mL) was added followed by sodium triacetoxyborohydride (34.4 mg, 0.162 mmol). The reaction mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with ammonia (3 mL, 30% in water) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with saturated NaCl (5 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as a yellow solid. The crude product was purified by silica gel chromatography eluting with 5% MeOH/CH2Cl2 to give 6-(3-(5-fluoro-6-methoxypyridin-3-ylamino)-6-(1-(4-(methylsulfonyl)piperazin-1-yl)ethyl)pyrazin-2-yl)-2-methylpyrimidin-4-amine (4.8 mg, 9.27 μmol, 23% yield). 1H NMR (300 MHz, CDCl3) δ 1.44 (d, J=6.58 Hz, 3H) 2.46-2.69 (m, 7H) 2.77 (s, 3H) 3.23 (t, J=4.24 Hz, 4H) 3.55 (q, J=6.77 Hz, 1H) 4.03 (s, 3H) 5.42 (s, 2H) 8.04 (d, J=2.19 Hz, 1H) 8.20-8.37 (m, 2H) 8.70 (d, J=1.90 Hz, 1H) 11.90 (s, 1H). m/z (ESI, +ve ion) 518.2 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:3][CH:2]=1>C(O)C.[Pt]=O>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: c1ccc2ncc(-c3ccncc3)cc2c1
Agent: O=[Pt]
Solvent: CCO
Product: c1ccc2c(c1)CC(c1ccncc1)CN2
Reaction time: 10 h
Yield: 39.2 %

Procedure:
3-(Pyridin-4-yl)quinoline (1 g, 0.00485 mol) was dissolved in ethanol (30 mL). To this was added platinum oxide (0.4 g) under nitrogen atmosphere, and the reaction mixture was hydrogenated at 50 psi for 10 h. After completion of reaction (monitored by TLC), the catalyst was removed by filtration, the filtrate concentrated under reduced pressure and the residue purified by column chromatography (30% EtOAc:hexane on silica 100-200 mesh, diameter of column—2.5 cm, height of silica—approx. 5 inch) to provide the desired compound (0.4 g, 40% yield).
Reaction SMILES: C(OCC)(=O)C.Cl.[NH2:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1.[CH2:21]([O:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O>[CH2:21]([O:28][C:29]([NH:8][C@@H:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[O:11][CH2:10]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(N[C@H]1COc2ccccc2NC1=O)OCc1ccccc1

Procedure:
To a mixture of 100 ml of ethyl acetate and 50 ml of water is added 1.5 g of 3(S)-amino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one hydrochloride, and 1.5 ml of benzyloxycarbonyl chloride is added dropwise to the mixture at ice bath temperature with stirring. After stirring for 1 hour, the ethyl acetate layer separated, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the residue is added ethyl ether and the deposited crystals are collected by filtration to give 2 g of 3(S)-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1,5-benzoxazepine-4-one. This product is recrystallized from a mixture of ethyl acetate and ether to give colorless needles melting at 157°-159° C.
Reaction SMILES: Cl[C:2]1C=[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[F:21])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.COS(OC)(=O)=O.C(N(CC)CC)C.CC(O)=O.[CH3:40][CH2:41][OH:42]>C(Cl)(Cl)Cl>[F:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]([CH3:2])[C:41](=[O:42])[CH:40]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc(C)cc1F
Reactant: CCO
Solvent: ClC(Cl)Cl
Solvent: COS(=O)(=O)OC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc(C)cc1F
Yield: 84 %

Procedure:
Ethyl 6-chloro-4-(2-fluoro-4-methylanilino)nicotinate) was dissolved in CHCl3 and reacted with Me2SO4, followed by triethylamine, AcOH and EtOH as described for example 33, step B. Purification by recrystallisation (EtOAc/Hexane) afforded ethyl 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (84%); m.p. (EtOAc/Hexane) 148-150° C. 1H NMR [400 MHz, CDCl3] δ 9.17 (br s, 1H), 8.20 (s, 1H), 7.27-7.21 (m, 1H), 6.99-6.92 (m, 2H), 5.76 (s, 1H), 4.35 (q, J=7.1 Hz, 2H), 3.53 (s, 3H), 2.35 (s, 3H), 1.39 (t, J=7.1 Hz, 3H). LCMS (ACPI−) 303 (100%). Anal. Calcd for C16H17FN2O3: C, 63.2; H, 5.6; N, 9.2. Found C, 63.1; H, 5.7; N, 9.2.
Reaction SMILES: O.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:34][O:35][CH2:36][CH3:37])[C:9]([NH:11][CH:12]2[C:32](=[O:33])[N:14]3[C:15]([C:19]([O:21]CC4C=CC([N+]([O-])=O)=CC=4)=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.CO.C(O)(=O)C>[Pd].O1CCCC1>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:34][O:35][CH2:36][CH3:37])[C:9]([NH:11][CH:12]2[C:32](=[O:33])[N:14]3[C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Reaction time: 2 h
Yield: 35 %

Procedure:
Palladium on carbon (1.0 g.) moistened with water (3 ml.) was added to a solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.3 g.) in a mixture of tetrahydrofuran (30 ml.), methanol (15 ml.) and acetic acid (0.3 ml.), and the suspension was subjected to catalytic reduction at room temperature under ordinary pressure for 2 hours. After removing the catalyst from the resultant mixture by filtration, the filtrate was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the solution was adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. After removing the insoluble substance by filtration, the aqueous solution was separated, washed with ethyl acetate, adjusted to pH 5.5 and then treated with activated charcoal. The aqueous solution was adjusted to pH 3.2, and the precipitates were collected by filtration and dried to give 7-[2-(2-amino-4-thiazolyl)-2-ethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.6 g.).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C([O:13][C:14](=O)[CH2:15][C:16]([CH3:18])=O)C.[OH-].[Na+]>C(O)(=O)C.O.C(Cl)Cl>[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:14](=[O:13])[CH:15]=[C:16]([CH3:18])[NH:10]1
Reactant: NNc1ccccc1F
Reactant: CCOC(=O)CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1cc(=O)n(-c2ccccc2F)[nH]1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
A stirred suspension of 2-fluorophenylhydrazine hydrochloride (1000 g, 5535 mmol) in acetic acid (1000 ml) and water (1000 ml) was heated at 45° C. Ethylacetoacetate (700 ml) was added dropwise over 30 mins and this was stirred at 88° C. for 2 hr. The resulting mixture was cooled to 5° C. and poured onto ice (3000 g) and DCM (4500 ml). 30% NaOH (aq) (2400 ml) was added and the mixture was stirred for 15 mins, then separated and extracted with DCM (1500 ml). The organic extracts were washed with 1M NaOH (aq) (1500 ml). The aqueous phases were combined and ice (1500 g) and DCM (3600 ml) were added. To the stirred mixture was added 32% HCl (aq) (2400 ml) until the pH was adjusted to pH 1-2. The biphasic mixture was separated, extracted with DCM (1500 ml) and the organic extracts washed with brine/water 4:1 (2000 ml), dried over MgSO4 and evaporated to dryness to give a dark solid. To a stirred solution of the crude product in DCM (2000 ml) was added silica gel (350 g). This was filtered and the filtrate was evaporated. Purification by chromatography with MeOH in EtOAc gave the title compound as a light yellow solid.
Reaction SMILES: Br.[NH:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH2:3]1.Br.N1CCC[C@H](C2N3C4C=CNC=4N=CC3=NC=2)C1.CCN(C(C)C)C(C)C.[F:48][C:49]1([F:56])[CH2:52][CH:51]([C:53](O)=[O:54])[CH2:50]1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:19]1[C:13]2[N:12]3[C:8]([C@@H:4]4[CH2:5][CH2:6][CH2:7][N:2]([C:53]([CH:51]5[CH2:52][C:49]([F:56])([F:48])[CH2:50]5)=[O:54])[CH2:3]4)=[CH:9][N:10]=[C:11]3[CH:16]=[N:15][C:14]=2[NH:17][CH:18]=1
Reactant: O=C(O)C1CC(F)(F)C1
Reactant: c1cc2c(ncc3ncc([C@@H]4CCCNC4)n32)[nH]1
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(C1CC(F)(F)C1)N1CCC[C@@H](c2cnc3cnc4[nH]ccc4n23)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 30 %

Procedure:
To a solution of (R)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine hydrobromide and (S)-8-(piperidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine hydrobromide [er=80:20](0.30 g, 0.93 mmol), DIEA (0.52 mL, 3.0 mmol) and 3,3-difluorocyclobutanecarboxylic acid (0.35 g, 3.1 mmol, Waterstone) in DMF (4 mL) was added EDC•HCl (0.21 g, 1.1 mmol). The reaction was stirred at about 25° C. for about 4 h. The reaction was partitioned with aqueous Na2CO3 (2 M, 25 mL) and DCM (25 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concd in vacuo. The resulting residue was purified on silica gel (12 g) using 0-5% MeOH in DCM followed by purification using General Procedure AA (Table 2, Method 23, Rt=16.4 min, or =positive) to give (R)-(3-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)piperidin-1-yl)(3,3-difluorocyclobutyl)-methanone (0.10 g, 30%): LC/MS (Table 1, Method b) Rt=1.85 min; MS m/z: 360 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19](=[NH:22])[NH:20][OH:21])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.O.[CH:35](=O)[CH3:36]>C(O)C>[CH:1]1([C:4]2[C:5]([N:24]([CH2:29][CH2:30][CH:31]([CH3:33])[CH3:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)=[C:9]([C:19]4[NH:22][CH:35]([CH3:36])[O:21][N:20]=4)[C:8]=3[CH:23]=2)[CH2:2][CH2:3]1
Reactant: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C(=N)NO)c2cc1C1CC1)S(C)(=O)=O
Reactant: CC=O
Solvent: O
Solvent: CCO
Product: CC(C)CCN(c1cc2oc(-c3ccc(F)cc3)c(C3=NOC(C)N3)c2cc1C1CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 144 h
Yield: 47.7 %

Procedure:
A mixture of Example 10F (0.040 g, 0.084 mmol) and Amberlite® IRP-64 H-form (0.010 g) in ethanol (1 mL) and H2O (0.5 mL) was treated with acetaldehyde (1 mL, 17.7 mmol) and stirred in a sealed microwave tube at room temperature for 6 days. The mixture was filtered through a bed of diatomaceous earth that was washed thoroughly with ethyl acetate. The filtrate was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on an Isco silica gel cartridge (12 g) eluting with a gradient of hexane to 3:1 hexane/ethyl acetate to afford the title compound as a white foam (0.020 g, 47%). 1H NMR (DMSO-d6) δ ppm 0.48-0.61 (m, 1H), 0.78-0.88 (7H), 1.00-1.05 (m, 2H), 1.22-1.31 (m, 1H), 1.38 (dd, J=5.04, 2.90 Hz, 4H), 1.55-1.66 (m, 1H), 2.34-2.44 (m, 1H), 3.13 (s, 3H), 3.59-3.79 (m, 2H), 5.74-5.80 (m, 1H), 7.22 (s, 1H), 7.30 (dd, J=4.20, 2.37 Hz, 1H), 7.42 (t, J=8.85 Hz, 2H), 7.88 (s, 1H), 8.00-8.04 (m, 2H); MS (ESI+) m/z 500 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:13])[CH:5]=[C:6](OC)[C:7]([F:10])([F:9])[F:8])C.[C:14]([O:18][CH3:19])(=[O:17])[CH2:15][SH:16].[OH-].[K+].OS(O)(=O)=O>CO.O>[CH3:19][O:18][C:14]([C:15]1[S:16][C:6]([C:7]([F:8])([F:9])[F:10])=[CH:5][C:4]=1[OH:13])=[O:17]
Reactant: COC(=O)CS
Reactant: CCOC(=O)C=C(OC)C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)c1sc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
A solution of 4,4,4-trifluoro-3-methoxy-but-2-enoic acid ethyl ester (9.6 g, 48.5 mmol) and methyl thioglycolate (4.3 mL, 48.5 mmol) in MeOH (75 mL) is cooled to 5° C. A solution of KOH (3.3 g, 58.2 mmol) in MeOH (75 mL) is then added over 30 min. The reaction mixture is stirred overnight at room temperature. The reaction mixture is then poured over a stirred mixture of ice (75 g), H2O (75 mL) and concentrated H2SO4 (4.5 mL). The mixture is extracted with EtOAc (2×250 mL). The combined extracts are washed with saturated NaHCO3. The washings are back-extracted with EtOAc. The combined organic layers are washed with brine, then dried (Na2SO4), filtered and concentrated to afford the title compound (10 g, 91%) as a brown oil which is used without further purification.
Reaction SMILES: [CH:1](=[O:5])[CH:2]([CH3:4])[CH3:3].C(O)C.[F:9][C:10]([F:14])([F:13])[S:11]Cl>ClCCl>[F:9][C:10]([F:14])([F:13])[S:11][C:2]([CH3:4])([CH3:3])[CH:1]=[O:5]
Reactant: FC(F)(F)SCl
Reactant: CC(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C=O)SC(F)(F)F
Temperature: -78 °C

Procedure:
A mixture of isobutyraldehyde (0.25 mole), ethanol (0.4 g) and dichloromethane (75 ml) was placed in a three-necked flask fitted with a gas inlet tube, a Dry Ice condenser and a gas outlet tube connected to a gas trap cooled to -78°C. Trifluoromethanesulfenyl chloride (0.22 mole) was added to the cold solution which was maintained under a nitrogen atmosphere. (Caution: It should be noted that trifluoromethanesulfenyl chloride is a highly hazardous material which must be handled with care to avoid inhalation or contact with the skin.) The reaction mixture was then allowed to warm to about 25°C and stirred magnetically until the orange colored solution had become nearly colorless (about 6 hours). The reaction mixture was then distilled. The distillation assembly was connected to a -78°C gas trap to trap any unreacted trifluoromethylsulfenyl chloride. The 2-trifluoromethylthio-2-methylpropionaldehyde, b.p. 108°-116°C was identified by spectral and elemental analyses of a purified sample, b.p. 116°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CC1C2C(=CC=CC=2)C=CC=1.[C-]#N.[Na+].[CH3:28][N:29]1C=CN=C1>[Cu]I.O>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:28]#[N:29])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: Cn1ccnc1
Agent: [Cu]I
Agent: [C-]#N
Agent: [Na+]
Solvent: Cc1cccc2ccccc12
Solvent: O
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 25 °C

Procedure:
A 100-mL, three-necked flask equipped with a mechanical stirrer, thermometer and condenser was charged with 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.0 g, 0.02 mol, 99.1% purity) and 1-methylnaphthalene (20 g) while maintaining a flow of nitrogen through a gas inlet line connected to the condenser. The reaction mixture was stirred at room temperature and sodium cyanide (ground to a powder just prior to use) (1.25 g, 0.024 mol, assuming 95% purity), copper(I) iodide (0.57 g, 0.003 mol, 98% purity) and 1-methyl-1H-imidazole (1.40 g, 0.017 mol, 99%) were added. The mixture was heated to between 160 and 165° C. for 6 h and then transferred to a 200-mL flask and allowed to cool overnight. Water (20 mL) was added dropwise to the reaction mixture over 5 minutes while stirring. After stirring for an additional 2 h, the reaction mixture was filtered and the collected solid was washed with water (3×10 mL) and xylenes (10 mL) and dried to a constant weight in a vacuum-oven at 80° C. to give the title compound as a light brown solid (3.85 g).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([OH:19])=O)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CN(C=O)C.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32]>C(N(CC)CC)C>[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C:17]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:19])=[CH:11]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)s2)c1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 3.8 g (E)-3-[1-(5-bromo-thiophene-2-sulfonyl)-1H-pyrrol-3-yl]-acrylic acid with 200 ml DMF and 1.6 g HOBtxH2O and 15.0 ml triethylamine is stirred at ambient temperature for 0.5 h. Then 6.04 g EDCxHCL are added and the suspension is stirred again for 0.5 h. Finally 1.23 g O-(tetrahydro-2H-pyran-2-yl)hydroxylamine are added and the suspension is stirred at ambient temperature for 24 h. The DMF is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is dried over sodium sulfate and evaporated. The title product is isolated by flash chromatography. By this method 4.6 g of a yellow foam are obtained.