Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[CH:3]1[C:11]([OH:13])=[O:12].COC(/C=C\C1(C(O)=O)CC1)=O.[C:27]([C@H:29](O)[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]=1)#[N:28]>>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:13][C@@H:29]([C:27]#[N:28])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:31]=1)=[O:12]
Reactant: COC(=O)/C=C\C1C(C(=O)O)C1(C)C
Reactant: N#C[C@H](O)c1cccc(Oc2ccccc2)c1
Agent: COC(=O)/C=C\C1(C(=O)O)CC1
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)O[C@@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step D of Example 1, 1.5 g of (1R, cis) 2,2-dimethyl-3-([Z-2-(methoxycarbonyl)-ethenyl]-cyclopropane carboxylic acid and 1.9 g of (R)α-cyano-3-phenoxybenzyl alcohol were reacted to obtain 4.3 g of raw product. The latter was chromatographed over silica gel and was eluted with a 9-1 cyclohexane-ethyl acetate mixture to obtain 2.5 g of (R)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[Z-2-(methoxycarbonyl)-ethenyl]-cyclopropane carboxylate with a specific rotation of [α]D20 =+23.5°±2.5° (c=0.5% in benzene).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([OH:13])=O)=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([Cl:16])=[O:13])=[CH:8][CH:9]=2)[N:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc2nccnc2c1
Solvent: C1CCOC1
Product: O=C(Cl)c1ccc2nccnc2c1

Procedure:
In a 1 l 3 neck flask was placed Quinoxaline-6-carboxylic acid (20.2 g) in 500 ml of THF. To this solution was slowly added thionylchloride (42 ml, Seq.). The reaction mechanically stirred was warmed up to reflux and followed by HPLC quenching the sample with NH4OH. After 3 h at reflux no more starting material was present, the solvent was removed under reduced pressure and SOCl2 was chased with toluene 3 times. The solid was suspended in 100 ml EtOAc and filtered to obtain 23.47 g of a beige solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([O:10][CH3:11])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[ClH:12]>CO.[Pd]>[ClH:12].[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH:3]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ncccc1C
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)C1NCCCC1C

Procedure:
To a solution of methyl 3-methylpicolinate (5 g) and 36% HCl (2 eq) in methanol was added 10% Pd/C. The Parr shaker bottle was evacuated/H2 purged 3×, and then shaken at 50 psi until starting material was consumed (typically <1 h). The reaction was filtered through diatomaceous earth and concentrated to yield methyl 3-methylpiperidine-2-carboxylate hydrochloride salt without further purification. To a suspension of LiAlH4 (4 eq) in THF (40 ml) was added in portions the above crude salt at 0° C. The reaction was allowed to stir to rt overnight and then refluxed for 2 h. The reaction mixture was then quenched with saturated Na2SO4 at 0° C. and stirred for 1 h. The reaction mixture was filtered and concentrated in vacuo to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz) δ 3.4 (m, 2H), 2.9 (m, 1H), 2.8 (m, 1H), 2.6 (m, 1H), 1.7 (m, 1H), 1.6-1.4 (m, 4H), 0.8 (d, 3H).
Reaction SMILES: C(O[C:9]([N:11]([CH2:13][CH2:14][CH2:15][C:16]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[O:17])C)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:19]([NH:18][C:16](=[O:17])[CH2:15][CH2:14][CH2:13][NH:11][CH3:9])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: [H][H]
Reactant: CCCCCCNC(=O)CCCN(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCNC(=O)CCCNC

Procedure:
A solution of the 4-(N-benzyloxycarbonyl-N-methylamino)-N-n-hexylbutyramide thus obtained (6.6 g.) in ethanol (100 ml.) was shaken with hydrogen in the presence of a 10% palladium-on-charcoal catalyst (0.6 g.) for 18 hours, filtered and evaporated to dryness. There was thus obtained as residual oil N-n-hexyl-4-methylaminobutyramide.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][OH:12])=[N:9][CH:10]=1)[CH3:3].CC1(C)N([O])C(C)(C)CCC1.ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>CC(C)=O>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]=[O:12])=[N:9][CH:10]=1)[CH3:1]
Reactant: CC(C)Oc1ccc(CO)nc1
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: CC(C)=O
Product: CC(C)Oc1ccc(C=O)nc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 76.4 %

Procedure:
[5-(1-Methylethoxy)pyridin-2-yl]methanol (30 mg, 0.198 mmol) was dissolved in acetone (2.0 mL). The resultant mixture was added with 2,2,6,6-tetramethylpiperidine 1-oxyl (3.1 mg, 0.020 mmol) and trichloroisocyanuric acid (50 mg, 0.218 mmol) under ice-cold conditions, and stirred at 0° C. for 5 minutes. The reaction solution was concentrated in vacuo, added with an aqueous solution of sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using silica-gel column chromatography (hexane/ethyl acetate), and 5-(1-methylethoxy)picolinaldehyde (25 mg, yield 85%) was obtained as a yellow oil.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([OH:14])=O)[CH2:7][CH3:8].C[Si](C)(C)NC(=O)C.O.O.Cl.[Cl-].[NH2:33][CH:34]1[C:51](=[O:52])[N:36]2[C:37]([C:48]([OH:50])=[O:49])=[C:38]([CH2:41][N+:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:39][S:40][C@H:35]12>O1CCCC1.C(OCC)(=O)C.O.CN(C)C=O>[CH2:6]([O:9][N:10]=[C:11]([C:15]1[N:16]=[C:17]([NH2:20])[S:18][CH:19]=1)[C:12]([NH:33][CH:34]1[C:51](=[O:52])[N:36]2[C:37]([C:48]([O-:50])=[O:49])=[C:38]([CH2:41][N+:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH2:39][S:40][C@H:35]12)=[O:14])[CH2:7][CH3:8]
Reactant: CCCON=C(C(=O)O)c1csc(N)n1
Reactant: NC1C(=O)N2C(C(=O)O)=C(C[n+]3ccccc3)CS[C@H]12
Agent: CC(=O)N[Si](C)(C)C
Agent: Cl
Agent: [Cl-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccccc3)CS[C@H]12)c1csc(N)n1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (1.7 g) was added to a stirred suspension of 2-propoxyimino-2-(2-aminothiazol-4-yl)acetic acid (syn isomer) (2.0 g) in dry tetrahydrofuran (20 ml) and water (0.114 g) at 0° to 3° C. and the resulting mixture was stirred for 30 minutes and thereto was added N-trimethylsilylacetamide (1.2 g) at the same temperature. The resulting mixture was stirred for 15 minutes and thereto was added phosphorus oxychloride (1.7 g) at the same temperature and then stirred for 15 minutes. To the resulting mixture was added dry N,N-dimethylformamide (0.9 g) at the same temperature and then stirred for 30 minutes [Solution A]. N-trimethylsilylacetamide (11.4 g) was added to a stirred suspension of 1-[(7-amino-4-carboxy-3-cephem-3-yl)methyl]pyridinium chloride hydrochloride dihydrate (3.5 g) in tetrahydrofuran (70 ml). To the resulting solution was dropwise added the Solution A at -5° C. and stirred at 0° to -5° C. for 40 minutes. To the reaction mixture was added water and ethyl acetate at -5° C. The aqueous layer was separated, washed with ethyl acetate and then adjusted to pH 4.0 with 10% aqueous solution of sodium hydroxide under ice-cooling. The solution was subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark: Prepared by Mitsubishi Chemical Industries) and eluted with 20% aqueous solution of isopropyl alcohol. The fractions containing the object compound were collected, concentrated and lyophilized to give 7-[2-propoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-(1-pyridiniomethyl)-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [OH:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]3[C:13]4([CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH:9]([CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]4)[CH2:8][CH2:7]3.C(=O)([O-])[O-].[K+].[K+].[CH2:27](Cl)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.[I-].[Na+]>CN(C=O)C>[CH2:27]([O:1][C:2]1[CH:20]=[CH:19][C:5]2[CH:6]3[C:13]4([CH2:14][CH2:15][C:4]=2[CH:3]=1)[CH:9]([CH2:10][N:11]([C:16](=[O:18])[CH3:17])[CH2:12]4)[CH2:8][CH2:7]3)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)N1CC2CCC3c4ccc(O)cc4CCC23C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CC2CCC3c4ccc(OCc5ccccc5)cc4CCC23C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 41.1 %

Procedure:
1-(2-Hydroxy-5,6,6a,7,10,11-hexahydro-4bH-benzo[4,5]indeno[1,7a-c]pyrrol-8-yl)-ethanone (Example 5B) (10.0 mg, 0.037 mmol) and potassium carbonate (25 mg, 0.18 mmol) were dissolved in DMF (0.5 mL). Benzyl chloride (10.2 μL, 0.088 mmol) and sodium iodide (5 mg) were added. The mixture was stirred at rt for 24 hr, quenched with water (2 mL), and extracted with CH2Cl2 (5 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 5% methanol in dichloromethane, providing 5.5 mg (41.3%) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][C:5]([NH2:13])=[C:4]([NH2:14])[CH:3]=1.[C:15](=S)=[S:16].[OH-].[K+].C>C(O)C.O>[F:1][C:2]1[C:7]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:6][C:5]2[N:13]=[C:15]([SH:16])[NH:14][C:4]=2[CH:3]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(-n2ccnc2)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1cc2[nH]c(S)nc2cc1-n1ccnc1

Procedure:
The diamine (6.7 g, 0.035 mol) (obtained in step 4 above) was dissolved in ethanol (20 mL) and added to a stirred mixture of carbon disulfide (3.0 g, 0.04 mol), potassium hydroxide (2.3 g, 0.04 mol), water (5 mL) and ethanol (15 mL). The resultant solution was refluxed for 6 h. Animal charcoal (2.0 g) was added and further refluxed for 1 h. The mixture was filtered and washed with hot water. A mixture of acetic acid and water (1:2, 15 mL) was added to the filtrate slowly with vigorous stirring to separate 6-fluoro-5-(imidazol-1-yl)-2-mercapto-1H-benzimidazole (5.0 g, 60%) as a brown solid. mp 280° C. (decomp.); IR (KBr) 3078, 1481 cm-1 ; 1H NMR (DMSO-d6) δ 2.20 (s, 1H, SH), 7.10 (s, 1H), 7.24 (d, J=6.0 Hz, 1H), 7.26 (d, J=4.1 Hz, 1H), 7.56 (s, 1H), 8.00 (s, 1H), 12.90 (brs, 1H, NH); Mass (m/z) 234 (M+.).
Reaction SMILES: [CH:1]1([C:4]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=2)(O)[CH:5]=[CH2:6])[CH2:3][CH2:2]1.N1C=CC=CC=1.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:6][CH:5]=[C:4]([CH:1]1[CH2:3][CH2:2]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1
Reactant: C=CC(O)(c1ccc(OC(F)(F)F)cc1)C1CC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(C(=CCCl)C2CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Under a nitrogen atmosphere a solution of 130.0 grams (0.5 mole) of 1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-2-propen-1-ol and 49.3 grams (0.54 mole) of pyridine in 500 mL of methylene chloride was stirred, and 60.2 grams of thionyl chloride was added dropwise during a 30 minute period. The reaction mixture was maintained at 0° to 10° C. throughout the addition. Upon completion of addition the reaction mixture was stirred for 1 hour and then was diluted with 500 mL of methylene chloride and 500 mL of ice. The mixture was stirred until the ice melted. The organic layer was separated and was in turn washed with two 500 mL portions of aqueous 0.5N hydrochloric acid, two 500 mL portions of an aqueous solution saturated with sodium bicarbonate, two 500 mL portions of water, and two 500 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 113.5 grams of 3-chloro-1-cyclopropyl-1-(4-trifluoromethoxyphenyl)-1-propene.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=[CH:18][C:19]1[CH:29]=[CH:28][CH:27]=[CH:26][C:20]=1[O:21][CH2:22][CH:23]1[CH2:25][O:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][CH3:32]>O1CCCC1>[CH3:30][N:31]([CH3:32])[CH2:25][CH:23]([OH:24])[CH2:22][O:21][C:20]1[CH:26]=[CH:27][CH:28]=[CH:29][C:19]=1[CH:18]=[CH:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC
Reactant: C(=Cc1ccccc1OCC1CO1)CCc1ccccc1OCc1ccccc1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1C=CCCc1ccccc1OCc1ccccc1

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 328 mg of 2-{2-[4-(2-benzyloxyphenyl)-1-buten-1-yl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 5 ml of tetrahydrofuran was treated with 3 ml of 50% by volume aqueous dimethylamine. The crude product was purified as described in Example 1(b), to give 3-dimethylamino-1-{2-[4-(2-benzyloxyphenyl)-1-buten-1-yl]phenoxy}-2-propanol as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:8][C:9]([C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=1)=[O:10])[CH:5]([CH3:7])[CH3:6].[K+].[Br-]>>[F:32][C:29]1[CH:28]=[CH:27][C:26]([NH:25][C:23](=[O:24])[NH:22][C:19]2[CH:18]=[CH:17][C:16]([C:13]3[CH:12]=[C:11]([C:9]([NH:8][C@@H:4]([CH:5]([CH3:6])[CH3:7])[C:3]([OH:33])=[O:2])=[O:10])[O:15][N:14]=3)=[CH:21][CH:20]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)[C@@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1)C(C)C
Agent: [Br-]
Agent: [K+]
Product: CC(C)[C@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccc(F)cc3)cc2)no1)C(=O)O
Yield: 42 %

Procedure:
The title compound was prepared from (S)-2-[(3-{4-[3-(4-Fluoro-phenyl)-ureido]-phenyl}-isoxazole-5-carbonyl)-amino]-3-methyl-butyric acid methyl ester using the procedure as set forth in Example 8 and was obtained in 42% yield. Mass (ES+): 441 (M++1); IR (KBr): 3316 (br), 1718, 1668 (br), 1612, 1600, 1552, 1510; 1H NMR (DMSO-d6) δ: 0.95 (2×d, 6H), 2.20 (m, 1H), 4.27 (q, 2H), 7.12 (t, 2H), 7.46 (m, 2H), 7.60 (d, 2H), 7.68 (s, 1H), 7.82 (d, 2H), 8.79 (s, 1H), 8.93 (s, 1H), 8.95 (d, 1H).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH:10]([CH:11]([CH3:13])[CH3:12])[CH2:9][CH2:8][CH:7]([CH3:14])[CH2:6]1)=[O:3].[N:15]1C=CC=[CH:17][CH:16]=1.C(N)C.Cl>C1(C)C=CC=CC=1.O>[CH:11]([C@@H:10]1[CH2:9][CH2:8][C@@H:7]([CH3:14])[CH2:6][C@H:5]1[O:4][C:2](=[O:3])[NH:15][CH2:16][CH3:17])([CH3:13])[CH3:12]
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Reactant: c1ccncc1
Agent: CCN
Agent: Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CCNC(=O)O[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
58.7 g of menthyl chloroformate (80% in toluene) were added to a mixture of 16.6 g of pyridine and 150 mL ethylamine (2M solution in THF) in 100 mL toluene at 0° C. over a period of 30 minutes. After stirring for 12 hours at room temperature, 100 mL of 2M HCl and subsequently 50 mL water were added, the phases separated and the water phase discarded. After washing with saturated NaHCO3-solution and water the organic phase was dried and evaporated to yield 47.1 g of crude product which was recrystallized from 82.4 g n-heptane to give 24.4 g of the analytically pure product as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[CH:4][N:3]=1.N1C=CN=C1.[CH3:15][C:16]([Si:19](Cl)([CH3:21])[CH3:20])([CH3:18])[CH3:17]>CN(C=O)C.O.CCOC(C)=O>[Br:1][C:2]1[C:7]([CH2:8][O:9][Si:19]([C:16]([CH3:18])([CH3:17])[CH3:15])([CH3:21])[CH3:20])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccnc1Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a mixture of (2-bromopyridin-3-yl)methanol (20.0 g, 106.4 mmol, 1 eq.; refer to example 14) and imidazole (14.5 g, 212.8 mmol, 2 eq.) in DMF (50.0 mL) was added TBSCl (19.2 g, 150.7 mmol, 1.2 eq.) at RT. The mixture was stirred at RT for 1 h and diluted with a mixture of water (100 mL) and EtOAc (300 mL). The organic layer was washed with NH4Cl(sat.) solution and brine, dried over Na2SO4, concentrated, and purified on silica gel using 10% EtOAc/hexanes as eluent to give 2-bromo-3-((tert-butyldimethylsilyloxy)methyl)pyridine (30.1 g, 94%) as a colorless oil. MS (ESI) m/z 302.0 [M+H]+.
Reaction SMILES: CO[C:3](=O)[CH2:4][NH:5][C:6](=[O:37])[C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])=[CH:9][C:8]=1[Cl:36].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.NCC[S:75]([OH:78])(=[O:77])=[O:76]>CN(C)C=O>[Cl:36][C:8]1[CH:9]=[C:10]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[C:21]([N:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH:33]3[CH2:35][CH2:34]3)[CH2:25][CH2:24]2)=[O:22])[C:11]([Cl:13])=[CH:12][C:7]=1[C:6]([NH:5][CH2:4][CH2:3][S:75]([OH:78])(=[O:77])=[O:76])=[O:37]
Reactant: NCCS(=O)(=O)O
Reactant: COC(=O)CNC(=O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
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: O=C(NCCS(=O)(=O)O)c1cc(Cl)c(Oc2ccncc2C(=O)N2CCN(C3CC3)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 59 %

Procedure:
To a solution of 0.127 g (0.26 mmol) 2,5-dichloro-4-[3-(4-cyclopropyl-3,4-dihydro-2H-quinoxaline-1-carbonyl)-pyridin-4-yloxy]-benzoic acid (Example 29, intermediate) in 1.5 mL N,N-dimethylformamide were added 0.10 g (0.26 mmol) O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, commercially available, CAS RN 148893-10-1) and 0.13 mL (0.79 mmol) N,N-diisopropylethylamine. To the yellow solution 0.036 g (0.29 mmol) taurine (commercially available, CAS RN 107-35-7) was added and the reaction mixture stirred at room temperature for 4.5 hours. The solution was filtered using a syringe micro filter and purified on a preparative HPLC system (Phenomenex Gemini column) with a gradient of acetonitrile:water (containing 0.05% formic acid) (10:90 to 98:2) to give 0.092 g (59%) of the title compound as a brown solid. MS (ESI): m/z=591.086 [M+H]+.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[F:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13](I)[C:9]=1[C:10]([OH:12])=[O:11].[NH:19]1[CH:23]=[CH:22][N:21]=[N:20]1>CN(C=O)C>[F:7][C:8]1[C:16]([CH3:17])=[CH:15][CH:14]=[C:13]([N:20]2[N:21]=[CH:22][CH:23]=[N:19]2)[C:9]=1[C:10]([OH:12])=[O:11]
Reactant: Cc1ccc(I)c(C(=O)O)c1F
Reactant: c1c[nH]nn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2nccn2)c(C(=O)O)c1F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
The title compound was prepared in analogy to the procedure described in WO2008/069997. Cs2CO3 (6.98 g, 21.4 mmol) was added portionwise to a RT solution of 2-fluoro-6-iodo-3-methyl-benzoic acid (3.0 g, 10.7 mmol) in DMF (15 mL) under argon followed by 1H-1,2,3-triazole (1.24 mL, 21.4 mmol) and Cu(I)I (103 mg, 0.536 mmol) and the resulting blue suspension was stirred at 80° C. overnight. The reaction mixture was quenched with 2M aq. HCl and filtered through a celite plug before being extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a pale yellow solid. LC-MS B: tR=0.55 min; [M+H]+=222.01.
Reaction SMILES: [F:1][CH:2]([F:20])[CH:3]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][C:5](=[CH2:8])[CH2:6]Br.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:1][CH:2]([F:20])[CH:3]([N:9]1[C:13](=[O:14])[C:12]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]2[C:10]1=[O:19])[CH2:4][C:5](=[CH2:8])[CH2:6][N:25]1[C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]2[C:21]1=[O:31]
Reactant: C=C(CBr)CC(C(F)F)N1C(=O)c2ccccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: C=C(CC(C(F)F)N1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O

Procedure:
A mixture of 1,1-difluoro-2-phthalimido-4-methylene-5-bromo-pentane (impure, evaluated 67 mmoles) prepared as in Step C above, and potassium phthalimide (13.9 g, 75 mmoles) is heated at 75° C. in dry N,N-dimethylformamide (DMF) (100 mL) for 3 hours. After removal of the DMF under vacuum, the residue is dissolved in chloroform and extracted with 1 N potassium hydroxide and three times with water. Work-up as described in Example 1(D) affords a colored oil (30 g, containing solvents) which is chromatographed on silica gel (petroleum ether/ether acetate: 70/30). The oil obtained (11.3 g) is crystallized from chloroform/ether/petroleum ether to give 1,1-difluoro-2,5-diphthalimido-4-methylene-pentane slightly contaminated (about 15%) by 1,1-difluoro-2,5-diphthalimido-4-methyl-3-pentene (7.9 g of mixture, yield based on 1,1-difluoro-2-phthalimido-4-methyl-4-pentene: 29%).
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]1[CH2:8][CH:7]([CH2:9][N:10]2[CH2:15][CH2:14][CH2:13][NH:12][C:11]2=[N:16][N+:17]([O-:19])=[O:18])[CH2:6][O:5]1.[C:20](Cl)(=[O:22])[CH3:21]>C(#N)C>[CH3:21][C:20]([N:12]1[CH2:13][CH2:14][CH2:15][N:10]([CH2:9][CH:7]2[CH2:6][O:5][CH:4]([CH3:3])[CH2:8]2)[C:11]1=[N:16][N+:17]([O-:19])=[O:18])=[O:22]
Reactant: CC1CC(CN2CCCNC2=N[N+](=O)[O-])CO1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)N1CCCN(CC2COC(C)C2)C1=N[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a suspension of 0.20 g of sodium hydride (60%, oily) in 30 ml of acetonitrile was added a solution of 1.00 g of 1-[(2-methyl-4-tetrahydrofuryl)methyl]-2-(nitroimino) hexahydropyrimidine in 5 ml of acetonitrile at room temperature, followed by stirring for 30 minutes. Next, to the mixture was added a solution of 0.39 g of acetyl chloride in 5 ml of acetonitrile under ice-cooling, and the mixture was then stirred under ice-cooling for 30 minutes and at room temperature for 3 hours. Afterward, insolubles were removed by filtration, and the filtrate was then concentrated under a reduced pressure. The resultant oily substance was purified by silica gel column chromatography (20:1 chloroform/methanol) to obtain 1.15 g of 1-(methylcarbonyl)-3-[(2-methyl-4-tetrahydrofuryl) methyl]-2-(nitroimino)hexahydropyrimidine as a yellow oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([Si](C)(C)C)#[N:9].[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N+:32]=3[O-])[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]>C(#N)C>[CH2:14]([O:16][C:17]1[CH:18]=[C:19]([C:26]2[S:27][CH:28]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([C:8]#[N:9])[N:32]=3)[N:30]=2)[CH:20]=[CH:21][C:22]=1[O:23][CH2:24][CH3:25])[CH3:15]
Reactant: CCOc1ccc(-c2nc(-c3cccc[n+]3[O-])cs2)cc1OCC
Reactant: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOc1ccc(-c2nc(-c3cccc(C#N)n3)cs2)cc1OCC

Procedure:
21.3 ml of triethylamine and 30.7 ml of cyanotrimethylsilane were added to a suspension of 26.3 g of 2-[2-(3,4-diethoxyphenyl)-4-thiazolyl]pyridine-1-oxide in 500 ml of acetonitrile. The mixture was refluxed for 62 hours. The solvent in the reaction mixture was removed by distillation. To the residue was added an aqueous sodium carbonate solution. The mixture was subjected to extraction with methylene chloride. The methylene chloride layer was dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by silica gel column chromatography (elutant: methylene chloride) and recrystallized from ethanol to obtain 22.2 g of 2-(3,4-diethoxyphenyl)-4-(6-cyano-2-pyridyl)thiazole.