Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13]([NH2:15])=[O:14])=[C:4]([F:16])[CH:3]=1.[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([NH:12][C:13](=[O:14])[NH:15][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[C:4]([F:16])[CH:3]=1
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CC(C)Oc1cc(NC(N)=O)c(F)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1=C(NC(=O)Nc2cc(OC(C)C)c(Cl)cc2F)CCC1

Procedure:
7.00 g of 4-chloro-2-fluoro-5-isopropoxyphenylurea and 4.44 g of ethyl cyclopentanone-2-carboxylate are heated at reflux temperature for 1.5 hours with 0.3 g of toluene-4-sulphonic acid monohydrate in 150 ml of benzene. The water which forms is removed with a water separator. The reaction mixture is subsequently evaporated to dryness and the residue is purified by chromatography on a silica gel column using methylene chloride as the eluent and recrystallized from diethyl ether/n-hexane. There is obtained ethyl 2-[3-(4-chloro-2-fluoro-5 -isopropoxyphenyl)-ureido]-1-cyclopentenecarboxylate, m.p. 166°-169° C.
Reaction SMILES: [CH3:1][C:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:4]=2[N:3]=1.Br[C:19]1[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=1[CH2:26]C>>[CH3:1][CH:2]1[O:17][C:11]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:5]2[CH:6]=[C:7]([C:19]3[S:23][C:22]([C:24]#[N:25])=[CH:21][C:20]=3[CH3:26])[CH:8]=[CH:9][C:4]=2[NH:3]1
Reactant: CCc1cc(C#N)sc1Br
Reactant: CC1=Nc2ccc(Br)cc2C2(CCCCC2)O1
Product: Cc1cc(C#N)sc1-c1ccc2c(c1)C1(CCCCC1)OC(C)N2

Procedure:
The title compound was prepared according to the procedure for Example 13 from 2-methyl-6-bromospiro[4H-3,1-benzoxazine-4,1′-cyclohexane] and 5-bromo-4-ethyl-2-thiophenecarbonitrile. A brown solid: 1H-NMR (DMSO-d6) δ 7.78 (s, 1H), 7.17 (d, 1H, J=1.8 Hz), 7.14 (dd, 1H, J=8.4, 2.2 Hz), 6.64 (s, 1H), 6.63 (d, 1H, J=82 Hz), 4.74 (m, 1H), 2.26 (s, 3H), 2.14 (m, 1H), 1.87 (m, 1H), 1.4-1.7 (m, 8H), 1.31 d, 3H, J=5.3 Hz); MS (ESI) m/z 337 [M−-H]−.
Reaction SMILES: C(O)C.[CH3:4][C:5]([CH3:46])([CH:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)=[CH:30][CH:29]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:12][CH:11]=1)[C:6]([OH:8])=[O:7].[OH-].[Na+:48]>C1COCC1>[Na+:48].[CH3:4][C:5]([CH3:46])([CH:9]([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]2[CH:45]=[CH:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=2)=[CH:30][CH:29]=1)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)=[CH:12][CH:11]=1)[C:6]([O-:8])=[O:7]
Reactant: CC(C)(C(=O)O)C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C(=O)[O-])C(c1ccc(OCc2ccc3ccccc3n2)cc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a solution in THF (10 mL) and ethanol (8 mL) of 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid (0.128 g, 0.225 mmol), prepared as in step 3, was added one equivalent of NaOH (2.3 mL, 0.1N NaOH). The reaction was stirred for 1 hour at room temperature, concentrated, and dried under high vacuum to provide 2,2-dimethyl-3,3-bis(4-(2-quinolylmethoxy)phenyl)propionic acid sodium salt as a white powder 0.13 g (99%): mp 250°-255° C. (dec); 1H NMR (300 MHz, DMSO-d6) d 0.91 (s, 6H), 4.46 (s, 1H), 5.29 (s, 4H), 6.87 (d, 4H, J=9 Hz), 7.15 (d, 4H, J=9 Hz), 7.61 (m, 2H), 7.67 (d, 4H, J=9 Hz), 7.78 (m, 2H), 8.00 (t, 4H, J=9 Hz), 8.40 (d, 2H, J=9 Hz); MS m/e (FAB+) 569 (M+H)+, (FAB-) 567 (M-H)-. Anal. Calc'd. for C37H31N2O4Na.0.5 H2O: C, 74.10; H, 5.37; N 4.67. Found C, 74.02; H, 5.24; N, 4.50.
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][N:7]2[C:13]=1[C:14]([O:16]CC)=[O:15])[CH2:2][CH3:3].[OH-].[Na+]>C(O)C>[CH2:1]([C:4]1[N:5]=[C:6]2[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][N:7]2[C:13]=1[C:14]([OH:16])=[O:15])[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cccn2c1C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1nc2c(C)cccn2c1C(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
21.0 g (86 mMol) of 2-n-propyl-3-ethoxycarbonyl-8-methylimidazo[1,2-a]pyridine are dissolved in 200 ml of ethanol, mixed with 100 ml of 2N sodium hydroxide solution and stirred for 4 days at ambient temperature. The solvent is evaporated off in vacuo at 40° C., the residue is diluted with water and combined with 20 g of ammonium chloride. The pH is adjusted to 6.5 by the addition of glacial acetic acid. After 2 hours, the precipitate formed is suction filtered, washed with water and dried in vacuo at 40° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[C:18]([N+:26]([O-])=O)[CH:17]=2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+]>CO.O.[Zn]>[NH2:26][C:18]1[CH:17]=[C:16]([CH:7]([CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:8]([NH:10][C:11]2[S:12][CH:13]=[CH:14][N:15]=2)=[O:9])[CH:21]=[CH:20][C:19]=1[S:22]([CH3:25])(=[O:23])=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1[N+](=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1N
Temperature: 25 °C
Yield: 43.1 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-thiazol-2-yl-propionamide (prepared as in Example 67, 100 mg, 0.236 mmol) in methanol (2 mL) was treated with a solution of ammonium chloride (27 mg, 0.500 mmol) in water (200 μL). The reaction mixture was then treated with zinc dust (151 mg, 2.31 mmol). The reaction mixture was heated under reflux for 2 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The celite pad was washed well with methanol. The filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/1 hexanes/ethyl acetate) afforded 2-(3-amino-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide (40 mg, 43%) as a white solid: mp 207-209° C.; EI-HRMS m/e calcd for C18H23N3O3S2 (M+) 393.1181, found 393.1180.
Reaction SMILES: [C:1]12([O:11][C:12]3[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:19](OCC)=[O:20]>>[CH:19]([NH:16][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:1]23[CH2:8][CH:7]4[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]4)[CH2:2]2)[CH2:10]3)=[CH:18][CH:17]=1)=[O:20]
Reactant: Nc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC=O
Product: O=CNc1ccc(OC23CC4CC(CC(C4)C2)C3)cc1

Procedure:
A suspension of 10.0 g. (0.041 mole) of p-(1-adamantyloxy)aniline in 60 ml. ethyl formate was stirred at reflux for 48 hours. The mixture was then taken to dryness and the residue recrystallized from Me2CO:cyclohexane. There was obtained 9.67 g. (87%) of the amide, N-formyl-p- (1-adamentyloxy)aniline m.p. 149°-150°.
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][CH:7]=[C:8]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2].O.C(=O)(O)[O-].[Na+]>Cl.CCO>[N+:1]([C:4]1[C:5]([C:21]#[N:22])=[N:6][CH:7]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][CH:11]=2)[CH:9]=1)([O-:3])=[O:2]
Reactant: N#Cc1ncc(-c2ccnn2C2CCCCO2)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1ncc(-c2ccn[nH]2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
3-Nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)picolinonitrile (8.77 mmol) was dissolved in 10% HCl (g) in EtOH (15 ml) and stirred at RT overnight. 20 ml of water was added to the reaction mixture, followed by addition of sat. sodium bicarbonate solution until pH was neutral. Thus resulting precipitate was filtered, washed with water and dried in vacuum to yield 1.76 g (93%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 7.22 (m, 1H), 7.98 (m, 1H), 8.99 (d, 1H), 9.50 (d, 1H), 13.5 (bs, 1H).
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][CH2:11][CH:12](O)[C:13]3[S:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][C:14]=3[C:8]=2[CH:7]=1.C1OCCOCCOCCOCCOCCOC1.[C-:44]#[N:45].[K+]>ClCCl.CC#N.O>[Br:5][C:6]1[CH:25]=[CH:24][C:9]2[O:10][CH2:11][CH:12]([C:44]#[N:45])[C:13]3[S:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:15][C:14]=3[C:8]=2[CH:7]=1
Reactant: CCOC(=O)c1nc2c(s1)C(O)COc1ccc(Br)cc1-2
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1nc2c(s1)C(C#N)COc1ccc(Br)cc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
Thionyl chloride (3 mL) was added dropwise to a stirred solution of ethyl 9-bromo-4-hydroxy-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate (600 mg, 1.61 mmol, 1.00 equiv) in dichloromethane (10 mL) at 0° C. After being stirred for 4 h at room temperature the resulting mixture was concentrated under vacuum. This resulted in 600 mg (95%) ethyl 9-bromo-4-chloro-4,5-dihydrobenzo[2,3]oxepino[4,5-d]thiazole-2-carboxylate as a yellow solid; LC-MS (ES, m/z) 388, 390 [M+H]+. A suspension this intermediate (600 mg, 1.54 mmol, 1.00 equiv), 18-crown-6 (320 mg, 1.21 mmol, 0.50 equiv) and KCN (524 mg, 8.05 mmol, 5.00 equiv) in CH3CN (10 mL) was stirred overnight at room temperature. The reaction solution was diluted with of 10 mL of water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column with ethyl acetate/petroleum ether (1:6) to give 206 mg (35%) of the titled compound as a yellow solid; LC-MS (ES, m/z) 379, 381 [M+H]+
Reaction SMILES: [Li][CH2:2][CH2:3]CC.C[O:7][C:8]([C:10]12[C:27](=O)[CH:14]([CH:15]([CH2:24][CH:25]=[CH2:26])[C:16]3[C:21]1=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[N:17]=3)[CH:13]=[C:12]([CH3:29])[CH2:11]2)=[O:9].N(C(C)(C)C#N)=NC(C)(C)C#N.C1(S)C=CC=CC=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C1COCC1.C1(C)C=CC=CC=1>[CH2:24]([CH:15]1[C:16]2=[N:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=[C:21]2[C:10]2([C:8]([OH:7])=[O:9])/[C:27](=[CH:2]/[CH3:3])/[CH:14]1[CH:13]=[C:12]([CH3:29])[CH2:11]2)[CH:25]=[CH2:26]
Reactant: [Li]CCCC
Reactant: C=CCC1c2nc(OC)ccc2C2(C(=O)OC)CC(C)=CC1C2=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Sc1ccccc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CCC1c2nc(OC)ccc2C2(C(=O)O)CC(C)=CC1/C2=C\C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (5.24 g, 14.1 mmol) in dry THF (50 mL), n-BuLi (4.8 mL, 12 mmol, 2.5M in hexane) was added within 10 min. The reaction mixture was stirred at rt for 1 h and then cooled to 0° C. A solution of β-ketoester 6a (981 mg, 3.0 mmol) in dry THF (10 mL) was added dropwise over a period of 15 min. The resulting mixture was allowed to warm to rt and stirred for an additional 3 h. The reaction was quenched with water, the THF was removed by rotary evaporation, and the aqueous residue was extracted with ethyl acetate. The extracts were washed with brine, dried, and concentrated. Flash chromatography (5% and then 10% ethyl acetate in hexane) gave 864 mg of the Z olefmation product. To a solution of this olefin (864 mg, 2.55 mmol) in dry toluene (10 mL) were added azobis(isobutyronitrile) (418 mg, 2.55 mmol) and thiophenol (0.52 mL, 5.1 mmol). The resulting solution was heated at 85° C. for 24 h. The toluene was removed by rotary evaporation, MeOH (4 mL), THF (2 mL), and 20% NaOH (2 mL) were added, and the resulting mixture was refluxed for 24 h. THF and MeOH were removed by rotary evaporation, and the aqueous residue was adjusted to a pH of ~7 with 6M HCl. Extraction with ethyl acetate, drying, and concentration gave the crude acid which was further purified by column chromatography (10% and then 80% ethyl acetate in hexanes) to afford 583 mg (60% overall) of the acid 7a as a mixture of diastereoisomers. Crystallization from acetone/hexane afforded 204 mg (21% overall) of the pure major isomer: IR (KBr) 3300-2500, 1703, 1271, 1031 cm-1 ; 1H NMR δ7.29 (d, 1H, J=8.5 Hz), 6.61 (d, 1H, J=8.5 Hz), 6.02 (m, 1H), 5.46 (m, 2H), 5.16 m, 2H), 3.93 (s, 3H), 3.50 (d, 1H, J=4.7 Hz), 2.97 (m, 2H), 2.70 (m, 1H), 2.16 (m, 2H), 1.75 (d, 3H) J=6.7 Hz), 1.55 (s, 3H); 13C NMR δ180.0, 162.7, 155.8, 137.9, 137.7, 134.5, 132.3, 128.8, 125.0, 117.0, 116.1, 108.7, 54.7, 53.3, 48.9, 45.4, 38.7, 35.6, 22.7, 13.6.
Reaction SMILES: [F-:1].[F-].[F-].C(N(SN(CC)CC)CC)C.[C:15]([CH:17]([C:19]1[S:20][CH:21]=[C:22]([CH2:24][O:25]C2CCCCO2)[N:23]=1)O)#[CH:16].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:1][CH:17]([C:19]1[S:20][CH:21]=[C:22]([CH2:24][OH:25])[N:23]=1)[C:15]#[CH:16]
Reactant: C#CC(O)c1nc(COC2CCCCO2)cs1
Reactant: [F-]
Agent: CCN(CC)SN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C#CC(F)c1nc(CO)cs1
Temperature: -55 °C
Reaction time: 2 h

Procedure:
0.53 ml of diethylaminosulfide trifluoride (DAST) were added at about -60° C. to a solution of 1 g of the product of Stage C and 5 ml of methylene chloride and the reaction mixture was stirred for 2 hours at -55° C. and poured into a solution of sodium bicarbonate. Extraction was carried out with methylene chloride and the extracts were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was taken up in 5 ml of methanol and 20 mg of toluene-sulfonic acid were added. The reaction mixture was stirred for one hour at 20° C., followed by evaporation to dryness. The residue was chromatographed on silica eluting with a hexane-ethyl acetate mixture (7-3) to obtain 0.16 g of the desired product with a Rf=0.10.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.[CH:12]([Mg]Br)=[CH2:13].[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[C:6]2[C:7]=1[NH:8][CH:13]=[CH:12]2
Reactant: C=C[Mg]Br
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc(F)c2[nH]ccc2c1
Reaction time: 1 h

Procedure:
To a solution of 3-fluoro-4-nitrotoluene (3.1 g) in tetra hydrofuran (160 mL) was added vinyl magnesium bromide (1.0 mol/L tetra hydrofuran solution, 60.0 mL) at −40° C., and the mixture was stirred at the same temperature for 1 hour. To the mixture was added a saturated aqueous ammonium chloride solution, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous ammonium chloride solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on amino-propylated silica gel (eluent: n-hexane/ethyl acetate=19/1-4/1) to give 7-fluoro-5-methyl-1H-indole (0.96 g). The title compound was prepared in a similar manner to that described in Reference Example 1 using this material instead of 4-methyl-1H-indole.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>ClCCl>[O:18]1[CH2:19][CH2:20][N:15]([S:2]([C:5]2[CH:6]=[C:7]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9](=[O:14])[CH2:8]3)(=[O:4])=[O:3])[CH2:16][CH2:17]1
Reactant: C1COCCN1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: ClCCl
Product: O=C1Cc2cc(S(=O)(=O)N3CCOCC3)ccc2N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.9 %

Procedure:
A suspension of 2.3 g of 5-chlorosulfonyl-2-oxindole and 2.2 g of morpholine in 50 mL of dichloromethane was stirred at room temperature for 3 hours. The white precipitate was collected by vacuum filtration, washed with ethyl acetate and hexane and dried under vacuum at 40° C. overnight to give 2.1 g (74% yield) of 5-(morpholinosulfonyl)-2-oxindole.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]([OH:21])=O)=[N:14][CH:15]=[C:16]([CH3:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].Cl.[CH3:27][O:28][NH:29][CH3:30]>C1COCC1>[CH3:27][O:28][N:29]([CH3:30])[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:22]([F:25])([F:23])[F:24])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([CH3:18])=[CH:15][N:14]=1)=[O:21]
Reactant: Cc1cnc(C(=O)O)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ncc(C)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
10.49 g (26.6 mmol) of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-5-methyl-pyridine-2-carboxylic acid was reacted with 5.40 g (33.2 mmol) of N,N′-carbonyldiimidazole in 40 mL of refluxing THF for 3 h. The temperature was lowered to 50° C., 2.86 g (29.3 mmol) of O,N-dimethyl-hydroxylamine hydrochloride was added and the reaction was stirred overnight at 50° C. Half of the solvent was removed under reduced pressure and the reaction mixture was diluted with 200 mL of cold water. The solids were filtered off, washed with 100 mL of water and dried to give 9.8 g (84%) of the product as a tan powder.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([C:9](F)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]=1[NH2:4].[BH4-].[Na+].C(O)(=O)C>CS(C)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:8]=[C:7]([CH:9]([C:10]([F:11])([F:12])[F:13])[C:14]([F:16])([F:17])[F:15])[C:6]([CH2:19][CH2:20][CH3:21])=[CH:5][C:3]=1[NH2:4]
Reactant: CCCc1cc(N)c(C)cc1C(F)(C(F)(F)F)C(F)(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCc1cc(N)c(C)cc1C(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 5 h
Yield: 98.2 %

Procedure:
2-Methyl-5-n-propyl-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]aniline (1.6 g, 5 mmol) was dissolved in dimethyl sulfoxide (20 ml), sodium borohydride (378 mg, 10 mmol) was added by small portions, and the mixture was stirred at 60° C. for 5 hr. Ice was added to the reaction mixture by small portions, and then acetic acid was added dropwise. The reaction mixture was diluted with ethyl acetate, and the organic layer was washed 4 times with water, dried over magnesium sulfate and concentrated under reduced pressure to give the desired compound (1.47 g).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1.CN(C(ON1N=[N:37][C:32]2[CH:33]=CC=N[C:31]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.CC(N)C>O>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:11]([NH:37][CH:32]([CH3:33])[CH3:31])=[O:13])=[CH:9][N:8]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(Br)cnc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
2-Bromo-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1.12 g, 3.01 mmol) and HATU (1.37 g, 3.61 mmol) were combined with DMF (5.2 mL) then propan-2-amine (711 mg, 1.03 mL, 12.0 mmol) was added via syringe. The reaction mixture was stirred at 25° C. After 14 h, water (50 mL) was added and the mixture extracted with EtOAc (4×50 mL). The combined organics were washed with water (30 mL), saturated sodium chloride solution (3×20 mL) and dried with MgSO4. Solvents were evaporated and the residue purified by chromatography (silica, 0 to 30% EtOAc in hexanes over 15 min) to yield 2-bromo-N-isopropyl-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (1.17 g, 2.83 mmol, 94%) as a white solid. MS (M+Na)+=435; 1H NMR (CDCl3) δ: 8.41 (s, 1H), 8.35 (s, 1H), 7.72 (d, J=4.9 Hz, 1H), 5.65 (s, 2H), 4.19-4.45 (m, 1H), 3.41-3.69 (m, 2H), 1.34 (d, J=6.8 Hz, 6H), 0.82-0.97 (m, 2H), −0.13-0.09 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH:9]1[C:24](O)=[O:25])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:28][O:29][NH2:30].CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:15])[CH2:10][CH:9]1[C:24](=[O:25])[NH:30][O:29][CH3:28])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CONC(=O)C1CN(C(=O)OCc2ccccc2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 4-benzyl ester 1-tert-butyl ester (0.364 g, 1 mmol) in dichloromethane (3 mL) was added O-Methyl Hydroxylamine HCl (95 mg, 1.13 mmol), EDC HCl (0.3 g, 1.57 mmol) and DIEA (0.28 g, 2.17 mmol). The resulting mixture was stirred at room temperature overnight and partitioned between dichloromethane and water. The combined organic extracts were washed with brine, dried, and evaporated. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc/n-Hexane (30/70) to afford the title product.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][N:23]([CH:26]=[O:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[OH-].[Li+]>>[C:28]1([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([CH:20]3[CH2:21][CH2:22][N:23]([CH:26]=[O:27])[CH2:24][CH2:25]3)[C:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[CH:8]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH:29]=1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)C1CCN(C=O)CC1
Agent: [Li+]
Agent: [OH-]
Product: C[C@H]1CC[C@H](C(=O)N(c2cc(C3=CCCCC3)sc2C(=O)O)C2CCN(C=O)CC2)CC1

Procedure:
5-Cyclohex-1-enyl-3-[(1-formyl-piperidin-4-yl)-(trans-4-methyl-cyclohexane-carbonyl)-amino]-thiophene-2-carboxylic acid methyl ester was hydrolysed with lithium hydroxide according to previously described procedures (example 3, step VIII) to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:15][C:16]1[CH:17]=[C:18]2[C:23](=O)[O:22][C:20](=[O:21])[C:19]2=[CH:25][CH:26]=1>>[CH3:15][C:16]1[CH:17]=[C:18]2[C:19](=[CH:25][CH:26]=1)[C:20](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:23]2=[O:22]
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Product: CCOC(=O)C(CN1C(=O)c2ccc(C)cc2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(5-methyl-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.38 g, 40%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.60 g, 3.25 mmol) and 4-methylphthalic anhydride (0.79 g, 4.87 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH:9][C:10](=O)[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.N>CO.ClCCl>[CH3:11][C:10]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][CH2:8][N:9]=1
Reactant: CC(=O)NCCc1ccccc1
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CC1=NCCc2ccccc21
Temperature: 0 °C
Yield: 86.4 %

Procedure:
8.43 g of the compound(51.6 mM) prepared in Step 1 above was added to 84.36 g of polyphosporic acid, which was reacted at 160° C. for 1.5 hours with stirring. The reaction solution was poured into ice water, neutralized with ammonia water, and extracted from ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. The residue thus obtained was subjected to silica gel column chromatography using a mixed solvent of methanol:dichloromethane (1:20 (v/v)) as a developing solvent to give 6.48 g of the title compound as oily substance.