Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:52][CH3:53])[C:22](=O)[CH2:23][C@@H:24]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][C:35]=1[S:44]([C:47]([F:50])([F:49])[F:48])(=[O:46])=[O:45])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.C1COCC1>C1COCC1.N.CO>[Si:1]([O:18][CH2:19][CH2:20][N:21]([CH2:52][CH3:53])[CH2:22][CH2:23][C@@H:24]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:41])(=[O:42])=[O:43])=[CH:36][C:35]=1[S:44]([C:47]([F:49])([F:50])[F:48])(=[O:45])=[O:46])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:14]([CH3:16])([CH3:15])[CH3:17])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)C[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Agent: B
Agent: N
Solvent: CO
Solvent: C1CCOC1
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.3 %

Procedure:
(R)—N-(2-(tert-Butyldiphenylsilyloxy)ethyl)-N-ethyl-4-(phenylthio)-3-(4-sulfamoyl-2-(trifluoromethylsulfonyl)phenylamino)butanamide (INTERMEDIATE 24, 0.59 g, 0.73 mmol) was dissolved in THF (4.6 ml), under a nitrogen atmosphere, and a solution of borane-THF complex (1M in THF; 2.2 ml, 2.2 mmol) was added and the resulting solution was stirred at ambient temperature overnight. An additional solution of borane-THF complex (1M in THF; 2.2 ml, 2.2 mmol) was added. The resulting mixture was stirred at ambient for further 6 hrs. The mixture was diluted with NH3 in MeOH (7N, 20 ml) and stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, diluted with EtOAc (75 ml), washed with water (40 ml), and dried (Na2SO4). Evaporation of the volatiles under reduced pressure afforded a concentrate, which was purified by column chromatography (ISCO, 40 g silica gel column, eluting with 0→100% EtOAc/hexanes) to provide the title compound (280 mg, yield: 48%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>CC(O)=O.O.[Fe]>[NH2:1][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][N:10]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of tert-butyl 6-nitroindoline-1-carboxylate (270 mg, 1.02 mmol) in AcOH/H2O (2.5 mL, 10:1, v:v) was added iron powder (229 mg, 4.08 mmol) portionwise. The resulting mixture was stirred at rt. After 1.5 h, the reaction was filtered through Celite and the filtrate concentrated in vacuo. The residue was diluted with EtOAc and the resulting organic layer was washed with sat. NaHCO3 and brine. The organic layer was concentrated in vacuo to yield tert-butyl 6-aminoindoline-1-carboxylate as a grey solid. MS (ES+): m/z 235 [M+1]. 1H NMR (CDCl3, 400 MHz): δ1.55 (s, 9H), 2.96 (t, J=8.4 Hz, 2H), 3.61 (br.s, 2H), 3.93 (t, J=8.4 Hz, 2H), 6.27 (d, J=8.4 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 7.30 (s, 1H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][C@:9]([OH:55])([C@@H:17]([C:38](=[O:54])[NH:39][C@H:40]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])OCC[O:27]1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])(C)(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:78][C:79]#[C:80][CH3:81]>C(#N)C.CN(C=O)C.O>[CH2:78]([O:48][C:45]1[CH:44]=[CH:43][C:42]([CH2:41][C@H:40]([NH:39][C:38]([C@@H:17](/[CH:18]=[CH:19]/[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](=[O:27])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C@@:9]([OH:55])([CH2:8][CH2:7][OH:6])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])=[O:54])[C:49]([O:51][CH2:52][CH3:53])=[O:50])=[CH:47][CH:46]=1)[C:79]#[C:80][CH3:81]
Reactant: CC#CCBr
Reactant: CCCCCCCC1(CCCCCC/C=C/[C@H](C(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)OCC)[C@@](O)(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)OCCO1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC#N
Product: CC#CCOc1ccc(C[C@H](NC(=O)[C@@H](/C=C/CCCCCCC(=O)CCCCCCC)[C@@](O)(CCO)C(=O)OC(C)(C)C)C(=O)OCC)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
tert-Butyl (E)-(2S,3S)-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-3-[(S)-1-ethoxycarbonyl-2-(4-hydroxy-phenyl)-ethylcarbamoyl]-11-(2-heptyl-[1,3]dioxolan-2-yl)-2-hydroxy-undec-4-enoate (909 mg) was dissolved in acetonitrile (9.0 mL), and an aqueous solution (3.6 mL) of 0.5 M citric acid was added. The mixture was stirred at 60° C. for 3 hours. Water was then added to the reaction mixture, which was followed by extraction with a mixed solvent of ethyl acetate/n-hexane. The organic extract was dried over magnesium sulfate, and concentrated under reduced pressure to obtain a crude product (660 mg). The obtained crude product (182 mg) was dissolved in DMF, and potassium carbonate (49.4 mg) and 1-bromo-but-2-yne (28.9 μL) were added. The mixture was stirred at room temperature for 20 hours. Water was then added to the reaction mixture, which was followed by extraction with a mixed solvent of ethyl acetate/n-hexane. The organic layer was washed with a saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (74 mg).
Reaction SMILES: C1([Mg]Br)CC1.ICCCCCCC(OCC)=O.[Cl-].[NH4+].[CH:20]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:22][CH2:21]1.[OH-].[Na+]>C1COCC1.[Cu](I)I.O>[CH:20]1([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:21][CH2:22]1
Reactant: CCOC(=O)CCCCCCC1CC1
Agent: I[Cu]I
Agent: Br[Mg]C1CC1
Agent: CCOC(=O)CCCCCCI
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC1CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
All reactions reported in this example were carried out in an oven-dried three-necked, round-bottomed flasks equipped with a Teflon-coated magnetic stirring bar, copper iodide and a T-joint to which an argon-filled balloon had been attached. The flask was evacuated while being heated, then purged with argon from the balloon. This operation was repeated three times before addition of any reagents or solvents. To a stirred suspension of cuprous iodide (2.38 g, 12.5 mmol) in 30 mL of dried THF at ca −78° C. under argon, cyclopropylmagnesium bromide in THF solution (0.5M, 50 ml, 25 mmol) was added via syringe. After the addition had been completed, the mixture was stirred for 30 min and a solution of ethyl 7-iodoheptanoate (3.02 g, 10.63 mmol) in 10 ml of THF was added. After the addition, the reaction was allowed to warm to 0° C. and stirred for 2 h. It was allowed to warm to ambient temperature and stirred overnight. The reaction was poured into a saturated ammonium chloride solution. The organic product was extracted into an ether layer which was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to yield a residue. 1H NMR confirmed the desired ethyl 7-cyclopropylheptanoate. GC indicated a single peak material. To the residue were added 25 mL of water and a 25 ml of a solution of NaOH (2N). The mixture was stirred at ambient temperature overnight. The alkaline solution was washed with ether. The aqueous layer was separated and subjected to in vacuo evaporation to remove any residual ether. The alkaline solution was acidified with an aqueous solution of HCl (2N) leading to the precipitation of a white solid. Stirring was continued for an additional 30 minutes and then the precipitate was filtered off with suction through a sintered glass funnel. The collected solid was successively washed with water and two-50-ml of hexane, and was dried in vacuo at room temperature for 2 days to afford 0.72 g (40%) of 7-cyclopropylheptanoic acid as a white solid. 1H NMR (400 MHz DMSO-d6) δ: 0 (m, 2H), 0.37 (m, 2H), 0.66 (m, 1H), 1.16-1.18(m, 2H), 1.34-1.50 (m, 6H), 1.78 (m, 2H), 2.20 (m, 2H), 12.0 (s, 1H). 13C NMR (100 MHz DMSO-d6) δ: 4.27, 10.65, 24.50, 28.61, 29.05, 33.64, 34.01, 174.43. Anal. Calcd for C10H18O2: C, 70.22; H, 10.66. Found: C, 70.05, H, 10.34 with a Karl Fisher water content %: 0.46.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: Nc1ccccc1F
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Product: COc1cc2c(=O)[nH]c3nccc(Nc4ccccc4F)c3c2cc1OC
Yield: 3.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 2-fluoroaniline (25 mg, 0.22 mmol) to provide 216 (2 mg, 3% yield) as a white solid. LC-MS (M+H=366, obsd.=366).
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[Cl:5][C:6]1[C:11](Cl)=[CH:10][CH:9]=[N+:8]([O-:13])[C:7]=1[CH3:14]>CO>[Cl:5][C:6]1[C:11]([O:2][CH3:1])=[CH:10][CH:9]=[N+:8]([O-:13])[C:7]=1[CH3:14]
Reactant: C[O-]
Reactant: Cc1c(Cl)c(Cl)cc[n+]1[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1cc[n+]([O-])c(C)c1Cl
Temperature: 25 °C

Procedure:
To a solution of sodium methylate, prepared from 0.51 g of sodium and 20 ml of methanol, at -10° C. were added 3.5 g of 3,4-dichloro-2-picoline-N-oxide in 20 ml of anhydrous methanol. The mixture was allowed to warm slowly to room temperature and was then heated to reflux for 1 hour. The solvent was now removed by distillation under reduced pressure, water was added to the residue, the mixture was extracted with dichloromethane, and the solvent was evaporated off. Colorless crystals from diisopropyl ether, melting point 94°-97° C.
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.C(=O)([O-])O.[Na+]>CCOCC>[OH:2][CH2:3][CH2:5][CH2:6][C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=C(C)CCC(=O)OC
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C=C(C)CCCO
Temperature: -78 °C

Procedure:
Under stirring at -78° C., a solution of ethyl 5-methoxycarbonyl-3-methyl-2-pentenoate (3.0 g) in ether (30 ml) is added to a solution of LiAlH4 (1.0 g) in ether (50 ml). The mixture is further, stirred for 30 minutes, after which cold water and a saturated aqueous solution of sodium hydrogen carbonate are added followed by extraction with ethyl acetate. The extract is worked up in the conventional manner and the residue is purified by column chromatography on silica gel (100 g) with CCl4 -ethyl acetate (10:1) as the eluent. The above procedure provides a colorless oil of ethyl 6-hydroxy-3-methyl-2-hexenoate. This product (2.6 g) is mixed with 3,4-dihydro-α-pyran (5.2 g) and under ice-cooling, concentrated hydrochloric acid (0.04 ml) is added. The mixture is stirred for 3 hours, after which a saturated aqueous solution of sodium hydrogen carbonate is added followed by extraction with ethyl acetate. The extract is worked up in the conventional manner and the residue is purified by column chromatography on silica gel (100 g) with CCl4 -ethyl acetate (10:1) as the eluent. This procedure provides a colorless oil of ethyl 3-methyl-6-(α-tetrahydropyranyloxy)-2-hexenoate. A solution of this product (3.5 g) in ether (50 ml) is added to a solution of LiAlH4 (1.0 g) in ether (100 ml) at -78° C. with constant stirring. The mixture is further stirred at -20° C. for an hour, at the end of which time the excess LiAlH4 is decomposed with cold water. To this reaction mixture is added a saturated aqueous solution of sodium hydrogen carbonate followed by extraction with ethyl acetate. The extract is worked up in the conventional manner and the residue is purified by column chromatography on silica gel (70 g) with CCl4 -ethyl acetate (3:1) as the eluent. The above procedure provides a colorless oil of VII (R4 =H, n=O, m=2, R5 =THP). This product (1.9 g) and VI (R=H3C, X=Y=OH) (2.0 g) are dissolved in dioxane (30 ml), followed by addition of a mixture of BF3 -ether (10 ml) and dioxane (20 ml) at room temperature with stirring. The mixture is kept stirred for 2 hours, at the end of which time it is diluted with cold water and extracted with ethyl acetate. The extract is worked up in the conventional manner to recover IIIb (R=H3C, X=Y=OH, n=O, m=3).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:8]=2)[N:3]=1.[Na].[CH3:21][C:22]1[N:26]=[CH:25][NH:24][N:23]=1.CN(C)C=O>O>[CH3:21][C:22]1[N:26]=[CH:25][N:24]([C:2]2[CH:11]=[C:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:8]=3)[N:3]=2)[N:23]=1
Reactant: Cc1nc[nH]n1
Reactant: Clc1cc(C(Cl)(Cl)Cl)c2cc(C(Cl)(Cl)Cl)ccc2n1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncn(-c2cc(C(Cl)(Cl)Cl)c3cc(C(Cl)(Cl)Cl)ccc3n2)n1
Temperature: 100 °C
Reaction time: 20 h
Yield: 62 %

Procedure:
A mixture of 3.99 g of 2-chloro-4,6-bis-trichloromethyl-quinoline, 1.26 g of the sodium salt of 3-methyl-1,2,4-triazole and 10 ml of dimethyl formamide is stirred at 100° C. for 20 hours. The reaction mixture is poured into 100 ml of water, the precipitated product is filtered and recrystallized from 10 ml of ethanol. Thus 2.76 g of the desired compound are obtained, yield 62%. M.p.: 169°-170° C.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].Cl>ClCCl>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Cl)c(C(F)(F)F)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
At room temperature, 4-chloro-3-trifluoromethyl-aniline (4.9 g, 25 mmol, 1 eq) was dissolved in dichloromethane (50 mL). A solution of phenyl chloroformate (3.9 g, 25 mmol, 1 eq) in dichloromethane (10 mL) was added, and the mixture was stirred for 1 h at room temperature. Dilute hydrochloride (1 N, 50 mL) was added, and the mixture was washed with water (40 mL×3) and separated. The organic phase was dried over anhydrous sodium sulfate and filtered. The solvent in the filtrate was removed to give the title compound (7.5 g, purity 99%, yield 94%) as an off-white solid.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:19][C:20](=[O:53])[C@@H:21]([NH:35][C:36](=[O:52])[C@@H:37]([CH2:45][C:46](=[O:51])[C:47]([CH3:50])([CH3:49])[CH3:48])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:22][C:23]2[N:24](C(OC(C)(C)C)=O)[CH:25]=[N:26][CH:27]=2)[C@@H:9]([OH:18])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([CH2:7][C@H:8]([NH:19][C:20](=[O:53])[C@@H:21]([NH:35][C:36](=[O:52])[C@@H:37]([CH2:45][C:46](=[O:51])[C:47]([CH3:49])([CH3:50])[CH3:48])[CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:22][C:23]2[N:24]=[CH:25][NH:26][CH:27]=2)[C@@H:9]([OH:18])[CH2:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1cncc1C[C@H](NC(=O)[C@@H](CC(=O)C(C)(C)C)Cc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCCC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1CCCCC1=O

Procedure:
In an analogous manner to that described in Example 4, (S)-N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-(2-oxo-1-piperidinyl)propyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hy drocinnamamido]-3-t butoxycarbonylimidazole-4-propionamide was treated with potassium carbonate in methanol, whereby there was obtained (S)-N-[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-(2-oxopiperidino)propyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4propionamide as an amorphous solid, MS: 636 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C(Cl)(=O)C(Cl)=O.[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:23][NH:24][O:25][CH3:26]>C1C=CC=CC=1.ClCCl.N1C=CC=CC=1.Cl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:27]=[CH:28][C:29]=1[Cl:30])[CH2:23][N:24]([O:25][CH3:26])[C:8](=[O:10])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:1])([CH3:12])[O:6]1
Reactant: CONCc1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)C(=CC(=O)O)O1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CON(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
A suspension of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetic acid (4.37 g, 25.4 mmol) in benzene (30 mL) was refluxed for 1 h with oxalyl chloride (15 mL). The resulting solution was cooled and concentrated. The residue was dissolved in dichloromethane (30 mL) and cooled to 0° C. and N-(3,4-dichloro-benzyl)-O-methyl-hydroxylamine (5.3 g, 22 mmol) in dichloromethane (30 mL) and pyridine (18 mL) was added dropwise. The resulting mixture was stirred at room temp for 18 h. The mixture was diluted with 1N HCl and extracted with EtOAc. The organic phase was washed with 1N HCl, dried (sodium sulfate) and concentrated to give the title compound as a yellow solid (7.59 g, 83% yield). 1HNMR (300 MHz, CDCl3) δ: 7.44 (1H, s), 7.39 (2H, d, J=8.05 Hz), 7.19 (2H, d, J=8.05 Hz), 6.37 (1H, s), 4.75 (2H, s), 3.70 (3H, s), 1.74 (6H, s).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([F:19])=[C:12]([NH:20][C@H:21]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[CH3:22])[CH:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[Cl-].[NH4+].C([O-])(=O)C.[NH4+]>CO.C1COCC1.[Zn]>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:11]=[C:12]([NH:20][C@H:21]([C:23]4[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=4)[CH3:22])[C:13]([F:19])=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c([N+](=O)[O-])cc1F)c1ccc(F)cc1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(Nc2cc(C3CC3)[nH]n2)c(N)cc1F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of (S)-N1-(5-cyclopropyl-1H-pyrazol-3-yl)-4-fluoro-N3-[1-(4-fluorophenyl)ethyl]-6-nitrobenzene-1,3-diamine (Method 38; 0.33 g, 0.826 mmol) and Zinc dust (0.270 g, 4.13 mmol) in MeOH:THF (1:1, 10 ml) was slowly added saturated ammonium chloride (4 ml). The mixture was stirred at 25° C. for 2 hrs, to which was added saturated ammonium acetate solution (5 ml). The resulting mixture was stirred for another 30 min. The Zn dust was removed by filtration and washed with EtOAc (15 ml). The organic layer was separated and dried over Na2SO4. After removal of solvent, the title compound was used directly for the next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14]Cl)[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[C:28](=[O:29])[CH2:27][CH2:26][C:25]1=[O:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH2:14][N:24]2[C:28](=[O:29])[CH2:27][CH2:26][C:25]2=[O:30])[N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:10][C@H:9]1[CH3:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2C(=O)CCC2=O)CN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared following similar methods to those described in Preparation 356 starting from (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester and pyrrolidine-2,5-dione. 1H NMR (CDCl3): 7.37-7.01 (5H, m), 4.24-4.06 (1H, m), 3.89 (1H, d), 3.80-3.47 (4H, m), 3.22 (2H, d), 3.09-2.78 (1H, m), 2.70-2.55 (4H, m), 2.33 (1H, dd), 1.48 (9H, s), 1.19 (3H, d).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].O>CN(C=O)C>[CH3:20][N:21]([CH3:26])[S:22](=[O:24])(=[O:23])[O:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc(O)c(C=O)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Dissolve 16.2 g (0.0889 mol) of 3,4-dimethoxy-6-hydroxybenzaldehyde in 80 ml of DMF. Cool to 10° C. and add in portions 24.6 g (0.178 mol) of potassium carbonate. Allow to return to ambient temperature and stir for 30 minutes. Cool to approximately 10° C. and pour in dropwise 10.1 ml (0.093 mol) of N,N-dimethylsulphamoyl chloride. Allow to return to ambient temperature and stir for 2 h. Pour the reaction mixture into 600 g of water and ice and stir for 1 h at ambient temperature. The precipitate formed is filtered off and washed 3 times with 50 ml of water each time and then dried in vacuo. 21.3 g of title product are obtained.
Reaction SMILES: [Li]CCCC.CC1(C)CCCC(C)(C)N1.[Br:16][C:17]1[CH:44]=[CH:43][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][CH:35]([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:42])=[CH:19][CH:18]=1.CN(P(N(C)C)(N(C)C)=[O:49])C>C1COCC1>[Br:16][C:17]1[CH:44]=[CH:43][C:20]([CH2:21][N:22]2[C:30]3[C:25](=[CH:26][C:27]([O:31][CH3:32])=[CH:28][CH:29]=3)[C:24]([CH2:33][CH2:34][C:35]([OH:49])([CH3:41])[C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:23]2[CH3:42])=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(C)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)CCc1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 25.3 %

Procedure:
n-BuLi (1.6M in hexane, 1.5 mL, 2.4 mmol) was slowly added to 2,2,6,6-tetramethylpiperidine at 0° C. and the slurry was stirred 10 min, then cooled to -78° C. and diluted with 6 mL (oxygenated) THF. The ester from Example 3, Step 2 (880 mg, 1.92 mmol) dissolved in 3 mL THF (O2) was added and the resulting mixture was stirred-- h at -78° C. and 1 h at -45° C. HMPA (668 μL, 3.8 mmol) was added and the mixture was stirred another 2 h at -30° C., then warmed to 0° C. The reaction was quenched with aq. NaHSO3 and then partitioned between saturated NH4Cl and ethyl acetate; the organic layer was washed with water, brine and dried over MgSO4. Purification by flash chromatography (40% ethyl acetate in hexane) provided 230 mg of the title compound.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[CH:29]=1)[NH2:27]>>[CH3:34][C:30]1[CH:29]=[C:28]([N:26]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:15]=[CH:16][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:18][CH:19]=4)[N:8]=3)=[CH:4][CH:3]=[N:27]2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1cc(NN)ccn1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Product: Cc1cc(-n2nccc2-c2nn(-c3ccc(OC(F)(F)F)cc3)ccc2=O)ccn1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 4-hydrazino-2-methylpyridine according to the method described for example 91. MS: M=414.2 (M+H)+