Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].C(O)(=O)C.[N+:14]([O-])([OH:16])=[O:15]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:14]([O-:16])=[O:15])[C:3]=1[CH3:9]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)ccc1Br
Solvent: O
Solvent: CC(=O)O
Product: Cc1c(Br)ccc(O)c1[N+](=O)[O-]
Temperature: 2.5 °C
Yield: 13.7 %

Procedure:
A mixture of 10.0 g (53.5 mmol) of 4-bromo-3-methylphenol, 50 ml of acetic acid and 10 ml of water was stirred under cooling at 0 to 5° C. To the resulting mixture was dropwise added 3.71 g (58.8 mmol) of 70% nitric acid. After completion of the dropwise addition, the mixture was stirred at room temperature for about an hour. The reaction solution was then poured onto ice water. The mixture was extracted three times with diethyl ether. The combined extracts were washed with water. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain 1.70 g (13.7%) of 4-bromo-3-methyl-2-nitrophenol.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:15][C:12]=1[CH:13]=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CO.Cl>O1CCCC1>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:16]([O:19][C:20]2[C:28]([CH3:29])=[CH:27][C:26]([N+:30]([O-:32])=[O:31])=[C:25]3[C:21]=2[CH2:22][CH2:23][CH2:24]3)=[CH:15][C:12]=1[CH2:13][OH:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=O)c1)CCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(CO)c1)CCC2
Reaction time: 6 h
Yield: 94.4 %

Procedure:
To a suspension of sodium borohydride (340 mg) in tetrahydrofuran (10 mL) was added 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (3.30 g) under ice-cooling. After adding dropwise methanol (1 mL) at room temperature, the mixture was stirred for 6 hours. The reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (3.13 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][N:3]=1.O1CCCC1.C[Si](C)(C)[C:17]([F:20])([F:19])[F:18].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O.[Cl-].[Na+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:6]([OH:7])[C:17]([F:20])([F:19])[F:18])=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(Cl)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)nc1)C(F)(F)F
Temperature: 0 °C

Procedure:
6-Chloronicotinaldehyde (500 mg, 3.53 mmol) was added to tetrahydrofuran (23 mL) and cooled to 0° C. Trimethyl(trifluoromethyl)silane (0.66 mL, 4.24 mmol) was added followed by 1 M tetra-n-butylammonium fluoride in tetrahydrofuran (4.24 mL, 4.24 mmol). The reaction mixture was allowed to warm to room temperature over 1 hour. The reaction was then diluted with water and brine and extracted with ethyl acetate three times. The organic layers were combined and dried over magnesium sulfate, filtered, and concentrated in vacuo. The concentrated material was purified via silica gel chromatography (0-40% ethyl acetate in hexanes) to afford the title compound.
Reaction SMILES: [C:1]([NH:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(Cl)Cl.[OH-].[Na+]>O>[C:1]([N:5]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)N(NC(=O)c1ccc(Cl)cc1)C(=O)c1ccccc1
Temperature: 5 °C
Yield: 91 %

Procedure:
To a 5 L round bottom flask, equipped with a mechanical stirrer, containing the 571 g of wet N'-tert-butyl-N-(4-chlorobenzoyl)hydrazine intermediate and equipped with a 500 mL addition funnel containing 371 g of benzoyl chloride, is charged 1500 mL of methylene chloride, 250 mL of water and lastly 223 g of 50% by weight aqueous sodium hydroxide. The flask contents are stirred and cooled to 5° C. and the benzoyl chloride is added dropwise during a one hour period so that the temperature of the flask contents does not exceed 10° C. After allowing the flask contents to warm to room temperature, stirring is stopped and the organic and aqueous phases are allowed to separate overnight. The upper aqueous phase is removed by suction and is replaced by 500 mL of fresh water, the heterogeneous mixture is stirred, the phases are allowed to separate and the upper aqueous phase again is removed by suction. This washing procedure is repeated two more times and then 500-800 mL of hexane is added to the organic remainder. The contents are briefly stirred and then are poured onto a glass flitted Buchner funnel. The filter cake is washed extensively with a total of 2 L of hexane followed by 10 L of water and then is dried in vacuo at 65° C. for two days to give 758.2 g of N'-tert-butyl-N-(4-chlorobenzoyl)-N'-benzoylhydrazine as a white powder melting at 197°-198° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](OCC)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][CH:26]=1.[OH-].[Na+]>CN(C=O)C>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([NH:24]/[C:13](=[C:6]2\[C:5](=[O:23])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:26][CH:27]=1)#[N:30]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 1 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone and 4-aminobenzonitrile in DMF and subsequent treatment with sodium hydroxide solution.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[Si:1]([O:8][C@@H:9]1[CH2:13][O:12][C@H:11]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[C@@H:10]1[CH2:20][CH2:21][C:22]([OH:24])=[O:23])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: COC(=O)CC[C@H]1[C@@H](c2cccnc2)OC[C@H]1O[Si](C)(C)C(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H]1CO[C@H](c2cccnc2)[C@@H]1CCC(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.82 g of methyl (2S,3S,4S)-3-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)-tetrahydrofuran-3-yl]propanoate in 25 ml of methanol is added 10 ml (0.01 mol) of 1N sodium hydroxide, the mixture is stirred at room temperature overnight, evaporated to a small volume and extracted with ethyl acetate. The aqueous layer is diluted with 20 ml of methylene chloride, the mixture is cooled to 0° C. and the pH of the aqueous layer is adjusted with stirring to 5.5 with 2N aqueous hydrochloric acid. The methylene chloride layer is dried (MgSO4) and evaporated. The residue is triturated with ethyl acetate to give (2S,3S,4S)-3-[4-(t-butyldimethylsilyloxy)-2-(3-pyridyl)tetrahydrofuran-3-yl]propanoic acid with mp 93°-94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[CH:3]=1.[Li]CCCC.CCCCCC.[NH2:20][C:21]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:22]=1[C:23](N(OC)C)=[O:24].Cl>C1COCC1>[NH2:20][C:21]1[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][C:22]=1[C:23]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)=[O:24]
Reactant: Fc1cccc(I)c1
Reactant: CON(C)C(=O)c1cccc(C)c1N
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)c2cccc(F)c2)c1N
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.7 %

Procedure:
In a 500 mL round-bottomed flask a solution of 1-fluoro-3-iodobenzene (13.61 mL, 116 mmol) in THF (120 mL) was cooled in −78° C. bath. A solution BuLi, 2.5M in hexane (46.3 mL, 116 mmol) was added dropwise over 10 minutes to give a slightly cloudy yellow solution. The solution was stirred at −78° C. for 30 minutes and then treated with a solution of 2-amino-N-methoxy-N,3-dimethylbenzamide (6.43 g, 33.1 mmol) in THF (30 mL). After 1.5 hours the reaction mixture was added to a mixture of ice and 1N HCl (149 mL, 149 mmol) and reaction flask rinsed with THF (5 ml) and combined with the aqueous mixture. The resulting mixture was diluted with 10% aq LiCl and the pH was adjusted to 4.00 with 1N NaOH. The mixture was extracted with Et2O, washed with brine, dried over MgSO4, filtered and concentrated. The resulting residue was purified on silica gel column (220 g ISCO) eluting with a gradient from 10% EtOAc/hexane to 30% EtOAc/hexane. The product was collected and concentrated to give (2-amino-3-methylphenyl)(3-fluorophenyl)methanone (7.11 g, 94% yield) as an oil. MS(ES):m/z=230.1 [M+H+]; HPLC: RT=2.820 min Purity=99%. (H2O/MeOH with TFA, CHROMOLITH® ODS S5 4.6×50 mm, gradient=4 min, wavelength=220 nm);
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:18]=[CH:17][CH:16]=[N:15]3)=[CH:10][N:9]2[CH:19]=1)=[O:5])C>Cl>[N:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:9]([CH:19]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=3)[CH:10]=2)[CH:18]=[CH:17][CH:16]=[N:15]1
Reactant: CCOC(=O)c1cn2cc(-n3cccn3)ccc2n1
Agent: Cl
Product: O=C(O)c1cn2cc(-n3cccn3)ccc2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 58.7 %

Procedure:
A mixture of sulfuric acid (0.5 mL), acetic acid (12 mL) and water (2 mL) was added to a reaction flask containing 2-aminopyridine (2.0 g, 21.26 mmol) and the solution was stirred for 5 minutes. NaIO4 (1.81 g, 8.5 mmol) followed by 12 (2.16 g, 8.5 mmol) was added into the reaction flask and stirred at 80° C. for 4 hrs. The reaction mixture was cooled to ambient temperature, diluted with cold water, basified with 20% aqueous KOH solution and extracted with DCM. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. Purification by column chromatography (using silica gel 60-120 and 8% EtOAc in hexane as eluent) and subsequent recrystallisation from ethanol afforded 53 g (58.6% Yield) of 5-iodo-pyridin-2-ylamine. Ethyl bromopyruvate (4.89 g, 25.11 mmol) was added to solution of 5-iodo-pyridin-2-ylamine (5.0 g, 22.83 mmol) in DMF (25 mL) and stirring was continued at 80° C. for 2 hrs. The reaction mixture was diluted with cold water and extracted with ethyl acetate. The organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain the crude residue. The residue obtained was purified by recrystallisation from methanol to afford 4.2 g (57.8% Yield) of 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of imidazole (513 mg, 7.5 mmol), cuprous oxide (71 mg, 0.5 mmol), 6-iodo-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (1.6 g, 5.02 mmol), salox (137 mg, 1.0 mmol) and cesium carbonate (3.27 g, 10.05 mmol) in ACN (2 mL) in a seal tube were subjected to reaction in a microwave reactor (time: 15 min, temp: 85° C., power: zero, pressure: zero). The reaction mixture was filtered through celite and the filtrate collected was concentrated under reduced pressure. The residue was diluted with cold water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (using neutral alumina and 0.2% MeOH in DCM as eluent) to afford 400 mg (31% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester. A mixture of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid ethyl ester (250 mg, 0.97 mmol) in 8N aqueous HCl (3 mL) was stirred at 100° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford 130 mg (58.5% Yield) of 6-pyrazol-1-yl-imidazo[1,2-a]pyridine-2-carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][NH:13][C:12]2=[O:23])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:36][C:37]1[C:38]([CH3:43])=[N:39][O:40][C:41]=1[CH3:42]>>[F:32][C:29]([F:31])([F:30])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])[CH2:14][N:13]([CH2:36][C:37]3[C:38]([CH3:43])=[N:39][O:40][C:41]=3[CH3:42])[C:12]2=[O:23])[CH2:24][CH2:25]1)=[O:7]
Reactant: Cc1noc(C)c1CCl
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC2(CC1)C(=O)NCN2c1ccccc1Cl
Product: Cc1noc(C)c1CN1CN(c2ccccc2Cl)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=615.1 (M+H+), was prepared in accordance with the general method of example 71 from 8-(3,5-bis-trifluoromethyl-benzoyl)-1-(2-chloro-phenyl)-1,3,8-triaza-spiro[4.5]decan-4-one and 4-(chloromethyl)-3,5-dimethylisoxazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10]([NH:12][NH2:13])=[O:11])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]([F:38])([F:37])[C:27]1[N:31]2[CH2:32][CH2:33][NH:34][C:35](=S)[C:30]2=[N:29][N:28]=1.CO>C(OCC)C>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]([CH2:14][C:15]1[CH:20]=[C:19]([F:21])[C:18]([F:22])=[CH:17][C:16]=1[F:23])[CH2:9][C:10](=[O:11])[NH:12][NH:13][C:35]1[C:30]2[N:31]([C:27]([C:26]([F:38])([F:37])[F:25])=[N:28][N:29]=2)[CH2:32][CH2:33][N:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1nnc2n1CCNC2=S
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NN)Cc1cc(F)c(F)cc1F
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)NNC1=NCCn2c1nnc2C(F)(F)F)Cc1cc(F)c(F)cc1F

Procedure:
A mixture of 207 mg (0.6 mmol) of tert-butyl[(1R)-3-hydrazino-3-oxo-1-(2,4,5-trifluorobenzyl)propyl]carbamate (Intermediate 4), 110 mg (0.5 mmol) of 3-(trifluoromethyl)-6,7-dihydro[1,2,4]triazolo[4,3-a]pyrazine-8(5H)-thione (Intermediate 6), and 5.5 mL of methanol was stirred at reflux for 1 day. Diethyl ether was added to the cooled solution, resulting in precipitation. The solid was removed by filtration, and the filtrate was concentrated to dryness. Purification of the residue by preparative HPLC (C18 reverse phase column, 30-80% acetonitrile in water containing 0.05% trifluoroacetic acid) afforded the title compound. LC-MS 536 (M+1).
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[F:52])(=[O:44])=[O:43])([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.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][S:26]([C:29]2[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[F:52])(=[O:43])=[O:44])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(S(=O)(=O)CCc2c(CCNS(=O)(=O)Cc3ccccc3F)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 99 %

Procedure:
Methyl 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoate (1 eq), THF (0.1M), MeOH (1 mL/1 mL THF), and NaOH (1N) (11 eq) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and collected resulting precipitate by filtration. Obtained 4-({2-[1-benzhydryl-5-chloro-2-(2-{[(2-fluorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethyl}sulfonyl)benzoic acid (off-white solid) in 99% yield. HRMS calc for [C39H34ClFN2O6S2−H] 743.1458 found 743.14511.
Reaction SMILES: [F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13]O)=[CH:8][CH:7]=1)=[O:4].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P>O1CCCC1.C(OCC)C>[F:1][C:2]([F:22])([C:15]([F:21])([F:20])[C:16]([F:19])([F:18])[F:17])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][Br:24])=[CH:8][CH:7]=1)=[O:4]
Reactant: BrC(Br)(Br)Br
Reactant: O=C(Nc1ccc(CCO)cc1)C(F)(F)C(F)(F)C(F)(F)F
Agent: P
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(Nc1ccc(CCBr)cc1)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A mixture of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-hydroxyethyl)phenyl]butanamide (25 g), carbon tetrabromide (51 g), diethyl ether (140 mL) and tetrahydrofuran (140 mL) was cooled in ice and treated with triphenylphosphine (39.3 g), portionwise. When addition of the phosphine was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The precipitate was removed by filtration and the filtrate concentrated in vacuo. The residue was purified by chromatography on silica gel, eluted with dichloromethane to give 16.2 g of 2,2,3,3,4,4,4-heptafluoro-N-[4-(2-bromoethyl)phenyl]butanamide as a white solid.
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([C:29](=O)[CH2:30][CH2:31][CH2:32][CH3:33])[C:23](=NOC)[C:24]#[N:25])=[C:17]([F:35])[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.Cl.[NH:37]([C:39]1[CH:40]=[C:41]([CH:47]=[CH:48][C:49]=1[C:50]([F:53])([F:52])[F:51])[C:42]([O:44][CH2:45][CH3:46])=[O:43])[NH2:38]>>[CH2:30]([C:29]1[C:22]([CH2:21][C:18]2[CH:19]=[CH:20][C:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][C:17]=2[F:35])=[C:23]([C:24]#[N:25])[N:37]([C:39]2[CH:40]=[C:41]([C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH:47]=[CH:48][C:49]=2[C:50]([F:51])([F:52])[F:53])[N:38]=1)[CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)c(NN)c1
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F)C(C#N)=NOC
Agent: Cl
Product: CCCCc1nn(-c2cc(C(=O)OCC)ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F

Procedure:
The title compound is prepared by reaction of 3-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2-methoxyimino-4-oxooctanenitrile (from Step J) with ethyl 3-hydrazino-4-(trifluoromethyl)benzoate hydrochloride (from Step E) according to the procedure of Example 1, Step G.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11](=O)[CH3:12].O.[NH2:15][NH2:16]>C(OCC)(=O)C>[CH3:12][C:11]1[C:3]2[C:2](=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=2)[NH:16][N:15]=1
Reactant: NN
Reactant: CC(=O)c1cc([N+](=O)[O-])ccc1O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 150 °C
Reaction time: 0.08 h
Yield: 80 %

Procedure:
A solution of 1-(2-hydroxy-5-nitrophenyl)ethanone (0.54 g, 3 mmol) in anhydrous hydrazine (2 ml) was radiated with microwaves while being stirred at 150° C. for 5 min. Water (0.5 ml) was added at 0° C. to terminate the reaction. The reaction solution was diluted with ethyl acetate (10 ml) and washed with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated using vacuum evaporation. Recrystallization of the residue in dichloromethane produced the title compound (Yield 80%).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14]CC(O)=O)[C:9]1=[O:19].C(Cl)Cl>CN(C)C=O>[CH3:7][N:8]1[C:12](=[O:13])[CH2:11][N:10]([CH2:14][CH2:1][C:2]([Cl:4])=[O:3])[C:9]1=[O:19]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CN1C(=O)CN(CCC(=O)O)C1=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1C(=O)CN(CCC(=O)Cl)C1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
340.9 g (2.6857 mol) of oxalyl chloride are added dropwise over the course of 18 minutes at an internal temperature of 19°-23° C. to a solution of 100.0 g (0.537 mol) of 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionic acid, synthesized as described in Example 6, 350 ml of methylene chloride and 1 ml of dimethyl formamide, and the mixture is subsequently stirred at room temperature for 5 hours and 10 minutes. When the reaction is complete, the reaction mixture is evaporated in a rotary evaporator, the residue is stripped 3 times at 50° C. under reduced pressure with 100 ml of toluene in each case, and the residue is dried at 60° C./0.1 mbar to constant weight, giving 106.1 g (97.3% of theory) of solid, brownish 3-(3-methyl-2,4-dioxoimidazolidin-1-yl)propionyl chloride having the following analytical data:
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]CCC.OOS([O-])=O.[K+].[O-]S([O-])=O.[Na+].[Na+].CC[O:25][C:26]([CH3:28])=[O:27]>CN(C=O)C.O=[Os](=O)(=O)=O>[C:26]([OH:25])(=[O:27])[CH2:28][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCOC(C)=O
Reactant: C=CCCCCCCCC
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])OO
Agent: O=S([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCCCCC(=O)O
Reaction time: 0.08 h
Yield: 93 %

Procedure:
1-Decene (100 mg) was dissolved in DMF (6 mL), and OsO4 (0.088 mL, 2.5% in tBuOH) was added and stirred for 5 min. OXONE (1.75 g) was added in one portion and the reaction had a final volume (8 mL). The reaction was stirred at room temperature for 3 hours or until the solution becomes colorless. This usually marks the completion of the reaction which was verified by TLC or GC. Na2SO3 (600 mg) was added, to reduce the remaining Os(VIII), and stirred for an additional hour or until solution became dark brown/black. EtOAc was added to extract the products and 1N HCl was used to dissolve the salts. The organic extract was washed with 1N HCl (50 mL×3) and brine (50 mL), dried over Na2SO4, and the solvent was removed under reduced pressure to obtain the crude product. Nonanoic acid was obtained in 93% yield without the need for further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][CH:20]=[C:19](Cl)[N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].[CH3:25][OH:26].C[O-].[Na+].Cl>O>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@H:12]3[CH2:24][C@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[N:21][CH:20]=[C:19]([O:26][CH3:25])[N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: CO
Reactant: CC(C)(CO)NC(=O)c1nn(-c2cncc(Cl)n2)c2c1C[C@H]1C[C@@H]21
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1cncc(-n2nc(C(=O)NC(C)(C)CO)c3c2[C@@H]2C[C@@H]2C3)n1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
(1aR,5aR)-2-(6-Chloro-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (25 mg, 0.072 mmol) was added to a 3.7 M methanol solution of sodium methoxide (0.583 mL, 2.156 mmol). The white suspension was stirred at 23° C., for 30 min. 1 M HCl (2.5 mL) and water (5 mL) were added. The mixture was extracted with dichloromethane (3×5 mL). The combined organic extracts were concentrated under reduced pressure and purified by silica gel flash chromatography to provide the title compound (12 mg) as a white solid. LCMS m/z=344.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.47 (td, J=4.7, 3.3 Hz, 1H), 1.25 (td, J=7.9, 4.8 Hz, 1H), 1.419 (s, 3H), 1.422 (s, 3H), 2.26-2.32 (m, 1H), 2.71-2.76 (m, 1H), 2.92 (d, J=16.9 Hz, 1H), 3.02 (dd, J=16.6, 6.2 Hz, 1H), 3.71 (s, 2H), 4.03 (s, 3H), 4.70 (bs, 1H), 6.96 (s, 1H), 8.17 (d, J=0.5 Hz, 1H), 8.75 (d, J=0.5 Hz, 1H).