Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[F:8][C:9]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:32])[F:31])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([O:20]C)[CH:15]=1)=[O:12]>C(#N)C.O>[F:8][C:9]1[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[C:22]([C:30]([F:33])([F:31])[F:32])[C:10]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][NH:17][C:16](=[O:20])[CH:15]=1)=[O:12]
Reactant: COc1cc(NC(=O)c2c(F)cc(C(F)(F)F)cc2C(F)(F)F)ccn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(Nc1cc[nH]c(=O)c1)c1c(F)cc(C(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of sodium iodide (2.54 g, 16.95 mmol) in acetonitrile (75 mL) under nitrogen was added TMSCl (2.15 mL, 16.95 mmol) and the mixture was stirred at 25° C. for 30 min. Thereafter, anhydrous acetonitrile (130.0 ml) was added to this solution followed by 2-fluoro-N-(2-methoxy-4-pyridyl)-4,6-bis(trifluoromethyl)benzamide (1.2 g, 3.14 mmol). The resulting reaction mixture was heated with stirring at 80° C. for 5 h and at 60° C. for 12 hours. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered and concentrated to a dark yellow-orange solid. The solid was triturated with ethyl acetate/hexanes several times to remove dark red color, then with dichloromethane to remove yellow color, then finally with hexanes. The resulting solid was dried under vacuum to provide 2-fluoro-N-(2-oxo-1H-pyridin-4-yl)-4,6-bis(trifluoromethyl)benzamide (960 mg, 83%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.41 (s, 1H), 11.03 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 8.16 (d, J=1.7 Hz, 1H), 7.37 (d, J=7.1 Hz, 1H), 6.71 (d, J=2.0 Hz, 1H), 6.31 (dd, J=7.2, 2.1 Hz, 1H) ppm. ESI-MS m/z calc. 368.04. found 369.1 (M+1)+; Retention time: 1.28 minutes (3 minutes run).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([C:17]([F:20])([F:19])[F:18])([OH:16])[CH2:14][OH:15])[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.O.[C:24]1(C)[CH:29]=CC(S(O)(=O)=O)=C[CH:25]=1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]2([C:17]([F:20])([F:18])[F:19])[CH2:14][O:15][C:24]([CH3:29])([CH3:25])[O:16]2)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(Br)cc2c1OCC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: CC1(C)OCC(CC(C)(C)c2cc(Br)cc3c2OCC3)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 144 h
Yield: 372.1 %

Procedure:
A mixture of 7.6 g (20 mmol) of 4-(5-bromo-2,3-dihydrobenzofuran-7-yl)-4-methyl-2-trifluoromethylpentane-1,2-diol and 0.754 g (4 mmol) of p-toluenesulfonic acid monohydrate in 200 mL of acetone was stirred at room temperature for 6 days and the volatiles removed in vacuo. The residue was dissolved in EtOAc, washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated in vacuo. The residue was extracted with diethyl ether and the filtrate concentrated in vacuo to afford 6.3 g (75%) of 5-bromo-7-[2-(2,2-dimethyl-4-trifluoromethyl-[1,3]dioxolan-4-yl)-1,1-dimethylethyl]-2,3-dihydrobenzofuran.
Reaction SMILES: [CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8]([C:10]1[C:15]([N:16]2[N:20]=[CH:19][CH:18]=[N:17]2)=[CH:14][CH:13]=[CH:12]N=1)=[O:9].[CH3:32][C@]1(NC2C=NC(C(F)(F)F)=CN=2)CCC[C@@H]1N.N1N(C2C=CC=CC=2C(O)=O)N=CC=1>>[CH3:1][C@:2]1([NH:21][C:22]2[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][N:23]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:8](=[O:9])[C:10]1[CH:32]=[CH:12][CH:13]=[CH:14][C:15]=1[N:16]1[N:20]=[CH:19][CH:18]=[N:17]1
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1
Agent: O=C(O)c1ccccc1-n1nccn1
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-methyl-2-{[5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxamide (Example 77) from (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 510 mg, 1.96 mmol) and 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 445 mg, 2.35 mmol) except this was then partitioned between water (20 ml) and DCM (10 ml). The organics were washed with water (2×20 ml) and brine (20 ml), filtered through a hydrophobic frit and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) followed by a trituration with diethyl ether and recrystallised from IPA/water to afford the title compound.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[N:8][CH:9]=1.[CH3:12][O:13][CH2:14]Cl.[Cl-].[NH4+]>C(OCC)(=O)C.O.CN(C)C=O>[CH3:12][O:13][CH2:14][O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]#[N:11])=[N:8][CH:9]=1
Reactant: COCCl
Reactant: N#Cc1ccc(O)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1ccc(C#N)nc1
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
60% sodium hydride (3.62 g, 90.4 mmol) was added to an N,N-dimethylformamide (70 mL) solution of 5-hydroxypyridin-2-carbonitrile (7.24 g, 60.3 mmol) at 0° C., and the mixture was stirred at the same temperature for 15 minutes. Subsequently, chloromethyl methyl ether (9.16 ml, 121 mmol) was added to the mixture little by little, and the resulting mixture was further stirred at the same temperature for 45 minutes. A saturated aqueous solution of ammonium chloride and water were added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The organic layer thus obtained was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=75:25, v/v) to give the title compound (8.63 g, yield: 87%).
Reaction SMILES: N[CH:2]1C2(CC2)CN[CH2:3]1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].BrCCBr>>[C:11]([C:10]1([C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH2:3][CH2:2]1)(=[O:12])[CH3:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: NC1CNCC12CC2
Solvent: BrCCBr
Product: CCOC(=O)C1(C(C)=O)CC1

Procedure:
Taking 7-amino-5-azaspiro[2,4]heptane as an example, ethyl acetoacetate is first reacted with 1,2-dibromoethane in the presence of a base to give ethyl 1-acetyl-1-cyclopropanecarboxylate. Then, using bromine, the acetyl group of this compound is brominated to give ethyl 1-bromoacetyl-1-cyclopropanecarboxylate. This bromoacetyl compound is then cyclized with benzylamine to give 5-benzyl-4,7-dioxo-5-azaspiro[2,4]heptane. When this compound is reacted with hydroxylamine hydrochloride, the ketone in 7-position is converted to an oxime to give 5-benzyl-7-(hydroxyimino)-4-oxo-5-azaspiro[2,4]heptane. This oxime is reduced with lithium aluminum hydride to give a spiro ring-containing aminopyrrolidine compound, viz., 7-amino-5-benzyl-5-azaspiro[2,4]heptane. When the benzyl group of this compound is eliminated by an ordinary procedure, such as catalytic hydrogenolysis, 7-amino-5-azaspiro[2,4]heptane which is a racemic compound, is obtained When this cleavage of the benzyl group is preceded after the amino group is protected by the reaction of 2-(tert-butoxycarbonylamino)-2-phenylacetonitrile (hereinafter referred to briefly as BOC-ON), 7-tert-butoxycarbonylamino-5-azaspiro[2,4]heptane is obtained.
Reaction SMILES: C(CN1CC[C:13]2[NH:12][C:11](=[O:16])[N:10]3[N:17]=[C:18](C4C=CC=CC=4F)[N:19]=[C:9]3[C:8]=2C1)(OC)=O.[OH-].[Na+]>C(O)C>[N:19]1[CH:18]=[N:17][N:10]2[C:9]=1[CH:8]=[CH:13][NH:12][C:11]2=[O:16]
Reactant: COC(=O)CN1CCc2[nH]c(=O)n3nc(-c4ccccc4F)nc3c2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=c1[nH]ccc2ncnn12

Procedure:
To a suspension of the product of Example 42 (500 mg) in ethanol (20 mL) is added 4N aqueous sodium hydroxide (1 mL) and the whole stirred at reflux under nitrogen for 2 hours. It is cooled, filtered and the filtrate neutralized with glacial acetic acid with ice cooling to produce the solid 9-carboxymethyl-2-(2-fluorophenyl)-7,8,9,10-tetrahydropyrido[3,4-e][(1,2,4]triazolo[1,5-c]pyrimidin-5(6H)one.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[CH3:30][NH:31][CH2:32][CH3:33].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([CH2:32][CH3:33])[CH3:30])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCN(C)C(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 26.7 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (126 mg, 0.30 mmol) obtained in Example 12 in methylene chloride (3 ml), N-methylethylamine (0.060 ml, 0.66 mmol), 1-hydroxybenzotriazole (45 mg, 0.33 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (63 mg, 0.33 mmol) were added at room temperature. After stirring for 4 hours at room temperature, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of diethyl ether and hexane, and was collected by filtration, to obtain the title compound (38 mg, 0.08 mmol, 27%) as a white solid.
Reaction SMILES: [Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C:12]([CH3:26])([CH3:25])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([O:23]C)=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[OH-].[Li+].Cl>O1CCCC1>[Si:1]([O:8][C@H:9]([C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[C:29]([CH2:34][OH:35])[CH:28]=1)[CH2:10][NH:11][C:12]([CH3:26])([CH3:25])[CH2:13][C:14]1[CH:15]=[C:16]([CH2:20][C:21]([OH:23])=[O:22])[CH:17]=[CH:18][CH:19]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(Cc1cccc(CC(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 84 %

Procedure:
A mixture of methyl {3-[2-({(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)-2-methylpropyl]phenyl}acetate (preparation 153), (5 g, 10 mmol) and lithium hydroxide (1M in water, 30 mL, 30 mmol) in tetrahydrofuran (50 mL) was stirred for 48 hours at room temperature. The reaction mixture was then acidified with 1M hydrochloric acid (30 mL), concentrated in vacuo, and the residue was triturated with water and azeotroped (×3) with methanol to afford the title compound as a white solid in 84% yield, 4.1 g.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C:10](=O)[CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)N)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([N:40](CC)CC)C.ClC(Cl)(Cl)C(Cl)(Cl)Cl>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:8]([C:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)=[N:40][N:6]=2)[CH:7]=1
Reactant: NN(C(=O)CCN1CCCC1)c1ccc(F)cn1
Reactant: CCN(CC)CC
Agent: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc2nnc(CCN3CCCC3)n2c1
Reaction time: 18 h
Yield: 73.2 %

Procedure:
Intermediate 1a (400 mg) was dissolved in THF (20 mL) and cooled in an ice/water bath. Triphenylphosphine (643 mg, 2.45 mmol) was added followed by triethylamine (682 μL, 4.90 mmol) and hexachloroethane (581 mg, 2.45 mmol). The reaction mixture was stirred for 18 h and then loaded onto an SCX-2 cartridge, which was washed with MeOH then eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC using 0-10% [2M NH3 in MeOH] in DCM to give the title compound (292 mg, 1.16 mmol, 52%). NMR (400 MHz, CDCl3): 1.80-1.87 (4H, m), 2.60-2.68 (4H, m), 3.00-3.10 (2H, t, J 7.3), 3.24-3.34 (2H, t, J 7.3), 7.13-7.21 (1H, ddd, J 9.9, 7.6, 2.3), 7.70-7.77 (1H, dd, J 9.8, 4.5), 8.00-8.04 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]2[O:22][CH:21]=[C:20]([CH3:23])[C:19]=2[CH:24]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:20]1[C:19]2[CH:24]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[CH:16]=[CH:17][C:18]=2[O:22][CH:21]=1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Cc1coc2ccc(Br)cc12
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3occ(C)c3c2)C1=O
Yield: 28 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 105 mg, 0.8465 mol) was reacted with 5-bromo-3-methyl-benzofuran (197 mg, 0.9311 mmol), 1,4-dioxane (10 mL), copper iodide (20 mg), trans-1,2-diamino cyclohexane (40 mg) and potassium carbonate (359 mg, 1.6930 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in chloroform) afforded 80 mg of the product (30.76% yield).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=2)[O:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[OH-].[Na+]>C(O)C>[NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:14]=[C:15]([CH:25]=[CH:26][CH:27]=2)[O:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: CCOC(=O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCOc1cccc(-c2n[nH]c3c2Cc2ccccc2-3)c1

Procedure:
In a similar manner to example 34, ethyl 4-[3-(1,4-dihydroindeno-[1,2-c]pyrazol-3-yl)phenoxy]butyrate (0.36 g) was reacted with 1M sodium hydroxide solution (5 ml) in ethanol (10 ml) to give 4-[3-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)phenoxy]butyric acid, m.p. 216-217° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=O)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:28]([O:30][C:31](=[O:36])[CH2:32]C(O)=O)[CH3:29].CCN(CC)CC.[Mg+2].[Cl-].[Cl-].[K]>O1CCCC1.C(#N)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1ncc2cc(C(=O)O)ccc21
Reactant: CCOC(=O)CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [K]
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccc2c(cnn2C(C)=O)c1
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 75 %

Procedure:
To a solution of 1-acetyl-1H-indazole-5-carboxylic acid (8.5 g, 41.63 mmol) in tetrahydrofuran (200 ml) was added CDI (20 g), and the resulting mixture was stirred for 2.5 h at 40° C., and then added dropwise to a solution of the magnesium salt of malonic acid monoethyl ester [prepared via the addition of Et3N (14 g, 138.25 mmol) and MgCl2 (19 g, 200 mmol) to a solution of potassium monoethylonate (24 g, 147.17 mmol) in acetonitrile (200 ml)] followed by stirring at room temperature for 2.5 h at 0° C. The resulting solution was stirred for an additional 2.5 h at 80° C. The reaction was then quenched by the addition of water (500 ml) and the pH adjusted to 3 with HCl (3N). The solids were collected by filtration and washed with water (3×50 ml) to afford ethyl 3-(1-acetyl-1H-indazol-5-yl)-3-oxopropanoate as a light yellow solid (8.6 g, 75%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:17][C:18](=[O:37])[C@@H:19]([CH:24]([C:34](O)=[O:35])[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:42]([O:49][NH2:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]([N:16]([CH2:38][CH:39]([CH3:41])[CH3:40])[NH:17][C:18](=[O:37])[C@@H:19]([CH:24]([C:34](=[O:35])[NH:50][O:49][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:25][CH2:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH2:20][CH:21]([CH3:22])[CH3:23])=[O:15])[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)O
Reactant: NOCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)[C@@H](C)NC(=O)OCc1ccccc1)C(CCCc1ccccc1)C(=O)NOCc1ccccc1
Temperature: 25 °C
Yield: 60.2 %

Procedure:
A solution of 1.15 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-(carboxy)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was cooled to 0° C. under a nitrogen atmosphere. The mixture was then treated with 1.25 g of O-benzylhydroxylamine and 0.467 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and left to warm to room temperature overnight. The mixture was diluted with water and extracted twice with ethyl acetate. The ethyl acetate layer was then washed with aqueous 2M hydrogen chloride, water and brine. Drying over anhydrous magnesium sulphate and evaporation of the solvent gave 0.820 g of 2′-(N-benzyloxycarbonyl-D-alanyl)-2(R)-[1(RS)-[(benzyloxy)carbamoyl)-4-phenylbutyl]-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9](=[N:24][OH:25])[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:33]([CH3:35])[CH3:34].O>CN(C)C=O>[Cl:1][C:2]1[C:3](/[C:9](=[N:24]/[O:25][CH:33]([CH3:35])[CH3:34])/[CH2:10][NH:11][C:12](=[O:23])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:20])([F:22])[F:21])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=C(NCC(=NO)c1ncc(Cl)cc1Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)O/N=C(\CNC(=O)c1ccccc1C(F)(F)F)c1ncc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 77.7 %

Procedure:
To a suspension of 300 mg of N-[2-(3,5-dichloropyridin-2-yl)-2-(hydroxyimino)ethyl]-2-(trifluoromethyl)benzamide and 315 mg of potassium carbonate in 3 ml of N,N-dimethylformamide, 195 mg of 2-iodopropane was added, and the mixture was stirred at room temperature for 6 hours. After completion of the reaction, the reaction mixture was mixed with 20 ml of water and extracted with ethyl acetate (10 ml×2), the resulting organic layers were combined, washed with water (10 ml×2), the resulting organic layer was dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography using ethyl acetate-hexane (with a gradient of from 1:9 to 3:7) as the eluent to obtain 258 mg of the desired product as white crystals.
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[N:16]=[CH:17][C:18]([NH2:21])=[N:19][CH:20]=2)[CH2:11][C@@H:10]1[F:22])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C(=O)N([Br:30])C(=O)C1.C([O-])([O-])=O.[Na+].[Na+].CC(OC)(C)C>CS(C)=O.O>[Br:30][C:17]1[C:18]([NH2:21])=[N:19][CH:20]=[C:15]([C@H:12]2[CH2:13][CH2:14][C@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C@@H:10]([F:22])[CH2:11]2)[N:16]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2cnc(N)cn2)C[C@@H]1F
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](c2cnc(N)c(Br)n2)C[C@@H]1F
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amine (620.0 g, 1904.8 mmol) in DMSO (5 L) and water (400 mL) was cooled to ˜4° C. NBS (389.8 g, 2190.5 mmol) was added in 10 portions within 1 hour and the reaction temperature was controlled under 5° C. with continuous stirring for 30 minutes. After addition of 0.3 M aqueous Na2CO3 (8.5 kg), the reaction temperature was increased to 35° C. MTBE (4.5 kg) was added and the mixture was stirred for a further 10 minutes. After phase separation, the aqueous layer was extracted with MTBE (4 kg). The combined organic layers were washed successively with 0.3 M aqueous Na2CO3 (8.5 kg) and water (8 kg), and concentrated under vacuum at 30-40° C. to give crude product 3-bromo-5-((1S,3S,4S)-4-((tert-butyldimethylsilyl)oxy)-3-fluorocyclohexyl)pyrazin-2-amine as a foam (770 g). This crude product was used in next step without further purification. ESI-MS (m/z): 404.1105, 406.1093 ([M+H]+, 100). HPLC (method A), retention time=14.38 min. 1H NMR (400 MHz, CDCl3): 7.81 (s, 1H), 4.99 (br. s, 2H), 4.37-4.42, 4.25-4.30 (m, 1H), 3.66-3.72 (m, 1H), 2.67-2.73 (m, 1H), 2.26-2.29 (m, 1H), 1.97-2.02 (m, 1H), 1.74-1.87 (m, 2H), 1.44-1.63 (m, 2H), 0.91 (s, 9H), 0.10 (d, J=8 Hz, 6H).
Reaction SMILES: N.[CH3:2][O:3][C:4]1[N:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.C([O:17]O)(C)(C)C.Cl>C1COCC1.O>[OH:17][C:8]1[C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=[C:4]([O:3][CH3:2])[N:9]=1
Reactant: CC(C)(C)OO
Reactant: COc1ccc([N+](=O)[O-])cn1
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(O)n1
Temperature: -78 °C

Procedure:
To a cooled suspension of Na t-OBu (6.24 g, 64.9 mmol) in liquid ammonia was added dropwise a solution of 6-methoxy-3-nitropyridine (2.0 g, 12.98 mmol) and t-butyl hydrogenperoxide (1.53 mL, 14.31 mmol) in THF (20 mL). After the completion of addition, the resulting mixture was stirred at −78° C. under Ar and warmed gradually to room temperature, and then stirred at room temperature overnight, which gave a yellow solid. It was diluted with H2O (30 mL). The resulting mixture was neutralized with the addition of 1N HCl solution. The solid formed was collected and washed with H2O and DCM, and then dried (1.18 g). The filtrate was extracted with DCM (2×20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated to give the second portion (0.59 g, total 1.77 g, 80%). NMR (MeOD-d3, 400 MHz) □ 8.20 (d, J=8.8 Hz, 1H), 5.79 (d, J=8.8 Hz, 1H), 4.87 (s, 3H). MS: m/z=171 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])C.[NH2:24][C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=1[CH3:33]>>[Br:23][C:8]1[N:9]([CH:20]([CH3:21])[CH3:22])[C:10]([CH:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[NH:24][C:25]2[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[CH:27][C:26]=2[CH3:33])=[C:6]([C:4]([OH:3])=[O:5])[N:7]=1
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(C#N)ccc1N
Product: Cc1cc(C#N)ccc1NC(c1ccc(Cl)cc1)c1c(C(=O)O)nc(Br)n1C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 4-amino-3-methylbenzonitrile. The reaction mixture was stirred at rt for 20 h. The mixture was extracted with HCl 1M and with a saturated aqueous NaHCO3 solution. The organic layers were dried (Na2SO4), filtered and concentrated. The product was triturated in Et2O, the suspension was filtered and the solid was dried in HV. tR: 1.30 min (LC-MS 2); ESI-MS: 515.2/517.1 [M+H]+ (LC-MS 2).