Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([C:9]2[N:13]=[CH:12][NH:11][N:10]=2)[CH:3]=1.Cl[CH2:15][C:16](Cl)=[O:17].[OH-].[Na+].Cl>O1CCOCC1.N1C=CC=CC=1.C(OCC)C>[F:1][C:2]1[CH:8]=[CH:7][C:5]2[NH:6][C:16](=[O:17])[CH2:15][N:10]3[N:11]=[CH:12][N:13]=[C:9]3[C:4]=2[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)cc1-c1nc[nH]n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C1Cn2ncnc2-c2cc(F)ccc2N1
Temperature: 12 °C
Reaction time: 0.08 h

Procedure:
5. 4.3 g of 4-fluoro-2-(1H-1,2,4-triazol-3-yl)aniline are dissolved in 200 ml of dioxan and 2.3 ml of absolute pyridine. The solution is stirred under argon and cooled to 12° C. A solution of 2.2 ml of chloroacetyl chloride in 8.0 ml of diethyl ether is then added dropwise thereto within 5 min. at 12° to 15° C. The resulting suspension is stirred at 10° to 12° C. for 15 min. and then treated within 5 min. with 28.8 ml of aqueous 2N sodium hydroxide solution. The mixture is stirred at room temperature overnight. The pH thereby drops to about 9. The mixture is adjusted to pH 8 with 3N hydrochloric acid and the solution is evaporated at about 40° C. in a vacuum. The residue in 150 ml of water and 5 ml of ethyl acetate is stirred at 15° C. for 30 min. The crystals are then filtered off, washed with cold water and dried at 50° C. in a vacuum. 3.78 g of 10-fluoro-5H-[1,2,4]triazolo[1,5-d][1,4]benzodiazepin-6(7H)-one of m.p. 232.5° to 238° C. are obtained. Further substance can be obtained from the aqueous phase by evaporation to dryness in a vacuum, The residue is stirred in 10 ml of trifluoroacetic acid at room temperature overnight. The mixture is evaporated in a vacuum, the residue is taken up in 60 ml of saturated aqueous sodium carbonate solution and 2 ml of ethyl acetate, stirred at room temperature for 1 h. and the crystals are then filtered off. A further 0.5 g of 10-fluoro-5H-[1,2,4]triazolo[1,5-d][1,4]benzo-diazepin-6(7H)-one is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH:26]1(O)[CH2:30]CC[CH2:27]1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:22])[N:9]([CH3:21])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:30][CH2:26][CH2:27][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OC1CCCC1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1c(Cl)cccc1-2
Agent: [C-]#N
Agent: [K+]
Product: CN1Cc2c(C(=O)OC3CCCC3)ncn2-c2cccc(Cl)c2C1=O

Procedure:
3.19 g (10 mmol) of ethyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 70 mg of powdered potassium cyanide and 10 ml of cyclopentanol are stirred at 120° overnight, subsequently evaporated and the residue is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained cyclopentyl 7-chloro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 162°-163°.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Li]CCCC.[Br:29][C:30]1[C:31]([O:38][CH3:39])=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C1COCC1>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:32](/[CH:33]=[CH:2]/[O:3][CH3:4])[C:31]=1[O:38][CH3:39]
Reactant: COc1c(Br)cccc1C=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CO/C=C/c1cccc(Br)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 84.3 %

Procedure:
In a dried three-necked flask, to a solution of [(methyloxy)methyl](triphenyl) phosphonium chloride (3.59 g, 10.46 mmol) in THF (20 mL) was added BuLi (3.91 mL, 9.77 mmol) dropwise at −78° C. After addition, the reaction mixture was stirred at room temperature for 20 min. Then the reaction mixture was cooled to −78° C. A solution of 3-bromo-2-(methyloxy)benzaldehyde (D99) (1.5 g, 6.98 mmol) in THF (5 mL) to the reaction mixture dropwise. After addition, the reaction mixture was stirred at −78° C. for 2 hour and then warmed to room temperature. The mixture was stirred at room temperature overnight. Then the reaction was quenched with water. The organic phase was separated. The aqueous phase was extracted with EA (10 mL). The combined organic solution was dried over anhydrous sodium sulphate. After filtration, and concentration, the residue was purified by column chromatography (EA/Hexane: 0 to 30%) to give 1-bromo-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]benzene (D100) (1.43 g). MS (ES): C10H11BrO2 requires 241.9. found 243.0 (M+H+).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]([O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH2:14][Cl:15])(=O)=O)=CC=1.[I-:24].[Na+]>CC(C)=O>[C:20]([Si:17]([O:16][CH:13]([CH2:12][I:24])[CH2:14][Cl:15])([CH3:19])[CH3:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCC(CCl)O[Si](C)(C)C(C)(C)C)cc1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)OC(CCl)CI
Temperature: 80 °C
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a mixture of 2-{[tert-butyl(dimethyl)silyl]oxy}-3-chloropropyl 4-methylbenzenesulfonate (20.3 g) in acetone (200 mL) was added sodium iodide (19.7 g), and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated, water was added to the residue, and the mixture was extracted with hexane. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (13.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15]C)[CH:11]=2)[CH:6]=1)=[O:4].[Cl-].[Cl-].[Cl-].[Al+3].C(S)C.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2cc(OC)ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCS
Product: COC(=O)c1ccc2cc(O)ccc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-Methoxy-naphthalene-2-carboxylic acid methyl ester (0.68 g, 3.13 mmol) is stirred in dichloromethane (50 mL) in an ice/water bath. Aluminum trichloride (1.67 g, 12.5 mmol) is added followed by ethane thiol (1.2 mL, 15.7 mmol). The mixture is stirred at room temperature 2 hr. Water (25 mL) is added and the product is extracted into ethyl acetate (2×75 mL). The combined extracts are concentrated, and the residue is purified via silica gel chromatography eluting with 8:2 hexanes:ethyl acetate to afford the title compound as a white solid, 0.432 g, 69%. MS M++1 203. The structure is confirmed by 1H NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][C:25]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:26][CH:27]=2)[CH2:22][NH:21][C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][C:25]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:27]=3)[CH2:22][NH:21][C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)NCc2cc(Cc3ccccc3)ccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)NCc2cc(Cc3ccccc3)ccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-7-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 159-166° C.
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](Cl)=[O:15].[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:15]
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)NNC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 42.8 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (14 g, 241.12 mmol) in pyridine (100 ml) was added 3-chlorobenzoyl chloride (15 g, 85.71 mmol), and the reaction mixture was stirred for 10 h at room temperature. The resulting mixture was concentrated under vacuum to give a residue, which was dissolved in water (30 ml) and adjusted to pH 12 with sodium hydroxide (aq., sat.). The product was precipitated and collected by filtration and dried in an oven under reduced pressure to afford 2-(3-chlorobenzoyl)hydrazinecarboximidamide as a light yellow solid (7.8 g, 43%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]=2[CH2:11]O)[CH:7]=1.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][CH2:11][C:10]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][N:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[N:4][C:5]=12
Reactant: O=S(Cl)Cl
Reactant: Cc1cnc2c(CO)c(-c3ccccc3)nn2c1
Solvent: Cc1ccccc1
Product: Cc1cnc2c(CCl)c(-c3ccccc3)nn2c1
Temperature: 80 °C

Procedure:
To a solution of (6-methyl-2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)methanol x143 (2.4 mmol, 1 eq, 0.58 g) in toluene (20 ml) is added thionyl chloride (4.8 mmol, 2 eq, 353 μ□l). The mixture is heated at 80° C. for 2 hours. The resulting mixture is cooled down to room temperature and the solvent removed under reduced pressure to afford 3-(chloromethyl)-6-methyl-2-phenylpyrazolo[1,5-a]pyrimidine x146, to which 5 ml of dry DMF are added.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH:10]=O)=[CH:4][CH:3]=1.[C@@H:17]1([NH2:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1>>[F:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=2)[CH2:10][NH:27][C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Reactant: N[C@H]1CCCc2ccccc21
Product: Fc1ccc(Oc2cccc(CN[C@H]3CCCc4ccccc43)c2)cc1

Procedure:
3-(4-Fluorophenoxy)benzaldehyde, prepared as described in Tanaka, et al., J. Med. Chem., 41 (1998) 4408-4420, and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)(OC(C)(C)C)=O.Cl.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1.CC(C)([O-])C.[K+]>CS(C)=O.O1CCCC1.C(OCC)C>[N:8]1[CH:9]=[CH:10][C:11]([O:14][N:20]2[CH2:21][CH2:22][CH2:17][CH2:18][CH2:19]2)=[CH:12][CH:13]=1
Reactant: Clc1ccncc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1cc(ON2CCCCC2)ccn1
Reaction time: 16 h
Yield: 159.7 %

Procedure:
Part A: To a solution of N-BOC-4-hydroxypiperidine (3.00 g, 14.9 mmol) in dimethylsulfoxide (10 mL) are sequentially added 4-chloropyridine hydrochloride (2.35 g, 15.6 mmol) and potassium-t-butoxide (30.5 mL of a 1.0 M solution in tetrahydrofuran, 30.5 mmol). After 16 hours at ambient temperature, the reaction mixture is diluted with diethyl ether (100 mL) and washed with water (3×) and brine, and then dried over sodium sulfate. Concentration of the organic solution gives the desired 4-pyridyloxypiperidine (4.24 g, 100%) as a white solid. Analytical calculation for C15H22N2O3: C, 64.73; H, 7.97; N, 10.06. Found: C, 64.48; H, 8.14; N, 9.82.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.[C:42](Cl)(=O)[C:43](C)([CH3:45])[CH3:44]>ClCCl>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:31])=[O:32])[CH:28]=[CH:29][C:24]=1[NH:23][C:22]1[N:21]=[CH:20][N:19]=[C:18]2[N:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:43]([CH3:45])([CH3:44])[CH3:42])[CH2:9][CH2:10]3)[N:15]=[CH:16][C:17]=12
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)N1CCC(n2ncc3c(Nc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1

Procedure:
1-{4-[4-(2-Fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-yl}-2,2-dimethyl-propan-1-one was prepared according to General Procedure J by the reaction of 4-[4-(2-fluoro-4-methanesulfonyl-phenylamino)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (Example 1) with trifluoroacetic acid in dichloromethane followed by reaction with pivaloyl chloride (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA). 1H NMR (400 MHz, DMSO-d6) δ 1.23 (s, 9H), 1.98-2.03 (m, 4H), 3.06-3.12 (m, 2H), 3.30 (methyl sulfonyl and water peak), 4.40-4.46 (m, 2H), 4.99-5.03 (m, 1H), 7.79-7.81 (m, 1H), 7.88-7.92 (m, 1H), 8.21-8.25 (m, 1H), 8.30-8.43 (m, 2H), 10.38 (s, 1H). Mass spectrum MH+=475.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H-].[Na+].[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[CH:26]=[N:27][C:28](F)=[CH:29][C:30]=3[CH3:31])=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1.O>CN(C)C=O>[CH3:9][C:10]1[C:11]([N:17]2[CH2:22][CH2:21][N:20]([C:23]([C:25]3[C:30]([CH3:31])=[CH:29][C:28]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[N:27][CH:26]=3)=[O:24])[CH2:19][CH2:18]2)=[N:12][CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: O=C1CCCN1
Reactant: Cc1cnc(N2CCN(C(=O)c3cnc(F)cc3C)CC2)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(N2CCN(C(=O)c3cnc(N4CCCC4=O)cc3C)CC2)c(C)c1
Reaction time: 0.5 h
Yield: 16.8 %

Procedure:
Pyrrolidin-2-one (322 mg) was dissolved in N,N-dimethylformamide (4 mL), sodium hydride (159 mg) was added, and the mixture was stirred for 30 min. To the reaction mixture was further added [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](6-fluoro-4-methylpyridin-3-yl)methanone (620 mg) described in Preparation Example 146, and the mixture was stirred at 100° C. for 5 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (125 mg).
Reaction SMILES: [O:1]=[S:2]1(=[O:23])[C:7]2[CH:8]=[C:9]([O:12][C:13]3[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=3)[CH:10]=[CH:11][C:6]=2[N:5]2[CH2:20][CH2:21][CH2:22][CH:4]2[NH:3]1.CO[CH:26]1[CH2:30][CH2:29][CH:28](OC)O1.O.CC(O)=O>C(Cl)CCl>[N:19]1([C:15]2[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=2)[O:12][C:9]2[CH:10]=[CH:11][C:6]3[N:5]4[CH2:20][CH2:21][CH2:22][CH:4]4[NH:3][S:2](=[O:1])(=[O:23])[C:7]=3[CH:8]=2)[CH:26]=[CH:30][CH:29]=[CH:28]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cccc(Oc2ccc3c(c2)S(=O)(=O)NC2CCCN32)c1
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: O=S1(=O)NC2CCCN2c2ccc(Oc3cccc(-n4cccc4)c3)cc21
Reaction time: 1 h

Procedure:
250 mg (0.75 mmol) of {3-[(5,5-dioxido-2,3,3a,4-tetrahydro-1H-pyrrolo[2,1-c][1,2,4]-benzothiadiazin-7-yl)oxy]phenyl}amine and 137 μl (1.06 mmol) of 2,5-dimethoxytetra-hydrofuran are added to a two-phase mixture of 2.5 ml of water, 1.25 ml of AcOH and 3.75 ml of dichloro-1,2-ethane. Stirring is carried out at 80° C. for 1 hour; the mixture is allowed to return to ambient temperature and is extracted with CH2Cl2. The organic phase is washed with saturated aqueous NaCl solution and dried over MgSO4. The title product is purified by chromatography on a silica column (CH2Cl2/heptane 70/30).
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([O:20][NH2:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(OCC)C>[CH2:1]([CH:8]([CH2:12][NH:21][O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=C(Cc1ccccc1)C(=O)O
Reactant: NOCc1ccccc1
Solvent: CCOCC
Product: O=C(O)C(CNOCc1ccccc1)Cc1ccccc1
Temperature: 80 °C
Yield: 49.8 %

Procedure:
A mixture of 2-benzyl-acrylic acid (8.0 g, 55 mmol) and O-benzylhydroxylamine (16.0 g, 130 mmol) was heated at 80° C. for 18 hours. The reaction mixture was cooled, diluted with diethyl ether (100 mL) and extracted with 1 M sodium carbonate (3×100 mL). The combined aqueous extracts were acidified with 3 M citric acid and then re-extracted with DCM (3×100 mL). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield 2-(R,S)-benzyl-3-benzyloxyamino-propionic acid as a white crystalline solid (7.82 g, 53%). 1H-NMR; δ (CDCl3), 7.61-7.15 (10 H, m), 4.66 (2 H, d, J=1.7 Hz), 3.13-2.94 (4 H, m), 2.84-2.74 (1 H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:12])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[Br:13]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:13][CH2:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(C)ccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(CBr)ccc1[N+](=O)[O-]
Yield: 38.6 %

Procedure:
A mixture of 20 g of 3-methoxy-4-nitrotoluene, 21.6 g of N-bromosuccinimide and 0.3 g of dibenzoyl peroxide in 120 ml of CCl4 is heated at reflux for 5 hours. The solvent is evaporated off under vacuum, the residue is taken up in water, extracted with DCM, washed with water, dried over Na2SO4 and evaporated under vacuum. 11.35 g of the expected product are obtained after crystallization from EtOH, mp=98° C.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:23]=[CH:22][C:9]([C:10](=[O:21])[CH2:11][N:12](CC2C=CC=CC=2)[CH3:13])=[CH:8][CH:7]=1)(=[O:4])=[O:3]>C(O)C.[Pd]>[OH:21][CH:10]([C:9]1[CH:8]=[CH:7][C:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:22]=1)[CH2:11][NH:12][CH3:13]
Reactant: CN(CC(=O)c1ccc(NS(C)(=O)=O)cc1)Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CNCC(O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.5 %

Procedure:
N-(4-Methanesulphonamidophenacyl)-N-methyl-benzylamine (14.5 g) in ethanol (300 ml) containing 10% palladium on charcoal (2.0 g) was stirred under a hydrogen atmosphere (50 psi) at room temperature for 18 hours. Further catalyst (1.0 g) was added and hydrogenation was continued for a further 18 hours. The reaction was filtered and evaporated to afford an oil which was chromatographed on silica [Merck `Kieselgel 60` (trade Mark)], eluting with methylene chloride containing methanol (0% up to 20%) to give, after collection and evaporation of appropriate fractions, the title compound as a solid, yield 5 g. [Washing the column with methylene chloride:methanol:acetic acid (80:20:0.25) gave a further 4 g of the product as the acetate salt].
Reaction SMILES: [CH2:1]([NH2:5])[C:2]([OH:4])=[O:3].C[C:7]([CH3:9])=[O:8].[NH:10]([C:33]([CH3:35])=[O:34])[C@H:11]([C:23](ON1C(=O)CCC1=O)=[O:24])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:22])=[O:21])=[CH:15][CH:14]=1>C(=O)(O)[O-].[Na+]>[NH:10]([C:33]([CH3:35])=[O:34])[C@H:11]([C:23]([NH:5][CH2:1][C:2]([O:4][N:10]1[C:33](=[O:34])[CH2:35][CH2:9][C:7]1=[O:8])=[O:3])=[O:24])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([CH3:22])=[O:21])=[CH:15][CH:14]=1
Reactant: CC(C)=O
Reactant: NCC(=O)O
Reactant: CC(=O)N[C@@H](Cc1ccc(OC(C)=O)cc1)C(=O)ON1C(=O)CCC1=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)N[C@@H](Cc1ccc(OC(C)=O)cc1)C(=O)NCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
11 g of L-glycine was dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 36 g of Ac-Tyr(Ac)-OSu were added into the reaction mixture. The mixture was stirred for 5 h at RT. The mixture was washed with ether (1×300 ml). 500 ml of ethyl acetate was added into the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice-cooled 3 N HCl. The ethyl acetate layer was collected and washed with water (3×300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 28 g of the residue (Ac-Tyr(Ac)-Gly-OH) and 13 g of N-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene. The mixture was cooled to 0° C. 18 g of 1,3-dicyclohexylcarbodiimide was added into the reaction mixture. The mixture was stirred for 1 hour at 0° C. The solid was removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1×200 ml) and water (3×200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness to yield 20 g Ac-Tyr(Ac)-Gly-OSu.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15]([C:16]#[N:17])=[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:34])(=[O:33])[NH2:32])=[CH:21][C:20]=2[F:35])[C:13]([CH2:36][CH2:37][CH2:38][CH3:39])=[N:12]1.Cl[C:41]([F:47])([F:46])C(OC)=O.[F-:48].[K+].[Br-].[K+]>O.CN(C=O)C>[CH2:36]([C:13]1[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31](=[O:34])(=[O:33])[NH2:32])=[CH:21][C:20]=2[F:35])=[C:15]([C:16]#[N:17])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[C:41]([F:47])([F:48])[F:46])[N:12]=1)[CH2:37][CH2:38][CH3:39]
Reactant: [F-]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Br)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Reactant: COC(=O)C(F)(F)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(C#N)c1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Temperature: 120 °C
Reaction time: 15 h

Procedure:
A mixture of 1-(2-bromo-5-nitrophenyl)-3-n-butyl-4-[(3-fluoro-2'-sulfamoylbiphenyl-4-yl)methyl]-1H-pyrazole-5-carbonitrile (from Step A) (1 equivalent), methyl chlorodifluoroacetate (2 equiv), potassium fluoride (1 equiv), cuprous iodide (1 equiv), potassium bromide (1 equiv), and DMF (approximately 3 mL per gram of pyrazole compound) is stirred under N2 in a sealed tube at 120° C. for about 15 hours. The cooled mixture is diluted with H2O and extracted a few times with ethyl acetate. The combined organic fractions are washed with brine, dried over Na2SO4, and filtered. The filtrate is concentrated, and the residue is chromatographed on silica gel (elution with CH2Cl2 --MeOH) to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]#[N:17])[N:15]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1.C([Mg]Cl)(C)C.[Li]C(C)(C)C.CCCCC.[C:41]([O:45][CH2:46][CH3:47])(=[O:44])[CH:42]=[O:43].C1(C)C=CC=CC=1>C1COCC1>[CH2:46]([O:45][C:41](=[O:44])[CH:42]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[NH:15][C:14]([C:16]#[N:17])=[CH:13][N:12]=2)=[O:10])=[C:4]([C:18]2[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH:19]=2)[CH:3]=1)[OH:43])[CH3:47]
Reactant: CC1(C)CC=C(c2cc(Br)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Reactant: CCOC(=O)C=O
Agent: CC(C)[Mg]Cl
Agent: [Li]C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
To a suspension of 4-cyano-1H-imidazole-2-carboxylic acid [4-bromo-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (71 mg, 0.18 mmol) (as prepared in Example 14, step (c)) in 3 mL THF at −40° C. was added a 2M solution of isopropylmagnesium chloride (i-PrMgCl) in THF (0.23 mL, 0.46 mmol) and the solution was then warmed to 0° C. and stirred for 10 min. The solution was then cooled to −78° C. and a 1.7 M solution of t-BuLi in pentane (0.28 mL, 0.48 mmol) was added dropwise and then a 40% solution of ethyl glyoxalate in toluene (0.23 mL, 0.90 mmol) was added immediately thereafter. After 5 min at −78° C. the reaction was quenched with satd NH4Cl (10 mL) and extracted with EtOAc (3×10 mL) and dried over Na2SO4 and concentrated in vacuo. The title compound was purified by flash chromatography (silica gel) eluting with 50-100% EtOAc/hexanes to give 37 mg (50%) of the title compound as a white solid. Mass spectrum (ESI, m/z): Calcd. for C23H26N4O2, 423.2 (M+H). found 423.1.