Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[C:5]([O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=2)[CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:56][C:57]1[CH:58]=[C:59]([S:63]([NH2:66])(=[O:65])=[O:64])[CH:60]=[N:61][CH:62]=1>CN(C=O)C>[S:63]([C:59]1[CH:58]=[C:57]([NH:56][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:23])([F:24])[F:1])=[CH:4][C:5]=2[O:12][C:13]2[CH:14]=[N:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)[CH:62]=[N:61][CH:60]=1)(=[O:65])(=[O:64])[NH2:66]
Reactant: Nc1cncc(S(N)(=O)=O)c1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1Oc1ccc(C(F)(F)F)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)c1cncc(NC(=O)c2ccc(C(F)(F)F)cc2Oc2ccc(C(F)(F)F)nc2)c1
Temperature: 25 °C

Procedure:
A solution of 4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzoic acid (28 mg, 81 μmol), HATU (31 mg, 81 μmol), and Et3N (11 μL, 81 μmol) in DMF (1.0 mL) was stirred at room temperature for 5 min, then 5-aminopyridine-3-sulfonamide (14 mg, 81 μmol) was added. The reaction was stirred at room temperature then overnight at 70° C. The reaction was purified by reverse phase HPLC (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)) to give N-(5-sulfamoylpyridin-3-yl)-4-(trifluoromethyl)-2-(6-(trifluoromethyl)pyridin-3-yloxy)benzamide. LC/MS: m/z 507.3 (M+H)+ at 1.61 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH2:1]([N:5]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:33])([CH3:32])[C:22]=2[CH:21]=1)[C:6](=[O:19])[NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Li+]>CO.C1COCC1.O>[CH2:1]([N:5]([C:20]1[CH:29]=[CH:28][C:27]2[C:26]([CH3:31])([CH3:30])[CH2:25][CH2:24][C:23]([CH3:32])([CH3:33])[C:22]=2[CH:21]=1)[C:6](=[O:19])[NH:7][C:8]1[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)Nc1ccc(C(=O)OCC)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCN(C(=O)Nc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
A solution of ethyl 4-[3-butyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (11) (131 mg, 0.29 mmole) in 15 mL methanol, 5 mL of THF and 5 mL of water was treated with 62 mg of lithium hydroxide (5 eq.) and stirred at room temperature for eight hours. The mixture was concentrated in vacuo and the residue was acidified with concentrated HCl solution. The mixture was then extracted with three portions of 20 mL of ethyl acetate. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo to give a yellow solid which was purified by flash chromatography (SiO2, 20% ethyl acetate/hexanes+drops of acetic acid) to provide 34 mg (28%) of 4-[3-butyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid (5) as a pale yellow solid. MS (EI): (M++1) 423.
Reaction SMILES: CO.[CH3:3][NH2:4].CO.F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1>O>[CH3:3][NH:4][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: CN
Solvent: O
Solvent: CO
Product: CNc1ccc(C#N)cc1

Procedure:
A 40% methylamine methanol solution (7.5 mL) was added to a methanol (2.5 mL) solution of 4-fluorobenzonitrile (2.00 g) and the mixture was heated under reflux for fifteen hours under nitrogen atmosphere. After the solvent was removed under reduced pressure, to the residue obtained was added water (15 mL) and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine successively, and dried over anhydrous sodium sulfate. The oil obtained by removal of the solvent under reduced pressure was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=2:1) to obtain the titled compound (0.48 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:9])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1cc(C(O)c2ccccc2)ccc1Cl
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
To a stirred and cooled solution of 58.1 parts of (4-chloro-3-nitrophenyl)phenylmethanone in 240 parts of methanol were added portionwise 4.4 parts of sodium tetrahydroborate. Upon complete addition, stirring was continued for 30 minutes at room temperature. The reaction mixture was evaporated. The residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, yielding 58 parts (99.9%) of 4-chloro-3-nitro-α-phenylbenzenemethanol as a residue (int. 131).
Reaction SMILES: [Br:1][C:2]1[C:19]([CH3:20])=[C:18]([N+:21]([O-:23])=[O:22])[CH:17]=[C:16]([Br:24])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[C:7]([CH:13]([CH3:15])[CH3:14])[CH:6]=1>C(Cl)Cl>[Br:1][C:2]1[C:19]([CH3:20])=[C:18]([N+:21]([O-:23])=[O:22])[CH:17]=[C:16]([Br:24])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:13]([CH3:15])[CH3:14])[CH:6]=1
Reactant: COc1ccc(Oc2c(Br)cc([N+](=O)[O-])c(C)c2Br)cc1C(C)C
Solvent: ClCCl
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 46 %

Procedure:
4-(2,6-Dibromo-3-methyl-4-nitrophenoxy)-2-isopropylanisole of Part 8B (560-mg, 1.22 mmol) was dissolved in CH2Cl2 (10 mL) and cooled to 0° C. Ice-cold BF3-SMe2 (5 mL, 47.5 mmol) was added and the temperature was allowed to reach room temperature. After 16 hours stirring at room temperature, the reaction mixture was quenched by ice water and stirred for 30 minutes. A phase separator (IST) was used to separate the two phases and the aqueous phase was extracted by CHCl3. The collected organic phases were washed by brine and concentrated in vacuo. The residue was purified on column (MPLC, silica gel, gradient elution: n-heptane/EtOAc from 1:0 to 9:1) to give 250 mg (46%) of 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-isopropylphenol as light yellow syrup.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:21][C:22](=[O:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH2:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:21][C:22](=[O:32])[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[NH:25][C:11](=[O:13])[CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: NC(CC(=O)OCc1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Product: CC(C)(C)OC(=O)NCCC(=O)NC(CC(=O)OCc1ccccc1)c1ccccc1

Procedure:
N-(t-butoxycarbonyl)-β-alanine was reacted with DL-3-phenyl-β-alanine benzyl ester to give DL-N-[N-(t-butoxycarbonyl)-β-alanyl]-3-phenyl-β-alanine benzyl ester, m.p. 124.5°-126° C.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=1.[CH2:13]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20](=[O:23])[CH2:19]1)=[O:17])[CH3:14].[NH4+].[Cl-]>CCOCC>[CH2:13]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C:20]([OH:23])([C:3]2[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][CH:4]=2)[CH2:19]1)=[O:17])[CH3:14]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCOC(=O)N1CCC(O)(c2ccc(C(F)(F)F)cc2)C1
Temperature: 0 °C
Yield: 61 %

Procedure:
364 mg magnesium was suspended in 2 ml ether, under nitrogen. 150 ul 4-bromobenzo-trifluoride was added and then a solution of 12.6 mmol 4-bromobenzotrifluoride in 1.5 ml ether was added dropwise over a period of 10 minutes at room temperature. The mixture came mildly exothermic and turned red-brown while the grignard reagent formed during 1.5 h of stirring. The mixture was cooled down to 0° C. A solution of 12.5 mmol 1-N-ethoxycarbonyl-3-pyrrolidone in 14 ml ether was added dropwise. The reaction mixture was allowed to come to room temperature and stirred for 2 h30. 20% NH4Cl was added dropwise, at 0° C., to quench the reaction. The mixture was allowed to warm to room temperature. The aqueous layer was extracted 3 times with ether. The combined organic phases were washed with water and brine, dried over Na2SO4 and evaporated. The residue was purified on silica gel (eluent: heptane-ethyl acetate 1/1) to yield the title compound (61%) as a yellow solid. MS (m/e): 362.2 ([M+59], 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[C:17]([N:19]([CH3:25])[C:20](=[O:24])[CH:21](Br)[CH3:22])#[N:18].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.[I-].[K+]>[C:17]([N:19]([CH3:25])[C:20](=[O:24])[CH:21]([O:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5]2[C:4]([F:16])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)=[CH:14][CH:13]=1)[CH3:22])#[N:18]
Reactant: Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Reactant: CC(Br)C(=O)N(C)C#N
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(Oc1ccc(Oc2ncc(Cl)cc2F)cc1)C(=O)N(C)C#N
Temperature: 80 °C
Yield: 87.2 %

Procedure:
48.0 g (0.20 mole) of 4-(5-chloro-3-fluoropyridin-2-yloxy)phenol and 38.2 g (0.20 mole) of 2-bromopropionic acid N-cyano-N-methylamide are dissolved in 400 ml of acetonitrile. 35.9 g (0.26 mole) of potassium carbonate and 0.33 g (0.002 mole) of potassium iodide are added to the solution and the reaction mixture is heated for 13 hours at 80° C. The precipitate is removed by filtration, the filtrate is concentrated by evaporation and the residue is taken up in 500 ml of methlyene chloride. The solution is purified by treatment with activated carbon and filtration through silica gel. The filtrate is concentrated by evaporation and the residue is crystallised from a mixture of hexane and ethyl acetate, affording 61 g of 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionic acid N-cyano-N-methylamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[C:18]([N:23]=C(C3C=CC=CC=3)C3C=CC=CC=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.NO.CC([O-])=O.[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[C:18]([NH2:23])[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(N=C(c3ccccc3)c3ccccc3)c2C2CC2)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: NO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc(N)c2C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.6 %

Procedure:
To a stirred solution of 4-[6-(Benzhydrylidene-amino)-5-cyclopropyl-pyrimidin-4-yl]-piperazine-1-carboxylic acid tert-butyl ester (1.60 g, 3.31 mmol) in MeOH (70 mL) was added hydroxylamine hydrochloride (0.41 g, 6.0 mmol) and NaOAc (0.65 g, 7.9 mmol). After stirring at room temperature overnight, the reaction mixture was partitioned between 0.1N NaOH and DCM. The organic layer was dried and concentrated. The residue was purified by column (DCM:MeOH, 20:1) to give 4-(6-Amino-5-cyclopropyl-pyrimidin-4-yl)-piperazine-1-carboxylic acid tert-butyl ester (1.00 g, 95%) as a colorless syrup. 1H NMR (CDCl3, 400 MHz) δ 8.12 (s, 1H), 4.97 (s, 2H), 3.52 (m, 4H), 3.50 (m, 4H), 1.48 (s, 9H), 1.44 (m, 1H), 1.02 (m, 2H), 0.64 (m, 2H). LCMS (APCI+) m/z 320 [M+H]+; Rt=2.51 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH2:11][CH3:12])=[CH:6][CH:5]=1.C1CNC(=O)C1.[Br:21][Br-]Br.N1CCCC1=O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:13])[CH:11]([Br:21])[CH3:12])=[CH:6][CH:5]=1
Reactant: CCC(=O)c1ccc(C(=O)OC)cc1
Agent: O=C1CCCN1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=O)C(C)Br)cc1
Yield: 97.7 %

Procedure:
4-Propionyl-benzoic acid methyl ester (744 mg, 3.87 mmol), pyrrolidone hydrotribromide (1.98 g), and 2-pyrrolidinone (380 mg, 4.5 mmol) in THF (38 mL) were heated at 50° C. under nitrogen for 3 h. The mixture was cooled, filtered, concentrated, and then redissolved in ether (50 mL). The ether solution was washed successively with water (20 mL), saturated aqueous sodium thiosulphate (20 mL), saturated aqueous NaCl (20 mL), and water (20 mL), dried and evaporated to give crude 4-(2-Bromo-propionyl)-benzoic acid methyl ester as a yellow oil (1.025 g) that was used directly in the Hantzsch coupling. This material contained 91% of the desired bromoketone, 5% starting material, and 4% 4-bromo-1-butanol, as determined by 1H NMR.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[C:11]2[S:15][C:14](=[S:16])[NH:13][C:12]2=[O:17])=[CH:2]1.[CH3:18]I>[OH-].[Na+].CO>[CH3:18][S:16][C:14]1[S:15][C:11](=[CH:10][C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[C:12](=[O:17])[N:13]=1
Reactant: CI
Reactant: O=C1NC(=S)SC1=Cc1c[nH]c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSC1=NC(=O)C(=Cc2c[nH]c3ncccc23)S1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.4 %

Procedure:
To a solution of 5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-2-thioxo-1,3-thiazolidin-4-one (8 g, 30.6 mmol) in 12.6% aq. NaOH (12 mL) and methanol (80 mL), methyl iodide (2.25 mL, 36 mmol) was added and the reaction mixture stirred at RT for 4 h. Most of the solvent was distilled off and the precipitate was filtered and washed first with water, then with diethylether. The washings were concentrated and extracted with dichloromethane, dried over sodium sulphate and joined to the first solid crop. The whole crop was suspended in methanol, stirred 30′, filtered and dried to yield 2-(methylthio)-5-(1H-pyrrolo[2,3-b]pyridin-3-ylmethylene)-1,3-thiazol-4(5H)-one as a yellow solid (8.15 g, 29.5 mmol, 96%).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:25][CH:26]([OH:28])[CH3:27]>CN(C)C=O>[OH:28][CH:26]([CH3:27])[CH2:25][N:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:17]
Reactant: O=c1[nH]cc(-c2ccccc2)c2ccccc12
Reactant: CC(O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(O)Cn1cc(-c2ccccc2)c2ccccc2c1=O
Temperature: 0 °C
Yield: 81 %

Procedure:
44.2 g of 4-phenyl-1(2H)-isoquinolone and 55.2 g of potassium carbonate were mixed with 250 ml of dimethylformamide, and the mixture was heated at 110° C. to 120° C. for 2 hours. Thereafter, 35 g of 70% 1-chloro-2-propanol was added dropwise to the mixture, and then the resulting mixture was stirred and heated for 5 hours. After allowing the mixture to cool, the reaction mixture was poured into ice-water, and the precipitated crystals were collected by filtration, washed with water and then dried. The crystals were recrystallized from a mixture of methanol and diethyl ether to obtain 45.2 g (81% yield) of 2-(2-hydroxypropyl)-4-phenyl-1(2H)-isoquinolone having a melting point of 162° C. as colorless needles.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:20]([O:21][CH:22]([CH3:24])[CH3:23])=[CH:19][C:13]2[CH:14]=[CH:15][C:16](=[O:18])[O:17][C:12]=2[CH:11]=1)(=O)=O.[C:25]1([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CC(OC)(C)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:23][CH:22]([O:21][C:20]1[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:34]2[CH2:35][CH2:36][CH:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:32][CH2:33]2)=[CH:11][C:12]2[O:17][C:16](=[O:18])[CH:15]=[CH:14][C:13]=2[CH:19]=1)[CH3:24]
Reactant: CC(C)Oc1cc2ccc(=O)oc2cc1OCCCOS(C)(=O)=O
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Solvent: CCO
Product: CC(C)Oc1cc2ccc(=O)oc2cc1OCCCN1CCC(c2ccccc2)CC1
Yield: 69 %

Procedure:
Method B (24 h at 60° C.); starting materials: 7-[3-(methanesulfonyloxy)propoxy]-6-(1-methylethoxy)-2H-1-benzopyran-2-one (example 73) and 4-phenylpiperidine; yield 69%; fusion point 86°-87° C. (from TBME). Fumarate: method E; yield 90%; fusion point 164°-167° C. (from ethanol and acetone).
Reaction SMILES: C(O[CH2:8][N:9]1[C:13](=[O:14])[C:12]2[C:15]([CH:21]([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[S:10]1(=[O:25])=[O:24])(=O)C(C)(C)C.[BrH:26]>C(O)(=O)C.O>[Br:26][CH2:8][N:9]1[C:13](=[O:14])[C:12]2[C:15]([CH:21]([CH3:23])[CH3:22])=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:11]=2[S:10]1(=[O:25])=[O:24]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(COC(=O)C(C)(C)C)C2=O
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CBr)C2=O
Reaction time: 0.5 h
Yield: 92 %

Procedure:
A solution of 2-(pivaloyloxymethyl)-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide (1.33 kg, 3.62 mol), 48% HBr in acetic acid (1 L) and 3 L of acetic acid was stirred on a steam bath (90°-95° C.) for 1.5 hours. The solvent (acetic acid) was removed under vacuum to give a thick slurry of an off-white residue which was diluted with 10 L of cold water and stirred for 30 minutes. The crude product was collected by filtration, washed first with 6 L of water and then with 3 L of saturated sodium bicarbonate solution. The crude solid was dried at 60°-70° C. for 20 hours and then was recrystallized from a mixture of 5 L of ethyl acetate and 6 L of hexane. Two crops were collected to give 1.16 kg (92%) of 2-bromomethyl-4-isopropyl-6-methoxy-1,2-benzisothiazol-3(2H)-one 1,1-dioxide, as an off-white solid, m.p. 157°-159° C.
Reaction SMILES: Cl.[F:2][C:3]([F:17])([F:16])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C[O:19][C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH-].[Li+:35]>C(#N)C.O>[Li+:35].[F:17][C:3]([F:2])([F:16])[C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:23][CH2:22][CH2:21][C:20]([O-:25])=[O:19])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: COC(=O)CCCBr
Reactant: FC(F)(F)c1ccc(N2CCNCC2)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Solvent: O
Product: O=C([O-])CCCN1CCN(c2ccc(C(F)(F)F)nc2)CC1
Temperature: 100 °C
Yield: 92.7 %

Procedure:
A mixture of 1-(6-trifluoromethyl-pyridin-3-yl)-piperazine hydrochloride (440 mg; 1.65 mmol), 4-bromo-butyric acid methyl ester (322 g; 1.65 mmol), potassium carbonate (456 mg; 3.30 mmol) and potassium iodide (274 mg; 1.65 mmol) in acetonitrile (6 mL) is heated to 100° C. for 2 hours. The reaction mixture is allowed to attain room temperature, filtered and the filtrate is concentrated under high vacuum. The resulting residue is taken up in tetrahydrofuran (10 mL) and a solution of lithium hydroxide (119 mg; 4.95 mmol) in water (2 mL) is added. The resulting mixture is stirred at room temperature over night and is then diluted with acetonitrile (90 mL). The precipitate formed is then filtered and dried under high vacuum to afford the desired compound (495 mg; 1.53 mmol).
Reaction SMILES: O.[NH2:2][NH2:3].C([O:6][C:7](=O)[C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])C>>[CH3:11][C:8]([CH3:12])([CH2:9][CH3:10])[C:7]([NH:2][NH2:3])=[O:6]
Reactant: NN
Reactant: CCOC(=O)C(C)(C)CC
Solvent: O
Product: CCC(C)(C)C(=O)NN
Yield: 61.8 %

Procedure:
Reflux a mixture of hydrazine monohydrate (0.97 g, 19.4 mmol) and 2,2-dimethyl-butyric acid ethyl ester (1.4 g, 9.7 mmol) for 72 hours. Purify the crude material by flash chromatography (silica gel) using 5% (7 M ammoniated methanol) in dichloromethane to afford the title compound (0.78 g). 1H NMR (CDCl3) δ 0.81 (t, 3H), 1.13 (s, 6H), 1.53 (q, 2H), 3.88 (s, 2H), 7.05 (bs, 1H).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].CN(CCN(CCN(C)C)C)C.C([Li])CCC.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=[O:34]>O1CCCC1.CCCCCC.O>[F:1][C:2]1[C:3]([O:10][CH3:11])=[CH:4][C:5]([C:6]#[N:7])=[CH:8][C:9]=1[CH:33]([C:32]1[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=1)[OH:34]
Reactant: O=Cc1cccc(F)c1
Reactant: COc1cc(C#N)ccc1F
Agent: CN(C)CCN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C#N)cc(C(O)c2cccc(F)c2)c1F
Reaction time: 1 h

Procedure:
To a solution of 15.0 g of 4-fluoro-3-methoxybenzonitrile and 21.8 ml of N,N,N′,N′,N″-pentamethyldiethylenetriamine in 300 ml tetrahydrofuran was added 65.5 ml of a 1.59 M solution of n-butyllithium in hexane at −78° C. in an atmosphere of nitrogen gas, followed by stirring at the same temperature for 1 hour. At the same temperature, 10.5 ml of 3-fluorobenzaldehyde was added dropwise, followed by stirring at the same temperature for 1 hour. Then, water was added and the mixture was extracted with diethyl ether. The organic layer was washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:3), to give 7.1 g of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:12]([N:14]2[CH:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:24]1([CH2:30][O:31][NH2:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)CCl.CN1CCOCC1.N1C2C(=NC=CC=2)N(O)N=1>ClCCl>[CH:1]1([CH2:6][C@H:7]([CH2:8][C:9](=[O:11])[NH:32][O:31][CH2:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:12]([N:14]2[C@H:18]([C:19]([N:21]([CH3:23])[CH3:22])=[O:20])[CH2:17][CH:16]=[N:15]2)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(=O)C1CC=NN1C(=O)[C@@H](CC(=O)O)CC1CCCC1
Reactant: NOCc1ccccc1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1CC=NN1C(=O)[C@@H](CC(=O)NOCc1ccccc1)CC1CCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.7 %

Procedure:
To a solution of (3R)-3-(cyclopentylmethyl)-4-{5-[(dimethylamino)carbonyl]-4,5-dihydro-1H-pyrazol-1-yl}-4-oxobutanoic acid (269 mg, 0.83 mmol) in dichloromethane (DCM) (10 ml) was added O-(phenylmethyl)hydroxylamine (133 mg, 1.08 mmol), EDC (191 mg, 1.0 mmol), 4-methylmorpholine (0.24 ml, 2.16 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (113 mg, 0.83 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 5 hours. The reaction mixture was then washed with water (15 mL) and NaHCO3 solution (15 mL×3), and concentrated to provide the crude product as a mixture of diastereomers. This mixture was purified by Gilson HPLC (Sunfire Column 19×50 mm, flowrate 25 mL/min, 10 min, 5-65% MeCN:H2O) to afford (5S)-1-((2R)-2-(cyclopentylmethyl)-4-oxo-4-{[(phenylmethyl)oxy]amino}butanoyl)-N,N-dimethyl-4,5-dihydro-1H-pyrazole-5-carboxamide (120 mg, 33% yield). MS: 429 ([M+H]+).