Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1.[CH3:18][Si:19]([C:22]#[CH:23])([CH3:21])[CH3:20].C(N(CC)CC)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(#N)C>[CH3:18][Si:19]([CH3:21])([CH3:20])[C:22]#[C:23][C:2]1[CH:3]=[C:4]2[CH2:10][C@:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:8][C:5]2=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cnc2c(c1)C[C@@]1(CN3CCC1CC3)O2
Temperature: 100 °C
Yield: 90 %

Procedure:
(R)-(−)-5′-Bromospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine](295 mg, 1 mmol), trimethylsilylacetylene (0.355 mL, 2.5 mmol), tetrakis(triphenylphosphine)palladium (230 mg, 0.2 mmol), triethylamine (2 mL) and anhydrous acetonitrile (2 mL) were combined in a heavy-walled threaded glass tube containing a magnetic stir bar, purged with argon and sealed with a Teflon plug and FETFE O-ring. The mixture was stirred and heated at 100° C. for 4 hours, cooled to room temperature, dissolved in chloroform (25 mL), washed with saturated aqueous sodium carbonate (2 mL), dried (MgSO4), and evaporated under reduced pressure. Purification by flash chromatography through silica gel (eluting with ammoniated ether/methanol, 9:1) afforded the title compound (280 mg, 0.90 mmol, 90%): chemical ionization MS (m/z, relative intensity) 313 ([MH]+, 30).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:5]=[C:6]([CH:12]2[CH:17]([N+:18]([O-:20])=[O:19])[CH2:16][CH:15]=[CH:14][CH2:13]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10].[Br:21]N1C(=O)CCC1=O>CO.CO.C(OC(=O)C)C>[F:3][C:4]1[CH:5]=[C:6]([CH:12]2[C:17]([Br:21])([N+:18]([O-:20])=[O:19])[CH2:16][CH:15]=[CH:14][CH2:13]2)[CH:7]=[C:8]([F:11])[C:9]=1[F:10]
Reactant: O=[N+]([O-])C1CC=CCC1c1cc(F)c(F)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=[N+]([O-])C1(Br)CC=CCC1c1cc(F)c(F)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 56 mg (1 mmol) of KOH in 6 ml of methanol was added dropwise a solution of 257 mg (1 mmol) of 3,4,5-trifluoro-1-(6-nitrocyclohex-3-en-1-yl)-benzene from example 2.3 in 4 ml of methanol/ethylacetate (3:1) and the resulting mixture was stirred for 20 min at room temperature. 178 mg (1 mmol) of NBS (N-bromosuccinimide) were added and the mixture was stirred for another 30 min. The solvents were evaporated in vacuo. Column chromatography (SiO2, cyclohexane/ethylacetate 10:1) yielded 312 mg (0.93 mmol, 93% of theory) of the title compound as yellowish crystals.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][C:13]#[N:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[H-].[Na+].Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:22]([Br:28])=[CH:21][N:20]=1>O1CCCC1>[Br:28][C:22]1[CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:19]([C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:11][CH2:12][C:13]#[N:14])=[N:20][CH:21]=1
Reactant: CCOC(=O)C(CCC#N)C(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(CCC#N)(C(=O)OCC)c1ncc(Br)cc1[N+](=O)[O-]
Yield: 73 %

Procedure:
A solution of 2-(2-cyanoethyl)malonic acid diethyl ester (24.2 g) in tetrahydrofuran (15 ml) was added to a suspension of sodium hydride (2.45 g) in tetrahydrofuran (30 ml) at 20° C. under nitrogen. To this was added 2-chloro-3-nitro-5-bromopyridine (22 g) and the mixture so obtained was heated to 93°-95° C. A small amount of tetrahydrofuran was allowed to distil off. The mixture was heated under reflux for 2.5 hr. The reaction mixture was poured into water and neutralised to pH 7 with concentrated hydrochloric acid. The aqueous phase was extracted with chloroform, dried (MgSO4) decolourised with charcoal and filtered through a silica column. The chloroform eluant was evaporated to yield an oil which slowly crystallised. The crystals were washed in petroleum ether (40°-60° C.) and dried to yield 4-(5-bromo-3-nitropyrid-2-yl)-4,4-bis(carbethoxy)butyronitrile (28 g) m.p. 58°-62° C.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]1[C:30]([O:32]C)=[O:31])=[CH:11][C:10]([O:34][CH3:35])=[CH:9][CH:8]=2.C(OCC)C.O>O1CCOCC1>[Cl:3][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[CH2:14][CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19][CH:18]1[C:30]([OH:32])=[O:31])=[CH:11][C:10]([O:34][CH3:35])=[CH:9][CH:8]=2
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCC1CCCc1c(Cl)cnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOCC
Product: COc1ccc2ncc(Cl)c(CCCC3CCN(C(=O)OC(C)(C)C)CC3C(=O)O)c2c1
Temperature: 60 °C
Yield: 80.4 %

Procedure:
60 cm3 of a 1 N aqueous sodium hydroxide solution are added to 7.05 g of methyl (3RS,4RS)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylate in 100 cm3 of dioxane. The reaction medium is then heated at 60° C. for 2 hours and then concentrated to dryness under reduced pressure (45° C.; 5 kPa). The residue obtained is taken up with 300 cm3 of diethyl ether and 500 cm3 of distilled water. The aqueous phase is then washed with 200 cm3 of diethyl ether and then acidified with 55 cm3 of a 1 N aqueous hydrochloric acid solution. Re-extraction is then carried out with 2 times 250 cm3 of ethyl acetate. The pooled organic phases are dried over magnesium sulfate for 1 hour, then filtration is carried out through a sintered glass funnel and evaporation is carried out under reduced pressure (45° C.; 5 kPa). 5.5 g of (3RS,4RS)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-carboxylic acid, in the form of a white solid, are obtained.
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]2[N:6]=[CH:7][NH:8][C:4]=2[CH:3]=1.[H-].[Na+].[CH2:14](Cl)[CH2:15]Cl.[OH2:18]>CN(C)C=O>[OH:18][CH2:14][CH2:15][N:6]1[C:5]2[CH:9]=[C:10]([CH3:11])[C:2]([CH3:1])=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: O
Reactant: Cc1cc2nc[nH]c2cc1C
Reactant: ClCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc2ncn(CCO)c2cc1C
Reaction time: 0.5 h

Procedure:
A 1.46 g amount of 5,6-dimethylbenzimidazole was dissolved in 50 ml of dry N,N-dimethylformamide, 0.96 g of NaH was added to the solution, and the mixture was stirred in an ice-water bath for 30 minutes. Then to the mixture was added dropwise 5 ml of ethylene chloride, the mixture was stirred at room temperature for 15 hours, and the reaction was further carried out for 24 hours while adding 0.78 g of NaH. The reaction was stopped by an addition of 50 ml of water, and the obtained reaction mixture was washed with n-hexane, diluted with water, adjusted to a pH of 2.5 with HCl, and then applied to an ion exchange column (Dowex 50 (hydrogen ion form)). An elution was effected successively with water, 30% ethanol, and ammoniacal 30% ethanol, and the fractions eluted with ammoniacal 30% ethanol were concentrated to dryness under a reduced pressure to give crude 1-(2-hydroxy-ethyl)-5,6-dimethylbenzimidazole. The conversion to this compound from 5,6-dimethylbenzimidazole was found to be 75% by an assay according to thin layer chromatography.
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C1COCC1>[CH3:13][O:12][C:8](=[O:11])[CH2:9][CH2:10][NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCC1
Reactant: C=CC(=O)OC
Solvent: C1CCOC1
Product: COC(=O)CCNC1CCCCC1
Yield: 73.5 %

Procedure:
Cyclohexylamine (Aldrich; 17 g, 0.174 mol) was dissolved in THF (300 mL). To this was added methyl acrylate (Aldrich; 15 g, 0.174 mol) in one portion. The reaction mixture was stirred over the weekend. The solvent was evaporated with care due to the volatility of the product and the residue distilled at 72° C. at 0.30 mbar to yield the title compound as a clear oil (23.7 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[CH3:10][C:11]([CH3:16])([CH3:15])[C:12](Cl)=[O:13].CCN(CC)CC>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:12](=[O:13])[C:11]([CH3:16])([CH3:15])[CH3:10]
Reactant: NCc1cccc(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1cccc(Cl)c1
Reaction time: 2 h

Procedure:
3-chlorobenzylamine (3.54 g, 25 mmol) was added dropwise to trimethylacetyl chloride (2.65 ml, 21.5 mmol) and Et3N (3.5 ml, 25 mmol) in DCM (25 ml). After two hours, the reaction mixture was washed with 1N HCl and the organic layer collected and dried over MgSO4. N-3-chlorobenzyltrimethylacetamide was precipitated from DCM/hexane as a white solid, 3.95 g,
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:45][CH:46]1[CH2:51][CH2:50][N:49]([CH2:52][C:53]2[CH:60]=[CH:59][C:56]([C:57]#[N:58])=[CH:55][CH:54]=2)[CH2:48][CH2:47]1.Cl>CN(C)C=O.O>[C:57]([C:56]1[CH:55]=[CH:54][C:53]([CH2:52][N:49]2[CH2:48][CH2:47][CH:46]([NH:45][C:9]([C:8]3[CH:7]=[CH:6][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:13][CH:12]=3)=[O:11])[CH2:51][CH2:50]2)=[CH:60][CH:59]=1)#[N:58]
Reactant: N#Cc1ccc(CN2CCC(N)CC2)cc1
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
To a stirred mixture of 4-(methoxycarbonyl)benzoic acid (1 g, 5.55 mmol) in anhydrous N,N-dimethyformamide (5 mL) was added triethylamine (2.6 ml, 18.32 mmol), HATU (2.32 g, 6.11 mmol), and 4((4-aminopiperidin-1-yl)methyl)benzonitrile as its HCl salt (1.6 g, 5.55 mmol). The mixture was stirred at room temperature overnight and then poured into water. The resulting solids were collected by filtration, purified by column chromatography to yield 0.91 g (44%) of methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate as a white solid. LCMS (m/z): 379 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][N:10]=[C:9](Cl)[CH:8]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=2)[N:3]=1.[CH3:25][C@H:26]1[CH2:31][NH:30][CH2:29][C@@H:28]([CH3:32])[NH:27]1.CN1[C:38](=[O:39])[CH2:37]CC1>>[C:38]([N:27]1[CH:28]([CH3:32])[CH2:29][N:30]([C:9]2[CH:8]=[C:7]([N:6]3[C:2]([NH2:1])=[N:3][C:4]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:24])[CH3:23])=[CH:17][CH:16]=4)=[N:5]3)[CH:12]=[CH:11][N:10]=2)[CH2:31][CH:26]1[CH3:25])(=[O:39])[CH3:37]
Reactant: CN1CCCC1=O
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CC(=O)Nc1ccc(Nc2nc(N)n(-c3ccnc(Cl)c3)n2)cc1
Product: CC(=O)Nc1ccc(Nc2nc(N)n(-c3ccnc(N4CC(C)N(C(C)=O)C(C)C4)c3)n2)cc1
Temperature: 250 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
To a solution of 100 mg of N-{4-[5-Amino-1-(2-chloro-pyridin-4-yl)-1H-[1,2,4]triazol-3-ylamino]-phenyl}-acetamide (0.291 mMol, 1 equiv) in 5 mL of NMP was added 100 mg of cis-2,6-dimethylpiperazine (0.877 mMol, 3.0 equiv). The stirred solution was heated to 250° C. via microwave irradiation for 15 min. The reaction mixture was concentrated under vacuum by pouring and then redissolved in 5 mL of CH2Cl2 and 5 mL of DMF. To the stirred solution was added sequentially 1 mL of Hunig's base and 100 μL of acetic anhydridide. After 3 hr at 25° C., the reaction mixture was concentrated to a dark oil and purified by flash chromatography (EtOAc), yielding 15 mg of N-(4-{1-[2-(4-Acetyl-3,5-dimethyl-piperazin-1-yl)-pyridin-4-yl]-5-amino-1H-[1,2,4]triazol-3-ylamino}-phenyl)-acetamide (0.0323 mMol, 11% yield) as a yellow solid.
Reaction SMILES: CCN[C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].[OH:31][N:32]1[C:36](=[O:37])[C:35]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]2[C:33]1=[O:42].C(N=C=NC(C)C)(C)C.OS([O-])(=O)=O.[Na+]>C1COCC1.COC(C)(C)C>[O:37]=[C:36]1[C:35]2[C:34](=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:33](=[O:42])[N:32]1[O:31][C:4](=[O:5])[CH2:6][CH2:7][CH2:8][CH:9]=[CH:10][CH2:11][CH:12]1[CH:13]([OH:30])[CH2:14][CH:15]([OH:29])[CH:16]1[CH:17]=[CH:18][CH:19]([OH:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Agent: CC(C)N=C=NC(C)C
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: O=C(CCCC=CCC1C(O)CC(O)C1C=CC(O)CCc1ccccc1)ON1C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 58.4 %

Procedure:
2 g of bimatoprost acid is dissolved in 20 ml of THF and to this solution are added at room temperature 1 g of N-hydroxy-phtalimide and 1 ml of N,N′-diisopropylcarbodiimide. The reaction mixture is stirred for 2 hours and then poured onto they mixture of 1N NaHSO4 solution and tert-butyl methyl ether (TBME). The phases are separated, the organic phase is washed with 1N NaHCO3 solution and the aqueous-alkaline phase is extracted with TBME. The united organic phase is dried over Na2SO4, filtered and evaporated. The residue is crystallized from hexane:acetone mixture to obtain 1.5 g white crystalline material.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16]C)C(C#N)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.Br.[OH-].[Na+].CCCCCC.[C:27]([O:30]CC)(=[O:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([OH:16])[C:28]([C:27]([OH:30])=[O:29])=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(-c2cccc(Cl)c2)cnc1C#N
Reactant: CCOC(C)=O
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(O)c1ncc(-c2cccc(Cl)c2)cc1O
Reaction time: 3 h

Procedure:
To a 50 mL round bottom flask adapted for magnetic stirring and fitted with a reflux condenser was charged 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine, 2, (1 g, 4 mmol) and a 48% aqueous solution of HBr (10 mL). While being stirred, the reaction solution was heated to reflux for 20 hours. The reaction was determined to be complete due to the disappearance of 5-(3-chlorophenyl)-3-methoxy-2-cyanopyridine as measured by TLC analysis using hexane/ethyl acetate (6:3) as the mobile phase and UV 435 nm to visualize the reaction components. The reaction contents was then cooled to 0° C. to 5° C. with stirring and the pH was adjusted to approximately 2 by the slow addition of 50% aqueous NaOH. Stirring was then continued at 0° C. to 5° C. for 3 hours. The resulting solid was collected by filtration and washed with water, then hexane. The resulting cake was dried in vacuo at 40° C. to afford 1.03 g (quantitative yield) of the desired product as an off-white solid. 1H NMR (DMSO-d6) δ 8.52 (d, 1H), 7.99 (d, 1H), 7.95 (s, 1H) 7.81 (t, 1H), 7.57 (s, 1H), and 7.55 (s, 1H).
Reaction SMILES: [CH3:1][OH:2].Br[CH2:4][C:5]1[CH:14]=[C:13]([OH:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH:8]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[CH:9]1[CH2:18][CH2:17][CH2:16][CH:10]12.Cl>C(OCC)(=O)C>[OH:25][C:22]1[CH:21]=[CH:20][C:19]([CH:8]2[CH2:7][C:6]3[C:11](=[CH:12][C:13]([OH:15])=[CH:14][C:5]=3[CH2:4][O:2][CH3:1])[CH:10]3[CH2:16][CH2:17][CH2:18][CH:9]23)=[CH:24][CH:23]=1
Reactant: CO
Reactant: Oc1ccc(C2Cc3c(CBr)cc(O)cc3C3CCCC23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COCc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21
Yield: 37 %

Procedure:
Combine Na (0.013 g, 0.53 mmol) and methanol (2 ml) at 0-5° C. and stir until solution forms. Add 6-Bromomethyl-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalen-8-ol (0.037 g, 0.1 mmol) and stir for 3 hours. Remove solvent in vacuo. Take into ethyl acetate and 1N HCl. Separate organic layer and wash with water. Dry over anhydrous sodium sulfate and remove solvent in vacuo. The residue is chromatographed on silica gel with 25% ethyl acetate/hexanes to yield the titled compound (0.012 g, 37%). 1H NMR (DMSO-d6): 9.16(s, 1H), 9.04 (s, 1H), 7.11 (d, J=7.9 Hz, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.58 (s, 1H), 6.53 (s, 1H), 4.35 (dd, j=16 and 7 Hz, 2H), 3.4 (m, 1H presumed), 3.0 (m, 1H), 2.76 (m, 1H), 2.65 (m, 1H), 2.45(m, 1H) 2.15 (m, 1H), 1.6-1.2 (m, 5H). MS m/z 323 (M−1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[NH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(O[Na])(C)(C)C.O>COCCOCCOC>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: C1CNCCN1
Reactant: COc1ccccc1Br
Agent: CC(C)(C)O[Na]
Solvent: COCCOCCOC
Solvent: O
Product: COc1ccccc1N1CCNCC1
Temperature: 170 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a solution of 1-bromo-2-methoxybenzene (0.623 mL, 5.0 mmol) and piperazine (1722.8 mg, 20.0 mmol) in diglyme (5 mL) was added t-BuONa. The resulting mixture was stirred at rt for a few minutes before the addition of dichlorobis(tri-β-tolyphosphine)palladium (235.8 mg, 0.3 mmol). The resulting mixture was then stirred at 170° C. under microwave irradiation for 30 min. Water was added and the mixture was extracted with EtOAc. The combined organic layers were dried, concentrated, and purified by ISCO to give 1-(2-methoxyphenyl)piperazine (intermediate 65) (758 mg, 79%) as an off-white solid. HPLC: 95%, RT 2.641 min. MS (ESI) m/z 193.10 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(N)(=O)C1C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=O)=[CH:27][CH:26]=1>>[CH3:13][O:12][C:9]1[C:10]([CH3:11])=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:29]([C:28]3[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: NC(=O)c1ccccc1
Product: COc1ccc(-c2nc(O)c3ccc(OC)c(C)c3n2)cc1
Yield: 92 %

Procedure:
The general procedure described in Example 31 was followed using 2-amino-4-methoxy-3-methyl benzamide as benzamide derivative [A] and 4-methoxybenzoic acid chloride as acid chloride [B], which gave the title compound (5.5 g, 92%). 1H-NMR DMSO-D6 δ 2.38 (s, 3H), 3.82 (s, 3H), 3.92 (s, 3H), 7.04 (d, 2H), 7.20 (d, 1H), 8.00 (d, 1H), 8.20 (d, 2H), 12.18 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]#[CH:14])[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17]1)(=[O:3])[NH2:2].C(N(CC)CC)C.[OH:37]/[N:38]=[C:39](\Cl)/[CH3:40]>ClCCl>[C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:37][N:38]=[C:39]([CH3:40])[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:15][C@H:16]1[C@@H:20]([CH2:21][CH3:22])[CH2:19][N:18]([C:23]([O:25][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:24])[CH2:17]1)(=[O:3])[NH2:2]
Reactant: C/C(Cl)=N/O
Reactant: C#Cc1cc2c(N[C@@H]3CN(C(=O)OC(C)(C)C)C[C@@H]3CC)c(C(N)=O)cnn2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Temperature: 40 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-ethynylpyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate from Step 2 (88 mg, 0.221 mmol) in dichloromethane (2 mL) and triethylamine (0.046 mL, 0.332 mmol) was added (Z)—N-hydroxyacetimidoyl chloride (25.9 mg, 0.277 mmol). The solution was stirred at 40° C. overnight. After stirring overnight, the reaction was cooled to room temperature and diluted with dichloromethane. This solution was washed once with aqueous potassium carbonate, and once with water. It was then dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash chromatography, eluting with 0-100% ethyl acetate in hexanes. Concentration of the pure fractions afforded the title compound (64 mg, 60.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 11.20 (t, J=9.1 Hz, 1H), 8.31 (s, 1H), 8.24 (d, J=1.3 Hz, 1H), 7.30 (br. s., 1H), 6.72 (s, 1H), 5.01-4.74 (m, 1H), 3.81-3.58 (m, 2H), 3.48-3.34 (m, 1H), 3.10-2.96 (m, 1H), 2.42 (d, J=12.8 Hz, 1H), 2.28 (s, 3H), 1.60-1.46 (m, 2H), 1.37 (d, J=19.1 Hz, 9H), 0.96-0.75 (m, 3H). MS (ES+) m/z: 455.2 (M+H); LC retention time: 3.038 min (analytical HPLC Method O).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:28][CH2:29][O:30][CH3:31])([C:24]([F:27])([F:26])[F:25])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[CH2:32][CH2:33][CH3:34])=[CH:8][C:5]=1[C:6]#[N:7].B(F)(F)F.CCOCC.C([BH3-])#N.[Na+].O>O1CCCC1>[OH:1][CH2:3][CH2:2][C:4]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([O:28][CH2:29][O:30][CH3:31])([C:24]([F:25])([F:26])[F:27])[C:20]([F:23])([F:22])[F:21])=[CH:15][C:14]=2[CH2:32][CH2:33][CH3:34])=[CH:8][C:5]=1[C:6]#[N:7]
Reactant: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(C2CO2)c(C#N)c1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cc(C(OCOC)(C(F)(F)F)C(F)(F)F)ccc1Oc1ccc(CCO)c(C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.9 %

Procedure:
A solution of 2-oxiranyl-5-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-benzonitrile (5.0 mg, 0.0102 mmol) in tetrahydrofuran (200 μL) was sequentially added with boron trifluoride diethyl ether (2.5 μL, 0.0204 mmol) and sodium cyanoborohydride (2.6 mg, 0.0409 mmol) under ice-cold conditions, and stirred at room temperature for 2 hours. Subsequently, the resultant mixture was further sequentially added with boron trifluoride diethyl ether (2.5 μL, 0.0204 mmol) and sodium cyanoborohydride (2.6 mg, 0.0409 mmol) under ice-cold conditions, and stirred at room temperature overnight. After completion of the reaction, the reaction solution was added with water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate), and 2-(2-hydroxy-ethyl)-5-[2-propyl-4-(2,2,2-trifluoro-1-methoxymethoxy-1-trifluoromethyl-ethyl)-phenoxy]-benzonitrile (2.2 mg, yield 44%) was obtained as a yellow oil.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](O)[CH3:22].Cl.[Cl:25]CCl>CO>[ClH:25].[CH2:21]([O:19][C:18](=[O:20])[C@H:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:16])[NH2:17])[NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:22]
Reactant: N=C(N)NCCC[C@H](NC(=O)c1ccccc1)C(=O)O
Reactant: CCO
Reactant: ClCCl
Agent: Cl
Solvent: CO
Product: CCOC(=O)[C@H](CCCNC(=N)N)NC(=O)c1ccccc1

Procedure:
Nα -benzoyl-L-arginine was obtained from MTM Research Chemicals, Lancaster Synthesis, Inc., Windham, N.H. The Nα -benzoyl-L-arginine, 0.4 g, was placed in a two-necked round bottom flask equipped with a stirring bar and suspended in an excess (~5 ml) of ethyl alcohol. The outlet from the flask was attached to a mineral oil bubbler and dry hydrogen chloride gas was bubbled via the inlet into the stirred solution to the point of saturation; a mildly exothermic reaction ensued with gradual dissolution of the suspended starting material. The reaction was monitored by thin layer chromatography (TLC) in solvent system (dichloromethane:methanol: 80:20; v/v) until no starting material was left.