Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NCC#N.C1CN([P+](ON2N=N[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.C[N:49]([CH:51]=[O:52])C>>[C:51]([NH2:49])(=[O:52])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CN(C)C=O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture comprised of 2R-benzoylamino-3-benzylsulfanylpropionic acid (0.508 g, 1.61 mmol), aminoacetonitrile hydrochloride (0.149 g, 1.61 mmol), PyBOP® (0.838 g, 1.61 mmol), N,N-diisopropylethylamine (0.84 mL, 4.83 mmol) and DMF (10 mL) was stirred at room temperature for 2.5 hours. The mixture was concentrated and the residue was taken up into dichloromethane. The dichloromethane mixture was washed with 1N hydrochloric acid, water and aqueous sodium bicarbonate, dried (MgSO4), filtered and concentrated. Product was purified from the residue by silica gel chromatography using 5% methanol in dichloromethane to provide N-(2-benzylsulfanyl-1R-cyanomethylcarbamoyl)ethyl)benzamide (541 mg, 1.53 mmol) as an oil. MS: m/e 353.8 (theory 353.1); Proton NMR Spectrum (DMSO-d6): δ 8.85 (t, 1H), δ 8.75 (d, 1H), δ 7.99 (d, 2H), 7.5 (m, 3H), δ 7.3 (m, 5H), δ 4.7 (m, 1H), δ 4.15 (d, 2H), δ 3.75 (s, 2H), δ 2.8 (m, 2H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][O:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:9][O:10][C:11]1[C:16]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: Nc1cc(Br)ccn1
Reactant: COc1ncccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ncccc1-c1ccnc(N)c1
Temperature: 85 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
To 4-bromopyridin-2-amine (0.5 g, 2.8 mmol), 2-methoxypyridin-3-ylboronic acid (0.52 g, 3.4 mmol) in DMF (25 mL) was added 1N sodium carbonate (10 mL, 2.3 mmol), followed by 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.21 g, 0.26 mmol). The reaction mixture was stirred for 3 hours at 85° C. and then cooled to room temperature. The product was extracted with ethyl acetate (2×50 mL), dried with MgSO4, filtered, and concentrated in vacuo. The crude product was purified by chromotography (Biotage: 100 to 90/10% ethyl acetate-ethyl acetate/methanol) to yield 2-methoxy-3,4′-bipyridin-2′-amine (0.53 g, 2.63 mmol, 93% yield) as a brown powder. The product was taken directly to the next step.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[N:18]1([CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([NH:17][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([CH2:24][N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:26][CH:27]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(CN2CCCCC2)cc1
Reactant: Nc1cccc(Br)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(Br)c1)c1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
DIEA (433 μl, 2.49 mmol) was added into a suspension of 3-bromobenzenamine (90.34 μl, 0.829 mmol), 4-(piperidin-1-ylmethyl)benzoic acid (200 mg, 0.912 mmol), BOP (477 mg, 1.08 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature under argon atmosphere overnight. The reaction mixture was loaded onto a 5 g silica loading cartridge. After solvent in the cartridge was dried out under vacuum, the cartridge was put on the ICSO system for purification (yield: 80%). MS (ESI+) m/z 373.0 [M+H]+.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5]([NH:7][NH2:8])=[O:6].[CH2:9]([C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=O)[CH3:10].CCO.CCCCCC.C(OCC)(=O)C>C(O)(=O)C.CCOCC>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11](=[N:8][NH:7][C:5]([CH:3]2[CH2:4][CH:2]2[CH3:1])=[O:6])[CH2:9][CH3:10])[CH:14]=1
Reactant: CC1CC1C(=O)NN
Reactant: CCC(=O)c1cccnc1
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCC(=NNC(=O)C1CC1C)c1cccnc1
Temperature: 25 °C
Yield: 29.5 %

Procedure:
A mixture of 8.0 gm (0.07 mole) of 2-methylcyclopropanecarboxylic acid hydrazide, 9.46 gm (0.07 mole) of ethyl-3-pyridyl ketone, 10 drops of glacial acetic acid and 100 ml of EtOH was refluxed 20 hr. Tlc (9:1 Skellysolve B/Ethyl acetate on silica gel) shows no remaining starting material. The reaction mixture was cooled to room temperature and evaporated in vacuo to give a liquid. The liquid solidified on standing. The solid was slurried in ether, collected and dried to give 4.77 gm (29%) of the title compound having a melting point of 137.3° C.
Reaction SMILES: [CH3:1][C:2]([CH3:8])=[N:3][N:4]=[C:5]([CH3:7])[CH3:6].[CH2:9]([Mg]Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(OCC)C.O1CCCC1>[CH3:6][C:5]([NH:4][N:3]=[C:2]([CH3:8])[CH3:1])([CH3:7])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Br[Mg]Cc1ccccc1
Reactant: CC(C)=NN=C(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)=NNC(C)(C)Cc1ccccc1
Temperature: 45 °C
Reaction time: 24 h
Yield: 25.9 %

Procedure:
Acetone azine (1.50 g, 13.4 mmol) was dissolved in 10 mL of diethyl ether mixed with 32 mL (19.2 mmol) of 0.6 M benzylmagnesium bromide in tetrahydrofuran and stirred at 45° C. for 24 hours. The reaction was quenched with saturated aqueous ammonium chloride (100 ml), and the reaction solution was extracted with ethyl acetate. The resulting organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using hexane-ethyl acetate (9:1 to 6:1) as the eluent to give 710 mg of the desired product as a pale yellow oil.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:25])[CH2:22][CH2:23][CH3:24]>C(Cl)Cl>[C:21]([NH:3][CH2:4][CH2:5][CH2:6][S:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(=[O:25])[CH2:22][CH2:23][CH3:24]
Reactant: CCCC(=O)Cl
Reactant: NCCCSc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NCCCSc1ccncc1
Yield: 91.1 %

Procedure:
To a solution of 700 mg (2.90 mmol) of 4-(3-aminopropylthio)pyridine dihydrochloride and 1.62 ml (11.6 mmol) of triethylamine in 30 ml of methylene chloride was added 0.36 ml (3.48 mmol) of butyryl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was purified by column chromatography (eluent: methanol/ethyl acetate=1:1) to obtain 630 mg of the desired compound (91.1%, pale yellow oil).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13]I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:23])[C@@H:10]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:12][CH2:13][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCI)C(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H](CCCN1CCCCC1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.3 %

Procedure:
To a solution of N-t-butoxycarbonyl-(S)-2-amino-5-iodopentanoic acid benzyl ester(J.Org. Chem. 1998, 7875-7884)(100.8 mg, 0.23 mmol) in N,N-dimethylformamide (0.25 mL) was added piperidine (41.5 mg, 0.49 mmol) and the mixture was stirred for 3 hours at room temperature. To the reaction mixture was added chloroform (30 mL) and the mixture was washed with saturated aqueous sodium hydrogencarbonate solution (3×3 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum to obtain crude N-t-butoxycarbonyl-(S)-2-amino-5-(1-piperidinyl)pentanoic acid benzyl ester(83.8 mg) as a colorless oily material.
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.ON1C(=O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:34][O:35][C:36](=[O:58])[C@H:37]([CH2:54][CH2:55][S:56][CH3:57])[NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([NH2:46])=[CH:42][C:41]=1[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CN(C=O)C.C(OCC)(=O)C>[CH3:34][O:35][C:36](=[O:58])[C@H:37]([CH2:54][CH2:55][S:56][CH3:57])[NH:38][C:39](=[O:53])[C:40]1[CH:45]=[CH:44][C:43]([NH:46][C:7]([CH:2]2[NH:1][C:5](=[O:6])[CH2:4][CH2:3]2)=[O:9])=[CH:42][C:41]=1[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(N)cc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=c1c2ccccc2nnn1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(NC(=O)C2CCC(=O)N2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.6 %

Procedure:
To a solution of L-pyroglutamic acid (49 mg, 0.38 mmol) in 5 mL of DMF was added 3-hydroxy,1,2,3-benzotriazin-4(3H)-one (62 mg, 0.38 mmol), (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (58 mg, 0.30 mmol) and [4-amino-2-phenylbenzoyl-L-methionine methyl ester (90 mg, 0.38 mmol), prepared as in Example 192B, and the reaction mixture was stirred at 25° C. for 12 hours. The reaction mixture was taken up in ethyl acetate and washed with 10 mL 1N HCl, 5 mL satd aqueous NaHCO3 and brine (3×10 mL). The organic layer was dried over Na2SO4, filtered and evaporated. Purification by radial chromatography (2-5% methanol-ethyl acetate gradient) to give [4-(2-pyrrolidinone-5-ylcarbonylamino)-2-phenylbenzoyl]methionine methyl ester (92 mg, 79%) as a white solid.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(=O)(O)[O-].[Na+]>C1COCC1>[CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2nc3ccccc3cc2c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc2c(c1)Cc1ccccc1N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
Under a nitrogen atmosphere, acridine (17.19 g, 95.92 mmol) and THF (300 ml) were introduced into a round-bottom flask. At 0° C., LiAlH4 (14.56 g, 383.66 mmol) was slowly added in halves twice thereto, followed by stirring at room temperature for 4 hours. At 0° C., the resultant product was slowly added with a sodium bicarbonate solution, and then extracted with methylene chloride and distilled water. The extracted layer was dried with sodium sulfate so as to filtrate and concentrate an organic solvent. Then, the resultant product was columned by methylene chloride and hexane (n-Hexane:MC=8:2) so as to obtain a required compound, 9,10-dihydroacridine (white solid, 14 g, 82%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[C:12]1([CH:18]2[CH2:24][C:23](=O)[NH:22][C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[S:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH-].[Na+]>O>[C:12]1([CH:18]2[CH2:24][CH2:23][NH:22][C:21]3[CH:26]=[CH:27][CH:28]=[CH:29][C:20]=3[S:19]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CC(c2ccccc2)Sc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(C2CCNc3ccccc3S2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 24 g. of lithium aluminum hydride in 950 ml. of dry tetrahydrofuran is treated portionwise with 140 g. of finely-divided 2,3-dihydro-2-phenyl-1,5-benzothiazepin-4-one. The reaction is exothermic and the mixture is allowed to reflux during the addition. After stirring for 2 hours at room temperature, the mixture is refluxed for 3 hours, cooled and treated dropwise with 30 ml. of water and then a solution of 16 g. of sodium hydroxide in 100 ml. of water. The organic phase is filtered from the inorganic salt, washed with ether and the filtrate dried over magnesium sulfate. After evaporation of the solvent, the residue is fractionated to give 118.5 g. of liquid, b.p. 179°-181° (0.2 mm). The distillate slowly crystallized to a yellow solid, m.p. 62°-64°. A sample crystallized from isopropyl ether gave a granular colorless product, m.p. 65°-67°.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH2:12](O)[CH3:13]>>[CH2:12]([O:4][C:3](=[O:5])[C:2]([NH2:1])([CH3:7])[CH3:6])[CH3:13]
Reactant: CC(C)(N)C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(C)(C)N
Temperature: 0 °C
Yield: 63 %

Procedure:
2-Amino-2-methyl-propionic acid (1.0 g, 9.69 mmol) was dissolved in ethanol (15 ml) and cooled to 0° C. Thionyl chloride (1.7 g, 14.53 mmol, 1.5 eq) was added to the reaction mixture, which was then heated to reflux overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate. The organic layer was concentrated and dried to give 2-amino-2-methyl-propionic acid ethyl ester (0.8 g, 63%). The crude compound was used in the next stage without purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[O:55][CH2:54]1>CN(C=O)C>[O:53]1[C:57]2[CH:58]=[CH:59][C:60]([C:62]3[CH:63]=[C:64]([NH:68][C:24]([C:19]4[C:20](=[O:23])[O:21][C:22]5[C:17]([CH:18]=4)=[CH:16][CH:15]=[CH:14][C:13]=5[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=3)=[CH:61][C:56]=2[O:55][CH2:54]1
Reactant: Nc1cccc(-c2ccc3c(c2)OCO3)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2ccc3c(c2)OCO3)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 70 %

Procedure:
DIEA (0.014 mL, 0.077 mmol) was added to 8-trifluoromethoxy-3-carboxy-coumarin (0.019 g, 0.070 mmol) and HATU (0.029 g, 0.077 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Benzo[1,3]dioxol-5-yl-phenylamine (0.015 g, 0.070 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.023 g of product in 70% yield: LCMS (ESI) m/z 470 (MH+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[F:6][C:7]1[CH:8]=[C:9]([CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[C:11]([F:14])[C:12]=1[F:13].C(Br)C=C.[OH-].[Na+]>C1COCC1.C(OCC)C>[F:6][C:7]1[CH:8]=[C:9]([CH:15]([CH2:3][CH:2]=[CH2:1])[C:16]([OH:18])=[O:17])[CH:10]=[C:11]([F:14])[C:12]=1[F:13]
Reactant: O=C(O)Cc1cc(F)c(F)c(F)c1
Reactant: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)O)c1cc(F)c(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
n-Butyl lithium (7.89 mL; 2.66 M solution in hexane) was added to a solution of 3,4,5-trifluorophenylacetic acid (2 g) in THF (50 mL) at −78° C. The reaction solution was stirred at −78° C. for 20 minutes. Then, the reaction solution was heated to 0° C. and further stirred for 30 minutes. Allyl bromide (0.999 mL) was added dropwise to the reaction solution, and the reaction solution was stirred at room temperature for three hours. A 1 N sodium hydroxide solution and diethyl ether were added to the reaction solution, and the aqueous layer was separated. 5 N hydrochloric acid and ethyl acetate were added to the resulting aqueous layer, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 1.45 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([S:17](Cl)(=[O:19])=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[C:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:23]=1>O1CCCC1.O>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][S:17]([C:11]2[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:9]([O:8][CH3:7])[CH:10]=2)(=[O:19])=[O:18])=[C:24]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)[CH:23]=1
Reactant: Nc1ccc(Cl)cc1Cc1ccccn1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2Cc2ccccn2)cc1OC
Reaction time: 72 h

Procedure:
0.7 ml of pyridine and then 2.27 g of 3,4-dimethoxybenzenesulfonyl chloride are successively added at room temperature to 1.86 g of 4-chloro-2-(pyridin-2-ylmethyl)aniline in solution in 20 ml of tetrahydrofuran. After 72 hours at room temperature, the reaction medium is taken up in water and extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sulfate and concentrated in order to obtain 2.12 g of the expected product.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([O:15][CH3:16])[N:14]=1)[C:9]([OH:11])=O)[CH2:4][CH3:5])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:48]([C:50]1[CH:51]=[C:52]([CH:57]=[C:58]([CH3:61])[C:59]=1[OH:60])[C:53]([NH:55]O)=[NH:54])[CH3:49]>CN(C=O)C.C(Cl)Cl>[CH2:48]([C:50]1[CH:51]=[C:52]([C:53]2[N:55]=[C:9]([C:8]3[CH:12]=[C:13]([O:15][CH3:16])[N:14]=[C:6]([CH:3]([CH2:1][CH3:2])[CH2:4][CH3:5])[CH:7]=3)[O:11][N:54]=2)[CH:57]=[C:58]([CH3:61])[C:59]=1[OH:60])[CH3:49]
Reactant: CCc1cc(C(=N)NO)cc(C)c1O
Reactant: CCC(CC)c1cc(C(=O)O)cc(OC)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1O
Reaction time: 2 h
Yield: 47.7 %

Procedure:
To a solution of 2-(1-ethyl-propyl)-6-methoxy-isonicotinic acid (436 mg, 1.95 mmol) and DIPEA (759 mg, 5.86 mmol) in DMF (30 mL), TBTU (627 mg, 1.95 mmol) is added. The mixture is stirred at rt for 15 min before 3-ethyl-4,N-dihydroxy-5-methyl-benzamidine (379 mg, 1.95 mmol) is added. Stirring is continued at rt for 2 h. The mixture is diluted with DCM (100 mL) and washed three times with sat. aq. NaHCO3 solution. The org. extract is dried over MgSO4, filtered and concentrated. The residue is dissolved in dioxane (20 mL) and the mixture is stirred at 100° C. for 18 h. The mixture is concentrated and the crude product is purified by prep. HPLC to give 2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenol (355 mg) as a beige solid; LC-MS: tR=1.20 min, [M+H]+=382.04; 1H NMR (CDCl3): δ0.84 (t, J=7.3 Hz, 6H), 1.34 (t, J=7.5 Hz, 3H), 1.68-1.89 (m, 4H), 2.36 (s, 3H), 2.57-2.65 (m, 1H), 2.74 (q, J=7.8 Hz, 2H), 4.02 (s, 3H), 5.00 (s br, 1H), 7.33 (s, 1H), 7.45 (s, 1H), 7.85 (s, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1Br.[C:25]1(B(O)O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][N:19]([CH3:21])[C:18](=[O:22])[N:17]([CH3:23])[CH2:16]2)=[CH:11][C:10]=1[C:25]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH:26]=1
Reactant: OB(O)C1=CCCCCC1
Reactant: CN1CC(c2ccc(N)c(Br)c2)CN(C)C1=O
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN1CC(c2ccc(N)c(C3=CCCCCC3)c2)CN(C)C1=O
Temperature: 25 °C
Yield: 86.1 %

Procedure:
A solution of 5-(4-amino-3-bromo-phenyl)-1,3-dimethyl-tetrahydro-pyrimidin-2-one trifluoroacetic acid salt (as prepared in Example 7, step (b), 105 mg, 0.352 mmol), cycloheptene-1-yl boronic acid (74 mg, 0.52 mmol), K3PO4 (224 mg, 1.05 mmol), tris(dibenzylideneacetone) dipalladium (0) (Pd2(dba)3) (32 mg, 0.034 mmol), and 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (S-Phos) (57.5 mg, 0.350 mmol) in toluene (0.7 mL) was heated at 100° C. under Ar for 1 h. The reaction mixture was allowed to cool to RT and filtered. The filter cake was washed with DCM (2×10 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was purified on silica (20-100% EtOAc-hexane) to afford the title compound (95 mg, 86%): Mass spectrum (ESI, m/z): Calcd. for C19H27N3O, 314.2 (M+H). found 314.3.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.CN1CCOCC1.[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[C:22]([F:29])[CH:21]=1>ClCCl>[Br:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[O:25])=[C:22]([F:29])[CH:21]=1
Reactant: O=C(Cl)c1ccc(Br)cc1F
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
To a stirring solution of (S)-(+)-1-(2-pyrrolidinylmethyl)pyrrolidine (1.0 mmol) and N-methylmorpholine (1.0 mmol) in dichloromethane (0.10M), slowly add 4-Bromo-2-fluorobenzoic acid chloride (1.0 mmol) diluted in dichloromethane. Stir reaction at room temperature for one hour. After this time wash the reaction with saturated aqueous sodium bicarbonate while extracting with dichloromethane. Dry the organic layer with sodium sulfate, filter and concentrate in vacuo to give the title compound. MS (m/e): 355.1/357.1 (M+1).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[C:7](O)(=[O:11])[CH:8]([CH3:10])[OH:9].C(O)(C)C>O>[C:7]([O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])(=[O:11])[CH:8]([CH3:10])[OH:9]
Reactant: CN(C)CCO
Reactant: CC(O)C(=O)O
Solvent: O
Solvent: CC(C)O
Product: CC(O)C(=O)OCCN(C)C

Procedure:
A dimethyl ethanolamine lactate was prepared by admixing 13.3 parts of dimethyl ethanolamine and 18.0 parts of lactic acid (88 percent solution in water). The mixture was held at 40°-60°C. for a short time and there was then added 7.2 parts of isopropanol. The final composition consisted of 75 percent solids and contained 7.1 percent water.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([N+:14]([O-:16])=[O:15])[CH:6]=1)=[O:4].S(Cl)(Cl)=O.[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[C:29]2[NH2:35]>C1COCC1.N1C=CC=CC=1>[F:21][C:22]1[CH:23]=[C:24]([CH:36]=[C:37]([F:39])[CH:38]=1)[CH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[NH:31][N:30]=[C:29]2[NH:35][C:9]([C:8]1[CH:12]=[CH:13][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15])=[O:11]
Reactant: COC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1
Reactant: Nc1n[nH]c2ccc(Cc3cc(F)cc(F)c3)cc12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2n[nH]c3ccc(Cc4cc(F)cc(F)c4)cc23)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 65.2 %

Procedure:
4-(methoxycarbonyl)-2-nitrobenzoic acid (4.8 gr, 21.3 mmol) and thionyl chloride (15.5 mL) were stirred in THF dry (130 mL) at 70° C. for 2 hours. Volatiles were evaporated and the residue dissolved in dry pyridine (100 mL) at 0° C. A solution of 5-(3,5-difluoro-benzyl)-1H-indazol-3-ylamine (4.6 mg, 17.76 mmol) in dry pyridine (10 mL) was added to the cooled reaction mixture. Temperature was allowed to reach room temperature overnight. Reaction was quenched with NaHCO3 sat. sol and extracted with ethyl acetate. Collected organic phases were dried over Na2SO4, filtered and evaporated to dryness. Residue was purified by column chromatography over silica gel (DCM/EtOH/7N NH3 in MeOH=95/5/0.5) affording 5.4 gr (65% yield) of the title compound.