Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH2:30][CH3:31])[CH2:28]O)[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:13][C:14]1[CH:33]=[CH:32][C:17]2[C:18]([CH:21]3[CH2:26][CH2:25][N:24]([CH:27]([CH3:28])[CH2:30][CH2:31][N:38]4[C:34](=[O:44])[C:35]5=[CH:43][CH:42]=[CH:41][CH:40]=[C:36]5[C:37]4=[O:39])[CH2:23][CH2:22]3)=[N:19][O:20][C:16]=2[CH:15]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CCN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of diethyl azodicarboxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperdinyl]-butanol (6.9 g, 23.6 mmol), phthalimide (4.16 gm, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped and the residue was stirred in ether (200 ml). The insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g; eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and SIO2 100 g; eluted with DCM, 11; and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated. The lower compounds on TLC 3.66 g) was treated with HCl/ether in ethanol, and the solid salt was precipitated with hexane. Recrystallization from ethanol and isopropyl ether yielded white crystals 3.26 g, m.p. 210-214° C. dec.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Cl:13])[CH:11]=2)[C:6]([C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][C:23]3=[O:31])[CH2:18][CH2:17]2)=[O:15])=[CH:5]1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([N:16]3[CH2:17][CH2:18][CH:19]([N:22]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][C:23]4=[O:31])[CH2:20][CH2:21]3)=[O:15])=[CH:5][N:4]2[CH2:3][CH2:2][NH:1][C:32](=[O:34])[CH3:33])=[CH:8][CH:9]=1
Reactant: CC(=O)Cl
Reactant: NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCCn1cc(C(=O)N2CCC(N3C(=O)Cc4ccccc43)CC2)c2ccc(Cl)cc21

Procedure:
A solution of 1-{1-[1-(2-amino-ethyl)-6-chloro-1H-indole-3-carbonyl]-piperidin-4-yl}-1,3-dihydro-indol-2-one (1 eq) in dry CH2Cl2 was treated with acetyl chloride (1.1 eq) and triethylamine at RT for 15 h. Quenching with H2O and extraction into CH2Cl2 followed by concentration and purification by prep HPLC gave the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[F:11])[C:6]#[N:7].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15](Br)[N:14]=1>C1COCC1.[Zn].C1COCC1.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>[Br:12][C:13]1[N:14]=[C:15]([CH2:2][C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=2[F:11])[C:6]#[N:7])[CH:16]=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(F)c(CBr)c1
Reactant: Brc1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Zn]
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(Cc2cccc(Br)n2)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 34.4 %

Procedure:
A solution of 3-(bromomethyl)-4-fluorobenzonitrile (from Step A above, 17.7 g, 83.3 mmol) in THF was cooled to 0° C. and then 160 mL of Zn/THF solution (124.4 mmol) was added. After stirring at 0° C. for 45 minutes, the reaction was stirred at ambient temperature for an additional 20 minutes. To this reaction mixture was added 2,6-dibromo pyridine (19.73 g, 83.3 mmol) and tetrakis(triphenylphosphine)palladium (5.00 g, 4.30 mmol), and heated to 90° C. for 1.5 hours until the reaction was complete by TLC. The reaction was cooled to room temperature, filtered through celite, and concentrated. The crude residue was purified via silica gel chromatography (hexanes/methylene chloride) to give the title compound (8.34 g).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](I)[CH:10]=1)=[O:4].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][C:20]1=[O:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNC1CCCCC1NC>CN(C=O)C.[Cu]I>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([N:21]2[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:19][C:20]2=[O:28])[CH:10]=1)=[O:4]
Reactant: O=c1[nH]c2ccccc2o1
Reactant: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cc2)cc(-n2c(=O)oc3ccccc32)c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester (200 mg, 0.57 mmol) was dissolved in DMF (3 mL) and 2-benzoxazolinone (270 mg, 2.0 mmol), K3PO4 (424 mg, 2.0 mmol), CuI (15 mg), and 1,2-bis(methylamino)cyclohexane (0.15 mL) were added. The reaction mixture was stirred at 110° C. overnight, then cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was concentrated under reduced pressure and the residue was purified by preparative thin layer chromatography (3:1 hexanes/ethyl acetate) to give 4′-methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid methyl ester, which was used directly in the subsequent step.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH3:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[C:21]([C:11]1[CH:10]=[CH:9][C:8]([S:7][C:1]2[CH:2]=[CH:3][C:4]([C:21](=[O:22])[CH2:20][CH2:19][CH3:18])=[CH:5][CH:6]=2)=[CH:13][CH:12]=1)(=[O:22])[CH2:20][CH2:19][CH3:18]
Reactant: CCCC(=O)Cl
Reactant: c1ccc(Sc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC(=O)c1ccc(Sc2ccc(C(=O)CCC)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Diphenylsulfide (33.3 ml, 0.20 mol) is added to a suspension of AlCl3 (54.7 g, 0.41 mol) in 350 ml of CH2Cl2. n-Butyryl chloride (41.4 ml, 0.40 mol) is added dropwise slowly in an ice bath and the reaction solution is stirred at room temperature for 15 h. Then, the reaction solution is poured into ice-water. The crude product is extracted with CH2Cl2, washed with 1N NaOH and brine, dried over MgSO4, and concentrated. The product is obtained as a white solid. 1H NMR (CDCl3), δ[ppm]: 1.00 (t, 6H), 1.77 (tq, 4H), 2.92 (t, 4H), 7.40 (d, 4H), 7.90 (d, 4H).
Reaction SMILES: [NH:1]=[C:2]([C:10]1[N:11]=[CH:12][N:13]2[C:18](=[O:19])[N:17]([CH3:20])[N:16]=[N:15][C:14]=12)[S:3][CH2:4][C:5](=O)[C:6]([OH:8])=O.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH2:36]([NH2:39])[C:37]#[CH:38]>C1COCC1>[CH3:20][N:17]1[C:18](=[O:19])[N:13]2[CH:12]=[N:11][C:10]([C:2]3[S:3][CH:4]=[C:5]([C:6]([NH:39][CH2:36][C:37]#[CH:38])=[O:8])[N:1]=3)=[C:14]2[N:15]=[N:16]1
Reactant: C#CCN
Reactant: Cn1nnc2c(C(=N)SCC(=O)C(=O)O)ncn2c1=O
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C#CCNC(=O)c1csc(-c2ncn3c(=O)n(C)nnc23)n1
Reaction time: 1 h
Yield: 36 %

Procedure:
To a solution of 3-(imino(3-methyl-4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazin-8-yl)methylthio)-2-oxopropanoic acid (0.65 g; 2.2 mmol) in dry THF (30 mL) under nitrogen was added isobutyl chloroformate (0.60 mL; 4.4 mmol), followed by triethylamine (0.62 mL; 4.4 mmol). The mixture was stirred for 1 hour, and then propargylamine (0.28 mL; 4.4 mmol) was added, and stirring continued for a further 3 hours. The precipitate was washed with water (5×15 mL) and diethyl ether (2×15 mL) to yield the title compound as a pale yellow solid (0.250 g; 36%). δH (DMSO-d6) 3.13 (1H, m), 3.89 (3H, s), 4.10 (2H, m), 8.47 (1H, s), 8.68 (1H, t, J=5.9), 8.95 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:14]3[CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][NH:22][C@H:21]([CH3:25])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH3:9])=[C:4]([F:26])[CH:3]=1.C(OC([N:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[C:39](O)=[O:40])=O)(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([N:10]2[C:14]3[CH:15]=[C:16]([N:19]4[CH2:24][CH2:23][N:22]([C:39]([C@H:35]5[CH2:36][CH2:37][CH2:38][NH:34]5)=[O:40])[C@H:21]([CH3:25])[CH2:20]4)[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH3:9])=[C:4]([F:26])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccc3ncn([C@H](C)c4ccc(Cl)cc4F)c3c2)CCN1C(=O)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
To a stirred solution of 1-((R)-1-(4-chloro-2-fluorophenyl)ethyl)-6-((R)-3-methylpiperazin-1-yl)-1H-benzo[d]imidazole (0.044 g, 0.11 mmol) and (R)-1-(t-butoxycarbonyl)pyrrolidine-2-carboxylic acid (0.047 g, 0.22 mmol) in dichloromethane (1 mL) was added HATU (0.084 g, 0.22 mmol) and Et3N (0.10 mL, 0.72 mmol). The reaction mixture was stirred at room temperature for 2 h, and diluted with ethyl acetate. The mixture was washed with deionized water, and the aqueous layer was extracted with ethyl acetate (2×10 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 50% ethyl acetate in hexanes) to afford the desired product (0.018 g, 0.031 mmol, 28%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[CH2:27]([NH2:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:27]([NH:34][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCc1ccccc1
Reactant: Brc1ccc(CN2CCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(CNc2ccc(CN3CCCC3)cc2)cc1
Temperature: 70 °C

Procedure:
The mixture of 4-bromobenzyl-pyrrolidine (1 equiv, 120 mg), Pd2(dba)3 (2.0% equiv, 9.15 mg), t-Bu3P (1.6% equiv, 1.6 mg), benzylamine (1 equiv, 53.6 mg) and NaOtBu3 (1.5 equiv, 72 mg) in toluene (5 mL) was heated at 70° C. for 8 h.
Reaction SMILES: [N:1]([CH:4]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH2:5]I)=[N+]=[N-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[N-]=[N+]=[N-].[OH-].[Na+]>C(OC)(C)(C)C.O>[CH3:12][C:9]1([CH3:13])[O:8][CH:7]([CH:4]2[CH2:5][NH:1]2)[CH2:11][O:10]1
Reactant: CC1(C)OCC(C(CI)N=[N+]=[N-])O1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: CC1(C)OCC(C2CN2)O1
Reaction time: 8 h

Procedure:
Iodoazide 19 was added as a methyl t-butyl ether (MTBE) solution to LAH in MTBE at a slow rate such that the solvent undergoes very mild reflux. At the completion of the azide addition, the reaction is stirred overnight and then worked up by the addition of 4 n mL water and n mL 2 N aq. sodium hydroxide solution for every n g of LAH used. The slurry was filtered and the ethereal solution of 20 carried on the next step.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH3:7])(=[O:6])=[O:5].CS(C)=O.[CH3:12][N:13]([C:17]1[CH:18]=[C:19]([CH:24]=[C:25]([N:27](C)[C:28](=O)C)[CH:26]=1)[C:20](OC)=[O:21])C(=O)C>O.C(O)(=O)C>[CH3:28][NH:27][C:25]1[CH:24]=[C:19]([C:20](=[O:21])[CH2:3][S:4]([CH3:7])(=[O:6])=[O:5])[CH:18]=[C:17]([NH:13][CH3:12])[CH:26]=1
Reactant: CS(C)(=O)=O
Reactant: COC(=O)c1cc(N(C)C(C)=O)cc(N(C)C(C)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CNc1cc(NC)cc(C(=O)CS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 19.2 g. of sodium hydride (50% dispersion in oil) and 56.1 g. of dimethylsulfone in 200 ml. of absolute dimethylsulfoxide was stirred with the exclusion of moisture for 3 hours at 50° C. and then treated at 25° C. with 41.8 g. of methyl 3,5-bis-(N-methylacetamido)benzoate. The mixture was stirred for 18 hours at 25° C., diluted with 2 liters of water, adjusted to pH 7 with glacial acetic acid and extracted with 9 liters of ethyl acetate. The ethyl acetate solution was washed with 3 liters of water, dried over magnesium sulfate and evaporated in vacuo. Recrystallization of the residue from ethanol yielded 3',5'-bis(methylamino)-2-methylsulfonylacetophenone, having a melting point of 144°-146° C.
Reaction SMILES: [CH3:1][C:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=2[O:21]C)[CH2:6][CH2:5]1)=O.C(OCC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].[OH-].[Na+]>O>[CH2:2]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[C:12]=2[OH:21])[CH2:6][CH2:5]1)[CH3:1]
Reactant: COc1ccc(CN2CCN(C(C)=O)CC2)c(OC)c1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CCN1CCN(Cc2ccc(OC)c(OC)c2O)CC1
Reaction time: 12 h
Yield: 64.2 %

Procedure:
##STR6## 30.8 g (0.1 mol) of N-acetyltrimetazidine, 600 ml of diethyl ether and 11.1 g (0.3 mol) of LiAlH4 are heated to and then maintained at reflux for 24 hours with vigorous stirring, the mixture is subsequently allowed to return to room temperature, and stirring is continued for a further 12 hours, after which the mixture is hydrolysed in succession with 10 ml of water, 10 ml of 4N sodium hydroxide solution and finally 30 ml of water. The mixture is filtered and the residue is washed three times with 200 ml of diethyl ether each time. The ethereal phases are removed and the residue is then taken up three times with 300 ml of CH2C2 each time. The organic phase obtained after filtration is dried over magnesium sulphate, and the solvent is then removed by evaporation in vacuo. The residue (approximately 20 g) is filtered over 150 g of silica using a mixture of chloroform and ethanol (97.5% -2.5%) as eluants. 18 g of N-ethyl-N'-(2-hydroxy-3,4-dimethoxybenzyl)-piperazine are obtained directly (yield: 64%).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5].FC1C=C(OC)C=C(F)C=1[C:23](O)=[O:24]>>[F:19][C:15]1[CH:16]=[C:17]([O:24][CH3:23])[CH:18]=[C:2]([F:1])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]([OH:14])=[O:13])=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: COc1cc(F)c(C(=O)O)c(F)c1
Reactant: O=C(O)c1n[nH]cc1NC(=O)c1c(F)cccc1F
Product: COc1cc(F)c(C(=O)Nc2c[nH]nc2C(=O)O)c(F)c1

Procedure:
The compound was prepared in a manner analogous to 4-(2,6-difluoro-benzoylamino)-1H-pyrazole-3-carboxylic acid (Example 16D), but using 2,6-difluoro-4-methoxybenzoic acid as the starting acid, to give 4-(2,6-difluoro-4-methoxy-benzoylamino)-1H-pyrazole-3-carboxylic acid (1.58 g) as a white solid. (1H NMR (300 MHz, DMSO-d6) δ 13.0 (s, 2H), 10.7 (s, 1H), 8.0 (s, 1H), 6.9 (s, 1H), 6.8 (s, 1H), 3.7 (s, 3H)).
Reaction SMILES: F[C:2]1[N:23]=[CH:22][CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=1)=[O:5].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][N:31]=[CH:32]2)=[CH:27][CH:26]=1.C(O)(C(F)(F)F)=O>CC(O)(C)C>[CH:32]1[C:33]2[C:28](=[CH:27][CH:26]=[C:25]([NH:24][C:2]3[N:23]=[CH:22][CH:21]=[CH:20][C:3]=3[C:4]([NH:6][C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=3)=[O:5])[CH:34]=2)[CH:29]=[CH:30][N:31]=1
Reactant: Nc1ccc2ccncc2c1
Reactant: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1F
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)(C)O
Product: O=C(Nc1ccc(C(F)(F)C(F)(F)F)cc1)c1cccnc1Nc1ccc2ccncc2c1
Temperature: 90 °C
Reaction time: 24 h

Procedure:
To a mixture of 2-fluoro-N-(4-pentafluoroethyl-phenyl)-nicotinamide (112 mg) and 7-aminoisoquinoline (40 mg) in t-BuOH (0.5 mL) was added TFA (94 μL). The resulting mixture was stirred for 24 h at 90° C., cooled to RT and purified by flash chromatography (4:1:0.1; MeOH/CH2Cl2/MeOH) to give the title compound as a yellow solid. MS (ES+): 459 (M+H)+. Calc'd for C23H15F5N4O— 458.12.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([C:8]([F:11])([F:10])[F:9])([OH:7])[CH3:6].[OH-].[NH4+:14]>CO>[F:9][C:8]([F:11])([F:10])[C:5]([OH:7])([CH3:6])[CH2:4][C:3]([NH2:14])=[O:2]
Reactant: COC(=O)CC(C)(O)C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(O)(CC(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 40 h
Yield: 100 %

Procedure:
To a solution of the crude 4,4,4-trifluoro-3-hydroxy-3-methylbutyric acid (1.90 g, 10.0 mmol) in methanol (5 ml) was added concentrated aqueous ammonium hydroxide (10 ml), and the reaction stirred for 40 h at room temperature then evaporated to dryness to afford crude 4,4,4,-trifluoro-3-hydroxy-3-methyl butyramide (1.77 g, 100%) as a yellow oil.
Reaction SMILES: CN[C@@H:3]([CH3:14])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.NC1C=C(C=CC=1)C[OH:20].C1(=O)NC(=O)C2=CC=CC=C12.BrCC(O)C.BrC[C@H](C)OC1CCCCO1.[H-].[Na+]>O1CCCC1.CN(C)C=O>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][O:5][CH2:4][C@@H:3]([OH:20])[CH3:14])[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(CO)c1
Reactant: CN[C@@H](C)COCc1cccc(N)c1
Agent: CC(O)CBr
Agent: C[C@@H](CBr)OC1CCCCO1
Agent: O=C1NC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[C@H](O)COCc1cccc(N)c1

Procedure:
The manner in which optically active forms of arylmethoxy aliphatic amines, such as (2S)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine type compounds, are providcd can vary. In one approach, a 3-aminobenzyl alcohol type compound (N-protected as the phthalimide) can be alkylated with a chiral 1-bromo-2-propanol type compound containing an O-protecting group, such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran using a base such as sodium hydride and a solvent such as N,N-dimethylformamide or tetrahydrofuran. The tetrahydropyranyl protecting group of the resulting chiral arylmethyl ether type compound can be removed with aqueous sulfuric acid in methanol, affording (2S)-1-[(3-aminophenyl)methoxy]-propan-2-ol. The resulting chiral alcohol intermediate can be converted to its corresponding tosylate, followed by tosylate displacement with methylamine with inversion of configuration, and finally removal of the N-phthaloyl group to give the chiral amine (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine. Chiral side chain compounds such as (1S)-2-(2-bromo-1-methylethoxy)tetrahydro-2H-pyran can be prepared from (2S)-1-bromo-2-propanol by treatment with 3,4-dihydro-211-pyran in dichloromethane with p-tolucnesulfonic acid as a catalyst according to the method of S. A. M. Nieuwenhuis et al., Tetrahedron 50: 13207-13230 (1994). The required (2S)-l-bromo-2-propanol can be obtained from (S)-propylene oxide (commercially available from Fluka) by treatment with hydrogen bromide in acetic acid at 0° C. The corresponding optical antipode, (2R)-N-methyl-1-[(3-aminophenyl)methoxy]-propan-2-amine can be prepared in an analogous manner from (R)-propylene oxide (commercially available from Fluka) by using the synthetic procedure of S. A. M. Nieuwenhuis et al. to prepare the tetrahydropyranyl ether of (2R)-1-bromo-2-propanol and by using the synthetic sequence described above.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([S:39]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (20 mg, 0.065 mmol, 1 eq) in THF (1 mL) at 0° C. was added diisopropylethylamine (0.023 mL, 0.13 mmol, 2 eq) followed by addition of benzenesulfonylchloride (0.009 mL, 0.071 mmol, 1.1 eq) via syringe. Removed the cooling bath and let stir for 1 h. Quenched the reaction with saturated aqueous NaHCO3 and extracted 3× with CH2Cl2. Combined the organic extracts, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluted with 2:1 hexanes/acetone) to give 14 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.1-1.2 (1H, m), 1.6-1.9 (4H, m), 2.12 (1H, m), 2.42 (1H, t, J=10 Hz), 2.57 (1H, t, J=10 Hz), 3.4-3.6 (2H, m), 3.63 (1H, d, J=8.5 Hz), 5.6 (1H, br s), 6.84 (1H, d, J=5.5 Hz), 7.3-7.8 (7H, m), 7.88 (1H, d, J=7 Hz), 8.18 (1H, d, J=7 Hz), 8.41 (1H, d, J=5.5 Hz), 8.62 (1H, s). Mass spectrum (CI) 449.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:17]([OH:19])=[O:18])[CH:3]=1.[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1.C([O-])(=O)C.[NH4+:35]>C(O)C>[CH3:20][N:21]([CH3:30])[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[C:3]2[C:2](=[O:1])[N:6]([C:7]3[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:11][CH:12]=3)[N:5]=[C:4]2[C:17]([OH:19])=[O:18])=[CH:24][CH:23]=1.[NH4+:35]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: O=C(O)c1cc(O)n(-c2ccc(S(=O)(=O)O)cc2)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CCO
Product: CN(C)c1ccc(C=C2C(=O)N(c3ccc(S(=O)(=O)O)cc3)N=C2C(=O)O)cc1
Reaction time: 7 h

Procedure:
2.85 g of 5-hydroxy-1-(4-sulfophenyl)-1H-pyrazole-3-carboxylic acid, 1.65 g of 4-dimethylaminobenzaldehyde and 0.8 g of ammonium acetate in 25 mL of ethanol were heated at 60° C. After 7 hours, the mixture was cooled and filtered.