Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:17]=1>>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:26]1[CH2:27][CH2:28][CH:23]([NH:22][C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)[CH2:24][CH2:25]1)#[N:2]
Reactant: c1cncc(NC2CCNCC2)c1
Reactant: CC(C)C(C#N)(CCCI)c1cccs1
Product: CC(C)C(C#N)(CCCN1CCC(Nc2cccnc2)CC1)c1cccs1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(2-thienyl)-5-methylhexyl iodide and 4-(3-pyridylamino)piperidine. The physico-chemical data of the compound was as below.
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>[Ni].CO>[CH3:1][N:2]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:33])[C:20]2[CH:21]=[CH:22][C:23]([O:26][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][O:28]3)=[CH:24][CH:25]=2)=[CH:15][CH:14]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:6])[CH3:7]
Reactant: CN(CC#Cc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cc1)C(=O)OC(C)(C)C
Agent: [Ni]
Solvent: CO
Product: CN(CCCc1ccc(C(=O)c2ccc(OC3CCCCO3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.3 %

Procedure:
A flask was charged with tert-butyl methyl(3-(4-(4-(tetrahydro-2H-pyran-2-yloxy)benzoyl)phenyl)prop-2-ynyl)carbamate (450 mg, 1 mmol), Riney Ni (0.2 eq), and 20 mL of methanol. The mixture was stirred under hydrogen at room temperature and atmospheric pressure for 2 h. After complete conversion (TLC monitoring), the catalyst was filtered off through a pad of celite, and washed with EtOAc. The filtrate was concentrated under reduced pressure to give the product (364 mg, 80% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]1[CH3:14])(OC(C)(C)C)=O.C(O)(=O)C.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CCO.CC(O)C.Cl.C1(C)C=CC=CC=1>[CH:19]1([N:11]2[CH2:12][CH2:13][NH:8][C@H:9]([CH3:14])[CH2:10]2)[CH2:22][CH2:21][CH2:20]1
Reactant: O=C1CCC1
Reactant: C[C@@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@H]1CN(C2CCC2)CCN1
Temperature: 20 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
(R)-Boc-2-methylpiperazine (350 g, 1.71 moles, 98% w/w), which is commercially available from Lanzhou Boc Chemical Co., was dissolved in EtOH (2.75 L) at tjacket=20° C. Acetic acid (1.37 L) was added in one portion followed by the addition of cyclobutanone (184 g, 2.57 moles). The charging vessel was rinsed with EtOH (250 mL) and the light yellow solution was left stirring at tjacket=20° C. for 1 h. NaBH(OAc)3 (497 g, 2.48 moles, 95% w/w) was added in 20 portions over 90 min. EtOH (340 mL) was used for rinsing. The reaction mixture was left stirring for 2 h. A sample was analyzed on GC using HP-5MS column (length 25 m, ID 0.32 mm, Film 0.52 μm) with a gradient method (2 min at 60° C., followed by 25° C./min during 8 min then 2 min at 260° C.). Frontinlet temperature=200° C. using He as gas and a detector temperature=300° C. More NaBH(OAc)3 (30 g, 0.14 moles) was added to complete the reaction within 1 h. The reaction mixture was cooled to tjacket=0° C. before quenching with 5M NaOH (5.5 L). EtOH was distilled off under vacuum at tjacket=50° C. The H2O phase was extracted with toluene (5.5 L) at tjacket=20° C. The organic phase was combined with a second batch, started with (R)-Boc-2-methylpiperazine (300 g, 1.47 moles, 98% w/w). The combined organic phases were concentrated under vacuum at tjacket=50° C. to approximately 2 L. The obtained toluene solution with the intermediate can be stored at 5° C. for several days. The toluene solution was diluted with 2-propanol (2 L) at tjacket=10° C., and HCl in 2-propanol (1.06 L, 6.36 moles, 6M) diluted in 2-propanol (2 L) was added over 30 min. The reaction solution was heated to tjacket=48° C. HCl in 2-propanol (2.12 L, 12.72 moles, 6M) diluted in 2-propanol (2 L) was added over 2 h at tinner=46° C. The reaction solution was kept at tjacket=48° C. for an additional 3 h before being cooled to tjacket=0° C. over 1 h. A seed mixture (0.4 L reaction solution with Example 6 (0.2 g, 0.89 mmoles)) was added. The reaction mixture was left stirring at tjacket=0° C. overnight and the product was filtered off. Drying under vacuum at 40° C. gave Example 6 (620 g, 2.63 moles, 96.3% w/w), 83% yield. 1H-NMR (DMSO-d6): δ 12.46 (s, 1H), 10.13 (s, 2H), 3.35-3.74 (m, 6H), 3.09 (m, 1H), 2.92 (m, 1H), 2.39 (m, 2H), 2.16 (m, 2H), 1.72 (m, 2H), 1.32 (d, 3H, J=6.4 Hz); 13C-NMR (DMSO-d6): δ 58.50, 49.62, 48.13, 44.30, 24.48, 24.38, 15.25, 13.26
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[O:17][CH3:18])=[C:6]([Cl:19])[N:5]=[CH:4][N:3]=1.[K+].[CH:21]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH-:32])(=[O:31])=[O:30])=[CH:25][CH:24]=1)=[CH2:22].Cl>CO.CN(C)C=O>[Cl:19][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:32][S:29]([C:26]2[CH:27]=[CH:28][C:23]([CH:21]=[CH2:22])=[CH:24][CH:25]=2)(=[O:30])=[O:31])[C:7]=1[CH2:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18]
Reactant: COc1cccc(OC)c1Cc1c(Cl)ncnc1Cl
Reactant: C=Cc1ccc(S([NH-])(=O)=O)cc1
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: C=Cc1ccc(S(=O)(=O)Nc2ncnc(Cl)c2Cc2c(OC)cccc2OC)cc1
Temperature: 100 °C
Yield: 21 %

Procedure:
A mixture of 80 mg of 4,6-dichloro-5-(2,6-dimethoxybenzyl)pyrimidine and 170 mg of p-vinylbenzenesulfonamide monopotassium salt (J. Am. Chem. Soc. 1956, 78, 2169) from the corresponding sulfonamide with potassium t-butylate in absolute MeOH and 10 ml of dimethylformamide was heated at 100° C. for 6 hours. Thereafter, the mixture was left to cool to 25° C. overnight. Now, 30 ml of 0.5N HCl were added to the reaction solution while stirring. The precipitated substance was removed by filtration under suction and recrystallized from toluene/n-hexane. There were obtained 25 mg of N-(6-chloro-5-(2,6-dimethoxy-benzyl)-4-pyrimidinyl)-p-vinylbenzenesulfonamide, melting point 197°-198° C.
Reaction SMILES: C[O:2][C:3](=[O:14])/[CH:4]=[CH:5]/[C:6]1[CH:7]=[N:8][C:9]([Cl:13])=[C:10]([Cl:12])[CH:11]=1.[OH-].[Na+]>CO>[Cl:12][C:10]1[CH:11]=[C:6](/[CH:5]=[CH:4]/[C:3]([OH:14])=[O:2])[CH:7]=[N:8][C:9]=1[Cl:13]
Reactant: COC(=O)/C=C/c1cnc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/c1cnc(Cl)c(Cl)c1
Yield: 72.7 %

Procedure:
(E)-3-(5,6-Dichloro-pyridin-3-yl)-acrylic acid methyl ester (1.54 g, 7 mmol) was suspended in MeOH (20 ml) and aqueous sodium hydroxide (1.1 ml, 6M, 7 mmol) added. The mixture was heated to reflux for 20 min after which time the reaction was concentrated, the residue taken up in water and the pH adjusted to 1 by addition of 1M HCl. The product could then be isolated by filtration affording the title compound (1.11 g, 77%) as a white solid. MS: 216.0 (M−H−2Cl).
Reaction SMILES: [CH:1]([C:3]([CH:5]([CH3:7])[CH3:6])=[O:4])=[CH2:2].C(Cl)(=O)C(C)C.C([Si](C)(C)C)=C.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.C(N(CC)CC)C.[Cl-].OCCC1SC=C(CC2C=CC=CC=2)[N+]=1C>>[F:20][C:21]1[CH:28]=[CH:27][C:24]([C:25](=[O:26])[CH2:2][CH2:1][C:3](=[O:4])[CH:5]([CH3:7])[CH3:6])=[CH:23][CH:22]=1
Reactant: C=CC(=O)C(C)C
Reactant: O=Cc1ccc(F)cc1
Agent: C=C[Si](C)(C)C
Agent: CC(C)C(=O)Cl
Agent: C[n+]1c(Cc2ccccc2)csc1CCO
Solvent: CCN(CC)CC
Product: CC(C)C(=O)CCC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 58.3 %

Procedure:
Isopropyl vinyl ketone (1.97 g, 20 mmol), prepared from isobutyryl chloride and vinyl trimethylsilane in accordance with the method detailed in Tet. Letters, (1979), 1995, was mixed with 4-fluorobenzaldehyde (2.4 g, 20 mmol), 2 ml (14 mmol) of triethylamine, and 1.0 g (4.0 mmol) of 2-(2-hydroxyethyl)-3-methyl-4-benzylthiazolium chloride. The mixture was stirred and heated under nitrogen for five hours. After cooling to room temperature, the mixture was partitioned between ether (200 ml) and water (50 ml). The water layer was extracted with 200 ml of ether and the ether solutions were combined. The combined ether solution was washed successively with 50 ml of water, two 50-ml portions of 2M hydrochloric acid, and 50 ml of brine. The ether solution was dried over anhydrous magnesium sulfate. After removal of the ether, the remaining liquid was flash chromatographed on silica gel eluting with 20:1 (volume/volume) hexane-ethyl acetate. This procedure afforded 2.59 g of pure 1-(4-fluorophenyl)-5-methyl-1,4-hexanedione, mp 47°-49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([N:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]2)=[O:19])=[CH:12][C:11]=1[N+:33]([O-:35])=[O:34]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)/C=C/c2ccc(Sc3ccc(Cl)cc3Cl)c([N+](=O)[O-])c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(/C=C/c1ccc(Sc2ccc(Cl)cc2Cl)c([N+](=O)[O-])c1)N1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The compound (100 mg, 0.186 mmol) from Example 37 was dissolved in 0.5 mL of neat trifluoroacetic acid (TFA). The mixture was stirred at room temperature for 1 hour. The TFA was then removed under vacuum to give the title compound (105 mg) as a yellow solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH2:7]([N:9]([CH2:14][CH3:15])[C:10](=[O:13])[CH2:11]Cl)[CH3:8].CN(C=O)C.[Cl:21][C:22]1[C:31]([OH:32])=[C:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]>O>[Cl:21][C:22]1[C:31]([O:32][CH2:11][C:10]([N:9]([CH2:14][CH3:15])[CH2:7][CH3:8])=[O:13])=[C:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25]
Reactant: CCN(CC)C(=O)CCl
Reactant: CCS(=O)(=O)c1ccc(C(=O)OC)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)COc1c(S(=O)(=O)CC)ccc(C(=O)OC)c1Cl
Temperature: 120 °C

Procedure:
0.922 g (7.2 mmol) of K2CO3, 0.179 g (1.10 mmol) of Kl and 0.644 g (4.3 mmol) of N,N-diethylchloroacetamide were introduced into 30 ml of DMF. 1.000 g (3.6 mmol) of methyl 2-chloro-3-hydroxy-4-ethylsulfonylbenzoate were added at RT and the mixture was then heated for 7 hours at 120° C. The mixture was then poured into water and extracted with diisopropyl ether. The organic phases were washed with water, dried over Na2SO4 and concentrated completely. Chromatography on silica gel (eluent: n-heptane/ethyl acetate 1:1) gave methyl 2-chloro-3-(N,N-diethylaminocarbonylmethoxy) -4-ethylsulfonylbenzoate as a colorless viscous oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([CH2:19]OS(C)(=O)=O)[CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9]>C1COCC1>[C:8]([O:12][C:13]([N:15]1[CH2:18][CH:17]([CH2:19][N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(Cn2cccn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 17.9 mg (0.26 mmol) pyrazole in 2 mL dry THF at 0° C. was added 14 mg (0.35 mmol, 60% dispersion in mineral oil) NaH and the reaction was stirred for 30 minutes. 50 mg (0.17 mmol) 3-methanesulfonyloxymethyl-azetidine-1-carboxylic acid tert-butyl ester in 1 mL dry THF was added dropwise and the reaction was allowed to warm to room temperature for 16 hours. The solvent was evaporated and the remaining residue was partitioned between 25 mL H2O and 25 mL EtOAc. The organic phase was washed with 25 mL 1% citric acid solution, H2O (3×25 mL), 25 mL brine and dried with Na2SO4. After filtration and evaporation of the solvent the product was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO>[N:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([OH:3])[CH3:2]
Reactant: CC(=O)c1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1ccccn1

Procedure:
A solution of 2-Acetyl-pyridine (2.0 g, 16.5 mmol) in MeOH (33 mL) is treated by NaBH4 (624 mg, 16.5 mmol) at 0° C. After completion, the reaction mixture is quenched by H2O, EtOAc is added and the organic layer is washed with brine, dried over MgSO4 and evaporated in vacuo to provide crude product, which is submitted to the next step without further purification; ES-MS: M+=124.0; 1HNMR(DMSO-d6) 8.45 (d, 1H), 7.75 (td, 1H), 7.50 (d, 1H), 7.20 (dd, 1H), 5.30 (d, 1H), 4.70-4.60 (m, 1H), 1.30 (d, 3H).
Reaction SMILES: C[C:2]1C=C(C)C=C[C:3]=1[N:9]=[C:10]=S.[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[CH3:12][C:13]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:9]([CH3:10])[CH:3]=[CH:2][S:22]1
Reactant: Cc1ccc(N=C=S)c(C)c1
Reactant: Cc1cccc(N=C=S)c1C
Product: Cc1cccc(N=c2sccn2C)c1C

Procedure:
If 2,4-dimethyl-phenyl isothiocyanate in the above example is replaced by the same amount of 2,3-dimethyl-phenyl isothiocyanate and the procedure followed is an indicated, a solution of 2-(2,3-dimethyl-phenylimino)-3-methyl-thiazoline is obtained in a similar concentration and yield.
Reaction SMILES: C([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:9]2)C=C.CN(C)[C:21]1[CH:26]=CC=C[CH:22]=1>CCCCCC>[CH2:26]([C:13]1[C:5]([OH:4])=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7]2)[CH:21]=[CH2:22]
Reactant: CN(C)c1ccccc1
Reactant: C=CCOc1cccc2[nH]c(C(=O)OCC)cc12
Solvent: CCCCCC
Product: C=CCc1ccc2[nH]c(C(=O)OCC)cc2c1O
Temperature: 200 °C
Reaction time: 0.25 h
Yield: 50.1 %

Procedure:
2.79 g (11.4 mmol) of ethyl 4-allyloxyindole-2-carboxylate was added to 8.8 g of N,N-dimethylaniline, and the mixture was stirred for 15 minutes at 200° C. under a nitrogen atmosphere. 2.7 g of a crude product was obtained by adding n-hexane to the reaction mixture and collecting deposited crystals by filtration. This crude product was purified by column chromatography (silica gel, chloroform) to obtain 1.4 g (yield: 50.2%) of the target compound. This compound was recrystallized from a mixture of ethyl acetate and n-hexane to obtain colorless needles of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:43])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:27]=[CH:26][N:25]=2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[N:44]1([C:50](=[O:52])[CH3:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:50]([N:44]1[CH2:49][CH2:48][N:47]([CH2:2][C:3]2[N:8]=[C:7]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[C:24]3[CH:29]=[C:28]([C:30](=[O:43])[NH:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[CH:27]=[CH:26][N:25]=3)=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:46][CH2:45]1)(=[O:52])[CH3:51]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)n2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 65 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
Into a 8-mL sealed tube, was placed a solution of 6-(chloromethyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (120 mg, 0.20 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL), 1-(piperazin-1-yl)ethanone (37.9 mg, 0.30 mmol, 1.50 equiv), potassium carbonate (82 mg, 0.59 mmol, 3.00 equiv), and potassium iodide (7 mg, 0.04 mmol, 0.20 equiv). The resulting solution was stirred for 3 h at 65° C. The reaction was then quenched with 10 mL of water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The crude product (100 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 89.2 mg (56%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.56 (s, 1H), 9.54 (t, J=6.0 Hz, 1H), 9.08 (d, J=5.1 Hz, 1H), 8.38 (d, J=8.7 Hz, 1H), 8.25-8.17 (m, 3H), 7.84 (d, J=3.9 Hz, 2H), 7.71-7.58 (m, 5H), 7.51 (s, 1H), 4.63 (d, J=5.7 Hz, 2H), 4.49 (s, 2H), 3.31-3.21 (m, 10H), 2.01 (s, 3H), 1.72-1.59 (m, 6H). MS (ES, m/z): 700 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[CH:16]([NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1)(=[O:21])=[O:20])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:8][C:6]1[CH:5]=[CH:4][C:3]2[C:9]3[C:10]([CH:16]([CH3:17])[N:18]([S:19]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)(=[O:20])=[O:21])[C:2]=2[CH:7]=1)=[CH:11][CH:12]=[C:13]([F:15])[CH:14]=3
Reactant: COc1cccc(S(=O)(=O)NC(C)c2ccc(F)cc2-c2ccc(F)cc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(S(=O)(=O)N2c3cc(F)ccc3-c3cc(F)ccc3C2C)c1

Procedure:
The title compound was prepared from N-[1-(2′,4′,5-trifluoro-1,1′-biphenyl-2-yl)ethyl]-3-methoxybenzenesulfonamide (234 mg, 0.55 mmol), anhydrous N,N-dimethylformamide (1 mL), and potassium carbonate (154 mg, 1.1 mmol) according to the procedure and in the same manner as described in Example 105, step d resulting in the isolation of 211 mg (95%) of a white solid. This material was used without further purification in Example 115, step c;
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:12][CH:11]=2)=[O:8])=[CH:5][CH:4]=1.CCO.Cl.[Cl:31][C:32]1[C:41]2[C:36](=[CH:37][C:38]([N:42]([CH3:44])[CH3:43])=[CH:39][CH:40]=2)[N:35]=[CH:34][CH:33]=1>CC(O)=O.O.CCCCO>[ClH:31].[NH2:24][C:19]1[N:18]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:25]=[CH:26][C:3]([NH:2][C:32]4[C:41]5[C:36](=[CH:37][C:38]([N:42]([CH3:44])[CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[CH:4][CH:5]=3)=[CH:15][CH:14]=2)[CH:22]=[C:21]([CH3:23])[N:20]=1
Reactant: Cc1cc(Nc2ccc(NC(=O)c3ccc(N)cc3)cc2)nc(N)n1
Reactant: CN(C)c1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCO
Product: Cc1cc(Nc2ccc(NC(=O)c3ccc(Nc4ccnc5cc(N(C)C)ccc45)cc3)cc2)nc(N)n1

Procedure:
To a solution of amide E5 (306 mg, 0.83 mmol) in 1:2 EtOH:H2O (10 mL) were sequentially added c.HCl (0.23 mL) and 4-chloro-7-dimethylamino-quinoline (Z1) (188 mg, 0.91 mmol), and the resulting mixture was refluxed for 20 h. After this time [when MS and TLC analysis (5:4:1 n-BuOH:H2O:CH3CO2H) of the reaction mixture suggested the remaining small quantity of E5 was degrading], the reaction mixture was filtered, and the resulting solid washed sequentially with EtOAc and hexanes, to furnish Cpd. BB as an amorphous lemon-yellow solid (199 mg, 45%). 1H NMR [CD3)2SO]: 2.28 [s, 3H, ArCH3], 3.15 [s, 6H, ArN(CH3)2], 6.18 [br s, 1H, ArH], 6.70 [d, J=7.02 Hz, 1H, ArH], 6.88 [d, J=2.46 Hz, 1H, ArH], 7.38 [dd, J=9.62, 2.46 Hz, 1H, ArH], 7.61 [d, J=8.60, 2H, ArH], 7.81 [m, 5H, ArH & ArNH2], 8.14 [d, J=8.60 Hz, 2H, ArH], 8.31 [d, J=7.02 Hz, 1H, ArH], 8.55 [d, J=9.71 Hz, 1H, ArH], 10.41 [br s, 1H, ArH], 10.65 [m, 2H, ArNHAr & ArNHAr], 12.68 [v br s, 1H, ArC(O)NH], 13.77 [v br s, 1H, quinolinyl N+H]. LCMS (APCI+): 506 (100%). HPLC: 96.6%.
Reaction SMILES: [CH3:1][C:2]1[C:6](I)=[C:5]([CH3:8])[O:4][N:3]=1.[Br:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.BrC1C=C(C2C=NC=CC=2)C=CC=1>>[Br:9][C:10]1[CH:15]=[C:14]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:8])[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1noc(C)c1I
Reactant: OB(O)c1cccc(Br)c1
Agent: Brc1cccc(-c2cccnc2)c1
Product: Cc1noc(C)c1-c1cccc(Br)c1
Yield: 119 %

Procedure:
The reaction of 3,5-dimethyl-4-iodoisoxazole (Kochetkov, N. K. Zhurnal Obschchie Khimii, 31, 2167-2172 (1961)) (2.4 g, 11 mmol) with 3-bromophenylboronic acid (2.24 g, 11 mmol) using the procedure for the preparation of 3-(3'-bromophenyl)pyridine gave 3.3 g crude 4-m-bromophenyl-3,5-dimethylisoxazole. After a quick filtration on Si gel (eluting with CH2Cl2), the material was further purified by preparative TLC on 12-1000μ Si Gel GF plates (eluting with 10% acetone/hexane and extracting with 10% MeOH/CH2Cl2), to provide 1.2 g of the arylated isoxazole. Sublimation (ambient to 70° C., high vacuum) of 0.5 g provided 404 mg of analytically pure material.
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH:37]1([CH:44]2[CH2:55][CH:54]=[CH:53][CH2:52][CH2:51][CH:50]=[CH:49][CH2:48][CH:47]([CH:56]3[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)[N:46]=[N:45]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[NH2:45][CH:44]([CH:37]1[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1)[CH2:55][CH2:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH:47]([NH2:46])[CH:56]1[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]1
Reactant: C1=CCC(C2CCCCCC2)N=NC(C2CCCCCC2)CC=CCC1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: NC(CCCCCCCCC(N)C1CCCCCC1)C1CCCCCC1

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 106 g (0.3 mol) of 3,12-dicycloheptyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with otherwise the same procedure, there is obtained, after chromatographic purification, and 63 g (58% of theory) of 1,10-diamino-1,10-dicycloheptyldecane as colourless oil [nD20 =1.5018; IR (liquid) inter alia bands at 3390, 3310 and 3618 cm-1 ].
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[OH:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>N1C=CC=CC=1>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[O:29][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CC[C@H](NC(=O)c1c(O)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)Oc1c(-c2ccccc2)nc2ccccc2c1C(=O)N[C@@H](CC)c1ccccc1
Reaction time: 8 h
Yield: 42.3 %

Procedure:
0.5 g (1.3 mmol) of (S)-N-(α-ethylbenzyl)-3-hydroxy-2-phenylquinoline-4-carboxamide (compound of Description 1) were dissolved in 10 ml of pyridine; 0.5 ml (5.2 mmol) of ethyl chloroformate were added dropwise and the solution was refluxed under magnetical stirring for 8 hours. The reaction mixture was allowed to reach room temperature and left overnight. 1.0 ml (10.4 mmol) of ethyl chloroformate were added and the solution refluxed for 4 hours. The pyridine was evaporated off with toluene; the residue was dissolved in CH2Cl2, washed with H2O and the organic layer dried over na2SO4 and evaporated in-vacuo to dryness. The crude product was triturated with warm i-Pr2O to yield 0.25 g of the title compound as a yellow solid.