Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([NH:9][C:10]([C:12]2[N:13]=[CH:14][O:15][C:16]=2[C:17]2[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=2)=[O:11])[CH:6]=[N:5]1.CCN(CC)CC.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>C(Cl)Cl>[CH3:41][C:31]1[CH:36]=[CH:35][C:34]([S:37]([O:1][CH2:2][CH2:3][N:4]2[CH:8]=[C:7]([NH:9][C:10]([C:12]3[N:13]=[CH:14][O:15][C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[O:11])[CH:6]=[N:5]2)(=[O:39])=[O:38])=[CH:33][CH:32]=1
Reactant: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCO)c2)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCn2cc(NC(=O)c3ncoc3-c3cccc(C)c3)cn2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To an ice-cooled solution of N-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)-5-(m-tolyl)oxazole-4-carboxamide (2.57 g, 8.23 mmol) in DCM (70 mL), Et3N (3.44 mL, 24.69 mmol) was added. After stirring for 20 min at 0° C., p-toluenesulfonyl chloride (1.73 g, 9.05 mmol), was added dropwise, and the resulting suspension was stirred at 0° C. for 3 h, then quenched with water and extracted with DCM (2×). The combined org. layers were washed with 1 N aq. HCl-solution and brine, dried (MgSO4), filtered and concentrated in vacuo to obtain the title compound as an oil. LC-MS conditions A: tR=0.93 min, [M+H]+=467.46.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br[C:13]1C(C)=C(C=CC=1)C(O)=O.CI.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[CH3:11]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: Cc1ccc(Br)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 60:40 mixture of 5-bromo-2-methyl benzoic acid and 3-bromo-2-methyl benzoic acid (8.0 g, 0.037 mol) was dissolved in N,N′-dimethylformamide (130 mL). Methyl iodide (2.28 mL, 2.3 mol) and potassium carbonate (5.11 g, 0.037 mol) were added in sequence at room temperature. The mixture was stirred at room temperature for 2 hours at which point the reaction was determined to be complete by HPLC. The solvent was removed under high vacuum and the resulting residue was passed through a silica gel column using 5% ethyl acetate in hexanes as the eluent. The mixture of isomers was obtained as an oil and then separated by preparative normal phase HPLC using 0.5% isopropyl alcohol in hexanes as the eluent. The title compound was obtained as a white solid (1.38 g, 29%). 1H NMR (300.132 MHz, CDCl3) δ 8.04 (d, J=2.2 Hz, 1H), 7.50 (dd, J=8.2, 2.2 Hz, 1H), 7.12 (d, J=8.2 Hz, 1H), 3.89 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: [I:1][C:2]1[C:6]([CH:7]=O)=[CH:5][N:4]([CH2:9][O:10][CH3:11])[N:3]=1.[F:12][C:13]([F:25])([F:24])[C:14]1[CH:19]=[CH:18][C:17]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1.[Cl-].[Na+].O.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[I:1][C:2]1[C:6]([CH:7]=[N:23][S:20]([C:17]2[CH:16]=[CH:15][C:14]([C:13]([F:12])([F:25])[F:24])=[CH:19][CH:18]=2)(=[O:21])=[O:22])=[CH:5][N:4]([CH2:9][O:10][CH3:11])[N:3]=1
Reactant: COCn1cc(C=O)c(I)n1
Reactant: NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: [Ti+4]
Agent: CC[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: COCn1cc(C=NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c(I)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Iodo-1-(methoxymethyl)-1H-pyrazole-4-carbaldehyde (39) (2.0 g, 7.52 mmol) and 4-(trifluoromethyl)benzenesulfonamide (40) (1.69 g, 7.52 mmol) were dissolved in THF (20 mL) under nitrogen. Titanium(IV) ethoxide (7.8 mL, 37.6 mmol) was added via syringe and the reaction stirred for 16 hr at rt. The reaction was poured into brine (50 mL) and filtered through a pad of Celite. The filtrate was extracted with EtOAc (3×50 mL) and the combined organics were washed with brine (100 mL), dried over Na2SO4, and concentrated in vacuo to give N-((3-iodo-1-(methoxymethyl)-1H-pyrazol-4-yl)methylene)-4-(trifluoromethyl)benzenesulfonamide (41) as a clear oil that was used without further purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])C(C(F)(F)F)=[CH:10][C:9]=1[NH:23][C:24](=[O:47])[CH2:25][C:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[C:37]([CH2:38][O:39]C3CCCCO3)=[CH:36][N:35]=[N:34]2)[CH:28]=1)(C)(C)C.[C:49](O)([C:51]([F:54])([F:53])[F:52])=O>C(Cl)Cl>[OH:39][CH2:38][C:37]1[N:33]([C:29]2[CH:28]=[C:27]([C:26]3[CH2:25][C:24](=[O:47])[NH:23][C:9]4[CH:10]=[C:49]([C:51]([F:54])([F:53])[F:52])[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])=[CH:13][C:8]=4[N:7]=3)[CH:32]=[CH:31][CH:30]=2)[N:34]=[N:35][CH:36]=1
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3nncc3CO)c1)=N2

Procedure:
The title compound was prepared from (RS)-[5-(methyl-propyl-amino)-2-(3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M102) (0.15 g, 0.22 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (31 mg, 30%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: OB(O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=c1ccc(Br)cn1-c1ccccc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 209.9 %

Procedure:
Into a one-neck round-bottom flask were added 5-bromo-1H-pyridin-2-one (696 mg, 4.00 mmol), phenylboronic acid (975 mg, 8.00 mmol), cupric acetate (1450 mg, 8.00 mmol), triethylamine (1120 μl, 8.00 mmol), pyridine (647 μl, 8.00 mmol), 4 Å molecular sieves (1056 mg) and methylene chloride (24 ml). The flask was loosely capped and the above mixture was stirred at rt in the atmosphere of air for 20 h. The mixture was filtered through a celite pad, washed with CH2Cl2. After concentration in vacuo, a green oil (2100 mg) was obtained, which was then purified by chromatography on silica gel (64 g) eluting with 1000 ml 20%, 2000 ml 40% and 1000 ml 50% EtOAc/hexane to obtain the title compound as a light-yellow wax-like material. 1H NMR (CDCl3, 400 MHz): δ=5.59 (d, 1H, J=9.6 Hz), 7.35-7.38 (m, 2H), 7.41-7.46 (m, 2H), 7.49-7.52 (m, 3H). MS(ES+): m/z 250.06/252.02 (100/97) [MH+]. HPLC: tR=2.71 min (ZQ2000, polar—5 min).
Reaction SMILES: [ClH:1].C([O:9][C:10](=[O:26])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:25])[CH:22]([CH3:24])[CH3:23])=[CH:13][CH:12]=1)C1C=CC=CC=1.C(O)(C)C>[Pd].C(O)C>[ClH:1].[CH3:25][N:21]([CH2:20][CH2:19][CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([C:10]([OH:26])=[O:9])=[CH:16][CH:15]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CC(C)N(C)CCCOc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CCO
Product: CC(C)N(C)CCCOc1ccc(C(=O)O)cc1
Reaction time: 16 h
Yield: 75.3 %

Procedure:
A mixture of benzyl-4-[3-(N-methyl-N-isopropylamino)-propoxy]benzoate hydrogen chloride (300 mg), isopropyl alcohol (20 ml) and a catalyst of palladium on carbon (10% w/w, 30 mg) was hydrogenated at ambient temperature and pressure for 16 hours. Ethanol was then added to dissolve precipitated product and the mixture was then filtered to remove inorganic material. The filtrate was evaporated to give 4-[3-(N-methyl-N-isopropylamino)propoxy]benzoic acid hydrogen chloride as a solid (172 mg), m.p. 167.8° C.; microanalysis, found: C, 56.2; H, 7.40; H, 4.70; N, 4.70%, C14H21NO3. HCl 0.6H2O requires C, 56.3; H, 7.87; N, 4.63%; NMR([CD3 ]2SO): 1.2-1.35(6H,q), 2.1-2.4(2H,m), 2.6-2.7(3H,d), 3.0-3.65(3H,m), 4.1-4.2(2H,t). 7.0-7.1(2H,d), 7.85-7.95(2H,d) and 10.5-10.8(1H, br s); m/z 252 (M+H).
Reaction SMILES: B1([C:10]2[CH:15]=[N:14][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[N:12][CH:11]=2)OC(C)(C)C(C)(C)O1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1Br.C([O-])([O-])=O.[Na+].[Na+].CN(C=O)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:10]1[CH:11]=[N:12][C:13]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)=[N:14][CH:15]=1
Reactant: CC1(C)OB(c2cnc(N3CCOCC3)nc2)OC1(C)C
Reactant: Brc1ccccc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1-c1cnc(N2CCOCC2)nc1
Reaction time: 0.5 h
Yield: 39.4 %

Procedure:
2-(4-Morpholino)pyrimidine-5-boronic acid pinacol ester (300 mg, 1.03 mmol), 1,2-dibromobenzene (243 mg, 1.03 mmol), Bis(triphenylphosphine)palladium (II) chloride (72 mg, 0.10 mmol), aqueous Na2CO3 (2N, 2.58 mL, 5.15 mmol) and DMF (5 mL) are added to a 10 mL microwave tube. Reaction is carried out in a microwave oven at 100° C. for 30 min. The reaction mixture turns black. The mixture is poured into water and extracted with EtOAc. The organic layers are washed with water, brine, dried (Na2SO4) and concentrated. The crude product is purified using biotage eluting with 0-30% EtOAc/Hexane. The desired mono-coupled product elutes at 30% EtOAc. The di-coupled by-product elutes earlier. Removal of the solvent gives 4-[5-(2-bromo-phenyl)-pyrimidin-2-yl]-morpholine as a white solid (130 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:21][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:25][CH3:26])=[CH:11][C:12]([N:18]3[CH2:19][CH:20]([N:22]([CH3:24])[CH3:23])[CH2:21]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC(N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Yield: 98.3 %

Procedure:
A mixture of 5-chloro-N-[4-(3-dimethylaminoazetidin-1-yl)-2-methoxy-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 113, 285 mg, 0.56 mmol), iron (188 mg, 3.37 mmol) and NH4Cl (22.51 mg, 0.42 mmol) in ethanol (9 mL) and water (3 mL) was heated at reflux for 2 h. The mixture was then cooled and filtered through diatomaceous earth (Celite™). The filtrate was concentrated in vacuo and the resulting residue was dissolved in CH2Cl2. This solution was washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-20% 7N methanolic ammonia in CH2Cl2 gave the title compound (263 mg, 98%) as a brown dry film; 1H NMR: (CDCl3) 2.21 (6H, s), 3.08-3.18 (1H, m), 3.30 (2H, br s), 3.58 (2H, t), 3.86 (3H, s), 3.88 (3H, s), 3.93 (2H, t), 6.38 (1H, s), 7.2-7.42 (3H, m, partially obscured by chloroform signal), 7.50 (1H, s), 7.99 (1H, s), 8.20 (1H, s), 8.31 (1H, s), 8.63 (1H, d); m/z: ES+ MH+ 478.
Reaction SMILES: [OH:1][C:2]([CH:13]1[S:18][CH2:17][CH2:16][CH2:15][S:14]1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.Cl[Si:25]([CH3:28])([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[C:7]1([C:2]([CH:13]2[S:14][CH2:15][CH2:16][CH2:17][S:18]2)([O:1][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:4][C:5]#[CH:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C#CCCC(O)(c1ccccc1)C1SCCCS1
Reactant: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: C#CCCC(O[Si](C)(C)C)(c1ccccc1)C1SCCCS1
Reaction time: 8 h
Yield: 100.1 %

Procedure:
2-(1-Hydroxy-1-phenylpent-4-ynyl)-1,3 -dithiane (1.7 g 6.1 mmol) and 1.2 g (15 mmol) of imidazole was stirred in 25 mL of methylene chloride and 0.9 mL (15 mmol) of chlorotrimethylsilane was added. The mixture was stirred overnight when it was poured onto 20 mL of 10% aqueous K2CO3. The organics were washed with brine, dried (Na2SO4) and concentrated at reduced pressure. The residue was mixed with Celite and chromatographed on 110 g of silica (99:1, hexane:ethyl acetate, then 2% ethyl acetate) to give 2.14 g (90%) of a product that crystallized upon concentration at reduced pressure. Analytical TLC (silica, 9:2, hexane:ethyl acetate) Rf0.56; 1H NMR (CDCl3) δ1.65-2.05 (m, 5H), 2.05-2.2 (m, 1H), 2.28-2.4 (m, 1H), 2.45-2.6 (m, 1H), 2.7-2.87 (m, 4H), 4.37 (s, 1H), 7.25-7.4 (m, 3H), 7.42-7.5 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:22])[CH3:21])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5]>[OH-].[Na+]>[OH:1][C:2]1[CH:11]=[C:10]([NH:12][C:13]([C:15]2[S:16][C:17]([CH:23]([CH3:25])[CH3:24])=[C:18]([CH:20]([CH3:21])[CH3:22])[CH:19]=2)=[O:14])[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1cc(C(=O)Nc2ccc(C(=O)O)c(O)c2)sc1C(C)C
Yield: 72 %

Procedure:
The aforementioned ester (42 mg, 0.116 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (41, 29 mg, 73%) as colorless prisms.
Reaction SMILES: [Li+].C[Si]([N-:6][Si](C)(C)C)(C)C.C(Cl)(Cl)Cl.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.[H+].[B-](F)(F)(F)F.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>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].C1(C)C=CC=CC=1>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][CH:42]1[C:46]1[CH:51]=[CH:50][C:49]([NH2:6])=[CH:48][CH:47]=1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCCC1c1ccc(N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
LiHMDS (1.6 g, 9.6 mmol) is added to a 100 mL round bottom flask. Toluene (20 mL) is added followed by addition of Pd2(dba)3.CHCl3 (50 mg, 0.05 mmol) and P(tBu)3.HBF4 (40 mg, 0.14 mmol). 2-(4-Bromo-phenyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 4.6 mmol) is added to the flask. After degasing, the mixture is stirred at room temperature overnight. After TLC suggested no starting bromide is left, the reaction mixture is diluted with ether and poured into dilute HCl (aq). The ether layer is discarded, the aqueous layer is basified with NH4OH and extracted with EtOAc. The EtOAc layer is dried and concentrated to provide the desired product (1.0 g, 83%). 1H NMR (300 MHz, CDCl3) ∂ 6.94-6.96 (2H, m), 6.60-6.67 (2H, m), 4.67-4.85 (1H, m), 3.58 (4H, br), 2.24 (1H, m), 1.73-1.97 (3H, m), 1.44 (3H, s), 1.21 (6H, s).
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]([OH:12])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[C:46]1([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:78])[C@H:57]([CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[NH:58][CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C([O-])(=O)C>O1CCCC1>[C:46]1([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:78])[C@H:57]([CH2:67][CH2:68][CH2:69][NH:70][C:71]([O:73][C:74]([CH3:76])([CH3:75])[CH3:77])=[O:72])[N:58]([C:10](=[O:12])[CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])[CH2:59][CH2:60][C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NCCc1ccccc1)C(=O)NCCCc1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NCCC[C@@H](C(=O)NCCCc1ccccc1)N(CCc1ccccc1)C(=O)CNC(=O)OC(C)(C)C
Yield: 70.2 %

Procedure:
cold solution (0° C.) of Boc-glycine (543 mg, 3.1 mmol), diisopropylethylamine (1 ml, 6.2 mmol), and tetrahydrofuran (10 ml) was treated with PyBrop (1.45 g, 3.1 mmol), followed by the addition of Nα-phenethyl-Nδ-Boc-ornithine 3-phenylpropylamide (1.28 g, 2.8 mmol) in tetrahydrofuran (5 ml). The resulting solution was acetate. The filtrate was concentrated in vacuo and the product purified by chromatography (silica gel—hexane/ethyl acetate) to give N-Boc-glycyl-Nα-phenethyl-Nδ-Boc-ornithine 3-phenylpropylamide (1.2 g).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)([C:19]#[N:20])[CH2:15][CH2:14]2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH-:32].[NH4+]>>[C:6]1([CH2:12][N:13]2[CH2:18][CH2:17][C:16]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)([C:19]([NH2:20])=[O:32])[CH2:15][CH2:14]2)[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N#CC1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)C1(Nc2cccc(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Reaction time: 8 h

Procedure:
To 1656 parts of concentrated sulfuric acid are added portionwise 249.5 parts of 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarbonitrile. Upon completion, stirring is continued overnight at room temperature. The reaction mixture is poured onto crushed ice and while cooling, the whole is alkalized with ammonium hydroxide. Upon stirring vigorously, the product precipitates. The supernatant aqueous phase is decanted and the residual solid product is dissolved in trichloromethane. The solution is shaken with ammonium hydroxide. The organic phase is washed with water, dried, filtered and evaporated. The solid residue is stirred in 2,2'-oxybispropane. The product is filtered off, washed with hexane and dried in vacuo, yielding 1-(phenylmethyl)-4-{[3-(trifluoromethyl)phenyl]amino}-4-piperidinecarboxamide; mp. 179.3° C.
Reaction SMILES: [C:1](O)(=[O:3])C.C(O)=O.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[CH:23]=1>C1COCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]([CH:1]=[O:3])[CH2:17][CH2:16][C:15]([C:19]([O:21][CH3:22])=[O:20])=[CH:14][C:13]=2[CH:23]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCC1
Reactant: CC(=O)O
Solvent: C1CCOC1
Solvent: O=CO
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To anhydrous acetic acid (0.84 ml) was added dropwise formic acid (0.4 ml), under ice-cooling, and the mixture was stirred, under nitrogen atmosphere, at 50° C. for 2 hours. To the mixture was added THF (5 ml), and to the mixture was added dropwise, under ice-cooling, a solution of methyl 7-bromo-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.0 g) in THF (15 ml). The mixture was stirred at room temperature overnight. The solvent was evaporated, and to the residue was added water. The mixture was extracted with ethyl acetate. The organic layer was washed with sodium hydrogen carbonate solution, water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give methyl 7-bromo-1-formyl-2,3-dihydro-1H-1-benzazepine-4-carboxylate (1.07 g) as colorless crystals.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2.C([O:30][CH2:31][CH2:32][CH2:33][CH2:34]Br)(=O)C.[OH-].[Na+]>CO>[CH3:2][C:3]1([CH3:26])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3[N:19]=[C:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:34][CH2:33][CH2:32][CH2:31][OH:30])[CH2:22][CH2:21]4)[O:17][N:16]=3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCNCC4)n3)ccc21
Reactant: CC(=O)OCCCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(-c3noc(C4CCN(CCCCO)CC4)n3)ccc21

Procedure:
The preparation was carried out as already described starting from 95 mg (0.25 mmol) of 4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,2,4-oxadiazol-5-yl]piperidine hydrochloride and 55 μl (0.38 mmol) of 4-bromobutyl acetate. The protecting group was cleaved off by means of a 1N NaOH solution in methanol. The product was purified by means of preparative HPLC and is in the form of the hydrochloride.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][CH:17]([CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C:18]([OH:20])=[O:19]>CN(C=O)C>[CH2:25]([NH:24][C:22]([CH2:21][CH:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[C:18]([OH:20])=[O:19])=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: NC(CC(=O)NCc1ccccc1)C(=O)O
Solvent: CN(C)C=O
Product: O=C(CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O)NCc1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with 2-amino-N-benzyl-succinamic acid [J. Pharm. Sci. 1980, 69 (5), 553-555.] in DMF to provide the title compound in good yield.
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].Cl.[NH2:11][OH:12].C(N(CC)CC)C.O>C(O)C>[C:1](=[N:11][OH:12])([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: NO
Reactant: CC(=O)c1ncccn1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(=NO)c1ncccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 136.3 %

Procedure:
A mixture of 2-acetylpyrimidine (2.90 g), hydroxylamine hydrochloride (2.48 g) and triethylamine (5.3 ml) in ethanol (40 ml) was stirred at room temperature overnight. The reaction mixture was poured into water, and extracted with methylene chloride. The organic layer was washed with a saturated aqueous ammonium sulfate solution and brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 2-acetylpyrimidine oxime (4.44 g) as colorless powder.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:15]Br.[OH-].[K+]>C(Cl)Cl>[Br:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: BrBr
Reactant: Cc1ccc(NC2CCCCC2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: Cc1ccc(NC2CCCCC2)c(Br)c1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
In a 100-mL flask, N-cyclohexyl-4-methylaniline (2.00 g, 10.6 mmol) was dissolved in methylene chloride (20 mL) and a solution of bromine (Br2) (1.69 g, 10.6 mmol) dissolved in methylene chloride (16 ml) was injected at 0° C. for 30 minutes. Then, the solution was further stirred for 2 hours, and a 1 N aqueous KOH (20 mL) solution was added. The solution added with the aqueous solution was transferred to a separatory funnel and extracted from methylene chloride (40 mL) twice. Water was removed from the combined organic layer over MgSO4, and filtered with a glass filter. The rotary evaporator was used to remove the solvent, thereby obtaining a residue. The obtained residue was separated by column chromatography to obtain colorless oil (2.67 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH3:13])[CH:7]=[CH:6]2.[Se](=O)=[O:15]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([CH:13]=[O:15])[CH:7]=[CH:6]2
Reactant: COc1ccc2nc(C)ccc2c1
Reactant: O=[Se]=O
Product: COc1ccc2nc(C=O)ccc2c1
Yield: 68 %

Procedure:
The title compound was prepared from 6-methoxy-2-methylquinoline (6g) and selenium dioxide using methods as described in the literature for similar compounds (Mathes et al., 1957) in 68% yield.