Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:15][S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:21][CH:20]=1)(=[O:18])=[O:17].[CH3:32][CH:33]([C:35]1[N:39]=[C:38]([N:40]2[CH2:45][CH2:44][CH:43]([CH2:46]O)[CH2:42][CH2:41]2)[O:37][N:36]=1)[CH3:34].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH3:34][CH:33]([C:35]1[N:39]=[C:38]([N:40]2[CH2:41][CH2:42][CH:43]([CH2:46][O:31][C:28]3[CH:27]=[CH:26][C:25]([C:22]4[CH:21]=[CH:20][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[CH:24][CH:23]=4)=[N:30][CH:29]=3)[CH2:44][CH2:45]2)[O:37][N:36]=1)[CH3:32]
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cn2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)nc3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 81.7 %

Procedure:
Diisopropyl azodicarboxylate (0.175 mL, 0.89 mmol) was added dropwise to a solution of 6-[4-(methylsulfonyl)phenyl]-3-pyridinol (150 mg, 0.59 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Steps 1-3, 200 mg, 0.89 mmol), PPh3 (233 mg, 0.89 mmol), and THF (10 mL) at ambient temperature. The mixture was stirred at ambient temperature for 4 h. The mixture was concentrated, and the resulting crude was purified by reverse-phase preparative HPLC using a CH3CN:H2O gradient (10:90 to 100:0) with 0.05% TFA as a modifier, then taken up in CH2Cl2 and free-based with saturated NaHCO3 (aq) to give 5-[({1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methyl)oxy]-2-[4-(methylsulfonyl)phenyl]pyridine (220 mg) as a white solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[Cl:14][C:15]1[CH:20]=[N+:19]([O-])[C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1.O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:19][C:20]=1[OH:4]
Reactant: CCOC(=O)c1ccc(Cl)c[n+]1[O-]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c(O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
Trifluoroacetic anhydride (147 mL) was added dropwise to a solution of ethyl 5-chloropyridine-2-carboxylate 1-oxide (36.8 g) in N,N-dimethylformamide (220 mL) under ice-cooling over 20 minutes, and the mixture was stirred at 50° C. for one hour. The reaction solution was ice-cooled and water was added. Sodium bicarbonate was slowly added to effect neutralization, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was suspended with ethyl acetate, stirred and then filtered. The filtrate was concentrated under reduced pressure. The same operation was further repeated twice. The resulting solids were combined and dried under reduced pressure to give ethyl 5-chloro-6-hydroxypyridine-2-carboxylate as a white solid (24.2 g, 75%). The filtrate was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give ethyl 5-chloro-6-hydroxypyridine-2-carboxylate as a white solid (1.84 g, 6%).
Reaction SMILES: C([Li])CCC.[CH3:6][C@H:7]1[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9](=[O:18])[NH:8]1.[Br:19][CH2:20][C:21](Cl)=[O:22].[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CCCCCC.O1CCCC1.O>[Br:19][CH2:20][C:21]([N:8]1[C@@H:7]([CH3:6])[C@@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:10][C:9]1=[O:18])=[O:22]
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1ccccc1
Reactant: O=C(Cl)CBr
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1C(=O)CBr
Temperature: -70 °C
Yield: 76.1 %

Procedure:
82 ml of a 2.5 molar solution of butyllithium in hexane is added to a solution of 33.06 g (186.6 mmol) of (4S,5R)-4-methyl-5-phenyloxazolidin-2-one in 500 ml of tetrahydrofuran within 30 minutes at −70° C. under argon. Then, a solution of 15.55 ml (187 mmol) of bromoacetyl chloride in 250 ml of tetrahydrofuran is added in drops in such a way that the internal temperature does not exceed −65° C. Then, it is stirred for one more hour at −70° C. Then, the reaction mixture is poured onto 50 ml of saturated aqueous ammonium chloride solution. 90 ml of saturated aqueous sodium bicarbonate solution is then added, allowed to come to 25° C., diluted with water and extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride solution, dried on sodium sulfate and chromatographed on silica gel. 42.32 g (76%) of the title compound is obtained.
Reaction SMILES: [CH2:1]([CH:3]([CH2:20][CH3:21])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:16](OC)=[O:17])[CH:9]=[C:10]([CH:15]=1)[C:11](OC)=[O:12])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:20]([CH:3]([CH2:1][CH3:2])[CH2:4][O:5][C:6]1[CH:15]=[C:10]([CH2:11][OH:12])[CH:9]=[C:8]([CH2:16][OH:17])[CH:7]=1)[CH3:21]
Reactant: CCC(CC)COc1cc(C(=O)OC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)COc1cc(CO)cc(CO)c1
Reaction time: 8 h

Procedure:
To a solution of dimethyl 5-(2-ethylbutoxyl)isophthalate (0.62 g, 2.10 mmol) in THF (20 mL) was added LiAlH4 (0.24 g, 6.32 mmol). The reaction mixture was stirred for 8 h and subsequently quenched with 2N HCl (10 mL) and extracted with Et2O (2×25 mL) and EtOAc (2×25 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-])=O)(=[O:12])=[O:11])=[CH:5][CH:4]=1>[Pd]>[NH2:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][C:6]1[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:12]
Reactant: COc1ccc(NS(=O)(=O)c2ccccc2[N+](=O)[O-])cn1
Agent: [Pd]
Product: COc1ccc(NS(=O)(=O)c2ccccc2N)cn1
Yield: 92.6 %

Procedure:
The title compound (419 mg 1.50 mmol) was prepared from N-(6-Methoxypyridin-3-yl)-2-nitrobenzenesulfonamide (500 mg, 1.62 mmol) and 10% palladium on charcoal (50 mg) using the methods of (IntA14), step 2.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([OH:29])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[C:8]([CH3:30])[N:7]=1.[CH3:31]O.Cl>C(Cl)Cl.O1CCOCC1>[NH2:5][C:6]1[N:11]=[C:10]([NH:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([CH2:17][C:18]2[CH:19]=[C:20]([CH2:26][C:27]([O:29][CH3:31])=[O:28])[CH:21]=[CH:22][C:23]=2[O:24][CH3:25])=[C:8]([CH3:30])[N:7]=1
Reactant: CO
Reactant: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)O)ccc1OC
Agent: BrB(Br)Br
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCCCNc1nc(N)nc(C)c1Cc1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of boron tribromide (13.95 ml, 1M in DCM) was added portionwise over 30 min to a stirred suspension of the product from example 83 step (iv) (1 g) in DCM (15 mL) at 0° C. The suspension was allowed to warm to rt and stirred for 5 h. The suspension was cooled to 0° C. and then MeOH (10 mL) and 4M HCl in dioxane (2 mL) were added and the mixture stirred for 1 h. The solvent was evaporated under reduced pressure and the residue was purified by flash silica chromatography (5% MeOH/DCM) to give the title compound (minor product) as a white solid, 51 mg.
Reaction SMILES: [H][H].[F:3][C:4]1[C:9]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:8][C:7]([NH2:16])=[C:6]([N+:17]([O-])=O)[CH:5]=1>C(O)C.[Pd]>[F:3][C:4]1[CH:5]=[C:6]([NH2:17])[C:7]([NH2:16])=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: COCCCOc1cc(N)c([N+](=O)[O-])cc1F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COCCCOc1cc(N)c(N)cc1F
Yield: 100.2 %

Procedure:
In a 25 ml autoclave, dissolve 330 mg of 4-fluoro-5-(3-methoxypropoxy)-2-nitrophenylamine, obtained in the previous stage, in 20 ml of ethanol, add 40 mg of 10% palladium-on-charcoal and then subject to an initial hydrogen pressure of 1 bar at 20° C. for 16 hours. After cooling, the volume of hydrogen absorbed is 91 ml. After filtration of the catalyst and then concentration to dryness under reduced pressure, we obtain 290 mg of 4-fluoro-5-(3-methoxypropoxy)benzene-1,2-diamine, in the form of a viscous black oil, which is used as it is in the following stage, with the following characteristic:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Cl:12])=[C:4](OC)[N:3]=1.[NH3:15]>>[NH2:15][C:4]1[C:5]([Cl:12])=[CH:6][C:7]([C:8]([F:11])([F:10])[F:9])=[C:2]([Cl:1])[N:3]=1
Reactant: N
Reactant: COc1nc(Cl)c(C(F)(F)F)cc1Cl
Product: Nc1nc(Cl)c(C(F)(F)F)cc1Cl

Procedure:
If, in contrast, the novel 2,5-dichloro-6-methoxy-3-trifluoromethylpyridine is reacted with ammonia, the undesired 2-amino-3,6-dichloro-5-trifluoromethylpyridine is predominantly formed while the methoxy group is lost.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][OH:14])=[C:11]([C:15]([F:18])([F:17])[F:16])[S:10][N:9]=2)=[CH:4][CH:3]=1.[F:19][C:20]1[C:25]([F:26])=[C:24](O)[CH:23]=[CH:22][C:21]=1/[CH:28]=[CH:29]/[C:30]([O:32]CC)=[O:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:24]3[CH:23]=[CH:22][C:21](/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31])=[C:20]([F:19])[C:25]=3[F:26])=[C:11]([C:15]([F:16])([F:18])[F:17])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: OCc1c(-c2ccc(Cl)cc2)nsc1C(F)(F)F
Reactant: CCOC(=O)/C=C/c1ccc(O)c(F)c1F
Product: O=C(O)/C=C/c1ccc(OCc2c(-c3ccc(Cl)cc3)nsc2C(F)(F)F)c(F)c1F

Procedure:
The title compound was prepared according to the procedure described in Example 1 following Steps 5 and 6 by coupling of (3-(4-chlorophenyl)-5-(trifluoromethyl)isothiazol-4-yl)methanol and (E)-ethyl 3-(2,3-difluoro-4-hydroxyphenyl)acrylate then hydrolysis to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.80 (d, J=9.5 Hz, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 1H), 6.52 (d, J=9.0 Hz, 2H), 7.28 (t, J=6.8 Hz, 1H), 6.82 (t, J=6.8 Hz, 1H), 5.14 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[C:19]([C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)=[O:24])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:29]4[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])=[CH:27][CH:28]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CC(C)(C)C(=O)Nc1ccc(B(O)O)cc1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc(NC(=O)C(C)(C)C)cc4)cc3CC[C@@H]12
Yield: 39.6 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis(triphenylphosphine) palladium (0) (50 mg, 0.04 mmol), 4-t-butylcarbonylaminophenylboronic acid (172 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 104 mg (40%) of the title compound as a brown solid. mp>265° C. FDMS: m/e=404. α[D]589 =+49.42 (c=0.56, chloroform).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[N:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH:13]1[CH2:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]1=O.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[N:9]([N:10]=1)[C:13]1[CH2:21][C:20]3[C:15]([C:14]=1[N:11]=2)=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:2][CH3:3]
Reactant: O=C1c2ccccc2CC1Br
Reactant: CCCOc1ccc(N)nn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCOc1ccc2nc3c(n2n1)Cc1ccccc1-3

Procedure:
A stirred mixture of 6-propoxypyridazin-3-amine (145 mg) and 2-bromo-1-indanone (200 mg) in ethanol (10 mL) was heated under reflux for 3 hours. The mixture was cooled and sodium bicarbonate (80 mg) was added. The mixture was stirred refluxed for 1 hour and then the ethanol was evaporated. The residue was extracted with chloroform and the extract washed with saturated, aqueous, sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by flash chromatography on silica gel. Elution with 1-2% methanol in dichloromethane afforded Compound 123 (30 mg) as a white solid. 1H n.m.r. (CDCl3) δ 1.12, t, 3H; 1.87, sextet, 2H; 3.85, s, 2H; 4.30, t, 2H; 6.64, d, 1H; 7.30, d, 1H; 7.40, t, 1H; 7.53, d, 1H; 7.80-7.88, m, 2H.
Reaction SMILES: C=O.[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]([CH3:15])([CH3:14])[C:7]1=[O:16].[CH:17](O)=O.[OH-].[Na+]>C(O)(CC)(C)C.O.C1(C)C=CC=CC=1>[OH:3][CH2:4][CH2:5][N:6]1[CH2:11][C:10]([CH3:12])([CH3:13])[N:9]([CH3:17])[C:8]([CH3:15])([CH3:14])[C:7]1=[O:16]
Reactant: CC1(C)CN(CCO)C(=O)C(C)(C)N1
Reactant: O=CO
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCC(C)(C)O
Solvent: Cc1ccccc1
Solvent: O
Product: CN1C(C)(C)CN(CCO)C(=O)C1(C)C
Temperature: 80 °C

Procedure:
24.3 g (0.78 mol) of paraformaldehyde are added to a solution of 120 g (0.6 mol) of 1-(2-hydroxyethyl)-3,3,5,5-tetramethylpiperazin-2-one in 300 ml of tert-amyl alcohol. The mixture is then heated to 80° C. and 35.8 g (0.78 mol) of formic acid dissolved in 30 ml of tert-amyl alcohol are slowly added. Then, the mixture is maintained at 80° C. for further 1 hour and cooled to 50° C. Subsequently, 250 ml of toluene and 100 ml of water are added. The mixture is then stirred and 33 g (0.825 mol) of sodium hydroxide dissolved in 60 ml of water are slowly added. The organic phase is separated, washed with water, dried over anhydrous sodium sulfate, filtered and evaporated under vacuum (60° C./10 mbar). A white solid with a melting point of 77°-80° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:31]1[CH:35]=[C:34]([NH2:36])[N:33]=[CH:32]1)([CH3:30])[CH2:23][NH:24][CH2:25][C:26]([F:29])([F:28])[F:27]>>[CH3:30][C:22]([N:31]1[CH:35]=[C:34]([NH:36][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:33]=[CH:32]1)([CH3:21])[CH2:23][NH:24][CH2:25][C:26]([F:27])([F:28])[F:29]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: CC(C)(CNCC(F)(F)F)n1cnc(N)c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CNCC(F)(F)F)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 2) was reacted with 1-[1,1-Dimethyl-2-(2,2,2-trifluoro-ethylamino)-ethyl]-1H-imidazol-4-ylamine to afford the title compound: C13 MR (100 MHz, CDCl3) 14.1, 19.5, 26.0, 28.2, 28.8, 29.8, 36.6, 38.8, 50.5, 50.8, 51.1, 51.4, 52.7, 58.6, 58.7, 60.8, 100.8, 101.0, 101.3, 104.3, 110.7, 110.8, 110.9, 118.0, 118.1, 124.2, 127.0, 131.2, 138.0, 139.8, 159.9, 172.6; MS m/z 502.2 (M+1).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[C:3]1[CH:4]=[C:5]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:6][NH:7][CH2:8][CH:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[O:28][CH3:29])[N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:11]1.FC(F)(F)C1C=C(C=C(C(F)(F)F)C=1)C(O)=[O:45].C(P(C#N)(CC)=O)C.C(N(CC)CC)C>CN(C=O)C>[CH3:29][O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[CH:9]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)[CH2:8][NH:7][C:6](=[O:45])[C:5]1[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:3]([C:2]([F:1])([F:37])[F:38])[CH:4]=1
Reactant: COc1ccccc1C(CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2ccccc2)CC1
Reactant: O=C(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCP(=O)(C#N)CC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccccc1C(CNC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(C2CCCCC2)CC1
Temperature: 3 °C
Reaction time: 8 h
Yield: 32 %

Procedure:
317 mg (1 mmol) of 2-Methoxyphenyl-2-(4-cyclohexylpiperazine-1-yl)-ethylamine (prepared as described in Example 1) are combined with 272 mg (1 mmol) of 3,5-bistrifluoromethylbenzoic acid in 30 ml of DMF. The mixture is cooled to about 3° C. and combined with 501 ml (3.3 mmol) of diethylphosphorylcyanide and 1.4 ml triethylamine. After about 1 hour the ice bath is removed and the mixture is stirred overnight at ambient temperature. It is evaporated down in vacuo and the residue is stirred with a little water and 20% sodium hydrogen carbonate solution. It is suction filtered and washed thoroughly with water. The crude product is chromatographed over silica gel with ethyl acetate/methanol 1:1. The fractions which are uniform according to TLC are combined and freed from solvent in vacuo. The residue is dissolved in a little isopropanol and the N-[2-(2-methoxyphenyl)-2-(4-cyclohexylpiperazine-1-yl)-ethyl]-3,5-bistrifluoromethyl-benzamide is precipitated therefrom in the form of the hydrochloride using ethereal hydrochloric acid and diisopropylether. The product is suction filtered, washed with diisopropylether and dried in vacuo at about 50° C. 200 mg of the substance are obtained as a slightly beige solid (yield 32%).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]2[CH:16]=[C:15]([CH3:17])[S:14][C:5]=2[NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[N:9]=1.C(#N)C.O.[CH3:22][N:23]1[CH2:28][CH2:27]N[CH2:25][CH2:24]1>>[CH3:17][C:15]1[S:14][C:5]2[NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=3[N:9]=[C:3]([N:2]3[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]3)[C:4]=2[CH:16]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Agent: Cl
Solvent: CC#N
Solvent: O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
4-Amino-2-methyl-10H-thieno[2,3-b][1,5] benzodiazepine hydrochloride (100 g) is taken in N-methyl piperazine (500 ml). Reaction mixture is heated at 120° C. for 3 hours. The reaction mass is cooled and acetonitrile (400 ml) is added under stirring for 30 minutes. Water (500 ml) is added and the mixture is cooled up to room temperature and stirred to precipitate the solid. The solid is filtered off, washed with acetonitrile (100 ml) and dried at ambient temperature to obtain the crude title compound (64 g).
Reaction SMILES: C(O[C:4](=[O:25])[CH2:5][C:6]1[N:7]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:10]=1)C.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][N:31]=[C:30]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:29]=1.O>CN1C(=O)CCC1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([N:7]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=[C:6]2[CH2:5][C:4]([N:37]2[CH2:38][CH2:39][N:34]([C:30]3[CH:29]=[C:28]([O:27][CH3:26])[CH:33]=[CH:32][N:31]=3)[CH2:35][CH2:36]2)=[O:25])=[CH:19][CH:20]=1
Reactant: COc1ccnc(N2CCNCC2)c1
Reactant: CCOC(=O)Cc1nc(-c2ccc(F)cc2)cn1-c1ccc(F)cc1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccnc(N2CCN(C(=O)Cc3nc(-c4ccc(F)cc4)cn3-c3ccc(F)cc3)CC2)c1
Yield: 31 %

Procedure:
70 mg (1,4-bis-(4-fluoro-phenyl)-1H-imidazol-2-yl)-acetic acid ethyl ester, 58 mg 1-(4-methoxy-pyridin-2-yl)-piperazine and 0.05 mLN,N-diisopropylethylamine in 2 mL NMP was stirred 50 min. at 180° C. under microwave condition. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried and evaporated. The residue was purified by HPLC (column: Waters Symmetry 50×140 mm 7 μm, mobile layer: water+0.3% HCOOH/methanol 10% until 90% in 14 min) to give 31 mg desired product.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH2:25][OH:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>N1C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH:25]=[O:26])=[C:5]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1=C(C)NC(CO)=C(C(=O)OCC)C1c1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CCOC(=O)C1=C(C)NC(C=O)=C(C(=O)OCC)C1c1ccccc1Cl
Temperature: 80 °C
Yield: 17 %

Procedure:
Stirring a solution of diethyl 2-methyl-4-(2-chlorophenyl)-6-hydroxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (1.1395 g) in dried pyridine (10 ml) at room temperature, a solution of p-toluenesulfonyl chloride (629.1 mg) in dried pyridine (10 ml) was dropwise added gradually thereto. The resultant mixture was stirred at room temperature for 1.5 hours and then heated at 80° C. for 4.5 hours with stirring. After removal of the pyridine, water was added to the residue and the resultant aqueous mixture was acidified with dil. hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with dil. hydrochloric acid and then water, and dried. The resultant brown viscous oil was purified by column chromatography on silica-gel using an eluent (benzene: diethyl ether=1:1) to give an orange oil, which was crystallized by treating with diethyl ether. The resultant crystals were collected by filtration and recrystallized from a mixture of diethyl ether and n-hexane to give orange-yellowish prisms (0.1926 g) of diethyl 2-methyl-4-(2-chlorophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate, m.p. 87° to 88° C., which was identified with an authentic sample.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10](=[O:26])[NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)[CH3:9])(C)(C)C.[ClH:28]>>[ClH:28].[NH2:7][C@@H:8]([CH3:9])[C:10]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[NH:19][C:20]1[CH:25]=[N:24][CH:23]=[CH:22][N:21]=1)=[O:26]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Agent: Cl
Product: C[C@H](N)C(=O)Nc1ccc(F)cc1Nc1cnccn1
Temperature: 60 °C
Yield: 99 %

Procedure:
{(S)-1-[4-Fluoro-2-(pyrazin-2-ylamino)phenylcarbamoyl]ethyl}carbamic acid tert-butyl ester (144 mg, 0.38 mmol) was suspended in hydrochloric acid (4.0 M in 1,4-dioxane, 5.0 ml) and heated at 60° C. for 20 minutes, then concentrated in vacuo to yield the title compound (118 mg, 0.38 mmol, 99%). 1H NMR (MeOD, 400 MHz): δ 8.20 (2H, m), 7.96 (1H, d, J=2.7 Hz), 7.59 (1H, dd, J 10.1, 2.7 Hz), 7.53 (1H, dd, J 9.2, 5.9 Hz), 6.96 (1H, td, J 8.3, 2.9 Hz), 4.10 (3H, m), 1.49 (3H, d, J=7.0 Hz).
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].C1COCC1.[Cl-].[Li+].[BH4-].[Na+]>C(O)C>[CH2:9]([O:8][C:6](=[O:7])[NH:5][C@H:4]([CH2:16][NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:3][OH:2])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)[C@@H](CNS(C)(=O)=O)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)NC[C@H](CO)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 77 %

Procedure:
To a mixed liquid of 4.40 g of N-[(benzyloxy)carbonyl]-3-[(methylsulfonyl)amino]-D-alanine methyl ester, 100 ml of THF, and 50 ml of ethanol was added 1.13 g of lithium chloride, and 1.01 g of sodium borohydride was further added thereto under ice-cooling. The reaction solution was stirred at room temperature for 14 hours, and the solvent was then evaporated under reduced pressure. After adding 150 ml of water, concentrated hydrochloric acid was added thereto until the pH reached 2 to 3. The solution was extracted with ethyl acetate, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain 3.10 g of benzyl[(1R)-2-hydroxy-1-{[(methylsulfonyl)amino]methyl}ethyl]carbamate as a white solid.