Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH:7]=O.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[CH2:7][N:12]1[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]1
Reactant: O=Cc1occc1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2occc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.5 %

Procedure:
To a solution of 3-bromofuran-2-carbaldehyde (500 mg, 2.85 mmol) and tert-butyl piperazine-1-carboxylate (1.1 g, 5.71 mmol) in CH2Cl2 (10 mL) was added sodium triacetoxyborohydride (1.2 g, 5.71 mmol). The mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with EtOAc (100 mL). The organic phase was washed with aqueous NaHCO3 and brine then dried (MgSO4), filtered and concentrated to dryness. The residue was purified by column chromatography (silica, 0-10% MeOH in CH2Cl2) to afford the sub-title compound (910 mg, 92%).
Reaction SMILES: [CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26][CH:27]=[CH2:28])[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16])[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[CH3:31][C:32]1[CH:33]=[C:34](Br)[CH:35]=[CH:36][C:37]=1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(N1CCOCC1)C>C(#N)C>[CH3:1][C:2]([CH3:30])([CH3:29])[C@H:3]([NH:14][C:15]([C@H:17]([CH2:26]/[CH:27]=[CH:28]/[C:34]1[CH:35]=[CH:36][C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:32]([CH3:31])[CH:33]=1)[CH2:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[O:16])[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1cc(Br)ccc1-c1ccccc1
Reactant: C=CC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc1ccccc1)C(C)(C)C
Agent: CCN1CCOCC1
Solvent: CC#N
Product: Cc1cc(/C=C/C[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)OCc2ccccc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 75.5 %

Procedure:
By the method of Preparation 3 a), tert-butyl (3R)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)hex-5-enoate (2.085 g, 5.0 mmol) was reacted with 3-methyl-4-phenylbromobenzene (1.855 g, 7.5 mmol) under palladium catalysis, using N-ethylmorpholine as base at reflux in acetonitrile for 16.5 h. Work-up as before followed by purification by repeated flash chromatography (first column hexane:ether=4:1; second column toluene:ether=20:1) gave mainly tert-butyl (3R,5E)-3-({[(1S)-2,2-dimethyl-1-(benzyloxycarbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hex-5-enoate as a pale yellow gum (2.205 gm, 75%). 1H nmr suggested that two alkene isomers, the (5Z) and (4E) were also present. The mixture of alkenes was taken onto the next step (see c, below). δH (400 MHz, CDCl3) 0.95 (9H, s), 1.42 (9H, s), 2.26 (3H, s), 2.35 (1H, m), 2.45 (1H, dd, 3 and 17 Hz), 2.54 (1H, dt, J=15 and 6.5),2.69 (1H, dd, J=9 and 17 Hz), 2.77 (1H, m), 4.52 (1H, d, J=10 Hz), 4.97 (1H, d, J=12 Hz), 5.06 (1H, d, J=12 Hz), 6.16 (1H, dt, J=18 and 7 Hz), 6.42 (2H, m), 7.29 (13H, complex).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)[CH2:5][C:6]([NH2:8])=[O:7].N1C=CN=C1.[Si:24](Cl)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[Si:24]([O:1][CH2:2][CH2:3][CH:4]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:11][CH:10]=1)[CH2:5][C:6]([NH2:8])=[O:7])([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)CC(CCO)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCCC(CC(N)=O)c1ccc(C(F)(F)F)cc1)(c1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
5-Hydroxy-3-(4-trifluoromethylphenyl)pentanoic acid amide (350 mg) was dissolved in dimethylformamide (13 mL), and imidazole (365 mg) and tert-butyldiphenylsilyl chloride (697 μL) were added at room temperature. After stirring for one hour, the reaction solution was partitioned with ethyl acetate and water. The organic layer was washed with water (twice), 1 N hydrochloric acid and brine. After drying over magnesium sulfate, concentration under reduced pressure and purification by silica gel column chromatography (mobile phase:ethyl acetate/heptane=0 to 90%) gave the title compound (680 mg).
Reaction SMILES: O[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:13])[C:5]1=[O:14].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:13])[C:5]1=[O:14]
Reactant: O=S(Cl)Cl
Reactant: Cn1c(=O)n(CCO)c2ccccc21
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)n(CCCl)c2ccccc21
Reaction time: 6 h

Procedure:
To a stirred mixture of 30 parts of 1,3-dihydro-1-(2-hydroxyethyl)-3-methyl-2H-benzimidazol-2-one and 600 parts of trichloromethane are added dropwise 200 parts of thionyl chloride. Upon completion, stirring is continued for 6 hours at reflux temperature. The reaction mixture is allowed to cool and the solvent is evaporated. The residue is crystallized from 2-propanol (activated charcoal), yielding 18.2 parts of 1-(2-chloroethyl)-1,3-dihydro-3-methyl-2H-benzimidazol-2-one.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[NH2:13][CH2:14][C@:15]1([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]1.CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:12][C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([NH:13][CH2:14][C@:15]2([F:28])[CH2:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:16]2)[N:11]=1
Reactant: Clc1cc2ncccc2c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CNc2nc(Cl)cc3ncccc23)C1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
To 5,7-dichloro-1,6-naphthyridine (5.01 g, 25.2 mmol) and 1,1-dimethylethyl (3R)-3-(aminomethyl)-3-fluoro-1-piperidinecarboxylate (5.32 g, 22.90 mmol) in NMP (20 ml) was added DIPEA (8.00 ml, 45.8 mmol) and the mixture was stirred at 100° C. for 72 h under nitrogen. The reaction was cooled and partitioned between ethyl acetate and water (200 ml each). The aqueous was washed with ethyl acetate. The combined organics were washed with water and the solvent was removed. The residue was dissolved in DCM and loaded onto a 100 g silica SNAP column and purified on the SP4 eluting with 0-50% ethyl acetate in cyclohexane over 17 CVs. Appropriate fractions were combined and the solvent was removed to give the title compound as a pale orange solid which was dried under high vacuum for 2 h (7.61 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17](=[O:25])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.CCOCC>CO>[C:19]1([CH2:18][C:17]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOC(=O)Cc2ccccc2)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=C(Cc1ccccc1)OCCC1CCNCC1
Reaction time: 8 h
Yield: 87.4 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-[2-(phenylacetoxy)ethyl]piperidine (431 mg, 1.24 mmol) in MeOH (0.2 mL) was added 2N anhydrous HCl/ether (1.5 mL, 3.0 mmol). The reaction mixture was stirred overnight. After evaporation, the residue was dissolved in deionized water. EtOAc was used to wash the aqueous layer before the pH was altered to approx. 9-10. The aqueous layer was extracted three times with CH2Cl2, and the combined organic phases were dried over Na2SO4. After evaporation, 4-[2-(phenylacetoxy)ethyl]piperidine (268 mg, 87%) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2].[CH2:14](O)[CH2:15]C>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([CH:14]=[CH2:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12])[CH3:2]
Reactant: CCOc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CCCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc([N+](=O)[O-])c(OCC)c1
Temperature: 100 °C
Yield: 81 %

Procedure:
To 5-bromo-2-nitrophenyl ethyl ether (8.8 g, 35.76 mmol) in 80 mL of n-propanol was added, PdCl2(dppf)*DCM (0.523 g, 0.72 mmol), potassium ethenyl(trifluoro)borate (6.71 g, 50 mmol), and TEA (3.61 g, 35.76 mmol). The mixture was heated to 100° C. for 3 h. The solvent was rotovaped down and the residue dissolved in DCM, and filtered to remove insoluble solids. 20 g of silica gel was added and the solvent rotovaped down, and purified by flash chromatography to give the title compound of step B (5.58 g, 28.89 mmol, 81%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J=8.97 Hz, 1H), 7.01-7.03 (m, 1H), 6.68 (dd, J=17.67, 10.71 Hz, 1H), 5.84 (d, J=17.58 Hz, 1H), 5.44 (d, J=11.17 Hz, 1H), 4.19 (q, J=6.96 Hz, 2H), 1.47 (t, J=6.96 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH:10]=[C:11]([CH2:13]O)[N:12]=2)=[CH:4][C:3]=1[CH3:15].S(Cl)([Cl:18])=O>ClCCl>[Cl:18][CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:15])[CH:4]=2)[O:9][CH:10]=1
Reactant: Cc1cc(-c2nc(CO)co2)ccc1Cl
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(-c2nc(CCl)co2)ccc1Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
136 mg (0.61 mmol) of the compound from Example 27A are suspended in 2 ml of dichloromethane. The suspension is cooled to 0° C., and 49 μl (0.67 mmol) of thionyl chloride are added slowly. The reaction solution is stirred at RT overnight. The solvent is then removed on a rotary evaporator. The residue is used without further purification in the subsequent reactions.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16](S(C)=O)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][CH2:33][CH2:34][NH2:35])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:20][C:19]3[C:14](=[N:15][C:16]([NH:35][CH2:34][CH2:33][NH:32][CH2:31][C:28]4[CH:27]=[CH:26][N:25]=[CH:30][CH:29]=4)=[N:17][CH:18]=3)[NH:13][C:12]2=[O:24])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: NCCNCc1ccncc1
Reactant: COc1cc(OC)cc(N2Cc3cnc(S(C)=O)nc3NC2=O)c1
Product: COc1cc(OC)cc(N2Cc3cnc(NCCNCc4ccncc4)nc3NC2=O)c1
Yield: 13 %

Procedure:
Using the general procedure above, 3-(3,5-dimethoxy-phenyl)-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.1423 g (0.941 mmol) of N-(4-picoly)ethylenediamine were reacted. The residue was chromatographed eluting with ethyl acetate/ethanol/triethylamine (9:2:1 v/v/v) then ethyl acetate/ethanol/triethylamine (9:3:2 v/v/v) to give 0.0162 g (13%) of the title compound: HPLC=92% pure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11](=[NH:14])[NH:12][NH2:13])=[N:9][N:8]([CH2:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=3[F:24])[C:5]2=[N:6][CH:7]=1.[CH3:25][C:26]([CH3:37])([C:31](=O)[C:32](OC)=[O:33])[C:27]([O:29][CH3:30])=[O:28]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[N:13][C:31]([C:26]([CH3:37])([CH3:25])[C:27]([O:29][CH3:30])=[O:28])=[C:32]([OH:33])[N:14]=3)=[N:9][N:8]([CH2:15][C:16]3[C:21]([F:22])=[CH:20][CH:19]=[C:18]([F:23])[C:17]=3[F:24])[C:5]2=[N:6][CH:7]=1
Reactant: N=C(NN)c1nn(Cc2c(F)ccc(F)c2F)c2ncc(F)cc12
Reactant: COC(=O)C(=O)C(C)(C)C(=O)OC
Solvent: CCO
Product: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3c(F)ccc(F)c3F)c3ncc(F)cc23)nc1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
6.85 g (20.271 mmol) of the compound from Example 81A were dissolved in 300 ml of ethanol, 7.629 g (40.542 mmol) of dimethyl 2,2-dimethyl-3-oxobutanedioate (described in J. Am. Chem. Soc. 124(14), 3680-3691; 2002) were added and the mixture was stirred at 50° C. overnight. After cooling, a precipitate was filtered off and washed with ethanol. The filtrate was concentrated and then purified by preparative HPLC (methanol:water-75:25). This gave 3.30 g (33% of theory) of the title compound.
Reaction SMILES: [CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][N:21](COCC[Si](C)(C)C)[C:22](=[O:23])[C:17]=4[C:16]=3[CH3:33])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:14])[F:13])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1([O:4][C:5]2[CH:6]=[C:7]([C:15]3[NH:32][C:18]4[CH:19]=[N:20][NH:21][C:22](=[O:23])[C:17]=4[C:16]=3[CH3:33])[CH:8]=[CH:9][C:10]=2[O:11][CH:12]([F:13])[F:14])[CH2:2][CH2:3]1
Reactant: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cnn(COCC[Si](C)(C)C)c(=O)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2ccc(OC(F)F)c(OC3CC3)c2)[nH]c2cn[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 67.6 %

Procedure:
To 1.10 g (2.30 mmol) of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-3-methyl-5-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Example 4-(b) were added 30 ml of dichloromethane and 6 ml of trifluoroacetic acid, and the mixture was stirred under room temperature for 2.5 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, 20 ml of methanol and 2 ml of 28% aqueous ammonia were added to the obtained solid, and the mixture was stirred under room temperature for 12 hours. Then, water was added to the solution, precipitated solid was collected by filtration, washed with water, and then, dried under reduced pressure. To the obtained dried material was added ethyl acetate to dissolve therein, diisopropyl ether was added to the solution and precipitated solid was collected by filtration. The obtained solid was dried under reduced pressure to obtain 0.54 g of the title compound as a white solid. (Yield: 67%)
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([C:6](=[O:8])[CH2:7][Cl:4])=[C:10]([CH:15]=1)[N:11]([CH3:14])[CH:12]=[O:13]
Reactant: CC(=O)c1ccc(Cl)cc1N(C)C=O
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: CN(C=O)c1cc(Cl)ccc1C(=O)CCl
Reaction time: 0.08 h

Procedure:
A solution of sulphuryl chloride (9 ml) in dichloromethane (15 ml) was added dropwise to the solution of 2'-acetyl-5'-chloro-N-methylformanilide under nitrogen whilst maintaining the temperature at 0 to Water (40 ml) was then added dropwise whilst maintaining the temperature at 0 to 10°. The mixture was stirred for a further 5 minutes and then the dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 5'-chloro-2'-(2-chloroacetyl)-N-methylformanilide.
Reaction SMILES: [F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>N1C=CC=CC=1.N1CCCCC1>[F:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:13]/[C:14]([OH:16])=[O:15]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1ccc(F)c(O)c1F
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)/C=C/c1ccc(F)c(O)c1F
Yield: 86.7 %

Procedure:
A mixture of 2,4-difluoro-3-hydroxybenzaldehyde (0.255 g, 1.613 mmol) and malonic acid (0.168 g, 1.613 mmol) in pyridine (6 ml) and piperidine (0.06 ml) was heated to reflux for 1 h. All the volatile were removed and the residue was partitioned between NaHCO3 sat. and Et2O. The aqueous phase was acidified with 37% HCl until pH <3 and extracted with AcOEt. The organic layer was dried over sodium sulphate and evaporated to give (E)-3-(2,4-difluoro-3-hydroxyphenyl)acrylic acid (280 mg) as pale a brown solid. The compound was used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([NH2:13])=[NH:12])([O-:3])=[O:2].C(=O)([O-])[O-].[C:18](OCC)(=[O:23])[CH2:19][C:20]([CH3:22])=O.C(=O)=O>COCCOCCOC>[OH:23][C:18]1[N:13]=[C:11]([NH:10][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[N:12]=[C:20]([CH3:22])[CH:19]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: N=C(N)Nc1ccccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=C=O
Solvent: COCCOCCOC
Product: Cc1cc(O)nc(Nc2ccccc2[N+](=O)[O-])n1

Procedure:
121 g (0.5 mol) of 2-nitrophenyl-guanidine-carbonate, 100 g of ethyl acetoacetate and 200 ml of diethylene glycol dimethyl ether are heated first to 65° and, when the evolution of CO2 has ceased, to 140°. In the course of this ethanol and water are distilled off. After 31/2 hours the suspension is cooled, water is added and the pH is adjusted to 4-5 with concentrated hydrochloric acid. The yellow precipitate is filtered off, washed with water and dried in vacuo at 80° C. 80.3 g (65.2% of the theoretical amount) of the title compound of formula ##STR17## (compound No. 2.071) are obtained in the form of crystals having a melting point of 240°-242°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:31]1N=C(CC)C(NC2C3C(=CC=CC=3)CCC2)=NC=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][CH:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][CH2:31][CH2:19]2)=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCc1nc(NC2CCCc3ccccc32)c(CC)nc1Br
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1NC1CCCc2ccccc21

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting 5-bromo-3,6-diethyl-N-(1,2,3,4-tetrahydronaphthalen-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.40, 7.32, 7.20, 7.08, 5.41, 4.57, 2.80, 2.53, 2.41, 2.06, 1.96, 1.90, 1.18; 13C NMR (100 MHz, CDCl3) δ 151.50, 150.93, 140.37, 138.53, 138.37, 137.87, 137.123, 135.36, 134.43, 132.95, 129.78, 129.62, 129.44, 127.57, 127.51, 125.63, 60.82, 49.01, 29.96, 27.62, 26.93, 14.61, 13.32, 11.67; HRMS (FAB) calcd for C18H22BrN3+H 360.1076, found 360.1065.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:30][C:31]1[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:30][C:31]2[CH:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=2)([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1ccnc(CCl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2cc(C)ccn2)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a cold (-78° C.) solution of ethyl N-tert-butoxycarbonyl-piperidine-4-carboxylate (5.1 g, 19.8 mmol; Example 30, Step A) in anhydrous THF (50 mL), a solution of solution of sodium bis(trimethylsilyl)amide (20 mL, 1M, 20 mmol) was added over a period of 15 min. The resultant mixture was stirred at -78° C. for 1 h., and 2-chloromethyl-4-methylpyridine (3.5 g, 24.7 mmol) was added. The reacting mixture was allowed to warm to room temp. and stirred overnight. The product mixture was diluted with dichloromethane was washed with brine. The organic extract was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 25-40% ethyl acetate in hexane gradient. Collection and concentration of appropriate fractions provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[CH2:21]([NH2:24])[CH2:22][CH3:23]>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:24][CH2:21][CH2:22][CH3:23])[N:3]=1
Reactant: CCCN
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CCCNc1nc(Cl)nc2c1ncn2C(C)CC
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.132 ml 1-propanamine in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, followed by taking up in 5 ml of ethyl acetate, evaporating to dryness, impasting in 5 ml of pentane at ambient temperature, separating, washing with 5 ml of pentane and drying at a temperature of approximately 50° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](OCC)=[O:15])[N:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[BH4-].[Li+]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:14][OH:15])[N:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:12])([F:13])[F:11]
Reactant: CCOC(=O)c1cc(C)c(OCC(F)(F)F)nn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)nnc1OCC(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of ethyl 5-methyl-6-(2,2,2-trifluoroethoxy)pyridazine-3-carboxylate (1.70 g, 6.43 mmol, Step-2 of Amine-48) in THF (32 mL) is added a solution of lithium borohydride in THF (3 M, 3.22 mL, 9.65 mmol) at 0° C. After stirring at 0° C. for 4 hours, the reaction is quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture is filtered through a pad of Celite, and the filtrate is extracted with EtOAc (200 mL). The separated organic layer is washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by column chromatography on silica gel eluting with n-hexane/EtOAc (1:2) to give 1.22 g (85% yield) of the title compound as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:29]=[CH:28][C:7]2[N:8]([C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[C:14]([N:21]5[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]5)[CH:15]=[CH:16][CH:17]=4)[N:12]=3)[CH:9]=[N:10][C:6]=2[CH:5]=1)[CH3:2].[CH:30]1([NH2:33])[CH2:32][CH2:31]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH:30]1([NH:33][CH:24]2[CH2:23][CH2:22][N:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([N:8]3[C:7]5[CH:28]=[CH:29][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=5[N:10]=[CH:9]3)[CH:20]=[CH:19]4)[CH2:26][CH2:25]2)[CH2:32][CH2:31]1
Reactant: CCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(=O)CC3)c2n1
Reactant: NC1CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOc1ccc2c(c1)ncn2-c1ccc2cccc(N3CCC(NC4CC4)CC3)c2n1
Reaction time: 0.17 h
Yield: 103.2 %

Procedure:
1-[2-(5-Ethoxy-benzoimidazol-1-yl)quinolin-8-yl]-piperidin-4-one 18 (130 mg, 0.340 mMol) was dissolved in 1.5 mL of DCE under an atmosphere of dry N2. To this solution was added cyclopropyl amine (110 μL, 1.70 mMol) and 200 μL of AcOH and the solution was stirred for 10 minutes. To this solution was added NaHB(OAc)3 (107 mg, 0.50 mMol) and the solution was stirred at ambient temperature for 5 hours. The reaction mixture was then partitioned between DCM and aqueous 0.1 N NaOH. The DCM layer was again washed with aqueous 0.1 N NaOH, dried over Na2SO4, filtered and concentrated under vacuum to give 150 mg of a green foam. The foam was chromatographed on flash silica gel eluting with a gradient from MeOH/DCM (299) to MeOH/DCM (496) to give the title compound 20 as a yellow solid.