Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N#N.[Si]([O:10][CH2:11][C:12]1[O:13][CH:14]=[C:15]([C:17]2([CH3:22])[O:21][CH2:20][CH2:19][O:18]2)[N:16]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].[NH4+].[Cl-]>C1COCC1>[CH3:22][C:17]1([C:15]2[N:16]=[C:12]([CH2:11][OH:10])[O:13][CH:14]=2)[O:21][CH2:20][CH2:19][O:18]1
Reactant: CC1(c2coc(CO[Si](C)(C)C(C)(C)C)n2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [Cl-]
Solvent: C1CCOC1
Product: CC1(c2coc(CO)n2)OCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-{[(tert-butyldimethylsilyl)oxy]methyl}-4-(2-methyl-[1,3]dioxolan-2-yl)oxazole (3.50 g, 11.69 mmol) in dry THF (70 mL) was treated at 0° C. with TBAF (15.2 mL of a 1M solution in THF, 15.20 mmol). The reaction mixture was stirred at 0° C. for 1 h. Sat. aq. NH4Cl was added, the layers separated and the aq. layer extracted with EA. The combined org. extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (2:3 to 1:0 EA-Hept) gave the title compound as a pale yellow oil. TLC: rf (EA)=0.20. LC-MS-conditions 01: tR=0.45 min, [M+H]+=186.00.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][CH2:21][CH:22]=[O:23])=[CH:17][CH:18]=1
Reactant: OCCCCc1ccc(Cl)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=CCCCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of pyridinium chlorochromate (PCC) (5 g) in CH2Cl2 (200 mL) and 4 angstrom molecule sieves (5 g) was added the alcohol (2 g) (Step II). The mixture was stirred 2 hr at RT, filtered through celite and evaporated. Flash chromatography using 25% ethyl acetate in hexane afforded the title compound.
Reaction SMILES: N#N.[F:3][C:4]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[N:14]2)[S:10][CH:11]=1)([F:6])[CH3:5].[NH4+].[Cl-]>CCO.O.[Fe]>[F:3][C:4]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]2)[S:10][CH:11]=1)([F:6])[CH3:5]
Reactant: CC(F)(F)c1csc(Cn2ncc([N+](=O)[O-])n2)n1
Agent: [Fe]
Agent: N#N
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(F)(F)c1csc(Cn2ncc(N)n2)n1
Temperature: 85 °C
Reaction time: 0.33 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a mixture of 2-[4-(1,1-difluoro-ethyl)-thiazol-2-ylmethyl]-4-nitro-2H-[1,2,3]triazole (491 mg, 1.78 mmol), iron powder (302 mg, 5.35 mmol) and NH4Cl (482 mg, 8.92 mmol) in a mixture of EtOH (8.0 mL) and water (4.0 mL) was stirred at 85° C. for 20 min. The reaction mixture was filtered while hot and concentrated under reduced pressure. CH2Cl2 (20 mL) was added followed by water (20 mL). The aq. layer was extracted with CH2Cl2 (2×10 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as a yellow oil. LC-MS-conditions 02: tR=0.76 min; [M+H]+=246.16.
Reaction SMILES: C(OC([N:8]([CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33]([OH:35])=O)[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1)[CH2:9][C@H:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O)(C)(C)C.[CH3:36][N:37](C)[CH2:38]CCN=C=NCC.Cl.CNC>ClCCl.C(OCC)(=O)C>[OH:19][C@H:10]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:9][NH:8][CH:20]1[CH2:26][C:25]2[CH:27]=[C:28]([O:31][CH2:32][C:33]([N:37]([CH3:38])[CH3:36])=[O:35])[CH:29]=[CH:30][C:24]=2[CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N(C[C@H](O)COc1ccccc1)C1CCCc2ccc(OCC(=O)O)cc2C1
Reactant: CCN=C=NCCCN(C)C
Agent: CNC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(C)C(=O)COc1ccc2c(c1)CC(NC[C@H](O)COc1ccccc1)CCC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.9 %

Procedure:
To a solution of 2-[8-[N-tert-butoxycarbonyl-N-[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]acetic acid (200 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (122 mg) and 1-hydroxyenzotriazole hydrate (66 mg) in dichloromethane (20 ml) was added dimethylamine hydrochloride (38.4 mg), and the mixture was stirred at room temperature for 18 hours. The resulting mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed (hexane-ethyl acetate) over silica gel and treated with 4N hydrogen chloride in ethyl acetate to afford 2-[8-[[(2S)-2-hydroxy-3-phenoxypropyl]amino]-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yloxy]-N,N-dimethylacetamide (100 mg).
Reaction SMILES: [CH:1]1([C:5]2[C:14](I)=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>C1COCC1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[CH:1]1([C:5]2[C:14]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: COC(=O)c1cc(I)c(C2CCC2)cc1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(C#C[Si](C)(C)C)c(C2CCC2)cc1C
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A mixture of methyl 4-cyclobutyl-5-iodo-2-methylbenzoate (compound 152.3, 1.32 g, 4 mmol), trimethylsilylacetylene (663 μl, 4.8 mmol), Pd(PPh3)2Cl2 (85 mg, 0.12 mmol) and copper iodide (CuI, 46 mg, 0.24 mmol) in THF (8 ml) and triethylamine (2 ml) was degassed and then heated to 80° C. for 1.5 hours under nitrogen. After cooling to ambient temperature, the reaction was filtered through celite and concentrated. The residue was dissolved in ethyl acetate (EtOAc), washed with brine, dried over MgSO4 and concentrated. The residue was purified by flash chromatography (SiO2; 3% EtOAc in Hexane) to give 1.17 g (97%) of the title compound as a liquid. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.15 (s, 1H), 4.01-3.75 (m, 4H), 2.63 (s, 3H), 2.54-2.31 (m, 2H), 2.27-2.12 (m, 2H), 2.12-1.98 (m, 1H), 1.94-1.80 (m, 1H), 0.28 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]([N:16]([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:15])[C:5](=[O:24])[CH:4]([NH:25]C(=O)OCC2C=CC=CC=2)[N:3]=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH2:25][CH:4]1[N:3]=[C:2]([CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]([N:16]([CH3:23])[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:15])[C:5]1=[O:24]
Reactant: CC1=NC(NC(=O)OCc2ccccc2)C(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC1=NC(N)C(=O)N(CC(=O)N(C)c2ccccc2)c2ccccc21
Reaction time: 1 h
Yield: 84.5 %

Procedure:
A mixture of 5% palladium on carbon (300 mg) and phenylmethyl [2,3-dihydro-5-methyl-1-[2-(methylphenylamino)-2-oxoethyl]-2-oxo-1H-1,4-benzodiazepin-3-yl]carbamate (500 mg) in MeOH-water 4:1(40 ml) at 40° under nitrogen was treated with ammonium formate (201 mg) and the mixture stirred at 40° for 1 h. The mixture was cooled to 23° and was filtered through hyflo. The filtrate was evaporated in vacuo and the residue partitioned between 2 N sodium carbonate solution and chloroform. The organic phase was dried and the solvent evaporated in vacuo. The residue was purified by chromatography, elution with MeOH-DCM (1:9) gave the title compound(302 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3](=[O:26])[C@@H:4]([N:8]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)[CH2:10][CH2:9]1)[CH2:5][CH:6]=O.Cl.[CH2:29]1[C:31]2([CH2:36][CH2:35][NH:34][CH2:33][C@H:32]2[OH:37])[CH2:30]1>>[OH:37][C@@H:32]1[CH2:33][N:34]([CH2:6][CH2:5][C@H:4]([N:8]2[C:14](=[O:15])[CH2:13][CH2:12][N:11]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:23])[F:25])[CH:17]=3)[CH2:10][CH2:9]2)[C:3]([N:2]([CH3:1])[CH3:27])=[O:26])[CH2:35][CH2:36][C:31]21[CH2:30][CH2:29]2
Reactant: O[C@@H]1CNCCC12CC2
Reactant: CN(C)C(=O)[C@H](CC=O)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Agent: Cl
Product: CN(C)C(=O)[C@H](CCN1CCC2(CC2)[C@H](O)C1)N1CCN(c2cccc(C(F)(F)F)c2)CCC1=O
Yield: 57 %

Procedure:
In analogy to the procedure described in example 1K, (S)—N,N-dimethyl-4-oxo-2-[7-oxo-4-(3-trifluoromethyl-phenyl)-[1,4]diazepan-1-yl]-butyramide and (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2) gave the title compound in 57% yield as white foam. MS: 497.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14].[H][H]>CCOC(C)=O.CO.[Pd]>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[O:13][CH3:14]
Reactant: [H][H]
Reactant: COc1cc(C=CC(=O)O)ccc1O
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(CCC(=O)O)ccc1O
Yield: 89.1 %

Procedure:
To a solution of 3-(4-Hydroxy-3-methoxy-phenyl)-acrylic acid (20 g, 103 mmol) in EtOAc (100 ml) and MeOH (100 ml) was added carefully 10% Pd/C (2.0 g), the reaction mixture was shaken in Parr apparatus for 5 hs under 30-40 psi of hydrogen, then the solution was passed through a celite pad and the catalyst was washed with methanol, the filtrate was concentrated and dried at 50° C. under reduced pressure to give product (18 g, 89.16%). LC-MS: m/e 195 (M−1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:23])=[C:8]([NH:10][C:11]2[N:16]=C(C3C=NC=CC=3)C=C[N:12]=2)[CH:9]=1)([O-:3])=[O:2].CC1C=CC([N+]([O-])=O)=CC=1N.N#CN.[ClH:38]>>[ClH:38].[CH3:23][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][C:8]=1[NH:10][C:11]([NH2:16])=[NH:12]
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Agent: Cc1ccc([N+](=O)[O-])cc1N
Agent: Cl
Agent: N#CN
Product: Cc1ccc([N+](=O)[O-])cc1NC(=N)N

Procedure:
In other aspects the invention provides a process for the preparation of N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine comprising: (a) reacting 2-methyl-5-nitroaniline with cyanamide in the presence of hydrochloric acid to obtain 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride; (b) converting 1-(2-methyl-5-nitrophenyl)guanidine hydrochloride to 1-(2-methyl-5-nitrophenyl)guanidine nitrate; (c) condensing 3-acetylpyridine with N,N-dimethylformamide dimethyl acetal to obtain 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one; and (d) reacting 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one with 1-(2-methyl-5-nitrophenyl)guanidine nitrate to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-2-pyrimidineamine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH:16]([C:40]([O:42]CC)=[O:41])[N:17]([C:25](=[O:39])[CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18]3)=[CH:7][CH:6]=1)([O:3]C)=[O:2]>CO.[OH-].[Na+]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]([O:23][CH3:24])=[CH:21][CH:20]=[C:19]3[C:14]=2[CH2:15][CH:16]([C:40]([OH:42])=[O:41])[N:17]([C:25](=[O:39])[CH:26]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:18]3)=[CH:7][CH:6]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C1Cc2c(ccc(OC)c2OCc2ccc(C(=O)OC)cc2)CN1C(=O)C(c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1OCc1ccc(C(=O)O)cc1)CC(C(=O)O)N(C(=O)C(c1ccccc1)c1ccccc1)C2

Procedure:
A solution of 1.10 g (0.0019 mole) of the diester from Example 32 in 100 mL of methanol and 15 mL of 2N sodium hydroxide is heated to the boiling point, allowing the methanol to distill off. After 1 hour (pot temperature=90° C.), 1N hydrochloric acid (35 mL) is added to precipitate a gum. On addition of 10 mL of ether, crystals develop; wt. 0.84 g. Recrystallization from ethyl acetate-petroleum ether gives pure product; mp 190°-192° C.
Reaction SMILES: C([NH:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([N:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH3:23])[CH2:18][CH2:17]2)=[CH:11][C:10]=1[F:24])(OC(C)(C)C)=O.Cl.[OH-].[Na+]>C(OCC)(=O)C>[CH2:22]([N:19]1[CH2:20][CH2:21][N:16]([C:12]2[CH:11]=[C:10]([F:24])[C:9]([NH2:8])=[C:14]([F:15])[CH:13]=2)[CH2:17][CH2:18]1)[CH3:23]
Reactant: CCN1CCN(c2cc(F)c(NC(=O)OC(C)(C)C)c(F)c2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCN1CCN(c2cc(F)c(N)c(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
To a solution of N-Boc-4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine (2.4 g, 7.03 mmol) obtained in Step B in ethyl acetate (20 ml), 6M−HCl aqueous solution (10 ml) was added, followed by stirring at room temperature for 1 hour. To this, 5M-NaOH aqueous solution was added to adjust the pH to 8, followed by extraction with ethyl acetate (50 ml×2). The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. This was purified by silica gel column chromatography (dichloromethane/methanol=50/1 to 20/1), followed by further dissolution in a minimum amount of dichloromethane. n-Hexane was added, and an oily component was removed, to obtain the desired compound as a brown solid (1.33 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][NH:19][CH:20]2[CH3:25]>>[Cl:14][C:15]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:16]=1[CH2:17][CH2:18][N:19]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH:20]2[CH3:25]
Reactant: CC1NCCc2c(Cl)cccc21
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Product: CC1c2cccc(Cl)c2CCN1C(=O)c1cc2ncc(Cl)cn2n1
Yield: 61 %

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-Chloro-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound.
Reaction SMILES: Cl[CH2:2][C@:3]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15])([OH:7])[C@@H:4]([OH:6])[CH3:5].C[O-].[Na+].O.C(OCC)(=O)C>CO>[O:7]1[C@:3]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])([C@@H:4]([OH:6])[CH3:5])[CH2:2]1
Reactant: C[C@H](O)[C@@](O)(CCl)c1ccc(F)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: C[C@H](O)[C@]1(c2ccc(F)cc2F)CO1
Reaction time: 2 h
Yield: 95.5 %

Procedure:
A solution of 0.12 g (0.45 mmol) of (2R,3S)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol in methanol 3 mL was cooled in ice, and 0.12 g (0.6 mmol) of a 28% solution of NaOMe in methanol was added. Reaction was performed for 2 hours. Then, 10 mL of water was added to stop the reaction, and extraction was performed with ethyl acetate (10 mL). After drying over anhydrous sodium sulfate, concentration was performed under reduced pressure to obtain a crude product. The resulting crude product was purified by column on silica gel to obtain 0.086 g of the title compound (yield: 96%).
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH:24]1[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:24]3[CH2:30][CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: C1CNCCNC1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCCNCC2)nc1

Procedure:
50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide was reacted with 1,4-diazepane via Procedure F. The reaction was evaporated to dryness and purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(1,4-diazepan-1-yl)nicotinamide. MS (Q1) 408 (M)+.
Reaction SMILES: C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1(C(C2C=CC=CC=2)=[N:22][CH:23]([C:29]2[C:34]([Cl:35])=[CH:33][C:32]([C:36]([F:39])([F:38])[F:37])=[CH:31][N:30]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])C=CC=CC=1>>[Cl:35][C:34]1[C:29]([CH:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH2:22])=[N:30][CH:31]=[C:32]([C:36]([F:39])([F:37])[F:38])[CH:33]=1
Reactant: CCOC(=O)C(N=C(c1ccccc1)c1ccccc1)c1ncc(C(F)(F)F)cc1Cl
Agent: O=C(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(N)c1ncc(C(F)(F)F)cc1Cl

Procedure:
Two liquid phases were separated. The bottom aqueous phase containing ethyl 2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate hydrochloride salt was separated and was ready for the following decarboxylation reaction (preparation of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine hydrochloride). The top organic phase contains all the benzophenone from ethyl N-(diphenylmethylene)-2-(3-chloro-5-trifluoromethyl-2-pyridyl)glycinate and the excess from the BPGI preparation, and was recovered for recycle at step 1. A 93% recovery yield of benzophenone with respect to the 182 g (1 mole) introduced in beinzophenone glycine imine ethyl ester preparation was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](OC(C)(C)C)=O)[CH2:7][CH2:8][CH3:9])[CH3:2].Cl.O1CCOCC1.[NH:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH2:35][N:36]([CH2:44][C:45]1[CH:52]=[CH:51][C:48](C=O)=[CH:47][CH:46]=1)[CH2:37][C:38]1[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)C.C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][C:48]1[CH:51]=[CH:52][C:45]([CH2:44][N:36]([CH2:35][C:31]2[NH:30][CH:34]=[CH:33][N:32]=2)[CH2:37][C:38]2[N:39]([CH3:43])[CH:40]=[CH:41][N:42]=2)=[CH:46][CH:47]=1)[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: Cn1ccnc1CN(Cc1ccc(C=O)cc1)Cc1ncc[nH]1
Reactant: CCCN(CCCCNC(=O)OC(C)(C)C)CC(=O)OCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCO
Product: CCCN(CCCCNCc1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1)CC(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
The compound (273.0 mg) obtained in Example 84-2 was dissolved in ethanol (2.7 ml) and added with a 4 mol/l hydrogen chloride/dioxane solution (2.7 ml) and the whole was stirred at room temperature for 1 hour. Further, the solution was added with a 4 mol/l hydrogen chloride/dioxane solution (1.0 ml) and the whole was stirred at room temperature for 30 minutes. After completion of the reaction, the solvent was distilled off, thereby obtaining a crude product (350.0 mg) of [(4-amino-butyl)-propyl-amino]-acetic acid ethyl ester as a colorless oily substance. The resultant crude product (350.0 mg) was dissolved in ethanol (4.5 ml) and added with an ethanol solution (2.6 ml) containing the compound (258 mg) obtained in Example 84-5, acetic acid (0.10 ml), and sodium triacetoxyborohydride (267.0 mg) and the whole was stirred at room temperature for 2 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution, followed by extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (238.0 mg) as a pale-yellow oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[C:9]1([N:15]=[C:16]=[O:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:16]([NH:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:17])[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccnc(Cl)c1
Reactant: O=C=Nc1ccccc1
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 257 mg. (2 mmol) of 2-chloro-4-aminopyridine dissolved in ten ml. of dry acetone, 238 mg. (2 mmol) of phenyl isocyanate is added and the mixture is stirred at room temperature for 8 hrs. The solvent is evaporated under a reduced pressure, the residue is chromatographed over alumina, and the column is developed with chloroform. Eluates containing the objective substance are collected, and the solvent is evaporated under a reduced pressure. The residue is recrystallized from acetone-ether mixture and 364 mg. of N-(2-chloro-4-pyridyl)-N'-phenylurea is obtained. Yield, 73.5%, mp 173°-174° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[C:12]([NH:19][C@H:20]([CH:28]=[CH2:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13]>C(Cl)Cl>[C:12]([NH:19][C@H:20]([C@@H:28]1[CH2:29][O:9]1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13]
Reactant: C=C[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 9.74 g of m-chloroperbenzoic acid in 50 ml of methylene chloride is added over the course of 15 min at from 0° to 5° C. to a solution of 1.45 g of N-Boc-1-phenyl-3-buten-2(S)-amine in 20 ml of methylene chloride. The batch is stirred for 18 h at that same temperature and is then stirred for a further 8 h, with heating to RT, to complete the reaction and poured onto ice-cold 10% sodium carbonate solution. The aqueous phase is extracted three times with ether. The combined organic phases are washed in succession three times with 10% sodium sulfite solution, three times with saturated sodium hydrogen carbonate solution, with sodium thiosulfate solution and with brine and dried over sodium sulfate. After concentrating the solvents, the title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4/1) and recrystallised from hexane. M.p. 51°-52° C.; TLC Rf (C)=0.33; FAB-MS (M+H)+=264.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[C:29]([N:8]([CH2:9][C:10]1([N:13]([CH3:21])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:11][CH2:12]1)[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CN(C(=O)OC(C)(C)C)C1(CNc2ccc(Cl)nc2)CC1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)OC(C)(C)C)C1(CN(C(=O)c2ccccc2)c2ccc(Cl)nc2)CC1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
10.17 g of the compound obtained in Step 1 of Example 9 are dissolved in 200 ml of tetrahydrofuran, 4.88 ml of triethylamine are added, cooling to 5° C. is carried out and, over a period of 30 minutes, 5.05 g of benzoyl chloride are poured in. Stirring is carried out for one hour at 5° C. and then for one hour at ambient temperature, and subsequently refluxing is carried out for 2 hours. Concentration to dryness is carried out and the residue is taken up in dichloromethane and washed with 50% aqueous potassium carbonate solution. The organic phase is dried over sodium sulphate and concentrated, and chromatography of the residue on silica gel (dichloromethane/tetrahydrofuran: 96/4) allows 13.9 g of expected product to be obtained.