Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][O:39][CH3:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1)[C:15]([CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])(C)(C)C.ClCCl.Cl>O1CCOCC1>[NH2:7][C@@H:8]([C@@H:9]([CH3:12])[CH2:10][CH3:11])[CH2:13][N:14]([C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][O:39][CH3:40])=[CH:36][CH:37]=2)=[CH:28][CH:27]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:16]
Reactant: CC[C@H](C)[C@@H](CN(C(=O)C1CC1c1ccccn1)c1ccc(-c2ccc(COC)cc2)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H](C)[C@H](N)CN(C(=O)[C@@H]1C[C@H]1c1ccccn1)c1ccc(-c2ccc(COC)cc2)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A solution of ((1S,2S)-1-{[(4′-methoxymethyl-biphenyl-4-yl)-(2-pyridin-2-yl-cyclopropanecarbonyl)-amino]-methyl}-2-methyl-butyl)-carbamic acid tert-butyl ester (25 mg, 0.045 mmol) and dichloromethane (4 mL) was treated with a solution of HCl in dioxane (4 N, 0.5 mL) and the resulting reaction mixture was maintained at room temperature for 12 h. The reaction was then concentrated to dryness to afford (1R,2R)-2-pyridin-2-yl-cyclopropanecarboxylic acid ((2S,3S)-2-amino-3-methyl-pentyl)-(4′-methoxymethyl-biphenyl-4-yl)-amide (18 mg, 95% yield) as a white solid: 1H NMR (400 MHz, MeOD) δ 8.49 (d, J=5.8 Hz, 1H), 8.23 (t, J=7.8 Hz, 1H), 7.61-7.71 (m, 3H), 7.44-7.54 (m, 5H), 7.34 (d, J=8.1 Hz, 2H), 4.40 (s, 2H), 4.22 (dd, J=14.9, 9.1 Hz, 1H), 3.70 (dd, J=14.9, 2.5 Hz, 1H), 3.62-3.66 (m, 1H), 3.54-3.59 (m, 1H), 3.46-3.50 (m, 1H), 3.31 (s, 3H), 2.83-2.90 (m, 1H), 2.07-2.13 (m, 1H), 1.84-1.92 (m, 1H), 1.64-1.74 (m, 1H), 1.60 (dt, J=8.7, 5.5 Hz, 1H), 1.24-1.36 (m, 1H), 1.06-1.22 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.76 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 458.1 [(M+H)+, calcd for C29H36N3O2 458.3].
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(Cl)Cl>[C:1]1([C:7]2[N:11]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:10]=[N:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: c1ccc(-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A solution of 5-phenyl-1H-tetrazole (50.0 g, 342.1 mmol, 1.00 equiv) in DCM (dried) (150 mL) was placed in a flask that had been purged and maintained with an inert atmosphere of nitrogen. Triethylamine (45.0 g, 444.7 mmol, 1.30 equiv) at 0° C. was added to the mixture, followed by the addition of chlorotriphenylmethane (100.0 g, 358.7 mmol, 1.05 equiv) in several batches at 0° C. The resulting solution was stirred for 3 hours at room temperature. The solids were collected by filtration, and the filtrate cake was washed with cold EtOAc (1×100 mL) and water (3×300 mL). The solid was dried under reduced pressure to yield 125 g (94%) of 5-phenyl-1-trityl-1H-tetrazole as a white solid. ES m/z: [M+H]+ calcd for C26H20N4, 389.1, found 389.1.
Reaction SMILES: [CH2:1]([NH:3][C@@H:4]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=2)[CH2:8][CH2:7][N:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:5]1)[CH3:2].Cl.CN(C)CCCN=C=NCC.[C:36](O)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>C(Cl)Cl.C(N(CC)CC)C>[C:36]([O:16][C:12]1[CH:11]=[C:10]([C@H:9]2[CH2:8][CH2:7][N:6]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:5][C@@H:4]2[NH:3][CH2:1][CH3:2])[CH:15]=[CH:14][CH:13]=1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCN[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(O)c1
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a solution of tert-butyl (rac.)-(3R,4R)-3-(ethylamino)-4-(3-hydroxyphenyl)piperidine-1-carboxylate (1.76 g) in methylene chloride (16 ml) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.37 g), N,N-dimethylaminopyridine (872 mg), triethylamine (995 μl), and benzoic acid (610 mg), and the mixture was stirred at room temperature for one hour. To the reaction mixture was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=1/1) to give the title compound (968 mg).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH:13]([NH2:17])[CH2:14][CH:15]=[CH2:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33](O)=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]>>[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH2:32][C:33]([NH:17][CH:13]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:14][CH:15]=[CH2:16])=[O:34])[CH:24]=[CH:25][C:26]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:19]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: C=CCC(N)c1ccccc1N1CCCCC1
Product: C=CCC(NC(=O)Cc1ccc(C(=O)OCC)c(OCC)c1)c1ccccc1N1CCCCC1

Procedure:
Prepared analogously to Example 19 from 1-(2-piperidino-phenyl)-3-buten-1-yl-amine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH2:6]([NH2:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.P(O)(O)O>O>[CH2:6]([NH:13][CH2:1][CH:2]([CH3:4])[CH3:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCc1ccccc1
Reactant: CC(C)C=O
Agent: OP(O)O
Solvent: O
Product: CC(C)CNCc1ccccc1

Procedure:
To the imine from isobutyraldehyde and benzylamine (48.4 g; 0.3 mole) was added phosphorous acid (24.6 g; 0.3 mole) and the mixture slowly warmed while stirring. As the internal temperature reached 70°-75° a vigorous exothermic reaction ensued taking the temperature to 130°-135°. After maintaining at 130°-140° for 30 mins. the viscous product was cooled to 100° and diluted with water. Basification and extraction with chloroform gave crude amine after solvent evaporation. Distillation gave pure N-benzylisobutylamine, 13.6 g (28%) bp 94°-99°/5.6 mm. Nmr confirmed the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.[N:14]1[CH:19]=[CH:18][N:17]=[CH:16][C:15]=1[C:20](O)=O>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]2=[N:12][N:13]=[C:20]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][N:14]=3)[N:4]2[N:3]=1
Reactant: NNc1nnc(Cl)c2ccccc12
Reactant: O=C(O)c1cnccn1
Product: Clc1nn2c(-c3cnccn3)nnc2c2ccccc12

Procedure:
The title-compound was prepared from 1-chloro-4-hydrazinophthalazine and pyrazine-2-carboxylic acid as described for Intermediate 1 part c, 1H NMR (250 MHz, CDCl3) δ 7.99 (1H, t, J=7.2 Hz, Ar—H), 8.09 (1H, t, J=8.2 Hz, Ar—H), 8.33 (1H, d, J=6.8 Hz; Ar—H), 8.80 (1H, m, Ar—H), 8.82-8.88 (2H, m, 2 of Ar—H), 9.67 (1H, d, J=1.5 Hz, Ar—H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][N:10]([CH3:18])[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].S([O-])([O-])(=O)=O.[Al+3].S([O-])([O-])(=O)=O.S([O-])([O-])(=O)=O.[Al+3].[S:36]([O-])([O-:39])(=[O:38])=[S:37].[Na+].[Na+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>Cl.O.C(O)(=O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([N:10]([CH2:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH3:18])=[CH:12][C:13]=1[S:36]([OH:39])(=[O:38])=[S:37]
Reactant: O=S([O-])([O-])=S
Reactant: CCOC(=O)CCCCN(C)c1ccc(N)cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)CCCCN(C)c1ccc(N)c(S(=O)(O)=S)c1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
N-(4-Ethoxycarbonylbutyl)-N-methyl-p-phenylenediamine (1.7 g) was dissolved in 1N hydrochloric acid (13.6 ml) and to the solution was added a solution of aluminium sulfate 14-18 hydrate in water (10 ml). The mixture was ice-cooled. A solution of sodium thiosulfate 5 hydrate (2 g) in water (8 ml) was added thereto and further a solution of sodium dichromate 2 hydrate (0.798 g) in water (5 ml) was added dropwise. The resulting mixture was stirred for 30 minutes under ice-cooling. Then acetic acid (0.6 ml) was added and the mixture was further stirred at room temperature for 2 hours. The reaction mixture was concentrated to dryness. The concentrate was made alkaline with an aqueous sodium bicarbonate and insoluble materials were filtered off. The filtrate was adjusted to pH 4 with acetic acid, concentrated to about 50 ml and cooled. The resulting crystalline precipitate was filtered off, washed with cold water and dried to obtain the desired compound (2.1 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]3[CH2:10][CH2:11][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]3=[N:7][C:6]=2[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[C:30]([C:39]([F:42])([F:41])[F:40])[CH:29]=1>CN(C=O)C.O>[CH:34]1([C:31]2[CH:32]=[CH:33][C:28]([CH2:27][O:1][C:2]3[CH:3]=[CH:4][C:5]4[N:9]5[CH2:10][CH2:11][CH:12]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:8]5=[N:7][C:6]=4[CH:19]=3)=[CH:29][C:30]=2[C:39]([F:40])([F:41])[F:42])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CCOC(=O)CC1CCn2c1nc1cc(O)ccc12
Reactant: FC(F)(F)c1cc(CCl)ccc1C1CCCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC1CCn2c1nc1cc(OCc3ccc(C4CCCC4)c(C(F)(F)F)c3)ccc12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.4 %

Procedure:
Ethyl 2-(6-hydroxy-2,3-dihydro-1H-benzo[d]pyrrolo[1,2-a]imidazol-3-yl)acetate (0.1 g, 0.384 mmol) was dissolved in DMF (1.0 mL) and cesium carbonate (0.150 g, 0.461 mmol) and 4-(chloromethyl)-1-cyclopentyl-2-(trifluoromethyl)benzene (0.111 g, 0.423 mmol) were added. The reaction mixture was stirred at room temperature for 1.5 h and then warmed to 40° C. After stirring for 1 h, the reaction mixture was diluted with water and extracted three times with EtOAc. The combined extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (126 mg). LCMS m/z=487.4 [M+H]+; 1H NMR (400 MHz, CDCl3) 5 ppm 1.26 (t, J=7.2 Hz, 3H), 1.55-1.65 (m, 2H), 1.67-1.78 (m, 2H), 1.81-1.91 (m, 2H), 2.04-2.14 (m, 2H), 2.36-2.47 (m, 1H), 2.62 (dd, J=16.4, 9.7 Hz, 1H), 2.97-3.07 (m, 1H), 3.16 (dd, J=16.8, 3.8 Hz, 1H), 3.33-3.43 (m, 1H), 3.64-3.74 (m, 1H), 3.97-4.05 (m, 1H), 4.09-4.21 (m, 3H), 5.09 (s, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.93 (dd, J=8.6, 2.4 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 7.56-7.61 (m, 2H), 7.68 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]23[CH2:16][C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=4)([CH2:15]2)[C:13](=[O:26])[N:12]([CH2:27][CH2:28][CH3:29])[C:11]3=[O:30])=[CH:6][CH:5]=1)([O-])=O.CCOCC.C(Cl)Cl>C(OCC)(=O)C.[Pd]>[NH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]23[CH2:16][C:10]([C:7]4[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=4)([CH2:15]2)[C:11](=[O:30])[N:12]([CH2:27][CH2:28][CH3:29])[C:13]3=[O:26])=[CH:22][CH:21]=1
Reactant: CCCN1C(=O)C2(c3ccc([N+](=O)[O-])cc3)CC(c3ccc([N+](=O)[O-])cc3)(C2)C1=O
Agent: [Pd]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCCN1C(=O)C2(c3ccc(N)cc3)CC(c3ccc(N)cc3)(C2)C1=O

Procedure:
In a manner analogous to that described in Example 12a, 0.4 g of 1,5-di-(4-nitrophenyl)-3-n-propyl-3-azabicyclo[3.1.1]heptane-2,4-dione are dissolved in 15 ml of ethyl acetate, hydrogenated in the presence of 80 mg of 5% palladium-on-carbon and worked up. Melting point 149°-150° (from ether/methylene chloride).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33]([OH:35])=O)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:37]([C:40]1[N:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1)([CH3:39])[CH3:38].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C@@H:15]([C:33](=[O:35])[NH:47][CH2:46][C:43]3[CH:44]=[N:45][C:40]([CH:37]([CH3:39])[CH3:38])=[CH:41][CH:42]=3)[CH2:14]2)=[N:10][C:9]=1[CH3:36])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)O)C2)sc1C(=O)OC(C)(C)C
Reactant: CC(C)c1ccc(CN)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)NCc3ccc(C(C)C)nc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a mixed solution of the compound (55 mg) obtained in Step 6, [(6-isopropylpyridin-3-yl)methyl]amine (24 mg) and 1-hydroxybenzotriazole hydrate (23 mg) in N,N-dimethylformamide (660 μl) was added, with stirring at room temperature, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (29 mg). After stirring at room temperature for 3 hr, the reaction mixture was partitioned by adding saturated aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by thin layer chromatography (ethyl acetate:n-hexane=3:2) to give the title compound (59 mg).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:17]2[C:22](F)=[CH:21][C:20]([F:24])=[CH:19][N:18]=2)=O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:25][NH:26][NH2:27].CC(O)C>O>[F:24][C:20]1[CH:21]=[C:22]2[N:26]([CH3:25])[N:27]=[C:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:17]2=[N:18][CH:19]=1
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1ncc(F)cc1F
Reactant: CNN
Solvent: CC(C)O
Solvent: O
Product: Cn1nc(-c2ccc(O)cc2)c2ncc(F)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 55.7 %

Procedure:
A mixture of [4-(benzyloxy)phenyl](3,5-difluoropyridin-2-yl)methanone (300 mg), methylhydrazine (212 mg) and 2-propanol (5 mL) was stirred at room temperature for 30 min, and then at 90° C. for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude material was dissolved in EtOH (20 mL) and 10% Pd—C (50% wet, 98 mg) was added. The mixture was stirred for 1 h under H2 atmosphere, filtered and evaporated. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (125 mg).
Reaction SMILES: [N:1]1[N:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][C:4]2=[CH:3][CH:2]=1.C1C(=O)N([I:31])C(=O)C1>CN(C=O)C>[I:31][C:3]1[CH:2]=[N:1][N:5]2[CH:6]=[CH:7][C:8]([NH:10][CH2:11][C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[N:9][C:4]=12
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2nccc2n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ccn2ncc(I)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 93.3 %

Procedure:
The (S)-tert-butyl 2-((pyrazolo[1,5-a]pyrimidin-5-ylamino)methyl)pyrrolidine-1-carboxylate (790 mg, 2.490 mmol) was dissolved in 10 mL of DMF, was added NIS (617 mg, 2.740 mmol). This mixture is stirred for 4 hr at rt, and then quenched with 10 mL of water. It was then diluted with 50 mL EtOAc and the organic layer was separated, washed twice with brine, and dried over MgSO4. It was concentrated and purified on the silica gel eluting with 20-100% EtOAc/hex to obtain 1.03 g (93%) an off-white solid.
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:13][C@H:12]1[C@@H:30]([NH:32][C:33]1[N:38]=[C:37]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([C:48]4[CH:53]=[CH:52][N:51]=[C:50]([NH2:54])[N:49]=4)=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH:36]=[CH:35][N:34]=1)[CH3:31])=O)C1C=CC=CC=1.C=O.[BH3-]C#N.[Na+]>>[CH3:9][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:29])[NH:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH2:13][CH:12]1[CH:30]([NH:32][C:33]1[N:38]=[C:37]([N:39]2[C:43]3[CH:44]=[CH:45][C:46]([C:48]4[CH:53]=[CH:52][N:51]=[C:50]([NH2:54])[N:49]=4)=[CH:47][C:42]=3[N:41]=[CH:40]2)[CH:36]=[CH:35][N:34]=1)[CH3:31]
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccnc(N)n4)ccc32)n1)[C@@H]1CN(C(=O)Nc2cccc3ccccc23)CCN1C(=O)OCc1ccccc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(Nc1nccc(-n2cnc3cc(-c4ccnc(N)n4)ccc32)n1)C1CN(C(=O)Nc2cccc3ccccc23)CCN1C

Procedure:
The title compound was prepared from (S,S)-2-[1-(1-(benzyloxycarbonyl)-4-(N-naphth-1-yl-carbamoyl)-piperazine-2-yl)-ethylamino]-4-[5-(2-amino-pyrimidin-4-yl)benzimidazol-1-yl]pyrimidine (5.5 mg), 37% aqueous formaldehyde (0.7 μL), and NaBH3CN (1 mg) according to the procedure described in EXAMPLE 14, Step G. 1H NMR (500 MHz, CDCl3): δ8.64 (s, 1H); 8.47 (d, J=1.5 Hz, 1H); 8.34-8.41 (m, 2H); 8.20 (d, J=8.5 Hz, 1H); 8.09 (dd, J=1.6, 8.5 Hz, 1H); 7.76-7.83 (m, 2H); 7.61 (t, J=7.1 Hz, 2H); 7.37-7.55 (m, 3H); 7.12 (d, J=5.5 Hz, 1H); 6.78 (d, J=5,5 Hz, 1H); 5.77 (br s, 1H); 5.13 (s, 2H); 4.50-4.60 (m, 1H); 4.09 (br d, J=12 Hz, 1H); 3.88 (br d, J=12 Hz, 1H); 3.20 (br t, J=11 Hz, 1H); 3.09 (dd, J=10, 13 Hz, 1H); 2.92 (br d, J=12 Hz, 1H) 2.40-2.60 (m, 5H); 1.36 (d, J=6.5 Hz, 3H). Mass spectrum (ESI) 431.2 (M-(N-naphthyl carbamoyl)+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[C:1]([O:5][C:6](=[O:29])[N:7]([C@@H:9]1[C@@H:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][NH:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CN(C(=O)OC(C)(C)C)[C@H]1CNC[C@@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
To a stirred solution of [(3RS,4SR)-1-benzyl-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (928 mg, 2.13 mmol) in CH3CN (10 ml) at RT, was added 2,2,2-trichloroethyl chloroformate (0.45 ml, 2.13 mmol). The reaction mixture was stirred at RT for 3 hours, concentrated under vacuo. The residue was dissolved in AcOH (5 ml) and zinc dust (400 mg) was added portion wise over 1 hours. The solvent was evaporated, the residue diluted in EtOAc and the organic phase was washed with an aqueous solution of NaHCO3. The organic phase was dried over Na2SO4 and concentrated under vacuo to afford 415 mg (98%) of the tile compound as a light yellow oil. ES-MS m/e: 345.2 (M+H+).
Reaction SMILES: [CH:1]([CH:3]=[O:4])=[O:2]>O>[CH2:3]([OH:4])[C@H:1]1[O:2][C:1](=[O:2])[C@H:3]([OH:4])[C@@H:1]([OH:2])[C@@H:3]1[OH:4]
Reactant: O=CC=O
Solvent: O
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Example 3 is repeated, except that the glyoxal solution is added dropwise to the mixture in the course of 4 hours and at the same time the water used as solvent and the water formed in the course of the reaction are distilled off azeotropically. 2.5 hours after the addition of glyoxal solution the total amount of water which has been distilled off is 167 g. 101 g are obtained of a solid product in which gluconolactone is not detectable.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH:24]=[O:25])[CH:21]=[N:20]2)=[CH:15][CH:14]=1.C[Si](C)(C)[C:34]([F:37])([F:36])[F:35].[F-].[Cs+].Cl>ClCCl>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:31])[C:5]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]=[C:22]([CH:24]([OH:25])[C:34]([F:37])([F:36])[F:35])[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(-n3cc(C=O)cn3)cc2)c2cccc(F)c2c1=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: CCOC(=O)c1cn(Cc2ccc(-n3cc(C(O)C(F)(F)F)cn3)cc2)c2cccc(F)c2c1=O
Reaction time: 3 h

Procedure:
To a solution of ethyl 5-fluoro-1-[4-[4-formyl-1H-pyrazol-1-yl)benzyl]-4-oxo-1,4-dihydroquinoline-3-carboxylate (0.100 g, 0.238 mmol) in 2 mL of dichloromethane was added trimethyl(trifluoromethyl)silane (0.045 g, 0.25 mmol) and cesium fluoride (3.6 mg, 0.024 mmol). After 3 hours, 4 N HCl (0.36 mL, 1.4 mmol) was added. After 1 hour, the reaction mixture was diluted with an additional 20 mL dichloromethane and washed with water and brine. The organic extracts were dried, filtered and concentrated in vacuo to provide the title compound (crude) which gave a mass ion (ES+) of 489.9 for M+H+. This compound could be further hydrolyzed to the corresponding carboxylic acid, as described in Example 1.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([O:9][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc(Cl)nn2)cc1
Yield: 86.1 %

Procedure:
3,6-Dichloropyridazine (3.00 g, 20.1 mmol), 4-hydroxybenzaldehyde (2.46 g, 20.1 mmol), potassium carbonate (2.78 g, 20.1 mmol) and 60 mL of N,N-dimethylformamide were mixed and the mixture was refluxed for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The extracted solution was washed with brine, then dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel chromatography (eluate n-hexane:ethyl acetate=1:1 v/v) to obtain 4.06 g (86%) of the title compound as colorless crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:24])C(=O)C1>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:16])[NH:7][CH2:8][C:9]1[C:14]([Br:24])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)NCc1ccnc(N)c1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCc1cc(N)ncc1Br
Temperature: -18 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
A solution of crude (2-amino-pyridin-4-ylmethyl)-carbamic acid tertbutyl ester (17.55 g) in DMF (50 mL) was cooled to −18° C. (ice/MeOH bath), treated with NBS (12.6 g, 70.7 mmol), and stirred at −18° C. for 1 h. The reaction mixture was diluted in AcOEt (800 mL) and washed with water (2×100 mL) and brine (50 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The residue was purified by Combi-Flash Companion™ (Isco Inc.) column chromatography (SiO2; gradient elution, hexane/DCM/TBME 100:10:1→TBME 100%) to yield the title compound (13.95 g, 46.2 mmol, 50% for 2 steps) as a pale yellow solid. MS: 303 [M+1]+ HPLC: AtRet=1.10; TLC: RF 0.18 (hexane/DCM/TBME 1:1:2).