Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:33])[CH:23]([NH:25]C(=O)OC(C)(C)C)[CH3:24])[CH2:17][CH2:16]1)=[N:11][C:10]([C:34]1[CH:39]=[C:38]([Cl:40])[C:37]([OH:41])=[C:36]([Cl:42])[CH:35]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[ClH:43]>>[ClH:40].[ClH:43].[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21][C:22](=[O:33])[CH:23]([NH2:25])[CH3:24])[CH2:17][CH2:16]1)=[N:11][C:10]([C:34]1[CH:35]=[C:36]([Cl:42])[C:37]([OH:41])=[C:38]([Cl:40])[CH:39]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(C)NC(=O)OC(C)(C)C)CC1
Agent: Cl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](NC(=O)C(C)N)CC1

Procedure:
Following general procedure IV-1, crude tert-butyl 1-{trans-4-[3-acetyl-6-(3,5-dichloro-4-hydroxyphenyl)-1,5-naphthyridin-4-ylamino]cyclohexylamino}-1-oxopropan-2-ylcarbamate (0.13 mmol) was reacted with HCl (5 mL, 2 M in ether) to afford the desired product (32 mg, 41% over two steps) as a brown solid: 1H NMR (500 MHz, CD3OD) δ 9.14 (s, 1H), 8.45 (d, J=8.5 Hz, 1H), 8.34 (d, J=8.5 Hz, 1H), 8.10 (s, 2H), 5.65-5.55 (m, 1H), 3.90 (q, J=6.9 Hz, 1H), 3.85-3.76 (m, 1H), 2.76 (s, 3H), 2.50-2.39 (m, 2H), 2.21-2.10 (m, 2H), 1.78-1.69 (m, 2H), 1.65-1.52 (m, 2H), 1.51 (d, J=6.9 Hz, 3H); ESI MS m/z 516 [M+H]+; HPLC>99% (AUC), tR=9.65 min.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25]CCCCC)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]>>[CH3:12][O:13][C:14](=[O:31])[C:15]1[C:16](=[C:21]([NH:25][CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:22]=[CH:23][CH:24]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCCCNc1cccc(C(=O)OC)c1C(=O)OC
Reactant: O=CCOCc1ccccc1
Product: COC(=O)c1cccc(NCCOCc2ccccc2)c1C(=O)OC
Yield: 78 %

Procedure:
Benzyloxyacetaldehyde (5.27 ml, 37.5 mmol) was treated in the same manner as described above for the synthesis of 3-pentylamino-phthalic acid dimethyl ester. The residue (oil) was purified by chromatography (6:3:1 methylene chloride/hexane/ethyl acetate) to give 7.98 g (78%) of yellow oil: 1H NMR (DMSO-d6) d 7.38-7.26 (m, 5H), 6.89-6.77 (m, 3H), 4.57 (s, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.69 (t, J=5.5 Hz, 2H), 3.38 (q, J=5.4 Hz, 2H).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH3:2]>CCO.[Pd]>[CH2:1]([C@H:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH3:2]
Reactant: CC[C@H]1CN(Cc2ccccc2)CCN1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC[C@H]1CNCCN1C(=O)OC(C)(C)C

Procedure:
A solution of the product from example 69 part c) (6.09 g) and 10% Pd/C (1.14 g) in EtOH (85 mL) was hydrogenated at 3.8 bar for 16 h. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo to give the sub-title compound as an oil (3.65 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][CH3:26])=[N:8][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=O)C.[Na].C(O)(=O)C.O>C(O)C>[CH3:26][N:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:7]2[N:8]=[C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:10]=[CH:11][C:6]=2[C:4]1=[O:3]
Reactant: CCOC(=O)c1cnc(-c2ccccc2)nc1Nc1ccccc1NC
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CN1C(=O)c2cnc(-c3ccccc3)nc2Nc2ccccc21
Reaction time: 0.5 h

Procedure:
34.8 g (0.1 mol) of 5-ethoxycarbonyl-4-(2-methylaminoanilino)-2-phenylpyrimidine are added to a freshly prepared, hot solution of 6.8 g (0.296 mol) of sodium in 99 ml of absolute ethanol, while stirring. The orange-colored suspension which has been formed thereby is heated for a further 30 minutes under reflux and is allowed to cool; 19.7 ml of glacial acetic acid and 19.4 ml of water are added and the mixture is stirred for a further 30 minutes. The yellow precipitate is filtered off, washed with water and dried in vacuo; yield: 26 g, with m.p. 227° C. (from ethanol).
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](OC(=O)C)(=[O:18])[CH3:17]>S(=O)(=O)(O)O.[OH-].[Na+]>[C:1]1([C:7]2[C:15]([C:16](=[O:18])[CH3:17])=[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]3[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2cc3ccccn3n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)c1c(-c2ccccc2)nn2ccccc12
Yield: 47.7 %

Procedure:
2-Phenylpyrazolo[1,5-a]pyridine (2.00 g) was added to a stirred solution of acetic anhydride (4.20 g) and two drops of sulfuric acid at room temperature. After being stirred under reflux for 14 hours, the reaction mixture was poured onto 80 ml of 4 N NaOH aqueous solution and extracted with chloroform (30 ml×2). The extracts were combined and washed with water (30 ml), saturated sodium chloride aqueous solution (30 ml), then dried over magnesium sulfate and evaporated in vacuo. The residual crystals were recrystallized from diisopropyl ether to give 2-phenyl-3-acetylpyrazolo-[1,5-a]pyridine (1.16 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]([F:19])([F:18])[F:17].[F:20][C:21]([F:36])([F:35])[C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[N:30]=1)[C:25](O)=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[N:14]([CH2:15][C:16]([F:19])([F:17])[F:18])[C:25](=[O:26])[C:24]1[CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[N:30]=[C:22]([C:21]([F:36])([F:20])[F:35])[CH:23]=1
Reactant: Fc1ccccc1-c1ccncc1NCC(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Product: O=C(c1cc(C(F)(F)F)nc(C(F)(F)F)c1)N(CC(F)(F)F)c1cnccc1-c1ccccc1F

Procedure:
The title compound was prepared in analogy to example 90, from [4-(2-fluoro-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 2,6-bis(trifluoromethyl)isonicotinic acid (Key Organics Ltd.) after a reaction time of 25 hours. The compound was purified by silica gel chromatography on a 10 g column using a MPLC system eluting with a gradient of n-heptane:EtOAc (100:0 to 50:50). Light brown solid (38%). MS (ESI): m/z=512.08 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH2:21]([Cl:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>C(Cl)(Cl)Cl.C(O)C.C(#N)C>[ClH:29].[CH2:21]([NH:1][CH:2]1[C:10]2[C:5](=[C:6]([CH3:13])[CH:7]=[C:8]([CH3:12])[C:9]=2[OH:11])[CH2:4][CH2:3]1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCl
Reactant: Cc1cc(C)c2c(c1O)C(N)CC2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC1CCc2c(C)cc(C)c(O)c21
Reaction time: 4 h
Yield: 15.1 %

Procedure:
To a solution containing 1.77 g of 1-amino-2,3-dihydro-4,6-dimethyl-7-hydroxy-1H-indene and 2 ml of triethylamine in 100 ml of chloroform was added dropwise 2.23 g of octyl chloride at room temperature. Then the reaction micture was stirred at the same temperature for 4 hours. The reaction mixture was washed with a diluted hydrochloric acid, water, an aqueous solution saturated with sodium bicarbonate, water and an aqueous soluction saturated with sodium chloride in this order, then dried with anhydrous sodium sulfate. The solvent was removed by evaporation and the residue thus obtained was dissolved in ethanol, tna an ethanol saturated with hydrogen chloride gas was added thereto form a hydrochlodide. Recrysttallized form acetonitrile to obtain 0.49 g of 2,3-dihydro-1-octylamino-4,6-dimethyl-7-hydroxy-1H-indene hydrochloride. Colorless needle-like crystals. Melting point: 120°-121° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:16][CH2:15]2)=[O:13])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[CH3:8].[H-].[Na+].Br[CH2:31][CH:32]1[CH2:34][CH2:33]1>CN(C)C=O>[CH:32]1([CH2:31][N:11]([C:4]2[C:5]([O:9][CH3:10])=[N:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[C:12]([N:14]2[CH2:15][CH2:16][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])[CH2:18][CH2:19]2)=[O:13])[CH2:34][CH2:33]1
Reactant: COc1ccccc1N1CCN(C(=O)Nc2cc(C)c(C)nc2OC)CC1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccccc1N1CCN(C(=O)N(CC2CC2)c2cc(C)c(C)nc2OC)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
1-[(5,6-Dimethyl-2-methoxypyridin-3-yl)aminocarbonyl]-4-(2-methoxyphenyl)piperazine(100 mg, 0.26 mmol) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(6.2 mg, 0.26 mmol) was added, followed by stirring at room temperature for 15 min, and successively bromomethylcyclopropane(21.8 mg, 0.26 mmol) was added. The resulting mixture was stirred at room temperature for 16 hrs, concentrated under the reduced pressure and purified by column chromatography(ethylacetate:hexane=1:2) to obtain the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[C:11]1[CH:12]=[C:13]2[CH:19]=[CH:18][N:17]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:14]2=[CH:15][N:16]=1)[CH3:2].C1C(=O)N([Br:36])C(=O)C1>C(Cl)Cl>[Br:36][C:19]1[C:13]2[C:14](=[CH:15][N:16]=[C:11]([C:4]3[C:5]([CH2:9][CH3:10])=[CH:6][CH:7]=[CH:8][C:3]=3[CH2:1][CH3:2])[CH:12]=2)[N:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=2)[CH:18]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCc1cccc(CC)c1-c1cc2ccn(-c3ccc(C(C)C)cc3)c2cn1
Solvent: ClCCl
Product: CCc1cccc(CC)c1-c1cc2c(Br)cn(-c3ccc(C(C)C)cc3)c2cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine (2.36 g, 6.4 mmol) in DCM (50 mL), NBS (1.25 g, 7.0 mmol) is added and the mixture is stirred at room temperature for 1 h. The mixture is concentrated under reduced pressure, and the product is dissolved in a 5:1 EtOAc/Hexane mixture and filtered over a small pad of silica gel. The solvent is removed under reduced pressure to afford 3-bromo-5-(2,6-diethyl-phenyl)-1-(4-isopropyl-phenyl)-1H-pyrrolo[2,3-c]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]4[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:19][CH:18]=3)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]2[CH3:34])[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH:36]1[CH2:39][CH2:38][CH2:37]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C)C=O.O>[CH:36]1([O:8][C:7]2[CH:6]=[CH:5][C:4]([N:9]3[C:14](=[O:15])[C:13]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=5)=[CH:19][CH:18]=4)=[C:12]([CH2:31][CH2:32][CH3:33])[N:11]=[C:10]3[CH3:34])=[CH:3][C:2]=2[F:1])[CH2:39][CH2:38][CH2:37]1
Reactant: CCCc1nc(C)n(-c2ccc(O)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrC1CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCCc1nc(C)n(-c2ccc(OC3CCC3)c(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 80 °C
Reaction time: 15 h
Yield: 85.8 %

Procedure:
To a solution of 4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.0 g) and bromocyclobutane (0.90 g) in N,N-dimethylformamide (10 mL) was added cesium carbonate (1.44 g), and the mixture was stirred at 80° C. for 15 hr. After allowing to cool, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.96 g, 86%).
Reaction SMILES: C(OC(=O)[N:7]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][C:27]([C:30](=[O:34])[NH:31][CH2:32]C)=[CH:26][N:25]=2)=[CH:19][CH:18]=1)[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:32][NH:31][C:30](=[O:34])[C:27]1[CH:28]=[CH:29][C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH2:16][NH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:18][CH:19]=2)=[N:25][CH:26]=1
Reactant: CCNC(=O)c1ccc(Oc2ccc(CN(CCc3ccccc3)C(=O)OC(C)(C)C)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)c1ccc(Oc2ccc(CNCCc3ccccc3)cc2)nc1
Reaction time: 24 h
Yield: 95 %

Procedure:
Combine [4-(5-Ethylcarbamoyl-pyridin-2-yloxy)-benzyl]-phenethyl-carbamic acid tert-butyl ester (55.4 mg, 0.12 mmol), CH2Cl2 (4 mL), and TFA 99% (0.8 mL) in a 7 mL reaction vial. After reaction shakes on shaker at room temperature for 24 hours, concentrate under reduced pressure. Add the reaction mixture to a 2 g SCX column, wash with MeOH, and elute with 1N NH3 MeOH. Concentrate sample to afford 41.2 mg (95% yield) of the title compound: 1H NMR (500 MHz, CDCl3); 1.5 (1H, br m), 2.7-3.0 (7H, m), 3.7 (2H, s), 6.2 (1H, br s), 6.9 (1H, d), 7.0-7.4 (9H, m), 8.0 (1H, d), 8.4 (1H, s); MS m/z 363 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[N:25][C:24]=2[CH:34]=1.[C:35](O)(=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O>[F:8][C:9]1[CH:14]=[C:13]([N:15]2[CH:19]=[N:18][N:17]=[N:16]2)[CH:12]=[CH:11][C:10]=1[C:20]1[CH:21]=[CH:22][C:23]2[O:27][C:26]([CH:28]3[CH2:29][CH2:30][N:31]([C:35](=[O:40])[CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:32][CH2:33]3)=[N:25][C:24]=2[CH:34]=1
Reactant: Fc1cc(-n2cnnn2)ccc1-c1ccc2oc(C3CCNCC3)nc2c1
Reactant: CC(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)CC(=O)N1CCC(c2nc3cc(-c4ccc(-n5cnnn5)cc4F)ccc3o2)CC1
Yield: 76.9 %

Procedure:
5-[2-fluoro-4-(1H-tetrazol-1-yl)-phenyl]-2-(piperidin-4-yl)benzo[d]oxazole 2,2,2-trifluoroacetate (140 mg, 0.29 mmol) was dissolved in DMF (4 ml) and added isovaleric acid (38 mg, 0.37 mmol), EDC.HCl (147 mg, 0.73 mmol), HOBt (47 mg, 0.35 mmol) and TEA (88 mg, 0.88 mmol). After completion of the reaction, work up (EtOAc/H2O) followed by purification of crude on combiflash using a gradient mixture of EtOAc and Petether (7:3) as eluent afforded the titled compound (100 mg) as a pale-yellow solid. M.P.: 168-172° C. MS (m/z): 449.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([NH2:16])=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.B(F)(F)F.CCOCC.B.C1COCC1.Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:14][NH2:16])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: B
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: CO
Solvent: C1CCOC1
Product: NCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Reaction time: 0.08 h

Procedure:
To a solution of 0.93 g (2.3 mmol) (+) or (−)-2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-acetamide in tetrahydrofuran were added 0.29 ml (2.3 mmol) boron trifluoride ethyl etherate. The mixture was stirred for 5 min. and then 4.61 ml (4.61 mmol) borane THF complex (1M solution in tetrahydrofuran) were added dropwise. The mixture was stirred at 50° C. for 55 h. The solution was poured onto 12 ml tetrahydrofuran and 5 ml methanol (gas evolution) and stirred for 1 h. Then 50 ml 1M aqueous hydrochloric acid were added and the layers were separated. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were washed with 10 ml 1M aqueous hydrochloric acid. The combined aqueous layers were adjusted to pH 10 using 32% aqueous sodium hydroxide and 1M aqueous sodium hydroxide solution. The turbid mixture was extracted three times with dichloromethane. The organic layers were washed with brine, dried over magnesium sulfate and evaporated to dryness. White foam (22%). MS (Turbo Spray): m/z=390.3 [M+H].
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1.C[O:14][C:15](=[O:28])[CH2:16][CH:17]1[CH2:19][CH:18]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([F:27])[CH:21]=1>>[F:27][C:22]1[CH:21]=[C:20]([CH:18]2[CH2:19][CH:17]2[CH2:16][C:15]([OH:28])=[O:14])[CH:25]=[CH:24][C:23]=1[O:26][CH2:2][C:3]1[C:4]([S:9][CH2:10][CH2:11][CH3:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCCSc1ncccc1CCl
Reactant: COC(=O)CC1CC1c1ccc(O)c(F)c1
Product: CCCSc1ncccc1COc1ccc(C2CC2CC(=O)O)cc1F
Yield: 95.4 %

Procedure:
3-Chloromethyl-2-propylsulfanyl-pyridine (0.024 g, 0.12 mmol) obtained in Step C of Preparation Example 14 and [2-(3-fluoro-4-hydroxy-phenyl)-cyclopropyl]-acetic acid methyl ester (0.027 g, 0.12 mmol) obtained in Step F of Preparation Example 53 were used to react sequentially in the same manner as in Steps A and B of Example 1 to obtain the title compound (0.043 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([OH:14])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([O:17][C:18]([C:20]1([CH2:34]I)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH2:21]1)=[O:19])[CH3:16]>>[CH2:15]([O:17][C:18]([C:20]1([CH2:34][O:14][C:11]2[CH:12]=[N:13][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:9][CH:10]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:33])[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: Oc1cnc(-c2ccc(Cl)cc2)nc1
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccc(F)cc2)C1
Product: CCOC(=O)C1(COc2cnc(-c3ccc(Cl)cc3)nc2)CCN(C(=O)c2ccc(F)cc2)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-chloro-phenyl)-pyrimidin-5-ol (Preparation 27) and 1-(4-fluoro-benzoyl)-3-iodomethyl-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 12) to afford the racemate as a pale yellow solid (89 mg, 37%)
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=O)=[CH:6][N:5]=[C:4]2[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:14]=[C:15]([CH3:16])[C:3]=12.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH2:23]([NH:30][C:8]([C:7]1[C:2]([OH:1])=[C:3]2[C:15]([CH3:16])=[N:14][N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[C:4]2=[N:5][CH:6]=1)=[O:10])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CCOC(=O)c1cnc2c(c(C)nn2-c2ccccn2)c1O
Solvent: CCOC(C)=O
Product: Cc1nn(-c2ccccn2)c2ncc(C(=O)NCc3ccccc3)c(O)c12
Temperature: 180 °C
Reaction time: 16 h
Yield: 62.3 %

Procedure:
A mixture of ethyl 4-hydroxy-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (2.0 g, 6.7 mmol) and benzylamine (8.0 mL, 73 mmol) was stirred at 180° C. for 16 hours under an argon atmosphere. The mixture was cooled to room temperature, ethyl acetate was added thereto. The resulting crude crystals were collected by filtration, and washed with ethyl acetate. The crude crystals thus obtained were purified by silica gel column chromatography (chloroform:methanol=20:1 to 5:1), and recrystallized from ethanol to give the title compound (1.5 g, 60% yield).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:31][CH3:32])[C:23]4=[O:33])=[CH:18][CH:17]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1.CO.[OH:36]OS([O-])=O.[K+]>O>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH2:10][C:11]2[N:12]=[N:13][N:14]([C:16]3[CH:17]=[CH:18][C:19]([N:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH2:29][CH2:30][S:31]([CH3:32])=[O:36])[C:23]4=[O:33])=[CH:20][CH:21]=3)[CH:15]=2)=[O:8])=[CH:4][CH:3]=1
Reactant: CSCCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CS(=O)CCOc1cccn(-c2ccc(-n3cc(CNC(=O)c4ccc(Cl)s4)nn3)cc2)c1=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of Example 48 in a 2:1 mixture of methanol and water was added 1.0 equivalent of oxone. The mixture was stirred at room temperature for 10 min and directly subjected to reverse phase HPLC to isolate the title compound as a white powder after lyophilization. MS found for C22H20ClN5O4S2 (M+H)+ 518.1, 520.1 (Cl pattern).
Reaction SMILES: C[C:2]([C:5]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])(C)[C:6]([O-:8])=[O:7])(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:20][C:11]1[C:12]2[CH2:16][O:15][C:14](=[O:17])[C:13]=2[CH:18]=[CH:19][C:10]=1[CH:5]([CH3:2])[C:6]([OH:8])=[O:7]
Reactant: Cc1c(C(C)(C(=O)[O-])C(C)(C)C)ccc2c1COC2=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(C)C(=O)O)ccc2c1COC2=O
Reaction time: 1 h

Procedure:
To a solution of 1,1-dimethylethyl-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoate (400 mg, 1.4 mmol) in 10 mL of anhydrous DCM was added TFA (2.5 mL) dropwise at r.t. Then the mixture was stirred for 1 hour. The solvent was removed under vacuum to give the crude 2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)propanoic acid, which was used for next step without purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][NH:21][S@@](C(C)(C)C)=O.[ClH:28]>CO>[ClH:28].[NH2:21][CH2:20][C:3]1[C:2]([CH3:1])=[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)[CH:6]=[N:5][CH:4]=1
Reactant: Cc1c(CN[S@](=O)C(C)(C)C)cncc1-c1ccc2c(c1)CCC(=O)N2C
Agent: Cl
Solvent: CO
Product: Cc1c(CN)cncc1-c1ccc2c(c1)CCC(=O)N2C

Procedure:
In analogy to the procedure described for the preparation of example 42, reaction of (R)-2-methyl-propane-2-sulfinic acid [4-methyl-5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 221) with hydrogen chloride (in dixoane) in methanol gave the title compound as a yellow solid. MS: 282.5 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)[OH:9])=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][O:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: OC(c1ccc(Cl)cc1)C1CCCCO1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1)C1CCCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (4-chloro-phenyl)-(tetrahydro-pyran-2-yl)-methanol (70.00 mg, 0.30 mmol) in DCM (10 mL) was added NaHCO3 (259.4 mg, 3.08 mmol) and Dess-Martin periodinane (196.4 mg, 0.46 mmol) at 0° C. The mixture was stirred at 0° C. for 2 hrs. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (eluting with 5% AcOEt in Hexane). 1H NMR (400 MHz, MeOD) δ 1.52-2.02 (m, 6H), 3.65-3.77 (m, 1H), 4.04-4.17 (m, 1H), 4.82-4.88 (m, 1H), 7.54 (d, J=8.50 Hz, 2H), 8.02 (d, J=8.50 Hz, 2H).