Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][CH:11]([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4].[CH2:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+]>O1CCCC1>[CH3:1][N:2]([CH3:15])[C:3]([N:5]1[CH2:9][CH:8]2[CH2:10][C:11]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:13]#[N:14])[CH2:12][CH:7]2[CH2:6]1)=[O:4]
Reactant: CN(C)C(=O)N1CC2CC(C#N)CC2C1
Reactant: ClCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CC2CC(C#N)(Cc3ccccc3)CC2C1
Yield: 45.3 %

Procedure:
5-Cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 12a (4.0 g, 19.3 mmol) was dissolved in 60 mL of tetrahydrofuran with stirring followed by addition of benzyl chloride (5.4 g, 42.5 mmol) and lithium hexamethyldisilazide (42.5 mL, 42.5 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 hours. The reaction was monitored by TLC until the disappearance of the starting materials and quenched with 50 mL of water. The mixture was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 5-benzyl-5-cyano-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid dimethylamide 14a (2.6 g, yield 46%) as a light yellow solid.
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:30])([F:31])[F:29])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:34][CH2:33]1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCc2ccccc21)c1ccncc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.1 %

Procedure:
Isonicotinoyl chloride hydrochloride (669 mg, 3.76 mmol, commercially available product) and triethylamine (773 μl, 5.58 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 1-[2-amino-4-(trifluoromethyl)phenyl]indoline (518 mg, 1.86 mmol), obtained as described in Referential Example 19-2. The resulting mixture was warmed to room temperature and stirred for 2.5 hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=1/1). Thus, N-[2-(1-indolinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0619) (643 mg, 90.1%) was yielded as a colorless solid.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[NH:30]1[C:38]2[CH:37]=[CH:36][N:35]=[CH:34][C:33]=2[N:32]=[CH:31]1.COCC(O)C>>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([N:30]3[C:38]4[CH:37]=[CH:36][N:35]=[CH:34][C:33]=4[N:32]=[CH:31]3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: c1cc2[nH]cnc2cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: COc1ccccc1-c1ccc2cnc(-n3cnc4cnccc43)nn12
Yield: 29.4 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (125.0 mg, 0.0004350 mol), N,N-Diisopropylethylamine (0.114 mL, 0.000652 mol) and 1H-Imidazo[4,5-c]pyridine (0.104 g, 0.000870 mol) were dissolved in 1-Methoxy-2-propanol (1.2 mL, 0.013 mol) and the reaction was irradiated at 300 watts, 180° C. for 40 minutes or until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 43.80 mg of 1-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-1H-imidazo[4,5-c]pyridine (mixture of regioisomers) as a lyophilized powder. (M+H)=343.7. 1H NMR (400 MHz, DMSO, d6) δ 9.35 (s, 1H), 9.15 (s, 1H), 8.47 (d, 1H, J=5.52 Hz), 8.09 (d, 1H, J=5.45 Hz), 7.81 (m, 2H), 7.57 (m, 1H), 7.32 (m, 3H), 7.23 (m, 1H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([O:3][CH2:4][CH3:5])#[CH:2].B.O1CCCC1.Cl[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([S:20][CH3:21])[N:14]=1.[OH-].[Na+]>O1CCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[CH2:1]([O:3]/[CH:4]=[CH:5]/[C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([S:20][CH3:21])[N:14]=1)[CH3:2]
Reactant: CSc1nc(C)cc(Cl)n1
Reactant: C#COCC
Agent: [Pd+2]
Agent: B
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCO/C=C/c1cc(C)nc(SC)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
15 g of ethyl ethynyl ether (40% hexane solution) was dissolved in 50 mL of tetrahydrofuran, and 29 mL of a borane-tetrahydrofuran complex (1M tetrahydrofuran solution) was added to the solution at 0° C. After stirring at room temperature for 4 hours and a half, 150 mL of a tetrahydrofuran solution containing 4.0 g of the 4-chloro-6-methyl-2-(methylthio)pyrimidine [42-1], 35 mL of a 3 N aqueous solution of sodium hydroxide, 0.46 g of triphenylphosphine and 0.34 g of palladium acetate were added thereto. The obtained reaction solution was stirred at room temperature for 16 hours, and then 200 mL of water was added to the reaction solution. The reaction solution was extracted with ethyl acetate, and the organic layer was washed with saturated brine. After drying the organic layer over anhydrous magnesium sulfate, the insolubles were filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography, and 4.9 g of 4-[(E)-2-ethoxyvinyl]-6-methyl-2-(methylthio)pyrimidine [42-2] was obtained as a brown oily product.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[N:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][CH2:29][C:30](OCC)=[O:31])=[CH:22][CH:21]=1.[Li+].CC([N-]C(C)C)C>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:5]([CH:6]=[C:29]([CH2:28][CH2:27][CH2:26][C:23]3[CH:24]=[CH:25][N:20]=[CH:21][CH:22]=3)[C:30](=[O:31])[N:10]2[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCCc1ccncc1
Reactant: Cc1ccc(C=O)c(Nc2cccc([N+](=O)[O-])c2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Product: Cc1ccc2cc(CCCc3ccncc3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c2n1

Procedure:
The procedure of Example 1 was repeated using 6-methyl-2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq., prepared in Synthetic Example 1), ethyl 5-(pyridin-4-yl)pentanoate (1.5 eq.) and LDA (1.5 eq.) to obtain 7-methyl-1-(3-nitrophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one, mp 165 to 166° C./AcOEt, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: C(N(CC)CC)C.C(Cl)Cl.[O:11]([CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:24](\[CH3:27])/[CH2:25][OH:26])[Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13]>CS(C)=O>[O:11]([CH2:19][CH2:20][CH2:21][CH2:22]/[CH:23]=[C:24](\[CH3:27])/[CH:25]=[O:26])[Si:12]([C:15]([CH3:17])([CH3:18])[CH3:16])([CH3:14])[CH3:13]
Reactant: C/C(=C\CCCCO[Si](C)(C)C(C)(C)C)CO
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C(C=O)=C\CCCCO[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 94.9 %

Procedure:
After the addition of triethylamine (36.5 ml) to a methylene chloride solution (53 ml) of Alcohol 5 (13.6 g) and cooling to 0° C., a dimethylsulfoxide solution (53 ml) of SO3-pyridine (25 g) is added thereto at 0° C. and the whole is stirred for 1.5 hours. After stirring, the resultant solution is quenched using a buffer solution (5 ml) and the organic compound is extracted three times with ethyl acetate, followed by the wash of the organic layer in a saturated saline solution and drying over anhydrous sodium sulfate. After anhydrous sodium sulfate is filtered and the solvent is distilled off under reduced pressure, the residue is separated and purified by column chromatography to produce Aldehyde 6 (12.8 g) of 94% in yield.
Reaction SMILES: [C:1]([C:5]1[CH:41]=[CH:40][C:8]([C:9]([NH:11][C:12]2[C:13]([NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[N:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:25]=4[CH:39]=3)=[O:20])=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1>C1COCC1>[N:26]1[C:25]2[CH:39]=[C:21]([C:19]([NH:18][C:13]3[C:12]([NH:11][C:9](=[O:10])[C:8]4[CH:7]=[CH:6][C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:41][CH:40]=4)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:20])[CH:22]=[CH:23][C:24]=2[NH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)n2cnc3ccc(C(=O)Nc4ccccc4NC(=O)c4ccc(C(C)(C)C)cc4)cc32)cc1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(C(=O)Nc2ccccc2NC(=O)c2ccc3[nH]cnc3c2)cc1
Reaction time: 24 h
Yield: 53.9 %

Procedure:
To a stirring solution of N2-(4-t-butylbenzoyl)-N1-(1-tosylbenzimidazol-6-ylcarbonyl)-1,2-benzenediamine (360 mg, 0.63 mmol) in THF (10 mL) was added HOBT (1.36 g, 10 mmol). After stirring for 24 h, the solvent was removed in vacuo. The residue was dissolved in dichloromethane and washed with satd aq NaHCO3. The organic phase was allowed to stand overnight, and the resulting precipitate was filtered and dried to give 140 mg (54%) of white solid.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:22][C:23]1([CH3:27])[O:26][CH:24]1C.CCO>C(Cl)Cl>[CH3:21][O:20][C:18](=[O:19])[C@H:13]([CH2:14][CH:15]([CH3:17])[CH3:16])[NH:12][C:10](=[O:11])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH:1][CH2:22][C:23]([OH:26])([CH3:27])[CH3:24]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC1OC1(C)C
Solvent: CCO
Solvent: ClCCl
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1ccccc1)NCC(C)(C)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Phe-Leu-OMe (0.69 mmol) in CH2Cl2 (1 mL) was added dimethyl propylene oxide (0.075 mL). The reaction mixture was stirred at room temperature overnight, however, no change was observed. Two additional mLs of the oxide were added and then the reaction mixture was transferred with EtOH (excess) to a closed tube reactor, heated to 100° C. for 5 hours, stirred at room temperature for 2 days, and concentrated to yield 0.24 g of N-(2-hydroxy-2-methylpropyl)-L-phenylalanyl-L-leucine methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[C:20]([NH:28][C:29]1[CH:38]=[C:37](Br)[CH:36]=[CH:35][C:30]=1[C:31]([O:33]C)=[O:32])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C(=O)C>[C:20]([NH:28][C:29]1[CH:38]=[C:37]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=2)[CH:36]=[CH:35][C:30]=1[C:31]([OH:33])=[O:32])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)cc1NC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)c1ccc(-c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)cc1
Temperature: 90 °C
Reaction time: 21 h
Yield: 11.9 %

Procedure:
56 mg of (4-(tert-butyl)phenyl)boronic acid, 55 mg of sodium carbonate and 30 mg of polymer supported bis(acetate)triphenylphosphine palladium(11) were added to 2.5 mL of N,N-dimethylacetamide solution containing 70 mg of methyl 2-(benzamido)-4-bromobenzoate, and stirred at 90° C. for 21 hours. After the reaction mixture was cooled to room temperature, insoluble were removed by filtration and ethyl acetate and 1.0 mol/L hydrochloric acid were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and she solvent was evaporated under reduced pressure. 1.0 mL of 2.0 mol/L aqueous sodium hydroxide and 5.0 mL of ethanol were added to the obtained residue and stirred at room temperature for 1 hour and 30 minutes. 0.5 mol/L hydrochloric acid and ethyl acetate were added to the reaction mixture. The organic layer was separated and the solvent was evaporated under reduced pressure to obtain 9.3 mg of 2-(benzamido)-4-(4-(tert-butyl)phenyl)benzoic acid as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([C:26]([NH:28][CH2:29][CH:30]=[CH2:31])=O)[CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[CH:11]([CH2:26][NH:28][CH2:29][CH:30]=[CH2:31])[CH2:10]1
Reactant: C=CCNC(=O)C1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCNCC1CN(c2c(Cl)cccc2Cl)CCN1Cc1ccc(OC)c(OC)c1

Procedure:
In a manner similar to Preparation 2, react 4-(2,6-dichlorophenyl)-1-[(3,4-dimethoxyphenyl)methyl]-N-(2-propenyl)-2-piperazinecarboxamide with lithium aluminium hydride to obtain the title compound.
Reaction SMILES: C([O:8][CH2:9][C:10]1[O:11][C:12]2[C:21]3[CH:20]([CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][C:13]=2[N:14]=1)C1C=CC=CC=1>CO.[C].[Pd]>[OH:8][CH2:9][C:10]1[O:11][C:12]2[C:21]3[CH:20]([CH2:22][CH2:23][NH:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:18][C:17]=3[CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: CC(=O)NCCC1CCc2ccc3nc(COCc4ccccc4)oc3c21
Agent: [Pd]
Solvent: CO
Product: CC(=O)NCCC1CCc2ccc3nc(CO)oc3c21
Temperature: 50 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
To a solution of N-(2-{2-[(benzyloxy)methyl]-7,8-dihydro-6H-indeno[5,4-d][1,3]oxazol-8-yl}ethyl)acetamide (50.0 mg, 0.131 mmol) in methanol (1 mL) was added a 10% palladium-carbon powder (100 mg), and the mixture was stirred at 50° C. for 24 hr under a hydrogen atmosphere. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→5/95) and recrystallized (ethyl acetate/hexane) to give the title compound (19.0 mg, yield 53%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH:18]=O)[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])[CH:9]=1)=[O:4].NO.[N:22]1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CO.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([C:18]#[N:22])[N:8]([CH2:10][O:11][CH2:12][CH2:13][Si:14]([CH3:15])([CH3:16])[CH3:17])[CH:9]=1)=[O:4]
Reactant: c1ccncc1
Reactant: COC(=O)c1cn(COCC[Si](C)(C)C)c(C=O)n1
Agent: NO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1cn(COCC[Si](C)(C)C)c(C#N)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a solution of 2-formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid methyl ester (0.11 g, 0.38 mmol) (as prepared in the previous step) in methanol (2 mL) was added a 50% aqueous hydroxylamine solution (30 μL) and the reaction stirred for 3 h at RT and then concentrated. The residue was dissolved in DCM (2 mL), pyridine (0.13 mL), and trifluoroacetic anhydride (0.17 mL, 1.1 mmol) was added and the reaction stirred for 10 h at RT. The reaction was diluted with EtOAc (10 mL) and washed with satd. NaHCO3 (2×10 mL) and the organic layer dried over Na2SO4 and then concentrated. The title compound was eluted from a 10-g SPE cartridge (silica) with 30% EtOAc/hexane to give 0.085 g (76%) of a colorless oil. 1H-NMR (400 MHz, CDCl3): δ 7.99 (s, 1H), 5.50 (s, 2H), 3.92 (s, 3H), 3.58 (m, 2H), 0.94 (m, 214), 0.00 (s, 9H).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[C:9](Cl)[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:16][NH2:17]>>[CH2:1]([C:5]1[CH:10]=[C:9]([NH:16][NH2:17])[N:8]2[N:12]=[CH:13][CH:14]=[C:7]2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc(Cl)n2nccc2n1
Reactant: NN
Solvent: O
Product: CCCCc1cc(NN)n2nccc2n1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Hydrazine monohydrate (50 ml) was slowly added dropwise to 21.0 g of 5-n-butyl-7-chloropyrazolo[1,5-a]pyrimidine prepared in step (2) of Reference Example 1 at room temperature and stirred at room temperature for 10 hours. After completion of the reaction, the crystals precipitated were collected, washed with water and recrystallized from chloroform-n-hexane to provide 12.6 g of the object compound as colorless crystals (melting point: 126°-129° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]=[C:13]([NH:19][C@@H:20]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH3:21])[N:14]=[C:15]([OH:18])[C:16]=3[N:17]=2)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.[N:39]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1.CCN(C(C)C)C(C)C>C1COCC1>[N:39]1([O:18][C:15]2[C:16]3[N:17]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH:9]=[CH:10][C:11]=3[N:12]=[C:13]([NH:19][C@@H:20]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=3)[CH3:21])[N:14]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[N:40]1
Reactant: C[C@@H](Nc1nc(O)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@@H](Nc1nc(On2nnc3ccccc32)c2nc(-c3ccc(F)cc3)ccc2n1)c1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-4-(1-(6-(4-fluorophenyl)-4-hydroxypyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide (200 mg), BOP (479 mg) and DIEA (314 μl) in THF (10 ml) was stirred at room temperature overnight. The reaction mixture was concentrated and purified by silicon gel column chromatography (eluting with EtOAc/CH2Cl2) to provide (R)-4-(1-(4-(1H-benzo[d][1,2,3]triazol-1-yloxy)-6-(4-fluorophenyl)pyrido[3,2-d]pyrimidin-2-ylamino)ethyl)benzenesulfonamide as a yellow solid.
Reaction SMILES: [NH2:1][CH:2]([C:4]([OH:6])=[O:5])[CH3:3].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:19](Cl)(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[C:19]([NH:1][CH:2]([CH3:3])[C:4]([OH:6])=[O:5])(=[O:25])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(N)C(=O)O
Reactant: CCCCCC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(=O)NC(C)C(=O)O

Procedure:
The preparation is carried out analogously to the procedure of Example 4A using 16.5 g (0.185 mol) of D,L-alanine, 41.23 g (0.407 mol) of triethylamine, 44.27 g (0.407 mol) of trimethylsilyl chloride and 24.93 g (0.185 mol) of hexanoyl chloride. The product crystallizes from toluene/n-hexane.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([F:13])[CH:21]=3)[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2ccc(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4-difluorobenzonitrile (255 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 188 mg, yield: 59%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[C:4]([F:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:16]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:16]/[C:15]2[CH:18]=[CH:19][C:20]([Cl:21])=[C:13]([Cl:12])[CH:14]=2)/[C:9]#[N:10])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: N#CCc1ccc(Cl)cc1F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#C/C(=C\c1ccc(Cl)c(Cl)c1)c1ccc(Cl)cc1F
Yield: 76.6 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-fluorophenyl acetonitrile (4.5 g, 26 mmol) was reacted with 3,4-dichlorobenzaldehyde (Aldrich) (5.5 g, 32 mmol), methanolic solution (25 wt %) of sodium methoxide (6.6 mL, 29 mmol) in methanol (150 mL) at 50° C. for 3 h to give (Z)-2-(4-chloro-2-fluoro-phenyl)-3-(3,4-dichloro-phenyl)-acrylonitrile as a white powder (6.5 g, 76%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:15][CH2:14][C:13]2([CH3:19])[C:16]([OH:18])=O)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:31][O:32][C:33](=[O:44])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:31][O:32][C:33](=[O:44])[CH2:34][N:35]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:16]([C:13]1([CH3:19])[CH2:14][CH2:15][N:12]1[C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:18]
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)O)c1
Reactant: COC(=O)CNCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 119 (1 eq.) in DCM under nitrogen, was added DMF (0.01 eq.) then oxalyl chloride (2 eq.). The solution was stirred at 20° C. for 30 min, then cooled to 0° C. A solution of (4-Chloro-benzylamino)-acetic acid methyl ester (1.5 eq.) and either TEA or DIPEA (2 to 7 eq.) in DCM was then added to the previous mixture. The solution was stirred at 0° C. for 1 h then at 20° C. until completion (1 h). The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1) to afford ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid methyl ester.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[CH:18]=[C:17]([CH3:25])[N:16]=1>CN(C)C=O>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH:18]=[C:17]([CH3:25])[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(Cl)n1
Solvent: CN(C)C=O
Product: Cc1cc(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c(Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
A solution of tert-butyl 4-aminobutylcarbamate (32.12 g, 170.6 mmol) in N,N-dimethylformamide (200 mL) was added over a period of 90 minutes to a solution of 2,4-dichloro-6-methyl-3-nitropyridine (35.09 g, 169.5 mmol) in N,N-dimethylformamide (500 mL). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed by vacuum distillation using a 24/40 short path distillation head and warm water. The residue was dissolved in ethyl acetate (700 mL), washed with water (3×100 mL), dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography (50×450 mm silica gel eluting with 1:1 hexane:ethyl acetate) to provide 59.90 g of tert-butyl 4-[(2-chloro-6-methyl-3-nitropyridin-4-yl)amino]butylcarbamate.