Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[CH3:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[CH:4][C:5]([N:8]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:26]5[CH:27]=[CH:28][C:23]([CH3:22])=[CH:24][CH:25]=5)=[CH:17][N:16]=4)[CH2:10][CH2:9]3)=[N:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: Brc1ccc(N2CCCN(c3ccc(Br)cn3)CC2)nc1
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(N3CCCN(c4ccc(-c5ccc(C)cc5)cn4)CC3)nc2)cc1
Yield: 42.8 %

Procedure:
Following the procedure of Example 1, crude crystals were obtained from the 1,4-bis(5-bromo-2-pyridyl)hexahydro-1,4-diazepine (206.0 mg, 0.500 mmol) synthesized in Reference Example 1 and 4-methylphenylboronic acid (163.0 mg, 1.20 mmol). The crude crystals were recrystallized from chloroform-hexane to yield the title compound as pale yellow needles (melting point: 245.0–247.0° C.)(93.0 mg, yield: 42%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7](C(OC(C)(C)C)=O)[C@@H:6]([C:17]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[O:18])[CH2:5]1)([CH3:3])[CH3:2].[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40](=O)[O:41]C2C=CC=CC=2)[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C1COCC1>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([NH:39][C:40]([N:22]2[CH2:21][CH2:20][N:19]([C:17]([C@H:6]3[CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8][NH:7]3)=[O:18])[CH2:24][CH2:23]2)=[O:41])[CH:36]=[CH:37][CH:38]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)N2CCNCC2)C1
Reactant: O=C(Nc1cccc(OCc2ccccc2)c1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)N1CCN[C@@H](C(=O)N2CCN(C(=O)Nc3cccc(OCc4ccccc4)c3)CC2)C1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of tert-butyl (2R)-4-isopropyl-2-(piperazin-1-ylcarbonyl)piperazine-1-carboxylate (0.2 g, 0.59 mmol) and phenyl [3-(benzyloxy)phenyl]carbamate (0.189 g, 0.59 mmol) in THF (5 μL) was added triethylamine (91 uL, 0.65 mmol) and the reaction heated to 60° C. for 6 hours. The solvents were then removed in vacuo and the residue dissolved in DCM (3 ml), added TFA (3 ml) and stirred at room temperature for a further 90 mins. The reaction mixture was then concentrated under reduced pressure, residue partitioned between DCM/1M NaOH, extracted twice, combined organics passed through phase separating cartridge and evaporated to dryness to give a yellow gum. This was then purified by silica gel chromatography (Isco Companion™; 12 g column; 10% methanolic ammonia/DCM)
Reaction SMILES: Cl[C:2]1[C:3]([CH:15]([CH3:17])[CH3:16])=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1.[O-:18][CH2:19][CH3:20].[Na+].O>C(O)C>[CH2:19]([O:18][C:2]1[C:3]([CH:15]([CH3:17])[CH3:16])=[C:4]([CH:12]([CH3:14])[CH3:13])[C:5]2[N:6]([C:8]([NH2:11])=[N:9][N:10]=2)[N:7]=1)[CH3:20]
Reactant: CC[O-]
Reactant: CC(C)c1c(Cl)nn2c(N)nnc2c1C(C)C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1nn2c(N)nnc2c(C(C)C)c1C(C)C
Reaction time: 1 h
Yield: 96.4 %

Procedure:
6-Chloro-7,8-diisopropyl-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine (W2.015, 0.1 g) was dissolved in ethanol (15 ml) while stirring and under argon. Thereafter, the reaction mixture was admixed with sodium ethoxide (110 mg) and stirred at RT for 1 h, then at 55° C. for 1 h. Subsequently, the mixture was left to stand overnight, then stirred again at 55° C. for 7.5 h and then the solvent was drawn off, and the residue was admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 100 mg of the title compound were obtained. LC-MS rt: 0.90 min [M+H]+: 264.2 (met. b)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].[Cl:10][S:11](O)(=[O:13])=[O:12]>>[Cl:1][C:2]1[C:3]([CH3:9])=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[S:11]([Cl:10])(=[O:13])=[O:12]
Reactant: Cc1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)Cl
Product: Cc1c(Cl)ccc(S(=O)(=O)Cl)c1Cl
Temperature: 25 °C
Yield: 85 %

Procedure:
10 ml of chlorosulfonic acid were dropwise added with 4.8 ml of 2,6-dichlorotoluene in two hours, under magnetic stirring at room temperature. After completion of the addition, the mixture was heated at 40° C. for two hours, thereby obtaining a purple solution, which was cooled and carefully poured into ice-water (0.5 l), stirring vigorously. The separated white solid was filtered, triturated, washed with water, dried over KOH and purified by washing with n-hexane, adding 200 ml of solvent under strong stirring. The mixture was filtered, the solid was discarded and the solvent was evaporated to dryness to obtain 2,4-dichloro-3-methyl-benzenesulfonyl chloride as a crystalline white solid. Yield: 85%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]3[O:20][CH2:21][S:22](=[O:32])(=[O:31])[N:23]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C:18]=3[CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:33].CCOCC>CO>[ClH:33].[CH2:24]([N:23]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[C:19]=2[O:20][CH2:21][S:22]1(=[O:32])=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2OCS(=O)(=O)N3Cc2ccccc2)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: O=S1(=O)COc2c(N3CCNCC3)cccc2N1Cc1ccccc1
Temperature: 100 °C

Procedure:
4-(1-Benzyl-2,2-dioxo-2,3-dihydro-1H-benzo[4,2,1]oxathiazin-5-yl)-piperazine-1-carboxylic acid tert-butyl ester was dissolved in 1 mL methanol and 1 mL of 2N ethanolic HCl was added. The solution is heated at 100° C. for 30 minutes, at which time was added approximately. 2 mL Et2O. On cooling to room temperature, 30 mg of 1-benzyl-5-piperazin-1-yl-1H-benzo[4,2,1]oxathiazine 2,2-dioxide hydrochloride precipitated as a white solid (61%). (M+H)+=360.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)CCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[N:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCn2c(Br)nnc2C1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCn2c(nnc2-c2ccccn2)C1
Temperature: 130 °C

Procedure:
To a solution of 1,1-dimethylethyl 3-bromo-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazine-7(8H)-carboxylate (200 mg, 0.660 mmol, commercially available) in 1,4-dioxane (2 mL), 2-(tributylstannanyl)pyridine (364 mg, 0.990 mmol) was added and mixture was degassed with a stream of argon for few minutes. Pd(Ph3P)4 (38.1 mg, 0.033 mmol) was then added followed by copper(I) iodide (39.2 mg, 0.206 mmol) and the mixture was submitted to microwave irradiation heating at 130° C. for 25 minutes until the reaction was complete by LCMS. Volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel (Snap 11 g NH column) eluting with a gradient from 0 to 100% ethyl acetate in iso-hexane (10CV) and then with 100% ethyl acetate (7CV). A colourless oil was obtained. The product was still impure and so was further purified by chromatography on silica gel (Si 5 g) eluting with a 80% ethyl acetate in iso hexane (5CV) and then with 10% MeOH in DCM (5 CV) then by chromatography on silica gel (Si column 5 g) eluting first with ethyl acetate (4CV) and then with 10% MeOH in DCM (6CV). Colourless oil was obtained of the desired product in 115 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[C:4]([NH:14]S(C2C=CC=CC=2)(=O)=O)[CH:3]=1.Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:28]>>[CH3:11][O:10][C:8](=[O:9])[CH2:7][C:6]1[C:5]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:13][CH:12]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:35])[N:30]=1)=[O:28]
Reactant: COC(=O)/C=C/c1ccc(Cl)cc1NS(=O)(=O)c1ccccc1
Reactant: Cc1cccc(C(=O)CBr)n1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cccc(C)n2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-4-chloro-2-(phenylsulfonylamino)cinnamate (step 1 of Example 8, Method A) and 2-bromoacetyl-6-methylpyridine hydrobromide (H. Erlenmeyer, J. Jenni, and B. Prijs, J. Med. Pharm. Chem., 1961, 3, 561-566).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.Cl[C:19]([O:21][CH3:22])=[O:20]>ClCCl>[CH3:22][O:21][C:19]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:20]
Reactant: COC(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Solvent: ClCCl
Product: COC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.2 %

Procedure:
To a mixture of 10 mg (0.0437 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 15.0 mg (0.131 mMol) polyvinylpyridine in 3.0 mL dichloromethane were added 4.3 mg (0.0458 mMol) methyl chloroformate. The reaction mixture was mixed for 18 hours at ambient temperature. To this mixture were then added 170 mg (0.137 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 10.2 mg (81%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[CH3:24][C:25]1[N:26]([CH2:34][CH2:35][CH2:36][CH2:37][NH2:38])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[N:33]=1.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:24][C:25]1[N:26]([CH2:34][CH2:35][CH2:36][CH2:37][NH:38][C:10](=[O:12])[CH2:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[O:13])[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][C:28]=2[N:33]=1
Reactant: Cc1nc2cnccc2n1CCCCN
Reactant: O=C(O)CC(=O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: Cc1nc2cnccc2n1CCCCNC(=O)CC(=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
To an ice cold mixture of 3-(4-fluorophenyl)-3-oxoproprionic acid (prepared by standard saponification of the commercially available ester) (0.69 g), 1-hydroxybenzotriazole (0.56 g), and 4-(2-methylimidazo[4,5-c]pyrid-1-yl)butylamine (see Preparation 24) (0.71 g) in methylene chloride (20 cm3) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.8 g) over 5 minutes. The mixture was stirred at 0° for 1 hour and then at room temperature for 30 minutes, poured into 5% sodium bicarbonate solution (50 ml) and extracted with methylene chloride (3×50 ml). The combined extracts were dried over Na2SO4, filtered and evaporated under vacuum. The residue was chromatographed on silica eluting with a methylene chloride/methanol mixture and the fractions containing the product were evaporated to give the title compound (0.82 g, 64%), which was used directly.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][NH2:16])=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.ClCCl.[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34]Cl)=[CH:32][CH:31]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:29][C:30]1[CH:37]=[CH:36][C:33]([CH2:34][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[CH:10][CH:11]=2)[NH2:16])=[CH:32][CH:31]=1
Reactant: NNc1ccc(OCc2ccccn2)cc1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: NN(Cc1ccc(Cl)cc1)c1ccc(OCc2ccccn2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
4-(Pyrid-2-ylmethoxy)phenylhydrazine (66.2 g; 308 mmol), prepared as in step 3, was added to a solution of 86 mL diisopropylethylamine and 900 mL dichloromethane. 4-Chlorobenzyl chloride (74.4 g; 462 mmol) and tetrabutylammonium bromide (29.8 g; 92.4 mmol) and an additional 100 mL dichloromethane were added and the reaction was stirred at ambient temperature for 24 hours. The reaction mixture was diluted with water and the layers were separated. The aqueous layer was extracted with dichloromethane. The combined organics were dried over magnesium sulfate and concentrated. The residue was washed with 9:1 diethyl ether, methanol to afford 1-(4-chlorobenzyl)-1-[4-(pyrid-2-ylmethoxy)phenyl] hydrazine as a beige solid.
Reaction SMILES: [O:1]1[CH2:5][CH:4]([CH2:6]O)[O:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][CH3:82])/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:72]4[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=4)[C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)=[S:63])=[C:56](C(=O)C)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.N1CCOCC1.[F:89][C:90]([F:102])([F:101])[S:91]([O:94][CH2:95][CH:96]1[CH2:100][O:99][CH2:98][O:97]1)(=[O:93])=[O:92]>C(N(CC)CC)C.N1C=CC=CC=1>[F:102][C:90]([F:89])([F:101])[S:91]([O:94][CH2:95][CH:96]1[CH2:100][O:99][CH2:98][O:97]1)(=[O:93])=[O:92].[C:23]([NH:42][C:43]1[S:44][CH:45]=[C:46](/[C:48](=[N:80]/[O:81][CH3:82])/[C:49]([NH:51][CH:52]2[C:78](=[O:79])[N:54]3[C:55]([C:62]([O:64][CH:65]([C:72]4[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=4)[C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)=[S:63])=[C:56]([CH2:6][CH:4]4[CH2:5][O:1][CH2:2][O:3]4)[CH2:57][S:58][C@H:53]23)=[O:50])[N:47]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(C(C)=O)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: OCC1COCO1
Agent: O=S(=O)(OCC1COCO1)C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: C1COCCN1
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=S)OC(c3ccccc3)c3ccccc3)=C(CC3COCO3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 94 %

Procedure:
1,3-Dioxolan-4-ylmethyl trifluoromethanesulfonate was prepared in the same manner as in Example 27 (a) from 1,3-dioxolan-4-ylmethanol (180 mg), pyridine (0.15 ml) and trifluoromethanesulfonic acid anhydride (537 mg). On the other hand, diphenylmethyl 7-[(Z)-2-(2 -tritylaminothiazol-4-yl)-2-methoxyiminoacetamido]-3-acetylthio-3-cephem-4-carboxylate (500 mg) was reacted with morpholine and triethylamine in the same manner as in Example 27 (b), followed by reacting the resulting reaction product with the 1,3-dioxolan-4-ylmethyl trifluoromethanesulfonate in the same manner as in Example 27 (b). The reaction solution so obtained was post-treated in the same manner as in Example 27 (b) and the produced compound was recovered and purified similarly to Example 27 (b) to afford the titled compound (494 mg; 94%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([OH:31])=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32].C[N:34]1CCO[CH2:36][CH2:35]1.CN1CCCC1=O.Cl.CN(C)CCCN=C=NCC.C(N)C>CCOC(C)=O>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:27][CH2:28][C:29]([NH:34][CH2:35][CH3:36])=[O:31])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:32]
Reactant: CN1CCOCC1
Reactant: Cc1cc(F)ccc1-c1nc(NCC(=O)O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCNC(=O)CNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reaction time: 1 h
Yield: 68.1 %

Procedure:
The product of Example 191 (50 mg, 0.11 mmol), n-hydroxybenzotriazole (21 mg, 0.34 mmol), 1-methylmorpholine (19 uL, 0.172 mmol), N-methylpyrrolidinone (2.5 mmol) were dissolved together, then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (66 mg, 0.34 mmol) was added, stirred 1 h, and then ethylamine (2 M in THF) (1.0 mL, 2.0 mmol) was added and the reaction was stirred at 23° for 16 h, diluted with EtOAc (50 mL), and washed with 10% aq citric acid (2×20 mL), H2O (20 mL), and satd aq NaCl (20 mL), dried (MgSO4) concentrated and purified by chromatotron chromatography (CH2Cl2/CH3OH) to afford 35 mg of the title compound 2-[[8-(2,6-difluorophenyl)-4-(4-fluoro-2-methylphenyl)-7,8-dihydro-7-oxopyrido[2,3-d]pyrimidin-2-yl]amino]-N-ethylacetamide as a white powder. mp=250-253 (dee). LC MS (m/e)=468.2 (MH+). Rt=1.87 min.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1.CC[O:16][C:17]([CH:19]1[C:24](=O)[CH2:23][CH2:22][CH2:21][CH2:20]1)=O.[OH-].[Na+]>O>[CH3:1][C:2]1[C:6]2[C:17](=[O:16])[C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[NH:7][C:5]=2[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:3]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: Cc1cc(N)n(-c2ccccn2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nn(-c2ccccn2)c2[nH]c3c(c(=O)c12)CCCC3
Temperature: 130 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
A mixture of polyphosphoric acid (4.02 g) and 3-methyl-1-(2-pyridinyl)-1H-pyrazol-5-ylamine (1.75 g, 10.0 mmol) was heated at 130° C. The mixture was stirred at the same temperature, while ethyl 2-cyclohexanone carboxylate(1.70 mL, 10.6 mmol) was added thereto gradually. The mixture was stirred at the same temperature further for 4 hours. The solution was allowed to cool to room temperature, and water was added to the mixture. The solution was neutralized by the addition of a sodium hydroxide solution and the organic matter was extracted with chloroform. The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=100:1 to 50:1 to 20:1), and recrystallized from ethyl acetate to give the title compound (0.39 g, 14% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[C:31]([O:35][C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][C:42]([O:48][CH2:49]Cl)=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].[Cl-].[NH4+]>O1CCCC1.O>[C:31]([O:35][C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][C:42]([O:48][CH2:49][C:6]3([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10][N:9]([C:12]4[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=4)[CH2:8][CH2:7]3)=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(OCCl)cc2C1
Reactant: CCOC(=O)C1CCN(c2ccncc2)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C1(COc2ccc3c(c2)CN(C(=O)OC(C)(C)C)CC3)CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 1-(pyridin-4-yl)piperidine-4-carboxylic acid ethyl ester (Tetrahedron, vol. 44, No. 23, p. 7095 (1988)) (13.4 g) in tetrahydrofuran (300 ml) was dropwise added a 2M-lithium diisopropylamide-tetrahydrofuran solution (31 ml) at −70° C. under an argon atmosphere, and the mixture was stirred at the same temperature for 45 min. To this solution was dropwise added a solution of 7-chloromethoxy-1,2,3,4-tetrahydroisoquinoline-2-carboxylic acid tert-butyl ester (7.4 g) in tetrahydrofuran (80 ml) at the same temperature, and the mixture was allowed to warm to room temperature in 5.5 hours in stirring. After completion of the reaction, aqueous ammonium chloride solution (50 ml) and water (50 ml) were added, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated and the obtained residue was dissolved in methanol (150 ml). Thereto was dropwise added 1N aqueous sodium hydroxide solution (50 ml) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was evaporated and the obtained residue was extracted with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1-10:1) and dried under reduced pressure to give the title compound (10.87 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH2:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([O-])([O-])=O.[K+].[K+].ClC(OCC)=O.B>C1COCC1.O>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH:10]([NH:21][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: NC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Agent: B
Agent: CCOC(=O)Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1CN(Cc2ccccc2)CC1c1ccc(Cl)c(F)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 70.6 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-ylamine (0.46 g, 1.51 mmol) in THF (5 ml) was added a solution of K2CO3 (0.419 g, 3.0 mmol) in H2O (2 ml). After 10 minutes, ethyl chloroformate (0.3 ml, 3.0 mmol) was added and stirring was continued at RT for an additional 4 h. The intermediate carbamate was then extracted with Et2O, dried over Na2SO4 and concentrated under vacuo to give viscous oil. The oil was taken up in THF (10 ml) and a solution of borane in THF (1M) was added (6.0 ml). The reaction mixture was then heated at 65° C. over night, cooled to RT and carefully quenched with cone. HCl (5 ml). The mixture was then heated at 80° C. for 2 h, cooled to RT, concentrated under vacuo, diluted with Et2O (10 ml) and neutralized with an aqueous solution of NaHCO3. The organic phases were dried over Na2SO4 and the product purified by flash chromatography (SiO2, CH2Cl2/MeOH 9:1) to afford 0.34 g (70%) of the title compound as a colorless oil. ES-MS m/e: 319.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]([CH2:26][N:27]([C@@H:35]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[CH3:36])C(=O)OC(C)(C)C)[CH2:15]1.[ClH:47].O1CCOCC1>O1CCOCC1>[ClH:47].[F:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[C:4]([F:13])[C:3]=1[N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:16]([CH2:26][NH:27][C@@H:35]([C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)[CH3:36])[CH2:15]1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(-c3nnn[nH]3)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H](NCC1CN(c2c(F)cc(-c3nnn[nH]3)cc2F)CCC1c1ccccc1)c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 206 mg of the crude product of tert-butyl ({1-[2,6-difluoro-4-(1H-tetrazol-5-yl)phenyl]-4-phenylpiperidin-3-yl}methyl)[(1R)-1-(1-naphthyl)ethyl]carbamate were added 2.0 mL of 1,4-dioxane and 2.0 mL of a 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, and to the residue were then added ethyl acetate and a small amount of ethanol, followed by heating for dissolution. Hexane was added thereto, and the precipitate was isolated by filtration, and dried under reduced pressure to obtain 153 mg of (1R)—N-({1-[2,6-difluoro-4-(1H-tetrazol-5-yl)phenyl]-4-phenylpiperidin-3-yl}methyl)-1-(1-naphthyl)ethaneamine hydrochloride as a beige solid.