Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([C@@H:48]5[CH2:52][CH2:51][CH2:50][N:49]5[CH3:53])=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)(C)C)(C)C)=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([C:5]1[CH:6]=[C:7]([NH:24][C:25]([NH:27][C@@H:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C@H:31]([O:38][C:39]3[CH:40]=[CH:41][C:42]4[N:43]([C:45]([C@@H:48]5[CH2:52][CH2:51][CH2:50][N:49]5[CH3:53])=[N:46][N:47]=4)[CH:44]=3)[CH2:30][CH2:29]2)=[O:26])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O[Si](C)(C)C(C)(C)C)cc4)c4ccccc43)cn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)cc4)c4ccccc43)cn12

Procedure:
A solution of Intermediate 73a (160 mg, 0.21 mmol) and TBAF (1M in THF, 0.26 mL, 0.26 mmol) in THF (2 mL) was stirred at RT for 30 min, then diluted with water and extracted with DCM (3×20 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-5% [2M NH3 in MeOH] in DCM, to give the title compound as a white powder after freeze-drying (107 mg, 79%). LCMS (Method 5): Rt 3.24 min, m/z 621 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.81-2.25 (11H, m), 2.34-2.36 (1H, m), 3.12-3.14 (1H, m), 3.99 (1H, t, J 8.2), 4.81-4.84 (1H, m), 5.39 (1H, t, J 4.3), 6.29 (1H, s), 6.85-6.88 (2H, m), 7.09 (1H, d, J 8.6), 7.28-7.39 (7H, m), 7.75 (1H, dd, J 9.9, 0.8), 7.92 (1H, s), 8.24 (1H, d, J 2.1), 9.72 (1H, s).
Reaction SMILES: [N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].O[N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18].C(Cl)CCl>C1COCC1>[N:1]1([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:7][CH2:6][C@H:2]1[C:3]([O:5][N:16]1[C:21](=[O:22])[CH2:20][CH2:19][C:17]1=[O:18])=[O:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: O=C1CCC(=O)N1O
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)ON1C(=O)CCC1=O
Reaction time: 8 h
Yield: 50.7 %

Procedure:
A mixture of Boc-Aze-OH (5 g, 25 mmol) and HOSu (2.88 g, 25 mmol) in 25 ml of THF was cooled on an ice bath. EDC (4.3 ml, 25 mmol) was added and the solution was stirred overnight. It was evaporated, dissolved in ethyl acetate, washed with KHSO4 (aq, 0.3 M), Na2CO3 (aq, 10%), dried (MgSO4) and evaporated. Crystallization from ethyl acetate:petroleum ether afforded 3.78 g (51%) of sub-title compound.
Reaction SMILES: [NH:1]1[C:5]2=[C:6]([NH:10][C:11](=[O:13])[CH3:12])[N:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:14][C:15]1[CH:20]=[C:19]([C:21](=[O:25])[NH:22][CH2:23][CH3:24])[CH:18]=[C:17]([Cl:26])[C:16]=1[C:27](Cl)=[O:28]>>[C:11]([NH:10][C:6]1[N:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:27]([C:16]3[C:17]([Cl:26])=[CH:18][C:19]([C:21]([NH:22][CH2:23][CH3:24])=[O:25])=[CH:20][C:15]=3[Cl:14])=[O:28])=[CH:2][NH:1][C:5]=12)(=[O:13])[CH3:12]
Reactant: CCNC(=O)c1cc(Cl)c(C(=O)Cl)c(Cl)c1
Reactant: CC(=O)Nc1nccc2cc[nH]c12
Product: CCNC(=O)c1cc(Cl)c(C(=O)c2c[nH]c3c(NC(C)=O)nccc23)c(Cl)c1

Procedure:
4-{[7-(Acetylamino)-1H-pyrrolo[2,3-c]pyridin-3-yl]carbonyl}-3,5-dichloro-N-ethylbenzamide was prepared from N-(1H-pyrrolo[2,3-c]pyridin-7-yl) acetamide and 2,6-dichloro-4-(ethylcarbamoyl)benzene carbonyl chloride (Compound No. 9).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][N:8]=[N:7][C:6]=1[CH3:10])=[O:4].[OH-].[Na+].Cl>CO>[CH3:10][C:6]1[N:7]=[N:8][S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1snnc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1nnsc1C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid methyl ester (1.7 g) is dissolved in methanol (15 mL) and treated with 1N sodium hydroxide (16 mL). After stirring at room temperature for 1 hour, the reaction is treated with concentrated hydrochloric acid (1.5 mL) and concentrated under reduced pressure. The resulting turbid aqueous layer is extracted twice with diethyl ether and the pooled organic layers are dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the desired compound as a white powder.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][NH:10][CH2:9][C:7]=2[N:8]=1.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21].C([O-])(O)=O.[Na+]>C1COCC1>[Cl:2][C:3]1[N:4]=[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@@H:13]2[CH3:18])[C:6]2[CH2:11][N:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:9][C:7]=2[N:8]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1
Yield: 112.3 %

Procedure:
(S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine hydrochloride (intermediate 6) (330 mg, 1.3 mmol), was dissolved in dry THF with srirring and treated with ethyl chloroformate (136 uL, 1.4 mmol) and NaHCO3 (218 mg, 2.6 mmol) at room temperature (20° C.) overnight. The mixture was concentrated in vacuo and the residue purified by flash chromatography using a mixture of 0-100% petrol ether/ethyl acetate as eluent, yielding the title compound (475 mg, 1.46 mmol, 41%).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[Cl:13][CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19].[ClH:21].CCOCC>C(O)(C)C>[ClH:13].[ClH:21].[CH2:1]([N:7]1[CH2:8][CH2:9][N:10]([CH2:14][CH2:15][C:16](=[O:20])[CH2:17][CH2:18][CH3:19])[CH2:11][CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC(=O)CCCl
Reactant: CCCCCCN1CCNCC1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: CCCCCCN1CCN(CCC(=O)CCC)CC1
Temperature: 100 °C

Procedure:
A mixture of 15.3 g (0.09 mole) of n-hexyl piperazine and 12.3 g (0.091 mole) of 1-chloro-3-hexanone was heated to 100° C. for 5 minutes, cooled and dissolved in isopropanol. Isopropanolic HCl was added until acidic. Ether was added and the salt was filtered off. The product was crystallized from acetonitrile to yield 16.5 g of product with a melting point of 225°-230° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[CH:10]=[C:9](Br)[S:8]1)=[O:5])[CH3:2].C([SnH](CCCC)CCCC)CCC.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>O1CCCC1>[CH2:1]([O:3][C:4]([N:6]=[C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=2)[CH:10]=[CH:9][S:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N=c1sc(Br)cn1-c1cccc(C(F)(F)F)c1
Agent: CCCC[SnH](CCCC)CCCC
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N=c1sccn1-c1cccc(C(F)(F)F)c1
Yield: 75.8 %

Procedure:
A solution of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl)-5-bromothiazoline (4.7 g), tributyltin hydride (6.9 g) and a catalytic amount of benzoyl peroxide in tetrahydrofuran (100 ml) was refluxed for 10 hours. The solvent was removed by distillation, and the residue was washed with hexane. Recrystallization from a mixture of hexane and ethanol gave 2.85 g of 2-ethoxycarbonylimino-3-(3-trifluoromethylphenyl) thiazoline (Compound (xii)).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24](N(OC)C)=[O:25])=[CH:18][CH:17]=1.[Cl-].[NH4+]>O1CCCC1>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([C@@H:22]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])[CH2:23][C:24]([C:7]2[CH:8]=[N:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=2)=[O:25])=[CH:20][CH:21]=1
Reactant: COc1ncc(Br)cn1
Reactant: CON(C)C(=O)C[C@@H](c1ccc(Br)cc1)c1ccccc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ncc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccccc2C)cn1
Temperature: 25 °C
Yield: 38.5 %

Procedure:
A solution of n-butyllithium (1.6 M in hexane, 3.31 mL, 5.3 mmol) in tetrahydrofuran (12 mL) was cooled to −95° C. and added dropwise, under nitrogen, to a stirred, cooled (−95° C.) solution of 5-bromo-2-methoxypyrimidine (1.00 g, 5.3 mmol) in dry tetrahydrofuran (40 mL). To the resulting yellow solution was immediately added a solution of (S)-3-(4-bromophenyl)-N-methoxy-N-methyl-3-o-tolylpropanamide (example 142, step 1; 1.6 g, 4.42 mmol) in dry THF (12 mL), with the temperature of the reaction mixture being kept between −90° C. and −100° C. The solution was stirred and allowed to warm to room temperature over 2 h. The reaction mixture was poured onto sat. aq. ammonium chloride solution and extracted with ethyl acetate. The organic layer was washed with brine dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; heptane-ethyl acetate gradient) produced the title compound (700 mg, 35%), Colourless gum, MS (ESI+): m/z=: 411.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH2:14][CH2:13]2)=[O:11])=[C:4]([O:26][CH3:27])[CH:3]=1.[H-].[Na+].I[CH:31]([CH3:33])[CH3:32]>CN(C)C=O>[CH:31]([N:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[O:26][CH3:27])[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:33])[CH3:32]
Reactant: COc1cc(C)c(C)cc1NC(=O)N1CCN(c2cc(F)cc(F)c2)CC1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C)c(C)cc1N(C(=O)N1CCN(c2cc(F)cc(F)c2)CC1)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
1-[(4,5-Dimethyl-2-methoxyphenyl)aminocarbonyl]-4-(3,5-difluorophenyl)piperazine(0.2 g, 0.52 mmole) was dissolved in dimethylformamide(15 ml) and thereto sodium hydride(12.48 mg, 0.52 mmole) was slowly added. The resulting mixture was stirred at room temperature for 15 min. After 2-iodopropane(87.88 mg, 0.52 mmole) was added thereto, the resulting mixture was stirred at room temperature for 16 hours. The resulting mixture was concentrated under the reduced pressure to remove the used solvent, extracted with methylene chloride, dryed, filtered and purified by column chromatography to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][OH:13].CCN(CC)CC.[Cl:21][C:22](OC(Cl)(Cl)Cl)=[O:23]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH2:11][CH2:12][O:13][C:22]([Cl:21])=[O:23]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cccc(F)c1CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cl)OCCc1c(F)cccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A solution of 2-(2-fluoro-6-nitrophenyl)ethanol (500 mg, 2.7 mmol) and Et3N (273 mg, 2.7 mmol, dist. over KOH) in THF (6.75 ml, dist. over CaH2) was dropped into a solution, cooled to 0° C., of trichloromethyl chloroformate (641 mg, 3.24 mmol) in THF (6.75 ml, see above) for 5 min. It was stirred for 1 h while cooling in an ice bath and then stirred for 1 h at room temperature. The mixture was filtered over Celite. Rewashing the filter cake with THF and removing the solvent and excess reagent from the pooled filtrates by distillation at 30° C. in a high vacuum yielded 2-(2-fluoro-6-nitrophenyl)ethoxycarbonyl chloride (620 mg, 93%) as a light-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.[C:10](O)(=[O:14])[CH:11]([CH3:13])[CH3:12].CN([P+](ON1N=NC2C1=CC=CC=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])=[N:6][CH:7]=1
Reactant: NCc1ccc(Br)cn1
Reactant: CC(C)C(=O)O
Agent: 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: CN(C)C=O
Product: CC(C)C(=O)NCc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.6 %

Procedure:
A mixture of (5-bromopyridin-2-yl)methanamine (200 mg, 1.069 mmol), isobutyric acid (0.159 mL, 1.711 mmol), BOP-reagent (757 mg, 1.711 mmol) and diisopropylethylamine (0.747 mL, 4.28 mmol) in DMF (6 mL) was stirred at rt for 2 hr. The reaction mixture was partitioned between EtOAc (60 ml) and saturated NaHCO3 solution (60 ml). The organic layer was washed with 10% LiCl solution (2×50 ml) and brine (50 ml). After drying (MgSO4) and filtration, the organic layer was concentrated to afford an orange oil that was chromatographed on a 24 gm ISCO silica gel cartridge, eluting with a 0-100% EtOAc/Hex gradient. The pure fractions were concentrated to afford N-((5-bromopyridin-2-yl)methyl)isobutyramide (230 mg, 0.894 mmol, 84% yield) as an orange oil. 1H NMR (400 MHz, METHANOL-d4) δ 8.57 (d, J=2.2 Hz, 1H), 7.95 (dd, J=8.4, 2.4 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 4.42 (s, 2H), 2.53 (dt, J=13.8, 6.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 6H). MS (ES+) m/z: 257.0, 259.0 (M+H); LC retention time: 1.200 min (analytical HPLC Method O).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].CO.Cl>C1COCC1>[C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])=[N:8][O:9][C:10]=1[CH3:11])([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(-c2ccc(F)cc2F)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1onc(-c2ccc(F)cc2F)c1C(=O)O
Yield: 104.9 %

Procedure:
4-Ethoxycarbonyl-5-methyl-3-(2,4-difluorophenyl)isoxazole (305 mg, 1.14 mmol), 5N NaOH (1.0 ml, 5 mmol), methanol (5 ml), and THF (1 ml) were heated at 50° C. for 16 h. Ice was added and the pH was adjusted to 2-3 with 1N HCl. Extraction with EtOAc followed by washing (brine), drying (Na2SO4), filtering, and concentration gave the crude 4-carboxy-5-methyl-3-(2,4-difluorophenyl)isoxazole (286 mg, 99%) which was used without further purification.
Reaction SMILES: FC(F)(F)S(O[C@H:7]1[C@H:12]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:10][CH2:9][C:8]1([F:22])[F:21])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@H:7]1[C:8]([F:22])([F:21])[CH2:9][CH2:10][CH2:11][C@H:12]1[NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@H]1OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC(F)(F)[C@@H]1N=[N+]=[N-]
Temperature: 100 °C
Yield: 56.2 %

Procedure:
A solution of (1S,6R)-6-[(tert-butoxycarbonyl)amino]-2,2-difluorocyclohexyl trifluoromethanesulfonate 34 (2.32 g, 6.05 mmol) and sodium azide (2.36 g, 36.3 mmol) in DMF was sealed and heated to 100° C. for 3 hours in a microwave reactor. The reaction was partitioned between water and ethyl acetate. The organics were washed with water, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (0-15% ethyl acetate in hexanes) gave 0.94 g (56%) of tert-butyl [(1R,2R)-2-azido-3,3-difluorocyclohexyl]carbamate 36 as a white solid: NMR (500 MHz, CDCl3) δ 4.75 (1H, m), 3.98 (1H, bs), 3.88 (1H, bm), 1.96 (2H, m), 1.70 (2H, m), 1.46 (9H, s), 1.37 (2H, m).
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C@@H:21]([CH2:25][CH:26]1[CH2:28][CH2:27]1)[C:22]([NH2:24])=[O:23]>>[C:22]([C@@H:21]([NH:20][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])[CH2:25][CH:26]1[CH2:28][CH2:27]1)(=[O:23])[NH2:24]
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)CC1CC1
Product: NC(=O)[C@H](CC1CC1)NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and (S)-2-amino-3-cyclopropyl-propionamide (CAN 156077-93-9) as starting materials, MS (EI): m/e=372.3 [M+H]+.
Reaction SMILES: N[C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@@H:3]1[C:15]([O:17][CH3:18])=[O:16].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>C(Cl)Cl>[CH2:30]([O:29][C:27]([C@@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[C:15]([O:17][CH3:18])=[O:16])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1C(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 64.1 %

Procedure:
A solution of 257A (447 mg, 1.7 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.3 mL, 2.2 mmol) followed by benzyl chloroformate (0.27 mL, 1.9 mmol) at room temperature. The reaction mixture was stirred for 18 hours, then washed with water (25 mL). The aqueous layer was extracted with CH2Cl2 (25 mL) and the combine organics were washed with saturated aqueous NaHCO3, 0.1N HCl, and brine. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to an oil. The crude material was purified by flash chromatography (30% EtOAc/hexanes) on silica gel to afford 411 mg (yield: 75%) of Compound 257B as an oil.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[C:10](=[O:28])[C:11]([C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:14]=1[NH:20]C(=O)OC(C)(C)C)=O.[F-].[Cs+].C[Si]([N:35]=[C:36]=[N:37][Si](C)(C)C)(C)C.Cl>C(#N)C.ClCCl>[NH2:35][C:36]1[N:37]=[C:11]([C:10]([N:2]2[CH2:3][C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:1]2)=[O:28])[C:13]2[C:14](=[CH:15][CH:16]=[C:17]([I:19])[CH:18]=2)[N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1C(=O)C(=O)N1Cc2ccccc2C1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Solvent: ClCCl
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(I)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
24.50 g of tert-butyl {2-[2-(1,3-dihydroisoindol-2-yl)-2-oxoacetyl]-4-iodophenyl}carbamate are dissolved in 500 ml of acetonitrile under argon. 0.756 g of caesium fluoride is added, and 16.887 ml of bis(trimethylsilyl)carbodiimide are added dropwise to the solution over the course of 5 min. The mixture is stirred at room temperature for 15 min, and 400 ml of dichloromethane are added. After addition of 400 ml of hydrochloric acid (1N), the product precipitates out as white solid; yield: 14 g of (2-amino-6-iodoquinazolin-4-yl)-(1,3-dihydroisoindol-2-yl)methanone; LC-MS retention time: 1.66 min;
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:35])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:18]=[CH:17][C:16]=2[F:35])=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CSc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Product: CN(C)CCNc1ncc2cc(-c3ccc(F)c(NC(=O)Nc4cccc(C(C)(C)C)c4)c3)c(=O)n(C)c2n1
Yield: 69.3 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylphenyl)-3-(2-fluoro-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.200 g, 0.407 mmol) and N,N-dimethylethylenediamine (0.181 mL, 1.65 mmol) were combined to afford 1-(3-tert-butylphenyl)-3-(5-(2-(2-(dimethylamino)ethylamino)-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-2-fluorophenyl)urea (0.150 g, 86% yield) as a light yellow solid. It was converted to corresponding HCl salt by reacting with HCl (4.0 M HCl in dioxane, 1.0 eq.). 1H NMR (400 MHz, DMSO-d6): δ 9.28 (s, 1H), 8.73 (s, 1H), 8.64 (d, J=1.6 Hz, 1H), 8.39 (d, J=7.6 Hz, 1H), 8.04 (s, 1H), 7.93 (s, 1H), 7.43 (s, 1H), 7.28-7.24 (m, 3H), 7.18 (t, J=8.0 Hz, 1H), 6.99 (tt, J=7.6, 0.8 Hz, 1H), 3.74 (broad, 2H), 3.63 (s, 3H), 3.30 (broad, 2H), 2.81 (d, J=4.8 Hz, 6H), 1.25 (s, 9H); MS (ESI) m/z: 532.3 (M+H+).
Reaction SMILES: [CH3:1][CH2:2][C:3](=O)[CH2:4][C:5](=O)[CH2:6][CH3:7].O.[NH2:11][NH2:12]>C(O)(=O)C.O>[CH2:2]([C:3]1[CH:4]=[C:5]([CH2:6][CH3:7])[NH:12][N:11]=1)[CH3:1]
Reactant: NN
Reactant: CCC(=O)CC(=O)CC
Solvent: O
Solvent: CC(=O)O
Product: CCc1cc(CC)[nH]n1
Yield: 91.7 %

Procedure:
A solution of 3,5-heptanedione (2.4 g, 18.8 mmol) and hydrazine hydrate (1.0 g, 19.0 mmol) and acetic acid (1 drop) in water (10 mL) was heated to reflux for 1 h. The reaction mixture was then cooled in an ice bath to form a white precipitate. The precipitate was then filtered, dissolved in chloroform and dried over MgSO4. The resulting reaction was concentrated under reduced pressure to provide 2.14 g of the title compound. This compound was of sufficient purity to use in subsequent reactions.
Reaction SMILES: [CH2:1]([N:8]([CH2:12][Si](C)(C)C)[CH2:9]OC)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:26][C@H:25]1/[CH:37]=[CH:38]/[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:19])[CH3:18].FC(F)(F)C(O)=O.C(Cl)Cl.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:17]([O:21][C:22]([N:24]1[CH2:28][C@H:27]([O:29][Si:30]([C:33]([CH3:34])([CH3:35])[CH3:36])([CH3:31])[CH3:32])[CH2:26][C@H:25]1[CH:37]1[CH2:9][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][CH:38]1[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: CCOC(=O)/C=C/[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine (40.2 g, 135.6 mmol, purity: 80%) was added to a solution of ethyl (E)-3-[(2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxypyrrolidin-2-yl]acrylate (37.4 g, 93.5 mmol, compound of Reference Example 1-4 of U.S. patent application Ser. No. 07/674,971) in methylene chloride (190 ml) in a nitrogen stream, and a 1M trifluoroacetic acid-methylene chloride solution (9.35 ml, 9.35 mmol) was dropwise added under cooling with ice. The reaction solution was stirred at room temperature for 1.5 hours, and poured into a saturated sodium hydrogen carbonate aqueous solution. The organic layer was washed sequentially with water, a 10% citric acid aqueous solution, water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a (2S, 4R)-N-tert-butoxycarbonyl-4-tert-butyldimethylsiloxy-2-(N-benzyl-3-ethoxycarbonylpyrrolidin-4-yl)pyrrolidine diastereomer mixture (50.2 g, yield: 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[CH2:30][CH2:31][O:32][CH2:33][CH:34]=5)[N:24]=4)=[O:22])[CH2:17][C:16]3([CH3:36])[CH3:35])=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1>[Pd].CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]5[CH2:30][CH2:31][O:32][CH2:33][CH2:34]5)[N:24]=4)=[O:22])[CH2:17][C:16]3([CH3:36])[CH3:35])=[O:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)CN(C(=O)c2cccc(C3=CCOCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC1(C)CN(C(=O)c2cccc(C3CCOCC3)n2)CCN1C(=O)c1ncn(-c2cccc(Cl)c2)n1
Reaction time: 96 h

Procedure:
A mixture of 17 mg (34 μmol) [1-(3-chloro-phenyl)-1H-[1,2,4]-triazol-3-yl]-{4-[6-(3,6-dihydro-2H-pyran-4-yl)-pyridine-2-carbonyl]-2,2-dimethyl-piperazin-1-yl}-methanone and 4 mg palladium on carbon in 5.0 mL EtOAc was hydrogenated at RT for 4 days. The catalyst was removed by filtration and the solvent was evaporated in vacuo. The resulting residue was purified by HPLC.