Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[C:22]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][N:12](C(=O)C(F)(F)F)[CH2:11][CH2:10][C:9]=3[CH:21]=2)[O:5][N:4]=1)[CH3:2].C([O-])([O-])=O.[Na+].[Na+]>CO>[CH2:1]([C:3]1[C:22]2[C:6](=[CH:7][C:8]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10][C:9]=3[CH:21]=2)[O:5][N:4]=1)[CH3:2]
Reactant: CCc1noc2cc3c(cc12)CCN(C(=O)C(F)(F)F)CC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1noc2cc3c(cc12)CCNCC3

Procedure:
Treatment of 3-ethyl-7-(trifluoroacetyl)-6,7,8,9-tetrahydro-5H-isoxazolo[4,5-h][3]benzazepine (21 mg) with Na2CO3 (1 mL, 1 M in water) in MeOH (2 mL) at reflux for 3 h followed by partitioning between water and dichloromethane and evaporation of the volatiles from the organic phase gave the title compound as a solidifying yellow oil in quantitative yield. The material was used as such without further characterisation.
Reaction SMILES: C[Si](C)(C)[O:3][C:4]1[N:5]=[N:6][CH:7]=[C:8]([O:10][Si](C)(C)C)[N:9]=1.Cl[CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1>CN(C)C=O>[O:19]1[CH2:20][CH2:21][CH2:22][CH2:23][CH:18]1[N:5]1[C:4](=[O:3])[N:9]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:8](=[O:10])[CH:7]=[N:6]1
Reactant: C[Si](C)(C)Oc1cnnc(O[Si](C)(C)C)n1
Reactant: ClC1CCCCO1
Solvent: CN(C)C=O
Product: O=c1cnn(C2CCCCO2)c(=O)n1C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.6 %

Procedure:
3,5-Bis(trimethylsilyloxy)-1,2,4-triazine (2.5 g) and 2-chlorotetrahydropyran (1.8 g) are dissolved in dimethylformamide (1 ml), and the mixture is stirred overnight at room temperature and concentrated in vacuo. The residue is column-chromatographed over silica gel using a mixture of acetone/n-hexane (1/3) as an eluent. The first major fraction gives 1.0 g (40%) of 2,4-bis(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 87) (yield, 1.0 g; 36%), the second gives 4-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 88) (yield, 0.8 g; 40%) and the third gives 2-(tetrahydro-2-pyranyl)-3,5-dioxo-2,3,4,5-tetrahydro-1,2,4-triazine (Compound No. 100) (yield, 0.6 g; 30%). Compound Nos. 87 and 88 melt at 32° C. and 116° C., respectively.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]=[C:8]=[O:9])=[N:4][CH:3]=1.[CH3:10][NH:11][CH2:12][CH:13]=[O:14]>C1C=CC=CC=1>[CH3:10][N:11]([CH2:12][CH:13]=[O:14])[C:8]([NH:7][C:5]1[S:6][C:2]([Br:1])=[CH:3][N:4]=1)=[O:9]
Reactant: CNCC=O
Reactant: O=C=Nc1ncc(Br)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1ncc(Br)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Bromothiazol-2-yl isocyanate dimer (17.0 grams), benzene (70 ml) and the dimethyl acetal of 2-methylaminoacetaldehyde (13.5 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The reaction mixture was then stirred at room temperature for a period of about one hour. After this time the reaction mixture was filtered, and the filtrate was stripped of solvent under reduced pressure, leaving an oil. This oil was chromatographed on silica gel using ethyl acetate as the diluant. The eluant was dissolved in an ethanol-water mixture, and the solution was filtered. The filtrate was then stripped of solvents under vacuum to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-bromothiazol-2-yl)ureido]-acetaldehyde as a crystalline solid having a melt point of 72° to 73° C.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].Cl.[CH:30]1([NH:33][NH2:34])[CH2:32][CH2:31]1>CCO.C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:34][N:33]([CH:30]4[CH2:32][CH2:31]4)[C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Reactant: NNC1CC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 92.1) (630 mg, 1.588 mmol) and cyclopropylhydrazine hydrochloride (517 mg, 4.76 mmol) in EtOH (8 mL) and toluene (8 mL) was stirred for 2 hr at reflux. The reaction mixture was concentrated, diluted with CH2Cl2/saturated aq. NaHCO3 solution, and extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) to afford the title product (412 mg, 0.952 mmol, 59.9% yield) as a yellow foam. tR: 0.95 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.28 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.11 (m, 2H) 1.18-1.29 (m, 2H) 1.92 (s, 3H) 2.43 (s, 3H) 2.61 (s, 3H) 3.75-3.87 (m, 1H) 6.41 (s, 1H) 7.27-7.39 (m, 5H) 8.33-8.48 (m, 1H).
Reaction SMILES: [ClH:1].C(OC([NH:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([NH:21][CH2:22][CH2:23][NH:24]C(OC(C)(C)C)=O)=[C:16]3[C:32](=[O:39])[C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[C:14]([C:15]=23)=[N:13]1)=O)(C)(C)C>C(O)C>[ClH:1].[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([NH:21][CH2:22][CH2:23][NH2:24])=[C:16]3[C:32](=[O:39])[C:33]4[CH:34]=[CH:35][N:36]=[CH:37][C:38]=4[C:14]([C:15]=23)=[N:13]1
Reactant: CC(C)(C)OC(=O)NCCNc1ccc2c3c(nn2CCNC(=O)OC(C)(C)C)-c2cnccc2C(=O)c13
Agent: Cl
Solvent: CCO
Product: NCCNc1ccc2c3c(nn2CCN)-c2cnccc2C(=O)c13
Temperature: 40 °C

Procedure:
Under a nitrogen atmosphere an ethanolic solution of anhydrous HCl (5N; 0.40 mL) is dropped into a stirred suspension of 2-[2-(N-tert-butoxycarbonylamino) ethyl]-5-[[2-(N-tert-butoxycarbonylamino) ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one of Example 10 (0.104 g) in absolute ethanol (2.1 mL). Initial dissolution of the starting material followed by precipitation of a dark-red solid is observed during the addition of ethanolic HCl. This solid is redissolved with absolute ethanol and the solution is heated to 40° C. for 2 h, 30'. The gradual formation of a red-amaranth precipitate is observed during the heating. After cooling to room temperature diethyl ether (10 mL) is added and the precipitate is collected by suction filtration under a nitrogen blanket, to give 2-[2-(amino)ethyl]-5-[[2-(amino)ethyl]amino]isoquino[8,7,6-cd]indazole-6(2H)-one trihydrochloride (0.070 g).
Reaction SMILES: C([O:8][CH2:9][CH2:10][C:11]1([C:21]#[N:22])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1)C1C=CC=CC=1>[C].[Pd].C(O)C>[OH:8][CH2:9][CH2:10][C:11]1([C:21]#[N:22])[CH2:20][CH2:19][C:14]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:13][CH2:12]1
Reactant: N#CC1(CCOCc2ccccc2)CCC2(CC1)OCCO2
Agent: [Pd]
Solvent: CCO
Product: N#CC1(CCO)CCC2(CC1)OCCO2
Temperature: 42.5 °C
Reaction time: 0.5 h

Procedure:
To 10 mL of an ethanol solution containing 1.0 g of 8-(2-(benzyloxy)ethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile, 0.50 g of 10% palladium-carbon was added at room temperature, and the mixture was stirred at 40 to 45° C. for 1 hour and 30 minutes under a hydrogen atmosphere. The insoluble material filtered off, and the solvent was removed under reduced pressure to obtained 0.80 g of a colorless oily substance, 8-(2-hydroxyethyl)-1,4-dioxaspiro[4.5]decane-8-carbonitrile.
Reaction SMILES: [O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([OH:18])=O)=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN1CCOCC1.[CH3:50][C:51]1([CH3:65])[C:55]([CH3:57])([CH3:56])[O:54][B:53]([C:58]2[CH:59]=[C:60]([CH:62]=[CH:63][CH:64]=2)[NH2:61])[O:52]1>CN(C=O)C.O>[O:1]=[C:2]1[C:8]2=[CH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]([NH:61][C:60]4[CH:62]=[CH:63][CH:64]=[C:58]([B:53]5[O:54][C:55]([CH3:57])([CH3:56])[C:51]([CH3:65])([CH3:50])[O:52]5)[CH:59]=4)=[O:18])=[CH:14][C:15]=3[N:7]2[CH2:6][CH2:5][CH2:4][NH:3]1
Reactant: CC1(C)OB(c2cccc(N)c2)OC1(C)C
Reactant: O=C(O)c1ccc2cc3n(c2c1)CCCNC3=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC1(C)OB(c2cccc(NC(=O)c3ccc4cc5n(c4c3)CCCNC5=O)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a solution of 1-oxo-2,3,4,5-tetrahydro-1H-[1,4]diazepino[1,2-a]indole-8-carboxylic acid (Intermediate J, 2.3 g, 9.2 mmol) in DMF (30 mL) are added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (3.7 g, 9.7 mmol) and N-methylmorpholine (2.5 mL, 22.5 mmol). The reaction mixture is stirred for 1 h at room temperature and 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.4 g, 11.1 mmol) is added. The reaction mixture is stirred for 16 h at room temperature and is poured into water (200 mL). The resulting solid is collected by filtration, rinsed with water and dried to afford the title compound (3.8 g, 92%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]1([N:18]([OH:30])[C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2O)[CH2:17][CH2:16][CH2:15][CH2:14]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:13]1([N:18]2[C:19](=[O:29])[C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=3[O:30]2)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: COc1ccc(C(=O)N(O)C2CCCC2)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(C3CCCC3)oc2c1
Temperature: 25 °C
Yield: 45.9 %

Procedure:
Diethyl azodicarboxylate was added dropwise to a cooled solution of N-cyclopentyl-N, 2-dihydroxy-4-methoxybenzamide (0.71 g, 2.8 mmol), and triphenylphosphine (0.89 g, 3.4 mmol) in tetrahydrofuran (30 mL) The reaction mixture was warmed to room temperature and quenched with 1:1 CH3OH:CH3CO2H (0.2 mL). Removal of the solvent in vacuo followed by chromatographic separation on silica gel afforded 2-cyclopentyl-6-methoxybenzo[d]isoxazol-3(2H)-one as pale yellow solid (0.3 g, 46%). 1H NMR (300 MHz, DMSO-d6): δ 7.67 (d, 1H, J=8.7 Hz), 6.78 (d, 1H, J=8.6 Hz), 6.32 (s, 1H), 4.35-4.33 (m, 1H), 3.84 (s, 3H), 1.89-1.68 (m, 8H). LC-MS (ESI) Calcd for C13H15NO3 [M+H]+: 234.10. Found: 233.90.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:17]([O-])=O)=[C:11]([CH:14]=[CH:15][CH:16]=1)[NH:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:17][C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=[CH:14][C:11]=1[NH:12][CH3:13]
Reactant: CNc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Agent: NN
Solvent: CO
Solvent: O
Product: CNc1cccc(OCc2ccccc2)c1N
Reaction time: 5 h
Yield: 87.1 %

Procedure:
To a mixture of 3-benzyloxy-N-methyl-2-nitroaniline (453.3 mg), 80% methanol (6.8 ml), anhydrous ferric chloride (13.6 mg) and carbon (13.6 mg) was dropwise added hydrazine monohydrate (255.6 μl) at 70° C., and the mixture was stirred for 5 hours at the same temperature. Insoluble material was filtered off, and the filtrate was concentrated in vacuo. Ethyl acetate and saturated sodium bicarbonate solution were added to the residue, and the organic layer was washed with water and brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate-n-hexane) to give 2-amino-3-benzyloxy-N-methylaniline (348.9 mg).
Reaction SMILES: C([O-])(=O)C.[Na+].[CH3:6][C:7]([CH3:12])([CH3:11])[CH2:8][CH:9]=O.C([BH3-])#N.[Na+].Cl.[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH2:28])=[O:22])[CH3:19]>CO.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH2:18]([O:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[NH:28][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[CH3:6])=[O:22])[CH3:19]
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1N
Reactant: CC(C)(C)CC=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC(C)(C)C
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 33.7 %

Procedure:
Sodium acetate (0.423 g, 5.16 mmol), powdered 4 Å molecular sieves (1.0 g), 3,3-dimethylbutyraldehyde (0.324 mL, 2.58 mmol) and sodium cyanoborohydride (0.324 mg, 5.16 mmol) were added sequentially to a solution of (1R,2S)-2-amino-cyclopentanecarboxylic acid ethyl ester hydrochloride (prepared as described in Example 28b, 0.500 g, 2.58 mmol) in methanol (13 mL) at 25° C. The reaction mixture was stirred at 25° C. for 3.5 h, and then was diluted with ethyl acetate (50 mL) and half-saturated aqueous sodium bicarbonate solution (100 mL). After stirring for 20 min at 25° C., the mixture was filtered through Celite and the filtrate was partitioned between half-saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (2×100 mL). The organic layers were washed with saturated aqueous brine solution (100 mL), dried over sodium sulfate, filtered, and were concentrated in vacuo. The residue was purified by flash column chromatography (Analogix SuperFlash Column; 0-40% ethyl acetate in hexanes) to afford the desired product, (1R,2S)-2-(3,3-dimethyl-butylamino)-cyclopentanecarboxylic acid ethyl ester (0.210 g, 0.87 mmol, 33%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 0.90 (s, 9H), 1.28 (t, 3H, J=7.1 Hz), 1.31-1.40 (m, 2H), 1.55-1.66 (m, 3H), 1.82-2.02 (m, 5H), 2.58 (septet, 2H, J=3.3 Hz), 2.94 (q, 1H, J=7.1 Hz), 3.27 (q, 1H, J=7.0 Hz), 4.14 (q, 2H, J=7.3 Hz). LC-MS (ESI) calcd for C14H27NO2 241.2, found 242.2 [M+H+].
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2)=O)C.[H-].C([Al+]CC(C)C)C(C)C.CO>C1(C)C=CC=CC=1.C(Cl)Cl.C1(C)C=CC=CC=1>[OH:3][CH2:4][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([O:16][CH3:17])=[CH:11][CH:10]=2
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2ncc(CO)cc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.4 %

Procedure:
To a suspension of 5.9 g (25 mmol) of 3-ethoxycarbonyl-6-methoxyquinoline in 120 mL of 1:1 toluene/methylene chloride were added dropwise at -50° C., 36.7 mL (55 mmol) of diisobutylaluminium hydride as a 1.5M solution in toluene. The reaction mixture was gradually warmed to room temperature. To this mixture were added about 4 mL of methanol to quench excess reducing agent, and then water was added with vigorous stirring. After 30 minutes, 150 mL of ethyl acetate and anhydrous magnesium sulfate were added and the mixture was stirred for an additional 30 minutes. The solid was removed by filtration and washed thoroughly with ethyl acetate. The filtrate and washings were combined and evaporated in vacuo. The residue was chromatographed on silica gel, using first ethyl acetate and then 2% ethanol in ethyl acetate as eluents, to give 1.72 g (36.4%) of the title compound as a solid which melts at 92°-93° C. after crystallization from a mixture of benzene and isopropyl ether. TLC Rf =0.17 (ethyl acetate); NMR (CDCl3) δ 8.6 (1H, d), 7.9 (2H, m), 7.3 (1H, q), 6.95 (1H, d), 4.8 (2H, s), 3.85 (3H, s); IR (KBr) ν 3070, 1625, 1500, 1215 cm-1.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)=O)(C)(C)C.Cl[C:19]1[C:20]([C:25]#[N:26])=[N:21][CH:22]=[CH:23][N:24]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CO.ClCCl.O>[N:24]1[C:19]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[C:25]([NH2:26])[C:20]=2[N:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1B(O)O
Reactant: N#Cc1nccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: Nc1nc2ccccc2c2nccnc12
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A solution of 2-(tert-butoxycarbonylamino)phenylboronic acid (1.0 eq.) and 3-chloropyrazine-2-carbonitrile (1.0 eq.) in toluene (0.44 M) was mixed with tetrakis(triphenyl-phosphine)palladium (5 mol %) and 2N aqueous potassium carbonate solution (2.0 eq.). The reaction was heated to 100° C. and stirred overnight. After cooling to ambient temperature, the reaction content was diluted with 2% methanol in dichloromethane and water. The two phases were separated, and the aqueous layer was extracted twice with 2% methanol in dichloromethane. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vacuo. The crude product was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-50% ethyl acetate in hexane to give a solid. 1H NMR (acetone d-6): δ 9.14 (s, 1H), 8.95 (s, 1H), 8.77 (d, 1H), 7.63-7.66 (m, 2H), 7.38 (t, 1H), 6.77 (br, 2H). LRMS [M+H]=197.1
Reaction SMILES: [CH2:1]([NH:3][C:4]1[N:9]=[C:8](O)[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=1)[CH3:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:8]1[CH:7]=[C:6]([CH2:11][CH2:12][CH3:13])[N:5]=[C:4]([NH:3][CH2:1][CH3:2])[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCc1cc(O)nc(NCC)n1
Product: CCCc1cc(Cl)nc(NCC)n1
Temperature: 100 °C
Yield: 90 %

Procedure:
A mixture of 2-ethylamino-4-hydroxy-6-propylpyrimidine (1.81 g, 10 mM) and phosphorus oxychloride (15 ml) was heated at 100° C. for 18 hours. The excess of phosphorus oxychloride was removed under reduced pressure and the residual was decomposed with ice-water (50 ml). The solution was made basic with concentrated aqueous ammonia and extracted with ethyl acetate (3×50 ml). The extracts were combined, dried and the solvent evaporated to give 4-chloro-2-ethylamino-6-propylpyrimidine (1.79 g; 90% yield) as an oil which was used without purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:12])([CH3:11])[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6]1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33](Cl)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]>C(Cl)Cl>[Cl:21][C:22]1[CH:23]=[C:24]([CH:32]([CH2:36][C@H:37]2[CH2:41][CH2:40][C:39]([F:43])([F:42])[CH2:38]2)[C:33]([NH:10][C:7]2[CH:8]=[CH:9][N:5]([CH2:4][C:3]([O:2][CH3:1])([CH3:12])[CH3:11])[N:6]=2)=[O:34])[CH:25]=[CH:26][C:27]=1[S:28]([CH3:31])(=[O:30])=[O:29]
Reactant: COC(C)(C)Cn1ccc(N)n1
Reactant: CS(=O)(=O)c1ccc(C(C[C@H]2CCC(F)(F)C2)C(=O)Cl)cc1Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: COC(C)(C)Cn1ccc(NC(=O)C(C[C@H]2CCC(F)(F)C2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a round bottom flask was placed 1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-ylamine (prepared as in Example 94, 61 mg, 0.36 mmol), 2,6-lutidine (54 μL, 0.49 mmol) and methylene chloride (10 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-propionyl chloride (prepared as in Example 106, ˜0.16 M solution, 2 mL, 0.33 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and then diluted with methylene chloride (10 mL) transferred to a separatory funnel and the layers separated. The aqueous layer was then extracted methylene chloride (3×10 mL). The organics were combined and then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 35% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3,3-difluoro-cyclopentyl)-N-[1-(2-methoxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (as a mixture of two diastereomers, 130 mg, 77%) as an off-white foam: ES-HRMS m/e calcd for C23H30N3O4SClF2 (M+H)+ 518.1687, observed 518.1684; 1H NMR (300 MHz, DMSO-d6) δ 1.04 (s, 3H, CH3), 1.05 (s, 3H, CH3), 1.42 (m, 1H, CH), 1.64-2.31 (m, 8H, 4×CH2), 3.14 (s, 3H, OCH3), 3.34 (s, 3H, SO2CH3), 3.91 (m, 1 H, ArCHCO), 3.97 (s, 2 H, NCH2), 6.45 (d, J=2.2 Hz, 1H, Ar), 7.48 (d, J=2.2 Hz, 1H, Ar), 7.60 (d, Jo=8.2 Hz, 1H, Ar), 7.71 (s, 1H, Ar), 8.02 (d, Jo=8.2 Hz, 1H, Ar), 10.84 (s, 1H, NH).
Reaction SMILES: C(O[C:6]([NH:8][NH:9][CH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1)=O)(C)(C)C.Cl.[C:16]([C:19](=CN(C)C)[C:20]([O:22][CH2:23][CH3:24])=[O:21])(=O)[CH3:17]>C(O)C>[CH:10]1([N:9]2[C:16]([CH3:17])=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=[N:8]2)[CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NNC1CCCC1
Reactant: CCOC(=O)C(=CN(C)C)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCC2)c1C
Yield: 76.3 %

Procedure:
To a solution of 1-cyclopentylhydrazine-2-carboxylic acid tert-butyl ester (18.4 g, 92 mmol) in a mixture of ethanol (300 mL) and conc. HCl (7.7 mL, 92 mmol) was added ethyl 2-acetyl-3-(dimethylamino)acrylate (25.5 g, 0.138 mol). The resulting mixture was refluxed for 2 h. The reaction was concentrated in vacuo, dissolved in CH2Cl2 (300 mL), washed with satd NaHCO3, and brine, dried (Na2SO4), concentrated in vacuo and purified by chromatography on silica gel to give ethyl 1-cyclopentyl-5-methyl-1H-pyrazole-4-carboxylate (15.6 g, 76% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1 H), 4.61 (m, 1 H), 4.15 (q, J=8 Hz, 2 H), 2.29 (s, 3 H), 2.04-1.97 (m, 2 H), 1.89-1.85 (m, 2 H), 1.78-1.71 (m, 2 H), 1.62-1.59 (m, 2 H), 1.23 (t, J=8 Hz, 3 H).
Reaction SMILES: B.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([N:12]([CH2:14][CH2:15][OH:16])[CH3:13])=O.Cl>O1CCCC1>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][N:12]([CH3:13])[CH2:14][CH2:15][OH:16]
Reactant: CN(CCO)C(=O)Cc1ccccc1Cl
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCO)CCc1ccccc1Cl

Procedure:
To 400 ml. of a 1 mol solution of borane in tetrahydrofuran was added dropwise a solution of 43 g. of the above amide in 350 ml. of tetrahydrofuran at a rate sufficient to maintain a gentle reflux. After addition was complete, the solution was refluxed for two hours, cooled in an ice bath and treated carefully with dilute hydrochloric acid to destroy excess borane. The majority of the solvent was removed under vacuum and the residue heated on a steam bath for one hour. The mixture was diluted with 300 ml. of water and extracted with ether. The aqueous layer was made basic with 40% sodium hydroxide and extracted with ether. The combined basic extracts were washed with water and saturated sodium chloride, dried and evaporated to give 2-[[2-(2-chlorophenyl)-ethyl]methylamino]ethanol.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9](=[O:33])[C@@H:10]([NH:22]C(=O)OCC1C=CC=CC=1)[C:11]12[CH2:20][CH:15]3[CH2:16][CH:17]([CH2:19][C:13]([OH:21])([CH2:14]3)[CH2:12]1)[CH2:18]2)#[N:2]>C(#N)C.[Pd]>[CH2:8]1[C@@H:3]([C:1]#[N:2])[N:4]([C:9]([C@@H:10]([NH2:22])[C:11]23[CH2:12][C:13]4([OH:21])[CH2:19][CH:17]([CH2:16][CH:15]([CH2:14]4)[CH2:20]2)[CH2:18]3)=[O:33])[C@@H:5]2[C@H:7]1[CH2:6]2
Reactant: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](NC(=O)OCc1ccccc1)C12CC3CC(CC(O)(C3)C1)C2
Agent: [Pd]
Solvent: CC#N
Product: N#C[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)[C@@H](N)C12CC3CC(CC(O)(C3)C1)C2

Procedure:
To a solution of benzyl N-[(1S)-2-[(1S,3S,5S)-3-cyano-2-azabicyclo[3.1.0]hexan-2-yl]-1-(3-hydroxyadamantan-1-yl)-2-oxo-ethyl]carbamate (10 gm) (formula-IX) in acetonitrile, 5% Pd/C (50% wet, 1 gm) was added. Hydrogen gas was bubbled through the reaction mass for 4 hrs at 20-25° C. After complete conversion of starting material, the reaction mass was filtered, the filtrate was evaporated to yield SAXAGLIPTIN free base of formula-I as a foamy solid. The solid was dissolved in ethyl acetate (50 ml) and concentrated hydrochloric acid (2.4 ml) was added at 5-10° C. The white solid formed was filtered to yield 7.8 gm (99%) of SAXAGLIPTIN dihydrate mono-hydrochloride M.P: 228-230° C., HPLC: 99.7% (A) and the content of the impurity cyclic amidine: 0.05% (A), H1NMR (300 MHz, Methanol-d4): 0.87-1.13 (m, 2H), 1.48-1.7 (m, 12H), 1.89-1.96 (ddd, 1H), 2.19 (s, 1H), 2.22-2.28 (dd, 1H), 2.49 (ddd, 1H), 3.83-3.88 (ddd, 1H), 4.19 (s, 1H), 5.08-5.12 (dd, 1H).