Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH3:17])[C:6]2([CH2:8][CH2:7]2)[C:5](=O)[N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1.C1(C)C=CC=CC=1>[NH2:1][C:2]1([CH3:17])[C:6]2([CH2:8][CH2:7]2)[CH2:5][N:4]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1
Reactant: CC1(N)CN(Cc2ccccc2)C(=O)C12CC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(N)CN(Cc2ccccc2)CC12CC2
Yield: 97.4 %

Procedure:
7-Amino-5-benzyl-4-oxo-7-methyl-5-azaspiro[2.4]heptane (27 g) was dissolved in anhydrous tetrahydrofuran (265 mL) in an argon atmosphere, and the solution was cooled with ice. Lithium aluminum hydride (13.3 g) was added thereto, and the mixture was returned to room temperature. After disappearance of the starting materials had been confirmed, the reaction mixture was cooled with ice. Water (200 mL) and 28% aqueous sodium hydroxide solution (70 mL) were added to cooled mixture, followed by stirring. Toluene was added to the mixture for extraction to separate the organic layer, and the organic layer was washed with saturated brine, followed by drying with sodium sulfate. The desiccant was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield the title product (24.7 g, yield: 98.6%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][NH:25][C:26]([NH:28][NH2:29])=[O:27]>>[CH3:24][NH:25][C:26]([NH:28]/[N:29]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])=[O:27]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CNC(=O)NN
Product: CNC(=O)N/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1

Procedure:
The title compound was prepared in analogy to the synthesis of example 52 from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone and N-methylhydrazine-carboxamide. 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.04 (s, 1H), 9.88 (s, 1H), 8.89 (m, 1H), 8.36 (d, 1H), 8.02 (m, 2H), 7.82 (d, 1H), 7.52 (dd, 1H), 7.45 (m, 1H), 6.17 (s, 2H), 2.74 (d, 3H), 2.31 (s, 3H). LCMS (method B): [MH]+=376, tR=2.95 min.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:13]([O:15][CH2:16][CH3:17])=[O:14])([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:18](O)[CH2:19][OH:20].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.CCOCC>[O:20]1[C:2]2([CH2:3][CH2:4][C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:7]2)[O:1][CH2:18][CH2:19]1
Reactant: OCCO
Reactant: CCOC(=O)C1(C(=O)OCC)CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
The procedure described in Pearson at al., J. Org. Chem., 1997, 62, 5284 was followed with a minor modification. A mixture of diethyl 4-oxocyclohexane-1,1-dicarboxylate, Intermediate 2, (120.6 g, 463 mmol), ethane-1,2-diol (110 mL, 1973 mmol), and para-toluene sulfonic acid mono hydrate (1.0 g, 5.26 mmol) in Benzene (250 mL) was stirred at room temp under N2 for 2 days. The mixture was diluted with Et2O (1 L) and washed with water (300 mL×3), sat'd NaHCO3 (100 mL) and then with brine, dried (MgSO4), and concentrated to dryness to provide the title compound (132.7 g, 463 mmol, 100% yield) as an amber oil HPLC: 2.38 min (AP 70% at 220 nm). LCMS: m/z 287 (M+H). 1H NMR (500 MHz, CDCl3) δ ppm 1.17 (6H, t, J=7.2 Hz, 9,12-CH3), 1.60 (4H, t, J=6.4 Hz, 2,6-CH2), 2.09 (4H, t, J=6.4 Hz, 3,5-CH2), 3.86 (4H, s, 13,14-OCH2), 4.11 (4H, q, J=7.2 Hz, 8,11-OCH2). 13C NMR (126 MHz, CDCl3) δ ppm 14.1 (9,12-CH3), 29.0 (3,5-CH2), 31.6 (2,6-CH2), 53.9 (4-C), 61.3 (8,11-OCH2), 64.3 (13,14-OCH2), 107.7 (1-OCO), 171.2 (7,10-OC═O).
Reaction SMILES: C([O:4][C@H:5]1[C@H:9]([O:10]C(=O)C)[C@@H:8]([CH2:14][O:15]C(=O)C)[O:7][C@H:6]1[N:19]1[C:27]2[CH:26]=[CH:25][NH:24][C:23](=[S:28])[C:22]=2[N:21]=[CH:20]1)(=O)C.[Na]>CO>[C@@H:6]1([N:19]2[C:27]3[CH:26]=[CH:25][NH:24][C:23](=[S:28])[C:22]=3[N:21]=[CH:20]2)[O:7][C@H:8]([CH2:14][OH:15])[C@@H:9]([OH:10])[C@@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(=S)[nH]ccc32)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na]
Solvent: CO
Product: OC[C@H]1O[C@@H](n2cnc3c(=S)[nH]ccc32)[C@@H](O)[C@@H]1O

Procedure:
A solution of 5.0 g of 1-(2,3,5-tri-O-acetyl-β-D-arabinofuranosyl)-1,5-dihydro-4H-imidazo[4,5-c]pyridine-4-thione, 200 ml of methanol, and 54 mg of sodium metholate is heated under reflux for 2 hours and treated with IRC-50 ion exchange resin. The filtrate is evaporated in vacuo and the resulting residue is recrystallized from ethanol-water to provide 1-β-D-arabinofuranosyl-1,5-dihydro-4H-imidazo[4,5-c]pyridine-4-thione.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][O:10][CH3:11].OB(O)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH3:24])=[C:17]([F:25])[CH:16]=1.Cl>[Pd].CO>[F:25][C:17]1[CH:16]=[C:15]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH2:9][O:10][CH3:11])=[C:2]([F:1])[CH:3]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][CH2:23][CH3:24]
Reactant: COCOc1ccc(Br)cc1F
Reactant: CCCOc1ccc(B(O)O)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCCOc1ccc(-c2ccc(OCOC)c(F)c2)cc1F

Procedure:
First, 10.0 g (32.4 mmol) of 3,3′-difluoro-4′-methoxymethoxy-4-propoxybiphenyl [which was obtained by cross-coupling reaction of 3-fluoro-4-methoxymethoxybromobenzene with dihydroxy(3-fluoro-4-propoxyphenyl)borane in the presence of Pd catalyst], 50 ml of methanol, and 10 ml of a concentrated hydrochloric acid were heated to reflux for 3 hours. Then, 50 ml of water was added to the reaction solution and extracted with 150 ml of diethyl ether. The organic layer thus obtained was washed with a diluted aqueous sodium bicarbonate solution twice and with water thrice, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure to obtain 8.5 of a crude 3,3′-difluoro-4′- hydroxy-4-propoxybiphenyl. (Yield: 99.8%)
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([O:30][CH3:31])=[C:27]([OH:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:24]1/[C:23]([NH2:22])=[CH:28][C:27](=[O:29])[C:26]([O:30][CH3:31])=[CH:25]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: COc1ccc(N)cc1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: COC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=CC1=O

Procedure:
0.05 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulfonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.05 mmol of 5-amino-2-methoxyphenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:26])[CH2:9][CH:10]([OH:25])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)([CH3:6])([CH3:5])[CH3:4].[CH3:27]I>CN(C)C=O>[C:3]([O:7][C:8](=[O:26])[CH2:9][CH:10]([O:25][CH3:27])[CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:17][CH:18]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)CC(O)CCc1ccc(-c2ccccc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(CCc1ccc(-c2ccccc2)cc1)CC(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 35.2 %

Procedure:
Sodium hydride (60%; 7.0 mg, 0.17 mmol) was added to a stirred solution of 5-biphenyl-4-yl-3-hydroxy-pentanoic acid tert-butyl ester (Intermediate 3, 50 mg, 0.15 mmol) in dimethylformamide (0.5 mL) at 0° C. under nitrogen. After stirring for 5 minutes methyl iodide (14 μL, 0.23 mmol) was added and stirring continued for 12 hours. The volatiles were evaporated under reduced pressure and the residue partitioned between dichloromethane (5 mL) and water (5 mL). The phases were separated and the organic phase dried (MgSO4), then the solvent evaporated. The residue was purified by column chromatography on silica gel (1:8 diethyl ether:cyclohexane) to give the title compound (18 mg, 35%) as a colourless gum. LC/MS: 3.87 min; z/e 358, calcd (M+NH4) 358. 1H NMR (400 MHz: CDCl3): 7.59 (2 H), 7.53 (2 H), 7.42 (2 H), 7.28 (3 H), 3.68 (1 H), 3.40 (3 H), 2.77 (2 H), 2.56 (1 H), 2.38 (1 H), 1.88 (2 H), 1.47 (9 H).
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[C:13]([CH:15]=[CH:16][O:17][CH3:18])[CH:12]=[CH:11][C:10]=1[O:19][CH3:20].C1(N=C=O)C=CC=CC=1.[N+:30]([CH2:33][CH3:34])([O-])=[O:31]>C1(C)C=CC=CC=1.O>[Br:8][C:9]1[CH:14]=[C:13]([CH:15]2[CH:16]([O:17][CH3:18])[O:31][N:30]=[C:33]2[CH3:34])[CH:12]=[CH:11][C:10]=1[O:19][CH3:20]
Reactant: CC[N+](=O)[O-]
Reactant: COC=Cc1ccc(OC)c(Br)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccc(C2C(C)=NOC2OC)cc1Br
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Triethylamine (0.050 mL, 0.36 mmol) was added in portions to a mixture of 2-bromo-1-methoxy-4-(2-methoxyvinyl)benzene (500 mg, 2.06 mmol, 1:1 ratio of E- and Z-isomers), phenylisocyanate (0.489 mL, 4.5 mmol), and nitroethane (0.180 mL, 2.5 mmol) in dry toluene (2.0 mL) at room temperature. After stirring at room temperature for 5 h followed by 1 h at 100° C. for 1 h, the mixture was allowed to stand overnight at room temperature. Water (6 mL) was then added and stirring was continued at room temperature for 4 h. The mixture was filtered, the layers of the filtrate were separated, and the aqueous layer was extracted with 2×30 mL of toluene. The combined organic layers were dried over sodium sulfate and evaporated. Flash column chromatography on 50 g of silica gel eluting with 2 L of 10% of ethyl acetate/hexane yielded 4-(3-bromo-4-methoxyphenyl)-5-methoxy-3-methyl-4,5-dihydroisoxazole as 0.28 g of yellow oil containing some remaining impurity. 1H NMR (400 MHz, CDCl3): δ 7.33 (d, 1H, J=2 Hz), 7.03(dd, 1H, J=9, 2 Hz), 6.87 (d, 1H, J=9 Hz), 5.15 (d, 1H, J=1 Hz), 3.89 (s, 3H), 3.88 (s, 1H), 3.47 (s, 3H), 1.83 (s, 3H). Mass spectrum (NH3CI): m/e=300 (M+1).
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([S:16][CH3:17])[N:14]=3)[CH:9]=[CH:8][S:7]2(=[O:19])=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1>ClCCl.CO>[CH:1]1([N:6]2[C:15]3[C:10](=[CH:11][N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=3)[CH:9]=[CH:8][S:7]2(=[O:18])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSc1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1ncc2c(n1)N(C1CCCC1)S(=O)(=O)C=C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
1-Cyclopentyl-7-methylsulfanyl-2-thia-1,6,8-triaza-naphthalene 2,2-dioxide (6.0 g, 20 mmol) prepared as in Example 1 and 2-benzenesulfonyl-3-phenyl-oxaziridine (6.3 g, 24 mmol) were dissolved in 50% dichloromethane in methanol (75 ml) and stirred overnight at room temperature. Following evaporation of the solvent, the crude product was purified by recrystallization in diethyl ether/methanol to yield 5.22 g (83% yield) 1-Cyclopentyl-7-methylsulfinyl-1H-thia-1,6,8-triaza-naphthalene 2,2-dioxide as a white solid MS: APCI: M+1: 314.1 (M: 314.3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]([O:15]CC)=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8].ClC1C=C(C(OCC)=O)C(=O)N(C(C)C)C=1C>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([OH:15])=[O:14])[C:5](=[O:12])[N:6]([CH:9]([CH3:11])[CH3:10])[C:7]=1[CH3:8]
Reactant: CCOC(=O)c1cc(Br)c(C)n(C(C)C)c1=O
Agent: CCOC(=O)c1cc(Cl)c(C)n(C(C)C)c1=O
Product: Cc1c(Br)cc(C(=O)O)c(=O)n1C(C)C

Procedure:
The title compound was prepared according to the procedure of Example 1(7), but using ethyl 5-bromo-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate as prepared in 4(1) instead of ethyl 5-chloro-1-isopropyl-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH2:9][CH2:8][CH2:7][C:6]=1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C4C(=CC=CC=4)N=C(C)C=3)=[CH:17][CH:16]=2)[CH2:11]1)=[O:4]>C(OCC)(=O)C.CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][C@@H:6]1[CH:10]1[O:14][N:13]=[C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH2:11]1)=[O:4]
Reactant: COC(=O)C1=C(C2CC(c3ccc(OCc4cc(C)nc5ccccc45)cc3)=NO2)CCC1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCC[C@@H]1C1CC(c2ccc(O)cc2)=NO1
Reaction time: 3 h
Yield: 100 %

Procedure:
2-{3-[4-(2-Methyl-quinolin-4-ylmethoxy)-phenyl]-4,5-dihydro-isoxazol-5-yl}-cyclopent-1-enecarboxylic acid methyl ester intermediate from Example 27, was dissolved in ethyl acetate:methanol (1:1) (20 mL), degassed with nitrogen, and charged with 10% palladium on carbon and 50 PSI hydrogen. The reaction was shaken for 3 h, filtered, and concentrated to give cis-2-[3-(4-hydroxy-phenyl)-4,5-dihydro-isoxazol-5-yl]-cyclopentanecarboxylic acid methyl ester (0.127 g, 100%) as an oil. MS found: (M+H)+=290.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:18]([O:21][CH:22]1[CH2:27][CH2:26][CH:25]([CH:28]2[CH2:33][CH2:32][CH:31](OS(C)(=O)=O)[CH2:30][CH2:29]2)[CH2:24][CH2:23]1)[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([CH:31]3[CH2:30][CH2:29][CH:28]([CH:25]4[CH2:24][CH2:23][CH:22]([O:21][CH2:18][CH2:19][CH3:20])[CH2:27][CH2:26]4)[CH2:33][CH2:32]3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)[CH3:2]
Reactant: CCCOC1CCC(C2CCC(OS(C)(=O)=O)CC2)CC1
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOC1CCC(C2CCC(N3CCN(c4ccc(C(=O)OCC)cc4)CC3)CC2)CC1
Temperature: 130 °C
Reaction time: 8 h
Yield: 13 %

Procedure:
A mixture of 4-piperazinylbenzoic acid ethyl ester (1.03 g), 4′-propoxy-4-methylsulfonyloxy-1,1′-bicyclohexane (1.4 g), potassium carbonate (0.91 g) in N,N-dimethylformamide (10 ml) was stirred for 8 hours at 130° C. The reaction mixture was poured into water, and extracted with ethyl acetate. The organic layer was washed with brine and dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on a column of silica gel eluting with dichloromethane/methyl alcohol (200:1) to give 4-[4-(4′-propoxy-1,1′-bicyclohexan-4-yl)piperazin-1-yl]benzoic acid ethyl ester (0.26 g).
Reaction SMILES: [ClH:1].O1CCO[CH2:4][CH2:3]1.Cl.[C:9]1([C@H:19]([NH:21][CH2:22][C@@H:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][N:25]([C:34](=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])[CH2:24]2)[CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1>C(O)C>[ClH:1].[C:9]1([C@H:19]([NH:21][CH2:22][C@@H:23]2[C@@H:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:26][N:25]([C:34](=[O:42])[CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:3][CH3:4])=[O:40])[CH2:24]2)[CH3:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1
Reactant: C[C@@H](NC[C@H]1CN(C(=O)CCCCC(=O)O)C[C@@H]1c1ccccc1)c1cccc2ccccc12
Reactant: C1COCCO1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CCCCC(=O)N1C[C@H](CN[C@H](C)c2cccc3ccccc23)[C@@H](c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 2.0 ml portion of 4 M hydrogen chloride/1,4-dioxane was added to a 5.0 ml ethanol solution of 200 mg of 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoic acid hydrochloride and stirred at room temperature for 1Hour. By evaporating the solvent and crystallizing the residue from ethyl acetate-hexane, 154 mg of ethyl 6-[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]-6-oxohexanoate hydrochloride was obtained as a colorless solid.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N:19][CH:20]=1)([O-:14])=[O:13].[O-]S([O-])(=S)=O.[Na+].[Na+].[OH-].[Na+]>C(Cl)Cl>[N+:12]([C:15]1[C:16]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])[CH2:25]2)=[C:17]2[CH2:23][CH2:22][CH2:21][C:18]2=[N+:19]([O-:9])[CH:20]=1)([O-:14])=[O:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CCCN(c2c([N+](=O)[O-])c[n+]([O-])c3c2CCC3)C1
Temperature: 25 °C
Reaction time: 67 h
Yield: 88.1 %

Procedure:
m-Chloroperbenzoic acid (198 mg, 0.883 mmol) was slowly added to a solution of tert-butyl [(3S)-1-(3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)piperidin-3-yl]carbamate (301.0 mg, 0.8305 mmol) in DCM (1.06 mL) at 0° C. The reaction mixture was stirred at room temperature for 67 h. The mixture was treated with aq, Na2S2O3 and 1 M NaOH, and then stirred for 30 min. at room temperature. The reaction mixture was extracted three times with DCM. The combined organic extract was dried over Na2SO4, filtered and concentrated under reduced pressure to give the sub-title compound (277 mg, 88%) as light orange powder. LCMS calc. for C18H27N4O5 (M+H)+: m/z=379.3. Found: 379.2.
Reaction SMILES: I[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[N:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[N:3]=2)[CH:28]=[N:29][CH:30]=1
Reactant: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(I)nc21
Reactant: OB(O)c1cncc(Cl)c1
Product: CC(C)n1cnc2c(NCCc3ccc(O)cc3)nc(-c3cncc(Cl)c3)nc21

Procedure:
Following the procedure of Example 15d, 4-(2-(2-iodo-9-isopropyl-9H-purin-6-ylamino)ethyl)phenol (b) was reacted with 5-chloropyridin-3-ylboronic acid. The crude product was purified by reverse-phase HPLC(C18 column, eluting with ACN—H2O 0.05% TFA) to afford the title compound as an off-white solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]2[CH:9]=[CH:10][N:11]=[C:5]2[CH:4]=1)#[CH:2].C[Si]([N:16]=[N+:17]=[N-:18])(C)C.CN(C=O)C>[Cu]I.CO>[NH:16]1[CH:2]=[C:1]([C:3]2[CH:8]=[CH:7][N:6]3[CH:9]=[CH:10][N:11]=[C:5]3[CH:4]=2)[N:18]=[N:17]1
Reactant: C#Cc1ccn2ccnc2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Product: c1cn2ccc(-c3c[nH]nn3)cc2n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 57.2 %

Procedure:
Combine 7-ethynyl-imidazo[1,2-a]pyridine (1.10 g, 7.74 mmol), copper (I) iodide (0.074 g, 0.387 mmol), and trimethylsilyl azide (1.53 mL, 11.61 mmol) in a 9:1 mixture of DMF:methanol (13.8 mL) in a pressure flask. Seal the flask with a Teflon screw cap and heat the reaction mixture to 100° C., stir overnight (15 hours), and cool to room temperature. Concentrate the mixture to dryness in vacuo. Slurry the resulting solid into dichloromethane and filter through Celite® 521. Concentrate the solution in vacuo to an orange solid. Purify by column chromatography (ethyl acetate→5% methanol in dichloromethane→8% methanol in dichloromethane) to afford product (0.82 g, 57%). MS(ES), m/z 186 (M+1).
Reaction SMILES: [C:1]([C:5]1[CH:25]=[CH:24][C:8]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=O)=[C:7]([Cl:26])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C1COCC1>[C:1]([C:5]1[CH:25]=[CH:24][C:8]([CH2:9][NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[C:7]([Cl:26])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C(=O)NCCc2cccc(C(F)(F)F)c2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)c(Cl)c1
Yield: 89.9 %

Procedure:
2.31 ml (2.31 mmol) of a 1M borane-THF complex solution in THF were added under nitrogen at rt to 295 mg (0.77 mmol) of 4-tert-butyl-2-chloro-N-[2-(3-trifluoromethyl-phenyl)-ethyl]-benzamide dissolved in 4 ml THF. The reaction mixture was heated to reflux over night. At rt 7 ml 2N aqueous HCl solution were added and the reaction mixture was heated to reflux for 3 h. The reaction mixture was basified with 7 ml 2N aqueous NaOH solution and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated. The residue was purified by column chromatography (45 g silica gel; DCM/methanol 19:1) to yield 256 mg (81%) (4-tert-butyl-2-chloro-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine as a yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.58-7.52 (m, 5H), 7.6 (d, 1H), 7.34 (s, 1H), 7.30 (d, 1H), 3.75 (s, 2H), 2.81 (m, 4H), 1.26 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][N:6]=1)=[O:4].[F:12][C:13]([F:20])([F:19])[C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:16]2[CH:17]=[CH:18][C:14]([C:13]([F:20])([F:19])[F:12])=[N:15]2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(Cl)cn1
Reactant: FC(F)(F)c1cc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2ccc(C(F)(F)F)n2)cn1
Temperature: 105 °C
Yield: 3.2 %

Procedure:
A mixture of 5-chloro-pyridine-2-carboxylic acid methyl ester (1.37 g), 3-trifluoromethyl-1H-pyrazole (1.63 g) and powdered K2CO3 (1.67 g) in DMF (20 ml) was heated to 105° C. for 20 h. The mixture was evaporated and the residue partitioned between water and dichloromethane, the organic layer was washed with water, dried and evaporated. The residue was chromatographed on silica using n-heptane/ethyl acetate (gradient from 3:1 to 1:1) to give 5-(3-trifluoromethyl-pyrazol-1-yl)-pyridine-2-carboxylic acid methyl ester (70 mg) as a colorless solid. MS (ESI): m/z=272.1 [ M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:13]1([C@@H:19]([NH2:21])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>FC(F)(F)S([O-])(=O)=O.[Yb+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[C:13]1([C@@H:19]([NH:21][C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=2[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: C[C@H](N)c1ccccc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Product: CCOC(=O)C1=C(N[C@@H](C)c2ccccc2)CCCC1
Temperature: 3 °C
Yield: 111.6 %

Procedure:
Ethyl 2-oxocyclohexane carboxylate (6, 484.9 g) and (S)-(−)-1-phenylethylamine (7, 362.5 g) were charged into an RB flask followed by heptanes (1.5 L) and Ytterbium (III) trifluoromethane sulfonate (8.8 g). The contents were heated to reflux for 3 hours and the liberated water was removed simultaneously and then cooled to 22° C. (±3° C.). The insoluble material was filtered and the filtrate was concentrate on a rotary evaporator under vacuum to afford 869.4 g of (S)-ethyl 2-(1-phenylethylamino)cyclohex-1-enecarboxylate (8) as an oil.