Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[CH:12]=1.C(O)(=O)C.[N-:17]=[N+]=[N-].[Na+].S(=O)(=O)(O)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[NH:17][C:6]=2[CH:12]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCSc2ccc(F)cc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCSc2ccc(F)cc2N1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75.1 %

Procedure:
6-fluoro-2,3-dihydro-4H-1-benzothiopyran-4-one (100 mg, 0.54 mmol) was dissolved in acetic acid (0.5 mL, 1.1 eq), sodium azide (71.2 mg, 1.1 mmol) was added and mixture was heated to 50° C. Sulfuric acid (0.13 mL, 4.3 eq) was added slowly and stirred at 50° C. for 1.5 hours. Ice chips (150 mg) were added and a green solid precipitated, this was filtered, washed with water and dried to give 7-fluoro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one (80 mg, 24%). 1H NMR (CDCl3, 300 MHz): δ 7.77 (s-broad, 1H), 7.69 (t, 1H, J=7.3 Hz), 6.94–6.82 (m, 2H), 3.42 (t, 2H, J=7 Hz), 2.63 (t, 2H, J=6.7 Hz) ppm.
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=12.[NH2:13][C@@H:14]([CH3:30])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[C:23]([Cl:29])[CH:22]=2)=[N:17]1>>[Cl:29][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[N:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[CH3:30])[N:17]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: O=C(O)c1cn2ccncc2n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccncc2n1
Yield: 90 %

Procedure:
The title compound was prepared as described in Example 34(d), starting from imidazo[1,2-a]pyrazine-2-carboxylic acid (0.163 g, 0.997 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.2 g, 0.767 mmol). The product was purified with flash-chromatography. Yield 90%. 1H-NMR (400 MHz; CDCl3): δ 1.18 (d, 3H), 4.35 (dd, 1H), 4.43 (dd, 1H), 4.47-4.57 (m, 1H), 6.93 (d, 1H), 7.85 (d, 1H), 7.94-8.00 (m, 3H), 8.03-8.06 (m, 1H), 8.47 (d, 1H), 8.60 (dd, 1H), 8.73 (d, 1H), 9.14-9.16 (m, 1H).
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1.Cl[C:42]1[N:47]=[C:46]([O:48][CH3:49])[N:45]=[C:44]([O:50][CH3:51])[N:43]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:51][O:50][C:44]1[N:45]=[C:46]([O:48][CH3:49])[N:47]=[C:42]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:43]=1
Reactant: COc1nc(Cl)nc(OC)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)nc(OC)n1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
Palladium acetate (5.0 mg, 0.022 mmol) and (2-biphenylyl) dicyclohexylphosphine (16 mg, 0.046 mmol) were dissolved under an atmosphere of argon in dioxane (2 mL) and stirred for 10 min at 20° C. This solution was added at 20° C. under an atmosphere of nitrogen to a flask containing 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (116 mg, 0.57 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (100 mg, 0.57 mmol) and potassium carbonate (1.57 g, 11.4 mmol) in 3 ml of dioxane. The resulting mixture was refluxed over night under argon, poured into a saturated aqueous solution of sodium chloride and extracted 3 times with ethyl acetate. The organic layer was dried, evaporated and the residue purified by column chromatography on silica gel using dichloromethane/methanol (98:2 v/v) as eluent to yield the title compound (18 mg, 9%) as a yellowish solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>O.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(O)C.C1(C)C=CC=CC=1>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[N:7]=[C:6]([CH3:8])[NH:5][C:4]3=[CH:9][C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:11][C:3]=23)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: [Pd]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(Cl)cc2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 25 °C
Yield: 47.7 %

Procedure:
A mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (50 mg, 0.21 mmol), 4-chlorophenylboronic acid (Aldrich Chemical Company) (39 mg, 0.25 mmol), tris(dibenzylide-neacetone) dipalladium(0) (Aldrich Chemical Company) (4.7 mg, 0.0051 mmol) and triphenylphosphine (Aldrich Chemical Company) (5.4 mg, 0.021 mmol) in a mixed solvent (600 μL of toluene, 300 μL of 1.0 M Na2CO3, and 150 μL of ethanol) was heated at reflux under N2 for 20 h. Upon cooling to the room temperature, the reaction mixture was diluted with H2O (20 mL) and extracted with CHCl3 (3×15 mL), dried over Na2SO4 and concentrated with a rotary evaporator. The crude material was purified by flash chromatography on silica gel with a gradient eluant of EtOAc(0-25%):hexanes(100-75%) to afford 32 mg (49%) of the title compound as a yellow solid. Mp: 281-283° C. 1H NMR (Acetone-d6; 400 MHz): δ 10.89 (s, 1), 8.18 (d, 2, J=8.5), 8.02 (d, 2, J=7.4), 7.60 (d, 2, J=8.5), 7.53 (t, 2, J=7.4) 7.46 (t, 1, J=7.4), 7.01 (s, 1), 2.72 (s, 3). MS m/z: 320 (M+1), 318 (M−1). HRMS (NBA-NaI) m/z Calcd for M+H, C19H14ClN3: 320.0955. Found: 320.0961.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12](B3OC(C)(C)C(C)(C)O3)=[CH:13][C:8]=2[O:7][C:6]=1[CH3:23])=[O:4].Br[C:25]1[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31]2[N:35]([C:36]3[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=3[Cl:43])[N:34]=[CH:33][C:32]=2[CH:44]([CH3:46])[CH3:45])=[CH:27][C:26]=1[CH3:49].N#N.C1(P(C2CCCCC2)C2(OC)CC=CC(OC)=C2C2C=CC=CC=2)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[C:9]2[CH:10]=[CH:11][C:12]([C:25]3[CH:48]=[CH:47][C:28]([O:29][CH2:30][C:31]4[N:35]([C:36]5[C:41]([Cl:42])=[CH:40][CH:39]=[CH:38][C:37]=5[Cl:43])[N:34]=[CH:33][C:32]=4[CH:44]([CH3:45])[CH3:46])=[CH:27][C:26]=3[CH3:49])=[CH:13][C:8]=2[O:7][C:6]=1[CH3:23])=[O:4]
Reactant: COC(=O)c1c(C)oc2cc(B3OC(C)(C)C(C)(C)O3)ccc12
Reactant: Cc1cc(OCc2c(C(C)C)cnn2-c2c(Cl)cccc2Cl)ccc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COC1=C(c2ccccc2)C(OC)(P(C2CCCCC2)C2CCCCC2)CC=C1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(C)oc2cc(-c3ccc(OCc4c(C(C)C)cnn4-c4c(Cl)cccc4Cl)cc3C)ccc12
Temperature: 110 °C
Reaction time: 16 h
Yield: 30.8 %

Procedure:
A solution of 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzofuran-3-carboxylic acid methyl ester (162 mg, 0.512 mmol) and 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-pyrazole (256 mg, 0.563 mmol) in toluene (5 mL) is evacuated and refilled with N2 three times. Pd(OAc)2 (11.5 mg, 0.051 mmol), 2-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl (42 mg, 0.102 mmol), and potassium phosphate (tribasic, N-hydrate, 218 mg, 1.02 mmol) in 0.5 mL of water are added. The resulting mixture is evacuated and refilled with N2 three times. The mixture is stirred at 110° C. for 16 hours and cooled to room temperature. The mixture is filtered through a pad of celite, and the filtrate is concentrated. The residue is purified by silica gel chromatography with 25% EtOAc/Hexanes to provide the product 6-{4-[2-(2,6-dichloro-phenyl)-4-isopropyl-2H-pyrazol-3-ylmethoxy]-2-methyl-phenyl}-2-methyl-benzofuran-3-carboxylic acid methyl ester (89 mg, 31%). ES/MS m/e 564.8 (M+1).
Reaction SMILES: [Na+].[Cl-].[OH:3]C1C(CC=C(C)C)=C(O)C=CC=1CCCC1C=CC(O)=CC=1.CC(C)=CC[C:30]1[C:31]([OH:49])=[CH:32][CH:33]=[C:34]2[C:39](=[O:40])[CH2:38][C@@H:37]([C:41]3[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][C:46]=3O)[O:36][C:35]=12>CO>[CH2:38]1[C:39](=[O:40])[C:34]2[C:35](=[CH:30][C:31]([OH:49])=[CH:32][C:33]=2[OH:3])[O:36][C@@H:37]1[C:41]1[CH:42]=[CH:43][C:44]([OH:48])=[CH:45][CH:46]=1
Reactant: CC(C)=CCc1c(O)ccc(CCCc2ccc(O)cc2)c1O
Reactant: CC(C)=CCc1c(O)ccc2c1O[C@H](c1ccc(O)cc1O)CC2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Product: O=C1C[C@@H](c2ccc(O)cc2)Oc2cc(O)cc(O)c21

Procedure:
Colorless needles; [α]D20 −7.3° (c 0.15, MeOH); UV (MeOH) λmax (log ε) 288 (3.79), 226 (3.93), 216 (3.92) nm; CD (MeOH) nm Δε271 −5.5; IR (NaCl) γmax 3350, 2927, 1636, 1558 cm−1; 1H NMR (CD3OD, 500 MHz) δ 2.69 (1H, dd, J=2.9 and 17.1 Hz, H-3), 3.10 (1H, dd, J=13.0 and 17.2 Hz, H-3), 5.33 (1H, dd, J=2.9 and 12.9 Hz, H-2), 5.87 (1H, d, J=2.2 Hz, H-6), 5.88 (1H, d, J=2.2, 8.7 Hz, H-8), 6.80 (2H, d, J=8.6 Hz, H-3′), 7.30 (2H, d, J=8.4 Hz, H-2′); 13C NMR (CD3OD, 125 MHz) δ 42.6 (C-3), 79.1 (C-2), 94.8 (C-8), 95.7 (C-6), 101.9 (C-10), 114.9 (C-3′), 127.6 (C-2′), 129.7 (C-1′), 157.6 (C-4′), 163.5 (C-9), 164.1 (C-5), 167.2 (C-7), 196.3 (C-4); EIMS m/z 272 (M+, 88), 239 (6), 190 (15), 179 (24), 153 (100), 120 (50).
Reaction SMILES: [F:1][CH:2]([F:16])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].[Cl:17][C:18]1[C:31]([N:32]=[C:33]=S)=[C:30]([Cl:35])[CH:29]=[CH:28][C:19]=1[CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].FC(F)(F)C(=N[Si](C)(C)C)O[Si](C)(C)C.CC(C)N=C=NC(C)C>CC(O)=O.CC#N>[Cl:17][C:18]1[C:19]([CH2:20][NH:21][C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])=[CH:28][CH:29]=[C:30]([Cl:35])[C:31]=1[NH:32][C:33]1[NH:14][C:12]2[CH:13]=[C:5]([O:4][CH2:3][CH:2]([F:16])[F:1])[C:6]([C:7]([OH:9])=[O:8])=[CH:10][C:11]=2[N:15]=1
Reactant: Nc1cc(OCC(F)F)c(C(=O)O)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Agent: C[Si](C)(C)N=C(O[Si](C)(C)C)C(F)(F)F
Solvent: CC#N
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(Nc2nc3cc(C(=O)O)c(OCC(F)F)cc3[nH]2)c1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-(2,2-difluoro-ethoxy)-4,5-diamino-benzoic acid (732 mg, 3.15 mmol), N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (1.00 g, 3.15 mmol) and MeCN (15 mL) is stirred for 48 h, then BSTFA (1.03 mL, 3.15 mmol) is added and it is stirred at reflux for 10 min. Then DIC (0.494 mL, 3.15 mmol) is added and it is stirred for another 4 h. The mixture is cooled to rt, diluted with HOAc and concentrated. The residue is stirred with 1N NaOH, filtered and the filtrate is acidified with 4N HCl, extracted with EtOAc and purified via chromatography [DCM→DCM+10% EtOH/HOAc (95:5)] to give the subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([CH2:21][O:22][CH3:23])[N:3]=1.[OH-].[Na+].[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][Cl:33].Cl.[N:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41]Cl>O.CO>[N:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][Cl:33].[CH3:23][O:22][CH2:21][C:4]1[N:3]=[C:2]([NH2:1])[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH2:41][C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][N:35]=4)=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=1
Reactant: COCc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Agent: Cl
Agent: ClCc1ccccn1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCc1ccc(-c2cc(Cc3ccc(OCc4ccccn4)cc3)no2)c(N)n1
Reaction time: 1.67 h
Yield: 52 %

Procedure:
To a methanol (1.5 mL) solution of 4-(5-(2-amino-6-methoxymethyl-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (50 mg, 0.16 mmol) described in Manufacturing Example 166-1-1 was added a 1 N sodium hydroxide aqueous solution (160 μL, 0.16 mmol), which was concentrated under a reduced pressure. N,N-dimethylformamide (1.5 mL) was added to the residue thus obtained at room temperature, and 2-picolyl chloride (29 mg, 0.23 mmol; this 2-picolyl chloride was prepared by adding a 5 N sodium hydroxide aqueous solution to 2-picolyl chloride hydrochloride) was added to the reaction mixture at the same temperature. The reaction mixture was stirred for 100 minutes at the same temperature. Water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=4:1) to obtain the title compound (32 mg, 52%).
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].[Cl:28]N1C(=O)CCC1=O.O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+]>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Cl:28])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1Br)-c1c(Cl)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a solution of 66 mg of 19d in 1 ml of DMF was added at 0° C. 27 mg of N-chlorosuccinimide. The mixture was stirred for 2 h. Then, 5 ml of water was added and 1 drop of a sat. Na2S2O3 solution. Stirring was continued for 5 min and the product was extracted into ethyl acetate. The extract was washed with water, dried, concentrated and the residue was treated with cold pentane, to provide 65 mg of 19e as a white crystalline material; Mp 203-205° C. MS-ESI: [M+1] 464.12, 465.10, 466.09, 467.08, 468.08 and 469.07.
Reaction SMILES: C[O:2][C:3](=[O:29])[CH2:4][CH:5]1[CH2:28][CH2:27][C:8]2([CH2:13][CH2:12][N:11]([C:14]([O:16][CH:17]3[CH:24]4[CH2:25][CH:20]5[CH2:21][CH:22]([CH2:26][CH:18]3[CH2:19]5)[CH2:23]4)=[O:15])[CH2:10][CH2:9]2)[CH2:7][CH2:6]1.O.O[Li].O.C(O)(C(F)(F)F)=O>C1COCC1.C(O)(=O)C.CO>[CH:18]12[CH2:26][CH:22]3[CH2:21][CH:20]([CH2:25][CH:24]([CH2:23]3)[CH:17]1[O:16][C:14]([N:11]1[CH2:10][CH2:9][C:8]3([CH2:27][CH2:28][CH:5]([CH2:4][C:3]([OH:29])=[O:2])[CH2:6][CH2:7]3)[CH2:13][CH2:12]1)=[O:15])[CH2:19]2
Reactant: COC(=O)CC1CCC2(CC1)CCN(C(=O)OC1C3CC4CC(C3)CC1C4)CC2
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1CCC2(CC1)CCN(C(=O)OC1C3CC4CC(C3)CC1C4)CC2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(2-Adamantyl) 9-(2-methoxy-2-oxoethyl)-3-azaspiro[5.5]undecane-3-carboxylate (30 mg, 74 μmol) was dissolved in THF (0.25 mL), water (0.25 mL) and MeOH (0.5 mL) and LiOH.H2O (8 mg, 0.19 mmol) was added. The mixture was stirred at rt for 2 d and TFA (10 mL, 0.14 mmol) was added. The solution was submitted directly to prep HPLC to afford 2-(34(2-adamantyl)oxycarbonyl)-3-azaspiro[5.5]undecan-9-yl)acetic acid (10.5 mg, 36%). LC-MS Method 1 tR=2.17 min, m/z=390; 1H NMR (CDCl3) δ=1.0-2.05 (27H), 2.27 (d, 2H), 3.44 (m, 4H), 4.83 (s, 1H).
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:11]1[CH:12]=[N:13][CH:14]=[N:15][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.O1CCOCC1>[N:13]1[CH:12]=[C:11]([NH:9][C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:8])[CH:16]=[N:15][CH:14]=1
Reactant: Brc1cncnc1
Reactant: NC(=O)C1CCCCC1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C(Nc1cncnc1)C1CCCCC1
Temperature: 110 °C
Yield: 75 %

Procedure:
An oven-dried resealable Schlenk tube containing a stirbar was charged with CuI (20 mg, 0.1 mmol, 10 mol %), cyclohexanecarboxamide (153 mg, 1.2 mmol), 5-bromopyrimidine (160 mg, 1 mmol), and K3PO4 (425 mg, 2 mmol), evacuated and backfilled with argon. N,N′-Dimethylethylenediamine (8.9 mg, 0.1 mmol) and dioxane (1 ml) were injected, and under a flow of argon, the septum was replaced by a Teflon screw cap. The tube was sealed, and the mixture was stirred and heated in an oil bath at 110° C. for 16 h. The contents of the tube were then partitioned between water and dichloromethane. The aqueous layer was separated, and extracted two times with additional dichloromethane. The organics were then combined, dried over Na2SO4, filtered, concentrated under reduced pressure. The residue was chromatographed on silica gel followed by recrystallization from dichloromethane/hexane to give 154 mg (75%) of the title compound as a solid. 1H NMR (CDCl3, 300 MHz): δ 9.02 (s, 2H), 8.97 (s, 1H), 7.40 (br s, 1H), 2.32 (tt, 1H, J=3.6, 11.4 Hz), 2.10-1.20 (m, 10H).
Reaction SMILES: [CH:1]1[N:6]=[C:5](Cl)[C:4]2[N:8]=[CH:9][N:10]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:3]=2[N:2]=1.[NH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>C(O)C>[N:23]1([CH2:22][CH2:21][NH:20][C:5]2[C:4]3[N:8]=[CH:9][N:10]([C:3]=3[N:2]=[CH:1][N:6]=2)[C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2[OH:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCCN1CCCCC1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Solvent: CCO
Solvent: CCN(CC)CC
Product: OC[C@H]1O[C@@H](n2cnc3c(NCCN4CCCCC4)ncnc32)[C@H](O)[C@@H]1O

Procedure:
The experiment of Example 1 was repeated in every essential detail except for the following. The suspension was prepared using 2.0 g (6.98 mmol) of the 6-chloropurine riboside in 30 ml of absolute ethanol. 1-(2-Aminoethyl) piperidine (commercially available) was added in an amount of 1.07 g (0.7 ml, 8.3 mmol). Also added to this suspension was 1.5 ml (10.5 mmol) of triethylamine. The reaction mixture was refluxed for 72 hours. The resulting residue was chromatographed on a silica gel column eluting with an eluent of 20 parts methanol, 79 parts dichloromethane and one part ammonium hydroxide. The title product was produced in a yield of 1.1 g (42%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[O:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[C:4]=1[CH3:16].[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([CH2:25][OH:26])[CH2:20]1.C1COCC1.N1CCCCC1>C(N(CC)CC)C>[OH:26][CH2:25][CH:21]1[CH2:22][CH2:23][CH2:24][N:19]([C:13]([C:11]2[S:12][C:8]([C:5]3[C:4]([CH3:16])=[C:3]([C:2]([F:1])([F:18])[F:17])[O:7][N:6]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20]1
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Reactant: OCC1CCCNC1
Solvent: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(-c2ccc(C(=O)N3CCCC(CO)C3)s2)noc1C(F)(F)F

Procedure:
Prepared from 5-(5-Trifluoromethyl-4-methyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 3-piperdinemethanol by the method described in Example 2 Method B reversing the order of addition such that solid acid chloride was added to a THF solution of triethylamine and piperdine derivative. The reaction mixture was evaporated to an oil then partitioned between EtOAc (5 mL) and water (5 mL). The organic fraction was further washed with brine (2×5 mL), dried over MgSO4, filtered, and evaporated to an oil. The crude product was then chromatographed on silica gel with EtOAc/hexanes (75%) as eluant to (190 mg, 75%). 1H NMR (CDCl3) 1.28-1.35 (m, 1 H), 1.44-1.56 (m, 1 H), 1.67-1.82 (m, 3 H), 2.28 (d, J=0.9, 3 H), 2.99 (dd, J=13.2, 9.7, 1 H), 3.32 (br s, 1 H), 3.41-3.52 (m, 2 H), 4.10 (br s, 1 H), 4.21 (d, J=11.4, 1 H), 7.29 (d, J=4.0, 1 H), 7.37 (d, J=4.0, 1 H). 13C NMR 7.8, 24.9, 27.2, 39.1, ˜49 (br), 64.5, 114.8, 118.7 (q, J=271), 128.1, 129.3, 131.2, 140.3, 155.0 (q, J=40), 157.9, 162.9. 19F NMR −63.2. LC/MS 5.91 min, [M+1]+ 375.
Reaction SMILES: [Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]2[C:4]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19][C:5]=3[N:6]([CH2:11][C:12]([O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[O:13])[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCN(C(=O)OC(C)(C)C)CC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)COC(=O)Cn1c2c(c3c(Br)cccc31)CCNCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.8 %

Procedure:
tert-butyl 10-bromo-6-(2-isobutoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0412 g, 0.0859 mmol) was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid (1.0 mL, 1.48 g, 13.0 mmol, 151 equiv.) was added. The resulting solution was stirred at rt for 2.5 h. The reaction mixture was concentrated to dryness. The residue was taken up in EtOAc (2 mL), then treated with 1N HCl in Et2O. Hydrochloride salt formation did not occur and the resulting solution were concentrated to dryness. The residue was partitioned between EtOAc and 1N NaOH. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude isobutyl (10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate (0.0260 g) was obtained in 80% yield. 1H NMR (300 MHz, CD3OD) δ 0.85, 1.86, 2.98-3.03, 3.11-3.14, 3.53-3.56, 3.91, 5.02, 6.94, 7.18, 7.25; MS (ESI+) for C18H23BrN2O2 m/z 379.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:40])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([O:31][CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:37](O)=[O:38])=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:46](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O.O>[C:37]([C:21]1[C:22]2[NH:23][C:24]3[C:29]([C:30]=2[C:18]([C:14]2[C:13]([CH3:40])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:17]=[CH:16][CH:15]=2)=[CH:19][N:20]=1)=[CH:28][CH:27]=[C:26]([O:31][CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1)[CH:25]=3)(=[O:38])[NH2:46]
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(OC4CCOC4)ccc3c12
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(OC4CCOC4)ccc3c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A mixture of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-(tetrahydrofuran-3-yloxy)-9H-pyrido[3,4-b]indole-1-carboxylic acid (0.195 g, 0.363 mmol), ammonium chloride (0.078 g, 1.451 mmol), N,N-diisopropylethylamine (0.304 mL, 1.741 mmol), BOP (0.209 g, 0.472 mmol), and N-methylmorpholine (0.156 mL, 1.415 mmol) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 1.5 hr. To the reaction mixture was added water (30 mL), and the resulting mixture was stirred at room temperature for 30 min. The insoluble product (0.189 g, 0.352 mmol, 97% yield) was collected as a beige solid by suction filtration and dried over Drierite under vacuum.