Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:16][CH:15]=2)[N:9]=1)(C)(C)C>Cl.CO>[NH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:19]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(CNS(C)(=O)=O)cc2)n1
Agent: Cl
Solvent: CO
Product: CS(=O)(=O)NCc1ccc(-c2cccc(N)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
A mixture of {6-[4-(methanesulfonylamino-methyl)-phenyl]-pyridin-2-yl}carbamic acid tert-butyl ester (11 g, 29 mmol) in HCl/MeOH (4M, 300 mL) was stirred at room temperature overnight. The mixture was concentrated to dryness. The residue was filtered and washed with ether to give N-(4-(6-aminopyridin-2-yl)benzyl)methane sulfonamide (C-3) (7.6 g, 80%) 1H NMR (300 MHz, DMSO-d6) δ 14.05 (br s, 1H), 8.24 (br s, 2H), 7.91-7.98 (m, 3H), 7.70 (t, J=6.0 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 7.22 (d, J=6.9 Hz, 1H), 6.96 (d, J=9 Hz, 1H), 4.23 (d, J=5.7 Hz, 2H), 2.89 (s, 3H). MS (ESI) m/z (M+H)+: 278.0,
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([NH:12]C(=O)C)=[CH:7][C:6]=1[CH3:16])=[O:4]>C(O)C.Cl>[NH2:12][C:8]1[CH:7]=[C:6]([CH3:16])[C:5]([C:3](=[O:4])[CH2:2][Br:1])=[C:10]([CH3:11])[CH:9]=1
Reactant: CC(=O)Nc1cc(C)c(C(=O)CBr)c(C)c1
Agent: Cl
Solvent: CCO
Product: Cc1cc(N)cc(C)c1C(=O)CBr
Yield: 85.3 %

Procedure:
A solution of N-(4-(2-bromoacetyl)-3,5-dimethylphenyl)acetamide (1-1, 6.92 g, 24.4 mmol) in 20.0 mL of ethanol and 10.2 mL of concentrated hydrochloric acid was heated at reflux for 1.5 h. The solution was concentrated and added with ethyl acetate (100 mL) and saturated aqueous Na2CO3 (100 mL). The organic layer was collected, dried over anhydrous MgSO4(s), and concentrated under reduced pressure to give 1-(4-amino-2,6-dimethylphenyl)-2-bromoethanone (1-2, 5.04 g) as yellow solids, which was used directly for the next step without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2.C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][Si:39]([C:42]#[CH:43])([CH3:41])[CH3:40]>CN(C=O)C.[Cu]I>[CH3:38][Si:39]([C:42]#[C:43][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[NH:8][CH2:7]2)([CH3:41])[CH3:40]
Reactant: C#C[Si](C)(C)C
Reactant: O=C1NCc2cccc(I)c21
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc2c1C(=O)NC2
Temperature: 100 °C
Yield: 49 %

Procedure:
To a nitrogen de-gassed solution of 7-iodoisoindolin-1-one (I59) (0.233 g, 0.899 mmol) in dry DMF (6 mL) were added triethylamine (0.501 mL, 3.598 mmol) followed by triphenylphosphine (0.035 g, 0.14 mmol), trans-dichlorobis(triphenylphosphine) palladium(II) (0.063 g, 0.090 mmol), CuI (0.026 g, 0.14 mmol) and finally (trimethylsilyl)acetylene (0.292 mL, 1.63 mmol). The reaction mixture was then heated under microwave irradiation at 100° C. for 30 then 10 minutes. The reaction mixture was concentrated in vacuo, then absorbed onto silica gel and purified by silica gel chromatography (Biotage Isolera, 40 g Si cartridge, 0-46% EtOAc in dichloromethane) to give the title compound (I60) (0.120 g, 49% yield) as an off-white solid; 1H NMR (400 MHz, d6-DMSO) δ 8.47 (s, 1H), 7.60-7.51 (m, 2H), 7.49 (dd, J=6.7, 2.0 Hz, 1H), 4.32 (s, 2H), 1.03 (t, J=7.9 Hz, 9H), 0.66 (q, J=7.9 Hz, 6H). LCMS Method C: rt 6.44 min; m/z 272.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:31])=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[Br:1][C:2]1[C:3]([Cl:31])=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(Br)c3Cl)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(Br)c4Cl)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 28 (0.280 g, 0.550 mmol) and pyridine hydrochloride (0.780 g, 6.74 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[C:16]([F:21])[CH:15]=2)([OH:13])[CH2:9]1)C1C=CC=CC=1.C([SiH](CC)CC)C>[Pd].CO>[F:21][C:16]1[CH:15]=[C:14]([C:10]2([OH:13])[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:19]=[CH:18][C:17]=1[F:20]
Reactant: OC1(c2ccc(F)c(F)c2)CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: CC[SiH](CC)CC
Solvent: CO
Product: OC1(c2ccc(F)c(F)c2)CCNC1

Procedure:
Preparation according to Preparation 18: Enantiomer E2 of 1-benzyl-3-(3,4-difluorophenyl)pyrrolidin-3-ol (0.835 g, 2.89 mmol), methanol (15 mL), palladium on carbon (165 mg), triethyl silane (6.7 g, 57.7 mmol). Reaction restart: Methanol (15 mL), palladium on carbon (165 mg), triethyl silane (6.7 g, 57.7 mmol). Purification on a Biotage Isolute SCX-3 SPE column (washed with methanol and eluted with methanol/triethylamine 4:1). Yield: 0.54 g. MS m/z (relative intensity, 70 eV) 199 (M+, 85), 141, (bp), 127 (58), 114 (53), 113 (98).
Reaction SMILES: [C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][CH:22]2[CH2:28][CH2:29][CH2:30][CH:21]12)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:3]CC)=[O:2].[OH-].[Na+]>>[C:1]([CH:6]([NH:15][C@H:16]([C:18]([N:20]1[C@H:24]([C:25]([OH:27])=[O:26])[CH2:23][CH:22]2[CH2:28][CH2:29][CH2:30][CH:21]12)=[O:19])[CH3:17])[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)([OH:3])=[O:2]
Reactant: CCOC(=O)C(CCc1ccccc1)N[C@@H](C)C(=O)N1C2CCCC2C[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1C2CCCC2C[C@H]1C(=O)O

Procedure:
As described in Example 2, hydrolyze the ester (prepared as described in Example 20) with sodium hydroxide to obtain the title compound.
Reaction SMILES: [CH2:1]([CH:4]1[CH:8]([OH:9])[CH:7]=[CH:6][C:5]1=[O:10])[CH:2]=[CH2:3].C1(C)C(S(O)(=O)=O)=CC=CC=1.[C:22](OC(=O)C)(=[O:24])[CH3:23]>>[C:22]([O:10][CH:5]1[CH:6]=[CH:7][C:8](=[O:9])[CH:4]1[CH2:1][CH:2]=[CH2:3])(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCC1C(=O)C=CC1O
Agent: Cc1ccccc1S(=O)(=O)O
Product: C=CCC1C(=O)C=CC1OC(C)=O

Procedure:
In a flask, dl-2-allyl-3-hydroxy-4-cyclopentenone (13.8 g), toluenesulfonic acid (0.1 g) and acetic anhydride (27.6 g) were charged, and the resultant mixture was heated at 90°-100° C. for 3 hours. The reaction mixture was treated as in Example 28 to give 16.0 g of dl-3-acetoxy-2-allyl-4-cyclopentenone. Yield, 89%. B.P., 80°-85° C./0.6-1 mmHg.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH2:15])=[CH:5][CH:4]=1.[CH3:16][O:17][CH2:18][C:19](Cl)=[O:20].[K+].[Br-]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:13][CH2:14][NH:15][C:19](=[O:20])[CH2:18][O:17][CH3:16])=[CH:5][CH:4]=1
Reactant: COCC(=O)Cl
Reactant: COc1ccc2c(c1)C(CCN)CCC2
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: COCC(=O)NCCC1CCCc2ccc(OC)cc21

Procedure:
N-[2-(1,2,3,4-tetrahydro-7-methoxynaphthalen-1-yl)ethyl]amine was resolved according to the general procedure described in example 1 using L-tartartic add and was shown to have an enantiomeric excess of ≤99% by HPLC analysis. The HPLC analyses were carried out as described in example 3. The amine was converted to the amide according to General Procedure A using methoxyacetyl chloride. The final product was purified by reversed phase HPLC using acetonitrile/water to give a white solid. m.p.=58°-60° C.; 1H NMR (300 MHz, CDCl3) δ6.96 (d, J=8 Hz, 1H), 6.67 (s, 1H), 6.65 (m, 1H), 6.50 (bs, 1H), 3.86 (s, 2H), 3.76 (s, 3H), 3.43 (m, 2H), 3.38 (s, 3H), 2.79 (m, 1H), 2.66 (bm, 2H), 1.9-1.7 (bm, 4H), 1.67-1.63 (m, 2H); 3C NMR (75 MHz, CDCl3) δ169.44, 157.57, 141.26, 130.03, 129.24, 113.36, 111.82, 72.03, 59.17, 55.30, 36.94, 36.47, 35.66, 28.74, 27.52, 20.02; IR (KBr) 1658 cm-1 ; MS (DCI) m/e (MH)278; Analysis calc'd for C16H23N1O3 : C, 69.29; H, 8.36; N, 5.05; found: C, 69.17; H, 8.37; N, 4.92; [α] (20° C., 589 nm, CHCl3)=+6.96.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1.N1C=CN=C1.[Si:14](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[Si:14]([CH:2]([OH:1])[C@H:3]1[O:7][C:6](=[O:8])[CH2:5][CH2:4]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: O=C1CC[C@@H](CO)O1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](c1ccccc1)(c1ccccc1)C(O)[C@@H]1CCC(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of 3 (7.0 g, 60 mmol) and imidazole (9.19 g, 135 mmol) in anhydrous DMF (70 mL) was added tert-butyldiphenylsilyl chloride (18.14 g, 66 mmol, 17.2 mL), and the solution was stirred at room temperature under a nitrogen atmosphere for 1 h. After removal of the solvent by evaporation, the residue was dissolved in CHCl3, washed with water and brine, dried (Na2SO4), filtered, and concentrated. After crystallization from hexane, the oily residue gave the title compound 4 as a white crystalline solid (20.6 g, 97%). M.P. 76° C.; 1H NMR (CDCl3) δ 7.68-7.65 (m, 4H, arom.), 7.47-7.39 (m, 6H, arom.), 4.63-4.61 (m, 1H, H-5), 3.90-3.87 (dd, J=3 & 11 Hz, 1H, CH2OH), 3.70-3.67 (dd, J=3 & 11 Hz, 1H, CH2OH), 2.69-2.65 (m, 1H, H-3), 2.56-2.52 (m, 1H, H-3), 2.32-2.23 (m, 2H, H-4), 1.06 (s, 9H, t-Bu).
Reaction SMILES: C([O:5][C:6](=[O:42])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([S:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)(=[O:31])=[O:30])[CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:39][CH2:40][CH3:41])(C)(C)C.C(O)(C(F)(F)F)=O>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([S:29]([N:17]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][C:6]([OH:42])=[O:5])[C:9]([CH2:39][CH2:40][CH3:41])=[N:10][C:11]=3[CH:16]=2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: CCCc1nc2cc(N(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2cc(N(Cc3cccc(C(F)(F)F)c3)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)O

Procedure:
{5-[(4-Fluoro-benzenesulfonyl)-(3-trifluoromethyl-benzyl)-amino]-2-propyl-benzoimidazol-1-yl}-acetic acid tert-butyl ester was treated with TFA (2 mL) for 2 hours, concentrated, and purified by preparative LCMS to give the title compound. MS calculated for C26H23F4N3O4S—H: 548, observed: 548.
Reaction SMILES: I[C:2]1[C:7](=[O:8])[N:6]2[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]2[C:19]=1[N:20]=[CH:21][NH:22]2)[CH2:15][CH3:16].[F:27][C:28]1[CH:29]=[C:30](B(O)O)[CH:31]=[N:32][CH:33]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:29]=[C:30]([C:2]2[C:7](=[O:8])[N:6]3[C:9]([CH3:13])=[CH:10][CH:11]=[CH:12][C:5]3=[N:4][C:3]=2[CH:14]([NH:17][C:18]2[N:26]=[CH:25][N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[CH2:15][CH3:16])[CH:31]=[N:32][CH:33]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(Nc1ncnc2[nH]cnc12)c1nc2cccc(C)n2c(=O)c1-c1cncc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 3-iodo-6-methyl-2-[1-(9H-purin-6-ylamino)propyl]-4H-pyrido[1,2-a]pyrimidin-4-one (0.030 g, 0.065 mmol) and (5-fluoropyridin-3-yl)boronic acid (Combi-Blocks, 11.0 mg, 0.0780 mmol) in 1,4-dioxane (0.5 mL) was added a 1 M solution of sodium carbonate (8.27 mg, 0.0780 mmol) in water (0.077 mL) and tetrakis(triphenylphosphine)palladium (0) (3.76 mg, 0.00325 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to rt, the mixture was diluted with EtOAc, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified on RP-HPLC at pH 10 conditions (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.15% NH4OH) to provide the desired product. LCMS calculated for C22H20FN8O (M+H)+: m/z=431.2. Found: 431.3.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10](Br)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16](=[O:21])[O:17][CH:18]([CH3:20])[CH3:19])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].CC1(C)C(C)(C)OB([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)O1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:15][C:16]([O:17][CH:18]([CH3:20])[CH3:19])=[O:21])[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccc3c(c2)[C@H](NC(=O)OC(C)C)C[C@H](C)N3C(C)=O)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 80.7 %

Procedure:
To a solution of isopropyl ((2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)carbamate (5 g, 13.54 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.90 g, 14.89 mmol) in DME (50 mL) and water (10.0 mL) were successively added palladium tetrakis(triphenylphosphine) (1.565 g, 1.354 mmol) and potassium carbonate (5.61 g, 40.6 mmol). The resulting mixture was stirred at 100° C. for 1 h, whereupon it was allowed to cool down to room temperature and was filtered through Celite™. The filtrated was concentrated in vacuo and the residue was partitioned between EtOAc and water. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude compound was purified by flash chromatography on a silica gel cartridge (50 g) eluting with EtOAc in cyclohexane (5-60%). The appropriate fractions were combined and concentrated under reduced pressure to give methyl 4-((2S,4R)-1-acetyl-4-((isopropoxycarbonyl)amino)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (4.64 g, 81%) as a white gum. LCMS (Formate, 2 min), Rt=1.09 min, MH+=425.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[O:10][CH2:9][C:8]1([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=1)[CH3:21])=[N+]=[N-].C(Cl)(Cl)Cl.O.N>CO.O1CCCC1.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[O:10][CH2:9][C:8]1([C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:26][CH:27]=1)[CH3:21]
Reactant: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCN=[N+]=[N-])cc1
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COCOc1ccc(C2(C)COc3cc(OCOC)ccc3C2CCCN)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 7.2 %

Procedure:
(3RS,4RS)-4-(3-Azidopropyl}7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (170 mg, 4.0 mmol) was dissolved in methanol (20 ml) and tetrahydrofuran (5 ml), 10% palladium on carbon (50 mg) was added to this solution, which was then stirred at room temperature under hydrogen for 12 hours. The reaction solution was filtered through cellite and concentrated under reduced pressure to give a crude product. This crude product thus obtained was subjected to silica gel column chromatography (chloroform:methanol:ammonia water=10:1:0.1) to give (3RS,4RS)-4-(3-aminopropyl)-7-methoxymethoxy-3-(4-methoxymethoxyphenyl)-3-methylchroman (116 mg, yield 73%).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH2:17])[N:4]=1.[C:19]1([CH2:25][C:26](Cl)=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:18][N:2]([CH3:1])[C:3]1[CH:8]=[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:6]=[C:5]([NH:17][C:26](=[O:27])[CH2:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:4]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1ccc(Nc2cc(N(C)C)nc(N)n2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Nc2cc(N(C)C)nc(NC(=O)Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of N4,N4-dimethyl-N6-(4-methylphenyl)-2,4,6-pyrimidinetriamine (122 mg, 0.50 mmol), phenylacetyl chloride (84 mg, 0.55 mmol), and triethylamine (100 mg, 1.00 mmol) in CH2Cl2 was stirred at room temperature for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC using hexane/EtOAc (1:3), giving the desired product (60 mg, 33%).
Reaction SMILES: [CH3:1][C:2]([CH3:13])=[CH:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1.S(=O)(=O)(O)[OH:15].O>O1CCOCC1.O>[CH3:1][C:2]([OH:15])([CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[N:6]1)[CH3:13]
Reactant: CC(C)=CCn1ccc([N+](=O)[O-])n1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(O)CCn1ccc([N+](=O)[O-])n1
Temperature: 85 °C
Yield: 43 %

Procedure:
1-(3-Methyl-but-2-enyl)-3-nitro-1H-pyrazole (1.29 g, 7.13 mmol) was dissolved in dioxane (30 mL). While stirring, a solution containing 50% concentrated sulfuric acid/water (3 mL) was added dropwise. The reaction was heated to 85° C. while stirring for 12 h. The reaction was diluted with water (50 mL) and the product extracted into ethyl acetate (3×60 mL). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo to an oil. Purification by flash column chromatography (Merck silica gel 60, 40-63 μm; 15% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded 2-methyl-4-(3-nitro-pyrazol-1-yl)-butan-2-ol (608 mg, 43%) as a thick golden oil: H1-NMR (400 MHz, CDCl3) δ 1.30 (6H, s), 1.54 (1H, bs), 2.11-2.15 (2H, m), 4.36-4.39 (2H, m), 6.87 (1H, d, J=2.8 Hz), 7.48 (1H, d, J=2.8 Hz).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.[CH3:23][O:24][C@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](O)=[O:27].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:23][O:24][C@H:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26]([O:1][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[C:9]([NH:12][C:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])[CH:8]=[CH:7][CH:6]=2)[CH2:11]1)=[O:27]
Reactant: CO[C@@H](C(=O)O)c1ccccc1
Reactant: O=C(Nc1cccc2c1CC(O)CC2)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CO[C@@H](C(=O)OC1CCc2cccc(NC(=O)OCc3ccccc3)c2C1)c1ccccc1
Yield: 89.5 %

Procedure:
A mixture of Example 24B (1.03 g, 3.46 mmol), (R)-2-methoxy-2-phenylacetic acid (0.633 g, 3.81 mmol), 1,3-dicyclohexylcarbodiimide (1.14 g, 5.54 mmol), and 4-dimethylaminopyridine (0.846 g, 6.93 mmol) in dichloromethane (35 mL) was stirred at ambient temperature for 18 hr. The reaction mixture was diluted with CH2Cl2 and washed with saturated aqueous NH4Cl solution, brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was placed on a silica gel column and eluted with 30% ethyl acetate/hexanes to afford 1.38 g (89% yield) of the title compound as a colorless syrup. MS (ESI+) m/z 446 (M+H)+, 463 (M+NH4).
Reaction SMILES: [CH:1]1([C@@H:4]2[C@H:10]([N:11](CC3C=CC=CC=3)CC3C=CC=CC=3)[C:9](=[O:26])[NH:8][C:7]3[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:6]=3[O:5]2)[CH2:3][CH2:2]1>CO.[Pd]>[NH2:11][C@@H:10]1[C:9](=[O:26])[NH:8][C:7]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:6]=2[O:5][C@@H:4]1[CH:1]1[CH2:3][CH2:2]1
Reactant: O=C1Nc2cc(F)ccc2O[C@H](C2CC2)[C@@H]1N(Cc1ccccc1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: N[C@@H]1C(=O)Nc2cc(F)ccc2O[C@@H]1C1CC1

Procedure:
The title compound was prepared by hydrogenation of (−)-(6R,7S)-6-cyclopropyl-7-dibenzylamino-2-fluoro-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one in methanol with Pd/C (10%), MS m/e (%): 235.1 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:19]1
Reactant: IC1CCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCCN(C4CCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(3-piperidinyl)propyl]-9H-purin-6-amine and iodocyclopentane.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[N:14]=1)[N:11]([CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(-c2cccnc2)c2c(cc(-c3ccccc3)c(=O)n2CC2CCCCC2)c1O
Temperature: 120 °C
Yield: 67.2 %

Procedure:
A mixture of 8-bromo-1-cyclohexylmethyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (62 mg, 0.13 mmol), 3-tributylstannanyl-pyridine (0.063 mL, 0.20 mmol) and PdCl2(PPh3)2 (18 mg, 0.026 mmol) in 3 mL of DMF was heated at 120° C. for 3 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-70% EtOAc/hexanes+1% AcOH) to give 41 mg of the title compound. MS: (+) m/z 470.39 (M+1).