Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=O)=[N:9][C:8]2[C:3]1=[N:4][CH:5]=[N:6][C:7]=2[N:14]1[CH2:19][CH2:18][CH:17]([N:20]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[NH:22][C:21]2=[O:29])[CH2:16][CH2:15]1.CCN(C(C)C)C(C)C.Cl.[CH3:40][NH:41][O:42][CH3:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.ClCCl>[CH3:43][O:42][N:41]([CH3:40])[C:11]([C:10]1[N:2]([CH3:1])[C:3]2[C:8]([N:9]=1)=[C:7]([N:14]1[CH2:15][CH2:16][CH:17]([N:20]3[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[NH:22][C:21]3=[O:29])[CH2:18][CH2:19]1)[N:6]=[CH:5][N:4]=2)=[O:13]
Reactant: CNOC
Reactant: Cn1c(C(=O)O)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9-Methyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxylic acid (450 mg, 1.14 mmol) was dissolved in dimethylacetamide (3 mL) and DIPEA (0.57 mL, 3.43 mmol). N,O-Dimethylhydroxylamine hydrochloride salt (123 mg, 1.26 mmol) was added to the solution, followed by dichloromethane (3 mL) and HATU (522 mg, 1.37 mmol). The reaction was stirred at room temperature for 1 hour. The crude reaction mixture was concentrated, diluted with 80 mL of dichloromethane, was washed with 2×50 mL of water and 3×50 mL of saturated potassium carbonate. The organic layer was collected, dried over magnesium sulfate, was filtered and was concentrated to afford N-methoxy-N,9-dimethyl-6-[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]-9H-purine-8-carboxamide (quantitative yield) as an oil. 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 8.32 (s, 1H), 7.18-7.12 (m, 1H), 6.96-6.88 (m, 3H), 5.38 (br s, 2H), 4.55 (tt, 1H), 3.76 (s, 3H), 3.75 (s, 3H), 3.49-3.09 (m, 5H), 2.40-2.23 (m, 2H), 1.83 (br d, 2H). MS (EI) for C21H24N8O3: 437 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][C:13](=[O:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>[Pd].O1CCOCC1>[OH:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH:13]([OH:32])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]34[CH2:31][CH:26]5[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]5)[CH2:23]3)[CH2:29]4)[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(C(=O)COc2ccc(C(=O)O)c(O)c2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [Pd]
Solvent: C1COCCO1
Product: COc1ccc(C(O)COc2ccc(C(=O)O)c(O)c2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 4 h

Procedure:
1.3 g (2.98 mmol) of 2-hydroxy-4-[[3-(1-adamantyl)-4-methoxybenzoyl]methoxy]benzoic acid, 200 mg of 10% palladium on charcoal and 50 ml of dioxane are introduced into a reactor. The mixture is hydrogenated at room temperature and under a pressure of 7 bar for 4 hours, the catalyst is filtered and washed with 50 ml of THF, and the filtrates are evaporated. The residue obtained is purified by chromatography on a silica column, eluting with a dichloromethane/methanol mixture (98:2). After evaporation of the solvents, 1 g (77%) of the expected acid of melting point 178°-179° C. is collected.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[S:15])[CH:13]=[CH:12][O:11][CH:10]=1.[Cl:16][CH:17]([CH3:21])[C:18](Cl)=[O:19]>ClCCl>[Cl:16][CH:17]([CH3:21])[C:18]([O:8][C:9]1[C:14](=[S:15])[CH:13]=[CH:12][O:11][CH:10]=1)=[O:19]
Reactant: Oc1coccc1=S
Reactant: CC(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Cl)C(=O)Oc1coccc1=S
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 77.2 %

Procedure:
Triethylamine (190 mg, 1.9 mmol) was added to a stirred solution of 7 (200 mg, 1.6 mmol) in dichloromethane (10 mL) at 0° C. A solution of 2-chloropropionyl chloride (240 mg, 1.9 mmol) diluted in dichloromethane (1 mL) was added dropwise and the reaction mixture stirred at 0° C. for 10 min. The red solution was evaporated to dryness in vacuo and the resulting residue was purified by rapid silica filtration (dichloromethane) to give 8 as a red oil (270 mg, 79%).
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10](Br)=[CH:9][C:7]=2[N:8]=1.CC1(C)C(C)(C)OB([C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:41][O:40][C:39](=[O:42])[O:38]3)=[CH:33][CH:32]=2)O1>>[NH2:1][C:2]1[CH2:3][C:4]([C:14]([N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18][CH3:19])=[O:15])=[CH:5][C:6]2[CH:12]=[CH:11][C:10]([C:31]3[CH:32]=[CH:33][C:34]([CH:37]4[CH2:41][O:40][C:39](=[O:42])[O:38]4)=[CH:35][CH:36]=3)=[CH:9][C:7]=2[N:8]=1
Reactant: CC1(C)OB(c2ccc(C3COC(=O)O3)cc2)OC1(C)C
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(N)C1
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C4COC(=O)O4)cc3)cc2N=C(N)C1
Yield: 9 %

Procedure:
Reaction of (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3-dioxolan-2-one as follows yielded (1E,4E)-2-amino-8-(4-(2-oxo-1,3-dioxolan-4-yl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (9%). (1E,4E)-2-amino-8-bromo-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (75.0 mgs, 0.206 mmol), 4-(methoxycarbonyl)phenylboronic acid (55.6 mgs, 0.309 mmol, tetrakis(triphenylphosphine)palladium(0) (23.8 mgs, 0.021 mmol), 2M aqueous potassium carbonate (0.309 ml, 0.618 mmol) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) was then used. 1H NMR (400 MHz, DMSO-d6) δ 7.74-7.80 (m, 2H), 7.55-7.60 (m, 2H), 7.26-7.42 (m, 3H), 6.78 (s, 1H), 5.89-5.96 (m, 1H), 4.88-4.95 (m, 1H), 4.45-4.52 (m, 1H), 2.78 (s, 2H), 1.50-1.63 (m, 4H), 0.71-0.93 (m, 6H); m/z (APCI-pos) M+1=448.2. (1E,4E)-2-amino-8-(4-(1,2-dihydroxyethyl)phenyl)-N,N-dipropyl-3H-benzo[b]azepine-4-carboxamide (19%) was obtained as the more polar product. (19%). 1H NMR (400 MHz, DMSO-d6) δ 7.59-7.64 (m, 2H), 7.39-7.44 (m, 2H), 7.33-7.38 (m, 1H), 7.26-7.28 (m, 1H), 7.20-7.24 (m, 1H), 6.84 (br s, 1H), 6.74 (s, 1H), 5.23-5.27 (m, 1H), 4.71-4.75 (m, 1H), 4.54-4.62 (m, 1H), 3.44-3.50 (m, 2H), 3.28-3.35 (m, 4H), 2.74 (s, 2H), 1.51-1.61 (m, 4H), 0.73-0.90 (m, 6H); m/z (APCI-pos) M+1=422.2.
Reaction SMILES: [NH2:1][C:2]1([C:13]([O:15][CH3:16])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1.[OH-].[Na+]>[Cl-].[Na+].Cl>[NH2:1][C@:2]1([C:13]([O:15][CH3:16])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: COC(=O)C1(N)CCOc2ccc(F)cc21
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Product: COC(=O)[C@]1(N)CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 73 %

Procedure:
Methyl 4-amino-6-fluorochroman-4-carboxylate (11.5 g., 0.051 mole), the racemic spiro-amino acid methyl ester prepared in Example 20, was dissolved in 0.125M aqueous sodium chloride solution (100 ml.) at pH 5 by the addition of 6N hydrochoric acid. α-Chymotrypsin (750 mg.), available from the Sigma Chemical Company of St. Louis, MO., was then added to the mixture with stirring at room temperature (~20° C.). After an initial induction period of several hours, hydrolysis commenced as evidenced by the uptake of 0.5N aqueous sodium hydroxide from a pHstat to maintain the pH of the reaction solution at pH 5.1. The reaction was then continued until the uptake of base ceased. The reaction mixture was then acidified with 6N hydrochloric acid to pH 2 and activated carbon (1 g.) was added. After stirring for two hours, supercel (0.5 g.) was added and stirring was continued for another three hours. The spent reaction mixture was then filtered through supercel and extracted with ethyl acetate. The acqueous layer so obtained was adjusted to pH 10 with 6N aqueous sodium hydroxide and thereafter extracted with ethyl acetate (three times). The combined organic layers were then washed with brine and dried over anhydrous magnesium sulfate. After removal of the drying agent by means of filtration and the solvent by means of evaporation under reduced pressure, there were obtained 4.17 g. of pure (S)-methyl 4-amino-6-fluorochroman-4-carboxylate (73% yield based on available enantiomer) in the form of a colorless oil, [α]D25° +51.2° (c=0.64, CHCl3); NMR (CDCL3) identical with the racemic amino acid ester.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]([NH:9][C:10]3[O:11][CH2:12][C:13]4[CH:19]=[C:18]([NH2:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH2:7][O:8][C:4]=2[CH:3]=1.[Cl:23][CH2:24][C:25](Cl)=[O:26]>>[Cl:23][CH2:24][C:25]([NH:20][C:18]1[CH:17]=[CH:16][C:14]2[N:15]=[C:10]([NH:9][CH:6]3[C:5]4[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=4[O:8][CH2:7]3)[O:11][CH2:12][C:13]=2[CH:19]=1)=[O:26]
Reactant: Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)Nc1ccc2c(c1)COC(NC1COc3cc(F)ccc31)=N2
Yield: 26.6 %

Procedure:
Prepared from rac-N2-(6-fluoro-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 34) (748 mg, 2.5 mmol, HPLC 0.641 min) and chloroacetyl chloride (0.21 ml, 2.625 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as a white solid (250 mg, 27%, HPLC 1.056 min), MS (ISP) m/e=376.1 [(M+H)+] and 378 [(M+2+H)+].
Reaction SMILES: [O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br.[OH:23][C:24]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:25]=1[CH2:26][CH2:27][NH:28][CH2:29]2>>[O:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:18]=[C:17]([C:19]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[C:33]([OH:34])[C:24]=4[OH:23])[CH2:29]3)=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: Oc1ccc2c(c1O)CCNC2
Reactant: COc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Agent: Br
Product: COc1ccc(-c2nc(C(=O)N3CCc4c(ccc(O)c4O)C3)c3ccccc3n2)cc1
Yield: 9 %

Procedure:
Reaction of 2-(4-methoxylphenyl)quinazoline-4-carboxylic acid with 5,6-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrobromide gave compound 23 (9% yield) as brown oil. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.88 (2t, 2H), 3.46 and 4.01 (2t, 2H), 3.87 (s, 3H), 4.33 and 4.87 (2s, 2H), 6.16 and 6.62 (2d, 1H), 6.51 and 6.72 (2d, 1H), 7.09-7.15 (m, 2H), 7.63-7.74 (m, 1H), 7.80-7.92 (2d, 1H), 8.02-8.12 (m, 2H), 8.44-8.51 (m, 2H); MS (ESI) m/z 428 ([M+H]+).
Reaction SMILES: [CH2:1]1[C:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=4[NH:8][C:7]=3[CH:6]=[CH:5][C:4]=2[C:3](=[O:17])[CH2:2]1.[H-].[Na+].Cl.Cl[CH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29].C(Cl)(Cl)Cl.CO>C(Cl)Cl.O>[CH3:29][N:25]1[CH2:26][CH2:27][CH2:28][CH:24]1[CH2:23][CH2:22][N:8]1[C:7]2[CH:6]=[CH:5][C:4]3[C:3](=[O:17])[CH2:2][CH2:1][C:16]=3[C:15]=2[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1=2
Reactant: CN1CCCC1CCCl
Reactant: O=C1CCc2c1ccc1[nH]c3ccccc3c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CN1CCCC1CCn1c2ccccc2c2c3c(ccc21)C(=O)CC3
Temperature: 25 °C
Reaction time: 0.12 h

Procedure:
Carbazole 46 (0.4 g, 1.81 mmol) was dissolved in CH2Cl2 (7 mL), then NaH (0.22 g, 5.50 mmol) was added. The mixture was stirred at room temperature for 5-10 min, and 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (0.4 g, 2.17 mmol) was added. The mixture was heated to 60° C. and kept at this temperature for 4 h (TLC monitoring, eluent: CHCl3-MeOH, 9:1). The resulting mixture was poured into water. The product was extracted with ethyl acetate, dried over Na2SO4, and evaporated. The residue was triturated with ether. The precipitate was filtered off. Yield of 65: 0.365 g (61%)—S-isomer and 0.336 g (55%)—R-isomer.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][C:7]([CH3:10])([CH3:9])[CH2:6][CH2:5][NH:4][C:3]1=[O:11].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][C:7]([CH3:9])([CH3:10])[CH2:6][CH2:5][NH:4][C:3]1=[O:11]
Reactant: CC1(C)CCNC(=O)C(Cl)(Cl)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CCNC(=O)C(Cl)C1
Yield: 90 %

Procedure:
15.2 g (0.086 moles) of 3,3-dichloro-5,5-dimethyl-2-oxoperhydroazepine were dissolved in 900 ml of glacial acetic acid and shaked at 40 psi of hydrogen with 7 g of 10% Pd/C as in Description 14, to yield 13.6 g of the title compound.
Reaction SMILES: [C:1]([C@@:8]([NH2:19])([CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)C(O)=O)([O:3][C:4](C)(C)C)=[O:2].C(N1CCC[C@H]1C(O)=O)(OC(C)(C)C)=O.[ClH:35].CN(C)CCCN=C=NCC.[H-].ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CO.Cl.O1CCOCC1.C(Cl)Cl.C(OCC)(=O)C>[ClH:35].[CH3:4][O:3][C:1](=[O:2])[C@H:8]([NH2:19])[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)(C)OC(=O)[C@@](N)(CC1CCCCC1)C(=O)O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)[C@H](N)CC1CCCCC1
Reaction time: 8 h
Yield: 93 %

Procedure:
(2R)-2-Amino-3-cyclohexylpropanoic acid methyl ester hydrochloride was prepared from Boc-(2R)-2-Amino-3-cyclohexylpropanoic acid (30 g, 0.11 mole) in 500 mL of methanol and 250 mL of 4N hydrochloric acid in dioxane for overnight at room temperature in 93% yield. This (22.58 g, 0.101 mole) was coupled with Boc-Proline (25.89 g, 0.11 mole) in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (21.31 g, 0.11 mole), 1-hydroxybenzotriazole monohydride (HOBT) (15.0 g, 0.11 mole) and N-methylmorpholine (NMM) (12.2 mL, 0.11 mole) (EDC and HOBT method) in methylene chloride. The reaction was carried out at room temperature for overnight. Ethyl acetate was added and the organic layer was washed with saturated sodium bicarbonate, brine, 0.2M phosphoric acid, brine and dried over sodium sulfate. Evaporation of the solvent gave 35.03 g of dipeptide in 91% yield (MS: (M+H)+ =383). This was followed by deprotection of Boc-group, then coupling with N-alpha-Cbz-N-epsilon-Boc-Lysine to yield N-alpha-Cbz-Lysyl(N-epsilon-Boc)-Prolyl-{(2R)-2-Amino-3-cyclohexylpropanoyl}-OMe (MS: (M+H)+ =645) in 89% yield using the conditions mentioned above (EDC and HOBT method).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([N+:16]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1CCC=CC1.C(O)C.Cl>[Pd].O>[C:1]([C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[C:7]([CH:6]=1)[NH2:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: CC1CC=CCC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1c(N)cc(C(C)(C)C)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Under N2 was charged 4-tert-butyl-2,6-dinitroanisole (620 g, 2.439 mol), IMS (4774 mL) and 10% Pd/C (31.8 g). The reaction mixture was heated to reflux (78° C.) and 4-methyl-1-cyclohexene (500 mL, 4.159 mol) was added dropwise over 4.5 h. The reaction was stirred at reflux overnight, whereupon HPLC analysis indicated 72.13% product and 27.17% starting material. Further 4-methyl-1-cyclohexene (160 mL, 1.331 mol) was added dropwise over 3 h and the reaction was stirred at reflux for 72 h. HPLC analysis indicated 92.72% product and 0% starting material. The reaction was cooled to room temperature and the catalyst was removed via vacuum filtration and washed with IMS (500 mL). The solvents were concentrated to ca. 1200 mL to give a ratio of 1:4.45 product:ethanol (target 1:5). 2 M HCl (124 mL) was charged dropwise to the remainder while maintaining the temperature below 23° C. Water (3100 mL) was charged and the resulting suspension was stirred at room temperature for 1.5 h. The solid was collected via vacuum filtration and washed with water (2×1000 mL). The resulting orange needles were dried, under vacuum, at 40° C. overnight. Yield=475.2 g (86.9%). Purity >97% by 1H NMR. HPLC purity 98.8%. KF 0.36%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH2:17][CH:16]2[NH:18][CH:13]([CH2:14][CH2:15]2)[CH:12]=1>CCOC(C)=O.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]1[CH2:17][CH:16]2[NH:18][CH:13]([CH2:14][CH2:15]2)[CH2:12]1
Reactant: C1=C(c2ccc3ccccc3c2)CC2CCC1N2
Agent: [Pd]
Solvent: CCOC(C)=O
Product: c1ccc2cc(C3CC4CCC(C3)N4)ccc2c1
Reaction time: 47 h
Yield: 62 %

Procedure:
To 313 mg (1.33 mmol) 3-naphthalen-2-yl-8-aza-bicyclo[3.2.1]oct-2-ene in 10 mL EtOAc is added 100 mg of 10% Pd/C. This mixture is placed under 40 psi of H2 and shaken in a Parr hydrogenator for 47 h. The resulting mixture is then filtered through celite and evaporated to give 197 mg (0.83 mmol, a 62% yield) of the title compound as a white solid. mp: 189-194° C.; MS (ES) m/z 238 (MH)+.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:11][C:3]=12.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30](B(O)O)[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.O>[F:8][C:7]1[C:2]([C:28]2[CH:27]=[C:26]([F:25])[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])=[C:3]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[NH:9][C:4]2=[N:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc3c(Cl)c(F)cnc3[nH]2)CC1
Reactant: COc1ccc(F)cc1B(O)O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(F)cc1-c1c(F)cnc2[nH]c(C3CCN(C(=O)OC(C)(C)C)CC3)cc12
Temperature: 120 °C

Procedure:
A mixture of Example 255B (600 mg, 1.696 mmol), (5-fluoro-2-methoxyphenyl)boronic acid (403 mg, 2.374 mmol), phenylallylchloro[1,3-bis(diisopropylphenyl)-2-imidazol-2-ylidene]palladium(II) (110 mg, 0.170 mmol), and potassium phosphate (1080 mg, 5.09 mmol) in 12 mL tetrahydrofuran and 3 mL water was degassed with nitrogen and heated in a Biotage microwave for 40 minutes at 120° C. The mixture was extracted with ethyl acetate and purified by silica gel column chromatography eluting with 0-5% methanol in dichloromethane to afford the title compound. MS (ESI(+)) m/e 444 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[CH3:9][C:10]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.[Pd].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>[CH:9]([C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1)=[CH2:10]
Reactant: C=CB1OC(C)(C)C(C)(C)O1
Reactant: Nc1cc(Cl)ncn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(N)ncn1
Temperature: 90 °C
Reaction time: 15 h
Yield: 79.2 %

Procedure:
A mixture of 6-chloropyrimidin-4-amine (6.5 g, 0.050 mol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (9.24 g, 0.060 mol), tetrakis(triphenylphosphine)-palladium(0) (3.9 g, 0.0030 mol) and sodium carbonate (21 g, 0.20 mol) in dioxane (300 mL) and H2O (30 mL) was stirred at 90° C. under nitrogen for 15 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc (400 mL) and water (150 mL). The organic layer was separated, dried over Na2SO4, and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with DCM/MeOH (20:1) to give the desired product as a white solid (4.8 g, 80% yield). LCMS (ESI) m/z: 122.1 [M+H+].
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:52][C@@H:53]3[CH2:55][C@H:54]3[C:56]([O:58][CH2:59][CH3:60])=[O:57])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)Cl>[CH:1]1([N:4]([CH2:39][C:40]2[CH:41]=[C:42]([CH:43]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:45]=2)[O:51][CH2:52][C@@H:53]2[CH2:55][C@H:54]2[C:56]([O:58][CH2:59][CH3:60])=[O:57])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H]1C[C@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution tert-butyl (3R,4S)-3-({cyclopropyl[3-{[(1R,2R)-2-(ethoxy-carbonyl)cyclopropyl]methoxy}-5-(3-methoxypropyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in DCM (0.05 M) was added 4 M HCl in dioxane (10 eq.) and stirred at rt for 5 h. The reaction was concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% [2 M NH3 in MeOH] in DCM) to afford the title compound as a colorless oil.
Reaction SMILES: C([O-])(=O)C.[NH4+].[C:6]([C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3([C:33]([NH2:35])=[O:34])[CH2:32][CH2:31]3)[C:19]([Cl:36])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)(=O)[CH3:7].C([BH3-])#[N:38].[Na+].Cl>CO.C1COCC1.O>[NH2:38][CH:6]([C:9]1[N:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3([C:33]([NH2:35])=[O:34])[CH2:31][CH2:32]3)[C:19]([Cl:36])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[CH3:7]
Reactant: CC(=O)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(N)c1ccc(Nc2ncc(Cl)c(CCc3ccccc3C3(C(N)=O)CC3)n2)cn1
Reaction time: 0.33 h
Yield: 85.6 %

Procedure:
Ammonium acetate (0.587 g, 7.61 mmol) was added to a solution of 1-(2-(2-(2-((6-Acetylpyridin-3-yl)amino)-5-chloropyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 32 (0.166 g, 0.381 mmol) in MeOH (5 mL) and THF (5 mL) and the mixture was stirred for 20 minutes under a nitrogen atmosphere. Sodium cyanoborohydride (0.017 g, 0.27 mmol) was added and the mixture was stirred for 5 hours. Additional sodium cyanoborohydride (0.017 g, 0.27 mmol) was added and the mixture was stirred for 22 hours at 35° C. Water (10 mL) was added to the mixture which was then acidified with 20% aqueous hydrochloride (10 mL). The aqueous phase was washed with Et2O (2×30 mL) and then basified with solid potassium hydroxide to pH 10. The aqueous phase was extracted with DCM (3×30 mL) and the combined organics were washed with brine, dried (Na2SO4), adsorbed onto silica and purified by silica column chromatography (Combiflash Rf, 12 g SiO2 Cartridge, 0-30% MeOH in DCM) to give the title compound 33 as a white solid (0.101 g, 60%). LCMS-B: rt 4.32 min; m/z 437 [M+H]+.