Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:11]1[CH2:15][C@@H:14]([F:16])[C@@H:13]([CH2:17][NH:18][CH:19]2[CH2:21][CH2:20]2)[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[C].[Pd]>[CH:19]1([NH:18][CH2:17][C@@H:13]2[C@H:14]([F:16])[CH2:15][NH:11][CH2:12]2)[CH2:21][CH2:20]1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CNC2CC2)[C@H](F)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: F[C@@H]1CNC[C@@H]1CNC1CC1
Yield: 92 %

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine (2.29 g) was dissolved in ethanol (25 mL). To this solution, 10% palladium carbon (229 mg) was added and the mixture was stirred at room temperature for 1.5 hours under a stream of hydrogen gas. The catalyst in the reaction mixture was filtered and was washed with ethanol. The filtrate and the washings were combined and concentrated under reduced pressure. The resulting residue was distilled under reduced pressure to give (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a colorless oil (1.14 g). This compound was identical to the compound obtained in Reference Example 8 (Process I).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH2:2]1.[Li]CCCC.[CH3:12][O:13][CH2:14][CH2:15]Br>C1COCC1>[CH3:12][O:13][CH2:14][CH2:15][CH:2]1[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: C1CSCSC1
Reactant: COCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC1SCCCS1
Temperature: -78 °C
Yield: 96 %

Procedure:
A solution of 1,3-dithiane (15.12 g, 126.0 mmol) in dry THF (150 mL) was treated at 0° C. with BuLi (53.0 mL of a 2.5 M solution, 132.5 mmol, 1.05 eqiuv) for 1.5 h. The reaction mixture was cooled to −78° C., and 2-bromoethyl methyl ether was added (11.3 mL, 16.7 g, 120.2 mmol). The reaction mixture was allowed to warm overnight to room temperature. The reaction was quenched by addition of saturated aqueous NH Cl. The mixture was extracted with Et2O. The combined organic extracts were washed with water. The mixture was dried over Na2SO4. The mixture was filtered. The filtrate was concentrated at reduced pressure. The residue was chromatographed [silica, ethyl acetate/hexanes (1:19)] affording a viscous, colorless liquid (21.53 g, 96%): 1H NMR δ 1.84-1.93 (m, 1H), 1.96-2.03 (m, 2H), 2.07-2.15 (m, 1H), 2.78-2.93 (m, 4H), 3.34 (s, 3H), 3.51-3.55 (m, 4H), 4.19 (t, J=6.9 Hz, 1H); 13C NMR δ 26.16, 30.40, 35.58, 44.16, 58.84, 68.92; EI-MS: 178 (M+), 146, 133, 119/121, 71/73, 45.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].P(Cl)(Cl)([Cl:22])=O>>[Cl:1][C:2]1[C:3]([Cl:22])=[N:4][C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Cl)c[n+]([O-])c1-c1cccc(F)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COC(=O)c1cc(Cl)c(Cl)nc1-c1cccc(F)c1
Temperature: 90 °C
Yield: 75 %

Procedure:
Methyl 5-chloro-2-(3-fluorophenyl)nicotinate 1-oxide (3.0 g, 11 mmol) was stirred in phosphoryl chloride (30 mL) and heated at 90° C. for 1 hour. Evaporation and purification by flash column chromatography using ethyl acetate in hexanes (0-20%) gave the desired compound (2.4 g, 75%). LCMS calculated for C13H9Cl2FNO2 (M+H)+: m/z=300.0, 302.0. found: 299.8, 301.8. 1H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H), 7.40 (m, 2H), 7.22 (m, 1H), 7.17 (m, 1H), 3.73 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[C:12]([N:16]([CH3:21])[S:17]([CH3:20])(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.Br[C:24]1[CH:37]=[CH:36][C:27]([O:28][CH2:29][CH2:30][N:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)=[CH:26][CH:25]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:21][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:1][C:24]4[CH:25]=[CH:26][C:27]([O:28][CH2:29][CH2:30][N:31]5[CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:36][CH:37]=4)[N:22]=3)[CH:9]=[CH:8][CH:7]=2)[CH:11]=1)[S:17]([CH3:20])(=[O:19])=[O:18]
Reactant: CN(c1cccc(-c2cccn3nc(N)nc23)c1)S(C)(=O)=O
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN(c1cccc(-c2cccn3nc(Nc4ccc(OCCN5CCCC5)cc4)nc23)c1)S(C)(=O)=O

Procedure:
N-Methyl-N-(3-{2-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-[1,2,4]triazolo[1,5-a]pyridin-8-yl}-phenyl)-methanesulfonamide was prepared from N-[3-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-8-yl)-phenyl]-N-methyl-methanesulfonamide (75.0 mg, 0.236 mmol) and 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (71.0 mg, 0.263 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (25.0 mg, 0.0457 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan foam (0.018 g, 15%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.31 (d, J=6.4 Hz, 1H), 8.13 (s, 3H), 7.93 (d, J=7.8 Hz, 1H), 7.60 (d, J=7.4 Hz, 1H), 7.56-7.46 (m, 3H), 7.46 (d, J=8.9 Hz, 1H), 6.98-6.90 (m, 3H), 6.68 (s, 1H), 4.11 (t, J=6.0 Hz, 2H), 3.41 (s, 3H), 2.96-2.88 (m, 5H), 2.64 (br s, 4H), 1.87-1.77 (m, 4H). MS=507 (MH)+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH:9]1[C:14]2[NH:15][C:16]3[C:21]([C:13]=2[CH:12]=[C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:10]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3>C(O)(=O)C>[Br:1][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14]1[CH:9]=[N:10][C:11]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:12][C:13]2=1
Reactant: CCOC(=O)c1cc2c(cn1)[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(cn1)[nH]c1ccc(Br)cc12
Temperature: 25 °C
Yield: 98 %

Procedure:
Following a procedure in Chem. Bio. Chem, 2009, 10, 889-895, N-bromosuccinimide (37 mg, 0.208 mmol) was added to a solution of ethyl 9H-pyrido[3,4-b]indole-3-carboxylate (50 mg, 0.208 mmol) in acetic acid (1.5 ml) and stirred at room temperature. After 45 minutes the acetic acid was removed and the solid material was partitioned between EtOAc and NaHCO3. The organic layer was washed with water, brine, and dried over Na2SO4 to afford the desired compound in 98% yield.
Reaction SMILES: [CH:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][C:2]=1[CH2:11][OH:12].[H][H]>O1CCCC1.[C].[Pd]>[CH2:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][CH:2]1[CH2:11][OH:12]
Reactant: OCC1=CC2(CCCCC2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: OCC1CCC2(CCCCC2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.3 %

Procedure:
To a solution of spiro[4.5]dec-1-en-2-yl-methanol (50 mg) obtained in Step 5 of Example 15 in tetrahydrofuran (1 mL) was added 5% palladium carbon (5 mg), followed by stirring the reaction mixture under normal pressure in an atmosphere of hydrogen at room temperature for 20 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated. The residue was dissolved in methanol (1 mL). To the solution was added sodium borohydride (10 mg), followed by stirring the reaction mixture at room temperature for 1 hour. Then, after addition of 1N aqueous hydrochloric acid solution, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give spiro[4.5]dec-2-yl-methanol (30 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39]>>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][N:48]([C:21]2[N:20]=[C:19]([O:18][C:11]3[C:12]4[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:29]=[C:30]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:31]=[C:2]([F:1])[CH:3]=4)=[CH:9][CH:10]=3)[CH:24]=[CH:23][N:22]=2)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: CC(C)(C)OC(=O)N1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCOCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and piperazine-1-carboxylic acid t-butyl ester according to conditions described in general procedure C. Mp: 131-133° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.38 (s, 9 H), 3.27-3.34 (m, 8H), 3.50 (bs, 4 H), 3.77 (t, J=4.38 Hz, 4 H), 6.24-25 (m, 1 H), 7.04 (d, J=11.3 Hz, 1 H), 7.26 (d, J=8.4 Hz, 1 H), 7.44 (d, J=8.0 Hz, 1 H), 7.50 (s, 1 H), 7.56-7.63 (m, 3 H), 7.85 (d, J=8.4 Hz, 1 H), 8.01 (d, J=8.8 Hz, 1 H), 8.29-8.30 (m, 1 H), 10.48 (s, 1 H).
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][CH2:44][C:45]1[N:46]=[C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH2:56])[CH:53]=[N:52]2)[O:48][CH:49]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][CH2:44][C:45]1[N:46]=[C:47]([CH2:50][N:51]2[N:55]=[C:54]([NH:56][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:53]=[N:52]2)[O:48][CH:49]=1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: COCc1coc(Cn2ncc(N)n2)n1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCc1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (1.14 g, 5.26 mmol) in CH2Cl2 (30 mL) was treated at rt with DMAP (160 mg, 1.31 mmol), HOBt (854 mg, 6.32 mmol), EDC (2.52 g, 13.15 mmol) and DIPEA (3.60 mL, 21.03 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(methoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (1.10 g, 5.26 mmol) in CH2Cl2 (22 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (45 mL), the layers were separated and the org. phase was washed with water (45 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.20. LC-MS-conditions 07: tR=0.88 min, [M+H]+=409.11.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH:18][S:22]([CH3:21])(=[O:24])=[O:23])[CH:15]=[CH:16][CH:17]=1)[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: CC1(C)CC(c2cccc(N)c2)Nc2ccc(Cl)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(C)CC(c2cccc(NS(C)(=O)=O)c2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
3-(6-Chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (150 mg, 0.53 mmol) and methanesulfonyl chloride (60 mg, 0.63 mmol) were dissolved in pyridine (5 ml). The mixture was stirred at room temperature overnight. The solvent was removed and the residue was purified on column chromatography using petroleum ether/ethyl acetate=5:1 as eluent to afford N-[3-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-methanesulfonamide (149 mg, yield: 55%) as yellow solid. MS (ESI+APCI) M+1=445.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[CH:4][C:3]=1[C:11]([OH:13])=O.C(N(CC)CC)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.[O:48]([C:55]1[S:59][C:58]([CH2:60][NH2:61])=[CH:57][CH:56]=1)[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C)C=O.[Cl-].[Na+].O>[O:48]([C:55]1[S:59][C:58]([CH2:60][NH:61][C:11]([C:3]2[CH:4]=[C:5]3[CH2:10][CH2:9][CH2:8][C:6]3=[N:7][C:2]=2[NH2:1])=[O:13])=[CH:57][CH:56]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: NCc1ccc(Oc2ccccc2)s1
Reactant: Nc1nc2c(cc1C(=O)O)CCC2
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: CCN(CC)CC
Product: Nc1nc2c(cc1C(=O)NCc1ccc(Oc3ccccc3)s1)CCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3carboxylic acid described in Preparation Example C-5 (100 mg, 0.56 mmol), triethylamine (0.188 mL, 1.35 mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (298 mg, 0.67 mmol) were dissolved in N,N-dimethylformamide (3 mL), C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation Example 26 (138 mg, 0.67 mmol) was added, followed by stirring for 15 hours 20 minutes at room temperature. After the reaction was completed, the reaction solution was poured into brine, and the solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then concentrated, the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and the title compound (77 mg, 0.21 mmol, 38%) was obtained.
Reaction SMILES: [Br:1][C:2]1[C:3](O[C:6](=[O:8])[CH:7]=1)=[O:4].[CH3:9][NH2:10].C1COCC1.C([O-])(=O)C.[Na+]>C(OCC)C>[CH3:9][N:10]1[C:6](=[O:8])[CH:7]=[C:2]([Br:1])[C:3]1=[O:4]
Reactant: CN
Reactant: O=C1C=C(Br)C(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1C(=O)C=C(Br)C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Pursuant to steps a and b of Reaction Scheme 14, a solution of bromomaleic anhydride (52.8 g, 0.298 mol) in diethyl ether (250 mL) was cooled to 5° C. A 2 M solution of methylamine in THF (298 mL, 0.596 mol, 2 eq.) was added dropwise over 1 hour and the reaction stirred for a further 30 minutes, maintaining the temperature below 10° C. The resulting precipitate was filtered, washed with diethyl ether (2×100 mL) and air-dried for 30 minutes, then suspended in acetic anhydride (368 mL) and sodium acetate (12.2 g, 0.149 mol, 0.5 eq.) added. The reaction was heated to 60° C. for 2 hours and solvent was then removed in vacuo. The residue was taken up in DCM (500 mL) and washed with saturated sodium bicarbonate solution (2×500 mL) and water (2×300 mL). Organics were dried over MgSO4 (89 g), filtered and reduced in vacuo. The resulting oil was azeotroped with toluene (4×100 mL) to give N-methyl bromomaleimide as a beige solid. Yield=41.4 g (73%); 1H NMR (300 MHz, CDCl3) δ 6.95 (1H, s, CH), 3.07 (3H, s, NCH3).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.OC1C2N=NNC=2C=CC=1.Cl.[CH2:26]([O:28][C:29](=[O:49])[CH:30]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1)[CH3:27].C(N(CC)CC)C>CN(C)C=O.O>[CH2:26]([O:28][C:29](=[O:49])[CH:30]([NH:42][C:43]([O:45][CH2:46][CH:47]=[CH2:48])=[O:44])[CH2:31][C:32]1[O:36][N:35]=[C:34]([CH:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:11](=[O:13])[CH2:10][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH:33]=1)[CH3:27]
Reactant: C=CCOC(=O)NC(Cc1cc(C2CCCN2)no1)C(=O)OCC
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)NC(Cc1cc(C2CCCN2C(=O)Cc2ccc([N+](=O)[O-])cc2)no1)C(=O)OCC
Reaction time: 0.5 h
Yield: 16.3 %

Procedure:
A dimethyl formamide (82 mL) solution of 4-nitrophenylacetic acid (1.61 g, 8.87 mmol) in dimethyl formamide (82 mL) was stirred with 4-hydroxybenzotriazole monohydrate (1.40 g, 10.4 mmol) for 10 minutes. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride (1.86 g, 9.72 mmol) was added and the mixture was stirred until all 1-(3-dimethylaminopropyl)-3-ethylcarbodiimde hydrochloride had dissolved. To this solution, 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester hydrochloride from Example 1C (3.16 g, 8.25 mmol) was added and the mixture stirred 30 minutes followed by addition of triethyl amine (1.26 mL, 9.04 mmol). After the reaction had stirred at room temperature over night it was poured into water and extracted with ethyl acetate three times. The combined extracts were washed with a saturated solution of sodium bicarbonate, water (2×) and brine. The organic portion was dried over magnesium sulfate and concentrated. The resulting residue was chromatographed on a Biotage Flash 40S column eluting with ethyl acetate/hexanes (5:1) to yield the title compound as a yellow oil (674 mg, 15%). MS (CI) m/z 501.3 (M+1). Additionally, starting material 2-allyloxycarbonylamino-3-(3-pyrrolidin-2-yl-isoxazol-5-yl)-propionic acid ethyl ester was recovered (2.15 9, 75%). MS (CI) m/z338.1 (M+1)
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>CS(C)=O>[CH2:21]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@H:9]([CH2:12][C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[F:20])[CH:10]=[O:11])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: OC[C@@H](Cc1cc(F)ccc1F)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C[C@@H](Cc1cc(F)ccc1F)N(Cc1ccccc1)Cc1ccccc1
Temperature: 1.5 °C
Reaction time: 0.25 h

Procedure:
To a solution of (R)-2-Dibenzylamino-3-(2,5-difluoro-phenyl)-propan-1-ol (5.10 g, 13.9 mmol) in DMSO (1 mL) and Triethylamine (7.83 mL, 56.2 mmol) at −9° C. is added a solution of Sulfur Trioxide Pyridine Complex (4.43 g, 27.3 mmol) in DMSO (19.6 mL) over a period of 60 min, the reaction temperature is maintained below 4° C. The reaction is allowed to stir an additional 15 min at 0-3° C. after which the reaction is quenched by addition of water (50 mL) over a period of 60 min, the reaction temperature is maintained below 10° C. The product is extracted into MTBE, the organic phase is dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].I[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11]([CH2:17][CH2:18][CH3:19])=[N:10][C:9]=1[C:20]#[N:21].Cl.[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][C:25]=1B(O)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O.C(O)CC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:15][CH:14]([CH3:16])[CH2:13][N:12]1[C:8]2[C:29]3[CH:28]=[N:27][CH:26]=[CH:25][C:24]=3[N:23]=[C:20]([NH2:21])[C:9]=2[N:10]=[C:11]1[CH2:17][CH2:18][CH3:19]
Reactant: CCCc1nc(C#N)c(I)n1CC(C)C
Reactant: Nc1ccncc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CCCO
Solvent: O
Product: CCCc1nc2c(N)nc3ccncc3c2n1CC(C)C
Yield: 37.1 %

Procedure:
A solution of sodium carbonate (572 mg, 5.4 mmol) in deionized water (6 mL) was added to a solution of 5-iodo-1-(2-methylpropyl)-2-propyl-1H-imidazole-4-carbonitrile (634 mg, 2.0 mmol) and 4-aminopyridin-3-ylboronic acid hydrochloride salt (383 mg, 2.2 mmol) in n-propanol (15 mL), and nitrogen was bubbled through the resultant solution for 15 minutes. Palladium (II) acetate (22 mg, 0.1 mmol) and triphenylphosphine (79 mg, 0.3 mmol) were added. The reaction was evacuated and purged with nitrogen several times and then heated at reflux for 18 hours. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted several times with ethyl acetate. The combined organic fractions were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with 7% methanol in dichloromethane) to provide 210 mg of 1-(2-methylpropyl)-2-propyl-1H-imidazo[4,5-c][1,6]naphthyridin-4-amine as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(O)(=O)C.C(#N)[CH:14]([CH2:16][C:17]#[N:18])O>C(O)C.C(Cl)Cl>[O:8]1[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:14]1[CH2:16][C:17]#[N:18]
Reactant: Nc1ccccc1O
Reactant: N#CCC(O)C#N
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: N#CCc1nc2ccccc2o1
Yield: 71.8 %

Procedure:
To a solution of 2-aminophenol (5.0 g, 45.8 mmol) dissolved in 115 mL of anhydrous ethanol and 8 mL of glacial acetic acid was added malonitrile (9.08 g, 140 mmol) at 100° C. The resulting homogeneous solution was refluxed for 24 hours and the solvent was removed in vacuo to yield a red/brown oil. The oil was diluted with CH2Cl2 (100 mL) and any remaining solids were then removed by filtration. The mother liquor was washed twice with a saturated sodium bicarbonate solution and twice with water, dried over magnesium sulfate, filtered and evaporated to yield 5.2 g (71%) of the product as a yellow oil. This material was used in the subsequent reaction without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.[H-].[Na+].[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].O>CN(C)C=O>[OH:8][C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[CH:19][CH:20]=2)=[N:11][CH:10]=1
Reactant: CCCCCCCCBr
Reactant: Oc1ccc(-c2ncc(OCc3ccccc3)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(-c2ncc(O)cn2)cc1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 74.9 %

Procedure:
5-Benzyloxy-2-(4-hydroxyphenyl)pyrimidine (2 g, 0.0072 moles, Example 30) was dissolved in 15 ml of N,N-dimethylformamide in a 50 ml flask and 0.2 g of dry sodium hydride was added. After stirring the mixture for 15 minutes, 1.39 g (0.0072 moles) of octylbromide was added and the mixture was heated to 100° C. for 2 hours. Upon cooling to room temperature, 15 ml of water was added. The resulting solid was collected by filtration and the solid was then slurried in boiling methanol, cooled to room temperature, and again collected by filtration. The solid was hydrogenated on a Parr Hydrogenator with catalytic 10% palladium on carbon in tetrahydrofuran under 413.7 kPa hydrogen pressure for about 18 hours. When the hydrogenation was complete, the catalyst was removed by filtration, and the solvent was removed on a rotary evaporator to yield 1.62 g (75% yield) of 5-hydroxy-2-(4-(octyloxy)phenyl)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([C:5]([CH:7](C(=O)C)[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH2:4][CH2:3]1.N>C(O)C>[CH3:1][C:2]1([C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6])[CH2:3][CH2:4]1
Reactant: CCOC(=O)C(C(C)=O)C(=O)C1(C)CC1
Agent: N
Solvent: CCO
Product: CCOC(=O)CC(=O)C1(C)CC1
Temperature: 25 °C
Yield: 97.5 %

Procedure:
A solution comprising 55 grams of ethyl 2-(1-methylcyclopropanecarbonyl)-3-oxobutanoate and 160 ml of ethanol was stirred at room temperature and 60 ml of a 30% aqueous ammonia solution was added dropwise to this solution over a period of 10 minutes. Subsequently, the mixture was stirred for 1 hour and extracted with 300 ml of ethyl acetate and dilute aqueous hydrochloric acid. After neutralization and washing with water, the organic layer was dried over anhydrous sodium sulfate. The solvent was then removed and 43 grams of ethyl (1-methylcyclopropanecarbonyl)acetate was obtained as an oily material.