Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH2:30][CH3:31])[C:23](=[O:29])[N:24]([CH2:27][CH3:28])[C:25]=2[CH3:26])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.[ClH:34]>O1CCOCC1>[ClH:34].[CH3:1][O:2][C:3](=[O:33])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[C:21](=[O:32])[N:22]([CH2:30][CH3:31])[C:23](=[O:29])[N:24]([CH2:27][CH3:28])[C:25]=2[CH3:26])=[CH:18][CH:19]=1)[NH2:5]
Reactant: CCn1c(C)c(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc2)c(=O)n(CC)c1=O
Agent: Cl
Solvent: C1COCCO1
Product: CCn1c(C)c(-c2ccc(C[C@H](N)C(=O)OC)cc2)c(=O)n(CC)c1=O
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of N-[(1,1-dimethylethoxy)carbonyl]-4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrirnidinyl)-L-phenylalanine methyl ester (3.87 mmol, 1.78 g) in dioxane (10 mL) was added 4N hydrochloric acid in dioxane (20 mmol, 5 mL) at room temperature and the solution was stirred for 1 h. The solution was concentrated and was diluted with diethyl ether to form a white solid. The mother liquor was decanted and the residue was dried on a rotary evaporator and then under high vacuum to afford 0.72 g (47% yield) of 4-(1,3-diethyl-6-methyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester hydrochloride salt as an amorphous solid. ES-HRMS m/e calcd for C19H25N3O4 (M+Na) 382.1737, found 382.1736.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6][C:5](=[O:12])[O:4][C:2]2=[O:3].[CH2:13](I)[CH2:14][CH3:15].[H-].[Na+]>>[CH2:13]([N:6]1[C:5](=[O:12])[O:4][C:2](=[O:3])[C:1]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12)[CH2:14][CH3:15]
Reactant: CCCI
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Product: CCCn1c(=O)oc(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of isatoic anhydride (100 g) and propyl iodide (66 ml) in dimethylfomamide (600 ml) at 0° C., under nitrogen, was added sodium hydride (28 g of a 55% dispersion in mineral oil) portionwise. The mixture was allowed to warm to room temperature and stirred for 18 h. The solvent was then removed in vacuo and the residue partitioned between ethyl acetate (1000 ml) and water (500 ml). The organic phase was separated, washed with brine (2×500 ml), dried (MgSO4) and evaporated. The residue was triturated with anhydrous diethyl ether to give the title compound (57 g). 1H NMR (360 MHz, CDCl3) δ1.06 (3H, t, J=7.5 Hz), 1.75-1.86 (2H, m), 4.01-4.05 (2H, m), 7.17 (1H, d, J=8.5 Hz), 7.26-7.32 (1H, m), 7.73-7.78 (1H, m), 8.17 (1H, dd, J=7.9 and 1.7 Hz). MS (CI) m/e 205 [MH]+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[N:26][C:25]([NH2:28])=[C:24]4[O:29][C:30]([C:32]5[CH:41]=[CH:40][CH:39]=[C:38]6[C:33]=5[CH:34]=[CH:35][N:36]=[CH:37]6)=[CH:31][C:23]=34)[CH:19]=[N:18]2)[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[NH2:28][C:25]1[N:26]=[CH:27][C:22]([C:20]2[CH:19]=[N:18][N:17]([CH:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][OH:8])[CH2:16][CH2:15]3)[CH:21]=2)=[C:23]2[CH:31]=[C:30]([C:32]3[CH:41]=[CH:40][CH:39]=[C:38]4[C:33]=3[CH:34]=[CH:35][N:36]=[CH:37]4)[O:29][C:24]=12
Reactant: CC(C)(C)[Si](C)(C)OCCN1CCC(n2cc(-c3cnc(N)c4oc(-c5cccc6cnccc56)cc34)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Nc1ncc(-c2cnn(C3CCN(CCO)CC3)c2)c2cc(-c3cccc4cnccc34)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
4-{1-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)piperidin-4-yl]-1H-pyrazol-4-yl}-2-(isoquinolin-5-yl)furo[2,3-c]pyridin-7-amine (60.8 mg, 0.112 mmol) was dissolved in THF (1.2 mL) and tetra-n-butylammonium fluoride (1.0 M in THF, 1.35 mL, 1.35 mmol) was added to the reaction. The reaction stirred 16 h at RT. The reaction was washed with sodium carbonate (2×), brine 2× and extracted with EtOAc (3×). The organic layers were collected, dried with sodium sulfate, filtered and then concentrated in vacuo to a solid. Purification by flash chromatography (0 to 15% NH3/MeOH:EtOAc) afforded 10.1 mg (34%) of the title compound. 1H NMR (400 MHz, CD3OD): δ 9.32 (s, 1 H), 8.54-8.58 (m, 1 H), 8.49 (d, J=6.32 Hz, 1 H), 8.34 (dd, J=7.33, 1.01 Hz, 2 H), 8.23 (d, J=8.08 Hz, 1 H), 8.13 (s, 1 H), 7.91 (d, J=7.07 Hz, 1 H), 7.81 (dd, J=8.08, 7.33 Hz, 1 H), 7.49 (s, 1 H), 4.18-4.32 (m, 1 H), 3.71 (t, J=6.06 Hz, 2 H), 3.14 (d, J=12.13 Hz, 2 H), 2.60 (t, J=6.06 Hz, 2 H), 2.25-2.36 (m, 2 H), 2.12-2.24 (m, 4 H); MS (ESI): 455.21 [M+H]+; HPLC tR=0.74 min (TOF: polar—3 min).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:5]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1.[CH3:22][N:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[C:25]([CH3:38])[C:24]1=[O:39].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:22][N:23]1[C:24](=[O:39])[C:25]([CH3:38])=[CH:26][C:27]([C:2]2[CH:3]=[C:4]([NH:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])[CH:5]=[C:6]([O:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=2)=[CH:28]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cn(C)c1=O
Reactant: CCS(=O)(=O)Nc1cc(Br)cc(OCc2ccccc2)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CCS(=O)(=O)Nc1cc(OCc2ccccc2)cc(-c2cc(C)c(=O)n(C)c2)c1
Temperature: 75 °C
Yield: 104.5 %

Procedure:
A mixture of N-(3-bromo-5-phenylmethoxyphenyl)ethanesulfonamide (60 mg, 0.16 mmol), 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-one (40 mg, 0.16 mmol), Pd(dppf)Cl2 (12 mg) and K3PO4 (88 mg, 0.40 mmol) in dioxane (1.5 mL) and water (150 uL) was purged with nitrogen, capped, and heated to 75° C. for 2 h. After the mixture was filtered through a short bed of celite, the filtrate was concentrated in vacuo and purified by silica gel column chromatography using a gradient of MeOH (0 to 10%) in DCM to afford the title compound (69 mg, 94%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.15-1.24 (m, 3H) 2.04-2.13 (m, 3H) 3.04-3.17 (m, 2H) 3.48-3.54 (m, 3H) 5.08-5.17 (m, 2H) 6.74-6.80 (m, 1H) 6.90-6.98 (m, 2H) 7.33-7.49 (m, 5H) 7.59-7.63 (m, 1H) 7.90-7.95 (m, 1H) 9.57-10.01 (b.s., 1H). LCMS (M+H)+=413.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(O)cc1)c1ccccc1
Reaction time: 18 h
Yield: 71.5 %

Procedure:
A solution of benzoyl chloride (2.30 ml, 20.0 mmol) in tetrahydrofuran (25 ml) was added dropwise to a solution of 4-aminophenol (2.18 g, 20.0 mmol) and triethylamine (10 ml) in tetrahydrofuran (75 ml) at ambient temperature and the reaction allowed to stir for a further 18 hours. The reaction was poured into water and the solid material which formed was collected by suction filtration. Recrystallisation from ethyl acetate/isohexane (1:1), followed by solvent evaporation in vacuo, yielded N-benzoyl 4-hydroxyaniline (3.05 g, 72% yield) as a white solid:
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:22]2[CH2:24][CH2:23]2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[N:7][C:8]=1[CH2:9][O:10][CH3:11].[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][C:34]=1[CH3:40])([CH3:31])[CH3:30])[CH3:26].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.CCOCC>[CH2:25]([O:27][C:28](=[O:41])[C:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:2][C:3]2[C:4]([CH:22]3[CH2:24][CH2:23]3)=[N:5][C:6]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:7][C:8]=2[CH2:9][O:10][CH3:11])=[CH:35][C:34]=1[CH3:40])([CH3:30])[CH3:31])[CH3:26]
Reactant: COCc1nc(-c2ccc(C(F)(F)F)cc2)nc(C2CC2)c1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(COC)nc(-c3ccc(C(F)(F)F)cc3)nc2C2CC2)cc1C

Procedure:
A solution of 200 mg (0.56 mmol) 5-chloromethyl-4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 113H]), 134 mg (0.56 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 237 mg (0.73 mmol) cesium carbonate in 3 ml DMF was stirred for 3 h at RT. The reaction mixture was taken up in ether and washed with 1N HCl and water. After purification of the crude product by chromatography over silica gel with AcOEt/heptane 1:3, 257 mg of pure 2-{4-[4-cyclopropyl-6-methoxymethyl-2-(4-trifluoromethyl-phenyl)-pyrimidin-5-ylmethoxy]-2-methyl-phenoxy-2-methyl-propionic acid ethyl ester could be isolated.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][P:11]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]([NH:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25](Cl)=[CH:24][N:23]=3)=[C:17]([O:42][CH3:43])[CH:16]=2)(=[O:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[CH3:43][O:42][C:17]1[CH:16]=[C:15]([P:11]2(=[O:14])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:20]=[CH:19][C:18]=1[NH:21][C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([CH:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(P2(=O)CCN(Cc3ccccc3)CC2)ccc1Nc1ncc(Cl)c(Nc2ccccc2S(=O)(=O)C(C)C)n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: COc1cc(P2(=O)CCNCC2)ccc1Nc1nccc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Yield: 42.2 %

Procedure:
A flask was charged with N2-[4-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-2-methoxyphenyl]-5-chloro-N4-[2-(propan-2-ylsulfonyl)phenyl]pyrimidine-2,4-diamine (40.0 mg, 0.0625 mmol) and 10% Pd—C (40.0 mg). The flask was evacuated and filled with nitrogen. Anhydrous methanol (2 mL) was added to the flask and the flask was equipped with a reflux condenser with a nitrogen inlet. Ammonium formate (31.5 mg, 0.500 mmol) was added in one portion at room temperature. The resulting mixture was stirred at reflux for 3 h. The reaction was filtered through a Celite pad and the Celite was washed with 2×5 mL methanol. The combined filtrate and washing was evaporated in vacuo. The crude residue was purified by prep-HPLC to afford the final compound (13.6 mg, 42% yield). MS/ES+: m/z=516.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2].Br[CH2:20][CH2:21]CCCC.BrCC(CC)CCCC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH:14]([CH2:20][CH3:21])[CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2]
Reactant: C#Cc1c(CCCCCC)ccc2ccccc12
Reactant: CCCCCCBr
Agent: CCCCC(CC)CBr
Product: C#Cc1c(CC(CC)CCCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-(2-ethylhexyl)naphthalene was prepared in a similar manner to 1-ethynyl-2-hexylnaphthalene, except that bromohexane was replaced by 1-bromo-2-ethylhexane.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.9 %

Procedure:
To a solution of 5-bromoindanone (2.2 g, 0.01 mol) in a mixture of methanol (50 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.78 g, 0.02 mol) and the reaction mixture was stirred at room temperature overnight. The solution was concentrated and the residue was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated to give 2.15 g of crude material. 1H NMR (300 MHz, CDCl3) 6 ppm 157 (s, 1 H) 1.87-2.02 (m, 1 H) 2.40-2.59 (m, 1 H) 2.73-2.88 (m, 1 H) 2.95-3.11 (m, 1 H) 5.12-5.25 (m, 1 H) 7.29 (s, 1 H) 7.32-7.43 (m, 2 H). MS (ESI), m/z 416.0 (M+205)+.
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([C:20]([NH:22][CH:23]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26])=[O:21])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[C:27]1([CH:23]([NH:22][C:20](=[O:21])[C@H:11]([CH2:10][C:9]([OH:33])=[O:8])[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])[CH2:24][CH2:25][CH3:26])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCCC(NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(NC(=O)[C@H](CC(=O)O)NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.9 %

Procedure:
3.50 g of Compound 1 obtained in Synthesis Example 1 was dissolved in 15 mL of ethyl acetate, and 0.656 g of 5% palladium carbon (50% moisture content) was added thereto. Then, the inside of the reaction system was substituted with hydrogen, and the reaction system was stirred at room temperature overnight and subjected to hydrogenolysis. The 5% palladium carbon was filtered off, and washed with 80 mL of ethyl acetate. Then, the organic layers were combined, distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 2.58 g of Compound 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19](OC)=O)[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=2)=[CH:4][C:3]=1[CH3:23].FC1C=CC(C2C=[C:33](COS(C)(=O)=O)[C:34](=O)[N:35]([CH2:37][CH:38](C)C)N=2)=CC=1C.C(NCC)C>>[CH2:34]([N:35]([CH2:19][C:10]1[C:11](=[O:18])[N:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:23])[CH:4]=2)[CH:9]=1)[CH2:37][CH3:38])[CH3:33]
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)ccc1F
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O
Solvent: CCNCC
Product: CCN(CC)Cc1cc(-c2ccc(F)c(C)c2)nn(CC(C)C)c1=O

Procedure:
Following the procedure of Example 9 (4), 6-(4-fluoro-3-methylphenyl)-2-isobutyl-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and diethylamine were reacted to yield the title compound as a slightly yellow oil (yield: 94.7%).
Reaction SMILES: ClC1C=CC2OC(NC[C@@H]3[C@H](C)CCCN3C(OCC=C)=O)=NC=2C=1.[NH2:26][CH2:27][C@@H:28]1[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]1[C:35]([C:37]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=1[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=1)=[O:36].Cl[C:51]1[O:52][C:53]2[CH:59]=[C:58]([F:60])[CH:57]=[CH:56][C:54]=2[N:55]=1>>[F:60][C:58]1[CH:57]=[CH:56][C:54]2[N:55]=[C:51]([NH:26][CH2:27][C@@H:28]3[C@H:33]([CH3:34])[CH2:32][CH2:31][CH2:30][N:29]3[C:35]([C:37]3[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:38]=3[C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:36])[O:52][C:53]=2[CH:59]=1
Reactant: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Fc1ccc2nc(Cl)oc2c1
Agent: C=CCOC(=O)N1CCC[C@@H](C)[C@H]1CNc1nc2cc(Cl)ccc2o1
Product: Cc1ccc(-c2ccccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3ccc(F)cc3o2)c1

Procedure:
The title compound was synthesized following the same general protocol as described for (2S,3R)-allyl 2-(((5-chlorobenzo[d]oxazol-2-yl)amino)methyl)-3-methylpiperidine-1-carboxylate in Example A27, using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(pyridin-2-yl)phenyl)methanone and 2-chloro-6-fluorobenzo[d]oxazole. ESI-MS (m/z): 459 [M+1]+.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)=O.O.[NH2:15]N>>[NH:2]1[CH:3]=[CH:4][C:5]([C:7]2[CH:12]=[N:11][CH:10]=[CH:9][N:8]=2)=[N:15]1
Reactant: NN
Reactant: CN(C)C=CC(=O)c1cnccn1
Solvent: O
Product: c1cnc(-c2cc[nH]n2)cn1

Procedure:
A mixture of 496 mg of 3-dimethylamino-1-(2-pyrazinyl)-2-propen-1-one and 10 ml of hydrazine hydrate was heated at 90°-100° C. for 16 hours, then allowed to cool, giving 210 mg of 1H-pyrazol-3-yl-pyrazine.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:10](=[N:12][NH:13]C(OC(C)(C)C)=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S:21](Cl)(Cl)=O>C(OCC)(=O)C>[CH3:1][O:2][N:3]=[C:4]([C:10]1[N:12]=[N:13][S:21][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=NOC)C(C)=NNC(=O)OC(C)(C)C
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)C(=NOC)c1csnn1
Temperature: 50 °C
Reaction time: 0.05 h

Procedure:
A mixture of ethyl 2-methoxyimino-3-t-butoxycarbonylhydrazonobutyrate (a mixture of syn and anti isomers) (28.7 g.) and thionyl chloride (30 ml.) was warmed with stirring on a water bath of 50° C. for 3 minutes and then stirred for 5 minutes at ambient temperature to give black solution. To the reaction mixture was added ethyl acetate (200 ml.) and the mixture was poured into ice-water (300 ml.). The ethyl acetate layer was separated, washed in turn with water, with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride. After drying over magnesium sulfate, the ethyl acetate solution was treated with activated charcoal and concentrated to give black oil. The oil was purified by column chromatography on silica gel using a mixture of benzene and ethyl acetate (19:1) as an eluent to give ethyl 2-methoxyimino-2-(1,2,3-thiadiazol-4-yl)acetate (anti isomer) (4 g.).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([O:12]CC)=O)[C:3]1=[O:15].[NH2:16][C:17]1[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=1.BrC1C=CC=CC=1>>[CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([NH:16][C:17]2[CH:21]=[CH:20][N:19]([CH3:22])[N:18]=2)=[O:12])[C:3]1=[O:15]
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1c(O)cc(C)n(C)c1=O
Solvent: Brc1ccccc1
Product: Cc1cc(O)c(C(=O)Nc2ccn(C)n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 62.8 %

Procedure:
213 mg of ethyl 1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 79 mg of 3-amino-1-methylpyrazole were added to 2.5 ml of bromobenzene, then, the mixture was stirred for 6.5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature. The resulting solid was collected by filtration, and washed with a mixed solvent of t-butyl methyl ether and hexane and dried to obtain 134 mg of 1,6-dimethyl-4-hydroxy-N-(1-methylpyrazol-3-yl)-2-oxo-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 25) represented by the formula:
Reaction SMILES: [Br:1][CH:2]([CH3:12])[C:3]([O:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1)=O.O1C=CC=C1C[SH:19]>>[Br:1][CH:2]([CH3:12])[C:3](=[S:19])[O:5][CH2:6][C:7]1[O:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(Br)C(=O)OCc1ccco1
Reactant: SCc1ccco1
Product: CC(Br)C(=S)OCc1ccco1

Procedure:
The synthetic procedure is similar to the reaction protocol for furfuryl 2 bromopropionate except that 2 furylmethanethiol (5.94 g, 0.052 mol) is used in place of 2-furylmethanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:4][CH2:3]1.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:1][C:2]1([CH3:34])[C:11]2[CH:10]=[C:9]([Se:12][C:13]#[C:14][C:15]3[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:4][CH2:3]1
Reactant: COC(=O)c1ccc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)cc1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C#C[Se]c2ccc3c(c2)C(C)(C)CC=C3c2ccc(C)cc2)ccc1C(=O)O
Reaction time: 15 h

Procedure:
0.55 g (1.1 mmol) of methyl 4-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-2-naphthylselanylethynyl)-2-methoxybenzoate is dissolved in 15 ml of tetrahydrofuran and 2 drops of water. 0.26 g (6.4 mmol) of sodium hydroxide is added. The medium is stirred for 15 hours, acidified with 2N hydrochloric acid solution and then extracted with ethyl acetate. The solid obtained is purified by chromatography (eluent: 3/7 heptane/ethyl acetate). A white solid is obtained (0.53 g; yield=99%; m.p.=150° C.).
Reaction SMILES: Cl.[C:2]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1)#[N:3].C[O:13][C:14](=O)[C:15]1[C:20]([I:21])=[C:19]([F:22])[CH:18]=[CH:17][C:16]=1[CH2:23]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:22][C:19]1[C:20]([I:21])=[C:15]2[C:16]([CH2:23][N:3]([CH2:2][C:4]3[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=3)[C:14]2=[O:13])=[CH:17][CH:18]=1
Reactant: N#Cc1ccc(CN)cc1
Reactant: COC(=O)c1c(CBr)ccc(F)c1I
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(CN2Cc3ccc(F)c(I)c3C2=O)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
A mixture of 4-cyano-benzyl amine hydrochloride (0.218 g, 5.0 mmol), 2-bromomethyl-5-fluoro-6-iodo-benzoic acid methyl ester (0.373 g, 1.0 mmol), and K2CO3 (0.276 g, 2 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 6-fluoro-7-iodo-2-(4-cyano-benzyl)-2,3-dihydro-isoindol-1-one (0.100 g, 26%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.19 (s, 2H), 4.84 (s, 2H), 7.22-7.68 (m, 6H). GC-MS: m/z 392 (M)+.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=C[C:42]([O:43]C2C=NC=CC=2)=CC=1OC)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=5)=[CH:26][C:25]=4[O:43][CH3:42])[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Oc2cccnc2)cc1OC
Reactant: O=C1C(n2cc(-c3ccc(Oc4cccnc4)cc3)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Product: COc1cc(Oc2cccnc2)ccc1-c1cn(C2CCc3c(F)cccc3N(CC(F)(F)F)C2=O)nn1

Procedure:
Prepared as for 6-fluoro-3-{4-[4-(pyridin-3-yloxy)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 3-(4-ethynyl-3-methoxyphenoxy)pyridine as the alkyne.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:18](=O)[CH3:19])[CH:15]=[CH:16][CH:17]=1.[C:21]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22].C(Cl)Cl>C(O)(=O)C.O>[C:21]([C:23](=[C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=1)[CH3:19])[C:24]([O:26][CH2:27][CH3:28])=[O:25])#[N:22]
Reactant: COc1cccc(C(C)=O)c1
Reactant: CCOC(=O)CC#N
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(C#N)=C(C)c1cccc(OC)c1
Temperature: 25 °C
Yield: 86.3 %

Procedure:
Hexamethyldisilazane (17.45 mL, 83 mmol) was added dropwise to acetic acid (38.1 mL, 666 mmol) (caution exothermic, maintain below 70° C.) stirred under an atmosphere of nitrogen. The resulting mixture was added to a solution of 1-[3-(methyloxy)phenyl]ethanone (9.14 mL, 66.6 mmol) and ethyl cyanoacetate (11.75 mL, 110 mmol) in acetic acid (16 mL), which was then stirred at 70° C. for 18 h. The mixture was then allowed to cool to RT and DCM (350 mL) and water (125 mL) were added. The organic layer was then separated and washed with additional water (125 mL) and dried with anhydrous MgSO4, filtered and evaporated to dryness. The residue was purified on silica, eluting with a gradient of 0-30% ethyl acetate in isohexane and further purified on silica, eluting with a gradient of 0-25% ethyl acetate in isohexane, to afford the title compound (14.1 g). LCMS (A) m/z: 246 [M+1]+, Rt 1.28 min (basic).