Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[C:16]1(=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:9][C:10]1[C:15]([C:16]2([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: Brc1ccccn1
Reactant: O=C1CCCC1
Agent: CC(C)[N-]C(C)C
Agent: O=C([O-])O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2cccnc2Br)CCCC1
Temperature: 25 °C
Reaction time: 1.33 h
Yield: 39.5 %

Procedure:
To a cold (−78° C.) solution of LDA (24.5 mmol) in dry THF (100 mL) was added 2-bromopyridine (2.0 mL, 20.9 mmol) and the resultant solution was stirred for 90 minutes. Cyclopentanone (4.0 mL, 45.2 mmol) was added and the mixture was stirred for and additional 80 minutes. The mixture was treated with saturated aqueous NaHCO3 (20 mL) and warmed to room temperature. The mixture was diluted with EtOAc (300 mL) and the phases were separated. The organic phase was washed with saturated aqueous NaHCO3 (3×25 mL) and brine (3×25 mL), dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (3:1 hexanes-EtOAc) provided 2.00 g (40%) of 1-(2-Bromo-pyridin-3-yl)-cyclopentanol as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[NH:12][CH2:11][CH2:10][C:9]=2[N:8]=1.Br[C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.NC1CCCCC1N.[Li+].[Cl-]>[Cu]I.CCOC(C)=O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:13](=[O:17])[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH2:11][CH2:10][C:9]=2[N:8]=1
Reactant: Fc1ccc(Br)nc1
Reactant: O=C1NCCc2nc(OCc3cccc(F)c3)ccc21
Agent: [Cu]I
Agent: NC1CCCCC1N
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccc(OCc3cccc(F)c3)nc2CCN1c1ccc(F)cn1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
2-((3-fluorobenzyl)oxy)-7,8-dihydro-1,6-naphthyridin-5(6H)-one (20 mg, 0.07 mmol) was dissolved into DMF (1 mL) and treated with 2-bromo-5-fluoropyridine (17 mg, 0.1 mmol), 1,2-diaminocyclohexane (4 mg, 0.04 mmol) and CuI (2 mg, 0.01 mmol). The reaction was stirred at 100° C. over 72 h and then poured onto 3M LiCl and EtOAc (5 mL each). The organic layers were dried over Na2SO4, concentrated and the residue purified RP-HPLC to give the compound, 2-((3-fluorobenzyl)oxy)-6-(5-fluoropyridin-2-yl)-7,8-dihydro-1,6-naphthyridin-5(6H)-one. LC-MS (M+H)=368.1.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li][C:17]([CH3:20])([CH3:19])[CH3:18].CCCCC.C(Br)C(=C)C>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[CH2:19][C:17]([CH3:20])=[CH2:18])([CH3:7])([CH3:6])[CH3:5]
Reactant: [Li]C(C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(F)cc1
Agent: C=C(C)CBr
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(C)Cc1cc(F)ccc1NC(=O)OC(C)(C)C
Temperature: -20 °C
Reaction time: 2.5 h
Yield: 80 %

Procedure:
A solution of N-Boc-4-fluoroaniline (9.02 g, 42.7 mmol) in THF (112 mL) was cooled to −60° C. using a cryocool instrument. The solution was treated with 1.7 M t-BuLi in pentane (63 mL, 106.7 mmol) dropwise. After the first equivalent of base was consumed, a yellow solution formed. The reaction was allowed to warm to −20° C. and was stirred at that temperature for 2.5 hours. The reaction was then treated with a solution of methallyl bromide (5.67 g, 42.7 mmol) in THF (35 mL) dropwise and stirred for an additional 1.5 hours at −20° C. The reaction was then quenched by addition of water. After coming to room temperature, the reaction was treated with ethyl acetate and extracted with water and brine, dried over MgSO4 and filtered. The solvent was then removed and the residue was purified on silica gel using a gradient of 0-25% ethyl acetate in hexane to afford 11.3 g (80% yield) of [4-Fluoro-2-(2-methyl-allyl)-phenyl]-carbamic acid tert-butyl ester as a white solid; 1H NMR (CDCl3, 400 MHz) δ 1.50 (s, 9H), 1.72 (s, 3H), 3.28 (s, 2H), 4.71 (s, 1H), 4.92 (s, 1H), 6.32-6.50 (m, 1H), 6.86 (dd, 1H, J1=3.0, J2=9.1), 6.93 (ddd, 1H, J1=3.0, J2=8.5, J3=11.5), 7.65-7.82 (m, 1H); HPLC-MS calcd. for C15H20FNO2 (M+H+-tBu) 210.1, found 210.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=O)=[CH:17][C:16]=1[NH2:24]>>[NH2:24][C:16]1[CH:17]=[C:18]([C:19]2[O:12][C:3]3[CH:4]=[C:5]4[C:10]([CH:9]=[CH:8][CH:7]=[CH:6]4)=[CH:11][C:2]=3[N:1]=2)[CH:22]=[CH:23][C:15]=1[O:14][CH3:13]
Reactant: Nc1cc2ccccc2cc1O
Reactant: COc1ccc(C(=O)O)cc1N
Product: COc1ccc(-c2nc3cc4ccccc4cc3o2)cc1N

Procedure:
Prepared by the method of Example 1a), from 3-amino-2-naphthol (476 mg, 2.9 mmol) and 4-methoxy-3-aminobenzoic acid (500 mg, 2.9 mmol) the subtitle compound was obtained, 120 mg (14%). 1H NMR (CDCl3) δ 8.06(s, 1H), 7.92–7.83(m, 3H), 7.67(dd, J=1.9, 8.2 Hz, 1H), 7.60(d, J=1.9 Hz, 1H), 7.38(m, 2H), 6.85(d, J=8.3 Hz, 1H), 3.88(s, 3H). MS 291 m/z (M+H)+.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][NH2:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:23](OCC)(=[O:28])[CH2:24][C:25]([CH3:27])=O>>[CH2:1]([O:13][CH2:14][CH2:15][NH:16][CH2:17][CH2:18][N:19]1[C:23](=[O:28])[CH2:24][C:25]([CH3:27])=[N:22][CH2:21][CH2:20]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCOCCNCCNCCN
Reactant: CCOC(=O)CC(C)=O
Product: CCCCCCCCCCCCOCCNCCN1CCN=C(C)CC1=O

Procedure:
Into an apparatus similar to that in Example 1, were charged 315.1 g (1 mole) of N-dodecoxyethyldiethylenetriamine and 130.1 g (1 mole) of ethyl acetoacetate at 150° to 160° C., 18 g of water and 46 g of ethanol were distilled off to obtain 4-dodecoxyethylaminoethyl-7-methyl-3,6-dihydro-2H-1,4-diazepin-5-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#N)[CH:6]=1.C(O)=[O:15]>[Ni]>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]=[O:15])[CH:6]=1
Reactant: COC(=O)Cc1cccc(C#N)c1
Reactant: O=CO
Agent: [Ni]
Product: COC(=O)Cc1cccc(C=O)c1
Temperature: 110 °C

Procedure:
A solution of (3-cyanophenyl)acetic acid methyl ester 47 (0.86 g, 4.9 mmol) in 88% formic acid (6 mL) is combined with Raney nickel alloy (0.48 g) and heated to reflux for 24 hours at 110° C. After cooling to room temperature, the alloy is removed by filtration over Celite. The filtrate is concentrated to ˜10% of the original volume and diluted with EtOAc (50 mL) and washed three times with water (20 mL). The organic layer is dried (MgSO4), filtered and concentrated to afford crude product, which is purified by silica gel chromatography using an EtOAc/hexane gradient to give (3-formylphenyl)-acetic acid methyl ester 48 as an oil: 1H-NMR (400 MHz, CDCl3) δ=9.97 (s, 1H), 7.40-7.52 (m, 4H), 3.68 (s, 3H), 3.67 (s, 2H). MS calculated for C10H11O3 (M+H+) 179.1, found 179.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[CH:4][N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]CC)=[O:14]>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([O:9][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([OH:15])=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: Fc1ccc(Br)nc1
Product: O=C(O)c1cccc(Oc2ccc(Br)nc2)c1

Procedure:
Prepared from 2-bromo-5-fluoropyridine and ethyl 3-hydroxybenzoate. 1H NMR (400 MHz, DMSO-d5) δ 13.12 (br. s., 1H), 8.28 (d, 1H), 7.78 (d, 1H), 7.69 (d, 1H), 7.56 (t, 1H), 7.48-7.54 (m, 2H), 7.39 (dd, 1H)
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](=[O:14])[CH2:3][CH2:2]1.C(O)CO.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>[Cu](Cl)Cl.O1CCOCC1>[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([OH:14])=[CH:3][CH:2]=1
Reactant: O=C1CCCc2[nH]c3ccccc3c21
Agent: Cl[Cu]Cl
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: OCCO
Solvent: C1COCCO1
Product: Oc1cccc2[nH]c3ccccc3c12
Temperature: 120 °C
Yield: 18.5 %

Procedure:
To a mixture of 1,2,3,9-tetrahydro-4H-carbazol-4-one (6.02 g, 32.5 mmol) in 1:1 ethylene glycol: p-dioxane (100 mL) at 80° C. is added copper (II) chloride (21 g, 156.2 mmol). The mixture is heated for 20 minutes. The mixture is then partitioned between water and ethyl acetate. The layers are separated and the organic layer is washed three times with water (200 mL). The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated. The residue is dissolved in DMF (100 mL) to which is added lithium bromide (7.04 g, 81.25 mmol) and lithium carbonate (6.0 g, 81.25 mmol). The mixture is heated at 120° C. for 4.5 hours. The mixture is then partitioned between water and ether. The ether layer is washed three times with water (200 mL). The ether layer is dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography, silica gel (800 mL), using CH2Cl2 as eluent gave 1.1 g (18%) of the title compound; 1H NMR (CDCl3) δ5.26, 6.57, 7.01, 7.26, 7.41, 8.05, 8.26; Anal. Calcd for C12H9NO: C, 78.67; H, 4.95; N, 7.64. Found: C, 78.04; H, 4.94; N, 7.58.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].N1CCCCC1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:10]=1/[CH:11]=[CH:19]\[C:20]([OH:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C=O)c1OCc1ccccc1
Reactant: O=C(O)CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: Cc1cccc(/C=C\C(=O)O)c1OCc1ccccc1

Procedure:
Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-(benzyloxy)-3-methylbenzaldehyde (20 g, 88.39 mmol, 1.00 equiv), propanedioic acid (27.6 g, 265.23 mmol, 3.00 equiv), piperidine (1.5 g, 17.62 mmol, 0.20 equiv) and pyridine (200 mL). The resulting solution was heated to reflux for 2 h in an oil bath. The reaction was then quenched by the addition of 1.5 L of water/ice. The pH value of the solution was adjusted to 2-3 with hydrogen chloride. The solids were collected by filtration. The filter cake was washed with 2×500 mL of water and 2×500 mL of hexane. This resulted in 21 g (89%) of (2Z)-3-[2-(benzyloxy)-3-methylphenyl]prop-2-enoic acid as a white solid. MS (ESI) m/z 269 ([M+H]+).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:25][C:22]1[CH:23]=[CH:24][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:13]=2[CH:21]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(Cl)cc2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(Cl)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.7 %

Procedure:
To a solution of [(S)-1-(6-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tert-butyl ester (1.20 g, 3.23 mmol) in DCM (5 mL) was added TFA (5 mL) and the mixture stirred at RT for 3 h. The crude mixture was loaded into an Isolute® SCX-2 cartridge then washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined and concentrated in vacuo to afford (S)-1-(6-chloro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a yellow oil (796 mg, 91%).
Reaction SMILES: [CH3:1][C:2](=C)[CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.I([O-])(=O)(=O)=[O:23].[Na+]>O1CCOCC1.O.ClCCl.[Os](=O)(=O)(=O)=O>[O:23]=[C:2]([CH3:1])[CH2:3][C:4]1([C:17]([O:19][CH3:20])=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=C(C)CC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)C1(CC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-(2-methylallyl)piperidine-1,4-dicarboxylate (2.2 g, 7.4 mmol) in dioxane/water (60 mL, 1/1) under nitrogen was added osmium tetroxide (0.038 g, 0.15 mmol) and sodium periodate (2.88 g, 13.5 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was then diluted with dichloromethane (50 mL), and washed with 20% Na2S2O3 (20 mL). The organic layers were combined and washed with brine (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrates were concentrated and the residue was purified by column chromatography eluting with 0-60% ethyl acetate/hexane to afford 1-tert-butyl 4-methyl 4-(2-oxopropyl)piperidine-1,4-dicarboxylate. LC-MS (IE, m/z): 322.26 (M+23)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=2)[C:22]([NH:24][C:25]2[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=2[F:32])=[O:23])[CH:5]=[CH:4][N:3]=1.[Cl:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([CH:44]=1)[NH2:43].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.N>CC(O)C.CO>[Cl:37][C:38]1[C:39]([N:47]2[CH2:52][CH2:51][N:50]([CH2:53][CH2:54][S:55]([CH3:58])(=[O:57])=[O:56])[CH2:49][CH2:48]2)=[CH:40][C:41]([O:45][CH3:46])=[C:42]([NH:43][C:2]2[N:7]=[C:6]([C:8]3[N:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]4=[N:10][C:9]=3[C:17]3[CH:18]=[CH:19][C:20]([O:34][CH2:35][CH3:36])=[C:21]([CH:33]=3)[C:22]([NH:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])=[O:23])[CH:5]=[CH:4][N:3]=2)[CH:44]=1
Reactant: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)cc1C(=O)Nc1c(F)cccc1F
Reactant: COc1cc(N2CCN(CCS(C)(=O)=O)CC2)c(Cl)cc1N
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: N
Agent: c1cc[nH+]cc1
Solvent: CC(C)O
Solvent: CO
Product: CCOc1ccc(-c2nc3ccccn3c2-c2ccnc(Nc3cc(Cl)c(N4CCN(CCS(C)(=O)=O)CC4)cc3OC)n2)cc1C(=O)Nc1c(F)cccc1F
Temperature: 80 °C
Yield: 38 %

Procedure:
In a 10 mL vial with septum cap, 5-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(ethyloxy)benzamide (Intermediate Example 6) (0.200 g, 0.395 mmol), 5-chloro-2-(methyloxy)-4-{4-[2-(methylsulfonyl)ethyl]-1-piperazinyl}aniline (0.165 g, 0.474 mmol) were taken up in iPrOH (3 mL) and pyridinium p-toluenesulfonate (0.238 g, 0.949 mmol) was added. The vial was sealed and heated to 80° C. overnight. When reaction was complete by MS, it was cooled to rt, neutralized with 7N ammonia in MeOH, absorbed onto silica gel and flash chromatographed. Fractions containing the desired product were concentrated and the resulting solid was triturated with diethyl ether, filtered and air dried to give the title compound (0.12 g, 0.15 mmol, 37%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.71 (s, 1H), 9.38 (dd, J=4.4, 1.1 Hz, 1H), 8.53 (s, 1H), 8.25 (d, J=5.3 Hz, 1H), 8.02 (d, J=0.4 Hz, 1H), 7.87 (s, 1H), 7.63-7.79 (m, 2H), 7.28-7.50 (m, 2H), 7.10-7.28 (m, 3H), 6.97 (t, J=6.9 Hz, 1H), 6.82 (s, 1H), 6.60 (d, J=5.2 Hz, 1H), 4.23 (q, J=6.7 Hz, 2H), 3.83 (s, 3H), 3.27-3.34 (m, 2H), 3.03 (s, 3H), 2.93-3.01 (m, 4H), 2.75 (t, J=6.6 Hz, 2H), 2.51-2.64 (m, 4H), 1.40 (t, J=6.8 Hz, 3H). MS (M+H, ES+) 817.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([O:14]C2C=CC=CC=2)=O)[CH:6]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>O1CCCC1>[NH2:25][C:23]1[CH:22]=[CH:21][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)=[O:14])[CH:6]=2)=[C:2]([Cl:1])[CH:24]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2Cl)ccn1)Oc1ccccc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCOCC3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A crude product of 4-(2-chloro-4-nitrophenoxy)-2-(phenoxycarbonylamino)pyridine (634.8 mg) was dissolved in tetrahydrofuran (6.5 ml), and then morpholine (0.942 ml) was added thereto at room temperature, followed by stirring overnight and evaporating the solvent under a reduced pressure. The resultant residue was dissolved in ethanol (20 ml)-water (5 ml), and then electrolytic iron powder (500 mg) and ammonium chloride (1 g) were added thereto, followed by heating under reflux for 1 hr. The reaction mixture was cooled down to room temperature, and filtered through celite to remove an insoluble portion, which was washed with ethyl acetate-tetrahydrofuran (1:1) and water. The organic layer of the filtrate was separated, washed with water and brine in this order, dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was purified by silica gel column chromatography (eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (283.3 mg) as pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:8])=[N:6][CH:7]=1.O[CH:10]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH:10]2[CH2:14][CH2:13][NH:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: Oc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1ccc(OC2CCNC2)nc1
Reaction time: 8 h

Procedure:
To a stirred solution of 5-chloro-2-pyridinol (323.9 mg; 2.5 mmol), tert-butyl 3-hydroxy-1-pyrrolidinecarboxylate (468.0 mg, 2.5 mmol) and triphenylphosphine polymer bound (1 g, 3 mmol) in THF/CH2Cl2 (1:1, 5 ml) slowly was added diethyl azodicarboxylate (435.5 mg 2.5 mmol). The solution was slowly stirred overnight Resin was then removed by filtration and washed with THF. The combined filtrates were evaporated to dryness. The resulting residue was purified by RP-HPLC (10-40% CH3CN). The pure material was treated with 95% TFA/5% H2O, 30 min. The TFA phase was then evaporated to give the desired product as a solid.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][C@@H:10]([N:12]3[C:20](=[O:21])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:22])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.[F-].[Na+].[F:32][C:33]([F:45])(S(F)(=O)=O)C(O[Si](C)(C)C)=O>CCOC(C)=O>[F:32][C:33]1([F:45])[C@@H:9]2[C@H:8]1[C@@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:11][C@H:10]2[N:12]1[C:20](=[O:21])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:22]
Reactant: C[Si](C)(C)OC(=O)C(F)(F)S(=O)(=O)F
Reactant: O=C1c2ccccc2C(=O)N1[C@H]1C=C[C@@H](c2ccccc2)C1
Agent: [F-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1C[C@H](c2ccccc2)[C@@H]2[C@H]1C2(F)F
Reaction time: 2 h
Yield: 29.4 %

Procedure:
A mixture of Example 54A (419 mg, 1.45 mmol), toluene (0.2 mL), and sodium fluoride (21.3 mg, 0.507 mmol) was heated in a 120° C. oil bath and trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.43 mL, 7.24 mmol) was added via syringe pump over 2 hours. After 2 hours, the mixture was diluted with EtOAc (50 mL) and washed with saturated aqueous NaHCO3 (25 mL) and brine (10 mL), dried (Na2SO4), and concentrated. The residue was purified by flash column chromatography (0-25% EtOAc/hexanes, gradient elution) to provide the title compound (145 mg, 0.427 mmol, 30% yield). MS (DCI) M/Z 357 [M+NH4]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36](Br)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[Cl:44][C:45]1[CH:46]=[C:47](B(O)O)[CH:48]=[C:49]([Cl:51])[CH:50]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:24][C:25]2[O:26][C:27]([CH3:43])([CH3:42])[C:28]([F:41])([F:40])[C@:29]([C:32]3[CH:37]=[C:36]([C:47]4[CH:46]=[C:45]([Cl:44])[CH:50]=[C:49]([Cl:51])[CH:48]=4)[CH:35]=[CH:34][C:33]=3[F:39])([CH3:31])[N:30]=2)([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(Br)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(-c4cc(Cl)cc(Cl)c4)ccc3F)C(F)(F)C(C)(C)O2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
In a manner analogous to that described in Example 9 a), the cross-coupling reaction of [bis-(4-methoxy-phenyl)-phenyl-methyl]-[(R)-4-(5-bromo-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-yl]-amine (intermediate C4.1) with 3,5-dichlorophenylboronic acid yielded the title compound (80% yield) as a white foam. MS (ISP): m/z=719.4 [M+H]+ and 721.0 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:18])=[C:6]([CH:17]=1)[CH2:7][N:8]1[C:12]([O:13][CH3:14])=[N:11][N:10]([CH3:15])[C:9]1=[O:16].C[Sn](C)(C)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(OCC)(=O)C>CN(C)C=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.[Cu]=O>[CH3:14][O:13][C:12]1[N:8]([CH2:7][C:6]2[CH:17]=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:3]=[CH:4][C:5]=2[CH3:18])[C:9](=[O:16])[N:10]([CH3:15])[N:11]=1
Reactant: COc1nn(C)c(=O)n1Cc1cc(Br)ccc1C
Reactant: C[Sn](C)(C)c1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1nn(C)c(=O)n1Cc1cc(-c2ccccn2)ccc1C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 41.4 %

Procedure:
To a solution of 0.44 g (1.4 mmol) of 4-(5-bromo-2-methylbenzyl)-5-methoxy-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 299 of the present invention) in 8 ml of N,N-dimethylformamide were added 30 mg (0.042 mmol) of PdCl2(PPh3)2 and 0.12 g (1.4 mmol) of copper (II) oxide powder and the mixture was stirred at 80° C. under an atmosphere of nitrogen for 30 minutes. To the reaction mixture was added a solution of 0.48 g (2.0 mmol) of trimethyl(2-pyridyl)tin in 4 ml of N,N-dimethylformamide and the mixture was stirred at 80° C. under an atmosphere of nitrogen for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water, and ethyl acetate was added thereto. The mixture was filtered with cotton and separated, and the organic layer was washed twice with water, dried and concentrated. The residue (0.43 g) was subjected to silica gel preparative thin layer chromatography (developed with ethyl acetate) to obtain 0.18 g of 5-methoxy-2-methyl-4-{2-methyl-5-(2-pyridyl)benzyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (the compound 152 of the present invention) as a viscous oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].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.[Fe+2]>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[C:15]([C:2]2[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Product: Nc1cnc(-c2cccc(C(F)(F)F)c2)nc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
To 2-chloropyrimidin-5-amine (1.7 g, 13.18 mmol, 1.00 equiv) was added 3-(trifluoromethyl)phenylboronic acid (3.8 g, 20.00 mmol, 1.50 equiv), Pd(OAc)2 (0.15 g, 0.05 equiv), dppf (0.37 g, 0.05 equiv) and potassium carbonate (3.6 g, 26.09 mmol, 2.00 equiv) and the mixture was stirred overnight at 100° C. in an oil bath. The reaction was diluted with 300 mL of ethyl acetate and the solids were filtered out. The filtrate was washed with water and the organic layer dried over anhydrous sodium sulfate and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:15) to afford 1.2 g (38%) of 2-(3-(trifluoromethyl)phenyl)pyrimidin-5-amine as a white solid.