Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[C:7]([NH2:12])[C:6]3[N:13]=[C:14]([CH2:20][CH3:21])[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]=3[C:4]=2[CH:3]=1.[C:22]1(B(O)O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:5]2[C:4]3[CH:3]=[C:2]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([NH2:12])[C:6]=2[N:13]=1)[CH3:21]
Reactant: OB(O)c1ccccc1
Reactant: CCc1nc2c(N)nc3ccc(Br)cc3c2n1CC(C)C
Product: CCc1nc2c(N)nc3ccc(-c4ccccc4)cc3c2n1CC(C)C

Procedure:
8-Bromo-2-ethyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and benzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. Chromatography on silica gel (5%-7% methanol in CH2Cl2 gradient) afforded 2-ethyl-1-isobutyl-8-phenyl-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, m.p. 233-235° C.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][C@@H:14]([OH:16])[CH2:13][NH:12]1)=O)C1C=CC=CC=1.[NH3:17]>>[OH:16][C@H:14]1[CH2:13][NH:12][C@H:11]([C:9]([NH2:17])=[O:8])[CH2:15]1
Reactant: O=C(OCc1ccccc1)[C@@H]1C[C@@H](O)CN1
Reactant: N
Product: NC(=O)[C@@H]1C[C@@H](O)CN1

Procedure:
A solution of (2S,4R)-4-hydroxy-pyrrolidine-2-carboxylic acid benzyl ester (1 g) in 880 ammonia (5 ml) was stirred for 18 h then evaporated and triturated with Et2O to give the title compound as a white solid. 1H-NMR (d6-DMSO, 400 MHz): 9.15 (s, br, 1H), 8.04 (s, 1H), 7.63 (s, 1H), 5.56 (s, 1H), 4.40 (s, 1H), 4.27-4.16 (m, 1H), 3.27 (d, 1H), 3.02 (d, 1H), 2.33 -2.19 (m, 1H), 1.89-1.76 (m, 1H).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]#[N:31])=[CH:20][CH:19]=2)[C:7](=[O:16])[N:8]([CH:10]([C:12](=[O:15])[NH:13][CH3:14])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4].[NH:32]1C=N[N:34]=[N:33]1>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:22][CH:23]=2)[C:7](=[O:16])[N:8]([CH:10]([C:12](=[O:15])[NH:13][CH3:14])[CH3:11])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: c1nnn[nH]1
Reactant: CCCCc1nn(C(C)C(=O)NC)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: ClCCl
Product: CCCCc1nn(C(C)C(=O)NC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 43 %

Procedure:
The conversion of 5-n-butyl-2,4-dihydro-2-[1-(N-methylcarbamoyl)ethyl]-4-[(2'-cyanobiphenyl-4-yl)methyl]-3H-1,2,4-triazol-3-one to the corresponding tetrazole was accomplished by the procedure of Example 9, Step E, except that the mixture was stirred at 120° C. for 2 days. After work-up, the residue was taken up in CH2Cl2 and flash chromatographed over silica gel (15 mL for 0.19 mmole, gradient elution using 5-30% MeOH/CH2Cl2 to give the desired compound as a white powder in 43% yield, homogeneous by TLC in 30% MeOH/CH2Cl2, mass spectrum (FAB) 461 (M+1)+, mp 153°-155° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8](=[CH:11]Cl)[CH:9]=O.[NH2:13][C:14]1[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[CH:15]=1>C(Cl)Cl.CN(C)C=O.C([O-])(O)=O.[Na+]>[Cl:7][C:8]1[CH:9]=[N:13][C:14]2[CH2:19][CH2:18][CH2:17][C:16](=[O:20])[C:15]=2[CH:11]=1
Reactant: O=CC(Cl)=CCl
Reactant: NC1=CC(=O)CCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCCc2ncc(Cl)cc21
Temperature: 25 °C

Procedure:
Chloromalondialdehyde (19 grams, 0.178 mol) was suspended in methylene chloride (100 ml) with dry dimethylformamide (DMF) (2.5 ml). This was mechanically stirred under a nitrogen atmosphere while a solution of oxalyl chloride (23.7 grams/16.3 ml, 0.185 mol) in methylene chloride (50 ml) was added dropwise over 20 minutes. The reaction mixture at first started to warm from 22° to 28°, but as the evolution of gases increased the temperature fell to 18°. The reaction was stirred at room temperature and was followed by thin layer chromatography (ethyl acetate/hexanes, 1:1) until conversion to 2,3-dichloroacrolein was complete. A solution of 1-amino-cyclohexen-3-one (19.85 grams, 0.18 mol) in DMF (125 ml) was added dropwise and the reaction was heated to 70° C. overnight. The reaction mixture was cooled to room temperature, diluted with saturated NaHCO3, and twice extracted with ethyl acetate (400 ml and 200 ml). The combined organic layers were washed with water (3×) and brine (1×). The organic solution was stirred with MgSO4 and decolorizing carbon (Darco (trademark)); then filtered through Super Cel (trademark)) and concentrated to a brown solid. Yield 21 grams (65%); mp 90°-91° C. NMR (CDCl3, 300 MHz) δ8.6 (d, 1), 8.24 (d, 1), 3.1 (t, 2), 2.7 (m, 2), 2.15 (m, 2).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[N:4][C:3]=1Cl.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][C:22]([O:26][CH3:27])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][CH:12]=2)=[O:10])[CH:5]=[N:4][C:3]=1[C:20]1[CH:21]=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([Cl:25])[C:19]=1[Cl:18]
Reactant: COc1cc(Cl)c(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cn1nccc1C(=O)Nc1cnc(Cl)c(N)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(Cl)c(-c2ncc(NC(=O)c3ccnn3C)nc2N)c1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
N-(6-Amino-5-chloropyrazin-2-yl)-1-methyl-1H-pyrazole-5-carboxamide (Preparation 2, 0.1 g, 0.396 mmol) was combined with 2,(2,3-dichloro-5-methoxy-phenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (Preparation 18), (0.156 g, 0.515 mmol), cesium carbonate (0.129 g, 0.396 mmol) and palladium tetrakistriphenylphosphine (0.046 g, 0.04 mmol) and suspended in a mixture of 1,4-dioxane (1 ml) and water (0.5 ml). The reaction was heated at 80° C. for 5 hours. The reaction was allowed to cool to room temperature and then concentrated in vacuo. The residue was partitioned between aqueous sodium carbonate solution (20 ml) and ethyl acetate (20 ml) and the organic layer dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with ethyl acetate:heptane 2:3 to 1:1, to afford the product as an off-white solid (72 mg).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]([NH2:28])=O)=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1>C(Cl)Cl.CO>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[C:25]([C:26]#[N:28])=[CH:24][CH:23]=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NC(=O)c1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Solvent: CO
Solvent: ClCCl
Product: N#Cc1cccc2c1[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 66 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-10-carboxylic acid amide following a procedure analogous to that described in Example 42. Yield: 66% of theory; TLC: rf=0.45 (silica gel, CH2Cl2/MeOH/32% aqueous NH3 90:10:1); Mass spectrum (ESI+): m/z=357 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: Cc1cc(Oc2cnccn2)cc(C)c1C(=O)CBr
Reactant: NC(N)=S
Solvent: CCO
Product: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(N)n1
Yield: 53.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)ethanone (7-2, 6.16 g, 19.2 mmol) and thiourea (1.46 g, 19.2 mmol) in 95% EtOH (27.4 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-amine (7-3, 3.07 g) as brown solids in 54% yield: 1H NMR (500 MHz, CDCl3) δ 8.40 (s, 1 H), 8.25 (d, 1 H), 8.14 (s, 1 H), 6.86 (s, 2 H), 6.31 (s, 1 H), 5.09 (s, 2 H), 2.18 (s, 6 H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14].Cl>CC(O)C>[CH2:11]([NH:15][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)[CH2:12][CH2:13][CH3:14]
Reactant: Clc1ncc2[nH]ccc2n1
Reactant: CCCCN
Agent: Cl
Solvent: CC(C)O
Product: CCCCNc1ncc2[nH]ccc2n1
Temperature: 170 °C
Yield: 95.9 %

Procedure:
A suspension of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (0.62 g, 4 mmol) in 5 mL iPrOH was added nBuNH2 (2.5 mL, 25.3 mmol) and followed by HCl (2.0 mL, 4.0 M in dioxanes, 8 mmol). The resulting solution was heated at 170° C. for 1 h under microwave irradiation. The reaction was monitored by LC-MS. The reaction time should be extended whenever it is necessary. After evaporation of solvents, the crude product was washed with minimal amount of MeOH. The solid was collected. And the MeOH filtrate was purified by ISCO to provide the desired product (0.73 g, 96%). 1H NMR (400 MHz, CD3OD) δ 8.42 (d, J=0.8 Hz, 1H), 7.53 (d, J=3.1 Hz, 1H), 6.27 (dd, J=3.0, 0.8 Hz, 1H), 3.37 (t, J=7.1 Hz, 2H), 1.68-1.57 (m, 2H), 1.52-1.36 (m, 2H), 0.97 (t, J=7.4 Hz, 3H); MS m/z 191.2 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:9][N:8]2[C@@H:4]([C@H:5]([OH:11])[C@H:6]([OH:10])[CH2:7]2)[C@H:3]([OH:12])C1.C1(=O)O[C@@H]([C@@H]([C@@H](CO)O)O)[C@H](O)[C@@H]1[OH:15]>>[OH:12][C@H:3]1[CH:4]2[N:8]([CH2:7][C@@H:6]([OH:10])[C@H:5]2[OH:11])[CH2:9][C@H:1]1[OH:15]
Reactant: O=C1O[C@@H]([C@H](O)[C@H](O)CO)[C@H](O)[C@@H]1O
Reactant: O[C@H]1[C@H]2[C@H](O)CCCN2C[C@H]1O
Product: O[C@@H]1CN2C[C@@H](O)[C@@H](O)C2[C@@H]1O

Procedure:
The tetrahydroxypyrrolizidone (1) is an analogue of 1,8-diepiswainsonine. A similar analogue of swainsonine can be made by analogous methods starting with D-glycero-D-talo-heptono-1,4-lactone to produce the novel (1S, 2R, 6R, 7S)-1,2,6,7-tetrahydroxypyrrolizidine.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C@H:12]([NH2:17])[C:13]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=1[Cl:18])[CH:2]=[CH2:3].[CH2:19]([O:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](O)=[O:26])[CH:20]=[CH2:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:16][O:15][C:13](=[O:14])[C@@H:12]([NH:17][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[O:22][CH2:19][CH:20]=[CH2:21])[CH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[C:6]([Cl:18])[CH:7]=1
Reactant: C=CCOc1ccccc1C(=O)O
Reactant: C=CCOc1ccc(C[C@H](N)C(=O)OC)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOc1ccc(C[C@H](NC(=O)c2ccccc2OCC=C)C(=O)OC)cc1Cl
Temperature: 22 °C
Reaction time: 16 h

Procedure:
In a 10 mL round-bottomed flask, (S)-methyl 3-(4-(allyloxy)-3-chlorophenyl)-2-aminopropanoate (65 mg, 241 μmol, Eq: 1.00) was combined with DMF (2 mL) to give a colorless solution. 2-(allyloxy)benzoic acid (54.2 mg, 289 μmol, Eq: 1.20), HATU (183 mg, 482 μmol, Eq: 2.00) and Hunig's base (62.3 mg, 84.2 μL, 482 μmol, Eq: 2.00) were added. The reaction mixture was stirred at 22° C. for 16 h. The reaction mixture was poured into saturated aqueous NaHCO3 solution and extracted with DCM (2×). The organic layers were combined, washed with 0.1M aqueous HCl (1×), water (3×), and brine (1×). The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, n-heptane/AcOEt 4/1) to yield a light yellow oil (96 mg; 93%). m/z=430.2 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:32][CH:33]([CH3:35])[CH3:34])[NH:5][C:6](=[O:31])[C@H:7]([CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1)[NH:8][C:9](=[O:24])[CH2:10][NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20]C(=O)C)=[CH:16][CH:15]=1)=[O:13].[OH-].[Na+].Cl.O>CO>[OH:20][C:17]1[CH:16]=[CH:15][C:14]([C:12](=[O:13])[NH:11][CH2:10][C:9]([NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:32][CH:33]([CH3:35])[CH3:34])=[O:31])[CH2:25][C:26]2[N:30]=[CH:29][NH:28][CH:27]=2)=[O:24])=[CH:19][CH:18]=1
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccc(OC(C)=O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)CNC(=O)c1ccc(O)cc1)C(=O)O

Procedure:
5.1 g of p-acetoxyhippuryl-L-histidyl-L-leucine methyl ester is dissolved in 20 ml of methanol, and to this solution is added 20 ml of a 1 N.aqueous solution of NaOH at a temperature of 4° C., and after stirring for one hour, the pH of the solution is lowered to 5 by adding HCl, and water and methanol are distilled off. The residue is dissolved in methanol and filtered, and to this solution is added ethyl ether. The crystals deposited after standing at -20° C. are filtered to obtain p-hydroxyhippuryl-L-histidyl-L-leucine.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:28](=[O:29])[CH2:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1
Reactant: Nc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3cccc(NC(=O)Cc4ccccc4)c3C2=O)C(=O)N1
Yield: 92 %

Procedure:
To a stirred suspension of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.55 g, 2.0 mmol) in THF (30 ml) was added 2-phenylacetyl chloride (0.62 g, 4.0 mmol). The mixture was heated to reflux for 18 hours. The solvent was evaporated in vacuo and the resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.72 g (92%) of product as an off-white solid: mp 217-218° C.; 1H NMR (DMSO-d6) δ 11.15 (s, 1H), 9.79 (s, 1H), 8.49 (d, J=8.4 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.60 (t, J=7.3 Hz, 1H), 7.41-7.27 (m, 5H), 5.13 (dd, J=5.1 and 12.7 Hz, 1H), 3.85 (s, 2H), 2.98-2.83 (m, 1H), 2.64-2.44 (m, 2H), 2.08-2.04 (m, 1H); 13C NMR (DMSO-d6) δ 172.71, 170.07, 169.74, 167.60, 166.61, 136.38, 136.10, 134.70, 131.41, 129.41, 128.58, 126.97, 125.96, 118.39, 116.90, 48.89, 43.47, 30.90, 21.91; Anal. Calcd For C21H17N3O5: C, 64.45; H, 4.38; —N, 10.74. Found: C, 64.23; H, 4.34; N, 10.53.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([Cl:23])[C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH:9]([CH:12]3[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]3)[C:8]2=[O:20])=[C:4]([Cl:24])[CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:24][C:4]1[CH:3]=[C:2]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)[CH:22]=[C:21]([Cl:23])[C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH:9]([CH:12]2[CH2:17][CH2:16][CH:15]([O:18][CH3:19])[CH2:14][CH2:13]2)[C:8]1=[O:20]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC1CCC(C2CCN(Cc3c(Cl)cc(Br)cc3Cl)C2=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COC1CCC(C2CCN(Cc3c(Cl)cc(-c4ccc(F)cc4)cc3Cl)C2=O)CC1
Temperature: 80 °C
Yield: 108.6 %

Procedure:
A mixture of 1-(4-Bromo-2,6-dichloro-benzyl)-3-(4-methoxy-cyclohexyl)-pyrrolidin-2-one (0.4 g, 0.92 mmol) and 4-fluorophenylboronic acid (0.19 g, 1.38 mmol) in THF (15 mL) and water (5 mL) and sodium carbonate (0.29, 0.75 g) is purged with N2. Treat the reaction with Pd(PPh3)4 (0.05 g, 0.046 mmol) and heat to 80° C. for 2 hour under N2. Cool the reaction, dilute with ethyl acetate, and wash with HCl (1N) and water. Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify with a 35% ethyl acetate in hexanes to afford 0.45 g of the titled product. MS (m/z): 451 (M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=[C:7](Cl)[N:6]=1)=[O:4].[CH2:21]([O:23][C:24]1[CH:25]=[C:26]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:27][N:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:22]>CC(N(C)C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[Cl:19])[N:8]=[C:7]([NH:34][CH:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:26]3[CH:35]=[CH:36][C:37]([O:38][CH3:39])=[C:24]([O:23][CH2:21][CH3:22])[CH:25]=3)[CH2:29][CH2:30]2)[N:6]=1)=[O:4]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1OC
Reactant: COC(=O)c1cc(Oc2ccc(Cl)cc2Cl)nc(Cl)n1
Solvent: CC(=O)N(C)C
Product: CCOc1cc(CN2CCC(Nc3nc(Oc4ccc(Cl)cc4Cl)cc(C(=O)OC)n3)CC2)ccc1OC
Yield: 17.8 %

Procedure:
A solution of 2-chloro-6-(2,4-dichloro-phenoxy)-pyrimidine-4-carboxylic acid methyl ester (50.0 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 15.0 mg (15%) of the title compound. MS (ISP): 561.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:15]2[C:19](=[O:20])[CH:18]([C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=3)[O:17][C:16]2=[O:28])C=CC=CC=1>O>[OH:27][C:24]1[CH:23]=[CH:22][C:21]([CH:18]2[O:17][C:16](=[O:28])[NH:15][C:19]2=[O:20])=[CH:26][CH:25]=1
Reactant: O=C1OC(c2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1NC(=O)C(c2ccc(O)cc2)O1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 10 ml of trifluoroacetic acid was added 500 mg of 3-triphenylmethyl-5-p-hydroxyphenyl-2,4-oxazolidinedione and the reaction mixture stirred at room temperature for 10 minutes. The reaction was poured into 50 ml of water and extracted with ethyl acetate. The organic layer was separated, washed with water (2×40 ml) and dried over sodium sulfate. Removal of the solvent in vacuo gave a yellow solid which was recrystallized from ethyl acetate-cyclohexane, 226 mg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1>C1COCC1.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:2]1
Reactant: Nc1ccc(Oc2nccnc2C2=CCCOC2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2nccnc2C2CCCOC2)cc1
Temperature: 25 °C
Reaction time: 23 h

Procedure:
Palladium (10 mg, 0.0094 mmol, 10% wt. on activated carbon) was added to a stirred solution of 4-(3-(5,6-dihydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline (0.16 g, 0.59 mmol) in THF (3 mL). The reaction mixture was placed under a hydrogen atmosphere (balloon) and stirred at room temperature for 23 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated in vacuo to give 4-(3-(tetrahydro-2H-pyran-3-yl)pyrazin-2-yloxy)aniline. [M+1]=272.1.
Reaction SMILES: [H-].[Na+].[N:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:17]1[CH:18]=[CH:19][C:20]([N+:32]([O-:34])=[O:33])=[C:21]([N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:22]=1>CN(C)C=O>[N+:32]([C:20]1[CH:19]=[CH:18][C:17]([O:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:3]2[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:22][C:21]=1[N:23]([CH3:31])[C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])([O-:34])=[O:33]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccccc1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccccc2N2CCCCC2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Sodium hydride (55 wt. %, 1.04 g) was added to a solution of 2-piperidinophenol (3.4 g) in N,N-dimethylformamide (35 ml) in an ice bath under a nitrogen atmosphere. The mixture was stirred at ambient temperature for 15 minutes. To the reaction mixture was added t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (5.25 g) in small portions. This mixture was stirred at 60° C. for 2 hours. At the end of this time the solvent was evaporated and water added to the residue. The mixture was neutralized with concentrated hydrogen chloride and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using c-hexane/isopropyl ether=5/1 as the eluant to afford t-butyl N-[2-nitro-5-(2-piperidinophenoxy)phenyl]-N-methylcarbamate, of which Rf value was 0.27 in thin layer chromatography on a silica gel plate using c-hexane/isopropyl ether=5/1 as the eluant. A mixture of a solution of this product in toluene/methanol=7/3 (100 ml) and palladium on carbon (10%, 0.63 g) was vigorously stirred at room temperature under a hydrogen atmosphere for 14.5 hours. The catalyst was removed by filtration and the filtrate was concentrated. The residue was washed with cooled methanol and n-hexane to give the title compound (4.2 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([N+:9]([O-])=O)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1>[Pd].C(O)C>[NH2:9][C:3]1[C:2]([OH:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(O)c(N)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.2 %

Procedure:
A mixture of 3-hydroxy-6-methyl-2-nitropyridine (4.2 g, 27 mmol) and 10% palladium on carbon (0.25 g, 0.24 mmol) in ethanol (75 mL) was stirred at rt under an atmosphere of hydrogen for 24 hr. The catalyst was removed by filtration through celite and the filtrate concentrated to dryness under vacuum. The residue was subjected to chromatography on silica gel using Biotage SP1 employing a 40+M cartridge and eluting with MeOH/DCM 10% 2 CV, 10-35% in 10 CV, 35% 2 CV. The purified product 2-amino-6-methyl-3-pyridinol (D145, 2.72 g, 80%) was isolated as pale brown solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:11])([CH2:9][CH3:10])[CH2:7][CH3:8].C1COCC1.N[C@H]([C:21]([OH:23])=[O:22])C[SeH].[Li]CCCC.Cl>O.C(OCC)(=O)C>[C:21]([C:5]1[O:1][C:2]([C:6]([OH:11])([CH2:9][CH3:10])[CH2:7][CH3:8])=[CH:3][CH:4]=1)([OH:23])=[O:22]
Reactant: N[C@@H](C[SeH])C(=O)O
Reactant: CCC(O)(CC)c1ccco1
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(C(=O)O)o1
Temperature: -78 °C
Yield: 71.7 %

Procedure:
3-(2-Furanyl)pentan-3-ol (3.0 g, 19 mmol) is added to THF (20 mL) under a nitrogen atmosphere. The solution is stirred and cooled to −78° C. Sec-BuLi (1.3 M in cyclohexane, 31 mL, 41 mmol) is added dropwise maintaining the temperature below −55° C. After complete addition, the ice bath is removed and the solution slowly warmed to room temperature where it is stirred for 18 hours. The mixture is cooled to 48° C. and CO2 gas is bubbled through the solution. A thick yellow past results and the temperature is increased to −10° C. Water (50 mL) is added and the solution is stirred at room temperature for 30 minutes. Ethyl acetate is added followed by water and the ph is adjusted to 1 with 1 N HCl. The organic layer is separated and the water layer was discarded. The organic layer is added to 1N NaOH solution and extracted. The pH of the water layer is adjusted to 1 with 1N HCl followed by addition of EtOAc. The organic layer is separated, dried over sodium sulfate, filtered, and evaporated under vacuum to give 2.7 grams of an oil.