Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[CH2:28][C:29]([NH2:31])=[O:30]>CN(C)C=O>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:28][C:29]([NH2:31])=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNc3ccccc32)cc1
Reactant: NC(=O)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)CN1CCN(Cc2ccccc2)c2ccccc21
Temperature: 100 °C
Yield: 97.5 %

Procedure:
A solution of 1 g (4.46 mmol) 1-benzyl-1,2,3,4-tetrahydroquinoxaline in 10 ml of dimethylformamide was treated with 3.14 ml (18.15 mmol) of N-Ethyl-N-isopropylpropan-2-amine, and subsequently 863 mg (9.23 mmol) 2-chloroacetamide was added. The reaction mixture was heated in a microwave system at 100° C. for four hours. The resulting mixture was quenched with water and extracted once with ethylacetate. The aqueous phase was set to pH 10 with sodium hydroxide solution and extracted 3× with ethylacetate. The combined organic extracts were dried with magnesium sulfate, evaporated till dryness and directly purified by column chromatography on silica (eluent: starting with heptane and then up to 100% ethylacetate) to yield 1.224 g of the title compound.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[O:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26]Cl)[N:23]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:16])([CH3:15])[CH3:14]>C(#N)C>[C:13]([O:17][C:18]([N:20]1[CH2:25][C@H:24]([CH2:26][N:9]2[CH2:10][CH2:11][O:7][C:8]2=[O:12])[N:23]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][C@H:21]1[CH3:35])=[O:19])([CH3:14])([CH3:15])[CH3:16]
Reactant: C[C@@H]1CN(Cc2ccccc2)[C@@H](CCl)CN1C(=O)OC(C)(C)C
Reactant: O=C1NCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H]1CN(Cc2ccccc2)[C@@H](CN2CCOC2=O)CN1C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 72 h
Yield: 78.6 %

Procedure:
K2CO3 (610 mg, 4.4 mmol), KI (730 mg, 4.4 mmol) and oxazolidinone (170 mg, 2.2 mmol) were added to a solution of (2R,5R)-4-benzyl-5-chloromethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (500 mg, 1.47 mmol) in acetonitrile (10 mL). The reaction was stirred at 60° C. for 3 days. The solids were filtered off and the solvent was removed in vacuo. Chromatography (40% EtOAc in petrol) gave the title compound (450 mg) as a white solid, MS: [M+H]+=390.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9](I)[C:8]=1[CH3:14].[F:15][CH:16]([F:23])[C:17]1[CH:22]2[CH:20]([CH2:21]2)[O:19][N:18]=1.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1.C(OCC)C>[F:15][CH:16]([F:23])[C:17]1([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([F:6])[C:8]=2[CH3:14])[CH:22]2[CH:20]([CH2:21]2)[O:19][NH:18]1
Reactant: Cc1c(F)cccc1I
Reactant: FC(F)C1=NOC2CC12
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1c(F)cccc1C1(C(F)F)NOC2CC21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 44.3 %

Procedure:
To a flame dried RBF was added a solution of n-butyllithium (2.5M in hexanes; 3.01 ml, 7.51 mmol) and diethyl ether (15 ml). The solution was cooled to −78° C., and 2-fluoro-6-iodotoluene (0.981 ml, 7.51 mmol) was added dropwise and the reaction was stirred at −78° C. for 10 minutes. A −78° C. premixed solution of 4-(difluoromethyl)-2-oxa-3-azabicyclo[3.1.0]hex-3-ene (1.00 g, 7.51 mmol) and boron trifluoride diethyl etherate (0.927 ml, 7.51 mmol) in toluene (10 ml) was added to the reaction via syringe. The reaction was stirred at −78° C. for 10 minutes, quenched with saturated ammonium chloride and warmed to RT. The reaction was diluted with water and EtOAc. The organic layer was separated and concentrated under reduced pressure. The crude residue was purified via silica gel flash chromatography eluting with 0-20% ethyl acetate in hexanes to afford 4-(difluoromethyl)-4-(3-fluoro-2-methylphenyl)-2-oxa-3-azabicyclo[3.1.0]hexane (0.81 g, 3.33 mmol, 44.3% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N(CC)C(C)C)(C)C.[CH3:20][S@:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[NH:23])=[O:22]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:23]=[S@@:21]([CH3:20])(=[O:22])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:9]
Reactant: C[S@](=N)(=O)c1ccccc1
Reactant: O=C(O)c1cncc(Br)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
To a solution of 5-bromonicotinic acid (1.21 g, 6.0 mmol), N,N-diisopropylethylamine (2.1 mL, 12.0 mmol), and (S)-(+)-S-methyl-S-phenylsulfoximine (931 mg, 6.0 mmol) in DMF (11.0 mL) cooled to 0° C. was treated with 1-benzotriazolyloxytripyrrolidinylphosphonium hexafluorophosphate (PyBOP) (3.43 g, 6.6 mmol). The reaction mixture was stirred 10 minutes, the ice bath removed, and the reaction continued at room temperature for 2 hours. The mixture was taken up in EtOAc and washed with H2O, Na2CO3 solution, brine, AcOH solution, H2O, Na2CO3 solution, brine, dried with anhydrous Na2SO4 and concentrated. The residual brown oil was purified by chromatography (silica gel, hexane/EtOAc). The product containing eluent was concentrated and then triturated with hexane to give the title compound as an off-white solid (1.88 g, 92%).
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[C:4](=[O:5])[O:3]1>O1CCCC1.[Pd]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]([OH:1])[O:3][C:4]2=[O:5]
Reactant: O=C1OC(O)c2c1cccc2[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1cccc2c1C(O)OC2=O

Procedure:
10 g of 3-hydroxy-4-nitro-phthalide are dissolved in 100 ml of tetrahydrofuran and, after addition of 1 g of palladium on barium sulphate (5%), the mixture is hydrogenated at atmospheric pressure and 20°-25° C. The catalyst is filtered off and the filtrate is concentrated. The evaporation residue is stirred with ether and filtered off with suction. 5.8 g (68.5% of theory) of a colourless substance of melting point 280°-285° C. (dec.) are obtained.
Reaction SMILES: CB1OB(C)OB(C)O1.[C:10]([O-])([O-])=O.[Cs+].[Cs+].Cl[C:17]1[N:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=2)=[CH:19][N:18]=1.O>O1CCOCC1.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]>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[C:24]([NH:23][C:20]1[CH:19]=[N:18][C:17]([CH3:10])=[N:22][CH:21]=1)=[O:33]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cnc(Cl)nc1)c1ccc(F)c(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB1OB(C)OB(C)O1
Solvent: C1COCCO1
Solvent: O
Product: Cc1ncc(NC(=O)c2ccc(F)c(F)c2)cn1
Yield: 58.4 %

Procedure:
A mixture of trimethylboroxine (27 μL, 0.19 mmol), Pd(dppf)2Cl2 (22 mg, 0.019 mmol), Cs2CO3 (185 mg, 0.57 mmol) and N-(2-chloro-pyrimidin-5-yl)-3,4-difluoro-benzamide (H) (50 mg, 0.19 numol) in dioxane (1 mL)/H2O (0.1 mL) was heated at 110–130° C. (bath temperature) for 1 h. The crude reaction mixture was filtered through a pad of celite and concentrated under reduced pressure. Purification of the crude material by column chromatography (hexanes/EtOAc) gave the desired product as white solid (27 mg, 57%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([I:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.N1C=CC=CC=1>C(O)C.[I-].[K+]>[I:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)=[CH:3][C:4]([CH3:13])=[N:5]2)=[CH:10][CH:9]=1
Reactant: Cc1cc(Cl)c2ccc(I)cc2n1
Reactant: C1CCNC1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: c1ccncc1
Product: Cc1cc(N2CCCC2)c2ccc(I)cc2n1
Yield: 87.5 %

Procedure:
A suspension of 4-chloro-7-iodo-2-methylquinoline (EP497371, 2.00 g, 6.59 mmol) in ethanol (20 mL) was treated sucessively with pyrrolidine (1.28 g, 18.0 mmol), pyridine (0.2 mL) and potassium iodide (50 mg, 0.30 mmol), and the resulting mixture was refluxed for 24 h. After concentration in vacuo, the residue was taken up in water (50 mL) and basified to pH 12 by addition of 2 M aq. sodium hydroxide solution. The precipitate was collected by filtration, washed with water (20 mL) and ether (20 mL) and dried to afford the title compound (1.95 g, 87%). Off-white solid, m.p. 99–102° C.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](F)=[CH:5][CH:4]=1)#[N:2].[CH2:14]([N:16]([CH2:25][CH3:26])[C:17](=[O:24])[CH:18]1[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]1)[CH3:15]>N1C=CC=CC=1>[CH2:25]([N:16]([CH2:14][CH3:15])[C:17]([CH:18]1[CH2:23][CH2:22][CH2:21][N:20]([C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:19]1)=[O:24])[CH3:26]
Reactant: N#Cc1ccc(F)c2ccccc12
Reactant: CCN(CC)C(=O)C1CCCNC1
Solvent: c1ccncc1
Product: CCN(CC)C(=O)C1CCCN(c2ccc(C#N)c3ccccc23)C1

Procedure:
A solution of 1-cyano-4-fluoronaphthalene in pyridine (0.6 M, 1 mL) was transferred to a Pyrex tube and N,N-diethylnipecotamide (447 mg, 2.4 mmol) was added. The tube was capped and the reaction tube was exposed to microwave irradiation (220° C., 10 min). The reaction mixture was concentrated and purified according to Purification Method A.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:5]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=O)[CH:2]=[CH2:3].[O-:30][C:31]#[N:32].[Na+].[OH-].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[C:9]([OH:10])=[CH:8][CH:7]=[C:6]2[C:5]=1[C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=1)=[N:32][C:31](=[O:30])[N:11]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)ccc(NCc2ccccc2)c1C(=O)c1ccc(C(C)C)cc1
Reactant: N#C[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: C=CCc1c(O)ccc2c1c(-c1ccc(C(C)C)cc1)nc(=O)n2Cc1ccccc1

Procedure:
A solution of 15 mg (39 μmol) (2-allyl-6-benzylamino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone and 2.5 mg sodium cyanate in 0.2 ml acetic acid is stirred at r.t. for 16 h. Aqueous sodium hydroxide solution is added and the product is extracted with dichloromethane.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH:13]([O:15][CH3:16])[CH3:14])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[Br:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH:13]([O:15][CH3:16])[CH3:14])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: C1COCCN1
Reactant: COc1cc2c(Nc3c(Br)cc(C#CC(C)OC)c4c3OCO4)ncnc2cc1OCCCCl
Product: COc1cc2c(Nc3c(Br)cc(C#CC(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[5-bromo-7-(3-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (0.12 g, 0.22 mmol) in morpholine (2 ml) was heated at 40 C for 5 hours and then stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue purified directly by flash chromatography on silica eluting with increasingly polar solutions of methanol 0-8% in dichloromethane followed by trituration with diethyl ether to give the product as a racemate and in the form of a pale yellow solid (0.040 g). NMR Spectrum: (d6DMSO) 1.54 (d, 3H), 2.02-2.13 (m, 2H), 2.46-2.53 (m, 4H), 2.54-2.60 (m, 2H), 3.47 (s, 3H), 3.67-3.73 (m, 4H), 4.04 (s, 3H), 4.27-4.33 (m, 2H), 4.51 (q, 1H), 6.27 (s, 2H), 7.30 (s, 1H), 7.40 (s, 1H), 7.94 (s, 1H), 8.43 (s, 1H), 9.62 (s(broad), 1H). Mass Spectrum: M+H+ 599/601.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:23][CH:24]([CH3:26])[CH3:25])[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: CC(C)C[C@H](N)C(N)=O
Product: CC(C)C[C@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(N)=O

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (2S)-2-amino-4-methyl-pentanamide (CAN 687-51-4) as starting materials, MS (LC/MS): m/e=346.2 [M+H]+.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:20]C(OC(C)(C)C)=O)([CH2:8][C:9](=[CH2:19])[CH2:10][NH:11]C(OC(C)(C)C)=O)[C:4]([O:6][CH3:7])=[O:5].[ClH:28]>CCOCC>[ClH:28].[ClH:28].[F:1][CH2:2][C:3]([NH2:20])([CH2:8][C:9](=[CH2:19])[CH2:10][NH2:11])[C:4]([O:6][CH3:7])=[O:5]
Reactant: C=C(CNC(=O)OC(C)(C)C)CC(CF)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl
Solvent: CCOCC
Product: C=C(CN)CC(N)(CF)C(=O)OC

Procedure:
Methyl 2-fluoromethyl-2,5-di(tert-butoxycarbonylamino)-4-methylene pentanoate (0.72 g) obtained in Step C above is treated with dry ether saturated with HCl gas. After stirring overnight the title compound is collected (0.38 g, 78%). Recrystallisation from isopropanol/ethyl acetate gives the pure product yield 300 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](S(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-:21])(=[S:20])[CH3:19].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:20][C:18](=[O:21])[CH3:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC([O-])=S
Reactant: CC(C)(C)OC(=O)N1CCC(S(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Yield: 64.8 %

Procedure:
A mixture of 4-methanesulfonyl-piperidine-carboxylic acid tert-butyl ester (2.82 g), sodium thioacetate (2.31 g) and DMF (40 ml) was stirred at 60° C. After 4 hours the reaction mixture was cooled and partitioned between ethyl acetate and brine. The combined organics were dried (MgSO4) and the solvents removed in vacuo. The resulting crude mixture was purified by flash chromatography to yield 4-acetylsulfanyl-piperidine-1-carboxylic acid tert-butyl ester (1.8 g).
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O-:24])=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([S:34]([NH2:37])(=[O:36])=[O:35])=[CH:30][CH:29]=1>>[CH3:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([S:34]([NH:37][C:23]([NH:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([N:4]3[CH:5]=[C:6]([C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[N:7]=[C:3]3[CH2:1][CH3:2])=[CH:19][CH:18]=2)=[O:24])(=[O:36])=[O:35])=[CH:32][CH:33]=1
Reactant: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)[O-])cc1
Reactant: COc1ccc(S(N)(=O)=O)cc1
Product: CCc1nc(-c2ccccc2)cn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(OC)cc2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 18 from 2-[4-(2-ethyl-4-phenyl-1H-imidazol-1-yl)phenyl]ethylcarbamate and 4-methoxybenzenesulfonamide. MS (ESI) m/z 505 [M+H]+, 503 [M−H]−, 1H-NMR (CDCl3) δ 1.25 (3H, t, J=7.5 Hz), 2.72 (2H, q, J=7.5 Hz), 2.91 (2H, t, J=6.8 Hz), 3.40-3.55 (2H, m), 6.64 (1H, br), 6.96 (2H, d, J=9.0 Hz), 7.20-7.30 (5H, m), 7.38 (2H, t, J=7.3 Hz), 7.74 (2H, d, J=9.0 Hz), 7.79 (2H, d, J=8.4 Hz).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][N:22]=1>CCCCCC.C(OCC)(=O)C>[O:17]1[CH2:18][CH2:19][N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([C:24]3[CH:23]=[N:22][C:21]([NH2:20])=[N:26][CH:25]=3)[N:3]=2)[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cn1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 2-aminopyrimidine-5-boronic acid pinacol ester with reaction time of 17 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [O:1]=[C:2]([CH:24]=[CH2:25])[CH:3]([C:11]1[CH:23]=[CH:22][C:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:13][CH:12]=1)[CH2:4][CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][CH2:33][C:34]1[S:38][C:37]([CH:39]=[O:40])=[N:36][CH:35]=1.C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:1]=[C:2]([CH2:24][CH2:25][C:39](=[O:40])[C:37]1[S:38][C:34]([CH2:33][O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:35][N:36]=1)[CH:3]([C:11]1[CH:12]=[CH:13][C:14]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])=[CH:22][CH:23]=1)[CH2:4][CH:5]1[CH2:6][CH2:7][O:8][CH2:9][CH2:10]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(C(=O)OC(C)(C)C)cc1
Reactant: O=Cc1ncc(COC2CCCCO2)s1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(COC3CCCCO3)s2)cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
To a solution of tert-butyl 4-[2-oxo-1-(tetrahydro-2H-pyran-4-ylmethyl)but-3-en-1-yl]benzoate (1.50 g) in ethanol (15 mL) were added 5-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1,3-thiazole-2-carbaldehyde (1.20 g), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (130 mg) and triethylamine (260 μL), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (2.37 g, yield 95%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). MS: 488 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].C([Al](CC)CC)C.[CH2:23]=[C:24]([CH3:26])[CH3:25]>CCCCCC>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([C:24]([CH3:26])([CH3:25])[CH3:23])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Reactant: C=C(C)C
Agent: CC[Al](CC)CC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
By the method used in Examples 1-33, 171 g (0.83 mol) 2,4-di-tert-butylphenol (2,4-DTBP) was dissolved in 350 ml hexane, and the amount (if any) of various polyhalophenols indicated in Table VI was added to the mixture, followed by addition of 5.8 mmol triethylaluminum to said mixture, at room temperature. The 2,4-DTBP was then reacted with 1.2-1.6 mol isobutene at 1.7 bar and 30° C., to form 2,4,6-tri-tert-butylphenol (2,4,6-TTBP).
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:15]([O-])=O)=[C:4]([S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H][H]>[Pd].C(O)C>[NH2:15][C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][C:4]=1[S:8]([NH:11][CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9]
Reactant: [H][H]
Reactant: Cc1cccc(S(=O)(=O)NC(C)C)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(S(=O)(=O)NC(C)C)c1N
Yield: 100 %

Procedure:
To a mixture of 4.13 g of the material from Step A and 0.25 g of 10% palladium on carbon was added 150 mL of ethanol. The reaction mixture was stirred under a balloon of hydrogen for three days. The mixture was filtered through celite and the solvent was removed with a rotary evaporator to afford 3.65 g of the title compound as a brown oil.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][NH2:8])[CH2:2][CH2:3][CH3:4].C(O[C:12](=[O:18])[C:13]([O:15]CC)=O)C>C(O)(C)C>[CH2:1]([N:5]1[CH2:6][CH2:7][NH:8][C:12](=[O:18])[C:13]1=[O:15])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNCCN
Reactant: CCOC(=O)C(=O)OCC
Solvent: CC(C)O
Product: CCCCN1CCNC(=O)C1=O
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of N-butylethylenediamine (4.78 ml, 34.4 mmol) in isopropanol (60 ml) at 0° C. under a nitrogen atmosphere was added diethyloxalate (4.67 ml, 34.4 mmol). The reaction was allowed to warm to rt and heated to reflux for 6 h. The reaction was concentrated in vacuo and purified via flash chromatography (silica) to yield 1-butylpiperazine-2,3-dione (44%).
Reaction SMILES: [CH:1](=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OC)=O.CCCCCC.[C:42]([O:45]CC)(=[O:44])[CH3:43]>C(Cl)Cl>[C:42]([OH:45])(=[O:44])/[CH:43]=[CH:1]/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C=O
Reactant: CCOC(C)=O
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCCCC/C=C/C=C/C(=O)O
Reaction time: 2 h

Procedure:
To trans-2-decenal (5.0 g) dissolved in methylene chloride (80 ml) was added (carbomethoxymethylene)triphenylphosphorane (11.99 g), and the mixture was stirred for 2 hours. The reaction mixture was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 100:1 to 20:1) to give the methyl ester of trans,trans-2,4-dodecadienoic acid (6.1 g). Potassium hydroxide (8.1 g) was dissolved in a mixed solvent of ethanol-water (1:1) (100 ml). The methyl ester of trans,trans-2,4-dodecadienoic acid (6.1 g) was added to the mixture, and the resulting mixture was stirred at 60° C. for 40 minutes. After the reaction mixture was cooled, it was adjusted to the weak acidic range of pH with citric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated to give trans,trans-2,4-dodecadienoic acid (5.4 g). To trans,trans-2,4-dodecadienoic acid dissolved in N,N-dimethylformamide (DMF, 50 ml) were added para-nitrophenol (3.8 g) and N,N'-dicyclohexylcarbodiimide (5.8 g), and the mixture was stirred for 12 hours. After precipitates obtained were removed by filtration and the solvent (DMF) was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of n-hexane-ethyl acetate (from 200:1 to 50:1) to give the active ester of trans,trans-2,4-dodecadienoic acid (3.4 g). To the active ester (800 mg) dissolved in DMF (30 ml) were added 6-(4'-N-glycyl-spicaminyl-amino)purine hydrochloride (800 mg) and triethylamine (2.0 ml). The mixture was stirred for 12 hours. After the solvent was removed by distillation, the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK282 in the yield of 310 mg.
Reaction SMILES: [CH3:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][C@H:8]3[C@H:9](O)[N:10](C(OCC(Cl)(Cl)Cl)=O)[C:4]=2[C:3]=1[O:28][CH3:29]>C1COCC1.CCOC(C)=O>[CH3:1][C:2]1[C:25]([O:26][CH3:27])=[CH:24][C:5]2[C:6](=[O:23])[N:7]3[CH2:22][CH2:21][CH2:20][CH:8]3[CH:9]=[N:10][C:4]=2[C:3]=1[O:28][CH3:29]
Reactant: COc1cc2c(c(OC)c1C)N(C(=O)OCC(Cl)(Cl)Cl)[C@@H](O)[C@@H]1CCCN1C2=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(c(OC)c1C)N=CC1CCCN1C2=O
Yield: 94.4 %

Procedure:
10% Cd/Pb couple (1.34 g; 10.7 mmol Cd) was added to a rapidly stirring solution of 193 (1 g; 2.14 mmol) in a mixture of THF (15 mL) and 1 N NH4OAc (15 mL). After 3.5 hours the reaction was diluted with EtOAc (150 mL). The solution was dried over anhydrous MgSO4 and the solids were filtered and rinsed with EtOAc (50 mL). Removal of excess solvent yielded the product (194) as a white glass (554 mg, 2.021 mmol, 94%). 1H NMR (270 MHz, CDCl3) (mixture of imine and methyl ether forms) δ7.72 (imine, d, J=4.39, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 3.88-3.51 (m, 3H+2H+1H), 2.37-2.04 (m, 4H), 2.22 (s, 3H); 13C NMR (67.8 MHz, CDCl3) δ164.65, 161.41, 156.79, 153.47, 133.87, 126.29, 124.27, 105.71, 60.98, 55.80, 55.70, 53.71, 46.70, 29.52, 29.34, 24.13, 9.33.