Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([O:16]CCC#N)=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([C:22]2[CH:27]=[CH:26][C:25]([N:28]3[C:36]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[N:30]=[C:29]3[CH3:37])=[CH:24][CH:23]=2)=[C:9]1[C:38]([O:40][CH2:41][CH3:42])=[O:39].[OH-].[Na+].Cl>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([CH3:21])[NH:11][C:10]([C:22]2[CH:23]=[CH:24][C:25]([N:28]3[C:36]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[N:30]=[C:29]3[CH3:37])=[CH:26][CH:27]=2)=[C:9]1[C:38]([O:40][CH2:41][CH3:42])=[O:39]
Reactant: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(C)=C(C(=O)OCCC#N)C1c1ccccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOC(=O)C1=C(c2ccc(-n3c(C)nc4cnccc43)cc2)NC(C)=C(C(=O)O)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.1 %

Procedure:
A mixture of the (-)-cyanoethyl ester of Example 8 (271 mg, 0.466 mmol) and aqueous sodium hydroxide (2.54 ml, 0.55M, 1.40 mmol) in dioxane (7.5 ml) was stirred at room temperature under nitrogen for 1 hour. Hydrochloric acid (1.40 ml, 1M, 1.40 mmol) was added dropwise, and the mixture was concentrated under reduced pressure. The resulting yellow solid was suspended in water, filtered off, and dried in vacuo, to give the title compound, (200 mg, 81%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([OH:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[CH3:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(C(O)c2ccccc2)C1
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccccc1OC(c1ccccc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Yield: 72.4 %

Procedure:
Under air, the RS/SR mixture of enantiomers of 3-(hydroxyphenylmethyl)pyrrolidine-1-carboxylic acid t-butyl ester (156 mg, 0.56 mmol), 2-iodotoluene (144 μl, 1.1 mmol), CuI (22 mg, 112 μmol), 1,10-phenanthroline (41 mg, 224 μmol) and Cs2CO3 (365 mg, 1.1 mmol) in dry toluene (0.5 mL) were combined in a scaled tube and heated at 120° C. for 48 hours. The mixture was cooled to room temperature and diluted with DCM, passed through a pad of Celite. The filtrate was purified by flash chromatography on silica gel (hexane/EtOAc:10/1) to yield title compound 3a (149 mg) as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ (ppm)=7.41-7.32 (m, 4H), 7.31-7.24 (m, 1H), 7.10 (m, 1H), 6.95 (m, 1H), 6.71 (m, 2H), 5.29 (d, J=7.2, 1H), 3.44-3.35 (m, 1H), 3.26-3.18 (m, 1H), 3.16-3.04 (m, 2H), 2.73-2.68 (m, 1H), 2.24 (s, 3H), 2.10-1.96 (m, 1H), 1.94-1.81 (m, 1H), 1.37 (m, 9H).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]=[CH:9][NH:8][CH:7]=1.O.[OH-].[K+].[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]>C(O)C>[CH:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]2[C:7]3[N:8]=[CH:9][NH:10][C:6]=3[CH2:5][CH2:4][NH:3]2)=[CH:19][CH:18]=1)([CH3:16])[CH3:15]
Reactant: NCCc1c[nH]cn1
Reactant: CC(C)c1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Yield: 94.9 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([NH2:10])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][C:32]=1[Br:33])[CH2:27][NH:28][NH2:29]>C(O)C>[NH2:10][C:6]1[NH:29][N:28]([CH2:27][C:26]2[CH:30]=[CH:31][C:32]([Br:33])=[C:24]([Br:23])[CH:25]=2)[C:4](=[O:3])[CH:5]=1
Reactant: NNCc1ccc(Br)c(Br)c1
Reactant: CCOC(=O)C=C(N)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Nc1cc(=O)n(Cc2ccc(Br)c(Br)c2)[nH]1
Reaction time: 8 h

Procedure:
12.2 g of β-amino-β-ethoxyacrylic acid ethyl ester together with 1 g of p-toluenesulphonic acid were dissolved in 200 ml of ethanol. A solution of 21.6 g of 3,4-dibromobenzylhydrazine in 50 ml of ethanol was added dropwise thereto, under nitrogen. After stirring overnight, the solvent was concentrated in vacuo and the compound identified above, which had separated out as a precipitate, was filtered off and recrystallised from ethanol. Melting point: 182°, 11 g (41%).
Reaction SMILES: Cl[C:2]1[N:12]=[C:11]2[C:5]([NH:6][C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:35]=[CH:34][C:23]([C:24]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:25])=[CH:22][C:21]=1[O:36][CH3:37].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C.CO>[CH3:37][O:36][C:21]1[CH:22]=[C:23]([CH:34]=[CH:35][C:20]=1[NH:19][C:2]1[N:12]=[C:11]2[C:5](=[CH:4][N:3]=1)[NH:6][C:7](=[O:18])[CH2:8][CH2:9][N:10]2[CH:13]([CH3:17])[CH2:14][O:15][CH3:16])[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]1)=[O:25]
Reactant: COCC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Reactant: COc1cc(C(=O)NC2CCN(C)CC2)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CC(C)CC(C)O
Solvent: O
Product: COCC(C)N1CCC(=O)Nc2cnc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)nc21
Temperature: 100 °C
Yield: 20.1 %

Procedure:
10-chloro-2-(1-methoxypropan-2-yl)-2,6,9,11-tetrazabicyclo[5.4.0]undeca-7,9,11-trien-5-one (Intermediate 137; 35 mg, 0.13 mmol)), 4-amino-3-methoxy-N-(1-methyl-4-piperidyl)benzamide (WO06/018220; 34 mg, 0.13 mmol) and p-toluenesulphonic acid monohydrate (61 mg, 0.32 mmol) were dissolved in 4-methyl-2-pentanol (2 mL) and heated at 100° C. for 18 hrs. The reaction mixture was cooled to room temperature dissolved in MeOH and added to a 2 g SCX-2 column pre wet with MeOH (2 column volumes). Flushed with MeOH (2 column volumes) and the product eluted with 2M ammonia in MeOH. Product containing fractions were evaporated and the resultant material purified by base modified reverse phase HPLC to yield the title compound as a cream coloured solid (13 mg, 20%)
Reaction SMILES: [CH2:1]([OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:9][S:10](Cl)(=[O:12])=[O:11]>N1C=CC=CC=1>[CH3:9][S:10]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:8][S:10]([CH3:9])(=[O:12])=[O:11])(=[O:12])=[O:11]
Reactant: OCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCCCCOS(C)(=O)=O
Temperature: 5.5 °C
Reaction time: 8 h
Yield: 32.8 %

Procedure:
A solution of 1,6-hexanediol (13.15 g, 111.3 mmol) in 70 mL of anhydrous pyridine was cooled to 0° C. using ice bath. To this methanesulfonyl chloride (27 g, 235.7 mmol) was slowly added under mixing such that the temperature was maintained at 5-6° C. The combined mixture was stirred overnight at the temperature below 10° C. and the precipitate formed was filtered off, washed with 20% HCl (3×), water (3×), 5% solution of sodium bicarbonate (3×), and then again with water (3×). Product was dried under vacuum to obtain Compound 1 as a white solid (yield 32.8%). The structure of Compound 1 is given below:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][N:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=2[N:7]([CH2:16][C:17]([OH:19])=O)[C:6]1=[O:20].[NH2:22][C:23]1[CH:24]=[C:25]2[CH2:40][C:30]3([C:38]4[C:33](=[N:34][CH:35]=[CH:36][CH:37]=4)[NH:32][C:31]3=[O:39])[CH2:29][C:26]2=[N:27][CH:28]=1.C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[C:9]2[N:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])[C:6](=[O:20])[N:7]([CH2:16][C:17](=[O:19])[NH:22][C:23]3[CH:24]=[C:25]4[CH2:40][C:30]5([C:38]6[C:33](=[N:34][CH:35]=[CH:36][CH:37]=6)[NH:32][C:31]5=[O:39])[CH2:29][C:26]4=[N:27][CH:28]=3)[C:8]=2[CH:13]=1
Reactant: COC(=O)Cn1c(=O)n(CC(=O)O)c2cc(C)cc(C)c21
Reactant: Nc1cnc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)Cn1c(=O)n(CC(=O)Nc2cnc3c(c2)CC2(C3)C(=O)Nc3ncccc32)c2cc(C)cc(C)c21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of [3-(2-methoxy-2-oxoethyl)-4,6-dimethyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl]acetic acid (67 mg, 0.23 mmol, described in Intermediate 9), (±)-3-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 4), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:17]([O:21][C:22]([NH:24][C@@H:25]([C:33](O)=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])([CH3:20])([CH3:19])[CH3:18].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)(Cl)Cl.CCN(CC)CC>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][C:33](=[O:34])[C@@H:25]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:24][C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)O
Reactant: NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 1-(4-chlorobenzyl)-4-(aminomethyl)piperidine (100 mg) in CHCl3 (3 mL) was treated with Et3N (0.090 mL), N-(tert-butoxycarbonyl)-D-phenylalanine (122 mg), EDCI (89 mg) and HOBt (62 mg). The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was washed with 1 N aqueous NaOH solution (2 mL×2) and brine (2 mL). The organic layer was dried and concentrated to afford 1-(4-chlorobenzyl)-4-[{N-(tert-butoxycarbonyl)-D-phenylalanyl}aminomethyl]piperidine.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:6]([CH3:31])=[C:7]([C:18](=[O:30])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][C:10]([C:14]([O:16]C)=[O:15])=[CH:9]2>CO>[CH3:3][O:4][C:5]1[C:6]([CH3:31])=[C:7]([C:18](=[O:30])[C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[C:21]([O:28][CH3:29])[CH:20]=2)[N:8]2[C:13]=1[CH:12]=[CH:11][C:10]([C:14]([OH:16])=[O:15])=[CH:9]2
Reactant: COC(=O)c1ccc2c(OC)c(C)c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)n2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C(=O)c2c(C)c(OC)c3ccc(C(=O)O)cn23)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
1.21 mL (0.00121 mol) of 1N sodium hydroxide are added to 440 mg (0.0011 mol) of methyl [1-methoxy-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-6-yl]carboxylate (obtained in Example 10) in 10 mL of methanol and the medium is stirred at room temperature overnight. The reaction medium is concentrated under vacuum and the residue is taken up in water and ethyl acetate. The aqueous phase is separated by decantation and then acidified with 1.21 mL of 1N hydrochloric acid. The precipitate formed is filtered, washed with water and dried. 280 mg of an orange-coloured solid are obtained.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][NH:5][CH2:4][C@H:3]1[NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1.[CH3:24][O:25][C:26]1[N:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>CO.ClCCl>[OH:1][C@H:2]1[CH2:6][N:5]([CH:35]2[CH2:36][CH2:37][N:32]([C:29]3[CH:30]=[N:31][C:26]([O:25][CH3:24])=[CH:27][CH:28]=3)[CH2:33][CH2:34]2)[CH2:4][C@@H:3]1[NH:7][C:8](=[O:23])[CH2:9][NH:10][C:11](=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:21])[F:19])[CH:13]=1
Reactant: COc1ccc(N2CCC(=O)CC2)cn1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CNC[C@H]1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N2CCC(N3C[C@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)[C@@H](O)C3)CC2)cn1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of rac-N-(2-{[(3R,4R)-4-hydroxypyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide (50 mg, 0.152 mmol; prepared according to WO2004/050024A2), 1-(6-methoxypyridin-3-yl)piperidin-4-one (31 mg, 0.151 mmol) in methanol (4 mL) was added sodium triacetoxyborohydride (37 mg, 1.74 mmol) and stirred overnight. To the mixture was added NaHCO3 (sat. aq., 10 mL) and dichloromethane (10 mL). The organic layer was separated and the aqueous layer was washed with an addition portion of dichloromethane (10 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The resulting crude product was subjected to flash chromatography (15% MeOH, 1% NH4OH in EtOAc) to afford N-[2-({(3S,4S)-4-hydroxy-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide (73 mg, 93%) as a white solid. 1H-NMR (CD3OD) δ: 1.56-1.70 (m, 1H), 1.95-2.06 (m, 1H), 2.20-2.30 (m, 1H), 2.54-2.75 (m, 5H), 3.05-3.14 (m, 3H), 3.30-3.37 (m, 3H), 3.45-3.54 (m, 2H), 3.80-3.86 (s, 3H), 4.03-4.09 (m, 2H), 4.10-4.20 (m, 2H), 6.70-6.76 (in 1H), 7.40-7.50 (m, 1H), 7.69 (t, J=7.8 Hz, 1H), 7.70-7.78 (m, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 8.21 (s, 1H). MS m/z: 522 (M+1).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])[CH:11]=[CH2:12]>O.C(O)(C)(C)C>[C:2]([C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:12][CH2:11][C:10]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])(=[O:1])[CH3:9]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)CC(C)=O
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)(CCC(=O)OC(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of ethyl 3-oxobutanoate (45 g, 345 mmol) and Triton-B (40%, weight % solution in water, 1.08 mg, 6.90 mmol) in tert-BuOH (54 mL) was added tert-butyl acrylate (100.72 g, 691 mmol) dropwise over a period of 30 min under N2 atmosphere. The solution was stirred at room temperature for 24 h. The reaction mixture was partitioned between water (200 mL) and EtOAc (200 mL). The aqueous layer washed with EtOAc (2×50 mL). The combined organic layers were washed with water (200 mL), brine (200 mL), dried over Na2SO4 and concentrated under reduced pressure to provide compound D28-1 (140 g, quant) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz): δ 4.20 (q, J=7.2 Hz 2H), 2.24-2.09 (m, 8H), 1.58 (s, 3H), 1.43 (s, 18H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:18]=[C:17]([NH:19][C@H:20]3[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]3[NH:26]C(=O)OC(C)(C)C)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[CH:15]=3)[N:10]=2)=CC=1>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]1[NH:19][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH3:34])[CH:15]=2)[N:10]=[C:9]([NH2:8])[N:18]=1
Reactant: COc1ccc(CNc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c3cc(C)ccc3n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2nc(N)nc(N[C@H]3CCCC[C@H]3N)c2c1
Reaction time: 72 h
Yield: 88.9 %

Procedure:
To a solution of 9.37 g of tert-butyl (1R,2S)-2-({2-[(4-methoxybenzyl)amino]-6-methylquinazolin-4-yl}amino)cyclohexylcarbamate in 30 ml of methylene chloride, 95 ml of trifluoroacetic acid was added under ice cooling, and then the mixture was stirred for 72 hours. The reaction solution was concentrated, neutralized with a saturated sodium hydrogencarbonate solution, extracted with chloroform:methanol=10:1 and then dried. The solvent was distilled off and the residue was purified by Fuji Silysia NH silica gel column chromatography (chloroform:methanol=50:1) to obtain 4.60 g of the desirable compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]2S[CH:21]=[CH:22][N:23]=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Cl:34][C:35]1N=CC=C[N:36]=1>>[ClH:34].[CH3:2][O:3][C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[CH2:6][NH:7][C@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]2[N:36]=[CH:35][CH:21]=[CH:22][N:23]=2)[C@H:9]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccccc1CN[C@H]1CCCN(CCCCNc2nccs2)[C@H]1c1ccccc1
Reactant: Clc1ncccn1
Agent: Cl
Product: COc1ccccc1CN[C@H]1CCCN(CCCCNc2ncccn2)[C@H]1c1ccccc1

Procedure:
The title compound was prepared in a similar manner to the compound of Example 1 by replacing 2-bromothiazole with 2-chloropyrimidine; mp 123°-127° C. (dec.) 1H NMR (CDCl3) 67 1.46 (m, 5H), 1.94 (m, 6H), 2.54 (m, 2H), 3.24 (m, 4H), 3.35 (d, 1H, J=15), 3.48 (s, 3H), 3.64 (d, 1H, J=15), 6.42 (t, 1H, J=5), 6.59 (d, 1H, J=9), 6.68 (t, 1H, J=6), 6.80 (d, 1H, J=6), 7.05 (t, 1H, J=9), 7.22 (m, 5H), 8.18 (d, 2H, J=5). HRMS calc'd for C27H35N5O: 445.2836. Found: 445.2813.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH3:17])[CH2:12][CH2:11]2)=O)=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:3]=1>C1COCC1>[CH2:16]([N:13]1[CH2:14][CH2:15][N:10]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=2[C:18]([F:21])([F:19])[F:20])[CH2:11][CH2:12]1)[CH3:17]
Reactant: CCN1CCN(C(=O)c2ccc(N)cc2C(F)(F)F)CC1
Solvent: C1CCOC1
Product: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 69.3 %

Procedure:
To a mixture of (4-amino-2-trifluoromethyl-phenyl)-(4-ethyl-piperazin-1-yl)-methanone (20 g, 66.4 mmol) in THF (500 mL) was added BH3DMS (19.91 mL, 199 mmol) dropwise. Then the mixture was stirred at 80° C. for 4 h. The mixture was quenched by adding MeOH and then concentrated. The residue was purified by silica column chromatography on silica gel (PE:EA=2:1, Rf=0.35) to give a white solid of 4-(4-ethyl-piperazin-1-ylmethyl)-3-trifluoromethyl-phenylamine (14 g, 46.0 mmol, 69.4% yield): 1H NMR (400 MHz, CDCl3) δ: 7.48 (d, J=8.4 Hz, 1H), 6.91 (d, J=2.8 Hz, 1H), 6.79 (dd, J=2.4, 8.4 Hz, 1H), 3.76 (s, 2H), 3.53 (s, 2H), 2.45-2.39 (m, 8H), 1.08 (t, J=7.2 Hz, 3H); ES-LCMS m/z 288 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH2:16](O)[CH3:17]>>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]=[CH:7][C:8]([O:10][CH2:16][CH3:17])=[O:9]
Reactant: O=C(O)C=Cc1nccs1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C=Cc1nccs1

Procedure:
A solution of 2-thiazoleacrylic acid (26.76 g) and concentrated sulphuric acid (10 ml) in ethanol (150 ml) was refluxed for 18 hours. The solution was partially evaporated and dissolved in water. This solution was extracted with ether and the etheral extracts were evaporated to give ethyl 2-thiazoleacrylate.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[CH:16][C:15]=1[F:29])(=[O:7])[CH3:6]>>[C:5]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[C:14]1[C:15]([F:29])=[CH:16][C:17]([NH:20][C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[O:22])=[C:18]([N+:1]([O-:4])=[O:2])[CH:19]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)N1CCC(C)C1c1ccc(NC(=O)c2ccccn2)cc1F
Reactant: O=[N+]([O-])O
Product: CC(=O)N1CCC(C)C1c1cc([N+](=O)[O-])c(NC(=O)c2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 ml of fuming nitric acid was added to 70 mg of N-(4-(1-acetyl-3-methylpyrrolidin-2-yl)-3-fluorophenyl)pyridine-2-carboxamide, and the reaction liquid was stirred at room temperature for 2 hours. The reaction liquid was poured into a mixture of ice-aqueous saturated sodium bicarbonate, extracted with chloroform, and dried with anhydrous sodium carbonate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), chloroform/methanol=20/1) to obtain the entitled compound as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:3]=1.[Mg].[C:17]1(=[O:27])[O:22][C:20](=[O:21])[C@H:19]2[CH2:23][CH:24]=[CH:25][CH2:26][C@@H:18]12>O1CCCC1>[CH:11]1([O:10][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=2[O:8][CH3:9])[C:17]([C@H:18]2[CH2:26][CH:25]=[CH:24][CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:27])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)[C@H]2CC=CC[C@H]2C(=O)O)cc1OC1CCCC1
Reaction time: 18 h

Procedure:
A solution of 100 mmol of 1-Bromo-3-cyclopentyloxy-4-methoxybenzene in tetrahydrofuran was added slowly to a mixture of 1.1 equivalent of magnesium. After complete addition, the mixture was refluxed for 5 h and left at room temperature for additional 18 h. The mixture was added slowly to a solution of (cis)-1,2,3,6-tetrahydrophthalic anhydride in tetrahydrofuran at 0° C. After complete addition the mixture was refluxed for 6 h and left at room temperature for addition 18 h after which the reaction was quenched with ammonium chloride and the solvent removed under reduced pressure. The residue was acidified with concentrated hydrochloric acid and the mixture extracted with diethyl ether. The organic layer was dried over magnesium sulfate and evaporated. The residue was dissolved in dichloromethane and the solution filtered over silica. After evaporating this dichloromethane solution, the compound was crystallized from diethyl ether. M.p. 114-115° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:25])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:24])([C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:15])[CH2:6][CH2:5]2.[O:26]=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>>[OH:26][C:7]([CH3:24])([CH2:6][CH2:5][C:4]1[C:9](=[O:8])[C:10]([CH3:13])=[C:11]([CH3:12])[C:2](=[O:1])[C:3]=1[CH3:25])[C:14]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[O:15]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)NCCCCCCO)O2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Product: CC1=C(C)C(=O)C(CCC(C)(O)C(=O)NCCCCCCO)=C(C)C1=O
Yield: 59.8 %

Procedure:
Oxidation as described in protocol B, using 64.2 mg (0.183 mmol) of 6-hydroxy-N-(6-hydroxyhexyl)-2,5,7,8-tetramethylchroman-2-carboxamide and 230 mg CAN (0.419 mmol) yielded 40 mg of 2-hydroxy-N-(6-hydroxyhexyl)-2-methyl-4-(2,4,5-trimethyl-3,6-dioxocyclohexa-1,4-dienyl)butanamide as a yellow oil.