Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:33])/[C:10](/[CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)[CH2:4][CH2:3]1.Cl.C(N=C=NCCCN(C)C)C.[O:46]1[CH2:51][CH2:50][CH2:49][CH2:48][CH:47]1[O:52][NH2:53].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:33])/[C:10](/[CH2:21][O:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:53][O:52][CH:47]3[CH2:48][CH2:49][CH2:50][CH2:51][O:46]3)=[O:17])=[CH:19][CH:20]=2)[CH2:4][CH2:3]1
Reactant: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)O)cc2)COc2cccc3ccccc23)CC1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(NC(=O)/C(=C/c2ccc(C(=O)NOC3CCCCO3)cc2)COc2cccc3ccccc23)CC1
Temperature: 0 °C
Reaction time: 12 h
Yield: 80.3 %

Procedure:
(E)-4-(3-(1-Methylpiperidin-4-ylamino)-2-((naphthalen-1-yloxy)-methyl)-3-oxo-prop-1-enyl)benzoic acid (339 mg, 0.56 mM) obtained in Example (1-1-2) was dissolved in dimethylformamide (4 ml) and cooled to 0° C. To the resulting mixture, triethylamine (0.16 ml, 1.14 mM), N-hydroxy-6-trifluorobenzotriazole (FOBt; 171 mg, 0.84 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide.hydrochloride (EDC.HCl; 190 mg, 0.99 mmol) and tetrahydro-2H-pyran-2-yloxyamine (THPONH2; 107 mg, 0.91 mmol) were added at 0° C. and the resulting mixture was stirred at room temperature for 12 hrs. To the mixture, 10% potassium carbonate solution (20 ml) was added thereto. Then, the resultant was extracted with ethyl acetate (20 ml, 15 ml×2). The organic layer was separated, washed with brine (20 ml) and dried over anhydrous sodium sulfate, followed by removing the solvent under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 333 mg of the title compound as a white solid (yield 80%).
Reaction SMILES: [OH:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)=[NH:4].[C:18](OC(=O)C)(=O)[CH3:19].O>N1C=CC=CC=1>[CH3:18][C:19]1[O:1][N:2]=[C:3]([N:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[N:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCN(C(=N)NO)CC1
Solvent: c1ccncc1
Solvent: O
Product: Cc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)no1
Temperature: 80 °C
Yield: 91.3 %

Procedure:
To a solution of tert-butyl 4-(N-hydroxycarbamimidoyl)piperazine-1-carboxylate (771 mg, 3.16 mmol) in pyridine (8 mL) was added acetic anhydride (320 L, 3.42 mmol) and the reaction was heated to 80° C. for 3 h. The mixture was cooled to room temperature, poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated under reduced pressure to yield 774 mg of a yellow solid. After purification by flash chromatography (silica, gradient of 0.5 to 3% methanol in dichloromethane) 509 mg of an off-white solid were obtained (1.897 mmol, 60%). MS (ESI) m/z=291.1 [M+Na]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[C:13](=[O:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@@H:11]2[C@H:13]([OH:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H]2CN(Cc3ccccc3)C[C@H]12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Temperature: -40 °C

Procedure:
(3aR,6aS)-2-Benzylhexahydrocyclopenta[c]pyrrol-4(5H)-one (1.462 g, 6.79 mmol) [prepared as described by Santora, V. J. et. al. Bioorganic & Medicinal Chemistry Letters (2008), 18, 1490-1494] was dissolved in methanol (20 mL) and cooled in a dry ice/acetone bath to −40° C. Sodium borohydride (0.514 g, 13.58 mmol) was added in portions over 5 minutes. The reaction mixture was allowed to warm to room temperature overnight, then it was quenched with saturated aqueous ammonium chloride, diluted with water, and extracted with 3×150 mL of ethyl acetate. The combined extracts were dried (Na2SO4) and the solvent was removed in vacuo to give (3aR,4R,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ol: 1H NMR (300 MHz, CDCl3) δ ppm 7.45-7.38 (m, 2H), 7.34 (dd, J=10.2, 4.7, 2H), 7.30-7.24 (m, 1H), 5.63 (s, 1H), 4.30 (dd, J=11.4, 6.2, 1H), 3.54 (q, J=13.0, 2H), 3.17 (dd, J=9.3, 3.3, 1H), 2.57 (dtd, J=10.0, 7.1, 3.2, 1H), 2.48 (dtt, J=17.5, 8.7, 4.3, 1H), 2.44-2.38 (m, 2H), 2.31 (dd, J=9.2, 7.4, 1H), 2.04-1.96 (m, 1H), 1.76-1.61 (m, 2H), 1.47-1.40 (m, 1H); MS (ESI+) m/z 217 (M+H)+.
Reaction SMILES: [Cl:1][Si](C)(C)C.O.[CH3:7][N:8]([CH3:31])[C:9]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])[CH2:11][CH2:10]1>CC(CC)=O>[ClH:1].[CH3:31][N:8]([CH3:7])[C:9]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:14][CH2:13][CH:12]([CH2:15][C:16]([NH:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:17])[CH2:11][CH2:10]1
Reactant: C[Si](C)(C)Cl
Agent: CN(C)C1(c2ccccc2)CCC(CC(=O)Nc2ccccc2)CC1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 18 h

Procedure:
Chlorotrimethylsilane (0.124 ml) and water (9 μl) were added to a solution of the less polar diastereoisomer of 2-(4-dimethylamino-4-phenyl-cyclohexyl)-N-phenyl-acetamide (300 mg, 0.9 mmol) in ethyl methyl ketone (2 ml). After 18 h it was possible to isolate the hydrochloride as a colourless solid in a yield of 64% (210 mg) (Example 55).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.I.[NH2:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[NH:15].C(O)(=O)C.[OH-].[Na+]>CCOCC.C(O)C.O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[N:12][NH:13][C:14]([NH:16][CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[NH:15]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: N=C(NN)NCc1ccco1
Agent: I
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: N=C(NCc1ccco1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 1.75 g. of 2,6-dichlorobenzaldehyde and 2.82 g. of 1-amino-3-furfurylguanidine hydriodide in 15 ml. of glacial acetic acid is heated at 100° C. for one hour, cooled, and diluted with absolute ether until crystallization occurs. Filtration gives 3.51 g. of gray-colored crystals. The crystals are dissolved by warming in absolute ethanol and the solution is treated with excess 10N sodium hydroxide and diluted with water to turbidity. Chilling and filtration give 2.00 g. of nearly colorless crystals. Two recrystallizations from aqueous ethanol, using activated charcoal, give the desired product as colorless crystals, m.p. 134°-135.5° C.
Reaction SMILES: C(CC(O)=O)C.[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])[C:25](=[N:32][OH:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[CH3:8].[Cl:36][CH2:37][CH2:38][N:39]=[C:40]=[O:41].Cl.P([O-])([O-])([O-])=O>CN(C)C=O.C(N(CC)CC)C>[C:7]([O:10][CH2:11][C:12]1[CH2:13][S:14][C@@H:15]2[C@H:22]([NH:23][C:24](=[O:34])[C:25](=[N:32][O:33][C:40](=[O:41])[NH:39][CH2:38][CH2:37][Cl:36])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:21](=[O:35])[N:16]2[C:17]=1[C:18]([OH:20])=[O:19])(=[O:9])[CH3:8]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: O=C=NCCCl
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCCC(=O)O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)NCCCl)c3ccccc3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylic acid ethyl acetate solvate (syn-isomer) (1.0 g.) in dimethylformamide (21 ml.) containing triethylamine (0.425 g) was added 2-chloroethylisocyanate (0.274 g.) and the mixture was stirred at room temperature for one hour. The reaction mixture was acidified (2 N hydrochloric acid) and extracted with ethyl acetate. The extracts were combined and extracted with saturated aqueous sodium bicarbonate. The combined aqueous extracts were acidified (2 N-hydrochloric acid) and extracted with ethyl acetate, dried, concentrated and added dropwise to petroleum with vigorous stirring. The precipitated solid was filtered, dissolved in ethyl acetate (10 ml.) and added dropwise to petroleum (300 ml.). The precipitate was filtered and dried giving the title acid (0.76 g; 74%), [α]D +28° (c 1.0 DMSO), λmax. (pH 6 phosphate buffer) 257.5 nm. (ε 20,780), νmax. (Nujol) 3270 (NH), 1780 (β-lactam), 1660 and 1520 cm.-1 (amide), τ (DMSO-d6) values include -0.10 (doublet, J 8 Hz; NH), 6.2-6.7 (multiplet; C-2 CH2 +--CH2CH2Cl), 7.95 (singlet; OCOCH3).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])=[C:17]([OH:18])[C:12]=3[C:11](=[O:22])[N:10]([CH:23]3[CH2:25][CH2:24]3)[C:9]2=[O:26])=[CH:4][CH:3]=1.C(#N)C.[S:30](Cl)([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]>C(N(CC)CC)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]([CH3:21])[C:15](=[O:20])[C:16]([CH3:19])=[C:17]([O:18][S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:12]=3[C:11](=[O:22])[N:10]([CH:23]3[CH2:24][CH2:25]3)[C:9]2=[O:26])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(O)c2c(=O)n(C3CC3)c(=O)n(-c3ccc(Br)cc3)c2n(C)c1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2c(C)c(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Yield: 74.3 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-5-hydroxy-6,8-dimethyl-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 38 (400 mg) obtained in Step 5 was added acetonitrile (8.0 ml), tosyl chloride 11 (458 mg) and triethylamine (0.34 ml) were added under a nitrogen atmosphere, and the mixture was stirred under reflux for 30 hrs. After allowing to cool to room temperature, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (chloroform:acetone=25:1→20:1) to give toluene-4-sulfonic acid 1-(4-bromo-phenyl)-3-cyclopropyl-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 39 (407 mg, yield 74%) as ocher crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH2:8][C:9]#[CH:10])([CH3:4])([CH3:3])[CH3:2].[CH3:12][O:13][C:14]([C:16]1[S:17][C:18](Br)=[CH:19][CH:20]=1)=[O:15]>C(#N)C.CCOC(C)=O.[Cu]I.C(N(CC)CC)C>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:10]#[C:9][CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])=[CH:19][CH:20]=1)=[O:15]
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: COC(=O)c1ccc(Br)s1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)s1
Temperature: 25 °C
Yield: 63406.2 %

Procedure:
A mixture of prop-2-ynyl-carbamic acid tert-butyl ester (1.67 g, 0.011 mmol), 5-bromo-thiophene-2-carboxylic acid methyl ester (2.50 g, 0.011 mmol), tetrakistriphenylphosphine(0) palladium (0.622 g, 0.0538 mmol), CuI (0.102 g, 0.538 mmol) and triethylamine (1.57 mL, 0.011 mmol) in 50 mL acetonitrile under nitrogen was heated at reflux for 16 h. The reaction was cooled to room temperature, diluted with 75 mL EtOAc, washed with 5.5% HCl, water and brine, dried over MgSO4, filtered and concentrated in vacuo to an oil. The product was purified via flash chromatography (9:1 to 4:1 hexanes:EtOAc) to afford the title compound as an oil (2.06 g). MS 313 (M+18).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1.[C:10]([O-:13])([O-])=[O:11].[K+].[K+].Cl>CCO.O>[C:3]([O:13][C:10]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([OH:9])=[O:8])[CH2:2]1)=[O:11])([CH3:7])([CH3:4])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)C1CCCNC1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 249.7 %

Procedure:
A 250-mL 3-necked round-bottomed flask was charged with a solution of piperidine-3-carboxylic acid (4.0 g, 30.39 mmol, 1.00 equiv, 98%) in EtOH (70 mL), tert-butoxycarbonyl (8.2 g, 36.86 mmol, 1.21 equiv, 98%) and K2CO3 (4.3 g, 30.54 mmol, 1.00 equiv, 98%). The resulting mixture was stirred overnight at room temperature overnight. Then, the mixture was diluted with water. The pH was adjusted to 3 with aqueous 10% HCl resulting in a precipitate. The mixture was then filtered to collect solids that were washed with water and dried in a vacuum oven under reduced pressure to afford 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid as white solid (8.7 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O.[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[N:1]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ClCc1ccccc1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Temperature: 90 °C

Procedure:
A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90±15° C. for 10–24 hours. The reaction mixture was cooled to 60° C. and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil,which was carried on in the next step without purification.
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:38][CH3:39])([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.C1(OC)C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].O>[N+](C)([O-])=O>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:38][CH3:39])([O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=1)=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C(F)(F)F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: COc1ccccc1
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C(F)(F)F)cc1
Reaction time: 1 h
Yield: 62.6 %

Procedure:
Next, 1.40 g (2.48 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[methyl(4-trifluoromethylphenyl)phosphono]butanoate and 1.61 g (14.9 mmol) of anisole were dissolved in 10 mL of dry nitromethane and mixed with 0.99 g (7.44 mmol) of aluminum trichloride at room temperature. After stirring was carried out at room temperature for 1 hour, 20 mL of water was added and stirred for 10 minutes. The mixture was washed with 50 mL of ether three times and the water layer was separated, and methanol was added to the final concentration of methanol to be 30%. The solution was passed through a short column of neutral silica gel 60N to remove aluminum hydroxide. Without being concentrated, the effluent was purified by medium pressure reversed-phase column chromatography ODS-S-50B. The column was eluted with a linear gradient of 30 to 60% methanol (flow rate of 6 mL/min) and the fractions containing the compound eluted at 60% methanol were collected. The elution and purity of the compound were confirmed by TLC (BuOH/AcOH/H2O=5:2:2, ninhydrin coloration). After vacuum concentration, freeze drying was carried out to obtain 2-amino-4-[methyl(4-trifluoromethylphenyl)phosphono]butanoic acid (0.53 g, yield 63%) as a colorless solid.
Reaction SMILES: C([C:4]1([C:17]([O:19][CH2:20][CH3:21])=[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)C=C.ClCCl.[BH4-].[Na+].CC(C)=O>CO.O>[O:18]=[C:17]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH2:8][CH2:9]2)[CH2:21][CH2:20][O:19]1
Reactant: C=CCC1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC2(CCOC2=O)CC1
Temperature: -78 °C
Reaction time: 1.25 h
Yield: 87.4 %

Procedure:
1-(1,1-Dimethylethyl) 4-ethyl 4-(2-propenyl)-1,4-piperidinedicarboxylate (Description 82, 20.0 g, 67.2 mmol) was dissolved in methanol (300 mL) and dichloromethane (300 mL) and cooled to −78° C. Oxygen was bubbled through the solution for 10 minutes, then ozone for 75 minutes, to give a persistant blue coloration. Oxygen was bubbled through the solution for 10 minutes, then nitrogen for 10 minutes. Sodium borohydride (5.1 g, 135 mmol) was added and the mixture was stirred at −78° C. for 1 hour. Further sodium borohydride (5.1 g, 135 mmol) was added and the mixture was stirred at room temperature for 16 hours. Acetone (75 mL) was added and the mixture was stirred at room temperature for 10 minutes. Water (50 mL) was added and the organic solvent was evaporated under reduced pressure. Saturated aqueous ammonium chloride (500 mL) was added and the mixture was extracted with ethyl acetate (2×500 mL). The combined organic fractions were washed with aqueous citric acid (10%, 500 mL), saturated aqueous sodium hydrogen carbonate (500 mL) and brine (200 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure to give the title compound (15.0 g, 88%). 1H NMR (400 MHz, CDCl3) δ 4.31 (2H, t, J 7 Hz), 3.97–3.87 (2H, m), 3.17–3.07 (2H, m), 2.20 (2H, t, J 7 Hz), 1.92–1.82 (2H, m), 1.60–1.45 (2H, m), and 1.45 (9H, s).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([N:15]2[N:19]=[C:18]3[C:20]([Br:25])=[CH:21][CH:22]=[C:23]([Br:24])[C:17]3=[N:16]2)[C:6]=1[OH:26])([CH3:4])([CH3:3])[CH3:2].[C:27](=O)([O-])[O-].[K+].[K+].IC.C(Cl)Cl>CN(C=O)C.O>[C:1]([C:5]1[C:6]([O:26][CH3:27])=[C:7]([N:15]2[N:16]=[C:17]3[C:23]([Br:24])=[CH:22][CH:21]=[C:20]([Br:25])[C:18]3=[N:19]2)[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(-n2nc3c(Br)ccc(Br)c3n2)c(O)c(C(C)(C)C)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CI
Solvent: CN(C)C=O
Product: COc1c(-n2nc3c(Br)ccc(Br)c3n2)cc(C(C)(C)C)cc1C(C)(C)C
Temperature: 65 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
2,4-Di-tert-butyl-6-(4,7-dibromo-benzotriazol-2-yl)-phenol (Monomer T1) (1.0 g, 2.08 mmol) and potassium carbonate (0.431 g, 96% GC purity, 3.12 mmol) were mixed in anhydrous DMF (20 mL) in a round-bottomed 100-mL flask. The flask was capped with a rubber septum and purged with nitrogen for 0.5 h. The mixture was heated to 65° C. and iodomethane (0.591 g, 4.16 mmol) was added. The mixture was stirred at 60-65° C. for 1 h. The flask was cooled to room temperature. DCM (20 mL) and water (20 mL) were added and the organic phase was separated and the aqueous phase extracted with DCM (20 mL). All the organic phases were combined and washed with water (3×20 mL) and brine (20 mL). The solution was dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness with a rotary evaporator. The product was crystallized from DCM/hexanes and filtered. Purity: 99% (GC). Yield: 34%.
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:24])[C@H:4]([NH:20]CC#N)[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7].O.C1(C)C=CC(S(O)(=O)=[O:33])=CC=1.ClC1C=C(C=CC=1)C(OO)=O>>[CH3:1][O:2][C@H:3]([CH3:24])[C@H:4]([NH:20][OH:33])[CH2:5][S:6]([CH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)(=[O:8])=[O:7]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NCC#N
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: O
Product: CO[C@H](C)[C@@H](CS(=O)(=O)Cc1cnc2ccccc2c1)NO
Temperature: 60 °C
Yield: 357.7 %

Procedure:
An ice-cold stirred solution of (2S,3R)-3-methoxy-2-(N-cyanomethylamino)-1-(3-quinolylmethanesulfonyl)butane (590 mg) in MDC (20 ml) was treated with 4-toluenesulphonic acid monohydrate (50 mg) and 70% 3-chloroperoxybenzoic acid (281 mg). After 45 min the reaction was quenched with 10% sodium thiosulphate (5 ml) followed by saturated sodium hydrogen carbonate (5 ml) solution. After 5 min the organic layer was collected and the aqueous re-extracted with MDC (10 ml). The combined MDC phases were dried (MgSO4) and evaporated. The residue was redissolved in methanol (10 ml) treated with 4-toluenesulphonic acid monohydrate and hydroxylamine hydrochloride (2.36 g) and heated at 60° C. for 1.5 h. The cooled solution was evaporated, then dissolved in water (5 ml) and saturated sodium hydrogen carbonate solution (5 ml). After extraction with MDC (2×5 ml), the combined extracts were dried (MgSO4) and evaporated. The residue was flash chromatographed (silica gel, step gradient: 80–100% ethyl acetate in hexane) to give the subtitle compound (305 mg). MS (APCI+ve ion) 325(MH+); 1H NMR δ(CDCl3): 8.91 (1H, m), 8.32 (1H, d, J=2 Hz), 8.14 (1H, d, J=8 Hz), 7.85 (1H, d, J=8 Hz), 7.76 (1H, t, J=8 Hz), 7.6 (1H, t, J=8 Hz), 4.83 (1H, broad), 4.58 (2H, m), 3.0–3.7 (4H, m), 3.38 (3H, s), 0.92 (3H, d, J=6.3 Hz).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]3[CH:16]=[CH:17][C:18]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([N:28]5[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]5)=[O:27])=[CH:22][CH:21]=4)=[CH:19][C:14]3=[N:13][CH:12]=2)=[CH:7][CH:6]=1.ClC(Cl)(Cl)C[O:38][C:39](=O)[NH:40][C:41]1[CH:45]=[C:44]([C:46]([CH3:49])([CH3:48])[CH3:47])[O:43][N:42]=1.C(N(CC)CC)C>CS(C)=O>[C:46]([C:44]1[O:43][N:42]=[C:41]([NH:40][C:39]([NH:3][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[N:15]4[CH:16]=[CH:17][C:18]([C:20]5[CH:21]=[CH:22][C:23]([C:26]([N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[O:27])=[CH:24][CH:25]=5)=[CH:19][C:14]4=[N:13][CH:12]=3)=[CH:9][CH:10]=2)=[O:38])[CH:45]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Reactant: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)Nc6cc(C(C)(C)C)on6)cc5)cnc4c3)cc2)CC1
Temperature: 70 °C
Reaction time: 5 h
Yield: 14.5 %

Procedure:
Combine {4-[3-(4-aminomethyl-phenyl)-imidazo[1,2-a]pyridin-7-yl]-phenyl}-(4-methyl-piperazin-1-yl)-methanone, bis hydrochloride (0.30 g, 0.56 mmol), (5-tert-butyl-isoxazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.2 g, 0.63 mmol) and triethylamine (0.4 mL, 2.9 mmol) in DMSO (10 mL). Heat the mixture to 70° C., stir five hours, and cool to room temperature. Filter the solution through 10 g SCX column eluting with methanol→2 N ammonia in methanol. Concentrate fractions containing product to give a residue. Purify by chromatography (5% methanol in dichloromethane→10% methanol in dichloromethane→10% 2 N ammonia methanol in dichloromethane) to afford product (0.048 g, 15%). MS(ES), m/z 592 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:19])([CH3:18])[CH3:17])=[CH:12][C:11]=2[F:20])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:22]1[N:27]=[CH:26][C:25]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=1>>[F:20][C:11]1[CH:12]=[C:13]([C:16]([OH:19])([CH3:17])[CH3:18])[CH:14]=[CH:15][C:10]=1[C:4]1[S:3][C:2]([NH:1][C:22]2[CH:23]=[CH:24][C:25]([CH:28]([OH:33])[C:29]([F:32])([F:31])[F:30])=[CH:26][N:27]=2)=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=1
Reactant: OC(c1ccc(Cl)nc1)C(F)(F)F
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3ccc(C(O)C(F)(F)F)cn3)s2)c(F)c1

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.51 mmol) and 1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethanol (108 mg, 0.51 mmol) as starting materials.