Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH:45]=O)=[CH:41][CH:40]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[O-]S(S([O-])=O)=O.[Na+].[Na+]>CCO.CN(C=O)C.C(Cl)Cl.N>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:45]([C:42]3[CH:41]=[CH:40][C:39]([CH2:38][N:35]4[CH2:34][CH2:33][N:32]([C:30]([O:29][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:31])[CH2:37][CH2:36]4)=[CH:44][CH:43]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C=O)cc2)CC1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: ClCCl
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCN(C(=O)OC(C)(C)C)CC5)cc4)nc23)CC1
Temperature: 85 °C
Yield: 37.8 %

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.050 g, 0.13 mmol, 1 eq) in EtOH (2.2 mL) and DMF (0.3 mL), tert-butyl-4-(4-formylbenzyl)piperazine-1-carboxylate (0.042 g, 0.14 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.38 mL, 0.38 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 92:8) to give the title compound as a solid (0.032 g, 39%); 1H-NMR (500 Mz, DMSO-d6): 1.39 (s, 9H, C(CH3)3), 2.34 (t, J=5.0 Hz, 4H), 2.56-2.62 (m, 4H), 3.29-3.35 (m, 4H), 3.54 (s, 2H, NCH2), 3.55 (s, 2H, NCH2), 3.61-3.66 (m, 4H), 3.68 (s, 3H, CH3), 6.80 (s, 1H, imidazole 4-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.14 (d, J=8.5 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H); LC (Method B)-MS (ESI, m/z) 2.33 min—650/652 [(M+H)+], Br isotopic pattern]. ESI-HRMS: Found: 650.2565, calculated for C31H41BrN9O2 (M+H)+: 650.2567.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH2:9]1[C:13]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[S:16][C:12]=2[C:11](=O)[CH2:10]1>CO>[CH2:9]1[C:13]2[C:14]3[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=3[S:16][C:12]=2[C:11](=[N:2][OH:3])[CH2:10]1
Reactant: O=C1CCc2c1sc1c2CCCC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: ON=C1CCc2c1sc1c2CCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a mechanical stirrer and nitrogen inlet was charged with hydroxylamine hydrochloride (573 mg, 8.25 mmol) and methanol (10 mL). The mixture was cooled to 0° C. using an ice bath. Sodium acetate (677 mg, 8.25 mmol) was added. The mixture was stirred at 0° C. for 30 min. After this time, 103c (319 mg, 1.65 mmol) was added, and the reaction was stirred at room temperature for 16 h. After this time, the mixture was concentrated, and the resulting residue was triturated with water (10 mL). The resulting solid was collected and dried in a vacuum oven at 45° C. to afford an 84% yield (287 mg) of 103d as an off-white solid: mp 173-174° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.38 (s, 1H), 2.97 (m, 2H), 2.77-2.73 (m, 4H), 2.47 (m, 2H), 1.75 (m, 4H); MS (APCI+) m/z 208.3 (M+H)
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:23][CH2:24][O:25][CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][O:27]3)[C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: BrCCOC1CCCCO1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CCOC2CCCCO2)c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
To a solution of 8-bromo-7-(4-chlorobenzyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (2.0 g, 5.4 mmol, intermediate 8) in DMF (10 mL) was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (1.35 g, 6.5 mmol, intermediate 2), potassium carbonate (1.49 g, 10.8 mmol). The mixture was stirred at 50° C. overnight. It was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried under vacuum to give 8-bromo-7-(4-chlorobenzyl)-3-methyl-1-(2-(tetrahydro-2H-pyran-2-yloxy)ethyl)-1H-purine-2,6(3H,7H)-dione (2.10 g, 74.4%) as a white solid. LCMS retention time 1.669 min LCMS MH+-THP 415.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:19][NH:20][C:21]([NH2:23])=[O:22]>C(O)(=O)C>[CH3:19][N:20]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:23][C:21]1=[O:22]
Reactant: CNC(N)=O
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: Cn1c(-c2ccccc2)cc(-c2ccccc2)nc1=O
Reaction time: 8 h

Procedure:
A solution of 15 g. of dibenzoylmethane and 43.5 g. of M-methylurea in 250 ml. of glacial acetic acid is refluxed for 8 hours while dry hydrogen chloride gas is bubbled through the reaction mixture. An additional amount of 5 equivalents of N-methylurea is then added and refluxing continued for another 8 hours while bubbling hydrogen chloride through the reaction system. The N-methylurea addition is again repeated and refluxing procedure continued for a further 8 hours. The resulting mixture is filtered and the filtrate evaporated in vacuo to dryness. The residue is taken up with methylene chloride, treated with 2N. sodium hydroxide and the methylene chloride layer separated. The aqueous layer is extracted three times with methylene chloride. All methylene chloride fractions are combined and extracted several times with water, dried, filtered and evaporated in vacuo to dryness. The residue is crystallized from methylene chloride/diethyl ether to obtain 1-methyl-4,6-diphenylpyrimidin-2(1H)-one, m.p. 183°-185°C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[CH:6]=1>CC(=O)CC>[CH3:1][C:2]1[NH:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[C:6]=1[CH:2]([CH2:6][CH3:5])[CH3:1]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Solvent: CCC(C)=O
Product: CCOC(=O)c1[nH]c(C)c(C(C)CC)c1C

Procedure:
The crude product, obtained as in Example 74 but using 2,4-dimethyl-5-carbethoxypyrrole with 2-butanone and stirring at 30°-35° C, was sublimed then thrice recrystallized from ethanol as colorless plates (130 mg), m.p. 102°-104° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>>[CH3:19][O:18][C:16](=[O:17])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C1CC[C@@H](c2ccc(O)cc2)C1
Reactant: COC(=O)CBr
Product: COC(=O)COc1ccc([C@@H]2CCC(=O)C2)cc1
Yield: 100.7 %

Procedure:
(R)-3-(4-Hydroxyphenyl)cyclopentanone (0.82 g, 4.6 mmol) and methyl bromoacetate (0.9 mL, 10 mmol) were used and treated in a similar manner to (Step 4) of (Example 10) to give the title compound (1.15 g, 100%).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:13][C:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[NH:16][N:15]=1>>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([C:17]2[CH:18]=[C:14]([NH:13][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[NH:15][N:16]=2)=[CH:24][CH:23]=1
Reactant: O=C(O)CCCN1CCCCC1
Reactant: COc1ccc(-c2cc(N)n[nH]2)cc1
Product: COc1ccc(-c2cc(NC(=O)CCCN3CCCCC3)[nH]n2)cc1
Reaction time: 10 h

Procedure:
To a suspension of 4-piperidin-1-yl-butyric acid (1.32 g, 7.93 mmol) in 12,2-dichloroethane (20 mL), N,N′-carbonyldiimidazole (1.2 g, 7.4 mmol) was added and the mixture was stirred at room temperature for 2 hours (when all the aminoacid was activated complete dissolution of the suspension was generally observed). 3-Amino-5-(4-methoxyphenyl)pyrazole (1 g, 5.29 mmol) was then added and the reaction was stirred for further 10 hours. Upon reaction completion (as monitored by LC-MS) the formation of two isomers was observed, and the mixture was heated at 50° C. until the conversion of the less stable isomer to the title compound was observed (as monitored by LC-MS). The solvent was washed with sat. Na2CO3 solution, extracted and removed under reduced pressure. The crude was crystallised from acetonitrile to give 1.2 g of the title compound (Yield: 70%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>>[ClH:27].[NH:8]1[CH2:9][CH2:10][CH:11]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[N:22]=[CH:23][CH:24]=[CH:25][N:26]=3)=[CH:19][CH:20]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-c3ncccn3)cc2)CC1
Agent: Cl
Product: c1cnc(-c2ccc(NC3CCNCC3)cc2)nc1

Procedure:
Stirred 4-(4-Pyrimidin-2-yl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (110 mg, 0.310 mmol) in 4M HCl (20 ml) at room temperature for 1 hour. Solvent was evaporated yielding desired product piperidin-4-yl-(4-pyrimidin-2-yl-phenyl)-amine, hydrochloride (114 mg).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([CH3:32])[CH:13]=[CH:12][C:11]([S:14]([O:17][CH2:18][C@H:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:20]C(OC)(C)C)(=[O:16])=[O:15])=[CH:10][CH:9]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:8]1([CH3:32])[CH:9]=[CH:10][C:11]([S:14]([O:17][CH2:18][C@H:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[OH:20])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: COC(C)(C)O[C@H](COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Into toluene (10 ml) were added (S)-2-phenyl-2-(1-methoxy-1-methylethyloxy)ethyl p-toluenesulfonate (3.0 g), p-toluenesulfonic acid monohydrate (1.7 g) and methanol (0.5 g), and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, then with a saturated aqueous sodium chloride solution, and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then the solvent was distilled off under reduced pressure to obtain a colorless oily compound mentioned above (2.1 g, 88.0%).
Reaction SMILES: Br[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[CH3:17][N:18]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[NH:21][CH2:20][C:19]1=[O:27]>N1C=CC=CC=1.[Cu-]=O>[O:26]=[S:22]1(=[O:25])[CH2:23][CH2:24][N:18]([CH3:17])[C:19](=[O:27])[CH2:20][N:21]1[C:2]1[N:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[C:9]([OH:16])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Reactant: CN1CCS(=O)(=O)NCC1=O
Agent: O=[Cu-]
Solvent: c1ccncc1
Product: COC(=O)c1nc(N2CC(=O)N(C)CCS2(=O)=O)c2cccnc2c1O
Temperature: 115 °C
Reaction time: 5 h

Procedure:
A mixture of methyl 5-bromo-8-hydroxy[1,6]naphthyridine-7-carboxylate (0.28 g, 1.0 mmol), 5-methyl-1,2,5-thiadiazepan-4-one 1,1-dioxide from step 2 (0.178 g, 1.0 mmol) and copper (I) oxide (0.143 g, 1.0 mmol) in pyridine (5 mL) was heated in an oil bath at 115° C. overnight. The resultant mixture was filtered, and the filtrate concentrated under vacuum. The residue was treated with a mixture of chloroform (50 mL) and ethylenediamine tetraacetic acid, disodium salt (5 g) in water (30 mL) and stirred vigorously at room temp in the presence of air for 5 hours. The slurry was filtered through a pad of Celite. The organic extract was separated, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with methanol (25 mL) and the resultant suspension stirred at room temperature overnight. The solid was filtered, washed with cold (0° C.) methanol, and dried under vacuum to provide methyl 5-(1,1-dioxido-5-methyl-4-oxo-1,2,5-thiadiazepan-2-yl)-8-hydroxy[1,6]-naphthyridine-7-carboxylate as light brown solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][C:10]=2[C:18]([F:21])([F:20])[F:19])[CH2:4][CH2:3]1.[I:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[CH3:30])[NH2:26].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1>C(N(CC)CC)C.C(Cl)Cl>[I:22][C:23]1[CH:24]=[C:25]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][C:9]([CH2:8][N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[C:10]([C:18]([F:21])([F:20])[F:19])[CH:11]=2)[CH:27]=[CH:28][C:29]=1[CH3:30]
Reactant: Cc1ccc(N)cc1I
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)c(C(F)(F)F)c2)cc1I
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a flask containing 1.0 g (2.67 mmol) of 4-[(4-methyl-1-piperazinyl)methyl]-3-(trifluoromethyl)-benzoic acid (CAS#859027-02-4; prepared according to Asaki, T. et al. Bioorg. Med. Chem. Lett. (2006), 16, 1421-1425), 0.62 g (2.67 mmol) of 3-Iodo-4-methylaniline, 0.77 g (4.0 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDAC), and 0.43 g (3.2 mmol) of N-hydroxybenzotriazole monohydrate (HOBt.H2O) was added 5 mL of DCM and 5 mL of triethylamine. The solution was stirred at ambient temperature under an atmosphere of N2 for 3 days, concentrated, and the crude product purified by silica gel chromatography (eluted with 100% EtOAc then 10% MeOH/EtOAc), to provide 0.69 g of product as a white solid.
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4](OC)=[O:5].[BH4-].[Li+].O.C(OCC)(=O)C>C1COCC1>[I:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[CH:9]=[CH:8][C:3]=1[CH2:4][OH:5]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1I
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(CO)c(I)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of methyl 2-iodo-4-nitrobenzoate (25.6 g, 83.4 mmol) in THF (400 mL) was added lithium tetrahydroborate (2.2 g, 92 mmol). The reaction solution was stirred at rt for 2 h and cooled down to 0° C., and water was added dropwise. After stirring for 10 min, ethyl acetate was added. The organic solution was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified with flash chromatography (30% ethyl acetate/hexs) to give the desired product as yellow solid (15.6 g, 67%). LCMS calculated for C7H71NO3(M+H)+: m/z=280.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10]Br)=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][N:13]([CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCCBr)cc1
Reactant: CNC
Product: CN(C)CCOc1ccc(Cl)cc1
Yield: 61 %

Procedure:
The title compound was prepared in 61% yield (26% SM recovered) by essentially following the procedure outlined in Example 34, Part A from 2-bromoethyl 4-chlorophenyl ether and dimethylamine.
Reaction SMILES: C1([C@H](CO)N)C=CC=CC=1.[F:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]2)=[CH:19][CH:18]=1>C(#N)C.O>[F:11][C:12]1[CH:13]=[C:14]([CH:32]=[CH:33][CH:34]=1)[CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[C:27](=[O:28])[CH2:26][C@H:25]([C:29]([OH:31])=[O:30])[CH2:24]2)=[CH:21][CH:22]=1
Reactant: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: N[C@@H](CO)c1ccccc1
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Yield: 44.1 %

Procedure:
The salt of the (S)-(II) compound with (R)-(−)-2-phenylglycinol was prepared in an analogous manner as described in Example 2a) from rac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (5 g, 15.2 mmol) in acetonitrile/water 95:5 (50 mL) using a solution of only 1.46 g (R)-(−)-2-phenylglycinol (10.6 mmol, 0.7 eq) in acetonitrile/water 95:5 (3.3 mL). From the salt (3.2 g, 45% based on racemic acid) obtained in 99.7:0.3 diastereomeric ratio the (S)-(II) compound was liberated and purified in a similar manner as described in Example 2b) to afford (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid (2.21 g, 44% based on racemic acid) in high purity (HPLC: 99.4% area) and with >99.9:0.1% er.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([O:21][CH3:22])=[CH:19][N:18]=[C:17]([Cl:23])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>ClCCl.Cl.O1CCOCC1>[ClH:23].[ClH:23].[Cl:23][C:17]1[N:16]=[C:15]([NH:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:20]([O:21][CH3:22])=[CH:19][N:18]=1
Reactant: COc1cnc(Cl)nc1NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cnc(Cl)nc1NC1CCNCC1

Procedure:
A solution of 4-(2-chloro-5-methoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.43 g, 4.17 mmol) in dichloromethane (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 243.3 [M+H]+.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=[O:5].[C:11]1([CH:21]=O)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[H-].[Na+]>C(O)C>[CH2:9]([O:8][C:1]([C:2](=[CH:21][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:3][C:4]([OH:6])=[O:5])=[O:7])[CH3:10]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CCC(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=Cc1cccc2ccccc12)CC(=O)O
Yield: 83 %

Procedure:
To a solution of 17.40 g of ethyl succinate and 15.62 g of 1-naphthaldehyde in 100 ml of absolute ethanol was added 6.00 g of sodium hydride (50% dispersion in mineral oil), and the mixture was heated under reflux for 3 hours. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral materials. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with diethyl ether. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 23.60 g of 3-ethoxycarbonyl-4-(1-naphthyl)-3-butenoic acid as a yellow oil. A mixture of 200 ml of a 1N-aqueous sodium hydroxide solution and 170 ml of ethanol was added to 23.50 g of the butenoic acid obtained. The mixture was heated at 50° C. for 1.5 hours. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral materials. The ethereal layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to obtain 15.30 g of 2-(1-naphthylmethylene)succinic acid as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH2:32]O)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.C1(P([N:57]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[NH2:57][CH2:32][C:21]1[C:20]([C:18]([C:10]2[N:9]=[N:8][N:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:39])([F:38])[F:40])[CH:34]=3)[C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:19])=[C:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])[O:23][N:22]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1)c1c(CO)noc1-c1ccccc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: NCc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccncc1
Reaction time: 8 h
Yield: 47.1 %

Procedure:
Combine [1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-4-yl-1H-[1,2,3]triazol-4-yl]-[5-(2-chloro-phenyl)-3-hydroxymethyl-isoxazol-4-yl]-methanone (0.30 g, 0.49 mmol), diphenyl phosphoryl azide (0.13 mL, 0.59 mmol), 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL, 0.59 mmole) in THF (2 mL) and stir at RT overnight. Filter off the solid and concentrate the filtrate. Dissolve the crude product in THF (2 mL), add triphenylphosphine (0.16 g, 0.59 mmole), and a few drops of water. Stir the mixture overnight. Purify the resulting amine by sequentially passing through a short silica gel column (gradient elution with EtOAc, 2% MeOH in EtOAc, 5% MeOH/2% NH4OH(aq) in EtOAc), a SCX column (elution with 1:1 MeOH/CH2Cl2 and then 3.5 M NH3 in MeOH) and again a short silica gel column (gradient elution with EtOAc, 5% MeOH/2% NH4OH (aq) in EtOAc) to provide a yellow oil (0.14 g, 47%). 1H NMR (400 MHz, CDCl3) δ 4.07 (s, 2H), 5.45 (s, 2H), 7.18–7.25 (m, 3H), 7.30–7.40 (m, 3H), 7.44 (t, J=7.42 Hz, 1H), 7.74 (d, J=7.62 Hz, 1H), 7.87 (s, 1H), 8.81 (m, 2H); MS (ESI) m/z 607.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[ClH:27]>C(O)(C)C>[ClH:1].[ClH:27].[ClH:1].[Cl:27][C:11]1[CH:10]=[CH:9][C:8]([O:19][CH3:20])=[CH:7][C:6]=1[NH:5][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[CH:9][C:10]=2[N:12]2[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]2)[N:5]=[CH:4][N:3]=1
Reactant: CN1CCN(c2cc(OCCN3CCCC3)cc3ncnc(Cl)c23)CC1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OCCN4CCCC4)cc(N4CCN(C)CC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 5, 4-chloro-5-(4-methylpiperazin-1-yl)-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.11 g) was reacted with 2-chloro-5-methoxyamine hydrochloride (0.064 g) in the presence of a 6M solution of hydrogen chloride in isopropanol (0.05 ml) to give the title compound, as a trihydrochloride salt (0.092 g), a portion of which was converted into the free base using an analogous procedure to that described in Example 3. The free base gave the following characterising data: NMR Spectrum: (CDCl3) 1.8-1.9 (m, 4H), 2.32 (s, 3H), 2.48 (m, 2H), 2.65 (br s, 4H), 2.82 (d, 2H), 2.98 (m, 4H), 3.2 (d, 2H), 3.82 (s, 3H), 4.25 (m, 2H), 6.65 (m, 1H), 6.95 (m, 1H), 7.3 (d, 1H), 8.02 (d, 1H), 8.52 (s, 1H); Mass Spectrum: M+H+ 497 and 499.