Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[Cl:5][C:6]1[CH:15]=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16]C)[CH:12]=2)[N:7]=1.C1(C)C=CC=CC=1.CCCCCC.C(OCC)(=O)C>O>[Cl:5][C:6]1[CH:15]=[N:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:16])[CH:12]=2)[N:7]=1
Reactant: COc1ccc2nc(Cl)cnc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Oc1ccc2nc(Cl)cnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
Aluminium trichloride (85 mg, 638 μmol) was added as a single portion to a stirred mixture of 2-chloro-6-methoxyquinoxaline (73 mg, 375 μmol) and anhydrous toluene (3 ml) under an Argon atmosphere. The reaction mixture was heated at reflux for approx. 1 hr, then allowed to stir overnight at room temperature. Tlc (silica; 2:1 hexane/ethyl acetate) showed no remaining starting material and new polar material. Water (1 ml) and ice were added and the mixture stirred. The contents were partitioned between water (5 ml) and ethyl acetate (100 ml). The aqueous phase was extracted into ethyl acetate (50 ml), then the organic extracts combined and washed with water (10 ml), followed by brine (10 ml) and dried (Na2SO4). Concentration gave a brown solid, which was pre-adsorbed onto silica, then chromatographed on silica (9 g); eluent: 20% ethyl acetate in hexane then 25% ethyl acetate in hexane to give 2-chloro-6-hydroxyquinoxaline 54 mg (79%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14]OS(C)(=O)=O)[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8].[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@@H:12]([CH2:14][N:25]3[C:21](=[O:31])[C:22]4[C:23](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:24]3=[O:26])[O:11][C:10]2=[O:20])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
A solution of mesylate 94 (26.38 g, 63.57 mmol) in anhydrous N,N-dimethylformamide (DMF, 120 mL) was treated with solid potassium phthalimide (12.95 g, 70.0 mmol, 1.1 equiv) at 25° C., and the resulting reaction mixture was warmed to 70° C. for 2 h. When TLC and HPLC showed the reaction was complete, the reaction mixture was cooled to room temperature before being quenched with H2O (400 mL). The resulting mixture was stirred at room temperature for 10 min before being cooled to 0–5° C. for 1 h. The white precipitate was collected by filtration, washed with water (3×100 mL), and dried in vacuo to afford the desired (5R)-2-[3-(3-fluoro-4-iodo-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-isoindole-1,3-dione (phthalimide 95, 27.85 g, 94%) as an off-white powder. This product was directly used in subsequent reactions without further purification. C18H12FIN2O4, LCMS (EI) m/e 467 (M++H).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].Cl.SC1C=CC([N+]([O-])=O)=C(C=1)C(O)=O>>[CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][CH:13]5[C:14]([CH:16]=[CH:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: Cl
Agent: O=C(O)c1cc(S)ccc1[N+](=O)[O-]
Product: COc1ccc2c3c1OC1C(=O)C=C[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Reaction time: 1.5 h

Procedure:
A sample of the oxycodone hydrochloride (579 mg, 1.65 mmol) was placed in an 8 mL reaction vial, to which was added 3.5 ml of the previously prepared solution of 5-mercapto-2-nitro-benzoic acid. The pH of the mixture was raised to 4.5 by addition of 100 mg/mL aqueous NaH2PO4 solution (0.47 mL), and a 1.0 ml aliquot was removed, diluted with pH 4.5, 0.01 M NaOAc/HOAc buffer solution (10 uL), and stirred. The remainder (2.5 mL) was reserved for separate spike experiments where known amounts of 14-hydroxycodeinone were added to the mixture. After 90 minutes, the pH was lowered to 2 with concentrated HCl (10 uL) and the suspension extracted with ethyl acetate (3×1 mL) by adding the solvent to the vial, capping it, and shaking vigorously. The organic layer was then completely removed from the vial by Pasteur pipet. The aqueous layer was analyzed by HPLC, wherein an analyte in the effluent stream was quantified from its absorbance at 325 nm. The 14-hydroxycodeinone content, and thus the sum of the 8-hydroxyoxycodone content and the 14-hydroxycodeinone content of the product of EXAMPLE 24, was 2.3 ppm as determined from a plot of the area under the 5-(oxycodone-8-sulfanyl)-2-nitro-benzoic acid peak per milligram of oxycodone analyzed versus the amount of 14-hydroxycodeinone added (ppm, i.e. microrams 14-hydroxycodeinone added per gram oxycodone) as shown in FIG. 11.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([O:16][CH3:17])=[C:8]([CH3:15])[C:9]([CH3:14])=[C:10]([O:12][CH3:13])[CH:11]=1)(=O)C>CO.[OH-].[Na+]>[CH3:13][O:12][C:10]1[CH:11]=[C:6]([CH2:5][OH:4])[C:7]([O:16][CH3:17])=[C:8]([CH3:15])[C:9]=1[CH3:14]
Reactant: COc1cc(COC(C)=O)c(OC)c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(CO)c(OC)c(C)c1C
Temperature: 0 °C
Yield: 4.4 %

Procedure:
A solution of intermediate D (5.1 g, 0.21 mole) in 100 ml of methanol and 25 ml of 10% sodium hydroxide was refluxed for one hour, then poured into ice water. The resulting solid was collected by filtration and dried to give 1.8 g of 1,4-dimethoxy-2,3-dimethyl-5-hydroxymethylbenzene (intermediate E).
Reaction SMILES: [OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[NH:4][CH2:3]1.[H-].[Na+].[N:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1>CN(C=O)C>[OH:1][CH:2]1[C:7]2[CH:8]=[CH:9][S:10][C:6]=2[S:5](=[O:12])(=[O:11])[N:4]([CH2:21][C:18]2[CH:19]=[CH:20][N:15]=[CH:16][CH:17]=2)[CH2:3]1
Reactant: O=S1(=O)NCC(O)c2ccsc21
Reactant: ClCc1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2sccc2C(O)CN1Cc1ccncc1
Temperature: -10 °C
Reaction time: 0.67 h
Yield: 84.8 %

Procedure:
The product from Step C of Example 2 (4.0 g, 19.5 mmol) was dissolved in anhydrous DMF (20 mL) and cooled to -10° C. and sodium hydride (21.5 mmol) was added. After stirring for 40 min at room temperature, a solution of 4-picolyl chloride (3.7 g, 29.2 mmol) in DMF (15 mL) was added to the chilled (0° C.) reaction mixture. The mixture was allowed to warm to room temperature and stir for 18 h. The solution was concentrated and the residue was suspended in saturated sodium bicarbonate (50 mL) and the desired subject was collected by filtration. Recrystallization from ethanol gave a beige solid (4.9 g, 85%): mp 183°-185° C.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>Cl>[CH3:2][N:3]([CH3:24])[C:4]1([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccc3ccccc3c2)CCC2(CC1)OCCO2
Agent: Cl
Product: CN(C)C1(c2ccc3ccccc3c2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 32 h
Yield: 95.7 %

Procedure:
Dimethyl-(8-naphthalen-2-yl-1,4-dioxa-spiro[4.5]dec-8-yl)-amine hydrochloride (6.09 g) was dissolved in 7.5N hydrochloric acid, stirred for 32 hours at RT and then extracted with diethyl ether (3×30 ml). The aqueous phase was rendered alkaline with 25% ammonia solution, while cooling with ice, and extracted with 1,2-dichloroethane (3×30 ml). The combined extracts were dried with Na2SO4 and concentrated. 4.48 g of 4-dimethylamino-4-naphthalen-2-yl-cyclohexanone were obtained as a white solid (m.p. 81-83° C.).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH2:14])[CH:8]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)[CH:17]=1>>[CH3:2][O:3][C:4](=[O:15])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][NH:14][CH2:26][C:25]2[CH:24]=[CH:23][C:22]([C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH:8]=1
Reactant: COC(=O)CCc1cccc(CN)c1
Reactant: O=Cc1ccc(-c2cccnc2)cc1
Agent: Cl
Product: COC(=O)CCc1cccc(CNCc2ccc(-c3cccnc3)cc2)c1

Procedure:
The title compound of Step A was prepared from 3-(3-aminomethyl-phenyl)-propionic acid methyl ester hydrochloride salt, of Preparation 44, and 4-pyridin-3-yl-benzaldehyde, of Preparation 23, using the method described in Example 1, Step A. 1H NMR (400 MHz, CDCl3) δ 8.81 (d, 1H), 8.55 (dd, 1H), 7.84 (m, 1H), 7.53 (d, 2H), 7.44 (d, 2H), 7.33 (m, 1H), 7.26-7.18 (m, 3H), 7.07 (d, 1H), 3.84 (s, 2H), 3.79 (s, 2H), 3.64 (s, 3H), 2.92 (t, 2H), 2.61 (t, 2H); MS 361 (M+1).
Reaction SMILES: BrBr.[OH-:3].[Na+].[Br:5][C:6]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:7]=1[C:8](C1C=CC=CC=1)=[O:9]>>[Br:5][C:6]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:7]=1[C:8]([OH:9])=[O:3]
Reactant: [OH-]
Reactant: COc1ccc(C(=O)c2ccccc2)c(Br)c1
Agent: BrBr
Agent: [Na+]
Product: COc1ccc(C(=O)O)c(Br)c1

Procedure:
Bromine is added into aqueous sodium hydroxide, and then 2-bromo-4-methoxy benzophenone is added to give 2-bromo-4-methoxy benzoic acid (IV).
Reaction SMILES: C([O:4][C:5]1[C:15]([O:16][CH3:17])=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][C:6]=1[O:18][CH3:19])(=O)C.COC1C=C(C=C(OC)C=1O)C=CC(O)=O.P(Cl)(OCC)(OCC)=O.[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][NH:49][C@H:50]1[CH2:55][CH2:54][C@H:53]([CH3:56])[CH2:52][CH2:51]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:45][N:46]([CH3:57])[CH2:47][CH2:48][N:49]([C@H:50]1[CH2:51][CH2:52][C@H:53]([CH3:56])[CH2:54][CH2:55]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:7]=[C:6]([O:18][CH3:19])[C:5]([OH:4])=[C:15]([O:16][CH3:17])[CH:14]=1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Reactant: COc1cc(C=CC(=O)O)cc(OC)c1OC(C)=O
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: COc1cc(C=CC(=O)O)cc(OC)c1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc(OC)c1O

Procedure:
Using 2.9 g of 4-acetoxy-3,5-dimethyoxycinnamic acid derived from 3,5-dimethoxy-4-hydroxycinnamic acid by the acetylation thereof, 2.8 ml of diethyl chlorophosphate, 2.7 ml of triethylamine, 100 ml of methylene chloride, 3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.5 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 75 was carried out. As a result, 1.95 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-3,5-dimethoxy-4-hydroxycinnamamide (a compound of the present invention) was obtained as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: [OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH2:4][OH:5].[OH-].[K+].[CH2:40]1OCCOCCOCCOCCOCCOC1.IC>C1COCC1>[OH:1][C@H:2]([CH3:37])[C@H:3]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][C:23]([F:27])=[CH:24][CH:25]=4)[N:20]([CH3:28])[N:19]=3)[N:16]=2)[N:11]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:10]=1)=[O:8])[CH2:4][O:5][CH3:40]
Reactant: C[C@@H](O)[C@@H](CO)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Reactant: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CI
Product: COC[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@@H](C)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
In a 10 mL round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-hydroxymethyl-propyl)-amide (81 mg, 0.152 mmol) was dissolved in THF (1.5 ml) to give a colorless solution. The reaction was cooled in an ice bath and crushed KOH (86 mg, 1.52 mmol), 18-crown-6 (40 mg, 0.152 mmol), and iodomethane (10 μl, 0.152 mmol) were added successively. The reaction mixture was stirred at 0° C. for 1 h after which the ice bath was removed. The reaction mixture was stirred at room temperature for 2 h then diluted with dichloromethane (10 mL) and washed with aqueous ammonium chloride (10 mL), water (10 mL), and saturated sodium bicarbonate (10 mL). The organic layer was dried over Na2SO4 and concentrated. The crude material was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0%-60% EtOAc) to afford 30 mg (36%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((1R,2R)-2-hydroxy-1-methoxymethyl-propyl)-amide as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ: 9.22 (s, 1H), 8.78 (dd, J=8.9, 5.5 Hz, 1H), 8.66 (s, 1H), 8.14 (d, J=9.4 Hz, 1H), 7.67 (dd, J=9.8, 2.3 Hz, 1H), 7.17 (td, J=9.2, 2.1 Hz, 1H), 5.75 (s, 2H), 5.21 (d, J=4.2 Hz, 1H), 4.22-4.34 (m, 1H), 4.17 (s, 3H), 3.97-4.12 (m, 1H), 3.61 (app t, J=8.2 Hz, 3H), 3.52 (dd, J=9.8, 6.4 Hz, 1H), 3.28 (s, 3H), 1.14 (d, J=6.4 Hz, 3H), 0.87 (t, J=7.9 Hz, 2H), −0.07 (s, 9H).
Reaction SMILES: Cl.[N:2]1([CH2:11][C:12]([OH:14])=O)[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.[NH2:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[O:18]>>[N:2]1([CH2:11][C:12]([NH:15][C@@H:16]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:17]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[CH:24][CH:25]=2)=[O:18])=[O:14])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)Cn1nnc2ccccc21
Agent: Cl
Product: O=C(Cn1nnc2ccccc21)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 59 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-benzo[d][1,2,3]triazol-1-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 151, (S)-2-(2-(1H-benzo[d][1,2,3]triazol-1-yl)acetamido)-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (41 mg, 59%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.25 (br s, 1H), 9.04-9.02 (d, 1H), 8.05-8.03 (d, 1H), 7.78-7.76 (d, 1H), 7.64-7.60 (d, 2H), 7.53-7.49 (t, 1H), 7.41-7.38 (t, 1H), 7.33-7.28 (m, 5H), 7.23-7.19 (t, 2H), 7.05-6.98 (m, 4H), 5.59 (s, 1H), 4.77-4.72 (m, 1H), 4.56 (s, 1H), 3.73-3.72 (d, 2H). MS (EI) for C30H26FN5O4. found 540.0 (MH+).
Reaction SMILES: [NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([OH:23])=[O:22])[C:15]2=[O:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+:27]>C(O)C>[NH:1]([C:8]1[S:9][CH:10]=[C:11]([CH:13]=[C:14]2[S:18][C:17](=[S:19])[N:16]([CH2:20][C:21]([O-:23])=[O:22])[C:15]2=[O:24])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+:27]
Reactant: O=C(O)CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C([O-])CN1C(=O)C(=Cc2csc(Nc3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 35, the desired compound was prepared from 1 g of 5-(2-anilinothiazol-4-ylmethylene)rhodanine-3-acetic acid, 280 mg of sodium methoxide and 20 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11](Cl)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[C:33]3([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)[C:32](=[O:39])[NH:31][CH2:30]2)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][CH:11]([N:36]3[CH2:35][CH2:34][C:33]4([N:29]([C:26]5[CH:25]=[CH:24][C:23]([Br:22])=[CH:28][CH:27]=5)[CH2:30][NH:31][C:32]4=[O:39])[CH2:38][CH2:37]3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C2(c3ccc(F)cc3)C=CC(Cl)CC2)cc1
Reactant: O=C1NCN(c2ccc(Br)cc2)C12CCNCC2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1NCN(c2ccc(Br)cc2)C12CCN(C1C=CC(c3ccc(F)cc3)(c3ccc(F)cc3)CC1)CC2
Reaction time: 3.5 h

Procedure:
A mixture of 3.7 g of 4,4-bis(p-fluorophenyl)-1-chloro-2-cyclohexene, 3.1 g of 1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one (m.p. 204°-207° C), 1.7 g of potassium carbonate, 2 g of potassium iodide and 25 ml of dimethylformamide is stirred at 65°-75° C for 3.5 hours. The reaction mixture is then poured into water. The precipitated powder is collected by filtration and dissolved in methanol. The solution is concentrated to some degree, and acetone is added thereto, and the whole mixture is cooled. The precipitated crystals are collected by filtration and purified in the same manner to give 8-[4,4-bis(p-fluorophenyl)-2-cyclohexenyl]-1-(p-bromophenyl)-1,3,8-triazaspiro[4.5]decan-4-one as white crystals, melting at 219°-221° C.
Reaction SMILES: Cl.[NH:2]([CH2:4][C:5]([O:7]CC)=O)[NH2:3].[N:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])=[C:11]=[S:12].C(N(C(C)C)CC)(C)C>ClCCl>[NH2:3][N:2]1[CH2:4][C:5](=[O:7])[N:10]([C:13]2[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=2)[C:11]1=[S:12]
Reactant: O=C(O)c1cccc(N=C=S)c1
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NN1CC(=O)N(c2cccc(C(=O)O)c2)C1=S
Reaction time: 96 h
Yield: 19.9 %

Procedure:
Ethyl hydrazinoacetate hydrochloride (155 mg, 1.00 mmol) was added to a stirred solution of 3-isothiocyanatobenzoic acid (179 mg, 1.00 mmol) and di-isopropylethylamine (523 uL, 3.00 mmol) in dichloromethane (4 mL). The mixture was stirred for 96 h, evaporated under reduced pressure and partitioned between aqueous acetic acid and ethyl acetate. The organic extracts were washed with water, saturated aqueous sodium chloride, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was chromatographed (silica gel, 5-15% methanol/ethyl acetate, then 20% methanol/ethyl acetate ±0.5% acetic acid) to give 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 51%) contaminated with 6% uncyclised by-product, suitable for the next step. A solution of 1-amino-3-(3-carboxyphenyl)-2-thioxoimidazolidin-4-one (50 mg, 0.199 mmol) and 1-(3,4-dimethylphenyl)-5-hydroxy-3-methyl-1H-pyrazole-4-carbaldehyde (55 mg, 0.239 mmol) in ethanol/methanol (2:1, 15 mL) was allowed to stand a room temperature for 96 h. The solid was filtered off, washed with ether and dried to give the title compound (42 mg, 46%) as a powder. LCMS, m/e 464 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCF)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OCCF)nc1Cl
Yield: 47.7 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2-fluoroethoxy)piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (123f) (0.25 g, 0.8 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (8 mL) and THF (8 mL), to obtain 0.17 g of the title compound as a light brown solid (72%).
Reaction SMILES: [H-].[Na+].[C:3](=O)([O:6]C)[O:4][CH3:5].[C:9]([O:13][C:14]([N:16]1[CH:21]2[CH2:22][CH2:23][CH:17]1[CH2:18][C:19](=[O:24])[CH2:20]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].[NH4+].[Cl-]>C1CCCCC1.CO>[CH3:5][O:4][C:3]([C:20]1[C@@H:21]2[N:16]([C:14]([O:13][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:15])[C@H:17]([CH2:18][C:19]=1[OH:24])[CH2:23][CH2:22]2)=[O:6]
Reactant: COC(=O)OC
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCCCC1
Product: COC(=O)C1=C(O)C[C@@H]2CC[C@H]1N2C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 92.8 %

Procedure:
To a suspension of NaH (55-65% mineral oil, 9.82 g, about 225 mmol) in cyclohexane (87.5 mL) was added dimethyl carbonate (21.0 mL, 250 mmol). The mixture was heated to reflux, and a sol. of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (25.6 g, 113 mmol) in MeOH (0.25 mL) and cyclohexane (62.5 mL) was added over 35 min. The mixture was heated to reflux for 3 h, and was cooled to 0° C. Aq. sat. NH4Cl was added carefully until the phases separated. The org. layer was extracted with CH2Cl2 several times. The combined org. extracts were washed with brine, dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (EtOAc/heptane 3:7) yielded the title compound (29.7 g, 93%). LC-MS: tR=0.96 min.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[C:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:6]=1)[CH2:2][CH3:3].Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[C:55]([NH:62][CH2:63][CH2:64][CH2:65][NH2:66])([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[CH2:1]([NH:4][C:5]1[C:10]([C:11]([NH:66][CH2:65][CH2:64][CH2:63][NH:62][C:55](=[O:56])[O:57][C:58]([CH3:60])([CH3:59])[CH3:61])=[O:13])=[CH:9][N:8]=[C:7]([NH:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)O
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCNc1nc(NCCc2ccncc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Temperature: 40 °C
Reaction time: 2 h
Yield: 70.1 %

Procedure:
To 4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxylic acid (A3, 452 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (575 mg) and 1-hydroxybenzotriazole monohydrate (405 mg), N,N-dimethylformamide (10 mL) was added at room temperature, and the mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, then N,N-diisopropylethylamine (765 μL) and N-Boc-1,3-propanediamine (330 mg) were added to the mixture, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (eluent, 100 to 95% ethyl acetate in methanol) to obtain tert-butyl (3-(4-(propylamino)-2-((2-(pyridin-4-yl)ethyl)amino)pyrimidine-5-carboxamido)propyl)carbamate (B3, 481 mg) as white solid.