Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]([Cl:14])[C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[Cl:23][CH:16]([CH2:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6]([Cl:14])[CH:5]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CCc1cc(Cl)c(C2CCCCC2)c(Cl)c1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(Cl)c(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a mixture of 23.8 g. (0.077 moles) of ethyl β-(3,5-dichloro-4-cyclohexylphenyl)propionate in 35 ml. of benzene is added 19.2 g. (0.092 moles) of phosphorous pentachloride in small portions over 11/2 hours. The mixture is stirred for 20 hours and then poured into an ice-cold mixture. The reaction mixture is extracted with petroleum ether which is then washed with cold 10% sodium bicarbonate solution followed by water. On drying, the mixture is evaporated in vacuo to ethyl α-chloro-β-(3,5-dichloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:58][C:59]1[S:60][CH:61]=[CH:62][N:63]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]([OH:23])([CH3:22])[CH2:20][CH3:21])=[CH:13][CH:12]=2)[C:8]([NH:58][C:59]2[S:60][CH:61]=[CH:62][N:63]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(C)(O)C#Cc1ccc(C(CC2CCCC2)C(=O)Nc2nccs2)cc1
Yield: 57 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-propionic acid (157 mg, 0.50 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (332 mg, 0.75 mmol), triethylamine (0.21 mL, 1.50 mmol) and 2-aminothiazole (86 mg, 0.75 mmol) in methylene chloride (5 mL) was stirred at 25° C. for 2 h. At this time, the reaction was diluted with methylene chloride (10 mL). This solution was washed with water (1×10 mL), a 1N aqueous sodium hydroxide solution (1×10 mL), a 1N aqueous hydrochloric acid solution (1×10 mL), and a half-saturated aqueous sodium chloride solution (1×10 mL). The aqueous layers were back extracted with methylene chloride (1×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-[4-(3-hydroxy-3-methyl-pent-1-ynyl)-phenyl]-N-thiazol-2-yl-propionamide (113 mg, 57.1%) as a white solid: mp 172-174° C.; EI-HRMS m/e calcd for C23H28N2O2S (M+) 396.1871, found 396.1866.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:26])([F:27])[F:25])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:31][CH:32]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Reactant: Fc1ccc(Br)cc1
Product: O=C(c1ccc(F)cc1)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1

Procedure:
This compound is prepared by method C using compound 12f and 1-bromo-4-fluorobenzene
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[N+:16]([O-])=O)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[C:12]([C:14]#[N:15])[CH:11]=[CH:10][C:9]=1[NH2:16])[CH3:2]
Reactant: CCOC(=O)CCNc1cc(C#N)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)CCNc1cc(C#N)ccc1N
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of 3-(5-Cyano-2-nitro-phenylamino)-propionic acid ethyl ester (1.53 g, 5.8 mmol) in MeOH (10 mL) was added a slurry of Pd/C (0.3 g) in MeOH. The reaction mixture was saturated with H2 and stirred for 2 h. When the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated to afford 0.65 g (48%) of the desired product as a brown solid. The resulting residue was used for the next reaction without further purification. LCMS (ESMS): m/z 233.66 (M+H+).
Reaction SMILES: [C:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:9](O)(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.COC1C=CC(O)=CC=1>C1(C)C=CC=CC=1>[C:9]([O:8][CH2:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)(=[O:12])[CH:10]=[CH2:11]
Reactant: OCC1=CCCCC1
Reactant: C=CC(=O)O
Agent: COc1ccc(O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=CC(=O)OCC1=CCCCC1
Yield: 73 %

Procedure:
CHA was prepared by the above procedure from cyclohexenyl methanol (100 gram, 0.89 mole), acrylic acid (57.6 grams, 0.8 mole), p-toluenesulfonic acid (4 grams, 21 mmole), MEHQ (2 grams, 5.7 mmole), and toluene (500 ml) in a 1 liter reaction flask. The aqueous washes were performed with 400 ml portions each. The CHA was obtained in an amount of 96.5 grams (73% yield). The CHA was determined to have a boiling point in the range of 68-69° C. at a reduced pressure of 0.35 Torr.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)=[O:14])[C:5]([O:7]C)=[O:6].O.[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[NH:12][C:13]([N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:26])([CH3:27])[CH2:21][CH2:20][C:19]([CH3:28])([CH3:29])[C:18]=2[CH:17]=1)=[O:14])[C:5]([OH:7])=[O:6]
Reactant: CCCCCN(C(=O)Nc1ccc(C(=O)OC)cc1F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCN(C(=O)Nc1ccc(C(=O)O)cc1F)c1ccc2c(c1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
A solution of methyl 3-fluoro-4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoate (17 mg) in 10 mL THF/3 mL methanol/3 mL water was treated with lithium hydroxide hydrate (20 mg). The mixture was stirred at room temperature for two hours. The mixture was diluted with 5 mL water and the pH was adjusted to 2 with conc. HCl. The mixture was extracted with three 10 mL portions of ether. The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo, giving a brown solid. The product was purified by trituration in hexanes, yielding 12 mg 3-fluoro4-[3-pentyl-3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ureido]-benzoic acid as a yellow solid. M.P. 151-157° C.
Reaction SMILES: [CH2:1]1[CH:3]([CH2:4][N:5]2[C@@H:15]3[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]5[O:24][CH:9]6[C:10]([CH2:12][CH2:13][C@:14]3([OH:25])[C@:8]6([C:18]=45)[CH2:7][CH2:6]2)=[O:11])[CH2:2]1>C(O)C1C=CC=CC=1>[CH2:2]1[CH:3]([CH2:4][N:5]2[CH:15]3[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[C:19]5[O:24][CH:9]6[C:10]([CH2:12][CH2:13][C:14]3([OH:25])[C:8]6([C:18]=45)[CH2:7][CH2:6]2)=[O:11])[CH2:1]1.[CH2:19]([OH:24])[C:18]1[CH:8]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)C1O5
Solvent: OCc1ccccc1
Product: O=C1CCC2(O)C3Cc4ccc(O)c5c4C2(CCN3CC2CC2)C1O5
Yield: 30 %

Procedure:
A 1 kg batch of naltrexone microspheres were prepared as follows. Polymer solution was formed by dissolving 75:25 DL PLGA (poly(lactide)-co-glycolide) in ethyl acetate (EtAc) to form a solution of 16.7% polymer and 83.3% EtAc. A naltrexone solution was formed by dissolving naltrexone base in benzyl alcohol (BA) to form a solution of 30% naltrexone base anhydrous and 70% BA. The polymer solution and the naltrexone solution were mixed together to form a drug/polymer solution that was the “organic” or “oil” phase of the emulsion.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([O:24]C)=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[C:7]([O:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:6]=1.Cl>O.C1COCC1>[F:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:13]3[C:20]([CH3:21])=[C:19]([C:22]([OH:24])=[O:23])[S:18][C:14]=3[N:15]=[CH:16][N:17]=2)=[C:7]([O:26][CH:27]2[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]2)[CH:6]=1
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(F)cc3OC3CCNCC3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCNCC3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Lithium hydroxide monohydrate (0.05 g, 1.2 mmol) in water (1.0 mL) was added into a stirred suspension of methyl 4-(4-fluoro-2-(piperidin-4-yloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.10 g, 0.2 mmol) in THF (3 mL) and the reaction stirred at ambient temperature overnight. The solution was cooled in an ice-bath and 2N hydrochloric acid added until the solution reached pH 5. The precipitate was collected, washed with water and dried over P2O5 to yield colourless solid (0.056 g, 58%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH2:22])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:19][CH:18]([O:20][CH3:21])[CH2:17]1.N1C=CC=CC=1.[C:30](Cl)(=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][N:5]([CH3:23])[C:6]=1[C:7]1[CH:8]=[C:9]([NH:22][C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH:18]([O:20][CH3:21])[CH2:19]1
Reactant: COC1CN(CCOc2ccc(N)cc2-c2c(Br)cnn2C)C1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1CN(CCOc2ccc(NC(=O)CC(C)C)cc2-c2c(Br)cnn2C)C1
Reaction time: 2 h
Yield: 73 %

Procedure:
To a solution of 3-(4-bromo-1-methyl-1H-pyrazol-5-yl)-4-(2-(3-methoxyazetidin-1-yl)ethoxy)benzenamine (40.3 mg, 0.107 mmol) and pyridine (35 μL) in CH2Cl2 (2 mL) was added isovaleryl chloride (15 μL, 0.122) and stirred for two hours. The resulting material was purified by HPLC. The product was dried in vacuo to afford the title compound as a white solid (36.0 mg, 73%). LCMS m/z (%)=465 (M+H 79Br, 75), 467 (M+H 81Br, 90). 1H NMR (400 MHz, DMSO-d6) δ: 10.00 (bs, 1H), 7.69 (dd, J=8.99, 2.65 Hz, 1H), 7.60 (s, 1H), 7.48 (d, J=2.63 Hz, 1H), 7.09 (d, J=9.06 Hz, 1H), 4.03-3.86 (m, 2H), 3.82 (quint, J=5.76 Hz, 1H), 3.65 (s, 3H), 3.35-3.28 (m, 1H), 3.24-3.17 (m, 1H), 3.08 (s, 3H), 2.73-2.55 (m, 41H), 2.16 (d, J=6.96 Hz, 2H), 2.12-2.00 (m, 1H), 0.92 (d, J=6.55 Hz, 6H).
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][O:17][C:18]1[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][N:19]=1.C(=O)=O.[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][C:34]([CH:35]=[O:36])=[C:33]([CH:41]([CH3:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:32]=1>C1COCC1>[CH3:29][O:30][C:31]1[C:38]([O:39][CH3:40])=[CH:37][C:34]([CH:35]([C:21]2[C:22]([O:24][CH3:25])=[N:23][C:18]([O:17][CH3:16])=[N:19][CH:20]=2)[OH:36])=[C:33]([CH:41]([CH3:49])[CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:32]=1
Reactant: COc1cc(C=O)c(C(C)Cc2ccccc2)cc1OC
Reactant: COc1ccnc(OC)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ncc(C(O)c2cc(OC)c(OC)cc2C(C)Cc2ccccc2)c(OC)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
Freshly distilled 2,2,6,6-tetramethyl piperidine (0.85 mL, 5.0 mmol) was dissolved in 20 mL THF and cooled to 0° C. n-Butyllithium (2.0 mL, 2.5 M in hexanes) was added drop-wise over 5 minutes and the mixture was allowed to stir for 30 minutes and then cooled to −78° C. 2,4-Dimethoxypyrimidine (0.353 g, 2.52 mmol) was added drop-wise over 5 min. After 45 min the solution was transferred via a dry ice cooled cannula to a solution of 4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-benzaldehyde (0.717 g, 2.52 mmol) in 20 mL THF at −78° C. After stirring for 1 hour the solution was warmed to room temperature and quenched by the slow addition of 50 mL 10% NH4Cl. After 100 mL of H2O was added the mixture was extracted with ethyl acetate, washed with H2O and washed with brine. The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give an orange oil. Purification via flash chromatography (3:2 hexane/ethyl acetate) afforded [4,5-dimethoxy-2-(1-methyl-2-phenyl-ethyl)-phenyl]-(2,4-dimethoxy-pyrimidin-5-yl)-methanol (0.551 g, 52%) as a clear oil.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:5][CH:4]1[C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[CH:7]=1.[FH:16].F.F.C(N(CC)CC)C>>[F:16][CH:4]([C:6]1[CH:15]=[CH:14][C:9]2[C:10](=[O:13])[O:11][CH2:12][C:8]=2[CH:7]=1)[CH:3]([OH:5])[CH2:2][OH:1]
Reactant: O=C1OCc2cc(C3OC3CO)ccc21
Reactant: F
Solvent: CCN(CC)CC
Product: O=C1OCc2cc(C(F)C(O)CO)ccc21
Temperature: 25 °C

Procedure:
A solution of 5-[3-(Hydroxymethyl)oxiran-2-yl]-2-benzofuran-1(3H)-one (1.2 g, 5.8 mmol) in TEA.3HF (triethylamine trihydrofluoride) (10 mL) was warmed to 110° C. for 8 hours, and then cooled to RT. The reaction mixture was extracted with EtOAc (200 mL), washed with NaHCO3 (30 mL) and brine (30 mL). The organic layer was dried over Na2SO4, and then concentrated in vacuo. The residue was separated and purified with prep-TLC to give product the title product.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:24])[CH:10]([CH2:14][CH:15]2[C:20](=[O:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)C(=O)C)=[CH:5][CH:4]=1>Cl>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:24])[CH2:10][CH2:14][CH:15]2[C:20](=[O:21])[CH:19]3[CH2:22][CH2:23][N:16]2[CH2:17][CH2:18]3)=[CH:7][CH:8]=1
Reactant: CC(=O)C(CC1C(=O)C2CCN1CC2)C(=O)c1ccc(Cl)cc1
Agent: Cl
Product: O=C(CCC1C(=O)C2CCN1CC2)c1ccc(Cl)cc1

Procedure:
Reflux 105.28 g (0.28 mole) 1-(4-chlorophenyl)-2-[(3-oxo-1-azabicyclo[2.2.2]oct-2-yl)methyl]-1,3-butanedione hydrochloride in 500 ml concentrated hydrochloric acid for 5 hours. Stir with mechanical stirrer. Chill the reaction mixture in an ice bath and collect the title compound via filtration.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.[C:14]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[C:14]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][Br:1])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:23])=[CH:25][CH:26]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: NS(=O)(=O)c1ccc(CCBr)cc1
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)c1ccc(C(=O)NS(=O)(=O)c2ccc(CCBr)cc2)cc1

Procedure:
A mixture of 26.41 g (0.10 mol) of 4-(2-bromoethyl)benzenesulfonamide, 19.67 g (0.10 mol) of 4-t-butylbenzoyl chloride and 160 ml of xylene was heated at reflux for 20 hrs. The hot solution was cooled and the solid which crystallized was collected, recrystallized from isopropanol collected, washed with ligroine and dried.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[C:12]([CH2:13][OH:14])=[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:10]([O:21][CH3:22])=[CH:9][CH:8]=2)=N1>Cl>[CH3:22][O:21][C:10]1[C:11]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:4](=[O:5])[O:14][CH2:13]2
Reactant: CCCCCOc1c(OC)ccc(C2=NC(C)(C)CO2)c1CO
Agent: Cl
Product: CCCCCOc1c(OC)ccc2c1COC2=O
Temperature: 25 °C
Yield: 97030.2 %

Procedure:
[6-(4,4-Dimethyl-4,5-dihydrooxazol-2-yl)-3-methoxy-2-pentyloxyphenyl]-methanol (4.69 g, 0.014 mmol, 1 eq) was dissolved in 3N hydrochloric acid (50 ml), and the solution was stirred under heating for 3 hours. After the completion of the reaction, the mixture was cooled to room temperature and extracted twice with diethyl ether (50 ml). The organic layers were combined, washed with saturated brine (100 ml) and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give 5-methoxy-4-pentyloxy-3H-isobenzofuran-1-one (3.4 g, 82.4%) as a colorless oil.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:22]([CH3:23])[C:21]4[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=4[N:19]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5])C.[ClH:28]>>[ClH:28].[CH3:23][N:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[C:18]1[C:14]1[CH:13]=[C:12]([N:9]2[CH2:10][CH2:11][CH:6]([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1CCN(c2cccc(-c3nc4ccccc4n3C)c2)CC1
Agent: Cl
Product: Cn1c(-c2cccc(N3CCC(C(=O)O)CC3)c2)nc2ccccc21
Temperature: 120 °C

Procedure:
Method 11—Step b A mixture of 1-[3-(1-Methyl-1H-benzoimidazol-2-yl)-phenyl]-piperidine-4-carboxylic acid ethyl ester (3.10 g, 8.54 mmol) in 6N HCl (25.0 mL) was heated in microwave at 120° C. for 20 minutes. Then solvent was removed to obtain the title compound in quantitative yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]([O:12]CC)=O)=[CH:4][CH:3]=1.Cl.[C:17]([NH2:20])(=[NH:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([OH:12])[N:20]=[C:17]([CH3:18])[N:19]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(F)cc1
Reactant: CC(=N)N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cc1nc(O)cc(-c2ccc(F)cc2)n1
Temperature: 65 °C
Reaction time: 16 h
Yield: 63 %

Procedure:
A mixture of 145 g of ethyl 3-(4-fluorophenyl)-3-oxopropionate, 97.8 g of acetamidine hydrochloride, 191 g of powdered potassium carbonate, and 1.16 L of ethanol was stirred at 60-70° C. for 16 hours. This reaction mixture was filtered to remove insolubles and the filtrate was concentrated. To the residue was added water and the resultant was neutralized with acetic acid. The crystals that separated out were collected by filtration, washed with water, and dried to provide 88.7 g of the title compound as white crystals. m.p. 290-292° C. (decomp.)
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=O.[OH:7][PH:8]([OH:10])=[O:9].P(Cl)(Cl)Cl>O>[NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1([P:8]([OH:10])(=[O:7])[OH:9])[P:8]([OH:10])(=[O:7])[OH:9]
Reactant: O=C1CCCN1
Reactant: O=[PH](O)O
Solvent: O
Solvent: ClP(Cl)Cl
Product: O=P(O)(O)C1(P(=O)(O)O)CCCN1
Reaction time: 8 h

Procedure:
85.0 gm of 2-pyrrolidone (1.0 mol) and 164 gm of H3PO3 (2.0 mols) were melted at 80°C. While stirring this melt, 176 ml of PCl3 (2.0 mols) were added thereto. The mixture was stirred for three additional hours and was left standing at 70°C overnight. Then, three liters of H2O were used for the hydrolysis. The solution was boiled with activated carbon; and after filtration, the reaction product was precipitated with acetone. The white substance was dissolved in water, and passed over a cation exchanger. The solution was concentrated; and the substance was separated upon the addition of ethanol. The yield of crystalline azacyclopentane-2,2-diphosphonic acid was 95 gm, or about 41% of the theory. The molecular weight of the compound was determined by titration to be 230 (calculated: 231.09).
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]#[C:29][Si](C)(C)C)[CH:22]=3)=[CH:15][C:14]=2[C:35]([F:38])([F:37])[F:36])[CH2:8][CH2:7]1)([CH3:4])=[O:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:34])[C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[C:23]([C:28]#[CH:29])[CH:22]=3)=[CH:15][C:14]=2[C:35]([F:38])([F:36])[F:37])[CH2:8][CH2:7]1)([CH3:4])=[O:3]
Reactant: Cc1ccc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)cc1C#C[Si](C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(C(=O)Nc2ccc(CN3CCN(CP(C)(C)=O)CC3)c(C(F)(F)F)c2)ccc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-[4-({4-[(dimethylphosphoryl)methyl]piperazin-1-yl}methyl)-3-(trifluoromethyl)phenyl]-4-methyl-3-[(trimethylsilyl)ethynyl]benzamide (4.1 mmol) in THF (15 mL) is added 5 mL of TBAF in THF (1.0M). After stirring at rt for 1 h, the mixture is partitioned between H2O and EtOAc. The combined organic layers are dried over Na2SO4, filtered, and then concentrated on a rotavap and the residue is purified on a silica gel column (eluent: 10% MeON in CH2Cl2, MeOH is pre-saturated with ammonia gas).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:7]#[C:8][CH:9]=[O:10])[CH3:6])(=[O:3])[CH3:2].CC(=CC)C.[O-:16]Cl=O.[Na+]>CC(O)(C)C.O>[C:1]([O:4][C@@H:5]([CH3:6])[C:7]#[C:8][C:9]([OH:16])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C)C#CC=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(=O)O[C@@H](C)C#CC(=O)O
Reaction time: 0.33 h
Yield: 100.6 %

Procedure:
To a solution of 9 (133 mg, 0.949 mmol) and 2-methyl-2-butene (1.20 mL, 14.2 mmol) in tBuOH (1.9 mL) was added the mixture of NaClO2 (257 mg, 2.84 mmol) and NaH2PO4 (393 mg, 2.84 mmol) in H2O (1.9 mL) at 23° C. The resulting mixture was stirred for 20 min at the same temperature and quenched by 1 N aqueous HCl (3 mL) at 0° C. The mixture was poured into a separatory funnel and diluted with EtOAc (3 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×4 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the residue via flash chromatography (silica gel 15 mL; 50→100% EtOAc in hexanes containing 1.0% acetic acid) afforded acid 10 (149 mg, quantitative yield) as a pale yellow oil.
Reaction SMILES: [OH:1][C:2]([CH3:28])([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH:6]1[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].O>C(O)(=O)C>[OH:1][C:2]([CH3:28])([CH2:23][CH2:24][O:25][CH2:26][CH3:27])[CH:3]=[CH:4][CH:5]1[CH:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:7](=[O:8])[CH2:12][CH2:13]1
Reactant: CCOCCC(C)(O)C=CC1CCC2(OCCO2)C1CCCCCCC(=O)O
Solvent: O
Solvent: CC(=O)O
Product: CCOCCC(C)(O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Reaction time: 6 h
Yield: 106.5 %

Procedure:
Crude 7-{7-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-1,4-dioxaspiro[4,4]non-6-yl}heptanoic acid (0.38 g.), water (8 ml.) and glacial acetic acid (16 ml.) were left to stand at room temperature for 6 hours. The solution was then evaporated in vacuo at a temperature lower than 50° C. Ethyl acetate (150 ml.) was added, and then the solution washed with water (until the pH of the washings was pH 5), dried over sodium sulphate, and evaporated to give 7-[5-(3-hydroxy-3-methyl-5-ethoxypent-1-enyl)-2-oxocyclopentyl]heptanoic acid (0.36 g.), νmax 980 cm-1, 1700 cm-1, 1730 cm-1.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[S:7][C:6]([CH2:8][C:9](Cl)=[O:10])=[CH:5][CH:4]=1.[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH2:25])[C:18]=1[C:27]([OH:29])=[O:28])(=[O:14])[CH3:13]>C(OCC)(=O)C>[C:12]([O:15][CH2:16][C:17]1[CH2:24][S:23][CH:22]2[N:19]([C:20](=[O:26])[CH:21]2[NH:25][C:9](=[O:10])[CH2:8][C:6]2[S:7][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=2)[C:18]=1[C:27]([OH:29])=[O:28])(=[O:14])[CH3:13]
Reactant: O=C(Cl)Cc1ccc(CCl)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)Cc3ccc(CCl)s3)C2SC1

Procedure:
A mixture of 1.2 equivalents of 5-chloromethyl-2-thienylacetyl chloride and 1 equivalent of 3-[(acetyloxy)-methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is refluxed for 50 minutes in ethyl acetate after which the solvent is removed and the remaining product is purified by column chromatography on silica gel to give 3-[(acetyloxy)methyl]-7-[[2-[5-(chloromethyl)-2-thienyl]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.