Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:40]>C(Cl)Cl>[Si:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:40])=[CH:11][C:10]=1[CH2:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Yield: 89.9 %

Procedure:
To a solution of 1.00 g (3.57) of 4-tert-butyldimethylsilyloxy-3-propylbenzyl alcohol and 1.12 g (4.00 mmol) of triphenylphosphine in 10 mL methylene chloride was added 1.42 g (4.00 mmol) of carbon tetrabromide in portions as the reaction mixture was magnetically stirred at 0°-5° C. After the addition was complete, the ice-water bath was removed and the reaction was stirred for an additional 30 minutes and allowed to warm to room temperature. The methylene chloride was removed in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with 5% EtOAc-hexane. The purified fractions were combined, evaporated and dried in vacuo to afford 1.10 g (90%) of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH2:10][C:11]2=[CH:14][C:15]#[N:16])=[CH:6][CH:5]=1)([O-])=O.[C:17]([O-:20])(=O)[CH3:18].[Na+].[C:22](OC(=O)C)(=[O:24])[CH3:23]>[Ni]>[C:22]([NH:16][CH2:15][CH2:14][CH:11]1[C:12]2[CH:13]=[C:4]([NH:1][C:17](=[O:20])[CH3:18])[CH:5]=[CH:6][C:7]=2[CH2:8][CH2:9][CH2:10]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)[O-]
Reactant: N#CC=C1CCCc2ccc([N+](=O)[O-])cc21
Agent: [Ni]
Agent: [Na+]
Product: CC(=O)NCCC1CCCc2ccc(NC(C)=O)cc21
Reaction time: 6 h

Procedure:
9 mmol of the compound obtained in Step B are dissolved in acetic anhydride (100 ml) and then a small spatula of sodium acetate is added. The mixture is introduced into an autoclave, Raney nickel is added and autoclaving under a pressure of 40 bars is carried out for 6 hours, with stirring at 50–60° C. The mixture is filtered and is rinsed with alcohol at 95° C.; the solvent is then evaporated off. Hydrolysis is carried out using 100 ml of distilled water and extraction with 3 volumes of dichloromethane is carried out. The organic phase is washed with 2 volumes of water, dried over magnesium sulphate, filtered and evaporated. Rinsing with an ether/dichloromethane mixture and trituration in ether are carried out. The light-beige solid obtained is recrystallised.
Reaction SMILES: [CH:1]1([CH2:6]I)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:19]2[N:20]=[C:21]([O:25][CH2:26][C:27]3[N:28]([CH3:32])[N:29]=[CH:30][N:31]=3)[C:22](I)=[CH:23][C:18]2=[N:17][N:16]=1>>[CH:1]1([CH2:6][C:22]2[C:21]([O:25][CH2:26][C:27]3[N:28]([CH3:32])[N:29]=[CH:30][N:31]=3)=[N:20][N:19]3[C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[F:8])=[N:16][N:17]=[C:18]3[CH:23]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: ICC1CCCC1
Reactant: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1I
Product: Cn1ncnc1COc1nn2c(-c3ccccc3F)nnc2cc1CC1CCCC1

Procedure:
This compound was prepared using the procedure described in Example 27 Step c) with cyclopentylmethyl iodide used instead of neopentyl iodide and 3-(2-fluorophenyl)-7-iodo-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine used instead of 7-bromo-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine. Data for the title compound: m.p. 135-137° C.; 1H NMR (360 MHz, CDCl3) δ 1.18-1.28 (2H, m), 1.36-1.74 (4H, m), 1.76-1.86 (2H, m), 2.16-2.28 (1H, m), 2.66 (2H, d, J=7 Hz), 3.84 (3H, s), 5.49 (2H, s), 7.25-7.30 (1H, m), 7.36 (1H, dd, J=7 and 7 Hz), 7.50-7.60 (1H, m), 7.82-7.86 (2H, m), 7.89 (1H, s); MS (ES+) m/e 382 [MH]+. Anal. Found C, 60.85; H, 5.38%. C21H22FN7O.0.4H2O requires C, 60.83; H, 5.54%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:17])[C:13]([O:15]C)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@H:12]([CH3:17])[C:13]([OH:15])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H](C)COCOCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](COCOCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl (S)-3-benzyloxymethyloxy-2-methylpropionate (1.20 g; 5 mmole) was dissolved in methanol (12 ml), and a lN sodium hydroxide solution (5.5 ml) was added thereto with ice-cooling, followed by stirring at room temperature for overnight. The reaction mixture was diluted with water (30 ml) and washed with ether (20 ml) two times. The aqueous layer was acidified with 6N hydrochloric acid with ice-cooling and extracted with ethyl acetate (30 ml) three times. The extracts were combined together, washed with water and dried over anhydrous sodium sulfate and concentrated under reduced pressure to give (S)-3-benzyloxymethyloxy-2-methylpropionic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([CH:12]([C:33]#[N:34])[CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:35][O:36][CH2:37][CH2:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O>>[C:33]([CH:12]([C:9]1[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]([C:45]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37][O:36][CH3:35])=[CH:11][CH:10]=1)[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]2[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=2[Cl:32])=[CH:16][CH:15]=1)#[N:34]
Reactant: COCCCc1ccccc1B(O)O
Reactant: COC(=O)c1cc(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)ccc1Br
Product: COCCCc1ccccc1-c1ccc(C(C#N)Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)cc1C(=O)OC

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using methyl 2-bromo-5-(1-cyano-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}ethyl)benzoate from step 3 and [2-(3-methoxypropyl)phenyl]boronic acid from EXAMPLE 3, step 1 as starting materials. Purification by column chromatography on silica gel, eluting with Hex/EtOAc (5 then 10%) afforded the desired compound as a colorless oil.
Reaction SMILES: CC([S@]([NH:7][CH:8]([CH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[CH3:9])=O)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[O:13]1[CH2:14][CH2:15][CH:10]([C@@H:8]([NH2:7])[CH3:9])[CH2:11][CH2:12]1
Reactant: CC(N[S@](=O)C(C)(C)C)C1CCOCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@H](N)C1CCOCC1
Reaction time: 2 h
Yield: 150.5 %

Procedure:
To a solution of (R)-2-methyl-N-(1-(tetrahydro-2H-pyran-4-yl)ethyl)Propane-2-sulfinamide (1.2 g) in CH2Cl2 (4 mL) was added HCl-dioxane (4 mL) at 25° C. The reaction was stirred for 2 hrs. Then the mixture was concentrated in vacuo, diluted with water and washed with ethyl acetate to give crude (S)-1-(tetrahydro-2H-pyran-4-yl)ethanamine (1.0 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3](CC2C=CC(OC)=CC=2)[CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12.C(O)(C(F)(F)F)=O.FC(F)(F)S(O)(=O)=O>C(Cl)Cl>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]2[N:10]3[C@H:11]4[CH2:16][CH2:15][CH2:14][C@H:12]4[N:13]=[C:9]3[N:8]([CH3:17])[C:7](=[O:18])[C:6]=12
Reactant: COc1ccc(Cn2cc3c(c2Cl)C(=O)N(C)C2=N[C@@H]4CCC[C@@H]4N23)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)c2c(c[nH]c2Cl)N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 25 °C
Reaction time: 8 h
Yield: 116.4 %

Procedure:
To a solution of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-2-(4-methoxy-benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (95 mg, 0.25 mmol) in CH2Cl2 is slowly added TFA and trifluoromethanesulfonic acid (TFMSA). The mixture is stirred at room temperature overnight. Solvents and TFA are removed under reduced pressure. The residue is neutralized and dissolved in DMF, and then purified by a semi-preparative HPLC to give 77 mg of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one. A suspension of (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-3-chloro-5-methyl-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (79 mg, 0.3 mmol), 2-(4-(chloromethyl)phenyl)pyridine (61 mg, 0.3 mmol) and cesium carbonate (192 mg, 0.6 mmol) in anhydrous DMF is stirred at room temperature for 4 h. The mixture is filtered through a 0.2 μL microfilter. The filtrate is purified by a semi-preparative HPLC to give pure product. MS (ESI) m/z 432.2 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(Cl)Cl>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]([CH2:8][CH2:9][CH2:10][S:11][C:12]1[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=1)[C:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: c1csc(CNCCCSc2ccncc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)N(CCCSc1ccncc1)Cc1cccs1
Yield: 35.9 %

Procedure:
To a solution of 2.5 g (9.45 mmol) of 4-[3-(N-(2-thienylmethyl)amino)propylthio]pyridine and 1.32 ml (9.45 mmol) of triethylamine in 50 ml of methylene chloride, 1.1 ml (9.45 mmol) of benzoyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium bicarbonate and water and dried, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 1.25 g of the desired compound (yield: 35.9%, yellow oil).
Reaction SMILES: [CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][OH:12])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[N:4]=[C:3]([C:15]([NH2:17])=[O:16])[N:2]=1.O.P(Cl)(Cl)(Cl)=O.[P:24](OC)([O:28]C)([O:26]C)=[O:25]>>[CH:1]1[N:5]([C@@H:6]2[O:10][C@H:9]([CH2:11][O:12][P:24]([OH:28])([OH:26])=[O:25])[C@@H:8]([OH:13])[C@H:7]2[OH:14])[N:4]=[C:3]([C:15]([NH2:17])=[O:16])[N:2]=1
Reactant: COP(=O)(OC)OC
Reactant: NC(=O)c1ncn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: NC(=O)c1ncn([C@@H]2O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]2O)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The manufacture and synthesis Ribavirin (ICN Pharmaceuticals, Costa Mesa Calif.) are described in U.S. Pat. No. 4,211,771, incorporated herein by reference. A dry 1 L ml 3-neck round bottom flask, equipped with a stir bar, gas inlet adapter, and thermometer, was charged with 50 g Ribavirin (0.204 moles), 500 ml trimethyl phosphate, and 0.367 ml de-ionized water (0.0204 moles). The mixture was cooled under nitrogen with an ice/water bath. When the temperature reached 10° C., 23.3 ml phosphorous oxychloride was added, the flask was removed from the ice bath, and the mixture was stirred under nitrogen. After 30 min., the flask was cooled in the ice/water bath. When the temperature reached 10° C., the mixture was poured into a 2 L beaker containing 1000 ml ice water. The pH was adjusted to pH=9.0 using 4 M LiOH and the mixture was stirred overnight. After final adjustment to pH 9, the white precipitate that has formed is filtered away using a 0.2 mm filter. The mixture was evaporated at 40° C. under reduced pressure to 1 L. The solution was added to 1 L hot ethanol dropwise. The white precipitate was collected on a 2 L glass fritted funnel, coarse grade, washing the solid with two 100 ml portions of ethanol, re-suspending the solid each time. The product was dried under vacuum overnight, yield: 89 g. The solid was dissolved in 200 ml de-ionized water, and 5 g activated carbon was added. The mixture was filtered through a 0.2 mm filter, washing the carbon with 50 ml de-ionized water. The filtered solution was added dropwise to 1200 ml hot ethanol The mixture was cooled to room temperature, and the precipitate was collected on the 2 L glass fritted funnel. The solid was washed with 2×100 ml ethanol in the funnel, and dried under vacuum. Yield: 66.6 g. The dried product was dissolved in 200 ml de-ionized water. Amberlite IR-120 H.C.P. resin (H+ form) was added until the pH of the mixture reached pH=2.18. The resin was filtered off using a 0.2 mm filter, and the final solution was lyophilized. Yield: 54.8 g (0.160 moles), 78.5%, Ribavirin 5'-monophosphate. Elemental analysis indicates the product contains 1 mole water/mol ribavirin 5'-monophosphate.
Reaction SMILES: [OH-:1].[Na+].Br[CH:4]([CH3:23])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:6]>O.CN(C=O)C>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:18][CH2:17][C@H:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH:4]([CH3:23])[OH:1]
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)Br)cc2)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1CC[C@H](c2ccc(C(=O)C(C)O)cc2)CC1
Reaction time: 0.67 h

Procedure:
Sodium hydroxide (370 mg, 9.25 mmol) in water (2 mL) was added to a stirred solution of methyl trans-4-[4-(2-bromopropanoyl)phenyl]cyclohexanecarboxylate (prepared as described in Patent Application WO2004/047755) (3.264 g, 9.25 mmol) in DMF (10 mL). The mixture was stirred for 40 minutes then extracted with ether (5×20 mL). The extracts were combined, dried and concentrated. The crude product was purified by flash column chromatography eluting with 20-40% EtOAc/hexanes to give the title compound (1.76 g, 66%) as a solid; 1H NMR δ 7.94 (2H, d), 7.39 (2H, d), 5.29 (1H, d), 5.08-4.98 (1H, m), 3.62 (3H, s), 2.68-2.54 (1H, m), 2.48-2.35 (1H, m), 2.08-1.94 (2H, m), 1.90-1.79 (2H, m), 1.60-1.40 (4H, m), 1.28 (3H, s); MS 313 (M+Na)+.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([C:15]1[CH:16]=[CH:17][C:18]2[O:22][C:21]([CH2:23][CH:24]([C:30]3[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:20][C:19]=2[CH:37]=1)#[N:14].[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50]O)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:38]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH2:50][O:36][C:33]1[CH:32]=[CH:31][C:30]([CH:24]([CH2:23][C:21]2[O:22][C:18]3[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:37][C:19]=3[CH:20]=2)[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:35][CH:34]=1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2o1)c1ccc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.1 %

Procedure:
1.04 g of diethyl azodicarboxylate was added to 300 ml of a tetrahydrofuran solution containing 1 g of ethyl 3-(5-cyano-2-benzofuranyl)-2-(4-hydroxyphenyl)propionate, 1.2 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol and 1.56 g of triphenylphosphine, and the thus prepared mixture was stirred at room temperature for 18 hours. To the resulting reaction solution were added 0.6 g of (2S)-1-tert-butoxycarbonyl-2-pyrrolidinemethanol, 0.78 g of triphenylphosphine and 0.52 g of diethyl azodicarboxylate, followed by additional stirring at room temperature for 18 hours. Thereafter, the reaction solution thus obtained was concentrated to dryness, and the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/ethyl acetate mixture as an eluant. In this way, 790 mg of the title compound was obtained in the form of colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[C:12](=[O:13])[NH:11][N:10]=[C:9]1[CH2:14][C@@H:15]1[CH2:19][CH2:18][N:17]([C:20]([O:22]C(C)(C)C)=O)[CH2:16]1.Cl.C(N(CC)C(C)C)(C)C.[CH3:45][C:46](C)([CH3:50])[C:47](Cl)=O.[NH4+].[Cl-]>O1CCOCC1.ClCCl>[CH3:45][C:46]([CH3:50])([CH3:47])[C:20]([N:17]1[CH2:18][CH2:19][C@@H:15]([CH2:14][C:9]2[N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)=[CH:3][C:2]=3[F:1])[C:12](=[O:13])[NH:11][N:10]=2)[CH2:16]1)=[O:22]
Reactant: CC(C)(C)C(=O)Cl
Reactant: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)OC(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COc1ccc(-c2ccc(-n3c(C[C@@H]4CCN(C(=O)C(C)(C)C)C4)n[nH]c3=O)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 8 mL screwcap vial was placed 1,1-dimethylethyl (3S)-3-({4-[3-fluoro-4′-(methyloxy)-4-biphenylyl]-5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl}methyl)-1-pyrrolidinecarboxylate (0.162 mmol). Added to the vial was 4N HCl in dioxane (1 mL). The reaction was capped and stirred at room temperature for 2 h. The solution was concentrated in vacuo. Added to the vial were dichloromethane (1 mL) and N,N-diisopropylethylamine (0.573 mmol). In a separate vial, trimethylacetyl chloride (0.163 mmol) was taken up in 1 mL dichloromethane and was added to the starting material dropwise via pipette. The vial was capped and the reaction was stirred at room temperature for 2 h. Dichloromethane (2 mL) was added to the vial, followed by the addition of saturated aq NH4Cl. The vial was capped and lightly agitated for 1 min. The organic layer was separated, filtered through a plug of sodium sulfate, and concentrated in vacuo. Reverse phase HPLC (10-80% acetonitrile/water+0.1% NH4OH) was utilized in purifying the title compound (37 mg, 50%). MS(ES)+ m/e 453.1 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([NH:4][OH:5])[CH3:3].[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:26])[C:23](Cl)=[O:24])=[CH:21][C:8]1=2>N1C=CC=CC=1.O1CCCC1>[O:6]=[C:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH2:11][O:10][C:9]2[CH:18]=[CH:19][C:20]([CH:22]([CH3:26])[C:23]([N:4]([CH2:2][CH3:3])[OH:5])=[O:24])=[CH:21][C:8]1=2
Reactant: CC(C(=O)Cl)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: CCNO
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCN(O)C(=O)C(C)c1ccc2c(c1)C(=O)c1ccccc1CO2
Reaction time: 8 h
Yield: 30.6 %

Procedure:
A stirring solution of 10.14 g of N-ethylhydroxylamine hydrochloride in 350 ml of dry pyridine was chilled and treated dropwise over several minutes with a solution of 8.0 g of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)propionyl chloride in 400 ml of tetrahydrofuran. The solution was allowed to equilibrate to room temperature overnight (16 hours) with continued stirring. The reaction was quenched with 500 ml of water and concentrated in vacuo to remove solvents. The product mixture was partitioned against a total of 500 ml of methylene chloride and 1000 ml of 10% HCl (pH of aqueous layers <1). The organic phase was washed with 500 ml of water, dried (Na2SO4) and concentrated in vacuo to an oil. Thin layer analysis indicated a mixture, which was separated twice via preparative HPLC to give 2.65 g of 2-(6,11-dihydro-11-oxodibenz[b,e]-oxepin-2-yl)-N-ethyl-N-hydroxypropanamide, as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:22][C:21]([C:30]([F:33])([F:32])[F:31])=[N:20]2)=[CH:15][CH:14]=1)=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2-c2ccccc2)cc1)c1cc(Cl)ccc1O
Yield: 73.2 %

Procedure:
Using 5-chlorosalicylic acid and 1-(4-aminophenyl)-5-phenyl-3-(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 16 gave the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7](O)=[O:8])[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3]1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:27]=[C:28]([CH:45]=[CH:46][CH:47]=1)[O:29][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[N:38]=2)[CH:35]=1>CN(C)C=O.CN(C)C(=O)C>[CH:42]1([C:40]([NH:39][C:37]2[N:38]=[C:33]3[CH:32]=[CH:31][C:30]([O:29][C:28]4[CH:27]=[C:26]([NH:25][C:7]([C:5]5[C:4]([C:10]([F:13])([F:12])[F:11])=[N:3][N:2]([CH3:1])[CH:6]=5)=[O:8])[CH:47]=[CH:46][CH:45]=4)=[CH:35][N:34]3[N:36]=2)=[O:41])[CH2:43][CH2:44]1
Reactant: Cn1cc(C(=O)O)c(C(F)(F)F)n1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)nn4c3)c2)c(C(F)(F)F)n1
Yield: 69.7 %

Procedure:
In the same manner as in Example 18-4 and using 1-methyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid (175 mg, 0.904 mmol), tetrahydrofuran (8 mL), oxalyl chloride (118 μL, 1.36 mmol), N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (70.0 mg, 0.226 mmol), N,N-dimethylformamide (1 drop) and N,N-dimethylacetamide (3 mL) as starting materials, the title compound (76.5 mg, 70%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:12][N:13]([CH3:14])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[CH:4][N:3]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1c(Cl)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)c1ncnc(Cl)c1[N+](=O)[O-]
Temperature: -70 °C

Procedure:
Dissolve 50 g (0.26 mol) of 4,6-dichloro-5-nitropyrimidine in 500 mL of CH2Cl2 and cool to -70° C. Add a solution of 24 mL (0.28 mol) dimethylamine, 70 mL (0.40 mol) of diisopropylethylamine, and 100 mL of CH2Cl2 over 30 minutes. Warm to ambient temperature and wash the reaction mixture with 500 mL of 20% K2CO3. Dry the CH2Cl2 portion over MgSO4, treat with charcoal filter, and remove the filtrate under vacuum. Crystallize the residue with ether to provide 4-dimethylamino-6-chloro-5-nitropyrimidine.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][NH:3][C:2]1=[O:6].[C:7](Cl)(=[O:11])[CH2:8][CH2:9][CH3:10].[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[O:11]=[C:7]([C:5]1[NH:1][C:2](=[O:6])[NH:3][CH:4]=1)[CH2:8][CH2:9][CH3:10]
Reactant: O=c1[nH]cc[nH]1
Reactant: CCCC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CCCC(=O)c1c[nH]c(=O)[nH]1
Reaction time: 2 h

Procedure:
In 10 ml of dichloromethane is placed 1.0 g of 1,3-dihydro-2H-imidazol-2-one, 1.28 g of butyryl chloride and 4.8 g of aluminum chloride. The mixture is refluxed and stirred for 2 hours after which it is poured into water. The precipitate is collected, washed with water, and recrystallized from ethanol:water, to give the title compound, m.p. 268°-270° C.
Reaction SMILES: [C:1]([S:4][C:5]1[C:10]([CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C([O-])(=O)C.[Na+]>C(O)(C)(C)C>[C:1]([S:4][C:5]1[C:10]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCc1ccccc1SC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(=O)Sc1ccccc1CCC(=O)O
Temperature: 25 °C

Procedure:
Ten (10.0) or 100.0 mg of racemic ethyl 2-acetylthio-3-benzenepropanoate was added to 1000 μl of 90% tert-butanol and 10% 200 mM sodium acetate buffer (pH 4.0) which contained 10 mg of immobilized lipase from Mucor meihei (Novo). The glass vessel was tightly capped and stirred for 0–40 hours at room temperature. Thirty μl aliquots were removed to ascertain conversion and optical purity. The aliquots were analyzed using an chiral HPLC column (Chiralcel AD, Daicel Chemical Industries) with a mobile phase of hexane:ethanol:trifluoroacetic acid 98:2:0.1%. The flow rate is 1 ml/minute and detection was at 230 nm. This experiment was also performed in 90% acetonitrile, acetone, and isopropanol as described above. Other racemic esters were also evaluated: butyl, isobutyl, and trifluoroethyl. The results described in Table 1 (above) were obtained.