Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:10]([O:12][CH3:13])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:24]([C:1]1([C:10]([O:12][CH3:13])=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C1CCc2ccccc21
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccccc2)CCc2ccccc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 78.9 %

Procedure:
To a −78° C. tetrahydrofuran solution containing methyl indane-1-carboxylate (2.10 g, 11.9 mmol) from Step A, was added a 1M tetrahydrofuran solution of NaHMDS (23.8 mL, 23.8 mmol). The mixture was stirred at −78° C. for 30 minutes. Benzyl bromide (1.49 mL, 12.5 mmol) was added and the reaction was warmed to 0° C. and stirred for 90 minutes. The reaction was quenched with aqueous sodium bicarbonate and then extracted into EtOAc (3×50 mL) and the combined organic washings were dried over MgSO4 and evaporated. The resulting residue was purified by column chromatography (98/2 hexanes/EtOAc) to afford of methyl 1-benzylindane-1-carboxylate (2.5 g, 79%) as a partially pure oil that was taken to the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1S(N)(=O)=O.[Cl:15]C1C=CC(O)=CC=1.C1(=O)OCCO1.OCCOC1C=CC=CC=1Cl.C(Cl)(Cl)=O>>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:15]
Reactant: NS(=O)(=O)c1ccccc1OCCCl
Reactant: Oc1ccc(Cl)cc1
Agent: O=C(Cl)Cl
Agent: OCCOc1ccccc1Cl
Solvent: O=C1OCCO1
Product: ClCCOc1ccccc1Cl

Procedure:
A process for the preparation of 2-(2-chloroethoxy)-benzenesulfonamide of formula I ##STR15## which process comprises the etherification of 4-chlorophenol of formula II ##STR16## with ethylene carbonate at a temperature between +130° C. and +150° C. and chlorination of the resulting 2-(2-hydroxyethoxy)-chlorobenzene of formula III ##STR17## with phosgene at a temperature between +70° C. and +90° C. to give 2-(2-chloroethoxy)-chlorobenzene of formula IV ##STR18## which is converted with chlorosulfonic acid, at a temperature between +20° C. and +60° C. and subsequent neutralization with sodium hydroxide to the sulfonic acid sodium salt of formula V ##STR19## which is hydrogenated at a temperature between +20° C. and +70° C. to the compound formula VI ##STR20## which is subsequently reacted with phosgene at a temperature between +60° C. and +120° C. to the sulfonic acid chloride of formula VII ##STR21## which is reacted with ammonia at a temperature between 0° C. and +100° C. to the sulfonamide of formula I.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4].O=P(Cl)(Cl)Cl.[OH-].[Na+].CN([CH:26]=[O:27])C>>[CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH:26]=[O:27])=[CH:10][N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1)=[O:4]
Reactant: CN(C)C=O
Reactant: CCn1ccc2ccc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCn1cc(C=O)c2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1-Ethyl-1H-indole-6-carboxylic acid methyl ester (900 mg, 4.45 mmol) is dissolved in DMF (3.3 mL). This is added dropwise to an ice-cold solution of POCl3 (430 μL, 4.5 mmol) in DMF (1.5 mL). The reaction mixture is stirred at room temperature for 90 minutes. The reaction mixture is then treated with 6N NaOH (3.5 ml). The mixture is then partitioned between H2O and ethyl acetate. Purification by silica gel chromatography (5-10% EtOAc/CH2Cl2) yields 1-ethyl-3-formyl-1H-indole-6-carboxylic acid methyl ester (985 mg, 96%) as a white solid.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.[CH2:11]([Mg]Br)[CH3:12].C(=O)=O.CC(C)=O>CCOCC>[O:4]=[C:2]([CH2:11][CH3:12])[C:1]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC[Mg]Br
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC
Yield: 85.9 %

Procedure:
Diethyl oxalate (10 g; 68 mmol) was dissolved in Et2O (100 ml) and cooled to −78 C. Ethyl magnesium bromide (1.0 M in THF; 72 ml; 71.8 mmol; 1.05 equiv.) was added slowly via syringe. The dry ice/acetone bath was allowed to melt and warm to 10 C. Monitored the reaction by 1H NMR. The reaction was cooled to 0 C and quenched with saturated NH4Cl. Dilute with H2O and separate phases. The organic layer was dried over Na2SO4, filtered and concentrated. Isolation gave 7.6 g of a crude yellow oil in 86% yield. No further purification.
Reaction SMILES: [F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.C([O:21][C:22]1[C:23]([CH:28]=O)=[N:24][CH:25]=[CH:26][N:27]=1)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[F:1][CH:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[CH2:3][CH:4]1[CH2:5][CH2:6][N:7]([CH2:28][C:23]2[C:22](=[O:21])[NH:27][CH:26]=[CH:25][N:24]=2)[CH2:8][CH2:9]1
Reactant: Fc1ccccc1C(F)CC1CCNCC1
Reactant: CC(C)(C)Oc1nccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=c1[nH]ccnc1CN1CCC(CC(F)c2ccccc2F)CC1
Reaction time: 8 h
Yield: 5.3 %

Procedure:
After dissolving 64 mg of 4-[2-fluoro-2-(2-fluorophenyl)ethyl]piperidine in 3 ml of tetrahydrofuran, 61 mg of 3-tert-butoxy-2-pyrazinecarboxaldehyde and 90 mg of sodium triacetoxyborohydride were added while stirring, and the stirring was continued overnight at room temperature. A 1N sodium hydroxide solution was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: n-hexane/ethyl acetate). Two milliliters of a 4N hydrogen chloride/ethyl acetate solution was added to the obtained product while stirring, and the stirring was continued for 2.5 hours at room temperature. A 1N sodium hydroxide solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether/n-hexane was added to the residue and the insoluble portion was filtered out to obtain the title compound (5 mg, 5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[C:13]([O:19][CH2:20][CH3:21])(=[O:18])[CH2:14]C([O-])=O.N1CCCCC1.C(=O)=O.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][C:13]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: COc1ccc(C=O)c(OC)c1
Agent: Cl
Agent: O=C=O
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOC(=O)C=Cc1ccc(OC)cc1OC
Reaction time: 0.33 h

Procedure:
83 g of 2,4-dimethoxybenzaldehyde and 66 g of monoethyl malonate are dissolved in 100 ml of dry pyridine and, after addition of 1 ml of piperidine and 40 g of molecular sieves, refluxed until evolution of CO2 has ceased. The reaction mixture is cooled and then poured onto crushed ice, and the pH is adjusted to 1-2 with concentrated hydrochloric acid, while stirring. Stirring is continued for 20 minutes, and the product which has separated out is filtered off with suction, washed with 1 N hydrochloric acid and water and dried in a desiccator. Yield: 100.2 g, melting point 58° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)[S:3]1.[OH:32][C@@H:33]([CH2:46][NH2:47])[CH2:34][O:35][C:36]1[C:44]2[NH:43][C:42](=[O:45])[NH:41][C:40]=2[CH:39]=[CH:38][CH:37]=1>>[O:1]=[C:2]1[NH:6][C:5](=[O:7])[CH:4]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:30][CH2:29][CH:28]([NH:47][CH2:46][C@H:33]([OH:32])[CH2:34][O:35][C:36]5[C:44]6[NH:43][C:42](=[O:45])[NH:41][C:40]=6[CH:39]=[CH:38][CH:37]=5)[CH2:27][CH2:26]4)=[CH:21][CH:20]=3)(=[O:16])=[O:17])=[CH:13][CH:14]=2)[S:3]1
Reactant: O=C1CCN(c2ccc(NS(=O)(=O)c3ccc(CC4SC(=O)NC4=O)cc3)cc2)CC1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Product: O=C1NC(=O)C(Cc2ccc(S(=O)(=O)Nc3ccc(N4CCC(NC[C@H](O)COc5cccc6[nH]c(=O)[nH]c56)CC4)cc3)cc2)S1

Procedure:
The title compound was prepared from 4-(2,4-dioxo-thiazolidin-5-ylmethyl)-N-[4-(4-oxo-piperidin-1-yl)-phenyl]-benzenesulfonamide (which was obtained in Example 231) and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 278 as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.40–1.60 (m, 2 H), 1.90–2.10 (m, 2 H), 2.50–2.70 (m, 2 H), 2.70–3.50 (m, 5 H), 3.60 (brd, J=11.6 Hz, 2 H), 4.00 (brs, 3 H), 4.60 (dd, J=9.4, 4.2 Hz, 1 H), 6.58 (d, J=7.8 Hz, 1 H), 6.62 (d, J=8.1 Hz, 1 H), 6.70–6.90 (m, 5 H), 7.35 (d, J=8.4 Hz, 2 H), 7.55 (d, J=8.4 Hz, 2 H), 9.70 (brs, 1 H), 10.61 (brs, 1 H), 10.72 (brs, 1 H); MS (ES) m/z: 667.0 (MH+); HRMS Calcd. for C31H35N6O7S2 (MH+): 677.2009. Found: 677.1999.
Reaction SMILES: FC(F)(F)S(O)(=O)=O.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[C@H:10]([CH3:12])[OH:11].ClC(Cl)(Cl)C(=N)O[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1CCCCC1.C(Cl)Cl>[CH2:21]([O:11][C@@H:10]([CH3:12])[C:9]([O:14][CH2:15][CH3:16])=[O:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@H](C)O
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCCCC1
Solvent: ClCCl
Product: CCOC(=O)[C@H](C)OCc1ccccc1
Reaction time: 18 h
Yield: 62.3 %

Procedure:
Trifluoromethanesulfonic acid (1.13 g) was added to a stirred mixture of ethyl (S)-(−)-lactate (5.90 g) and benzyl 2,2,2-trichloroacetimidate (15.15 g) in cyclohexane (70 ml) and methylene chloride (35 ml) at room temperature under nitrogen atmosphere. After being stirred for 18 hours, the reaction mixture was filtered. The filtrate was diluted with cyclohexane, and then washed successively with saturated NaHCO3 solution (100 ml)and H2O (100 ml). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel (260 g) chromatography eluted with hexane/ethyl acetate (30:1) to give ethyl (S)-2-(benzyloxy)propionate (6.48 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[NH:3]1.[O:11]1[CH:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)[CH2:12]1>CCCCCO>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][C:4]([CH3:9])([CH3:8])[N:3]1[CH2:12][CH:13]([OH:11])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:17]=1
Reactant: CC1(C)CCCC(C)(C)N1
Reactant: c1ccc(Cc2cccc(OCC3CO3)c2)nc1
Solvent: CCCCCO
Product: CC1(C)CCCC(C)(C)N1CC(O)COc1cccc(Cc2ccccn2)c1
Yield: 18.9 %

Procedure:
8.9 g of 2,2,6,6-tetramethylpiperidine is added to a solution of 15.0 g of 1,2-epoxy- 3-[3-(2-pyridylmethyl)phenoxy]propane in 45 ml of n-amyl alcohol, and the resulting mixture is heated on a water bath for 2 hours. The solvent is then removed, 200 ml of benzene is added to the residue, and the insoluble matter is filtered off with activated charcoal. The filtrate is washed with water, and extracted with two 100 ml portions of 5% hydrochloric acid. The aqueous layer is made alkaline with sodium hydroxide, and the separated oil is extracted with benzene. The benzene layer is washed with water, dried over anhydrous potassium carbonate, and the solvent is removed. The residual oil is purified by distillation to give 4.5 g of 1-(2,2,6,6-tetramethylpiperidino)-3-[3-(2-pyridylmethyl)phenoxy]-2 -propanol, boiling at 230°-235°C/0.15 mmHg.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14]CC)=[O:13])[CH2:6][CH2:5]2.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:24][CH2:25][O:26][C:27]1[CH:39]=[CH:38][C:30]2[C:31]([C:34](F)(F)F)=[N:32][O:33][C:29]=2[C:28]=1[CH2:40][CH2:41][CH3:42]>CN(C=O)C.O>[CH3:34][C:31]1[C:30]2[CH:38]=[CH:39][C:27]([O:26][CH2:25][CH2:24][O:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[C@H:7]([CH2:11][C:12]([OH:14])=[O:13])[CH2:6][CH2:5]4)=[C:28]([CH2:40][CH2:41][CH3:42])[C:29]=2[O:33][N:32]=1
Reactant: CCCc1c(OCCBr)ccc2c(C(F)(F)F)noc12
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1c(OCCOc2ccc3c(c2)CC[C@H]3CC(=O)O)ccc2c(C)noc12
Temperature: 60 °C
Reaction time: 10 h

Procedure:
Ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6) (62.4 mg, 0.28 mmol) was dissolved in DMF (5 mL), and Cs2CO3 (111 mg, 0.34 mmol), and 3 drops of water were added. 6-(2-bromoethoxy)-7-propyl-3-(trifluoromethyl)-1,2-benzisoxazole (100 mg, 0.28 mmol) was added and the reaction mixture was stirred for 10 h at 60° C. The solvent was removed under reduced pressure, and the crude product was taken up in EtOAc, filtered through silica gel, and the filtrate was concentrated under reduced pressure. The crude product was dissolved in THF (2 mL), and LiOH (0.5 M aqueous solution, 0.9 mL) and MeOH (4 drops) were added. After stirring for 18 h at 50° C. the reaction mixture was concentrated under reduced pressure. Water and HCl (1 N aqueous solution) were added until the mixture was acidic which was followed by extraction using EtOAc. The product was purified by silica gel filtration (gradient 1:6 EtOAc/Hexane to 100% EtOAc), yielding 12 mg (9% over 2 steps) of the title compound as white crystals. 1H NMR (300 MHz, CD3OD): δ 0.91 (t, 3H), 1.70 (m, 3H), 2.33 (m, 2H), 2.68 (m, 2H), 2.87 (m, 3H), 3.46 (m, 1H), 4.33 (m, 2H), 4.48 (m, 2H), 6.73 (dd, 1H), 6.82 (d, 1H), 7.11 (d, 1H), 7.34 (d, 1H), 7.67 (d, 1H).
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.C(O)(C(F)(F)F)=O.CC[NH+](CC)CC.CC[NH+](CC)CC.C([O-])([O-])=O>C(Cl)Cl>[F:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:7][NH:8][C:9](=[O:10])[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)OCc2ccccc2)[C@H](F)C1
Agent: CC[NH+](CC)CC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@@H]1CNC[C@@H]1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.4 %

Procedure:
To a solution of (±)-1,1-dimethylethyl trans-3-fluoro-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (1.0 g, 2.84 mmole) in DCM (50 mL) at RT was added TFA (25 mL). After 2 h, the reaction solution was concentrated under vacuum and the residue placed under high vacuum for 3 hr. The residue was dissolved in DCM (200 mL) and MP-carbonate resin (11.4 mmole, 4.2 g) was added with vigorous stirring at RT. After 4 h, the reaction contents were filtered through a scintered-glass funnel washing with MeOH (100 mL). The filtrate was concentrated under vacuum to give the title compound (0.54 g, 75%) as a light orange oil: LC-MS (ES) m/e 253 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[NH2:1][C:2]1([C:9]2[CH:17]=[CH:16][C:12]3[O:13][CH2:14][O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:6][CH:5]([N:18]2[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=3)=[O:24])[CH2:19]2)[CH2:4][CH2:3]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: NC1(c2ccc3c(c2)OCO3)CCC(=O)CC1
Product: NC1(c2ccc3c(c2)OCO3)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-amino-4-benzo[1,3]dioxol-5-yl-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [Mg].[CH3:2][N:3]([CH3:14])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][CH:8]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:25])[CH2:23][CH3:24])[CH:19]=[CH:20][CH:21]=1>O1CCCC1>[CH2:23]([C:22]([OH:25])([C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=1)[C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][CH2:4][N:3]([CH3:14])[CH3:2])=[CH:8][CH:9]=1)[CH3:24]
Reactant: CN(C)CCOc1ccc(Br)cc1
Reactant: CCC(=O)c1cccc(Cl)c1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(OCCN(C)C)cc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Grignard reactant prepared from 2.2 g. of magnesium turnings and 23.4 g. of 4-[2-(dimethylamino)-ethoxy]-bromobenzene in 100 ml. of dry tetrahydrofurane a solution of 10 g. of m-chloro-propiophenone in 30 ml. of tetrahydrofurane is added dropwise, at 20° C. The reaction mixture is stirred at room temperature for another two hours, cooled, and filtered onto a 20% aqueous ammonium chloride solution. Tetrahydrofurane is distilled off in vacuo. The residue is extracted with ether, the ethereal phase is washed with water, dried over anhydrous magnesium sulfate, filtered, and ether is distilled off. Crystallization of the residue from a mixture of n-hexane and ethyl acetate yields 14.2 g. of the named compound, melting at 108° to 109° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]1([C:21]([F:24])([F:23])[F:22])[CH2:20][O:19]1)=[O:15].[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O1CCOCC1>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:19])([CH2:20][NH:32][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:21]([F:22])([F:23])[F:24])=[O:15]
Reactant: NCc1ccccc1
Reactant: Nc1c(C(=O)NCC2(C(F)(F)F)CO2)cnn1-c1ccc(F)cc1
Solvent: C1COCCO1
Product: Nc1c(C(=O)NCC(O)(CNCc2ccccc2)C(F)(F)F)cnn1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 5-amino-1-(4-fluorophenyl)-N-{[2-(trifluoromethyl)-2-oxiranyl]methyl}-1H-pyrazole-4-carboxamide (15.3 g) in dioxane (250 ml) was added benzylamine (5.76 ml). The mixture was stirred at room temperature for 16 hours and then for a further 4 hours to ensure the reaction was complete. The orange solution was concentrated in vacuo to give an orange oil (which still contained some solvent). The oil was dried on the vacuum line to give the title compound (20.50 g) as an orange solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:29]=[CH:28][C:27]([NH2:30])=[CH:26][N:25]=1>>[CH3:19][O:20][CH2:21][CH2:22][N:23]([CH3:31])[C:24]1[N:25]=[CH:26][C:27]([NH:30][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][C:9]=2[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:28][N:29]=1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: COCCN(C)c1ncc(N)cn1
Product: COCCN(C)c1ncc(NC(=O)c2nc(-c3ccccc3)oc2C(F)(F)F)cn1

Procedure:
With a procedure similar to example 1 above, 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C19H18F3N5O3 (m/e) 421, obsd 422 (M+H).
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[NH2:7][C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12]>C(Cl)(Cl)Cl.CO>[CH3:1][O:12][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][CH:16]=[C:8]([NH2:7])[CH:9]=1
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(N)c1
Reaction time: 8 h

Procedure:
To a chilled solution of methanol (100) was added thionyl chloride (21.25 ml, 0.29 mol). The solution was stirred for a further 30 minutes after which time m-aminobenzoic acid (10 g, 73 mmol) was added. The reaction was allowed to proceed overnight at room temperature and the solvents were then removed under reduced pressure. The product was obtained on tituration of the residue with diethyl ether. Yield 12.2 g (89%), m.p. 216°-218° C. The product was judged homogeneous by tlc in chloroform/methanol (4:1) (Rf 0.688) or chloroform/methanol (1:1) (Rf 0.597). (Found: C, 50.16; H, 5.27; N, 7.29. C8H10O2N1Cl1 requires C, 50.26; H, 5.23; N, 7.33%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[C:7](/[CH2:9]P(OCC)(OCC)=O)\[CH3:8])=[O:5].[Li]CCCC.[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH:26]=O>C1COCC1.CN1C(=O)N(C)CCC1>[CH2:2]([O:3][C:4](=[O:5])[CH:6]=[C:7]([CH3:8])[CH:9]=[CH:26][C:25]1[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:24]=1[Cl:23])[CH3:1]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(\C)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)C=Cc1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 81.7 %

Procedure:
Triethyl 3-methyl-4-phosphonocrotonate (34.24 g, 0.129 mol, 1.3 eq) was dissolved in THF/DMPU (100 mL/200 mL) and the mixture was cooled to −78° C. BuLi (51.8 mL of a 2.5M solution in hexanes, 1.3 eq) was added dropwise. The mixture was stirred for 20 min and then a solution of 2,4-dichlorobenzaldehyde (17.6 g, 0.1 mol) in THF/DMPU (20 mL/40 mL) was added dropwise. The resulting mixture was stirred for 1 hour and then allowed to warm to room temperature. NH4Cl(sat) was added and the mixture extracted with EtOAc. The organic layers were washed with, water, brine, and dried (MgSO4). Removal of solvent under reduced pressure followed by silica gel chromatography (0-1-2-3% EtOAc in hexanes) gave 23.3 g of 5-(2,4-dichlorophenyl)-3-methylpenta-2,4-dienoic acid ethyl ester.
Reaction SMILES: C(OCC(COC(=O)C)CCN1C=NC2C1=NC(N)=NC=2)(=O)C.OCC(CO)CCN1C=NC2C(=O)NC(N)=NC1=2.[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([NH:47][CH:48]=[N:49]2)=[C:45]([Cl:52])[N:44]=1.Br[CH2:54][CH2:55][C:56]([C:67]([O:69][CH2:70][CH3:71])=[O:68])([C:62]([O:64][CH2:65][CH3:66])=[O:63])[C:57]([O:59][CH2:60][CH3:61])=[O:58]>>[NH2:42][C:43]1[N:51]=[C:50]2[C:46]([N:47]=[CH:48][N:49]2[CH2:54][CH2:55][C:56]([C:57]([O:59][CH2:60][CH3:61])=[O:58])([C:67]([O:69][CH2:70][CH3:71])=[O:68])[C:62]([O:64][CH2:65][CH3:66])=[O:63])=[C:45]([Cl:52])[N:44]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C(CCBr)(C(=O)OCC)C(=O)OCC
Agent: CC(=O)OCC(CCn1cnc2cnc(N)nc21)COC(C)=O
Agent: Nc1nc2c(ncn2CCC(CO)CO)c(=O)[nH]1
Product: CCOC(=O)C(CCn1cnc2c(Cl)nc(N)nc21)(C(=O)OCC)C(=O)OCC

Procedure:
Nucleosides and Nucleotides, 15(5), 981-994 (1996) and WO 95/28404 disclose a process for the manufacture of the anti-viral agents 9-(4-acetoxy-3-acetoxymethylbut-1-yl)-2-aminopurine (famciclovir) and 9-(4-hydroxy-3-hydroxymethylbut-1-yl)guanine (penciclovir). According to this process, the ‘bromotriester’ route, 2-amino-6-chloropurine is reacted with triethyl 3-bromopropane-1,1,1-tricarboxylate in the presence of base to form diethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]-2-carbethoxymalonate. The crude isolate from this alkylation reaction is then treated with sodium methoxide in methanol to form dimethyl 2-[2-(2-amino-6-chloropurin-9-yl)ethyl] malonate. This product is purified by crystallisation and then successively reduced using sodium borohydride and O-acetylated to give 9-(4-acetoxy-3-acetoxymethylbutyl)-2-amino-6-chloropurine. Famciclovir is produced directly from the latter compound by hydrogenation over a supported palladium catalyst; and penciclovir is produced from this compound by acid hydrolysis of the acetoxy groups.