Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6](Br)[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1.Cl.[F:22][C:23]([F:28])([F:27])[C@@H:24]([NH2:26])[CH3:25].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[Br:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([F:15])=[CH:10][C:9]=2[F:16])=[C:6]([NH:26][C@@H:24]([CH3:25])[C:23]([F:28])([F:27])[F:22])[N:5]2[N:18]=[CH:19][N:20]=[C:4]2[N:3]=1
Reactant: C[C@H](N)C(F)(F)F
Reactant: Fc1cc(F)c(-c2c(Br)nc3ncnn3c2Br)c(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Br)nc2ncnn12)C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.5 %

Procedure:
A mixture of 5,7-dibromo-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine (320 mg, 0.78 mmol), (1S)-2,2,2-trifluoro-1-methylethylamine hydrogen chloride (235 mg, 1.57 mmol), and diisopropylethylamine (260 mg, 2.0 mmol) in 5 mL of N,N-dimethylformamide is stirred at room temperature for 18 h. Water is added to quench the reaction, and the product is extracted with ethyl acetate. The combined organic extracts are washed with saturated sodium chloride (x3), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 9:1 hexanes/ethyl acetate to 2:1 hexanes/ethyl acetate. Concentration provides 5-bromo-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a light tan solid (60 mg, mp 95-97° C.). MS: m/z 440.0, 442.0 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([I:17])[CH:13]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:20])=[CH:13][C:12]([I:17])=[CH:11][CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c[nH]c2ccc(I)cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(I)cc2c1Cl
Yield: 98 %

Procedure:
A mixture of 6-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester (56 g, 0.16 mol) in phosphorus oxychloride (180 mL) was refluxed under N2 for 14 h. After cooling, the solvent was removed by rotary evaporator and then by the oil pump. Sat. sodium bicarbonate (200 mL) was slowly added. The solid was collected by filtration, washed with sat. sodium bicarbonate, water and dried to obtain 4-chloro-6-iodo-quinoline-3-carboxylic acid ethyl ester (58 g, 98%) as a yellow solid.
Reaction SMILES: [Br:1]Br.[S:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[CH:4]1.P([O-])([O-])(O)=O.[K+].[K+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl>[Br:1][C:5]1[C:6]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[S:3][CH:4]=1
Reactant: c1cnc2sccc2c1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: ClC(Cl)Cl
Product: Brc1csc2ncccc12

Procedure:
Bromine (2.08 g, 13 mmol) was dropwise added to a mixture of thieno[2,3-b]pyridine (J-2) (1.35 g, 10 mmol), dipotassium monohydrogen orthophosphate (940 mg, 5.4 mmol), sodium bicarbonate (840 mg 10 mmol), and magnesium sulfate (2.0 g, 16.7 mmol) in chloroform (40 mL) which has been stirred at reflux for 16 h, the resulting mixture was stirred under reflux for 24 h, then filtered and washed with DCM. The filtrate was concentrated, and purified by chromatography. MS (m/z): 214 (M+1)+.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.O=S(Cl)Cl.[CH3:18]O>>[CH3:18][O:12][C:11](=[O:13])[C@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)[NH2:1]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of L-tyrosine (45.3 g, 0.25 mol) in CH3OH (680 mL), SOCl2 (44.6 g, 0.375 mol) was added dropwise at 0° C. After addition, the mixture was allowed to warm to rt and then refluxed for overnight. The reaction mixture was concentrated to give L-tyrosine methyl ester (49.2 g, 100%), which was used in the next step without purification.
Reaction SMILES: C[O:2][C:3](=[O:44])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:43])[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([S:23]([C:26]2[CH:30]=[C:29]([C:31]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[NH:32])[S:28][C:27]=2[S:41][CH3:42])(=[O:25])=[O:24])[CH:18]=1.[Li+].[OH-].CO>CCOC(C)=O>[C:37]([O:36][C:34]([NH:33][C:31](=[NH:32])[C:29]1[S:28][C:27]([S:41][CH3:42])=[C:26]([S:23]([C:19]2[CH:18]=[C:17]([C:11]3[C:12]([CH3:16])=[CH:13][CH:14]=[CH:15][C:10]=3[NH:9][C:8]([CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:44])=[O:2])=[O:43])[CH:22]=[CH:21][CH:20]=2)(=[O:25])=[O:24])[CH:30]=1)=[O:35])([CH3:40])([CH3:38])[CH3:39]
Reactant: COC(=O)CCCCC(=O)Nc1cccc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)CCCCC(=O)O)c1
Temperature: 60 °C

Procedure:
5-{3′-[5-(tert-Butoxycarbonylamino-imino-methyl)-2-methylsulfanyl-thiophene-3-sulfonyl]-6-methyl-biphenyl-2-ylcarbamoyl}-pentanoic acid methyl ester (125 mg, 0.19 mmol, Example 137: step a) and LiOH (12.5 mg, 0.54 mmol) were dissolved into MeOH (3 mL) and heated to 60° C. for 12 hours. The reaction was dissolved into EtOAc and washed with 20% citric acid. The aqueous layers were acidified with acetic acid (pH 3) and extracted with EtOAc. The organic layers were combined and dried (MgSO4) followed by removal of solvents in vacuo. The resulting material was purified by preparative RP-HPLC (0–100% water/acetonitrile—both solvents were free of TFA, 45 minutes, λ=245 nm). 1H-NMR (CDCl3): δ 7.95–7.93 (d, 1H, J=9.3 Hz), 7.81–7.78 (d, 1H, J=7.91 Hz), 7.63–7.59 (m, 1H), 7.55–7.53 (t, 1H, J=8.35, Hz, J=7.59 Hz), 7.38–7.36 (d, 1H, J=9.35 Hz), 7.25–7.21 (m, 1H), 7.07–7.05 (d, 1H, J=7.07 Hz), 6.78 (s, 1H), 3.55 (s, 2H), 2.51 (s, 3H), 2.15–2.12 (m, 2H), 1.96–1.95 (m, 2H), 1.93 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[C:8]#[N:9].[S-2:12].[Na+].[Na+]>C(O)(C)(C)C.CC(O)C>[CH3:10][C:6]1[C:5]([CH3:11])=[N:4][NH:3][C:2](=[S:12])[C:7]=1[C:8]#[N:9]
Reactant: Cc1nnc(Cl)c(C#N)c1C
Reactant: [S-2]
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: CC(C)O
Product: Cc1n[nH]c(=S)c(C#N)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-5,6-dimethylpyridazine-4-carbonitrile (100 mg, 0.60 mmol) and sodium sulfide was stirred in tert-butanol (2.0 mL) in a microwave reaction vial. The vial was sealed and irradiated at 100° C. for 10 minutes. LC/MS indicated product and no remaining starting material. The reaction solution was diluted with IPA (˜10 mL) and stirred at ambient temperature for about 15 minutes, then filtered. The solids on the filter were washed with IPA. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.24 min., m/z=166 [M+H]+.
Reaction SMILES: [NH:1]1[C@H:5]([C:6]([OH:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[OH-].[CH2:11]([P+:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH3:14]>>[NH:1]1[C@H:5]([C:6]([O-:8])=[O:7])[CH2:4][CH2:3][C:2]1=[O:9].[CH2:24]([P+:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:25][CH2:26][CH3:27]
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [OH-]
Product: O=C1CC[C@@H](C(=O)[O-])N1
Reaction time: 0.17 h
Yield: 105.5 %

Procedure:
At 0° C., 4.2 g of (S)-(−)-2-pyrrolidone-5-carboxylic acid (by Wako Pure Chemical Industry) was added to 21.3 g of tetrabutylphosphonium hydroxide (aqueous 41.4% solution, by Hokko Chemical), and stirred for 10 minutes. Using an evaporator, the pressure was reduced to 40 to 50 mmHg, and this was concentrated at 60 to 80° C. for 2 hours, and then at 90° C. for 3 hours. Thus, 13.3 g of tetrabutylphosphonium (S)-(−)-2-pyrrolidone-5-carboxylate (purity: 94.1%) was obtained as an oily compound. The obtained ionic liquid had the same properties as in Production Example 1.
Reaction SMILES: C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15]O)[N:10]=[CH:9]2)C=CC=CC=1.[OH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:32][CH:31]=1>>[NH:8]1[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][O:29][C:30]2[CH:31]=[CH:32][C:33]([C:36]([CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42]3)=[O:37])=[CH:34][CH:35]=2)[N:10]=[CH:9]1
Reactant: O=C(c1ccc(O)cc1)C1CCCC1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: O=C(c1ccc(OCCCc2c[nH]cn2)cc1)C1CCCC1

Procedure:
5 mmol of 3-(1-triphenylmethyl-1H-imidazol-4-yl)propanol and 6 mmol of cyclopentyl 4-hydroxyphenyl ketone are treated as described in Example 76.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([NH:18][NH2:19])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22].[Cl:23][CH2:24][C:25](OC(=O)CCl)=O.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CN(C)C=O.CCOCC>[Cl:1][C:2]1[C:7]2[C:8](=[O:21])[N:9]([CH3:20])[CH2:10][C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[O:17][C:25]([CH2:24][Cl:23])=[N:19][N:18]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[F:22]
Reactant: CN1Cc2c(C(=O)NN)ncn2-c2ccc(F)c(Cl)c2C1=O
Reactant: O=C(CCl)OC(=O)CCl
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN1Cc2c(-c3nnc(CCl)o3)ncn2-c2ccc(F)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.8 %

Procedure:
A suspension of 0.50 g (0.00154 mol) of 7-chloro-8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a ][1,4]benzodiazepine-3-carboxylic acid hydrazide in 5 ml of N,N-dimethylformamide was treated with 0.33 g (0.00193 mol) of chloroacetic anhydride. The solution obtained was stirred at room temperature for 11/2 hr., whereby a suspension resulted. The suspension was cooled to 0°, treated with 40 ml of ether and suction filtered. The white crystals obtained (0.643 g, m.p. 264°-266° (dec.)) were treated with 4.5 ml of methanesulphonic acid and 0.5 g of phosphorus pentoxide, whereupon the mixture warmed up and the solution was stirred at room temperature for 1 hr. The yellow solution was poured into 75 ml of ice-water, whereupon the mixture was made basic with aqueous sodium hydroxide solution and extracted with methylene chloride. The crystalline product was chromatographed over silica gel with ethyl acetate as the eluent. There was obtained 0.193 g (33%) of 7-chloro-3-(5-chloromethyl-1,3,4-oxadiazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. :234°-236°.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[NH:18][CH2:19][C:20]([OH:22])=[O:21])[C:9]2=[O:23])[CH2:6][CH2:5][C:4](=[O:24])[NH:3]1.CI.[C:27](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:27][O:21][C:20](=[O:22])[CH2:19][NH:18][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:16](=[O:17])[N:8]([CH:7]1[CH2:6][CH2:5][C:4](=[O:24])[NH:3][C:2]1=[O:1])[C:9]2=[O:23]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)CNc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
To a stirred solution of [2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylamino]acetic acid (0.66 g, 2.0 mmol) in DMF (20 mL), were added methyl iodide (0.34 g, 2.4 mmol) and potassium carbonate (0.33 g, 2.4 mmol). The mixture was stirred overnight at room temperature. The solvent was evaporated in vacuo, giving a yellow oil. The oil was dissolved in CH2Cl2 (100 mL), washed with sat. aq. sodium bicarbonate (100 mL), water (100 mL) and brine (100 mL), and dried (MgSO4). The solvent was evaporated in vacuo to give a yellow solid. This material was triturated with diethyl ether and then filtered, and the resulting solid was chromatographed, eluting with 9:1 methylene chloride-ethyl acetate. The resulting solid was triturated in 1:1 ethyl ether-water, filtered, and dried under high vacuum, providing 0.42 g (61%) of the product as a yellow solid: mp 210-212° C.; 1H NMR (DMSO-d6) δ 2.03-2.07 (m, 1H), 2.47-2.63 (m, 2H), 2.96-2.83 (m, 1H), 3.69 (s, 3H), 4.23 (d, J=6.0 Hz, 2H), 5.08 (dd, J=12.4 Hz, J=5.2 Hz, 1H), 6.91-7.11 (m, 3H), 7.61 (t, J=7.7 Hz, 1H), 11.12 (s, 1H); 13C NMR (DMSO-d6) δ 22.10, 30.96, 43.62, 48.51, 51.90, 109.76, 111.22, 117.65, 132.01, 136.09, 145.76, 167.21, 168.70, 170.12, 170.65, 172.77; Anal. calcd. for C16H15N3O6: C, 55.65; H, 4.38; N, 12.17. Found: C, 55.64; H, 4.28; N, 11.98.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([CH:11]([CH3:13])[CH3:12])=[C:4]([Br:14])[C:3]=1[OH:15].CO[CH2:18][Cl:19]>C(=S)=S>[Br:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH2:18][Cl:19])[C:5]([CH:11]([CH3:13])[CH3:12])=[C:4]([Br:14])[C:3]=1[OH:15]
Reactant: CC(C)c1cc(C(C)C)c(Br)c(O)c1Br
Reactant: COCCl
Solvent: S=C=S
Product: CC(C)c1c(Br)c(O)c(Br)c(C(C)C)c1CCl

Procedure:
Three hundred thirty-six parts of 2,6-dibromo-3,5-diisopropylphenol [prepared as described in Canad, J. Chem., Vol. 41, p. 1653 (1963)] is allowed to react with 130 parts of chloromethyl methyl ether and 80 parts of stannic chloride in 400 parts of carbon disulfide under general conditions set forth in "Organic Reactions", Vol. 1, p. 68 and 69. The reaction mixture is poured on ice, and the organic layer is separated and dried over anhydrous calcium sulfate. The solvent is allowed to evaporate and the residue is crystallized to give a pure sample of the title compound. Chloromethylation of the following monohalo- or dihalodialkylphenols gives the corresponding chloromethyl derivatives.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)[O:12][C:13]=2[CH3:14])=[C:5]([O:22][CH3:23])[CH:4]=1.[OH:24]/[N:25]=[C:26](/[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)\[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30].[H-].[Na+].Cl>CN(C)C=O.O>[O:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:6]2[CH:20]=[CH:21][C:3]([CH2:2][O:24]/[N:25]=[C:26](/[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)\[CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:4][C:5]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: COC(=O)CC/C(=N\O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CC/C(=N\OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)c1ccccc1
Reaction time: 1 h
Yield: 64.1 %

Procedure:
To a stirred solution of 4-(4-chloromethyl-2-methoxyphenoxymethyl)-2-(2-furyl)-5-methyloxazole (1.65 g) and methyl E-4-hydroxyimino-4-phenylbutyrate (1.04 g) in N,N-dimethylformamide (20 ml) was added sodium hydride (60% in oil, 200 mg) at 0° C. After stirring for 1 hour, the reaction mixture was poured into water, neutralized with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel. Elution with ethyl acetate-hexane (1:4, v/v) gave methyl E-4-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxybenzyloxyimino]-4-phenylbutyrate (1.60 g, yield 64%) as crystals. Recrystallization from ethyl acetate-hexane gave pale yellow prisms. m.p. 67-69° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[CH:16]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:17][CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35].Cl>O>[CH3:33][S:34]([O:19][CH2:18][CH2:17][CH:16]([C:10]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=[O:36])=[O:35]
Reactant: OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCC(c1ccccc1)c1cc(Br)ccc1OCc1ccccc1
Reaction time: 0.5 h

Procedure:
500 ml MDC was added in the residue of 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropan-1-ol of formula (C) followed by the addition of 50.1 g triethyl amine at 25° C. to 35° C. Reaction mass was cooled to 20° C. to 25° C. followed by the addition of 48.96 g methane sulphonyl chloride. Temperature was raised to 25° C. to 30° C. and maintained for 30 minutes. Further, 300 ml water was added and reaction mass was cooled to 0° C. to 5° C. and pH adjusted to 2 to 3 using 20% hydrochloric acid solution. The reaction temperature was raised to 25° C. to 35° C. and stirred for 30 minutes. The layers were separated and to the MDC layer added 5 g of activated charcoal and stirred for 30 minutes. MDC was distilled out under vacuum below 50° C. and co-distil by 2×50 ml methanol. The residue was treated with 300 ml methanol and heated up to 60° C. to 65° C. and maintained for 1 hour. Further, reaction mass was cooled to 25° C. to 35° C. and further cooled to 0° C. to 5° C. Finally the product was washed with 2×50 ml chilled methanol and dried in hot air oven at 55° C. to 60° C. to afford the title compound 3-(2-(benzyloxy)-5-bromophenyl)-3-phenylpropyl methanesulfonate of formula (D).
Reaction SMILES: [C:1]([O:4][NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])(=[O:3])[CH3:2].[H-].[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[S:24](Cl)(=[O:26])=[O:25]>>[C:1]([O:4][N:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])[S:24]([C:16]1[O:15][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=1)(=[O:25])=[O:26])(=[O:3])[CH3:2]
Reactant: CC(=O)ONC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: [H-]
Agent: [Na+]
Product: CC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1cc2ccccc2o1

Procedure:
N-[(tert-Butoxy)carbonyl]1-benzofuran-2-sulfonamido acetate (105) is prepared from [(tert-butoxy)carbonyl]amino acetate, sodium hydride and 1-benzofuran-2-sulfonyl chloride according to Scheme 2. δH (250 MHz, DMF) 8.07 (1H, d, 0.9 Hz), 7.91 (1H, d, 7.3 Hz), 7.82 (1H, dd, 8.5, 0.8 Hz), 7.64 (1H, td, 7.8, 1.4 Hz), 7.41-7.52 (1H, m), 2.32 (3H, s), 1.37 (9H, s).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[F:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][C:2]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])=[CH:18][C:17]=1[NH:23][C:24](=[O:36])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:33])[F:34])[CH:27]=1
Reactant: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(O)ccc1F
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(NC(=O)Cc2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
To a solution of methyl 2-fluoro-5-nitrobenzoate (1.65 g, 8.29 mmol) and N-(2-fluoro-5-hydroxyphenyl)-2-[3-(trifluoromethyl)phenyl]acetamide (2.60 g, 8.30 mmol) produced in Example 53(i) in N,N-dimethylformamide (17 mL) was added potassium carbonate (1.72 g, 12.5 mmol), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (90 mL), washed successively with water (2×90 mL) and saturated brine (90 ml), and dried over anhydrous magnesium sulfate. Insoluble material was filtered off. The obtained organic layer was purified by basic silica gel column chromatography (eluate: ethyl acetate), and the obtained solution was concentrated under reduced pressure to give the title compound (3.78 g, 93%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][O:22][CH2:23][C:24]1[N:25]=[CH:26][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH:28]=1)=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)n1cnc(CON)c1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1cnc(CONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (10.0 mL) was added tert-butyl 4-[(aminooxy)methyl]-1H-imidazole-1-carboxylate 122 (0.289 g, 1.358 mmol), 1-hydroxybenzotriazole (0.183 g, 1.358 mmol) and 1-ethyl-(3-dimethylaminapropyl) carbodiimide hydrochloride (0.260 g, 1.358 mmol) sequentially at room temperature. The mixture was stirred at room temperature overnight, diluted with DCM and concentrated to provide a residue which was subjected to chromatography to give 123 (0.40 g, 94%) as a colorless oil.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].C([Li])CCC.[CH3:12][C:13]([CH3:24])([C:15](=[O:23])[CH:16]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[CH3:17])[CH3:14]>C1COCC1>[CH3:24][C:13]([CH3:12])([C:15]([CH:16]([N:18]1[CH:22]=[CH:21][N:20]=[CH:19]1)[CH3:17])([OH:23])[C:1]#[C:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:14]
Reactant: CC(C(=O)C(C)(C)C)n1ccnc1
Reactant: C#CCCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC#CC(O)(C(C)n1ccnc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.7 %

Procedure:
To a stirred solution of hex-1-yne (0.61 g, 7.5 mmol) in dry THF (30 ml) was added n-butyl lithium (3 ml of 2.6M, 7.5 mmol) at -78° C. under a nitrogen atmosphere. After 15 minutes, a solution of 2,2-dimethyl-4-(1H-imidazol-1-yl)-pentan-3-one (1.26 g, 7 mmol) in dry THF (30 ml) was added dropwise. Upon complete addition the mixture was allowed to warm to room temperature and stirred for 18 hours. The reaction mixture was then poured onto ice and extracted with ether (2×250 ml). The ethereal solution was washed with saturated brine solution then dried over anhydrous magnesium sulphate and the solvent removed. The resulting yellow oil was chromatographed (silica gel, petrol/diethyl ether elution) to give the product as a white solid (1.39 g, 76%), mp. 57-59% (Found C, 72.2; H, 10.1; N, 10.8. C16H26N2O requires C 73.3; H, 9.9; N, 10.7%); IR 2950, 1460, 1360, 1270, 1220, 1080 980, 920, 810, 730, 660 cm-1.
Reaction SMILES: C1([C@@H:4]([C:23]2[CH:28]=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[N:5]2[CH2:10][CH2:9][C@:8]([CH2:17][C:18]([OH:21])(C)C)(C3C=CC=CC=3)OC2=O)CC1.Br[C:39]1[CH:44]=[CH:43][C:42]([C@H:45]([CH:64]2[CH2:66][CH2:65]2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])=[CH:41][CH:40]=1.BrC1C=CN(C2CC2)C(=O)C=1>>[CH:64]1([C@@H:45]([C:42]2[CH:43]=[CH:44][C:39]([C:8]3[CH:9]=[CH:10][N:5]([CH:4]4[CH2:23][CH2:28]4)[C:18](=[O:21])[CH:17]=3)=[CH:40][CH:41]=2)[N:46]2[CH2:51][CH2:50][C@:49]([CH2:58][C:59]([OH:62])([CH3:61])[CH3:60])([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)[O:48][C:47]2=[O:63])[CH2:66][CH2:65]1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C2CC2)C(=O)O1
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(Br)cc2)C2CC2)C(=O)O1
Agent: O=c1cc(Br)ccn1C1CC1
Product: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H](c2ccc(-c3ccn(C4CC4)c(=O)c3)cc2)C2CC2)C(=O)O1

Procedure:
The title compound was prepared from 3-{(S)-cyclopropyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methyl}-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one {prepared in analogy to the intermediate in Example 3 from 3-[(S)-(4-bromo-phenyl)-cyclopropyl-methyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one} and 4-bromo-1-cyclopropyl-1H-pyridin-2-one following a procedure analogous to that described in Example 3. LC-MS (Method 1): tR=3.49 min; Mass spectrum (ESI+): m/z=513 [M+H]+.