Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC)(=O)CCCCC.C[O-].[Na+].[C]=O.[CH3:15][O:16][C:17](=[O:25])[CH:18]([CH:23]=[O:24])[CH2:19][CH2:20][CH2:21][CH3:22].[Cl:26][CH2:27][CH2:28][CH2:29][CH2:30]Br>CC(N(C)C)=O.CO>[CH3:15][O:16][C:17](=[O:25])[C:18]([CH2:19][CH2:20][CH2:21][CH3:22])=[CH:23][O:24][CH2:30][CH2:29][CH2:28][CH2:27][Cl:26]
Reactant: ClCCCCBr
Reactant: CCCCC(C=O)C(=O)OC
Agent: C[O-]
Agent: [C]=O
Agent: [Na+]
Solvent: CCCCCC(=O)OC
Solvent: CC(=O)N(C)C
Solvent: CO
Product: CCCCC(=COCCCCCl)C(=O)OC
Reaction time: 5 h
Yield: 60 %

Procedure:
162.5 g Methyl caproate (1.25 mole), 28 g 96% sodium methylate (0.5 mole), and 10 ml methanol were reacted with carbon monoxide in the manner described in Example 4, and approximately 100 g crude sodium enolate of 2-formylcaproic acid methyl ester was obtained as an evaporation residue. It was suspended in 180 ml dimethylacetamide and mixed with 103 g 4-chlorobutyl bromide. The mixture was stirred about 4-6 hours at 65°-70° C., and worked up in a manner analogous to the procedure of Example 5. 74.5 g 3-(4-chlorobutoxy)-2-butyl-acrylic acid methyl ester boiling at 155° C./2 torr was obtained for a 60% yield based on the sodium methylate employed.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH:14]([CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1>C(O)C>[ClH:3].[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[CH:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:19][CH:20]=1)([OH:26])=[O:25]
Reactant: CCOC(=O)c1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cl
Product: O=C(O)c1ccc(NC(=O)C(COc2cccnc2)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2N NaOH (143 μl) was added to a solution of (RS)-2-(4-chlorobenzenesulfonylamino)-N-(4-ethoxycarbonylphenyl)-3-(pyridin-3-yloxy)propanamide (48.1 mg) in ethanol (5 ml), and the whole was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. A small amount of purified water was added to the residue, and the mixture was concentrated under reduced pressured. The concentration step was repeated 3 times to remove ethanol. The residue was dissolved in 1N HCl (20 ml), diluted with water (20 ml), and then washed 3 times with ethyl acetate (10 ml). The aqueous layer was concentrated under reduced pressure. A small amount of purified water was added, and the mixture was concentrated under reduced pressure. The concentrating step was repeated 3 times to evaporate excess HCl. The residue was dried under reduced pressure in a desiccator, and ethanol was added. The insoluble materials were removed by filtration. The combined filtrates were concentrated and dried under reduced pressure to obtain (RS)-N-(4-carboxyphenyl)-2-(4-chlorobenzenesulfonylamino)-3-(pyridin-3-yloxy)propanamide hydrochloride (21.8 mg).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@H:12]2[O:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13]2[O:30][C:31](=[O:33])[CH3:32])(=O)=O)=CC=1.CC(C)=O.[I-:39].[Na+]>O>[I:39][CH2:11][C@H:12]1[O:21][C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:15]([O:22][C:23](=[O:25])[CH3:24])[C@@H:14]([O:26][C:27](=[O:29])[CH3:28])[C@@H:13]1[O:30][C:31](=[O:33])[CH3:32]
Reactant: CC(=O)O[C@@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)O[C@@H]1O[C@H](CI)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
6-O-(p-Toluenesulfonyl)-1,2,3,4-tetra-O-acetyl-β-D-glucose (5, 18.5 g, 36.8 mmol) was place in a 500-mL round-bottomed flask. Acetone (200 ml) and sodium iodide (18.5 g, 123 mmol) were added. The resulting mixture was heated at reflux for 20 h. The reaction proceeded gradually. The mixture was poured into 1000 ml of water, and the resulting solid was filtered with a glass filter. Recrystalization from ethanol afforded 6-deoxy-6-iodo-1,2,3,4-tetra-O-acetyl-β-D-glucose (compound 6) in 65% yield (11.0 g, 24.0 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([OH:21])=O)=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[CH:43]([O:45][CH2:46][CH2:47][O:48][NH2:49])=[CH2:44]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:19]([NH:49][O:48][CH2:47][CH2:46][O:45][CH:43]=[CH2:44])=[O:21])=[N:12][N:13]([CH3:18])[C:14](=[O:17])[C:15]=1[CH3:16]
Reactant: C=COCCON
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)nn(C)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=COCCONC(=O)c1nn(C)c(=O)c(C)c1Nc1ccc(I)cc1F
Reaction time: 1.5 h

Procedure:
To a suspension of 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 mL) was added EDCI (40 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours. O-(2-Vinyloxy-ethyl)-hydroxylamine (21 mg, 0.20 mmol) and TEA (0.030 mL, 0.22 mmol) was added to the activated ester at room temperature. After stirring for 1.5 hours, the reaction mixture was diluted with EtOAc and washed with saturated aqueous NH4Cl, brine, saturated aqueous NaHCO3 (2×), and brine. The organic layer was separated, dried over MgSO4, filtered, and concentrated under reduced pressure to give 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy) 1,6-dihydropyridazine-3-carboxamide that was used directly without further purification. The title compound was prepared by the procedure previously described in Example 1 (step J) using the crude 4-(2-fluoro-4-iodophenylamino)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridazine-3-carboxamide (40% yield over two steps). MS APCI (−) m/z 461 (M−1) detected; 1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].C(Cl)Cl.[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH2:22])=[N:11]1>N1C=CC=CC=1>[CH3:9][N:10]1[C:14]2[C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[S:17][C:13]=2[C:12]([NH:22][C:1](=[O:4])[CH2:2][CH3:3])=[N:11]1
Reactant: CCC(=O)Cl
Reactant: Cn1nc(N)c2sc3ccccc3c21
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)Nc1nn(C)c2c1sc1ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 1.8 g. of propionyl chloride in 10 ml. of methylene chloride was added to a stirred solution of 0.01 mole of the above-referred amine in 50 ml. of methylene chloride containing 2.0 ml. of pyridine. The resulting clear solution was stirred overnight at room temperature and then washed with water, 5% aqueous hydrochloric acid, water, 10% aqueous sodium bicarbonate and finally with water. The upper organic layer was dried over magnesium sulfate and concentrated in vacuo to give a solid residue. This residue was recrystallized from ethanol to give N-(1-methyl-1H-(1)-benzothieno[3,2-c]pyrazol-3-yl)propanamide, m.p. 88°-89° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:23]1[CH:28]=[C:27]([SH:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([S:29][C:27]2[CH:26]=[C:25]([C:30]([CH3:31])([CH3:32])[CH3:33])[C:24]([OH:34])=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:28]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 54.6 %

Procedure:
To 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Ex. 3a, 22 g) and 2,6-di-tert-butyl-4-mercapto-phenol (16.58 g) in 300 mL of DMF was added sodium hydride (3.8 g, 60% in oil). The mixture was stirred at 60° C. for 20 h and then poured onto ice and quenched with 1 N HCl. The gooey solid obtained via filtration was dissolved in Ethyl acetate, dried over Na2SO4, and concentrated. The crude product was dissolved in a minimal amount of diethyl ether and triturated with hexanes to give 4-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-piperidine-1-carboxylic acid tert-butyl ester as an off-white solid (16 g), mp 151-152° C. 1H-NMR (400 MHz, CDCl3): δ 7.28 (s, 2H), 5.28 (s, 1H), 3.98 (s, 2H), 3.03-2.96 (m, 1H), 2.87 (t, 2H, J=10.4 Hz), 1.91-1.87 (m, 2H), 1.54-1.48 (m, 2H), 1.44 (s, 9H), 1.43 (s, 18H). HRMS (ESI) Calcd. for C24H39NO3S: 421.2651 (M+). Found: 421.2656. Anal. Calcd. for C24H39NO3S, C, 68.37; H, 9.32; N, 3.32; S, 7.60. Found: C, 68.20; H, 9.42; N, 3.23; S, 7.77.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([NH:34][C:35](=[O:47])[C:36]([NH:39]C(=O)OC(C)(C)C)([CH3:38])[CH3:37])[C:11]([N:13]1[CH2:33][CH2:32][CH2:31][C:15]2([C:19](=[O:20])[N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH:16]2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:14]1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.CO>C(Cl)Cl>[NH2:39][C:36]([CH3:38])([CH3:37])[C:35]([NH:34][C@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:11]([N:13]1[CH2:33][CH2:32][CH2:31][C:15]2([C:19](=[O:20])[N:18]([CH:21]([CH3:22])[CH3:23])[CH2:17][CH:16]2[C:24]2[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=2)[CH2:14]1)=[O:12])=[O:47]
Reactant: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)N1CC(c2ccc(F)cc2)C2(CCCN(C(=O)[C@@H](COCc3ccccc3)NC(=O)C(C)(C)N)C2)C1=O

Procedure:
A mixture comprising tert-butyl 1-((2R)-3-(benzyloxy)-1-(4-(4-fluorophenyl)-2-isopropyl-1-oxo-2,7-diazaspiro[4.5]decan-7-yl)-1-oxopropan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (378 mg, 0.579 mmol) (step 1) and TFA (0.892 ml, 11.58 mmol) in DCM (4 ml) was stirred at room temperature for 4 hours. The solvent was removed in vacuo to afford a colourless oil. The oil was dissolved with methanol (3 ml) and passed through a 10 g SCX-2 cartridge eluting with 2M NH3 in methanol (70 ml). The solvent was removed in vacuo to yield the title compound as diastereomeric mixture.
Reaction SMILES: [S:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([OH:17])=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1.P(Cl)(Cl)(Cl)(Cl)Cl.N1C=CC=[CH:26][CH:25]=1.C(O)C>C(Cl)Cl>[S:1]=[C:2]1[N:11]2[N:12]=[C:13]([C:15]([O:17][CH2:25][CH3:26])=[O:16])[CH:14]=[C:10]2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[NH:3]1
Reactant: c1ccncc1
Reactant: O=C(O)c1cc2c3ccccc3[nH]c(=S)n2n1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
1.5 g (0.006 mole) of 5,6-dihydro-5-thioxopyrazolo-[1,5-c]quinazoline-2-carboxylic acid (prepared as described in Example 1) and 1.26 g (1 equivalent) of phosphorus pentachloride are heated together in 50 ml of methylene chloride at 60° for 30 minutes. The reaction mixture is cooled and the solvent stripped off and replaced with 50 ml of dry pyridine. The solution is treated with 1.1 ml of absolute ethanol and refluxed under N2 for 2 hours.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:12]1[CH:17]=[N:16][CH:15]=[C:14]([N:18]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]2)[N:13]=1.O>CS(C)=O>[Cl:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:12]2[CH:17]=[N:16][CH:15]=[C:14]([N:18]3[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[N:19]3)[N:13]=2)=[CH:6][CH:5]=1
Reactant: Cc1cc(C)n(-c2cncc(Cl)n2)n1
Reactant: Nc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(C)n(-c2cncc(Nc3ccc(Cl)cc3)n2)n1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Sodium hydride (60% in mineral oil, 161 mg, 4.03 mmol) was added to a suspension of 4-chloroaniline (489 mg, 3.83 mmol) in dimethylsulfoxide (10 mL). The mixture was stirred at 130° C. for 5 minutes. 2-Chloro-6-(3,5-dimethyl-pyrazol-1-yl)-pyrazine was added and the resulting mixture was stirred at 130° C. for 30 minutes. Cooling, followed by addition of water gave a brown precipitate. The brown solid was collected by filtration, re-dissolved in ethyl acetate, washed with brine, dried over sodium sulphate, filtrated and evaporated. The crude product was purified by flash chromatography to give (4-chloro-phenyl)-[6-(3,5-dimethyl-pyrazol-1-yl)-pyrazin-2-yl]-amine (318 mg, 55%) as a brown solid.
Reaction SMILES: [C:1]1(=O)O[C:4](=[O:5])[CH:3]=[CH:2]1.CC(C)=O.CCC[CH2:15][CH2:16][CH2:17][CH3:18]>C1C=CC=CC=1>[CH2:4]([O:5][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCC
Reactant: O=C1C=CC(=O)O1
Solvent: c1ccccc1
Solvent: CC(C)=O
Product: CCCCOCCCC

Procedure:
Amines can be reacted with maleic anhydride to give the corresponding half-amide derivative. Generally, a polymer containing maleic anhydride is reacted in solution or suspension with an amine in an inert or non-reactive solvent, such as acetone, heptane, benzene or dibutylether, to provide the desired half-amide derivative. This material then must be isolated and repackaged into a useful product.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:8]2)=[O:4].[H-].[Na+].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=1)[C:9]([CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:8]2)=[O:4]
Reactant: FC(F)(F)Sc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2[nH]c(COc3ccccc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)cc(COc1ccccc1)n2Cc1ccc(SC(F)(F)F)cc1
Reaction time: 1.5 h

Procedure:
30 mg of 2-phenoxymethyl-1H-indole-5-carboxylic acid methyl ester were dissolved in 1 ml of THF and treated with 5 mg NaH (60%) at 0° C. for 15 min. 1.2 eq. of 1-bromomethyl-4-trifluoromethylsulfanyl-benzene were added and the reaction stirred for 1.5 h. The solvent was evaporated and the product extracted from methylenchloride/water. The product was purified by preparative HPLC. MS(ISP): 472.5 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[NH:14][C:13](=[O:18])[C:12]=2[CH:19]=1.[CH2:20]([O:22][C:23](=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]Br)[CH3:21]>CC(N(C)C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[O:16][C:15](=[O:17])[N:14]([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:32])[C:13](=[O:18])[C:12]=2[CH:19]=1
Reactant: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Reactant: CCOC(=O)CCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCCCCCCn1c(=O)oc2ccc(Cl)cc2c1=O
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 101.7 %

Procedure:
Sodium carbonate (194.0 g, 1.8 mol) was added to a 5 liter, 4-neck, round bottomed, flask containing 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (323.1 g, 1.6 mol) and dimethylacetamide (970 ml). Ethyl-8-bromooctanoate (459.0 g, 1.8 mol) was added in one portion to the stirring reaction mixture. The atmospheric pressure in the reaction vessel was reduced to 550 mm Hg and heating of the reaction mixture was started. The reaction temperature was maintained at 70° C. for approximately 5 hours before heating and vacuum were discontinued. The reaction mixture was allowed to cool to room temperature overnight. The reaction mixture was vacuum filtered and the filter cake was washed with ethyl alcohol (525 ml). Deionized water (525 ml) was slowly added to the stirred filtrate and a white solid precipitated. An ice/water bath was placed around the reaction vessel and the slurry was cooled to 5° C. After stirring at this temperature for approximately 15 minutes the solids were recovered by vacuum filtration and the filter cake was washed first with ethanol (300 ml) and then with heptane (400 ml). After drying overnight at room temperature in vacuo, 598.4 g (99.5%) of ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate was obtained. An additional 66.6 g of ethyl 8-(6-chloro-2H-1,3-benzoxazine-2,4(3H)-dionyl)octanoate was made by this same method.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14](=[O:18])[C:15]([OH:17])=O)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:52]1([CH2:57][C@H:58]2[NH:61][C:60](=[O:62])[C@H:59]2[NH2:63])[CH:56]=[N:55][CH:54]=[N:53]1>C(Cl)Cl.CN(C=O)C.CN(C=O)C>[N:52]1([CH2:57][C@@H:58]2[C@H:59]([NH:63][C:15](=[O:17])[C:14]([C:12]3[N:13]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[S:10][CH:11]=3)=[O:18])[C:60](=[O:62])[NH:61]2)[CH:56]=[N:55][CH:54]=[N:53]1
Reactant: N[C@@H]1C(=O)N[C@@H]1Cn1cncn1
Reactant: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(C(=O)C(=O)N[C@@H]2C(=O)N[C@@H]2Cn2cncn2)cs1
Reaction time: 48 h
Yield: 67.8 %

Procedure:
To a slurry of 2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-oxoacetic acid (2.72 g, 9.99 mmol) and HATU (3.80, 10.0 mmol) in DCM:DMF (3:1, 33.3 mL) at 0° C. was added DIPEA (2.91 mL, 16.7 mmol). A soln of (3S,4R)-4-((1H-1,2,4-triazol-1-yl)methyl)-3-aminoazetidin-2-one (1.39 g, 8.33 mmol) in DCM:DMF (1:1, 32 mL) was added followed by a DMF (3 mL) wash. After stirring for 48 h the dark solution was diluted with EtOAc (150 mL)/brine (140 mL) and the layers were separated. The aqueous was extracted with EtOAc (3×) and the combined organic layers were washed with brine (70 mL). The brine layer wash was re-extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concd in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), affording the title compound (2.38 g, 68%) as a red solid. LCMS: Rt=0.59 min, m/z=422.0 (M+1) Method 2m_acidic; 1H NMR (400 MHz, DMSO-d6) δ 11.85 (s, 1H), 9.70 (d, J=9.3 Hz, 1H), 8.52 (d, J=1.6 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 5.28 (ddd, J=9.3, 5.2, 1.5 Hz, 1H), 4.45 (dd, J=14.2, 5.3 Hz, 1H), 4.36 (dd, J=14.1, 7.6 Hz, 1H), 4.18 (dt, J=7.6, 5.3 Hz, 1H), 1.47 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[N:3]=1.[CH3:20][C:21]([S-:24])([CH3:23])[CH3:22].[Na+].C(O)CO.O>CN1CCCC1=O.[Cu]I>[C:21]([S:24][C:16]1[CH:17]=[CH:18][C:13]([N:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]2=[O:12])=[CH:14][CH:15]=1)([CH3:23])([CH3:22])[CH3:20]
Reactant: O=c1c2ccccc2c(O)nn1-c1ccc(I)cc1
Reactant: CC(C)(C)[S-]
Agent: [Cu]I
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Solvent: OCCO
Product: CC(C)(C)Sc1ccc(-n2[nH]c(=O)c3ccccc3c2=O)cc1
Temperature: 150 °C
Reaction time: 96 h

Procedure:
4-Hydroxy-2-(4-iodo-phenyl)-2H-phthalazin-1-one (see Method Q) (0.30 g, 0.8 mmol), sodium 2-methyl-propane-2-thiolate (0.094 g, 0.8 mmol), CuI (0.011 g, 0.06 mmol) and ethylene glycol (0.10 g, 1.6 mmol) were dissolved in N-methyl-pyrrolidinone (NMP) (0.5 ml) under argon and heated to 150° C. Stirring at this temperature was continued for 4 d before the mixture was allowed to warm to RT. H2O (50 ml) was added and the precipitated solid was collected by filtration. The title compound was obtained after purification of the raw product by chromatography over silica gel with DCM (0.21 g, 78%). 1H-NMR: (400 MHz, D6-DMSO) 12.35 (1H, s), 8.73 (1H, d), 8.33-8.41 (3H, m), 8.14 (2H, d), 8.01 (2H, d), 1.70 (9H, s); MS (ESI+)=327.14 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:20][CH:19]=1)[CH:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)C(O)=O.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C([N:50]([CH2:53]C)CC)C.[OH2:55]>O1CCCC1>[O:24]([C:21]1[CH:20]=[CH:19][C:18]([CH:2]2[O:1][C:53](=[O:55])[NH:50][CH:3]2[CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:17])[F:16])=[CH:10][CH:9]=2)=[CH:23][CH:22]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Oc2ccccc2)cc1
Reactant: O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2ccc(C(F)(F)F)cc2)C(c2ccc(Oc3ccccc3)cc2)O1
Yield: 92 %

Procedure:
To a solution of (2RS,3RS)-3-hydroxy-3-(4-phenoxyphenyl)-2-((4-(trifluoromethyl)phenyl)methyl)propionic acid (7.0 g, 16.8 mmol) in tetrahydrofuran (180 ml) were added diphenylphosphoryl azide (4.0 ml,18.5 mmol) and triethylamine (3.5 ml, 25.2 mmol), and the mixture was heated under reflux for 6 hrs. The reaction solution was allowed to cool and water (200 ml) was added. The mixture was extracted with ethyl acetate (200 ml×2). The extract was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel-column chromatography (ethyl acetate) and recrystallized from ethyl acetate-hexane to give (4RS,5SR)-5-(4-phenoxyphenyl)-4-((4-(trifluoromethyl)phenyl)methyl)-1,3-oxazolidin-2-one (6.40 g, 92%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:33])[C:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:10][O:11][CH2:12][CH2:13][NH:14]C(OCC1C=CC=CC=1)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.C(Cl)(Cl)Cl.[Pd]>[C:1]([O:5][C:6]([N:8]([CH3:33])[C:9]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[N:10][O:11][CH2:12][CH2:13][NH2:14])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C(=O)OC(C)(C)C)C(=NOCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C(=NOCCN)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
A mixture of [N,N'-di(tert-butoxycarbonyl)] 2-(benzyloxycarbonylamino)ethoxy-N-methylguanidine (700 mg, 1.5 mmol), as prepared in the preceding step, 10% Pd/C (70 mg) in methanol (20 mL) and chloroform (5 mL) was hydrogenated under hydrogen (balloon) for 1 h. The catalyst was removed by filtration through Celite, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (95:5 methylene chloride:methanol saturated with ammonia) to give the title compound as a colorless foam (250 mg, 50%). 1H-NMR (300 MHz, CDCl3) δ 4.14 (t, J=5.0 Hz, 2H), 3.09 (s, 3H), 3.06 (q, J=5.0 Hz, 2H), 1.50 (s, 9H), 1.46 (s, 9H).