Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][C:11]1[CH:24]=[CH:23][C:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[OH:22])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O[C@@H:29]1[O:46][C@H:45]([CH2:47][O:48]C(=O)C)[C@@H:40]([O:41]C(=O)C)[C@H:35]([O:36]C(=O)C)[C@H:30]1[O:31]C(=O)C)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.ClCCl>[O:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:24][CH:23]=1)[C@@H:29]1[O:46][C@H:45]([CH2:47][OH:48])[C@@H:40]([OH:41])[C@H:35]([OH:36])[C@H:30]1[OH:31]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: Oc1ccccc1Cc1ccc(CCOCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: OC[C@H]1O[C@@H](Oc2ccccc2Cc2ccc(CCOCc3ccccc3)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 70.4 %

Procedure:
To a solution of 2-[4-(2-benzyloxyethyl)benzyl]phenol (3.2 g) and 1,2,3,4,6-penta-O-acetyl-β-D-glucopyranose (12 g) in toluene (34 mL) and dichloromethane (17 mL) was added boron trifluoride diethyl-ether complex (3.8 mL), and the mixture was stirred at room temperature for 14 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was dissolved in methanol (50 mL), sodium methoxide (28% methanol solution, 0.39 mL) was added to the solution, and the mixture was stirred at room temperature for 2.5 hours. The solvent of the reaction mixture was removed under reduced pressure, water was added to the residue, and the resulting mixture was extracted with ethylacetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 2-[4-(2-benzyloxyethyl)benzyl]phenyl β-D-glucopyranoside (3.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH:36]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:25][C@H:24]([CH2:26][O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@@H:22]([OH:23])[C@@:20]4([CH3:35])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:56](Cl)(=[O:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]([CH:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)[C:10]2[C:11]3[CH:18]=[CH:17][N:16]([C@@H:19]4[O:25][C@H:24]([CH2:26][O:27][Si:28]([C:31]([CH3:32])([CH3:33])[CH3:34])([CH3:30])[CH3:29])[C@@H:22]([O:23][C:56](=[O:64])[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[C@@:20]4([CH3:35])[OH:21])[C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N(c2ncnc3c2ccn3[C@@H]2O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@@]2(C)O)C(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)O[C@@H]1[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H](n2ccc3c(N(c4ccc(OC)cc4)C(c4ccccc4)c4ccccc4)ncnc32)[C@]1(C)O
Reaction time: 1.5 h
Yield: 71.5 %

Procedure:
To a solution of the compound from Step H (400 mg, 0.6 mmol) and anhydrous DMAP (73 mg, 0.6 mmol) in anhydrous CH2Cl2 (7 mL) was added slowly triethylamine (250 μL, 1.8 mmol). To the stirred solution was added octanoyl chloride (200 μL, 1.2 mmol) over 15 min. The reaction mixture was stirred for an additional 1.5 h. It was then diluted with methylene chloride (30 mL) and washed with saturated aqueous sodium bicarbonate solution (3×10 mL) and water (10 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated. The residue was subjected to column chromatography on silica gel eluting with 5% MeOH in CH2Cl2 to afford the title compound as a light yellow foam (340 mg).
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]2[NH:15][C:14](=O)[CH2:13][CH2:12][C:11]2=[N:17]O)[CH:7]=[CH:8][CH:9]=1.Cl.[OH-].[Na+]>O1CCCC1.CO.[Cl-].[Zr+4].[Cl-].[Cl-].[Cl-]>[Br:3][C:4]1[CH:5]=[C:6]([C@H:10]2[C@@H:11]([NH2:17])[CH2:12][CH2:13][CH2:14][NH:15]2)[CH:7]=[CH:8][CH:9]=1
Reactant: O=C1CCC(=NO)C(c2cccc(Br)c2)N1
Agent: [Zr+4]
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CO
Product: N[C@H]1CCCN[C@H]1c1cccc(Br)c1
Temperature: 25 °C

Procedure:
Dry tetrahydrofuran (100 ml) was added to a flask containing zirconium (IV) chloride (6.17 g) cooled to 0° under nitrogen. Sodium borohydride (4.0 g) was added and the mixture stirred as it warmed to room temperature over 15 mins. A suspension of 6-(3-bromo-phenyl)-piperidine-2,5-dione 5-oxime (×g) in dry tetrahydrofuran (50 ml) was added dropwise and the mixture was stirred at room temperature for 18 h. Concentrated hydrochloric acid (10 ml) in methanol (60 ml) was cautiously added and the mixture was heated to reflux for 3 h. The mixture was evaporated in vacuo and the residue was partitioned between 0.88 ammonia (40 ml) in water (200 ml) and chloroform (100 ml). The aqueous phase was extracted with chloroform (100 ml×3). The combined organic extracts were dried (Na2SO4) and evaporated to an oil. This was dissolved in ethanol (50 ml) and acidified by adding ethereal hydrogen chloride. The solution was evaporated and the residue recrystallised from i-propanol-hexane to give a white solid. The solid was treated with 2N sodium hydroxide solution (200 ml) and extracted with dichloromethane (200 ml×3). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound as a yellow-brown oil (1.10 g). T.l.c. (Dichloromethane/ethanol/ammonia (91:8:1)) Rf 0.51.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]([S:16]([C:19]1[CH:28]=[C:27]2[C:22]([C:23]([Cl:33])=[CH:24][N:25]=[C:26]2[NH:29][C:30]([NH2:32])=[NH:31])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)(C)C.C(Cl)Cl.[C:38]([C:42]([OH:44])=[O:43])([F:41])([F:40])[F:39]>C1(C)C=CC=CC=1>[F:39][C:38]([F:41])([F:40])[C:42]([OH:44])=[O:43].[Cl:33][C:23]1[C:22]2[C:27](=[CH:28][C:19]([S:16]([N:8]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:7][C:6]([OH:34])=[O:5])(=[O:17])=[O:18])=[CH:20][CH:21]=2)[C:26]([NH:29][C:30]([NH2:32])=[NH:31])=[N:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1ccccc1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-benzylglycine t-butyl ester (50 mg, 0.10 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was azeotroped with PhMe and then CH2Cl2 to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-benzylglycine trifluoroacetate (52 mg, 0.10 mmol) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:34]=[CH:33][C:25]([C:26]([O:28]C(C)(C)C)=O)=[CH:24][CH:23]=1.C(Cl)(=O)C(Cl)=O.[NH3:41]>ClCCl.CN(C=O)C.O1CCOCC1>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[N:5]=[CH:4][N:3]1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH2:41])=[O:28])=[CH:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Reactant: N
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: NC(=O)c1ccc(Cn2cnc3ccc(C#CCc4ccccc4)cc3c2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.1 g (0.254 mmol) of the compound of Example 18 is suspended in 50 ml of dichloromethane. 35.4 mg of oxalyl chloride (0.279 mmol) is added, followed by 1 drop of DMF. The reaction is refluxed under nitrogen for 2 hours, and stirred at room temperature for an additional 12 hours. Then an excess amount of 0.5 M ammonia in dioxane is added. The reaction is stirred at room temperature for 1 hour. The solvent is then removed in vacuum and the residue is washed with 1:1 water:methanol to yield 70 mg of an off-white powder as the desired product.
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:10]C(=O)C)[CH2:4][C:5]1[S:9][CH:8]=[N:7][CH:6]=1.[ClH:14]>>[ClH:14].[NH2:10][CH:3]([CH2:4][C:5]1[S:9][CH:8]=[N:7][CH:6]=1)[CH2:2][OH:1]
Reactant: CC(=O)NC(CO)Cc1cncs1
Agent: Cl
Product: NC(CO)Cc1cncs1

Procedure:
a solution of 0.63 g of N-[(1RS)-1-hydroxymethyl-2-(5-thiazolyl)ethyl]acetamide in 7.86 cm3 of 6N hydrochloric acid is heated to a temperature in the region of 110° C. for 3 hours. The reaction mixture is filtered, concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C., taken up in isopropyl ether, concentrated under the above conditions, taken up in 10 cm3 of isopropyl ether, filtered and dried in a desiccator under reduced pressure (0.1 kPa) at a temperature in the region of 40° C. 0.56 g of (2RS)-2-amino-3-(5-thiazolyl)-1-propanol hydrochloride is obtained in the form of a beige-colored solid melting at 192° C. [1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm): 3.21 (d, J=7 Hz: 2H); 3.35 (mt: 1H); 3.48 (dd, J=11.5 and 5.5 Hz: 1H); 3.61 (dd, J=11.5 and 4 Hz: 1H); 7.83 (broad s: 1H); 8.19 (unresolved complex: 3H); 9.10 (broad s: 1H)].
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1([CH3:30])[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]2[CH2:16][C:15]([CH2:28][OH:29])([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:14][C:13]1=2.C(N(CC)CC)C>C(Cl)Cl>[CH3:21][C:18]1([CH3:22])[CH2:19][CH2:20][C:12]([CH3:11])([CH3:30])[C:13]2[CH2:14][C:15]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH:28]=[O:29])[CH2:16][C:17]1=2
Reactant: CCCCCC1(CO)CC2=C(C1)C(C)(C)CCC2(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC1(C=O)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: -60 °C
Reaction time: 0.25 h
Yield: 97.3 %

Procedure:
2 ml of oxalyl chloride were dissolved in 100 ml of methylene chloride and treated at −70° C. dropwise with 2.8 g of dimethylsulfoxide. The reaction mixture was warmed for 5 minutes to −35° C., cooled again to −60° C. and treated dropwise with a solution of 2.9 g of (4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-inden-2-yl)-methanol in 20 ml of methylene chloride. After 15 minutes of stirring at −50° C., 5 ml of triethylamine were added dropwise. The reaction mixture was stirred at room temperature for 3 hours, then poured onto ice/water, extracted with methylene chloride, dried (Na2SO4) and the solvent was evaporated. The yellow, oily residue was purified with flash chromatography (silica gel, hexane/ethyl acetate=20:1) to yield 2.8 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carbaldehyde as colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)([CH2:16][CH2:17][CH2:18][OH:19])[O:12][C:11]2=[O:27])[CH3:9])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[CH3:35][S:36]([O:19][CH2:18][CH2:17][CH2:16][C@@:13]1([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[O:12][C:11](=[O:27])[N:10]([C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)[CH3:9])[CH2:15][CH2:14]1)(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](c1cccc(Br)c1)N1CC[C@](CCCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 29 %

Procedure:
To a solution of (R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (20 mg, 0.046 mmol) in CH2Cl2 (2 mL) was added Et3N (13 μL, 2 equiv) and MsCl (6 μL, 1.55 equiv) at 0° C. After 5 min, the mixture was warmed to rt and stirred for 1 h. The mixture was concentrated, acidified with 5% aq HCl to pH=˜6 and purified by preparative HPLC to afford 3-((R)-3-((S)-1-(3-bromophenyl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propyl methanesulfonate (6.8 mg, 29%). LC-MS (3 min) tR=1.83 min., m/z 514, 516 (M+1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[C:2]#[CH:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.O1CCCC1.C(C1C=CC=CC=1)C.[CH3:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[O:42])=[C:39]([N+:45]([O-:47])=[O:46])[CH:38]=1.[Cl-].[NH4+].C(O)(=O)C>O1CCCC1.O>[OH:42][CH:41]([C:40]1[CH:43]=[CH:44][C:37]([CH3:36])=[CH:38][C:39]=1[N+:45]([O-:47])=[O:46])[C:3]#[C:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: Cc1ccc(C=O)c([N+](=O)[O-])c1
Reactant: C#CC(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C#CC(O)c1ccc(C)cc1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 98.8 %

Procedure:
(a-2) To a solution of ethyl propiolate (1.2 ml, 12.0 mmole) in tetrahydrofuran (20 ml) was added at -65° C. under the argon atmosphere a solution of 2.0M lithium diisopropylamide in a mixed solvent of heptane-tetrahydrofuran-ethylbenzene (6.0 ml, 12.0 mole), and the mixture was stirred for 20 minutes. A solution of 4-methyl-2-nitrobenzaldehyde (1.65 g, 10 mmole) in tetrahydrofuran (10 ml) was added, and the reaction mixture was further stirred at 65° C. for 3 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution (20 ml) or a solution of acetic acid (13.0 ml, 220 mmole) in tetrahydrofuran (20 ml), followed by water, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous saline in this sequence, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give ethyl 4-hydroxy-4(4-methyl-2-nitrophenyl)-2-butynoate as an oil (2.60 g).
Reaction SMILES: OC(C(F)(F)F)=O.[C:8]([O:27][CH2:28][CH2:29][NH:30][CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].Cl.[CH3:54][N:55]([CH3:62])[CH2:56][CH2:57][CH2:58][C:59](O)=[O:60].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>C(Cl)Cl>[C:8]([O:27][CH2:28][CH2:29][N:30]([C:59](=[O:60])[CH2:58][CH2:57][CH2:56][N:55]([CH3:62])[CH3:54])[CH2:31][CH2:32][O:33][C:34](=[O:52])[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]/[CH:42]=[CH:43]\[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])(=[O:26])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN(C)CCCC(=O)O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCNCCOC(=O)CCCCCCC/C=C\CCCCCCCC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CCCN(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Synthesis of (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt previously described. (Z)-azanediylbis(ethane-2,1-diyl) dioleate TFA salt (1.00 g, 1.58 mmol) was diluted with DCM (5 mL) and added to a pre-activated mixture of 4-(Dimethylamino) butyric acid HCl salt (317 mg, 1.89 mmol), HATU (719 mg, 1.89 mmol) and DIEA (606 uL, 3.48 mmol) in DCM (5 mL). The flask was flushed with argon and the reaction mixture stirred at room temperature overnight, then concentrated. Purification by silica gel chromatography with a DCM/MeOH gradient yielded (Z)-((4-(dimethylamino)butanoyl)azanediyl)bis(ethane-2,1-diyl) dioleate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:12][O:13]/[N:14]=[C:15](/[C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)\[C:16]([OH:18])=[O:17])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[OH:8].[NH2:25][C@@H:26]1[C:33](=[O:34])[N:32]2[C@@H:27]1[S:28][CH2:29][C:30]([CH2:38][S:39][C:40]1[N:41]([CH3:48])[N:42]=[C:43]([OH:47])[C:44](=[O:46])[N:45]=1)=[C:31]2[C:35]([OH:37])=[O:36].[OH-].[Na+:50]>>[Na+:50].[Na+:50].[NH2:24][C:21]1[S:22][CH:23]=[C:19](/[C:15](=[N:14]/[O:13][CH2:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)(=[O:10])=[O:11])/[C:16]([NH:25][C@@H:26]2[C:33](=[O:34])[N:32]3[C@@H:27]2[S:28][CH2:29][C:30]([CH2:38][S:39][C:40]2[N:41]([CH3:48])[N:42]=[C:43]([OH:47])[C:44](=[O:46])[N:45]=2)=[C:31]3[C:35]([O-:37])=[O:36])=[O:18])[N:20]=1.[NH2:24][C:21]1[S:22][CH:23]=[C:19](/[C:15](=[N:14]/[O:13][CH2:12][S:9]([C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)(=[O:10])=[O:11])/[C:16]([NH:25][C@@H:26]2[C:33](=[O:34])[N:32]3[C@@H:27]2[S:28][CH2:29][C:30]([CH2:38][S:39][C:40]2[N:41]([CH3:48])[N:42]=[C:43]([OH:47])[C:44](=[O:46])[N:45]=2)=[C:31]3[C:35]([O-:37])=[O:36])=[O:17])[N:20]=1
Reactant: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Nc1nc(/C(=N/OCS(=O)(=O)c2ccc(O)c(O)c2)C(=O)O)cs1
Agent: [Na+]
Agent: [OH-]
Product: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCS(=O)(=O)c3ccc(O)c(O)c3)c3csc(N)n3)[C@H]2SC1

Procedure:
37 mg of 2-amino-4-thiazoleglyoxylic acid (Z)-O-[[(3,4-dihydroxyphenyl)-sulphonyl]methyl] oxime were reacted with 47 mg of (6R,7R)-7-amino-3-[[(2,5-dihydro-6-hydroxy-2-methyl -5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid according to the procedure described in Example 5. The product fractions obtained upon chromatography on MCI gel according to the method described in Example 1 were concentrated and the pH of solution thus obtained was adjusted to 7 with dilute sodium hydroxide solution. By lyophilization, there was obtained (6R,7R)-7-[(Z)-2-(2-amino-4-thiazolyl)-2-[[[(3,4-dihydroxyphenyl)sulphonyl]methoxy]imino]acetamido]-3-[[(2,5-dihydro-6-hydroxy-2-methyl-5-oxo-as-triazin-3-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid disodium salt as a pale yellow powder.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][NH2:15])[CH:11]=[CH:12][C:4]=2[O:3]1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH:20]=O.[BH4-].[Na+].O>CO.O1CCCC1>[CH3:1][CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[C:10]([CH2:13][CH2:14][NH:15][CH2:20][C:19]3[CH:22]=[CH:23][CH:24]=[C:17]([Cl:16])[CH:18]=3)[CH:11]=[CH:12][C:4]=2[O:3]1
Reactant: O=Cc1cccc(Cl)c1
Reactant: CC1Oc2ccc(CCN)cc2NC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC1Oc2ccc(CCNCc3cccc(Cl)c3)cc2NC1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
915 mg (4.437 mmol) of 2-methyl-3-oxo-6-(2-amino-ethyl)-3,4-dihydro-2H-1,4-benzoxazine is dissolved in 16 ml of a methanol/tetrahydrofuran mixture (4:1). After adding 623.7 mg (4.437 mmol) of 3-chlorobenzaldehyde, the batch is stirred for two hours at room temperature. Then, 91.1 mg (2.408 mmol) of sodium borohydride is added in portions and stirred for another two hours at room temperature. The batch is added to 50 ml of water, and after three-fold extraction with ethyl acetate, the combined organic extracts are washed with brine, dried and the solvent is spun off. The remaining residue is chromatographed on silica gel (mobile solvent: ethyl acetate/methanol). Yield 584.6 mg (39.8%).
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:40])[CH2:20][NH:21][C:22](=[O:39])[NH:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([O:29]CC[Si](C)(C)C)=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([C@@H:8]1[CH2:12][S:11][C@H:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[N:9]1[C:19](=[O:40])[CH2:20][NH:21][C:22](=[O:39])[NH:23][C:24]1[CH:25]=[C:26]([CH:36]=[CH:37][CH:38]=1)[C:27]([OH:29])=[O:28])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccnc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)OCC[Si](C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC(C)(C)OC(=O)[C@@H]1CS[C@H](c2cccnc2)N1C(=O)CNC(=O)Nc1cccc(C(=O)O)c1
Yield: 45.7 %

Procedure:
The operation is carried out in a fashion similar to that described in Example 41, but starting from 0.95 g of 2-trimethylsilylethyl (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-pyridyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoate in 3.2 cm3 of 1M tetrabutylammonium fluoride solution. The crude product is purified by chromatography on silica [eluent: ethyl acetate]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. After vigorous stirring in diisopropyl ether, 0.36 g of (2R,4R)-3-{3-{2-[4-tert-butoxycarbonyl-2-(3-pyridyl)-3-thiazolidinyl]-2-oxoethyl}ureido}benzoic acid, melting at 147° C., is thus obtained ([α]D20 =+51.1°±17° (C=0.49%; DMF)) [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., characteristic chemical shifts at 120° C.: 7.3 to 7.6 (m, 5H, aromatic); 8.0 (bs, 1H, N--C6H4 --C in position 2); 8.5 (bs, 1H, H in position 2 of pyridyl); 8.8 (bs, 1H, H in position 6 of pyridyl). Infrared spectrum (KBr), characteristic bands in cm-1 : 3385, 2975, 2930, 2600, 2500, 1730, 1660, 1610, 1590, 1560, 1485, 1370, 1240, 1150, 760, 710, 685].
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH:8][CH2:9][C:10]2([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[C:28](B(O)O)=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O.C(OCC)(=O)C>[F:20][C:19]1[C:14]([C:10]2([CH2:9][NH:8][C:5]3[N:6]=[N:7][C:2]([C:28]4[C:23]([O:22][CH3:21])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:3][CH:4]=3)[CH2:13][CH2:12][CH2:11]2)=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ncccc1B(O)O
Reactant: Fc1cccnc1C1(CNc2ccc(Cl)nn2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ncccc1-c1ccc(NCC2(c3ncccc3F)CCC2)nn1
Temperature: 90 °C
Yield: 74.7 %

Procedure:
To a 20 dram vial was added 6-chloro-N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)pyridazin-3-amine (1.8 g, 6.23 mmol, 1.0 equiv), 2-methoxypyridin-3-ylboronic acid (1.0 g, 6.54 mmol, 1.1 equiv), Cl2Pd(dppf) (350 mg, 0.43 mmol, 0.07 equiv), 2M potassium carbonate (8 mL, 15.5 mmol, 2.5 equiv), and dioxane (21 mL). The reaction was stirred and heated to 90° C. for 2 h and then diluted with water (20 mL) and ethyl acetate (50 mL). After transferring to a separatory funnel and shaking, the organic layer was separated from the aqueous layer and then washed with lithium chloride (1×20 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated to give a crude solid that was purified by silica gel column chromatography to give N-((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)-6-(2-methoxypyridin-3-yl)pyridazin-3-amine (1.7 g, 77%) as an off-white solid.