Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:20][CH:21]=1.[Cl:28][C:29]1[CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:28].[Cl:28][C:29]1[CH:34]=[C:33]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:17]=[N:18][C:19]([O:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[CH:20][CH:21]=2)[CH:32]=[C:31]([O:44][CH3:45])[C:30]=1[OH:46]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(OCCN(C)C)nc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(Cl)c1O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1cc(-c2ccc3ncc(C(C)=O)c(Nc4ccc(OCCN(C)C)nc4)c3n2)cc(Cl)c1O
Yield: 75.7 %

Procedure:
Following general procedure II, 1-(6-chloro-4-{6-[2-(dimethylamino)ethoxy]pyridin-3-ylamino}-1,5-naphthyridin-3-yl)ethanone (20 mg, 0.052 mmol) was reacted with 2-chloro-6-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (28 mg, 0.10 mmol) followed by formation of the dihydrochloride salt to afford the desired product (22 mg, 74%) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.33 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.35 (d, J=9.0 Hz, 1H), 8.26 (d, J=2.7 Hz, 1H), 7.74 (dd, J=8.8, 2.7 Hz, 1H), 7.29 (br s, 1H), 6.96 (d, J=8.8 Hz, 1H), 6.85 (br s, 1H), 4.70-4.64 (m, 2H), 3.95 (s, 3H), 3.62-3.56 (m, 2H), 2.99 (s, 6H), 2.83 (s, 3H); ESI MS m/z 508 [M+H]+; HPLC>99% (AUC), tR=9.36 min.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[Br:1]
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(C)cc1Br
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-4-methyl-benzoic acid (5.50 g, 25.6 mmol) in methanol (250 mL) was added concentrated sulfuric acid (1 mL). The reaction mixture was heated to reflux overnight (approximately 16 hours), allowed to cool to room temperature and then concentrated to approximately ¼ volume under reduced pressure. The residue was then partitioned between water and ethyl acetate, the layers were separated and the aqueous layer was extracted with one additional portion of ethyl acetate. The combined organics were washed one time with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered through a plug of silica gel and concentrated under reduced pressure. 2-Bromo-4-methyl-benzoic acid methyl ester was obtained as an oil (4.95 g, 85%). To a solution of this oil (2.50 g, 10.9 mmol) in carbon tetrachloride (100 mL) was added N-bromosuccinimide (2.04 g, 11.5 mmol) and benzoylperoxide (0.106 g, 0.44 mmol). The reaction mix was heated to reflux. After approximately 1 hour, the reaction mixture became colorless. At this time the heat was removed to allow the mixture to cool to room temperature and the mixture was filtered. The filtrate was concentrated under reduced pressure. The crude mixture was purified by HPLC (40% methylene chloride in hexane) to give 2-bromo-4-bromomethyl-benzoic acid methyl ester (1.50 g, 45%) as a white powder. 1H NMR (400 MHz, CDCl3); δ 7.75 (d, 1H), 7.66 (s, 1H), 7.35 (d, 1H), 4.39 (s, 2H), 3.90 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1.Cl.CN(C)C.[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C)CCCN>C(Cl)Cl.C(OCC)(=O)C>[CH3:24][C:25]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:46])[CH2:35][CH2:36][CH2:37][CH:38]([CH3:45])[CH2:39][CH2:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:26][CH2:27][CH2:28][CH2:29][O:30][S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:18])=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: CC(=CCCCO)CCCC(C)CCCC(C)CCCC(C)C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)C
Agent: CN(C)CCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.28 mL (9.23 mmol) of triethylamine, 1.06 g (5.56 mmol) of p-toluenesulfonyl chloride, 43 mg (0.45 mmol) of trimethylamine hydrochloride were added to a solution of 1.50 g (4.63 mmol) of 5,9,13,17-tetramethyloctadec-4-en-1-ol in dry methylene chloride (9 mL) at 0° C., sequentially. After being stirred for 3 hours at room temperature, 0.14 mL (1.1 mmol) of N,N-dimethyl-1,3-propanediamine was added to the reaction mixture at 0° C. After being stirred for 3 hours, the mixture was diluted with ethyl acetate. The resulting solution was washed with water, 1M hydrochloric acid, saturated sodium bicarbonate aqueous solution, and saturated brine, successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain (5,9,13,17-tetramethyloctadec-4-enyl)tosylate as a crude product.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([CH2:43][NH2:44])=[CH:42][C:37]=2[O:36][CH2:35]1>>[O:34]1[C:38]2[CH:39]=[CH:40][C:41]([CH2:43][NH:44][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([C:31]3[CH:30]=[CH:29][C:28]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:33][CH:32]=3)=[O:7])=[O:18])=[CH:42][C:37]=2[O:36][CH2:35]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCc1ccc2c(c1)OCO2
Product: CON=C1C[C@@H](C(=O)NCc2ccc3c(c2)OCO3)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, [1,1′-biphenyl]4-carbonyl chloride, and 1,3-benzodioxol-5-ylmethylamine the title compound was obtained in 64% purity by LC/MS. MS(ESI+): m/z=472.4.
Reaction SMILES: O.C([NH:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:50][O:51][CH:52]([F:54])[F:53])[C:28]([NH:30][CH:31]2[C:48](=[O:49])[N:33]3[C:34]([C:45]([OH:47])=[O:46])=[C:35]([CH2:38][S:39][C:40]4[S:41][CH:42]=[N:43][N:44]=4)[CH2:36][S:37][C@H:32]23)=[O:29])[N:26]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)=O>[NH2:21][C:22]1[S:23][CH:24]=[C:25]([C:27](=[N:50][O:51][CH:52]([F:53])[F:54])[C:28]([NH:30][CH:31]2[C:48](=[O:49])[N:33]3[C:34]([C:45]([OH:47])=[O:46])=[C:35]([CH2:38][S:39][C:40]4[S:41][CH:42]=[N:43][N:44]=4)[CH2:36][S:37][C@H:32]23)=[O:29])[N:26]=1
Reactant: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2C(NC(=O)C(=NOC(F)F)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: O
Product: Nc1nc(C(=NOC(F)F)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Reaction time: 4 h
Yield: 64 %

Procedure:
Water (2.7 ml) was added to a stirred solution of 7-[2-(2-tritylaminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.9 g) in formic acid (9 ml) at 7° C. under ice-cooling and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was poured into a mixture of water (150 ml) and ethyl acetate (50 ml) and adjusted to pH 2.5 with an aqueous solution of sodium bicarbonate. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-difluoromethoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (0.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1([C:15](OC)=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C.CCOCC>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1([CH2:15][OH:16])[CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(CNC(=O)OC(C)(C)C)CCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC1(CO)CCCC1
Temperature: -10 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
To a solution of methyl 1-[(tert-butoxycarbonyl)amino]methylcyclopentanecarboxylate (1.50 g, 5.83 mmol) in THF (25.0 mL) at −78° C. was added dropwise 1.0 M diisobutylaluminum hydride in DCM (17.5 mL). The reaction was stirred for 2 hours with slow warming to −10° C. A saturated solution of K/Na tartrate was added, followed by ether. This mixture was stirred for 30 minutes at ambient temperature and the organic layer was separated and washed with water, and brine. The organic layer was then dried over sodium sulfate, and the solvent was removed in vacuo to afford the product (1.03 g, 77%). 1H NMR (300 MHz, CDCl3): δ 4.90 (br s, 1H), 3.27 (s, 2H), 3.06 (d, 2H), 1.5-1.17 (m, 8H), 1.44 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:13](O)=O)=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12].S(Cl)(Cl)=O.[C:20]([OH:23])(=[O:22])C.Cl.[CH2:25](Cl)Cl>C(OCC)(=O)C.O>[F:1][C:2]1[C:3]([CH2:13][C:20]([O:23][CH3:25])=[O:22])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:10]=1[O:11][CH3:12]
Reactant: ClCCl
Reactant: CC(=O)O
Reactant: COc1c(F)c(C(=O)O)cc2ccsc12
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1cc2ccsc2c(OC)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 40 mL of methylene chloride is suspended 4.00 g of 6-fluoro-7-methoxybenzo[b]thiophene-5-carboxylic acid, to which is added 1.55 mL of thionyl chloride. The mixture is heated under reflux for 2 hours. The reaction mixture is concentrated under reduced pressure, and the residue is dissolved in 40 mL of methylene chloride. At an ice-cooled temperature, 200 mL of 0.5 mol/L solution of diazomethane in diethyl ether is added to the solution obtained above, and the mixture thus formed is stirred at ambient temperature for one hour. Then, 6.1 mL of acetic acid is added to the reaction mixture, and the mixture is stirred at ambient temperature for 10 minutes. Then, water and ethyl acetate are added, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue is suspended in 40 mL of methanol, a mixture of 2.03 g of silver benzoate and 17.3 mL of triethylamine is added at 5° C., and the mixture thus formed is stirred at ambient temperature for one hour. Water and ethyl acetate are added to the reaction mixture, pH is adjusted to 1 with 6 mol/L hydrochloric acid, the insoluble matter is filtered off, and the organic layer is separated. The organic layer is washed with saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue thus obtained is purified by column chromatography (eluent: hexane:ethyl acetate=5:1) to obtain 3.87 g of methyl 2-(6-fluoro-7-methoxybenzo[b]thiophen-5-yl)-acetate.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]#[C:7]1)[CH2:2][CH:3]=[CH2:4].[CH2:14]([O:16][SiH:17]([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[CH3:15]>>[CH:6]1([O:5][CH2:1][CH2:2][CH2:3][CH2:4][Si:17]([O:21][CH2:22][CH3:23])([O:18][CH2:19][CH3:20])[O:16][CH2:14][CH3:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]#[C:7]1
Reactant: C=CCCOC1C#CCCCCC1
Reactant: CCO[SiH](OCC)OCC
Product: CCO[Si](CCCCOC1C#CCCCCC1)(OCC)OCC
Yield: 97 %

Procedure:
The compound 3 (1.28 g, 7.18 mmol) is mixed with triethoxysilane (3.6 ml). The Karstedt catalyst is added very slowly in a catalytic amount (10 drops). The reaction takes place at 45° C. over three days. The product is purified by flash chromatography (100% AcOEt) to give a brown liquid (2.4 g, 7 mmol, 97%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]3[C:17]([C:20]([O-:22])=O)=[CH:18][N:19]=[C:13]3[CH:12]=2)[CH2:4][CH2:3]1.[Li+].C(Cl)(=O)C(Cl)=O.[CH2:30]([N:37]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([NH2:46])[C:40]=2[CH:39]=[N:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH2:30]([N:37]1[C:45]2[C:40](=[C:41]([NH:46][C:20]([C:17]3[N:14]4[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:12][C:13]4=[N:19][CH:18]=3)=[O:22])[CH:42]=[CH:43][CH:44]=2)[CH:39]=[N:38]1)[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Nc1cccc2c1cnn2Cc1ccccc1
Reactant: CN1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: [Li+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4cnn5Cc4ccccc4)cnc3c2)CC1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
To a solution of lithium 7-(2-(4-methylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (0.0585 g, 0.189 mmol) in CH2Cl2 was added a drop of DMF. Oxalyl chloride (1.1 equivalents, 2M CH2Cl2) was added and the reaction stirred at ambient temperature until bubbling ceased (about 5 minutes). 1-Benzyl-1H-indazol-4-amine (0.042 g, 0.189 mmol) was added followed by DIEA (1.2 equivalents). The reaction was stirred at ambient temperature for 4 hours. The reaction was concentrated and washed with Et2O, water, and finally with Et2O again. The pale yellow solid was dried, providing 0.027 g of crude product. The crude material was purified using reverse phase chromatography eluting with a gradient of 0 to 90% ACN/water to give 0.007 g (7%) of the desired product. MS (ES+APCI) m/z=510 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=3)=[CH:4][C:3]=1[Cl:24].Cl[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH:20]3[CH2:23][CH2:22][CH2:21]3)[C:10]3[C:15]([C:16]=2[C:17]#[N:18])=[CH:14][CH:13]=[C:12]([O:19][C:26]2[N:31]=[CH:30][CH:29]=[CH:28][N:27]=2)[CH:11]=3)=[CH:4][C:3]=1[Cl:24]
Reactant: Clc1ncccn1
Reactant: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1c(-c2ccc(N)c(Cl)c2)n(C2CCC2)c2cc(Oc3ncccn3)ccc12
Reaction time: 1 h
Yield: 91.4 %

Procedure:
2-(4-Amino-3-chloro-phenyl)-1-cyclobutyl-6-hydroxy-1H-indole-3-carbonitrile (0.67 g, 2 mmol), prepared in step ZA, was dissolved in DMF (7 mL), followed by the addition of 2-chloro-pyrimidine (0.34 g, 3 mmol) and cesium carbonate (1.3 g, 4 mmol). The mixture was brought to 70° C. and stirred for 1 h. After cooling, the solid was filtered and washed with EtOAc. The filtrate was washed with water and brine, dried, concentrated and triturated with ether to provide 2-(4-amino-3-chloro-phenyl)-1-cyclobutyl-6-(pyrimidin-2-yloxy)-1H-indole-3-carbonitrile (0.76 g, 91%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH2:16])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:5][CH:4]=1)#[N:2].[C:29](O)(=[O:35])[CH2:30][CH2:31][C:32]([NH2:34])=[O:33].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1.C(Cl)CCl>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C@@:8]23[CH2:15][C@H:14]([NH:16][C:29](=[O:35])[CH2:30][CH2:31][C:32](=[O:33])[NH2:34])[CH2:13][N:12]2[C:11](=[O:17])[N:10]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([Cl:25])[CH:19]=2)[C:9]3=[O:26])=[CH:27][CH:28]=1)#[N:2]
Reactant: NC(=O)CCC(=O)O
Reactant: N#Cc1ccc(C[C@@]23C[C@H](N)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: N#Cc1ccc(C[C@@]23C[C@H](NC(=O)CCC(N)=O)CN2C(=O)N(c2cc(Cl)cc(Cl)c2)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
A mixture of (5S,7S)-5-(4-cyanobenzyl)-3-(3,5-dichlorophenyl)-7-amino-1,3-diazabicyclo[3.3.0]octane-2,4-dione (82.7 mg), succinamic acid (45.86 mg), EDC (93.12 mg), HOBT (61.24 mg) and DIEA (104.79 μL) in THF (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and purified by high performance liquid chromatography (HPLC) (Beckman 5μ C18 column; eluted with a gradient of H2O/MeCN (10-100%)/0.1% TFA) to give 72 mg of the titled compound. MS (m/z) 536 (MNa+).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:6][N:7]=1.Cl[CH:19]([CH:22]([C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][CH:28]=[CH:27]2)[CH3:23])[CH:20]=O.C(N(CC)CC)C>C(O)(C)C>[N:30]1[C:31]2[C:26](=[CH:25][C:24]([CH:22]([C:19]3[N:3]4[N:4]=[C:5]([C:8]5[CH:9]=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=5)[CH:6]=[N:7][C:2]4=[N:1][CH:20]=3)[CH3:23])=[CH:33][CH:32]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(-c2cnc(N)nn2)cc1
Reactant: CC(c1ccc2ncccc2c1)C(Cl)C=O
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(-c2cnc3ncc(C(C)c4ccc5ncccc5c4)n3n2)cc1
Temperature: 110 °C
Yield: 22.5 %

Procedure:
A mixture of methyl 4-(3-amino-1,2,4-triazin-6-yl)benzoate (50 mg, 0.217 mmol) and 2-chloro-3-quinolin-6-ylbutanal (61 mg, 0.26 mmol) in isopropyl alcohol (3.0 mL) was heated at 110° C. for 48 h. The mixture was adjusted to pH 9 by adding triethylamine. The volatiles were removed under reduced pressure and the residue was purified by chromatography on silica gel with EtOAc in methylene chloride (0-60%) to afford the desired product (0.020 g, 22%). LCMS: (M+H)=410.0.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[OH:21][C:22]([C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[CH:28]=O)([CH3:24])[CH3:23].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.CCOC(C)=O>[OH:20][C@H:3]([CH2:2][NH:1][CH2:28][C:27]1[CH:30]=[CH:31][CH:32]=[C:25]([C:22]([OH:21])([CH3:23])[CH3:24])[CH:26]=1)[C@@H:4]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(O)c1cccc(C=O)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(C)(C)O)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A solution of tert-butyl (2S,3R)-4-amino-3-hydroxy-1-phenylbutan-2-ylcarbamate (230 mg, 0.82 mmol) in THF was added 3-(2-hydroxypropan-2-yl)benzaldehyde (180 mg, 01.06 mmol) and stirred for 30 min at room temperature, NaB(OAc)3H (302.5 mg, 1.43 mmol) was then added portionwise in 30 min, and the resulting mixture was stirred at the same temperature overnight. The reaction mixture was diluted with EtOAc, and washed with saturated aqueous NaHCO3. The organic layer was separated and dried (Na2SO4). Concentration in vacuo, followed purification with flash chromatography to give the desired product as a white solid (230 mg, 65% yield). 1H NMR (CDCl3): d: 8.514 (m, 2H), 7.717 (s, 1H), 7.321-7.203 (m, 5H), 3.831 (s, 3H), 3.580 (m, 1H), 2.978 (m, 1H), 2.890-2.755 (m, 3H), 1.724 (d, J=11.1 Hz, 6H), 1.364 (s, 9H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:23])([CH3:22])[CH:19]([OH:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1.CCN(CC)CC>C(Cl)Cl>[Cl:11][C:12]1[CH:13]=[C:14]([C:18]([CH3:23])([CH3:22])[C:19](=[O:21])[CH3:20])[CH:15]=[CH:16][CH:17]=1
Reactant: CC(O)C(C)(C)c1cccc(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)C(C)(C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a stirred solution of oxalyl chloride (3.4 mL, 40 mmol, 2 eq) in CH2Cl2 (100 mL) at −78° C. was added DMSO (4.9 mL, 70 mmol, 3.5 eq) dropwide. After stirring 1 h, the reaction mixture was treated dropwise with a solution of 3-(3-chlorophenyl)-3-methylbutan-2-ol (3.98 g, 20 mmol) in CH2Cl2 (100 mL). After stirring 1 h, Et3N (13.9 mL, 100 mmol, 5 eq) was added to the reaction mixture and the resulting mixture was slowly warmed to room temperature. The reaction mixture was partitioned in CH2Cl2 and water. The organic layer was separated, washed with 1N HCl and water, dried over MgSO4 and evaporated in vacuo to give 3-(3-chlorophenyl)-3-methylbutan-2-one (3.9 g, 99%). 1H NMR (400 MHz, CDCl3) δ 7.29 (m, 3H), 7.13 (m, 1H), 1.97 (s, 3H), 1.47 (s, 6H).
Reaction SMILES: [N:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([OH:14])[CH:8]=2)=[N+:2]=[N-:3].[C:16](OC(=O)C)(=[O:18])[CH3:17]>C(Cl)Cl.N1C=CC=CC=1>[N:1]([C:4]1[C:5](=[O:15])[O:6][C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([O:14][C:16](=[O:18])[CH3:17])[CH:8]=2)=[N+:2]=[N-:3]
Reactant: CC(=O)OC(C)=O
Reactant: [N-]=[N+]=Nc1cc2ccc(O)cc2oc1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1ccc2cc(N=[N+]=[N-])c(=O)oc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.6 %

Procedure:
To a stirred suspension of 3-azido-7-hydroxycoumarin (203 mg, 1.0 mmol) in dry CH2Cl2 (15 mL), acetic anhydride (1.5 mmol) and pyridine (one drop) were added. Upon stirring overnight at room temperature, the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with H2O. The organic layer was dried over anhydrous Na2SO4 and concentrated. Purification with column chromatography over silica gel (hexane-EtOAc 4:1) afforded the final product as a yellow solid (210 mg, 86%). 1H-NMR (DMSO-d6, 300 MHz) δ 2.29 (s, 3H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.67 (s, 1H), 7.70 (d, J=7.9 Hz, 1H). 13C NMR (DMSO-d6, 75 MHz) δ 21.5, 110.6, 117.8, 119.9, 125.8, 126.8, 129.2, 151.9, 152.3, 157.5, 169.6. IR (KBr): 2133 (vs), 1749, 1730 (vs), 1622 (s), 1234 (s). EI-HRMS m/e calculated for M+ C11H7N3O4 245.0437; found 245.0432.
Reaction SMILES: [C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[OH:25])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:32][CH2:33][CH:34](O)[CH3:35]>C(O)C>[C:1]1([B:7]([CH:9]([O:16][CH:17]([B:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[O:25][CH:34]([CH3:35])[CH2:33][NH2:32])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:8][CH:34]([CH3:35])[CH2:33][NH2:32])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(O)CN
Reactant: OB(c1ccccc1)C(OC(B(O)c1ccccc1)c1ccccc1)c1ccccc1
Solvent: CCO
Product: CC(CN)OB(c1ccccc1)C(OC(B(OC(C)CN)c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
The entitled compound (42 mg) was obtained by allowing 41 mg of bis(3,3′-(phenylhydroxyboryl)benzyl) ether and 17 mg of 1-amino-2-propanol to act in 1 mL of ethanol.