Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[NH2:54][C@H:55]([CH2:64][CH:65]([CH3:67])[CH3:66])[CH2:56][C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58].C(O)(C(F)(F)F)=O>CN(C=O)C.O>[F:24][C:20]1[CH:21]=[CH:22][CH:23]=[C:2]([F:1])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15]([NH:54][C@H:55]([CH2:64][CH:65]([CH3:67])[CH3:66])[CH2:56][C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])=[O:16])=[C:10]2[CH:9]=[C:8]([CH3:19])[CH:7]=1
Reactant: CC(C)C[C@@H](N)CC(=O)OC(C)(C)C
Reactant: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: Cc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)N[C@@H](CC(=O)OC(C)(C)C)CC(C)C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.9 %

Procedure:
A mixture of 100 mg (0.30 mmol, 1.0 eq.) of 7-[(2,6-difluorobenzyl)oxy]-2,5-dimethylpyrazolo[1,5-a]pyridine-3-carboxylic acid from Example 4A, 116 mg of TBTU (0.36 mmol, 1.2 eq.) and 0.132 ml (1.2 mmol, 4.0 eq.) of 4-methylmorpholine in 2.2 ml of DMF was admixed with 121 mg (0.60 mmol, 2.0 eq.) of tert-butyl (3R)-3-amino-5-methylhexanoate, and the mixture was stirred at RT overnight. The reaction mixture was admixed with water and TFA and purified by means of preparative HPLC (RP18 column, eluent:acetonitrile/water gradient with addition of 0.1% TFA). The product fractions were combined and concentrated. Subsequently, the residue was taken up in dichloromethane and a little methanol, and washed twice with saturated aqueous sodium hydrogencarbonate solution. The aqueous phase was extracted twice with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered, concentrated and lyophilized. 88 mg of the target compound were obtained (57% of theory).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].BrBr>[OH-].[OH-].[Pd+2].CO.[Pd]>[C:12]([C:10]1[CH:9]=[C:4]([CH:3]=[CH:2][CH:11]=1)[C:5]([OH:7])=[O:6])([CH3:15])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Pd+2]
Agent: [Pd]
Agent: BrBr
Solvent: CO
Product: CC(C)(C)c1cccc(C(=O)O)c1
Reaction time: 22 h
Yield: 81.8 %

Procedure:
Preparation C2, Step 1: A mixture of the commercially available methyl 3-bromo-5-tert-butylbenzoate (700 mg, 2.58 mMol), aqueous NaOH (1 N, 7.75 mL, 7.75 mMol), and Pearlman's catalyst (100 mg) in methanol (20 mL) was hydrogenated at 50 psi for 22 hours. The catalyst was removed by filtration and rinsed with a small amount of methanol. The filtrate was concentrated in-vacuo to remove methanol, and the aqueous mixture was acidified with 1 N HCl (10 mL), then extracted with ethyl acetate (3×20 mL). The combined organic phases were dried over sodium sulfate, then concentrated in-vacuo. Analysis of the resulting material by LC/MS showed that the ester had hydrolyzed to the carboxylic acid, but that the bromide was still present. The material was dissolved in methanol (20 mL), and hydrogenated overnight at 50 psi in the presence of 1 N aqueous NaOH (5.2 mL, 5.2 mMol) and 10% palladium on activated carbon (50 mg). Analysis of the crude reaction mixture by LC/MS showed that the bromine was still present, so Pearlman's catalyst (200 mg) was added, and hydrogenation at 50 psi was continued for 23 hours. MS showed that the reaction was now complete, so the reaction was worked up as described previously in this example to yield 376 mg (81% yield) of white powder as product. MS (AP−)=177 (M−H)
Reaction SMILES: [C:1]([N:4]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][C:10]=1[Cl:19])=[O:7])(O)=[O:2]>C(OC(=O)C)(=O)C>[C:20]1([N:4]2[CH2:5][C:6](=[O:7])[N:8]([C:9]3[CH:14]=[CH:13][C:12]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:11][C:10]=3[Cl:19])[C:1]2=[O:2])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CN(C(=O)O)c2ccccc2)c(Cl)c1
Solvent: CC(=O)OC(C)=O
Product: NS(=O)(=O)c1ccc(N2C(=O)CN(c3ccccc3)C2=O)c(Cl)c1

Procedure:
2-(N-carboxy-phenylamino)-N-(2-chloro-4-sulphamoylphenyl)-acetamide (5.0 g) was heated in acetic anhydride (20 ml) 2 hr at 80°. The anhydride was then distilled off and the residue digested with water, filtered off and further washed with water to yield 3.5 g, m.p. 241°-243° on recrystallisation from ethyl acetate.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1.[C:28](O)(=[O:32])[C:29]#[C:30][CH3:31]>>[O:4]1[C:8]2=[C:9]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:32])[C:29]#[C:30][CH3:31])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[N:10]=[CH:11][CH:12]=[C:7]2[CH2:6][CH2:5]1
Reactant: CC#CC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1
Agent: Cl
Product: CC#CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3OCC4)CC2)CC1

Procedure:
The title compound, white solid (80 mg, 81%), MS (ISP) m/z=397.3 [(M+H)+], mp 176° C., was prepared in accordance with the general method of example 6 from trans-4-{2-[4-(2,3-dihydro-furo[2,3-c]pyridin-7-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate B) (110 mg, 0.25 mmol) and but-2-ynoic acid.
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:31][CH:30]=2)[C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>C(O)C>[CH:1]1([NH:9][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[CH:20]([C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][O:11][CH3:10])=[CH:19][CH:18]=2)[C:29]2[CH:30]=[CH:31][C:32]([O:35][CH2:36][O:37][CH3:38])=[CH:33][CH:34]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCCCCC1
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2ccccc2CNC2CCCCCCC2)cc1
Reaction time: 8 h
Yield: 89.4 %

Procedure:
In 50 ml of ethanol was dissolved 0.69 g of cyclooctylamine. To the solution was added 1.96 g of 2-[bis(4-methoxymethoxyphenyl)methyl]benzaldehyde obtained by Reference Example 3, and the mixture was stirred overnight. Then, 0.85 g of sodium borohydride was added thereto, and the reaction mixture was stirred for 2 hours. Thereafter, the solvent was evaporated under reduced pressure, and water was added to the residue. The aqueous mixture was extracted with chloroform, and the organic layer was separated. The aqueous layer was extracted with chloroform, and the organic layer was combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to afford 2.25 g of the desired product (Compound 77) as an oily matter.
Reaction SMILES: [SH2:1].[CH2:2]([S:4][C:5](=N)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH3:3].Cl.CCOCC>O1CCCC1.O>[CH2:2]([S:4][C:5](=[S:1])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[CH2:13][CH2:14][C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[O:22][CH3:23])[CH3:3]
Reactant: CCSC(=N)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Reactant: S
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: CCSC(=S)c1cccc(Cl)c1CCc1cc(Br)ccc1OC
Temperature: 45 °C
Reaction time: 8 h

Procedure:
As shown in Scheme 11, hydrogen sulfide gas (˜2 mL) was condensed into a cooled (−78° C.) solution of 2.8 grams (6.8 mmol) of 2-[2-(5-Bromo-2-methoxy-phenyl)-ethyl]-3-chloro-thiobenzimidic acid ethyl ester and 13.6 mL (13.6 mmol) of 1.0 M HCl/ether in 100 mL of tetrahydrofuran. The reaction was heated to 45° C. and stirred overnight in a sealed tube. The reaction mixture was diluted with water and extracted with methylene chloride once. The organic layer was washed with brine, dried (MgSO4), filtered and evaporated to give a crude orange oil. The oil was partially purified by chromatography through a short column of silica gel (eluting with 5:95 ethyl acetate/hexanes) which resulted in 1.8 g of an orange powder which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)([Cl:12])=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][Cl:12]
Reactant: O=S(Cl)Cl
Reactant: OCc1ccncc1Br
Solvent: ClCCl
Product: ClCc1ccncc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.2 %

Procedure:
To a solution of 3-bromo-4-(hydroxymethyl)pyridine (1.6 g, 8.4 mmol) in methylene chloride (90 mL) was added thionyl dichloride (1.6 mL, 22.0 mmol) dropwise over at 0° C. The reaction was stirred at room temperature for 2 h and then concentrated. The yellow solid was dried in a vacuum to afford the compound 5 (2.05 g, 100%).
Reaction SMILES: ClC1C=CN=C(C(Cl)=O)C=1.CNC.Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:16]=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1>>[CH3:24][N:23]([CH3:25])[C:21]([C:17]1[CH:16]=[C:15]([O:33][C:30]2[CH:31]=[CH:32][C:27]([NH2:26])=[CH:28][CH:29]=2)[CH:20]=[CH:19][N:18]=1)=[O:22]
Reactant: Nc1ccc(O)cc1
Reactant: CN(C)C(=O)c1cc(Cl)ccn1
Agent: CNC
Agent: O=C(Cl)c1cc(Cl)ccn1
Product: CN(C)C(=O)c1cc(Oc2ccc(N)cc2)ccn1

Procedure:
Entry 91: 4-Chloropyridine-2-carbonyl chloride was reacted with dimethylamine according to Method A2, Step 3b. The resulting 4-chloro-N,N-dimethyl-2-pyridinecarboxamide was reacted with 4-aminophenol according to Method A2, Step 4 to give 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline. 4-Bromo-3-(trifluoromethyl)aniline was converted into 4-bromo-3-(trifluoromethyl)phenyl isocyanate according to Method B1. According to Method C1a, 4-bromo-3-(trifluoromethyl)phenyl isocyanate was reacted with 4-(2-(N,N-dimethylcarbamoyl)-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[H-].[Na+].C([C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[O-:17])=O.[Na+].[Na].[Cl-].[NH4+]>C1COCC1.CO>[O:17]([CH2:8][CH2:9][CH2:2][CH2:3][CH2:4][CH:5]([C:4]1[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=1)[OH:6])[C:16]1[CH:15]=[CH:14][CH:20]=[CH:19][CH:18]=1
Reactant: O=Cc1cccc(O)c1
Reactant: O=Cc1cccc([O-])c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Product: Oc1cccc(C(O)CCCCCOc2ccccc2)c1
Reaction time: 1 h

Procedure:
A solution of 3-hydroxybenzaldehyde (5.0 g, 41 mmole) in dry THF (50 ml) was added dropwise to a well-stirred suspension of sodium hydride (2.5 g, 52 mmol; 50% oil dispersion) in dry THF (50 ml) at room temperature. The temperature was not allowed to go above ca. 40° C. After the addition of 3-hydroxybenzaldehyde was complete (ca. 30 min.) the slightly cloudy solution was warmed to 45°-50° C. and stirred for 1 hour at this temperature. The resulting clear solution of sodium 3-formyl phenoxide was cooled to room temperature and added dropwise using a cannula, to the well-stirred solution of the Grignard reagent (whose preparation was described above). A thick precipitate immediately formed. This mixture was maintained at 40°-45° C. during the addition of the sodium salt. After the addition was complete (ca. 2 hours), the reaction mixture was stirred at this temperature for another hour, and then cooled in an ice bath. The excess reactive materials (sodium hydride, Grignard reagent, etc.) were dsstroyed slowly by carefully adding methanol (30 ml), and then a saturated ammonium chloride solution (350 ml) was added to dissolve all solids. The organic layer was separated, and the aqueous layer was extracted with ether (2×75 ml). The combined organics were washed with water, brine, and then dried over anhydrous magnesium sulfate. After drying the extract, all volatiles were removed to obtain a dark liquid. This oil was triturated with a 1:1 mixture of ether and petroleum ether (35°-55° C.) when an off-white solid was obtained (12 g). This can be crystallized from methanol-ethyl acetate to give a white solid, mp 148°-9° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH3:13])[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[OH-].[Na+].[C:24]1(=[O:38])[N:28]([CH2:29][C:30](Cl)=[O:31])[C:27](=[O:33])[C:26]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]12>C(Cl)(Cl)Cl>[C:14]([C:3]1[C:2]([NH:1][C:30](=[O:31])[CH2:29][N:28]2[C:27](=[O:33])[C:26]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:25]3[C:24]2=[O:38])=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:5][C:4]=1[CH3:13])(=[O:21])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1
Reactant: O=C(Cl)CN1C(=O)c2ccccc2C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1[nH]c(-c2ccccc2)c(NC(=O)CN2C(=O)c3ccccc3C2=O)c1C(=O)c1ccccc1

Procedure:
4-Amino-3-benzoyl-2-methyl-5-phenylpyrrole (22.4 g.) is dissolved in 1400 ml. of chloroform and 160 ml. of 1N sodium hydroxide are added to the mixture. By keeping the temperature at 0°-5° C., 17.6 g. of phthalimidoacetyl chloride in 120 ml. of chloroform are added with stirring. After one hour the reaction mixture is cooled and the solid precipitated is recovered on filter and then crystallized from ethanol. Yield 27.8 g.; M.p. 288°-90° C.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH3:19])[C:14](OC)=[O:15])=[CH:9][CH:8]=1.[Na+].[Cl-].[NH3:22]>>[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH3:19])[C:14]([NH2:22])=[O:15])=[CH:9][CH:8]=1
Reactant: CCC(C(=O)OC)c1ccc(N)cc1
Reactant: N
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Product: CCC(C(N)=O)c1ccc(N)cc1
Temperature: 17.5 °C
Reaction time: 16 h
Yield: 90 %

Procedure:
The methyl 4-aminophenylbutyrate hydrogensulfate, FW=291.11, 10.0 grams, 34.35 mmol, 1 eq) was dissolved in 20 ml of solution of 20% w/w aqueous NaCl (16 ml H2O and 4 grams of NaCl). To this solution aqueous ammonia (10 eq, 350 mmol, 14.8 molar solution, 24 ml) containing dissolved NaCl (4 grams) was added maintaining temperature 15-20° C. The mixture was stirred for 16 hours at RT. After that the mixture was cooled to 0-5° C. and held at this temperature for at least one hour. The resultant crystalline product was isolated by filtration. Washed with cold water (2 times for 10 ml) and dried under vacuum at 50° C. giving 5.5 g (90% yield) of 4-aminophenylbutyramide. C10H14N2O (MW 178.11); 1H NMR (500 MHz, DMSO-d6) δ: 7.23 ppm (br. s, 1H); 6.83 ppm (d, 2H, J=8.30 Hz); 6.68 ppm (br. s, 1H); 6.49 ppm (d, 2H, J=8.35 Hz); 4.80 ppm (br. s, 2H); 2.38 ppm (t, 2H, J=7.60 Hz); 2.03 ppm (t, 2H, J=7.53 Hz); 1.69 ppm (pentet, 2H, J=7.57 Hz).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:26][C:27]#[CH:28])[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]3[N:22]=[N:23][N:24]=[C:16]3[C:15]=2[N:25]=1)[CH3:9].[OH:29][N:30]=[C:31](Cl)[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.ClN1C(=O)CCC1=O>C1COCC1>[CH2:8]([O:10][CH2:11][C:12]1[N:13]([CH2:26][C:27]2[O:29][N:30]=[C:31]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[CH:28]=2)[C:14]2[C:19]([CH3:20])=[C:18]([CH3:21])[N:17]3[N:22]=[N:23][N:24]=[C:16]3[C:15]=2[N:25]=1)[CH3:9]
Reactant: C#CCn1c(COCC)nc2c1c(C)c(C)n1nnnc21
Reactant: ON=C(Cl)c1cccnc1
Agent: O=C1CCC(=O)N1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOCc1nc2c(c(C)c(C)n3nnnc23)n1Cc1cc(-c2cccnc2)no1

Procedure:
In the presence of triethylamine (0.50 mL, 3.4 mmol), 8-(ethoxymethyl)-5,6-dimethyl-7-prop-2-ynyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine (0.442 g, 1.55 mmol) was reacted with N-hydroxypyridine-3-carboximidoyl chloride generated from 3-pyridinecarboxyaldehyde oxime (prepared as described in Part A of Example 5, 0.38 g, 3.11 mmol) and N-chlorosuccinimide (0.42 g, 3.11 mmol) in THF (5 mL) using the method described in Part B of Example 5. After purification by flash chromatography (silica gel, elution with 95:5 dichloromethane/methanol) and trituration in diethyl ether, the product 8-(ethoxymethyl)-5,6-dimethyl-7-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridine was obtained (0.171 g) as a white powder.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].[OH-].[Na+]>C(O)C>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=2[C:6]([OH:8])=[O:7])=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: COC(=O)c1cccc(Nc2ccc(C(C)(C)C)cc2)c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)c1ccc(Nc2cccc(C(=O)O)c2C(=O)O)cc1
Yield: 78 %

Procedure:
A mixture of 3-(4-tert-butylphenylamino)phthalic acid dimethyl ester (0.70 g, 2.1 mmol) and 3N NaOH (50 mL) in ethanol (100 mL) was heated to reflux for 90 minutes. The mixture was cooled, and the solvent was removed under vacuum. The residue was dissolved in water (100 mL), washed with ethyl acetate (3×75 mL), acidified (HCl) and extracted with ethyl acetate (3×75 mL). The combined organic extracts were washed with water (3×75 mL), dried (MgSO4), and evaporated. The brown residue was dissolved in 15 mL of 1:1 hexanes-ether. Addition of 35 mL hexanes resulted in precipitation of the product as a bright yellow solid, providing 0.50 g in 78% yield: 1H NMR (CDCl3) δ 1.33 (s, 9H), 7.11-7.15 (m, 3H), 7.33-7.39 (m, 4H).
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:38])=[C:19]([C@@:21]23[O:29][CH2:28][CH2:27][C@@H:26]2[CH2:25][S:24][C:23]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:22]3)[CH:20]=1.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>CN(C=O)C.O>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([F:38])=[C:19]([C@@:21]34[O:29][CH2:28][CH2:27][C@@H:26]3[CH2:25][S:24][C:23]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[N:22]4)[CH:20]=2)=[O:12])=[N:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ccc(OC(F)F)cn4)ccc3F)OCC[C@@H]2CS1
Yield: 36.7 %

Procedure:
A solution of 5-(difluoromethoxy)picolinic acid (8.49 mg, 0.045 mmol), tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol) and Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 10 h. The crude product was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(5-(5-(difluoromethoxy)picolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.011 mmol, 37.2% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.88 (br. s., 1H), 8.50 (br. s., 1H), 8.34 (d, J=8.7 Hz, 1H), 8.01 (dd, J=9.1, 3.4 Hz, 1H), 7.70 (dd, J=8.6, 2.4 Hz, 2H), 7.19-7.07 (m, 1H), 6.89-6.47 (m, 1H), 4.25-4.07 (m, 2H), 3.33 (d, J=12.7 Hz, 1H), 3.07-2.82 (m, 2H), 2.41 (dd, J=12.8, 7.2 Hz, 1H), 2.29-2.14 (m, 1H), 1.51 (br. s., 9H). MS (M+H)+: 539.22.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][C:8](=O)[CH2:7][CH2:6]2.[N+](C1C=CC=CC=1S([N:26]([CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH2:35])=[CH:30][CH:29]=1)(=O)=O)([O-])=O.[BH3-]C#N.[Na+].C(OC)(OC)OC>CO.C(O)(=O)C>[N:38]1[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=1[CH2:36][NH:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:34][NH:35][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)=[CH:32][CH:33]=1
Reactant: NCc1ccc(CN(Cc2ccccn2)S(=O)(=O)c2ccccc2[N+](=O)[O-])cc1
Reactant: COc1ccc2c(c1)CCC(=O)C2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: COc1ccc2c(c1)CCC(NCc1ccc(CNCc3ccccn3)cc1)C2
Yield: 58.5 %

Procedure:
Using General Procedure G: 6-methoxy-2-tetralone (112 mg, 0.63 mmol), N-(2-nitrobenzenesulfonyl)-N-(2-pyridinylmethyl)-1,4-benzenedimethanamine (186 mg, 0.45 mmol) and NaBH3CN (110 mg, 1.76 mmol) in a mixture of MeOH (5 mL), trimethyl orthoformate (2.8 mL) and acetic acid (5 drops) were reacted for 3.5 hours. Purification of the crude material by chromatography on silica gel (CH2Cl2/MeOH/NH4OH 98:1:1) gave the desired product (102 mg, 40%) as a yellow foam.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.II.[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]([NH:41][NH:42][C:43](=[O:55])[CH2:44][CH2:45][N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][N:30]1[C:36](=[O:37])[N:35]2[CH2:38][C@H:31]1[CH2:32][CH2:33][C@H:34]2[C:39]1[O:55][C:43]([CH2:44][CH2:45][N:46]([CH3:54])[C:47](=[O:53])[O:48][C:49]([CH3:50])([CH3:51])[CH3:52])=[N:42][N:41]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN(CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(CCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To a solution of PPh3 (5.3 g, 20.0 mmol) in CH2Cl2 (250 mL) at rt was added I2 (5.2 g, 20.0 mmol). After I2 was dissolved completely, the solution was cooled to 0° C. and TEA (7.0 mL, 50.0 mmol) was added. Tert-butyl 3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl) hydrazinyl)-3-oxopropyl(methyl)carbamate (4.8 g, 10.0 mol) was added and the mixture was stirred at rt for 1 hr. The mixture was concentrated, EtOAc (250 mL) was added, and the solution was filtered to remove POPh3. The filtrate was concentrated and the residue was purified by silica gel column chromatography (gradient elution 30 to 50% EtOAc/petroleum ether) to afford tert-butyl 2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl(methyl)carbamate (4.1 g, 85%) as a white solid. ESI-MS (EI+, m/z): 458 [M+H]+.