Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Sn](Cl)Cl.[N+:5]([C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[N:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([O-])=O.C(=O)(O)[O-].[Na+]>CO>[N:18]1([C:9]2[CH:10]=[CH:11][C:12]([C:14]([F:15])([F:16])[F:17])=[CH:13][C:8]=2[NH2:5])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCC1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Solvent: CO
Product: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 90.1 %

Procedure:
Concentrated hydrochloric acid (2.00 ml, 24.0 mmol) and anhydrous tin dichloride (2.50 g, 13.1 mmol) were sequentially added at 0° C. to a methanol (10 ml) solution containing 1-[2-nitro-4-(trifluoromethyl)phenyl]piperidine (559 mg, 2.03 mmol), obtained as described in Referential Example 1-1A. The resulting mixture was warmed to room temperature and then stirred for 17.5 hours. A saturated aqueous solution of sodium bicarbonate was added to the mixture. The resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50 g, hexane/ethyl acetate=14/1)). Thus, 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (448 mg, 1.83 mmol, 90.4%) was yielded as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[Br-].[CH2:42]([O:44][C:45](=[O:48])[CH2:46][Zn+])[CH3:43]>O1CCCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH2:42]([O:44][C:45](=[O:48])[CH2:46][C:2]1[C:10]2[O:9][CH:8]=[CH:7][C:6]=2[CH:5]=[C:4]([O:11][CH3:12])[CH:3]=1)[CH3:43]
Reactant: CCOC(=O)C[Zn+]
Reactant: COc1cc(Br)c2occc2c1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cc(OC)cc2ccoc12
Temperature: 55 °C

Procedure:
Dissolve 7-bromo-5-methoxybenzofuran (6.0 g, 26.43 mmol), bis(dibenzylideneacetone)palladium (1.32 g, 2.3 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (2.7 g, 6.86 mmol) in anhydrous tetrahydrofuran (36 mL), add freshly prepared 2-ethoxy-2-oxoethylzinc bromide in tetrahydrofuran (66 mL). Heat at 50-60° C. for 5 h. Cool and filter mixture through celite and evaporate to a thick red-brown oil (30 g). Purify by flash chromatography using a gradient of ethyl acetate in hexanes yields the pure compound as a thick yellow oil (6.2 g, quant). ESMS m/z (relative intensity) 235.2 (M++H+, 10), 161.1 (M+−CO2Et+H+, 100).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1)[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:27]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:27])[C:3](=[O:2])[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=2)[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C=CC(C(=O)OC)=C(C)NCc1ccc(C#N)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(Cc2ccc(C#N)cc2)c1C
Temperature: 25 °C
Yield: 53 %

Procedure:
MeOH (90 mL) was added to a flask containing 4-[1-(4-cyano-benzylamino)-ethylidene]-pent-2-enedioic acid dimethyl ester (3.35 g, 10.7 mmol). NaOMe solution (2.44 mL, 10.7 mmol, 4.375 M in MeOH) and N-bromosuccinimide (2.28 g, 12.8 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. Saturated NH4Cl (120 mL) was added, and the resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The crude product was chromatographed (0-40% EtOAc/hexanes) to give 2.05 g of the title compound. MS: (+) m/z 361.18, 363.14 (M+Na, 79/81Br).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][C:17]([CH3:22])([CH2:20][OH:21])[CH2:18][OH:19]>CO.O>[CH3:22][C:17]([NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([OH:9])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)([CH2:20][OH:21])[CH2:18][OH:19]
Reactant: CC(N)(CO)CO
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CO
Solvent: O
Product: CC(CO)(CO)NC(c1ccccc1)C(O)c1ccccc1
Temperature: 150 °C
Yield: 81.6 %

Procedure:
A mixture of trans-stilbene oxide (2.00 g, 0.010 mol) and 2-amino-2-methyl-1,3-propanediol (3.15 g, 0.030 mol) was heated at 150° C. for 3 hours. The reaction mixture was dissolved in 20 mL of methanol and diluted with water to form a white solid. The solid was collected, washed with water and dried for 18 hours under ambient conditions to obtain 2.46 g (82%) of the product. Recrystallization from toluene gave 2.38 g of material; mp 144°-145° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)C(=O)C)=[N:4][CH:3]=1.[C:17]1([CH3:26])[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Li+].[OH-]>O1CCOCC1>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:7][C:5]1[S:6][C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH3:26])=[CH:3][N:4]=1
Reactant: Cc1ccccc1B(O)O
Reactant: CC(=O)N(c1ccccn1)c1ncc(Br)s1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: [Li+]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1cnc(Nc2ccccn2)s1
Temperature: 100 °C
Reaction time: 20 h

Procedure:
To a flame dried round bottom flask previously flushed with argon was added N-(5-bromo-thiazol-2-yl)-N-pyridin-2-yl-acetamide (5-5) (50 mg, 1.7 mmol, o-tolylboronic acid (2.6 mmol), potassium phosphate tribasic (108 mg, 5.1 mmol), palladium tetrakistriphenyl phosphine (20 mg, 0.2 mmol), and 3 mL of anhydrous dioxane. The vessel was flushed twice with argon and was heated to 100° C. under Argon. After 20 h workup was performed as follows: The reaction was cooled to ambient temperature and the dioxane was removed via rotary evaporation. The crude mixture was diluted in 1.5 mL CH2Cl2 and 2 mL water, and the resulting biphasic mixture was transferred to a Whatman 12 mL 1PS filter tube. The layers were mixed and the organic layer was drained into a collection tube; the extraction was repeated with an additional 2 mL of CH2Cl2. The organic layer was concentrated and the resulting solid was dissolved in DMSO. Purification was performed via Gilson reverse phase automated column chromatography. Only pure desired fractions were combined into a reaction vessel, contaminated fractions were discarded. An equal portion of methanol was added corresponding to the volume of acetonitrile/water present in the combined samples. LiOH monohydrate (5.0 eq.) was added to the stirred solution. The reaction was complete via MS within 10 min or less after the addition of the LiOH. The reaction was concentrated to almost complete dryness. The product was obtained as a precipitate which was filtered, washed with water, and dried. 1H NMR (CDCl3): δ8.38 (d, 1H, J=4.2 Hz), 7.68 (t, 1H, J=7.5 Hz), 7.42 (d, 1H, J=9.7 Hz), 7.33 (s, 1H), 7.27-7.31 (m, 3H), 7.08 (d, 1H, J=8.2 Hz), 6.97 (t, 1H, J=4.9 Hz), 2.46 (s, 3H). Mp: 155-160° C. MS [M+H]+=268.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH3:20])=[CH:5][CH:4]=1.C([O-])(=O)C.[K+].[Br:26]Br.[OH-].[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Br:26][C:4]1[CH:5]=[C:6]([C:9]2[C:18]([CH3:19])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=2[CH3:20])[CH:7]=[N:8][C:3]=1[O:2][CH3:1]
Reactant: BrBr
Reactant: COC(=O)c1cc(C)c(-c2ccc(OC)nc2)c(C)c1
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(Br)c2)c(C)c1
Temperature: 80 °C

Procedure:
Methyl 4-(6-methoxypyridin-3-yl)-3,5-dimethylbenzoate (Step B, 1.31 g, 4.83 mmol) and potassium acetate (2.369 g, 24.14 mmol) were dissolved in acetic acid (24 mL). Bromine (0.622 mL, 12.07 mmol) was added and the reaction was stirred at 80° C. The reaction was monitored by LCMS. Once complete, it was cooled to room temperature, diluted with ethyl acetate and added to a separatory funnel. Aqueous sodium hydroxide was added to neutralize the reaction. The reaction was partitioned between water and ethyl acetate, and the aqueous was extracted a second time with ethyl acetate. The combined organics were washed with brine, then dried over sodium sulfate, filtered and evaporated. The crude isolate was purified by silica gel chromatography, eluting with 2 column volumes of 4% Ethyl acetate in hexanes, followed by a gradient of 4-10% ethyl acetate/hexanes over 6 column volumes, followed by a gradient of 10-20% ethyl acetate/hexanes over 5 column volumes to give the title compound. 1H NMR (CDCl3, 500 MHz) δ7.88 (d, 1H), 67.79 (s, 2H), 67.63 (d, 1H), 64.07 (s, 3H), 63.93 (s, 3H), 62.11 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH3:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[C:21]([NH2:23])=[N:22][C:11]1=2)([CH3:4])([CH3:3])[CH3:2].[CH2:29](N1C2C(=CC=CC=2)C2C=C(C(N)=O)C(NC)=NC1=2)C>>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH3:27])[CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:24]([NH2:26])=[O:25])[C:21]([NH:23][CH3:29])=[N:22][C:11]1=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H](Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21)NC(=O)OC(C)(C)C
Reactant: CCn1c2ccccc2c2cc(C(N)=O)c(NC)nc21
Product: CNc1nc2c(cc1C(N)=O)c1ccccc1n2C[C@H](C)NC(=O)OC(C)(C)C
Yield: 89 %

Procedure:
tert-butyl{(1S)-2-[2-amino-3-(aminocarbonyl)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xvi-b, 20 mg, 0.052 mmol) was alkylated according to procedure detailed in the preparation of 48, to afford tert-butyl{(1S)-2-[3-(aminocarbonyl)-2-(methylamino)-9H-pyrido[2,3-b]indol-9-yl]-1-methylethyl}carbamate (xxxii-a, 20 mg, 89%). NH4OAc QC conditions. M+H=398.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17](O)=[O:18])=[N:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[C:8]2=[O:22])=[CH:4][CH:3]=1.S(Cl)([Cl:27])=O>>[F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[CH2:16][CH2:15][C:14]3[C:13]([C:17]([Cl:27])=[O:18])=[N:12][CH:11]=[C:10]([O:20][CH3:21])[C:9]=3[C:8]2=[O:22])=[CH:4][CH:3]=1
Reactant: COc1cnc(C(=O)O)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reactant: O=S(Cl)Cl
Product: COc1cnc(C(=O)Cl)c2c1C(=O)N(Cc1ccc(F)cc1)CC2
Reaction time: 0.5 h

Procedure:
A solution of 6-(4-fluorobenzyl)-4-methoxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylic acid (1.11 g, 3.36 mmol) in thionyl chloride (0.4 g, 3.36 mmol) was heated to 110° C. After 0.5 hours, the product mixture was concentrated under vacuum. The residue was suspended in toluene, evaporated, then suspended in chloroform and evaporated to give the title compound. The product was assayed by quenching in methanol solution to produce the methyl ester. ES MS M+1=345 (methyl ester forms after quench in methanol)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:26][S:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:30][CH:29]=1
Reactant: CSc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Product: CSc1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cc1

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-methylsulfanyl-phenylboronic acid following a procedure analogous to that described for Example 2; PdCl2[1,1′-bis(diphenylphosphino)-ferrocene]*CH2Cl2 complex is used as catalyst source. LC (method 3): tR=1.04 min; Mass spectrum (ESI+): m/z=453 [M+H]+.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17](B3OC(C)(C)C(C)(C)O3)[CH:18]=2)[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:40]1[N:45]=[CH:44][CH:43]=[CH:42][N:41]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:40]3[N:45]=[CH:44][CH:43]=[CH:42][N:41]=3)[CH:18]=2)[C:13]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1ncccn1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2c1-c1ccc(Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(-c3ncccn3)ccc2c1-c1ccc(Cl)cc1
Temperature: 50 °C

Procedure:
(S)-Ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)acetate (0.072 g, 0.13 mmol), 2-bromopyrimidine (0.032 g, 0.20 mmol), PdCl2(dppf) (0.005 g, 0.007 mmol) were taken up in 3/1 PhMe/EtOH (1 mL). The resulting solution was treated with 2 M K2CO3 (0.35 mL, 0.70 mmol), sealed and sparged with Ar for 10 min. After 2.5 h of heating at 50° C. and cooling to room temperature, the crude reaction mixture was purified by Yamazen column chromatography (20-100% EtOAc/Hex) to produce 0.042 g (64%) of a colorless film. LCMS-ESI+ (m/z): [M]+ calcd for C29H29ClN2O3: 489.01; found: 489.51.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=[O:9])=[N:6][CH:7]=1.[CH3:11]N(C=O)C.C(Cl)(=O)C(Cl)=O.CO>C(Cl)Cl>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C(O)c1ccc(O)cn1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc(O)cn1
Reaction time: 1 h

Procedure:
To 5-hydroxypyridine-2-carboxylic acid (5.0 g, 36 mmol) suspended in CH2Cl2 (120 mL) was added DMF (1 mL) followed by oxalyl chloride (4.7 g, 37 mmol). After 1 hour, excess MeOH was added. The resulting mixture was stripped of solvent in vacuo yielding a brown solid that was washed with hot EtOAc. Yielded 4.6 g of product.
Reaction SMILES: C([C@H:4]1[CH2:7][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:5]1)(=O)C.O.OO.FC(F)(F)C(OC(=O)C(F)(F)F)=[O:42].C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[OH:42][C@H:4]1[CH2:5][C@H:6]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:20][CH:21]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:7]1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](C(C)=O)C2)c2ncnn12
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: OO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2C[C@H](O)C2)c2ncnn12
Temperature: 60 °C
Reaction time: 24 h
Yield: 23 %

Procedure:
To a mixture of 4′-{[4-(trans-3-acetylcyclobutyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.3 g), 30% hydrogen peroxide water (3.5 g) and chloroform (20 mL) was gradually added trifluoroacetic acid anhydride (7.7 mL) at room temperature, and the reaction mixture was warmed to 60° C. and stirred for 24 hr. Saturated aqueous sodium hydrogen carbonate and sodium thiosulfate were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), 1N aqueous sodium hydroxide solution (5 mL) was added, and the mixture was stirred at room temperature for 30 min. 1N Aqueous hydrochloric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.28 g, 23%).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5])C.[CH3:18][C:19]1[CH:47]=[CH:46][C:22]([CH2:23][N:24]2[CH2:28][CH:27]([CH2:29][CH2:30]OS(C3C=CC(C)=CC=3)(=O)=O)[N:26]([CH2:42][CH2:43][CH3:44])[C:25]2=[O:45])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].N#N.[OH-].[Na+]>C(O)C>[CH3:18][C:19]1[CH:47]=[CH:46][C:22]([CH2:23][N:24]2[CH2:28][CH:27]([CH2:29][CH2:30][O:17][C:14]3[CH:13]=[CH:12][C:11]([C:6]4([C:4]([OH:3])=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10]4)=[CH:16][CH:15]=3)[N:26]([CH2:42][CH2:43][CH3:44])[C:25]2=[O:45])=[CH:21][CH:20]=1
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C1(c2ccc(O)cc2)CCCC1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOc1ccc(C2(C(=O)O)CCCC2)cc1
Yield: 39.7 %

Procedure:
A mixture of 1-(4-hydroxy-phenyl)-cyclopentanecarboxylic acid ethyl ester (0.042 g, 0.179 mmol), toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethyl ester (0.085 g, 0.197 mmol) and 325 mesh K2CO3 (0.050 g, 0.362 mmol) in ethanol (5 mL) was heated at ref lux for under N2 for 16 h. The reaction was then treated with aqueous 5 N NaOH (0.5 mL) and heated to reflux 1.5 h. The reaction mixture was cooled, the solvent removed in vacuo. The resultant residue was acidified with aqueous 1 N HCl (10 mL) and extracted with Et2O. The organic layer was dried (MgSO4) and the solvent removed in vacuo to afford 0.058 g crude acid that was purified by preparative HPLC to afford 0.033 g (40%) 1-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-cyclopentanecarboxylic acid. MS (ES+) Calc'd for C28H37N2O4 (M+1) 465. Found m/z 465 (100%). 1H NMR.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:16][CH3:17])=[C:6]([CH:11]=[C:12]([Cl:15])[C:13]=1[NH2:14])[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].C1C[O:21]CC1>C1COCC1.COCCOCCOC>[OH:21][CH2:3][CH2:2][CH2:1][C:4]1[C:5]([O:16][CH3:17])=[C:6]([CH:11]=[C:12]([Cl:15])[C:13]=1[NH2:14])[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=CCc1c(N)c(Cl)cc(C(=O)OC)c1OC
Reactant: C1CCOC1
Solvent: COCCOCCOC
Product: COC(=O)c1cc(Cl)c(N)c(CCCO)c1OC
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
A mixture of a 1M solution of BH3 in THF(8 ml) and the compound of step 3 above (2 g) in THF-diglyme (10 ml/16 ml) is stirred under N2 for 30 minutes at 20° C. Me3NO.2H2O (2.2 g) is added to the mixture and refluxed in a preheated oil bath allowing the THF to evaporate, followed by refluxing the mixture for one hour. The mixture is cooled to 20° C., partitioned between CHCl3 and sat'd aqueous NaHCO3, and stirred for 30 minutes. The organic layer is separated, washed with H2O, dried (MgSO4), evaporated and the residue is chromatographed on silica gel affording the desired product as a solid which is determined to be the correct product by NMR.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[C:10]([F:21])[CH:9]=2)=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[O:37]=[C:38]1[CH:42]=[C:41](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:40][N:39]1[C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:41]2[CH2:40][N:39]([C:54]([O:56][C:57]([CH3:59])([CH3:58])[CH3:60])=[O:55])[C:38](=[O:37])[CH:42]=2)=[CH:6][C:7]=1[C:8]1[CH:20]=[CH:19][C:11]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[C:10]([F:21])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)OC2=CC(=O)N(C(=O)OC(C)(C)C)C2)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2cc(B3OC(C)(C)C(C)(C)O3)cnc2N)cc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)c1ccc(-c2cc(C3=CC(=O)N(C(=O)OC(C)(C)C)C3)cnc2N)cc1F
Temperature: 90 °C
Yield: 66 %

Procedure:
To tert-butyl 4-(2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-2-fluorobenzoate (158 mg, 0.382 mmol) in DME (3 mL) and sodium carbonate (0.509 mL, 1.019 mmol) was added tert-butyl 2-oxo-4-(tosyloxy)-2,5-dihydro-1H-pyrrole-1-carboxylate (90 mg, 0.255 mmol) and PdCl2(dppf)-CH2Cl2 (41.6 mg, 0.051 mmol). The reaction mixture was heated in microwave at 90° C. for 30 min. LCMS showed starting material remained. More catalysts were added and heated again at 90° C. for 20 min. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude product was purified by flash chromatography using 0-50% EtOAc (contains 10% MeOH)/heptane to provide product as a yellow solid (66%). LCMS (m/z): 470.2 (MH+), 0.846 min.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]([NH:42][NH:43][C:44]([CH:46]1[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]1)=O)=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH2:23]([O:30][N:31]1[C:37](=[O:38])[N:36]2[CH2:39][C@H:32]1[CH2:33][CH2:34][C@H:35]2[C:40]1[S:10][C:44]([CH:46]2[CH2:51][CH2:50][N:49]([C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:48][CH2:47]2)=[N:43][N:42]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)s2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
Lawesson's reagent (0.16 g, 6 mol) was added to a solution of tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonyl)piperidine-1-carboxylate (0.16 g, 0.319 mmol) in THF (20 mL). The reaction mixture was stirred at 70° C. for 0.5 h. The solution was cooled to room temperature and sat. NaHCO3 was added. The organic layer was separated and the aqueous layer was exacted with EtOAc (2×). The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (gradient elution 20%-50% EtOAc/petroleum ether) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperidine-1-carboxylate (90 mg, 50%) as a white solid. ESI-MS (EI+, m/z): 500.2 [M+H]+. 1H NMR (500 MHz, DMSO-d6): δ 7.48-7.37 (m, 5H), 4.99-4.94 (m, 2H), 4.77 (d, J=7.0 Hz, 1H), 3.99 (d, J=11 Hz, 2H), 3.69 (s, 1H), 3.39-3.35 (m, 1H), 2.88-2.85 (m, 3H), 2.68 (d, J=12 Hz, 1H), 2.44 (dd, J=7.5, 5.5 Hz, 1H), 2.05-1.96 (m, 4H), 1.79-1.77 (m, 1H), 1.62-1.55 (m, 2H), 1.40 (s, 9H).