Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([OH:9])=O.C(Cl)CCl.[O:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.O>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([N:23]1[CH2:24][CH2:25][CH2:26][O:20][CH2:21][CH2:22]1)=[O:9]
Reactant: O=C(O)c1cc(-c2ccccc2)sc1Cl
Reactant: C1CNCCOC1
Solvent: O
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(c1cc(-c2ccccc2)sc1Cl)N1CCCOCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-chloro-5-phenyl-thiophene-3-carboxylic acid (1 eq.) in DCM (1 mL/100 mg SM) was added EDC (1.5 eq.). This mixture was stirred at room temperature for 5 minutes and then [1,4]oxazepane (1.2 eq.) was added and the mixture was allowed to stir for 18 hours. Water (1 mL/100 mg SM) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane). LCMS m/z 322 [M+H]+ R.T.=3.34 mins (Analytical Method 3).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[O:14]C=CC=2)=[CH:11][C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:9]1.O.C(Cl)(Cl)(Cl)Cl.I([O-])(=O)(=O)=[O:29].[Na+]>C(#N)C.[Ru](Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]([OH:14])=[O:29])=[CH:11][C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:9]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: COC(=O)c1cc(C(=O)O)n(-c2ccccc2Cl)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 43.2 %

Procedure:
To a stirred mixture of compound 6 (3.0 g, 9.9 mmol) in a mixture of acetonitrile (60 mL), water (80 mL) and carbon tetrachloride (60 mL) was added sodium periodate (8.3 g, 39 mmol) and ruthenium chloride (125 mg, 0.03 mmol) and the reaction mixture was stirred at room temperature for 72 h. On completion, solvent was removed, crude mass was dissolved in saturated sodium bicarbonate solution, extracted with ether (50 ml×3). Aqueous layer was acidified with 1N HCl and extracted with ethyl acetate (60 mL×4). The combined ethyl acetate layer was washed with brine, dried over sodium sulphate and concentrated to afford the title compound 7 (1.2 g, 44%) which was used for further reaction.
Reaction SMILES: II.[CH3:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1>C1COCC1>[C:4]1([CH3:3])[CH:11]=[CH:10][C:7]([CH2:8][CH2:3][C:4]2[CH:11]=[CH:10][C:7]([CH3:8])=[CH:6][CH:5]=2)=[CH:6][CH:5]=1
Reactant: Cc1ccc(CCl)cc1
Agent: II
Solvent: C1CCOC1
Product: Cc1ccc(CCc2ccc(C)cc2)cc1
Yield: 93 %

Procedure:
To a suspension of 9.55 g Mg (0.39 mol) and a crystal of I2 in 500 ml anhydrous THF was added a solution of 100 g p-methylbenzylchloride (0.71 mol) in 150 ml anhydrous THF under an inert atmosphere in 30 minutes. The exothermic reaction caused the mixture to reflux. Subsequently the reaction mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure and the remaining white solid was treated with 400 ml pentane and 400 ml aqueous 10% HCl. The organic layer was extracted with 150 ml saturated NaCl (2 times) and dried with MgSO4. The solvent was evaporated under reduced pressure giving 69.8 g (0.33 mol, 93%) product as a white powder.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][CH:12]3[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]1[CH:29]=[CH:28][C:18]([CH2:19][N:20]2[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]2=[O:27])=[CH:17][CH:16]=1>CO.[Pd]>[CH:12]1([CH2:11][N:7]2[C:6]3[CH:5]=[CH:4][C:3]([C:15]4[CH:29]=[CH:28][C:18]([CH2:19][N:20]5[CH2:24][C:23](=[O:25])[N:22]([CH3:26])[C:21]5=[O:27])=[CH:17][CH:16]=4)=[CH:2][C:10]=3[N:9]=[N:8]2)[CH2:14][CH2:13]1
Reactant: CN1C(=O)CN(Cc2ccc(-c3ccc4c(nnn4CC4CC4)c3Br)cc2)C1=O
Agent: [Pd]
Solvent: CO
Product: CN1C(=O)CN(Cc2ccc(-c3ccc4c(c3)nnn4CC3CC3)cc2)C1=O
Reaction time: 2 h

Procedure:
1-{4-[4-Bromo-1-(cyclopropylmethyl)-1H-benzotriazol-5-yl]benzyl}-3-methylimidazolidine-2,4-dione (Example 10, 20 mg, 0.044 mmol) was dissolved in methanol (7 mL) and sparged under nitrogen. The vessel was charged with Pd/C (4.7 mg, 1 equiv), sparged under an atmosphere of hydrogen (1 atm) and vigorously stirred for 2 hours. The mixture was sparged under and atmosphere of nitrogen, filtered through a pad of Celite and the pad was washed with methanol (20 mL). The mixture was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (95:5 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (400 MHz, d6-DMSO) δ 8.29 (1H, s), 8.02 (1H, d, J=9.2 Hz), 7.78 (1H, dd, J=8.7, 1.4 Hz), 7.78 (2H, d, J=8.3 Hz), 7.42 (2H, d, J=8.1 Hz), 4.64 (2H, d, J=7.3 Hz), 4.56 (2H, s), 3.93 (2H, s), 2.90 (3H, s), 1.43-1.35 (1H, m), 0.59-0.55 (2H, m), 0.51-0.48 (2H, m) ppm; high resolution mass spectrometry (ES+) m/z 376.1763 [(M+H)+; calculated for C21H22N5O2: 376.1768].
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11]/[CH:12]=[CH:13]/[CH2:14][C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24]C(=O)OC(C)(C)C)=[O:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O-])([O-])=O.[K+].[K+]>CC(O)C>[NH2:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[NH:17][C:15](=[O:16])[CH2:14]/[CH:13]=[CH:12]/[CH2:11][CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)C/C=C/CCNC(=O)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Product: Nc1ccccc1NC(=O)C/C=C/CCNC(=O)c1ccccc1
Yield: 20.1 %

Procedure:
To a solution of (E)-tert-butyl 2-(6-benzamidohex-3-enamido)phenylcarbamate (15)(130 mg, 0.307 mmol) in propan-2-ol (10 mL) was bubbled HCl gas for 1 hour at 0° C. To the reaction mixture was added 10% K2CO3 to adjust the pH value to 7-8, then the mixture was extracted with DCM (3×50 mL), the combined organic layers were washed with brine, dried over Na2SO4 and concentrated to give the desired compound of (E)-N-(6-(2-aminophenylamino)-6-oxohex-3-enyl)benzamide (16) (20 mg, 20%) as an off-white solid after purification by column chromatography (eluent: DCM:MeOH=50:1). 1H NMR (300 MHz, DMSO): δ 2.418 (m, 2H), 3.257 (m, 2H), 4.847 (s, 2H), 5.572-5.716 (m, 2H), 6.519-6.570 (m, 1H), 67.424-7.549 (m, 3H), 7.833-7.861 (t, 2H). 8.532-8.576 (t, 2H), 9.149 (s, 1H); LC-MS found 324 (M+H)+; HPLC (214 nm, 98%, 254 nm, 98%).
Reaction SMILES: [O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]\[C:12]1[O:16][C:15]([C:17]3[CH:18]=[C:19]([NH:23]C(=O)OC(C)(C)C)[CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2>Cl.O1CCOCC1>[NH2:23][C:19]1[CH:18]=[C:17]([C:15]2[O:16][C:12](/[CH:11]=[C:10]3/[C:2](=[O:1])[NH:3][C:4]4[C:9]/3=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:13][CH:14]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc(-c2ccc(/C=C3/C(=O)Nc4ccccc43)o2)c1
Yield: 111.7 %

Procedure:
A solution of (E)-tert-butyl 3-(5-((2-oxoindolin-3-ylidene)methyl)furan-2-yl)phenylcarbamate (600 mg, 1.49 mmol) in HCl/dioxane (4M, 3.0 mL) was stirred over night. The resulting precipitate was collected by filtration to yield desired (E)-3-((5-(3-aminophenyl)furan-2-yl)methylene)indolin-2-one (503 mg). LCMS (ES): m/z 303 [M+1]+.
Reaction SMILES: CO[C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[CH2:13]Br.[CH2:16]([NH2:18])[CH3:17]>>[CH2:16]([N:18]1[CH2:13][C:5]2[C:4](=[CH:9][CH:8]=[C:7]([N+:10]([O-:12])=[O:11])[CH:6]=2)[C:3]1=[O:15])[CH3:17]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1CBr
Reactant: CCN
Product: CCN1Cc2cc([N+](=O)[O-])ccc2C1=O
Reaction time: 3 h
Yield: 85 %

Procedure:
2-Bromomethyl-4-nitro-benzoic acid methyl ester (1.0 g, 3.64 mmol) was stirred in ethylamine (30 ml, 2.0M solution in THF) at room temperature. The reaction was stirred for 3 hrs, after which time the solvent was evaporated in vacuo and the crude residue triturated with diethyl ether. The resulting orange solid was filtered and dried in a vacuum oven (40° C.) to afford the title compound (634 mg, 85%). HPLC retention time 3.56 min. Mass spectrum (ES+) m/z 207 (M+H).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[C:5]1=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)(=[O:3])[CH3:2]>[Pd].CCO>[C:1]([N:4]1[C:5]2[CH:14]=[C:15]3[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]3)=[N:21][C:6]=2[C:7]2[C:12]1=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N1C(=Cc2ccccc2[N+](=O)[O-])C(=O)c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: CC(=O)n1c2ccccc2c2nc3ccccc3cc21
Reaction time: 3 h
Yield: 49.8 %

Procedure:
A suspension of 1-acetyl-2-(2-nitrophenyl methylene)-3-oxo-2,3-dihydroindole from Example 33 (220 mg, 0.71 mmol), 10% Pd/C (33 mg) and absolute EtOH (25 mL) was shaken on a Parr Shaker at 50 psi of H2 for 3 hours. The Pd catalyst was filtered off over a celite pad and the solvent was evaporated. The crude yellow product (209 mg, >100%) was purified by LPLC, eluting with hexane-EtOAc (2:1), to afford 92 mg (50%) of the title compound as a light yellow solid (90% pure by NMR) , Rf 0.38 (hexane-EtOAc 1:1), mp 163.2°-164.6° C. [(lit 177°-178° C. (Fichter, F.; Boehringer, R. Chem. Ber. 1906, 39, 3932)]; 1H NMR (CDCl3) δ 9.04 (s, 1H), 8.52 (d, J=8.0, 1H), 8.28 (d, J=8.8, 1H), 8.16 (d, J=8.4, 1H), 8.02 (d, J=8.4, 1H), 7.77 (m, 1H), 7.68 (m, 1H), 7.61 (m, 1H), 7.52 (m, 1H), 2.99 (s, 3H); 13C NMR (CDCl3) 169.7, 147.3, 145.9, 141.5, 137.5, 131.4, 130.6, 128.8, 128.6, 128.5, 127.3, 126.1, 124.4, 122.0, 121.6, 115.8, 27.6; MS (EI, m/z) 260 (M+) .
Reaction SMILES: [CH2:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([O:7]C)=[O:6])[CH2:2][CH3:3].[OH-].[Na+].O>C(O)C>[CH2:1]([CH:4]([CH2:9][CH2:10][CH2:11][CH:12]=[CH2:13])[C:5]([OH:7])=[O:6])[CH2:2][CH3:3]
Reactant: C=CCCCC(CCC)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C=CCCCC(CCC)C(=O)O
Yield: 75.2 %

Procedure:
A mixture of methyl 2-propyl-6-heptenoate (1.8 g), sodium hydroxide (0.65 g), water (2 ml) and ethanol (100 ml) was heated under reflux for 2 hours. The solvent was removed under reduced pressure and the resulting residue was shaken with water and hexane. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer was dried and concentrated to give oil of 2-propyl-6-heptenoic acid (1.25 g).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][NH:14]2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C>CN(C=O)C.CN(C)C1C=CN=CC=1>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([C@@H:13]2[CH2:18][CH2:17][CH2:16][CH2:15][N:14]2[S:27]([C:24]2[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=2)(=[O:29])=[O:28])=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2)no1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(NC(=O)[C@@H]2CCCCN2S(=O)(=O)c2ccc(Cl)cc2)no1

Procedure:
To a solution of (S)-Piperidine-2-carboxylic acid (5-tert-butyl-isoxazol-3-yl) amide; hydrochloride (110 mg; 0.382 mmol) in DMF (1.5 mL) is added 4-chlorobenzenesulfonyl chloride (80.6 mg; 0.382 mmol) and N,N-diisopropylethylamine (0.133 mL; 0.764 mmol). The reaction mixture is left stirring at room temperature for 18 hours in the presence of catalytic amount of 4-dimethylaminopyridine. The reaction mixture is quenched with water and extracted with ethyl acetate twice. The combined organics are washed with water then brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography on silica gel using ethyl acetate/Hexanes provides the title compound, m/z 426 [M+H+].
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8]NC(=O)C(C)C)[CH:5]=[CH:6][CH:7]=1.[OH2:16].Cl.[OH-].[Na+]>C1C2C(=CC=CC=2)CCC1.CCOC(C)=O.CO>[Br:1][C:2]1[C:3]([CH3:15])=[C:4]2[C:5]([C:3]([CH3:15])([CH3:4])[C:2](=[O:16])[NH:8]2)=[CH:6][CH:7]=1
Reactant: O
Reactant: Cc1c(Br)cccc1NNC(=O)C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2c(c1)CCCC2
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c(Br)ccc2c1NC(=O)C2(C)C
Temperature: 200 °C
Reaction time: 17 h

Procedure:
A mixture of N′-(3-bromo-2-methylphenyl)isobutyrohydrazide (1.14 g, 4.23 mmol) and CaH (0.356 g, 8.46 mmol) in 1,2,3,4-tetrahydronaphthalene (10 mL) was heated to 200° C., and stirred at 200° C. for 17 h. The mixture was cooled to 0° C. and to the mixture was added water (1.63 mL) and MeOH (1.63 mL) slowly. At 0° C. the PH of the mixture was adjusted to PH1 by adding conc. HCl. The mixture then was heated to reflux for 1 h. The reaction mixture was cooled to rt, and NaOH (3N) was added to the mixture, adjusting to pH 5. The resultant mixture was diluted with EtOAc, washed with water and brine, dried and concentrated. Purification of the residue by flash chromatography over silica gel, using 30% EtOAc in hexane, gave 6-bromo-3,3,7-trimethylindolin-2-one. 1H-NMR (DMSO-d6) δ 10.58 (1H, s), 7.21 (1H, d, J=8.0 Hz), 7.07 (1H, d, J=8.0 Hz), 2.27 (3H, s), 1.24 (6H, s). Mass Spectrum (ESI) m/e=254.0 (M+1).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:13]([NH:16][C:17]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]=[O:45])=[CH:40][CH:39]=1)([CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:15])[CH3:14].Cl>O1CCCC1>[C:13]([NH:16][C:17]([CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][C:41]([CH:44]([OH:45])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:40][CH:39]=1)([CH2:27][O:28][Si:29]([C:32]([CH3:33])([CH3:34])[CH3:35])([CH3:31])[CH3:30])[CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])(=[O:15])[CH3:14]
Reactant: BrCCCCc1ccccc1
Reactant: CC(=O)NC(CCc1ccc(C=O)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(=O)NC(CCc1ccc(C(O)CCCCc2ccccc2)cc1)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Reaction time: 1.5 h
Yield: 83.2 %

Procedure:
To a solution of magnesium (0.27 g) in anhydrous tetrahydrofuran (5 ml) was dropwise added a solution of 1-bromo-4-phenylbutane (2.35 g) in anhydrous tetrahydrofuran (5 ml) under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours. To this solution was dropwise added a solution of 2-acetamido-1,3-bis(tert-butyldimethylsilyloxy)-2-(2-(4-formylphenyl)ethyl)propane (1.2 g) in anhydrous tetrahydrofuran (15 ml) and the mixture was stirred for 1 hour. 3% Hydrochloric acid was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate=2:1) to give the title compound (1.27 g) as a colorless transparent oily substance.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28]([OH:30])=O)=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[CH3:32][NH:33][CH3:34].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[CH:1]([O:4][C:5]([N:7]1[CH2:8][CH2:9][CH:10]([O:13][N:14]=[C:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([F:27])[C:24]([C:28](=[O:30])[N:33]([CH3:34])[CH3:32])=[CH:23][C:22]=3[F:31])[CH2:17][CH2:16]2)[CH2:11][CH2:12]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)O)cc3F)CC2)CC1
Reactant: CNC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(ON=C2CCN(c3cc(F)c(C(=O)N(C)C)cc3F)CC2)CC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
9-1 (30 mg, 0.071 mmol), dimethylamine (0.1 mmol) and HOBT (0.2 mmol) were combined in DCM (1 mL) and stirred at room temperature for 10 minutes. EDC(0.2 mmol) was added and the mixture was stirred for 18 h. The solution was washed with 2 mL of aqueous NaHCO3, concentrated, taken up with 1 mL of methanol and purified on preparative HPLC to give 29-1: LC-MS 467.4 (MH).
Reaction SMILES: [NH2:1][CH2:2][C@@:3]1([CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[CH:6][CH2:7]2>Cl.C(OCC)(=O)C>[NH2:1][CH2:2][C@@:3]1([CH2:10][C:11]([OH:13])=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH:5]=[CH:6][CH2:7]2
Reactant: CC(C)(C)OC(=O)C[C@]1(CN)C[C@@H]2CC=C[C@@H]21
Agent: Cl
Solvent: CCOC(C)=O
Product: NC[C@@]1(CC(=O)O)C[C@@H]2CC=C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
A 4 N hydrochloric acid-ethyl acetate solution (10 mL) was added to tert-butyl(±)-[(1S,5R,6R)-6-(aminomethyl)bicyclo[3.2.0]hept-3-en-6-yl]acetate (0.99 g, 4.17 mmol), and the mixture was stirred at room temperature for 1 hour. Then, the solvent was distilled off under reduced pressure. The residue was suspended by the addition of dichloromethane. To the suspension, triethylamine was then added dropwise, and the resulting powder was collected by filtration. The obtained powder was washed with dichloromethane and then dried under reduced pressure to obtain the compound of interest as a white powder (211.6 mg, 35%).
Reaction SMILES: II.[CH2:3](I)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CO[CH2:14][CH2:15][O:16]C>>[CH2:3]([C:15]1([OH:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:14]1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: ICCc1ccccc1
Reactant: COCCOC
Agent: II
Product: OC1(CCc2ccccc2)CCCCC1
Yield: 96 %

Procedure:
Since TmI2(DME)x exhibits such high reactivity at room temperature, its viability at reduced temperature is examined. In these reactions, TmI2(DME)x is added as a DME solution by syringe using a saturated stock solution generated in situ from Tm and I2. Phenethyl iodide reacts smoothly at −22° C. in 10 minutes to form phenethylcyclohexanol in 96% yield (entry f). The reaction of phenethyl bromide with cyclohexanone at 0° C. produces a 96% yield of phenethylcyclohexanol in 20 minutes (entry g), while reaction at −22° C. gave a 94% yield in 60 minutes (entry h). Phenethyl chloride reacts at 0° C. to give a 90% yield after 1 hour (entry j). This variation of reaction time as a function of temperature could be used to control regiochemistry in sequenced reactions.
Reaction SMILES: Cl.O1CCOCC1.C([O:10][C:11](=O)[C@H:12]([OH:42])[CH2:13][C@H:14]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1)C.[F:44][C:45]([F:49])([F:48])[CH2:46][OH:47]>>[F:44][C:45]([F:49])([F:48])[CH2:46][O:47][C:11](=[O:10])[C@H:12]([OH:42])[CH2:13][C@H:14]([NH:29][C:30]([C:32]1[CH:41]=[CH:40][C:35]2[N:36]=[N:37][N:38]([OH:39])[C:34]=2[CH:33]=1)=[O:31])[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=2)=[CH:18][CH:17]=1
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(N[C@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C[C@@H](O)C(=O)OCC(F)(F)F)c1ccc2nnn(O)c2c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 27.5 %

Procedure:
4.0 M HCl in 1,4-dioxane (196 μL, 786 μmol) was added to a solution of (2R,4R)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-4-[(3-hydroxy-3H-benzotriazole-5-carbonyl)amino]pentanoic acid ethyl ester (50.0 mg, 98.2 μmol) in 2,2,2-trifluoroethanol (215 μL, 3.0 mmol), and the resulting mixture was stirred at 100° C. for 3 hours. The mixture was concentrated in vacuo to yield a clear colorless liquid, which was purified by preparative HPLC (C18 column chromatography using 40-90% MeCN in water with 0.05% TFA) to yield the title compound as a white solid (15.2 mg, purity 99%). MS m/z [M+H]+ calc'd for C26H22ClF3N4O5, 563.12. found 563.2.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)[CH:5]=[C:4]([N:19]2[CH2:23][CH2:22][C:21]([F:25])([F:24])[CH2:20]2)[N:3]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:68][C:69]1[CH:74]=[C:73]([C:75]([F:78])([F:77])[F:76])[CH:72]=[CH:71][N:70]=1.O1CCOCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:25][C:21]1([F:24])[CH2:22][CH2:23][N:19]([C:4]2[CH:5]=[C:6]([CH:8]3[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[CH2:9]3)[CH:7]=[C:2]([NH:68][C:69]3[CH:74]=[C:73]([C:75]([F:77])([F:76])[F:78])[CH:72]=[CH:71][N:70]=3)[N:3]=2)[CH2:20]1
Reactant: Nc1cc(C(F)(F)F)ccn1
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(Cl)nc(N3CCC(F)(F)C3)c2)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC(c2cc(Nc3cc(C(F)(F)F)ccn3)nc(N3CCC(F)(F)C3)c2)C1
Reaction time: 1 h
Yield: 117.9 %

Procedure:
To a solution of tert-butyl 3-[2-chloro-6-(3,3-difluoropyrrolidin-1-yl)-4-pyridyl]azetidine-1-carboxylate (1-b, 582 mg, 1.557 mmol), Pd2(dba)3 (147 mg, 0.10 equiv., 0.1557 mmol), XantPhos (186 mg, 0.20 equiv., 0.3114 mmol), 2-amino-4-(trifluoromethyl)pyridine (765 mg, 3.0 equiv., 4.671 mmol) in 1,4-dioxane (5.3 mL, 62.28 mmol) was added cesium carbonate (2.03 g, 4.0 equiv., 6.228 mmol), and the reaction was kept at 150° C. for 60 min. The crude was purified by silica gel chromatography (0-60% EtOAc/Heptane) to yield 917 mg yellow powder (contaminated by 2-amino-4-(trifluoromethyl)pyridine). 1H NMR (400 MHz, CDCl3) δ (delta) 8.57 (s, 1H), 8.36 (d, J=5.1 Hz, 1H), 7.04 (d, J=5.2 Hz, 1H), 6.29 (s, 1H), 5.87 (s, 1H), 4.30 (t, J=8.6 Hz, 2H), 4.02-3.93 (m, 2H), 3.87 (t, J=13.1 Hz, 2H), 3.74 (t, J=7.2 Hz, 2H), 3.67-3.54 (m, 1H), 2.60-2.43 (m, 2H), 1.47 (s, 9H). LCMS: m/z 500 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[CH3:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>>[Cl:22][C:17]1[CH:16]=[C:15]([C:13]2[N:14]=[C:10]([C:8]3[CH:9]=[C:4]([C:3]([OH:2])=[O:24])[C:5]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[CH3:25])=[CH:6][CH:7]=3)[S:11][CH:12]=2)[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: Cc1ccccc1B(O)O
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)cc1C(=O)O
Yield: 71.5 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 2-methylphenylboronic acid (available from Combi-Blocks Inc.; 54 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-2′-methyl-biphenyl-2-carboxylic acid (63 mg, 72%). 1H NMR (400 MHz, DMSO-d6) δ 12.92 (br s, 1H), 8.46 (d, J=4.8 Hz, 2H), 8.34 (s, 1H), 8.22 (d, J=8.0 Hz, 1H), 8.09 (d, J=8.5 Hz, 1H), 7.77 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.0 Hz, 1H), 7.17-7.32 (m, 3H), 7.09 (d, J=7.0 Hz, 1H), 2.08 (s, 3H).