Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:30](Cl)(Cl)=[O:31].C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[Cl:23][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[Cl:22])[O:15][CH:12]1[CH2:13][CH2:14][N:9]([CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:27][CH:26]=[C:25]([O:28][CH3:29])[CH:24]=3)[NH:1][C:30]2=[O:31])[CH2:10][CH2:11]1
Reactant: O=C(Cl)Cl
Reactant: COc1ccc(N)c(C(=O)NCCN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc2[nH]c(=O)n(CCN3CCC(Oc4ccc(Cl)c(Cl)c4)CC3)c(=O)c2c1

Procedure:
The product of step (i) above was dissolved in toluene (10 ml). A solution of phosgene 2.0M in toluene (10 ml) was added, the solution heated under reflux for 1 hour and cooled. Ethyl acetate and aqueous NaHCO3 solution were added, the organic phase separated, dried and concentrated to leave a residue which was purified by chromatography (dichloromethane:methanol, 95:5). The titled product was obtained as a solid (0.11 g).
Reaction SMILES: [I-:1].[Na+].[C:3]([CH:5]1[CH2:8][N:7]([C:9](=[O:33])[C@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH3:11])[CH2:6]1)#[N:4].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[C:3]([CH:5]1[CH2:8][N:7]([C:9](=[O:33])[C@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([I:1])[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH3:11])[CH2:6]1)#[N:4]
Reactant: [I-]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(I)nc12)C(=O)N1CC(C#N)C1
Temperature: 110 °C

Procedure:
In a 5 mL microwave vial were placed copper(I) iodide (6 mg, 0.03 mmol), sodium iodide (133 mg, 0.89 mmol), 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (150 mg, 0.30 mmol), 1,4-dioxane (1 mL) and trans-N,N′-dimethylcyclohexane-1,2-diamine (9 mg, 0.06 mmol). The vial was purged with a stream of nitrogen then sealed and heated in an oil bath at 110° C. for 48 h. The reaction mixture was cooled to room temperature and quenched with sat'd aqueous NH4OH (3 mL) then diluted with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to afford 2-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a maroon oil which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20](Cl)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:35][N:36]1[C:40]([CH3:41])=[C:39]2[S:42][C:43]([Sn](CCCC)(CCCC)CCCC)=[CH:44][C:38]2=[N:37]1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C@H:14]([NH:15][C:16]2[N:21]=[C:20]([C:43]3[S:42][C:39]4[C:38](=[N:37][N:36]([CH3:35])[C:40]=4[CH3:41])[CH:44]=3)[C:19]3[C:23](=[O:33])[N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25][C:18]=3[C:17]=2[F:34])[CH2:13][CH2:12][O:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2nn(C)c(C)c2s1
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1Nc1nc(Cl)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c2sc(-c3nc(N[C@@H]4CCOC[C@@H]4NC(=O)OC(C)(C)C)c(F)c4c3C(=O)N(C(=O)OC(C)(C)C)C4)cc2nn1C
Temperature: 90 °C

Procedure:
In a 30 mL sealed cap glass tube, tert-butyl 6-((3R,4R)-3-(tert-butoxycarbonylamino)tetrahydro-2H-pyran-4-ylamino)-4-chloro-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (100 mg, 0.200 mmol), 2,3-dimethyl-5-(tributylstannyl)-2H-thieno[3,2-c]pyrazole (176 mg, 0.399 mmol) and tetrakis(triphenylphosphine)palladium(0) (115 mg, 0.100 mmol) were dissolved in toluene (5 mL). The cap was sealed and the reaction mixture was heated at 90° C. in an oil bath for 2 hours. The mixture was concentrated to give the intermediate, tert-butyl 6-(((3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl)amino)-4-(2,3-dimethyl-2H-thieno[3,2-c]pyrazol-5-yl)-7-fluoro-3-oxo-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate. The intermediate was dissolved in TFA (5 mL) and the reaction mixture was stirred for 2 hours. The mixture was concentrated, dissolved in DMSO (5 mL), and purified via preparatory HPLC eluting with a gradient of 10-60% ACN (0.035% TFA) and H2O (0.05% TFA). The pure fractions were combined, evaporated to a minimal volume, and lyophilized to give a TFA salt of the title compound as a white solid (65 mg, 61%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.80 (d, J=12.38 Hz, 1H), 1.96-2.25 (m, 1H), 2.46 (s, 3H), 3.55-3.71 (m, 1H), 3.82 (d, J=11.87 Hz, 1H), 3.92 (s, 3H), 4.05 (d, J=11.12 Hz, 3H), 4.28-4.38 (m, 1H), 4.40-4.51 (m, 2H), 7.37 (d, J=4.80 Hz, 1H), 7.96 (d, J=4.80 Hz, 3H), 8.63 (s, 1H), 9.26 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C19H21FN6O2S, 417. found, 417.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([O:17]C)=[O:16])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH3:19])[C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15]([OH:17])=[O:16])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C(=O)O)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl trans-4-[(t-butoxycarbonyl)(methyl)amino]cyclohexanecarboxylate (44.78 g) obtained in Reference Example 3(1) is dissolved in methanol (300 ml), and thereto is added 2 N aqueous sodium hydroxide solution (100 ml). The mixture is then stirred at room temperature for 6 hours. The reaction solution is concentrated under reduced pressure. To the residue are added ice-water, ethyl acetate and 10% hydrochloric acid under ice-cooling, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in a small amount of ethyl acetate, and n-hexane is poured to the mixture. The resulting crystals are collected by filtration, washed with n-hexane/diisopropyl ether several times and dried to give the title compound (39.20 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[C:14]3[C:19]=1[CH:18]=[CH:17][CH:16]=[CH:15]3)[C:12]1[CH:20]=[CH:21][CH:22]=[CH:23][C:11]=1C1[C:5]2=[CH:6][CH:7]=[CH:8]C=1.C([Li])C[CH2:26][CH3:27].[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[CH:21]1[C:20]2[C:2]3[C:3]([C:4]4[C:13]([C:12]=2[CH:11]=[CH:23][CH:22]=1)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:27][C:26]([B:29]([OH:34])[OH:30])=[C:14]1[C:19]=3[CH:18]=[CH:17][CH:16]=[CH:15]1
Reactant: [Li]CCCC
Reactant: Brc1cc2c3ccccc3c3ccccc3c2c2ccccc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: OB(O)c1cc2c3ccccc3c3ccccc3c2c2ccccc12
Temperature: -40 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under an atmosphere of argon, 5.87 g of 10-bromobenzo[g]chrysene was placed in a flask. Then, 200 mL of dehydrated ether and 200 mL of dehydrated toluene were added. After cooling the reaction solution to −40° C., 11 mL of a 1.6M hexane solution of n-butyl lithium was added, and the temperature was elevated to 0° C., followed by stirring for 1 hour. After cooling the reaction solution to −60° C., 10 mL of a dehydrated ether solution of 7.72 g of triisopropyl borate was added dropwisely. The stirring was conducted for 5 hours while heating the reaction solution to room temperature. Then, 100 ml of an aqueous 10% hydrochloric solution was added, followed by stirring for 1 hour. An aqueous phase was removed and an organic phase was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The resulting solids were washed with hexane, whereby 3.18 g (yield: 60%) of intended benzo[g]chrysene-10-boronic acid was obtained.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.[Cl:28][C:29]1[C:30]([C:55]([F:58])([F:57])[F:56])=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]([CH2:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][OH:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)C>[ClH:28].[Cl:28][C:29]1[C:30]([C:55]([F:56])([F:57])[F:58])=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]([CH2:38][CH:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:34][CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=1[S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]
Reactant: OCCCN(Cc1cccc(Cl)c1C(F)(F)F)CC(c1ccccc1)c1ccccc1
Reactant: CN(C)S(=O)(=O)c1cccc(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CN(C)S(=O)(=O)c1ccccc1OCCCN(Cc1cccc(Cl)c1C(F)(F)F)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
DIAD (48 uL, 0.24 mmol) was added dropwise to a RT solution of 3-hydroxy-N,N,-dimethyl-benzenesulfonamide (0.040 g, 0.2 mmol), 3-[(3-chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.088 g, 0.2 mmol) and triphenylphosphine (0.063 g, 0.24 mmol). The mixture was stirred for 48 at rt than was concentrated and purified by reverse phase HPLC to provide a solid which was dissolved in CH2Cl2 and treated with excess 4M HCl in diethyl ether. The mixture was concentrated to provide 35 mg (25%) of the title compound. MS (ESI) 632 (M+H+).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:37]([O:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[O:22])[C@@H:14]([CH3:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:11])[C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].S(O)(C1C=CC(C)=CC=1)(=O)=O.O.[NH:68]([C:77]([O:79][CH2:80][C:81]1[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=1)=[O:78])[C@H:69]([C:74]([OH:76])=O)[C@H:70]([CH2:72][CH3:73])[CH3:71].CN1CCOCC1.ClC(OCC(C)C)=O>CN(C=O)C.[Pd]>[C:40]1([O:39][C:37](=[O:38])[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28][NH:29][C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[NH:23][C:21](=[O:22])[C@H:13]([C@@H:14]([CH3:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[NH:12][C:10](=[O:11])[C@H:2]([C@@H:3]([CH3:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])[NH:1][C:74](=[O:76])[C@H:69]([C@H:70]([CH2:72][CH3:73])[CH3:71])[NH:68][C:77]([O:79][CH2:80][C:81]2[CH:86]=[CH:85][CH:84]=[CH:83][CH:82]=2)=[O:78])[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: C[C@@H](OC(C)(C)C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C
Agent: [Pd]
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCCCNC(=O)OC(C)(C)C)C(=O)Oc1ccccc1)[C@@H](C)OC(C)(C)C)[C@@H](C)OC(C)(C)C
Temperature: -35 °C
Reaction time: 0.08 h

Procedure:
A solution of Z-Thr(tBu)-Thr(tBu)-Lys(Boc)-OPh (346.9 g, 450 mmol) in 1 l DMF was hydrogenated in the presence of Tos-OH.H2O (85.6 g, 450 mmol) and 10% Pd-C. After the hydrogenation was completed the catalyst was filtered off. Z-Ile-OH (132.66, 500 mmol) was dissolved in 700 ml DMF and cooled to -35° C. While stirring at -35° C., N-methylmorpholine (55 ml, 500 mmol) was added, followed by the addition of isobutyl chloroformate (65 ml, 500 mmol). The reaction mixture was activated for 5 min. at -15° C. and quickly cooled to -20° C. The precooled DMF solution (-25° C.) from the hydrogenation step and N-methylmorpholine (50 ml, 450 mmol) were added simultaneously. The reaction mixture was stirred for 15 min. at -15° C. and 1 h at 25° C. and evaporated in vacuo. The residue was dissolved in 3 l ethyl acetate and washed with 10% Na2CO3 sol. (2×1.5 l), satd. NaCl-sol. (1×1 l), 5% KHSO4 /10% K2SO4 sol. (2×1.5 l) and satd. NaCl-sol., dried over Na2SO4, filtered and evaporated in vacuo. The residue was crystallized from ethyl acetate (2 l)/ether (2 l).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>>[CH:32]1([C:35]([N:29]2[CH2:28][CH2:27][N:26]([C:24]([C:6]3[N:5]([CH:2]([CH3:3])[CH3:4])[C:13]4[C:8]([CH:7]=3)=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=4)=[O:25])[CH2:31][CH2:30]2)=[O:36])[CH2:34][CH2:33]1
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Reactant: O=C(Cl)C1CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)C4CC4)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and cyclopropanoyl chloride. Light-yellow solid. MS (m/z): 481.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][NH:22][CH2:21][C@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>CN(C=O)C>[Si:11]([O:18][C@@H:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:21][C@H:20]1[NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNCC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CN(c2ccncc2[N+](=O)[O-])CC[C@H]1O[Si](C)(C)C(C)(C)C
Yield: 98 %

Procedure:
Method 1 was followed using 1 eq each of 4-chloro-3-nitropyridine, tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)piperidin-3-ylcarbamate and triethylamine in DMF yielding tert-butyl (3R,4R)-4-(tert-butyldimethylsilyloxy)-1-(3-nitropyridin-4-yl)piperidin-3-ylcarbamate, (98%). LCMS (m/z): 453.3 (MH+); LC Rt=4.01 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([NH:11][CH3:12])=[O:10].[CH3:13][O:14][C:15](=[O:44])[N:16]=[C:17]([S:42][CH3:43])[C:18]([C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([O:39][CH2:40][CH3:41])[CH:33]=1)=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1.O>CC(C)=O.C(OCC)(=O)C>[CH3:13][O:14][C:15](=[O:44])[N:16]=[C:17]([S:42][CH3:43])[C:18]([C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:8][C:9](=[O:10])[NH:11][CH3:12])=[C:34]([O:39][CH2:40][CH3:41])[CH:33]=1)=[N:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[N:30]=[C:29]([CH3:31])[O:28][N:27]=2)=[CH:22][CH:21]=1
Reactant: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1O
Reactant: CNC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C(=Nc2ccc(-c3noc(C)n3)cc2)C(=NC(=O)OC)SC)ccc1OCC(=O)NC
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
After adding 200 mg of potassium carbonate and 78 mg of 2-bromo-N-methyl-acetamide to a solution of 154 mg of {2-(3-ethoxy-4-hydroxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene}carbamic acid methyl ester in 1 ml of acetone, the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed with ethyl acetate, and the organic layer was washed with 0.5N hydrochloric acid and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (161 mg) as a yellow solid.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]=1)=O.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[NH:29]N>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[N:29]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccccc2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: O=c1ccn(-c2ccccc2)nc1-c1ccnn1-c1cc(F)ccc1F
Yield: 24 %

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-phenyl-1H-pyridazin-4-one (A-1) and 2,5-difluorophenylhydrazine according to the method described for Example 1 in 24% yield. MS: M=351.1 (M+H)+
Reaction SMILES: [C:1]1([C@H:7]([CH3:11])[CH2:8][CH2:9]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.CS(Cl)(=O)=O.[Na+].[I-:27]>C(Cl)Cl.CC(C)=O>[I:27][CH2:9][CH2:8][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: [I-]
Reactant: C[C@H](CCO)c1ccccc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CCI)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 900 mg (6.0 mmol) of 3-(R)-phenylbutan-1-ol (from EXAMPLE 104, Step A) and 3.0 mL (18.0 mmol) of DIEA in 10 mL of CH2Cl2 was treated with 0.7 mL (9.0 mmol) of methanesulfonyl chloride and the resulting mixture was stirred at rt for 1 h. The reaction was quenched with H2O and 50 mL of 1.0 N HCl. The quenched mixture was extracted 3× with CH2Cl2. The organic extracts were washed with sat'd NaCl, dried over Na2SO4, filtered and the filtrate concentrated. A mixture of the residue and 9.0 g (60.0 mmol) of NaI in 10 mL of acetone was heated at reflux for 2 h. The reaction mixture cooled and concentrated. The residue was diluted with H2O and extracted 3× with CH2Cl2. The extracts were washed with sat'd NaCl, dried over Na2SO4, filtered and the filtrate concentrated. The residue was purified by flash chomatography on 50 g of silica eluting with 0-20% EtOAc/hexanes (v/v) to give 1.4 g (90%) of the title compound: 1H NMR (500 MHz) δ 1.31 (d, J=6.9, 31), 2.10-2.14 (2H), 2.87-2.92 (m, 1H), 2.96-3.01 (m, 1H). 3.11-3.15 (m, 1H), 7.22-7.35 (5H).
Reaction SMILES: [CH2:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[I:29]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[I:29][C:13]1[C:12]([O:11][C@H:8]2[CH2:7][CH2:6][C@@H:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][C:17]([C@:22]1([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]1)=[CH:18]2
Reactant: O=C1CCC(=O)N1I
Reactant: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCC[C@H]1CC[C@@H](Oc2ccc3cc([C@]4(C)COC(=O)N4)ccc3c2I)CC1
Yield: 85.6 %

Procedure:
A mixture of (R)-4-(6-(cis-4-butylcyclohexyloxy)naphthalen-2-yl)-4-methyloxazolidin-2-one (Example 5, 113.2 mg, 0.0002967 mol), N-iodosuccinimide (74.8 mg, 0.000332 mol) and zirconium tetrachloride (10 mg, 0.000044 mol) in methylene chloride (2.43 mL, 0.0380 mol) was heated to reflux under argon in a vial overnight. The precipitate was filtered off and the residue was purified with Isco column eluted with EtOAc in hexane from 0 to 40% to give the product as a solid (128.9 mg, 86% yield). NMR showed identity.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])C1C=CC=CC=1.N#N.[H][H]>[Pd].CO>[OH:8][C:9]1[CH:10]=[C:11]([CH2:17][CH2:18][O:19][C@@H:20]2[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]2[N:26]2[CH2:30][CH2:29][C@@H:28]([OH:31])[CH2:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH3:16]
Reactant: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: N#N
Solvent: CO
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2CC[C@@H](O)C2)cc1O
Reaction time: 3 h

Procedure:
To compound (3R)-1-[(1R,2R)-2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol (35.0 g, 75.8 mmol) was added methanol (150 mL). This solution was transferred to a Parr bottle and Pd/C (10% wt/wt on activated carbon) was added portion-wise while maintaining a N2 atmosphere through the reaction mixture. Hydrogen pressure (60 psi) was then applied and the vessel shaken for 3 hours, after which HPLC showed complete consumption of the starting material. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to give (3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup. The crude product was dissolved in 1 M aqueous HCl solution (450 mL) and washed with chloroform (8×250 mL). The aqueous layer was then saturated with solid NaCl (100 g) and the solution was extracted with dichloromethane (8×200 mL). The combined dichloromethane extracts were dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to give 3R)-1-[(1R,2R)-2-[2-(3-hydroxy-4-methoxy-phenyl)ethoxy]cyclohexyl]-3-pyrrolidinol as a colorless syrup; 1H NMR (400 MHz, D2O) δ 7.01 (d, H, J=8.0), 6.86-6.83 (m, 2H), 4.42-4.36 (m, 1H), 4.02 (overlapping dt, 1H, J=5.2, J=10.1), 3.85 (s, 3H), 3.67-3.55 (m, 1H), 3.46-2.81 (m, 7H), 2.77-2.70 (m, 1H), 2.34-2.27 (m, 1H), 2.11-1.74 (m, 5H), 1.41-1.10 (m, 4H); IR: 3439 (O—H stretch), 1592, 1510, 1098, 1022 cm−1; MS (ESI) 336.1 (M+H)+.