Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH:19]=O)[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:4].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl-].[NH4+]>O1CCCC1.O>[CH3:1][O:2][C:3]([C:5]1([CH2:17][CH2:18][CH2:19][NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9][CH2:8][CH2:7][N:6]1[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[O:4]
Reactant: NCc1ccccc1
Reactant: COC(=O)C1(CCC=O)CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C1(CCCNCc2ccccc2)CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(3-oxopropyl)pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.68 g) in tetrahydrofuran (57 ml) was added benzylamine (6.53 ml) at room temperature, and the mixture was stirred for 1 hour. The mixture was cooled to 0° C., and thereto was added sodium triacetoxyborohydride (5.07 g). The mixture was stirred at room temperature for 12.5 hours. To the reaction mixture were added water (12 ml) and saturated aqueous ammonium chloride solution (200 ml), and the mixture was extracted with n-hexane/ethyl acetate (1/2, 210 ml×2, 120 ml×2) 4 times. To the combined organic layer was added n-hexane (150 ml), and the mixture was extracted with 10% aqueous potassium bisulfate solution (180 ml×3) 3 times. The combined aqueous layer was neutralized by 4M aqueous sodium hydroxide solution to pH 7 to 8, and thereto was added saturated aqueous sodium bicarbonate solution (100 ml). The mixture was extracted with ethyl acetate (200 ml). The separated aqueous layer was extracted with ethyl acetate (200 ml×2) twice, and the combined organic layer was washed with saturated aqueous sodium chloride solution (200 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the titled compound (7.69 g).
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1[C:16]1[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=1.[NH2:25][C:26]1[CH:27]=[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:29]([Cl:32])=[N:30][CH:31]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:32][C:29]1[C:28]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])=[CH:27][C:26]([NH:25][C:2]2[C:3]([C:16]3[CH:21]=[C:20]([S:22][CH3:23])[N:19]=[C:18]([CH3:24])[N:17]=3)=[CH:4][C:5]([CH:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[CH3:9])=[CH:6][N:7]=2)=[CH:31][N:30]=1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Reactant: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2F)nc(C)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CSc1cc(-c2cc(C(C)N3CCOCC3)cnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)nc(C)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.3 %

Procedure:
To a flame dry 15 mL round-bottom flask was added 4-(1-(6-fluoro-5-(2-methyl-6-(methylthio)pyrimidin-4-yl)pyridin-3-yl)ethyl)morpholine (0.160 g, 0.459 mmol), N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (0.122 g, 0.551 mmol), and THF (4.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (Aldrich) (1.837 mL, 1.837 mmol) was then added to the solution in one portion. The now dark burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl. The reaction mixture was partitioned between water and CHCl3. The aqueous layer was extracted with CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, DCM:EtOAc:MeOH=65%:32%:3%) to afford the product as a yellow solid (175 mg). MS (ESI pos. ion) m/z: 550.0. 1H NMR (300 MHz, CDCl3) 8 ppm 1.41 (d, J=6.58 Hz, 3H) 2.34-2.48 (m, 2H) 2.49-2.60 (m, 2H) 2.66 (s, 3H) 2.81 (s, 3H) 3.13 (s, 3H) 3.39 (d, J=6.58 Hz, 1H) 3.72 (t, J=4.38 Hz, 4H) 6.75 (br. s., 1H) 7.45 (s, 1H) 8.01 (d, J=1.90 Hz, 1H) 8.30 (d, J=1.90 Hz, 1H) 8.52 (d, J=2.48 Hz, 1H) 8.76 (d, J=2.48 Hz, 1H) 12.43 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:6]=1[O:12][C:13]([F:16])([F:15])[F:14])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C=O)C>[CH2:18]([N:3]([CH2:1][CH3:2])[C:4](=[O:17])[C:5]1[CH:10]=[CH:9][C:8]([O:11][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])=[CH:7][C:6]=1[O:12][C:13]([F:14])([F:16])[F:15])[CH3:19]
Reactant: CCN(CC)C(=O)c1ccc(O)cc1OC(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C(=O)c1ccc(O[Si](C)(C)C(C)(C)C)cc1OC(F)(F)F
Reaction time: 16 h
Yield: 72.9 %

Procedure:
To a stirring solution of N,N-diethyl-4-hydroxy-2-(trifluormethoxy)benzamide (1876 mg, 6.8 mmol) and diisopropylethylamine (1747 mg, 13.5 mmol) in dry DMF (60 mL) was added chloro(1,1-dimethylethyl)dimethylsilane (1123 mg, 7.5 mmol). The reaction was stirred for 16 h and then quenched with 1M HCl. The reaction was extracted with EtOAc (3×50 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pale yellow oil. The oil was purified by flash chromatography (silica gel, 0–40% EtOAc in hexanes) to give 1941 mg of the desired product as a colorless oil. MS (ESI) 392 (M+H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:31]5[CH:32]=[CH:33][C:28]([C:26]([N:25]([CH3:37])[CH3:24])=[O:27])=[CH:29][CH:30]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4ccc(C(=O)N(C)C)cc4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and 4-(N,N-dimethylaminocarbonyl)phenylboronic acid (Combi-Blocks, San Diego, USA, 25 mg, 0.126 mmol) to give the title compound as a white solid. (HPLC: tR 2.51 min (Method A); M+H=441 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.97 (s, 1H), 8.17 (s, 1H), 8.12-8.10 (m, 1H), 7.96-7.93 (m, 1H), 7.59-7.58 (m, 1H), 7.55-7.50 (m, 4H), 3.93 (s, 3H), 3.58 (s, 3H), 2.99 (s, 3H), 2.94 (s, 3H), 1.95 (s, 3H))
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.CN1CCOCC1.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>C1COCC1>[CH3:25][C:26]1[CH:27]=[C:28]([NH:32][C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[O:34])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Reaction time: 1 h
Yield: 94.8 %

Procedure:
An 0° C. suspension of Example 1D (1.94 g, 8.68 mmol) in THF (44 mL) was sequentially treated dropwise with N-methylmorpholine (0.95 mL, 8.68 mmol) and 3-methylphenyl isocyanate (1.12 mL, 8.68 mmol). The mixture was stirred for 1 hour, diluted with THF (20 mL), stirred at room temperature for 3 hours, and quenched with water (20 mL). The organic phase was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was suspended in 5% methanol/dichloromethane and filtered. The filter cake was washed with dichloromethane and dried to provide 2.94 g of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.29 (s, 3H), 4.52 (s, 2H), 6.80 (d, J=7.5 Hz, 1H), 7.17 (t, J=7.6 Hz, 1H), 7.23–7.27 (m, 1H), 7.31 (s, 1H), 7.53–7.60 (m, 5H), 7.64–7.67 (m, 2H), 8.63 (s, 1H), 8.65 (s, 1H), 8.80 (s, 1H); MS (ESI(+)) m/e 358.1 (M+H)+.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][C:11]2[CH:25]=[CH:24][C:14]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=2)C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][C:11]1[CH:25]=[CH:24][C:14]([O:15][CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:13]([N+:26]([O-:28])=[O:27])[CH:12]=1
Reactant: CC(C)(C)OC(=O)COc1ccc(CCN2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)COc1ccc(CCN)cc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
5 ml of ethanol solution of 1.02 g of hydrazine hydrate were added to 35 ml of ethanol solution of 4.36 g of t-butyl 4-[2-(phthalimido)ethyl]-2-nitrophenoxyacetate and heated under reflux for 2 hours at 100° C. in an argon stream. After cooling, the reaction mixture was filtered through celite, and the filtrate concentrated under reduced pressure. The yellow crystals of t-butyl 4-(2-aminoethyl)-2-nitrophenoxyacetate thus obtained were used in the next reaction without purification.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[F:4][C:5]1[CH:6]=[C:7](I)[C:8]([NH2:11])=[N:9][CH:10]=1.C(N(CC)CC)C>C1COCC1.[Cu]I>[F:4][C:5]1[CH:6]=[C:7]([C:1]#[C:2][CH3:3])[C:8]([NH2:11])=[N:9][CH:10]=1
Reactant: C#CC
Reactant: Nc1ncc(F)cc1I
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC#Cc1cc(F)cnc1N
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
Propyne (15.4 g, 0.39 mol) was condensed into a pre-weighed flask cooled to ca. −40° C. containing THF (80 mL). The solution was added via cannula to a cooled (0-5° C.), degassed mixture of 5-fluoro-3-iodo-pyridin-2-ylamine (61.0 g, 0.26 mol), bis(triphenylphosphine)dichloropalladium(0) (9.0 g, 13.0 mmol), copper (I) iodide (2.95 g, 15.6 mmol) and triethylamine (77.7 g, 107 mL, 0.78 mol) in THF (650 mL). The mixture was stirred at 0-5° C. for 30 minutes then for a further 30 minutes at ambient temperature. The solid was removed by filtration and the cake washed with THF. The filtrate was diluted with ethyl acetate and extracted with 2M hydrochloric acid (×3). The combined acid extract was washed with diethyl ether and then made basic by careful addition of potassium carbonate then extracted with diethyl ether (×3). The combined organic layer was dried (Na2SO4), filtered and evaporated to afford the title compound as a brown solid (32.2 g, 84%). 1H NMR (400 MHz, CDCl3): 7.90 (s, 1H), 7.24 (dd, J=8.4, 2.8 Hz, 1H), 4.84 (s, 2H), 2.11 (s, 3H).
Reaction SMILES: C([O:9][C@@H:10]1[C@@H:15]([O:16]C(=O)C2C=CC=CC=2)[C@H:14]([O:25]C(=O)C2C=CC=CC=2)[C@@H:13]([CH2:34][O:35]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[O:44][C@@H:45]1[C@@H:50]([CH2:51][O:52]C(=O)C2C=CC=CC=2)[O:49][C@H:48]([O:61][C@@H:62]2[C@@H:67]([CH2:68][O:69]C(=O)C3C=CC=CC=3)[O:66][C@H:65]([O:78][C@@H:79]3[C@@H:108]([CH2:109][O:110]C(=O)C4C=CC=CC=4)[O:107][C@@H:82]([O:83][CH2:84][CH2:85][CH2:86][NH:87][C:88](=[O:106])[CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH3:105])[C@H:81]([O:119]C(=O)C4C=CC=CC=4)[C@H:80]3[O:128]C(=O)C3C=CC=CC=3)[C@H:64]([O:137]C(=O)C3C=CC=CC=3)[C@H:63]2[O:146]C(=O)C2C=CC=CC=2)[C@H:47]([O:155]C(=O)C2C=CC=CC=2)[C@H:46]1[O:164]C(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C[O-].[Na+]>CO.C1COCC1>[C@H:11]1([O:44][C@@H:45]2[C@@H:50]([CH2:51][OH:52])[O:49][C@H:48]([O:61][C@@H:62]3[C@@H:67]([CH2:68][OH:69])[O:66][C@H:65]([O:78][C@@H:79]4[C@@H:108]([CH2:109][OH:110])[O:107][C@@H:82]([O:83][CH2:84][CH2:85][CH2:86][NH:87][C:88](=[O:106])[CH2:89][CH2:90][CH2:91][CH2:92][CH2:93][CH2:94][CH2:95][CH2:96][CH2:97][CH2:98][CH2:99][CH2:100][CH2:101][CH2:102][CH2:103][CH2:104][CH3:105])[C@H:81]([OH:119])[C@H:80]4[OH:128])[C@H:64]([OH:137])[C@H:63]3[OH:146])[C@H:47]([OH:155])[C@H:46]2[OH:164])[O:12][C@H:13]([CH2:34][OH:35])[C@@H:14]([OH:25])[C@H:15]([OH:16])[C@H:10]1[OH:9]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](O[C@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](O[C@H]3O[C@H](COC(=O)c4ccccc4)[C@@H](O[C@H]4O[C@H](COC(=O)c5ccccc5)[C@@H](OC(=O)c5ccccc5)[C@H](OC(=O)c5ccccc5)[C@H]4OC(=O)c4ccccc4)[C@H](OC(=O)c4ccccc4)[C@H]3OC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)NCCCO[C@@H]1O[C@H](CO)[C@@H](O[C@H]2O[C@H](CO)[C@@H](O[C@H]3O[C@H](CO)[C@@H](O[C@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)[C@H](O)[C@H]3O)[C@H](O)[C@H]2O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.7 %

Procedure:
Glycoside 126 (377 mg, 161 μmol) was dissolved in MeOH/THF 1:1 (10 mL). NaOMe (60 μL of an 11M solution) was added and the solution was stirred at room temperature for 24 hrs. The mixture was neutralized with acidic resin and the solution filtered before the solvent was evaporated to yield the white solid product which was triturated with EtOAc and the solvent decanted (×3). The solid was dried under vacuum to yield 159 mg of the white solid product (quantitative) which was reacted on without further purification or characterisation.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]([CH2:14][CH2:15][CH3:16])[CH:11]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)C1C=CC=CC=1.Cl[C:45]([O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[O:46]>>[CH2:37]([O:36][C:34]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[C:26]([CH2:25][O:24][CH:10]2[CH:11]([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH:12]([CH2:14][CH2:15][CH3:16])[CH2:13][N:8]([C:45]([O:47][CH2:48][CH2:49][Si:50]([CH3:53])([CH3:52])[CH3:51])=[O:46])[CH2:9]2)[CH:35]=1)[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CCCC1CN(Cc2ccccc2)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1
Reactant: C[Si](C)(C)CCOC(=O)Cl
Product: CCCC1CN(C(=O)OCC[Si](C)(C)C)CC(OCc2cc(OCc3ccccc3)c3ccccc3c2)C1c1ccc(F)cc1

Procedure:
In an analogous manner to that described in Example 1(d), by reacting (3RS,4RS,5SR)-1-benzyl-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine with β-trimethylsilylethyl chloroformate [Synthesis 346 (1987)] there was obtained 2-trimethylsilanylethyl (3RS,4RS,5SR)-3-(4-benzyloxy-naphthalen-2-ylmethoxy)-4-(4-fluoro-phenyl)-5-propyl-piperidine-1-carboxylate as a pale yellow syrup, MS: 628 (M+H)+.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][O:27][C@@H:28]1[CH2:32][CH2:31][C@@H:30]([CH2:33][C:34](OC)=[O:35])[CH2:29]1>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:34](=[O:35])[CH2:33][C@@H:30]5[CH2:31][CH2:32][C@@H:28]([O:27][CH3:26])[CH2:29]5)[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: COC(=O)C[C@@H]1CC[C@@H](OC)C1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: CO[C@@H]1CC[C@@H](CC(=O)N[C@H]2CC[C@H](CCN3CCC(c4cccc5c4OCO5)CC3)CC2)C1

Procedure:
The title compound, white solid (22.2 mg, 77.4%), MS (ISP) m/z=471.5 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25.7 mg, 0.070 mmol) and methyl 2-((1R,3R)-3-methoxycyclopentyl)acetate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)=[CH:18][CH:17]=1)C1C=CC=CC=1.CCOC(C)=O>CO.C(Cl)Cl.[Pd]>[F:15][C:13]1[CH:12]=[CH:11][C:10]([C:16]2[N:21]=[N:20][C:19]([N:22]([CH3:33])[CH:23]3[CH2:28][C:27]([CH3:29])([CH3:30])[NH:26][C:25]([CH3:32])([CH3:31])[CH2:24]3)=[CH:18][CH:17]=2)=[C:9]([OH:8])[CH:14]=1
Reactant: CN(c1ccc(-c2ccc(F)cc2OCc2ccccc2)nn1)C1CC(C)(C)NC(C)(C)C1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(c1ccc(-c2ccc(F)cc2O)nn1)C1CC(C)(C)NC(C)(C)C1
Reaction time: 4 h
Yield: 81.6 %

Procedure:
Following GENERAL METHOD 4-1, Pd/C (10% wt, 47.0 mg, 0.044 mmol) was added to a solution of 6-(2-(benzyloxy)-4-fluorophenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (198 mg, 0.441 mmol) in MeOH (2 mL)/EtOAc (2 mL) at RT. The reaction mixture was evacuated and filled with H2 (2×), then stirred under H2 atmosphere for 4 h and filtered through celite using MeOH. The filtrate was concentrated in vacuo affording a yellow oil, which was redissolved in DCM and concentrated in vacuo affording the title compound as a yellow solid (129 mg, 82% yield). LCMS Rt=0.49 min (LCMS method Q); MS (M+1)=359.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 14.10 (br. s, 1H), 8.11 (d, J=9.60 Hz, 1H), 7.83-7.92 (m, 1H), 7.32 (d, J=10.11 Hz, 1H), 6.67-6.77 (m, 2H), 4.83-4.98 (m, 1H), 2.95 (s, 3H), 1.54 (dd, J=12.13, 3.54 Hz, 2H), 1.43 (t, J=12.13 Hz, 2H), 1.25 (s, 6H), 1.09 (s, 6H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S(O[CH2:29][C@H:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(C1C=CC(C)=CC=1)(=O)=O>CN(C=O)C>[C:38]([O:37][C:35]([N:31]1[CH2:32][CH2:33][CH2:34][CH:30]1[CH2:29][O:17][C:14]1[CH:13]=[CH:12][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:16][CH:15]=1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC1COc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 55.6 %

Procedure:
To a 15 mL of anhydrous DMF was added NaH (60% dispersion in oil, 338 mg, 8.44 mmol), and the resulting reaction mixture was cooled to 0° C. p-benzyloxy phenol (1.41 g, 7.03 mmol) was added and the reaction mixture was stirred at rt for 45 min. It was then cooled to −5° C., and (R)-Boc-prolinol tosylate (2.5 g, 7.03 mmol) in anhydrous DMF (5 mL) was cooled in a separate ice-bath and added dropwise to the reaction mixture. It was then allowed to warm to rt and stirred at 92° C. for 5 h and at rt overnight. The resulting mixture was poured into 200 mL ice/water and stirred for an hour. The resulting precipitate was filtered, washed with ether, dried over MgSO4, concentrated, recrystallized with ether/hexane to give shiny yellow crystals (1.5 g, 55%).
Reaction SMILES: [C:1]1(C)[CH:6]=CC(S(OCCC#C)(=O)=O)=[CH:3][CH:2]=1.[F:16][C:17]([F:29])([F:28])[CH2:18][CH2:19][S:20]([CH2:23][C:24]([O:26][CH3:27])=[O:25])(=[O:22])=[O:21].[H-].[Na+].Cl>CS(C)=O>[F:29][C:17]([F:16])([F:28])[CH2:18][CH2:19][S:20]([CH:23]([CH2:3][CH2:2][C:1]#[CH:6])[C:24]([O:26][CH3:27])=[O:25])(=[O:21])=[O:22]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C#CCCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F
Reaction time: 96 h
Yield: 35.3 %

Procedure:
To a solution of 2.0 g of 3-butynyl p-toluenesulfonate and 2.1 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 30 ml of dimethyl sulfoxide, 0.4 g of sodium hydride (60% in oil) was added at room temperature, and stirred at the same temperature for 4 days. To the reaction mixture, 10% hydrochloric acid was added, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 0.90 g of methyl 2-(3,3,3-trifluoropropylsulfonyl)-5-hexynoate (hereinafter referred to as the present compound (8)).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])=[O:9].[Br:18]N1C(=O)CCC1=O.ClCCl>FC(F)(F)C(O)=O>[CH3:6][O:7][C:8]([C:10]1[S:11][C:12]([Br:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1sc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sulfuric acid (98% strength; 12 mL) was added to a solution of 3-nitrothiophene-2-carboxylic acid methyl ester (Barker et al., Synth. Commun. 1995, 25, 3729; 20.8 g) in trifluoroacetic acid (60 mL). At 0° C., N-bromosuccinimide (21.9 g) was added in portions over a period of 45 minutes. After a further 30 minutes, the mixture was warmed to room temperature and poured into ice-water. The organic phase obtained by extraction with dichloromethane was dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product with the molecular weight of 266.07 (C6H4BrNO4S) was obtained in this way; MS (ESI): 266 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([OH:36])[C@H:19]([CH3:37])[O:18][C:17]1=[O:38])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O[CH:46]1[CH2:50][CH2:49][CH:48]=[CH:47]1)OC(C)(C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].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.[Fe+2]>[C:11]([O:10][C:9]([N:8]([C@H:16]1[CH2:24][O:23][CH2:22][C@H:21]([CH2:25][C:26]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:29]=[CH:28][CH:27]=2)[C@@H:20]([O:36][CH:50]2[CH2:49][CH2:48][CH:47]=[CH:46]2)[C@H:19]([CH3:37])[O:18][C:17]1=[O:38])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:15])([CH3:13])([CH3:14])[CH3:12]
Reactant: CC(C)(C)OC(=O)OC1C=CCC1
Reactant: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1OC(=O)[C@@H](N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)COC[C@H](Cc2cccc3ccccc23)[C@H]1OC1C=CCC1
Temperature: 95 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-hydroxy-9-methyl-7-(1-naphthylmethyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (205 mg, 0.387 mmol), [Pd2(dba)3] (26.6 mg, 0.029 mmol), and dppf (32.5 mg, 0.058 mmol) in toluene (1.94 mL) was added (E) tert-butyl cyclopent-2-en-1-yl carbonate (250 mg, 1.355 mmol), and the mixture was warmed to 95° C. and stirred for 2 h. An additional portion of (E)-tert-butyl pent-2-en-1-yl carbonate (150 mg, 0.6 equiv.) was added to the reaction and stirring continued for an additional 2 h. The mixture was cooled to room temperature and the toluene was removed under reduced pressure. The residue was dissolved in CH2Cl2 (12 mL), adsorbed to Celite® and purified by flash chromatography (SiO2, 35 mL/min, 0→25 EtOAc/hexanes) to provide tert-butyl N-tert-butoxycarbonyl-N-[(3S,7S,8R,9S)-8-cyclopent-2-en-1-yloxy-9-methyl-7-(1-naphthylmethyl)-2-oxo-1,5-dioxonan-3-yl]carbamate (205 mg, 89%) as a mixture of diastereomers (about 1:1) in the form of a white solid: IR (thin film) 2928, 1755, 1709, 1117 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.09 (m, 1H), 7.82 (m, 1H), 7.74-7.66 (m, 1H), 7.53-7.39 (m, 2H), 7.42-7.28 (m, 2H), 6.13-6.01 (m, 1.5H), 6.01-5.92 (m, 0.5H), 5.07 (app t, J=7.7 Hz, 1H), 4.90-4.79 (m, 2H), 4.02-3.83 (m, 2H), 3.76 (dd, J=13.6, 2.8 Hz, 1H), 3.55-3.39 (m, 3H), 2.82-2.66 (m, 1H), 2.60-2.47 (m, 1H), 2.34-2.17 (m, 2H), 2.11-1.92 (m, 3H), 1.57 (app dd, J=12.6, 6.4 Hz, 3H), 1.39 (app d, J=5.9 Hz, 18H); ESIMS m/z 618 ([M+Na]+).