Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:12]([CH3:14])=[N:11][C:10]=2[C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)[CH3:5])=[N+]=[N-].CP(C)C.CCOC(C)=O>O1CCCC1.O>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:4]([NH2:1])[CH3:5])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc2c(-c3cccc(F)c3)c(C(C)N=[N+]=[N-])ccc2s1
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2c(-c3cccc(F)c3)c(C(C)N)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-(1-azidoethyl)-4-(3-fluorophenyl)-2-methyl-1,3-benzothiazole (0.088 g, 0.28 mmol) in tetrahydrofuran (0.8 mL) and water (0.203 mL) was added 1.00 M of trimethylphosphine in tetrahydrofuran (0.338 mL, 0.338 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added EtOAc and the mixture was extracted with 1 N HCl two times. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue, showing two peaks with the same desired mass, was used directly in next step (74 mg, 91%). LCMS calculated for C16H16FN2S(M+H)+: m/z=287.1; found: 287.1.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[N-:35]=[N+]=[N-].[Na+]>CS(C)=O.O.[Cu]I.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>[NH2:35][C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([NH:14][CH2:15][CH3:16])=[O:13])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: [Cu]I
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(N)c2s1
Temperature: 110 °C
Yield: 92.3 %

Procedure:
Ethyl 1-(5-(7-bromo-2-(3-ethylureido)benzo[d]thiazol-5-yl)pyrimidin-2-yl)-4-methylpiperidine-4-carboxylate (306 mg, 0.56 mmol), trans-(1R,2R)—N,N′-bismethyl-1,2-cyclohexane (24 mg, 0.17 mmol), sodium azide (73 mg, 1.12 mmol) and sodium ascorbate (6 mg, 0.028 mmol) were stirred in DMSO-water 1:1 (3 ml) which had been degassed with N2. CuI (1.1 mg, 0.0056 mmol) was added and the tube purged with N2, sealed and heated to 110° C. for 2 h. The mixture turned black and evolution of gas was observed. LCMS after this time indicated 34% conversion to the desired amine and starting material remaining. Additional equivalents of all reagents were added and the reaction was heated to 110° C. for a further 2 h. LCMS after this time indicated 75% conversion to the desired material. The solvents were removed under reduced pressure and the resulting residue was triturated with water. The resulting solid was isolated by filtration and dried to afford the crude product (250 mg, 73% purity by LCMS) (92%). This material was used directly in the next step without further purification.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([S:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:15][CH2:14]2)=O>C1COCC1>[C:23]1([S:20]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH2:9][OH:8])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)(=[O:21])=[O:22])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2S(=O)(=O)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCc2cc(CO)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
LAH (0.10 g, 2.52 mmol) was added to a solution of 11 (0.40 g, 1.26 mmol) in THF (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2 h before it was quenched with water and then extracted with CH2Cl2 (15 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure. The reaction mixture was purified by silica gel chromatography (EtOAc:n-hexane=1:1) to afford 12 (0.24 g). 1H NMR (500 MHz, CDCl3): δ 2.83 (t, J=8.4 Hz, 2H), 3.92 (t, J=8.5 Hz, 2H), 4.49 (s, 2H), 7.09 (s, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.46-7.49 (m, 2H), 7.53 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.76 (d, J=7.7 Hz, 2H).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:27]([O:37][C@H:38]3[C@H:42]4[O:43][CH2:44][C@@H:45]([O:46][CH2:47][CH:48]=[O:49])[C@H:41]4[O:40][CH2:39]3)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1.[OH2:50]>C(Cl)(Cl)(Cl)Cl.C(#N)C.CCOC(C)=O.C(Cl)Cl.CO.CC(O)=O.O.[Ru](Cl)(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:27]([O:37][C@H:38]3[C@H:42]4[O:43][CH2:44][C@@H:45]([O:46][CH2:47][C:48]([OH:50])=[O:49])[C@H:41]4[O:40][CH2:39]3)=[N:26][C:11]2=[N:12][C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: O
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OCC=O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3OCC(=O)O)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium periodate (19.4 mg, 0.091 mmol) and ruthenium (III) chloride hydrate (1.3 mg, 5.77 μmol) were added to a stirred biphasic mixture of 2-[[(3R,3aR,6R,6aR)-6-[6-chloro-5-(4-phenylphenyl)-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-yl]oxy]acetaldehyde (13.8 mg, 0.022 mmol) in carbon tetrachloride (0.12 ml), acetonitrile (0.09 ml), and water (0.15 ml). The reaction mixture was stirred at room temperature. After 3 hours, the reaction mixture was partitioned between EtOAc (30 ml) and water (30 ml). The aqueous layer was extracted with EtOAc (2×20 ml). The organic layers were combined, washed with brine (1×20 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a colorless residue. The residue was dissolved in EtOAc and loaded onto a 500 micron 20 cm×20 cm silica gel plate, which was developed twice using a 94:5:1 DCM/MeOH/AcOH solvent mixture (fresh solvent was used for each development). The silica containing the product band was collected and eluted with a 90:9:1 DCM/MeOH/AcOH solvent mixture (80 ml). The solvent was evaporated under reduced pressure to give the desired product as a colorless residue. LC-MS: calculated for C32H36ClN3O7Si 637.2 observed m/e: 638.33 (M+H)+ (Rt 1.35/2 min)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:20]=[C:19]3[N:21](COCC[Si](C)(C)C)[N:22]=[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH:31]([C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[CH2:32][CH2:33][NH:34]C(OC(C)(C)C)=O)[N:25]=4)[C:18]3=[CH:17][N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>ClCCl>[NH2:34][CH2:33][CH2:32][CH:31]([NH:30][C:26]1[N:25]=[C:24]([C:23]2[C:18]3[C:19](=[N:20][C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)=[N:16][CH:17]=3)[NH:21][N:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)NCCC(Nc1cccc(-c2nn(COCC[Si](C)(C)C)c3nc(NC4CCC(NC(=O)OC(C)(C)C)CC4)ncc23)n1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCC(Nc1cccc(-c2n[nH]c3nc(NC4CCC(N)CC4)ncc23)n1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of {4-[3-[6-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyridin-2-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-6-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (71 mg, 0.09 mmol) in dichloromethane (2 mL) was added CF3COOH (2.2 mL). This mixture was stirred at room temperature for 4 hours. The solvent was then removed under reduced pressure. A saturated aqueous solution of NaHCO3 was added to the residue, and then extracted with ethyl acetate (3×15 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC to give product which was treated with conc. HCl acid to give N-{3-[6-(3-amino-1-phenyl-propylamino)-pyridin-2-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}-cyclohexane-1,4-diamine; hydrochloride as a yellow solid. (Yield 22 mg, 53.3%).
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]([OH:30])[CH2:14][N:15]2[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=3[CH2:19][CH2:18][C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]2=3)[CH2:7]1)=[O:5])C.[OH-].[Na+].O>C(O)C>[CH:26]1[C:17]2[CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N:15]([CH2:14][CH:13]([OH:30])[CH2:12][N:8]3[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]3)[C:16]=2[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@@H]1CCCN(CC(O)CN2c3ccccc3CCc3ccccc32)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CC(O)CN2c3ccccc3CCc3ccccc32)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65 %

Procedure:
The above ester (0.38 g, 0.93 mmol) was dissolved in ethanol (5 ml), 2 N sodium hydroxide (1.54 ml, 3.07 mmol) was added and the homogeneous mixture was stirred at room temperature for 24 h. Water (15 ml) was added and the ethanol was removed in vacuo. The aqueous solution was washed with ether (2×10 ml) and pH was adjusted to 6 by addition of 1N hydrochloric acid. The acidic mixture was extracted with dichloromethane (2×15 ml). The combined organic extracts were washed with water (20 ml), dried (MgSO4) and concentrated in vacuo. The residue was triturated with ether and the product collected by filtration to give 0.23 g (66%) of the title compound as a powder.
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[NH2:18][C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1.C(=O)=O>>[NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([NH:18][C@H:19]([C:30]([O:32][CH3:33])=[O:31])[CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)=[O:7])[CH2:3][OH:4]
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: O=C=O
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1

Procedure:
The dipeptide Ser-Trp was synthesized according to standard peptide technology. In a first step Z-Ser-OH and Trp-OMe were coupled via the carbonic anhydride methodology (J. Am. Chem. Soc. 1967, 5012) to yield the protected dipetide Z-Ser-Trp-OMe. To that end Trp-OMe.HCl was suspended in tetrahydrofuran (THF) and subsequently N-methylmorpholine (NMM) was added. The mixture was stirred for one hour and subsequently added to a solution of Z-Ser in tetrahydrofuran/dimethylformamide (THF/DMF). A second equivalent of NMM was added and the mixture was cooled to −15° C. Isobutyl chloroformate is added at such a rate that the internal temperature does not exceed −15° C. Subsequently, the mixture was stirred for 3 hours, the temperature was allowed to rise to ambient temperature and the precipitated NMM.HCl was removed by filtration. The filtrate was kept at 4° C. overnight after which any additional precipitate was filtered and the filtrate is concentrated in vacuo. The residue was purified by column chromatography (SiO2, ethyl acetate/heptane). The combined fractions were concentrated, washed with water to remove any remaining DMF and concentrated in vacuo.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[CH3:12][O:13][C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:21]=2[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[NH:16][N:15]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[C:57]([O:61][C:62]([N:64]([CH:77]([CH3:79])[CH3:78])[CH2:65][C@H:66]([C:70]1[CH:75]=[CH:74][C:73]([Cl:76])=[CH:72][CH:71]=1)[C:67](O)=[O:68])=[O:63])([CH3:60])([CH3:59])[CH3:58]>C(Cl)Cl>[Cl:76][C:73]1[CH:74]=[CH:75][C:70]([C@H:66]([C:67]([N:26]2[CH2:25][CH2:24][N:23]([C:21]3[C:20]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:19][N:18]=[C:17]4[NH:16][N:15]=[C:14]([O:13][CH3:12])[C:22]=34)[CH2:28][CH2:27]2)=[O:68])[CH2:65][N:64]([CH:77]([CH3:78])[CH3:79])[C:62](=[O:63])[O:61][C:57]([CH3:59])([CH3:58])[CH3:60])=[CH:71][CH:72]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCNCC3)c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1n[nH]c2ncc(-c3ccccc3)c(N3CCN(C(=O)[C@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)CC3)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.0558 mL, 0.320 mmol) was added to 3-methoxy-5-phenyl-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.034 g, 0.080 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (0.0308 g, 0.0961 mmol) and (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0274 g, 0.080 mmol, see Example B) in DCM (1 mL) and stirred at room temperature for 1 hour. The reaction was concentrated to dryness. The resulting residue was dissolved in THF/MeOH (2 mL, 1:1), and an aqueous LiOH solution (1 mL, 2M) was added. It was stirred for 30 minutes, and then ether (20 mL) was added. The organic layer was separated, washed with brine (10 mL), and dried over sodium sulfate. After removal of solvent, the resulting residue was purified by column chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.4 mL) was added. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-3-(isopropylamino)-1-(4-(3-methoxy-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)propan-1-one dihydrochloride (0.029 g, 60%). MS APCI (+) m/z 533.3 detected.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.C([Sn](CCCC)(CCCC)[C:28]([O:30][CH2:31][CH3:32])=[CH2:29])CCC>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>[CH2:31]([O:30][C:28]([C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH3:22])[N:17]=[CH:16]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1)=[CH2:29])[CH3:32]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CC(c1ccc2c(cnn2C)c1)c1cnc2ccc(Cl)nn12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: C=C(OCC)c1ccc2ncc(C(C)c3ccc4c(cnn4C)c3)n2n1
Yield: 95.6 %

Procedure:
The title compound (415.0 mg, 86%, 90% pure) was synthesized from 6-chloro-3-[1-(1-methyl-1H-indazol-5-yl)-ethyl]-imidazo[1,2-b]pyridazine (390.0 mg, 1.25 mmol), tributyl(1-ethoxyvinyl)stannane (497.0 mg, 1.38 mmol) and Pd(PPh3)4 (145 mg, 0.13 mmol) using the same procedure as described in the synthesis of compound 69.3. LCMS (method A): [MH]+=348, tR=5.86 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][N:8](C(OCC2C=CC=CC=2)=O)[CH2:7]1.Cl.C(Cl)[Cl:24].CO>O1CCOCC1>[ClH:24].[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1
Reactant: ClCCl
Reactant: O=C(OCc1ccccc1)N1CCCC(c2ncc[nH]2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: c1c[nH]c(C2CCCNC2)n1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A 250-mL round-bottomed flask was charged with a solution of benzyl 3-(1H-imidazol-2-yl)piperidine-1-carboxylate (1.5 g, 5.26 mmol, 1.00 equiv) in dioxane (15 mL). To this was added conc. HCl (9 mL). The resulting mixture was stirred for 4 hours at 70° C. in an oil bath. The reaction progress was monitored by TLC (DCM: MeOH=10:1). Upon completion, the resulting solution was diluted with dioxane (10 mL) and concentrated on a rotary evaporator affording 3-(1H-imidazol-2-yl)piperidine hydrochloride as black solid in (0.48 g, 57%).
Reaction SMILES: C(N(CC)[CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21])C.N#C[Br:26]>C(OCC)C>[Br:26][CH2:4][C:5]#[C:6][CH2:7][N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:9]1=[O:21]
Reactant: CCN(CC)CC#CCN1CC[C@H](O[Si](C)(C)C(C)(C)C)C1=O
Reactant: N#CBr
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CC#CCBr)C1=O
Yield: 81.5 %

Procedure:
A solution of 2.4 g of (S)-1-[4-diethylamino-2-butynyl]-3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]-2-pyrrolidinone and 0.8 g of cyanogen bromide in 40 ml of diethyl ether is stirred at room temperature for 18 hours. The solution is washed with 30 ml of 1N hydrochloric acid and saturated sodium bicarbonate, dried and concentrated in vacuo. The residue is purified by chromatography (silica gel, methylene chloride) to give 2.0 g of the desired product as a colorless oil. [α]D26° =-31° (methylene chloride).
Reaction SMILES: [NH2:1][C:2](=O)[CH:3]([C:26]1[C:34]2[C:30](=[CH:31][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:33]=2)[CH:29]=[C:28]([Cl:43])[CH:27]=1)[O:4][CH2:5][C:6]1([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C)C=O>[Cl:43][C:28]1[CH:27]=[C:26]([CH:3]([C:2]#[N:1])[O:4][CH2:5][C:6]2([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:34]2[C:30](=[CH:31][N:32]([CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])[N:33]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(N)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(C#N)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 5 h

Procedure:
To a solution of tert-butyl 4-((2-amino-1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-oxoethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (64 mg, 0.099 mmol) in dimethylformamide (0.7 mL) at 0° C. was added cyanuric chloride (18.2 mg, 0.10 mmol). The ice bath was removed and stirring continued for 5 h. The reaction was diluted with diethyl ether and quenched by addition of water. After stirring for 10 min, the ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (18%→25% ethyl acetate/n-hexane) gave 31 mg (50%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ0 8.08 (s, 1H), 7.68 (d, J=1.2 Hz, 1H), 7.29 (dd, J=8.6, 5.2 Hz, 2H), 7.24 (s, 1H), 7.00 (dd, J=8.9, 8.5 Hz, 2H), 5.71 (s, 1H), 5.69 (d, J=10.7 Hz, 1H), 5.64 (d, J=10.7 Hz, 1H), 3.76 (m, 3H), 3.61 (t, J=8.2 Hz, 2H), 3.58 (d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.14 (m, 2H), 1.90 (m, 2H), 1.43 (s, 9H), 0.92 (m, 2H), −0.03 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.5 (d, J=246 Hz), 155.0, 144.3, 137.6, 128.9 (d, J=8.6 Hz), 127.6, 125.9, 124.4, 122.92, 122.87, 121.0, 116.6, 115.4(d, J=21 Hz), 82.1, 79.6, 78.6, 68.0, 66.5, 41.2, 40.0 (br), 32.0, 28.5, 17.9, −1.3. Mass spec.: 629.35 (MH)+
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:13])(=[NH:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N+](C1C=C(S(C)(=NC(OCC)=O)=O)C=CC=1)([O-])=O.[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([CH3:13])(=[N:12][C:36](=[O:37])[NH:35][CH:32]([CH3:34])[CH3:33])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)N=C=O
Reactant: CS(=N)(=O)c1cccc([N+](=O)[O-])c1
Agent: CCOC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)N=S(C)(=O)c1cccc([N+](=O)[O-])c1
Temperature: 104 °C
Reaction time: 60 h

Procedure:
8.24 g (41.2 mmol) (RS)-S-(3-nitrophenyl)-S-methylsulfoximide (Intermediate 4, step 1) in 370 ml toluene were treated with 13.6 mL (138.3 mmol) isopropyl isocyanate. The mixture was stirred under argon at 104° C. for 5 hours and at room temperature for 60 hours. 4.5 mL (46 mmol) isopropyl isocyanate were added and the mixture was stirred under argon at 104° C. for 6 hours and at room temperature for 16 hours. 4.5 ml (46 mmol) isopropyl isocyanate were added and the mixture was stirred under argon at 104° C. for 7 hours and at room temperature for 17 hours. The mixture was cooled with ice for 40 minutes.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C([Li])(C)(C)C.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:16][C:15]=1[CH:26]=[O:27].[Cl-].[NH4+]>C1COCC1.CCCCC>[NH:5]1[CH:6]=[C:2]([CH:26]([C:15]2[CH:16]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:18]=[CH:19][C:14]=2[O:13][CH3:12])[OH:27])[N:3]=[CH:4]1
Reactant: COc1ccc(-c2ccccc2)cc1C=O
Reactant: Brc1c[nH]cn1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ccc(-c2ccccc2)cc1C(O)c1c[nH]cn1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 34.3 %

Procedure:
4-Bromo-1H-imidazole (5.20 g) was dissolved in THF (50 ml) and the mixture was cooled to −78° C. A solution (1.7 M; 50 ml) of t-butyllithium in pentane was added. The mixture was stirred at 0° C. for 1.5 h and cooled to −78° C. again. A solution (30 ml) of 4-methoxy[1,1′-biphenyl]-3-carbaldehyde (2.54 g) in THF was added, and the mixture was heated from −78° C. to room temperature and further stirred at room temperature for 24 h. Aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The organic layer was dried and concentrated. The residue was purified by silica gel column chomatography (eluent, dichloromethane:methanol=15:1) and recrystallized from ethyl acetate to give the title compound (1.15 g) as a colorless solid.
Reaction SMILES: [NH:1]1[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].[C:16](ON1C(=O)CCC1=O)([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17]>C1COCC1.O.C1COCC1.O>[N:1]1([C:16]([O:18][CH2:19][CH:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]3[C:32]2=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:17])[CH2:9][C@H:7]([OH:8])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of H-trans-Hyp-OH (122.5 g, 362 mmol) in THF/H2O (100 mL/200 mL) is added 2N Na2CO3 (250 mL), along with addition of a suspension of Fmoc-OSu in THF (700 mL). The mixture is stirred at room temperature overnight. The mixture is diluted with H2O (2700 mL) and extracted with ether/petroleum ether (500 mL/500 mL) The aqueous layer is acidified by 6N HCl and then extracted with ethyl acetate (1×1000 mL, 1×500 mL). The combined extract is washed with brine once and dried over Na2SO4. After removal of most of solvent, the residue is treated with ethyl ether (200 mL). The white solid is filtered and dried under vacuum. Yield: 125.8 g (356 mmol, 98%)