Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:10]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:18][C@H:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C@H:19]([NH:18][CH2:10][C@@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:33])=[CH:23][CH:24]=1)=[O:30]
Reactant: CC(C)(C)[Si](C)(C)O[C@H](C=O)c1ccccc1
Reactant: COC(=O)Cc1ccc(OC[C@@H](C)N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(OC[C@@H](C)NC[C@@H](O[Si](C)(C)C(C)(C)C)c2ccccc2)cc1

Procedure:
Following a procedure similar to that described in Preparation 29, but using 1.5 g of (S)-α-(t-butyldimethylsilyloxy)-α-phenylacetaldehyde (prepared as described in Preparation 26), 1.1 g of methyl 4-[2(R)-amino-1-propoxy]phenylacetate (prepared as described in Preparation 27), 10 ml of absolute methanol and 950 mg of sodium cyanoborohydride, the title compound was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH2:19][NH:18][CH2:17][C:16]1=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1.[N:27]([CH2:30][CH3:31])=[C:28]=[O:29].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:30]([NH:27][C:28]([N:18]1[CH2:17][C:16]2=[C:25]3[N:26]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]2)[N:9]2[C@H:5]([CH2:6][CH2:7][CH2:8]2)[C:4]2[C:22](=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=2)[O:21][CH2:20][CH2:19]1)=[O:29])[CH3:31]
Reactant: Fc1ccc2c(c1)[C@H]1CCCN1c1ccn3ncc(c3n1)CNCCO2
Reactant: CCN=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCNC(=O)N1CCOc2ccc(F)cc2[C@H]2CCCN2c2ccn3ncc(c3n2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
To a DCM (0.5 mL) solution of (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaene (Example 21, 5.5 mg, 0.016 mmol) was added isocyanatoethane (1.5 mg, 0.022 mmol), followed by DIEA (1.9 μL, 0.011 mmol). After stirring at ambient temperature overnight the reaction was concentrated and purified by reverse-phase column chromatography, eluting with 0-80% acetonitrile/H2O to afford the title compound (3.3 mg, 50% yield). MS (apci) m/z=425.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[NH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2.[O:21]1CCC[CH2:23][CH:22]1OCCBr.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[CH:9][C:10]1[N:11]([CH2:23][CH2:22][OH:21])[C:12]2[C:17]([CH:18]=1)=[CH:16][C:15]([O:19][CH3:20])=[CH:14][CH:13]=2
Reactant: COc1ccc2[nH]c(C=Cc3ccccc3Cl)cc2c1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)cc(C=Cc1ccccc1Cl)n2CCO
Yield: 86 %

Procedure:
Alkylation of 2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-1H-indole (27) prepared according to example 37 with 2-bromoethyl tetrahydro-2H-pyran-2-yl ether using the procedure described in example 38 followed by reaction of the crude product with 2N HCl in methanol gave 2-{2-[2-(2-Chlorophenyl)ethenyl]-5-methoxy-1H-indol-1-yl}ethanol (III; Ar=2-chlorophenyl, R10═CH2CH2OH) (44) in a yield of 86% as a mixture of E/Z isomers, which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([C:13]1[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([O:26][CH3:27])=[CH:18][C:19]=3[O:24][CH3:25])[N:14]=1)=[CH:8][CH:7]=2.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>CN(C=O)C>[CH3:25][O:24][C:19]1[CH:18]=[C:17]([O:26][CH3:27])[CH:16]=[C:15]2[C:20]=1[C:21](=[O:23])[NH:22][C:13]([C:9]1[CH:10]=[C:11]3[C:6](=[CH:7][CH:8]=1)[NH:5][C:4]([CH2:3][CH2:2][N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[CH:12]3)=[N:14]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCBr)cc4c3)nc2c1
Reactant: C1CCNC1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc4[nH]c(CCN5CCCC5)cc4c3)nc2c1
Temperature: 45 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[2-(2-bromo-ethyl)-1H-indol-5-yl]-5,7-dimethoxy-3H-quinazolin-4-one (6.10 g, 14.2 mmol) in anhydrous DMF (45 mL) was added pyrrolidine (6.07 g, 85.4 mmol) and the reaction mixture was stirred at 45° C. for 15 hours. DMF was removed under reduced pressure, the residue was taken in water (150 mL), and stirred for 30 minutes. Separated solid was filtered, washed with water, and dried under vacuum. Crude compound was purified by column chromatography (silica gel 230-400 mesh, eluting with 5% 7.0 M ammonia in methanol solution in dichloromethane) to give the title compound as a white solid. Yield: 3.4 g (57%). MP 215-217° C. 1H NMR (400 MHz, DMSO-d6): δ 11.79 (s, 1H), 11.21 (s, 1H), 8.31 (s, 1H), 7.88 (dd, J=8.8 and 1.6 Hz, 1H), 7.35 (d, J=8.8 Hz, 1H), 6.71 (d, J=2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.28 (s, 1H), 3.87 (s, 3H), 3.83 (s, 3H), 2.89 (t, J=8.0 Hz, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.48 (m, 4H), 1.67 (m, 4H).
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:15][CH2:14][C:12](=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])[CH3:3].Cl.[CH3:17][O:18][C:19](=[O:28])[C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[C:2]([O:5][C:6]([NH:8][CH:9]1[CH2:15][CH2:14][CH:12]([NH:21][C@@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([O:18][CH3:17])=[O:28])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: COC(=O)[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Product: COC(=O)[C@@H](NC1CCC(NC(=O)OC(C)(C)C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flask charged with 4-N-boc-aminocyclohexanone (commercially available from Combi-Blocks, San Diego, Calif.) (11.00 g, 51.6 mmol) was added DCE (206 mL) followed by (S)-(+)-2-phenylglycine methyl ester hydrochloride (commercially available from Sigma-Aldrich, Milwaukee, Wis.) (10.40 g, 51.6 mmol). The resulting mixture was stirred at room temperature for 15 minutes prior to the addition of sodium triacetoxyborohydride (21.86 g, 103 mmol). The resulting suspension was stirred overnight at room temperature leading to conversion to desired product (˜1:1 cis:trans). To the mixture was added water, and the resulting mixture was transferred to a separatory funnel. The mixture was extracted with EtOAc (2×). The combined organics were dried with Na2SO4, filtered, and dried under reduced pressure. The crude material was purified with a 100 g SNAP column ramping DCM:MeOH (90:10) in DCM (0-25%), then isocratic at 25% (monitoring at 215 nm) to yield (S)-methyl 2-(((1 r,4S)-4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-2-phenylacetate (12.43 g, 34.3 mmol, 66.5% yield) as a mixture of isomers and as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:20][N:19]=2)=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(F)cc2)n[nH]1
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a solution of Intermediate 1A (120 g, 504 mmol) in ethanol (1200 mL) was added hydrazine monohydrate (25.7 mL, 529 mmol) slowly and the resulting reaction mixture was refluxed for 1 h. Reaction mixture was cooled to RT, poured into ice cold water, and the resultant solid dried under vacuum to afford Intermediate 1B (80 g, 67%). MS(ES): m/z=235 [M+H]+; 1H NMR (300 MHz, CDCl3) δ ppm 7.75 (m, 2H), 7.12 (m, 2H), 7.07 (s, 1H), 4.42 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H).
Reaction SMILES: O.[NH2:2][NH2:3].[CH:4](=O)[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CC(O)(C)C>[C:7]1([CH:6]2[NH:3][N:2]=[CH:4][CH2:5]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: O=CC=Cc1ccccc1
Solvent: O
Solvent: CC(C)(C)O
Product: C1=NNC(c2ccccc2)C1

Procedure:
Under N2 atmosphere, hydrazine hydrate (9.2 mL) was added to a solution of cinnamaldehyde (10.0 g) in t-BuOH (20 mL). The mixture was refluxed overnight, followed by concentration under reduced pressure. Water was added to the residue, and the aqueous phase was extracted twice with DCM. The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. This gave 10.46 g of a yellow oil containing 85% of the desired product, which was used in subsequent steps without further purification. 1H NMR (200 MHz, CDCl3) δ 2.61-2.80 (m, 1H), 3.04-3.23 (m, 1H), 4.72 (dd, J=8 and 10 Hz, 1H), 5.60-6.10 (br s, 1H), 6.77-6.87 (m, 1H), 7.18-7.47 (m, 5H).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH:6]=[C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-])=O)[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1>C(O)C.O1CCCC1.[Pd]>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([NH2:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN4CCCC4C3)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Nc1ccc2[nH]cc(C3CCN4CCCC4C3)c2c1
Reaction time: 24 h
Yield: 85.7 %

Procedure:
The 3-(1,2,3,4,5,8-hexahydroindolizin-7-yl)-5-nitro-1H-indole (2.21 g, 6.90 mmol) was dissolved in 95 ml of ethanol and 50 ml of tetrahydrofuran. 5% palladium over carbon was added (550 mg) and the mixture was placed under an atmosphere of hydrogen, at an initial pressure of 60 psi, at room temperature, for 24 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give 1.51 g of a purple foam. (85%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[CH:18])[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[C:18][C:21]2[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C#CC(O)c1ccc(N2CCCC2)c(C(C)(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CC(C)(C)c1cc(C(O)C#Cc2ccc(C(=O)O)cc2)ccc1N1CCCC1
Yield: 45.4 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 640 mg (2.5 mmol) of 1-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)prop-2-yn-1-ol with 520 mg (2.1 mmol) of 4-iodobenzoic acid, 20 mg (0.1 mmol) of copper iodide and 37 mg (0.05 mmol) of bis(triphenylphosphine)palladium chloride. 360 mg of 4-[3-(3-tert-butyl-4-pyrrolidin-1-ylphenyl)-3-hydroxyprop-1-ynyl]benzoic acid are obtained in the form of a beige solid (Mp=150° C., yield=46%).
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH:16](OS(C)(=O)=O)[C:17]([F:20])([F:19])[F:18])[N:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1.C(O)C>CO.[Pd]>[OH:8][C:9]1[C:10](=[O:26])[CH:11]=[C:12]([CH2:16][C:17]([F:18])([F:19])[F:20])[N:13]([CH3:15])[CH:14]=1
Reactant: Cn1cc(OCc2ccccc2)c(=O)cc1C(OS(C)(=O)=O)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: Cn1cc(O)c(=O)cc1CC(F)(F)F
Reaction time: 1.5 h
Yield: 77 %

Procedure:
In a 500-mL reaction vessel was placed methanesulfonic acid 1-(5-benzyloxy-1-methyl-4-oxo-1,4-dihydro-pyridin-2-yl)-2,2,2-trifluoro-ethyl ester (1.80 g, 4.60 mmol), and ethanol (120 mL). The mixture was sonicated to give a clear solution. To the solution was added 1.80 g of Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W). Hydrogenation was carried out under a hydrogen atmosphere set at a pressure of 50 psi. The reaction was completed within 90 min. The reaction mixture was diluted with methanol (120 mL), and the resulting mixture was sonicated for 10 min. The reaction mixture was then filtered through a short hydrochloric acid pre-treated CELITE™ bed. The filtrate was collected, and concentrated in vacuo to a volume of about 100 mL. To the resulting solution was added morpholine polymer-bound beads (1% cross-linked w/DVB, 200-400 mesh, 2.5-4.0 mmol N/g, 5.2 g), and the mixture was vortexed for 3 h. The morpholine beads were removed by filtration. Upon partial concentration in vacuo, a solid separated and the first crop of the title compound was obtained as the free base (0.74 g, 77% yield, HPLC Method 1 (Example 24); RT=8.2 min, HPLC purity (peak percent area): 98.7% at λ=280 nm). 1H NMR (CD3OD) δ ppm: 7.55 (s, 1H), 6.52 (s, 1H), 3.77 (q, J=10 Hz, 2H), 3.78 (s, 3H); MS-ESI (m/z): 208.2 ([M+1]+, 100%), 188.2, 139.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@@H:7]([OH:11])[CH:6]=[C:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1N2CCN(CC2)C1>C1COCC1.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][C@H:5]2[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccc2c(c1)C(c1ccccc1)=C[C@@H]2O
Agent: C1CN2CCN1CC2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)[C@H](c1ccccc1)CC2=O
Yield: 91 %

Procedure:
5-Methyl-3-phenyl-(S)-1H-inden-1-ol (750 mg, 3.41 mmol) and DABCO (190 mg, 1.71 mmol) were dissolved in dry THF:triethylamine 20:1 (15 ml) and refluxed for 3 h. The reaction mixture was evaporated to dryness. Flash chromatography eluting with ethyl acetate:pentane 5:95 gave 690 mg (92%) of the title compound. Rf 0.62 (ethyl actetate:penttanie 20:80) (ChiralCel OD-H) 0.5 ml/min of hexane/isopropanol: 95/5 (S)-isomer 19.12 min, (R)-isomer 22.33 min, 89% ee. IR (neat cm−1): 3027, 2361, 1710, 1605, 1280, 1238, 1040. 1H NMR δ: 2.39 (s, 3H), 2.69 (dd, J=3.0, 19.2Hz, 1H), 3.23 (dd, J=8.0, 19.2Hz, 1H), 4.53 (q, J=4Hz, 1H), 7.07 (s, 1H), 7.14 (d, J=8.4Hz, 1H), 7.15 (s, 1H), 7.26 (m, 2H), 7.33 (m, 2H), 7.72 (d, J=7.6Hz, 1H). 13C NMR δ: 22.1, 44.3, 46.9, 123.2, 126.9, 127.0, 127.6, 128.9, 134.5, 143.8, 146.3, 158.4, 205.5. MS (EI 70 eV) m/z (rel. intensity): 220 (100) [M+], 207 (55), 194 (19), 178 (60), 144 (10).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[F:10].[CH3:11][NH2:12]>>[F:10][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:2]=1[NH:12][CH3:11])[C:8]#[N:9]
Reactant: N#Cc1cncc(F)c1Cl
Reactant: CN
Product: CNc1c(F)cncc1C#N
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
4-Chloro-5-fluoro-nicotinonitrile (3.5 g, 22.4 mmol) was suspended in 41% aqueous methylamine solution (35 mL). The resultant mixture was heated, with stirring, at 80° C. for 30 minutes. The mixture was cooled to room temperature and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and concentrated in vacuo and the resultant residue triturated in diethyl ether to provide the title compound (2.35 g, 70%) as a white solid. 1H NMR (CDCl3) 8.29 (1H, s), 8.18 (1H, d, J=4.0 Hz), 5.04 (1H, s, br), 3.34 (3H, dd, J=2.2, 5.5 Hz).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N:23]2[C:27](=[O:28])[CH2:26][NH:25][C:24]2=[O:29])[CH:18]=1)(=O)=O.[NH2:30][CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38][C:39]([CH3:43])([CH3:42])[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:42][C:39]1([CH3:43])[O:38][C:37]2[CH:44]=[CH:45][C:34]([C@@H:32]([OH:33])[CH2:31][NH:30][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[CH:18]=[C:19]([N:23]4[C:27](=[O:28])[CH2:26][NH:25][C:24]4=[O:29])[CH:20]=[CH:21][CH:22]=3)=[CH:35][C:36]=2[CH2:41][O:40]1
Reactant: CS(=O)(=O)OCCCCCCOCCCCc1cccc(N2C(=O)CNC2=O)c1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H](O)CNCCCCCCOCCCCc3cccc(N4C(=O)CNC4=O)c3)ccc2O1
Temperature: 20 °C
Reaction time: 72 h
Yield: 41.9 %

Procedure:
A solution of 6-{4-[3-(2,5-dioxoimidazolidin-1-yl)phenyl]butoxy}hexyl methanesulfonate (766 mg) in DMF (8 ml) was treated with tetrabutylammonium bromide (578 mg) and (1R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (544 mg) and the mixture was stirred at 20° C. for 3 d. The solvent was removed under reduced pressure, the residue was dissolved in CH2Cl2, washed with water and purified by chromatography on Biotage (40 g) eluting with 3% 2M NH3 in MeOH:CH2Cl2 to give the title compound (417 mg). ES+ve 554 (MH)+.
Reaction SMILES: [NH2:1][CH:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].[OH-].[Na+].[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:19][C:20](Cl)=[O:21]>O.C(OCC)C>[O:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH:18]=[CH:19][C:20]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:21]
Reactant: NC(CCC(=O)O)C(=O)O
Reactant: O=C(Cl)C=Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(O)CC[C@H](NC(=O)C=Cc1ccco1)C(=O)O
Reaction time: 1 h
Yield: 52 %

Procedure:
In 75 ml of water was suspended 6.5 g of DL-glutamic acid, and 5.2 g of sodium hydroxide was added, after which the resulting mixture was cooled to -10° C. to -7° C., and a solution of 6 g of β-(2-furyl)acrylic acid chloride in 75 ml of diethyl ether was added thereto dropwise over a period of 1 hour. After the addition, the mixture thus obtained was subjected to reaction at the same temperature for 5 hours, after which the aqueous layer was separated and then adjusted to pH 5.5 with diluted hydrochloric acid. The aqueous layer was washed with two 50-ml portions of ethyl acetate, and the aqueous layer was separated. This aqueous layer was adjusted to pH 2 with diluted hydrochloric acid and then extracted with 100 ml of ethyl acetate, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 5.5 g (yield 52%) of DL-N-[β-(2-furyl)acryloyl]glutamic acid having a melting point of 174.5°-175.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[F-:12].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[CH:3]=[C:4]([S:8]([F:12])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: [F-]
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Product: O=S(=O)(F)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
To a stirred solution of 3-bromophenylsulfonyl chloride (5 g, 0.0196 mol) in acetonitrile (20 ml) was added potassium fluoride (2.27 g, 0.0391 mol) followed by 18-crown-6 ether (0.08 g) and the reaction stirred at room temperature for 18 h. The reaction mixture was then washed with water (60 ml), extracted with ethyl acetate (3×80 ml) and the combined organic extracts dried (Na2SO4). Solvents were evaporated in vacuo to give a yellow oil (3.79 g, 81%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:13][C:12](=[O:14])[CH2:11][N:10]1[CH:15]1[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1>ClCCl>[NH:18]1[CH2:17][CH2:16][CH:15]([N:10]2[CH2:11][C:12](=[O:14])[NH:13][C:9]2=[O:8])[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(=O)NC2=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CN(C2CCNCC2)C(=O)N1
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (0.300 mL) was added to a solution of tert-butyl 4-(2,4-dioxoimidazolidin-1-yl)piperidine-1-carboxylate (32 mg, 0.113 mmol) in dichloromethane (1 mL). After 4 h, the reaction was concentrated to give the title compound. MS184.04 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][O:20][CH2:21][CH2:22]Br>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]([O:11][CH2:22][CH2:21][O:20][CH3:19])[CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12]
Reactant: COCCBr
Reactant: O=C1NCc2c(Br)cc(O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCOc1cc(Br)c2c(c1)C(=O)NC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
A mixture of Example 104B (100 mg, 0.44 mmol), Cs2CO3 (163 mg, 0.5 mmol) and 2-bromoethyl methyl ether (0.045 mL, 0.46 mmol) in DMF (2.2 mL) was warmed to 60° C. for 4 hours, stirred at room temperature overnight, and partitioned between water and ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated to give 128 mg of the desired product. MS (ESI(+)) m/e 286,288 (M+H)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=O)[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>O.C(O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:19](=[N:2][OH:3])[CH3:20])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: NO
Reactant: COc1ccc(C(C)=O)cc1OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(C)=NO)cc1OC
Reaction time: 8 h
Yield: 79.9 %

Procedure:
A solution of hydroxylamine hydrochloride (3.33 grams, 48 mmol) and sodium acetate (4.92 grams, 60 mmol) in 20 milliliters of water was added to a stirring solution of 3′,4′-dimethoxyacetophenone (5.41 grams, 30.0 mmol) in a mixture of water (30 milliliters) and ethanol (30 milliliters), the solution was stirred overnight. The resulting mixture was filtered and the solid was dried in vacuo (60° C., <1 mm) to afford 4.68 grams (80%) of product as a yellow solid: mp 137-138° C.; 1H NMR (CDCl3) δ7.34-7.08 (m, 2H), 6.94-6 80 (m, 1H), 3.92 (s, 3H ), 3.90 (s, 3H), 2.28 (s , 3H); 13C NMR (CDCl3) δ155.6, 150.1, 148.8, 129.2, 119.2, 110.6, 108.6, 55.8.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].C(N(CC)CC)C.[N+:14](=[CH:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[N-:15]>FC(F)(F)S([O-])(=O)=O.[Zn+2].FC(F)(F)S([O-])(=O)=O.O>[OH:6][C:2]([C:4]1[NH:15][N:14]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=1)([CH3:3])[CH3:1]
Reactant: C#CC(C)(C)O
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)c1cc(C(C)(C)O)[nH]n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 27.9 %

Procedure:
Zinc trifluoromethanesulfonate (2.378 mmol, 0.864 g), 2-methyl-3-butyn-2-ol (11.89 mmol, 1 g) and triethylamine (17.83 mmol, 1.804 g) were added into a flask under nitrogen atmosphere. Ethyl diazoacetate (14.27 mmol, 1.628 g) was added slowly and the temperature was carefully raised to 100° C. and stirred for 8 h. Water was added and the mixture was extracted twice with DCM. The combined DCM phases were dried, filtered and evaporated. The crude product was purified by flash chromatography. 0.658 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.28 (t, 3H), 1.45 (s, 6H), 4.24 (q, 2H), 5.34 (s, 1H), 6.52 (s, 1H), 13.22 (bs, 1H).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31](=[O:33])[NH2:32])=[CH:27][N:26]=3)[CH:21]=2)[CH2:16]1)(C)(C)C>C(Cl)Cl>[NH2:14][CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([NH2:32])=[O:33])=[CH:27][N:26]=3)[CH:21]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CC(N)C3)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
Add TFA (5.37 g, 47.1 mmol) to a suspension of [5-(5-carbamoyl-pyridin-2-yloxy)-indan-2-yl]-carbamic acid tert-butyl ester (870 mg, 2.35 mmol) in DCM (30 ml) and stir at ambient temperature overnight. Concentrate mixture on rotary evaporator and purify on cation exchange column (5 g, Varian) to give the title compound (479 mg) as a white solid. Mass spectrum (ion spray): m/z=270 (M+1); 1HNMR (MeOH-d4): 8.61 (s, 1H), 8.22 (d, 1H), 7.24 (d, 1H), 6.98 (s, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 3.80 (m, 1H), 3.18 (m, 2H), 2.72 (m, 2H).