Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH:15]=[O:16])=[CH:4][C:3]=1[CH2:19][OH:20].[O:21]1[CH:26]=[CH:25][CH2:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[Na+].[Na+].O.C(Cl)(Cl)Cl>ClCCl.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O>[Br:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=2[CH:15]=[O:16])=[CH:4][C:3]=1[CH2:19][O:20][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26][O:21]1
Reactant: N#Cc1ccc(Oc2ccc(Br)c(CO)c2)c(C=O)c1
Reactant: C1=COCCC1
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(Oc2ccc(Br)c(COC3CCCCO3)c2)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
A mixture of 4-[4-bromo-3-(hydroxymethyl)phenoxy]-3-formylbenzonitrile (25.5 g, 76.8 mmol), 3,4-dihydro-2H-pyran (10.4 mL, 115 mmol), and dl-10-camphorsulfonic acid (356 mg, 2 mol %) in dichloromethane (300 mL) was stirred at room temperature for 2 h. Sodium carbonate (3 g) was added, and the mixture was poured into water/chloroform. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column (85:15 hexane/ethyl acetate) to give 4-[4-bromo-3-(2-tetrahydropyranyloxymethyl)phenoxy]-3-formylbenzonitrile (28.0 g, 88%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([F:10])=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([B:19]2[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]2)[CH:18]=1)[NH2:15].CS(O)(=O)=O>O1CCOCC1.C(OCC)(=O)C>[F:10][C:5]1[C:6]([O:8][CH3:9])=[N:7][C:2]([NH:15][C:14]2[CH:16]=[C:17]([B:19]3[O:23][C:22]([CH3:24])([CH3:25])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:18]=[C:12]([CH3:11])[CH:13]=2)=[N:3][CH:4]=1
Reactant: COc1nc(Cl)ncc1F
Reactant: Cc1cc(N)cc(B2OC(C)(C)C(C)(C)O2)c1
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1nc(Nc2cc(C)cc(B3OC(C)(C)C(C)(C)O3)c2)ncc1F
Temperature: 25 °C

Procedure:
A solution of 2-chloro-5-fluoro-4-methoxypyrimidine (0.32 g, 1.97 mmol) and 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.40 g, 1.72 mmol) in dioxane (17 mL) and methanesulfonic acid (0.13 mL, 1.97 mmol) was heated to 100° C. overnight. The reaction was then cooled to room temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated in reduced pressure. The residue was purified by chromatography on silica gel to afford 5-fluoro-4-methoxy-N-[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-2-amine. MS ESI calc'd for C18H24BFN3O3 [M+H]+ 360. found 360. 1H NMR (500 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.27 (d, J=3.2, 1H), 8.00 (s, 1H), 7.57 (s, 1H), 7.07 (s, 1H), 4.01 (s, 3H), 2.25 (s, 3H), 1.26 (s, 12H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]2[O:8][CH2:9][O:10][C:5]2=[CH:4][C:3]=1[C:11]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][C:17]([O:21][CH3:22])=[CH:18]2)=[CH:13][CH:12]=1.Cl.[N:24]([O-])=O.[Na+].O>C(O)(=O)C>[CH3:22][O:21][C:17]1[CH:16]=[CH:15][C:14]2=[CH:13][CH:12]=[C:11]3[C:20]([N:24]=[N:1][C:2]4[CH:7]=[C:6]5[O:8][CH2:9][O:10][C:5]5=[CH:4][C:3]3=4)=[C:19]2[CH:18]=1
Reactant: O=N[O-]
Reactant: COc1ccc2ccc(-c3cc4c(cc3N)OCO4)cc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2ccc3c4cc5c(cc4nnc3c2c1)OCO5
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
7-(2-Amino-4,5-methylenedioxyphenyl)-2-methoxynaphthalene 49 (70 mg, 0.24 mmol) was dissolved in acetic acid (2.0 mL) and concentrated hydrochloric acid (0.4 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.16 g in 1.6 mL water). The resulting diazonium solution was allowed to warm slowly to room temperature and left overnight. To the resulting red solution containing some precipitate was added 50 mL water and the reaction mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 55:45 hexanes:ethyl acetate to give compound 44 (60 mg 83%); mp 259-261° C.; IR (KBr) 2923, 1612, 1498, 1468, 1234, 1199 cm−1; UV (MeOH) 270, 250, 228 nm (log ε=4.68, 4.37, 4.44); 1H NMR (CDCl3) δ4.12 (3H, s), 6.24 (2H, s), 7.37 (1H, dd, J1=8.8, J2=2.7), 7.80 (1H, s), 7.88 (1H, d, J=8.8), 7.96 (1H, s), 8.03 (1H, d, J=9.1), 8.09 (1H, d, J=9.0), 9.15 (1H, d, J=2.7); 13C NMR δ56.32, 98.31, 102.93, 104.03, 107.49, 116.36, 120.40, 120.50, 121.09, 127.96, 130.00, 132.54, 133.34, 141.99, 146.10, 150.53, 152.09, 160.28; HRMS (EI) calcd for C18H12N2O3 m/z: 304.0848; found: 304.0852.
Reaction SMILES: [CH2:1]([C:3]1[CH:16]=[CH:15][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2].[H-].[Na+].CC1C=CC(S(O[CH2:30][CH2:31][C@@:32]2([O:71][CH3:72])[C@H:37]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:36]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@H:35]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C@@H:34]([CH2:62][O:63][CH2:64][C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[O:33]2)(=O)=O)=CC=1.[O-]C1C=CC=CC=1.C1(O)C=CC=CC=1>CN(C=O)C.CCOC(C)=O>[CH2:39]([O:38][C@@H:37]1[C@@H:36]([O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C@H:35]([O:54][CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[C@@H:34]([CH2:62][O:63][CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)[O:33][C@:32]1([CH2:31][CH2:30][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[O:71][CH3:72])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CO[C@@]1(CCOS(=O)(=O)c2ccc(C)cc2)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CCc1ccc(Cc2ccc(O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1ccc(Cc2ccc(OCC[C@]3(OC)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cc2)cc1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
4-(4-Ethylbenzyl)phenol (3) (28 mg, 0.13 mmol) was dissolved in DMF (200 μL). NaH (5 mg, 60%/mineral oil, 0.13 mmol) was added. After 5 min, a solution of 2-((2S,3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-2-methoxytetrahydro-2H-pyran-2-yl)ethyl 4-methylbenzenesulfonate (9) (50 mg in 200 μL DMF) was added to the phenoxide solution. After 2 h, the reaction was heated to 60° C. for 2 h, then stirred overnight at room temperature (15h). The reaction mixture was diluted with EtOAc and washed with NaHCO3 (2×). The aqueous layers were combined and back-extracted with EtOAc (2×). The organic layers were combined, dried, and concentrated provide 72 mg. 1HNMR indicated that the product was present, but with extraneous phenol contamination. The sample was purified by preparative thin-layer chromatography (SiO2, eluting with 40% EtOAc/hexanes) to provide a film (26.1 mg, approx 50%) that still had contaminating phenol present. The material was carried forward to the next step. 1H NMR (300 MHz, CDCl3) δ ppm: 6.99-7.32 (m, 25H), 6.69 (m, 3H), 4.48-4.97 (m, 8H), 4.13 (t, J=9 Hz, 1H), 3.94 (m, 1H), 3.86 (s, 2H), 3.55-3.80 (m, 6H), 3.26 (s, 3H), 2.60 (q, J=15.3, 7.8 Hz, 2H), 2.27 (m, 2H), 1.21 (t, J=8.1 Hz). LC/MS tR=6.47 min, calcd for C52H56O7: 792.4, found 815.4 (M+Na)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6].C(=O)([O-])[O-].[K+].[K+].[N:29]1[CH:34]=[CH:33][C:32]([C:35]([OH:48])([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:31][CH:30]=1>O.C(OCC)(=O)C.C1(C)C=CC=CC=1>[OH:48][C:35]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH:32]1[CH2:33][CH2:34][N:29]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([C:19]([O:21][CH3:22])=[O:20])[C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:30][CH2:31]1
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccncc1
Reactant: COC(=O)C(Cc1ccc(C(=O)CCCCl)cc1)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(Cc1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 120 h
Yield: 75.4 %

Procedure:
Mix together [4-(4-chloro-1-oxobutyl)phenyl]methyl-propanedioic acid, dimethyl ester (300 mg, 0.92 mmol), potassium carbonate (350 mg, 2.5 mmol), α-(4-pyridyl)benzhydrol (500 mg, 1.9 mmol), water (3 mL) and toluene (7 mL). Heat the mixture to reflux. After 5 days, cool to room temperature. Add ethyl acetate and water. Wash the organic phase with brine, dry over anhydrous magnesium sulfate and concentrate. Purify by flash chromatography (150 g of silica gel, 10% methanol/chloroform as eluent) to give the title compound (387 mg, 76%).
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[NH:10]([CH2:20][CH2:21][NH:22][C:23](=[O:28])[O:24][CH2:25][CH2:26][OH:27])[CH2:11][CH2:12][NH:13][C:14](=[O:19])[O:15][CH2:16][CH2:17][OH:18]>CC(C)=O.O>[OH:27][CH2:26][CH2:25][O:24][C:23]([NH:22][CH2:21][CH2:20][N:10]([C:8]1[N:1]=[C:2]([N:10]([CH2:11][CH2:12][NH:13][C:14]([O:15][CH2:16][CH2:17][OH:18])=[O:19])[CH2:20][CH2:21][NH:22][C:23]([O:24][CH2:25][CH2:26][OH:27])=[O:28])[N:4]=[C:5]([Cl:6])[N:7]=1)[CH2:11][CH2:12][NH:13][C:14]([O:15][CH2:16][CH2:17][OH:18])=[O:19])=[O:28]
Reactant: O=C(NCCNCCNC(=O)OCCO)OCCO
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCN(CCNC(=O)OCCO)c1nc(Cl)nc(N(CCNC(=O)OCCO)CCNC(=O)OCCO)n1)OCCO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To 50 g water in a 3-neck flask equipped with stirrer and a thermometer, were added 9.2 g (0.05m) of cyanuric chloride, dissolved in 50 g acetone below 10° C. To the white slurry of cyanuric chloride, 27.9 g of bis(2-hydroxyethyl) (iminodiethylene)biscarbamate (HEC), NH(CH2CH2NHCO2CH2CH )2 dissolved in 50 g of water was added over a period of 15 minutes. During the addition, the reaction temperature was maintained below 12° C. After complete addition of HEC, the slurry turned into a clear solution. To this was added 10% caustic to maintain the reaction pH at about 7 and the reaction mixture was allowed to warm up to 25° C. At 25° C., as the reaction progressed, a white crystalline solid slowly separated out. After 4 hrs. at 25-35° C, the solids were separated by filtration, washed with water and recrystallized from ethanol. The product yield was 24 g and m.p. 174° C. The structure of the product was confirmed by nuclear magnetic resonance (nmr) and fast atomic bombardment (fab), mass spectrometry to be that of FORMULA I: ##STR19##
Reaction SMILES: [O-2:1].[Mg+2].O.[OH:4][CH2:5][CH2:6][NH:7][CH2:8][CH2:9][NH:10][CH2:11][CH2:12][OH:13].[C:14](Cl)(=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O1CCOCC1>[OH:4][CH2:5][CH2:6][N:7]([C:29](=[O:1])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH2:8][CH2:9][N:10]([C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:11][CH2:12][OH:13]
Reactant: [O-2]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: OCCNCCNCCO
Agent: [Mg+2]
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)N(CCO)CCN(CCO)C(=O)CCCCCCCCCCCCCCC
Yield: 78.9 %

Procedure:
Into other 500 ml rounded-flask, were introduced 4.0 g of magnesium oxide and 80 g of distilled water. The mixture was stirred. Thereto was added 7.3 g of N,N'-bis(2-hydroxyethyl)-1,2-diaminoethane prepared above and 250 ml of 1,4-dioxane. 27.5 g of palmitoyl chloride was gradually added dropwise to the resulting mixture for 1 hour under violent stirring at a room temperature. After stirring for 2 hours, the mixture was filtered, and then the filtrate was mixed with 200 ml of chloroform and washed twice with 200 ml of distilled water. Organic phase was cooled to produce solid material, which was recovered by filtration. The solid material was dried and recrystallized from chloroform/acetone and chloroform/hexane, to give 24.3 g of the title compound as white powder, which was identified by IR and NMR. The results are shown in Table 3.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH:12]1[CH:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[N:14]=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1.C(OCC)(=O)C>[CH3:20][O:19][C:17]([C:15]1[N:14]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:13]=[N:12][CH:16]=1)=[O:18]
Reactant: COC(=O)c1c[nH]cn1
Reactant: OC1CCCc2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cncn1C1CCCc2ccccc21
Reaction time: 16 h

Procedure:
To a solution of 1,2,3,4-tetrahydro-1-naphthol (CAS#529-33-9, 1.00 g, 6.74 mmol), which can be prepared as described in Ollivier, R.; et al. Journal of Medicinal Chemistry, 1997, 40, 952-960, in THF (60 mL), at 0° C. is added methyl 4-imidazolecarboxylate (CAS#17325-26-7, 0.85 g, 6.74 mmol) and triphenylphosphine, followed by diisopropyl azodicarboxylate (1.36 g, 6.74 mmol). The cooling bath is then removed. After 16 hours, the solvent is evaporated in vacuo and the residue is purified by silica gel flash chromatography (elution with ethyl acetate) to give a partially purified product, which is dissolved in ethyl acetate and extracted with 1M aqueous HCl. The aqueous layer is basified to a pH of ca. 9 with 2M aqueous NaOH, and then extracted three times with dichloromethane. The organic layers are combined, dried with MgSO4, filtered, and concentrated to furnish 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; MS: (ESI) m/z 257.2 (M+H)+. The HNO3 salt of the title compound is prepared by dissolving the free base in methanol, followed by treatment with an excess of a 1:1 solution of HNO3—H2O. Concentration and trituration with diethyl ether and methanol, provides the nitric acid salt of 3-(1,2,3,4-tetrahydro-naphthalen-1-yl)-3H-imidazole-4-carboxylic acid methyl ester; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.66-1.87 (m, 2 H), 2.11-2.33 (m, 2 H), 2.81 (dt, J=17.2, 6.5 Hz, 1 H), 2.93 (dt, J=17.2, 6.0 Hz, 1 H), 3.87 (s, 3 H), 6.33 (t, J=5.9 Hz, 1 H), 6.99 (d, J=7.6 Hz, 1 H), 7.10-7.21 (m, 1 H), 7.21-7.35 (m, 2 H), 8.34 (s, 1 H), 8.58 (s, 1 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25](=[O:38])[C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:28]#[CH:29].COC(=O)C(NC(OC(C)(C)C)=O)CC#C>C1COCC1.C(N(CC)CC)C.[Cu]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>[CH3:23][O:24][C:25](=[O:38])[C@H:26]([NH:30][C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:27][C:28]#[C:29][C:18]1[CH:19]=[CH:20][C:15]([C:14]#[C:13][CH2:12][CH2:11][NH:10][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:22])=[CH:16][CH:17]=1
Reactant: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Reactant: C#CC[C@@H](NC(=O)OC(C)(C)C)C(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCC(NC(=O)OC(C)(C)C)C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
Compound 22, [4-(4-iodophenyl)-but-3-ynyl]carbamic acid benzyl ester (0.52 g, 1.283 mmol) was dissolved in a mixture of anhydrous THF and triethylamine (8 mL, 1/1, v/v). To the solution was added copper (I) iodide (0.025 g, 0.128 mmol). The mixture was stirred at room temperature for 15 min. The flask was then evacuated and re-filled with Argon. The procedure was repeated three more times to ensure no oxygen remained. The catalyst, dichlorobis(triphenylphosphine)palladium(II) (0.09 g, 0.128 mmol) was added into the mixture under Argon protection. The mixture was further stirred at room temperature for 30 min. The other starting material 23, 2-tert-butoxycarbonylamino-pent-4-ynoic acid methyl ester (0.32 g, 1.412 mmol), dissolved in THF (4 mL) was added dropwise over 15 min. The newly formed reaction mixture was further stirred overnight at room temperature. The solid in the reaction mixture was vacuum filtered. The filtrate was concentrated. The residue was re-dissolved in dichloromethane and purified by column chromatography, eluting with a mixture of ethyl acetate (0-25%) and hexanes (100-75%) to afford the product 24 (0.64 g, 99%) as a gummy, yellowish solid. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 2.64 (t, J=6.3 Hz, 2H), 2.95 (t, J=4.1 Hz, 2H), 3.42 (m, 2H), 3.79 (s, 3H), 4.56 (m, 1H), 5.12 (s, 2H), 5.38 (br s, 1H), 7.29 (s, 4H), 7.35 (m, 5H). m/z (APCI) 502 [C29H32N2O6—H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].[CH3:13][CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCCC1>[Cl:1][C:2]1[C:3]([O:12][CH:14]([CH3:15])[CH3:13])=[CH:4][C:5]([F:11])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(O)cc1F
Reactant: CC(C)O
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)Oc1cc(F)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 22 h
Yield: 43.7 %

Procedure:
A mixture of 2-chloro-5-fluoro-4-nitrophenol (287 mg, 1.5 mmol), propan-2-ol (90 mg, 1.5 mmol), diphenyl-2-pyridylphosphine (592 mg, 2.25 mmol) and di-tert-butyl azodicarboxylate (518 mg, 2.25 mmol) in tetrahydrofuran (10 ml) was stirred at room temperature under argon for 22 hrs. The mixture was treated with 1M HCl/diethyl ether (10 ml) and stirred at room temperature for 1 hr, then concentrated under vacuum and the residue dissolved in diethyl ether (10 ml), treated with 5M HCl acid (10 ml) and stirred for 30 mins. The organic layer was separated, washed with 5M HCl acid (10 ml), then 10% Na2CO3 solution (2×10 ml), dried (MgSO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel eluting with 5-70% ethyl acetate/60-80 petrol ether to afford the title compound as a yellow solid (153 mg, 43%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:23])[C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25].CC(C)(C)CC(N1CCN(C2C=CC(C(NC3C=CC(C)=C(I)C=3)=O)=CN=2)CC1)=O>>[CH2:24]([O:26][C:27]([N:20]1[CH2:19][CH2:18][N:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10](=[O:23])[NH:9][C:4]3[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([I:1])[CH:3]=3)=[CH:12][N:13]=2)[CH2:22][CH2:21]1)=[O:28])[CH3:25]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(NC(=O)c2ccc(N3CCNCC3)nc2)cc1I
Agent: Cc1ccc(NC(=O)c2ccc(N3CCN(C(=O)CC(C)(C)C)CC3)nc2)cc1I
Product: CCOC(=O)N1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1

Procedure:
4-[5-(3-Iodo-4-methyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carboxylic acid ethyl ester was synthesized from N-(3-iodo-4-methyl-phenyl)-6-piperazin-1-yl-nicotinamide and ethylchloroformate in a manner similar to the one described in the synthesis of 6-[4-(3,3-dimethyl-butyryl)-piperazin-1-yl]-N-(3-iodo-4-methyl-phenyl)-nicotinamide above. LCMS calcd for C20H23IN4O3 (m/e) 494, obsd 495 (M+H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1.[NH2:21][CH2:22][CH2:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H][H]>CO.[Pt]>[OH:1][CH:2]([CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([NH:21][CH2:22][CH2:23][NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:6][CH2:5]1
Reactant: NCCNc1ccccc1
Reactant: [H][H]
Reactant: COc1ccccc1OCC(O)CN1CCC(=O)CC1
Agent: [Pt]
Solvent: CO
Product: COc1ccccc1OCC(O)CN1CCC(NCCNc2ccccc2)CC1

Procedure:
A solution of 16.7 g of 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-piperidine-4-one and 10.5 g of N-(2-aminoethyl)-aniline in 250 ml of methanol, with the addition of 1 g of a 5% platinum on charcoal catalyst is hydrogenated at room temperature and under normal pressure until 1 molar equivalent of hydrogen has been taken up. The catalyst is thereafter removed by filtration and the filtrate is concentrated under reduced pressure. The residue is freed from excess starting material in a bulb tube at 0.3 mm Hg and 120° C oven temperature to yield as distillation residue 1-[2-hydroxy-3-(2-methoxyphenyloxy)-propyl]-4-(2-anilino-ethylamino)-piperidine, which can be used without further purification.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.I[CH2:15][CH3:16].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:15]([N:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 73.9 %

Procedure:
A mixture of tert butyl (S)-pyrrolidin-3-ylcarbamate (1.048 g), iodoethane (0.90 g) and potassium carbonate (1.55 g) in acetonitrile (15 mL) was stirred at room temperature for 17 hours then filtered. The filtrate was concentrated in vacuo and the residue was triturated with DCM and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-35% to give tert-butyl ((S)-1-ethylpyrrolidin-3-yl)carbamate (0.891 g) as a light coloured gum.
Reaction SMILES: [C:1]1([O:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:11]1C=CC=CC=1>CC#N.CCOC(C)=O>[C:8](=[O:9])([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH2:11]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Intermediates 10 to 18 were prepared by treatment of the appropriate aminoheterocycle intermediate with 1 equivalent of phenylchloroformate in dry CH3CN and 1 equivalent of pyridine. The reagents were stirred at rt for 4 h, diluted with EtOAc, washed with NaHCO3, and dried over MgSO4. The material was purified by FCC to provide pure phenyl carbamate intermediates.
Reaction SMILES: [CH:1]1([C@:7](C)(O)[C:8]([OH:10])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[N:19]([CH2:23][CH2:24][NH2:25])[CH2:18][CH2:17]2.CN([C:29]([O:33]N1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:7][C@H:8]([OH:10])[C:29]([NH:25][CH2:24][CH2:23][N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:33])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: C[C@@](O)(C(=O)O)C1CCCCC1
Reactant: NCCN1CCc2cc(F)ccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCc2cc(F)ccc21)[C@@H](O)CC1CCCCC1
Temperature: 25 °C
Yield: 28 %

Procedure:
To a stirring suspension of (S)-cyclohexyl lactic acid (558 mg, 3.42 mmol) in CH2Cl2 was added 2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethylamine (616 mg, 3.42 mmol), HATU (1.429 g, 3.76 mmol), and DIEA (1.79 mL, 10.3 mmol). The reaction mixture was stirred at room temperature for several hours until the starting material had disappeared by LCMS. Ethyl acetate (100 mL) was added and the solution was washed with 1M NaHSO4 (2×100 mL), sat'd aq NaHCO3 (2×100 mL) and brine (1×100 mL). The solvent was removed in vacuo and the crude material was purified by silica gel chromatography (hexanes/EtOAc) to afford 320 mg of 3-Cyclohexyl-N-[2-(5-fluoro-2,3-dihydro-indol-1-yl)-ethyl]-2-(S)-hydroxy-propionamide as a white powder.