Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3](=[C:8]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:17]=1[CH3:18])SC)[C:4]([O:6]C)=O)#[N:2].Cl.[CH:20]1([CH2:25][C:26]([NH2:28])=[NH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:20]1([CH2:25][C:26]2[NH:28][C:4](=[O:6])[C:3]([C:1]#[N:2])=[C:8]([NH:11][C:12]3[CH:13]=[N:14][CH:15]=[CH:16][C:17]=3[CH3:18])[N:27]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: N=C(N)CC1CCCC1
Reactant: COC(=O)C(C#N)=C(Nc1cnccc1C)SC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccncc1Nc1nc(CC2CCCC2)[nH]c(=O)c1C#N
Temperature: 90 °C
Reaction time: 72 h

Procedure:
0.2 g (0.76 mmol) of methyl 2-cyano-3-[(4-methyl-3-pyridinyl)amino]-3-(methylsulfanyl)-2-propenoate are dissolved with 0.13 g (0.85 mmol) of 2-cyclopentylethanamidine hydrochloride and 0.23 g (1.67 mmol) of potassium carbonate in 4 ml of DMF and stirred at 90° C. for 3 days. After cooling, the product is purified by preparative HPLC (YMC Gel ODS-AQ S 5/15 μm; eluent A: water, eluent B: aceto-nitrile; gradient: 0 min 30% B, 5 min 30% B, 50 min 95% B) purified. 60 mg (25% of theory) of the product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([NH:27][C:28](=[O:36])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3C=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1.C(C1C=CC=CC=1)#C.C(C1C=CC=C[N:48]=1)#C>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:25]([NH:27][C:28](=[O:36])[CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[S:26])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:10]2[NH:17][C:16]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:48]=3)=[CH:15][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: C#Cc1ccccn1
Reactant: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(-c4ccccc4)[nH]c23)c(F)c1
Solvent: C#Cc1ccccc1
Product: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ncnc3cc(-c4ccccn4)[nH]c23)c(F)c1

Procedure:
Following the procedures described above for the synthesis of compound 255a (example 213, scheme 57) but replacing ethynylbenzene in the step 1 with 2-ethynylpyridine, title compound 255b was obtained. 1H NMR (DMSO-d6) δ (ppm): 12.85 (br, 1H), 12.65 (br, 1H), 11.75 (br, 1H), 8.71 (m, 1H), 8.33 (s, 1H), 8.21 (d, J=8 Hz, 1H), 7.96 (m, 1H), 7.89 (m, 1H), 7.52-7.42 (m, 3H), 7.34-7.32 (m, 5H), 7.28 (m, 1H), 3.83 (s, 2H). MS (m/z): 499.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)C4=CC=CC=C4C3=O)=[N:19][N:18]=[C:17]2[CH2:33][N:34]([CH2:37][CH3:38])[CH2:35][CH3:36])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=O.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:16]3[C:17]([CH2:33][N:34]([CH2:35][CH3:36])[CH2:37][CH3:38])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]=2[CH:15]=1
Reactant: CCN(CC)Cc1nnc(CN2C(=O)c3ccccc3C2=O)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 27, 5chloro-2-[3-[(diethylamino)methyl]-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone is heated in ethanol with hydrazine hydrate to give 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH:5]([O:28][CH2:29][CH3:30])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[CH:9][C:8]=1[CH3:27])C.[Li+].[OH-]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[S:18][CH:19]=[C:15]([CH2:14][O:13][C:10]3[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:28][CH2:29][CH3:30])[C:4]([OH:31])=[O:3])=[C:8]([CH3:27])[CH:9]=3)[N:16]=2)=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], [rac]-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid ethyl ester was treated with LiOH to obtain [rac]-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as light yellow liquid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1F)[CH:11]=[O:12].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1.O>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[O:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([O:18][CH3:17])[CH:20]=1)[CH:11]=[O:12]
Reactant: COc1cccc(O)c1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(Oc2ccc(C=O)cc2F)c1
Temperature: 120 °C
Yield: 57.7 %

Procedure:
Cesium carbonate (2.757 g, 8.44 mmol) was added to a solution of 3,4-difluoro-benzaldehyde (1.0 g, 7.037 mmol) and 3-methoxyphenol (875 mg, 7.05 mmol) dissolved in DMF (20 mL). The reaction was heated to 120° C. for 24 hours. The reaction mixture was then poured into 300 mL of water and extracted 3 times with 60 mL of ethyl acetate. The combined organic layers were washed with water (2 times), brine, and dried over sodium sulfate. The organic layer was filtered and concentrated under reduced pressure. 3-Fluoro-4-(3-methoxy-phenoxy)-benzaldehyde (1.0 g) was isolated using flash silica gel and eluting with 10% ethyl acetate and heptane.
Reaction SMILES: [NH2:1][S:2]([N:5]([CH3:43])[CH2:6][CH2:7][N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C@H:15]1[CH2:22][N:21]2[C:23]3[CH:24]=[C:25]([C:36](O)=[O:37])[CH:26]=[CH:27][C:28]=3[C:29]([CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[C:20]2[C:19]2[CH:39]=[CH:40][CH:41]=[CH:42][C:18]=2[O:17][CH2:16]1)(=[O:4])=[O:3].C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CS(C)=O>[CH:30]1([C:29]2[C:28]3[C:23]4=[CH:24][C:25](=[CH:26][CH:27]=3)[C:36](=[O:37])[NH:1][S:2](=[O:3])(=[O:4])[N:5]([CH3:43])[CH2:6][CH2:7][N:8]3[CH:9]([CH2:10][CH2:11][CH2:12]3)[CH2:13][O:14][C@H:15]3[CH2:22][N:21]4[C:20]=2[C:19]2[C:18]([O:17][CH2:16]3)=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CN(CCN1CCCC1CO[C@@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1)S(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: ClCCCl
Product: CN1CCN2CCCC2CO[C@@H]2COc3ccccc3-c3c(C4CCCCC4)c4ccc(cc4n3C2)C(=O)NS1(=O)=O
Temperature: 40 °C
Yield: 34 %

Procedure:
To a solution (7 mM) of (7S)-7-[(1-{2-[(aminosulfonyl)(methyl)amino]ethyl}pyrrolidin-2-yl)methoxy]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylic acid in DCM, DMAP (5 eq) and EDC (2 eq) were added and the resulting mixture heated at 40° C. for 2 h and then at RT over night. Volatiles were eliminated in vacuo and the residue redissolved in DMSO. Purification was by RP-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 um, 19×100 mm) eluting with MeCN/TFA buffered with 0.1% TFA gradient. Fractions containing the product were combined and freeze dried to afford the product as a white powder (34%) as a mixture of isomers. 1H NMR (600 MHz, DMSO-d6+TFA, 320 K) δ 1.15-2.02 (m, 14H), 2.68-2.70 (m, 1H), 2.94-3.08 (m, 3H), 3.14-4.11 (m, 1H), 4.32-4.61 (m, 2H), 4.81-4.90 (m, 1H), 7.16-7.39 (m, 2H), 7.40-7.49 (m, 1H), 7.50-7.57 (m, 2H), 7.85-7.94 (m, 1H), 8.13-8.43 (m, 1H); (ES+) m/z 593 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]=[O:17])[CH:11]=1.C(N(CC)CC)C>[Br-].C([N+]1C(C)=C(CCO)SC=1)C.C(O)C>[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[O:17])[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[Cl:1])[OH:5])[CH:11]=1
Reactant: O=Cc1cccnc1
Reactant: O=Cc1ccccc1Cl
Agent: CC[n+]1csc(CCO)c1C
Agent: [Br-]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1)C(O)c1ccccc1Cl

Procedure:
160 g (1.14 mol) of 2-chlorobenzaldehyde, 122 g (1.14 mol) of 3-pyridinealdehyde, 50 g (0.2 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazoliumbromide and 60.6 g (0.6 mol) of triethylamine in one liter of ethanol were heated at 75° C. for 13 hours. Thereafter, the ethanol was distilled off and the residue was dissolved in methylene chloride. The solution was washed twice with water and then extracted twice with 300 ml of 4N hydrochloric acid. The acidic aqueous phase was then rendered slightly alkaline with 4N sodium hydroxide solution and extracted three times with fresh methylene chloride. After the solvent had been distilled off, the crude product was stirred with isopropanol, filtered off under suction and dried to give a product of melting point 92° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:12]2[NH:11][CH2:10][CH2:9]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[CH:21][CH:20]=3)[C:16]([C:17]([NH2:18])=[O:36])=[C:12]2[NH:11][CH2:10][CH2:9]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(OC3CCOCC3)cc2)nn2c1NCCC2c1ccccc1N
Product: NC(=O)c1c(-c2ccc(OC3CCOCC3)cc2)nn2c1NCCC2c1ccccc1N

Procedure:
The desired product was prepared from 7-(2-aminophenyl)-2-(4-(tetrahydro-2H-pyran-4-yloxy)phenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.38 (d, J=8.8 Hz, 2H), 7.02 (d, J=8.8 Hz, 2H), 6.95 (t, J=7.6 Hz, 1H), 6.75 (s, 1H), 6.67 (d, J=7.8 Hz, 1H), 6.49 (t, J=7.6 Hz, 1H), 6.26 (d, J=7.8 Hz, 1H), 5.56 (s, 1H), 5.16 (s, 2H), 4.64-4.54 (m, 1H), 3.91-3.79 (m, 2H), 3.53-3.42 (m, 2H), 3.29-3.19 (m, 1H), 3.01-2.92 (m, 1H), 2.25-2.05 (m, 2H), 2.02-1.91 (m, 2H) and 1.64-1.52 (m, 2H). MS (ESI) m/e [M+1]+ 433.9.
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:22])([CH3:21])[C:8]1[O:12][N:11]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[CH2:19][OH:20])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][N:27]=1>C1COCC1>[CH3:33][O:32][C:30](=[O:31])[C:29]1[CH:34]=[CH:35][C:26]([O:20][CH2:19][C:9]2[C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][O:12][C:8]=2[C:7]([CH3:22])([CH3:21])[O:6][SiH2:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[N:27][CH:28]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1onc(-c2ccccc2)c1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(C)(C)O[SiH2]C(C)(C)C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
A solution of [5-(tert-butyl-dimethyl-silanyloxymethyl)-3-phenyl-isoxazol-4-yl]-methanol (4.09 g, 12.8 mmol) in THF (20 mL) was added dropwise to a suspension of sodium hydride (0.73 g of a 55% dispersion in mineral oil, 16.7 mmol). After stirring for 30 min at room temperature, the mixture was cooled in an ice bath and a solution of methyl 6-chloronicotinate (2.20 g, 12.8 mmol) in THF (20 mL) was added dropwise. The ice bath was removed and the reaction mixture was allowed to reach room temperature and was stirred for 2 h. After quenching with water and extractive workup (ethyl acetate/water) the organic phase was dried over sodium sulfate, filtered and concentrated. Chromatographic purification (silica, heptane:ethyl acetate=100:0 to 8:2) afforded the title compound as a colorless oil (2.76 g, 47%). MS: m/e=455.4 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:10])[CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>ClCCl.CN(C1C=CN=CC=1)C.[Cl-].[NH4+]>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:10][C:20](=[O:21])[C:19]([CH3:24])([CH3:23])[CH3:18])[CH:8]=2)[CH:3]=[N:2]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc2cn[nH]c2c1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Oc1ccc2cn[nH]c2c1
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To a solution of 1H-indazol-6-ol (0.88 g, 6.6 mmol) in dichloromethane (10 ml) at room temperature was added triethylamine (0.98 ml, 7.0 mmol) and DMAP (0.05 g) followed by trimethylacetyl chloride (0.82 ml, 6.6 mmol). After stirring for 1 h, the mixture was diluted with saturated aqueous solution of ammonium chloride (20 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (10 ml), dried (MgSO4), and evaporated to a residue which was purified by chromatography (silica, 10% to 20% ethyl acetate in hexane) to give an oil (1.1 g, 76%): 1H NMR (CDCl3) δ 8.15 (d, J=0.8 Hz, 1H), 8.01 (s, 1H), 7.75 (s, 1H), 7.58 (d, J=8.6 Hz, 1H), 7.01 and 6.96 (dd, J=2.0 and 8.6 Hz, 1H), 1.59 (s, 9H); MS(ES) m/z 219 (M+).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+]>O1CCCC1>[OH:11][CH2:10][C@H:9]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H](CO)Cc1ccccc1
Reaction time: 2 h
Yield: 56.3 %

Procedure:
To the resultant acid from Example 99 (1.03 g, 3.90 mmol) in tetrahydrofuran (4 ml, THF) at 0° C. was added BH3 in THF (5.8 ml, 5.8 mmol, 1.0 molar) over 2 min. After 2 h at 0° C. the mixture was brought to room temperature and stirred for 2 h. The reaction was poured into saturated NaHCO3 solution and extracted into ethyl acetate which was dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with ethyl acetate/hexane mixtures afforded 0.55 g (56%) of the desired product as an oil. 1H NMR (CDCl3, TMS) δ 7.15-7.35 (m,5H), 3.65 (m,1H), 3.52 (m,1H), 2.65 (m,2H), 2.30 (m,2H), 1.90 (m,1H), 1.46 (s,9H).
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[CH3:16][O:17][CH2:18][CH2:19]Br>CN(C=O)C.CCOC(C)=O>[NH2:4][CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:19][CH2:18][O:17][CH3:16])[C:6]1=[O:15]
Reactant: COCCBr
Reactant: NC1Cc2ccccc2NC1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(N)Cc2ccccc21
Yield: 77.7 %

Procedure:
Sodium hydride (60% in oil, 321 mg, 8.03 mmol) was added to 3-amino-3,4-dihydroquinolin-2(1H)-one hydrochloride (J. Med. Chem., 28, 1985; 1511-16; 759 mg, 3.82 mmol) in anhydrous DMF (10 mL) at 0° C. over a period of 5 min. After 1 hour 2-bromoethyl methyl ether (0.40 mL, 4.20 mmol) was added and stirring maintained for 18 hours. The reaction was diluted with EtOAc (100 mL) and washed with sat. aqueous K2CO3 (20 mL). The aqueous was extracted with DCM (3×50 mL) and the combined organics dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (4:1)) to afford the title compound (654 mg, 78%) as a brown oil.
Reaction SMILES: [C:1]([Si:5]([CH3:24])([CH3:23])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH2:12][CH2:13][C:14]([CH3:18])=[CH:15][CH:16]=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:25][Mg]I.[Mg].CI.[Cl-].[NH4+]>CCOCC>[C:1]([Si:5]([CH3:23])([CH3:24])[O:6][CH:7]([C:20]([CH3:22])=[CH2:21])[CH2:8][CH2:9]/[C:10](/[CH3:19])=[CH:11]/[CH:12]=[CH:13][C:14]([CH3:18])=[CH:15][C:16]([OH:17])=[CH2:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C(C)C(CC/C(C)=C/CCC(C)=CC=O)O[Si](C)(C)C(C)(C)C
Reactant: C[Mg]I
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: C=C(O)C=C(C)C=C/C=C(\C)CCC(O[Si](C)(C)C(C)(C)C)C(=C)C
Reaction time: 2 h

Procedure:
A solution of 7.3 g of (6E)-10-(tert.-butyldimethylsiloxy)-3,7,11-trimethyl-2,6,11-dodecatrienal in 10 ml of ether is added dropwise at -20° to a methylmagnesium iodide solution prepared from 0.56 g of magnesium shavings and 3.1 g of methyl iodide in 80 ml of ether. After stirring at -20° for 2 hours the reaction mixture is poured into a mixture of ice and saturated ammonium chloride solution and extracted twice with ether. The combined organic extracts are washed with saturated sodium chloride solution, dried over sodium sulphate, filtered and evaporated. The oil which remains behind as the residue is chromatographed on silica gel with hexane-ethyl acetate-triethylamine 90:10:0.1, whereby (7E)-11-(tert.-butyldimethylsiloxy)-4,8,12-trimethyl-3,7,12-tridecadien-trien-2-ol is obtained as a colourless oil. NMR (250 MHz, CDCl3): 5.2 (d, J=8 H-C(3)); 5.1 (t, J=6.5, H-C(7)); 4.84 and 4.75 (2m, 2H-C(13)); 4.57 (m, H-C(2)); 4.0 (t, J=6.5, H-C(11)); 2.25-1.4 (m, 4CH2, 3CH3); 1.22 (d, J=6.5, 3H-C(1)); 0.89 (s, SiC(CH3)3); 0.04 and 0.0 (2s, Si(CH3)2).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].[OH-].[Na+]>CO>[CH3:15][O:14][C:10](=[O:13])[CH2:11][CH2:12][N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: C=CC(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)CCn1cc(C)c(=O)[nH]c1=O

Procedure:
Thymine (14.0 g, 0.11 mol) was suspended in methanol. Methyl acrylate (39.6 ml, 0.44 mol) was added, along with catalytic amounts of sodium hydroxide. The solution was refluxed in the dark for 45 h, evaporated to dryness, in vacuo, and the residue dissolved in methanol (8 ml) with heating. After cooling on an ice bath, the product was precipitated by addition of ether (20 ml), isolated by filtration, washed with ether (3×15 ml), and dried over sicapent, in vacuo. Yield 11.23 g (48%). M.p. 112°-119° C. Anal. for C9H12N2O4, found (calc.) C: 51.14 (50.94) H: 5.78 (5.70) N: 11.52 (13.20). The compound showed satisfactory 1H and 13C-NMR spectra.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1)#[CH:2].P(Br)(Br)[Br:12]>C(Cl)Cl>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Br:12])=[CH:5][CH:4]=1)#[CH:2]
Reactant: C#Cc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: ClCCl
Product: C#Cc1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Ethynylbenzyl alcohol a (1 g, 7.57 mmol) was diluted in 20 ml DCM, and cooled to 0° in ice bath. Phosphorus tribromide (4.1 g, 15 mmol) was added dropwise. The reaction was allowed to warm to room temperature gradually, and stirred under nitrogen overnight. The reaction was quenched by addition of H2O in ice bath, extracted by DCM. Combined organic layers were washed with brine, dried over Na2SO4 and concentrated to dryness. The crude material was purified by chromatography (ISCO) using 100% hexane to give pure 4-ethynylbenzyl bromide b (220 mg). M+H+ 195.1
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[F:9][C:10]([F:21])([F:20])[C:11]([O:13]C(=O)C(F)(F)F)=[O:12].C(N(CC(O)=O)CC(O)=O)CCCC#C.FC(F)(F)C([O-])=O.N#N>CN(C=O)C.CS(C)=O.C(#N)C.C(N(CC)CC)C.C(OCC)(=O)C>[F:9][C:10]([F:21])([F:20])[C:11]([OH:13])=[O:12].[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: C#CCCCCN(CC(=O)O)CC(=O)O
Agent: N#N
Agent: O=C([O-])C(F)(F)F
Solvent: CS(C)=O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(O)C(F)(F)F
Reaction time: 8 h

Procedure:
N-hydroxysuccinimide trifluoroacetate was prepared by stirring N-hydroxysuccinimide (NHS) and 4 eq trifluoroacetic anhydride for 5 h. The mixture was concentrated under reduced pressure and further dried under high vacuum overnight. The product was obtained as a white, highly hygroscopic solid and stored in an anhydrous desiccator before use. The obtained approximately 1.1 g 2,2′-(hex-5-ynylazanediyl)diacetic acid was activated by 2.4 eq N-hydroxysuccinicimide trifluoroacetate in 10 mL anhydrous DMF under a stream of dry N2. The mixture was stirred overnight and monitored by TLC using hexanes:ethyl acetate (=2:1) as the mobile phase. After completion of the reaction, the mixture was concentrated to approximately 500 μL by rotary evaporation and subjected to flash chromatography using hexanes:ethyl acetate (=2:1) as the mobile phase. The final product, NHS-activated 2,2′-(hex-5-ynylazanediyl)diacetic acid (CXL-1) was concentrated by rotary evaporation, and obtained as a pale yellow oil. Several 200 μL aliquots of 50 mM stock solution dissolved in anhydrous dimethyl sulfoxide (DMSO) were prepared and stored at −80° C. The sealed stock aliquots were opened immediately before use, and NHS activation was verified by ESI-MS in 100% ACN. ESI-MS [M+H]+ m/z 408.1, [M+Na]+ m/z 420.0. This reaction yield can be improved by adding stoichiometric equivalents of triethylamine.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:11][CH2:12][C:13](O)=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C.[BH4-].[Na+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:16][C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NC(CCC(=O)O)C(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)NC(CCCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.5 %

Procedure:
The 2-tert-butoxycarbonylamino-pentanedioic acid 1-benzyl ester (4.06 g, 12 mmol) and TEA (5 mL, 35.87 mmol) were dissolved in THF (60 mL) and cooled to 0° C. Ethylchloroformate (3.4 mL, 35.7 mmol) was added dropwise. The mixture was stirred at 0° C. for 5 minutes and warmed to r.t. for 1 h. NaBH4 (1.88 g, 49.7 mmol) was added followed by addition of 1 drop of H2O. The reaction mixture was stirred at r.t. overnight. 4 N HCl was added at 0° C. and extracted with EtOAc (100 mL). The aqueous layer was washed with H2O (100 mL), NaOH (2×100 mL), H2O (100 mL) and brine (100 mL). The organic layer was dried with Na2SO4, filtered, and concentrated. The crude product was purified by combi-flash to give 2.89 g of 2-tert-butoxycarbonylamino-5-hydroxy-pentanoic acid benzyl ester in 75% yield.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].C(O[CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)C>>[CH2:3]([O:4][CH:10]1[NH:14][C:13](=[O:15])[CH2:12][CH2:11]1)[C:2]([CH3:6])([CH3:5])[CH3:1]
Reactant: CC(C)(C)CO
Reactant: CCOC1CCC(=O)N1
Product: CC(C)(C)COC1CCC(=O)N1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
35 g 2,2-dimethyl propanol (previously melted at 45° C.), 6 g of 5-ethoxy pyrrolidin-2-one and 3 g of Amberlite-15 resin are agitated at 40° C. for 2 hours 15 minutes. After filtering, the 2,2-dimethyl propanol is distilled off under 0.8 mm/Hg at 35° C. The residue is dissolved in hexane and iced for 2 hours. 3.2 g of the expected product is obtained, m.p. 67°-69° C., crystallized from hexane.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.CC(O)=O.C(OCC)C>CO>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:24]([OH:26])=[O:25])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:23])[NH:19][N+:20]([O-:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CO
Solvent: CC(=O)O
Product: N=C(NCCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)O)N[N+](=O)[O-]
Yield: 148 %

Procedure:
34.3 Grams (0.057 mole) of BOC-Phe-Arg(NO2)-CHA was dissolved in 171 ml (0.342 Mole) of 2N HCl/AcOH with a small amount of MeOH, and reacted at room temperature for 2 hours. After the reaction was completed, 2 liters of dried diethyl ether was added to the reaction mixture so as to precipitate crystals. The precipitated crystals were collected by filtration and dried to obtain 30.9 g (100%) of H-Phe-Arg(NO2)-CHA.HCl.