Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@:11]1([F:27])[CH2:25]I)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O-])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Na+].C1OCCOCCOCCOCCOCCOC1.O>CS(C)=O>[C:1]([O:9][C@H:10]1[C@:14]([F:16])([CH3:15])[C@H:13]([N:17]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:18]2=[O:24])[O:12][C@@:11]1([F:27])[CH2:25][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@](F)(CI)[C@H]1OC(=O)c1ccccc1
Reactant: O=C([O-])c1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@]1(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@@](F)(CC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 62.8 %

Procedure:
Chiral (2R,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2,4-difluor-O-2-(iodomethyl)-4-methyl-tetrahydrofuran-3-yl benzoate (0.56 g, 1.15 mmol), sodium benzoate (0.825 g, 5.73 mmol) and 18-crown-6 (0.03 g, 0.115 mmol) were suspended in DMSO (20 mL), the solution was heated to 100° C. and stirred under nitrogen atmosphere for 18 h, then cooled to r.t., water (30 mL) was added into it, the mixture was extracted by EA (30 mL×3), the organic layer was washed with H2O, brine and H2O, removed solvent by reduced pressure, the residue was purified by silica gel column chromatography (PE:EA=1:2) to afford the title compound as a colorless oil (0.34 g, 61%).
Reaction SMILES: [ClH:1].[CH2:2]([C:7]1[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=1)[CH2:3][CH2:4][C:5]#[CH:6].[N:13]([CH2:16][C:17]1[CH:21]=[CH:20][O:19][CH:18]=1)=[N+:14]=[N-:15]>>[ClH:1].[O:19]1[CH:20]=[CH:21][C:17]([CH2:16][N:13]2[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][C:7]3[N:8]=[C:9]([NH2:12])[NH:10][CH:11]=3)[N:15]=[N:14]2)=[CH:18]1
Reactant: C#CCCCc1c[nH]c(N)n1
Reactant: [N-]=[N+]=NCc1ccoc1
Agent: Cl
Product: Nc1nc(CCCc2cn(Cc3ccoc3)nn2)c[nH]1
Yield: 58.1 %

Procedure:
4-Pent-4-ynyl-1H-imidazol-2-ylamine hydrochloride (0.063 g, 0.340 mmol) was reacted with 3-azidomethyl-furan (0.050 g, 0.406 mmol) following the general procedure for click reactions outlined above to produce 4-[3-(1-Furan-3-ylmethyl-1H-[1,2,3]triazol-4-yl)-propyl]-1Himidazol-2-ylamine hydrochloride (0.061 g, 58%) as a pale yellow solid. 1H NMR (300 MHz, CD3OD) δ 7.70 (s, 1H), δ 7.56 (s, 1H), δ 7.41 (s, 1H), δ 6.44 (s, 1H), δ 6.35 (s, 1H), δ 5.35 (s, 2H), δ 2.65 (t, 2H), δ 2.45 (t, 2H), δ 1.86 (m, 2H) ppm; 13C NMR (75 MHz, CD3OD) δ 147.3, 147.3, 144.2, 141.6, 127.2, 122.1, 120.2, 109.9, 108.8, 44.7, 27.8, 24.2, 23.6 ppms; HRMS (ESI) calcd for C13H16N6O (M+) 272.1458. found 272.1462.
Reaction SMILES: Cl.[CH3:2][O:3][NH2:4].C(N(CC)CC)C.[CH3:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)=O>CO>[CH3:2][O:3][N:4]=[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([I:21])[CH:16]=1)[CH3:12]
Reactant: CON
Reactant: CC(=O)c1cccc(I)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CON=C(C)c1cccc(I)c1
Temperature: 60 °C

Procedure:
To a solution of O-methyl hydroxylamine hydrochloride (2.5 g, 30.48 mmol) in methanol (25 ml), was added triethylamine (30.48 mmoles) followed by 3-iodo acetophenone (5 g, 20.3 mmol) and the mixture was heated at 60° C. for 3 hours. On completion of the reaction, the mixture was concentrated to remove methanol, to give 1-(3-iodo-phenyl)-ethanone O-methyl-oxime (crude), which was dissolved in glacial acetic acid (50 ml). Sodium cyanoborohydride (2.5 g, 40 mmol) was added portion wise. The mixture was allowed to stirr overnight at ambient temperature. The reaction mixture was concentrated to remove acetic acid and diluted with water. The aqueous layer was extracted with ethyl acetate (3×80 ml), the combined organic layer is washed with brine (40 ml) and dried over sodium sulphate. Organic layer was concentrated under vacuum to obtain 5.6 g crude material, which was subjected to column purification (60-120μ mesh silica gel, 15% ethyl acetate in hexane) to give 3.4 g (54% of theory) of N-[1-(3-Iodo-phenyl)-ethyl]-O-methyl-hydroxylamine.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1.[CH2:10](O)[CH2:11][CH:12]=[CH2:13].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH2:13][CH2:12][CH:11]=[CH2:10])=[CH:6][CH:5]=[C:4]([Br:9])[N:3]=1
Reactant: C=CCCO
Reactant: Oc1ccc(Br)nc1Br
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCCOc1ccc(Br)nc1Br

Procedure:
To a stirred mixture of 2,6-dibromopyridin-3-ol (47.3 g, 0.188 mol) and but-3-en-1-ol (13.8 g, 0.191 mol) in anhydrous THF (200 ml) at 0° C. was added PPh3 (59.4 g, 0.226 mol), followed by diethyl azodicarboxylate (41.77 g, 0.207 mol). The mixture was heated at reflux for 1 h and then concentrated in vacuo to give a dark brown oil. The oil was dissolved in EtOAc, washed with saturated NaHCO3 solution and brine, dried with Na2SO4, and concentrated in vacuo. Petroleum (300 ml) was added to the crude product mixture. The white solid was removed by filtration, and the filtrate was purified by silica gel chromatography (petroleum/EtOAc, 30/1) to afford the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[NH2:4].[CH:10](=O)[C:11]1[C:12](=[CH:14][CH:15]=[CH:16][CH:17]=1)[OH:13].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Br:9])[C:3]=1[N:4]=[CH:10][C:11]1[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=1[OH:13]
Reactant: Nc1c(Br)cccc1Br
Reactant: O=Cc1ccccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Oc1ccccc1C=Nc1c(Br)cccc1Br
Yield: 109.8 %

Procedure:
A solution of 2,6-dibromoaniline (9 g, 35.9 mmol), salicylaldehyde (2.79 mL, 35.9 mmol) and p-toluenesulfonic acid (20 mg, 0.1 mmol) in toluene (180 mL) was heated to reflux in a Dean-Stark apparatus for 2 h. After adding some triethylamine the reaction mixture was evaporated resulting in crude compound 2-[(2,6-dibromophenyl)iminomethyl]phenol (14 g, 100%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1O)[C:17](O)=O.C(OC)(OC)OC>>[CH2:22]([CH:14]([NH:13][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:12])[CH2:15][CH2:16][CH3:17])[CH2:21][CH3:20]
Reactant: Nc1cc(C(=O)O)ccc1O
Reactant: O=C(O)c1ccc2ocnc2c1
Solvent: COC(OC)OC
Product: CCCC(CCC)NC(=O)c1ccc2ocnc2c1
Temperature: 65 °C
Yield: 15 %

Procedure:
benzooxazol-5-carboxylic acid: A mixture of 3-amino-4-hydroxybenzoic acid (500 mg, 3.26 mmol) and trimethyl orthoformate (5 mL) was heated at 65° C. for 2 h under argon. The reaction mixture was cooled to room temperature, filtered and washed with hexanes. The filtrate was concentrated in vacuo to afford the product as a white solid (78 mg, 15%): 1H NMR (500 MHz, CDCl3): δ 8.57 (d, J=1.5 Hz, 1H), 8.20 (dd, J=8.4, 1.8 Hz, 1H), 8.20 (s, 1H), 7.67 (d, J=9.0 Hz, 1H). MS (M+H, 164).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@@H:7](S(C)(=O)=O)[CH2:6][N:5]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][C@H:7]([N:21]=[N+:22]=[N-:23])[CH2:6][N:5]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C

Procedure:
N-Boc-(2S,4R)-4-methanesulfonylproline methylester was taken in DMF (10 mL) to which sodium azide (1.30 g, 20.0 mmol) was added and heated at 75–80° C. overnight. DMF was removed and the product was extracted with ethyl acetate (100 mL) and washed with water (50 mL). The azide product 9c (P=Boc, m=1, R9=azide) was obtained (0.98 g, 90%) on removal of solvent.
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(OCc2ccccc2)nc1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
To an ice-cold solution of 0.5 g (2.5 mmol) 6-benzyloxy-3-hydroxypyridine (commercially available) in 5 mL tetrahydrofuran 0.12 g (2.7 mmol) sodium hydride (55% dispersion in mineral oil) was added. After the vigorous gas evolution had ceased the reaction mixture was stirred for 15 min. and then 0.41 mL (3.72 mmol) ethyl bromoacetate were added dropwise. The light brown suspension was stirred for 1 h at room temperature, poured on water and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, treated with silica gel and evaporated. The resulting solid is purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) with a gradient of heptane:ethyl acetate (100:0 to 70:30) to give the desired product as a colorless oil (90%). MS (Turbo Spray): m/z=288.0 [M+H].
Reaction SMILES: [O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[CH:10][C:11](F)=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([OH:20])[C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:34]([O:38]CC)(=[O:37])[CH2:35][SH:36].O>CN(C=O)C>[O:1]=[S:2]1(=[O:27])[C:8]2[CH:9]=[CH:10][C:11]([S:36][CH2:35][C:34]([OH:38])=[O:37])=[CH:12][C:7]=2[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]([OH:20])[C:4]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:21][CH3:22])[CH2:3]1
Reactant: CCOC(=O)CS
Reactant: CCCCC1(CC)CS(=O)(=O)c2ccc(F)cc2C(c2ccccc2)C1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCC1(CC)CS(=O)(=O)c2ccc(SCC(=O)O)cc2C(c2ccccc2)C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 48.3 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-4-hydroxy-5-phenyl-7-fluoro-2,3,4,5-tetrahydrobenzothiepine (prepared according to WO 98/40375; 300 mg, 0.77 mmol) was dissolved in DMF (3 ml) and caesium carbonate (540 mg, 1.66 mmol) was added followed by ethyl thioglycolate (0.17 ml, 1.54 mmol) and the reaction mixture was subjected to microwave irradiation in a Smith Synthesiser at 100° C. for 5 min. The reaction mixture was added to water (25 ml), extracted with DCM (5×5 ml) and concentrated. The crude ethyl ester was dissolved in THF (4 ml) and water (2 ml) and NaOH (1 M, 4 ml) was added. The reaction mixture was stirred at ambient temperature for 6 hours, quenched with HCl (1 M), diluted with water (25 ml) and extracted with DCM (4×5 ml). The combined organic layers were purified with preparative HPLC using MeCN/ammonium acetate buffer as the eluent (50:50) to give the title compound (172 mg, 48%). NMR (400 MHz, DMSO-d6): 0.74 (t, 3H), 0.84 (t, 3H), 1.01 (m, 1), 1.18-1.46 (m, 5H), 1.60 (m, 1H), 2.02 (m, 1H), 3.07/3.12 (ABq, 2H), 3.33/3.39 (ABq, 2H), 3.95 (s, 1H), 5.23 (s, 1H), 6.38 (d, 1H), 7.19 (dd, 1H), 7.34 (m, 1H), 7.42 (m, 4H), 7.73 (d, 1H).
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:25][C:26]1[CH:27]=[C:28]([NH:32]N)[CH:29]=[CH:30][CH:31]=1>>[F:25][C:26]1[CH:27]=[C:28]([N:32]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:29]=[CH:30][CH:31]=1
Reactant: NNc1cccc(F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(S(C)(=O)=O)cc2)ccc1=O
Product: CS(=O)(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3cccc(F)c3)n2)cc1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-methansulfonyl-phenyl)-1H-pyridazin-4-one (A-16) and 3-fluoro-phenylhydrazine according to the method described for example 43. MS: M=411.1 (M+H)+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.[CH:21]1([N:27]=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:30]1([NH:29][C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[N:27][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: NCCCCCCCCOc1cccc2ccccc12
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Product: c1ccc2c(OCCCCCCCCNC(=NC3CCCCC3)NC3CCCCC3)cccc2c1
Temperature: 120 °C

Procedure:
700 Milligrams (mg) of 1-amino-8-(1-naphthyloxy)octane and 505 mg of dicyclohexylcarbodiimide were mixed well and heated to 120° C. for 1 hour. The crude product was chromatographically separated on a silica gel column eluting with a mobile phase of 25 parts 2-propanol to 1 part water to 1 part acetic acid affording 1,2-dicyclohexyl-3-[8-(1-naphthyloxy)octyl]guanidine as a gum.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:9]=[C:8]([OH:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[N:6]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](Cl)=[O:29])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[N:7]1[C:8]([OH:10])=[C:9]([C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:18])=[N:6]1
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: C1COCCO1
Product: COC(=O)Cc1nn(-c2ccccc2Cl)c(O)c1C(=O)Cc1ccc(OC)cc1
Yield: 70 %

Procedure:
The mixture of the above obtained methyl[1-(2-chlorophenyl)-5-hydroxy-1H-pyrazol-3-yl]acetate (Compound of Formula (IV), 1 g, 3.76 mmol, 1 eq.), was suspended in dioxane (10 mL) and Ca(OH)2 (0.557 g, 2 equiv.) and (4-methoxyphenyl)acetyl chloride (0.694 g) under nitrogen, was heated at 120° C. for 45-60 minutes. The resulting red solution was concentrated in vacuo to afford a red syrup that was partitioned between ethylacetate and cold 0.1M HCl. Organic phases were washed with brine and dried over Na2SO4. Evaporation of solvent gave methyl {1-(2-chlorophenyl)-5-hydroxy-4-[(4-methoxyphenyl)acetyl]-1H-pyrazol-3-yl}acetate as a pink solid (1.09 g, 70% yield, 89% HPLC purity). MS (ESI+): 415.9; MS (ESI−): 413.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:26](=[O:28])[CH3:27])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:25])[C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=2F)[CH2:10][CH2:9]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>O>[N:29]1([C:16]2[CH:17]=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:7]3[CH:6]=[CH:5][C:4]([C:26](=[O:28])[CH3:27])=[CH:3][C:2]=3[F:1])[CH2:13][CH2:12]2)=[O:25])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3F)CC2)c(F)c1
Solvent: O
Product: CC(=O)c1ccc(N2CCN(C(=O)c3cc([N+](=O)[O-])ccc3N3CCOCC3)CC2)c(F)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
A solution of 1-{3-Fluoro-4-[4-(2-fluoro-5-nitro-benzoyl)-piperazin-1-yl]-phenyl}-ethanone (0.065 g, 0.167 mmol) in morpholine (0.29 ml) was heated for 30 minutes at 100° C. then cooled to room temperature and diluted with water. The resulting solid was filtered and dried to provide the title compound (71 mg, 93%) as a yellow solid, MS (m/e): 457.3 (M+H+, 100%)
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[I:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:29]=[C:28](C(Cl)(Cl)Cl)[O:27][N:26]=3)[CH:23]=2)[N:18]([S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:17]=1>C1COCC1>[I:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[N:29]=[C:28]([NH:4][C:1](=[O:3])[CH3:2])[O:27][N:26]=3)[CH:23]=2)[N:18]([S:34]([C:37]2[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=2)(=[O:35])=[O:36])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4noc(C(Cl)(Cl)Cl)n4)ccc32)cc1
Reactant: CC(N)=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(-c2ccc3c(c2)c(I)cn3S(=O)(=O)c2ccc(C)cc2)no1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
To a solution of acetamide (91.5 mg, 1.54 mmol in dry THF (10 mL) was added 1.0M lithium bis(trimethylsilyl)amide (LHMDS) (1.2 mL, 1.54 mmol) at −78° C. and the mixture was stirred for 45 min at −78° C. and 10 min at −10° C. Again the reaction was cooled back to −78° C. To the mixture at −78° C. was added 3-(3-iodo-1-tosyl-1H-indol-5-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (600 mg, 1.03 mmol) and the reaction was stirred at RT for 12 h. The solvent was then removed in vacuo and the residue was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The combined organic layers were dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified with basic alumina column chromatography (eluent: 35% EtOAc in petroleum ether) to give N-(3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-oxadiazol-5-yl)acetamide (300 mg, 55.5%) as an off brown solid. MS (ESI, pos. ion) m/z: 523.0 (M+1); 1H-NMR (400 MHz, DMSO-d6): δ 12.22 (brs, 1H), 8.22 (s, 1H), 8.15 (d, J=8.8 Hz, 1H), 8.02-7.90 (m, 4H), 7.44 (d, J=8.0 Hz, 2H), 2.33 (m, 3H), 2.19 (s, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.[CH:30]1([C:33](Cl)=[O:34])[CH2:32][CH2:31]1>>[CH:30]1([C:33]([N:1]2[CH2:2][CH2:3][CH:4]([NH:7][C:8]([C:10]3[C:14]4[N:15]=[CH:16][N:17]=[C:18]([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[O:25][CH2:26][CH:27]5[CH2:28][CH2:29]5)[C:13]=4[NH:12][CH:11]=3)=[O:9])[CH2:5][CH2:6]2)=[O:34])[CH2:32][CH2:31]1
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12
Reactant: O=C(Cl)C1CC1
Product: O=C(NC1CCN(C(=O)C2CC2)CC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from 4-(2-cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A162) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([NH:15]C(OC(C)(C)C)=O)[CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[C:9]([OH:13])=[C:8]([Br:14])[CH:7]=1.[CH3:24][C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([CH3:33])[CH:32]=1)[CH2:28]Br>>[NH2:15][CH:4]([CH2:5][C:6]1[CH:7]=[C:8]([Br:14])[C:9]([O:13][CH2:24][C:25]2[CH:26]=[C:27]([CH3:28])[CH:30]=[C:31]([CH3:33])[CH:32]=2)=[C:10]([Br:12])[CH:11]=1)[C:3]([OH:2])=[O:23]
Reactant: Cc1cc(C)cc(CBr)c1
Reactant: COC(=O)C(Cc1cc(Br)c(O)c(Br)c1)NC(=O)OC(C)(C)C
Product: Cc1cc(C)cc(COc2c(Br)cc(CC(N)C(=O)O)cc2Br)c1
Yield: 34.8 %

Procedure:
Methyl-2-tert-butoxycarbonylamino-3-(3,5-dibromo-4-hydroxyphenyl)-propionate (0.20 g, 0.44 mmol) was coupled with 3,5-dimethyl benzylbromide (0.22 g, 1.1 mmol), using the method described in Example 2. After deprotection and final purification on HPLC, using the same conditions as described in Example 1(b), 70 mg (35%) of 2-amino-3-[3,5-dibromo-4-(3,5-dimethylbenzyloxy)phenyl]propionic acid was obtained. LC-MS (electrospray): m/z 458 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][OH:18]>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:16][CH2:17][OH:18]
Reactant: Oc1cccc(Br)c1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: OCCOc1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-bromophenol (36.38 g, 210.3 mmol) in acetone (175 ml) was added K2CO3 (0.033 g, 237 mmol) and 2-bromoethanol (20 ml, 283.3 mmol). The reaction mixture was heated at reflux under argon for 4 days. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was dissolved in diethyl ether (150 ml) and the solution was washed successively with water, 10% aqueous NaOH, 5% aqueous NaOH, water, and brine. The solution was dried over MgSO4 and concentrated under reduced pressure to give 2-(3-bromophenoxy)ethanol (106) as a light brown oil. Yield (21.07 g, 46%): 1H NMR (400 MHz, CDCl3) δ 7.14 (t, J=7.8 Hz, 1H), 7.07-7.12 (m, 2H), 6.85 (ddd, J=7.8, 2.4, 1.3 Hz, 1H), 4.05-4.07 (m, 2H), 3.93-3.97 (m, 2H), 2.11 (t, J=12.3 Hz. 1H).
Reaction SMILES: [CH:1]1([C:4]2[N:22]=[C:7]3[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:12](=O)[CH:13]([CH3:18])[CH2:14][C:15](O)=[O:16])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.CC(O)=O.[NH2:27][NH2:28]>CCO>[CH:1]1([C:4]2[N:22]=[C:7]3[C:8]([O:20][CH3:21])=[CH:9][CH:10]=[C:11]([C:12]4[CH:13]([CH3:18])[CH2:14][C:15](=[O:16])[NH:27][N:28]=4)[N:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: NN
Reactant: COc1ccc(C(=O)C(C)CC(=O)O)n2nc(C3CC3)nc12
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C2=NNC(=O)CC2C)n2nc(C3CC3)nc12

Procedure:
Under an argon atmosphere 4-(2-Cyclopropyl-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-3-methyl-4-oxo-butyric acid (0.1 g, ca. 0.33 mmol) was dissolved in EtOH (1.5 mL). AcOH (0.11 mL, 1.98 mmol) and NH2NH2*H2O (0.048 mL, 0.99 mmol) were added. The solution was heated at reflux for 17 h after which it was concentrated in vacuo and co-concentrated with toluene. Aq. NaHCO3 was added and the aqueous phase was extracted with ÉtOAc (×2). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography using EtOAc as the eluent to afford the title compound as a solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:36][CH2:37][C:38]1[CH:39]=[C:40]([CH:44]([C:51]#[C:52][CH3:53])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=[CH:42][CH:43]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O>C1COCC1>[OH:36][CH2:37][C:38]1[CH:39]=[C:40]([CH:44]([C:51]#[C:52][CH3:53])[CH2:45][C:46]([O:48][CH2:49][CH3:50])=[O:47])[CH:41]=[CH:42][CH:43]=1
Reactant: CC#CC(CC(=O)OCC)c1cccc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC#CC(CC(=O)OCC)c1cccc(CO)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution (5.0 mL) of tetrabutylammonium fluoride in THF was added to a solution of ethyl 3-(3-(((tert-butyldiphenylsilyl)oxy)methyl)phenyl)hex-4-ynoate in THF (10 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (181 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][C:21]=1[F:29]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][C:21]=1[F:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCc1ccc(Br)c(F)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: COCc1ccc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c(F)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 1-bromo-2-fluoro-4-(methoxymethyl)benzene (obtained in Step 1), the title compound was obtained as a dark orange sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.