Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@@H:8]([OH:33])[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:21]=[C:22]([CH2:25][C:26]([N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])[O:23][CH:24]=3)=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>CO.C(OCC)C.[Pd]>[OH:33][C@H:8]([C:5]1[CH:6]=[N:7][CH:2]=[CH:3][CH:4]=1)[CH2:9][NH:10][CH2:11][CH2:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([CH2:25][C:26]([N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:27])[O:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: O=C(Cc1nc(-c2ccc(OCCNC[C@H](O)c3ccc(Cl)nc3)cc2)co1)N1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Product: O=C(Cc1nc(-c2ccc(OCCNC[C@H](O)c3cccnc3)cc2)co1)N1CCCC1
Reaction time: 8 h
Yield: 60 %

Procedure:
In a nitrogen-purged, round-bottomed flask, (R)-2-[4-(4-{2-[2-(6-chloro-pyridin-3-yl)-2-hydroxy-ethylamino]-ethoxy}-phenyl)-oxazol-2-yl]-1-pyrrolidin-1-yl-ethanone 1-1A (200 mg, 0.42 mmol) was dissolved in methanol (15 ml). 10% Pd/C (160 mg, 80 wt %), and ammonium formate (321 mg, 5.1 mmol) were then added sequentially. The reaction mixture was stirred overnight, and was then filtered through a pad of diatomaceous earth, and the filter cake rinsed with ethyl acetate. The filtrate was concentrated to a white solid, which was taken up in ethyl acetate and saturated aqueous sodium carbonate, and extracted. The organic extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford a crude solid. This material was suspended in diethylether and isolated by vacuum filtration to afford a crystalline solid 1-1B (110 mg, 59% yield). This material was then converted to the corresponding hydrochloride salt. Analytical data for the HCl salt: LRMS ([M+H]+): 437.4. 1H NMR: (400 MHz, CD3OD): δ1.91 (m, 2H), 2.02 (m, 2H), 3.37-3.29 (m, 2H), 3.45 (m, 2H), 3.54-3.63 (m, 5H), 3.97 (s, 2H), 4.37 (t, 2H, J=4.8 Hz), 5.38 (dd, 1H, J=3.2,10.4 Hz), 7.07 (dd, 2H, J=2.8, 9.6 Hz), 7.69 (dd, 2H, J=1.8, 6.4 Hz), 8.14 (m, 2H), 8.75 (m, 1H), 8.86 (d, 1H, J=6.0 Hz), 8.99 (m, 1H). Preparation for 2-[4-(4-{2-[2(R)-Hydroxy-2-(6-methyl-pyridin-3-yl)-ethylamino]-ethoxy}-phenyl)-oxazol-2-yl]-N,N-dimethyl-acetamide (1-1C)
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34]CC3C=CC=CC=3)[C:29]=2[O:42]CC2C=CC=CC=2)[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[H][H]>[Pd].C1COCC1>[CH2:1]([O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[C:29]=2[OH:42])[CH:20]=1)[C:15]([OH:17])=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(OCc3ccccc3)c2OCc2ccccc2)cc(C(=O)O)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1cc(OCCCCCCc2cccc(O)c2O)cc(C(=O)O)c1
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
A mixture of 1.7 g of 3-(decyloxy)-5-[[6-[2,3-bis(phenylmethoxy) phenyl]hexyl]oxy]benzoic acid and 0.3 g of 10% palladium on carbon in 75 ml of THF was stirred in a hydrogen atmosphere until uptake ceased after 2.5 hours. The usual workup followed by trituration of the crude product from hexane and filtration gave 1.13 g (91% yield, mp 86°-88°) of 3-(decyloxy)-5-[[6-(2,3-dihydroxyphenyl)hexyl]oxy]benzoic acid.
Reaction SMILES: [CH2:1]([CH:4]([N:8]1[C:12]2[N:13]=[C:14]([CH3:27])[N:15]=[C:16]([NH:17][C:18]3[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[C:11]=2[N:10]=[N:9]1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O.O>[CH2:30]([N:17]([C:18]1[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=1[CH3:24])[C:16]1[C:11]2[N:10]=[N:9][N:8]([CH:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[C:12]=2[N:13]=[C:14]([CH3:27])[N:15]=1)[CH3:31]
Reactant: CCI
Reactant: CCCC(CCC)n1nnc2c(Nc3c(C)cc(C)nc3C)nc(C)nc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCC(CCC)n1nnc2c(N(CC)c3c(C)cc(C)nc3C)nc(C)nc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The product from Example 47, Part B (400 mg, 1.09 mmol) was treated with sodium hydride (40 mg, 1.31 mmol, 80%) and ethyl iodide (0.130 ml, 1.63 mmol) in dry dimethylformamide (10 ml) and stirred at room temperature for 15 hours. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 373 mg (87%) as a clear viscous oil.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[NH2:16][CH:17]([CH3:20])[CH2:18][OH:19].O>CO>[OH:19][CH2:18][CH:17]([NH:16][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH3:20]
Reactant: CC(N)CO
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: O
Solvent: CO
Product: CC(CO)NC(c1ccccc1)C(O)c1ccccc1
Yield: 79 %

Procedure:
A mixture of trans-stilbene oxide (3.93 g, 0.020 mole) and 2-amino-1-propanol (4.51 g, 0.060 mole) was heated on a steam bath for 18 hours. The reaction mixture was dissolved in methanol (20 ml) and the solution poured into water (200 ml). The viscous oil which separated from the solution crystallized on standing. The solid was collected to obtain 4.29 g (79%) of material which was recrystallized from toluene to give 3.36 g of a white solid. The solid was dried in vacuo for 2 hours, m.p. 104°-105° C.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][C@H:6]([NH2:11])[CH2:7][C:8]([O-:10])=[O:9])([CH3:4])[CH3:3].C(N(C(C)C)CC)(C)C.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CO>[CH2:30]([C:27]1[CH:26]=[CH:25][C:24]([NH:21][C:22](=[O:23])[NH:11][C@@H:6]([CH2:5][N+:2]([CH3:3])([CH3:4])[CH3:1])[CH2:7][C:8]([O-:10])=[O:9])=[CH:29][CH:28]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C[N+](C)(C)C[C@H](N)CC(=O)[O-]
Reactant: CCCCCCCCc1ccc(N=C=O)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCCCCCCCc1ccc(NC(=O)N[C@H](CC(=O)[O-])C[N+](C)(C)C)cc1
Reaction time: 18 h

Procedure:
To a solution of (R)-aminocarnitine (22 mg, 0.14 mmol) and diisopropylethylamine (71 uL, 0.41 mmol) in MeOH (2 mL) was added 1-isocyanato-4-octylbenzene (63 uL, 0.27 mmol) and the reaction stirred for 18 h. The MeOH was removed in vacuo and the residue stirred with 1:1 ether/EtOAc. Impurities dissolved into the ether/EtOAc which were discarded and the remaining material taken up into 90:10 CH2Cl2/MeOH and then loaded onto a short SiOH plug. The title compound was eluted by increasing MeOH content in 10% steps to 60%. The compound was then taken up into 90:10 CH2Cl2/MeOH and filtered through a plug of celite which gave after drying the title compound as a white powder (9 mg, 17%). 1H NMR (400 MHz, CD3OD) δ 7.27 (d, 2H, J=8.4 Hz), 7.09 (d, 2H, J=8.4 Hz), 4.73-4.71 (m, 1H), 3.78-3.53 (m, 2H), 3.25 (s, 9H), 2.75-2.72 (m, 2H), 2.55 (t, 2H, J=8.0 Hz), 1.60-1.29 (m, 12H), 0.90 (t, 3H, J=6.8 Hz); MS ESI 392.3 [M+H]+, calcd for [C22H37N3O3+H]+ 392.55.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24](I)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)=[O:10])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[S:42]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43]1>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=1)[C:9](=[O:10])[N:11]1[CH2:16][CH2:15][N:14]([C:17]2[C:18]3[S:25][C:24]([C:44]4[CH:45]=[CH:46][S:42][CH:43]=4)=[CH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(I)sc23)CC1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1ccc(Cl)cc1)C(=O)N1CCN(c2ncnc3cc(-c4ccsc4)sc23)CC1
Temperature: 90 °C
Yield: 34.2 %

Procedure:
To a solution of {1-(4-chlorobenzyl)-2-[4-(6-iodothieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (50 mg, 0.080 mmol) in DMF (3 mL) were added 2M Na2CO3 (0.1 mL) and 3-thiophenyl boronic acid (15 mg, 0.117 mmol). The mixture was bubbled N2 for 20 minutes and then Pd(PPh3)4 (10 mg, 0.012 mmol) was added. The mixture was heated to 90° C. for 12 hours. The solvent was removed under vacuum and the residue was subject to chromatography on silica gel to afford the product {1-(4-chlorobenzyl)-2-oxo-2-[4-(6-thiophen-3-yl-thieno[3,2-d]pyrimidin-4-yl)-piperazin-1-yl]-ethyl}-carbamic acid tert-butyl ester (16 mg, 34.4%). 1H NMR (CDCl3, 400 Hz) δ 8.57 (s, 1H), 7.70-7.42 (m, 4H), 7.27 (d, J=8.4, 2H), 7.16 (d, J=8.4 Hz, 2H), 5.36 (d, J=8.8 Hz, 1H), 4.87-4.84 (m, 1H), 3.91-3.59 (m, 7H), 3.27-3.24 (d, J=11.2 Hz, 1H), 3.00-2.99 (d, J=7.2 Hz, 2H), 1.43 (s, 9H). MS (ESI+) [M+H]+ 584.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)=[CH:9]\[CH3:10])=[CH:4][CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)=[N:15][CH:16]=2)[CH2:9][CH3:10])=[CH:4][CH:3]=1
Reactant: C/C=C(\c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.6 %

Procedure:
To a solution of (E)-5-(1-(4-fluorophenyl)prop-1-enyl)-2-(piperazin-1-yl)pyrimidine (170 mg, 0.57 mmol) in methanol (10 mL) was added Pd/C (30 mg). The mixture was exposed to 1 atm hydrogen (balloon) and stirred at RT for 1 h. The mixture was filtrated, and the filtrate was concentrated to an oil, which was purified by combiflash with dichloromethane:methanol=50:1 to give the title compound (racemate, 90 mg, 53%) as a yellow oil.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([N+:13]([O-])=O)[CH:12]=1)[C:8]#[N:9])([O-])=O.[OH-].[Na+]>>[NH2:2][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([NH2:13])[CH:12]=1)[C:8]#[N:9]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)cc(N)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 210 grams of stannous chloride dihydrate in 590 ml. of concentrated hydrochloric acid is added portionwise 25 grams of 3,5 -dinitrobenzonitrile. The mixture is stirred for three hours at room temperature, then cooled to 0° in an ice-salt bath and a cold 50% sodium hydroxide solution added to the mixture until the mixture is strongly basic. During the addition the temperature is kept below 5°.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C(N)(=[O:31])C>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:31])=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C#N)cc3)CC2)nc1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Temperature: 25 °C

Procedure:
The product of step A (150 mg, 0.398 mmol), acetamide (101 mg, 1.71 mmol) and Pd(OAc)2 (13.4 mg, 0.02 mmol) in THF (4.5 mL) and H2O (1.5 mL) was heated at 65° C. for 24 h. The mixture was cooled to RT and diluted with H2O. The solution was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 20:1 DCM:MeOH) to yield the desired compound. MS (ESI) m/z 395 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][C:27]([CH3:33])=[N:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:30]([C:29]3[N:25]([CH3:24])[N:26]=[C:27]([CH3:33])[CH:28]=3)=[O:31])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1cc(C(=O)NC[C@@H]2C[C@@H]3C[C@@H]3N2C(=O)c2nc(N)sc2-c2cccc(F)c2)n(C)n1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 2,5-dimethyl-2H-pyrazole-3-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=455.2.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH2:16]([N:23]1[N:27]=[N:26][C:25]([NH2:28])=[N:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([N:23]1[N:27]=[N:26][C:25]([NH:28][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])=[N:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1nnn(Cc2ccccc2)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3nnn(Cc4ccccc4)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 2-benzyl-2H-tetrazol-5-ylamine (Journal of the American Chemical Society 76, 923 (1954)). The title compound was obtained as a yellowish solid (Yield=29%). MS ISP (m/e): 357.1 (100) [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH:10]([CH2:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1.CO.Cl.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][Cl:35])[CH:29]=1>O.[OH-].[Na+]>[ClH:1].[ClH:35].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[C:10]([CH2:34][C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)([CH2:17][C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[C:9]2=[O:24])=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: O=C1C(Cc2ccncc2)c2cccnc2N1c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C1N(c2ccc(Cl)cc2)c2ncccc2C1(Cc1ccncc1)Cc1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 1,3-dihydro-1-(4-chlorophenyl)-3-(4-pyridinylmethyl)-2H-pyrrolo[2,3-b]pyridin-2-one (3.0 g, 8.93 mmol) and 20 ml 1N NaOH was treated with enough MeOH to effect solution. The mixture was treated dropwise with 3-picolyl chloride hydrochloride (1.6 g, 9.82 mmol) in 10 ml water. The mixture was stirred at room temperature for 2 h, and treated with an additional 20 ml IN NaOH. The mixture was stirred at room temperature for 24 h and concentrated in vacuo. The residue was partitioned between 200 ml CH2Cl2, washed with brine, dried over MgSO4, filtered, and treated with 20 ml 1N HCl/Et2O. The resulting precipitate was collected by filtration, washed with ether, and dried to give the desired product in 90% (4.0 g) yield; mp 208°-211° C., dec.; IR(nujol): 1720 cm-1 (CO); 1H NMR(DMSOd6TMS): d 3.65 [m, 2H, CH2 -(3-Pyr)], 3.71-3.91 [q, 2H, CH2 -(4-Pyr)], [7.06 (d, 2H), 7.22 (m, 1H), 7.53 (d, 2H), 7.60 (d, 2H), 7.85 (dd, 1H), 8.04 (dd, 2H), 8.22 (d, 1H), 8.52 (s, 1H), 8.84 (d, 3H), Ar]; mass spec m/e 427 (M+1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][C:53](O)=[O:54])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.B#B>C(Cl)Cl.O1CCCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]1([CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][OH:54])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=C(O)CCCCCCCc1ccccc1
Agent: B#B
Agent: OCCCCCCCCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: BrCCCCCCCCc1ccccc1

Procedure:
8-Phenyloctyl bromide was prepared from 8-phenyloctanol, carbon tetrabromide and triphenylphosphine in methylene chloride. A solution of 8-phenyloctanoic acid (19.8 mmol) in sieve dried tetrahydrofuran (5 ml) was reduced with diborane in tetrahydrofuran (30 ml, 29.1 mmol) at 20° C. for 4 hours to give 8-phenyloctanol. To an ice cold solution of the octanol (ca. 19.8 mmol) and carbon tetrabromide (21.98 mmol) in methylene chloride (50 ml) was added triphenylphosphine (22.30 mmol) in methylene chloride (50 ml) and the resulting solution was stirred for 2.5 hours. The volatiles were evaporated and the residue was taken up in ether (100 ml), cooled in ice, and filtered. The filtrate was evaporated and distilled to afford 8-phenyloctyl bromide as an oil. To 8-phenyloctyl bromide and 21.27 mmol of magnesium) in distilled tetrahydrofuran (40 ml) was added 2-(2-methoxyphenyl)-4,4-dimethyloxazoline (17.10 mmol) in tetrahydrofuran (20 ml). After stirring for 24 hours, the reaction mixture was similarly worked up to yield 2-[2-(8-phenyloctyl)phenyl]-4,4-dimethyloxazoline as an oil. A solution of the oxazoline (11.58 mmol) in methyl iodide (20 ml) as refluxed under argon for 18 hours. Removal of the volatiles afforded the corresponding 3,4,4-trimethyloxazolinium iodide as a white solid (mp 76.5°-78° D.). To an ice cold solution of the iodide (9.46 mmol) in methanol (35 ml) was added in portions sodium borohydride (9.20 mmol). Treatment of the reaction mixture as in Example 1(c) results in the isolation of the desired product as an oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:22][C:23]2[N:24]=[C:25]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([CH3:38])[CH3:37])=[CH:31][CH:30]=3)[O:26][C:27]=2[CH3:28])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 f], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 47 c]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole (example 2 b]) in N,N-dimethylformamide in the presence of potassium carbonate to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 g], to yield [rac]-2-ethoxy-3-{2-ethoxy-4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[CH:4]=1.[Sn](Cl)Cl>C(O)C>[CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[CH:4]=1
Reactant: CN(C)c1cccc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CN(C)c1cccc(N)c1
Yield: 81.5 %

Procedure:
N,N-dimethyl-3-nitroaniline (3.00 g, 18.1 mmol) was dissolved in ethanol (40 cm3). Tin dichloride (16.3 g, 72.0 mmol) was added and the reaction heated under reflux for 16 h. The reaction mixture was allowed to cool before the bulk of the solvent was removed under reduced pressure. The remaining residue was poured in to water (100 cm3), and basified with sodium hydroxide (3M). The mixture was extracted with chloroform (3×30 cm3). The combined extracts were dried over sodium sulphate, filtered and the solvent removed under reduced pressure to give the product as a brown oil (2.01 g, 82%).
Reaction SMILES: C(O[CH:4]=[N:5][C:6]1[NH:10][N:9]=[N:8][N:7]=1)C.[C:11]([O:20][CH3:21])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14]>C(OCC)(=O)C>[NH:7]1[C:6]([NH:5][CH:4]=[N:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]([O:20][CH3:21])=[O:19])=[N:10][N:9]=[N:8]1
Reactant: CCOC=Nc1nnn[nH]1
Reactant: COC(=O)c1ccccc1N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccccc1N=CNc1nnn[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 5 g of 5-(ethoxymethyleneamino)tetrazole in 50 ml of ethyl acetate, stirred at room temperature under nitrogen, there was added a solution of 10.2 g of methyl anthranilate in 50 ml of ethyl acetate and the mixture was stirred for 24 hours. The white solid which formed was separated by filtration, washed with ethyl acetate and vacuum oven dried to give crude N1 -(1H-tetrazol-5-yl)-N2 -(2-carbomethoxyphenyl)formamidine. This was recrystallized from a mixture of N,N-dimethylformamide and ethyl acetate to give pure product identical with authentic material.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[N:11]=[CH:12][S:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[Li+].CC([N-]C(C)C)C.[N:25]1([C:30]2[CH:35]=[CH:34][C:33]([CH:36]([O:43][CH3:44])[C:37](N(OC)C)=[O:38])=[CH:32][CH:31]=2)[CH:29]=[CH:28][CH:27]=[N:26]1>C1COCC1.C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C>[N:25]1([C:30]2[CH:31]=[CH:32][C:33]([CH:36]([O:43][CH3:44])[C:37]([C:12]3[S:13][CH:14]=[C:10]([C:5]4[CH:6]=[C:7]([O:8][CH3:9])[C:2]([Br:1])=[C:3]([O:15][CH3:16])[CH:4]=4)[N:11]=3)=[O:38])=[CH:34][CH:35]=2)[CH:29]=[CH:28][CH:27]=[N:26]1
Reactant: COC(C(=O)N(C)OC)c1ccc(-n2cccn2)cc1
Reactant: COc1cc(-c2cscn2)cc(OC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: COc1cc(-c2csc(C(=O)C(OC)c3ccc(-n4cccn4)cc3)n2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 19.1 %

Procedure:
To a −20° C. solution of 4-(4-bromo-3,5-dimethoxyphenyl)thiazole (0.092 g, 0.305 mmol) in anhydrous THF (2 mL) under argon was added a solution of LDA (0.18 mL of a 2.0 M solution in THF/heptane/ethylbenzene, 0.37 mmol) dropwise. After stirring for 30 min, the reaction was cooled to −78° C. and a solution of 2-(4-(1H-pyrazol-1-yl)phenyl)-N,2-dimethoxy-N-methylacetamide (0.15 g, 0.55 mmol) in anhydrous THF (1.5 mL, 1.0 mL) was added dropwise. After stirring for 90 min, the mixture was quenched with brine and diluted with EtOAc. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated. Purification by chromatography (0-35% EtOAc-hexanes) gave 2-(4-(1H-pyrazol-1-yl)phenyl)-1-(4-(4-bromo-3,5-dimethoxyphenyl)thiazol-2-yl)-2-methoxyethanone as a yellow solid (0.030 g, 20% yield). MS: m/z 514.0 [M+H]+.