Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([NH:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=O.[CH:12]1C([N+]([O-])=O)=CC=C(O)C=1.CO[O:24][CH2:25][CH2:26][O:27][CH3:28].C([O-])=O.[NH4+]>C(O)C>[CH3:28][O:27][CH2:26][CH2:25][O:24][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([NH2:4])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COCCOOC
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COCCOCOc1ccc(N)cc1

Procedure:
For the synthesis of an acetaminophen FP tracer having an acyclic linker, p-Nitrophenol was protected as a methoxyethoxy methyl ether (FIG. 6). The nitro group was reduced to an amino in the presence of ammonium formate and 10% Pd--C in ethanol to yield 4-[(2-methoxyethoxy)methoxy]benzenamine (22). The amino group was succinylated and the acid derivative produced was coupled to 4'-aminomethylfluorescein. Deprotection of the methoxyethoxy ether (27) in the presence of trifluoroacetic acid yielded rac-4-[[[3',6'-dihydroxy-3-oxospiro-[isobenzofuran-1(3H),9'-[9H] xanthen]-4'-yl)methyl]amino]-N-(4-hydroxyphenyl)-4-oxobutamide (28) .
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]2.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH2:11][CH2:10]4)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2N1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-3,4-dihydro-carbostyril (m.p.: 142°-147° C.) and 4-cyclohexyl-thiophenol.
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][NH:16][CH2:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26](O)=[O:27])([CH3:22])[CH3:21]>>[CH:20]([O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33]([CH3:36])(=[O:35])=[O:34])=[CH:29][C:25]=1[C:26]([N:16]1[CH2:15][CH2:14][C:13]2[C:18](=[CH:19][C:10]([S:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)(=[O:9])=[O:8])=[CH:11][CH:12]=2)[CH2:17]1)=[O:27])([CH3:22])[CH3:21]
Reactant: O=S(=O)(c1ccc2c(c1)CNCC2)N1CCOCC1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(S(=O)(=O)N3CCOCC3)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-(morpholine-4-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline (CA [185059-05-6]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1). MS (m/e): 523.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1.[Li+].[OH-]>C1COCC1.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1
Reactant: COC(=O)CCc1cccc(OCc2ccc(-c3cccc(OC)c3)c(C)c2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1cccc(-c2ccc(COc3cccc(CCC(=O)O)c3)cc2C)c1
Temperature: 23 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of 1.4 (0.0532 g, 0.136 mmol) in THF/MeOH (2/1) (1.5 mL) was added LiOH (0.50 mL, 0.500 mmol). The resulting mixture was stirred overnight at 23° C., quenched with excess 1N HCl, and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude residue was purified by combiflash (0 to 40% EtOAc/hexane) to afford 1 (0.0426 g, 83.1% yield). MS ESI (neg.) m/e: 375.1 (M−H)+. 1H NMR (400 MHz, CDCl3) δ ppm 7.32-7.39 (3H, m), 7.24-7.31 (2H, m), 6.85-6.95 (6H, m), 5.08 (2H, s), 3.87 (3H, s), 2.99 (2H, t, J=7.8 Hz), 2.73 (2H, t, J=7.8 Hz), 2.34 (3H, s).
Reaction SMILES: S(=O)(=O)(O)O.[O:6]=[C:7]1[CH:14]2[CH2:15][C:10]3(O)[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2.[CH:18]([OH:20])=[O:19]>>[O:6]=[C:7]1[CH:14]2[CH2:15][C:10]3([C:18]([OH:20])=[O:19])[CH2:11][CH:12]([CH2:16][CH:8]1[CH2:9]3)[CH2:13]2
Reactant: O=CO
Reactant: O=C1C2CC3CC1CC(O)(C3)C2
Agent: O=S(=O)(O)O
Product: O=C1C2CC3CC1CC(C(=O)O)(C3)C2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To 60% fuming sulfuric acid (135 ml) stirred under heating at 80° C., a solution of 4-oxoadamantan-1-ol (15.69 g) in formic acid (250 ml) was added dropwise over 2 hours. After completion of the dropwise addition, the reaction mixture was stirred at 80° C. for 3 hours, to which formic acid (100 ml) was then added at room temperature and stirred overnight at room temperature. After addition of additional formic acid (50 ml), the reaction mixture was stirred at 80° C. for 12 hours and then stirred overnight at room temperature. The reaction mixture was poured into ice-cold water, filtered to remove insoluble materials and then extracted three times with toluene. After the combined organic layers were extracted with 4M aqueous sodium hydroxide, the aqueous layer was washed three times with chloroform. The aqueous layer was adjusted to pH 1 to 2 by addition of 12M aqueous hydrochloric acid and then extracted with chloroform. The organic layer was washed with brine and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the solvent was distilled off under reduced pressure to give 4-oxoadamantane-1-carboxylic acid (9.84 g) as a colorless powder. To a solution of 4-oxoadamantane-1-carboxylic acid thus obtained (1.50 g) in 8M ammonia/methanol (30 ml), 10% palladium on activated carbon (150 mg) was added and stirred overnight under a hydrogen atmosphere at room temperature. After addition of water (10 ml), the reaction mixture was filtered through celite and washed with methanol, and the filtrate was concentrated under reduced pressure. To the resulting crystal, acetonitrile (30 ml) was added and stirred at room temperature for 3 hours. The crystal was collected by filtration to give 4-aminoadamantane-1-carboxylic acid (1.28 g) as a colorless powder. To a solution of 4-aminoadamantane-1-carboxylic acid thus obtained (1.28 g) in methanol (13 ml), acetyl chloride (2.34 ml) was added under ice cooling and stirred at room temperature for 20 minutes and then at 45° C. for 8 hours. The reaction mixture was stirred overnight at room temperature and then further stirred at 45° C. for 4 hours. After the reaction mixture was cooled to room temperature and then concentrated, the resulting crystal was dissolved in chloroform and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was converted into a powder form by addition of acetonitrile (10 ml). The crystal was collected by filtration and washed sequentially with acetonitrile and n-hexane to give the titled compound, i.e., methyl 4-aminoadamantane-1-carboxylate (1.22 g) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5C=CN=CC=5)=[CH:26][C:25]=4F)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(C1C=CC(C2[O:49][N:48]=[C:47]([CH3:50])[N:46]=2)=CC=1)#C>>[F:1][C:2]1[C:7]2[CH2:8][CH2:9][CH:10]([N:19]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]5[O:49][N:48]=[C:47]([CH3:50])[N:46]=5)=[CH:26][CH:25]=4)[N:21]=[N:20]3)[C:11](=[O:18])[N:12]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C(n2cc(-c3ccc(-c4ccncc4)cc3F)nn2)CCc2c(F)cccc2N1CC(F)(F)F
Reactant: C#Cc1ccc(-c2nc(C)no2)cc1
Product: Cc1noc(-c2ccc(-c3cn(C4CCc5c(F)cccc5N(CC(F)(F)F)C4=O)nn3)cc2)n1

Procedure:
The title compound was prepared by the same route as 6-fluoro-3-{-4-[2-fluoro-4-(pyridin-4-yl)phenyl]-1H-1,2,3-triazol-1-yl}-1-(2,2,2-trifluoroethyl)-1,3,4,5-tetrahydro-2H-1-benzazepin-2-one, using 5-(4-ethynyl-phenyl)-3-methyl-1,2,4-oxadiazole as the alkyne.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][C:18](N(C)C)=[N+](C)C)[C:12]2N=CC=CC=2N=N1.CONC.C(N(CC)CC)C.[CH:36]1([CH2:39][C:40]([OH:42])=O)[CH2:38][CH2:37]1>C(Cl)Cl>[CH:36]1([CH2:39][C:40]([N:8]([O:17][CH3:18])[CH3:12])=[O:42])[CH2:38][CH2:37]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)CC1CC1
Agent: CNOC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)CC1CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (19.0 g), N-methoxymethanamine (5.0 g), and triethylamine (15.1 g) were added to a solution of 2-cyclopropylacetic acid (5.0 g) in CH2Cl2 (200 mL) at 0° C. The mixture was stirred at room temperature for 3 h. The reaction mixture was then washed with water and the aqueous washing phase was extracted with ethyl acetate (5×50 mL). The combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 20:1→5:1) to give the title compound. Yield: 4.1 g (58% of theory).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[CH2:27]([O:29][C:30](=[O:52])[CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([C:42]2[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=2[OH:50])(O)[C:33]1=[O:51])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:52])[CH2:31][N:32]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]([C:42]2[CH:47]=[C:46]([F:48])[C:45]([F:49])=[CH:44][C:43]=2[OH:50])[C:33]1=[O:51])[CH3:28]
Reactant: CCOC(=O)CN1C(=O)C(O)(c2cc(F)c(F)cc2O)c2ccccc21
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: CCOC(=O)CN1C(=O)C(c2cc(F)c(F)cc2O)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with ethyl[3-(4,5-difluoro-2-hydroxyphenyl)-3-hydroxy-2-oxo-2,3-dihydro-1H-indol-1-yl]acetate, the title compound was obtained (83%) as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.39 (t, 1H), 7.34 (d, 1H), 7.26-7.22 (m, 1H), 6.92-6.82 (m, 2H), 6.73 (dd, 1H), 5.11 (br, 1H), 4.50 (d, 1H), 4.43 (d, 1H), 4.21 (q, 2H), 1.23 (t, 3H); MS (ES+) m/z 448.5 (M+1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:10][CH3:11])[C:4](=[O:9])[C:5]#[C:6][CH2:7][CH3:8]>CCCCCC.N1C2C(=CC=CC=2)C=CC=1>[CH3:11][O:10][CH:3]([O:2][CH3:1])[C:4](=[O:9])/[CH:5]=[CH:6]\[CH2:7][CH3:8]
Reactant: CCC#CC(=O)C(OC)OC
Solvent: CCCCCC
Solvent: c1ccc2ncccc2c1
Product: CC/C=C\C(=O)C(OC)OC

Procedure:
Six grams of the 1,1-dimethoxy-3-hexyne-2-one (of Example I) is stirred under hydrogen gas at one atmosphere in 40 ml hexane containing 0.6 g Lindlar catalyst (palladium on calcium carbonate poisoned with lead acetate) and 4.0 g quinoline. The reaction is terminated when one percent of the starting material (1,1-dimethoxy-3-hexyne-2-one) remains after about 11/2 hours.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>N1C=CC=CC=1.C(Cl)Cl>[S:33]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)(=[O:35])=[O:34]
Reactant: COC(=O)CCCCCCCCCCCCCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)CCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reaction time: 1 h
Yield: 94.7 %

Procedure:
In a mixed solvent of 15 ml pyridine and 120 ml of methylene chloride was dissolved methyl 22-hydroxydocosanoate (1.70 g, 4.59 mmoles). p-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was gradually added to the obtained solution under ice-cooled condition, over a period of 1 hour, and the mixture was stirred for 14 hours in a refrigerator. Then, p-toluenesulfonyl chloride (1.75 g, 9.18 mmoles) was added to the reaction mixture, and reaction was effected for 24 hours. After the completion of reaction, the reaction mixture was treated in the same manner as in Reference Example 1, to give methyl 22-tosyloxydocosanoate (2.28 g, 75%) having the following properties.
Reaction SMILES: [N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=NC=[C:16]([C:18](F)(F)[F:19])[CH:17]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1.N1(CCN2C=C(C3C=CC(F)=[C:50]([O:55][CH3:56])C=3)N=C2C2CCNCC2)CCC1>>[N:1]1([CH2:5][CH2:6][N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:18]([F:19])=[C:50]([O:55][CH3:56])[CH:13]=3)[N:9]=[C:8]2[CH:22]2[CH2:27][CH2:26][N:25]([C:28]3[N:33]=[CH:32][N:31]=[C:30]([NH2:34])[C:29]=3[CH2:35][CH3:36])[CH2:24][CH2:23]2)[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(-c2cn(CCN3CCC3)c(C3CCNCC3)n2)ccc1F
Reactant: CCc1c(N)ncnc1N1CCC(c2nc(-c3cncc(C(F)(F)F)c3)cn2CCN2CCC2)CC1
Product: CCc1c(N)ncnc1N1CCC(c2nc(-c3ccc(F)c(OC)c3)cn2CCN2CCC2)CC1

Procedure:
The title compound was prepared in an analogous manner as 6-(4-(1-(2-(azetidin-1-yl)ethyl)-4-(5-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-2-yl)piperidin-1-yl)-5-ethylpyrimidin-4-amine of using 4-(1-(2-(azetidin-1-yl)ethyl)-4-(4-fluoro-3-methoxyphenyl)-1H-imidazol-2-yl)piperidine instead of 3-(1-(2-(azetidin-1-yl)ethyl)-2-(piperidin-4-yl)-1H-imidazol-4-yl)-5-(trifluoromethyl)pyridine hydrochloride salt. LC-MS: (M+1=480, obsd.=480).
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:19])[CH2:13][C:14](=[CH2:18])[C:15]([OH:17])=[O:16])=[CH:8][CH:7]=1)(=[O:4])=[O:3].[CH2:20](S)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO.O[O:31][S:32]([O-:34])=O.[K+]>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][S:2]([NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:19])[CH2:13][CH:14]([CH2:18][S:32]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:34])=[O:31])[C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: C=C(CC(=O)c1ccc(NS(C)(=O)=O)cc1)C(=O)O
Reactant: O=S([O-])OO
Reactant: SCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: CS(=O)(=O)Nc1ccc(C(=O)CC(CS(=O)(=O)Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-(4-Methylsulfonylamino-phenyl)-2-methylene-4-oxo-butyric acid (800 mg, 2.83 mmol) was dissolved in DMF (5 mL). Benzyl mercaptan (0.5 mL, 4.25 mmol) and DMAP (200 mg, 1.6 mmol) were added. The mixture was stirred at ambient temperature for 16 hours. Methanol (200 mL) was added and, under vigorous stirring, a saturated aqueous solution of Oxone® (15 g, 24.4 mmol) was added in one portion. Stirring was continued for 2 hours. Methanol was removed under vacuum and the aqueous residue was diluted with 100 mL water. The crystallized product, 4-(4-Methylsulfonylamino-phenyl)-4-oxo-2-benzylsulfonylmethyl-butyric acid (380 mg), was filtered, washed with water, and dried under vacuum.
Reaction SMILES: C([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)(=O)C.S(O)(O)(=O)=O.[NH2:21]O.C(=O)([O-])[O-].[Na+].[Na+].[C:29]([OH:32])(=O)[CH3:30]>S(=O)(=O)(O)O.O>[C:29]([NH:21][C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1)(=[O:32])[CH3:30]
Reactant: CC(=O)c1ccc(OC(C)C(=O)O)cc1
Reactant: CC(=O)O
Reactant: NO
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1ccc(OC(C)C(=O)O)cc1
Yield: 95 %

Procedure:
A solution of 2-(4-acetylphenoxy)propionic acid (1.5 g, 7.2 mmol), hydroxylamine sulfate (0.72 g, 4.4 mmol), and concentrated sulfuric acid (2 drops) in acetic acid (30 mL) is refluxed for 4.25 hours. The reaction is quenched with sodium carbonate (0.25 g, 2.4 mmol) and concentrated to give a residue. The reaction residue is dissolved in water (50 mL) and extracted with ethyl acetate (2×100 mL). The ethyl acetate extract is dried and concentrated to give 2-(4-acetamidophenoxy)propionic acid (1.53 g) (yield 95%): m.p. 170°-172° C.; IR (KBr) 3400 (vs), 2900 (s) 1730 (vs), 1630 (vs), and 1603 (vs); 1H NMR (DMSO-d6) delta 1.47 (d, J=6.8 Hz, 3H), 1.87 (s,3H), 2.06 (s,3H), 4.65 (q, J=6.8 Hz, 1H), 6.73 and 7.42 (dd, J=9.0 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][C:6]=2[CH:19]=1.C(O)C.[ClH:23].O1CCOCC1>C(OCC)C>[ClH:23].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(Br)cc2C1
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Solvent: C1COCCO1
Product: Brc1ccc2c(c1)CNCCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
1,1-dimethylethyl 7-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (10 g, 30.5 mmol) was taken into hot ethanol (10 mL) followed by addition of 4 M hydrogen chloride in dioxane solution (2.1 eq, 16 mL) and the resulting solution was allowed to slowly cool to ambient temperature over one hour. An excess of ethyl ether was then added and the resulting slurry was filtered. The filter cake was washed with ethyl ether and dried to give 7-bromo-2,3,4,5-tetrahydro-1,4-benzoxazepine hydrochloride (7.9 g, 98% yield) as a colorless crystalline solid. MS (EI) for C9H10NOBr: 229 (MH+).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)C2[CH2:20][CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][C:12]1=2)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CSC.[CH3:34][OH:35]>>[CH2:4]([N:11]1[C:19]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C:34](=[O:35])[CH2:20][CH2:21][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:23][C:12]1=[O:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CO
Reactant: O=[O+][O-]
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(Cc3ccccc3)c3ccccc23)C1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1CCC(=O)c2ccccc2N(Cc2ccccc2)C(=O)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ozone was bubbled through a solution of 9-benzyl-2-tert-butyloxycarbonyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (6.0 g, 16.6 mmol) in methanol (90 ml) at -78° C. until a blue colour persisted. Nitrogen was then bubbled through the solution until clear, followed by the addition of dimethyl sulphide (12.0 ml, 163 mmol). The solution was allowed to warm to room temperature and stirring continued for a further 2 hours, followed by evaporation to dryness. The crude product was purified by chromatography on silica gel with ethyl acetate-hexane (1:1) as eluant. (6.0 g, 92%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Mg].[B:19](OC)([O:22]C)[O:20]C>BrCCBr.C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[C:3]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1
Reactant: COc1ccc(Br)c(OCc2ccccc2)c1
Reactant: COB(OC)OC
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCCBr
Product: COc1ccc(B(O)O)c(OCc2ccccc2)c1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 84.3 %

Procedure:
A 2 L three-necked flask equipped with thermometer, reflux condenser and mechanical stirrer was charged with 1-bromo4-methoxy-2-(phenylmethoxy)benzene (43.0 g, 0.147 mol), anhydrous THF (600 mL) under nitrogen. Magnesium turnings (4.2 g, 0.17 mol) and 1,2-dibromoethane (0.5 mL, 6 mmol) was then added and the mixture heated to reflux. After 1.5 h, the reaction was cooled to −78° C. and B(OMe)3 (33.4 mL, 0.294 mol) added dropwise while maintaining an internal temperature below −60° C. Upon complete addition, the reaction was quenched with 5% HCl (15 mL) to pH=3.0, partioned with EtOAc (100 mL), the organic phase separated, washed with brine (100 mL), dried (MgSO4) and concentrated in vacuo giving a pale yellow solid. The solid was triturated with hexane (90 mL), filtered and dried to afford [4-methoxy-2(phenylmethoxy)phenyl]boronic acid as a pale white solid (32 g, 85%): mp 127.0-129.0° C.; 1H NMR δ7.8 (d, 3=8.2 Hz, 1H), 7.5-7.3 (m, 5H), 6.6 (dd, J=8.2, 2.7 Hz, 1H), 6.55 (d, J=5 Hz, 1H), 5.65 (s, 2H), 5.15 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.Br[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[O:13].BrCC(Br)=O.C(C1C=CC(N)=CC=1)(C)(C)C>>[N:1]1([CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=2)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)c1ccc(NC(=O)CBr)cc1
Reactant: c1ccc2[nH]cnc2c1
Agent: CC(C)(C)c1ccc(N)cc1
Agent: O=C(Br)CBr
Product: CC(C)(C)c1ccc(NC(=O)Cn2cnc3ccccc32)cc1

Procedure:
The title compound was synthesised according to the procedure described in Example 94 from 1H-benzoimidazole and 2-bromo-N-(4-tert-butyl-phenyl)-acetamide. The latter was synthesized from bromoacetyl bromide and 4-tert-butyl-aniline. Calculated for C19H21N3O m/z: 307.3, found 308.4 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][N:6]([CH3:8])[CH2:5][NH:4][C:3]1=[N:9][N+:10]([O-:12])=[O:11].[H-].[Na+].[H][H].[Cl:17][C:18]1[S:19][C:20]([CH2:23]Cl)=[CH:21][N:22]=1>CN(C=O)C>[Cl:17][C:18]1[S:19][C:20]([CH2:23][N:4]2[CH2:5][N:6]([CH3:8])[CH2:7][N:2]([CH3:1])[C:3]2=[N:9][N+:10]([O-:12])=[O:11])=[CH:21][N:22]=1
Reactant: ClCc1cnc(Cl)s1
Reactant: [H][H]
Reactant: CN1CNC(=N[N+](=O)[O-])N(C)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CN(C)C(=N[N+](=O)[O-])N(Cc2cnc(Cl)s2)C1
Temperature: 50 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
1.7 g of 1,5-dimethyl-2-nitroiminohexahydro-1,3,5-triazine was dissolved in 20 ml of dried DMF. To the solution, 0.28 g of 60% sodium hydride was added portionwise with cooling. The mixture was stirred for 1 hour at room temperature until evolution of hydrogen was ceased and then the mixture was heated with stirring further for 1 hour at 50° C. To the mixture, a solution of 1.7 g of 2-chloro-5-thiazolylmethyl chloride in 8 ml of dried DMF was added dropwise at 40-50° C. After this addition, the reaction mixture was heated with stirring for two hours at 70-80° C. The mixture was poured into ice-water and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and dichloromethane was distilled off. The residue was purified by a column chromatography to obtain 0.82 g of the title compound. This compound is No.6 in Table 1. m.p.: 125-126° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16].C(N(C(C)C)C(C)C)C.Cl[C:27]([O:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)=[O:28].O>C(Cl)Cl>[Cl:36][C:33]1[CH:34]=[CH:35][C:30]([O:29][C:27]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][OH:16])=[C:2]([F:1])[CH:10]=3)[CH2:6][CH2:7]2)=[O:28])=[CH:31][CH:32]=1
Reactant: OCCCC#Cc1cc2c(cc1F)NCC2
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Oc1ccc(Cl)cc1)N1CCc2cc(C#CCCCO)c(F)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
A solution of 99 mg (0.45 mmol) 5-(6-Fluoro-2,3-dihydro-1H-indol-5-yl)-pent-4-yn-1-ol and 0.155 ml (0.90 mmol) N-Ethyldiisopropylamine in 2 ml CH2Cl2 was treated with 0.125 ml (0.90 mmol) 4-chlorophenyl chloroformate and stirred at room temperature during 1 hour. The mixture was poured into water, extracted with EtOAc and the combined organic layers were dried with MgSO4. Evaporation of the solvent, chromatography on silica gel with CH2Cl2/MeOH 49:1 gave 125 mg (74%) of 6-Fluoro-5-(5-hydroxy-pent-1-ynyl)-2,3-dihydro-indole-1-carboxylic acid 4-chloro-phenyl ester as a viscous light yellow oil, MS: 374 (MH+, 1Cl).