Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][OH:6].C[O:8][C:9](=O)[CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[OH:6][NH:5][C:9]([CH2:10][CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16](=[O:27])/[CH:17]=[CH:18]/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:8]
Reactant: NO
Reactant: COC(=O)CCSCCNC(=O)/C=C/C=C/c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(/C=C/C=C/c1ccccc1)NCCSCCC(=O)NO
Reaction time: 0.17 h
Yield: 47 %

Procedure:
A solution of sodium methylate (6 mmol) in methanol (5 ml) was added to a solution of hydroxylamine hydrochloride (0.28 g, 4 mmol) in methanol (8 ml). A mixture was stirred for 10 min. and the precipitate was filtered off. 3-{2-[(2E)(4E)-5-phenylpenta-2,4-dienoylamino]ethylsulfanyl}propionic acid methyl ester (3/28) (1 mmol) was added to the filtrate and the mixture was heated to the complete dissolving. The resultant mixture was stirred for 4 hours at ambient temperature and the solvent was removed under reduced pressure. The product was dissolved in water (10 ml) and acidified with 3% HCl. Precipitate was filtered off and crystallized from methanol. Yield 47%, m.p. 158-160° C. 1H NMR (90 MHz, DMSO-d6) δ: 2.24 (2H, t, J=6.8 Hz, CH2); 2.56-2.87 (4H, m, CH2); 3.29 (2H, q, J=6.0 Hz, CH2); 6.14 (1H, d, J=15.0 Hz, CH); 6.83-7.14 (2H, m, CH—CH); 7.14-7.66 (6H, m, C6H5, CH); 8.21 (1H, t, J=5.5 Hz, NH); 8.74 (1H, s, NH), 10.42 (1H, s, OH). HPLC analysis on Symmetry C18 column: impurities 2.6% (column size 3.9×150 mm; mobile phase acetonitrile—0.1M phosphate buffer (pH 2.5), 35:65; detector UV 230 nm; sample concentration 0.3 mg/ml). Anal. Calcd for C16H20N2O3S: C, 59.98; H, 6.29; N, 8.74. Found: C, 59.82; H, 6.23; N, 8.68.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH2:10][OH:11])=[C:4](F)[CH:3]=1.[H-].[Na+].O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:4]=2[CH:3]=1
Reactant: O=C(CO)Nc1ccc(Br)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2cc(Br)ccc2N1
Temperature: 140 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A solution of N-(4-bromo-2-fluorophenyl)-2-hydroxyacetamide (8.0 g, 32.3 mmol) in 50 ml dry DMF was added drop wise to a suspension of sodium hydride (5.2 g, 129 mmol) in 30 ml dry DMF and the mixture was stirred for 2 h under an atmosphere of nitrogen at 140° C. After cooling to ambient temperature water was added and the mixture was extracted several times with ethyl acetate. After washing the combined organic layers with brine and drying over MgSO4 the solvent was removed under reduced pressure and the crude product was obtained as a pale yellow solid. Purification by flash chromatography on silica gel (dichloromethane/methanol, 97/3, Rf=0.35) yielded 7-bromo-2H-benzo[b][1,4]oxazin-3(4H)-one (2.3 g, 10.1 mmol, 31%) as off-white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[CH:5]2.CN(C=O)C.[Br:19][C:20]1[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=1>CCOC(C)=O>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([N:6]2[CH:5]=[C:4]3[C:8]([C:9]([C:11]([NH2:13])=[O:12])=[CH:10][C:2]([F:1])=[CH:3]3)=[N:7]2)=[CH:22][CH:21]=1
Reactant: Fc1ccc(Br)cc1
Reactant: NC(=O)c1cc(F)cc2cn[nH]c12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(F)cc2cn(-c3ccc(Br)cc3)nc12
Temperature: 180 °C

Procedure:
To a solution of D2 (1.0 eq) in DMF (0.2 M) K2CO3 (1.3 eq) and 4-bromofluorobenzene (10.0 eq) were added and the reaction mixture was heated under MW conditions at 180° C. for 20 min. The reaction mixture was cooled to RT and diluted with EtOAc. The organic phase was washed with brine; dried (Na2SO4). Evaporation of the solvent gave (D3) which was purified by chromatography on silica gel eluting with 50-70% EtOAc/Petroleum ether to obtain the title compound as a yellow powder. 1H NMR (400 MHz, DMSO-d6, 300K) δ 9.34 (1H, s), 8.50 (1H, br. s), 8.17 (2H, d, J=9.0 Hz), 8.03 (1H, br. s), 7.90-7.80 (4H, m). MS (ES+) C14H9BrFN3O requires: 334/336. Found: 335/337 (M+H)+.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]1=[O:29])[CH3:2]
Reactant: CCCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(OC)cc2)c2cc(F)ccc21
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CCCCCN1C(=O)[C@@H](CC)N(C(=O)c2ccc(O)cc2)c2cc(F)ccc21
Yield: 96 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-pentyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-pentyl-3,4-dihydroquinoxalin-2(1H)-one (96%). [α]D 25=−294° (c=0.0095 G/ML, CHCl3); MS (ESI) m/z 385 ([M+H]+); MS (ESI) m/z 383 ([M−H]−); HRMS: calcd for C22H25FN2O3.0.10H2O, 385.9860; found (ESI_FT), 385.19204.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:10]([O:12]C)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:20]1[CH2:24]OCC1.[CH2:25]([Mg]Br)[CH3:26].CCOC(C)=O>CCCCCC>[CH2:20]([C:10]([OH:12])([CH2:25][CH3:26])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:24]
Reactant: C1CCOC1
Reactant: COC(=O)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: CC[Mg]Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCC(O)(CC)[C@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 90 %

Procedure:
To a two-necked 50 mL round bottom flask were added (R)-methyl 2-((tert-butoxycarbonyl)amino)-2-phenylacetate (1.2 g, 5.68 mmol) and dry THF (30 mL). The resulting mixture was cooled to 0° C. Ethyl magnesium bromide (3.02 g, 22.72 mmol) (3M solution in diethyl ether) was added dropwise, and the mixture was slowly allowed to warm to ambient temperature. The mixture was then stirred at ambient temperature for 24 hours. After completion of reaction (monitored by TLC, TLC eluent: 30% EtOAc in hexane), the mixture was quenched in NH4Cl solution and extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to yield 1.2 g (90.0%) of (R)-tert-butyl (2-ethyl-2-hydroxy-1-phenylbutyl)carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ: 7.35-7.26 (m, 5H), 5.56 (d, J=9.1 Hz, 1H), 4.61 (d, J=9.4 Hz, 1H), 1.68-1.63 (m, 2H), 1.39 (s, 9H), 1.32-1.22 (m, 2H), 0.92 (t, J=7.4 Hz, 3H), 0.80 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11](O)=[O:12])=[CH:8][CH:9]=2)[C:4]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:3]1.[NH2:23][C:24]([CH3:29])([CH2:27][OH:28])[CH2:25][OH:26]>>[OH:26][CH2:25][C:24]([NH:23][C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[CH:3]=[C:4]2[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1)=[O:12])([CH2:27][OH:28])[CH3:29]
Reactant: CC(N)(CO)CO
Reactant: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(C(=O)O)ccc21
Product: Cn1cc(-c2cc3cccnc3[nH]2)c2cc(C(=O)NC(C)(CO)CO)ccc21

Procedure:
By proceeding in a manner similar to Example 14(a) above but using 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-carboxylic acid [Example 15(d)] and 2-amino-2-methyl-1,3-propanediol, there was prepared 1-methyl-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-1H-indole-5-arboxylic acid (2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-amide as a yellow solid, m.p. 180-182° C. MS: 379 (MH+).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=[O:10])=O>>[C:8]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:10])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=O
Reactant: [Li]c1ccccc1
Product: O=C(c1ccccc1)c1ccccc1
Yield: 70 %

Procedure:
In the preferred embodiment the chemical cocktail of the invention is a low-cost solution of an organometallic compound which rapidly absorbs and reacts with gaseous carbon dioxide to form benzophenone--a compound which has well separated infrared absorption bands when labeled in the carbonyl position with 13C or 12C. Exemplary of organometallic compounds, which in solution react with carbon dioxide to form benzophenone, are phenyl lithium and phenyl magnesium halides. M. I. Volpin and I. S. Kolomnikov, "The Reactions of Organometallic Compounds with Carbon Dioxide", Organomet. React. (1975) p. 320 and H. Gilman and P. R. VanEss, JACS, 55, 1258 (1933), the teachings of which are incorporated herein by reference, report that a 70% yield of benzophenone can be obtained by passing gaseous carbon dioxide through a phenyl lithium solution: ##STR1##
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH3:42][O:43][C:44]([C:47]1[N:48]=[C:49]([CH2:52][N:53]2[N:57]=[C:56]([NH2:58])[CH:55]=[N:54]2)[O:50][CH:51]=1)([CH3:46])[CH3:45]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:42][O:43][C:44]([C:47]1[N:48]=[C:49]([CH2:52][N:53]2[N:57]=[C:56]([NH:58][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:55]=[N:54]2)[O:50][CH:51]=1)([CH3:46])[CH3:45]
Reactant: COC(C)(C)c1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(C)(C)c1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (40.0 mg, 0.18 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (5.6 mg, 0.05 mmol), HOBt (29.9 mg, 0.22 mmol), EDC (88.3 mg, 0.46 mmol) and DIPEA (0.13 mL, 0.74 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(2-methoxypropan-2-yl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (43.7 mg, 0.18 mmol) in CH2Cl2 (0.8 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (2.0 mL), the layers were separated and the org. phase was washed with water (2.0 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a colorless oil: TLC: rf (4:6 hept-EA)=0.35. LC-MS-conditions 06: tR=0.94 min, [M+H]+=437.34.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([CH3:21])[CH2:12][O:13]C2C=CC(C)=CC=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]>CN(C)C1C=CC=CC=1.C(OC(C)C)(C)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([C:11]2[CH:21]=[C:4]([CH3:5])[CH:1]=[CH:2][C:12]=2[OH:13])[C:7]([CH3:8])=[CH2:6])=[CH:8][CH:9]=1)([CH3:2])[CH3:3]
Reactant: CC(=Cc1ccc(C(C)C)cc1)COc1ccc(C)cc1
Solvent: CC(C)OC(C)C
Solvent: CN(C)c1ccccc1
Product: C=C(C)C(c1ccc(C(C)C)cc1)c1cc(C)ccc1O
Temperature: 215 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A solution of 1-isopropyl-4-(2-methyl-3-(4-methylphenoxy)propene-1-yl)benzene obtained in Reference Example 87 (8.2 g, 29.2 mmol) in N,N-dimethylaniline (50 mL) was stirred under argon atmosphere at 215° C. for 16 hours. After cooling, the reaction mixture was diluted with diisopropyl ether, washed with 5 N hydrochloric acid and water, dried over magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to obtain 7.80 g (yield 95%) of the title compound. Oily matter.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12](N)=[N:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[I-:16].[K+].N(OC(C)(C)C)=O>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[N:13][C:12]([I:16])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [I-]
Reactant: Nc1ccc(Oc2ccnc(Cl)c2)cn1
Agent: CC(C)(C)ON=O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Clc1cc(Oc2ccc(I)nc2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
A mixture of 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine (1.00 g, 4.51 mmol) and potassium iodide (3.74 g, 22.5 mmol) in DCM (15 mL) was treated dropwise with t-butyl nitrite (4.65 g, 45.1 mmol) and the mixture was stirred overnight at RT. The mixture was diluted with EtOAc (75 mL) and washed with 10% Na2CO3 (50 mL), then water (50 mL) and finally brine (50 mL) and dried over sodium sulfate. The solvents were evaporated at reduced pressure to give a thick oily solution. EtOAc (100 mL) was added and the solution was washed with 0.1M sodium thiosulfate (75 mL), brine (50 mL) and dried over sodium sulfate. The solvents were evaporated at reduced pressure, and the residual oil was purified by silica gel chromatography to provide 2-chloro-4-((6-iodopyridin-3-yl)oxy)pyridine (695 mg, 46%). 1H NMR (400 MHz, DMSO-d6): δ 8.80 (d, J=3.0 Hz, 1H), 8.73 (d, J=5.8 Hz, 1H), 8.35 (d, J=8.6 Hz, 1H), 7.91 (dd, J=8.6, 3.1 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.48 (dd, J=5.8, 2.3 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[C:4]([F:21])[CH:5]=[C:6]2[C:11]=1[N:10]([CH:12]1[CH2:14][CH2:13]1)[CH:9]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]2=[O:20].C([Sn]([C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.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>[CH:12]1([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:21])=[C:3]([F:22])[C:2]=3[C:36]#[C:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:7](=[O:20])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9]2)[CH2:14][CH2:13]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(Br)c(F)c(F)cc2c1=O
Reactant: CCCC[Sn](C#C[Si](C)(C)C)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(C2CC2)c2c(C#C[Si](C)(C)C)c(F)c(F)cc2c1=O
Temperature: -18 °C
Yield: 80.9 %

Procedure:
22.2 g of ethyl 8-bromo-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 30.2 g of tributylstannyl-trimethylsilyl-acetylene and 3.48 g of tetrakis(triphenylphosphine)palladium(0) are refluxed for 3 hours in 300 ml of absolute toluene under a nitrogen atmosphere. After the reaction mixture has cooled to approx. -18° C., the solid is filtered off with suction, washed with toluene and dried. 18.8 g of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-(trimethylsilylethinyl)-4-oxo-3-quinolinecarboxylate (80% of theory) are obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23.[BH4-].[Na+]>C(Cl)Cl.CO>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[NH:8][CH2:7][C:6](=[O:12])[N:5]3[CH2:13][C@@H:14]([NH:15][CH2:16][CH2:17][CH2:18][C@@H:19]4[O:23][C:22](=[O:24])[N:21]([C:25]5[CH:26]=[CH:27][C:28]6[S:33][CH2:32][C:31](=[O:34])[NH:30][C:29]=6[CH:35]=5)[CH2:20]4)[C:3]=1[C:4]=23
Reactant: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4Cn5c(=O)cnc6ccc(F)c4c65)OC3=O)cc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: O=C1CSc2ccc(N3C[C@H](CCCN[C@@H]4CN5C(=O)CNc6ccc(F)c4c65)OC3=O)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
A solution of the compound of Example 79 (42 mg) in DCM/MeOH (2:1; 6 mL) was treated with NaBH4 (3.2 mg). After 30 min stirring at rt, the reaction mixture was quenched with 1M HCl (1 mL) and partitioned between DCM and aq. NH4OH. The org. layer was washed with water, dried over MgSO4, concentrated under reduced pressure and purified by CC (EA/MeOH 19:1 to 9:1), affording a beige solid (29 mg; 69% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[Br:11][C:12]1[CH:13]=[C:14]([CH:22]=[CH:23][CH:24]=[O:25])[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].N1CC[O:29][CH2:28]C1>>[Br:11][C:12]1[CH:13]=[C:14]([CH:22]2[C:10]3[C:2](=[C:3]4[CH:4]=[CH:5][NH:6][C:7]4=[CH:8][CH:9]=3)[O:1][CH:24]([OH:25])[CH2:23]2)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19].[CH3:28][OH:29]
Reactant: C1COCCN1
Reactant: COc1cc(C=CC=O)cc(Br)c1OC
Reactant: Oc1cccc2[nH]ccc12
Product: CO
Product: COc1cc(C2CC(O)Oc3c2ccc2[nH]ccc32)cc(Br)c1OC
Yield: 33 %

Procedure:
The title compound was prepared following the procedure described in Example 18 from 4-hydroxy indole (10 mg; 0.075 mmol) and 3-(3-bromo-4,5-dimethoxyphenyl)-propenal (20 mg; 0.074) using morpholine (7 μl) as a base in refluxing methanol (0.6 ml) (yield: 33% ). 1H NMR (acetone-d6): 10.16 (s, 1H), 7.20 (d, J=3.0 Hz) and 7.19 (d, J=2.5 Hz) (1H), 7.02 (broad d, J=2.0 Hz), 6.97 (broad signal) and 6.93 (d, J=1.8 Hz) (2H), 6.89 and 6.88 (d each, J =8.4 Hz; 1H), 6.49 (d, J=8.8 Hz), 6.47-6.48 (m) and 6.44 (d, J=8.4 Hz) (2H), 6.18 (d, J=6.8 Hz) and 6.10 (d, J=4.5 Hz) (1H), 5.68-5.71 and 5.56-5.62 (m each, 1H), 4.33-4.38 (broad dd, J=5.8, 9.9 Hz; 1H), 3.83, 3.81 and 3.79 (s each, 6H), 2.41 (ddd, J=2.0, 6.1, 12.9 Hz) and 2.08-2.26 (m) (2H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH3:2].[CH2:26](Br)[CH:27]=[CH2:28].N12CCCC1=NCCC2>O1CCCC1>[CH2:28]([CH2:2][CH2:1][NH:3][C:4]1[CH:25]=[CH:24][C:7]([CH2:8][CH2:9][C:10]([NH:12][CH:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[O:11])=[CH:6][CH:5]=1)[CH:27]=[CH2:26]
Reactant: CCNc1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1
Reactant: C=CCBr
Agent: C1CN=C2CCCN2C1
Solvent: C1CCOC1
Product: C=CCCCNc1ccc(CCC(=O)NC(C(=O)OCC)C(=O)OCC)cc1

Procedure:
Working as in Example F, but starting with 8 g of diethyl 4-ethylaminobenzylacetamidomalonate, 4 ml of allyl bromide and 5.82 ml of 1,5-diazabicyclo-[4.3.0] non-5-ene in 50 ml of tetrahydrofuran, and after purification by flash chromatography (eluent: 90/10 CH2Cl2/EtOAc by volume), 5.6 g of a solid are obtained, which solid is recrystallized from 35 ml of cyclohexane. 5.43 g of diethyl 4-(allylethylamino)benzylacetamidomalonate are thus obtained in the form of a white solid melting at 86° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13](F)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:12][CH:11]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: C1CCNCC1
Reactant: Fc1ccc(-c2nc3cc(Cl)ccc3o2)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1ccc2oc(-c3ccc(N4CCCCC4)cc3)nc2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
A mixture containing 2.48 g (10 mmoles) of 5-chloro-2-(4-fluorophenyl)benzoxazole, 2.55 g (30 mmoles) of piperidine and 15 ml of NMP is heated with stirring under nitrogen atmosphere at 100° C. for 16 hours. The reaction is complete as judged by GC analysis. The mixture is cooled, poured into 100 ml of water and stirred for 30 minutes. The title compound (3.05 g, 97 percent yield) is filtered and washed. It has a melting point of 162° C.-164° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3.C(N(CC)CC)C.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][S:36]([CH3:35])(=[O:38])=[O:37])[O:10][C:9]2=[O:15])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:20][CH:19]2[CH2:21][C:22]3([CH2:27][CH:18]2[CH2:17]1)[O:26][CH2:25][CH2:24][O:23]3
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CC3CC4(CC3C2)OCCO4)c(F)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(N3CC4CC5(CC4C3)OCCO5)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
21.4 g (56.6 mmol) of 2-[2-fluoro-4-[(5R)-5-(hydroxymethyl)-2-oxo-3-oxazolidinyl]phenyl]-hexahydro-1H-spiro[cyclopenta[c]pyrrol-5,2′-[1,3]dioxolane] prepared in the step 7 was dissolved in 200 ml of methylene chloride, 19.7 ml (141.5 mmol) of triethylamine was added, the temperature was lowered to 0° C., and then, 8.76 ml (113.2 mmol) of methansulfonyl chloride was added dropwise over 15 minutes, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction mixture was diluted with 200 mL of methylene chloride, washed with water and a saturated aqueous solution of sodium chloride, and then, dried over magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound.
Reaction SMILES: Cl[Sn](Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1.[C:20](Cl)(=[O:22])[CH3:21]>C1C=CC=CC=1>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[CH:12][C:13]=1[C:20](=[O:22])[CH3:21]
Reactant: COc1cccc(-c2ccccc2)c1
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(-c2ccccc2)ccc1C(C)=O
Yield: 97.8 %

Procedure:
52 g of SnCl4 are added dropwise at 5°, while stirring vigorously, to a solution of 36.8 g of 3-methoxy biphenyl and 15.6 g of acetyl chloride in 700 cc of benzene. The mixture is stirred over night at 23°. The reaction mixture is washed twice with 2 N sodium hydroxide and twice with water. Extraction is again effected twice with toluene. The organic phases are combined, dried over anhydrous sodium sulphate and concentrated. 44 g of a crude product are obtained, which are chromatographed on a 20-fold quantity of silica gel. Solvent for absorption and elution: methylene chloride. The crude fractions are crystallized from ether/petroleum ether, whereby 4-acetyl-3-methoxy biphenyl, having an M.P. of 74°-75°, is obtained.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[O:23][CH3:24])[NH:19][N:18]=[C:17]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(B(O)O)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.N1C=CC=CC=1.C(Cl)[Cl:50]>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[ClH:50].[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][C:22]=2[O:23][CH3:24])[N:19]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:18]=[C:17]3[S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(=[O:26])=[O:27])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCl
Reactant: COc1cc2[nH]nc(S(=O)(=O)c3ccccc3)c2cc1N1CCN(Cc2ccccc2)CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Product: COc1cc2c(cc1N1CCN(Cc3ccccc3)CC1)c(S(=O)(=O)c1ccccc1)nn2-c1ccccc1
Product: Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 25 %

Procedure:
A mixture of 5-(4-benzylpiperazin-1-yl)-6-methoxy-3-(phenylsulfonyl)-1H-indazole (448 mg, 0.97 mmol), phenylboronic acid (242 mg, 1.94 mmol), copper(II) acetate (271 mg, 1.50 mmol), pyridine (160 mg, 2.00 mmol) and 4 Å molecular sieves (1.0 g) in methylene chloride is stirred at room temperature for 48 h and filtered. The filtercake is washed with THF. The filtrates are combined and concentrated in vacuo. The resultant residue is chromatographed (silica gel, 60:40 and 80:20 ethyl acetate:hexanes as eluents) to afford the free amine of the title product as a white solid, 130 mg (25% yield). The free amine is dissolved in ethanol, treated with 4.0 M HCl in dioxane, and concentrated in vacuo to a solid residue. This solid is triturated with ethyl acetate to afford the title product as a white solid, mp: 210–212° C., identified by NMR and mass spectral analyses.