Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[CH3:9].[Cl:10][C:11]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:12]=1[NH2:13]>C1(C)C(C)=CC=CC=1>[NH2:13][C:12]1[C:11]([Cl:10])=[CH:17][C:16]([CH2:3][C:4]2[N:5]=[CH:6][NH:7][C:8]=2[CH3:9])=[CH:15][C:14]=1[Cl:18]
Reactant: Cc1[nH]cnc1CCl
Reactant: Nc1c(Cl)cccc1Cl
Agent: Cl
Solvent: Cc1ccccc1C
Product: Cc1[nH]cnc1Cc1cc(Cl)c(N)c(Cl)c1
Reaction time: 3 h

Procedure:
A mixture of 6.0 g of 4-chloromethyl-5-methylimidazole hydrochloride, 9.0 g of 2,6-dichloroaniline and 40 ml of xylene is refluxed with stirring for 3 hours. The mixture is then filtered and the precipitate is washed with xylene. The precipitate is dissolved in 50 ml of water and the pH is adjusted to 8. The solution is extracted with toluene (3×30 ml). The combined toluene extracts are washed with 10 ml of water and evaporated to dryness. The residue, which is crude 4-(4'-amino-3',5'-dichlorobenzyl)-5-methylimidazole, is converted to the hydrochloride in isopropanol with HCl-ethyl acetate. The free base is liberated from the hydrochloride in water with sodium hydroxide. The melting point of the base is 172°-175° C.
Reaction SMILES: [H-].[Na+].[C:3](OCC)(=[O:5])[CH3:4].[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([C:23](=[O:25])[CH3:24])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:13][CH2:12][CH2:11][CH2:10]1>O1CCCC1.C(O)C.C1OCCOC2C(=CC=CC=2)OCCOCCOC2C(=CC=CC=2)OC1>[CH:9]1([O:14][C:15]2[CH:16]=[C:17]([C:23](=[O:25])[CH2:24][C:3](=[O:5])[CH3:4])[CH:18]=[CH:19][C:20]=2[O:21][CH3:22])[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CCOC(C)=O
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Agent: [H-]
Agent: [Na+]
Agent: c1ccc2c(c1)OCCOCCOc1ccccc1OCCOCCO2
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(C)=O)cc1OC1CCCC1
Temperature: 25 °C
Yield: 88.3 %

Procedure:
To a stirred suspension of 60% sodium hydride (200 mg, 5 mmol) and ethyl acetate (0.49 ml, 5 mmol) in tetrahydrofuran (25 ml) were sequentially added a solution of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (European Patent Application EP470805) (590 mg, 2.5 mmol) in tetrahydrofuran (5 ml), two drops of ethanol and a solution of dibenzo-18-crown (15 mg, 0.04 mmol) in tetrahydrofuran (5 ml). The reaction mixture was refluxed for 5 h, allowed to cool to room temperature and finally quenched with aqueous 10% sulphuric acid solution (5 ml). The resulting mixture was diluted with diethyl ether, washed with saturated ammonium chloride solution, dried and concentrated under reduced pressure to yield a crude product which was purified by column chromatography (SiO2, hexane-ethyl acetate 4:1) to afford the title compound (610 mg, 86% yield) as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1[OH:32]>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:26]2[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:25]=2[Cl:24])=[N:3][CH:4]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Reactant: Oc1ccc(F)cc1Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(F)cc2Cl)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 48 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 2-chloro-4-fluorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8,12 (1H, br.s), 8.09 (1H, d, J=2.6 Hz), 8.04–7.98 (2H, m), 7.48–7.41 (2H, m), 7.32–7.25 (2H, m), 7.15–7.07 (1H, m), 5.45–5.33 (1H, m), 3.90 (3H, s), 1.61 (3H, d, J=7.0 Hz); MS (ESI) m/z 463 (M+H)+, 461 (M−H)−.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.FC(S(O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[N:29](S(C(F)(F)F)(=O)=O)[CH:30]=[CH:31][N:32]=2)=[C:24]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:41]=2[Cl:47])[N:23]=1)(=O)=O)(F)F>CN(C)C(=O)C>[Cl:47][C:41]1[CH:42]=[C:43]([Cl:46])[CH:44]=[CH:45][C:40]=1[C:24]1[N:23]=[C:22]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)[CH:27]=[CH:26][C:25]=1[C:28]1[NH:32][CH:31]=[CH:30][N:29]=1
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: O=S(=O)(Oc1ccc(-c2nccn2S(=O)(=O)C(F)(F)F)c(-c2ccc(Cl)cc2Cl)n1)C(F)(F)F
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1ccc(NCCNc2ccc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A suspension of (2-aminoethyl)(5-nitro(2-pyridyl))amine (255 mg, 1.40 mmol) in N,N-dimethylacetamide (3 ml) containing dry powdered 4 Å molecular sieves (50 mg) was added to a suspension of 6-(2,4-dichlorophenyl)-5-{1-[(trifluoromethyl)sulfonyl]imidazol-2-yl}-2-pyridyl (trifluoromethyl)sulfonate (200 mg, 0.35 mmol) in N,N-dimethylacetamide (3 ml) containing dry powdered 4 Å molecular sieves (50 mg). After stirring at 40° C. for 24 h, ethylenediamine (0.5 ml) and water (0.5 ml) were added to the reaction to hydrolyze the one remaining triflate from the product. The reaction was stirred at 85° C. for 2 h and left at room temperature for 12 h. The reaction was then diluted with ethyl acetate (100 ml), filtered, extracted with sat. aq. NaHCO3 (6×30 ml), brine (30 ml), dried with Na2SO4, filtered, and concentrated under reduced pressure. The product [6-(2,4-dichlorophenyl)-5-imidazol-2-yl(2-pyridyl)]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine (79859) was obtained as a yellow glass weighing 143 mg in 85% yield.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[N:7][C:8]=1[CH3:9].I[CH3:18]>>[CH3:18][O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([NH:10][C:11](=[O:16])[C:12]([CH3:13])([CH3:15])[CH3:14])=[N:7][C:8]=1[CH3:9]
Reactant: CI
Reactant: Cc1nc(NC(=O)C(C)(C)C)ccc1CO
Product: COCc1ccc(NC(=O)C(C)(C)C)nc1C

Procedure:
This material was prepared in analogy to example 86 step A] from N-(5-hydroxymethyl-6-methyl-pyridin-2-yl)-2,2-dimethyl-propionamide (0.6 g, product of example 112 step B]) and iodomethane (0.421 g) as a white solid (0.4 g). MS (ESI): 237.2 (MH+).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:45][C:46](=[O:49])[CH2:47]Br)(C)(C)C>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.[OH-].[Na+]>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:47][C:46]([OH:49])=[O:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-glucopyranose, 1.39 g (5 mmol) of tetrabutylammonium chloride in 350 ml of toluene and 200 ml of 50% aqueous sodium hydroxide solution is cooled to 0° C. At 0° C., 29.3 g (150 mmol) of bromoacetic acid-tert-butyl ester is added in drops over 20 minutes while being stirred vigorously. It is stirred for 0.5 hour at 0° C. 250 toluene is added, the organic phase is separated, and the aqueous phase is extracted twice with 150 ml of toluene. The solvent of the combined organic phases is distilled off in a vacuum, and the residue is taken up in 400 ml of methanol. 50 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of dichloromethane, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of dichloromethane. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/n-hexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[O:8][C:7]([C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[N:6][C:5]2=[C:16]([C:18]([OH:20])=O)[CH:17]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:16]1[CH:17]=[C:2]([Cl:1])[CH:3]=[C:4]3[O:8][C:7]([C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=4)=[N:6][C:5]=13)=[O:20])[CH2:25]2
Reactant: Cc1ccc(-c2nc3c(C(=O)O)cc(Cl)cc3o2)cc1
Reactant: CN1C2CCCC1CC(N)C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nc3c(C(=O)NC4CC5CCCC(C4)N5C)cc(Cl)cc3o2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 26.5 %

Procedure:
A mixture of 6-chloro-2-p-tolylbenzoxazole-4-carboxylic acid (45 mg, 0.16 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (43 mg, 0.19 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60 mg, 0.31 mmol) and 1-hydroxybenzotriazole (43 mg, 0.31 mmol) in DMF (5 mL) was stirred for 10 min at room temperature, then triethylamine (0.07 mL, 0.63 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The mixture was diluted with ethyl acetate (20 mL), and then washed with a saturated solution of sodium bicarbonate. The aqueous layer was further extracted with ethyl acetate (2×22 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-6-chloro-2-p-tolylbenzoxazole-4-carboxamide (18 mg, 26%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.94 (d, J=7.3 Hz, 1H), 8.18 (d, J=1.9 Hz, 1H), 8.11 (d, J=8.2 Hz, 2H), 7.67 (d, J=1.9 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 4.63-4.50 (m, 1H), 3.12 (d, J=10.4 Hz, 2H), 2.70-2.57 (m, 2H), 2.54 (s, 3H), 2.48 (s, 3H), 2.20-1.90 (m, 2H), 1.65-1.52 (m, 2H), 1.51-1.48 (m, 2H), 1.20-1.10 (m, 2H); MS (ESI+) m/z 424 (M+H); HPLC 95.0% (AUC), tR=13.80 min.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][N:4]1[CH2:5][C@H:6]([CH3:8])[O:7][C@H:2]([CH3:1])[CH2:3]1)[CH3:15]
Reactant: C[C@@H]1CNC[C@H](C)O1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CN1C[C@@H](C)O[C@@H](C)C1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
cis-2,6-Dimethylmorpholine (2.0 g) was dissolved in acetonitrile (70 ml). Ethyl bromoacetate (2.5 ml) and potassium carbonate (3.1 g) were added and the mixture was heated with stirring at 60° C. for 12 hours. The solvent was evaporated and then ethyl acetate was added to the residue. The organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (developed with ethyl acetate-hexane) to give the title compound (2.9 g) as a colorless oil.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[S:18][C:17]([CH:19]3[N:23]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=4[F:31])[N:22]=[C:21]([C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])[CH2:20]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[F:31][C:25]1[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=1[N:23]1[CH:19]([C:17]2[S:18][C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)=[CH:15][CH:16]=2)[CH2:20][C:21]([C:32]([F:37])([F:38])[C:33]([F:35])([F:36])[F:34])=[N:22]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3ccc(F)cc3F)s2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(N2N=C(C(F)(F)C(F)(F)F)CC2c2ccc(C3=CCNCC3)s2)c(F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
5-[5-(1-BOC-1,2,3,6-tetrahydropyridin-4-yl)-thiophen-2-yl]-1-(2,4-difluoro-phenyl)-3-pentafluoroethyl-4,5-dihydro-1H-pyrazole (480.0 mg, 0.85 mmol) prepared in Example 197 and trifluoroacetic acid (600.0 uL, 7.84 mmol) were added at 0° C. to dichloromethane (5.0 mL). The reaction mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure to give 450.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][CH3:10])[C:3]=1[F:11].[Br:12]Br>>[Br:12][C:7]1[CH:6]=[CH:5][C:4]([O:8][CH2:9][CH3:10])=[C:3]([F:11])[C:2]=1[Cl:1]
Reactant: CCOc1cccc(Cl)c1F
Reactant: BrBr
Product: CCOc1ccc(Br)c(Cl)c1F
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
504 g of the compound (b44) was added to a reactor in a nitrogen atmosphere, to which 434 g of bromine was added dropwise over 1 hour in a temperature range of 20 to 40° C., followed by stirring for 30 minutes. The resulting reaction mixture was washed with a saturated sodium thiosulfate aqueous solution, a 10% sodium hydroxide aqueous solution, and water. The residue was subjected to fractional distillation under reduced pressure to obtain 605 g of 1-bromo-2-chloro-4-ethoxy-3-fluorobenzene (C12). The resulting compound (C12) was white solid and had a melting point of 48.0 to 48.5° C. and a boiling point of 88 to 90° C./1 mmHg.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH2:7][NH:8][CH2:9][CH2:10][C:5]=2[CH:4]=[CH:3]1.[C:11]1([C:17]2([C:20]3[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=3)[CH2:19][CH2:18]2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>CN(C)C=O.O>[C:11]1([C:17]2([C:20]3[CH:21]=[CH:22][C:23]([C:24]([N:8]4[CH2:9][CH2:10][C:5]5[CH:4]=[CH:3][O:2][C:6]=5[CH2:7]4)=[O:25])=[CH:27][CH:28]=3)[CH2:18][CH2:19]2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)c1ccc(C2(c3ccccc3)CC2)cc1
Reactant: c1cc2c(o1)CNCC2
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(C2(c3ccccc3)CC2)cc1)N1CCc2ccoc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.209 g (7.575 mmol) of 4,5,6,7-tetrahydrofuro[2,3-c]pyridine hydrochloride, 1.80 g (7.58 mmol) of 4-(1-phenylcyclopropyl)benzoic acid and 4.22 ml (30.3 mmol) of triethylamine in 50 ml of N,N-dimethylformamide, 1.38 ml (9.09 mmol) of diethyl cyanophosphonate was added dropwise, followed by overnight stirring at room temperature. This mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=6/1 to 3/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(=O)C(Cl)=O>CN(C)C=O.ClCCl>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 60 ml of dichloromethane were added 21.0 g of 2,6-dichloro-5-fluoronicotinic acid, 10 ml of oxalylchloride, and 10 drops of N,N-dimethylformamide, and the mixture was stirred at room temperature for one day. The solvent and the excess reagents were distilled off under reduced pressure, and the residue was dissolved in 50 ml of chloroform. 10 ml of methanol was added dropwise to the solution, and the solution was stirred at room temperature for 60 minutes, and 15 g of anhydrous potassium carbonate was added to the solution and the solution was stirred for another 30 minutes. The solution was separated by adding 150 ml of chloroform and 150 ml of distilled water, and the chloroform layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 26.6 g of the title compound as a colorless crude oily residue.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C@H:14]2[O:20][C@H:18]([OH:19])[C@H:17]([OH:21])[C@@H:16]([OH:22])[C@@H:15]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].S([O-])([O-])(=O)=O.[Ca+2].[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:30]([O:11][CH2:10][C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@H:14]2[O:20][C@H:18]([OH:19])[C@H:17]([OH:21])[C@@H:16]([OH:22])[C@@H:15]2[OH:23])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@H:6]1[OH:7])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](CO[C@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H](O)[C@H](O)[C@H]2O)[C@H]1O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 5.13 g portion of anhydrous 6-O-α-D-galactopyranosyl-α-D-glucopyranose is suspended in 50 ml of pyridine and 5.0 g of anhydrous calcium sulfate is added. This mixture is heated at 90° C. for 30 minutes, then 4.6 g of trityl chloride is added and heating and stirring are continued for 2 hours. The solution is cooled to room temperature, 10 ml of acetic anhydride is added and the mixture is allowed to stand overnight. The mixture is poured into crushed ice and the solid is filtered, washed with water and dried, giving 10 g of 6-O-(6-O-trityl-α-D-galactopyranosyl)-α-D-glucopyranose, heptaacetate as a colorless granular solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:16])[CH:12]=2)[CH:7]=1)[CH3:2].C1C(=O)N([Br:25])C(=O)C1.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:16][Br:25])[CH:12]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc2cc(C)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1ccc2cc(CBr)ccc2c1
Temperature: 82 °C

Procedure:
To a solution of the product of Step 1, above (50) (3.07 mmol), in 6 ml of CCl4 was added NBS (3.07 mmol) and azobisisobutyronitrile (0.09 mmol) and the mixture was heated to 82° C. for 2 hours. The reaction was cooled to ambient temperature and filtered through celite, washing the cake thoroughly with CCl4. The organics were then concentrated to dryness to obtain the title compound (51).
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.[CH3:14][C@@H:15]1[CH2:19]OS(=O)(=O)[N:16]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:14][C@@H:15]([NH:16][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH2:19][N:2]1[CH2:3][CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH2:1]1
Reactant: C[C@@H]1COS(=O)(=O)N1c1ccccn1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](CN1CCc2c([nH]c3ccccc23)C1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A mixture of 1, 2, 3, 4-tetrahydro-9H-pyrido[3, 4-b]indole (1.7 g, 9.8 mmol) and (R)-4-methyl-3-(pyridin-2-yl)-[1, 2, 3]-oxathiazolidine-2, 2-dioxide (1.90 g, 8.9 mmol) in 30 ml of anhydrous dimethylformamide was stirred under nitrogen at room temperature for two hours. The dimethylformamide was removed under reduced pressure and the residue was dissolved in 15 ml of tetrahydrofuran plus 5 ml of water. Concentrated sulfuric acid (470 μl, 8.9 mmol) was added dropwise and the reaction stirred at room temperature for 30 minutes. Sodium bicarbonate (3.0 g, 35 mmol) is then added and the mixture stirred at room temperature overnight. The reaction was partitioned between ethyl acetate and water. The organic layer was separated. The aqueous layer was made basic with sodium bicarbonate and then extracted with ethyl acetate. The organic layers were combined, washed two times with water, dried (MgSO4) and the solvent removed under reduced pressure to give 2.68 g (98%) of (R)-[1-methyl-2-(1, 3, 4, 9-tetrahydro-2H-pyrido [3, 4-b]indol-2-yl)-ethyl]-pyridin-2-yl-amine as a light yellow oil, MS [M+HI+ 307.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.B([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=1)(O)O>>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:30]3[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[CH:32][CH:31]=3)=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Product: Cc1cc(C(=O)C[C@H](c2ccc(-c3ccc(C(=O)O)cc3)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 74, step 6, from (R)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (example 282, step 1) and 4-boronobenzoic acid was prepared the title compound a brown foam, MS (ESI+): m/z=470.1 ([M+H]+).
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][CH2:5]1.[CH3:15]S([O-])(=O)=O.C[S+](C)C.ClCCl>O>[O:3]1[C:4]2([CH2:5][CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9]2)[CH2:15]1
Reactant: CS(=O)(=O)[O-]
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: C[S+](C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CCC2(CC1)CO2
Yield: 72 %

Procedure:
A solution of 47% sodium hydroxide (15 ml), ethyl 4-oxopiperidine-1-carboxylate (4.53 ml, 30 mmol), trimethylsulphonium methanesulphonate (7.36 g, 39 mmol) (Syn. Comm., 1985, 15, 749) and dichloromethane (30 ml) was heated to 50° C. for 16 h, cooled, diluted with water (30 ml), and extracted with dichloromethane. The combined extracts were dried over sodium sulphate and evaporated. The residue was purified by flash column chromatography on silica, eluting with 2% methanol/dichloromethane to give the product as a mobile yellow oil (4.0 g), MS (+EI)m /z 185; 1H NMR (360 MHz) (CDCl3) 4.15 (2H, q, J7.1 Hz), 3.78 (2H, brs), 3.46 (1H, ddd, J3.7, 9.6, 13.3 Hz), 2.71 (2H, s), 1.87-1.79 (2H, m), 1.49-1.43 (2H, m), 1.28 (3H, t, J7.1 Hz).