Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].Cl[C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1.[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][OH:16]>>[CH3:12][N:13]([CH3:17])[CH2:14][CH2:15][O:16][C:3]1[CH:4]=[CH:5][C:6]2[N:7]([CH:9]=[CH:10][N:11]=2)[N:8]=1
Reactant: Clc1ccc2nccn2n1
Reactant: CN(C)CCO
Agent: [Na]
Product: CN(C)CCOc1ccc2nccn2n1

Procedure:
Sodium metal (0.25 g) and 6-chloroimidazo[1,2-b]-pyridazine are added to 25 ml of 2-dimethylaminoethanol and the mixture is heated in a sealed tube for 3 hours at 130°0 C. After cooling, the solvent is evaporated and the residue is treated with water and extracted with methylene chloride. The organic layer is separated, washed with saturated sodium chloride solution and dried over MgSO4. Evaporation of the solvent gives the title compound as a viscous oil which solidified on standing. The yield is 2.5 g.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22][C:21]3=[O:30])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[O:30]=[C:21]1[N:20]([C:17]2[CH:16]=[N:15][C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[CH:19][CH:18]=2)[CH2:24][C@H:23]([CH2:25][NH:26][C:27](=[O:29])[CH3:28])[O:22]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)nc2)C(=O)O1
Agent: Cl
Solvent: CO
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCNCC3)nc2)C(=O)O1

Procedure:
0.54 g of 4-{5-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-pyridin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (1.28 mmol) was dissolved in a 1.25 M HCl solution in methanol. The solution was stirred and the reaction monitored by TLC. The methanol was evaporated, the residue dissolved in water, neutralized with sodium bicarbonate and the water evaporated to dryness. The residue was digested in a 9/1 dichloromethane/methanol. The insoluble salt was filtered off, the filtrate evaporated to dryness to leave a pale brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.CCCCCC.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:32]([NH:31][C:27]2[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=2)=[O:33])=[CH:18][CH:17]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1cccc(NC(=O)Nc2ccc(Oc3ncnc4cc(OC)c(OC)cc34)cc2)c1
Yield: 21 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinazoline (100 mg) was dissolved in toluene (10 ml) with heat, 3-methoxyphenyl isocyanate (0.36 ml) was added, and the admixture was refluxed with heat for 40 minutes. After removing the solvent by distillation, the resulting residue was purified by column chromatography on silica gel eluting with chloroform/methanol (100/1) and then with chloroform/acetone (5/1) to obtain 31 mg of the title compound (yield: 21%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][OH:25])[O:21][C:20]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1.C(N(CC)CC)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][O:25][S:35]([CH3:34])(=[O:37])=[O:36])[O:21][C:20]2=[O:26])[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][O:16][CH3:17])[C:10](=[O:18])[CH2:9]1
Reactant: COCCN1CCN(c2ccc(N3C[C@H](CO)OC3=O)cc2F)CC1=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COCCN1CCN(c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)CC1=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(5R)-3-(3-Fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-hydroxymethyloxazolidin-2-one (1.0 g) was dissolved in pyridine (25 ml), and cooled to 0° C. Triethylamine (0.46 ml) and methanesulfonyl chloride (0.23 ml) were added, and stirring continued at ambient temperature for 2 hours. Solvent was evaporated and the residue dissolved in ethyl acetate, washed with water, dried (MgSO4), and evaporated to give (5R)-3-(3-fluoro-4-{4-(2-methoxyethyl)-3-oxopiperazin-1-yl}phenyl)-5-(methanesulfonyloxymethyl)oxazolidin-2-one (1.01 g) which was used without further purification.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[C:11]1(=O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13](=[O:20])[O:12]1>C(Cl)Cl>[OH:4][CH2:3][C@@H:2]([N:1]1[C:11](=[O:12])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:20])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Temperature: 150 °C

Procedure:
(S)-2-amino-2-phenylethanol (2 g, 14.58 mmol) and isobenzofuran-1,3-dione (2.267 g, 15.31 mmol) were combined in a 20 mL microwave tube, sealed and heated to 150° C. for 6 hrs. The tube was cooled to ambient temperature, dilluted with DCM, loaded directly onto a 50 g SNAP column and purified 10-60% hexane/EtOAc to provide (S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione. MS: [M+H]+ m/z 268.
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.I(O)(=O)(=O)=[O:19].O>C(#N)C>[CH3:1][S:2]([C:3]1[O:7][C:6]2[C:8](=[O:17])[C:9]3[C:14]([C:15](=[O:16])[C:5]=2[CH:4]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[O:19]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: CSc1cc2c(o1)C(=O)c1ccccc1C2=O
Solvent: O
Solvent: CC#N
Product: CS(=O)c1cc2c(o1)C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
To a solution of 0.5 gram (2.05 mmoles) of 2-methylthio-naphtho[2,3-b]furan-4,9-dione in 20 mL of acetonitrile at room temperature, 0.49 grams (2.15 mmoles) of periodic acid followed by 2 mg of ferric chloride was added. The mixture was stirred for 10 minutes at room temperature, then 50 mL of water was added, and the resulting mixture was evaporated to remove acetonitrile. The remaining aqueous suspension was filtered, and the obtained solid was washed with water and dried under vacuum. The crude solid product was purified with silica gel chromatograph using dichloromethane/ethyl acetate (9:1) as elution solvent. 0.43 grams of product (yield 80%) was obtained and characterized by 1H NMR and mass spectrum. 1H NMR (in DMSO) δ 3.14 (s, 3H), 7.81 (s, 1H), 7.92-7.94 (m, 2H), 8.12-8.17 (m, 2H). Mass (M+H) is 261.
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([NH:32][C:33]2[N:34]=[CH:35][C:36]([C:44]([OH:46])=O)=[N:37][C:38]=2[O:39][CH2:40][CH2:41][O:42][CH3:43])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:47][O:48][C:49](=[O:56])[C:50]([NH2:55])([CH2:53][CH3:54])[CH2:51][CH3:52]>>[CH3:47][O:48][C:49](=[O:56])[C:50]([NH:55][C:44]([C:36]1[CH:35]=[N:34][C:33]([NH:32][CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)=[C:38]([O:39][CH2:40][CH2:41][O:42][CH3:43])[N:37]=1)=[O:46])([CH2:53][CH3:54])[CH2:51][CH3:52]
Reactant: COCCOc1nc(C(=O)O)cnc1NC1CCCCC1
Reactant: CCC(N)(CC)C(=O)OC
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(NC2CCCCC2)c(OCCOC)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-cyclohexylamino-6-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 423.4 (M+H).
Reaction SMILES: CC(C)(C)C[O:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[N:19]=[C:18]([C:20]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=4)[CH:23]=[C:22]([CH3:36])[N:21]=3)[CH:17]=[CH:16][CH:15]=2)[CH:9]=1)(=[O:7])=[O:6].C([O-])CC.[Na+].C(N(CC)CCS)C.Cl>C(O)CC.O>[CH3:36][C:22]1[N:21]=[C:20]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([C:10]3[CH:9]=[C:8]([S:5]([OH:7])(=[O:4])=[O:6])[CH:13]=[CH:12][CH:11]=3)[N:19]=2)[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=2)[CH:23]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)OCC(C)(C)C)c3)n2)n1
Agent: CCC[O-]
Agent: CCN(CC)CCS
Agent: Cl
Solvent: CCCO
Solvent: O
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cccc(-c3cccc(S(=O)(=O)O)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80.6 %

Procedure:
The title compound was prepared from the above described 3-[6′-methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonic acid 2,2-dimethyl-propyl ester (7.7 g, 14.24 mmol) by refluxing in 1-propanol (15 mL) with sodium propanolate (1.7 M in n-propanol, 20.95 ml, 35.6 mmol) and 2-(diethylamino)ethanthiol (2.48 mL, 16.38 mmol) for 18 h. Cooled to rt, added water (300 mL), added 1 N HCl (ca. 50 mL) until pH 3-4 was reached, stirred for 10 min, filtered the solid off, washed thrice with water, and then with acetone and dried in HV to give the title compound (5.4 g, 81%) as an off-white solid. MS (ISN) 469.1 [(M−H)−].
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn](CCCC)(CCCC)CCCC)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Br[C:26]1[N:27]=[C:28]2[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][N:32]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C:29]2=[N:30][CH:31]=1>CN(C=O)C.[Cu]I.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>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:26]3[N:27]=[C:28]4[C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][N:32]([CH2:39][O:40][C:41](=[O:46])[C:42]([CH3:44])([CH3:43])[CH3:45])[C:29]4=[N:30][CH:31]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nn(C)c2cc(F)ccc12
Reactant: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12
Temperature: 90 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
To a stirred solution of 6-fluoro-1-methyl-3-(tributylstannyl)-1H-indazole (0.51 g, 0.616 mmol), methyl 2-bromo-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.18 g, 0.486 mmol) in 6 mL of DMF were added CuI (0.04 g, 0.21 mmol) and Pd(PPh3)4 (0.057 g, 0.045 mmol) in one portion under nitrogen at room temperature. Then the reaction mixture was degassed by bubbling nitrogen for 10 minutes and stirred at 90° C. under nitrogen for 16 hours. The solvent was evaporated at 70° C. under reduced pressure and the residue was purified by column chromatography (silica gel, 200-300 mesh, eluting with a mixture of ethyl acetate and petroleum ether (1:1, v/v) to give methyl 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(pivaloyloxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylate (0.182 g, 85.2%) as a yellow solid. LCMS: (M+H)+=440; 1H NMR (300 MHz, DMSO): δ 9.13 (s, 1H), 8.83-8.78 (m, 1H), 8.70 (s, 1H), 7.63 (dd, 1H, J1=9.6 Hz, J2=2.1 Hz), 7.23 (dt, 1H, J1=9.3 Hz, J2=2.1 Hz), 6.30 (s, 2H), 4.13 (s, 3H), 3.92 (s, 3H), 1.08 (s, 9H).
Reaction SMILES: [CH2:1]([NH:3][C:4]([N:19]1[CH2:23][CH:22]([CH2:24][CH3:25])[CH:21]=[N:20]1)=[N:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][C:10]=1Br)(=[O:8])=[O:7])[CH3:2].C(N(CC)CC)C>CCO>[CH2:1]([NH:3][C:4]([N:19]1[CH2:23][CH:22]([CH2:24][CH3:25])[CH:21]=[N:20]1)=[N:5][S:6]([C:9]1[CH:17]=[C:16]2[C:12]([CH2:13][CH2:14][NH:15]2)=[CH:11][CH:10]=1)(=[O:7])=[O:8])[CH3:2]
Reactant: CCNC(=NS(=O)(=O)c1cc2c(cc1Br)CCN2)N1CC(CC)C=N1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCNC(=NS(=O)(=O)c1ccc2c(c1)NCC2)N1CC(CC)C=N1
Reaction time: 8 h
Yield: 81.7 %

Procedure:
To a solution of 0.30 g 5-Bromo-2,3-dihydro-1H-indole-6-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide in 50 mL EtOH was added 0.94 mL of triethylamine. The mixture was degassed thoroughly, and 10 mol % of palladium on carbon was added. The mixture was hydrogenated overnight at a H2 pressure of 1 atm. The mixture was filtered over Hyflo, the Hyflo was washed with EtOH, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (DCM→DCM/EA 95:5→DCM/EA 9:1) to give 0.20 g (76%) of 2,3-Dihydro-1H-indole-6-sulfonic acid ethylamino-(4-ethyl-4,5-dihydro-pyrazol-1-yl)-methyleneamide as a red oil. 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J=7.52 Hz, 3H), 1.14 (t, J=7.22 Hz, 3H), 1.43-1.67 (m, 2H), 3.04 (t, J=8.43 Hz, 3H), 3.42-3.52 (m, 2H), 3.60 (t, J=8.43 Hz, 2H), 3.66 (dd, J=11.44, 7.83 Hz, 1H), 4.06 (t, J=11.29 Hz, 1H), 6.89 (d, J=1.50 Hz, 1H), 7.10-7.15 (m, 2H), 7.24-7.27 (m, 1H). [NH's invisible].
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH:7]1[CH:11]=[C:10]([C:12]2([C:21](OCC)=[O:22])[CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[N:9]=[CH:8]1.C(OCC)(=O)C.Cl>C1COCC1>[NH:7]1[CH:11]=[C:10]([C:12]2([CH2:21][OH:22])[CH2:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:20]2)[N:9]=[CH:8]1
Reactant: CCOC(=O)C1(c2c[nH]cn2)Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCC1(c2c[nH]cn2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,8 g of LiAlH4 were added to 75 ml of dry tetrahydrofurane in nitrogen atmosphere. 15,0 g of ethyl 2,3-dihydro-2-(1H-imidazol-4-yl)-1H-indene-2-carboxylate (prepared according to EP 247764) were dissolved in 150 ml of dry THF and slowly added dropwise at room temperature. After the addition the mixture was stirred for 2 h at room temperature and then for an additional 2 h at +40° C. Excess of LiAlH4 was decomposed by slow addition of ethyl acetate. Then the mixture was poured into dilute hydrochloric acid. The aqueous solution was washed with methylene chloride and made alkaline with sodium hydroxide. The product was extracted in ethyl acetate. The precipitate formed during the extraction was filtered and washed several times with hot ethyl acetate and methylene chloride. The organic solutions were combined, dried and evaporated. The hydrochloride of the product was made in ethyl acetate by HCl-ethyl acetate, m.p. 181°-184° C.
Reaction SMILES: N1(CCOC2C=CC(CCNC3C=C(OC)C=CC=3C3CCC4C(=CC=C(OC)C=4)C3)=CC=2)CCCCCC1.[N:40]1([CH2:47][CH2:48][O:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][N:58]([CH2:79][CH3:80])[C:59]3[CH:64]=[C:63]([O:65]C)[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:76][CH2:75][C:74]4[C:69](=[CH:70][CH:71]=[C:72]([O:77]C)[CH:73]=4)[CH2:68]3)=[CH:52][CH:51]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1>>[N:40]1([CH2:47][CH2:48][O:49][C:50]2[CH:55]=[CH:54][C:53]([CH2:56][CH2:57][N:58]([CH2:79][CH3:80])[C:59]3[CH:64]=[C:63]([OH:65])[CH:62]=[CH:61][C:60]=3[CH:67]3[CH2:76][CH2:75][C:74]4[CH:73]=[C:72]([OH:77])[CH:71]=[CH:70][C:69]=4[CH2:68]3)=[CH:52][CH:51]=2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: CCN(CCc1ccc(OCCN2CCCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCCN3CCCCCC3)cc1)C2
Product: CCN(CCc1ccc(OCCN2CCCCCC2)cc1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1
Yield: 77 %

Procedure:
Synthesized from {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Example 36, {2-[4-(2-azepan-1-ylethoxy)phenyl]ethyl}ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (130 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (95 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1[CH3:8].C(N(C(C)C)C(C)C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:9][S:20]([CH3:19])(=[O:22])=[O:21])=[N:6][C:7]=1[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(N)ccc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(NS(C)(=O)=O)ccc1Br
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 5-bromo-6-methylpyridin-2-amine (0.3 g, 1.604 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.559 mL, 3.21 mmol) in DCM (10 mL) was added methanesulfonyl chloride (0.137 mL, 1.764 mmol) at 0° C. The reaction mixture was stirred at room temperature for 48 hours and was subsequently concentrated in vacuo to give the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[SH-:16].[Na+].Cl>O>[CH2:14]([O:13][C:11]([C:4]1[CH:3]=[C:2]([SH:16])[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[N:5]=1)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cc(Cl)n2ncnc2n1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(S)n2ncnc2n1
Temperature: 25 °C
Yield: 69 %

Procedure:
The product obtained in Step 1 (4.1 g) and sodium hydrosulfide (2.6 g) were dissolved in 30 ml of water, the solution was refluxed for one hour, the reaction mixture was cooled to room temperature, its pH was lowered to 1.0 with 6N hydrochloric acid, and the colorless crystals thus formed were collected by filtration, giving 2.8 g of the objective compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([CH2:34][C:35]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:36])(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH2:34][C:35]([N:37]([CH2:40][CH3:41])[CH2:38][CH3:39])=[O:36])(=[O:33])=[O:32])=[CH:7][C:2]=2[F:1])=[CH:18][N:19]=1
Reactant: CCN(CC)C(=O)CS(=O)(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Product: CCN(CC)C(=O)CS(=O)(=O)c1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 6 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and 2-((2-bromophenyl)sulfonyl)-N,N-diethylacetamide. MS (ESI): mass calcd. for C22H23FN4O3S, 442.52; m/z found, 443.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.55 (d, J=1.4, 2H), 8.13 (dd, J=8.0, 1.3, 1H), 7.81-7.73 (m, 1H), 7.71-7.63 (m, 1H), 7.62-7.55 (m, 1H), 7.44 (dd, J=7.6, 1.3, 1H), 7.39 (dd, J=4.5, 1.7, 1H), 7.37 (dd, J=8.0, 1.3, 1H), 3.29-3.27 (m, 4H), 1.07 (t, J=7.2, 3H), 1.04 (t, J=7.2, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([NH2:13])=[O:12])(O)=[O:2].Cl[C:15]1C=CC=CC=1Cl>>[CH3:15][N:13]1[C:11](=[O:12])[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:1]1=[O:2]
Reactant: NC(=O)Cc1ccccc1C(=O)O
Reactant: Clc1ccccc1Cl
Product: CN1C(=O)Cc2ccccc2C1=O

Procedure:
A mixture of 2.28 g (11.8 mmol) of N-methyl-(2-carboxybenzeneacetamide and 24 ml of 1,2-dichlorobenzene is refluxed for 1 h and evaporated to dryness. The residue is recrystallized from EtOAc-hexane to give an off-white solid, 1.55 g (75%), mp 113-115° C.; MS (ES+) m/z 176.1 (M+H)+1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][C:14](Br)=[CH:15][CH:16]=2)[N:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]([C:26]1([CH:32]=[CH2:33])[CH2:31][O:30][CH2:29][CH2:28][O:27]1)=[O:25].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C1(CNCC2CCCCC2)CCCCC1>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:22][O:23][C:24]([C:26]1(/[CH:32]=[CH:33]/[C:14]2[CH:13]=[C:12]3[C:17]([CH:18]=[CH:19][C:10]([C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[CH3:9])=[N:11]3)=[CH:16][CH:15]=2)[CH2:31][O:30][CH2:29][CH2:28][O:27]1)=[O:25]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc2ccc(Br)cc2n1
Reactant: C=CC1(C(=O)OC)COCCO1
Agent: [Pd+2]
Agent: C1CCC(CNCC2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: COC(=O)C1(/C=C/c2ccc3ccc([C@@H](C)NC(=O)OC(C)(C)C)nc3c2)COCCO1
Yield: 39.4 %

Procedure:
A solution of [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-carbamic acid tert-butyl ester (316 mg, 0.9 mmol), 2-vinyl-[1,4]dioxane-2-carboxylic acid methyl ester (154 mg, 0.9 mmol), palladium(II) acetate (41 mg, 0.18 mmol), tri(o-tolyl)phosphine (54 mg, 0.18 mmol) and N,N-dicyclohexylmethylamine (351 mg, 0.38 mL, 1.8 mmol) in acetonitrile (8 mL) was heated at 120° C. in a microwave reactor for 30 minutes. The reaction mixture was filtered and the solvent was evaporated. The residue was dissolved in dichloromethane; brine and ice-cold 1 M hydrochloric acid were added to acidify the mixture to pH 2. The organic layer was separated and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of iso-hexanes/ethyl acetate 7:3 to 6:4 to afford the title compound (157 mg, 40%) as a yellow gum and as a 1:1 mixture of diastereoisomers. LCMS (m/z) 443.1 [M+H], Tr=2.34 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8]>>[C:3]([CH2:4][CH2:5][NH:11][CH2:10][CH:9]([CH2:7][CH3:8])[CH2:12][CH2:13][CH2:14][CH3:15])([O:2][CH3:1])=[O:6]
Reactant: C=CC(=O)OC
Reactant: CCCCC(CC)CN
Product: CCCCC(CC)CNCCC(=O)OC
Temperature: 35 °C
Reaction time: 2 h

Procedure:
While stirring at a temperature of 20° C., 90.3 grams (1.05 mole) of methylacrylate were dripped into 129 grams (1 mole) of 2-ethylhexylamine within a period of 30 minutes. The temperature was increased to 35° C. The mixture was stirred at 100° C. for 2 hours and was subsequently degassed at 50° C. under a high vacuum for 1 hour. The remaining residue was 210 grams (98 percent of theory) liquid N-(2'-carbomethoxy-ethyl)-2-ethylhexylamine. The 60 MHz-Nuclear Magnetic Resonance Spectrum s 3.7 ppm COOCH3 ; m 2.9 ppm; m 2.5 ppm; 0.7 to 1.5 ppm confirms the structure.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH:10]([CH3:13])[CH2:11][Cl:12].[OH-].[Na+]>C(O)C>[C:1]1([S:7][CH2:9][CH:10]([CH3:13])[CH2:11][Cl:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: CC(CCl)CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(CCl)CSc1ccccc1
Temperature: 40 °C
Yield: 97.1 %

Procedure:
A mixture of 22 g (0.2 mol) of thiophenol and 37.7 g (0.22 mol) of 3-bromo-1-chloro-2-methylpropane in 200 ml of ethanol is stirred at 40° C and 40 ml (0.2 mol) of 5N sodium hydroxide solution is added dropwise. The mixture is stirred for a further 2 hours at 40° C and evaporated to dryness in vacuo, the residue is extracted with methylene chloride and the extract is washed with water, dried and evaporated in vacuo. 39 g (97%) of a yellow oil are obtained.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:13]1=[O:26])=O)C1C=CC=CC=1>[Pd].C(O)C>[NH2:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:25])[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:13]1=[O:26]
Reactant: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: [Pd]
Solvent: CCO
Product: C[C@@H](C(=O)OC(C)(C)C)N1CC[C@H](N)C1=O
Reaction time: 18 h
Yield: 101.3 %

Procedure:
A mixture of tert-butyl (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoate (2.82 g), 10% palladium on carbon (0.3 g) and ethanol (150 ml) was stirred under an atmosphere of hydrogen for 18 h. The reaction mixture was filtered through Harbolite™ and the filtrate was concentrated under reduced pressure to give the title compound (1.8 g) as a pale yellow oil.