Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[C@@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])(=O)=O.[C:35]([O-:38])(=[S:37])[CH3:36].[K+]>CN(C=O)C>[C:35](=[O:38])([S:37][C@H:6]1[C@@H:11]([CH3:12])[CH2:10][C@@H:9]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH:19][C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:8][C@H:7]1[NH:27][C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH3:36]
Reactant: CC([O-])=S
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)S[C@H]1[C@@H](C)C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of (+/−)-(1R,2R,4R,6S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate (1.0 equiv.) in DMF (0.25 M) was added potassium thioacetate (6.0 equiv.). The mixture was stirred for 6 hours in a 60° C. bath under Ar. Upon cooling and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O (3×), Na2CO3(sat.), NaCl(sat.), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)S-((1S,2R,4R,6S)-2-((tert-butoxycarbonyl)amino)-4-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-6-methylcyclohexyl) ethanethioate in 87% yield. LC/MS (m/z)=480.3 (MH+), Rt=0.82 min.
Reaction SMILES: [CH:1]([CH:3]1[O:8][C:6](=O)[CH2:5][CH2:4]1)=[CH2:2].[CH3:9][NH2:10]>>[CH:1]([CH:3]1[N:10]([CH3:9])[C:6](=[O:8])[CH2:5][CH2:4]1)=[CH2:2]
Reactant: CN
Reactant: C=CC1CCC(=O)O1
Product: C=CC1CCC(=O)N1C
Yield: 46 %

Procedure:
21 g (179 mmol) of gamma-vinylbutyrolactone prepared as in Example 1 were stirred with 125 g of 40% strength aqueous methylamine in an autoclave at 280° C. for two hours. After cooling, the reaction mixture was concentrated at 50° C./20 mbar. The residue (22.7 g) was distilled using a spinning band column to yield 10.3 g (46%) of 5-vinyl-N-methylpyrrolidone.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH3:10])[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[C:4]2[CH:15]=[CH:16][CH:17]=[CH:18][C:3]1=2.[F:19][C:20]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:21][CH2:22][NH:23][C:24](=[O:29])[CH2:25][C:26](O)=[O:27]>>[CH3:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:26](=[O:27])[CH2:25][C:24]([NH:23][CH2:22][CH2:21][C:20]([F:19])([F:34])[C:30]([F:33])([F:31])[F:32])=[O:29])[C:3]2[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=2[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][C:6]1=2
Reactant: CN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: O=C(O)CC(=O)NCCC(F)(F)C(F)(F)F
Product: CN1C(=O)[C@@H](NC(=O)CC(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
(S)-7-Amino-5-methyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with N-(3,3,4,4,4-pentafluoro-butyl)-malonamic acid in analogy to the description example 73 to yield N-((S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-N′-(3,3,4,4,4-pentafluoro-butyl)malonamide as white solid.
Reaction SMILES: [CH2:1]1[C:5]2=[CH:6][N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]2[CH:3]=[CH:2]1.B.O1CCCC1>O1CCCC1.O>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C@@H:25]([OH:29])[C:24]=4[CH3:30])=[C:19]([CH3:31])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: CC1=C(c2ccc(C(=O)N3C=C4CC=CN4Cc4ccccc43)cc2C)CCCC1=O
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: CC1=C(c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2C)CCC[C@H]1O
Yield: 92.2 %

Procedure:
(S)-(−)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaboro-borane [(S)-2-methyl-CBS-oxazaborolidine] (1.0 M in tetrahydrofuran, 1.06 mL, 1.06 mmol) was dissolved in anhydrous tetrahydrofuran (53.1 mL, distilled from sodium/benzophenone ketyl). To this solution was simultaneously added a solution of 3-[4-(5H,1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10-carbonyl)-2-methyl-phenyl]-2-methyl-cyclohex-2-enone of Example 4 (2.18 g, 5.31 mmol) in anhydrous tetrahydrofuran (20 mL) via syringe pump (1.6 mL/min) and borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran, 3.19 mL, 3.19 mmol) at a rate such that enone addition was complete upon addition of approximately ⅔ of the borane-tetrahydrofuran complex. Upon completion of the borane-tetrahydrofuran complex addition, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed with 1 N sodium hydroxide, 1 N hydrochloric acid and brine and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50% ethyl acetate in hexane followed by reprecipitation from diethyl ether upon addition of petroleum ether, to afford 2.02 g of the title compound as a white solid, [α]589=+34.30 (c=1, chloroform). Analytical HPLC (Chiralpak AD, 4.6×250 mm, 50% ethanol/hexane, 0.5 mL/min.) indicated an enantiomeric excess of 96.4%.
Reaction SMILES: [CH:1]1C=C[NH+]=C[CH:6]=1.[O-][Cr](Cl)(=O)=O.[OH:12][CH:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]([OH:18])=[O:17].Cl>ClCCl>[O:12]=[C:13]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:14][CH2:15][C:16]([O:18][CH2:1][CH3:6])=[O:17]
Reactant: c1cc[nH+]cc1
Reactant: CCCCCCC(O)CCC(=O)O
Agent: O=[Cr](=O)([O-])Cl
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC(=O)CCC(=O)OCC
Temperature: 25 °C
Reaction time: 5 h
Yield: 75.8 %

Procedure:
PCC (1.2 g, 2.71 mmol) was added to a solution of 4-hydroxydecanoic acid (830 mg, 4.4 mmol) in dichloromethane (30 ml), and the mixture was stirred at room temperature for five hours. The reaction mixture was adjusted to pH 1 by adding 1 N hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then concentrated under reduced pressure. The resulting residue was then dissolved in ethanol (15 ml). Five drops of sulfuric acid were added and the mixture was stirred at 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give ethyl 4-oxodecanoate (440 mg, 46% in two steps).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([OH:21])=[CH:13][CH:12]=1.[K].[O-]CCCC>CN1C(=O)CCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:21][C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH2:10])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(O)c2ccccc12
Reactant: Fc1ccnc(Cl)c1
Agent: CCCC[O-]
Agent: Cl
Agent: [K]
Solvent: O
Solvent: CN1CCCC1=O
Product: Nc1ccc(Oc2ccnc(Cl)c2)c2ccccc12
Temperature: 25 °C
Yield: 98.4 %

Procedure:
To a stirred solution of 2-chloro-4-fluoropyridine (1.26 g, 9.58 mmol) and 4-amino-1-naphthol hydrochloride (2a) (750 mg, 3.83 mmol) in NMP (40 mL), at −20° C., was added potassium tart-butoxide (1.290 g, 11.50 mmol). The reaction mixture was allowed to warm to RT and after 2.5 hr the reaction mixture was diluted with water (100 mL) and extracted with EtOAc (100 mL then 2×80 mL). The combined organic extracts were washed with brine (150 mL), dried and evaporated in vacuo. The crude product was subjected to SCX capture and release and the solvent was removed in vacuo to give the title compound (72) (1.02 g, 92%) as a brown solid: m/z 271 (M+H)+ (ES+).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]3[O:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[C:30]([Cl:38])[CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.O>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]2[C:37]3[O:36][CH2:35][CH2:34][N:33]([S:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)(=[O:13])=[O:12])[C:32]=3[CH:31]=[C:30]([Cl:38])[CH:29]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3)CC1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3S(=O)(=O)c2cccc(S(C)(=O)=O)c2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
3-Methanesulfonyl-benzenesulfonyl chloride (80 mg, 0.314 mmol) was added in small portions under nitrogen to an ice-cold solution of 4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (101 mg, 0.285 mmol) and pyridine (50 mg, 0.628 mmol) in dichlormethane (2 mL). After 1.5 hours at ambient temperature, water was added. The layers were separated and the organic phase was washed with saturated aqueous solution of sodium bicarbonate (20 mL), dried (Na2SO4) and concentrated to give 4-[6-chloro-4-(3-methanesulfonyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylic acid tert-butyl ester as an oil (150 mg, 91%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:31])[C:5]([O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=1)([CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)c(F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reaction time: 20 h

Procedure:
2-(3,4-Difluorophenoxy-3-(4-benzyloxyphenyl)-2-methyl-propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][CH:13]=[N:12][C:11]=2[CH3:15])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[CH3:15][C:11]1[N:12]=[CH:13][O:14][C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2ocnc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ncoc1-c1ccc(C(=O)O)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-(4-methyl-oxazol-5-yl)-benzoic acid methyl ester (1.50 g), 1 M aqueous NaOH solution (7.00 mL) and methanol (20 mL) is kept at room temperature overnight. The precipitate is filtered off, dissolved in water and neutralized with 4 M HCl. The precipitate is filtered off, dissolved in dichloromethane and a small amount of methanol, and the solution is dried over Na2SO4 and concentrated in vacuo. The residue is triturated with diethylether to afford the title compound. Mass spectrum (ESI+): m/z=204 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[CH:8]=1)=[O:4].[H][H]>CC(O)C.[Pd]>[NH2:13][C:9]1[CH:8]=[C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:1])([F:16])[F:17])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cccc(CNC(=O)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[(3-nitrophenyl)methyl]acetamide (0.5 g, 2.0 mmol) in i-PrOH was added 10% Pd/C (40 mg, 0.04 mmol). A balloon filled with hydrogen gas was installed, and the reaction was stirred vigorously at rt. After 15 h, the reaction mixture was filtered through celite, adsorbed onto silica gel, and purified by column chromatography to generate the title compound in 85% yield. 1H NMR (400 MHz, CDCl3) δ 7.14-7.27 (m, 1H), 6.59-6.68 (m, 3H), 4.43 (s, 2H), 3.74 (s, 2H). ES-LC/MS m/z=219 [M+H]+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38](N4CCN(C)CC4)[CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].[N:49]1([CH2:54][CH2:55][O:56]C2C=CC(O)=CC=2)[CH2:53][CH2:52][CH2:51][CH2:50]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([CH2:32][CH2:33][CH2:34][O:35][C:36]3[CH:41]=[CH:40][C:39]([O:56][CH2:55][CH2:54][N:49]4[CH2:53][CH2:52][CH2:51][CH2:50]4)=[CH:38][CH:37]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: CN1CCN(c2cccc(OCCCc3ccc(N4CCc5cccc(C(=O)Nc6nc7ccccc7s6)c5C4)nc3C(=O)O)c2)CC1
Reactant: Oc1ccc(OCCN2CCCC2)cc1
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(CCCOc3ccc(OCCN4CCCC4)cc3)c(C(=O)O)n1)CC2

Procedure:
The title compound 106 was prepared in a similar manner to the synthesis of compound 105 by substituting compound 87C with compound 106B: 1H NMR (DMSO-d6): δ 12.84 (s, 1H), 9.68 (s, 1H), 8.04 (d, J=7.93 Hz, 1H), 7.79 (d, J=8.24 Hz, 7.60 (d, J=7.32 Hz, 1H), 7.56 (d, J=8.54 Hz, 1H), 7.34-7.50 (m, 4H), 6.86-6.97 (m, 6H), 4.92 (s, 2H), 4.19-4.21 (m, 2H), 3.86-3.89 (m, 6H), 3.08-3.13 (m, 4H), 2.98 (t, J=5.8 Hz, 1H), 2.79-2.82 (m, 2H), 1.87-2.05 (m, 6H) ESI (+)/MS: 678 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([C:11](OCC)=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1.O.C(OCC)(=O)C>[NH2:1][C:2]1[O:3][C:4]2[CH:10]=[C:9]([CH2:11][OH:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOC(=O)c1ccc2nc(N)oc2c1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nc2ccc(CO)cc2o1
Reaction time: 1.25 h
Yield: 50.7 %

Procedure:
A solution of 2-amino-6-ethoxycarbonylbenzoxazole (14.3 g) in tetrahydrofuran (570 ml) was dropwise added to a mixture of lithium aluminum hydride (7.9 g) in tetrahydrofuran (300 ml) at -30° C. to -20° C. for 35 minutes, and the mixture was stirred for 75 minutes at the same temperature. To the reaction mixture was dropwise added a mixture of water (3 ml) and tetrahydrofuran (3 ml), and the mixture of ethyl acetate and water was added to a resulting mixture. The mixture was adjusted to pH 7 with 6N-hydrochloric acid and the isolated precipitate was removed by filtration. The separated organic layer from filtrate was washed with brine and dried over magnesium sulfate. Evaporation of a solvent gave a residue, which was purified by a column chromatography on silica gel eluting with a mixture of chloroform and methanol (9:1, V/V). The eluted fractions containing the desired product were collected and evaporated in vacuo to give 2-amino-6-hydroxymethylbenzoxazole (5.77 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([NH:13][NH2:14])=[O:12])[CH:9]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:3]=1.C1COCC1.[N:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[C:31]=S.Cl.C(N=C=NCCCN(C)C)C>O>[C:33]([NH:30][C:31]1[O:12][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]([S:15]([C:18]2[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=2)(=[O:16])=[O:17])[CH:3]=[C:2]3[I:1])=[N:13][N:14]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(C(=O)NN)ccc32)cc1
Reactant: CC(C)(C)N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nnc(NC(C)(C)C)o4)ccc32)cc1
Temperature: 60 °C
Yield: 51.4 %

Procedure:
3-Iodo-1-tosyl-1H-indole-5-carbohydrazide (625 mg, 1.373 mmol) in a 250 mL RBF was treated with THF (25 mL) and 2-isothiocyanato-2-methylpropane (0.871 mL, 6.86 mmol) (Aldrich). The flask was fitted with a reflux condenser and heated at 60° C. for 2.5 h. The reaction was cooled to RT, the THF was removed in vacuo and replaced with DMF (10.00 mL). The solution was treated with N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (395 mg, 2.059 mmol), fitted with a reflux condenser and heated to 80° C. for 2 h. The mixture was treated with H2O and extracted with EtOAc (2×50 mL), washed with brine and dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography (eluting with 0-100% EtOAc in Hex) to give N-tert-butyl-5-(3-iodo-1-tosyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-amine (378.7 mg, 0.706 mmol, 51.4) as a white amorphous solid. MS (ESI, pos. ion) m/z: 536.9 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.19 (s, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.98 (s, 1H), 7.90 (dd, J=8.7, 1.5 Hz, 1H), 7.69 (s, 2H), 7.43 (d, J=8.2 Hz, 2H), 2.33 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:30]([CH3:31])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26](Br)[CH:27]=3)[S:21][C:17]=2[C:16]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:39][N:40]1[C:48]2[C:43](=[CH:44][C:45](B(O)O)=[CH:46][CH:47]=2)[CH:42]=[N:41]1.C(OCC)(=O)C>O>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:30]([CH3:31])=[CH:29][C:18]2[N:19]=[C:20]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([C:45]4[CH:44]=[C:43]5[C:48](=[CH:47][CH:46]=4)[N:40]([CH3:39])[N:41]=[CH:42]5)[CH:27]=3)[S:21][C:17]=2[C:16]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: Cn1ncc2cc(B(O)O)ccc21
Reactant: Cc1cc2nc(-c3cncc(Br)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc2nc(-c3cncc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 115 °C

Procedure:
(S)-2-(2-(5-bromopyridin-3-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate was telescoped into the subsequent reaction. 1-Methyl-1H-indazol-5-ylboronic acid (0.024 g, 0.14 mmol) was added to the one-half of the previous reaction mixture and reaction heated in microwave at 115° C. for 30 minutes. Reaction mixture was portioned between ethyl acetate and H2O, the organic layer removed and concentrated to give (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)ethyl pivalate. LCMS-ESI+: calc'd for C38H40ClN4O3S: 667.2 (M+H+); found: 667.3 (M+H+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10](=[O:17])[NH:9][C:8]2[CH:18]=[CH:19][CH:20]=[N:21][C:7]1=2)=[O:5].[CH2:22]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C)C>[CH2:22]([N:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][C:4]([N:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[C:10](=[O:17])[NH:9][C:8]3[CH:18]=[CH:19][CH:20]=[N:21][C:7]2=3)=[O:5])[CH2:31][CH2:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCCl)c2ccccc21
Solvent: CC(C)O
Product: O=C1Nc2cccnc2N(C(=O)CCN2CCN(Cc3ccccc3)CC2)c2ccccc21
Yield: 78 %

Procedure:
A mixture of 8.0 g of 11-(3-chloropropionyl)-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one and 30 ml of 1-benzyl-piperazine in 100 ml of isopropanol was refluxed for 1 hour. Then, the mixture was evaporated in vacuo to dryness and the residue was treated with sodium hydroxide solution. The base was extracted therefrom with chloroform and the chloroform extract was distilled to dryness. The residue was crystallized from xylene to obtain a 78% yield of 11-[3-(4-benzyl-1-piperazinyl)-propionyl]-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one with a melting point of 205°-207° C. The dihydro chloride salt of the acid base melted at 212°-214° C. after crystallization from methanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:18][CH2:17]2)[C@H:13]([O:24][Si](C(C)(C)C)(C)C)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]2([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]2)[C@H:13]([OH:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2O)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
1-Benzyloxycarbonyl-3-(S)-tert-butyldimethylsilyloxy-4-(R)-(1-ethoxycarbonylcyclopropyl)pyrrolidine (1.79 g, 4.00 mmol) was dissolved in tetrahydrofuran (40 ml) to which, cooled in an ice bath, was subsequently added dropwise a tetrahydrofuran solution of 1.0 M tetrabutylammonium fluoride (5.33 ml, 5.33 mmol). The reaction solution was stirred at room temperature for 30 minutes and then tetrahydrofuran was evaporated under reduced pressure. Thereafter, the resulting residue was subjected to flash silica gel chromatography and eluted with an eluant of n-hexane:ethyl acetate=1:1, to thereby obtain 1.04 g (76%) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3]O.P(Br)(Br)[Br:13]>CCOCC>[F:1][C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][Br:13]
Reactant: BrP(Br)Br
Reactant: OCC(F)=Cc1ccccc1
Solvent: CCOCC
Product: FC(=Cc1ccccc1)CBr
Reaction time: 2 h

Procedure:
To the above alcohol (1.27 g, 8.34 mmol) in 50 ml ether at 0° under nitrogen is added phosphorus tribromide (2.25 g, 8.31 mmol). The reaction mixture is stirred about 2 hours as followed by TLC. The reaction mixture is worked up by pouring onto ice, then extracting with ether/water. The aqueous layer is extracted with ether. The combined ether phases are washed with water and brine, dried (Na2SO4) and evaporated to yield 2-fluoro-3-phenyl-2-propen-1-yl bromide.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH2:12][C:13]([O:15]CC)=[O:14])=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([O:33]C)=[O:32])=[CH:21][CH:20]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].Cl.C(=O)(O)[O-:37].[Na+].C(O)(=O)C>O>[CH2:1]([C:5]1[N:6]=[C:7]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([OH:33])=[O:32])=[CH:21][CH:20]=2)[C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:9]([OH:37])[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CC(=O)OCC)c(Cc2ccc(-c3ccccc3C(=O)OC)cc2)n1
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCc1nc(O)c(CC(=O)O)c(Cc2ccc(-c3ccccc3C(=O)O)cc2)n1
Reaction time: 0.5 h

Procedure:
50 mg of the product of Example 7 were introduced into 1 ml of 6N hydrochloric acid and the mixture was heated to gentle reflux. The mixture was stirred for 2 hours 30 minutes and after cooling, the mixture was diluted with 2 ml of water. The pH was adjusted to 7-8 by the addition of sodium bicarbonate, then returned to pH 5-4 by the addition of acetic acid. The mixture was stirred for approximately 30 minutes, followed by separating, and rinsing with water to obtain 30 mg of the expected product melting approx. 220° C.
Reaction SMILES: NC1C=CC=C2C=1C(=O)NCC2.[NH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[C:22](=[O:24])[NH:21][CH2:20][C:19]2(C)[CH3:25]>>[NH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[C:22](=[O:24])[NH:21][CH2:20][CH:19]2[CH3:25]
Reactant: CC1(C)CNC(=O)c2c(N)cccc21
Agent: Nc1cccc2c1C(=O)NCC2
Product: CC1CNC(=O)c2c(N)cccc21

Procedure:
8-amino-3,4-dihydro-2H-isoquinolin-1-one and 8-amino-4,4-dimethyl-3,4-dihydro-2H-isoquinolin-1-one and the following compounds are prepared analogously to this method.