Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.Cl.C(OCC)(=O)C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCCOc2ccc(Br)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Brc1ccc(OCCCN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.3 %

Procedure:
To a mixture of tert-butyl 4-(3-(4-bromophenoxy)propyl)piperazine-1-carboxylate (200 mg, 0.50 mmol) in ethyl acetate (10 mL) was added HCl/ethyl acetate (20 mL). The mixture was stirred at rt for 4 hours. The mixture was concentrated to give the title compound (150 mg, 100% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.[N:10]12CCN(CC1)C[CH2:11]2.O>C(#N)C.[C-]#N.C([N+](CC)(CC)CC)C>[CH3:9][O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([C:11]#[N:10])[CH:7]=1
Reactant: COc1cc(Cl)ncn1
Reactant: C1CN2CCN1CC2
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CC#N
Solvent: O
Product: COc1cc(C#N)ncn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of 4-chloro-6-methoxypyrimidine (10.6 g) in acetonitrile (150 mL) was added 1,4-diazabicyclo[2.2.2]octane (8.18 g), and the mixture was stirred at room temperature for 10 min. Tetraethylammonium cyanide (11.5 g) was added to the obtained reaction mixture, and the mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (6.00 g) as a pale-yellow oil.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=2[CH:9]=O)=[N:3]1.OS(O)(=O)=O.O.[NH2:24]N.C([O-])(O)=O.[Na+]>C(O)(=O)C.O.C(O)C>[CH3:16][O:15][C:12]1[CH:11]=[C:8]2[C:7](=[CH:14][CH:13]=1)[C:4](=[O:5])[NH:3][N:24]=[CH:9]2
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C=O)c1
Reactant: NN
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1ccc2c(=O)[nH]ncc2c1
Reaction time: 4 h
Yield: 72.8 %

Procedure:
A solution of 2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-benzaldehyde (2 g, 8.58 mmoles), prepared as described in example 2, in 30 ml of a mixture of water (5 ml), ethanol (50 ml) and concentrated H2SO4 (4 ml) up to 100 ml with ethanol, was stirred under reflux for 20 hours, then concentrated to small volume, taken up in water, extracted with ethyl ether and the organic phase was washed with water, anhydrified and brought to dryness. The resultant oil was dissolved in acetic acid (14 ml) and dropwise added, under N2, with hydrazine monohydrate (1.25 ml, 25.7 mmoles) dissolved in acetic acid (6 ml). The mixture was stirred for 3.5 hours at room temperature, then at 80° C. for 4 hours, then cooled, brought to almost complete dryness, taken up in water, neutralised with NaHCO3, extracted more times with CH2Cl2. The organic phases were washed with water, anhydrified and concentrated. The residue was triturated in CH2Cl2 (10 ml) and filtered to give 1.1 g of the title compound (yield: 73.4%). m.p.: 200-205° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][N:3]=1.[OH:9][S:10](O)(=[O:12])=[O:11].O=S(=O)=O>CO.CC(C)=O>[OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:10]([OH:12])(=[O:11])=[O:9])=[CH:4][N:3]=1
Reactant: O=S(=O)(O)O
Reactant: Oc1ccnc(O)c1
Agent: O=S(=O)=O
Solvent: CO
Solvent: CC(C)=O
Product: O=S(=O)(O)c1cnc(O)cc1O
Temperature: -50 °C

Procedure:
5 g of 2,4-dihydroxypyridine are slowly added, at a temperature in the region of -10° C., to 12.5 cm3 of sulfuric oleum containing 20% SO3 and containing 250 mg of HgSO4. After having left to return to ordinary temperature, the mixture is progressively brought to 150° C. and then maintained at this temperature for 16 hours. The mixture is poured onto a MeOH/acetone (50/50) mixture cooled to around -50° C. A beige precipitate is formed which is recrystallized from the same MeOH/acetone mixture.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23](Cl)[N:22]=3)[CH:16]=2)[CH2:10][CH:9]1[CH2:28][CH:29]([CH3:31])[CH3:30])=O)(C)(C)C.[NH2:32][CH2:33][CH2:34][C:35]1[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=1>>[CH2:28]([C@@H:9]1[NH:8][CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]3[CH:26]=[CH:25][N:24]=[C:23]([NH:32][CH2:33][CH2:34][C:35]4[CH:40]=[CH:39][C:38]([OH:41])=[CH:37][CH:36]=4)[N:22]=3)[CH:18]=[CH:19][CH:20]=2)[CH2:10]1)[CH:29]([CH3:30])[CH3:31]
Reactant: CC(C)CC1CN(Cc2cccc(-c3ccnc(Cl)n3)c2)CCN1C(=O)OC(C)(C)C
Reactant: NCCc1ccc(O)cc1
Product: CC(C)C[C@H]1CN(Cc2cccc(-c3ccnc(NCCc4ccc(O)cc4)n3)c2)CCN1

Procedure:
Intermediate 113 was coupled with tyramine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 447. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.65 (s, 1H), 8.36 (d, 1H), 8.32 (s, 1H), 7.95 (d, 1H), 7.71 (t, 1H), 7.65 (d, 1H), 7.11 (d, 1H), 6.68 (s, 1H), 4.70 (d, 1H), 4.57 (d, 1H), 3.96 (m, 2H), 3.81 (m, 2H), 3.58 (m, 4H), 3.40 (t, 1H), 2.92 (t, 2H), 1.75 (m, 1H), 1.62 (t, 2H), 1.00 (d, 3H), 0.98 (d, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]1([C@@H:13]([N@@:15]2[CH2:17][CH:16]2[C:18](OC)=[O:19])[CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1([C@@H]([N@]2CC2C(OC)=O)C)C=CC=CC=1.[OH-].[K+]>C1COCC1>[C:7]1([C@@H:13]([N@:15]2[CH2:17][CH:16]2[CH2:18][OH:19])[CH3:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: COC(=O)C1C[N@]1[C@@H](C)c1ccccc1
Agent: COC(=O)C1C[N@@]1[C@@H](C)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)[N@]1CC1CO
Temperature: 0 °C
Yield: 90 %

Procedure:
A 250 mL round bottom flask was charged with anhydrous THF (100 mL) and LiAlH4 (2.77 g, 73.1 mmol). While the suspension is stirred at 0° C., a solution of (S)-methyl 1-((S)-1-phenylethyl)aziridine-2-carboxylate EBE 06044B (10.0 g, 48.7 mmol) in THF (50 mL) was added dropwise over 20 min. The dropping funnel was washed with THF (2×3 mL) and allowed to react 20 min at 0° C. Maintaining the reaction mixture at 0° C., a solution of KOH (10%, 20 mL) was added dropwise for 20 min (caution the reaction is exothermic). The mixture was stirred for 0.5 h at 25° C. and the white precipitate removed by filtration through a celite pad that was washed with diethyl ether (30 mL). The combined organic filtrates were washed with NaH2PO4 and the aqueous layer was extracted with Et2O (3×30 mL). The combined organic phase were dried with Na2SO4 and concentrated to give ((R)-1-((S)-1-phenylethyl)aziridin-2-yl)methanol EBE 06046 as a white solid (10.4 g, 90% yield).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=4[C:18]([CH3:21])([CH3:20])[O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2].[N+:26]([O-])([OH:28])=[O:27]>C(O)(=O)C>[C:1]([C:4]1[O:5][C:6]2[C:14]([Cl:15])=[CH:13][C:12]3[C:16]4[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:17]=4[C:18]([CH3:21])([CH3:20])[O:19][C:11]=3[C:7]=2[C:8](=[O:10])[CH:9]=1)([OH:3])=[O:2]
Reactant: CC1(C)Oc2c(cc(Cl)c3oc(C(=O)O)cc(=O)c23)-c2ccccc21
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC1(C)Oc2c(cc(Cl)c3oc(C(=O)O)cc(=O)c23)-c2ccc([N+](=O)[O-])cc21

Procedure:
1.6 gm (4.5 millimols) of 2-carboxy-4-oxo-6,6-dimethyl-12-chloro-4H,6H-[2]-benzopyrano-[3,4-f]-[1]-benzopyran (see Example 6) were stirred for 24 hours in a mixture of 35 ml of acetic acid and 5 ml of fuming nitric acid. The yellow precipitate formed thereby was filtered off and recrystallized from methanol/acetone. 1.5 gm (83.3% of theory) of the compound named in the heading, m.p. 278°-279° C, were obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7]([OH:11])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OC1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 145.9 %

Procedure:
A suspension of 5-bromo-2,3-dihydro-1H-inden-1-one (2.07 g, 9.81 mmol) in ethanol (49 mL) was treated with the sodium borohydride (186 mg, 4.90 mmol) all at once. After a few minutes, the solution warmed slightly and all solids dissolved. After stirring at room temperature for 1 h, the mixture was concentrated in vacuo to remove ethanol. The gum obtained was partitioned between ethyl acetate and water. The organic layer was extracted with saturated sodium bicarbonate solution (2×) and saturated sodium chloride solution. Drying (Na2SO4) and concentration in vacuo afforded the title compound (3.05 g, 98%) as a colorless oil, which crystallized upon pumping under high vacuum overnight.
Reaction SMILES: [NH2:1][C:2](=[O:16])/[C:3](/[C:14]#[N:15])=[N:4]/[NH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[Br:13].[Al+3].[Cl-].[Cl-].[Cl-].C1(C)C=CC=CC=1.Cl>CCO>[NH2:15][C:14]1[C:11]2[C:6](=[C:7]([Br:13])[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[N:4][C:3]=1[C:2]([NH2:1])=[O:16]
Reactant: N#C/C(=N\Nc1cc(F)ccc1Br)C(N)=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: NC(=O)c1nnc2c(Br)ccc(F)c2c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15 %

Procedure:
(E)-2-Amino-N′-(2-bromo-5-fluorophenyl)-2-oxoacetohydrazonoyl cyanide (10 g, 35 mmol), AlCl3 (20 g, 4.0 eq), and toluene (200 mL) were stirred at 120° C. overnight under N2. The reaction mixture was subsequently cooled to 0° C. and 2N HCl (200 mL) was added. The reaction mixture was stirred at 0° C. for 10 minutes and then filtered to afford a crude solid (4.5 g), which was dispersed in EtOH (500 mL). The mixture was stirred at RT for 4 hours and filtered. The filtrate was concentrated to give the title compound (1.5 g, 15%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.72 (1H, s), 8.62 (1H, s), 8.23-8.20 (1H, m), 8.00 (1H, s), 7.80 (1H, s), 7.47-7.42 (1H, m); LC-MS (5-95% ACN in H2O gradient with 0.02% NH4OAc, tR 3.020 minutes) ESI+APCI m/z [M+H]+ 285.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11]1([O:17][P:18]([CH2:27][NH:28][C@@H:29]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:41][CH:40]=2)[C:30]([NH:32][CH2:33][CH2:34][C:35](O)=[O:36])=[O:31])([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.CN(CCCN=C=NCC)C.C(OCC)(=O)C>C(Cl)Cl.CN(C1C=CN=CC=1)C.O>[C:11]1([O:17][P:18]([CH2:27][NH:28][C@@H:29]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)=[CH:43][CH:44]=2)[C:30]([NH:32][CH2:33][CH2:34][C:35]([O:10][C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[CH2:1][CH2:2][CH2:3]3)=[O:36])=[O:31])([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Oc1ccc2c(c1)CCC2
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1)Oc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Indanol (52.9 mg, 0.394 mmol) is added in one portion to a solution of (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (200 mg, 0.394 mmol) in methylene chloride (25 ml). 4-(N,N-Dimethylamino)pyridine (48.1 mg, 0.394 mmol) is added followed by N-dimethylaminopropyl-N'-ethylcarbodiimide hydrochloride (151 mg, 0.788 mmol). The solution is stirred at room temperature for 3 hours. Ethyl acetate (60 mL) and water (15 mL) are added. The organic layer is subsequently washed with a saturated solution of sodium bicarbonate (2×15 mL), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel, eluting with ethyl acetate-hexane (1:1). Evaporation of the pure fraction yields 5-indanyl (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate, as a thick colorless oil that can be crystallized from ether, m.p. 89°-91°.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH:20][C:22]4[CH:23]=[C:24]([NH:28][C:29](=[O:31])[CH3:30])[CH:25]=[CH:26][CH:27]=4)[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Reactant: CC(=O)Nc1cccc(Br)c1
Product: CC(=O)Nc1cccc(Nc2nc3c(-c4ccc(S(C)(=O)=O)cc4)cccn3n2)c1

Procedure:
N-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-acetamide was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (70.6 mg, 0.245 mmol) and N-(3-bromo-phenyl)-acetamide (52.4 mg, 0.245 mmol) in a manner analogous to Example 2d. Product isolated as a white lyophilate (19 mg, 18%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.89 (s, 1H), 9.77 (s, 1H), 8.83 (d, J=6.5 Hz, 1H), 8.46 (d, J=8.4 Hz, 2H), 8.07 (d, J=8.6 Hz, 2H), 7.99-7.95 (m, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.21-7.12 (m, 3H), 3.29 (s, 3H), 2.06 (s, 3H). MS=422 (MH)+.
Reaction SMILES: C[O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:18][CH2:19][C:20]([O:22]CC)=[O:21])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5](=[O:25])[CH:4]=1>CO.[OH-].[Na+]>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][C:6]1([O:18][CH2:19][C:20]([OH:22])=[O:21])[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3](=[O:2])[CH2:4][C:5]1=[O:25]
Reactant: CCOC(=O)COC1(CCC(C)C)C(=O)C=C(OC)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CCC1(OCC(=O)O)C(=O)CC(=O)c2ccccc21
Yield: 90.6 %

Procedure:
A solution of Example 40A (30 mg, 0.087 mmol) in methanol (0.2 mL) and 1 N NaOH (0.2 mL) was stirred at 25° C. for 16 hours. The methanol was evaporated. The resulted solution was acidified with 1N HCl to pH 3, extracted with ethyl acetate, dried (Na2SO4), and filtered. The filtrate was concentrated in vacuo to afforded the title compound (24 mg, 91%) and used for the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.35-0.49 (m, 1H,) 0.69 (dd, J=13.05, 6.43 Hz, 6H), 0.77-0.96 (m, 1H), 1.24-1.36 (m, 1H), 1.83-1.94 (m, 1H), 2.04-2.22 (m, 1H), 3.18 (d, 1H), 3.67 (d, J=15.44 Hz, 1H), 5.76 (s, 1H), 7.45-7.55 (m, 1H), 7.59-7.73 (m, 2H), 7.90 (d, J=7.72 Hz, 1H), 11.83-12.71 (br. s, 1H); MS (ESI) m/z 304.9 (M+H)+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:12]=[N:13][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][CH2:18]3)=[CH:15][CH:16]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)nc(Nc2ccc(N3CCN(C4COC4)CC3)nc2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc(N4CCN(C5COC5)CC4)nc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 197e (200 mg, 0.48 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (364 mg, 0.95 mmol), PdCl2(dppf) (40 mg, 0.049 mmol), K3PO4 3H2O (250 mg, 0.95 mmol), sodium acetate (80 mg, 0.95 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 80° C. for 3 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 1:20 methanol/dichloromethane to afford 197f as a red solid (230 mg, 70%). MS-ESI: [M+H]+ 680
Reaction SMILES: Cl.[NH2:2][OH:3].N1C=CC=CC=1.[C:10]([O:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[CH:25]=O)([CH3:13])([CH3:12])[CH3:11]>C(O)C>[C:10]([O:14][C:15](=[O:27])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[CH:25]=[N:2][OH:3])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)C=Cc1ccc(O)cc1C=NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.5 %

Procedure:
A slurry of hydroxylamine hydrochloride (8.33 g, 0.12 mol), pyridine (9.49 g, 0.12 mol), and ethanol (100 mL) was stirred at ambient temperature for 30 min. 3-(2-Formyl-4-hydroxy-phenyl)-acrylic acid tert-butyl ester (14.90 g, 0.06 mol) was added followed by an ethanol (49 mL) rinse. The resulting brown solution was stirred at ambient temperature for 16 h and concentrated. The residue was suspended in water (150 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with saturated NaCl solution (2×100 mL), dried (Na2SO4), and filtered through a plug of silica gel to remove trace polar impurities. The filtrate was concentrated to give crude product (16.04 g). A 13.56 g sample of the crude material was crystallized from heptane (70 mL) and ethyl acetate (80 mL) to the title compound (7.41 g, 55%), mp 146-149° C. 1H NMR (CD3OD): δ 1.53 (s, 9H), 4.83 (s, 2H), 6.15-6.23 (d, 1H), 6.82-6.87 (dd, 1H), 7.10-7.12 (d, 1H), 7.52-7.55 (d, 1H), 7.98-8.03 (d, 1H), 8.37 (s, 1H). MS (ES+) m/z 286.1 ([M+Na]+). MS (ES−) m/z 262.2 ([M−H]−). Anal. Calculated for C14H17NO4: C: 63.8658; H: 6.5081; N: 5.3198. Found: C: 63.71; H: 6.38; N: 5.51.
Reaction SMILES: [CH:1]1([NH2:13])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1.C(=O)([O-])[O-].[K+].[K+].C(O)C.[I-].C([N+]1(C)[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)C>O>[CH:1]1([N:13]2[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]2)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH2:6][CH2:5][CH2:4][CH:3]3[CH2:2]1
Reactant: NC1CC2CCCc3cccc1c32
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C1CCN(C2CC3CCCc4cccc2c43)CC1
Yield: 14 %

Procedure:
To a mixture of 1,2,2a,3,4,5-hexahydroacenaphthylen-1-ylamine, potassium carbonate (3.89 g) and ethanol (60 ml) was added 1-ethyl-1-methyl-4-oxopiperidinium iodide (8.36 g) dissolved in water (15 ml), and the mixture was heated under reflux for 2 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 1-(1,2,2a,3,4,5-hexahydroacenaphthylen-1-yl)piperidin-4-one (1.01 g, 14%) as an oil.
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH2:4][C:3]1([CH3:18])[CH3:17].[OH-].[Na+].Cl>O.CO>[OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH2:4][C:3]1([CH3:18])[CH3:17]
Reactant: CCOC(=O)COC1CC(C)(C)N(O)C(C)(C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CC(OCC(=O)O)CC(C)(C)N1O
Reaction time: 1 h

Procedure:
1.0 g (39 mmol) of the compound of Example 6 is added to a solution of 0.2 g sodium hydroxide in 20 mL of 1:1 water/methanol. The mixture is stirred for one hour, carefully acidified with 1% aqueous hydrogen chloride and then extracted with ethyl acetate. The organic extract is dried over anhydrous magnesium sulfate and then contentrated to afford the title compound as an orange solid.
Reaction SMILES: [Br: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]=[C:5]2[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(N(CC)CC)C.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>ClCCl>[Br: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]=[C:5]2[CH:14]1[CH2:15][CH2:16][N:17]([S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:18][CH2:19]1
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(Br)cc2c(C3CCNCC3)n[nH]c12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reaction time: 2 h
Yield: 31.5 %

Procedure:
The crude 5-bromo-3-(4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 6) (1.23 mmol) was suspended in dichloromethane (20 mL) and treated with triethyl amine (0.856 mL, 6.15 mmols), and ethane sulfonyl chloride (0.175 mL, 1.85 mmols) at 0° C. After 2 hrs, the mixture was concentrated to dryness in vacuo at ambient temperature, treated with water (25 mL), and extracted with dichloromethane (100 mL). The organic phase was washed with water, dried over MgSO4, filtered, and concentrated to give a light brown solid. This was purified by combiflash (column 10 g, eluting with 100% dichloromethane, 5% ethyl acetate/dichloromethane, 30% ethyl acetate/dichloromethane) to give the title compound (0.161 g, 32%).
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[NH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]>>[C:1]([NH:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)Cl
Reactant: NCCC(=O)O
Product: C=CC(=O)NCCC(=O)O

Procedure:
This amide monomer was prepared from acryloyl chloride and beta-alanine per Example 1 procedure, with the recrystallized (ethyl acetate solvent) product having a melting point of 97°-99° C.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-[1-Benzyl-2-(4-hydroxy-piperidin-1-yl)-2-oxo-ethyl]-carbamic acid tert-butyl ester (3.66 g, 10.5 mmol) was dissolved in 4M HCl-dioxane (39 mL) at 0° C. The mixture was stirred at 25° C. for 1 hour, concentrated and the residue triturated with ether. Yield 3.06 g, 102%.