Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:14]=[O:15].[OH-].[K+].Cl.[CH3:31]O>O>[Cl:10][C:11]1[CH:12]=[C:13]([CH2:14][O:15][C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[N:1]([CH3:31])[CH:2]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(OCc2ccc(Cl)cc2)c(Cl)c1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(OCc2ccc(OCc3ccc(Cl)cc3)c(Cl)c2)c2cccnc21
Temperature: 50 °C

Procedure:
1H-Pyrrolo[2,3-b]pyridine (94, 0.3 g, 2.8 mmol) was mixed with 3-chloro-4-(4-chloro-benzyloxy)-benzaldehyde (558, 0.8 g, 3 mmol), potassium hydroxide (0.9 g, 17 mmol) and methanol (90.0 mL). The reaction was heated to 50° C. under an atmosphere of nitrogen for six days. After neutralization with 6N hydrochloric acid the reaction was poured into water, extracted with ethyl acetate, and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (ethyl acetate: hexanes) to give a yellow solid (559, 0.6 g, 41%). MS(ESI) [M+H+]+=413.2, 415.2 [M−H+]−=411.1, 413.1.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])[CH:14]([CH3:16])[CH3:15].[CH3:21][O:22][C:23]1[C:31]([CH3:32])=[C:30]2[C:26]([C:27](=[O:33])[O:28][CH2:29]2)=[C:25]([O:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[C:24]=1[CH2:41]/[CH:42]=[C:43](\[CH3:46])/[CH:44]=[O:45].[NH4+].[Cl-]>C1COCC1>[CH3:40][O:39][CH2:38][CH2:37][O:36][CH2:35][O:34][C:25]1[C:24]([CH2:41]/[CH:42]=[C:43](\[CH3:46])/[CH:44]([OH:45])[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH2:19][CH3:20])=[O:17])=[C:23]([O:22][CH3:21])[C:31]([CH3:32])=[C:30]2[C:26]=1[C:27](=[O:33])[O:28][CH2:29]2
Reactant: CCOC(=O)C(C)C
Reactant: COCCOCOc1c(C/C=C(\C)C=O)c(OC)c(C)c2c1C(=O)OC2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)(C)C(O)/C(C)=C/Cc1c(OC)c(C)c2c(c1OCOCCOC)C(=O)OC2
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87 %

Procedure:
Freshly distilled diisopropylamine (0.425 ml) was dissolved in anhydrous THF (10 ml) and cooled to 0° C. n-BuLi (0.63 ml, 2.35M) was added slowly and the reaction was stirred at 0° C. for 20 minutes and cooled to -78°. Ethyl isobutyrate (0.200 ml) was added and the resulting solution was stirred at -78° C. for 40 minutes. A solution of (E)-4-(1,3-dihydro-6-methoxy -4-methoxyethoxymethoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2-methylbut-2-enaldehyde (365 mg) in THF (10 ml) was added and stirred for 30 min. The reaction mixture was poured to a concentrated solution of NH4Cl, and extracted with ethyl acetate (3×30 ml), the organic layers were dried over Na2SO4, and evaporated to give 420 mg (87%) of ethyl (E)-6-(1,3-dihydro-4-methoxyethoxymethoxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl) -2,2,4-trimethyl-3-hydroxy-4-hexenoate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([F:19])[CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C(OCC)C>N1C=CC=CC=1>[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26]([O:13][CH2:12][CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][C:4]3[CH:3]=[C:2]([F:1])[CH:18]=[C:17]([F:19])[CH:16]=3)=[CH:15][CH:14]=2)(=[O:28])=[O:27])=[CH:22][CH:21]=1
Reactant: OCCOc1ccc(Oc2cc(F)cc(F)c2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(Oc3cc(F)cc(F)c3)cc2)cc1
Temperature: -20 °C
Yield: 92.8 %

Procedure:
To a solution of 2-[4-(3,5-difluorophenoxy)phenoxy]ethanol (2.66 g, 10.0 mmol) in pyridine (2.8 g), p-toluenesulfonyl chloride (1.91 g, 10.0 mmol) was gradually added with stirring while cooling at -20° C., and the resultant mixture was allowed to stand in a refrigerator overnight. Diethyl ether was added to the reaction mixture, which was washed with dilute hydrochloric acid until the aqueous layer became acidic, followed by washing with an aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution. The obtained ether layer was dried over anhydrous magnesium sulfate, and the solvent was removed to give 2-[4-(3,5-difluorophenoxy)phenoxy]ethyl p-toluenesulfonate (3.90 g).
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=3)[CH:20]=2)[O:7][C@@H:6]1[CH2:36][O:37]C(=O)C)(=O)C.O.[OH-].[Li+]>O1CCCC1.CO.O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:36][OH:37])[O:7]2)=[CH:20][C:21]=1[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([C:33](=[O:35])[CH3:34])=[CH:29][CH:28]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(C(C)=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.3 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(3-(4-acetylbenzyl)-4-chlorophenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (95 mg, 0.17 mmol) in a mixture of tetrahydrofuran/methanol/water (2.4 mL, 2:3:1) was added lithium hydroxide monohydrate (11.2 mg, 0.27 mmol). After stirring overnight at RT, volatiles were removed under reduced pressure. The residue was partitioned between water and ethyl acetate (3×), and the combined organic phases were washed with brine, dried over sodium sulfate, and concentrated to give crude product 48 (68 mg), which was used in the next step without further purification. MS ESI: 407 [M+H]+, 451 [M+HCO2]−.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OC=[C:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16]>>[C:11]1(=[O:16])[C:10]2[NH:1][C:2]3[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:15]=2[CH2:14][CH2:13][CH2:12]1
Reactant: Nc1ccccc1
Reactant: O=C1CCCCC1=CO
Product: O=C1CCCc2c1[nH]c1ccccc21

Procedure:
2,3,4,9-Tetrahydro-1H-carbazol-1-one was prepared from aniline and 2-(hydroxymethylene)cyclohexanone in a similar manner as described in Example 1 to give a brown solid. 1H-NMR (DMSO-d6): δ 11.6 (s, 1H), 7.66 (d, 1H), 7.38 (d, 1H), 7.30 (t, 1H), 7.07 (t, 1H), 2.90 (t, 2H), 2.56 (t, 2H), 2.15 (quint, 2H); MS m/z 186 (M+1).
Reaction SMILES: [OH:1][C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:33]([NH:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:34]>CN(C)C=O>[CH2:33]([N:35]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:2]([C@@H:4]1[CH:19]=[C:18]2[C@@H:8]([CH2:9][C:10]3[C:20]4[C:13](=[CH:14][CH:15]=[CH:16][C:17]2=4)[NH:12][CH:11]=3)[N:6]([CH3:7])[CH2:5]1)=[O:1])[CH3:34]
Reactant: CCNCCC(=O)OCC
Reactant: CN1C[C@H](C(=O)O)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(CC)C(=O)[C@@H]1C=C2c3cccc4[nH]cc(c34)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of lysergic acid 5 (934 mg, 3.27 mmol) in 40 ml of dry dimethylformamide (DMF) was treated with 1,1′-carbonydidimidazole (CDI, 795 mg, 4.91 mmol) and stirred under nitrogen at room temperature for 1 hour. The N-ethyl N-(2-carbethoxy)ethyl amine linker 10 (1.90 g, 13.08 mmol) in 10 ml of dry dimethylformamide (DMF) was added dropwise and the reaction solution was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in 200 ml of chloroform. The chloroform solution was washed twice with 100 ml of water, dried over anhydrous sodium sulphate, and concentrated under reduced pressure to yield the crude title compound 6 (2.2 g) as an oil. This was used without further purification in the following Example. υmax/cm−1 3121.90, 2987.10, 2848.65, 1735.30, 1676.97, 1202.97 (FT-IR: FIG. 9)
Reaction SMILES: [F:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[O:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:17]([Br:18])=[CH:16][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2cc(F)c(Br)cc2n1C1CCNCC1
Reactant: O=C1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1[nH]c2cc(F)c(Br)cc2n1C1CCN(C2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of fluoro-6-bromo-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (D46) (50 mg, 0.16 mmol), tetrahydro-4H-pyran-4-one (112 mg, 1.12 mmol) and triethylamine (49 mg, 0.48 mmol) in dichloromethane (5 ml) under argon was added portionwise sodium triacetoxyborohydride (240 mg, 1.12 mmol). The mixture was stirred at room temperature for 24 hrs, diluted with dichloromethane (5 ml) washed with 0.5N sodium hydroxide solution, dried (MgSO4) and concentrated in approx half volume before adding to a silica gel column which was subsequently eluted with 2-20% methanol in dichloromethane to afford 5-fluoro-6-bromo-1-[1-(tetrahydro-2H-pyran-4-yl)-4-piperidinyl]-1,3-dihydro-2H-benzimidazol-2-one. The isolated product was converted to the hydrochloride salt which was obtained as a colourless solid, 34 mg, 49%. MH+=398, and 400, 1H NMR (HCl salt) (DMSO-d6) δ: 1.24 (2H, m), 1.73 (3H, m), 1.89 (2H, m), 2.03 (2H, m), 2.83 (2H, m), 3.17 (2H, m), 3.58 (2H, m), 3.76 (1H, m), 4.59 (2H, m) 7.04 (1H, d, J=8 Hz), 7.94 (1H, d, J=5 Hz), 10.89 (1H, bs) and 11.32 (1H, s).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:21][C@@H:22]([C:25]1[CH:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1)[CH2:23][OH:24].C(N(CC)C(C)C)(C)C>C(#N)C>[OH:24][CH2:23][C@@H:22]([NH:21][C:2]1[C:3]2[CH2:11][N:10]([C:12]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:13]=3[C:14]#[N:15])[CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:25]1[CH:26]=[N:27][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:29][CH:30]=1
Reactant: N[C@H](CO)c1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(N2CCc3ncnc(Cl)c3C2)c(C#N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(N2CCc3ncnc(N[C@H](CO)c4ccc(C(F)(F)F)nc4)c3C2)c(C#N)c1

Procedure:
A reaction mixture of 2-(4-chloro-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)-5-methylbenzonitrile (160 mg, 0.56 mmol) and (S)-2-amino-2-(6-(trifluoromethyl)pyridin-3-yl)ethanol (118 mg, 0.57 mmol) (prepared similarly according to the method for Intermediate 10) in acetonitrile (2 mL) and N,N-diisopropylethylamine (0.4 mL) was subjected to microwave irradiation at 185° C. for 3.5 h. The reaction mixture was concentrated and the residue was purified by semi-preparative HPLC (100×20.2 mm, C18 column; 40-60% acetonitrile-water [10 mM diethylamine]) to yield a light brown solid.
Reaction SMILES: [CH2:1]([N:4]([C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[C:20]([C:25](=[O:37])[NH:26][CH2:27][C:28]2[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=2[CH3:34])[C:19]=1[CH3:38])[CH:5]1[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[CH2:1]([N:4]([CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[C:18]1[C:19]([CH3:38])=[C:20]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[C:25]([NH:26][CH2:27][C:28]1[C:29](=[O:36])[NH:30][C:31]([CH3:35])=[CH:32][C:33]=1[CH3:34])=[O:37])[CH:2]=[CH2:3].[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]
Reactant: C=CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCN(c1cc(Cl)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A stirred solution of compound tert-butyl 4-(allyl (5-chloro-3-(((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamoyl)-2-methylphenyl)amino)piperidine-1-carboxylate (0.2 g, 0.36 mmol) in DCM (5 mL) was cooled to 0° C. and TFA (0.5 mL) was added. The mixture was stirred at room temperature for 18 h. and concentrated to dryness. The residue was washed with diethyl ether and then purified by preparative HPLC to afford the title compound as TFA salt (0.06 g, 37%). LCMS: 443.25 (M+1)+; HPLC: 97.14% (@ 254 nm) (Rt; 5.074; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.38 (bs, 1H), 8.21 (t, 1H), 8.05 (d, 1H), 7.21 (d, 1H, J=4.4 Hz), 6.97 (d, 1H, J=1.6 Hz), 5.86 (s, 1H), 5.56-5.64 (m, 1H), 4.97-5.09 (m, 2H), 4.24 (d, 2H, J=4.4 Hz), 3.62 (d, 2H, J=5.2 Hz), 3.23 (m, 2H), 3.10-3.16 (m, 1H), 2.85-2.88 (m, 2H), 2.19 (s, 3H), 2.18 (s, 3H), 2.10 (s, 3H), 1.83-1.86 (m, 2H), 1.68-1.73 (m, 2H).
Reaction SMILES: C([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)=O.Cl.[F:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][NH2:29])=[CH:24][CH:23]=1>C(O)(=O)C>[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:28]([C:25]3[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=3)[N:29]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:11]=2)=[CH:6][CH:5]=1
Reactant: NNc1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(NC=O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccc(N)cc2)n(-c2ccc(F)cc2)n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
A mixture of ethyl 4-[4-(formylamino)phenyl]-2,4-dioxobutanoate (6 g) and 4-fluorophenylhydrazine hydrochloride (4.1 g) in acetic acid (30 ml) was stirred at 100° C. for 2 hours. The mixture was concentrated, and the residue was treated with 10% hydrochloric acid (10 ml) and methanol (40 ml) at 60° C. for 2 hours. The solvent was evaporated, and the residue was dissolved in water. The obtained solution was neutralized and extracted with ethyl acetate. The extract was washed with water, dried, and concentrated in vacuo. The residue was washed with ethanol to give crystals of ethyl 5-(4-aminophenyl)-1-(4-fluorophenyl)pyrazole-3-carboxylate (3.4 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[C:15]3[C:16](=[O:30])[N:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]=3[NH:13][N:12]=2)[CH:6]=[CH:7][CH:8]=1)#N.S(=O)(=O)(O)[OH:32].[OH2:36]>CS(C)=O>[C:1]([C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[C:15]3[C:16](=[O:30])[N:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[N:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:14]=3[NH:13][N:12]=2)[CH:6]=[CH:7][CH:8]=1)([OH:32])=[O:36]
Reactant: O
Reactant: N#Cc1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Reactant: O=S(=O)(O)O
Solvent: CS(C)=O
Product: O=C(O)c1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 28 %

Procedure:
To a solution of 3-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (300 mg, 0.77 mmol, prepared in Example 18) in DMSO (30 ml) was added 50% sulfuric acid (15 ml), and the mixture was heated under reflux overnight. The reaction mixture was admixed with water, and filtered to give precipitates which were dried to afford 3-[2-(3-carboxyphenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (87 mg, 28%).
Reaction SMILES: [CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.Cl>ClCCl>[CH2:1]([O:8][C@H:9]([CH3:13])[C:10]([NH:14][CH:15]1[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: C[C@@H](OCc1ccccc1)C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a dichloromethane solution (1000 ml) of (2R)-2-(benzyloxy)propionic acid (51.7 g) and tert-butyl 4-aminopiperidine-1-carboxylate (63.2 g) were added at room temperature 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (60.5 g) and 1-hydroxybenzotriazole monohydrate (42.7 g), followed by stirring overnight. The reaction solution was poured into a 0.5 N aqueous hydrochloric acid solution, and extracted with dichloromethane. The organic layer was washed sequentially with water, a saturated aqueous sodium hydrogen carbonate solution, water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to afford tert-butyl 4-{[(2R)-2-(benzyloxy)propanoyl]amino}piperidine-1-carboxylate (100 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][C@H:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13]C(C)(C)C)=O)[CH2:7]1)[CH3:2].O1CCOCC1.C(N(CC)[CH:29]([CH3:31])[CH3:30])(C)C.C1(C(Cl)=O)CC1>Cl.C(OCC)C.ClCCl>[CH:29]1([C:11]([N:8]2[CH2:9][CH2:10][C@H:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH2:7]2)=[O:13])[CH2:31][CH2:30]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)C[C@H]1CCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: C1COCCO1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C[C@H]1CCN(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
In a round bottom flask, a solution of 1,1-dimethylethyl (3R)-3-[2-(ethyloxy)-2-oxoethyl]-1-pyrrolidinecarboxylate (2.08 mmol) in 4M HCl in dioxane (10 mL, 40 mmol) was stirred at room temperature for 1 h. Analysis of an aliquot by LCMS confirmed complete removal of the BOC group from the starting material. The reaction was concentrated in vacuo to give a pale yellow liquid, which was dissolved in diethyl ether and concentrated to dryness in vacuo to yield a white solid. A solution of this intermediate as the HCl salt in dichloromethane (100 mL) was treated with N,N-diisopropylethylamine (4.16 mmol) and stirred for 5 min at room temperature. The yellow solution was treated with cyclopropanecarbonyl chloride (2.287 mmol) dropwise by syringe. The solution was allowed to warm to room temperature and stirred for 1 h. The reaction was diluted with dichloromethane (100 mL) and was washed with water, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as a yellow oil (quantitative). MS(ES)+ m/e 226.1 [M+H]+.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[O:42][C@H:8]([O:9][C@H:10]2[C@H:14]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C@@H:11]2[CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C@H:7]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C@H:6]1[O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(OCC)(=O)C>[CH2:54]([O:53][C@@H:7]1[C@@H:6]([O:61][CH2:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C@H:5]([OH:4])[C@@H:43]([CH2:44][O:45][CH2:46][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)[O:42][C@@H:8]1[O:9][C@H:10]1[C@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:13][N:12]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[C@@H:11]1[CH2:33][O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CC(=O)O[C@H]1[C@H](OCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H](O[C@@H]2[C@@H](COCc3ccccc3)N(C(=O)OCc3ccccc3)C[C@H]2OCc2ccccc2)O[C@@H]1COCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1C[C@@H](OCc2ccccc2)[C@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94.2 %

Procedure:
The compound (1.57 g, 1.70 mmol) synthesized in Example 19 (19a) was dissolved in methanol (30 mL) and potassium carbonate (235 mg, 1.70 mmol) was added thereto, followed by stirring of the mixture at room temperature for 14 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and the mixture was washed with saturated aqueous sodium hydrogencarbonate (10 mL) and saturated brine (10 mL). After the organic layer was dried with anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 3:1, V/V) to obtain the desired title compound (1.41 g, 94.0%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([OH:11])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>CN(C)C=O>[CH2:14]([N:3]1[CH:4]=[CH:5][C:6]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]1=[O:1])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c([N+](=O)[O-])c(OCc2ccccc2)ccn1Cc1ccccc1
Reaction time: 0.25 h

Procedure:
A solution of 4.68 g (30 mmol) of 2,4-dihydroxy-3-nitro-pyridine in 100 ml of dimethylformamide was combined batchwise at ambient temperature with 2.88 g (60 mmol) of a 50% suspension of sodium hydride in paraffin oil and stirred for 15 minutes. Then 8.91 ml (75 mmol) of benzylbromide were added and the mixture was stirred for 24 hours at 80° C. The solution was then carefully stirred into approx. 250 ml of water and extracted three times with 70 ml of ethyl acetate. The extracts were washed with saturated sodium chloride solution, dried and evaporated down in vacuo. The residue was triturated with diethyl ether, suction filtered and dried. The product thus obtained was further processed without any purification.
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[C:53](Cl)(=[O:55])[NH2:54].N1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[C:13]([O:16][CH:17]4[CH2:22][CH2:21][N:20]([C:53]([N:54]5[CH2:62][CH2:61][O:60][CH2:59][CH2:58]5)=[O:55])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:8]=3[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: NC(=O)Cl
Reactant: C1COCCN1
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(N1CCOCC1)N1CCC(Oc2ccc3c(c2)CCN(C2CCC2)CC3)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-Cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was stirred in dichloromethane (5 ml) with diethylaminomethyl polystyrene (3.2 mmol/g, 625 mg, 2 mmol). Morpholine carbamoyl chloride (70 μL, 0.6 mmol) was added and the mixture stirred at room temperature for 16 hours. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo. The residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title product (E52). MS (ES+) m/e 414 [M+H]+.