Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[CH:28]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:37]=1[C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])([CH3:30])[CH3:29].ClCCl.C(=O)([O-])[O-].[Na+].[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].C(O)C.C1(C)C=CC=CC=1>[OH:1][C@H:2]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:34]2[CH:35]=[CH:36][C:37]([C:38]([NH:40][S:41]([CH3:44])(=[O:43])=[O:42])=[O:39])=[C:32]([O:31][CH:28]([CH3:30])[CH3:29])[CH:33]=2)=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)Oc1cc(B(O)O)ccc1C(=O)NS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N(CCOc1ccc(I)cc1)C[C@H](O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)Oc1cc(-c2ccc(OCCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 8 %

Procedure:
In a reaction vessel were added tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-(4-iodophenoxy)ethyl]carbamate (200 mg), [3-isopropoxy-4-[[(methylsulfonyl)amino]carbonyl]-phenyl]boronic acid (150 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1, 33.8 mg), toluene (3.2 ml), ethanol (0.8 ml), and 2N sodium carbonate solution (0.66 ml). The vessel was placed in a microwave and irradiation was adjusted to keep the temperature 100° C. and the reaction was performed for 2 hours. After cooling to room temperature, the mixture was quenched by the addition of 1N hydrochloric acid (1.32 ml) and partitioned between ethyl acetate (20 ml) and water (20 ml). The organic layer was separated, washed with brine (20 ml), and dried over magnesium sulfate. Filtration followed by evaporation gave a brown foam which was chromatographed on silica gel (eluent: hexane/ethyl acetate) to give tert-butyl [(2R)-2-hydroxy-2-phenylethyl]-[2-[[3′-isopropoxy-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]oxy]ethyl]carbamate (20.4 mg) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([O:25][C:26](=[O:36])[NH:27][CH2:28][C@H:29]1[CH2:33][CH2:32][C@H:31]([O:34][NH2:35])[CH2:30]1)([CH3:24])([CH3:23])[CH3:22].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:21]([O:25][C:26](=[O:36])[NH:27][CH2:28][C@H:29]1[CH2:33][CH2:32][C@H:31]([O:34][NH:35][C:18]([C@@H:13]2[CH2:12][CH2:11][C@@H:10]3[CH2:17][N:14]2[C:15](=[O:16])[N:9]3[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:20])[CH2:30]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ON)C1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](ONC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.25 g, 0.90 mmol, US2005/20572 A1, 2005) in DCM (20 was added tert-butyl[trans-3-(aminooxy)cyclopentyl]methylcarbamate 116 (0.32 g, 1.39 mmol), 1-hydroxybenzotriazole (0.18 g, 1.33 mmol), and 1-ethyl-(3-dimethylamino propyl) carbodiimide hydrochloride (0.26 g, 1.36 mmol) sequentially at room temperature. The mixture was stirred at room temperature for 6 hours, then concentrated in vacuo to provide a residue which was subjected to chromatography to give 117 (0.45 g, contains some byproduct) as a white foam.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:13]2[C:12]3[CH:11]=[C:10]([CH3:16])[CH:9]=[CH:8][C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3]1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:29]2[CH2:31][O:30]2)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>CN(C=O)C>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:29]([OH:30])[CH2:31][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:16])=[CH:11][C:12]=3[C:13]3[CH2:14][CH2:15][N:2]([CH3:1])[CH2:3][CH2:4][C:5]2=3)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)CC3
Reactant: COc1ccc(C2CO2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(O)Cn2c3c(c4cc(C)ccc42)CCN(C)CC3)cc1OC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.4 %

Procedure:
3,9-Dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (500 mg, 2.33 mmol) was dissolved in DMF (6 ml). A solution of sodium hydride (50%) (168 mg, 7.00 mmol) was added in portions at RT and stirred at RT for 10 min. A solution of 2-(3,4-dimethoxyphenyl)oxirane (630 mg, 3.50 mmol) in DMF (4 ml) was added dropwise for 10 min and stirred for 14 h at RT. Reaction was monitored by LCMS. The reaction mixture was quenched with ice water, extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The crude product was purified by column chromatography to get 50 mg of pure product. 1H NMR (CDCl3, Oxalate salt) δ (ppm): 7.40-7.30 (m, 2H), 7.10-7.00 (m, 1H), 6.90-6.80 (t, 2H), 6.80-6.60 (t, 1H), 5.00-4.80 (t, 2H), 4.30-4.20 (m, 2H), 3.95 (s, 3H), 3.80 (s, 3H), 3.00-2.90 (m, 4H), 2.80 (s, 3H), 2.75-2.70 (m, 2H), 2.35 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Fc1ccc(-n2cc(Br)cn2)cc1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(-c4ccc(F)cc4)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1-(4-fluoro-phenyl)-1H-pyrazole.
Reaction SMILES: C(C1C=CC=CC=1[OH:11])CCC.[C:12]([C:16]1[CH:21]=[CH:20][C:19](O)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCCCc1ccccc1O
Product: CC(C)(C)c1ccccc1O

Procedure:
The procedure of Example 5 was repeated in all respects except 2-butylphenol was substituted for 4-t-butylphenol. 40% bleach number=0.5, 100% bleach number=4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].[Cl:11][C:12]1[CH:17]=[N:16][CH:15]=[C:14](Cl)[N:13]=1>>[Cl:11][C:12]1[N:13]=[C:14]([NH:6][CH2:5][C:4]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=2)[CH:15]=[N:16][CH:17]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1cncc(Cl)n1
Product: Clc1cncc(NCc2ccc(Cl)c(Cl)c2)n1
Yield: 89 %

Procedure:
In a procedure analogous to Example 21, reaction of 3,4-dichlorobenzylamine and 2,6-dichloropyrazine furnished the product (89%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[CH3:31]OC(OC)N(C)C>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[C:14]([CH3:31])[N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1
Reactant: COC(OC)N(C)C
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3ccccc3c2ncn1[C@H]1CCCC[C@@H]1O
Product: Cc1nc2c(cc(Cc3ccc(Cl)nc3)c3ccccc32)c(=O)n1[C@H]1CCCC[C@@H]1O

Procedure:
Using the procedures described in Example 2 for the preparation of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]benzo[h]quinazolin-4(3H)-one, substituting N, N-dimethylacetamide dimethylacetal for N,N-dimethylformamide dimethylacetal, the title compound was obtained that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 433.9 for [M+H]+: 1H NMR (400 MHz, d6-DMSO) δ 9.05-9.03 (m, 1H), 8.28 (s, 1H), 8.06 (d, J=7.7, 1H), 7.92 (s, 1H), 7.75-7.63 (m, 3H), 7.34 (d, J=8.4 Hz, 1H), 4.80-4.74 (m, 1H), 4.53 (s, 2H), 4.15-4.09 (m, 1H), 2.87 (s, 3H), 2.81-2.70 (m, 1H), 2.19-2.12 (m, 1H), 1.90-1.80 (m, 3H), 1.53-1.35 (m, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:19]([O:21][C:22]([C@@:24]1([NH:29][C:30]([N:32]2[CH2:36][C@H:35](O)[CH2:34][C@H:33]2[C:38](=[O:47])[N:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH3:40])=[O:31])[CH2:26][C@@H:25]1[CH:27]=[CH2:28])=[O:23])[CH3:20].C(N(CC)CC)C>C(Cl)Cl.C(Cl)Cl.CO.CN(C=O)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([O:10][C@@H:35]2[CH2:34][C@@H:33]([C:38](=[O:47])[N:39]([CH2:41][CH2:42][CH2:43][CH2:44][CH:45]=[CH2:46])[CH3:40])[N:32]([C:30](=[O:31])[NH:29][C@:24]3([C:22]([O:21][CH2:19][CH3:20])=[O:23])[CH2:26][C@H:25]3[CH:27]=[CH2:28])[CH2:36]2)=[O:9])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)N[C@]1(C(=O)OCC)C[C@@H]1C=C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCCCCN(C)C(=O)[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)CN1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 4-nitrobenzoic acid (3.1 g, 1.5 eq) in CH2Cl2 (61 mL) were added dropwise 3.1 mL oxalyl chloride (3 eq), followed by 60 μL DMF. The reaction mixture was stirred at room temperature for 2 hrs and concentrated in vacuo. A solution of the resulting solid in CH2Cl2 (30 mL) was added dropwise to a solution of compound 50 (5.0 g, 1 eq) and triethylamine (3.4 mL, 2 eq) in CH2Cl2 (30 mL). The reaction mixture was stirred at room temperature for 2 hrs, and then washed with water and a saturated aqueous solution of sodium carbonate. The aqueous layer was extracted with CH2Cl2. The combined organic phases were dried on sodium sulphate, filtered, and concentrated to dryness. Recrystallisation with TBME gave compound BI as a yellow powder, and the filtrate was submitted to flash chromatography using CH2Cl2/MeOH as an eluant, affording a total of 6.42 g of compound BI in 93% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24](Cl)=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:37][C:38]1[C:43]([NH2:44])=[CH:42][CH:41]=[C:40]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[CH3:51])[CH:39]=1>O1CCCC1>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][CH2:7][C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[C:21]([C:24]([NH:44][C:43]4[CH:42]=[CH:41][C:40]([C:45]5[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=5[CH3:51])=[CH:39][C:38]=4[CH3:37])=[O:25])=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2ccccc2C)ccc1N
Reactant: O=C(Cl)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2C)ccc1NC(=O)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 10-[2-(4-chloro-phenoxy)-acetyl]-10,11-dihydro-5H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-3-carbonyl chloride of step B (0.415 mmol) in anhydrous tetrahydrofuran (3 mL) was added triethylamine (0.829 mmol) and 3,2′-dimethylbiphen-4-ylamine hydrochloride (0.415 mmol). The solution was stirred for 18 hours at ambient temperature. The solvent was evaporated, the residue was taken up in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. Chromatography on silica gel using 55:23:22 hexane/ethyl acetate/dichloromethane as eluant gave the title compound as an amorphous solid. This was crystallized from ethyl acetate/hexane to afford 0.17 g of the title product (71% yield), m.p. 159-161° C. MS [(+)ESI, m/z]: 576 [M+H]+ Anal. Calcd for C35H30CIN3O3: C, 72.97; H, 5.25; N, 7.29. Found: C, 72.59; H, 5.28; N, 7.24.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=O)=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1.[S:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[S:15].C([O-])(=O)C.[Na+].O>C(O)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[C:19]3[S:13][C:14](=[S:15])[NH:16][C:17]3=[O:18])=[CH:8][CH:9]=2)[CH:4]=[N:3][CH:2]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccc2ncncc2c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1ccc2ncncc2c1
Temperature: 130 °C
Reaction time: 12 h
Yield: 100.1 %

Procedure:
The suspension of 6-quinazolinecarboxaldehyde (example 1a, 1.5 g, 9.5 mmol), rhodanine (1.26 g, 9.5 mmol) and sodium acetate (3.11 g, 38 mmol) in acetic acid (10 mL) was stirred at 130° C. for 12 h. After cooling to room temperature, water (40 mL) was added. The solid was collected by filtration, washed with water and dried to obtain 5-quinazolin-6-ylmethylene-2-thioxo-thiazolidin-4-one (2.6 g, 100%) as a solid. LC-MS m/e 274 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([OH:14])[CH:12]=2)[NH:7][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CC(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:27][CH2:26][O:25][C:22](=[O:24])[CH3:23])[CH:12]=2)[NH:7][CH:6]=1
Reactant: CC(=O)OCCBr
Reactant: COC(=O)Cc1c[nH]c2ccc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)Cc1c[nH]c2ccc(OCCOC(C)=O)cc12

Procedure:
To a solution of (5-hydroxy-1H-indol-3-yl)-acetic acid methyl ester (670 mg, 3.26 mmol) in acetone (15 mL) was added cesium carbonate (1.17 g, 3.59 mmol) and 2-bromoethyl acetate (395 μL, 3.59 mmol). The suspension was refluxed overnight under nitrogen. Acetone was concentrated and the residue was dissolved in water and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 6:4) to give the desired material. TLC, Rf (c-hexane/EtOAc 1:1)=0.45; MS (LC-MS): 292.1 [M+H]+, 314.0 [M+Na]+, 290.0 [M−H]−; tR (HPLC conditions f): 1.70 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([C:21](O)=[O:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[C@H:10]([CH2:21][OH:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](C(=O)O)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.5 %

Procedure:
To a solution of (−)-(3S,4R)-4-(4-fluoro-phenyl)-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester (1.71 g, 5.29 mmol) in 35 ml THF was added a 2 M borane dimethylsulfide complex solution in THF (5.44 ml, 10.9 mmol) at 0° C. The mixture was stirred for 15 min at 0° C. and then at room temperature over night. After cooling to 0° C. the reaction was quenched by the addition of methanol. Stirring was continued until no evolution of gas was observed any more. The reaction mixture was diluted with water and extracted with 3 portions of tert-butyl methyl ethyl. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Flash chromatography gave 1.58 g (94%) of the title compound as a colorless viscous oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:9][C:10](OCC)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:9][C:10](=[O:11])[CH:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCN(CC(=O)OCC)Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CN(Cc2ccccc2)CC1=O

Procedure:
Above-prepared ethyl 3-[N-benzyl-N-(ethoxycarbonylmethyl)amino]propionate (14.0 g, 0.0479 mol) was dissolved in toluene (100 mL), and the solution was mixed with potassium tert-butoxide (5.9 g, 0.0525 mol) gradually added under ice-cooling, followed by stirring under ice-cooling for two hours. The reaction mixture was mixed with diluted hydrochloric acid (about 1 mol/L, 100 mL) under ice-cooling, followed by shaking and separation, to yield an aqueous layer. Saturated aqueous sodium bicarbonate solution (300 mL) was added dropwise to the aqueous layer, and ethyl acetate (400 mL) was further added thereto, followed by shaking and separation. After drying the organic layer over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, to thereby yield ethyl 1-benzyl-4-oxopyrrolidine-3-carboxylate (9.23 g, in a yield of 78%).
Reaction SMILES: C(C1C=CC([N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=CC=1)#N.[H-].C([Al+]CC(C)C)C(C)C.CO.O>C1(C)C=CC=CC=1>[C:15]([N:12]1[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C#N)cc2)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCNCC1
Temperature: 50 °C

Procedure:
To t-butyl 4-(4-cyanophenyl)piperazine-1-carboxylate (2.30 g, 8.0 mmol, prepared by reaction of the aryl-piperazine with Boc-anhydride) in toluene (20 ml) add DIBAH (diisobutylaluminum hydride) (1.0M in toluene, 12.8 ml, 12.8 mmol). Heat at 50° C. 1.5 h, allow to cool, add MeOH (10 ml) and water (10 ml). Filter and concentrate. Chromatograph the residue over silica to obtain the Boc-piperazine as a yellow solid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].O.[CH2:9]([O:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][CH:28]=[C:29]([O:31][CH2:32][C@@H:33]3[CH2:36][CH2:35][N:34]3C(OC(C)(C)C)=O)[CH:30]=2)=[CH:21][CH:20]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:34]1[CH2:35][CH2:36][C@H:33]1[CH2:32][O:31][C:29]1[CH:28]=[N:27][CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][C:19]([CH2:18][CH2:17][O:16][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=2)[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(-c2ccc(CCOCc3ccccc3)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: c1ccc(COCCc2ccc(-c3cncc(OC[C@@H]4CCN4)c3)cc2)cc1
Temperature: 30 °C
Reaction time: 24 h

Procedure:
Trifluoroacetic acid (1.0 mL) and water (0.11 mL) were added to CH2Cl2 (5.5 mL). This mixture was added to 3-[4-[2-(benzyloxy)ethyl]phenyl]-5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]pyridine (220 mg, 0.46 mmol) in a 25 mL round-bottom flask with a magnetic stirrer under N2. After stirring at 30° C. for 24 h, TLC analysis indicated that the starting material had disappeared. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (SunFire Prep C18 column, 19×150 mm, 5 μm particle size; UV detection at 254 nm; flow 15 mL/min; CH3CN/water gradient with addition of 0.05% CF3COOH, from 20-40% CH3CN in 6 min) to provide the title compound (140 mg, light-yellow solid) as a partial trifluoroacetate.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:14]2[NH:13][C:12]3[CH:11]=[C:10]([C:15]([NH2:17])=O)[CH:9]=[CH:8][C:7]=3[C:6]=2[C:5](=[O:18])[C:4]2[CH:19]=[N:20][C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[CH:22][C:3]1=2.S(Cl)(Cl)=O>CN(C=O)C.O>[CH3:1][C:2]1([CH3:35])[C:14]2[NH:13][C:12]3[CH:11]=[C:10]([C:15]#[N:17])[CH:9]=[CH:8][C:7]=3[C:6]=2[C:5](=[O:18])[C:4]2[CH:19]=[N:20][C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH2:27][CH2:28]3)=[CH:22][C:3]1=2
Reactant: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ncc2C(=O)c2c1[nH]c1cc(C(N)=O)ccc21
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC1(C)c2cc(N3CCC(N4CCOCC4)CC3)ncc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.1 %

Procedure:
5,5-Dimethyl-3-(4-morpholin-4-yl-piperidin-1-yl)-11-oxo-6,11-dihydro-5H-pyrido[4,3-b]carbazole-8-carboxylic acid amide (54 mg) was dissolved in DMF (1 ml), added with thionyl chloride (25 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with water. The precipitated matters were collected by filtration to obtain the title compound (25 mg, 49%).
Reaction SMILES: [CH2:1]([C@@:3]12[CH2:16][C@H:15]([OH:17])[C@:14]([OH:21])([C:18]#[C:19][CH3:20])[CH2:13][C@H:12]1[CH2:11][CH2:10][C:9]1[CH:8]=[C:7]([C:22](O)=[O:23])[CH:6]=[CH:5][C:4]2=1)[CH3:2].C(N(C(C)C)CC)(C)C.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:55][C:56]1[C:61]([CH2:62][NH2:63])=[CH:60][CH:59]=[CH:58][N:57]=1>O1CCCC1>[CH3:55][C:56]1[C:61]([CH2:62][NH:63][C:22]([C:7]2[CH:6]=[CH:5][C:4]3[C@@:3]4([CH2:1][CH3:2])[C@@H:12]([CH2:13][C@@:14]([OH:21])([C:18]#[C:19][CH3:20])[C@@H:15]([OH:17])[CH2:16]4)[CH2:11][CH2:10][C:9]=3[CH:8]=2)=[O:23])=[CH:60][CH:59]=[CH:58][N:57]=1
Reactant: Cc1ncccc1CN
Reactant: CC#C[C@]1(O)C[C@H]2CCc3cc(C(=O)O)ccc3[C@]2(CC)C[C@@H]1O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC#C[C@]1(O)C[C@H]2CCc3cc(C(=O)NCc4cccnc4C)ccc3[C@]2(CC)C[C@@H]1O
Temperature: 25 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
To a solution of (6S,7R,4bR,8aR)-4b-ethyl-6,7-dihydroxy-7-prop-1-ynyl-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carboxylic acid (20 mg, 0.061 mmol) in tetrahydrofuran (2 mL) was added sequentially diisopropylethylamine (0.042 mL, 0.24 mmol), 1-[3-(dimethylamino)propyl]-3-ethyl carbodiimide (14 mg, 0.073 mmol), 1-hydroxybenzotriazole (9 mg, 0.064 mmol) and C-(2-methylpyridin-3-yl)-methylamine (0.025 mL, approximately 0.2 mmol). The mixture was stirred at room temperature for 1 day and was then quenched with saturated aqueous ammonium chloride solution. After extracting twice with ethyl acetate, the combined organic layers were washed with brine, dried (MgSO4) and concentrated under vacuum. The title compound (10 mg, 38%) was isolated by flash chromatography eluting with 50% acetone in methylene chloride. Mass spectrum: m/e 433 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:27][C:19]3[C:20]4[CH:21]=[N:22][NH:23][C:24]=4[CH:25]=[CH:26][C:18]=3[CH2:17][C@@H:16]([NH:28]C(OCC3C=CC=CC=3)=O)[C:15]2=[O:39])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:40]([OH:43])(=[O:42])[CH3:41].[H][H]>[Pd].CO>[C:40]([OH:43])(=[O:42])[CH3:41].[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]2[CH2:27][C:19]3[C:20]4[CH:21]=[N:22][NH:23][C:24]=4[CH:25]=[CH:26][C:18]=3[CH2:17][C@@H:16]([NH2:28])[C:15]2=[O:39])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](NC(=O)OCc3ccccc3)C2=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(N2Cc3c(ccc4[nH]ncc34)C[C@@H](N)C2=O)CC1
Reaction time: 3 h

Procedure:
A catalytic amount of 10% palladium on carbon was added to a solution of 4-(7-(R)-Benzyloxycarbonylamino-8-oxo-6,7,8,10-tetrahydro-3H-2,3,9-triaza-cyclohepta[e]inden-9-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.37 mmol) and acetic acid (100 μL, 1.7 mmol) in methanol (10 mL). Reaction vessel was placed on a Parr apparatus and charged with 30 psi of hydrogen gas. Mixture was allowed to shake at room temperature for 3 hours. Mixture was filtered. Filtrate was concentrated in vacuo. Crude compound was obtained as a dark oil in quantitative yield. Material was carried forward without further purification. 1H NMR (300 MHz, CDCl3): δ=8.06 (s, 1H), 7.36 (d, J=8.8, 1H), 7.12 (d, J=8.8, 1H), 4.92 (d, J=17.6, 1H), 4.67 (m, 1H), 4.49 (d, J=17.2, 1H), 4.26 (m, 1H), 3.98 (m, 2H), 3.05 (m, 1H), 2.83 (m, 2H), 2.64 (m, 1H), 1.89 (m, 1H), 1.73 (m, 1H), 1.45 (d, J=2.9, 9H), 1.25 (m, 2H).MS m/e (M−C4H8+H)+=344.2.