Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5].C([BH3-])#N.[Na+].C(O)(=O)C>C1COCC1.CO>[CH2:4]([O:6][C:7](=[O:22])[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([CH2:19][N:2]([CH3:3])[CH3:1])=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[Cl:21])[CH3:5]
Reactant: CNC
Reactant: CCOC(=O)Cc1c(Cl)ccc2cc(C=O)ccc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(Cl)ccc2cc(CN(C)C)ccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dimethylamine (5.6 M solution in EtOH, 0.28 ml, 1.53 mmol) is added under an atmosphere of argon to a solution of (2-chloro-6-formyl-naphthalen-1-yl)-acetic acid ethyl ester (284 mg, 1.02 mmol) in THF (10 ml). The mixture is stirred at RT for 18 h, before a solution of sodium cyanoborohydride (78 mg, 1.23 mmol) in MeOH (2 ml) and glacial acetic acid (0.29 ml, 5.13 mmol) are added. After stirring at RT for 1 h, TLC analysis indicates complete consumption of starting material. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of conc. aq. NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent yields the crude reaction product. Purification by FCC (CH2Cl2/EtOH/NH3 190:9:1) affords the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.26 (t, J=9 Hz, 3H), 2.30 (s, 6H), 3.59 (s, 2H), 4.18 (q, J=9 Hz, 2H), 4.30 (s, 2H), 7.49 (d, J=10 Hz, 1H), 7.54-7.58 (m, 1H), 7.69-7.76 (m, 2H), 7.91 (d, J=10 Hz, 1H). ES+-MS: 306.4, 308.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]=1[N+:17]([O-])=O)=[O:3]>[Pd].C(OCC)(=O)C>[NH2:17][C:5]1[CH:6]=[C:7]([CH:15]=[CH:16][C:4]=1[C:2]([NH2:1])=[O:3])[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9]
Reactant: CC(C)(C)OC(=O)c1ccc(C(N)=O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(C(N)=O)c(N)c1
Reaction time: 4 h
Yield: 95.2 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(aminocarbonyl)-3-nitrobenzoate (213 mg, 0.80 mmol), 10% palladium on charcoal (Degussa type, 200 mg) in ethyl acetate (20 mL) was shaken in a Parr hydrogenation apparatus at 35 psi for 4 hours. The reaction mixture was filtered and concentrated to give 1,1-dimethylethyl 3-amino-4-(aminocarbonyl)benzoate (180 mg, 95% yield). MS (EI) for C12H16N2O3: 237 (MH+).
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:6][C@@H:5]1[OH:34])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:46](OC(=O)C)(=[O:48])[CH3:47]>C(Cl)(Cl)Cl.C(O)C>[C:46]([O:34][C@@H:5]1[C@@H:4]([O:3][CH2:1][CH3:2])[CH2:21][C@@:20]2([CH3:22])[C@@H:7]([CH2:8][CH2:9][C@@H:10]3[C@@H:19]2[C@H:18]([NH:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:6]1)(=[O:48])[CH3:47]
Reactant: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](OC(C)=O)[C@@H](OCC)C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.33 h

Procedure:
Ethyl 2β-ethoxy-3α-hydroxy-11α-(3-methylbutylamino)-5α-androstane-17β-carboxylate (200 mg) in chloroform (2.15 ml) containing dry toluene-4-sulphonic acid (PTSA; 172 mg) was stirred for 20 min, then treated with acetic anhydride (0.5 ml) and the mixture left for 18 h. The reaction mixture was diluted with ethanol and evaporated. The residue in ethyl acetate was washed with dilute ammonia solution (2×) and water (1×), dried and evaporated to give the title compound as an oil (220 mg), [α]D +25.8° (CHCl3C=1%), νmax 1720 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][C:6](=O)[NH:7]2.[BH4-].[Na+].C(O)(=O)C>O1CCOCC1>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][NH:7]2
Reactant: O=C1CCc2c(Cl)cccc2N1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: Clc1cccc2c1CCCN2
Yield: 91.8 %

Procedure:
42.5 g of 5-chloro-3,4-dihydrocarbostyril was suspended in 250 ml of dioxane and 44.3 g of NaBH4 was added to the suspension. Then 67 ml of acetic acid (d=1.05) was added dropwise to the mixture at room temperature. After heat-refluxing the resulting mixture for 2 hours the solvent was removed under reduced pressure. Water was added to the residue and insoluble materials were removed by filtration followed by washing with diethyl ether. The residue was extracted with diethyl ether, dried over anhydrous sodium sulfate and distilled under reduced pressure to obtain 36.0 g of 5-chloro-1,2,3,4-tetrahydroquinoline having a boiling point of 116° to 120° C./0.2 mmHg.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=2[N+:31]([O-])=O)[O:14][CH2:15][CH2:16][O:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1.C(O)C.[Pd]>[NH2:31][C:30]1[CH:29]=[CH:28][C:13]([O:14][CH2:15][CH2:16][O:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[CH:12][C:11]=1[CH2:10][S:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:8])=[O:9]
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc([N+](=O)[O-])c(CS(=O)(=O)c3ccccc3)c2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OCCOc2ccc(N)c(CS(=O)(=O)c3ccccc3)c2)cc1
Yield: 94.9 %

Procedure:
A solution of toluene-4-sulfonic acid 2-(3-benzenesulfonylmethyl-4-nitro-phenoxy)-ethyl ester (13.1 g, 26.7 mmol) in THF (350 mL) and ethanol (250 mL) was added to 10% palladium on carbon (5.8 g) and hydrogenated on the Parr apparatus with for one hour (starting pressure of 30-40 psi.). The mixture was filtered over Celite, concentrated and dried in vacuo at 80° C. for 30 minutes to yield toluene-4-sulfonic acid 2-(4-amino-3-benzenesulfonylmethyl-phenoxy)-ethyl ester as a light yellow solid (11.7 g, 95.1%): MP: 144-6° C.; Mass spectrum (+EI, [M+H]+) m/z 462.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][C:9]=2[F:15])[CH2:5][C:4](=[O:16])[CH:3]=1.[OH-].[K+]>C(O)C.C1(C)C=CC=CC=1>[F:15][C:9]1[CH:10]=[CH:11][C:12]([CH3:14])=[CH:13][C:8]=1[CH:6]1[CH2:7][C:2]2[N:1]=[CH:7][CH:2]=[C:3]([CH3:4])[C:3]=2[C:4](=[O:16])[CH2:5]1
Reactant: Cc1ccc(F)c(C2CC(=O)C=C(N)C2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(F)c(C2CC(=O)c3c(C)ccnc3C2)c1
Reaction time: 2 h
Yield: 162.8 %

Procedure:
In ethanol (35 ml) and toluene (60 ml) was dissolved 1-amino-5-(2-fluoro-5-methylphenyl)cyclohexen-3-one (1.3 g), and to the solution were added 3-oxobutylaldehydedimethylacetal (2.0 g) and powdery potassium hydroxide (0.32 g). The mixture was refluxed, and to the mixture was added powdery potassium hydroxide (0.07 g), 30 minutes later; were added powdery potassium hydroxide (0.07 g) and 3-oxobutylaldehydedimethylacetal (0.16 g), 1 hour later; and was added powdery potassium hydroxide (0.07 g), 1.5 hours later. The mixture was stirred at the same temperature for 2 hours and cooled. Under reduced pressure, the solvent was evaporated, and to the residue was added ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, ethyl acetate was evaporated, and the residue was purified with silica gel column (ethyl acetate-hexane). The resulting crystals were recrystallized from ethyl acetate-hexane to give 7-(2-fluoro-5-methylphenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (1.3 g).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12]([C@H:14]1[C@@H:19]([NH2:20])[C@H:18]2[CH2:21][C@@H:15]1[CH2:16][CH2:17]2)=[O:13])[CH3:10].C([BH3-])#N.[Na+]>C(O)(=O)C.CO>[CH2:9]([O:11][C:12]([C@H:14]1[C@@H:19]([NH:20][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@H:18]2[CH2:21][C@@H:15]1[CH2:16][CH2:17]2)=[O:13])[CH3:10]
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72 %

Procedure:
Benzaldehyde (0.454 mL, 4.47 mmol) and 10 drops glacial acetic acid were added sequentially to a solution of (1S,2R,3S,4R)-3-amino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 6k, 0.82 g, 4.47 mmol) in methanol (15 mL) at 25° C. Sodium cyanoborohydride (0.703 g, 11.2 mmol) was added, and the reaction mixture was stirred at 25° C. for 2 h, and then was partitioned between half-saturated aqueous sodium bicarbonate solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (Teledyne Isco RediSep column; 0 to 35% ethyl acetate in hexanes) to afford the desired product, (1S,2R,3S,4R)-3-benzylamino-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (0.875 g, 3.22 mmol, 72%), as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.06-1.16 (2H, m), 1.20-1.23 (2H, m), 1.28 (3H, t, J=7.0 Hz), 1.46-1.61 (2H, m), 1.93-1.97 (1H, m), 2.33-2.34 (1H, m), 2.43-2.44 (1H, m), 2.59-2.62 (1H, m), 2.98-3.00 (1H, m), 3.71 (1H, d, J=14.0 Hz), 3.85 (1H, d, J=13.3 Hz), 4.14 (2H, q, J=7.3 Hz), 7.20-7.24 (1H, m), 7.27-7.33 (4H, m).
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)([O-])[O-].[K+].[K+].Br[C:21]1[CH:22]=[C:23]([C:29]2[S:33][C:32]([C:34]([O:36]CC)=[O:35])=[N:31][C:30]=2[CH3:39])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:28][O:27][C:26]1[C:21]([C:8]2[CH:9]=[CH:10][C:5]([S:2](=[O:4])(=[O:3])[NH2:1])=[CH:6][CH:7]=2)=[CH:22][C:23]([C:29]2[S:33][C:32]([C:34]([OH:36])=[O:35])=[N:31][C:30]=2[CH3:39])=[CH:24][CH:25]=1
Reactant: CCOC(=O)c1nc(C)c(-c2ccc(OC)c(Br)c2)s1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2sc(C(=O)O)nc2C)cc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 92.5 °C
Yield: 88.1 %

Procedure:
4-aminosulfonylbenzene boronic acid (1.15 g, 5.73 mmol) and potassium carbonate (1.97 g, 14.31 mmol) were added to a solution of ethyl 5-(3-bromo-4-methoxyphenyl)-4-methylthiazole-2-carboxylate (Step 1, 1.70 g, 4.77 mmol) in a mixture of toluene:ethanol (15 ml:40 ml) in a tube at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes and to it was added tetrakis(triphenylphosphine)palladium (0) (0.28 g, 0.24 mmol) under nitrogen and the tube was sealed. The reaction mixture was heated at 90-95° C. for 18 hr with stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite. The celite cake was then washed with 10% methanol in dichloromethane (3×30 ml). The filtrate was dried over sodium sulphate and was concentrated under reduced pressure to obtain the title compound 8b (1.70 g, 88.08%).
Reaction SMILES: Br[C:2](=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:3]=[O:4].[CH:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19].C(N(CC)CC)C.[Al]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[C:6]1(/[CH:5]=[C:2](\[C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[CH:19])/[CH:3]=[O:4])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C#CCCCCC#C
Reactant: O=CC(Br)=Cc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Al]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCCCCC#C/C(C=O)=C\c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
To a solution of Pd(PPh3)4 (0.55 g, 0.24 mmol) and α-bromocinnamaldehyde Compound 1 (2.08 g, 4.74 mmol) in degassed THF (170 mL) cooled in an ice-water bath was added a solution of 1,7-octadiyne (2.23 g, 9.48 mmol), triethylamine (15 mL), and CuI (0.36 g, 0.95 mmol) in degassed THF (30 mL) via a syringe under a nitrogen atmosphere. The reaction flask was then covered by a sheet of aluminum foil. After stirring at room temperature for 8 hours the reaction was quenched with saturated aqueous NH4Cl (50 mL) and diluted with EtOAc (100 mL). The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 10 percent EtOAc in hexane) to give 2.13 g (91 percent) of Compound 2: yellow oil; Rf=0.50 (15 percent EtOAc in hexane); IR (neat) 3294, 2944, 2230, 2116, 1692, 1598, 1450, 1324, 1180 cm−1; 1H NMR (300 MHz, CDCl3) δ9.56 (s, 1H), 8.11-8.07 (m, 2H), 7.48-7.43 (m, 3H), 7.43 (s, 1H), 2.60 (t, J=6.65 Hz, 2H), 2.27 (td, J=6.78, 2.64 Hz, 2H), 1.97 (t, J=2.64 Hz, 1H), 1.86-1.69 (m, 4H); 13C NMR (75 MHz, CDCl3) δ192.4, 151.8, 134.9, 132.0, 131.1, 129.4, 124.1, 103.4, 84.6, 75.4, 69.4, 28.2, 28.0, 20.3, 18.7; MS (+FAB) m/z (relative intensity) 237 (M+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[O:10][C:11]=2[C:12]([F:15])([F:14])[F:13])=[CH:3][CH:2]=1.ClCCl.[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29](Cl)=[O:30]>N1C=CC=CC=1>[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[CH:32][C:28]=1[C:29]([NH:22][C:19]1[CH:20]=[CH:21][C:16]([C:9]2[O:10][C:11]([C:12]([F:15])([F:13])[F:14])=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[N:8]=2)=[CH:17][CH:18]=1)=[O:30]
Reactant: Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2nc(-c3ccncc3)c(C(F)(F)F)o2)cc1)c1ccccc1Cl

Procedure:
to a stirred mixture of 4-(4-(pyridin-4-yl)-5-(trifluoromethyl)oxazol-2-yl)benzenamine (214 mg, 701 mop and pyridine, anhydrous (0.567 ml, 7011 μmol) in dichloromethane (5.00 ml, 77709 μmol) at room temperature was added 2-chlorobenzoyl chloride (0.0979 ml, 771 μmol) all at once by metered pipet. The reaction was stirred for an hour then concentrated under reduced pressure, taken up in heptane and concentrated under reduced pressure again. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic separation was dried over magnesium sulfate, filtered and filtrate concentrated under reduced pressure to afford a colorless solid. ESI+ m/z=444.1 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[C:19](=[O:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[CH2:5][NH:6][C:7]1[C:8]2[C:13]([N:14]=[C:15]3[C:20]=1[CH:19]([OH:21])[CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Cc1cccc(CNc2c3c(nc4ccccc24)CCCC3=O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(CNc2c3c(nc4ccccc24)CCCC3O)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3,4-Dihydro-9-(3-methybenzylamino)acridin-1(2H)-one (3.70 g) was dissolved in 100 ml of dry THF and chilled in ice-water. 1M lithium aluminum hydride in THF (7.0 ml) was added and the reaction stirred 30 minutes in the cold. The reaction mixture was quenched by the sequential addition of 0.5 ml of water, 0.5 ml of 15% sodium hydroxide and 1.5 ml of water. The inorganic salts were filtered from the reaction mixture and the organic phase was evaporated to an oil. Trituration with ether gave a solid that was recrystallized from ethyl acetate/pentane to obtain 3.22 g, mp 133°-134° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][C:18]([S:22][C:23]1[N:27]3[CH:28]=[C:29]([C:32]4[CH:33]=[N:34][N:35]([CH3:37])[CH:36]=4)[CH:30]=[CH:31][C:26]3=[N:25][N:24]=1)=[CH:17][CH:16]=2)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH3:37][N:35]1[CH:36]=[C:32]([C:29]2[CH:30]=[CH:31][C:26]3[N:27]([C:23]([S:22][C:18]4[CH:19]=[C:20]5[C:15](=[CH:16][CH:17]=4)[N:14]=[CH:13][C:12]([NH:11][CH2:10][CH2:9][OH:8])=[CH:21]5)=[N:24][N:25]=3)[CH:28]=2)[CH:33]=[N:34]1
Reactant: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(NCCO[Si](C)(C)C(C)(C)C)cc5c4)n3c2)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1cc(-c2ccc3nnc(Sc4ccc5ncc(NCCO)cc5c4)n3c2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 28 %

Procedure:
To a solution of (53.1) (100 mg, 0.188 mmol) in THF (10 ml), TBAF (98 mg, 0.376 mmol) was added. The reaction mixture was stirred at rt for 3 h. The solvent was then removed under reduced pressure. The residue was dissolved in 30 ml of DCM, washed with water (10 ml×3) and brine (10 ml) successively. The organic phase was dried over Na2SO4, then filtered and concentrated. The residue was purified by silica gel chromatography (DCM/MeOH=10/1) to afford the title compound as pale yellow solid (22 mg, 28% yield). [Method 3]
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:25]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:27]=[CH:28][CH:29]=2)[CH2:20][CH2:19]1>>[C:31]([NH:30][C:26]1[CH:25]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][CH2:16][CH2:15][NH:14][C:9](=[O:11])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)([CH3:13])[CH3:12])[CH2:19][CH2:20]2)[CH:29]=[CH:28][CH:27]=1)(=[O:33])[CH3:32]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Reactant: CC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC(=O)Nc1cccc(C2CCN(CCCNC(=O)C(C)(C)c3ccc(Cl)cc3)CC2)c1

Procedure:
Example 79 was prepared from 2-(4-chlorophenyl)-2-methylpropanoic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}acetamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43 (s, 2H), 7.34–7.25 (m, 6H), 6.95 (d, 1H, J=7.2 Hz), 6.65 (br s, 1H), 3.33 (dd, 2H, J=6.0, 12.0 Hz), 2.92 (d, 2H, J=12.0 Hz), 2.45 (m, 1H), 2.36 (t, 2H, J=6.0 Hz), 2.20 (s, 3H), 1.94 (t, 2H, J=12.4 Hz), 1.78 (d, 2H, J=13.2 Hz), 1.65 (m, 2H), 1.57 (s, 6H), 1.55–1.46 (m, 2H); ESMS m/e: 456.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14](B3OC(C)(C)C(C)(C)O3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[N:32][CH:33]=1>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:28]3[CH:33]=[N:32][CH:31]=[C:30]([OH:34])[CH:29]=3)=[CH:15][N:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Oc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Product: CC(C)(C)OC(=O)N1CCCc2cc(-c3cncc(O)c3)cnc21

Procedure:
6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester is coupled with 5-bromo-pyridin-3-ol to give 6-(5-hydroxy-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using Suzuki Coupling Method VI.
Reaction SMILES: C([O:5][C:6]([NH:8][C@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])(C)(C)C.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+]>C(#N)C.O.[O-]S([O-])(=O)=O.[Cu+2]>[CH3:13][O:12][CH2:10][CH2:9][O:21][C:18]1[CH:17]=[CH:16][C:15]([C@@H:14]2[O:7][C:6](=[O:5])[NH:8][C@H:9]2[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=1
Reactant: COC(=O)[C@@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: [Cu+2]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CC#N
Product: COCCOc1ccc([C@@H]2OC(=O)N[C@H]2C(=O)OC)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 110 %

Procedure:
To a solution of (R)-methyl 2-((tert-butoxycarbonyl)amino)-3-(4-hydroxyphenyl)-propanoate (5.34 g, 14.35 mmol) in acetonitrile (260 mL) was added under argon a solution of potassium persulfate (7.76 g, 28.7 mmol) in H2O (190 mL) and a solution of CuSO4 (0.458 g, 2.87 mmol) dissolved in H2O (70 mL). The resulting mixture was stirred for 3 h at 70° C. The reaction mixture was extracted with EtOAc. Combined extracts were washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using EtOAc in heptane from 20% to 100% in order to give the title compound as a yellow oil (2.33 g, 52%). TLC (heptane/EtOAc 1:2) Rf=0.19; tR=0.680 min (UPLC 1); LC-MS: [M+H] 296; Rt 0.68 min; (LCMS method 2); 1H NMR (400 MHz, CDCl3): 7.36 (d, 2H), 6.99 (d, 2H), 5.86 (br d, 1H), 5.62 (d, 1H), 4.30 (d, 1H), 4.16 (dd, 2H), 3.88 (s, 3H), 3.79 (dd, 2H), 3.48 (s, 3H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][N:12]3[C:16]4[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=4[N:14]=[CH:13]3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:25]1([CH2:31][NH2:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH:25]1([CH2:31][NH:32][C:2]2[S:3][C:4]3[CH:10]=[C:9]([CH2:11][N:12]4[C:16]5[CH:17]=[C:18]([O:23][CH3:24])[C:19]([O:21][CH3:22])=[CH:20][C:15]=5[N:14]=[CH:13]4)[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NCC1CCCCC1
Reactant: COc1cc2ncn(Cc3ccc4nc(Br)sc4c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc2ncn(Cc3ccc4nc(NCC5CCCCC5)sc4c3)c2cc1OC
Temperature: 100 °C
Yield: 33.1 %

Procedure:
A stirred mixture of 2-bromo-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazole (70 mg, 0.173 mmol) from Example 2, cyclohexanemethylamine (39 mg, 0.346 mmol) and DIEA (67 mg, 0.519 mmol) in anhydrous DMA (1.5 mL) was heated at 100° C. for 2.5 h. After cooling to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford N-(cyclohexylmethyl)-6-((5,6-dimethoxy-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-amine (25 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.15 (br s, 1H), 8.04 (t, J=5.4 Hz, 1H), 7.63 (s, 1H), 7.31 (m, 1H), 7.12-7.24 (m, 3H), 5.40 (s, 2H), 3.76 (s, 6H), 3.17 (t, J=6.1 Hz, 2H), 1.49-1.78 (m, 6H), 1.07-1.27 (m, 3H), 0.84-1.02 (m, 2H). LCMS (ESI) m/z 437 (M+H)+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16](=[O:32])[CH2:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:14])([CH3:13])[CH3:12].[C:33]([O:37][C:38](=[O:48])[NH:39][C:40]1[CH:45]=[CH:44][C:43]([CH2:46]Br)=[CH:42][N:41]=1)([CH3:36])([CH3:35])[CH3:34]>C1COCC1.O>[C:19](=[N:18][CH:17]([CH2:46][C:43]1[CH:42]=[N:41][C:40]([NH:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:48])=[CH:45][CH:44]=1)[C:16]([O:15][C:11]([CH3:14])([CH3:12])[CH3:13])=[O:32])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(CBr)cn1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(N=C(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)cn1
Reaction time: 0.25 h
Yield: 103.8 %

Procedure:
84.64 ml (84.64 mmol) of a 1M solution of lithium bis(trimethylsilyl)amide in THF were added dropwise to a solution of 25.00 g (84.64 mmol) of N-(diphenylmethylene)glycine tert-butyl ester in 185 ml of THF under argon at 0° C. After stirring at this temperature for 15 min, 24.31 g (84.64 mmol) of tert-butyl(5-bromomethylpyridin-2-yl)carbamate were added as solid, and stirring was continued for 1 h. The reaction mixture was cautiously diluted with water and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and concentrated. 44.08 g of the crude product were obtained and were reacted further without further purification.