Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][C:6]=2[N+:15]([O-])=O)[CH2:4][CH2:3][CH2:2]1>CO>[NH2:15][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][C:5]=1[CH:1]1[CH2:4][CH2:3][CH2:2]1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1ccc(C2CCC2)c([N+](=O)[O-])c1
Solvent: CO
Product: COC(=O)c1ccc(C2CCC2)c(N)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
A flask containing a solution of methyl 4-cyclobutyl-3-nitrobenzoate (compound 443.1, 2.50 g, 10.6 mmol, 1.00 equiv) in methanol (30 mL) was purged with nitrogen. Palladium on carbon (10%, 60% water, 1.2 g) was added and the flask was carefully purged further with nitrogen. The atmosphere was then changed to hydrogen and the mixture was stirred overnight at 20° C. After purging the system with nitrogen, the solids were then removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:5) as eluent to yield 1.60 g (73%) of the title compound as a white solid.
Reaction SMILES: CCN=C=[N:5][CH2:6][CH2:7][CH2:8]N(C)C.Cl.[C:13]1([CH2:19][C:20]([OH:22])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N)CC.C1C=CC2N(O)N=NC=2C=1>CC#N.CCOC(C)=O>[C:13]1([CH2:19][C:20]([NH:5][CH2:6][CH2:7][CH3:8])=[O:22])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)Cc1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCCN
Solvent: CCOC(C)=O
Product: CCCNC(=O)Cc1ccccc1
Reaction time: 72 h

Procedure:
EDAC.HCl (959 mg, 5 mmol) was added to a mixture of phenylacetic acid (681 mg, 5 mmol), propylamine (411 μL, 5 mmol) and HOBT (676 mg, 5 mmol) in 5 mL of CH3CN. The reaction was stirred for 72 hours. After this time, the mixture was diluted with AcOEt. The organic layer was washed three times with HCl 2N, three times with NaOH 2N, dried over MgSO4 and concentrated. A with solid was obtained (576 mg, 65%). NMR 1H (ppm, CDCl3): 7.39-7.24 (m, 5H), 5.38 (br. s., 1H), 3.57 (s, 2H), 3.20-3.13 (m, 2H), 1.45 (sex. J3=7.19 Hz, 2H), 0.83 (t, J3=7.40 Hz, 3H).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][NH:14][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:16])[CH:6]=1)=[O:4].CO.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[N:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:15]([NH:14][CH2:13][CH2:12][N:7]1[C:8](=[O:11])[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[CH:6]1)=[O:16]
Reactant: COC(=O)c1ccc(=O)n(CCNC(=O)c2ccccn2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(=O)n(CCNC(=O)c2ccccn2)c1
Temperature: 60 °C

Procedure:
To a 10 ml round bottomed flask fitted with a magnetic stirrer bar was added 1,6-dihydro-1-[2-(2-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid methyl ester (0.177 g, 0.59 mmol), methanol (1.4 ml), water (1.4 ml), and 15% aqueous sodium carbonate (1.4 ml). The resulting suspension was heated in a 60° C. oil bath for 1 hour during which time the mixture was completely solvated. Upon cooling to room temperature, acetic acid was added dropwise, with stirring, to a final pH of 5.5. The precipitated product was recovered by filtration, washed with water, and dried at 50° C. under high vacuum, MP: 266°-268° C.
Reaction SMILES: [P:1]([O-:26])([O:22][CH2:23][CH2:24]Br)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2].[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1>C1(C)C=CC=CC=1>[P:1]([O-:26])([O:22][CH2:23][CH2:24][N+:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:2]
Reactant: c1ccnnc1
Reactant: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCCBr
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOCCOCCOP(=O)([O-])OCC[n+]1ccccn1
Temperature: 60 °C
Yield: 40 %

Procedure:
3,6-Dioxaoctadecyl 2-bromoethyl phosphate (3.0 g) and pyridazine (5 g) are dissolved in toluene (60 ml) and warmed at 60° C. The solvent is distilled off, silver carbonate and methanol are added, and the mixture is refluxed. The insolubles are filtered off, the filtrate is concentrated to dryness, and the residue is purified by silica gel chromatography (developing solvent: chloroform-methanol-water) to give 1.2 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][NH:19][C:20]2[CH:25]=[C:24]([O:26]C)[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[C:30](=[CH:31][CH:32]=[C:33]([O:38]C)[CH:34]=3)[CH2:29]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.F[C:41]1C=C(CCNCC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)C=CC=1OCCN1CCCCC1>>[F:1][C:2]1[CH:3]=[C:4]([CH2:17][CH2:18][N:19]([CH3:41])[C:20]2[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=2[CH:28]2[CH2:37][CH2:36][C:35]3[CH:34]=[C:33]([OH:38])[CH:32]=[CH:31][C:30]=3[CH2:29]2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1CNCCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Product: CN(CCc1ccc(OCCN2CCCCC2)c(F)c1)c1cc(O)ccc1C1CCc2cc(O)ccc2C1

Procedure:
Synthesized from {2-[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine according to an analogous synthetic method to Preparation Example 18, {2-[3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl]ethyl}[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]methylamine (180 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (110 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[O:21])[NH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)([OH:3])=[O:2].C(N(CC)CC)C.Cl[C:32]([O:34][CH2:35][CH:36]([CH3:38])[CH3:37])=[O:33].O>CN(C=O)C>[CH2:35]([O:34][C:32]([O:2][C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([C:22]#[N:23])[C:17](=[O:21])[NH:18][C:19]=2[CH3:20])=[CH:10][CH:9]=1)=[O:3])=[O:33])[CH:36]([CH3:38])[CH3:37]
Reactant: CC(C)COC(=O)Cl
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCC(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc(OCCCC(=O)OC(=O)OCC(C)C)cc1
Yield: 74.6 %

Procedure:
A solution of 820 mg (2.6 mmol) of 5-(4-carboxypropyloxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile (prepared as described in Example 2 above), 750 μl (5.38 mmol) of triethylamine, and 15 ml of DMF is cooled in an ice-water bath while stirring under N2. A solution of 540 mg (3.9 mmol) of isobutyl chloroformate in 5 ml of DMF is added dropwise. After 4 hr of stirring at 0°C., the reaction mixture is poured into water (75 ml), and extracted with EtOAc (2×50 ml). The combined EtOAc extracts are washed with water, dried (MgSO4), filtered and the solvent removed to leave 800 mg of 5-(4-isobutyloxycarbonyloxycarbonylpropoxyphenyl)-6-methyl-2-oxo-1,2-dihydro-3-pyridinecarbonitrile as a tan-colored solid. 1H-NMR (CDCl3) δ1.00 (d, 6H); 1.60 (m, 1H); 2.16 (m, 2H); 2.50 (s, 3H); 2.70 (t, 2H); 4.10 (m, 4H); 6.93 (d, H); 7.20 (d, 2H); 7.80 (s, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][CH2:9]1.N1C=CC=CC=1>C1C=CC=CC=1>[Cl:3][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[CH2:10][CH2:9]1
Reactant: O=S(Cl)Cl
Reactant: OCCN1CCN(c2ccccc2F)CC1
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Fc1ccccc1N1CCN(CCCl)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
Thionyl chloride (1 mL) was added dropwise to an ice-cooled solution of 1-(2-hydroxyethyl)-4-(2-fluorophenyl)piperazine (300 mg) and pyridine (1 mL) in benzene (20 mL). After 30 minutes the solution was brought to room temperature and then the flask was immersed in a 60° C. oil bath for 1 hour. The layers were separated and the aqueous fraction was extracted with ethyl acetate (2×20 mL). The combined organic fractions were dried over sodium sulfate and the solvent was removed in vacuo, giving the desired product as a yellow solid (58.6 mg, 18%). ESI-MS m/z 243 (MH+).
Reaction SMILES: Br[C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16])=O.[CH3:17][NH:18][NH2:19]>C(O)CO>[CH3:16][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:7]1[C:3]2[S:4][CH:5]=[CH:6][C:2]=2[N:18]([CH3:17])[N:19]=1
Reactant: COc1ccccc1C(=O)c1sccc1Br
Reactant: CNN
Solvent: OCCO
Product: COc1ccccc1-c1nn(C)c2ccsc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (3-bromothien-2-yl) (2-methoxyphenyl)methanone (10 g), methyl hydrazine (10 ml) and ethylene glycol (70 ml) was stirred at 110°-120° C. for two hours under nitrogen. The reaction mixture was then allowed to cool to room temperature, quenched with 125 ml of water and the organics were extracted into a 50:50 ether/ethyl acetate solution. Washing, drying (over anhydrous magnesium sulfate) and then evaporation of the solvents left 10 g of an oil. This oil was passed through a silica gel column packed in hexane and eluted with dichloromethane to give 7 g of an oil which subsequently crystallized. Recrystallization from ether/hexane gave 4 g of a crystalline solid, m.p. 94°-97° C.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](OC(=O)C)(=[O:24])[CH3:23].CCOCC>C(=O)(O)[O-].[Na+]>[C:22]([C:3]1([OH:4])[C:5]2[O:9][C@@H:8]3[C@@:7]45[CH2:21][CH2:20][N:18]([CH3:19])[C@@H:15]([C@@H:14]4[CH:13]=[CH:12][C@@H:10]3[OH:11])[CH2:16][C:17]([C:6]5=2)=[CH:1][CH2:2]1)(=[O:24])[CH3:23]
Reactant: CC(=O)OC(C)=O
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)C1(O)CC=C2C[C@@H]3[C@@H]4C=C[C@H](O)[C@@H]5OC1=C2[C@]45CCN3C
Temperature: 0 °C
Yield: 80 %

Procedure:
To a stirred suspension of morphine (4 g, 14 mmol) in 10% aqueous sodium bicarbonate (377 ml) was added acetic anhydride (19 ml) over 8.5 minutes. 15 minutes after the addition, ice cold water (300 ml) was added and the solution was extracted with dichloromethane (200 ml). The organic extract was washed with brine, dried over Na2SO4, and the solvent removed in vacuo to leave a sticky white residue. Trituration with ether gave 3-acetylmorphine (3.68 g, 80%). The corresponding 3-pivalyl, 3-isobutyryl, 3-propionyl and other 3-acyl derivatives of morphine were also prepared.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:14])[F:13])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[OH-].[K+].[CH3:18][O:19][CH2:20][CH2:21]Br>CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C:12]([F:15])([F:13])[F:14])=[C:6]2[C:10]=1[N:9]([CH2:21][CH2:20][O:19][CH3:18])[CH:8]=[CH:7]2
Reactant: COCCBr
Reactant: Fc1ccc(OC(F)(F)F)c2cc[nH]c12
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COCCn1ccc2c(OC(F)(F)F)ccc(F)c21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.6 %

Procedure:
A mixture of 5 (16 g, 72.8 mmol) and powder KOH (20.4 g, 364.2 mmol) in DMSO (150 mL) is stirred at rt for 10 min. 2-Methoxyethyl bromide (10.3 mL, 109.2 mmol) is added. This mixture is stirred at rt overnight. LC/MS indicates the reaction is completed. The mixture is partitioned between H2O and Et2O. The two layers are separated, and the aqueous layer is extracted with Et2O (2×). The combined organic layers are washed with H2O and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material is purified on silica gel with heptane/EtOAc (100/0 to 50/50) as eluant to give 19.3 g (95%) of 6 as a yellow liquid. 1H NMR (CDCl3) δ 7.15 (d, J=2.1 Hz, 1H), 6.90-6.75 (m, 2H), 6.56 (t, J=2.5 Hz, 1H), 3.72 (t, J=5.2 Hz, 2H), 3.72 (t, J=5.2 Hz, 2H), 3.31 (s, 3H); 19F NMR (CDCl3) δ −57.54 (s, 3F), −137.00 (d, J=11.3 Hz, 1F); MS 278 (M+1, 100%).
Reaction SMILES: [C:1]1([CH3:10])[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.[NH:11]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12]1>>[CH3:10][C:1]1[CH:6]=[CH:5][C:4]([C:7]([C:15]2[NH:11][CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=2)=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1cc[nH]c1
Product: COC(=O)c1c[nH]c(C(=O)c2ccc(C)cc2)c1

Procedure:
Following the procedure of Example 64, p-toluoyl chloride (3.09 g., 20 mmoles) and methyl pyrrole-3-carboxylate were reacted to form methyl 5-(4-methylbenzoyl)pyrrole-3-carboxylate (2.9 g., m.p. 155°-159° C., m/e 243).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5](Br)=[CH:4][N:3]=1.C(=O)(O)[O-].[Na+].[CH3:17][N:18]([CH3:28])[C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>O1CCOCC1>[NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:22]2[CH:23]=[CH:24][C:19]([N:18]([CH3:28])[CH3:17])=[CH:20][CH:21]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(Br)cc1[N+](=O)[O-]
Reactant: CN(C)c1ccc(B(O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN(C)c1ccc(-c2cnc(N)c([N+](=O)[O-])c2)cc1
Temperature: 110 °C
Yield: 66 %

Procedure:
4.36 g of 2-amino-5-bromo-3-nitropyridine are dissolved in 73 ml of anoxic dioxane under a nitrogen atmosphere. Subsequently, 60 ml of an aqueous sodium bicarbonate solution (2.0 M), 7.3 g of 4-dimethylaminophenyl-boronic acid, and 0.886 g of trans-dichloro-bis(tricyclohexylphosphane)palladium-(II) are added. The reaction mixture is refluxed at 110° C. for 19 hours. Thereafter, the volatile components are removed in vacuo and the remaining residue is redissolved in 1.0 l of a mixture of water/dichloromethane (1:1). The aqueous phase is extracted four times each with 500 ml of dichloromethane. The organic layer is separated, dried using sodium sulfate, and evaporated to dryness to yield a colorless, crude solid. Subsequently, the residue is purified by flash chromatography on silica gel (eluent: dichloromethane/ethanol 50:1) to afford 3.41 g of the title compound as a colorless solid of m.p. 212° C. MS: 259.2 (MH+). TLC: Rf=0.55 (dichloromethane/ethanol 50:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([O:13][CH3:14])=[CH:7][C:4]=1[CH:5]=O.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[CH:18][CH:17]=1>C(O)C.[OH-].[Na+]>[C:23]([C:22](=[CH:5][C:4]1[CH:7]=[C:8]([O:13][CH3:14])[C:9]([O:11][CH3:12])=[CH:10][C:3]=1[O:2][CH3:1])[C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][CH:18]=1)#[N:24]
Reactant: N#CCc1ccc(Br)cc1
Reactant: COc1cc(OC)c(OC)cc1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(OC)c(OC)cc1C=C(C#N)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 95.7 %

Procedure:
A mixture of 1.96 g (10.0 mmol) of 2,4,5-trimethoxybenzaldehyde (purchased from Lancaster), and 1.96 g (10.0 mmol) of 4-bromophenylacetonitrile (purchased from Tokyo Kasei) in 5 ml of ethanol (purchased from Kokusan Kagaku) was heated to dissolve. Two drops of 20% aqueous sodium hydroxide solution was then added and the reaction mixture was stirred over night at ambient temperature. To the resultant reaction mass was added ethanol and crushed, and the precipitate was collected and washed with ethanol twice and with hexane twice, and dried to give 3.58 g (yield: 95.6%) of α-cyano-4-bromo-2',4',5'-trimethoxystilbene (as a yellow crystalline).
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[NH2:11][C:12]1[C:13]([Cl:30])=[CH:14][C:15]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C@H:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1>C1COCC1>[CH:1]([NH:11][C:12]1[C:13]([Cl:30])=[CH:14][C:15]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][C@H:17]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:16]=2[CH:29]=1)=[O:3]
Reactant: O=CO
Reactant: CN1CCc2cc(Cl)c(N)cc2[C@@H](c2ccccc2)C1
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)=O
Product: CN1CCc2cc(Cl)c(NC=O)cc2[C@@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Formic acid (2.25 g, 95-97%) was added dropwise to acetic anhydride (4.10 g.) at 0° C. with stirring. The resulting solution was heated under nitrogen in a water bath at 50°-60° C. with stirring for 2 hours longer. The solution was cooled down to room temperature and diluted with 5 ml of THF. A solution of (R)-8-amino-7-chloro-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (5.10 g, 0.018 mol) in 25 ml of THF was added dropwise with stirring to the above solution. The resulting solution was stirred at room temperature for 3.5 hours longer and left standing at room temperature for 24 hours. The THF was evaporated in vacuo and the residue was treated with ether and 1N Na2CO3. The dried ether solution was evaporated in vacuo. The residue crystallized from acetonitrile, m.p. 135°-136° C. [α]26D +72.6° C. (DMF, c=1).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:14]=[CH:15][CH:16]=1.[N:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][C:32](=O)[C:33](O)=[O:34])[CH:26]=1>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([N:17]2[C:33](=[O:34])[C:32]([CH2:31][C:27]3[CH:26]=[N:25][CH:30]=[CH:29][CH:28]=3)=[N:24][C:23]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]2=3)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(O)C(=O)Cc1cccnc1
Reactant: Nc1cccnc1Nc1cccc(-c2ccc3ccccc3c2)c1
Solvent: CCO
Product: O=c1c(Cc2cccnc2)nc2cccnc2n1-c1cccc(-c2ccc3ccccc3c2)c1

Procedure:
A mixture of 2-[3-(2-naphthyl)phenylamino]-3-aminopyridine and 3-(3-pyridyl)pyruvic acid in ethanol was stirred under reflux for 40 hours. After evaporation of the solvent, crude residue was chromatographed on silica gel to give 4-[3-(2-naphthyl)phenyl]-2-(3-pyridylmethyl)-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine. Crystallization from ether and recrystallization with methanol afforded colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=2)[C:10](=[O:21])[CH2:9]1)=O)(C)(C)C.Cl>CCOC(C)=O>[Cl:20][C:16]1[CH:15]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]2=[O:21])[CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2)C(=O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C1CNCCN1c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
Through a solution of Boc-protected piperazinone from Step I (17.19 g, 55.4 mmol) in 500 mL of EtOAc at −78° C. was bubbled anhydrous HCl gas. The saturated solution was warmed to 0° C., and stirred for 12 hours. Nitrogen gas was bubbled through the reaction to remove excess HCl, and the mixture was warmed to room temperature. The solution was concentrated in vacuo to provide the hydrochloride as a white powder. This material was taken up in 300 mL of CH2Cl2 and treated with dilute aqueous NaHCO3 solution. The aqueous phase was extracted with CH2Cl2 (8×300 mL) until the analysis indicated complete extraction. The combined organic mixture was dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled free amine as a pale brown oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:13]2[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[C:13]=2[CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
{(S)-1-[6-Fluoro-1-(4-fluorophenyl)-1H-benzoimidazol-2-yl]ethyl}carbamic acid tert-butyl ester (0.8 g, 2.14 mmol) was dissolved in DCM (10 mL) and TFA (5 mL) added. The reaction mixture was stirred at RT for 1 h. The resultant mixture was concentrated in vacuo to afford a dark green gum. This was dissolved in DCM (40 mL) and stirred vigorously with saturated aqueous NaHCO3 (20 mL) for 10 minutes. The layers were separated and the organic fraction dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 10% MeOH in DCM) to afford the title compound (0.33 g, 57%). LCMS (Method C): RT 1.86 min [M+H]+ 274.2
Reaction SMILES: C(O)C.O.C(O)(=O)C.[C:9]([NH:13][C:14]([CH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>C(O)C.[Pd]>[C:9]([NH:13][C:14]([CH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)NC(=O)CCc1ccc(C#N)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)NC(=O)CCc1ccc(CN)cc1

Procedure:
Add 10% Pd/C (Degussa type E101, 62 mg) to a solution of ethanol/water/acetic acid (10:5.6:0.6 mL). Add a solution of 4-[2-(tert-butylcarbamoyl)-ethyl]-benzonitrile (306 mg, 1.33 mmol) in ethanol (3.5 mL) and submit the mixture to hydrogenation at 60 psi overnight. Filter the catalyst through Celite® and concentrate in vacuo to obtain the acetate salt of the title compound. Wash with diethyl ether and filter the solid in vacuo. Add saturated aqueous NaHCO3 and extract twice with EtOAc. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to obtain the title compound as a yellow oil (70 mg, 26%). MS (ES+) m/z: 235 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([O:29]C)=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:27]([OH:29])=[O:28])=[CH:12][C:13]=3[N:14]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]4[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CCNCc1cc(F)ccc1-3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20 %

Procedure:
To a solution of methyl 14-cyclohexyl-3-fluoro-5,6,7,8-tetrahydroindolo[2,1-a][2,5]benzodiazocine-11-carboxylate (prepared as described in Example 18, Step 5) in DCM (0.01 M) was added dropwise 5 eq of a solution of BBr3 in DCM (1 M). The solution was stirred at RT for 30 min. Volatiles were removed in vacuo. The crude was then purified by automated RP-MS-HPLC (stationary phase: column Waters XTERRA prep. C18, 5 μm, 30×100 mm. Mobile phase: MeCN/H2O buffered with 0.1% TFA). Fractions containing the pure compound were combined and freeze dried to afford the title compound as a white powder (20%); MS (ES+) m/z 393 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][O:9][C:8]=2[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH3-]C#[N:16].[Na+]>CO>[C:1]1([C:7]2[CH:11]=[CH:10][O:9][C:8]=2[CH2:12][NH2:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=Cc1occc1-c1ccccc1
Agent: [Na+]
Solvent: CO
Product: NCc1occc1-c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 13.1 %

Procedure:
Stir a solution of 3-phenylfuran-2-carbaldehyde (401 mg, 2.33 mmol) and NH4OAc (1.79 g, 23.30 mmol) in methanol (8 mL) at room temperature under nitrogen. Add NaCNBH3 (102 mg, 1.63 mmol). After stirring at room temperature for 24 hours, concentrate the mixture, dilute with water (2 mL), basify with 1N sodium hydroxide, and extract with diethyl ether (4×10 mL). Dry the combined organic phases (magnesium sulfate), filter and concentrate. Perform flash chromatography on silica gel eluting with 9:1 ethyl acetate/MeOH to afford 37 mg of the title compound as a yellow solid. 1H NMR (CDCl3) δ 7.19-7.41 (m, 6H), 6.49 (d, J=2 Hz, 1H), 3.95(s, 2H), 1.80 (br s, 2H).