Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[C:14](=[O:16])[CH:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]1)[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.CO.[BH4-].[Na+]>O>[NH2:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]([OH:16])[CH:13]([CH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:21][CH2:20]1)[CH2:12][CH2:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2
Reactant: Nc1c2c(nc3ccccc13)CCC(CCC1CCN(Cc3ccccc3)CC1)C2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Nc1c2c(nc3ccccc13)CCC(CCC1CCN(Cc3ccccc3)CC1)C2O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
0.41 gm of 9-amino-2-(2-(1-benzylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroacridin-1-one was dissolved into 10 ml of methanol. To the solution was added 0.15 gm of sodium borohydride, and the mixture was stirred for 2 hours at room temperature. After the addition of 30 ml of water, the reaction mixture was extracted with chloroform. The extract was washed with saturated brine, dried, and evaporated under reduced pressure. 0.28 gm of 9-amino-2-(2-(1-benzylpiperidin-4-yl)ethyl)-1,2,3,4-tetrahydroacridin-1-ol (Compound (I) with R1 =R3 =H, R2 =--NH2, A=>CH(CH2)n --, Y=>CHOH, m=2 and n=2) was obtained by recrystallizing the residue from ethyl acetate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:31][OH:32])[CH:17]=2)=[CH:12][CH:11]=1>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:28])=[O:29])=[CH:23][CH:22]=3)[N:19]=[C:18]([CH2:31][OH:32])[CH:17]=2)=[CH:12][CH:11]=1
Reactant: OB(O)c1ccco1
Reactant: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(Br)cc2)cc1
Product: CS(=O)(=O)c1ccc(-n2nc(CO)cc2-c2ccc(-c3ccco3)cc2)cc1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2-furanboronic acid instead of 2-thiophenboronic acid acid and 4-[5-[4-Bromophenyl]-3-hydroxymethyl-[4-(methylsulfonyl)phenyl]-1H-pyrazole instead of 1-[4-(Methylsulfonyl)phenyl]-5-(4-bromophenyl)-3-trifluoromethyl-1H-pyrazole in step 2.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH:8]([CH3:15])[N:7]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:21]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH:16]1([N:7]2[CH:8]([CH3:15])[CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:6]2=3)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CC1C(=O)N(C)c2cnc(Cl)nc2N(C2CCCC2)C1C
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)C(C)C(C)C(=O)N2C
Yield: 72.1 %

Procedure:
A mixture of 0.092 g (0.0003 mole) of (rac)-2-chloro-9-cyclopentyl-5,7,8-trimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-41), 0.1 g (0.00036 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.095 g of (rac)-4-(9-cyclopentyl-5,7,8-trimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-41a) as an off-white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:19][CH:18]=2)[CH3:16])[CH2:10][CH2:9]1)(=O)=O.[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH2:43].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[NH:38]1[CH:42]=[CH:41][N:40]=[C:39]1[NH:43][CH2:6][CH2:7][C@@:8]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])=[CH:21][CH:22]=2)[CH3:16])[CH2:10][CH2:9]1
Reactant: Nc1ncc[nH]1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCOS(C)(=O)=O)(c2ccc(F)cc2)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCNc2ncc[nH]2)(c2ccc(F)cc2)OC1=O
Yield: 19.2 %

Procedure:
A mixture of 2-((S)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl methanesulfonate (40 mg, 0.07 mmol), 1H-imidazol-2-amine (18 mg, 0.21 mmol), K2CO3 (29 mg, 0.21 mmol) in acetonitrile (4 mL) was heated to reflux overnight. The solvent was removed and the residue was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc and the combined organic layer was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product. It was purified by preparative HPLC to give (R)-6-(2-(1H-imidazol-2-ylamino)ethyl)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (7 mg, 17%). LC-MS Method 3 tR=1.15, min, m/z=521; 1H NMR (CDCl3): 1.55 (m, 3H), 2.16-2.33 (m, 7H), 2.94 (m, 1H), 3.56 (m, 1H), 4.02 (m, 1H), 5.66 (m, 1H), 6.25 (m, 1H), 6.52 (m, 1H), 6.90 (m, 2H), 7.04 (m, 4H), 7.18 (m, 2H), 7.26 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 550 mg, 1.63 mmol) was dissolved in 20 mL DMF. To it was added NaH (60% in mineral oil, 98 mg, 2.45 mmol). The mixture was stirred at RT for 30 min, and then iodomethane (305 μL, 4.89 mmol) was added. It was stirred for 1.5 hour, diluted with 120 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to flash column using 0 to 50% EtOAc in hexane to isolate (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl(methyl)carbamate (293). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1 hour, and the mixture was concentrated in vacuo to dryness. It was dissolved in 5 mL DMF and 15 mL dioxane. To it were added DIEA (1.45 mL, 8.15 mmol) and then dimethylcarbamoyl chloride (300 μL, 3.26 mmol). The mixture was stirred at RT for overnight, diluted with 120 mL EtOAc, washed with water ×2, dried, concentrated, and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 490 mg, 93% overall) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH2:26])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[C:27]1([N:33]=[C:34]=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:34]([NH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:35])[CH:21]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(N)c3)c12
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C#Cc3ccnc(NC(=O)Nc4ccccc4)c3)c12
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-amine (24 mg, 0.07 mmol) in dichloromethane (1400 μl) was added phenyl isocyanate (9.09 μl, 0.084 mmol) and the mixture was allowed to stir for 72 hours at room temperature. The precipitated solid was filtered was filtered and the washed with 10 mL of dichloromethane. The solid was dried in vacuo to afford N-(4-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}pyridin-2-yl)-N′-phenylurea. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H); 9.46 (s, 1H); 8.69 (s, 1H); 8.28 (s, 1H); 8.23-8.21 (m, 2H); 8.01 (s, 1H); 7.56 (s, 1H); 7.47 (d, 2H); 7.26 (t, 2H); 7.04 (s, 1H); 6.98-6.96 (m, 2H); 4.05 (s, 3H); 3.82 (s, 3H). LRMS (ESI) calculated for C26H21N7O2 [M+H]+, 464.2; found 464.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH2:14](OC(=O)C1C=C(N2CCCCC2)C=CC=1N)C.S(Cl)(Cl)=O>CO>[CH3:14][O:8][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([NH2:1])[CH:3]=[CH:4][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1ccc([N+](=O)[O-])c(C(=O)O)c1
Reactant: CCOC(=O)c1cc(N2CCCCC2)ccc1N
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)c1cc(N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 42 %

Procedure:
5-Amino-2-nitro-benzoic acid (compound A′) (910 mg) was dissolved in methanol (50 ml). Thionyl chloride (0.74 ml) was added dropwise to the solution on an ice bath, and a reaction was allowed to proceed under reflux with heating for 12 hr. After the completion of the reaction, the reaction solution was allowed to stand for cooling to room temperature and was then concentrated under the reduced pressure. The residue was purified by column chromatography eluted with a chloroform-methanol system to give 5-amino-2-nitro-benzoic acid methyl ester (410 mg, yield 42%).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Br:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)=[O:21]
Reactant: CC(C)c1ccc(N)cc1
Reactant: CCCC(C)(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCC(C)(Br)C(=O)Nc1ccc(C(C)C)cc1
Yield: 65.3 %

Procedure:
410 mg (3.04 mmoles) of 4-isopropylaniline was dissolved in 10 ml of benzene, and 500 mg of triethylamine was added. With stirring under ice cooling, 800 mg (4.10 mmoles) of 2-bromo-2-methylvaleryl chloride was added dropwise. After the addition, the mixture was further stirred at room temperature for 1 hour. The crystals that precipitated were separated by filtration. The filtrate was concentrated, and the residue was recrystallized from benzene to give 620 mg of 2-bromo-2-methyl-4'-isopropylvaleranilide. m.p. 87.2°-88.2° C. IR νmaxcm-1 3300 and 1650. Yield 65.4%.
Reaction SMILES: [F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([N+:11]([O-])=O)=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:3]=1[F:23].[NH4+].[Cl-]>C1COCC1.O.[Zn]>[F:1][C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([NH2:11])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([I:21])=[CH:17][C:16]=2[F:22])[C:3]=1[F:23]
Reactant: O=[N+]([O-])c1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: C1CCOC1
Product: Nc1c(Nc2ccc(I)cc2F)c(F)c(F)c2ccoc12
Reaction time: 1.5 h

Procedure:
For scale up synthesis, a solution of (4,5-difluoro-7-nitro-benzofuran-6-yl)-(2-fluoro-4-iodo-phenyl)-amine (165 g) and NH4Cl in 2.5 L of THF and 2.5 L of water was cooled to between 0° C. and 5° C. Zinc dust was added (portionwise) at a temperature of less than 25° C. (exothermic during first half of addition) over 30 minutes. The addition of zinc dust resulted in a color change from yellow to dark purple and to pale yellow. Complete conversion was achieved with the addition of NH4Cl (50 g) and zinc (60 g), followed by vigorous stirring for 20 minutes and a further 1.5 hours. Purity was 89.5%. The suspension was filtered and rinsed with 1 L of water and 1.5 L of THF. The combined solution was concentrated to remove THF (87.7% purity). 3 L of EA was added with stirring for 30 minutes. The layers were separated; the EA layer was washed with 2 L of water twice and then dried of MgSO4. The EA was filtered and concentrated to dryness. The crude was used in the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 8.06 (d, 1H), 7.46 (dd, 1H), 7.40 (bs, 1H), 7.19 (d, 1H), 7.07 (d, 1H), 6.11 (t; 1H); 5.33 (bs, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:7].C1N2CN3CN(C2)CN1C3.C(O)(=[O:25])C.Cl>O>[C:6]([C:5]1[CH:4]=[C:3]([C:10]([O:11][CH3:12])=[CH:9][CH:8]=1)[CH:2]=[O:25])#[N:7]
Reactant: COc1ccc(C#N)cc1CBr
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: O
Product: COc1ccc(C#N)cc1C=O

Procedure:
To 5 g of 3-bromomethyl-4-methoxybenzonitrile, were added 6.2 g of hexamethylenetetramine, 10 ml of acetic acid, and 10 ml of water. The mixture was heated under reflux for 2 hours. After addition of 10 ml of concentrated hydrochloric acid, the mixture was further refluxed for 15 minutes. The reaction mixture was cooled in ice and extracted with 200 ml of ethyl acetate. The ethyl acetate layer was washed twice with 200 ml of water, then with saturated aqueous sodium hydrogencarbonate solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. Ether was added to the residue and the precipitated crystals were collected by filtration to yield 1.6 g of 3-cyano6-methoxybenzaldehyde; m.p. 119°-120° C.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[O:19]([C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:27][CH:28]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(Oc2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 4-phenoxybenzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.92 min.; [M+H]+: 404.15 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([OH:23])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:26][O:27][CH2:28][CH2:29]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([O:23][CH2:29][CH2:28][O:27][CH3:26])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COCCBr
Reactant: Cc1nc2c(cc1O)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Agent: [H-]
Agent: [Na+]
Product: COCCOc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to example 1 intermediate d), from (4R,9aR)-7-hydroxy-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 7, intermediate), sodium hydride and 2-bromoethyl methyl ether.
Reaction SMILES: [C:1]([N:4]1[CH2:9][C:8](=[O:10])[NH:7][C:6](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1=[O:18])(=[O:3])[CH3:2].CI.[C:21]([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:1]([N:4]1[CH2:9][C:8](=[O:10])[N:7]([CH3:21])[C:6](=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]1=[O:18])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(=O)NC(=Cc2ccccc2)C1=O
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CC(=O)N1CC(=O)N(C)C(=Cc2ccccc2)C1=O
Yield: 45 %

Procedure:
1-Acetyl-3-benzylidene-2,5-piperazinedione (compound 18 prepared in Reference Example 2) was N-methylated by treatment with methyl iodide (2.0 equivalents) in the presence of Na2CO3 (1.0 equivalents) in DMF at room temperature for 24 hours. The solvent was removed and the residue purified by flash chromatography. The product 1-acetyl-3-benzylidene-4-methyl-2,5-piperazinedione, obtained in 45% yield, was treated with 4-methoxybenzaldehyde (1.0-1.1 equivalents) in the presence of Cs2CO3 in DMF at 80° C. for 206 hours to give compound 121, which is (3Z,6Z)-6-benzylidene-3-(4-methoxybenzylidene)-1-methyl-2,5-piperazinedione, in 35% yield.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1>>[C:1]([CH2:2][CH2:3][CH:8]1[CH:7]=[CH:6][CH:5]=[CH:9]1)#[N:4]
Reactant: C=CC#N
Reactant: C1=CCC=C1
Product: N#CCCC1C=CC=C1

Procedure:
U.S. Pat. No. 3,409,659 by R. L. Pruett and S. Raines teaches a modification of Bruson's addition of acrylonitrile to cyclopentadiene. By using a 4-6 molar excess of cyclopentadiene, maintaining the temperature of the reaction mass at between -5° and 0° C., and extending the addition and post-addition reaction periods, Pruett and Raines were able to obtain low yields (from 11 percent to a maximum of 30 percent) of mono-(β-cyanoethyl)cyclopentadiene.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15].[C:29]([N:32]1[CH2:37][CH2:36][CH:35]([C:38](O)=[O:39])[CH2:34][CH2:33]1)(=[O:31])[CH3:30].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([N:4]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:3][CH2:2][NH:1][C:38]([CH:35]3[CH2:34][CH2:33][N:32]([C:29](=[O:31])[CH3:30])[CH2:37][CH2:36]3)=[O:39])([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:6](=[O:15])[NH:7]2)=[CH:12][CH:11]=1
Reactant: CC(=O)N1CCC(C(=O)O)CC1
Reactant: CC(C)(C)CN(CCN)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(C(=O)NCCN(CC(C)(C)C)C2(Cc3cccc(Cl)c3)C(=O)Nc3cc(Cl)ccc32)CC1
Yield: 32.9 %

Procedure:
The mixture 3-[(2-Amino-ethyl)-(2,2-dimethyl-propyl)-amino]-6-chloro-3-(3-chloro-benzyl)-1,3-dihydro-indol-2-one (120 mg, 0.286 mmol), 1-Acetyl-piperidine-4-carboxylic acid (59 mg, 0.344 mmol), EDC.HCl (66 mg, 0.344 mmol), HOBt (46 mg, 0.344 mmol) and DIPEA (111 mg, 0.860 mmol) in dichloro-methane (2 mL) was stirred at room temperature for overnight. The crude was then purified with Prep-HPLC to give 54 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide of as a white solid. Then 18 mg rac-1-Acetyl-piperidine-4-carboxylic acid{2-[[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide was separated by chiral preparative HPLC to obtain 7 mg 1-Acetyl-piperidine-4-carboxylic acid{2-[[(S)-6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-(2,2-dimethyl-propyl)-amino]-ethyl}-amide MS: [M+H]+=573.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH2:16]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1)[CH3:17]>>[CH2:16]([C:18]1[N:23]=[CH:22][C:21]([CH2:24][N:25]([C:26]2[CH:27]=[CH:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:20][CH:19]=1)[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CCc1ccc(CNc2ccc(C(C)C)cc2)cn1
Product: CCc1ccc(CN(C(=O)C2CCCc3ccc(OC)cc32)c2ccc(C(C)C)cc2)cn1
Yield: 55.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.58 g) and [(6-ethylpyridin-3-yl)methyl](4-isopropylphenyl)amine (0.71 g) as starting materials, N-[(6-ethylpyridin-3-yl)methyl]-N-(4-isopropylphenyl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.69 g) was obtained.
Reaction SMILES: Cl[CH:2]1[C:14]2[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[C:17]1([CH:23]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1>[C:30]1([CH:23]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:24]2[CH2:25][CH2:26][N:27]([CH:2]3[C:14]4[NH:13][C:12](=[O:15])[C:11](=[O:16])[NH:10][C:9]=4[C:8]4[CH:7]=[CH:6][CH:5]=[CH:4][C:3]3=4)[CH2:28][CH2:29]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]c2c([nH]c1=O)C(Cl)c1ccccc1-2
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c2c([nH]c1=O)C(N1CCN(C(c3ccccc3)c3ccccc3)CC1)c1ccccc1-2
Reaction time: 20 h
Yield: 23.4 %

Procedure:
9-Chloro-9H-indeno[1,2-b]pyrazine-2,3(1H, 4H)-dione (1.0 g, 4.26 mmol) was suspended in 10 ml of dry tetrahydrofuran, while cooling in an ice bath. 1-(Diphenylmethyl)piperazine (1.1 g, 4.26 mmol) dissolved in 10 ml of dry tetrahydrofuran was added over 10 min., thereafter triethylamine (0.59 ml, 4.26 mmol) in 3 ml tetrahydrofuran was added. The ice bath was removed and stirring was continued for 20 hours at room temperature. The precipitate was filtered off and washed with tetrahydrofuran to give 1.36 g of the crude product which was recrystallized two times from acetic acid to yield 0.45 g (20%) of the title compound as a hydrochloride. M.p. 212°14 216° C. 1H-NMR (DMSO-d6, δ): 2.5-3.3 (m, 8H), 4.64 (s, 1H), 5.62 (d, 1H), 7.1-7.9 (m, 14H), 11.25 (s, 1H), 11.74 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [Cl-].[CH3:2][CH:3]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH:4]=[CH:5][C:6]1[C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][CH2:8][C:7]=1[CH3:14].[CH:34]([CH:36]=[C:37]([CH3:45])[CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=O>CO>[CH3:45][C:37](=[CH:36][CH:34]=[C:3]([CH3:2])[CH:4]=[CH:5][C:6]1[C:11]([CH3:12])([CH3:13])[CH2:10][CH2:9][CH2:8][C:7]=1[CH3:14])[CH:38]=[CH:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)C=CC(C)=CC=O
Reactant: CC1=C(C=CC(C)[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: [Cl-]
Solvent: CO
Product: CCOC(=O)C=CC(C)=CC=C(C)C=CC1=C(C)CCCC1(C)C

Procedure:
In a manner analogous to that described in Example 1, from 1-methyl-3-(2,6,6-trimethyl-1-cyclohexen-1-yl)allyl-triphenylphosphonium chloride and ethyl 5-formyl-4-methyl-2,4-pentadienoate there is obtained ethyl 4,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexen-1-yl)-2,4,6,8-nonatetraenoate of melting point 65°-66° C. (from methanol).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:10]2[N:15]3[CH2:16][CH2:17][C:18]4[NH:19][C:20](=[O:23])[CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12][N:11]=2)[CH:7]=[CH:8][CH:9]=1.[K+].[Br-]>CO.C(Cl)(Cl)Cl>[O:23]=[C:20]1[NH:19][C:18]2[CH2:17][CH2:16][N:15]3[C:10]([C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[CH:3]=[O:2])=[N:11][CH:12]=[C:13]([C:14]=23)[CH:22]=[CH:21]1
Reactant: COC(OC)c1cccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1cccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)c1

Procedure:
1-(3-Dimethoxymethyl-phenyl)-8,9-dihydro-7H-2,7,9a-triaza-benzo[cd]azulen-6-one (31a) was isolated during flash silica gel column chromatography as a by-product in the form of a white solid: mp=182-185° C.; Rf=0.15 (5% MeOH/CHCl3); IR (KBr) 2361, 1653, 1458, 1091, 1046 cm−1; 1H NMR (DMSO-d6) δ 3.31 (s, 6H), 3.52-3.54 (m, 2H), 4.45-4.46 (m, 2H), 5.50 (s, 1H), 7.36 (t, 1H, J=7.8 Hz), 7.58-7.60 (m, 2H), 7.81-7.92 (m, 4H), 8.43-8.45 (m, 1H). HRMS calcd for C19H19N3O3 337.1426 (M+), found 337.1415. Anal. (C19H19N3O3) C, H, N, O.