Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[CH:33]([NH2:36])([CH3:35])[CH3:34]>CN(C=O)C.O>[CH:33]([NH:36][C:15]([C@@H:12]1[CH2:11][CH2:10][C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:14][CH2:13]1)=[O:17])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(=O)O)CC1
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)NC(=O)[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of cis-4-(tert-butoxycarbonylamino)cyclohexanecarboxylic acid (54.58 g, 224 mmol) in dry DMF (200 mL) was added 1,1′-carbonyldiimidazole reagent grade (70 g, 432 mmol) portionwise with stirring. After the evolution of CO2 had ceased, the resulting solution was stirred at RT for 10 minutes. The solution was cooled to 0° C., and isopropylamine (38.5 mL, 449 mmol) was added with stirring. The reaction was stirred at 0° C. for 10 minutes and at RT for 24 hours. The reaction was diluted slowly with water (1 L) with stirring in an ice-water bath and then allowed to age for 1 hour. The precipitate was collected by filtration, washed with water, and dried in vacuo to generate tert-butyl cis-4-(isopropylcarbamoyl)cyclohexyl-carbamate as a white solid (39.11 g, 61% yield).
Reaction SMILES: C(O[CH:5]1[O:26][C@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([NH:36][C:37](=[O:39])[CH3:38])[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=O)C.Cl.C([Cl:44])(=O)C>O1CCOCC1>[C:37]([NH:36][C@H:15]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C@@H:25]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:26][C@H:5]([Cl:44])[C@@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:39])[CH3:38]
Reactant: CC(=O)N[C@H]1[C@@H](OCc2ccccc2)[C@@H](COCc2ccccc2)OC(OC(C)=O)[C@@H]1OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N[C@@H]1[C@@H](OCc2ccccc2)[C@@H](Cl)O[C@H](COCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 16 h

Procedure:
Dissolve 1.5 g. of 3-acetamido-3-deoxy-2,4,6-tri-O-benzyl-D-galactopyranosyl acetate in 75 ml. of dioxane containing 4% by weight of hydrogen chloride and add 35 ml. of acetyl chloride to the solution. Allow the mixture to stand in a dry nitrogen atmosphere for 16 hours at 40°. Evaporate the mixture to dryness in vacuo to a syrup. Repeatedly co-distil this residue with dry toluene until all hydrogen chloride is removed. Crystallize the resultant residue with hexane to obtain the title product of this example. Yield 1.1 g., m.p. 158°-159° (decomp.), [α]D26 + 169.9°.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10](=[O:13])[NH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14]N1C(=O)CCC1=O.CN(C=O)C>O>[Br:14][C:9]1[C:10](=[O:13])[NH:11][CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: O=c1cnc(-c2ccccc2)c[nH]1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: O=c1[nH]cc(-c2ccccc2)nc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 14.4 %

Procedure:
A mixture of 5-phenylpyrazin-2(1H)-one (0.86 g), N-bromosuccinimide (0.89 g) and DMF (16 mL) was stirred at room temperature for 2 hr. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title compound (0.18 g).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[C:12]2[C:11]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)=[N:10][CH:9]=[N:8][C:7]=2[CH2:6][CH2:5]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.C(N(CC)CC)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:16]2[CH2:17][CH2:18][N:13]([C:11]3[C:12]4[C@H:4]([CH3:3])[CH2:5][CH2:6][C:7]=4[N:8]=[CH:9][N:10]=3)[CH2:14][CH2:15]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: C[C@@H]1CCc2ncnc(N3CCNCC3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2[C@H](C)CC3)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.1 %

Procedure:
To a solution of (R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine dihydrochloride (30 mg, 0.1 mmol) in DCM (10 mL) and triethylamine (1 mL) were added 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (35 mg, 0.1 mmol) and HBTU (39 mg, 0.1 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed and the residue was purified by silica gel chromatography, eluting with ethyl acetate to give tert-butyl 2-(4-chlorophenyl)-3-(4-((R)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (25 mg, 44%). 1H NMR (CDCl3, 400 MHz) δ 8.44 (s, 1H), 7.30-7.20 (m, 4H), 3.90-3.18 (m, 9H), 3.18-2.70 (m, 4H), 2.28 (m, 1H), 1.83 (m, 1H), 1.65 (m, 1H), 1.47 (s, 9H), 1.12 (m, 3H), 0.98 (m, 3H), 0.68 (m, 3H). MS (APCI+) [M+H]+542.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([O:24]C)[CH:22]=3)[N:17]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH:16]=2)[CH:3]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([OH:24])[CH:22]=3)[N:17]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:27])=[O:28])[CH:16]=2)[CH:5]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]=1
Reactant: COc1cnc2c(c1)c(-c1cc(Cl)nc(NC3CCCCC3)c1)cn2S(=O)(=O)c1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1cc(-c2cc(Cl)nc(NC3CCCCC3)c2)c2cc(O)cnc21
Temperature: 25 °C
Yield: 68.3 %

Procedure:
To a solution of Example 178a (250.0 mg, 0.503 mmol) in CH2Cl2 (20 mL) was added 1M BBr3 in dichloromethane (3.0 mL, 3.02 mmol) at −78° C. The reaction was slowly warmed to room temperature overnight. The clear solution was decanted. The solids remaining in the flask were stirred in saturated NaHCO3 and EtOAc till all the solids were dissolved. The organic layer was dried over MgSO4, filtered, concentrated, and purified on an 80 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (90:10 to 85:15) to give 0.166 g of the title compound.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([CH:19]1[CH2:23][CH2:22][C:21]([CH3:27])([C:24](O)=[O:25])[C:20]1([CH3:29])[CH3:28])=[O:18].C(N(CC)CC)C>C(#N)C>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:24]([C:21]1([CH3:27])[CH2:22][CH2:23][CH:19]([C:17]([O:16][CH3:15])=[O:18])[C:20]1([CH3:29])[CH3:28])=[O:25])[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Reactant: COC(=O)C1CCC(C)(C(=O)O)C1(C)C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)OC)C1(C)C
Temperature: 60 °C

Procedure:
To a 20-mL scintillation vial containing a magnetic stir bar were added the product from Example 92B (637 mg, 3.00 mmol), racemic 3-(methoxycarbonyl)-1,2,2-trimethylcyclopentanecarboxylic acid (Maybridge, 771 mg, 3.60 mmol), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium tetrafluoroborate (TBTU, Bachem, 1.16 g, 3.60 mmol). Anhydrous acetonitrile (8 mL) was added to form a white slurry. Neat triethylamine (Aldrich, 1.09 g, 10.8 mmol) was added via syringe to form a tan solution. The reaction flask was heated to 60° C. in a shaker block and mixed for 2 hours. The volatiles were removed by rotary evaporator to give a brown oil. The product was purified by flash chromatography (silica gel: 2-20% ethyl acetate in hexanes) to afford the title compound. 1H NMR (DMSO-d6) δ 0.50 (s, 3H), 0.90 (t, J=7.5 Hz, 3H), 1.21 (s, 3H), 1.24-1.36 (m, 2H), 1.30 (s, 3H), 1.41-1.51 (m, 1H), 1.57 (s, 9H), 1.57-1.67 (m, 2H), 1.73-1.87 (m, 1H), 2.01-2.11 (m, 1H), 2.62-2.67 (m, 2H), 2.70-2.81 (m, 1H), 2.85-2.91 (m, 1H), 3.60 (s, 3H), 8.50 (s, 1H). MS (ESI+) m/z 409 (M+H)+. Anal. calcd. for C22H36N2O3S: C, 64.67; H, 8.88; N, 6.86. Found: C, 64.20; H, 8.71; N, 6.59.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7]([P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])([P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])=[CH2:8]>>[N:1]1([CH2:8][CH:7]([P:9]([O:13][CH2:14][CH3:15])(=[O:16])[O:10][CH2:11][CH3:12])[P:17]([O:18][CH2:19][CH3:20])(=[O:24])[O:21][CH2:22][CH3:23])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: C=C(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Product: CCOP(=O)(OCC)C(CN1CCNCC1)P(=O)(OCC)OCC

Procedure:
Reaction of piperazine with tetraethyl ethenylidenebisphosphonate according to the procedure described in Example 1, above, gives tetraethyl 2-(1-piperazyl)-1,1-ethanediphosphonate. Reaction of the latter with 9-chloro-10-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benz-oxazine-6-carboxylic acid yields the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:17][C:18]([F:23])([F:22])[C@@H:19]1[CH2:21][O:20]1.C(=O)([O-])[O-]>C(#N)C>[F:17][C:18]([F:23])([F:22])[C@@H:19]([OH:20])[CH2:21][N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][C:6]=2[CH2:7][CH2:8]1
Reactant: FC(F)(F)[C@@H]1CO1
Reactant: COc1cc2c(cc1[N+](=O)[O-])CCNCC2
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C[C@H](O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
7-Methoxy-8-nitro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (215 mg, 0.967 mmol) was placed into a sealable vial, suspended in Acetonitrile (10 mL) then (S)-2-Trifluoromethyl-oxirane (130 uL, 1.5 mmol) was added, followed by Macroporous carbonate resin (3.16 mmol/g loading; 0.810 g, 2.56 mmol). The reaction was stirred at room temperature for 24 h, filtered and concentrated in vacuo to afford (S)-1,1,1-Trifluoro-3-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-propan-2-ol as an orange oil (316 mg, 97%), which was used without further purification. 1H-NMR (CDCl3, 400 MHz) δ 7.67 (s, 1H), 6.83 (s, 1H), 4.05 (m, 1H), 3.95 (s, 3H), 2.6-3.0 (m, 10H); 19F-NMR (CDCl3, 376 MHz) δ−78.7 (s).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5](C(OCC)OCC)(=[O:9])[O:6]CC>Cl>[NH2:1][CH2:2][CH:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:4][P:5]([OH:9])[OH:6]
Reactant: CCOC(OCC)P(=O)(CC(CN)c1ccccc1)OCC
Agent: Cl
Product: NCC(CP(O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A solution of 4.0 g of ethyl 3-amino-2-phenylpropyl(diethoxymethyl)phosphinate in 40 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 2 h. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure and co-evaporated twice with 20 ml of water under reduced pressure. The crude product is dissolved in 20 ml of water, washed twice with 20 ml of diethyl ether and the aqueous layer is then separated and evaporated under reduced pressure. The crude product is dissolved in 50 ml ethanol and 5 ml of propylene oxide is added dropwise. The precipitated solid is collected by filtration and dried to give 3-amino-2-phenylpropylphosphonous acid m.p. 228°-235° C., 31 p=+24.3 ppm (D2O).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[C:8](C)[CH:9]=[CH:10][C:11]=2[F:13])[C:6]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)=[N:5]1)[CH2:2][CH3:3].B(Br)(Br)Br.C1CCCCC=1>>[F:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[N:4]([CH2:1][CH2:2][CH3:3])[N:5]=[C:6]2[C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1
Reactant: CCCn1nc(-c2ccc(OC)cc2)c2c(C)ccc(F)c21
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: CCCn1nc(-c2ccc(O)cc2)c2cccc(F)c21
Yield: 95.8 %

Procedure:
Prepared according to Method D step C from 1-propyl-7-fluoro-3-(4-methoxyphenyl)-methyl-1H-indazole (0.051 g, 0.197 mmol), boron tribromide (0.10 mL, 1.05 mmol) and 0.3 mL of cyclohexene to give the product (0.051 g) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([OH:30])[CH:3]=1.Cl.CO>>[ClH:1].[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([CH:19]3[CH2:22][NH:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])=[C:4]([OH:30])[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(N2CCN(C(=O)CNc3cc(Cl)c(Cl)cc3O)CC2)C1
Agent: Cl
Solvent: CO
Product: O=C(CNc1cc(Cl)c(Cl)cc1O)N1CCN(C2CNC2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 199.1 %

Procedure:
A mixture of tert-butyl 3-(4-(2-(4,5-dichloro-2-hydroxyphenylamino)acetyl)piperazin-1-yl)azetidine-1-carboxylate (150 mg, 0.33 mmol) in HCl-MeOH (20 mL, 57 mmol) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to afford the crude product (130 mg) which was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].S(=O)(O)[O-].[Na+].[Cl:19][C:20]1[CH:25]=[C:24]([NH2:26])[C:23]([NH2:27])=[CH:22][C:21]=1[Cl:28]>C(O)C>[Cl:19][C:20]1[C:21]([Cl:28])=[CH:22][C:23]2[NH:27][C:7]([C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[C:4]([N+:11]([O-:13])=[O:12])[CH:5]=3)=[N:26][C:24]=2[CH:25]=1
Reactant: COc1ccc(C=O)cc1[N+](=O)[O-]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1[N+](=O)[O-]

Procedure:
4-Methoxy-3-nitrobenzaldehyde (4.65 g, 27.6 mmol) and sodium bisulfite (5.79 g, 55.2 mmol) were added to ethanol (200 mL) and refluxed for 4 hours at which time, 1,2-dichloro-4,5-phenylenediamine (4.56 g, 27.6 mmol) was added and the mixture was refluxed overnight. The reaction mixture was filtered while hot and the pea-green solid washed with ethanol (3.09 g), mp>250° C.
Reaction SMILES: [C:1]1([CH:7]([N:12]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>CO.O>[C:1]1([CH:7]([N:12]([CH2:18][CH:19]([O:22][CH3:23])[O:20][CH3:21])[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)C(c1ccccc1)N(CC(OC)OC)C(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(CN(C(=O)C(C)C)C(C(=O)O)c1ccccc1)OC
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
A solution of methyl 2-phenyl-2-[N-(2,2-dimethoxyethyl)-2-methylpropanamido]acetate (72.3 g) in methanol (800 ml) was treated with a solution of sodium hydroxide (30 g) in water (200 ml). The mixture was stirred for 2.5 hours and then left to stand at room temperature for 18 hours. It was then concentrated to 500 ml and diluted with water (500 ml), washed with diethyl ether (2×200 ml), cooled to below 10° C., and acidified by treatment with hydrochloric acid (4N), maintaining the temperature below 10° C. The precipitated product was extracted with ethyl acetate (3×750 ml) and the combined extracts were washed with brine (300 ml), and evaporated, to give an off-white solid, which was recrystallised from a mixture of ethanol and ethyl acetate and washed with light petroleum, to give 2-phenyl-2-[N-(2,2-dimethoxyethyl)-2-methylpropanamido]acetic acid (67.2 g), in the form of a white solid, m.p. 147°-149° C. [Elemental analysis: C,62.3;H,7.6;N,4.54%; calculated: C,62.1; H,7.4;N,4.53%].
Reaction SMILES: [CH3:1][C:2]1CC=C[CH:3]=1.[CH3:7][C:8]1[CH2:12][CH:11]=[C:10]([CH3:13])[CH:9]=1>>[CH3:13][C:10]1[C:11](=[C:2]([CH3:3])[CH3:1])[CH:12]=[C:8]([CH3:7])[CH:9]=1
Reactant: CC1=CC=CC1
Reactant: CC1=CCC(C)=C1
Product: CC1=CC(=C(C)C)C(C)=C1

Procedure:
The synthetic procedure according to Example 1 step A, is followed but the methylcyclopentadiene is replaced by 1,3-dimethylcyclopentadiene.
Reaction SMILES: [C:1]([C:3]1[C:4](=O)[NH:5][C:6]([CH3:16])=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]=1[CH3:9])#[N:2].C1(P(Cl)([Cl:26])=O)C=CC=CC=1.[OH-].[NH4+]>>[Cl:26][C:4]1[C:3]([C:1]#[N:2])=[C:8]([CH3:9])[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH3:16])[N:5]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Cc1[nH]c(=O)c(C#N)c(C)c1-c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Cc1nc(Cl)c(C#N)c(C)c1-c1ccccc1
Temperature: 0 °C

Procedure:
3-Cyano-4,6-dimethyl-5-phenyl-2-pyridone (7.0 grams) and phenylphosphonic dichloride (12.1 grams) were heated at 175°-180° C. for 2-3 hours. The solution was cooled, poured into ice water and made basic with ammonium hydroxide. A precipitate formed which was collected, air dried, and determined by NMR to be the desired product, yield 7.6 grams, m.p. 118°-123° C.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[CH:11][C:3]=1[CH2:4][CH:5]([CH2:9][CH3:10])[C:6](Cl)=[O:7].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:14]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:12]=[C:11]2[C:3]=1[CH2:4][CH:5]([CH2:9][CH3:10])[C:6]2=[O:7]
Reactant: CCC(Cc1ccc(C(C)(C)C)cc1Br)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC1Cc2c(Br)cc(C(C)(C)C)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
A solution of 116 g (0.35 mol) of 2-(2-bromo-4-tert-butylbenzyl)butanoyl chloride in 150 ml of dry dichloromethane was added dropwise to a suspension of 56.2 g (0.42 mol) of powdered AlCl3 in 500 ml of dry dichloromethane for 1.5 hours at 0° C. The resulting mixture was stirred overnight at room temperature and then poured on 500 cm3 of ice. The organic layer was separated, and the aqueous layer was extracted by 3×100 ml of dichloromethane. The combined organic extract was washed by saturated aqueous NaHCO3, dried over K2CO3, and evaporated to dryness. Fractional rectification of the residue gave 92.2 g (89%) of the title product, b.p. 142° C.-147° C./1 mm Hg. Anal. calc. for C15H19BrO: C, 61.03; H, 6.49. Found: C, 59.88; H, 6.37. 1H NMR (CDCl3): δ 7.80 (d, J=1.5 Hz, 1H, 5-H), 7.71 (d, J=1.5 Hz, 1H, 7-H), 3.22 (dd, J=17.4 Hz, J=7.6 Hz, 1H, 3-H), 2.75-2.62 (m, 2H, 3′-H and 2-H), 1.98 (m, 1H, CHH′Me), 1.55 (m, 1H, CHH′Me), 1.34 (s, 9H, tBu), 1.03 (t, J=1.4 Hz, CH2Me). 13C{1H} NMR (CDCl3): δ 208.4, 153.3, 150.7, 138.7, 135.1, 121.8, 119.3, 49.2, 35.0, 32.9, 31.2, 24.4, 11.5.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[N:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13][CH2:12]1.C(N(CC)CC)C.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][N:30]=1>C(Cl)Cl>[CH3:28][C:29]1[N:30]=[CH:31][C:32]([NH:35][C:36](=[O:37])[NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH2:5][CH:6]3[N:11]2[CH2:12][CH2:13][N:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:15][CH2:16]2)=[CH:33][CH:34]=1
Reactant: COC(=O)N1CCN(C2CCc3c(N)cccc32)CC1
Reactant: Cc1ccc(N=C=O)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(C2CCc3c(NC(=O)Nc4ccc(C)nc4)cccc32)CC1
Reaction time: 1 h
Yield: 51.1 %

Procedure:
To a room temperature solution of Methyl 4-(4-amino-2,3-dihydro-1H-inden-1-yl)piperazine-1-carboxylate (175 mg, 0.635 mmol, 1.0 equiv) and triethylamine (90 μL, 0.635 mmol, 1.0 equiv) in dry DCM (1.7 mL) was added freshly filtered 2-methyl-5-isocyanatopyridine (94 mg, 0.699 mmol, 1.1 equiv) in dry DCM (1.7 mL) dropwise via cannula. After 1 h, the reaction was diluted with DCM and washed with water and with brine. The resulting solution was dried over sodium sulfate, filtered, and concentrated in vacuo. The solid was dissolved in a minimal volume of DMF and water was added to precipitate the product. The resulting solid was filtered, washed three times with water and twice with hexane to provide the title compound as a light brown solid (133 mg, 51%). LCMS [M+H]+=410.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:18][CH2:17][C:5]2[N:6]([CH2:14][CH2:15][NH2:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:16][CH2:15][CH2:14][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:18][CH2:17][C:5]2=3)=[O:25])=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Cc1ccc2c(c1)c1c(n2CCN)CCN(C)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)c1c(n2CCNC(=O)c2ccc(F)cc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 12.8 %

Procedure:
A mixture of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethanamine (0.1 g, 0.41 mmol), 4-fluoro benzoic acid (57 mg, 0.41 mmol), N,N′-dicyclohexylcarbodiimide (93 mg, 0.45 mmol) and 4-dimethylaminopyridine (55 mg, 0.45 mmol) in dry dichloromethane (2.5 ml) were stirred at room temperature for 3 h. The reaction mixture was filtered through Celite and concentrated by rotary evaporation to obtain 19.22 mg of 4-fluoro-N-(2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)ethyl)benzamide as TFA salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 ml). 1H NMR (DMSO) 9.98 (bs, 1H), 8.72 (t, 1H), 7.80-7.84 (m, 2H), 7.45 (d, 1H), 7.25-7.30 (m, 2H), 7.20 (s, 1H), 7.0 (d, 1H), 4.50-4.59 (m, 1H), 4.17-4.30 (m, 2H), 3.73-3.80 (m, 2H), (3.50-3.59 (m, 3H), 3.05-3.15 (m, 2H), 2.92 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1([CH3:19])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.CO[CH:22]1[CH2:26][CH2:25][CH:24](OC)O1>C(O)(=O)C.O>[CH3:19][C:2]1([N:1]2[CH:22]=[CH:26][CH:25]=[CH:24]2)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CC1(N)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Reactant: COC1CCC(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: CC1(n2cccc2)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
To a solution of 1.3 g of 10-amino-10-methyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one in 25 ml of acetic acid is added 0.66 g of 2,5-dimethoxytetrahydrofuran. The mixture is stirred at boiling for 1 hour, cooled to 20° C. and concentrated to dryness under reduced pressure (15 mmHg; 2 kPa) at 60° C. The product obtained is suspended in 100 ml of distilled water and the insoluble product formed is isolated by filtration, washed successively 4 times with 40 ml in total of distilled water, 3 times with 30 ml in total of methanol and 3 times with 30 ml in total of acetone, and then dried under reduced pressure (1 mmHg; 0.13 kPa) at 100° C. 0.82 g of 10-methyl-10-(1-pyrrolyl)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, melting at 320° C. (decomposition) (Analysis, % calculated C: 71.51, H: 4.67, N: 18.53, O: 5.29, % found C: 71.7, H: 4.5, N: 18.3).
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[C:8]([NH2:3])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Product: NC(=O)c1ccccc1

Procedure:
To a stirred mixture of 2.5 parts of compound 36, 0.44 parts of N,N-diethylethanamine and 399 parts of dichloromethane were added 0.85 parts of benzoyl chloride. The whole was refluxed for 18 hours. After cooling, the reaction mixture was washed with 50 parts of water, dried, filtered and evaporated. The residue was solidified in acetonitrile. The product was filtered off and dried, yielding 2.3 parts (75.4%) of N-5-[2-[4-[bis (4-fluorophenyl)-methylene]-1-piperidinyl]ethyl]-3,4-dihydro-3,6-dimethyl-4-oxo-2-pyrimidinyl]benzamide; mp. 239.6° C. (comp. 56).