Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH3:4])[CH3:3].Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:28]=[C:27]3[C:23]([C:24]4[CH2:33][CH2:32][NH:31][CH2:30][C:25]=4[N:26]3[CH3:29])=[CH:22][CH:21]=2)[C:16](=[O:34])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:28]=[C:27]3[C:23]([C:24]4[CH2:33][CH2:32][N:31]([CH:2]([CH3:4])[CH3:3])[CH2:30][C:25]=4[N:26]3[CH3:29])=[CH:22][CH:21]=2)[C:16](=[O:34])[CH:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)Br
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CCNC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)N1CCc2c(n(C)c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc23)C1
Temperature: 55 °C
Reaction time: 72 h

Procedure:
2-Bromopropane (1.5 mL, 16 mmol) was added to a mixture of 4-(benzyloxy)-1-(9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one hydrochloride (138 mg, 0.327 mmol) and Cs2CO3 (1.2 g, 3.7 mmol) in acetonitrile (25 mL). The mixture was stirred at 55° C. for 72 h. The resulting mixture was cooled, and the precipitate was filtered off. The mother liquor was concentrated under vacuum. The residue was purified by preparatory TLC (silica gel, 10:1:0.1 dichloromethane/methanol/concentrated ammonium hydroxide) to afford 4-(benzyloxy)-1-(2-isopropyl-9-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-7-yl)pyridin-2(1H)-one. The free base was converted to the HCl salt using 1.25 M HCl in methanol to provide the title compound (26 mg, 19%) as a off white solid: 1H NMR (500 MHz, DMSO-d6) δ 10.50 (s, 1H), 7.56 (d, J=4.5 Hz, 2H), 7.52-7.38 (m, 6H), 7.01 (dd, J=4.5, 1.0 Hz, 1H), 6.11 (dd, J=4.5, 1.0 Hz, 1H), 5.97 (s, 1H), 5.16 (s, 2H), 4.60-4.53 (m, 2H), 3.78-3.70 (m, 2H), 3.70 (s, 3H), 3.40-3.28 (m, 1H), 3.18-2.98 (m, 2H), 1.44-1.39 (m, 6H); ESI MS m/z 428 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=15.1 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.[NH2:36][N:37]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:28]([NH:36][N:37]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[O:34])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NN4CCCCCC4)c(F)c3)c2cc1OC
Yield: 59.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminohomopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (43 mg, yield 55%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[C:11]([C:23](O)=[O:24])[C@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH3:29].C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:16]([O:15][CH2:14][C@@H:13]1[CH:12]=[C:11]([C:23](=[O:24])[N:28]([CH3:29])[CH3:27])[C@H:10]([OH:26])[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(C(=O)O)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of (3S,6S)-1-(tert-butoxycarbonyl)-6-((tert-butyldimethylsilyloxy)methyl)-3-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylic acid (Intermediate 136, 4.07 g, 10.50 mmol) in DMF (20 mL) at room temperature was added 2M dimethylamine in THF (5.25 mL, 10.50 mmol), HATU (5.99 g, 15.75 mmol) and then DIEA (5.50 mL, 31.51 mmol). The reaction mixture was stirred at room temperature. The reaction ran until the starting material was consumed, then it was quenched with water and extracted with EtOAc. The organic solutions was then washed with brine, and purified via flash chromatography (35-100% EA/Hex) to isolate the desired product (3.05 g, 70.0%) as a pink glassy solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8]C)=[O:7])=[O:2].[OH-].[Na+].C(OCC)(=O)C.Cl>CO>[CH:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([OH:8])=[O:7])=[O:2]
Reactant: COC(=O)c1cccc(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=Cc1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A mixture of methyl 3-formylbenzoate (6.15 g, 37.46 mmol) in methanol (61.5 mL) and 2 M sodium hydroxide aqueous solution (37.5 mL, 75 mmol) was stirred at r.t. for 1 h, Thin layer chromatography (Petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was acidified with 80 mL of 1 M hydrochloric acid aqueous solution to pH=2 and the resulting mixture was concentrated in vacuo. The residue was extracted with ethyl acetate for 3 times and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate. Removal of the solvent in vacuo gave 5.59 g of 3-formylbenzoic acid as a white solid. Yield: 99.5%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([CH:9]=O)=[CH:7][N:6]=[C:5]([S:11][CH3:12])[N:4]=1.[N+:13]([C:16]1[CH:17]=[C:18]([CH2:22][C:23]#[N:24])[CH:19]=[CH:20][CH:21]=1)([O-:15])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][N:2]1[C:3]2[N:4]=[C:5]([S:11][CH3:12])[N:6]=[CH:7][C:8]=2[CH:9]=[C:22]([C:18]2[CH:19]=[CH:20][CH:21]=[C:16]([N+:13]([O-:15])=[O:14])[CH:17]=2)[C:23]1=[NH:24]
Reactant: CNc1nc(SC)ncc1C=O
Reactant: N#CCc1cccc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1ncc2cc(-c3cccc([N+](=O)[O-])c3)c(=N)n(C)c2n1
Temperature: 100 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 4-(methylamino)-2-(methylsulfanyl)pyrimidine-5-carbaldehyde (10.0 g, 55 mmol) and (3-nitrophenyl)acetonitrile (10.5 g, 65 mmol) in DMF (150 mL) was added K2CO3 (38 g, 275 mmol) at RT. The mixture was stirred at 100° C. for 18 h. After cooling, the reaction was diluted with DMF (50 mL) and filtered. The filtrate was concentrated to give crude 8-methyl-2-(methylsulfanyl)-6-(3-nitrophenyl)-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine (9.0 g, 50% yield) which was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.C(N(CC)CC)C.[C:38](O)([CH3:41])([CH3:40])[CH3:39]>C(Cl)(Cl)Cl>[CH3:39][C:38]([O:23][C:22](=[O:24])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][NH:11][C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:10])=[CH:20][CH:19]=1)([CH3:41])[CH3:40]
Reactant: CC(C)(C)O
Reactant: O=C(O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Cc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A solution of 3 g (9.1 mmol) of 4-[2-[[(phenylmethoxy)carbonyl]amino]-ethoxy]benzeneacetic acid in 60 ml of chloroform is cooled to −30° C. and 1.18 g (10.9 mmol) of ethyl chloroformate and 1.52 ml (10.9 mmol) of triethylamine are added. The mixture is stirred for 1 hour at −30° C. and 1.63 g (22 mmol) of t-butanol and 1.52 ml (10.9 mmol) of triethylamine are then added. The mixture is stirred for 16 hours at room temperature and then concentrated under reduced pressure. The evaporation residue is taken up in 100 ml of ethyl acetate and the organic phase obtained is washed with water and then dried over magnesium sulfate and concentrated under reduced pressure. The crude product is purified by chromatography on silica gel using a dichloromethane/methylcyclohexane mixture (1/1; v/v) as the eluent to give 930 mg of the expected compound (yield=26%).
Reaction SMILES: Br[C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:10]=1.[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]>>[CH2:21]([O:23][C:24]([C:26]1([C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][C:38]([C:2]4[CH:6]=[N:5][N:4]([CH3:7])[C:3]=4[NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=5)[N:10]=4)=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[CH2:28][CH2:27]1)=[O:25])[CH3:22]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)cc2)CC1
Reactant: Cn1ncc(Br)c1Nc1cccc(-c2ccccc2)n1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4cnn(C)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 5, Step 2, using the following starting materials: (4-bromo-2-methyl-2H-pyrazol-3-yl)-(6-phenyl-pyridin-2-yl)-amine and 1-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6][CH2:5]2.[Br:14]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:14][CH:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[C:8]([CH3:13])([CH3:12])[CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)CCCc2cc(Br)ccc21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)CCC(Br)c2cc(Br)ccc21

Procedure:
To a solution of 1.2 g (5.0 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1-dimethylnaphthalene (Compound F) in 20 ml of CCl4 was added 0.97 g (5.5 mmol) of N-bromosuccinimide followed by 20 mg (0.08 mmol) of benzoylperoxide. The mixture was refluxed for 3 hours, filtered and the filtrate washed with water (5 ml). The organic phase was dried over MgSO4 and then concentrated in vacuo to yield the title compound as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=2)[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=1
Reactant: Cc1c2n(c3c(Br)cc(F)cc13)CCNC2=O
Reactant: OB(O)c1ccncc1
Product: Cc1c2n(c3c(-c4ccncc4)cc(F)cc13)CCNC2=O

Procedure:
The title compound, light yellow solid (46 mg, 62%), MS (ISP) m/z=296.5 [(M+H)+], mp 290° C., was prepared in accordance with the general method of example 1 from 6-bromo-8-fluoro-10-methyl-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 14) (74.3 mg, 0.25 mmol) and commercially available pyridine-4-ylboronic acid (39.9 mg, 0.325 mmol).
Reaction SMILES: Br[CH:2]([CH3:20])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>CO.C(Cl)(Cl)Cl>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:8]([CH:14]2[CH2:18][NH:17][C:16](=[O:19])[CH2:15]2)=[CH:7][C:6]=1[O:5][CH2:4][CH2:3][CH:2]([CH3:20])[N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OCCC(C)Br
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc(C2CNC(=O)C2)cc1OCCC(C)N1CCN(c2ccccc2)CC1
Yield: 19.8 %

Procedure:
Analogously to Example 7, using 10 mmol of 4-[3-(3-bromobutoxy)-4-methoxyphenyl]-2-pyrrolidone and 11 mmol of 1-phenylpiperazine (95% strength), 4-{4-methoxy-3-[3-methyl-3-(4-phenylpiperazin-1-yl)propoxy]phenyl}-2-pyrrolidone is obtained in a 19.8% yield, m.p. 88°-90° (ethanol; after chromatography methanol/chloroform 1:9).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][F:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)(=O)C>C(Cl)Cl>[NH2:7][CH2:8][C:9]1[CH:36]=[CH:35][C:12]2[N:13]([CH2:30][CH2:31][CH2:32][CH2:33][F:34])[C:14]([CH2:16][N:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]([O:27][CH3:28])=[CH:19][C:18]3=[O:29])=[N:15][C:11]=2[CH:10]=1
Reactant: COc1cc(=O)n(Cc2nc3cc(CNC(=O)OC(C)(C)C)ccc3n2CCCCF)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC(=O)Cl
Product: COc1cc(=O)n(Cc2nc3cc(CN)ccc3n2CCCCF)c2ccccc12
Reaction time: 3 h

Procedure:
To a cooled (0° C.) solution of [1-(4-fluoro-butyl)-2-(4-methoxy-2-oxo-2H-quinolin-1-ylmethyl)-1H-benzoimidazol-5-ylmethyl]-carbamic acid tert-butyl ester (20 mg, 0.039 mmol) in DCM (1 mL) was added TFA (91 μL, 1.2 mmol). The solution was allowed to reach room temperature and stirred for 3 hrs. The volatiles were removed in vacuo and the residue was stripped with DCM and methanol. The TFA salt was dissolved in methanol followed by the addition of acetyl cloride (28 μL, 0.39 mmol) and concentrated. The product was dissolved in methanol and dichloromethane and concentrated (twice) then the resiude was triturated in diethyl ether to give 1-[5-aminomethyl-1-(4-fluoro-butyl)-1H-benzoimidazol-2-ylmethyl]-4-methoxy-1H-quinolin-2-one; HCl salt (11 mg, 65%) as an off white solid:
Reaction SMILES: [C:1]1([CH2:7][C:8](O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14].N.[CH2:17]1[CH:26]2[CH:21]([CH2:22][CH2:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=32)[NH:20][C:19](=[O:31])[CH2:18]1>C(O)CO.C(COC)OC>[CH2:21]([N:20]1[C:11]2[C:7]([CH3:8])([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=3[CH2:13][CH:12]=2)[CH2:17][CH2:18][C:19]1=[O:31])[CH2:26][CH2:25][CH3:27].[CH2:11]([N:15]1[C@@H:21]2[C@:26]([CH3:1])([C:25]3[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=3[CH2:23][CH2:22]2)[CH2:17][CH2:18][C:19]1=[O:31])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(O)Cc1ccccc1
Reactant: CCCCN
Reactant: O=C1CCC2c3ccccc3CCC2N1
Agent: N
Solvent: COCCOC
Solvent: OCCO
Product: CCCCN1C(=O)CCC2(C)C1=CCc1ccccc12
Product: CCCCN1C(=O)CC[C@@]2(C)c3ccccc3CC[C@H]12
Reaction time: 7 h

Procedure:
By following the procedures described in Example 40, Steps A, B, C, D, E and F using phenylacetic acid as the starting material and in Step F using n-butylamine rather than ammonia and dimethoxyethane rather than ethylene glycol, the compound 4-n-butyl-10b-methyl-1,2,3,4,6,10b-hexahydrobenzo[f]quinolin-3-one was prepared. This hexahydrobenzo[f]quinolin-3-one was hydrogenated by following the procedures described Example 22 except that the reaction was carried out at 60° C. over 7 hours and worked up according to the procedures described in Example 42 to afford 61 mg of the title compound as a colorless oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1.O.[NH2:32][NH2:33]>CN(C=O)C>[C:28]([C:24]1[CH:23]=[C:22]([CH2:21][CH2:20][C:19]2[C:3]3[C:4](=[O:18])[N:5]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:6]4[N:7]=[CH:8][CH:9]=[CH:10][C:11]=4[C:2]=3[NH:33][N:32]=2)[CH:27]=[CH:26][CH:25]=1)#[N:29]
Reactant: N#Cc1cccc(CCC(=O)c2c(O)c3cccnc3n(-c3ccccc3)c2=O)c1
Reactant: NN
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc(CCc2n[nH]c3c2c(=O)n(-c2ccccc2)c2ncccc32)c1
Yield: 93.2 %

Procedure:
To a suspension of 4-hydroxy-3-[1-oxo-3-(3-cyanophenyl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (495 mg, 1.25 mmol, prepared in Synthetic Example 12) in DMF (12 ml) was added hydrazine monohydrate (80%, 148 μl, 3.69 mmol, 3.0 eq.), and the mixture was treated in the same manner as in Example 16 to give 3-[2-(3-cyanophenyl)ethyl]-5-phenyl-1H-pyrazolo[4,3-c][1,8]naphthyridin-4 (5H)-one (456 mg, 93%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)C1C=CC=CC=1.C(OC1C2N(C=CN=2)C=CC=1)C1C=CC=CC=1>>[CH3:1][O:8][C:9]1[N:14]2[CH:15]=[CH:16][N:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1
Reactant: c1ccc(COc2cccc3nccn23)cc1
Agent: c1ccc(COc2cccn3ccnc23)cc1
Product: COc1cccc2nccn12

Procedure:
5-benzyloxyimidazo[1,2-a]pyridine and 8-benzyloxyimidazo[1,2-a]-pyridine.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+]>O1CCCC1>[C:1]1([N:7]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:9]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[CH2:12][CH2:11]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Fc1ccccc1C(=NNc1ccccc1)N1CCN(c2ccccc2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: c1ccc(N2CCN(c3nn(-c4ccccc4)c4ccccc34)CC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 24.4 %

Procedure:
To a stirred solution, under nitrogen, of 9.1 g of 1-[(phenylhydrazono)(2-fluorophenyl)methyl]-4-phenylpiperazine in 100 ml of tetrahydrofuran was added, dropwise, a solution of 3.3 g of potassium t-butoxide in 35 ml of tetrahydrofuran. The reaction mixture was stirred at ambient temperature for 4 hours and concentrated. The concentrate was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated to a solid. The solid was flash chromatographed on silica gel utilizing hexane/ethyl acetate (30%) as the eluent. Concentration of the appropriate fractions followed by recrystallization from ethyl acetate/hexane gave 2.1 g (25%) of 1-phenyl-3-(4-phenyl-1-piperazinyl)-1H-indazole, mp 129-130°.
Reaction SMILES: [CH2:1]([C@H:3]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[CH2:4][OH:5])[CH3:2].C([OH:14])(C)C.N[C@H](C(OC)=O)CC1C=CC=CC=1.N[C@@H](C(OC)=O)CC1C=CC=CC=1>CC(C)=O.C(Cl)(Cl)Cl>[CH2:1]([C@H:3]([CH2:6][CH2:7][N+:8]([O-:10])=[O:9])[C:4]([OH:14])=[O:5])[CH3:2]
Reactant: CC(C)O
Reactant: CC[C@@H](CO)CC[N+](=O)[O-]
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: COC(=O)[C@H](N)Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: CC[C@H](CC[N+](=O)[O-])C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
To 1.0 mmol alcohol 2b dissolved in 10 mL acetone at 0° C. was added 1.5 mmol H2Cr2O7 (3 mL Jones reagent). The mixture was stirred for 5 h, during which time the mixture warmed to room temperature. Excess isopropanol was added, and the mixture was stirred for 10 min. The mixture was filtered, and the solution was diluted with 2 mL 2 N HCl and extracted with Et2O. Complete extraction of the product into the Et2O phase was monitored by TLC. The organic layers was washed with saturated NaCl, dried over MgSO4, filtered and concentrated to give a viscous oil, of which the desired product 3 was purified via column chromatography eluting with EtOAc/hexane (1:10 to 1:3; v/v) to give pure product as a yellow oil in 92% yield. TLC Rf=0.45 (EtOAc/hexanes, v/v, 1:1) 1H NMR (300 MHz, CDCl3) 4.56-4.41 (m, 2H), 2.53-2.44 (m, 1H), 2.38-2.19 (m, 2H), 1.84-1.60 (m, 2H), 1.00 (t, J=7.4 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.66, 73.55, 43.57, 28.41, 25.24, 11.41. HRMS m/z (ESI): calc. for C6H11NO4Na [M+Na]+184.0586, found 184.0578. Optical rotation: [α]rtD+17.51 (c=3.82, CHCl3). The ee of this compound (>95%) was determined by coupling one portion to L-Phe-OMe and another portion to D-Phe-OMe and then analyzing the products by 1H NMR spectroscopy.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=[CH2:8])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[SH:21])C=CC=CC=1.N(C(C)(C)C#N)=NC(C)(C)C#N.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:1]([CH:3]1[CH2:7][CH:6]([CH2:8][SH:21])[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2]
Reactant: C=C1CC(CC)C(C(=O)OCC)C1
Reactant: S[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C1CC(CS)CC1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.6 %

Procedure:
Ethyl 2-ethyl-4-methylenecyclopentanecarboxylate (0.720 g, 3.95 mmol), triphenylsilanethiol (1.329 g, 4.54 mmol) and 2,2′-azobis(2-methylpropionitrile) (0.195 g, 1.185 mmol) in toluene (3.95 mL) was heated at reflux for about 6 h. The reaction mixture was cooled to ambient temperature and then concd under reduced pressure. The material was purified by silica gel (40 g) chromatography eluting with a gradient of 0-10% EtOAc in heptane to give a colorless oil. The resulting oil was dissolved in DCM (4 mL) and TFA (1.52 mL, 19.7 mmol) was added. After stirring at ambient temperature for about 1 h, the solvent was removed under reduced pressure. The material was purified by silica gel (40 g) chromatography eluting with a gradient of 0-15% EtOAc in heptane to provide ethyl 2-ethyl-4-(mercaptomethyl)cyclopentanecarboxylate (0.620 g, 72%) as a colorless oil: 1H NMR (DMSO-d6) δ 4.13-4.01 (m, 2H), 2.50-2.30 (m, 3H), 2.24 (m, 1H), 2.15-1.87 (m, 3H), 1.66-1.54 (m, 1H), 1.50-1.37 (m, 2H), 1.31-1.23 (m, 2H), 1.17 (t, 3H), 0.83 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5]=[CH:4][C:3]=1[NH2:12].[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18]>ClCCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: Nc1cnc2cccnc2c1Cl
Reactant: O=C(Cl)CCCCl
Solvent: ClCCCl
Product: O=C(CCCCl)Nc1cnc2cccnc2c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-chloro[1,5]naphthyridin-3-amine (2.0 g, 11 mmol) and 4-chlorobutyryl chloride (4.7 g, 33 mmol) in 1,2-dichloroethane (75 mL) was heated at reflux for 20 hours. The reaction mixture was then concentrated under reduced pressure and the residue washed with two 25 mL portions of hexane. The solid was then taken up in methanol (35 mL), 1.0 mL of 10% solution of sodium hydroxide in water was added, and the solution was stirred at room temperature for 4 hours. The reaction mixture was then concentrated under reduced pressure to provide 4-chloro-N-(4-chloro[1,5]naphthyridin-3-yl)butanamide which was used directly in the next step without further purification.