Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.C([N:12]1[C:17]2=[N:18][N:19]3[CH:23]=[CH:22][NH:21][C:20]3=[C:16]2[C:15](=[O:24])[N:14]([CH2:25][CH2:26][CH3:27])[C:13]1=[O:28])C1C=CC=CC=1>CO>[CH2:25]([N:14]1[C:15](=[O:24])[C:16]2=[C:20]3[NH:21][CH:22]=[CH:23][N:19]3[N:18]=[C:17]2[NH:12][C:13]1=[O:28])[CH2:26][CH3:27]
Reactant: CCCn1c(=O)c2c(nn3cc[nH]c23)n(Cc2ccccc2)c1=O
Agent: BrB(Br)Br
Solvent: CO
Product: CCCn1c(=O)[nH]c2nn3cc[nH]c3c2c1=O
Temperature: 25 °C
Yield: 44.4 %

Procedure:
Boron tribromide (0.35 ml) was added to a stirred suspension of 1-benzyl-3-propyl-1,2,3,4-tetrahydro-5H-imidazo [2',1':5,1]pyrazolo[3,4-d]pyrimidine-2,4-dione (0.5 g) at room temperature. The reaction mixture was refluxed for 22 hours and then cooled to room temperature, followed by addition of methanol (10 ml). The mixture was stirred for a while and was concentrated to dryness. After addition of ethyl acetate, resulting crystals were collected by filtration and washed with water to give crude crystals. Recrystallization from ethyl acetate gave colorless crystals (0.16 g, 44%), m.p. 326°-328° C. (decomp.).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:26]=[C:25]([O:27][C@@H:28]3[CH2:32][C@H:31]([O:33][CH3:34])[C@@H:30]([OH:35])[C@H:29]3[OH:36])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CO.[Pd]>[OH:36][C@@H:29]1[C@H:30]([OH:35])[C@@H:31]([O:33][CH3:34])[CH2:32][C@H:28]1[O:27][C:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[C:17]([N:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)[N:26]=1
Reactant: CO[C@H]1C[C@@H](Oc2nc(N3CCN(C(=O)OCc4ccccc4)CC3)nc3ccccc23)[C@H](O)[C@@H]1O
Agent: [Pd]
Solvent: CO
Product: CO[C@H]1C[C@@H](Oc2nc(N3CCNCC3)nc3ccccc23)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 75 %

Procedure:
To a solution of 2-[4-(benzyloxycarbonyl)piperazin-1-yl]-4-[(1R,2R,3S,4S)-(2,3-dihydroxy-4-methoxycyclopentan-1-yl)oxy]quinazoline (5.40 g) in methanol (108 ml) is added 10% palladium/carbon (1.00 g), and the mixture is stirred under hydrogen atmosphere and under atmospheric pressure at room temperature for 16.5 hours. The reaction mixture is filtered, and the filtrate is evaporated to dryness under reduced pressure, and the residue is crystallized from diethyl ether to give 4-[(1R,2R,3S,4S)-(2,3-dihydroxy-4-methoxycyclopentan-1-yl)oxy]-2-(1-piperazinyl)quinazoline (2.95 g) as crystals. A part of this product is recrystallized from ethanol-diethyl ether to give a pure crystalline product, which has the following physical properties.
Reaction SMILES: BrC1C=CC=C(Br)C=1C(O)C.BrC1C=CC=C(Br)C=1C(O)C(F)(F)F.[Br:26][C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=1[C:34](=[O:39])[C:35](F)(F)F>>[Br:26][C:27]1[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][C:28]=1[CH:34]([OH:39])[CH3:35]
Reactant: O=C(c1cc(Br)ccc1Br)C(F)(F)F
Agent: CC(O)c1c(Br)cccc1Br
Agent: OC(c1c(Br)cccc1Br)C(F)(F)F
Product: CC(O)c1cc(Br)ccc1Br

Procedure:
This compound was made as described above for Intermediate 7, 1-(2,6-dibromophenyl)-2,2,2-trifluoroethanol, starting with 1-(2,5-dibromophenyl)-2,2,2-trifluoroethanone to provide a light yellow oil.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:14]([C:23]4[CH:28]=[CH:27][C:26]([C:29]5([NH:33]C(=O)OC(C)(C)C)[CH2:32][CH2:31][CH2:30]5)=[CH:25][CH:24]=4)=[N:13][C:10]=3[O:11][CH2:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]>C(O)(C(F)(F)F)=O>[CH:1]([C:4]1[N:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:14]([C:23]4[CH:24]=[CH:25][C:26]([C:29]5([NH2:33])[CH2:30][CH2:31][CH2:32]5)=[CH:27][CH:28]=4)=[N:13][C:10]=3[O:11][CH2:12][C:7]2=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc1OC2
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nnc2n1-c1cc(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc1OC2
Reaction time: 0.01 h
Yield: 91.4 %

Procedure:
Tert-butyl (1-(4-(1-isopropyl-8-phenyl-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (24 mg, 0.045 mmol) was dissolved in TFA (1 ml) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexanes (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (18 mg, 92% yield). LCMS (Method D) RT=0.815 min, M+1=438. 1H-NMR (500 MHz, CD3OD) δ 8.18 (1H, s), 7.52-7.47 (2H, m), 7.45-7.41 (2H, d), 7.38-7.34 (3H, m), 7.31-7.26 (2H, m), 5.64 (2H, s), 2.82-2.72 (2H, m), 2.63-2.54 (2H, m), 2.30-2.19 (1H, m), 2.02-1.92 (1H, m), 1.51 (6H, d).
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:9]1[C:10](=[O:15])[CH2:11][CH:12]([NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCCCCCCCN1C(=O)C=CC1=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCCCCNC1CC(=O)N(CCCCCCCC)C1=O

Procedure:
A mixture of N-octyl maleimide (0.01 M) prepared as described in Example 10 above, octylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[CH2:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:12]#[N:13].[K+]>CS(C)=O.O>[O:9]1[C:5]2[CH:4]=[C:3]([CH2:2][C:12]#[N:13])[CH:11]=[CH:10][C:6]=2[CH2:7][CH2:8]1
Reactant: ClCc1ccc2c(c1)OCC2
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCc1ccc2c(c1)OCC2
Reaction time: 2 h
Yield: 72.3 %

Procedure:
To a solution of 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 73 mmol) in DMSO (100 mL) was added KCN (7.1 g, 109.5 mmol). The reaction mixture was stirred at 100 □ for 2 hours. The mixture was diluted with water and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried, concentrated in vacuo and purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford 2-(2,3-dihydrobenzofuran-6-yl)acetonitrile (8.4 g, 70.4% yield). 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J=7.6, 1H), 6.79 (d, J=7.2, 1H), 6.72 (s, 1H), 4.58 (t, J=8.4, 2H), 3.67 (s, 2H), 3.19 (t, J=8.4, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:47])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([CH:44]([CH3:46])[CH3:45])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:39]=[CH:38][C:33]([C:34]([O:36]C)=[O:35])=[CH:32][CH:31]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7].[OH-].[Na+]>O1CCOCC1>[CH3:47][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6]([C@:8]12[CH2:43][CH2:42][C@@H:41]([CH:44]([CH3:45])[CH3:46])[C@@H:9]1[C@@H:10]1[C@@:23]([CH3:26])([CH2:24][CH2:25]2)[C@@:22]2([CH3:27])[C@@H:13]([C@:14]3([CH3:40])[C@@H:19]([CH2:20][CH2:21]2)[C:18]([CH3:29])([CH3:28])[C:17]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([OH:36])=[O:35])=[CH:38][CH:39]=2)=[CH:16][CH2:15]3)[CH2:12][CH2:11]1)=[O:7]
Reactant: COC(=O)c1ccc(C2=CC[C@]3(C)[C@H]4CC[C@@H]5[C@H]6[C@H](C(C)C)CC[C@]6(C(=O)NCCN(C)C)CC[C@@]5(C)[C@]4(C)CC[C@H]3C2(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCCN(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 78 °C
Yield: 0 %

Procedure:
A mixture of methyl 4-((1S,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)ethylcarbamoyl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (6 mg, 9.30 mmol) and sodium hydroxide (0.037 mL, 0.037 mmol) in dioxane (1 mL) was heated for 3 hours at 78° C. The reaction mixture was filtered and purified by prep HPLC to provide the title compound as a white solid (2.2 mg, 36%). LCMS: m/e 631.59 (M+H)+, 2.29 min (method 1). 1H NMR (500 MHz, Acetic Acid-d4) δ ppm 8.03 (d, J=8.24 Hz, 2H), 7.30 (d, J=8.24 Hz, 2H), 5.38 (d, J=4.58 Hz, 1H), 3.74 (t, J=6.10 Hz, 2H), 3.46-3.33 (m, 2H), 2.96 (s, 6H), 2.63-2.47 (m, 1H), 2.44-2.27 (m, 1H), 2.25-1.15 (m, 22H), 1.08 (s, 3H), 1.06 (s, 3H), 1.05 (s, 3H), 1.01 (s, 3H), 1.00 (s, 3H), 0.91 (d, J=6.71 Hz, 3H), 0.82 (d, J=6.71 Hz, 3H).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8](O)[CH:9]=[CH2:10].COC(OC)(C)C>C1(C)C=CC=CC=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>[CH2:10]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH:9]=[CH2:8]
Reactant: C=CCO
Reactant: O=C1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCC1CCCCC1=O
Yield: 71.7 %

Procedure:
A solution of cyclohexanone (98.1 g, 1 mol), allyl alcohol (127.8 g, 2.2 mol), dimethoxypropane (114.6 g, 1.1 mol), and PTSA.H2O (0.1 g, 0.5 mmol) in toluene (0.51) was heated at reflux in a flask equipped with a microdistillation column (30×2.5 cm, filled with Raschig rings). After collecting the fractions distilling at 25-60° C. and 60-110° C., the residue (120 g) was distilled using a 10 cm-Vigreux-column (0.07-0.06 mbar, head temperature: 57° C.) giving 2-allylcyclohexanone (99.1 g, 72%).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][CH2:39][C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([O:14][CH3:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:39](=[O:38])[CH2:40][OH:41])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: COc1cc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1cc(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-fluoro-5-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f21) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[C:7](=[O:12])[N:6]([CH2:13][CH2:14][N:15]([CH3:17])[CH3:16])[C:5]2=[O:18].[CH3:19][O:20][C:21]1[N:28]=[CH:27][CH:26]=[C:25]([O:29][CH:30]([CH3:38])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:22]=1[CH:23]=O>CO.C(O)(=O)C>[CH3:17][N:15]([CH3:16])[CH2:14][CH2:13][N:6]1[C:5](=[O:18])[C:4]2[CH:3]=[C:2]3[NH:1][C:23]([C:22]4[C:21]([O:20][CH3:19])=[N:28][CH:27]=[CH:26][C:25]=4[O:29][CH:30]([CH3:38])[CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[N:11][C:10]3=[CH:9][C:8]=2[C:7]1=[O:12]
Reactant: CN(C)CCN1C(=O)c2cc(N)c(N)cc2C1=O
Reactant: COc1nccc(OC(C)Cc2ccccc2)c1C=O
Solvent: CC(=O)O
Solvent: CO
Product: COc1nccc(OC(C)Cc2ccccc2)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(CCN(C)C)C3=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.2 %

Procedure:
5,6-Diamino-2-(2-(dimethylamino)ethyl)isoindoline-1,3-dione (0.47 g, 1.88 mmol) was dissolved in MeOH (30 mL) and acetic acid (10 mL). 2-Methoxy-4-((1-phenylpropan-2-yl)oxy)nicotinaldehyde (0.51 g, 1.88 mmol) was added under air at rt. The reaction mixture was stirred at rt under air overnight. The volatile was removed. The residue was subjected to column chromatography (silica-gel, CH2Cl2/MeOH=17/3 v/v) to give a white solid product, 0.65 g, 69.2% yield. MS: 500.3 [M+H]+. 1H-NMR (DMSO-d6, 500 MHz): δ 13.23 (s, 1H), 8.20 (d, 1H, J=6.0 Hz), 8.12 (s, 1H), 7.95 (s, 1H), 7.09-7.07 (m, 1H), 7.11-7.95 (m, 5H), 4.84-4.81 (m, 1H), 3.82 (s, 3H), 3.72 (t, 2H, J=6.5 Hz), 2.78 (d, 2H, J=6.0 Hz), 2.53 (t, 2H, J=6.5 Hz), 2.19 (s, 6H), 1.17 (d, 3H, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4[N:17]=[CH:18][CH:19]=[C:20]([CH:21]=O)[C:15]=4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:25])=[O:26])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:36][CH:37]5[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]5)=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: CN1CCC(N)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(C=O)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC4CCN(C)CC4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 77.8 %

Procedure:
The product is prepared by following the procedure described in example 34 stage (j), starting with 0.3 g of 2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-carbaldehyde and 0.348 g of 4-amino-1-methylpiperidine instead of the cyclopropylamine used in example 34 stage (j). After purification by flash-pack chromatography (SiO2, dichloromethane/methanol 98/02 by volume as eluents), 0.28 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]-(1-methylpiperidin-4-yl)amine is obtained with the following characteristics:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]([CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:16]1=[N:17][C:18]([NH2:25])=[N:19][C:20]=2Cl)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[OH-:27].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:9][C@@H:10]([CH2:13][CH2:14][N:15]1[CH:23]=[N:22][C:21]2[C:20](=[O:27])[NH:19][C:18]([NH2:25])=[N:17][C:16]1=2)[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1nc(Cl)c2ncn(CC[C@@H](CO)COCc3ccccc3)c2n1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2c(ncn2CC[C@@H](CO)COCc2ccccc2)c(=O)[nH]1
Temperature: 60 °C

Procedure:
To a stirred solution of the chloropurine (13a) (325 mg, 0.9 mmol) in tetrahydrofuran (15 ml) was added hydrochloric acid (2M, 15 ml) and stirred at 60° C. under argon, for 26H. The reaction mixture was cooled in a water bath and sodium hydroxide solution (10M) added until pH9. The aqueous phase was extracted with methanol:ethyl acetate. (7:93, 4×35 ml). The organic phase was dried over sodium sulphate, filtered and evaporated in vacuo to give an oil (150 mg). On standing a white solid crystallised from the aqueous phase which was filtered off, washed with water (5 ml) and diethylether and dried in vacuo to give the title compound (14a) (175 mg, 56.8%). 1H NMR (400 MHz, DMSO-d6) 10.55 (1H, s), 7.66 (1H, s), 7.40 to 7.22 (5H, m), 6.44 (2H, bs), 4.51 (1H, t), 4.42 (2H, t), 4.00 (2H, t), 3.49 to 3.30 (4H, m), 1.76 (2H, q), 1.64 (1H, m). HPLC purity (Method) 98.3%, chiral HPLC (Method D) 89.6% e.e., retention time major peak 10.3 mins, minor peak 6.9 minutes. (C17H11N5O3,−7.7 ppm, NH3Cl) m/z 343.1617. The oil was purified by column chromatography on silica gel eluting with an increasing gradient of methanol (8–22%) in methylene chloride to yield (14a) (87 mg, 28.2%) as an oil.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][C:16](=[O:24])[CH:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])[CH3:18])[CH3:14].IC>C1(C)C=CC=CC=1.CCCCCC>[CH2:13]([O:15][C:16](=[O:24])[C:17]([N:19]([CH2:22][CH3:23])[CH2:20][CH3:21])([CH3:1])[CH3:18])[CH3:14]
Reactant: CCOC(=O)C(C)N(CC)CC
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CI
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)(C)N(CC)CC
Temperature: -78 °C
Reaction time: 1 h
Yield: 454.5 %

Procedure:
Diisopropyl amine (0.15 moles) was added to a flask and diluted with 50 mL of toluene. The resultant was cooled to −78° C. under nitrogen, and then a hexane solution of n-butyl lithium (0.13 moles) was added thereto, followed by stirring at −78° C. for 1 hour. Further, the mixture was heated to 0° C. and stirred for 1 hour. To this, 2-diethylaminopropionic acid ethyl ester (0.11 moles) was added and the resultant was further stirred for 1 hour, and iodomethane (0.23 moles) was added thereto, and then the temperature was restored to room temperature and the mixture was stirred for 1 hour. The reaction mixture was quenched with ice water, extracted with ethyl acetate and washed with a saturated sodium chloride aqueous solution, and then the organic layer was dried over magnesium sulphate. The solvent was distilled away, and then the residue was purified by column chromatography (hexane/ethyl acetate=4/1) to obtain α-diethylamino isobutyric acid ethyl ester (0.50 moles).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[NH:15][C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[H-].[Na+].[Cl:24][C:25]1[CH:30]=[C:29]([CH2:31]Cl)[CH:28]=[CH:27][N:26]=1>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:19])([CH3:20])[N:15]([CH2:31][C:29]3[CH:28]=[CH:27][N:26]=[C:25]([Cl:24])[CH:30]=3)[C:14]2=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: ClCc1ccnc(Cl)c1
Reactant: CC1(C)NC(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccnc(Cl)c1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 98.1 %

Procedure:
To a solution of 4.9 g of 3-[3-amino-4-(trifluoromethoxy)-phenyl]-5,5-dimethylimidazolidine-2,4-dione obtained in stage b) below in 200 mL of dimethylformamide are added, under argon, 0.68 g of 60% sodium hydride and stirring is continued for 20 minutes at room temperature. To this solution are added 2.85 g of 2-chloro-4-chloromethylpyridine obtained in stage b) of Example 3 dissolved in 20 mL of dimethylformamide, and the reaction mixture is then heated at 70° C. for 3.5 hours and then poured into 500 mL of ice-water and extracted with three times 300 mL of ethyl acetate. The combined organic phases are dried over magnesium sulphate, filtered and concentrated under reduced pressure. The residue is taken up in 500 mL of diethyl ether, washed with water, dried over magnesium sulphate, filtered and concentrated under vacuum to give 6.8 g of 3-[3-amino-4-(trifluoromethoxy)phenyl]-1-[(2-chloropyridin-4-yl)methyl]-5,5-dimethylimidazolidine-2,4-dione, the characteristics of which are as follows:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([NH2:13])[O:10][N:9]=1.[OH-].[K+].C(O)(=O)C.[CH2:20](O)[CH2:21][CH2:22][CH3:23]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([O:10][CH2:20][CH2:21][CH2:22][CH3:23])[NH:13][N:9]=1
Reactant: Nc1nc(-c2ccccc2Cl)no1
Reactant: CCCCO
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCCCOc1nc(-c2ccccc2Cl)n[nH]1

Procedure:
To the product of Example 36, stage (a), (9.7 g) in n-butanol (110 ml) was added potassium hydroxide (9.7 g), and the mixture was refluxed for 4 hours. It was then cooled, and excess potassium hydroxide was neutralised with acetic acid. The mixture was then evaporated to give 12.2 g of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=O)=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:30].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:30])=[O:27])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 48 h
Yield: 76.7 %

Procedure:
A 10-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate (0.036 g, 0.09 mmol) and ammonium chloride (0.015 g, 0.27 mmol). To this was added methanol (2 mL) followed by NH3 (4 mL, 7N in methanol, 27.6 mmol). The vial was sealed and the resulting mixture was stirred at 100° C. for 48 hr. After this time, the crude reaction solution concentrated under reduced pressure. The residue was adsorbed onto silica then purified by chromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) as eluent to afford 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamide (0.026 g, 79%) as a white solid. MW=376.88. 1H NMR (CDCl3, 500 MHz) δ 7.93-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.39-7.30 (m, 2H), 7.26-7.14 (m, 5H), 5.55-5.25 (m, 2H), 3.97 (s, 2H), 3.56 (s, 2H), 3.08 (t, J=8.0 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.14 (quin, J=7.5 Hz, 2H). MS: APCI+, m/z 377 [M+H]+. Treatment of 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamide with 1.25M HCl in methanol afforded the title compound (0.037 g, 99%) as a white solid. MW=413.34. M.p. 178-180° C. 1H NMR (DMSO-d6, 500 MHz) δ 8.11-8.07 (m, 1H), 8.00-7.93 (m, 1H), 7.81 (s, 1H), 7.57-7.47 (m, 2H), 7.43 (br s, 1H), 7.25-7.34 (m, 4H), 6.84 (br s, 1H), 4.60 (br s, 1H), 4.00 (s, 2H), 3.31 (s, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.07 (quin, J=7.5 Hz, 2H); APCI MS m/z 377 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4].[NH4+].[Cl-]>C1COCC1>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([OH:11])[N:6]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:4]
Reactant: COC(=O)C1CCCC(=O)N1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(O)N1C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 6-oxo-piperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, 35, (5.1 g, 19.8 mmol) in THF (100 mL) at −78° C., a 1M solution of LiEt3BH in THF (22.0 mL, 22 mmol) is added. After stirring for 1 hr at −78° C., the solution is cautiously quenched aqueous NH4Cl. The crude product is extracted with EtOAc and the combined EtOAc extracts are washed with brine, dried (MgSO4), and concentrated in vacuo. The desired product is used without further purification.