Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]2)=[C:4]([C@H:10]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])[C:5]([CH3:9])=[N:6][C:7]=1[CH3:8].[F:30][C:31]1[CH:56]=[CH:55][C:34]([CH2:35][CH2:36][O:37][C:38]2[CH:43]=[CH:42][C:41](B3OC(=O)CN(C)CC(=O)O3)=[CH:40][CH:39]=2)=[CH:33][CH:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:18]([O:17][C@@H:10]([C:4]1[C:5]([CH3:9])=[N:6][C:7]([CH3:8])=[C:2]([C:41]2[CH:40]=[CH:39][C:38]([O:37][CH2:36][CH2:35][C:34]3[CH:33]=[CH:32][C:31]([F:30])=[CH:56][CH:55]=3)=[CH:43][CH:42]=2)[C:3]=1[N:22]1[CH2:27][CH2:26][C:25]([CH3:29])([CH3:28])[CH2:24][CH2:23]1)[C:11]([O:13][CH:14]([CH3:16])[CH3:15])=[O:12])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1Br
Reactant: CN1CC(=O)OB(c2ccc(OCCc3ccc(F)cc3)cc2)OC(=O)C1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(C)(C)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 82 %

Procedure:
A mixture of (S)-isopropyl 2-(5-bromo-4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethylpyridin-3-yl)-2-(tert-butoxy)acetate (1.0 g, 2.13 mmol), 2-(4-(4-fluorophenethoxy)phenyl)-6-methyl-1,3,6,2-dioxazaborocane-4,8-dione (0.87 g, 2.434 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.175 g, 0.426 mmol) and 2M K3PO4 (7.99 mL, 15.98 mmol) in 1,4-Dioxane (200 mL) and Water (40.0 mL) was degassed for 10 min. Then, PdOAc2 (0.048 g, 0.213 mmol) was added, degassed for 5 min and mixture was heated at 80° C. for 3 h. After cooling to room temp, water was added and the mixture was extracted with ethyl acetate, washed with brine, dried (Na2SO4), filtered and concentrated the residue was then purified by Biotage (5-40% EtOAc/hexane) to afford (S)-isopropyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-(4-fluorophenethoxy)phenyl)-2,6-dimethylpyridin-3-yl)acetate (1.056 g, 82% yield) as white foam. 1H NMR (500 MHz, CDCl3) δ 7.32-7.26 (m, 2H), 7.18-7.14 (m, 1H), 7.09-7.01 (m, 3H), 6.99-6.93 (m, 2H), 6.07 (br. s., 1H), 5.10 (spt, J=6.2 Hz, 1H), 4.28-4.19 (m, 2H), 3.21 (d, J=12.0 Hz, 1H), 3.13 (t, J=6.9 Hz, 2H), 2.87 (t, J=12.1 Hz, 1H), 2.60 (s, 3H), 2.28 (d, J=12.8 Hz, 1H), 2.20 (s, 3H), 2.10-2.01 (m, 1H), 1.60-1.52 (m, 1H), 1.42-1.34 (m, 1H), 1.25 (d, J=6.3 Hz, 3H), 1.23 (d, J=6.3 Hz, 3H), 1.20 (s, 9H), 1.08 (d, J=12.3 Hz, 1H), 0.91 (s, 3H), 0.66 (s, 3H). 1H of piperidine was not resolved. LCMS (M+H)=606.5.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([O:12][CH3:13])=[O:11].CC(C)([O-])C.[K+].Br[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].Cl>C1COCC1>[CH3:13][O:12][C:10](=[O:11])[CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:14])([F:15])[F:1])[CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]
Reactant: CC(C)(C)OC(=O)CCBr
Reactant: COC(=O)Cc1ccccc1C(F)(F)F
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)C(CCC(=O)OC(C)(C)C)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 2-trifluoromethylphenylacetate (5 g) was dissolved in THF (75 mL). Potassium tert-butoxide (2.71 g) was added under ice-cooling, and the reaction solution was stirred for 30 minutes. tert-Butyl 3-bromopropionate (3.83 mL) was added to the reaction solution. The reaction solution was gradually heated until room temperature and stirred for four hours. A 1 N hydrochloric acid aqueous solution was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (carrier: Chromatorex Si; elution solvent: heptane:ethyl acetate=19:1→heptane:ethyl acetate=1:1) to obtain the title compound (6 g). The property values of the compound are as follows.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:10][C:9]2([CH3:30])[CH3:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[P:32]1[O:37][CH2:36][C:35]2([CH2:42][O:41][P:40](Cl)[O:39][CH2:38]2)[CH2:34][O:33]1>>[CH:1]1([O:7][N:8]2[C:9]([CH3:29])([CH3:30])[CH2:10][CH:11]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[P:32]3[O:37][CH2:36][C:35]4([CH2:42][O:41][P:40]([N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:11]5[CH2:12][C:13]([CH3:14])([CH3:15])[N:8]([O:7][CH:1]6[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]6)[C:9]([CH3:29])([CH3:30])[CH2:10]5)[O:39][CH2:38]4)[CH2:34][O:33]3)[CH2:12][C:13]2([CH3:14])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCCCCCCCCCCCNC1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1
Reactant: ClP1OCC2(CO1)COP(Cl)OC2
Product: CCCCCCCCCCCCN(C1CC(C)(C)N(OC2CCCCC2)C(C)(C)C1)P1OCC2(CO1)COP(N(CCCCCCCCCCCC)C1CC(C)(C)N(OC3CCCCC3)C(C)(C)C1)OC2

Procedure:
The title compound is prepared as a viscous oil from 1-cyclohexyloxy-4-dodecylamino-2,2,6,6-tetramethylpiperidine (made in Example 12A) and 3,9-dichloro-2,4,8,10-tetraoxa-3, 9-diphosphaspiro-[5.5]undecane according to the procedure of Example 14.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C(OP([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C>>[N:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:3][CH:4]=1
Reactant: O=Cc1ccncc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Product: CCOC(=O)CCc1ccncc1

Procedure:
The procedure of Synthetic Example 4 was repeated using isonicotinaldehyde and ethyl diethylphosphonoacetate to obtain ethyl 3-(pyridin-4-yl)propionate.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=O)=[C:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH:26]1[CH2:32][C:30](=[O:31])[NH:29][C:27]1=[O:28].N1CCCCC1>CCO>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:20]=[CH:19][N:18]4[N:21]=[CH:22][C:23]([CH:24]=[C:32]5[NH:26][C:27](=[O:28])[NH:29][C:30]5=[O:31])=[C:17]4[N:16]=3)=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc(Nc3ccn4ncc(C=O)c4n3)cc2)CC1
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN1CCN(c2ccc(Nc3ccn4ncc(C=C5NC(=O)NC5=O)c4n3)cc2)CC1
Temperature: 70 °C

Procedure:
To 5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (56 mg, 0.167 mmol) in EtOH was added hydantoin (17 mg, 0.167 mmol) and piperidine (17 μL, 0.167 mmol). The mixture was heated at 70° C. Solvent was removed under reduced pressure and then the solid was redissolved in MeOH and sonicated. Insolubilities were filtered off and the filtrate was purified by HPLC to yield 5-((5-(4-(4-methylpiperazin-1-yl)phenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione. LCMS (M+1=419)
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1>>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]3[NH:1][C:2]4=[N:3][CH:4]=[CH:5][C:6]([NH:9][C@@H:10]5[C@@H:15]6[CH2:16][C@@H:12]([CH:13]=[CH:14]6)[C@@H:11]5[C:17]([NH2:19])=[O:18])=[C:7]4[N:8]=3)=[CH:29][CH:28]=2)[CH2:23][CH2:22]1
Reactant: CN1CCN(c2ccc(C=O)cc2)CC1
Reactant: NC(=O)[C@@H]1[C@H](Nc2ccnc(N)c2N)[C@H]2C=C[C@@H]1C2
Product: CN1CCN(c2ccc(-c3nc4c(N[C@H]5[C@@H](C(N)=O)[C@@H]6C=C[C@H]5C6)ccnc4[nH]3)cc2)CC1
Yield: 18.7 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.0 mg, 0.193 mmol) and 4-(4-methyl-piperazin-1-yl)-benzaldehyde (43.3 mg, 0.212 mmol) were reacted to produce 16 mg (19%) of the title compound. mp: 220-222° C., 1H NMR (300 MHz, DMSO-d6): 12.81 (s, 1H), 7.98 (d, J=8 Hz, 2H), 7.85 (d, J=5 Hz, 1H), 7.66 (s, 1H), 7.16 (s, 1H), 7.04 (d, J=8 Hz, 2H), 6.75 (m, 1H), 6.37 (d, J=8 Hz, 1H), 6.33 (s, 2H), 3.88 (br s, 1H), 3.32 (s, 6H), 2.88 (s, 1H), 2.75 (s, 1H), 2.60 (d, J=8 Hz, 1H), 2.45 (br s, 4H), 1.42 (d, J=8 Hz, 1H). MS: 444 (M+H), HPLC: 1.57 min (G method).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:25]>C(OCC)(=O)C>[ClH:25].[ClH:25].[C:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2C(C)(C)C)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccccc1NC1CCNCC1
Yield: 72 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) was stirred under an atmosphere of nitrogen for 10 minutes. 2-Tert-butylaniline (0.974 g, 0.00652 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) were then added portionwise and stirring was continued at ambient temperature for 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1-2% ethyl acetate in hexane) to afford 1.4 g (83%) of 4-(2-tert-butyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.25 (m, 1H), 7.15 (t, 1H), 6.8-6.6 (m, 2H), 4.0 (dd, 2H), 3.9-3.8 (dd, 2H), 3.6 (bs, 1H), 3.1 (t, 2H), 2.2-2.2 (dd, 2H), 1.5-1.4 (d, 18H). A solution of 4-(2-tert-butyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.35 g, 0.00406 mole) in ethyl acetate.HCl (10 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ether and dried to afford 0.9 g (72%) of (2-tert-butyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 233.19 (M+1)+, 86.32%, 1H NMR (DMSO-d6): δ 9.1 (d, 2H), 7.2 (d, 1H), 7.1 (s, 3H), 6.8 (d, 1H), 6.6 (t, 1H), 3.7 (m, 1H), 3.4 (m, 3H), 3.0 (q, 3H), 2.6 (t, 1H), 2.2 (d, 2H), 1.7 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [F:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>Cl.O1CCOCC1>[F:1][CH:2]1[CH2:3][CH2:4][N:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(F)CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: FC1CCN(C2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 133.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-fluoro-1,4′-bipiperidine-1′-carboxylate (0.300 g, 1.047 mmol) in 10 mL of 4N HCl/dioxane was stirred at room temperature for 18 h. The solid material was collected by filtration, washed with ether and dried to afford 4-fluoro-1,4′-bipiperidine (0.261 g, 96% yield). MS (m/z) 187 (M+H+).
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[N:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[C:18]1([C:16]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:30]=[CH:31][C:2]([C:35]4[CH:36]=[CH:37][N:32]=[CH:33][CH:34]=4)=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)[OH:17])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccc(Br)cc2)CC1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: OC(c1ccccc1)(c1ccccc1)C1CCN(CCCOc2ccc(-c3ccncc3)cc2)CC1
Temperature: 90 °C
Yield: 41.8 %

Procedure:
Bromide intermediate (1-(3-(4-bromophenoxy)propyl)piperidin-4-yl)diphenylmethanol (A1) (75 mg, 0.15 mmol), Pd(dppf)Cl2 (15 mg), CsCO3 (150 mg), and pyridin-4-ylboronic acid (30 mg) was placed under an argon atmosphere in a microwave vial. Degassed THF (3 mL) and 0.1 mL of water was added via syringe and the mixture heated for 30 min. at 90° C. in a Biotage microwave reactor. The reaction was partitioned between EtOAc (10 mL) and water (3 mL) and the organic phase isolated. The organic phase was subsequently washed with brine, dried over Na2SO4, and concentrated to dryness. Purification by RP-HPLC afforded the title compound (30 mg, 41%): LC-MS (>98%) m/z=479.1 [M+H].
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]([NH:17][C:18]3[CH:27]=[CH:26][C:21]([C:22](OC)=[O:23])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[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]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH2:22][OH:23])=[CH:26][CH:27]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1ccc(Nc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.5 %

Procedure:
To a solution of methyl 4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzoate (0.075 g, 0.19 mmol) in THF (5 mL) at 0° C. was added lithium aluminum hydride (1.0 M, 0.6 mL, 0.6 mmol). The mixture warmed to rt and stirred for 2 d. After this time, the reaction was quenched with water and NaOH (2 M), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes/ethyl acetate) to afford the title compound (0.049 g, 71%) as an off-white solid. MW=350.84. 1H NMR (DMSO-d6, 500 MHz) δ 8.15 (s, 1H), 7.91-7.89 (m, 1H), 7.76-7.73 (m, 1H), 7.45-7.40 (m, 2H), 7.32 (d, J=8.5 Hz, 2H), 7.23-7.19 (m, 3H), 5.11 (t, J=6.0 Hz, 1H), 4.48 (d, J=6.0 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.08 (quin, J=7.5 Hz, 2H); APCI MS m/z 351 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]>[Pd].C(O)C>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2cc(N)ccc12
Yield: 51.7 %

Procedure:
3-Acetylamino-2-benzoyl-6-nitroindole (Example 152, 180 mg. 0.56 mmol) was hydrogenolyzed in the presence of palladium on activated carbon (5%, 18 mg) in ethanol (30 ml) at atmospheric pressure for 4 h. Catalyst was removed by filtration and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with 0 to 50% ethyl acetate in hexanes and the product recrystallized from a mixture of methanol/ethyl acetate/hexane to give 85 mg of the title compound. m.p.: 219-221° C. 1H-NMR (DMSO-d6) δ: 10.9 (1H, br s), 9.54 (1H, s), 7.44-7.66 (5H, m), 7.38(1H, d, J=9.2 Hz), 6.47-6.45 (2H, m), 5.35 (2H, s), 1.69 (3H, s)
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.[CH2:21]([O:23][C:24](=[O:29])[C:25](Br)([CH3:27])[CH3:26])[CH3:22]>O>[CH2:21]([O:23][C:24](=[O:29])[C:25]([O:15][C:12]1[CH:13]=[N:14][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:10][CH:11]=1)([CH3:27])[CH3:26])[CH3:22]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccc(OCc2ccccc2)nc1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccccc2)nc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 38 %

Procedure:
To an ice-cold solution of 0.5 g (2.48 mmol) 6-benzyloxy-3-hydroxypyridine (commercially available) in 5 mL tetrahydrofuran 0.12 g (2.7 mmol) sodium hydride (55% dispersion in mineral oil) was added in portions. After the vigorous gas evolution had ceased the reaction mixture was stirred for another 20 min., then 0.44 mL (3.0 mmol) ethyl-alpha-bromoisobutyrate (commercially available) were added dropwise. The light brown suspension was stirred for 23 h at room temperature and then poured into water. The aqueous phase was extracted three times with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and filtered. Silica gel was added to the filtrate and the slurry evaporated. The resulting solid is purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (100:0 to 70:30) to give the product as a colorless oil (38%). MS (Turbo Spray): m/z=316.1 [M+H].
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1.C([O:37][CH2:38][C:39](Cl)=[O:40])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[C:21]([C:25]([NH:27][CH:28]4[CH2:29][CH2:30][N:31]([C:38](=[O:37])[CH2:39][OH:40])[CH2:32][CH2:33]4)=[O:26])=[C:22]([CH3:24])[NH:23][C:16]=23)[CH2:4][CH2:3]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: COc1ccc(-c2ccnc3c(C(=O)NC4CCN(C(=O)CO)CC4)c(C)[nH]c23)c(OCC2CC2)c1

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-N-(piperidin-4-yl)-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f11) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]([NH2:13])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:14][CH2:15][C:16]([CH2:18]Cl)=O>C1(C)C=CC=CC=1>[Cl:14][CH2:15][C:16]1[N:13]=[C:11]([CH:10]=[CH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:12][CH:18]=1
Reactant: NC(=O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(CCl)CCl
Solvent: Cc1ccccc1
Product: ClCc1coc(C=Cc2ccc(Cl)c(Cl)c2)n1

Procedure:
2.3 g (10.6 mmol) 3-(3,4-Dichloro-phenyl)-acrylamide, 4.73 g (37,2 mmol) 1,3-dichloro acetone and 15.0 ml toluene were kept at reflux temperature for 16 h with continuous removal of water by use of a Dean-Stark trap. After removal of solvents in vacuo, the residue was purified by flash column chromatography (heptane/ethyl acetate 2:1). Yield: 2.88 g (94%) 4-Chloromethyl-2-[2-(3,4-dichloro-phenyl)-vinyl]-oxazole as tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([OH:30])=O)[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1.Cl.[NH:32]1[CH2:35][CH:34]([OH:36])[CH2:33]1>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([Cl:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:32]4[CH2:35][CH:34]([OH:36])[CH2:33]4)=[O:30])[CH:26]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)O)c4)c3cn2)c1Cl
Reactant: OC1CNC1
Agent: Cl
Product: COc1cc(OC)c(Cl)c(-c2cc3[nH]nc(-c4cnn(CC(=O)N5CC(O)C5)c4)c3cn2)c1Cl

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 36, Step 2, starting from {4-[6-(2,6-dichloro-3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-c]pyridin-3-yl]-1H-pyrazol-1-yl}acetic acid and azetidin-3-ol hydrochloride (Aldrich, Cat. No. 680079). LCMS (M+H)+=503.1/505.3.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].CC[O-].[Na+].CN(C)[CH:11]=[C:12]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)[C:13](=O)[CH3:14]>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:12]2[C:13]([CH3:14])=[N:1][C:2](=[O:3])[NH:4][CH:11]=2)=[CH:17][CH:18]=1
Reactant: NC(N)=O
Reactant: COc1ccc(C(=CN(C)C)C(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2c[nH]c(=O)nc2C)cc1
Temperature: 0 °C
Yield: 49.4 %

Procedure:
24.4 g of urea and 120 ml of a 25 percent ethanolic solution of sodium ethylate are added to a solution of 40.0 g of 4-dimethylamino-3-(4-methoxyphenyl)-3-buten-2-one in 120 ml of ethanol. The mixture is heated at the reflux temperature for 8 hours, then cooled to 0° C., and the reaction product is filtered off with suction and washed with cold ethanol. The residue is dissolved in water and, while cooling in ice, is neutralised with dilute hydrochloric acid. The precipitated product is filtered off with suction, washed with water and dried. 19.5 g of 5-(4-methoxyphenyl)-4-methyl-2-(1H)-pyrimidinone are obtained. Melting point 210° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:5]2=[N:6][CH:7]=1.[B:18]1(B2OC(C)(C)C(C)(C)O2)[O:22]C(C)(C)C(C)(C)[O:19]1.C([O-])(=O)C.[K+]>CN(C=O)C>[C:14]([O:13][C:11]([N:8]1[C:5]2=[N:6][CH:7]=[C:2]([B:18]([OH:22])[OH:19])[CH:3]=[C:4]2[CH2:10][CH2:9]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Br)cnc21
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2cc(B(O)O)cnc21
Temperature: 100 °C

Procedure:
To a mixture of tert-butyl 5-bromo-2,3-dihydropyrrolo[2,3-b]pyridine-1-carboxylate (B-12-2) (725 mg, 2.42 mMoles) and bis(pinacolato) diboron (894 mg, 3.52 mMoles) in 20 ml DMF were added potassium acetate (691 mg, 7.04 mMoles) and [1,1-Bis(diphenylphosphino)-ferrocene]dichloropalladium (II) dichloromethane (1:1) complex (34.3 mg, 0.0469 mMoles). The mixture was heated in 100° C. microwave reactor for 60 min. LCMS indicated reaction was complete. RXN was filtered and the filtrate was concentrated to dryness under high vacuum. The residual was partitioned between EtOAc and saturated aqueous NaCl. The aqueous layer was extracted with EtOAc (3×40 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a 25 g silica gel cartridge with 1˜4% MeOH in DCM as solvent. The crude product and was used as is in the next step.
Reaction SMILES: [C:1]([O:9][C@:10]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH:24]=[CH:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)[C:11](=[O:14])[CH2:12][OH:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36](OC(=O)C)(=[O:38])[CH3:37]>>[C:36]([O:13][CH2:12][C:11](=[O:14])[C@:10]1([O:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@H:28]([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:34])[CH:24]=[CH:25]2)[C@@H:20]([CH3:35])[CH2:19]3)[CH2:16][CH2:15]1)(=[O:38])[CH3:37]
Reactant: C[C@H]1C[C@@H]2[C@H]([C@@H](O)C[C@@]3(C)[C@H]2CC[C@]3(OC(=O)c2ccccc2)C(=O)CO)[C@@]2(C)C=CC(=O)C=C12
Reactant: CC(=O)OC(C)=O
Product: CC(=O)OCC(=O)[C@@]1(OC(=O)c2ccccc2)CC[C@H]2[C@@H]3C[C@H](C)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
1.9 g of 17-benzoyloxy-11β,21-dihydroxy-6α-methyl-1,4-pregnadiene-3,20-dione is reacted, analogously to Example 2c, with acetic anhydride and worked up. The crude product is purified on 200 g of silica gel with a methylene chloride-acetone gradient (0-12% acetone), thus isolating 1.8 g of 21-acetoxy-17-benzoyloxy-11β-hydroxy-6α-methyl-1,4-pregnadiene-3,20-dione, mp 258° C.