Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][CH:9](O)[C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH:9]([NH:8][C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: Cc1ccc(C(=O)NC(O)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC(Cl)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.6 %

Procedure:
A stirred solution of Example 1A (3.48 g, 15.0 mmol) in CH2Cl2 (60 mL) at 0° C. was treated with pyridine (1.20 mL). The reaction mixture was treated dropwise with thionyl chloride (1.10 mL, 15.0 mmol), and the reaction flask was equipped with a calcium chloride drying tube. The reaction mixture was stirred at 0° C. for 4 hours, the cooling bath was removed, and the solution was stirred at ambient temperature for an additional 12 hours. Concentration of the reaction mixture provided a white solid which was triturated with diethyl ether (2×200 mL) to provide 2.40 g of the desired product as a white solid.
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][NH+:7]=1.[C:16](=[C:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)([CH3:18])[CH3:17]>CN(C)C=O.CO>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:18][C:16]1[C:19]2[C:23]([CH:22]=[CH:21][CH:20]=2)=[N+:7]2[C:6]([CH:17]=1)=[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[CH:9][CH2:8]2
Reactant: CC(C)=C1CCCC1=O
Reactant: c1ccc2c[nH+]ccc2c1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc2[n+](c3c1=CC=C3)CC=c1ccccc1=2

Procedure:
Isoquinolinium perchlorate (2.3 g) and 2-isopropylidene cyclopentanone (1.5 g) in dimethylformamide (5 ml) were refluxed for 18 hours. The reaction mixture was cooled, diluted with methanol and filtered. Purification was effected by recrystallization from acetonitrile (norite). Yield 1.5 g, m.p. > 300°,
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([CH2:36][O:37]C(=O)C)=[O:35]>>[OH:37][CH2:36][C:34]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH2:30][O:31][CH3:32])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:35]
Reactant: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](N)CC3)c[nH]c12
Reactant: CC(=O)OCC(=O)Cl
Product: COCCOc1cc(OC)ccc1-c1ncnc2c(C(=O)N[C@H]3CC[C@H](NC(=O)CO)CC3)c[nH]c12

Procedure:
Starting from trans-4-[4-methoxy-2-(2-methoxy-ethoxy)-phenyl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A182) and acetic acid chlorocarbonyl-methyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.C(Cl)Cl.[F:22][C:23]([F:35])([F:34])[C:24]1[CH:25]=[C:26]([CH2:30][C:31](Cl)=[O:32])[CH:27]=[CH:28][CH:29]=1.C(NCC)(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:18]=[CH:17][C:14]([CH2:15][NH:16][C:31](=[O:32])[CH2:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([C:23]([F:34])([F:22])[F:35])[CH:25]=4)=[CH:13][CH:12]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Reactant: O=C(Cl)Cc1cccc(C(F)(F)F)c1
Agent: CCNC(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(Cc1cccc(C(F)(F)F)c1)NCc1ccc(-c2cnc3cc(Cl)ccn23)cc1
Temperature: 40 °C

Procedure:
In a 40 mL septum capped vial purged with N2, add 4-(7-chloro-imidazo[1,2-a]pyridin-3-yl)-benzylamine (125 mg, 0.48 mmol), magnetic stir bar, CH2Cl2 (6 mL), cool the vial in an ice bath and slowly add 1 mL (CH2Cl2 solution of m-trifluoromethyl-phenylacetyl chloride, 0.48 mmol). Add isopropyl ethyl amine (0.8 mL) with THF (2 mL). Remove the vial from the ice bath and heat to 40° C. for 6 hours. Add a trace of MeOH and evaporate the solvents under vacuum and take up the oil into a minimal amount of CH2Cl2 and chromatograph using SiO2 eluting with a gradient of 0.5% to 5% of 2 M NH3 in MeOH with the balance CH2Cl2. Isolate the product, dry in a vacuum oven at 40° C. for 24 hours to give 144 mg (67%) MS (ES), m/z 444 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[NH:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2.CI.[C:17](=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:17][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH3:12])=[C:7]([CH3:13])[CH:6]=2)[N:11]=[C:2]([CH3:1])[C:3]1=[O:14]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc2nc(C)c(=O)[nH]c2cc1C
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cc1cc2nc(C)c(=O)n(C)c2cc1C
Temperature: 25 °C

Procedure:
A mixture of 3,6,7-trimethyl-2(1H)-quinoxalinone (5.0 g., 0.027 mol.), methyl iodide (15 ml.), sodium carbonate (5.0 g., 0.047 mol.) and dimethylformamide (75 ml.) was stirred at room temperature for eighteen hours, then heated at 75°-80° C. for three hours. Removal of the dimethylformamide under reduced pressure and dilution with water gave a brown solid. Crystallization from acetone (Darco) gave light tan needles. (2.85 g., m.p. 164°-166°, 53%)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.O[C@H:16]1[CH2:20][CH2:19][O:18][CH2:17]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[N+:8]([C:6]1[CH:7]=[C:2]([CH:3]=[C:4]([C:11]([F:12])([F:13])[F:14])[CH:5]=1)[O:1][CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Reactant: O[C@H]1CCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(OC2CCOC2)cc(C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 72 h

Procedure:
3-Hydroxy-5-nitrobenzotrifluoride (5 g, 24.1 mmol, 1 eq), (S)-3-hydroxytetrahydrofuran (1.9 mL, 24.1 mmol, 1 eq), PPh3 (6.3 g, 24.1 mmol, 1 eq) were dissolved in 43 mL of THF. The solution was cooled to −20° C. DIAD (4.8 mL, 24.6 mmol, 1.02 eq) was added in 22 mL of THF over the course of 2 h while the temperature was maintained between −10 and −20° C. After the addition was complete the reaction was stirred for 3 days at RT. The solvent was removed in vacuo. The residue was stirred with ˜250 mL of hexane for 45 min during which time triphenylphosphine oxide precipitated as a white solid. The solid was removed by filtration and the filtrate was washed twice with 2 N NaOH and once with brine. After drying over Na2SO4 the solution was filtered and the solvent removed under reduced pressure. The crude material was purified by chromatography on a Biotage system eluting with a gradient of 5 to 15% EtOAc:hexane to yield the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[Na+].[Br-]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH:13]1([C:2]2[CH:3]=[C:4]([F:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=2)[CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1c(F)cc(Br)cc1F
Reactant: OB(O)C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [Br-]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1c(F)cc(C2CC2)cc1F
Temperature: 160 °C
Yield: 141 %

Procedure:
5-bromo-1,3-difluoro-2-nitrobenzene (D24, 560 mg, 2.35 mmol), cyclopropylboronic acid (1 eq., 2.35 mmol, 0.2 g), K3PO4 (3 eq., 7.1 mmol, 1.50 g), NaBr (1 eq., 2.35 mmol, 0.24 g) and Pd(PPh3)4 (280 mg) were added to 3 ml of dry toluene and the mixture was heated by microwave at 160° C. for 40 minutes. The mixture was then poured onto water (10 ml) and extracted with ethyl acetate (3×20 ml). The combined organics were dried over MgSO4, filtered and the solvent was evaporated to afford 660 mg of brown crude product which was purified by silica gel chromatography (5-20% diethyl ether-40-60° petroleum ether) to afford the title compound as a yellow oil, 300 mg, 64%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([O:22]C)=[O:21])[NH:17]2)=[CH:13][CH:12]=1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[C:16]([C:20]([OH:22])=[O:21])[NH:17]2)=[CH:13][CH:12]=1
Reactant: COC(=O)c1cc2ccc(OCCOCCOCCO)cc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2ccc(OCCOCCOCCO)cc2[nH]1

Procedure:
Methyl 6-[(2-(2-hydroxyethoxy)ethoxy)ethoxy]indole-2-carboxylate (V, EXAMPLE 3, 2.9 g) and potassium hydroxide (1.0 g) are dissolved in dioxane (25 ml) and water (5 ml). The reaction is warmed to 50° for 3 hours. The reaction is neutralized by the addition of hydrochloric acid (1N, 17 ml), extracted with THF/chloroform (50/50, 3×), washed with saline and concentrated under reduced pressure with heat. The material is purified by flash column chromatography eluting with methanol/chloroform/acetic acid (5/94/1). The appropriate fractions are pooled and concentrated to give the title compound, MS theory=309.1212, found=309.1208.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[C:22]([C:24]3[CH:33]=[C:32]4[C:27]([CH2:28][CH2:29][NH:30][CH2:31]4)=[CH:26][CH:25]=3)[N:21]=[C:20]([NH2:34])[N:19]=2)[CH2:14][CH2:13]1>>[NH2:34][C:20]1[N:21]=[C:22]([C:24]2[CH:33]=[C:32]3[C:27]([CH2:28][CH2:29][N:30]([C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:9])[CH2:31]3)=[CH:26][CH:25]=2)[CH:23]=[C:18]([N:15]2[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]2)[N:19]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from phenyl isocyanate and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 5. Analytic LCMS (M+H)+: m/z=444.4.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14]2(OCC[O:15]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:14](=[O:15])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)OCCO2
Agent: Cl
Solvent: C1CCOC1
Product: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 18 h
Yield: 92 %

Procedure:
To a stirred solution of 8-benzyloxycarbonyl 1,4-dioxa-8-azaspiro[4,5] decane (0.037 mol, 10 g) in tetrahydrofuran (150 mL) was added a solution of hydrochloric acid 5% (20 mL) dropwise at room temperature. The solution was stirred for 18 h (TLC control) and then evaporated under vacuum to small volume (20 mL) and neutralized with a saturated sodium bicarbonate solution. The aqueous solution was extracted with ethyl acetate (3×100 mL) and the organic layers were dried over sodium sulfate and finally evaporated under vacuum to give 1-benzyloxycarbonyl piperidin-4-one which was substantially pure and which was used in the next step without any purification (92% yield). 1H-NMR (CDCl3): 1.63 (m, 4H); 3.56 (m,4H); 5.09 (s, 2H); 7.28 (s, 5H).
Reaction SMILES: C[Al](C)C.CCCCCC.[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH2:18])=[N:16][CH:17]=1.[CH:19]([O:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25](OC)=[O:26])([CH3:21])[CH3:20]>C1(C)C=CC=CC=1>[CH:19]([O:22][CH2:23][C@H:24]([O:29][C:30]1[N:35]=[CH:34][N:33]=[C:32]2[N:36]([C:39]3[C:44]([CH3:45])=[CH:43][CH:42]=[CH:41][N:40]=3)[N:37]=[CH:38][C:31]=12)[C:25]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([CH3:11])=[CH:17][N:16]=1)=[O:26])([CH3:21])[CH3:20]
Reactant: Cc1ccc(N)nc1
Reactant: COC(=O)[C@H](COC(C)C)Oc1ncnc2c1cnn2-c1ncccc1C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1ccc(NC(=O)[C@H](COC(C)C)Oc2ncnc3c2cnn3-c2ncccc2C)nc1
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 51.1 %

Procedure:
A 2M solution of trimethylaluminium in hexane (0.404 mL, 0.81 mmol) was added to 5-methylpyridin-2-amine (84 mg, 0.77 mmol) in toluene (22 mL) at 5° C. under nitrogen. The resulting solution was stirred at 5° C. for 20 minutes. (2S)-Methyl 3-isopropoxy-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanoate (300 mg, 0.70 mmol) (Intermediate J5) in toluene (6 mL) was added dropwise at 5° C. After the addition was complete, the solution was allowed to warm to ambient temperature and was then heated to reflux for 16 hours. The solution was allowed to cool to ambient temperature. The reaction mixture was concentrated, diluted with EtOAc (100 mL) and washed sequentially with 1M citric acid (50 mL), then saturated brine (50 mL). The organic layer was separated, dried (MgSO4) and evaporated. The residue was purified by flash silica chromatography, eluting with EtOAc to afford (2S)-3-isopropoxy-N-(5-methylpyridin-2-yl)-2-(1-(3-methylpyridin-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)propanamide (160 mg, 51%). 1H NMR (400 MHz, CDCl3) δ 1.09-1.12 (6H, m), 2.23 (3H, s), 2.26 (3H, s), 3.62-3.68 (1H, m), 4.00-4.09 (2H, m), 5.97 (1H, t), 7.30-7.33 (1H, m), 7.56-7.59 (1H, d), 7.70-7.73 (1H, d), 8.01-8.01 (1H, s), 8.21 (1H, d), 8.44 (1H, s), 8.46 (1H, m) 8.53 (1H, s), 9.5 (1H, broad s); m/z (ESI+) (M+H)+=448; HPLC tR=1.98 min.
Reaction SMILES: [OH-:1].[Na+:2].[F:3][C:4]([F:13])([S:9](F)(=[O:11])=[O:10])[C:5]([O:7]C)=[O:6].Cl>O>[F:3][C:4]([F:13])([S:9]([OH:1])(=[O:11])=[O:10])[C:5]([O-:7])=[O:6].[Na+:2]
Reactant: [OH-]
Reactant: COC(=O)C(F)(F)S(=O)(=O)F
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=C([O-])C(F)(F)S(=O)(=O)O
Temperature: 100 °C

Procedure:
230 Parts of 30% aqueous sodium hydroxide solution was added into a mixture of 100 parts of methyl difluoro(fluorosulfonyl)acetate and 250 parts of ion-exchanged water in a ice bath. The added mixture was heated and refluxed at 100° C. for 3 hours. After cooling, the cooled mixture was neutralized with 88 parts of conc. hydrochloric acid and concentrated to obtain 164.8 parts of sodium difluorosulfoacetate (containing inorganic salt, purity: 62.6%). (2) 5.0 Parts of sodium difluorosulfoacetate (purity: 62.8%), 2.6 parts of 4-oxo-1-adamantanol and 100 parts of ethylbenzene were charged in a vessel, 0.8 parts of conc. sulfuric acid was added thereto, and the mixture was refluxed for 42 hours. After cooling, the resultant mixture was filtrated to obtain crystals, and the crystals were washed with tert-butyl methyl ether to obtain 5.5 parts of sodium salt of 4-oxo-1-adamantyl difluorosulfoacetate. The purity thereof was 35.6%, which was determined by 1H-NMR.
Reaction SMILES: C(O[C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.[NH:24]1C2C(=CC=CC=2C(C2C=CC=CC=2)=CC(NC)=O)C=[CH:25]1>>[CH3:25][NH:24][C:4](=[O:23])[CH:5]=[C:6]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1
Reactant: CNC(=O)C=C(c1ccccc1)c1cccc2cc[nH]c12
Product: CNC(=O)C=C(c1ccccc1)c1ccc2[nH]c(C)cc2c1

Procedure:
N-Methyl-3-(2-methyl-1H-indol-5-yl)-3-phenyl-acrylamide LXVIII (990 mg, 83%) was prepared from 3-(2-methyl-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester using the procedure described for 3-(1H-indol-7-yl)-N-methyl-3-phenyl-acrylamide XVIII (see Example 4).
Reaction SMILES: C(OC([N:8]([CH3:18])[C@@H:9]([CH2:13][C:14]([CH3:17])([CH3:16])C)[C:10]([OH:12])=O)=O)(C)(C)C.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:31][C@@H:30]3[C@@H:32]([NH2:35])[CH2:33][CH2:34][C@@H:29]3[CH2:28]2)=[CH:23][CH:22]=1.FC(F)(F)C1N=C(N2C[C@@H]3[C@@H](N)CC[C@@H]3C2)C=CC=1>>[CH3:18][NH:8][C@H:9]([C:10]([NH:35][C@@H:32]1[C@@H:30]2[C@@H:29]([CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([C:20]([F:37])([F:19])[F:36])=[CH:26][CH:25]=3)[CH2:31]2)[CH2:34][CH2:33]1)=[O:12])[CH2:13][CH:14]([CH3:16])[CH3:17]
Reactant: N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CC(C)(C)C)C(=O)O
Agent: N[C@H]1CC[C@@H]2CN(c3cccc(C(F)(F)F)n3)C[C@@H]21
Product: CN[C@@H](CC(C)C)C(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cc3)C[C@@H]21

Procedure:
The title compound was prepared by substituting N-(tert-butoxycarbonyl)-N-methyl-L-leucine for (S)-2-(tert-butoxycarbonyl(methyl)amino)-4,4-dimethylpentanoic acid and (3aR,4S,6aS)-2-[4-(trifluoromethyl)phenyl]octahydrocyclopenta[c]pyrrol-4-amine from Example 607 for (3aR,4S,6aS)-2-(6-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-amine in the procedure described in Example 587: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.34 (d, J=7.4, 1H), 7.57 (d, J=4.2, 2H), 6.63 (d, J=8.7, 2H), 4.44-4.37 (m, 1H), 3.56 (dd, J=10.2, 2.9, 1H), 3.39 (dd, J=10.0, 7.6, 1H), 3.30-3.21 (m, 2H), 3.03 (dd, J=9.9, 3.5, 1H), 2.79-2.68 (m, 2H), 2.47 (s, 3H), 2.12 (dt, J=12.4, 6.9, 1H), 2.08-2.01 (m, 1H), 2.00-1.88 (m, 2H), 1.79-1.57 (m, 3H), 1.39 (dtd, J=13.1, 8.0, 5.1, 1H), 0.94 (d, J=6.6, 3H), 0.88 (d, J=6.6, 3H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:11]2[NH:12][CH:13]=[CH:14][C:15](=O)[N:10]2[N:9]=1.C(N(CC)CC)C.O=P(Cl)(Cl)[Cl:27].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:27][C:15]1[N:10]2[N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:17]=[C:11]2[N:12]=[CH:13][CH:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc[nH]c2cc(-c3ccccc3Cl)nn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccccc1-c1cc2nccc(Cl)n2n1
Temperature: 95 °C
Yield: 54.3 %

Procedure:
To a slurry of 2-(2-chlorophenyl)-4H-pyrazolo[1,5-a]pyrimidin-7-one (I-1A-1b; 30.0 g, 122 mmol) and triethylamine (25.5 ml, 183 mmol) in toluene (1.3 liters) at room temperature was added POCl3 (58 ml, 0.62 mol), dropwise. The mixture was heated at 95° C. for 4 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, sodium bicarbonate (300 g) and ethyl acetate (1 liter), keeping the temperature at 0° C. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were dried (MgSO4), and then concentrated, in vacuo, to afford an amber solid. This material was purified by silica gel chromatography using 2:1:0.1 methylene chloride/hexanes/methanol as eluant to afford I-1A-1c as a colorless solid (17.5 g, 54%): +APcI MS (M+1) 264.2; 1H NMR (400 MHz, CD2Cl2) δ 8.40 (d, J=4.6 Hz, 1H), 8.00–7.97 (m, 1H), 7.56–7.53 (m, 1H), 7.45–7.39 (m, 2H), 7.34 (s, 1), 7.03 (d, J=4.6 Hz, 1H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([NH:8][NH2:9])=[O:7])[N:3]=[CH:2]1.[C:10](OC)(OC)(OC)[CH2:11][CH2:12][CH3:13]>C(O)C>[CH2:11]([C:10]1[N:3]2[CH:2]=[N:1][CH:5]=[C:4]2[C:6](=[O:7])[NH:8][N:9]=1)[CH2:12][CH3:13]
Reactant: CCCC(OC)(OC)OC
Reactant: NNC(=O)c1c[nH]cn1
Solvent: CCO
Product: CCCc1n[nH]c(=O)c2cncn12

Procedure:
A mixture of 3.8 gm. of imidazole-4-carboxylic acid hydrazide, 30 ml. of trimethyl orthobutyrate and 150 ml. of ethanol is refluxed overnight. The mixture is evaporated giving a solid which is washed with petroleum ether and filtered. This solid is combined with 100 ml. of diphenyl ether and heated at 240°-250° C. for 15 minutes. The mixture is cooled, petroleum ether is added and the mixture is filtered. The solid is triturated with hot petroleum ether and filtered giving the desired product, m.p. 116°-117° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1B(O)O)(=[O:20])[CH3:19].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:18]([O:21][CH2:22][C:23]1[C:24]([N:32]2[CH2:43][CH2:42][N:41]3[C:34](=[CH:35][C:36]4[CH2:37][C:38]([CH3:45])([CH3:44])[CH2:39][C:40]=43)[C:33]2=[O:46])=[N:25][CH:26]=[CH:27][C:28]=1[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH3:17])[N:12]=2)[CH:3]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: COc1ncc(Cl)cc1Nc1ccnc(C)n1
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(-c2ccnc(N3CCn4c(cc5c4CC(C)(C)C5)C3=O)c2COC(C)=O)cc1Nc1ccnc(C)n1
Temperature: 110 °C
Yield: 24.8 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 222a (550 mg, 2.2 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo-[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (2.18 g, 5.5 mmol), Pd2(dba)3 (201 mg, 0.22 mmol), tricyclohexylphospine (84 mg, 0.30 mmol), Cs2CO3 (1.43 g, 4.4 mmol), dioxane (12 mL), and water (1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. for 4 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 30:1 ethyl acetate/methanol to afford 222b (310 mg, 25%) as a yellow solid. MS-ESI: [M+H]+ 568.6
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[C:11](=[C:12]([O:17]CC4C=CC=CC=4)[CH:13]=[CH:14][CH:15]=3)[C:10]([CH3:25])=[CH:9]2)[CH:5]=[CH:4][C:3]=1[OH:26]>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([OH:17])[C:11]=3[C:10]([CH3:25])=[CH:9]2)[CH:5]=[CH:4][C:3]=1[OH:26]
Reactant: Cc1cn(-c2ccc(O)c(F)c2)c2cccc(OCc3ccccc3)c12
Agent: [Pd]
Solvent: CCO
Product: Cc1cn(-c2ccc(O)c(F)c2)c2cccc(O)c12
Yield: 45.7 %

Procedure:
A solution of 2-fluoro-4-{3-methyl-4-[(phenylmethyl)oxy]-1H-indol-1-yl}phenol (D2) (140 mg, 0.40 mmol) in ethanol (20 mL) was hydrogenated in an H-cube over a 10% Pd/C catalyst. The resulting solution was concentrated and the product purified by silica gel chromatography eluting with 5-50% ethyl acetate in hexane to yield the title compound (E2) (47 mg).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20]([NH2:22])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](Cl)(=[O:34])[CH3:33].[OH-].[NH4+]>N1C=CC=CC=1>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:25]=[CH:24][C:18]4[N:19]([CH3:23])[C:20]([NH:22][C:32](=[O:34])[CH3:33])=[N:21][C:17]=4[CH:16]=3)[CH2:10][CH2:9]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cn1c(N)nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc21
Reactant: CC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cc(CN3CCN(C(c4ccccc4)c4ccccc4)CC3)ccc2n1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of 4.1 parts of 5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-amine and 25 parts of pyridine are added dropwise 0.79 parts of acetyl chloride while cooling at 0°-5° C. Upon completion, stirring is continued for one hour at 80° C. The reaction mixture is cooled to room temperature, poured onto ice-water and alkalized with ammonium hydroxide. The product is extracted with methylbenzene. The extract is washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The residue is crystallized from 2-propanol. The product is filtered off, washed with 2-propanol and 2,2'-oxybispropane, and dried, yielding 3 parts of N-{5-[4-(diphenylmethyl)-1-piperazinylmethyl]-1-methyl-1H-benzimidazol-2-yl}acetamide; mp. 202.5° C.