Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][CH2:9]Br.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[C:17]([C:21]([OH:24])([CH3:23])[CH3:22])[NH:18]2)=[C:14]([Cl:25])[N:13]=1>CN(C=O)C>[Cl:25][C:14]1[C:15]2[N:16]=[C:17]3[N:18]([CH2:8][CH2:9][O:24][C:21]3([CH3:23])[CH3:22])[C:19]=2[N:20]=[C:12]([Cl:11])[N:13]=1
Reactant: CC(C)(O)c1nc2c(Cl)nc(Cl)nc2[nH]1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OCCn2c1nc1c(Cl)nc(Cl)nc12
Temperature: 100 °C
Yield: 27.4 %

Procedure:
Cesium carbonate (9.3 g, 28.5 mmol) and 1,2-dibromoethane (4.1 mL, 47.6 mmol) were added to a solution of 2-(2,6-dichloro-9H-purin-8-yl)-propan-2-ol (3.3 g, 13.36 mmol) in DMF (100 mL) and the reaction mixture was heated at 100° C. for 2 h, then partitioned between water and ethyl acetate. The organic extract was separated and washed with brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 10 to 20% ethyl acetate in cyclohexane) affording 1,3-Dichloro-8,8-dimethyl-5,6-dihydro-8H-7-oxa-2,4,4b,9-tetraaza-fluorene as a yellow solid (1.0 g, 27%). 1H NMR (400 MHz, CDCl3): δ 4.26 (2H, dd, J=6, 4 Hz), 4.19 (2H, dd, J=6, 4 Hz).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[C:9]1=[N:10][NH:11][C:12]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=3)=[C:8]1[CH2:7]2.C(NC(C)C)(C)C.Cl[C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35]>C1COCC1>[CH:37]([O:36][C:34]([N:10]1[C:9]2[C:21]3[C:6]([CH2:7][C:8]=2[C:12]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=2)=[N:11]1)=[CH:5][C:4]([O:3][CH3:2])=[C:23]([O:24][CH3:25])[CH:22]=3)=[O:35])([CH3:39])[CH3:38]
Reactant: CC(C)OC(=O)Cl
Reactant: COc1cc2c(cc1OC)-c1n[nH]c(Nc3cccc(F)c3)c1C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1cc2c(cc1OC)-c1c(c(Nc3cccc(F)c3)nn1C(=O)OC(C)C)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (6,7-Dimethoxy-2,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-(3-fluoro-phenyl)-amine HCl (Compound 14) (0.50 g, 0.0014 mole), THF (10 mL), and Diisopropyl amine (0.512 mL, 0.00295 mole) was stirred until the solid completely dissolved. Isopropyl chloroformate (1.5 mL, 0.0015 mole) was added slowly at room temperature. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo from the resulting organics. Attempt to separate resulting isomers with reverse-phase chromatography was not successful. Placed isomer containing fractions in refrigerator. Much of major isomer crystallized. Filtered white crystals of title compound from solution (Compound 436). MS m/z 412 (M+H)+;
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:26]=[CH:25][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:44][C:45]1[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH:53]2[CH2:55][O:54]2)=[CH:47][CH:46]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[OH:54][C@H:53]([CH2:52][O:51][C:48]1[CH:49]=[CH:50][C:45]([OH:44])=[CH:46][CH:47]=1)[CH2:55][NH:4][CH2:5][CH2:6][C:7]1[CH:26]=[CH:25][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Solvent: O=CO
Product: CCCCCC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 28 %

Procedure:
1-{4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}-1-hexanone formate (0.234 g, 0.645 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.26 g, 0.644 mmol) according to Procedure G to give the title compound (0.13 g, 0.180 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH2:10][C:11]([NH:13][CH3:14])=[O:12].[N+](C1C=C(S(O[CH2:28][C@@H:29]2[CH2:31][O:30]2)(=O)=O)C=CC=1)([O-])=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:10][C:11]([NH:13][CH3:14])=[O:12])=[C:2]([O:1][CH2:28][C@@H:29]2[CH2:31][O:30]2)[CH:7]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: CNC(=O)Cc1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CNC(=O)Cc1ccc(OC)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
A mixture of 2-(2-hydroxy-4-methoxyphenyl)-N-methylacetamide (15 mg, 0.076 mmol), (2S)-oxiran-2-ylmethyl 3-nitrobenzenesulfonate (20 mg, 0.076 mmol) and Cs2CO3 (30 mg, 0.091 mmol) in DMF (1.5 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and H2O. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-100% ethyl acetate in petroleum spirit) to give the subtitled compound (18 mg).
Reaction SMILES: Cl[O-].[F:3][C:4]([F:16])([F:15])[CH2:5][N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][C:9](=[O:14])[CH2:10]2.Cl.[C-:18]#[N:19].[K+]>O.C(OCC)C>[C:18]([C:9]1([OH:14])[CH2:8][CH:7]2[N:6]([CH2:5][C:4]([F:3])([F:15])[F:16])[CH:11]([CH2:12][CH2:13]2)[CH2:10]1)#[N:19]
Reactant: O=C1CC2CCC(C1)N2CC(F)(F)F
Reactant: [C-]#N
Agent: Cl
Agent: [K+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOCC
Product: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 96.5 %

Procedure:
A 50 ml 3-necked round bottom flask was equipped with a magnetic stirrer, thermometer and hypochiorite scrubber. 8-(2,2,2-Trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one (1.06 g, 5 mmol) was charged to the reaction flask followed by hydrochloric acid (5M, 10 ml) and the mixture was cooled to 0° C. Diethyl ether (7 g) was added and the mixture stirred for 5 minutes. Potassium cyanide (3.69 g, 55 mmol) was added portionwise to the stirred, cooled reaction mixture over 0.25 hour. After complete addition the resultant pink mixture was stirred for 3 hours at 5° C. Water (10 ml) was added, the organic layer separated and the aqueous phase extracted with diethyl ether (2×10 ml). The combined ether extracts were dried (Na2SO4), filtered and concentrated in vacuo (without heat) to give 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane (1.13 g) as a dark red oil which solidified on standing and this was used directly in Step 2.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@@H:13]([CH2:17][N+:18]([O-:20])=[O:19])[CH2:14][CH2:15][OH:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:16][CH2:15][CH2:14][C@@H:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:17][N+:18]([O-:20])=[O:19])(=[O:24])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](CCO)C[N+](=O)[O-]
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](CCOS(C)(=O)=O)C[N+](=O)[O-]

Procedure:
A 3.5 g sample of the alcohol from step 471a above was dissolved in 25 mL of methylene chloride and treated with methanesulfonyl chloride an TEA at 0° C. for 2 hours. The reaction mixture was washed with NaHCO3 solution and water, and the solvent was removed. The residue was chromatographed on silica gel to give 3 g of the title compound.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.Br[CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[C:16]1([CH:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O[C@H]1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O[C@H]1CCN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 89.4 %

Procedure:
(3S)-3-Hydroxypyrrolidine (2.0 g) was dissolved in acetonitrile (10.0 mL) under cooling with ice. Triethylamine (4.8 mL) was added to the solution, and bromodiphenylmethane (5.7 g) in acetonitrile (10.0 mL) was added dropwise to the mixture, followed by stirring at room temperature for 4.5 hours. After completion of reaction, the insoluble material was removed through filtration, and water and toluene were added to the filtrate, whereby the organic layer was extracted. The formed aqueous layer was again extracted with toluene, and the organic layers were combined together, washed with saturated brine, and dried over sodium sulfate. The drying agent was removed through filtration, and the filtrate was concentrated under reduced pressure, to thereby yield crystalline residue. The residue was subjected to silica gel chromatography, to thereby give the target compound (5.2 g, yield 89.7%). The thus-obtained compound can be crystallized through treatment with hexane-ethyl acetate, alcohol-water, and so on.
Reaction SMILES: [CH2:1]([C:5]([CH3:36])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:25][CH:24]=2)=[CH:14][CH:13]=1)[C:6]([O:8]CC)=[O:7])[CH2:2][CH2:3][CH3:4].[OH-].[Na+].[OH-].[K+]>ClCCl.CO>[CH2:1]([C:5]([CH3:36])([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][NH:21][C:22](=[O:35])[C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)=[CH:27][CH:28]=2)=[CH:14][CH:13]=1)[C:6]([OH:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)OCC
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCCCC(C)(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)C(=O)O
Yield: 40.3 %

Procedure:
In a similar manner to that described in Example 6, ethyl 2-butyl-2-methyl-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (350 mg), which is the product of Example 19, was reacted with aqueous sodium hydroxide solution (1N, 2.00 ml) and aqueous potassium hydroxide solution (85%, 0.1g) and the reaction mixture was treated. The residue was subjected to chromatography on a silica gel column using dichlorometane/methanol=19/1 as the eluant to afford a solid which was washed with a mixture of diisopropyl ether and hexane to give the title compound (133 mg) as a white powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:31])([CH2:25][N:26]1[CH:30]=[N:29][N:28]=[N:27]1)[C:10]([C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[CH2:21][O:22][CH2:23][CH3:24])=[CH:15][N:14]=1)([F:12])[F:11]>CCO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:31])([CH2:25][N:26]1[CH:30]=[N:29][N:28]=[N:27]1)[C:10]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][O:22][CH2:23][CH3:24])=[CH:15][N:14]=1)([F:11])[F:12]
Reactant: CCOC/C=C/c1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Agent: [Pd]
Solvent: CCO
Product: CCOCCCc1ccc(C(F)(F)C(O)(Cn2cnnn2)c2ccc(F)cc2F)nc1
Reaction time: 2 h
Yield: 66.7 %

Procedure:
To a stirred solution of (E)-2-(2,4-difluorophenyl)-1-(5-(3-ethoxyprop-1-en-1-yl)pyridin-2-yl)-1,1-difluoro-3-(1H-tetrazol-1-yl)propan-2-ol (51; 80 mg, 0.21 mmol) in EtOH (10 mL) was added 10% Pd/C (8 mg), and the mixture was stirred under hydrogen atmosphere for 2 h. After consumption of the starting material (by TLC), the reaction mixture was filtered through a pad of Celite®, and the Celite® cake was washed thoroughly with EtOAc (3×10 mL). The filtrate was concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 30% EtOAc/hexanes) afforded 53 (65 mg, 0.14 mmol, 68%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.74 (s, 1H), 8.36 (s, 1H), 7.88 (s, OH), 7.64 (dd, J=8.0, 2.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 7.37-7.32 (m, 1H), 6.77-6.73 (m, 1H), 6.67-6.63 (m, 1H), 5.56 (d, J=14.0 Hz, 1H), 5.09 (d, J=14.0 Hz, 1H), 3.46 (q, J=7.0 Hz, 2H), 3.39 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H), 1.90-1.85 (m, 2H), 1.20 (t, J=7.0 Hz, 3H). MS (ESI): m/z 440 (M+H)+. HPLC: 95%.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]1[CH2:31][CH2:30][C@:12]2([O:16][CH2:15][C@@:14](O)([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH3:28])[CH2:13]2)[C@@H:11]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)(=O)C>[CH2:1]([O:8][CH2:9][C@H:10]1[CH2:31][CH2:30][C@:12]2([O:16][CH2:15][C@@H:14]([C:17]3[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:18]=3[O:27][CH3:28])[CH2:13]2)[C@@H:11]1[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1[C@]1(O)CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(F)(F)F)cc1[C@@H]1CO[C@]2(CC[C@H](COCc3ccccc3)[C@H]2c2ccc(F)cc2)C1
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A solution was prepared by dissolving 10 mg (0.019 mmol) of (3S,5R,6S,7S)-7-(benzyloxymethyl)-6-(4-fluorophenyl)-3-hydroxy-3-(2-methoxy-5-(trifluoromethyl)phenyl)-1-oxaspiro[4.4]nonane in 0.20 mL of trifluoroacetic acid at RT, and triethylsilane (0.009 mL, 7 mg, 0.06 mmol) was added immediately. After 30 min., the reaction was diluted with 25 mL of ethyl acetate and washed with 5 m L of saturated aqueous sodium bicarbonate and 5 mL of saturated aqueous sodium chloride. The organic solution was dried over sodium sulfate, decanted, and evaporated. The crude product was purified by preparative TLC, eluting with 3% ethyl ether in toluene, to yield 2.4 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35]1([S:41](Cl)(=[O:43])=[O:42])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[S:41]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)(=[O:43])=[O:42])=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)S(=O)(=O)c3ccccc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, benzenesulfonyl chloride.
Reaction SMILES: IC.[Br:3][C:4]1[CH:13]=[CH:12]C2N[C:9](=O)[NH:10][C:6]=2[CH:5]=1.CC(C)([O-])C.[K+].Cl.C[C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>>[Br:3][C:4]1[CH:13]=[CH:12][C:25]2[N:24]([CH3:26])[C:22](=[O:23])[N:10]([CH3:9])[C:6]=2[CH:5]=1
Reactant: CC(=O)N(C)C
Reactant: O=c1[nH]c2ccc(Br)cc2[nH]1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CI
Product: Cn1c(=O)n(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Iodomethane (2.41 g) was added to a suspension of 5-bromo-1,3-dihydro-benzoimidazol-2-one (1.65 g) and potassium tert-butoxide (1.91 g) in DMA (20 ml). The mixture was stirred overnight at room temperature. The mixture was poured to 2.5N aqueous HCl (80 ml) and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. Heptane (50 ml) was added to the residue and the mixture was filtered. The residue was washed with diethyl ether and dried in vacuo to give the title compound (1.1 g) as a light brown solid. MS (m/e)=241.1 [M+H+].
Reaction SMILES: [C:1]1([C:7]2[NH:11][C:10]([C:12]3[CH:13]=[CH:14][C:15]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:16][CH:17]=3)=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.C(O[C:31]1(O[Si](C)(C)C)[CH2:33][CH2:32]1)C.C([BH3-])#N.[Na+]>CO>[CH:31]1([N:21]2[CH2:22][CH2:23][N:18]([C:15]3[CH:14]=[CH:13][C:12]([C:10]4[NH:9][CH:8]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[N:11]=4)=[CH:17][N:16]=3)[CH2:19][CH2:20]2)[CH2:33][CH2:32]1
Reactant: c1ccc(-c2cnc(-c3ccc(N4CCNCC4)nc3)[nH]2)cc1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(-c2c[nH]c(-c3ccc(N4CCN(C5CC5)CC4)nc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 66.9 %

Procedure:
(Reference: Tetrahedron Lett. 1995, 36 (41), 7399) To a solution of 1-[5-(5-phenyl-1H-imidazol-2-yl)-pyridin-2-yl]-piperazine (99 mg, 0.32 mmol) in anhydrous methanol (5 ml) under nitrogen atmosphere was added 3A molecular sieves (50 mg). This solution was stirred for 5 min, then glacial acetic acid (0.19 ml, 200 mg, 3.3 mmol, 10 equiv), (1-ethoxy-cyclopropoxy)-trimethyl-silane (0.32 ml, 281 mg, 1.62 mmol, 5 equiv), and sodium cyanoborohydride (81 mg, 1.29 mmol, 4.0 equiv) were added. The reaction was heated at reflux overnight, then cooled to room temperature. The mixture was filtered, then diluted with an aqueous solution of 1N NaOH and extracted with ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the desired product (74 mg, 66%). MS m/z 346 (M++1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][CH:21]=[CH:20]3)=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:33]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:14][CH2:13][C:12]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:15]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([CH3:33])[CH:21]=[CH:20]3)=[O:16])[CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccccc2)(C(=O)c2ccc3[nH]ccc3c2)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cc(C(=O)C3(Cc4ccccc4)CCN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.6 %

Procedure:
Sodium hydride (60% in mineral oil, 12 mg, 0.296 mmol) was added at room temperature to a solution of 3-benzyl-3-(1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (100 mg, 0.247 mmol) in DMF (3 mL). The resulting mixture was stirred at room temperature for 20 minutes, and then methyliodide (18 μL, 0.296 mmol) was added. The reaction mixture was then stirred for 30 minutes, then quenched by addition of water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried over MgSO4, filtered and evaporated under reduced pressure to give 105 mg of 3-benzyl-3-(1-methyl-1H-indole-5-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a white foam that was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[NH:12]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:13]([C:22](O)=[O:23])[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([I:21])=[CH:17][CH:16]=1>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:22](=[O:23])[C@@H:13]([NH:12][C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([I:21])=[CH:19][CH:20]=2)[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Product: CCOC(=O)N1CCN(C(=O)[C@H](Cc2ccc(I)cc2)NC(=O)OC(C)(C)C)CC1

Procedure:
This compound was prepared using a method analogous to that of Example 8, step 8.3, piperazine-1-carboxylic acid ethyl ester replacing piperazine-1-carboxylic acid butyl ester and Boc-Phe(4-I)-OH replacing intermediate 8.2.
Reaction SMILES: [N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:7]([C:15]2[N:19]3[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2].[CH3:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>O1CCOCC1>[N+:1]([C:4]1[N:8]([CH2:9][CH2:10][O:11][C:12](=[O:14])[CH3:13])[C:7]([C:15]2[N:19]3[N:20]=[C:21]([N:29]4[CH2:30][CH2:31][N:26]([CH3:25])[CH2:27][CH2:28]4)[CH:22]=[CH:23][C:18]3=[N:17][N:16]=2)=[N:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(Cl)nn12
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CC(=O)OCCn1c([N+](=O)[O-])cnc1-c1nnc2ccc(N3CCN(C)CC3)nn12
Reaction time: 8 h

Procedure:
In a manner analogous to that described in Example 21, 4.22 g. crude 3-(5-nitro-1-β-acetoxyethyl-2-imidazolyl)-6-chloro-s-triazolo[4,3-b]pyridazine were reacted with 4 g. 4-methylpiperazine in 20 ml. dioxan; after evaporation of the reaction mixture, the residue remaining behind was repeatedly digested with petroleum ether and then recrystallized from 15 ml. isopropanol, left to stand overnight and the crystals then filtered off with suction and washed with water. There were thus obtained 2.4 g. 3-(5-nitro- 1-β-acetoxyethyl-2-imidazolyl)-6-(4-methyl-1-piperazinyl)-s-triazolo[4,3-b]pyridazine, which has a melting point of 168° - 170° C.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][C:7]=1[C:8]([OH:11])([CH3:10])[CH3:9].Br[C:16]1[CH:17]=[CH:18][C:19]([F:28])=[C:20]([N:22]2[CH2:26][CH2:25][CH2:24][C:23]2=[O:27])[CH:21]=1>>[F:28][C:19]1[CH:18]=[CH:17][C:16]([C:12]2[N:4]3[CH:5]=[CH:6][C:7]([C:8]([OH:11])([CH3:10])[CH3:9])=[C:2]([F:1])[C:3]3=[N:14][CH:13]=2)=[CH:21][C:20]=1[N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27]
Reactant: O=C1CCCN1c1cc(Br)ccc1F
Reactant: CC(C)(O)c1ccn2ccnc2c1F
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(N4CCCC4=O)c3)cnc2c1F
Yield: 31 %

Procedure:
2-(8-Fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 1-(5-bromo-2-fluorophenyl)pyrrolidin-2-one as described in Example 6 to give 1-{2-fluoro-5-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]phenyl}pyrrolidin-2-one as a pale yellow solid (114 mg, 31%): m/z (ES+) 372 [MH+].
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH:2]1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[C:17]1([C:23](Cl)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl>[C:23]([N:4]1[CH2:5][CH2:6][NH:1][CH:2]([C:7]([NH2:9])=[O:8])[CH2:3]1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NC(=O)C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: NC(=O)C1CN(C(c2ccccc2)(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1.29 g (10 mmol) of piperazine-2-carboxamide were dissolved in 20 ml of absolute methylene chloride, 1.01 g (10 mmol) of triethylamine were added, a solution of 2.79 g (10 mmol) of triphenylmethyl chloride in 20 ml of absolute methylene chloride was added dropwise and the mixture was subsequently stirred at room temperature for 5 hours. The reaction solution was washed twice with water, dried and concentrated and the crude product was purified by flash chromatography on silica gel with CH2Cl2 /CH3OH 95:5.