Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([OH:8])=O.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH:48]1[CH2:53][CH2:52][CH:51]([N:54]2[CH2:57][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][N:69](COCC[Si](C)(C)C)[C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:55]2)[CH2:50][CH2:49]1>O1CCCC1>[F:16][CH:2]([F:1])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:11]=1)[C:6]([N:48]1[CH2:49][CH2:50][CH:51]([N:54]2[CH2:55][C:56]([CH2:80][C:81]#[N:82])([N:58]3[CH:62]=[C:61]([C:63]4[C:64]5[CH:71]=[CH:70][NH:69][C:65]=5[N:66]=[CH:67][N:68]=4)[CH:60]=[N:59]3)[CH2:57]2)[CH2:52][CH2:53]1)=[O:8]
Reactant: CN(C)Cc1cc(C(=O)O)cc(C(F)F)c1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(C5CCNCC5)C4)c3)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc(C(=O)N2CCC(N3CC(CC#N)(n4cc(-c5ncnc6[nH]ccc56)cn4)C3)CC2)cc(C(F)F)c1
Reaction time: 0.25 h

Procedure:
A mixture of 3-(difluoromethyl)-5-[(dimethylamino)methyl]benzoic acid (14.0 mg, 0.0609 mmol, from Step D), Triethylamine (28.3 μL, 0.203 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21.2 mg, 0.0558 mmol) in tetrahydrofuran (0.56 mL) was stirred for 15 minutes. {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (25.0 mg, 0.0507 mmol, prepared as described in Example 1, Step H, except worked up to provide the free base) was added and the reaction was stirred for two hours. The reaction mixture was partitioned between ethyl acetate and water. The organic portion was washed with water, 0.1N NaOH and sat. NaCl, dried over sodium sulfate, filtered and concentrated. The residue was stirred in 1:1 DCM:TFA for 1 hour, solvents were removed in vacuo, and the resulting residue stirred in methanol (1 mL) containing ethylenediamine (0.2 mL) until deprotection was complete. Purification via preparative HPLC-MS (C18 eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as a white powder. Yield: 0.012 g (40%); LC-MS: 574.3 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.09 (br s, 1H), 8.82 (s, 1H), 8.69 (s, 1H), 8.42 (s, 1H), 7.61 (d, 1H), 7.56 (s, 1H), 7.46-7.41 (m, 2H), 7.07 (t, 1H), 7.07 (d, 1H), 4.17-4.03 (m, 1H), 3.75 (d, 2H), 3.62-3.25 (m, 7H), 3.22-3.03 (m, 2H), 2.58-2.51 (m, 1H), 2.15 (s, 6H), 1.85-1.55 (m, 2H), 1.33-1.12 (m, 2H).
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([C@H:26]([C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[S:29])[CH3:27])[NH:24][C:23]1=[O:36])[CH3:21])([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].P(=O)(O)(O)O>CN(C)C=O.C(OCC)C>[Si:12]([O:19][C@@H:20]([C@@H:22]1[C@@H:25]([C@H:26]([C:28]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[S:29])[CH3:27])[N:24]([CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[C:23]1=[O:36])[CH3:21])([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:14])[CH3:13]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1[C@@H](C)C(=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=P(O)(O)O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(CC(=O)OC(C)(C)C)[C@@H]1[C@@H](C)C(=S)c1ccccc1

Procedure:
To a suspension of sodium hydride (31 mg) in dry dimethylformamide (4.3 ml), there were added successively t-butyl alpha-bromoacetate (835 mg) and (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]azetidin-2-one (0.42 g), and the resultant mixture was stirred at room temperature for 1 hour under a nitrogen stream. The reaction mixture was diluted with diethyl ether and adjusted to pH 6.86 with a phosphoric acid buffer solution. The aqueous layer was separated from the organic layer and extracted with diethyl ether three times. The extracts were combined with the organic layer, washed three times with brine, dried over sodium sulfate and evaporated. The residue was purified by silica gel chromatography to give (3S,4S)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4[(1R)-1-phenylthiocarbonylethyl]-1-(t-butyloxycarbonylmethyl)azetidin-2-one.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][CH:4]=1)[CH3:2].[C:16](Cl)(=[O:19])[CH2:17][CH3:18]>>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:16](=[O:19])[CH2:17][CH3:18])[CH3:2]
Reactant: CCc1c[nH]c2cc(C(=O)OC)ccc12
Reactant: CCC(=O)Cl
Product: CCC(=O)c1[nH]c2cc(C(=O)OC)ccc2c1CC

Procedure:
Methyl 3-ethyl-2-propionylindole-6-carboxylate (65.7 mg) was prepared from methyl 3-ethylindole-6-carboxylate (184 mg) and propionyl chloride (0.17 ml) in a similar manner to that of Preparation 1 (5).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[CH:7]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][N:26]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[CH:7]2)[CH2:25][CH2:24]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: ClCCCCn1cnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCCn2cnc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 70.4 %

Procedure:
1-(4-chlorobutyl)-1H-benzimidazole (7.51 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 2-methoxyphenyl piperazine (5.77 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred for 10 min at ambient temperature, and then heated and refluxed to react for 10-15 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3, eluted with dichloromethane/methanol mixture to produce 7.7 g compound (I-4) with a yield of 70.6%. ESI-MS [M+H]+: m/z 365.2.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8](I)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1>>[OH:1][C:2]1[CH:14]=[CH:13][C:12]2[NH:11][C:10]3[CH:9]=[C:8]([C:26]4[CH:27]=[CH:28][C:23]([CH2:22][OH:21])=[CH:24][CH:25]=4)[C:7]4[C:16](=[O:20])[NH:17][C:18](=[O:19])[C:6]=4[C:5]=3[C:4]=2[CH:3]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: O=C1NC(=O)c2c1c(I)cc1[nH]c3ccc(O)cc3c21
Product: O=C1NC(=O)c2c1c(-c1ccc(CO)cc1)cc1[nH]c3ccc(O)cc3c21
Yield: 34 %

Procedure:
The reaction of 9-hydroxy-4-iodopyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione, prepared as in example 7, with 4-hydroxymethylbenzeneboronic acid according to the procedure described in example 8 gave 9-hydroxy-4-(4-hydroxymethylphenyl)pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione (21) (I, Ar=4-hydroxymethylphenyl) in a 34% yield; mp 266–271° C. 1H NMR δ [(CD3)2SO] 11.74 (br s, 1H), 11.00 (br s, 1H), 9.25 (br s, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.56 (s, 1H), 7.43 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.3 Hz, 1H), 7.06 (dd, J=8.7, 2.4 Hz, 1H), 5.27 (t, J=5.7 Hz, 1H), 4.59 (d, J=5.7 Hz, 2H). Found: C, 69.74; H, 4.04; N, 7.57. C21H14N2O4,1/4H2O requires C, 69.51; H, 4.02; N, 7.72.
Reaction SMILES: [Li]CCCC.[CH3:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[C:12]([O:16][C:17]([N:19]1CCC[C@@H]1C=O)=[O:18])([CH3:15])([CH3:14])[CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:12]([O:16][C:17]([N:19]1[CH2:11][CH2:10][CH2:9][C@@H:8]1[CH:7]=[CH2:6])=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCCCC
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=C[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 78.5 %

Procedure:
A flask containing a suspension of methyltriphenylphosphonium bromide (24.04 g, 67.3. mmol) and THF (375 mL) is stirred under nitrogen at −78° C. To this was added a 2.5 M solution of nBuLi in hexane (26.92 mL, 67.3 mmol) over 1 h. A solution of 2-(R)-Formyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6.70 g, 33.65 mmol) in THF (30 mL) is added over 10 minutes and the reaction is warmed to RT. The reaction is quenched with H20 (180 mL) and the mixture concentrated. The residue is extracted with EtOAc (3×150 mL) and the combined extracts are dried over MgSO4 and concentrated. Purification by flash chromatography 20% EtOAc/Hexanes yields the title compound as a yellow oil (5.2 g, 26.4 mmol). 1H NMR (CDCl3, 300 MHz) 5.81-5.63(m, 1H), 5.03(d, 2H), 4.40-4.15(m, 1H), 3.45-3.25(m, 2H), 2.05-1.90(m, 1H), 1.89-1.75(m, 2H), 1.74-1.61(m, 1H), 1.43(s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:8]
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: Cc1ccc(OCC(=O)O)c(Br)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(=O)N(NC(=O)c2ccccc2)C(C)C)c(Br)c1
Yield: 34.2 %

Procedure:
A solution of (2-bromo-4-methyl-phenoxy)-acetic acid (879 mg, 3.34 mmol) and benzoic acid N′-isopropyl-hydrazide (714 mg, 4.00 mmol) in DMF (20 mL) was treated with diisopropylethyl amine (1.45 ml, 8.35 mmol) and PyBroP (2.33 g, 5.01 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with saturated sodium bicarbonate and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-30% ethyl acetate/hexanes gradient to afford the product as a white solid (463 mg, 34%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([N+:14]([O-])=O)[C:9]=1[C:17]#[N:18])=[O:6])[CH3:2].C1CCCCC=1>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[C:9]=1[C:17]#[N:18])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)Nc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)C(=O)Nc1cccc(N)c1C#N

Procedure:
The title compound is prepared by reduction of [3-nitro-2-cyanophenylamino]oxoacetic acid ethyl ester with 10% Pd. on charcoal and with cyclohexene in ethanol according to the procedure of I. D. Entwistle and R. A. W. Johnstone, J. Chem. Soc., Perkin I. 1300 (1975). The crude product is chromatographed on silica gel with chloroform and recrystallized from ethanol, m.p. 133°-136° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[O:6][CH:5]([OH:7])[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]1[C:15]1[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>ClCCl.CN(C1C=CN=CC=1)C>[C:33]([O:7][CH:5]1[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:3]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[C:2]([CH3:25])([CH3:1])[O:6]1)(=[O:35])[CH3:34]
Reactant: CC1(C)OC(O)C(c2cccc(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC1OC(C)(C)C(c2ccc(S(C)(=O)=O)cc2)=C1c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5,5-Dimethyl-3-(3-fluorophenyl)-2-hydroxy-4-(4-methylsulfonylphenyl)-2,5-dihydrofuran (Example 1, 0.8 g) and triethylamine (2 mL) in dichloromethane (20 mL) was added DMAP (5 mg) and acetic anhydride (1 mL). The resulting mixture was stirred at room temperature for 10 min, then quenched with saturated aqueous NaHCO3. The mixture was extracted with CH2 Cl2 and the organic phase was dried over Na2SO4, filtered and evaporated. The resulting solid was swished in 1:1 EtOAc/hexanes to provide 0.5 g of the title compound as a white solid.
Reaction SMILES: [CH2:1]([C:13]1[O:14][CH:15]=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCCCC.C([Li])CCC.[C:29](=[O:31])=[O:30]>CCOCC>[CH2:1]([C:13]1[O:14][C:15]([C:29]([OH:31])=[O:30])=[CH:16][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCc1ccco1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CCCCCCCCCCCCc1ccc(C(=O)O)o1
Reaction time: 1 h

Procedure:
A solution of 30.4 g (0.2 moles) of 2-dodecylfuran in 300 ml of anhydrous ether is stirred at -20° C. after which 0.22 moles (92 ml of a 2.4 molar hexane solution) of butyllithium is added slowly with stirring. The reaction mixture is stirred for 1 hour then poured over 200 g of crushed dry ice (solid CO2) after which the mixture is allowed to stand for 1 hour prior to dilution with a saturated ammonium chloride solution The organic layer is separated, washed with water and brine, dried over sodium sulfate and evaporated to give 5-dodecyl-2-furancarboxylic acid. The thus obtained acid in 500 ml of anhydrous ether is stirred at room temperature during which time 200 ml of a 2 molar solution of methyllithium in ether is added slowly. The reaction mixture is allowed to stand at room temperature for 2 hours after which it is poured into a saturated ammonium chloride solution The organic layer is separated and washed with water and brine, dried over sodium sulfate and evaporated to dryness to give white crystals of methyl 2-(5-dodecylfuryl) ketone. M.P. 35°-7° C.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[CH:4]=[CH2:5].[CH:7]([NH2:10])([CH3:9])[CH3:8]>CO>[CH3:1][NH:2][C:3](=[O:6])[CH2:4][CH2:5][NH:10][CH:7]([CH3:9])[CH3:8]
Reactant: C=CC(=O)NC
Reactant: CC(C)N
Solvent: CO
Product: CNC(=O)CCNC(C)C
Yield: 108.2 %

Procedure:
N-Methylacrylamide (851 mg, 10.00 mmol) and isopropylamine (1.71 mL, 1.18 g, 20.00 mmol) in MeOH (10 mL) were irradiated to 140° C. for 30 mins in a microwave reaction vessel. The reaction mixture was cooled and loaded onto a SCX-2 column and washed with MeOH (100 mL). The crude product was then eluted from the SCX-2 column with NH3 (100 mL, 7M in MeOH) and the volatiles removed under reduced pressure to afford the title compound (1.56 g, Quant.) as an oil, which was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=1[CH3:20])=[O:8].[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:21][O:22][C:23](=[O:35])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH3:17])=[C:11]([O:18][CH3:19])[C:10]=2[CH3:20])=[O:8])=[C:26]([CH2:31][CH2:32][CH3:33])[C:25]=1[OH:34]
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Reactant: COc1c(C)cc(C(=O)CCCCCBr)c(C)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCC(=O)c2cc(C)c(OC)c(OC)c2C)ccc(C(=O)OC)c1O
Yield: 98.7 %

Procedure:
A mixture of 2.50 g (7.29 mmol) of 6-bromo-1-(3,4-dimethoxy-2,5-dimethylphenyl)-1-hexanone, 1.53 g (7.29 mmol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester and 3.30 g (24 mmol) of potassium carbonate in 50 mL of acetone and 5 mL of DMF was stirred and heated at reflux for 26 hours. After workup as in Example 16 the crude product was purified by HPLC using 10% ethyl acetate-hexane to give 3.40 g (98% yield) of 4-[[6-(3,4-dimethoxy-2,5-dimethylphenyl)-6-oxohexyl]oxy]-2-hydroxy-3-propyl benzoic acid methyl ester as an oil. The nmr spectrum was consistent with the structure.
Reaction SMILES: [C:1]([C:3]1[N:7](O)[C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2]>O.CO>[C:1]([C:3]1[NH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: COC(=O)c1ccc(C#N)n1O
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C#N)[nH]1
Temperature: 70 °C

Procedure:
A 20% solution of TiCl3 (25 ml, 32 mmol) in water was added to a solution of methyl 5-cyano-1-hydroxy-1H-pyrrole-2-carboxylate (Intermediate 128, 2.55 g, 15 mmol) in MeOH. The reaction was heated to an external temperature of 70° C. for 3 hours. The reaction mixture was concentrated to remove MeOH and the residue was partitioned with EtOAc and water. The organic portion was dried with MgSO4 and concentrated to an orange oil.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:24]=1[C:25]([O:27]C(C)(C)C)=[O:26])=[O:18]>ClCCl>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[C:9]1[C:17]([NH:19][C:20]1[S:21][CH:22]=[C:23]([C:32]2[N:36]([CH3:37])[N:35]=[C:34]([C:38]([F:39])([F:40])[F:41])[CH:33]=2)[C:24]=1[C:25]([OH:27])=[O:26])=[O:18]
Reactant: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)c2cc3ccccc3o2)c1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nc(C(F)(F)F)cc1-c1csc(NC(=O)c2cc3ccccc3o2)c1C(=O)O
Reaction time: 0.75 h
Yield: 18.2 %

Procedure:
Under an atmosphere of argon, trifluoroacetic acid (1.0 mL) was added to a stirred solution of 13 (21 mg, 43 μmol) in dichloromethane (1.0 mL) at room temperature. The reaction was stirred for 45 minutes then concentrated under reduced pressure. The material was washed with dichloromethane to provided 14 (3.4 mg, 18%) as a solid: 1H NMR (500 MHz, d6-DMSO) δ 13.60 (bs, 1H), 12.55 (bs, 1H), 7.87 (m, 2H), 7.76 (dd, J=8.4, 1.3 Hz, 1H), 7.58 (ddd, J=7.8, 7.8, 1.2 Hz, 1H), 7.42 (ddd, J=7.7, 7.7, 0.7 Hz, 1H), 7.34, (s, 1H), 6.76 (s, 1H), 6.37 (s, 3H); LRESIMS m/z 436 [M+H]+, calcd. for C19H12F3N3O4S1 436.1.
Reaction SMILES: C(OC(=O)[NH:6][C@@H:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27]CC=C)=[CH:23][CH:22]=1)[CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12])C=C.N1CCOCC1>C1COCC1.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>[NH2:6][C@H:7]([CH2:8][O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:11]([CH3:13])[CH3:12])[CH:14]([CH3:16])[CH3:15])[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1
Reactant: C=CCOC(=O)N[C@H](CO[Si](C(C)C)(C(C)C)C(C)C)Cc1ccc(OCC=C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: CC(C)[Si](OC[C@@H](N)Cc1ccc(O)cc1)(C(C)C)C(C)C
Temperature: 47 °C
Reaction time: 10 h
Yield: 89.3 %

Procedure:
To a solution of 21 (6.05 g, 13.5 mmol, 1.0 equiv) in THF (135 mL) at room temperature, was added morpholine (11.8 mL, 135.6 mmol, 10 equiv), then tetrakis(triphenylphosphine)palladium(0) (1.56 g, 1.35 mmol, 0.1 equiv) in the dark. The solution was warmed to 47° C. The reaction was stirred at 47° C. for 10 hours, after which time the solution was cooled to room temperature and the THF was removed under reduced pressure. Purification by flash chromatography (30% EtOAc/hexane→100% EtOAc) afforded 22 (3.9 g, 90%) as a brown solid with a minor amount of Ph3PO. Rf=0.2 (EtOAc); FTIR (film, cm−1) 2938, 2866, 1515, 1462, 1251, 1105; 1H NMR (500 MHz, CDCl3) δ7.01 (d, J=8.5 Hz, 2H), 6.71 (d, J=8.5 Hz, 2H), 4.5 (br s, 2H), 3.75 (dd, J=10.0, 3.5 Hz, 1H), 3.61, (dd, J=9.5, 6.5 Hz, 1H), 3.19 (br s, 1H), 2.79 (dd, J=13.3, 6.0 Hz, 1H), 2.64 (dd, J=13.8, 7.5 Hz, 1H), 1.05 (m, 21H); 13C NMR (100 MHz, CDCl3) δ155.1, 130.3, 129.1, 115.8, 115.6, 66.2, 54.9, 37.9, 18.1, 11.9; HRMS (ES+) calculated for C18H33NO2Si (M+H)+: 324.2281, found: 324.2374.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])=[N:17][N:18]=1.Br[CH2:38][CH3:39].O>CN(C=O)C>[NH2:7][C:8]1[N:9]=[CH:10][C:11]([C:26]2[CH:36]=[CH:35][C:29]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])=[CH:28][CH:27]=2)=[N:12][C:13]=1[C:14]1[O:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH2:38][CH3:39])=[N:17][N:18]=1
Reactant: CCBr
Reactant: CN(C)C(=O)c1ccc(-c2cnc(N)c(-c3nnc(-c4ccccc4O)o3)n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1ccccc1-c1nnc(-c2nc(-c3ccc(C(=O)N(C)C)cc3)cnc2N)o1
Temperature: 62.5 °C
Reaction time: 0.33 h
Yield: 72.5 %

Procedure:
Potassium carbonate (25.46 mg, 0.1842 mmol) was added to a mixture of 4-[5-amino-6-[5-(2-hydroxyphenyl)-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-N,N-dimethyl-benzamide (50 mg, 0.1228 mmol) in DMF (1 mL) at room temperature. Colour change observed from yellow to orange. The resulting suspension was heated at 60-65° C. and bromoethane (14.72 mg, 10.01 μL, 0.1351 mmol) was added slowly. After the addition is complete the reaction heated at 60-65° C. for 30 min. The reaction mixture was cooled to room temperature. Water (2 mL) was added slowly at and the mixture stirred at room temperature for 20 min. A precipitate formed and was filtered and washed with water. The solid was re-dissolved in DCM and dried over MgSO4, filtered and evaporated to dryness. The solid was triturated with acetonitrile to give the product as a yellow solid (38.3 mg, 73% yield); 1H NMR (400.0 MHz, DMSO) d 1.49 (t, 3H), 2.97-3.02 (m, 6H), 4.24-4.29 (m, 2H), 7.17-7.18 (m, 1H), 7.20 (d, 1H), 7.32-7.35 (m, 2H), 7.53 (d, 1H), 7.65 (br s, 2H), 8.05 (d, 1H), 8.17 (d, 2H) and 8.99 (s, 1H) ppm; MS (ES+) 431.24
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])[C:6]=2[CH:25]=1.[CH2:26]([NH:29][CH2:30][CH:31]1[CH2:33][CH2:32]1)[CH2:27][CH3:28]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:29]([CH2:30][CH:31]4[CH2:33][CH2:32]4)[CH2:26][CH2:27][CH3:28])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])[C:6]=2[CH:25]=1
Reactant: CCCNCC1CC1
Reactant: Fc1cccc(F)c1C1=NCc2nnc(CCl)n2-c2ccc(Cl)cc21
Product: CCCN(Cc1nnc2n1-c1ccc(Cl)cc1C(c1c(F)cccc1F)=NC2)CC1CC1

Procedure:
In the manner given in Preparation 29, 8-chloro-1-(chloromethyl)-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine is treated with propyl(cyclopropylmethyl)amine to give 8-chloro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-(2,6-difluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine. Preparation 34 8-Nitro-1-[[(cyclopropylmethyl)propylamino]methyl]-6-phenyl-4-H-s-triazolo[4,3-a][1,4]-benzodiazepine
Reaction SMILES: [CH3:1][C:2]([S:5]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)(=[O:7])=[O:6])([CH3:4])[CH3:3]>CO.Cl.[Pd]>[CH3:4][C:2]([S:5]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][NH2:14])=[CH:15][CH:16]=1)(=[O:7])=[O:6])([CH3:1])[CH3:3]
Reactant: CC(C)(C)S(=O)(=O)Cc1ccc(C#N)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)(C)S(=O)(=O)Cc1ccc(CN)cc1

Procedure:
Dissolve 4-(2-methyl-propane-2-sulfonylmethyl)-benzonitrile (300 mg, 1.26 mmol) in methanol (50 mL). Add concentrated HCl (10 drops), 10% Pd/C (Degussa type E101, 60 mg) and submit the mixture to hydrogenation at atmospheric pressure for 1 h. Filter over Celite® and wash with methanol. Concentrate the filtrate in vacuo to give the hydrochloride salt of the title compound as a solid that was washed with diethyl ether (366 mg, 87%). Partition the solid between saturated NaHCO3 and EtOAc and extract the aqueous phase twice with EtOAc. Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo to give the title compound (195 mg, 74%). MS (ES+) m/z: 242 (M+H)+.