Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[O:3][C:4](=[O:29])[C@H:5]([CH2:19][C:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)[NH:6][C:7](=[O:18])[C@@H:8]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:9][CH3:10].[CH3:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37](O)=[O:38])[CH2:32]1>>[CH3:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH:33]([C:37]([N:9]([CH3:10])[C@@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:3])=[O:29])[CH2:19][C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:38])[CH2:32]1
Reactant: CN[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC
Reactant: CC1CCCC(C(=O)O)C1
Agent: Cl
Product: CC1CCCC(C(=O)N(C)[C@H](Cc2ccccc2)C(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)O)C1

Procedure:
Coupling of N-methyl-(D)-phenylalanyl-(L)-tryptophan methyl ester hydrochloride (see example 1) with 3-methyl-1-cyclohexanecarboxylic acid according to example 12 followed by hydrolysis of the methyl ester moiety according to example 1 gives N-(3-methyl-1-cyclohexylcarbonyl)-N-methyl-(D)-phenylalanyl-(L)-tryptophan; FAB-MS m/e 490 (M+H)+.
Reaction SMILES: [SH:1][CH2:2][C:3]([OH:5])=[O:4].C[O-].[Na+].[CH:9]12[O:14][CH:10]1[CH2:11][CH2:12][CH2:13]2>CO>[OH:14][C@@H:10]1[CH2:11][CH2:12][CH2:13][C@H:9]1[S:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: O=C(O)CS
Reactant: C1CC2OC2C1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CS[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Mercaptoacetic acid (22.5g 0.244 mole) was added to a cold (+5° C.) solution of sodium methoxide [prepared from sodium (11.2 g, 0.488 mole)] in methanol (125 ml). After stirring for 20 minutes, cyclopentene oxide (19.5 g, 0.23 mole) was added dropwise over 20 minutes to the cold solution. The ice bath was removed and the reaction was refluxed for 45 minutes. The reaction was cooled to room temperature and made acidic by the addition of 4N hydrochloric acid. Water (100 ml) was added and the mixture was extracted twice with 150 ml of diethyl ether. The combined diethyl ether extracts were washed with water (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated to an oil with a rotary evaporator. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][NH:21][C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C.ClCCl>[F:1][C:2]1[C:10]2[N:9]([CH3:11])[C:8]3[CH2:12][CH2:13][N:14]([CH2:17][C:18]4[N:19]=[CH:20][N:21]([CH3:27])[C:22]=4[CH3:23])[C:15](=[O:16])[C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1[nH]cnc1CN1CCc2c(c3cccc(F)c3n2C)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1c(CN2CCc3c(c4cccc(F)c4n3C)C2=O)ncn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.1 %

Procedure:
A stirred solution of 6-fluoro-2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol -4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (347 mg) in dry DMF was treated with sodium hydride (73% dispersion in oil; 49 mg) and stirred under nitrogen for 30 min. The reaction mixture was then cooled to 0° and iodomethane (217 mg) was added dropwise. The reaction mixture was then allowed to warm to room temperature, with stirring being continued for 2 h. DMF was removed in vacuo and the residue was dissolved in dichloromethane (75 ml) and washed with water (3×75 ml) and brine (2×50 ml). The combined aqueous washings were extracted with dichloromethane (2×50 ml) and the combined organic extracts were dried and concentrated in vacuo to give an oil. This was dissolved in dichloromethane and adsorbed onto silica. Purification by FCC eluting with System A (200:10:1) gave a solid which was triturated with ether and then dried in vacuo to give the title compound (62 mg), m.p. 174°-175°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([O:50][C@H:51]([CH3:55])[C:52](O)=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(N(CC)CC)C>ClCCl>[CH2:43]([O:50][C@@H:51]([C:55]1[O:18][C:5]2[C:6]([C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH3:52])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: C[C@@H](OCc1ccccc1)C(=O)O
Reactant: O=C(Cc1cccc(F)c1)c1cc(F)ccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](OCc1ccccc1)c1oc2ccc(F)cc2c(=O)c1-c1cccc(F)c1
Reaction time: 0.17 h
Yield: 62.7 %

Procedure:
To 1-(5-fluoro-2-hydroxyphenyl)-2-(3-fluorophenyl) ethanone (11 g, 44.31 mmol), in Dichloromethane (110 ml), HATU (33.7 g, 88.63 mmol) and (R)-Benzyloxypropionic acid (9.58 g, 53.17 mmol) were added and stirred for ˜10 min. Triethylamine (67 ml, 478 mmol) was added dropwise and stirred at room temperature (RT) for 24 h. The reaction mixture was quenched with water and extracted with Dichloromethane (2×250 ml). The organic layer was dried with sodium sulphate and concentrated under vacuum. The crude product was purified by column chromatography with ethyl acetate:Petroleum ether to afford the title compound as a off-white solid (10.9 g, 63%). 1H-NMR (δ ppm, CDCl3, 400 MHz): 7.85 (dd, J=8.1, 3.0 Hz, 1H), 7.58 (dd, J=9.1, 4.1 Hz, 1H), 7.47-7.39 (m, 1H), 7.39-7.34 (m, 1H), 7.28-7.20 (m, 3H), 7.20-7.14 (m, 2H), 7.16-7.14 (m, 1H), 6.99-7.89 (m, 2H), 4.50-4.31 (m, 3H), 1.56 (d, J=6.4 Hz, 3H). Mass: 392.9 (M+).
Reaction SMILES: [C:1]1([N:7]2[CH2:13][CH2:12][C:11]([C:14]([C:38](OC(C)(C)C)=[O:39])([C:16](=[O:37])[C@H:17]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[N:18]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH3:19])[NH2:15])=[CH:10][CH:9]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[C:8]2=[O:56])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.C(N(CC)CC)C.C(Cl)(=O)[C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1>>[C:1]1([N:7]2[CH2:13][CH2:12][C:11]([C:14]([C:38](=[O:39])[C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)([C:16](=[O:37])[C@H:17]([CH2:30][CH2:31][CH2:32][NH:33][C:34](=[NH:36])[NH2:35])[N:18]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH3:19])[NH2:15])=[CH:10][CH:9]([CH2:45][C:46]([O:48][CH2:49][C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)=[O:47])[C:8]2=[O:56])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)N(C)[C@@H](CCCNC(=N)N)C(=O)C(N)(C(=O)OC(C)(C)C)C2=CC(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)CC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N(C)[C@@H](CCCNC(=N)N)C(=O)C(N)(C(=O)c2ccccc2)C2=CC(CC(=O)OCc3ccccc3)C(=O)N(c3ccccc3)CC2)cc1
Yield: 60.9 %

Procedure:
Compound (16) (69 mg, 0.087 mmol) from above was treated with anhydrous HCl/dioxane (5 mL) at room temperature for 4 h. The reaction mixture was then evaporated at reduced pressure and then re-evaporated at reduced pressure 2× from toluene to remove any excess HCl. The residue was dissolved in N,N-dimethylformamide (5 mL) and treated with triethylamine (24 μL, 0.174 mmol) and benzoyl chloride (20 μL, 0.174 mmol) at room temperature for 18 h. The reaction mixture was then evaporated under high vacuum and the residue was purified by flash chromatography (silica gel, 2.5×20 cm, 2% methanol in chloroform) to yield the title compound (17) (42 mg, 61%) as an inseparable mixture of diastereoisomers. Compound (17): TLC Rf 0.58 (silica gel, 9:1 chloroform: methanol).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1[CH:18]=[CH:17]OC1=O.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[O:12][CH:17]=[CH:18][N:13]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NC(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: O=c1occo1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=[N+]([O-])c1ccc(Cc2ncco2)cc1
Temperature: 100 °C
Yield: 22.1 %

Procedure:
A mixture of 2-(4-nitrophenyl)acetamide (1.0 g, 5.55 mmol), 1,3-dioxol-2-one (0.955 g, 11.10 mmol), and Eaton's Reagent (9.9 g, 34.97 mmol) was heated to 100° C. overnight under a nitrogen atmosphere. After this time, the reaction was cooled, diluted with ice water, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.250 g, 25%). MW=204.18. 1H NMR (DMSO-d6, 500 MHz) δ 8.26-8.18 (m, 2H), 8.05 (d, J=0.8 Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.16 (s, 1H), 4.34 (s, 2H); APCI MS m/z 205 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:8]([C:9]([F:12])([F:11])[F:10])=[N:7][N:6]=[C:5]1[SH:13])[CH:2]=[CH2:3].[Cl:14][C:15](Cl)=[C:16]([Cl:19])[C:17]#[N:18].C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([N:4]1[C:8]([C:9]([F:11])([F:12])[F:10])=[N:7][N:6]=[C:5]1[S:13][C:15]([Cl:14])=[C:16]([Cl:19])[C:17]#[N:18])[CH:2]=[CH2:3]
Reactant: N#CC(Cl)=C(Cl)Cl
Reactant: C=CCn1c(S)nnc1C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCn1c(SC(Cl)=C(Cl)C#N)nnc1C(F)(F)F
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A mixture of 4.0 g (0.019 mole) 4-allyl-5-trifluoromethyl-3-mercapto-1,2,4-triazole (the product of Example 2), 3.0 g (0.019 mole) trichloroacrylonitrile (the product of Example 3A), and 2.65 ml (0.019 mole) triethylamine in 100 ml methylene chloride was stirred at room temperature for several days. The reaction mixture washed with water, dried over magnesium sulfate, and stripped to give a yellow oil. Further purification by chromatography gave 3.6 g of the product as an oil which later crystallized, melting point 45°-48° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][CH:27]1[CH2:30][N:29]([CH2:31][C@H:32]([O:43][C:44]2[N:49]=[CH:48][N:47]=[C:46]3[N:50]([C:53]4[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=4[Cl:59])[N:51]=[CH:52][C:45]=23)[C:33]([NH:35][C:36]2[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=2)=[O:34])[CH2:28]1)(C(C)(C)C)(C)C>O1CCCC1>[Cl:59][C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=1[N:50]1[C:46]2[N:47]=[CH:48][N:49]=[C:44]([O:43][C@@H:32]([CH2:31][N:29]3[CH2:28][CH:27]([OH:26])[CH2:30]3)[C:33]([NH:35][C:36]3[CH:41]=[N:40][C:39]([CH3:42])=[CH:38][N:37]=3)=[O:34])[C:45]=2[CH:52]=[N:51]1
Reactant: Cc1cnc(NC(=O)[C@H](CN2CC(O[Si](C)(C)C(C)(C)C)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1cnc(NC(=O)[C@H](CN2CC(O)C2)Oc2ncnc3c2cnn3-c2ccccc2Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
Tetrabutylammonium fluoride (1M in THF) (0.87 mL, 0.87 mmol) was added to (2S)-3-(3-(tert-butyldimethylsilyloxy)azetidin-1-yl)-2-(1-(2-chlorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-4-yloxy)-N-(5-methylpyrazin-2-yl)propanamide (Intermediate BB1) (520 mg, 0.87 mmol) in tetrahydrofuran (25 mL) under nitrogen. The resulting mixture was stirred at ambient temperature for 2 hours. Further tetrabutylammonium fluoride (1M in THF) (1.7 mL, 1.7 mmol) added and the mixture stirred overnight. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL), diluted with ethyl acetate (50 mL) and stirred for 10 minutes. The organic layer was separated, washed with water (50 mL) and brine (50 mL), dried (MgSO4), filtered and evaporated. The crude product was purified by flash silica chromatography, eluting with 0 to 10% methanol in ethyl acetate, to afford the product (130 mg). 1H NMR (400 MHz, DMSO-d6) δ 2.50 (3H, m), 2.98-3.09 (3H, m), 3.15-3.21 (1H, m), 3.67-3.77 (2H, m), 4.19-4.29 (1H, m), 5.31 (1H, d), 5.77-5.84 (1H, m), 7.60-7.76 (3H, m), 7.80-7.82 (1H, m), 8.35-8.37 (1H, m), 8.57 (1H, s), 8.64 (1H, s), 9.11-9.12 (1H, m), 11.17 (1H, s); m/z (ESI+) (M+H)+=481; HPLC tR=1.52 min.
Reaction SMILES: [NH:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:20]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@@H:21]([C:32](O)=[O:33])[C@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[NH:20]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[C@@H:21]([C:32]([N:1]1[CH2:19][CH2:18][CH2:17][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:33])[C@H:22]([CH3:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@@H]1CCCN1)C(=O)O
Reactant: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 18 h
Yield: 72.7 %

Procedure:
0.959 g (2.0 mmole) of the 2HCl.H-Pro-Arg-CHA was dissolved in 8 ml of 0.75N NEM/DMF, to which was added 0.863 g (2.0 mmole) of BOC-D-Thr(OBzl)-SDP at0°-5° C., and the reaction was effected at room temperature for 18 hours, after which the reaction mixture was poured into 2000 ml of cold 1/1 solution of 10% citric acid/sat. aqueous Nacl. The precipitate was filtered out and dried, to obtain 1.07 g (72.7%) of BOC-D-Thr(OBzl)-Pro-Arg-CHA.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][N:6]=[CH:5][CH:4]=1.[CH2:8]([NH2:10])[CH3:9]>C1COCC1>[CH2:8]([NH:10][CH2:2][C:3]1[O:7][N:6]=[CH:5][CH:4]=1)[CH3:9]
Reactant: CCN
Reactant: BrCc1ccno1
Solvent: C1CCOC1
Product: CCNCc1ccno1

Procedure:
prepared by reaction of the 5-bromomethyl-isoxazole (Deshong P. et al J. Org. Chem. 1988, 53, 7, 1356-1364) with 2M ethylamine in THF.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([OH:16])=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[N:20]=[CH:19][CH:18]=[CH:17][C:13]=3[C:14]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([C:29]([OH:32])([CH3:30])[CH3:31])=[CH:25][CH:24]=3)=[O:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccnc1Oc1ccc2c(c1)OCCO2
Reactant: CC(C)(O)c1ccc(CN)cc1
Product: CC(C)(O)c1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCCO3)cc1

Procedure:
Prepared from 2-(2,3-Dihydro-benzo[1,4]dioxin-6-yloxy)-nicotinic acid and 2-(4-Aminomethyl-phenyl)-propan-2-ol. MS: m/e 421 (M++1), 1HNMR (CDCl3) δ1.51 (6H, s), 4.24 (4H, s), 4.66(2H, d), 6.57 (1H, dd), 6.85 (1h, d), 7.11(1H, dd), 7.28(2H, d), 7.41(2H, d), 8.19(2H, m), 8.61(1H, d).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].CC([O-])(C)C.[K+].F[C:17]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].CN(C)C=O>CC1CCCO1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([O:8][C:17]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:4][C:3]=1[F:9]
Reactant: Oc1cnc(Cl)c(F)c1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(F)cc1Oc1cnc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 6-chloro-5-fluoropyridin-3-ol (0.977 g) in 2-methyltetrahydrofuran (12 mL) was added potassium 2-methylpropan-2-olate (1.0M in tetrahydrofuran, 7.28 mL). After stirring for 15 minutes at room temperature, methyl 2,4-difluorobenzoate (1.710 g) was added as a solution in 2-methyltetrahydrofuran (2 mL) followed by N,N-dimethylformamide (2 mL) then the reaction was heated to 75° C. under a nitrogen atmosphere. After stirring overnight the reaction was cooled, diluted with ethyl acetate (100 mL) and washed with water (50 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography (GraceResolv 40 g) eluting with a gradient of 2% to 15% ethyl acetate/hexanes gave the title compound.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[C:23](=[O:24])[C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C:7]=3[N:8]([CH2:13][CH2:14][CH2:15][Br:16])[C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.N([O-])=O.[Na+].[I-:32].[K+]>O1CCOCC1.O.[Cu]I>[Br:16][CH2:15][CH2:14][CH2:13][N:8]1[C:7]2[C:17]3[CH:18]=[CH:19][C:20]([O:25][CH3:26])=[CH:21][C:22]=3[C:23](=[O:24])[C:6]=2[C:5]2[C:10](=[CH:11][C:2]([I:32])=[CH:3][CH:4]=2)[C:9]1=[O:12]
Reactant: [I-]
Reactant: COc1ccc2c(c1)C(=O)c1c-2n(CCCBr)c(=O)c2cc(N)ccc12
Agent: [Cu]I
Agent: Cl
Agent: O=N[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc2c(c1)C(=O)c1c-2n(CCCBr)c(=O)c2cc(I)ccc12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3-Amino-6-(3-bromopropyl)-9-methoxy-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione (81, 420 mg, 1.01 mmol) was dissolved in dioxane (10 mL). Concentrated hydrochloric acid (0.65 mL, 3.3 mmol) was added and the reaction mixture was stirred for 10 min and then cooled down to 0° C. A solution of sodium nitrite (114 mg, 1.65 mmol) in water (5 mL) was slowly added with stirring while the temperature was −20° C. The reaction mixture was stirred for 30 min and then slowly added to a solution of copper (I) iodide (200 mg) and potassium iodide (300 mg) in water (15 mL). The reaction mixture was stirred at room temperature for 8 h and then heated at reflux for 1 h. The reaction mixture was diluted with water (200 mL) and extracted with chloroform (3×100 mL). The combined organic extracts were washed with an aqueous solution of sodium thiosulfate (2×200 mL), aqueous sodium bicarbonate (2×200 mL), water (100 mL) and brine (100 mL). The organic solution was dried over sodium sulfate and the solvent removed under vacuum. The residue was purified by silica gel column chromatography, eluting with chloroform-methanol, 30:1. Compound 82 was obtained as a dark red solid (402 mg, 76%): mp 207-209° C. IR (Film) 2922, 1765, 1655, 1599, 1532, 1478, 1455, 1430, 1379, 1295, 1225, 1047, 969, 812, 788, 691, 666, 592 cm−1; 1H NMR (CDCl3, 500 MHz) δ 8.60 (d, J=1.5 Hz, 1H), 8.32 (d, J=8.6 Hz, 1H), 7.93 (dd, J=8.5 Hz, J=1.5 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.15 (d, J=2.3 Hz, 1H), 6.82 (dd, J=8.3 Hz, J=2.4 Hz, 1H), 4.58 (t, J=7.2 Hz, 2H), 3.89 (s, 3H), 3.64 (t, J=6.2 Hz, 2H), 2.44 (t, J=7.2 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 189.3, 162.5, 162.0, 156.6, 142.4, 137.6, 137.0, 131.4, 127.6, 124.7, 124.1, 123.9, 115.8, 111.1, 107.6, 91.2, 55.8, 44.2, 31.1, 30.2; ESIMS m/z (rel intensity) 523 (MH+, 60), 403 [(MH+—C3H6Br)+, 100]; HRESIMS m/z calcd for C20H15NO3IBr 523.9358 (MH+). found, 523.9362 (MH+).
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19]>C(Cl)Cl>[O:12]=[C:13]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19]
Reactant: CC(=O)NCCCC(O)c1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)NCCCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.9 %

Procedure:
Pyridinium chlorochromate (10.08 g, 46.8 mmol) was added to a solution of N-(4-hydroxy-4-phenyl-butyl)-acetamide (6.46 g, 31.2 mmol), prepared in the previous step, in 200 ml of methylene chloride and the mixture stirred at room temperature for 1.5 hours. The entire reaction mixture was poured onto 200 g of silica gel (230-400 mesh) and the material eluted with ethyl acetate. Isolation of the major fraction gave N-(4-oxo-4-phenyl-butyl)-acetamide (4.35 g, 68%) as a light brown solid, mp 92-95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:22])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])[CH2:7][CH2:6]2.O1CCCC1>CO.[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:22])[C@@H:16]1[CH2:20][CH2:19][CH2:18][N:17]1[CH3:21])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)[C@@H]1CCCN1C)CC2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc2c(cc1N)N(C(=O)[C@@H]1CCCN1C)CC2
Temperature: 65 °C
Reaction time: 24 h
Yield: 98.9 %

Procedure:
A suspension of 5-(methyloxy)-1-(1-methyl-L-prolyl)-6-nitro-2,3-dihydro-1H-indole (2.50 g, 8.19 mmol) in methanol (100 mL)/tetrahydrofuran (100 mL) was warmed to 65° C. and maintained until all solids had dissolved. The solution was cooled, purged with nitrogen for 40 minutes, and 10% palladium on carbon (1.1 g, 8.19 mmol) was added and the suspension was maintained under 40 psi of H2 gas with rapid stirring for 24 hours. The solution was carefully purged with nitrogen, filtered through a pad of celite, and all solvents removed under reduced pressure to afford 5-(methyloxy)-1-(1-methyl-L-prolyl)-2,3-dihydro-1H-indol-6-amine (2.23 g, 99% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.57 (s, 1 H), 6.70 (s, 1 H), 4.76 (s, 2 H), 4.06-4.17 (m, 1 H), 3.93-4.06 (m, 1 H), 3.70 (s, 3 H), 3.46 (s, 1 H), 3.06-3.18 (m, 1 H), 2.98 (t, J=8.25 Hz, 2 H), 2.41-2.47 (m, 1 H), 2.37 (s, 3 H), 2.12-2.29 (m, 1 H), 1.66-1.92 (m, 3 H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[Si]([O:31][CH2:32][C:33]1[C:34]2[N:35]([N:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=2)[C:36]([CH2:39][O:40][CH3:41])=[CH:37][CH:38]=1)(C(C)(C)C)(C)C.O>O1CCCC1>[OH:31][CH2:32][C:33]1[C:34]2[N:35]([N:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=2)[C:36]([CH2:39][O:40][CH3:41])=[CH:37][CH:38]=1
Reactant: COCc1ccc(CO[Si](C)(C)C(C)(C)C)c2cc(C(F)(F)F)nn12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COCc1ccc(CO)c2cc(C(F)(F)F)nn12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
A 1 mol/L tetrabutylammonium fluoride-tetrahydrofuran solution (35.1 mL) was added dropwise to a solution of the compound of Example 325 (8.76 g) in tetrahydrofuran (120 mL) at 0° C. The mixture was stirred at 0° C. for 30 min. Subsequently, water was added and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to afford the title compound as a colorless powder (6.00 g).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3].S(Cl)(Cl)=O.[CH3:30]O>>[CH3:4][C:2]([C:5]1[CH:6]=[C:7]([S:16][CH2:17][CH2:18][S:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:30])=[O:24])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:1])[CH3:3]
Reactant: CC(C)(C)c1cc(SCCSCCCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CCCSCCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The title compound was prepared according to the method of Example 8 from the title compound of Example 14 (6.5 g) and thionyl chloride (10 ml) in methyl alcohol (75 ml).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]1[N:11]([CH2:24][CH2:25][OH:26])[CH:12]=[C:13]([C:15]2[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=2)[N:14]=1.[H-].[Na+].O>CN(C=O)C>[CH:21]([N:16]1[C:15]([C:13]2[N:14]=[C:10]3[N:11]([CH2:24][CH2:25][O:26][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=43)[CH:12]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: COc1cc(Cl)c(-c2nc(-c3nc(C)nn3C(C)C)cn2CCO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cn1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of 2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (2.25 g, 5.97 mmol) in DMF (30 mL) was cooled to 0° C. and treated with sodium hydride (239 mg, 5.97 mmol), the reaction mixture stirred at 0° C. for 30 min then allowed to warm to RT and stirred for 2 h. The reaction mixture was re-cooled to 0° C. and treated with water (400 mL), the precipitated product filtered off and washed with water then dried in vacuo to give the title compound as a white solid (1.02 g, 50%). LCMS RT=2.68 min, [M+H]+=341. 1H NMR 400 MHz (DMSO-d) δ: 9.15 (1H, s), 7.87 (1H, s), 6.42 (1H, s), 5.84 (1H, m), 4.57-4.56 (4H, m), 3.89 (3H, s), 2.25 (3H, s), 1.46 (6H, d, J=6.60 Hz).