Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([O:31]COC)=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)\[CH:16]([CH3:18])[CH3:17])=[CH:8][CH:7]=1.Cl.C([O-])(O)=O.[Na+]>CO.O1CCOCC1.O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([NH:12][C:13](=[O:35])/[C:14](/[C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[C:15](/[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)\[CH:16]([CH3:18])[CH3:17])=[CH:10][CH:11]=1
Reactant: COCOc1ccc(/C(C(=O)Nc2ccc(OCCN(C)C)cc2)=C(\c2ccccc2)C(C)C)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)/C(=C(\C(=O)Nc1ccc(OCCN(C)C)cc1)c1ccc(O)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
To a solution of 5b (90 mg, 0.184 mmol) in MeOH (3 ml) was added 4N HCl in 1,4-dioxane (0.5 ml) under ice cooling, and the mixture was stirred at room temperature for 2 h. A solution of NaHCO3 in H2O was poured into the reaction mixture under ice cooling, and the whole was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, and then concentrated. The residue was crystallized with Et2O to give 6b (84%). 6b: colorless powder; 1H-NMR (CD3OD) δ 1.07 (6H, d, J=6.8 Hz), 2.37 (6H, s), 2.79 (2H, t, J=5.4 Hz), 3.12 (1H, sep, J=5.4 Hz), 4.11 (2H, t, J=5.4 Hz), 6.46 (2H, d, J=8.8 Hz), 6.94 (2H, d, J=9.1 Hz), 6.95 (2H, d, J=8.8 Hz), 7.10 (2H, m), 7.16-7.25 (3H, m), 7.52 (2H, d, J=9.1 Hz). HRMS calcd for C28H33N2O3 [M+H]+: 445.2491. Found: 445.2510.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5](Br)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].[P:14]([O:21]CC)([O:18][CH2:19][CH3:20])[O:15][CH2:16][CH3:17]>>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([P:14]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:21])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: CCOP(OCC)OCC
Reactant: CCCCCCC(Br)C(=O)OCC
Product: CCCCCCC(C(=O)OCC)P(=O)(OCC)OCC
Yield: 80.6 %

Procedure:
2-Bromo octanoic acid ethyl ester (50 g, 0.2M) was heated at 150° with triethyl phosphite (75 g, 0.44M) and the distillate, Bpt 37°-60° condensed as the temperature was raised to 200° over 6 h. The reaction mixture was cooled and distilled under high vacuum (1.00 mm Hg) to afford 2 main fractions (a) Triethyl phosphite b.p. 40°-70° and (b) 2-(diethylphosphono)octanoic acid ethyl ester (49.5 g, 0.16M); b.p. 120°-130° at 0.5 mm Hg. (Found: C, 52.9; H, 9.4. C14H29O5P+0.5H2O requires: C, 53.0; H, 9.5%; δ(CDCl3) 0.88 (3H, m, CH3); 1.32 (17H, m, (CH2)4, 3×CH3); 1.9 (2H, m, CH2); 2.92 (1H, d, d, d, J= 22 Hz, J=10 Hz, J=4 Hz, CH--P); 4.18 (6H, m, 3×CH2O).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH:15]([OH:18])[CH2:16][OH:17]>CO>[Cl-:13].[OH:18][CH:15]([CH2:16][OH:17])[CH2:14][N+:10]1[CH:11]=[CH:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: OCC(O)CCl
Reactant: c1ccc(Cn2ccnc2)cc1
Solvent: CO
Product: OCC(O)C[n+]1ccn(Cc2ccccc2)c1
Product: [Cl-]
Reaction time: 48 h
Yield: 96.7 %

Procedure:
1-Benzylimidazole (3.95 g, 25.0 mmol) and 3-chloro-1,2-propanediol (2.76 g, 25.0 mmol) were stirred in a 130° C. oil bath for 48 h, after which the flask was placed under vacuum and stirring continued at 130° C. for another 48 h. The residue was then dissolved in CH3OH and transferred to a tared flask and concentrated to afford the product as a viscous brown oil (6.50 g, 97%). 1H NMR: δH ppm (400 MHz; DMSO-d6) 3.18-3.30 (m, 1H) 3.37-3.49 (m, 1H) 3.73-3.86 (m, 1H) 4.15 (dd, J=13.74, 7.69 Hz, 1H) 4.36 (dd, J=13.74, 3.11 Hz, 1H) 5.21 (t, J=5.50 Hz, 1H) 5.49 (s, 2H) 5.62 (d, J=5.50 Hz, 1H) 7.32-7.50 (m, 5H) 7.80 (t, J=1.83 Hz, 1H) 7.86 (t, J=1.83 Hz, 1H) 9.49 (t, J=1.56 Hz, 1H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[CH3:33][CH:34]([CH3:38])[C:35](O)=[O:36].C(N(C(C)C)CC)(C)C.[CH3:48][S:49]([C:52]1[CH:57]=[CH:56][C:55]([C:58]2[N:63]=[CH:62][C:61]([O:64][CH2:65][CH:66]3[CH2:71][CH2:70][N:69]([C:72]([NH:74][NH2:75])=[O:73])[CH2:68][CH2:67]3)=[CH:60][CH:59]=2)=[CH:54][CH:53]=1)(=[O:51])=[O:50]>CN(C=O)C.O>[CH3:33][CH:34]([CH3:38])[C:35]([NH:75][NH:74][C:72]([N:69]1[CH2:68][CH2:67][CH:66]([CH2:65][O:64][C:61]2[CH:62]=[N:63][C:58]([C:55]3[CH:56]=[CH:57][C:52]([S:49]([CH3:48])(=[O:50])=[O:51])=[CH:53][CH:54]=3)=[CH:59][CH:60]=2)[CH2:71][CH2:70]1)=[O:73])=[O:36]
Reactant: CC(C)C(=O)O
Reactant: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)NN)CC3)cn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C(=O)NNC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 84.8 %

Procedure:
TBTU (279 mg, 0.87 mmol) and HOBT (24 mg, 0.17 mmol) were added to a mixture of 2-methylpropanoic acid (81 μL, 0.87 mmol), diisopropylethylamine (0.758 mL, 4.35 mmol) in DMF (5 mL) at ambient temperature. The mixture was stirred at ambient temperature for 15 min. The mixture was charged with 4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbohydrazide (352 mg, 0.87 mmol), and was stirred at ambient temperature overnight. The mixture was charged with water and set at ambient temperature overnight. The resulting tan precipitate was filtered, washed with water, and dried in a vacuum oven to give 350 mg (85%) of N′-(2-methylpropanoyl)-4-[({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)methyl]-1-piperidinecarbohydrazide as a tan solid. 1H NMR (400 MHz, DMSO-d6): δ 9.31 (d, 1H, J=1.9 Hz), 8.44 (d, 1H, J=2.9 Hz), 8.36 (d, 1H, J=1.9 Hz), 8.29 (d, 2H, J=8.6 Hz), 8.06 (d, 1H, J=8.8 Hz), 7.99 (d, 2H, J=8.6 Hz), 7.55 (dd, 1H, Ja=8.8 Hz, Jb=3.0 Hz), 4.08-3.96 (m, 4H), 3.25 (s, 3H), 2.80-2.70 (m, 2H), 2.41 (septet, 1H, J=6.8 Hz), 2.08-1.92 (m, 1H), 1.82-1.73 (m, 2H), 1.30-1.10 (m, 2H), 1.02 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 475 (M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@H:17]2[CH2:22][CH2:21][C@@H:20]([NH:23][C:24](=O)OC(C)(C)C)[CH2:19][C@H:18]2[CH2:31][S:32]([C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:34])=[O:33])[C:13]1=[O:39])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:41](F)(F)[C:42](O)=O.[CH2:47](Cl)Cl>>[C:35]([S:32]([CH2:31][C@@H:18]1[CH2:19][C@H:20]([N:23]([CH:41]([CH3:42])[CH3:47])[CH3:24])[CH2:21][CH2:22][C@@H:17]1[N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:13]1=[O:39])(=[O:34])=[O:33])([CH3:36])([CH3:37])[CH3:38]
Reactant: O=C(O)C(F)(F)F
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Product: CC(C)N(C)[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](CS(=O)(=O)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
tert-Butyl (1R,3R,4S)-4-((S)-3-benzyloxycarbonylamino-2-oxopyrrolidin-1-yl)-3-(tert-butylsulfonylmethyl)cyclohexylcarbamate (880 mg) was dissolved in CH2Cl2 (5 mL) at 0° C. prior to the addition of trifluoroacetic acid (10 mL). After 1 h at rt, the reaction was concentrated in vacuo. The resultant residue was dissolved in EtOAc and was washed with sat. Na2CO3 solution. The organic phase was dried (MgSO4), filtered, and concentrated. This residue was dissolved in dichloroethane (6 ml) and acetone (6 mL) prior to the addition of NaBH(OAc)3 (637.6 mg). After 2 h, formaldehyde (6.0 mL of a 37% aq. solution) was added along with NaBH(OAc)3 (310 mg). The mixture was stirred for 1 h, quenched with sat. Na2CO3, and extracted with EtOAc (2×). The organic extracts were combined, dried (MgSO4), filtered, and concentrated to afford benzyl (S)-1-((1S,2R,4R)-2-(tert-butylsulfonylmethyl)-4-(isopropyl(methyl)amino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (1.0 g). MS found: (M+H)+=522.5.
Reaction SMILES: [F:1][C:2]1([C:6]2[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=2)[CH2:5][CH2:4][CH2:3]1.[NH2:22][C:23]1([CH2:29][C:30]([NH2:32])=[O:31])[CH2:26][S:25](=[O:28])(=[O:27])[CH2:24]1>>[NH2:32][C:30](=[O:31])[CH2:29][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][C@@H:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])[C:6]([C:2]3([F:1])[CH2:3][CH2:4][CH2:5]3)=[CH:11][N:10]=2)=[O:14])[CH2:24][S:25](=[O:27])(=[O:28])[CH2:26]1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1(F)CCC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC2(CC(N)=O)CS(=O)(=O)C2)ncc1C1(F)CCC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(1-fluorocyclobutyl)-4-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine-2-carboxylic acid (example 305e) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (19 mg, 49%); MS (ESI, m/z): 468.3 (M+H+).
Reaction SMILES: CCN(CC)CC.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([F:30])[CH:27]=2)[NH:22][C:21]1=O.CCN=C=NCCCN(C)C.Cl[C:44]1[S:54][C:47]2[NH:48][C:49]([C:51](O)=[O:52])=[CH:50][C:46]=2[CH:45]=1>CN(C=O)C.O>[F:30][C:26]1[CH:27]=[C:28]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH2:21][CH:20]([NH:19][C:51]([C:49]1[NH:48][C:47]3[S:54][CH:44]=[CH:45][C:46]=3[CH:50]=1)=[O:52])[CH2:29]2
Reactant: NC1Cc2cc(F)ccc2NC1=O
Reactant: O=C(O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(NC1CNc2ccc(F)cc2C1)c1cc2ccsc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
Et3N (184 μL, 1.32 mmol), HOBT (89 mg, 0.66 mmol), 3-amino-6-fluoro-3,4-dihydro-2(1H)-quinolinone monohydrochloride (CAS Reg. No: 82420-54-0) (143 mg, 0.66 mmol), and EDAC (127 mg, 0.66 mmol) were added to a solution of 2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxylic acid (133 mg, 0.66 mmol) in anhydrous DMF (3.5 mL). The reaction was stirred at ambient temperature for approximately 16 h, and then poured into water (50 mL). This was stirred vigorously for about 10 mins. and filtered. The collected precipitate was washed with water and dried in vacuum at 40° C., to give the title compound (203 mg, 84%) as an amorphous solid.
Reaction SMILES: C1(S([N:10]2[C:14]3[CH:15]=[N:16][C:17]([C:28]#[N:29])=[C:18]([O:19][CH:20]4[CH2:25][CH2:24][N:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[C:13]=3[C:12]3[CH:30]=[C:31](Br)[CH:32]=[N:33][C:11]2=3)(=O)=O)C=CC=CC=1.[CH3:35]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:26]([N:23]1[CH2:24][CH2:25][CH:20]([O:19][C:18]2[C:13]3[C:12]4[CH:30]=[C:31]([CH3:35])[CH:32]=[N:33][C:11]=4[NH:10][C:14]=3[CH:15]=[N:16][C:17]=2[C:28]#[N:29])[CH2:21][CH2:22]1)[CH3:27]
Reactant: CB1OB(C)OB(C)O1
Reactant: CCN1CCC(Oc2c(C#N)ncc3c2c2cc(Br)cnc2n3S(=O)(=O)c2ccccc2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCN1CCC(Oc2c(C#N)ncc3[nH]c4ncc(C)cc4c23)CC1
Temperature: 100 °C
Yield: 51.4 %

Procedure:
A mixture of 9-benzenesulfonyl-3-bromo-5-(1-ethyl-piperidin-4-yloxy)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (215 mg, 0.40 mmol), trimethylboroxine (167 μL, 1.2 mmol), cesium carbonate (156 mg, 0.48 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (96 mg, 0.04 mmol) in dioxane (2.0 mL) was degassed with argon and heated under microwave irradiation at 100° C. for 90 minutes. The reaction mixture was allowed to cool to ambient temperature, diluted with saturated aqueous ammonium chloride (10 mL) and extracted with dichloromethane (3×10 mL). The combined organic phase was washed with brine (2×10 mL) and concentrated in-vacuo. The resultant residue was diluted with THF (10 mL), 1N aqueous potassium hydroxide (1 mL) added and the reaction mixture was then heated at 50° C. for 1 hour. The solvent was evaporated in-vacuo and the resultant residue was purified by chromatography (silica, 2 g column, Si-SPE, 0-10% 2-propanol in dichloromethane). The appropriate fractions were combined and evaporated in-vacuo and the resultant residue triturated with pentane (2×2 mL) to afford the title compound as an off-white solid (69 mg, 52%). LCMS (Method A): RT=2.46 min, M+H+=336.2. 1H NMR (400 MHz, CD3OD): 8.71 (s, 1H), 8.52 (dd, J=2.1, 0.7 Hz, 1H), 8.47 (dd, J=2.1, 0.9 Hz, 1H), 4.91-4.88 (m, 1H), 3.02-2.99 (m, 2H), 2.57 (s, 3H), 2.50 (q, J=7.2 Hz, 2H), 2.26-2.19 (m, 4H), 2.12-2.11 (m, 2H), 1.13 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])=[N:10][CH:9]([NH:25]C(OC(C)(C)C)=O)[C:8]1=[O:33])=[O:5])[CH3:2].Cl.O.C(=O)(O)[O-].[Na+]>CO.C(OCC)(=O)C>[NH2:25][CH:9]1[N:10]=[C:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:7]([CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[C:8]1=[O:33]
Reactant: CCOC(=O)CN1C(=O)C(NC(=O)OC(C)(C)C)N=C(c2ccccc2F)c2ccccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1C(=O)C(N)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.2 %

Procedure:
To a solution of (3RS)-1-ethoxycarbonylmethyl-3-tert-butoxycarbonylamino-5-(2-fluorophenyl)-2,3-dihydro-1H -1,4-benzo-diazepin-2-one (7.2 g) in methanol (100 ml) was added 4N solution of hydrogen chloride in ethyl acetate (55 ml) under stirring at ambient temperature. The mixture was stirred for 4 hours under the same condition and allowed to stand overnight. The solvent was removed in vacuo to give residue, to which was added water. The mixture was adjusted to pH 8 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate twice. The combined extract was washed with water and dried over magnesium sulfate. Removal of the solvent afford (3RS)-3-amino-1-ethoxycarbonylmethyl-5-(2-fluorophenyl)-2,3-dihydro-1H-1,4-benzodiazepin-2-one (5.46 g) as an amorphous mass, which was used in a following reaction step without further purification,
Reaction SMILES: Cl[C:2]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:3]=1[O:4][CH2:5][C:6]1[N:7]([CH3:28])[C:8]2[C:13]([C:14]=1[C:15](=[O:27])C(N(C)C1CCN(C)CC1)=O)=[CH:12][CH:11]=[CH:10][CH:9]=2.B.[CH2:35]1[CH2:39]O[CH2:37][CH2:36]1>>[Cl:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][CH2:5][C:6]2[N:7]([CH3:28])[C:8]3[C:13]([C:14]=2[CH:15]([OH:27])[CH2:8][N:7]2[CH2:6][CH2:5][CH:35]([CH3:39])[CH2:36][CH2:37]2)=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:2][CH:32]=1
Reactant: CN1CCC(N(C)C(=O)C(=O)c2c(COc3ccc(Cl)cc3Cl)n(C)c3ccccc23)CC1
Reactant: C1CCOC1
Agent: B
Product: CC1CCN(CC(O)c2c(COc3ccc(Cl)cc3)n(C)c3ccccc23)CC1
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere a round bottom flask was charged with 2-[(2,4-dichlorophenoxy)methyl]-1-methyl-3-[2-[N-methyl-N-(1-methylpiperidin-4-yl)amino]-1,2-ethanedionyl]-1H-indole (0.3349 g, 0.686 mmol) and placed in an ice bath Borane-tetrahydrofuran complex (4.11 ml of a 1.0 M borane solution in THF, 4.11 mmol) was added slowly and the ice bath was removed. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was stirred for about one hour and then 0.33 ml of a 1:1 tetrahydrofuran:methanol solution was added. Sodium hydroxide (1.74 ml of a 5.0 N solution) was then added and the resulting mixture was heated to reflux and maintained at this temperature overnight.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.C(N(CC)CC)C.[NH2:15][CH2:16][CH:17]([OH:33])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:21]=1>C1COCC1>[NH2:7][C:5]1[S:6][C:2]([NH:15][CH2:16][CH:17]([OH:33])[CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH:21]=2)=[N:3][N:4]=1
Reactant: NCC(O)COc1cccc(CN2CCCCC2)c1
Reactant: Nc1nnc(Br)s1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1nnc(NCC(O)COc2cccc(CN3CCCCC3)c2)s1

Procedure:
0.54 g (3 mmol) of 5-bromo-1,3,4-thiadiazole-2-amine and 0.45 ml of triethylamine are added to 0.8 g (3 mmol) of 1-amino-3-[3-(1-piperidinylmethyl)phenoxy]-2-propanol in 20 ml of THF and the mixture is reacted in a manner analogous to Example 51. The oil obtained is purified by column chromatography (silica gel; ammoniacal. Methanolchloroform solution (5+95)).
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:11][C:12](=O)[C:13](=O)[CH3:14].[OH-:17].[Na+]>O>[CH3:11][C:12]1[NH:10][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:9][C:13]=1[CH2:14][OH:17]
Reactant: CC(=O)C(C)=O
Reactant: N=C(N)c1ccccc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1[nH]c(-c2ccccc2)nc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 100 gm. portion of benzamidine hydrochloride is dissolved in a minimum of water (350 ml.) at room temperature. A 67 gm. portion of freshly distilled 2,3-butanedione is added giving a yellow solution. Adjusting the pH to 6-7 with 2N NaOH gives a solid which is allowed to stand at 0° C. for 2 hours, collected, pressed dry and then washed with 100 ml. of acetone. This material is heated with stirring on a steam bath with 855 ml. of concentrated HCl and 2437 ml. of water for 4 hours giving a solution. Cooling to room temperature overnight and then to 0° C. produces a solid which is collected and air dried. This solid is dissolved in 350 ml. of ethanol, filtered and cooled producing a gel, which is taken up in 250 ml. of 50°-60° C. water, adjusted to pH 5.5 with concentrated NaOH and then to pH 7-8 with solid KHCO3. The mixture is cooled to 0° C. and the product is collected, washed with water, and air dried. This product is recrystallized from one liter of methanol giving the final product, m.p. 197°- 199° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1COCC1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[O:17][C:18]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=4)[C:32]([NH:34][C:35]([CH3:40])([CH3:39])[C:36](O)=[O:37])=[O:33])=[CH:25][C:19]=3[C:20]=2[C:21](=[O:24])[NH:22][CH3:23])=[CH:12][CH:11]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][N:2]([CH3:3])[C:36](=[O:37])[C:35]([NH:34][C:32]([C:31]1[CH:30]=[C:29]([C:26]2[CH:27]=[CH:28][C:18]3[O:17][C:16]([C:13]4[CH:12]=[CH:11][C:10]([F:9])=[CH:15][CH:14]=4)=[C:20]([C:21]([NH:22][CH3:23])=[O:24])[C:19]=3[CH:25]=2)[CH:43]=[CH:42][CH:41]=1)=[O:33])([CH3:39])[CH3:40]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cccc(C(=O)NC(C)(C)C(=O)N(C)C)c3)cc12
Reaction time: 3 h
Yield: 71 %

Procedure:
A solution of dimethylamine in THF (2 molar, 0.10 mL, 0.20 mmol) was added to 2-(3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzamido)-2-methylpropanoic acid (17 mg, 0.036 mmol) and HATU (15 mg, 0.039 mmol) in a 1 dram vial. DMF (0.3 mL) was added, the vial was capped, and the homogeneous solution was stirred at r.t. for 1 h, at which point DIPEA (50 μL, 0.29 mmol) was added. Stirring was continued for 3 h, at which point the reaction was filtered and purified directly by prep HPLC. Concentration of the collected fractions afforded the title compound as a white solid (13 mg, 71% yield). 1H NMR (500 MHz, CD3OD) δ ppm 8.09-8.17 (m, 1 H) 7.90-7.98 (m, 3 H) 7.86 (d, J=7.94 Hz, 1 H) 7.79-7.84 (m, 1 H) 7.63-7.72 (m, 2 H) 7.57 (t, J=7.63 Hz, 1 H) 7.20-7.32 (m, 2 H) 3.14 (br. s., 3 H) 2.98 (s, 6 H) 1.61 (s, 6 H). LC/MS was performed on a Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. LC/MS method: solvent A=5% CH3CN/95% H2O/10 mM NH4OAc, solvent B=95% CH3CN/5% H2O/10 mM NH4OAc, start % B=0, final % B=100, gradient time=2 min, stop time=3 min, flow rate=5 ml/min, column: XBridge C18 5 μm 4.6×50 mm; HPLC Rt=1.29 min, (ES+) m/z (MH+)=502. Analytical HPLC method: solvent A=5% CH3CN/95% H2O/0.1% TFA, solvent B=95% CH3CN/5% H2O/0.1% TFA, start % B=10, final % B=100, gradient time=15 min, stop time=18 min, flow rate=1 ml/min. Column: Waters Sunfire C-18, 3.5 μm 4.6×150 mm, Rt=14.80 min, purity=100%; column: Waters Xbridge Phenyl 3.5 μm 4.6×150 mm, Rt=10.37 min, purity=100%.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29]Cl)[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1.[OH:34][CH:35]([C:39]1[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=1)[CH2:36][NH:37][CH3:38].O>CN(C=O)C>[Cl:10][C:11]1[CH:33]=[CH:32][C:14]([CH2:15][NH:16][C:17]([C:19]2[C:20](=[O:31])[C:21]3[CH:28]=[C:27]([CH2:29][N:37]([CH2:36][CH:35]([C:39]4[S:43][C:42]([C:44]#[N:45])=[CH:41][CH:40]=4)[OH:34])[CH3:38])[O:26][C:22]=3[N:23]([CH3:25])[CH:24]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CCl)oc21
Reactant: CNCC(O)c1ccc(C#N)s1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2o1)CC(O)c1ccc(C#N)s1
Temperature: 90 °C
Yield: 31.7 %

Procedure:
N,N-Diisopropylethylamine (0.18 mL) and N-(4-chlorobenzyl)-2-(chloromethyl)-7-methyl-4-oxo-4,7-dihydrofuro[2,3-b]pyridine-5-carboxamide (Example 2, 0.250 g) were added to a solution of rac-5-(1-hydroxy-2-(methylamino)ethyl)thiophene-2-carbonitrile (Preparation 51, 0.188 g) in DMF (15 mL). The reaction mixture was heated to 90° C. for 2 h. The mixture was allowed to cool to room temperature and was poured into water (30 mL). The suspension was filtered and the resulting solid was purified by column chromatography (CH2Cl2/methanol; 98/2) followed by recrystallization from ethyl acetate/methanol to yield 0.111 g of the title compound as a pale yellow solid. Physical characteristics. M.p. 190-195° C. (dec); 1H NMR (400 MHz, DMSO-d6) δ 10.63, 8.56, 7.80, 7.41-7.32, 7.14, 6.88, 6.06, 5.01-4.97, 4.55, 3.92, 3.76, 2.69-2.64, 2.34; 13C NMR (100 MHz, CDCl3) δ 173.7, 164.6, 154.3, 153.2, 150.0, 141.2, 137.4, 137.2, 132.8, 128.9, 128.7, 123.3, 116.9, 114.7, 114.3, 108.5, 106.9, 66.3, 63.9, 54.1, 42.6, 41.8, 37.8; MS (ESI+) m/z 511 (M+H)+.
Reaction SMILES: C1C2C(C[O:15][C:16]([N:18]([C:39]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=O)C3C(=CC=CC=3)C=2C=CC=1.[OH:58][C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=1[OH:68])C(O)=O>>[OH:58][C:59]1[CH:60]=[C:61]([CH:65]=[CH:66][C:67]=1[OH:68])[C:16]([N:18]([C:39]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][CH2:21][C:22](=[O:25])[NH:23][CH3:24])=[O:15]
Reactant: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)OCC1c2ccccc2-c2ccccc21)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Product: CNC(=O)CC[C@@H](C(=O)NCCc1ccc(O)c(O)c1)N(C(=O)c1ccc(O)c(O)c1)C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
This compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-Nδ-methyltrityl-L-glutaminyl]dopamine (705 mg, 0.9 mmol, example 48, step A) as described for example 48 (step B) using 3,4-dihydroxybenzoic acid (215 mg, 1.4 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 40%, 50% and 60% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a white powder (100 mg, 16%).