Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[C:12]([O:16][CH:17]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[CH2:18][CH3:19])(=[O:15])[CH2:13][CH3:14]>CC(OC)(C)C.CC(C)=O.O>[C:12]([O:16][CH:17]([O:20][C:21]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:22])[CH2:18][CH3:19])(=[O:15])[CH2:13][CH3:14]
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CCC(=O)OC(CC)OC(=O)ON1C(=O)CCC1=O
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: CCC(=O)OC(CC)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (472 mg, 3.0 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]propyl propanoate (281 mg, 1.03 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 28 (173 mg, 53% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.82-0.94 (br. m, 5H), 1.01 (t, J=7.2 Hz, 3H), 1.17-1.37 (br. m, 3H), 1.64-1.75 (m, 4H), 1.83-1.91 (br. m, 2H), 2.10 (tt, J=12.0, 3.6 Hz, 1H), 2.23-2.38 (m, 2H), 2.76-2.87 (br. m, 2H), 6.54 (t, J=6.0 Hz, 1H), 7.42 (t, J=6.0 Hz, 1H), 11.97 (br. s, 1H). MS (ESI) m/z 338.16 (M+Na)+; 314.12 (M−H)−.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]2[C@H:18]3[CH2:19][CH2:20][N:21]([C:22]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:23])[C@H:17]3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:32]I.O>CN(C=O)C>[CH3:32][N:10]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=2[C@@H:17]2[N:21]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])[CH2:20][CH2:19][C@@H:18]2[C@@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CI
Reactant: O=C(OCc1ccccc1)N1CC[C@@H]2[C@H](c3ccccc3)Nc3ccccc3[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1c2ccccc2[C@H]2[C@H](CCN2C(=O)OCc2ccccc2)[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33.1 %

Procedure:
Sodium hydride (60% in oil, 120 mg, 3.0 mmol) was suspended in DMF (12 ml), benzyl (3aR*,4R,9bR)-4-phenyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo[3,2-c]quinoline-1-carboxylate (960 mg, 2.5 mmol) was added, and the mixture was stirred at room temperature for 10 min. Thereto was added methyl iodide (426 mg, 3.0 mmol), and the mixture was stirred at room temperature for 3 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried (over anhydrous Na2SO4), and the solvent was evaporated. The residue was subjected to column chromatography using silica gel (30 g) and eluted with hexane-ethyl acetate (5:1, v/v) to give the title compound (330 mg, 33%) as an amorphous form.
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[CH2:5][O:4][CH2:3]1.Br[CH2:9][CH:10]1[CH2:12][CH2:11]1.[H-].[Na+]>CN(C=O)C>[CH:10]1([CH2:9][O:1][C@H:2]2[C@@H:6]([OH:7])[CH2:5][O:4][CH2:3]2)[CH2:12][CH2:11]1
Reactant: BrCC1CC1
Reactant: O[C@@H]1COC[C@@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O[C@H]1COC[C@H]1OCC1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
To a stirred solution of cis-3,4-dihydroxytetrahydrofuran (5.8 g, 56 mmol) and bromomethylcyclopropane (5.0 g, 37 mmol) in DMF (100 mL) at 0° C. was added sodium hydride (1.6 g of a 60% suspension in mineral oil, 40 mmol) in portions over a period of 2 h. The resulting solution was stirred at 0° C. for 1 h and then at ambient temperature for 18 h. The solution was concentrated in vacuo and partitioned between EtOAc and water. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using 1:1 EtOAc:hexanes as eluant to give the title compound as a colorless liquid (1.8 g; TLC Rf=0.4, 1:1 EtOAc:hexanes).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[S:13]1[CH2:18][CH:17]=[C:16](OS(C(F)(F)F)(=O)=O)[CH2:15][CH2:14]1.[Cl-].[Li+].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH2:17][CH2:18][S:13][CH2:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: O=S(=O)(OC1=CCSCC1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(C2=CCSCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a mixture of 4-nitrophenylboronic acid (418 mg, 2.50 mmol), trifluoromethanesulfonic acid 3,6-dihydro-2H-thiopyran-4-yl ester (as prepared in the previous step, 931 mg, 3.75 mmol), Pd(PPh3)4 (433 mg, 0.375 mmol) and lithium chloride (LiCl) (212 mg, 5.0 mmol) in 20 mL of 1,4-dioxane was added 2.0 M aq Na2CO3 solution (3.13 mL, 6.25 mmol). The resulting mixture was stirred at 80° C. for 2 h and then cooled to RT. Treated with 200 mL of EtOAc, the mixture was washed with H2O (2×30 mL), brine (30 mL) and dried (Na2SO4). Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (1-3% EtOAc/hexane) gave 470 mg (85%) of the title compound as a light brown oil. 1H-NMR (CDCl3; 400 MHz): δ 8.19 (d, 2H, J=9.1 Hz), 7.48 (d, 2H, J=9.1 Hz), 6.36 (m, 1H), 3.39 (m, 2H), 2.91 (t, 2H, J=5.7 Hz), 2.72 (m, 2H). Mass spectrum (ESI, m/z): Calcd. for C11H11NO2S, 222.1 (M+H), found 222.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[CH3:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[Cs+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].N(P(Cl)Cl)(C1CCCCC1)C1CCCCC1>[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[O:8][CH3:9])=[CH:13][CH:12]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccccc1Cl
Agent: [Pd]
Agent: ClP(Cl)N(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1ccccc1-c1ccc(C)cc1
Reaction time: 24 h
Yield: 83.2 %

Procedure:
The general procedure from Example 12 was followed using 2-chloro-anisole (143 mg, 1.0 mmol) and 4—MeC6H4B(OH)2 (204 mg, 1.5 mmol) with Pd2(dba)3 (13.3 mg, 0.0145 mmol) and (Me3C)2PH(O) from Experiment 2 (9.6 mg, 0.058 mmol) and CsF (456 mg, 3.0 mmol) in 4.0 mL of 1,4-dioxane. After 24 h, the reaction mixture was chromatographed with 5% ethyl acetate/hexane to give 165 mg (83% yield) of 2-(4-methylphenyl)anisole. It was >95% pure by 1H NMR and GC/MS. 1H NMR (500 MHz, CDCl3): δ7.32 (d, J=8.06 Hz, 2H), 7.18 (m, 2H), 7.10 (d, J=7.88 Hz, 2H), 6.92−6.84 (m, 2H), 3.67 (s, 3H), 2.28 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ156.5, 136.5, 135.6, 130.7, 129.4, 128.7, 128.3, 120.8, 111.2, 55.5, 21.1 ppm.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>>[CH2:6]([O:5][C:1](=[O:4])[CH2:2][CH2:3][N:12]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: CC(C)(C)N
Product: CCOC(=O)CCN(CCC(=O)OCC)C(C)(C)C
Yield: 14.5 %

Procedure:
A mixture of ethyl acrylate (0.735 mol) and tert-butyl amine (0.210 mol) was refluxed for 6 days. The crude mixture was purified by fractionated distillation in vacuo (5 mbar). One fraction was collected (boiling point: 120° C. at 5 mbar), yielding to 8.3 g of the desired product as a light yellow oil. MS (m/e): 274.4 (MH+, 100%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccncc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)n1ncc2c(C(=O)O)cc(-c3ccncc3)nc21

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-(4-pyridinyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (100 mg, 0.322 mmol), ethanol (4 mL), THF (0.8 mL), and sodium hydroxide (0.537 mL, 1.611 mmol). The final product was collected as 88 mg (97%). LCMS E-S (M+H)=283.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (d, J=6.4 Hz, 6H), 5.40 (m, 1H), 8.25 (d, J=5.6 Hz, 2H), 8.32 (s, 1H), 8.44 (s, 1H), 8.79 (d, J=5.6 Hz, 2H), 14.12 (br. s., 1H).
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19](O)=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:22])=[C:11]2[CH3:23])[CH2:5][CH2:4]1)#[N:2].[CH:27]1([C:30]2[CH:31]=[C:32]([C@@H:36]([NH2:38])[CH3:37])[CH:33]=[CH:34][CH:35]=2)[CH2:29][CH2:28]1>>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:24]=[CH:25][CH:26]=2)[CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]([NH:38][C@H:36]([C:32]4[CH:33]=[CH:34][CH:35]=[C:30]([CH:27]5[CH2:29][CH2:28]5)[CH:31]=4)[CH3:37])=[O:20])=[CH:16][CH:17]=3)[C:12]([CH3:22])=[C:11]2[CH3:23])[CH2:5][CH2:4]1)#[N:2]
Reactant: Cc1c(C)n(Cc2cccc(C3(C#N)CC3)c2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Product: Cc1c(C)n(Cc2cccc(C3(C#N)CC3)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 5, Example 35, using 1-(3-(1-cyanocyclopropyl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and (S)-1-(3-cyclopropylphenyl)ethanamine.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[O:22])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[BH4-].[Na+]>C(O)C>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH2:21][OH:22])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CC=O)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CCO)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.7 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (50.0 mg, 0.107 mmol) in ethanol (1.00 mL) was added sodium tetrahydroborate (4.05 mg, 0.107 mmol). The mixture was stirred at rt for 1 hr. The reaction was quenched with 1.00 M of hydrochloric acid in water (0.428 mL) and distributed between NaHCO3(aq) saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was dried and concentrated to provide a white solid. Purification on a silica gel column (gradient elution 0-5% MeOH) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-hydroxypropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate as a colorless syrup (38 mg, 75.7% yield). 1H NMR (400 MHz, CDCl3) δ 7.46-7.35 (dd, J=5.2, 3.1 Hz, 2H), 7.30-7.19 (m, 1H), 5.65-5.52 (t, J=8.0 Hz, 1H), 4.42-4.26 (q, J=7.1 Hz, 2H), 3.85-3.77 (t, J=4.9 Hz, 4H), 3.76-3.65 (ddt, J=13.0, 9.0, 4.6 Hz, 1H), 3.57-3.44 (t, J=4.8 Hz, 5H), 2.69-2.58 (dd, J=8.4, 4.1 Hz, 1H), 2.56-2.43 (dt, J=8.1, 4.9 Hz, 2H), 1.44-1.32 (t, J=7.1 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>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.COCCOC>[CH3:15][S:12]([C:10]1[CH:11]=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1)(=[O:14])=[O:13]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)cc1Cl
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(S(C)(=O)=O)cc1-c1ccccc1
Temperature: 160 °C

Procedure:
To a mixture of methyl 2-chloro-4-(methylsulfonyl)benzoate (2.2 g, 8.9 mmol), PhB(OH)2 (1.31 g, 10.8 mmol), DME (12 mL), and 2M Na2CO3 (6 mL) was added Pd(PPh3)4 (515 mg). The mixture was heated for 20 min at 160° C. in a microwave reactor, and then extracted with EtOAc, dried over sodium sulfate and concentrated in vacuo. Purification on normal phase silica gel (hexane/EtOAc) provided methyl 5-(methylsulfonyl)-[1,1′-biphenyl]-2-carboxylate as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22](O)=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6].[CH3:25][CH:26]1[CH2:30][CH2:29][CH:28]([CH3:31])[NH:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[C:22]([N:27]1[CH:28]([CH3:31])[CH2:29][CH2:30][CH:26]1[CH3:25])=[O:23])[C:5]([NH:7][CH2:8][C:9]1[NH:13][C:12]2[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:11]=2[N:10]=1)=[O:6]
Reactant: CC1CCC(C)N1
Reactant: O=C(NCc1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)O)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC1CCC(C)N1C(=O)c1ccc(C(=O)NCc2nc3cc(Cl)ccc3[nH]2)cc1Cl

Procedure:
Prepared analogously to Example 1d from 3-chloro-N-(5-chloro-1H-benzimidazol-2-ylmethyl)-4-carboxybenzamide, 2,5-dimethylpyrrolidine, TBTU, and triethylamine in DMSO at ambient temperature. HPLC-MS results: retention time: 3.77 minutes; C22H22Cl2N4O2 (445.35); mass spectrum: (M+H)+=445.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C@@H:24]([OH:26])[CH3:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([CH2:23][C@@H:24]([OH:26])[CH3:25])=[CH:21][CH:22]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)cc1Cl
Reactant: C[C@H](O)Cc1ccc(N)cc1
Product: C[C@H](O)Cc1ccc(Nc2cc(Cl)c(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 162 from 2,4-dichloro-5-nitrobenzotrifluoride and (2S)-1-(4-aminophenyl)-2-propanol (step 2 of Example 248).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:22][C:23]1[CH:24]=[N:25][CH:26]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:28]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CCO>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1(C)C=CC=CC=1.O>[F:22][C:23]1[CH:28]=[C:27]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)[CH:26]=[N:25][CH:24]=1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(Br)c1
Reactant: CC1(C)OB(c2cncc(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cncc(-c2cncc(F)c2)c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 42.1, 5 g, 13.85 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.5 g, 15.23 mmol), PdCl2(dppf) (0.507 g, 0.692 mmol), K3PO4 (8.82 g, 41.5 mmol), EtOH (9.33 mL), water (14 mL) and toluene (70 mL) was stirred at 100° C. for 1 h. The solvent was evaporated off under reduced pressure and the residue was treated with water and extracted with EtOAc. The combined extracts were washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 500 g, EtOAc/MeOH from 0 to 2% MeOH). Fractions containing the pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was dissolved in THF, stirred overnight with Si-Thiol (1 g), filtered and the filtrate was evaporated off under reduced pressure to give the title compound as a white solid. UPLC-MS (Condition 7) tR=1.03 min, m/z=376 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.43 (d, J=8.93 Hz, 2H) 7.91 (d, J=9.0 Hz, 2H) 8.32 (dd, J=2.20 Hz, 1H) 8.71 (d, J=2.32 Hz, 1H) 9.0 (d, J=5.1 Hz, 1H) 9.15 (s, 1H) 9.22 (s, 1H) 10.69 (s, 1H).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CN(C=O)C.[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[CH:18]=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:41])[CH3:40])=[O:37].O>C(OCC)(=O)C>[NH2:14][C:15]1[N:20]=[C:19]([NH:21][C@H:22]2[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:18]([Cl:1])=[CH:17][C:16]=1[C:36]([NH:38][C:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)([CH3:40])[CH3:41])=[O:37]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1ccc(C(=O)NC(C)(C)c2ccccc2)c(N)n1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Reaction time: 1 h
Yield: 78.2 %

Procedure:
N-chlorosuccinimide (17 mg) was added to a DMF (5 ml) solution containing tert-butyl cis-2-(6-amino-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (60 mg) at 0° C., followed by stirring for 1 hour. Water and ethyl acetate were added to the reaction mixture. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and then the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel: silica gel 60 (spherical shape) (Kanto Chemical Co., Inc.); hexane:ethyl acetate=3:1), and a white solid of tert-butyl cis-2-(6-amino-3-chloro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (50 mg) was thus obtained.
Reaction SMILES: [C:1]([C:5](=[O:36])[CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[O:8])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:38]>>[C:1]([C:5](=[O:36])[CH:6]([Cl:38])[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:32]=[CH:33][C:34]=1[Cl:35])[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:14])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)CC(=O)C(C)(C)C)c1
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(Cl)c(NC(=O)C(Cl)C(=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a suspension of 52.22 g (0.1 mol) of hexadecyl 3-[3-t-butyl-3-oxopropanamido]-4-chlorobenzoate 1 in 350 mL of CH2Cl2 was added 13.52 g (0.1 mol) of SO2Cl2. The mixture was gently refluxed for one hr, then stirred at room temperature for 0.5 hr. The solvent was removed under vacuum to yield a solid that was washed with ligroin and dried. There was thus obtained 52.62 g (94.5% yield) of 2, which was used in the following step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:23]([CH2:27][CH2:28][C:29](Cl)=[O:30])([O:25][CH3:26])=[O:24].N1C=CC=CC=1>CC(N(C)C)=O>[CH3:26][O:25][C:23](=[O:24])[CH2:27][CH2:28][C:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:22])[N:7]3[CH2:14][CH2:13][C:12](=[CH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:8]3=[N:9][C:10]=2[CH:11]=1)=[O:30]
Reactant: COC(=O)CCC(=O)Cl
Reactant: Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1ccc2c(=O)n3c(nc2c1)C(=Cc1ccccc1)CC3
Temperature: 0 °C

Procedure:
6-amino-3-benzylidene-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazoline-9-one (2.5 g) was reacted with 3-carbometoxy propionyl chloride (1.95 g) in dimethylacetamide (110 ml) in the presence of pyridine (2 ml) at room temperature for 18 hours. The reaction mixture was then diluted with ice water and the precipitate was filtered and washed with water to give 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid methyl ester, m.p. 288°-291° C. (3.3 g) which was dissolved in dimethylformamide (120 ml) and treated with 5% aqueous NaOH (32.5 ml) at room temperature for 3 hours. The precipitate, 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid, sodium salt, m.p. >300° C., was filtered and washed with water, then it was dissolved in formic acid and the solution was diluted with water to give a precipitate which was filtered and washed with water until neutral to give 2.07 g of 3-[N-(3-benzylidene-9-oxo-1,2,3,9-tetrahydro-pyrrolo[2,1-b]quinazolin-6-yl)-aminocarbonyl]-propanoic acid, m.p. 250°-255° C. dec., NMR (DMSO d6) δ ppm., 2.62 (bs) (4H, --COCH2CH2 --COOH), 3.18 (m) (2H, C-2 protons), 4.08 (t) (2H, C-1 protons), 7.30-7.70 (m) (7H, C-5 and C-7 protons and phenyl protons), 7.98 (d) (1H, C-8 proton), 8.07 (t) (1H, --CH=), 10.31 (ds) (1H, --NHCO--).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:65][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(C)C

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-ethoxycarbonyl-(L)-valine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11b) in 5.2 ml of DMF to form the title compound: m.p: 200-203° C.; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([OH:17])=O)[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1.[S:27]1[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][C:15]([N:29]1[CH2:30][CH2:31][S:27][CH2:28]1)=[O:17])[CH:7]=[C:6]2[C:18]1[NH:26][C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[CH:19]=1
Reactant: C1CSCN1
Reactant: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)O)c2cc1OC
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(CC(=O)N3CCSC3)c2cc1OC
Yield: 55.3 %

Procedure:
2-[5,6-Dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)-indol-1-yl]-1-thiazolidin-3-ylethanone is prepared by following the procedure described in example 93, but using 0.2 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]acetic acid and 0.061 g of thiazolidine. 0.133 g of 2-[5,6-dimethoxy-3-(1H-pyrrolo[2,3-b]pyridin-2-yl)indol-1-yl]-1-thiazolidin-3-ylethanone is obtained, the characteristics of which are as follows: