Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1.[CH2:19]([N:26]1[CH:31]=[C:30]([CH:32]=[N:33][OH:34])[C:29](=[O:35])[NH:28][C:27]1=[O:36])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C>[CH2:19]([N:26]1[CH:31]=[C:30]([CH:32]=[N:33][OH:34])[C:29](=[O:35])[N:28]([CH2:2][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])[CH2:7][CH2:6]2)[C:27]1=[O:36])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1ccccc1N1CCN(CCCBr)CC1
Reactant: O=c1[nH]c(=O)n(Cc2ccccc2)cc1C=NO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CCCn2c(=O)c(C=NO)cn(Cc3ccccc3)c2=O)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.1 %

Procedure:
A mixture of 1-bromo-3-[4-(2-methoxyphenyl)piperazin-1-yl]propane (1.09 g, 3.5 mmol), prepared as in Example 25, 1-benzyl-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (0.86 g, 3.5 mmol), tetrabutylammonium fluoride (4.5 g, 17.5 mmol) and acetonitrile (50 mL) was stirred 24 hours at 25° C. The reaction mixture then was concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL). The solution was washed with water (3×50 mL) and brine (1×50 mL) and purified by preparative thin, layer chromatography on silica gel eluting with methylene chloride/methanol (95:5) and 1% ammonium hydroxide to give 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione (250 mg, 0.6mmol). The free base was recrystallized from a solution of fumaric acid in alcohol to give 1-benzyl-3-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}-5-hydroxyiminomethyl-2,4(1H,3H)-pyrimidinedione fumarate, m.p. 198°-200° C.; Anal.: Calcd. for C26H31N5O4.C4H4O4 : C, 59.78; H, 6.02; N, 11.62%; Found: C, 59.74; H, 6.03; N, 11.83%.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][C:7]3[O:8][CH2:9][CH2:10][O:11][C:12]=3[CH:13]=[C:4]2[N:3]=[CH:2]1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24](Cl)[CH:23]=[CH:22]2>CN1CCCC1=O>[Br:16][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[C:24]([N:1]1[C:5]3=[CH:6][C:7]4[O:8][CH2:9][CH2:10][O:11][C:12]=4[CH:13]=[C:4]3[N:3]=[CH:2]1)[CH:23]=[CH:22]2
Reactant: Clc1ccc2cccc(Br)c2n1
Reactant: c1nc2cc3c(cc2[nH]1)OCCO3
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Brc1cccc2ccc(-n3cnc4cc5c(cc43)OCCO5)nc12
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 135 %

Procedure:
6,7-Dihydro-1H-5,8-dioxa-1,3-diaza-cyclopenta[b]naphthalene 81B (600 mg, 3,4 mMol) was dissolved in 15 mL of 1-methyl-2-pyrrolidinone under an atmosphere of dry N2. To this solution was added 60% sodium hydride in oil (136 mg, 3.40 mMol) and the reaction mixture was stirred for 15 minutes. 8-Bromo-2-chloro-quinoline 81A (750 mg, 3.10 mMol) was then added to the reaction mixture which was subsequently heated to 65° C. and reacted at this temperature overnight. The reaction mixture was then cooled to ambient temperature, partitioned between DCM and saturated aqueous NaHCO3, washed again with saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum to give 1.60 g of an orange solid. The solid was chromatographed on flash silica gel eluting with a gradient from DCM to MeOH/DCM (0.5/99.5) to give 700 mg of the title compound 81C as a light yellow solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][CH:20]([C:22]3[N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:24]=[CH:25][CH:26]=3)[OH:21])[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])=[O:7])(C)(C)C>C(Cl)Cl.O=[Mn]=O>[C:38]([O:37][C:35]([O:34][C:9]1[N:8]([C:6]([OH:7])=[O:5])[C:16]2[C:11]([CH:10]=1)=[C:12]([C:18]#[C:19][C:20]([C:22]1[N:23]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[CH:24]=[CH:25][CH:26]=1)=[O:21])[C:13]([F:17])=[CH:14][CH:15]=2)=[O:36])([CH3:39])([CH3:40])[CH3:41]
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-hydroxy-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 3 above) (7.60 g, 13.3 mmol) in CH2Cl2 (400 ml) was added MnO2 (Aldrich, 11.5 g, 130 mmol) in one portion. The reaction mixture was stirred at room temperature overnight and then filtered through Celite® and the solid was washed with CH2Cl2 (200 mL). The combined filtrates was concentrated in vacuo. 2-tert-Butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tent-butyl ester was obtained as a light orange amorphous solid which was used in the next step without further purification. (Yield 7.0 g, 92.5%).
Reaction SMILES: [Na].CO.[CH2:4]([NH:6][S:7]([C:10]([F:34])([F:33])[C:11]([F:32])([F:31])[C:12]([F:30])([F:29])[C:13]([F:28])([F:27])[C:14]([F:26])([F:25])[C:15]([F:24])([F:23])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[CH3:5].[N:35]1[C:42](Cl)=[N:41][C:39](Cl)=[N:38][C:36]=1[Cl:37]>CC(C)=O>[Cl:37][C:36]1[N:35]=[C:42]([N:6]([CH2:4][CH3:5])[S:7]([C:10]([F:34])([F:33])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:21])([F:22])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[N:41]=[C:39]([N:6]([CH2:4][CH3:5])[S:7]([C:10]([F:33])([F:34])[C:11]([F:31])([F:32])[C:12]([F:29])([F:30])[C:13]([F:27])([F:28])[C:14]([F:25])([F:26])[C:15]([F:23])([F:24])[C:16]([F:22])([F:21])[C:17]([F:20])([F:19])[F:18])(=[O:9])=[O:8])[N:38]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na]
Solvent: CO
Solvent: CC(C)=O
Product: CCN(c1nc(Cl)nc(N(CC)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)n1)S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Metallic sodium (4.08 g, 177 mmols) was reacted with methanol (150 mls). N-Ethyl perfluorooctyl sulphonamide (93.28 g, 177 mmols) was added, and the resulting solution was stirred for 30 minutes. The methanol was removed at the pump (a vacuum pump was required to remove the final traces of solvent). The resulting sticky solid was dissolved in acetone (300 mls) and cooled to −65° C. under argon. Recrystalised cyanuric chloride (16.33 g, 88.5 mmols) dissolved in acetone (100 mls) was added to the reaction mixture dropwise such that the temperature did not rise above −50° C. (˜1 hour). After the addition, the reaction mixture was allowed to slowly warm to room temperature (1 hour) and then stirred for a further 3 hours. The precipated solid was removed by filtration and dried under vacuum. Purification by soxhlet extraction with acetone afforded 61 g (56.9%) of a fine white powder.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=3)[N:12]=[C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[OH:26])[N:10]=2)[CH2:4]1.Cl[C:28]([O:30][C@H:31]1[CH2:35][CH2:34][O:33][CH2:32]1)=[O:29].C(N(CC)CC)C>CN(C=O)C>[OH:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:10]=[C:9]([N:5]2[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:28](=[O:29])[O:30][C@H:31]3[CH2:35][CH2:34][O:33][CH2:32]3)[CH2:4]2)[C:18]2[C:13](=[CH:14][C:15]([CH3:19])=[CH:16][CH:17]=2)[N:12]=1
Reactant: O=C(Cl)O[C@H]1CCOC1
Reactant: Cc1ccc2c(N3CCC[C@@H](CN)C3)nc(-c3ccccc3O)nc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCC[C@@H](CNC(=O)O[C@H]4CCOC4)C3)nc(-c3ccccc3O)nc2c1
Yield: 64.9 %

Procedure:
To a solution of 2-(4-((S)-3-(aminomethyl)piperidin-1-yl)-7-methylquinazolin-2-yl)phenol (175 mg, 0.5 mmol) in DMF at 0° C. were added (S)-tetrahydrofuran-3-yl chloroformate (75 mg, 0.5 mmol) and triethylamine (137 μL, 1.0 mmol) simultaneously. Ten to fifteen minutes after addition, the reaction was complete, and it was quenched with water and extracted with CH2Cl2. The combined organic layers were dried over MgSO4, filtered, and concentrated. Purification via silica gel chromatography using 98% CH2Cl2/2% MeOH gave (S)-tetrahydrofuran-3-yl ((S)-1-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperidin-3-yl)methylcarbamate (150 mg, 54%). LC/MS: m/z 463.5 (M+H)+ at 2.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:19]=[CH:18][C:17](B3OC(C)(C)C(C)(C)O3)=[CH:16][CH:15]=2)[CH3:13])[CH2:7][CH2:6]1.Br[C:36]1[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=1>>[OH:1][CH2:2][CH2:3][CH2:4][C@@:5]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:10][C:9](=[O:11])[N:8]([C@H:12]([C:14]2[CH:15]=[CH:16][C:17]([C:36]3[CH:41]=[CH:40][C:39]([C:42]#[N:43])=[CH:38][N:37]=3)=[CH:18][CH:19]=2)[CH3:13])[CH2:7][CH2:6]1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Reactant: N#Cc1ccc(Br)nc1
Product: C[C@@H](c1ccc(-c2ccc(C#N)cn2)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-6-(3-hydroxypropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromo-5-cyanopyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.159, m/z=442.4; 1H NMR (CD3OD) 1.21 (m, 1H), 1.48 (d, 3H), 1.53 (m, 1H), 1.85 (m, 2H), 2.15 (m, 1H), 2.22 (m, 1H), 2.42 (m, 1H), 3.05 (m, 1H), 3.38 (m, 2H), 5.50 (m, 1H), 6.98 (d, 2H), 7.25 (m, 3H), 7.28 (m, 2H), 7.79 (d, 2H), 7.89 (d, 1H), 8.08 (m, 1H), 8.82 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]3[C:15]([CH2:16][CH2:17][C:8]=2[CH:7]=1)=[N:14][NH:13][C:12](=[O:18])[CH:11]=3.[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][NH2+:23]1.C1(S([O-])(=O)=O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH3:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:20]=[CH:19][C:9]2[C:10]3[C:15]([CH2:16][CH2:17][C:8]=2[CH:7]=1)=[N:14][NH:13][C:12](=[O:18])[CH:11]=3
Reactant: C[C@@H]1CCC[NH2+]1
Reactant: O=c1cc2c(n[nH]1)CCc1cc(OCCCCl)ccc1-2
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])c1ccccc1
Agent: [I-]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCCOc1ccc2c(c1)CCc1n[nH]c(=O)cc1-2

Procedure:
In a 25 mL round bottom flask, 8-(3-chloro-propoxy)-5,6-dihydro-3H-benzo[f]cinnolin-2-one (100 mg, 0.34 mmol), benzenesulfonate (R)-2-methyl-pyrrolidinium (168 mg, 0.68 mmol), potassium carbonate (190 mg, 1.36 mmol), and potassium iodide (1 mg, 0.006 mmol) in acetonitrile (10 mL) was heated to reflux 14 h. The reaction was cooled and the solvent concentrated under vacuum. The slurry was partitioned between methylene chloride and water, and then washed with water 3 times. The organics were chromatographed through silica gel with methylene chloride/methanol (95:5) eluent to produce 10 mg (9%). Mp 225° C. (dec.). MS m/z 340 (M+H).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:11]([CH3:19])[C:12](=O)[CH2:13][C:14]([O:16][CH3:17])=[O:15]>C1(C)C=CC=CC=1>[CH3:19][C:11]1[O:8][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:9][C:12]=1[CH2:13][C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)CC(=O)C(C)Br
Reactant: NC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1nc(-c2ccccc2)oc1C

Procedure:
A solution of benzamide (0.606 g, 5.00 mmoles) and methyl 4-bromo-3-oxopentanoate (1.05 g, 5.00 mmoles, example 31) are heated in toluene (6 ml) to 120° C. for 18 hours. The reaction is then purified by column chromatography (silica, 4:1 hex: EtOAc) to give the title compound as a clear oil. MS (APcI) 232 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[CH3:43][NH:44][C:45](=[O:49])[CH2:46][NH:47][CH3:48].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:47]([CH2:46][C:45]([NH:44][CH3:43])=[O:49])[CH3:48])=[O:24]
Reactant: CNCC(=O)NC
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)CN(C)C(=O)CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and methylamino-acetic acid methylamide with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]([C:26]3[CH:30]=[C:29]([CH3:31])[O:28][N:27]=3)[CH2:21][C:22]([O:24]C)=[O:23])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1.CO>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:32]=[CH:33][CH:34]=2)[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C@@H:20]([C:26]3[CH:30]=[C:29]([CH3:31])[O:28][N:27]=3)[CH2:21][C:22]([OH:24])=[O:23])=[CH:18][CH:19]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)C[C@@H](c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1)c1cc(C)on1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc([C@@H](CC(=O)O)c2ccc(OCc3cccc(-c4ccc(C(F)(F)F)cc4)c3)cc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 39.3 (25 mg) in THF/MeOH (1:1, 4 mL) was treated with 2N aqueous NaOH solution (0.2 mL) and stirred for 2 hours at room temperature. The reaction mixture was acidified with aqueous 3N HCl while cooled with ice-water, and extracted with EtOAc to obtain 39, which was chromatographed on a silica gel column, eluting with 5˜10% MeOH in DCM. MS ESI (neg.) m/e: 480.1 (M−H). 1HNMR (CDCl3) δ 7.13 (s, 1H), 7.04 (d, 2H, J=7.27 Hz), 7.01-6.98 (m, 2H), 6.80 (s, 1H), 6.69 (d, 2H, J=Hz, J=8.62 Hz), 6.46 (d, 2H, J=8.61 Hz), 4.99 (s, 1H), 4.59 (s, 2H), 3.95 (t, 1H, J=7.60 Hz), 2.80 (m, 1H), 2.46 (m, 1H), 1.82 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[CH2:25][C:9]3([CH2:24][C:11]4([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]4)[CH2:10]3)[O:8][C:5]2=[CH:6][N:7]=1.[CH2:26]([NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)=[O:30])[CH3:27]>>[CH2:26]([NH:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([C:2]2[CH:3]=[C:4]3[CH2:25][C:9]4([CH2:24][C:11]5([CH2:12][CH2:13][N:14]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:15][CH2:16]5)[CH2:10]4)[O:8][C:5]3=[CH:6][N:7]=2)=[CH:33][CH:32]=1)=[O:30])[CH3:27]
Reactant: CCNC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC1(Cc3cc(Cl)ncc3O1)C2
Product: CCNC(=O)c1ccc(-c2cc3c(cn2)OC2(C3)CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)cc1

Procedure:
The title compound is prepared from 5-chloro-1″-tert-butoxycarbonyl-dispiro[2,3-dihydrofuro[2,3-c]pyridine-2,1′-cyclobutane-3′,4″-piperidine] and 4-ethylaminocarbonyl-phenylboronic acid following a procedure analogous to that described for Example 1; the reaction is conducted in a microwave oven at 140° C. LC (method 3): tR=1.26 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Si](CC)(CC)CC)=[C:6]2[CH2:19][CH2:20][NH:21][C:22](=[O:37])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[CH:25][CH:24]=1)#[N:2]>FC(F)(F)C(O)=O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:19][CH2:20][NH:21][C:22](=[O:37])[C:23]1[CH:28]=[CH:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=2)=[CH:25][CH:24]=1)#[N:2]
Reactant: CC[Si](CC)(CC)c1[nH]c2ccc(C#N)cc2c1CCNC(=O)c1ccc(Cc2cccc(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2[nH]cc(CCNC(=O)c3ccc(Cc4cccc(F)c4)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
N-(2-(5-Cyano-2-(triethylsilyl)-1H-indol-3-yl)ethyl)-4-(3-fluorobenzyl)benzamide (0.056 g; 0.109 mmol) was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 3 hours. The solution was concentrated under reduced pressure and the crude material was purified by flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) to afford 0.013 g (29%) of the title compound as a white solid.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[CH3:31][C:32]1[C:36](B2OC(C)(C)C(C)(C)O2)=[C:35]([CH3:46])[NH:34][N:33]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:36]4[C:32]([CH3:31])=[N:33][NH:34][C:35]=4[CH3:46])=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: Cc1n[nH]c(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1cccc(-c2c(-c3c(C)n[nH]c3C)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a solution of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (Example 33) (140 mg, 0.267 mmol) in 1,4-dioxane (2 mL) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (89 mg, 0.401 mmol), bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) and potassium carbonate (111 mg, 0.802 mmol). Water (1 mL) was added and the mixture heated at 100° C. in a microwave for 15 min (×2). Another portion of bis(triphenylphosphine)palladium(II) chloride (18.76 mg, 0.027 mmol) was then added and the reaction mixture degassed with nitrogen for 5 min and then heated at 100° C. in a microwave for 15 min (×2). The solvent was then removed in vacuo and the residue dissolved in ethyl acetate (20 mL) and washed with water (20 mL). The aqueous phase was re-extracted with ethyl acetate (20 mL×2). All organic phases were combined, dried over MgSO4, filtered and concentrated. The residue was purified on silica, eluting with a gradient of 0-80% ethyl acetate in cyclohexane and then further purified using MDAP (acidic conditions), to give the title compound (36 mg). LCMS (A) m/z: 539 [M+1]+, Rt 1.47 min (acidic).
Reaction SMILES: C([O:3][C:4](=[O:30])[C:5]([CH3:29])([O:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][C:21]=2[CH3:22])=[CH:10][CH:9]=1)[CH3:6])C.[OH-].[Na+].Cl>CCO>[CH3:29][C:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([S:14][CH2:15][CH2:16][C:17]2[N:18]=[C:19]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:20][C:21]=2[CH3:22])=[CH:12][CH:13]=1)([CH3:6])[C:4]([OH:30])=[O:3]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SCCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1CCSc1ccc(OC(C)(C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105 %

Procedure:
2-Methyl-2-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)ethylsulfanyl]phenoxy}propionic acid ethyl ester (98 mg, 0.23 mmol) was dissolved in EtOH (10 mL) and 5N NaOH (0.5 mL) was added. The reaction was stirred overnight at rt. The reaction was acidified with 5N HCl and the product was extracted into EtOAc, dried (MgSO4) and concentrated to give 96 mg crude product. Purification by reverse phase HPCL gave 47.5 mg (52%) as a light tan solid: mp 104-106° C., 1H NMR (DMSO-d6) δ 1.47 (s, 6H), 2.26 (s, 3H), 2.71 (t, 2H), 3.16 (t, 2H), 6.78 (d, 2H), 7.30 (d, 2H), 7.48 (m, 3H), 7.90 (m, 2H), 13.08 (br s, 1H).
Reaction SMILES: F[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[F:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][O:22][CH2:23][C:24]([NH2:26])=[NH:25])[CH:17]=[CH:18][CH:19]=1>>[F:11][C:4]1[CH:5]=[CH:6][C:7]2[C:8](=[O:10])[NH:26][C:24]([CH2:23][O:22][CH2:21][CH2:20][C:16]3[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=3)=[N:25][C:2]=2[N:3]=1
Reactant: N=C(N)COCCc1cccc(F)c1
Reactant: O=C(O)c1ccc(F)nc1F
Agent: Cl
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2nc(F)ccc12

Procedure:
The title compound was prepared in analogy to example 85 from 2,6-difluoropyridine-3-carboxylic acid and 2-[2-(3-fluoro-phenyl)-ethoxy]-acetamidine hydrochloride. Light brown solid. MS: m/e=318.1 [M+H+].
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:7][CH:6]([NH:8][C:9](=[O:15])[C:10]([O:12]CC)=O)[CH2:5][C:4]([CH3:17])([CH3:16])[NH:3]1.[CH3:19][NH:20][NH2:21]>CO>[CH3:18][C:2]1([CH3:1])[CH2:7][CH:6]([NH:8][C:9]([C:10]([NH:21][NH:20][CH3:19])=[O:12])=[O:15])[CH2:5][C:4]([CH3:16])([CH3:17])[NH:3]1
Reactant: CNN
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CNNC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1

Procedure:
N-(2,2,6,6-tetramethyl-4-piperidinyl)-N'-methylaminooxamide was prepared by reacting ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate with 97% methyl hydrazine in methanol.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21]O[CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1.C(OC(N1CCC(=C(Br)C2C=CC(C(N3CCCC3)=O)=CC=2)CC1)=O)(C)(C)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([N:17]3[CH2:22][CH2:21][CH2:19][CH2:18]3)=[O:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(C(c2cccc(F)c2)C2CCNCC2)cc1)N1CCOCC1
Agent: CC(C)(C)OC(=O)N1CCC(=C(Br)c2ccc(C(=O)N3CCCC3)cc2)CC1
Product: O=C(c1ccc(C(c2cccc(F)c2)C2CCNCC2)cc1)N1CCCC1

Procedure:
Same procedure as for the preparation of compound 85, but using compound 84 as starting material.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C:13]1[CH:21]=[CH:20][C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[BrH:22].Br.CCN(C(C)C)C(C)C.[NH:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C:35](O)=[O:36]>CN(C=O)C>[NH:33]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][C:35]([NH:1][C@H:2]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([N+:17]([O-:19])=[O:18])=[CH:20][CH:21]=1)=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])=[O:36].[BrH:22]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)Nc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 75 %

Procedure:
1 g (2.19 mmol) of H-L-Arg-pNA.2HBr is dissolved in 10 ml of DMF, and 0.854 ml (6.57 mmol) of DIEA is then added. In another vessel, a solution of 384 mg (2.19 mmol) of Boc-Gly-OH in 5 ml of DMF is neutralized with 0.285 ml of DIEA. The two solutions obtained in this way are mixed and 970 mg of Bop are added to the resulting medium, the latter being kept at RT; also, the pH is kept at a value of between 7 and 8 by the addition of small portions of DIEA throughout the reaction. After one hour, the reaction has completely finished and the reaction medium is evaporated to dryness under vacuum; the evaporation residue is taken up with an AcOEt/MeOH mixture and extracted with a 0.5M aqueous solution of NaHCO3. The organic phase is dried over sodium sulfate, concentrated under vacuum and then precipitated in ether (MeOMe or EtOEt) to give 874 mg (yield: 75%) of the expected product.