Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:32]1[O:33][CH:34]=[CH:35][CH:36]=1)CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[CH:24]=3)[N:19]=[CH:18][N:17]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Reactant: Brc1ccc2ncnc(Nc3ccc(OCc4ccccc4)cc3)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(Nc3ncnc4ccc(-c5ccco5)cc34)cc2)cc1
Yield: 99.6 %

Procedure:
The (4-benzyloxy-phenyl)-(6-bromo-quinazolin-4-yl)-amine (300 mg, 0.74 mmol), 2-(tributylstannyl)furan (290 mg, 0.81 mmol) and bis(triphenylphosphine) palladium(II) chloride (catalytic) were dissolved in dioxane (3.5 ml) and heated at reflux under nitrogen for 2 hr. The cooled reaction mixture was absorbed onto silica and purified by flash column chromatography (silica gel, eluting with 1:1 ethyl acetate/iso-hexane) to give the title product (290 mg, 79%) as a pale yellow solid; δH [2H6]-DMSO 9.94 (1H, b, NH), 8.85 (1H, s, 5-H), 8.53 (1H, s, 2-H), 8.21 (1H, d, 7-H), 7.91 (1H, d, furan-H), 7.81 (1H, d, 8-H), 7.72 (2H, d, 2′-H, 6′-H), 7.57-7.33 (5H, m, 5×Ph-H), 7.16 (1H, d, furan-H), 7.10 (2H, d, 3′-H, 5′-H), 6.72, (1H, dd, furan-4H), 5.17 (2H, s, CH2); m/z 394 (M+1)+.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:9][N:10]([CH3:14])[SH:11](=[O:13])=[O:12].N(OC(C)(C)C)=O.O1CCCC1.[F-:27].[NH+]1C=CC=CC=1>ClCCl>[F:27][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[CH3:8].[CH3:9][N:10]([CH3:14])[SH:11](=[O:13])=[O:12]
Reactant: Cc1ccccc1N
Reactant: [F-]
Agent: CC(C)(C)ON=O
Agent: CN(C)[SH](=O)=O
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccccc1F

Procedure:
The compound 3-amino-4-methyl-benzene-N,N-dimethylsulfonamide is diazotized with an alkyl nitrite like tert-butyl nitrite under anhydrous conditions in a non-reactive solvent like tetrahydrofuran or dichloromethane. The intermediate diazonium species is then treated with pyridinium fluoride to give the product, which may be purified by chromatography or crystallization.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])[CH:2]=1.I[C:14]1[CH:22]=[CH:21][C:17]2[S:18][CH:19]=[CH:20][C:16]=2[CH:15]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[S:18]1[CH:19]=[CH:20][C:16]2[CH:15]=[C:14]([N:9]3[CH2:10][CH2:11][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[C:8]3=[O:12])[CH:22]=[CH:21][C:17]1=2
Reactant: O=C1NCCN1c1cccnc1
Reactant: Ic1ccc2sccc2c1
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cccnc2)CCN1c1ccc2sccc2c1
Yield: 41.2 %

Procedure:
Using the same reaction conditions as in Example 1, 1-pyridin-3-yl-imidazolidin-2-one (I-1b: 93.6 mg, 0.5747 mmol) was reacted with 5-iodo-benzo[b]thiophene (150 mg, 0.5747 mmol), 1,4-dioxane (5 mL), copper iodide (10 mg, 0.05747 mmol), trans-1,2-diamino cyclohexane (9 mg, 0.0862 mmol) and potassium carbonate (158.9 mg, 1.149 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in chloroform), afforded 70 mg of the product (41.42% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6](N)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.N(OCCCCC)=O.[CH:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:1][S:2][C:3]1[CH:9]=[CH:8][C:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CSc1ccc(N)c([N+](=O)[O-])c1
Reactant: c1ccccc1
Agent: CCCCCON=O
Product: CSc1ccc(-c2ccccc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-methylthio-2-nitroaniline (27.6 g), amyl nitrite (22.5 ml) and cupric chloride (4.5 g) in dry benzene (250 ml) was heated under reflux for 9 hours to give 4-methylthio-2-nitrobiphenyl (m.p. 51°-52° C.).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:12]2[N:13]([C:18]#[C:19][CH3:20])[CH:14]=[CH:15][C:16](=[O:17])[C:11]=2[C:10]2[CH:21]=[C:22]([CH3:24])[O:23][C:9]=2[C:8](=[O:25])[CH:7]=1)=[O:5])C.[OH-].[K+]>O>[O:25]=[C:8]1[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:12]2[N:13]([C:18]#[C:19][CH3:20])[CH:14]=[CH:15][C:16](=[O:17])[C:11]=2[C:10]2[CH:21]=[C:22]([CH3:24])[O:23][C:9]1=2
Reactant: CC#Cn1ccc(=O)c2c3cc(C)oc3c(=O)cc(C(=O)OCC)c21
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC#Cn1ccc(=O)c2c3cc(C)oc3c(=O)cc(C(=O)O)c21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 7,10-dihydro-4,10-dioxo-2-methyl-7-propynyl-4H-furo[3',2': 3,4]cyclohepta[1,2-b]pyridine-6-carboxylic acid ethyl ester (1.2 g, described in Example 24), 1N potassium hydroxide (4 ml) and water (6 ml) is stirred at room temperature for 16 hr. The precipitate is removed and the solution is acidified with 10% hydrochloric acid. The precipitate is collected, washed with water and crystallized from pyridine to obtain crystals of the title compound, mp 237°-238° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH3:26])=[C:19]([CH2:23][CH:24]=O)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH:27]1[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[S:16][N:15]=[C:14]([C:17]3[C:18]([CH3:26])=[C:19]([CH2:23][CH2:24][N:27]4[CH2:28][CH2:29][CH:30]([C:33]([OH:35])=[O:34])[CH2:31][CH2:32]4)[CH:20]=[CH:21][CH:22]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: Cc1c(CC=O)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Reactant: CCOC(=O)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Cc1c(CCN2CCC(C(=O)O)CC2)cccc1-c1nsc(-c2ccc(OC(C)C)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.6 %

Procedure:
To a solution of [3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]acetaldehyde (D106) (120 mg, 0.310 mmol) in Dichloromethane (DCM) (20 mL) stirred at room temperature was added ethyl 4-piperidinecarboxylate (195 mg, 1.241 mmol) and AcOH (0.15 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 10 min, and sodium triacetoxyborohydride (131 mg, 0.620 mmol) was added. The reaction mixture was continuously stirred overnight. The reaction was quenched with water and DCM was evaporated in vacuo. The residue was dissolved in Isopropanol (8 mL), and sodium hydroxide (50 mg, 1.250 mmol) was added. The reaction was stirred for 2 hours. 1M HCl solution was added until pH=6-7. Isopropanol was removed. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed with brine. The solution was concentrated and purified by Mass Directed AutoPrep to afford 1-{2-[3-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-thiadiazol-3-yl)-2-methylphenyl]ethyl}-4-piperidinecarboxylic acid (E74) (35 mg) as a off-white solid. δH (DMSO-d6, 400 MHz): 1.35 (6H, d), 1.55 (2H, m), 1.81 (2H, m), 2.05 (2H, m), 2.19 (1H, m), 2.46 (3H, s), 2.50 (2H, m), 2.87 (4H, m), 4.86 (1H, dt), 7.26 (1H, m), 7.36 (2H, m), 7.68 (1H, d), 8.02 (1H, dd), 8.14 (1H, d), 12.18 (1H, br. s.). MS (ES): C26H30ClN3O3S requires 499.2. found 500.2 (M+H+).
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.O=[CH:17][CH2:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]1>ClCCCl.CO>[O:15]1[C:11]2[CH:10]=[CH:9][N:8]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH:25][C:26](=[O:28])[CH3:27])[CH2:21][CH2:20]4)[CH2:5][CH2:6]3)[C:12]=2[CH:13]=[CH:14]1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Reactant: CC(=O)N[C@H]1CC[C@H](CC=O)CC1
Solvent: CO
Solvent: ClCCCl
Product: CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of commercially available 4-piperazine-1-yl-furo[3,2-c]pyridine [CAS-Nr. 81078-84-4] (125 mg, 0.62 mmol) in 1,2-dichloroethane (1.25 ml) were added trans-N-[4-(2-oxo-ethyl)-cyclohexyl]-acetamide [CAS-Nr. 946599-01-5, WO 2007/093540] (124 mg, 0.68 mmol) and 3 drops of MeOH. The resulting yellow solution was stirred 18 h at room temperature before addition of Na(AcO)3BH (196 mg, 0.92 mmol). After stirring 18 h at room temperature the reaction mixture was partitioned between sat. aq. NaHCO3 sol. (50 ml) and EtOAc (50 ml). The aqueous layer was extracted with more EtOAc (2×25 ml). The combined organic layers were washed with H2O (40 ml) and brine (40 ml) and dried over MgSO4. After evaporation of the solvent, the crude product (yellow crystals) was purified by flash chromatography on silica gel (CH2Cl2/MeOH, 100:0 to 95:5) to yield the title compound as light yellow crystals (95 mg, 42%), MS (ISP) m/z=371.2 [(M+H)+].
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]([CH3:28])[O:11][C:12]1[CH:13]=[C:14]([CH:24]=[C:25]([OH:27])[CH:26]=1)[C:15]([NH:17][C:18]1[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=1)=[O:16])(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].[Cl:35][C:36]1[CH:46]=[C:45](F)[C:44]([F:48])=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]>C(#N)C>[Cl:35][C:36]1[CH:46]=[C:45]([O:27][C:25]2[CH:24]=[C:14]([C:15]([NH:17][C:18]3[CH:22]=[CH:21][N:20]([CH3:23])[N:19]=3)=[O:16])[CH:13]=[C:12]([O:11][C@@H:10]([CH3:28])[CH2:9][OH:8])[CH:26]=2)[C:44]([F:48])=[CH:43][C:37]=1[C:38]([N:40]([CH3:42])[CH3:41])=[O:39]
Reactant: CN(C)C(=O)c1cc(F)c(F)cc1Cl
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C[C@@H](CO)Oc1cc(Oc2cc(Cl)c(C(=O)N(C)C)cc2F)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Yield: 16.7 %

Procedure:
A suspension of 3-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyloxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (200 mg, 0.477 mmol), potassium carbonate (136 mg, 0.95 mmol) and 2-chloro-4,5-difluoro-N,N-dimethylbenzamide (106 mg, 0.45 mmol) in acetonitrile (3.5 mL) was heated in a microwave reactor at 160° C. for 2 hours. The reaction mixture was quenched with water and extracted with DCM (2×6 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was then chromatographed by preparatory reverse phase HPLC using a gradient of 5-95% acetonitrile in water (containing 0.2% TFA) on a Phenomenex Luna 10u C18 (2) 100A (150×21.2 mm) column to give the title compound (37 mg).
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].C([N+]1(C)[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)C>C(O)C.O>[C@H:1]1([N:11]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1CCN([C@@H]2CCCc3ccccc32)CC1

Procedure:
(R)-1,2,3,4-Tetrahydro-1-naphthylamine (16 mmol) was dissolved in ethanol (30 ml). Potassium carbonate (9.3 mmol) and 1-ethyl-1-methyl-4-oxo-piperidinium iodide (23 mmol) dissolved in water (30 ml) were added and the mixture was refluxed for 1 h. Water was added, ethanol was removed in vacuo and the residue was extracted with ethyl acetate. Organic phases were pooled, dried with sodium sulfate and concentrated. Chromatography on silica gel (ethyl acetate) yielded (R)-1-(1,2,3,4-tetrahydro-naphtalen-1-yl)-piperidine-4-one which was dissolved in acetic acid (11 ml). Aniline (14 mmol) and trimethylsilylcyanide (13 mmol) were added and the mixture was stirred for 1.5 h at room temperature. The reaction mixture was poured into cold ammonia solution (water/28% ammonia, 70 ml/30 ml). The solution was adjusted to pH 10 and extracted with methylene chloride. Organic phases were pooled, dried with sodium sulfate and concentrated. Crystallization from diethylether yielded the desired product as a solid. 8.1 g (80%) of (R)4-phenylamino-1-(1,2,3,4-tetrahydro-naphtalen-1-yl)-piperidine-4-carbonitrile, m.p. 152-153° C. and MIS: m/e=332.3 (M+H+).
Reaction SMILES: [C:1]([C:9]1[CH:35]=[CH:34][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:33]=[CH:32][C:23]([O:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:36][O:37][NH2:38]>>[CH3:36][O:37][N:38]=[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:35]=[CH:34][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([O:24][CH:25]([CH3:31])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:32][CH:33]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)C(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: CON
Product: CCOC(=O)C(C)Oc1ccc(OCCn2c(=O)sc3cc(C(=NOC)c4ccccc4)ccc32)cc1

Procedure:
Starting from the compound obtained in Step A, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[N:32]=1.CN(C)C=O>O.C(OCC)(=O)C>[F:40][C:37]([F:38])([F:39])[C:33]1[N:32]=[C:31]([CH2:30][N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]3([C:21]4[C:12](=[CH:13][C:14]5[O:19][CH2:18][CH2:17][O:16][C:15]=5[CH:20]=4)[O:11][CH2:10]3)[C:2]2=[O:22])[CH:36]=[CH:35][CH:34]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: FC(F)(F)c1cccc(CCl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1N(Cc2cccc(C(F)(F)F)n2)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 25 °C
Reaction time: 16 h
Yield: 69.2 %

Procedure:
A heterogeneous mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.41 g, 1.4 mmol), cesium carbonate (1.1 g, 3.5 mmol), 2-(chloromethyl)-6-(trifluoromethyl)pyridine (0.33 g, 1.7 mmol) and N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The mixture was diluted with water (100 mL) and ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×70 mL). The combined organic layers was washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography and eluted with a 25% to 35% gradient of ethyl acetate in hexanes to afford 1′-{[6-(trifluoromethyl)pyridin-2-yl]methyl}-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.44 g, 70%) as a colorless solid: mp 195-196° C.; 1H NMR (300 MHz, DMSO-d6) δ8.15-8.07 (m, 1H), 7.85-7.79 (m, 1H), 7.75-7.70 (m, 1H), 7.28-7.15 (m, 2H), 7.07-7.00 (m, 1H), 6.97-6.91 (m, 1H), 6.52 (s, 1H), 6.29 (s, 1H), 5.16 (ABq, J=42.6, 16.9 Hz, 2H), 4.75 (ABq, J=37.3, 9.3 Hz, 2H), 4.22-4.08 (m, 4H); 13C NMR (300 MHz, DMSO-d6) δ 176.8, 156.5, 154.6, 146.0 (q, JC-F=33.7 Hz), 144.1, 142.3, 139.4, 137.8, 131.7, 128.6, 125.4, 123.5, 123.0, 121.4 (q, JC-F=272.7 Hz), 121.1, 119.5 (m), 111.4, 109.1, 98.6, 79.5, 64.1, 63.5, 57.2, 44.2; MS (ES+) m/z 455.0 (M+1).
Reaction SMILES: [CH:1]1([C:6]([OH:30])([C:17]#[C:18][C:19]2[CH:24]=[C:23]([F:25])[C:22]([CH2:26][OH:27])=[CH:21][C:20]=2[O:28][CH3:29])[CH2:7][C:8]2[O:13]C(C)(C)[O:11][C:10](=O)[CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C(O)(C#CC2C(OC)=CN=C(CC)C=2)CC2OC(C)(C)OC(=O)C=2)CCCC1>>[CH:1]1([C:6]2([CH2:17][CH2:18][C:19]3[CH:24]=[C:23]([F:25])[C:22]([CH2:26][OH:27])=[CH:21][C:20]=3[O:28][CH3:29])[O:30][C:10](=[O:11])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(CO)c(F)cc1C#CC(O)(CC1=CC(=O)OC(C)(C)O1)C1CCCC1
Agent: CCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)c(OC)cn1
Product: COc1cc(CO)c(F)cc1CCC1(C2CCCC2)CC(=O)CC(=O)O1

Procedure:
The desired product was prepared analogously to example A(2), where 6-[2-cyclopentyl-4-(5-fluoro-4-hydroxymethyl-2-methoxy-phenyl)-2-hydroxy-but-3-ynyl]-2,2 dimethyl-[1,3]dioxin-4-one (1.28 g, 3.03 mmol) was substituted in place 6-[2-Cyclopentyl-4-(2-ethyl-5-methoxy-pyridin-4-yl)-2-hydroxy-but-3-ynyl]-2,2-dimethyl-[1,3]dioxin-4-one. Yield: 1.4 g, 38%. 1H NMR (400 MHz, CDCl3) δ: 1.37-1.49 (1 H, m) 1.53-1.97 (9 H, m) 2.53-2.6 (1 H, m) 2.64-2.7 (1 H, m) 2.75 (2 H, s) 3.41 (2H, s) 3.79 (3 H, s) 4.71 (2 H, s) 6.79 (1 H, d, J=9.85 HZ) 6.87 (1 H, d, J=5.81 Hz). MS (ESI): 363 (M−H).
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:35])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22]([CH:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])[C:18]2[CH:30]=[CH:31][CH:32]=[CH:33][C:17]=2[NH:16][C:15]1=[O:34])=[O:12])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].Br[CH2:37][C:38]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]([C:47]2[CH:54]=[CH:53][CH:52]=[CH:51][C:48]=2[C:49]#[N:50])[N:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:49]([C:48]1[CH:51]=[CH:52][CH:53]=[CH:54][C:47]=1[N:40]1[C:41]2[C:46](=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:38]([CH2:37][N:16]2[C:15](=[O:34])[C@@H:14]([NH:13][C:11](=[O:12])[C@@H:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8])[CH3:35])[C@H:20]([CH3:21])[N:19]([C:22]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])[C:18]3[CH:30]=[CH:31][CH:32]=[CH:33][C:17]2=3)=[N:39]1)#[N:50]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: N#Cc1ccccc1-n1nc(CBr)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](C(=O)N[C@@H]1C(=O)N(Cc2nn(-c3ccccc3C#N)c3ccccc23)c2ccccc2N(C(=O)C2CCOCC2)[C@H]1C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 60 h
Yield: 78.3 %

Procedure:
To a rt solution of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-4-oxo-1-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (111 mg, 227 μmol) in DMF (568 μl) was added 2-(3-(bromomethyl)-1H-indazol-1-yl)benzonitrile (85.1 mg, 273 μmol), cesium carbonate (96.2 mg, 295 μmol), and sodium iodide (44.3 mg, 295 μmol). The reaction was stirred at rt for 2.5 days, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-1-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-methyl-2-oxo-5-(tetrahydro-2H-pyran-4-carbonyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (128 mg, 78%) as an off-white solid. MS m/z 742 (MNa)+.
Reaction SMILES: [C:1]([NH:9][C@@H:10]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH:11]([OH:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([OH:20])=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39]O)[CH:34]=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]([NH:9][C@@H:10]([CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH:11]([OH:25])[CH2:12][N:13]([CH3:24])[C:14]([N:16]1[CH2:23][CH2:22][CH2:21][C@H:17]1[C:18]([O:20][CH2:39][C:35]1[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=1)=[O:19])=[O:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccnc1
Reactant: CN(CC(O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CN(CC(O)[C@H](Cc1ccccc1)NC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1cccnc1
Reaction time: 8 h

Procedure:
1-[[[(3S)-3-(Benzoylamino)-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]-L-proline (isomer A), 4-dimethylamino pyridine, 3-pyridinylcarbinol and dicyclohexylcarbodiimide are taken up into tetrahydrofuran with stirring in an ice bath. The reaction proceeds overnight at room temperature. The dicyclohexylurea is filtered off and the filtrate is concentrated to dryness. The crude product is chromatographed on silica gel to give 1-[[[(3S)-3-(benzoylamino)-2-hydroxy-4-phenylbutyl]methylamino]carbonyl]-L-proline, 3-pyridinylmethyl ester (isomer A).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[C:30](O)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.CN(C=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:30](=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccccc1N
Yield: 19.6 %

Procedure:
N-(2-aminophenyl)acetamide (59 mg, 57%) as a yellow solid was synthesized from 1,2-diaminobenzene (216 mg, 2.00 mmol), EDCI (764 mg, 4.00 mmol), HOBt (540 mg, 4.00 mmol), DMAP (488 mg, 4.00 mmol), acetic acid (120 mg, 2.00 mmol) and DMF (1 mL) using the procedure similar to that described for compound 1 (Example 1): LCMS: 531 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 2.03 (s, 3H), 4.85 (s, 2H), 6.52 (m, 1H), 6.70 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 9.11 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:15]([NH:17][C@H:18]([C:26]([O:28]CC)=[O:27])[CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[O:16])[S:13][CH:14]=2)[CH:6]=[N:5][C:4]2=[N:31][C:32]([NH:34]C(=O)C(C)(C)C)=[CH:33][C:3]=12.Cl>[OH-].[Na+]>[OH:1][C:2]1[N:7]([CH2:8][CH2:9][C:10]2[CH:11]=[C:12]([C:15]([NH:17][C@H:18]([C:26]([OH:28])=[O:27])[CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:16])[S:13][CH:14]=2)[CH:6]=[N:5][C:4]2=[N:31][C:32]([NH2:34])=[CH:33][C:3]=12
Reactant: CCOC(=O)CC[C@H](NC(=O)c1cc(CCn2cnc3nc(NC(=O)C(C)(C)C)cc-3c2O)cs1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1cc2c(O)n(CCc3csc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)c3)cnc-2n1

Procedure:
A solution of 0.3 g of diethyl N-{4-[2-(4-hydroxy-6-pivaloylaminopyrrolo[2,3-d]pyrimidin-3-yl)ethyl]-thien-2-ylcarbonyl}-L-glutamate in 9 ml of 1N aqueous sodium hydroxide is stirred under nitrogen at ambient temperature for 72 hours. The reaction mixture is rendered slightly acidic (pH=~4) with 1N hydrochloric acid and filtered. The solid thus collected is washed with water (5 ml) and cold ethanol (5 ml) and dried to give N-{4-[2-(4-hydroxy-6-aminopyrrolo[2,3-d]pyrimidin-3-yl)ethyl]thien-2-ylcarbonyl}-L-glutamic acid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12](O)[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:21]>>[CH2:1]([N:8]1[CH2:17][C:16]2[N:15]=[CH:14][CH:13]=[C:12]([Cl:21])[C:11]=2[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2c1CCN(Cc1ccccc1)C2
Product: Clc1ccnc2c1CCN(Cc1ccccc1)C2

Procedure:
7-Benzyl-5,6,7,8-tetrahydro-[1,7]naphthyridin-4-ol (0.1 g, 0.417 mmol) in 3 ml of POCl3 was refluxed for 40 minutes. LCMS indicated complete coversion to the desired product. The excess POCl3 was removed under reduced pressure and taken on to the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:5]([NH:13][S:14](/[CH:17]=[CH:18]/[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)(=[O:16])=[O:15])[CH:4]=1)#[N:2].C([O-])(=O)C.[Na+].C1(C)C=CC(S(NN)(=O)=O)=CC=1>O1CCCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH2:12])(=[O:10])=[O:11])=[C:5]([NH:13][S:14]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)(=[O:16])=[O:15])[CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(S(N)(=O)=O)c(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)c1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(S(N)(=O)=O)c(NS(=O)(=O)CCc2ccc(Cl)c(Cl)c2)c1
Temperature: 180 °C
Yield: 3.9 %

Procedure:
(E)-4-Cyano-2-(2-(3,4-dichlorophenyl)vinylsulfonamido)benzenesulfonamide (123 mg, 0.28 mmol), sodium acetate (93 mg, 1.14 mmol) and para-toluenesulfonhydrazide (212 mg, 1.14 mmol) were dissolved in anhydrous tetrahydrofuran (3 mL) in a microwave vial. The vial was capped and evacuated two times with argon. The mixture was heated in a microwave at 180° C. for 15 min. The mixture was filtered and the solvent was evaporated in vacuo. Purification twice by preparative HPLC gave 4.8 mg (4% yield) of the title compound.