Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4]1.C(OC([NH:23][CH2:24][C:25](O)=[O:26])=O)(C)(C)C>>[NH2:23][CH2:24][C:25]([NH:1][CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:4]1)=[O:26]
Reactant: NC[C@H]1CCCN(CC2CCCCC2)C1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Product: NCC(=O)NC[C@H]1CCCN(CC2CCCCC2)C1

Procedure:
The title compound was prepared by conducting procedures similar to Steps 1-2 of Example 17, using (3R)-3-aminomethyl-1-(cyclohexylmethyl)piperidine and (tert-butoxycarbonyl)-glycine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=3)[CH:11]([C:22]3[CH:27]=[CH:26][C:25]4[O:28][CH2:29][O:30][C:24]=4[CH:23]=3)[CH:10]2[C:31]([O:33][CH3:34])=[O:32])=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[Cl-].[Li+]>CN(C)C=O>[CH2:8]([C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=1[CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH2:19][CH2:20][CH3:21])[CH:16]=2)[CH:11]([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[CH:10]1[C:31]([O:33][CH3:34])=[O:32])[CH2:3][CH2:4][CH3:5]
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C(C(=O)OC)C2c1ccc2c(c1)OCO2
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCc1cc(OC)ccc1C1c2cc(OCCC)ccc2C(c2ccc3c(c2)OCO3)C1C(=O)OC
Yield: 77.4 %

Procedure:
Methyl (1RS,2SR,3RS)-3-(4-methoxy-2-trifluoromethanesulfonyloxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.118 g, 0.19 mmol), lithium chloride (0.058 g, 1.37 mmol), tetrakis(tri-phenylphosphine)-palladium(0) (0.018 g, 0.016 mmol) and ethyl 3-[tri-(butyl-1-yl)stannyl]benzoate (0.253 g, 0.58 mmol) were mixed in dry dimethylformamide (5 ml) and refluxed for 24 h. The product was filtered through celite and the celite washed with ethyl acetate. The combined filtrate was evaporated in vacuo and was shown to be a mixture of two components by TLC. Purification by column chromatography on silica-gel gave a less polar fraction: methyl (1RS,2SR,3SR)-3-[2-(but-1-yl)-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane-2-carboxylate (0.038 g) which was obtained as a colorless oil. The title compound was the more polar component (0.08 g) which while contaminated with tin residues (1H-NMR) was used without further purification.
Reaction SMILES: [N:1]1([CH:7]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:25]4[C:24]5[C@@H:23]([CH2:26][CH2:27][OH:28])[CH2:22][CH2:21][C:20]=5[S:19][C:18]=4[N:17]=[CH:16][N:15]=3)[CH2:9][CH2:8]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:29][S:30]([O:28][CH2:27][CH2:26][C@H:23]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14]([O:13][CH:10]4[CH2:9][CH2:8][CH:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)[CH2:12][CH2:11]4)[C:25]=3[C:24]1=2)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethan-1-ol (202 mg, 0.50 mmol, 1.00 equiv) in N,N-dimethylformamide (5 mL) was added MsCl (86 mg, 0.75 mmol, 1.50 equiv) and triethylamine (153 mg, 1.51 mmol, 3.00 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature and diluted with DCM (80 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the desired 2-[(3R)-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]ethyl methanesulfonate (230 mg, 95%) as a white solid. MS (ES): m/z 482 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([OH:12])=O)[CH2:7][C:6]=2[CH:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:41][N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([C:10]([N:45]3[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]3)=[O:12])[CH2:7][C:6]=2[CH:13]=1
Reactant: O=C(O)C1Cc2cc(Br)ccc2O1
Reactant: CN1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)C2Cc3cc(Br)ccc3O2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.9 %

Procedure:
A mixture of 5-bromo-2,3-dihydro-1-benzofuran-2-carboxylic acid (0.243 g, 1.00 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.464 g, 1.05 mmol), 1-methyl-piperazine (116 μL, 1.05 mmol) and N,N-diisopropylethylamine (696 μL, 4.00 mmol) was stirred at r.t. for 2 h. The volatiles were removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (gradient: 0-50%) to afford the desired product (0.325 g, 95%). LCMS (M+H)+=324.9/327.0.
Reaction SMILES: I[CH3:2].[SH:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[N:6][N:5]=1.[OH-].[Na+]>CO>[CH3:2][S:3][C:4]1[N:8]([CH2:9][CH2:10][CH2:11][CH3:12])[CH:7]=[N:6][N:5]=1
Reactant: CI
Reactant: CCCCn1cnnc1S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCn1cnnc1SC

Procedure:
Iodomethane (9.05 g. or 0.0637 mole) was added to a solution of 10 g. of 3-mercapto-4-n-butyl-1,2,4-triazole, methanol (100 ml.), and sodium hydroxide (2.55 g. or 0.0637 mole). This solution was then refluxed for 2 hours. The solvent was then removed in vacuum and the residue was dissolved in benzene. This solution was washed with water, dried and the benzene removed in vacuum. The residual oil was distilled to give 3-methylmercapto-4-n-butyl-1,2,4-triazole, b.p. 128°-131° C./2 mm. The structure was confirmed by its nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11](S)=[N:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.O.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:11]1[O:12][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Sc1ncc(-c2ccc(Cl)cc2)o1
Solvent: O
Solvent: CCN(CC)CC
Product: Clc1ccc(-c2cnc(Cl)o2)cc1
Temperature: 105 °C
Reaction time: 4 h
Yield: 13 %

Procedure:
2-amino-1-(4-chlorophenyl)ethanone hydrochloride (0.80 g, 3.88 mmol) and carbon disulfide (0.47 mL, 0.59 g, 7.76 mmol) was suspended in ethanol (10 mL). To this was slowly added a solution of sodium carbonate (0.44 g, 4.08 mmol) in water (4 mL) at ambient temperature. After heating to 80° C. ext. temp. for 18 h the cold mixture was filtered. The filtrate was diluted with acetic acid (40 mL) and stirred for 15 min. at room temperature. Evaporation of the solvents in vacuo gave 1.42 g of a crude 5-(4-chlorophenyl)oxazole-2-thiol which was of ca. 61% purity (HPLC-MS) and used as is in the next step. The crude oxazole-2-thiol compound (1.42 g, max. 3.88 mmol) was suspended in phosphorous oxychloride (5 mL). To this was added dropwise triethyl amine (1.15 mL, 0.84 mg, 8.27 mmol) and the mixture heated to 105° C. ext. temperature for 4 h. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were washed with aq. sat. bicarbonate (100 mL) and water (50 mL). Drying (sodium sulfate) and concentration in vacuo yielded crude product (615 mg), which was purified by column chromatography (SiO2, 5-40% ethyl acetate in heptanes) to give pure 2-chloro-5-(4-chlorophenyl)oxazole (105 mg, 0.49 mmol, 13%, purity 96% HPLC-MS).
Reaction SMILES: [F:1][C:2](=[C:7]([F:9])[F:8])[CH2:3][C:4](Cl)=[O:5].O.[CH2:11]([NH2:15])[CH2:12][CH2:13][CH3:14]>ClCCl>[CH2:11]([NH:15][C:4](=[O:5])[CH2:3][C:2]([F:1])=[C:7]([F:9])[F:8])[CH2:12][CH2:13][CH3:14]
Reactant: O=C(Cl)CC(F)=C(F)F
Reactant: CCCCN
Solvent: O
Solvent: ClCCl
Product: CCCCNC(=O)CC(F)=C(F)F
Temperature: 0 °C
Yield: 92.4 %

Procedure:
2.5 g (0.0158 mole) 3,4,4-trifluoro-3-butenoyl chloride is added to a mixture of water (15 mL), dichloromethane (15 mL) and n-butyl amine (2.34 g, 0.032 mole) with stirring at 0° C. After stirring for 30 min, the organic layer is successively washed with 2N HCl, water, 5% sodium bicarbonate and brine, and dried. Evaporation of the solvent gave 2.85 g of title compound as a white solid, a 92% yield. m.p. 34°-36° C.
Reaction SMILES: C[O:2][C:3]1[CH:31]=[CH:30][C:6]2[N:7]=[C:8]([C:10]3[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][C:19]=4[C:26]([F:29])([F:28])[F:27])=[CH:12][CH:11]=3)[S:9][C:5]=2[CH:4]=1.CCCCCC.CCOC(C)=O>C(Cl)Cl.B(Br)(Br)Br>[OH:24][C:21]1[CH:22]=[CH:23][C:18](/[CH:17]=[CH:16]/[C:13]2[CH:12]=[CH:11][C:10]([C:8]3[S:9][C:5]4[CH:4]=[C:3]([OH:2])[CH:31]=[CH:30][C:6]=4[N:7]=3)=[CH:15][CH:14]=2)=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:20]=1
Reactant: COc1ccc(/C=C/c2ccc(-c3nc4ccc(OC)cc4s3)cc2)c(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: Oc1ccc(/C=C/c2ccc(-c3nc4ccc(O)cc4s3)cc2)c(C(F)(F)F)c1
Yield: 81.5 %

Procedure:
Prepared as described in the Demethylation section above using 6-methoxy-2-(4-{(E)-2-[4-methoxy-2-(trifluoromethyl)phenyl]ethenyl}phenyl)-1,3-benzothiazole (0.30 g, 0.68 mmol) in dry DCM (10 ml) and BBr3 in DCM (1.0 M, 1.40 ml, 1.40 mmol) at −78° C. give the title compound (0.229 g, 81%) as a yellow solid after work-up and flash chromatography (1:1 Hexane/EtOAc).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:8]=2)=[CH:4][CH:3]=1.[CH2:30](N(CC)CC)C.[S:37](Cl)(Cl)(=[O:39])=[O:38]>C(Cl)Cl.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:15]3[CH2:16][CH2:17][CH:18]([NH:21][S:37]([CH3:30])(=[O:39])=[O:38])[CH2:19][CH2:20]3)=[O:14])[N:10]=[C:9]([C:22]3[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=3)[CH:8]=2)=[CH:28][CH:29]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Reactant: CCN(CC)CC
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)NC1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-{[5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetyl}piperidin-4-amine (1.13 g, 2.87 mmol) in CH2Cl2 (10 mL) was added triethylamine (442.0 μL, 3.20 mmol) followed by sulfonyl chloride (223.0 μL, 2.87 mmol) and the reaction stirred at 25° C. for 1 hour. The solvent was removed in vacuo, and the residue was taken up in EtOAc (200 mL) and washed with water (2×50 mL), brine (100 mL), dried over MgSO4, filtered and stripped. The resulting gum was azeotroped with EtOAc (2×200 mL) to yield a white solid. The white solid was taken up in MeOH (25 mL) with heating, and left to crystallize overnight to afford small colorless needles. The MeOH was decanted and the crystals washed with MeOH (3×15 mL), EtOAc (3×30 mL) and finally hexane (2×25 mL, then 100 mL) and dried at room temperature to yield the title compound as white needles, 968 mg, 72 %. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.53 (d, 2 H), 7.65 (d, 2 H), 7.30 (t, 2 H), 7.20 (s, 1 H), 7.15 (t, 2 H), 6.52 (s, 1 H), 5.18 (q, 2 H), 4.10 (d, 1 H), 3.93 (s, 2 H), 3.83 (d, 1 H), 3.36-3.46 (m, 1 H), 3.17 (t, 1 H), 2.94 (s, 3 H), 2.80 (t, 1 H), 1.79-1.92 (m, 2 H), 1.41-1.52 (m, 1 H), 1.23-1.34 (m, 1 H); m/z (APCI+) for C23H26N5O3FS 472.1 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](B(O)O)=[CH:3][N:2]=1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([Cl:24])[CH:23]=1)[NH:20][N:19]=[CH:18]2.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.C(COC)OC>[Cl:24][C:22]1[CH:23]=[C:15]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=[N:2][CH:3]=2)[CH:16]=[C:17]2[C:21]=1[NH:20][N:19]=[CH:18]2
Reactant: Clc1cc(Br)cc2cn[nH]c12
Reactant: OB(O)c1cncc2ccccc12
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: Clc1cc(-c2cncc3ccccc23)cc2cn[nH]c12
Temperature: 85 °C
Yield: 72.1 %

Procedure:
A mixture of isoquinolin-4-ylboronic acid (1.00 g, 5.78 mmol), 5-bromo-7-chloro-1H-indazole (892 mg, 3.85 mmol), 2.0 M sodium carbonate (3.85 mL, 7.71 mmol) and dimethoxyethane was degassed with argon. Tetrakis(triphenylphosphine)palladium(0) (233 mg, 0.193 mmol) was added, the mixture degassed again with argon, then heated to 85° C. for 24 hours. The reaction was cooled and partitioned between ethyl acetate and water, the organic layer washed with and dried with sodium sulfate. The solvent was removed under vacuum and the residue purified by column chromatography (9/1 to 6/4 hexanes/ethyl acetate gradient) to give 4-(7-chloro-1H-indazol-5-yl)-isoquinoline (777 mg, 72%): 1H NMR (300 MHz, CDCl3) δ 10.52 (s, 1H) 9.31 (s, 1H), 8.53 (s, 1H), 8.22 (s, 1H), 8.09 (dd, J=7.4, 1.62 Hz, 1H), 7.28 (dd, J=7.4, 1.2 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.81 (d, J=1.2 Hz, 1H), 7.72-7.64 (m, 2H), 7.57 (d, J=1.3 Hz, 1H).
Reaction SMILES: C(O[C:6]([C:8]1[CH:20]=[C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:24]([F:32])[CH:23]=2)[C:11]2[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=2[CH:9]=1)=[O:7])(C)(C)C.[NH2:33][C:34]1[CH:38]=[CH:37][N:36]([CH3:39])[N:35]=1>>[CH3:39][N:36]1[CH:37]=[CH:38][C:34]([NH:33][C:6]([C:8]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:29])=[O:30])=[C:24]([F:32])[CH:23]=3)[C:11]3[CH2:12][C:13]([CH2:16][O:17][CH3:18])([CH3:15])[O:14][C:10]=3[CH:9]=2)=[O:7])=[N:35]1
Reactant: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)c(F)c3)cc(C(=O)OC(C)(C)C)cc2O1
Reactant: Cn1ccc(N)n1
Product: COCC1(C)Cc2c(Oc3ccc(S(C)(=O)=O)c(F)c3)cc(C(=O)Nc3ccn(C)n3)cc2O1

Procedure:
The title compound was prepared in a similar manner as described for Example 200, from 4-(3-fluoro-4-methanesulfonyl-phenoxy)-2-methoxymethyl-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid tert-butyl ester (237a) and 3-amino-1-methyl-pyrazole. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1 H) 7.92 (t, J=8.38 Hz, 1 H) 7.29 (d, J=2.26 Hz, 1 H) 7.12 (d, J=1.13 Hz, 1 H) 7.08 (d, J=1.13 Hz, 1 H) 6.88 (dd, J=8.76, 2.35 Hz, 1 H) 6.76-6.84 (m, 2 H) 3.81 (s, 3 H) 3.42-3.56 (m, 2 H) 3.41 (s, 3 H) 3.23 (s, 3 H) 3.15 (d, J=16.58 Hz, 1 H) 2.79 (d, J=16.58 Hz, 1 H) 1.48 (s, 3 H); LCMS for C23H24FN3O6S m/z 490.00 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]3([CH2:20][O:19][C:18]4[CH:21]=[C:22]5[C:26](=[CH:27][C:17]3=4)[CH2:25][CH2:24][O:23]5)[C:9]2=[O:28])[CH2:4][CH2:3]1.[H-].[Na+].I[CH3:32]>CN(C)C=O>[CH3:32][N:6]1[C:2](=[O:1])[CH2:3][CH2:4][C@H:5]1[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]2([CH2:20][O:19][C:18]3[CH:21]=[C:22]4[C:26](=[CH:27][C:17]2=3)[CH2:25][CH2:24][O:23]4)[C:9]1=[O:28]
Reactant: CI
Reactant: O=C1CC[C@@H](CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@H]1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Reaction time: 0.25 h
Yield: 61.7 %

Procedure:
To a stirred solution of 1′-{[(2S)-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one (0.235 g, 0.623 mmol) in dry N,N-dimethylformamide (10 mL) was added sodium hydride (60% in mineral oil, 0.04 g, 1.04 mmol) at ambient temperature. The mixture was stirred for 15 min, and iodomethane (0.28 g, 2.0 mmol) was added in one portion. The reaction mixture was stirred at ambient temperature for 1 h, and concentrated to dryness. The residue was purified by flash chromatography (hexanes/ethyl acetate; gradient 0% to 30%) to afford 1′-{[(2S)-1-methyl-5-oxopyrrolidin-2-yl]methyl}-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1H)-one (0.15 g, 62%) as colorless solid: mp 72-76° C.; 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.5, 7.5 Hz, 1H), 7.20 (d, J=7.5 Hz, 1H), 7.09 (dd, J=7.5, 7.5 Hz, 1H), 6.91 (d, J=7.5 Hz, 1H), 6.46-6.38 (m, 2H), 4.77 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 4.03-3.75 (m, 3H), 3.11-2.83 (m, 5H), 2.61-2.42 (m, 1H), 2.42-2.27 (m, 1H), 2.26-2.07 (m, 1H), 2.03-1.84 (m, 1H); 13C NMR (75 MHz, CDCl3) δ178.4, 178.4, 175.1, 175.0, 161.8, 161.3, 161.2, 142.1, 141.9, 132.5, 132.4, 128.9 (2C), 124.3, 124.2, 123.7 (2C), 120.0, 119.9, 119.7, 119.6, 118.6, 118.5, 108.0, 93.2, 80.5, 72.3, 58.1, 58.0, 57.5 (2C), 43.0, 42.9, 29.3, 29.2, 28.9, 28.7 (2C), 22.6 (2C); MS (ES+) m/z 391.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>CN(C)C=O.CC(C)=O>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:3]1=[O:12]
Reactant: Brc1cccnc1
Reactant: Cn1c(=O)[nH]c2nc(Cl)ccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Cn1c(=O)n(-c2cccnc2)c2nc(Cl)ccc21
Temperature: 30 °C
Reaction time: 2 h
Yield: 47.8 %

Procedure:
7.36 g of 1-methyl-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one were dissolved in 160 ml of hot dimethylformamide and after cooling the solution to 30° C., 4.64 g of a 50% sodium hydride-oil suspension were slowly added thereto. The mixture was stirred at 40°-50° C. for 2 hours and then 80 ml or 128.8 g of 3-bromo-pyridine and 1.5 g of cuprous chloride were added thereto. The mixture was refluxed for 9 hours and was then cooled and evaporated to dryness. The residue was taken up in ammonium hydroxide solution and was filtered. The product was washed with water to obtain 8 g of raw product which was dissolved in acetone. The solution was chromatographed over silica gel and was eluted with acetone. The product was crystallized from 95% ethanol to obtain 5 g of 1-methyl-3-(3-pyridyl)-5-chloro-1,3-dihydro-imidazo-(4,5-b)-pyridin-2-one in the form of white needles melting at 206°-208° C.
Reaction SMILES: [Br:1][C:2]([Br:10])([Br:9])[CH:3]([OH:8])[CH:4]=[C:5]([CH3:7])[CH3:6].[CH2:11]=[C:12]1[O:16][C:14](=[O:15])[CH2:13]1>CCOCC.C([O-])(=O)C.[Na+]>[C:14]([O:8][CH:3]([C:2]([Br:10])([Br:9])[Br:1])[CH:4]=[C:5]([CH3:7])[CH3:6])(=[O:15])[CH2:13][C:12]([CH3:11])=[O:16]
Reactant: CC(C)=CC(O)C(Br)(Br)Br
Reactant: C=C1CC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(=O)CC(=O)OC(C=C(C)C)C(Br)(Br)Br
Yield: 99.1 %

Procedure:
1,1,1-Tribromo-4-methyl-3-penten-2-ol (6.72 g, 0.02 mole) and anhydrous sodium acetate (0.008 g) were melted together at 90°. The temperature of the mixture was then reduced to 80°, and diketene (about 2.6 ml, 0.022 mole) was added dropwise over a 10 minute period. The resulting mixture was heated at 80° for three additional hours. After cooling, the mixture was diluted with ether, and the ethereal solution was washed with 1N aqueous hydrochloric acid and then ten times with saturated aqueous sodium bicarbonate. The washed mixture was treated with activated charcoal and dried over magnesium sulfate. Evaporation of the ether afforded 3-methyl-1-tribromomethyl-2-butenyl acetoacetate (8.34 g, 99% yield) as an oily residue.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].[NH2:19][C@H:20]([C:25]([NH:27][C@H:28]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:44])=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23].C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>CO.CN(C)C=O>[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@@H:2]([C:6]([NH:19][C@H:20]([C:25]([NH:27][C@H:28]([C:39]([N:41]1[CH2:52][CH2:51][CH2:50][C@H:42]1[C:43]([NH:45][CH2:46][C:47]([NH2:49])=[O:48])=[O:44])=[O:40])[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[NH:38])[NH:34][N+:35]([O-:37])=[O:36])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Solvent: CO
Solvent: CN(C)C=O
Product: CCC[C@@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Temperature: 0 °C
Reaction time: 10 h

Procedure:
To a solution of Z-(D)-Nva-OH(380 mg), H-Leu-Arg(NO2)-Pro-Gly-NH2 (690 mg.) and HONB (300 mg.) in 5 ml. of dimethylformamide is added 340 mg. of DCC at 0°C with stirring. The mixture is stirred for 2 hours at 0°C and for additional 10 hours at room temperature. The reaction mixture is filtered to remove the formed dicyclohexyl-urea, and the filtrate is evaporated to dryness. The resulting residue is dissolved in 100 ml. of chloroform and the solution is washed with 4 % aqueous sodium bicarbonate solution and water. The washed solution is dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is then triturated with a mixture of ethylacetate (25 ml.) and ether (25 ml.) to give a white powder, which is collected by filtration and reprecipitated from ethanol-ether: yield, 1.12 g., [α]D23 -50.5°(c=1.1 in Methanol), Rf1 =0.32.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[C:36]([CH2:37][NH2:38])=[N:35][N:34]=[N:33]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:38][CH2:37][C:36]3[NH:35][N:34]=[N:33][N:32]=3)=[O:28])=[CH:30][CH:31]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: NCc1nnn[nH]1
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cn1c(N(Cc2ccc(C(=O)NCc3nnn[nH]3)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Reaction time: 8 h

Procedure:
To a solution of the title compound of Example 5 Step A (0.06 mmol, 25 mg) 1H-tetraazol-5-ylmethylamine (0.09 mmol, 12 mg), HOBt (0.15 mmol, 23 mg) and EDC (0.18 mmol, 35 mg) in 0.5 mL of DMF was added DIEA (0.3 mmol, 52 μL). The reaction was allowed to proceed overnight at ambient temperature. The mixture was partitioned between EtOAc/brine. The organic phase was concentrated under reduced pressure and the residue was purified by reverse-phase chromatography (Condition A) and lyophilized, affording the title compound as a white solid. MS (ESI): m/z 517 (M+H). HPLC A: 1.94 min.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=C[O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[CH3:32][NH:33][CH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.[CH2:43](Cl)Cl>>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:32][N:33]([CH3:43])[CH2:34][CH2:35][CH2:36][N:37]1[CH2:38][CH2:39][O:40][CH2:41][CH2:42]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: CNCCCN1CCOCC1
Reactant: ClCCl
Product: COCC1OC(=O)C(=CN(C)CCCN2CCOCC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added methyl-(3-morpholin-4-yl-propyl)amine (74 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 590 (M+H).