Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([O:27][Si](C(C)(C)C)(C)C)[CH:21]=[CH:20]2)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:35]=[CH:36][CH:37]=1)[C:15]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20]2)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)c2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCOc1cccc(C(=O)c2ccc3cc(O)ccc3c2)c1

Procedure:
Silyl ether 330d (1.0 g, 1.9 mmol) and tetrabutylammonium fluoride (1M in THF, 1.9 mL, 1.9 mmol) were stirred in THF (40 mL) at room temperature under N2 for 2h. After solvent evaporation, the mixture was extracted with EtOAc and 5% aq. KHSO4, then water, finally brine. Concentration and chromatography on silica gel, eluting with 0% to 40% EtOAc in hexane yielded, after drying, a colorless foam (0.70 g). IR(KBr): cm-1 3334, 1686. MS(NH3): 425 (M+NH4), 402 (M+H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[C:16](=O)(OC1C=CC=CN=1)[O:17]C1C=CC=CN=1.C(N(CC)CC)C>ClCCl>[N:14]([C:12]1[CH:11]=[N:10][N:9]([CH2:8][C:7]2[C:3]([CH3:2])=[N:4][O:5][C:6]=2[CH3:15])[CH:13]=1)=[C:16]=[O:17]
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1Cn1cc(N=C=O)cn1

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (400 mg, 2.08 mmol), dipyridin-2-yl carbonate (450 mg, 2.08 mmol) and triethylamine (0.290 mL, 2.08 mmol) were stirred in dichloromethane (7 mL) for 12 hours at room temperature. The reaction was concentrated under vacuum to afford 4-((4-isocyanato-1H-pyrazol-1-yl)methyl)-3,5-dimethylisoxazole as an off-white solid in quantitative yield. Ethanol (1 mL) was added along with methyl 2-amino-3-(3-methoxyphenyl)propanoate (68 mg, 0.327 mmol) and triethylamine (0.064 mL, 0.461 mmol). The reaction was stirred at reflux for 12 hours, then allowed to cool to room temperature. The solvent was removed under a stream of nitrogen. The crude product was re-suspended in MeOH (1 mL) and purified by reversed phase HPLC (5 to 95% acetonitrile in H2O:16 minutes gradient). The pure fractions were combined and solvent removed under vacuum to afford 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-5-(3-methoxybenzyl)imidazolidine-2,4-dione as a white solid yield: 50% 1H NMR (CDCl3, 400 MHz): δ 2.19 (s, 3H), 2.41 (s, 3H), 3.34-3.33 (d, J=3.2 Hz, 1H), 3.31-3.29 (d, J=8 Hz, 1H), 3.76 (s, 3H), 4.33-4.30 (m, 1H), 5.05 (s, 2H), 5.95 (bs, 1H), 7.25-7.21 (t, 1H), 6.82-6.78 (m, 3H), 7.85 (s, 1H), 7.99 (s, 1H). The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.13 μM.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][CH2:24][C@H:25]([OH:27])[CH3:26]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:23][CH2:24][C@H:25]([OH:27])[CH3:26])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C[C@@H](O)CN
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: C[C@@H](O)CNc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cn1
Temperature: 140 °C
Yield: 17.4 %

Procedure:
Following the procedure described above in Example 51, 4-(3-Chloro-4-fluoro-phenylamino)-6-fluoro-[1,7]naphthyridine-3-carbonitrile (0.10 g, 0.32 mmol) was reacted with (R)-1-amino-2-propanol (0.47 g, 6.32 mmol) in 2 mL of THF. The reaction mixture was heated up in a sealed vial in a microwave reactor at 140° C. for 40 min. The crude product was purified by preparative HPLC and lyophilized to give a yellow solid (20.7 mg, 17.6% yield): 1H NMR (400 MHz, DMSO-D6) δ ppm 1.08 (d, J=6.32 Hz, 3 H) 3.08-3.20 (m, 2 H) 3.76-3.90 (m, 1 H) 4.73 (d, J=4.55 Hz, 1 H) 6.55-6.68 (m, 1 H) 6.95 (s, 1 H) 7.25-7.34 (m, 1 H) 7.36-7.47 (m, 1 H) 7.50-7.60 (m, 1 H) 8.21 (s, 1 H) 8.78 (s, 1 H) 9.60 (s, 1 H); HRMS (ESI+) calcd for C18H15ClFN5O 372.10219, found (MH+) 372.1019.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].Cl.[CH3:14][N:15]([CH2:17][C:18]1[N:23]=[C:22]([CH2:24]Cl)[CH:21]=[CH:20][CH:19]=1)[CH3:16]>>[C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][S:8][CH2:24][C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:17][N:15]([CH3:14])[CH3:16])[N:23]=1)#[N:2]
Reactant: CN(C)Cc1cccc(CCl)n1
Reactant: C#CCNC(=NCCS)NC#N
Agent: Cl
Product: C#CCNC(=NCCSCc1cccc(CN(C)C)n1)NC#N

Procedure:
A ethanolic solution of the product of Step A of Example 6 is reacted with about an equimolar amount of 6-dimethylaminomethyl-2-chloromethylpyridine hydrochloride and about three equivalents of base, and the title compound is produced.
Reaction SMILES: [CH3:1][CH:2]([C@H:4]1[CH:8]2[CH:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[CH:12]([C@:13]2([CH3:30])[CH:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([OH:29])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[CH3:3].C(Cl)(Cl)Cl.[CH3:38][OH:39]>>[CH3:3][CH:2]([C@H:4]1[C@@H:8]2[C@@H:9]3[C@@:22]([CH3:25])([CH2:23][CH2:24][C@@:7]2([C:31]([OH:33])=[O:32])[CH2:6][CH2:5]1)[C@@:21]1([CH3:26])[C@@H:12]([C@:13]2([CH3:30])[C@@H:18]([CH2:19][CH2:20]1)[C:17]([CH3:28])([CH3:27])[C@@H:16]([O:29][C:38]([CH2:6][C:7]([C:31]([OH:33])=[O:32])([CH3:24])[CH3:8])=[O:39])[CH2:15][CH2:14]2)[CH2:11][CH2:10]3)[CH3:1]
Reactant: CO
Reactant: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)C(CCC4[C@@]5(C)CC[C@H](O)C(C)(C)C5CC[C@]43C)C12
Solvent: ClC(Cl)Cl
Product: CC(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 24.5 %

Procedure:
yield 24.5% (starting with 155.9 mg of dihydrobetulinic acid); crystallization from MeOH-H2O gave colorless needles; mp 291°-292° C.; [α]D20−13.4° (c=1.1, CHCl3-MeOH [1:1], 1H NMR (pyridine-d5): 0.85, 0.94 (each 3H, d, J=7.0 Hz; 20-(CH3)2), 0.75, 0.93, 0.97, 1.01, 1.03 (each 3H, s; 4-(CH3)2, 8-CH3, 10-CH3, 14-CH3), 1.55 (6H, s; 3′-CH3×2), 2.89, 2.97 (each 1H, d, J=15.5 Hz; H-2′), 4.77 (1H, dd, J=5.0, 11.0 Hz, H-3); Anal. Calcd for C36H58O6.5/2H2O: C, 68.43; H, 10.04. found C, 68.64; H, 9.78.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[N:3]=1.C(N)C[NH2:12]>>[CH3:9][O:8][C:4]1[N:3]=[C:2]([NH2:12])[CH:7]=[CH:6][CH:5]=1
Reactant: NCCN
Reactant: COc1cccc(Cl)n1
Product: COc1cccc(N)n1

Procedure:
2-Chloro-6-methoxypyridine (5.0 g) was heated with ethylenediamine (30 ml) at 120° C. overnight. The excess ethylenediamine was removed by rotary evaporation. The residue was dissolved in a small volume of 2.5 M aqueous sodium hydroxide and extracted thoroughly with dichloromethane. The combined organic layers were washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated in vacuo to give (2-aminoethyl)(6-methoxy(2-pyridyl)amine as an orange syrup. The amine (2.58 g) was treated with benzotriazole carboxamidinium 4-methylbenzenesulfonate (0.86 g) and DIEA (0.45 mmol) in acetonitrile (6 ml) and stirred overnight at room temperature. Trituration with ether gave the guanidine, amino-{2-[(6-methoxy(2-pyridyl))amino]ethyl}carboxamidinium 4-methylbenzenesulfonate, as an oil. The oily guanidine (200 mg) was reacted with 100 mg of resin according to Resin Method C (90° C., overnight) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]([Br:40])=[CH:28][C:24]=1[C:25](Cl)=[O:26])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:15]([O:22][C:23]1[CH:31]=[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:29]([Br:40])=[CH:28][C:24]=1[C:25]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8])=[O:26])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1ccccc1N
Reactant: O=C(Cl)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccccc1NC(=O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 8 h
Yield: 82 %

Procedure:
2.8 l of o-toluidine and 2.5 l of pyridine are added to 50 l of dichloromethane at 3° C. 13.6 kg of 2,4-bisbenzyloxy-5-bromobenzoyl chloride (toluene-moist) suspended in 35 l of dichloromethane are added to this solution over the course of 2 h. The mixture is subsequently stirred overnight at 23° C., and the solid is filtered off and rinsed with dichloromethane (2× with 5 l each time). The crude product obtained in this way (8 kg) is dissolved in 40 l of dichloromethane and extracted successively with 40 l of distilled water, 50 l of hydrochloric acid (˜1 mol/l; prepared from 5 l of HCl w: 37% and 50 l of water). The organic phase is subsequently washed with 50 l of water. The organic phase is dried for 3 days using 6 kg of sodium sulfate. The drying agent is filtered off with suction via a suction filter, and the filtrate is evaporated to dryness in a rotary evaporator. Recrystallisation from ethanol (35 l, 65° C.) and drying (50° C./35 mbar) to constant weight gives 10.84 kg (82%) of 2,4-bisbenzyloxy-5-bromo-N-o-tolylbenzamide (m.p. 174.5° C.-176° C.; MW 502.4).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:5]([NH2:20])=[N:4][CH:3]=1.[N:21]([O-])=O.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:9][C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)[N:21]=[N:20][C:5]2=[N:4][CH:3]=1
Reactant: Nc1ncc(Br)nc1NCc1ccc2ncccc2c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of 6-bromo-N2-(quinolin-6-ylmethyl)pyrazine-2,3-diamine (6.55 g, 19.84 mmol) in acetic acid (15 mL), was added a the solution of sodium nitrite (2.74 g, 39.7 mmol) in water (3 mL). After stirring at rt for 3 h, the solution was concentrated in vacuo. The residue was taken with NaHCO3(aq), extracted with DCM. The organic layer was washed with NH4Cl(aq), dried over Na2SO4, filtered, concentrated in vacuo and purified by silica gel chromatography with EA:Hexanes to provide 6-((6-bromo-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)quinoline (3.35 g, 47%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.05 (s, 1H), 8.89 (d, 1H), 8.34 (d, 1H), 8.02 (d, 1H), 7.9 3 (s, 1H), 7.76 (dd, 1H), 7.53 (dd, 1H), 6.19 (s, 2H). LCMS (method B): [MH]+=343, tR=2.11 min.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][N:17](S(C5C=CC(C)=CC=5)(=O)=O)[C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C:5](=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:4]1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][C:5](=[CH:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)C=C1C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C=C1C[C@@H](CC)[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Yield: 99.5 %

Procedure:
To a solution of ethyl 2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (1.9 g, 3.85 mmol, Preparation #III.1) in THF (30 mL) at about 0° C. was added a solution of TBAF (11.55 mL, 11.55 mmol, 1M in THF). After about 30 min additional TBAF (7.70 mL, 7.70 mmol, 1M in THF) was added. After about 1 h EtOAc and brine were added to the reaction mixture. The organic layer was separated, concd in vacuo and purified by chromatography on silica gel eluting with EtOAc to provide ethyl 2-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (1.3 g, 100%) as a mixture of stereoisomers. LC/MS (Table 1, Method a) Rt=1.86 and 1.90 min.; MS m/z: 340 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([OH:14])=O.[NH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17][CH2:16]1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:11][C:12]([N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH2:17][CH2:16]1)=[O:14]
Reactant: c1ccc2c(c1)NCCN2
Reactant: O=C(O)CSc1nc2ccccc2s1
Product: O=C(CSc1nc2ccccc2s1)N1CCNc2ccccc21
Yield: 51 %

Procedure:
The title compound was synthesized according to General Procedure B using 2-(benzo[d]thiazol-2-ylthio)acetic acid and 1,2,3,4-tetrahydroquinoxaline to yield 41 as a white solid (51%) MS m/z: 342 (M+H)+. Anal. Calcd. For, C17H15N3OS2.0.2H2O: C, 59.18; H, 4.50; N, 12.18; S, 18.52. Found: C, 59.32; H, 4.65; N, 12.18; S, 18.25.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH3:11])[C:4]=1[CH3:12].B(Br)(Br)Br>C(Cl)Cl.O>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[C:5]([CH3:11])[C:4]=1[CH3:12]
Reactant: COc1ccc(C=O)c(C)c1C
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Cc1c(O)ccc(C=O)c1C
Temperature: -78 °C
Reaction time: 12 h
Yield: 10.2 %

Procedure:
4-Methoxy-2,3-dimethyl-benzaldehyde (2.0 g, 12.18 mmol) was dissolved in DCM (48 mL), and the solution was cooled to −78° C. 1M BBr3(24 mL, 24.13 mmol) was added slowly thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the residue was diluted with water and extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (187 mg, 10%).
Reaction SMILES: [ClH:1].C(NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(OCC1C=CC=CC=1)=O)C.Cl.Cl.[CH2:43]([NH:45][C:46](=[O:71])[C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[C:52](=[O:70])[C@H:53]([CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:69])[NH2:68])[NH:54][C:55](=[O:62])[C@H:56]([CH2:58][CH:59]([CH3:61])[CH3:60])[NH2:57])[CH3:44].[N+](C1C=CC([O:81][C:82](=O)[C@@H:83]([CH:92]([CH3:94])[CH3:93])[NH:84][C:85]([O:87][C:88]([CH3:91])([CH3:90])[CH3:89])=[O:86])=CC=1)([O-])=O>CN(C)C=O>[ClH:1].[CH2:43]([NH:45][C:46](=[O:71])[C@@H:47]1[CH2:51][CH2:50][CH2:49][N:48]1[C:52](=[O:70])[C@H:53]([CH2:63][CH2:64][CH2:65][NH:66][C:67](=[NH:68])[NH2:69])[NH:54][C:55](=[O:62])[C@H:56]([CH2:58][CH:59]([CH3:60])[CH3:61])[NH:57][C:82](=[O:81])[C@@H:83]([CH:92]([CH3:93])[CH3:94])[NH:84][C:85]([O:87][C:88]([CH3:89])([CH3:90])[CH3:91])=[O:86])[CH3:44]
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C
Agent: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Reaction time: 96 h

Procedure:
Nα -t-butoxycarbonyl-D-valyl-L-leucyl-L-arginyl-L-proline N-ethylamide hydrochloride is prepared from 3.8 g., 6.5 mmol, of Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-proline N-ethylamide hydrochloride by de-protection by the hydrogenation procedure as described in Example 2, to yield 2.9 g., 6.5 mmol, of L-leucyl-L-arginyl-L-proline N-ethylamide dihydrochloride as a glassy solid. This material is dissolved in 25 ml. of dimethylformamide and treated with 2.2 g., 6.5 mmol, of Nα -t-butoxycarbonyl-D-valine p-nitrophenyl ester. The reaction is held at room temperature for four days and is then evaporated to dryness under reduced pressure. The residue is dissolved in 10 ml. of methanol and the product precipitated by the addition of 500 ml. of anhydrous ether. The solid product is purified by chromatography over silica gel with toluene-methanol (70:30); 1.1 g.; [α]D23 -53.5° (c 1.0, methanol).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:18])[N:8]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:19]=O.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][C:30]=1[NH2:31])[NH:27][C:26](=[O:32])[CH2:25]2>>[NH2:31][C:30]1[CH:29]=[C:28]2[C:24]([C:25](=[CH:19][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[C:7](=[O:18])[C:6]=4[C:2]=3[CH3:1])[C:26](=[O:32])[NH:27]2)=[CH:23][C:22]=1[F:21]
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(N)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCC1)CC2
Yield: 54 %

Procedure:
The title compound was prepared under the same conditions as described in Example 13 with 3-methyl-4-oxo-5-(2-pyrrolidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-pyrrolidin-1-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (22 mg, 54%) as a red solid.
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])C>CO>[F:8][C:6]1[CH:7]=[CH:2][C:3]([CH:9]=[O:11])=[CH:4][CH:5]=1
Reactant: CC(=O)c1ccc(F)cc1O
Solvent: CO
Product: O=Cc1ccc(F)cc1
Yield: 100 %

Procedure:
To a mixture of (2-hydroxy-4-fluoro phenyl)-1-ethanone (3 g, 19.7 mmol) obtained in Preparation 5, and 4-fluorobenzaldehyde (4.37 g, 19.7 mmol) in methanol was slowly added sodium hydroxide solution at 0° C., under N2 atm. The reaction mixture was allowed to stir for 10 hours at 0-10° C. Water (100 mL) was added to it followed by 6 N HCl (15 mL). Solid separated was filtered off and dried under vacuum to afford 3 g (41%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[C:11]1[CH:12]=[CH:13][C:14]([N+:26]([O-:28])=[O:27])=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=1.[H-].[Na+]>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][C:11]2[CH:12]=[CH:13][C:14]([N+:26]([O-:28])=[O:27])=[C:15]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH:16]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C#N)cc2)ccc1[N+](=O)[O-]
Yield: 57 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4-cyanophenol (5.1 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (11.5 g), sodium hydride (55 wt. %, 1.19 g) and anhydrous N,N-dimethylformamide/anhydrous tetrahydrofuran=5/3 (80 ml) and the reaction mixture was purified to give the title compound (8.45 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][C:13]([C:15]3[C@@:21]([CH3:22])([C@H:5]1[CH2:4][CH2:3]2)[CH:20]=[CH:19][C:17](=[O:18])[CH:16]=3)=[CH2:14].[BH4-].[Na+]>CO.O>[CH3:1][C@@:2]12[CH:10]([OH:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][C:13]([C:15]3[C@@:21]([CH3:22])([C@H:5]1[CH2:4][CH2:3]2)[CH:20]=[CH:19][C:17](=[O:18])[CH:16]=3)=[CH2:14]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Reaction time: 72 h

Procedure:
17-dihydroexemestane is prepared from exemestane as described in Mareck, U. et al., Rapid Commun Mass Spectrom, 20: 1954-62, 2006 with minor modifications. Briefly, exemestane and NaBH4 are individually dissolved in methanol/water (4:1, v/v). For reduction of the 17-keto functional group of exemestane, NaBH4 is slowly added to the suspended exemestane in a 1:2 molar ratio. The mixture is left at ambient temperature for at least 1 h and then assayed by thin layer chromatography to ensure reaction completeness prior to solvent removal by vacuum. After dissolving the dry residue in 1.5M HCl, 1M KOH (500 μL) is added. The mixture is extracted by ethyl ether, dried by vacuum, and re-dissolved in 30 ml ethyl ether:hexane (1:1) at 50° C. After 3 days, the formed crystals are washed with hexane and dried by vacuum. The synthesized 17-dihydroexemestane structure is characterized by a Bruker 500 MHz nuclear magnetic resonance (NMR) spectrometer and HPLC/MS/MS, with the MS spectrum resulting in a clear peak at m/z 299 [M]+ and a daughter product at m/z 135.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C@H:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C@@H:34]([OH:41])[CH2:33]2)=[CH:24]1.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCCCCCC.C(OCC)(=O)C>[NH:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C@H:32]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34](=[O:41])[CH2:33]2)=[CH:24]1
Reactant: O[C@H]1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1C[C@@H](c2c[nH]c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Dess-Martin Periodane (1.08 g, 2.55 mmol ) in 10 mL CH2Cl2 was added to (1S,3R)-3-(1H-Indol-3-yl)-indan-1-ol (2.52 mmol ) in 10 mL CH2Cl2 at 0° C. The reaction mixture was allowed to warm to room temperature and stirred 40 min—TLC showed full conversion. To the reaction mixture ethyl acetate and sat. NaHCO3 was added. The organic phase was isolated, washed with 2N NaOH and brine, dried over MgSO4 and concentrated in vacuo. A quantitative yield of (R)-3-(1H-indol-3-yl)-indan-1-one was obtained after flash chromatography (heptane/ethyl acetate, silica gel).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1([CH3:39])[C:35](=[O:36])[O:34][C:33]([CH:37]=[CH2:38])=[N:32]1>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:38]=[CH:37]/[C:33]2[O:34][C:35](=[O:36])[C:31]([CH3:39])([CH3:30])[N:32]=2)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: C=CC1=NC(C)(C)C(=O)O1
Product: CC1(C)N=C(/C=C/c2ccc(N3CC(=O)N(CC[Si](C)(C)C)S3(=O)=O)c(OCc3ccccc3)c2)OC1=O

Procedure:
The title compound is prepared using 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and 4,4-dimethyl-2-vinyl-4H-oxazol-5-one analogous to Example 108, step A.
Reaction SMILES: C(OC(N1CCN([C:14]([Cl:16])=[O:15])CC1)=O)(C)(C)C.[C:17]([O:21][C:22]([N:24]1[C@H:29]([CH3:30])[CH2:28][NH:27][CH2:26][C@@H:25]1[CH3:31])=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22]([N:24]1[C@H:29]([CH3:30])[CH2:28][N:27]([C:14]([Cl:16])=[O:15])[CH2:26][C@@H:25]1[CH3:31])=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@@H]1CNC[C@H](C)N1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cl)CC1
Product: C[C@@H]1CN(C(=O)Cl)C[C@H](C)N1C(=O)OC(C)(C)C

Procedure:
cis-4-chlorocarbonyl-2,6-dimethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared in analogy to 4-chlorocarbonyl-piperazine-1-carboxylic acid tert-butyl ester from cis-2,6-dimethylpiperazine-1-carboxylic acid tert-butyl ester (A. Muehlebach, P. Pino, Helv. Chim. Acta 73, 839 (1990)) by a modified procedure of Rhone-Poulenc DE 25 50 111 (Rhone-Poulenc).