Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24](O)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C[O:28][C:29](=[O:39])[CH:30]=[CH:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([NH2:38])[CH:33]=1>>[C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:15][C:14]=3[C:24]([NH:38][C:34]3[CH:33]=[C:32](/[CH:31]=[CH:30]/[C:29]([OH:28])=[O:39])[CH:37]=[CH:36][CH:35]=3)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1nc(C2CCCCC2)[nH]c1CCC12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)C=Cc1cccc(N)c1
Product: O=C(O)/C=C/c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2CCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-cyclohexyl-1H-imidazole-4-carboxylic acid (Example 252) was reacted with 3-(3-amino-phenyl)-acrylic acid methyl ester (prepared in two steps from 3-nitro-benzaldehyde) according to the procedure of Example 20, step d. The methyl ester was hydrolysed using the same procedure as in Example 36, step d to afford the title compound. 1H NMR (300 MHz, d6-DMSO) 12.00 (1H, br s), 9.55 (1H, br s), 8.00 (1H, s), 7.86 (1H, m), 7.57 (1H, d), 7.36 (2H, m), 6.50 (1H, d), 2.89 (2H, m), 2.68 (1H, m), 1.94 (5H, br s), 1.80-1.51 (17H, m), 1.39-1.19 (5H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 60.52; H, 8.50; N, 7.59%. C38H56N4O8.3.0 mols H2O requires: C, 60.78; H, 8.32; N, 7.46%.
Reaction SMILES: [C:1]([C:9]1[CH:10]=[C:11]([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].C(Cl)(Cl)Cl>CO>[C:2]1([CH:1]([OH:8])[C:9]2[CH:10]=[C:11]([CH:15]([CH3:20])[C:16]([O:18][CH3:19])=[O:17])[CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1cccc(C(=O)c2ccccc2)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)C(C)c1cccc(C(O)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
To a solution of 164 g of methyl 2-(3-benzoylphenyl)propionate in 1100 mL methanol at a 0° C., 14 of sodium borohydride were added, keeping the temperature between 7 and 10° C. After 2 hours of stirring at 0° C., TLC (silica-gel/chloroform) showed total consumption of starting material. The solvent was evaporated under vacuum. The residue was dissolved in 400 mL of methylene chloride. The solution was washed three times with 250 ml of 1% hydrochloric acid, until acid pH, and then with saturated sodium chloride solution, until neutral pH. After evaporation of the solvent, the oily colourless residue wheighted 160,0 g (97% yield) and was identified as the title compound. IR Spectrum (film), cm-1 : 3480 (broad), 3080-2880, 1730, 1455, 1200, 1175, 1110, 700. In the 200 MHz 1H-NMR apparatus the signal of CH3 appears as two doublets of similar intensity, indicating the presence of the two possible diasteromers. By following analogous procedures, compounds IVc of Table 2 were obtained.
Reaction SMILES: [CH2:1]1[C:3]2([CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5][CH2:4]2)[CH2:2]1.[ClH:16].C(OCC)(=O)C>O1CCCC1>[ClH:16].[CH2:2]1[C:3]2([CH2:8][CH2:7][NH:6][CH2:5][CH2:4]2)[CH2:1]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC2
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C1CC2(CCN1)CC2
Temperature: 50 °C
Reaction time: 24 h
Yield: 85.4 %

Procedure:
Tert-butyl 6-azaspiro[2.5]octane-6-carboxylate (261 mg, 1.23 mmol) was dissolved in tetrahydrofuran (5 mL), 4N hydrochloric acid/ethyl acetate solution (2 mL, 8.00 mmol) was added, and the mixture was stirred at 50° C. for 24 hr. The reaction mixture was concentrated under reduced pressure to give the title compound (155 mg, 85%) as white crystals.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH:27]=[N:26][C:7]([CH2:8][C@H:9]([C:11]([N:13]2[CH2:18][CH2:17][CH:16]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH2:15][CH2:14]2)=[O:12])[NH2:10])=[CH:6]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37](O)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1>>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:37]([NH:10][C@@H:9]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)[CH2:15][CH2:14]3)=[O:12])[CH2:8][C:7]3[N:26]=[CH:27][N:5]([CH3:4])[CH:6]=3)=[O:38])[CH:35]=2)[CH:30]=[CH:29]1
Reactant: CN1CCC(C2CCN(C(=O)[C@H](N)Cc3cn(C)cn3)CC2)CC1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Agent: Cl
Product: CN1CCC(C2CCN(C(=O)[C@@H](Cc3cn(C)cn3)NC(=O)c3ccc4cc[nH]c4c3)CC2)CC1

Procedure:
Using methods substantially equivalent to those described in Method D-1, the subtitled compound was prepared from 1-(1-methyl-D-histidinyl)-4-(1-methylpiperidin-4-yl)piperidine trihydrochloride and indole-6-carboxylic acid (23%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:20](O)=[O:21])[N:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:23][C:24]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH2:33])[N:31]=1)([CH3:26])[CH3:25]>>[C:24]([C:27]1[S:28][CH:29]=[C:30]([CH2:32][NH:33][C:20]([C:10]2[N:11]=[N:12][C:13]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[CH:9]=2)=[O:21])[N:31]=1)([CH3:26])([CH3:23])[CH3:25]
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nn1
Reactant: CC(C)(C)c1nc(CN)cs1
Product: CC(C)(C)c1nc(CNC(=O)c2cc(-c3ccc(Cl)cc3)c(OCC(F)(F)F)nn2)cs1

Procedure:
The title compound was synthesized in analogy to Example 41 using 5-(4-chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridazine-3-carboxylic acid (example M) and 2-(1,1-dimethylethyl)-4-thiazolemethanamine (CAS Registry No. 937656-81-0) as starting materials; LC-MS (UV peak area/ESI) 99.1%, 485.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[Cl:10][CH2:11][C:12](Cl)=[O:13].Cl>O>[Cl:10][CH2:11][C:12]([NH:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4])=[O:13]
Reactant: O=C(Cl)CCl
Reactant: CC(C)(N)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)CCl)C(=O)O
Temperature: 5 °C

Procedure:
To a stirring mixture of 2-aminoisobutyric acid (165.8 g, 1.61 mol), sodium hydroxide (64.4 g, 1.61 mol), and 800 mL water cooled to 5° C., was added two separate solutions of chloroacetyl chloride (200 g, 1.77 mol) and sodium hydroxide (70.8 g, 1.77 mol) in 143 mL water. The temperature was maintained between 5 to 10° C. during the addition. The reaction mixture was then allowed to warm to room temperature and the solution was acidified with 165 mL of concentrated aq. HCl. The precipitated solid was filtered and dried under vacuum. A yield of 180.4 g (62%) was obtained.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[C:8]([Cl:15])[C:9]([Cl:14])=[C:10]([Cl:13])[C:11]([Cl:12])=[C:4]2[C:3]1=[O:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>O1CCCC1.C(Cl)Cl>[S:23]([O:1][N:2]1[C:3](=[O:16])[C:4]2=[C:11]([Cl:12])[C:10]([Cl:13])=[C:9]([Cl:14])[C:8]([Cl:15])=[C:5]2[C:6]1=[O:7])([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)ON2C(=O)c3c(Cl)c(Cl)c(Cl)c(Cl)c3C2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.9 %

Procedure:
N-Tosyloxytetrachlorophthalimide was prepared by the following procedure. To a flask equipped with a stirrer and addition funnel were added N-hydroxytetrachlorophthalimide (10.00 g, 0.033 mol), p-toluenesulfonyl chlorde (6.57 g, 0.033 mol) and 100 mL of dried tetrahydrofuran (THF). A solution of triethylamine (4.5 mL, 0.033 mol) in 20 mL of THF was added dropwise while the reaction vessel was cooled to between -20° and -10°. A red color formed after each drop, and quickly disappeared. After stirring for 2 h at room temperature the reaction mixture was diluted with 200 mL of methylene chloride, and the solution was washed twice with water. The organic layer containing much crystallized product was evaporated, leaving 13.5 g of pale yellow N-tosyloxytetrachlorophthalimide: mp 206°-210°. Recrystallization from toluene (50 mL)-heptane (25 mL) gave 10.7 g (71.5%) of pale yellow product: mp 214°-216°; ir (KBr) 1800 (w), 1740 (vs), 1380 (m), 1190 (m), 1180 (m), 1140 (m), 1025 (m), 810 (m), 790 (m), 725 (m), 705 (m), 506 (m); uv (CH3CN) 240 (58,500), 275 (2990), 328 (2790), 339 nm (3020); mass spectrum 452.8782 (calcd for C15H7NO5Cl4S: m+, 452.8805). Anal. Calcd for C15H7NO5Cl4S: C, 39.59; H, 1.55; N, 3.08; O, 17.58; Cl, 31.16; S, 70.4. Found: C, 40.04, 40.16, 39.70, 39.72; H, 1.95, 1.81, 1.52, 1.70; N, 2.99, 2.89; Cl, 31.30.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
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: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2Cl)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (100 mg, 0.269 mmol), 2-chlorophenylboronic acid (50.5 mg) and cesium carbonate (350 mg) in THF (10.5 mL) and degassed water (2.5 mL) was added tetrakis(triphenylphosphine)palladium (8.4 mg) and the reaction mixture was stirred under argon for 2 hours at 80° C. After such time water was added and the precipitate was isolated, washed with water and dried in vacuo to yield 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH:13]C(OCC1C=CC=CC=1)=O)[CH2:5][C:6]([F:12])([F:11])[CH2:7][CH:8]([CH3:10])[CH3:9].[ClH:25].O1CCOCC1>CO.[Pd]>[ClH:25].[CH3:1][O:2][C:3](=[O:24])[C@@H:4]([NH2:13])[CH2:5][C:6]([F:12])([F:11])[CH2:7][CH:8]([CH3:9])[CH3:10]
Reactant: COC(=O)[C@H](CC(F)(F)CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: COC(=O)[C@@H](N)CC(F)(F)CC(C)C
Reaction time: 7 h

Procedure:
A solution of (S)-2-benzyloxycarbonylamino-4,4-difluoro-6-methyl-heptanoic acid methyl ester: (333 mg, 0.97 mmol) in methanol (10 mL) and 4 M HCl in dioxane (4 mmol, 1 mL) is hydrogenated over 10% Pd/C (150 mg) at 55 psi. After 7 hr, another portion of 10% Pd/C (200 mg) is added and the hydrogenation resumed. After 5.5 hr, the reaction did not progress. Catalyst is filtered and the filtrate is concentrated in vacuum and subjected to the hydrogenation conditions. After 6.5 hr, the catalyst is removed by filtration over a pad of Celite, and the filtrate is concentrated in vacuum to afford (S)-2-amino-4,4-difluoro-6-methyl-heptanoic acid methyl ester hydrochloride as a sticky solid (240 mg, quant.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18]Br)=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2].O.C([O-])(O)=[O:22].[Na+]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH2:18][OH:22])=[C:8]2[C:13]([Cl:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10][N:9]2[CH:17]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CBr
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cn2ncc(C#N)c(Cl)c2c1CO
Temperature: 50 °C
Reaction time: 72 h
Yield: 100.1 %

Procedure:
To a solution of compound 16A (102 mg, 0.30 mmol) in THF (12 mL) was added water (3 mL) dropwise. The reaction was kept at room temperature for 3 days and then heated to 50° C. for 3 hours. Upon cooling to room temperature, NaHCO3 (70 mg) was added to the reaction mixture. The reaction was concentrated to dryness, redissolved in CH2Cl2 and filtered. The filtrate was concentrated to give compound 16B as a yellow solid (84 mg, 100%). This compound was used in the following steps without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.[O:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][C:30](=O)[C:31]([OH:33])=[O:32])[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][N:13]=[C:30]([C:31]([OH:33])=[O:32])[CH2:29][CH2:28][CH2:27][N:24]3[CH2:23][CH2:22][O:21][CH2:26][CH2:25]3)[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: O=C(O)C(=O)CCCN1CCOCC1
Reactant: NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1
Product: O=C(O)C(CCCN1CCOCC1)=NNC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1

Procedure:
In the manner given in Example 13, 7-chloro-2-hydrazino-5-phenyl-3H-1,4-benzodiazepine can be stirred with 5-morpholino-2-oxopentanoic acid to give 7-chloro-2-[(1-carboxy-4-morpholinobutylidene)hydrazino]-5-phenyl-3H-1,4-benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:6]=[C:5]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCCC1.[F:29][C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(N(CC)CC)C>[C:14]([O:13][C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:36]([C:32]3[CH:33]=[CH:34][CH:35]=[C:30]([F:29])[CH:31]=3)(=[O:38])=[O:37])=[CH:10][CH:9]=2)[C:5]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:6]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(N)ccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1nc(-c2ccccc2)c2cc(NS(=O)(=O)c3cccc(F)c3)ccc21
Yield: 74.4 %

Procedure:
N-(N-tert-Butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.4 g of 5-amino-N-tert-butoxycarbonyl-3-phenyl-1H-indazole, 15 ml of tetrahydrofuran, 0.36 ml of triethylamine and 0.27 g of 3-fluorobenzenesulfonyl chloride. 0.45 g of N-(N-tert-butoxycarbonyl-3-phenyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of an ochre solid melting at 100° C.
Reaction SMILES: C(O[C:5]12[CH2:14][CH:9]3[CH2:10][CH:11]([CH2:13][C:7]([O:15]CC=C)([CH2:8]3)[CH2:6]1)[CH2:12]2)C=C.ClC1C=CC=C(C(OO)=[O:27])C=1>ClCCl>[C:7]12([OH:15])[CH2:8][CH:9]3[CH2:10][CH:11]([CH2:12][CH:5]([CH2:14]3)[CH:6]1[OH:27])[CH2:13]2
Reactant: C=CCOC12CC3CC(C1)CC(OCC=C)(C3)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: OC1C2CC3CC(C2)CC1(O)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.8 %

Procedure:
The obtained 1,3-bis(2-propenyloxy)adamantane {5.96 g, yield: 80.1%, purity by gas chromatography: 96.0%, purity by gel permeation chromatography (hereinafter referred to as GPC): 99.5%} was dissolved in 30 ml of dichloromethane. Thereto was added 14.3 g (0.058 mol) of 70% m-chloroperbenzoic acid, followed by stirring at room temperature for 16 hours. Then, the reaction mixture was washed with 30 ml of a 25% aqueous sodium sulfite solution and further with water twice. The reaction mixture was subjected to distillation to remove dichloromethane, whereby was obtained crude 1,3-bis(glycidyloxy)adamantane {6.70 g, yield: 79.8% (from adamantanediol), purity by gas chromatography: 96.1%, GPC purity: 99.7%, colorless liquid}. The liquid was subjected to distillation at 0.1 mmHg at 140° C. to obtain, as a colorless transparent liquid, 1,3-bis(glycidyloxy)adamantane {5.36 g, yield: 63.8% (from adamantanediol), purity by gas chromatography: 98.3%, GPC purity: 99.8%}.
Reaction SMILES: C[N:2]1[CH2:19][CH2:18][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=4[N:5]([C:6]=23)[CH2:4][CH2:3]1.ClC(OC(Cl)C)=O>ClC(Cl)C>[CH2:4]1[N:5]2[C:6]3[C:11]([C:12]4[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=42)=[CH:10][CH:9]=[CH:8][C:7]=3[CH2:18][CH2:19][NH:2][CH2:3]1
Reactant: CN1CCc2cccc3c4c(n(c23)CC1)CCCC4
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: c1cc2c3c(c1)c1c(n3CCNCC2)CCCC1
Temperature: 25 °C
Yield: 52.7 %

Procedure:
To a solution of 3-methyl-2,3,4,5,9,10,11,12-octahydro-1H-[1,4]diazocino[7,8,1-jk]carbazole (0.20 g, 0.79 mmole) in dichloroethane (15 mL) was added 1-chloroethyl chloroformate (0.80 mL, 7.2 mmole) and the solution refluxed for 24 hours under nitrogen. The reaction mixture was cooled to room temperature and the solvent removed in vacuo and replaced with methanol (100 mL) and refluxed for another 3 hours under nitrogen. The solvent was removed in vacuo and the residue purified by flash column chromatography (silica gel, 1.5% methanol in dichloromethane) to provide 0.10 g of the title compound as a light yellow oil. The oil was further treated with one equivalent of fumaric acid in ethanol, the resulting solid collected by filtration and washed with ether to give 0.12 g of a fumarate salt, mp 174-176° C. MS (ESI) m/z 241 ([M+H]+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[CH:16][C:10]=3[C:9]([NH2:21])=[N:8][C:7]=2[CH:22]=1.[CH3:23][O:24][CH2:25][CH2:26][CH2:27][C@H:28]1[CH2:33]N[CH2:31][CH2:30][NH:29]1.C(N(C(C)C)CC)(C)C>C1(C)C=CC=CC=1.CS(C)=O>[F:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([F:18])([F:20])[F:19])=[CH:16][C:10]=3[C:9]([N:21]3[CH2:31][CH2:30][NH:29][CH:28]([CH2:27][CH2:26][CH2:25][O:24][CH3:23])[CH2:33]3)=[N:8][C:7]=2[CH:22]=1
Reactant: COCCC[C@H]1CNCCN1
Reactant: NC1=Nc2cc(F)ccc2Nc2ccc(C(F)(F)F)cc21
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: COCCCC1CN(C2=Nc3cc(F)ccc3Nc3ccc(C(F)(F)F)cc32)CCN1
Temperature: 110 °C
Reaction time: 24 h
Yield: 57.1 %

Procedure:
Combine 8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride (0.201 g, 0.606 mmol), (S)-2-(3-methoxy-propyl)-piperazine (0.192 g, 1.21 mmol), and diisopropylethyl amine (0.106 mL, 0.606 mmol) in a mixture of toluene (3 mL) and dimethylsulfoxide (1 mL) and stir at 110° C. for 24 hours. Evaporate the mixture then purify by flash chromatography, eluting with a step gradient starting with dichloromethane going to 7% 2N ammonia-methanol in dichloromethane gives 8-fluoro-11-[3-(3-methoxy-propyl)-piperazin-1-yl]-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine (0.151 g, 0.346 mmol, 57%) as a yellow oil. Mass spectrum (APCI): m/z=437.2 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:19][OH:20])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1.[Cu][C:22]#[N:23].N>CN1CCCC1=O>[OH:20][CH2:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[C:2]([CH:3]=1)[C:22]#[N:23]
Reactant: N#C[Cu]
Reactant: OCc1cnc(Oc2cccc(C(F)(F)F)c2)c(Br)c1
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(CO)cnc1Oc1cccc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 24 h
Yield: 107.2 %

Procedure:
To a solution of (5-bromo-6-(3-(trifluoromethyl)phenoxy)pyridin-3-yl)methanol (530 mg, 1.522 mmol) in N-methyl-2-pyrrolidone (NMP) (5 mL) was added copper(I) cyanide (545 mg, 6.09 mmol). The reaction mixture was stirred at 150° C. for 24 h, then poured into aq. NH3 (100 mL) and extracted with ethyl acetate (100 mL). Separated organic part was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated. Purification via flash chromatography with (EtOAc/hexanes: 5% to 80%) afforded the title product (480 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B(O)O)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.[OH:29][C:30]1[CH:31]=[CH:32][C:33]2[O:37][C:36]([CH3:38])=[N:35][C:34]=2[CH:39]=1>>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C@H:16]1[C:15]2[CH:24]=[CH:25][C:12]([O:11][C@H:9]3[C:10]4[C:6](=[C:5]([O:29][C:30]5[CH:31]=[CH:32][C:33]6[O:37][C:36]([CH3:38])=[N:35][C:34]=6[CH:39]=5)[CH:4]=[CH:3][C:2]=4[F:1])[CH2:7][CH2:8]3)=[CH:13][C:14]=2[O:18][CH2:17]1
Reactant: Cc1nc2cc(O)ccc2o1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B(O)O)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Oc5ccc6oc(C)nc6c5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from (R)-7-fluoro-1-[(S)-3-methoxycarbonylmethyl-2,3-dihydrobenzofuran-6-yloxy]-2,3-dihydro-1H-inden-4-ylboronic acid and 5-hydroxy-2-methyl-benzoxazole following a procedure analogous to that described for Intermediate 6. LC (method 10): tR=0.85 min; Mass spectrum (ESI+): m/z=490 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]=O.C(N(CC)CC)C.[ClH:21].[NH2:22][CH:23]([CH3:32])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25].[BH4-].[Na+]>CO.O>[ClH:21].[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][NH:22][CH:23]([CH3:32])[CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]
Reactant: O=Cc1ccc2ccccc2c1Br
Reactant: CC(N)C(O)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(NCc1ccc2ccccc2c1Br)C(O)c1ccccc1
Yield: 89.3 %

Procedure:
A mixture of 38.4 g (0.164 mole) 1-bromo-2-naphthaldehyde, 16.4g (0.164 mole) triethylamine, and 30.6 g (0.164 mole) of 2-amino-1-phenyl-1-propanol hydrochloride in 500 ml CH3OH was stirred and refluxed for 60 minutes, then cooled to 10°-20° while 6.23 g (0.164 mole) of sodium borohydride was added over 5 minutes. The reaction mixture was stirred at ambient temperature (15°-21°) for 60 minutes and diluted with 500 ml H2O. The mixture was stirred for 15 minutes and extracted with 2 × 350 ml CHCl3. The combined extracts were dried (MgSO4) and concentrated to dryness in vacuo to give 59.6 g (99%) of the free base.
Reaction SMILES: [CH:1]([N:4](CC)C(C)C)(C)[CH3:2].BrCC#N.[N:14]([C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:30]([OH:32])=[O:31])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]>C(#N)C>[N:14]([C:17]1[CH:42]=[CH:41][C:20]([CH2:21][O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][C@H:29]([NH:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:30]([O:32][CH2:2][C:1]#[N:4])=[O:31])=[O:24])=[CH:19][CH:18]=1)=[N+:15]=[N-:16]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)O
Reactant: CCN(C(C)C)C(C)C
Agent: N#CCBr
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccc(N=[N+]=[N-])cc1)C(=O)OCC#N
Reaction time: 1 h
Yield: 103.7 %

Procedure:
N,N-Diisopropylethylamine (173 μL, 0.991 mmol) and subsequently bromoacetonitrile (314 μL, 4.50 mmol) were added to a solution of (S)-5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoic acid (Compound tk57) (367 mg, 0.901 mmol) in acetonitrile (1 mL) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at the same temperature for 1 hour and then concentrated under reduced pressure, and the resulting crude product was purified by normal-phase silica gel column chromatography (hexane/ethyl acetate) to afford (S)-cyanomethyl 5-((((4-azidobenzyl)oxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk58) (417.2 mg, quant.).