Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N)CCC.[CH3:6][C:7]1[C:13](=[O:14])[NH:12][C:10](=[O:11])[N:9]([C@@H:15]2[O:19][C@H:18]([CH2:20][O:21]C(C3C=CC=CC=3)=O)[CH:17]=[CH:16]2)[CH:8]=1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]>C(OCCCC)(=O)C>[C@@H:15]1([N:9]2[CH:8]=[C:7]([CH3:6])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:19][C@H:18]([CH2:20][OH:21])[CH:17]=[CH:16]1.[CH3:30][N:31]1[CH2:35][CH2:34][CH2:33][C:32]1=[O:36]
Reactant: Cc1cn([C@H]2C=C[C@@H](COC(=O)c3ccccc3)O2)c(=O)[nH]c1=O
Solvent: CCCCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CCCCN
Product: Cc1cn([C@H]2C=C[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To n-butylamine (133 ml) was added 5'-benzoyl-d4T (7', 70.0 g). The reaction was heated at 70° C. for six hours. After cooling to 20°-25° C., N-methylpyrrolidinone (NMPO, 41.3 ml) and n-butyl acetate (350 ml) were added. Excess n-butylamine (~112.4 ml) along with 175 ml of n-butyl acetate was removed via vacuum distillation at 50° C. The resulting slurry was cooled to 20°-25° C. over one hour and stirred for 30 minutes. The slurry was then cooled to -10° to -15° C. and stirred for 1.5 hours. The cake was filtered and washed with 2×50 ml cold (-10° to -15° C.) n-butyl acetate and dried to give d4T.NMPO complex, 59.0 g (85.6%).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@@H:27]([CH3:31])[C:28]([OH:30])=O.CCN(C(C)C)C(C)C.[F:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[C:49]1[S:53][C:52]([CH2:60][O:61][CH2:62][C:63]#[N:64])([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[NH:51][N:50]=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[F:41][C:42]1[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=1[C:49]1[S:53][C:52]([CH2:60][O:61][CH2:62][C:63]#[N:64])([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[N:51]([C:28](=[O:30])[C@@H:27]([O:26][CH3:25])[CH3:31])[N:50]=1
Reactant: CO[C@@H](C)C(=O)O
Reactant: N#CCOCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CO[C@@H](C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(COCC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of HATU (0.0776 g, 0.2041 mmol) in 0.5 mL of DMF was added (S)-2-methoxy propanoic acid (0.0150 ml, 0.2041 mmol) and DIEA (0.0711 ml, 0.4083 mmol). This mixture was stirred at room temperature for 10 minutes and the crude mixture from Step D (0.047 g) was then added followed by 0.2 mL of DMF. The reaction mixture was stirred at room temperature for 40 hours. The reaction mixture was as diluted with saturated NaHCO3 and extracted with EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated. Purification of the residue by silica gel chromatography (20% EtOAc in hexanes) provided 3.5 mg of a cloudy film that contained the desired product as the primary component. This mixture was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1B(O)O.Br[C:12]1[C:17]([O:18][CH3:19])=[CH:16][C:15]([NH:20]C(=O)C)=[C:14]([CH3:24])[CH:13]=1.CC1C=C(C=CC=1C1C=NC=CC=1C)N>>[CH3:19][O:18][C:17]1[C:12]([C:3]2[CH:4]=[N:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[CH:13][C:14]([CH3:24])=[C:15]([CH:16]=1)[NH2:20]
Reactant: Cc1ccncc1B(O)O
Reactant: COc1cc(NC(C)=O)c(C)cc1Br
Agent: Cc1cc(N)ccc1-c1cnccc1C
Product: COc1cc(N)c(C)cc1-c1cnccc1C

Procedure:
Intermediate 22 was prepared from Intermediate 1A and Intermediate 22B by the procedures described for the preparation of Intermediate 1, and was obtained as a pale yellow solid (55% yield). MS (ES): m/z=229.3 [M+H]+. Intermediate 22 was used in the synthesis of Example 20.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C@@H:15]1[CH2:20][NH:19][CH2:18][CH2:17][NH:16]1.[BH4-].[Na+]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-].CO>[CH3:14][C@H:15]1[NH:16][CH2:17][CH2:18][N:19]([CH:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH:7]2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:20]1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: C[C@@H]1CNCCN1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CO
Product: C[C@@H]1CN(C2CCCCC2c2ccccc2)CCN1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 70.5 %

Procedure:
A mixture of 2-phenylcyclohexanone (1.74 g, 9.99 mmol), (R)-2-methylpiperazine (3.00 g, 30.0 mmol) and titanium (4+) isopropoxide (5.85 ml, 20.0 mmol) was heated at 80° C. under N2 overnight. After cooling to rt, 10 mL of MeOH was added followed by slow addition of NaBH4 (1.13 g, 30.0 mmol). After stirring for 30 min, the solvent was evaporated and the residue was redissolved in EtOAc. The solution was treated with 15 g of NaHCO3 and 1 mL of water to generate slurry. This was filtered with large excess of EtOAc. The solvent was evaporated and the residue was submitted to flash chromatography (SiO2, DCM to DCM/MeOH=100:5 to 100:10 to 100:20) to give (3R)-3-methyl-1-(2-phenylcyclohexyl)-piperazine (1.82 g, 70.5% yield) as a colorless oil.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(O)=O.[BH3-]C#N.[Na+]>C1(C)C=CC=CC=1.CO>[CH2:18]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2])=[CH:12][CH:13]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1ccc(NCc2ccccc2)cc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A mixture of 4-(N-Boc-2-aminoethyl)aniline 28 (10 g, 42.34 mmole), benzaldehyde (4.52 mL, 44.47 mmole), and molecular sieves 4A (10 g) in toluene (100 mL) was refluxed at 95° C. for 15 h. The reaction mixture was filtered and the filtrate was concentrated in vacuo to give a colorless oil. The oil was dissolved in MeOH (150 mL) and AcOH (0.5 mL) and NaCNBH3 (2.79 g, 44.4 mmole) were added. The reaction mixture was stirred at 0° C. for 1 h and at rt for 2 h and then concentrated in vacuo to give a pale yellow oily residue. Purification by flash silica column chromatography: 1/1 hexane/EtOAc gave N-benzyl-4-(N-Boc-2-aminoethyl)aniline 41 as colorless oil (11.5 g, 83%). Rf=0.75 in 1/1 hexane/EtOAc. H1-NMR (CD3OD, 299.96 MHz): δ (ppm) 7.38-7.2 (m, 5H), 6.87-6.84 (d, 2H), 6.58-6.55 (d, 2H), 4.27 (s, 2H), 3.2-3.15 (m, 2H), 2.6-2.56 (t, 2H), 1.41 (s, 9H); ESMS (C20H26N2O2): calcd. 326.4. obsd. 328 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:56]=[CH:55][C:6]([CH2:7][C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:19][C@H:18]([CH2:20][O:21]CC4C=CC=CC=4)[C@@H:17]([O:29]CC4C=CC=CC=4)[C@H:16]([O:37]CC4C=CC=CC=4)[C@H:15]3[O:45]CC3C=CC=CC=3)[CH:11]=[CH:10][C:9]=2[O:53][CH3:54])=[CH:5][CH:4]=1)[CH3:2]>C1COCC1.CO.[OH-].[Pd+2].[OH-]>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[CH:13]=[C:12]([C@@H:14]3[CH2:19][C@H:18]([CH2:20][OH:21])[C@@H:17]([OH:29])[C@H:16]([OH:37])[C@H:15]3[OH:45])[CH:11]=[CH:10][C:9]=2[O:53][CH3:54])=[CH:55][CH:56]=1)[CH3:2]
Reactant: CCc1ccc(Cc2cc([C@@H]3C[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2OC)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@@H]3C[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)ccc2OC)cc1
Temperature: 25 °C
Reaction time: 13 h
Yield: 77.6 %

Procedure:
To a solution of 2-(4-ethylbenzyl)-1-methoxy-4-[(1S,2S,3R,4R,5R)-2,3,4-tris-benzyloxy-5-(benzyloxymethyl)cyclohexyl]benzene (10 mg, 0.013 mmol) in THF (0.2 mL) and methanol (1 mL), a 20% palladium hydroxide catalyst (10 mg) was added and the mixture was stirred under a hydrogen atmosphere at room temperature for 13 hours. After filtering the catalyst, the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative TLC [developing solution=methanol:methylene chloride (1:10)] to obtain the title compound (3.9 mg, 75%).
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3](=[CH2:7])[C:4](O)=[O:5].[NH2:10][C:11]([NH2:13])=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[F:1][C:2]([F:9])([F:8])[CH:3]1[CH2:7][NH:13][C:11](=[O:12])[NH:10][C:4]1=[O:5]
Reactant: NC(N)=O
Reactant: C=C(C(=O)O)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C1NCC(C(F)(F)F)C(=O)N1
Temperature: 90 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
A mixture of α-trifluoromethylacrylic acid (700 mg; 5.0 mmoles) and urea (318 mg; 5.3 mmoles) in DMF (5 ml) was heated at 90° C. with stirring for 5 hours. After cooling to 0° C., a solution of DCC (1.09 g; 5.3 mmoles) in DMF (3 ml) was added dropwise. The mixture was stirred for 1 hour, and the precipitated solid was filtered off and washed with ethyl acetate. The solvents were evaporated under reduced pressure from the combined filtrates. The residue was purified by a column chromatography on silica gel (ethyl acetate) to give 382 mg (yield: 42%) of 5-trifluoromethyl-5,6-dihydrouracil. m.p.: 203°-205° C. (dec.) [value reported in the literature 203°-205° C. (dec.)].
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:20][C:21]1[O:25][N:24]=[C:23]([CH2:26]OS(C)(=O)=O)[CH:22]=1>CC#N.O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:26][C:23]2[CH:22]=[C:21]([CH3:20])[O:25][N:24]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: Cc1cc(COS(C)(=O)=O)no1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)no1
Yield: 89.1 %

Procedure:
To a solution of N-BOC-piperazine (300 mg) in MeCN (5 mL) was added potassium carbonate (289 mg) followed by methanesulfonic acid 5-methyl-isoxazol-3-ylmethyl ester (369 mg). The reaction mixture was heated to reflux for 24 h. After cooling the reaction mixture was diluted with water, extracted into ethyl acetate, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(5-methyl-isoxazol-3-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (404 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]1)[CH:7]=[N:6]2.[H-].[Na+].[CH3:25]I>C1COCC1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:15][CH:16]1[CH2:21][CH2:20][CH:19]([O:22][CH3:25])[CH2:18][CH2:17]1)[CH:7]=[N:6]2
Reactant: CI
Reactant: COc1cc2ncc(O[C@H]3CC[C@H](O)CC3)nc2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncc(OC3CCC(OC)CC3)nc2cc1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
A mixture of cis/trans-4-(6,7-dimethoxy-quinoxalin-2-yloxy)-cyclohexanol (170 mg, 0.56 mmole) and NaH (60%, 22.4 mg, 0.56 mmole) in anhydrous THF/DMF (10 mL/2 mL) is stirred at 0° C. for 10 min. before addition of methyl iodide (50 μL, 0.56 mmole). After being stirred at ROOM TEMPERATURE for four hours, the reaction is quenched with water (0.5 mL) and concentrated. The aqueous layer is extracted with methylene chloride (2×20 mL) and the combined organic solutions are washed with brine (5 mL). The residue after concentration is chromatographed on silica gel (30% ethyl acetate/hexane) to give 80 mg (45%) of the desired product (m.p. 85-90° C.).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]([OH:8])[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1>>[CH3:1][N:2]1[CH2:7][CH:6]([O:8][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1
Reactant: CN1Cc2ccsc2C(O)C1
Reactant: O=[N+]([O-])c1cccc(F)c1
Product: CN1Cc2ccsc2C(Oc2cccc([N+](=O)[O-])c2)C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 14) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and 1-fluoro-3-nitro benzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[NH2:9][C@@H:10]([CH:25]([CH3:27])[CH3:26])[C:11]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12].C(N(CC)CC)C.[OH-].[Na+]>C(Cl)Cl.[Cl-].[Na+].O>[CH:25]([C@H:10]1[C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:12][C:2](=[O:3])[NH:9]1)([CH3:27])[CH3:26]
Reactant: CC(C)[C@H](N)C(O)(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@@H]1NC(=O)OC1(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 86.5 %

Procedure:
Trichloromethyl chloroformate (2.71 g, 13.7 mmol) was added to a mixture of (S)-2-amino-3-methyl-1,1-diphenyl-1-butanol (2) (3.18 g, 12.45 mmol) and triethylamine (2.68 g, 26.52 mmol) in CH2Cl2 at 0° C. The reaction mixture was stirred for 2 h at the same temperature and then poured into a brine solution (250 ml). The aqueous layer was made basic with NaOH pellets and organic products were extracted into AcOEt (5×200 ml). Combined organic extracts were dried over MgSO4 and concentrated under reduced pressure. The resulting crude product was washed with diethyl ether to obtain the title compound (3) (3.03 g, 86%) as a white solid. m.p. 250–251° C. (liti 250–251° C.). [α]D25=−201.59° (c, 0.0252 in DMSO). δH (DMSO-d6) 0.51 (3H, d, 3J=6.60 Hz, CH3), 0.92 (3H, d, 3J=7.20 Hz, CH3), 1.86 (1H, ds, 3J=2.10 and 6.60 Hz, CH—Me2), 4.46 (1H, d, 3J=6.5 Hz, CH—NH2), 7.24–7.72 (10H, m, Ar—H), 8.14 (1H, s, NH). δC 15.2 and 20.9 (CH3), 29.8 (CH), 64.9 (CH—NHCO), 88.4 (C—O), 125.8, 126.2, 127.9, 128.4, 128.8 and 129.1 (Ar), 140.5 and 146.1 (α-Ar), 158.1 (C═O). Ir 3295 (NH2), 1765 and 1745 (C═O). m/e (CI—NH3) 282 (MH+, 25%), 299 (MNH4+, 8%), 238 (96%), 223 (100%), 72 (100%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.[CH3:9][C:10]([CH3:12])=[O:11]>C(OCC)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:10]([OH:11])([CH3:12])[CH3:9])=[N:3][CH:4]=1
Reactant: Fc1ccc(Br)nc1
Reactant: CC(C)=O
Solvent: CCOCC
Product: CC(C)(O)c1ccc(F)cn1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.7 %

Procedure:
To a stirred solution of 2-bromo-5-fluoropyridine (1.0 g, 5.7 mmol) in diethyl ether (20 ml) under a nitrogen atmosphere at −78° C. was added sesBuLi (4.87 ml of a 1.4 M solution in heptanes, 6.8 mmol). The resulting dark orange solution was stirred for 30 minutes at −78° C. and acetone (0.84 ml, 11.4 mmol) was then added dropwise. After a further 1 hour the reaction temperature was raised to room temperature giving a clear yellow solution. This was quenched with water (2 ml), diluted with EtOAc (30 ml) and washed with water (2×20 ml), dried (MgSO4), filtered and concentrated. The residue was purified via silica FCC (using a gradient of eluents; 9:1 to 4:6 hexane/diethyl ether) to give the title product as colourless oil (395 mg, 45%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:13])[CH3:12]>CO>[CH2:11]([NH:13][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1)[CH3:12]
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CCN
Solvent: CO
Product: CCNc1ccc(C(N)=O)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of 6-chloropyridazine-3-carboxamide (28.5 g, 0.18 mol) in methanol (200 ml) was treated with aqueous ethylamine (70% solution, 77 ml). The reaction was heated at reflux for 31/2 hours. The reaction was allowed to cool to ambient temperature and stand overnight. The precipitate was filtered and washed with a small volume of water and dried to give 6-(ethylamino)pyridazine-3-carboxamide as pink solid (8.9 g). [The filtrates were evaporated to a small volume diluted with cold water (100 ml) and more of the desired solid was filtered-off, washed with water and dried (12.8 g). Total yield (21.7 g, 72%)].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22](O)=[O:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH2:35][CH2:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:27](=[O:34])[C@@H:28]([CH2:30][CH2:31][S:32][CH3:33])[NH2:29]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:29][C@@H:28]([C:27]([N:26]([CH3:25])[CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)=[O:34])[CH2:30][CH2:31][S:32][CH3:33])=[O:23])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:15][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CSCC[C@@H](N)C(=O)N(C)CCCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)O
Product: CSCC[C@@H](NC(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)OC(C)(C)C)C(=O)N(C)CCCc1ccccc1
Yield: 27 %

Procedure:
By the method of part A of this sample N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosine (2.59 g.) was condensed with N-methyl-N-(3-phenylpropyl)-D-methioninamide (1.4 g.). The product was crystallized twice from ethyl acetate, affording [N-(tert-butyloxycarbonyl)-O-(tert-butyl)-L-tyrosyl]-N-methyl-N-(3-phenylpropyl)-D-methioninamide (810 mg., m.r. 130°-131° C.).
Reaction SMILES: COC1C=C(OC)[CH:47]=[CH:46][C:4]=1[CH2:5][NH:6][CH:7]1[C:16]2[CH2:15][S:14][N:13]=[C:12]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:11]3=[N:32][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:34]=[C:9]([C:10]=23)[CH2:8]1.C(N(CC)CC)C.ClCCCC(Cl)=[O:64].[OH-].[Na+]>ClCCl>[NH2:17][C:12]1[C:11]2[C:10]3[C:9](=[N:34][N:33]([CH2:35][C:36]4[C:41]([CH3:42])=[C:40]([O:43][CH3:44])[C:39]([CH3:45])=[CH:38][N:37]=4)[N:32]=2)[CH2:8][CH:7]([N:6]2[CH2:47][CH2:46][CH2:4][C:5]2=[O:64])[C:16]=3[CH2:15][S:14][N:13]=1
Reactant: COc1ccc(CNC2CC3=NN(Cc4ncc(C)c(OC)c4C)N=C4C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)=NSCC2=C34)c(OC)c1
Reactant: O=C(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)cnc(CN2N=C3CC(N4CCCC4=O)C4=C3C(=N2)C(N)=NSC4)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 46 %

Procedure:
A mixture composed of di-tert-butyl {8-[(2,4-dimethoxybenzyl)amino]-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]-2,7,8,9-tetrahydro-6-thia-1,2,3,5-tetraazabenzo[cd]azulen-4-yl}imidodicarbonate of Example 42 (47 mg), triethylamine (36 μl), dichloromethane (1 ml) and 4-chlorobutyryl chloride (14 μl) was stirred at room temperature for 12 hours. A 0.1 N sodium hydroxide solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dehydrated dichloromethane (1.5 ml). 1,3-Dimethoxybenzene (16 μl) and trifluoroacetic acid (1.5 ml) was added and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and a 0.1 N sodium hydroxide solution was added to the resulting residue, followed by extraction with ethyl acetate. The organic layer was dried over sodium sulfate and filtered. Then, the filtrate was concentrated under reduced pressure. Dimethylformamide (1 ml) and potassium tert-butoxide (15 mg) were added to the resulting residue, and the mixture was stirred at room temperature for two hours. The reaction mixture was separated with water and chloroform. Then, the organic layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel thin-layer chromatography (chloroform-methanol) to obtain the title compound (13 mg, 46%) as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(CC)CC.[C:14]1([C:20](Cl)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)Cl>[C:14]1([C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: c1ccc(C(c2ccccc2)(c2ccccc2)N2CCNCC2)cc1
Reaction time: 3 h

Procedure:
Piperazine (5.0 g, 58.04 mmol) was dissolved in CHCl3 (100 ml) and Et3N (9 ml, 64.6 mmol) was added. This solution was heated to reflux and a solution of triphenylmethyl chloride (16.36 g, 58.68 mmol) in CHCl3 (100 ml) was added dropwise, via the reflux condenser, over a period of 4 hours. The reflux was then continued for 3 hours more and then was cooled and allowed to stand at room temperature overnight. A solid precipitated and was filtered off. The filtrate was evaporated to dryness to an oil which was partitioned between 10% aqueous Na2CO3 (150 ml) and CHCl3 (150 ml). The aqueous layer was washed with two additional portions of CHCl3 (2×150 ml) and the pooled organic layers were dried (MgSO4), filtered and evaporated to dryness to give a straw-colored syrup. This was purified on a silica gel 60 column (800 g) wet packed in CHCl3 and then developed with CHCl3 :MeOH (9:1) and then CHCl3 :MeOH (4:1). Fractions containing the required product were pooled and evaporated to dryness to give the title compound. Mass spec showed M+ at m/e 328. NMR (CDCl3, δ from TMS): 3.04 (br) piperazine methylenes; 7.06-7.58 (m) aromatics.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([OH:31])[C@@H:14]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=1)[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)=O)(C)(C)C.Cl>CO>[F:30][C:26]1[CH:25]=[C:24]([C@@H:14]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[CH:16]2)[C@H:13]([C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[OH:31])[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@H](O)[C@@H](c1cccc(F)c1)n1ccc2ccccc21
Agent: Cl
Solvent: CO
Product: O[C@@H]([C@@H]1CCCN1)[C@@H](c1cccc(F)c1)n1ccc2ccccc21
Yield: 15.4 %

Procedure:
(S)-2-[2-(R)-(3-Fluoro-phenyl)-1-hydroxy-2-indol-1-yl-ethyl]-(S)-pyrrolidine-1-carboxylic acid tert-butyl ester (50 mg, 0.12 mmol) was dissolved in methanol (1 mL) and a 1N ethereal solution of hydrochloric acid (0.96 mL, 0.96 mmol) was added. After 6 hours the mixture was concentrated and purified via flash column chromatography (silica, 10% methanol saturated with ammonia in chloroform) to give 6 mg (15%) (1S,2R)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethanol. The freebase was dissolved in diethyl ether (2 mL) and treated with a 1N ethereal solution of hydrochloric acid (0.02 mL, 0.02 mmol, 1 equivalent). The white precipitate was collected and dried under vacuum to give 4 mg of (1S,2R)-2-(3-fluorophenyl)-2-(1H-indol-1-yl)-1-[(2S)-pyrrolidin-2-yl]ethanol hydrochloride. HRMS: calcd for C20H21FN2O+H+, 325.17107; found (ESI, [M+H]+), 325.1712
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1.Cl.N1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>CO>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:18])[CH:17]=2)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=3[C@@H:23]2[CH2:27][CH2:26][N:25]([CH3:28])[C@H:24]2[CH2:29][OH:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c2c(=O)cc(-c3cccc(I)c3)oc2c1[C@@H]1CCN(C)[C@H]1CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CO
Product: CN1CC[C@@H](c2c(O)cc(O)c3c(=O)cc(-c4cccc(I)c4)oc23)[C@@H]1CO
Temperature: 180 °C

Procedure:
A mixture of compound of example 68 (0.4 g, 0.70 mmol) and pyridine hydrochloride (0.327 g, 2.83 mmol) was heated at 180° C. for a period of 2.5 hours. The reaction mixture was diluted with methanol (60 mL) and basified with solid Na2CO3 to pH 10. The reaction mixture was filtered, and washed with methanol. The organic layer was concentrated and the residue purified by column chromatography using 0.01% ammonia and 4.5% methanol in chloroform as eluent to afford the title compound.