Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:18])([F:17])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@H:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:44])[F:43])[CH:37]=3)[CH2:26][C:27]([NH:29][C:30]([CH3:35])([C:32]([OH:34])=O)[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=[N:56]C=2C=1.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH2:13][C@H:14]([OH:19])[C:15]([F:17])([F:18])[F:16])[C:11](=[O:20])[N:10]([CH2:21][C:22]([NH:24][C@H:25]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([C:42]([F:45])([F:43])[F:44])[CH:37]=3)[CH2:26][C:27]([NH:29][C:30]([CH3:35])([C:32]([NH2:56])=[O:34])[CH3:31])=[O:28])=[O:23])[N:9]=2)=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(NC(=O)C[C@H](NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(=O)O
Agent: N
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)C[C@H](NC(=O)Cn1nc(-c2ccc(Cl)cc2)n(C[C@H](O)C(F)(F)F)c1=O)c1cccc(C(F)(F)F)c1)C(N)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 50 mg (75 μmol) of the compound of Example 39, 29 mg (0.15 mmol) of EDC and 20 mg (0.15 mmol) of HOBt in 2 ml of DMF was stirred at RT for 20 min and then poured into 5 ml of ammonia (35% strength solution in water). The reaction mixture was stirred at RT for 30 min and then concentrated on a rotary evaporator, acidified with 2.5 N hydrochloric acid and separated by preparative HPLC [Method 6]. The appropriate fraction was concentrated on a rotary evaporator and the residue was dried under high vacuum. This gave 42 mg (84% of theory) of the title compound.
Reaction SMILES: Cl.[C:2]([NH:9][C@@H:10]([C:18]([OH:20])=O)[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([NH:28][C:18](=[O:20])[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14][C:15](=[NH:17])[NH2:16])[NH:9][C:2]([O:4][C:5]([CH3:6])([CH3:7])[CH3:8])=[O:3])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N)C(=O)O
Reactant: NCc1ccccc1
Agent: Cl
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=N)N)C(=O)NCc1ccccc1

Procedure:
N-Boc-D-Arginine hydrochloride (100 mg, 0.3 mmol) was coupled with benzylamine (40 uL, 0.4 mmol) using the mixed anhydride method described in Example 322 to give N-Boc-D-arginine benzylamide. The Boc group was removed by treatment with 4 M hydrochloric acid in dioxane for 1 h. The resulting D-arginine benzylamide was coupled to N-Boc-(N-methyl)phenylalanyl-lysyl(N-epsilon-Boc)-prolyl-{(2R)-2-amino-3-cyclohexylpropanoyl}-{(2S)-2-amino-3-cyclohexylpropanoyl}-OH, which was prepared as described in Example 322, using 1-(3-dimethyl-aminopropyl)-3-ethyl carbodiimide hydrochloride in dimethylformamide using the method described in Example 322. The crude product was deprotected with 50% trifluoroacetic acid in methylene chloride. The material thus obtained was purified by HPLC as described in Example 2 to give the title compound in 26% overall yield.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13]2[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14]2)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:13]2[C:17]=1[C:16](=[O:18])[CH2:15][CH2:14]2
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccccc2)c2c1CCC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccc(O)c2c1CCC2=O
Temperature: 15 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask was placed ethyl (2E)-3-[7-(benzyloxy)-1-oxo-2,3-dihydro-1H-inden-4-yl]prop-2-enoate (500 mg, 1.49 mmol, 1.00 equiv), ethyl acetate (10 mL), Palladium on carbon (250 mg), and hydrogen was introduced last. The resulting solution was stirred overnight at 15° C. The reaction progress was monitored by LCMS. The solids were removed by filtration, the filtrate dried over anhydrous sodium sulfate, and concentrated under reduced pressure. This resulted in 350 mg (90%) of ethyl 3-(7-hydroxy-1-oxo-2,3-dihydro-1H-inden-4-yl)propanoate as a light yellow solid. Mass spectrum (ESI, m/z): Calcd. for C14H16O4, 247.1 (M−H). found 247.1.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[N:4][CH:5]=[CH:6][N:7]=1.C1C(=O)N([Br:23])C(=O)C1>C(Cl)Cl.O>[Br:23][C:6]1[N:7]=[C:2]([Cl:1])[C:3]([NH:8][NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])=[N:4][CH:5]=1
Reactant: O=C(NNc1nccnc1Cl)C(F)(F)F
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: O=C(NNc1ncc(Br)nc1Cl)C(F)(F)F
Temperature: -40 °C
Reaction time: 1 h

Procedure:
N′-(3-chloropyrazin-2-yl)-2,2,2-trifluoroacetohydrazide E-1 (19.5 g; 81.1 mmol) is dissolved in 300 ml anhydrous DCM and cooled down to −40° C. Afterwards NBS (18.8 g; 105 mmol) is added and stirred for 1 hour. The solution is diluted with water and extracted with DCM. The organic phase is then purified with flash chromatography: cHex/(EtOAc/CH3COOH=9/1)=80%/20% to 70%/30% within 10 column volumes.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:20])[CH2:8][O:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([NH2:19])[C:15]=1[C:16]([NH2:18])=O)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:18][CH2:16][C:15]1[C:10]([O:9][CH2:8][CH:7]([OH:20])[CH2:6][NH:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:12]=[CH:13][C:14]=1[NH2:19]
Reactant: CC(C)(C)NCC(O)COc1cccc(N)c1C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)NCC(O)COc1cccc(N)c1CN

Procedure:
12 g of crude 6-(3-tert.-butylamino-2-hydroxy-propoxy)-anthranilamide are dissolved in 400 ml of tetrahydrofurane and reduced, analogously to Example 4(e), with 6.1 g of lithium aluminium hydride for 48 hours. After working up, 2-aminomethyl-3-(3-tert.-butylamino-2-hydroxy-propoxy)-aniline is obtained in the form of an oil which is further used as such. It forms a tri-hydrochloride with a melting point of 250°-260° (with sublimation).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([Mg]Br)=[CH2:10]>C1COCC1>[CH:9]([CH:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:8])=[CH2:10]
Reactant: C=C[Mg]Br
Reactant: O=Cc1ccccc1
Solvent: C1CCOC1
Product: C=CC(O)c1ccccc1
Reaction time: 12 h

Procedure:
Benzaldehyde (342 mg) was mixed with THF (4 ml) and further mixed with vinylmagnesium bromide (1 N solution) (4 mL), followed by stirring for 12 hours to obtain the title compound (320 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:12]1[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][NH2:19])[N:13]=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1>>[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[CH:29]=[C:28]([C:30]([NH:19][CH2:18][CH2:17][N:14]2[CH:15]=[CH:16][C:12]([C:4]3[CH:5]=[CH:6][C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]=3[O:2][CH3:1])=[N:13]2)=[O:31])[NH:27][N:26]=1
Reactant: COc1cc([N+](=O)[O-])ccc1-c1ccn(CCN)n1
Reactant: O=C(O)c1cc(-c2ccco2)n[nH]1
Product: COc1cc([N+](=O)[O-])ccc1-c1ccn(CCNC(=O)c2cc(-c3ccco3)n[nH]2)n1

Procedure:
The title compound was prepared from 2-(3-(2-Methoxy-4-nitrophenyl)-1H-pyrazol-1-yl)ethanamine (0.11 g) and 3-(furan-2-yl)-1H-pyrazole-5-carboxylic acid (0.079 g) using the method of Example 34(d). Yield 0.11 g. 1H-NMR (400 MHz; d6-DMSO): δ 3.71 (t, 2H), 4.01 (s, 3H), 4.39 (t, 2H), 6.57-6.68 (m, 2H), 6.85-6.89 (m, 2H), 7.76-7.93 (m, 4H), 8.15-8.22 (m, 1H), 8.53 (br s, 1H), 13.71 (br s, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)[O:14][C:12](=O)[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]1=2)=O.[OH2:23]>>[CH3:7][C:6]1[O:23][C:9]([CH3:8])=[CH:10][C:11]=1[CH:12]=[O:14]
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: O
Product: Cc1cc(C=O)c(C)o1
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
To a solution of (2,5-dimethylfuran-3-yl)methanol (3.8 g) obtained by the above-mentioned reaction in methylene chloride (30 mL) was added a Dess-Martin reagent (15.3 g) at 0° C., and the mixture was stirred at 0° C. for 3 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (0% ethyl acetate/hexane to 20% ethyl acetate/hexane) to give the title compound (2.1 g, 56%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1cc(C(=O)O)ccc1Cl
Solvent: CO
Product: COC(=O)c1ccc(Cl)c(OC)c1

Procedure:
4-chloro-3-methoxybenzoic acid (4.5 g) and 0.5 g of PTSA in 100 mL of dry methanol was refluxed for 3 hours. Evaporation and redissoving in ethyl acetate followed by washing with sodium bicarbonate, and concentration, gave methyl 4-chloro-3-methoxybenzoate without purification.
Reaction SMILES: C(Cl)CCl.[C:5]([O:9][C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[CH2:12][C:13]([OH:15])=[O:14])([CH3:8])([CH3:7])[CH3:6].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:29][C:30](=[O:65])/[C:31](/[CH3:64])=[CH:32]/[C@:33]34[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]3[C@@H:35]3[C@@:48]([CH3:51])([CH2:49][CH2:50]4)[C@@:47]4([CH3:52])[C@@H:38]([C@:39]5([CH3:56])[C@@H:44]([CH2:45][CH2:46]4)[C:43]([CH3:54])([CH3:53])[C@@H:42](O)[CH2:41][CH2:40]5)[CH2:37][CH2:36]3)[CH2:28][CH2:27]2)=[CH:22][CH:21]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:16][C:11]([CH3:17])([CH2:12][C:13]([O:15][C@H:42]1[CH2:41][CH2:40][C@@:39]2([CH3:56])[C@@H:44]([CH2:45][CH2:46][C@:47]3([CH3:52])[C@@H:38]2[CH2:37][CH2:36][C@H:35]2[C@@:48]3([CH3:51])[CH2:49][CH2:50][C@@:33]3(/[CH:32]=[C:31](\[CH3:64])/[C:30]([NH:29][C:26]4([C:23]5[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=5)[CH2:27][CH2:28]4)=[O:65])[CH2:59][C:58](=[O:60])[C:57]([CH:61]([CH3:63])[CH3:62])=[C:34]32)[C:43]1([CH3:53])[CH3:54])=[O:14])[C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:18]
Reactant: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)C(C)(C)CC(=O)O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: C/C(=C\[C@@]12CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@]43C)C1=C(C(C)C)C(=O)C2)C(=O)NC1(c2ccc(Cl)cc2)CC1
Temperature: 20 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
To a solution of DMAP (415 mg, 3.40 mmol), EDC (652 mg, 3.40 mmol) and 4-tert-butoxy-3,3-dimethyl-4-oxobutanoic acid (425 mg, 2.039 mmol) in DCM (10 mL) stirred at 20° C. for 30 min was added (E)-N-(1-(4-chlorophenyl)cyclopropyl)-3-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-9-hydroxy-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-3a-yl)-2-methylacrylamide (650 mg, 0.680 mmol). The reaction mixture was stirred at 20° C. for 2 h. The mixture was washed with saturated ammonium chloride, water, and saturated NaHCO3, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column eluting with petroleum ether/Ethyl acetate (3:1) to afford 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-((1-(4-chlorophenyl)cyclopropyl)amino)-2-methyl-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (300 mg, 52%) as a light yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=7.30-7.22 (m, 2H), 7.22-7.14 (m, 2H), 6.59 (s, 1H), 6.32 (s, 1H), 4.51 (dd, J=5.4, 10.9 Hz, 1H), 3.28-3.10 (m, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.55 (s, 3H), 2.41-2.21 (m, 2H), 2.12-0.71 (m, 61H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]#[N:13])=[CH:4][CH:3]=1.C[Al](C)C.[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C@@:26]([OH:52])([CH2:46][N:47]1[CH:51]=[N:50][CH:49]=[N:48]1)[C@H:27]([S:29][C@@H:30]1[CH2:35][O:34][C@@H:33]([C:36]2[CH:45]=[CH:44][C:39]([C:40](OC)=[O:41])=[CH:38][CH:37]=2)[O:32][CH2:31]1)[CH3:28]>>[C:12]([C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:44]=[CH:45][C:36]([C@H:33]3[O:32][CH2:31][C@H:30]([S:29][C@H:27]([CH3:28])[C@:26]([C:20]4[CH:21]=[CH:22][C:23]([F:25])=[CH:24][C:19]=4[F:18])([OH:52])[CH2:46][N:47]4[CH:51]=[N:50][CH:49]=[N:48]4)[CH2:35][O:34]3)=[CH:37][CH:38]=2)=[CH:3][CH:4]=1)#[N:13]
Reactant: COC(=O)c1ccc([C@H]2OC[C@H](S[C@H](C)[C@](O)(Cn3cncn3)c3ccc(F)cc3F)CO2)cc1
Reactant: N#Cc1ccc(N)c2ccccc12
Agent: C[Al](C)C
Product: C[C@@H](S[C@H]1CO[C@H](c2ccc(C(=O)Nc3ccc(C#N)c4ccccc34)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F

Procedure:
In the same manner as that described in Example 3(4), a reaction was carried out using commercially available 4-amino-1-naphthalenecarbonitrile (200 mg, 1.2 mmol), trimethylaluminium (1.1 ml, 1.07M n-hexane solution, 1.2 mmol) and methyl 4-[trans-5-[[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]thio]-1,3-dioxan-2-yl]benzoate (150 mg, 0.30 mmol), obtained in Example 12(1), and the reaction mixture was treated using a similar procedure to that described in Example 3(4) to afford the title compound (73 mg, yield 38%) as a pale yellow oil which was recrystallized from ethyl acetate-hexane to give white powdery crystals.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:21]([C:22]([OH:24])=O)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:28][CH:27]=4)[CH2:15][N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:75][O:76][C:77](=[O:95])[C@@H:78]([NH2:94])[CH2:79][C:80]1[CH:85]=[CH:84][C:83]([C:86]2[CH:91]=[CH:90][C:89]([C:92]#[N:93])=[CH:88][CH:87]=2)=[CH:82][CH:81]=1>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH:21]([C:22](=[O:24])[NH:94][C@H:78]([C:77]([O:76][CH3:75])=[O:95])[CH2:79][C:80]2[CH:81]=[CH:82][C:83]([C:86]3[CH:91]=[CH:90][C:89]([C:92]#[N:93])=[CH:88][CH:87]=3)=[CH:84][CH:85]=2)[CH2:20][C:19]2[CH:18]=[C:17]3[C:12]([O:13][C@@H:14]([C:26]4[CH:27]=[CH:28][C:29]([O:32][CH2:33][C:34]5[CH:39]=[CH:38][C:37]([Cl:40])=[C:36]([Cl:41])[CH:35]=5)=[CH:30][CH:31]=4)[CH2:15][N:16]3[CH3:25])=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1C[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(C#N)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(C#N)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CN3C

Procedure:
To a stirring solution of (S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-1-methyl-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester, HBTU (95 mg) and DIEA in DMF (5 mL) was added (S)-2-amino-3-(4′-cyano-biphenyl-4-yl)-propionic acid methyl ester (79 mg). After 4 hours a sufficient amount of water was added and the mixture was extracted with ethyl acetate. The organic was washed with 1 N HCl, saturated NaHCO3 and brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to provide the crude amide. The residue was purified by column chromatography on silica gel (hexanes/ethyl acetate from 80:20 to 60:40) to afford the product (180 mg).
Reaction SMILES: [C:1]([C:4]1[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[CH:6][N:5]=1)([OH:3])=[O:2].[C:12](=O)([O-])O.[Na+].CI.CN(C)C=O>C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:12][O:2][C:1]([C:4]1[C:9]([Cl:10])=[N:8][C:7]([Cl:11])=[CH:6][N:5]=1)=[O:3]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ncc(Cl)nc1Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 2-carboxy-3,5-dichloropyrazine (prepared in the above (1)) 226 mg, sodium hydrogen carbonate 118 mg, methyl iodide 0.5 ml and dimethylformamide 1.8 ml is stirred at room temperature for 14 hours. The mixture is diluted with a 10% aqueous citric acid solution and extracted with ethyl acetate. The combined organic layer is washed with water and an aqueous saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to give 2-methoxycarbonyl-3,5-dichloropyrazine as a pale brown crystalline powder 245 mg. mp 60–63° C., MS(m/z): 206(M+)
Reaction SMILES: [N+](=[CH:3][C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:5])=[N-].S(=O)(=O)(O)[OH:32]>O1CCOCC1.O>[C:4]([CH:6]([CH2:18][CH2:19][CH2:20][CH:21]([O:27][C:28](=[O:30])[CH3:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])(=[O:5])[CH2:3][OH:32]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)C=[N+]=[N-])OC(C)=O
Reactant: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)CO)OC(C)=O
Yield: 96 %

Procedure:
A clear, yellow solution of ethyl 8-diazoacetyl-12-acetoxyheptadecanoate (8.4 g., 0.02 mole) in dioxane (50 ml.) is vigorously stirred at 20° and treated with 2N sulfuric acid (30 ml.) added dropwise over 5 minutes. The resulting turbid solution is warmed to and maintained at 65° for 30 minutes. The reaction solution is cooled to 20°, diluted with water to a total volume of one liter and extracted with ether (5 × 200 ml.). The organic extract is washed with water (2 × 200 ml.), 5% aqueous sodium bicarbonate (200 ml.), water (200 ml.), and saturated brine (2 × 200 ml.), dried over sodium sulfate and filtered. Evaporation (in vacuo at 40°-65°) of the filtrate gives the title compound as a deep yellow oil (7.9 g., 96%), pmr (CDCl3) δ0.86 (3H,t), 1.28 (27H,e), 2.0 (3H,s), 2.25 (3H,t), 3.36 (H,b), 4.10 (2H,q), 4.21 (2H,s) and 4.84 (H,b).
Reaction SMILES: [CH2:1]([Zn]CC)C.[CH:6]([O:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][CH2:15][C:16]([CH3:34])=[CH:17][CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])=[CH2:7].ICI>CCOCC>[CH:6]1([O:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:35])=[CH:13][CH2:14][CH2:15][C:16]([CH3:34])=[CH:17][CH2:18][CH2:19][CH:20]=[C:21]([CH3:33])[CH2:22][CH2:23][CH:24]=[C:25]([CH3:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[CH2:1][CH2:7]1
Reactant: CC[Zn]CC
Reactant: C=COCCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C
Solvent: CCOCC
Solvent: ICI
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCCOC1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diethyl zinc (0.606 ml, 1.0 M in hexane) was added to 4,8,13,17,21-pentamethyl-4,8,12,16,20-docosapentaen-1-ol vinyl ether (0.250 g, 0.606 mmol) in 6 ml ether under argon. Diiodomethane (0.240 g, 0.606 mmol, 73.3 μl), in 2 ml ether, was added dropwise over 0.5 hour. After stirring overnight at room temperature, the reaction was quenched with saturated ammonium chloride. An additional 40 ml of ether and 20 ml of saturated ammonium chloride were added and the layers separated. The ether layer was washed with brine and dried over magnesium sulfate. Removal of the solvent in vacuo yielded 0.32 g of crude product, which wasshown to be a 3:1 mixture by capillary gas chromatography of 4,8,13,17,21-pentamethyl-4,8,12,16,20-docosapentane-1-ol cyclopropyl etherand a dicyclopropyl compound.
Reaction SMILES: N1C=CC=C(C[O:8][C:9]2[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]([CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[N:10]=2)C=1>[Pd].O1CCCC1>[OH:8][C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][N:11]([CH2:19][C:20]2[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=2)[N:10]=1
Reactant: CCOC(=O)c1cn(Cc2cccnc2)nc1OCc1cccnc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(Cc2cccnc2)nc1O
Yield: 74.4 %

Procedure:
Ethyl 3-(pyridin-3-ylmethoxy)-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate (1.14 g), 5% palladium on carbon (1.0 g) and tetrahydrofuran (100 mL) were stirred under a hydrogen atmosphere to perform catalytic reduction. After removing palladium on carbon by filtration, the filtrate was concentrated to give ethyl 3-hydroxy-1-(pyridin-3-ylmethyl)-1H-pyrazole-4-carboxylate as colorless crystals (0.62 g, yield 74%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 148-149° C.
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[CH2:5][CH2:6][CH3:7])#[N:2].[C:11]([C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([CH3:24])([CH3:23])[C@@H:19]([OH:22])[C@H:20]([NH2:21])[C:15]=2[CH:14]=1)#[N:12]>C(OCC)(=O)C>[C:11]([C:13]1[CH:26]=[CH:25][C:16]2[O:17][C:18]([CH3:24])([CH3:23])[C@@H:19]([OH:22])[C@H:20]([NH:21][C:4](=[N:3][C:1]#[N:2])[CH2:5][CH2:6][CH3:7])[C:15]=2[CH:14]=1)#[N:12]
Reactant: CCCC(=NC#N)OCC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCOC(C)=O
Product: CCCC(=NC#N)N[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1O
Reaction time: 2 h

Procedure:
To 3.09 g of ethyl N-cyanobutyrimidate, 4.38 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added, and the mixture was reacted under stirring at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed twice with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was purified by silica gel column chromatography to obtain 3.54 g of the above identified compound in the form of crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([F:17])[C:9]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:10]([F:17])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[F:7])[CH:6]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)c(F)c1
Reactant: Clc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Temperature: 50 °C
Reaction time: 16 h
Yield: 80.3 %

Procedure:
Step J (1): A mixture of 4-chloro-1H-imidazole (1.18 g, 11.5 mmol), 1,2,3-trifluoro-5-nitrobenzene (1.7 g, 9.60 mmol) and potassium carbonate (1.86 g, 13.4 mmol) in DMF (10 mL) was heated at 50° C. for 2 h. The reaction mixture was allowed to cool to rt and was stirred for 16 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (50% EtOAc/hexane) to afford 4-chloro-1-(2,6-difluoro-4-nitrophenyl)-1H-imidazole (2.0 g, 80% yield). LC-MS (M+H)+=260.1. 1H NMR (500 MHz, chloroform-d) δ ppm 8.03-8.10 (m, 2 H) 7.71 (q, J=1.83 Hz, 1 H) 7.19 (q, J=1.93 Hz, 1 H).