Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:25][C:21]1[C:13]2[N:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:10]([C@@H:8]([NH2:7])[CH3:9])=[N:11][C:12]=2[CH:24]=[CH:23][CH:22]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(F)c2n1-c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)c1nc2cccc(F)c2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of [(S)-1-(7-fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethyl]carbamic acid tertbutyl ester (625 mg) in DCM (3 mL) was added TFA (3 mL) and the resulting mixture was stirred at RT for 3 h. The crude reaction mixture was loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording (S)-1-(7-Fluoro-1-phenyl-1H-benzoimidazol-2-yl)ethylamine as a pale orange oil (372 mg, 83%). LCMS: RT 1.97 and 2.11 min [M+H]+ 255.9.
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][C@@H:30]([CH3:33])[CH2:31][OH:32].O>CO>[OH:32][CH2:31][C@@H:30]([NH:29][C:3]([C:4]1[CH:5]=[CH:6][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:8][CH:9]=1)=[O:28])[CH3:33]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Reactant: C[C@H](N)CO
Solvent: CO
Solvent: O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)N[C@@H](C)CO)cc2)CC1
Temperature: 20 °C
Reaction time: 1 h
Yield: 82.9 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.8 g) and (S)-(+)-2-amino-1-propanol (0.71 g) were dissolved in methanol (30 ml) and heated to reflux for 12 hours. The reaction mixture was cooled and with the slow addition of excess of water at 40° C. to precipitate the crystals, the mixture was cooled again and stirred at 20° C. for 1 hour. Following with filtration and washing with water, the filtered solid was recrystallized using isopropanol and ether, filtered and dried to give 1.66 g (yield: 83%) of the desired compound.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:8]([O:10]C(C)(C)C)=[O:9])[CH2:3][CH2:4][C:5](=[O:7])O.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:56][C:57]1[CH:58]=[C:59]([P:63](=[O:66])([OH:65])[OH:64])[CH:60]=[CH:61][CH:62]=1>CN(C=O)C.C(N(CC)CC)C>[P:63]([C:59]1[CH:58]=[C:57]([NH:56][C:5](=[O:7])[CH2:4][CH2:3][C@@H:2]([C:8]([OH:10])=[O:9])[NH2:1])[CH:62]=[CH:61][CH:60]=1)([OH:66])([OH:65])=[O:64]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Nc1cccc(P(=O)(O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N[C@@H](CCC(=O)Nc1cccc(P(=O)(O)O)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OtBu (236 mg, 0.78 mmol), HOAt (127 mg, 0.936 mmol) and HATU (356 mg, 0.936 mmol) were dissolved in 1 mL of DMF, and triethylamine (0.21 ml) was added thereto. 10 minutes later, the crude product of (3-aminophenyl)phosphonic acid was added thereto and stirred at room temperature overnight. After removing a solvent, purification was conducted in accordance with the purification process A to obtain a title compound.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]2[N:34]=[C:35]([CH:37]=O)[N:36]=[C:29]2[N:28]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[C:18]([F:25])[CH:17]=3)[O:11][C:10](=[O:12])[C:9]([CH2:37][C:35]3[N:36]=[C:29]4[N:28]=[C:27]([CH3:26])[CH:32]=[C:31]([CH3:33])[N:30]4[N:34]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Reactant: CCOc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Product: CCOc1ccc(CCC2(C3CCCC3)CC(O)=C(Cc3nc4nc(C)cc(C)n4n3)C(=O)O2)cc1F

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-[2-(4-ethoxy-3-fluoro-phenyl)-ethyl]-dihydro-pyran-2,4-dione from Step 1 to 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31). 1H NMR (DMSO-d6): d 1.33 (t, 3H, J=7.0 Hz), 1.39-1.71 (br m, 8H), 2.11 (m, 2H), 2.40-2.58 (m, 10H), 2.78 (d, 1H, J=17.5 Hz), 3.72 (d, 1H, J=16.1 Hz), 3.84 (d, 1H, J=16.1 Hz), 4.06 (q, 2H, J=7.0 Hz), 7.05 (m, 4H), 10.90 (s, 1H). Anal. Calcd. For C28H33N4O4F.0.4AcOH: C, 64.94; H, 6.55; N, 10.52. Found: C, 65.05; H, 6.53; N, 10.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].[F:15][CH:16]1[C@H:20]([O:21][CH3:22])[CH2:19][NH:18][CH2:17]1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:18]3[CH2:19][C@@H:20]([O:21][CH3:22])[CH:16]([F:15])[CH2:17]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CO[C@@H]1CNCC1F
Agent: [Li+]
Product: CO[C@@H]1CN(C(=O)c2cc3nccc(Cl)c3s2)CC1F

Procedure:
This material was prepared by the coupling of lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate and (4R)-3-fluoro-4-methoxypyrrolidine in a manner as previously described for Example 1(a), step (iv). 1H NMR (CD3OD) δ 8.57 (1H, d, J=5.1 Hz), 7.94 (1H, d, J=7.2 Hz), 7.48 (1H, d, J=5.1 Hz), 5.27-5.05 (1H, m), 4.18-3.93 (4H, m), 3.78-3.75 (1H, m), 3.35 (3H, d, J=14.1 Hz). ESIMS (MH+): 315.05
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[CH:16][CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:24](Cl)(=[O:28])[CH:25]([CH3:27])[CH3:26]>>[C:24]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:13]=[N:14][C:15]([O:18][CH2:19][C:20]([F:22])([F:23])[F:21])=[CH:16][CH:17]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:28])[CH:25]([CH3:27])[CH3:26]
Reactant: Nc1nccc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)n1
Reactant: CC(C)C(=O)Cl
Product: CC(C)C(=O)Nc1nccc(C(=O)NCc2ccc(OCC(F)(F)F)nc2)n1

Procedure:
The title compound is prepared from 2-amino-N-((6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)pyrimidine-4-carboxamide (17 mg, 0.05 mmol, Step-1) and isobutyryl chloride (17 mg, 0.16 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:9]2[C:18]3[N:19]=[CH:20][NH:21][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:31]([O:33][CH2:34]Cl)[CH3:32]>O1CCCC1.C(OCC)C>[C:23]1([CH2:22][N:8]([CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:9]2[C:18]3[N:19]=[CH:20][N:21]([CH2:34][O:33][CH2:31][CH3:32])[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: c1ccc(CN(Cc2ccccc2)c2nc3ccccc3c3[nH]cnc23)cc1
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOCn1cnc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of N,N-bis(phenylmethyl)-1H-imidazo[4,5-c]quinolin-4-amine (2 g, 5.49 mmole) in tetrahydrofuran (10 mL) was added to a suspension of sodium hydride (0.21 g, 6.58 mmole) in tetrahydrofuran (25 mL). After 30 minutes chloromethyl ethyl ether (0.61 mL, 6.58 mmole) was added and the reaction mixture was stirred for 2 hours. The reaction mixture was diluted with diethyl ether, washed with water, dried over magnesium sulfate, and then concentrated under vacuum to provide crude product as a brown oil. The oil was purified by column chromatography (silica gel eluting with 20-30% ethyl acetate in hexanes v/v) to provide 1.77 g of N,N-bis(phenylmethyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine as a white/tan solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([O:14]C(=O)C)(=[O:13])[CH3:12].C([O-])(=O)C.[Na+]>C(O)(=O)C>[C:11]([O:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CBr)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 2-bromoacetophenone (199 g, 1.0M), acetic acid (200 mL) and acetic anhydride (30 mL) was stirred and heated to about 60° C. Anhydrous sodium acetate (100 g, 1.2M) was added and the reaction mixture was heated and stirred at about 130° C. for 6.0 hrs and then allowed to cool. To remove most of the salt, the reaction mixture was filtered through a sintered glass funnel. The acetic acid and acetic anhydride were removed from the filtrate using a rotary evaporator. A white solid was obtained upon cooling (yield--97.0 g). Mass spectroscopy supported the proposed structure.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:19])[C:12]2[S:16][C:15]([NH2:17])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([N:22]=[C:23]=[O:24])[CH3:21]>O1CCOCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Br:19])[C:12]2[S:16][C:15]([NH:17][C:23]([NH:22][CH2:20][CH3:21])=[O:24])=[N:14][C:13]=2[CH:18]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)Nc1nc2cc(OCc3ccccc3)cc(Br)c2s1
Temperature: 82.5 °C
Yield: 75.4 %

Procedure:
To a suspension of vii (216 g, 0.64 mol) in 1,4-dioxane (4 L) was added ethylisocyanate (380 mL, 4.81 mol). The mixture was heated up to 80-85° C. overnight. The solvent was distilled off and the residue was co-evaporated with hexane. The residue was treated with H2O at 78-80° C. for 3-5 h. The resulting solid was filtered off and washed with hot H2O, dried under high vacuum to obtain viii (196 g, 75%). 1H-NMR (DMSO-d6, 400 MHz): δ 1.08 (t, J=7.20 Hz, 3H), 3.18 (q, J=6.80 Hz, 2H), 5.17 (s, 2H), 6.71 (br s, 1H), 7.15 (d, J=2.0 Hz, 1H), 7.26 (br s, 1H), 7.31-7.47 (m, 5H) and 10.82 (br s, 1H). MS: 405.90 [M+H]+.
Reaction SMILES: [C:1]12([NH:11][C:12]3[NH:16][C:15]4[CH:17]=[C:18]([CH2:21][O:22][Si](C(C)C)(C(C)C)C(C)C)[CH:19]=[CH:20][C:14]=4[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.F[C:34]1[CH:63]=[CH:62][C:37]([C:38](/N=C2\NC3C=CC(CO)=CC=3N\2[C@@H]2CC[C@H](C(OC)=O)CC2)=[O:39])=[CH:36][CH:35]=1>>[C:1]12([N:11]3[C:15]4[CH:17]=[C:18]([CH2:21][OH:22])[CH:19]=[CH:20][C:14]=4[N:13]=[C:12]3[NH:16][C:38](=[O:39])[C:37]3[CH:62]=[CH:63][CH:34]=[CH:35][CH:36]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)[Si](OCc1ccc2nc(NC34CC5CC(CC(C5)C3)C4)[nH]c2c1)(C(C)C)C(C)C
Reactant: COC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Product: O=C(Nc1nc2ccc(CO)cc2n1C12CC3CC(CC(C3)C1)C2)c1ccccc1

Procedure:
The title compound was prepared in 2 steps from N-1-adamantyl-6-((triisopropylsilyloxy)methyl)-1H-benzo[d]imidazol-2-amine using a method analogous to the preparation of cis-methyl 4-((E)-2-(4-fluorobenzoylimino)-6-(hydroxymethyl)-2,3-dihydro-1H-benzo[d]imidazol-1-yl)cyclohexanecarboxylate. The yield was 200 mg (37.7%, 2 steps). MS m/z=402.2 [M+H]. Calc'd for C25H27N3O2: 401.2.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:13]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:13][C:9]1[C:10]([I:12])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccc(I)cc1O
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(I)cc1O
Temperature: 100 °C

Procedure:
A mixture of methyl 2-hydroxy-4-iodobenzoate (10.0 g, 36.0 mmol, from Aldrich) and N-chlorosuccinimide (5.76 g, 43.2 mmol) in acetic acid (40 mL) was heated at 100° C. for 1 hour and then cooled to room temperature overnight. The precipitate was collected by filtration and washed with ethyl acetate and then air dried to give the desired product. In addition, the filtrate was concentrated to dryness and partitioned between water and ethyl acetate. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated to dryness. The residue was purified on silica gel, eluting with 0 to 20% ethyl acetate in hexane, to give additional desired product (total 9.03 g, 82%). LCMS calculated for C8H7ClIO3 (M+H)+: m/z=312.9; Found: 313.0.
Reaction SMILES: C[O-].[Na+].[SH:4][C:5]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13](=[O:21])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:22])[CH:11]=2)[N:6]=1.Cl.Cl[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1>CO>[CH3:22][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[N:6]=[C:5]([S:4][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=1)[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:13]2=[O:21]
Reactant: ClCc1ccccn1
Reactant: Cc1ccc2nc(S)n(-c3ccccc3)c(=O)c2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(SCc3ccccn3)n(-c3ccccc3)c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.3 %

Procedure:
9.5 ml of 28% methanolic solution of sodium methoxide were added to a solution of 6.0 g of 2-mercapto-6-methyl-3- phenyl-4(3H)-quinazolinone and 4.0 g of 2-chloromethylpyridine hydrochloride in methanol, the mixture was stirred at room temperature for 2 hours and allowed to stand overnight. Crystals precipitated were collected by filtration and recrystallized from ethyl acetate to give 4.2 g (52.2%) of the title compound.
Reaction SMILES: Br[CH:2]([C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])[CH:3]=O.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[C:26]([C:27](=[O:29])[CH3:28])=[C:25]([CH3:30])[NH:24][C:23](=[S:31])[NH:22]2)=[CH:17][CH:16]=1>O1CCCC1>[Cl:12][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:5]=1[C:2]1[S:31][C:23]2=[N:24][C:25]([CH3:30])=[C:26]([C:27](=[O:29])[CH3:28])[CH:21]([C:18]3[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:20][CH:19]=3)[N:22]2[CH:3]=1
Reactant: COc1ccc(C2NC(=S)NC(C)=C2C(C)=O)cc1
Reactant: O=CC(Br)c1c(Cl)cccc1Cl
Solvent: C1CCOC1
Product: COc1ccc(C2C(C(C)=O)=C(C)N=C3SC(c4c(Cl)cccc4Cl)=CN32)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 67.9 %

Procedure:
A mixture of 1.9 g (7.09 mmol) of α-bromo-2,6-dichlorophenyl-acetaldehyde and 1.78 g (6.45 mmol) of (RS)-1-[4-(4-methoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]ethanone in 50 ml of tetra- hydrofuran was stirred at RT for 65 h. Subsequently, the mixture was cooled to 0° C. and the precipitated solid was filtered off, dissolved in 75 ml of conc. acetic acid and heated at reflux while stirring for 8 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (dichloromethane/methanol 95:5). There were obtained 1.95 g (68%) of (RS)-1-[2-(2,6-dichlorophenyl)-5-(4-methoxyphenyl)-7-methyl-5H-thiazolo[3,2-a]pyrimidin-6-yl]ethanone as a yellow foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O.[CH:18]1([C:23](=O)[CH2:24][C:25]#[N:26])[CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:23]2[C:24]([C:25]#[N:26])=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]3[C:2](=[CH:7][C:6]([O:8][CH3:9])=[CH:5][CH:4]=3)[N:1]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: N#CCC(=O)C1CCCC1
Reactant: COc1ccc(C(=O)c2ccccc2)c(N)c1
Product: COc1ccc2c(-c3ccccc3)c(C#N)c(C3CCCC3)nc2c1

Procedure:
The title compound was prepared in analogy to example 101 step B from (2-amino-4-methoxy-phenyl)-phenyl-methanone (prepared as described in example 121 step A) and 3-cyclopentyl-3-oxo-propionitrile (prepared as described in example 105 step A). White solid. MS (ESI): 329.4 (M+H)+.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[CH:11][NH:12][CH:13]=1)=O)C.[H-].[Na+].[CH3:16][Si:17](Cl)([CH3:19])[CH3:18]>O1CCCC1>[CH:4]([CH2:6][CH2:7][CH2:8][C:9]1[N:10]=[CH:11][N:12]([Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:13]=1)=[O:3]
Reactant: CCOC(=O)CCCc1c[nH]cn1
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)n1cnc(CCCC=O)c1
Reaction time: 0.08 h

Procedure:
A solution of 1.82 g of 4-(3-ethoxycarbonylpropyl)-1H-imidazole in 30 ml of tetrahydrofuran under nitrogen is treated with 0.5 g of sodium hydride (50% oil dispersion) at 0° for 30 minutes and 1.45 ml of trimethylsilyl chloride at 0° for 3 hours. The reaction mixture is washed with cold 0.5N sodium bicarbonate solution, dried over sodium sulfate and evaporated to dryness. The oil is redissolved in 100 ml of methylene chloride at -78° under nitrogen and 12.82 ml of diisobutyl-aluminum hydride (1.56M) is added dropwise. The reaction mixture is stirred for 5 minutes at -78°, quenched with 1 ml of methanol followed by 10 ml of water and filtered through Celite®. The organic phase is separated, dried over sodium sulfate and evaporated to yield the title compound (a).
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.O=C1CCC(=O)N1[O:25][C:26](=O)[CH2:27][CH:28]([C:34](=[O:56])[NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH2:2]([O:9][NH:10][C:26](=[O:25])[CH2:27][CH:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:34]([NH:35][CH:36]([C:40]([N:42]1[CH2:46][CH2:45][CH2:44][CH:43]1[CH2:47][O:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:56])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: CCCCCC(CC(=O)ON1C(=O)CCC1=O)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCCC(CC(=O)NOCc1ccccc1)C(=O)NC(C(=O)N1CCCC1COCc1ccccc1)C(C)C

Procedure:
The coupling of fragment A and B is comprised of the following steps: (a) a solution of 14 in dimethylformide or any suitable solvent is treated with triethylamine followed by a solution of 8 in dimethylformamide or any suitable solvent to yield 3-(1-(2-(S)-benzyloxymethylpyrrolidine-1-carbonyl)-2-(S)-methylpropyl-carbamoyl)-octanoic acid tert-butyl ester 15; (b) treatment of 15 in dichloromethane with trifluoroacetic acid to yield 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl carbamoyl)-octanoic acid 16; (c) treatment of a solution 16 and hydroxysuccinamide 7 with dicyclohexylcarbodiimide or any suitable imide to afford 3-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methylpropylcarbamoyl)-octanoic acid 2,5-dioxo-pyrrolidin-1-yl ester 17; (d) fragment C is introduced by treatment of a suspension of O-benzylhydroxyamine hydrochloride 18 in dimethylformamide with triethylamine followed by a solution of 17 in dimethylformamide to afford N4-benzyloxy-N 1-(1-(2-benzyloxymethyl-pyrrolidine-1-carbonyl)-2-methyl-propyl)-2-pentyl-succinamide 19. (f) hydrogenating 19 with hydrogen gas and palladium hydroxide in activated carbon wherein actinonin 1 is thereby formed (Scheme 4, FIG. 3C).
Reaction SMILES: [C:1]([NH:4][C:5]1[NH:10][C:9](=[O:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[CH3:21][C:22]([O:24][CH2:25][C@H:26]1[O:31][C@H:30](Br)[C@H:29]([O:33][C:34]([CH3:36])=[O:35])[C@@H:28]([O:37][C:38]([CH3:40])=[O:39])[C@@H:27]1[O:41][C:42]([CH3:44])=[O:43])=[O:23]>ClCCl.C(=O)([O-])[O-].[Ag+2]>[C:1]([NH:4][C:5]1[N:10]=[C:9]([O:11][C@@H:30]2[O:31][C@H:26]([CH2:25][O:24][C:22](=[O:23])[CH3:21])[C@@H:27]([O:41][C:42](=[O:43])[CH3:44])[C@H:28]([O:37][C:38](=[O:39])[CH3:40])[C@H:29]2[O:33][C:34](=[O:35])[CH3:36])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCc1ccc(Cc2ccc(NC(C)=O)[nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCc1ccc(Cc2ccc(NC(C)=O)nc2O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc1
Reaction time: 3 h
Yield: 107.2 %

Procedure:
To a solution of 6-(N-acetylamino)-3-(4-ethylbenzyl)-1H-pyridin-2-one (0.034 g) in dichloromethane (2.5 mL) were added acetobromo-α-D-glucose (0.10 g) and silver carbonate (0.17 g), and the mixture was stirred under shading for 3 hours at 50° C. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/2) to give 6-(N-acetylamino)-2-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyloxy)-3-(4-ethylbenzyl)pyridine (0.081 g).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]3[C:7](=[CH:18][NH:19][CH:20]=3)[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.CC(C)([O-])C.[K+].Cl[C:30]([O:32][CH3:33])=[O:31]>CN(C)C=O.O>[CH3:33][O:32][C:30]([N:19]1[CH:20]=[C:6]2[C:7]([CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]3[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=32)=[CH:18]1)=[O:31]
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1c[nH]cc1-2
Reactant: COC(=O)Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)n1cc2c(c1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Reaction time: 0.25 h

Procedure:
In one portion 6.0 g (18.3 mmol) of 8-chloro-6-(2-chlorophenyl)-2H,4H-pyrrolo[3,4-d][2]benzazepine was added to a solution of 3.0 g (26.5 mmol) of potassium t-butoxide in 50 ml of dimethylformamide which was cooled to 0°. When solution was complete 1.8 ml (2.3 g; 24.5 mmol) of methyl chloroformate was added and the resulting mixture was stirred for 15 min. The mixture was diluted with 150 ml of water and the resulting precipitate was collected by filtration. The precipitate was dissolved in methylene chloride and washed with water. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue crystallized from ether to give an off-white solid. Recrystallization from a mixture of methylene chloride and ether gave off-white fine needles, mp 185°-186° (dec.).
Reaction SMILES: [CH3:1][C:2]12[CH:9](Br)[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2.[C:12]([O-:15])(=[O:14])[CH3:13].[Na+]>C(O)(=O)C.[Cu]Cl>[CH3:1][C:2]12[CH:9]([O:15][C:12](=[O:14])[CH3:13])[C:6]([CH3:11])([CH2:7][CH2:8]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CC(=O)[O-]
Reactant: CC12CCCC(C)(CC1)C2Br
Agent: Cl[Cu]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)OC1C2(C)CCCC1(C)CC2

Procedure:
5 g of 1,5-dimethyl-8-bromobicyclo[3,2,1]octane was boiled under reflux for 18 hours in acetic acid in the presence of sodium acetate and copper(I) chloride. The reaction mixture was cooled and filtered, diluted with water and extracted with pentane. The pentane solution was washed with water and an aqueous sodium bicarbonate solution, dired, evaporated and fractionally distilled. 1,5-dimethyl-8-acetoxy-bicyclo[3,2,1]octane was obtained in good yield. 1,5-dimethyl-8-acetoxybicyclo[3,2,1]octane was also obtained in a similar manner starting from the 8-iodo compound described in Example 3.
Reaction SMILES: Cl.[Br:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[N+:13]([O-])=O)[CH:6]=[N:5][CH:4]=1.O.O.Cl[Sn]Cl>C(O)C>[NH2:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[C:3]([Br:2])=[CH:4][N:5]=[CH:6]2
Reactant: O=[N+]([O-])c1cccc2cncc(Br)c12
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: Nc1cccc2cncc(Br)c12
Reaction time: 3 h

Procedure:
100 ml of concentrated hydrochloric acid are added to a suspension of 16 g of the compound obtained in Step 1 in 55 ml of ethanol. The mixture is cooled with ice and stirred whilst a solution of 62.6 g of SnCl2.2H2O in 100 ml of ethanol is being introduced and then for a further 3 hours. After removal of the solvent by evaporation, the residue is diluted with 140 ml of ice-cold water and rendered basic with 2N sodium hydroxide solution. The resulting aqueous phase is extracted 3 times with 350 ml of methylene chloride each time. The combined organic phases are dried over MgSO4 and evaporated. The residue is purified by flash chromatography (CH2Cl2/MeOH: 98/2) to yield the expected product.