Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:21][C:22]1[N:23]=[CH:24][NH:25][CH:26]=1)[C:3]([NH:5][C@@H:6]([CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C@@H:7]([OH:13])[C@H:8]([CH:10]1[CH2:12][CH2:11]1)[OH:9])=[O:4].[C:27]([O:31][C:32]([NH:34][CH2:35][C:36]([S:39]([CH2:42][C@@H:43]([CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:44](O)=[O:45])(=[O:41])=[O:40])([CH3:38])[CH3:37])=[O:33])([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[CH:15]1([CH2:14][C@H:6]([NH:5][C:3]([C@@H:2]([NH:1][C:44]([C@H:43]([CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:42][S:39]([C:36]([CH3:37])([CH3:38])[CH2:35][NH:34][C:32](=[O:33])[O:31][C:27]([CH3:30])([CH3:28])[CH3:29])(=[O:40])=[O:41])=[O:45])[CH2:21][C:22]2[N:23]=[CH:24][NH:25][CH:26]=2)=[O:4])[C@@H:7]([OH:13])[C@H:8]([CH:10]2[CH2:11][CH2:12]2)[OH:9])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reactant: CC(C)(C)OC(=O)NCC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(C)(C)S(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 200 mg (0.5 mmol) of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide, 197 mg (0.5 mmol) of (S)-α-[[[2-(1-tert-butoxyformamido)-1,1-dimethylethyl]sulphonyl]methyl]hydrocinnamic acid, 56 mg (0.5 mmol) of triethylamine, 89 mg (0.5 mmol) of HOBT and 209 mg (0.5 mmol) of HBTU in 15 ml of dimethylformamide is stirred at room temperature for 4 hours. Thereafter, the reaction mixture is evaporated to dryness in a high vacuum, the residue is taken up in 50 ml of ethyl acetate and washed twice with 20 ml of saturated sodium bicarbonate solution. After drying the organic phase over sodium sulphate the solvent is evaporated under reduced pressure. For purification, the residue (420 mg) is chromatographed on 20 g of silica gel using a 95:5:0.1 mixture of methylene chloride, methanol and ammonia as the eluent. After lyophilization from dioxan/water there is obtained tert-butyl [2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl)carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulphonyl]-2-methylpropyl]carbamate as a colourless, amorphous powder; MS: 746 (M+H)+.
Reaction SMILES: I[C:2]1[C:7]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[C:6]([O:15][CH:16]([CH3:18])[CH3:17])[C:5]([O:19][CH3:20])=[CH:4][CH:3]=1.[CH:21](N(CC)C(C)C)([CH3:23])[CH3:22].C#CC>CN(C=O)C.[Cu]I>[CH:16]([O:15][C:6]1[C:5]([O:19][CH3:20])=[CH:4][CH:3]=[C:2]([C:22]#[C:21][CH3:23])[C:7]=1[NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])([CH3:18])[CH3:17]
Reactant: COc1ccc(I)c(NC(=O)C(F)(F)F)c1OC(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cu]I
Agent: C#CC
Solvent: CN(C)C=O
Product: CC#Cc1ccc(OC)c(OC(C)C)c1NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
A mixture of the product of Step B (0.275 g; 0.681 mmol), Cl2Pd(PPh3)2 (0.058 g; 0.083 mmol); CuI (0.025 g; 0.13 μmol), anhydrous N,N-diisopropyl ethylamine (1 ml) in anhydrous DMF (5 ml) was cooled to −40° C., degassed under reduced pressure and saturated with dry N2. To it, propyne gas (0.5 g; 12.4 mmol) was added at −40° C. The reaction flask was sealed with septum and allowed to warm up to room temperature and stirred overnight at room temperature than evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography (SiO2, hexane/ethyl acetate, 8:2) to give the title compound (0.171 g; 79% yield) as creamy solid. 1H-NMR (CDCl3) 1.21 (d, 6H, J=6.16 Hz); 2.00 (s, 3H); 3.86 (s, 3H); 4.43 (m, 1H, J=6.16 Hz); 6.79 (d, 1H, J=8.67 Hz); 7.14 (d, 1H, J=8.67 Hz); 7.72 (broad s, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44]O)[CH2:38][CH2:37][CH2:36][CH2:35]1>C(Cl)Cl>[CH:34]1([O:39][C:40](=[O:54])[C@@H:41]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:42][CH2:43][CH2:44][Br:1])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO)C(=O)OC1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](CCCBr)C(=O)OC1CCCC1
Reaction time: 18 h
Yield: 55.4 %

Procedure:
To a slurry of N-bromo succinimide (3.54 g, 19.9 mmol, 3 eq) in DCM (30 ml) was added a solution of triphenyl phosphine (4.87 g, 18.8 mmol, 2.8 eq) in DCM (15 ml). The solution was stirred for a further 5 minutes before addition of pyridine (644 μl, 7.96 mmol, 1.2 eq) and a solution of (S)-2-tert-butoxycarbonylamino-5-hydroxy-pentanoic-acid cyclopentyl ester (2.0 g, 6.64 mmol) in DCM (20 ml). The solution was stirred for 18 hours, concentrated in vacuo and the residual solvent azeotroped with toluene (3×30 ml). The residue was triturated with diethyl ether (30 ml) and ethyl acetate:heptane (1:9, 2×30 ml). The combined ether and ethyl acetate/heptane solutions was concentrated onto silica and purified by column chromatography using ethyl acetate/heptane (1:9 to 2:8) to provide the title compound as a clear oil (1.34 g, 55% yield).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O:20][CH2:21][C@@:22]2([CH3:25])[CH2:24][O:23]2)(=[O:19])=[O:18])=[CH:13][CH:12]=1>C(#N)C.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[Cl:1][C:2]1[N:3]([CH2:25][C@:22]([OH:23])([CH3:24])[CH2:21][O:20][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@]2(C)CO2)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)n1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OC[C@](C)(O)Cn2cc([N+](=O)[O-])nc2Cl)cc1
Yield: 41.3 %

Procedure:
2-Chloro-4-nitro-1H-imidazole (18.4 g, 125 mmol) and (R)-2-methyloxiran-2-ylmethyl 4-methylbenzene sulfonate (36.2 g, 149 mmol) were suspended in acetonitrile (150 ml). Benzyl(triethyl)ammonium chloride (5.7 g, 25 mmol) was added to the suspension, and the resulting mixture was stirred under reflux for 8 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=20/1) to afford (R)-2-chloro-1-[2-hydroxy-2-methyl-3-(4-methylbenzenesulfonyloxy)propyl]-4-nitroimidazole (20.1 g, 43%) as a white amorphous form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CN(C)C=O>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([C:17]([NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:18])[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: Nc1nc(=O)n(C(=O)Nc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a suspension of 4-amino-5-fluoro-pyrimidin-2-ol* (0.25 g, 1.94 mmol) in dry N,N-dimethylformamide (DMF; 5 mL) was added phenyl isocyanate (0.231 mL, 2.13 mmol), and the mixture was stirred at room temperature for 1 h. The suspension was suction filtered, and washed with diethyl ether (Et2O; 3×10 mL). The resulting solid was air-dried overnight to yield 4-amino-5-fluoro-2-oxo-N-phenylpyrimidine-1(2H)-carboxamide (0.32 g, 66%) as a white solid: mp 275-277° C. dec; 1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.63 (s, 1H), 8.43 (d, J=7.25 Hz, 1H), 8.35 (s, 1H), 7.55 (d, J=7.58 Hz, 2H), 7.37 (t, J=7.58 Hz, 2H), 7.13 (t, J=7.25 Hz, 1H); ESIMS m/z 247.1 ([M−H]−).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59](O)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[CH3:41][N:42]([C:52]([NH:54][C@H:55]([C:59]([NH:1][C@@H:2]([CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:3][C@H:4]([OH:23])[C@@H:5]([NH:13][C:14]([O:16][CH2:17][C:18]1[S:22][CH:21]=[N:20][CH:19]=1)=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:60])[CH:56]([CH3:58])[CH3:57])=[O:53])[CH2:43][C:44]1[N:45]=[C:46]([CH:49]([CH3:51])[CH3:50])[S:47][CH:48]=1
Reactant: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)O)C(C)C)cs1
Reactant: N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)c1nc(CN(C)C(=O)N[C@H](C(=O)N[C@@H](Cc2ccccc2)C[C@H](O)[C@H](Cc2ccccc2)NC(=O)OCc2cncs2)C(C)C)cs1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the product of Example 70 (9.1 g, 21.4 mmol), HOBT (3.6 g, 23.5 mmol) and N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (7.37 g, 23.5 mmol) in THF (170 mL) was added DCC (4.85 g, 23.5 mmol). The solution was stirred at ambient temperature for 16 hours (DCU precipitates). THF was removed under vacuum and the resulting paste was stirred with cold 1N HCl (106 mL at 5° C.) for 3 hours to dissolve the the crude product. The DCU was removed by filtration and the filter cake was washed with 1N HCl (30 mL). KH2PO4 (3.2 g) was dissolved in the combined HCl filtrates. The solution was mixed with ethyl acetate (80 mL) and neutralized to pH 7 with aqueous NaOH (60.3 g of 10% w/w NaOH). The aqueous layer was extracted with another 25 mL ethyl acetate and the combined ethyl acetate extracts were washed with aqueous NaHCO3 (2×37 mL of 5% w/w NaHCO3). The organic layer was dried with Na2SO4 (13 g), filtered, and concentrated under vacuum at ≦45° C. The residue was dissolved in a 1:1 ethyl acetate/heptane mixture (200 mL) at 70° C. The solution was allowed to cool slowly and stirred overnight at room temperature to provide a thick slurry. The product was collected by filtration and washed with 1:1 ethyl acetate/heptane (20 mL). The product was dried briefly at 55° C. in a vacuum oven to obtain an approximate weight prior to the second crystallization (12.85 g, 83%).
Reaction SMILES: [C:1]1([C:7]([CH3:9])=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:10](Cl)([Cl:13])(=[O:12])=[O:11]>CN(C)C=O>[C:1]1([C:7]([CH3:9])=[CH:8][S:10]([Cl:13])(=[O:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=CS(=O)(=O)Cl)c1ccccc1

Procedure:
Following the procedure of Preparation A, 2-phenylpropene is reacted with sulfuryl chloride in N,N-dimethylformamide to give 2-phenylpropene-1-sulfonyl chloride, which is then treated with ammonia to give 2-phenylpropene-1-sulfonamide, m.p. 101°-102.5° C.
Reaction SMILES: [SH:1]CCC(OC)=O.[H-].[Na+].[Cl:10][C:11]1[C:12]([C:27]([NH2:29])=[O:28])=[C:13]2[N:18]([C:19]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:15](Cl)=[CH:14]2.Cl>CN(C)C=O.O>[Cl:10][C:11]1[C:12]([C:27]([NH2:29])=[O:28])=[C:13]2[N:18]([C:19]=1[C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)[CH2:17][CH2:16][C:15]([SH:1])=[CH:14]2
Reactant: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(Cl)CC2
Reactant: COC(=O)CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1c(Cl)c(-c2cccnc2)n2c1C=C(S)CC2
Temperature: 68 °C
Yield: 36 %

Procedure:
2.4 g of methyl 3-mercaptopropionate are dissolved in 100 cm3 of dimethylformamide. 0.8 g of sodium hydride is added in small fractions, and then 3.08 g of 2,7-dichloro-3-pyridin-3-yl-5,6-dihydroindolizine-1-carboxamide in 80 cm3 of dimethylformamide are poured in. The mixture is heated at 68° C. for 2 hours 30 minutes, and then poured into 25 cm3 of hydrochloric acid (4 N). The mixture is concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 60° C. The yellow residue obtained is taken up in 280 cm3 of water and 10 cm3 of hydrochloric acid (2 N), and then filtered and washed with twice 5 cm3 of water. 1.1 g of 2-chloro-3-pyridin-3-yl-7-mercapto-5,6-dihydroindolizine-1-carboxamide are thus obtained in the form of a yellow powder melting at 232° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CC(O)=O.[H][H]>CO>[NH2:11][C:9]1[C:8]([O:14][CH3:15])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(C(=O)O)c(F)cc1N
Yield: 97.5 %

Procedure:
A solution of 2-fluoro-5-methoxy-4-nitrobenzoic acid (10 g, 46 mmol), HOAc (50 mL) and MeOH (50 mL) was hydrogenated using a hydrogen balloon overnight. The solution was then filtered through celite and concentrated to a residue, which was triturated with ether and ethyl acetate. The solid was filtered and dried to give the product as light yellow powder (8.3 g, 98%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.76 (s, 3H) 5.88 (br s, 2H) 6.36 (d, J=16 Hz, 1H) 7.13 (d, J=8 Hz, 1H) 12.32 (br s, 1H). [M+H] calc'd for C8H8FNO3, 186. found 186.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([CH:16]=[N:17][OH:18])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:22][CH:23]([O:26][CH2:27][CH3:28])[C:24]#[CH:25])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:19])[NH:10][CH:11]([C:16]1[CH:25]=[C:24]([CH:23]([O:26][CH2:27][CH3:28])[O:22][CH2:20][CH3:21])[O:18][N:17]=1)[CH2:12][CH:13]([CH3:15])[CH3:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CC(C=NO)NC(=O)OCc1ccccc1
Reactant: C#CC(OCC)OCC
Solvent: ClCCl
Product: CCOC(OCC)c1cc(C(CC(C)C)NC(=O)OCc2ccccc2)no1
Yield: 52.4 %

Procedure:
A mixture of [1-(hydroxyimino-methyl)-3-methyl-butyl]-carbamic acid benzyl ester (1.2 g, 4.5 mmol), 3,3-diethoxy-propyne (1.5 g, 11.4 mmol), CH2Cl2 (40 ml) and TEA (6 drops) was stirred until homogeneous, then Clorox bleach (20 ml) was added. After stirring vigorously for 12 h the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried over Na2SO4; filtered; and concentrated under reduced pressure to give a yellow oil. Purification by Flash 40(small) chromatography eluting with 10% EtOAc in hexanes gave 920 mg of the title compound as a colorless oil. MS [M+1]+ 391.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[NH:4][CH:5]([C:9]([N:11]1[CH:17]([C:18]2[NH:19][C:20]([C:23]3[CH:28]=[CH:27][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:25][CH:24]=3)=[CH:21][N:22]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[C:39]([O:43][C:44]([N:46]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62](Br)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH:50]2[CH2:68][CH:47]1[CH2:48][CH2:49]2)=[O:45])([CH3:42])([CH3:41])[CH3:40].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.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>[C:39]([O:43][C:44]([N:46]1[CH:51]([C:52]2[NH:53][C:54]([C:57]3[CH:66]=[CH:65][C:64]4[C:59](=[CH:60][CH:61]=[C:62]([C:26]5[CH:25]=[CH:24][C:23]([C:20]6[NH:19][C:18]([CH:17]7[CH2:16][C:13]8([CH2:14][CH2:15]8)[CH2:12][N:11]7[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:38])[CH:6]([CH3:8])[CH3:7])=[N:22][CH:21]=6)=[CH:28][CH:27]=5)[CH:63]=4)[CH:58]=3)=[CH:55][N:56]=2)[CH:50]2[CH2:68][CH:47]1[CH2:48][CH2:49]2)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
Reactant: CC(C)(C)OC(=O)N1C2CCC(C2)C1c1ncc(-c2ccc3cc(Br)ccc3c2)[nH]1
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: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Yield: 37.1 %

Procedure:
To a solution of [2-Methyl-1-(6-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-propyl]-carbamic acid methyl ester (0.95 g, 1.82 mmol) and 3-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.96 g, 1.82 mmol, 1 equiv.) in DME (20 mL) was added K2CO3 (aqueous, 2 M, 3.6 mL, 7.2 mmol, 4 equiv.) and Pd(PPh3)4 (0.11 g, 0.09 mmol, 0.05 equiv.). The slurry was degassed with argon for 5 minutes and heated to 80° C. for 12 hours. The resulting reaction mixture was diluted with EtOAc and washed with water. The aqueous layer was back-extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by column chromatography (SiO2, 50→100% EtOAc in Hexanes) to provide 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.53 g, 37%) as a yellow powder. LCMS-ESI+: calc'd for C46H53N7O5: 783.4 (M+). Found: 784.3 (M+H+).
Reaction SMILES: [C:1]([CH2:4][C@@H:5]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])([OH:3])=O.CN1CCOCC1.ClC(OCC(C)C)=O.[F:38][C:39]([F:48])([F:47])[CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[CH2:16]([C@H:5]([CH2:4][C:1]([N:44]1[CH2:43][CH2:42][N:41]([CH2:40][C:39]([F:47])([F:48])[F:38])[CH2:46][CH2:45]1)=[O:3])[C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(O)C[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: FC(F)(F)CN1CCNCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(OCc1ccccc1)[C@@H](CC(=O)N1CCN(CC(F)(F)F)CC1)Cc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
The resultant acid from Example 23 (0.500 g, 1.68 mmol) in CH2Cl2 (7 ml) at -10° C. was treated with N-methylmorpholine (0.20 ml, 1.82 mmol) and then isobutyl chloroformate (0.22 ml, 1.68 mmol). After 5 min 1-trifluoroethylpiperazine (0.30 g, 1.78 mmol) was added and the mixture was stirred at -10° C. for 15 min and then at room temperature for 2 h. The solvent was evaporated and the residue was taken up in ethyl acetate which was washed with saturated NaHCO3 solution, water and brine, and then dried over Na2SO4 and evaporated. Chromatography of the residue on silica gel with 20-33% ethyl acetate in hexane provided 0.61 g (81%) of an oil. 1H NMR (CDCl3) δ7.10-7.40 (m,10H), 5.15 (d,1H), 5.05 (d,1H), 3.25-3.70 (m,5H), 3.04 (dd,1H), 2.97 (q,2H), 2.81 (dd,1H), 2.72 (dd,1H), 2.60 (m,4H), 2.32 (dd,1H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][CH:34]=1>O1CCCC1.C(OCC)(=O)C>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([S:39]([N:11]2[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]2)(=[O:41])=[O:40])=[CH:35][CH:34]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cn1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2)cn1
Yield: 17.3 %

Procedure:
Under an argon atmosphere, 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg) was dissolved in absolute tetrahydrofuran (20 mL), and sodium hydride (60% in oil, 200 mg) was added at room temperature while stirring. After stirring at the same temperature for 15 min, 15-crown-5 (1.01 mL) was added, and the mixture was further stirred at the same temperature for 15 min. 6-Methoxypyridin-3-ylsulfonyl chloride (623 mg) was added, and the mixture was stirred at the same temperature for 1 hr. The reaction mixture was diluted with ethyl acetate, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give the title compound as an oil (yield 59 mg, 17%).
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][N:2]=1.Br[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[O:11]=[C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:1]=[N:2][N:3]1[CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=c1[nH]nnc2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1nnc2ccccc2c1=O
Temperature: 25 °C
Yield: 76.6 %

Procedure:
In a dry round bottom flask, 1,2,3-benzotriazin-4(3H)-one (50 g), ethyl 4-bromobutanoate (86.2 g) and potassium carbonate (141 g) were taken and dissolved in dimethylformamide (350 mL) and heated to 60° C. to 70° C. for 3 to 4 hours. After cooling to room temperature, water was added to the reaction mixture and extracted with ethyl acetate. The combined organic layer was washed with water and brine and dried over anhydrous sodium sulfate. Solvents were evaporated under reduced pressure and the crude product was purified by silica gel flash column chromatography over silica gel using 20% ethylacetate in hexane as eluant to afford the title compound (68 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1.CN1C(=O)CCC1.Cl>O>[F:8][C:5]1[CH:6]=[CH:7][C:2]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=[N+]([O-])c1cc(F)ccc1F
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: O=C(O)C1CCN(c2ccc(F)cc2[N+](=O)[O-])CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
The mixture consisting of 1.62 g of 2,5-difluoronitrobenzene, 1.9 g of piperidine-4-carboxylic acid and 10 ml of NMP was heated with stirring to 80° C. for 2 hours. After it had been allowed to cool, 30 ml of water were added and the mixture was made weakly acidic using 2N hydrochloric acid and stirred at RT. The precipitated solid was filtered off with suction and dried under reduced pressure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][NH:17][CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.[CH2:19]=O>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CNCCC1(c2cccc(OC)c2)C=CCCC1
Reactant: C=O
Solvent: O=CO
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Reaction time: 2 h

Procedure:
5.0 g of 1-(m-methoxyphenyl)-N-methyl-2-cyclohexene-1-ethylamine are treated with a mixture of 1.5 liters of 35% aqueous formaldehyde solution and 2.0 ml of 90% formic acid, and the resulting mixture is held at 100° C. for 2 hours. After distillation of the solvent, the residue is treated with 1 N hydrochloric acid solution. The neutral portion is taken up in ether, the aqueous phase is made alkaline by the addition of 3 N sodium hydroxide and the rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. After distillation of the solvent, the oil obtained is purified on a 10-fold amount of aluminium oxide. The fractions eluted with toluene are combined and evaporated, and pure rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine remains as the residue. The hydrochloride of this compound melts at 161°-162° C. (after recrystallization from ethyl acetate/ethanol).