Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.[OH:32][C@@H:33]([C@@H:43]([NH:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=1)=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:34][C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)=[O:36]>O1CCCC1>[OH:32][C@@H:33]([C@@H:43]([NH:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=1)=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:34][C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][N:40]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:29])[CH2:39]1)=[O:36]
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Reactant: O=C(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)C[C@@H](O)[C@H](Cc4ccccc4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (2.23 g) in anhydrous tetrahydrofuran (50 ml), N,N'-carbonyldiimidazole (0.97 g) was added, followed by stirring at 30° C. for 30 minutes. To the reaction mixture, a solution of (3S)-3-[(3R,4S)-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)amino-5-phenylpentanoylamino]pyrrolidine (2.28 g) in anhydrous tetrahydrofuran (50 ml) was added. The resulting mixture was treated in a similar manner to that described in Referential Example 18-(1), whereby 2.14 g of the title compound were obtained as a powder.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[N+:17]([O-:19])=[O:18])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=1.Cl.[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[C:24]([F:30])[CH:23]=1.CCN(C(C)C)C(C)C>C(#N)C>[Br:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:2]2[CH:3]=[C:4]([O:5][CH2:6][C:7]3[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][N:8]=3)[CH:14]=[CH:15][C:16]=2[N+:17]([O-:19])=[O:18])=[C:24]([F:30])[CH:23]=1
Reactant: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Reactant: NCc1ccc(Br)cc1F
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(COc2ccc([N+](=O)[O-])c(NCc3ccc(Br)cc3F)c2)nc1
Temperature: 75 °C

Procedure:
A mixture of 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine (1.50 g, 5.72 mmol), 4-bromo-2-fluorobenzylamine hydrochloride (1.51 g, 6.29 mmol), DIPEA (2.96 mL, 17.2 mmol) and acetonitrile (19.1 mL) was sealed in reaction vessel and heated to 75° Celsius for 18 h. The mixture was then cooled to RT, transferred to a round bottomed flask and concentrated to dryness. The resulting residue was then heated in a minimum amount of i-PrOH to 70° Celsius until homogeneous. The resulting solution was then cooled to RT where yellow solids precipitated, which were collected by filtration. (2.40 g, 94%). MS (ESI): mass calcd. for C20H17BrFN3O3, 445.04; m/z found, 446.0 [M+H]+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:21]=[CH:20][C:7]([O:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH:16]3[CH2:18][CH2:19][CH:13]2[CH2:14][CH2:15]3)=[CH:6][CH:5]=1)#[CH:3].[Li]CCCC.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[CH:13]12[CH2:14][CH2:15][CH:16]([CH2:18][CH2:19]1)[CH2:17][N:12]2[CH2:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:2]#[C:3][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:21][CH:20]=1
Reactant: C#Cc1ccc(OCCCN2CC3CCC2CC3)cc1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C#Cc1ccc(OCCCN2CC3CCC2CC3)cc1

Procedure:
In the b) route of scheme 2,2-azabicyclo[2.2.2]octane hydrochloride (isoquinuclidine hydrochloride) (8) is reacted with TMS-ethynyl-phenyl ether derivative (3) in the presence of K2CO3 and potassium iodide (KI). The resulting 2-[3-(4-ethynylphenoxy)propane-1-yl]-2-azabicyclo[2.2.2]octane (9) is treated with ethyl ether solution in saturated hydrochloride gas (HCl gas in ether) to obtain 2-[3-(4-ethynylphenoxy)propane-1-yl]-2-azabicyclo[2.2.2]octane hydrochloride (compound 10). Further, this compound 10 is treated with n-BuLi, then it is reacted with ethyl chloroformate in tetrahydrofuran (THF) to give an ethyl 4-[3-(2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolate (11), then it is treated by the same method as mentioned above to provide an ethyl 4-[3-(2-azabicyclo[2.2.2]octan-2-yl)propoxy]phenylpropiolate hydrochloride (compound 12). In case of both R1 and R2 are hydrogen and m is 0 or 2 in the compounds of general formula (1), compound 13 (m=0) and compound 14 (m=2), it is prepared by the same method of scheme 1 and a) route of scheme 2 using either a 1,2-dibromoethane or a 1,4-dibromobutane in the place of a 1-bromo-3-chloropropane. ##STR4##
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[NH:46][C:44](=[O:45])[CH:43]([C@H:47]([OH:54])[C@@H:48]([CH2:50]/[CH:51]=[CH:52]/[CH3:53])[CH3:49])[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:58])[CH3:57])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:63])[CH3:62])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:68])[CH3:67])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:75])[CH3:74])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][C:81]([OH:84])([CH3:83])[CH3:82])[N:10]([CH3:85])[C:8](=[O:9])[CH2:7][N:6]([CH3:86])[C:4]1=[O:5].[H][H]>C(O)C.[Pd]>[CH3:53][CH2:52][CH2:51][CH2:50][C@H:48]([C@@H:47]([OH:54])[CH:43]1[N:42]([CH3:55])[C:40](=[O:41])[C@H:39]([CH:56]([CH3:57])[CH3:58])[N:38]([CH3:59])[C:36](=[O:37])[C@H:35]([CH2:60][CH:61]([CH3:62])[CH3:63])[N:34]([CH3:64])[C:32](=[O:33])[C@H:31]([CH2:65][CH:66]([CH3:67])[CH3:68])[N:30]([CH3:69])[C:28](=[O:29])[C@@H:27]([CH3:70])[NH:26][C:24](=[O:25])[C@H:23]([CH3:71])[NH:22][C:20](=[O:21])[C@H:19]([CH2:72][CH:73]([CH3:74])[CH3:75])[N:18]([CH3:76])[C:16](=[O:17])[C@H:15]([CH:77]([CH3:79])[CH3:78])[NH:14][C:12](=[O:13])[C@H:11]([CH2:80][C:81]([OH:84])([CH3:82])[CH3:83])[N:10]([CH3:85])[C:8](=[O:9])[CH2:7][N:6]([CH3:86])[C:4](=[O:5])[C@H:3]([CH2:2][CH3:1])[NH:46][C:44]1=[O:45])[CH3:49]
Reactant: C/C=C/C[C@@H](C)[C@@H](O)C1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)(C)O)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCCC[C@@H](C)[C@@H](O)C1C(=O)N[C@@H](CC)C(=O)N(C)CC(=O)N(C)[C@@H](CC(C)(C)O)C(=O)N[C@@H](C(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@H](C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](CC(C)C)C(=O)N(C)[C@@H](C(C)C)C(=O)N1C

Procedure:
To a suspension of 200 mg pre-hydrogenated 10% palladium/charcoal in 4 ml ethanol is added 1.2 g of [γ-hydroxy-MeLeu]4 -Ciclosporin (compound e) in 10 ml ethanol and hydrogenation is carried out at room temperature until no more hydrogen is taken up. After removal of the catalyst by filtration the solution is evaporated, yielding the title compound as an amorphous white powder, m.p. 154-156°, [α]D20 -225° (c=0.87 in CHCl3), -169° (c=0.70 in CH3OH).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2F)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2F)Cc2ccccc2C1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: CCOC(=O)C1(NC(=O)c2ccncc2N2CCCCC2)Cc2ccccc2C1
Reaction time: 0.01 h
Yield: 200.6 %

Procedure:
A 10 mL microwave reaction vessel is charged with 2-[(3-fluoro-pyridine-4-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (354, 500 mg, 1.52 mmol), 1,4-dioxane (1.5 mL) and piperidine (1.51 mL, 15.23 mmol). A stirring bar is added. The reaction vial is crimped sealed. The reaction vial is placed in a Smith Microwave reaction apparatus. The temperature is set for 150° C. with a fixed hold time of 10 min. Pre-stir time is set for 20 sec. The reaction vial is removed from the apparatus. The stirring bar is extracted. The contents of the flask are transferred to a round bottom flask and the solvent removed under reduced pressure. Pumping to a constant weight gives 1.2 g of yellow semi-solid. The residue is dissolved in DCM (10 mL) and applied to an ISCO Companion that is fitted with a 40 g column (silica). The column is eluted with EtOAc/heptanes (5%) for 4 column volumes followed by a linear gradient to 65% EtOAc/heptanes over 10 column volumes and then 90% EtOAc/heptanes for 2 column volumes. 14 mL fractions are collected. Fractions 42-50 are combined and evaporated by pumping to constant weight to give white solid (0.56 g, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[C:12]([OH:14])[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1.[C:16]([O:20][C:21](=[O:37])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br)([CH3:19])([CH3:18])[CH3:17].C([O-])([O-])=O.[K+].[K+].C(#N)C>CCCCCCC.CCOC(C)=O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[C:12]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:21]([O:20][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:37])[CH:13]=[C:4]([C:3]([O:2][CH3:1])=[O:15])[CH:5]=1
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: COC(=O)c1cc(OCCCCCCCCCCCCCCC(=O)OC(C)(C)C)cc(C(=O)OC)c1
Yield: 98.7 %

Procedure:
5-Hydroxy-isophthalic acid dimethyl ester (420 mg, 2 mmol), 15-bromo-pentadecanoic acid tert-butyl ester (755 mg, 2 mmol) and K2CO3 (415 mg, 3 mmol) were placed in a flask with acetonitrile (25 ml) and refluxed under N2. The reaction was followed by TLC (4:1 heptane/AcOEt), which indicated reaction completion after 6 h. The sample was concentrated to near dryness. AcOEt (50 ml) and water (25 ml) were added to the residue. The phases were separated and the organic phase was washed with water and brine (25 ml each), dried over MgSO4 and concentrated to yield a white crystalline solid (1.0 g, 100%).
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26](OCC)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[O:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[CH2:39][NH2:40]>>[F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([NH:40][CH2:39][CH:35]4[CH2:36][CH2:37][CH2:38][O:34]4)=[O:27])[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Reactant: NCC1CCCO1
Product: O=C(NCC1CCCO1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and (tetrahydro-2-furanylmethyl)amine using conditions similar to those employed in Example 563 to provide a white solid: 1H NMR (d6-DMSO) δ 10.39 (1H, t, J=6 Hz), 8.55 (1H, s), 8.12 (1H, s), 7.40 (2H, dd, J=6, 9 Hz), 7.13 (2H, t, J=9 Hz), 4.38 (2H, b), 4.15 (2H, s), 3.95-4.02 (1H, m), 3.80 (1H, q, J=8 Hz), 3.66 (1H, q, J=8 Hz), 3.50-3.57 (1H, m), 3.32-3.46 (5H, m), 1.89-1.99 (3H, m), 1.78-1.87 (2H, m), 1.70-1.78 (2H, m), 1.49-1.58 (1H, m); ES+ MS: 509 (+H+).
Reaction SMILES: [Li].N.[CH2:3]1[CH2:27][O:26][C:5]2([CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[C@@H:17]3[O:24][C@@H:18]32)[CH:13]=[CH:12]4)[O:4]1.C=CC(=C)C.[Cl-].[NH4+]>CCOCC.O1CCCC1.CCOCC>[CH2:27]1[CH2:3][O:4][C:5]2([CH2:10][CH2:9][C@H:8]3[C@H:11]4[C@H:21]([CH2:22][CH2:23][C@:6]23[CH3:7])[C@:19]2([CH3:20])[C:14]([CH2:15][C@@H:16]([OH:25])[CH2:17][C@@H:18]2[OH:24])=[CH:13][CH2:12]4)[O:26]1
Reactant: C[C@@]12C(=CC(=O)[C@@H]3O[C@@H]31)C=C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: CCOCC
Solvent: C=CC(=C)C
Solvent: C1CCOC1
Product: C[C@]12C(=CC[C@@H]3[C@@H]1CC[C@@]1(C)[C@H]3CCC13OCCO3)C[C@@H](O)C[C@@H]2O
Reaction time: 0.08 h

Procedure:
1.543 g (0.22 g-atom) of lithium are added to 1.3 liters of dry liquid ammonia at -31° C. to -33° C. with stirring in an argon atmosphere. After 5 minutes, there is added dropwise during 40 minutes to the resulting dark blue mixture a solution of 10.83 g (0.0316 mol) of 17,17-ethylenedioxy-1α,2α-epoxyandrosta-4,6-dien-3-one in 765 ml of ether/tetrahydrofuran (2:1). After stirring for 15 minutes, 5.3 ml of isoprene are added dropwise to the mixture. The resulting yellow mixture is treated with stirring with 13.49 g (0.252 mol) of ammonium chloride in portions and then 0.22 g (0.0316 g-atom) of lithium is added. As soon as the lithium has dissolved, 1.69 g (0.0316 mol) of ammonium chloride and subsequently a further 0.22 g (0.0316 g-atom) of lithium are added. This procedure, i.e. the addition of 0.0316 mol of ammonium chloride and 0.0316 g-at of lithium, is repeated a further fourteen times, for which a total of 23.66 g (0.442 mol) of ammonium chloride and 3.08 g (0.442 g-atom) of lithium are required. As soon as the lithium of the last addition has dissolved, 24 g (0.44 mol) of ammonium chloride are added and the mixture is cautiously diluted with 1 liter of ether. Ammonia is evaporated while stirring until an internal temperature of 0° C. has been reached and the remaining suspension is treated with 1 liter of water. The organic phase is separated, the aqueous phase is back-extracted with ethyl acetate, the organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated at 40° C./11 Torr. Chromatography of the residue on 300 g of silica gel with benzene/ethyl acetate (3:2) and benzene/ethyl acetate (2:3) gives 8.8 g (80%) of uniform, crystalline 17,17-ethylenedioxy-1α,3β-dihydroxy-androst-5-ene. The analytical sample is obtained by recrystallisation from methanol; white needles of melting point 205°-206° C.; [α]D25 =-89.8° (c=0.5 in chloroform).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])([O-:3])=[O:2].Cl.[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1([CH2:24][NH2:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CCN(C(C)C)C(C)C>ClCCl>[CH3:14][O:15][C:16](=[O:26])[CH2:17][C:18]1([CH2:24][NH:25][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[N+:1]([O-:3])=[O:2])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)CC1(CN)CCCCC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC1(CNC(=O)c2ccccc2[N+](=O)[O-])CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.2 %

Procedure:
To a mixture of 2-nitrobenzoyl chloride (0.3 mL, 2.05 mmol) and (1-aminomethyl-cyclohexyl)-acetic acid methyl ester hydrochloride (500 mg, 2.25 mmol) (prepares according to example A) in dichloromethane (10 mL) is added DIPEA (0.75 mL, 4.02 mmol). The mixture is stirred at room temperature for 16 hours. The reaction mixture is concentrated and the resulting residue is purified by flash chromatography with 50% EtOAc in Hexane as the eluent to afford the desired {1-[(2-nitro-benzoylamino)-methyl]-cyclohexyl}-acetic acid methyl ester (680 mg, 99%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][N:4]2[CH2:3][CH2:2]1)=[CH:13][CH:12]=[CH:11][N:10]=4.[H-].[Na+].[O:19]1[CH2:21][CH:20]1[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>CN(C=O)C>[N:25]1[CH:26]=[CH:27][C:22]([CH:20]([OH:19])[CH2:21][N:8]2[C:7]3[CH2:6][CH:5]4[N:4]([CH2:3][CH2:2][CH2:1]4)[CH2:16][C:15]=3[C:14]3[CH:13]=[CH:12][CH:11]=[N:10][C:9]2=3)=[CH:23][CH:24]=1
Reactant: c1cnc2[nH]c3c(c2c1)CN1CCCC1C3
Reactant: c1cc(C2CO2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(Cn1c2c(c3cccnc31)CN1CCCC1C2)c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2,3,4,9,10,10a-hexahydro-1H-3a,8,9-triaza-cyclopenta[b]fluorene (1 g, 4.6 mmol) in DMF (20 mL) were portion wise added NaH (60%, 0.552 g, 13.8 mmol) and 4-(oxiran-2-yl)pyridine (0.709 g, 5.6 mmol). The reaction mixture was stirred at RT overnight. The progress of reaction mass was monitored by LCMS. The reaction mixture was quenched with ice cold water (300 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water (10×100 mL) followed by brine (2×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography followed by reverse phase HPLC to yield the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].C1([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)C=CC=CC=1>CN(C)C=O>[C:7]1([CH:35]2[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][C:4]([NH:6][C:7]3[CH:19]=[CH:18][C:10]([C:11]([CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:12])=[CH:9][CH:8]=3)=[O:5])[CH2:37][CH2:36]2)[CH:19]=[CH:18][CH:10]=[CH:9][CH:8]=1
Reactant: c1ccc(N2CCCCC2)cc1
Reactant: O=C(O)CCC(=O)c1ccc(NC(=O)CCCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CCC(=O)c1ccc(NC(=O)CCN2CCC(c3ccccc3)CC2)cc1
Temperature: 0 °C
Yield: 171.4 %

Procedure:
56 g (200 millimoles) of 3-[p-(3-chloropropionylamino)-benzoyl]-propionic acid were stirred with 60.7 g (440 millimoles) of potassium carbonate and 35.5 g (220 millimoles) of phenylpiperidine in 900 ml of dimethylformamide for 8 hours at 80° C. 2 kg of ice/water were added, after which the crystals were filtered off under suction and recrystallized from dimethylformamide/water, and the product was dried at 50° C. under greatly reduced pressure. 70 g (86%) of 3-{p-[3-(4-phenylpiperidino)propionylamino]-benzoyl}-propionic acid were obtained as colorless crystals of melting point 237°-238° C.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][CH:6]1[CH2:10][NH:9][CH2:8][CH2:7]1.Br[C:16]1[S:20][C:19]([C:21]#[N:22])=[N:18][N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:2][C:3]1[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=1[O:5][C@H:6]1[CH2:7][CH2:8][N:9]([C:16]2[S:20][C:19]([C:21]#[N:22])=[N:18][N:17]=2)[CH2:10]1
Reactant: Brc1ccccc1OC1CCNC1
Reactant: N#Cc1nnc(Br)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1nnc(N2CC[C@H](Oc3ccccc3Br)C2)s1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-(2-bromophenoxy)pyrrolidine hydrochloride (0.5 g, 1.87 mmol) and 5-bromo-1,3,4-thiadiazole-2-carbonitrile (0.36 g, 1.87 mmol) in DMF (10 mL) was added K2CO3 (0.77 g, 5.61 mmol) under a nitrogen atmosphere. The mixture was stirred at 70° C. for 4 h. After dilution with water, the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered and purified by preparative TLC with petroleum:EtOAc (2:1) to give the title compound. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, 1H), 7.52 (t, 1H), 7.08 (t, 1H), 6.99 (d, 1H), 5.24 (m, 1H), 3.69-3.93 (m, 4H), 2.33-2.56 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:6]2=[N:7][C:8]([C:11](OC)=[O:12])=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[C:6]2=[N:7][C:8]([CH2:11][OH:12])=[CH:9][CH:10]=[C:5]2[S:4][CH:3]=1
Reactant: COC(=O)c1ccc2scc(Br)c2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: OCc1ccc2scc(Br)c2n1
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a -78° C. solution of the methyl ester (0.388 g, 1.42 mmol) of Step 1 in 5 mL of THF was added DIBAL (3.55 mmol) over 5 min. The reaction mixture was left 30 min after which time the solution was brought to 0° C. and quenched with MeOH. Sodium potassium tartrate solution was added and the mixture extracted with EtOAc. The organic phase was dried over Na2SO4, and the solvent evaporated. The crude oil was purified by flash chromatography on silica with EtOAc:hexane 2:3 to give 0.338 g (98%) of the title alcohol.
Reaction SMILES: [CH3:1][O:2][C:3]([CH3:8])([CH3:7])[C:4]([OH:6])=[O:5].[OH-].[K+].[OH-].[Na+].[C:13](OC=C)(=O)[CH3:14]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:13]([O:5][C:4](=[O:6])[C:3]([O:2][CH3:1])([CH3:8])[CH3:7])=[CH2:14]
Reactant: COC(C)(C)C(=O)O
Reactant: C=COC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [K+]
Product: C=COC(=O)C(C)(C)OC
Reaction time: 4 h

Procedure:
A mixture of 2-methoxy-2-methylpropanoic acid (5.9 g), vinyl acetate (5 ml), mercuric acetate (172 mg), palladium acetate (27 mg) and potassium hydroxide (225 mg) was stirred under nitrogen at ca 50° for 4 hours. More vinyl acetate (10 ml) was added and the reaction was allowed to proceed for a further 181/2 hours. The mixture was cooled to 2° and N aqueous sodium hydroxide (45 ml) was added. The layers were separated and the aqueous layer was extracted with ether (50 ml). The combined organic layers were washed with saturated brine (20 ml), dried over magnesium sulphate and concentrated on a rotary evaporator to give a yellow liquid (4.44 g) which was distilled under reduced pressure to give the title ethenyl ester (2.52 g); b.p. 43°-45°/ca 20 mm Hg.
Reaction SMILES: Br[C:2]1[C:3]([C:18]#[N:19])=[CH:4][C:5]([F:17])=[C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])[CH:7]=1.Cl.[NH2:21][C:22]1[S:26][N:25]=[C:24]([CH3:27])[CH:23]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:18]([C:3]1[C:2]([NH:21][C:22]2[S:26][N:25]=[C:24]([CH3:27])[CH:23]=2)=[CH:7][C:6]([NH:8][C@H:9]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:10]([NH2:12])=[O:11])=[C:5]([F:17])[CH:4]=1)#[N:19]
Reactant: Cc1cc(N)sn1
Reactant: CC(C)C[C@@H](Nc1cc(Br)c(C#N)cc1F)C(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)c(F)cc2C#N)sn1
Reaction time: 18 h

Procedure:
A mixture of (R)-2-(5-bromo-4-cyano-2-fluorophenylamino)-4-methylpentanamide (175 mg, 0.533 mmol), 5-amino-3-methylisothiazole hydrochloride (97 mg, 0.644 mmol), BINAP (50 mg, 0.080 mmol), Pd(OAc)2 (35 mg, 0.156 mmol) and K2CO3 (250 mg, 1.81 mmol) in dioxane (4 mL) was degassed with Ar, then was stirred at 120 C for 18 h. Water and EtOAc were added. After being filtered, the filtrate was washed with water, dried over Na2SO4, concentrated in vacuo to give (R)-2-(4-cyano-2-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide as a crude residue.