Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]=[C:9]([CH3:18])[C:8]2=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20]N1C(=O)CCC1=O.C(OOCC1C=CC=CC=1)C1C=CC=CC=1>C1C=CC=CC=1>[C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[F:17])[CH:10]=[C:9]([CH2:18][Br:20])[C:8]2=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cc2cccc(F)c2n(-c2ccccc2)c1=O
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(COOCc2ccccc2)cc1
Solvent: c1ccccc1
Product: O=c1c(CBr)cc2cccc(F)c2n1-c1ccccc1

Procedure:
Reflux a solution of 1-phenyl-8-fluoro-3-methyl-2(1H)-quinolone (0.54 g), N-bromosuccinimide (0.38 g) and benzyl peroxide (0.04 g) in dry benzene (11 mL) for 6 hours. Evaporate, partition between dichloromethane and water, dry and evaporate the organic phase, and dry the residue at room temperature and high vacuum to obtain 1-phenyl-8-fluoro-3-bromomethyl-2(1H)-quinolone, suitable for further reactions (see example 32).
Reaction SMILES: [H-].[Na+].[N:3]1[N:12]2[C:6]([CH2:7][O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11]2)=[CH:5][C:4]=1[CH2:17][OH:18].C[N+]1([O-])CCOCC1.C(#N)C>CN(P(N(C)C)(N(C)C)=O)C.C1(C)C=CC=CC=1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[N:3]1[N:12]2[C:6]([CH2:7][O:8][C:9]3[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=3[CH2:11]2)=[CH:5][C:4]=1[CH:17]=[O:18]
Reactant: OCc1cc2n(n1)Cc1ccccc1OC2
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: Cc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC#N
Product: O=Cc1cc2n(n1)Cc1ccccc1OC2
Temperature: 95 °C

Procedure:
The diol compound (3.83 g, 16.21 mmol) in HMPA (24 ml) was added to a suspension of NaH (60%, 1.34 g, 33.5 mmol) in toluene (330 ml) under N2. Rapidly heated to 95° C. for three hours and cooled to room temperature. Quenched with water and extracted with EtOAc. Washed organics with water and brine. Dried organics over sodium sulfate and filtered and concentrated. Purified with silica gel column and 2% MeOH in CH2Cl2. Obtained 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol (white solid). Yield: 0.71 g 20%. 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepin-2-ylmethanol (0.71 g, 3.28 mmol), 4-methylmorpholine N-oxide (1/198 g, 10.23 mmol), molecular sieves (powder, 4 angstroms) (3.32 g), and acetonitrile (0.07M) were placed together under N2. Tetrapropylammoniumperruthenate (0.113 g, 0.322 mmol) was added and after three hours the reaction solution was filtered through celite and concentrated. Purified with silica gel column and 1:1 EtOAc/Hexane. Obtained 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine-2-carbaldehyde (white solid). Yield: 0.31 g 44%.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CP(=O)(O)CCCCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (1.0 g, 0.005 mole) in chloroform (20 ml) was added triethylamine (1.6 ml, 0.011 mole) and the solution was cooled in an ice bath to 0° C. Trimethyl silyl chloride (1.4 ml, 0.011 mole) was added to the above solution dropwise, followed by ethyl bromoacetate (0.84 g, 0.56 ml, 0.011 mole). The ice bath was removed and the mixture stirred at room temperature overnight. The mixture was poured into 10% aqueous HCl (10 ml) and crushed ice HCl (10 ml) and crushed ice (10 g). After shaking the mixture in a separatory funnel, the chloroform layer was separated and the aqueous layer extracted with dichloromethane (2×50 ml). The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and the solvents removed on a rotavap. The resulting crude thick oil (1.42 g) was vacuum dried to get 1.42 g (99%) of title compound in the form of an oil. TLC: silica gel, CH2Cl2 :MeOH:HOAc shows one main spot, but elongated, Rf =0.29.
Reaction SMILES: [F:1][C:2]1[C:7]([N:8]2[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:6][C:5]([NH2:15])=[C:4]([N+:16]([O-])=O)[CH:3]=1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([NH2:16])[C:5]([NH2:15])=[CH:6][C:7]=1[N:8]1[CH2:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Nc1cc(N2CCCOCC2)c(F)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)c(N2CCCOCC2)cc1N
Yield: 48.6 %

Procedure:
7 g of 4-fluoro-2-nitro-5-perhydro-1,4-oxazepin-4-ylphenylamine in solution in 170 mL of methanol are hydrogenated under 1 bar of hydrogen pressure in the presence of 700 mg of palladium-on-charcoal at 22° C. for 10 hours. The reaction crude is filtered through celite and the filtrate is concentrated under vacuum in a rotary evaporator. After evaporation, the reaction crude is purified by flash chromatography (elution dichloromethane/methanol). 3 g of 4-fluoro-5-perhydro-1,4-oxazepin-4-ylbenzene-1,2-diamine are isolated. 1H NMR spectrum (400 MHz, DMSO-d6, δ in ppm): 1.88 (m, 2H); 3.11 (m, 4H); from 3.64 to 3.74 (m, 4H); 4.20 (broad s, 2H); 4.26 (broad s, 2H); from 6.25 to 6.31 (m, 2H).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11]([C@:14]1([CH2:28][OH:29])[CH2:18][N:17]([C@@H:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[CH:12]=[CH2:13].CN(C)C=O>O1CCCC1.CO>[CH2:11]([C@:14]1([CH2:28][O:29][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:18][N:17]([C@@H:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH3:20])[C:16](=[O:27])[CH2:15]1)[CH:12]=[CH2:13]
Reactant: BrCc1ccccc1
Reactant: C=CC[C@@]1(CO)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: C=CC[C@@]1(COCc2ccccc2)CC(=O)N([C@H](C)c2ccccc2)C1
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
Benzyl bromide (17.1 mL, 0.144 mol) and sodium hydride (55% in liquid paraffin, 6.27 g, 0.144 mol) were sequentially added to a solution of (4R)-4-allyl-4-hydroxymethyl-1-[(1R)-1-phenylethyl]pyrrolidin-2-one (31.1 g, 0.120 mol) in tetrahydrofuran (300 mL)-dimethylformamide (75 mL) in a nitrogen atmosphere at 0° C. The mixture was stirred at the same temperature for 30 minutes. Methanol (5 mL) was carefully added and stirred until gas was not generated. Then, the reaction was quenched with a saturated ammonium chloride solution (50 mL). The reaction solution was poured into a mixture of ethyl acetate (1000 mL) and water (150 mL), followed by extraction with ethyl acetate (1500 mL). The organic layer was sequentially washed with water (200 mL) and brine (200 mL×2), dried over anhydrous sodium sulfate, and filtered. The filtrate was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1→2:1→1:1) to give 41.3 g (99%) of the title compound as a pale yellow oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:7](=O)[CH2:6][C:5](=[O:9])[C:4]([CH3:11])([CH3:10])[O:3]1.P(Cl)(Cl)(Cl)(Cl)[Cl:14]>C(Cl)(Cl)Cl>[Cl:14][C:7]1[C:2]([CH3:12])([CH3:1])[O:3][C:4]([CH3:11])([CH3:10])[C:5](=[O:9])[CH:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC1(C)OC(C)(C)C(=O)CC1=O
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(C)(C)C(Cl)=CC1=O
Yield: 84.9 %

Procedure:
To a suspension of 2,2,6,6-tetramethylpyran-3,5-dione (741 mg, 4.35 mmol) in chloroform (10 ml) is added phosphorus pentachloride (454 mg, 2.18 mmol), and the reaction is heated to reflux for 5 hours. Silica gel is added to the cooled crude reaction mixture, the solvent is evaporated under reduced pressure and the residue is purified by flash chromatography on silica gel to give 5-chloro-2,2,6,6-tetramethyl-6H-pyran-3-one (349 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[N:16][C:17]=4[NH2:19])[N:12]([CH3:20])[N:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:21][N:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[CH2:27][C:28](O)=[O:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>O>[CH3:20][N:12]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:19])=[C:18]2[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:1]([C:28](=[O:29])[CH2:27][C:23]2[N:22]([CH3:21])[CH:26]=[CH:25][CH:24]=2)[CH2:2][CH2:3]3)=[N:11]1
Reactant: Cn1nc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Reactant: Cn1cccc1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1cccc1CC(=O)N1CCc2cc(-c3nn(C)c4ncnc(N)c34)ccc21
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A solution of 3-(2,3-dihydro-1H-indol-5-yl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.330 mmol), (1-methyl-1H-pyrrol-2-yl)acetic acid (46 mg, 0.33 mmol), HATU (126 mg, 0.330 mmol), and DIEA (0.231 mL, 1.321 mmol) was stirred at room temperature overnight. LCMS indicated good converison, so the crude was poured into water and stirred for 30 minutes. The precipitate that formed was collected by filtration, washed with water and dried at the pump for 30 minutes. The crude was adsorbed onto silica and purified by flash chromatography (0-10% methanol in DCM) to afford 1-methyl-3-{1-[(1-methyl-1H-pyrrol-2-yl)acetyl]-2,3-dihydro-1H-indol-5-yl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine (57.9 mg, 0.149 mmol, 45.2% yield) as a white solid. LC-MS (ES) m/z=388 [M+H]+. 1H NMR (400 MHz, DMSO-d6) 3.25 (m, 2H), 3.55 (s, 3H), 3.86-3.90 (m, 2H), 3.94 (s, 3H), 4.21-4.32 (m, 2H), 5.86-5.93 (m, 2H), 6.66-6.71 (m, 1H), 7.41-7.48 (m, 1H), 7.49-7.53 (m, 1H), 8.13-8.22 (m, 1H), 8.23-8.27 (m, 1H). Note: NH's are not observed in the NMR spectrum.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1.[NH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:21]1>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:20]4[CH2:24][CH2:23][CH:22]([C:25]5[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=5)[CH2:21]4)[CH:12]=3)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(F)c(F)cc2c1=O
Reactant: c1cncc(C2CCNC2)c1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCC(c4cccnc4)C3)c(F)cc2c1=O
Yield: 73 %

Procedure:
Starting from 1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (1.06 g, 4.0 mmol) and 3-(3-pyrrolidinyl)pyridine, a procedure analogous to that given in Example 1 provided the title compound (1.15 g, 73%) as an off-white solid, mp 233°-236° C.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[C:4]2[C:21]([CH3:24])=[N:22][O:23][C:3]1=2.[C:25](OC(=O)C)(=[O:27])[CH3:26].C(N(CC)CC)C>CN(C1C=CN=CC=1)C>[C:13]([C:12]1[CH:11]=[CH:10][C:9]([C:7]2[C:6]3[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=3[C:4]3[C:21]([CH3:24])=[N:22][O:23][C:3]=3[CH:2]([NH:1][C:25](=[O:27])[CH3:26])[N:8]=2)=[CH:16][CH:15]=1)#[N:14]
Reactant: Cc1noc2c1-c1ccccc1C(c1ccc(C#N)cc1)=NC2N
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)NC1N=C(c2ccc(C#N)cc2)c2ccccc2-c2c(C)noc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.6 %

Procedure:
To a round bottomed flask was added 4-(4-amino-1-methyl-4H-benzo[c]isoxazolo[4,5-e]azepin-6-yl)benzonitrile (69 mg, 0.22 mmol) and DMAP (2.7 mg, 0.022 mmol). The flask was purged with nitrogen, MeCN was added (5 mL), and the solution was cooled to 0° C. Acetic anhydride (49.5 μL, 0.53 mmol) and triethylamine (79 μL, 0.57 mmol) were added and the reaction was allowed to warm to ambient temperature and stirred for 2 h. The reaction was quenched with a 1:1 mixture of sat. aq. NaHCO3:brine and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, concentrated, and purified on a Biotage (isocratic elution 50% EtOAc:50% Hexanes) to provide the title compound as white solid (64 mg). LC/MS m/z 357 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[CH2:13][C:12](=[O:17])[CH2:11]2)[CH:7]=1.ClC1C=C(CCC2(C3CCCC3)OC(=O)CC(=O)C2)C=CC=1OC(C)C.[CH3:53][C:54]1[NH:55][CH:56]=[C:57]([CH:59]=O)[N:58]=1.CC1C=C(C)N2N=C(C=O)N=C2N=1>>[Cl:1][C:2]1[C:3]([O:25][CH3:26])=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH2:8][CH2:9][C:10]2([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[O:15][C:14](=[O:16])[C:13]([CH2:59][C:57]3[N:58]=[C:54]([CH3:53])[NH:55][CH:56]=3)=[C:12]([OH:17])[CH2:11]2)[CH:7]=1
Reactant: Cc1nc(C=O)c[nH]1
Reactant: COc1cc(OC)c(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: CC(C)Oc1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1Cl
Agent: Cc1cc(C)n2nc(C=O)nc2n1
Product: COc1cc(OC)c(CCC2(C3CCCC3)CC(O)=C(Cc3c[nH]c(C)n3)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared analogously to Example B(31), where 6-[2-(5-Chloro-2,4-dimethoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione (described below), as substituted in place of 6-[2-(3-Chloro-4-isopropoxy-phenyl)-ethyl]-6-cyclopentyl-dihydro-pyran-2,4-dione and 2-methyl-1H-imidazole-4-carbaldehyde was substituted in place of 5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-carbaldehyde of that example.
Reaction SMILES: [CH2:1]([C:3]1([C:39]2[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]C(CCCCCCC(F)(F)C(F)(F)F)C(O)=O)[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2].[F:46][C:47]([F:72])([C:68]([F:71])([F:70])[F:69])[CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH:54]([CH2:60]CCCCCC=C)[C:55]([O:57]CC)=[O:56]>>[CH2:1]([C:3]1([C:39]2[CH:40]=[CH:41][C:42]([OH:45])=[CH:43][CH:44]=2)[CH:12]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:60][CH:54]([CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][C:47]([F:46])([F:72])[C:68]([F:71])([F:70])[F:69])[C:55]([OH:57])=[O:56])[C:11]2[C:6](=[CH:7][C:8]([OH:38])=[CH:9][CH:10]=2)[S:5][CH2:4]1)[CH3:2]
Reactant: C=CCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)OCC
Reactant: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O
Product: CCC1(c2ccc(O)cc2)CSc2cc(O)ccc2C1CCCCCCCCCC(CCCCCCC(F)(F)C(F)(F)F)C(=O)O

Procedure:
Starting with the allyl compound prepared in Example 13 and the ethyl 2-(7,7,8,8,8-pentafluorooctyl)-9-decenoate prepared in Example 8, the same procedure as shown in Example 13 was repeated to give 11-[(3RS,4RS)-3-ethyl-7-hydroxy-3-(4-hydroxyphenyl)thiochroman-4-yl]-2-(7,7,8,8,8-pentafluorooctyl)undecanoic acid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]2[C:7]=1[C:8]([CH3:26])=[C:9]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)[C:10]([CH3:17])=[N:11]2.C(#N)C.[OH-].[Li+]>O1CCCC1>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][C:9]2[C:10]([CH3:17])=[N:11][C:12]3[C:7]([C:8]=2[CH3:26])=[C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])[CH:15]=[C:14]([CH3:16])[CH:13]=3)=[CH:24][CH:23]=1
Reactant: COC(=O)COc1cc(C)cc2nc(C)c(Cc3ccc(Cl)cc3)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)O)c2c(C)c(Cc3ccc(Cl)cc3)c(C)nc2c1

Procedure:
A solution of [3-(4-chlorobenzyl)-2,4,7-trimethylquinolin-5-yloxy]acetic acid methyl ester (0.045 g), acetonitrile (2.0 mL), tetrahydrofuran (1.0 mL) and 4.0 M aqueous lithium hydroxide solution (2.0 mL) was stirred at room temperature for 2 hours. The organic solvents were removed under reduced pressure and the pH of the residue adjusted to 5-6 by the addition of saturated aqueous sodium dihydrogenphosphate solution. The resulting mixture was extracted with chloroform and the combined extracts dried over magnesium sulfate. The solvent was removed under reduced pressure and trituration of the residue with diethyl ether and then methanol gave title compound, 0.025 g.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][C@:10]2([CH3:12])[C@@H:8]([CH2:9]2)[N:7]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:5])C.[OH-].[K+].Cl.C(Cl)Cl>CO.C1COCC1.O>[C:16]([O:15][C:13]([N:7]1[C@H:6]([C:4]([OH:5])=[O:3])[CH2:11][C@:10]2([CH3:12])[C@H:8]1[CH2:9]2)=[O:14])([CH3:19])([CH3:17])[CH3:18]
Reactant: CCOC(=O)[C@@H]1C[C@@]2(C)C[C@H]2N1C(=O)OC(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)N1[C@H](C(=O)O)C[C@@]2(C)C[C@@H]12
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (1R,3S,5R)-5-methyl-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester 3-ethyl ester (185 mg, 0.69 mmol) in MeOH (1.1 mL), THF (1.1 mL) and H2O (1.1 mL) was added KOH (77 mg, 1.37 mmol). The solution was stirred 2.5 h at RT, HCl (0.1N) was added (until pH 1), CH2Cl2 was added and the layers were separated (×2). The combined organic layers were dried (Na2SO4), filtered and concentrated. The material (yellow oil) thus obtained was used without further purification in the next step. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 12.46 (m, 1H), 3.86 (m, 1H), 3.06 (m, 1H), 2.40 (dd, 1H), 1.86 (m, 1H), 1.37 (m, 9H), 1.18 (s, 3H) 0.65 (m, 2H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH2:15].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:49](O)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>CN(C=O)C.C(OCC)(=O)C.O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:16]1[C:25]2[N:24]=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][NH:15][C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21
Reactant: O=C(O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.4 %

Procedure:
To a solution of N1-(1H-benzoimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-propane-1,3-diamine (166 mg, 0.50 mmol) in DMF (3 mL) was added 1-hydroxybenzotriazole hydrate (100 mg, 0.74 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (142 mg, 0.74 mmol), and benzoic acid (73 mg, 0.59 mmol). The reaction mixture was stirred overnight at room temperature. Then it was diluted with ethyl acetate (40 mL) and water (25 mL). The organic layer was washed with saturated NaHCO3 (30 mL) and brine (30 mL), dried (Na2SO4), filtered, concentrated, and dried in vacuo to afford a yellow oil. Purification by radial chromatography on silica gel (1 mm plate; using NH4OH/CH 3OH/CH2Cl2; 1:1:100→1:3:100) afforded the product as a yellow foam (80 mg, 37%). 1H NMR (CDCl3) δ 1.68-1.74 (m, 4H), 2.02-2.04 (m, 1H), 2.22 (m, 1H), 2.62-2.69 (m, 2H), 2.81 (t, 1H, J=4.8 Hz), 2.84-2.90 (m, 2H), 3.34-3.38 (m, 1H), 3.55-3.59 (m, 1H), 4.01-4.05 (m, 2H), 7.10-7.18 (m, 4H), 7.32 (t, 2H, J=7.8 Hz), 7.42-7.48 (m, 2H), 7.59 (dd, 2H, J=8.0, 1.5 Hz), 7.65 (br s, 1H), 8.43 (dd, 1H, J=3.9, 1.2 Hz).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1.[IH:19]>>[I:19][C:2]1[N:3]=[C:4]2[S:11][C:10]([S:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[N:9][N:5]2[C:6](=[O:8])[CH:7]=1
Reactant: CCCCCCSc1nn2c(=O)cc(Cl)nc2s1
Reactant: I
Product: CCCCCCSc1nn2c(=O)cc(I)nc2s1
Reaction time: 2 h
Yield: 80 %

Procedure:
A solution of 8.4 g of the thus obtained 7-chloro-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one and 88.2 g of a 57% hydroiodic acid aqueous solution was heated to 95°~110° C. and stirred for 2 hours. After cooling, the solution was filtered. The residue was washed with water and dissolved in toluene. The toluene solution was washed with a sodium hydrogen carbonate aqueous solution, a sodium thiosulfate aqueous solution and water respectively and dried over anhydrous sodium sulfate. The solvent was distilled off and thus 9.8 g of 80% pure 7-iodo-2-hexylthio-5H-1,3,4-thiadiazolo[3,2-a]pyrimidin-5-one was obtained.
Reaction SMILES: [CH:1]([C:4](C([O-])=O)(O)[C:5](C(C)C)(O)[C:6]([O-])=[O:7])(C)C.[C:17]([O:21]O)([CH3:20])([CH3:19])C.CC(O)/C=C/CCC.C(O)(=O)C(C(C(O)=O)O)O>C(Cl)Cl.O.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH3:19][C@H:17]([OH:21])[C@@H:20]1[O:7][C@H:6]1[CH2:5][CH2:4][CH3:1]
Reactant: CC(C)(C)OO
Reactant: CC(C)C(O)(C(=O)[O-])C(O)(C(=O)[O-])C(C)C
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: CCC/C=C/C(C)O
Solvent: ClCCl
Solvent: O
Product: CCC[C@@H]1O[C@H]1[C@H](C)O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Powdered, activated molecular sieves (4 Å, 1.80 g) were suspended in 205 ml of CH2Cl2 and the suspension was cooled to about -30° C. (+)-Diisopropyltartrate (0.76 ml, 0.06 eq.) and titanium (IV) isopropoxide (0.88 ml, 0.05 eq.) was added to the cooled suspension via syringe. A 3.8 M CH2Cl2 solution of t-butylhydroperoxide (4.4 ml, 0.28 eq.) was then added dropwise to the suspension over 5 min. while the temperature of the suspension was maintained between -20° C. and -30° C. After 30 min., a CH2Cl2 solution of trans-3-hepten-2-ol was added dropwise to the reaction mixture The reaction mixture was then held in the freezer (at -20° C.) for about 23 hours, after which it was warmed to 0° C. and poured onto a precooled (0° C.) solution of ferrous sulfate heptahydrate (19 g) and tartaric acid (6 g) in 6 ml of water. The resulting solution was stirred at room temperature for 10 min. The organic and aqueous phases were separated and the aqueous phase was extracted (2×38 ml) with ether. The organic layer and extracts were combined and vigorously stirred (0° C., 1 hour) after addition of 6 ml of a 30% (w/v) solution of NaOH in brine. After addition of 30 ml of water, the phases were separated and the aqueous phase was extracted (2×30 ml) with ether. The combined organic phases were dried over sodium sulfate. Evaporation of solvent, followed by flash chromatography of the residue (30% by volume ethyl acetate in hexane) gave a colorless liquid. The liquid was distilled to give 1(S)-methyl-2(S),3(S)-epoxyhexanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.CO[CH:19](OC)[N:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH3:19][N:20]([CH3:22])[CH:21]=[C:9]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:16]
Reactant: Cc1ccc(C(=O)Cc2ccccc2)cc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)C(=CN(C)C)c2ccccc2)cc1

Procedure:
The solution of 1-(4-methylphenyl)-2-phenylethanone (2-1) (Renault, O; Dallemagne, P.; and Rault, S. Org. Prep. Proced. Int. 1999, 31, 324) (3.29 g, 15.65 mmol) and N,N-dimethylformamide dimethylacetal (4.66 g, 39.12 mmol) in DMF (15 mL) was stirred at 110° C. for 1 h. The mixture was concentrated in vacuo to give 3-(dimethylamino)-1-(4-methylphenyl)-2-phenylprop-2-en-1-one (2-2. LRMS m/z (M+H) Calcd: 266.4, found: 266.2.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH2:5][NH:6][C:7](=[O:30])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:22][C:23]2[CH:28]=[CH:27][C:26](Br)=[CH:25][CH:24]=2)[CH2:15][CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[CH:10][CH:9]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[F:19][C:18]([F:20])([F:21])[CH2:17][CH2:16][CH2:15][CH:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:31])=[O:30])=[CH:9][CH:10]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([C:37]2[CH:38]=[CH:39][C:34]([C:33]([F:44])([F:43])[F:32])=[CH:35][CH:36]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(Br)cc2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(O)CCNC(=O)c1ccc(C(CCCC(F)(F)F)Oc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 128 starting from 3-{4-[1-(4-bromo-phenoxy)-5,5,5-trifluoro-pentyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 552.2 [M−H]−; Isomer 2 MS: 552.2