Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][CH:11]([CH:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH3:14])[CH:10]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OCC(Cl)(Cl)Cl)=O>CC#N>[Cl:33][C:28]1[CH:27]=[C:26]([CH:10]2[CH:11]([CH:13]([O:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:24])([F:25])[F:23])=[CH:20][CH:21]=3)[CH3:14])[CH2:12][NH:8][CH2:9]2)[CH:31]=[CH:30][C:29]=1[Cl:32]
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(Cc2ccccc2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: CC#N
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reaction time: 4 h
Yield: 66.8 %

Procedure:
To a solution of (3RS,4SR)-1-benzyl-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine (XI-B-1) 0.99 g (2.00 mmol) dissolved in CH3CN (25 mL) was added 0.40 mL (3.00 mmol) of 2,2,2-trichloroethyl chloroformate and stirring was continued for 4 hours at RT. Volatiles were removed under vacuo, and the crude was dissolved in AcOH (20 mL) before a total of 800 mg of Zn dust was added portion wise. After three hours at RT, the reaction mixture was filtered on celite, the solvent removed under vacuo, followed by extraction with EtOAc/aq. NaHCO3 (basic pH). The organic phases were dried on Na2SO4 and column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 0.54 g (67%) of the title compound as a colorless oil. ES-MS m/e: 404.2 (M+H+).
Reaction SMILES: O[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1.[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C>C1(C)C=CC=CC=1>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:12])[O:9]2)=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=c1ccc2ccc(O)cc2o1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1ccc2ccc(CCCCCCCl)cc2o1

Procedure:
Preparation can be carried out analogously to Synthetic Example 1 using 16.2 g (100 mmol) 7-Hydroxycoumarin, 14.3 g (105 mmol) 6-chlorohexanol, 28.8 g (110 mmol) triphenylphosphine and 47.9 g (110 mmol) of a 40% solution of azodicarboxylic acid diethyl ester in toluene to yielded 7-(6-chlorohexyl) coumarin.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[N:5]2>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C@@H:7]([CH3:12])[CH2:6][NH:5]2
Reactant: Cc1cnc2cc(Cl)ccc2n1
Solvent: Cc1ccccc1
Product: C[C@H]1CNc2cc(Cl)ccc2N1
Temperature: 40 °C
Reaction time: 16 h
Yield: 97.3 %

Procedure:
To an argon-purged pressure-resistant glass vessel (100 mL) equipped with a magnetic stir bar, RuCl[(R)-daipena][(R)-dm-segphos] (1.1 mg, 0.94 μmol) and KO(t-Bu) (5.3 mg, 0.047 mmol) were added, and the vessel was purged with argon again. To this vessel, a toluene (2.5 mL) solution containing 6-chloro-2-methylquinoxaline (33.6 mg, 0.188 mmol) and being degassed by the freeze-pump-thaw technique in advance was added by pressure transfer using a cannula. An operation in which hydrogen was introduced into the pressure-resistant vessel up to 0.8 MPa and then released was repeated 10 times to completely substitute the inside with hydrogen. Then, hydrogen was introduced up to 2.0 MPa, and the vessel was stirred in a water bath at 40° C. for 16 hours. After hydrogen was released, the solution was concentrated under reduced pressure, and the residue was purified through a silica gel short path column (dichloromethane) to obtain (S)-6-chloro-1,2,3,4-tetrahydro-2-methylquinoxaline (33.4 mg, 97%). A result of an analysis was conducted by high performance liquid chromatography (column: CHIRALCEL OD-H, mobile phase: hexane:IPA=90:10, 1 mL/min) showed that the optical purity of this product was 99% ee or higher.
Reaction SMILES: Cl.[CH3:2][C:3]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)([CH3:7])[C:4]([OH:6])=O.[CH2:28]([NH:30][CH2:31][CH3:32])[CH3:29]>>[CH2:28]([N:30]([CH2:31][CH3:32])[C:4](=[O:6])[C:3]([CH3:2])([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH3:20])[C:13]([CH3:21])=[C:12]2[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)[CH3:7])[CH3:29]
Reactant: CCNCC
Reactant: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)O)ccc21
Agent: Cl
Product: CCCn1c(C)c(-c2ccncc2)c2cc(OC(C)(C)C(=O)N(CC)CC)ccc21

Procedure:
The above compound was prepared from 2-methyl-2-[2-methyl-1-propyl-3-(4-pyridyl)-1H-indole-5-yloxy]propanoic acid hydrochloride and diethylamine using a procedure analogous to that of Example 128.
Reaction SMILES: C[CH2:2][N:3]=[C:4]=NCCCN(C)C.Cl.[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](O)=[O:17].CNC.C1COCC1>ClCCl.ON1C2C=CC=CC=2N=N1>[NH2:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:3]([CH3:4])[CH3:2])=[O:17]
Reactant: CCN=C=NCCCN(C)C
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Agent: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.8 %

Procedure:
EDC.HCl (2.47 g, 12.88 mmol) was added to a stirred mixture of 2-amino-3-nitrobenzoic acid (2.18 g, 11.98 mmol) (Mickelson, J. Med. Chem., 39(23) 4662 (1996)), 2M dimethylamine in THF (6.45 ml, 12.9 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.74 mmol) in dichloromethane (100 ml). The reaction mixture was stirred at room temperature for 18 h, washed with saturated aqueous sodium bicarbonate and the organic layer dried (Na2SO4) and evaporated in vacuo to afford the title compound as a pale orange gum (2.5 g, 100%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:15][CH2:14][CH2:13][N:12]([S:16]([C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][C:28]=2Br)[C:22]([O:24][CH3:25])=[O:23])(=[O:18])=[O:17])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)CCCC)[CH:31]=[CH2:32].CCOC(C)=O.O>C1(C)C=CC=CC=1.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>[CH2:32]([C:28]1[CH:27]=[CH:26][C:21]([C:22]([O:24][CH3:25])=[O:23])=[CH:20][C:19]=1[S:16]([N:12]1[CH2:13][CH2:14][CH2:15][CH:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:10][CH2:11]1)(=[O:18])=[O:17])[CH:31]=[CH2:30]
Reactant: COC(=O)c1ccc(Br)c(S(=O)(=O)N2CCCC(OCc3ccccc3)CC2)c1
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCc1ccc(C(=O)OC)cc1S(=O)(=O)N1CCCC(OCc2ccccc2)CC1
Temperature: 110 °C
Yield: 52.8 %

Procedure:
Methyl 3-(4-benzyloxyazepan-1-yl)sulfonyl-4-bromo-benzoate (1.30 g, 2.69 mmol, 1.00 Eq), allyl(tributyl)stannane (1.07 g, 3.23 mmol, 1.20 Eq) LiCl (136.83 mg, 3.23 mmol, 1.20 Eq) and Pd(PPh3)4 (310.85 mg, 269.00 umol, 0.10 Eq) in TOLUENE (20 mL) was de-gassed and then heated to 110° C. for 16 hr under N2. TLC (PE:EtOAc=1:1) showed the starting material and the product was the same spot. The reaction mixture was poured into H2O, extracted with EA. The organic phase was dried over anhydrous Na2SO4, concentrated in vacuum to give a residue, which was purified by column chromatography (silica gel, eluting with PE:EA=1:1) to afford the pure methyl 4-allyl-3-(4-benzyloxyazepan-1-yl)sulfonyl-benzoate (630.00 mg, 1.42 mmol, 52.80% yield) as light yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:6][N:5]2[CH:15]=[CH:16][N:17]=[C:4]2[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+]>C(COC)OC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3][C:4]3[N:5]([CH:15]=[CH:16][N:17]=3)[CH:6]=2)=[CH:9][CH:10]=1
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: Fc1ccc(-c2cn3ccnc3nc2Cl)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=Cc1ccc(-c2nc3nccn3cc2-c2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 22 h
Yield: 42.4 %

Procedure:
2.8 g (11.3 mmol) 7-Chloro-6-(4-fluorophenyl)-imidazo[1,2-a]pyrimidine are given in 39 mL dimethoxyethane (not completely dissolved). 1.86 g (12.4 mmol) 4-formylphenylboronic acid and 22 mL Na2CO3 solution (10%) are added. After addition of 0.42 g (0.51 mmol) 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) the reaction mixture is purged 3× with argon and heated to 90° C. After 22 h stirring at 90° C. complete dissolution has taken place. The reaction mixture is cooled down and treated with 100 mL water and 150 mL dichloromethane. After vigorous stirring at rt for one hour the organic phase is separated. The aqueous phase is extracted twice with dichloromethane (100 mL each). The combined organic phases are washed twice with water (50 mL each), dried (Na2SO4) and the solvent is removed. The crude product is purified via chromatography (silicagel, dichloromethane/methanol). 1.52 g (42.4%) of the pure compound and two other fractions (224.6 mg=6.3% and 456.9 mg=12.7%) with contaminated product are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[NH:9])[CH:5]=[CH:4][CH:3]=1.[C:11](OC)(=[O:17])[CH2:12][C:13](OC)=[O:14].C[O-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[N:10]=[C:13]([OH:14])[CH:12]=[C:11]([OH:17])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1cccc(C(=N)N)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2nc(O)cc(O)n2)n1
Temperature: 25 °C

Procedure:
A solution of 6-methyl-pyridine-2-carboxamidine (step 2) (1.2 eq, 8.23 mmol, 1.41 g) in MeOH (5 ml) under an inert atmosphere of argon, at room temperature is treated with dimethyl malonate (1 eq, 6.86 mmol, 1.04 ml) and 0.5 M sodium methoxide in MeOH (3eq, 20.6 mmol, 41.2 ml). The resulting mixture is heated at reflux overnight and then allowed to cool to room temperature. The mixture is dry loaded onto silica and purification by flash chromatography eluting with 0-5% MeOH in DCM affords the title compound as a pale yellow solid [M+H]+=204.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][OH:38]>CN(C)C=O>[OH:38][CH2:37][CH2:36][CH2:35][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[C:14]([C:23](=[O:25])[CH3:24])=[N:15][C:16]4[C:21]([CH:22]=3)=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:26][CH3:27]
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1O
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCCCO
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
1-[3-(7-Hydroxy-6-methoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 390) (50 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (58 mg) and 3-bromo-1-propanol (0.03 ml) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-acetone to give the title compound (44 mg, yield 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=O.[N+:13]([CH3:16])([O-:15])=[O:14].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[CH:5]=[CH:16][N+:13]([O-:15])=[O:14]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: COc1ccc(C=C[N+](=O)[O-])c(OC)c1

Procedure:
A mixture of 100 g of 2,4-dimethoxybenzaldehyde, 102 ml of nitromethane, 46.4 g of ammonium acetate and 500 ml of glacial acetic acid was heated at reflux for 2 hours and quenched in 700 ml of water. The crude precipitate was recrystallized from ethanol to give 105.57 g of 1-(2,4-dimethoxyphenyl)-2-nitroethylene as a yellow solid.
Reaction SMILES: [OH-:1].[Na+].BrBr.Br[O-].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH2:24][CH:20]4[CH2:21][CH:22]([CH2:23]2)[C:18]([C:25](=[O:27])C)([CH2:19]4)[CH2:17]3)=[CH:12][CH:11]=1)([O-:9])=[O:8].Cl>O1CCOCC1.O>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]23[CH2:24][CH:20]4[CH2:21][CH:22]([CH2:23]2)[C:18]([C:25]([OH:1])=[O:27])([CH2:19]4)[CH2:17]3)=[CH:12][CH:11]=1)([O-:9])=[O:8]
Reactant: CC(=O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reactant: [OH-]
Agent: BrBr
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 75 %

Procedure:
To a stirred solution of NaOH (6.3 g, 158.0 mmol), H2O (54.0 mL) and 1,4 dioxane (7 mL) at ice bath temperature was added Br2 (3.2 mL, 59.0 mmol) and stirred for 5 minutes. The formed hypobromite solution was added dropwise to a stirred solution of 1-[1-(4-nitrophenyl)tricyclo[3.3.1.03,7]non-3-yl]ethanone (3.0 g, 10.53 mmol) obtained in step I, in 1,4-dioxane (14 mL) at ice bath temperature. The reaction mixture was gradually warmed to r.t. and after 1 h, it was cooled to ice bath temperature and acidified with conc. HCl, diluted with water, and extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and the solvent was removed under reduced pressure to obtain 1-(4-nitrophenyl)tricyclo[3.3.1.03,7]nonane-3-carboxylic acid (2.27 g) in 75% yield as off-white solid; M.R: 145-150° C. m/z (M−1) 286; IR cm−1 3437, 2945, 1693, 1596, 1511, 1408, 1352, 946, 839, 749. 1H NMR (CDCl3) 300 MHz δ 8.16 (d, J=8.8 Hz, 2H), 7.42 (d, J=8.8 Hz, 2H), 2.96-2.88 (m, 1H), 2.59-2.52 (m, 1H), 2.44-2.33 (m, 1H), 2.23-2.03 (m, 4H), 2.02-1.68 (m, 5H).
Reaction SMILES: [CH3:1][C:2]12[CH2:9][O:8][C:5]([CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][C@@H:16]3[C@@H:20]([CH2:21][S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)(=[O:24])=[O:23])[C@H:19]([O:31][Si](CC)(CC)CC)[CH2:18][C@@H:17]3[OH:39])([O:6][CH2:7]1)[O:4][CH2:3]2.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[CH3:1][C:2]12[CH2:7][O:6][C:5]([CH2:10][CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15][C@@H:16]3[C@@H:20]([CH2:21][S:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)(=[O:24])=[O:23])[C@H:19]([OH:31])[CH2:18][C@@H:17]3[OH:39])([O:4][CH2:3]1)[O:8][CH2:9]2
Reactant: CC[Si](CC)(CC)O[C@@H]1C[C@H](O)[C@H](C/C=C\CCCC23OCC(C)(CO2)CO3)[C@H]1CS(=O)(=O)c1ccccc1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CC12COC(CCC/C=C\C[C@@H]3[C@@H](CS(=O)(=O)c4ccccc4)[C@H](O)C[C@@H]3O)(OC1)OC2

Procedure:
The mixture of (1R,2R,3R,4S)-3-[(Z)-6-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)hexe-2-nyl]-2-[(phenylsulfonyl)methyl]-4-(triethylsilyloxy)cyclopentanol (ca. 65%) and (1S,2R,3R,4R)-2-[(Z)-6-(4-methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)hex-2-enyl]-3-[(phenylsulfonyl)methyl]-4-(triethylsilyloxy)cyclopentanol (ca. 35%) (584 mg of the mixture, yield 15.4%), colorless glaze was obtained; 1H-NMR (CDCl3; 200 MHz) δ 0.57 (6H, 2×q), 0.79 (1.95H, s), 0.80 (1.05H, s), 0.93 (9H, 2×t), 1.34-1.54 (3.5H, m), 1.56-1.78 (3H, m), 1.82-2.20 (6.6H, m), 3.01 (0.65H, dd: 14.4, 11.2 Hz), 3.32 (0.65H, dd: 14.4, 2.6 Hz), 3.56 (0.65H, m), 3.88 (3.9H, s), 3.89 (2.1H, s), 3.90 (0.35H, m), 4.13 (1.30H, m), 5.15-5.38 (2H, m), 7.54-7.74 (3H, m), 7.93-7.99 (2H, m); fractions prepared after washing out with Phase II were combined on the basis of TLC chromatograms, concentrated and dried under vacuum. Glaze was obtained (3.597 g) containing slight amount of triphenylphosphine oxide, which was removed by two-time maceration with Et2O (8 mL, 4 mL). (1R,3S,4R,5R)-4-[(Z)-6-(4-Methyl-2,6,7-trioxabicyclo[2.2.2]octan-1-yl)hex-2-enyl]-5-[(phenylsulfonyl)methyl]cyclopentane-1,3-diol was prepared (2.0 g, 65.5%); 1H-NMR (CDCl3; 200 MHz) δ 0.80 (3H, s), 1.36-1.52 (3H, m), 1.61 (2H, m), 1.8-2.29 (8H, m), 3.05 (1H, dd: 14.3, 11.2 Hz), 3.33 (1H, dd: 14.3, 2.6 Hz), 3.53 (1H, bs, OH), 3.88 (6H, s), 4.09 (1H, m), 4.31 (1H, m), 5.17-5.39 (2H, m), 7.47-7.74 (3H, m), 7.93-7.99 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([O:19]C)[CH:13]=[C:12]([O:21]C)[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34]C)=[CH:30][CH:29]=2)[C@H:24]1[CH2:36][OH:37].Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([OH:19])[CH:13]=[C:12]([OH:21])[C:11]=2[C@@H:23]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][C:31]([OH:34])=[CH:32][CH:33]=2)[C@H:24]1[CH2:36][OH:37]
Reactant: COc1ccc(N2CC[C@@H](c3c(OC)cc(OC)c4c(=O)cc(-c5ccccc5Cl)oc34)[C@@H]2CO)cc1
Agent: Cl
Solvent: c1ccncc1
Product: O=c1cc(-c2ccccc2Cl)oc2c([C@@H]3CCN(c4ccc(O)cc4)[C@H]3CO)c(O)cc(O)c12

Procedure:
Compound of example 124 (0.7 g, 1.3 mmol) was demethylated using pyridine hydrochloride (10.5 g, 90.9 mmol) as described in example 17 to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH2:9])=[N:6][CH:7]=1.[CH2:10]([N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[C:17](O)=[O:18])[CH3:11].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][NH:9][C:17]([C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH2:10][CH3:11])=[O:18])=[N:6][CH:7]=1
Reactant: NNc1ccc(F)cn1
Reactant: CCN1CCC[C@H]1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCCl
Product: CCN1CCC[C@H]1C(=O)NNc1ccc(F)cn1
Reaction time: 4 h
Yield: 54.2 %

Procedure:
To a solution of (5-fluoro-pyridin-2-yl)-hydrazine (178 mg, 1.39 mmol) in DMF (10.0 mL) was added (S)-1-ethyl-pyrrolidine-2-carboxylic acid (200 mg, 1.39 mmol), EDC (293 mg, 1.53 mmol) and HOBt.H2O (18.0 mg, 0.14 mmol). The reaction was stirred for 4 h then partitioned between EtOAc and water. The aqueous layer was then extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (190 mg, 54%). LCMS (Method 4): Rt 0.29 min, ink 253.1 [MH+].
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:22][CH2:21]2)=[O:19])[C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2].O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH2:11][C@@H:12]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH2:32][CH2:31][C:30]4[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=4[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[CH2:9][CH3:10])[CH3:2]
Reactant: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)OC)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
74.4 g (0.147 mol) methyl (R)-3-(3,4-diethyl-phenyl)-2-{[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carbonyl]-amino}-propionate dissolved in 600 mL THF was combined with 5.4 g (0.221 mol) lithium hydroxide hydrate in 300 mL water while cooling with an ice bath and stirred overnight at RT. The reaction mixture was evaporated down under reduced pressure, 300 mL water was added and the mixture was extracted three times with 200 mL EtOAc. The aqueous phase was freed from the organic solvent under reduced pressure and combined with 500 mL 2 M HCl with stirring and cooling with the ice bath. The precipitate formed was suction filtered, washed with water and dried.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9].S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:24][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][N:13]=2)=[C:7]([CH:10]=1)[C:8]#[N:9]
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Solvent: ClCCl
Product: N#Cc1cc(CCl)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To the solution of 5-(hydroxymethyl)-2-((5-(trifluoromethyl)pyridin-2-yl)oxy)benzonitrile (269 mg, 0.999 mmol) in DCM (20 mL), was added thionyl chloride (0.7 mL, 9.59 mmol) dropwise. The mixture was stirred at room temperature for 2 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice, dried over Na2SO4, and concentrated in vacuo to afford the title compound (275 mg, 96% yield) as a light green solid. LCMS: rt=3.54 min, [M+H+]=313
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].S(=O)(=O)(O)O.[CH3:20]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:20])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Fluoro-3-nitrophenylacetic acid (31.0 g, 0.156 mol) was added to a mixture of concentrated sulfuric acid (1.6 ml) and methanol (160 ml) and the mixture was stirred for 3 days at room temperature. Most of the solvent was removed in vacuo and the residue was partitioned between diethyl ether and water. The organic phase was washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate was evaporated in vacuo to give methyl 4-fluoro-3-nitrophenylacetate (27.2 g) as a yellow oil.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:16])[CH3:15])[CH:12]=2)=[CH:6][CH:5]=1)(=O)[CH3:2].[BH4-].[Na+].[OH-].[K+]>COCCOCCOC.CCOCC.B(F)(F)F>[CH2:1]([C:4]1[C:13]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]([CH:14]([CH3:15])[CH3:16])[CH:12]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CC(=O)c1ccc2cccc(C(C)C)cc1-2
Agent: FB(F)F
Agent: [BH4-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCc1ccc2cccc(C(C)C)cc1-2

Procedure:
The compound (20) (1.95 g) was dissolved in a mixture of diglyme (120 ml) and ether (120 ml), and BF3 etherate (2.1 ml) was added to the mixture while stirring and cooling with ice. To thus produced solution, while stirring and cooling with ice, a diglyme (8 ml) solution of NaBH4 (700 mg) was added dropwise. After stirring for 30 minutes, the reaction solution was poured into 5% potassium hydroxide aqueous solution. The thus obtained solution was extracted with hexane, washed with water and dried. The solvent was distilled off, and the thus obtained crude product was purified by column chromatography with silica gel (200 g), eluting with hexane. The first eluted part gave the product (22) at a yield of 1.28 g (65.6%) as a blue oily substance.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[Cl:10][C:11]1[N:16]=CC=C[N:12]=1.CCN(C(C)C)C(C)C>CCOC(C)=O>[Cl:10][C:11]1[NH:16][C:5](=[O:6])[C:4]2[C:3](=[CH:2][CH:9]=[CH:8][CH:7]=2)[N:12]=1
Reactant: Clc1ncccn1
Reactant: O=Cc1cccc(O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=c1[nH]c(Cl)nc2ccccc12
Temperature: 105 °C
Yield: 54.8 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (2.00 g, 16.38 mmol), 2-chloropyrimidine (1.88 g, 16.38 mmol) and iPr2NEt (5.71 mL, 32.75 mmol), under N2 atmosphere was heated at 105° C. for 24 h. The reaction mixture was allowed to cool to room temperature. The crude was subjected to column chromatography (silica gel, 20% EtOAc in hexanes) to furnish 1.62 g of the desired aryl ether (1) as an off-white solid.