Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29]#[N:30])=[CH:28][C:17]=3[N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]([CH:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:18]3[CH:25]=[CH:26][C:27]([C:29](=[N:32][OH:33])[NH2:30])=[CH:28][C:17]=3[N:16]=2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=NO)c1ccc2c(c1)nc(-c1ccc(OCc3ccccc3)cc1)n2C1CCCC1
Yield: 72 %

Procedure:
2-(4-Benzyloxyphenyl)-5-cyano-1-cyclopentylbenzimidazole (400 mg) obtained in Example 14 was suspended in ethyl alcohol (3 ml) and water (1.5 ml), and hydroxylamine hydrochloride (141 mg) and sodium hydrogencarbonate (170 mg) were added. The mixture was refluxed under heating overnight. The reaction mixtures was allowed to cool and the precipitated crystals were collected by filtration to give the title compound (312 mg, yield 71%).
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[C:8]2[CH2:14][CH:13]3[NH:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:28][CH:29]=[C:30]([CH3:32])[CH3:31]>C(#N)C>[CH3:31][C:30]([CH3:32])=[CH:29][CH2:28][N:15]1[CH:10]2[CH2:11][CH2:12][CH:13]1[CH2:14][C:8](=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1)[CH2:9]2
Reactant: c1ccc(C(=C2CC3CCC(C2)N3)c2ccsc2)cc1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)=CCN1C2CCC1CC(=C(c1ccccc1)c1ccsc1)C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 100 mg (355 μmol) of 3-(phenyl-thiophen-3-yl-methylene)-8-aza-bicyclo[3.2.1]octane in 1 mL of acetonitrile was added 98 mg (710 μmol) of K2CO3 and 41 μL (355 μmol) of 4-bromo-2-methyl-2-butene at room temperature. The reaction mixture was allowed to stir overnight at room temperature. Next day, the crude was filtered and washed with acetonitrile. The combined filtrates were concentrated. The concentrated sample was purified by reverse phase chromatography (20×100 mm J'sphere H-80 YMC column using a gradient of 0.1% TFA/water to 5% water/0.1% TFA/acetonitrile). The eluent was evaporated to yield the title compound as a white solid; MS m/z (MH+) 350; 1H NMR 300 MHz (MeOD-d4) δ 6.87-7.39 (m, 8H), 5.35 (t, 1H), 3.94-4.00 (m, 2H), 3.29-3.31 (m, 2H), 2.58-2.89 (m, 4H), 1.62-2.25 (m, 10H).
Reaction SMILES: [C:1]([CH2:5][CH2:6][Si:7]([Cl:10])(Cl)[Cl:8])([F:4])([F:3])[F:2].[C:11]([CH2:15][CH2:16][SiH](Cl)Cl)([F:14])([F:13])[F:12]>[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Si:7]([CH2:6][CH2:5][C:1]([F:4])([F:3])[F:2])([CH2:16][CH2:15][C:11]([F:14])([F:13])[F:12])([Cl:10])[Cl:8]
Reactant: FC(F)(F)CC[SiH](Cl)Cl
Reactant: FC(F)(F)CC[Si](Cl)(Cl)Cl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Product: FC(F)(F)CC[Si](Cl)(Cl)CCC(F)(F)F
Temperature: 50 °C

Procedure:
2 moles CF3CH2CH2SiCl3, 3.5 moles Me2SiHCl, and 2.6 moles tetra(n-butyl)ammonium chloride were introduced into a flask and heated under reflux for 3 days with stirring. A mixture of chlorosilanes was then recovered by distillation in vacuo. According to analysis by gas chromatography, the main components of the reaction product were CF3CH2CH2SiCl3, CF3CH2CH2SiHCl2, Me2SiHCl, and Me2SiCl2. The CF3CH2CH2SiCl3 and CF3CH2CH2SiHCl2 fraction was isolated by distillation in vacuo. The CF3CH2CH2SiCl3 and CF3CH2CH2SiHCl2 mixture was placed in a flask, 5 g isopropanolic chloroplatinic acid solution (concentration=10%) was added, and, while stirring and heating to 50° C., CF3CH=CH2 gas was then continuously injected through a glass tube inserted into the liquid. Its addition was halted when the peak for CF3CH2CH2SiHCl2 had disappeared in gas chromoatographic analysis. (CF3CH2CH2)2SiCl2 (bp=128° C./20 mmHg) was then isolated by distillation in vacuo.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=O.[CH2:28]([NH2:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CC(O)=O.O>CCO>[CH2:28]([NH:36][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:27])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=3[O:25][CH3:26])[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:2])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: NCCc1ccccc1
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccc(OC)cc3OC)ccc2c1O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2ccc3c(O)c(C(=O)NCCc4ccccc4)ncc3c2=O)c(OC)c1
Temperature: 25 °C
Yield: 69 %

Procedure:
A mixture of 7-(2,4-dimethoxy-benzyl)-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (15 mg, 0.041 mmol) and phenethylamine (0.020 mL, 0.142 mmol) in EtOH (2 mL) was refluxed for 16 h. After cooling the mixture to r.t., AcOH (0.1 mL) and water (2 mL) were added. The resulting precipitate was isolated by filtration, washed with cold MeOH/H2O (5 mL, 1:1), and purified by silica gel chromatography (0-2% MeOH/CH2Cl2) to give 13 mg of the title compound. MS: (+) m/z 460.36 (M+1).
Reaction SMILES: [NH2:1][N:2]=[C:3]([NH2:7])[N:4]([NH2:6])[NH2:5].[S:8](=[O:12])(=[O:11])([OH:10])[OH:9]>O.C(O)C>[S:8]([O-:12])([O-:11])(=[O:10])=[O:9].[NH2:1][NH+:2]=[C:3]([NH2:7])[N:4]([NH2:6])[NH2:5].[NH2:1][NH+:2]=[C:3]([NH2:7])[N:4]([NH2:6])[NH2:5]
Reactant: O=S(=O)(O)O
Reactant: NN=C(N)N(N)N
Solvent: CCO
Solvent: O
Product: N[NH+]=C(N)N(N)N
Product: O=S(=O)([O-])[O-]
Yield: 103.2 %

Procedure:
Triaminoguanidine (5.2 g, 0.05 mole) was dissolved in a mixture of water and ethanol and sulfuric acid (4.9 g, 0.05 mole) added. A white precipitate formed which was filtered, ethanol washed and dried to give 7.9 g of product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:23][OH:24]>O.CCO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[NH:15])[NH:23][OH:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=N)NO)CC1
Temperature: 25 °C

Procedure:
To a mixture of 4-cyano-piperidine-1-carboxylic acid tert-butyl ester (6.3 g, 30 mmol), K2CO3 (4.2 g, 30 mmol) in H2O (50 mL) and EtOH (30 mL) was added hydroxylamine hydrogenchloride (4.17 g, 60 mmol). The mixture was heated under reflux overnight, cooled to room temperature and ethanol was removed in vacuo. The residue was extracted with EtOAc (300 mL). The organic layer was washed successively with H2O and brine. After drying (Na2SO4), the solvent was removed to afford the desired product.
Reaction SMILES: [CH3:1][C:2]1(C)O[O:3]1.C=C.[C:8]1([CH:14]2[CH2:19][C:18](=[O:20])[CH2:17][CH:16]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)=[O:29]>>[CH2:2]1[O:3][C:18]2([CH2:19][CH:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:15]([OH:29])[CH:16]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:17]2)[O:20][CH2:1]1
Reactant: CC1(C)OO1
Reactant: O=C1CC(c2ccccc2)NC(c2ccccc2)C1
Reactant: CC(C)=O
Agent: C=C
Product: ON1C(c2ccccc2)CC2(CC1c1ccccc1)OCCO2
Temperature: 0 °C
Yield: 72 %

Procedure:
812 mL (40.6 mmol) of dimethyldioxirane, 0.050M in acetone, is added via a cannula to a 0° C. solution of 12.0 g (40.6 mmol) of 2,6-diphenyl-4-piperidone ethylene petal in 100 mL acetone. After stirring for ten minutes at 0° C., the reaction mixture is concentrated under reduced pressure and the residue is recrystallized from methanol to yield 9.0 g (72%) of the title compound as a white solid, melting at 161°-162° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[C:23]1([C:29]#[CH:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:30]#[C:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#Cc3ccccc3)cc1C(c1ccccc1Cl)=NC2

Procedure:
The title compound was obtained by reacting 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with phenylacetylene under the conditions described in EXAMPLE 37. The product was isolated by chromatography over the 50-fold amount of silica gel using 5% (v/v) of ethanol in methylene chloride for elution. The combined clean fractions were evaporated and the residue was crystallized from ethyl acetate to give colorless crystals of 4-(2-chlorophenyl)-9-methyl-2-(phenylethynyl)-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]-diazepine with m.p. 215°-217°.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:11])=[CH:5][C:6]=1[S:7]([Cl:10])(=[O:9])=[O:8].[S][Cl:13].O>S(Cl)(Cl)(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3]>[Cl:1][C:2]1[S:3][C:4]([Cl:11])=[C:5]([Cl:13])[C:6]=1[S:7]([Cl:10])(=[O:8])=[O:9]
Reactant: [S]Cl
Reactant: O=S(=O)(Cl)c1cc(Cl)sc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: O=S(=O)(Cl)Cl
Product: O=S(=O)(Cl)c1c(Cl)sc(Cl)c1Cl
Temperature: 60 °C
Yield: 991.6 %

Procedure:
A mixture of 2,5-dichlorothiophene-3-sulfonyl chloride (1.2 g, 5 mmol) and sulfur monochloride (10 mg) in sulfuryl chloride (500 mg) was heated at 60° C. for 30 min, at which time was added dropwise a mixture of aluminum trichloride (10 mg) in sulfuryl chloride (500 mg). The reaction was heated at 60° C. for an additional 3 hours, at which time it was allowed to cool to ambient temperature. Cold water (20 mL) was added and the reaction extracted with dichloromethane (2×20 mL). The combined organic layers were washed with saturated sodium bicarbonate solution, dried (Mg2SO4) and concentrated to furnish a tan solid (420 mg, 33%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.CC[N:45](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N>CO.C(Cl)Cl>[C:35]([C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)(=[O:36])[NH2:45]
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(N)=O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Reaction time: 0.03 h

Procedure:
In a 10 mL round-bottomed flask, 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (200 mg, 324 μmol, Eq: 1.00) was combined with CH2Cl2 (5.43 ml) to give a suspension. DIPEA (50.3 mg, 68.0 μl, 389 μmol, Eq: 1.2) and HATU (136 mg, 357 μmol, Eq: 1.1) were added. The reaction was stirred for 2 minutes and 2M ammonia (811 μl, 1.62 mmol, Eq: 5) in methanol was added. The reaction mixture was stirred for 4 h.
Reaction SMILES: [NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9][CH3:10])[C:5]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:14][C:4]=2[S:3]1.[Cl:20]C1C=CC=C(C(OO)=[O:28])C=1>C(O)C>[ClH:20].[NH:1]=[C:2]1[N:6]([CH2:7][CH2:8][S:9]([CH3:10])=[O:28])[C:5]2[CH:11]=[CH:12][C:13]([O:15][C:16]([F:19])([F:17])[F:18])=[CH:14][C:4]=2[S:3]1
Reactant: CSCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCO
Product: CS(=O)CCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Product: Cl
Reaction time: 0.5 h
Yield: 34.6 %

Procedure:
The procedure is as in Example 8, starting with 2-imino-3-(2-methylthioethyl)-6-trifluoromethoxybenzothiazoline (3.7 g) and m-chloroperbenzoic acid (2.3 g) in absolute ethanol (60 cc). After 30 minutes at -20° C., the precipitate formed is filtered off and the hydro-chloride prepared in acetone (60 cc). (RS)-2-Imino-3-(2-methylsulphinylethyl)-6-trifluoromethoxybenzo-thiazoline hydrochloride (1.5 g), m.p. 186° C., is obtained.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C([O:8][C:9](=[O:25])[CH:10]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17](F)[CH:16]=1)[CH2:11][CH:12]([CH3:14])[CH3:13])C.O.[CH:27]1([CH2:30][OH:31])[CH2:29][CH2:28]1>>[CH:4]1([CH2:5][O:8][C:9](=[O:25])[CH:10]([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[C:17]([O:31][CH2:30][CH:27]3[CH2:29][CH2:28]3)[CH:16]=2)[CH2:11][CH:12]([CH3:13])[CH3:14])[CH2:2][CH2:3]1
Reactant: OCC1CC1
Reactant: CCOC(=O)C(CC(C)C)c1ccc([N+](=O)[O-])c(F)c1
Reactant: [Li]CCCC
Solvent: O
Product: CC(C)CC(C(=O)OCC1CC1)c1ccc([N+](=O)[O-])c(OCC2CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Cyclopropylmethanol (80.0 g, 1.11 mol) was treated with n-BuLi (2.5 M in hexane, 9.1 g, 57 mL, 0.14 mol) at a temperature ranging from −15 to 0° C. The reaction mixture was stirred for 1 h at 25° C. Then, a solution of 2-(3-fluoro-4-nitro-phenyl)-4-methyl-pentanoic acid ethyl ester in cyclopropylmethanol (30 mL) was added at 25° C. and the reaction mixture was stirred for 16 h. Water (100 mL) was added and the reaction mixture was extracted with EtOAc (3×100 mL). The combined organic phases were washed with water (3×100 mL), brine (100 mL), and dried (MgSO4). Evaporation of the solvent under reduced pressure gave a brown oil, which was purified by silica gel gradient column chromatography by use of Heptane-EtOAc (9:1-4:1) to give 2-(3-cyclopropylmethoxy-4-nitro-phenyl)-4-methyl-pentanoic acid cyclopropylmethyl ester as a yellow oil (34.0 g, 93%). 1H NMR (300 MHz, CDCl3/TMS): δ 7.78 (d, J=8.4 Hz, 1H), 7.06 (s, 1H), 6.97 (d, J=8.4 Hz, 1H), 4.00-3.83 (m, 4H), 3.69 (t, J=8.0 Hz, 1H), 2.07-1.92 (m, 1H), 1.69-1.60 (m, 1H), 1.52-1.42 (m, 1H), 1.32-1.20 (m, 1H), 1.19-1.00 (m, 1H), 0.92 (d, J=6.3 Hz, 6H), 0.68-0.62 (m, 2H), 0.56-0.48 (m, 2H), 0.42-0.38 (m, 2H), 0.26-0.21 (m, 2H); 13C NMR (75 MHz, CDCl3/TMS): δ 172.9, 152.3, 146.2, 138.8, 125.6, 119.8, 114.4, 74.2, 69.8, 49.8, 42.6, 26.0, 22.5, 22.2, 10.0, 9.7, 3.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O>C1COCC1.CCO.[Pd]>[NH2:21][C:3]1[CH:4]=[C:5]([C:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)c(N)c2)CC1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of compound 14 (2.1 g, 6.58 mmol) in a mixture of THF (15 mL) and EtOH (30 mL) was added Pd—C (0.21 g, 10% wet basis), and the mixture was subjected to hydrogenation in a Parr apparatus at 10 psi for 3 hours. After filtering over the pad of celite, the solution was concentrated and loaded over a silica column, eluting with ethyl acetate:hexanes (50:50), and then changing to (90:10) to get compound 18. Yield 96%, light brown gum. IR KBr, cm−1) 3429, 3330 (NH2), 3036 (Ar—H), 2983 (Alph-H), 1691 (CO), 1628, 1520, 1415 (C═C), 1229 (C—N), 1160 (CO); 1H NMR (500 MHz, CDCl3) δ 1.46 (s, 91-1, OC(CH3)3), 2.40 (br. s, 2H, CH2), 3.43 (m, 2H, CH2), 4.02 (br. s, 2H, CH2), 4.38 (br. s, 4H, 2NH2), 5.93 (br. s, 1H, CH), 7.06 (dd, J=2.6, 8.2 Hz, 1H, H-6), 730 (d, J=2.5 Hz, 1H, H-2), 7.46 (d, J=8.2 Hz, 1H, H-5). 13C NMR (125.7 MHz, CDCl3) δ 26.89 (CH2), 28.33 (OC(CH3)3), 29.39 (CH2), 42.84 (CH2), 79.99 (OC(CH3)3), 118.77 (CH), 119.19 (C-5), 120.37 (C-2), 129.19 (C-1), 130.65 (C-3), 131.16 (C-6), 141.82 (C4), 154.63 (CO). Anal. Calcd for C16H23N3O2. C, 66.41; H, 8.01; N, 14.52%. Found: C, 66.33; H, 8.07; N, 14.43%.
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]1([C@@:14]2([C:26]#N)[CH2:16][C@H:15]2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH2:38]>O1CCCC1>[C:8]1([C@@:14]2([CH:26]=[O:38])[CH2:16][C@H:15]2[CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O
Reactant: N#C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C[C@]1(c2ccccc2)C[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
To a solution of 300 mL toluene and (1R,2R)-1-phenyl-2-{[(phenylmethyl)oxy]methyl}cyclopropanecarbonitrile (12.0 g, 45.57 mmol, 1 eq), accessed via the method of Preparation 3B, at 0° C. was added 59.3 mL 1M diisobutylaluminum hydride (59.3 mmol, 1.3 eq) in tetrahydrofuran. The mixture was stirred at 0° C. for 4 h and then at ambient temperature for 18 h before dilution with 500 mL toluene and 500 mL water. The mixture was stirred for 30 min and then filtered through a pad of celite. The organics were isolated, dried over Na2SO4, filtered and concentrated to give the title compound (7.8 g, 29.3 mmol, 64%) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 9.39 (s, 1H), 7.39-7.19 (m, 10H), 4.33-4.23 (m, 2H), 3.36-3.33 (m, 1H), 3.03-2.98 (m, 1H), 2.16-2.11(m, 1H), 1.77-1.73 (m, 1H), 1.46-1.43 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Cl)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C=O)C.CC(=O)OCC>[CH2:18]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH2:11][C:5]1[CH:6]=[CH:10][CH:2]=[CH:3][CH:4]=1)=[O:8])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCc1ccccc1
Reactant: Cc1ccc(O)cc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of 2.6 g of 5-hydroxy-2-methylbenzoic acid (see below), 7.0 g potassium carbonate and 3.8 ml benzyl chloride in 50 ml DMF are stirred at 50° C. for two hours, until the reaction is completed according to TLC analysis. The reaction mixture is portioned between water and EA, and the phases are separated. The organic phase is washed three times with 1 M sodium carbonate solution and once with brine, dried over MgSO4, and the solvent is removed under reduced pressure yielding benzyl 5-(benzyloxy)-2-methylbenzoate, which is used for the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([O:14][CH2:15][C:16]([OH:18])=O)=[CH:10][CH:9]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[N:12][C:11]([O:14][CH2:15][C:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:18])=[CH:10][CH:9]=1
Reactant: O=C(O)COc1ccc(-c2ccccc2F)nn1
Reactant: C1CCNCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Product: O=C(COc1ccc(-c2ccccc2F)nn1)N1CCCCC1

Procedure:
20 mg (0.08 mmol) of [6-(2-fluoro-phenyl)-pyridazin-3-yloxy]-acetic acid, 10.3 mg (0.12 mmol) of piperidine, 27.8 mmol (0.24 mmol) of NEM and 29.1 mg (0.089 mmol) of TOTU in THF were stirred at room temperature for 3 h. After filtration and evaporation, the product was purified by RP18 chromatography. Yield: 7 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([OH:16])=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1.[C:26]1([C:32]2[CH:33]=[CH:34][C:35]([CH2:38]Cl)=[N:36][CH:37]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CCOC(C)=O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][C:12]([O:16][CH2:38][C:35]4[CH:34]=[CH:33][C:32]([C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=5)=[CH:37][N:36]=4)=[C:11]4[S:17][CH:18]([CH3:20])[CH2:19][C:9]([C:10]=34)=[C:8]2[CH2:21][CH2:22][OH:23])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(-c2ccccc2)cn1
Reactant: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(O)c(c23)S1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC1Cc2c(CCO)n(Cc3ccc(Cl)cc3)c3ccc(OCc4ccc(-c5ccccc5)cn4)c(c23)S1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of product from Step 5 (150 mg, 0.39 mmol), 5-phenyl-2-picolyl chloride (95 mg, 0.47 mmol) and Cs2CO3 (152 mg, 0.47 mmol) in CH3CN (5 mL) was stirred at r.t. for 20 hours, then at 60° C. for 1.5 hours. The mixture was diluted with EtOAc (25 mL), washed 3× with H2O, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel, eluting with a 1:1 mixture of EtOAc and hexane, to afford the title product as an oil which solidified.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[F:8][C:9]([F:16])([F:15])[C:10](OCC)=[O:11].CN(C1C=CC=CN=1)C>O1CCCC1>[F:8][C:9]([F:16])([F:15])[C:10]([N:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][NH:3]1)=[O:11]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1ccccn1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: O=C(N=c1cccc[nH]1)C(F)(F)F
Reaction time: 22 h
Yield: 13.7 %

Procedure:
2-aminopyridine in an amount of 0.94 g (10 mmol) was dissolved in 20 mL of tetrahydrofuran (THF), following which 2.84 g (20 mmol) of ethyl trifluoroacetate and 1.22 g (10 mmol) of dimethylaminopyridine were added, and refluxing was carried out for 22 hours. THF was removed by distillation, following which purification was carried out with a silica gel column (developing solvent: 4:1 solution of hexane and ethyl acetate), giving 0.26 g of 2,2,2-trifluoro-N-(pyridin-2(1H)-ylidene)acetamide (yield, 13.7%).
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C:5]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)([C:8](OCC)=[O:9])[CH2:4][CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1.CCOCC>[CH2:1]=[C:2]1[CH2:3][CH2:4][C:5]([CH2:8][OH:9])([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=2)[CH2:6][CH2:7]1
Reactant: C=C1CCC(C(=O)OCC)(c2cccc(Oc3ccccc3)c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C1CCC(CO)(c2cccc(Oc3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.1 %

Procedure:
To a solution of ethyl 4-methylene-1-(3-phenoxyphenyl)cyclohexanecarboxylate (96 mg, 0.285 mmol) in THF (5 mL) at 0° C. was added lithium aluminum hydride (0.314 mL of a 1.0 M in Et2O; 0.314 mmol). The solution was warmed to rt and stirred for 1 h. The reaction was then quenched at 0° C. by adding EtOAc followed by a saturated aq sodium sulfate. The mixture was diluted with EtOAc and filtered through a pad of CELITE®. The filtrate was dried (Na2SO4) and concentrated in vacuo to afford the title compound (84 mg, 100% yield) as a colorless oil. LCMS, [M+Na]+=317.1. 1H NMR (500 MHz, CDCl3) δ 7.38-7.32 (m, 3H), 7.20-7.16 (m, 1H), 7.15-7.09 (m, 2H), 7.04-7.00 (m, 2H), 6.88 (ddd, J=8.1, 2.3, 0.8 Hz, 1H), 4.63 (s, 2H), 3.53 (s, 2H), 2.28-2.19 (m, 4H), 2.16-2.07 (m, 2H), 1.72-1.64 (m, 2H).